SELECT - Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity
Phase: PHASE3
Conditions: Overweight, Obesity
Sponsor: Novo Nordisk A/S

C o v e r  P a g e   f o r P r ot o c ol  
S p o ns or  n a  m e:  
N o v o   N or dis k   A/ S   
N  C T  n u  m b er   
N  C T 0 3 5 7 4 5 9 7   
S p o ns or t ri al I  D: 
E  X 9 5 3 6 -4 3 8 8  
Offi ci al titl e  of st u d y:     
S E L E  C T  - S e  m a gl uti d e  eff e cts  o n  c ar di o v as c ul ar  o ut c o  m es i n 
p e o pl e   wit h  o v er  w ei g ht  or  o b esit y  
D oc u me nt date: 
0 6 J u ne 2 0 2 3  

Li n k
Li n k
List of c o nte nts
Pr ot oc ol ...............................................................................................................................................
Pr ot oc ol att ac h me nt ...........................................................................................................................
Date:
N o v o N or di s k
Versi o n:
Stat us:
Se ma gl uti de
Trial I D: E X 9 5 3 6- 4 3 8 8
Cli nical Trial Re p ort
A p pe n di x 1 6. 1. 1
0 6 J u ne 2 0 2 3
1. 0
Fi nal
1 6. 1. 1 Pr ot oc ol a n d pr ot oc ol a me n d me nts
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
Stat us:  
Fi nal  
P a ge:  
1  of 1 0 0  
Pr ot oc ol
I n cl u di n g: 
A me n d me nt 1 , date d 2 7-N o ve m ber -2 0 1 8  
A me n d me nt 2, date d 1 5 -Oct o ber -2 0 1 8   
A me n d me nt 3, date d 1 2 -Dec e m b er-2 0 1 8  
A me n d me nt 4 , date d 0 7 -Ma rc h-2 0 1 9  
A me n d me nt 5 , date d 1 2 -J u ne-2 0 1 9  
A me n d me nt 6,  date d 2 3 -A u g ust -2 0 1 9   
A me n d me nt 7, date d 2 3 -Oct o ber -2 0 1 9  
A me n d me nt 8, date d 0 4 -J a n uar y-2 0 2 1  
A me n d me nt 9, date d 0 9 -Fe br uar y -2 0 2 2  
Pr ot oc ol titl e: S E L E C T - Se m a gl uti de effects o n c ar di o v asc ul ar o utc o mes i n pe o ple wit h 
o ver wei g ht or o besit y  
S u bst a nce n a me: Se m a gl uti de  
U ni vers al Tri al N u m ber: U 1 1 1 1 -1 2 0 0 -5 5 6 4  
E U dr a C T N u m ber: 2 0 1 7 -0 0 3 3 8 0 -3 5  
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”. 
    
    
   
    
     
    
  
    
    
    
    
    
 
 
    
    
    
    
    
    
    
    
    
    
    
 
   
     
 
 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
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1 0 0
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 oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
Stat us:  
Fi nal  
P a ge:  
2  of 1 0 0  
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  
Pr ot oc ol v ersi o n  
U p date d pr ot oc ol i ncl u di n g 
a me n d me nt 9 ( Gl o bal ) 
0 9 -Fe br uar y -2 0 2 2
7. 0  
U p date d pr ot oc ol i ncl u di n g  t he l ocal 
a me n d me nts 6 a n d 7 a n d t he gl o bal 
a me n d me nt 8.  
0 4 -Ja n uar y-2 0 2 1
6. 0  
U p date d pr ot oc ol i ncl u di n g 
a me n d me nt 7 (o nl y a p plica ble f or 
c o u ntries i n v ol ve d i n t he V H P a n d 
Net herla n ds )  
2 3 -Oct o ber -2 0 1 9
5. 0  
U p date d pr ot oc ol i ncl u di n g 
a me n d me nt 6 (o nl y a p plica ble f or 
c o u ntries i n v ol ve d i n t he V H P a n d 
Net herla n ds)   
2 3 -A u g ust -2 0 1 9
4. 0  
A me n d me nt 5 ( Greece)  
1 2 -J u ne-2 0 1 9
T he a me n d me nt was d ue t o l ocal 
c ha n ges re q uire d f or tra nslati o n a n d 
lea d t o n o c ha n ges t o t he pr ot oc ol 
a n d n o c ha n ges  i n pr ot oc ol versi o n  
n u m ber.   
U p date d pr ot oc ol i ncl u di n g 
a me n d me nt 2  ( R ussia), 3 ( Fra nce) 
a n d 4  (all c o u ntries, e xce pt f or 
c o u ntries i n v ol ve d i n t he V H P a n d 
Net herla n ds ) 
0 7 -Marc h -2 0 1 9
3. 0  
U p date d pr ot oc ol i ncl u di n g 
a me n d me nt 1  
O nl y a p plica ble f or c o u ntries 
i n v ol ve d i n t he V H P a n d 
Net herla n ds  
2 7 -N o ve m ber -2 0 1 8
2. 0  
Ori gi nal pr ot oc ol  
1 5 -Ma y -2 0 1 8
1. 0  
Pr ot oc ol a me n d me nt n o. 9  ( pr ot oc ol versi o n 7 . 0 d ate d 0 9  Fe br u ar y 2 0 2 2 ) 
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 criteria 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 p re p ari n g pr ot oc ol, versi o n 7 : 
A be nefit of G L P -1 R A i n pre ve nti n g heart fail ure h os pitalizati o ns ( H H F) has e mer ge d wit h a 
gr o wi n g b o d y of scie ntifi c e vi de nce i n rece nt years. Acr oss C V O Ts wit h G L P -1 R A i n T 2 D 
patie nts, t he o verall data i n dicates a be neficial  effect of G L P -1 R A. I ncl usi o n of H F c o m p osite 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
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1
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  Pr ot oc ol  Pr ot oc ol V 7
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1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
3  of 1 0 0  
 
e n d p oi nt i n t he testi n g hierarc h y is a n o p p ort u nit y t o i ncrease t h e le vel of e vi de nce f or se ma gl uti de 
a n d H F.  
F or Al geria a n d Ger ma n y , c o-partici p ati o n i n C O VI D -1 9 trials is n ot all o we d d ue t o l ocal 
re 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 safet 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  
Secti o n 4. 2 . 2 
O bj ecti ves a n d e n d p oi nts  
Sec o n dar y e n d p oi nts  
H F c o m p osite e n d p oi nt m o ve d fr o m 
s u p p orti ve sec o n dar y e n d p oi nts t o 
c o nfir mat or y sec o n dar y e n d p oi nts  
See o verall rati o nale  
 
Secti o n 8. 1  
Disc o nti n uati o n/ Wit h dra wal criteria  
Se nte nce relate d t o 
disc o nti n uati o n/ wit h dra wal 
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’s discreti o n wit h o ut 
disc o nti n ui n g trial treat me nt.‘ is n ot 
a p plica ble f or Al geria a n d Ger ma n y.  
C o -partici pati o n i n C O VI D -1 9 trials 
is n ot all o we d i n Al geria a n d 
Ger ma n y d ue t o l ocal re q uire me nts  
Secti o n 1 0. 3. 2  
Statistical c o nsi derati o ns  
Sec o n dar y e n d p oi nts  
H F c o m p osite e n d p oi nt m o ve d fr o m 
s u p p orti ve sec o n dar y e n d p oi nts t o 
c o nfir mat or y sec o n dar y e n d p oi nts 
See o verall rati o nale  
A p pe n di x 9  
C o u ntr y -s pecific re q uire me nts f or 
Al geria a n d Ger ma n y  
Secti o n 8. 1, Se nte nce relate d t o 
disc o nti n uati o n/ wit h dra wal 
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 uat i 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’s discreti o n wit h o ut 
disc o nti n ui n g trial treat me nt.‘ is n ot 
a p plica ble f or Al geria  a n d Ger ma n y.  
C o -partici pati o n i n C O VI D -1 9 trials 
is n ot all o we d i n Al geria a n d 
Ger ma n y d ue t o l ocal re q uire me nts  
 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
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V V- T M F- 5 0 5 7 8 4 9
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1
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  Pr ot oc ol  Pr ot oc ol V 7
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1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
4  of 1 0 0  
 
Ta ble of C o nte nts    
 
P a ge  
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  ........................................................................................... 2  
T a ble of C o nte nts .............................................................................................................................................. 4  
1  
S y n o psis  ...................................................................................................................................................... 7  
2  
Fl o wc h art  ................................................................................................................................................... 9  
3  
I ntr o d ucti o n ............................................................................................................................................. 1 3  
3. 1    
Trial rati o nale  ............................................................................................................................... 1 3  
3. 2    
Bac k gr o u n d  .................................................................................................................................. 1 3  
3. 3    
Be nefit -ris k assess me nt ................................................................................................................ 1 4  
3. 3. 1    
Ris ks a n d preca uti o ns  ................................................................................................ 1 4  
3. 3. 2    
Be nefits  ...................................................................................................................... 1 5  
3. 3. 3    
Ris k -be nefit c o ncl usi o n  ............................................................................................. 1 6  
4  
O bjecti ves a n d e n d p oi nts  ........................................................................................................................ 1 7  
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 7  
4. 2    
Pri mar y e n d p oi nt a n d sec o n dar 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 8  
4. 2. 2. 1    
C o nfir mat or y sec o n dar y e n d p oi nts  ..................................................... 1 8  
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    
S u bj ect a n d trial c o m pleti o n  ........................................................................................................ 2 0  
5. 3    
E n d of trial defi niti o n  ................................................................................................................... 2 1  
5. 4    
Sc ie ntific rati o nale f or trial desi g n ............................................................................................... 2 2  
5. 5    
J ustificati o n f or d ose .................................................................................................................... 2 2  
6  
Tri al p o p ul ati o n  ....................................................................................................................................... 2 4  
6. 1    
I ncl usi o n criteria .......................................................................................................................... 2 4  
6. 2    
E xcl us i o n criteria ......................................................................................................................... 2 4  
6. 3    
Scree n fail ures  .............................................................................................................................. 2 5  
6. 4    
Ra n d o misati o n criteria  ................................................................................................................. 2 5  
6. 4. 1    
Assess me nt of eli gi bilit y  ............................................................................................ 2 5  
7  
Tre at me nts  ............................................................................................................................................... 2 6  
7. 1    
Treat me nts a d mi nistere d  .............................................................................................................. 2 6  
7. 1. 1    
Me dical de vices  ......................................................................................................... 2 8  
7. 2    
D ose m o dificati o n  ........................................................................................................................ 2 8  
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 9  
7. 5. 1    
S hi p me nt of trial pr o d uct t o s u bject’s h o me  .............................................................. 3 0  
7. 6    
Treat me nt c o m plia nce  .................................................................................................................. 3 0  
7. 7    
Sta n dar d of care  ........................................................................................................................... 3 0  
7. 8    
C o nc o mita nt me dicati o n  .............................................................................................................. 3 1  
7. 9    
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    
Te 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  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
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C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
5  of 1 0 0  
 
8. 2. 1    
Re place me nt of s u bjects  ............................................................................................ 3 3  
8. 3    
L ost t o f oll o w -u p  ......................................................................................................................... 3 3  
8. 4    
Ter mi nati o n or m o dificati o n of t he trial  ...................................................................................... 3 4  
9  
Tri al assess me nts a n d pr oce d ures  ......................................................................................................... 3 5  
9. 1    
Efficac y assess me nts  .................................................................................................................... 3 6  
9. 1. 1    
B o d y meas ure me nts  ................................................................................................... 3 6  
9. 1. 2    
Cli n ical efficac y la b orat or y assess me nts ................................................................... 3 6  
9. 1. 3    
Patie nt re p orte d o utc o mes  .......................................................................................... 3 7  
9. 1. 4    
H os pitalisati o ns  .......................................................................................................... 3 7  
9. 1. 4. 1    
N o n -S A E h os pitalisati o ns  ................................................................... 3 7  
9. 2    
A d verse e ve nts  ............................................................................................................................. 3 7  
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 9  
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    
Car di o vasc ular e ve nts a n d deat hs  .............................................................................. 4 2  
9. 2. 6    
Disease -relate d e ve nts a n d/ or disease-relate d o utc o mes n ot q ualifie d as a n A E 
or S A E ........................................................................................................................ 4 2  
9. 2. 7    
Pre g na ncies a n d ass ociate d a d verse e ve nts  ................................................................ 4 2  
9. 2. 8    
Tec h nical c o m plai n ts ................................................................................................. 4 2  
9. 3    
Treat me nt of o ver d ose  ................................................................................................................. 4 3  
9. 4    
Safet y assess me nts  ....................................................................................................................... 4 3  
9. 4. 1    
Brea st ne o plas ms f oll o w-u p a n d c ol o n ne o plas ms f oll o w -u p  ................................... 4 4  
9. 4. 2    
P h ysical e xa mi nati o ns  ................................................................................................ 4 4  
9. 4. 3    
Vital si g ns  .................................................................................................................. 4 4  
9. 4. 4    
Cli nical s afet y la b orat or y assess me nts  ....................................................................... 4 4  
9. 5    
P har mac o ki netics  ......................................................................................................................... 4 4  
9. 6    
P har mac o d y na mics  ...................................................................................................................... 4 4  
9. 7    
Ge netics  ....................................................................................................................................... 4 5  
9. 8    
Bi o mar kers  ................................................................................................................................... 4 5  
1 0  St atistic al c o nsi der ati o ns  ........................................................................................................................ 4 5  
1 0. 1   
Sa m ple size deter mi nati o n  ........................................................................................................... 4 5  
1 0. 2   
Defi niti o n of a nal ysis sets  ............................................................................................................ 4 8  
1 0. 3   
Statistical a nal yses  ....................................................................................................................... 4 9  
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 1  
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  
1 2  A p pe n dices  ............................................................................................................................................... 5 6  
  
A b bre vi ati o ns a n d Tr a de m ar ks  .......................................................................................... 5 6  
  
Cli nic al l a b or at or y tests  ....................................................................................................... 5 8  
  
Tri al g o ver n a nce c o nsi der ati o ns  ......................................................................................... 6 1  
  
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 0  
  
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 4  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
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C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
6  of 1 0 0  
 
  
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 7  
  
Rete nti o n of h u m a n bi os a m ples a n d ge netics  ..................................................................... 7 8  
  
M o nit ori n g of c alcit o ni n  ....................................................................................................... 7 9  
  
C o u ntr y -s pecific re q uire me nts ............................................................................................ 8 2  
 Pr ot oc ol a me n d me nt hist or y  ................................................................................................ 9 0  
 
Attac h me nt I Gl o bal li st 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  
 
 
 
 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
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1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y  2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
7  of 1 0 0  
 
1  
S y n o psis  
R ati o n ale:  
Pe o ple wit h o ver wei g ht or o besit y are at hi g h ris k f or car di o vasc ular ( C V ) disease. Se ma gl uti de has 
s h o w n C V ris k re d ucti o n a n d i m pact o n C V ris k fact ors i ncl u di n g o ver wei g ht, d ys gl ycae mia a n d 
i ncreas e d bl o o d press ure  i n s u bjects wit h t y pe 2 di a betes ( T 2 D). W het her s e ma gl uti de will re d uce 
C V D ris k a n d m ortalit y i n s u bjects wit h esta blis he d C V disease a n d o ver wei g ht or o besit y  is n ot 
k n o w n . 
O bjecti ves a n d e n d p oi nts:  
T he pri m ar y o bjecti ve  
T o de m o nstrate t hat se m a gl uti de s u bc ut a ne o usl y (s.c) 2. 4 m g o nce -wee kl y l o wers t he i nci de nce of 
maj or a d verse car di o vasc ular e ve nts ( M A C E) vers us se ma gl uti de place b o , b ot h a d de d t o sta n dar d 
of care i n s u bjects wit h esta blis he d C V disease a n d o ver wei g ht or o besit y. 
Ke y sec o n d ar y o bjecti ve s 
T o c o m pare t h e effect of se ma gl uti de s. c. 2. 4 m g o nce-wee kl y vers us se ma gl uti de place b o , b ot h 
a d de d t o sta n dar d of care i n s u bjects wit h esta blis he d C V disease a n d o ver wei g ht or o besit y wit h 
re gar ds t o: 
 
•  M ortalit y  
•  C V ris k fact ors  
 
T he pri m ar y esti m a n d  
T he pri mar y 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 uati n g t he effect of t h e 
ra n d o mise d treat me nt i nt er ve nti o n irres p ecti ve of a d here nce 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.  
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 fi rst 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, n o n -fatal m y ocar dial i nfarcti o n, or n o n-fatal str o ke 
Ke y sec o n d ar y e n d p oi nts  
C o nfir mat or y s ec o n dar y e n d p oi nts  
Ti me fr o m ra n d o misati o n t o:  
•  C V deat h  
•  First occ urre n ce of a c o m p osite heart fail ure  e n d p oi nt c o nsisti n g of: heart fail ure 
h os pitalisati o n, ur ge nt heart fail ure visit or C V deat h  
•  All -ca use d eat h  
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 se ma gl uti de 
2. 4 m g wit h se ma gl uti de place b o b ot h a d mi nistere d  s u bc uta ne o usl y (s.c.) o nce -wee kl y i n s u bjects 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
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7
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y  2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
8  of 1 0 0  
 
wit h esta blis he d C V disease a n d o ver wei g ht or o besit y. S u bjects will be ra n d o mise d i n a 1: 1 rati o t o 
recei v e eit her se ma gl uti de 2. 4 m g or se ma gl uti de place b o as a n a dj u nct t o sta n dar d of care.  
Ke y i ncl usi o n criteri a  
•  Male or fe m ale, a ge ≥ 4 5 years at t he ti me of si g ni n g i nf or m e d c o nse nt  
•  B o d y mass i n de x ( B MI) ≥ 2 7 k g/ m 2  
•  Ha ve esta blis he d C V dis ease as e vi de nce d b y at l east o ne of t he f oll o wi n g:  
•  pri or m y o car dial i nfarcti o n  
•  pri or str o ke (isc h e mic or hae m orr ha gic str o ke) or 
•  s y m pt o matic peri p heral arterial diseas e ( P A D), as e vi de nce d b y i nter mitte nt 
cla u dicati o n wit h a n kle -brac hial i n de x ( A BI) < 0. 8 5 (at rest), or peri p heral arterial 
re vasc ul arizati o n pr oce d ure, or a m p utati o n d ue t o at her oscler otic disease  
Ke y e xcl usi o n criteri a  
•  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 da y of scree ni n g  
•  H b A 1c ≥ 4 8 m m ol/ m ol ( 6. 5 %) as mea s ure d b y t he ce ntral la b orat or y at s cree ni n g  
•  Hist or y of t y p e 1 or t y pe 2 dia betes ( hist or y of gestati o nal dia betes is all o we d)  
 
N u m ber of s u bjects:  
I n t his trial a p pr o xi matel y 1 7, 5 0 0 s u bjects will be ra n d o ml y assi g ne d t o trial pr o d ucts.  
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 u p t o 5 9 m o nt hs f oll o wi n g ra n d o misati o n of t he first 
s u bject. 
Tri al pr o d ucts:  
T he f oll o wi n g tri al pr o d u cts will be s u p plie d b y N o v o N or dis k A/ S:  
•  Se ma gl uti de B 3. 0 m g/ m L P D S 2 9 0, s ol uti o n f or i njecti o n, 3 m L pre -fille d pe n i nject or 
•  Se ma gl uti de place b o, s ol uti o n f or i njecti o n, 3 m L P D S 2 9 0 pre -fille d pe n-i nject or  
 
 
 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
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8
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Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
1 3  of 1 0 0  
 
3  
I ntr o d ucti o n 
3. 1    
Tri al r ati o n ale  
Pe o ple  wit h o ver wei g ht or o besit y are at hi g h ris k f or car di o vasc ular ( C V) disease. I n s pite of 
a d va nces i n i m pr o vi n g C V ris k fact ors, t h ese pe o ple c o nti n ue t o be at c o nsi dera ble i ncrease d ris k  of 
a d verse car di o vasc ular e ve nts 2, 3.T he car di o vasc ul ar ( C V) s afet y of se ma g l uti de s.c. 0. 5 a n d 1. 0 m g 
o nce -wee kl y was assesse d i n a p hase 3a C V o utc o mes trial ( N N 9 5 3 5 -3 7 4 4, S U S T AI N 6) desi g ne d 
t o r ule o ut a n 8 0 % i ncrease d C V ris k i n s u bjects wit h t y pe 2 dia bet es a n d hi g h C V ris k. T he trial, 
h o we ver i n dicate d a statisticall y si g nific a nt 2 6 % ris k re d ucti o n wit h se ma gl uti de c o m pare d wit h 
place b o f or t he maj or a d verse C V e v e nt ( M A C E) 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 nce of 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 or 
n o n -fatal str o ke) 4. T he c urre nt trial is desi g ne d t o e val uate t he h y p ot hesis of C V ris k re d ucti o n f or 
se ma gl uti de 2. 4 m g o nce -wee kl y vers us se ma gl uti de place b o b ot h a d de d t o sta n dar d of care i n 
s u bjects wit h esta blis he d C V disease a n d o ver wei g ht or o besit y a n d wit h o ut dia betes.  
3. 2    
B ac k gr o u n d  
Gl uca g o n -li ke pe pti de-1 ( G L P -1) is a p h ysi ol o gi cal re g ulat or of a p petite 5 a n d p har mac o l o gical 
le vels of G L P-1 rece pt or a g o nists ( R As) ha ve bee n s h o w n t o i n d uce wei g ht l oss. Se ma gl uti de is a 
ne xt ge nerati o n l o n g -acti n g G L P -1 R A c urre ntl y u n der de vel o p me nt b y N o v o N or dis k.  
Besi des effects o n a p petite,  G L P -1 re g ulates bl o o d gl uc ose b y a gl uc o se-de pe n de nt sti m ulat or y 
effect o n i ns uli n a n d i n hi bit or y effect o n gl u ca g o n secreti o n (i.e. w he n plas ma gl uc ose le vels are 
a b o ve n or mal) 6, 7. G L P -1 has  als o se veral effects i n t he C V  s yste m. I n t he T 2 D de vel o p me nt 
pr o gra m me, t he C V  safet y of se ma gl uti de s.c. 0. 5 m g a n d 1. 0 m g o nce-wee kl y was assesse d i n a 
pre -a p pr o val C V  o utc o m es trial ( S U S T AI N 6 ; N N 9 5 3 5-3 7 4 4) i n s u bjects wit h T 2 D a n d hi g h C V  
ris k. Se ma gl uti de-treate d s u bjects ( 0. 5 a n d 1. 0 m g d ose gr o u ps c o m bi ne d) ha d a si g nifica nt 2 6 % 
lo wer ris k of t he pri mar y c o m p osite o utc o me of deat h fr o m C V  ca uses, n o nfatal m y ocar dial 
i nfarcti o n ( MI), or n o nfatal str o ke t ha n di d t h ose recei vi n g place b o ( hazar d ratio ( H R): 0. 7 4 [ 0. 5 8; 
0. 9 5] 9 5 % CI) 4. T he e x act mec ha nis m  be hi n d t he C V  effect of se ma gl uti de is n ot k n o w n. H o we ver, 
b ot h pre -cli nical a n d cli nical st u dies s u g gest t hat G L P -1 R As, i ncl u di n g se ma gl uti de 4, ha ve direct 
a n d be neficial effects o n t he C V  s yste m (i ncl u di n g re d ucti o ns i n li pi d le vels a n d bl o o d press ure as 
well as a nti -i nfla m mat or y effects) res ulti n g i n atte n uati o n of at her oscl er osis 8 -1 0. Wei g ht l oss of t he 
ma g nit u de see n i n t he rece nt p hase 2 d ose-fi n di n g trial i n s u bjects wit h o besit y ( B MI ≥ 3 0 k g/ m 2) 
(trial N N 9 5 3 6-4 1 5 3) mi g ht als o l o wer C V  ris k i n de pe n de ntl y. S pecificall y, se ma gl uti de s.c. i n 
d oses of 0. 0 5 t o 0. 4 m g o nce -dail y was acc o m pa nie d b y a n i m pr o ve me nt i n C V  ris k fact ors 1 1. 
S e ma gl uti de s.c. 2. 4 m g o nce-wee kl y is c urre ntl y als o i n p hase 3a de vel o p me nt f or wei g ht 
ma na ge me nt . 
I n s u m mar y, t hese dat a i n dicate t hat se ma gl uti de s.c. has be neficial effects o n t he C V  s yste m. 
Acc or di n gl y, se ma gl uti d e s.c. ma y tar get a n u n met me dical nee d i n s u bjects wit h esta blis he d C V 
disease a n d o v er wei g ht or o besit y.  
Detaile d i nf or mati o n f or se ma gl uti de s.c.  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 ure1 2.   
E X 9 5 3 6- 4 3 8 8
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V V- T M F- 5 0 5 7 8 4 9
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1
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1 3
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
1 4  of 1 0 0  
 
3. 3    
Be nefit -ris k assess me nt  
3. 3. 1    
Ris ks a n d prec a uti o ns  
T he secti o ns bel o w des cri be t he ris ks ass ociate d wit h se ma gl uti de s.c. treat me nt. Ris ks are i ncl u de d 
if t here is e vi de n ce or s us pici o n of a n ass ociati o n, mai nl y fr o m cli nical data wit h se ma gl uti de s.c. 
b ut als o base d o n fi n di n gs i n n o n -cli nical st u dies a n d data wit h ot her G L P -1 R A. F or details pleas e 
refer t o t he c urre nt versi o n of t he I B 1 2 or a n y u p dat es here of.  
Base d o n cli nical trials a ca usal relati o ns hi p wit h se ma gl uti de was s u g geste d f or t he f oll o wi n g ris ks.  
•  Gastr oi ntesti nal dis or ders  
F or se ma gl uti de as f or ot her gl uca g o n -li ke pe pti de-1 ( G L P -1) rece pt or a g o nists, t he m ost fre q ue ntl y 
re p orte d a d verse reacti o ns i n cli nical trials were gastr oi ntesti nal disor ders, i ncl u di n g na usea, 
diarr h oea a n d v o miti n g. I n ge n eral, t hes e reacti o ns were mil d or m o derate i n se verit y a n d of s h ort 
d urati o n.  T he gastr oi ntesti nal a d verse reacti o ns s h o ul d be  c o nsi dere d w he n treati n g s u bj ects wit h 
i m paire d re n al f u ncti o n as na usea, v o miti n g, a n d diarr h oea ma y ca use de h y drati o n w hic h c o ul d 
ca use a d eteri orati o n of re nal f u ncti o n.  A l o w starti n g d ose a n d d ose es calati o n ste ps will be 
i m ple me nte d i n t he trial t o miti gate t he ris k of gastr oi ntesti nal A Es. 
•  C h olelit hiasis  
E ve nts of c h ol elit hiasis were re p orte d m ore fre q ue ntl y wit h se ma gl uti de t ha n wit h c o m parat or 
pr o d ucts i n t he se ma gl uti de cli nical de vel o p me nt pr o gra m me. I n t he p hase 2 wei g ht ma na ge me nt 
trial ( N N 9 5 3 6-4 1 5 3), e ve nts of c h olelit hiasis were t he m ost fre q ue ntl y re p orte d gall bla d der e ve nts 
a n d were i n a fe w i nsta nces c o -re porte d wit h ac ute pa ncreatitis ( data o n file).  
Ris ks f or s u bjects wit h t y pe 2 di a betes  
Bel o w ris ks o nl y a p plies t o s u bjects w h o de vel o p dia betes d uri n g t he trial.  
•  H y p o gl ycae mia (i de ntifie d f or T 2 D s u bjects) 
S u bject s wit h T 2 D 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 urea ( S U) or i ns uli n ma y 
ha ve a n i ncreas e d ris k of h y p o gl ycae mia. T here is a l o w ris k of h y p o gl ycae mic e pis o des w he n 
se ma gl uti de is use d as m o n ot hera p y. S u bjects i nitiati n g S U or i ns uli n s h o ul d perf or m a de q uate 
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. 
R ussia: F or c o u ntr y s pecific re q uire me nt, please see A p pe n di x 9 . 
•  Dia betic reti n o pat h y c o m plicati o n (i de ntifie d f or T 2 D s u bjects)  
T he car di o vasc ular o utc o me trial i n t he se ma gl uti de T 2 D de vel o p me nt pr o gra m me s h o we d a n 
i ncreas e d ris k of e v e nts r elate d t o dia betic reti n o pat h y c o m plicati o ns i n s u bjects treate d wit h 
sema gl uti de c o m pare d t o place b o, al b eit t he pr o p orti o n of s u bjects wit h a n e ve nt of dia betic 
reti n o pat h y c o m plicati o ns was l o w. T he i m bala nce was dri ve n b y s u bj ects wit h a hist or y of dia betic 
reti n o pat h y at baseli ne a n d s u bjects w h o were treate d wit h i ns uli n 1 3. Ra pi d i m pr o ve me nt i n gl uc ose 
c o ntr ol has bee n ass ociat e d wit h a te m p orar y w ors e ni n g of dia betic reti n o pat h y, b ut ot her 
mec ha nis ms ca n n ot be e x cl u de d
1 4. L o n g-ter m im pr o ve d gl ycae mic c o ntr ol has bee n s h o w n t o 
decrease t he ris k of pr o gressi o n of dia betic reti n o pat h y 1 5. S u bjects de vel o pi n g T 2 D d uri n g t h e trial 
s h o ul d be treate d acc or di n g t o l ocal cli nical g ui d eli nes i ncl u di n g o p ht hal m ol o gic care.  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
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V V- T M F- 5 0 5 7 8 4 9
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1
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1 4
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
1 5  of 1 0 0  
 
I n a d diti o n, f or t he ris ks bel o w, t here is s o me basis f or s us pici o n of a n ass o ciati o n wit h se ma gl uti de, 
h o we ver, t he relati o ns hi p has n ot bee n c o nfir me d.  
•  Me d ullar y t h yr oi d ca n cer ( M T C)  
E x pecte d pr oliferati ve t h yr oi d C -cell c ha n ges were see n i n t he m o use 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 h y per plasia was o bser ve d i n m o n ke ys 
after 5 2 wee ks e x p os ure u p t o 1 3 -f ol d a b o ve t he cli nical plas ma e x p os ure at 2. 4 m g/ wee k. T he C-
cell c ha n ges i n r o de nts are me diate d b y t he G L P -1 rece pt or, w hic h is n ot e x presse d i n t he n or mal 
h u ma n t h yr oi d. Acc or di n gl y, t he ris k of G L P -1 rece pt or -me diate d C -cell c ha n ges i n h u ma ns is 
c o nsi dere d t o be l o w. As a preca uti o n, e xcl usi o n a n d disc o nti n uati o n criteria relate d t o me di cal 
hist or y of m ulti ple e n d ocri ne ne o plasia t y pe 2 ( M E N 2) or M T C a n d el e vate d plas ma le vels of 
calcit o ni n ( bi o mar ker f or M T C) ha ve bee n i m ple me nte d i n t he trial.  
•  Ac ute pa n creatitis  
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, 
s u bjects wit h a hist or y of c hr o nic pa n creatitis or rece nt ac ut e pa ncreatitis will n ot be e nr olle d i n t he 
trial. I n a d diti o n, trial pr o d uct s h o ul d be disco nti n ue d i n case of s us pici o n of ac ute pa ncreatitis i n 
acc or da nce t o secti o n 8. 1 . 
 
