A Phase 3, Randomized, Double-Blind Study to Investigate the Efficacy and Safety of Once Daily Oral LY3502970 Compared With Placebo in Adult Participants With Type 2 Diabetes and Inadequate Glycemic Control With Diet and Exercise Alone
Phase: PHASE3
Conditions: Type 2 Diabetes
Sponsor: Eli Lilly and Company



C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
1  
Title P a ge  
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 p r 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 n i c al 
i n v e sti g ati o n of orf or gli pr o n  (L Y 3 5 0 2 9 7 0 ), 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 e l 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 . 
Pr ot oc ol Title:  
A P hase 3, Ra n d o mize d, D o u ble -Bli n d St u d y t o I n vesti gate t h e Efficac y a n d Safet y of O nce 
Dail y  Oral L Y 3 5 0 2 9 7 0 C o m pare d  wit h Place b o i n A d ult Partici pa nts wit h T y pe 2 Dia betes  a n d 
I n a de q uat e Gl yce mic C o ntr ol wit h  Diet a n d E x ercise Al o ne ( A C HI E V E -1)
Pr ot oc ol N u m ber:  J 2 A-M C -G Z G T  
A me n d me nt N u m ber: b  
C o m p o u n d : orf or gli pr o n  (L Y 3 5 0 2 9 7 0 ) 
Brief Title:  Effect of L Y 3 5 0 2 9 7 0 C o m pare d wit h Place b o i n Partici pa nts wit h T y pe 2 Dia b etes 
I n a de q uat el y C o ntr olle d wit h Diet a n d E xercise Al o ne ( A C HI E V E-1)  
St u d y P h ase:  3  
Acr o n y m : A C HI E V E -1  
S p o ns or N a me:  Eli Lill y a n d C o m pa n y  
Le g al Re gistere d A d dress:  I n di a na p olis, I n dia na, U S A  4 6 2 8 5  
Re g ul at or y A ge nc y I de ntifier N u m bers : 
I N D: 1 4 2 8 4 2  
W H O:  U 1 1 1 1 -1 2 9 0 -5 1 5 7  
A p pr o v al D ate:  Pr ot oc ol A me n d me nt  (b ) Electr o nicall y  Si g ne d a n d  A p pr o ve d  b y Lill y  o n  date 
pr o vi de d bel o w.  
D oc u me nt  I D: V V -C LI N -1 2 7 5 6 0  
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
2  
Me dic al m o nit or n a me a n d co nt act inf or m ati o n will be pr o vi de d se p ar atel y . 
 
 
 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
3  
Pr ot oc ol A me n d me nt S u m m ar y of C h a n ges T a ble   
 
D O C U M E N T HI S T O R Y  
D oc u me nt  
D ate  
A m e n d m e nt a  
2 2 -M a y -2 0 2 3  
Ori gi n al Pr ot o c ol  
1 8 -A pr -2 0 2 3  
A me n d me nt [b ]  
O ver all R ati o n ale f or t he A me n d me nt:  
T he pri mar y rati o nale f or t his a me n d me nt is t o  
 u p date t he ke y sec o n dar y o bjecti ves f or certai n li pi d e n d p oi nts  t o c o ntr ol f or T y p e I err or 
 re m o ve “f ull partici pa nts ” a n d re pl ace d wit h “ra n d o mize d partici pa nts” i n statistical 
c o nsi derati o ns as part of a nal ysis s ets  
 i ncreas e m o nit ori n g of cli nical c he mistr y res ults, a n d 
 u p date e x cl usi o n criteria f or p ote ntial dr u g -dr u g i nteracti o ns . 
Mi n or e dit o rial a n d f or m atti n g c h a n ges are n ot i ncl u de d i n t his ta ble. 
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  
Gl o bal ( m ulti ple 
secti o ns affecte d) 
Re place d “ L Y 3 5 0 2 9 7 0” wit h 
“orf or gli pr o n” , e x ce pt f or t he title 
Per n o w a vaila ble ge neric 
na me  
1. 1 S y n o psis   
“ Bri ef S u m mar y”, first se nte nce: a d de d t he 
d oses of orf or g li pr o n us e d i n t his st u d y, 
 m g, 
 m g, or  
 m g 
Clarit y  
1. 1 . S y n o psis a n d 
3.  O bjecti ves  
“ Ke y Sec o n d ar y” o bjecti ves: M o ve d t he 
f oll o wi n g li pi d e n d p oi nts f or orf or gli pr o n 
m g a n d/ or 
 m g fr o m “ Ot her 
S ec o n dar y” o bjecti ves t o “ Ke y S ec o n d ar y” 
o bjecti ves:  
 Perce nta ge c ha n ge fr o m baseli ne i n 
n o n -H D L c h olest er ol at Wee k 4 0  
 Perce nta ge c ha n ge fr o m baseli ne i n 
tri gl yceri des at Wee k 4 0 
U p date d t o c o ntr ol f or 
T y pe I err or  
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI
C CI
C CI
C CI
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
4  
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  
 
“Ot her Sec o n dar y” o bjecti ves:  
 delete d t he f oll o wi n g e n d p oi nts f or t he 
li pi d para meters o bjecti ve for 
orf or gli pr o n   m g, 
 m g, a n d 
 m g  
vers us  place b o : 
o  N o n -H D L c h ol ester ol  
o  Tri gl yceri des  
Per re visi o ns t o t he “ Ke y 
Sec o n dar y” o bjecti ves  
 
 A d de d a se p arat e o bjecti ve f or 
orf or gli pr o n  m g c o m pare d wit h  
place b o o n li pi d para m eters  
 
 
 Patie nt -re p orte d o utc o m es o bjecti ve: 
a d de d “a n d s u m mar y [sc ores]” t o t he 
S F -3 6 v 2 e n d p oi nt  
C orrecti o n  
 
“ Treat me nt re gi m en esti ma n d attri b utes” 
a n d “Effi cac y esti ma n d attri b utes ”: 
re place d “d ose re-escal ati o n” wit h “ d ose 
m o dificati o n”  
 
1. 3. Sc he d ule of 
Acti vities ( S o A)  
“ Earl y disc o nti n uati o n ( E D) ”, first 
se nte nce: re vise d t o rea d “Partici pa nts w h o 
are u na bl e or u n willi n g t o c o nti n ue t he 
st u d y treat me nt peri o d  f or a n y reas o n will 
pe rf or m a n E D of treat m e nt visit .” 
Clarit y  
 
“Visit n u m ber” r o w a n d f o ot n ote “a”: 
m o ve d t he f o ot n ote “a” t o t he “ C o m me nts” 
c ol u m n (“Visit 2 ma y o cc ur as s o o n as 
criteria f or Visit 1 are c o nfir me d; Visit 3 t o 
occ ur n o s o o ner t ha n 1 8 da ys after 
Visit  1. ”) 
F or ease of na vi gati o n  
 
“ F u n d us p h ot o gra p h y a n d f urt her 
o p ht hal m ol o gical ass ess me nt” r o w a n d 
f o ot n otes “ b” a n d “c”:  
 C o ns oli date d f o ot n otes “ b” a n d “c” wit h 
t he S o A c o m me nt 
 Place d t he re vis e d c o m m e nt h oriz o ntall y  
F or ease of na vi gati o n  
 
“ Cli nical c he mistr y” r o w:  
 A d de d X’s f or Wee ks 4, 8, 1 6, 2 0, a n d 
3 2  
 
 
T o i ncreas e m o nit ori n g of 
cli nical c he mistr y res ults  
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI
C CI
C CI
C CI
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
5  
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  
2 . 3. 1. Ris k 
Assess me nt  
U p date d t he last b ullet t o rea d “ t h yr oi d C-
cell effects ( o nl y  o bser ve d i n r o de nts)” 
Clarificati o n  
4. 3. J ustificati o n f or 
D ose  
First para gra p h:  
 delete d t he me nti o n of P hase 1 st u dies  
 a d de d t he rati o nale f or selecti o n of 
 
m g Q D  as t he hi g hest d ose i n t his st u d y 
Clarificati o n  
5. 2. E x cl usi o n 
Crite ria (e x cl usi o n 
criteri o n # 2 7), 6. 9. 1. 
Pr o hi bite d or 
Restricte d Use 
Me dicati o ns, a n d 
 
 
 
 
 
T o mi ni mi ze p ote ntial 
dr u g -dr u g i nteracti o n ris k 
t o st u d y partici pa nts 
5 . 3. 2. Meals a n d 
Dietar y Restricti o ns  
 F irst se nte nce: m o difie d t o rea d “ … i n a 
fasti n g state, after a n o ver ni g ht fast,  
e x ce pt f or water, of at least 8 h o urs as 
s pecifie d i n t he S o A.” 
Fle xi bilit y a n d 
c o nsiste nc y 
5. 3. 2. Meals a n d 
Dietar y Restricti o ns  
a n d  
 
 
 
 
 
Clarificati o n  
6. 1. St u d y 
I nter ve nti o n(s) 
A d mi nistere d  
Ta ble: a d de d a r o w a b o ut t he E U 
a ut h orizati o n  
Clarificati o n  
6. 6 . D ose 
M o dificati o n  
U p date d t o rea d “ N o D d ose m o dificati o n 
will be all o we d e x ce pt as s pecifie d i n 
Secti o ns 6. 6. 1 a n d 6. 6. 2.”  
Clarit y  
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI
C CI
C CI
C CI
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
6  
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  
Clarificati o n  
6. 9. 3. Resc ue  
T hera p y f or Se vere 
Persiste nt 
H y p er gl yce mia  
“Resc ue me di cati o n” , t hir d para gra p h 
(i nitiati o n of i ns uli n as t he first resc u e 
i nter ve nti o n f or h y per gl yce mia):  
 re-str uct ur e d as a b ullete d list, a n d 
 i n t he sec o n d b ullet, a d de d “ partici pa nts 
wit h s y m pt o ms of h y p er gl yce mia, if 
t here is e vi de n ce of o n g oi n g cata b olis m 
or ” a n d refere n ce t o A D A 2 0 2 3 
Clarificati o n  
8 . 3. 3. 9. T h yr oi d 
Mali g na n cies a n d 
C -Cell H y per plasia  
“ Calcit o ni n meas ure me nts”, first se nte nce: 
re place d ≥3 5 n g / m L wit h ≥3 5 n g / L 
C orrecti o n  
9 . 1. Statistical 
H y p ot hes es  
A d de d t he h y p ot heses f or c o m pari n g 
orf or gli pr o n  
 m g, 
 m g wit h place b o o n 
c ha n ges i n n o n -H D L c h olester ol  a n d 
tri gl yceri des  
Per re vise d o bjecti ves  
9. 2. A nal ys es Sets  
 delete d “ F ull partici pa nts ”  
T o pr otect t he i nte grit y of 
ra n d o mizati o n 
 
Sec o n d ta ble:  
 first r o w: re vise d t o rea d “All data 
p oi nts o btai ne d d uri n g t h e treat me nt 
peri o d defi ne d as at or after baseli ne 
a n d u p t o t he last visit wit hi n t he 
treat me nt peri o d … ” 
 sec o n d r o w: re vise d t o rea d “All data 
p oi nts o btai ne d d uri n g t h e treat me nt 
peri o d a n d t he f oll o w -u p peri o d defi ne d 
as at or aft er bas eli ne a n d u p t o t he date 
of st u d y wit h dra wal i ncl u di n g t he 
f oll o w-u p peri o d  …”  
 last r o w: re vise d t o rea d “All data p oi nts 
o btai ne d d uri n g t h e treat me nt peri o d 
defi ne d as at or after bas eli ne …”  
 a d de d f o ot n ote “a”, “‘A d diti o nal 
a nti h y per gl yce mic me di cati o ns ’ refers 
t o a n y a nti h y p er gl yce mic t hera p y t hat 
is use d f or m ore t ha n 2 wee ks 
( 1 4 da ys).”  
Clarificati o n  
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI
C CI 
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
7  
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  
9. 3. 2. 1. Partici pa nt 
Dis p ositi o n  a n d 
9. 3. 2. 3. 
C o nc o mita nt 
T hera p y  
R e place d “s afet y p artici p a nts” wit h 
“ra n d o mize d partici pa nts ”.  
C orrecti o n  
9. 3. 3. Pri mar y 
E n d p oi nt a n d 
Esti ma n d A nal ysis  
Re place d “f ull partici pa nts” wit h 
“ra n d o mize d partici pa nts ”  
Per c orrecti o n i n 
Secti o n  9. 2  
 
F o urt h para gra p h, last se nte nce: delete d 
“acc or di n g t o t he reas o ns f or st u d y 
disc o nti n uati o n”  
C orrecti o n /clarifi cati o n 
 
Sec o n d fr o m last para gra p h: a d de d 
“M ulti ple i m p utati o n -base d ti p pi n g -p oi nt 
a nal ysis is pla n ne d as a s e nsiti vit y a nal ysis 
t o assess t he r o b ust ness of pri mar y efficac y 
res ults.” 
Clarificati o n  
9. 3. 4. Sec o n dar y 
E n d p oi nt(s) a n d 
Esti ma n d(s) 
A nal ys es a n d 1 1. 
Refere n ce s 
Re m o ve d Ge et al. 2 0 1 1, a n d a d de d t hree 
ne w refere nces: Stei n gri mss o n et al. 2 0 1 7, 
F D A 2 0 2 3 , a n d Ye et al. 2 0 2 3  
U p date d per ne w  
g ui da nce o n a n al ysis  
9. 3. 5. Tertiar y 
E n d p oi nts a n d 
Esti ma n ds A nal yses  
A d de d “ U nless s p ecifie d ot her wise”   
Clarificati o n  
9. 3. 8. Ot her 
A nal ys es  
Last se nt e nce : re place d “( < 1 0 %)” wit h 
“(f or e x a m ple, < 1 0 %)”  
Fle xi bilit y  
9. 5. Sa m ple Size 
Deter mi nati o n  
 Re m o ve d t he 1 5 % dr o p-o ut rate 
ass u m pti o n  
 U p date d t he c o m m o n S D fr o m 1. 1 % t o 
1. 2 %  
 Last p ara gra p h: a d de d “ T hese 
ass u m pti o ns are c o nsi dere d t o e ns ure 
t he p o wer f or t he pri mar y e n d p oi nt 
u n der t heefficac y esti ma n d as well.”  
Clarificati o n  
1 0. 2. 1. Prescree ni n g 
Visit ( O p ti o nal) 
I n t he t a ble,  
 c o m bi ne d micr osa m pli n g wit h t he 
ve ni p u nct ure r o w, a n d  
  a d de d “(if a vaila ble)” after 
micr osa m pli n g  
Fle xi bilit y a n d re d uci n g 
patie nt b ur de n, t o all o w 
l ocal la b orat or y a nal ysis 
f or micr osa m pli n g, if 
a p plica ble  
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
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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  
1 0. 4. C o ntrace pti ve 
a n d Barrier 
G ui da nce  
U p date d t he defi niti o ns a n d fe male 
c o ntrace pti o n criteria  
Per c urre nt Lill y 
g ui da nce, f or clarit y  
 
 
 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
9  
T a ble of C o nte nts   
1.  
Pr ot oc ol S u m m ar y  ........................................................................................................1 3  
1. 1.  
S y n o psis  ..........................................................................................................................1 3  
1. 2.  
Sc he ma  ............................................................................................................................2 0  
1. 3.  
Sc he d ule of Acti vities ( S o A)  ..........................................................................................2 1  
2.  
I ntr o d ucti o n ...................................................................................................................3 3  
2. 1.  
St u d y R ati o nale  ...............................................................................................................3 3  
2. 2.  
Bac k gr o u n d  .....................................................................................................................3 3  
2. 3.  
Be nefit/ Ris k Assess me nt  ................................................................................................3 5  
2. 3. 1.  
Ris k Assess me nt  .............................................................................................................3 5  
2. 3. 2.  
Be nefit Assess me nt  .........................................................................................................3 5  
2. 3. 3.  
O verall Be nefit Ris k C o ncl usi o n  ....................................................................................3 6  
3.  
O bjecti ves, E n d p oi nts, a n d Esti m a n ds  .......................................................................3 7  
4.  
St u d y Desi g n  ..................................................................................................................4 1  
4. 1.  
O verall Desi g n  ................................................................................................................4 1  
4. 2.  
Sci e ntific Rati o nale f or St u d y Desi g n  ............................................................................4 1  
4. 3.  
J ustificati o n f or D ose ......................................................................................................4 1  
4. 4.  
E n d of St u d y Defi niti o n  ..................................................................................................4 2  
5.  
St u d y P o p ul ati o n  ...........................................................................................................4 3  
5. 1.  
I n cl usi o n Criteria ............................................................................................................4 3  
5. 2.  
E xcl usi o n Criteria  ...........................................................................................................4 4  
5. 3.  
Lif est yle C o nsi derati o ns  .................................................................................................4 7  
5. 3. 1.  
Dia betes E d ucati o n  .........................................................................................................4 7  
5. 3. 2.  
Meals a n d Dietar y Restri cti o ns  .......................................................................................4 8  
5. 3. 3.  
Bl o o d D o nati o n  ...............................................................................................................4 8  
5. 4.  
Scree n Fail ures  ................................................................................................................4 8  
5. 5.  
Criteria f or T e m p oraril y Dela yi n g E nr oll me nt of a Partici pa nt  .....................................4 8  
6.  
St u d y I nter ve nti o n(s) a n d C o nc o mit a nt T her a p y  .....................................................4 9  
6. 1.  
St u d y I nter v e nti o n(s) A d mi nistere d ................................................................................4 9  
6. 2.  
Pre parati o n, Ha n dli n g, St ora ge, a n d Acc o u nta bilit y  ......................................................5 0  
6. 3.  
Assi g n me nt t o St u d y I nt er ve nti o n  ..................................................................................5 0  
6. 4.  
Bli n di n g  ..........................................................................................................................5 1  
6. 5.  
St u d y I nt er ve nti o n C o m plia nce  ......................................................................................5 1  
6. 6.  
D ose M o dificati o n  ..........................................................................................................5 2  
6. 6. 1.  
Ma na ge me nt of Gastr oi ntesti nal S y m pt o ms  ...................................................................5 2  
 
 ..........................................5 3  
6. 7.  
C o nti n ue d Access t o St u d y I nter ve nti o n After t he E n d of t he 
St u d y  ...............................................................................................................................5 3  
6. 8.  
Treat me nt of O v er d ose  ...................................................................................................5 3  
6. 9.  
Pri or a n d C o nc o mita nt T hera p y  ......................................................................................5 4  
6. 9. 1.  
Pr o hi bite d or Restricte d Use Me dicati o ns  ......................................................................5 4  
6. 9. 2.  
Pr o hi bite d S ur gical Treat me nts or Pr oce d ures f or Wei g ht 
Ma na ge me nt  ....................................................................................................................5 5  
6. 9. 3.  
Resc ue T hera p y f or Se vere Persiste nt H y per gl yce mia ...................................................5 5  
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI

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1 0  
6. 9. 4.  
S y m pt o matic M e dicati o n f or Gastr oi ntesti nal S y m pt o ms  ..............................................5 6  
7.  
Disc o nti n u ati o n of St u d y I nter ve nti o n a n d P artici p a nt 
Disc o nti n u ati o n/ Wit h dr a w al ........................................................................................5 7  
7. 1.  
Disc o nti n uati o n of St u d y I nter ve nti o n  ............................................................................5 7  
7. 1. 1.  
Per ma ne nt Disc o nti n uati o n fr o m St u d y I nter ve nti o n  .....................................................5 7  
7. 1. 2.  
He patic Criteria f or St u d y I nter ve nti o n I nterr u pti o n or 
Disc o nti n uati o n  ...............................................................................................................5 8  
7. 1. 3.  
Te m p orar y I nt err u pti o n of St u d y I nter ve nti o n  ...............................................................5 8  
7. 2.  
Partici pa nt Disc o nti n uati o n/ Wit h dra wal fr o m t he St u d y  ................................................5 8  
7. 3.  
L ost t o F oll o w -u p ............................................................................................................5 8  
8.  
St u d y Assess me nts a n d Pr o ce d ures .............................................................................5 9  
8. 1.  
Efficac y Assess me nts  .....................................................................................................5 9  
8. 1. 1.  
Pri mar y Efficac y Assess me nt  .........................................................................................5 9  
8. 1. 2.  
Sec o n dar y Efficac y Assess me nts  ....................................................................................5 9  
8. 1. 3.  
Tertiar y Efficac y Assess me nts  ........................................................................................5 9  
8. 1. 4.  
Patie nt -Re p orte d O utc o mes  ............................................................................................5 9  
8. 2.  
Safet y Assess me nts  .........................................................................................................6 2  
8. 2. 1.  
P h ysical E x a mi nati o ns  ....................................................................................................6 2  
8. 2. 2.  
Vital Si g ns  .......................................................................................................................6 2  
8. 2. 3.  
Electr ocar di o gra ms  .........................................................................................................6 2  
8. 2. 4.  
Cli nical Safet y La b orat or y Tests  ....................................................................................6 3  
8. 2. 5.  
Pre g n a nc y T esti n g  ...........................................................................................................6 3  
8. 2. 6.  
He patic Safet y M o nit ori n g, E val u ati o n, a n d Criteria f or St u d y 
I nter ve nti o n I nterr u pti o n or Disc o nti n uati o n ..................................................................6 3  
8. 2. 7.  
H y p erse nsiti vit y Reacti o ns  .............................................................................................6 9  
8. 2. 8.  
Dia betic Reti n o pat h y Scree ni n g a n d E val u ati o n  ............................................................6 9  
8. 3.  
A d verse E v e nts, Seri o us A d verse E ve nts, a n d Pr o d uct 
C o m plai nts  ......................................................................................................................7 0  
8. 3. 1.  
Ti mi n g a n d Mec ha nis m f or C o llecti n g E ve nts ...............................................................7 1  
8. 3. 2.  
Pre g n a nc y  ........................................................................................................................7 2  
8. 3. 3.  
A d verse E v e nts of S peci al I nt erest a n d Ot her Safet y T o pics  .........................................7 3  
8. 4.  
P har mac o ki netics  ............................................................................................................7 8  
8. 5.  
P har mac o d y na mics  .........................................................................................................7 8  
8. 6.  
Ge netics  ..........................................................................................................................7 9  
8. 7.  
Bi o mar kers  ......................................................................................................................7 9  
8. 8.  
I m m u n o ge nicit y Assess me nts.........................................................................................7 9  
8. 9.  
Healt h Ec o n o mics  ...........................................................................................................7 9  
9.  
St a tistic al C o nsi der ati o ns .............................................................................................8 0  
9. 1.  
Statistical H y p ot heses  .....................................................................................................8 0  
9. 1. 1.  
M ulti plicit y A dj ust me nt  ..................................................................................................8 0  
9. 2.  
A nal ys es Sets  ..................................................................................................................8 1  
9. 3.  
Stati stical A nal yses .........................................................................................................8 1  
9. 3. 1.  
Ge neral C o nsi derati o ns  ...................................................................................................8 1  
9. 3. 2.  
Treat me nt Gr o u p C o m para bilit y  .....................................................................................8 2  
9. 3. 3.  
Pri mar y E n d p oi nt a n d Esti ma n d A nal ysis  ......................................................................8 3  
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
1 1  
9. 3. 4.  
Sec o n dar y E n d p oi nt(s) a n d Esti ma n d(s) A nal yses  .........................................................8 4  
9. 3. 5.  
Tertiar y E n d p oi nts a n d Esti ma n ds A nal yses  ..................................................................8 4  
9. 3. 6.  
P har m ac o ki netic/ P har mac o d y n a mic A nal yses  ...............................................................8 4  
9. 3. 7.  
Safet y A nal yses  ...............................................................................................................8 5  
9. 3. 8.  
Ot her A nal yses  ................................................................................................................8 5  
9. 4.  
I nteri m A nal ysis ..............................................................................................................8 6  
9. 5.  
S a m ple Size Deter mi nati o n  ............................................................................................8 6  
1 0.  
S u p p orti n g D oc u me nt ati o n a n d O per ati o n al C o nsi der ati o ns  ..................................8 7  
1 0. 1.  
A p pe n di x 1: Re g ulat or y, Et hical, a n d St u d y O versi g ht 
C o nsi derati o ns  ................................................................................................................8 7  
1 0. 1. 1.  Re g ulat or y a n d Et hical C o nsi derati o ns  ...........................................................................8 7  
1 0. 1. 2.  Fi na ncial Discl os ur e ........................................................................................................8 7  
1 0. 1. 3.  I nf or me d C o nse nt Pr ocess ..............................................................................................8 8  
1 0. 1. 4.  Data Pr otecti o n ................................................................................................................8 8  
1 0. 1. 5.  C o m mittees Str uct ure ......................................................................................................8 9  
1 0. 1. 6.  Disse mi nati o n of Cli nical St u d y Data .............................................................................8 9  
1 0. 1. 7.  Data Q ualit y Ass ura nce  ..................................................................................................8 9  
1 0. 1. 8.  S o urce D oc u m e nts  ..........................................................................................................9 1  
1 0. 1. 9.  St u d y a n d Site Start a n d Cl os ure  ....................................................................................9 1  
1 0. 1. 1 0.  P u blicati o n P olic y  ...........................................................................................................9 2  
1 0. 1. 1 1.  I n v esti gat or I nf or mati o n .................................................................................................9 2  
1 0. 1. 1 2.  Sa m ple Rete nti o n  ............................................................................................................9 2  
1 0. 2.  
A p pe n di x 2: Cli nical La b orat or y Tests  ...........................................................................9 3  
1 0. 2. 1.  Prescree ni n g Visit ( O pti o nal)  .........................................................................................9 3  
1 0. 2. 2.  Ot her St u d y Visits  ...........................................................................................................9 3  
1 0. 2. 3.  La b orat or y Sa m ples t o b e O btai ne d at t he Ti me of a S yste mic 
H y p erse nsiti vit y E v e nt  ....................................................................................................9 6  
1 0. 3.  
A p pe n di x 3: A d verse E v e nts a n d Seri o us A d verse E ve nts: 
Defi niti o ns a n d Pr oce d ures f or Rec or di n g, E val uati n g, F oll o w -
u p, a n d Re p orti n g  ............................................................................................................9 7  
1 0. 3. 1.  Defi niti o n of A E  .............................................................................................................9 7  
1 0. 3. 2.  Defi niti o n of S A E  ...........................................................................................................9 8  
1 0. 3. 3.  Defi niti o n of Pr o d uct C o m plai nts  ...................................................................................9 9  
1 0. 3. 4.  Rec or di n g a n d F oll o w -U p of A E a n d/ or S A E a n d Pr o d uct 
C o m plai nts  ......................................................................................................................9 9  
1 0. 3. 5.  Re p orti n g of S A Es  ........................................................................................................1 0 1  
1 0. 3. 6.  Re g ulat or y Re p orti n g Re q uire me nts  .............................................................................1 0 1  
1 0. 4.  
A p pe n di x 4: C o ntrace pti ve a n d Barri er G ui da nce  ........................................................1 0 3  
1 0. 4. 1.  Defi niti o ns .....................................................................................................................1 0 3  
1 0. 4. 2.  C o ntrace pti o n G ui da nce ................................................................................................1 0 4  
1 0. 5.  
A p pe n di x 5: Ge netics ....................................................................................................1 0 6  
1 0. 6.  
A p pe n di x 6: Li ver Safet y: S u g geste d Acti o ns a n d F oll o w -u p 
Assess me nts  ..................................................................................................................1 0 7  
1 0. 7.  
A p pe n di x 7: W orl d Healt h Or ga nizati o n Classificati o n of 
Dia betes a n d Dia g n ostic Criteria  ..................................................................................1 0 9  
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
1 2  
1 0. 8.  
A p pe n di x 8: Pr o hi bite d Me dicati o ns or Me dicati o ns wit h S pecial 
Use Restricti o ns  ............................................................................................................1 1 0  
1 0. 8. 1.  E xcl u de d/ Pr o hi bite d Me dicati o ns  .................................................................................1 1 0  
1 0. 8. 2.  Me dicati o ns wit h S pecial Use Restricti o ns ...................................................................1 1 3  
1 0. 9.  
A p pe n di x 9: Sta n dar dize d Pr ot oc ols f or t he Meas ure me nt of 
Hei g ht, Wei g ht, Waist Circ u mfere nce, a n d Vital Si g ns  ...............................................1 1 4  
1 0. 1 0.  
A p pe n di x 1 0: C o u ntr y -s p ecific Re q uire me nts .............................................................1 1 6  
1 0. 1 1.  
A p pe n di x 1 1: Pr o visi o ns f or C ha n ges i n St u d y C o n d uct D uri n g 
E xce pti o nal Circ u msta nces  ...........................................................................................1 1 7  
1 0. 1 2.  
A p pe n di x 1 2: A b bre viati o ns a n d Defi niti o ns  ...............................................................1 2 1  
1 0. 1 3.  
A p pe n di x 1 3: Pr ot oc ol A me n d me nt Hist or y  ................................................................1 2 6  
1 1.  
Refere nces  ....................................................................................................................1 3 0  
 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
1 3  
1.   
Pr ot oc ol S u m m ar y   
1. 1.   
S y n o psis   
Pr ot oc ol Title:  
A P hase 3, Ra n d o mize d, D o u ble -Bli n d St u d y t o I n vesti gate t h e Efficac y a n d Safet y of O nce 
Dail y Oral L Y 3 5 0 2 9 7 0 C o m pare d wit h Place b o i n A d ult Partici pa nts wit h T y pe 2 Dia betes a n d 
I n a de q uat e Gl yce mic C o ntr ol wit h Diet a n d E x ercise Al o ne ( A C HI E V E-1)  
Brief T itle:  
Effect of L Y 3 5 0 2 9 7 0 C o m pare d wit h Place b o i n Partici pa nts wit h T y pe 2 Dia betes I n a de q uat el y 
C o ntr olle d wit h Diet a n d E x ercise Al o ne ( A C HI E V E -1)  
Re g ul at or y A ge nc y I de ntifier N u m bers:   
I N D: 1 4 2 8 4 2  
W H O: U 1 1 1 1 -1 2 9 0 -5 1 5 7  
R ati o n ale : 
T his st u d y will i n vesti gat e t he a ntih y per gl yce mic  effect of o nce dail y oral treat me nt wit h 
orf or gli pr o n   m g, 
 m g, a n d 
 m g, c o m pare d wit h place b o, i n partici pa nts wit h t y pe 2 
dia betes ( T 2 D ) a n d i na de q uate gl yce mic c o ntr ol wit h diet a n d e x ercise al o n e w h o are naï ve of 
i ns uli n use a n d ha ve n ot bee n treate d wit h a n y a nti h y per gl yce mic a ge nts f or at least 9 0 da ys 
prece di n g t o t he st u d y start. A d diti o nall y, t he st u d y will c o m pare t he effects of orf or gli pr o n  a n d 
place b o o n b o d y wei g ht a n d o verall safet y pr ofile.  
O bjecti ves , E n d p oi nt s, a n d Esti m a n ds: 
O bjecti ves  
E n d p oi nts  
Pri mar y  
 
T o de m o nstrate t hat orf or gli pr o n   m g, 
 m g, a n d/ or 
 m g are s u peri or t o place b o 
i n gl yce mic c o ntr ol 
 C ha n ge fr o m baseli ne i n H b A 1c at 
Wee k  4 0  
Ke y Sec o n dar y  
 
T o de m o nstrate t hat orf or gli pr o n   m g, 
 m g, a n d/ or 
 m g are s u peri or t o place b o 
i n a d diti o nal meas ures of gl yce mic c o ntr ol 
 Pr o p orti o n of partici pa nts wit h a n H b A 1c 
tar get val ue of < 7. 0 % ( 5 3 m m ol/ m ol)  at 
Wee k 4 0  
 Pr o p orti o n of partici pa nts wit h a n H b A 1c 
tar get val ue of ≤6. 5 % ( 4 8 m m ol/ m o l) at 
Wee k 4 0  
 C ha n ge fr o m baseli ne i n fasti n g ser u m 
gl uc ose (ce ntral la b orat or y)  at Wee k 4 0  
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
1 4  
O bjecti ves  
E n d p oi nts  
T o de m o nstrate t hat orf or gli pr o n
 m g, 
 m g, a n d/ or 
 m g are s u peri or t o place b o 
i n wei g ht ma n a ge me nt 
 Perce nta ge c ha n ge fr o m baseli ne i n b o d y 
wei g ht at Wee k 4 0  
 C ha n ge fr o m baseli ne i n b o d y wei g ht at 
Wee k 4 0  
T o de m o nstrate t hat orf or gli pr o n  
 m g 
a n d/ or 
 m g are s u p eri or t o place b o o n li pi d 
para meters  
 Perce nta ge c ha n ge fr o m baseli ne i n n o n -
H D L c h olester ol at Wee k 4 0  
 Perce nta ge c ha n ge fr o m baseli ne i n 
tri gl yceri des at Wee k 4 0 
Ot her Sec o n d ar y  
 
T o c o m pare orf or gli pr o n  m g, 
 m g, a n d 
 m g wit h place b o o n a d diti o nal meas ures of 
gl yce mic c o ntr ol  
 Pr o p orti o n of partici pa nts wit h a n H b A 1c 
tar get val ue of < 5. 7 % ( 3 9 m m ol/ m ol) at 
Wee k 4 0  
 C ha n ge fr o m baseli ne i n dail y a v era ge 
7 -p oi nt S M B G at Wee k  4 0  
T o c o m pare orf or gli pr o n   m g, 
 m g, a n d 
 m g wit h place b o o n a d diti o nal 
meas ure me nts of wei g ht ma na ge me nt  
 Pr o p orti o n of partici pa nts w h o ac hie ve d 
wei g ht l oss of ≥5 %, ≥1 0 %, a n d ≥1 5 % 
fr o m baseli ne at Wee k 4 0 
 C ha n ge  fr o m baseli ne i n waist 
circ u mfere nce at Wee k 4 0  
 C ha n ge fr o m baseli ne i n B MI at Wee k  4 0  
T o c o m pare orf or gli pr o n   m g, 
 m g, a n d 
 m g wit h place b o o n meas ures of bl o o d 
press ure  
 C ha n ge fr o m baseli ne at Wee k 4 0 i n:  
o  S yst olic bl o o d press ure  
o  Diast olic bl o o d press ure  
T o c o m pare orf or gli pr o n   m g, 
 m g, a n d 
 m g wit h place b o o n li pi d para meters  
 Perce nta ge c ha n ge fr o m baseli ne i n li pi d 
para meters at Wee k 4 0  
o  T otal c h olester ol  
o  H D L -c h olester ol  
o  L D L -c h olester ol  
o  V L D L -c h olest er ol  
T o c o m pare orf or gli pr o n   m g wit h place b o 
o n li pi d para meters  
 Perce nta ge c ha n ge fr o m baseli ne i n li pi d 
para meters at Wee k 4 0  
o  N o n -H D L c h ol ester ol  
o  T ri gl yceri des 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
1 5  
O bjecti ves  
E n d p oi nts  
T o c o m pare orf or gli pr o n   m g, 
 m g, a n d 
 m g wit h place b o o n p atie nt -re p ort e d 
o utc o mes  
 C ha n ge fr o m baseli ne at Wee k 4 0 i n:  
o  S F -3 6 v 2 Ac ute F or m d o mai n a n d 
s u m mar y s c ores 
o  E Q -5 D -5 L h ealt h state utilities a n d 
 
o  A P P A D L sc ores  
o  I W-S P sc ore  
o  D T S Qs sc ores  
 D T S Qc  sc ores at Wee k 4 0  
T o descri be t he s afet y of orf or gli pr o n  i n 
partici pa nts wit h T 2 D  
S u m mar y of safet y dat a, i ncl u di n g n u m ber 
a n d i nci de nce of:  
 S A Es  
 T E A Es  
 disc o nti n uati o ns fr o m st u d y 
i nter ve nti o n or st u d y d u e t o A Es 
A b bre viati o ns: A E = a d verse e ve nt; A P P A D L = A bilit y t o P erf or m P h ysical Acti vities of Dail y Li vi n g; B MI = b o d y 
mass i n de x; D T S Q c = Dia betes Treat me nt Satisfacti o n Q uesti o n naire -C ha n ge Versi o n ; D T S Qs = Dia betes 
Treat me nt Satisfacti o n Q uesti o n naire -Stat us Versi o n ; H b A 1 c  = he m o gl o bi n A 1c; H D L = hi g h -de nsit y 
li p o pr otei n; I W-S P = I m pact of Wei g ht o n Self -P erce pti o n; L D L = l o w -de nsit y li p o pr otei n; Q D = o nce dail y; 
S A E = seri o us a d verse e ve nt; S F -3 6 v 2, Ac ute = S h ort F or m -3 6 versi o n 2 Healt h S ur ve y a c ute f or m; S M B G = 
self-m o n it ore d bl o o d gl uc ose; T 2 D = t y pe 2 dia betes; T E A E = treat me nt-e mer ge nt a d verse e ve nt;  
; V L D L = ver y l o w -de nsit y li p o pr otei n.  
Pri m ar y esti m a n ds  
T here will be 2 esti ma n ds f or t he pri mar y o bjecti ve pla n ne d i n t he st u d y. T he 2 esti ma n ds , 
treat me nt re gi me n esti ma n d a n d effi cac y esti ma n d, a d dress i nterc urre nt e ve nts (I C Es) usi n g t he 
treat me nt p olic y strate g y a n d t he h y p ot hetical strat e g y, res pecti vel y.  
Tre at m e nt p olicy str ate gy  
T he occ urre n ce of t h e I C E is c o nsi dere d irrele va nt i n defi n i n g t he treat me nt effect of i nterest; t he 
val ues f or t he v aria ble of i nterest are us e d re gar dless of w het her t he I C E occ urs.  
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI
C CI
C CI
C CI
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
1 6  
Hy p ot hetic al str ate gy  
A sce nari o is e n visa ge d i n w hic h t he I C E w o ul d n ot occ ur. T he v al ue of t h e varia ble t o reflect 
t he cli nical questi o n of i nterest is t he val ue t hat t he varia ble w o ul d ha ve ta ke n i n t he h y p ot h etical 
sce nari o d efi ne d. 
Tre at me nt re gi me n esti m a n d  
T he cli nical q uesti o n of i nterest is: W h at is t he tre at me nt differe nce i n t he c h a n ge i n H b A 1c fr o m 
b aseli ne at Week 4 0 bet wee n orf or gli pr o n  m g, 
 m g, a n d/ or 
 m g c o m p are d wit h pl ace b o i n 
i n divi d u als w h o meet eli gi bility criteri a re g ar dless of a d here nce t o st u dy i nterve nti o n or 
i niti ati o n of a d diti o n al a nti hy per glyce mi c me dic ati o ns ? 
R ati o n ale f or t he  tre at me nt re gi m e n esti m a n d 
T he esti ma n d ai ms t o e val uate t he efficac y of orf or gli pr o n  t hat reflects t he real-life b e ha vi or of 
t he tar get p o p ulati o n. 
Tre at m e nt re gi m e n esti m a n d attri b utes  

P o p ul ati o n : i n di vi d uals w h o meet t he eli gi bilit y criteria.

E n d p oi nts : c ha n ge fr o m baseli ne i n H b A 1c at Wee k 4 0.

Tre at me nt c o n diti o n : t he ra n d o mize d treat me nt wit h all o wa nce f or p ote ntial d ose
i nterr u pti o ns a n d d ose m o dificati o n  re gar dless of a d here n ce t o st u d y i nter ve nti o n or i nitiati o n
of a d diti o nal a nti h y p er gl yce mic me dicati o ns.

I nterc urre nt eve nts: n o I C Es are defi ne d beca use treat me nt a d here nce a n d t he i nitiati o n of
a d diti o nal a nti h y per gl yce mic me dicati o ns are a part of t he treat me nt c o n diti o n.

P o p ul ati o n -level s u m m ar y a n d tre at me nt effect of i nterest: differe nce i n mea n c ha n ges i n
H b A 1c fr o m b aseli ne at Wee k 4 0 bet wee n orf or gli pr o n   m g, 
 m g, a n d/ or 
 m g c o m pare d
wit h place b o.
Effic ac y esti m a n d  
T he cli nical q uesti o n of i nterest is: W h at is t he tre at m e nt differe nce i n t he c h a n ge i n H b A 1c fr o m 
b aseli ne at Week 4 0 bet wee n orf or gli pr o n   m g, 
 m g, a n d/ or 
 m g c o m p are d wit h pl ace b o i n 
i n divi d u als w h o meet t he eli gi bility criteri a if t hey w o ul d re m ai n o n t heir r a n d o mly assi g ne d 
st u dy i nterve nti o n f or 
 weeks a n d w o ul d n ot i niti ate a d diti o n al  a nti hy per glyce mic 
me dic ati o ns ?  
R ati o n ale f or t he effic acy esti m a n d 
T his esti ma n d ai ms t o e val uate t he efficac y of orf or gli pr o n  u n d er t he i deal c o n diti o n t hat all 
partici pa nts w o ul d a d here t o t he ra n d o ml y assi g ne d st u d y i nter ve nti o n wit h o ut bei n g c o nf o u n de d 
b y t he i nitiati o n of a d diti o nal a nti h y p er gl yce mic me dicati o ns.  
Effic acy esti m a n d attri b utes  

P o p ul ati o n : i n di vi d uals w h o meet t he eli gi bilit y criteria.

E n d p oi nts : c ha n ge fr o m baseli ne i n H b A 1c at Wee k 4 0.

Tre at me nt c o n diti o n : t he ra n d o mize d treat me nt wit h all o wa nce f or p ote ntial d ose
i nterr u pti o ns a n d d ose m o dificati o n .
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
1 7  
 I nterc urre nt eve nts: I C Es i ncl u de per ma n e nt disc o nti n uati o n of st u d y i nter ve nti o n a n d 
i nitiati o n of a d diti o nal a nti h y per gl yce mic me dicati o ns a n d will be ha n dle d b y t he 
h y p ot hetical strate g y. T h e p ote ntial o utc o me of i nterest is t he res p o nse i n t he effi cac y 
meas ure me nt if p artici pa nts w o ul d re mai n o n t heir ra n d o ml y  assi g ne d st u d y i nter ve nti o n f or 
 wee ks a n d w o ul d n ot i nitiate a d diti o nal a nti h y per gl yce mic me di cati o ns. D ose 
m o dificati o n  a n d i nterr u pti o n will n ot be c o nsi dere d a n I C E beca use t he y are part of t he 
treat me nt c o n diti o n. 
 P o p ul ati o n -level s u m m ar y a n d tre atme nt effect of i nterest : differe n ce i n mea n c ha n ges i n 
H b A 1c fr o m b aseli ne at Wee k 4 0 bet wee n orf or gli pr o n   m g, 
 m g, a n d/ or 
 m g c o m pare d 
wit h place b o.  
O ver all Desi g n  
A C HI E V E -1 ( St u d y G Z G T) is a P hase 3, m ultice nter, ra n d o mize d, parallel -ar m, d o u ble-bl i n d, 
place b o -c o ntr olle d st u d y t o c o m pare t he effect of orf or gli pr o n  wit h t hat of place b o o n t he 
gl yce mic c o ntr ol i n i n di vi d uals wit h T 2 D w h o ha v e i na de q uat e gl yce mic c o ntr ol wit h diet a n d 
e x ercise al o ne, are n aï ve t o i ns uli n use a n d ha ve n ot bee n treat e d w it h a n y a ntih y per gl yce mic  
me dicati o n d uri n g t h e 9 0 da ys prece di n g Visit 1 . 
Brief S u m m a r y:  
T he p ur p ose of t his st u d y is t o meas ure h o w differe nt d oses of orf or gli pr o n  (  m g, 
 m g, or 
 m g)  c o m pare wit h place b o i n i m pr o vi n g bl o o d s u gar  c o ntr ol i n partici p a nts  wit h  T 2 D  treate d 
wit h diet a n d e x ercise al o ne . 
T his st u d y i ncl u des 3 peri o ds as f oll o ws:  
 scree ni n g a n d lea d-i n p eri o d, wit h a n o pti o nal prescree ni n g visit 
 treat me nt peri o d, a n d 
 safet y f oll o w-u p p eri o d.  
T he st u d y d urati o n will be a p pr o xi matel y 
 wee ks  if a prescree ni n g visit is use d, a n d 
a p pr o xi matel y 4 6  wee ks if it is n ot.  
T he treat me nt d ur ati o n will be u p t o 
 wee ks.  T he treat me nt peri o d will be d o u ble -bli n d, w hic h 
mea ns neit her t he p artici pa nts n ot t he researc h ers will k n o w w hic h st u d y i nt er ve nti o n 
partici pa nts are recei vi n g u ntil t he st u d y is o ver.  
D uri n g t h e treat me nt p eri o d, t he visit fre q ue nc y will be e ver y 
 
 
St u d y P o p ul ati o n:  
I n ge neral, a n i n di vi d ual ma y ta ke part i n t his st u d y if t he y  
 Are ≥1 8 years of a ge i ncl usi ve, or t he le gal a ge of c o nse nt i n t he j uris dicti o n i n w hic h t he 
st u d y is ta ki n g pl ace at scree ni n g. 
 Ha ve a cli nical dia g n osis of T 2 D base d o n t h e W orl d Healt h Or ga nizati o n classificati o n 
or ot her l oca ll y a p plica ble dia g n ostic sta n dar ds. 
 Ha ve H b A 1 c ≥7. 0 % ( 5 3 m m ol/ m ol) t o ≤9. 5 % ( 8 0 m m ol/ m ol) at Visit 1 (scree ni n g), 
des pite diet a n d e x ercise treat me nt.  
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
1 8  
 Are naï ve t o i ns uli n t hera p y e x ce pt f or gestati o nal dia betes or ≤1 4 da ys use f or ac ut e 
treat me nt a n d ha ve n ot use d a n y oral or i njecta ble a nti h y per gl yce mic me di cati o ns d uri n g 
t he 9 0 da ys prece di n g Visit 1, a n d bet wee n Visit 1 a n d Visit 3 (ra n d o mizati o n). 
N u m ber of P artici p a nt s: 
A p pr o xi matel y  
 p arti ci pa nts will be ra n d o ml y assi g ned  i n a   
 rati o t o orf or gli pr o n  3 m g 
o nce dail y ( Q D ), 
 m g Q D, 
 m g Q D, or place b o, res pecti vel y. 
I nter ve nti o n Gr o u ps  a n d D ur ati o n : 
T his ta ble lists t he i nter ve nti o ns use d i n t his cli nical st u d y.  
I nter ve nti o n N a me 
O rf or gli pr o n 
Place b o  
D os a ge Le vel(s)  
 m g,  m g,  m g, 
 m g, 
 m g, a n d 
 m g ca ps ules 
N ot a p plica ble  
R o ute of A d mi nistr ati o n   
Oral Q D  
Oral Q D  
All partici pa nts will i nitiate treat me nt wit h a 1 m g Q D d ose of orf or gli pr o n  or matc hi n g pl ace b o 
a n d 
 (  m g, 
 m g, or 
 m g) is reac h e d, as o utli ne d i n t his fi g ure.  
 
