Clinical trial NCT03574597
Conditions: Overweight Obesity
Sponsor: Novo Nordisk A/S
Start date: 2018-10-24; Completion date: 2023-06-29
Enrollment: 17604 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The researchers are doing the study to see if semaglutide may reduce the risk of having cardiovascular events in patients with overweight or obesity and with prior cardiovascular disease. The participant will either get semaglutide (active medicine) or placebo ("dummy" medicine). Which treatment the participants get is decided by chance. The participant's chance of getting semaglutide or placebo is the same. The participant will get the study medicine in a pen. The participants will need to use the pen to inject the study medicine in a skinfold once a week. The study will last for about 2.5 to 5 years. Participants will have up to 25 clinic visits with the study doctor.

Detailed description:

Arms: arm 1: Participants will receive semaglutide as an adjunct to standard-of-care. Estimated trial duration for an individual subject is from 31 to 59 months. arm 2: Participants will receive placebo (semaglutide) as an adjunct to standard-of-care. Estimated trial duration for an individual subject is from 31 to 59 months.
Interventions: intervention 1: Semaglutide intervention 2: Placebo (semaglutide)
Intervention descriptions: intervention 1: Semaglutide will be injected into a skin fold, in the stomach, thigh or upper arm once a week at the same day of the week (to the extent possible) throughout the trial. Subjects will start semaglutide treatment at 0.24 mg; dose will gradually be increased every 4 weeks up to 2.4 mg. intervention 2: Placebo will be injected into a skin fold, in the stomach, thigh or upper arm once a week at the same day of the week (to the extent possible) throughout the trial. Participants will receive placebo at an equivalent dose to semaglutide.

Protocol documents:
Prot_002.pdf: 
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”. 
    
    
   
    
     
    
  
    
    
    
    
    
 
 
    
    
    
    
    
    
    
    
    
    
    
 
   
     
 
 
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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
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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:  
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
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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:  
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
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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:  
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
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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:  
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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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
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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:  
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
0
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V V- T M F- 5 0 5 7 8 4 9
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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
E X 9 5 3 6
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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 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
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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:  
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
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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:  
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
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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
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
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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
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
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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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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
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V V- T M F- 5 0 5 7 8 4 9
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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
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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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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
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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
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1
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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
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V V- T M F- 5 0 5 7 8 4 9
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 |
 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
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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
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
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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
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
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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 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
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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 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
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 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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  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
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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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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
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1
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 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
 |
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 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
 |
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 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
 |
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 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
 |
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 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
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5 9
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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 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
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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
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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 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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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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1
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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
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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 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
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V V- T M F- 5 0 5 7 8 4 9
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6 9
1 0 0
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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:  
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
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 of
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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
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V V- T M F- 5 0 5 7 8 4 9
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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
 .
-
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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
 .
-
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1
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 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
 .
-
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1
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 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
 .
-
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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
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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
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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
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8 7
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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:  
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
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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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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
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1
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 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
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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 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
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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 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
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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 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
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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 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
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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 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
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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 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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  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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1
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 of
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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
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1
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 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
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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 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

SAP_003.pdf: 
C o ver P a ge  f or St atistic al A n al ysis Pl a n  
S p o ns or na me:  
N o v o N or dis k A/ S  
N C T n u m ber  
N C T 0 3 5 7 4 5 9 7  
S p o ns or t rial I D: 
E X 9 5 3 6 -4 3 8 8  
Official title of st u d y:  
S E L E C T - Se ma gl uti de effects o n car di o vasc ular o utc o mes i n 
pe o ple wit h o ver wei g ht or o besit 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
St atistic al a n al ysis pl a n ......................................................................................................................
St atistic al D oc u me nt ati o n ..................................................................................................................
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. 9
0 6 J u ne 2 0 2 3
1. 0
Fi nal
1 6. 1. 9 D oc u me nt ati o n of st atistic al met h o ds
C O N FI D E N TI A L
Re d acte d st atistic al a n alysis pl a n 
I ncl u des red acti o n of  pers o n al i de ntifi a ble inf or m ati o n o nly.  
. 


Statistical A nal ysis Pla n  
 
Date:  
2 2 A pril 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:  
3. 0  
U T N: U 1 1 1 1 -1 2 0 0 -5 5 6 4  
Stat us:  
Fi n al  
E u dra C T N o.: 2 0 1 7 -0 0 3 3 8 0 -3 5  
P a ge:  
1  of 3 4  
St atistic al A n al ysis Pl a n  
Tri al I D: E X 9 5 3 6 -4 3 8 8  
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 
A ut h or :  
 Statisticia n 
Bi ost atisti cs G L P -1 & C V 1
  
  
   
  
   
  
  
  
  
  
  
  
 
 
  
  
  
  
  
  
  
  
   
  
 
 
  
  
 
 
V V- C LI N- 1 1 1 2 7 3
3 .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.


Statistical A nal ysis Pla n  
 
Date:  
 
 
2 2 A pril 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:  
3. 0  
U T N: U 1 1 1 1 -1 2 0 0 -5 5 6 4  
Stat us:  
Fi n al  
E u dra C T N o.: 2 0 1 7 -0 0 3 3 8 0 -3 5  
P a ge:  
2  of 3 4  
 
 
Ta ble of c o nte nts     
 
P a ge  
T a ble of c o nte nts  ............................................................................................................................................... 2  
List of a b bre vi ati o ns  ......................................................................................................................................... 3  
1  
I ntr o d ucti o n ............................................................................................................................................... 4  
1. 1  
Trial i nf o r mati o n ............................................................................................................................ 4  
1. 1. 1  
Rati o nale  ...................................................................................................................... 4  
1. 1. 2  
O bjecti ves, e n d p oi nts a n d esti ma n d  ............................................................................. 4  
1. 1. 3  
Desi g n  .......................................................................................................................... 5  
1. 2  
Sc o pe of t he statistical a nal ysis pla n  .............................................................................................. 5  
2  
St atistic al c o nsi der ati o ns  .......................................................................................................................... 6  
2. 1  
Sa m ple size deter mi nati o n  ............................................................................................................. 6  
2. 2  
Ge neral c o nsi derati o ns  ................................................................................................................... 8  
2. 2. 1  
Defi niti o n of a nal ysis set  ............................................................................................. 9  
2. 2. 2  
Defi niti o n of o bser vati o n peri o ds  ................................................................................ 9  
2. 2. 3  
Esti ma n ds  ................................................................................................................... 1 0  
2. 2. 4  
Ti me -t o-e ve nt e n d p oi nts, ce ns ori n g a n d c o m peti n g ris ks  ......................................... 1 1  
2. 2. 5  
C o nti n u o us a n d bi nar y e n d p oi nts  ............................................................................... 1 3  
2. 3  
Pri mar y e n d p oi nt  .......................................................................................................................... 1 3  
2. 3. 1  
Pri mar y a nal ysis  ......................................................................................................... 1 3  
2. 3. 2  
Se nsiti vit y a nal yses  .................................................................................................... 1 4  
2. 3. 3  
S u p ple me ntar y a nal yses  ............................................................................................. 1 5  
2. 3. 4  
S u b gr o u p a nal yses  ..................................................................................................... 1 6  
2. 3. 5  
S u p ple me ntar y a nal yses e val uati n g i m pact of t he C O VI D -1 9 pa n de mic  .................. 1 6  
2. 3. 6  
S u p ple me ntar y a nal yses e val uati n g i m pact of c o -partici pati o n i n C O VI D -1 9 
treat me nt or pre ve nti o n trials ..................................................................................... 1 7  
2. 4  
Sec o n dar y e n d p oi nts  .................................................................................................................... 1 7  
2. 4. 1  
C o nfir mat or y sec o n dar y e n d p oi nts ............................................................................ 1 8  
2. 4. 2  
S u p p orti ve sec o n dar y e n d p oi nts  ................................................................................ 1 9  
2. 4. 2. 1  
T T E s u p p orti ve sec o n dar y e n d p oi nts  .................................................. 1 9  
2. 4. 2. 2  
C o nti n u o us s u p p o rti ve sec o n dar y e n d p oi nts ....................................... 2 0  
2. 4. 2. 3  
S u p p orti ve sec o n dar y e n d p oi nts base d o n s u bsets of F A S  ................. 2 1  
2. 5  
E x pl orat or y e n d p oi nts  .................................................................................................................. 2 1  
2. 6  
Ot her assess me nts  ........................................................................................................................ 2 2  
3  
I nteri m testi n g ......................................................................................................................................... 2 3  
3. 1  
R ole of D M C  ............................................................................................................................... 2 3  
3. 2  
St o p pi n g  b o u n dar y f or s u peri orit y at i nteri m  ............................................................................... 2 4  
3. 3  
A nal ysis o n ter mi nati o n  ............................................................................................................... 2 4  
4  
C h a n ges t o t he st atistic al a n al ysis pl a n  ................................................................................................. 2 4  
5  
Ref ere nces  ................................................................................................................................................ 2 8  
6  
A p pe n di x  .................................................................................................................................................. 3 0  
 
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C O N FI D E N TI A L


Statistical A nal ysis Pla n  
 
Date:  
 
 
2 2 A pril 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:  
3. 0  
U T N: U 1 1 1 1 -1 2 0 0 -5 5 6 4  
Stat us:  
Fi n al  
E u dra C T N o.: 2 0 1 7 -0 0 3 3 8 0 -3 5  
P a ge:  
3  of 3 4  
 
 
List of a b bre vi ati o ns  
A N C O V A  
anal ysis of  c ovari a nce  
B MI  
b o d y mass i n de x  
B P  
bl o o d press ure  
CI  
co nfi de nce i nter val  
C V  
car di o vas c ular  
D B L  
data base l oc k  
D M C  
d ata m o nit ori n g c o m mittee  
E A C  
eve nt a dj u dicati o n c o m mittee  
e G F R  
esti mate d gl o mer ular filtr ati o n rate 
E Q -5 D -5 L  E ur o Q ol fi ve di me nsi o ns fi ve le vel  
E Q -5 D -V A S  E ur o Q ol fi ve di me nsi o ns vis ual a nal o g u e scale  
H b A 1 c 
g l yc os ylate d h ae m o gl o bi n 
H D L  
hi g h de nsit y li p o pr otei n  
H F  
heart fail ure  
H H F  
h os pitalisati o n f or heart fail ure  
H R  
hazar d rati o  
hs C R P  
hi g h -se nsiti vit y C-reacti ve pr otei n  
L D L  
l o w de nsit y li p o pr otei n 
M A C E  
maj or a d vers e car di o vasc ular e ve nt  
MI  
m y ocar dial i nfarcti o n  
M M R M  
mi x e d m o del f or re peate d meas ure me nts  
P A D  
peri p heral arterial diseas e  
S A P  
statistical a nal ysis pla n 
s.c. 
su bc uta ne o us  
T 2 D  
ty pe 2 dia b etes  
T T E  
ti me-t o-e ve nt  
U A C R  
uri nar y al b u mi n t o creati ni ne rati o  
W R S S M  
w ei g ht -relat e d si g n a n d sy m pt o m m eas ure  
 
 
 
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C O N FI D E N TI A L


Statistical A nal ysis Pla n  
 
Date:  
 
 
2 2 A pril 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:  
3. 0  
U T N: U 1 1 1 1 -1 2 0 0 -5 5 6 4  
Stat us:  
Fi n al  
E u dra C T N o.: 2 0 1 7 -0 0 3 3 8 0 -3 5  
P a ge:  
4  of 3 4  
 
 
1  
I ntr o d ucti o n 
1. 1  
Tri al i nf or m ati o n  
1. 1. 1  
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 f act 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 ur e 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  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 v er wei g ht or o besit y is n ot 
k n o w n . 
1. 1. 2  
O bjecti ves, e n d p oi nts  a n d esti m a n d  
P ri 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 n ce wee kl y l o wers t he i nci de n ce 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 b esit y.  
Ke y sec o n d ar y o bjecti ve  
T o c o m pare t h e effect of se ma gl ut i de s. c. 2. 4 m g o nce wee kl y vers us se m a 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 mortalit y.  
 
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 o cc urre nce of a m aj or a d verse 
car di o vas c ular e v e nt, a c o m p osite e n d p oi nt c o nsisti n g of: car di o vasc ular deat h, n o n -fatal 
m y ocar dial i nfarcti o n or n o n -fatal str o ke. 
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  
 F irst 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 he art fail ure visit or C V deat h  
 All -ca use d eat h  
P ri m ar y esti m a n d  
T he pri mar y esti ma n d f or all o bjecti ves is a n 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 n ce t o treat me nt a n d c ha n ges t o 
bac k gr o u n d me dicati o n . 
V V- C LI N- 1 1 1 2 7 3
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C O N FI D E N TI A L


Statistical A nal ysis Pla n  
 
Date:  
 
 
2 2 A pril 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:  
3. 0  
U T N: U 1 1 1 1 -1 2 0 0 -5 5 6 4  
Stat us:  
Fi n al  
E u dra C T N o.: 2 0 1 7 -0 0 3 3 8 0 -3 5  
P a ge:  
5  of 3 4  
 
 
1. 1. 3  
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 us) 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 ver wei g ht or o b esit y. S u bjects are ra n d o mise d i n a 1: 1 rati o t o 
recei v e eit her s e 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; t heref ore, e n d of trial is sc he d ule d acc or di n g t o accr ual of e ve nts . T he trial 
will e m pl o y a gr o u p s e q u e ntial desi g n wit h  o ne i nt eri m testi n g f or s u peri orit y. U n der t he desi g n 
ass u m pti o ns, t he t rial d urati o n is a p pr o xi matel y 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. 1 7, 5 0 0 s u bjects are pla n n e d t o be ra n d o ml y assi g ne d t o trial pr o d u cts. A sc he matic 
o ver vie w of t h e trial desi g n is s h o w n i n Fi g ure 1 – 1 . 
 