•  Pa ncreatic ca n cer  
S u bjects wit h T 2 D ha ve a n i ncrease d ris k of certai n t y pes of ca ncer s uc h as pa ncreatic ca ncer. I n t h e 
de vel o p me nt pr o gra m me f or t he T 2 D i n dicati o n, rates of pa ncreatic ca ncer d o n ot s u p p ort a ca usal 
ass ociati o n wit h se ma gl uti de, a n d n o safet y c o ncer ns relate d t o t he pa ncreas were i de ntifie d i n t he 
n o ncli nical pr o gra m me wit h se ma gl uti de. H o we ver, pa ncreatic ca ncer has bee n classifie d as a 
p ote ntial class ris k f or all mar ket e d G L P -1 rece pt or a g o nists.  
•  Aller gi c reacti o ns  
As is t he case wit h all pr otei n -base d p har mace uticals, s u bjects treate d wit h se ma gl uti de are at ris k 
of de vel o pi n g i m m u n o ge nic a n d aller gic reacti o ns.  
 
•  Pre g n a nc y a n d fertilit y ( base d o n n o n -cli nical data)  
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 are 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, se ma gl uti de s h o ul d n ot be use d d uri n g pre g na nc y. 
E xcl usi o n a n d disc o nti n uati o n criteria relate d t o pre g na nc y ha ve bee n i m ple m e nte d i n t he trial.  
3. 3. 2    
Be nefits  
I n cli nical trials se ma gl uti de has pr o vi de d cli nicall y rele va nt re d ucti o ns i n b o d y wei g ht as c o m pare d 
t o place b o. T he C V safet y of se ma gl uti de has bee n esta blis he d i n s u bjects wit h T 2 D i n a C V 
o utc o mes trial ( S U S T AI N -6) 4 a n d t he trial s u g geste d a cli nicall y rel e va nt C V ris k re d ucti o n wit h 
se ma gl uti de c o m pare d t o place b o.  
D uri n g t his trial it is e x pecte d t hat all s u bjects, 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 ug h fre q ue nt c o ntact wit h t he trial site, w here C V diseases a n d ris k fact ors 
are m o nit ore d a n d treat e d f oll o wi n g caref ul me dical e xa mi nati o ns. T o e ns ure all s u bjects, i ncl u di n g 
t h ose recei vi n g place b o h a ve a n a de q uat e C V ris k fact or ma na ge me nt, i n vesti gat ors are e nc o ura ge d 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
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V V- T M F- 5 0 5 7 8 4 9
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1
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 of
  Pr ot oc ol  Pr ot oc ol V 7
1 5
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
1 6  of 1 0 0  
 
t o o pti mise treat me nt wit h me dicati o ns affecti n g C V ris k fact ors t hr o u g h o ut t he trial i n acc or da nce 
wit h treat me nt g ui d eli nes or l ocal cli nical practice. I n a d diti o n, all s u bjects will be offere d healt h y 
lifest yle c o u nselli n g. All s u bjects i n t his trial will recei ve tri al 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 -be nefit c o ncl usi o n  
Data fr o m t he de vel o p me nt pr o gra m me f or s e ma gl uti de f or t he T 2 D i n dicati o n has n ot re veale d a n y 
safet y iss ues t hat w o ul d o ut wei g h t he be nefits. T h e rece ntl y c o m plete d p hase 2 pr o gra m me wit h 
se ma gl uti de s.c. i n o besit y di d n ot re v eal a n y ne w safet y iss ues eit her 1 1. T he trial p o p ulati o n will 
c o nsist of s u bjects wit h esta blis he d C V disease a n d o ver wei g ht or o besit y. Assess me nt a n d 
treat me nt of t he s u bjects’ C V ris k fact ors, i ncl u di n g o ver wei g ht or o besit y, a n d wit h a p pr o priat e 
atte nti o n t o t he sta n dar d of care treat me nt will be pr o vi de d t hr o u g h o ut t he trial. It is t heref ore 
c o ncl u de d t hat t he p ote ntial be nefits fr o m t he trial will o ut wei g h t he p ote nti al ris ks f or t he 
se ma gl uti de as well as t h e place b o treate d s u bjects. 
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 e x pecte d A Es of 
se ma gl uti de s.c. ma y be f o u n d i n t he c urre nt e diti o n of t he I n vesti gat or’s Br oc h ure (I B) 1 2 a n d a n y 
u p dates here of . 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
1 6
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
1 7  of 1 0 0  
 
4  
O bjecti ves a n d e n d p oi nts  
All ti me t o e ve nt e n d p oi nts will be assesse d wit hi n t he i nter val fr o m ti me of ra n d o misati o n ( visit 2) 
t o t he f oll o w-u p visit ( u p t o 5 9 m o nt hs or l o n ger) a n d re p orte d i n m o nt hs.  
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 se m a gl uti de s.c. 2. 4 m g o nce -wee kl y l o wers t he i nci de nce of maj or a d verse 
car di o vas c ular e v e nts ( M A C E) vers us se ma gl uti de place b o b ot h a d de d t o sta n dar d of care i n 
s u bjects wit h esta blis he d C V disease a n d o ver wei g ht or o besit y.  
T he sec o n d a r y o bjecti ves  
T o c o m pare t h e effect of se ma gl uti de s.c. 2. 4 m g o nce -wee kl y vers us se ma gl uti de place b o b ot h 
a d de d t o sta n dar d of care i n s u bjects wit h esta blis he d C V disease a n d o ver wei g ht or o besit y wit h 
re gar ds t o: 
•  M ortalit y  
•  C V ris k fact ors  
•  Gl uc ose meta b olis m  
•  B o d y wei g ht  
•  Re nal f u ncti o n  
T he e x pl or at or y o bjecti ves  
T o c o m pare t h e effect of se ma gl uti de s.c. 2. 4 m g o nce -wee kl y vers us se ma gl uti de place b o as a n 
a dj u nct t o sta n dar d of care i n s u bjects wit h esta blis he d C V disease a n d o ver wei g ht or o besit y wit h 
re gar ds t o: 
•  S m o ki n g stat us  
•  H os pitalisati o ns  
T he pri m ar y esti m a n d  
T he pri mar y 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 uati n g t he effect of t h e 
ra n d o mise d treat me nt i nt er ve nti o n irres p ecti ve of a d here nce 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.  
4. 2    
Pri m ar y e n d p oi nt a n d sec o n d ar y e n d p oi nt(s)  
4. 2. 1    
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 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, or n o n-fatal str o ke 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
1 7
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
1 8  of 1 0 0  
 
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  
Ti me fr o m ra n d o misati o n t o:  
•  C V deat h  
•  First occ urre n ce of a  c o m p osite heart fail ure e n d p oi nt c o nsisti n g of: heart fail ure 
h os pitalisati o n, ur ge nt heart fail ure visit or C V deat h  
•  All -ca use d eat h   
4. 2. 2. 2    
S u p p orti ve sec 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 n e x pa n de d c o m p osite C V 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 or u nsta ble a n gi na re q uiri n g 
h os pitalisati o n  
•  A c o m p osite e n d p oi nt c o nsisti n g of: all -ca us e deat h, n o n -fatal m y ocar dial i nfarcti o n, or n o n-
fatal str o ke 
•  N o n -fatal m y ocardial i nfarcti o n  
•  N o n -fatal str o ke 
•  C or o nar y re v asc ularisati o n  
•  U nsta ble a n gi na re q uiri n g h os pitalisati o n  
•  Heart fail ure h os pitalisati o n or ur ge nt heart fail ure visit  
•  H b A 1c ≥ 4 8 m m ol/ m ol ( 6. 5 %)  
•  A 5 -c o m p o ne nt c o m p osit e ne p hr o pat h y e n d p oi nt c o nsisti n g of: o nset of persiste nt 
macr oal b u mi n uria ( U A C R > 3 0 0 m g/ g), persiste nt 5 0 % re d ucti o n i n e G F R c o m pare d wit h 
baseli ne (ra n d o misati o n), o nset of persiste nt e G F R < 1 5 ml/ 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 tra ns pla ntati o n) or re nal d eat h * 
F or s u bjects wit h a s cree ni n g H b A 1c < 3 9 m m ol/ m ol ( 5. 7 %):  
•  Ti me fr o m ra n d o misati o n t o H b A 1c ≥ 3 9 m m ol/ m ol ( 5. 7 %)  
F or s u bjects wit h a s cree ni n g H b A 1c ≥ 3 9 m m ol/ m ol ( 5. 7 %):  
•  Pr o p orti o n of s u bjects wit h H b A 1c < 3 9 m m ol/ m ol ( 5. 7 %) at eac h visit w here H b A 1c is 
assesse d  
                                                 
*T his c o m p o ne nt c o nsists of e ve nts fr o m ce ntral la b orat or y a n d o utc o me fr o m e ve nt a dj u dicati o n. U A C R: uri nar y 
al b u mi n -t o-creati ni ne rati o. A persiste nt c ha n ge i n esti mate d gl o mer ular filt rati o n rate (e G F R) is defi ne d as ha vi n g 2 
c o nsec uti ve sa m ples meeti n g t he criteria. T he 2 sa m ples m ust be at least 4 wee ks a part. A p ersiste nt c ha n ge i n 
macr oal b u mi n uria is defi ne d as ha vi n g 2 o ut of 3 c o nsec uti ve p ost -baseli ne sa m ples a b o ve t he li mit f or 
macr oal b u mi n uria. T he 2 sa m ples a b o ve t he li mit m ust be at least 4 wee ks a part.  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
1 8
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
1 9  of 1 0 0  
 
C ha n ge fr o m ra n d o misati o n  t o year 2 ( visit 1 4) i n: 
•  S yst olic bl o o d press ure ( m m H g)  
•  Diast olic bl o o d press ure ( m m H g)  
•  P ulse ( b p m)  
•  Hi g h se nsiti vit y C -Reacti ve Pr otei n ( hs C R P) ( m g/ L)  
•  Li pi ds ( m g/ d L)  
•  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  
•  B o d y wei g ht ( %)  
•  Waist circ u mfere n ce (c m)  
•  Patie nt re p orte d o utc o mes:  
•  E ur o Q ol  fi ve di me nsi o ns fi ve le vel ( E Q-5 D -5 L) q uesti o n naire ( E Q -5 D i n de x sc ore 
(ra n ge 0 t o 1) a n d E Q-5 D -V A S (ra n ge 0 t o 1 0 0). A hi g her sc ore i n dicates better self -
re p orte d h ealt h stat us.) 
•  H b A 1c ( %, m m ol / m ol) c ha n ge fr o m scree ni n g ( visit 1) t o year 2 ( visit 1 4) 
4. 2. 2. 3    
E x pl or at or y e n d p oi nts  
•  Bei n g c urre nt s m o ker at year 2 ( visit 1 4) ( yes/ n o)  
•  T otal n u m ber of h os pitalise d da ys fr o m ra n d o misati o n a n d t o e n d of trial  
•  T otal n u m ber of h os pitalisati o ns fr o m ra n d o misati o n a n d t o e n d of trial  
C ha n ge fr o m ra n d o misati o n t o wee k 1 1 7 i n: 
•  Gl ycae mic stat us ( n or m o gl ycae mia, pre -dia bet es or t y pe 2 dia betes)  
 
C ha n ge fr o m ra n d o misati o n t o year 2 ( visit  1 4) i n:  
•  Patie nt re p orte d o utc o mes:  
o  T otal sc ore wei g ht relate d si g n a n d s y m pt o m meas ure ( W R S S M)  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
1 9
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
2 0  of 1 0 0  
 
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 se ma gl uti de 
2. 4 m g wit h se ma gl uti de place b o b ot h a d mi nistere d s.c. o nce -wee kl y i n s u bjects wit h esta blis he d 
C V disease a n d o v er wei g ht or o besit y. S u bjects will be ra n d o m ise d i n a 1: 1 rati o t o recei ve eit her 
se ma gl uti de 2. 4 m g or se ma gl uti de place b o as a n a dj u nct t o sta n dar d-of -care.  
T he trial is e ve nt dri ve n wit h trial cl os ure bei n g perf 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 has bee n reac h e d. A n i n de pe n de nt Data M o nit ori n g C o m mittee ( D M C) will 
o versee effi cac y a n d s u bject safet y a n d ma y rec o m me n d st o p pi n g t he trial earl y (see s ecti o n 8. 4 , 
1 0. 3. 5 , A p pe n di x 3 , A p pe n di x 4 ). T he trial will e m pl o y a gr o u p s e q ue ntial desi g n a n d i nteri m 
testi n g f or efficac y will b e perf or me d b y t he D M C.  
Wit h t he ass u me d e ve nt rate (see secti o n 1 0. 1 ) a n d a recr uit me nt peri o d of 2 8 m o nt hs, t he esti mate d 
trial d urati o n will be 5 9 m o nt hs fr o m start of ra n d o misati o n t o e n d of f oll o w-u p of t he last s u bject, 
i ncl u di n g 2 8 m o nt hs of recr uit me nt a n d 5  wee ks of f oll o w -u p. Esti mate d tri al d urati o n f or a n 
i n di vid ual s u bject is fr o m 3 1 t o 5 9 m o nt hs.  
 
Fi g ure  5 -1  
Tri al desi g n  
 
 
 
5. 2    
S u bject a n d tri al c o m pl eti o n  
I n t his trial a p pr o xi matel y 1 7, 5 0 0 s u bjects will 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 2 8 m o nt hs. 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
2 0
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
2 1  of 1 0 0  
 
Tri al peri o d c o m pleti o n f or a s u bject:  
Trial peri o d c o m pleti o n is defi ne d as:  
•  w he n t he ra n d o mise d s u bject has c o m plete d t he fi nal sc he d ule d visit ('e n d of trial' ( P -F U) 
acc or di n g t o t he fl o wc hart).  
-or -  
•  w he n t he ra n d o mise d s u bject has die d d uri n g trial.  
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 e n d of trial visit ( P -F U) will 
be sc he d ule d acc or di n g t o pr ojecte d trial cl os ure. If t he e ve nt rate is l o wer t ha n a ntici pate d, t he n 
visits a n d relate d a ssess me nts will be re peat e d e ver y 1 3 wee ks be y o n d V 2 4 u ntil t he necessar y 
n u m ber of pri mar y o ut c o me e ve nts ha ve bee n accr ue d. W he n t he trial is a p pr oac hi n g t he e n d 
i n vesti gat ors will be n otifie d a n d i nstr ucte d b y N o v o N or dis k re gar di n g t h e visit sc he d ules f or t heir 
s u bjects. 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 as certai n 
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 s u bjects. T his 
s h o ul d be d o ne b y direct c o ntact t o t he s u bject w hene ver p ossi ble. If a s u bj ect 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 bel 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 din g electr o nic healt h rec or ds, t he s u bj ects’ pri mar y p h ysicia n or ot her 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 blic a vaila ble 
data s o urces s h o ul d als o be searc he d. A searc h a ge nc y ma y be us e d t o f acilitate i de ntif yi n g u p dat e d 
c o ntact details f or a missi n g s u bject or pr o vi de vital stat us ( date of deat h 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 n d ma y be m o difie d 
acc or di n g t o practical as pect s. 
I n case s e veral atte m pts are re q uire d t o esta blis h direct c o ntact t o a s u bject, e xcee di n g t h e visit 
wi n d o w of t he f oll o w -u p visit ma y b e nee de d. I n or der f or t he data 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.  
As a mi ni m u m t he f oll o wi n g c o nt act atte m pts s h o ul d be ma de a n d als o d oc u me nte d i n t he s o urce 
d oc u me nts:  
•  T o s u bjects: 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 ne writte n c o ntact  
•  Searc h/c o ntact p u blicl y a vaila ble data s o urces, if a vaila ble a n d u nless pr o hi bite d b y l ocal 
re g ulati o n 
If c o ntact t o a s u bject is l ost d uri n g t he trial b ut c o ntact is re -est a blis he d at t he e n d of trial eff orts 
m ust be ma de t o u n derta ke t he sa me pr oce d ures as t h ose f or t he e n d of trial visit wit h s pecial f oc us 
o n A E stat us.  
 
P u blicall y a vaila ble data s o urces s h o ul d  als o be searc he d f or wit h dra w n s u bjects t o esta blis h vital 
stat us ( u nless pr o hi bite 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 of t he last s u bject i n t he trial.  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
2 1
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
2 2  of 1 0 0  
 
5. 4    
Scie ntific r ati o n ale f or t ri 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 d a n d place b o -c o ntr olle d. Bli n de d treat me nt 
wit h se ma gl uti de 2. 4 m g or se ma gl uti de place b o offers a r o b ust met h o d f or assess me nt of 
se ma gl uti de’s effects. A br oa d s pectr u m of treat m e nts f or co -m or bi dities a n d C V ris k fact ors s h o ul d 
be i ntr o d uce d or a dj uste d t hr o u g h o ut t he trial b ase d o n sta n dar d of care 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 m atic a p pr oac h t o c o m pare t w o treat me nts: o ne w here 
se ma gl uti de is a v aila ble a n d a n ot her w here it is n ot.  
T o s u p p ort t he s u bject d uri n g t he d ose 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, t he s u bject is i n c o ntact wit h t he i n vesti gat or e ver y 1 3t h wee k t hr o u g h o ut t he tri al. 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 s u bjects a n d t o reflect 
t he a ntici pate d s u bject p o p ulati o n. T he l o n g half-life of se ma gl uti de s u p p orts o nce-wee kl y  
a d mi nistrati o n a n d t he 5 -wee k f oll o w -u p 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 p o p ulati o n will c o nsist of s u bjects wit h esta blis he d C V disease a n d o ver wei g ht or o besit y.  
T his p o p ulati o n re prese nts a cli nicall y rele va nt p o p ulat i o n as t he y are li kel y t o be nefit b ot h fr o m t he 
re d ucti o n of t heir ris k of a C V e ve nt as well as wei g ht re d ucti o n. S u bjects wit h dia betes are 
e x cl u de d fr o m t his trial t o eli mi nate a n y c o nf o u n di n g t hat a dia betes dia g n osis c o ul d ha ve o n C V 
ris k. 
5. 5    
J ustific ati o n f or d ose  
I n t he trial, a tar get d ose of se ma gl uti de s.c. 2. 4 m g o nce-wee kl y will be i n vesti gate d. T he d ose 
selecti o n is base d o n a n i nte grate d e v al uati o n of e xisti n g efficac y a n d safet y dat a as well as 
e x p os ure c o nsi derati o ns ( C a v g a n d C ma x ) fr o m t he p hase 2 d ose-fi n di n g trial i n wei g ht ma na ge me nt 
( N N 9 5 3 6-4 1 5 3), i n a d diti o n t o t he de vel o p me nt pr o gra m me of se ma gl uti de s.c. i n T 2 D.  
T he p hase 2 trial ( N N 9 5 3 6 -4 1 5 3) i n vesti gate d se m a gl uti de s.c. d os es of 0. 0 5 -0. 4 m g o nce -dail y, 
a n d s h o we d t hat se ma gl uti de s.c. 0. 4 m g o nce -dail y was m ost effecti ve i n ter ms of wei g ht l oss 
w hile dis pla yi n g a n acce pta ble t olera bilit y pr ofile. H o we ver, si nce a o nce -wee kl y a d mi nistrati o n is 
preferre d t o ease t he b ur de n of dr u g a d mi nistrati o n i n cli nical practice a n d si n ce data fr o m t he 
se ma gl uti de s.c. T 2 D de v el o p me nt pr o gra m me ( S U S T AI N trials wit h o nce -wee kl y d osi n g a n d trial 
N N 9 5 3 5 -4 1 9 1 wit h o nce -dail y s. c. d osi n g of u p t o 0. 3 m g/ da y) di d n ot s u p p ort t he h y p ot hesis t hat 
dail y d osi n g pr o vi des better gastr oi ntesti nal t ol era bilit y as c o m pare d t o wee kl y d osi n g, o nce -wee kl y 
d osi n g is i n vesti gat e d i n t he p hase 3a c o nfir mat or y pr o gra m me a n d i n S E L E C T.   
P o p ulati o n p har mac o ki netic m o delli n g was use d t o select t he wee kl y tar get d ose, base d o n dat a 
fr o m t he p hase 2 tri al ( N N 9 5 3 6-4 1 5 3). Usi n g t his, it was esti mate d t hat a o nce -wee kl y mai nte na nce 
d ose of 2. 4 m g s e ma gl uti de s.c. will n ot e xcee d t he C ma x  at stea d y-state t hat was o btai ne d wit h t he 
o nce -dail y 0. 4 m g se ma gl uti de s.c. d ose i n vesti gat e d i n trial N N 9 5 3 6 -4 1 5 3. A wee kl y d ose of 2. 8 
m g se ma gl uti de (i. e., 7 d ail y d oses of 0. 4 m g s e ma gl uti de) was f o u n d t o e xcee d t his C
ma x . F urt her, 
w he n c o m pari n g t he si m ulate d h u ma n e x p os ure at 2. 4 m g/ wee k t o t he a ni mal e x p os ures at t he n o -
o bser ve d -a d verse-effect -l e vel ( N O A E L), e x p os ure rati os are a b o ve 1, i n dicati n g t hat e x p os ure at 
2. 4 m g is s u p p orte d b y t h e n o ncli nical st u dies. C o nse q ue ntl y, t he pr o p ose d se ma gl uti de s.c. tar get 
d ose f or t he p hase 3 wei g ht ma na ge me nt de vel o p me nt pr o gra m me is 2. 4 m g o nce -wee kl y. S E L E C T 
will i ncl u de s u bjects wit h a B MI ≥ 2 7 k g/ m 2 wit h esta blis he d C V disease (i.e. a s u b gr o u p of t h ose 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
2 2
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
2 3  of 1 0 0  
 
eli gi ble t o be i ncl u de d i n t he wei g ht ma na ge m e nt de vel o p me nt pr o gra m me), c o nse q ue ntiall y, t he 
sa me d ose of se m a gl uti de s.c. 2. 4 m g o nce-wee kl y will als o be use d i n S E L E C T.  
F urt her, it is well k n o w n t hat t o miti gate gastr oi ntesti nal si de effects wit h G L P-1 R A treat me nt, 
d ose escal ati o n t o t he tar get d ose is re q uire d. Bas e d o n e x perie nce fr o m t he se ma gl uti de s.c. T 2 D 
de vel o p me nt pr o gra m me, a n d si milar t o t he p hase 3a pr o gra m me, s u bjects w ill be i nitiate d o n a l o w 
d ose a n d f oll o w a fi xe d -d ose escal ati o n re gi me n, wit h d ose escalati o n e ver y 4 wee ks u ntil t he tar get 
d ose of 2. 4 m g is r eac he d after 1 6 wee ks.  
T he d osi n g re gi me n, r o ut e a n d a d mi nistrati o n f or m are des cri be d i n secti o n 7  of t he pr ot oc ol. Pleas e 
refer t o secti o n 7. 1  f or more details o n treat me nt d oses.  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
2 3
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
2 4  of 1 0 0  
 
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 i ncl usi o n, e xcl usi o n a n d ra n d o misati o n criteria, als o 
k n o w n as pr ot oc ol wai v ers or e x e m pti o ns, is n ot per mitte d.  
6. 1    
I ncl usi o n criteri a 
All i ncl usi o n criteria are  base d o n t he s u bjects’ m e dica l rec or ds, e xce pt f or # 1 a n d # 3 (scree ni n g 
assess me nt). S u bjects 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 criteria 
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 ated 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 ≥ 4 5 years at t he ti me of si g ni n g i nf or m e d c o nse nt  
3.  B o d y mass i n de x ( B MI) ≥ 2 7 k g/ m 2  
4.  Ha ve esta blis he d C V dis ease as e vi de nce d b y at l east o ne of t he f oll o wi n g:  
a. pri or m y o car dial i nfarcti o n  
b.  pri or str o ke (isc h e mic or  he m orr ha gic str o ke)   
c. sy m pt o matic peri p heral arterial diseas e ( P A D), as e vi de nce d b y i nter mitte nt 
cla u dicati o n wit h a n kle -brac h ial i n de x ( A BI) < 0. 8 5 (at rest), or peri p heral arterial 
re vasc ul arizati o n pr oce d ure, or a m p utati o n d ue t o at her oscler otic disease 
6. 2    
E xcl usi o n criteri a  
All e xcl usi o n criteria are base d o n t he s u bjects’ m e dical rec or ds, e xce pt f or # 4 ( H b A
1c, ce ntral 
la b orat or y) a n d t he uri ne pre g na nc y t est ( # 1 7). S u bjects are e xcl 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: 
C ar di o v asc ul ar -rel ate d : 
1.  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 pitali sati 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 da y of scree ni n g  
2.  Pla n ne d c or o nar y, car oti d or peri p heral art er y re vasc ularisati o n k n o w n o n t he da y of scree ni n g  
3.  Prese ntl y classifie d as b ei n g i n Ne w Y or k Heart Ass ociati o n ( N Y H A) Class I V  heart fail ure  
Gl yc ae mi a -rel ate d:  
4.  H b A 1c ≥ 4 8 m m ol/ m ol ( 6. 5 %) as meas ure d b y t he ce ntral la b orat or y at scree ni n g  
5.  Hist or y of t y p e 1 or t y pe 2 dia betes ( hist or y of gestati o nal dia betes is all o we d)  
6.  Treat me nt wit h gl uc ose -l o weri n g a ge nt(s) wit hi n 9 0 da ys b ef ore scree ni n g 
7.  Treat me nt wit h a n y G L P -1 R A wit hi n 9 0 da ys b ef ore scree ni n g  
Ge ner al s af et y a: 
8.  Hist or y or prese n ce of c hr o nic pa ncreatitis   
9.  Prese nce of ac ut e pa ncreatitis wit hi n t he past 1 8 0 da ys pri or t o t he da y of scree ni n g  
1 0.  Pers o nal or first de gree relati ve(s) hist or y of m ulti p le e n d ocri ne ne o plasia t y pe 2 or me d ullar y 
t h yr oi d carci n o ma 
1 1.  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  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
2 4
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
2 5  of 1 0 0  
 
