Semaglutide Cardiovascular Outcomes Trial in Patients With Type 2 Diabetes
Phase: PHASE3
Conditions: Diabetes Mellitus, Type 2
Sponsor: Novo Nordisk A/S

C o ver P a ge  f or Pr ot oc ol  
S p o ns or na me:  
N o v o N or dis k A/ S  
N C T n u m ber  
N C T 0 3 9 1 4 3 2 6  
S p o ns or t rial I D: 
E X 9 9 2 4 -4 4 7 3  
Official title of st u d y:  
Se ma gl uti de car di o vasc ular o utc o mes trial i n patie nts wit h 
t y pe 2 dia betes ( S O U L)
D oc u me nt date: 
2 6  Ja n uar y 2 0 2 1

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
1  of 8 9  
Pr ot oc ol
U p date d pr ot oc ol i ncl u di n g:  
Pr ot oc ol versi o n 1. 0 , date d 1 7-J a n-2 0 1 9  
Pr ot oc ol versi o n 2. 0, i ncl u di n g p r ot oc ol am e n d me nt n o. 1, Ar ge nti na, Ca na da, C ol o m bia, 
Me xic o, S pai n, U nite d Ki n g d o m a n d U nite d States, date d 1 2 -J u n-2 0 1 9  
Pr ot oc ol versi o n 3. 0, i ncl u di n g pr ot oc ol a m e n d me nt n o. 2, date d 1 7 -N o v -2 0 2 0  
Pr ot oc ol versi o n 4. 0, i ncl u di n g pr ot oc ol a m e n d me nt n o. 3, C hi na, dat e d 2 6 -J a n-2 0 2 1  
Pr ot oc ol titl e: Se ma gl uti de car di o v asc ular o ut c o mes trial i n patie nts wit h t y pe 2 dia betes 
( S O U L) 
S u bst a nce: Oral s e ma gl uti de 
U ni vers al Tri al N u m ber: U 1 1 1 1 -1 2 1 8 -5 3 6 8  
E U dr a C T N u m ber: 2 0 1 8 -0 0 3 1 4 1 -4 2 
Tri al p h ase:  3 b  
I n t he f oll o wi n g, N o v o N or dis k A/ S a n d its affiliates will be state d as “ N o v o N or dis k”.  
T his c o nfi de ntial d oc u me nt is t he pr o pert y of N o v o N or dis k. N o u n p u blis he d i nf or mati o n c o ntai ne d herei n ma y be 
discl ose d wit h o ut pri or writte n a p pr o val fr o m N o v o N or dis k. Access t o t his d oc u me nt m ust be restricte d t o rele va nt 
parties.  
C O N FI D E N TI A L
T his c o nfi de ntial d oc u me nt is t he pr o pert y of N o v o N or dis k. N o u n p u blis he d i nf or mati o n c o ntai ne d herei n ma y be 
discl ose d w it h o ut pri or writte n a p pr o val fr o m N o v o N or dis k. Access t o t his d oc u me nt m ust be restricte d t o rele va nt 
parties.

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
2  of 8 9  
 
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  
Date  
Versi o n  
U p date d pr ot oc ol i ncl u di n g a me n d me nt 3  
( C hi na) 
2 6  J a n uar y 2 0 2 1 
4 . 0 
U p date d pr ot oc ol i ncl u di n g a me n d me nt 2  
1 7  N o ve m ber 2 0 2 0  
3. 0  
U p date d pr ot oc ol i ncl u di n g a me n d me nt 1 
( Ar ge nti na, Ca na d a, C ol o m bia, Me xic o, 
S pai n, U nite d Ki n g d o m a n d U nite d States)  
1 2 J u ne 2 0 1 9  
2. 0  
Ori gi nal pr ot oc ol  
1 7 J a n uar y 2 0 1 9  
1. 0  
Pr ot oc ol a me n d me nt n o. 3 ( pr ot oc ol versi o n 4. 0 date d 2 6  J a n uar y 2 0 2 1)  
T his a me n d me nt is c o nsi dere d t o be s u bsta ntial base d o n t he criteri a set f ort h i n Article 1 0(a) of 
Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n 1. 
F or C hi na , co -partici pati o n i n C O VI D -1 9  trials is n ot all o we d d ue t o l ocal r e q uire me nts, a n d n ot 
all o wi n g c o -partici p ati o n i n C O VI D -1 9 trials d oes n ot affect patie nt s afet y.  
Secti o n # a n d n a me  
Descri pti o n of c h a n ge  
R ati o n ale  
A p pe n di x 8                            
C o u ntr y -s pecific re q uire me nts f or 
C hi na, a me n d me nt 3  
Secti o n 6. 2, e xcl usi o n criteria  # 4 : 
* Si m ulta ne o us partici pati o n i n a trial wit h 
t he pri mar y o bj ecti ve of e val uati n g a n 
a p pr o ve d or n o n -a p pr o ve d i n vesti gati o nal 
me dici nal pr o d uct f or pre ve nti o n or 
treat me nt of C O VI D-1 9 disease or 
p osti nfecti o us c o n diti o ns is all o we d if t he 
last d ose of t he i n vesti gati o nal me dici nal 
pr o d uct has bee n recei ve d m or e t ha n 3 0 da ys 
b ef ore scree ni n g  is n ot a p plica ble f or C hi na. 
C o -partici pati o n i n C O VI D -1 9  
trials is n ot all o we d i n C hi na 
d ue t o l ocal re q uire me nts  
A p pe n di x 8                            
C o u ntr y -s pecific re q uire me nts f or 
C hi na, a me n d me nt 3  
Secti o n 8. 1, disc o nti n uati o n/ wit h dra wal 
criteria: * Si m ulta ne o us partici pati o n i n a 
trial wit h t he pri mar y o bj ecti ve of e val uati n g 
a n a p pr o ve d or n o n -a p pr o ve d i n vesti gati o nal 
me dici nal pr o d uct f or pre ve nti o n or 
treat me nt of C O VI D-1 9 disease or 
p osti nfecti o us c o n diti o ns is all o we d at t he 
i nvesti gat or discreti o n wit h o ut disc o nti n ui n g 
trial pr o d uct is n ot a p plica ble f or C hi na. 
C o -partici pati o n i n C O VI D -1 9 
trials is n ot all o we d i n C hi na 
d ue t o l ocal re q uire me nts  
 
 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
3  of 8 9  
Ta ble of C o nte nts  
P a ge  
P r ot oc ol a me n d me nt s u m m ar y of c h a n ges t a ble  ........................................................................................... 2  
T a ble of C o nte nts .............................................................................................................................................. 3  
1  
S y n o psis  ...................................................................................................................................................... 6  
2  
Fl o wc h art  ................................................................................................................................................... 9  
3  
I ntr o d ucti o n ............................................................................................................................................. 1 2  
3. 1  
Trial rati o nale  ............................................................................................................................... 1 2  
3. 2  
Bac k gr o u n d  .................................................................................................................................. 1 2  
3. 3  
Be nefit -ris k assess me nt ................................................................................................................ 1 3  
3. 3. 1  
Ris ks  .......................................................................................................................... 1 3  
3. 3. 2  
Be nefits  ...................................................................................................................... 1 5  
3. 3. 3  
Ris k a n d be n efit c o ncl usi o n ....................................................................................... 1 5  
4  
O bjecti ves a n d e n d p oi nts  ........................................................................................................................ 1 6  
4. 1  
Pri mar y, sec o n dar y a n d e x pl orat or y o bj ecti ve(s)  ........................................................................ 1 6  
4. 2  
Pri mar y, sec o n dar y a n d e x pl orat or y e n d p oi nt(s)  ......................................................................... 1 7  
4. 2. 1  
Pri mar y e n d p oi nt  ........................................................................................................ 1 7  
4. 2. 2  
Sec o n dar y e n d p oi nts  .................................................................................................. 1 7  
4. 2. 2. 1  
C o nfir mat or y sec o n dar y e n d p oi nts  ..................................................... 1 7  
4. 2. 2. 2  
S u p p orti ve sec o n dar y e n d p oi nts  .......................................................... 1 8  
4. 2. 2. 3  
E x pl orat or y e n d p oi nts  ......................................................................... 1 9  
5  
Tri al desi g n  .............................................................................................................................................. 2 0  
5. 1  
O verall desi g n  .............................................................................................................................. 2 0  
5. 2  
Patie nt a n d trial c o m pleti o n  ......................................................................................................... 2 1  
5. 3  
E n d of trial defi niti o n  ................................................................................................................... 2 2  
5. 4  
Scie ntific rati o nale f or trial desi g n  ............................................................................................... 2 2  
6  
Tri al p o p ul ati o n  ....................................................................................................................................... 2 2  
6. 1  
I ncl usi o n criteria .......................................................................................................................... 2 3  
6. 2  
E xcl usi o n criteria  ......................................................................................................................... 2 4  
6. 3  
J ustificati o n f or d ose .................................................................................................................... 2 4  
6. 4  
Li fest yle restricti o ns .................................................................................................................... 2 5  
6. 5  
Scree n fail ures  .............................................................................................................................. 2 5  
6. 6  
Assess me nt  of eli gi bilit y  .............................................................................................................. 2 5  
7  
Tre at me nts  ............................................................................................................................................... 2 5  
7. 1  
Treat me nts a d mi nistere d  .............................................................................................................. 2 5  
7. 2  
D ose m o dificati o n  ........................................................................................................................ 2 6  
7. 2. 1  
D osi n g i nstr ucti o ns  .................................................................................................... 2 7  
7. 2. 2  
Misse d d oses  .............................................................................................................. 2 7  
7. 3  
Met h o d of treat me nt assi g n me nt .................................................................................................. 2 8  
7. 4  
Bli n di n g  ....................................................................................................................................... 2 8  
7. 5  
Pre parati o n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y  ............................................................................. 2 8  
7. 5. 1  
S hi p me nt of trial pr o d uct t o patie nt’s h o me ............................................................... 2 9  
7. 6  
Treat me nt c o m plia nce  .................................................................................................................. 3 0  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4  of 8 9  
 
7. 7  
C o nc o mita nt me dicati o n  .............................................................................................................. 3 0  
7. 8  
Treat me nt after t he e n d of t he trial  .............................................................................................. 3 1  
8  
Disc o nti n u ati o n/ Wit h dr a w al criteri a  .................................................................................................... 3 2  
8. 1  
Disc o nti n uati o n of trial treat me nt  ................................................................................................ 3 2  
8. 1. 1  
T e m p orar y disc o nti n uati o n of trial treat me nt  ............................................................ 3 3  
8. 2  
Wit h dra wal fr o m t he trial ............................................................................................................. 3 3  
8. 2. 1  
Re place me nt of patie nts  ............................................................................................. 3 4  
8. 3  
L ost t o f oll o w -u p  ......................................................................................................................... 3 4  
9  
Tri al assess me nts a n d pr oce d ures  ......................................................................................................... 3 4  
9. 1  
Efficac y assess me nts  .................................................................................................................... 3 5  
9. 1. 1  
H b A 1c p oi nt of care  .................................................................................................... 3 5  
9. 1. 2  
Self -meas ure d plas ma gl uc ose  ................................................................................... 3 5  
9. 1. 3  
Cli nical efficac y la b orat or y assess me nts  ................................................................... 3 6  
9. 1. 4  
C o g niti ve testi n g, patie nt s ur ve ys a n d visits t o e mer ge nc y r o o m/ ur ge nt care u nit .... 3 6  
9. 2  
A d verse e ve nts  ............................................................................................................................. 3 6  
9. 2. 1  
Ti me peri o d a n d fre q ue nc y f or c ollecti n g A E a n d S A E i nf or mati o n  ........................ 3 8  
9. 2. 1. 1  
E ve nts f or a dj u dicati o n  ........................................................................ 4 0  
9. 2. 2  
Met h o d of detecti n g A Es a n d S A Es  .......................................................................... 4 1  
9. 2. 3  
F oll o w -u p o n A Es a n d S A Es  ..................................................................................... 4 1  
9. 2. 4  
Re g ulat or y re p orti n g re q uire me nts f or S A Es ............................................................. 4 2  
9. 2. 5  
Pre g na ncies a n d ass ociate d a d verse e ve nts  ................................................................ 4 2  
9. 2. 6  
T ec h nical c o m plai nts  ................................................................................................. 4 3  
9. 3  
Treat me nt of o ver d ose  ................................................................................................................. 4 3  
9. 4  
Safet y assess me nts  ....................................................................................................................... 4 3  
9. 4. 1  
P h ysical e xa mi nati o ns  ................................................................................................ 4 4  
9. 4. 2  
Vital si g ns  .................................................................................................................. 4 5  
9. 4. 3  
Cli nical la b orat or y assess me nts  ................................................................................. 4 5  
9. 4. 4  
E ye e xa mi nati o n  ........................................................................................................ 4 5  
9. 4. 5  
Disa bilit y after a str o ke or TI A e ve nt  ........................................................................ 4 6  
9. 5  
P har mac o ki netics  ......................................................................................................................... 4 6  
9. 6  
P har mac o d y na mics  ...................................................................................................................... 4 6  
9. 7  
Ge netics  ....................................................................................................................................... 4 6  
9. 8  
Bi o mar kers  ................................................................................................................................... 4 6  
1 0  St atistic al c o nsi der ati o ns  ........................................................................................................................ 4 7  
1 0. 1  
Sa m ple size deter mi nati o n  ........................................................................................................... 4 7  
1 0. 2  
Defi niti o n of a nal ysis sets  ............................................................................................................ 4 8  
1 0. 3  
Statistical a nal yses  ....................................................................................................................... 4 8  
1 0. 3. 1  
Pri mar y e n d p oi nt  ........................................................................................................ 4 9  
1 0. 3. 2  
Sec o n dar y e n d p oi nts  .................................................................................................. 5 0  
1 0. 3. 2. 1  
C o nfir mat or y sec o n dar y e n d p oi nts  ..................................................... 5 0  
1 0. 3. 2. 2  
S u p p orti ve sec o n dar y e n d p oi nts  .......................................................... 5 1  
1 0. 3. 3  
E x pl orat or y e n d p oi nts  ................................................................................................ 5 2  
1 0. 3. 4  
I nteri m testi n g f or efficac y......................................................................................... 5 2  
1 0. 3. 5  
Se q ue ntial safet y a nal ysis a n d safet y m o nit ori n g  ...................................................... 5 2  
1 0. 4  
P har mac o ki netic a n d/ or p har mac o d y na mic m o delli n g  ................................................................ 5 2  
1 1  Ref ere nces  ................................................................................................................................................ 5 3  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5  of 8 9  
 
1 2  A p pe n dices  ............................................................................................................................................... 5 5  
A p pe n di x 1  
A b bre vi ati o ns a n d Tr a de m ar ks .............................................................................. 5 6  
A p pe n di x 2  
Cli nic al l a b or at or y tests  .......................................................................................... 5 9  
A p pe n di x 3  
Tri al g o ver n a nce c o nsi der ati o ns  ............................................................................. 6 1  
A p pe n di x 4  
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 o n, 
f oll o w-u p, a n d re p orti n g  ......................................................................................... 7 1  
A p pe n di x 5  
C o ntr ace pti ve g ui d a nce a n d c ollecti o n of pre g n a nc y i nf or m ati o n  ...................... 7 6  
A p pe n di x 6  
Tec h nic al c o m pl ai nts: Defi niti o n a n d pr oce d ures f or rec or di n g, e v al u ati o n, 
f oll o w-u p a n d re p orti n g  .......................................................................................... 7 9  
A p pe n di x 7  
Rete nti o n of h u m a n bi os a m ples f or bi o m ar kers a n d ge netic a n al yses  ............... 8 0  
A p pe n di x 8  
C o u ntr y -s pecific re q uire me nts ............................................................................... 8 1  
A p pe n di x 9  
P r ot oc ol a me n d me nt hist or y  ................................................................................... 8 6  
 
Attac h me nt I Gl o bal list of ke y staff a n d rel e va nt de part me nts a n d s u p pliers  
Attac h me nt II C o u ntr y list of ke y st aff a n d rele va nt de part me nts  
 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6  of 8 9  
 
1  
S y n o psis  
R ati o n ale  
T o e val uate t he h y p ot h esis t hat oral se ma gl uti de l o wers t he ris k of car di o v asc ular e ve nts i n patie nts 
wit h t y pe 2 dia b etes at hi g h ris k f or car di o vasc ular disease.  
O bjecti ves a n d e n d p oi nts  
T he pri m ary o bjective  
T o de m o nstrate t hat or al se ma gl uti de l o w ers t he ris k of maj or a d verse car di o vasc ular e ve nts 
c o m pare d t o place b o, b ot h a d de d t o sta n dar d of care i n patie nts wit h t y p e 2 dia betes a n d at hi g h ris k 
of car di o v asc ular e ve nts.  
T he key sec o n d ary o bjectives  
T o c o m pare t h e effects of oral se ma gl uti de vers us place b o, b ot h a d de d t o sta n dar d of care i n 
patie nts wit h t y pe 2 dia b etes a n d at hi g h ris k of car di o vasc ular e ve nts wit h re gar ds t o:  
•  C hr o nic ki d ne y dise ase  
•  Car di o vasc ular e ve nts  
•  Peri p heral arter y dise ase  
•  Gl ycae mic c o ntr ol a n d b o d y w ei g ht  
•  Safet y  
T he pri m ar y e n d p oi nt  
T he pri mar y e n d p oi nt is ti me fr o m ra n d o misati o n t o first occ urre nce of a m aj or a d verse 
car di o vas c ular e v e nt, a c o m p osite e n d p oi nt c o nsisti n g of: car di o vasc ular deat h, n o n -fatal 
m y ocar dial i nfarcti o n or n o n -fatal str o ke. 
Ke y c o nfir m at or y se c o n d ar y e n d p oi nts  
Ti me fr o m ra n d o misati o n t o first occ urre nce of:  
•  A c o m p osite c hr o nic ki d ne y dise ase e n d p oi nt c o nsisti n g of: car di o v asc ular deat h, re n al 
deat h, o nset of persiste nt ≥ 5 0 % re d ucti o n i n esti mate d gl o mer ular filtrati o n rate ( C K D -E PI) 
c o m pare d w it h bas eli ne, o nset of persiste nt e G F R ( C K D-E PI) < 1 5 m L/ mi n/ 1. 7 3 m 2 or 
i nitiati o n of c hr o nic re nal re place me nt t hera p y ( dial ysis or ki d ne y tra ns pla nt ati o n) 
•  car di o vas c ular deat h  
•  Maj or a d vers e li m b e ve nts, a c o m p osite e n d p oi nt c o nsisti n g of: ac ut e li m b isc h e mia 
h os pitalisati o n or c hr o nic li m b isc he mia h os pitalisati o n  
Esti m a n d  
T he esti ma n d f or all o bjecti ves is t he i nte nti o n -t o-treat esti ma n d e val u ati n g t he effect of t he 
ra n d o mise d treat me nt i nt er ve nti o n irres p ecti ve of a d here n ce t o treat me nt a n d c ha n ges t o 
bac k gr o u n d me dicati o n.  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
7  of 8 9  
 
O ver all desi g n  
T his is a ra n d o mise d, d o u ble -bli n d, parallel -gr o u p, place b o -c o ntr olle d trial c o m pari n g oral 
se ma gl uti de v ers us place b o b ot h a d mi nistere d o nce dail y a n d a d d e d t o sta n dar d of care i n p atie nts 
wit h t y pe 2 dia b etes at hi g h ris k of car di o v asc ular e ve nts. Patie nts will be ra n d o mise d 1: 1 t o recei v e 
eit her oral se m a gl uti de or place b o.  
All i ncl usi o n criteria are base d o n t he patie nts’ me dical rec or ds, e x ce pt f or i ncl usi o n criteri o n f or 
H b A 1 c (l ocal la b orat or y or p oi nt-of -care d e vice). T he ke y i ncl usi o n criteri a are:  
•  Male or fe m ale, a ge ≥5 0 years at t he ti me of si g ni n g i nf or m e d c o nse nt  
•  Dia g n os e d wit h t y p e 2 dia betes mellit us  
•  H b A 1c 6. 5 % - 1 0. 0 % ( 4 7 - 8 6 m m ol/ m ol) ( b ot h i ncl usi ve) a 
•  At least o ne of t he b el o w c o n diti o ns (a -d):  
a)  C or o nar y heart disease d efi ne d as at least o ne of t he f oll o wi n g:  
i. 
Pri or m y ocar dial i nfarcti o n  
ii. 
Pri or c or o nar y re v asc ularisati o n pr oce d ure  
iii. 
≥5 0 % ste n osis i n c or o nar y arter y d o c u me nte d b y car diac cat heterisati o n, 
c o m p uterize d t o m o gra p h y c or o nar y a n gi o gra p h y  
i v. 
C or o nar y heart disease wit h isc hae mia d oc u me nte d b y stress test wit h a n y 
i ma gi n g m o dalit y 
b)  Cere br o vas c ular dise ase defi ne d as at least o ne of t he f oll o wi n g:  
i. 
Pri or str o ke  
ii. 
Pri or  car oti d art er y re vas c ularisati o n pr oce d ure  
iii. 
≥5 0 % ste n osis i n car oti d arter y d o c u me nte d b y X -ra y a n gi o gra p h y, ma g netic 
res o na nce a n gi o gra p h y, c o m p uterize d t o m o gra p h y a n gi o gra p h y or D o p pl er 
ultras o u n d  
c)  S y m pt o matic p eri p heral arter y dise ase ( P A D) defi ne d as at least o n e of t he f oll o wi n g:  
i. 
I nter mitte nt cla u dicati o n wit h a n A n kle-brac hial i n de x ( A BI) < 0. 8 5 at r est  
ii. 
I nter mitte nt cla u dicati o n wit h a ≥5 0 % ste n osis i n peri p heral arter y (e x cl u di n g 
car oti d) d oc u m e nte d b y X -ra y a n gi o gra p h y, ma g netic res o na n ce a n gi o gra p h y, 
c o m p uterize d t o m o gra p h y a n gi o gra p h y or D o p pl er ultras o u n d  
iii. 
Pri or peri p heral arter y ( e x cl u di n g car oti d) re vasc ularizati o n pr oce d ure  
i v. 
L o w er e xtre mit y a m p utati o n at or a b o ve a n kl e d ue t o at her oscler otic dis eas e 
(e x cl u di n g e. g. tr a u ma or oste o m yelitis) 
d)  C hr o nic ki d ne y dise ase d efi ne d as:  
i. e G F R < 6 0 m L/ mi n/ 1. 7 3 m 2 b 
a  Lat est a vaila ble a n d n o m ore t ha n 3 0 da ys ol d l o cal la b orat or y assess me nt base d o n me dical 
rec or ds or p oi nt of care meas ure me nt. 
b  Base d o n m e dical r ec or ds usi n g latest a vaila bl e a n d n o m ore t ha n 6 m o nt hs ol d assess me nt.  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
8  of 8 9  
 
T he ke y e x cl usi o n criteri a are:  
•  A n y of t he f oll o wi n g: m y ocar dial i nfarcti o n, str o ke, h os pitalisati o n f or u nsta ble a n gi na 
pect oris or tra nsie nt isc h ae mic attac k wit hi n t he past 6 0 da ys pri or t o t he d a y of scree ni n g  
•  Pla n ne d c or o nar y, car oti d or peri p heral art er y re v asc ularisati o n k n o w n o n t he da y of 
scree ni n g 
•  H eart fail ure prese ntl y cl assifie d as bei n g i n Ne w Y or k Heart Ass ociati o n Class I V  
•  Treat me nt wit h a n y gl uc a g o n -li ke pe pti de-1 rece pt or a g o nist wit hi n 3 0 da ys bef ore 
scree ni n g 
N u m ber of p atie nts  
I n t his trial, 9, 6 4 2 patie nts are pla n n e d t o be ra n d o ml y assi g ne d t o trial pr o d uct.  
Tre at me nt gr o u ps a n d d ur ati o n  
T he trial is e ve nt dri ve n; t heref ore, e n d of trial will be sc he d ule d acc or di n g t o pr ojecte d trial 
cl os ure. Trial d urati o n is e x pecte d t o be 6 1 m o nt hs or m ore f oll o wi n g ra n d o misati o n of t he first 
patie nt. T rial d urati o n f or eac h s u bject is e x pecte d t o be a p pr o xi matel y 3. 5 t o 5 years. 
Tri al pr o d ucts  
Oral se ma gl uti de 3 m g, 7 m g a n d 1 4 m g ta blets  
Place b o ta blets  
 
C O N FI D E N TI A L

Pr ot o c ol  
Date:  
2 6 Ja n uar y 2 0 2 1  
Stat us:  
Fi n al  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
P a ge:  
9  of 8 9  
2  
Fl o w c h art  
Trial Peri o ds  
Pr ot oc ol 
Secti o n  
Scree ni n g  
Ra n d o misati o n  
First year  
Re mai ni n g peri o d  
E n d of treat me nt  
F oll o w -u p  
Site visit ( V)/ P h o ne c o ntact ( P)  
V 1  
V 2  
V 3  
V 4  
V 5  
V 6  
V 7 a 
V 8  
V 9/ V 1 0/ V 1 1/  
V 1 3/ V 1 4/ V 1 5  
V 1 7/ V 1 8/ V 1 9  
V 2 1/ V 2 2/ V 2 3  
V 1 2  
V 1 6  
V 2 0  
V 2 4  
V -E O T b  
P -F U
Ti mi n g of visit ( wee ks)  
U p t o  
-3 wee ks
0  
4  
8  
1 3  
2 6  
3 9  
5 2  
E ver y  
1 3 wee ks  
Yearl y  
E O T  
V -E O T  
+ 5 wee ks
Visit wi n d o w ( da ys)  
± 3  
± 3  
± 3  
± 7  
± 7  
± 7  
± 7  
± 7  
± 7  
+ 7  
P A TI E N T -R E L A T E D I N F O/ A S S E S S M E N T S  
I nf or me d c o nse nt 
A p pe n di x 
3  
X  
Ha n d o ut I D car d  
X  
I ncl usi o n/e xcl usi o n criteria 
6. 1 ; 6. 2  
X  
T o bacc o use c
X  
X
De m o gra p h y d
X  
Me dical hist or y/c o nc o mita nt 
ill ness 
9. 4  
X  
C o nc o mita nt me dicati o n  
7. 7  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
E ns ure u p date d c o ntact pers o ns list  
9  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Trial pr o d uct d ose  
7. 2  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Trai ni n g i n trial pr o d uct a n d 
d osi n g i nstr ucti o ns  
7. 1  
X  
( X)e
( X)e
( X)e
( X)e
( X)e
( X)e
( X)e
( X)e
Ha n d o ut a n d i nstr uct i n B G meter i 
7. 1  
( X)i
( X)i
( X)i
( X)i
( X)i
( X)i
( X)i
( X)i
( X)i
( X)i
C LI NI C A L A S S E S S M E N T S  
Hei g ht  
9. 4. 1  
X  
B o d y wei g ht  
X  
X  
X  
X  
X f
W aist circ u mfere nce  
X  
P h ysical e xa mi nati o n  
X  
X  
E ye e xa mi nati o n  
9. 4. 4  
X g  
X h
X h  
X f
Vital si g ns  
9. 4. 2  
X  
X  
X  
X  
X f

Pr ot o c ol  
Date:  
2 6 Ja n uar y 2 0 2 1  
Stat us:  
Fi n al  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
P a ge:  
1 0  of 8 9  
Trial Peri o ds  
Pr ot oc ol 
Secti o n  
Scree ni n g  
Ra n d o misati o n  
First year  
Re mai ni n g peri o d  
E n d of treat me nt  
F oll o w -u p  
Site visit ( V)/ P h o ne c o ntact ( P)  
V 1  
V 2  
V 3  
V 4  
V 5  
V 6  
V 7 a 
V 8  
V 9/ V 1 0/ V 1 1/  
V 1 3/ V 1 4/ V 1 5  
V 1 7/ V 1 8/ V 1 9  
V 2 1/ V 2 2/ V 2 3  
V 1 2  
V 1 6  
V 2 0  
V 2 4  
V -E O T b  
P -F U
Ti mi n g of visit ( wee ks)  
U p t o  
-3 wee ks
0  
4  
8  
1 3  
2 6  
3 9  
5 2  
E ver y  
1 3 wee ks  
Yearl y  
E O T  
V -E O T  
+ 5 wee ks
Visit wi n d o w ( da ys)  
± 3  
± 3  
± 3  
± 7  
± 7  
± 7  
± 7  
± 7  
± 7  
+ 7  
H b A 1c p oi nt of care
6. 1 ;9. 1. 1  
X  
X  
X  
X  
X  
X
X  
X
X  
X  
M o ntreal c o g niti ve assess me nt  
9. 1. 4  
X  
X  
P R O T E C T c o g niti ve tests o 
9. 1. 4  
X o 
X o 
X o 
P atie nt s ur ve ys j
9. 1. 4  
X j 
X j 
X j 
X j 
X j 
X j 
X j 
A d verse e ve nts  
9. 2  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Se vere h y p o gl ycae mic e pis o des  
9. 2  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
T ec h nical c o m plai nts  
9. 2. 6  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Uri ne pre g na nc y test k  
9. 2. 5  
X  
X  
X l 
C E N T R A L L A B O R A T O R Y A S S E S S M E N T S  
H b A 1c 
A p p e n di x 2  
X  
X  
X  
X  
X f
Creati ni ne  
X  
X  
X  
X  
X f
Hi g h se nsiti vit y C -Reacti ve 
Pr otei n 
X  
X  
X n 
Li ver para meters  
X  
Li pi ds  
X  
X  
X  
X  
X f 
Bi osa m ples f or f ut ure a nal ysis  
( bi o ba n k, ge netics)m  
X  
Bi osa m ples f or f ut ure a nal ysis  
( bi o ba n k, bi o mar kers)m  
X  
X  
X n  
T RI A L M A T E RI A L  
I W R S sessi o n 
X  
X  
X  
X  
X  
X  
X  
X  
X
X  
X  
Dis pe nsi n g visit  
X  
X  
X  
X  
X  
X  
X  
X
X
Dr u g acc o u nta bilit y  
7. 5  
X  
X  
X  
X  
X  
X  
X  
X
X  
X  
E n d of trial  
5. 3  
X  

Pr ot o c ol  
Date:  
2 6 Ja n uar y 2 0 2 1  
Stat us:  
Fi n al  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
P a ge:  
1 1  of 8 9  
a After V 6, all o d d n u m bere d visits ( V 7, V 9, V 1 1 etc.) ca n be c o n d ucte d as a p h o ne c o ntact, h o we ver t he i n vesti gat or ne e ds t o e ns ure t hat t he s u bj ect h as e n o u g h trial 
pr o d uct wit hi n t he e x pir y date . 
b Will be sc he d ule d acc or di n g t o trial c o m pleti o n. 
c T o bacc o use/s m o ki n g is defi ne d as s m o ki n g at least o ne ci garette or e q ui vale nt dail y.  
d De m o gra p h y: d ate of birt h, s e x, et h nicit y a n d race (acc or di n g t o l ocal re g ulati o n).  
e As nee de d.  
f If d o ne wit hi n t he past 5 wee ks, assess me nt ca n be s ki p pe d.  
g M ust b e perf or me d wit hi n 9 0 da ys bef ore scree ni n g or i n t he peri o d bet wee n scree ni n g a n d ra n d o misati o n, a n d res ults a vaila ble  at ra n d o misati o n.  
h M ust b e perf or me d bet wee n 8  wee ks bef ore t he visit a n d t he da y of visit ( b ot h i ncl u de d).  
i La ncet s, test stri ps a n d c o ntr ol s ol uti o ns will be pr o vi de d wit h t he B G meter (if s u p plie d) a n d d uri n g t he trial as nee de d. Trai ni n g will als o be pr o vi de d as nee de d.  
j P atie nt e n ga ge me nt assess me nt will be perf or me d e ver y half year, i.e. V 2, V 6, V 8, V 1 0, V 1 2, V 1 4, V 1 6, V 1 8, V 2 0, V 2 2, V 2 4 a n d V -E O T at all U S sites. P atie nt 
e x pectati o ns a n d e x perie nce s ur ve y will be perf or me d at Visit 2, Visit 1 2 a n d at e n d -of -treat me nt at o nl y a s u b-set of U S sites. 
Visits t o e mer ge nc y r o o m/ ur ge nt care u nit will be rec or de d at e ve r y visit fr o m V 3 at all U S sites. 
k O nl y a p plica ble f or w o me n of c hil d beari n g p ote ntial; uri ne H C G.  
l Ca n be d o ne at h o me.
m  O nl y a p plica ble f or patie nts t hat ha ve pr o vi de d i nf or me d c o nse nt f or bi osa m ples f or bi o mar kers a n d ge netic a nal yses.
n O nl y a p plica ble f or t he year t w o visit ( V 1 2).
o O nl y f or E n glis h a n d/ or S pa nis h s pea ki n g patie nts i n Ar ge nti na, Ca na da, C ol o m bia, Me xic o, S pai n, U nite d Ki n g d o m a n d U nite d States . O nli ne c o g niti ve testi n g will be
perf or me d e ver y year, i.e. V 2, V 8, V 1 2, V 1 6, V 2 0 a n d V 2 4.