T he mai nte na nce d ose (  m g, 
 m g, or 
 m g) of orf or gli pr o n  or matc h e d place b o will be 
c o nti n ue d f or t he re mai n der of t he treat me nt peri o d , u nless te m p orar y i nterr u pti o n of t he st u d y 
i nter ve nti o n is necessar y. 
As state d i n t he “ Brief S u m mar y” secti o n of t his S y n o psis, t he st u d y d urati o n will be 
a p pr o xi matel y  
 wee ks, de p e n di n g o n w het her t he prescree ni n g visit will be i ncl u de d. 
Et hic al C o nsi der ati o ns of Be nefit/ Ris k:  
T he safet y a n d effi cac y pr ofile see n t o dat e f or orf or gli pr o n  s u p p orts t he o v erall be nefit/ris k f or 
partici pa nts i n t his st u d y. T he a ntici pate d ris ks are t h ose ass ociate d wit h k n o w n p har mac ol o gic 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
O rf o r gli p r o n  3  m g  Q D 
1 m g 
3 m g 
O rf o r gli p r o n  1 2  m g  Q D 
1 m g 
3 m g 
6 m g 
1 2 qi 
_ _ _ _ _ _ _ _ O_ rf_ o r gli p r o n  3 6  m g  Q D 
1 m g 
3 m g 
6 m g 
1 2 qi 
3 6 m g 
Pl a c e b o Q D 
Vi sit 
3 
4 
5 
6 
7 
8 
1 1 
W e e k o 
4 
8 
1 2 
1 6 
2 0 
4 0 
t 
t 
R a n d o mi z a ti o n 
Pri m ar y  e n d p o int 
E n d  of  tr e a tm e nt 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
1 9  
effects of Gl uca g o n -Li ke Pe pti de -1 rece pt or ag o nists  (G L P -1 R As ), i ncl u di n g 
 
. T hes e ris ks are m o nit ora ble, us uall y mil d t o m o derate i n 
se verit y, re v ersi ble, a n d rea dil y m a na gea ble. T o d ate t here are n o rec o g nize d a d verse e v e nts  
fr o m orf or gli pr o n  ot her t ha n t h ose relat e d t o G L P -1 rece pt or a g o nis m.  
T he p ote ntial ris ks base d o n t he k n o wle d ge f or t he G L P -1 R A class are c o nsi dere d bei n g 
acce pta ble i n t he c o nte xt of t he p ote ntial be nefits a ntici pate d fr o m treat me nt wit h orf or gli pr o n  i n 
a d ult partici pa nts wit h T 2 D . 
D at a M o nit ori n g C o m mittee: N o  
 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
2 0  
1. 2.   
Sc he m a   
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
2 1  
1. 3.   
Sc he d ule of Acti vities  ( S o A)  
T he S o A descri b e d bel o w s h o ul d be f oll o we d f or all partici pa nts e nr olle d i n A C HI E V E -1 ( St u d y 
J 2 A-M C -G Z G T ). H o we v er, f or t h ose w h ose partici pati o n i n t his st u d y is affecte d b y e x ce pti o nal 
circ u msta nces, s uc h as p a n de mics or nat ural disasters, please refer t o Secti o n  1 0. 1 1  f or a d diti o nal 
g ui da nce.  
Prescree ni n g visit  
T he prescree ni n g visit ( Visit 6 0 1) is o pti o nal . Pr oce d ures ma y b e c o n d uct e d at a site or alter nate  
l ocati o n u n der t he o versi g ht of a n i n v esti gat or t o e na ble m ore access t o p ote ntial partici pa nts, 
i ncl u di n g u n der-re prese nte d p o p ulati o ns. 
T he p ur p ose of t his visit is t o  
 assess ke y eli gi bilit y fact ors ass ociate d wit h scree n fail u res at t he earliest ti me p oi nt 
 i m pr o ve t he effecti ve n ess of scree ni n g acti vities, a n d  
 re d uce b ur de n f or p ote nti al partici pa nts a n d i n vesti gat ors. 
F asti n g visits  
T he fasti n g state is defi n e d as n ot ha vi n g ha d a n yt hi n g t o eat or dri n k b ut water f or a mi ni m u m 
of 8 h o urs.  
 Visit 1 (scree ni n g): Fasti n g is n ot re q uire d.  
 Visit 3 (ra n d o mizati o n): Partici pa nt m ust atte n d Visit 3 i n a fasti n g state. All pr oce d ures,  
i ncl u di n g patie nt -re p orte d o utc o mes, la b orat or y pr oce d ures a n d E C Gs, s h o ul d be 
c o m plete d pri or t o t he partici pa nt ta ki n g st u d y i nter ve nti o n  at t his visit. 
 Visits 4 t hr o u g h 1 1: If a partici pa nt atte n ds t hese visits i n a n o nfasti n g state, sa m ples f or 
la b orat or y testi n g s h o ul d n ot be c ollecte d a n d t he partici pa nt s h o ul d be as k e d t o ret ur n t o 
t he site i n a fasti n g st ate as s o o n as p ossi ble wit hi n t he visit wi n d o w . A ll ot her pr oce d ures 
sc he d ule d at t he visit ma y be p erf or me d. At Wee ks 4, 1 6, a n d 3 2  ( Visits 4, 7, a n d 10 ), P K 
sa m ple s h o ul d be c ollect e d pri or t o partici pa nt ta ki n g st u d y i nter ve nti o n f or t hat da y.  
E arl y disc o nti n u ati o n ( E D)  
Partici pa nts w h o are u n a ble or u n willi n g t o c o nti n ue t he st u d y treat me nt peri o d f or a n y reas o n 
will perf or m a n E D visit. If t he partici p a nt is disc o nti n ui n g d uri n g a n u nsc h e d ule d visit or a 
sc he d ule d visit, t hat visit s h o ul d be perf or me d as t he E D visit. 
S afet y f oll o w -u p visit  
All partici pa nts are re q uire d t o c o m plete a s afet y f oll o w-u p visit ( Visit 8 0 1), acc or di n g t o t he 
S o A. Partici pa nts disc o nti n ui n g t he st u d y earl y a n d perf or mi n g a n E D visit will als o be as ke d t o 
perf or m t he s afet y f oll o w-u p visit.  
 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
2 2  
A C HI E V E -1  
( St u d y J 2 A -M C -G Z G T)  
Scree ni n g a n d  
Le a d -i n 
Tre at me nt  
S afet y 
f oll o w-
u p  
C o m me nts  
 
 
  
 
Visit n u m ber  
6 0 1   
1   
2   
3   
4   
5   
6   
7   
8   
9   
1 0   
1 1   
E D   
8 0 1  
  V 6 0 1 is o pti o nal.  
  Visit 2 ma y occ ur as s o o n as 
criteria f or Visit 1 are 
c o nfir me d; Visit 3 t o occ ur n o 
s o o ner t ha n 1 8 da ys after 
Visit  1.  
Wee ks fr o m Visit  3 
(r a n d o miz ati o n ) 
  
 w k 
p ost 
e n d of 
T x P   
 
Visit i nter v al t oler a nce 
( d a ys) 
  
  
 
F asti n g visit  
  
  
  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
  
 
Prescree ni n g ( V 6 0 1) assess m e nts o nly 
A b bre viate d i nf or me d 
c o nse nt  t o pr o vi de c o nse nt 
f or prescree ni n g 
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
T he a b bre viate d i nf or me d c o nse nt 
gra nts c o nse nt o nl y  for pr oce d ures 
a n d assess me nts mar ke d u n der 
V 6 0 1  ( prescree ni n g). 
F or ge neral i nf or mati o n a b o ut t he  
I C F pr ocess, see Secti o n 1 0. 1. 3 . 
De m o gra p hics  
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
I ncl u des et h nicit y ( w here 
per missi ble), year of birt h, se x, a n d 
race. 
A b bre viate d self-re p orte d 
q uesti o n naire o n me dical 
hist or y a n d me dicati o ns  
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
 
A d verse e ve nts ( A Es)   
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
Re p ort o nl y pr oce d ure -relate d 
e ve nts f or V 6 0 1.  
Hei g ht  
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
See Secti o n 1 0. 9 . 
Wei g ht  
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
Meas ure i n k g. See Secti o n  1 0. 9 . 
He m o gl o bi n A 1c ( H b A 1c)   
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
F or l ocati o n of t his la b orat or y 
a nal ysis, see Secti o n 1 0. 2 . 
Rec o m me n d  w het her 
partici pa nt ma y pr ocee d 
t o V 1  
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
Re vie w res ults of prescree ni n g 
pr oce d ures c o m plete d a n d 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI
C CI
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
2 3  
A C HI E V E -1  
( St u d y J 2 A -M C -G Z G T)  
Scree ni n g a n d  
Le a d -i n 
Tre at me nt  
S afet y 
f oll o w-
u p  
C o m me nts  
 
 
  
 
Visit n u m ber  
6 0 1   
1   
2   
3   
4   
5   
6   
7   
8   
9   
1 0   
1 1   
E D   
8 0 1  
  V 6 0 1 is o pti o nal.  
  Visit 2 ma y occ ur as s o o n as 
criteria f or Visit 1 are 
c o nfir me d; Visit 3 t o occ ur n o 
s o o ner t ha n 1 8 da ys after 
Visit  1.  
Wee ks fr o m Visit  3 
(r a n d o miz ati o n ) 
  
 w k 
p ost 
e n d of 
T x P   
 
Visit i nter v al t oler a nce 
( d a ys) 
  
  
 
F asti n g visit  
  
  
  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
  
 
rec o m me n d w het her partici pa nt 
ma y pr ocee d t o V 1.  
N ote: If at a n y ti me a partici pa nt is 
deter mi ne d t o n ot meet criteria f or 
pr ocee di n g t o V 1, t he a d diti o nal 
pr oce d ures are n ot re q uire d.  
N o n -prescree ni n g assess m e nts  
I nf or me d c o nse nt 
  
X   
  
  
  
  
  
  
  
  
  
  
  
  
T he I C F m ust be si g ne d bef or e a n y 
tests or pr oce d ures are perf or me d. 
See Secti o n 1 0. 1. 3  f or a d diti o nal 
details.  
I ncl usi o n/e xcl usi o n 
criteria; c o nfir mati o n  of 
eli gi bilit y  
  
X   
X   
X   
  
  
  
  
  
  
  
  
  
  
C o nfir m i ncl usi o n a n d e xcl usi o n 
criteria pri or t o ra n d o mizati o n a n d 
a d mi nistrati o n of first d ose of st u d y 
i nter ve nti o n. 
De m o gra p hics  
  
X   
  
  
  
  
  
  
  
  
  
  
  
  
I ncl u des et h nicit y ( w here 
per missi ble), year of birt h, se x, a n d 
race. 
Pree xisti n g c o n diti o ns a n d 
me dical hist or y, i ncl u di n g 
rele va nt s ur gical hist or y 
  
X   
  
  
  
  
  
  
  
  
  
  
  
  
C ollect all o n g oi n g c o n diti o ns a n d 
rele va nt past s ur gical a n d me dical 
hist or y.  
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI
C CI
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
2 4  
A C HI E V E -1  
( St u d y J 2 A -M C -G Z G T)  
Scree ni n g a n d  
Le a d -i n 
Tre at me nt  
S afet y 
f oll o w-
u p  
C o m me nts  
 
 
  
 
Visit n u m ber  
6 0 1   
1   
2   
3   
4   
5   
6   
7   
8   
9   
1 0   
1 1   
E D   
8 0 1  
  V 6 0 1 is o pti o nal.  
  Visit 2 ma y occ ur as s o o n as 
criteria f or Visit 1 are 
c o nfir me d; Visit 3 t o occ ur n o 
s o o ner t ha n 1 8 da ys after 
Visit  1.  
Wee ks fr o m Visit  3 
(r a n d o miz ati o n ) 
  
w k 
p ost 
e n d of 
T x P   
 
Visit i nter v al t oler a nce 
( d a ys) 
  
  
 
F asti n g visit  
  
  
  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
  
 
Pres pecifie d me dical 
hist or y  
  
X   
  
  
  
  
  
  
  
  
  
  
  
  
 
Pri or treat me nts f or 
i n dicati o n 
  
X   
  
  
  
  
  
  
  
  
  
  
  
  
I ncl u des pri or treat me nts f or 
dia betes  
C o nc o mita nt me dicati o ns   
  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
 
A d verse e ve nts ( A Es)   
  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
A n y e ve nts t hat occ ur after si g ni n g 
t he i nf or me d c o nse nt are 
c o nsi dere d A Es as defi ne d i n 
Secti o n 8. 3. 1  a n d Secti o n 1 0. 3 .  
A d diti o nal data are c ollecte d f or  
certai n A Es. See Secti o n  8. 3. 3 . 
S u bsta nce use (alc o h ol, 
caffei ne, t o bacc o, nic oti ne 
re place me nt) 
  
  
  
X   
  
  
  
  
  
  
  
  
  
  
 
P h ysic al e v al u ati o n   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Hei g ht  
  
X   
  
  
  
  
  
  
  
  
  
  
  
  
See Secti o n 1 0. 9 . 
Wei g ht  
  
X   
  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
Meas ure i n k g. See Secti o n  1 0. 9 . 
Waist circ u mfere nce   
  
  
  
X   
  
X   
  
X   
  
X   
X   
X   
X   
  
Meas ure i n c m. See Secti o n  1 0. 9 . 
P h ysical e xa mi nati o n   
  
X   
  
  
  
  
  
  
  
  
  
  
  
  
E xcl u des pel vic, rectal a n d breast 
e xa mi nati o ns u nless cli nicall y 
i n dicate d. See Secti o n 8. 2. 1 . 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI
C CI
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
2 5  
A C HI E V E -1  
( St u d y J 2 A -M C -G Z G T)  
Scree ni n g a n d  
Le a d -i n 
Tre at me nt  
S afet y 
f oll o w-
u p  
C o m me nts  
 
 
  
 
Visit n u m ber  
6 0 1   
1   
2   
3   
4   
5   
6   
7   
8   
9   
1 0   
1 1   
E D   
8 0 1  
  V 6 0 1 is o pti o nal.  
  Visit 2 ma y occ ur as s o o n as 
criteria f or Visit 1 are 
c o nfir me d; Visit 3 t o occ ur n o 
s o o ner t ha n 1 8 da ys after 
Visit  1.  
Wee ks fr o m Visit  3 
(r a n d o miz ati o n ) 
  
w k 
p ost 
e n d of 
T x P   
 
Visit i nter v al t oler a nce 
( d a ys) 
  
  
 
F asti n g visit  
  
  
  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
  
 
S y m pt o m -directe d p h ysical 
assess me nt  
  
  
  
  
  
  
  
X   
  
  
  
  
  
  
S y m pt o m -directe d p h ysical 
assess me nt ma y be c o n d ucte d at 
t he discreti o n of t he PI or q ualifie d 
pers o n nel as i n dicate d per l ocal 
re g ulati o ns base d o n partici pa nt 
stat us a n d sta n dar d of care. 
Vital si g ns  (tri plicate)  
  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
I ncl u des p ulse rate a n d bl o o d 
press ure.  
Meas ure d i n tri plicate after 
partici pa nt has bee n sitti n g at l east 
5 mi n utes. Vital si g ns s h o ul d be 
ta ke n bef ore E C G traci n g. See 
Secti o ns  8. 2. 2  a n d 1 0. 9 . 
E C G 1 2 -lea d ( 
; 
ce ntral)  
  
  
  
X   
  
  
  
  
  
  
  
X   
X   
X   
C ollect E C G bef ore bl o o d sa m ples 
f or la b orat or y testi n g. 
E C G ma y be re peate d at t he 
i n vesti gat or’s discreti o n at a n y 
visit.   
See Secti o n 8. 2. 3 . 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI
C CI
C CI
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
2 6  
A C HI E V E -1  
( St u d y J 2 A -M C -G Z G T)  
Scree ni n g a n d  
Le a d -i n 
Tre at me nt  
S afet y 
f oll o w-
u p  
C o m me nts  
 
 
  
 
Visit n u m ber  
6 0 1   
1   
2   
3   
4   
5   
6   
7   
8   
9   
1 0   
1 1   
E D   
8 0 1  
  V 6 0 1 is o pti o nal.  
  Visit 2 ma y occ ur as s o o n as 
criteria f or Visit 1 are 
c o nfir me d; Visit 3 t o occ ur n o 
s o o ner t ha n 1 8 da ys after 
Visit  1.  
Wee ks fr o m Visit  3 
(r a n d o miz ati o n ) 
  
 w k 
p ost 
e n d of 
T x P   
 
Visit i nter v al t oler a nce 
( d a ys) 
  
  
 
F asti n g visit  
  
  
  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
  
 
F u n d us p h ot o gra p h y a n d 
f urt her o p ht hal m ol o gical 
assess me nt  
  
  
X   
  
  
  
  
  
  
X   
  
X   
X   
  
 
 
Eli gi bilit y (see e xcl usi o n criteri o n # 1 3, Secti o n 5. 2 ) M U S T be c o nfir me d base d o n f u n d us p h ot o gra p hs a n d a n y a d diti o nal 
o p ht hal m ol o gical e val uati o n. Scree ni n g f u n d us p h ot o gra p h y s h o ul d be perf or me d o nl y f or partici pa nts eli gi ble base d o n scree ni n g 
acti vities perf or me d at Visit 1 , i ncl u di n g la b orat or y res ults. 
F oll o w -u p f u n d us p h ot o gra p h y a n d a n y a d diti o nal o p ht hal m ol o gical e val uati o n will be perf or me d at Visit 9/ Wee k 2 4 ( ± 4 wee ks) o nl y 
if reti n o pat h y or D M E were prese nt at baseli ne. At Visit 1 1/ W ee k 4 0, t he f u n d us p h ot o gra p h y a n d f urt her assess me nt s h o ul d be 
c o m plete d wit hi n 4 wee ks pri or t o t hat visit.  
All f u n d us p h ot o gra p hs a n d a n y a d diti o nal o p ht hal m ol o gical e val uati o n f or reti n o pat h y or D M E o n p h ot o gra p hs m ust be assesse d b y 
a n o p ht hal m ol o gist or ot her q ualifie d healt hcare pr ofessi o nal. See Secti o n 8. 2. 8 . 
P artici p a nt di ar y (electr o nic)   
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Dis pe nse e Diar y  
  
  
X   
  
  
  
  
  
  
  
  
  
  
  
I ncl u des h y p o gl yce mia, dail y st u d y 
i nter ve nti o n a d mi nistrati o n ( oral 
orf or gli pr o n  or place b o), a n d 4 -
p oi nt a n d 7 -p oi nt S M B G, as 
a p plica ble (see Secti o n 5 . 3. 1). 
e Diar y re vie w  
  
  
  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
e Diar y re vie w t o i ncl u de S M B G 
data, dail y d osi n g, a n d 
h y p o gl yce mia e ve nts.  
Re mi n d partici pa nts a b o ut 
7 -p oi nt S M B G  
  
  
X   
  
  
  
  
  
X   
  
X   
  
  
  
See Secti o n 5. 3. 1 . Site staff will 
re mi n d partici pa nts of c ollecti o n 
ti mes at s pecifie d visits a n d 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI
C CI
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
2 7  
A C HI E V E -1  
( St u d y J 2 A -M C -G Z G T)  
Scree ni n g a n d  
Le a d -i n 
Tre at me nt  
S afet y 
f oll o w-
u p  
C o m me nts  
 
 
  
 
Visit n u m ber  
6 0 1   
1   
2   
3   
4   
5   
6   
7   
8   
9   
1 0   
1 1   
E D   
8 0 1  
  V 6 0 1 is o pti o nal.  
  Visit 2 ma y occ ur as s o o n as 
criteria f or Visit 1 are 
c o nfir me d; Visit 3 t o occ ur n o 
s o o ner t ha n 1 8 da ys after 
Visit  1.  
Wee ks fr o m Visit  3 
(r a n d o miz ati o n ) 
  
w k 
p ost 
e n d of 
T x P   
 
Visit i nter v al t oler a nce 
( d a ys) 
  
  
 
F asti n g visit  
  
  
  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
  
 
a p pr o xi matel y 1 wee k bef ore 
s u bse q ue nt visits.  
Re vie w 7 -p oi nt S M B G   
  
  
  
X   
  
  
  
  
  
X   
  
X   
  
  
P artici pa nt will c ollect  t w o 7-p oi nt 
S M B Gs o n 2 n o n -c o nsec uti ve da ys 
d uri n g t he wee k prece di n g eac h 
visit s pecifie d.  
e Diar y ret ur n  
  
  
  
  
  
  
  
  
  
  
  
  
  
X   
 
P atie nt -re p orte d o utc o mes (electr o nic)   
  
  
  
  
  
  
  
  
  
  
  
  
 
S h ort F or m -3 6 versi o n 2 
Healt h S ur ve y ac ute f or m 
( S F-3 6 v 2, Ac ute)  
  
  
  
X   
  
  
  
  
  
  
  
X   
X   
  
 
E Q -5 D -5 L  
  
  
  
X   
  
  
  
  
  
  
  
X   
X   
  
 
A bilit y t o P erf or m P h ysical 
Acti vities of Dail y Li vi n g 
( A P P A D L) 
  
  
  
X   
  
  
  
  
  
  
  
X   
X   
  
 
I m pact of Wei g ht o n Self-
P erce pti o n (I W -S P)  
  
  
  
X   
  
  
  
  
  
  
  
X   
X   
  
 
Dia betes Treat me nt 
Satisfacti o n Q uesti o n naire -
Stat us Versi o n  ( D T S Qs) 
  
  
  
X   
  
  
  
  
  
  
  
X   
X   
  
 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI
C CI
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
2 8  
A C HI E V E -1  
( St u d y J 2 A -M C -G Z G T)  
Scree ni n g a n d  
Le a d -i n 
Tre at me nt  
S afet y 
f oll o w-
u p  
C o m me nts  
 
 
  
 
Visit n u m ber  
6 0 1   
1   
2   
3   
4   
5   
6   
7   
8   
9   
1 0   
1 1   
E D   
8 0 1  
  V 6 0 1 is o pti o nal.  
  Visit 2 ma y occ ur as s o o n as 
criteria f or Visit 1 are 
c o nfir me d; Visit 3 t o occ ur n o 
s o o ner t ha n 1 8 da ys after 
Visit  1.  
Wee ks fr o m Visit  3 
(r a n d o miz ati o n ) 
  
 w k 
p ost 
e n d of 
T x P   
 
Visit i nter v al t oler a nce 
( d a ys) 
  
  
 
F asti n g visit  
  
  
  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
  
 
Dia betes Treat me nt 
Satisfacti o n Q uesti o n naire -
C ha n ge Versi o n  ( D T S Qc) 
  
  
  
  
  
  
  
  
  
  
  
X   
X   
  
 
P artici p a nt e d uc ati o n   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Dia betes e d ucati o n 
(i ncl u des B G meter a n d 
S M B G trai ni n g)  
  
  
X   
  
  
  
  
  
  
  
  
  
  
  
See Secti o n 5. 3. 1 . 
All trai ni n g s h o ul d be re peate d as 
nee de d t o e nc o ura ge partici pa nt 
c o m plia nce.  
Dis pe nse B G meter a n d 
s u p plies as nee de d 
  
  
X   
  
  
  
  
X   
  
  
  
  
  
  
 
L a b or at or y tests a n d s a m ple 
c ollecti o ns  
  
  
  
  
  
  
  
  
  
  
  
  
 
He mat ol o g y  
  
X   
  
  
  
  
  
  
  
X   
  
X   
X   
  
 
Cli nical c he mistr y  
  
X   
  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X  
 
 
  
 
. 
Gl uc ose  
  
  
  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
  
See “ Fasti n g visits” i n t he S o A 
prea m ble.  
He m o gl o bi n A 1c ( H b A 1c)   
  
X   
  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
  
 
Li pi ds  
  
  
  
X   
  
  
X   
  
  
X   
  
X   
X   
  
 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI
C CI
C CI
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
2 9  
A C HI E V E -1  
( St u d y J 2 A -M C -G Z G T)  
Scree ni n g a n d  
Le a d -i n 
Tre at me nt  
S afet y 
f oll o w-
u p  
C o m me nts  
 
 
  
 
Visit n u m ber  
6 0 1   
1   
2   
3   
4   
5   
6   
7   
8   
9   
1 0   
1 1   
E D   
8 0 1  
  V 6 0 1 is o pti o nal.  
  Visit 2 ma y occ ur as s o o n as 
criteria f or Visit 1 are 
c o nfir me d; Visit 3 t o occ ur n o 
s o o ner t ha n 1 8 da ys after 
Visit  1.  
Wee ks fr o m Visit  3 
(r a n d o miz ati o n ) 
  
 w k 
p ost 
e n d of 
T x P   
 
Visit i nter v al t oler a nce 
( d a ys) 
  
  
 
F asti n g visit  
  
  
  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
  
 
Li pase  
  
X   
  
  
  
  
X   
  
  
X   
  
X   
X   
X   
 
P a ncreatic a m ylase  
  
X   
  
  
  
  
X   
  
  
X   
  
X   
X   
X   
 
I ns uli n 
  
  
  
X   
  
  
X   
  
  
X   
  
X   
X   
  
 
Gl uca g o n  
  
  
  
X   
  
  
  
  
  
  
  
X   
X   
  
 
C -pe pti de  
  
  
  
X   
  
  
X   
  
  
X   
  
X   
X   
  
 
Ser u m pre g na nc y  
  
X   
  
  
  
  
  
  
  
  
  
  
  
  
C ollect f or W O C B P. See 
Secti o n  1 0. 4 . 
Uri ne pre g na nc y (l ocal)   
  
  
  
X   
  
  
  
  
  
  
  
X   
X   
  
T he res ult m ust be a vaila ble bef ore 
t he first d ose of st u d y i nter ve nti o n 
f or W O C B P.  
P erf or m a d diti o nal pre g na nc y tests 
if a me nstr ual peri o d is misse d, if 
t here is cli nical s us pici o n of 
pre g na nc y, or as re q uire d b y l ocal 
la w or re g ulati o n. 
F ollicle -sti m ulati n g 
h or m o ne ( F S H)  
  
X   
  
  
  
  
  
  
  
  
  
  
  
  
P erf or m as nee de d t o c o nfir m 
p ost me n o pa usal stat us. See 
Secti o n  1 0. 4 . 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI
C CI
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
3 0  
A C HI E V E -1  
( St u d y J 2 A -M C -G Z G T)  
Scree ni n g a n d  
Le a d -i n 
Tre at me nt  
S afet y 
f oll o w-
u p  
C o m me nts  
 
 
  
 
Visit n u m ber  
6 0 1   
1   
2   
3   
4   
5   
6   
7   
8   
9   
1 0   
1 1   
E D   
8 0 1  
  V 6 0 1 is o pti o nal.  
  Visit 2 ma y occ ur as s o o n as 
criteria f or Visit 1 are 
c o nfir me d; Visit 3 t o occ ur n o 
s o o ner t ha n 1 8 da ys after 
Visit  1.  
Wee ks fr o m Visit  3 
(r a n d o miz ati o n ) 
  
 w k 
p ost 
e n d of 
T x P   
 
Visit i nter v al t oler a nce 
( d a ys) 
  
  
 
F asti n g visit  
  
  
  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
  
 
He p atitis C vir us ( H C V) 
scree ni n g tests 
  
X   
  
  
  
  
  
  
  
  
  
  
  
  
If H C V a nti b o d y test is p ositi ve, it 
m ust be f oll o we d b y a n H C V R N A 
test. P artici pa nts w h o are p ositi ve 
f or H C V a nti b o d y a n d ne gati ve f or 
H C V R N A ma y be e nr olle d. See 
e xcl usi o n criteri o n # 1 7, 
Secti o n  5. 2 . 
He p atitis B vir us ( H B V) 
scree ni n g tests 
  
X   
  
  
  
  
  
  
  
  
  
  
  
  
F or partici pa nts w h o are p ositi ve 
f or H B c A b, testi n g f or H B V D N A 
will be perf or me d. See e xcl usi o n 
criteri o n # 1 7, Secti o n 5. 2 . 
Calcit o ni n  
  
X   
  
  
  
  
X   
  
  
X   
  
X   
X   
X   
 
C ystati n -C  
  
X   
  
X   
  
  
X   
  
  
X   
  
X   
X   
  
 
e G F R  
  
X   
  
X   
  
  
X   
  
  
X   
  
X   
X   
  
C K D -E PI c ystati n -C ( 2 0 1 2)  
Uri nar y al b u mi n/creati ni ne 
rati o ( U A C R) 
  
  
  
X   
  
  
  
  
  
X   
  
X   
X   
  
 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI
C CI
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
3 1  
A C HI E V E -1  
( St u d y J 2 A -M C -G Z G T)  
Scree ni n g a n d  
Le a d -i n 
Tre at me nt  
S afet y 
f oll o w-
u p  
C o m me nts  
 
 
  
 
Visit n u m ber  
6 0 1   
1   
2   
3   
4   
5   
6   
7   
8   
9   
1 0   
1 1   
E D   
8 0 1  
  V 6 0 1 is o pti o nal.  
  Visit 2 ma y occ ur as s o o n as 
criteria f or Visit 1 are 
c o nfir me d; Visit 3 t o occ ur n o 
s o o ner t ha n 1 8 da ys after 
Visit  1.  
Wee ks fr o m Visit  3 
(r a n d o miz ati o n ) 
  
w k 
p ost 
e n d of 
T x P   
 
Visit i nter v al t oler a nce 
( d a ys) 
  
  
 
F asti n g visit  
  
  
  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
  
 
P har mac o ki netics ( P K) 
sa m ples 
  
  
  
  
X   
X   
  
X   
  
X   
X   
  
X   
  
C ollect P K sa m ples at t hese ti mes:  
 Wee ks 4, 1 6, a n d 3 2: pre -d ose  
 Wee k 8: 4 t o 1 2 h o urs p ost -
d ose  
 Wee k 2 4: 1 t o 4 h o urs p ost -
d ose  
 E D: a n y ti me  
P artici pa nts s h o ul d ta ke st u d y 
i nter ve nti o n o nl y after P K sa m ples 
are ta ke n o n t he visit da ys of 
Wee ks 4, 1 6, a n d 3 2.  
P artici pa nts ma y be re q uire d t o 
c o me bac k f or p ost -d ose P K 
sa m ples. 
St o re d s a m ples  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Ge netics sa m ple  
  
  
  
X   
  
  
  
  
  
  
  
  
  
  
 
E x pl orat or y bi o mar ker 
sa m ples 
  
  
  
X   
  
  
X   
  
  
X   
  
X   
X   
  
 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI
C CI
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
3 2  
A C HI E V E -1  
( St u d y J 2 A -M C -G Z G T)  
Scree ni n g a n d  
Le a d -i n 
Tre at me nt  
S afet y 
f oll o w-
u p  
C o m me nts  
 
 
  
 
Visit n u m ber  
6 0 1   
1   
2   
3   
4   
5   
6   
7   
8   
9   
1 0   
1 1   
E D   
8 0 1  
  V 6 0 1 is o pti o nal.  
  Visit 2 ma y occ ur as s o o n as 
criteria f or Visit 1 are 
c o nfir me d; Visit 3 t o occ ur n o 
s o o ner t ha n 1 8 da ys after 
Visit  1.  
Wee ks fr o m Visit  3 
(r a n d o miz ati o n ) 
  
 w k 
p ost 
e n d of 
T x P   
 
Visit i nter v al t oler a nce 
( d a ys) 
  
  
 
F asti n g visit  
  
  
  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
  
 
R a n d o miz ati o n a n d d osi n g -r el ate d acti vities   
  
  
  
  
  
  
  
  
  
  
  
 
Re gister visit wit h I W R S   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
  
X   
 
Ra n d o mizati o n  via I W R S   
  
  
  
X   
  
  
  
  
  
  
  
  
  
  
 
Dis pe nse st u d y 
i nter ve nti o n via I W R S 
  
  
  
X   
X   
X   
X   
X   
X   
X   
X   
  
  
  
 
Dis pe nse st u d y 
i nter ve nti o n t o partici pa nt 
(f or at-h o me d osi n g)  
  
  
  
X   
X   
X   
X   
X   
X   
X   
X   
  
  
  
 
P artici pa nt ret ur ns u n use d 
st u d y i nter ve nti o n 
  
  
  
  
X   
X   
X   
X   
X   
X   
X   
X   
X   
  
 
Assess st u d y i nter ve nti o n 
c o m plia nce  
  
  
  
  
X   
X   
X   
X   
X   
X   
X   
X   
X   
  
 
A b bre viati o ns: B G = bl o o d gl uc ose; C K D -E PI = C hr o nic Ki d ne y  Disease -E pi de mi ol o g y C olla b orati o n ; D M E = dia betic mac ular e de ma; 
D N A  =  de o x yri b o n ucleic aci d; E C G = electr ocar di o gra m; E D = earl y disc o nti n uati o n; e G F R = esti mate d gl o mer ular filtrati o n rate; H B c A b = he patitis B c ore 
a nti b o d y; I C F = i nf or me d c o nse nt f or m; I W R S = i nteracti ve we b res p o nse s yste m; PI = pr i nci pal i n vesti gat or; R N A = ri b o n ucleic aci d ; S M B G = self-
m o nit ori n g of b l o o d gl uc ose; S o A = Sc he d ule of Acti vities; T x P = treat me nt peri o d; w k = wee k; W O C B P = w o me n of c hil d beari n g p ote ntial . 
 
 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI
C CI
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
3 3  
2.   
I ntr o d ucti o n  
G L P -1 rece pt or a g o nis m is a n  esta blis he d t hera p e utic mec ha nis m f or gl yce mic c o ntr ol i n T 2 D , 
as well as wei g ht ma n a ge me nt i n i n di vi d uals wit h o besit y or o ver wei g ht. U nli ke i njecta ble or 
orall y a d mi nistere d  pe pti de G L P -1 R A s a p pr o ve d b y re g ulat or y a ut h orities t o date, orf or gli pr o n  
(L Y 3 5 0 2 9 7 0 ) is a n oral, s mall m olec ule G L P-1 R A . 
Orf or gli pr o n  is bei n g de v el o pe d f or t he treat me nt of T 2 D a n d o ver wei g ht or o besit y .  
2. 1.   
St u d y R ati o n ale   
A C HI E V E -1 ( St u d y J 2 A -M C -G Z G T [ G Z G T]) is desi g ne d t o pr o vi de e vi d e nce of safet y a n d 
efficac y of orf or gli pr o n  i n pe o ple wit h T 2 D  c urre ntl y treat e d wit h diet a n d e x ercise al o ne. I n 
a d diti o n t o healt h y lifest yl e b e ha vi ors, a nti h y per gl yce mic  me dicati o ns are us u all y re q uire d f or 
i m pr o vi n g gl yce mic c o ntr ol i n patie nts wit h T 2 D ( A D A 2 0 2 3). Rec o m me n dati o ns i n t he 2 0 2 2 
A D A -E A S D c o nse ns us g ui deli nes ( Da vies et al. 2 0 2 2) state t hat metf or mi n ma y c o nti n ue t o be 
use d as first -li ne t hera p y d ue t o its hi g h effi cac y, s afet y pr ofile, p ot e ntial f or m o dest wei g ht l oss, 
p ote ntial t o l o wer C V ris k, a n d l o w c ost. H o we v er, t he c o nse ns us rec o m me n dati o ns i ncl u de 
i ncreas e d f oc us o n a nti h y per gl yce mic  me di cati o ns t hat als o ha ve a p ositi ve effect o n wei g ht 
ma na ge me nt a n d car di ore nal pr ot ecti o n. I n p e o ple wit h T 2 D w h o ha ve  o v er wei g ht or o bes it y, a 
me dicati o n wit h a si g nifi ca nt wei g ht l oss effect, s pecificall y a G L P -1 R A, is a d vise d.  
Orf or gli pr o n  is bei n g de v el o pe d as a n 
 t o i m pr o ve gl yce mic c o ntr ol i n 
a d ults wit h T 2 D.  
T his st u d y will i n vesti gat e t he a nti h y per gl yce mi c effect of o nce dail y oral treat me nt wit h 
orf or gli pr o n   m g, 
 m g, a n d 
 m g, c o m pare d wit h place b o, i n partici pa nts wit h T 2 D a n d 
i na de q uate gl yce mic c o ntr ol wit h diet a n d e x ercise al o ne w h o are naï ve of i ns uli n use a n d ha ve 
n ot bee n treat e d wit h a n y a nti h y per gl yce mic  a ge nt s f or at least 9 0 da ys prece di n g  t o t he st u d y 
start. A d diti o nall y, t he st u d y will c o m pare t he effects of orf or gli pr o n  a n d place b o o n b o d y 
wei g ht a n d o verall safet y pr ofile.  
2. 2.   
B ac k gr o u n d   
T y pe 2 di a betes  
T 2 D is a meta b olic c o n diti o n c haract erize d b y i m p aire d gl yce mic c o ntr ol ca use d b y i n crease d 
i ns uli n resista nce a n d pr o gressi ve beta-cell fail ure a n d c o ns e q ue ntl y i na de q uate i ns uli n secreti o n. 
T 2 D  is fre q ue ntl y ass o ciate d wit h c o m or bi dities s uc h as o ver wei g ht or o besit y, h y perte nsi o n, 
i ncreas e d bl o o d li p o pr otei n c o nce ntrati o ns, a n d a hi g her ris k f or macr o - a n d micr o vasc ular 
c o m plicati o ns . Ac hie vi n g A 1 C tar g ets of < 7 % has bee n s h o w n t o re d u ce micr o vasc ular 
c o m plicati o ns of T 2 D w he n i nstit ute d earl y i n t he c o urse of disease  ( A D A 2 0 2 3 ). Data h a ve  
s h o w n t hat earl y i nte nsi v e gl u c ose c o ntr ol  is esse ntial t o ma xi mize re d ucti o n of t he l o n g-ter m 
ris k of gl yce mic c o m plicati o ns  (H ol ma n et al. 2 0 0 8  a n d Li n d et al. 2 0 2 1 ). F oll o wi n g pers o n -
ce ntere d strate g y, A D A 2 0 2 3 g ui deli nes s u g gest t h at m ore stri n ge nt gl yce mic g o als ma y b e 
a p pr o priate f or i n di vi d uals earl y i n t heir c o urse of disease  ( A D A 2 0 2 3).  
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
Pr ot o c ol J 2 A- M C- G Z G T( b)
A P h a s e 3, R a n d o mi z e d, D o u bl e- Bli n d St u d y t o I n v e sti g at e t h e Effi c a c y a n d S af et y of O n c e
D ail y Or al L Y 3 5 0 2 9 7 0 C o m p ar e d wit h Pl a c e b o i n A d ult P arti ci p a nt s wit h T y p e 2 Di a b et e s a n d
I n a d e q u at e Gl y c e mi c C o ntr ol wit h Di et a n d E x er ci s e Al o n e ( A C HI E V E- 1)
C CI
C CI
C CI
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
3 4  
U n met nee ds f or di a betes tre at me nt  
Wit h t he pre vale nce of T 2 D i ncreasi n g w orl d wi de, ne w a nti h y per gl yce mic a ge nts offeri n g 
si g nifica nt i m pr o ve m e nts i n gl yce mic c o ntr ol a n d a d diti o nal wei g ht l oss as well as ot her 
p ote ntial healt h be nefits, w hic h w o ul d res ult i n i m pr o ve d hea lt h o utc o mes, are hi g hl y desire d. 
C urre ntl y t here are G L P -1  R A t hera pies a p pr o ve d f or b ot h gl yce mic c o ntr ol i n patie nts wit h T 2 D 
a n d c hr o nic wei g ht ma na ge m e nt i n patie nts wit h o besit y or o ver wei g ht wit h 1 or m ore 
wei g ht -relat e d c o m or bi dit y. T he m ost c o m m o nl y use d G L P -1  R As are a d mi nistere d o nce wee kl y 
t hr o u g h s u bc ut a ne o us i njecti o n. E ve n wit h m ulti ple mar kete d G L P-1  R As a vaila ble f or use i n 
a d ults, t he i njecti o n ma y be  a barrier f or ma n y pati e nts t o i nitiate a n d t o a d here t o a t hera p y l o n g -
ter m. 
Oral se ma gl uti de is a pe pti de c o m bi ne d wit h salca pr ozate s o di u m t hat pr o vi des patie nts wit h a 
via ble alter nati ve t o s u bc uta ne o us i njecti o n deli ver y. H o we v er, its a d mi nistrati o n re q uires t h e 
patie nt t o a d here t o certai n restricti o ns  of meal ti mi n g a n d a m o u nt of water c o ns u me d t o e ns ure 
pr o per deli ver y of t he me dicati o n t hr o u g h t he gastric li ni n g.  T here is a n u n met me dical nee d f or 
efficaci o us, safe , a n d well -t olerate d oral f or m ulati o ns of G L P -1 R As for t h e ma na ge m e nt of 
T 2 D. Oral f or m ulati o ns wit h fe wer a d mi nistrati o n barriers w o ul d all o w f or f urt her tail ori n g of 
t hera p y t o meet i n di vi d ual patie nt prefere n ces a n d nee ds. 
Cli nic al d at a f or orf or gli pr o n  
A detaile d descri pti o n of t he c he mistr y, p har mac ol o g y, efficac y, a n d s afet y of orf or gli pr o n  is 
pr o vi de d i n t he I B.  
T he cli nical p har m ac ol o g y, P K, a n d P D of orf or gli pr o n  were i nitiall y st u die d i n 2 c o m plete d 
P hase 1 st u dies, J 2 A -M C -G Z G A ( G Z G A) i n healt h y v ol u nteers a n d J 2 A -M C -G Z G C ( G Z G C) i n 
partici pa nts wit h T 2 D. Res ults fr o m t hese st u dies de m o ns trate d a P K pr ofile a p pr o priate f or o nce 
dail y oral d osi n g t hat ca n be a d mi nistere d wit h o ut li mitati o ns pertai ni n g t o f o o d or water i nta k e 
or ti me of da y . 
St u d y  J 2 A-M C -G Z G E ( G Z G E ) was a P hase 2, ra n d o mize d, d o u ble -bli n d, parallel, place b o - a n d 
acti ve c o m parat or ( 1. 5 m g d ula gl uti de o nce wee kl y) -c o ntr olle d 2 6 -wee k st u d y.  T he o bjecti ve of 
t he st u d y was t o i n vesti gate a nti h y per gl yce mic  a n d b o d y wei g ht -l o weri n g efficac y, as well as 
t olera bilit y a n d s afet y of orf or gli pr o n  i n partici pa nts wit h T 2 D w h o faile d t o ac hie ve a de q u ate 
gl yce mic c o ntr ol o n diet a n d e x ercise al o n e or w h e n treate d wit h metf or mi n.  
Statisticall y si g nifica nt d ose -de pe n d e nt re d u cti o ns f or H b A 1c were o bser ve d f or c ha n ge fr o m 
baseli ne a n d place b o -a dj uste d c ha n ge acr oss all orf or gli pr o n  d oses . Differe nces were  statisticall y 
si g nifica ntl y greater f or all orf or gli pr o n  treat me nt gr o u ps be gi n ni n g at Wee k 4. Place b o -a dj uste d 
c ha n ges ra n ge d fr o m -0. 7 7 % ( 3 m g) t o -1. 6 7 % at ( 4 5 m g)  c o m pare d wit h  d ula gl uti de -0. 6 7 %.  
Partici pa nts i n St u d y G Z G E e x perie nce d a d ose-d e pe n de nt pr o gressi ve decrease i n b o d y wei g ht 
u p t o t he 2 6 -wee k ti me p oi nt f or all orf or gli pr o n  d oses wit h  si g nifica nt w ei g ht l oss c o m pare d 
wit h place b o f or 
 m g d ose or greater at Wee k 2 6  (
 m g -4. 4  k g;  
 m g -7. 8  k g; 
 m g -7. 4  k g;  
 m g -7. 4 k g) . Orf or gli pr o n   m g s h o we d a wei g ht re d ucti o n  si milar t o 
d ula gl uti de 1. 5 m g  (-1. 5 k g vs -1. 9 k g, res pecti vel y ). 
T he o verall safet y pr ofile of orf or gli pr o n  was c o nsiste nt wit h t hat esta blis he d f or t he G L P -1 R A 
class, 
). 
Data fr o m t hese P hase 2 st u dies s u p p orte d t he f urt her cli nical de vel o p me nt of orf or gli pr o n . 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI
C CI
C CI
C CI
C CI
C CI
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
3 5  
2. 3.   
Be nefit/ Ris k As sess me nt  
D etaile d i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be nefits a n d ris ks a n d reas o na bl y e x pecte d 
A Es  of orf or gli pr o n  m a y be f o u n d i n t he I B. 
2. 3. 1.   
Ris k Assess me nt   
St u d y inter ve nti o n  
T he p ote ntial ris ks ass oci ate d wit h orf or gli pr o n  are si milar t o t h ose of mar kete d G L P -1 R As. T he 
m ost c o m m o nl y re p orte d T E A Es o bser ve d i n t he orf or gli pr o n  cli nical st u dies, i n  healt h y 
partici pa nts or partici pa nts wit h T 2 D a n d/or o besit y, are 
 
 
 
