Investigation of Once-weekly Semaglutide S.C. Dose-Response in Patients With Type 2 Diabetes and Overweight - a Participant- and Investigator-blinded and Sponsor Open-label Study
Phase: PHASE2
Conditions: Diabetes Mellitus, Type 2
Sponsor: Novo Nordisk A/S

C o ver P a ge  f or Pr ot oc ol  
S p o ns or na me:  
N o v o N or dis k A/ S  
N C T n u m ber  
N C T 0 5 4 8 6 0 6 5  
S p o ns or t rial I D: 
N N 9 5 3 5- 4 9 8 4  
Official title of st u d y:  
I n vesti gati o n of o nce- wee kl y se ma gl uti de s.c. d ose-res p o nse i n 
patie nts wit h t y pe 2 dia betes a n d o ver wei g ht – a partici pa nt- 
a n d i n vesti gat or- bli n de d a n d s p o ns or o pe n-la bel st u d y
D oc u me nt date: 
0 3 Fe br uar y 2 0 2 3 
Re d acte d pr ot oc ol 
incl u d es re d acti o n  c o m p a ny c o nfi de n ti al inf or m ati o n   o nly. 
. 

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
Stat us:  
Fi n al  
P a ge:  
1  of 1 0 0  
Pr ot oc ol
Pr ot oc ol Title:  
In v esti gati o n of o nce -wee kl y se m a gl uti de s.c. d os e -res p o ns e i n patie nts wit h t y pe 2 dia betes a n d 
o ver wei g ht  –  a p artici pa nt - a n d i n vesti gat or -bli n de d a n d s p o ns or o pe n -la bel st u d y 
S u bst a nce n a me: Se ma gl uti de  
U ni vers al Tri al N u m ber: U 1 1 1 1 -1 2 7 1 -9 2 0 9 
E u dr a C T N u m ber:  2 0 2 2 -0 0 0 8 8 2 -4 1  
I N D N u m ber: 0 7 9 7 5 4 
St u d y p h ase : 2 
I n t he f oll o wi n g, N o v o N or dis k A/ S a n d its affiliates will be state d as “ N o v o N or dis k”. 
T his c o nfi de ntial d oc u me nt is t he pr o pert y of N o v o N or dis k. N o u n p u blis he d i nf or mati o n c o ntai ne d herei n ma y be 
discl ose d wit h o ut pri or writte n a p pr o val fr o m N o v o N or dis k. Access t o t his d oc u me nt m ust be res tricte d t o rele va nt 
parties.  
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
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V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
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 of
  Pr ot oc ol  4 9 8 4 v 3. 0
1
1 0 0
C O N FI D E N TI A L
T his c o nfi de ntial d oc u me nt is t he pr o pert y of N o v o N or dis k. N o u n p u blis he d i nf or mati o n c o ntai ne d herei n ma y be 
discl ose d w it h o ut pri or writte n a p pr o val fr o m N o v o N or dis k. Access t o t his d oc u me nt m ust be restricte d t o rele va nt 
parties.

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
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 versi o n  
D ate  
A p plic a ble i n c o u ntr y( -ies) a n d/ or 
site(s)  
Pr ot oc ol versi o n 3. 0  
0 3  Fe br uar y 2 0 2 3  
Gl o bal  
Pr ot oc ol versi o n 2. 0  
1 6 J u ne 2 0 2 2  
Gl o bal  
Ori gi nal pr ot oc ol versi o n 1. 0  
0 7 A pril 2 0 2 2  
Gl o bal  
Pr ot oc ol ve rsi o n 3. 0 ( 0 3  Fe br u ar y 2 0 2 3)  
T his a me n d me nt is c o nsi dere d t o be n o n -s u bsta ntial base d o n t he criteria s et 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, beca use 
it neit her si g nifica ntl y i mpacts t he safet y n or p h ysical/ me ntal i nte grit y of s u bjects n or t he scie ntific 
val ue of t he st u d y. 