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
1 2  of 8 9  
3  
I ntr o d ucti o n 
I n t his d oc u me nt, t he t er m i n vesti gat or refers t o t he i n di vi d ual res p o nsi ble f or t he o verall c o n d uct of 
t he cli nical trial at a trial site. 
3. 1  
Tri al r ati o n ale  
T he car di o vasc ular ( C V) effect of oral se ma gl uti de 1 4 m g o n ce dail y ( O D) a n d s.c. se ma gl uti de 0. 5 
a n d 1 m g o n ce w ee kl y w ere ass esse d i n 2 C V o utc o mes trials ( N N 9 9 2 4 -4 2 2 1, PI O N E E R 6 a n d 
N N 9 5 3 5 -3 7 4 4, S U S T AI N 6), eac h desi g ne d t o r ule o ut a n 8 0 % i ncrease d C V ris k i n patie nts wit h 
t y pe 2 dia b etes ( T 2 D) at hi g h ris k f or C V disease ( C V D) i n acc or da n ce wit h F D A g ui da nce. 
PI O N E E R 6 de m o nstrate d C V safet y wit h a fa v o ura ble p oi nt esti mate. S U S T AI N 6 h o we v er 
de m o nstrate d a statisticall y si g nifica nt 2 6 % ris k re d ucti o n wit h s.c. se ma gl uti de c o m pare d wit h 
place b o f or t he pri mar y e n d p oi nt (ti me fr o m ra n d o misati o n t o first occ urre n ce of a m aj or a d v erse 
car di o vas c ular e v e nt ( M A C E) c o nsisti n g of: C V deat h, n o n -fatal m y o car dial i nfarcti o n ( MI) or n o n-
fatal str o ke).2 Cli nical p har mac ol o g y a n d cli nical efficac y da t a i n dicate t hat t he acti o n of 
se ma gl uti de is t he sa m e w het her a d mi nistrate d vi a a s u bc uta ne o us i njecti o n or orall y i n a ta blet. 
He nce, o n ce se m a gl uti de has e ntere d s yst e mic cir c ulati o n, t he pr o perties a n d acti o ns of t he 
m olec ule are si milar a n d i n de pe n de n t of t he r o ute of a d mi nistrati o n. Acc or di n gl y it is h y p ot hesise d 
t hat oral se ma gl uti de i n t he d ose of 1 4 m g O D ca n re d uce C V ris k. 
T he c urre nt trial ser v es t he p ur p ose of c o nfir mi n g t hat oral se ma gl uti de re d uces t he ris k of M A C E 
i n patie nts wit h T 2 D a n d esta blis he d C V D a n d/ or c hr o nic ki d ne y dise ase ( C K D). 
3. 2  
B ac k gr o u n d  
T o pre ve nt t he c o m plicati o ns ass ociate d wit h T 2 D, t he g o al of t he t hera p y is t o miti gate t he 
m ulti ple heter o ge ne o us meta b olic defects ass ociate d wit h t he disease, i ncl u di n g h y per gl ycae mia.
3 
H o we ver, ma n y patie nts wit h T 2 D d o n ot ac hie ve gl ycae mic c o ntr ol, s o a n u n met nee d f or si m ple 
a n d c o n ve nie nt as well as safe a n d effi caci o us treat me nt o pti o ns e xists. 4, 5 I n a d diti o n, C V disease is 
t he pre d o mi na nt ca us e of deat h i n patie nts wit h T 2 D, a n d dia betes i ncrease d t he ris k f or c or o nar y 
heart diseas e, str o ke a n d C V deat h 6 wit h a n a b o ut a t w o -f ol d e x cess, u n dersc ori n g t h e nee d f or 
t hera pies l o weri n g t h e ris k of C V e ve nts i n patie nts wit h T 2 D.  
Se ma gl uti de is a ne xt -ge nerati o n gl uca g o n -li ke pe pti de-1 ( G L P -1) a nal o g u e wit h a hi g h d e gree of 
h o m ol o g y t o h u ma n G L P -1. 7 F or oral a d mi nistrati o n, se ma gl uti de has bee n c o -f or m ulate d wit h a n 
a bs or pti o n e n ha ncer ( S N A C, 3 0 0 m g) i n a t a bl et f or m ulati o n. N o n -cli nical a n d cli nical st u dies ha ve 
esta blis he d t hat oral se m a gl uti de is safe a n d well t olerate d a n d t h at it pr o vi des d ose -de p e n de nt 
re d ucti o ns i n H b A1c a n d b o d y w ei g ht w h e n use d i n c o m plia nce wit h t he s p ecifie d si m ple d osi n g 
c o n diti o ns. 8 Detaile d i nf or mati o n f or oral se m a gl uti de is a vaila ble i n t he c urre nt e diti o n a n d a n y 
u p dates of t he I n v esti gat or’s Br oc h ure (I B).  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
1 3  of 8 9  
 
T he trial will i ncl u de patie nts wit h T 2 D a n d hi g h C V ris k defi ne d as h a vi n g esta blis he d C V D a n d/ or 
C K D. A p o p ulati o n at hi g h ris k f or C V e ve nts is a n a p pr o priate t ar get p o p ulati o n f or a ris k 
re d ucti o n i nter ve nti o n a n d will e ns ure t hat t he pri mar y o bj ecti ve of t h e trial ca n be met wit hi n a 
reas o na bl e ti mefra me a n d sa m ple siz e. 
3. 3  
Be nefit -ris k assess me nt  
3. 3. 1  
Ris ks  
T he secti o ns bel o w des cri be i de ntifie d a n d p ote nti al ris ks ass ociate d wit h oral se ma gl uti de 
treat me nt. F or classificati o n a n d furt her details of t he ris ks, please refer t o t he c urre nt e diti o n a n d 
a n y u p d ates of t he I B. T h e i de ntifie d/ p ote ntial ris ks are bas e d o n fi n di n gs i n n o n -cli nical st u dies a n d 
cli nical trials wit h se ma gl uti de (s.c. as well as oral) as well as ot her gl uca g o n -li ke pe pti de-1 
rece pt or a g o nists ( G L P-1  R As). F or eac h of t hese ris ks, miti gati n g acti o ns ha ve bee n i m ple me nte d 
t o mi ni mise t he ris ks f or patie nts e nr olle d i n t his trial. 
G astr oi ntesti n al a d verse e ve nts  
C o nsiste nt wit h t he ot her G L P -1 R As, t he m ost fre q ue n t a d verse e v e nts ( A Es) wit h oral 
se ma gl uti de are gastr oi ntesti nal A Es ( na usea, v o miti n g, diarr h oea, d ys pe psi a a n d c o nsti pati o n). A 
l o w starti n g d ose a n d gra d ual d ose escalati o n wit h 4 wee ks d ose escal ati o n i ncre me nts ha v e bee n 
i m ple me nte d i n t he rece nt clinical trials wit h t he i nte nt t o l o wer t he ris k of gastr oi ntesti nal A Es.  
I m p aire d ki d ne y f u ncti o n 
I n p atie nts treate d wit h G L P-1 R As i ncl u di n g oral se ma gl uti de, gastr oi ntesti nal A Es s uc h as na us ea, 
v o miti n g a n d diarr h oea ma y le a d t o si g nifi ca nt d e h y drati o n.  T his s h o ul d be c o nsi dere d w he n 
treati n g p atie nts wit h i m paire d re nal f u ncti o n wit h G L P-1 R As as it ma y ca use a det eri orati o n of 
re nal f u n cti o n. I m p aire d re nal f u n cti o n ma y i n crease t he ris k of metf or mi n ass ociate d lactic 
aci d osis.   
Patie nts a n d pr o vi ders  s h o ul d be a d vise d t o m o nit or h y drati o n le vels i n or der t o a v oi d de h y drati o n 
i n c o n necti o n wit h gastr oi ntesti nal A Es.   
H y p o gl yc ae mi a  
T he ris k of h y p o gl ycae mic e pis o des ass ociat e d wit h t he use of G L P -1 R As, i ncl u di n g oral 
se ma gl uti de, is l o w w h e n use d as mo n ot hera p y. Patie nts treate d wit h se ma gl uti de i n c o m bi nati o n 
wit h a s ulf o n yl ur ea or i ns uli n ma y ha v e a n i ncreas e d ris k of h y p o gl ycae mia c o m pare d t o patie nts 
treate d wit h se ma gl uti de as m o n ot hera p y or i n c o m bi nati o n wit h ot her a nti-h y p er gl ycae mic 
me dicati o n s. T he ris k of h y p o gl ycae mia ca n be l o were d b y re d uci n g t he d ose of s ulf o n yl urea or 
i ns uli n w he n i nitiati n g treat me nt wit h oral se ma gl uti de. It is als o r ec o m me n de d t hat t he i n vesti gat or 
e ns ures t hat patie nts ta ki n g or i nitiati n g s ul p h o n yl urea or i ns uli n pe rf or m a de q uatel y fre q ue nt bl o o d 
gl uc ose m o nit ori n g t o e ns ure patie nt safet y.  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
1 4  of 8 9  
 
Aller gic re acti o ns  
As e x pecte d f or a pr otei n -base d dr u g, p atie nts treate d wit h oral se ma gl uti de ma y d e vel o p l ocalise d 
or ge neralise d i m m u ne a n d aller gic reacti o ns i ncl u di n g urtica ria, ras h or pr urit us. Se vere aller gic 
reacti o ns s uc h as a na p h yl actic reacti o ns c o ul d p ote ntiall y als o p ose a ris k t o patie nts treate d wit h 
oral se ma gl uti de. Dat a fr o m t he b ot h t he s.c. a n d t he oral se ma gl uti de de vel o p me nt pr o gra m mes 
i n dicate t hat t he p otential ris k of aller gic reacti o ns is l o w.  
Ac ute p a ncre atitis  
Ac ute pa n creatitis has bee n o bser ve d wit h t he use of G L P -1 R A dr u g class. As a preca uti o n, trial 
pr o d uct s h o ul d be disc o nti n ue d i n case of s us pici o n of ac ute pa ncreatitis i n acc or da nce wit h 
Secti o n  8. 1 . 
Ac ute g allst o ne dise ase (c h olelit hi asis)  
Patie nts wit h T 2 D are oft e n o ver wei g ht or o bese a n d ha ve a n i n here nt ris k of de vel o pi n g gall st o nes 
(c h olelit hiasis). E ve nts of c h olelit hiasis ha ve bee n ass ociate d wit h t he use of G L P-1 R As i ncl u di n g 
se ma gl uti de. I n t he cli nic al de vel o p me nt pr o gra m me, e ve nts were mai nl y mil d a n d n o n -seri o us a n d 
di d n ot lea d t o a n i ncreas e d ris k of c o m plicati o ns s u c h as c h olec ystitis or pa ncreatitis.  
Di a betic reti n o p at h y c o m plic ati o ns  
T he car di o vasc ular o utc o me trial i n t he s.c.  se ma gl uti de de vel o p me nt pr o gra m me ( S U S T AI N 6) 
s h o we d a n i ncreas e d ris k of e ve nts rel ate d t o dia betic reti n o pat h y c o m plicati o ns i n patie nts treate d 
wit h se ma gl uti de c o m p are d t o place b o, al beit t he pr o p orti o n of patie nts wit h a n e ve nt of dia betic 
reti n o pat hy c o m plicati o ns was l o w. T he i m bala nce was dri ve n b y p atie nts wit h a hist or y of dia b etic 
reti n o pat h y at baseli ne a n d patie nts w h o were treate d wit h i ns uli n. As a preca uti o n, patie nts wit h a 
hist or y of u nc o ntr olle d a n d p ote ntiall y u nsta ble di a betic reti n o pa t h y or mac ul o pat h y will be 
e x cl u de d fr o m t he trial, a n d e ye e x a mi nati o n will be perf or me d acc or di n g t o fl o wc hart (s ee 
Secti o n  2 ). 
P a ncre atic c a ncer  
T here is c urre ntl y n o s u p p ort fr o m n o n -cli nical st u dies, cli nical trials or p ost -mar keti n g d ata t hat 
G L P -1 R A -b ase d t hera pi es i ncrease t he ris k of p a ncreatic ca n cer. H o we v er, pa ncreatic ca ncer has 
bee n classifie d as a p ote ntial class ris k f or all mar k ete d  G L P -1 R As b y re g ul at or y a ge n cies base d o n 
t he u n k n o w n l o n g-ter m effects o n β-cell sti m ulati o n a n d α -cell s u p pressi o n.  
Me d ull ar y t h yr oi d c a ncer ( M T C) ( b ase d o n n o n -cli nic al d at a)  
T h yr oi d C -cell t u m o urs were s ee n i n t he mice a n d rat carci n o ge nicit y st u dies,  after dail y e x p os ure 
t o se ma gl uti de f or 2 years. N o C-cell t u m o urs were o bser ve d i n m o n ke ys after 5 2 wee ks e x p os ure 
of u p t o 4 0 -f ol d hi g h er d oses t ha n t he cli nical plas ma e x p os ure at 1 4 m g/ da y. T he G L P-1 rece pt or is 
n ot e x presse d i n t he n or mal h u ma n t h yr o i d9; a n d t heref ore, t hese fi n di n gs are n ot li kel y t o be 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
1 5  of 8 9  
 
cli nicall y rele va nt. T o miti gate t his ris k, patie nts wit h a fa mil y 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 t y pe 2 ( M E N 2) are e x cl u de d fr o m cli nical trials 
wit h se ma gl uti de.  
Pre g n a nc y a n d fertilit y  
St u dies i n a ni mals ha ve s h o w n re pr o d ucti ve t o xicit y. T here a re li mite d data fr o m t he use of 
se ma gl uti de i n pre g na nt w o me n. T heref ore, oral s e ma gl uti de s h o ul d n ot be use d d uri n g pre g n a nc y. 
If a patie nt wis hes t o b ec o me pre g na nt, or pre g na nc y o cc urs, treat me nt wit h oral se ma gl uti de s h o ul d 
be disc o nti n ue d i m me diatel y.  E x cl usi o n a n d disc o nti n uati o n criteria rel ate d t o pre g n a nc y h a ve bee n 
i m ple me nte d i n t he trial. 
3. 3. 2  
Be nefits  
I n cli nical trials oral se m a gl uti de h as pr o vi de d s u peri or l o n g-ter m gl ycae mic c o ntr ol i n T 2 D a n d 
cli nicall y rele va nt r e d ucti o ns i n b o d y wei g ht as c o m p are d t o c o m m o nl y us e d mar kete d pr o d u cts a n d 
place b o. A statistical si g nifica nt re d u cti o n i n C V e ve nts has bee n de m o nstrate d f or se ma gl uti de s.c. 
( S U S T AI N 62) a n d t his fi n di n g was s u p p orte d b y t he res ults fr o m t he PI O N E E R 6 trial wit h oral 
se ma gl uti de. 
D uri n g t his trial it is e x pecte d t hat al l patie nts, i ncl u di n g t h ose ra n d o mise d t o place b o will be nefit 
fr o m partici pati o n t hr o u g h fre q ue nt c o ntact wit h t he trial site, w here dia bet es a n d C V diseases are 
m o nit ore d a n d treat e d f oll o wi n g caref ul me dical e x a mi nati o ns. T o e ns ure all patie nts, i ncl u di n g 
t h ose recei vi n g pla ce b o h a ve a n a de q uat e gl ycae mic c o ntr ol a n d C V ris k fact or ma na ge m e nt, 
i n vesti gat ors are e nc o ura ge d t o o pti mise treat me nt wit h a nti-dia betic me dicati o ns as well as 
me dicati o ns affecti n g C V ris k fact ors t hr o u g h o ut t he trial. All patie n ts i n t his trial will recei ve trial 
pr o d uct a n d a u xiliar y s u p plies free of c har ge.  
3. 3. 3  
Ris k a n d be nefit c o ncl usi o n  
Data fr o m t he cli nical de vel o p me nt pr o gra m me f or se ma gl uti de has n ot re v eale d a n y s afet y iss ues 
t hat w o ul d o ut wei g h t he be nefits. T he trial p o p ulati o n will c o nsist of T 2 D patie nts wit h hi g h ris k of 
C V e ve nts. Assess me nt of dia betes a n d C V ris k fact ors a n d a p pr o priate atte nti o n t o t he sta n dar d of 
care treat me nt will be e ns ure d t hr o u g h o ut t he trial. It is t heref ore c o ncl u d e d t hat t he p ote ntial 
be nefi ts fr o m t he trial will o ut wei g h t he p ote ntial ris ks f or t he oral se ma gl uti de as well as t he 
place b o treate d patie nts.  
M ore detaile 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 n a bl y 
e x pecte d a d vers e e v e nts of oral se ma gl uti de ma y b e f o u n d i n t he I n vesti gat or’s Br oc h ure a n d a n y 
u p dates t here of.  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
1 6  of 8 9  
4  
O bjecti ves a n d e n d p oi nts 
4. 1  
Pri m ar y, sec o n d ar y a n d e x pl or at or y o bjecti ve(s)  
T he pri m ar y o bjecti ve  
T o de m o nstrate t hat or al se ma gl uti de l o wers t he ris k of maj or a d verse car di o vasc ular e ve nts 
( M A CE) c o m pare d t o place b o, b ot h a d de d t o sta n dar d of care i n p atie nts wit h T 2 D a n d at hi g h ris k 
of C V e ve nts.  
T he sec o n d ar y o bjecti v es  
T o c o m pare t h e effects of oral se ma gl uti de vers us place b o, b ot h a d de d t o sta n dar d of care i n 
patie nts wit h T 2 D a n d at hi g h r is k of C V e v e nts wit h re gar ds t o: 
•
C K D
•
C V e ve nts
•
Peri p heral arter y dise ase ( P A D)
•
Gl ycae mic c o ntr ol a n d b o d y w ei g ht
•
Safet y
T he e x pl or at or y o bjecti ves  
T o c o m pare t h e effects of oral se ma gl uti de vers us place b o, b ot h a d de d t o sta n dar d of care i n 
patie nts wit h T 2 D a n d at hi g h ris k of C V e v e nts wit h re gar ds t o:  
•
C o g niti ve f u ncti o n
•
S m o ki n g
Esti m a n d  
T he esti ma n d f or all o bjecti ves is t he i nte nti o n -t o-treat esti ma n d e val u ati n g t he effect of t he 
ra n d o mise d treat me nt i nt er ve nti o n irres p ecti ve of a d here n ce t o treat me nt a n d c ha n ges t o 
bac k gr o u n d me dicati o n.  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
1 7  of 8 9  
4. 2  
Pri m ar y, sec o n d ar y a n d e x pl or at or y e n d p oi nt(s)  
4. 2. 1  
Pri m ar y e n d p oi nt  
E n d p oi nt title  
Ti me Fr a me 
U nit  
Ti me t o first occ urre nce of M A C E, a 
c o m p osite e n d p oi nt c o nsisti n g of:  
•
C V deat h
•
n o n -fatal m y ocar dial i nfarcti o n
•
n o n -fatal str o ke
Fr o m ra n d o misati o n ( wee k 0) t o 
e n d -of -trial ( u p t o 6 1 m o nt hs or 
m ore a) 
M o nt h(s)  
a Trial is e ve nt dri ve n.  
4. 2. 2  
Sec o n d ar y e n d p oi nts  
4. 2. 2. 1  
C o nfir m at or y s ec o n d ar y e n d p oi nts  
E n d p oi nt title  
Ti me Fr a me 
U nit  
Ti me t o first occ urre nce of a 
c o m p osite e n d p oi nt c o nsisti n g of: 
•
C V deat h
•
re nal deat h
•
o nset of persiste nt ≥ 5 0 %
re d ucti o n i n e G F R ( C K D-E PI) b
•
o nset of persiste nt e G F R ( C K D -
E PI) < 1 5 m L/ mi n/ 1. 7 3 m 2
•
i nitiati o n of c hr o nic re nal
re place me nt t hera p y ( dial ysis or
ki d ne y tra ns pla ntati o n)
Fr o m ra n d o misati o n ( wee k 0) t o 
e n d -of -trial ( u p t o 6 1 m o nt hs or 
m ore a) 
M o nt h(s)  
Ti me t o occ urre nce of C V deat h  
Fr o m ra n d o misati o n ( wee k 0) t o 
e n d -of -trial ( u p t o 6 1 m o nt hs or 
m ore a) 
M o nt h(s)  
Ti me t o first occ urre nce of maj or 
a d verse li m b e ve nts ( M A L E), a 
c o m p osite e n d p oi nt c o nsisti n g of: 
•
ac ute li m b isc he mia
h os pitalisati o n
•
c hr o nic li m b isc he mia
h os pitalisati o n
Fr o m ra n d o misati o n ( wee k 0) t o 
e n d -of -trial ( u p t o 6 1 m o nt hs or 
m ore a) 
M o nt h(s)  
a Trial is e ve nt dri ve n.  
b C o m pare d wit h baseli ne.  
A b bre viati o ns: e G F R, esti mat e d gl o mer ular filtrati o n rate; 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 
Defi niti o ns  
Esti mate d gl o mer ular filtrati o n rate (e G F R) will be calc ul ate d usi n g t h e –  C K D -E PI f or m ula. 1 0 A 
persiste nt c ha n ge i n e G F R is defi ne d as ha vi n g 2 c o nsec uti ve sa m ples me eti n g t he criteria. T he 2 
sa m ples m ust be at least 4 wee ks a p art.  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
1 8  of 8 9  
4. 2. 2. 2  
S u p p orti ve sec o n d ar y e n d p oi nts  
E n d p oi nt title  
Ti me Fr a me 
U nit  
Ti me t o first occ urre nce of a n e x pa n de d 
M A C E c o m p osite e n d p oi nt c o nsisti n g of: 
•
C V deat h
•
n o n -fatal m y ocar dial i nfarcti o n
•
n o n -fatal str o ke
•
c or o nar y re vasc ularisati o n
•
u nsta ble a n gi na re q uiri n g h os pitalisati o n
Fr o m ra n d o misati o n ( wee k 0) t o e n d -
of -trial ( u p t o 6 1 m o nt hs or m orea) 
M o nt h(s)  
Ti me t o first occ urre nce of a c o m p osite heart 
fail ure e n d p oi nt c o nsisti n g of:  
•
C V deat h
•
heart fail ure re q uiri n g h os pitalisati o n
•
ur ge nt heart fail ure visit
Fr o m ra n d o misati o n ( wee k 0) t o e n d -
of -trial ( u p t o 6 1 m o nt hs or m orea) 
M o nt h(s)  
Ti me t o first occ urre nce of a c o m p osite C K D 
e n d p oi nt c o nsisti n g of:  
•
re nal deat h
•
o nset of persiste nt ≥ 5 0 % re d ucti o n i n
esti mate d gl o mer ular filtrati o n rate
(e G F R) ( C K D-E PI) b
•
o nset of persiste nt e G F R ( C K D -E PI) <
1 5 m L/ mi n/ 1. 7 3 m 2
•
i nitiati o n of c hr o nic re nal re pl ace me nt
t hera p y ( dial ysis or ki d ne y
tra ns pla ntati o n)
Fr o m ra n d o misati o n ( wee k 0) t o e n d -
of -trial ( u p t o 6 1 m o nt hs or m orea) 
M o nt h(s)  
Ti me t o occ urre nce of all -ca us e deat h  
Fr o m ra n d o misati o n ( wee k 0) t o e n d -
of -trial ( u p t o 6 1 m o nt hs or m orea) 
M o nt h(s)  
Ti me t o first occ urre nce of n o n -fatal 
m y ocar dial i nfarcti o n ( MI)  
Fr o m ra n d o misati o n ( wee k 0) t o e n d -
of -trial ( u p t o 6 1 m o nt hs or m orea) 
M o nt h(s)  
Ti me t o first occ urre nce of n o n -fatal str o ke 
Fr o m ra n d o misati o n ( wee k 0) t o e n d -
of -trial ( u p t o 6 1 m o nt hs or m orea) 
M o nt h(s)  
Ti me fr o m ra n d o misati o n t o heart fail ure 
re q uiri n g h os pitalisati o n  or ur ge nt heart 
fail ure visit 
Fr o m ra n d o misati o n ( wee k 0) t o e n d -
of -trial ( u p t o 6 1 m o nt hs or m orea) 
M o nt h(s)  
Ti me t o first occ urre nce of c or o nar y 
re vasc ularisati o n 
Fr o m ra n d o misati o n ( wee k 0) t o e n d -
of -trial ( u p t o 6 1 m o nt hs or m orea) 
M o nt h(s)  
Ti me t o first occ urre nce of u nsta ble a n gi na 
re q uiri n g h os pitalisati o n 
Fr o m ra n d o misati o n ( wee k 0) t o e n d -
of -trial ( u p t o 6 1 m o nt hs or m orea) 
M o nt h(s)  
Ti me t o occ urre nce of re nal d eat h  
Fr o m ra n d o misati o n ( wee k 0) t o e n d -
of -trial ( u p t o 6 1 m o nt hs or m orea) 
M o nt h(s)  
Ti me t o first occ urre nce of o nset of persiste nt 
≥ 5 0 % re d ucti o n i n e G F R ( C K D -E PI) b  
Fr o m ra n d o misati o n ( wee k 0) t o e n d -
of -trial ( u p t o 6 1 m o nt hs or m orea) 
M o nt h(s)  
Ti me t o first occ urre nce of o nset of persiste nt 
e G F R ( C K D -E PI) < 1 5 m L/ mi n/ 1. 7 3 m 2 
Fr o m ra n d o misati o n ( wee k 0) t o e n d -
of -trial ( u p t o 6 1 m o nt hs or m orea) 
M o nt h(s)  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
1 9  of 8 9  
 
E n d p oi nt title  
Ti me Fr a me  
U nit  
Ti me t o first occ urre nce of i nitiati o n of 
c hr o nic re nal re place me nt t her a p y ( dial ysis or 
ki d ne y tra ns pla ntati o n)  
Fr o m ra n d o misati o n ( wee k 0) t o e n d -
of -trial ( u p t o 6 1 m o nt hs or m ore a) 
M o nt h(s)  
Ti me t o first occ urre nce of a c o m p osite 
e n d p oi nt c o nsisti n g of:  
•  
all-ca use deat h  
•  
n o n -fatal m y ocar dial i nfarcti o n 
•  
n o n -fatal str o ke 
Fr o m ra n d o misati o n ( wee k 0) t o e n d -
of -trial ( u p t o 6 1 m o nt hs or m orea) 
M o nt h(s)  
Ti me t o first occ urre nce of ac ute li m b 
isc he mia h os pitalisati o n 
Fr o m ra n d o misati o n ( wee k 0) t o e n d -
of -trial ( u p t o 6 1 m o nt hs or m orea) 
M o nt h(s)  
Ti me t o first occ urre nce of c hr o nic li m b 
isc he mia h os pitalisati o n 
Fr o m ra n d o misati o n ( wee k 0) t o e n d -
of -trial ( u p t o 6 1 m o nt hs or m orea) 
M o nt h(s)  
A n n ual rate of c ha n ge i n e G F R ( C K D -E PI) 
(t otal e G F R sl o pe) 
Fr o m ra n d o misati o n ( wee k 0) t o e n d of 
treat me nt ( u p t o 6 0 m o nt hs or m orea)  
ml/ mi n/ 1. 7 3 m 2 per year  
C ha n ge i n gl yc os ylate d hae m o gl o bi n ( H b A 1c)  Fr o m ra n d o misati o n ( wee k 0) t o 2 
years ( visit 1 2) 
% -p oi nts  
C ha n ge i n b o d y wei g ht  
Fr o m ra n d o misati o n ( wee k 0) t o 2 
years ( visit 1 2)  
Kil o gra m  
N u m ber of se vere h y p o gl ycae mic e pis o des 1 1 
Fr o m ra n d o misati o n ( wee k 0) t o e n d -
of -trial ( u p t o 6 1 m o nt hs or m orea) 
N u m ber  of e ve nts  
Ti me t o first occ urre nce of a s e vere 
h y p o gl ycae mic e pis o de  1 1 
Fr o m ra n d o misati o n ( wee k 0) t o e n d -
of -trial ( u p t o 6 1 m o nt hs or m orea) 
M o nt h(s)  
a Trial is e ve nt dri ve n.  
b C o m pare d wit h baseli ne.  
4. 2. 2. 3  
E x pl or at or y e n d p oi nts  
E n d p oi nt title  
Ti me Fr a me  
U nit  
C ha n ge i n M o ntreal C o g niti ve 
Assess me nt ( M o C A) sc ore  
Fr o m ra n d o misati o n ( wee k 0) t o 2 
years ( visit 1 2)  
Sc ore ( 0 -3 0)  
C ha n ge i n M o ntreal C o g niti ve 
Assess me nt ( M o C A) sc ore  
Fr o m ra n d o misati o n ( wee k 0) t o 3 
years ( visit 1 6)  
Sc ore ( 0 -3 0)  
C urre nt s m o ki n g  
At year 2  
Yes/ n o  
 
E n glis h a n d/ or S pa nis h s pea ki n g patie nts i n  Ar ge nti na, Ca na da, C ol o m bia, Me xic o, S pai n, U nite d 
Ki n g d o m a n d U nite d States:  
E n d p oi nt title  
Ti me Fr a me  
U nit  
C ha n ge i n W or ki n g Me m or y I n de x  
Fr o m ra n d o misati o n ( wee k 0) t o 2 
years ( visit 1 2)  
Sc ore  
C ha n ge i n Ver bal Reas o ni n g  
Fr o m ra n d o misati o n ( wee k 0) t o 2 
years ( visit 1 2)   
Sc ore  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
2 0  of 8 9  
 
C ha n ge i n Atte nti o nal I nte nsit y I n de x 
 
 
 
Fr o m ra n d o misati o n ( wee k 0) t o 2 
years ( visit 1 2)  
msec  
C ha n ge i n C o g niti ve Reacti o n Ti me
 
 
 
Fr o m ra n d o misati o n ( wee k 0) t o 2 
years ( visit 1 2)  
msec  
C ha n ge i n S ustai ne d Atte nti o n I n de x 
 
 
Fr o m ra n d o misati o n ( wee k 0) t o 2 
years ( visit 1 2)   
% -p oi nts  
5  
Tri al desi g n  
5. 1  
O ver all desi g n  
T his is a ra n d o mise d, d o u ble -bli n d, parallel -gr o u p, place b o -c o ntr olle d trial c o m pari n g oral 
se ma gl uti de v ers us place b o O D a d de d to sta n d ar d of care i n patie nts wit h T 2 D at hi g h ris k of C V 
e ve nts. Patie nts will be ra n d o mise d 1: 1 t o recei v e eit her oral se m a gl uti de or place b o.  
T he trial is e ve nt dri ve n wit h trial cl os ure bei n g p erf or me d w he n t he tar get e d n u m ber of pri mar y 
e n d p oi nt e ve nts ( 1 2 2 5) h as bee n reac he d. T he trial will e m pl o y a gr o u p se q ue ntial desi g n a n d 
i nteri m testi n g f or effic ac y will be perf or me d b y a n i n de pe n de nt e xter nal D ata M o nit ori n g 
C o m mittee ( D M C). Wit h t he ass u me d e ve nt r ate a n d a recr uit me nt peri o d of a p pr o xi ma tel y 1 8 
m o nt hs, e x pecte d trial d urati o n f or a n i n di vi d ual p atie nt is a p pr o xi matel y 3. 5 t o 5 years i ncl u di n g 
t he f oll o w-u p peri o d. T h e f oll o w -u p peri o d is 5 wee ks aft er e n d of treat me nt.  
Patie nts will be f oll o we d f or t he c o m plete d urati o n of t he trial a n d e xte nsi ve eff orts will be ma de t o 
c ollect o utc o me data f or all ra n d o mise d patie nts. A sc he matic o ver vie w of t he trial desi g n is s h o w n 
i n Fi g ure  5 -1  b el o w.  
T he trial is desi g n e d t o e val uate C V o utc o mes a n d will a p pl y a tar gete d a p pr oac h t o c ollecti o n of 
safet y data f oc usi n g o n s eri o us A Es ( S A Es), A Es lea di n g t o disc o nti n uati o n of trial pr o d uct a n d 
ot her select e d A Es. A n a de q uate c h aracterisati o n of t h e less seri o us a n d m ore c o m m o n A Es are 
e val uate d i n t he p h ase 3a trials c o n d ucte d wit h oral se ma gl uti de c o m prisi n g m ore t ha n 
5, 5 0 0  patie nts wit h T 2 D.  
A n e xter nal e ve nt a dj u di cati o n c o m mittee ( E A C) will perf or m o n g oi n g a dj u dicati o n of pre d efi ne d 
C V e ve nts a n d ot her s ele cte d A Es i n a n i n de p e n de nt a n d bli n de d ma n ner.  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
2 1  of 8 9  
 
Fi g ure  5 -1  
Tri al desi g n  
 
5. 2  
P ati e nt a n d tri al c o m pleti o n  
I n t his trial 9, 6 4 2 patie nts are pla n n e d t o be ra n d o ml y assi g ne d t o trial pr o d uct. T he recr uit me nt 
peri o d is e x pecte d t o be a p pr o xi matel y 1 8 m o nt hs.  
Trial peri o d c o m pleti o n f or a patie nt is defi ne d as w he n t he ra n d o mise d patie nt has:  
•  atte n de d t he fi nal s c he d ule d visit (f oll o w -u p visit ( P -F U) acc or di n g t o t he fl o wc hart)  
or  
•  die d d uri n g tri al.  
T he trial is e ve nt dri ve n; t heref ore, e n d of treat me nt visit ( V -E O T) a n d f oll o w -u p c o ntact ( P -F U) 
will be sc he d ule d acc or di n g t o pr ojecte d trial cl os ure. W he n trial cl os ure is i nitiate d t he 
i n vesti gat ors will be n otifie d a n d i nstr ucte d b y No v o N or dis k re gar di n g t h e visit sc he d ules f or t heir 
patie nts.  
W he n t he trial c o mes t o a n e n d, t he i n vesti gat or m ust ma ke e ver y eff ort t o ascert ai n effi cac y 
e n d p oi nt data a n d A Es wit h a f oc us o n t h ose rel ate d t o t he pri mar y o bjecti ve f or all patie nts. T his 
s h o ul d be d o ne b y direct c o ntact wit h t he patie nt w he ne ver p ossi ble. If a p atie nt pr o ves diffic ult t o 
reac h f or t he F U visit, all atte m pts t o re-esta blis h direct c o ntact m ust be ma de as n ote d b el o w. If 
esta blis hi n g direct c o ntact is n ot p ossi ble, A E stat us  s h o ul d be o btai ne d fr o m a n y a vaila ble s o urce 
i ncl u di n g ele ctr o nic me di cal rec or ds, t he patie nts’ pri mar y p h ysicia n or ot h er healt h care 
pr ofessi o nals a n d, as a last res ort, vital stat us ( dea d or ali ve) s h o ul d be o btai ne d. P u blicl y a vaila ble 
data s o urces s h o ul d als o be searc he d. A s earc h a ge nc y ma y be us e d t o facilitate i de ntif yi n g u p dat e d 
c o ntact details f or a missi n g patie nt or pr o vi de vital stat us ( dea d or last ali ve date). T he a b o ve 
s u g gesti o ns s h o ul d be f oll o we d u nless pr o hi bite d b y l ocal re g ulati o n a nd m a y b e m o difie d 
acc or di n g t o pr actical as pects.  
I n a cas e w here se v eral atte m pts are re q uir e d t o esta blis h direct c o ntact t o a patie nt, it ma y be 
necessar y t o e x cee d t he visit wi n d o w of a f oll o w -u p visit. I n or der f or t he d ata set t o be as c o m plete 
as p ossi ble, e n d of trial f oll o w-u p i nf or mati o n ca n be c ollecte d u ntil t he ra n d o misati o n c o des are 
br o ke n.  
 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
2 2  of 8 9  
 
As a mi ni m u m t he f oll o wi n g c o nt act atte m pts will be ma de a n d d oc u m e nte d i n t he s o urce 
d oc u me nts:  
•  T o patie nts: t hree p h o ne calls a n d o ne writte n c o ntact  
•  T o pri mar y p h ysicia n a n d/ or ot her healt h care pr ofessi o nals: calls u ntil c o ntact is 
esta blis he d  
•  T o relati ves or ot her(s) o n t he c o ntact pers o ns list: t hree p h o ne calls a n d o n e writte n c o ntact  
•  Searc h/c o ntact t o p u blic re gistries of deceas e d pers o ns, if a vai la ble a n d all o we d b y l ocal 
re g ulati o n 
5. 3  
E n d of tri al defi niti o n  
T he e n d of t he tri al is defi ne d as t he date of t he last visit ( P -F U) of t he last patie nt i n t he trial.  
5. 4  
Scie ntific r ati o n ale f or tri al desi g n  
T o mi ni mise bias t he trial is ra n d o mise d, d o u ble -bli n de d a n d place b o -c o ntr olle d. Bli n de d treat me nt 
wit h oral se ma gl uti de or place b o offers a r o b ust met h o d f or assess me nt of t he effects of oral 
se ma gl uti de. A br oa d s pectr u m of c o nc o mita nt a nti-h y per gl ycae mic me dicati o n, as well as 
treat me nts f or c o-m or bi diti es a n d C V ris k fact ors ca n be i ntr o d uce d or a dj uste d t hr o u g h o ut t he trial 
base d o n i n di vi d ual re q uire me nts a n d at i n vesti gat or’s discreti o n. T his is i n acc or da nce wit h a 
pra g matic a p pr oac h t o c o m pare t w o treat me nt re gi me ns: o ne w here oral se ma gl uti de is a v aila bl e 
a n d a n ot her w here it is n ot.  
T o s u p p ort t he patie nt d uri n g t he d os e escalati o n peri o d site visits will occ ur m ore fre q ue ntl y d uri n g 
t he first m o nt hs of t he trial. T o ma xi mise rete nti o n a n d c o m plia nce, a n d t o o pti mise treat me nt, e. g. 
re gar di n g gl ycae mic c o ntr ol, t he patie nt is i n c o ntact wit h t he i n vesti gat or e ver y 1 3 t h wee k 
t hr o u g h o ut t he trial. A m ulti nati o nal desi g n has bee n c h ose n t o e ns ure a s ufficie nt scree ni n g p o ol of 
patie nts a n d t o reflect t he a ntici pate d patie nt p o p ul ati o n. T he 5 -wee k f oll o w u p is c h ose n d ue t o t he 
half -life of oral se ma gl uti de a n d is c o nsi dere d a p pr o priate f or e n d of s yste mic e x p os ure. 
T he trial will i ncl u de a p o p ulati o n of patie nts wit h T 2 D a n d esta blis he d C V disease a n d/ or C K D 
w hic h is a n a p pr o priate hi g h ris k tar get p o p u lati o n f or a C V ris k r e d ucti o n i nter ve nti o n a n d will 
e ns ure t hat t he pri mar y o bjecti ve of t he trial ca n b e e val uat e d wit hi n a reas o na ble ti mefra me a n d 
sa m ple siz e. 
6  
Tri al p o p ul ati o n  
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 ol me nt cr iteria, 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.  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
2 3  of 8 9  
 
6. 1  
I ncl usi o n criteri a 
All i ncl usi o n criteria are base d o n t he patie nts’ me dical rec or ds, e x ce pt f or i ncl usi o n criteri o n f or 
H b A 1 c (l ocal la b orat or y or p oi nt-of -care d e vice). Patie nts are  eli gi ble t o be i ncl u de d i n t he trial o nl y 
if all of t he f oll o wi n g crit eria a p pl y: 
1.  I nf or me d c o ns e nt o btai ne d bef ore a n y trial-relate d acti vities. Trial-rel ate d acti vities are a n y 
pr oce d ures t hat are carrie d o ut as part of t he trial, i ncl u di n g acti vities t o  deter mi ne s uita bilit y f or 
t he trial. 
2.  Male or fe m ale, a ge ≥5 0 years at t he ti me of si g ni n g i nf or m e d c o nse nt.  
3.  Dia g n os e d wit h t y p e 2 dia betes mellit us.  
4.  H b A 1 c 6. 5 % - 1 0. 0 % ( 4 7 - 8 6 m m ol/ m ol) ( b ot h i ncl usi ve). a 
5.  At least o ne of t he b el o w c o n diti o ns (a -d):  
a)  C or o nar y heart disease d efi ne d as at least o ne of t he f oll o wi n g:  
i. 
Pri or m y ocar dial i nfarcti o n  
ii. 
Pri or c or o nar y re v asc ularisati o n pr oce d ure  
iii. 
≥5 0 % ste n osis i n c or o nar y arter y d o c u me nte d b y car diac cat heterisati o n or C T 
c or o nar y a n gi o gra p h y  
i v. 
C or o nar y heart disease  wit h isc hae mia d oc u me nte d b y stress test wit h a n y 
i ma gi n g m o dalit y 
b)  Cere br o vas c ular dise ase defi ne d as at least o ne of t he f oll o wi n g:  
i. 
Pri or str o ke  
ii. 
Pri or  car oti d art er y re vas c ularisati o n pr oce d ure  
iii. 
≥5 0 % ste n osis i n car oti d arter y d o c u me nte d b y X -ra y a n gi o grap h y, M R 
a n gi o gra p h y, C T a n gi o gra p h y or D o p pler ultras o u n d  
c)  S y m pt o matic p eri p heral arter y dise ase ( P A D) defi ne d as at least o n e of t he f oll o wi n g:  
i. 
I nter mitte nt cla u dicati o n wit h a n A n kle-brac hial i n de x ( A BI) < 0. 8 5 at r est  
ii. 
I nter mitte nt cla u dicati o n wit h a ≥5 0% ste n osis i n peri p heral arter y (e x cl u di n g 
car oti d) d oc u m e nte d b y X -ra y a n gi o gra p h y, M R a n gi o gra p h y, C T a n gi o gra p h y 
or D o p pler ultras o u n d  
iii. 
Pri or peri p heral arter y (e x cl u di n g car oti d) re vasc ularizati o n pr oce d ure  
i v. 
L o w er e xtre mit y a m p utati o n at or a b o ve a n kl e d ue t o at her oscler otic dis eas e 
(e x cl u di n g e. g. tr a u ma or oste o m yelitis) 
d)  C hr o nic ki d ne y dise ase d efi ne d as:  
i. e G F R < 6 0 m L/ mi n/ 1. 7 3 m 2 b 
a Latest a v aila ble a n d n o m ore t ha n 3 0 da ys ol d l o cal la b orat or y assess me nt base d o n me dical 
rec or ds or p oi nt of care meas ure me nt.  
b  Base d o n m e dical r ec or ds usi n g latest a vaila bl e a n d n o m ore t ha n 6 m o nt hs ol d assess me nt.  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
2 4  of 8 9  
 