P ote ntial ris ks ass ociate d wit h orf or gli pr o n  i ncl u d e 
 ac ute pa n creatitis  
 i ncreas es i n heart rate 
 h y p o gl yce mia w he n use d wit h i ns uli n or i ns uli n secreta g o g u es  
 h y perse nsiti vit y reacti o ns, a n d  
 t h yr oi d C-cell effects ( o nl y o bser ve d i n r o de nts) . 
Ra pi d i m pr o ve me nts i n gl uc ose c o ntr ol ha ve bee n ass ociate d wit h te m p orar y w orse ni n g of 
dia betic reti n o pat h y a n d is t h us a n ot her p ote ntial ris k ass ociate d wit h t he st u d y.  
Secti o ns  5. 1 , 5. 2 , a n d 8. 2  a d dress miti gati o n, ma na ge me nt, a n d m o nit ori n g of t he k n o w n 
p ote ntial ris ks ass ociate d wit h orf or gli pr o n . 
St u d y p r oce d ures  
Bl o o d dr a ws  
Ris ks of bl o o d dra ws f or cli nical la b orat or y assess me nts i ncl u de t he p ote ntial f or s o me pai n a n d 
a s mall ris k of br uisi n g or i nfecti o n at t he site.  
E C G c ollecti o n  
C ollecti o n of E C Gs ma y ca use mil d disc o mf ort d uri n g place me nt a n d re m o val of lea ds fr o m t he 
s ki n. S o me partici pa nts ma y e x perie nce l ocal irritati o n or re d ness at t he sites of lea d attac h me nt.  
Reti n al assess m e nt  
Dilati n g dr o ps if use d f or p u pil dilati o n f or t he e ye e x a mi nati o n ma y sti n g t e m p oraril y, a n d ma y 
ca use te m p orar y bl urre d visi o n, diffic ult y f oc usi n g, a n d li g ht se nsiti vit y. P har mac ol o gic 
dilatati o n ma y be c o ntrai n dicate d i n s o me partici p a nts wit h e ye c o n diti o ns, f or e x a m ple, cl ose d 
a n gl e gla uc o ma.  
2. 3. 2.   
Be nefit Assess me nt   
T he k n o w n p har m ac ol o g y of G L P -1 rece pt or a g o nis m a n d t he data fr o m t he P hase 2 st u dies of 
orf or gli pr o n  s u p p ort a n e x pectati o n of be nefits o n gl yce mic c o ntr ol a n d wei g ht l oss wit h 
orf or gli pr o n . I m pr o v e me nts i n s o me car di o meta b olic ris k fact ors, i ncl u di n g B P a n d ser u m li pi ds, 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
Pr ot o c ol J 2 A- M C- G Z G T( b)
A P h a s e 3, R a n d o mi z e d, D o u bl e- Bli n d St u d y t o I n v e sti g at e t h e Effi c a c y a n d S af et y of O n c e
D ail y Or al L Y 3 5 0 2 9 7 0 C o m p ar e d wit h Pl a c e b o i n A d ult P arti ci p a nt s wit h T y p e 2 Di a b et e s a n d
I n a d e q u at e Gl y c e mi c C o ntr ol wit h Di et a n d E x er ci s e Al o n e ( A C HI E V E- 1)
n ct
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
3 6  
ma y als o be e x pecte d. G L P -1 R As ha v e ge nerall y bee n ass oci ate d wit h re d uce d ris k of C V 
e ve nts i n pe o ple wit h T 2 D ( Gi u g lia n o et al. 2 0 2 1). 
Partici pa nts ma y als o be nefit fr o m recei vi n g pers o nal healt h i nf or mati o n, dia betes e d ucati o n, 
r o uti ne safet y ass ess me nts, a n d fre q u e nt e n ga ge me nt wit h healt h care pr o vi ders d uri n g t he st u d y, 
w hic h pr o vi de o p p ort u nities f or c oac hi n g a n d s u p p ort. 
2. 3. 3.   
O ver all Be nefit Ris k C o ncl usi o n   
T he safet y a n d efficac y pr ofile see n t o dat e f or orf or gli pr o n  s u p p orts t he o v erall be nefit/ris k f or 
partici pa nts i n t his st u d y. T he a ntic i pate d ris ks are t h ose ass ociate d wit h k n o w n p har mac ol o gic 
effects of G L P -1 R As, i n cl u di n g GI t olera bilit y a n d i ncreas e d heart rate. T hese ris ks are 
m o nit ora ble, us uall y mil d t o m o derate i n se verit y, re versi ble, a n d rea dil y m a na gea ble. T o date 
t here are n o rec o g nize d A Es fr o m orf or gli pr o n  ot her t ha n t h ose relate d t o G L P -1 rece pt or 
a g o nis m.  
T he p ote ntial ris ks base d o n t he k n o wle d ge f or t he G L P -1 R A class are c o nsi dere d bei n g 
acce pta ble i n t he c o nte xt of t he p ote ntial be nefits a ntici pate d fr o m treat me nt wit h orf or gli pr o n  i n 
a d ult partici pa nts wit h T 2 D . 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
3 7  
3.   
O bjecti ves , E n d p oi nts , a n d Esti m a n ds   
O bjecti ves  
E n d p oi nts  
Pri mar y  
 
T o de m o nstrate t hat orf or gli pr o n   m g, 
 m g, a n d/ or 
 m g are  s u peri or t o place b o 
i n gl yce mic c o ntr ol 
 C ha n ge fr o m baseli ne i n H b A 1c at 
Wee k  4 0  
Ke y Sec o n dar y  
 
T o de m o nstrate t hat orf or gli pr o n   m g, 
 m g, a n d/ or 
 m g are s u peri or t o place b o 
i n a d diti o nal meas ures of gl yce mic c o ntr ol 
 Pr o p orti o n of partici pa nts wit h a n H b A 1c 
tar get val ue of < 7. 0 % ( 5 3  m m ol/ m ol)  at 
Wee k 4 0  
 Pr o p orti o n of partici pa nts wit h a n H b A 1c 
tar get val ue of ≤6. 5 % ( 4 8  m m ol/ m ol)  at 
Wee k 4 0  
 C ha n ge fr o m baseli ne i n fasti n g ser u m 
gl uc ose (ce ntral la b orat or y)  at Wee k 4 0  
T o de m o nstrate t hat orf or gli pr o n   m g, 
 m g, a n d/ or 
 m g are s u peri or t o place b o 
i n wei g ht ma n a ge me nt 
 Perce nt a ge c ha n ge fr o m baseli ne i n b o d y 
wei g ht at Wee k 4 0  
 C ha n ge fr o m baseli ne i n b o d y wei g ht at 
Wee k 4 0  
T o de m o nstrate t hat orf or gli pr o n  
 m g 
a n d/ or 
 m g are s u p eri or t o place b o o n li pi d 
para meters  
 Perce nta ge c ha n ge fr o m baseli ne i n n o n -
H D L c h olester ol at Wee k 4 0  
 Perce nta ge c ha n ge fr o m baseli ne i n 
tri gl yceri des at Wee k 4 0 
Ot her Sec o n d ar y  
 
T o c o m pare orf or gli pr o n   m g, 
 m g, a n d 
 m g wit h place b o o n a d diti o nal meas ures of 
gl yce mic c o ntr ol  
 Pr o p orti o n of partici pa nts wit h a n H b A 1c 
tar get val ue of < 5. 7 % ( 3 9 m m ol/ m ol) at 
Wee k 4 0  
 C ha n ge fr o m baseli ne i n dail y a v era ge 7 -
p oi nt S M B G at Wee k  4 0  
T o c o m pare orf or gli pr o n   m g, 
 m g, a n d 
 m g wit h place b o o n a d diti o nal 
me as ure me nts of wei g ht ma na ge me nt  
 Pr o p orti o n of partici pa nts w h o ac hie ve d 
wei g ht l oss of ≥5 %, ≥1 0 %, a n d ≥1 5 % 
fr o m baseli ne at Wee k 4 0 
 C ha n ge fr o m baseli ne i n waist 
circ u mfere nce at Wee k 4 0  
 C ha n ge fr o m baseli ne i n B MI at Wee k  4 0  
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
3 8  
O bjecti ves  
E n d p oi nts  
T o c o m pare orf or gli pr o n   m g, 
 m g, a n d 
 m g wit h place b o o n meas ures of bl o o d 
press ure  
 C ha n ge fr o m baseli ne at Wee k 4 0 i n:  
o  S yst olic bl o o d press ure  
o  Diast olic bl o o d press ure  
T o c o m pare orf or gli pr o n   m g, 
 m g, a n d 
 m g wit h place b o o n li pi d para meters  
 Perce nta ge c ha n ge fr o m baseli ne i n li pi d 
para meters at Wee k 4 0  
o  T otal c h olester ol  
o  H D L -c h olester ol  
o  L D L -c h olester ol  
o  V L D L -c h olest er ol  
T o c o m pare orf or gli pr o n   m g wit h place b o 
o n li pi d para meters  
 Perce nta ge c ha n ge fr o m baseli ne i n li pi d 
para meters at Wee k 4 0  
o  N o n -H D L c h ol ester ol  
o  Tri gl yceri des  
T o c o m pare orf or gli pr o n   m g, 
 m g, a n d 
 m g wit h place b o o n p atie nt -re p orte d 
o utc o mes  
 C ha n ge fr o m baseli ne at Wee k 4 0 i n:  
o  S F -3 6 v 2 Ac ute F or m d o mai n a n d 
s u m mar y s c ores 
o  E Q -5 D -5 L h ealt h state utilities a n d 
 
o  A P P A D L sc ores  
o  I W-S P sc ores  
o  D T S Qs sc ores  
 D T S Qc sc ores at Wee k 4 0  
T o descri be t he s afet y of orf or gli pr o n  i n 
partici pa nts wit h T 2 D  
S u m mar y of safet y dat a, i ncl u di n g n u m ber 
a n d i nci de nce of:  
 S A Es  
 T E A Es  
 disc o nti n uati o ns fr o m st u d y 
i nter ve nti o n or st u d y d u e t o A Es 
Tertiar y  
 
T o c haracterize t he P K of orf or gli pr o n  a n d 
e x pl ore t he relati o ns hi ps bet wee n orf or gli pr o n  
c o nce ntr ati o n a n d efficac y, safet y, a n d 
t olera bilit y meas ures. 
 P o p ulati o n P K a n d P D para meters  
A b bre viati o ns: A E = a d verse e ve nt;  A P P A D L = A bilit y t o P erf or m P h ysical Acti vities of Dail y Li vi n g; B MI = b o d y 
mass i n de x; D T S Qc = Dia betes Treat me nt Satisfacti o n Q uesti o n naire -C ha n ge Versi o n ; D T S Qs = Dia betes 
Treat me nt Satisfacti o n Q uesti o n naire -Stat us Versi o n ; H b A 1 c  = he m o gl o bi n A 1c; H D L = hi g h -de nsit y 
li p o pr otei n; I W-S P = I m pact of Wei g ht o n Self -P erce pti o 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 mic; P K  =  p har mac o ki netic; Q D = o nce dail y; S A E = seri o us a d verse e ve nt; S F -3 6 v 2, Ac ute = 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
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S h ort F or m -3 6 versi o n 2 Healt h S ur ve y ac ute f or m; S M B G = self -m o nit ore d bl o o d gl uc ose ; T 2 D = t y pe 2 
dia betes; T E A E = treat me nt -e mer ge nt a d verse e ve nt; 
 V L D L = ver y  l o w-de nsit y 
li p o pr otei n. 
Pri m ar y esti m a n d s 
T here  will be 2 esti ma n ds f or t he pri mar y o bjecti ve pla n ne d i n t he st u d y. T he 2  esti ma n ds, 
treat me nt re gi me n esti ma n d a n d effi cac y esti ma n d, a d dress I C Es usi n g t he treat me nt p olic y 
strate g y a n d t he h y p ot hetical strate g y, res pecti vel y. 
Tre at m e nt p olicy str ate gy  
T he occ urre n ce of t h e I C E is c o nsi dere d irrele va nt i n defi ni n g t he treat me nt effect of i nterest; t he 
val ues f or t he v aria ble of i nterest are us e d re gar dless of w het her t he I C E occ urs . 
Hy p ot hetic al str ate gy  
A sce nari o is e n visa ge d i n w hic h t he I C E w o ul d n ot  occ ur. T he v al ue of t h e varia ble t o reflect 
t he cli nical q uesti o n of i nterest is t he val ue t hat t he varia ble w o ul d ha ve ta ke n i n t he h y p ot h etical 
sce nari o d efi ne d. 
Tre at me nt re gi me n esti m a n d  
T he cli nical q uesti o n of i nterest  is: W h at is t he tre at me nt diff ere nce i n t he c h a n ge i n H b A 1c fr o m 
b aseli ne at Week 4 0  bet wee n orf or gli pr o n  m g, 
 m g , a n d/ or 
 m g c o m p are d wit h  pl ace b o i n 
i n divi d u als w h o meet eli gi bility criteri a re g ar dless of a d here nce t o st u dy i nterve nti o n or 
i niti ati o n of a d diti o n al a nti hy per glyce mi c me dic ati o n s?  
R ati o n ale f or t he  tre at me nt re gi m e n esti m a n d 
T he esti ma n d ai ms t o e val uate t he efficac y of orf or gli pr o n  t hat reflects t he real-life b e ha vi or of 
t he tar get p o p ulati o n. 
Tre at m e nt re gi m e n esti m a n d attri b utes  
 P o p ul ati o n : in di vi d uals w h o meet t he eli gi bilit y criteria. F urt her details ca n be f o u n d i n 
Secti o ns 5  a n d 9 . 
 E n d p oi nts : cha n ge fr o m baseli ne i n H b A 1c at Wee k 4 0.  
 Tre at me nt c o n diti o n : the ra n d o mize d treat me nt wit h all o wa nce f or p ote ntial d ose 
i nterr u pti o ns a n d d ose m o dificati o n re gar dless of a d here n ce t o st u d y i nter ve nti o n or i nitiati o n 
of a d diti o nal a nti h y p er gl yce mic me dicati o n s. 
 I nterc urre nt eve nts: n o I C Es are defi ne d beca use  treat me nt a d here nce a n d t he i nitiati o n of 
a d diti o nal a nti h y per gl yce mic me dicati o ns  are a part of t he treat me nt c o n diti o n.  
 P o p ul ati o n -level s u m m ar y a n d tre at me nt effect of i nterest : differe nce  i n mea n c ha n ges i n 
H b A 1c  fr o m b aseli ne at Wee k 4 0 bet wee n orf or gli pr o n   m g, 
 m g, a n d/ or 
 m g c o m pare d 
wit h place b o . 
Effic ac y esti m a n d  
T he cli nical q uesti o n of i nterest  is: W h at is t he tre at me nt differe nce i n t he c h a n ge i n H b A 1c fr o m 
b aseli ne at Week 4 0  bet wee n orf or gli pr o n   m g, 
 m g, a n d/ or 
 m g c o m p are d wit h  pl ace b o i n 
i n divi d u als w h o meet t he eli gi bility criteri a if t hey w o ul d re m ai n o n t heir r a n d o mly assi g ne d 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
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J 2 A-M C -G Z G T (b ) 
4 0  
st u dy i nterve nti o n f or 
 weeks a n d w o ul d n ot i niti ate a d diti o n al  a nti hy per glyce mic 
me dic ati o n s?  
R ati o n ale f or t he effic acy esti m a n d  
T his esti ma n d ai ms t o e val uate t he efficac y of orf or gli pr o n  u n d er t he i deal c o n diti o n t hat all 
partici pa nts w o ul d a d here t o t he ra n d o ml y assi g ne d st u d y i nter ve nti o n wit h o ut bei n g c o nf o u n de d 
b y t he i nitiati o n of a d diti o nal a nti h y p er gl yce mic me dicati o ns.  
Effic acy esti m a n d attri b utes  
 P o p ul ati o n : in di vi d uals w h o meet t he eli gi bilit y criteria. F urt her details ca n be f o u n d i n 
Secti o ns 5  a n d 9 . 
 E n d p oi nts : cha n ge fr o m baseli n e i n H b A 1c at Wee k 4 0 . 
 Tre at me nt c o n diti o n : the ra n d o mize d treat me nt wit h all o wa nce f or p ote ntial d ose 
i nterr u pti o ns a n d d ose  m o dificati o n s. 
 I nterc urre nt eve nts: I C Es i ncl u de per ma n e nt disc o nti n uati o n of st u d y i nter ve nti o n a n d 
i nitiati o n of a d diti o nal a nti h y per gl yce mic me dicati o n s a n d will be ha n dle d b y t he 
h y p ot hetical strate g y. T h e p ote ntial o utc o me of i nterest is t he res p o nse i n t he effi cac y 
meas ure me nt if p artici pa nts w o ul d re mai n o n t heir ra n d o ml y assi g ne d st u d y i nter ve nti o n f or 
 wee ks a n d w o ul d n ot i nitiate a d diti o nal a nti h y per gl yce mic me di cati o n s. D ose 
m o dificati o n s a n d i nterr u pti o n s will n ot be c o nsi dere d a n I C E beca use  t he y are part of t he 
treat me nt c o n diti o n. 
 P o p ul ati o n -level s u m m ar y a n d tre at me nt effect of i nterest : differe n ce i n m ea n c ha n ge s i n 
H b A 1c  fr o m b aseli ne at Wee k 4 0 bet wee n orf or gli pr o n   m g, 
 m g, a n d/ or 
 m g c o m pare d 
wit h  place b o.  
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
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J 2 A-M C -G Z G T (b ) 
4 1  
4.   
St u d y Desi g n   
4. 1.   
O ver all  Desi g n   
A C HI E V E -1 ( St u d y G Z G T ) is a P hase 3, m ultice nter, ra n d o mize d, parallel -ar m, d o u ble -bli n d , 
place b o -c o ntr olle d  st u d y t o c o m pare t he effect of orf or gli pr o n  wit h t hat of place b o o n t he 
gl yce mic c o ntr ol i n i n di vi d uals wit h T 2 D  w h o ha v e i na de q uat e gl yce mic c o ntr ol wit h diet a n d 
e x ercise al o ne , are n aï ve t o i ns uli n use a n d ha ve n ot bee n treat e d wit h  a n y a nti h y per g l yce mic 
me dicati o n d uri n g t h e 9 0 da ys  prece di n g  Visit 1 . 
T his st u d y will c o nsist of 3 peri o ds:  
 a scree ni n g a n d lea d -i n p eri o d : u p t o 4  wee ks  
F or t he ra n d o mizati o n rati o, see Secti o n 6. 3 . 
4. 2.   
Scie ntific R ati o n ale f or St u d y Desi g n   
C h oice of pri m ar y e n d p oi nt  
T he pri mar y e n d p oi nt of H b A 1c is a c o m m o nl y us e d e n d p oi nt i n cli nical trials e val uati n g t he 
efficac y a n d s afet y of a nti h y per gl yce mic a ge nts.  
C h oice of pl ace b o as c o m p ar at or  
Place b o was c h ose n as t h e c o m parat or t o meet a re g ulat or y re q uire m e nt t o c o m pare orf or gli pr o n  
wit h  place b o.  
D o u ble -bli n d desi g n  
A d o u ble -bli n d desi g n was selecte d t o mi ni mize partici pa nt a n d i n vesti gat or bias i n assess me nts 
f or efficac y, safet y, a n d st u d y i nter ve nti o n t olera bilit y. 
D ur ati o n of t he st u d y  tre at me nt 
T he pla n ne d d urati o n of t he st u d y tr eat me nt f or 
 wee ks is c o nsi dere d s ufficie nt a n d a p pr o priate 
f or partici pa nts t o o pti mize d osi n g of orf or gli pr o n  a n d t o assess t he f ull effects a n d be n efit/ris k 
of eac h treat me nt d ose of orf or gli pr o n  o n gl yce mi c c o ntr ol.  
C ollecti o n of r ace a n d et h nicit y d at a  
I n t his st u d y, c ollecti o n of dem o gra p hic i nf or mati o n i ncl u des race a n d et h nicit y. T he s cie ntific 
rati o nale is base d o n t he nee d t o assess varia ble res p o nse i n safet y a n d/ or efficac y b ase d o n race 
or et h nicit y. T his q uesti o n ca n be a ns were d o nl y if all t he rele va nt data are c ollecte d.  
4. 3.   
J u stific ati o n f or D ose  
T he orf or gli pr o n  d os es of  m g, 
 m g , a n d 
 m g Q D a d mi nistere d orall y will be e val uate d as 
t he tar get mai nte na n ce d oses i n t his st u d y. T hese d oses were select e d f or t he T 2 D pr o gra m base d 
o n assess me nt of safet y, efficac y ( gl yce mic c o ntr ol a n d wei g ht be nefit ), a n d GI t olera bilit y d ata 
fr o m P hase 2 st u dies. T h e P hase 2 data a n d e x p os ure -res p o nse a n al ysis h a ve de m o nstrate d a 
d ose res p o nse i n H b A 1 c l o weri n g fr o m  bas eli ne fr o m  m g t hr o u g h  
-m g d ose,  wit h little 
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J 2 A-M C -G Z G T (b ) 
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a d diti o nal effect of  t he 
-m g d ose c o m pare d wit h 
 m g a n d n o n ota bl e i ncreas e of GI e ve nts 
bet wee n t he 
-m g  a n d 
-m g  d oses . 
T he d ose escalati o n met h o d was select e d t o o pti mize GI t olera bilit y b ase d o n  assess me nt of 
differe nt starti n g d os es a n d escalati o n i nter v als use d i n t he P hase 2 st u dies. T he t otalit y of t hes e 
res ults a n d P K/ P D m o deli n g of GI t olera bilit y s u g geste d a starti n g d ose of  m g f or  wee ks 
pri or t o escalati n g t o  m g, f oll o w e d b y n o m ore  t ha n a d o u bli n g of d ose at 4-wee k i nter vals 
t hereafter u ntil t he tar get mai nte na nce d os e is attai ne d ( Secti o n 6. 1 ). T his d ose re gi me n s h o ul d 
per mit a de q uate ti me f or de vel o p me nt of t olera nce t o GI e ve nts a n d is pre dicte d t o i m pr o ve GI 
t olera bilit y i n t he P hase 3 st u dies. 
T he  select e d d oses a n d d ose escal ati o n w o ul d e na ble f urt her e val uati o n of t he be nefit/ris k 
c o nsi derati o ns f or t he  m g, 
 m g , a n d 
 m g d oses of orf or gli pr o n . 
4. 4.   
E n d of St u d y  Defi niti o n   
T he e n d of t he st u d y is d efi ne d as t he d ate of  t he l ast visit or last sc he d ule d pr oce d ure s h o w n i n 
t he S o A ( Secti o n 1. 3 ) f or t he last partici pa nt. 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
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J 2 A-M C -G Z G T (b ) 
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5.   
St u d y P o p ul ati o n   
Partici pa nt eli gi bilit y f or e nr oll me n t i n t he st u d y is base d o n t he criteria liste d i n t his secti o n. T he 
i ncl usi o n a n d e x cl usi o n criteria use d t o deter mi ne eli gi bilit y s h o ul d o nl y a p pl y at scree ni n g or 
ot her s pecifie d visits, a n d n ot c o nti n u o usl y t hr o u g h o ut t he st u d y . 
Pr os pecti ve a p pr o val of pr ot oc ol de viati o ns t o recr uit me nt a n d e nr oll me nt criteria, als o k n o w n as 
pr ot oc ol wai vers or e x e m pti o ns, is n ot per mitte d.  
5. 1.   
I ncl usi o n Criteri a  
Partici pa 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 all of t he f oll o wi n g criteria a p pl y:  
A ge  
1.  Partici pa nt m ust be at least 1 8  years of a ge or t he l e gal a ge of c o nse nt i n t he j uris dicti o n i n 
w hic h t he st u d y is ta ki n g place  at t he ti me of si g ni n g t h e i nf or me d c o nse nt , w hic he ver is 
ol der . 
T y pe of p artici p a nt a n d d ise ase ch ar acteristics  
2.  Ha ve a cli nical dia g n osis of T 2 D base d o n t h e W orl d Healt h Or ga nizati o n classificati o n or 
ot her l ocall y a p plica bl e dia g n ostic sta n d ar ds.  
3.  Ha ve H b A 1 c ≥7. 0 % ( 5 3 m m ol/ m ol) t o ≤9. 5 % ( 8 0 m m ol/ m ol) des pite diet a n d e x ercise 
treat me nt, as deter mi ne d b y t he ce ntral la b orat or y at Visit 1 (scree ni n g). 
4.  Are naï ve t o i ns uli n t hera p y e x ce pt f or gestati o nal dia betes or ≤1 4 da ys use f or ac ut e 
treat me nt a n d ha v e n ot use d a n y oral or i njec ta ble a nti h y per gl yce mic  me di cati o ns d uri n g 
t he 9 0 da ys prece di n g Visit 1, or  bet wee n Visit 1 a n d Visit 3  (ra n d o mizati o n). 
5.  Are m oti vate d a n d willi n g t o ma ke t h e msel ves a v aila ble f or t he d urati o n of t he st u d y a n d 
are a bl e t o f oll o w st u d y pr oce d ures as re q uir e d, i n cl u di n g  
 perf or m S M B G per pr ot oc ol  
 mai ntai n a st u d y e Diar y, a n d  
 c o m plete patie nt q uesti o n naires.  
Wei g ht  
6.  Are of sta ble wei g ht ( ± 5 %) f or at least 9 0 da ys pri or t o Visit 1 a n d a gree t o n ot i nitiate a n 
i nte nsi ve diet or e x ercise pr o gra m d uri n g t he st u d y wit h t he i nte nt of re d uci n g b o d y 
wei g ht ot her t ha n t he lifest yl e a n d / or di etar y meas ures f or dia betes treat me nt.  
7.  Ha ve a B MI  ≥2 3. 0  k g/ m 2 at Visit 1. 
Se x  a n d co ntr ace pti ve/ b arrier re q uire me nts  
8.  Males, W O C B P,  or W N O C B P ma y p artici pate i n t his trial.  
C o ntrace pti ve use b y p artici pa nts  s h o ul d be c o nsiste nt wit h l ocal re g ulati o ns re gar di n g 
t he met h o ds of c o ntrace pti o n f or t h ose partici pati n g i n cli nical st u dies. F or t he 
c o ntrace pti o n re q uire m e nts of t his pr ot oc ol, see Secti o n  1 0. 4 . 
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I nf or me d C o nse nt 
9.  Are c a pa ble of gi vi n g si g ne d i nf or me d c o ns e nt as descri be d i n  Secti o n 1 0. 1 , w hic h 
i ncl u des c o m plia nce wit h t he re q uire m e nts a n d restricti o ns liste d i n t he I C F a n d i n t his 
pr ot oc ol . 
5. 2.   
E xcl usi o n Criteri a   
Partici pa nts are e x cl u de d fr o m t he st u d y if a n y of t he f oll o wi n g criteria a p pl y:  
Me dic al co n diti o ns  
Di a betes rel ate d  
1 0.  Ha ve T 1 D . 
1 1.  Ha ve a hist or y of ket oaci d osis or h y per os m olar st ate or c o ma  wit hi n t he last 6 m o nt hs  
pri or t o Visit 1 , or bet wee n Visit 1 a n d Visit 3 . 
1 2.  Ha ve a hist or y of se vere h y p o gl yce mia or h y p o gl yce mia u na ware n ess wit hi n t he last 
6  m o nt hs  pri or t o Visit 1 , or bet wee n Visit 1 a n d Visit 3 . 
1 3.  Are c urre ntl y recei vi n g or pla n ni n g t o recei ve  treat me nt f or dia betic reti n o pat h y a n d/ or 
mac ul ar e d e ma, f or e x a m ple, laser p h ot oc oa g ulati o n or i ntra vitreal i njecti o ns of a nti–
vasc ular e n d ot helial gr o wt h fact or [ V E G F] i n hi bit ors.  
N ote: A ll partici pa nts will ha ve a bas eli ne f u n d us p h ot o gra p h y assess me nt. I n t he prese n ce 
of a n y de gree of  di a betic retin o pat h y  a n d/ or mac ular e de m a, f urt her o p ht hal m ol o gic 
assess me nt will f oll o w l ocal sta n dar ds of care t o c o nfir m eli gi bilit y .  
C ar di o v asc ul ar  
1 4.  Ha ve Ne w Y or k Heart Ass ociati o n f u ncti o nal classificati o n I V c o n gesti ve heart fail ure.  
1 5.  Ha ve ha d a n y of t he f oll o wi n g  C V c o n diti o ns wit hi n 6 0 da ys pri or t o Visit 1 , or bet wee n 
Visit 1 a n d Visit 3  
 ac ute m y ocar dial i nfarcti o n  
 cere br o vasc ul ar acci de nt (str o ke), or  
 h os pitalizati o n f or c o n gesti ve heart fail ure.  
G astr oi ntesti n al  
1 6.  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 x a m ple, se vere 
dia betic gastr o paresis or gastri c o utlet o bstr ucti o n, ha ve u n der g o ne gastric b y pass 
( bariatric) s ur ger y or restricti ve bariatri c s ur ger y, f or e x a m ple, La p-Ba n d ® , or c hr o nicall y 
ta ke dr u gs t hat directl y affect GI m otilit y. 
He p atic  
1 7.  Ha ve ac ute or c hr o nic h e patitis, i ncl u di n g a hist or y of a ut oi m m u ne he patitis, si g ns or 
s y m pt o ms of a n y ot her li ver disease ot h er t ha n n o nalc o h olic fatt y li ver disease, or a n y of 
t he f oll o wi n g as d eter mi ne d b y t h e ce ntral la b orat or y d uri n g s cree ni n g. 
 A L T or A S T le vel  > 5 . 0 x t he U L N f or t he refere nce ra n ge 
 A L P le vel ≥1. 5 x t he U L N f or t he refere nce ra n ge  
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T

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J 2 A-M C -G Z G T (b ) 
4 5  
 T B L le vel ≥1. 5 x t he U L N f or t he refere nce ra n ge, e x ce pt f or cas es of k n o w n 
Gil bert’s s y n dr o me  
 He patitis B i nfecti o n, defi ne d as  
i. p ositi ve he pat itis B c ore a nti b o d y a n d p ositi ve f or H B V D N A or 
ii. p ositi ve he patitis B s urface a nti ge n  
 P ositi ve he patitis C a nti b o d y a n d p ositi ve f or H C V R N A  
N ote: Partici pa nts wit h n o nalc o h olic fatt y li ver disease are eli gi ble t o partici pate o nl y 
if t heir A L T le vel is ≤5 .0 x t he U L N f or t he refere nce ra n ge.  
Re n al  
1 8.  Ha ve a n e G F R < 1 5 m L/ mi n/ 1. 7 3 m 2 as deter mi ne d b y t h e ce ntral la b orat or y at Visit 1 
(calc ulat e d b y C hr o nic Ki d ne y Dis ease-E pi de mi ol o g y c ystati n -c e q u ati o n).  
He m at ol o gic  
1 9.  Ha ve a n y h e mat ol o gical c o n diti o n t hat ma y i nterfere wit h H b A 1c meas ure me nt, f or 
e x a m ple, he m ol ytic a ne mias or sic kle cell diseas e.  
M ali g n a nc y  
2 0.  Ha ve a hist or y of a n acti ve or u ntreate d mali g na n c y or are i n re missi o n fr o m a cli nicall y 
si g nifica nt mali g na n c y f or less t ha n 5 years. 
E x ce pti o ns: 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 
or Gra d e 1 (f or e x a m ple, Gleas o n 6 or l o wer) pr ost ate ca n cer.  
E n d ocri ne  
2 1.  Ha ve fa mil y (first -de gree relati ve) or pers o nal hist or y of me d ullar y t h yr oi d carci n o ma or 
m ulti ple e n d ocri ne ne o pl asia s y n dr o me t y pe 2.  
2 2.  Ha ve a s er u m calcit o ni n le vel of ≥3 5 n g/ L, as det er mi ne d b y t he ce ntral la b orat or y 
at Visit  1.  
Ge ner al  
2 3.  Ha d c hr o nic or ac ute pa n creatitis a n y ti me.  
2 4.  Ha ve ha d a tra ns pla nt e d or ga n or a waiti n g a n or ga n tra ns pla nt.  
E x ce pti o n: c or neal tr a ns pla nts ( kerat o plast y).  
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Pri or/ co nc o mit a nt ther a p y  
2 5.  Wit hi n 9 0 da ys pri or t o Visit 1 , or  bet wee n Visit 1 a n d Visit 3  
 Are recei vi n g or ha ve recei ve d c hr o nic ( > 1 4 d a ys) s yste mic gl uc oc ortic oi d 
t hera p y, e x cl u di n g t o pical, i ntra oc ular, i ntra n asal, i nter p hala n geal, or i n hale d 
pre parati o ns , or  
 ha ve e vi de nce of a si g nifica nt, acti ve a ut oi m m u ne a b n or malit y (f or e x a m ple, 
l u p us or r he u mat oi d art hritis) t hat is li kel y t o re q uire, i n t he o pi ni o n of t he 
i n vesti gat or, s uc h treat m e nt d uri n g t he st u d y. 
2 6.  Ha ve use d a n y wei g ht l oss dr u gs or alter nati ve re me dies, i ncl u di n g her bal or n utriti o nal 
s u p ple me nts, wit hi n 9 0 da ys pri or t o Visit 1, or  bet wee n Visit 1 a n d Visit 3 (see 
Secti o n  1 0. 8  f or e x a m ples). 
Pri or/ co nc urre nt cli nic al st u d y ex perie nce  
2 8.  Are c urre ntl y e nr olle d i n a n y ot h er cli nica l st u d y i n v ol vi n g a n i n vesti gati o n al pr o d uct or 
a n y ot h er t y pe of m e dical researc h j u d ge d n ot t o b e scie ntificall y or me di call y c o m pati ble 
wit h t his st u d y.  
2 9.  Ha ve pre vi o usl y c o m plete d or wit h dra w n fr o m t his st u d y or a n y ot h er st u d y i n vesti gati n g 
orf or gli pr o n  after recei vi n g at least 1 d ose of st u d y i nter ve nti o n.  
3 0.  Ha ve partici pate d i n a cli nical st u d y a n d recei ve d treat me nt, w het h er acti ve or place b o, 
wit hi n t he last 3 0 da ys or d urati o n e q ual t o 5 ti mes t he half -life of st u d y i nter ve nti o n, 
w hic he ver is l o n ger.  
Ot her excl usi o n  criteri a  
3 1.  Ha ve a n y c o n diti o n, u n willi n g ness, or i na bilit y n ot c o vere d b y a n y of t he ot her e x cl usi o n 
criteria, t hat, i n t he o pi ni o n of t he i n vesti gat or, mi g ht  
 je o par dize t he safet y of t he partici pa nt; f or e x a m ple, h y p erse nsiti vit y t o trial 
pr o d uct(s) or e x ci pie nt or c o ntrai n dicati o n  
 c o m pr o mise c o m plia nce wit h t he pr ot oc ol ; f or e x a m ple, recreati o nal dr u g use or 
alc o h ol a b use , or 
 c o nf o u n d data i nter pretati o n . 
3 2.  Are i n vesti gat or site pers o n nel directl y affi liate d wit h t his st u d y a n d/ or t heir i m me diate 
fa milies. I m me di ate fa mil y is defi ne d as a s p o use, pare nt, c hil d, or si bli n g, w het her 
bi ol o gical or le gall y a d o pte d.  
3 3.  Are Eli Lill y a n d C o m pa n y e m pl o yees or are e m pl o yees of a n y t hir d part y i n v ol ve d i n t he 
st u d y w h o re q uires e x cl usi o n of t heir e m pl o yees.  
3 4.  Are pre g na nt or i nte n d t o bec o me pre g na nt or t o breastfee d d uri n g t he st u d y.  
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5. 3.   
Lifest yle C o nsi der ati o ns   
Per t he S o A ( Secti o n  1. 3 ), partici pa nts will ha ve access t o q ualifie d me di cal staff w h o will 
pr o vi de dia betes ma n a ge me nt c o u nseli n g, w hi c h will i ncl u de i nstr ucti o ns o n diet a n d e x ercis e 
a n d e d ucati o n 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.  
 
 
Diet ar y c o u ns eli 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 d e d. Per i ncl usi o n criteri o n # 6  
( Secti o n 5. 1 ), partici pa nts s h o ul d n ot i nitiate d uri n g the st u d y a n or ga nize d diet or e x ercise 
wei g ht r e d ucti o n pr o gra m ot her t ha n t he lifest yl e a n d / or dietar y meas ures f or dia betes treat me nt.  
5. 3. 1.   
Di a betes E d uc ati o n   
Dia betes e d u cati o n is t o be perf or me d b y pers o n nel w h o are q u alifie d t o e d ucate partici pa nts o n 
s y m pt o ms a n d ma na ge me nt of h y p er gl yce mia a n d h y p o gl yce mia a n d dia betes ma na ge me nt.  All 
trai ni n gs s h o ul d be re peate d as nee d e d t o e ns ure p artici pa nt c o m plia nce. 
Self -M o nit ore d Bl o o d G l uc ose ( S M B G) 
Partici pa nts will recei ve a st u d y -a p pr o ve d gl uc o meter a n d relate d testi n g s u p plies f or use d uri n g 
t he st u d y. 
Site pers o n nel will trai n t he partici pa nt o n c orrect use of t he gl uc o meter f or self -m o nit ori n g 
bl o o d gl uc ose a n d re p orti n g of h y p o gl y ce mia.  
F o ur -p oi nt S M B G  
Partici pa nts will be i nstr ucte d t o perf or m 4 -p oi nt S M B G meas ure me nts o n ce wee kl y a n d t o 
rec or d all res ults i n t he e Diar y acc or di n g t o i nstr u cti o ns; t hese res ults will be use d f or assess me nt 
of se vere persiste nt h y per gl yce mia ( Secti o n 6. 9. 3 ). F o ur -p oi nt S M B G pr ofiles will c o nsist of 
meas ure me nts o btai ne d o n a si n gle da y per wee k  
 bef ore 3 m ai n meal s, a n d 
 at be dti me. 
D uri n g t h e wee ks w he n t he 7 -p oi nt S M B G pr ofiles are t o be c ollecte d, partici pa nts will n ot be 
re q uire d t o c ollect 4-p oi nt S M B G pr ofiles, a n d t he 4 -p oi nt B G val ues i ncl u de d i n t he 7 -p oi nt 
pr ofiles ma y be use d f or assess me nt of se vere p ersiste nt h y per gl yce mi a.  
Seve n -p oi nt S M B G  
Partici pa nts will als o be i nstr ucte d t o c ollect t w o  7 -p oi nt S M B G pr ofiles o n n o n -c o nsec uti ve 
da ys d uri n g t h e wee k a n d rec or d all res ults i n t he e Diar y acc or di n g t o i nstr u cti o ns prece di n g 
pres pecifi e d visits as s h o w n i n t he S o A ( Secti o n 1. 3 ); t hese res ults will be use d f or t he efficac y 
a nal ysis. Se v e n -p oi nt S M B G pr ofiles will c o nsist of mea s ure me nts o btai n e d o n a si n gle da y 
 bef ore 3 m ai n meal s 
 a p pr o xi matel y 2 h o urs after 3 mai n meal s, a n d 
 at be dti me. 
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5. 3. 2.   
Me als a n d Diet ar y Restricti o ns   
F or certai n ass ess me nts, t he parti ci pa nts will be re q uire d t o c o me t o t he site i n a fasti n g stat e, 
e x ce pt f or water, of at least 8 h o urs as s pecifie d i n t he S o A.  
Orf or gli pr o n  is a   
 s u bstrate. Partici pa nts s h o ul d refrai n fr o m 
 
 w hile partici patin g i n t he st u d y d u e t o t he effect o n   
.  
5. 3. 3.   
Bl o o d D o n ati o n   
St u d y p artici 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 , 
starti n g at Visit 1, a n d f or   
 f oll o wi n g t he st u d y.  
5. 4.   
Scree n F ail ures   
A scree n fail ure occ urs w he n a partici p a nt  w h o c o nse nt s t o partici pate i n t he cli nical st u d y is n ot 
s u bse q ue ntl y assi g n e d t o  st u d y i nter ve nti o n. A mi ni mal set of scree n fail ure i nf or mati o n is 
re q uire d t o e ns ure tra ns p are nt r e p orti n g of scree n fail ure partici pa nt s t o meet t he C O N S O R T 
p u blis hi n g re q uire m e nts a n d t o res p o n d t o q ueries fr o m re g ulat or y a ut h orities. Mi ni mal 
i nf or mati o n i ncl u des de m o gra p h y, scree n fail ure details, a n d a n y S A E . 
I n di vi d uals w h o d o n ot meet t he criteria f or p arti ci pati o n i n t his st u d y (scree n fail ure) will n ot  be 
rescree ne d. 
5. 5.   
Criteri a f or Te m p or aril y Del a yi n g E nr oll m e nt of a P artici p a nt   
N ot a p plica ble.  
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6.   
St u d y I nter ve nti o n (s) a n d C o nc o mit a nt T her a p y  
St u d y i nter ve nti o n is defi ne d as a ny me dici n al  pr o d uct(s) or me dical de vice (s) i nte n de d t o be 
a d mi nistere d t o  or use d b y  a st u d y p artici pa nt acc or di n g t o t he st u d y pr ot oc ol.  
6. 1.   
St u d y I nter ve nti o n(s) A d mi nistere d   
T his ta ble lists t he i nter ve nti o ns use d i n t his cli nical st u d y.  
I nter ve nti o n N a me 
Orf or gli pr o n  
Place b o  
D os a ge Le vel(s)  
 m g,  m g,  
m g, 
 m g, 
 m g, a n d 
 m g ca ps ules 
N ot a p plica ble  
R o ute of A d mi nistr ati o n   
Oral Q D  
Oral Q D  
A ut h orize d as defi ne d b y 
E U Cli nic al Tri al 
Re g ul ati o n  
N ot a ut h orize d i n E U   
N ot a ut h orize d  
D ose esc al ati o n  sc he m a 
All partici pa nts will i nitiate treat me nt wit h a  m g Q D d ose of orf or gli pr o n  or matc hi n g pl ace b o 
a n d 
 (  m g, 
 m g , or 
 m g)  is r eac h e d, as o utli ne d i n t his fi g ure. 
 
T he mai nte na nce d ose (  m g, 
 m g, or 
 m g) of orf or gli pr o n  or matc h e d place b o will be 
c o nti n ue d f or t he re mai n der of t he tr eat me nt peri o d, u nless te m p orar y i nterr u pti o n of t he st u d y 
i nter ve nti o n is necessar y. F or ma n a ge me nt of p artici pa nts wit h  i nt olera ble GI s y m pt o ms, see 
Secti o n 6. 6. 1 . 
St u d y i nter ve nti o n is a d mi nistere d orall y o n ce d ail y. I n ge n eral, t here are n o restricti o ns o n t he 
ti me of da y eac h d ose is ta ke n, b ut it is rec o m me n de d t o ta ke t he d ose at a p pr o xi matel y t he sa me 
ti me eac h da y. F or d osi n g relate d t o P K visits, refer t o Secti o n 1. 3 . 
 
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Partici pa nts s h o ul d a d mi nister t heir first d ose of st u d y i nter ve nti o n at t he e n d of Visit 3 pri or t o 
lea vi n g t h e st u d y site, aft er ot her st u d y pr oce d ures a n d ra n d o mizati o n are c o m plete d.  T he date 
a n d ti me of t he first d ose of st u d y i nter ve nti o n s h o ul d be re c or de d o n t he C R F. Partici pa nts will 
rec or d t h e act u al date a n d ti me of all d ose a d mi nistrati o ns i n t heir e Diar y. 
P ac k a gi n g a n d l a beli n g  
St u d y i nter ve nti o ns will be s u p plie d b y t he s p o ns or or its desi g n ee i n acc or da nce wit h c urre nt 
G o o d Ma n ufact uri n g Practice. St u d y i nter ve nti o ns will be la bele d as a p pr o priate f or c o u ntr y 
re q uire me nts. 
6. 2.   
Pre p ar ati o n , H a n dli n g , St or a ge , a n d Acc o u nt a bilit y   
T he i n vesti gat or or desi g nee m ust c o nfir m a p pr o priate st ora ge c o n diti o ns ha ve bee n mai ntai ne d 
d uri n g tr a nsit f or all st u d y i nter ve nti o n recei ve d a n d a n y dis cre p a ncies are re p orte d a n d res ol ve d 
bef ore us e of t he st u d y i nter ve nti o n. 
O nl y partici pa nts e nr olle d i n t he st u d y ma y recei v e st u d y i nter ve nti o n . Onl y a ut h orize d st u d y 
pers o n nel  ma y s u p pl y st u d y i nter ve nti o n.  
At t he st u d y sites w here st u d y i nter ve nti o n is st or e d, all st u d y i nter ve nti o n m ust 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 m o nit ore d ( ma n ual or a ut o mat e d) area i n acc or da n ce 
wit h t he la bele d st ora ge c o n diti o ns wit h access li mite d t o t he i n vesti gat or a n d a ut h orize d  st u d y 
pers o n nel . F or at -h o me a d mi nistrati o n, s p o ns or will pr o vi de st ora ge i nstr uct i o ns. 
T he i n vesti gat or  or a ut h orize d st u d y pers o n nel are  res p o nsi ble f or st u d y i nter ve nti o n 
acc o u nta bilit y, rec o nciliati o n, a n d rec or d mai nte na nce ( t hat is, recei pt, rec o nciliati o n, a n d fi nal 
dis p ositi o n rec or ds).  
F urt her g ui d a nce a n d i nf or mati o n f or t he f i nal dis p ositi o n of u n use d st u d y i nter ve nti o ns are 
pr o vi de d i n t he  st u d y tr ai ni n g materi als. 
6. 3.   
Assi g n me nt t o St u d y I nter ve nti o n   
Met h o d of tre at me nt assi g n me nt  
Partici pa nts w h o meet a ll criteria f or e nr oll me nt will be ra n d o ml y assi g ne d t o st u d y i nter ve nti o n 
usi n g a n I W R S.  
St u d y i nter ve nti o n will be dis pe nse d at t he st u d y visits s u m marize d i n t he S o A. Ret ur ne d st u d y 
i nter ve nti o n s h o ul d n ot be re-dis pe ns e d t o t he partici pa nts.  
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R a n d o miz ati o n r ati os  a n d str atific ati o n f act ors  
Partici pa nts will be ra n d o ml y assi g ne d i n a  
 rati o t o a o nce d ail y d ose of orf or gli pr o n  
 m g, 
 m g, 
 m g, or place b o . All d oses of st u d y i nter ve nti o n   
 a p pear t he s a me. 
F urt her m ore, place b o  
 l o o k li ke t he orf or gli pr o n   
 t o mai ntai n bli n di n g. 
Partici pa nts will be stratifie d base d o n  
 c o u ntr y 
 H b A 1c ( ≤8. 0 %, > 8. 0 %)  at Visit 1, a n d 
 pri or use of a n y a n ti h y p er gl yce mic me dicati o n ( Yes or N o).  
6. 4.   
Bli n di n g   
T his is a d o u ble -bli n d st u d y. I n v esti gat ors, site staff, cli nical m o nit ors, a n d partici pa nts will 
re mai n bli n de d t o st u d y i nter ve nti o n u ntil t he fi nal data base l oc k. 
T o mai ntai n  t he bli n d, a mi ni m u m n u m ber of Lill y pers o n nel will see t he ra n d o mizati o n ta ble 
a n d treat me nt assi g n me nts bef ore t he st u d y is c o m plete.  
U n bli n di n g details are s p ecifie d i n t he bli n di n g a n d u n bli n di n g pla n.  
E mer ge nc y u n bli n di n g  
I n case of a n e m er ge n c y, the i n vesti gat or has t he s ole res p o nsi bilit y f or d eter mi ni n g if u n bli n di n g 
of a partici p a nt’s treat me nt assi g n me nt is warra nte d f or me dical ma n a ge me nt of t he e ve nt. T he 
partici pa nt’s safet y m ust al wa ys be t he first c o nsi derati o n i n ma ki n g s u c h a deter mi nati o n. If a 
partici pa 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 bilit y of t he i n vesti gat or 
t o pr o m ptl y d o c u me nt t h e 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.  
E mer ge nc y u n bli n di n g m a y b e perf or me d t hr o u g h t he I W R S. T his o pti o n ma y b e use d O N L Y if 
t he partici pa nt’s w ell-bei n g re q uires k n o wl e d ge of t he partici pa nt’s tr eat me nt assi g n me nt. All 
u n bli n di n g e ve nts are rec or de d a n d re p orte d b y t h e I W R S.  
Disc o nti n u ati o n fr o m t he st u d y i nter ve nti o n i n c ase of u n bli n di n g 
If a n i n vesti gat or, site pers o n nel perf or mi n g assess me nts, or partici pa nt is u n bli n de d, t he 
partici pa nt m ust be per m a ne ntl y disc o nti n ue d fr o m st u d y i nter ve nti o n ( Secti o n 7. 1. 1 ), b ut s h o ul d 
be c o nti n ue d i n t he st u d y t o be e val uate d f or efficac y a n d safet y e n d p oi nts a n d m o nit ore d f or all 
visits a n d testi n g.  
6. 5.   
St u d y I nte r ve nti o n C o m pli a nce   
Partici pa nt c o m plia nce wit h st u d y i nter ve nti o n will be assesse d as i n dicate d i n t he S o A 
( Secti o n 1. 3 ). C o m plia nce will be assesse d b y direct q uesti o ni n g a n d c o u nti n g ret ur ne d   
, 
re vie wi n g t he e Diar y, a n d d oc u me nte d i n t he s o urce d oc u me nts a n d C R F.  
Partici pa nts will be i nstr ucte d t o ret ur n a n y u n use d   
 at t he ti mes s p ecifie d i n t he S o A.  
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 i nter ve nti o n. Si milarl y, a partici pa nt will be c o nsi dere d si g nifica ntl y 
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n o nc o m plia nt if he or s he is j u d ge d b y t he i n vesti gat or t o ha ve i nte nti o nall 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 o n ( m ore t ha n 1 2 5 %).  
I n a d diti o n t o t he assess me nt of a partici p a nt’s c o m plia nce wit h t he st u d y i nter ve nti o n 
a d mi nistrati o n, ot her as p ects  of c o m plia nce wit h t he st u d y will be ass esse d at eac h visit base d o n 
t he partici pa nt’s a d h ere n ce t o t he visit sc he d ule, c o m pleti o n of st u d y e Diaries, a n d a n y ot her 
para meters t he i n vesti gat or c o nsi ders necessar y.  
Partici pa nts c o nsi dere d t o be p o orl y c o m pl ia nt wit h t heir me dicati o n a n d/ or t he st u d y pr oce d ures 
will recei ve a d diti o nal 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 o m pl yi n g wit h t he pr ot oc ol. 
A rec or d of t he n u m ber of t he  
 dis pe ns e d t o a n d ta ke n b y ea c h p artici pa nt m ust be 
mai ntai ne d a n d rec o ncile d wit h st u d y i nter ve nti o n a n d c o m plia nce rec or ds. I nter ve nti o n start a n d 
st o p dates, i ncl u di n g dat es f or i nter ve nti o n i nterr u pti o n will als o be rec or de d i n t he C R F.  
6. 6.   
D ose M o dific ati o n   
D ose m o dificati o n  will be all o we d  as s p ecifie d i n Secti o ns 6. 6. 1  a n d 6. 6. 2 . 
6. 6. 1.   
M a n a ge me nt of G astr oi ntesti n al S y m pt o ms   
F or partici pa nts w h o re p ort i nt olera ble GI s y m pt o ms d uri n g t he treat me nt peri o d, t he i n vesti gat or 
s h o ul d i m ple me nt t he f oll o wi n g ste ps: 
1.  A d vise partici pa nts t o eat s maller meals ; f or e x a m ple, s plitti n g 3 dail y meals i nt o 4 or 
m ore s maller meals, a n d t o st o p eati n g w he n t h e y feel f ull.  
2.  C o nti n ue Ste p # 1, a n d prescri be s y m pt o matic me dicati o n , f or e x a m ple, a ntie metic or 
a nti diarr heal me dicati o n, per l ocal c o u ntr y a vaila bilit y a n d i n di vi d ual partici pa nt nee ds. 
Use of s y m pt o matic me dicati o n s h o ul d be ca pt ure d as c o nc o mita nt me dicati o n i n t he 
C R F.  
3.  C o nti n ue Ste ps # 1 a n d # 2 a n d c o nsi der te m p oraril y i nterr u pti n g st u d y i nter ve nti o n: o mit 
1 d ose or  a ma xi m u m of 2 c o nsecu ti ve d oses . After t he i nterr u pti o n, t he i n v esti gat or 
s h o ul d a d vise t he partici pa nt t o res u me orf or gli pr o n  at t he sa me d ose, wit h t he partici pa nt 
ta ki n g me dicati o n 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 pti o n of st u d y tr eat me nt s h o ul d be d oc u me nte d in s o urce d oc u m e nts.  
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI
C CI

A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T 

A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T 

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
5 5  
t hera pies (f or e x a m ple, tirze pati de), pra mli nti de (a m yli n a nal o gs), or D P P -4 
i n hi bit ors ( Secti o n 1 0. 8. 1. 1 ). 
o  S h ort -ter 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 x a m ple, electi ve s ur ger y, d uri n g h os pitalizati o n, h y per os m olar states) a n d 
m ust be differe ntiat e 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 
C R F.  
 Me dicati o ns i n te n de d t o pr o m ote wei g ht l oss, i ncl u di n g pres cri be d, o v er-t h e-c o u nter, or 
alter nati ve re me dies. E x a m ples are pr o vi de d i n Secti o n 1 0. 8. 1. 2 . 
 