O ver all r ati o n ale f or pre p ari n g pr ot oc ol, versi o n 3 . 0: 
T he o verall rati o nale f or t he c ha n ges i m ple me nte d i n t he a me n de d pr ot oc ol is t o i ncl u de p ote ntial 
i nteri m a nal ys es i n t he st u d y t o get a n earl y u n d ersta n di n g of t he s afet y , efficac y, a n d P K of hi g h er 
d oses of se ma gl uti de s.c.  
Secti o n # a n d n a me  
Descri pti o n of c h a n ge  
Brief r ati o n ale  
Secti o n 4. 3  J ustificati o n f or d ose 
N o ncli nical te xt relate d t o dr u g, d ose, 
a n d res ults is a d de d  
T o e x plai n w h y we disre gar d t he 
m o n ke y N O A E L  relate d t o car diac 
safet y f or safet y assess me nt 
Secti o n 6. 1  St u d y i nter ve nti o n(s) 
a d mi nistere d  
F o ot n ote is a d de d i n T a ble  6 -3 f or 
N o v o P e n ® 4  
T o i nf or m t hat N o v o P e n ® 4  is use d 
o utsi de a p pr o val  
Secti o n 8. 4. 1 P har mac o ki netics  
A d de d w or d i nteri m  a nal ys es  
T o ali g n wit h secti o n 9. 4  
Secti o n 9. 3. 2. 1 Pri mar y esti ma n d  
Sta n dar d de viati o ns is c ha n ge d t o 
sta n dar d err ors  
T o c orrect t y p o err or  
Secti o n 9. 3. 6 Ot her a nal yses  
A d de d te xt relate d t o i nteri m a nal yses 
T o ali g n wit h secti o n 9. 4  
Secti o n 9. 4 I nteri m a nal ysis  
A d de d i nf or mati o n o n i nteri m 
a nal ysis wit h ti me p oi nts  t hat ma y be 
c o n d ucte d d uri n g t he st u d y  
T o i ncl u de p ote ntial i nteri m 
a nal yses i n t he st u d y t o get a n earl y 
u n dersta n di n g of t he safet y , 
efficac y, a n d P K of hi g her d oses of 
se ma gl uti de s.c. 
Secti o n 1 0. 2  A p pe n di x 2: Cli nical 
la b orat or y tests 
T a ble 1 0 -3 f o ot n ote te xt is u p date d t o 
i ncl ude  i nteri m a nal yses te xt 
T o ali g n wit h secti o n 9. 4  
 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
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V V- T M F- 5 9 0 1 0 6 5
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-
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1
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 of
  Pr ot oc ol  4 9 8 4 v 3. 0
2
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
Stat us:  
Fi n al  
P a ge:  
3  of 1 0 0  
Ta ble of C o nte nts  
P a ge  
P r ot oc ol a me n d me nt s u m m ar y of c h a n ges t a ble  ........................................................................................... 2
T a ble of C o nte nts .............................................................................................................................................. 3
1  P r ot oc ol s u m m ar y  ....................................................................................................................................... 7
1. 1
S y n o psis  .............................................................................................................................................. 7
1. 2
Fl o wc hart  .......................................................................................................................................... 1 0
2  I ntr o d ucti o n ............................................................................................................................................... 1 2
2. 1
St u d y rati o nale  .................................................................................................................................. 1 2
2. 2
Bac k gr o u n d  ....................................................................................................................................... 1 2
2. 3
Be nefit -ris k assess me nt ..................................................................................................................... 1 3
2. 3. 1  
Ris k assess me nt  ................................................................................................................. 1 3
2. 3. 2  
Be nefit assess me nt  ............................................................................................................. 1 7
2. 3. 3  
O verall be nefit -ris k c o ncl usi o n ......................................................................................... 1 7
3  O bjecti ves, e n d p oi nts a n d esti m a n ds  ....................................................................................................... 1 8
3. 1  
O bjecti ves a n d e n d p oi nts  .................................................................................................................. 1 8
3. 2  
Esti ma n ds  .......................................................................................................................................... 1 8
3. 2. 1  
A d dressi n g t he pri mar y o bjecti ve  ...................................................................................... 1 8
3. 2. 1. 1
Pri mar y esti ma n d  ........................................................................................... 1 8
3. 2. 1. 2
A d diti o nal esti ma n d  ....................................................................................... 1 9
3. 2. 2  
A d dressi n g t he sec o n dar y o bj ecti ve  .................................................................................. 1 9