1 2.  Prese nce or hist or y of mali g na nt ne o plas ms wit hi n t he past 5 years pri or t o t he da 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 are all o we d 
1 3.  Se vere ps yc hi atric dis or d er w hic h i n t he i n vesti gat or’s o pi ni o n c o ul d c o m pr o mise c o m plia nce 
wit h t he pr ot oc ol  
1 4.  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(s) or relate d pr o d ucts  
1 5.  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  
1 6.  Recei pt of a n y i n vesti gati o nal me dici nal pr o d uct wit hi n 3 0 da ys bef ore s cree ni n g  
1 7.  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 na nt or is of c hil d-beari n g 
p ot e 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  
1 8.  A n y dis or d er, u n willi n g n ess or i na bilit y, 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 
t he s u bject’s safet y or c o m plia nce wit h t he pr ot oc ol 
 
aF or c o u ntr y s pecific re q uire me nts, please r efer t o A p pe n di x 9 .  
6. 3    
Scree n f ail ures  
Scree n fail ures are defi ne d as s u bjects w h o c o nse nt t o partici pate i n t he cli nical trial b ut are n ot 
eli gi ble f or partici pati o n acc or di n g t o i n/e xcl usi o n criteria a n d ra n d o mis ati 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 pare nt re p orti n g of scree n fail ure s u bj ects t o 
meet re q uire me nts fr o m re g ul at 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, s cree n 
fail ure det ails, a n d eli gi bilit y criteria. A scree n fail ure sessi o n m ust be ma 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 be ca pt ure d i n t he case electr o nic re p ort f or m 
(eC R F). D u e t o t he l o n g recr uit me nt peri o d re -s cree ni n g is all o we d f or all i ncl usi o n a n d e xcl usi o n 
criteria. A ne w s u bject n u m ber m ust be assi g ne d i n t he I W R S.  
6. 4    
R a n d o mis ati o n criteri a  
T o be ra n d o mise d, t he ra n d o misati o n criterio n  m ust be a ns were d " yes". T he I W R S ra n d o misati o n 
sessi o n s h o ul d o nl y o cc ur after e val uati o n of t h e ra n d o misati o n criteria.  
1.  N o ne of t he f oll o wi n g: m y o car 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 has occ urre d a n d n o re vasc ul arisati o n has bee n pla n ne d bet wee n 
scree ni n g a n d ra n d o misati o n 
6. 4. 1    
Assess me nt of eli gi b ilit 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 nce t o e ns ure eli gi bilit y. If a 
s u bject 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 
s u bjects’ me dical rec or ds fr o m rele va 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 me 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 s u bject is eli gi ble. T he 
val ues us e d t o assess eli gi bilit y m ust reflect t he s u bjects’ c urre nt healt h stat us.  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
2 5
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
2 8  of 1 0 0  
 
T a ble  7 -3    
A u xili ar y s u p plies pr o vi de d b y N o v o N or dis k A/ S  
A u xili ar y s u p pl y    
Det ails  
Nee dles  
Nee dles f or pre -fille d pe n s yst e m. Details pr o vi de d i n t he T M M. 
O nl y nee dles pr o vi de d a n d a p pr o ve d b y N o v o N or dis k m ust be use d f or a d mi nistrati o n 
of trial pr o d uct.  
Directi o n f or use ( D F U)    
D F U f or 3 m L P D S 2 9 0 pre -fille d pe n-i nj ect or. 
N ot i ncl u de d i n t he dis pe nsi n g u nit a n d t o be ha n de d o ut se p aratel y . 
7. 1. 1    
Me dic al de vice s 
I nf or mati o n a b o ut t he P D S 2 9 0 pre-fille d pe n-i nject or ma y be f o u n d i n t he I B 1 2 a n d a n y u p dates 
here of.  
I nf or mati o n a b o ut t he use of t he P D S 2 9 0 pre-fille d pe n-i nject or f or se ma gl uti de B 3. 0 m g/ m L a n d 
se ma gl uti de place b o ca n be f o u n d i n t he D F U.  
Tr ai ni n g i n t he P D S 2 9 0 pre -fille d pe n-i nject or 
T he i n vesti gat or m ust d oc u me nt t hat D F U  are gi v e n t o t he s u bjects orall y a n d i n writi n g at t he first 
dis pe nsi n g visit (as s pecifie d i n t he fl o wc hart). Trai ni n g m ust  be re peat e d  as s pecifie d i n t he 
fl o wc hart a n d, if nee d e d, d uri n g t he tri al at re g ular i nter vals i n or der t o e ns ure c orrect us e of t he 
me dical de vice. Trai ni n g is t he res p o nsi bilit y of t he i n vesti gat or or dele gate.  
7. 2    
D ose m o dific ati o n  
Please refer t o secti o n 7. 1  f or descri pti o n of misse d d oses. 
7. 3    
Met h o d of tre at me nt assi g n me nt  
All s u bjects will be ce ntrall y ra n d o mise d usi n g a n I W R S a n d assi g ne 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 od 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 s u bject will be assi g ne d a u ni q ue 6 -di git n u m be r w hic h will re mai n t he sa me 
t hr o u g h o ut t he trial. F or re -scree ne d s u bj ects pleas e see secti o n 6. 3 . 
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 dr u g are vis uall y i de 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 be 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 treat me nt w o ul d i nfl ue nce t h e treat me nt of t he s u bject. 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 de 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 he reas o n a n d si g n a n d date t he 
d oc u me nt.  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
2 8
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
2 9  of 1 0 0  
 
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 . Treat me nt wit h trial 
pr o d uct ca n b e res u me d if t here are n o s afet y c o ncer ns a t t he discreti o n of t he i n vesti gat or. 
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 s u bjects 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.  
T a ble  7 -4    
Tri al pr o d uct st or a ge c o n diti o ns  
Tri al pr o d uct n a me  
St or a ge c o n diti o ns  
( n ot-i n-use)  
I n-use c o n diti o ns    
I n-use ti me a 
Se ma gl uti de B 3. 0 m g/ ml P D S 2 9 0  
 
St ore i n refri gerat or  
( 2oC -8 oC/ 3 6 oF -4 6 oF)  
 
D o n ot freeze  
 
Pr otect fr o m li g ht  
 
I n-use c o n diti o ns will 
be a vaila ble o n t he 
trial pr o d uct la bel 
 
I n-use c o n diti o ns 
will be a vaila ble o n 
t he trial pr o d uct 
la bel 
Se ma gl uti de place b o P D S 2 9 0  
a I n-use ti me starts w he n t he pr o d uct is ta ke n o ut of t he refri gerat or i n t he s u bj ect’s h o me.  
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 basis 
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 will be tri g gere d b y first s u bject 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 orte d a n d res ol ve d bef ore us e of 
t he trial pr o d ucts. 
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 la belle 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 di atel 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 ure 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 bee n st ore d i m pr o perl y m ust n ot be dis pe nse d t o a n y s u bject 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. S u bjects m ust ret ur n all use d, partl y 
use d a n d u n use d trial pr o d uct 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. rec ei pt, 
acc o u nta bilit y a n d fi nal dis p ositi o n rec or ds). Dr u g acc o u nta bilit y s h o ul d be perf or me d at pe n le vel 
f or se ma gl uti de/ place b o. 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
2 9
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
3 0  of 1 0 0  
 
Destr ucti o n of trial pr o d ucts ca n be p erf or me d o n a n o n g oi n g basis a n d will be d o ne acc or di n g t o 
l ocal pr oce d ures after acc o unta bilit y is fi nalise d b y t he site a n d rec o ncile d b y t he m o nit or. 
Destr ucti o n of trial pr o d ucts 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 ucts (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 ucts i ncl u di n g e x pire d or da ma ge d pr o d ucts 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 pr o d uct t o s u bject’s h o me  
F or selecte 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 se n d trial 
pr o d uct a n d a u xiliaries fr o m t he trial site or  p har mac y t o t he s u bject’s h o me b y c o urier ser vice.  
T he pr ocess f or se n di n g trial pr o d uct fr o m t he tri al site or p har mac y t o a s u bject’s h o me m ust be  
descri be d i n an i nstr ucti o n  d oc u me nt . T he i nstr ucti o n d oc u me nt m ust c o ntai n detaile d i nstr ucti o ns 
f or pre p ari n g pac 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 trial site or p har mac y staff t o t he c o urier, re q uire d te m perat ure m o nit ori n g of tri al pr o d uct, 
deli ver y t o a n d recei pt of trial pr o d uct b y t he s u bject. 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 m ust als o be descri be d i n t h e i nstr ucti o n . 
I n v esti gat ors, trial site/ p har mac y staff a n d s u bjects w h o will be i n v ol ve d i n s hi p me nt of trial 
pr o d uc t t o t he s u bject’s h o me will be a de q uat el y trai ne d i n t his pr ocess. 
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 s u bjects 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 ure s u bject c o m plia nce. If a s u bject 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 s u bject 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. T he meas ures t hat will be ta ke n t o e ns ure a n d d oc u m e nt 
treat me nt c o m plia nce als o i ncl u de re p orti n g of c ha n ges i n t he d ose ta ke n (see secti o n 7. 1 ). 
7. 7    
 St a n d ar d of c are  
S u bjects will be treate d wit h se ma gl uti de s.c. 2. 4 m g o nce -wee kl y or place b o o n t o p of sta n dar d of 
care, w hic h c o v ers ma na ge m e nt of C V ris k fact ors i ncl u di n g me dical treat me nt a n d healt h y lifest yl e 
c o u nselli n g. T hr o u g h o ut t his trial i n vesti gat ors are e nc o ura ge d t o o pti mise treat me nt wit h 
me dicati o ns affecti n g C V ris k i n acc or da nce wit h treat me nt g ui deli nes or l ocal cli nical practice. At 
e ver y visit s u bjects s h o ul d be offere d i n di vi d ualise d healt h y lifest yle c o u ns elli n g (i ncl u di n g diet a n d 
p h ysical acti vit y). It will be d oc u me nte d i n t he e C R F w het her t h e s u bject recei ve d t he healt h y 
lifest yle c o u nselli n g. Rec o m me n dati o ns f or ma na ge me nt of C V ris k fact ors a n d t he healt h y lifest yle 
c o u nselli n g 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 or gl o bal e x pert 
pa nel d uri n g trial c o n d uct.  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
3 0
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
3 1  of 1 0 0  
 
7. 8    
C o nc o mit a nt me dic ati o n  
O nl y me dic ati o n, ot her t ha n trial pr o d uct, t hat t he s u bject is recei vi n g at t he ti me of scree ni n g or 
recei v es 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 or pre ve nt C V diseases (f or e xa m ple a nti -h y perte nsi ves, li pi d -l o weri n g a gents, 
a ntic oa g ula nts, as piri n a n d ot her a nti platelet a ge nts)  
•  T o treat o ver wei g ht or o besit y  
•  T o treat dia betes a n d dia betes c o m plicati o ns (f or s u bjects w h o de vel o p dia betes d uri n g t he 
trial) 
•  T o treat a n S A E or m e dicati o n w hic h ma y pr o vi d e f urt her i nf or mati o n  o n t he S A E i.e. 
alter nati ve aeti ol o g y.  
•  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  
•  i n relati o n t o a n a p 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 me dicati o n, start date  a n d st o p 
date or c o nti n uati o n, d os e ( o nl y t o b e c ollect e d f or dia betes me dicati o n) a n d relate d A E n u m b er 
w he n a p plica bl e.  
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 S A E, t he n t his m ust be re p ort e d if re q uire d acc or di n g t o secti o n 9. 2 . 
I nitiati n g ot her 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 trial. Ot her c ha n ges t o 
bac k gr o u n d me dicati o ns ca n ta ke pl ace d uri n g t h e trial. I m p ort a ntl y, i n vesti gat ors s h o ul d e ns ure 
t hat s u bjects 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 C V ris k ma na ge me nt. If 
all o we d acc or di n g t o l ocal re g ulati o n, N o v o N or dis k ma y c o m pe nsate f or ne w c o nc o mita nt 
me dicati o ns prescri be d d uri n g t he tri al f or C V dis ease ma na ge me nt.  
F or s u bjects w h o de vel o p di a betes d uri n g t he tri al or w h o are st arte d o n a n ot her gl uc ose 
l o w eri n g dr u g: 
F or gl uc ose -l o weri n g me dicati o n, t he t otal dail y d ose o n t he da y prece di n g t he visit (if a vaila ble) 
s h o ul d be rec or 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 dicati o n wit h t he rele va nt start a n d st o p date. H y p o gl ycae mic e pis o des ha ve mai nl y 
bee n o bser ve d w he n s e m a gl uti de is c o m bi ne d wit h s ul p h o n yl urea or i ns uli n. It is t heref ore 
rec o m me n de d t h at t he i n vesti gat or e ns ures t hat s u bjects i nitiati n g s ul p h o n yl urea or i ns uli n perf or m 
a de q uatel y fre q u e nt bl o o d gl uc ose m o nit ori n g t o e ns ure s u bject safet y d uri n g i nitiati o n.   
If i nitiati n g gl uc ose-l o weri n g treat me nt aft er t he disc o nti n uati o n of trial pr o d uct, t he l o n g 
se ma gl uti de half-life of a p pr o xi matel y o ne wee k s h o ul d be ke pt i n mi n d.  
7. 9    
Tre at me nt after t he e n d of t he tri al  
After t he e n d of t he trial t he s u bject s h o ul d be treate d at t he discreti o n of t he i n vesti gat or.  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
3 1
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
3 2  of 1 0 0  
 
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 s u bject m ust be disc o nti n ue d fr o m trial pr o d uct, if a n y of t he f oll o wi n g a p plies:  
1.  Pre g n a nc y  
2.  I nte nti o n of bec 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 pa ncreatitis is s us pecte d, trial pr o d uct m ust be disc o nti n ue d; if c o nfir me d, trial pr o d uct s hall 
n ot be restarte d  
5.  Calcit o ni n ≥ 1 0 0 n g/ L (see A p pe n di x 8 ) 
6.  Treat me nt wit h a n ot her G L P -1 R A  
7.  Ot her safet y c o ncer ns, at t he discreti o n of t he i n vesti gat or  
A d 1 a n d 2: If a s u bj ect 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 s u bject 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 preg na nc y, a n d d uri n g breast fee di n g. T he 
s u bject will c o nti n ue t he ot her trial pr oce d ures or will be f oll o we d-u p via p h o ne c o ntacts.  
A d 3: S u bjects m ust n ot recei ve i n v esti gati o nal me dical pr o d uct fr o m a n ot her cli nical trial, w hile 
partici pati n g i n t his tria l. If d o ne, treat me nt wit h trial pr o d uct s h o ul d be disc o nti n ue d. If t he use of 
i n vesti gati o nal me dical pr o d uct i n t he ot her trial is disc o nti n ue d, treat me nt wit h trial pr o d uct ca 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. T he s u bject 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, be h a vi o ural, c o m plia nce or a d mi nistrati ve reas o ns. T he s u bj ect s h o ul d c o nti n ue t he ot her 
trial pr oce d ures. Treat me nt with trial pr o d uct ca n be res u me d lat er if it is e val uate d as bei n g s afe b y 
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 bjecti ve of e val u ati 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 m e 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 ’s discreti o n wit h o ut 
disc o nti n ui n g trial treat m e nt.  
Al geria a n d Ger ma n y: F or c o u ntr y s pecific re q uire me nt, please s ee A p pe n di x 9 . 
S u bjects w h o d o n ot f ull y meet eli gi bilit y (i ncl usi o n/e xcl usi o n/ra n d o misati o n) criteria m ust n ot be 
ra n d o mise d. If a s u bject is ra n d o mise d i n err or t his will be ha n dle d as a n i m p orta nt pr otoc ol 
de viati o n a n d t he I R B/I E C a n d re g ulat or y a ut h orities m ust be n otifie d acc or di n g t o l ocal 
re q uire me nts. If t here are n o safet y c o ncer ns, treat me nt wit h trial pr o d uct ca n be c o nti n ue d or 
res u me d at t he discreti o n of t he i n vesti gat or after a disc ussi o n wit h a N o v o N or dis k me dical e x pert. 
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.  
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 bilit y m ust be p erf or me d.  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
3 2
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
3 3  of 1 0 0  
 
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 treat 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 vesti 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 s u bjects 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 ura ge d t o res u me t he treat me nt (secti o n 7. 1 ). At b ot h i nstances 
d ose escal ati o n ma y b e n ecessar y (secti o n 7. 1 ). Date a n d trial pr o d uct d ose s h o ul d be rec or de d i n 
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 s u bject 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 s u bject ma y wit h dra w c o nse nt at a n y ti me at his/ her o w n re q uest.  
If c o nsi deri n g wit h dra wi n g fr o m t he trial, t he s u bj ect 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 uct, 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 s u bject 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 nce last c o ntact t o t he s u bject. T his is i m p orta nt t o 
e ns ure t hat t he i nf or mati o n gai n e d is c o m plete a n d acc urate, a n d t h at t he c orrect c o ncl usi o ns are 
dra w n. O nl y if t he s u bject decli nes all alter nati ves, s h o ul d t he s u bject be rec or de d as wit h dra 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 s u bject is n ot a ble t o c o me t o t he trial site.  
If a s u bject 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 sa 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 s u bject 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 dra wal of c o nse nt.  
Alt h o u g h a s u bject 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 s u bject'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 CR F.  
8. 2. 1    
Re pl ace me nt of s u bjects  
S u bjects 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 s u bject will be c o nsi dere d p ote ntiall y 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 trial site.  
•  Bef ore a s u bj ect is dee m e 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 o ntact wit h t he s u bject as descri be d i n secti o n 5. 2 . 
•  A s u bject ca n n ot be decl are d l ost t o f oll o w -u p bef ore all t he atte m pts ha ve bee n re peate d 
a n d t he trial has c o m e t o a n e n d  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
3 3
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
3 4  of 1 0 0  
 
T he atte m pts m ust be d oc u me nte d at site.  
8. 4    
Ter mi n ati o n or m o dific ati o n of t he tri al  
T he D M C will m o nit or acc u m ulati n g efficac y a n d safet y data at eac h D M C meeti n g a n d ma ke 
rec o m me n dati o ns t o t he i nter nal N o v o N or dis k se ma gl uti de s.c. s afet y c o m mittee w het her t o 
c o nti n ue, m o dif y or ter mi nate t he trial. Rec o m me n dati o ns t o m o dif y or st o p t he  trial s h o ul d be 
gi ve n if t here is clear e vi de nce of cli nical har m t o t he patie nts w hic h c ha n ges t he be nefit -ris k 
e val uati o n t o a sit uati o n w here t he be nefit n o l o n ger o ut wei g hs t he ris ks (see secti o n 5. 1 , 1 0. 3. 5 , 
A p pe n di x 3 , A p pe n di x 4 ). 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
3 4
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
3 5  of 1 0 0  
 
9  
Tri al 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, see 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 s u bjects 
meet all eli gi bilit y criteria.  
•  T he i n vesti gat or will mai ntai n a scree ni n g l o g t o rec or d det ails of all s u bjects 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, s u bjects 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 s u bjects’ pri m ar y p h ysicia n, if a p plica ble, a b o ut t he 
s u bjects’ partici pati o n i n t he trial a n d if t he s u bject a grees t o t he pri mar y p h ysicia n bei n g 
i nf or me d. 
•  Eac h s u bject s h o ul d b e as ke d t o pr o vi de c o ntact i nf or mati o n f or pers o ns ( 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 s u bject d uri n g t h e 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.  
•  If necessar y, i n or der t o retai n t he s u bject i n t he tri al sites visits ca n be re place d b y p h o ne 
c o ntact. H o we ver  as a mi ni m u m, s u bjects s h o ul d be as ke d t o atte n d visit 1, visit 2, visit 7, 
visit 1 0, visit 1 4, visit 1 8, visit 2 2 a n d V -E O T face t o face ( ke y ass ess me nt visits). If a site 
visit is c ha n ge d t o a p h o ne c o ntact 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 tri al pr o d uct wit hi n t he e x pir y date.  
•  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 s u bject 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 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 ve all s u bjects 
f oll o we d f or M A C E-relat e d o utc o mes. T he site m ust atte m pt t o c o ntact t he s u bject a n d 
resc he d ul e t he misse d visit as s o o n as p ossi ble a n d c o u nsel t he s u bject 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 t he s u bject wis hes t o c o nti n ue 
i n t he trial. 
•  Assess me nts s h o ul d be carrie d o ut acc or di n g t o t he cli nic’s sta n da r d of practice u nless 
ot her wise s pecifie d i n t he c urre nt secti o n. Eff orts s h o ul d be ma de t o li mit t he bias bet wee n 
assess me nts (i.e. perf or mi n g s u bject -rec or de d assess me nts bef ore ot her assess me nts, 
meas uri n g vital si g ns bef ore bl o o d dra ws).  
•  T he barri ers a n d m oti vati o n i nter vie w i de ntif y barriers t o a n d m oti vati o n c o m plia nce wit h 
t he pr ot oc ol. T he i nter vie w s h o ul d be c o n d ucte d at scree ni n g t o assist i n i de ntif yi n g s u bjects 
w h o are u n a ble or u n willi n g t o c o m pl y wit h pr ot oc ol pr oce d ures as p er t he e xcl usi o n 
criteria. I n a d diti o n, t he i nter vie w will e ns ure t h at a n y mi n or barriers are a d dresse d d uri n g 
site visits. 
•  T he res ults of t he i nter vie w will n ot be e ntere d i nt o t he C R F a n d will n ot be 
tra nsferre d t o t he trial d ata base. It will be at t he i n vesti gat or’s discreti o n t o e val uate 
t he m oti vati o n of t he s u bject a n d rel ate d eli gi bilit y. 
•  R e vie w of la 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 m e nts or i n t he 
s u bject's s o urce d o c u me nts.  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
3 5
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
3 6  of 1 0 0  
 
•  T here are n o fasti n g visits.  
•  Re peat sa m ples ma y be t a ke n f or t ec h nical iss ues a n d re -rest sa m ples or assess me nts ma y be 
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 details o n la b orat or y 
sa m ples. 
•  T he s u bject’s gl ycae mic stat us will be cate g orise d as n or m o -gl ycae mia, pre dia betes or 
dia g n ose d wit h t y pe 2 di a betes bas e d o n t he i n vesti gat or's e val uati o n of all a vaila ble 
rele va nt i nf or m ati o n e. g. me dical rec or ds, c o nc o mita nt me dicati o n, bl o o d gl uc ose 
para meters (refere nce t o A D A sta n dar d of care 2 0 1 8) 1 6 (see A p pe n di x 2 ) a n d A Es.  
•  T he i n vesti gat or ma y pr o vi de t he s u bjects 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 R B/I E C. T he i n vesti gat or s h o ul d 
c o nsi der se n di n g te xt messa ges t o t he s u bjects 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 tri al re q uire me nts. N o v o N or dis k will e ns ure t he a vaila bilit y of pre -pai d 
p h o ne car ds or si milar.  
•  If warra nte d b y s p ecial circ u msta nces a n d if per mitte d b y l ocal re g ulati o ns, t he i n vesti gat or 
ma y e n ga ge wi t h a Healt h Care Pr ofessi o nal fr o m a t hir d part y h o me healt h care s er 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 nate 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 bt ai n t he s u bject’s c o ns e nt b y mea ns of 
separat e a n d l ocall y a p pr o ve d c o nse nt f or m. T he t hir d part y Healt h Care Pr ofessi o nal m ust 
ha ve a lice nce t o practice a n d ha ve recei ve d a de q uate pr ot oc ol trai ni n g. Detaile d pr oce d ure 
a n d s pecific re q uire me nts s h o ul d be a vaila ble f or rele va nt site staff i n a w ritte n i nstr ucti o n. 
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 wc hart secti o n 2 . 
9. 1. 1    
B o d y me as ure me nt s 
•  B o d y wei g ht s h o ul d be meas ure d wit h o ut s h oes a n d o nl y weari n g li g ht cl ot hi n g. It s h o ul d be 
meas ure d o n a di gital scale a n d rec or de d i n k g or l b ( o ne deci mal wit h a precisi o n of 0. 1 k g 
or l b) usi n g prefera ble t h e sa me scale t hr o u g h o ut t he trial. T he scale  m ust be cali brat e d 
yearl y as a mi ni m u m, u nless t he ma n ufact urer certifies t hat cali brati o n of t h e wei g hi n g 
scales is vali d f or t he life-ti me of t he scale. 
•  Hei g ht is meas ure d wit h o ut s h oes i n  ce nti metres or i nc hes ( o ne deci mal  wit h a precisi o n of 
0. 1 ce nti metres or i nc h es ). At scree ni n g B MI will be calc ulate d b y t he eC R F a n d m ust be i n 
a gree m e nt wit h i ncl usi o n criteri o n # 3.  
•  Waist circ u mfere n ce is d efi ne d as t he a b d o mi nal circ u mfere nce l o cate d mi d wa y bet wee n t he 
l o wer ri b mar gi n a n d t h e iliac crest. Meas ures m ust be o btai ne d i n sta n di n g p ositi o n wit h a 
n o n -stretc ha ble m eas uri n g ta pe a n d t o t he nearest c m or i nc h. T he ta pe s h o ul d t o uc h t he s ki n 
b ut n ot c o m press s oft tiss ue a n d t wists i n t he ta pe s h o ul d be a v oi de d. T he s u bject s h o ul d be 
as ke d t o breat he n or mall y.  
9. 1. 2    
Cli nic al effic ac y l a b or at or y assess me nts  
All pr ot oc ol -re q uire 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 a n d t he l a b orat or y ma n ual.  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
3 6
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
3 7  of 1 0 0  
 
9. 1. 3    
P atie nt re p orte d o utc o mes  
Bel o w  dat a will n ot be e ntere d i nt o t he eC R F, b ut will b e tra nscri be d directl y i nt o a site-pa d/ we b -
s ol uti o n.   
E ur o Q ol fi ve di me nsi o ns fi ve le vel  
T he E Q -5 D -5 L q uesti o n naire is a patie nt re p orte d o utc o me ( P R O) t o ol.  T he P R O will be use d t o 
esti mate t he i m pact o n s u bjects’ healt h-relate d q ualit y of life a n d pr o vi des a descri pti o n of s u bjects’ 
pr o ble ms b y di me nsi o ns ( descri pti ve s yste m), a sc ore f or o verall self -rat e d healt h ( vis ual a nal o g ue 
scale ( V A S) as well as a n i n de x sc ore ( E Q-5 D -5 L i n de x)). If clarifi cati o n of t he test is nee de d, care 
m ust be ta ke n n ot t o bias t he s u bject. 
Wei g ht rel ate d si g n a n d s y m pt o m me as ure  
T he wei g ht rel ate d si g n a n d s y m pt o m meas ure ass esses t he pres e nce a n d b ot her ass ociate d wit h 
wei g ht -relat e d s y m pt o ms usi n g a self-rate d V A S. It is a t o ol t o assess t he m ultifacete d as p ects of 
o besit y o n s y m pt o m e x perie nce i n s u bjects wit h o ver wei g ht or o besit y.  
S u bject e n g a ge me nt  ass ess me nt  
A s u bject  e n ga ge me nt assess me n t will be perf or me d i n a s u bset of s u bjects t o m o nit or e n ga ge me nt 
a n d pr oacti vel y i de ntif y rete nti o n c halle n ges. T he assess me nt ma y be use d f or E n glis h s pea ki n g 
s u bjects i n t he U S a n d U K. T his data will n ot be tra nsferre d t o t he tri al data base.  
9. 1. 4    
H os pit alis a ti o ns 
H os pitalisati o ns w hic h are relate d t o a S A E (see A p pe n di x 4 ), i ncl u di n g re-a d missi o ns f or t he  sa me 
e ve nt, s h o ul d  be re p orte d o n t he A E f or m.  
9. 1. 4. 1    
N o n -S A E h os pit alis ati o ns  
H os pitalisati o ns t hat are n ot relate d t o S A Es s h o ul d be re p orte d o n t he ‘ N o n-S A E  h os p italisati o ns’ 
f or m. T his i ncl u des t he bel o w t y p es of h os pitalisati o ns: 
•  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 
ra n d o misati o n 
•  H os pitalisati o ns f or a d mi nistrati ve, trial relate d a n d s ocial p ur p oses  
•  H os pita l a d missi o ns f or s ur gical pr oce d ures, pl a n ne d bef ore ra n d o misati o n 
9. 2    
A d verse e v e nts  
T he i n vesti gat or is res p o nsi ble f or detecti n g, d oc u me nti n g, rec or di n g a n d f oll o wi n g u p o n:  
•  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, irres pecti ve of seri o us ne ss 
•  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 prese nt ati o n is s u g gesti ve of 
C O VI D -1 9, e v e 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 test 
res ult. I n t h e 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 orte d, if a vaila ble 
•  A Es re q uiri n g a d diti o nal data c ollecti o n ( via s pecific e ve nt f or m) a n d e ve nts f or 
a dj u dicati o n, irres pecti ve of seri o us ness, see Ta ble  9 -1   
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
3 7
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
4 0  of 1 0 0  
 
p oss i 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 usalit 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 tra ns mitt i 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 a n d e v e 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 . 
 