Partici pa nts w h o ha ve  t o i nitiate certai n pr o hi bite d c o nc o mita nt me dicati o ns 
d uri n g t his st u d y  will be disc o nti n ue d fr o m t he st u d y i nter ve nti o n ( Secti o n 7. 1. 1 ). 
6. 9. 2.   
Pr o hi bite d S ur gic al Tre at me nts or Pr oce d ures f or Wei g ht M a n a ge me nt   
S ur gical treat me nts, e n d osc o pic t hera p y, a n d / or de vice-bas e d t hera p y f or wei g ht ma n a ge me nt are 
n ot per mitte d d uri n g t he st u d y.  
6. 9. 3.   
Resc ue T her a p y f or Se vere Persiste nt H y per gl yce mi a   
Criteri a f or se v ere persiste nt h y per gl yce mi a  
I n v esti gat ors will be trai ne d o n h o w t o a p pl y decisi o n criteria f or t h e ti mi n g a n d m et h o d of 
i nter ve nti o n i n partici pa nts w h o d o n ot reac h gl yce mic tar gets d uri n g t he treat me nt peri o d. 
Partici pa nts s h o ul d c o nti n ue a d mi nisteri n g assi g n e d st u d y i nter ve nti o n s. A n a d diti o nal 
t hera pe utic i nter ve nti o n s h o ul d be c o nsi dere d i n p artici pa nts w h o are f ull y c o m plia nt wit h t he 
assi g ne d t h era p e utic re gi me n i n t he a bse nce of a n y  ac ute c o n diti o n t hat raises B G , A N D  w h o  
meet a n y of t he f oll o wi n g criteria: 
 A vera ge B G fr o m the o n ce -wee kl y 4 -p oi nt S M B G pr ofile  is 
o  > 2 7 0 m g/ d L ( 1 5. 0 m m ol/ L) o ver at least a c o ns ec uti ve 2 -wee k p eri o d a n y ti me 
d uri n g t he first 6 wee ks  p ost ra n d o mizati o n  
O R  
o  > 2 4 0 m g/ d L ( 1 3. 3 m m ol/ L) o ver at least a c o ns ec uti ve 2 -wee k p eri o d fr o m 7 t o 
1 2 wee ks  p ost ra n d o mizati o n  
O R  
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
5 6  
o  > 2 0 0 m g/ d L ( 1 1. 1 m m ol/ L) o v er at least a c o ns ec uti ve 2 -wee k p eri o d at a n y ti me 
be y o n d t h e first  1 2 wee ks p ost ra n d o mizati o n  
O R  
 H b A 1c ≥8. 5 % ( 6 9 m m ol/ m ol) at or after Wee k 2 4 .  
D uri n g t h e wee ks w he n 7 -p oi nt S M B G pr ofiles are c ollecte d,  t he o nce-wee kl y  4 -p oi nt S M B G 
val ues are i ncl u de d i n t he 7-p oi nt pr ofiles . 
 
Resc ue me dic ati o n  
F or partici pa nts w h o meet criteria f or se vere persiste nt h y per gl yce mia, t he i n vesti gat or will 
deci de o n a n a p pr o pri ate a nti h y per gl yce mic  i nter ve nti o n (resc u e t hera p y) t hat is n ot a pr o hi bite d 
me dicati o n liste d i n Secti o n s 6. 9. 1  a n d 1 0. 8 .  
If a ne w a nti h y per gl yce mic me dicati o n is i ntr o d uce d, metf or mi n s h o ul d be t he first c h oice of 
t hera p y u nless c o ntr ai n dicate d.  
I nitiati o n of i ns uli n as t he first resc u e i nter ve nti o n f or h y per gl yce mia s h o ul d be reser ve d f or  
 pa rtici pa nts wit h se vere persiste nt h y p er gl yce mia wit h a n a vera ge B G fr o m t he o nce-
wee kl y 4 -p oi nt S M B G  pr ofile  ≥3 0 0  m g/ d L ( ≥1 6. 7 m m ol/ L) , or   
 partici pa nts wit h s y m pt o ms of  h y per gl yce mia, if t here is e vi de n ce of o n g oi n g cata b olis m 
or i n ot her cli nical sit uati o ns w here t he i n v esti gat or belie ves m ore ra pi d gl yce mic c o ntr ol 
is warra nte d ( A D A 2 0 2 3). 
Partici pa nt s w h o recei ve resc ue m e dici ne f or h y per gl yce mia ma na ge me nt s h o ul d als o c o nti n ue 
a d mi nisteri n g st u d y i nter ve nti o n f or t he re m ai ni n g peri o d i n t he trial.  Rec or d t he use of res c ue 
me dicati o n as c o nc o mita nt me dicati o n i n t he C R F.  
If a n y ne w a nti h y per gl yce mic me dicati o n is i nitiate d d uri n g t he safet y f oll o w -u p peri o d, it will 
n ot be classifie d as resc u e t hera p y.  
6. 9. 4.   
S y m pt o m ati c Me dic ati o n f or G astr oi ntesti n al S y m pt o ms   
T he i n vesti gat or ma y prescri be s y m pt o matic me dicati o n f or ma n a ge me nt of GI s y m pt o ms as 
nee de d d uri n g t he st u d y; f or e x a m ple, a ntie metic or a nti diarr heal me dicati o n, per l ocal c o u ntr y 
a vaila bilit y a n d sta n d ar d of care (see Secti o n  6. 6. 1 ). Rec or d t he us e of s y m pt o matic me dicati o n 
as c o nc o mita nt me dicati o n i n t he C R F.  
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
5 7  
7.   
Disc o nti n u ati o n of St u d y I nter ve nti o n a n d P artici p a nt 
Disc o nti n u ati o n/ Wit h dr a w al   
Disc o nti n uati o n of s pecific sites or of t he st u d y as a w h ole are ha n dle d as p art of Secti o n 1 0. 1 . 
7. 1.   
Disc o nti n u ati o n of St u d y I nter ve nti o n  
7. 1. 1.   
Per m a ne nt Disc o nti n u ati o n fr o m St u d y I nter ve nti o n   
W he n  necessar y , a partici pa nt ma y b e per ma n e ntl y disc o nti n ue d fr o m  st u d y i nter ve nti o n. If s o, 
t he partici pa nt will disc o nti n ue t he st u d y i nter ve nti o n a n d will re mai n i n t he st u d y a n d f oll o w 
pr oce d ures f or all re mai ni n g st u d y visits , as s h o w n i n t he S o A.  
A partici pa nt m u st be per ma ne ntl y disc o nti n ue d  fr o m st u d y i nter ve nti o n if 
 t he partici pa nt is dia g n os e d wit h ac ute or c hr o nic pa ncreatitis, c o nfir me d b y a dj u dicati o n. 
See Secti o n  8. 3. 3. 8 . 
 t he partici pa nt is dia g n os e d wit h M T C a n d M E N 2 s y n dr o me   
 t he partici pa nt de v el o ps si g nifica nt ele vati o n of ser u m calcit o ni n. See Secti o n  8. 3. 3. 9 . 
 t he partici pa nt is dia g n os e d wit h a n acti ve m ali g n a 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 [f or e x a m ple, 
Gleas o n 6 or l o wer])  
 a partici pa nt is dia g n ose d wit h T 1 D  
 i n t he o pi ni o n of t he i n vesti gat or, f or safet y reas o ns 
 a partici pa nt has i nt olera ble GI s y m pt o ms des pite ma na ge me nt as d escri be d i n 
Secti o n  6. 6. 1  
 a partici pa nt i nitiates a n y ot her G L P-1 R A or ot her i ncreti n -bas e d t hera pies (f or e x a m ple, 
tirze pati de), pra mli nti de (a m yli n a n al o gs), or D P P -4 i n hi bit ors  (see Secti o n 1 0. 8. 1. 1 ), if 
t he partici pa nt will n ot or ca n n ot disc o nti n ue t he me dicati o n 
 a partici pa nt de v el o ps a n y ot her T E A E, S A E, or cli nicall y si g nifica nt la b orat or y v al ue f or 
w hic h t he  i n vesti gat or belie ves t hat per ma n e nt st u d y i nter ve nti o n d isc o nti n uati o n is t he 
a p pr o priate m eas ure t o be ta ke n  
 a n i n vesti gat or, site pers o n nel perf or mi n g ass ess me nts, or partici pa nt is u n bli n de d . 
St u d y i nter ve nti o n ma y b e disc o nti n ue d if t he i n ve sti gat or det er mi nes t hat a s yste mic 
h y perse nsiti vit y reacti o n has occ urre d relate d t o st u d y i nter ve nti o n a d mi nistrati o n, a n d t he 
s p o ns or’s desi g n ate d me dical m o nit or s h o ul d be n otifie d. If t he i n vesti gat or is u ncertai n a b o ut 
w het her a s yst e mic h y p erse nsiti vit y reacti o n has o cc urre d a n d w het her disc o nti n uati o n of st u d y 
i nter ve nti o n is warra nte d, t he i n vesti gat or m a y c o ns ult t he s p o ns or me dical m o nit or. 
A nti h y per gl yce mic t her a p y after per m a ne nt disc o nti n u ati o n of st u d y i nter ve nti o n  
F oll o wi n g p er ma ne nt dis c o nt i n uati o n of st u d y i nt er ve nti o n f or a n y reas o n, partici pa nts ma y 
re q uire a d diti o nal a nti h y per gl yce mic t hera p y t o mai ntai n gl yce mic c o ntr ol. A n y l ocall y a p pr o ve d 
a nti h y per gl yce mic t hera p y t hat is n ot me nti o ne d as a disc o nti n uati o n criteri o n i n t his secti o n an d 
is n ot c o ntrai n dicate d f or use i n t he partici pa nt ma y be prescri be d i n acc or da nce wit h l ocal 
prescri bi n g i nf or mati o n.  
T he ne w a nti h y per gl yce mic  i nter ve nti o n will be rec or de d o n t h e c o nc o mit a nt me dicati o ns C R F. 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
5 8  
7. 1. 2.   
He p atic Criteri a f or St u d y I nter ve nti o n I nterr u pti o n or Disc o nti n u ati o n  
See Secti o n 8. 2. 6. 3  f or h e patic criteria f or st u d y i nter ve nti o n i nterr u pti o n or disc o nti n uati o n. 
7. 1. 3.   
Te m p or a r y I nterr u pti o n of St u d y I nter ve nti o n  
Refer t o Secti o n s 6. 6. 1 , 6. 6. 2 , 7. 1. 2 , a n d 8. 3. 3. 8  f or i nf or mati o n o n te m p orar y d os e i nterr u pti o ns. 
7. 2.   
P artici p a nt Disc o nti n u ati o n/ Wit h dr a w al fr o m t he St u d y   
Disc o nti n u ati o n is e x pecte d t o be u nc o m m o n.  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 ass ess me nt of st u d y o bjecti ves as pla n ne d i n t he st u d y pr ot oc ol, e ver y atte m pt will be 
ma de t o kee p p artici pa nts i n t he st u d y  re gar dless of st u d y i nter ve nti o n use. 
P artici pa nts will be disc o nti n ue d fr o m t he st u d y if t he partici pa nt bec o mes pre g na nt.  
A partici pa nt  ma y wit h dr a w fr o m t he st u d y : 
● at a n y ti me at t he partici p a nt’s o w n re q u est  f or a n y reas o n or wit h o ut pr o vi di n g 
a n y reas o n  
● at t he re q uest of t h e parti ci pa nt’s desi g nee (f or e x a m ple, pare nts or l e gal 
g uar dia n)  
● at t he discreti o n of t he i n vesti gat or f or safet y, be h a vi oral, c o m plia nce, or 
a d mi nistrati ve reas o ns , or 
● if 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 o nal pr o d uct, or 
e nr olle d i n a n y ot her t y p e of me dical researc h j u d ge d n ot t o be s cie ntificall y or 
me dicall y c o m pati ble wit h t his st u d y . 
At t he ti me of disc o nti n ui n g fr o m t he st u d y, if p ossi ble,  t he partici pa nt will c o m plete pr oce d ures 
f or a n E D  visit a n d safet y f oll o w-u p, as s h o w n i n t he  S o A. If t he partici pa nt has n ot alrea d y 
disc o nti n ue d t he st u d y i nter ve nti o n, t he partici pa nt will be per ma ne ntl y disc o nti n ue d fr o m t he 
st u d y i nter ve nti o n at t he ti me of t he decisi o n t o disc o nti n ue t he st u d y.  
If t he partici p a nt  wit h dra ws c o nse nt  f or discl osure of f ut ure i nf or mati o n, t he s p o ns or ma y ret ai n 
a n d c o nti n ue t o use a n y d ata c ollecte d bef ore s uc h a wit h dra wal of c o nse nt . If a partici pa nt  
wit h dra ws fr o m t he st u d y, t he partici pa nt ma y re q uest destr ucti o n of a n y s a m ples ta ke n a n d n ot 
teste d, a n d t he i n vesti gat or m ust d oc u me nt t his i n t he site st u d y rec or ds . 
7. 3.   
L ost t o F oll o w -u p   
A partici pa nt will be c o nsi dere d l ost t o f oll o w -u p if t he y re peate dl y fail t o ret ur n f or sc he d ule d 
visits a n d are u na ble t o b e c o ntact e d b y t he st u d y site. Site pers o n nel or desi g nee are e x pecte d t o 
ma ke dili ge nt atte m pts t o c o ntact partici p a nts w h o fail t o ret ur n f or a sc h e d ule d visit or were 
ot her wise u na ble t o b e f oll o we d u p b y t he site . 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
5 9  
8.   
St u d y  Assess me nts a n d Pr oce d ures   
St u d y pr oce d ures a n d t heir ti mi n g are s u m marize d i n t he S o A.   
Secti o n  1 0. 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. 
I m me diat e safet y c o ncer ns s h o ul d be disc usse d wit h t he sp o ns or i m me diatel y u p o n 
occ urre nce or a ware ness t o deter mi ne if t he p artici pa nt s h o ul d c o nti n ue or disc o nti n ue 
st u d y i nter ve nti o n. 
A d here n ce t o t he st u d y d esi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he S o A, is 
esse ntial a n d re q uire d f or st u d y c o n d u ct.  
All scree ni n g e v al uati o ns m ust be c o m plete d a n d re vie we d t o c o nfir m  t hat p ote ntial 
partici pa nt s meet all eli gi bilit y criteria. T he i n vesti gat or will mai ntai n a scree ni n g l o g t o 
rec or d details of all parti ci pa nt s scree ne d a n d t o c o nfir m eli gi bilit y or rec or d reas o ns f or 
scree ni n g fail ure, as a p plica ble. 
See Secti o n 3  f or s pecific safet y a n d efficac y e n d p oi nts. 
8. 1.   
Effic ac y Assess me nts   
8. 1. 1.   
Pri m ar y Effic ac y Assess me nt   
T he pri mar y efficac y ass ess me nt i n t his st u d y is mea n c ha n ge i n H b A 1c v al ues fr o m bas eli ne t o 
 wee ks, as d eter mi ne d b y t he ce ntral la b orat or y  ( Secti o n 1 0. 2 ). Bl o o d sa m ples f or H b A 1c 
meas ure me nts will be c ollecte d at visits s pecifie d i n t he S o A ( Secti o n 1. 3 ). 
8. 1. 2.   
Sec o n d ar y Effic ac y Assess me nts   
 H b A 1c  ( meas ure d t hr o u g h ce ntral la b orat or y; Secti o n 1 0. 2 ) 
 Fasti n g gl uc ose ( meas ure d t hr o u g h ce ntral la b orat or y ; Secti o n 1 0. 2 ) 
 B o d y wei g ht ( meas uri n g met h o d is descri be d i n Secti o n 1 0. 9 ) 
 7 -p oi nt S M B G (see Secti o n 5. 3. 1 ) 
 Waist circ u mfere n ce ( m eas uri n g m et h o d is descri be d i n Secti o n 1 0. 9 ) 
 B MI ( deri ve d usi n g b o d y wei g ht i n kil o gra ms di vi de d b y t h e s q uare of hei g ht i n meters)  
 Bl o o d press ur e ( meas uri n g met h o d is descri be d i n Secti o n 1 0. 9 ) 
 Li pi d para meters  (meas ure d t hr o u g h ce ntral la b orat or y; Secti o n 1 0. 2 ) 
 Patie nt -re p orte d o utc o m es (see Secti o n 8. 1. 4 ) 
8. 1. 3.   
Terti ar y Effic ac y Assess me nts   
 P K a n d P D para met ers ( Secti o n 8. 4 ) 
8. 1. 4.   
P ati e nt -Re p orte d O utc o mes   
8. 1. 4. 1.  
S h ort F or m 3 6 Versi o n 2 He alt h S ur ve y, Ac ute F o r m, 1 -W ee k Rec all Versi o n  
( S F-3 6 v 2, Ac ute)   
T he S F -3 6 v 2  ass esses healt h -relate d q u alit y of life. T he S F-3 6 v 2 ac ute f or m, 1 -wee k recall 
versi o n is a 3 6 -ite m ge neric, partici pa nt-c o m plete d meas ure d esi g n e d t o assess t he f oll o wi n g 8 
d o mai ns.  
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
6 0  
 p h ysical f u ncti o ni n g  
 r ole-p h ysical  
 b o dil y pai n  
 ge n eral h ealt h  
 vitalit y  
 social f u ncti o ni n g  
 r ole-e m oti o nal, a n d  
 me ntal healt h  
T he p h ysi cal f u ncti o ni n g d o mai n assesses li mitati o ns d ue t o healt h “ n o w,” w hereas t he 
re mai ni n g d o m ai ns assess f u ncti o ni n g “i n t he p ast wee k.” Eac h d o mai n is s c ore d i n di vi d uall y 
a n d i nf or mati o n fr o m t hese 8 d o mai ns is f urt her a g gre gate d i nt o 2 healt h c o m p o ne nt s u m mar y 
sc ores: P h ysic al C o m p o ne nt S u m mar y a n d M e ntal C o m p o ne nt S u m mar y. It e ms are a ns were d o n 
Li kert scales of v ar yi n g l e n gt hs ( 3 -p oi nt, 5 -p oi nt, or 6 -p oi nt scales). Sc ori n g of eac h d o m ai n a n d 
b ot h s u m mar y sc ores are n or m base d a n d prese nte d i n t he f or m of T-sc ores, wit h a mea n of 5 0 
a n d S D  of 1 0; hi g h er sc ores i n dicate better le vels of f u ncti o n a n d/ or better healt h ( Mar uis h 
2 0 1 1).  
8. 1. 4. 2.  
E Q -5 D -5 L   
T he E Q -5 D -5 L ( E ur o Q ol Researc h F o u n d ati o n 2 0 1 9) is a sta n dar dize d 5 -it e m, self-a d mi nistere d 
i nstr u me nt f or use as a m eas ure of healt h o utc o me. It pr o vi d es a si m ple des cri pti 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 uati o n of 
healt h care as w ell as p o p ulati o n healt h s ur ve ys. T he E Q -5 D -5 L assess es 5 di me nsi o ns of healt h:  
 m o bilit y  
 self-care  
 us ual acti vities  
 pai n/ disc o mf ort,  a n d  
 a n xiet y/ d e pressi o n.  
Eac h di me nsi o n has 5 le v els: n o pr o ble ms, sli g ht pr o ble ms, m o derate pr o ble ms, se vere pr o ble ms, 
a n d e xtre me pr o ble ms.  
T he   
 rec or ds t he res p o n de nt’s self -rate d healt h o n a vertical   
 w here t he e n d p oi nts are 
la bele d as “ b est ima gi na ble healt h state” ( 1 0 0) a n d “ w orst i ma gi na ble healt h state” ( 0).  
8. 1. 4. 3.  
A bilit y t o Perf or m P h ysic al Acti vities of D ail y Li vi n g ( A P P A D L )  
T he A P P A D L ( Ha yes et al. 2 0 1 2) is a patie nt -re p orte d o utc o me i nstr u me nt t hat assesses t he 
“c urre nt” a bilit y of pe o pl e li vi n g wit h T 2 D a n d o b esit y t o perf or m p h ysical acti vities of dail y 
li vi n g.  
T he A P P A D L c o ntai ns 7 ite ms t hat assess h o w diffic ult it is f or partici pa nts t o e n ga ge i n certai n 
acti vities c o nsi dere d t o b e 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 ( Ha yes et al. 2 0 1 2). Ite ms are s c ore d o n a 5 p oi nt n u meric rati n g scale, w here 5  =  “ n ot at all 
diffic ult” a n d 1  =  “ u na bl e 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 s c 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 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
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C CI

C O N FI D E N TI A L  
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6 1  
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 m e d o verall 
sc ore are i n dicati ve of better self-re p orte d a bilit y t o perf or m p h ysical acti vities of dail y li vi n g.  
8. 1. 4. 4.  
I m p act of Wei g ht o n Self-Perce pti o ns Q uesti o n n aire ( I W-S P )  
T he I W -S P ( Ha yes a n d Del ozier 2 0 1 5) is a patie nt -re p orte d o utc o m e i nstr u me nt t hat assesses t he 
“c urre nt” i m pact of wei g ht o n t he self -perce pti o n of pe o ple wit h T 2 D  mellit us a n d o besit y.  
T he I W -S P c o ntai ns 3 ite ms t hat assess h o w ofte n a partici pa nts’ b o d y wei g ht  affects h o w ha p p y 
t he y are wit h t heir a p peara nce a n d h o w ofte n t he y feel self-c o nsci o us w h e n o ut i n p u blic. Eac h 
ite m is rate d o n a 5-p oi nt scale ra n gi n g fr o m 1 = “al wa ys” t o 5 = “ ne ver.” T otal sc ores f or t he 
I W-S P are d eri ve d b y s u m mi n g t he ite m sc ores a n d di vi di n g b y t h e 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 pti o n.  
8. 1. 4. 5.  
Di a betes Tre at me nt S atisf acti o n Q uesti o n n aire -St at us Versi o n  ( D T S Qs)  
T he D T S Qs  ( Bra dle y a n d Le wis 1 9 9 0; Bra dle y 1 9 9 4) is a n 8-ite m dia betes-s pecific p atie nt-
re p orte d o utc o m e i nstr u me nt t hat assesses t he o v erall treat me nt satisfacti o n a n d percei ved 
fre q ue n c y of h y per gl yce mia a n d h y p o gl yce mia o ver t he past f e w wee ks, pri or t o t he visit. It is 
a p pr o priate f or use i n b ot h T 1 D  a n d T 2 D.  
Eac h ite m is rate d o n a 7 -p oi nt Li kert scale. Ite ms 1, 4 t o 7, a n d 8 are rate d fr o m 0 t o 6 . T hese 6 
ite ms ca n be s u m med u p t o pr o d uce a treat me nt satisfacti o n sc ore , wit h hi g her sc ores i n dicati n g 
greater satisfacti o n. Ite ms 2 a n d 3 e val uate t h e percei ve d fre q ue n c y of h y per gl yce mia a n d 
h y p o gl yce mia a n d are rat e d fr o m 0 ( n o ne of t he ti me) t o 6 ( m ost of t he ti me) , wit h l o wer  s c ores 
i n dicati n g better gl yce mi c  c o ntr ol.  
8. 1. 4. 6.  
Di a betes Tre at me nt S atisf acti o n Q uesti o n n aire -C h a n ge Versi o n  ( D T S Qc)  
T he D T S Qc  ( Bra dle y 1 9 9 9) has t he sa me 8 ite ms as t he stat us versi o n b ut is re w or d e d sli g htl y t o 
meas ure t he c ha n ge i n treat me nt satisfacti o n rat her t ha n a bs ol ute treat me nt s atisfacti o n.  
Eac h ite m is sc ore d o n a 7 -p oi nt scale ra n gi n g fr o m -3 t o + 3. F or m ost ite ms (ite ms 1, 4 -7, a n d 
8) , hi g her sc ores i n dicate greater  i m pr o ve me nt i n treat me nt satisfacti o n, l o wer sc ores i n dicate 
greater deteri orati o n i n treat me nt satisfacti o n, a n d a sc ore of 0 re prese nts n o c ha n ge. F or  ite m 2 
( percei ve d fre q ue n c y of h y per gl yce mia) a n d ite m 3 ( percei ve d fre q ue n c y of h y p o gl yce mia), 
l o wer sc ores i n dicate better gl yce mic  c o ntr ol.  
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8. 2.   
S afet y Assess me nts   
Pla n ne d ti me p oi nts f or all safet y assess me nts are pr o vi de d i n t he S o A.  
8. 2. 1.   
P h ysic al E x a mi n ati o ns   
C o m plete p h ysic al e x a mi n ati o n  
A c o m plete p h ysical e xa mi nati o n will i ncl u de, at a mi ni m u m, assess me nts of t hese 
s yste ms: 
 C V  
 res pirat or y 
 GI, a n d  
 ne ur ol o gi cal . 
A c o m plete p h ysical e xa mi nati o n e x cl u des pel vic, rectal a n d breast e xa m i nati o ns u nless 
cli nicall y i n dicat e d.  
I n v esti gat ors s h o ul d pa y s pecial atte nti o n t o cli nical si g ns relate d t o pre vi o us seri o us 
ill nesses. 
A d diti o n al assess me nts  
Hei g ht, w ei g ht, waist cir c u mfere nce , a n d vital si g ns will als o be  meas ure d a n d rec or de d. See 
Secti o n  1 0. 9  f or f urt her details. 
8. 2. 2.   
Vit al Si g ns   
F or eac h partici pa nt, vital si g ns meas ure me nts s h o ul d be c o n d ucte d i n tri plicate 
acc or di n g t o t he S o A ( Secti o n 1. 3 ) a n d f oll o wi n g t he st u d y-s p ecific rec o m me n dati o ns 
i ncl u de d i n Secti o n  1 0. 9 . 
A n y cli nicall y si g nifi ca nt fi n di n gs fr o m vital si g ns meas ure me nt t hat res ult i n a dia g n osis a n d 
occ ur d uri n g t he st u d y s h o ul d be re p orte d t o t he s p o ns or as a n A E via C R F. 
8. 2. 3.   
Electr oc a r di o gr a ms   
 1 2 -lea d E C Gs will be o btai ne d as o utli ne d i n t he S o A ( Secti o n 1. 3 ) usi n g ce ntrall y 
pr o vi de d E C G e q ui p me nt. Partici pa nts s h o ul d be s u pi ne f or a p pr o xi matel y 5 t o 1 0 mi n utes 
bef ore E C G c ollecti o ns a n d re mai n s u pi ne b ut a wa ke d uri n g t he E C G c ollecti o n.
 
 C ollect E C G bef o re bl o o d s a m ples f or la b orat or y 
testi n g. 
E C Gs will be i nter prete d b y t he i n vesti gat or or q ualifie d desi g n ee at t he site as s o o n after t h e 
ti me of E C G c ollecti o n as p ossi ble, a n d i deall y w hile t he partici pa nt is still prese nt f or i m me diat e 
partici pa nt ma na g e me nt, s h o ul d a n y cli nicall y rele va nt fi n di n gs be i d e ntifie d. A n y cli nicall y 
rele va nt fi n di n gs fr o m E C Gs t hat res ult i n a dia g n osis s h o ul d be re p orte d as a n A E via C R F. 
All di gital E C Gs will be electr o nicall y tra ns mitte d t o a desi g n ate d ce ntral E C G la b orat or y. T he 
ce ntral E C G la b orat or y will perf or m a basi c q ualit y c o ntr ol c hec k (f or e x a m ple, de m o gra p hics 
a n d st u d y d etails) a n d t he n st ore t he E C Gs i n a dat a base. At a f ut ure ti me, t he st ore d E C G data 
ma y b e o verrea d b y a car di ol o gist at t he ce ntral E C G la b or at or y f or f urt her e val uati o n of 
mac hi ne -rea d meas ure m e nts or t o meet re g ulat or y re q uire me nts. T h e mac hi ne-rea d E C G 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
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C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
6 3  
i nter vals a n d heart rate ma y b e use d f or data a nal ysis a n d re p ort-writi 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 pri or t o c o m pleti o n of t he fi nal st u d y re p ort 
(i n w hic h cas e, t he o verrea d data w o ul d be use d). 
T he i n vesti gat or, or q ualifie d desi g nee, m ust d oc u me nt t heir re vie w of t he E C G pri nte d at t he 
ti me of e val uati o n a n d a n y al ert re p orts. 
8. 2. 4.   
Cli nic al S afet y L a b or a t or y Tests   
See Secti o n 1 0. 2  f or t he list of cli nical la b orat or y t ests t o be perf or me d a n d t he S oA f or 
t he ti mi n g a n d fre q ue n c y. 
T he i n vesti gat or m ust re vie w t he la b orat or y res ults, d oc u me nt t his re vie w, a n d re p ort a n y 
cli nicall y rele va nt c ha n ges occ urri n g d uri n g t he st u d y as a n A E. T he la b orat or y res ults 
m ust be retai ne d wit h s o urce d oc u m e nts u nless a S o urce D oc u m e n t A gree me nt or 
c o m para ble d oc u me nt cit es a n electr o nic l ocati o n t hat acc o m m o dates t h e e x pecte d 
rete nti o n d urati o n. Cli nicall y si g nifica nt a b n or mal la b orat or y fi n di n gs are t h ose w hic h are 
n ot ass ociate d wit h t he u n derl yi n g disease, u nless j u d ge d b y t he i n v esti gat or t o be m ore 
se vere t h a n e x pecte d f or t he partici pa nt’s c o n diti o n. 
All la b orat or y tests wit h val ues c o nsi dere d cli nicall y si g nifi ca ntl y a b n or mal d uri n g 
partici pati o n i n t he st u d y s h o ul d be re peate d u ntil t he val ues ret ur n t o n or mal or baseli ne 
or are n o l o n ger c o nsi dere d cli nicall y si g nifica nt b y t he i n vesti gat or or me dical m o nit or.  
● If s uc h val ues d o n ot ret ur n t o n or mal/ baseli ne wit hi n a peri o d of ti me j u d ge d reaso n a ble 
b y t he i n vesti gat or, t h e eti ol o g y s h o ul d be i de ntifi e d a n d t he s p o ns or n otifie d.  
● All pr ot oc ol -re q uir e d la b orat or y assess me nts, as defi ne d i n Secti o n  1 0. 2 , m ust be 
c o n d ucte d i n acc or da nce wit h t he S o A, sta n dar d c ollecti o n re q uire me nts, a n d la b orat or y 
ma n ual . 
If la b orat or y val ues fr o m n o n-pr ot oc ol s pecifi e d la b orat or y assess me nts perf or me d at a n 
i n vesti gat or-d esi g nate d l ocal la b orat or y re q uire a c ha n ge i n partici pa nt ma na ge me nt or 
are c o nsi d ere d cli nicall y si g nifica nt b y t he i n v esti gat or , f or e x a m ple, S A E or A E, t he n 
re p ort t he i nf or m ati o n as a n A E. 
8. 2. 5.   
Pre g n a nc y Testi n g   
P re g n a nc y testi n g will occ ur as o utli ne d i n t he S o A. 
Partici pa nts w h o bec o me pre g na nt d uri n g t he st u d y s h o ul d be p er ma ne ntl y disc o nti n ue d fr o m t he 
st u d y ( Secti o n 7. 2 ). Partici pa nts w h o bec o me pre g na nt will c o m plete pr oce d ures f or a n E D visit 
a n d safet y f oll o w-u p, as s h o w n i n t he S o A.  
Details of all pre g n a ncies i n fe male partici pa nts a n d, if i n dicate d, fe m ale part ners of male 
partici pa nts will be c ollec te d as o utli ne d i n Secti o ns 8. 3. 1  a n d 8. 3. 2 . 
8. 2. 6.   
He p atic S afet y M o nit ori n g, E v al u ati o n, a n d Criteri a f or St u d y I nter ve nti o n 
I nterr u pti o n or Disc o nti n u ati o n  
T he f o ll o wi n g 2 t a bles s u m marize acti o ns t o ta ke base d o n a b n or mal he patic la b orat or y or 
cli nical c ha n ges.  
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S u m m ar y of acti o ns t o t a ke wit h p artici p a nts wit h n or m al or ne ar n or m al b aseli ne ( A L T, 
A S T, or A L P < 1. 5 x U L N)  
If t his l a b or at or y v al ue is o bser ve d … 
T he n …  
I niti ate or 
c o nti n ue cl ose 
he p atic 
m o nit ori n g  
 (see Secti o n 
8. 2. 6. 1 ) 
I niti ate 
c o m pre he nsi ve  
e v al u ati o n 
 (see Secti o n 
8. 2. 6. 2 ) 
I nterr u pt or 
disc o nti n ue  
st u d y 
i nter ve nti o n 
 (see Secti o n 
8. 2. 6. 3 ) 
A L T or A S T ≥3 x U L N  
X  
 
 
A L P ≥2 x U L N  
X  
 
 
T B L ≥2 x U L N b 
X  
 
 
A L T or A S T ≥5 x U L N  
X  
X  
 
A L P ≥2. 5 x U L N  
X  
X  
 
A L T or A S T ≥3 x U L N wit h he patic si g ns or s y m pt o ms a   
X  
X  
X  
A L T or A S T ≥5 x U L N f or m ore t ha n 2 wee ks  
X  
X  
X  
A L T or A S T ≥8 x U L N  
X  
X  
X  
A L T or A S T ≥3 x U L N a n d T B L ≥2 x U L N b or I N R ≥1. 5  
X  
X  
X  
A L P ≥3 x U L N  
X  
X  
X  
A L P ≥2. 5 x U L N a n d T B L ≥2 x U L N b 
X  
X  
X  
A L P ≥2. 5 x U L N wit h he patic si g ns or s y m pt o ms a 
X  
X  
X  
a E xa m ples of he patic  si g ns or s y m pt o ms: se vere fati g ue, na usea, v o miti n g, ri g ht u p per q ua dra nt a b d o mi nal pai n, 
fe ver, ras h, a n d/ or e osi n o p hili a > 5 %. 
b I n partici pa nts wit h Gil bert’s s y n dr o me t he t hres h ol d f or T B L ma y be hi g her. 
 
 
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C O N FI D E N TI A L  
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6 5  
S u m m ar y of acti o ns t o t a ke wit h p artici p a nts wit h ele v ate d b aseli ne ( A L T, A S T, or A L P ≥ 
1. 5 x U L N)  
If t his l a b or at or y v al ue is o bser ve d … 
T he n …  
I niti ate or c o nti n ue 
cl ose he p atic 
m o nit ori n g  (see 
Secti o n  8. 2. 6. 1 ) 
I niti ate 
c o m pre he nsi ve  
e v al u ati o n  (see 
Secti o n  8. 2. 6. 2 ) 
I nterr u pt or 
disc o nti n ue  
st u d y 
i nter ve nti o n 
(see 
Secti o n  8. 2. 6. 3 ) 
A L T or A S T ≥2 x baseli ne  
X  
 
 
A L P ≥2 x baseli ne  
X  
 
 
T B L ≥2 x U L N b 
X  
 
 
A L T or A S T ≥3 x baseli ne or ≥2 5 0 U/ L  
( w hic he ver occ urs first) 
X  
X  
 
A L P ≥2. 5 x baseli ne  
X  
X  
 
A L T or A S T ≥2 x baseli ne or  ≥2 5 0 U/ L  
( w hic he ver occ urs first) wit h he patic si g ns or 
s y m pt o ms a  
X  
X  
X  
A L T or A S T ≥3 x baseli ne or ≥2 5 0 U/ L  
( w hic he ver occ urs first) f or m ore t ha n 2 wee ks  
X  
X  
X  
A L T or A S T ≥4 x baseli ne or ≥4 0 0 U/ L ( w hic he ver 
occ urs first)  
X  
X  
X  
A L T or A S T ≥2 x baseli ne or ≥2 5 0 U/ L  
( w hic he ver occ urs first) a n d T B L ≥2 x U L N b or 
I N R ≥1. 5  
X  
X  
X  
A L P ≥3 x baseli ne  
X  
X  
X  
A L P ≥2. 5 x baseli ne a n d T B L ≥2 x U L N b 
X  
X  
X  
A L P ≥2. 5 x baseli ne wit h he patic si g ns or 
s y m pt o ms a 
X  
X  
X  
a E xa m ples of he patic si g ns or s y m pt o ms: se vere fati g ue, na usea, v o miti n g, ri g ht u p per q ua dra nt a b d o mi nal pai n, 
fe ver, ras h, a n d/ or e osi n o p hili a > 5 %. 
b I n partici pa nts wit h Gil bert’s s y n dr o me t he t hres h ol d f or T B L ma y be hi g her. 
 