4  St u d y desi g n  ............................................................................................................................................... 2 1
4. 1
O verall desi g n  ................................................................................................................................... 2 1
4. 2
Scie nt ific rati o nale f or st u d y desi g n .................................................................................................. 2 2
4. 3
J ustificati o n f or d ose ......................................................................................................................... 2 2
4. 4
E n d of st u d y defi niti o n  ...................................................................................................................... 2 3
5  St u d y p o p ul ati o n  ....................................................................................................................................... 2 4
5. 1
I ncl usi o n criteria ............................................................................................................................... 2 4
5. 2
E xcl usi o n criteria  .............................................................................................................................. 2 4
5. 3
Lifest yle c o nsi derati o ns  .................................................................................................................... 2 5
5. 3. 1  
Meals a n d dietar y restricti o ns  ............................................................................................ 2 5
5. 3. 2  
Caffei ne, alc o h ol a n d t o bacc o  ........................................................................................... 2 5
5. 3. 3  
Acti vit y  .............................................................................................................................. 2 5
5. 4
Scree n fai l ures ................................................................................................................................... 2 6
5. 5
Ra n d o misati o n criteria  ...................................................................................................................... 2 6
6  St u d y i nter ve nti o n(s) a n d c o nc o mit a nt t her a p y  ..................................................................................... 2 7
6. 1
St u d y i nter ve nti o n(s) a d mi nistere d  ................................................................................................... 2 7
6. 2
Pre parati o n, ha n dli n g, st ora ge a n d acc o u nta bilit y  ............................................................................ 3 0
6. 3
Meas ures t o mi ni mise bias: Ra n d o misati o n a n d bli n di n g ................................................................. 3 0
6. 4
St u d y i nter ve nti o n c o m plia nce .......................................................................................................... 3 1
6. 5
D ose m o dificati o n  ............................................................................................................................. 3 2
6. 6
C o nti n ue d access t o st u d y i nter ve nti o n after e n d of st u d y  ................................................................ 3 2
6. 7
Treat me nt of o ver d ose  ...................................................................................................................... 3 2
6. 8
C o nc o mita nt t hera p y  ......................................................................................................................... 3 3
6. 8. 1  
Resc ue me dici ne  ................................................................................................................ 3 3
7  Disc o nti n u ati o n of st u d y i nter ve nti o n a n d p artici p a nt disc o nti n u ati o n/ wit h dr a w al  .......................... 3 4
7. 1
Disc o nti n uati o n of st u d y i nter ve nti o n  ............................................................................................... 3 4
7. 1. 1  
T e m p orar y disc o nti n uati o n of st u d y i nter ve nti o n  .............................................................. 3 4
7. 1. 2  
Resc ue criteria  ................................................................................................................... 3 5
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
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V V- T M F- 5 9 0 1 0 6 5
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-
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1
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 of
  Pr ot oc ol  4 9 8 4 v 3. 0
3
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4  of 1 0 0  
 
7. 2  
Partici pa nt disc o nti n uati o n/ wit h dra wal fr o m t he st u d y  .................................................................... 3 5  
7. 2. 1  
Re place me nt of partici pa nts  .............................................................................................. 3 6  
7. 3  
L ost t o f oll o w -u p ............................................................................................................................... 3 6  