6. 2  
E xcl usi o n criteri a  
All e x cl usi o n criteria are base d o n t he patie nts’ me dical rec or ds, e x ce pt f or e x cl usi o n criteri o n 3, 
uri ne pre g n a nc y test. Patie nts are e x cl u de d fr o m t he trial if a n y of t he f oll o wi n g criteria a p pl y:  
1.  K n o w n or s us pect e d h y p erse nsiti vit y t o trial pr o d uct or relat e d pr o d ucts.  
2.  Pre vi o us partici pati o n i n t his trial. Partici pati o n is defi ne d as ra n d o misati o n.  
3.  Fe male w h o is pre g na nt, breast -fee di n g or i nte n ds t o bec o me pre g n a nt or is of c hil d-beari n g 
p ote ntial a n d n ot usi n g a hi g hl y effecti ve c o ntrace pti ve met h o d.  
4.  Partici pati o n i n a n y cli nical trial of a n a p pr o ve d or n o n -a p pr o ve d i n vesti gati o nal me dici nal 
pr o d uct wit hi n 3 0 da ys b ef ore s cree ni n g.*  
5.  A n y dis or d er, w hic h i n t he i n vesti gat or’s o pi ni o n mi g ht je o par dise p atie nt’s safet y or 
c o m plia nce wit h t he pr ot oc ol.  
6.  A n y of t he f oll o wi n g: m y ocar dial i nfarcti o n, str o ke, h os pitalisati o n f or u nsta ble a n gi na pect oris 
or tra nsie nt isc hae mic attac k  ( TI A) wit hi n t he past 6 0 da ys pri or t o t he da y of scree ni n g 
7.  Pla n ne d c or o nar y, car oti d or peri p heral art er y re v asc ularisati o n.  
8.  Heart fail ure prese ntl y cl assifie d as bei n g i n Ne w Y or k Heart Ass ociati o n ( N Y H A) Class I V.  
9.  Treat me nt wit h a n y G L P -1 rece pt or a g o n ist ( R A) wit hi n 3 0 da ys bef ore s cree ni n g. 
1 0.  U nc o ntr olle d a n d p ote nti all y u nsta ble dia b etic reti n o pat h y or mac ul o pat h y. Verifie d b y a f u n d us 
e x a mi nati o n perf or me d wit hi n t he past 9 0 da ys pri or t o scree ni n g or i n t he peri o d bet wee n 
scree ni n g a n d ra n d o misati o n. P har mac ol o gi cal p u pil -dilati o n is a re q uire me nt u nless usi n g a 
di gital f u n d us p h ot o gra p h y ca mera s pecifi e d f or n o n -dilate d e x a mi nati o n.  
1 1.  Prese nce or hist or y of mali g na nt ne o plas m wit hi n 5 years pri or t o t he d a y of scree ni n g. Basal 
a n d s q ua m o us cell s ki n ca ncer a n d a n y carci n o ma i n -sit u is all o we d. 
1 2.  Pers o nal or first de gree relati ve(s) hist or y of M E N 2 or M T C.  
1 3.  E n d sta ge re n al disease or c hr o nic or i nter mitte nt hae m o dial ysis or perit o n eal dial ysis.  
1 4.  Hist or y of m aj or s ur gical pr oce d ures i n v ol vi n g t he st o mac h or s mall i ntesti ne p ote ntiall y 
affecti n g a bs or pti o n of dr u gs a n d/ or n utrie nts, as j u d ge d b y t h e i n vesti gat or.  
* Si m ulta ne o us partici pati o n i n a trial wit h t he pri mar y o bj ecti ve of e val uati n g a n a p pr o ve d or n o n -
a p pr o ve d i n vesti gati o nal me dici nal pr o d uct f or pre v e nti o n or treat me nt of C O VI D -1 9 disease or 
p osti nfecti o us c o n diti o ns is all o we d if t he last d ose of t he i n vesti gati o nal me dici nal pr o d uct has 
bee n recei ve d m ore t ha n 3 0 da ys b ef ore scree ni n g.    
Ar ge nti na, A ustria, Bel gi u m, Brazil, C hi na, De n mar k, T haila n d a n d U nite d Ki n g d o m: F or c o u ntr y 
s pecific re q uire me nts, pl ease see A p pe n di x 8 . 
6. 3  
J ustific ati o n f or d ose  
T hree d oses of oral s e ma gl uti de ha v e bee n i n v esti gat e d i n t he p hase 3 a de v el o p me nt pr o gra m me: 
3  m g, 7 m g a n d 1 4 m g. T he selecte d d os es are bas e d o n t he data deri ve d fr o m t he N N 9 9 2 4 -3 7 9 0 
d ose -fi n di n g trial. F or f urt her details re gar di n g t he res ults o btai ne d i n t he p hase 2 d ose-fi n di n g trial 
( N N 9 9 2 4-3 7 9 0), pl ease refer t o t he c urre nt e diti o n of t he I B f or oral a d mi nistrati o n of se ma gl uti de 
( N N 9 9 2 4), or a n y u p dates t heret o. 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
2 5  of 8 9  
 
Si milar t o ot her car di o vasc ular o utc o mes trials, t h e ma xi m u m treat me nt d ose ( 1 4 m g oral  se ma-
gl uti de) will be i n vesti gate d a n d c o m pare d t o place b o i n t he prese nt trial.  
6. 4  
Lif est yle restricti o ns  
N ot a p plica ble.  
6. 5  
Scree n f ail ures  
Scree n fail ures are defi ne d as patie nts w h o c o nse nt t o partici pate i n t he cli ni cal trial b ut are n ot 
eli gi ble f or part ici pati o n acc or di n g t o i n/e xcl usi o n criteria. 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 re p orti n g of scree n fail ure patie nts t o meet 
re q uire me nts 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 eli gi bilit y crit eria. A scree n fail ure s essi o n m ust be ma de i n t he i nteracti ve we b res p o ns e 
s yste m (I W R S).  
If patie nts wit h dra w t h eir c o nse nt pri or t o ra n d o misati o n or d o n ot ret ur n f or ra n d o misati o n a scree n 
fail ure sessi o n m ust be m a de i n t he i nteracti ve we b res p o nse s yste m (I W R S). T he reas o n f or fail ure 
will i n all cases be ca pt ur e d i n t he electr o ni c cas e re p ort f or ms (e C R F).  
D ue t o t he l o n g recr uit me nt peri o d re -scree ni n g is all o we d. A ne w patie nt n u m ber m ust be assi g n e d 
i n t he I W R S. 
6. 6  
Assess me nt of eli gi bilit y  
It is t he res p o nsi bilit y of t he i n vesti gat or t o h a ve s ufficie nt e vi de n ce t o e ns ure eli gi bilit y. If a patie nt 
is n ot fr o m t he i n vesti gat ors practice; reas o na ble eff orts m ust be ma de t o o btai n a c o p y of t he 
patie nt’s me dical r ec or ds fr o m rele v a nt part y e. g. t he pri mar y p h ysicia n a n d h os pitals. It is at t he 
i n vesti gat or’s discreti o n o n a case b y cas e basis t o deci de if t he c o m plete m e dical rec or ds are 
nee de d or if t he a v aila ble d oc u me ntati o n is e n o u g h t o deter mi ne w het her a patie nt is eli gi ble. T he 
val ues  use d t o assess eli gi bilit y m ust refl ect t he patie nt’s c urre nt h ealt h stat us.  
7  
Tre at me nts  
7. 1  
Tre at me nts a d mi nistere d  
T he f oll o wi n g tri al pr o d u cts will be pr o vi de d b y N o v o N or dis k A/ S, De n mar k:  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
2 6  of 8 9  
 
T a ble  7 -1  
Tri al pr o d ucts pr o vi de d b y N o v o N or dis k A/ S  
Tri al pr o d uct  
Stre n gt h  
D os a ge f or m  
R o ute of 
a d mi nistr ati o n  
C o nt ai ner/  
deli ver y de vice  
Se ma gl uti de 3 m g ta blet  
(I M P, test pr o d uct) 
3 m g  
T a blet  
Oral  
D ose -pac k a 
Se ma gl uti de 7 m g ta blet  
(I M P, test pr o d uct) 
7 m g  
Se ma gl uti de 1 4 m g ta blet  
(I M P, test pr o d uct) 
1 4 m g  
Place b o ta blet  
(I M P, refere nce t hera p y) 
N A  
a A  d ose -pac k c o ntai ns o ne blister car d wit h 7 ta blets  
T he acti ve trial pr o d uct a n d t he c orres p o n di n g place b o are pac ke d bli n de d a n d are i d e ntical wit h 
re gar d t o vis ual a p p eara n ce. F urt her m ore, all ta blets are vis uall y i d e ntical t o eac h ot her, irres p ecti ve 
of  d ose le vels. Stre n gt h will be writte n o n t he d ose -pac k e. g. Se ma gl uti de 3  m g or place b o.  
All baseli ne assess me nts m ust be d o ne pri or t o a d mi nistrati o n of t he first d ose of trial pr o d uct. T h e 
patie nts m ust be trai ne d i n d osi n g i nstr ucti o ns (see Secti o n 7. 2. 1 ). T he i n vesti gat or m ust d oc u me nt 
t hat patie nts are tr ai ne d i n t he d osi n g i nstr ucti o ns acc or di n g t o Secti o n 2 . 
A u xiliar y s u p plies are pr o vi de d b y N o v o N or dis k:  
•  bl o o d gl uc ose met ers i ncl u di n g la ncets, test stri ps, c o ntr ol s ol uti o ns a n d i nstr ucti o ns f or use  
At ( or after) t he ra n d o misati o n visit patie nts ma y be pr o vi de d wit h a bl o o d gl uc ose  m eter. T h e 
patie nts will be i nstr ucte d i n h o w t o use t he de vice a n d t he i nstr ucti o ns will be re peate d d uri n g t he 
trial as nee d e d. T he i n vesti gat or or t h e i n di vi d ual patie nt ma y c h o ose t o c o nti n ue usi n g t heir o w n 
gl uc ose m eter or deci de t hat self -meas ure me nt of gl uc ose is n ot nee de d. If circ u msta nces c ha n ge, 
t he n t he gl u c ose meter ca n be pr o vi de d. 
7. 2  
D ose m o dific ati o n  
Ra n d o mise d patie nts will i nitiate treat me nt wit h 3 m g oral s e ma gl uti de/ place b o O D a n d f oll o w a 
fi x e d 4-wee k d ose escalati o n re gi me n u ntil reac hi n g t he treat me nt d ose of 1 4 m g oral se ma gl uti de/ 
place b o O D as ill ustrate d i n Ta ble  7 -2 .  
T he 4 -wee k d ose escalati o n i nter val is a p plie d i n or der t o mi ti gat e t he ris k of gastr oi ntesti nal A Es.  
Patie nts s h o ul d re mai n o n t he 1 4 m g d ose le vel u ntil t he e n d of treat me nt visit; h o we ver, d ose 
re d ucti o ns, e xte nsi o ns of d ose escal ati o n i nter vals a n d treat me nt pa us es are all o we d e. g. if treat me nt 
wit h t he trial p r o d uct is ass ociate d wit h u nacce pta ble A Es or d ue t o ot her circ u msta nces.  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
2 7  of 8 9  
 
T a ble  7 -2  
Tre at me nt a n d tri al peri o ds  
Tri al peri o ds  
Scree ni n g  
D ose esc al ati o n  
D ose esc al ati o n  
M ai nte n a nce  
F oll o w -u p  
Visits i n e a c h 
peri o d  
Visit 1 t o  
Visit 2  
Visit 2 t o Visit 3  
Visit 3 t o Visit 4  
Visit 4 t o e n d of 
treat me nt Visit 
E n d of treat me nt 
Visit t o F oll o w -u p 
Visit  
D ur ati o n  
U p t o  
3 wee ks  
4 wee ks  
4 wee ks  
U p t o ~ 5 8 m o nt hs  
5 wee ks  
D ail y d ose  
- 
3 m g  
7 m g  
1 4 m g  
- 
A n y c ha n ge t o trial pr o d uct d ose i ncl u di n g d ate of c ha n ge or disc o nti n uati o n s h o ul d be rec or de d i n 
t he e C R F t hr o u g h o ut t he trial. 
If trial pr o d uct is disc o nti n ue d, patie nts s h o ul d c o nti n ue t o f oll o w t he trial sc he d ule wit h o ut bei n g 
wit h dra w n fr o m t he tri al. Treat me nt wi t h trial pr o d uct s h o ul d be res u me d if dee me d s afe at t he 
discreti o n of t he i n vesti gat or.  
7. 2. 1  
D osi n g i nstr ucti o ns  
A bs or pti o n of oral se ma gl uti de is si g nifica ntl y affecte d b y f o o d a n d fl ui d i n t he st o mac h, t heref ore 
d osi n g s h o ul d be i n t he m or ni n g i n a fasti n g s tat e a n d at least 3 0 mi n utes b ef ore t h e first meal of t h e 
da y. Oral se m a gl uti de ca n be ta ke n wit h u p t o half a gl ass of wat er (a p pr o xi matel y 1 2 0 m L/ 4 fl ui d 
oz.). T he ta blet s h o ul d be ta ke n i m me diatel y after re m o val fr o m t he blister a n d s wall o we d w h ol e 
a n d m ust n ot be br o ke n or c he w e d. Ot her oral me dicati o n s h o ul d n ot be ta ke n t o get her wit h trial 
pr o d uct b ut ca n be t a ke n 3 0 mi n utes after trial pr o d uct.  
7. 2. 2  
Misse d d oses  
T he trial pr o d uct s h o ul d be a d mi nistere d o nce dail y; h o we v er, if o ne or m ore d oses of tri al  pr o d uct 
are misse d d ue t o circ u msta nces n ot relat e d t o t he safe use of t he trial pr o d u ct (as j u d ge d b y t he 
i n vesti gat or) a n d treat me nt wit h trial pr o d uct is res u me d, t he bel o w rec o m me n dati o ns f or d ose 
a dj ust me nt a p pl y:  
•  If ≤ 2 1 c o nsec uti ve d oses of 1 4 m g oral se ma gl uti de/ place b o are misse d, t h e o nce d ail y 
re gi me n ca n b e res u me d as prescri be d wit h o ut d ose re d ucti o n.  
•  If 2 2-3 5 c o ns ec uti ve d os es of 1 4 m g oral se ma gl uti de/ place b o are misse d, it is 
rec o m me n de d t o res u me treat me nt at 7 m g oral se ma gl uti de/ place bo a n d s u bse q ue ntl y, 
escalate t o t he hi g h er d os e after 4 wee ks of treat me nt.  
•  If ≥ 3 6 c o nsec uti ve d oses of 1 4 m g oral se ma gl uti de/ place b o are misse d, it is rec o m me n de d 
t o res u me treat me nt at 3 m g oral s e ma gl uti de/ place b o a n d s u bse q ue ntl y, es calate t o t he 
hi g her d os es wit h 4 -wee k d ose escal ati o n ste ps.  
Please refer t o secti o n 8. 1. 1  f or i nstr ucti o ns o n h o w t o use t he I W R S i n rel ati o n t o patie nts 
disc o nt i n ui n g a n d res u mi n g trial pr o d u ct treat me nt. 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
2 8  of 8 9  
 
I n case of q uesti o ns relat e d t o res u mi n g tri al treat me nt, t he i n vesti gat or ca n c o ns ult N o v o N or dis k.  
7. 3  
Met h o d of tre at me nt assi g n me nt  
All patie nts will be ce ntr all y ra n d o mise d usi n g a n I W R S a n d assi g n e d t o t he ne xt a vaila ble 
treat me nt acc or di n g t o ra n d o misati o n sc he d ule. Trial pr o d uct will be dis pe nse d at t he trial visits 
s u m marise d i n t he fl o wc hart, Secti o n 2 .  
At scree ni n g, eac h p atie nt will be assi g ne d a u ni q ue 6 -di git patie nt n u m ber w hic h will re mai n t he 
sa me t hr o u g h o ut t he trial. Eac h site is assi g n e d a 3-di git n u m ber a n d all p atie nt n u m bers will start 
wit h t he site n u m ber.  
7. 4  
Bli n di n g  
T he trial pr o d ucts c o nt ai ni n g t he acti ve dr u g a n d t he place b o are vis u all y i d e ntical a n d will be 
pac ke d i n a m a n ner t hat mai ntai ns bli n di n g.  
T he I W R S is use d f or bli n d -brea ki n g i nstr ucti o ns. T he bli n d ma y b e br o ke n i n a me dical e mer ge nc y 
if k n o wi n g t he act ual tr eat me nt w o ul d i nfl ue nce t h e treat me nt of t he patie nt. N o v o N or dis k will be 
n otifie d i m me diatel y after brea ki n g t he bli n d. T he date w he n a n d reas o n w h y t he bli n d was br o ke n 
m ust be rec or de d i n t he s o urce d oc u m e ntati o n.  
W he ne ver t he bli n d is br o ke n, t he pers o n brea ki n g t he bli n d m ust pri nt t he "c o d e brea k 
c o nfir mati o n" n otificati o n ge n erat e d b y t he I W R S, rec or d t h e reas o n a n d si g n a n d d ate t he 
d oc u me nt.  
W he n t he bli n d is br o ke n, t he treat me nt all ocati o n will be accessi ble t o t he i n vesti gat or a n d t he 
N o v o N or dis k Gl o bal Safet y d e part me nt. If I W R S is n ot accessi ble at t he ti me of bli n d brea k, t he 
I W R S hel p des k s h o ul d be c o ntact e d. C o ntact details are liste d i n Attac h me nt I .   
7. 5  
Pre p ar ati o n/ H a n dli n g/ St or a ge/ Acc o u nt a bilit y  
O nl y patie nts e nr olle d i n t he trial ma y us e trial pr o d uct a n d o nl y a ut h orise d site staff ma y s u p pl y or 
a d mi nister trial pr o d uct.  
Pr o d uct st ora ge, i n -use c o n diti o ns a n d i n -use ti me will be a vaila ble o n t he l a bel a n d i n t he Tri al 
Materials Ma n ual ( T M M).  
Eac h trial site will be s u p plie d wit h s ufficie nt trial pr o d ucts f or t he trial o n a n o n -g oi n g b asis 
c o ntr olle d b y t h e I W R S. Trial pr o d uct will be distri b ute d t o t he trial sites acc or di n g t o scree ni n g 
a n d ra n d o misati o n. T he first s hi p me nt t o eac h site will be tri g gere d b y t he first patie nt scree ne d.  
T he i n vesti gat or m ust c o nfir m t hat a p pr o priat e te m perat ure c o n diti o ns ha ve bee n mai ntai ne d d uri n g 
tra nsit f or all trial pr o d ucts recei ve d a n d a n y discre pa ncies are re p ort e d a n d res ol ve d bef ore us e of 
t he trial pr o d ucts. 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
2 9  of 8 9  
 
All trial pr o d ucts m ust be st ore d i n a sec ure, c o ntr olle d, a n d m o nit ore d ( ma n ual or a ut o mate d) area 
i n acc or da nce wit h t he labelle 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 orise d site staff.  
T he i n vesti gat or m ust i nf or m N o v o N or dis k i m me diatel y if a n y trial pr o d uct has bee n st ore d o utsi de 
s pecifie d c o n diti o ns. A d diti o nal details re gar di n g ha n dli n g of te m p erat ur e de viati o ns ca n be f o u n d 
i n t he T M M.  
Trial pr o d uct t hat has b ee n st ore d i m pr o perl y m ust n ot be dis pe nse d t o a n y patie nt bef ore it has 
bee n e v al uate d a n d a p pr o ve d f or f urt her use b y N o v o N or dis k.  
Patie nts m ust e ns ure t hat all use d, partl y use d a n d u n use d trial pr o d ucts i ncl u di n g e m pt y pac ka gi n g 
material is ret ur ne d as i nstr ucte d b y t he i n vesti gat or.  
T he i n vesti gat or is res p o nsi ble f or dr u g acc o u nta bilit y a n d rec or d mai nte na nce (i.e. recei pt, 
acc o u nta bilit y a n d fi nal dis p ositi o n rec or ds).  
Dr u g ac c o u nta bilit y is perf or me d b y usi n g t he I W R S a n d m ust be d o ne o n ta blet le vel.  
Destr ucti o n of trial pr o d u cts ca n be p erf or me d o n a n o n g oi n g b asis a n d will be d o ne acc or di n g t o 
l ocal pr oce d ures after acc o u nta bilit y is fi nalise d b y t he site.  
Destr ucti o n of t rial pr o d u cts m ust be d oc u me nte d i n t he I W R S.  
All ret ur ne d, e x pire d or da ma ge d trial pr o d u cts (f or tec h nical c o m plai nt sa m ples see A p pe n di x 6 ) 
m ust  be st ore d se paratel y fr o m n o n -all ocat e d trial pr o d ucts. N o te m perat ure m o nit ori n g is re q uire d.  
N o n -all ocate d trial pr o d u cts i ncl u di n g e x pire d or da ma ge d pr o d u cts m ust be acc o u nte d as u n use d, 
at t he latest at cl os ure of t he trial site.  
7. 5. 1  
S hi p me nt of tri al p r o d uct t o p atie nt’s h o me  
F or sele cte d c o u ntri es a n d if per mitte d b y l o cal re g ulati o ns t he i n vesti gat or ma y offer t o s e n d trial 
pr o d uct a n d a u xiliaries fr o m t he trial site or p har m ac y t o t he patie nt’s h o me b y c o urier ser vice.  
T he pr ocess f or se n di n g trial p r o d uct fr o m t he tri al site or p har mac y t o a patie nt’s h o me is descri be d 
i n t he “ Trial site/ p har mac y i nstr ucti o n f or s hi p me nt of trial pr o d uct t o patie nts’ h o mes” d oc u me nt. 
T his d oc u me nt c o ntai ns detaile d i nstr ucti o ns f or pre pari n g p ac ka gi n g a n d setti n g u p t he pic k-u p of 
trial pr o d uct, ha n d o ver of trial pr o d uct fr o m t he tri al site or p har mac y staff t o t he c o urier, re q uir e d 
te m perat ur e m o nit ori n g of trial pr o d uct, deli ver y t o a n d recei pt of trial pr o d uct b y t he patie nt. T he 
pr ocess f or ret ur ni n g trial pr o d uct  t o t he trial site or p har mac y b y c o urier is als o descri be d i n t his 
d oc u me nt.  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 0  of 8 9  
 
I n v esti gat ors, trial site/ p har mac y staff a n d p atie nts w h o will be i n v ol ve d i n s hi p me nt of trial pr o d uct 
t o t he patie nt’s h o me will be a de q u atel y trai ne d i n t his pr ocess. 
J a pa n: For c o u ntr y s pecific re q uire m e nts, please s ee A p pe n di x 8 . 
7. 6  
Tre at me nt c o m pli a nce  
T hr o u g h o ut t he tri al, t he i n vesti gat or will re mi n d t he patie nt t o f oll o w  t he trial pr oce d ures a n d 
re q uire me nts t o e ns ur e p atie nt c o m plia nce. 
Treat me nt c o m plia nce will be assesse d b y m o nit ori n g of dr u g acc o u nta bilit y a n d b y dis c ussi n g 
treat me nt c o m plia nce a n d d osi n g c o n diti o ns wit h t he patie nt. Treat me nt c o m plia nce is defi ne d as 
ta ki n g bet w ee n 8 0 %-1 2 0 % of t he d ose as prescri b e d bet wee n visits. T he i n vesti gat or m ust assess 
t he a m o u nt of trial pr o d u cts ret ur ne d c o m pare d t o w hat was dis pe nse d at t he pre vi o us visit a n d, i n 
case of discre p a ncies, q u esti o n t he patie nt.  
If a patie nt is f o u n d t o be n o n-c o m plia nt, t he i n vesti gat or will re mi n d t he patie nt of t he i m p orta nce 
of f oll o wi n g t he i nstr ucti o ns gi ve n i ncl u di n g ta ki n g t he trial pr o d ucts as prescri be d a n d s h o ul d 
d oc u me nt t his disc ussi o n i n t he patie nt’s me dical r ec or d.  
If t he patie nt has b ee n off treat me nt, c o nti n uati o n of trial pr o d uct s h o ul d be e nc o ura ge d if 
c o nsi dere d safe as per t h e i n vesti gat or’s discreti o n. Pre vi o us d ose a n d gastr oi ntesti nal a d verse 
reacti o ns as w ell as n u m ber of misse d d oses s h o ul d be ta ke n i nt o c o nsi derati o n whe n e val u ati n g 
w het her t o r e peat d ose es calati o n (see secti o n 7. 2. 2 ). 
7. 7  
C o nc o mit a nt me dic ati o n  
O nl y me dicati o n ot her t h a n t he trial pr o d uct t hat t he patie nt is recei vi n g at t he ti me of 
ra n d o misati o n or recei ves d uri n g t he trial f or t he f oll o wi n g reas o ns m ust be rec or de d i n t he e C R F: 
•  T o treat dia betes  
•  T o treat or pre ve nt C V diseases (f or e x a m ple a nti -h y perte nsi ves, li pi d -l o weri n g a ge nts, 
a ntic oa g ula nts,  as piri n a n d ot her a nti platelet a ge nts)  
•  I n relati o n t o a n S A E, if rele va nt 
•  i n relati o n t o a cli nical tri al f or C O VI D-1 9 pre v e nti o n or treat me nt  
•  I n relati o n t o a n ap pr o ve d C O VI D -1 9 vacci ne  
T he i nf or mati o n c ollect e d f or eac h c o n c o mita nt me dicati o n i ncl u des m e dicati o n; start date a n d st o p 
date or c o nti n uati o n, a n d relate d A E n u m b er w he n a p plica ble.  
F or a nti dia betic m e dicati o n, t he t otal dail y d ose n ee ds t o be i ncl u de d i n t he e C R F. Sta ble d ose 
c ha n ges ( 2 wee ks or m ore) s h o ul d be ca pt ure d as ne w c o nc o mita nt me d icati o n wit h t he ne w d ose 
a n d rele v a nt start a n d st o p date.  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 1  of 8 9  
 
C ha n ges i n c o nc o mita nt me dicati o n liste d a b o ve m ust be rec or de d at eac h visit. If a c ha n ge is d u e t o 
a n S A E, t he n t his m ust be re p ort e d acc or di n g t o Secti o n 9. 2 . 
I nitiati n g treat me nt wit h a n y ot h er G L P-1 rece pt or a g o nists are n ot per mitte d d uri n g t he e ntire tri al. 
Ot her c ha n ges t o bac k gr o u n d me dicati o ns ca n ta ke place d uri n g t h e trial. Ris k of h y p o gl ycae mic 
e pis o des is descri be d i n s ecti o n 3. 3. 1 . 
I m p ort a ntl y, i n vesti gat ors s h o ul d e ns ure t hat patie nts are treate d acc or di n g t o rec o m me n de d 
sta n dar d of care f or b ot h gl ycae mic ma na ge me nt as well as C V ris k ma na ge me nt. Rec o m me n -
dati o ns f or t his will be pr o vi de d i n g ui da nce d oc u me nts fr o m t he steeri n g c o m mittee a n d gl o bal 
e x pert pa nel d uri n g trial c o n d uct. S ur veilla nce of a d here n ce t o sta n d ar d of care will be perf or me d 
ce ntrall y b y N o v o N or dis k. F or patie nts w h ere sta n dar d of care is n ot ac hie ve d, i n vesti gat ors ma y 
be as ke d f or a n o pti misati o n pla n w hic h will be rec or de d i n t he e C R F or a p pr oac he d t o disc uss 
treat me nt o pti o ns. If all o we d acc or di n g t o l ocal r e g ulati o n, N o v o N or dis k ma y c o m pe nsate parts of 
t he c ost of s o me c o nc o mita nt me dicati o n use d t o e ns ure gl ycae mic c o ntr ol a n d C V ris k 
ma na ge me nt.  
Brazil a n d T ur k e y: F or c o u ntr y s pecific re q uire m e nts, please see A p pe n di x 8 . 
7. 8  
Tre at me nt after t he e n d of t he tri al  
W he n disc o nti n ui n g trial pr o d uct at t he e n d of t he treat me nt peri o d, t he p atie nt s h o ul d be tra nsferre d 
t o a s uita ble mar kete d pr o d uct at t he discreti o n of t he i n vesti gat or. G L P-1 R As are n ot all o we d t o b e 
pre scri be d d uri n g t he 5 wee k f oll o w-u p p eri o d. Oral se ma gl uti de will n ot be a vaila ble f or 
prescri pti o n u ntil mar keti n g a ut h oris ati o n is iss ue d.  
Ar ge nti na a n d Brazil: F or c o u ntr y s pecific re q uire me nts, please see A p pe n di x 8 . 
 
 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 2  of 8 9  
 
8  
Disc o nti n u ati o n/ Wit h dr a w al criteri a  
8. 1  
Disc o nti n u ati o n of tri al tre at me nt  
T he patie nt m ust be disc o nti n ue d fr o m trial pr o d u ct at a n y ti me d uri n g t he trial, if a n y of t he 
f oll o win g a p plies:  
1.  Pre g n a nc y  
2.  I nte nti o n of b ec o mi n g pre g n a nt 
3.  Si m ulta ne o us partici pati o n i n a n ot her cli nical trial of a n a p pr o ve d or n o n -a p pr o ve d 
i n vesti gati o nal me dici nal pr o d uct*  
4.  If ac ut e pa ncreatitis is s us pecte d, trial pr o d u ct s h o ul d be disc o nti n ue d; if c o nfir me d, trial 
pr o d uct s h o ul d n ot be restarte d  
5.  Ot her safet y c o ncer ns, at t he discreti o n of t he i n vesti gat or  
* Si m ulta ne o us partici pati o n i n a trial wit h t he pri mar y o bj ecti ve of e val uati n g a n a p pr o ve d or n o n -
a p pr o ve d i n vesti gati o nal me dici nal pr o d uct f or pre ve nti o n or treat me nt of C O VI D -1 9 disease or 
p osti nfecti o us c o n diti o ns is all o we d at t he i n vesti gat or discreti o n wit h o ut disc o nti n ui n g trial 
pr o d uct.   
A d 1 a n d 2: If a p atie nt i nte n ds t o bec o me pre g na nt, trial pr o d uct m ust be disc o nti n ue d at least 5 
wee ks bef ore t he c o ntrace pti ve met h o d is st o p pe d. If a patie nt b ec o mes pre g na nt u ni nte nti o nall y, 
trial pr o d uct m ust be disc o nti n ue d i m me diatel y d uri n g pre g na n c y, a n d d uri n g breast fee di n g. T he 
patie nt will c o nti n ue t he ot her trial pr oce d ures or will be f oll o w e d-u p via p h o ne c o ntacts.  
A d 3: Patie nts s h o ul d be a d vise d n ot t o partici pate i n ot her cli nical trials, w hile partici pati n g i n t his 
trial. If d o ne, tr eat me nt wit h trial pr o d uct s h o ul d be disc o nti n ue d. If partici pati o n i n t he ot her trial is 
st o p pe d, treat me nt c a n be res u me d if t here are n o s afet y c o n cer ns at t he discreti o n of t he 
i n vesti gat or after disc ussi n g wit h a N o v o N or dis k me dical e x pert. 
T he patie nt ma y be disc o nti n ue d fr o m trial pr o d uct at a n y ti me d uri n g t he trial at t he discreti o n of 
t he i n vesti gat or f or safet y, c o m plia n ce or a d mi nistrati ve reas o ns. Treat me nt wit h trial pr o d uct ca n 
be res u me d if lat er dee m e d safe.  
Te m p orar y or per ma n e nt disc o nti n uati o n of treat me nt wit h trial pr o d uct will n ot lea d t o wit h dra wal 
fr o m t he trial.  
W he n i nitiati n g ne w  a nti-dia betic treat me nt after t he disc o nti n uati o n of trial pr o d uct, t he half -life of 
se ma gl uti de of a p pr o xi matel y o n e wee k s h o ul d be ke pt i n mi n d. 
T he pri mar y reas o n f or disc o nti n uati o n of trial pr o d uct m ust be s pecifie d i n t he e C R F, a n d dr u g 
acc o u nta bili t y m ust be p erf or me d.  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 3  of 8 9  
 
8. 1. 1  
Te m p or a r y disc o nti n u ati o n of tri al tre at me nt  
Te m p orar y tr eat me nt dis c o nti n uati o n is all o we d at t he discreti o n of t he i n v esti gat or a n d t he reas o n 
f or disc o nti n uati o n m ust be rec or de d i n t he e C R F. Treat me nt wit h trial pr o d uct s h o ul d be res u me d 
if t he circ u msta nces later all o w ( Secti o n 7. 1 ). Si milarl y, patie nts w h o disc o nti n ue trial pr o d uct o n 
t heir o w n i nitiati ve s h o ul d be e nc o urage d t o r es u me t he treat me nt ( Secti o n 7. 1 ). At b ot h i nsta nces 
d ose escal ati o n ma y b e n ecessar y ( Secti o n 7. 2. 2 ). Date a n d last trial pr o d u ct d ose s h o ul d be 
rec or de d i n t he e C R F. A treat me nt stat us sessi o n i n t he I W R S s h o ul d be perf or me d w he n a p atie nt 
is o n treat me nt pa use or res u mes treat me nt. 
8. 2  
Wit h dr a w al fr o m t he tri al  
A patie nt ma y wit h dra w c o nse nt at a n y ti me at his/ her o w n re q u est.  
If c o nsi deri n g wit h dr a wi n g fr o m t he trial, t he pati e nt s h o ul d, as a n alter nati ve, be offere d fle xi ble 
partici pati o n i n t he trial. T his c o ul d be atte n di n g fe wer visits (i.e. re d uce d visit sc he d ule), 
c o n verti n g site visits t o p h o ne c o ntacts, treat me nt  pa use, or o nl y bei n g f oll o we d -u p f or A Es, 
es peciall y t h ose relate d t o t he pri mar y o bjecti ve. A n ot her alter nati ve c o ul d be t o ceas e all trial 
relate d acti vities i ncl u di n g trial pr o d u ct, a n d si m pl y recei v e a p h o ne call at trial e n d t o c ollect A Es. 
It m ust be e x plai ne d t o t he patie nt t hat t his m ust i ncl u de i nf or mati o n o n t heir A Es, es peciall y t h ose 
relate d t o t he pri mar y o bjecti ve t hat occ urre d si n ce last c o ntact t o t he patie nt. O nl y if t he patie nt 
decli nes all alter nati ves, s h o ul d t he patie nt be rec or de d as wit h dr a w n.  
Fi nal dr u g acc o u nta bilit y m ust be perf or me d e ve n if t he patie nt is n ot a ble t o c o me t o t he trial site.  
If a patie nt wit h dra ws fr o m t he trial, he/s he 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 me dical rec or d. 
If t he patie nt wit h dra ws c o nse nt, N o v o N or dis k ma y retai n a n d c o nti n ue t o use a n y data c ollecte d 
bef ore s u c h a wit h dr a wal of c o nse nt.  
Alt h o u g h a p atie nt is n ot o bli ge d t o gi ve his/ her reas o n(s) f or wit h dra wi n g, t he i n vesti gat or  m ust 
ma ke a reas o na bl e eff ort t o ascertai n t he reas o n(s), w hile f ull y res pecti n g t h e patie nt's ri g hts. W here 
t he reas o ns are o btai n e d, t he pri mar y reas o n f or wit h dra wal m ust be s pecifie d i n t he e n d of trial 
f or m i n t he e C R F. 
F or patie nts w h o are wit h dra w n , w h e n t he trial c o mes t o a n e n d, t he i n vesti gat or m ust scr uti nise 
p u blicl y a v aila ble re gistri es t o deter mi ne vital stat us, u nless pr o hi bite d b y l ocal re g ulati o ns or 
s pecificall y pr o hi bite d b y t he patie nt u p o n wit h dra wal of c o nse nt. Pleas e als o refer t o se cti o n 5. 2  f or 
f urt her det ails. 
Me xic o: F or c o u ntr y s pecific re q uir e me nts, pleas e see  A p pe n di x 8 . 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 4  of 8 9  
 