 
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6 6  
8. 2. 6. 1.  
Cl ose He p atic M o nit ori n g   
If a partici pa nt de vel o ps a n y o n e of t hes e c ha n ges, i nitiate cl ose he patic m o nit ori n g: 
P artici p a nts wit h n or m al or ne ar n or m al b aseli ne 
( A L T a n d/ or  A S T a n d/ or A L P < 1. 5 x U L N)  
P artici p a nts wit h ele v ate d b aseli ne ( A L T  a n d/ or  A S T 
a n d/ or A L P ≥ 1. 5 x U L N)  
A L T or A S T ≥3 x U L N or  
A L T or A S T ≥2 x baseli ne  
A L P ≥2 x U L N or  
A L P ≥2 x baseli ne  
T B L ≥2 x U L N a  
T B L ≥2 x U L N a 
a I n partici pa nts wit h Gil bert’s s y n dr o me t he t hres h ol d f or T B L ma y be hi g her. 
Cl ose he patic m o nit ori n g s h o ul d i ncl u de t hese acti o ns:  
 La b orat or y tests ( Secti o n 1 0. 6 ), i ncl u di n g A L T, A S T, A L P, T B L, D. Bil, G G T, C K, a n d 
C B C wit h differe ntial, s h o ul d be c hec k e d wit hi n 4 8 t o 7 2 h o urs of t he detecti o n of ele vate d 
li ver tests t o c o nfir m t he a b n or malit y a n d t o deter mi ne if it is i ncreasi n g or decreasi n g.  
 If t he a b n or m alit y persists, cli nical a n d la b orat or y m o nit ori n g s h o ul d c o nti n ue at a fre q ue n c y 
of 2 -3 ti mes wee kl y u ntil le vels n or malize or ret ur n t o a p pr o xi mate baseli ne val ues.  
 I n a d diti o n t o la b tests, basic e val uati o n f or p ossi ble ca uses of a b n or mal li v er tests s h o ul d be 
i nitiate d b y t he i n vesti gat or i n c o ns ultati o n wit h t he Lill y-d esi g n ate d me dical m o nit or. At a 
mi ni m u m, t his e val uati o n s h o ul d i ncl u de p h ysical e xa mi nati o n a n d a t h or o u g h me dical 
hist or y, i n cl u di n g 
o  c urre nt s y m pt o ms  
o  rece nt ill nesses, f or e x a m ple, heart fail ure, s yste mi c i nfecti o n, h y p ote nsi o n, or 
seiz ures 
o  rece nt tra vel 
o  c o nc o mita nt me dicati o ns (i ncl u di n g o ver -t he-c o u nter), her bal a n d dietar y 
s u p ple me nts 
o  hist or y of alc o h ol dri n ki n g , a n d  
o  ot her s u bsta nce a b use. 
8. 2. 6. 2.  
C o m pre he nsi ve He p ati c E v al u ati o n   
If a partici pa nt de vel o ps a n y o n e of t he f oll o wi n g la b orat or y or cli nical c ha n ges, i nitiate a 
c o m pre he nsi ve h e patic e val uati o n:  
P artici p a nts wit h n or m al or ne ar n or m al 
b aseli ne ( A L T  a n d/ or  A S T  a n d/ or A L P < 1. 5 x 
U L N)  
P artici p a nts wit h ele v ate d b aseli ne ( A L T  a n d/ or  A S T  
a n d /or A L P ≥ 1. 5 x U L N)  
A L T or A S T ≥5 x U L N or  
A L T or A S T ≥3 x baseli ne or ≥2 5 0 IU/ L  
( w hic he ver occ urs first) or  
A L P ≥2. 5 x U L N or  
A L P ≥2. 5 x baseli ne or  
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P artici p a nts wit h n or m al or ne ar n or m al 
b aseli ne ( A L T  a n d/ or  A S T  a n d/ or A L P < 1. 5 x 
U L N)  
P artici p a nts wit h ele v ate d b aseli ne ( A L T  a n d/ or  A S T  
a n d /or A L P ≥ 1. 5 x U L N)  
A L T or A S T ≥3 x U L N wit h he patic si g ns or 
s y m pt o ms a or  
A L T or A S T ≥2 x baseli ne or ≥2 5 0 IU/ L  
( w hic he ver occ urs first) wit h he patic si g ns or s y m pt o ms a or  
A L T or A S T ≥5 x U L N f or m ore t ha n 2 wee ks or  
A L T or A S T ≥3 x baseli ne or ≥2 5 0 IU/ L  
( w hic he ver occ urs first) f or m ore t ha n 2 wee ks or  
A L T or A S T ≥8 x U L N or  
A L T or A S T ≥4 x baseli ne or ≥4 0 0 IU/ L ( w hic he ver occ urs 
first) or  
A L T or A S T ≥3 x U L N a n d T B L ≥2 x U L N b or 
I N R ≥ 1. 5 
A L T or A S T ≥2 x baseli ne or ≥2 5 0 IU/ L  
( w hic he ver occ urs first) a n d T B L ≥2 x U L N b or I N R  ≥1. 5  
a E xa m ples of he patic si g ns or s y m pt o ms: se vere fati g ue, na usea, v o miti n g, ri g ht u p per q ua dra nt a b d o mi nal pai n, 
fe ver, ras h, a n d/ or e osi n o p hili a  > 5 %.  
b I n partici pa nts wit h Gil bert’s s y n dr o me t he t hres h ol d f or T B L ma y be hi g her. 
C o m pre he nsi ve he patic e val uati o n s h o ul d i ncl u de t hese acti o ns:  
 At a mi ni m u m, c o m pre he nsi ve he patic e val uati o n s h o ul d i ncl u de  
o  p h ysical e x a mi nati o n a n d a t h or o u g h me dical hist or y, as o utli ne d i n 
Secti o n s 1. 3  a n d 8. 2. 1  
o  tests f or 
▪ P T -I N R 
▪ viral he patitis A, B, C, a n d E  
▪ a ut oi m m u ne he patitis , a n d 
▪ a n a b d o mi nal i ma gi n g st u d y, f or e x a m ple, ultras o u n d or C T sca n.  
 Base d o n t h e partici pa nt’s hist or y a n d i nitial res ul ts, f urt her testi n g s h o ul d be 
c o nsi dere d i n c o ns ultati o n wit h t he Lill y -desi g nat e d me dical m o nit or, i ncl u di n g tests 
f or 
o  he patitis D vir us  
o  c yt o me gal o vir us  
o  E pstei n -Barr vir us  
o  aceta mi n o p he n le vels  
o  aceta mi n o p he n pr otei n a d d ucts  
o  uri ne t o xic ol o g y s cree n  
o  Wils o n’s  disease  
o  bl o o d alc o h ol le vels  
o  uri nar y et h yl gl uc ur o ni de, a n d  
o  bl o o d p h os p hati d yl et ha n ol.  
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
6 8  
 Base d o n t h e circ u msta n ces a n d t he i n vesti gat or’s assess me nt of t he partici pa nt’s 
cli nical c o n diti o n, t he i n vesti gat or s h o ul d c o nsi d er referri n g t he partici pa nt f or a 
he pat ol o gist or gastr oe nt er ol o gist c o ns ultati o n, a n d a d diti o nal tests i ncl u di n g 
ma g n etic res o n a nce c h ol a n gi o p a ncreat o gra p h y, e n d osc o pic retr o gra de 
c h ola n gi o pa ncreat o gra p h y, car diac ec h o car di o gra m, or a li ver bi o ps y.   
 Cli nical a n d la b orat or y m o nit ori n g s h o ul d c o nti n ue at a fre q ue n c y of 1 -2 ti mes 
wee kl y u ntil le vels n or m alize or ret ur n t o a p pr o xi mate baseli ne val u es.  
 If t he he p atic e ve nt c o nti n ues past t he a ntici pate d e n d of t he st u d y (t hat is, data l oc k), 
t he i n vesti gat or s h o ul d c o ns ult wit h t he Lill y-d esi g nat e d me dical m o nit or t o 
deter mi ne t he nee d f or f urt her data c ollecti o n be y o n d t he e n d date of t h e st u d y (t hat 
is, data base l oc k date). 
 All t he me dical i nf or mati o n a n d tests res ults relate d t o t he he patic m o nit ori n g a n d 
c o m pre he nsi ve h e patic e val uati o n s h o ul d be c ollecte d a n d rec or de d i n a he patic 
safet y C R F .  
8. 2. 6. 3.  
St u d y I nter ve nti o n I nterr u pti o n or Disc o nti n u ati o n  
If a partici pa nt de vel o ps a n y o n e of t he f oll o wi n g la b orat or y or cli nical c ha n ges, i nterr u pt t he 
st u d y-dr u g a n d c o nti n ue cl ose m o nit ori n g a n d c o m pre he nsi ve he p atic e v al uati o n as descri be d i n 
Secti o n s 8. 2. 6. 1  a n d 8. 2. 6. 2 . 
P artici p a nts wit h n or m al or ne ar n or m al 
b aseli ne ( A L T, A S T, or A L P < 1. 5 x U L N)  
P artici p a nts wit h ele v ate d b aseli ne ( A L T, A S T, or A L P ≥ 
1. 5 x U L N)  
A L T or A S T ≥3 x U L N wit h he patic si g ns or 
s y m pt o ms a or  
A L T or A S T ≥2 x baseli ne or ≥2 5 0 IU/ L  
( w hic he ver occ urs first) wit h he patic si g ns or s y m pt o ms a or  
A L T or A S T ≥5 x U L N f or m ore t ha n 2 wee ks 
or  
A L T or A S T ≥3 x baseli ne or ≥2 5 0 IU/ L  
( w hic he ver occ urs first) f or m ore t ha n 2 wee ks or  
A L T or A S T ≥8 x U L N or  
A L T or A S T ≥4 x baseli ne or ≥4 0 0 IU/ L ( w hic he ver occ urs 
first) or  
A L T or A S T ≥3 x U L N a n d T B L ≥2 x U L N b or 
I N R ≥ 1. 5 or  
A L T or A S T ≥2 x baseli ne or ≥2 5 0 IU/ L  
( w hic he ver occ urs first) a n d T B L ≥2 x U L N b or I N R  ≥1. 5 or  
A L P ≥3 x U L N or  
A L P ≥3 x baseli ne or  
A L P ≥2. 5 x U L N a n d T B L ≥2 x U L N b or   
A L P ≥2. 5 x baseli ne a n d T B L ≥2 x U L N b or  
A L P ≥2. 5 x U L N wit h he patic si g ns or 
s y m pt o ms a 
A L P ≥2. 5 x baseli ne wit h he patic si g ns or s y m pt o ms a  
a E xa m ples of he pa tic si g ns or s y m pt o ms: se vere fati g ue, na usea, v o miti n g, ri g ht u p per q ua dra nt a b d o mi nal pai n, 
fe ver, ras h, a n d/ or e osi n o p hili a > 5 %. 
b I n partici pa nts wit h Gil bert’s s y n dr o me t he t hres h ol d f or T B L ma y be hi g her. 
I nterr u pti o n or disc o nti n uati o n of st u d y i nter ve nti o n s h o ul d i ncl u de t hese acti o ns: 
 W hile t he partici pa nt is n ot recei vi n g t he st u d y i nter ve nti o n, cli nical a n d l a b orat or y 
m o nit ori n g s h o ul d c o nti n ue at a fre q ue n c y of 1 t o 2 ti mes wee kl y u ntil li ver tests 
n or malize or ret ur n t o a p pr o xi mate baseli ne  val ues.  
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T

C O N FI D E N TI A L  
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6 9  
 If t he he p atic e ve nt c o nti n ues past t he a ntici pate d e n d of t he st u d y (t hat is, data l oc k) t he 
i n vesti gat or s h o ul d c o ns ult wit h t he Lill y-d esi g n at e d me dical m o nit or t o deter mi ne t he 
nee d f or f urt her d ata c oll ecti o n be y o n d t he e n d d ate of t he st u d y  (t hat is, data l oc k date). 
 All t he me dical i nf or mati o n a n d tests res ults relate d t o t he he patic m o nit ori n g a n d 
c o m pre he nsi ve h e patic e val uati o n s h o ul d be c ollecte d a n d rec or de d i n a he patic safet y 
C R F.  
 Res u m pti o n of t he st u d y i nter ve nti o n after i nterr u pti o n f or a he patic reas o n ca n be 
c o nsi dere d o nl y i n c o ns ultati o n wit h t he Lill y -d esi g nat e d me dical m o nit or a n d o nl y if t he 
li ver test res ults ret ur ne d t o near bas eli ne a n d if a s elf-li mite d n o n-st u d y-dr u g eti ol o g y is 
i de ntifie d. Ot her wise, the st u d y i nter ve nti o n s h o ul d be per ma n e ntl y disc o nti n ue d. 
8. 2. 7.   
H y perse nsiti vit y Re acti o ns   
Ma n y dr u gs, i ncl u di n g oral a ge nts a n d bi ol o gic a ge nts, carr y t h e ris k of s yste mic h y p erse nsit i vit y 
reacti o ns. If s uc h a reacti o n occ urs, a d diti o nal dat a s h o ul d be pr o vi de d t o t he s p o ns or i n t he 
desi g nat e d C R Fs.  
Sites s h o ul d ha ve a p pr o priatel y trai ne d me dical staff a n d a p pr o priate me di cal e q ui p me nt 
a vaila ble w h e n st u d y p artici pa nts are recei vi n g st u d y i nter ve nti o n. It is rec o m me n de d t hat 
partici pa nts w h o e x perie nce a s yste mic h y p erse nsiti vit y reacti o n be treate d per nati o nal a n d 
i nter nati o nal g ui d eli nes. 
I n t he cas e of a s us p ecte d s yste mic h y perse nsiti vit y e v e nt, a d diti o nal bl o o d sa m ples s h o ul d be 
collecte d as d escri be d i n Secti o n  1 0. 2. 3 . La b orat or y res ults are pr o vi de d t o t he s p o ns or via t he 
ce ntral la b orat or y.  
8. 2. 8.   
Di a betic Reti n o p at h y Scree ni n g a n d E v al u ati o n   
Baseli ne f u n d us p h ot o gra p h y s h o ul d be p erf or me d o n partici pa nts w h o re m ai n eli gi ble bas e d o n 
scree ni n g acti vities perf or me d at Visit 1, i ncl u di n g la b orat or y res ults. T he o verall 
o p ht hal m ol o gical e val uati o n of t he baseli ne f u n d us p h ot o gra p hs m ust be c o m plete d pri or t o 
ra n d o mizati o n t o c o nfir m eli gi bilit y. Partici pa nts wit h a n y d e gree of dia b etic reti n o pat h y or 
mac ular e d e ma o n t he b aseli ne assess me nt t hat warra nts treat me nt base d o n t he cli nical 
j u d ge me nt of t h e o p ht hal m ol o gist will be e x cl u de d (see e x cl usi o n criteri o n # 1 3 ). 
All partici pa nts will ha ve f oll o w -u p f u n d us p h ot o gra p h y perf or me d acc or di n g t o t he S o A 
( Secti o n 1. 3 ). O nl y partici pa nts  wit h a n y de gree of reti n o pat h y  prese nt at baseli n e will re peat t he 
f u n d us p h ot o gra p h y at W ee k 2 4 (± 4 wee ks) , a n d all partici pa nts will re peat t he f u n d us 
p h ot o gra p h y at t he Wee k 4 0 visit (-4 wee ks ), t hat is, wit hi n t he 4 wee ks pri or t o Visit 1 1 . F u n d us 
p h ot o gra p h y ma y be perf or me d m ore fre q ue ntl y if warra nte d base d o n t he se verit y of reti n o pat h y 
or mac ular e de ma at baseli ne or d uri n g t h e st u d y c o nsiste nt wit h scree ni n g g ui deli nes f or 
dia betic reti n o pat h y ( S ol o m o n et al. 2 0 1 7; Fla xel et al. 2 0 2 0).  
F u n d us p h ot o gra p h y s h o ul d be perf or me d i n b ot h e yes ( u nless precl u de d d ue t o se vere cat aract, 
pr ost hesis, or ot her c o n diti o ns) usi n g t he br oa d est fiel d of vie w a v aila ble t o t he site or ass ociate d 
q ualifie d e ye care pr ofessi o nal, i ncl u di n g 7 -sta n dar d vie ws, 4-wi de fiel d vie ws, or at a mi ni m u m 
2 -fiel d vie ws wit h at least 6 0-de gree fiel d of vie w. P h ot o gra p hs ma y b e perf or me d at t he st u d y 
site if e q ui p me nt a n d staff trai ne d i n c ollecti n g t he re q uire d vie ws are avail a ble; ot her wise, t he y 
s h o ul d be referre d t o a n o p ht hal m ol o gist or ot her s uita ble q ualifie d healt h care pr o vi der.  
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7 0  
All f u n d us p h ot o gra p hs will be e val uate d b y a n o p ht hal m ol o gist or ot her q ualifie d healt h care 
pr o vi der e x perie nce d i n t he assess me nt of dia b etic reti n o pat h y a n d mac ul ar e de ma. T he 
e val uati o n will i ncl u de w het her dia betic reti n o pat h y a n d/ or m ac ular e de m a are prese nt a n d 
w het her tr eat me nt is rec o m me n de d. F u n d us p h ot o gra p hs dee m e d u ne val u a ble f or a n y reas o n will 
be re peate d as rec o m me n de d b y t h e  o p ht hal m ol o gical e val uat or. W he n e ver p ossi ble, t he sa me 
q ualifie d e val uat or s h o ul d re vie w all p h ot o gra p hs f or a n i n di vi d ual partici p a nt t hr o u g h o ut t he 
st u d y. A n y e vi d e nce of dia betic reti n o pat h y, mac ular e de ma, or ot her cli nicall y si g nifica nt 
fi n di n gs o n t he f u n d us p h ot o gra p hs will re q uire a d diti o nal o p ht hal m ol o gical f oll o w-u p per l ocal 
sta n dar ds of care. T he us e of o ptical c o here n ce t o m o gra p h y s h o ul d b e e nc o ura ge d t o c o nfir m 
cases of mac ular e de ma.  
Res ults fr o m t he o verall o p ht hal m ol o gical e val uati o n, i nc l u di n g fi nal dia g n oses of 
n o n pr oliferati ve reti n o pat h y, pr oliferati ve reti n o pat h y, or di a betic mac ular e de ma, will be 
pr o vi de d t o t he i n vesti gat or a n d rec or de d o n a s pecific reti n o pat h y C R F. A n y i nter ve nti o ns 
i nitiate d f or dia betic reti n o pat h y or mac ular ede m a d uri n g t he st u d y will be ca pt ure d o n t he 
c o nc o mita nt me dicati o n C R F.  
8. 3.   
A d verse E ve nts , Seri o us A d verse E ve nts , a n d Pr o d uct C o m pl ai nts  
T he defi niti o ns of t he f oll o wi n g e v e nts ca n be f o u n d i n Secti o n 1 0. 3 : 
 A Es  
 S A Es , a n d 
 P Cs . 
T hese e v e nts will be re p orte d b y t h e partici p a nt ( or, w he n a p pr o priate, b y a care gi v er, s urr o gate, 
or t he partici pa nt ’s l e gall y a ut h orize d re pres e ntati ve). 
T he i n vesti gat or a n d a n y q ualifie d desi g nees are res p o nsi ble f or detecti n g, d oc u me nti n g, a n d 
rec or di n g e ve nts t hat meet t hese defi niti o ns a n d re mai n res p o nsi ble f or f oll o wi n g u p e v e nts t hat 
are seri o us, c o nsi dere d relate d t o t he st u d y i nter ve nti o n or st u d y  pr oce d ures, or t hat ca use d t h e 
partici pa nt t o disc o nti n ue t he st u d y i nter ve nti o n or st u d y (see Secti o n 7 ). 
Care will be ta ke n n ot t o i ntr o d uce bias w he n d etecti n g  e v e nts. O pe n -e n de d a n d n o n -lea di n g 
ver bal q uesti o ni n g of t he partici pa nt is t he preferre d met h o d t o i n q uire a b o ut e ve nt occ urre n ces.  
After t he i nitial re p ort, t he i n vesti gat or is re q uire d t o pr oacti vel y f oll o w eac h partici pa nt at 
s u bse q ue nt visits/c o ntacts. All S A Es a n d A Es of s pecial i nterest ( as defi ne d i n Secti o n 8. 3. 3 ) will 
be f oll o we d u ntil res ol uti o n, sta bilizati o n, t he e ve nt is ot her wise e x plai ne d, or t he partici pa nt is 
l ost t o f oll o w-u p (as defi ne d i n Secti o n 7. 3 ). F or P C s, t he i n vesti gat or is res p o nsi ble f or e ns uri n g 
t hat f oll o w-u p i ncl u des a n y s u p ple me ntal i n vesti gati o ns as i n dicate d t o el u ci date t he nat ure or 
ca usalit y. F urt h er i nf or m ati o n o n f oll o w -u p pr oce d ures is pr o vi de d i n Secti o n  1 0. 3 . 
 
 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T

C O N FI D E N TI A L  
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7 1  
8. 3. 1.   
Ti mi n g a n d Mec h a nis m f or C ollecti n g E ve nts   
T h is ta ble descri bes t he ti mi n g, dea dli nes, a n d mec ha nis m f or c ollecti n g e v e nts.  
E ve nt  
C ollecti o n 
St a rt  
C ollecti o n 
St o p  
Ti mi n g f or Re p orti n g 
t o S p o ns or or 
D esi g nee  
M ec h a nis m f or 
Re p orti n g  
B ac k -u p 
M et h o d of 
Re p orti n g  
A d verse E ve nt  
A E  
S i g ni n g of 
t he I C F 
P artici pati o n 
i n st u d y has 
e n de d  
As s o o n as p ossi ble 
u p o n site a ware ness  
A E C R F  
N/ A  
Seri o us A d verse E ve nt  
S A E a n d S A E 
u p dates –  pri or 
t o start of st u d y 
i nter ve nti o n a n d  
dee me d 
reas o na bl y 
p ossi bl y relate d 
t o st u d y 
pr oce d ures  
Si g ni n g of 
t he I C F 
S tart of 
i nter ve nti o n 
Wit hi n 2 4 h o urs of 
a ware ness  
S A E C R F  
S A E pa per 
f or m 
S A E  a n d S A E 
u p dates  –  after 
start of st u d y 
i nter ve nti o n 
Start of 
i nter ve nti o n 
P artici pati o n 
i n st u d y has 
e n de d 
Wit hi n 2 4 h o urs of 
a ware ness  
S A E C R F  
S A E pa per 
f or m 
S A E a –  after 
partici pa nt’s 
st u d y 
partici pati o n has 
e n de d a n d  t he 
i n vesti gat or 
bec o mes a ware  
After 
partici pa nt’s 
st u d y 
partici pati o n 
has e n de d  
N/ A   
Pr o m ptl y  
S A E pa per f or m   
N/ A  
Pre g n a nc y  
Pre g na nc y i n 
fe male 
partici pa nts a n d 
fe male part ners 
of male 
partici pa nts  
After t he 
start of st u d y 
i nter ve nti o n 
At least 3 0  
da ys after t he 
last d ose 
Wit hi n 2 4 h o urs (see 
Secti o n  8. 3. 2 ) 
Pre g na nc y C R F   
Pre g na nc y 
pa per f or m  
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C O N FI D E N TI A L  
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E ve nt  
C ollecti o n 
St a rt  
C ollecti o n 
St o p  
Ti mi n g f or Re p orti n g 
t o S p o ns or or 
D esi g nee  
M ec h a nis m f or 
Re p orti n g  
B ac k -u p 
M et h o d of 
Re p orti n g  
Pr o d uct C o m pl ai nts  
P C  ass ociate d 
wit h a n S A E  or 
mi g ht ha ve le d 
t o a n S A E 
Start of st u d y 
i nter ve nti o n 
E n d of st u d y 
i nter ve nti o n 
Wit hi n 2 4 h o urs of 
a ware ness  
Pr o d uct C o m plai nt 
f or m 
N/ A  
P C n ot 
ass ociate d wit h 
a n S A E  
Start of st u d y 
i nter ve nti o n 
E n d of st u d y 
i nter ve nti o n 
Wit hi n 1 b usi ness da y 
of a ware ness  
Pr o d uct C o m plai nt 
f or m 
N/ A  
U p date d P C 
inf or mati o n  
—   
—  
As s o o n as p ossi ble 
u p o n site a ware ness  
Ori gi nall y 
c o m plete d Pr o d uct 
C o m plai nt f or m 
wit h all c ha n ges 
si g ne d a n d date d b y 
t he i n vesti gat or 
N/ A  
P C (if 
i n vesti gat or 
bec o mes a ware)  
P artici pati o n 
i n st u d y has 
e n de d  
N/ A   
Pr o m ptl y  
Pr o d uct C o m plai nt 
f or m 
 
a S A E s s h o ul d n ot be re p orte d u nless t he i n vesti gat or dee ms t he m t o be p ossi bl y relate d t o st u d y treat me nt or st u d y 
partici pati o n . 
8. 3. 2.   
Pre g n a nc y   
C ollecti o n of pre g n a nc y i nf or m ati o n  
M ale p artici p a nts wit h p art ners w h o bec o m e  pre g n a nt  
T he i n vesti gat or will atte m pt t o c ollect pre g na nc y i nf or mati o n o n a n y male partici pa nt’s fe male 
part ner w h o b ec o mes pre g na nt w hile t h e male partici pa nt is i n t his st u d y. T his a p plies o nl y t o 
male partici pa nts w h o recei ve st u d y i nter ve nti o n. 
After  lear ni n g of a pre g n a nc y i n t he fe m ale part ner of a st u d y partici p a nt, t he i n vesti gat or will 
 o btai n a c o nse nt  t o rel eas e i nf or mati o n fr o m t he pre g n a nt fe mal e part ner 
directl y, a n d  
 wit hi n 2 4 h o urs after o bt ai ni n g t his c o nse nt will rec or d pre g na n c y i nf or mati o n 
o n t he a p pr o priat e f or m a n d s u b mit it t o t he s p o ns or.  
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C O N FI D E N TI A L  
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7 3  
T he fe mal e part ner will als o be f oll o we d t o deter mi ne t he o utc o me of t he pre g n a nc y. 
I nf or mati o n o n t he stat us of t he m ot her a n d c hil d will be f or war de d t o t he s p o ns or. 
Ge nerall y, t he f oll o w -u p will be n o l o n ger t ha n 6 t o 8 wee ks f oll o wi n g t he esti mate d 
deli ver y date. A n y t er mi nati o n of t he pre g n a nc y will be re p orte d re gar dless of gestati o nal 
a ge, fet al stat us ( pres e nce or a bse n ce of a n o malies) or i n dicati o n f or t he pr oce d ure.  
Fe m ale p artici p a nts w h o bec o m e pre g n a nt  
T he i n vesti gat or will c ollect pre g n a nc y i nf or m ati o n o n a n y fe male p artici pa nt w h o bec o mes 
pre g na nt w hile partici pati n g i n t his st u d y. T he i nitial i nf or mati o n will be rec or de d o n t he 
a p pr o priate f or m a n d s u b mit te d t o t he s p o ns or wit hi n 2 4 h o urs of lear ni n g of a partici p a nt's 
pre g na nc y.  
T he partici pa nt will be f oll o we d t o deter mi ne t he o utc o me of t he pre g na nc y. T he i n vesti gat or 
will c ollect f oll o w -u p i nf or mati o n o n t he partici pa nt a n d t he ne o nate a n d t h e i nf or ma ti o n will be 
f or war de d t o t he s p o ns or. Ge nerall y, f oll o w-u p will n ot be re q uire d f or l o n ger t ha n 6 t o 8 wee ks 
be y o n d t h e esti mate d deli ver y d ate. A n y ter mi nati o n of pre g na n c y will be re p orte d, re gar dless of 
gestati o nal a ge,  fetal stat us ( prese n ce or a bse nce of a n o malies) , or i n dicati o n f or t he pr oce d ure.  
W hile pre g na n c y itself is n ot c o nsi dere d t o be a n A E or S A E, a n y pre g na n c y c o m plicati o n or 
electi ve ter mi nati o n of a pre g na nc y f or me dical reas o ns will be re p orte d as a n A E or S A E.  
A s p o nta ne o us a b orti o n ( occ urri n g at < 2 0 wee ks gestati o nal a ge) or still birt h ( occ urri n g at ≥2 0 
wee ks gestati o nal a ge) is al wa ys c o nsi dere d t o be a n S A E a n d will be re p orte d as s uc h.  
A n y p ost -st u d y pre g na nc y-relate d S A E c o nsi dere d reas o na bl y relate d t o th e st u d y i nter ve nti o n 
b y t he i n vesti gat or will be re p ort e d t o t he s p o ns or as descri be d i n pr ot oc ol Secti o n  8. 3. 1 . W hile 
t he i n vesti gat or is n ot o bli gate d t o acti vel y see k t his i nf or mati o n i n f or mer st u d y partici p a nts, he 
or s he ma y lear n of a n S A E t hr o u g h s p o nt a ne o us re p orti n g.  
A n y fe male p artici pa nt w h o bec o mes pre g na nt w hile partici pati n g i n t he st u d y will be wit h dra w n 
fr o m t he st u d y. If t he partici pa nt is disc o nti nue d fr o m t he st u d y, f oll o w t he sta n dar d 
disc o nti n uati o n pr ocess a n d c o nti n ue directl y t o t he f oll o w -u p p has e. T he f oll o w -u p o n t he 
pre g na nc y o ut c o me s h o ul d c o nti n ue i n de pe n de nt of i nter ve nti o n or st u d y disc o nti n uati o n.  
8. 3. 3.  A d verse E ve nts of S peci al I nterest  a n d Ot her S afet y T o pics  
8. 3. 3. 1.  
M aj or A d verse C ar di o v asc ul ar E ve nts   
N o nfatal C V A Es a n d all deat hs 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 wit h car di ol o g y e x pertise. T his c o m mittee will be bli n de d t o treat me nt assi g n me nt. T he 
n o nfatal C V A Es t o be a dj u dicate d i ncl u de  
 m y ocar dial i nfarcti o n  
 h os pitalizati o n f or u nsta ble a n gi na  
 h os pitalizati o n f or heart fail ure  
 c or o nar y i nter ve nti o ns (s uc h as c or o nar y arter y b y pass graft or p erc ut a ne o us c or o nar y 
i nter ve nti o n), a n d 
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 cere br o vasc ul ar e v e nts, i ncl u di n g cere br o vasc ul ar acci de nt (str o k e) a n d tra nsie nt 
isc he mic attac k. 
T he i n vesti gat or m ust first re p ort t hese e v e nts as a n A E as descri be d i n Secti o n 8. 3. 1  a n d t he n 
re p ort t he m as a n e n d p oi nt o n t he C R F wit h all re q uire d s o urce d oc u me nts pr o vi de d f or 
a dj u dicati o n t o t he C E C (see Secti o n 1 0. 1. 5 ). 
8. 3. 3. 2.  
Arr h yt h mi as a n d C ar di ac C o n d ucti o n Dis or ders   
Treat me nt -e mer ge nt car diac arr h yt h mias a n d c o n d ucti o n dis or ders will be f urt her e v al uate d. 
Par tici pa nts w h o de vel o p a n y e ve nt fr o m t hese gr o u ps of dis or ders s h o ul d 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 ntr al E C G la b orat or y . A d diti o nal dia g n ostic tests t o 
deter mi ne e x act dia g n osis s h o ul d be perf or me d, as nee de d. T he s pecifi c dia g n osis w ill be 
rec or de d as a n A E. E ve nts t hat meet criteria f or seri o us c o n diti o ns as descri be d i n Secti o n 1 0. 3. 2  
m ust be re p orte d as S A Es.  
8. 3. 3. 3.  
H y p ote nsi o n , Ort h ost atic H y p ote nsi o n , a n d S y nc o pe   
All e ve nts of h y p ote nsi o n  or ort h ostatic h y p ot e nsi o n  a n d s y n c o pe s h o ul d b e e val uat e d a n d 
a d diti o nal dia g n ostic tests perf or me d as nee de d.  
8. 3. 3. 4.  
H y p o gl yce mi a   
Partici pa nts will be trai ne d b y a ut h orize d st u d y p ers o n nel a b o ut si g ns a n d s y m pt o ms of 
h y p o gl yce mia a n d h o w t o treat h y p o gl yce mia, a n d i nstr ucte d t o rec or d rel e va nt i nf or mati o n f or 
eac h e pis o de of h y p o gl yce mia i n t he st u d y e Diar y . 
Partici pa nts will rec or d i nf or mati o n o n e pis o des of h y p o gl yce mia starti n g fr o m Visit 2 u ntil t he 
last st u d y visit. 
All h y p o gl yce mic e pis o des will be rec or de d i n t he st u d y e Di ar y. Beca use all h y p o gl yce mic 
epis o des will be rec or de d i n t he st u d y e Diar y, t he y s h o ul d n ot be rec or de d o n t he A E C R F u nless 
t he e ve nt meets criteria of se vere h y p o gl yce mia w hic h s h o ul d t he n 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 t he s p o ns or 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 ol/ L) occ urri n g 
wit hi n a 1 -h o ur peri o d ma y be c o nsi dere d 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).  
If a partici pa nt  e x perie nces h y p o gl yce mia as d escri 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 sites m ust e ns ure t hat t he partici pa nt  has b ee n f ull y c o m plia nt wit h t he assi g n e d t hera pe utic 
re gi me n a n d 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 ycemia (f or e x a m ple, 
o missi o n of meal, u ne x pecte d i ncreas e i n e xercise).  
H y p o gl yce mi a defi niti o ns a n d c ate g ories  
I n v esti gat ors s h o ul d use t he f oll o wi n g classificati o n of h y p o gl yce mia. T he plas ma gl uc ose 
val ues i n t his secti o n refer t o val ues deter mi ne d b y a la b orat or y or I nter n ati o nal Fe d erati o n 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 gl uc ose meters a n d stri ps . 
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Level 1 hy p o glyce mi a  - Gl uc ose < 7 0 m g/ d L ( 3. 9 m m ol/ L) a n d ≥5 4 m g/ d L ( 3. 0 m m ol/ L)  
Le v el 1 h y p o gl yce mia s h o ul d  alert t he partici pa nt t o ta ke acti o n s uc h as tr eat me nt wit h fast -
acti n g car b o h y drates. Pr o vi ders s h o ul d c o nti n ue t o c o u nsel partici pa nts t o treat h y p o gl yce mia at 
t his gl uc ose al ert val ue. 
Level 2 hy p o glyce mi a - Gl uc ose < 5 4 m g/ d L ( 3. 0 m m ol/ L)  
Le vel 2 h y p o gl yce mia is  a gl uc ose val ue of < 5 4 m g/ d L ( 3. 0 m m ol/ L). T his gl uc ose t hres h ol d is 
cli nicall y rele va nt re gar dless of t he prese nce or a bse nce of s y m pt o ms of h y p o gl yce mia.  
Level 3 hy p o glyce mi a - Severe hy p o gl yce mi a  
A se vere e ve nt c haracterize d b y altere d me ntal a n d/ or p h ys ical stat us re q uiri n g assista nce f or 
treat me nt of h y p o gl yce mia. F or e x a m ple, partici pa nts ha d  altere d me ntal  stat us, a n d c o ul d n ot 
assist i n t heir o w n care, or were  se mic o nsci o us or u nc o nsci o us, or e x perie nce d c o ma wit h  or  
wit h o ut  seiz ures, a n d t he assista nce of a n ot her pers o n was nee d e d 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  acti o ns. Gl uc ose  meas ure me nts  ma y  n ot be 
a vaila ble d uri n g s uc h a n e ve nt, b ut ne ur ol o gical rec o ver y attri b uta ble t o t he rest orati o n of  
gl u c os e c o nce ntrati o n  t o n or mal  is c o nsi dere d  s ufficie nt e vi de nce t hat t he e ve nt was i n d uce d b y 
a l o w gl u c os e c o nce ntrati o n. 
 T he deter mi nati o n of a h y p o gl yce mic e ve nt as a n e pis o de of se v ere h y p o gl yce mia, as 
defi ne d a b o v e, is ma de b y t he i n vesti gat or base d o n t he me dical nee d of t he 
partici pa nt t o ha ve re q uir e d assista nce a n d is n ot pre dicate d o n t h e re p ort of a 
partici pa nt si m pl y ha vi n g recei v e d assista nce.  
 If a h y p o gl yce mic e ve nt meets t he criteria of se v ere h y p o gl yce mia, t he i n v esti gat or 
m ust rec or d t he e v e nt as  seri o us o n t he A E C R F a n d re p ort it t o t he s p o ns or as a n 
S A E.  
N oct ur n al h y p o gl yce mi a  
N oct ur nal h y p o gl yce mia is  a h y p o gl yce mia e v e nt (i ncl u di n g se vere h y p o gl yce mia) t hat occ urs at 
ni g ht  a n d pres u ma bl y d uri n g sle e p.  
8. 3. 3. 5.  
Se vere Persiste nt H y per gl yce mi a   
Criteria f or se v ere p ersist e nt h y p er gl yce mia are pr o vi de d i n Secti o n  6. 9. 3 . 
Occ urre nces of se v ere p ersiste nt h y per gl yce mia t h at meet t hese criteria f or resc ue t h era p y s h o ul d 
be re p ort e d as a n A E  o n t he C R F.  
8. 3. 3. 6.  
Se vere G astr oi ntesti n al A d verse E ve nts   
Orf or gli pr o n  ma y ca use 
. I nf or mati o n 
a b o ut se vere GI A Es, as well as a ntie metic or a nti diarr heal use, will be c oll ecte d i n t he A E a n d 
c o nc o mita nt me dicati o ns C R Fs, res pecti vel y.  F or detaile d i nf or mati o n c o n cer ni n g  t he 
ma na ge me nt of GI A Es, please refer t o Secti o ns  6. 6. 1  a n d  6. 9. 4 . 
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8. 3. 3. 7.  
Ac ute Re n al E ve nts   
Re nal safet y will be ass esse d base d o n re peat e d re nal f u ncti o nal assess me nt as well as 
assessme nt of A Es s u g gesti ve of ac ute re nal fail ure or w orse ni n g of pree xisti n g c hr o nic re n al 
fail ure. GI A Es ha v e bee n re p orte d wit h orf or gli pr o n  i ncl u di n g na us ea, diarr hea, a n d v o miti n g. 
T his is c o nsiste nt wit h ot her G L P -1 R A ( Ar o da a n d Rat ner 2 0 1 1). T he e ve nt s ma y lea d t o 
de h y drati o n, w hic h c o ul d ca use a d eteri orati o n i n re nal f u ncti o n, i ncl u di n g ac ute re n al fail ure. 
Partici pa nts s h o ul d be a d vise d t o n otif y i n vesti gat ors i n case of se vere na us ea, fre q ue nt v o miti n g, 
or s y m pt o ms of de h y drati o n.  
8. 3. 3. 8.  
P a ncre atitis   
Di a g n osis of ac ute p a ncre atitis  
Ac ute pa n creatitis is a n A E of i nterest i n all st u dies wit h orf or gli pr o n , i ncl u di n g t his st u d y. T he 
dia g n osis of ac ute pa n creatitis re q uires 2 of t he f oll o wi n g 3 feat ures ( Ba n ks a n d Free ma n 2 0 0 6, 
K oiz u mi 2 0 0 6):  
 a b d o mi nal pai n, c haracteristic of ac ute pa ncreatitis (t hat is, e pi gastri c pai n ra diati n g t o t he 
bac k, ofte n ass ociate d wit h na usea a n d v o miti n g)  
 ser u m a m yl ase a n d/ or li pase ≥3 x U L N 
 c haracteristic  fi n di n gs of ac ute pa n creatitis o n C T sca n or M RI. 
If ac ut e pa ncreatitis is s us pecte d, t he i n vesti gat or s h o ul d 
 o btai n a p pr o priate l a b orat or y tests, i ncl u di n g pa ncreatic a m ylase a n d li pase  
 perf or m 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, or 
a b d o mi nal M RI 
N ote : A b d o mi nal ultras o u n d ma y b e use d as a n alter nati ve met h o d o nl y if C T a n d M RI 
ca n n ot be perf or me d.  
a n d 
 e val uate f or p ossi ble ca uses of ac ute pa ncreatitis, i ncl u di n g alc o h ol use, gallst o ne or gall 
bla d der diseas e, h y pertri gl yc eri de mia, a n d c o nc o mita nt me dicati o ns.  
Disc o nti n u ati o n f or ac ute p a ncre atitis  
If ac ut e pa ncreatitis is s us pecte d b y t he i n vesti gat or, t he partici pa nt m ust te m p oraril y disc o nti n ue 
use of t he st u d y i nter ve nti o n  ( Secti o n 7. 1. 3 ). I n t his case, t he partici pa nt ma y  recei v e a n 
a p pr o priate alter nati ve a nti h y per gl yce mic  re gi me n. After war ds, if pa n creatitis is c o nfir me d b y 
t he a dj u dicati o n c o m mittee, t he st u d y i nter ve nti o n m ust be per ma ne ntl y disc o nti n ue d 
( Secti o n 7. 1. 1 ), a n d t he partici pa nt s h o ul d be f oll o we d t hr o u g h o ut t he d urati o n of t he st u d y. If 
t he case is n ot c o nfir me d, t he n t he partici pa nt ca n restart t he st u d y i nter ve nti o n if t he i n vesti gat or 
dee ms as cli nicall y a p pr o priate as des cri be d i n Secti o n  6. 6. 2 . 
C ase a dj u dic ati o n a n d d at a e ntr y  
A n i n de pe n de nt C E C will a dj u dicate all s us pecte d cases of ac ute pa ncreati tis. T he i n vesti gat or 
m ust first re p ort t hese e v e nts as a n A E as descri be d i n Secti o n  8. 3. 1  a n d t he n re p ort t he m as a n 
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e n d p oi nt o n t he C R F wit h all re q uire d s o urce d o c u me nts pr o vi de d f or a dj u dicati o n t o t he C E C 
(see Secti o n 1 0. 1. 5 ). Cli nical e ve nt r e p orti n g be gi ns after ra n d o mizati o n. 
As y m pt o m atic ele v ati o n of ser u m a m yl ase a n d/ or li p ase  
Serial meas ures of pa ncreatic e nz y m es ha ve li mite d cli nical val ue f or pre dicti n g e pis o des of  
ac ute pa n creatitis i n as y m pt o matic partici pa nts ( Na uc k et al. 2 0 1 7 ; Stei n ber g et al. 2 0 1 7a, 
2 0 1 7 b). T heref ore, f urt her dia g n ostic f oll o w -u p of cases of as y m pt o matic el e vati o n of pa ncreatic 
e nz y mes (li pase a n d/ or p a ncreatic a m ylase  ≥3 x U L N) is n ot ma n date d  b ut ma y b e perf or me d 
base d o n t he i n vesti gat or’s cli nical j u d g m e nt a n d assess me nt of t he partici pa nt’s o verall cli nical 
c o n diti o n.  
Cases of pa ncreatic h y p ere nz y me mia wit h s y m pt o ms or as y m pt o matic cases of pa ncreatic 
h y pere nz y m e mia t hat u n der g o a d diti o nal dia g n ostic f oll o w -u p will be s u b mitte d f or 
a dj u dicati o n.  
8. 3. 3. 9.  
T h yr oi d M ali g n a ncies a n d C -Cell H y per pl asi a   
Partici pa nts w h o are di a g n ose d wit h M T C a n d/ or M E N 2 d uri n g t h e st u d y will ha v e st u d y 
i nter ve nti o n st o p pe d ( Secti o n 7. 1 . 1) a n d s h o ul d c o nti n ue f oll o w -u p wit h a n e n d ocri n ol o gist.  
T he assess me nt of t h yr oi d safet y d uri n g t he trial will i ncl u de re p orti n g of a n y case of t h yr oi d 
ne o plas ms (i ncl u di n g M T C, pa pillar y car ci n o ma, a n d ot hers) a n d meas ure me nts of calcit o ni n.  
T he p ur p ose of calcit o ni n meas ure me nts is t o ass ess t he p ote ntial of orf or gli pr o n  t o affect t h yr oi d 
C -cell f u ncti o n, w hic h m a y i n dicate de v el o p me nt of C -cell h y per plasia a n d ne o plas ms.  
C alcit o ni n me as ure me nts  
A si g nifica nt i ncrease i n calcit o ni n f or partici pa nts is defi ne d as p ostra n d o mizati o n  calcit o ni n 
val ue of  ≥3 5 n g/ L t hat has i ncrease d at least 5 0 % o ver baseli ne.   
If t his i ncreas e d cal cit o ni n val ue is o bser ve d i n a partici pa nt w h o has b ee n a d mi nistere d a 
me dicati o n t hat is k n o w n t o i ncrease s er u m calcit o ni n, t he n t his me dicati o n s h o ul d be st o p pe d, 
a n d calcit o ni n le vels s h o ul d be meas ure d after a n a p pr o priate was h o ut peri o d of t hat c o nc o mita nt 
me dicati o n ( t hat is, 5 ti mes t he half-life). 
S t u d y i nter ve nti o n s h o ul d be disc o nti n ue d if t he i ncreas e d c o n ce ntrati o n of calcit o ni n is 
c o nfir me d. T he p artici pa nt m ust be rec o m me n de d t o i m me diatel y u n der g o a d diti o nal e n d ocri ne 
assess me nts a n d l o n ger -ter m f oll o w-u p b y a n e n d ocri n ol o gist t o e xcl u de A E s o n t he t h yr oi d 
gla n d.  
F or partici pa nts  w h o re q uire a d diti o nal e n d ocri ne assess me nt beca use of i ncreas e d calcit o ni n 
c o nce ntr ati o n as defi ne d i n t his secti o n, data fr o m t he f oll o w -u p assess me nt will be c ollecte d i n 
t he s pecific secti o n of t he C R F. 
8. 3. 3. 1 0.  Di a betic Reti n o p at h y C o m plic ati o ns   
Dia betic reti n o pat h y a n d mac ular e d e ma will be m o nit ore d usi n g reti nal f u n d us p h ot o gra p h y a n d 
a d diti o nal o p ht hal m ol o gical f oll o w -u p as warra nte d t hr o u g h o ut t he  st u d y ( S ecti o n 8. 2. 8 ). 
Dia betic reti n o pat h y will be assesse d as n o n pr oliferati ve ( mil d, m o derate, or se vere), 
pr oliferati ve, a n d dia beti c mac ular e de ma as pres e nt  or a bse nt. All T E A Es of ne w or w orse ni n g 
dia betic reti n o pat h y, mac ular e de ma, a n d ot her rel ate d c o m plicati o ns will als o be assesse d.  
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8. 3. 3. 1 1.  M ali g n a ncies   
All e ve nts of mali g n a nc y or ot her s us pect e d e ve nts relate d t o mali g na nc y s h o ul d be e val uate d 
a n d a d diti o nal dia g n ostic tests perf or me d as nee d e d.  
8. 3. 3. 1 2.  He p atic Dis or ders   
All e ve nts of he patic dis or ders or ot her s us pect e d e ve nts relate d t o he patic dis or ders s h o ul d be 
e val uate d a n d a d diti o nal dia g n ostic tests perf or me d as nee de d. I n cases of ele vate d li ver mar k ers, 
he patic m o nit ori n g s h o ul d be i nitiate d as o utli ne d i n Secti o n  8. 2. 6 . 
8. 3. 3. 1 3.  G all bl a d der a n d Bili ar y Tr act Dis or ders   
All e ve nts of T E biliar y c olic, c h olec ystitis, c h olelit hiasis, or ot her s us pec te d e ve nts relat e d t o 
ac ute gall bla d der diseas e s h o ul d be e val uate d a n d a d diti o nal dia g n ostic tests perf or me d, as 
nee de d.  
8. 3. 3. 1 4.  H y perse nsiti vit y Re acti o ns   
Refer t o Secti o n  8. 2. 7 . 
8. 3. 3. 1 5.  A b use P ote nti al   
All e ve nts of a b use p ote ntial s h o ul d be e val uate d, a n d a d diti o nal i n vesti gati o ns perf or me d as 
nee d e d.  
8. 4.   
P h ar m ac o ki netics   
P har mac o ki netic sa m ples will be c ollecte d fr o m all ra n d o ml y assi g ne d p arti ci pa nts.  
Plas ma c o nce ntr ati o ns of orf or gli pr o n  will be deter mi ne d o nl y fr o m bl o o d sa m ples o btai ne d 
fr o m partici pa nts recei vi n g orf or gli pr o n . Bl o o d sa m ples f or P K assess me nt will be c ollecte d pre - 
or p ost d ose, as s pecifi e d i n t he S o A ( Secti o n 1. 3 ). 
T he date a n d ti me of t he m ost rece nt st u d y i nter ve nti o n a d mi nistrati o n bef ore c ollecti n g t he P K 
sa m ple m ust be rec or de d o n t he C R F fr o m t he st u d y e Diaries. 
T he date a n d ti me at w hic h eac h sa m ple was dra w n m ust be rec o r de d o n t he la b orat or y accessi o n 
pa ge.  
C o nce ntrati o ns of orf or gli pr o n  will be assa ye d usi n g a v ali 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 oa nal ytical s a m ples c ollecte d t o meas ure t he orf or gli pr o n  c o nce ntrati o n will be retai ne d as 
s pecifie d i n Secti o n 1 0. 1. 1 2 . D uri n g t his ti me, sa m ples re mai ni n g after t he bi oa nal ys es ma y be 
use d f or e x pl orat or y a n al ys es s u c h as meta b olis m w or k, pr otei n bi n di n g, a n d/ or bi oa nal ytical 
met h o d cr oss -vali dati o n . 
8. 5.   
P h ar m ac o d y n a mics   
Efficac y meas ures will be use d as i n dicat ors of P D res p o nse.  
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
7 9  
8. 6.   
Ge netics  
A w h ole bl o o d sa m ple will be c ollecte d fr o m partici pa nts t o e na ble D N A is olati o n f or 
e x pl orat or y p har mac o ge netics a nal ysis as s pecifie d i n t he S o A, w here l ocal re g ulati o ns all o w.  
Sa m ples will n ot be use d t o c o n d uct u ns pecifie d disease or p o p ulati o n ge n etic researc h eit her 
n o w or i n t he f ut ure.  
Sa m ples ma y be us e d t o i n vesti gate varia bl e e x p os ure or res p o nse t o orf or gli pr o n  a n d t o 
i n vesti gate ge netic varia nts t h o u g ht t o pla y a r ole i n o besit y, dia bet es mellit us, a n d relate d 
cli nical traits or c o m plicati o ns, i ncl u di n g n o nalc o h olic steat o he patitis. Assess me nt of varia ble 
res p o nse ma y i ncl u de e v al uati o n of A Es or differe nces i n P D, mec h a nistic, safet y, or efficac y 
meas ures.  
See Secti o n 1 0. 5  f or i nf or mati o n re gar di n g ge neti c researc h a n d Secti o n 1 0. 1. 1 2  f or details a b o ut 
sa m ple rete nti o n a n d c ust o d y. 
8. 7.   
Bi o m ar kers  
Plas ma a n d ser u m  sa m pl es will be c ollecte d a n d st ore d t o e na ble e x pl orat or y 
n o n p har mac o ge netic bi o mar ker researc h.  
Bi o mar ker res earc h is perf or me d o n st ore d sa m ples t o a d dress q uesti o ns of rele va n ce t o  

dr u g dis p ositi o n

tar get e n ga ge me nt

P D

mec ha nis m of acti o n

varia bilit y of partici pa nt res p o nse, i ncl u di n g safet y, a n d

cli nical o utc o mes.
Sa m ples ma y be us e 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 orf or gli pr o n

pat h wa ys ass oci ate d  wit h dia betes mellit us, o besit y, a n d relate d cli nical traits or
c o m plicati o ns, i ncl u di n g n o nalc o h olic steat o he patitis

mec ha nis m of acti o n of orf or gli pr o n , or

researc h met h o d or v ali dati n g dia g n ostic t o ols or assa y(s) relate d t o o besit y, dia betes
mellit us, or relate d cli nical traits or c o m plicati o ns.
Sa m ples will be c ollecte d acc or di n g t o t he s c he d ule descri be d i n t he S o A.  
Sa m ple rete nti o n is descri be d i n Secti o n 1 0. 1. 1 2 . 
8. 8.   
I m m u n o ge nicit y Assess me nts 
I m m u n o ge nicit y para met ers are n ot e val uat e d i n t his st u d y. 
8. 9.   
He alt h Ec o n o mic s 
Healt h ec o n o mics p ara m eters are n ot e val u ate d i n t his st u d y.  
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T

C O N FI D E N TI A L  
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8 0  
9. 
St atistic al C o nsi der ati o ns
T he S A P will be fi nalize d pri or t o st u d y u n bli n di n g f oll o wi n g t he fi n al data base l oc k, a n d it will 
i ncl u de a m ore tec h nical a n d detaile d des cri pti o n of t he statistical a nal yses descri be d i n t his 
secti o n. T his secti o n is a s u m mar y of t he pla n ne d statistical a nal ys es of t he m ost i m p orta nt 
e n d p oi nts, i ncl u di n g pri mar y a n d ke y s ec o n dar y e n d p oi n ts. 
U n bli n di n g details are s p ecifie d i n t he bli n di n g a n d u n bli n di n g pla n. 
9. 1.   
St atistic al H y p ot heses  
T he n ull h y p ot hes es c orres p o n di n g t o t he pri mar y o bjecti ve are as f oll o ws:  

H 1 ,3 6 , 0, H 1 , 1 2, 0, a n d  H 1 , 3, 0: N o differe nce i n orf or gli pr o n  3 6 m g , 1 2 m g, 3 m g  c o m pare d t o
place b o wit h res p ect t o t he mea n  c h a n ge fr o m bas eli ne i n H b A 1c at Wee k 4 0 ,
res pecti vel y.
T he n ull h y p ot hes es c orres p o n di n g t o t he ke y s ec o n dar y o bjecti ve s are as f oll o ws:  

H 2, 3 6 , 0, H 2, 1 2 , 0, a n d  H 2, 3, 0: N o differe nce i n orf or gli pr o n  
 m g, 
 m g,  m g c o m pare d t o
place b o wit h res p ect t o t he pr o p orti o n of partici pa nts w h o ac hie ve d H b A 1 c  < 7. 0 % at
Wee k 4 0 , res pecti vel y.