8  St u d y assess me nts a n d pr oce d ures  .......................................................................................................... 3 7  
8. 1  
Efficac y assess me nts  ......................................................................................................................... 3 8  
8. 1. 1  
B o d y wei g ht  ....................................................................................................................... 3 8  
8. 1. 2  
Waist circ u mfere nce  .......................................................................................................... 3 8  
8. 1. 3  
S pir o metr y  ......................................................................................................................... 3 8  
8. 1. 4  
Cli nical efficac y la b orat or y assess me nts  ........................................................................... 3 9  
8. 2  
Safet y assess me nts  ............................................................................................................................ 3 9  
8. 2. 1  
P h ysical e xa mi nati o ns  ....................................................................................................... 4 0  
8. 2. 2  
Vital si g ns  .......................................................................................................................... 4 0  
8. 2. 3  
E ye e xa mi nati o n  ................................................................................................................ 4 1  
8. 2. 4  
Electr ocar di o gra ms  ............................................................................................................ 4 1  
8. 2. 5  
Cli nical safet y la b orat or y assess me nts  .............................................................................. 4 1  
8. 2. 6  
Plas ma gl uc ose meas ure me nts  ........................................................................................... 4 2  
8. 2. 7  
Pre g na nc y testi n g  ............................................................................................................... 4 2  
8. 3  
A d verse e ve nts a n d ot her safet y re p orti n g  ........................................................................................ 4 2  
8. 3. 1  
Ti me peri o d a n d fre q ue nc y f or c ollecti n g A E i nf or mati o n  ............................................... 4 3  
8. 3. 2  
Met h o d of detecti n g A Es  ................................................................................................... 4 3  
8. 3. 3  
F oll o w -u p of A Es  .............................................................................................................. 4 4  
8. 3. 4  
Re g ulat or y re p orti n g re q uire me nts f or S A Es  .................................................................... 4 4  
8. 3. 5  
Pre g na nc y  .......................................................................................................................... 4 4  
8. 3. 6  
T ec h nical c o m plai nts  ......................................................................................................... 4 4  
8. 4  
P har mac o ki netics a n d p har mac o d y na mics  ....................................................................................... 4 4  
8. 4. 1  
P har mac o ki netics  ............................................................................................................... 4 4  
8. 4. 2  
P har mac o d y na mics  ............................................................................................................ 4 5  
8. 5  
Ge netics  ............................................................................................................................................ 4 5  
8. 6  
Bi o mar kers  ........................................................................................................................................ 4 5  
8. 7  
I m m un o ge nicit y assess me nts  ............................................................................................................ 4 6  
8. 7. 1  
A nti -se ma gl uti de a nti b o dies .............................................................................................. 4 6  
8. 7. 2  
H y perse nsiti vit y  ................................................................................................................. 4 6  
8. 8  
H u ma n bi osa m ples f or f ut ure researc h  ............................................................................................. 4 7  
8. 9  
Healt h ec o n o mics  .............................................................................................................................. 4 7  
9  St atistic al c o nsi der ati o ns  .......................................................................................................................... 4 8  
9. 1  
Statistical h y p ot heses  ........................................................................................................................ 4 8  
9. 1. 1  
M ulti plicit y a dj ust me nt ...................................................................................................... 4 8  
9. 2  
A nal ysis sets ...................................................................................................................................... 4 8  