 
Fi g ure 1 – 1  
Tri al desi g n  
1. 2  
Sc o pe of t he st atistic al a n al ysis pl a n  
T he S A P  i ncl u des ela b orati o ns o n statistical a nal yses o utli ne d i n t he pr ot oc ol f or t he S E L E C T tri al 
(E X 9 5 3 6 -4 3 8 8 ) as well as details o n t he i nteri m testi n g  f or s u peri orit y. A n y c ha n ges t o t he S A P 
fi nal versi o n 1. 0 will be  d oc u me nte d i n a c h a n ge l o g.  
A n e xter nal i n de pe n de nt statistical ser vice pr o vi der  will c o n d uct t he i nteri m a nal ysis, s ee als o 
secti o n 3 . N o v o N or dis k is res p o nsi ble f or all ot her statistical a nal yses a n d re p orti n g of data b ut will 
re mai n bli n de d t o treat m e nt all ocati o ns u ntil data base l oc k ( DB L) .  
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C O N FI D E N TI A L


Statistical A nal ysis Pla n  
 
Date:  
 
 
2 2 A pril 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:  
3. 0  
U T N: U 1 1 1 1 -1 2 0 0 -5 5 6 4  
Stat us:  
Fi n al  
E u dra C T N o.: 2 0 1 7 -0 0 3 3 8 0 -3 5  
P a ge:  
6  of 3 4  
 
 
2  
St atistic al c o nsi der ati o ns  
2. 1  
S a m ple size deter mi n ati o n  
T he trial is desi g n e d wit h 9 0 % p o wer t o c o nfir m s u peri orit y f or t he pri mar y e n d p oi nt, i.e. , reject t he 
n ull -h y p ot hesis of a h azar d rati o ( H R) ≥ 1. 0 a gai nst t he o ne -si de d alter nati ve of H R < 1. 0, w here 
H R is t he hazar d rati o of se ma gl uti de 2. 4 m g vers us se ma gl uti de place b o . 
T he trial is desi g n e d wit h o ne i nteri m testi n g f or s u peri orit y of t he pri mar y e n d p oi nt w he n t w o 
t hir ds of t he t otal pla n ne d n u m ber of pri mar y e n d p oi nt e ve nts has bee n accr ue d. Testi n g f or f utilit y 
is n ot i ncl u de d. T he La n -De Mets al p ha s p e 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 t o test s uperi orit y at a st u d y -wise o ne -si d e d t y pe I err or rate of 2. 5 %. 
T he o ne -si de d al p ha s pe n di n g f u ncti o n is gi ve n b y  
𝑓(𝑡) = mi n {2 −2 ∙Φ (𝑧𝛼
2 / √𝑡),𝛼} 
w here t is t he pr o p orti o n of i nf or mati o n i ncl u de d i n t he i nteri m a nal ysis (accr ue d pri mar y e n d p oi nt 
e ve nts rel ati ve t o t he t otal pla n ne d pri mar y e n d p oi nt e ve nts), Φ de n otes t he sta n dar d n or mal 
c u m ulati ve distri b uti o n f u ncti o n, 𝛼 is t he o verall o n e -si de d al p ha of 2. 5 % a n d 𝑧𝛼/ 2  is t he 98 . 75 % 
q ua ntile of t he sta n dar d n or mal distri b uti o n.  Base d o n a ra n d o misati o n r ati o of 1: 1 a n d a desi g n H R 
of 0. 8 3 a t otal of 1 ,2 2 5 pri mar y e n d p oi nt e ve nts are re q uir e d.  
 
F or calc ulati n g t he n u m b er of ra n d o mise d s u bjects, t he f oll o wi n g is ass u m e d:  
 u nif or m recr uit me nt i n 2 8 m o nt hs ( 2, 5 0 0 s u bjects e ver y 4 m o nt hs)  
 a n n ual pri mar y e n d p oi nt rate i n t he se ma gl uti de pl ace b o gr o u p of 2. 2 %  
 a n n ual l ost t o f oll o w -u p rate i n b ot h treat me nt gr o u ps of 1 %  
 
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 bj ects wit h a first M A C E 
( pri mar y e n d p oi nt) is bas e d o n t he e ve nt r ates see n i n S U S T AI N 6 a n d E X 22 1 1 -3 7 4 8 ( L E A D E R). 
T hese e v e nt rates were c o m pare d t o t he e v e 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 ,2 ,3) a n d a dj uste d t o t he i ncl usi o n a n d e xcl usi o n criteria of t h e c urre nt trial. I n t he S C O U T 
trial, w hic h was c o n d u cte d i n s u bjects wit h o ver wei g ht or o besit y, t he s u b gr o u p t hat o nl y ha d 
esta blis he d C V disease h a 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 h a d 
esta blis he d C V disease a n d T 2 D.  Bas e d o n t his literat ur e, a n e v e 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 u alise d e v e 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 2. 4 m g ar m a n d 2. 2 % i n t he 
se ma gl uti de pla ce b o ar m). Wit h t hese ass u m pti o ns t he n u m ber of e v e nts accr ue d o ver a p eri o d of 7 
years wit h vari o us s a m ple siz es is see n o n t he bel o w fi g ure.  
V V- C LI N- 1 1 1 2 7 3
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C O N FI D E N TI A L


Statistical A nal ysis Pla n  
 
Date:  
 
 
2 2 A pril 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:  
3. 0  
U T N: U 1 1 1 1 -1 2 0 0 -5 5 6 4  
Stat us:  
Fi n al  
E u dra C T N o.: 2 0 1 7 -0 0 3 3 8 0 -3 5  
P a ge:  
7  of 3 4  
 
 
 
Fi g ur e 2 – 1  
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 siz e of 1 7, 5 0 0 s u bjects, a n d u n der t he alter nati ve h y p ot h esis, t he 1, 2 2 5 e ve nts are 
accr ue d bet w ee n m o nt hs 5 8 a n d 5 9.  
A C o x m o del as descri be d i n secti o n  2. 3  is use d f or t he i nteri m testi n g usi n g t he fi x e d sa m ple o ne-
si de d l o wer p-v al ue fr o m t he sc ore test.  O nl y a fi x e d sa m ple p -v al u e bel o w  t he b o u n dar y s pecifie d 
b y t he err or s p e n di n g f u ncti o n will all o w t he D M C t o rec o m me n d earl y trial ter mi nati o n f or 
s u peri orit y. T a ble 2 -1  pr o vi des t he b o u n daries base d o n a nal yses p erf or m e d after 8 1 7 a n d 1 ,2 2 5 
e ve nts, al o n g wit h t he a p pr o xi mate hazar d rati o esti mates t hat c orres p o n d t o t h ose b o u n daries if t he 
a nal ys e are ti me d e x actl y t o t hat sc he d ule. T he act ual st o p pi n g b o u n dari es will be base d o n t he 
e x act n u m ber of e v e nts a vaila ble f or t he i nteri m a nal ysi s. 
T a ble 2 -1  
St o p pi n g b o u n d ar y sc ales at i nteri m a n d sc he d ule d ter mi n ati o n  
St o p pi n g b o u n d ar y sc ale  
I nteri m 
8 1 7 e ve nts  
Sc he d ule d ter mi n ati o n  
1 ,2 2 5 e ve nts  
Hazar d rati o  
0. 8 3 8 9  
0. 8 9 2 4  
N o mi nal si g nifica nce le vel  
0. 0 0 6 0 5  
0. 0 2 3 1 4  
 
Fi g ure 2 – 2  b el o w s h o ws t he pr o ba bil it y of st o p pi n g t he trial at t he i nteri m ( bl ue c ur ve) a n d t he 
o verall p o wer f or c o nfir mi n g s u peri orit y f or t h e pri mar y e n d p oi nt (re d das he d c ur ve) as a f u ncti o n 
of alter nati ve v al ues f or t he tr ue H R. T he d esi g n H R of 0. 8 3 is mar ke d wit h a das he d vertical 
refere nce li ne. T he st o p pi n g pr o ba bilit y at t he i nteri m a n d o verall p o wer f or t he desi g n H R of 0. 8 3 
ca n be see n t o be 5 6 % a n d 9 0 %, res pec ti vel y. 
V V- C LI N- 1 1 1 2 7 3
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C O N FI D E N TI A L


Statistical A nal ysis Pla n  
 
Date:  
 
 
2 2 A pril 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:  
3. 0  
U T N: U 1 1 1 1 -1 2 0 0 -5 5 6 4  
Stat us:  
Fi n al  
E u dra C T N o.: 2 0 1 7 -0 0 3 3 8 0 -3 5  
P a ge:  
8  of 3 4  
 
 
 
Fi g ure 2 – 2  
St o p pi n g pr o b a bilit y at i nteri m a n d o ver all p o wer as a f u ncti o n of t he h az ar d 
r ati o 
I n s u m mar y, u n der t he ass u me d desi g n ass u m pti o ns, t he sa m ple siz e calc ul ati o n pr o vi des 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 2 -2  
Ke y n u m bers a n d ti meli nes  
R a n d o mis ati o n  
r ati o 
N u m ber of 
r a n d o mise d 
s u bjects  
N u m ber of 
e v e nts 
i nteri m/t ot al 
D ur ati o n of 
recr uit me nt 
peri o d  
D ur ati o n 
of tri al  
Ti m i n g  
of i nteri m  
M e a n o bser v ati o n 
ti me 
i nteri m/t ot al 
1: 1  
1 7, 5 0 0  
8 1 7/ 1, 2 2 5  
2 8 m o nt hs  
5 9 m o nt hs  4 4 m o nt hs  
3 0 /4 4  m o nt hs  
2. 2  
Ge ner al c o nsi der ati o ns  
F or c o nfir mat or y e n d p oi nts  c o ntr olle d f or m ulti plicit y (see secti o n 2. 4. 1 ), esti mate d treat me nt 
effects are pres e nte d t o get her wit h t w o -si de d 9 5 % c o nfi de nce i nter vals ( CIs) a n d o ne-si de d p-val ues 
f or tests of t he h y p ot heses  of s u peri orit y . F or re p orti n g of res ults,  t he H R  a n d t he 9 5 % CI are 
acc o m pa ni e d b y t he t w o -si de d p-val ue.  
V V- C LI N- 1 1 1 2 7 3
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C O N FI D E N TI A L


Statistical A nal ysis Pla n  
 
Date:  
 
 
2 2 A pril 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:  
3. 0  
U T N: U 1 1 1 1 -1 2 0 0 -5 5 6 4  
Stat us:  
Fi n al  
E u dra C T N o.: 2 0 1 7 -0 0 3 3 8 0 -3 5  
P a ge:  
9  of 3 4  
 
 
F or n o n -c o nfir mat or y e n d p oi nt s, esti mate d treat me nt effects are re p orte d t o get h er wit h t w o-si de d 
9 5 %  CI  a n d t w o-si de d p-val ues.  
Baseli ne v al ue is defi n e d as t he eli gi ble m eas ure me nt ass ociate d wit h t he ra n d o misati o n visit , if t his 
meas ure me nt is ta ke n b ef ore or at t he d ate of first d ose. If a ra n d o misati o n assess me nt is missi n g or 
if it is ta ke n after t he d ate of first d ose, t he n t he ass ess me nt fr o m scree ni n g is use d as t he baseli ne 
assess me nt, if a vaila ble. F or meas ure me nts o nl y t a ke n at scree ni n g (e. g. H b A 1c) t he eli gi ble 
scree ni n g me as ure m e nt will be t he baseli ne val ue.If m ore t ha n o ne meas ure me nt is ass ociate d wit h 
t he sa me visit, t he earliest  meas ure me nt is c o nsi dere d eli gi ble.  
Mi ssi n g data are defi ne d as data t hat are pla n ne d t o be c ollecte d a n d ca n be o bser ve d b ut are n ot 
prese nt i n t he data b ase. T his i m plies t hat data t hat are str uct urall y missi n g d ue t o deat h or 
a d mi nistrati ve ce ns ori n g are n ot c o nsi dere d missi n g.  U nless e x plic itl y state d u n o bser ve d dat a 
pertai ni n g t o s u bjects w h o are l ost t o f oll o w-u p or wit h dra w n  a n d w o ul d n ot ha ve bee n 
a d mi nistrati vel y ce ns ore d at t he ti me p oi nt i n q uesti o n, are c o nsi dere d missi n g ir res p ecti vel y of 
vital stat us as c ollecte d at e n d of trial .  
2. 2. 1  
Defi niti o n of a n al ysis set  
T he  f ull a nal ysis set ( F A S) is defi ne d as a ll u ni q u e ra n d o mise d s u bjects a n d gr o u pe d acc or di n g t o 
t he treat me nt assi g ne d at ra n d o misati o n . 
If a s u bject is r a n d o mise d m ore t ha n o nce, o nl y t h e s u bject I D a n d treat me nt c orres p o n di n g t o t he 
first ra n d o misati o n will be i ncl u de d i n F A S. T he a d diti o nal ra n d o mise d s u bject I Ds will be 
e x cl u de d fr o m F A S. T he list of s u bject I D’s t o e x cl u de will be part  of t he D B L mi n utes.     
2. 2. 2  
Defi niti o n of o bser v ati o n peri o ds  
A trial c o m pleter is defi ne d as a s u bject t hat eit her atte n ds t he e n d -of -trial f oll o w-u p visit or w h o 
die s w hile acti ve i n t he trial.  
 
A s u bject is c o nsi dere d l ost t o f oll o w -u p ( L T F U) if t he s u bjec t d oes n ot c o m plete t he trial a n d d oes 
n ot wit h dra w c o nse nt.  T h e date a n d stat us f or L T F U are d eter mi ne d b y i n vesti gat or at trial 
c o m pleti o n, eit her f oll o wi n g i nteri m testi n g or after accr ual of t he t otal pla n ne d n u m ber of pri mar y 
e n d p oi nt e ve nts.  
 
I n-tri al o bser v ati o n peri o d 
T he i n -trial o bser v ati o n peri o d f or a s u bj ect is defi ne d as t he peri o d fr o m date of ra n d o misati o n t o 
t he first of ( b ot h i ncl usi ve): 
 d ate of f oll o w-u p  visit  
 d ate w he n s u bject wit h dre w c o nse nt  
 d ate of last c o nta ct wit h s u bject f or s u bjects w h o are L T F U 
V V- C LI N- 1 1 1 2 7 3
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C O N FI D E N TI A L


Statistical A nal ysis Pla n  
 
Date:  
 
 
2 2 A pril 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:  
3. 0  
U T N: U 1 1 1 1 -1 2 0 0 -5 5 6 4  
Stat us:  
Fi n al  
E u dra C T N o.: 2 0 1 7 -0 0 3 3 8 0 -3 5  
P a ge:  
1 0  of 3 4  
 
 
 d ate of deat h  
 
O n -tre at me nt o bser v ati o n peri o d 
A ti me -p oi nt i n t he i n-trial o bser vati o n peri o d is c o nsi dere d as o n -treat me nt if a n y d os e of trial 
pr o d uct has bee n a d mi ni stere d wit hi n t he pre vi o us 5  wee ks  (3 5  d a ys) . T he o n-treat me nt o bser vati o n 
peri o d is defi ne d as all ti mes w hic h are c o nsi dere d o n -treat me nt , s o it ma y c o nsist of se veral ti me 
i nter vals wit h ga ps bet wee n. 
 