8. 2. 1  
Re pl ace me nt of p atie nts  
Patie nts w h o disc o nti n ue trial pr o d uct or wit h dra w fr o m trial will n ot be re place d.  
8. 3  
L ost t o f oll o w -u p  
A patie nt will be c o nsi dere d l ost t o f oll o w -u p if he or s he re peat e dl y fails t o ret ur n f or sc he d ule d 
visits a n d is u na ble t o be c o ntacte d b y t he tri al site.  
•  Bef ore a p atie nt is dee me d l ost t o f oll o w -u p, t he i n vesti gat or m ust ma ke e ver y eff ort t o 
re gai n c onta ct wit h t he p atie nt as descri b e d i n Secti o n 5. 2 . 
•  A patie nt ca n n ot be d eclare d l ost t o f oll o w -u p bef ore all t he atte m pts ha ve b ee n re p eate d a n d 
t he trial has c o me t o a n e n d as descri be d i n Secti o n 5. 2 . 
T he atte m pts t o c o ntact t he patie nt m ust be d oc u me nte d i n me dical rec or ds at t he site.  
9  
Tri a l assess me nts a n d pr oce d ures 
•  Trial pr oce d ures a n d t h eir ti mi n g are s u m marise d i n t he fl o wc hart, Secti o n 2 .  
•  I nf or me d c o ns e nt m ust be o btai ne d bef ore a n y trial relate d acti vit y, see A p pe n di x 3 . 
•  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 patie nts 
meet all e li gi bilit y criteri a.  
•  T he i n vesti gat or will mai ntai n a scree ni n g l o g t o r ec or d det ails of all patie nts scree ne d a n d 
t o c o nfir m eli gi bilit y or rec or d reas o n f or scree n fail ure, as a p plica ble. 
•  At scree ni n g, p atie nts will be pr o vi de d wit h a car d stati n g t hat t he y are partici pati n g i n a 
trial a n d gi vi n g c o nt act d etails of rele va nt trial site staff.  
•  A d here n ce t o t he trial 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 fl o wc hart, is 
esse ntial a n d re q uire d f or trial c o n d uct.  
•  T he i n vesti gat or s h o ul d i nf or m  t he patie nts’ pri mar y p h ysici a n a b o ut t he patie nts’ 
partici pati o n i n t he trial if t he patie nt has a pri mar y p h ysicia n a n d if t he patie nt a grees t o t he 
pri mar y p h ysicia n bei n g i nf or me d.  
•  Eac h patie nt s h o ul d be as ke d t o pr o vi de c o ntact i nf or mati o n f or pers o n s ( prefera bl y at least 
3), e. g. rel ati ves, pri mar y care pr o vi der or ot her, w h o m i n vesti gat or ca n c o ntact i n case of 
iss ues w he n tr yi n g t o c o ntact t he patie nt d uri n g t he trial. T he sites are e nc o ura ge d t o 
mai ntai n t hese details as c urre nt as p ossi ble t hr o u g h o ut t he c o urse of t he trial.  
•  T he ra n d o misati o n visit ca n be perf or me d o n t he s a me da y as t he s cree ni n g visit if t he 
patie nt is assesse d as eli gi ble ( Secti o n 6 ) a n d if s ufficie nt trial pr o d uct is a v aila ble.  
•  It is t he res p o nsi bilit y of t he i n vesti gat or t o sc he d ule t he visits a n d c o ntacts as per pr ot oc ol 
(fl o wc hart, Secti o n 2 ) a n d t o e ns ure t he y ta ke place. 
•  After V 6, all o d d n u m bere d site visits ( V 7, V 9, V 1 1 etc.) ca n be c o n d u cte d as a p h o ne 
c o ntact, h o we v er  t he i n v esti gat or n ee ds t o e ns ure t hat t he s u bject has e n o u g h trial pr o d u ct 
wit hi n t he e x pir y d ate . 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 5  of 8 9  
 
•  T he i n vesti gat or m ust e ns ure t he y kee p re g ular c o ntact wit h eac h p atie nt t hr o u g h o ut t he 
e ntire trial, a n d at all ti mes ha ve u p dat e d c o ntact i nf or mati o n. E ve n if a visit ( or p h o ne 
c o ntact) is misse d a n d it is n ot p ossi ble t o re -sc he d ule, t he i n vesti gat or m ust ta ke e ver y 
eff ort t o ha v e all patie nts f oll o we d f or e n d p oi nt relate d o utc o mes i ncl u di n g M A C E.  
•  T he site m ust atte m pt t o c o ntact t he patie nt a n d resc he d ule  t he misse d visit as s o o n as 
p ossi ble a n d c o u nsel t he patie nt o n t he i m p orta nce of mai ntai ni n g t he assi g ne d visit 
sc he d ule a n d ascertai n w het her or n ot t he p atie nt wis hes t o a n d/ or s h o ul d c o nti n ue i n t he 
trial. 
•  Re vie w of c o m plete d l a b orat or y re p orts etc. m ust be d oc u me nte d eit her o n t he d oc u me nts 
or i n t he patie nt's s o urce d oc u me nts.  
•  Re peat sa m ples ma y be t a ke n f or t ec h nical iss ues a n d u nsc he d ule d s a m ples or assess me nts 
ma y b e ta ke n f or safet y reas o ns. Please refer t o A p pe n di x 2  f or f urt her det ails o n la b orat or y 
sa m ples. 
•  T he i n vesti gat or ma y pr o vi de t he patie nts wit h a m o bile p h o ne t o me diate easier c o ntact if 
all o we d acc or di n g t o l ocal re g ulati o n a n d  a p pr o ve d b y i nstit uti o nal re vie w b oar d 
(I R B)/i n de p e n de nt et hics c o m mittee (I E C). T he i n vesti gat or s h o ul d c o nsi d er se n di n g t e xt 
messa ges t o t he patie nts t o re mi n d t he m of site visits, d osi n g of trial pr o d uct, a n d ot her trial 
re q uire me nts.  
•  If warra nte d b y s p ecial circ u msta nces, t he i n v esti gat or ma y e n ga ge wit h a healt h care 
pr ofessi o nal fr o m a t hir d part y h o m e healt h care ser vice pr o vi der t o perf or m pr ot oc ol 
pr oce d ures at t he s u bject’s h o me or ot her alter nat e l ocati o n. Pri or t o t he arra n ge me nt, t he 
i n vesti gat or m ust o btai n t he s u bject’s c o ns e nt b y mea ns of se parate a n d l o call y a p pr o ve d 
c o nse nt f or m. T he t hir d part y h ealt h care pr ofessi o nal m ust ha ve a lice n ce t o practice a n d 
ha ve recei ve d a de q u ate pr ot oc ol trai ni n g.  
9. 1  
Effic ac y assess me nts  
Pla n ne d ti me p oi nts f or all efficac y assess me nts are pr o vi de d i n t he fl o w c hart Secti o n 2 . 
9. 1. 1  
H b A 1c p oi nt of c are  
H b A 1 c ca n be meas ur e d w hile patie nt is  at site f or assessi n g eli gi bilit y at Visit 1 a n d at site visits 
d uri n g t he tri al as a s u p p orti ve meas ure m e nt f or i n vesti gat or’s treat me nt d ecisi o ns. Sites will eit her 
use t heir o w n e q ui p me nt or a de vic e pr o vi de d b y N o v o N or dis k. L ocal la b orat or y ca n be us e d if t h e 
H b A 1 c p oi nt of care de vi ce f or a n y reas o n ca n n ot be use d. P oi nt of care de vice meas ure me nts 
perf or me d at sc he d ul e d visits s h o ul d be rec or de d i n t he e C R F starti n g at Visit 3.  
9. 1. 2  
Self -me as ure d pl as m a gl uc ose  
If dee m e d hel pf ul b y t he i n vesti gat or, p atie nts ma y be pr o vi de d wit h a B G meter i ncl u di n g 
a u xiliaries as well as i nstr ucti o ns f or use. T h e pati e nts will be i nstr ucte d i n h o w t o use t he de vice 
a n d t he i nstr ucti o n will be re peate d as n ee d e d. T h e i n vesti gat or will a d vise t he i n di vi d ual patie nt of 
w he n t he self -m eas ur e d plas ma gl uc os e val ues s h o ul d be meas ure d a n d h o w t o n ote t he val ues a n d 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 6  of 8 9  
 
dates. T he me as ure me nts are s u p p orti ve f or i n vesti gat or’s treat me nt d ecisi o ns w he n o pti misi n g 
gl ycae mic c o ntr ol, a n d s h o ul d be file d at site.  
9. 1. 3  
Cli nic al effic ac y l a b o r at or y assess me nts  
All pr ot oc ol -re q uir e d la b orat or y assess me nts, as defi ne d i n A p pe n di x 2 , m ust be c o n d ucte d i n 
acc or da nce wit h t he fl o wc hart (see Secti o n 2 ) a n d t he la b orat or y ma n ual. 
9. 1. 4  
C o g niti ve testi n g, p atie nt s ur ve ys a n d visits t o e mer g e nc y r o o m/ ur g e nt c are u nit  
T he M o ntreal C o g niti ve Assess me nt ( M o C A) is t he c o g niti ve testi n g us e d i n t his trial. If 
clarificati o n of t he test is nee de d, care m ust be ta ke n n ot t o bias t he patie nt.  
Ar ge nti na, Ca na d a, C ol o m bia, Me xic o, S pai n, U nite d Ki n g d o m a n d U nite d States:  
O nli ne c o g niti ve testi n g will be perf or me d usi n g t he P R O T E C T C o g niti ve Test Batter y i n E n glis h 
a n d/ or S pa nis h s pea ki n g patie nts. T he test batter y i ncl u des t he f oll o wi n g t ests:  
•  
Ver bal  Reas o ni n g  
•  
Paire d Ass ociate Lear ni n g  
•  
Self -Or dere d Searc h  
•  
Di git Vi gila nce  
•  
Si m ple Reacti o n Ti me  
•  
C h oice Reacti o n Ti me  
Perf or mi n g t he tests c o m prise d oi n g a pre -test f or practice as well as a n act ual test. T he tests s h o ul d 
be perf or me d at visits s pecifie d i n t he fl o wc hart (see Secti o n 2 ). 
Patie nt s ur ve ys will be perf or me d i n a s u bset of p atie nts i n selecte d c o u ntri es:  
•  A patie nt e x pectati o ns a n d e x perie nce s ur ve y. T his data will n ot be tra nsferre d t o t he trial 
data base.  
•  A patie nt e n ga ge me nt assess me nt. T his data will n ot be tra nsferre d t o t he trial data bas e.  
Visits t o e mer ge n c y r o o m/ ur ge nt c are u nit will be rec or de d i n t he e C R F f or t he U S.  
9. 2  
A d verse e v e nts  
T he defi niti o ns of A Es a n d S A Es ca n be f o u n d i n A p pe n di x 4 . 
J a pa n: F or A E re p orti n g re q uire me nts please see A p pe n di x 8 . 
T his trial e m pl o ys a sel ecti ve a p pr oac h f or c ollecti o n of safet y d ata. T he i n v esti gat or is r es p o nsi ble 
f or dete cti n g, d o c u me nti n g, rec or di n g a n d f oll o wi n g u p o n: 
•  S A Es  
•  A Es  re q uiri n g e v e nt a dj u dicati o n or a d diti o nal dat a c ollecti o n o n s pecific e ve nt f or ms, 
irres pecti ve of seri o us ness, see Ta ble  9 -1  
•  A Es lea di n g t o disc o nti n uati o n of trial pr o d uct, irres pecti ve of seri o us ness 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 7  of 8 9  
 
•  A Es of  C O VI D -1 9, irres pecti ve of seri o us ness. N ote: S us pecte d C O VI D -1 9 s h o ul d be 
re p orte d if t he cli nical pr ese ntati o n is s u g gesti ve of C O VI D-1 9, e ve n i n t he a bse nce of a 
C O VI D -1 9 test or wit h o ut a p ositi ve C O VI D -1 9 t est res ult. I n t he a bse n ce of cli nical 
s y m pt o ms, a p ositi ve C O VI D-1 9 test (a nti ge n or a nti b o d y) s h o ul d be re p ort e d, if a vaila ble.  
•  Pre g n a ncies  
•  Tec h nical c o m plai nts  
T a ble  9 -1  
A Es re q u iri n g e ve nt a dj u dic ati o n or a d diti o n al d at a c ollecti o n  
E ve nt t y pe (seri o us a n d n o n -seri o us) i ncl u di n g descri pti o n 
A dj u dic ati o n 
o utc o me  
A d diti o n al 
f or m(s) re q uire d  
De at h  
All ca use deat h  
•  Car di o vasc ular 
deat h  
•  Re nal deat h  
•  N o n -car di o vasc ular, 
n o n -re nal deat h 
•  A dj u dicati o n 
f or m 
Ac ute c o r o n ar y s y n dr o me ( A C S)  
All t y pes of ac ute m y ocar dial i nfarcti o n  
U nsta ble a n gi na pect oris re q uiri n g h os pitalisati o n  
•  Ac ute m y ocar dial 
i nfarcti o n 
•  H os pitalisati o n f or 
u nsta ble a n gi na 
pect oris  
•  A dj u dicati o n 
f or m a n d 
•  S pecific e ve nt 
f or m i n case of 
re vasc ularisati o n 
E ve nts le a di n g t o c o r o n ar y arter y re v asc ul aris ati o n ( n o n -A C S)  
N o n -A C S e ve nts (e. g. sta ble a n gi na pect oris) lea di n g t o a cat heter -
base d ( perc uta ne o us c or o nar y i nter ve nti o n ( P CI)) or a s ur gic al 
pr oce d ure ( C or o nar y arter y b y pass  s ur ger y ) desi g ne d t o i m pr o ve 
m y ocar dial bl o o d fl o w  
N ote: T he u n derl yi n g c o n diti o n s h o ul d be re p orte d as t he A E 
dia g n osis  
•  N ot a p plica ble  
•  S pecific e ve nt 
f or m 
Str o ke or tr a nsie nt isc he mic att ac k  
E pis o de of f ocal or gl o bal ne ur ol o gical d ysf u ncti o n t hat c o ul d be 
ca use d b y brai n, s pi nal c or d, or reti nal vasc ular i nj ur y as a res ult of 
hae m orr ha ge or isc he mia, wit h or wit h o ut i nfarcti o n  
•  Str o ke  
•  A dj u dicati o n 
f or m 
•  M o difie d Ra n ki n 
scale f or m * 
He a rt f ail ure re q uiri n g h os pit alis ati o n or ur ge nt he art f ail ure 
visits  
Ne w e pis o de or w orse ni n g of e xisti n g heart fail ure lea di n g t o a n 
ur ge nt, u nsc he d ule d h os pital a d missi o n or cli nic/ office/e mer ge nc y 
de p art me nt visit  
•  Heart fail ure 
h os pitalisati o n  
•  Ur ge nt heart fail ure 
visit  
•  A dj u dicati o n 
f or m 
Ac ute or c hr o nic li m b isc he mi a re q uiri n g h os pit alis ati o n  
Ac ute li m b isc he mia is defi ne d as a s u d de n decrease i n li m b 
perf usi o n t hreate ni n g via bilit y of t he li m b a n d lea di n g t o a n ur ge nt, 
u nsc he d ule d h os pitalisati o n  
C hr o nic li m b isc he mia is defi ne d as a c hr o nic c o n diti o n wit h rest 
pai n, n o n -heali n g ulcers or ga n gre ne a n d lea di n g t o a n ur ge nt, 
u nsc he d ule d h os pitalisati o n wit h nee d f or i nter ve nti o n s uc h as a 
re vasc ularizati o n pr oce d ure, a m p utati o n or p har mac ol o gical 
t hera p y  
•  Ac ute li m b isc he mia 
h os pitalisati o n  
•  C hr o nic li m b 
isc he mia 
h os pital isati o n 
•  A dj u dicati o n 
f or m 
Ac ute p a ncre atitis  
E ve nts of ac ute pa ncreatitis  
•  Ac ute pa ncreatitis  
•  A dj u dicati o n 
f or m 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 8  of 8 9  
 
E ve nt t y pe (seri o us a n d n o n -seri o us) i ncl u di n g descri pti o n 
A dj u dic ati o n 
o utc o me  
A d diti o n al 
f or m(s) re q uire d  
E ve nts le a di n g t o re n al re pl ace me nt t her a p y  
Dial ysis treat me nt ( hae m o dial ysis or perit o neal dial ysis)  
Ki d ne y tra ns pla ntati o n  
N ote: T he u n derl yi n g c o n diti o n s h o ul d be re p orte d as t he A E 
dia g n osis  
•  C hr o nic re nal 
re place me nt t hera p y 
•  A dj u dicati o n 
f or m 
M ali g n a nt ne o pl as m  
Mali g na nt ne o plas m b y hist o p at h ol o g y or ot her s u bsta ntial cli nical 
e vi de nce  
•  N ot a p plica ble  
•  S pecific e ve nt 
f or m 
Di a betic reti n o p at h y  
Ne w o nset or w orse ni n g of dia betic reti n o pat h y  
•  N ot a p plica ble  
•  S pecific e ve nt 
f or m 
Ac ute g all bl a d der dise ase  
E ve nts of s y m pt o matic ac ute gall bla d der disease (i ncl u di n g 
gallst o nes a n d c h olec ystitis)  
•  N ot a p plica ble  
•  S pecific e ve nt 
f or m 
M e dic ati o n  err o rs rel ate d t o tri al pr o d uct  
Me dicati o n err or (acci de ntal err ors relate d t o trial pr o d uct):  
Wr o n g dr u g a d mi nistere d i nst ea d of trial pr o d uct.  
Wr o n g r o ute of a d mi nistrati o n or acci de ntal a d mi nistrati o n of a 
l o wer or hi g her d ose t ha n i nte n de d w here cli nical c o nse q ue nces f or 
t he patie nt were li kel y t o ha p pe n, alt h o u g h t he y di d n ot necessaril y 
occ ur  
•  N ot a p plica ble
 
 
•  S pecific e ve nt 
f or m 
Se vere h y p o gl yc a e mic e pis o de  
A n e pis o de re q uiri n g assista nc e of a n ot her pers o n t o acti vel y 
a d mi nister car b o h y drate, g l uc a g o n, or ta ke ot her c orrecti ve acti o ns. 
Plas ma gl uc ose val ues ma y n ot b e a vaila ble d uri n g a n e ve nt, b ut 
ne ur ol o gical rec o ver y f oll o wi n g t he ret ur n of plas ma gl uc os e 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 plas ma g l uc ose c o nc e ntrati o n ( A merica n Dia betes 
Ass ociati o n 1 1) 
•  N ot a p plica ble  
•  S pecific e ve nt 
f or m 
•  If t he e pis o de 
f ulfils t he criteria 
of a n S A E, a n 
A E f or m a n d a 
safet y 
i nf or mati o n f or m 
m ust als o be 
c o m plete d  
J a pa n: F or c o u ntr y 
s pecific re q uire-
me nts, see 
A p pe n di x 8 .  
* Disa bilit y after a str o ke or TI A e ve nt, see secti o n 9. 4. 5  
Descri pti o n of e v e nts is t o g ui de i n vesti gat ors wit h re gar ds t o re p orti n g of A Es. E ve nt defi niti o ns 
are i ncl u de d i n t he c harter f or t he e v e nt a dj u dicati o n c o m mittee ( E A C).  
9. 2. 1  
Ti me peri o d a n d fre q ue nc y f or c ollecti n g A E a n d S A E i nf or m ati o n 
All e ve nts meeti n g t h e defi niti o n of a n S A E (see A p pe n di x 4 ) a n d A Es lea di n g t o disc o nti n uati o n of 
trial pr o d uct, pre g n a ncies a n d e ve nts s pecifie d i n Ta ble  9 -1  m ust be c ollecte d a n d re p orte d. T hes e 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 9  of 8 9  
 
e ve nts will be c ollecte d fr o m t he da y of ra n d o misati o n a n d u ntil t he f oll o w -u p visit, at t he ti me 
p oi nts s pecifie d i n t he fl o wc hart.  
All S A Es will be rec or de d a n d re p ort e d t o N o v o N or dis k or desi g nee wi t hi n 2 4 h o urs of 
i n vesti gat or’s k n o wle d ge of t he S A E, as i n dicate d i n A p pe n di x 4 . T he i n vesti gat or m ust s u b mit a n y 
u p date d S A E data t o N o v o N or dis k wit hi n 2 4 h o urs of it bei n g a v aila ble.  
I n v esti gat ors are n ot o bli gat e d t o acti vel y see k f or A Es or S A Es i n f or mer trial patie nts. H o we v er, if 
t he i n vesti gat or l ear ns of a n y S A E, i n cl u di n g a d eat h, at a n y ti me after a patie nt has bee n 
disc o nti n ue d fr o m/c o m p lete d t he trial, a n d t he i n v esti gat or c o nsi ders t he e v e nt t o be 
p ossi bl y/ pr o ba bl y rel ate d t o t he i n vesti gati o nal trial pr o d uct or trial partici p ati o n, t he i n vesti gat or 
m ust pr o m ptl y n otif y N o v o N or dis k.  
T he met h o d of rec or di n g, e val uati n g a n d ass essi n g ca u salit y of A E a n d S A E a n d t he pr oce d ures f or 
c o m pleti n g a n d tr a ns mitti n g S A E re p orts are pr o vi de d i n A p pe n di x 4 . 
Ti meli nes f or re p orti n g of A Es, i ncl u di n g e ve nts f or a dj u dicati o n, Secti o n 9. 2. 1. 1 , are liste d i n 
Fi g ure  9 -1 . 
S o me A Es re q uire a d diti o nal data c ollecti o n via a s pecific e v e nt f or m. T he rele va nt A Es are liste d 
i n Ta ble  9 -1  a n d t he re p orti n g ti meli nes i n Fi g ure  9 -1 . 
Fi g ure  9 -1  
S afet y re p orti n g ti meli nes  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 0  of 8 9  
 
9. 2. 1. 1  
E ve nts f or a dj u dic ati o n  
T he list of e ve nts f or a dj u dicati o n ca n be f o u n d i n Ta ble  9 -1  a n d t h e re p orti n g ti meli nes i n 
Fi g ure  9 -1 . E ve nt a dj u dic ati o n will be perf or me d f or e ve nts i n ra n d o mise d patie nts. T hese e v e nts 
are re vie we d b y a n i n de p e n de nt e xter nal e ve nt a dj u dicati o n c o m mittee i n a bli n de d ma n ner, refer t o 
A p pe n di x 3  f or f urt her d etails. 
T here are f o ur wa ys t o i d e ntif y e ve nts rel e va nt f or a dj u dicati o n as descri be d bel o w:  
1.  I n v esti gat or-re p orte d e ve nts f or a dj u dicati o n: W he n re p orti n g A Es, t he i n vesti gat or m ust select 
t he ap pr o priat e A E cate g or y b ase d o n pre -defi ne d criteria (see T a ble  9 -1 ). If t he select e d A E 
cate g or y is i n sc o pe f or a dj u dicati o n, a n a dj u dicati o n f or m s h o ul d be c o m plete d. Rele va nt 
s o urce d oc u m e nts (as s pe cifie d i n t he E ve nt A dj u dicati o n Site Ma n ual) m ust, if o btai na ble, be 
c ollecte d a n d u pl o a de d t o t he E ve nt A dj u dicati o n S yste m ( E A S).  
2.  Deat hs ( A Es re p orte d wit h fatal o utc o me): W he n a n A E is re p orte d wit h f atal o utc o me, a deat h 
a dj u dicati o n f or m will a p pear i n t he e C R F. T his f or m m ust be c o m plete d a n d all s o urce 
d oc u me nts ass ociate d wit h t he patie nts’ deat h m ust, if o btai na ble, be c ollecte d a n d u pl oa de d t o 
t he E A S. 
3.  A E searc h (sta n dar dise d scree ni n g): All A Es  n ot directl y re p ort e d b y t he i n vesti gat or as 
re q uiri n g a dj u dicati o n, will u n der g o scree ni n g t o i de ntif y p ote ntial e ve nts f or a dj u dicati o n. If 
 
A E i d e ntifi e d
Is t h e e v e nt t o b e 
a dj u dic at e d ?
A E f or m  ≤  2 4 h o urs
SIF ≤ 5 c al e n d ar d a ys
Si g n off  ≤ 7 c al e n d ar d a ys
Is t h e A E s eri o us or 
n o n-s eri o us ?
A E f or m *
Is t h e A E list e d as 
r e q uiri n g a S p ecific E v e nt 
F or m t o b e c o m plet e d ?
A dj u dic ati o n f or m
 ≤ 7 c al e n d ar d a ys
S o urc e d at a  ≤  4 w e e ks
N o n-s eri o us
S eri o us
Y es
N o a d diti o n al acti o n
N o
S p ecific e ve nt f or m
 ≤ 1 4 c al e n d ar d a ys
Y es
Ti m eli n es  ar e fr o m t h e a war e n ess of a n A E.
Q u eri es a n d f oll o w- u p  r e q u ests t o b e r es ol v e d ≤ 7 c al e n d ar d a ys.
* O nl y f or n o n-s eri o us a d v ers e e v e nts r e q uir e d t o b e r e p ort e d acc or di ng t o secti o n 9. 2
A E : A dv ers e E v e nts, S AE : S eri o us A d v ers e E v e nts , SI F: S af et y I nf or mati o n F or m
N o a d diti o n al acti o n
N o
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 1  of 8 9  
 
t he A E is dee me d rele va nt f or a dj u dicati o n, a n a dj u dicati o n f or m will be ge nerat e d i n t he e C R F. 
T his f or m m ust be  c o m plete d, a n d all s o urce d oc u me nts (as s pecifie d i n t he E ve nt A dj u dicati o n 
Site Ma n ual) m ust, if o btai na ble, be c ollecte d a n d u pl oa de d t o t he E A S.  
4.  E A C -i de ntifie d e ve nts: D uri n g re vie w of s o urce d oc u me nts pr o vi de d f or a n ot her e ve nt f or 
a dj u dicati o n, t he E A C ma y i d e ntif y a d diti o nal e ve nts i n sc o pe f or a dj u dicati o n t hat were n ot 
i nitiall y re p orte d b y t he i n vesti gat or. I n t hese i nsta nces, t he i n vesti gat or will be n otifie d of t he 
ne wl y i d e ntifie d e ve nt a n d has t he o pti o n t o re p ort t he E A C -i de ntifie d e v e nt. Re gar dless of 
w het her t he i n vesti gat or deci des t o re p ort t he e ve nt, it will u n der g o a dj u di cati o n. Occasi o nall y, 
E A C -i de ntifie d e ve nts m a y re q uir e t he i n vesti gat or t o c ollect a d diti o nal s o urce d oc u m e nts a n d 
u pl oa d t hese, if o btai na bl e, t o t he E A S.  
T he a dj u dica ti o n f or m f or t he e ve nt i n q uesti o n s h o ul d be c o m plete d i n t he e C R F wit hi n 7 cale n dar 
da ys fr o m t he A E is r e p orte d i n t he e C R F.  
C o pies of s o urce d o c u me nts s h o ul d be la belle d wit h trial I D, patie nt n u m ber, A E n u m ber (if 
a p plica ble), re dacte d (a n o n y mise d of p ers o nal i de ntifiers) a n d u pl oa de d t o t he E A S as s o o n as 
p ossi ble a n d prefera bl y wit hi n 4 wee ks. If n o, or i ns ufficie nt s o urce d o c u me nts are pr o vi de d t o t he 
a dj u dicati o n s u p plier, t he i n vesti gat or ca n be as ke d t o c o m plete a cli nical n arrati ve t o b e u pl oa de d 
t o t he E A S. 
If ne w i nf or mati o n bec o mes a vaila ble f or a n e v e nt se nt f or a dj u dicati o n, it is t he res p o nsi bilit y of 
t he i n vesti gat or t o e ns ure t he ne w i nf or mati o n is u pl oa de d t o t he E A S.  
A n E ve nt A dj u dicati o n Site Ma n ual will be pr o vi d e d t o eac h site detai li n g w hic h s o urce d o c u me nts 
are rele va nt a n d h o w t hes e s h o ul d be pr o vi de d t o t he a dj u dicati o n s u p plier. T he a n o n y mizati o n a n d 
la belli n g re q uire me nts are als o descri b e d i n t he site ma n ual. 
T he assess me nts ma de b y b ot h t he e v e nt a dj u dicati o n c o m mittee a n d t h e i n vesti gat or will be 
e val uate d a n d i ncl u de d i n t he cli nical trial re p ort.  
9. 2. 2  
Met h o d of detecti n g A Es a n d S A Es  
Care s h o ul d be ta ke n n ot t o i ntr o d uce bias w he n d etecti n g A Es a n d/ or S A Es. O pe n -e n d e d a n d n o n -
lea di n g v er bal q u esti o ni n g of t he p atie nt is t he preferre d met h o d t o i n q uire a b o ut e ve nts.  
9. 2. 3  
F oll o w -u p o n A Es a n d S A Es  
After t he i nitial A E/ S A E re p ort, t he i n vesti gat or is re q uire d t o pr o acti vel y f oll o w all e ve nts u ntil 
res ol uti o n, sta bilizati o n, or if t he e ve nt is ot her wise e x plai ne d (e. g. c hr o nic c o n ditio n). F urt her 
i nf or mati o n o n f oll o w-u p pr oce d ures is gi v e n i n A p pe n di x 4 . 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 2  of 8 9  
 
9. 2. 4  
Re g ul at or y re p orti n g re q uire me nts f or S A Es  
Pr o m pt n otificati o n b y t he i n vesti gat or t o N o v o N or dis k 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 ds t he safet y of patie nts a n d t he safet y of a trial pr o d u ct 
u n der cli nical i n vesti gati o n are met.  
N o v o N or dis k has a le gal res p o nsi bilit y t o n otif y b ot 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 trial pr o d uct u n der cli nical i n vesti gati o n. N o v o N or dis k 
will c o m pl y wit h c o u ntr y -s pecific re g ulat or y re q uire me nts relati n g t o safet y re porti n g t o t he 
re g ulat or y a ut h orit y, I R B/I E C, a n d i n vesti gat ors. 
T o a v oi d i ntr o d uci n g bi as a n d t o mai ntai n t he i nte grit y of t he pri mar y a n al ysis, N o v o N or dis k will 
e x e m pt S A Es t hat are part of t he pri mar y o bjecti ve e val uati o n ( M A C E) fr o m u n bli n di n g a n d 
re g ulat or y re p orti n g d uri n g trial c o n d uct, e ve n t h o u g h t he cases f ulfil t he defi niti o n of s us pecte d 
u ne x pecte d seri o us a d verse reacti o ns ( S U S A Rs). T he defi niti o n of M A C E is: Car di o vasc ular deat h, 
n o n -fatal m y ocar dial i nfarcti o n, n o n-fatal str o ke. T he i n de pe n dent D M C ( A p pe n di x 3 ) recei ves 
u n bli n de d data a n d ma k es rec o m me n dati o ns t o t he N o v o N or dis k safet y c o m mittee o n a n o n g oi n g 
basis. T his e ns ures a d e q u at e m o nit ori n g of safet y w hile mai ntai ni n g S A E re p orts relate d t o t he 
pri mar y e n d p oi nt bli n de d f or N o v o N or dis k.  
At t he e n d of t he trial, w he n treat me nt is re v eale d, all e x e m pte d cases w hic h meet t he criteri a f or 
e x pe dite d re p orti n g S U S A Rs will be s u b mitte d t o t he re g ulat or y a ut h orities. Beca use m ulti ple cas es 
will be i de ntifie d si m ulta ne o usl y, N o v o N or dis k will n ot be a ble t o f ulfil t he 7 da ys re q uire me nt f or 
fatal or life-t hreat e ni n g e ve nts b ut will wit hi n 6 0 da ys after c o de brea k h a v e all S U S A Rs s u b mitte d 
t o t he re g ulat or y a ut h orities. 
I n case a re g ul at or y a ut h orit y re q uires t he bli n de d re p ort o n a n e x pe dite d basis, N o v o N or dis k will 
s u b mit i n di vi d ual bli n de d case re p orts rel ate d t o i n vesti gati o nal pr o d u ct t o t he rele va nt re g ulat or y 
a ut h orities o n a n e x pe di te d basis. 
I n v esti gat or safet y re p orts m ust be pre pare d f or 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 
a n d N o v o N or dis k p olic y a n d f or war de d t o i n vesti gat ors as necessar y.  
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 o r ot her s pecific safet y 
i nf or mati o n (e. g. s u m mar y or listi n g of S A Es), fr o m N o v o N or dis k will re vie w a n d t he n file it 
al o n g wit h t he I n v esti gat or's Br oc h ure 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. 
9. 2. 5  
Pre g n a ncies a n d ass oci ate d a d verse e v e nts  
Details of pre g n a ncies i n fe male patie nts will be c ollecte d after ra n d o misati o n a n d u ntil pre g n a nc y 
o utc o me.  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 3  of 8 9  
 
If a pre g na nc y is r e p orte d i n fe male patie nts, t he i n vesti gat or s h o ul d i nf or m N o v o N or dis k wit hi n 
1 4  cale n dar da ys of lear ni n g of t he pre g na n c y a n d s h o ul d f oll o w t he pr oce d ures o utli ne d i n 
A p pe n di x 5 .  
Pre g n a nc y o utc o me s h o ul d be d oc u me nte d i n t he patie nt’s me dical r ec or d. A b n or mal pre g n a nc y 
o utc o me (e. g. s p o nta n e o us a b orti o n, f oetal deat h, still birt h, c o n ge nital a n o malies a n d ect o pic 
pre g na nc y) is c o nsi dere d a n S A E.  
T he i n vesti gat or s h o ul d r e p ort i nf or mati o n o n t he patie nt a n d t he pre g n a nc y o utc o me u ntil t he ne w -
b or n i nfa nt is o ne m o nt h of a ge i n a cc or da nce wit h E ur o pea n M e dici nes A ge n c y ( E M A).1 2 
I nf or mati o n a b o ut t he pre g n a nc y a n d pre g n a nc y o utc o me/ healt h of t he ne w-b or n i nfa nt has t o be 
re p orte d o n p a per pre g na nc y f or ms a n d b e f or war de d t o N o v o N or dis k eit h er b y fa x, e ncr y pt e d e-
mail or c o urier.    
9. 2. 6  
Tec h nic al c o m pl ai nts  
T he i n vesti gat or m ust assess w het her a tec h nical c o m plai nt is relate d t o a n A E. T he defi niti o ns a n d 
re p orti n g pr ocess f or te ch nical c o m plai nts ca n be f o u n d i n A p pe n di x 6 . 
9. 3  
Tre at me nt of o ver d ose  
T here is n o s pecific a nti d ote f or o ver d ose wit h se ma gl uti de. Li mite d data are a v aila ble wit h re gar d 
t o o ver d ose i n patie nts treate d wit h oral s e ma gl uti de. Bas e d o n data fr o m treat me nt wit h s.c. 
se ma gl uti de, t he m ost c o m m o nl y re p ort e d a d verse reacti o n was na usea a n d all patie nts rec o vere d 
wit h o ut c o m plicati o ns. I n t he e ve nt of a n o v er d os e, a p pr o pri ate s u p p orti ve treat me nt s h o ul d be 
i nitiate d acc or di n g t o t he patie nts’ cli nical si g ns a n d s y m pt o ms. A pr ol o n ge d peri o d of o bser vati o n 
a n d treat me nt f or t hese s y m pt o ms ma y b e necessar y, ta ki n g i nt o acc o u nt t h e half -life of se ma gl uti de 
of a p pr o xi matel y o ne wee k.  
I n t he e ve nt of a n o ver d ose, t he i n vesti gat or s h o ul d cl osel y m o nit or t he p atie nt f or o ver d ose-relate d 
A E/ S A Es . Decisi o ns re gar di n g d os e i nterr u pti o ns or m o dificati o ns will be ma de b y t he i n vesti gat or 
base d o n t he cli nical e val uati o n of t he patie nt. Acci de ntal o ver d ose m ust be re p orte d as a 
me dicati o n err or. Refer t o Secti o n 9. 2. 1  f or f urt her details. F or m ore i nf or mati o n o n o ver d ose, als o 
c o ns ult t he c urre nt v ersi o n of t he oral se ma gl uti de I B.  
9. 4  
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 fl o wc h art Secti o n 2 . 
A c o nc o mit a nt ill ness  is a n y ill ness t hat is pres e nt at t he start of t he trial or f o u n d as a res ult of a 
scree ni n g pr oce d ure or ot her trial pr oce d ures perf or me d bef ore e x p os ure t o trial pr o d uct.  
Me dic al hist or y is a me dical e ve nt t hat t he patie nt has e x perie nce d i n t he past, i.e. pri or t o 
ra n d o misati o n. 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 4  of 8 9  
 
T he f oll o wi n g c o nc o mita nt ill ness/ me dical hist or y s h o ul d  be rec or de d i n t he e C R F:  
•  T y pe 2 di a betes - d ate of dia g n osis  
•  Dia betes c o m plicati o ns  
•  Hist or y of car di o v asc ular a n d c hr o nic ki d ne y dis eases. T his als o i ncl u des eac h me dical 
c o n diti o n(s) t hat q ualifie d t he patie nt f or partici pati o n i n t he trial acc or di n g t o i ncl usi o n 
criteri o n # 5 a-d  
•  Hist or y of e ye dise ases  
•  Hist or y of gall bla d der diseases  
•  Hist or y of pa ncreatitis  
•  Ot her rel e va nt c o n c o mita nt ill ness/ me dical hist or y i ncl u di n g mali g na nt ne o plas ms  a n d 
C O VI D -1 9  
I n case of a n a b n or mal a n d cli nicall y si g nifica nt fi n din g, t he i n vesti gat or m ust rec or d t he fi n di n g o n 
rele va nt disease s pecific hist or y f or m or t he Me di cal Hist or y/ C o nc o mita nt Ill ness f or m if it is 
prese nt bef ore ra n d o misati o n. A n y ne w fi n di n g f ulfilli n g t he A E defi niti o n (see A p pe n di x 4 ) d uri n g 
t he trial a n d a n y cli nic all y si g nifica nt w orse ni n g fr o m baseli ne ( visit 2) m ust be re p orte d as a n A E, 
if a p plica ble, (s ee Secti o n 9. 2 ). 
9. 4. 1  
P h ysic al e x a mi n ati o ns  
P h ysical e x a mi nati o ns s h o ul d be perf or m e d acc or di n g t o l ocal pr o ce d ures, w he n i n dicate d i n 
Secti o n 2 . 
A p h ysic al e x a mi nati o n will i ncl u de assess me nts of t he:  
•  Ge neral a p peara n ce  
•  T h yr oi d gla n d  
•  Res pirat or y s yst e m  
•  Car di o vasc ular s yste m  
•  Gastr oi ntesti nal s yste m i ncl. m o ut h  
•  E xtre mities  
•  Ce ntral a n d peri p h eral n er v o us s yste m  
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. 
Rele va nt fi n di n gs prese nt at or pri or t o ra n d o misati o n s h o ul d be rec or de d o n t he c o nc o mita nt 
ill ness/ me dical hist or y f or ms i n t he e C R F i n acc or da nce wit h Secti o n 9. 4 . Fi n di n gs n ot prese nt at 
ra n d o misati o n s h o ul d be re p orte d as A Es acc or di n g t o Secti o n 9. 2 . 
B o d y meas ure me nts (e. g. hei g ht, w ei g ht a n d waist circ u mfere nce) will be meas ure d a n d rec or de d as 
s pecifie d i n t he fl o wc hart Secti o n 2 . 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 5  of 8 9  
 