9. 3  
Statis tical a nal yses ............................................................................................................................ 4 9  
9. 3. 1  
Ge neral c o nsi derati o ns  ...................................................................................................... 5 0  
9. 3. 2  
Pri mar y e n d p oi nt a nal ysis  ................................................................................................. 5 0  
9. 3. 2. 1  
Pri mar y esti ma n d  ........................................................................................... 5 0  
9. 3. 2. 2  
S u p ple me ntar y a nal ysis  .................................................................................. 5 1  
9. 3. 3  
Sec o n dar y e n d p oi nts a nal ysis  ............................................................................................ 5 1  
9. 3. 3. 1  
Pri mar y esti ma n d  ........................................................................................... 5 1  
9. 3. 3. 2  
S u p ple me ntar y a nal ysis  .................................................................................. 5 2  
9. 3. 3. 3  
S u p p orti ve  ...................................................................................................... 5 2  
9. 3. 4  
E x pl orat or y e n d p oi nts a nal ysis  .......................................................................................... 5 2  
9. 3. 5  
Safet y a nal yses  .................................................................................................................. 5 2  
9. 3. 6  
Ot her a nal yses  ................................................................................................................... 5 2  
9. 4  
I nteri m a nal ysis ................................................................................................................................. 5 2  
9. 5  
Sa m ple size deter mi nati o n  ................................................................................................................ 5 3  
1 0  S u p p orti n g d oc u me nt ati o n a n d o per ati o n al c o nsi der ati o ns .................................................................. 5 8  
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
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V V- T M F- 5 9 0 1 0 6 5
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1
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 of
  Pr ot oc ol  4 9 8 4 v 3. 0
4
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5  of 1 0 0  
 
1 0. 1  A p pe n di x  1: Re g ulat or y, et hical, a n d st u d y o versi g ht c o nsi derati o ns .............................................. 5 8  
1 0. 1. 1  
Re g ulat or y a n d et hical c o nsi derati o ns  ............................................................................... 5 8  
1 0. 1. 2  
Fi na ncial discl os ure  ........................................................................................................... 5 8  
1 0. 1. 3  
I nf or me d c o nse nt pr ocess .................................................................................................. 5 9  
1 0. 1. 4  
I nf or mati o n t o partici pa nts d uri n g t he st u d y ..................................................................... 5 9  
1 0. 1. 5  
Data pr otecti o n  .................................................................................................................. 6 0  
1 0. 1. 6  
C o m mittees str uct ure  ......................................................................................................... 6 0  
1 0. 1. 6. 1  
N o v o N or dis k safet y c o m mittee ..................................................................... 6 0  
1 0. 1. 7  
Disse mi nati o n of cli nical st u d y data  .................................................................................. 6 0  
1 0. 1. 8  
Data q ualit y ass ura nce  ....................................................................................................... 6 1  
1 0. 1. 8. 1  
Case re p ort f or ms  ........................................................................................... 6 1  
1 0. 1. 8. 2  
M o nit ori n g  ..................................................................................................... 6 1  
1 0. 1. 8. 3  
Pr ot oc ol c o m plia nce  ....................................................................................... 6 2  
1 0. 1. 9  
S o urce d oc u me nts  .............................................................................................................. 6 2  
1 0. 1. 1 0  Rete nti o n of cli nical st u d y d oc u me ntati o n  ........................................................................ 6 3  
1 0. 1. 1 1  St u d y a n d site cl os ure  ........................................................................................................ 6 3  
1 0. 1. 1 2  Res p o nsi bilities  .................................................................................................................. 6 3  
1 0. 1 . 1 3 I n de m nit y state me nt .......................................................................................................... 6 4  