First o n -tre at me nt o bse r v ati o n peri o d 
T he first o n-treat me nt o bser vati o n peri o d is defi n e d as t he o n-treat me nt o bser vati o n peri o d u ntil 
first ti me bei n g off treat me nt f or 5  c o nsec uti ve wee ks ( 3 5  da ys).  T h us it is t he first ti me i nter val i n 
t he o n-treat me nt p eri o d.  
 
2. 2. 3  
Esti m a n d s 
Pri m ar y esti m a n d  (i ntent i o n-t o-tre at) 
T he esti ma n d f or all o bjecti ves is a n i nte nti o n-t o-treat esti ma n d, e v al uati n g t he effect of t he 
ra n d o mise d treat me nt i nt er ve nti o n irres p ecti ve of a d here n ce t o treat me nt a n d c ha n ges t o 
bac k gr o u n d me dicati o n.  T he esti ma n d is a d dress e d usi n g F A S a n d t he i n-trial o bser vati o n peri o d.  
 
I nterc urre nt e ve nts 
Interc urre nt e v e nt s are e v e nts  i ncl u di n g, b ut n ot li mite d t o , or ass ociate d wit h  t he f oll o wi n g: 
 ra n d o mise d treat me nt a d here nce 
 c ha n ge i n ba c k gr o u n d m e dicati o n  m o dif yi n g C V ris k  
 bariatric s ur ger y  
 i nitiati o n of c hr o nic re nal re place me nt t hera p y 
 wit h dra wal  
 l ost-t o f oll o w u p 
 deat h (if n ot part of e n d p oi nt)  
T hese are re p orte d usi n g descri pti ve statistics . 
Ha n dli n g of  i nterc urre nt e ve nts f or t he statistical a nal yses of t he pri mar y e n d p oi nt is  descri be d  i n 
Ta ble 6 -1 . 
 
Sec o n d ar y esti m a n d  f or selecte d ti me -t o-e v e nt e n d p oi nts  
T his esti ma n d c o vers c o nfir mat or y e n d p oi nts a n d is e val uati n g t h e effect of t he ra n d o mise d 
treat me nt i nter ve nti o n i n all ra n d o mise d s u bjects h a d t he y re mai n e d o n t heir ra n d o mise d treat me nt 
V V- C LI N- 1 1 1 2 7 3
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C O N FI D E N TI A L


Statistical A nal ysis Pla n  
 
Date:  
 
 
2 2 A pril 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:  
3. 0  
U T N: U 1 1 1 1 -1 2 0 0 -5 5 6 4  
Stat us:  
Fi n al  
E u dra C T N o.: 2 0 1 7 -0 0 3 3 8 0 -3 5  
P a ge:  
1 1  of 3 4  
 
 
f or t he e ntire trial. T he esti ma n d is a d dresse d usi n g F A S a n d t he first o n -treat me nt o bser vati o n 
peri o d . 
 
Sec o n d ar y es ti m a n d f or b o d y w ei g ht 
T h is esti ma n d is e val uati n g t he effect of t he ra n d o mise d treat me nt i nter ve nti o n after 5 2 wee ks o n 
c ha n ge i n b o d y w ei g ht, i n all ra n d o mise d s u bjects ha d t he y re mai n e d o n t heir ra n d o mise d tr eat me nt 
f or 5 2 wee ks . T he esti ma n d is a d dresse d usi n g F A S a n d t he first o n -treat me nt o bser vati o n peri o d 
restricte d t o t he first 5 2 wee ks of t he trial . 
2. 2. 4  
Ti me -t o-e v e nt e n d p oi nts, ce ns ori n g  a n d c o m peti n g ris ks  
Ti me -t o-e ve nt e n d p oi nts are i n ge n eral ti me -t o-first-e ve nt e n d p oi nts b ut  will f or si m plicit y b e 
de n ote d ti me -t o-e v e nt ( T T E) e n d p oi nts.  
If a dj u dicat e d, t he T T E e n d p oi nts are defi ne d b ase d o n o utc o mes of t he E A C e val uati o ns. W hile 
vital stat us is ascertai ne d s yste maticall y t hr o u g h o ut t he trial u ntil D B L , ot h er e ve nt t y pes ca n n ot be 
s yste maticall y c ollecte d after wit h dra wal, l ost-t o-f oll o w-u p, or aft er e n d -of -trial visit as ill ustrate d 
i n Fi g ure 2 – 3 .  F or t his r eas o n, a n y e v e nt occ urri n g after t he i n -trial o bser v ati o n peri o d is n ot 
i ncl u de d i n a nal yses, u nl ess ot her wise state d. 
 
 
 
Fi g ure 2 – 3  
I n-tri al o bser v ati o n peri o ds use d i n a n al ysis of ti me-t o-e ve nt e n d p oi nts reflecte d 
b y b ol d li nes f or f o ur differe nt s u bject e x a m ples  
If a s u bject e x perie nce  t h e e ve nt of i nterest d uri n g t he i n-trial o bser vati o n p eri o d, t he o bser vati o n of 
t he T T E is t he ti me fr o m ra n d o misati o n t o t he date of e ve nt.  
T he o bser vati o n of t h e T T E  is ce ns ore d if t h e e ve nt of i nterest d oes  n ot ha p pe n d uri n g t he i n -trial 
o bser vati o n peri o d  a n d if t he s u bject is still ali ve at t he e n d of t he o bser vati o n peri o d . T he ge n eral 
V V- C LI N- 1 1 1 2 7 3
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C O N FI D E N TI A L




Statistical A nal ysis Pla n  
 
Date:  
 
 
2 2 A pril 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:  
3. 0  
U T N: U 1 1 1 1 -1 2 0 0 -5 5 6 4  
Stat us:  
Fi n al  
E u dra C T N o.: 2 0 1 7 -0 0 3 3 8 0 -3 5  
P a ge:  
1 3  of 3 4  
 
 
2. 2. 5  
C o nti n u o us a n d bi n ar y e n d p oi nts  
If 1 0 % or m ore of  s u bjects fr o m F A S ha ve misse d t he  wee k 1 0 4 visit d ue t o trial ter mi nati o n earlier 
t ha n pla n ne d (st o p pi n g after i nteri m testi n g or e ve nt rates hi g h er t ha n e x pecte d) t he ti mi n g of t he 
e n d p oi nt will c ha n ge t o wee k 5 2.   
T he p o p ulati o n -le vel s u m mar y me as ure f or c o nti n u o us e n d p oi nts is t he mea n differe n ce f or 
se ma gl uti de 2. 4 m g vers us se ma gl uti de place b o. Li pi d e n d p oi nts a n d hs C R P are l o garit h mic 
tra nsf or me d a n d t he mea n differe n ce o n t he l o garit h mic scale is bac k -tra nsf or me d t o ori gi n al scale 
a n d re p ort e d as ge o metric mea n rati os. T he p o p ulati o n-le vel s u m mar y meas ure f or bi nar y en d p oi nts 
is t he o d ds rati o f or se ma gl uti de 2. 4 m g vers us se ma gl uti de place b o.  
Ta ble 6 -3  gi ves a n o v er vi e w of t he c o nti n u o us a n d bi nar y e n d p oi nts.  
2. 3  
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 ( MI) 
 N o n -fatal str o ke. 
 
Fatal MI is defi ne d as a n E A C -c o nfir me d MI occ urri n g wit hi n ( ≤) 3 0 da ys of a n E A C -c o nfir me d 
C V deat h classifie d wit h ca use of deat h bei n g MI. All ot he r MIs are defi ne d as n o n-fatal. A si milar 
defi niti o n is a p plie d f or fatal/ n o n -fatal str ok e.  
 
Deat hs attri b ute d t o t he cate g or y “ u n d eter mi ne d ca use of deat h” are pres u me d car di o vas c ular d eat h.  
2. 3. 1  
Pri m ar y a n al ysis  
T he pri mar y a n al ysis will a d dress t he pri mar y esti ma n d (i nte nti o n -t o-treat). T he H R f or c o m p ari n g 
se ma gl uti de 2. 4 m g vers us se ma gl uti de place b o is 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 , se ma gl uti de place b o) as fi x e d fact or t o get her wit h t he 
t w o-si de d 9 5 % CI a n d o n e-si de d fi x e d desi g n p-val ue f or h y p ot hesis testi n g. T he sc ore t est fr o m t he  
C o x m o del is use d f or testi n g. T he f oll o wi n g s u peri orit y h y p ot hesis is teste d:  
H 0: H R ≥ 1. 0 a gai nst Ha: H R < 1. 0 
S u peri orit y of s e ma gl uti de 2. 4 m g v ers us se ma gl uti de place b o is c o nsi dere d c o nfir me d if t he 
ass ociate d H 0 is reject e d. T he n o mi nal si g nifica nc e le vel is calc ul ate d usi n g t he al p ha s pe n di n g 
f u ncti o n a n d t he act ual o bser ve d n u m ber of e v e nts a vaila ble f or t h e 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 se q u e ntial desi g n b y usi n g t h e li keli h o o d rati o or deri n g. 
V V- C LI N- 1 1 1 2 7 3
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.
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
 
Date:  
 
 
2 2 A pril 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:  
3. 0  
U T N: U 1 1 1 1 -1 2 0 0 -5 5 6 4  
Stat us:  
Fi n al  
E u dra C T N o.: 2 0 1 7 -0 0 3 3 8 0 -3 5  
P a ge:  
1 4  of 3 4  
 
 
C o m peti n g ris k f r o m n o n-C V deat h is ha n dle d as ce ns ori n gs i n t he C o x a nal ysis as d escri be d i n 
secti o n 2. 2. 4 . Please, refer t o Ta ble 6 -1  f or ha n dli n g of ot her i nterc urre nt e v e nts. 
E ac h c o m p o ne nt  of t he pri mar y e n d p oi nt is i ncl u de d as a sec o n dar y en d p oi nt , see secti o ns 2. 4. 1  a n d 
2. 4. 2 . 
2. 3. 2  
Se nsiti vit y a n al ys es 
If s u peri orit y is esta blis h e d f or t he pri mar y e n d p oi nt, t he f oll o wi n g se nsiti vit y a n al yses are 
perf or me d. T he pri mar y a nal ysi s ass u mes  i n de pe n de nt ce ns ori n g f or s u bjects w h o  ha ve wit h dra w n 
c o nse nt or are l ost t o f oll o w -u p . T o i n vesti gate t he i m pact of t his ass u m pti o n o n t he pri mar y 
a nal ysis, a 2 -w a y ti p pi n g p oi nt a nal ysis base d o n t he a p pr oac h des cri be d i n Z ha o et al. ( 2 0 1 4)4 is 
perf or me d . I n t his a nal ysis, s u bjects i n t he t w o treat me nt gr o u ps w h o ha ve wit h dra w n or are l ost t o 
f oll o w-u p will ha ve e v e nt  ti mes i m p ute d fr o m t he c on diti o nal e ve nt  distri b uti o n wit h a pe nalt y i n 
t he se nse t hat the  ris k ( hazar d) of M A C E is c ha n ge d  f oll o wi n g ce ns ori n g c o m pare d t o w hile u n der 
o bser vati o n. M ulti ple i m p ute d data sets are a n al ys e d wit h se parate C o x re gressi o ns a n d res ults are 
c o m bi ne d usi n g R u bi n’s r ule.  T he ti p pi n g p oi nts are t he n defi ne d as t he c o m bi nati o n of c ha n ges i n 
pe nalties (i n eac h of t he treat me nt gr o u ps) n ee d e d t o t ur n ar o u n d t he s u peri orit y c o n cl usi o n.  
T w o a d di ti o nal se nsiti vit y a n al ys es will be perf or me d b y m ulti ple i m p utati o n of  e ve nt ti mes f or 
s u bjects w h o  are wit h dra w n or l ost t o f oll o w -u p.  If t he i m p ute d e ve nt ti me occ urs after t he s u bjects 
pla n ne d e n d -of -trial ti me t he s u bject will be ce ns ore d at t he pla n ne d e n d-of -trial ti me 
T he first will be d o ne b y treat me nt ar m usi n g a n esti mate d a n n ual e ve nt r ate fr o m s u bjects w h o 
disc o nti n ue treat me nt per ma ne ntl y b ut r e mai n i n t he trial. T he e v e nt rate will be base d o n e ve nts 
a n d ti me w hile t hese s u bj ects are per ma n e n tl y off-treat me nt. A ti me-p oi nt i n t he i n -trial o bser vati o n 
peri o d is c o nsi dere d as b el o n gi n g t o t he per ma ne ntl y off -treat me nt p eri o d if a n y d ose of tri al 
pr o d uct has bee n a d mi nistere d m ore t h a n 5 wee ks ( 3 5 da ys) a g o a n d t he s u bject re mai ns off -
treat me nt for t he re mai n d er of t he trial. T his a nal ysis c o n diti o n o n t he f ut ure i n t he se nse t hat 
s u bjects are o nl y k n o w n t o be per ma n e ntl y off treat me nt b y t he e n d of t he trial.  
T he sec o n d a nal ysis a v oi ds c o n diti o ni n g o n t he f ut ure b y usi n g a n esti mate d a n n ual e ve nt  rate f or 
s u bjects w h o disc o nti n ue treat me nt at a n y p oi nt i n t he trial. T he i m p utati o ns are d o ne b y treat me nt 
ar m. T he e v e nt rate will be base d o n e ve nts occ urri n g fr o m t he first ti me s u bjects are off treat me nt 
c orres p o n di n g t o w h e n t heir first o n -treat me nt peri o d e n ds (secti o n 2. 2. 2 ) a n d u ntil e n d of t he i n -
trial o bser vati o n peri o d. T his ma y i ncl u de ti me peri o ds w here t h e s u bjects act uall y we nt bac k o n 
trial treat me nt. 
Tec h nicall y, t he first of t he t w o se nsiti vit y a nal ys es will be perf or me d i n t he f oll o wi n g ste ps:  
1.  F or t he p ur p os e of esti mati n g t he off -treat me nt e ve nt rates, a set of retrie v e d dr o p o uts are 
selecte d. T h e selecti o n criteria are t hat t he s u bject s hall be a trial c o m pleter, ha ve t heir dat e 
V V- C LI N- 1 1 1 2 7 3
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C O N FI D E N TI A L