Hei g ht s h o ul d be meas ur e d wit h o ut s h oes i n ce nti metres (c m) or i nc hes (i n) a n d rec or de d i n t he 
e C R F. 
B o d y wei g ht s h o ul d be meas ure d i n kil o gra m ( k g) or p o u n d (l b), wit h a n e m pt y bla d der, wit h o ut 
s h oes a n d o nl y weari n g li g ht cl ot hi n g. T he act ual val ue of t he wei g ht s h o ul d be rec or de d i n t he 
e C R F wit h o ut r o u n di n g a n d t he sa me e q ui p me nt s h o ul d be use d t hr o u g h o ut t he trial.  
Waist circ u mfere n ce is t he a b d o mi nal circ u mfere nce meas ure d m i d wa y b et wee n t he l o wer ri b 
mar gi n a n d t he iliac crest. It s h o ul d be meas ure d w he n t he patie nt is i n a st a n di n g p ositi o n wit h a 
n o n -stretc ha ble m eas uri n g ta p e a n d t o t he nearest c m or i nc h.  
Waist circ u mfere n ce a n d li ver para m eters are meas ure d at baseli ne  f or calc ulati o n of fatt y li ver 
i n de x.  
9. 4. 2  
Vit al si g ns  
Bl o o d press ur e a n d p ulse meas ure me nts s h o ul d be prece d e d b y at least 5 mi n utes of rest f or t h e 
patie nt i n a q uiet setti n g wit h o ut distracti o ns (e. g. tele visi o n, cell p h o nes). T he meas ure d val ues 
s h o ul d be rec or de d i n t he e C R F wit h o ut r o u n di n g. Bl o o d press ur e a n d p uls e meas ure me nts s h o ul d 
be assesse d i n a sitti n g p ositi o n wit h a c o m pletel y a ut o mate d de vice. Ma n u al tec h ni q ues s h o ul d be 
use d o nl y if a n a ut o mate d de vice is n ot a vaila ble.  
9. 4. 3  
Cli nic al l a b or at or y as sess me nts 
All pr ot oc ol -re q uir e d la b orat or y assess me nts, as defi ne d i n A p pe n di x 2 , m ust be c o n d ucte d i n 
acc or da nce wit h t he la b orat or y ma n ual a n d t he fl o wc hart i n Secti o n 2 . 
9. 4. 4  
E ye e x a mi n ati o n  
Patie nts wit h u nc o ntr olle d a n d p ote nt iall y u nsta bl e dia betic reti n o pat h y or mac ul o pat h y are n ot 
eli gi ble as t his i n dicates reti n o pat h y t hat h as rece ntl y pr o gresse d t o a le vel t hat re q uires i nter ve nti o n 
or is a p pr oac hi n g i nter ve nti o n, b ut has yet t o be br o u g ht u n der c o ntr ol.  
Res ults of a n e ye  e x a mi nati o n perf or me d b y a n o p ht hal m ol o gist or a n ot her s uita bl y q ualifie d h ealt h 
care pr o vi der (e. g. o pt o m etrist) m ust be a vaila ble a n d e val uat e d b y t he i n vesti gat or bef ore 
ra n d o misati o n t o assess eli gi bilit y. T he e ye e x a mi nati o n s h o ul d be perf or m e d as a f u n d us 
p h ot o gra p h y (e. g. 2 -fiel d 6 0 de gree or better, c ol o ur or re d-free) or b y slit-la m p bi o micr osc o p y 
e x a mi nati o n (e. g. usi n g a pre -c or neal or c or neal c o ntact le ns e x a mi nati o n). P har mac ol o gical p u pil -
dilati o n is a re q uire me nt u nless usi n g a di gital f u n d u s p h ot o gra p h y ca mera s pecifie d f or n o n-dilate d 
e x a mi nati o n. 
If t he patie nt ha d s u c h a n e ye e x a mi nati o n perf or me d wit hi n 9 0 da ys pri or t o scree ni n g, t he 
i n vesti gat or ma y b ase his/ her e val uati o n u p o n t he res ults of t hat e xa mi nati o n. T he e x a mi nati o n m ust 
be r e peate d bef ore ra n d o misati o n if t he patie nt has e x perie nce d w ors e ni n g of vis ual f u ncti o n si nce 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 6  of 8 9  
 
t he last e x a mi nati o n. If t he a p plica ble e ye e x a mi nati o n was perf or me d bef ore t he patie nt si g ne d t he 
i nf or me d c o nse nt f or m, it m ust be d oc u me nte d t hat t he reas o n f or perf or mi n g t he e x a mi nati o n was 
n ot relate d t o t his trial.  
After ra n d o misati o n a n e ye e x a mi nati o n perf or me d acc or di n g t o a b o ve m ust be perf or m e d as per 
t he fl o wc hart i n Secti o n 2 . T he i n vesti gat or s h o ul d i n dicate t he o utc o me of eac h e ye e x a mi nati o n. 
Rele va nt fi n di n gs pri or t o ra n d o misati o n m ust be rec or de d as c o n c o mita nt ill ness/ me dical hist or y. 
W hile rele va nt fi n di n gs o cc urri n g after ra n d o misati o n s h o ul d be re p orte d as a n A E acc o r di n g t o 
secti o n 9. 2 . 
9. 4. 5  
Dis a bilit y after a str o ke or TI A e ve nt  
T he m o difie d Ra n ki n Scale is use d t o meas ure t he de gree of disa bilit y i n d ail y acti viti es after a 
str o ke. A m o difie d Ra n ki n Scale f or m s h o ul d be c o m plete d f or all e v e nts se nt t o a dj u dicati o n f or 
str o ke i ncl u di n g e ve ns of TI A t o e ns ure t h at all e ve nts of a n E A C c o nfir me d str o ke will ha ve a 
disa bilit y o utc o m e rec or de d. T he de gree of disa bilit y  acc or di n g t o t he scale s h o ul d be assesse d after 
a mi ni m u m of 9 0 da ys p ost -e ve nt ( m ost ofte n t his will be at t he patie nt’s sec o n d site visit after t he 
str o ke or TI A). T he e ve nt s h o ul d be rec or de d i n t he e C R F.  
9. 5  
P h ar m a c o ki netics  
N ot a p plica ble.  
9. 6  
P h ar m a c o d y n a m i cs 
N ot a p plica ble.  
9. 7  
Ge neti cs  
A bl o o d sa m ple f or D N A a nal ysis will be c ollecte d fr o m patie nts w h o ha ve c o nse nte d t o partici p ate 
i n t he o pti o nal bi o ba n k c o m p o ne nt of t he trial. Refer t o Secti o n 9. 8  a n d A p pe n di x 7  f or f urt her 
details.  
Brazil, C hi na, C ol u m bia, Israel, S o ut h K orea a n d T ur ke y: F or c o u ntr y s pecific re q uire m e nts, please 
see A p pe n di x 8 . 
9. 8  
Bi o m ar kers  
C ollecti o n of sa m ples f o r bi o mar ker researc h is a c o m p o ne nt of t his trial. Partici pati o n i n t he 
bi o ba n k c o m p o ne nt is o pti o nal. Patie nts w h o d o n ot wis h t o partici pate i n t he bi o ba n k c o m p o ne nt 
ma y still partici pate i n t h e trial. F or t h e bi o ba n k, s a m ples will be c ollecte d acc or di n g  t o t he fl o w 
c hart a n d st ore d f or f ut ure use.  
T he sa m ples are c ollect e d f or t he p ur p ose of all o wi n g f ut ure a n al ys es of bi o mar kers, b ot h ge netic 
a n d circ ulati n g, at a later p oi nt i n ti me w he n ne w k n o wle d ge or i m pr o ve d m eas ure m e nt tec h ni q ues 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 7  of 8 9  
 
ma y h a ve bec o me a v aila ble. T he a nal ys es ma y i ncl u de bi o mar kers c urre ntl y k n o w n or disc o v ere d 
i n t he f ut ure.  
Ge netic a n al ys es will i ncl u de a nal ysis of ca n di d ate ge nes or ge netic mar kers t hr o u g h o ut t he ge n o me 
wit h t he p ur p ose of u n dersta n di n g a n d pre dicti n g res p o nse t o se m a gl uti de as well as t o u n dersta n d 
car di o meta b olic diseases. A nal ys es of cir c ulati n g bi o mar kers will meas ure h or m o nes, meta b olites 
or ot her n o n -ge netic ser u m e ntit y wit h t he p ur p ose of u n dersta n di n g a n d pre dicti n g res p o ns e t o 
se ma gl uti de as well as u n derstan di n g car di o meta b olic diseases.  
T hese sa m ples nee d t o be fr oze n a n d s h o ul d be se nt at m o nt hl y i nter vals i n batc hes t o t he ce ntral 
la b orat or y. T he a nal yses are li kel y t o be perf or m e d after t he tri al has c o me t o a n e n d, a n d res ults 
will t heref ore n ot b e part  of t he cli nical trial r e p ort. T he bi o ba n k sa m ples m a y b e st ore d u p t o 
1 5  years after e n d of trial at a ce ntr al la b orat or y (see A p pe n di x 7 ). 
Brazil,  C hi na, C ol u m bia, Israel, S o ut h K orea a n d T ur ke y: F or c o u ntr y s pecific re q uire m e nts, please 
see A p pe n di x 8 .  
1 0  St atistic al c o nsi der ati o ns  
1 0. 1  
S a m ple size deter mi n ati o n  
T he trial is desi g n e d wit h 9 0 % p o wer t o c o nfir m s u peri orit y f or t he pri mar y e n d p oi nt, i.e. reject t he 
n ull -h y p ot hesis of hazar d rati o ( H R) ≥ 1. 0 a gai nst t he o ne -si de d alter nati ve of H R < 1. 0, w here H R 
is t he hazar d rati o of oral se ma gl uti de v ers us place b o. A n al p ha s p e n di n g f u ncti o n will be use d t hat 
a p pr o xi mates O' Bri en Fl e mi n g st o p pi n g b o u n dari es f or t he o verall T y pe I err or pr o ba bilit y of 2. 5 % 
( o ne-si de d). Base d o n a ra n d o misati o n rati o of 1: 1 a n d ass u mi n g a tr ue H R of 0. 8 3 a t otal of 1, 2 2 5 
pri mar y e n d p oi nt e ve nts are re q uire d f or 9 0 % p o wer. F or calc ulati o n t he n u m ber of ra n d o mise d 
patie nts t he f oll o wi n g is ass u me d:  
•  a n n ual pri mar y e n d p oi nt rate i n t he place b o gr o u p of 3. 5 %  
•  u nif or m recr uit me nt occ urs i n 1 8 m o nt hs  
•  a n n ual l ost t o f oll o w -u p rat e i n b ot h treat me nt gr o u ps of 1 %  
•  trial d urati o n is fi ve years a n d fi ve wee ks 
U n der t hese ass u m pti o ns, a t otal of 9, 6 4 2 patie nts are nee de d f or ra n d o misati o n.  
C o nfir m at or y s ec o n d ar y e n d p oi nts  
If s u peri orit y is c o nfir m e d f or t he pri mar y e n d p oi nt t he bel o w c onfir mat or y sec o n dar y e n d p oi nts 
will be c o ntr olle d f or m ulti plicit y t hr o u g h a hi erarc hical testi n g str ate g y. T he mar gi nal p o wers 
bel o w are calc ul ate d u n d er t he ass u m pti o ns t hat t he trial c o nti n ues t o t he fi nal a nal ysis a n d a 
si g nifica n ce le v el of 2. 5 % ( o ne-si de d). 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 8  of 8 9  
 
T he mar gi nal p o w er f or s u peri orit y i n f a v o ur of oral se ma gl uti de f or t he C K D e n d p oi nt wit h 9, 6 4 2 
ra n d o mise d patie nts is 9 4 %. T his is base d o n a n ass u me d hazar d rati o of 0. 8 0 a n d a n a n n u al e ve nt 
rate of 2. 8 % i n t he pl ace b o gr o u p.  
T he mar gi nal p o w er  f or s u peri orit y i n f a v o ur of oral se ma gl uti de f or C V deat h wit h 9, 6 4 2 
ra n d o mise d patie nts is 5 6 %. T his is base d o n a n ass u me d hazar d rati o of 0. 8 3 a n d a n a n n u al e ve nt 
rate of 1. 4 % i n t he pl ace b o gr o u p.  
T he mar gi nal p o w er f or s u peri orit y i n f a v o ur of oral  se ma gl uti de f or t he M A L E e n d p oi nt wit h 
9, 6 4 2 ra n d o mise d patie nts is 4 4 %. T his is base d o n a n ass u me d hazar d rati o of 0. 7 5 a n d a n a n n ual 
e ve nt rate of 0. 4 4 % i n t h e place b o gr o u p.  
T he ass u m pti o ns f or a n n ual e ve nt rat e of pri mar y e n d p oi nt a n d c o nfir mat or y se c o n dar y e n d p oi nts, 
l ost t o f oll o w-u p rates a n d t he tr ue hazar d rati os are base d o n t he L E A D E R 1 3 a n d S U S T AI N 6 2 C V 
o utc o mes trials.  
1 0. 2  
Defi niti o n of a n al ysis sets  
T he f ull a nal ysis set ( F A S) is defi ne d as all ra n d o mise d patie nts a n d gr o u p e d i n a nal yses acc or di n g 
t o t he treat me nt assi g ne d at ra n d o misati o n. 
Patie nts c o nti n ue i n t he trial a n d are p art of F A S re gar dless of disc o nti n uati o n of ra n d o mise d 
treat me nt a n d a n y ot h er i nterc urre nt e ve nt. A p atie nt is c o nsi dere d l ost t o f oll o w-u p ( L T F U) if t he 
patie nt d oes n ot c o m plete t he trial a n d d oes n ot wit h dra w c o nse nt. Tri al c o m pleters are d efi ne d as 
patie nts t hat eit her atte n d t he e n d -of -trial f oll o w-u p visit or w h o die d uri n g t he i n -trial peri o d. 
T he i n -trial o bser v ati o n peri o d f or a p atie nt is defi ne d as t he peri o d fr o m date of ra n d o misati o n t o 
t he first of ( b ot h i ncl usi ve): 
•  date of f oll o w -u p visit  
•  date w he n p atie nt wit h dre w c o nse nt  
•  date of last c o nta ct wit h patie nt (f or patie nt l ost t o f oll o w -u p)  
•  date of deat h  
1 0. 3  
St atistic al a n al yses  
A c o m pre he nsi v e statistical a nal ysis pla n ( S A P) will be a vaila ble bef ore first patie nt first visit 
( F P F V), i ncl u di n g f urt her details of i nteri m testi n g.  
N o v o N or dis k will perf or m t he statistical a nal ys es e x ce pt i nteri m testi n g, see Secti o n  1 0. 3. 4 . A 
statisticia n i n de pe n de nt of trial c o n d uct, D M C a n al yses, i nteri m testi n g, a n d e xter nal t o N o v o 
N or dis k will re peat t he st atistical a nal yses of t he pri mar y e n d p oi nt a n d sec o n dar y c o nfir m at or y 
e n d p oi nts.  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 9  of 8 9  
 
Ge ner al c o nsi der ati o ns  
F or c o nfir mat or y e n d p oi nts c o ntr olle d f or m ulti plicit y, esti mate d treat me nt effec ts will be prese nt e d 
t o get her wit h t w o-si de d 9 5 % c o nfi de n ce i nter vals ( CIs) a n d o ne-si de d p-val ues f or test of t he 
h y p ot hesis of s u peri orit y. F or re p orti n g of res ults, t he esti mate d treat me nt effect a n d t he 9 5 % 
c o nfi de nce i nter val will be acc o m pa nie d b y t h e t w o-si de d p-val u e.  
F or n o n -c o nfir mat or y e n d p oi nts, t he esti mate d treat me nt effects will be re p orte d t o get her wit h t w o -
si de d 9 5 % CIs a n d t w o-si de d p-val ues.  
Baseli ne v al ue is defi n e d as t he latest a vaila ble m eas ure m e nt fr o m t he ra n d o misati o n visit or t he  
scree ni n g visit. T h us, if a ra n d o misati o n assess me nt is missi n g t he n t he assess me nt fr o m scree ni n g 
is use d as t he baseli ne assess me nt, if a vaila ble. 
Missi n g data are defi ne d as data t hat are pla n ne d a n d ca n be o bs er ve d b ut are n ot prese nt i n t he 
data base.  T his i m plies t hat data t hat are str uct ur all y missi n g d u e t o deat h or a d mi nistrati ve 
ce ns ori n g are n ot c o nsi dere d missi n g.  
If a dj u dicat e d, ti me-t o-e v e nt e n d p oi nts are d efi ne d base d o n o utc o mes of t h e E A C e val uati o ns. If a 
patie nt e x perie nces t he e ve nt of i nterest d uri n g t h e i n -trial o bser v ati o n peri o d, t he e n d p oi nt is t he 
ti me fr o m ra n d o misati o n t o t he date of e v e nt. W hile vital stat us is ascertai ne d s yste maticall y 
t hr o u g h o ut t he trial, n o n-fatal e ve nts ( e. g. n o n-fatal MI or n o n-fat al str o ke) ca n n ot be s yste maticall y 
c ollecte d after wit h dra wal of c o nse nt, l ost -t o-f oll o w-u p, or after e n d -of -tri al visit. F or t his reas o n, 
a n y e ve nt oc c urri n g after t he i n -trial o bser vati o n p eri o d is n ot i ncl u de d i n a nal yses, u nl ess ot her wise 
state d. 
Ti me -t o-e ve nt e n d p oi nts are c e ns ore d at t he e n d of t he i n -trial peri o d if t he e ve nt of i nterest di d n ot 
ha p pe n d uri n g t his peri o d a n d t he patie nt is ali ve at t he e n d of t he peri o d. Ce ns ori n g d u e t o L T F U 
a n d wit h dra w al of c o nse nt ass u me i n de pe n de nt ce ns ori n g. A d diti o nal a ntici pate d i nt erc urre nt 
e ve nts a n d ha n dli n g of t h ese i n c o nte xt of t he esti ma n d f or t he pri mar y a n d c o nfir mat or y sec o n dar y 
ti me-t o-e ve nt e n d p oi nts are descri be d i n Ta ble  1 0 -1 . 
1 0. 3. 1  
Pri m ar y e n d p oi nt  
T he H R f or c o m p ari n g oral se ma gl uti de vers us place b o will be esti mate d fr o m a C o x pr o p orti o nal 
hazar ds m o del wit h treat me nt gr o u p (se ma gl uti de, place b o) as fi x e d fact or t o ge t her wit h t he 2-si de d 
9 5 % CI a n d o ne -si d e d fi x e d desi g n p-val ue f or h y p ot hesis testi n g. T he sc ore test fr o m t he C o x 
m o del will be use d f or testi n g. T he f oll o wi n g s u peri orit y h y p ot hesis will be teste d:  
H 0: H R ≥ 1. 0 a gai nst Ha: H R < 1. 0. 
S u peri orit y of oral se ma gl uti de vers us place b o will be c o nsi dere d c o nfir me d if t he ass ociate d H 0 is 
rejecte d b ase d o n n o mi nal si g nifica n ce le vel d eri v e d fr o m t he pre-s pecifie d al p ha s pe n di n g base d 
o n t he act ual o bser ve d n u m ber of e v e nts a vaila ble f or t he a n al ysis. Fi nal i nf er e nce o n ter mi nati o n is 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 0  of 8 9  
 
a dj uste d f or t he gr o u p s e q ue ntial desi g n b y usi n g t he li keli h o o d rati o or deri n g f or t h e p -val ue, 9 5 % 
CI a n d H R.  
C o m peti n g ris k fr o m n o n -C V deat hs will be ha n dl e d as ce ns ori n gs i n t he pri mar y C o x a nal ysis. 
Please, refer t o Ta bl e  1 0 -1  f or ha n dli n g of ot her i nterc urre nt e ve nts. 
Se nsiti vit y a n al ysis  
If s u peri orit y is esta blis h e d f or t he pri mar y e n d p oi nt, t he f oll o wi n g se nsiti vit y a n al ysis is 
perf or me d. T he pri mar y a nal ysis ass u mes i n de pe n de nt ce ns ori n g f or patie nts w h o are L T F U or w h o 
wit h dra w n c o nse nt. T o i n vesti gate t h e i m pact of t his ass u m pti o n o n t he s u peri orit y res ults of t he 
pri mar y a nal ysis, a ti p pi n g p oi nt a nal ysis will be ma de.  I n t his a nal ysis, patie nts i n t he oral 
se ma gl uti de treat me nt gr o u p will ha ve t heir e ve nt ti mes i m p ute d wit h a n i ncreasi n g p e nalt y i n t he 
se nse t hat t heir ris k of M A C E is i ncrease d (t he pe nalt y) f oll o wi n g ce ns ori n g c o m p are d t o w hile 
u n der o bser vati o n. T he place b o patie nts will be i m p ute d wit h n o pe nalt y, i.e. ass u mi n g sa me e ve nt 
bef ore a n d aft er ce ns ori n g. M ulti ple i m p ute d data sets will be a nal ys e d f or eac h p e nalt y usi n g t he 
a b o ve C o x m o del a n d res ults will be c o m bi ne d usi n g R u bi n’s r ule. T h e ti p pi n g p oi nt  is t he n defi ne d 
as t he pe nalt y nee de d t o t ur n ar o u n d t he s u p eri orit y c o n cl usi o n.  
1 0. 3. 2  
Sec o n d ar y e n d p oi nts  
Sec o n dar y e n d p oi nts are cate g orise d as bei n g c o nfir mat or y w he n t he y are a nal yse d u n der 
m ulti plicit y c o ntr ol.  
1 0. 3. 2. 1  
C o nfir m at or y s ec o n d ar y e n d p oi nts  
If s u peri orit y is esta blis h e d f or t he pri mar y e n d p oi nt, t he s u peri orit y h y p ot h esis state d i n 
secti o n 1 0. 3. 1  is teste d f or t he c o nfir mat or y sec o n dar y e n d p oi nts u n der m ulti plicit y c o ntr ol via a 
hierarc hical testi n g sc he me usi n g t he f oll o wi n g or der:  
•  c o m p osite C K D e n d p oi nt  
•  C V deat h  
•  M A L E e n d p oi nt  
T he t esti n g pr oce d ure is st o p pe d t he first ti me a n a nal ysis fails t o c o nfir m s u peri orit y of t he 
e n d p oi nt i n q uesti o n. T he statistical si g nifica nce le vels of t he c o nfir m at or y sec o n dar y e n d p oi nt 
a nal ys es are s pecifie d i n t he S A P.  
T he c o nfir mat or y sec o n d ar y e n d p o i nts will be a nal yse d a n d teste d se paratel y wit h a C o x 
pr o p orti o nal hazar ds m o del as descri b e d f or t he pri mar y e n d p oi nt . 
T he f oll o wi n g T a ble  1 0 -1  descri bes h o w a ntici pat e d i nterc urre nt e ve nts d uri n g t he tri al are h a n dle d 
f or c o nfir m at or y e n d p oi nts. 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 1  of 8 9  
 
T a ble  1 0 -1  St atistic al h a n dli n g of i nterc urre nt e v e nts f or t he c o nfir m at or y e n d p oi nts  
E n d p oi nt  
I nterc urre nt e ve nt  
H a n dli n g  
Ti me t o first 
occ urre nce of M A C E  
•  Treat me nt disc o nti n uati o ns  
•  Me dicati o n m o dif yi n g car di o -re nal ris k 
•  I nitiati o n of c hr o nic re nal re place me nt t hera p y 
P atie nts will be f oll o we d a n d e ve nts 
c ollecte d after i nterc urre nt e ve nts a n d 
use d i n t he a nal ysis  
•  Trial disc o nti n uati o n ( wit h dra wal of c o nse nt or 
l ost-t o f oll o w-u p)  
Ce ns ori n g at ti me of trial 
disc o nti n uati o n  
•  N o n -C V deat h (c o m peti n g ris k)  
Ce ns ori n g at ti me of n o n -C V deat h i n 
t he C o x m o del 
Ti me t o first 
occ urre nce of 
c o m p osite C K D  
•  
Treat me nt  disc o nti n uati o ns  
•  
Me dicati o n m o dif yi n g car di o -re nal ris k 
 
E ve nts a n d f oll o w -u p ti me will b e 
c ollecte d after i nterc urre nt e ve nts a n d 
use d i n t he a nal ysis  
•  Trial disc o nti n uati o n ( wit h dra wal of c o nse nt or 
l ost-t o f oll o w-u p)  
Ce ns ori n g at ti me of trial 
disc o nti n uati o n  
•  N o n -re nal a n d N o n-C V deat h (c o m peti n g ris k)
 
 
Ce ns ori n g at ti me of n o n -re nal or n o n-
C V deat h i n t he C o x m o del  
Ti me t o occ urre nce of 
C V deat h  
•  Treat me nt disc o nti n uati o ns  
•  Me dicati o n m o dif yi n g car di o -re nal ris k 
•  I nitiati o n of c hr o nic re nal re place me nt t hera p y 
E ve nts a n d f oll o w -u p ti me will b e 
c ollecte d after i nterc urre nt e ve nts a n d 
use d i n t he a nal ysis  
•  Trial disc o nti n uati o n ( wit h dra wal of c o nse nt or 
l ost-t o f oll o w-u p)  
Ce ns ori n g at ti me of trial 
disc o nti n uati o n  
•  N o n -C V deat h (c o m peti n g ris k)  
Ce ns ori n g at ti me of n o n -C V deat h i n 
t he C o x m o del 
Ti me t o first 
occ urre nce of M A L E  
•  Treat me nt disc o nti n uati o ns  
•  Me dicati o n m o dif yi n g car di o -re nal ris k 
•  I nitiati o n of c hr o nic re nal re place me nt t hera p y 
P atie nts will be f oll o we d a n d e ve nts 
c ollecte d after i nterc urre nt e ve nts a n d 
use d i n t he a nal ysis  
•  Trial disc o nti n uati o n ( wit h dra wal of c o nse nt or 
l ost-t o f oll o w-u p)  
Ce ns ori n g at ti me of trial 
disc o nti n uati o n  
•  All ca use deat h (c o m peti n g ris k)  
Ce ns ori n g at ti me of deat h i n t he C o x 
m o del  
1 0. 3. 2. 2  
S u p p orti ve sec o n d ar y e n d p oi nts 
Eac h of t he s u p p orti ve sec o n dar y ti me -t o-e ve nt e n d p oi nts will be a nal yse d wit h t he sa me C o x 
pr o p orti o nal hazar ds m o del as t he pri mar y e n d p oi nt.  
T he c o nti n u o us s u p p orti ve sec o n dar y e n d p oi nts (c ha n ge fr o m b aseli ne t o 2 years) are a nal yse d  
usi n g m ulti ple i m p utati o n f or missi n g val ues. A n i m p utati o n m o del (li near re gressi o n) is esti mate d 
se parat el y f or eac h tr eat me nt gr o u p. It will i ncl u de baseli ne val u e as a c o variate esti mate d b ase d o n 
patie nts ha vi n g a n o bser ve d data p oi nt, irres p ecti v e o f a d here n ce t o ra n d o mise d treat me nt, at 2 
years. T he fitte d m o del is use d t o i m p ute val ues f or all patie nts t hat d o n ot ha ve a n o bser ve d d ata 
p oi nt at 2 years t o create 5 0 0 c o m plete data sets. T he c o m plete d data sets are a nal yse d b y a n 
A N C O V A a dj uste d f or tr eat me nt as fi x e d fact or a n d baseli ne val ue as c o variate. R u bi n’s r ule is 
use d t o c o m bi ne t he res ults.  
N u m ber of se v ere h y p o gl ycae mic e pis o des will be a nal ys e d usi n g a mar gi n al rec urre nt e ve nt 
re gressi o n m o del ta ki n g i nt o acc o u nt t he c o m p eti n g ris k of all-ca us e deat h.  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 2  of 8 9  
 
1 0. 3. 3  
E x pl or at or y e n d p oi nts  
T he statistical a nal yses of t he e x pl orat or y e n d p oi nts base d o n t he P R O T E C T c o g niti ve tests a n d t h e 
M o C A sc ore will be detaile d i n t he S A P.  
C urre nt s m o ki n g at year t w o ( yes/ n o) will be a n al yse d usi n g a bi n ar y re gressi o n m o del a dj uste d f or 
baseli ne s m o ki n g stat us ( yes/ n o).  
1 0. 3. 4  
I nteri m testi n g f or effic ac y 
I nteri m testi n g e v al uati n g t he pri mar y e n d p oi nt f or s u peri orit y will be perf or me d base d o n l oc ke d 
s na ps h ot of t he st u d y d ata base at t he ti me-p oi nt of a n i nteri m testi n g. Pati e nts wit h o ut a pri mar y 
e n d p oi nt e ve nt pri or t o t h e a nal ysis c ut -off date will be ce ns ore d wit h t he ce ns ori n g dat e defi ne d as 
t he first of i n-trial e n d-d ate a n d a nal ysis c ut -off date.  
I nteri m testi n g will be perf or me d b y a st atisticia n i n de pe n de nt of tri al c o n d uct a n d e xter nal t o N o v o 
N or dis k. T he D M C e val u ates t he u n bli n de d i nteri m testi n g usi n g t he gr o u p se q ue ntial st o p pi n g 
b o u n daries as g ui da n ce. St o p pi n g t he trial f or s u peri orit y is all o w e d if a st o p pi n g b o u n dar y is 
cr osse d a n d t h e D M C ma kes t he decisi o n t o rec o m me n d earl y trial ter mi nati o n.  
If t he trial is ter mi nate d earl y f or s u peri orit y f oll o wi n g a n i nteri m testi n g, defi niti ve e val uati o n of 
s u peri orit y f or t he pri mar y e n d p oi nt will be perf or me d base d o n u p date d n o mi nal si g nifica n ce 
le vels. All e ve nts fr o m t h e i n-trial o bser v ati o n peri o d i ncl u di n g e v e nts c ollecte d after i nteri m c ut-off 
date will be i ncl u de d i n t his c o nfir mat or y e v al uati o n.  
1 0. 3. 5  
Se q ue nti al s afet y a n al ysis a n d s afet y m o nit ori n g  
Bli n de d a n d u n bli n de d d ata a nal yses d uri n g trial c o n d uct will be p erf or m e d b y t he D M C, as 
descri be d i n t he D M C c h arter. Trial i nte grit y will be e ns ure d b y usi n g a statisticia n i n de pe n de nt of 
trial c o n d uct a n d e xter nal t o N o v o N or dis k t o pre p are dat a f or t he D M C. T he se q ue ntial a nal ys es 
perf or me d b y t h e D M C will be base d o n acc u m ulate d efficac y (see Secti o n  1 0. 3. 4 ) a n d safet y data 
a n d will be perf or me d t o ma ke rec o m me n dati o ns re gar di n g t he o n g oi n g c o n d uct of t he tri al t o 
e ns ure acce pta ble be n efit/ris k rati o f or patie nts i n t he trial.  
1 0. 4  
P h ar m a c o ki netic a n d/ or p h ar m a c o d y n a mic m o delli n g  
N ot a p plica ble.  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 3  of 8 9  
 
1 1  Refere nces  
1.  
T he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n C o u ncil. Directi ve 2 0 0 1/ 2 0/ E C 
of t he E ur o pea n Parlia me nt a n d of t he C o u ncil of 4 A pril 2 0 0 1 o n t he a p pr o xi mati o n of t he 
la ws, re g ulati o ns a n d a d mi nistrati ve pr o visi o ns of t he me m ber states relati n g t o t he 
i m ple me ntati o n of g o o d cli nical practice i n t he c o n d uct of cli nical trials o n me dicinal 
pr o d ucts f or h u ma n us e. 2 0 0 1.  
2.  
Mars o S P, Bai n S C, C o ns oli A, Eliasc he witz F G, J ó dar E, Leiter L A, et al. Se ma gl uti de a n d 
Car di o vasc ular O utc o mes i n Patie nts wit h T y p e 2 Dia betes. N E n gl J Me d. 2 0 1 6.  
3.  
De Fr o nz o R A, El d or R, A b d ul -G ha ni M. Pat h o p h ysi o l o gic a p pr oac h t o t hera p y i n patie nts 
wit h ne wl y dia g n os e d t y pe 2 dia betes. Dia betes C are. 2 0 1 3; 3 6 S u p pl 2: S 1 2 7 -3 8.  
4.  
Dia betes C o ntr ol a n d C o m plicati o ns Trial Researc h Gr o u p. T he effect of i nte nsi ve treat me nt 
of dia betes o n t he d e vel o p me nt a n d pr o gressi o n  of l o n g -ter m c o m plicati o ns i n i ns uli n-
de pe n de nt dia b etes mellit us. T he Dia betes C o ntr ol a n d C o m plicati o ns Trial Researc h Gr o u p. 
N E n gl J Me d. 1 9 9 3; 3 2 9( 1 4): 9 7 7 -8 6.  
5.  
U K Pr os pecti ve Dia b etes St u d y ( U K P D S) Gr o u p. I nte nsi v e bl o o d -gl uc ose c o ntr ol wit h 
s ul p h o nyl ureas or i ns uli n c o m pare d wit h c o n ve nti o nal treat me nt a n d ris k of c o m plicati o ns 
i n patie nts wit h t y p e 2 di a betes ( U K P D S 3 3). La n cet. 1 9 9 8; 3 5 2( 9 1 3 1): 8 3 7-5 3.  
6.  
E mer gi n g Ris k Fact ors C olla b orati o n, Sar war N, Ga o P, Ses hasai S R, G o bi n R, Ka pt o ge S, 
et al. Dia betes mellit us, f asti n g bl o o d gl uc ose c o n ce ntrati o n, a n d ris k of vasc ular diseas e: a 
c olla b orati ve meta -a nal ysis of 1 0 2 pr os pecti ve st u dies. La ncet. 2 0 1 0; 3 7 5( 9 7 3 3): 2 2 1 5 -2 2.  
7.  
Pratle y R E, Ar o da V R, Li n g va y I, L ü de ma n n J, A n dreasse n C, N a varria A, et al. 
Se ma gl uti de vers us d ula gl uti de o nce wee kl y i n p atie nts wit h t y pe 2 dia betes ( S U S T AI N 7): 
a ra n d o mise d, o pe n -la bel, p hase 3 b trial. La n cet Dia betes E n d ocri n ol. 2 0 1 8. 
8.  
Da vies M, Pie ber T R, H art oft -Nielse n M L, Ha nse n O K H, J a b b o ur S, R ose nst oc k J. Effect 
of Oral Se ma gl uti de C o m pare d Wit h Place b o a n d S u bc uta ne o us Se ma gl uti de o n Gl yce mic 
C o ntr ol i n Patie nts Wit h T y pe 2 Dia betes: A Ra n d o mize d Cli nical Trial. J A M A. 
2 0 1 7; 3 1 8( 1 5 ): 1 4 6 0-7 0.  
9.  
Waser B, Bla n k A, K ara mit o p o ul o u E, Perre n A, Re u bi J C. Gl uca g o n -li ke-pe pti de -1 
rece pt or e x pressi o n i n n or mal a n d disease d h u m a n t h yr oi d a n d p a ncreas. M o d Pat h ol. 
2 0 1 5; 2 8( 3): 3 9 1 -4 0 2.  
1 0.  
Ki d ne y Disease: I m pr o vi n g Gl o bal O ut c o mes ( K DI G O) C K D W or k Gr o u p. K DI G O 2 0 1 2 
Cli nical Practice G ui deli ne f or t he E v al uati o n a n d Ma na ge me nt of C hr o ni c Ki d ne y Disease. 
Ki d ne y I nt S u p pl. 2 0 1 3; 3( 1): 1 -1 5 0.  
1 1.  
Sea q uist E R, A n ders o n J, C hil ds B, Cr yer P, Da g o g o -J ac k S, Fis h L, et al. H y p o gl yce mia 
a n d dia betes: a re p ort of a w or k gr o u p of t he A merica n Dia bet es Ass ociati o n a n d t he 
E n d ocri ne S ociet y. Dia b etes Care. 2 0 1 3; 3 6( 5): 1 3 8 4 -9 5.  
1 2.  
G ui deli ne o n t he e x p os ure t o me dici nal pr o d ucts d uri n g pre g na n c y: Nee d f or p ost -
a ut h orisati o n data ( E M E A/ C H M P/ 3 1 3 6 6 6/ 2 0 0 5). 2 0 0 5.  
1 3.  
Mars o S P, Da niels G H, Br o w n -Fra n dse n K, Kriste nse n P, Ma n n J F, Na uc k M A, et al. 
Lir a gl uti de a n d Car di o vasc ular O utc o mes i n T y p e 2 Dia betes. N E n gl J Me d. 
2 0 1 6; 3 7 5( 4): 3 1 1 -2 2.  
1 4.  
W orl d Me dical Ass ociati o n. W M A Declarati o n of Helsi n ki - Et hical Pri nci ples f o r Me dical 
Researc h I n v ol vi n g H u ma n S u bjects. Last a me n de d b y t he 6 4t h W M A Ge n eral Asse m bl y, 
F ortaleza, Brazil. Oct o ber 2 0 1 3.  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 4  of 8 9  
 