1 0. 1. 1 4  P u blicati o n p olic y  .............................................................................................................. 6 4  
1 0. 1. 1 4. 1  
C o m m u nicati o n of res ults  .............................................................................. 6 5  
1 0. 1. 1 4. 2  
A ut h ors hi p  ...................................................................................................... 6 5  
1 0. 1. 1 4. 3  
Sit e -s pecific p u blicati o n(s) b y i n vesti gat or(s)................................................ 6 6  
1 0. 1. 1 4. 4  
I n vesti gat or access t o data a n d re vie w of res ults ........................................... 6 6  
1 0. 2  A p pe n di x  2: Cli nical la b orat or y tests ................................................................................................ 6 7  
1 0. 3  A p pe n di x  3: A d verse E ve nts a n d Seri o us A d verse E ve nts: Defi niti o ns a n d pr oce d ures f or 
rec or di n g, e val uati n g, f oll o w-u p, a n d re p orti n g  ............................................................................... 7 0  
1 0. 3. 1  
Defi niti o n of A E  ................................................................................................................ 7 0  
1 0. 3. 2  
Defi niti o n of a n S A E  ......................................................................................................... 7 0  
1 0. 3. 3  
Descri pti o n of A Es re q uiri n g a d diti o nal data c ollecti o n a n d o t her e ve nts re q uiri n g 
c ollecti o n of a d diti o nal i nf or mati o n  .................................................................................. 7 1  
1 0. 3. 4  
Rec or di n g a n d f oll o w -u p of A E a n d/ or S A E  ..................................................................... 7 3  
1 0. 3. 4. 1  
A E a n d S A E rec or di n g  ................................................................................... 7 3  
1 0. 3. 4. 2  
Assess me nt of se verit y  ................................................................................... 7 4  
1 0. 3. 4. 3  
Assess me nt of ca usalit y  ................................................................................. 7 4  
1 0. 3. 4. 4  
Fi nal o utc o me  ................................................................................................. 7 4  
1 0. 3. 4 . 5 
F oll o w -u p of A E a n d S A E  ............................................................................. 7 5  
1 0. 3. 5  
Re p orti n g of S A Es  ............................................................................................................. 7 5  
1 0. 4  A p pe n di x  4: 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  ............................... 7 8  
1 0. 4. 1  
Defi niti o ns  ......................................................................................................................... 7 8  
1 0. 4. 2  
C o ntrace pti ve g ui da nce  ..................................................................................................... 7 8  
1 0. 4. 3  
C ollecti o n of pre g na nc y i nf or mati o n  ................................................................................. 7 9  
1 0. 5  A p pe n di x  5: Tec 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  .................................................................................................................... 8 1  
1 0. 5. 1  
Defi niti o n of tec h nical c o m plai nt  ...................................................................................... 8 1  
1 0. 5. 2  
Rec or di n g a n d f oll o w -u p of tec h nical c o m plai nts  ............................................................. 8 1  
1 0. 5. 3  
Re p orti n g of tec h nical c o m plai nts f or 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  .................................................................................................................. 8 2  
1 0. 6  A p pe n di x  6: A Es, A D Es, S A Es, S A D Es, U S A D Es a n d de vice deficie ncies: Defi niti o ns a n d 
pr oce d ures f or rec or di n g, e val uati n g, f oll o w -u p, a n d re p orti n g i n  Me dical de vice st u dies  .............. 8 3  
1 0. 6. 1  
Defi niti o n of A E a n d a d verse de vice effects  ..................................................................... 8 3  
1 0. 6. 2  
Defi niti o n of S A E, seri o us a d verse de vice effect a n d u na ntici pate d seri o us a d verse 
de vice effect  ....................................................................................................................... 8 3  
1 0. 6. 3  
Defi niti o n of seri o us healt h t hreat  ..................................................................................... 8 4  
1 0. 6. 4  
Defi niti o n of de vice deficie nc y  ......................................................................................... 8 4  
1 0. 6. 5  
Defi niti o n of use err or  ....................................................................................................... 8 4  
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
5
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6  of 1 0 0  
 
1 0. 6. 6  