Fi g ure  9 -1  
S afet y re p orti n g ti meli nes  
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 dicati o n will be perf or me d f or e vents i n ra n d o mise d s u bjects. T hese e ve nts 
are re vie we d b y 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 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 a p pr o priat e A E cate g or y b ase d o n pre-defi ne d c riteria (see Ta 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 e ve nt s pecific 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 u rce d o c 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 ve nt A dj u dicati o n S yste m ( E A S).  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
4 0
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
4 1  of 1 0 0  
 
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 fatal o utc o me, a deat h 
a dj u dicat i 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 s u bjects’ 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 orte 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 
t he A E is dee me d rele va nt f or a dj u dicati o n, a n e ve nt s pecific a dj u dicati o n f or m will be 
ge n erat 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 pre defi ne d s o urce d oc u m e nts 
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 ve 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 uire 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 s pecific a dj u dicati 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 C R F wit hi n 7 
cale n dar da ys  of t he i n v esti gat or's first k n o wle d ge of t he e ve nt .  
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, s u bject 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 pers o nal i de ntifiers) a n d u pl oade 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 oc u m e nts are pr o vi d e 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 ve 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 S ite M a n ual will be pr o vi d e d t o eac h site detaili n g h o w t o pr o vi de t he 
rele va nt s o urce d oc u m e nts 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 des cri be 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 he 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 detecti n g A Es a n d/ or S A Es. O pe n -e n de d a n d n o n -
lea di n g v er bal q u esti o ni n g of t he s u bj ect 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 oacti vel y f oll o w all S A Es 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 diti o 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 . 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
4 1
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
4 2  of 1 0 0  
 
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 s u bjects a n d t he safet y of a trial 
pr o d uct 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 p orti 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. 
I n v esti gat or safet y re p orts must 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 (see A p pe n di x 9 ). 
A n i n vesti gat or w h o recei ves a n i n vesti gat or safet y re p ort descri bi n g a S A E or ot her s pecific safet y 
i nf or mati o n (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 vesti gat or's br oc h ure a n d will n oti f 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    
C ar di o v asc ul ar e ve nts a n d de at hs  
S pecifie d i n Ta ble  9 -1 . 
9. 2. 6    
Dise ase -rel ate d e v e nts a n d/ or dise ase -rel ate d o utc o mes n ot q u alifie d as a n A E or 
S A E  
N ot a p plica ble f or t his trial.  
9. 2. 7    
Pre g n a ncies a n d ass oci ate d a d verse e ve nts  
Details of pre g n a ncies i n fe male s u bjects will be c ollecte d fr o m t he first -trial-relate d acti vit y after 
o btai ni n g i nf or me d c o nse nt a n d u ntil pre g na nc y o utc o me.  
If a pre g na nc y is r e p orte d i n fe male s u bjects, 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 nc 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 . T he i n vesti gat or will re p ort i nf or mati o n o n t he s u bject a n d t he pre g na nc y o ut c 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 acc or da nce wit h E ur o pea n Me dici nes A ge nc y  
( E M A)1 7. I nf or m ati o n a b o ut t he pre g na nc y a n d pre g na 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 pa p er pre g n a nc y f or ms.  
Pre g n a nc y o utc o me s h o ul d be d oc u me n te d i n t he s u bject's me di cal rec or d. A b n or mal pre g na 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 S A E.  
9. 2. 8    
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 tec h nical c o m plai nts ca n be f o u n d i n A p pe n di x 6 . 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
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V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
4 2
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
4 3  of 1 0 0  
 
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. I n t he e ve nt of o ver d ose, a p pr o priate 
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 s u bjects’ cli nical si g ns a n d s y m pt o ms. 
O ver d oses of u p t o 4 m g i n a si n gle d ose ha ve bee n re p orte d i n cli ni cal trials. T he m ost c o m m o nl y 
re p orte d a d verse reacti o n was na usea. All s u bjects 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 ver d ose, t he i n vesti gat or s h o ul d cl osel y m o nit or t he s u bject f or o ver d ose-relate d 
A E/ S A Es a n d la b orat or y a b n or malities. A  pr ol o n ge d peri o d of o bs er vati o n a n d treat me nt f or t hese 
s y m pt o ms ma y b e necess ar y, ta ki n g i nt o acc o u nt t he l o n g half-life of se ma gl uti de of a p pr o xi matel y 
o ne wee k.  
Decisi o ns re gar di n g d ose i nterr u pti o ns or m o dificati o ns will be ma de b y t h e i n vesti gat or b ase d o n 
t he cli nical e val uati o n of t he s u bject.  
T he o ver d ose m ust be re p orte d as a me dicati o n err or or a b us e/ mis use acc or di n g t o t he defi niti o n i n 
Ta ble  9 -1 . 
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 versi o n of t he I B 1 2 a n d a n y u p dates 
here of.  
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 hart 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 u p u ntil ti me of ra n d o misati o n.  
Me dic al hist or y is a me dical e ve nt t hat t he s u bject has e x perie nce d i n t he past, i.e. pri or t o 
ra n d o misati o n.  
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.  
S pecific Me dical Hist or y f or ms:  
•  Hist or y of car di o vasc ular diseases. T his als o i ncl u des eac h m e dical c o n diti o n(s) t hat 
q ualifie d t he s u bject f or partici pati o n i n t he trial acc or di n g t o i ncl usi o n crit eri o n # 4 a -c 
•  O besit y c o m or bi d ities 
•  Hist or y of gall bla d der disease  
•  Hist or y of pa ncreatitis  
•  Hist or y of s ki n ca ncer  
•  Hist or y of c ol o n ne o plas m i ncl u di n g ris k fact ors  
•  Hist or y of breast n e o plas m i ncl u di n g ris k fact ors (f or all fe male s u bjects)  
Me dical Hist or y/ C o n c o mita nt Ill ness f or m:  
•  All ot her rele va nt c o nc o mita nt ill ness/ me dical hist or y t hat has n ot bee n rec or de d i n S pecific 
Me dical Hist or y f or ms (t his als o i ncl u des mali g na nt ne o plas m  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 di n g, t he i n vesti gat or m ust rec or d t he fi n di n g o n 
t he Me dical 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 or w orse ni n g f ulfilli n g t he S A E defi niti o n, A Es lea di n g t o treat me nt disc o nti n uati o n, A Es of 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
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V V- T M F- 5 0 5 7 8 4 9
 .
-
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1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
4 3
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
4 4  of 1 0 0  
 
C O VI D -1 9  or A Es re q uiri n g a d diti o nal data c ollecti o n (see A p pe n di x 4  a n d secti o n 9. 2 ) d uri n g t he 
trial fr o m ra n d o misati o n m ust be re p orte d (see secti o n 9. 2 ).  
9. 4. 1    
Bre ast ne o pl as ms f oll o w -u p a n d c ol o n ne o pl as ms f oll o w -u p  
F oll o w -u p q uesti o ns will be as ke d at t he e n d of treat me nt ( V -E O T) a n d e n d of trial ( P -F U) visits 
relate d t o a n y c ol o n osc o p y a n d m a m m o gra p h y’s carri e d o ut d uri n g t h e trial. 
9. 4. 2    
P h ysic al e x a mi n ati o ns  
A p h ysical e xa 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  
•  Breast (fe m ales)  
•  Car di o vasc ular s yste m  
•  Gastr oi ntesti nal s yste m  
•  Ce ntral a n d peri p heral 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 m 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 pres e 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 . 
9. 4. 3    
Vit al si g ns  
Bl o o d press ure a n d p ulse  
Bl o o d press ure a n d p ulse meas ure me nts s h o ul d be prece de d b y at least 5 mi n utes of rest f or t h e 
s u bject 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 wit h o ut r o u n di n g. Bl o o d press ure a n d p ulse meas ure m e nts will be assesse d wit h 
a c o m pletel y a ut o mate d de vice. Ma n u al tec h ni q u es will be use d o nl y if a n a ut o mate d de vice is n ot 
a vaila ble.  
9. 4. 4    
Cli nic al s afet y l a b or at or y assess me nts  
All pr ot oc ol -re q uire 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. 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 mi cs  
N ot a p plica ble.  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
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V V- T M F- 5 0 5 7 8 4 9
 .
-
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1
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 of
  Pr ot oc ol  Pr ot oc ol V 7
4 4
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
4 5  of 1 0 0  
 
9. 7    
Ge netics  
A bl o o d sa m ple f or D N A/ R N A a nal ysis will be c ollecte d fr o m s u bjects w h o ha ve c o nse nt e d t o 
partici pate 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 det ails. 
Al geria, Brazil, Israel: F or c o u ntr y s pecific re q uire me nts, please see A p pe n di x 9 . 
9. 8    
Bi o m ar kers  
C ollecti o n of bl o o d sa m ples f or bi o mar ker res earc 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. S u bject s 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 he bi o ba n k, sa 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 nal 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 
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 vere 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 ne s 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 ma 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 circ 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 neti c plas ma or 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 nse t o se ma gl uti de as well as u n dersta n 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 i n batc hes t o t he ce ntral la b orat or y. T he 
a nal ys es are l i kel y t o be perf or me d after t he trial has c o me t o a n e n d, a n d res ults will t heref ore n ot 
be part of t he cli nical trial re p ort. T he bi o ba n k sa m ples ma y be st ore d u p t o 1 5 years after e n d of 
trial at a ce ntral la b orat or y (see A p pe n di x 7 ). 
Al geria, Brazil, Israel: F or c o u ntr y s pecific re q uire me nts, please see  A p pe n di x 9 . 
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 his trial is desi g ne d t o h a ve 9 0 % o verall p o wer t o c o nfir m s u peri orit y of t he pri mar y e n d p oi nt 
(secti o n 1 0. 3. 1 ). T he f oll o wi n g i nf or m ati o n has bee n use d t o calc ulate t he n u m ber of e ve nts t hat 
nee d t o be accr ue d i n t his trial.  
T a ble  1 0 -1  
I nf or m ati o n use d t o c alc ul ate t he n u m ber of pri m ar y e n d p oi nt e ve nts nee de d  
E n d p oi nt  
St atistic al        
test 
H y p ot hesis 
Teste d  
O ne -si de d 
si g nific a nce   
le vel  
Ass u me d        
tr ue                 
H R  
Re q uire d   
p o w er  
Ti me t o first  
e ve nt  
L o g -ra n k   
S u peri orit y    
2. 5 %  
0. 8 3  
9 0 %  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
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V V- T M F- 5 0 5 7 8 4 9
 .
-
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1
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 of
  Pr ot oc ol  Pr ot oc ol V 7
4 5
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
4 6  of 1 0 0  
 
T he ass u me d tr ue H R is base d o n a c o nser vati ve assess me nt of t he o bser ve d p oi nt esti mate f or t he 
H R i n t he S U S T AI N 6, w hic h was 0. 7 4 [ CI 9 5 %: 0. 5 8 ; 0. 9 5] f or a si milar defi niti o n of M A C E
4.  
T he n u m ber of e ve nts nee de d t o be accr ue d is det er mi ne d base d o n t h e l o g -ra n k test a n d t he gr o u p 
se q ue ntial desi g n all o wi n g f or i nteri m testi n g. T he La n-De M ets al p ha s pe n di n g f u ncti o n, 
a p pr o xi mati n g t he O' Brie n -Fle mi n g’s  st o p pi n g b o u n daries, is use d wit h a st u d y-wise (c u m ulati ve) 
o ne -si de d t y pe I err or rat e of 2. 5 %. A t otal of 1 2 2 5 first M A C Es will pr o vi de 9 0 % p o wer . 
T he p o wer as a f u ncti o n of tr ue H R is see n fr o m t he bel o w fi g ure: 
 
Fi g ure  1 0 -1  P o wer as a f u ncti o n of tr ue ris k re d ucti o n (i.e. 1 - h az ar d r ati o) wit h 1 2 2 5 e ve nts  
T he ass u m pti o ns f or t he sa m ple size calc ulati o n are s h o w n i n  Ta ble  1 0 -2 . 
T a ble  1 0 -2  
Ass u m pti o ns be hi n d s a m ple size c alc ul ati o n  
Recr uit me nt  
A n n u alise d r ate of 
s u bjects f or w h o m 
M A C E i nf or m ati o n is 
u n a v ail a ble at tri a l 
cl os ure  
A n n u alise d r ate of 
s u bjects wit h a first 
M A C E  
D ur ati o n of tri al  
2, 5 0 0  
ra n d o mise d 
e ver y 4 m o nt h  
1. 0 %  
2. 0 %  
5 9 m o nt hs  
T he ass u m pti o n of 2, 5 0 0 s u bjects bei n g ra n d o mise d e ver y f o ur m o nt hs is base d o n w hat has bee n 
ac hie ve d i n trial E X 1 2 5 0 -4 0 8 0 ( D E V O T E).   
T he a n n ualise d rate of s u bjects wit h a first M A C E ( pri mar y e n d p oi nt) is base d o n t he e ve nt rates 
see n i n S U S T AI N 6 a n d EX 2 2 1 1 -3 7 4 8 ( L E A D E R). T hese e ve nt rat es were c o m pare d t o t he e ve nt 
rates i n ot her n o n-T 2 D C V O Ts ( F O U RI E R, S C O U T a n d I RI S 1 8 -2 0) a n d a dj uste d t o t he i ncl usi o n 
a n d e x cl usi o n criteria of t he c urre nt trial. I n t he S C O U T trial, w hic h was c o n d ucte d i n s u bjects wit h 
o ver wei g ht or o besit y, t h e s u b gr o u p t hat o nl y ha d esta blis he d C V disease ha d ~ 3 0 % fe wer M A C E 
e ve nts c o m pare d wit h t he s u b gr o u p t hat ha d esta blis he d C V disease a n d T 2 D 1 9. Base d o n t his 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
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V V- T M F- 5 0 5 7 8 4 9
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1
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 of
  Pr ot oc ol  Pr ot oc ol V 7
4 6
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
4 7  of 1 0 0  
 
literat ure, a n e ve nt rate ar o u n d half of t hat see n i n L E A D E R a n d S U S T AI N 6 is ass u me d w he n 
i ncl u di n g s u bjects wit h pri or MI, pri or str o ke or s y m pt o matic P A D b ut wit h o ut T 2 D.  
Acc or di n gl y, t he o verall a n n ualise d e ve nt rate acr oss t he t w o treat me nt ar ms is ass u me d t o be 2. 0 %, 
(i.e. 1. 8 % i n t he se ma gl uti de ar m a n d 2. 2 % i n t he place b o ar m). 
Wit h t hese ass u m pti o ns t he n u m ber of e ve nts accr ue d o ve r a peri o d of 7 ye ars wit h vari o us sa m ple 
sizes is see n o n t he bel o w fi g ure. 
 
Fi g ure  1 0 -2  N u m ber of e ve nts o ver ti me wit h v ari o us s a m ple sizes  
Wit h a sa m ple size of 1 7, 5 0 0 s u bjects ra n d o mise d 1: 1 t o se ma gl uti de 2. 4 m g or s e ma gl uti de 
place b o t he 1 2 2 5 e ve nts will be accr ue d at m o nt h 5 9 ( ~ 5 years).  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
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V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
4 7
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
4 8  of 1 0 0  
 
T o e x a mi ne t he se nsiti vit y of t he trial d urati o n de pe n di n g o n t he act ual e ve nt rate t he f oll o wi n g 
fi g ure pr o vi des a n o ver vie w:  
 
Fi g ure  1 0 -3  N u m ber of e ve nts o ver ti me wit h differe nt e ve nt r ates  
Fr o m t his fi g ure it is see n t hat t he ti me t o accr ue 1 2 2 5 first M A C Es will be less t ha n 4 9 m o nt hs ( 4. 1 
years) if t h e e ve nt rate is as hi g h as 2. 6 % a n d 7 9 m o nt hs ( 6. 5 year s) if t he e ve nt rate is 1. 4 %.  
I n s u m mar y t he sa m ple size calc ulati o ns pr o vi de t he f oll o wi n g i nf or mati o n a b o ut t he trial a n d 
e x pecte d trial c o n d uct:  
T a ble  1 0 -3  
Ke y n u m bers a n d ti meli nes  
R a n d o mis ati o n  
sc he me 
T ot al n u m ber 
of s u bjects t o be 
r a n d o mise d  
N u m ber of 
s u bjects 
wit h a n 
e ve nt  
D ur ati o n of 
recr uit me nt 
peri o d  
D ur ati o n of 
tri al 
Ti me fr o m 
L P F V t o 
L P L V  
M e a n 
o bser v ati o n 
ti me 
1: 1  
1 7, 5 0 0    
≥1, 2 2 5    
2 8 m o nt hs  
( 2 year a n d  
4 m o nt hs)  
5 9 m o nt hs  
( 4 years a n d 
1 1 m o nt hs)  
3 1 m o nt hs  
( 2 years a n d  
7 m o nt hs)  
4 4 m o nt hs  
( 3 years a n d  
8 m o nt hs)  
1 0. 2   
Defi niti o n of a n al ysis sets  
Data selecti o n f or statistical a nal yses will be a t w o -ste p pr ocess, first selecti n g s u bjects base d o n t h e 
a nal ysis p o p ulati o n a n d s u bse q ue ntl y e ve nts/ data o n t h ose s u bjects base d o n t he o bser vati o n peri o d. 
F ull a nal ysis set ( F A S): All ra n d o mise d s u bjects. S u bject s will be a nal ys e d acc or di n g t o t he 
treat me nt t o w hic h t he y were assi g n e d at ra n d o misati o n.   
I n-trial o bser v ati o n peri o d: T his o bser vati o n peri o d is defi ne d as t he peri o d fr o m date of 
ra n d o misati o n t o o ne of t he f oll o wi n g dates, w hic he ver c o m es first. 
•  Date of e n d -of -tri al visit 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
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V V- T M F- 5 0 5 7 8 4 9
 .
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1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
4 8
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
4 9  of 1 0 0  
 
•  Date of deat h  
•  Date w he n s u bj ect wit h dre w c o ns e nt  
•  Date of las t c o nt act wit h s u bject  
1 0. 3   
St atistic al a n al yses  
A statistical a nal ysis pla n ( S A P) will be pre pare d a n d fi nalise d pri or t o first u n bli n d e d D M C 
meeti n g . T he S A P will pr o vi de f urt her details re gar di n g t h e defi niti o n of a nal ysis varia bles a n d 
a nal ysis met h o d ol o g y i ncl u di n g a nal yses of sec o n dar y e n d p oi nts a n d se nsiti vit y a nal yses f or t he 
pri mar y e n d p oi nt.  A d diti o nall y, f urt her det ails of t he i nteri m testi n g will be pr o vi de d i n t he S A P.  
N o v o N or dis k will perf or m t he statistical a nal ys es e xce pt i nteri m testi n g, see s ecti o n 1 0. 3. 4 . 
Ge ner al c o nsi der ati o ns  
U nless ot her wise s pecifie d, all a nal ysis a n d s u m mar y of all e n d p oi nts will be base d o n t he f ull  F A S 
usi n g t he i n-trial o bser vati o n peri o d, see secti o n 1 0. 2 . I n statistical a nal yses of c o nfir mat or y 
e n d p oi nts, t he esti mate d treat me nt effects will be prese nte d t o get h er wit h 2 -si de d 9 5 % c o nfi de nce 
i nter vals ( CI) a n d o n e-si de d p-val ues f or tests of t he ass ociate d h y p ot h eses. F or n o n -c o nfir mat or y 
e n d p oi nts, t w o -si de d p-v al ues c orres p o n di n g t o testi n g h y p ot heses of n o differe nce will be 
prese nte d i nstea d of o ne -si de d p -val ues. Occ urre nce of ti me -t o-e ve nt e n d p oi nts will be s u m marise d 
b y c u m ulati ve i n ci de nce f u ncti o n pl ots a dj uste d f or c o m peti n g ris k of deat h / C V deat h (if n ot a 
c o m p o ne nt of t he s pecific e n d p oi nt) as well as descri pti ve s u m maries wit h pr o p orti o n of s u bjects 
wit h e ve nt, i nci de nce rat es f or occ urre nce of first e ve nt a n d rates of occ urre nce of all e ve nts. U nless 
ot her wise state d all ti me -t o-e ve nt e n d p oi nts will be deri ve d usi n g t he o utc o me of t he E A C 
e val uati o ns w he ne v er a p plica ble.  C o nti n u o us e n d p oi nts will  be s u m marise d i n descri pti ve ta bles 
usi n g arit h metic mea ns, ge o m etric mea ns, sta n dar d de viati o ns, ra n ges, a n d i nter q uartile ra n ges as 
a p pr o priate. E A C c o nfir me d e ve nts a n d i n vesti gat or re p orte d e ve nts will be s u m marise d b y n u m ber 
of s u bjects wit h e ve nts, pr o p orti o n of s u bjects wit h e ve nts, n u m ber of e ve nts a n d rate of e ve nts per 
1 0 0 P Y O.  
F or c o nti n u o us e n d p oi nts a n d cate g orical e n d p oi nts deri ve d fr o m c o nti n u o us s o urces, t he bas eli ne 
val ue is defi ne d as t he last assess me nt ta ke n pri or t o or at t he ra n d o misa ti o n visit a n d  bef ore first 
use of trial pr o d uct. F or e x a m ple, if t he assess me nt is missi n g at t he ra n d o misati o n visit ( or if t he 
assess me nt was d o ne after first use of trial pr o d uct) a n d t he assess m e nt als o has bee n ma de at 
scree ni n g, t he n t h e scree ni n g val ue will be use d as t he baseli ne val ue.  
S u b gr o u p a n al ys es will be perf or me d t o e xa mi ne t he  c o nsiste nc y of t he pri mar y a nal ysis. T he 
rele va nt s u b gr o u ps will b e i de ntifie d at baseli ne base d o n de m o gra p hics a n d disease stat us, a n d 
descri be d i n t he statistic al a nal ysis pla n . 
1 0. 3. 1    
Pri m ar y e n d p oi nt  
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 M A C E 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 or  
•  n o n -fatal str o ke 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
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V V- T M F- 5 0 5 7 8 4 9
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-
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1
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 of
  Pr ot oc ol  Pr ot oc ol V 7
4 9
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
5 0  of 1 0 0  
 
St atistic al a n al ysis of t he pri m a r y e n d p oi nt  
T he pri mar y a n al ysis of t he pri mar y e n d p oi nt will be base d o n t he F A S usi n g t he i n-tri al 
o bser vati o n peri o d. T he h azar d rati o ( H R) c o m pari n g se m a gl uti de 2. 4 m g  vers us  se ma gl uti de 
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 2. 4  m g , s e ma gl uti de place b o) as fi xe d fact or . 
S u bject s wit h o ut a pri mar y e n d p oi nt e ve nt pri or t o t he i n-trial e n d-dat e will be c o nsi dere d ce ns ore d 
at t his date.   
T he f oll o wi n g s u p eri orit y h y p ot hesis will be teste d:  
H 0: H R ≥ 1. 0 a gai nst H a: H R < 1. 0  
w here H R is t he hazar d rati o f or t he c o m paris o n of se ma gl uti de 2. 4 m g  vers us se ma gl uti de place b o. 
S u peri orit y of s e 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 base d o n n o mi nal si g nifica n ce le vel d eri ve 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 nal ysis. Fi nal i nfere nce o n ter mi nati o n is 
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.  
Se nsiti vit y a n al yses  
T he pri mar y a n al ysis reli es o n t he ass u m pti o n t hat missi n g data after ce ns ori n g f or s u bj ects t hat 
ha ve wit h dra w n c o nse nt or are l ost t o f oll o w -u p are missi n g at ra n d o m. T o i n vesti gate t he i m pact of 
t his ass u m pti o n o n t he res ults of t he pri mar y a nal ysis, a ti p pi n g p oi nt a nal ysis base d o n t he 
a p pr oac h d escri be d i n Z h a o et al. ( 2 0 1 4) 2 1 will be ma de. I n t his a nal ysis, s u bjects i n t he se ma gl uti de 
treat me nt gr o u p will ha v e t heir s ur vi val ti mes i m p ute d fr o m t heir c o n diti o n al s ur vi val distri b uti o n 
wit h a pe nalt y (se nsiti vit y para meter) i n t he se ns e t hat t heir ris k of M A C E is i ncrease d f oll o w i n g 
ce ns ori n g c o m pare d t o w hile u n der o bser vati o n. T he place b o s u bjects will be i m p ute d fr o m t heir 
c o n diti o nal s ur vi val wit h n o pe nalt y. M ulti ple i m p ute d data sets will be a nal yse d wit h se parate C o x 
re gressi o ns a n d res ults will be c o m bi ne d usi n g R u bi n’s r ule.2 2 
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 cat e 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, a n d as s u p p orti ve if t he e n d p oi nts are a nal yse d wit h o ut 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  
T he s u peri orit y h y p ot hesis state d i n secti o n 1 0. 3. 1  is teste d f or eac h of t he c o nfir mat or 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. T he c o nfir mat or y e n d p oi nts are 
pri oritise d acc or di n g t o t he bel o w or deri n g a n d t h e testi 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 l e vels of 
t he c o nfir mat or y s ec o n dar y e n d p oi nt a nal yses 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 oi nts are defi ne d as ti me fr o m ra n d o misati o n t o:  
•  C V deat h  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
5 0
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
5 1  of 1 0 0  
 