1 5.  
I C H Har m o nise d Tri p artite G ui deli ne. G ui deli ne f or G o o d Cli nical Practice E 6( R 2), Ste p 4 
versi o n. 0 9 N o v 2 0 1 6.  
1 6.  
I nter nati o nal C o m mittee of Me dical J o ur nal E dit ors. Rec o m me n dati o ns f or t he C o n d uct, 
Re p orti n g, E diti n g a n d P u blicati o n of Sc h olarl y W or k i n Me dical J o ur nals; c urre nt versi o n 
a vaila ble at w w w.ic mje. or g . 
1 7.  
De A n gelis C, Draze n J M, Frizelle F A, Ha u g C, H oe y J, H ort o n R, et al. Cli nical trial 
re gistrati o n: a state me nt fr o m t he I nter nati o nal C o m mittee of Me dical J o ur nal E dit ors. N 
E n gl J Me d. 2 0 0 4; 3 5 1( 1 2): 1 2 5 0 -1.  
1 8.  
U. S. De part me nt of Healt h a n d H u ma n Ser vices, F o o d a n d Dr u g A d mi nistrati o n. F o o d a n d 
Dr u g A d mi nistrati o n A me n d me nts Act of 2 0 0 7 as a me n de d b y t he Fi nal R ule " Cli nical 
Trials Re gistrati o n a n d Res ults I nf or mati o n S u b missi o n". 2 1 Se pte m ber 2 0 1 6.  
1 9.  
T he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n C o u ncil. Directi ve 2 0 0 1/ 2 0/ E C 
of t he E ur o pea n Parlia me nt a n d of t he C o u ncil of 4 A pril 2 0 0 1 o n t he a p pr o xi mati o n of t he 
la ws, re g ulati o ns a n d a d mi nistrati ve pr o visi o ns of t he Me m ber States relati n g t o t he 
i m ple me ntati o n of g o o d cli nical practice i n t he c o n d uct of cli nical trials o n me dici nal 
pr o d ucts f or h u ma n us e, article 1 1. Official J o ur nal of t he E ur o pea n C o m m u nities. 0 1 Ma y 
2 0 0 1.  
2 0.  
T he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n C o u ncil. Re g ulati o n ( E C) N o 
7 2 6/ 2 0 0 4 of t he E ur o pea n Parlia me nt a n d of t he C o u ncil of 3 1 Marc h 2 0 0 4 la yi n g d o w n 
C o m m u nit y pr oce d ures f or t he a ut h orisati o n a n d s u per visi o n of me dici nal pr o d ucts f or 
h u ma n a n d veteri n ar y us e a n d esta blis hi n g a E ur o pea n Me dici nes A ge nc y, article 5 7. 3 0 
A pril 2 0 0 4.  
 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 5  of 8 9  
 
1 2  A p pe n dic es  
 
 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 6  of 8 9  
 
 
A b bre vi ati o ns a n d Tr a de m a r ks  
 
A BI  
a n kle -brac hial i n de x  
A C S  
ac ute c or o nar y s y n dr o me  
A D A  
A merica n Dia b etes Ass ociati o n  
A E  
a d verse e ve nt  
A L T  
ala ni ne a mi n otra nsferase  
A S T  
as partate a mi n otra nsferase  
B G  
bl o o d gl uc ose  
CI  
c o nfi de nce i nter val  
C K D  
c hr o nic ki d ne y disease  
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  
C O VI D -1 9  
C or o na vir us disease 2 0 1 9  
C R F  
case re p ort f or m  
C T  
c o m p uterize d t o m o gra p h y  
C T R  
cli nical trial re p ort  
C V  
car di o vasc ular  
C V D  
car di o vasc ular disease  
C V O T  
car di o vasc ular o utc o me trial  
D M C  
data m o nit ori n g c o m mittee  
D N A  
de o x yri b o n ucleic aci d  
D U N  
dis pe nsi n g u nit n u m ber  
E A C  
e ve nt a dj u dicati o n c o m mittee  
E A S  
e ve nt a dj u dicati o n s yste m  
E C G  
electr ocar di o gra m  
e G F R  
esti mate d gl o mer ular filtrati o n rate  
E M A  
E ur o pea n Me dici nes A ge nc y  
E O T  
e n d of treat me nt  
e G F R  
esti mate d gl o mer ular filtrati o n rate  
F A S  
f ull a nal ysis set 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 7  of 8 9  
 
F D A  
U. S. F o o d a n d Dr u g A d mi nistrati o n  
F D A A A  
F D A A me n d me nts Act  
F P F V  
first patie nt first visit 
F S H  
f ollicle-sti m ulati n g h or m o ne  
G C P  
G o o d Cli nical Practice  
G L P -1 R A  
gl uca g o n -li ke pe pti de-1 rece pt or a g o nist  
H b A 1c 
gl yc os ylate d hae m o gl o bi n  
H D L  
hi g h -de nsit y li p o pr otei n  
h C G  
h u ma n c h ori o nic g o na d otr o pi n  
H R  
hazar d rati o  
H R T  
h or m o ne re place me nt t hera p y  
I B 
I n vesti gat or’s Br oc h ure 
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 p e n de nt et hics c o m mittee  
I M P 
i n vesti gati o nal me dici nal pr o d uct 
I R B 
i nstit uti o nal re vie w b oar d 
I U D 
i ntra uteri ne de vice 
I U S 
i ntra uteri ne h or m o ne-releasi n g s yste m  
I W R S 
i nteracti ve we b res p o nse s yste m 
L A R  
le gall y acce pta ble re prese ntati ve 
L D L  
l o w-de nsit y li p o pr otei n  
L P L V  
last patie nt last visit 
L T F U  
l ost t o f oll o w-u p  
M A C E  
maj or a d verse car di o vasc ular e ve nts  
M A L E  
maj or a d verse li m b e ve nts  
M E N 2  
m ulti ple e n d ocri ne ne o plasia t y pe 2  
MI  
m y ocar dial i nfarcti o n  
M CI  
Mil d c o g niti ve i m pair me nt  
M o C A  
M o ntreal C o g niti ve Assess me nt  
M R  
ma g netic res o na nce  
M T C  
me d ullar y t h yr oi d ca ncer  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 8  of 8 9  
 
N Y H A  
Ne w Y or k Heart Ass ociati o n  
O D  
o nce dail y  
P A D  
peri p heral arter y disease  
P C D  
pri mar y c o m pleti o n date  
P CI  
perc uta ne o us c or o nar y i nter ve nti o n  
P G  
plas ma gl uc ose  
P P  
per pr ot oc ol  
R A  
rece pt or a g o nist 
S A E  
seri o us a d verse e ve nt 
S A P  
statistical a nal ysis pla n 
s.c. 
s u bc uta ne o us(-l y) 
S M P G  
self-meas ure d plas ma gl uc ose  
S U S A R  
s us pecte d u ne x pecte d seri o us a d verse reacti o n  
TI A  
tra nsie nt isc he mic attac k 
T M M  
trial materials ma n ual 
T 2 D  
t y pe 2 dia betes  
U L N  
u p per li mit of n or mal  
W O C B P  
w o ma n of c hil d beari n g p ote ntial  
 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 9  of 8 9  
 
 
Cli nic al l a b or at or y tests  
•  T he la b orat or y a nal yses will be perf or me d b y a ce ntral la b orat or y, u nless ot her wise 
s pecifie d. A list of la b orat ory s u p plies a n d pr oce d ures f or o btai ni n g, ha n dli n g, 
tra ns p ortati o n a n d st ora ge of sa m ples, will be des cri be d i n la b orat or y fl o w c harts/ ma n ual 
a n d pr o vi de d t o all sites.  
•  Bl o o d sa m ples nee d t o b e o btai ne d. T he tests det aile d i n Ta ble  1 2 -1  will be perf or me d b y 
t he ce ntral la b orat or y. 
•  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 trial as deter mi ne d necessar y b y 
t he i n vesti gat or or re q uir e d b y l o cal re g ul ati o ns. O nl y la b orat or y sa m ples s pecifie d i n t he 
pr ot oc ol s h o ul d be se nt t o t he ce ntral la b orat or y f or a nal ysis; if a d diti o nal la b orat or y 
sa m pli n g is nee d e d, e. g. t o f oll o w u p o n A Es, t his m ust be d o ne at a l ocal la b orat or y  
•  T he la b orat or y e q ui p me nt ma y pr o vi de a nal yses n ot re q ueste d i n t he pr ot oc ol b ut pr o d uce d 
a ut o maticall y i n c o n n ecti o n wit h t he re q ueste d a nal yses acc or di n g t o s pecifi cati o ns i n t he 
la b orat or y sta n dar d o perati n g pr oce d ures. S uc h d ata will n ot be tra nsferre d t o t he trial 
data base. Brazil: F or c o u ntr y s pecific re q uire me nts, please see A p pe n di x 8 . 
•  T he i n vesti gat or m ust re vie w all la b orat or y res ults f or c o nc o mita nt ill nesses a n d A Es.  
•  A m bie nt la b orat or y sa m ples will be destr o ye d s h ortl y after t he a n al ys es ha v e ta ke n place.  
•  H u ma n bi osa m ples f or rete nti o n will be st ore d as descri be d i n A p pe n di x 7 . 
T a ble  1 2 -1  
Pr ot oc ol -re q uire d ce ntr al l a b or at or y assess me nts  
L a b or at or y assess me nts  
P ar a meters  
Gl uc ose meta b olis m  
•  
H b A 1c 
Re nal f u ncti o n  
•  
Creati ni ne  
•  
e G F R, calc ulate d per 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)  
•  
A c o nfir mat or y test is nee de d w he n  
•  
o nset of ≥ 5 0 % re d ucti o n i n e G F R ( C K D -E PI)  
•  
o nset of e G F R ( C K D -E PI) < 1 5 m L/ mi n/ 1. 7 3 m 2  
•  
W he n a c o nfir mat or y test is nee de d, it s h o ul d be d o ne at t he ne xt sc h e d ule d 
c o ntact, b ut n o earlier t ha n 4 wee ks after e G F R has reac he d t he t hres h ol d, b y 
o btai ni n g bl o o d sa m ples f or t he ce ntral la b orat or y f or meas ure me nt of 
creati ni ne  
•  
C o nfir mati o n of a ≥ 5 0 % re d ucti o n i n e G F R ( C K D -E PI) c o m pare d wit h 
baseli ne is nee de d u nle ss a persiste nt 5 0 % re d ucti o n i n e G F R c o m pare d wit h 
baseli ne, has pre vi o usl y bee n c o nfir me d f or t his patie nt  
•  
C o nfir mati o n of a e G F R ( C K D -E PI) < 1 5 m L/ mi n/ 1. 7 3 m 2 is nee de d u nless 
persiste nt e G F R bel o w < 1 5 m L/ mi n/ 1. 7 3 m 2 has pre vi o usl y bee n c o nfir me d 
f or t his patie nt  
•  
F or t he ce ntral la b orat or y calc ulati o n of t he e G F R i nf or mati o n o n race 
( blac k/ w hite/ ot her) a n d year of birt h will be c ollecte d o n t he la b orat or y 
re q uisiti o n f or m. 0 1-J a n of t he year of birt h will be use d f or t he calc ulati o n  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6 0  of 8 9  
 
Li ver para meters  
•  
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 yltra nsferase ( G G T)  
•  
T otal bilir u bi n  
Li pi ds ( n o n -fasti n g) 
•  
T otal c h olester ol  
•  
Hi g h de nsit y li p o pr otei n ( H D L) c h olester ol  
•  
L o w de nsit y li p o pr otei n ( L D L) c h olester ol  
•  
Tri gl yceri des  
Bi o ba n k  
•  
T hese sa m ples nee d t o be fr oze n a n d s h o ul d be se nt at m o nt hl y i nter vals i n 
batc hes t o t he ce ntral la b orat or y  
I nfla m mati o n 
•  
Hi g h se nsiti vit y C -Reacti ve Pr otei n ( hs C R P)  
Pre g na nc y testi n g  
•  
Uri ne h u ma n c h ori o nic g o na d otr o pi n ( h C G) pre g na nc y test (as nee de d f or 
w o me n of c hil d beari n g p ote ntial) 1 
N otes:  
1 L ocal uri ne testi n g will be st a n dar d u nless ser u m testi n g is re q uire d b y l ocal re g ulati o n or I R B/I E C.  
 
 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6 1  of 8 9  
 
 
Tri al g o ver n a nce c o nsi der ati o ns  
1) Re g ul at or y a n d et hic al c o nsi der ati o ns  
•  T his trial will be c o n d ucte d i n acc or da nce 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 Declarati o n 
of Helsi n ki 1 4 a n d a p plica ble I C H G o o d Cli nical Practice ( G C P) G ui deli ne 1 5 
•  A p plica ble la ws a n d re g ulati o ns  
•  T he pr ot oc ol, i nf or me d c o nse nt f or m, i n vesti gat or’s br oc h ure (as a p plica bl e) a n d ot her rele va nt 
d oc u me nts (e. g. a d v ertise me nt s), m ust be s u b mitte d t o a n I R B/I E C a n d re vi e 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 trial is i nitiate d.  
•  Re g ulat or y a ut h orities will recei ve t he cli nical trial a p plicati o n, pr ot oc ol a m e n d me nts, re p orts 
o n S A Es, a n d t he cli nical trial re p ort acc or di n g t o  nati o nal re q uire m e nts.  
•  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 trial desi g n, e x ce pt f or c ha n ges necess ar y t o eli mi nate a n i m me diate safet y 
hazar d t o trial patie nts.  
•  Bef ore a trial site is a ll o we d t o start scree ni n g patie nts, writte n n otificati o n fr o m N o v o N or dis k 
m ust be recei v e d.  
•  T he i n vesti gat or will be res p o nsi ble f or:  
•  pr o vi di n g writte n s u m maries of t he stat us of t he tri al a n n uall y or m ore fre q u e 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 
a n d/ or re g ulat or y a ut h orities  
•  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 uir e d b y I R B/I E C 
pr oce d ures  
•  pr o vi di n g o versi g ht of t h e c o n d uct of t he trial at t he site a n d a d here n ce t o r e q uire me nts of 
I C H g ui deli nes, t he I R B/I E C, a n d all ot her a p plica ble l ocal r e g ulati o ns 
•  e ns uri n g s u b missi o n of t he cli nical trial re p ort ( C T R) s y n o psis t o t he I R B/I E C.  
J a pa n, Me xic o a n d R ussia: F or c o u ntr y s pecifi c re q uire me nts please s ee A p pe n di x 8 . 
2) Fi n a nci al discl os ure  
I n v esti gat ors a n d s u bi n vesti gat ors will pr o vi de N o v o N or dis k wit h s ufficie nt, acc urate fi na ncial 
i nf or mati o n as re q u este d t o all o w N o v o N or dis k 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 
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 trial a n d on e 
year after c o m pleti o n of t he trial.  
F or U S trial sites: verific ati o n u n der discl os ures p er C o de of Fe d eral Re g ul ati o ns ( C F R) of 
Fi na ncial C o nflict of I nterest.  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6 2  of 8 9  
 
3) I nf or me d c o nse nt pr ocess  
•  T he i n vesti gat or or his/ her re prese nt ati ve will e x plai n t he nat ur e of t h e trial t o t he patie nt 
a n d a ns wer all q uesti o ns re gar di n g t he tri al. T his i ncl u des t he use of a n i m partial wit ness 
w here re q uire d acc or di n g t o l ocal re q uire m e nts.  
•  T he i n vesti gat or m ust e ns ure t he patie nt a m ple ti me t o c o me t o a decisi o n w het her or n ot t o 
partici pate i n t he trial.  
•  Patie nts m ust be i nf or me d t hat t heir partici pati o n is v ol u ntar y.  
•  Patie nts will be re q uire d t o si g n a n d date a state m e nt of i nf or me d c o ns e nt t hat meets t he 
re q uire me nts of l o cal re g ulati o ns, I C H g ui deli nes1 5, Declarati o n of Helsi n ki1 4  a n d t he 
I R B/I E C or trial site. 
•  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 a n y trial r elate d acti vit y a n d t he date w he n t he writte n c o nse nt w as o btai ne d.  T he 
a ut h orise 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 a n d date t he i nf or me d 
c o nse nt f or m bef ore a n y trial relate d acti vit y.  
•  T he res p o nsi bilit y of s ee ki n g i nf or me d c o nse nt m ust re mai n wit h t he i n vesti gat or, b ut t he 
i n vesti gat or ma y d ele gat e the tas k of i nf or mi n g t o a me dicall y q ualifie d p ers o n, i n 
acc or da nce wit h l ocal re q uire me nts.  
•  Patie nts a n d/ or t heir le gal a ut h orise d re prese ntati v e ( L A R) m ust be re -c o ns e nte d t o t he m ost 
c urre nt v ersi o n of t he i nf or me d c o nse nt f or m(s) d uri n g t heir p artici pati o n i n t he trial.  
•  A c o p y of t he i nf or me d c o nse nt f or m(s) m ust be pr o vi de d t o t he patie nt or t he patie nt’s 
L A R  
Brazil: F or c o u ntr y s pecific re q uir e me nts, please s ee A p pe n di x 8  
4) I nf or m ati o n t o p atie nts d uri n g tri al  
T he site will be offere d a c o m m u nicati o n pac ka ge f or t he patie nt d uri n g t he c o n d uct of t he trial. T h e 
pac ka ge c o nte nt is iss ue d b y N o v o N or dis k. T he c o m m u nicati o n pac ka ge will c o nt ai n writte n 
i nf or mati o n i nte n de d f or distri b uti o n t o t he patie nts. T he writte n i nf or mati o n will be tra nslate d a n d 
a dj uste d t o l ocal re q uir e me nts a n d distri b ute d t o t he patie nt at t he discreti o n of t he i n vesti gat or. T he 
patie nt ma y recei ve a “ w elc o me t o t he  trial letter” a n d a “t ha n k y o u f or y o ur partici pati o n letter” 
after c o m pleti o n of t he trial. F urt her t h e patie nt ma y recei ve ot her writte n i nf or mati o n d uri n g t h e 
trial.  
All writte n i nf or mati o n t o patie nts m ust be se nt t o I R B/I E C f or a p pr o val/fa v o ura ble o pi ni o n a n d t o 
re g ulat or y a ut h orities f or a p pr o val or n otificati o n acc or di n g t o l ocal re g ulati o ns. 
5) D at a pr otecti o n  
•  Patie nts will be assi g ne d a 6 -di git u ni q ue i de ntifier, a patie nt n u m ber. A n y patie nt rec or ds 
or datasets t hat are tra nsferre d t o N o v o N or di s k will c o ntai n t he i de ntifier o nl y; patie nt 
na mes or a n y i nf or mati o n w hic h w o ul d ma ke t he patie nt i de ntifia ble will n ot be tra nsferre d.  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6 3  of 8 9  
 
•  T he patie nt a n d a n y bi ol o gic al material o btai ne d fr o m t he patie nt will be i de ntifie d b y 
patie nt n u m ber, visit n u m ber a n d trial I D. A p pr o priate meas ures s uc h as e ncr y pti o n or 
lea vi n g o ut certai n i de ntifiers will be e nf orce d t o pr otect t he i de ntit y of patie nts as re q uire d 
b y l oc al, re gi o nal a n d n ati o nal re q uire me nts.  
•  T he patie nt m ust be i nf or me d t hat his/ her pers o nal trial relate d dat a will be use d b y N o v o 
N or dis k i n acc or da nce wit h l ocal data pr otecti o n l a w. T he discl os ur e of t he data m ust als o 
be e x plai ne d t o t he patie nt.  
•  T he patie nt m ust be i nf or me d t hat his/ her me dical rec or ds ma y b e e x a mi ne d b y a u dit ors or 
ot her a ut h or ise d pers o n n el a p p oi nte d b y N o v o N or dis k, b y a p pr o priate I R B/I E C me m bers, 
a n d b y i ns p ect ors fr o m re g ulat or y a ut h orities.  
6) C o m mittee str uct ure  
N o v o N or dis k s af et y c o m mittee  
N o v o N or dis k will c o nstit ute a n i nter nal safet y c o m mittee t o perf or m o n g oi n g safet y s ur veilla nce. 
T he safet y c o m mittee ma y rec o m me n d u n bli n di n g of a n y data f or f urt her a nal ysis, a n d i n t his cas e 
a n i n de pe n de nt a d h oc gr o u p will be esta blis he d i n or der t o mai ntai n t he bli n di n g of t he tri al 
pers o n nel.  
D at a m o nit ori n g c o m mittee  
T he data m o nit ori n g c o m mittee ( D M C) is a n i n de pe n de nt, e xter nal c o m mittee c o m p ose d of 
me m bers w h ose e x pertise c o vers rele v a nt s pecialties i ncl u di n g statistics. T he D M C is esta blis he d t o 
re vie w a n d e val uat e acc u m ulate d data fr o m t he tri al at pre defi ne d ti me p oi nts as well as a d h oc. 
T his is d o ne i n or der t o pr otect t he safet y of t he p atie nts a n d t o e val uate t he be nefit -ris k bal a nce. 
T he D M C will ha ve access t o u n bli n de d data, a n d will pr o vi de rec o m me n d ati o ns o n trial 
c o nti n uati o n, m o dificati o n or ter mi nati o n.  
I nf or matio n re gar di n g res p o nsi bilities, pr oce d ures a n d w or kfl o w t o be us e d b y t he D M C are 
s pecifie d i n t he D M C c h arter. 
E ve nt a dj u dic ati o n c o m mittee  
A n i n de pe n de nt e xter nal e ve nt a dj u dicati o n c o m mittee is esta blis he d t o perf or m o n g oi n g bli n de d 
a dj u dicati o n of sele c te d A Es a n d deat hs (s ee T a ble  9 -1 ). T he E A C will e val uate e ve nts se nt f or 
a dj u dicati o n usi n g pre -defi ne d defi niti o ns a n d g ui deli nes i n acc or da nce wit h t he E A C C harter. T h e 
e val uati o n is base d o n re vie w of pre -defi n e d cli nical data c ollecte d b y t he i n vesti gati o nal sites. T he 
E A C is c o m p ose d of per ma ne nt me m bers c o v eri n g all re q uire d me di cal s p ecialities. E A C me m bers 
m ust discl ose a n y p ote nti al c o nflicts of i nterest a n d m ust be i n de pe n de nt of N o v o N or dis k. T he 
E A C will ha ve n o a ut h orit y t o i m pact trial c o n d uct, trial pr ot oc ol or a me n d me nts.  
T he p ur p ose of t h e a dj u dicati o n is t o c o nfir m e ve nts i n a c o nsiste nt ma n ner acc or di n g t o 
sta n dar dize d criteria usi n g i n de p e n de nt e xter nal m e dical e x perts.  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6 4  of 8 9  
 
Steeri n g c o m mittee  
A steeri n g c o m mittee will pr o vi de scie ntific a n d o perati o nal lea d ers hi p f or t he trial. T he c o m mittee 
will c o nsist of e x perts fr o m o utsi de N o v o N or dis k, a n d desi g nate d N o v o N or dis k e m pl o yees. T he 
c o m mittee will o perate u n der a c h arter a gree d wit h N o v o N or dis k.  
S u p p orti ve p a nels  
Gl o b al e x pert p a nel  
A gl o bal e x pert pa nel ( G E P) will c o nsi st of selecte d pri nci pal i n vesti gat ors, i de ntifie d as nati o nal 
lea ders a n d scie ntific e x p erts, a n d of desi g n ate d N o v o N or dis k e m pl o yees. T he pa nel will disc uss 
a n d a d vise o n gl o bal a n d l ocal o perati o nal iss ues relate d t o trial c o n d uct. T he pa nel will o pera te 
u n der a c h arter a gree d wit h N o v o N or dis k. Nati o nal i n vesti gat ors t hat are n ot part of t he gl o bal 
pa nel ma y be a p p oi nte d i n s o me of t he lar ge c o u ntries.  
P atie nt recr uit m e nt a n d rete nti o n p a nel  
A patie nt recr uit me nt a n d rete nti o n pa nel ( P R R P) will c o nsist  of st u d y c o or di nat ors, hi g hl y 
e x perie nce d i n t he c o n d u ct of dia betes a n d C V o utc o mes trials, a n d desi g nate d N o v o N or dis k 
e m pl o yees. T he p a nel will disc uss a n d a d vise o n gl o bal recr uit me nt, r ete nti o n a n d a d here nce iss ues 
relate d t o trial c o n d u ct. T he pa nel will o perate u n der a c h arter a gree d wit h N o v o N or dis k.  
N ati o n al st u dy c o or di n at ors  
F or eac h c o u ntr y partici p ati n g i n t he trial, w h ere it is a p pr o priate, a n ati o nal st u d y c o or di n at or 
( N S C) will be selecte d. T he nati o nal st u d y c o or di n at ors will pr o vi de o perati o nal i n p ut t o patie nt 
recr uit me nt, r ete nti o n a n d a d here n ce relate d t o pics. T he nati o nal st u d y c o or di nat ors will o perate 
u n der a c h arter a gree d wit h N o v o N or dis k.  
7) P u blic ati o n p olic y  
T he i nf or mati o n o btai ne d d uri n g t he c o n d uct of t his trial is c o nsi der e d c o nfi de ntial, a n d ma y be 
use d b y or o n be half of N o v o N or dis k f or re g ulat or y p ur p oses as w ell as f or t he ge neral 
de vel o p me nt of t he trial pr o d uct. All i nf or mati o n s u p plie d b y N o v o N or dis k i n c o n necti o n wit h t his 
trial s hall re mai n t he s ole pr o pert y of No v o N or dis k a n d is t o be c o nsi dere d c o nfi de ntial 
i nf or mati o n. 
N o c o nfi de ntial i nf or mati o n s hall be discl ose d t o ot hers wit h o ut pri or writte n c o nse nt fr o m N o v o 
N or dis k. S uc h i nf or mati o n s hall n ot be use d e x ce pt i n t he perf or ma n ce of t his trial.  
T he i nf or mat i o n o btai ne d d uri n g t his trial ma y be ma de a vaila ble t o ot her i n vesti gat ors w h o are 
c o n d ucti n g ot h er cli nical trials wit h t he trial pr o d uct, if dee me d necess ar y b y N o v o N or dis k. 
Pr o vi de d t hat certai n c o n diti o ns are f ulfille d, N o v o N or dis k ma y gra nt access t o i nf or mati o n 
o btai ne d d uri n g t his trial t o researc hers w h o re q uire access f or researc h pr oj ects st u d yi n g t he sa m e 
disease a n d/ or tri al pr o d u ct st u die d i n t his trial.  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6 5  of 8 9  
 
N o v o N or dis k ma y p u blis h o n its cli nical trials we bsite a re dacte d cli nical trial re p ort  f or t his trial. 
A c hair of t h e steeri n g c o m mittee will be a p p oi nte d b y N o v o N or dis k t o re vie w a n d si g n t he cli nical 
trial re p ort (si g nat or y i n v esti gat or) o n be half of all partici pati n g i n v esti gat ors.   
C o m m u nic ati o n of res ults  
N o v o N or dis k c o m mits t o c o m m u nicate a n d discl ose res ults of trials re gar dless of o utc o me. 
Discl os ure i ncl u des p u bli cati o n of a ma n us cri pt i n a peer -re vi e we d s cie ntific j o ur nal, a bstract 
s u b missi o n wit h a p oster or oral pres e ntati o n at a s cie ntific meeti n g or discl os ure b y ot her mea ns .  
T he res ults of t his trial will be s u bject t o p u blic discl os ure o n e xter nal we b sites acc or di n g t o 
i nter nati o nal a n d nati o nal re g ulati o ns. N o v o N or dis k reser ves t he ri g ht t o defer t h e release of data 
u ntil s pecifie d milest o nes are reac he d, f or e x a m ple w h e n t he cli nical trial r e p ort is a vaila ble. T his 
i ncl u des t he ri g ht n ot t o release t he res ults of i nteri m testi n g, beca use t he rel ease of s uc h 
i nf or mati o n ma y i nfl u e nce t he res ults of t he e ntire trial. 
At t he e n d of t he trial, o n e or m ore sci e ntific p u blica ti o ns ma y b e pre pare d c olla b orati vel y b y t he 
i n vesti gat or(s) a n d N o v o N or dis k. N o v o N or dis k reser ves t he ri g ht t o p ost p o ne p u blicati o n a n d/ or 
c o m m u nicati o n f or u p t o 6 0 da ys t o pr ot ect i ntellect ual pr o pert y.  
I n all cases t he trial res ults will be re p orte d i n a n o bjecti ve, acc urat e, bala nce d a n d c o m plete 
ma n ner, wit h a disc ussi o n of t he stre n gt hs a n d li mitati o ns. I n t he e v e nt of a n y disa gree me nt o n t he 
c o nte nt of a n y p u blicati o n, b ot h t he i n vesti gat ors’ a n d N o v o N or dis k o pi ni o ns will be fairl y a n d 
s ufficie ntl y re prese nte d i n t he p u blicati o n. 
A ut h ors hi p  
T he steeri n g c o m mittee will be res p o nsi ble f or c o m m u nicati o n of pri mar y trial res ults. T his will 
i ncl u de a p p oi nti n g t he p u blicati o n gr o u p a n d a ut h ors hi p, o verseei n g t he pre parati o ns a n d fi nal 
a p pr o val of ma n us c ri pts a n d c o n gress c o m m u nicati o ns of trial res ults.  
A ut h ors hi p of p u blicati o ns s h o ul d be i n acc or da n ce wit h t he Rec o m me n d ati o ns f or t he C o n d uct, 
Re p orti n g, E diti n g a n d P u blicati o n of Sc h olarl y W or k i n Me dical J o ur nals b y t he I nt er nati o nal 
C o m mittee of Me d ical J o ur nal E dit ors.1 6 
All a ut h ors will be pr o vi de d wit h t he rele v a nt statistical ta bles, fi g ures, a n d re p orts nee d e d t o 
e val uate t he pla n n e d p u blicati o n.  
W here re q uir e d b y t he j o ur nal, t he i n vesti gat or fr o m eac h trial site will be na me d i n a n 
ac k n o wle d ge me nt or i n t he s u p ple me ntar y mat eri al, as s pecifie d b y t h e j o ur nal .  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6 6  of 8 9  
 
Site -s pecific p u blic ati o n(s) b y i n vesti g at or(s) 
F or a m ultice ntr e cli nical trial, a nal yses bas e d o n si n gle -site d ata us uall y ha ve si g nifica nt statistical 
li mitati o ns a n d fre q ue ntl y d o n ot pr o vi de mea ni n gf ul i nf or m ati o n f or healt hcare pr ofessi o nals or 
pa tie nts, a n d t heref ore m a y n ot b e s u p p orte d b y N o v o N or dis k. T h us, N o v o N or dis k ma y d e n y a 
re q uest or as k f or defer m e nt of t he p u blicati o n of i n di vi d ual site res ults u ntil t he pri mar y ma n uscri pt 
is acce pte d f or p u blicati o n. I n li ne wit h G o o d P u blicati o n Practice, s u c h i n di vi d ual re p orts s h o ul d 
n ot prece d e t he pri mar y ma n uscri pt a n d s h o ul d al wa ys refere nce t h e pri mar y ma n us cri pt of t he trial.  
I n vesti g at or access t o d at a a n d re vie w of res ults 
As o w ner of t h e trial data base, N o v o N or dis k h as t he discreti o n t o d eter mi n e w h o will ha ve access 
t o t he data base. I n di vi d ual i n vesti gat ors will ha v e t heir o w n res earc h patie nts' data, a n d will be 
pr o vi de d wit h t he ra n d o misati o n c o de after res ults are a v aila ble.  
8) Disse mi n ati o n of cli nic al tri al d at a  
I nf or mati o n of t he trial will be discl ose d at cli nicaltrials. g o v a n d n o v o n or dis k-trials.c o m. It will als o 
be discl ose d acc or di n g t o ot her a p plica ble re q uir e me nts s uc h as t h ose of t h e I nter n ati o nal 
C o m mittee of Me dical J o ur nal E dit ors (I C MJ E) 1 7, t he F o o d a n d Dr u g A d mi nistrati o n A me n d me nts 
Act ( F D A A A) 1 8 , 1 9 , 2 0, E ur o pea n C o m missi o n Re q uire me nts1 9 , 2 0 a n d ot her rele va nt 
rec o m me n dati o ns or re g ulati o ns. If a patie nt r e q uests t o be i ncl u de d i n t he trial via t he N o v o 
N or dis k e -mail c o ntact at t hese we b sites, N o v o N or dis k ma y discl ose t h e i n vesti gat or’s c o ntact 
details t o t he patie nt. As a res ult of i ncreasi n g re q uire me nts f or tra ns p are n c y, s o me c o u ntries re q uir e 
p u blic discl os ure of i n vesti gat or na m es a n d t heir affiliati o ns.  
T he trial is e ve nt -dri v e n. T he Pri mar y C o m p leti o n Date ( P C D) is t he last assess me nt of t he pri mar y 
e n d p oi nt, a n d is f or t his trial t he last patie nt last visit ( L P L V). T h e trial will t heref ore be re gistere d 
wit h a n esti mate d P C D c orres p o n di n g t o t he esti mate d L P L V, w hic h is first patie nt ra n d o mise d pl us 
6 1 m o nt hs. T he P C D deter mi nes t he dea dli ne f or res ults discl os ure at Cli nicaltrials. g o v acc or di n g t o 
F D A A me n d m e nts Act.  
C hi na: F or c o u ntr y s pecific re q uir e me nts, please s ee A p pe n di x 8 . 
9) D at a q u alit y ass ur a nce  
C ase Re p ort F or ms ( C R Fs)  
N o v o N or dis k or desi g nee is res p o nsi ble f or t he d ata ma na ge me nt of t his trial i ncl u di n g q ualit y 
c hec ki n g of t he d ata.  
All patie nt data relati n g t o t he trial will be  rec or de d o n electr o nic C R Fs u nl ess tra ns mitte d 
electr o nicall y t o N o v o N or dis k or desi g n ee (e. g. l a b orat or y d ata, c o g niti ve testi n g a n d patie nt 
s ur ve ys). T he i n v esti gat or is res p o nsi ble f or verif yi n g t hat data e ntries are acc urat e a n d c orrect b y 
p h ysicall y  or electr o ni call y si g ni n g t he e C R F a n d f or e ns uri n g t hat all rele va nt q uesti o ns are 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6 7  of 8 9  
 
a ns were d, a n d t hat n o e m pt y data fiel d e xists. If a t est or a n assess me nt h as n ot bee n d o ne a n d will 
n ot be a vaila ble, or if t he q uesti o n is irrele va nt (e. g. is n ot a p plic a ble), i n dicate t his b y c h o osi n g t he 
a p pr o priate o pti o n. Free -te xt c o m me nts are disc o ura ge d. 
T he f oll o wi n g will be pr o vi de d as pa per C R Fs t o all sites t o be use d w he n access t o t he electr o ni c 
C R F is re v o ke d or is u na vaila ble:  
•  A E f or ms  
•  Safet y i nf or mati o n f or ms  
•  Tec h nical c o m plai nt f or ms (als o t o be use d t o re p ort c o m plai nts t hat are n ot patie nt relate d, 
e. g. disc o vere d at trial site bef ore all ocati o n)  
T he f oll o wi n g will be pr o vi de d as pa per C R Fs, if nee de d:  
•  Pre g n a nc y f or ms  
•  Ot her C R Fs  
I n case of t he use of pa per f or ms, t he y nee d t o be f or war de d t o N o v o N or dis k eit her b y fa x, 
e ncr y pte d e-mail or c o uri er.  
C orrecti o ns t o t he C R F d ata ma y be ma de b y t he i n vesti gat or or t he i n vesti gat or’s dele gate d staff. 
A n a u dit trail will be mai ntai ne d i n t he C R F a p plicati o n c o ntai ni n g as a mi ni m u m: t he ol d a n d t he 
ne w data, i de ntificati o n of t he pers o n e nteri n g t he data, date a n d ti me of t he e ntr y a n d reas o n f or t he 
c orrecti o n. If c orrecti o ns are ma d e b y t he i n vesti gat or’s dele gate d st aff after t he date w he n t h e 
i n vesti gat or si g ne d t he C R F, t he C R F m ust be si g ne d a n d date d a gai n b y t he i n vesti gat or. 
T he i n vesti gat or m ust e ns ure t hat data is rec or de d i n t he C R F as s o o n as p ossi ble, prefera bl y wit hi n 
5 w or ki n g d a ys aft er t he visit. O nce data has b ee n e ntere d, it will be a v aila ble  t o N o v o N or dis k f or 
data verifi cati o n a n d vali dati o n p ur p oses.  
M o nit ori n g  
•  T he i n vesti gat or m ust per mit trial -relate d m o nit ori n g, a u dits, I R B/I E C re vi e w, a n d 
re g ulat or y a ge nc y i ns pe cti o ns a n d pr o vi de direct access t o s o urce data d oc u me nts ( ori gi nal 
d oc u me nts, data a n d rec or ds). Direct access i ncl u d es per missi o n t o e x a mi ne, a nal ys e, verif y 
a n d re pr o d uce a n y rec or d(s) a n d re p ort(s) t hat are i m p orta nt t o t he e val uati o n of t he trial. If 
t he electr o nic m e dical r ec or d d oes n ot ha v e a visi ble a u dit trail, t he i n vesti gat or m ust 
pr o vi de t he m o nit or wit h si g ne d a n d date d pri nt o uts. I n a d diti o n t he rele va nt trial site staff 
s h o ul d be a vaila ble f or disc ussi o ns at m o nit ori n g visits a n d bet wee n m o nit ori n g visits (e. g. 
b y tele p h o n e).  
•  Trial m o nit ors will perf or m o n g oi n g s o urce data verificati o n t o c o nfir m t hat data e ntere d 
i nt o t he C R F b y a ut h oris e 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 me nts; t hat t he safet y a n d ri g hts of patie nts are bei n g pr otect e d, t o m o nit or dr u g 
acc o u nta bilit y a n d c olle ct c o m plete d pa per C R F p a ges, if a p plica ble, a n d t h at t he trial is 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6 8  of 8 9  
 
bei n g c o n d ucte 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 trial 
a gree m e nts, I C H G C P, a n d all a p plica ble re g ulat or y re q uire m e nts.  
•  M o nit ori n g will be c o n d ucte d usi n g a ris k base d a p pr oac h i n cl u di n g ris k assess me nt, 
m o nit ori n g pla ns, ce ntr alise d m o nit ori n g (re m ote assess me nt of data b y N o v o N or dis k) a n d 
visits t o trial sites.  
•  M o nit ors will re vie w t he patie nt’s me dical r ec or ds a n d ot her s o urce data t o e ns ure 
c o nsiste nc y a n d/ or i de ntif y o missi o ns c o m pare d t o t he C R F.  
Pr ot oc ol c o m pli a nce  
De viati o ns fr o m t he pr ot oc ol s h o ul d be a v oi de d. If de viati o ns d o occ ur, t h e i n vesti gat or m ust  
i nf or m t he m o nit or wit h o ut a n y d ela y a n d t he i m plicati o ns of t he de viati o n m ust be re vie we d a n d 
disc usse d.  
De viati o ns m ust be d oc u me nte d a n d e x plai ne d i n a pr ot oc ol de viati o n b y st ati n g t he reas o n, d ate, 
a n d t he acti o n(s) t a ke n. S o me de viati o ns, f or w hic h  c orrecti o ns are n ot p ossi ble, ca n be 
ac k n o wle d ge d a n d c o nfir me d via e dit c hec ks i n t he C R F or via listi n gs fr o m t he trial data base.  
1 0) S o urce d oc u me nts  
•  All data e ntere d i n t he C R F m ust be verifia ble i n s o urce d oc u m e ntati o n ot her t ha n t he C R F.  
•  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 atie 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 tri al site. 
•  Data re p orte d o n t he p a p er C R F or e nt ere d i n t he electr o nic C R F t hat are tr a nscri be d fr o m 
s o urce d oc u m e nts m ust be c o nsiste nt wit h t he s o urce d oc u me nts or t h e discre pa ncies m ust 
be e x plai ne d. T he i n vesti gat or m a y nee d t o re q uest pre vi o us me dical rec or ds or tra nsfer 
rec or ds. Als o, c urre nt me dical rec or ds m ust be a vaila ble.  
•  It m ust be p ossi ble t o verif y patie nt’s me dical hist or y i n s o urce d o c u me nts s uc h as patie nt’s 
me dical rec or d    
•  T he i n vesti gat or m ust d oc u me nt a n y atte m pt t o o btai n e xter nal me dical i nf or mati o n b y 
n oti n g t he date(s) w he n i nf or mati o n was re q ueste d a n d w h o was c o ntacte d.  
•  Defi niti o n of w ha t c o nstit utes s o urce data ca n b e f o u n d i n a s o urce d o c u me nt a gree me nt at 
eac h trial site. T here will o nl y be o n e s o urce d oc u me nt defi ne d at a n y ti me f or a n y dat a 
ele me nt.  
1 1) Rete nti o n of cli nic al tri al d oc u me nt ati o n  
•  Rec or ds a n d d o c u me nts, i ncl u di n g si g n e d  i nf or me d c o nse nt f or ms, pertai ni n g t o t he c o n d u ct 
of t his trial m ust be retai ne d b y t h e i n vesti gat or f or 1 5 years after e n d of tri al 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 ret e nti o n peri o d. N o rec or ds ma y be 
destr 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 N o v o N or dis k. N o 
rec or ds ma y b e tra nsferre d t o a n ot her l ocati o n or p art y wit h o ut writte n n otificati o n t o N o v o 
N or dis k.  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6 9  of 8 9  
 