Rec or di n g a n d f oll o w -u p of A E a n d/ or S A E a n d de vice deficie ncies  .............................. 8 5  
1 0. 6. 6. 1  
A E, S A E a n d de vice deficie nc y rec or di n g  ..................................................... 8 5  
1 0. 6. 6. 2  
Assess me nt of se verit y  ................................................................................... 8 5  
1 0. 6. 6. 3  
Assess me nt of ca usalit y  ................................................................................. 8 5  
1 0. 6. 6. 4  
Fi nal o utc o me  ................................................................................................. 8 6  
1 0. 6. 6. 5  
F oll o w -u p of A E/ S A E/ de vice deficie nc y  ....................................................... 8 7  
1 0. 6. 7  
Re p orti n g of S A Es, Seri o us De vice Deficie nc y t hat c o ul d ha ve le d t o a n S A E a n d 
seri o us healt h t hreats ......................................................................................................... 8 7  
1 0. 7  A p pe n di x  7: Rete nti o n of h u ma n bi osa m ples  ................................................................................... 8 8  
1 0. 8  A p pe n di x  8: H y p o gl ycae mic e pis o des  .............................................................................................. 8 9  
1 0. 9  A p pe n di x  9: Miti gati o ns t o e ns ure partici pa nt safet y a n d data i nte grit y d uri n g a n e mer ge nc y 
sit uati o n ............................................................................................................................................. 9 1  
1 0. 9. 1  
Defi niti o n a n d sc o pe of a p pe n di x  ...................................................................................... 9 1  
1 0. 9. 2  
Visits  .................................................................................................................................. 9 1  
1 0. 9. 3  
Assess me nts  ....................................................................................................................... 9 1  
1 0. 9. 4  
St u d y i nter ve nti o n  ............................................................................................................. 9 2  
1 0. 1 0  A p pe n di x  1 0: C o u ntr y -s pecific re q uire me nts ................................................................................... 9 3  
1 0. 1 1  A p pe n di x  1 1: A b bre viati o ns  ............................................................................................................. 9 4  
1 0. 1 2  A p pe n di x  1 2: Pr ot oc ol a me n d me nt hist or y  ...................................................................................... 9 7  
1 1  Ref ere nces  .................................................................................................................................................. 9 8  
 
Pr ot oc ol attac h me nt I Gl o bal list of ke y staff a n d rele va nt de part me nts a n d s u p pliers  
Pr ot oc ol attac h me nt II C o u ntr y list of ke y staff a n d rele va nt de part me nts.  
 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
6
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
Stat us:  
Fi n al  
P a ge:  
7  of 1 0 0  
1  Pr ot oc ol s u m m ar y  
1. 1  
 S y n o psis  
T his is a n i nter ve nti o nal, m ulti -ce ntre, parallel -gr o u p, ra n d o mise d, place b o -c o ntr olle d, partici pa nt - 
a n d i n vesti gat or -bli n de d wit hi n d ose le vel,  s p o ns or o pe n-la bel, d ose -res p o nse st u d y of o n ce -wee kl y 
s u bc uta ne o usl y a d mi nistere d se m a gl uti de i n patie nts  wit h T 2 D a n d o ver wei g ht as a n a d d -o n t o a 
sta ble d ose of metf or mi n. 
R ati o n ale:  
Data s u g gests t hat p atie nts ca n ac hie v e a d diti o nal H b A 1c re d ucti o n a n d b o d y wei g ht l oss of hi g her 
d oses  of  o nce -wee kl y  s e ma gl uti de s.c. wit h o ut a si g nifica nt i m pact o n t olera bilit y. T his ne w 
i nf or mati o n, a n d t he acc u m ulati o n of e x perie nce wit h se ma gl uti de s.c., j ustifies c haracterisati o n of 
t he d ose-res p o ns e c ur ve, i ncl u di n g hi g her d oses t ha n t h ose pre vi o usl y i n vesti gate d. 
C o nse q ue ntl y, t his cli nic al st u d y is desi g ne d t o  c h aract erise t he d os e -res p o nse c ur ve of o nce -wee kl y 
se ma gl uti de s. c. u p t o 1 6 m g f or c ha n ge i n H b A 1c fr o m baseli ne t o wee k 4 0 i n patie nts  wit h T 2 D 
a n d a B MI ≥ 2 7  k g/ m 2 as a n a d d -o n t o a sta bl e d ose of metf or mi n.  
O bjecti ves, e n d p oi nts a n d esti m a n d(s):  
O bje cti ves 
E n d p oi nts  
Pri mar y  
Title  
Ti me fra me  
U nit  
T o c haracterise t he d ose -res p o nse 
c ur ve of o nce -wee kl y  se ma gl uti de s.c. 
f or c ha n ge i n H b A1c fr o m bas eli ne t o 
wee k 4 0 i n patie nts wit h T 2 D a n d B MI 
≥ 2 7 k g/ m 2 as a n a d d -o n t o a sta ble 
d ose of metf or mi n  
Pri mar y  
C ha n ge i n H b A 1c 
Fr o m baseli ne 
( wee k 0) t o e n d 
of treat me nt 
( wee k 4 0) 
% -p oi nt  
Sec o n dar y  
Title  
Ti me fra me  
U nit  
T o c haracterise t he d ose -res p o nse 
c ur ve of o nce -wee kl y se ma gl uti de s.c. 