H 3, 3 6 , 0, H 3, 1 2 ,0, a n d  H 3, 3 , 0: N o differe nce i n orf or gli pr o n  
 m g, 
 m g,  m g c o m pare d t o
place b o wit h res p ect t o t he pr o p orti o n of partici pa nts w h o ac hie ve d H b A 1 c ≤6. 5 % at
Wee k 4 0 , res pecti vel y.

H 4, 3 6 , 0, H 4, 1 2, 0, a n d  H 4, 3 , 0: N o differe nce i n orf or gli pr o n  
 m g, 
 m g,  m g c o m pare d t o
place b o wit h re s p ect t o t he mea n c h a n ge fr o m bas eli ne i n fasti n g s er u m gl u c ose at Wee k
4 0 , res pecti vel y.

H 5, 3 6 , 0, H 5, 1 2, 0, a n d  H 5, 3 , 0: N o differe nce i n orf or gli pr o n  
 m g, 
 m g,  m g c o m pare d t o
place b o wit h res p ect t o t he mea n perce nt a ge c h a n ge fr o m baseli ne i n b o d y wei g ht at
Wee k 4 0 , res pecti vel y.

H 6, 3 6 , 0, H 6, 1 2 , 0, a n d  H 6, 3 , 0: N o differe nce i n orf or gli pr o n  
 m g, 
 m g,  m g c o m pare d t o
place b o wit h res p ect t o t he mea n c h a n ge fr o m bas eli ne i n b o d y wei g ht at Wee k 4 0 ,
res pecti vel y.

H 7, 3 6, 0, a n d  H 7, 1 2, 0: N o differe n ce i n orf or gli pr o n  
 m g, 
 m g c o m pare d t o place b o wit h
res pect t o t he mea n  p erce nta ge c ha n ge fr o m b aseli ne i n n o n -H D L c h ol ester ol at Wee k 4 0 ,
res pecti vel y.

H 8 , 3 6, 0, a n d H 8 , 1 2, 0: N o differe n ce i n orf or gli pr o n  
 m g, 
 m g c o m pare d t o place b o wit h
res pect t o t he mea n  p erce nta ge c ha n ge fr o m b aseli ne i n tri gl yceri des at Wee k  4 0 ,
res pecti vel y.
9. 1. 1.   
M ulti plicit y A dj ust me nt  
A pres pecifie d gra p hical sc he me ( Bretz et al. 2 0 0 9, 2 0 1 1) will be i m ple me nte d t o c o ntr ol t he 
fa mil y-wise err or rate at a 2 -si de d al p ha l e vel of 0. 0 5 f or testi n g t he n ull h y p ot heses state d i n 
Secti o n 9. 1 . T his gra p hi cal a p pr oac h is a cl ose d testi n g pr oce d ure; he nce, it str o n gl y c o ntr ols t he 
fa mil y-wise err or rate acr oss all e n d p oi nts ( Bretz et al. 2 0 0 9, 2 0 1 1; Al os h et al. 2 0 1 4).  
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI 
C CI
C CI
C CI 
C CI
C CI
C CI 
C CI
C CI
C CI 
C CI
C CI
C CI 
C CI
C CI
C CI
C CI
C CI
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
8 1  
T he testi n g sc h e me will be f ull y d etaile d i n t he S A P. T here will be n o a dj ust me nt f or m ulti ple 
c o m paris o ns f or a n y ot her a nal yses o utsi de t he pri mar y a n d ke y s ec o n dar y e n d p oi nts.  N o 
m ulti plicit y a dj ust me nt is pla n ne d bet wee n esti ma n ds.  
9. 2.   
A n al yses  Sets   
T he f oll o wi n g p artici pa nt a nal ysis s ets are d efi ne d:  
P artici p a nt A n al ysis Set   
Descri pti o n  
E ntere d partici pa 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  partici pa nts   
All partici pa nts w h o are ra n d o ml y assi g ne d a st u d y i nter ve nti o n.  
Safet y partici pa nts  
All partici pa nts w h o are ra n d o ml y assi g ne d a st u d y i nter ve nti o n a n d w h o ta ke 
at least 1 d ose of st u d y i nter ve nti o n.  
T he f oll o wi n g d ata p oi nt sets are defi ne d:  
D at a P oi nts Sets  
Descri pti o n  
Treat me nt re gi me n esti ma n d 
data p oi nts set  
All data p oi nts o btai ne d d uri n g t he treat me nt peri o d defi ne d as at or after 
baseli ne a n d u p t o t he last visit wit hi n t he treat me nt peri o d, re gar dless of st u d y 
i nter ve nti o n disc o nti n uati o n or i nitiati o n of a d diti o nal a nti h y per gl yce mic 
me dicati o ns .a 
Safet y data p oi nts set  
All data p oi nts o btai ne d d uri n g t he treat me nt peri o d a n d t he f oll o w -u p peri o d 
defi ne d as at or after baseli ne a n d u p t o t he date of st u d y wit h dra wal i ncl u di n g 
t he f oll o w-u p peri o d re gar dless of st u d y i nter ve nti o n disc o nti n uati o n or 
i nitiatio n of a d diti o nal a nti h y p er gl yce mic me dicati o ns. a 
Efficac y esti ma n d data p oi nts 
set 
All data p oi nts o btai ne d d uri n g t he treat me nt peri o d defi ne d as at or after 
baseli ne a n d u p t o t he earliest date of disc o nti n uati o n of st u d y i nter ve nti o n or 
i nitiati o n of ad diti o nal a nti h y p er gl yce mic me dicati o ns. a  
a “A d diti o nal a nti h y per gl yce mic me dicati o ns” refers t o a n y a nti h y per gl yce mic t hera p y t hat is use d f or m ore t ha n 
2 wee ks ( 1 4  da ys).  
9. 3.   
St atistic al A n al yses   
9. 3. 1.  Ge ner al C o nsi der ati o ns   
Statistical a nal ysis will be t he res p o nsi bilit y of Lill y or its desi g nee.  
A n y c ha n ge t o t he d ata 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 m e 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 h er c h a n ge t o t he data a n al ysis 
met h o ds descri be d i n t he pr ot oc ol, a n d t he j ustificati o n 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 C S R. A d diti o nal e x pl orat or y a nal yses of data will be c o n d ucte d, as dee me d 
a p pr o priate.  
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
8 2  
U nless ot her wise n ote d, all tests of treat me nt effects will be c o n d ucte d at t he 2 -si de d al p ha l e vel 
of 0. 0 5, a n d CIs will be calc ulate d at 9 5 %, 2  si d e d.  
Baseli ne is defi ne d as t he last a vaila ble n o n -missi n g meas ure me nt pri or t o t he first d ose of st u d y 
i nter ve nti o n, u nless ot her wise s pecifie d. 
Ge ner al descri pti o ns of a n al yses  
F or c o nti n u o us meas ures, s u m mar y statistics will i ncl 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 f or b ot h t he act u al a n d t he c ha n ge fr o m baseli ne meas ure me nts. L S 
mea ns a n d sta n dar d err ors deri ve d fr o m t he a nal ysis m o dels will als o be dis pla ye d f or t he c ha n ge 
fr o m baseli ne meas ure m e nts. Treat me nt c o m p aris o ns will be dis pla ye d s h o wi n g t he treat me nt 
differe n ce L S mea ns a n d t he 9 5 % CIs f or t he treat me nt differe n ces, al o n g wit h t he p -val ues f or 
t he treat me nt c o m paris o ns. All baseli ne meas ures will be a nal yze d usi n g a n a nal ysis of varia n ce 
( A N O V A) m o del t hat has treat me nt gr o u p as t he fi x e d effect. 
F or cate g orical meas ures, s u m mar y statistics will i ncl u de sa m ple size, fre q ue nc y, a n d 
perce nt a ges. F or safet y cate g orical meas ures, ris k  differe n ce a n d its 9 5 % CI will be pr o vi de d.  If 
a p plica ble, Fis her’s e x a ct test or Pears o n’s c hi -s q uared  test will be use d f or treat me nt 
c o m paris o ns i n ot her cate g orical o utc o mes.  
U nless ot her wise s pecifie d, safet y a n d t olera bilit y assess me nts will be g ui d e d b y a n esti ma n d 
c o m pari n g safet y of orf or gli pr o n  d os es wit h place b o f or t he e ntire st u d y p eri o d (t he treat me nt 
peri o d pl us safet y f oll o w -u p)  irres p ecti ve of a d here nce t o st u d y i nter ve nti o n or i nitiati o n of 
a d diti o nal a nti -h y p er gl yce mic me dicati o ns f or all st u d y p o p ulati o n. 
Partici pa nts will be a nal yze d acc or di n g t o t he treat me nt gr o u p t o w hic h t h e y were ra n d o ml y 
assi g ne d.  
Ot her statistical met h o ds ma y b e use d, as a p pr o priate, a n d det ails will be descri be d i n t he S A P.  
Missi n g data s h o ul d be mi ni mize d as t he best preca uti o n. Ha n dli n g of missi n g, u n use d, a n d 
s p uri o us data is a d dress e d pr os pecti vel y i n t he o v erall statistical met h o ds descri be d i n t he 
pr ot oc ol a n d i n t he S A P, w here a p pr o priat e. A dj ust me nts t o t he pla n ne d a nal yses will be 
descri be d i n t he fi n al C S R.  
9. 3. 2.   
Tre at me nt Gr o u p C o m p ar a bilit y   
9. 3. 2. 1.  
P a rtici p a nt  Dis p ositi o n   
A detaile d descri pti o n of partici pa nt dis p ositi o n will be pr o vi de d.  
Fre q u e n c y c o u nts a n d perce nta ges of all ra n d o mize d partici pa nts will be prese nte d b y treat me nt 
gr o u ps. A listi n g of ra n d o mize d partici pa nts n ot recei vi n g st u d y i nter ve nti o n will be pr o vi de d. 
All partici pa nts w h o disc o nti n ue t he st u d y will be i de ntifie d a n d t he e x te nt of t heir partici pati o n 
i n t he st u d y will be re p orte d. If k n o w n, a reas o n f or t heir disc o nti n uati o n will be gi ve n. T h e 
pri mar y reas o ns f or disc o nti n uati o n will be liste d a n d will be s u m marize d b y treat me nt gr o u ps. 
T he perce nta ge of partici pa nts disc o nt i n ui n g fr o m treat me nt gr o u ps will be c o m pare d usi n g t he 
Fis her’s e x act test. Ka pla n -Meier a n al yses of ti me fr o m  ra n d o mizati o n t o pre mat ure 
disc o nti n uati o n fr o m st u d y a n d pre mat ure disc o nti n uati o n fr o m st u d y i nter ve nti o n b y treat me nt 
gr o u p will be pr o vi de d.  
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
8 3  
9. 3. 2. 2.  
P a rtici p a nt C h ar acteristics   
De m o gra p hics a n d ot her baseli ne c haracteristics will be s u m marize d b y treat me nt gr o u p f or all 
ra n d o mize d partici pa nts.  
9. 3. 2. 3.  
C o nc o mit a nt T her a p y   
C o nc o mita nt me dicati o ns, i ncl u di n g pre vi o us t hera p y, will be s u m marize d b y treat me nt gr o u p 
f or t he ra n d o mize d partici pa nts . 
9. 3. 2. 4.  
Tre at me nt C o m pli a nce   
Treat me nt c o m plia nce is defi ne d as ta ki n g at least 7 5 % of sc he d ul e d st u d y i nter ve nti o n d uri n g 
t he treat me nt peri o d. Fre q ue nc y c o u nts a n d p erce nta ges of partici p a nts c o m plia nt t o st u d y 
i nter venti o n will be s u m marize d b y tr eat me nt gr o u p usi n g t he safet y partici pa nts d uri n g t he 
treat me nt peri o d. 
9. 3. 3.   
Pri m ar y E n d p oi nt  a n d Esti m a n d  A n al ysis   
T he n ull h y p ot hes es c orres p o n di n g t o t he pri mar y o bjecti ve (c h a n ge fr o m baseli ne i n H b A 1c at 
Wee k 4 0) ca n b e f o u n d i n Secti o n 9. 1 .  
T he pri mar y o bjecti ve will be e val uate d relati ve t o 2 esti ma n ds, “treat me nt re gi me n” a n d 
“effi cac y” ( see Secti o n 3 ).  
T he pri mar y o bjecti ve ali g ne d t o t he “treat me nt re gi me n” esti ma n d will be e val uate d usi n g t he 
ra n d o mize d parti ci pa nts a n d t he treat me nt re gi me n esti ma n d data p oi nts set as descri be d i n 
Secti o n 9. 2 .  
F or t he ass ess me nt of t he pri mar y o bjecti ve g ui de d b y t he “treat me nt re gi me n” esti ma n d, data 
f or partici pa nts wit h missi n g val ues at Wee k 4 0 will be i m p ute d a n d t he n a n al yze d usi n g a n 
A N C O V A wit h a varia nce esti mat or t hat is r o b ust t o m o del miss pecificati o n  a n d 
heter osce dasticit y  ( Ye et al. 2 0 2 2). T he m o del will i ncl u de treat me nt gr o u p, strata, a n d t he 
c o nti n u o us c o variate of baseli ne val ues a n d t heir i nteracti o ns wit h treat me nt gr o u p 
(strata *treat me nt gr o u p a n d baseli ne *treat me nt gr o u p). If t here are occ urre nces of missi n g d ata 
des pite t he best preca uti o ns, missi n g data will be i m p ute d i n a ma n ner c o nsiste nt wit h w hat t he 
val ues w o ul d li kel y h a ve bee n ha d t he y b ee n c ollecte d. I n pri nci ple, missi n g dat a d ue t o 
per ma ne nt disc o nti n uati o n of st u d y  will be i m p ute d usi n g retrie ve d dr o p o uts, na mel y usi n g 
m ulti ple i m p utat i o n base d o n data retri e ve d fr o m partici pa nts w h o per ma n e ntl y disc o nti n ue d 
st u d y i nter ve nti o n b ut c o nti n ue d i n t he st u d y wit h n o n missi n g meas ure m e nts fr o m t he sa me 
treat me nt gr o u p. M ore details re gar di n g t he i m p utati o n f or missi n g val ues will be descri be d i n 
t he S A P.  
T he pri mar y o bjecti ve ali g ne d t o t he “efficac y” esti ma n d will be e val uate d usi n g t he ra n d o mize d 
partici pa nts a nal ysis set a n d t he efficac y esti ma n d data p oi nts set ( Secti o n 9. 2 ). F or t he 
assess me nt of t he pri mar y o bjecti ve g ui de d b y t he “effi cac y” esti ma n d, a restricte d ma xi m u m 
li keli h o o d-base d M M R M ( Wa n g a n d D u 2 0 2 2) a nal ysis will be use d. All t he l o n git u di nal 
o bser vati o ns at eac h sc h e d ule d p ost baseli ne visit will be i ncl u de d i n t he a n al ysis. T he m o del will 
i ncl u de fi x e d effects of tr eat me nt gr o u p, visits, strata, a n d bas eli ne meas ure me nts all neste d 
wit hi n visits. T he varia nce -c o varia nce matri x will be esti mate d usi n g s a n d wic h varia n ce 
esti mat ors ( Tsiati s 2 0 0 6 ). F or t he “effi cac y ” esti m a n d, t he h y p ot hetical strate g y is use d t o ha n dl e 
the I C Es, s o o nl y data c ollecte d bef ore t he occ urre nce of a n y I C Es will be use d i n t he M M R M 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T

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a nal ysis. T hr o u g h t he M M R M, t he p ote ntial efficac y meas ures (after t he I C Es) will be i m plicitl y 
i m p ute d as if partici pa nts di d n ot ha ve I C Es. 
F or eac h h y p ot hesis, orf or gli pr o n  will be d eclare d s u peri or t o place b o  i n c o ntr olli n g H b A 1c if 
t he p -val ue is less t ha n t h e al p ha  le vel all ocate d t o t he h y p ot hesis acc or di n g t o  t he gra p hical 
a p pr oac h.  
M ulti ple i m p utati o n -base d ti p pi n g -p oi nt a nal ysis is pla n ne d as a s e nsiti vit y a nal ysis t o ass ess t he 
r o b ust ness of pri mar y efficac y res ults.  
A d diti o nal details of t he statistical m o deli n g will be pr o vi de d i n t he S A P.  
9. 3. 4.   
Sec o n d ar y E n d p oi nt (s) a n d Esti m a n d(s)  A n al ys es  
T he n ull h y p ot hes es c orres p o n di n g t o t he ke y s ec o n dar y o bjecti ves ca n be f o u n d i n Secti o n  9. 1 .  
Ke y sec o n d ar y o bjecti ves will be e val uate d relati ve t o b ot h  t he “treat me nt re gi me n” a n d 
“effi cac y”  esti ma n ds, as descri be d i n Secti o n 9. 3. 3 . A nal ys es f or k e y sec o n dar y e n d p oi nts will 
be c o ntr olle d f or t y p e 1 err or t hr o u g h t he gra p hical a p pr oac h.  
T he assess me nt of c o nti n u o us ke y s ec o n dar y o bjecti ves will be e val uate d b y a n A N C O V A f or 
t he “treat me nt r e gi me n” esti ma n d a n d a n M M R M f or t he “efficac y” esti ma n d as descri be d i n 
Secti o n 9. 3. 3 . 
F or t he ass ess me nt of bi n ar y ke y sec o n dar y o bjecti ves, a l o gistic re gressi o n m o del wit h 
treat me nt gr o u p a n d strat a as fi x e d effects a n d t he c o nti n u o us baseli ne val u e as a c o v ariat e will 
be use d t o e xa mi ne t he treat me nt differe nce wit h missi n g e n d p oi nts i m p ute d. T he u nc o n diti o nal 
treat me nt gr o u p effect will be assesse d b y ris k differe nce a n d relati ve ris k usi n g t he mar gi n al 
sta n dar dizati o n met h o d, w here t he treat me nt gr o u p-s pecific ris k will be deri ve d fr o m t he 
c o u nterfact ual ris ks f or eac h partici p a nt t hat are pre dicte d wit h t he fitte d l o gistic m o del 
(Stei n gri mss o n et al. 2 0 1 7; F D A 2 0 2 3; Ye et al. 2 0 2 3 ). T he esti mate d treat me nt gr o u p-s pecifi c 
ris k, ris k differe nce, relati ve ris k, p-val ue a n d 9 5 % CI will be prese nte d.  
F or bi nar y effi cac y m eas ures deri ve d fr o m a c o nti n u o us varia ble, t he missi n g val u e i n t he 
u n derl yi n g c o nti n u o us varia ble will be i m p ute d first a n d t he n t he c orres p o n di n g bi nar y v aria ble 
will be  deri ve d. T he d etails a b o ut i m p utati o n u n der “treat me nt re gi me n ” esti ma n d is descri be d i n 
Secti o n 9. 3. 3 . U n der t he “effi cac y” esti ma n d, c o nti n u o us missi n g val ues at Wee k 4 0 will be 
i m p ute d t hr o u g h m ulti ple i m p utati o n usi n g all n o n missi n g data (e x cl u di n g data c ollecte d after 
I C Es) fr o m t he sa me treat me nt gr o u p u n der t he missi n g-at-ra n d o m ass u m pti o n. 
Details f or a d diti o nal sec o n dar y a nal ys es will be pr o vi de d i n t he S A P.  
9. 3. 5.   
Terti ar y  E n d p oi nt s a n d Esti m a n d s A n al ys es  
U nless s pecifie d ot her wise, d etails f or tertiar y a n al yses will be pr o vi de d i n t he S A P.  
9. 3. 6.   
P h ar m a c o ki netic/ P h ar m a c o d y n a mic A n al yses   
Orf or gli pr o n  c o n ce ntr ati o n data will be a nal yze d usi n g a p o p ulati o n P K a p pr oac h via n o nli near 
mi x e d -effects m o deli n g wit h N O N M E M s oft ware.  T he relati o ns hi ps bet wee n orf or gli pr o n  d oses 
a n d/ or c o nce ntrati o n a n d selecte d efficac y, t olera bilit y, a n d safet y e n d p oi nts ma y be 
c haracterize d. A d diti o nall y, t he i m pact of i ntri nsic a n d e xtri nsic  partici pa nt  fact ors s uc h as a ge, 
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wei g ht, ge n der, a n d re n al f u ncti o n o n orf or gli pr o n  P K a n d/ or P D para met ers ma y be e x a mi ne d as 
nee de d. F urt her details will be pr o vi de d i n t he P o p ulati o n P K/ P D A nal ysis Pla n .  
9. 3. 7.   
S afet y A n al yse s  
Safet y a nal yses will be c o n d ucte d usi n g t he safet y partici pa nts a n d t he safet y dat a p oi nts set , 
u nless ot her wise s pecifie d .  
A Es will be c o de d fr o m t he act ual ter m usi n g t he Me dical Dicti o nar y f or R e g ul at or y Acti vities 
a n d re p ort e d b y preferre d ter ms wit hi n s yste m or ga n class. Select e d n ota ble A Es of i nt erest ma y 
be re p ort e d usi n g hi g h -l e vel ter ms or Sta n dar dize d Me dical Dicti o nar y f or Re g ulat or y Acti vities 
Q ueries. 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 
disc o nti n uati o n d ue t o A Es, st u d y i nter ve nti o n dis c o nti n uati o n d ue t o  A Es, deat hs, a n d ot her C V 
e n d p oi nts. C o u nts a n d pr o p orti o ns of partici pa nts 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 x act test will be use d t o c o m pare t h e treat m e nt gr o u ps. 
9. 3. 7. 1.  
A d verse E ve nts of S peci al I nterest a n d Ot her S afe t y T o pics  
T he a nal ysis details f or t he A Es  of s pecial i nterest a n d ot her safet y t o pics (as defi ne d i n 
Secti o n  8. 3. 3 ) will be pr o vi de d i n t he S A P. 
9. 3. 7. 2.  
G astr oi ntesti n al E ve nts   
S u m maries a n d a nal yses f or i nci de nce, pre v ale nce,  o nset  a n d se verit y of na usea, v o miti n g, 
c o nsti pati o n, a n d diarr hea will be pr o vi de d b y treat me nt gr o u p.  
9. 3. 7. 3.  
Ce ntr al L a b or at or y Me as ures, Vit al Si g ns, a n d Electr oc a r di o gr a ms   
Act ual a n d c h a 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 
si g ns, a n d sel ecte d E C G para meters will be s u m marize d at eac h sc he d ule d visit. C o nti n u o us 
varia bles, as well as t he c ha n ge fr o m b aseli ne f or t hese varia bles, will be a n al yze d b y M M R M 
m o dels as descri be d i n S ecti o n 9. 3. 1 . T he perce nt a ges of partici pa nts wit h treat me nt-e mer ge nt 
a b n or mal, hi g h, or l o w m eas ures (i ncl u di n g l a b orat or y, vital, a n d E C G pa ra meters) 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 usi n g Fis her’s e x act t est or Pears o n’s chi -
s q uared  test. 
9. 3. 8.   
Ot her A n al yses   
S u b gr o u p a n al yses  
S u b gr o u p a n al ys es t o ass ess c o nsiste nc y of t he effect of orf or gli pr o n  acr oss s u b gr o u ps f or t he 
pri mar y e n d p oi nt  ( H b A 1c) will be detaile d i n t he S A P. T he f oll o wi n g s u b gr o u ps will be 
c o nsi dere d b ut n ot li mite d t o:  
 age gr o u p ( < 6 5, ≥6 5 years)  
 se x (fe male, male ) 
 b aseli ne H b A 1 c strat u m ( ≤8. 0 %, > 8. 0 %)  
 b aseli ne B MI ( ≤3 0 k g/ m 2, > 3 0 k g/ m2) 
 d urati o n  of T 2 D  ( < me dia n, ≥me dia n)  
 race  
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 et h nicit y, a n d 
 co u ntr y /re gi o n. 
A d diti o nal s u b gr o u p a n al ys es o n t he ke y sec o n dar y e n d p oi nts (f or e x a m ple, wei g ht) m a y als o be 
perf or me d.  
If t he n u m ber of partici p a nts is t o o s mall (f or e x a m ple, < 1 0 %) wit hi n a s u b gr o u p, t h e n t he 
s u b gr o u p cate g ories ma y be re defi ne d pri or t o u n bli n di n g t he st u d y. F urt her details o n t he 
statistical a nal ysis will be pr o vi de d i n t he S A P. 
9. 4.   
I nteri m A n al ysis  
N o i nteri m a nal yses are pla n ne d f or t his st u d y. If a n u n pla n ne d i nteri m a nal ysis is dee me d 
necessar y f or reas o ns ot h er t ha n a s afet y c o n cer n, t he pr ot oc ol m ust be a me n de d.  
9. 5.   
S a m ple Size Deter mi n ati o n   
A p pr o xi matel y  
 p arti ci pa nts will be ra n d o ml y assi g ne d i n a   
 rati o t o orf or gli pr o n   m g 
Q D, 
 m g Q D, 
 m g Q D, or place b o, res p ecti vel y.  
T his trial is p o we re d at o ver 9 0 % t o assess s u p eri orit y of orf or gli pr o n   m g, 
 m g, a n d 
 m g, 
eac h teste d i n p arallel, a gai nst place b o at a 2 -si de d si g nifica n ce le vel of 0. 0 1 67 , relati ve t o t he 
pri mar y e n d p oi nt ( mea n c ha n ge i n H b A 1c fr o m b aseli ne t o 
 wee ks), u n der t he f oll o wi n g 
ass u m pti o ns:  
 u se of a 2-s a m ple t-test t o c o m pare treat me nt mea ns usi n g  H b A 1c d ata  f or t he “treat me nt 
re gi me n” esti ma n d 
 0. 6 % great er mea n re d u cti o n i n H b A 1c fr o m baseli ne f or  m g,  
 m g, a n d 
 m g of 
orf or gli pr o n  c o m pare d wit h place b o , a n d 
 co m m o n  S D of 1. 2 % . 
T hese ass u m pti o ns are c o nsi dere d t o e ns ure t he p o wer f or t he pri mar y e n d p oi nt u n der t he 
efficac y esti ma n d  as well . 
 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

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1 0.   
S u p p orti n g D oc u me nt ati o n a n d O per ati o n al C o nsi der ati o ns   
1 0. 1.   
A p pe n di x 1: Re g ul at or y, Et hic al, a n d St u d y O versi g ht 
C o nsi der ati o ns   
1 0. 1. 1.   
Re g ul at or y a n d Et hic al C o nsi der ati o ns   
T his st u d y will be c o n d u cte d i n acc or da n ce wit h t he pr ot oc ol a n d wit h t he f oll o wi n g:  
 C o nse ns us et hical pri nci ples deri ve d fr o m i nter nati o nal g ui deli nes i ncl u di n g t he 
Decla rati o n 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 
I nter nati o nal Et hical G ui deli 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  
T he pr ot oc ol, pr ot oc ol a me n d me nts, I C F, I B, a n d ot her rele va nt d oc u me nts ( f or e x a m ple, 
a d vertise me nts) m ust be s u b mitte d t o a n I R B/I E C b y t he i n vesti gat or a n d re vie we d a n d a p pr o ve d 
b y t he I R B/I E C  bef ore t h e st u d y is i nitiate d.  
A n y a me n d me nts t o t he pr ot oc ol will re q uire I R B/I E C a p pr o val bef ore i m ple me ntati o n of 
c ha n ges ma d e t o t he s t u d y desi g n, e x ce pt f or c ha n ges n ecess ar y t o eli mi nat e a n i m me diate 
hazar d t o st u d y partici pa nts.  
Pr ot oc ols a n d a n y s u bsta ntial a me n d me nts t o t he pr ot oc ol will re q uire healt h a ut h orit y a p pr o val 
pri or t o i nitiati o n e xce pt f or c ha n ges necessar y t o eli mi nate a n i m me diate hazar d t o st u d y 
partici pa nts . 
T he i n vesti gat or will be res p o nsi ble f or t he f oll o wi n g:  
 p r o vi di n g writte n s u m maries of t he stat us of t he st u d y t o t he I R B/I E C a n n uall y or m ore 
fre q ue ntl y i n acc or da nce wit h t he re q uire me nts, p olicies, a n d pr oce d ures esta blis he d b y 
t he I R B/I E C 
 n otif yi n g t he I R B/I E C of S A Es  or ot her si g nifi ca nt safet y fi n di n gs as re q uire d b y 
I R B/I E C pr oce d ures 
 p r o vi di n g o versi g ht of st u d y c o n d u ct f or p artici pa nts u n der t heir res p o nsi bilit y a n d 
a d here n ce t o r e q uire me nts of 2 1 C o de of Fe deral Re g ulati o ns , I C H g ui deli nes, t he 
I R B/I E C, E ur o pea n re g ul ati o n 5 3 6/ 2 0 1 4 f or cli nical st u dies (if a p plica ble), a n d all ot her 
a p plica ble l ocal re g ulati o ns  
 re p orti n g t o t he s p o ns or or desi g n ee si g nifica nt iss ues relate d t o partici pa nt safet y, 
partici pa nt ri g hts, or data i nte grit y . 
I n v esti gat or sites are c o m pe nsate d f or partici pati o n i n t he st u d y as det aile d i n t he cli nical trial 
a gree m e nt . 
1 0. 1. 2.   
Fi n a nci al Discl os ure   
I n v esti gat ors a n d s u b-i n v esti gat ors will pr o vi de t he s p o ns or wit h s ufficie nt, acc urate fi n a ncial 
i nf or mati o n as re q u este d t o all o w t he s p o ns or t o s u b mit c o m plete a n d acc urate fi na ncial 
certificati o n or discl os ure state me nts t o t he a p pr o priate re g ul at or y a ut h orities. I n v esti gat ors are 
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res p o nsi ble f or pr o vi di n g i nf or mati o n o n fi na ncial i nterests d uri n g t h e c o urse of t he st u d y a n d f or 
1 year after c o m pleti o n of t he st u d y.  
1 0. 1. 3.   
I nf or me d C o nse nt Pr ocess  
T he i n vesti gat or or t he i n vesti gat or’s re prese ntati v e will e x plai n t he nat ure of t he st u d y, 
i ncl u di n g t he ris ks a n d b e nefits, t o t he p ote ntial partici pa nt ( or, w he n a p pr o priate, a care gi ver, 
s urr o gate, or t h e partici p a nt’s le gall y a ut h orize d re prese nt ati ve) a n d a ns wer all  q uesti o ns 
re gar di n g t he st u d y. 
P ote ntial p artici pa nts m ust be i nf or me d t hat t heir partici pati o n is v ol u ntar y. Partici pa nts ( or, 
w he n a p pr o priate, a care gi ver, s urr o gat e, or t he p artici pa nt’s le gall y a ut h orize d re pres e ntati ve)  
will be re q ui re d t o si g n a state me nt of i nf or me d c o nse nt t hat meets t he re q uire me nts of 2 1 C o de 
of Fe d eral Re g ulati o ns  5 0, l ocal re g ulati o ns, I C H g ui deli nes, pri v ac y a n d d ata pr otecti o n 
re q uire me nts, w h ere a p plica ble, a n d t he IR B/I E C or st u d y ce nter.  
T he me dical r ec or d m ust i ncl u de a state me nt t hat writte n i nf or me d c o ns e nt was o btai ne d bef ore 
t he partici pa nt was e nter e d i n t he st u d y a n d t h e date t he writte n c o nse nt w as o btai ne d. T he 
a ut h orize d pers o n o btai ni n g t he i nf or me d c o nse nt m ust als o si g n t he I C F.  
Re vise d c o nse nts m ust be a p pr o pri atel y o btai ne d usi n g t he c orrect a p pr o v e d I C Fs f or a p plica ble 
st u d y partici p a nts i n acc or da nce wit h s p o ns or a n d E R B c o nse nti n g g ui da nce.  
A c o p y of t he I C F(s) m ust be pr o vi de d t o t he partici pa nt ( or, w he n a p pr o priate, t o a care gi ver, 
s urr o gate, or t h e partici p a nt’s le gall y a ut h orize d re prese nt ati ve) a n d is ke pt o n file . 
1 0. 1. 4.   
D at a Pr otecti o n   
Partici pa nts will be assi g ne d a u ni q ue i de ntifier b y t he s p o n s or t o pr ot ect t he partici pa nt’s 
pers o nal data . A n y partici pa nt i nf or mati o n, s uc h as rec or ds, d atasets  or tiss ue sa m ples  t hat are 
tra nsferre d t o t he s p o ns or will c o ntai n t he i de ntifier o nl y. P artici p a nt na mes or a n y i nf or mati o n 
w hic h w o ul d ma ke t he partici pa nt i de nti fia ble will n ot be tra nsferre d. 
T he partici pa nt m ust be i nf or me d t hat t he partici pa nt’s pers o nal st u d y -relat e d data will be use d 
b y t he s p o ns or i n acc or da nce wit h l ocal dat a pr otecti o n la w. T he le vel of discl os ure m ust als o b e 
e x plai ne d t o t he p artici pa nt  w h o will be re q uire d t o gi ve c o nse nt f or t heir d ata t o be use d as 
descri be d i n t he i nf or me d c o nse nt . T his is d o ne b y t he site pers o n nel t hr o u g h t he i nf or me d 
c o nse nt pr ocess.  
T he partici pa nt m ust be i nf or me d t hr o u g h t he i nf or me d c o nse nt b y t he site pers o n nel t hat t heir 
me dical rec or ds ma y be e x a mi ne d b y Cli nical Q u alit y Ass ura n ce a u dit ors or ot her a ut h orize d 
pers o n nel a p p oi nte d b y t he s p o ns or, b y a p pr o priat e I R B/I E C me m bers, a n d b y i ns pect ors fr o m 
re g ulat or y a ut h orities. 
T he sp o ns or has pr ocesses i n place t o e ns ure i nf or mati o n sec urit y, d ata i nte grit y , a n d d ata 
pr otecti o n . T hese pr ocess es a d dress ma n a ge me nt of data tra nsfer a n d pre v e nti o n a n d 
ma na ge me nt of u n a ut h orize d access, discl os ure, disse mi nati o n, alterati o n , or l oss of i nf or mati o n 
or  pers o na l dat a. T hese pr ocesses i ncl u d e a p pr o priate c o nti n ge nc y pl a n(s) f or a p pr o priat e a n d 
ti mel y res p o nse i n t he e v e nt of a data sec urit y breac h. 
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T he tra nsfer of p ers o nal data is s u bject t o a p pr o priate safe g u ar ds t hr o u g h c o ntract ual a gree me nts 
a n d pr ocess es. T he  s p o ns or’s pr ocesses are c o m pli a nt wit h l ocal pri vac y la ws a n d rele va nt 
le gislati o ns i ncl u di n g t he Ge neral Data Pr otecti o n Re g ulati o n ( G D P R). 
1 0. 1. 5.   
C o m mittees Str uct ure   
1 0. 1. 5. 1.  Cli nic al E n d p oi nt  C o m mittee   
A n i n de pe n de nt C E C wit h me m bers hi p e xter nal t o t he s p o ns or will be res p o nsi ble f or e ve nt 
a dj u dicati o n i n a bli n de d fas hi o n.  
1 0. 1. 6.   
Disse mi n ati o n of Cli nic al St u d y D at a   
Re p orts  
T he s p o ns or will discl ose a s u m mar y of st u d y i nf or mati o n, i ncl u di n g ta b ular st u d y res ults, o n 
p u blicl y a v aila ble we bsit es w here re q uire d b y l ocal la w or re g ulati o n.  
T he s u m mar y of res ults will be p oste d wit hi n t he ti me fra me s pecifie d b y l ocal la w or re g ulati o n. 
If t he st u d y re mai ns o n g oi n g i n s o me c o u ntries a n d a statistical a nal ysis of a n i nc o m plete dataset 
w o ul d res ult i n a nal ys es l ac ki n g scie ntific ri g or (f or e x a m ple,  u n der p o were d) or c o m pr o mise t he 
i nte grit y of t he o v erall a n al yses (f or e x a m ple, trial n ot yet u n bli n de d), t he s u m mar y of res ults 
will be s u b mitte d wit hi n 1 year after t he e n d of t h e st u d y gl o ball y or as s o o n as a vaila ble, 
w hic he ver is earlier.  
D at a  
T he s p o ns or pr o vi des access t o all i n di vi d ual partici pa nt data c ollecte d d uri n g t he trial, after 
a n o n y mizati o n, wit h t he e x ce pti o n of p har mac o ki netic or ge netic d ata.  
Data are a v aila ble t o re q uest 6 m o nt hs after t he i n dicati o n st u die d has bee n a p pr o ve d i n t he U S  
a n d E U a n d after pri mar y p u blicati o n acce pt a nce, w hic he ver is lat er. N o e x pirati o n date of dat a 
re q uests is c urre ntl y s et o nce data are m a de a v aila ble. 
Access is pr o vi de d after a pr o p osal has bee n a p pr o ve d b y a n i n de pe n d e nt re vie w c o m mittee 
i de ntifie d f or t his p ur p os e a n d aft er recei pt of a si g ne d d ata-s h ari n g a gree me nt. 
Data a n d d o c u me nts, i ncl u di n g t he st u d y pr ot oc ol, S A P , C S R , a n d bla n k or a n n otate d C R Fs , will 
be pr o vi de d i n a sec ure d ata -s hari n g e n vir o n me nt f or u p t o 2 years per pr o p osal. 
F or details o n s u b mitti n g a re q uest, see t he i nstr ucti o ns pr o vi de d at w w w. vi vli. or g.  
1 0. 1. 7.   
D at a Q u alit y Ass ur a nce   
I n vesti g at or res p o nsi bilities 
All partici pa nt data relati n g t o t he st u d y will be r ec or de d o n pri nte d or electr o nic C R F s u nless 
tra ns mitte d t o t he s p o ns or or desi g nee electr o nicall y (f or e x a m ple, la b orat or y d ata). T he 
i n vesti gat or is r es p o nsi ble f or verif yi n g t hat data e ntries are acc urate a n d c orrect b y p h ysicall y or 
electr o nicall y si g n i n g t he C R F. 
T he i n vesti gat or m ust mai ntai n acc urate d oc u me nt ati o n (s o urce d ata) t hat s u p p orts t he 
i nf or mati o n e ntere d i n t h e C R F. T his i ncl u des la b orat or y tests, me dical rec or ds, a n d cli nical 
n otes.  
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T he i n vesti gat or m ust re vie w a n d c o nfir m t hat data e ntries are acc urate a n d c o m plete t hr o u g h o ut 
t he d urati o n of t he st u d y, b y p h ysic all y or electr o nicall y si gni n g t he C R F, as i nstr ucte d b y t he 
s p o ns or. A ll c o m plete d C R Fs m ust be si g ne d pri or t o arc hi val.  
T he i n vesti gat or m ust per mit st u d y -rel ate d m o nit ori ng, a u dits, I R B/I E C re vie w, a n d re g ul at or y 
a ge nc y i ns pe cti o ns a n d pr o vi de direct a ccess t o s o urce d oc u m e nts.  
D at a m o nit ori n g a n d m a n a ge me nt  
Q ualit y t olera nce li mits will be pre defi ne d t o i de ntif y s yste matic iss ues t h at ca n i m pact 
partici pa nt safet y a n d/ or r elia bilit y of st u d y res ults. T hese pre d efi ne d p ara meters will be 
m o nit ore d d uri n g t he st u d y a n d i m p orta nt e x c ursi o ns  fr o m t he q ualit y t olera nce li mits  a n d 
re me dial acti o ns ta ke n will be s u m marize d i n t he C S R . 
M o nit ori n g details descri bi n g strate g y , f or e x am ple , ris k-base d i nitiati ves i n o perati o ns a n d 
q ualit y s uc h as ris k ma na ge m e nt a n d miti gati o n strate gies a n d a nal ytical ris k-base d m o nit ori n g, 
met h o ds, res p o nsi bilities a n d re q uir e me nts, i ncl u di n g ha n dli n g of n o n c o m plia nce iss ues a n d 
m o nit ori n g tec h ni q ues are pr o vi de d i n t he M o nit ori n g Pla n.  
T he s p o ns or or desi g nee is res p o nsi ble f or t he dat a ma na ge m e nt of t his st u d y i ncl u di n g q ualit y 
c hec ki n g of t he d ata.  
T he s p o ns or ass u mes acc o u nta bilit y f or acti o ns dele gate d t o ot her i n di vi d uals , f or e x a m ple, 
c o ntract researc h or ga nizati o ns. 
T he s p o ns or or desi g nee will perf or m m o nit ori n g t o c o nfir m t hat data tra ns cri be d i nt o t he C R F 
b y a ut h orize d site pers o n nel are acc urate, c o m plete, a n d verifia ble fr o m s o urce d oc u m e nts; t hat 
t he safet y a n d ri g hts of p artici pa nts are bei n g pr otecte d; a n d t hat t he st u d y is bei n g c o n d u cte d i n 
acc or da nce wit h t he c urre ntl y a p pr o ve d pr ot o c ol a n d a n y ot her st u d y a gree me nts, I C H G C P, a n d 
all a p plica ble re g u lat or y re q uire me nts. 
Rec or ds rete nti o n a n d a u dits  
Rec or ds a n d d o c u me nts, i ncl u di n g si g n e d I C Fs, p ertai ni n g t o t he c o n d uct of t his st u d y m ust be 
retai ne d b y t he i n vesti gat or f or t he ti me peri o d o utli ne d i n t he cli nical trial agree m e nt u nless 
l ocal re g ulati o ns or i nstit uti o nal p olicies re q uire a l o n ger rete nti o n peri o d. N o rec or ds ma y be 
dest r o ye d d uri n g t he rete nti o n peri o d wit h o ut t he writte n a p pr o val of t h e s p o ns or. N o rec or ds 
ma y b e tra nsferre d t o a n ot her l ocati o n or part y wit h o ut writte n n otificati o n t o t he s p o ns or . 
I n a d diti o n, t he sp o ns or  or its re prese nt ati ves will peri o dicall y c hec k a  sa m ple of t he partici p a nt 
data rec or de d a gai nst s o urce d oc u m e nts at t he st u d y site. T he st u d y ma y b e a u dite d b y t h e 
sp o ns or  or its re pres e ntati ves, or re g ulat or y a ge n cies 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.  
D at a c apt ure  syste m  
T he i n vesti gat or is res p o nsi ble f or e ns uri n g t he acc urac y, c o m plete ness, le gi bilit y, a n d ti meli ness 
of t he data re p orte d t o t h e s p o ns or.   
Electr o nic d at a c a pt ure syste m  
A n E D C s yste m will be use d i n t his st u d y f or t he c ollecti o n of C R F data. T he i n vesti gat or 
mai ntai ns a se parate s o urce f or t h e 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 v esti gat or is res p o nsi ble f or t he i de ntificati o n of a n y data 
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t o be c o nsi dere d s o urce a n d f or t he c o nfir mati o n t hat dat a 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. 
Cli nic al o utc o m e assess m e nts  
T he e C O A dat a ( partici pa nt -f oc use d o utc o me i nstr u me nt) f or all ot her assess me nts will be 
directl y rec or de d b y t he partici pa nt  i nt o a n i nstr u me nt (f or e x a m ple, ha n d-hel d s mart p h o ne or 
ta blet). T he e C O A d ata will ser ve as t he s o urce d oc u me ntati o n, a n d t he i n vesti gat or d oes n ot 
mai ntai n a se parate writt e n or electr o nic rec or d of t hese data.  
D at a st or a g e a n d access  
Data c ollecte d via t he s p o ns or -pr o vi de d dat a ca pt ure s yste m (s) will be  st or e d at t hir d parties . T he 
i n vesti gat or will ha ve c o nti n u o us access t o t he dat a d uri n g t h e 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 yste m (s). Pri or t o dec o m missi o ni n g, t he i n vesti gat or will recei ve or access 
a n arc hi v al c o p y of pert i ne nt data f or rete nti o n. 
Data ma na ge d b y a ce ntr al ve n d or, s uc h as la b orat or y test d ata, will be st ore d electr o ni call y i n 
t he ce ntral v e n d or’s d ata base s yste m a n d re p orts will be pr o vi de d t o t he i n vesti gat or f or re vie w 
a n d rete nti o n. Dat a will s u bse q ue ntl y b e tra nsferre d fr o m t he ce ntral ve n d or t o t he s p o ns or data 
ware h o us e.  
Data fr o m c o m plai nt f or ms s u b mitte d t o t he s p o ns or will be e nc o de d a n d st ore d i n t he gl o b al P C 
ma na ge me nt s yste m.  
1 0. 1. 8.   
S o urce D oc u me nts   
S o urce d oc u me nts pr o vi d e e vi de nce f or t h e e xiste nce of t he p artici pa nt a n d s u bsta ntiate t he 
i nte grit y of t he d ata c ollecte d. S o urce d o c u me nts are file d at t he i n vesti gat or’s site. 
Data re p orte d  o n  or e ntere d i n t he C R F a n d are tra nscri be d fr o m s o urce d o c u me nts m ust be 
c o nsiste nt wit h t he s o urce d oc u me nts or t he discre pa ncies m ust be e x plai ne d. T he i n vesti gat or 
ma y n ee d t o re q u est pre vi o us me dical rec or ds or tra nsfer rec or ds, de pe n di n g o n t he st u d y. Als o, 
c urre nt me di cal rec or ds m ust be a vaila ble.  
Defi niti o n of w hat c o nstit utes s o urce data ca n b e f o u n d i n  t he site c o nfir mati o n of s o urce data. 
1 0. 1. 9.   
St u d y a n d Site St art a n d Cl os ure   
First a ct of recruit me nt  
T he st u d y start date a n d t he first act of recr uit me nt is t he date o n w hic h t he cli nical st u d y will be 
o pe n f or recr uit me nt of p artici pa nts.  
St u d y or site ter mi n ati o n  
T he s p o ns or or s p o ns or’s desi g nee reser ves t he ri g ht t o cl ose t he st u d y site or ter mi nate t he st u d y 
at a n y ti me f or a n y reas o n at t he s ole discreti o n of t he s p o ns or. St u d y sites will be cl ose d u p o n 
st u d y c o m pleti o n. A st u d y site is c o nsi dere d cl ose d w he n all re q uire d d oc u me nts a n d st u d y 
s u p plies ha ve bee n c ollecte d a n d a st u d y-site cl os ure visit has bee n perf or me d. 
T he i n vesti gat or ma y i nitiate st u d y -site cl os ure at a n y ti me, pr o vi d e d t here is reas o na ble ca use 
a n d s ufficie nt n otice is gi ve n i n a d va nce of t he i nt e n de d ter mi nati o n.  
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Reas o ns f or t he earl y cl os ure of a st u d y site b y t he s p o ns or or i n vest i gat or ma y i ncl u d e b ut are 
n ot li mite d t o  
 f or st u d y t er mi nati o n d ue t o disc o nti n uati o n of f urt her st u d y i nter ve nti o n de vel o p me nt 
 f or site ter mi nati o n d ue t o 
o  fail ure of t he i n v esti gat or t o c o m pl y wit h t he pr ot oc ol, t he re q uire me nts of t he 
I R B/I E C or l ocal h ealt h a ut h orities, t he s p o ns or ’s pr oce d ures, or G C P g ui deli nes 
o  i na de q uate recr uit me nt (e val uate d after a reas o n a ble a m o u nt of ti me) of 
partici pa nts b y t he i n vesti gat or  
o  t otal n u m ber of partici pa nts i ncl u de d earlier t ha n e x pecte d . 
If t he st u d y is pre mat urely ter mi nat e d or s us pe n d e d, t he s p o ns or s hall pr o m ptl y i nf or m t he 
in vesti gat ors, t he I E Cs/I R Bs, t he re g ulat or y a ut h orities, a n d a n y c o ntract researc h or ga nizati o n(s) 
use d i n t he st u d y of t he reas o n f or ter mi nati o n or s us pe nsi o n, as s pecifie d b y t he a p plica b le 
re g ulat or y re q uire me nts. T he in vesti gat or s hall pr o m ptl y i nf or m t he partici pa nt  a n d s h o ul d ass ure 
a p pr o priate p artici pa nt  t h era p y a n d/ or f oll o w-u p . 
1 0. 1. 1 0.  
P u blic ati o n P olic y   
I n acc or da n ce wit h t he s p o ns or’s p u blicati o n p olic y , t he res ults of t his st u d y will be s u b mitte d 
f or p u blicati o n b y a peer-re vie we d j o ur nal. 
1 0. 1. 1 1.  
I n vesti g at or I nf or m ati o n  
Researc h ers wit h a p pr o priate e d ucati o n, trai ni n g, a n d e x perie nce, as d eter mi ne d b y t h e s p o ns or, 
will partici pate as i n vesti gat ors i n t his cli nical trial.  
1 0. 1. 1 2.  
S a m ple Rete nti o n   
Sa m ple rete nti o n e na bl es use of ne w tec h n ol o gies, res p o nse t o re g ul at or y q uesti o ns, a n d 
i n vesti gati o n of varia ble res p o nse t hat ma y n ot be o bser ve d u ntil later i n t he de vel o p me nt 
of  orf or gli pr o n  or afte r orf or gli pr o n    bec o mes c o m merciall y a vaila bl e.  
T his ta ble lists t he ma xi m u m  rete nti o n peri o d f or sa m ple t y pes. T h e rete nti o n peri o d be gi ns after 
t he last partici pa nt’s last visit i n t his st u d y. 
 