Statistical A nal ysis Pla n  
 
Date:  
2 2 A pril 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:  
3. 0  
U T N: U 1 1 1 1 -1 2 0 0 -5 5 6 4  
Stat us:  
Fi n al  
E u dra C T N o.: 2 0 1 7 -0 0 3 3 8 0 -3 5  
P a ge:  
1 5  of 3 4  
of last d ose d uri n g t he tri al re p orte d as a tr eat me nt disc o nti n uati o n, ha ve e n de d t he o n-
treat me nt o bser vati o n peri o d bef ore t he e n d of t he i n-trial o bser vati o n peri o d, a n d n ot ha vi n g 
ha d a n e v e nt bef ore t he e n d of t he o n -treat me nt o bser vati o n peri o d. F or eac h selecte d 
s u bject, t he off-tr eat me nt e ve nt ti me is calc ulate d fr o m a start dat e set t o t he da y aft er t he 
e n d of t he o n -tr eat me nt o bser vati o n peri o d. T he e v e nt ti me is c o nsi dere d ce ns ore d at t he e n d 
of t he i n -trial o bser v ati o n peri o d. 
2.
T he off -tr eat me nt e v e nt ti me data are fitte d wit hi n treat me nt ar ms t o a n e x p o ne ntial
distri b uti o n usi n g Ba yesi a n a nal ysis a n d acc o u nti n g f or ce ns ori n g. A n o ni nf or mati ve pri or
distri b uti o n is use d f or t he rate para m eter i n eac h treat me nt ar m. 5 0 0 re plicates of t he t w o
off -treat me nt e ve nt r ates are t he n ra n d o ml y sa m ple d fr o m t he p osteri or distri b uti o n.
3.
T o pre pare t he i m p utati o n, 5 0 0 c o pies of t he ori gi nal data set are creat e d a n d li n ke d t o t he
c orres p o n di n g re plicate of t he off -tr eat me nt e ve nt rates. F or eac h s u bject w h o is ce ns ore d
d ue t o wit h dr a wal or b ei n g l ost t o f oll o w u p, t he e ve nt ti me is i m p ute d b y a d di n g a ra n d o m
varia ble t o t he ori gi nal ce ns ori n g dat e. T he ra n d o m varia bles are ge n erate d fr o m a n
e x p o ne ntial distri b uti o n usi n g t he off -treat me nt e ve nt rate f or t he c orres p o n di n g re plicate
a nd treat me nt ar m, a n d r o u n de d u p t o w h ole da ys. If t he i m p ute d e ve nt ti me lies be y o n d t he
pla n ne d date of e n d of tri al f or t he s u bject, it is c o nsi dere d ce ns ore d at t his date. T here will
n o w be 5 0 0 c o m plete d ata sets.
4.
Eac h c o m plete d ata set is a nal ys e d usi n g t he sa me C o x re gressi o n as i n t he pri mar y a nal ysis.
T he a nal ysis gi ves t he esti mate d l o g hazar d rati o a n d ass ociate d sta n dar d err or.
5.
T he l o g h azar d rati os a n d sta n dar d err ors fr o m t he 5 0 0 data sets are p o ole d usi n g R u bi n’s
r ule t o o btai n a si n gl e p oi nt esti mate, c o nfi de nce i nter val a n d p-v al ue.
T he pr oce d ure f or t he sec o n d se nsiti vit y a nal ysis is i de ntical t o t he first a nal ysis e x ce pt f or ste p 1. 
T he selecti o n criteria f or a retrie v e d dr o p o ut are i nstea d t hat t he s u bject s hall ha ve t heir date of last 
d ose  d uri n g t h e first o n -tr eat me nt o bser vati o n peri o d re p orte d as a treat me nt disc o nti n uati o n, ha ve 
e n de d t he first o n -treat m e nt o bser vati o n peri o d b ef ore t he e n d of t he i n-trial o bser vati o n peri o d a n d 
n ot ha vi n g ha d a n e v e nt d uri n g t he first o n -treat me nt o bser vati o n peri o d. T he selecti o n ma y i ncl u de 
s u bjects w h o are later wit h dra w n or l ost t o f oll o w-u p. T he off -tr eat me nt e ve nt ti me is calc ulate d 
fr o m a start dat e set t o t he da y aft er t he e n d of t he first o n-treat me nt o bser vati o n peri o d.  
2. 3. 3  
S u p ple me nt ar y a n al yses  
T he f oll o wi n g s u p ple m e ntar y a nal yses  are pl a n ne d : 

A bs ol ute ris k differe nce: Esti mati o n of t he a bs ol ute ris k differe nce (a n d 9 5 % CI) at wee k
1 5 6  bet wee n s e ma gl uti de 2. 4 m g a n d s e ma gl uti de place b o bas e d o n t he c u m ulati ve
i nci de nce f u ncti o n f or eac h treat me nt gr o u p. If t he trial is st o p pe d earl y f or s u peri orit y, wee k
1 0 4 will be use d.
V V- C LI N- 1 1 1 2 7 3
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C O N FI D E N TI A L


Statistical A nal ysis Pla n  
 
Date:  
 
 
2 2 A pril 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:  
3. 0  
U T N: U 1 1 1 1 -1 2 0 0 -5 5 6 4  
Stat us:  
Fi n al  
E u dra C T N o.: 2 0 1 7 -0 0 3 3 8 0 -3 5  
P a ge:  
1 6  of 3 4  
 
 
 O n -treat me nt: A n al ysis a d dressi n g t h e sec o n d ar y esti ma n d usi n g a C o x pr o p orti o nal hazar ds 
m o del  usi n g t he first o n-treat me nt peri o d. 
 A d diti o nall y, a n a n al ysis of n o n -C V  deat h usi n g t h e sa me C o x m o del as f or t he pri mar y 
e n d p oi nt will be d o ne t o e val uate t he i nfl u e nce of t he c o m peti n g ris k n o n -C V -deat h o n t he 
pri mar y res ults.  
 
2. 3. 4  
S u b gr o u p a n al ys es 
T he c o nsiste nc y i n t he tr eat me nt effect f or t he pri mar y e n d p oi nt is e x pl ore d b y s u b gr o u p a nal yses 
base d o n t he bel o w b aseli ne i nf or mati o n : 
 Se x : Fe males, Males  
 A ge : < 5 5 , [ 5 5, 6 5[, [ 6 5, 7 5[, ≥7 5  
 Race:  W hite, Blac k or Africa n -A m erica n, Asia n, Ot her  
 Et h nicit y : His pa nic/ Lati n o, N ot his pa ni nc /lati n o 
 H b A 1c < 5. 7 % ( yes/ n o)  
 B MI : < 3 0,  [ 3 0, 3 5[, [ 3 5, 4 0[, [ 4 0, 4 5[, ≥4 5  
 C V disease : MI al o ne, Str o ke al o ne, P A D al o ne, a n y c o m bi nati o n  
 e G F R ≥6 0 ml/ mi n/ 1. 7 3 m 2 per C K D -E PI ( yes/ n o)  
 Re gi o n:  E ur o pe , N ort h A merica Asia, Ot her w here t he re gi o ns are defi ne d as f oll o ws:   
o  E ur o pe : A ustria, Bel gi u m,  B ul garia, Cr oatia, Czec h Re p u blic, De n mar k, Fi nla n d, 
Fra n ce, G er ma n y, Greece, H u n gar y, Irela n d, Ital y, Lat via, Ne t herla n ds, N or wa y, 
P ola n d, P ort u gal, R o ma nia, Ser bia, S pai n, S we de n, U nite d Ki n g d o m,   
o  N ort h A meric a : Ca na d a, , U nite d States,  
o  Asi a : A ustralia ,  , I n dia, Israel, J a pa n, Mala ysia, , Tai wa n, T haila n d, T ur ke y,  
o  Ot her : Al geria, S o ut h Africa, R ussia, , U krai ne, Ar ge nti na, Brazil, C ol o m bia, 
Me xic o  
 C hr o nic heart fail ure ( yes/ n o)  
 
T he s u b gr o u p a n al ys es are base d o n C o x pr o p orti o nal hazar ds m o dels wit h a n i nteracti o n bet w ee n 
treat me nt gr o u p (s e ma gl uti de 2. 4 m g , se ma gl uti d e place b o) a n d t he s p ecifi c s u b gr o u p as a fact or. 
2. 3. 5  
S u p ple me nt ar y a n al yses e v al u ati n g i m p act of t he C O VI D -1 9  p a n de mi c   
T he f oll o wi n g s u p ple m e ntar y a nal yses will be ma de t o assess t he i m pact of t he C O VI D -1 9 
pa n de mic o n t he pri mar y e n d p oi nt. T he a nal yses a d dress t w o sce n ari os : o ne w here M A C Es are 
i m pacte d b y a n i ncreas e d M A C E rate a n d p ote ntiall y a differe nt treat me nt effect f or e v e nts 
occ urri n g  c o nc urre ntl y wit h C O VI D -1 9 i nfecti o n ; t he ot her wit h a re d uce d M A C E rate d ue t o 
c o nc urre nt C O VI D -1 9  i nfecti o n lea di n g t o f e wer C V deat hs as t he s u bjects die ( pre mat urel y) of 
C O VI D -1 9 i nfecti o n a n d n ot t heir u n derl yi n g at her oscler otic dise ase.   
V V- C LI N- 1 1 1 2 7 3
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C O N FI D E N TI A L


Statistical A nal ysis Pla n  
 
Date:  
 
 
2 2 A pril 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:  
3. 0  
U T N: U 1 1 1 1 -1 2 0 0 -5 5 6 4  
Stat us:  
Fi n al  
E u dra C T N o.: 2 0 1 7 -0 0 3 3 8 0 -3 5  
P a ge:  
1 7  of 3 4  
 
 
1.  Ti me fr o m r a n d o misati o n t o first M A C E wit h o ut c o nc urre nt C O VI D -1 9 S A E. T he 
defi niti o n of M A C E is m o difie d s o a n y M A C E occ urri n g  c o n c urre ntl y wit h a C O VI D -1 9 
S A E i n a s u bject is n ot c o nsi dere d a  M A C E . T h e o bser vati o n peri o d a n d ce ns ori n g are n ot 
c ha n ge d. A n y s u bs e q ue n t M A C E ca n t he n q ualif y t o be t he first M A C E f or t he s u bject. 
2.  Ti me fr o m ra n d o misati o n t o first M A C E wit h o ut c o nc urre nt C O VI D -1 9 A E. T he defi niti o n 
of M A C E is m o difie d s o a n y M A C E occ urri n g  c o nc urre ntl y wit h a C O VI D -1 9 A E i n a 
s u bject is n ot c o nsi dere d a M A C E . T he o bser vati o n peri o d a n d ce ns ori n g are n ot c ha n ge d. 
A n y s u bse q u e nt M A C E ca n t he n q ualif y t o be t h e first M A C E f or t he s u bj ect.  
3.  Ti me fr o m ra n d o misati o n t o first M A C E or n o n -C V deat h occ urri n g c o nc urre ntl y wit h a 
C O VI D -1 9 S A E . T he d efi niti o n of M A C E  is m o difie d t o i ncl u de n o n-C V deat hs p ote ntiall y 
relate d t o C O VI D-1 9. T h e o bser vati o n peri o d a n d ce ns ori n g are n ot c ha n ge d.  
T he a nal yses will be d o ne wit h t he sa me C o x re gressi o n m o del as f or t he pri mar y a nal ysis.  A n 
e ve nt is c o nsi dere d c o nc urri n g wit h a C O VI D -1 9 A E if t he e ve nt  o cc urs i n t he ti me peri o d fr o m t he 
start da y of t he C O VI D-1 9 A E a n d u ntil 3 0 da ys after t he last of t he f oll o wi n g t w o dat es: t he st o p 
date of t he C O VI D -1 9 A E or t he e n d of h os pitalis ati o n date f or a h os pitalisati o n re p orte d t o get h e r 
wit h t he C O VI D -1 9 A E .  
2. 3. 6  
S u p ple me nt ar y a n al yses e v al u ati n g i m p act of c o-p artici p ati o n i n C O VI D -1 9 
tre at me nt or pre ve nti o n tri als 
T o assess t he p ote ntial i m pact o n t he pri mar y a nal ysis  of s u bjects bei n g all o we d t o c o -partici pate i n 
trials wit h 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 dical 
pr o d uct  f or tr eat me nt or pre ve nti o n of C O VI D-1 9 disease t he f oll o wi n g s u p ple me ntar y a n al ysis will 
be d o ne:  A n a n al ysis of ti me t o first M A C E w here all s u bjects c o -partici pati n g i n a C O V I D-1 9 
treat me nt or pre ve nti o n trial are ce ns ore d at t he d a y t h e y recei ve t he first trial treat me nt f or 
pre ve nti n g or treati n g C O VI D -1 9.  T his will re d u ce t he o bser vati o n ti me . 
T he  a nal ysis will be d o ne wit h t he sa me C o x re gressi o n m o del as f or t he pri mar y anal ysis.  
T he a nal ysis c orres p o n ds t o t he sit uati o n w here patie nts wit h dra w fr o m t he trial w he n t he y start c o -
partici pati o n.  
If less t ha n 1 0 s u bjects h a ve c o-p artici pate d i n C O VI D -1 9 tr eat me nt or pre ve nti o n trials t he n t his 
a nal ysis will n ot be perf or me d.  
  
2. 4  
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 are a n al ys e d u n der m ulti plicit y c o ntr ol.  
V V- C LI N- 1 1 1 2 7 3
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C O N FI D E N TI A L


Statistical A nal ysis Pla n  
 
Date:  
 
 
2 2 A pril 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:  
3. 0  
U T N: U 1 1 1 1 -1 2 0 0 -5 5 6 4  
Stat us:  
Fi n al  
E u dra C T N o.: 2 0 1 7 -0 0 3 3 8 0 -3 5  
P a ge:  
1 8  of 3 4  
 
 
2. 4. 1  
C o nfir m at or y s ec o n d ar y e n d p oi nts  
If s u peri orit y is esta blis h e d f or t he pri mar y e n d p oi nt, t he s u peri orit y h y p ot h esis state d i n secti o n 
2. 3. 1  is teste d f or eac h of t he c o nfir mat or y s ec o n d ar y e n d p oi nts u n der m ulti plicit y c o ntr ol via a 
sta ge wise hierarc hi cal testi n g sc he me  usi n g t he b el o w  or der :    
1.  Ti me fr o m ra n d o misati o n t o C V deat h. 
2.  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 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  
3.  Ti me fr o m ra n d o misati o n t o all -ca use d eat h.  
 