•  T he i n vesti gat or m ust be a ble t o access his/ her trial d oc u me nts wit h o ut i n v ol vi n g N o v o 
N or dis k i n a n y wa y. If a p plica ble, electr o nic C R F a n d ot her patie nt dat a will be pr o vi de d i n 
a n electr o ni c rea da ble f or mat t o t he i n vesti gat or bef ore access is re v o ke d t o t he s yste ms 
s u p plie d b y N o v o N or dis k. Site-s pecific C R Fs a n d ot her patie nt data (in a n electr o nic 
rea da bl e f or mat or as pa p er c o pies or pri nts) m ust be retai ne d b y t h e trial site. If t he 
pr o vi de d electr o nic data (e. g. t he C D -R O M) is n ot rea da ble d uri n g t he e ntire st ora ge p eri o d, 
t he i n vesti gat or ca n re q u est a ne w c o p y. A c o p y of all data will be st ore d b y N o v o N or dis k.  
•  Patie nt’s me dical rec or ds m ust be ke pt f or t he ma xi m u m peri o d per mitte d b y t he h os pital, 
i nstit uti o n or pri vate practice. 
1 2) Tri al a n d site cl os ure  
N o v o N or dis k reser ves t he ri g ht t o cl os e t he trial site or ter mi nate t he trial at a n y ti me f or a n y 
reas o n at t he s ole dis creti o n of N o v o N or dis k. If t h e trial is s us pe n de d or ter mi nate d, t he 
i n vesti gat or m ust i nf or m t he patie nts pr o m ptl y a n d e ns ure a p pr o priate t h era p y a n d f oll o w-u p. T he 
i n vesti gat or a n d/ or N o v o N or dis k m ust also pr o m ptl y i nf or m t he re g ulat or y a ut h orities a n d 
I R Bs/I E Cs a n d pr o vi de a detaile d writte n e x pla nati o n. 
Trial sites will be cl ose d u p o n trial c o m pleti o n. A trial 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 trial s u p plies ha ve bee n c ollecte d a n d a trial site cl os ure visit has bee n perf or me d.  
T he i n vesti gat or ma y i nitiate trial site cl os ure at a n y ti me, pr o vi de d t here is reas o na ble ca us e a n d 
s ufficie nt n otice is gi ve n i n a d va nce of t he i nte n de d ter mi nati o n. 
Reas o ns f or t he earl y cl os ure of a tri a l site b y N o v o N or dis k or i n vesti gat or ma y i ncl u d e b ut are n ot 
li mite d t 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 o c ol, t he re q uir e me nts of t he I R B/I E C or 
l ocal healt h a ut h orities, N o v o N or dis k pr oce d ures or G C P g ui deli nes 
•  i na de q uate recr uit me nt of patie nts b y t h e i n vesti gat or 
•  disc o nti n uati o n of f urt her trial pr o d uct de vel o p me nt.  
Pre -pla n ne d i nteri m testi n g ma y all o w f or pre mat ure ter mi nati o n of t he tri al.  
1 3) Res p o nsi bilities  
T he i n vesti gat or is acc o u nta ble f or t he c o n d uct of t he trial at his/ her site a n d m ust e ns ure a de q u ate 
s u per visi o n of t he c o n d u ct of t he trial at t he trial site. If a n y tas ks are del e gate d, t he i n vesti gat or 
m ust mai ntai n a l o g of a p pr o priatel y q ualifie d p er s o ns t o w h o m he/s he has dele gate d s pecifie d trial-
relate d d uties. T he i n v esti gat or m ust e ns ure t hat t h ere is a d e q uate a n d d oc u me nte d trai ni n g f or all 
staff partici p ati n g i n t he c o n d uct of t he trial. It is t he i n vesti gat or’s res p o nsi bilit y t o s u per vise t he 
c o n d uct of t he trial a n d t o pr otect t he ri g hts, safet y, a n d well -bei n g of t h e patie nts.  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
7 0  of 8 9  
 
A q ualifie d p h ysicia n, w h o is a n i n vesti gat or or a s u b -i n vesti gat or f or t he trial, m ust be res p o nsi ble 
f or all trial-relate d me dical decisi o ns.  
T he i n vesti gat or is re s p o nsi ble f or fili n g esse ntial d oc u me nts (i.e. t h ose d oc u me nts w hic h 
i n di vi d uall y a n d c ollecti v el y p er mit e val uati o n of t he c o n d uct of a trial a n d t he q ualit y of t h e data 
pr o d uce d) i n t he i n v esti gat or trial master file. T h e d oc u me nts, i ncl u di n g t he patie nt  i de ntificati o n 
c o de list m ust be ke pt i n a sec ure l oc ke d facilit y s o t hat n o u na ut h orize d pers o ns ca n get access t o 
t he data.  
T he i n vesti gat or will ta ke all necessar y tec h nical a n d or ga nisati o nal safet y meas ures t o pre ve nt 
acci de nt al or wr o n gf ul d estr uct i o n, l oss or deteri orati o n of data. T he i n vesti gat or will pr e ve nt a n y 
u na ut h orise d access t o data or a n y ot her pr ocessi n g of data a gai nst a p plica ble la w. T he i n vesti gat or 
m ust be a ble t o pr o vi de t he necessar y i nf or m ati o n or ot her wise d e m o nstrate t o N o v o N o r dis k t hat 
s uc h tec h nical a n d or ga nisati o nal safet y meas ures ha ve bee n ta ke n.  
D uri n g a n y peri o d of u na vaila bilit y, t he i n vesti gat or m ust dele gate res p o nsi bilit y f or me dical care of 
patie nts t o a s pecific q u alifie d p h ysici a n w h o will be rea dil y a v aila ble t o  patie nts d uri n g t hat ti me.  
If t he i n vesti gat or is n o l o n ger a ble t o f ulfil t he r ole as i n vesti gat or (e. g. if he/s he m o ves or retires) a 
ne w i n vesti gat or will be a p p oi nte d i n c o ns ultati o n wit h N o v o N or dis k.  
T he i n vesti gat or a n d ot her site pers o n nel m ust h a v e s ufficie nt E n glis h s kills acc or di n g t o t heir 
assi g ne d t as k(s).  
1 4) I n de m nit y st ate me nt  
N o v o N or dis k carries pr o d uct lia bilit y f or its pr o d ucts, a n d lia bilit y as ass u me d u n der t he s pecial 
la ws, acts a n d/ or g ui deli n es f or c o n d u cti n g cli nical trials i n an y c o u ntr y, u nless ot hers ha ve s h o w n 
ne gli ge n ce.  
N o v o N or dis k ass u mes n o lia bilit y i n t he e v e nt of ne gli ge n ce or a n y ot her li a bilit y of t he sites or 
i n vesti gat ors c o n d u cti n g t he trial or b y pers o ns f or w h o m t he sai d site or i n vesti gat or are 
res p o nsi ble. 
A ustria, Bel gi u m, Fra n ce a n d Me xic o: F or c o u ntr y s pecific i n de m nit y state me nts, please see  
A p pe n di x 8 .  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
7 1  of 8 9  
 
 
A d verse e ve nts: d efi niti o ns a n d pr o ce d ures f or 
rec or di n g, e v al u ati o n, f oll o w -u p, a n d re p orti n g  
A E defi niti o n  
•  A n A E is a n y u nt o war d me dical occ urre n ce i n a cli nical trial patie nt t hat is te m p orall y 
ass ociate d wit h t he use of a me dici nal pr o d u ct, w het her or n ot c o nsi dere d relate d t o t he 
me dici nal pr o d uct.  
•  A n A E ca n b e a n y u nfa v o ura ble a n d u ni nte n d e 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 dise ase ( ne w or e x acer bate d) te m p orall y ass ociate d wit h t he use of a 
me dici nal pr o d uct.  
 
E ve nts meeti n g  t he A E defi niti o n 
•  
A n y a b n or mal la b orat or y test res ults or safet y assess me nts, i ncl u di n g t h ose t hat w orse n fr o m 
ra n d o misati o n, c o nsi dere d cli nicall y si g nifica nt i n t he me di cal a n d scie ntific j u d g me nt of t he i n vesti gat or.  
•  
A b use: P ersiste nt or s p ora dic, i nte nti o nal e xcessi ve use of a m e dici nal pr o d uct, w hic h is ac c o m pa nie d b y 
har mf ul p h ysical or ps yc h ol o gical effects (e. g. o ver d ose wit h t he i nte nti o n t o ca use har m)  
•  
Mis use: Sit uati o ns w here t he me dici nal pr o d uct is i nte nti o nall y or i na p pr o priatel y use d n ot i n acc or da nce 
wit h t he pr ot oc ol  
•  
E xacer bati o n of a c hr o nic 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 ue nc y 
a n d/ or i nte nsit y of t he c o n diti o n.  
•  
Si g ns, s y m pt o ms or t he cli nic al se q uelae of a s us pecte d dr u g -dr u g i nteracti o n.  
•  
Si g ns, s y m pt o ms or t he cli nic al se q uelae of a s us pecte d o ver d ose of trial pr o d uct re gar dless of i nte nt.  
E ve nts N O T  meeti n g t he A E defi niti o n  
•  
Pre -e xisti n g c o n diti o ns, a ntici pate d da y -t o-da y fl uct uati o ns of pre -e xisti n g c o n diti o ns, i ncl u di n g t h ose 
i de ntifie d d uri n g scree ni n g or ot her trial pr oce d ures perf or me d bef ore e x p os ure t o trial pr o d uct.  
N ote: pre -e xisti n g c o n diti o ns s h o ul d be rec or de d as me dical hist or y/c o nc o mita nt ill ness.  
•  
Pre -pla n ne d pr oce d ures, u nless t he c o n diti o n f or w hic h t he pr oce d ure was pla n ne d has w orse ne d fr o m 
ra n d o misati o n. 
 
Defi niti o n of a n S A E  
A n S A E is a n A E t h at f ulfils at le ast o ne of t he f oll o wi n g criteri a:  
•  
Res ults i n deat h  
•  
Is life-t hreate ni n g 
T he ter m 'life -t hreate 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 patie 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 pitalisati o n or pr ol o n gati o n of e xisti n g h os pitalisati o n  
•  
H os pitalisati o n si g nifies t hat t he patie nt has bee n detai ne d at t he h os pital or e mer ge nc y war d 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 offic e or o ut patie nt 
setti n g. C o m plicati o ns t hat occ ur d uri n g h os pitalisati o n are A Es. If a c o m plicati o n pr ol o n gs h os pitalisati o n 
or f ulfils 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 pitalis ati o n” 
occ urre d or was necessar y, t he A E s h o ul d be c o nsi dere d seri o us.  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
7 2  of 8 9  
 
•  
H os pitalisati 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 r a n d o misati o n is 
n ot c o nsi dere d a n A E.  
N ote:  
▪ H os pitalisati o ns f or a d mi nistr ati ve, trial relat e d a n d s ocial p ur p oses d o n ot c o nstit ute A Es a n d s h o ul d 
t heref ore n ot b e re p orte d as A Es or S A Es.  
▪ H os pital a d missi o ns f or s ur gic al pr oce d ures, pla n ne d bef ore trial i ncl usi o n, are n ot c o nsi dere d A Es or 
S A Es.   
•  
Res ults i n persiste nt or si g nifi ca nt disa bilit y/i nca pacit y  
•  
T he ter m disa bilit y mea ns a s u bsta ntial disr 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.  
•  
T his defi niti o n is n ot i nte n de d t o i ncl u de e x perie nce 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, na us ea, v o miti n g, diarr h oea, i nfl ue nza, a n d acci de ntal tra u ma (e. g. s prai ne d 
a n kle), w hic h ma y i nterfere wit h or pre ve 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 
•  
I m p orta nt me dical e ve nt: 
•  
Me dical or scie ntific j u d g me nt s h o ul d be e xercise d i n deci di n g w het her S A E re p orti n g is a p pr o priate i n 
ot her sit uati o ns. T his i ncl u des 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 pitalisati o n, b ut ma y j e opar dise t he patie 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 dere d seri o us a n d re p orte d as S A Es usi n g t he i m p orta nt me dical e ve nt criteri o n.  
•  
T he  f oll o wi n g a d verse e ve nts m ust al wa ys be re p orte d as S A Es usi n g t he i m p orta nt me di cal e ve nt criteri o n, 
if n o ot her seri o us ness criteria are a p plica ble: 
▪ s us pici o n of tra ns missi o n of i nfecti o us a ge nts via t he trial pr o d uct.  
▪ ris k of li ver i nj ur y defi ne d as ala ni ne a mi n otra nsferase ( A L T) or as partate a mi n otra nsferase  
( A S T) > 3 x U N L a n d t otal bilir u bi n > 2 x U N L, w here n o alt er nati ve aeti ol o g y e xists ( H y's la w).  
 
Descri pti o n of A Es re q uiri n g a d diti o n al d at a c ollecti o n ( vi a s pecific e ve nt f or m) a n d e ve nts f or a dj u dic ati o n 
c a n be f o u n d i n T a ble  9 -1  
M e dic ati o n err or:  
A me dicati o n err or is a n u ni nt e n de d fail ure i n t he trial dr u g treat me nt pr ocess t hat lea ds t o,  or has t he p ote ntial t o 
lea d t o, har m t o t he patie nt, s uc h as: 
•  
A d mi nistrati o n of wr o n g dr u g.  
N ote: Use of wr o n g D U N is n ot c o nsi dere d a me dicati o n err or u nless it res ults i n a d mi nistrati o n of wr o n g 
dr u g.  
•  
Wr o n g r o ute of a d mi nistrati o n  
•  
Acci de ntal a d mi nistrati o n of a l o wer or hi g her d ose t ha n i nte n de d. T he a d mi nistere d d ose m ust de viate 
fr o m t he i nte n de d d ose t o a n e xte nt w here cli nical c o nse q ue nces f or t he trial patie nt were li kel y t o ha p pe n 
as j u d ge d b y t he i n vesti gat or, alt h o u g h t he y d i d n ot necessaril y occ ur.  
Treat me nt pa uses are all o we d i n t he trial, t his s h o ul d n ot t o be re p orte d as a me dicati o n err or.   
 
A E a n d S A E rec o r di n g  
•  
All S A Es,  A Es lea di n g t o disc o nti n uati o n of trial pr o d uct, A Es descri be d i n T a ble  9 -1  m ust be rec or de d b y 
t he i n vesti gat or o n a n A E f or m. 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 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
7 3  of 8 9  
 
si g ns, s y m pto ms, a n d/ or ot her cli nical i nf or mati o n. I n s uc h c ases, t he dia g n osis ( n ot t he i n di vi d ual 
si g ns/s y m pt o ms) will be d oc u me nte d as t he A E/ S A E.  
•  
W he n a n A E/ S A E 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 nt ati o n (e. g. 
h os pital pr o gr ess n otes, la b orat or y a n d dia g n ostics re p orts) relate d t o t he e ve nt.  
•  
T here ma y be i nsta nces w he n c o pies of s o urce d oc u me nts (e. g. me dical rec or ds) f or certai n cases are 
re q ueste d b y N o v o N or dis k. I n s uc h cases, all patie nt i de ntifiers, wit h t he e xce pti o n of t he patie nt n u m ber, 
will b e re d acte d o n t he c o pies of t he s o urce d oc u me nts bef ore s u b missi o n t o N o v o N or dis k.  
•  
F or all n o n -seri o us A Es t he a p plica ble f or ms s h o ul d be si g ne d w he n t he e ve nt is res ol ve d or at t he e n d of 
t he trial at t he latest. F or si g n-off of S A E relate d f or ms refer t o “ S A E re p orti n g via pa p er C R F” later i n t his 
secti o n. 
•  
N o v o N or dis k pr o d ucts use d as c o nc o mita nt me dicati o n: if a n A E is c o nsi dere d t o ha ve a ca usal 
relati o ns hi p wit h a N o v o N or dis k mar kete d pr o d uct use d as c o nc o mita nt me dicati o n i n t he trial, it is 
i m p orta nt t hat t he s us pecte d relati o ns hi p is re p orte d t o N o v o N or dis k, e. g. i n t he alter nati ve aeti ol o g y 
secti o n o n t he safet y i nf or mati o n f or m. N o v o N or dis k ma y nee d t o re p ort t his a d verse e ve nt t o rele va nt 
re g ulat or y a ut h orities. 
 
Assess me nt of se v erit y  
T he i n vesti gat or will assess i nte nsit y f or eac h e ve nt re p orte d d uri n g t he trial a n d assi g n it t o o ne of t he f oll o wi n g 
cate g ories:  
•  
Mil d : A n e ve nt t hat is easil y t olerate d b y t he patie nt, ca usi n g mi ni mal disc o mf ort a n d n ot interferi n g wit h 
e ver y da y acti vities.  
•  
M o der ate : A n e ve nt t hat ca us es s ufficie nt disc o mf ort a n d i nterferes wit h n or mal e ver y da y acti vities. 
•  
Se vere : A n e ve nt t hat pre ve nts n or mal e ver y da y acti vities.  
N ote: Se vere is a cate g or y use d f or rati n g t he i nte nsit y o f a n e ve nt; a n d b ot h a n A E a n d S A E ca n be 
assesse d as se vere. A n e ve nt is defi ne d as ‘seri o us’ w he n it meets at least o ne of t he o utc o mes descri be d i n 
t he defi niti o n of a n S A E a n d n ot w he n it is rate d as se vere 
 
Assess me nt of c a 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 we e n trial pr o d uct a n d t he occ urr e nce of eac h A E/ S A E. 
Relati o ns hi p bet wee n a n A E/ S A E a n d t he rele va nt trial pr o d uct(s) s h o ul d be assesse d as:  
•  
Pr o ba ble - G o o d reas o n a n d s ufficie nt d oc u me ntati o n t o ass u me a ca usal  relati o ns hi p. 
•  
P ossi ble - A ca usal relati o ns hi p is c o ncei va ble a n d ca n n ot be dis misse d.  
•  
U nli kel y - T he e ve nt is m ost li kel y relate d t o aeti ol o g y ot her t ha n t he trial pr o d uct.  
Alter nati ve aeti ol o g y, s uc h as u n derl yi n g disease(s), c o nc o mita nt me dicati o n, a n d  ot her ris k fact ors, as well as t he 
te m p oral relati o ns hi p of t he e ve nt t o trial pr o d uct 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 s h o ul d use t he i n vesti gat or’s br oc h ure f or t he 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 rec or ds 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 be sit uati o ns i n w hic h a n S A E has occ urre d a n d t he 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. H o we ver, it is i m p ort a nt t h at t he i n vesti g at or al w a ys m a kes a n assess me nt of c a us alit y f or e v er y 
e v e nt bef ore t he i niti al tr a ns missi o n of t he S A E d at a . 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
7 4  of 8 9  
 
T he i n vesti gat or ma y c ha n ge his/ her o pi ni o n of ca usalit y i n li g ht of f oll o w -u p i nf or mati o n a n d u p date t he ca usalit y 
assess me nt i n t he C R F.  
T he ca usalit y assess me nt 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.  
 
Fi n al o utc o me  
T he i n vesti gat or will select t he m ost a p pr o priate o utc o me:  
•  
Rec o vere d/res ol ve d:  T he patie nt has f ull y rec o vere d, or b y me dical or s ur gical treat me nt t he c o n diti o n has 
ret ur ne d t o t he le vel o bser ve d at t he first trial-relate d acti vit y after t he patie nt si g ne d t he i nf or me d c o nse nt. 
•  
Rec o veri n g/res ol vi n g:  T he c o n diti o n is i m pr o vi n g a n d t he patie nt is e x pecte d t o rec o ver fr o m t he e ve nt. 
T his ter m is o nl y a p plica ble if t he patie nt has c o m plete d t he trial or has die d fr o m a n ot her A E.  
•  
Rec o vere d/res ol ve d wit h se q uel ae:  T he patie nt has rec o ver e d fr o m t he c o n diti o n, b ut wit h lasti n g effect 
d ue t o a disease, i nj ur y, treat me nt or pr oce d ure. If a se q uelae meets a n S A E criteri o n, t he A E m ust b e 
re p orte d as a n S A E. 
•  
N ot rec o vere d/ n ot res ol ve d: T he c o n diti o n of t he patie nt has n ot i m pr o ve d a n d t he s y m pt o ms are 
u nc ha n ge d or t he o utc o me is n ot k n o w n.  
•  
F at a l: T his ter m is o nl y a p plica ble if t he patie nt die d fr o m a c o n diti o n relate d t o t he re p orte d A E. 
O utc o mes of ot her re p orte d A Es i n a patie nt bef ore he/s he die d s h o ul d be assesse d as “rec o vere d/res ol ve d ”, 
“rec o veri n g/res ol vi n g”, “rec o vere d/res ol ve d wit h se q uelae” or “ n ot rec o vere d/ n ot res ol ve d”. A n A E wit h a 
fatal o utc o me m ust b e re p orte d as a n S A E. 
•  
U n k n o w n: T his ter m is o nl y a p plica ble if t he patie nt is l ost t o f oll o w -u p.  
 
F oll o w -u p of A E a n d S A E  
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 uct 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 ueste d b y N o v o N or dis k t o el uci date t he nat ure a n d/ or ca us alit y of t he A E or S A E as 
f ull y as p ossi ble (e. g. se vere h y perse nsiti vit y reacti o ns). T his ma y i ncl u de a d ditio nal la b orat or y tests (e. g. s ki n pric k 
test) or i n vesti gati o ns, hist o pat h ol o gical e xa mi nati o ns, or c o ns ultati o n wit h ot her healt h care pr ofessi o nals. 
Ne w or u p date d i nf or mati o n will b e rec or de d i n t he C R F.  
 
S A E re p orti n g vi a electr o nic C R F  
•  
Rele va nt f or ms ( A E a n d safet y i nf or mati o n f or m) m ust be c o m plete d i n t he C R F.  
•  
F or re p orti n g a n d si g n -off ti meli nes, see b o x bel o w.  
•  
If t he C R F is u na vaila ble f or m ore t ha n 2 4 h o urs, t he n t he site will use t he pa per A E f or m a n d if t he C R F is 
u na vaila ble f o r m ore t ha n 5 cale n dar da ys t he n t he site will use t he safet y i nf or mati o n f or m (see b o x 
bel o w).  
•  
T he site will e nter t he S A E data i nt o t he C R F as s o o n as it bec o mes a vaila ble, see secti o n 9. 2. 1 . 
•  
After t he trial is c o m plete d, t he C R F will be dec o m missi o ne d t o pre ve nt t he e ntr y of ne w data or c ha n ges t o 
e xisti n g data. If a site recei ves a re p ort of a ne w S A E fr o m a patie nt or recei ves u p date d data o n a 
pre vi o usl y re p orte d S A E after C R F dec o m missi o n, t he n t he site ca n re p ort t his i nf or mati o n o n a pa per A E 
a n d safet y i nf or mati o n f or m (s ee b o x bel o w) or t o N o v o N or dis k  b y tele p h o ne.  
 
S A E re p orti n g vi a p a per C R F  
•  
Rele va nt C R F f or ms ( A E a n d safet y i nf or mati o n f or m)  m ust be f or war de d t o N o v o N or dis k eit her b y fa x, 
e ncr y pte d e -mail or c o urier.  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
7 5  of 8 9  
 
•  
I nitial n otificati o n via tele p h o ne is acce pta ble, alt h o u g h it 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 t he A E a n d safet y i nf or mati o n f or m  wit hi n t he des i g nate d re p orti n g ti me fra mes (as ill ustrate d i n 
Fi g ure  9 -1 ): 
•  
A E f or m wit hi n 2 4 h o urs.  
•  
Safet y i nf or mati o n f or m  wit hi n 5 cale n dar da ys.  
•  
B ot h f or ms m ust b e si g ne d wit hi n 7 cale n dar da ys fr o m t he i n vesti gat ors k n o wle d ge of t he e ve nt.  
•  
C o ntact details f or  S A E re p orti n g ca n be f o u n d i n t he i n vesti gat or trial master file.  
 
 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
7 6  of 8 9  
 
 
C o ntr ace pti ve g ui d a nce a n d c ollecti o n of pre g n a nc y 
i nf or m ati o n 
It m ust be rec or de d i n t he C R F w het her fe mal e patie nts are of c hil d beari n g p ote ntial.  
Defi niti o ns  
W o m a n of C hil d be ari n g P ote nti al ( W O C B P)  
A w o ma n is c o nsi dere d fertile f oll o wi n g m e narc h e a n d u ntil bec o mi n g p ost me n o pa usal u nless 
per ma ne ntl y sterile.  
W o me n i n t he f oll o wi n g c ate g ori es are n ot c o nsi dere d W O C B P  
1.  Pre me n o pa usal f e male wit h o ne of t he f oll o wi n g:  
•  D oc u me nte d h ysterect o m y  
•  D oc u me nte d bilateral sal pi n gect o m y  
•  D oc u me nte d bilateral o o p h orect o m y  
N ote: D oc u me ntati o n ca n c o me fr o m t he site pers o n nel’s re vie w of patie nt’s me dical rec or ds, 
me dical e x a mi nati o n or me dical hist or y i nter vie w.  
2.  P ost me n o pa usal fe male  
•  A p ost me n o pa usal state is defi ne d as n o me ns es f or 1 2 m o nt hs wit h o ut a n alter nati ve 
me dical ca us e. A hi g h F ollicle Sti m ulati n g H or m o ne ( F S H) l e vel i n t he p ost me n o pa usal 
ra n ge ma y b e use d t o c o nfir m a p ost me n o pa usal st ate i n w o me n n ot usi n g h or m o nal 
c o ntrace pti o n or H or m o n al Re place me nt T h era p y ( H R T). H o we v er, i n t he a bse nce of 1 2 
m o nt hs of a me n orr hea, a si n gle F S H meas ure me nt is i ns ufficie nt.  
•  Fe males o n H R T a n d w h ose me n o pa usal stat us is i n d o u bt will be re q uire d t o use o ne of t he 
n o n -h or m o nal hi g hl y effecti ve c o ntr ace pti o n met h o ds if t he y wis h t o c o nti n ue t heir H R T 
d uri n g t he tri al. Ot her wis e, t he y m ust disc o nti n ue H R T t o all o w c o nfir mati o n of 
p ost me n o pa usal stat us bef ore trial e nr ol me nt.  
C o ntr ace pti o n g ui d a nce  
Male patie nts  
N o c o ntrace pti o n meas ur es are re q uir e d f o r mal e patie nts as t he ris k of terat o ge nicit y/f et ot o xicit y 
ca use d b y tr a nsfer of se m a gl uti de i n se mi nal fl ui d is u nli kel y.  
Fe male p atie nts  
Fe male p atie nts of c hil d b eari n g p ote ntial are eli gi ble t o partici pate if t he y a gree t o us e met h o ds of 
c o ntrace pti o n c o nsiste ntl y a n d c orrectl y as des cri b e d i n Ta ble  1 2 -2 . 
 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
7 7  of 8 9  
 
T a ble  1 2 -2  
Hi g hl y effecti ve c o ntr ace pti ve met h o ds  
Hi g hl y effecti ve c o ntr ace pti ve met h o ds  
Hi g hl y effecti ve c o ntr ace pti ve met h o ds t h at are user de pe n de nt
 a a n d b  
Fail ure rate of < 1 % per year w he n use d c o nsiste ntl y a n d c orrectl y.   
C o m bi ne d ( oestr o ge n a n d pr o gest o ge n c o ntai ni n g) h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n  
•  
oral  
•  
i ntra va gi nal  
•  
tra ns der mal  
Pr o gest o ge n o nl y h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n  
•  
oral  
•  
i nj ecta ble  
Hi g hl y effecti ve met h o ds t h at are user i n de pe n de nt
 a a n d b   
•  
I m pla nta ble pr o gest o ge n o nl y h or m o nal c o ntrace pti o n ass oci ate d wit h i n hi biti o n of o v ulati o n  
•  
I ntra uteri ne De vice (I U D) 
•  
I ntra uteri ne h or m o ne-releasi n g S yste m (I U S) 
•  
Bilateral t u bal occl usi o n  
V asect o mise d p art ner  
A vasect o mise d part ner is a hi g hl y effecti ve c o ntrace pti o n met h o d pr o vi de d t hat t he part ner is t he s ole male se x ual 
part ner of t he W O C B P a n d  t he a bse nce of s per m has bee n c o nfir me d. If n ot, a n a d diti o nal hi g hl y effecti ve met h o d of 
c o ntrace pti o n s h o ul d be use d.   
Se x u al a bsti ne nce  
Se x ual a bsti ne nce is c o nsi dere d a hi g hl y effecti ve met h o d o nl y if defi ne d as refrai ni n g fr o m heter ose x ual i nterc o urse 
d uri n g t he e ntire peri o d of ris k ass ociate d wit h t he trial pr o d uct. T he relia bilit y of se x ual a bsti ne nce nee ds t o be 
e val uate d i n relati o n t o t he d ur ati o n of t he trial a n d t he preferre d a n d us ual lifest yle of t he patie nt.   
N otes:  
a Fail ure rates ma y differ w he n use d c o nsiste ntl y a n d c orrectl y. 
b C o ntrace pti o n s h o ul d be utilise d d uri n g t he treat me nt peri o d a n d f or at least 5 wee ks after t he last d ose of trial 
pr o d uct.  
 
I n cert ai n cases, it is acce pte d t o use d o u ble barri er met h o ds (a c o n d o m c o m bi ne d wit h a n occl usi ve 
ca p, e. g. dia p hra g m, wit h/ wit h o ut t he use of s per mici de). T his s h o ul d o nl y be all o we d:  
•  i n fe males wit h k n o w n i nt olera nce t o t he hi g hl y effecti ve met h o ds me nti o n e d a b o ve or 
w here t he us e of a n y liste d hi g hl y effecti ve c o ntrace pti v e meas ures are c o ntrai n dicate d i n 
t he i n di vi d ual patie nt, a n d/ or 
•  if t he ris k of i nitiati n g treat me nt wit h a s pecific hi g hl y effecti ve met h o d o ut wei g h t he 
pre dicte d be n efits of trial partici pati o n f or t he fe m ale patie nt.  
J ustificati o n f or acce pti n g d o u ble b arrier met h o d s h o ul d be at t he discreti o n of t he i n vesti gat or. T he 
j ustificati o n m ust be state d i n t he me dical r ec or ds.   
Ar ge nti na, Bel gi u m, Brazil, De n mar k, T haila n d a n d U nite d Ki n g d o m: F or c o u ntr y s p ecific 
re q uire me nts, please see A p pe n di x 8 . 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
7 8  of 8 9  
 
Pre g n a nc y testi n g  
•  Hi g hl y se nsiti ve ser u m testi n g (se nsiti vit y of 5 -2 5 mI U / m L) is o nl y ma n dat or y if re q uir e d 
b y l oc al re g ulati o ns or et hics c o m mittees, or t o res ol ve a n i n deter mi nate test or t o c o nfir m a 
p ositi ve uri ne test.  
•  W O C B P s h o ul d o nl y b e i ncl u de d after a n e gati ve hi g hl y se nsiti ve uri ne pre g na n c y test.  
•  Pre g n a nc y testi n g s h o ul d be perf or me d w he ne ver a me nstr ual c ycl e is misse d or w he n 
pre g na nc y is ot her wise s us pecte d.  
•  A d diti o nal uri ne pre g na n c y t esti n g s h o ul d be p erf or me d d uri n g t he treat me nt peri o d, if 
re q uire d l oc all y (A p pe n di x 8 .). 
•  H o me uri ne pre g na nc y t esti n g ma y be perf or m e d bet wee n visits d uri n g t h e trial, if 
a d diti o nal uri ne pre g n a nc y testi n g is re q uir e d l ocall y.  
•  W O C B P nee ds t he last pre g na nc y t est at least 5 wee ks aft er t he last d ose. As t he F U visit is 
a p h o ne c o nta ct, t he patie nts ca n ta ke a uri ne test at h o me a n d i nf or m t he i n vesti gat or of t he 
res ult. 
A ustria: F or c o u ntr y s pecific re q uire m e nts, please see  A p pe n di x 8 . 
C ollecti o n of pre g n a nc y i nf or m ati o n  
Fe m ale p atie nts w h o bec o me pre g n a nt  
•  I n v esti gat or will c ollect pre g na nc y i nf or mati o n o n a n y fe male p atie nt, w h o bec o mes 
pre g na nt w hile partici pati n g i n t his trial. 
•  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 mitte d t o N o v o N or dis k wit hi n 
1 4 cale n dar da ys of lear ni n g of a p atie nt's pre g n a n c y.  
•  Patie nt will 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. T he i n vesti gat or will 
c ollect foll o w -u p i nf or m ati o n o n patie nt a n d ne o n ate, w hic h will be f or war de d t o N o v o 
N or dis k. 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 1 m o nt h be y o n d t h e 
deli ver y date.  
•  A n y ter mi nati o n of pre g n a nc y will be re p orte d, re gar dless of f o etal stat us ( pr ese nce or 
a bse nce of a n o malies) or i n dicati o n f or 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 n c y 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 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 S A E o cc urri n g as a res ult of a p ost -trial pr e g na nc y w hic h is c o nsi dere d 
p ossi bl y/ pr o ba bl y rel ate d t o t he trial pr o d uct b y t he i n vesti gat or will be re p orte d t o N o v o 
N or dis k as descri be d i n A p pe n di x 4 . W hile t he i n vesti gat or is n ot o bli gate d t o acti vel y s ee k 
t his i nf or mati o n i n f or mer patie nts, he or s he m a y lear n of a n S A E t hr o u g h s p o nta ne o us 
rep orti n g.  
•  F or a b n or mal pre g n a nc y o utc o mes c ollecti o n of i nf or mati o n o n t he pater n al f or m f or male 
part ners of fe male p atie nts re q uire si g ni n g of s pecific i nf or me d c o ns e nt. A n y fe male patie nt 
w h o bec o mes pre g na nt w hile partici pati n g i n t he trial will disc o nt i n ue trial pr o d uct. 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
7 9  of 8 9  
 
 
Tec h nic al c o m pl ai nts: Defi niti o n a n d pr oce d u res f or 
rec or di n g, e v al u ati o n, f oll o w -u p a n d re p orti n g  
Tec h nic al c o m pl ai nt defi niti o n  
•  
A tec h nical c o m plai nt is a n y writte n, electr o nic or oral c o m m u nicati o n t hat alle ges pr o d uct ( me dici ne or 
de vice) defects. T he tec h nical c o m plai nt ma y be ass ociate d wit h a n A E, b ut d oes n ot c o nc er n t he A E itself.   
E xa m ples of tec h nical c o m plai nts:  
•  
Pr o ble ms wit h t he p h ysical or c he mical a p peara nce of trial pr o d ucts (e. g. disc ol orati o n).  
•  
Pr o ble ms w it h pac ka gi n g mat erial i ncl u di n g la belli n g.  
Ti me peri o d f or detecti n g tec h nic al c o m pl ai nts  
All tec h nical c o m plai nts , w hic h occ ur fr o m t he ti me of recei pt of t he pr o d uct at trial site u ntil t he ti me of t he last 
usa ge of t he pr o d uct, m ust b e c ollecte d f or  pr o d ucts pre defi ne d o n t he tec h nical c o m plai nt f or m.  
 