•  First occ urre n ce of a c o m p osite heart fail ure e n d p oi nt c o nsisti n g of: heart fail ure 
h os pitalisati o n, ur ge nt heart fail ure visit or C V deat h  
•  All -ca use d eat h  
T he c o nfir mat or y sec o n d ar y e n d p oi nt will be a nal ys e d usi n g t he sa me pr o p orti o nal hazar ds 
re gressi o n m o del des cri be d f or t he pri mar y a nal y sis.     
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 esti mate d hazar d rati o f or t he effect of 
se ma gl uti de vers us se ma gl uti de place b o will be prese nte d.  
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 year 2) will be a nal yse d 
usi n g m ulti ple i m p utati o n. Missi n g val ues are defi ne d as data t hat are pla n ne d t o be o bser ve d b ut 
are n ot prese nt i n t he dat a base.  I n case t h e trial is ter mi nate d bef ore 9 0 % of s u bjects ha ve reac he d 
t he visit ar o u n d year 2 t he visit ar o u n d year 1 will be use d i nstea d of year 2. T h us if less t ha n 1 0 % 
of s u bjects ha ve missi n g val ues f or t he year 2 visit d ue t o te r mi nati o n earlier t ha n pla n ne d t he 
e ve nts rate e x cee de d e x pectati o ns) t he missi n g val ue i n q uesti o n will be i m p ute d.  
T he i m p utati o n m o del will i ncl u de baseli ne val ue as a c o variate a n d fitte d t o s u bjects t hat are off 
treat me nt f or t he first ti me, b ut ha ve a n o bs er ve d data p oi nt at t he s pecific visit. T he fitte d m o del 
will be use d t o i m p ute val ues f or all s u bjects t hat d o n ot ha ve a n o bser ve d data p oi nt at t he s pecific 
visit. Eac h of t he c o m plete d data sets will be a nal ys e d s e paratel y f or year 1 a n d year 2 assess me nts 
b y a n A N C O V A a dj uste d f or treat me nt as fi xe d fact or a n d baseli ne val u e as c o variate. R u bi n’s 
r ule2 2 will be use d t o c o m bi ne t he res ults t o dra w i nfere nce. A nal ysis of li pi ds a n d hs C R P will be o n 
l o garit h mic scale. T he esti mate d treat me nt differe nce (rati o f or li pi d a n d hs C R P e n d p oi nts ) f or t he 
effect of se ma gl uti de vers us se ma gl uti de place b o will be prese nte d. T he f oll o wi n g e n d p oi nt is 
defi ne d o nl y f or s u bjects wit h a scree ni n g H b A 1c ≥ 3 9 m m ol/ m ol ( 5. 7 %):  
•  H b A 1c < 3 9 m m ol/ m ol ( 5. 7 %) at eac h visit w here H b A 1c is assesse d 
T he e n d p oi nt will be a nal ys e d s e paratel y at year 1 a n d year 2 usi n g a l o gisti c re gressi o n m o del wit h 
treat me nt (se ma gl uti de, se ma gl uti de place b o) as fi xe d fact ors a n d bas eli ne H b A 1c as c o variate. T he 
rati o (se ma gl uti de vers us se ma gl uti de place b o) bet wee n t he esti mate d o d ds will be prese nte d 
t o get her wit h 9 5 % CIs.  
T he f oll o wi n g e n d p oi nt is defi ne d o nl y f or s u bjects wit h a scree ni n g H b A 1c < 3 9 m m ol/ m ol ( 5. 7 %):  
•  Ti me fr o m r a n d o misati o n t o H b A 1c ≥ 3 9 m m ol/ m ol ( 5. 7 %)  
T he e n d p oi nt will be a nal ys e d usi n g 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, se ma gl uti de place b o) as fi xe d fact or. T he rati o (se m a gl uti de vers us se ma gl uti de 
place b o) bet wee n t h e esti mate d hazar ds will be prese nte d t o get her wit h 9 5 % CIs.  
1 0. 3. 3    
E x pl or at or y e n d p oi nts  
T he e x pl orat or y s m o ki n g e n d p oi nt will be a nal ys e d se parat el y at year 1 a n d year 2 usi n g a bi n o mial 
re gressi o n m o del wit h treat me nt (se ma gl uti de, se ma gl uti de place b o) a n d baseli ne s m oki n g stat us as 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
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V V- T M F- 5 0 5 7 8 4 9
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1
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 of
  Pr ot oc ol  Pr ot oc ol V 7
5 1
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
5 2  of 1 0 0  
 
fi xe d fact ors. T he rati o (se ma gl uti de vers us se ma gl uti de place b o) bet wee n t he esti mate d o d ds will 
be prese nt e d t o get her wit h 9 5 % CIs.  
Deteri orati o n fr o m baseli ne t o 1 1 7 w i n gl ycae mic cate g or y ( yes/ n o, w here “ yes” is deter mi ne d b y a 
c ha n ge f r o m n or m o gl ycae mia at baseli ne t o pre-di a betes/ dia betes at year 2 or fr o m pre -dia betes at 
baseli ne t o dia betes at ye ar 2)  will be a nal ys e d usi n g bi n o mial re gressi o n m o del wit h treat me nt 
(se ma gl uti de, se ma gl uti de place b o) as fi xe d fact ors a n d baseli ne H b A 1 c as c o variate. T he rati o 
(se ma gl uti de vers us se m a gl uti de place b o) bet wee n t he esti mate d o d ds will be prese nt e d t o get her 
wit h 9 5 % CIs.   
C ha n ge fr o m ra n d o misati o n t o year 2 i n W R S S M will be prese nte d descri pti vel y.  
1 0. 3. 4    
I nteri m testi n g f or effic ac y 
I nteri m testin 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 t he i nteri m testi n g. S u bjects 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.  
Trial i nte grit y will be e ns ure d b y usi n g a n e xter nal i n de pe n de nt statistical ser vice pr o vi der 
(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 o perf or m interi m testi n g. T he D M C 
e val uates t he u n bli n de d i nteri m testi n g usi n g t h e gr o u p se q ue ntial st o p pi n g b o u n daries as g ui da nce. 
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 oss e d a n d t he 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 nce 
le vels. All e ve nts fr o m t h e i n-trial o bservati o n peri o d i ncl u di n g e ve nts c ollecte d after i nteri m c ut -off 
date will be i ncl u de d i n t his e val 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 p erf or me d b y t he e xter nal i n de pe n de nt statistical ser vice 
pr o vi de r d uri n g trial c o n d uct will be e val uate d b y t he D M C, as descri be d i n t he D M C c harter.  
T he se q ue ntial e val uati o ns a nal ys es perf or me d b y t he 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 s afet y data a n d will be perf or me d t o ma ke rec o m m e n dati o ns re gar di n g t h e 
o n g oi n g c o n d u ct of t he trial t o e ns ure acce pta ble be nefit/ris k rati o f or s u bjects i n t he trial.  
T he pre -s p ecifie d st o p pi n g criteria f or t he e ntire trial (accr ual of 1 2 2 5 first M A C Es) will be 
m o nit ore d b y N o v o N or dis k (see secti o n 5. 1 , 8. 4 , A p pe n di x 3 , A p pe n di x 4 ). 
1 0. 4   
P h ar m a c o ki netic a n d/ or p h ar m ac o d y n a mic m o delli n g  
N ot a p plica ble.  
 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
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V V- T M F- 5 0 5 7 8 4 9
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-
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1
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 of
  Pr ot oc ol  Pr ot oc ol V 7
5 2
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
5 3  of 1 0 0  
 
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 dici nal 
pr o d ucts f or h u ma n use, 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.    
Afs hi n A, F or o uza nfar M H, Reits ma M B, S ur P, Este p K, Lee A, et al. Healt h Effects of 
O ver wei g ht a n d O besit y i n 1 9 5 C o u ntries o ver 2 5 Years. N E n gl J Me d. 2 0 1 7; 3 7 7( 1): 1 3 -2 7.  
3.    
N g M, Fle mi n g T, R o bi ns o n M, T h o ms o n B, Graetz N, Mar g o n o C, et al. Gl o bal, re gi o nal, 
a n d nati o nal pre v ale nce of o ver wei g ht a n d o besit y i n c hil dre n a n d a d ults d uri n g 1 9 8 0 -2 0 1 3: 
a s yste m atic a nal ysis f or t he Gl o bal B ur de n of Dis ease St u d y  2 0 1 3. La ncet. 
2 0 1 4; 3 8 4( 9 9 4 5): 7 6 6 -8 1.  
4.    
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 pe 2 Dia betes. N E n gl J Me d. 
2 0 1 6; 3 7 5( 1 9): 1 8 3 4 -4 4.  
5.    
G utz willer J P, Dre we J, G o ke  B, Sc h mi dt H, R o hrer B, Larei da J, et al. Gl uca g o n -li ke 
pe pti de -1 pr o m otes satiet y a n d re d uces f o o d i nta ke i n patie nts wit h dia betes mellit us t y pe 2. 
A m J P h ysi ol. 1 9 9 9; 2 7 6( 5 Pt 2): R 1 5 4 1 -4.  
6.    
Kieffer TJ, Ha be ner J F. T he gl u ca g o n -li ke pe pti des. E n d ocr Re v. 1 9 9 9; 2 0( 6): 8 7 6-9 1 3.  
7.    
H olst JJ, Vils b øll T, Deac o n C F. T he i ncreti n s yst e m a n d its r ole i n t y pe 2 dia betes mellit us. 
M ol Cell E n d ocri n ol. 2 0 0 9; 2 9 7( 1 -2): 1 2 7 -3 6.  
8.    
Rizz o M, Riz vi A A, Patti A M, Ni k olic D, Gi gli o R V, Castelli n o G, et al. Lira gl uti de 
i m pr o ves meta b olic para meters a n d car oti d i nti ma -me dia t hic k ness i n dia betic patie nts wit h 
t he meta b olic s y n dr o me: a n 1 8-m o nt h pr os pecti ve st u d y. Car di o vas c Dia bet ol. 
2 0 1 6; 1 5( 1): 1 6 2.  
9.    
Dr uc ker DJ. T he Car di o vasc ular Bi ol o g y of Gl uca g o n -li ke Pe pti de-1. Cell Meta b. 
2 0 1 6; 2 4( 1): 1 5 -3 0.  
1 0.   
Her ma nse n K, Bae k d al T A, D uri n g M, Pietrasze k A, M orte nse n L S, J or ge nse n H, et al. 
Lira gl uti de s u p presses p ost pra n dial tri gl yceri de a n d a p oli p o pr otei n B 4 8 el e vati o ns after a 
fat-ric h meal i n patie nts wit h t y pe 2 dia betes: a ra n d o mize d, d o u ble-bli n d, place b o -
c o ntr olle d, cr oss -o v er tri al. Dia betes O bes Meta b. 2 0 1 3; 1 5( 1 1): 1 0 4 0 -8.  
1 1.   
O' Neil P M B, A L M B, et al. A Ra n d o mize d, P hase II, Place b o - a n d Acti ve -C o ntr olle d 
D ose -Ra n gi n g St u d y of Se ma gl uti de F or Treat me nt of O besit y i n S u bjects W it h o ut 
Dia betes. Pres e nte d at E N D O 2 0 1 8 ( O R 1 2) C hica g o, U S A. 1 7 -2 0 Marc h, 2 0 1 8.  
1 2.   
N o v o N or dis k A/ S. I n v esti gat or's Br oc h ure, Se ma gl uti de s.c. 2. 4 m g, N N 9 5 3 6, (e diti o n 2). 
2 8 Mar 2 0 1 8.  
1 3.   
Vils b øll T, Bai n S C, Leit er L A, Li n g va y I, Matt he ws D, Si m ó R, et al. Se ma gl uti de, 
re d ucti o n i n gl ycate d hae m o gl o bi n a n d t he ris k of dia betic reti n o pat h y. Dia betes O bes 
Meta b. 2 0 1 8; 2 0( 4): 8 8 9 -9 7.  
1 4.   
T he Dia betes C o ntr ol a n d C o m plicati o ns Trial Researc h Gr o u p. Earl y w ors e ni n g of dia betic 
reti n o pat h y i n t he Dia bet es C o ntr ol a n d C o m plicati o ns Trial. Arc h O p ht hal m ol. 
1 9 9 8; 1 1 6( 7): 8 7 4 -8 6.  
1 5.   
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 di a 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.  
1 6.   
A merica n Di a betes Ass o ciati o n. 2. Classificati o n a n d Dia g n osis of Dia betes: Sta n dar ds of 
Me dical Care i n Di a betes -2 0 1 8. Dia betes Care. 2 0 1 8 ; 4 1( S u p pl 1): S 1 3-S 2 7.  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
5 3
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
5 4  of 1 0 0  
 
1 7.   
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 nc 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 8.   
Sa bati ne M S, Gi u glia n o R P, Keec h A C, H o nar p o ur N, Wi vi ott S D, M ur p h y S A, et al. 
E v ol oc u ma b a n d C li nical O utc o mes i n Patie nts wit h Car di o vasc ular Diseas e. N E n gl J Me d. 
2 0 1 7; 3 7 6( 1 8): 1 7 1 3 -2 2.  
1 9.   
J a mes W P, Caters o n I D, C o uti n h o W, Fi ner N, Va n Gaal L F, Ma g gi o ni A P, et al. Effect of 
si b utra mi ne o n car di o vas c ular o utc o mes i n o ver wei g ht a n d o bese s u bjects . N E n gl J Me d. 
2 0 1 0; 3 6 3( 1 0): 9 0 5 -1 7.  
2 0.   
Ker na n W N, Visc oli C M, F urie K L, Y o u n g L H, I nz ucc hi S E, G or ma n M, et al. Pi o glitaz o ne 
after Is c he mic Str o ke or Tra nsie nt Isc he mic Attac k. N E n gl J Me d. 2 0 1 6; 3 7 4( 1 4): 1 3 2 1 -3 1.  
2 1.   
Z ha o Y, Herri n g A H, Z h o u H, Ali M W, K oc h G G. A m ulti ple i m p utati o n met h o d f or 
se nsiti vit y a nal yses of ti me-t o-e ve nt d ata wit h p ossi bl y i nf or mati ve ce ns ori n g. J Bi o p har m 
Stat. 2 0 1 4; 2 4( 2): 2 2 9 -5 3.  
2 2.   
Little R, R u bi n D. Statistical a nal ysis wit h missi n g dat a. S o ns. J W, e dit or. Ne w Y or k.: J o h n 
Wi le y & S o ns. 1 9 8 7. 
2 3.   
W orl d Me dical Ass ociati o n. Declarati o n of Helsi n ki - Et hical Pri nci ples f or 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 neral Asse m bl y, 
F ortaleza, Brazil. 1 Oct 2 0 1 3.  
2 4.   
I nter nati o nal C o nfere nce o n Har m onisati o n. I C H Har m o nise d Tri patite G ui deli ne. G ui deli ne 
f or G o o d Cli nical Practis e E 6( R 2), Ste p 4. 0 9 N o v 2 0 1 6. 
2 5.   
C o m mittee f or Me dici nal Pr o d ucts f or H u ma n Use ( C H M P).  G ui deli ne o n cli nical 
e val uati o n of me dici nal pr o d ucts use d i n wei g ht ma na ge me nt.  E M A / C H M P/ 3 1 1 8 0 5/ 2 0 1 4. 
2 0 1 6.  
2 6.   
K o ves d y C P, F urt h S L, Z occali C. O besit y a n d ki d ne y disease: Hi d de n c o ns e q ue nces of t he 
e pi de mic. Afr J Pri m Healt h Care Fa m Me d. 2 0 1 7; 9( 1):e 1 -e 3.  
2 7.   
D' A gati V D, C ha g nac A, de Vries A P, Le vi M, P orri ni E, Her ma n -E delstei n M, et al. 
O besit y -relate d gl o mer ul o pat h y: cli nical a n d pat h ol o gic c haracteristics a n d pat h o ge nesis. 
Nat Re v Ne p hr ol. 2 0 1 6; 1 2( 8): 4 5 3 -7 1.  
2 8.   
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 . 
2 9.   
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.  
3 0.   
U. S. 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.  
3 1.   
T h e 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.  
3 2.   
C osta nte G, Meri n g ol o D, D ura nte C, Bia nc hi D, N ocera M, T u mi n o S, et al. Pre dicti ve 
val ue of ser u m calcit o ni n le vels f or pre o perati ve dia g n osis of me d ullar y t h yr oi d carci n o ma 
i n a c o h ort of 5 8 1 7 c o ns ec uti ve patie nts wit h t h yr oi d n o d ules. J Cli n E n d ocri n ol Meta b. 
2 0 0 7; 9 2( 2): 4 5 0 -5.  
3 3.   
Sc he u ba C, Kaserer K, M oritz A, Dr oste n R, Vier ha p per H, Bi e gl ma yer C, et al. S p ora dic 
h y percal cit o ni ne mia: cli nical a n d t hera pe u tic c o ns e q ue nces. E n d ocr Rel at Ca ncer. 
2 0 0 9; 1 6( 1): 2 4 3 -5 3.  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
5 4
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
5 5  of 1 0 0  
 
3 4.   
Ver ga U, Ferrer o S, Vice nti ni L, Bra m billa T, Cirell o V, M uzza M, et al. Hist o pat h ol o gical 
a n d m olec ular st u dies i n patie nts wit h g oiter a n d h y percal cit o ni ne mia: reacti ve or ne o plastic 
C -cell h yp er plasia? E n d ocr Relat Ca ncer. 2 0 0 7; 1 4( 2): 3 9 3 -4 0 3.  
3 5.   
Ma n n J F E, Ørste d D D, Br o w n -Fra n dse n K, Mars o S P, P o ulter N R, Ras m usse n S, et al. 
Lira gl uti de a n d Re nal O utc o mes i n T y pe 2 Dia bet es. N E n gl J Me d. 2 0 1 7; 3 7 7( 9): 8 3 9 -4 8.  
3 6.   
Nati o nal Ki d ne y F o u n d ati o n. " K / D O QI cli nical practice g ui deli nes f or c hr o nic ki d ne y 
disease 1". 2 0 0 2.  
3 7.   
K h waja A. K DI G O cli nical practice g ui deli nes f or ac ute ki d ne y i nj ur y. Ne p hr o n Cli n Pract. 
2 0 1 2; 1 2 0( 4):c 1 7 9 -8 4.  
3 8.   
K DI G O Cli nical Practice G ui deli ne f or t he Ma na ge me nt of Bl o o d Pres s ure i n C hr o nic 
Ki d ne y Disease. Ki d ne y I nt S u p pl 2 0 1 2. p. 3 3 7 -4 1 4.  
3 9.   
Nati o nal i nstit ute f or healt h a n d care e xcelle nce ( NI C E). C hr o nic ki d ne y disease i n a d ults: 
assess me nt a n d ma na ge me nt (cli nical g ui deli ne c g 1 8 2). J ul y 2 0 1 4, U p date d J a n uar y 2 0 1 5 
2 0 1 5.  
 
 
 
 
 
 
 
 
 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
5 5
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
5 6  of 1 0 0  
 
1 2  A p pe n dices  
 
A b bre vi ati o ns a n d Tr a de m a r ks  
A D A    
A merica n Dia betes 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  
C L A E    
cli nical la b orat or y a d verse e ve nt  
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 R  
cli nical trial re p ort  
C V  
car di o vasc ular  
C V O T    
car di o vasc ular o utc o me trial  
D F U  
directi o n f or use  
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  
F A S  
f ull a nal ysis set 
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 G  
fasti n g plas ma gl uc ose 
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    
gl uca g o n -li ke-pe pti de -1  
H b A 1c   
gl ycate d hae m o gl o bi n  
H R T  
h or m o ne re place me nt t hera p y  
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n 
I E C 
i n de pe n de nt et hics c o m 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 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
5 6
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
5 7  of 1 0 0  
 
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 S L V    
last s u bj ect last visit 
M A C E    
maj or a d verse car di o vasc ular e ve nt  
N Y H A    
Ne w Y or k Heart Ass ociati o n  
P A D  
peri p heral arterial disease  
P C D  
pri mar y c o m pleti o n date  
P G  
plas ma gl uc ose  
P P  
per pr ot oc ol  
P R O  
patie nt re p orte d o utc o me  
R A  
Rece pt or a g o nist  
R N A  
ri b o n ucleic aci d 
S A E  
seri o us a d verse e ve nt 
S A P  
statistical a nal ysis pla n 
s.c. 
s u bc uta ne o us 
S U  
s ulf o n yl urea 
S U S A R    
s us pecte d u ne x pecte d seri o us a d verse reacti o n 
T 2 D  
t y pe 2 dia betes  
T M M    
trial materials ma n ual 
U N L  
u p per  n or mal li mit  
V A S  
Vis ual a nal o ge scales  
W O C B P    
w o ma n of c hil d beari n g p ote ntial  
 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
5 7
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
5 8  of 1 0 0  
 
 
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. Lists of la b orat or y 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 descri be d i n la b orat or y fl o w c harts/ ma n ual, p r o vi de d t o all 
sites. 
•  Bl o o d a n d prefera bl y m or ni n g uri ne sa m ples nee d t o be o btai ne d. T he tests detaile d i n 
Ta ble  1 2 -1  a n d Ta ble  1 2 -2  will be perf or me d b y t h e 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 uire d b y l ocal 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 necti 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. Brazil: F or c o u ntr y s pecific re q uire me nts, please 
see A p pe n di x 9 . 
•  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 n o l a ter t ha n at e n d of trial or n o later t ha n at 
fi nalisati o n of t he cli nical trial re p ort.  
•  F or hae mat ol o g y s a m ples ( differe ntial c o u nt) w here t he test res ult is n ot n or mal, t he n a part 
of t he sa m ple ma y be k e pt f or u p t o t w o years or acc or di n g t o l ocal re g ul ati o ns.  
•  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 effic ac y 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 
Li pi ds ( n o n -fasti n g) 
•   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 yce ri des 
•   Ver y l o w de nsit y ( V L D L) c h olester ol  
•   Free fatt y aci ds ( F F A)  
Uri nal ysis  
•   Uri ne al b u mi n t o creati ni ne rati o ( U A C R)  
 
A c o nfir mat or y test is nee de d i n case of:  
•   o nset of macr oal b u mi n uria ( > 3 0 0 m g/ g)   
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 he d ule d c o ntact, 
b ut n o earlier t ha n 4 wee ks aft er U A C R has reac he d t he t hres h ol d, b y o btai ni n g a 
uri ne sa m ple f or t he ce ntral la b orat or y f or meas ure me nt of U A C R.  
C o nfir mati o n of o nset of macr oal b u mi n uria is n ot nee de d if t his has pre vi o usl y bee n 
c o nfir me d f or t he patie nt.   
Bi o mar kers  
•   Hi g h se nsiti vit y C -reacti ve pr otei n 
Bi o ba n k  
•   T he bl o o d sa m ples are c ollecte d f or t he p ur p ose of all o wi n g a d diti o nal 
a nal yses of C V or meta b olic bi o mar kers 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 meas ure me nt tec h ni q ues ma y ha ve 
bec o me a vaila ble. T he a nal yses ma y i ncl u de bi o mar kers c urr e ntl y 
k n o w n or disc o vere d i n t he f ut ure.  
•   T hese sa m ples nee d t o be fr oze n  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
5 8
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
5 9  of 1 0 0  
 
•   T he a nal yses are li kel y t o be perf or me d after t he trial has c o me t o a n 
e n d, a n d res ults will t heref ore n ot be part of t he cli nical trial re p ort.  
•   T he bi o ba n k sa m ples ma y be st ore d u p t o 1 5 years after e n d of trial at 
a ce ntral la b orat or y.  
 
T a ble  1 2 -2  
Pr ot oc ol -re q uire d s afet y l a b or at or y assess me nts 
L a b or at or y assess me nts  
P ar a meters  
Hae mat ol o g y  
•   Er yt hr oc ytes  
•   Hae mat ocrit  
•   Hae m o gl o bi n  
•   Le uc oc ytes  
•   T hr o m b oc ytes  
•   Differe ntial c o u nt (e osi n o p hils, ne utr o p hils, bas o p hils, m o n o c ytes a n d 
l y m p h oc ytes) 
Bi oc he mistr y 1 , 4 
•   Ala ni ne A mi n otra nsferase ( A L T) 2  
•   Al b u mi n  
•   Al b u mi n c orrecte d calci u m  
•   Al kali ne p h os p hatase  
•   As partate A mi n otra nsferase ( A S T)
2 
•   Bilir u bi n  
•   Calcit o ni n  
•   Calci u m  
•   Creati ni ne  
•   Ga m ma gl uta m yltra nsferase ( G G T)  
•   P otassi u m  
•   S o di u m  
•   Urea  
 
Pre g na nc y T esti 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) 3 
Ot her tests  
•   e G F R calc ulate d b y t he ce ntral la b orat or y base d o n t he creati ni ne val ue  
usi n g t he C K D -E PI e q uati o n  
       A c o nfir mat or y test is nee de d i n case of:  
•   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 he 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 a bl o o d 
sa m ple 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 b ot h 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 
a n d e G F R ( C K D -E PI) < 1 5 m L/ mi n/ 1. 7 3 m 2 is n ot nee de d if t his has pre vi o usl y bee n 
c o nfir me d f or t he patie nt.  
N otes:  
1Details of re q uire d acti o ns a n d f oll o w -u p assess me nts f or i ncrease d li ver para meters i ncl u di n g a n y disc o nti n uati o n 
criteria are gi ve n i n A p pe n di x 4  ( H y’s La w) a n d secti o n 8. 1 . 
2If A L T or A S T > 3 u p per n or mal li mit ( U N L), a d diti o nal bl o o d sa m ples s h o ul d be ta ke n fr o m t he s u bj ect t o a nal yse 
i nter nati o nal n or malise d rati o (I N R) (e xce pt at scree ni n g visit). Re peate d testi n g of t he a b n or mal la b assess me nts 
s h o ul d be perf or me d f or t he s u bj ect u ntil a b n or malities ret ur n t o n or mal or baseli n e state.  
3L ocal uri ne testi n g will be sta n dar d u nless ser u m testi n g is r e q uire d b y l ocal re g ulati o n or I R B/I E C.  U A C R: uri nar y 
al b u mi ne t o creati ni ne rati o . 
4F or c o u ntr y s pecific re q uire me nts, please see A p pe n di x 9 . 
 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
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V V- T M F- 5 0 5 7 8 4 9
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1
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5 9
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
6 0  of 1 0 0  
 
•  F or e v al uati o n of gl ycae mic stat us eit her met h o d (fasti n g pl as ma gl uc ose ( F P G), plas ma 
gl uc ose ( P G) or H b A 1c  reflecti n g c urre nt healt h stat us) liste d i n Ta ble  1 2 -3  ca n be use d i n 
a d diti o n t o a vaila ble s u bject i nf or mati o n, i ncl u di n g prescri be d gl u c ose -l o weri n g m e dicati o n.    
T a ble  1 2 -3  
Cl assific ati o n of gl y c ae mic st at us 1 6 
 
F P G  
 
2 h P G d uri n g or al gl uc ose 
t oler a nce test 
H b A 1c 
 
N or m o -gl yc ae mi a  
3. 9 -5. 5 m m ol/ L  
 
(7 0 -9 9 m g/ d L ) 
 
< 7, 8 m m ol/ L  
 
(< 1 4 0 m g/ d L ) 
 
< 3 9 m m ol/ m ol  
 
(<  5. 6 % )  
 
 
Pre di a betes  
 
5. 6 -6. 9 m m ol/ L  
 
(1 0 0 -1 2 5 m g/ d L ) 
 
7. 8 -1 1. 0 m m ol/ L  
 
(1 4 0 -1 9 9 m g/ d L ) 
 
3 9 -4 7 m m ol/ m ol  
 
(5. 7 -6. 4 % ) 
 
 
Di a betes  
≥ 7. 0 m m ol/ L  
 
(≥ 1 2 6 m g/ d L ) 
 
≥ 1 1. 1 m m ol/ L  
 
(≥ 2 0 0 m g/ d L)  
 
≥ 4 8  m m ol/ m ol  
 
( ≥ 6. 5 %) 
 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
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V V- T M F- 5 0 5 7 8 4 9
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1
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  Pr ot oc ol  Pr ot oc ol V 7
6 0
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
6 1  of 1 0 0  
 
 
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 2 3 a n d a p plica ble I C H G o o d Cli nic al Practice ( G C P) G ui deli ne 2 4 
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 m e nts (e. g. a d vertise me nts), m ust be s u b mitte d t o a n I R B/I E C a n d re vie we d 
a n d ap pr o ve d b y t he I R B/I E C bef ore t he 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 de t o t he trial desi g n, e xce 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 s u bj ects. 
•  Bef ore a trial site is all o we d t o start scree ni n g s u bjects, writte n n otificati o n fr o m N o v o 
N or dis k m ust be recei ve 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 ue ntl y i n acc or da nce 
wit h t he re q uire me nts, p olicies, a n d pr oce d ures esta blis he d b y t he I R B/I E C 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 uire 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 nce t o re q uire me nts of I C H 
g ui deli nes, t he I R B/I E C, a n d al l ot her a p plica ble l ocal re 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  
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 ueste 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 vesti 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 o ne 
year after c o m pleti o n of t he trial.  
F or U S trial sites: verificati o n u n der discl os ures p er C o de of Fe deral Re g ul ati o ns ( C F R) of 
Fi na ncial C o nflict of I nterest.  
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 ure of t he trial t o t he s u bject 
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 s u bject 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.  
•  S u bjects m ust be i nf or me d t hat t heir partici pati o n is v ol u ntar y.  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
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6 1
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
6 2  of 1 0 0  
 
•  S u bjects 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 nes 2 4, Declarati o n of Helsi n ki2 3 a n d t he 
I R B/I E C or trial site. 
•  T he me dical rec 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 relate d acti vit y a n d t he date w he n t he writte n c o nse nt was 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 see 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 t he tas k of i nf or mi n g t o a me dicall y q ualifie d pers o n, i n 
acc or da nce wit h l ocal re q uire me nts.  
•  S u bject s (or t heir le gal a ut h orise d re prese ntati ve ( L A R)) m ust be re-c o nse 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 partici 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 s u bject or t he s u bject’s 
L A R.  
4) I nf or m ati o n t o s u bjects 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 s u bject d uri n g t h e c o n d uct of t he trial. 
T he pac k a ge c o nt e 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 ntai 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 s u bjects. 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 uire m e nts a n d distri b ute d t o t he s u bject at t he discreti o n of t he i n vesti gat or. T he 
s u bject ma y recei ve a “ welc 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. Differe nt i nitiati ves f or s u bject rete nti o n will be i m ple me nte d 
t hr o u g h o ut t his trial. Mat erials a n d ite ms will be s u p plie d if l ocall y acce pta ble. T he ret e nti o n ite ms 
will be rele va nt f or t he s u bjects’ partici pati o n i n t he trial a n d/or t heir healt h y lifest yle ma na ge me nt  
a n d will n ot e xcee d l ocal fair mar k et val ue.  
All writte n i nf or mati o n t o s u bjects 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  
•  S u bjects will be assi g ne d a 6 -di git u ni q ue i de ntifier, a s u bject n u m ber. A n y s u bject rec or ds 
or datasets t hat are tra nsferre d t o N o v o N or dis k will c o ntai n t he i de ntifier o nl y; s u bject 
na mes or a n y i nf or mati o n w hic h w o ul d ma ke t he s u bject i de ntifia ble will n ot be tra nsferre d.  
•  T he s u bject a n d a n y  bi ol o gical material o btai ne d fr o m t he s u bject will be i de ntifie d b y 
s u bject 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 s u bjects as re q uire d 
b y l ocal, re gi o nal a n d n ati o nal re q uire me nts.  
•  T he s u bject 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 ure of t he data m ust als o 
be e x plai ne d t o t he s u bject.  
•  T he s u bject m ust be i nf or me d t hat his/ her me dical rec or ds ma y be e xa mi ne d b y a u dit ors or 
ot her a ut h orise d pers o n nel 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.  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
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6 2
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
6 3  of 1 0 0  
 
6) C o m mittee str uct ure  
N o v o N or dis k  s afet 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 bli s 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 va 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 s u bjects 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 dati 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 mati o 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 use d b y t he D M C are 
s pecifie d i n t he D M C c harter. 
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 selecte d A Es a n d deat hs (s ee Ta ble  9 -1 ). T he E A C will e v al 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 he 
e val uati o n is base d o n re vie w of pre -defi ne 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 veri n g all re q uire d me dical s pecialities. E A C 
me m bers m ust discl ose a n y p ote ntial 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 orisati o ns t o i m pact o n trial c o n d uct, trial pr ot oc ol or 
a me n d me nts.  
T he p ur p o se of t he 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 dise d criteria usi n g i n de pe n de nt e xter nal m e dical e x perts.  
 