F or t he t y pe I er r or rate t o be str o n gl y c o ntr olle d at o ne-si de d le vel of 2. 5 %, a se parate al p h a 
s pe n di n g f u ncti o n f or t he c o nfir mat or y sec o n dar y e n d p oi nts is a p plie d as descri be d i n Gli m m et al. 
( 2 0 1 0)5. T he o ne-si de d al p ha s pe n di n g f u ncti o n is gi ve n b y 
    
𝑓(𝑡) = mi n {𝑧∗𝛼0 .7 6 6 8 ,𝑡} 
 
w here t is t he pr o p orti o n of i nf or mati o n i ncl u de d i n t he a nal ysis f or t he pri mar y e n d p oi nt a n d α is 
t he o verall o ne-si de d al p ha of 2. 5 %.  
 
T he 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 usi n g t he n o mi nal si g nifica n ce le vel.  N o a dj ust me nts of res ults f or t he 
c o nfir mat or y sec o n dar y e n d p oi nts d ue t o t he gr o u p se q ue ntial desi g n will be d o ne.  
 
Ta ble 2 -3  pr o vi des a n e x a m ple of t he b o u n daries at i nteri m a n d sc he d ule d ter mi nati o n i n t he case 
w here t he i nteri m is c o n d ucte d at 2/ 3 of t he pla n ne d  n u m ber of pri mar y e n d p oi nt e ve nts a n d w here 
t he n u m ber of e v e nts f or t he sec o n dar y e n d p oi nt at sc he d ule d ter mi nati o n is 3/ 2 ti mes t he n u m ber of 
sec o n dar y e n d p oi nt e ve nts at t he i nteri m. 
T he act ual n o mi nal si g nifica nce le vel will be bas e d o n t he e x act n u m ber of e ve nts a vaila ble at t he 
i nteri m a nal ysis.   
T a ble 2 -3  
N o mi n al si g nific a nce le vel f or c o nfir m at or y s ec o n d ar y e n d p oi nts  at i nteri m a n d 
sc he d ule d ter mi n ati o n –  a n e x a m ple  
St o p pi n g b o u n d ar y sc ale  
I nteri m 
 
Sc he d ule d ter mi n ati o n  
 
N o mi nal si g nifica nce le vel  
0. 0 1 8 3 2  
0. 0 1 3 2 9  
 
T he c o nfir mat or y sec o n d ar y e n d p oi nt s are a nal ys e d usi n g a C o x pr o p orti o nal hazar ds m o del  as 
descri be d f or t he pri mar y e n d p oi nt  a n d a d dressi n g t he pri mar y esti ma n d.  S u p ple me ntar y a n al ys es 
V V- C LI N- 1 1 1 2 7 3
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C O N FI D E N TI A L


Statistical A nal ysis Pla n  
 
Date:  
 
 
2 2 A pril 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:  
3. 0  
U T N: U 1 1 1 1 -1 2 0 0 -5 5 6 4  
Stat us:  
Fi n al  
E u dra C T N o.: 2 0 1 7 -0 0 3 3 8 0 -3 5  
P a ge:  
1 9  of 3 4  
 
 
descri be d i n secti o n 2. 3. 3  f or t he pri mar y e n d p oi nt, will als o be d o ne f or t he c o nfir mat or y 
sec o n dar y e n d p oi nts. 
T he t w o se nsiti vit y a nal yses wit h i m p utati o n fr o m s u bjects off treat me nt will be d o ne f or all 
c o nfir mat or y sec o n dar y e n d p oi nts. (secti o n 2. 3. 2 ) S u p ple me ntar y a nal yses descri be d i n secti o n 
2. 3. 5  wit h re gar ds t o t he i m pact of t he C O VI D -1 9 pa n de mic f or t h e pri mar y e n d p oi nt will als o be 
d o ne f or car di o vas c ular d eat h  a n d t he H F c o m p osite e n d p oi nt . T he a nal ysis assessi n g t he p ot e ntial 
i m pact of c o-p artici pati o n  i n C O VI D-1 9 trials  (secti o n 2. 3. 6 ) will be d o ne f or all c o nfir m at or y 
sec o n dar y e n d p oi nts. 
S u p ple me nt ar y a n al yses f or H F  c o m p osite e n d p oi nt  
F or t he H F c o m p osite e n d p oi nt a s u p ple me ntar y a nal ysis will be d o ne b y re placi n g t he C V deat h 
c o m p o ne nt wit h all -ca us e deat h.  
 
S u p ple me nt ar y a n al yses f or all -c a use de at h –  e xte n de d i n -tri al peri o d  
I n a d diti o n, all-ca use d eat h is a nal yse d usi n g F A S a n d a n e xte n de d i n -trial o bser vati o n peri o d 
i ncl u di n g t he f oll o w-u p f or vital stat us f or s u b jects w h o wit h dra w c o ns e nt or are L F T U. T he 
relati ve ris k f or t h e bi nar y e n d p oi nt deat h/ali ve will be c o m pare d b et wee n t he t w o treat me nt gr o u ps 
usi n g t he li keli h o o d rati o met h o d . T he m o del is c h ose n beca us e it d oes n’t d e pe n d o n t he 
o bser vati o n ti me w hic h i s o nl y e xte n de d f or s u bjects wit h dra w n or L T F U.  
 
2. 4. 2  
S u p p orti ve sec o n d ar y e n d p oi nts  
2. 4. 2. 1  
T T E s u p p orti ve sec o n d ar y e n d p oi nts  
Eac h of t he T T E s u p p orti ve sec o n dar y e n d p oi nts are a nal ys e d usi n g a C o x pr o p orti o nal hazar ds 
m o del as descri be d f or t h e pri mar y e n d p oi nt a n d a d dressi n g t h e pri mar y esti ma n d.  
F or t he e G F R c o m p o n e nts  of t he c o m p osite ne p hr o pat h y e n d p oi nt , a persiste nt o utc o me i n e G F R is 
defi ne d as h a vi n g t w o c o nsec uti ve ce ntral la b orat or y assess me nts at least 4 wee ks a p art meeti n g t he 
criteria. W he n classif yi n g t he e ve nts base d o n c o nsec uti ve la b orat or y assess me nts, t he date of t he 
e ve nt is t he date of t h e first sa m ple meeti n g t he criteri o n . If e G F R at bas eli ne is bel o w 1 5 
ml/ mi n/ 1. 7 3 m 2 t he s u bject will still be i ncl u de d i n t he a nal ysis as t he s u bject still ca n e x perie nce 
o ne of t he ot her f o ur c o m p o ne nt e ve nts.  
F or t he ma cr oal b u mi n uri a c o m p o ne nt a p ersiste nt o utc o me is defi ne d as h a vi n g 2 o ut of 3 
c o nsec uti ve ce ntral la b orat or y assess me nts of U A C R at least 4 wee ks a p art meeti n g t he criteri o n . 
W he n classif yi n g  t he e ve nts base d o n c o nsec uti ve la b orat or y ass ess me nts, t he date of t he e ve nt is 
t he date of t he first sa m ple meeti n g t he criteri o n .  
V V- C LI N- 1 1 1 2 7 3
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C O N FI D E N TI A L


Statistical A nal ysis Pla n  
 
Date:  
 
 
2 2 A pril 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:  
3. 0  
U T N: U 1 1 1 1 -1 2 0 0 -5 5 6 4  
Stat us:  
Fi n al  
E u dra C T N o.: 2 0 1 7 -0 0 3 3 8 0 -3 5  
P a ge:  
2 0  of 3 4  
 
 
 
S u p ple me nt ar y a n al yses f or MI  a n d str o ke  
F or  MI a n d str o ke , s u p pl e me ntar y a n al yses i ncl u di n g fat al MI a n d fatal str o ke are p erf or me d.  T h us, 
t he s u p ple me ntar y a n al ysis will a nal yse e n d p oi nts defi ne d as  
 Ti me fr o m ra n d o misati o n t o first MI (fatal or n o n -fatal) 
 Ti me fr o m ra n d o misati o n t o first str o ke (fatal or n o n-fatal). 
 
S u p ple me nt ar y a n al ys is f or 5-c o m p o ne nt M A C E  
F or t he 5 -c o m p o ne nt M A C E a s u p ple me ntar y a n al ysis will be d o ne b y re placi n g t h e C V deat h 
c o m p o ne nt wit h all -ca us e deat h . 
2. 4. 2. 2  
C o nti n u o us s u p p orti ve sec o n d ar y e n d p oi nts  
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 wee k 1 0 4 ) are a nal yse d 
usi n g m ulti ple i m p utati o n f or missi n g val ues. 
T he i m p utati o n m o del (li near re gressi o n) is d o n e se parat el y f or eac h tr eat m e nt ar m a n d  i ncl u des 
baseli ne val ue as a c o v ari ate a n d fitte d t o s u bjects ha vi n g  a n o bser ve d data p oi nt (irres pecti ve of 
a d here n ce t o r a n d o mise d treat me nt) at wee k 1 0 4 . T he fitte d m o del is use d t o i m p ute val ues f or all 
s u bjects wit h missi n g data (see s ecti o n 2. 2 ) at w ee k 1 0 4  t o create c o m plete data sets. S u bjects 
wit h o ut a baseli ne meas ure me nt will n ot be part of t he m o del. T he c o m plete data sets are a nal ys e d 
b y a n A N C O V A wit h  treat me nt as fi x e d fact or a n d baseli ne val ue as c o variate. R u bi n’s r ule is use d 
t o c o m bi ne t he results. A nal yse s of li pi ds a n d hs C R P are o n l o garit h mic scale.  
A d diti o nall y, a nal yses f or b o d y wei g ht a n d H b A 1c are carri e d o ut at wee k 5 2, 1 5 6, 2 0 8 if less t ha n 
1 0 % of s u bjects fr o m F A S ha ve misse d t he c orres p o n di n g visit  d ue t o trial ter mi nati o n , see secti o n 
2. 2. 5 . 
Se nsiti vit y a n al ys es f or b o d y w ei g ht  
Se nsiti vit y a n al ys es f or b o d y w ei g ht ( wee k 5 2, 1 0 4, 1 5 6, 2 0 8) usi n g a m ulti ple i m p utati o n a p pr oac h 
i n w hic h missi n g val ues  i n b ot h treat me nt ar ms are i m p ute d usi n g a n i m p utati o n m o del f or t he 
place b o gr o u p o nl y (irres pecti ve of a d h ere nce t o r a n d o mise d treat me nt at ti me-p oi nt ). T his 
a p pr oac h is r eferre d t o as a j u m p t o refere nce m ulti ple i m p utati o n a p pr oac h (J 2 R -MI).  
S u p ple me nt ar y a n al ysi s f or b o d y w ei g ht  
T he c ha n ge i n b o d y wei g ht fr o m ra n d o misati o n t o wee k 5 2 will a d diti o nall y be a nal yse d t o a d dress 
t he sec o n dar y esti ma n d (secti o n 2. 2. 3 ) usi n g a mi x e d m o del f or re peat e d meas ure me nts ( M M R M ). 
T he m o del will use assess me nts fr o m t he first o n -treat me nt o bser vati o n peri o d restricte d t o t he first 
V V- C LI N- 1 1 1 2 7 3
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C O N FI D E N TI A L


Statistical A nal ysis Pla n  
 
Date:  
 
 
2 2 A pril 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:  
3. 0  
U T N: U 1 1 1 1 -1 2 0 0 -5 5 6 4  
Stat us:  
Fi n al  
E u dra C T N o.: 2 0 1 7 -0 0 3 3 8 0 -3 5  
P a ge:  
2 1  of 3 4  
 
 
5 2 wee ks , see secti o n 2. 2. 2 . Pla n ne d assess me nts u p u ntil a n d i ncl u di n g t he wee k 5 2 asses me nts  
t hat are wit hi n t he first o n-treat me nt peri o d are i n cl u de d i n t he m o del. T he M M R M is fitte d wit h 
treat me nt (se ma gl uti de 2. 4 m g , se ma gl uti de place b o) as fi x e d fact or a n d bas eli ne b o d y wei g ht ( k g) 
as c o vari ate all neste d wit hi n visit. A n u nstr uct ure d c o vari a n ce matri x f or meas ure me nts wit hi n t he 
sa me s u bject is e m pl o ye d.  
2. 4. 2. 3  
S u p p orti ve sec o n d ar y e n d p oi nts b ase d o n s u bsets of F A S  
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 < 5. 7 %  
 Ti me fr o m baseli ne t o H b A 1c ≥ 5. 7 %  
T he  T T E  e n d p oi nt is 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 2. 4 m g , s e ma gluti de pla ce b o) as fi x e d fact or.  
T he f oll o wi n g e n d p oi nt s are defi ne d o nl y f or s u bj ects wit h a scree ni n g H b A 1c ≥ 5. 7 %  
 H b A 1c < 5. 7 %  ( yes/ n o) at eac h visit w here  H b A 1c is assesse d 
T he bi nar y e n d p oi nt s are a nal ys e d se p aratel y at wee k 5 2  a n d wee k 1 0 4 usi n g l o gistic re gressi o n 
m o del s wit h treat me nt ( s e ma gl uti de 2. 4 m g , se m a gl uti de place b o) as fi x e d fact ors a n d b aseli ne 
H b A 1 c as c o variate. Missi n g data are i m p ute d usi n g t he sa m e pri mar y i m p utati o n m o del as f or t he 
s u p p orti ve sec o n dar y e n d p oi nt c ha n ge i n H b A 1c. T he i m p utati o n m o del will o nl y i ncl u de s u bjects 
wit h a scree ni n g H b A 1c ≥ 5. 7 %.  
2. 5  
E x pl or at or y e n d p oi nts  
S m o ki n g  
S m o ki n g ( yes/ n o) is a nal ys e d s e paratel y at wee k 5 2 a n d wee k 1 0 4 usi n g l o gistic re gressi o n m o dels 
wit h treat me nt ( se ma gl uti de 2. 4 m g , se ma gl uti de place b o) a n d baseli ne s m o ki n g stat us ( yes/ n o) as 
fi x e d fact ors. Missi n g dat a are h a n dle d b y m ulti ple i m p utati o n. T he i m p utati o n m o del (l o gistic 
re gressi o n) is d o ne s e paratel y f or eac h tr eat me nt ar m a n d i ncl u des baseli ne s m o ki n g stat us as fi x e d 
fact or a n d fitte d t o s u bjects ha vi n g a n o bs er ve d d ata p oi nt (irres pecti ve of a d here nce t o ra n d o mise d 
treat me nt) at w ee k 5 2 a n d wee k 1 0 4 , res pecti vel y. T he fitte d mo del is use d t o i m p ute val ues f or all 
s u bjects wit h missi n g data (see s ecti o n 2. 2 ) at w ee k 5 2 a n d wee k 1 0 4 , res pecti vel y.  
Gl yc ae mi c st at us  
Deteri or ati o n fr o m baseli ne t o wee k 1 1 7 i n gl ycae mic stat us as assesse d b y i n vesti gat or ( yes/ n o, 
w here “ yes” is det er mi ne d b y a c ha n ge  fr o m n or m o gl ycae mia at bas eli ne t o pre-dia betes/ dia betes at 
wee k 1 1 7 or fr o m pre -dia betes at baseli ne t o dia b etes at wee k 1 1 7 ) is a nal yse d usi n g a l o gistic 
re gressi o n m o del wit h treat me nt (se ma gl uti de 2. 4 m g , se ma gl uti de place b o) as fi x e d fact or a n d 
basel i ne H b A1c as c o vari ate.  Missi n g data p ost b aseli ne are h a n dle d b y m ulti ple i m p utati o n  base d 
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C O N FI D E N TI A L