S a m ple T y pe  
C ust o di a n  
M a xi m u m Rete nti o n Peri o d After t he L ast 
P artici p a nt Visit  
E x pl orat or y bi o mar kers  
S p o ns or or desi g nee  
7  years  
P har mac o ki netic  
S p o ns or or desi g nee  
1 year  
Ge netics / P D 
S p o ns or or desi g nee  
7 years  
 
 
 
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1 0. 2.   
A p pe n di x 2: Cli nic al L a b or at or y Tests   
T he tests detaile d i n t his a p pe n di x will be perf or me d b y t h e la b orat or y(ies) state d i n 
Secti o ns 1 0. 2. 1  a n d 1 0. 2. 2  of t his a p pe n di x . 
F or visits ot her t ha n t he prescree ni n g visit ( Visit 6 0 1): L o cal la b orat or y res ults are o nl y re q uire d 
i n t he e ve nt t hat t he ce ntral la b orat or y res ults are n ot a vaila ble i n ti me f or eit her st u d y 
i nter ve nti o n a d mi nistrati o n a n d/ or res p o nse e val u ati o n. If a l ocal sa m ple is re q uire d, it is 
i m p orta nt t hat t he sa m ple f or ce ntr al a nal ysis is o btai ne d at t he sa me ti me. A d diti o nall y, if t he 
l ocal la b orat or y res ults are use d t o ma ke eit her a st u d y i nter ve nti o n decisi o n or res p o nse 
e val uati o n, t he res ults m ust be rec or de d. 
I n circ u msta nces w here t he s p o ns or a p pr o ves l ocal la b orat or y testi n g i n lie u of ce ntral la b orat or y 
testi n g, t he l ocal la b orat or y m ust be q u alifie d i n acc or da nce wit h a p plica bl e l ocal re g ulati o ns. 
Pr ot oc ol -s pecific re q uire me nts f or i ncl usi o n or e x cl usi o n of partici pa nts are detaile d i n Secti o n 5  
of t he pr ot oc ol.  
A d diti o nal tests ma y be p erf or me d at a n y ti me d uri n g t he st u d y as d eter mi ne d necessar y b y t he 
i n vesti gat or or re q uir e d b y l ocal re g ulati o ns. 
I n v esti gat ors m ust d oc u me nt t heir re vie w of t he l a b orat or y safet y res ults. 
La b orat or y/a nal yt e res ults  t hat c o ul d u n bli n d t he st u d y will n ot be re p orte d t o i n vesti gati ve sites 
or ot her bli n de d pers o n nel  u ntil t he st u d y h as bee n u n bli n de d . 
1 0. 2. 1.   
Prescree ni n g Visit  ( O pti o n al)  
A bl o o d sa m ple f or H b A 1c meas ure me nt will be o btai ne d per t he c ollecti o n met h o ds a vaila ble t o 
s u p p ort t he prescree ni n g visit ( Visit 6 0 1). T he l ocati o n of la b orat or y a nal ysis will be de pe n de nt 
o n c ollecti o n met h o d perf or me d a n d is des cri be d i n t his ta ble.  
C ollecti o n Met h o d   
L oc ati o n of L a b or at or y A n al ysis  
P oi nt of care   
Near patie nt assess me nt  
Micr osa m pli n g (if 
a vaila ble) or 
v e ni p u nct ure 
Lill y -desi g nate d la b orat or y or l ocal 
la b orat or y 
P oi nt -of -care testi n g m ust be per missi ble b y l ocal re g ulati o ns a n d re q uire m e nts.  
All prescree ni n g la b orat or y assess me nts m ust be c o n d ucte d acc or di n g t o t he S o A, wit h sta n dar d 
c ollecti o n re q uire m e nts a cc or di n g t o t he la b orat o r y ma n ual, if a p plica ble. 
1 0. 2. 2.   
Ot her St u d y Visits   
Cli nic al L a b or at or y Tests   
C o m me nts  
He m at ol o g y  
Assa ye d b y Lill y -desi g nate d l a b orat or y  
He m o gl o bi n  
  
He mat ocrit  
  
Er yt hr oc yte c o u nt ( R B Cs - Re d Bl o o d Cells)  
  
Mea n cell v ol u me  
  
Mea n cell he m o gl o bi n  
  
Mea n cell he m o gl o bi n c o nce ntrati o n  
  
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Cli nic al L a b or at or y Tests   
C o m me nts  
Le u k oc ytes ( W B Cs - W hite Bl o o d Cells)  
  
Differe ntial  
  
A bs ol utes c o u nt of  
 
  Ne utr o p hils  
 
  L y m p h oc ytes  
  
  M o n oc ytes  
  
  E osi n o p hils  
  
  Bas o p hils  
  
Platelets  
  
Cell m or p h ol o g y ( R B Cs a n d W B Cs)  
 T o be perf or me d if a b n or malities are detecte d  
  
  
Cli nic al che mistr y  
Assa ye d b y Lill y -desi g nate d l a b orat or y  
S o di u m  
  
P otassi u m  
  
C hl ori de  
  
Bicar b o nate  
  
T otal bilir u bi n  
  
Direct bilir u bi n  
  
Al kali ne p h os p hatase ( A L P)  
  
Ala ni ne a mi n otra nsferase ( A L T)  
  
As partate a mi n otra nsferase ( A S T)  
  
Ga m ma -gl uta m yl tra nsferase ( G G T)  
  
Bl o o d urea nitr o ge n ( B U N)  
  
Creati ni ne  
  
Creati ne ki nase ( C K)  
  
Uric aci d  
  
T otal pr otei n  
  
Al b u mi n  
  
Calci u m  
  
P h os p h or us  
  
Li pi d p a nel  
 
Hi g h de nsit y li p o pr otei n c h olester ol ( H D L -C)  
Assa ye d b y Lill y -desi g nate d l a b orat or y.  
T otal c h olester ol  
Tri gl yceri des  
L o w -de nsit y li p o pr otei n c h olester ol ( L D L -C)  
Calc ulate d b y Lill y -desi g nate d la b orat or y. 
If tri gl yceri des are > 4 0 0 m g/ d L, t he direct L D L will 
be assa ye d . 
Ver y L o w -de nsit y li p o pr otei n c h olester ol ( V L D L -C)  
Calc ulate d b y Lill y -desi g nate d la b orat or y.  
 N o n -Hi g h de nsit y li p o pr otei n c h olester ol ( n o n -H D L)   
Calc ulate d b y Lill y -desi g nate d la b orat or y. 
 
 
He p atitis ser ol o g y  
Assa ye d b y Lill y -desi g nate d l a b orat or y.  
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Cli nic al L a b or at or y Tests   
C o m me nts  
He p atitis C Vir us ( H C V) testi n g:  
 
   H C V a nti b o d y  
 
   H C V R N A  
P erf or me d o nl y f or partici pa nts w h o test p ositi ve 
f or H C V a nti b o d y. 
He p atitis B Vir us ( H B V) testi n g:  
 
  H B V D N A  
P erf or me d o nl y f or partici pa nts w h o test p ositi ve 
f or a nti-H Bc.  
  He p atitis B c ore a nti b o d y ( H B c -A b)  
 
  He p atitis B s urface a nti ge n ( H Bs A g)  
 
  He p atitis B s urface a nti b o d y (a nti -H Bs)  
 
 
 
H or m o nes (fe m ale)  
Assa ye d b y Lill y -desi g nate d l a b orat or y u nless 
state d ot her wise.  
Ser u m pre g na nc y  
 
Uri ne pre g na nc y  
E val uate d l ocall y . 
F ollicle -sti m ulati n g h or m o ne ( F S H)   
 
  
  
Uri ne c he mistr y  
Assa ye d b y Lill y -desi g nate d l a b orat or y.  
Al b u mi n  
  
Creati ni ne  
  
  
  
C alc ul ati o ns  
Ge nerate d b y Lill y -desi g nate d la b orat or y.  
e G F R ( C K D -E PI)  
C K D -E PI cystati n -C e q uati o n ( 2 0 1 2)  
Res ults will be use d f or eli gi bilit y criteria.  
Uri nar y al b u mi n/creati ni ne rati o ( U A C R)  
  
  
  
Ot her testi n g  
 
H b A 1c  
T esti n g ma y be perf or me d l ocall y  at V 6 0 1. All 
ot her visits ass a ye d b y Lill y-d esi g nate d la b orat or y.  
Calcit o ni n  
Assa ye d b y Lill y -desi g nate d l a b orat or y.  
P a ncreatic a m ylase  
Assa ye d b y Lill y -desi g nate d l a b orat or y.  
Li pase  
Assa ye d b y Lill y -desi g nate d l a b orat or y.  
Gl uc ose  
Ser u m  
Gl uca g o n  
Res ults will n ot be pr o vi de d t o i n vesti gati ve sites.  
I ns uli n 
Res ults will n ot be pr o vi de d t o i n vesti gati ve sites.  
C -pe pti de  
Res ults will n ot be pr o vi de d t o i n vesti gati ve sites.  
C ystati n -C  
Res ults will n ot be pr o vi de d t o i n vesti gati ve sites.  
P h ar m ac o ki netic s a m ples –  orf or gli pr o n  c o nce ntr ati o n  
Assa ye d b y Lill y -desi g nate d l a b orat or y.  
Res ults will n ot be pr o vi de d t o t he i n vesti gati ve 
sites. 
Ge netics s a m ple  
Assa ye d b y Lill y -desi g nate d l a b orat or y.  
Res ults will n ot be pr o vi de d t o t he i n vesti gati ve 
sites. 
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C O N FI D E N TI A L  
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Cli nic al L a b or at or y Tests   
C o m me nts  
 W h ole bl o o d ( E D T A)  
  
E x pl or at or y bi o m ar ker st or a ge s a m ples  
Assa ye d b y Lill y -desi g nate d l a b orat or y.  
Res ults will n ot be pr o vi de d t o t he i n vesti gati ve 
sites. 
  Ser u m  
 
  Plas ma ( E D T A)  
1 0. 2. 3.   
L a b or at or y S a m ples t o be O bt ai ne d at t he Ti me of a S yste mic H y perse nsiti vit y 
E ve nt   
P ur p ose of c ollecti n g s a m ples after a s yste mic h y perse nsiti vit y e ve nt  
T he sa m ples liste d i n t his a p pe n di x are n ot c ollect e d f or ac ute st u d y partici pa nt ma na ge me nt. 
T he s p o ns or will use t he la b orat or y tests res ults fr o m t hese sa m ples t o c haracterize 
h y perse nsiti vit y e v e nts a cr oss t he cli nical de vel o p me nt pr o gra m.  
W he n t o c ollect s a m ples after a s yste mic h y perse nsiti vit y e ve nt occ urs  
C ollect t he  sa m ples liste d bel o w if a s yste mic h y perse nsiti vit y e v e nt is s us pecte d. T he ti mi n g 
s h o ul d be as desi g nate d i n t he ta ble, ass u mi n g t h e partici pa nt has bee n sta bilize d. 
O btai n f oll o w -u p pre d os e sa m ples at t he ne xt re g ularl y s c he d ule d la b orat or y s a m ple c olle cti o n 
(i deall y pri or t o t he ne xt d ose after t h e e ve nt) t o assess p ost-e ve nt ret ur n -t o-baseli ne val u es.  
Ti mi n g  
L a b or at or y Test a  
C ollect fr o m 3 0 mi n utes  t o 4 ho u rs after t he start of 
t he e ve nt. 
● 
N ote: T he o pti mal c ollecti o n ti me is fr o m 1 t o 2 
h o u rs after t he start of e ve nt. 
t otal tr y ptase 
a All sa m ples f or h y perse nsiti vit y testi n g will be assa ye d b y Lill y -desi g nate d la b orat or y. Res ults will n ot be 
pr o vi de d t o t he st u d y site. If s a m ples are n ot c ollecte d or are c ollecte d o utsi de t he s pecifie d ti me peri o d, t his will 
n ot be c o nsi dere d a pr ot oc o l de viati o n. 
W h at i nf or m ati o n t o rec or d  
Rec or d t he dat e a n d ti me w he n t he sa m ples are c ollecte d.  
All o w e d a d diti o n al testi n g f or p artici p a nt m a n a ge me nt  
T he i n vesti gat or ma y perf or m a d diti o nal tests l ocall y, if cli nicall y i n dicate d, f or ac ut e st u d y 
partici pa nt ma na ge me nt.  
 
 
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1 0. 3.   
A p pe n di x 3: A d verse E ve nts  a n d Seri o us A d verse E ve nts : Defi niti o ns 
a n d Pr oce d ures f or Rec or di n g, E v al u ati n g, F oll o w -u p, a n d 
Re p orti n g   
1 0. 3. 1.   
Defi niti o n of A E   
 A n A E is a n y u nt o war d me dical occ urre n ce i n a partici pa nt a d mi nistere d a p har mace utical 
pr o d uct a n d  w hic h d oes n ot necessaril y ha v e a ca usal relati o ns hi p wit h t he st u d y 
i nter ve nti o n. A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n 
a b n or mal la b orat or y fi n di n g), s y m pt o m, or diseas e ( ne w or e x acer bate d) t e m p orall y 
ass ociate d wit h t he use of a me dici nal (i n v esti gati o nal) pr o d uct  or i n vesti gati o nal 
c o m bi nati o n 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 or 
i n vesti gati o nal c o m bi nati o n pr o d uct. 
E ve nts m eeti n g t he A E d efi niti o n 
 A n y a b n or mal la b orat or y test res ults ( he mat ol o g y, cli nical c he mistr y, or uri nal ysis) or 
ot her safet y assess me nts , f or e x a m ple, E C G, ra di ol o gical sca ns, a n d vital si g ns 
meas ure me nts, i ncl u di n g t h ose t hat w orse n fr o m baseli ne, c o nsi dere d cli nicall y 
si g nifica nt i n t he me dical a n d scie ntific j u d g me nt of t he i n vesti gat or, t hat is, n ot relate d t o 
pr o gressi o n of u n derl yi n g diseas e.  
 E x acer bati o n of a c hr o ni c or i nter mitte nt pre -e xisti n g c o n diti o n i ncl u di n g eit her a n 
i ncreas e i n fre q u e nc y a n d/ or i nte nsit y of t he c o n diti o n. 
 Ne w c o n diti o n detecte d or dia g n os e d after st u d y i nter ve nti o n a d mi nistrati o n e ve n t h o u g h 
it ma y ha v e bee n prese nt bef ore t h e start of t he st u d y. 
 Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d dr u g -dr u g i nteracti o n.  
 Me dicati o n err or, mis use, or a b use of I M P, i ncl u di n g si g ns, s y m pt o ms, or cli nical 
se q uelae. 
 Lac k of efficac y or fail ure of e x pecte d p har mac ol o gical acti o n per se will n ot be re p orte d 
as a n A E or S A E. S uc h i nsta nces will be ca pt ure d i n t he efficac y ass ess me nts. H o we ver, 
t he si g ns, s y m pt o ms, a n d/ or cli nical seq uelae res ulti n g fr o m lac k of efficac y will be 
re p orte d as A E or S A E if t he y f ulfill t he defi niti o n of a n A E or S A E. 
E ve nts N O T  m eeti n g t he A E d efi niti o n 
 A n y cli nicall y si g nifica nt a b n or mal la b orat or y fi n di n gs or ot her a b n or mal s afet y 
assess me nts t hat are ass o ciate d wit h t he u n derl yi n g diseas e, u nless j u d ge d b y t he 
i n vesti gat or t o be m or e s e vere t h a n e x pecte d f or t he partici pa nt’s c o n diti o n. 
 T he disease  or dis or der bei n g st u die d or e x pecte d pr o gressi o n, si g ns, or s y m pt o ms of t he 
disease  or dis or d er bei n g st u die d, u nless m ore se vere t ha n e x pecte d f or t he partici pa nt’s 
c o n diti o n.  
 Me dical or s ur gical pr oce d ure , f or e x a m ple, e n d osc o p y, a p pe n d ect o m y. T he c o n diti o n 
t hat lea ds t o t he pr oce d ure is t he A E. 
 Sit uati o ns i n w hic h a n u nt o war d me dical o cc urre n ce di d n ot occ ur (s ocial a n d/ or 
c o n ve nie nce a d missi o n t o a h os pital).  
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 A ntici pate d da y -t o-d a y fl uct uati o ns of pre -e xisti n g disease(s) or c o n diti o n(s) prese nt or 
detecte d at t he start of t h e st u d y t hat d o n ot w ors e n.  
1 0. 3. 2.   
Defi niti o n of S A E   
A n S A E is defi ne d as a n y u nt o w ar d me dic al o cc urre nce t h at, at a n y d ose, meets o ne or 
m o re of t he criteri a list e d:  
 Res ults i n deat h  
 Is life-t hreate ni n g 
o  T he ter m life-t hre ate ni n g i n t he defi niti o n of seri o us refers t o a n e ve nt i n w hic h 
t he partici pa nt was at ris k of deat h at t he ti me of t he e ve nt. It d oes n ot refer t o a n 
e ve nt, w hic h h y p ot heticall y mi g ht ha ve ca use d deat h, if it were m ore se vere.  
 Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pita lizati o n 
o  I n ge neral, h os pitalizati o n si g nifies t hat t he partici pa nt has bee n a d mitte d t o 
h os pital or e mer ge n c y war d ( us uall y i n v ol vi n g at least a n o ver ni g ht sta y) f or 
o bser vati o n a n d/ or treat me nt t hat w o ul d n ot ha ve bee n a p pr o priate i n t he 
p h ysicia n’s office or o ut patie nt setti n g. C o m plicati o ns t hat occ ur d uri n g 
h os pitalizati o n are A Es. If a c o m plicati o n pr ol o n gs h os pitalizati o n or f ulfills a n y 
ot her seri o us criteria, t he e ve nt is seri o us. W he n i n d o u bt as t o w het her 
h os pitalizati o n occ urre d or was nece ssar y, t he A E s h o ul d be c o nsi dere d s eri o us. 
o  H os pitalizati o n f or electi ve treat me nt of a pre -e xisti n g c o n diti o n t hat di d n ot 
w orse n fr o m b aseli ne is n ot c o nsi dere d a n A E.  
 Res ults i n persiste nt disa bilit y/i nca pacit y  
o  T he ter m disa bilit y mea ns a s u bsta ntial di sr u pti o n of a pers o n’s a bilit y t o c o n d uct 
n or mal life f u ncti o ns.  
o  T his defi niti o n is n ot i nte n de d t o i ncl u de e x perie n ces of relati vel y mi n or me dical 
si g nifica n ce s uc h as u nc o m plicate d hea dac he, n a usea, v o miti n g, diarr hea, 
i nfl ue nza, a n d acci de ntal tra u ma (for e x a m ple, s prai ne d a n kle) w hic h ma y 
i nterfere wit h or pre v e nt e ver y da y life f u ncti o ns b ut d o n ot c o nstit ute a s u bsta ntial 
disr u pti o n.  
 Is a c o n ge nital a n o mal y/ birt h defect 
o  A b n or mal pre g n a nc y o ut c o mes , f or e x a m ple, s p o nta ne o us a b orti o n, fet al deat h, 
still birt h, c o n ge nital a n o malies, a n d ect o pic pre g n a nc y, are c o nsi dere d S A Es.  
 Ot her sit uati o ns:  
o  Me dical or scie ntifi c j u d g me nt s h o ul d be e x ercise d b y t he i n vesti gat or i n d eci di n g 
w het her S A E re p orti n g is a p p r o priate i n ot her sit uati o ns s uc h as i m p orta nt 
me dical e ve nts t hat ma y n ot be i m me diatel y life -t hreate ni n g or res ult i n deat h or 
h os pitalizati o n b ut ma y j e o par dize t he partici pa nt or ma y re q uire me dical or 
s ur gical i nter ve nti o n t o pre ve nt o ne of t he ot her o utc o mes liste d i n t he a b o ve 
defi niti o n. T hese e ve nts s h o ul d us uall y be c o nsi d ere d seri o us.  
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o  E x a m ples of s uc h e ve nts i ncl u de i n vasi ve or mali g na nt ca ncers, 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 f or aller gic br o n c h os pas m, bl o o d 
d yscrasias or c o n v ulsi o ns t hat d o n ot res ult i n h os pitalizati o n, or de vel o p me nt of 
dr u g d e pe n de nc y or dr u g a b use.  
1 0. 3. 3.   
Defi niti o n of Pr o d uct C o m pl ai nts   
Pr o d uct co m pl ai nt  
A P C  is a n y writte n, electr o nic, or oral c o m m u nicati o n t hat alle ges defici e ncies relat e d t o t he 
i de ntit y, q ualit y, d ura bilit y, relia bilit y, safet y, effecti ve ness or perf or ma n ce of a st u d y 
i nter ve nti o n. W he n t he a bilit y t o use t he st u d y i nt er ve nti o n safel y is i m pacte d, t he f oll o wi n g are 
als o P C s: 
 d eficie nci es i n la beli n g i nf or mati o n, a n d  
 u se err ors f or de vice or dr u g-de vice c o m bi nati o n pr o d ucts d ue t o er g o n o mic desi g n 
ele me nts of t he pr o d u ct.  
P C s relate d t o st u d y i nter ve nti o ns use d i n cli nical trials are c ollecte d t o e ns ure t he safet y of 
partici pa nts, 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.  
I n v esti gat ors will i nstr uct partici pa nts t o c o ntact t h e site as s o o n as p ossi ble if he or s he has a P C  
or pr o ble m wit h t he st u d y i nter ve nti o n s o t hat t he sit uati o n ca n be assesse d.  
A n e ve nt ma y meet t he d efi niti o n of b ot h a P C  a n d a n A E/ S A E. I n s uc h cases, it s h o ul d be 
re p orte d as b ot h a P C  a n d as a n A E/ S A E.  
1 0. 3. 4.   
Rec or di n g a n d F oll o w -U p of A E a n d / or S A E  a n d Pr o d uct C o m pl ai nts   
A E, S A E , a n d P C  rec o r di n g 
W he n a n A E/ S A E /P C  occ urs, it is t he res p o nsi bilit y of t he i n vesti gat or t o re vie w all 
d oc u me ntati o n (f or e x a m ple, h os pital  pr o gress n otes, la b orat or y re p orts, a n d dia g n ostics re p orts) 
relate d t o t he e v e nt. 
T he i n vesti gat or will t he n rec or d all rele va nt A E/ S A E/ P C  i nf or mati o n i n t he partici pa nt’s 
me dical rec or ds, i n acc or da nce wit h t he i n vesti gat or’s n or mal cli nical practice. A E/ S A E 
i nf or mati o n is re p orte d o n t he a p pr o priat e C R F pa ge a n d pr o d uct c o m plai nt i nf or mati o n is 
re p orte d o n t he Pr o d u ct C o m plai nt F or m. 
N ote: A n e ve nt ma y meet t he defi niti o n of b ot h a P C  a n d a n A E/ S A E. I n s uc h cases, it s h o ul d be 
re p orte d as b ot h a P C  a n d as a n A E/ S A E.  
It is n ot  acce pta bl e f or t h e i n vesti gat or t o se n d p h ot oc o pies of t he partici p a nt’s me dical rec or ds 
t o t he sp o ns or or desi g nee i n lie u of c o m pleti o n of t he C R F pa ge f or A E/ S A E a n d t he Pr o d uct 
C o m pl ai nt F or m f or P C s. 
T here ma y b e i nsta nces w he n c o pies of m e dical rec or ds f or certai n cas es are re q u este d b y t he 
sp o ns or or desi g nee. I n t his case, all partici p a nt i de ntifiers, wit h t he e x ce pti o n of t he partici pa nt 
n u m ber, will be re d acte d o n t he c o pies of t he me di cal rec or ds bef ore s u b missi o n t o t he sp o ns or 
or desi g n ee.  
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C O N FI D E N TI A L  
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1 0 0  
T he i n vesti gat or will atte m pt t o esta blis h a dia g n osis of t he e ve nt base d o n si g ns, s y m pt o ms, 
a n d/ or ot her cli nical i nf or mati o n. W he ne ver p ossi ble, t he dia g n osis ( n ot t he i n di vi d ual 
si g ns/s ym pt o ms) will be d oc u me nte d as t he A E/ S A E.  
Assess me nt of inte nsit y  
T he i n vesti gat or will ma ke a n assess me nt of i nte nsit y f or eac h A E a n d S A E re p orte d d uri n g t h e 
st u d y a n d assi g n it t o 1 of t he f oll o wi n g cate g ories:   
 Mil d: A t y p e of A E  t hat is us uall y tra nsie nt a n d ma y re q uire o nl y mi ni mal treat me nt or 
t hera pe utic i nter ve nti o n. T he e ve nt d oes n ot ge nerall y i nterfere wit h us ual acti vities of 
dail y li vi n g.  
 M o derate: A t y pe of A E  t hat is us uall y alle viate d wit h a d diti o nal s pecific t hera pe utic 
i nter ve nti o n. T he e v e nt i nterferes wit h us ual acti vities of dail y li vi n g, ca usi n g disc o mf ort 
b ut p oses n o si g nifica nt or per ma n e nt ris k of har m t o t he researc h partici pa nt.  
 Se vere: A t y pe of A E  t hat i nterr u pts us ual acti vities of dail y li vi n g, or si g nifica ntl y 
affects cli nical stat us, or ma y re q uire i nte nsi ve t h era pe utic i nter ve nti o n. A n A E t hat is 
assesse d as se vere s h o ul d n ot be c o nf use d wit h a S A E. Se vere is a cate g or y utilize d f or 
rati n g t he i nte nsit y of a n e ve nt; a n d b ot h A Es a n d S A Es ca n be ass esse d as se vere.  
A n e ve nt is defi ne d as “s eri o us” w he n it meets at least o ne of t he pre defi ne d o utc o mes as 
descri be d i n t he d efi niti o n of a n S A E, N O T w h e n it is rate d as se vere.  
Assess me nt of ca us alit y  
T he i n vesti gat or is o bli gate d t o assess t he relati o ns hi p bet wee n st u d y i nter ve nti o n a n d eac h 
occ urre nce of eac h A E/ S A E. T he i n vesti gat or will use cli nical j u d g m e nt t o deter mi ne t he 
relati o ns hi p. 
A “reas o na ble p ossi bilit y” of a relati o ns hi p c o n ve ys t hat t here are facts, e vi de nce, a n d/ or 
ar g u me nts t o s u g gest a ca u sal relati o ns hi p, rat h er t ha n a relati o ns hi p ca n n ot be r ule d o ut. 
Alter nati ve ca uses, s uc h as u n derl yi n g disease(s), c o nc o mita nt t hera p y, a n d ot her ris k fact ors, as 
well as t he te m p oral r elati o ns hi p of t he e ve nt t o st u d y i nter ve nti o n a d mi nistrati o n will be  
c o nsi dere d a n d i n vesti gate d.  
T he i n vesti gat or will als o c o ns ult t he I B i n t heir assess me nt.  
F or eac h A E/ S A E, t he i n vesti gat or m ust  d oc u me nt i n t he me dical n otes t hat he/s he has re vie we d 
t he A E/ S A E a n d has pr o vi de d a n assess me nt of ca usalit y. 
T here ma y b e sit uati o ns i n w hic h a n S A E has occ urre d a n d t h e i n vesti gat or has mi ni mal 
i nf or mati o n t o i ncl u de i n t he i nitial re p ort t o t he sp o ns or or desi g nee. H o we ver, it is ver y 
i m p orta nt t hat t he i n vesti gat or al wa ys ma ke a n assess me nt of ca us alit y f or e ver y e ve nt b efore t he 
i nitial tra ns missi o n of t he S A E data t o t he sp o ns or or desi g n ee.  
T he i n vesti gat or ma y c h a n ge t h eir o pi ni o n of ca us alit y i n li g ht of f oll o w -u p i nf or mati o n a n d se n d 
a S A E f oll o w -u p re p ort wit h t he u p date d ca us alit y ass ess me nt.  
T he ca us alit y ass ess me n t is o ne of t he criteria use d w he n deter mi ni n g re g ulat or y re p orti n g 
re q uire me nts. 
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C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
1 0 1  
F oll o w -u p of A Es a n d S A Es  
 T he i n vesti gat or is o bli gate d t o perf or m or arra n ge f or t he c o n d u ct of s u p ple me ntal 
meas ure me nts a n d/ or e val uati o ns as me dicall y i n dicate d or as re q uest e d b y t he sp o ns or or 
desi g nee t o el uci dat e t he nat ure a n d/ or ca usalit y of t he A E or S A E as f ull y as p ossi ble. 
T his ma y i ncl u de a d diti o nal la b orat or y tests or i n v esti gati o ns, hist o pat h ol o gical 
e x a mi nati o ns, or c o ns ultati o n wit h ot her healt h care pr ofessi o nals.  
 If a partici pa nt dies d uri n g partici pati o n i n t he st u d y or d uri n g a rec o g nize d f oll o w-u p 
peri o d, t he i n vesti gat or will pr o vi de t he sp o ns or or desi g nee wit h a c o p y of a n y 
p ost m orte m fi n di n gs i ncl u di n g hist o pat h ol o g y.  
1 0. 3. 5.   
Re p orti n g of S A Es   
S A E re p orti n g vi a a n electr o nic d at a collecti o n to ol  
T he pri mar y mec ha nis m f or re p orti n g a n S A E will be t he electr o nic data c ollecti o n t o ol.  
If t he electr o nic s yste m is u na vailable, t he n t he sit e will use t he S A E pa per f or m (see n e xt 
secti o n) t o re p ort t he e ve nt wit hi n 2 4 h o urs.  
T he site will e nter t he S A E data i nt o t he electr o nic s yste m as s o o n as it bec o mes a vaila ble.  
After t he st u d y is c o m plete d at a gi ve n site, t he el ectr o ni c data c ollecti o n t o ol will be ta ke n off -
li ne t o pre ve nt t he e ntr y of ne w data or c h a n ges t o e xisti n g data. 
If a site recei v es a re p ort of a ne w S A E fr o m a st u d y partici pa nt or recei v es u p date d data o n a 
pre vi o usl y re p orte d S A E after t he electr o ni c data c o llecti o n t o ol has bee n ta ke n off-li ne, t he n t h e 
site ca n re p ort t his i nf or mati o n o n a S A E pa per f or m (see ne xt secti o n) or t o t he s p o ns or b y 
tele p h o ne. 
C o ntacts f or S A E re p orti n g ca n be f o u n d o n  t he S A E f or m. 
S A E re p orti n g vi a p a per for m  
Facsi mile tra ns missi o n of t he S A E pa per f or m is t he preferre d met h o d t o tra ns mit t his 
i nf or mati o n t o t he s p o ns or. 
I nitial n otificati o n via tel e p h o ne d oes n ot re place t he nee d f or t he i n vesti gat or t o c o m plete a n d 
si g n t he S A E C R F pa ges wit hi n t he desi g nate d re p orti n g ti me fra mes. 
C o ntacts f or S A E re p orti n g ca n be f o u n d o n t he S A E f or m . 
1 0. 3. 6.   
Re g ul at or y Re p orti n g Re q uire me nts   
S A E re g ul at or y re p orti n g  
Pr o m pt n otificati o n b y t he i n vesti gat o r t o t he s p o ns or of a S A E is esse ntial s o t hat le gal 
o bli gati o ns a n d et hical res p o nsi bilities t o war d t he safet y of partici pa nts a n d t he safet y of 
a st u d y i nter ve nti o n u n der cli nical i n vesti gati o n are met.  
T he s p o ns or has a l e gal r es p o nsi bilit y t o n otif y b o t h t he l ocal re g ulat or y a ut h orit y a n d ot her 
re g ulat or y a ge ncies a b o ut t he safet y of a st u d y i nt er ve nti o n u n der cli nical i n vesti gati o n. T he 
s p o ns or will e val uate t he re p orte d S A Es, i ncl u di n g c o nfir mati o n of relate d n ess a n d assess me nt 
of e x pecte d ness. T he s p o ns or has pr ocesses f or safet y re p orts f or i de ntificati o n, rec or di n g, a n d 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
1 0 2  
e x pe dite d re p orti n g of S U S A Rs acc or di n g t o l ocal re g ul at or y re q uire me nts.  T he s p o ns or will 
c o m pl y wit h c o u ntr y-s p ecific re g ul at or y re q uire m e nts relati n g t o safet y re p orti n g t o t he 
reg ulat or y a ut h orit y, I R B/I E C, a n d i n vesti gat ors. 
A n i n vesti gat or w h o recei ves a n i n vesti gat or safet y re p ort descri bi n g a S A E or ot her s pecific 
safet y i nf or mati o n (f or e x a m ple, s u m mar y or listi n g of S A Es) fr o m t he s p o ns or will re vie w a n d 
t he n file it al o n g wit h t he I B a n d will n otif y t he I R B/I E C, if a p pr o priate acc or di n g t o l ocal 
re q uire me nts. 
 
 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
1 0 3  
1 0. 4.   
A p pe n di x 4: C o ntr ace pti ve a n d B arrier G ui d a nce   
1 0. 4. 1.   
Defi niti o ns   
W or d/ P hr ase   
Defi niti o n  
W o me n of 
c hil d beari n g 
p ote ntial 
(W O C B P)  
A d ult fe males are c o nsi d ere d W O C B P u nless t he y are W N O C B P.  
W o me n n ot of 
c hil d beari n g 
p ote ntial  
( W N O C B P) 
Fe males are c o nsi dere d W N O C B P  if t he y 
 ha ve a c o n ge nital a n o mal y s uc h as M ülleria n a ge n esis  
 are i nf ertile d ue t o s ur gical sterilizati o n, or  
 are p ost me n o pa us al.  
E x a m ples of s ur gical sterilizati o n i ncl u de h ysterect o m y, bilateral s al pi n g o -
o o p h orect o m y, bilateral sal pi n gect o m y, or bilateral o o p h orect o m y.  
P ost me n o pa usal 
state 
T he p ost me n o pa usal stat e is defi ne d as a w o ma n:  
 at a n y a ge at least 6 wee ks p ost -s ur gical bilateral o o p h orect o m y 
wit h or wit h o ut h ysterect o m y, c o nfir me d b y o perati ve n ote or  
 a ge d at least 4 0 years a n d u p t o 5 5 years wit h a n i ntact uter us, n ot 
o n h or m o ne t hera p y a, w h o has ha d cess ati o n of me nses f or at least 
1 2 c o nsec uti ve m o nt hs wit h o ut a n alter nati ve me dical ca use, A N D 
wit h a f ollicle -sti m ulati n g h or m o ne > 4 0 mI U/ m L or  
 5 5 years or ol d er n ot o n h or m o ne t hera p y, w h o has ha d at least 1 2 
m o nt hs of s p o nta ne o us a me n orr hea, or  
 a ge d at least 5 5 years wit h a dia g n osis of me n o pa use pri or t o 
starti n g h or m o ne re place me nt t hera p y. 
a W o me n s h o ul d n ot be ta ki n g me di cati o ns d uri n g a me n orr hea s uc h as oral 
c o ntrace pti ves, h or m o nes, g o na d otr o pi n -releasi n g h or m o ne, a nti-estr o ge ns, 
S E R Ms, or c he m ot hera p y t hat c o ul d i n d uce tra nsi e nt a me n orr h ea.  
 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
1 0 4  
1 0. 4. 2.   
C o ntr ace pti o n G ui d a nce   
Fe m ales  
W O C B P w h o are c o m pletel y a bsti ne nt as t h eir preferre d a n d us ual lifest yle, or  i n a sa me-s e x 
relati o ns hi p as t heir preferre d a n d us u al lifest yl e: 
M ust …  
M ust n ot …  
a gree t o eit her 
re mai n a bsti ne nt or 
sta y i n a s a me-se x 
relati o ns hi p wit h o ut 
se x ual relati o ns hi ps 
wit h males , a n d n ot 
pla n a pre g n a nc y 
d uri n g t he st u d y  
 use peri o dic a bsti ne n ce met h o ds  
o  cale n dar  
o  o v ulati o n  
o  s y m pt ot her mal, or 
o  p ost -o v ulati o n  
 declare a bsti ne nce j ust f or t he d urati o n of a trial, or  
 use t he wit h dra wal met h o d  
 
W O C B P w h o are N O T c o m pletel y a bsti ne nt as t h eir preferre d a n d us u al lifest yle, or N O T i n a 
sa me-se x relati o ns hi p as t heir preferre d a n d us ual lifest yle: 
T o pic  
C o n diti o n  
C o ntrace pti o n  
A gree t o use 2 m et h o ds  of effecti ve c o ntrace pti o n, w here at least 1 f or m 
m ust be hi g hl y effecti ve.  
T hese met h o ds  of c o ntrace pti o n m ust be use d d uri n g t he st u d y a n d f or at 
least 3 0 da ys after t he last d ose of t he st u d y i nter ve nti o n.  
 
E x a m ples of differe nt f or ms of c o ntr ace pti o n:  
Met h o ds  
E x a m ples  
Hi g hl y effecti ve 
c o ntrace pti o n (less t ha n 
1 % fail ure rate)  
 fe male sterilizati o n
a (i ncl u di n g fall o pia n t u be li gati o n, 
h yster os c o pic sterilizati o n)  
 c o m bi nati o n oral c o ntrace pti ve pill  
 pr o gesti n -o nl y c o ntrace pti ve pill ( mi ni -pill)  
 i m pla nte d c o ntrace pti ves 
 i njecta ble c o ntrace pti ves 
 c o ntrace pti ve patc h ( o nl y w o me n < 1 9 8 p o u n ds or 9 0 k g)  
 t otal a bsti ne nce 
 vasect o m y ( f or me n i n cli nical trials a n d f or fe mal e part ner if 
o nl y se x ual part ner)  
 fall o pia n t u be i m pla nts (if c o nfir me d b y h yster osal pi n g o gra m) 
 c o m bi ne d c o ntrace pti ve va gi n al ri n g, or  
 i ntra uteri ne de vices 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
1 0 5  
Met h o ds  
E x a m ples  
Effecti ve c o ntrace pti o n  
 male or fe m ale c o n d o ms wit h s per mici de  
 dia p hra g ms wit h s per mici de or cer vical s p o n ges  
 barrier m et h o d wit h use of a s per mici de  
o  c o n d o m wit h s per mici de  
o  dia p hra g m wit h s per mici de, or  
o  fe male c o n d o m wit h s per mici de 
N ote: Male a n d fe male c o n d o ms s h o ul d n ot be use d i n 
c o m bi nati o n.  
I n effecti ve f or ms of 
c o ntrace pti o n w het her 
use d al o ne or i n a n y 
c o m bi nati o n  
 s per mici de al o ne 
 peri o dic a bsti ne nce  
 fertilit y a ware ness (cale n dar met h o d, te m perat ure met h o d, 
cer vical m uc us, or s y m pt ot her mal)  
 wit h dra wal  
 p ostc oital d o uc he,  or  
 lactati o nal a me n orr hea 
a  H ysterect o m y, bilateral sal pi n g o -o o p h orect o m y, bilateral sal pi n gect o m y, or bilateral o o p h orect o m y are t he o nl y 
t y pes of per ma ne nt fe male sterilizati o n t hat all o w a partici pa nt t o be a W N O C B P. 
M ales  
N o male c o ntrace pti o n is re q uire d e x ce pt i n c o m plia nce wit h s pecific l ocal g o ver n me nt st u d y 
re q uire me nts. 
 
 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
1 0 6  
1 0. 5.   
A p pe n di x  5 : Ge netics  
Use/ a n al ysis of D N A  
Ge netic variati o n ma y i m pact a partici pa nt’s res p o nse t o st u d y i nter ve nti o n, s usce pti bilit y t o, a n d 
se verit y a n d pr o gressi o n of disease. Varia ble res p o nse t o st u d y i nter ve nti o n ma y b e d ue t o 
ge n etic deter mi na nts t hat i m pact dr u g a bs or pti o n, distri b uti o n, meta b olis m, a n d e x creti o n; 
mec ha nis m of acti o n of t he st u d y i nter ve nti o n; disease eti ol o g y; a n d/ or m ol ec ular s u bt y pe of t he 
disease bei n g treate d. T h eref ore, w here l o cal re g ulati o ns a n d I R B/I E C all o w, a bl o o d  sa m ple will 
be c ollecte d f or D N A a n al ysis fr o m c o nse nti n g p artici pa nts.  
D N A sa m ples will be use d f or res earc h rel ate d t o orf or gli pr o n  or  dia betes , o besit y, a n d relate d 
traits or c o m plicati o ns, i ncl u di n g n o nal c o h olic steat o he patitis a n d relate d diseases. T he y m a y 
als o be use d t o de vel o p t ests/assa ys i n cl u di n g di a g n ostic tests rel ate d t o orf or gli pr o n , st u d y 
i nter ve nti o ns relate d t o t his dr u g cl ass, or dia betes , o besit y, a n d relate d traits or c o m plicati o ns, 
i ncl u di n g n o nalc o h olic st eat o he patitis a n d relate d diseases . Ge n etic res earc h ma y c o nsist of t he 
a nal ysis of 1  or m ore ca n di date ge nes or t h e a nal ysis of ge n etic mar k ers t hr o u g h o ut t he ge n o m e 
or a nal ysis of t he e ntire ge n o me  as a p pr o priate.  
T he sa m ples ma y be a nal yz e d as part of a m ulti-st u d y ass ess me nt of ge n etic fact ors i n v ol ve d i n 
t he res p o nse t o orf or gli pr o n  or st u d y i nter ve nti o ns relate d t o t his class o r t o u n dersta n d st u d y 
disease or relate d c o n diti o ns.  
T he res ults of ge n etic a n al yses m a y be re p orte d i n t he C S R or i n a se parate st u d y s u m mar y.  
T he s p o ns or will st ore t he D N A sa m ples i n a s ec ure st ora ge s p ace w it h a de q uate meas ures t o 
pr otect c o nfi d e ntialit y.  
T he sa m ples will be ret ai ne d w hile res earc h o n orf or gli pr o n  or dia betes , o b esit y, a n d relate d 
traits or c o m plicati o ns, i ncl u di n g n o nal c o h olic steat o he patitis a n d relate d diseases, c o nti n ues b ut 
n o l o n ger t h a n t he sa m pl e rete nti o n li mits descri be d i n Secti o n 1 0. 1. 1 2 , or ot her peri o d as p er 
l ocal re q uir e me nts. 
 