I n t his trial, car di o vasc ul ar e ve nts will be a dj u dicate d i n or der t o a de q uatel y c haracterize t he 
car di o vas c ul ar effects , si nce car di o vasc ul ar diseas e is a n i m p orta nt a n d seri o us c o m or bi dit y of 
o besit y 2 5. Ne p hr o pat h y is i ncreasi n gl y rec o g nise d t o be relate d t o o besit y a n d o ver wei g ht
2 6, 2 7. 
E ve nts of c hr o nic re nal re place m e nt t hera p y a n d re nal deat h will be c o nfir me d b y a dj u dicati o n a n d 
i ncl u de d i n t he Ne p hr o pat h y en d p oi nt. I n a d diti o n, e ve nts of ac ute pa ncreatitis will be c o nfir me d b y 
a dj u dicat i o n as treat me nt wit h G L P -1 R A has b ee n ass ociate d wit h ac ute pa ncreatitis.  
 
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 ders hi p f or t h e 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 nsist 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 nate d N o v o N or dis k e m pl o yees. T he pa nel will disc uss 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
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V V- T M F- 5 0 5 7 8 4 9
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1
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 of
  Pr ot oc ol  Pr ot oc ol V 7
6 3
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
6 4  of 1 0 0  
 
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 perate 
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 me 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 C V o utc o mes trials fr o m a fe w selecte d c o u ntries, a n d desi g nate 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 recr uit me nt, rete nti o n a n d 
a d here n ce iss ues relate d t o trial c o n d uct. T he pa nel will o perate u n der a c harter a gree d wit h N o v o 
N or dis k.  
N ati o n al st u d y 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 here it is a p pr o priate, a nati o nal st u d y c o or di nat or 
( N S C) will be selecte d. T he nati o nal st u d y c o or di nat ors will pr o vi de o perati o nal i n p ut t o s u bject 
recr uit me nt, rete 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 dere 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 well 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 nec ti o n wit h t his 
trial s hall re mai n t he s ole pr o pert y of N o 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 us e d e xce pt i n t he perf or ma nce of t his trial.  
T he i nf or mati 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 ojects st u d yi n g t he sa m e 
disease a n d/ or tri al pr o d uct st u die d i n t his trial.  
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.  
T he c o -c hairs of t he st eeri 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 n at or y i n vesti gat ors) o n be half of all partici p ati n g i n vesti 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 uscri 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 prese 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 he release of data 
u ntil s pecifie d milest o nes are reac he d, f or e xa m ple w he n t he cli nical trial re p ort is a vaila ble. At t he 
e n d of t he trial, o ne or m ore scie ntific p u blicati o ns ma y be pre pare d c olla b orati vel y b y t h e 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
6 4
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
6 5  of 1 0 0  
 
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 reserves 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 otect 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 l i mitati o ns. I n t he e ve 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 cri 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 a cc or da nce wit h t he 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 b y t he I nt er nati o nal 
C o m mittee of Me dical J o ur nal E dit ors 2 8. 
All a ut h ors will be pr o vi de d wit h t he rele va nt statistical ta bles, fi g ures, a n d re p orts nee de d t o 
e val uate t he pla n n e d p u blicati o n.  
W here re q uire 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 material, as s pecifie d b y t h e j o ur nal.  
Site -s pecific p u blic ati o n(s) b y i n vesti g at or(s) 
F or a m ultice ntre cli nical trial, a nal yses ba s e d o n si n gle-site data 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 
s u bjects, 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 de n y a 
re q uest or as k f or defer me 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 refer e nce t h e pri mar y ma n uscri 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 has t he discreti o n t o deter 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 ve t heir o w n res earc h s u bjects' 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 vaila 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 uire me nts s uc h as t h ose of t he I nter nati o nal 
C o m mittee of Me dical J o ur nal E dit ors (I C MJ E) 2 9, t he F o o d a n d Dr u g A d mi nistrati o n A me n d me nt 
Act ( F D A A A) 3 0, E ur o pea n C o m missi o n Re q uire me nts1, 3 1 a n d ot her rele va nt rec o m me n dati o ns or 
re g ulati o ns. If a s u bject re 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 he i n vesti gat or’s c o ntact details t o t he s u bject. As a 
res ult of i ncreasi n g re q uire me nts f or tra ns pare nc y, s o me c o u ntries re q uire p u blic discl os ure of 
i n vesti gat or na mes a n d t heir affiliati o ns. 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
6 5
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
6 6  of 1 0 0  
 
T he Pri mar y C o m pleti 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 last s u bject last visit (L S L V ). T he trial will t herefore 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 LS L V, w hic h is first  s u bject ra n d o mise d pl us 5 9 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 me nt 
Act.  
9) D at a q u alit y ass u r 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 data 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 s u bject data rel ati 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 nee (e. g. l a b orat or y data, P R O q uesti o n naires a n d s u bject 
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 C R F a n d f or e ns uri n g t hat all rel e va nt q uesti o ns are 
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 has 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 plica 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 be  use d w he n access t o t he C R F is re v o ke d or t he 
C R F is te m p oraril y u n a v aila 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 s u bject 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:  
Pre g n a nc y f or ms  
Ot her C R Fs  
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 de 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 after t he visit. O nce data has b ee n e ntere d, it will be a vaila ble t o N o v o N or dis k f or 
d ata 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 pecti 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 xa mi ne, a nal ys e, verif y 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
6 6
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
6 7  of 1 0 0  
 
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 rec or d d oes n ot ha ve 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 s u bjects are bei n g pr otecte d, t o m o nit or dr u g 
acc o u nta bilit y a n d c ollect c o m plete d pa per C R F  pa ges, if a p plica ble, a n d t h at t he trial is 
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 ntralise 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 s u bject’s me dical rec 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 he i n vesti gat or m ust 
i nf or m t he m o nit or 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 de e vi de nce f or t h e e xiste nce of t he s u bject 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 oc u me nts are file d at t he tri al site.  
•  Data re p orte d i n t he C R F t hat are tra 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 m e nts or t he 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 u est 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 s u bject’s me dical hist or y i n s o urce d oc u me nts s uc h as s u bject’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 di cal 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 hat c o nstit utes s o urce data ca n be f o u n d i n a s o urce d oc u me nt a gree me nt at 
eac h trial site. T here will o nl y be o ne s o urce d oc u me nt defi ne d at a n y ti m e f or a n y dat a 
ele me nt.  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
6 7
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
6 8  of 1 0 0  
 
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 ne 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 uct 
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 part y wit h o ut writte n n otificati o n t o N o v o 
N or dis k.  
•  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 s u bject d ata 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 b ef 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 s u bject data (i n 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 peri 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. 
•  S u bject’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 he 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 su bjects 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 als o 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 plet i 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 al site b y N o v o N or dis k or i n vesti gat or ma y i ncl u de 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 oc ol, t he re q uire 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 s u bjects b y t he 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 nat i 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 uate 
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 nt ai n a l o g of a p pr o priatel y q ualifie d pers 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 de 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 vestigat 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 he s u bjects.  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
6 8
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
6 9  of 1 0 0  
 
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 medical decisi o ns.  
T he i n vesti gat or is res 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 he data 
pr o d uce d) i n t he i n vesti gat or trial master fi le. T he d oc u me nts, i ncl u di n g t he s u bject 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 destr ucti o n, l oss or deteri orati o n of data. T he i n vesti gat or will pre 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 a ti o n or ot her wise de m o nstrate t o N o v o N or 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 
s u bjects t o a s pecific q u alifie d p h ysicia n w h o will be rea dil y a vaila ble t o s u bjects d uri n g t h at 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 ha ve 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 a n 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 ve nt of ne gli ge nce 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 site or i n vesti gat or are res p o nsi ble.   
F or a n y c o u ntr y s pecific i n de m nit y re q uire me nts s u p ple me nti n g t he a b o ve, please refer t o  A p pe n di x 
9 . 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
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V V- T M F- 5 0 5 7 8 4 9
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-
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1
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6 9
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
7 0  of 1 0 0  
 
 
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  
A E defi niti o n  
•  
A n A E is a n y u nt o war d me dical occ urre nce i n a cli nical trial s u bj ect t hat is te m p orall y ass ociate d wit h t he 
use of a me dici nal pr o d uct, 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 be a n y u nfa v o ura ble a n d u ni nte n de d si g n, i ncl u di n g  a n a b n or mal la b orat or y fi n di n g, s y m pt o m or 
disease ( ne w or e xacer 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 dical a n d scie ntifi c j u d g me nt of t he i n vesti gat or.  
•  
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 ncrease 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.  
•  
A "lac k of efficac y" or "fail ur e of e x pecte d p har mac ol o gical acti o n" per se will n ot be re p orte d as a n A E or 
S A E. S uc h i nsta nces will be ca pt ure d i n t he efficac y assess me nts. H o we ver, t he si g ns, s y m pt o ms a n d/ or 
cli nical se q uelae res ulti n g fr o m lac k of efficac y will be re p orte d as A E or S A E if t he y f ulfil t he defi niti o n.  
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 u p u ntil ti me of ra n d o misati o n.  
 
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.  
 
•  
Me dical or s ur gical pr oce d ures is n ot a n A E, t he ca use of t he pr oce d ure is t he A E. A n e xc e pti o n is c or o nar y 
arter y re vasc ularisati o n pr oce d ures w hic h m ust be re p orte d as a se parate A E i n a d diti o n t o t he ca use of t he 
pr oce d ure See Fi g ure  9 -1  
. 
 
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 de at h  
•   Is life-t hre ate 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 s u bj ect 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 p atie nt h os pit alis ati o n or pr ol o n g ati o n of e xisti n g h os pit alis ati o n 
•   H os pitalisati o n si g nifies t hat t he s u bj ect 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 of fic 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 pitalisati o n” 
occ urre d or was neces sar y, t he A E s h o ul d be c o nsi dere d seri o us.  
•   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 relate 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 be 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 dis a bilit y/i nc a p acit 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 nce s uc h as 
u nc o m plicate d hea dac he, na usea, 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.  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
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V V- T M F- 5 0 5 7 8 4 9
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1
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 of
  Pr ot oc ol  Pr ot oc ol V 7
7 0
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
7 1  of 1 0 0  
 
•   Is a c o n ge nit al a n o m al y/ birt h defect 
•   I m p ort a nt me dic al 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 o par dise t he s u bj ect 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 r e 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 alter 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) or e ve nts f or a dj u dic ati o n are 
f o u n d i n T a ble  9 -1 . 
 
A E a n d S A E rec or 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 E wit h a d diti o nal data c ollecti o n, e ve nts f or 
a dj u dicati o n a n d A Es i n c o n ne cti o n wit h pre g na ncies, m ust b e 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 si g ns, s y m pt o 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 r e vie w all d oc u me nt ati o n (e. g. 
h os pital pr o gress 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.  
•   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 per 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 verit 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 s u bj ect, ca usi n g mi ni mal disc o mf ort a n d n ot i nterferi n g wit h 
e ver y da y acti vities.  
•   M o der ate : A n e ve nt t hat ca uses 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 of 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 v esti 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. 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
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V V- T M F- 5 0 5 7 8 4 9
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1
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 of
  Pr ot oc ol  Pr ot oc ol V 7
7 1
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
7 2  of 1 0 0  
 
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 pr o vi des c a us alit y f or e ver y A E als o f or t he 
i niti al S A E re p orti n g. 
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 s u bj ect 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 s u bj ect 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 s u bj ect 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 s u bj ect 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 s u bj ect has rec o vere 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 be 
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 s u bj ect 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 s u bj ect 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 s u bj ect 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 be 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 s u bj ect 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 usalit 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 be 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 trial data base will be l oc ke d a n 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 
su bj ect 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 (see 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 n t 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-mail or c o urier.  
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 desi g nate d re p orti n g ti me fra mes ( as ill ustr ate d i n Fi g ure  9 -1 ): 
•   A E f or m wit hi n 2 4 h o urs.  
•   S afet 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 s h o ul d be si g ne d wit hi n 7 cale n dar da ys fr o m t he i n vesti gat or’s k n o wle d ge of t he e ve nt.  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
7 2
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
7 3  of 1 0 0  
 
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.  
Re p orti n g of tri al pr o d uct -rel ate d S U S A Rs b y  N o v o N or dis k:  
N o v o N or dis k will n otif y t he i n vesti gat or of trial pr o d uct -rel ate d s us pect e d u ne x pecte d seri o us 
a d verse reacti o ns ( S U S A Rs) i n acc or da nce wit h l ocal re q uire me nts a n d I C H G C P 2 4. I n a d diti o n, t he 
i n vesti gat or will be i nf or me d of a n y trial -relate d S A Es t hat ma y warra nt a c ha n ge i n a n y trial 
pr oce d ure.  
I n acc or da n ce wit h re g ul at or y re q uire me nts, N o v o N or dis k will i nf or m t he re g ulat or y a ut h orities, 
i ncl u di n g E M A, of tri al pr o d uct-rel ate d S U S A Rs. I n a d diti o n, N o v o N or dis k will i nf or m t he 
I R Bs/I E Cs of trial pr o d u ct-relat e d S U S A Rs i n acc or da nce wit h l ocal re q uire me nt a n d I C H G C P
2 4, 
u nless l ocall y t his is a n o bli gati o n of t he i n vesti gat or.  
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 nal 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 d uri n g 
re g ulat or y re p orti n g, e ve n t h o u g h t he cases f ulfil t he defi niti o n of 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, no n -fatal str o ke. T he D M C 
(A p pe n di x 3 ) recei v es u n bli n de d data a n d ma kes 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 de q uate m o nit ori n g of safet y w hile mai ntai ni n g S A E 
re p orts rel ate d to 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 veale d, all e xe m pte d cases w hic h meet t he criteria 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 ha ve 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 uct t o t he rele va nt re g ulat or y 
a ut h orities o n a n e x pe dite d basis.  
 
 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
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V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
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 of
  Pr ot oc ol  Pr ot oc ol V 7
7 3
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
7 4  of 1 0 0  
 
 
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 male s u bjects 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 he a n d u ntil bec o mi n g p ost me n o pa usal u nless 
per m a 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 narc heal  
2.  Pre me n o pa usal fe 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 s u bject’s me dical rec or ds, 
me dical e xa mi nati o n or me dical hist or y i nter vie w.  
3.  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 hera p y ( H R T). H o we ver, i n t he a bse nce of 1 2 
m o nt hs of a me n or r 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 ntrace 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 s u bjects  
N o c o ntrace pti o n meas ures are re q uire d f or male s u bjects as t he ris k of terat o ge nicit y/fet ot o xicit y 
ca use d b y tra nsfer of se m a gl uti de i n se mi nal fl ui d is u nli kel y.  
Fe male s u bjects  
Fe male s u bjects of c hil d beari 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 be d i n ta ble(s) bel o w:  
 
T a ble  1 2 -4  
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  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
7 4
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
7 5  of 1 0 0  
 
•   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  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  
Vasect o mise d part n er  
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 b   
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 s u bj ect.   
N otes:  
aFail ure rates ma y differ fr o m 1 % per year, if n ot 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 3 5  da ys after t he last d ose of trial pr o d uct.  
I n certai 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. di a 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 m ales  
wit h:  
1.  k n o w n i nt olera nce t o t he hi g hl y effecti ve m et h o ds me nti o ne d i n Ta ble  1 2 -4  or w here t he use of  
a n y of t he liste d hi g hl y effecti ve c o ntrace pti ve meas ures are c o ntrai n dicate d i n t he i n di vi d ual  
s u bject, a n d/ or 
2.  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 hs t he be nefit 
f or t he fe m ale 
J ustificati o n f or acce pti n g d o u ble barrier met h o d s h o ul d be at t he discreti o n of t he i n vesti gat or  
ta ki n g i nt o c o nsi derati o n his/ hers k n o wle d ge a b o ut t he fe male’s o besit y hist or y, c o nc o mita nt  
ill ness, c o nc o mita nt me dicati o n a n d o bser ve d A Es. T he j ustificati o n m ust be state d i n t he me dical 
rec or ds.  
Al geria, A ust ria, Bel gi u m, Ger ma n y, S pai n, S we de n, U nite d Ki n g d o m: F or c o u ntr y s pecific 
re q uire me nts, please see A p pe n di x 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 ma n dat or y if re q uire d b y l ocal 
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 ne gati ve hi g hl y se nsiti ve uri ne p re g na nc y test. 
•  H o me uri ne pre g na nc y t esti n g ma y be perf or me 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 uire d l ocall y.    
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
7 5
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
7 6  of 1 0 0  
 
•  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.  
•  W O C B P nee ds t he last uri ne pre g na nc y test at t he e n d of trial visit ( P -F U). If t he e n d of trial 
visit is a p h o ne c o ntact, t he s u bjects ca n t a ke t he uri ne test at h o me a n d i nf or m t he 
i n vesti gat or of t h e res ult. 
A ustria, Bel gi u m, Czec h Re p u bl ic, De n mar k, Fi nla n d, Fra nce, Ger ma n y, Greece, H u n gar y, Irela n d,  
Ital y, Lat via, T he Net herl a n ds, N or wa y, P ola n d, P ort u gal, R o ma nia, S pai n, S we de n 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 9 . 
C ollecti o n of pre g n a nc y i nf or m ati o n  
Fe m ale s u bjects 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 s u bj ect, 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 s u bj ect's pre g na nc y.  
•  S u bject will be f oll o we d t o deter mi ne t he o utc o me of t he pre g na nc y. T he i n vesti gat or will 
c ollect f oll o w-u p i nf or m ati o n o n s u bject a n d ne o nate, 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 oetal stat us ( pre se 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 nc y c o m plicati o n 
or electi ve ter mi nati o n of a pre g na nc 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.  
•  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 nal f or m f or male 
part ners of fe male s u bj ects re q uire si g ni n g of s pecific i nf or me d c o ns e nt.  
•  A n y S A E o cc urri n g as a res ult of a p ost -trial pre 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 s u bjects, he or s h e ma y lear n of a n S A E t hr o u g h s p o nta ne o us 
re p orti n g.  
A n y fe male s u bject w h o bec o mes pre g na nt w hile partici pati n g i n t he tri al will disc o nti n ue trial 
pr o d uct.  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
7 6
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
7 7  of 1 0 0  
 
 
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 ncer 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 tria l pr o d ucts (e. g. disc ol orati o n, 
particles or c o nt a mi nati o n).  
•  Pr o ble ms wit h pac ka gi n g material i ncl u di n g l a belli n g.  
•  Pr o ble ms relate d t o me di cal de vices (e. g.  t o t he i njecti o n mec ha nis m, d ose setti n g 
mec ha nis m, p us h b utt o n or i nterface bet wee n t he pe n -i nject or a n d t he nee dle). 
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 be 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 be 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 be 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 ni cal c o m plai nts wit hi n 5 cale n dar 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 s u bj ect relate d, t he i nf or mati o n m ust be 
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, wi t 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 parts m ust be 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 tec 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 nical c o m pl ai nt sa m ple m ust be 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.  
 
Re p orti n g of tec h nic al c o m pl ai nts f or N o v o N or dis k pr o d ucts n ot i ncl u de d i n tec h nic al c o m pl ai nt f or m  
T ec h nical c o m plai nts o n N o v o N or dis k pr o d ucts n ot i ncl u de d i n t he tec h nical c o m plai nt f or m s h o ul d be re p orte d t o 
l ocal N o v o N or dis k affiliate wit h a refere nce t o trial I D. 
 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
7 7
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
7 8  of 1 0 0  
 
 
Rete nti o n of h u m a n bi os a m ples a n d ge netics  
I n c o u ntries w here 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 sa m ples will be st ore d:  
•  W h ole bl o o d (f or ge netic a nal ysis)  
•  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 nd 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 ha n 1 5 years fr o m e n d of trial after w hic h t he y will be destr o ye d.  
 
S u bject s ma y wit h dra w fr o m t he bi o ba n k c o m p o n e nt of t he trial at a n y ti m e, i n de pe n de nt of 
partici pati o n i n t he trial. T he s u bject ca n c h o 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 s u bject wit h dra ws fr o m t he 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 heir 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 p r 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 .  
 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
7 8
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
7 9  of 1 0 0  
 
 
M o nit ori n g of c alcit o ni n  
B ac k gr o u n d  
Treat me nt wit h G L P -1 R As has bee n s h o w n t o b e ass ociate d wit h t h yr oi d C -cell c ha n ges i n r o de nts 
b ut n ot i n n o n -h u ma n pri mates. T he h u ma n rele va nce of t his fi n di n g is u n k n o w n. H o we ver, base d 
o n t he fi n di n gs i n r o de nts, m o nit ori n g of ser u m cal cit o ni n (a se nsiti ve bi o mar ker f or C -cell 
acti vati o n) is c urre ntl y b ei n g p erf or me d i n cli nical trials wit h se ma gl uti de.  
W hile t here is ge n eral a gree me nt o n t he cli ni cal i nter pretati o n of s u bsta ntiall y ele vate d calcit o ni n 
le vels ( > 1 0 0 n g/ L) as li kel y i n dicati ve of C-cell ne o plasia, t he i nter pretati o n of val ues bet wee n 
u p per n or mal ra n ge ( 5. 0 a n d 8. 4 n g/ L f or w o me n a n d me n, res p ecti vel y) a n d 1 0 0 n g/ L is less clear 
wit h  re gar ds t o i n dicati o n of disease. 
T here are s e veral k n o w n c o nf o u n di n g fact ors affecti n g calcit o ni n le vels, e. g.:  
•  re nal d ysf u ncti o n 
•  t o bacc o use 
•  a ut oi m m u ne t h yr oi ditis  
•  se veral dr u g classes (e. g. pr ot o n p u m p i n hi bit ors, beta-bl oc kers, H 2-bl oc kers a n d 
gl uc oc ortic oi ds)  
P h ysi ol o g y of C -cell acti vati o n i n vari o us cli nical c o n diti o ns a n d i n differe nt patie nt p o p ulati o ns 
(i.e. wit h vari o us c o m or bi dities) is p o orl y u n derst o o d. T here ma y be vari o us cli nical c o n diti o ns n ot 
i de ntifie d s o far w hi c h mil dl y or m o deratel y affect calcit o ni n secreti o n b y C-cells.  
C alcit o ni n m o nit ori n g  
A bl o o d sa m ple will be dra w n at pre -s pecifie d trial visits f or meas ure me nt of calcit o ni n. 
I n case a s u bject has a calcit o ni n val ue ≥ 1 0 n g/ L, t he al g orit h m o utli ne d i n Fi g ure  1 2 -1  a n d 
descri be d b el o w s h o ul d be f oll o we d. T he al g orit h m a p plies f or all cal cit o ni n val ues i n t he trial.  
 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
7 9
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
8 0  of 1 0 0  
 
Fi g ure  1 2 -1     
Fl o w of c alcit o ni n m o nit ori n g  
C alcit o ni n ≥ 1 0 0 n g/ L   
Acti o n : T he s ubject  m ust i m me diatel y be referre d t o a t h yr oi d s pecialist f or f urt her e val uati o n a n d 
t he trial pr o d uct m ust be disc o nti n ue d (see secti o n 8. 1 ). T he s u bject s h o ul d re mai n i n t he trial; 
h o we ver, all me dicati o ns s us pecte d t o relate t o t his c o n diti o n m ust be disc o nti n ue d u ntil dia g n osis 
has bee n est a blis he d.  
B ac k gr o u n d : T hese val ues were f o u n d i n 9 ( 0. 1 5 %) of a p o p ul ati o n of 5 8 1 7 s u bjects wit h t h yr oi d 
n o d ular disease 3 2. All of t hese s u bjects were dia g n ose d wit h M T C, res ulti n g i n a p ositi ve pre dicti ve 
val ue of 1 0 0 %.  
Dia g n ostic e val uati o n s h o ul d i ncl u de:  
•  t h yr oi d ultras o u n d e x a mi nati o n 
•  fi ne nee dle as pirati o n of a n y n o d ul es > 1 c m  
•  p ote ntiall y, s ur ger y wit h nec k dissecti o n  
I n case a s u bject is dia g n ose d wit h M T C, it is c o m m o n cli nical practice t o e x pl ore t he fa mil y 
hist or y of M T C or M E N 2 a n d perf or m a ge netic test f or R E T pr ot o -o nc o ge ne m utati o n.  
C alcit o ni n ≥ 5 0 a n d < 1 0 0 n g/ L  
Acti o n : T he s u bject s h o ul d be referre d t o a t h yr oi d s pecialist f or f urt h er e val uati o n. T he s u bject 
s h o ul d re mai n i n t he trial a n d ca n c o nti n ue o n trial pr o d uct. Retest of calcit o ni n s h o ul d be d o ne at 
t he ne xt visit.  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
8 0
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
8 1  of 1 0 0  
 
B ac k gr o u n d : T hese val ues were f o u n d i n 8 ( 0. 1 4 %) of t he p o p ulati o n of 58 1 7 s u bjects wit h t h yr oi d 
n o d ular disease 3 2. T w o of t hese s u bjects w ere dia g n ose d wit h M T C a n d t w o were dia g n os e d wit h C 
cell h y p er plasia, res ulti n g i n a p ositi ve pre dicti ve val ue of a C -cell a n o mal y of 5 0 %.  
Dia g n ostic e val uati o n s h o ul d i ncl u de:  
•  t h yr oi d ultras o u n d e x a mi nati o n  
•  if a vaila ble, a n d if t here are n o c o ntrai n dicati o ns, a pe nta gastri n sti m ulati o n test s h o ul d be 
d o ne. F or s u bjects wit h p ositi ve pe nta gastri n sti m ulati o n test, s ur ger y s h o ul d be c o nsi dere d.  
•  if pe nta gastri n sti m ulati o n test is n ot a vaila ble, t h yr oi d ultras o u n d a n d fi ne nee dle as pirati o n 
bi o ps y ma y a d d i m p or ta nt cli nical i nf or mati o n a b o ut t he nee d f or s ur ger y. 
C alcit o ni n ≥ 1 0 a n d < 5 0 n g/ L  
Acti o n : T he s u bject ca n c o nti n ue i n t he trial o n trial pr o d uct. C o nti n ue sa m pli n g of calcit o ni n 
acc or di n g t o t he pr ot oc ol.  
If t he s u bject is a scree n fail ure, or if t he value is fr o m t he last sa m ple ta ke n i n t he trial, t he s u bject 
s h o ul d be referre d t o a t h yr oi d s pecialist f or f urt h er e val uati o n.  
B ac k gr o u n d : Calcit o ni n val ues fr o m 2 0– 5 0 n g/ L were f o u n d i n u p t o 1 % of s u bjects of t he 
p o p ulati o n of 5 8 1 7 s u bjects wit h t h yr oi d n o d ular disease 3 2. T he pre dicti ve val ue of a C-cell 
a n o mal y f or t his calcit o ni n le vel was 8. 3 %. H o we ver, t he li keli h o o d of ha vi n g a me d ullar y 
carci n o ma > 1 c m wit h calcit o ni n i n t his ra n ge is e xtre mel y l o w.  
F or calcit o ni n val ues bet wee n 1 0 -2 0 n g/ L C osta nt e et al. 3 2 i de ntifie d 2 1 6 ( 3. 7 %) s u bjects. O ne 
s u bject o ut of t he 2 1 6 ha d a s u bse q ue nt basal ( u nsti m ulate d) calcit o ni n val ue of 3 3 n g/ L, a n d ha d C -
cell h y p er plasia at s ur ger y. T w o ot h er st u dies use d a c ut -off of calcit o ni n > 1 0 n g/ L t o scree n f or C -
cell disease, b ut t he y d o n ot pr o vi de s ufficie nt i nf or mati o n o n s u bjects wit h basal C T > 1 0 a n d < 2 0 
n g/ L t o all o w c o n cl usi o ns 3 3, 3 4. 
 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
8 1
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
8 3  of 1 0 0  
 