Statistical A nal ysis Pla n  
 
Date:  
 
 
2 2 A pril 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:  
3. 0  
U T N: U 1 1 1 1 -1 2 0 0 -5 5 6 4  
Stat us:  
Fi n al  
E u dra C T N o.: 2 0 1 7 -0 0 3 3 8 0 -3 5  
P a ge:  
2 2  of 3 4  
 
 
o n t he val ue of t he eit her o bser ve d or i m p ute d H b A 1c val ue at wee k 1 0 4 . T he i m p utati o n of H b A 1c 
val ues is descri be d i n secti o n 2. 4. 2. 2 . S u bjects wit h missi n g gl ycae mic stat us at baseli ne will n ot be 
i ncl u de d. 
All -c a use h os pit alis ati o ns  
T w o e x pl orat or y e n d p oi nts are defi n e d fr o m all -ca use h os pitalisati o ns. T hese are a nal yse d as a 
rec urre nt e v e nts pr ocess wit h all-ca use d eat h as a c o m peti n g ris k ( t er mi nal e ve nt) a n d w here e ve nts 
are ha vi n g a d urati o n , i.e. le n gt h of sta y i n h os pital. Ce ns ori n g of o bs er vati o ns are d o ne as f or T T E 
e n d p oi nts, see secti o n 2. 2. 4 . 
T ot al n u m ber of h os pit alis ati o ns  
N u m ber of h os pitalisati o ns is a nal ys e d i g n ori n g ti me peri o ds w he re s u bjects are h os pitalise d, a n d 
ac k n o wle d gi n g t he fact t hat deat h pre cl u des f urt her h os pitalisati o ns  6, 7. Mea n  n u m ber of 
h os pitalisati o ns is pl otte d as a  f u ncti o n of st u d y time  a n d a nal yse d  usi n g a mar gi n al mea n 
re gressi o n m o del f or rec urre nt e v e nts wit h treat m e nt gr o u p ( se ma gl uti de 2. 4 m g , se ma gl uti de 
place b o) as fi x e d fact or  a n d re p orte d as mea n rati o a n d c orres p o n di n g  9 5 % r o b ust C I 8. T his is d o ne 
f or t he f ull trial d urati o n. A d diti o nall y, descri pti ve c o m paris o ns of treat me nt gr o u ps at year  1,  2,  3,  
a n d 4 are pl a n ne d . 
T ot al n u m ber of h os pit al  d a ys  
T otal le n gt h of sta y ( da ys) i n h os pital as a f u ncti o n of st u d y ti me  is esti mate d usi n g met h o ds f or 
m ulti -state m o dels. S pecificall y, t h e mea n ti me s p e nt i n h os pital (state 1 i n Fi g ure 2 – 4 ) p er 
treat me nt gr o u p is esti mate d as t he i nte gral  of t h e  state occ u pati o n pr o ba bilit y  of  be i n g i n h os pital 
o ver d ur ati o n of t he i n -trial o bser vati o n peri o d9. C o m paris o ns of treat me nt gr o u ps are pla n ne d  at 
year 1, 2, 3, a n d 4  se paratel y usi n g t he met h o d of pse u d o o bser vati o ns 1 0. 
Ta ble 6 -4  gi ves a n o v er vi e w of pla n ne d a nal yses f or all e n d p oi nts.  
C ha n ge fr o m bas eli ne t o wee k 1 0 4 f or W R S S M t otal sc ore will be prese nte d descri pti vel y.  
 
2. 6  
O t her assess me nts 
A d verse e v e nts  
All s yste maticall y c ollecte d A Es, i.e. seri o us A Es a n d n o n -seri o us e v e nts re q uiri n g e xtra data 
c ollecti o n are s u m marise d as 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 b er of e v e nts a n d rat e of e ve nts acc or di n g t o treat me nt gr o u p. S u m maries of S A Es are 
cate g orise d b y s e verit y, relati o n t o treat me nt, a n d o utc o me.  
V V- C LI N- 1 1 1 2 7 3
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C O N FI D E N TI A L


Statistical A nal ysis Pla n  
 
Date:  
 
 
2 2 A pril 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:  
3. 0  
U T N: U 1 1 1 1 -1 2 0 0 -5 5 6 4  
Stat us:  
Fi n al  
E u dra C T N o.: 2 0 1 7 -0 0 3 3 8 0 -3 5  
P a ge:  
2 3  of 3 4  
 
 
Descri pti ve s u m maries  of c o nc o mita nt me dicati o n (li pi d l o weri n g, a nti -h y p erte nsi ve, gl uc ose -
l o weri n g) are prese nte d as well as d escripti ve s u m mar y of n o n -C V deat hs  b y treat me nt gr o u p . 
3  
I nteri m testi n g 
T he trial desi g n i ncl u des o ne  pre -pl a n ne d i nteri m t esti n g f or s u peri orit y of t he pri mar y e n d p oi nt. 
T he pla n ne d ti mi n g is w h e n 8 1 7 e ve nts ( t w o t hir ds of t he pla n ne d t otal e ve nts) of t he pri mar y 
e n d p oi nt ha ve bee n accr ue d . T he i nteri m testi n g is perf or me d b ase d o n a l oc ke d s na ps h ot of t he 
st u d y data b ase. T he d ate of t he s na ps h ot defi nes t h e i nteri m a nal ysis c ut -off date f or t he i nteri m 
a nal ysis. S u bject s wit h o ut an  E A C -c o nfir me d pri mar y e n d p oi nt e ve nt pri or t o t he date of a nal ysis 
c ut-off are c o nsi dere d 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 o bser vati o n peri o d e n d-date  
 i nteri m a nal ysis c ut -off d ate  
 
T he sa me C o x m o del as descri be d i n secti o n  2. 3  is use d f or t he i nteri m testi n g a d dressi n g t he 
pri mar y esti ma n d . 
3. 1  
R ole of D M C  
Bli n de d a n d u n -bli n de d d ata a nal yses d uri n g trial c o n d uct are e val uate d  b y t he D M C, as descri be d 
i n t he D M C c harter. Trial i nte grit y is e ns ure d b y usi n g a n e xter nal i n de p e n de nt statistical ser vice 
pr o vi der ( i n de p e n de nt of trial c o n d uct a n d e xter nal t o N o v o N or dis k) t o pre pare t hes e data a n d 
a nal ys es f or t h e D M C.  
 
T he D M C will e val uate t he i nteri m res ult a n d ma ke rec o m me n d ati o n t o ter mi nate t he trial earl y f or 
s u peri orit y if a p pr o pri ate. T he D M C e val uates t h e u n-bli n de d i nteri m res ults usi n g t he gr o u p 
se q ue ntial st o p pi n g b o u n dar y as g ui da nce. St o p pi n g t he trial earl y f or s u peri orit y is o nl y all o we d if 
t he st o p pi n g b o u n dar y is cr osse d a n d t h e D M C ma kes t he decisi o n t o rec o m me n d earl y trial 
ter mi nati o n base d o n t his a n d ot her c o nsi derati o ns as s pecifie d i n t he D M C c harter.  
 
If t he D M C rec o m me n ds t o ter mi nate t he trial earl y d ue t o efficac y a N o v o N or dis k i nter nal gr o u p 
referre d t o as t he S E L E C T i nteri m tea m ( SI T) ) will e nter a dial o gu e wit h t he D M C t o facilitate t he 
fi nal decisi o n t o ter mi nat e or c o nti n ue. T his dial o g ue will be base d o n t he u n bli n de d res ults a n d 
o ut p ut f or mi n g t he basis f or t he D M C rec o m me n d ati o n t o ter mi nate S E L E C T. T he SI T will o nl y 
see o ut p ut/res ults t hat t he D M C s h o ws t he m d uri n g t he dial o g u e. T he SI T  will c o m prise a li mite d 
n u m ber of N o v o N or dis k pers o n nel w h o ha v e n o direct i n v ol ve me nt i n t he c o n d uct of S E L E C T . F or 
all ot her  eit her at N o v o N or d is k or a n y ot her p art y  t he rec o m me n d ati o ns fr o m t he D M C will 
e x cl u de a n y d etails of t he i nteri m res ults as t o mai ntai ni n g trial i nte grit y.  F urt her details are o utli ne d 
i n t he Data Access Ma n a ge m e nt Pla n.  
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C O N FI D E N TI A L


Statistical A nal ysis Pla n  
 
Date:  
 
 
2 2 A pril 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:  
3. 0  
U T N: U 1 1 1 1 -1 2 0 0 -5 5 6 4  
Stat us:  
Fi n al  
E u dra C T N o.: 2 0 1 7 -0 0 3 3 8 0 -3 5  
P a ge:  
2 4  of 3 4  
 
 
3. 2  
St o p pi n g b o u n d ar y f or s u peri orit y at i nteri m  
T he e x act n u m ber of pri mar y e n d p oi nt e ve nts use d f or t he i nteri m testi n g is o nl y k n o w n at t he ti me 
of a nal ysis, a n d t he e x act b o u n dar y is re-calc ul ate d usi n g t he La n -De M ets al p ha s pe n di n g f u ncti o n . 
3. 3  
A n al ysis o n ter mi n ati o n  
If t he trial is ter mi nate d earl y for s u peri orit y f oll o wi n g t he 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 is perf or me d base d o n all t he a v aila ble data at t he e n d -of -trial, 
i ncl u di n g o verr u n data. O verr u n d ata i ncl u de e ve nts ha p pe ni n g b et wee n t h e c ut -off d ate f or t he 
D M C i nteri m a nal ysis a n d e n d-of -tri al as well as a d diti o nal c o nfir me d e ve nts t hat were u n der g oi n g 
a dj u dicati o n at t he i nteri m a nal ysis c ut -off ti me p oi nt. If t he tri al is n ot ter mi nate d earl y f or 
s u peri orit y f oll o wi ng t he i nteri m testi n g, t he a nal ysis at sc he d ule d ter mi nati o n is  perf or me d w he n 
t he pla n ne d n u m ber of 1,2 2 5 e ve nts has  bee n accr ue d. T he e x act n u m ber of pri mar y e n d p oi nts 
e ve nts use d f or t h e a nal ysis o n ter mi nati o n is o nl y k n o w n at t he ti me of a nal ysis, a n d n o mi nal 
si g nifica n ce le v el is u p date d base d o n t he e x act n u m ber of t otal accr ue d e ve nts a n d t he La n-De Mets 
al p ha s pe n di n g f u ncti o n . Si milarl y , t he si g nifica nce le vel f or t h e c o nfir m at or y s ec o n dar y e n d p oi nts 
is u p date d base d o n t he e x act n u m ber of e ve nts  a n d all a vaila ble data at e n d -of -trial are use d f or 
a nal ys es of b ot h sec o n dar y a n d e x pl orat or y e n d p oi nts.  
 
F or re p orti n g of res ults  f or t he pri mar y e n d p oi nt ( p-val ue, H R a n d 9 5 % CI) , t he a nal ysis o n 
ter mi nati o n (eit her earl y or at sc he d ule d t er mi nati o n) is a dj uste d f or t he gr o u p se q u e ntial desi g n 
usi n g t he li keli h o o d rati o or deri n g . 
 
4  
C h a n ges t o t he st atistic al a n al ys is pl a n  
I n ge neral, t his S A P descri bes i n m ore details t he statistical a nal ys es pla n n e d i n t he pr ot oc ol.  
 
S A P versi o n 0. 1 d ate d 2 7 -J u n -2 0 1 8  
A nal ys es  a d de d i n t he S A P a n d n ot descri be d i n t he pr ot oc ol are  
 S u p ple me ntar y a nal yses f or pri mar y e n d p oi nt  a n d c o nfir mat or y sec o n dar y e n d p oi nts  
(secti o n 2. 3. 3 ) 
o  esti mati o n of ris k differe nce at year 3  
o  i ncl u di n g o ut-of -trial o bser vati o ns  
o  Sec o n dar y  esti ma n d ( o n-treat me nt) 
 S u p ple me ntar y a nal yse s of MI a n d str o ke usi n g b ot h fatal a n d n o n -fatal e v e nts  i n t he 
e n d p oi nts  (secti o n 2. 4. 2. 1 ) 
 A nal ys es b y year of c h a n ge i n b o d y wei g ht a n d H b A 1c (secti o n 2. 4. 2. 2 ) 
 S u p ple me ntar y  a nal ysis  ( M M R M) f or c ha n ge i n b o d y wei g ht at wee k 5 2  a d dressi n g t h e 
sec o n dar y esti ma n d (secti o n 2. 4. 2. 2 ) 
 A nal ysis of s m o ki n g stat us at wee k 5 2  (secti o n 2. 5 ) 
V V- C LI N- 1 1 1 2 7 3
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C O N FI D E N TI A L


Statistical A nal ysis Pla n  
 
Date:  
 
 
2 2 A pril 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:  
3. 0  
U T N: U 1 1 1 1 -1 2 0 0 -5 5 6 4  
Stat us:  
Fi n al  
E u dra C T N o.: 2 0 1 7 -0 0 3 3 8 0 -3 5  
P a ge:  
2 5  of 3 4  
 
 
 
A nal ys es fr o m pr ot o c ol u p date d  i n t he S A P 
 I m p utati o n m o del f or c o nti n u o us e n d p oi nts (secti o n 2. 4. 2. 2 ) is fitte d t o all s u bjects ha vi n g 
o bser ve d val u es (irres pecti ve of a d here nce t o ra n d o mise d treat me nt) at wee k 1 0 4  a n d n ot 
o nl y t o s u bjects bei n g off -treat me nt f or t he first ti me. 
 F or s u bjects wit h scree ni n g ≥ 5. 7 % t he a nal ysis of prese nce of H b A 1c< 5. 7 % ( yes/ n o) is 
d o ne at wee k 5 2 a n d 1 0 4 a n d n ot at eac h visit w here H b A 1c is assesse d (secti o n 2. 4. 2. 3 ). 
 