Re p orti n g of tec h nic al c o m pl ai nts t o N o v o N or dis k  
C o ntact details (fa x, e -mail a n d a d dress) f or C ust o mer C o m plai nt Ce nter –  refer t o Attac h me nt I  
T ec h nical c o m plai nts m ust b e re p orte d o n a se parate tec h nic al c o m plai nt f or m: 
1.  O ne tec h nical c o m plai nt f or m m ust b e c o m plete d f or eac h affecte d D U N  
2.  If D U N is n ot a vaila ble, a tec h nical c o m plai nt f or m f or eac h batc h, c o de or l ot n u m ber m ust be c o m plete d  
 
Ti meli nes f or re p orti n g of tec h nic al c o m pl ai nts t o N o v o N or dis k  
T he i n vesti gat or m ust c o m plet e t he tec h nical c o m plai nt f or m i n t he C R F wit hi n 2 4 h o urs if relate d t o a n S A E. All 
ot her tec h nical c o m plai nts wit hi n 5 da ys.  
If t he C R F is u na vaila ble or w he n re p orti n g a tec h nical c o m plai nt t hat is n ot patie nt relate d, t he i nf or mati o n m ust b e 
pr o vi de d o n a pa per f or m b y fa x, e -mail or c o urier t o C ust o mer C o m plai nt Ce nter, N o v o N or dis k, wit hi n t he sa me 
ti meli nes as state d a b o ve. W he n t he C R F bec o mes a vaila ble a gai n, t he i n vesti gat or m ust e nter t he i nf or mati o n o n t he 
tec h nical c o m plai nt f or m i n t he C R F. 
 
F oll o w -u p of tec h nic al c o m pl ai nts  
T he i n vesti gat or is res p o nsi ble f or e ns uri n g t hat ne w or u p date d i nf or mati o n will be rec or de d o n t he ori gi nall y 
c o m plete d f or m.  
 
C ollecti o n, st or a ge a n d s hi p me nt of tec h nic al c o m pl ai nt s a m ples  
T he i n vesti gat or m ust c ollect t he tec h nical c o m plai nt sa m ple a n d all ass ociate d parts t hat were pac ke d i n t he sa me 
D U N a n d n otif y t he m o nit or wit hi n 5 cale n dar da ys of o btai ni n g t he sa m ple at trial site. T he sa m ple a n d all 
ass ociate d par ts m ust b e se nt as s o o n as p ossi ble t o C ust o mer C o m plai nt Ce nter, N o v o N or dis k, t o get her wit h a c o p y 
of t he c o m plete d tec h nical c o m plai nt f or m. T he tec h nical c o m plai nt sa m ple s h o ul d c o ntai n t he batc h, c o de or l ot 
n u m ber a n d, if a vaila ble, t he D U N. If t he t ec h nical c o m plai nt sa m ple is u n o btai na ble, t he reas o n m ust be state d o n 
t he tec h nical c o m plai nt f or m. If se veral sa m ples are s hi p pe d i n o ne s hi p me nt, t he sa m ple a n d t he c orres p o n di n g 
tec h nical c o m plai nt f or m s h o ul d be ke pt t o get her. 
St ora ge of t he tec h nica l c o m pl ai nt sa m ple m ust b e d o ne i n a cc or da nce wit h t he c o n diti o ns prescri be d f or t he pr o d uct. 
 
 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  
N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
8 0  of 8 9  
 
 
Rete nti o n of h u m a n bi os a m ples f or bi o m ar kers a n d 
ge netic a n al yses  
I n c o u ntries w h ere all o we d, t he trial will i n v ol ve c ollecti o n of h u ma n bi os a m ples t o be st ore d i n a 
ce ntral arc hi ve f or f ut ure use as n ote d i n secti o n 9. 7  a n d 9. 8 .  
T he f oll o wi n g s a m ples will be st ore d:  
•  W h ole bl o o d (f or ge netic a nal ys es)  
•  Ser u m (f or a n al yses of circ ulati n g bi o mar kers)  
T he sa m ples will be st ore d at a sec ure ce ntral bi o -re p osit or y after e n d of trial a n d u ntil t he researc h 
pr oject ter mi nates, b ut n o l o n ger t h a n 1 5 years fr o m e n d of trial after w hic h t he y will be d estr o ye d.  
Patie nts ma y wit h dra w fr o m t he bi o ba n k c o m p o ne nt of t he trial at a n y ti me, i n de pe n de nt of 
partici pati o n i n t he trial. T he patie nt ca n c h ose t o d o s o at a n y gi ve n ti me w hile i n t he trial or after 
t he e n d of t he trial. If a p atie nt wit h dra ws fr o m t h e bi o ba n k c o m p o ne nt all st ore d bi osa m ples 
o btai ne d fr o m t h eir o w n b o d y will be destr o ye d.  
C o nfi de ntialit y a n d pers o nal data pr otecti o n will be e ns ure d d uri n g st ora ge after t he e n d of trial.  
I n t he e ve nt t hat t he c ollecte d bi osa m ples will be use d i n t he f ut ure, care will be ta ke n t o tar get 
a nal ys es wit hi n t he sc o pe defi ne d i n secti o n 9. 8 ..  
Brazil, C hi na, C ol u m bia, Israel, S o ut h K orea a n d T ur ke y: F or c o u ntr y s pecific re q uire m e nts, please 
see A p pe n di x 8 . 
 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
8 1  of 8 9  
 
 
 
C o u ntr y -s pecific re q uire me nts  
Ar ge nti n a:  
•  Secti o n 6. 2, e x cl usi o n criteri o n # 3 a n d A p pe n di x 5 as descri be d i n T a ble  1 2 -2 : T he 
c o ntrace pti ve met h o ds a n d pre g na nc y t ests will be rei m b urse d b y t he s p o ns or. M o nt hl y testi n g 
wit h hi g hl y s e nsiti ve uri ne pre g na n c y tests are re q uire d f or W O C B P. Use of d o u ble 
c o ntrace pti ve met h o d is re q uire d f or W O C B P.  
•  Secti o n 7. 8: I n refere n ce t o Pr ot oc ol secti o n Treat me nt after disc o nti n uati o n of trial pr o d ucts: 
T he s p o ns or c o m mits t o c o m pl y wit h w hat is state d i n p oi nt 6. 8 of t he c urre nt l ocal re g ulati o n, 
dis p ositi o n 6 6 7 7/ 1 0. Acc or di n g t o it, c o m mits t o c o m pl y wit h t he f oll o wi n g: “ F or Ar ge nti na, 
after t he c o ncl usi o n of s u bjects partici pati o n i n t he st u d y, trial d oct or will disc uss wit h s u bjects 
t he best alter nati ves f or f ut ure treat me nt. If trial d oct or, base d o n his/ her a de q uatel y j ustifie d 
me dical a nal ysis, deci des t hat t he S p o ns or’s st u d y dr u g is t he b est a vaila ble treat me nt o pti o n f or 
t he s u bject, trial d oct or will prescri be t he st u d y dr u g, w hic h m ust be a p pr o ve d b y t h e Et hics 
C o m mittee. T he S p o ns or ( N o v o N or dis k P har ma Ar ge nti na S. A.) will pr o vi de access t o t he 
S p o ns or’s st u d y dr u g t o t he s u bj ect f or t he ti me t h e Et hics C o m mittee deci des or u ntil access is 
e ns ure d b y a n y ot h er mea ns a n d i n acc or da n ce wit h t he a p plica ble pr o visi o ns i n Ar ge nti na. 
S u bjects m ust visit trial d oct or t o recei ve t he S p o ns or’s st u d y dr u g a n d will ha ve t o pr o vi de 
i nf or mati o n a b o ut healt h stat us a n d a n y p ossi ble si de effects t hat ma y ha v e bee n e x perie nce d 
si nce last visit 
A ustri a:  
•  A p pe n di x 3: I n de m nit y state me nt: Arz nei mittel gesetz ( B G BI. Nr. 1 8 5/ 1 9 8 3) last a me n de d wit h 
B G Bl. I Nr. 5 9/ 2 0 1 8  
•  Secti o n 6. 2, e x cl usi o n criteri o n # 3 a n d A p pe n di x 5: A m o nt hl y pre g na n c y test ( uri ne) is 
re q uire d f or all w o me n of c hil d beari n g p ote ntial.  
Bel gi u m:  
•  A p pe n di x 3: I n de m nit y state me nt: La w c o n cer ni n g e x peri me nts o n t he h u ma n pers o n of 0 7 Ma y 
2 0 0 4 - Article 2 9: § 1. E v e n if wit h o ut fa ult, t he s p o ns or is lia ble f or t he da ma ge w hic h t he 
s u bject a n d/ or his ri g htf ul clai ma nts s ustai n a n d w hic h s h o ws eit her a dir ect or a n i n direct 
c o n necti o n wit h t he trial.  
•  Secti o n 6. 2, e x cl usi o n criteri o n # 3 a n d A p pe n di x 5: O nl y hi g hl y effecti ve m et h o ds of birt h 
c ontr ol are acce pte d (i. e. o ne t hat res ults i n less t ha n 1 % per year fail ure rat e w he n use d 
c o nsiste ntl y a n d c orrectl y s uc h as i m pla nts, i njecta bles, c o m bi ne d oral c o ntrace pti ves, s o me 
i ntra uteri ne de vic e), or tr ue se x ual a bsti ne nce (i.e. refrai ni n g fr o m heter ose x ual i nterc o urse 
d uri n g t he e ntire peri o d of ris k ass ociate d wit h t he st u d y treat me nts) or vas ect o mise d part ner.  
 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
8 2  of 8 9  
 
 
Br azil:  
•  Secti o n 6. 2, e x cl usi o n criteri o n # 3 a n d A p pe n di x 5: F or w o me n w h o e x pressl y decl are free of 
t he ris k of pre g n a nc y, eit her b y n ot e n ga gi n g i n se x ual acti vit y or b y h a vi n g se x ual acti vit y wit h 
n o birt h p ote ntial ris k, use of c o ntr ace pti ve met h o d will n ot be ma n dat or y.  
•  Secti o n 6. 2, e x cl usi o n criteri o n # 4: Partici pati o n i n ot her trials wit hi n o ne year pri or t o t he 
scree ni n g visit ( Visit 1) u nless t here is a direct be nefit t o t he researc h s u bject at t he 
i n vesti gat or's discreti o n. 
•  Secti o n 7. 7: N o v o N or dis k will rei m b urse c osts of sta n dar d -of -care tr eat me nt f or T 2 D.  
•  Secti o n 7. 8: At t he e n d of t he trial, all partici pa nt s u bjects s h o ul d be a ss ure d t he access t o t he 
best pr o ve d pr o p h yla ctic, dia g n ostic a n d t h era p e utic met h o ds i de ntifie d d uri n g t he st u d y 
(acc or di n g t o res ol uti o n C N S 4 6 6/ 1 2). 
•  Secti o n 9. 7, 9. 8 a n d A p p e n di x 7: N o s u bjects fr o m Brazil will ta ke part of t he o pti o nal bi o ba n k 
part of t he trial, a n d n o ge netic testi n g will be perf or me d as n ote d i n secti o n 9. 7  a n d 9. 8 . 
•  A p pe n di x 2: All la b orat or y res ults will be c o m m u nicate d t o t he i n vesti gat ors.  
•  A p pe n di x 3, secti o n 3: T w o ori gi n al i nf or me d c o nse nt f or ms will be si g ne d a n d date d a n d o n e 
ori gi nal will be gi ve n t o t he s u bject (a cc or di n g t o r es ol uti o n C N S 4 6 6/ 1 2).  
C hi n a:  
•  Secti o n 6. 2 , e x cl usi o n criteria # 4 : ‘Si m ulta ne o us partici pati o n i n a trial wit h t he pri mar y 
o bjecti ve of e v al uati n g a n a p pr o ve d or n o n -a p pr o ve d i n vesti gati o nal me di ci nal pr o d uct f or 
pre ve nti o n or treat me nt of C O V I D-1 9 disease or p osti nfecti o us c o n diti o ns is all o we d if t he last 
d ose of t he i n vesti gati o nal me dici nal pr o d uct has bee n recei ve d m ore t ha n 3 0 da ys b ef ore 
scree ni n g.’ is n ot a p plica ble f or C hi na. 
•  Secti o n 8. 1 , disc o nti n uati o n/ wit h dra wal criteria: ‘ Si m ulta ne o us partici pati o n i n a trial wit h t he 
pri mar y o bjecti ve of e val uati n g a n a p pr o ve d or n o n -a p pr o ve d i n v esti gati o n al me dici nal pr o d uct 
f or pre v e nti o n or treat me nt of C O VI D-1 9 disease or p osti nfecti o us c o n diti o ns is all o we d at t he 
i n vesti gat or discreti o n wit h o ut disc o nti n ui n g trial pr o d uct.’ is n ot a p plica bl e f or C hi na. 
•  Secti o n 9. 7, 9. 8 a n d A p p e n di x 7: N o s u bjects fr o m C hi na will partici pate i n t he o pti o nal 
bi o ba n k part of t he trial, a n d n o ge netic testi n g will be perf or me d as n ote d i n secti o n 9. 7  a n d 
9. 8 . 
•  A p pe n di x 2: La b orat or y sa m ples f or C hi nese s u bj ects will be destr o ye d acc or di n g t o l ocal 
re g ulat or y re q uire me nts, b ot h f or sa m ples teste d i nsi de a n d o utsi de C hi na. N o sa m ple will be 
st ore d after t he latest dat e of l ocal r e g ulat or y a p pr o val. 
•  A p pe n di x 3: I nf or mati o n of t he trial will  be discl ose d at cli nicaltrials. g o v, c hi na, 
dr u gtri als. or g.c n a n d n o v o n or dis k -trials.c o m as C hi na H A has re q ueste d t o discl ose trial 
i nf or mati o n ( p hase 1-3) at c hi na dr u gtrials. or g.c n si nce 2 0 1 3.  
C ol u m bi a:  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
8 3  of 8 9  
 
 
•  Secti o n 9. 7, 9. 8 a n d A p p e n di x 7: N o s u bjects fr o m C ol u m bia will partici pate i n t he o pti o nal 
bi o ba n k part of t he trial, a n d n o ge netic testi n g will be perf or me d as n ote d i n secti o n 9. 7  a n d 
9. 8 . 
De n m ar k:  
•  Secti o n 6. 2, e x cl usi o n criteri o n # 3 a n d A p pe n di x 5: C o ntrace pti ve meas ures c o nsi dere d 
a de q uate i n cl u des i ntra ut eri ne de vices or h or m o n al c o ntrace pti o n ( oral c o ntrace pti ve pills, 
i m pla nts, tra ns der mal pat c hes, va gi nal ri n gs or l o n g-acti n g i njecti o ns).  
Fr a nce:  
•  A p pe n di x 3, secti o n 1 4: I n de m nit y state me nt: T he s p o ns or is res p o nsi ble f or i de ntificati o n of 
t he har mf ul c o nse q u e nces of t he bi o me dical res earc h f or t he pers o n le n di n g hi mself t heret o a n d 
f or i n de m nificati o n of his be neficiaries, e x ce pt i n case of pr o of, i nc u m be nt o n it, t hat t he 
prej u dice is n ot attri b uta ble t o his fa ult of or t he fa ult of a n y i nter ve ni n g p art y, wit h o ut t he 
s p o ns or's bei n g e ntitle d t o call o n acts b y a t hir d part y or t he v ol u ntar y wit h dra wal of t h e pers o n 
w h o ha d i nitiall y c o nse nt e d t o c o o perati n g i n t he researc h (acc or di n g t o T h e Fre nc h P u blic 
Healt h C o de articl e L. 1 1 2 1 -1 0 (la w n° 2 0 0 4 -8 0 6 of 9 A u g ust 2 0 0 4 art. 8 8 I, I X J o ur na l Officiel 
of 1 1 A u g ust 2 0 0 4).  
Ger m a n y:  
•  S u bject's f ull Dat e of Birt h is n ot all o we d t o be c ollecte d a n d m ust be s h orte ne d t o year of birt h.  
Isr ael: 
•  Secti o n 9. 7, 9. 8 a n d A p p e n di x 7: N o s u bjects fr o m Israel will partici pate i n t he o pti o nal bi o ba n k 
part of t h e trial, a n d n o ge netic testi n g will be perf or me d as n ote d i n secti o n 9. 7  a n d 9. 8 . 
J a p a n:  
•  Secti o n 7. 5: T he hea d of t he st u d y site or t he tri al pr o d uct st ora g e ma na ger assi g ne d b y t h e hea d 
of t he st u d y site (a p har m acist i n pri nci ple) is res p o nsi ble f or c o ntr ol a n d acc o u nta bilit y of t he 
trial pr o d ucts. 
•  Secti o n 9. 2: Ta ble 9 -1: F or J a pa n all A Es, irres pecti ve of seri o us ness, s h o ul d be c ollecte d fr o m 
t he da y of ran d o misati o n a n d u ntil t he f oll o w -u p visit, at t he ti me p oi nts s pecifie d i n t he 
fl o wc hart. A n o n-se vere n o n-seri o us h y p o gl ycae mic e pis o de s h o ul d be re p orte d as a n A E. A 
se vere n o n-seri o us h y p o gl ycae mic e pis o de s h o ul d be re p ort e d as a n A E a n d i n a d diti o n a 
specific e v e nt f or m (s e vere h y p o gl ycae mic e pis o d e) s h o ul d be fille d o ut.  
•  A p pe n di x 3, secti o n 1: A na me a n d seal is acce pte d as a si g n at ure.  
Me xic o:  
•  Secti o n 8. 2: S h o ul d t he s u bject his/ her fa mil y me m bers pare nts or le gal r e prese ntati ve deci de t o 
wit h dra w t he  c o ns e nt f or partici pati o n i n t he trial, t he s u bject will be e ntitle d t o recei ve 
a p pr o priate, free of c h ar ge me dical care a n d/ or trial dr u g d uri n g t he f oll o w u p peri o d of t he 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
8 4  of 8 9  
 
 
pr ot oc ol w he n it will be esta blis he d wit h certai nt y t hat n o u nt o war d me dical c o ns e q ue nces of 
t he s u bject´s partici p ati o n i n t he researc h occ urre d. 
•  A p pe n di x 3, secti o n 1: T he f oll o wi n g res p o nsi bilities will be i ncl u de d f or t he hea d of t h e 
I nstit uti o n/ Healt h Care Esta blis h me nt, Et hics, Researc h a n d, w he n a p plica ble, Bi osafet y 
C o m mittees a n d s p o ns or wit hi n t heir sc o pe of res p o nsi bilit y:  
o  I n v esti gati o n f oll o w-u p  
o  Da ma ges t o healt h arisi n g fr o m t he i n vesti gati o n de vel o p me nt; as well as t h ose arisi n g 
fr o m i nterr u pti o n or a d v a nce d s us pe nsi o n of treat me nt d ue t o n o n-attri b uta ble reas o ns t o 
t he S u bject;  
o  Ti mel y c o m plia nce of t h e ter ms i n w hic h t he a ut h orizati o n of a res earc h f or healt h i n 
h u ma n bei n gs h a d bee n iss ue d;  
o  T o prese nt i n a ti mel y ma n ner t he i nf or mati o n re q uire d b y t h e Healt h A ut h orit y.  
•  A p pe n di x 3, secti o n 1 4:  
o  N o v o N or dis k carries pr o d uct lia bilit y f or its pr o d ucts ass u me d u n der t he s pecial la ws, 
acts/a n d/ or g ui deli nes f or c o n d ucti n g tri als i n a n y c o u ntr y, i n cl u di n g t h ose a p plica ble 
pr o visi o ns o n t he Me xica n U nite d States. If t he s u bject feels t hat s o met hi n g g oes wr o n g 
d uri n g t he c o urse of t his trial, t he s u bject s h o ul d c o ntact t he trial staff i n t h e first 
i nsta nce.  
o  If d uri n g t heir partici pati o n i n t he trial t he s u bject e x perie nces a dise ase or i nj ur y t hat, 
acc or di n g t o t he tri al d oct or a n d t he s p o ns or, is directl y ca use d b y t h e trial me dicati o n 
a n d/ or a trial pr o ce d ure t hat ot her wise w o ul d n ot ha ve bee n part of his/ her re g ular care, 
t he s u bject will recei ve fr o m t he I nstit uti o n or Me dical Care Esta blis h me nt a n d free of 
c har ge, t h e a p pr o priate m e dical treat me nt as re q uir e d. I n t his case, t he c osts res ulti n g 
fr o m s uc h treat me nt as well as t he c osts of a n y i n d e m nificati o n esta blis he d b y la w will 
be c o vere d b y t he trial s p o ns or i n acc or da nce wit h t he ter ms pr o vi de d b y all a p plica ble 
re g ulati o ns; e ve n if t he s u bject disc o nti n ues his/ her partici p ati o n i n t he trial b y his o w n 
will or b y a d ecisi o n fr o m t he i n vesti gat o r.  
o  B y si g ni n g t he i nf or me d c o nse nt, t he s u bject will n ot re n o u nce t o a n y c o m pe nsati o n or 
i n de m nificati o n he/s he ma y b e e ntitle d t o b y la w, n or will he/s he will i nc ur a n y 
a d diti o nal e x pe nse as a res ult of his/ her partici pati o n i n t he trial; a n y a d diti o nal e x pe nse 
res ulti n g fr o m t he s u bject’s partici pati o n i n t he trial will be c o vere d b y t he trial s p o ns or. 
 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
8 5  of 8 9  
 
 
R ussi a:  
•  A p pe n di x 3, secti o n 1: T he trial s h o ul d be c o n d ucte d i n c o m plia nce wit h t he pr ot oc ol, Mi nistr y 
of Healt hcare of R ussia n Fe derati o n’ or der # 2 0 0 н f r o m A pril, 0 1, 2 0 1 6 ” A p pr o val of r ules of 
g o o d cli nic al practice” a n d le gal re q uir e me nts of t he R ussia n Fe derati o n re g ulati n g cir c ulati o n 
of me dici nes.  
S o ut h K ore a:  
•  Secti o n 9. 7, 9. 8 a n d A p p e n di x 7: N o s u bjects fr o m S o ut h K orea will partici pate i n t he o pti o nal 
bi o ba n k part of t he trial, a n d n o ge netic testi n g will be perf or me d as n ote d i n secti o n 9. 7  a n d 
9. 8 . 
T h ail a n d:  
•  Secti o n 6. 2, e x cl usi o n criteri o n # 3 a n d A p pe n di x 5: A de q uate c o ntr ace pti ve meas ures are: 
dia p hra g m, c o n d o m ( b y t he part ner), i ntra uteri ne d e vice i n place f or last t hr ee m o nt hs bef o re 
trial starts, s p o n ge, ca p wit h s per mici de, c o ntrace pti ve patc h, a p pr o ve d h or m o nal i m pla nt (i.e. 
N or pla nt), oral c o ntrace pti ves ta ke n wit h o ut diffic ult y f or t he l ast t hree m o nt hs bef ore trial 
starts, p ost-me n o pa usal state or sterilisati o n.  
T ur ke y:  
•  Secti o n 7. 7: I n case a s u bject nee ds t o c h a n ge t heir re g ular d ose of a c o nc o mita nt me dicati o n 
d ue t o a pr ot oc ol re q uire me nt, t his me dicati o n will be rei m b urse d b y N o v o N or dis k.  
•  Secti o n 9. 7, 9. 8 a n d A p p e n di x 7: N o s u bjects fr o m T ur ke y will partici pate i n t h e o pti o nal 
bi o ba n k part of t he trial, a n d n o ge netic testi n g will be perf or me d as n ote d i n secti o n 9. 7  a n d 
9. 8 . 
U nite d Ki n g d o m:  
•  Secti o n 6. 2, e x cl usi o n criteri o n # 3 a n d A p pe n di x 5: C o ntrace pti ve meas ures c o nsi dere d 
a de q uate i n cl u de hi g hl y effecti ve c o ntr ace pti ve m et h o ds i n acc or da nce wit h t he C T F G ( Cli nical 
Trial Facilitati o n Gr o u p) g ui deli ne: Rec o m me n d ati o ns relate d t o c o ntrace pti o n a n d pre g na n c y 
testi n g i n cli nical trials, as liste d i n Ta ble  1 2 -2 : T his mea ns use of d o u ble barrier m et h o ds is n ot 
a p plica ble.  
 
 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
8 6  of 8 9  
 
 
 
Pr ot oc ol a me n d me nt hist or y   
Pr ot oc ol a me n d me nt n o. 1 ( versi o n 1. 0 date d 1 2 J u ne 2 0 1 9) 
T his a me n d me nt is c o nsi dere d t o be s u bsta ntial base d o n t he criteri a set f ort h i n Article 1 0(a) of 
Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n 1.      
O ver all r ati o n ale f or a me n d me nt n o. 1:  
Pe o ple wit h dia betes h a v e a hi g her ris k f or decli ne i n c o g niti ve f u ncti o n a n d a t w of ol d i ncrease d 
ris k f or de vel o pi n g de m e ntia c o m pare d t o pe o pl e wit h o ut dia betes. A ni mal st u dies a n d li mite d 
cli nical data i n dicate t h at G L P -1 R A ma y h a ve a n effect o n t he rat e of c o g niti ve decli n e. A batter y 
of o nli ne c o g niti ve testi n g is i ntr o d uce d t o f urt her e x pl ore c o g niti ve f u n cti o n a n d se ma gl uti de’s 
effects o n mil d c o g niti ve i m pair me nt ( M CI).  
Secti o n # a n d n a me  
Descri pti o n of c h a n ge  
R ati o n ale  
Secti o n 2 Fl o wc hart  
O nli ne c o g niti ve testi n g i ncl u de d 
See o verall rati o nale  
Secti o n 4. 2. 2. 3 E x pl orat or y 
e n d p oi nts  
O nli ne c o g niti ve testi n g i ncl u de d  
See o verall rati o nale  
Secti o n 9. 1. 4 C o g niti ve testi n g, 
patie nt s ur ve ys a n d visits t o 
e mer ge nc y r o o m/ ur ge nt care u nit  
O nli ne c o g niti ve testi n g i ncl u de d  
See o verall rati o nale  
A p pe n di x 2  
A b bre viati o n i ncl u de d  
See o verall rati o nale  
Pr ot oc ol a me n d me nt n o. 2 ( pr ot oc ol versi o n 3. 0 date d 1 7 N o ve m ber 2 0 2 0) 
T his a me n d me nt is c o nsi dere d t o be s u bsta ntial base d o n t he criteri a set f ort h i n Article 1 0(a) of 
Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n 1.      
O ver all r ati o n ale f or a me n d me nt n o. 2: 
D ue t o t he C O VI D -1 9 pa n de mic t he e x cl usi o n a n d disc o nti n uati o n criteria ha ve bee n a me n d e d t o 
all o w f or si m ulta ne o us p artici pati o n i n trials wit h t he pri mar y o bjecti ve of e val uati n g a n a p pr o ve d 
or n o n -a p pr o ve d i n vesti gati o nal me dici nal pr o d uct f or pre v e nti o n or treat m e nt of C O VI D -1 9 
disease or p osti nfecti o us c o n diti o ns. I n a d diti o n, t he A E c ollecti o n has b ee n e x pa n de d t o i ncl u de t he 
re p orti n g of n o n-s eri o us C O VI D-1 9 e v e nts.  
T his a me n d me nt als o a d dresses statistical c o nsi derati o ns, as we ll as a d mi nistrati ve c ha n ges. 
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
8 7  of 8 9  
 
 
Secti o n # a n d n a me  
Descri pti o n of c h a n ge  
R ati o n ale  
T hr o u g h o ut t he pr ot oc ol  
All i nf or mati o n relate d t o 
Al geria has bee n re m o ve d  
Al geria was n ot i ncl u de d i n t he 
trial 
T hr o u g h o ut t he pr ot oc ol  
Refere nce t o s pecific I B e diti o n 
re m o ve d  
 
T o e ns ure t hat t he m ost c urre nt 
versi o n of t he I B is al wa ys 
referre d t o 
Secti o n 2 Fl o wc hart a n d  
Secti o n 9 Trial assess me nts a n d pr oce d ures  
C ha n ges t o f o ot n ote a)  
Se nte nce re vise d  
T o s pecif y t hat t he i n vesti gat or  
nee ds t o e ns ure t hat t he s u bj ect 
has e n o u g h trial pr o d uct wit hi n 
t he e x pir y date 
Secti o n 2 Fl o wc hart  
C ha n ges t o f o ot n ote j) re m o ve d 
X at V 3, V 4, V 5 a n d V 7  
T o clarif y w he n t he patie nt 
e x pectati o ns & e x perie nce 
s ur ve y a n d t he patie nt 
e n ga ge me nt assess me nts  will 
ta ke place. 
Secti o n 2 Fl o wc hart  
E ns ure u p date d c o ntact pers o ns 
list: a d de d X at V-E O T  
T o e ns ure t hat t he c o ntact 
pers o ns list is u p date d  
Secti o n 4. 2. 2. 2 S u p p orti ve sec o n dar y 
e n d p oi nts  
T he t w o H F e n d p oi nts c o m bi ne d 
i nt o o ne e n d p oi nt: Ti me fr o m 
ra n do misati o n t o heart fail ure 
re q uiri n g h os pitalisati o n or 
ur ge nt heart fail ure visit.  
T o reflect t hat it differs acr oss 
c o u ntries w he n w orse ni n g of H F 
s y m pt o ms ca n be ha n dle d d uri n g 
a n ur ge nt H F visit or d uri n g 
h os pitalisati o n.  
Secti o n 4. 2. 2. 2 S u p p orti ve se c o n dar y 
e n d p oi nts  
Descri pti o n of e n d p oi nts u p date d 
t o ‘ Ti me t o first occ urre nce of 
ac ute li m b isc he mia 
h os pitalisati o n’ a n d ‘ Ti me t o 
first occ urre nce of c hr o nic li m b 
isc he mia h os pitalisati o n’ 
T o reflect t he descri pti o n of t he 
c o m bi ne d M A L E e n d p oi nt a n d 
mat c h t he data t hat we c ollect f or 
a dj u dicati o n.  
Secti o n 4. 2. 2. 3 E x pl orat or y e n d p oi nts  
E x pl orat or y e n d p oi nts relate d t o 
t he o nli ne P R O T E C T C o g niti ve 
T est Batter y f or mil d c o g niti ve 
i m pair me nt u p date d. 
T he P R O T E C T C o g niti ve T est 
Batter y c o nsists of 6 tests a n d 
pr o d uces 1 2 i n di vi d ual data 
p oi nts, w hic h i n di vi d uall y d o n ot 
pr o vi de r o o m f or a cli nicall y 
mea ni n gf ul i nter pretati o n. T h us, 
t he e x pl orat or y e n d p oi nts ha ve 
bee n u p date d t o c o nsist of 
c ha n ge fr o m ra n d o misati o n 
( wee k 0) t o 2 years ( visit 1 2) i n 5 
disti nct a n d cli nicall y mea ni n gf ul 
as pects of c o g niti ve f u ncti o n 
w hic h ca n be calc ulate d as 
c o m p osites base d o n t he 1 2 
i n di vi d ual data p oi nts.   
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
8 8  of 8 9  
 
 
Secti o n 6. 2 E xcl usi o n criteria  
A d diti o n t o e xcl usi o n criteri o n 4 
* Si m ulta ne o us partici pati o n i n a 
trial wit h t he pri mar y o bj ecti ve 
of e val uati n g a n a p pr o ve d or 
n o n -a p pr o ve d i n vesti gati o nal 
me dici nal pr o d uct f or pre ve nti o n 
or treat me nt of C O VI D -1 9 
disease or p osti nfecti o us 
c o n diti o ns is all o we d if t he last 
d ose of t he i n vesti gati o nal 
me dici nal pr o d uct has bee n 
recei ve d m ore t ha n 3 0 da ys 
bef ore scree ni n g    
T o all o w f or c o -partici pati o n i n 
C O VI D -1 9 trials  
Secti o n 7. 5 
Pre p arati o n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y  
T he se nte nce “..a n d rec o ncil e d 
b y t he m o nit or” re m o ve d  
T o s pecif y t he pr oce d ure of trial 
pr o d uct destr ucti o n  
Secti o n 7. 5 
Pre p arati o n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y  
‘ P atie nts m ust ret ur n all use d, 
partl y use d a n d u n use d trial 
pr o d ucts i ncl u di n g e m pt y 
pac ka gi n g material as i nstr uct e d 
b y t he i n vesti gat or’ c ha n ge d t o 
‘ P atie nts m ust e ns ure t hat all 
use d, partl y use d a n d u n use d 
trial pr o d ucts i ncl u di n g e m pt y 
pac ka gi n g mate rial is ret ur ne d as 
i nstr ucte d b y t he i n vesti gat or.’  
T o all o w fle xi bilit y i n case t he 
patie nt ca n’t c o me t o t he site.  
Secti o n 7. 7 C o nc o mita nt me di cati o n  
T e xt i ncl u de d f or c ollecti o n of 
C O VI D -1 9 c o nc o mita nt 
me dicati o n  
T o s pecif y t hat me dicati o n(s)i n 
relati o n t o a cli nical trial f or 
C O VI D -1 9 pre ve nti o n or 
treat me nt as well as a p pr o ve d 
C O VI D -1 9 vacci ne m ust b e 
rec or de d. 
Secti o n 8. 1 Disc o nti n uati o n/ Wit h dra wal 
criteria  
T e xt a d de d t o disc o nti n uati o n 
criteri o n 3  
* Si m ulta ne o us partici pati o n i n a 
trial wit h t he pri mar y o bj ecti ve 
of e val uati n g a n a p pr o ve d or 
n o n -a p pr o ve d i n vesti gati o nal 
me dici nal pr o d uct f or pre ve nti o n 
or treat me nt of C O VI D -1 9 
disease or p osti nfecti o us 
c o n diti o ns is all o we d at t he 
i n vesti gat or discreti o n wit h o ut 
disc o nti n ui n g trial pr o d uct.   
T o all o w f or c o -partici pati o n i n a 
C O VI D -1 9 trial  
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
2 6 Ja n uar y 2 0 2 1  N o v o N or di s k  
Trial I D: E X 9 9 2 4 -4 4 7 3  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
8 9  of 8 9  
 
 
Secti o n 9 Trial assess me nts a n d pr oce d ures  
I m ple me ntati o n of miti gati o ns 
f or t he i n vesti gat or t o e n ga ge 
wit h a healt h care pr ofessi o nal 
fr o m a t hir d part y h o me healt h 
care ser vice pr o vi der t o perf or m 
pr ot oc ol pr oce d ures at t he 
s u bj ect’s h o me or ot her alter nate 
l ocati o n. 
 
T o e ns ure s u bj ect safet y a n d data 
i nte grit y u n der s pecial 
circ u msta nces a n d i n case of 
restricti o ns d ue t o 
e pi de mics/ pa n de mics (e. g. 
C O VI D -1 9)  
S ecti o n 9. 2 A d verse e ve nts a n d Fi g ure 9 -1  
T e xt re gar di n g C O VI D -1 9 A Es 
i ncl u de d 
T o descri be t he i ncl usi o n of 
C O VI D -1 9 A Es i n t he selecti ve 
data c ollecti o n a p pr oac h of t his 
trial 
Secti o n 9. 4 Safet y assess me nts  
A d diti o n of C O VI D -1 9 i n te xt  
T o i ncl u de C O VI D -1 9 t o t he 
c o nc o mita nt ill ness/ me dical 
hist or y t hat s h o ul d be re p orte d i n 
t he e C R F 
Secti o n 1 0. 3. 2. 1 C o nfir mat or y sec o n dar y 
e n d p oi nts  
U p date d te xt f or t he statistical 
testi n g strate g y f or t he 
c o nfir mat or y sec o n dar y 
e n d p oi nts.  
 
T o preser ve c o ntr ol of t he t y p e  1 
err or f or c o nfir mat or y e n d p oi nts.  
Secti o n 1 0. 3. 2. 1 C o nfir mat or y sec o n dar y 
e n d p oi nts  
Delete d: ‘i ncl u di n g ti p pi n g p oi nt 
a nal yses’  
T o ali g n wit h t he S A P  
Secti o n 1 0. 3. 2. 1 C o nfir mat or y sec o n dar y 
e n d p oi nts  
Se nte nce delete d: F or t he 
c o m p osite C K D e n d p oi nt, t he 
a nal ysis will e xcl u de patie nts 
w h o alrea d y ha ve met rele va nt 
re nal c o m p o ne nts at baseli ne.  
P atie nts ca n be f oll o we d f or 
ot her c o m p o ne nts of t he 
e n d p oi nt. T o be detaile d i n S A P.  
Secti o n 1 0. 3. 2. 1 C o nfir mat or y sec o n dar y 
e n d p oi nts  
Se nte nce delete d: F urt he r m ore 
f or t his e n d p oi nt, missi n g data 
f or e G F R, d ue t o missi n g bl o o d 
sa m ples w hile patie nts are still 
bei n g f oll o we d, will be i m p ut e d 
usi n g m ulti ple i m p utati o n.  
T o ali g n wit h t he S A P  
Secti o n 1 0. 3. 3 E x pl orat or y e n d p oi nts  
T e xt u p date d  
T o reflect t he u p dates of t he 
P R O T E C T e n d p oi nts i n t he 
statistical a nal yses. 
 
C O N FI D E N TI A L