1 4.  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(s) or relate d pr o d ucts  
1 5.  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  
1 6.  Recei pt of a n y i n vesti gati o nal me dici nal pr o d uct wit hi n 3 0 da ys bef ore s cree ni n g  
1 7.  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 na 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  
1 8.  A n y dis or d er, u n willi n g n ess or i n a bilit y, 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 
t he s u bject’s safet y or c o m plia nce wit h t he pr ot oc ol 
1 9.  O ver wei g ht or o besit y i n d uce d b y a n e n d ocri n ol o gic dis or der (e. g. C us hi n g s y n dr o me) as per 
i n vesti gat or’s j u d ge me nt 
 
A ustri a, Bel gi u m, Czec h  Re p u blic, De n m ar k, Fi nl a n d , Ger m a n y, Greece, H u n g ar y, Irel a n d,  
It al y, L at vi a, T he Net herl a n ds, N or w a y, P ol a n d, P ort u g al, R o m a ni a, S p ai n, S we de n a n d U nite d 
Ki n g d o m : 
 
•  G ui d a nce o n st a n d ar d of c are f or p atie nts wit h c hr o nic ki d ne y dise ase  ( C K D):  
I n v esti gat ors ha ve t h e cli nical res p o nsi bilit y f or t h e trial partici pa nts. Si nce patie nts wit h 
c hr o nic ki d ne y disease (e x ce pt t h ose wit h e n d -sta ge re nal disease) ma y be i ncl u de d i n t he 
trial, g ui da nce f or t he sta n dar d of care f or t hese patie nts is descri be d bel o w:  
N o  safet y c o n cer n has bee n i de ntifie d re gar di n g ne p hr o pat h y w he n treati n g patie nts wit h 
se ma gl uti de or ot her G L P-1 rece pt or a g o nists. O n t he c o ntrar y, i n t he L E A D E R a n d 
S U S T AI N 6 tri als, car di o vasc ular o utc o mes trial wit h patie nts wit h t y pe 2 dia betes at hi g h 
ris k f or car di o vasc ular disease, t he G L P-1 rece pt or a g o nists res ulte d i n a l o wer ris k of a 
c o m p osite re nal o utc o me t ha n place b o .4, 3 5 T o st u d y t his effect, a c o m p osite ne p hr o pat h y 
e n d p oi nt has bee n i ncl u d e d i n S E L E C T.  
Defi niti o n a n d ev al u ati o n of C K D 3 6  
I n i nter nati o nal ki d ne y g ui deli nes, C K D  is defi ne d as a b n or malities of ki d ne y str uct ure or 
f u ncti o n, prese nt f or > 3 m o nt hs, wit h i m plicati o ns o n healt h. C K D is classifie d base d o n 
ca use, prese nce or a bse n ce of s yste mic disease, G F R cate g or y, a n d al b u mi n uria cate g or y 
( C G A) (Fi g ure  1 2 -2 ).  
M o nit ori n g ki d ney f u ncti o n
3 6  
It is rec o m me n de d t o ass ess gl o mer ular filtrati o n rate (G F R ) a n d al b u mi n uria at least 
a n n uall y i n p atie nts w it h C K D. Assess G F R a n d al b u mi n uria m ore ofte n f or i n di vi d uals at 
hi g her ris k of pr o gressi o n, a n d/ or w here meas ure me nt will i m pact t hera pe utic decisi o ns. I n 
Fi g ure  1 2 -2  a g ui de t o t h e fre q ue nc y of m o nit ori n g is o utli ne d. It mi g ht be nee de d t o 
m o nit or m ore fre q u e ntl y t ha n state d i n t he pr ot oc ol.  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
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V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
8 3
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
8 4  of 1 0 0  
 
 
Fi g ure  1 2 -2  G R F a n d al b u mi n uri a gri d t o reflect t he ris k of pr o gressi o n b y i nte nsit y of 
c ol ori n g ( gree n, yell o w, or a n ge, re d, dee p re d). T he n u m bers i n t he b o xes are a 
g ui de t o t he fre q ue nc y of m o nit ori n g ( n u m ber of ti mes per ye ar) 3 6.  
C K D a n d risk of ac ute ki d ney i nj ury ( A KI)3 6  
Patie nts wit h C K D are at i ncreas e d ris k of A KI. T he K DI G O A KI G ui deli ne 3 7 s h o ul d be 
f oll o we d f or ma na ge ment of t h ose at ris k of A KI d uri n g i nterc urre nt ill ness, or w he n 
u n der g oi n g i n vesti gati o n a n d pr oce d ures t hat are li kel y t o i ncreas e t he ris k of A KI. Si nce 
gastr oi ntesti nal a d verse e ve nts s uc h as na usea, v o miti n g a n d diarr hea wit h ris k of 
de h y drati o n are as s oci ate d wit h t he use of se ma gl uti de, it is rec o m me n de d t o re mi n d all 
patie nts, es peciall y t h ose wit h C K D, t hat re h y drati o n i n case a n y of t hese a d verse e ve nts is 
i m p orta nt.  
Referr al t o s peci alist 3 6  
It is rec o m me n de d t o refer t o s pecialist ki d ne y care ser vices f or pe o ple wit h C K D i n case of 
A KI or a br u pt s ustai ne d fall i n G F R, a G F R ≤3 0 ml/ mi n/ 1. 7 3 m 2 ( G F R cate g or ies G 4-G 5), 
a c o nsiste nt fi n di n g of si g nifica nt al b u mi n uria ( al b u mi n-t o-creati ni ne -rati o  ≥3 0 0 m g/ g [ ≥3 0 
m g/ m m ol] or  al b u mi n-e xcreti o n-rate ≥3 0 0 m g/ or h y perte nsi o n refract or y t o treat me nt wit h 
4 or m ore a nti h y perte nsi ve a ge nts.  
Tre at me nt of C K D : 
T hera p e utics 3 7, 3 8 
E ns ure o pti mal treat me nt of t he ca us e of C K D. A v oi d ne p hr ot o xic dr u gs. Bl o o d press ure 
c o ntr ol s h o ul d be e ns ure d i n acc or da nce wit h t he S E L E C T sta n dar d of care g ui d a nce. 
A n gi ote nsi n -c o n vertin g -e nz y me ( A C E) i n hi bit ors or a n gi ote nsi n-rece pt or bl oc kers ( A R Bs) 
are first li ne t hera p y u nless t he y are n ot t olerate d. F or patie nts wit h uri ne al b u mi n e xcreti o n 
of 3 0 t o 3 0 0 m g per 2 4 h o urs, ai m at t he l o wer tar get of < 1 3 0/ 8 0 m m H g. I n case of patie nts 
de vel o pi n g di a betes, g o o d gl yce mic  c o ntr ol is rec o m me n de d acc or di n g t o S E L E C T sta n dar d 
of care g ui da nce. A d diti o nal t hera pies ma y be c o nsi dere d i n s o me patie nts at t he 
i n vesti gat or´s discreti o n a n d i n acc or da nce wit h l ocal g ui deli nes a n d p olices.  
Diet 3 9  
It is rec o m me n de d t o offer dietar y a d vice a b o ut p otassi u m, p h os p hate, cal orie a n d salt i nta ke 
a p pr o priate t o t he C K D sta ge. A d diti o nall y, it is rec o m me n de d t o offer g ui d a nce o n li mite d 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
8 4
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
8 5  of 1 0 0  
 
c o ns u m pti o n of salt, re d meat, sat urate d or tra ns fats, s weets, a n d s u gar -s weete ne d 
be vera ges a n d t o restrict cal orie i nta ke i n p atie nts w h o will be nefit fr o m wei g ht l oss ( 5 0 0 
kcal/ da y deficit).   
 
F or a d diti o nal c o u ntr y s p ecific re q uire me nts, please refer t o bel o w.  
Al geri a:  
•  F or w o me n w h o e x pressl y declare free of t he ris k of pre g na 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 ha vi n g se x ual acti vit y wit h n o birt h p ote ntial ris k, use of c o ntrace pti ve 
met h o d will n ot be ma n dat or y.  
•  N o s u bjects fr o m Al geria 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 n etic testi n g will be perf or me d as n ot e d i n secti o n 9. 7  a n d 9. 8 . 
•  Secti o n  8. 1 : Se nte nce rel ate d t o disc o nti n uati o n/ wit h dra wal 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 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 ve nti o n or treat me nt of C O VI D-1 9 disease or 
p o sti nfecti o us c o n diti o ns is all o we d at t he i n vesti gat or’s discreti o n wit h o ut disc o nti n ui n g 
trial treat me nt.‘ is n ot a p plica ble.  
Ar ge nti n a : 
•  I n refere n ce t o Pr ot oc ol s ecti 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 p ati 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 di cal 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 best 
a vaila ble treat me nt o pti o n f or t he s u bject, trial d o ct 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 he 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 bject f or t he ti me t he Et hics 
C o m mittee deci des or u ntil access is e ns ure d b y a n y ot her m ea ns a n d i n ac c or da nce 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 ve b ee n e x perie nce d si nce last visi t 
•  I n refere n ce t o Pr ot oc ol E xcl usi o n criteria 1 7 : T he c o ntrace pti ve met h o ds will be rei m b urse d 
b y t he s p o ns or.  
 
A ustr ali a : 
•  C o m pl y wit h Me dici nes A ustralia G ui deli nes f or C o m pe nsati o n f or I nj ur y Res ulti n g fr o m 
Partici pati o n i n a C o m pa n y S p o ns ore d Cli nical T rial, versi o n 1 6 0 1 0 4 1 6 J a n uar y 2 0 0 4. 
A ustri a : 
•  A m o nt hl y pre g n a nc 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.  
•  I n d e m nit y state m e 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. 4 0/ 2 0 1 7  
 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
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V V- T M F- 5 0 5 7 8 4 9
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1
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  Pr ot oc ol  Pr ot oc ol V 7
8 5
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
8 6  of 1 0 0  
 
Bel gi u m:  
•  N o v o N or dis k acce pts lia bilit y i n acc or da nce wit h:   
I n d e m nit y state m e nt: La w c o ncer 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 ve n if wit h o ut fa ult, t he s p o ns or is lia ble f or t he da m a 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 direct or a n i n direct 
c o n necti o n wit h t he trial.  
C o ntrace pti o n: Hi g hl y effecti ve met h o ds of birt h c o ntr ol are defi ne d as t h ose, al o ne or i n 
c o m bi nati o n, t hat res ult i n a l o w fail ure rate (i.e., l ess t ha n 1 % per year) w he n use d c o n siste 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 U Ds, 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 vasect o mise d pa rt ner. 
 
Br azil : 
•  Res ol uti o n ( Res. C N S 4 6 6/ 1 2): At t he e n d of t he trial, all partici pa nt s u bjects s h o ul d be 
ass ure d t he access t o t he best pr o ve d pr o p h ylactic, dia g n ostic a n d t h era pe utic met h o ds 
i de ntifie d d uri n g t h e st u d y. 
•  E xcl usi o n criteri o n # 1 6 : Partici pati o n i n ot her trials wit hi n o ne year pri or t o 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 dis creti o n. 
•  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 tri al, a n d n o 
ge n etic testi n g will be perf or me d as n ot e d i n secti o n 9. 7  a n d 9. 8 . 
•  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.  
C ol u m bi a:  
•  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 n etic testi n g will be perf or me d as n ot e d i n secti o n 9. 7  a n d 9. 8 . 
 
Czec h Re p u blic:  
•  C o ntrace pti ve meas ures c o nsi dere d a de q uat e i ncl u de hi g hl y effecti ve c o ntrace pti ve m et h o ds 
as liste d i n  Ta ble  1 2 -4 ‘ Hi g hl y effecti ve c o ntrace pti ve met h o ds’ i n A p pe n di x 5 . T his mea ns 
t hat t he use of d o u ble barrier met h o ds is n ot a p plica ble f or t he Czec h Re p u blic 
Fi nl a n d:  
•  C o ntrace pti ve meas ures c o nsi dere d a de q uat e i ncl u de hi g hl y effecti ve c o ntrace pti ve m et h o ds 
as liste d i n Ta ble  1 2 -4 ‘ Hi g hl y effecti ve c o ntrace pti ve met h o ds’ i n A p pe n di x 5 . T his mea ns 
t hat t he use of d o u ble barrier met h o ds is n ot a p plica ble f or Fi nla n d. 
N o s u bjects fr o m Fi nla n d 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 n etictesti n g wi ll be perf or me d as n ote d i n secti o n 9. 7  a n d 9. 8 . 
 
Fr a nce : 
•  N o v o N or dis k acce pts lia bilit y i n acc or da nce wit h:  
     I n d e m nit y state m e nt: “ T he Fre nc h P u blic Healt h C o de article 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 nal Officiel of 1 1 A u g ust 2 0 0 4. 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 ue nces of t he bi o me dical researc 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 xce 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 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
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V V- T M F- 5 0 5 7 8 4 9
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1
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 of
  Pr ot oc ol  Pr ot oc ol V 7
8 6
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
8 7  of 1 0 0  
 
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 nte d t o c o o perati n g 
i n t he researc h.” 
Ger m a n y:  
•  C o ntrace pti ve meas ures c o nsi dere d a de q uat e i ncl u de hi g hl y effecti ve c o ntrace pti ve m et h o ds 
as liste d i n Ta ble  1 2 -4 ‘ Hi g hl y effecti ve c o ntrace pti ve met h o ds’ i n A p pe n di x 5 . T his mea ns 
t hat t he use of d o u ble barrier met h o ds is n ot a p plica ble f or Ger ma n y 
•  Secti o n  8. 1 : Se nte nce rel ate d t o disc o nti n uati o n/ wit h dra wal 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 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 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’s discreti o n wit h o ut disc o nti n ui n g 
trial treat me nt.‘ is n ot a p plica ble.  
 
Irel a n d: 
•  C o ntrace pti ve meas ures c o nsi dere d a de q uat e i ncl u de hi g hl y effecti ve c o ntrace 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): Rec o m me n dati o ns relate d 
t o c o ntrace pti o n a n d pre g na nc y testi n g i n cli nical trials.  
T his mea ns t hat t he f oll o wi n g c o ntrace pti ve met h o ds are n ot a p plica b le f or Irela n d: 
•  Pr o gest o ge n -o nl y oral h or m o nal c o ntrace pti o n, w here i n hi biti o n of o v ulati o n is n ot 
t he pri mar y m o de of acti o n 
•  Male or fe m ale c o n d o m wit h or wit h o ut s per mici de 5 ca p  
•  Dia p hra g m or s p o n ge wit h s per mici de 5  
•  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 3 5 da ys after 
t he last d ose of trial pr o d uct. Eli mi nati o n half-life f or se ma gl uti de is a p pr o xim atel y 1 wee k 
(F or details please refer t o t he c urre nt versi o n of t he I B 1 2 or a n y u p dates here of. ) a n d a was h 
o ut of 5 half -lifes w hile usi n g c o ntrace pti o n is c o nsi dere d s ufficie nt. 
Isr ael: 
•  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 he trial, a n d n o 
ge n etic testi n g will be perf or me d as n ot e d i n secti o n 9. 7  a n d 9. 8 . 
J a p a n : 
•  Acc or di n g t o J a pa nese G C P, st ora ge a n d dr u g acc o u nta bilit y of t he t rial pr o d ucts at t he 
st u d y site is n ot i n c har ge of I n vesti gat or, b ut i n c har ge of t he hea d of st u d y site.  
•  T he hea d of st u d y site s h o ul d assi g n s o me or all of t he res p o nsi bilities f or acc o u nta bilit y of 
t he trial pr o d ucts at t he sites t o a trial pr o d uct stora ge m a na ger (a p har macist i n pri nci ple). 
T he trial pr o d uct st ora ge ma na ger s h o ul d c o ntr ol a n d ta ke acc o u nta bilit y of t he trial 
pr o d ucts i n acc or da nce wit h pr oce d ures s p ecifie d b y t he s p o ns or. T he hea d of t he st u d y site 
or t he trial pr o d uct st ora ge ma na ge r (if assi g ne d b y t he hea d of t he st u d y site) m ust e ns ure 
t he a vaila bilit y of pr o per st ora ge c o n diti o ns of trial pr o d ucts, rec or d a n d e val uate t he 
te m perat ure. 
•  A seal is acce pte d as si g n at ure.  
•  A E re p orti n g re q uire me nts f or J a p a n : F or Ja 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 ra n d o misati o n a n d u ntil t he f oll o w-u p visit/e n d of trial 
visit, at t he ti me p oi nts s pecifie d i n t he fl o wc hart.  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
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V V- T M F- 5 0 5 7 8 4 9
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1
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 of
  Pr ot oc ol  Pr ot oc ol V 7
8 7
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
8 8  of 1 0 0  
 
Me xic o : 
•  S h o ul d t he s u bject his/ her fa mil y m e m bers pare nts or le gal re prese ntati ve deci d e 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 
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 nse q ue nces 
of t he s u bject´s partici pati o n i n t he researc h occ urre d.  
•  I n t he cas e of Me xic o, 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 he 
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:  
a) I n vesti gati o n f oll o w -u p  
b) Da ma ges t o h ealt h arisi n g fr o m t he i n v esti 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 va nce d s us pe nsi o n of treat me nt d ue t o n o n -attrib uta ble 
reas o ns t o t he S u bject;  
c) Ti mel y c o m plia nce of t he ter ms i n w hic h t he a ut h orizati o n of a researc h f or healt h 
i n h u ma n bei n gs ha d b ee n iss ue d;  
d) T o prese nt i n a ti mel y ma n ner t he i nf or m ati o n re q uire d b y t he Healt h A ut h orit y.  
•  N o v o N or dis k acce pts  lia bilit y i n acc or da nce wit h: 
I n d e m nit y state m e nt: 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 trials i n a n y c o u ntr y, i ncl u di n g t h ose 
a p plica ble pr o visi o ns o n t he Me xica n U n ite 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 he first 
i nsta nce. If d uri n g t h eir partici pati o n i n t he trial t he s u bject e x perie nces a disease or i nj ur y 
t hat, acc or di n g t o t he trial d oct or a n d t he s p o ns or, is directl y ca use d b y t he trial me dicati o n 
a n d/ or a trial pr oce 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 v e 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 he a p pr o priat e me dical treat me nt as re q uire 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 l a 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 by 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 pati o n i n t he trial b y his o w n will or b y a decisi o n 
fr o m t he i n vesti gat or. 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 be e ntitle d t o b y l a 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. 
N or w a y:  
•  C o ntrace pti ve meas ures c o nsi dere d a de q uat e i ncl u de hi g hl y effecti ve c o ntrace 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): Rec o m me n dati o ns relate d 
t o c o ntrace pti o n a n d pre g na nc y testi n g i n cli nical trials. T his mea ns use of d o u ble barrier 
met h o ds is n ot a p plica ble f or N or wa y.  
P ol a n d:  
•  C o ntrace pti ve meas ures c o nsi dere d a de q uat e i ncl u de hi g hl y effecti ve c o ntrace 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): Rec o m me n dati o ns relate d 
t o c o ntrace pti o n a n d pre g na nc y testi n g i n cli nical trials. T his mea ns use of d o u ble barrier 
met h o ds is n ot a p plica ble f or P ola n d.  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
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V V- T M F- 5 0 5 7 8 4 9
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-
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1
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 of
  Pr ot oc ol  Pr ot oc ol V 7
8 8
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
8 9  of 1 0 0  
 
R ussi a:  
•  N o v o N or dis k acce pts lia bilit y i n acc or da nce wit h:  
•  I n d e m nit y state m e nt: N o v o N or dis k acce pts lia bilit y i n acc or da nce wit h: Fe deral  la w of 1 2 
A pril 2 0 1 0 N o. 6 1 -F Z ‘ O n Me dici nal Dr u gs’ Circ ulati o n a n d Mi nistr y of Healt hcare of 
R ussia n Fe derati o n’ or der of 0 1 A pril 2 0 1 6 N o. 2 0 0 n “ A p pr o val of r ules of g o o d cli nical 
practice.  
•  S u bjects de vel o pi n g T 2 D will be pr o vi de d wit h a bl o o d gl uc ose m et er i ncl u di n g a ncillaries 
a n d i nstr ucti o n f or use.  
S o ut h Afric a:  
•  N o s u bjects fr o m S o ut h Africa 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 n etic 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 . 
 
S p ai n:  
•  C o ntrace pti ve meas ures c o nsi dere d a de q uat e i ncl u de hi g hl y effecti ve c o ntrace 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): Rec o m me n dati o ns relate d 
t o c ontrace pti o n a n d pre g na nc y testi n g i n cli nical trials. T his mea ns use of d o u ble barrier 
met h o ds is n ot a p plica ble f or S pai n.  
S we de n:  
•  C o ntrace pti ve meas ures c o nsi dere d a de q uat e i ncl u de hi g hl y effecti ve c o ntrace 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): Rec o m me n dati o ns relate d 
t o c o ntrace pti o n a n d pre g na nc y testi n g i n cli nical trials. T his mea ns use of d o u ble barrier 
met h o ds is n ot a p plica ble f or S we de n  
 
T ur ke y : 
•  I n case a s u bject nee ds t o c ha 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 m e nt, t his me dicati o n will be rei m b urse d b y N o v o N or dis k.  
•  N o s u bjects fr o m T ur ke y 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 n etic testi n g will be perf or me d as n ot e d i n secti o n 9. 7  a n d 9. 8 . 
 
U nite d Ki n g d o m:  
C o ntrace pti ve meas ures c o nsi dere d a de q uat e i ncl u de hi g hl y effecti ve c o ntrace pti ve m et h o ds as 
liste d i n Ta ble  1 2 -4  ‘ Hi g hl y effecti ve c o ntrace pti ve met h o ds’ i n A p pe n di x 5 . T his mea ns t hat t he 
use of d o u ble barrier met h o ds is n ot a p plica ble f or U K.  
 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
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V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
8 9
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
9 0  of 1 0 0  
 
 
 Pr ot oc ol a me n d me nt hist or y  
T he pr ot oc ol a me n d m e nt s u m mar y of c ha n ges ta ble f or t he c urre nt u p d ate d pr ot oc ol is  
l ocate d directl y b ef ore t he Ta ble of C o nte nts. 
 
Pr ot oc ol a me n d me nt n o. 8, i ncl u di n g a me n d me nt 6 a n d 7 ( 0 4-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 criteria 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. 
T his a me n d me nt a d dress es c ha n ges t o all o w f or si m ulta ne o us partici pati o n i n t he S E L E C T t rial a n d 
C O VI D -1 9 trials a n d e x pa nsi o n of t he A E c ollecti o n t o i ncl u de t he re p orti n g of n o n -seri 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 c h a n ges t o t he statistical c o nsi derati o ns rel ate d t o t he testi n g 
strate g y f or t he c o nfir mat or y s ec o n dar y e n dp oi nts, i m ple me ntati o n of h o me healt h care ser vice t o 
miti gate c halle n ges e. g. d ue t o t he C O VI D -1 9 pa n de mic a n d t he c ha n ge of t he was h -o ut peri o d a n d 
f oll o w-u p peri o d fr o m 7 t o 5 wee ks.  
T he a me n d me nt als o i ncl u des mi n or u p dates a n d a d mi nistrati ve c ha n ges, pl ease see ta ble bel o w.  
Secti o n # a n d n a me  
Descri pti o n of c h a n ge  
R ati o n ale  
C ha n ges fr o m pr ot oc ol V 3 t o V 6  
T hr o u g h o ut t he pr ot oc ol  
Was h -o ut peri o d a n d c o nse q ue ntl y 
f oll o w-u p peri o d a n d peri o d f or 
c o ntrace pti o n use after treat me nt 
disc o nti n uati o n, has bee n u p d ate d t o 
5 wee ks.  
S E L E C T c o ntai ns n o a nti b o d y 
sa m pli n g a n d t he f oll o w-u p peri o d 
ca n be re d uce d t o t he sta n dar d 5 
ti mes t he half-life of se ma gl uti de 
( 5 wee ks).  
Secti o n 4. 2. 2. 2 S u p p orti ve sec o n dar y 
e n d p oi nts a n d 4. 2. 2. 3 E x pl orat or y 
e n d p oi nts  
W R S S M delete d fr o m s u p p orti ve 
sec o n dar y e n d p oi nts a n d i ncl u de d i n 
e x pl orat or y e n d p oi nts.   
I n t he ps yc h o metric e val uati o n of 
W R S S M it beca me c lear t hat t he 
meas ure is n ot se nsiti ve t o wei g ht 
l oss.  
Secti o n 7. 5. 1 S hi p me nt of trial 
pr o d uct t o s u bj ect’s h o me  
T e xt re vise d  
T o si m plif y t he re q uire me nts f or t he 
na mi n g of t he s pecific d oc u me nt 
descri bi n g t he pr ocess f or s hi p pi n g 
trial pr o d uct directl y fr o m t he site t o 
t he s u bj ect’s h o me.   
Secti o n 7. 8 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 di cati 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 be 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 di ci nal 
D ue t o t he c urre nt C O VI D -1 9 
pa n de mic a n d t o pr otect t he rete nti o n 
of s u bj ects i n t he  S E L E C T trial, c o -
partici pati o n i n C O VI D -1 9 tri als is 
all o we d. Patie nt safet y is ke y a n d it 
has bee n e val uate d t hat t he 
i n di vi d ual patie nt safet y is n ot 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
9 0
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
9 1  of 1 0 0  
 
 
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.   
c o m pr o mise d b y all o wi n g f or c o -
partici pati o n.  
Secti o n 9 Trial assess me nts a n d 
pr oce d ures  
I m ple me ntatio 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 
w here o n -site visits are n ot feasi ble 
f or t he s u bj ect or f or t he site, e. g. d ue 
t o C O VI D-1 9.  
Secti o n 9. 2 A d verse e ve nts, S ecti o n 
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 
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 tar gete d data 
c ollecti o n a p pr oac h of t his trial (all 
C O VI D -1 9 A Es s h o ul d be c ollecte d 
b ot h pr os pecti vel y a n d 
retr os pecti vel y). T his will all o w f or 
se nsiti vit y a nal yses related t o 
C O VI D -1 9 i nfecti o n.  
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. T his will 
all o w f or se nsiti vit y a nal yses relate d 
t o C O VI D-1 9 i nfecti o n.  
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. 2 S u p p orti ve 
sec o n dar y e n d p oi nts 
I ncl u de d ’a n d hs C R P’ 
hs C R P is better descri be d b y a l o g -
n or mal distri b uti o n t ha n a n or mal 
distri b uti o n  
1 0. 3. 3 E x pl orat or y e n d p oi nts    
W R S S M will be prese nte d 
descri pti vel y.  
Si nce W R S S M is n ot se nsiti ve t o 
wei g ht l oss we j u d ge t hat data ca n be 
e val uate d b y d escri pti ve statistics  
A p pe n di x 4  
C ha n ge fr o m ‘ m ust’ t o ‘s h o ul d’ i n 
t he se nte nce: “ B ot h f or ms s h o ul d be 
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”.  
T o clarif y t he criticalit y of t he ti mi n g 
of i n vesti gat or si g nat ures o n t he  
f or ms. 
A p pe n di x 9  
 
U p date of c o u ntr y s pecific 
re q uire me nts f or: A ustria, Bel gi u m, 
Czec h Re p u blic, De n mar k, Fi nla n d, 
Ger ma n y, Greece, H u n gar y, Irela n d, 
Ital y, Lat via, T he Net herla n ds, 
N or wa y, P ola n d, P ort u gal, R o ma nia, 
S pai n, S we de n a n d U nite d Ki n g d o m 
i n re gar d t o sta n dar d of care f or 
patie nts wit h c hr o nic ki d ne y disease.  
I n a gree me nt wit h fee d bac k fr o m 
Bf Ar M o n 1 7 Oct o ber 2 0 1 9.  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
9 1
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
9 2  of 1 0 0  
 
 
A p pe n di x 9  
T e xt re gar di n g c o ntrace pti o n r e vise d 
f or Irela n d 
T o reflect t he c ha n ge of t he f oll o w -
u p peri o d fr o m 7 t o 5 wee ks a n d  t o 
refer t o t he c urre nt I B. 
A d diti o nal c ha n ges fr o m pr ot oc ol V 5 t o V 6  
T hr o u g h o ut t he d oc u me nt  
Refere nces t o t he I Bs f or Oral 
se ma gl uti de ( R y bels us ®) a n d 
Oze m pic ® re m o ve d.  
T he I B f or wei g ht ma na ge me nt ha ve 
s u bsta ntial safet y a n d efficac y data 
i n t he target p o p ulati o n a n d i ncl u des 
rele va nt data fr o m ot her 
pr o gra m mes, t heref ore I Bs f or ot her 
i n dicati o ns are n o l o n ger necessar y.   
Refere nce t o s pecific S A P versi o n 
re m o ve d. 
T o e ns ure t hat t he c orrect versi o n of 
t he d oc u me nt is al wa ys referre d t o. 
Refere nce t o s pecific D M C c harter 
versi o n re m o ve d.  
T o e ns ure t hat t he c orrect versi o n of 
t he d oc u me nt is al wa ys referre d t o. 
C o u ntr y s pecific re q uire me nts f or 
V H P c o u ntries a n d Net herla n ds 
m o ve d t o A p pe n di x 9 a n d li n ks 
i ncl u de d i n rele va nt secti o ns. 
T o m a ke t he pr ot oc ol a p plica ble f or 
all c o u ntries.  
A d diti o n of c o u ntr y s pecific 
re q uire me nt f or n o n-V H P c o u ntries, 
see A p pe n di x 9. 
T o ma ke t he pr ot oc ol a p plica ble f or 
all c o u ntries.  
 