S A P versi o n 1. 0,  d ate d 1 1 -M ar -2 0 1 9  
T he fi x e d desi g n  has b ee n c ha n ge d t o a gr o u p se q ue ntial desi g n wit h o ne pre -defi ne d i nteri m testi n g 
f or s u peri orit y (s ecti o ns 1. 1. 3 , 1. 2 , 2. 1 , 2. 3. 1 , 2. 4. 1 , 3 ). 
 
Secti o n 2. 1  re d uce d b y e x cl u di n g a d diti o nal sce nari os f or t he sa m ple siz e c o nsi derati o ns. 
 
R em o ve d t he w or di n g “ca use -s pecific” ( hazar d) f or t he pri mar y a n al ysis t o ma ke it clear t h at a 
sta n dar d C o x m o de l is use d a n d t o ali g n wit h pr ot oc ol w or di n g  (secti o n 2. 2. 4 ). 
 
Se nsiti vit y a n al ysis f or t he pri mar y e n d p oi nt u p dat e d t o a 2 -wa y ti p pi n g p oi nt a nal ysis (secti o n  
2. 3. 2 ). 
 
S u p ple me ntar y a nal yses i ncl u de d f or 5 -c o m p o ne nt M A C E a n d 2 -c o m p o ne nt H F b y re pl aci n g C V 
deat h c o m p o ne nt wit h all -ca use d eat h (s ecti o n 2. 4. 2 ). 
 
S u p ple me ntar y a nal ysis “i ncl u di n g o ut -of -trial o bser vati o ns” o nl y pla n ne d f or all-ca us e deat h  a n d 
re na me d “e xte n de d i n -tri al peri o d”. 
 
I n ge neral, e dit orial c h a n ges f or ali g nme nt  wit h S A Ps f or trials E X 9 9 2 4 -4 4 7 3  ( S O U L) a n d 
N N 9 5 3 5 -4 3 2 1  ( F L O W). 
 
S A P versi o n 2. 0,  d ate d 3 1 -M ar -2 0 2 1  
A ut h or c ha n ge d fr o m 
 t o 
. 
 
T he defi niti o n of baseli n e val ue has b ee n u p dat e d  (secti o n 2. 2 ). 
 
It has b ee n clarifie d h o w missi n g data fr o m s u bjects w h o are L T F U or wit h dra w n are ha n dl e d 
(secti o n 2. 2 ). 
 
It has b ee n clarifie d h o w s u bjects ra n d o mise d m or e t ha n o nce will c o ntri b ute t o t he F A S (secti o n 
2. 2. 1 ). 
V V- C LI N- 1 1 1 2 7 3
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C O N FI D E N TI A L


Statistical A nal ysis Pla n  
 
Date:  
 
 
2 2 A pril 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:  
3. 0  
U T N: U 1 1 1 1 -1 2 0 0 -5 5 6 4  
Stat us:  
Fi n al  
E u dra C T N o.: 2 0 1 7 -0 0 3 3 8 0 -3 5  
P a ge:  
2 6  of 3 4  
 
 
 
T he f oll o w -u p peri o d has bee n c h a n ge d fr o m 7 wee ks ( 4 9 da ys) t o 5 wee ks ( 3 5 da ys) i n secti o n 
2. 2. 2  a n d t hr o u g h o ut t he d oc u me nt  i n ali g n me nt wit h pr ot oc ol versi o n 6. 0 . 
 
A defi niti o n of t he first o n -treat me nt peri o d has bee n a d de d (secti o n 2. 2. 2 ). T he use of it has bee n 
a d de d t o s u p ple me ntar y a nal ys es re gar di n g o n treat me nt  (secti o n 2. 2. 3 , 2. 3. 3  a n d 2. 4. 2. 2 ).  
 
It has b ee n clarifie d t h at tied e ve nt ti mes  are ha n dl e d usi n g t he e x act met h o d a n d ris k li mits are 
base d o n t he pr ofile li keli h o o d  (secti o n 2. 2. 4 ). 
It has b ee n clarifie d t h at it is less t ha n 1 0 % of s u bjects fr o m F A S w h o ca n h a ve missi n g visits d ue 
t o earl y ter mi nati o n f or i m p utati o ns t o be d o ne (secti o n 2. 2. 5 ). 
 
hs C R P will be a nal ys e d usi n g a l o g -n or mal distri b uti o n i nstea d of a n or mal distri b uti o n  (secti o n 
2. 2. 5  , 2. 4. 2. 2 , a n d 6 ). 
 
A s u p ple me ntar y a n al ysis of n o n -C V  deat h has b ee n a d de d t o e val uate t he effect of c o m peti n g ris k 
o n t he pri mar y e n d p oi nt (secti o n 2. 3. 3 ). 
 
I n t he s p ecificati o n of s u b gr o u p a nal yses E U has bee n c h a n ge d t o E ur o pe a n d a descri pti o n of 
w hic h c o u ntries bel o n g t o eac h re gi o n has bee n a d de d (secti o n 2. 3. 4 ). 
 
A secti o n descri bi n g s u p ple me ntar y a n al ys es assessi n g t he i m pact of t he C O VI D -1 9 p a n de mic o n 
t he pri mar y e n d p oi nt has bee n a d d e d (secti o n 2. 3. 5 ). T he a n al ys es will als o be d o ne f or t h e 
c o nfir mat or y sec o n dar y e n d p oi nt  C V deat h  (secti o n 2. 4. 1 ).   
 
A secti o n descri bi n g s u p ple me ntar y a n al ys es assessi n g t he i m pact of c o -partici pati o n i n C O VI D -1 9 
trials o n t he pri mar y e n d p oi nt has bee n a d de d (secti o n 2. 3. 6 ). T he a n al ys es will als o be d o ne f or t h e 
c o nfir mat or y sec o n dar y e n d p oi nts (secti o n 2. 4. 1 ).   
 
F or c o nfir mat or y sec o n d ar y e n d p oi nts t he si g nifica nce le vel use d i n t he hierac hical testi n g 
pr oce d ure has bee n c h a n ge d t o f oll o w a se parate al p ha s pe n di n g f u ncti o n  (secti o n 2. 4. 1 ). 
 
T he s u p ple me ntar y a nal ysis f or all ca use d eat h has bee n c h a n ge d t o be a c o m paris o n of relati ve 
ris ks f or t he bi nar y e n d p oi nt deat h/ali ve (secti o n 2. 4. 1 ). 
 
A state me nt re gar di n g s u bjects wit h baseli ne e G F R bel o w 1 5 ml/ mi n/ 1. 7 3 m 2  bei n g e x cl u de d fr o m 
t he a nal ysis of t he c o m p osite ne p hr o pat h y e n d p oi nt has bee n re m o ve d , a n d a descri pti o n o n h o w t he 
s u bject ca n me et t he e n d p oi nt has bee n a d de d (secti o n 2. 4. 2. 1 ). 
 
V V- C LI N- 1 1 1 2 7 3
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C O N FI D E N TI A L


Statistical A nal ysis Pla n  
 
Date:  
 
 
2 2 A pril 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:  
3. 0  
U T N: U 1 1 1 1 -1 2 0 0 -5 5 6 4  
Stat us:  
Fi n al  
E u dra C T N o.: 2 0 1 7 -0 0 3 3 8 0 -3 5  
P a ge:  
2 7  of 3 4  
 
 
Clarificati o n of t he e x act defi niti o n of t he differe nt c o m p o ne nts i n t he ne p h r o pat h y e n d p oi nt has 
bee n a d d e d (secti o n 2. 4. 2. 1 ).  
 
Clarificati o n as t o h o w t h e A N C O V A f or c o nti n u o us sec o n dar y e n d p oi nts s h o ul d be d o ne has bee n 
a d de d (secti o n 2. 4. 2. 2 ). 
 
Clarificati o n as t o h o w t h e s u p ple me ntar y a nal ysis of b o d y wei g ht a d d ressi n g t he sec o n dar y 
esti ma n d s h o ul d be d o ne has bee n a d d e d (secti o n 2. 4. 2. 2 ) 
 
F or t he a nal ysis of s m o ki n g , det ails of t he i m p utati o n m o del has bee n a d d e d (secti o n 2. 5 ). 
 
It has b ee n a d de d t hat t he gl ycae mic stat us of a s u bject is assesse d b y t he i n vesti gat or. Details o n 
t he i m p utati o n m o del f or t he a nal ysis of gl ycae mic stat us has bee n a d d e d (secti o n 2. 5 ). 
 
C ha n ge fr o m bas eli ne t o wee k 1 0 4 f or W R S S M t otal sc ore has b ee n c h a n ge d fr o m a s u p p orti ve 
sec o n dar y e n d p oi nt t o a n e x pl orat or y e n d p oi nt  ( pr ot oc ol v. 6. 0), a n d it has b ee n a d d e d t hat it will be 
prese nte d d escri pti vel y (s ecti o n 2. 5 ). 
 
It has b ee n a d de d t hat t he si g nifica n ce le vel f or t he c o nfir mat or y sec o n dar y e n d p oi nts will be 
u p date d base d o n t he e x act n u m ber of e v e nts  a n d t hat all a vaila ble dat a at e n d -of -trial are use d f or 
b ot h sec o n dar y a n d e x pl orat or y e n d p oi nts  (secti o n 3. 3 ). 
 
T he part des cri bi n g t hat N o v o N or dis k will re plicate t he i nteri m a nal ysis h as bee n re m o ve d (s ecti o n 
3. 3 ). 
 
I n ge neral, e dit orial c h a n ges f or ali g n me nt wit h S A Ps f or trials E X 9 9 2 4-4 4 7 3 ( S O U L) a n d 
N N 9 5 3 5 -4 3 2 1 ( F L O W)  has bee n ma d e . 
 
S A P versi o n 3 . 0, d ate d 2 2 -A pr -2 0 2 2  
 
T he de p art me nt na me of t he a ut h or has bee n u p dat e d  
 
T he c o m p osite H F e n d p oi nt has bee n i nserte d i n t he list of c o nfir mat or y sec o n dar y e n d p oi nts after 
C V deat h a n d bef ore all -ca use deat h  i n ali g n m e nt wit h pr ot oc ol versi o n 7. 0 ( Secti o n 1. 1. 2 ) 
 
 Details has bee n a d de d t o t he descr ipti o n of bas eli ne asses me nts ( Secti o n 2. 2 )  
 
T w o se nsiti vit y a nal yses ha ve  bee n a d de d. T h e a n al yses i m p ute e ve nt ti mes f or t h ose t hat are l ost t o 
f oll o w-u p or wit h dra w n, base d o n t he o bser ve d e v e nt rates f or s u bjects t hat eit her g o per m a ne ntl y 
off treat me nt (first a nal ysis) or at least g o off tr eat me nt o nce. ( Secti o n 2. 3. 2  a n d 2. 4. 1 ) 
V V- C LI N- 1 1 1 2 7 3
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C O N FI D E N TI A L


Statistical A nal ysis Pla n  
 
Date:  
 
 
2 2 A pril 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:  
3. 0  
U T N: U 1 1 1 1 -1 2 0 0 -5 5 6 4  
Stat us:  
Fi n al  
E u dra C T N o.: 2 0 1 7 -0 0 3 3 8 0 -3 5  
P a ge:  
2 8  of 3 4  
 
 
 
F or t he s u b gr o u p a nal yses t he f oll o wi n g has b ee n i m ple me nte d: T he w or di n g of t he et h nicit y 
s u b gr o u ps h as bee n u p d ate d. C o u ntries t hat are n’t rele va nt ha v e  bee n re m o ve d fr o m t he R e gi o n 
s u b gr o u ps, Me xic o has m o ve d fr o m re gi o n “ N ort h A merica” t o re gi o n “Ot her ” a n d Ser bia has 
m o ve d fr o m re gi o n “ Ot her” t o r e gi o n “ E ur o pe”. A c hr o nic heart fail ure  s u b gr o u p a nal ysis has bee n 
a d de d. ( Secti o n 2. 3. 4 ) 
 
It has b ee n a d de d t hat if fe wer t ha n 1 0 s u bj ects c o -partici pate i n C O VI D -1 9 trials t he 
s u p ple me ntar y C O VI D-1 9 a nal ys es will n ot be ma de. ( Secti o n 2. 3. 6 ) 
 
T he H F c o m p osite e n d p oi nt has bee n a d de d i n t he testi n g hierarc h y a n d w here rele va nt i n t he 
f oll ow i n g te xt. T he s u p ple me ntar y a n al ysis of H F c o m p osite wit h all-ca use deat h has bee n m o ve d 
fr o m t he secti o n re gar di n g sec o n dar y s u p p orti ve e n d p oi nts. ( Secti o n 2. 4. 1  a n d 2. 4. 2. 1 ) 
 
It is clarifie d t hat f or n u m ber of h os pitalisati o ns t he c o m paris o ns at year 1, 2, 3 a n d 4 are descri pti ve.  
( Secti o n 2. 5 )   
 
It has b ee n a d de d t hat a s mall tea m at N o v o N or dis k ma y b e u n bli n de d after t he i nteri m a nal ysis if 
t he rec o m me n d ati o n fr o m t he D M C is t o ter mi nate t he trial earl y f or efficac y. ( Secti o n 3. 1 ) 
 
W here r ele va nt t he a b o v e c ha n ges is als o reflecte d i n t he ta bles i n t he a p pe n dices  ( Secti o n 6 ) 
 
I n ge neral, s mall e dit orial c ha n ges t o i m pr o ve cl arit y of the te xt ha ve  bee n ma de . 
 