 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
1 0 7  
1 0. 6.   
A p pe n di x 6: Li ver S afet y: S u g geste d Acti o ns a n d F oll o w -u p 
Assess me nts   
He p atic ev al u ati o n testi n g  
See pr ot oc ol Secti o n 8. 2. 6  f or g ui da nce o n a p pr o priate test selecti o n. 
T he Lill y -d esi g n ate d ce ntral la b orat or y s h o ul d c o m plete t he a nal ysis of all selecte d testi n g 
e x ce pt f or testi n g liste d i n t he i n vesti gat or -desi g n ate d l ocal la b orat or y ta bl e. T he ce ntral 
la b orat or y will re p ort res ults if a vali date d test or calc ulati o n is a vaila ble. 
I n circ u msta nces w here re q uire d i n acc or da nce wit h l ocal re g ulati o ns, l ocal la b orat or y 
testi n g ma y be p erf or me d i n lie u of Lill y-desi g nat e d ce ntral la b orat or y t esti n g (i n t he 
ta ble bel o w). 
L ocal testi n g m a y be perf or me d i n a d diti o n t o ce ntr al testi n g w he n necessar y f or i m me diate 
partici pa nt ma na ge me nt.  
T he l ocal la b orat or y m ust be q ualifie d i n acc or da n ce wit h a p plica ble l ocal re g ul ati o ns.  
Tests ass a ye d b y Lill y -desi g n ate d ce ntr al l a b or at or y  
He p atic He m at ol o g y P a nel  
He p atitis A vir us ( H A V) testi n g:  
   He m o gl o bi n  
    H A V t otal a nti b o d y  
   He mat ocrit  
    H A V I g M a nti b o d y  
   Er yt hr oc ytes ( R B Cs - re d bl o o d cells) 
He p atitis B vir us ( H B V) testi n g:  
   Le u k oc ytes ( W B Cs - w hite bl o o d cells)   
    He patitis B s urface a nti ge n ( H Bs A g)  
   Differe ntial:  
    He patitis B s urface a nti b o d y (a nti -H Bs)  
       Ne utr o p hils, se g me nte d  
    He patitis B c ore t otal a nti b o d y (a nti -H Bc)  
       L y m p h oc ytes  
    He patitis B c ore I g M a nti b o d y  
       M o n oc ytes  
    H B V D N A a 
       Bas o p hils  
He p atitis C vir us ( H C V) testi n g:  
       E osi n o p hils  
    H C V a nti b o d y  
   Platelets  
    H C V R N A a 
   Cell m or p h ol o g y ( R B C a n d W B C)  
He p atitis D vir us ( H D V) testi n g:  
He p atic Cli nic al C he mistr y P a nel  
    H D V a nti b o d y  
   T otal bilir u bi n  
    H D V I g M a nti b o d y  
   Direct bilir u bi n  
He p atitis E vir us ( H E V) testi n g:  
   Al kali ne p h os p hatase ( A L P)  
    H E V I g G a nti b o d y  
   Ala ni ne a mi n otra nsferase ( A L T)  
    H E V I g M a nti b o d y  
   As partate a mi n otra nsferase ( A S T)  
    H E V R N A a 
   Ga m ma -gl uta m yl tra nsferas e ( G G T)  
A nti -n ucle ar a nti b o d y ( A N A)  
   Creati ne ki nase ( C K)  
A nti -s m o ot h m uscle a nti b o d y ( A S M A)b  
He p atic C o a g ul ati o n P a nel  
A nti -acti n a nti b o d y
c 
   Pr ot hr o m bi n ti me, I N R ( P T -I N R) 
I m m u n o gl o b uli n I g A ( q u a ntit ati ve)  
Uri ne C he mistr y  
I m m u n o gl o b uli n I g G ( q u a ntit ati ve) 
   Dr u g scree n  
I m m u n o gl o b uli n I g M ( q u a ntit ati ve)  
H a pt o gl o bi n  
  
 
 
 
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C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
1 0 8  
 
Tests ass a ye d O N L Y b y i n vesti g at or -desi g n ate d l oc al l a b or at or y  
Acet a mi n o p he n  
C yt o me g al o vir us ( C M V) testi n g:  
Acet a mi n o p he n pr otei n a d d ucts  
    C M V a nti b o d y  
Al k ali ne p h os p h at ase is oe nz y mes  
    C M V D N A a 
Cer ul o pl as mi n  
Her pes si m ple x vir us ( H S V) testi n g:  
C o p per  
    H S V ( T y pe 1 a n d 2) a nti b o d y  
Et h yl alc o h ol ( Et O H)  
    H S V ( T y pe 1 a n d 2) D N A a 
P h os p h ati d ylet h a n ol ( P Et h)  
Li ver ki d ne y micr os o mal t y pe 1 ( L K M -1) a nti b o d y  
Uri ne C he mistr y  
Micr o bi ol o g y C ult ure:  
    Et h yl gl uc ur o ni de ( Et G)  
    Bl o o d  
E pstei n -B arr  vir us ( E B V) testi n g:  
    Uri ne  
    E B V D N A a 
 
    E B V a nti b o d y  
 
a 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, testi n g a vaila bilit y, or b ot h . 
b  N ot re q uire d if a nti -acti n a nti b o d y is teste d . 
c N ot re q uire d if a nti -s m o ot h m uscle a nti b o d y ( A S M A) is test e d. 
 
 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
1 0 9  
1 0. 7.   
A p pe n di x 7: W orl d He alt h Or g a niz ati o n Cl assific ati o n of Di a betes 
a n d Di a g n ostic Criteri a   
T y pe 1 di a betes  
T 1 D is j u d ge d t o be pres e nt w he n t he cl assical s y m pt o ms of dia betes (t hirst, p ol y uria, wasti n g 
a n d st u p or, or c o ma) are ass ociate d wit h rea dil y d etecta ble c o nce ntrati o ns of gl uc ose a n d k et 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 n ot 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 o us ket osis a n d deat h.  
T y pe 2 di a betes  
T 2 D, alt h o u g h ofte n as y m pt o matic, ma y als o pr ese 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 p er gl yce mia, ket o ne b o di es are prese nt i n o nl y l o w 
c o nce ntr ati o ns i n t he bl o o d a n d uri ne. C o ma is rare i n T 2 D  b ut ma y re s ult fr o m e xtre me 
h y per gl yce mia a n d h y per os m olarit y; lactic aci d osis or ket oaci d osis ca n als o occ ur i n f ul mi nati n g 
ill ness (f or e x a m ple, se vere i nfecti o n or mese nteri c arter y t hr o m b osis) d ue t o a n ac ute i ncreas e i n 
i ns uli n re q uire me nts, b ut s p o nta ne o us ketosis d oes n ot occ ur. S o me patie nts wit h T 2 D later 
pr o gress t o a state of a bs ol ute i ns uli n deficie nc y ( Al berti a n d Zi m met 1 9 9 8).  
 
 
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1 0. 8.   
A p pe n di x 8 : Pr o hi bite d  Me dic ati o ns or Me dic ati o ns wit h S peci al Use 
Restricti o ns   
1 0. 8. 1.   
E xcl u de d/ P r o hi bite d M e dic ati o ns   
Me dicati o ns wit hi n t he f oll o wi n g cat e g ories are strictl y pr o hi bite d d uri n g t he st u d y. T he lists 
bel o w pr o vi de e x a m ples of eac h cate g or y of me di cati o n, b ut t he e x a m ples are n ot e x ha usti ve.  As 
state d i n Secti o n 6. 9. 1 , partici pa nts w h o ha v e t o i nitiate certai n pr o hi bite d c o nc o mita nt 
me dicati o ns d uri n g t his st u d y will be disc o nti n ue d fr o m t he st u d y i nter ve nti o n ( Secti o n 7. 1. 1 ). 
1 0. 8. 1. 1.  A nti h y per gl yce mic Me dic ati o ns   
T he f oll o wi n g a nti h y p er gl yce mic  me dicati o ns are pr o hi bite d wit hi n 9 0 da ys of Visit 1 , or 
bet wee n Visit 1 a n d Visit 3, as we all as at  a n y ti me d uri n g t h e st u d y. 
 al o gli pti n 
 d ula gl uti de  
 e x e nati de 
 li na gli pti n 
 lira gl uti de 
 pra mli nti de  
 sa x a gli pti n 
 se ma gl uti de 
 sita gli pti n 
 tirze pati de 
 ot her i ncreti n -b ase d t hera p y  
1 0. 8. 1. 2.  W ei g ht L oss M e dic ati o ns   
Wei g ht l oss me dicati o ns are pr o hi bite d wit hi n 9 0 da ys of Visit 1 , or bet wee n Visit 1 a n d Visit 3 , 
as well as at  a n y ti me d uri n g t he st u d y.  
 i n geste d mat erial t hat tra nsie ntl y occ u pi es s pace i n t he st o mac h, f or e x a m ple, Ple nit y®  
 lira gl uti de 
 l orcaseri n 
 ma zi n d ol 
 naltre x o ne/ b u pr o pi o n  
 orlistat  
 o ver -t he-c o u nter m e dicati o ns, f or e x a m ple, allī ®  
 p he nter mi ne  
 p he nter mi ne/t o pira mate  
 p he n yl pr o pa n ola mi ne  
 se ma gl uti de 
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 si b utra mi ne 
 ot her i ncreti n -b ase d t hera pies  
 
  
Partici pa nts ca n n ot be ta ki n g 
, dr u gs t hat are 
 
 Partici pa nts ma y b e 
eli gi ble f or t his st u d y t hese me dicati o ns ca n b e was he d o ut f or at least 2 w ee ks a n d t he 
partici pa nt s h o ul d be o n a sta ble d ose of alter nati v e me dicati o ns f or at least 2 wee ks pri or t o 
ra n d o mizati o n ( Visit 3).  
N o n -e x ha usti ve lists of e x a m ples of t hese me dicati o ns are pr o vi de d i n t his ta ble. 
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C CI
C CI
C CI
C CI

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1 0. 8. 2.   
Me dic ati o ns wit h S peci al U se R estricti o ns   
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1 0. 9.   
A p pe n di x 9 : St a n d ar dize d Pr ot oc ols f or t he Me as ure me nt of Hei g ht, 
Wei g ht, W aist Circ u mfere nce, a n d Vit al Si g ns   
T he f oll o wi n g i nf or mati o n has bee n a d a pte d fr o m sta n dar dize d p h ysical meas ure me nt pr ot oc ols 
f or t he W H O’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 1 7). 
Me as uri n g hei g ht  
Ste p 1.  As k t he partici pa nt t o re m o ve t heir f o ot wear a n d a n y h ea d gear (li g ht hea d gear w or n f or 
reli gi o us r eas o ns ca n re m ai n, b ut t his s h o ul d be w or n b y t h e partici pa nt at e ver y visit w he n t heir 
hei g ht is meas ure d).  
Ste p 2.  As k t he partici pa nt t o sta n d o n t he cali brat e d hei g ht meas uri n g b oar d (sta di o meter) 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 
b ac k b oar d, t h e sta di o met er, or t he wall.  
Ste p 3.  As k t he partici pa nt t o l o o k strai g ht a hea d wit h o ut tilti n g t heir hea d u p.  
Ste p 4.  As k t he partici pa nt t o breat he i n a n d sta n d tall. Meas ure a n d rec or d t he partici pa nt’s 
hei g ht i n ce nti meters t o 1 deci mal plac e.  
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 
electr o nic s cale ca pa ble of meas uri n g wei g ht i n kil o gra ms t o 1 deci mal place.  
All wei g hts f or a gi ve n partici pa nt s h o ul d be meas ure d usi n g t h e sa me scale,  w he ne ver 
p ossi ble, at a p pr o xi matel y t he sa m e ti me i n t he m or ni n g after e vac u ati o n of bla d der 
c o nte nts. 
Ste p 1 . As k t he partici pa nt t o e m pt y t heir p oc k ets, re m o ve t heir f o ot w ear, o uter wear (c o at, 
jac ket, etc.), a n d a n y h ea d gear (li g ht hea d gear w or n f or reli gi o us r eas o ns ca n re mai n, b ut t his 
s h o ul d be w or n b y t he partici pa nt at e ver y visit w he n wei g ht is meas ure d).  
Ste p 2 . Ma ke s ure t he s cale 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 partici pa nt t o ste p o nt o t he scale wit h 1 f o ot o n eac h si de of t he scale.  
Ste p 4 . As k t he partici pa nt t o sta n d still wit h ar ms b y si des a n d t h e n rec or d wei g ht i n kil o gra ms 
t o t he nearest o n e-te nt h kil o gra m. 
Me as uri n g w aist circ u mfere nce  
 Waist circ u mfere n ce s h o ul d be meas ure d i n t he h oriz o ntal pla ne a n d at t he mi d p oi nt 
bet wee n t he l o wer mar gi n of t he last pal p a ble ri b a n d t he t o p of t he iliac crest . 
 Meas ure me nts s h o ul d be ta ke n at t he e n d of a n or mal e x pirati o n usi n g a n o n -stretc ha ble 
meas uri n g ta pe. T h e ta pe s h o ul d lie flat a gai nst t he s ki n wit h o ut c o m pressi n g t he s oft 
tiss ue. 
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 T he waist circ u mfere nce s h o ul d be  meas ure d t wice, r o u n de d t o t he nearest 0. 5  c m. T he 
meas uri n g ta pe s h o ul d be re m o ve d bet w ee n t he 2 meas ure me nts. B ot h meas ure me nts will 
be rec or de d i n t he C R F. If t he differe nce bet w ee n t he 2 meas ure me nts e x cee ds 1  c m, t his 
set of meas ure me nts s h o ul d be discar de d a n d t he 2 meas ure me nts re peate d. 
Ste p 1 : As k t he partici pa nt t o wear little cl ot hi n g (if a vaila ble, gar me nts c o ul d als o be use d).  
Ste p 2 : As k t he partici pa nt t o sta n d wit h t heir feet cl ose t o get her, ar ms at t heir si de, b o d y wei g ht 
e ve nl y distri b ute d.  
Ste p 3 : As k t he partici pa nt t o rela x a n d meas ure t he partici pa nt’s waist circ u mfere nce. 
Vit al si g n me as ure me nts  
 Vital si g n meas ure me nts ( B P a n d H R, meas ure d b y p ulse) s h o ul d b e ta ke n bef ore 
o btai ni n g a n E C G tr aci n g a n d b ef ore c ollecti o n of bl o o d sa m ples  f or la b orat or y t esti n g. 
 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 ns meas ure m e nts are 
ta ke n. 
 F or eac h para met er, 3 meas ure me nts will be ta ke n usi n g t he sa me ar m, prefera bl y t he 
n o n d o mi na nt ar m.  
 T he rec or di n gs s h o ul d be ta ke n at leas t 1 mi n ute a part. Eac h m eas ure me nt of sitti n g p ulse 
a n d B P nee ds t o be rec or de d i n t he C R F.  
 B P m ust be ta ke n wit h a n a ut o mate d B P i nstr u me nt.  
 If B P a n d p ulse m eas ure me nts are ta ke n se paratel y, p ulse s h o ul d be ta k e n pri or t o B P. 
N ote:  I n t he e ve nt p ulse meas ure me nt ca n n ot be t a ke n via a n a ut o mate d B P i nstr u me nt, t he 
preferre d l o cati o n f or meas ure me nt of p ulse is t he ra dial arter y.  
 
 
 
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1 0. 1 0.  
A p pe n di x 1 0 : C o u ntr y -s pecific Re q uire me nts  
C o u ntr y -s pecific re q uire me nts, if a n y, will be des cri be d i n a se p arat e pr ot oc ol a d de n d u m.   
 
 
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1 0. 1 1.  
A p pe n di x 1 1 : Pr o visi o ns f or C h a n ges i n St u d y C o n d uct D uri n g 
E xce pti o n al Circ u mst a nces   
I m ple me nt ati o n of t his a p pe n di x 
T he c ha n ges t o pr oce d ures descri be d i n t his a p pe n di x are te m p orar y meas ures i nte n de d t o be 
use d o nl y d uri n g s p ecific ti me peri o ds as direct e d b y t he  s p o ns or i n p art ners hi p wit h t he 
i n vesti gat or. 
E xce pti o n al circ u mst a nces  
E x ce pti o nal circ u msta nces are rare e v e nts  t hat ma y ca use disr u pti o ns t o t he c o n d uct of t he st u d y. 
E x a m ples i ncl u de pa n de mics or nat ural disasters. T hese disr u pti o ns ma y li mit t he a bilit y of t he 
i n vesti gat ors, partici pa nts, or b ot h t o atte n d o n-site visits or t o c o n d uct pla n ne d st u d y pr oce d ures. 
Im ple me nti n g c h a n ges u n der e xce pti o n al circ u mst a nces  
I n a n e x ce pti o nal circ u msta nce, after recei vi n g t h e s p o ns or’s writte n a p pr o val, sites ma y 
i m ple me nt c ha n ges if per mitte d b y l ocal re g ulati o ns. 
After a p pr o val b y l ocal Et hical Re vie w B o ar ds, re g ulat or y b o d ies a n d a n y ot her rele va nt l ocal 
a ut h orities, i m ple me ntati o n of t hese e x ce pti o nal circ u msta nce c ha n ges will n ot t y picall y re q uire 
a d diti o nal n otificati o n t o t hese gr o u ps, u nless t he y ha ve s pecific re q uire me nts i n w hic h 
n otificati o n is re q uire d (f or e x a m ple , u p o n i m ple me ntati o n a n d s us pe nsi o n of c ha n ges). All 
a p pr o vals a n d n otificati o ns m ust be retai ne d i n t he st u d y rec or ds.  
If t he s p o ns or gra nts writte n a p pr o val f or c ha n ges i n st u d y c o n d uct, t he s p o ns or will als o pr o vi de 
a d diti o nal writte n g ui da nce, if nee d e d.  
C o nsi der ati o ns f or m a ki n g a c h a n ge  
T he pre v aili n g c o nsi derati o n f or ma ki n g a c h a n ge is e ns uri n g t he safet y of st u d y partici p a nts. 
A d diti o nal i m p orta nt c o nsi derati o ns f or ma ki n g a c ha n ge are c o m plia nce wit h G C P, e na bli n g 
partici pa nts t o c o nti n ue s afel y i n t he st u d y a n d mai ntai ni n g t he i nte grit y of t he st u d y. 
I nf or me d c o nse nt 
A d diti o nal c o nse nt fr o m t he partici pa nt will be o btai ne d, if re q uire d, f or:  
 partici pati o n i n re m ote visits, as defi ne d i n Secti o n “ Re m ote Visits”  
 dis pe nsati o n of a d diti o nal st u d y i nter ve nti o n d uri n g a n e xte n de d treat me nt peri o d 
 alter nate deli ver y of st u d y i nter ve nti o n a n d a ncillar y s u p plies, a n d  
 pr o visi o n of t heir pers o nal or me dical i nf or m ati o n re q uire d pri or t o i m ple me ntati o n of 
t hese acti vities.  
C h a n ges i n st u d y c o n d uct d uri n g e xce pti o n al circ u mst a nces  
C ha n ges i n st u d y c o n d u ct n ot descri be d i n t his a p pe n di x, or n ot c o nsiste nt wit h a p plica ble l ocal 
re g ulati o ns, are n ot all o we d. 
T he f oll o wi n g c ha n ges i n st u d y c o n d u ct will n ot be c o nsi dere d pr ot oc ol de viati o ns.  
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Re m ote visits  
Ty pes of re m ote visits  
Tele me dici ne: Tel e p h o n e or tec h n ol o g y -assiste d virt ual visits, or b ot h, are acce pta ble t o 
c o m plete a p pr o priate ass ess me nts. Assess me nts t o be c o m plete d i n t his ma n ner i ncl u de, 
b ut are n ot li mite d t o, c ollecti o n of A Es, re vi e w S M B G val ues a n d c o n c o mita nt 
me dicati o ns.  
M o bile he alt hc are  or ot her alter n ati ve l o c ati o ns :  
Healt hcare visits ma y b e perf or me d b y a m o bile healt hcare pr o vi der at l ocati o ns ot her 
t ha n t he st u d y site w he n partici pa nts ca n n ot tra vel t o t he site d ue t o a n e x ce pti o nal 
circ u msta nce if writte n a p pr o val is pr o vi de d b y t he s p o ns or . Pr oce d ures perf or me d at 
s uc h visits i ncl u de, b ut are n ot li mite d t o, c o nc o mita nt me dicati o ns, vital si g ns ( B P a n d 
P R), b o d y wei g ht, c ollecti o n of bl o o d sa m ples, p h ysical assess me nts, a n d c ollecti o n of 
healt h i nf or mati o n . 
D at a c a pt ure  
I n s o urce d o c u me nts a n d t he C R F, t he st u d y site s h o ul d ca pt ure t he visit met h o d, wit h a s pecific 
e x pla nati o n f or a n y data missi n g beca us e of misse d i n -pers o n site visits.  
S afety re p orti n g  
Re gar dless of t he t y pe of re m ote visits i m ple me nte d, t he pr ot oc ol re q uire m e nts re gar di n g t he 
re p orti n g of A Es, S A Es, a n d P Cs  re mai n u nc ha n ge d.  
Ret ur n t o o n -site visits 
E v er y eff ort s h o ul d be m a de t o e na bl e partici pa nts t o ret ur n t o o n -site visits as s o o n as 
reas o na bl y p ossi ble, w hil e e ns uri n g t he safet y of b ot h t he partici pa nts a n d t he site staff.  
L oc al l a b or at ory testi n g o pti o n  
L ocal la b orat or y testi n g ma y b e c o n d uct e d i n lie u of ce ntral la b orat or y t esti n g. H o we ver, ce ntral 
la b orat or y testi n g m ust be retai ne d f or: Visit 1, Visit 3, Visit 9, Visit 1 1, E D, a n d V 8 0 1.  T he 
l ocal la b orat or y m ust be q ualifie d i n acc or da nce wit h a p plica ble l ocal re g ulati o ns. 
St u dy i nterve nti o n a n d a ncill ary s u p plies (i ncl u di n g p artici p a nt di aries)  
W he n a  partici pa nt is u na ble t o g o t o t he site t o recei ve st u d y s u p plies d uri n g n or mal o n -site 
visits, t he site s h o ul d w or k wit h t he s p o ns or t o deter mi ne a p pr o priate acti o ns. T hese acti o ns ma y 
i ncl u de:   
 as ki n g t he partici pa nt t o g o t o t he site a n d recei ve st u d y s u p plies fr o m site staff 
wit h o ut c o m pleti o n of a f ull st u d y visit,  
 as ki n g t he partici pa nt’s d esi g nee t o g o t o t he site a n d recei v e st u d y s u p plies o n a 
partici pa nt’s be h alf, a n d  
 arra n gi n g d eli ver y of st u d y s u p plies . 
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T hese re q uire me nts m ust be met bef ore acti o n is ta ke n:  
 Alter nate deli ver y of st u d y i nter ve nti o n s h o ul d be perf or me d i n a ma n ner t hat d oes 
n ot c o m pr o mise treat me nt bli n di n g a n d e ns ures pr o d uct i nte grit y. T he e xisti n g 
pr ot oc ol re q uire m e nts f or pr o d uct acc o u nta bilit y re mai n u nc ha n ge d, i ncl u di n g 
verificati o n of p artici pa nt’s recei pt of st u d y s u p pli es.  
 W he n deli veri n g s u p plies t o a l ocati o n ot her t ha n t he st u d y site (f or e x a m ple, 
partici pa nt’s h o me), t h e i n vesti gat or, s p o ns or, or b ot h s h o ul d e ns ure o versi g ht of t he 
s hi p pi n g pr ocess t o e ns ure acc o u nta bilit y a n d pr o d uct q ualit y (t hat is, st ora ge 
c o n diti o ns  mai ntai ne d a n d i ntact pac ka gi n g u p o n recei pt).  
 I nstr u cti o ns ma y b e pr o vi de d t o t he partici pa nt or desi g nee o n t he fi n al dis p ositi o n of 
a n y u n us e d or c o m plet e d st u d y s u p plies . 
Scree ni n g peri o d g ui d a nce   
T o e ns ure safet y of st u d y partici pa nts, la b orat or y val ues a n d ot her eli gi bilit y ass ess me nts ta ke n 
at scree ni n g visit are vali d f or a ma xi m u m of 3 0 da ys. T h e f oll o wi n g r ules will be a p plie d f or 
acti ve, n o nra n d o mize d p artici pa nts w h ose partici pati o n i n t he s t u d y m ust be i nterr u pte d d u e t o 
e x ce pti o nal circ u msta nces:  
 If scree ni n g is i nterr u pte d f or less t ha n 3 0 da ys fr o m V isit 1  t o ra n d o mizati o n visit: 
t he partici pa nt will pr ocee d t o t he ne xt st u d y visit per t he us ual S o A, pr o vi de d t hat 
ra n d o mizati o n visit m ust be c o n d ucte d wit hi n 3 0 da ys fr o m V isit 1 . 
o  T he site s h o ul d c o n d uct t he ne xt visit if t he partici pa nt’s eli gi bilit y criteria are 
c o nfir me d, a n d t h e site s h o ul d d oc u me nt t he reas o n f or dela y.  
o  T he site s h o ul d als o rec o nfir m t he i m pacte d partici pa nt’s c o nse nt a n d 
d oc u me nt t his c o nfir mati o n i n t he s o urce d oc u m e ntati o n.  
 If scree ni n g is i nterr u pte d f or m ore t ha n 3 0 da ys fr o m scree ni n g visits t o 
ra n d o mizati o n visit: T he partici pa nt m ust be disc o nti n ue d beca use of scree ni n g 
i nterr u pti o n d ue t o a n e x ce pti o nal circ u msta nce. T his is d oc u me nte d as a scree n 
fail ure i n t he C R F. T he p artici pa nt ca n rec o ns e nt a n d be rescree n e d as a ne w 
partici pa nt. T he scree ni n g pr oce d ures per t he us ual S o A s h o ul d be f oll o we d, starti n g 
at scree ni n g visit t o e ns ure partici pa nt eli gi bilit y b y ra n d o mizati o n visit. 
A dj ust m e nts t o visit wi n d o ws  
W he ne ver p ossi ble a n d s afe t o d o s o, as d eter mi ne d b y t he i n vesti gat or’s discreti o n, partici pa nts 
s h o ul d c o m plete t he us ual So A. T o ma xi mize t he p ossi bilit y t hat t hese visits ca n be c o n d ucte d as 
o n -site visits, t he wi n d o ws f or visits ma y b e a dj uste d, u p o n f urt her g ui da nce fr o m t he s p o ns or. 
T his mi ni mizes missi n g data a n d preser ves t he i nte n de d c o n d u ct of t he st u d y.  
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T his ta ble descri bes t he all o we d a dj ust me nts t o visit wi n d o ws.  
Visit N u m ber  
T oler a nce  
Visit  1 t hr o u g h 3  
≤3 0 da ys fr o m Vi sit 1 t o Visit 3  
Visit 4  t hr o u g h 9  
wit hi n 6  da ys bef ore or after t he i nte n de d d ate per t he S o A  
Visit s 1 0 a n d  1 1  
wit hi n 1 2  da ys bef ore or after t he i nte n d e d date per t he S o A  
Visit 8 0 1  
u p t o 2 8 da ys after t he i nt e n de d date  
 
F or partici pa nts w h ose visits ha ve e xte n de d wi n d o ws, a d diti o nal st u d y i nter ve nti o n ma y n ee d t o 
be pr o vi de d t o a v oi d i nterr u pti o n a n d mai ntai n o v erall i nte grit y of t he st u d y.  
D oc u me nt ati o n  
C h a n ges t o st u dy c o n d uct will be d oc u m e nte d  
Sites will i de ntif y a n d d o c u me nt t he details of h o w partici pa nts, visit t y pes, a n d c o n d ucte d 
acti vities were affecte d b y e x ce pti o nal circ u msta n ces. Dis pe nsi n g/s hi p me nt rec or ds of st u d y 
i nter ve nti o n a n d rel e va nt c o m m u nicati o ns, i ncl u di n g del e gati o n, s h o ul d be file d wit h site st u d y 
rec or ds. 
S o urce d oc u m e nts at alter n ate l oc ati o ns  
S o urce d oc u me nts ge n erate d at a l ocati o n ot her t h a n t he st u d y site s h o ul d b e part of t he 
i n vesti gat or’s s o urce d o c u me ntati o n a n d s h o ul d be tra nsferre d t o t he site i n a sec ure a n d ti mel y 
ma n ner.  
 
 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
1 2 1  
1 0. 1 2.  
A p pe n di x 1 2 : A b bre vi ati o ns a n d Defi niti o ns   
T er m  
D efi niti o n  
a b u s e  
Use of a st u d y i nter ve nti o n f or recreati o nal p ur p oses or t o mai ntai n a n a d dicti o n or 
de pe n de nce  
A D A -E A S D  
T he  A merica n Dia betes Ass ociati o n a n d t he E ur o pea n Ass ociati o n f or t he St u d y of 
Dia betes  
A E  
a d verse e ve nt  
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 P erf 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 si n gle -bli n d st u d y is o ne i n w hic h t he i n vesti gat or a n d/ or t he i n vesti gat or’s staff are 
a ware of t he treat me nt b ut t he partici pa nt is n ot, or vice v ersa, or w he n t he s p o ns or is 
a ware of t he treat me nt b ut t he i n vesti gat or a n d/t he i n vesti gat or’s staff a n d t he 
partici pa nt are n ot.  
A d o u ble -bli n d st u d y is o ne i n w hic h neit her t he partici pa 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 val uati o n of t he s u bj ects 
are a ware of t he treat me nt recei ve d.  
B MI  
b o d y mass i n de x  
B P  
bl o o d press ure  
C E C  
cli nical e n d p oi nt c o m mittee  
CI  
c o nfi de nce i nter val  
C K  
creati ne ki nase  
C K D -E PI  
C hr o nic Ki d ne y Disease -E pi d e mi ol o g y  
c o m pl ai nt  
A c o m plai nt is a n y writte n, el ectr 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 N S O R T  
C o ns oli date d Sta n dar ds of Re p orti n g Trials  
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
1 2 2  
T er m  
D efi niti o n  
C R F  
case re p ort f or m; a pri nte d, o ptical, or electr o nic d oc u me nt d esi g ne d t o rec or d all of t he 
pr ot oc ol -re q uire d i nf or mati o n t o be re p orte d t o t he s p o ns or f or eac h trial partici pa nt. 
C S R  
cli nical st u d y re p ort  
C T  
c o m p ute d t o m o gra p h y  
C V  
car di o vasc ular  
 
 
D.  Bil  
direct bilir u bi n  
D M C  
data m o nit ori n g c o m mittee. A data m o nit ori n g c o m mittee, or data m o nit ori n g b oar d 
( D M B) is a gr o u p of i n de pe n de nt scie ntists w h o are a p p oi nte d t o m o nit or t he safet y a n d 
scie ntific i nte grit y of a h u ma n researc h i nter ve nti o n, a n d t o ma ke rec o m me n dati o ns t o 
t he s p o ns or re gar di n g t he st o p pi n g of a st u d y f or efficac y, or f or har m , or f or f utilit y. 
T he c o m p ositi o n of t he c o m mittee is de pe n de nt u p o n t he sci e ntific s kills a n d 
k n o wle d ge re q uire d f or m o nit ori n g t he partic ular st u d y.  
D M E  
dia betic mac ular e de ma  
D N A  
de o x yri b o n ucleic aci d  
D P P -4  
d i pe pti d yl pe pti dase-4  
D T S Q c  
Dia betes Treat me nt Satisfacti o n Q uesti o n naire -C ha n ge Versi o n  
D T S Q s  
Dia betes Treat me nt Satisfacti o n Q uesti o n naire -Stat us Versi o n  
E C G  
electr ocar di o gra m 
e C O A  
electr o nic cli nical o utc o me assess me nt  
E D  
earl y disc o nti n uati o n  
E D C  
electr o nic data ca pt ure  
e G F R  
esti mate d gl o mer ular filtrati o n rate  
e nr oll  
T he act of assi g ni n g a partici p a nt t o a treat me nt. P artici pa 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 nt er  
P artici pa nts e ntere d i nt o a st u d y are t h ose w h o si g n t he i nf or me d c o nse nt f or m directl y 
or t hr o u g h t heir le gall y acce pta ble re prese ntati ves.  
E U  
E ur o pea n U ni o n  
G C P  
g o o d cli nical practice  
G D P R  
E U Ge neral Data Pr otecti o n Re g ulati o n  
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
1 2 3  
T er m  
D efi niti o n  
G G T  
ga m ma -gl uta m yltra nsferase  
GI  
gastr oi ntesti nal  
G L P -1 R A  
Gl uca g o n -Li ke P e pti de -1 rece pt or ag o nist  
H b A 1 c  
he m o gl o bi n A 1c  
H B c A b  
he patitis B c ore a nti b o d y  
H B V  
he patitis B vir us  
H C V  
he patitis C vir us  
H R  
heart rate  
I B 
I n vesti gat or’s Br oc h ure 
I C E 
i nterc urre nt e ve nt 
I C F 
i nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n 
I E C 
I n de pe n de nt Et hics C o m mitte e 
I M P 
I n vesti gati o nal Me dici nal Pr o d uct (see als o “i n vesti gati o nal pr o d uct”) 
A me dici nal pr o d uct w hic h is bei n g teste d or use d as a refere nce, i ncl u di n g as a 
place b o, i n a cli nical trial. 
i nf or m e d c o n s e nt 
A pr ocess b y w hic h a partici pa nt v ol u ntaril y c o nfir ms t heir 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 partici pa nt’s de cisi 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 R 
i nter nati o nal n or malize d rati o 
i nt eri m a n al y si s 
A n i nteri m a nal ysis is a n a nal ysis of cli nical st u d y data, se p arate d i nt o treat me nt gr o u ps, 
t hat is c o n d ucte d bef ore t he fi nal re p orti n g data base is creat e d/l oc ke d.  
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. See als o “I M P.”  
I R B 
I nstit uti o nal Re vie w B oar d 
I W-S P  
I m pact of Wei g ht o n Self-P erce pti o n  
I W R S 
i nteracti ve we b-res p o nse s yste m 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
1 2 4  
T er m  
D efi niti o n  
L S  
least s q uares 
m e di c ati o n err or  
Err ors i n t he prescri bi n g, dis p e nsi n g, or a d mi nistrati o n of a st u d y i nter ve nti o n, 
re gar dless of w het her or n ot t he me dicati o n is a d mi nistere d t o t he partici pa nt or t he 
err or lea ds t o a n A E. Me dicati o n err or ge nerall y i n v ol ve a fail ure t o u p h ol d o ne or m ore 
of t he fi ve “ri g hts” of me dicati o n use: t he ri g ht partici pa nt, t he ri g ht dr u g, t he ri g ht 
d ose, ri g ht r o ute, at t he ri g ht ti me.  
In a d diti o n t o t he c ore fi ve ri g hts, t he f oll o wi n g ma y als o re prese nt me dicati o n err ors:  
• d ose o missi o n ass ociate d wit h a n A E or a pr o d uct c o m plai nt 
• dis pe nsi n g or use of e x pire d me dicati o n 
• use of me dicati o n past t he re c o m me n de d i n-use date  
• dis pe nsi ng or use of a n i m pr o perl y st ore d me dicati o n  
• use of a n a d ulterate d d osa ge f or m or a d mi nistrati o n tec h ni q ue i nc o nsiste nt wit h t he 
me dicati o n's la beli n g (f or e xa m ple, S u m mar y of Pr o d uct C haracteristics, I B, l ocal 
la bel, pr ot oc ol), or 
• s hare d use of cartri dges, prefille d pe ns, or b ot h.  
M E N 2  
m ulti ple e n d ocri ne ne o plasias t y pe 2  
mi s u s e  
Use of a st u d y i nter ve nti o n f or self -treat me nt t hat eit her is i nc o nsiste nt wit h t he 
prescri be d d osi n g re gi me n, i n dicati o n, or b ot h, or is o btai ne d wit h o ut a prescri pti o n  
M M R M  
M i xe d M o del f or R e peate d M eas 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 ca ncer  
 
 
p arti ci p a nt  
E q ui vale nt t o C DI S C ter m “s u bj ect”: a n i n di vi d ual w h o partici pates i n a cli nical trial, 
eit her as rec i pie nt of a n i n vesti gati o nal me dici nal pr o d uct or as a c o ntr ol 
P C  
pr o d uct c o m plai nt  
 
 
P K/ P D  
p har mac o ki netics/ p har mac o d y na mics  
P T  
pr ot hr o m bi n ti me  
Q D  
o nce dail y  
R N A  
ri b o n ucleic aci d 
S A E  
seri o us a d verse e ve nt 
S A P  
statistical a nal ysis pla n  
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI
C CI
C CI
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
1 2 5  
T er m  
D efi niti o n  
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 F -3 6 v 2 , a c ut e 
S h ort F or m -3 6 versi o n 2 Healt h S ur ve y ac ute for m  
S M B G  
self-m o nit ori n g of bl o o d gl uc ose  
S o A  
Sc he d ule of Acti vities  
S U S A R  
S us pecte d u ne x pecte d seri o us a d verse reacti o ns  
Refers t o a n a d verse e ve nt t hat occ urs i n a cli nical trial parti ci pa nt, w hic h is assesse d b y 
t he s p o ns or a n d or st u d y i n vesti gat or as bei n g u ne x pecte d, seri o us a n d as ha vi n g a 
reas o na ble p ossi bilit y of a ca usal relati o ns hi p wit h t he st u d y i nter ve nti o n. 
T B L  
t otal bilir u bi n le vel 
T 1 D  
t y pe 1 dia betes 
T 2 D  
ty pe 2 dia betes  
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 o cc 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  
 
 
W N O C B P  
w o me n n ot of c hil d beari n g p ote ntial  
W O C B P  
w o me n of c hil d beari n g p ote ntial  
 
 
 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
1 2 6  
1 0. 1 3.  
A p pe n di x 1 3: Pr ot oc ol A me n d me nt Hist or y   
T he Pr ot oc ol A me n d me nt S u m mar y of C ha n ges T a ble f or t he c urre nt a me n d me nt is l ocate d 
directl y b ef ore t he Ta bl e of C o nte nts ( T O C). 
A me n d me nt [ a]: ([2 2 -M a y -2 0 2 3 ]) 
O ver all R ati o n ale f or t he A me n d me nt:  
T he pri mar y rati o nale f or t his a me n d me nt is t o u p date t he h e p atic m o nit ori n g c o nt e nt, pr o vi de 
clarificati o n o n f u n d us p h ot o gra p h y assess me nts, a n d re m o ve B C R P -relate d c o nte nt. C ha n ges 
are i ncl u de d i n t his ta ble.  
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  
1. 1. S y n o psis   
E dite d t he first se nte nce i n Pri mar y esti ma n ds 
s u bsecti o n, a d di n g t e xt f or t he treat me nt 
re gi me n esti ma n d a n d efficac y esti ma n d 
Clarificati o n  
1. 1. S y n o psis   
Mi n or ref or m atti n g t o d ose escal ati o n fi g ure   
Clarificati o n  
1. 2. Sc he ma   
Mi n or ref or m atti n g  
Clarificati o n  
1. 3. Sc he d ule of 
Acti vities ( S o A)  
A d de d “ patie nt -re p orte d o utc o mes” t o sec o n d 
b ullet of Fasti n g visits s u bsecti o n a b o ve t he 
S o A ta ble   
Clarificati o n  
1. 3. Sc he d ule of 
Acti vities ( S o A)  
Re m o ve d fasti n g visit at Visit  8 0 1  
N ot nee de d  
1. 3. Sc he d ule of 
Acti vities ( S o A)  
A d de d “(tri plicate)” t o left c ol u m n of vital 
si g ns li ne ite m 
Clarificati o n  
1. 3. Sc he d ule of 
Acti vities ( S o A)  
U p date d f u n d us p h ot o gra p h y li ne ite m b y 
m o vi n g f o ot n ote b t o Visit 9 ( Wee k 2 4) 
c ol u m n a n d ad di n g ne w f o ot n ote c t o a d dress 
f oll o w-u p at Visit 1 1 ( Wee k 4 0 ) 
Clarificati o n  
1. 3. Sc he d ule of 
Acti vities ( S o A)  
Re m o ve d gl uc ose sa m ple at Visit 8 0 1   
N ot nee de d  
1. 3. Sc he d ule of 
Acti vities ( S o A)  
A d de d uri ne pre g na n c y at Visit  1 1 ( Wee k 4 0) 
a n d E D visit  
A d diti o nal safet y 
m o nit ori n g  
1. 3. Sc he d ule of 
Acti vities ( S o A)  
A d de d e G F R at Visit 3 ( Wee k  0)  
A d diti o nal safet y 
m o nit ori n g  
3.  O bjecti ves, 
E n d p oi nts, a n d 
Esti ma n ds  
E dite d t he first se nte nce i n Pri mar y esti ma n ds 
s u bsecti o n, a d di n g t e xt f or t he treat me nt 
re gi me n esti ma n d a n d efficac y esti ma n d 
Clarificati o n  
5. 2. E x cl usi o n 
Criteria  
E x cl usi o n Criteri o n # 1 3: A d de d te xt re gar di n g 
f urt her o p ht hal m ol o gic assess me nt will f oll o w 
l ocal sta n dar ds of care 
Clarificati o n  
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
1 2 7  
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  
5. 2. E x cl usi o n 
Criteria  
5. 3. 1. Dia betes 
E d ucati o n  
I n t he F o ur-p oi nt S M B G a n d Se ve n -p oi nt 
S M B G s u bsecti o ns, s u bstit ute d “ 3” f or “eac h ” 
i n t he b ullete d te xt f or mai n meals 
Clarificati o n  
6. 1. St u d y 
i nter ve nti o n(s) 
A d mi nistere d  
Mi n or ref or m atti n g t o d ose escal ati o n fi g u re  
Clarificati o n  
6. 9. 1. Pr o hi bite d or 
Restricte d Use 
Me dicati o ns  
6. 9. 3.  Resc ue 
T hera p y f or Se vere 
Persiste nt 
H y p er gl yce mia  
E dite d fi nal b ullet  i n s u bsecti o n “ Criteria f or 
se vere p ersiste nt h y per gl yce mia” b y a d di n g “at 
or” bef ore “ Wee k 2 4” a n d deleti n g t he 
re mai n der of t he se nte nce after “ Wee k 2 4 ”  
F or safet y  
7. 1. 2.  He patic 
Criteria f or St u d y 
I nter ve nti o n 
I nterr u pti o n or 
Disc o nti n uati o n  
Re m o ve d all c o nte nt a n d re place d wit h a 
se nte nce cr oss refere nci n g t o Secti o n 8. 6. 2. 3 
U p date d base d o n 
latest g ui da nce 
8. 2. 6.  He patic Safet y 
M o nit ori n g, 
E val uati o n, a n d 
Criteria f or St u d y 
I nter ve nti o n 
I nterr u pti o n or 
Disc o nti n uati o n  
U p date d all te xt i n t his secti o n  
U p date d base d o n 
latest g ui da nce 
8. 2. 6. 1. Cl ose 
He patic M o nit ori n g  
U p date d all te xt i n t his secti o n  
U p date d base d o n 
latest g ui da nce 
8. 2. 6. 2. 
C o m pre he nsi ve 
He patic E val u ati o n  
U p date d all te xt i n t his secti o n  
U p date d base d o n 
latest g ui da nce 
8. 2. 6. 3. St u d y 
I nter ve nti o n 
I nterr u pti o n or 
Disc o nti n uati o n  
U p date d all te xt i n t his secti o n  
U p date d base d o n 
latest g ui da nce 
8. 2. 8. Dia betic 
Reti n o pat h y 
U p date d f u n d us p h ot o gra p h y la n g u a ge i n t he 
sec o n d para gra p h, ad di n g te xt t o a d dress t he 
Clarificati o n  
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
1 2 8  
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  
Scree ni n g a n d 
E val uati o n  
visit t olera nce at Wee k 2 4 a n d t he f oll o w -u p 
f u n d us p h ot o gra p h y at Wee k 4 0  
9. 1.  Statistical 
H y p ot hes es  
Delete d fi nal s e nte nce i n secti o n  
N ot nee de d  
9. 2. A nal ys es Sets   
E dite d descri pti o n of “ F ull partici pa nts” 
partici pa nt a nal ysis set. It  is n o w, “All 
ra n d o mize d partici pa nts w h o meet t he 
eli gi bilit y criteria ” 
Clarificati o n  
9. 3. 1. Ge neral 
C o nsi derati o ns  
I n “ Ge n eral d escri pti o n of a nal yses” 
s u bsecti o n: 
- M o ve d t he first se nte nce u p t o “ Ge neral 
C o nsi derati o ns” secti o n a n d re place d “f or 
s u peri orit y” wit h “ of treat me nt effects” 
- A d de d fi nal se nte n ce i n t he first para gra p h, 
n oti n g t he use of a nal ysis of varia n ce wit h 
treat me nt gr o u p as t he fi x e d effect t o 
a nal yze b aseli ne meas ures  
- A d de d t he first se nte n ce i n fi nal para gra p h 
re gar di n g mi ni mizi n g missi n g data 
Clarificati o n  
9. 3. 2. 1.  Partici pa nt 
Dis p ositi o n  
E dite d sec o n d t o last se nt e nce i n sec o n d 
para gra p h.  
Clarificati o n  
9. 3. 3. Pri mar y 
E n d p oi nt a n d 
Esti ma n d A nal ysis  
Re m o ve d se nte nce i n t he f o urt h para gra p h 
re gar di n g mi ni mizi n g missi n g data 
Cla rificati o n 
9. 3. 4. Sec o n dar y 
E n d p oi nt(s) a n d 
Esti ma n d(s) A nal yses  
Re place t he fi nal se nte nce of t he sec o n d 
para gra p h, s pecif yi n g us e of t he “ gra p hical 
a p pr oac h ”  
Clarificati o n  
9. 3. 7. Safet y 
A nal ys es  
E dite d t he first se nte nce i n secti o n t o i ncl u de 
“ u nless ot her wise s p ecifi e d”  
Clarificati o n  
1 0. 8. 1. 2.  Wei g ht L oss 
Me dicati o ns  
A d de d t he missi n g visit n u m ber i n t he first 
se nte nce: “ … or bet w ee n Visit 1 a n d Visit 3 ” 
C orrecti o n  
Clarificati o n  
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T
C CI

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
1 2 9  
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  
1 0. 1 0.  A p pe n di x 1 0: 
C o u ntr y -s pecific 
Re q uire me nts  
Delete d “(a)” fr o m e n d of o nl y se nt e nce i n t his 
secti o n 
C orrecti o n  
1 0. 1 1. A p pe n di x 1 1: 
Pr o visi o ns f or 
C ha n ges i n St u d y 
C o n d uct D uri n g 
E x ce pti o nal 
Circ u msta nces  
I n t he “C ha n ges i n st u d y c o n d uct d uri n g 
e x ce pti o nal circ u msta nces ” secti o n, a d de d 
“re vie w” t o state “re vie w S M B G val ues”  
Clarificati o n  
T hr o u g h o ut   
Mi n or gra m matical a n d f or matti n g e dits   
Mi n or, t heref ore, n ot 
liste d 
 
 
 
A p pr o ve d o n 0 6 Se p 2 0 2 3 G M T

C O N FI D E N TI A L  
J 2 A-M C -G Z G T (b ) 
1 3 0  
1 1.   
Refere nces   
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Si g nat ure Pa ge f or V V- C LI N- 1 2 7 5 6 0 v 1. 0
Si g nat ure Pa ge f or V V- C LI N- 1 2 7 5 6 0 v 1. 0
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0 6- Se p- 2 0 2 3 0 1: 0 0: 5 0 G M T + 0 0 0 0
A p pr o val
0 6- Se p- 2 0 2 3 0 2: 2 6: 4 8 G M T + 0 0 0 0
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P P D
P P D