Pr ot oc ol  a me n d me nt n o. 4  (0 7 M arc h  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 criteria 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 verall rati o nale f or a me n d me nt n o. 4 :   
 
T his a me n d me nt a d dress es i ncl usi o n of i nteri m testi n g f or s u peri orit y as well as a d mi nistrati ve 
c ha n ges . 
 
Secti o n # a n d n a me  
Descri pti o n of c h a n ge  
R ati o n ale  
Sec 5. 1 O verall desi g n  
 
I nteri m i ncl u de d 
Rece nt data f or se ma gl uti de a n d 
ot her G L P 1 -R As s u g gest a p ote ntial 
f or greater effect size i n S E L E C T 
t ha n ori gi nall y ass u me d a n d t o 
acc o m m o date s uc h sce nari os it has 
bee n deci de d t o i ncl u de i nteri m 
testi n g f or s u peri orit y. 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
9 2
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
9 3  of 1 0 0  
 
 
Sec 1 0. 1 Sa m ple size  
U p date d ue t o i ncl usi o n  of i nt eri m 
i ncl u de d 
Rece nt data f or se ma gl uti de a n d 
ot her G L P 1 -R As s u g gest a p ote ntial 
f or greater effect size i n S E L E C T 
t ha n ori gi nall y ass u me d a n d t o 
acc o m m o date s uc h sce nari os it has 
bee n deci de d t o i ncl u de i nteri m 
testi n g f or s u peri orit y. 
Ori gi nall y t he S E L E C T trial was 
desi g ne d as a gr o u p se q ue ntial 
desi g n wit h o ne i nteri m testi n g after 
t w o t hir ds of t he t otal 1, 2 2 5 pri mar y 
e n d p oi nt e ve nts. T his was c ha n ge d t o 
a fi xe d desi g n wit h o ut i nteri m 
testi n g, b ut wit h o ut c ha n gi n g t he 
sa m ple size. T h us, t he sa mple size is 
n ot c ha n ge d b y re -i ntr o d uci n g t he 
i nteri m testi n g i n t he S E L E C T trial. 
Sec 1 0. 3 Statistical a nal ysis    
I nteri m i ncl u de d 
Rece nt data f or se ma gl uti de a n d 
ot her G L P 1 -R As s u g gest a p ote ntial 
f or greater effect size i n S E L E C T 
t ha n ori gi nall y ass u me d a n d t o 
acc o m m o date s uc h sce nari os it has 
bee n deci de d t o i ncl u de i nteri m 
testi n g f or s u peri orit y. 
Sec 1 0. 3. 1 Pri mar y e n d p oi nt    
I nteri m i ncl u de d 
Rece nt data f or se ma gl uti de a n d 
ot her G L P 1 -R As s u g gest a p ote ntial 
f or greater effect size i n S E L E C T 
t ha n ori ginall y ass u me d a n d t o 
acc o m m o date s uc h sce nari os it has 
bee n deci de d t o i ncl u de i nteri m 
testi n g f or s u peri orit y. 
Sec 1 0. 3. 2. 1 C o nfir mat or y 
sec o n dar y e n d p oi nts 
I nteri m i ncl u de d 
Rece nt data f or se ma gl uti de a n d 
ot her G L P 1 -R As s u g gest a p ote ntial 
f or greater effect size i n S E L E C T 
t ha n ori gi nall y ass u me d a n d t o 
acc o m m o date s uc h sce nari os it has 
bee n deci de d t o i ncl u de i nteri m 
testi n g f or s u peri orit y. 
Sec 1 0. 3. 4 I nteri m testi n g f or 
efficac y 
I nteri m i ncl u de d 
Rece nt data f or se ma gl uti de a n d 
ot her G L P 1 -R As s u g gest a p ote ntial 
f or greater effect size i n S E L E C T 
t ha n ori gi nall y ass u me d a n d t o 
acc o m m o date s uc h sce nari os it has 
bee n deci de d t o i ncl u de i nteri m 
testi n g f or s u peri orit y. 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
9 3
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
9 4  of 1 0 0  
 
 
Sec 1 0. 3. 5 Se q ue ntial safet y a nal ysis 
a n d safet y m o nit ori n g  
I nteri m i ncl u de d 
Rece nt dat a f or se ma gl uti de a n d 
ot her G L P 1 -R As s u g gest a p ote ntial 
f or greater effect size i n S E L E C T 
t ha n ori gi nall y ass u me d a n d t o 
acc o m m o date s uc h sce nari os it has 
bee n deci de d t o i ncl u de i nteri m 
testi n g f or s u peri orit y. 
A p pe n di x 3  
I nteri m i ncl u de d 
Rece nt data f or se ma gl uti de a n d 
ot her G L P 1 -R As s u g gest a p ote ntial 
f or greater effect size i n S E L E C T 
t ha n ori gi nall y ass u me d a n d t o 
acc o m m o date s uc h sce nari os it has 
bee n deci de d t o i ncl u de i nteri m 
testi n g f or s u peri orit y. 
Sec 9. 2 A d verse e ve nts  
Tra nsie nt isc he mic at tac k i ncl u de d 
as a n e ve nt f or a dj u dicati o n  
E ve nt descri pti o n f or str o ke u p date d 
t o als o i ncl u de re p orti n g of tra nsie nt 
isc he mic attac k ( TI A) e ve nts t hat 
will be se nt f or a dj u dicati o n. T he 
p ur p ose of se n di n g p ote ntial e ve nts 
of TI A f or a dj u dicati o n is t o e ns ure 
t hat all p ote ntial str o ke e ve nts are 
ca pt ure d  
Sec 9. 2 A d verse e ve nts  
A dj u dicati o n o utc o me u p date d fr o m 
Ne p hr o pat h y t o C hr o nic re nal 
re place me nt t hera p y  
It was n ot dee me d t o be necessar y t o 
ha ve e x pert a dj u dicat ors e val uate 
ne p hr o pat h y e ve nts t hat are base d 
s olel y o n la b orat or y fi n di n gs a n d t hat 
ca n be deri ve d i n t he statistical 
a nal yses usi n g ce ntral la b orat or y 
data.  
Wit h t his c ha n ge t he 3 c o m p o ne nts 
of t he 5 -c o m p o ne nt ne p hr o pat h y 
c o m p osite will n o l o n ger be 
c o nfir me d b y a dj u dicati o n  
F urt her m ore, c ha n ges are ma d e t o 
clarif y t he re q uire me nts f or 
c o nfir mat or y la b orat or y testi n g of 
t hese c ha n ges i n re nal f u ncti o n. 
9. 2. 1. 1 E ve nts f or A dj u dicati o n    
Re m o val of la b orat or y tri g gere d 
e ve nts as t hese will n ot be use d f or 
i de ntificati o n of p ote ntial 
ne p hr o pat h y  
 
 
 
It was n ot dee me d t o be necessar y t o 
ha ve e x pert a dj u dicat ors e val uate 
ne p hr o pat h y e ve nts t hat are base d 
s olel y o n la b orat or y fi n di n gs a n d t hat 
ca n be deri ve d i n t he statistical 
a nal yses usi n g ce ntral la b orat or y 
data.  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
9 4
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
9 5  of 1 0 0  
 
 
 
Wit h t his c ha n ge t he 3 c o m p o ne nts 
of t he 5 -c o m p o ne nt ne p hr o pat h y 
c o m p osite will n o l o n ger be 
c o nfir me d b y a dj u dicati o n  
F urt her m ore, c ha n ges are ma d e t o 
clarif y t he re q uire me nts f or 
c o nfir mat or y la b orat or y testi n g of 
t hese c ha n ges i n re nal f u ncti o n. 
A p pe n di x 3 Trial g o ver na nce  
c o nsi derati o ns  
E ve nt a dj u dicati o n c o m mittee  
U p date d o nl y t o i ncl u de re nal 
re place me nt t hera p y a n d re nal deat h 
It was n ot dee me d t o be necessar y t o 
ha ve e x pert a dj u dicat ors e val uate 
ne p hr o pat h y e ve nts t hat are base d 
s olel y o n la b orat or y fi n di n gs a n d t hat 
ca n be deri ve d i n t he statistical 
a nal yses usi n g ce ntral la b orat or y 
data.  
Wit h t his c ha n ge t he 3 c o m p o ne nts 
of t he 5 -c o m p o ne nt ne p hr o pat h y 
c o m p osite will n o l o n ger be 
c o nfir me d b y a dj u dicati o n  
F urt her m ore, c ha n ges are ma d e t o 
clarif y t he re q uire me nts f or 
co nfir mat or y la b orat or y testi n g of 
t hese c ha n ges i n re nal f u ncti o n. 
A p pe n di x 2 Cli nical la b orat or y 
testi n g 
T a ble 1 2 -1  
Re m o val of ≥ 2 0 m g/ g i ncrease fr o m 
baseli ne i n t he defi niti o n of 
macr oal b u mi n uria a n d t o clarif y 
w he n c o nfir mait o n test is nee d e d.  
T o si m plif y t he pr oce d ure f or 
c o nfir mat or y testi n g t he re q uir e me nt 
f or ≥ 2 0 m g/ g i ncrease fr o m baseli ne 
was re m o ve d. F urt her m ore, t he te xt 
has bee n re vise d t o clarif y w he n 
c o nfir mat or y testi n g base d o n ce ntral 
la b is nee de d. 
 
A p pe n di x 2 Cli nical la b orat or y 
testi n g 
T a ble 1 2 -2  
U p date t o clarif y w he n c o nfir mat or y 
test is nee de d f or e G F R calc ul ati o n.  
T o clarif y w he n c o nfir mat or y test 
base d o n ce ntral la b nee d t o be 
perf or me d  
Sec 9. 4 Safet y assess me nts    
Clarifie d t hat c o nc o mita nt ill ness or 
me dical hist or y alrea d y re p orte d o n 
ot her me dical hist or y f or ms, s h o ul d 
n ot be i ncl u de d  
T o a v oi d d u plicate re p orti n g of 
Me dical Hist or y  
Ge neral  
E dit orial u p date d  
 
Sec 2 Fl o wc hart  
I ncl u de d ha n d o ut d ose re mi n der car d 
at visit 2  
E dit orial  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
9 5
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
9 6  of 1 0 0  
 
 
Sec 4. 2. 2. 2 S u p p orti ve sec o n dar y 
e n d p oi nts  
Defi niti o n of persiste nt u p date d f or 
e G F R a n d macr oal b u mi n uria  
F or clarificati o n.  
Secti o n 5. 1 O verall trial desi g n  
A p plica ble f or: pr ot oc ol versi o n 1. 0 
1 5 Ma y 2 0 1 8  
‘ Efficac y’ i ncl u de d i n descri pti o n of 
t he i n de pe n de nt Data M o nit ori n g 
C o m mittee ( D M C) t o clarif y t hat t he 
D M C will o versee b ot h effica c y a n d 
s u bj ect safet y as part of t he be nefit-
ris k e val uati o n of se ma gl uti de. 
T o hi g hli g ht t hat t he D M C will 
o versee efficac y as well as safet y.  
Secti o n 5. 5 J ustificati o n f or d ose  
A p plica ble f or: pr ot oc ol versi o n 1. 0 
1 5 Ma y 2 0 1 8  
D ose j ustificati o n u p date d  
J ustificati o n f or d ose descri be d i n 
m ore details t o clarif y w h y t he d ose 
of 2. 4 m g was c h ose n.  
Secti o n 6. 2 E xcl usi o n criteria  
A p plica ble f or: pr o t oc ol versi o n 1. 0 
1 5 Ma y 2 0 1 8  
C o u ntr y s pecific i ncl usi o n criteria 
m o ve d t o A p pe n di x 9 c o u ntr y 
s pecific re q uire me nts. Criteria 8, 9 
a n d 1 9 i n A p pe n di x 9 are o nl y 
a p plica ble f or V H P, Fra nce a n d 
Net herla n ds  
E dit orial  
 
 
Sec 8. 1 Disc o nti n uati o n of trial 
treat ment  
Disc o nti n uati o n of trial pr o d uct pri or 
t o i nte nti o n of bec o mi n g pre g na nc y, 
c ha n ges fr o m 2 m o nt hs t o 7 wee ks.  
T o ali g n wit h c urre nt versi o n of t he 
I n vesti gat or’s br oc h ure. 
Sec 8. 1 Disc o nti n uati o n of trial 
treat me nt 
A p plica ble f or: pr ot oc ol versi o n 1. 0 
1 5 Ma y 2 0 1 8  
Disc o nti n uati o n criteri o n 4 re p hrase d 
t o reflect t hat i n case of s us pici o n of 
pa ncreatitis trial treat me nt m ust be 
disc o nti n ue d  
Clarificati o n  
Secti o n 8. 4 T er mi nati o n or 
m o dificati o n of t he trial  
A p plica ble f or: pr ot oc ol versi o n 1. 0 
1 5 Ma y 2 0 1 8  
Secti o n 8. 4 i ncl u de d t o clarif y t hat 
t he D M C will e val uate als o t he 
efficac y data d uri n g t he trial as part 
of t he be nefit -ris k e val uati o n of 
se ma gl uti de. 
T o clarif y st o p pi n g criteria  
Sec 9. 1. 4. 1 N o n -S A E 
h os pitalisati o ns  
Sec 9. 4 Safet y assess me nts  
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 val uati o n, f oll o w-u p, a n d 
re p orti n g 
Clarificati o n of ‘ baseli ne’,  ‘trial 
i ncl usi o n’ a n d ‘ bef ore e x p os ur e of 
trial pr o d uct’ is t he ti me of 
ra n d o misati o n 
F or clarificati o n  
Sec 9. 2 A d verse e ve nts  
C orrecte d t hat e ve nt defi niti o ns f or 
e ve nts re q uiri n g a dj u dicati o n are 
i ncl u de d i n t he c harter 
C orrecti o n  
9. 2. 1. 1 E ve nts f or A dj u dicati o n    
Refere nces t o t he E ve nt 
A dj u dicati o n Ma n ual i ncl u de d  
F or clarificati o n  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
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V V- T M F- 5 0 5 7 8 4 9
 .
-
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1
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 of
  Pr ot oc ol  Pr ot oc ol V 7
9 6
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
9 7  of 1 0 0  
 
 
9. 2. 1. 1 E ve nts f or A dj u dicati o n    
Ti meli ne f or c o m pleti o n of s p ecific 
a dj u dicati o n f or m i n t he C R F 
u p date d  
C orrecti o n  
Secti o n 1 0. 3. 5 Se q ue ntial safet y 
a nal ysis a n d safet y m o nit ori n g  
A p plica ble f or: pr ot oc ol versi o n 1. 0 
1 5 Ma y 2 0 1 8  
U p date d t o descri be se q ue ntial 
a nal yses perf or me d b y t he D M C.  
Clarificat i o n of D M C res p o nsi bilit y 
A p pe n di x 2 Cli nical la b orat or y tests   
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 necti o n wit h t he re q ueste d 
a nal yses acc or di n g t o s pecific ati o ns 
i n t he la b orat or y sta n dar d o perati n g 
pr oce d ures.  
F or clarificati o n  
A p pe n di x 3 Trial g o ver na nce 
c o nsi derati o ns  
E ve nt a dj u dicati o n c o m mittee  
Descri pti o n of e ve nt a dj u dicati o n 
a d de d  
P ur p ose of e ve nt a dj u dicati o n 
descri be d  
A p pe n di x 4  
Re m o val of a cli nical la b orat or y 
a d verse e ve nt  
Cli nical la b orat or y A Es are alrea d y 
part of t he A E defi niti o n a n d d oes 
n ot nee d t o be defi ne d as a n e ntit y, if 
defi ne d t he y will nee d t o be 
descri be d t o get her i n t he C T R a n d 
a b n or mal la b val ues re p orte d as a n 
A E are better a d dresse d w he n 
s u m marise d wit h t he or ga n 
s yste m/ disease/f oc us area t he y 
bel o n g t o rat her t ha n as a gr o u p of 
n o n -relate d preferre d ter ms j ust 
beca use t he y res ult fr o m a n a b n or mal 
la b val ue.  
A p pe n di x 4  
B ullet re m o ve d: 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 w as pla n ne d has 
w orse ne d fr o m t he first trial relate d 
acti vit y after t he s u bj ect has si g ne d 
t he i nf or me d c o nse nt. 
Delete d as t his b ullet p oi nt is alrea d y 
descri be d u n der Sec 9. 1. 4. 1 N o n -
S A E h os pitalisati o n.  
 
 
A p pe n di x 4  
U p date t o s pecif y t hat sites will h a ve 
access t he C R F u ntil trial cl os ure.  
D ue t o N N practice w here sites ha ve 
access t o E D C s yste m u ntil data base 
l oc k. A C R F is n ot dec o m missi o ne d 
at site-le vel, o nl y at trial le vel. T he 
s yste m is a vaila ble f or safet y 
re p orti n g u ntil t he trial e n ds. 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
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V V- T M F- 5 0 5 7 8 4 9
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-
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1
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 of
  Pr ot oc ol  Pr ot oc ol V 7
9 7
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
9 8  of 1 0 0  
 
 
A p pe n di x 5 C o ntrace pti ve g ui da nce 
a n d c ollecti o n of pre g na nc y 
i nf or mati o n 
T he pater nal f or m has bee n 
descri be d w hic h is t o be use d i n case 
of a b n or mal pre g na nc y o utc o me.  
E dit orial  
A p pe n di x 6 T ec h nical c o m plai nts: 
Defi niti o n a n d pr oce d ures f or 
rec or di n g, e val uati o n, f oll o w-u p a n d 
re p orti n g 
Re m o ve d se nte nce stati n g t hat o nl y 
tec h nical c o m plai nts relate d will be 
re p orte d i n t he cli nical trial re p ort 
T ec h nical c o m plai nts s h o ul d al wa ys 
b e i ncl u de d i n t he C T R if c oll ecte d 
s yste maticall y 
A p pe n di x 8 M o nit ori n g of cal cit o ni n  
A p plica ble f or: pr ot oc ol versi o n 1. 0 
1 5 Ma y 2 0 1 8  
Fi g ure 1 2 -1 u p date d t o i ncl u d e retest 
of calcit o ni n a n d c o nti n uati o n of 
sa m pli n g acc or di n g t o fl o wc hart. 
T e xt f or calcit o ni n ≥ 5 0 a n d < 1 0 0 
n g/ L u p date d t o re q uire retest of 
calcit o ni n.  
Re q ueste d d uri n g t he V ol u ntar y 
Har m o nise d Pr oce d ure i n E ur o pe  
A p pe n di x 8 M o nit ori n g of cal cit o ni n  
Delete d t hat scree n fail ures s h o ul d 
be referre d t o t h yr oi d s pecialist  
Calcit o ni n is n ot sa m p les at 
scree ni n g 
A p pe n di x 3 a n d A p pe n di x 9    
Restr uct uri n g of c o u ntr y s pecific 
i n de m nit y state me nts  
E dit orial  
A p pe n di x 9  
U p date of c o u ntr y s pecific 
re q uire me nt f or Brazil, C ol u m bia, 
Fi nla n d, Ja pa n, S o ut h Africa a n d 
T ur ke y  
T o clarif y res p o nsi bilit y of tri al 
pr o d uct ha n dli n g ali g n t he 
descri pti o n wit h ot her cli nical trials 
i n Ja pa n 
C ol u m bia, Fi nla n d, S o ut h Afri ca a n d 
T ur ke y will n ot partici pate i n t he 
bi o ba n k set -u p  
Brazil re p orti n g of la b orat or y res ults 
clarifie d  
A p pe n di x 9  
A p plica ble f or: pr ot oc ol versi o n 1. 0 
1 5 Ma y 2 0 1 8  
I nf or mati o n a b o ut S U S A R re p orti n g 
i ncl u de d t o clarif y h o w S U S A Rs are 
t o be re p orte d. 
Re q ueste d d uri n g t he V ol u ntar y 
Har m o nise d Pr oce d ure i n E ur o pe  
 
 
 
U p d ate d pr ot oc ol i ncl u di n g a me n d me nt 1: 2 7 N o ve m ber 2 0 1 8,  versi o n 2  
 
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 criteria 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.  
 
O ver all r ati o n ale f or t he a me n d me nt :  
T his a me n d me nt a d dress es t he u p dates re q ueste d d uri n g V H P s u b missi o n pr ocess.  
 
Secti o n # a n d n a me  
Descri pti o n of c h a n ge  
R ati o n ale  
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
-
 |
1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
9 8
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
9 9  of 1 0 0  
 
 
Secti o n 6. 2 E xcl usi o n criteria    
W or di n g of e xcl usi o n criteri o n # 8,  
# 9 a n d # 1 9 c ha n ge d t o clarif y t he 
e xcl usi o n criteria.  
U p date re q ueste d d uri n g V H P 
s u b missi o n pr ocess. 
 
Secti o n 8. 1 Disc o nti n uati o n of trial 
treat me nt 
Re p hrasi n g of criteri o n # 4 t o clarif y 
t hat n o patie nts de vel o pi n g 
pa ncreatitis c o nti n ues i n t he trial.  
U p date re q ueste d d uri n g V H P 
s u b missi o n pr ocess. 
A p pe n di x 9 C o u ntr y s peci fic 
re q uire me nts 
I nf or mati o n a b o ut S U S A R re p orti n g 
i ncl u de d t o clarif y h o w S U S A Rs are 
t o be re p orte d. 
C o u ntr y s pecific para gra p h a d de d f or 
V H P c o u ntries wit h a d diti o n of 
m o nt hl y pre g na nc y test, a m yl ase a n d 
li pase i n bi oc he mistr y pa nel, f ull A E 
c ollecti o n irres pecti ve of 
seri o us ness. 
Fl o wc hart u p date d d uri n g d ose 
escalati o n peri o d t o i ncl u de 
a d diti o nal la b orat or y sa m ples.  
U p date re q ueste d d uri n g V H P 
s u b missi o n pr ocess. 
 
A p pe n di x 5 C o ntrace pti ve g ui da nce 
a n d c ollecti o n of pre g na nc y 
i nf or mati o n. 
A d diti o nal c o u ntries ha vi n g s pecific 
re q uire me nts relate d t o pre g na nc y 
testi n g i ncl u de d. 
U p date re q ueste d d uri n g V H P 
s u b missi o n pr ocess. 
A p pe n di x 8 M o nit ori n g of cal cit o ni n   Fi g ure 1 2 -1 u p date d t o i ncl u d e retest 
of calcit o ni n a n d c o nti n uati o n of 
sa m pli n g acc or di n g t o fl o wc hart. 
T e xt f or Calcit o ni n ≥ 5 0 a n d < 1 0 0 
n g/ L u p date d t o re q uire retest of 
calcit o ni n.  
U p date re q ueste d d uri n g V H P 
s u b missi o n pr ocess. 
 
Secti o n 9. 2 A d verse e ve nts    
A d diti o nal c o u ntries ha vi n g s pecific 
A E re p orti n g re q uire me nts i ncl u de d 
t o e ns ure f ull A E c ollecti o n 
irres pecti ve of seri o us ness.  
U p date re q ueste d d uri n g V H P 
s u b missi o n pr ocess. 
Secti o n 2: Fl o wc hart  
F o ot n otes f u p date d d ue t o c o u ntr y 
s pecific pre g na nc y re q uire me nts a n d 
g a d de d d ue t o i nf or mati o n a b o ut 
a d diti o nal la b orat or y sa m pli n g i n 
a p p e n di x 9.  
U p date re q ueste d d uri n g V H P 
s u b missi o n pr ocess. 
Secti o n 5. 1 O verall trial desi g n    
‘ Efficac y’ i ncl u de d i n descri pti o n of 
t he i n de pe n de nt Data M o nit ori n g 
C o m mittee ( D M C ) t o clarif y t hat t he 
D M C will o versee b ot h effica c y a n d 
s u bj ect safet y as part of t he be nefit -
ris k e val uati o n of se ma gl uti de. 
U p date re q ueste d d uri n g V H P 
s u b missi o n pr ocess. 
Secti o n 5. 5 J ustificati o n f or d ose    
J ustificati o n f or d ose descri be d i n 
m ore details t o clarif y w h y t he d ose 
of 2. 4 m g was c h ose n.  
U p date re q ueste d d uri n g V H P 
s u b missi o n pr ocess. 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
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V V- T M F- 5 0 5 7 8 4 9
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1
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 of
  Pr ot oc ol  Pr ot oc ol V 7
9 9
1 0 0
C O N FI D E N TI A L

Pr ot oc ol  
 
Date:  
0 9 Fe br uar y 2 0 2 2  N o v o N or di s k  
Trial I D: E X 9 5 3 6 -4 3 8 8  
V ersi o n:  
7. 0  
      
Stat us:  
Fi nal  
      
P a ge:  
1 0 0  of 1 0 0  
 
 
Secti o n 8. 4 T er mi nati o n or 
m o dificati o n of t he trial  
Secti o n 8. 4 i ncl u de d t o clarif y t hat 
t he D M C will e val uate als o t he 
efficac y data d uri n g t he trial as part 
of t he be nefit -ris k e val uati o n of 
se ma gl uti de. 
U p date re q ueste d d uri n g V H P 
s u b missi o n pr ocess. 
Secti o n 1 0. 3. 5 Se q ue ntial safet y 
a nal ysis a n d safet y m o nit ori n g  
U p date d t o descri be se q ue ntial 
a nal yses perf or me d b y t he D M C.  
U p date re q ueste d d uri n g V H P 
s u b missi o n pr ocess. 
 
 
 
 
 
 
 
E X 9 5 3 6- 4 3 8 8
E X 9 5 3 6
0
 |
V V- T M F- 5 0 5 7 8 4 9
 .
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1
 |
 of
  Pr ot oc ol  Pr ot oc ol V 7
1 0 0
1 0 0
C O N FI D E N TI A L

 
1 6. 1. 0 1  
Pr ot oc ol  Att ac h me nt  
Pr ot oc ol A ttac h me nt I is l ocate d i n t he Trial Mast er File. 
If a p plica bl e, Pr ot oc ol Attac h me nt II is als o l ocate d i n t he Trial Master File. 
C o nte nt: Gl o bal ke y staff a n d C o u ntr y ke y staff.  
Date:
N o v o N or di s k
Versi o n:
Stat us:
Se ma gl uti de
Trial I D: E X 9 5 3 6- 4 3 8 8
Cli nical Trial Re p ort
A p pe n di x 1 6. 1. 1
0 6 J u ne 2 0 2 3
1. 0
Fi nal
C O N FI D E N TI A L