5  
Refere nces  
1.  
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 Cli 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.  
2.  
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.  
3.  
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 o r ma n M, et al. Pi o glitaz o ne 
after Is c he mic Str o ke or Tra nsie nt Isc h e 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.  
4.  
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 n f 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.  
5.  
Gli m m E, Ma urer W, Bretz F. Hierarc hical testi n g of m ulti ple e n d p oi nts i n gr o u p -se q ue ntial 
trials. Stat Me d. 2 0 1 0; 2 9( 2): 2 1 9-2 8.  
6.  
C o o k R, La wless J. T he Statistical A nal ysis of Rec urre nt E v e nts. Ne w Y or k: S pri n ger. 2 0 0 7.  
7.  
G h os h D, Li n D Y. N o n p ara metri c a nal ysis of rec urre nt e ve nts a n d deat h. Bi o metrics. 
2 0 0 0; 5 6( 2): 5 5 4 -6 2.  
V V- C LI N- 1 1 1 2 7 3
3 .0
.
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
 
Date:  
 
 
2 2 A pril 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:  
3. 0  
U T N: U 1 1 1 1 -1 2 0 0 -5 5 6 4  
Stat us:  
Fi n al  
E u dra C T N o.: 2 0 1 7 -0 0 3 3 8 0 -3 5  
P a ge:  
2 9  of 3 4  
 
 
8.  
G h os h D, Li n D. M ar gi n al re gressi o n m o dels f or rec urre nt a n d  ter mi nal e ve nts. Statistica 
Si nica. 2 0 0 2; 1 2: 6 6 3 -8 8.  
9.  
P utter  H F M, Ges k us R B. T ut orial i n bi ostatistics: c o m peti n g ris ks a n d m ulti‐state m o dels. 
Stat Me d. 2 0 0 7; 2 6: 2 3 8 9 -4 3 0.  
1 0.  
A n derse n P K, Per m e M P. Pse u d o -o bser vati o ns i n s ur vi val a nal ysis. Stat Met h o ds Me d Res. 
2 0 1 0; 1 9( 1): 7 1 -9 9.  
 
 
V V- C LI N- 1 1 1 2 7 3
3 .0
.
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
 
Date:  
 
 
2 2 A pril 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:  
3. 0  
U T N: U 1 1 1 1 -1 2 0 0 -5 5 6 4  
Stat us:  
Fi n al  
E u dra C T N o.: 2 0 1 7 -0 0 3 3 8 0 -3 5  
P a ge:  
3 0  of 3 4  
 
 
6  
A p pe n di x  
T a ble 6 -1  
H a n dli n g of i nterc urre nt e ve nts f or t he pri m ar y esti m a n d a n d pri m ar y 
e n d p oi nt 
 
 
 
I nterc urre nt e v e nt 
A p pr o ac h f or esti m a n d  
M A C E e ve nts a v ail a ble 
after i nterc urre nt e ve nt 
St atistic al a p pr o ac h  
Treat me nt 
disc o nti n uati o ns  
 
Me dicati o n 
m o dif yi n g C V ris k  
 
B ariatric s ur ger y  
 
I nitiati o n of c hr o nic 
re nal re place me nt 
t hera p y 
C ollect e v e nts irres pecti ve 
of t he i nterc urre nt e ve nt  
Yes  
Use all a vaila ble e ve nts 
irres pecti ve of i nterc urre nt 
e ve nt  
Trial disc o nti n uati o n  
( wit h dra wal a n d l ost-
t o f oll o w-u p)  
Atte m pts is ma d e t o c ollect 
vital e ve nts via i n direct 
s o urces 
Vital e ve nts p ote ntiall y 
a vaila ble  
 
Ce ns ori n g at ti me of 
disc o nti n uati o n  
N o n -C V deat h  
W hile ali ve pers pecti ve  
N o  
C o m peti n g ris ks  
V V- C LI N- 1 1 1 2 7 3
3 .0
.
C O N FI D E N TI A L










Se ma gl uti de s.c. 2. 4 m g o nce we e kl y  
 
Date:  
0 4 Ma y 2 0 2 3  
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:  
1. 0  
Cli nical Trial Re p ort  
Stat us:  
Fi n al  
Me d D R A sear c hes  
P a ge:  
1  of 6  
 
Cli nic al Tri al Re p ort  
Tri al I D: E X 9 5 3 6 -4 3 8 8  (S E L E C T ) 
Me d D R A se arc hes f or s afet y f oc us are as 
A ut h or  
  
 
  
  
   
  
   
 
  
  
 
 
  
  
 
 
  
  
  
  
  
  
  
  
   
  
  
 
 
  
 
 
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.
C O N FI D E N TI A L


Se ma gl uti de s.c. 2. 4 m g o nce we e kl y  
 
Date:  
0 4 Ma y 2 0 2 3  
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:  
1. 0  
Cli nical Trial Re p ort  
Stat us:  
Fi n al  
Me d D R A sear c hes  
P a ge:  
2  of 6  
 
Ta ble of c o nte nts  
P a ge  
T a ble of c o nte nts  ............................................................................................................................................... 2
List of a b bre vi ati o ns a n d defi niti o ns of ter ms  ............................................................................................... 3
Me d D R A se arc hes f or s afet y f oc us are as i n pr oject E X 9 5 3 6  ....................................................................... 4
1  A b use a n d Mis use  ........................................................................................................................................ 4
2  Ac ute re n al f ail ure  ....................................................................................................................................... 4
3  Aller gic re acti o ns  ......................................................................................................................................... 4
4  A p pe n d icitis ................................................................................................................................................. 4
5  C o vi d 1 9  ........................................................................................................................................................ 5
6  Dr u g -rel ate d he p atic dis or ders  .................................................................................................................. 5
7  G all bl a d der -rel ate d dis or ders  .................................................................................................................... 5
8  G astr oi ntesti n al dis or ders  .......................................................................................................................... 5
9  H y p o gl yc ae mi a  ............................................................................................................................................ 5
1 0  M ali g n a nt t u m o urs  ...................................................................................................................................... 5
1 1  Me dic ati o n err ors  ........................................................................................................................................ 5
1 2  P a ncre atitis  .................................................................................................................................................. 5
1 3  R are e ve nts  ................................................................................................................................................... 6
1 4  S uici de/self -i nj ur y........................................................................................................................................ 6
1 5  S us pecte d tr a ns missi o n of a n i nfecti o us a ge nt .......................................................................................... 6
C O N FI D E N TI A L


Se ma gl uti de s.c. 2. 4 m g o nce we e kl y  
 
Date:  
0 4 Ma y 2 0 2 3  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:  
1. 0  
Cli nical Trial Re p ort  
Stat us:  
Fi n al  
Me d D R A sear c hes  
P a ge:  
3  of 6  
 
 
List of a b bre vi ati o ns a n d defi niti o ns of ter ms   
A E  
A d verse e ve nt  
H L T  
H i g h le vel ter m 
Me d D R A  
Me dical Dicti o nar y f or Re g ul at or y Acti vities  
N E C  
N ot else w here classifie d  
N N M Q  
N o v o N or dis k Me d D R A q uer y  
P T  
Pr eferre d ter m  
S M Q  
S ta n dar dise d Me d D R A q uer y 
S O C  
S yste m or ga n class  
 
 
C O N FI D E N TI A L


Se ma gl uti de s.c. 2. 4 m g o nce we e kl y  
 
Date:  
0 4 Ma y 2 0 2 3  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:  
1. 0  
Cli nical Trial Re p ort  
Stat us:  
Fi n al  
Me d D R A sear c hes  
P a ge:  
4  of 6  
 
 
Me d D R A se arc hes f or s afet y f oc us are as i n pr oject E X 9 5 3 6   
T he Me d D R A searc h stri n gs i n t his d oc u me nt ( or dere d al p h a beticall y) were use d f or t he E X 9 5 3 6 
s u b missi o n d oc u me nts. T he Me d D R A versi o n use d was 26. 0 . 
1  
A b use a n d Mis us e   
C ust o m q uer y  ( N N M Q A b use a n d Mis use): 
 S M Q Dr u g a b use a n d d e pe n de nce, all ter ms ( n ote c o ntai ns o nl y narr o w ter ms) 
 H L T I nte nti o nal pr o d uct mis uses (c o ntai ns o nl y pri mar y ter ms)  
 A d diti o nal P Ts:  
o  P ois o ni n g deli berate  
o  I nte nti o nal d os e o missi o n 
o  Perf or ma nce e n h a nci n g pr o d uct  use  
o  C o m plete d s uici de  
o  I nte nti o nal s elf-i nj ur y 
o  S uici de atte m pt  
o  Assiste d s uici de  
o  S us pecte d s uici de atte m pt  
o  S us pecte d s uici de.  
2  
Ac ute re n al f ail ure   
S M Q Ac ute re n al fail ure, narr o w ter ms o nl y. 
3  
Aller gic re acti o ns   
C ust o m Q uer y ( N N M Q Aller gi c reacti o ns) –  o nl y narr o w ter ms fr o m t he f oll o wi n g:  
 S M Q A na p h yl actic reacti o n  
 S M Q A n gi oe d e ma  
 S M Q Se vere c uta n e o us a d ve rse reacti o ns  
 S M Q A na p h yl actic/a na p h yla ct oi d s h oc k c o n diti o ns  
 S M Q H y perse nsiti vit y  
4  
A p pe n dicitis   
C ust o m Q uer y ( N N M Q A p pe n dicitis)  –  wit h t he f oll o wi n g P Ts :  
o  A p pe n diceal a bscess  
o  A p pe n dicect o m y  
o  A p pe n dicitis  
o  A p pe n dicitis n o ni nfecti v e  
o  A p pe n dicitis perf orate d  
o  A p pe n di x dis or der  
o  St u m p a p pe n dicitis  
o  C o m plicate d a p pe n dicitis  
C O N FI D E N TI A L


Se ma gl uti de s.c. 2. 4 m g o nce we e kl y  
 
Date:  
0 4 Ma y 2 0 2 3  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:  
1. 0  
Cli nical Trial Re p ort  
Stat us:  
Fi n al  
Me d D R A sear c hes  
P a ge:  
5  of 6  
 
 
5  
C o vi d 1 9   
S M Q C o vi d 1 9 , n arr o w ter ms o nl y . 
6  
C ar di o v asc ul ar dis or ders   
S O C Car di ac dis or ders , pri mar y ter ms o nl y. 
7  
Dr u g -rel ate d he p atic dis or ders   
S M Q Dr u g relate d h e pati c dis or ders - c o m pre h e nsi ve searc h , all ter ms. 
8  
E ye dis or ders    
S O C of E ye dis or d ers , pri mar y ter ms o nl y . 
9  
G all bl a d der -rel ate d dis or ders   
C ust o m q uer y ( N N M Q Gall bla d der -relate d dis or ders). Narr o w t er ms fr o m t he f oll o wi n g: 
 S M Q F u ncti o nal, i nfla m mat or y a n d gallst o ne rel ate d biliar y dis or d ers  
 S M Q I nfecti o us biliar y dis or ders  
1 0  G astr oi ntesti n al dis or ders   
C ust o m q uer y ( N N M Q Gastr oi ntesti nal dis or ders S O C):  
 S O C Gastr oi ntesti nal dis or ders, pri mar y t er ms o nl y  
1 1  H y p o gl yc ae mi a   
S M Q H y p o gl ycae mia, narr o w ter ms o nl y . 
1 2  M ali g n a nt ne o pl as ms   
S M Q Mali g na nt t u m o urs , all ter ms ( n ote c o ntai n o nl y narr o w ter ms). 
1 3  Me dic ati o n err ors   
S M Q Me dicati o n err ors , all ter ms.  
1 4  P a ncre atitis   
C ust o m q uer y ( N N M Q Pa ncreatitis ): 
 S M Q Ac ute pa ncreatitis ), narr o w ter ms o nl y 
C O N FI D E N TI A L


Se ma gl uti de s.c. 2. 4 m g o nce we e kl y  
 
Date:  
0 4 Ma y 2 0 2 3  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:  
1. 0  
Cli nical Trial Re p ort  
Stat us:  
Fi n al  
Me d D R A sear c hes  
P a ge:  
6  of 6  
 
 
 H L T Ac ute a n d c hr o nic pa ncreatitis, pri mar y a n d sec o n dar y t er ms  
1 5  R are e ve nts   
C ust o m q uer y ( N N M Q R are e v e nts) e x cl u di n g e ve nts t hat are i ncl u de d i n ot her safet y f oc us areas. 
T he f oll o wi n g is i ncl u de d : 
 S M Q A gra n ul oc yt osis, narr o w ter ms o nl y  
 S M Q G uillai n -Barre s y n dr o me, narr o w ter ms o nl y  
 S M Q Hae mat o p oietic c yt o pe nias affecti n g m ore t h a n o ne t y pe of bl o o d cell, br oa d a n d narr o w 
ter ms 
 S M Q Hae m at o p oietic le u k o pe nia, br oa d a n d narr o w ter ms  
 S M Q Hae mat o p oietic t hr o m b oc yt o pe ni a, narr o w t er ms o nl y  
 S M Q I nterstitial l u n g disease, narr o w ter ms o nl y  
 S M Q Ne ur ole ptic mali g n a nt s y n dr o m e, narr o w ter ms o nl y  
 S M Q Pse u d o me m bra n o us c olitis, narr o w ter ms o nl y  
 S M Q Retr o perit o neal fi br osis, narr o w ter ms o nl y  
 S O C C o n ge nital, fa milial a n d ge netic dis or d ers, (all ter ms are pri mar y P Ts)  
 H L T A n gi oe de mas, pri mar y a n d sec o n dar y r o ute d P Ts  
 H L T Gl o mer ul o ne p hritis a n d ne p hr otic s y n dr o me, pri mar y a n d sec o n dar y r o ute d P Ts  
 H L T Ne p hritis N E C, pri mar y a n d sec o n dar y r o ute d P Ts  
 A d diti o nal P Ts:  
o  Disse mi nate d i ntra vasc ul ar c oa g ul ati o n  
o  He patic l y m p h oc ytic i nfiltrati o n  
o  M ulti ple or ga n d ysf u n cti o n s y n dr o me  
1 6  S uici de/self -i nj ur y  
S M Q S uici de/self -i nj ur y, all ter ms ( n ote c o ntai n o nl y narr o w ter ms). 
1 7  S us pecte d tr a ns missi o n of a n i nfecti o us a ge nt   
C ust o m Q uer y ( N N M Q Tra ns missi o n) . Pri mar y t er ms fr o m t he f oll o wi n g: 
 H L T I nfecti o us dis or der carri er 
 H L T I nfecti o us tra ns missi o ns  
C O N FI D E N TI A L