f or c ha n ge i n b o d y wei g ht fr o m 
baseli ne t o wee k 4 0 i n patie nts wit h 
T 2 D a n d B MI ≥ 2 7 k g/ m 2 as a n a d d -o n 
t o a sta ble d ose of metf or mi n 
C o nfir mat or y  
C ha n ge i n b o d y wei g ht  
Fr o m baseli ne 
( wee k 0) t o e n d 
of treat me nt 
( wee k 4 0) 
k g  
T o c haracterise t he d ose -res p o nse 
c ur ve of o nce -wee kl y se ma gl uti de s.c. 
f or safet y a n d t olera bilit y fr o m 
baseli ne t o wee k 4 9 i n patie nts wit h 
T 2 D a n d B MI ≥ 2 7 k g/ m 2 as a n a d d -o n 
t o a sta ble d ose of metf or mi n 
S u p p orti ve  
N u m ber of treat me nt -e mer ge nt a d verse 
e ve nts ( T E A Es)  
Fr o m baseli ne 
( wee k 0) t o e n d 
of st u d y ( wee k 
4 9)  
C o u nt of e ve nts  
N u m ber of treat me nt -e mer ge nt se vere 
h y p o gl ycae mic e pis o des  
Fr o m baseli ne 
( wee k 0) t o e n d 
of st u d y ( wee k 
4 9)  
C o u nt of e ve nts  
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
7
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
8  of 1 0 0  
 
Esti m a n ds:  
F or t he pri mar y o bjecti ve, a pri mar y esti ma n d a n d a n a d diti o nal esti ma n d are defi ne d. T w o 
i nterc urre nt e ve nts w ere i de ntifie d: 
 Pre mat ure disc o nti n uati o n of ra n d o mise d treat me nt  
 I nitiati o n of resc ue m e dicati o n 
T he pri mar y esti ma n d a d dresses t he mai n q uesti o n of i nterest: W hat is t he d ose -res p o ns e c ur ve of 
o nce -w ee kl y se ma gl uti de s.c./p o ole d place b o  f or c ha n ge i n H b A 1c (% -p oi nt) fr o m baseli ne t o w ee k 
4 0 i n patie nts wit h T 2 D a n d B MI ≥ 2 7 k g/ m 2, as a n a d d-o n t o a sta ble d ose of metf or mi n re gar dless 
of pre mat ure disc o nti n uati o n of ra n d o mise d treat me nt a n d i nitiati o n of rec use me dicati o n?  N ota bl y, 
i n t he treat me nt re gi me n e val uate d, p artici pa nts w h o ca n n ot t olerate t h e recei ve d d ose will ha ve 
treat me nt disc o nti n ue d.   
T he a d diti o nal esti ma n d a d dresses a n a d diti o nal q uesti o n of i nterest: W hat is t he d ose -res p o nse 
c ur ve of o n ce -wee kl y s e ma gl uti de s.c./p o ole d place b o  f or c ha n ge i n H b A1c ( %-p oi nt) fr o m baseli ne 
t o wee k 4 0 i n patie nts wit h T 2 D a n d B MI ≥ 2 7 k g/ m 2, as a n a d d-o n t o a sta ble d ose of metf or mi n, if 
all partici pa nts ha d re mai ne d o n ra n d o mise d treat me nt wit h o ut i nitiati o n of resc u e me dicati o n?  
N ota bl y, i n t he tr eat me nt re g i me n e val u ate d, partici pa nts w h o ca n n ot t olerate t he recei ve d d os e will 
ha ve treat me nt disc o nti n ue d.    
O ver all desi g n:  
T he st u d y c o nsists of  a n u p t o 3 -wee k scree ni n g p eri o d  f oll o we d b y a 4 0-wee k  i nter ve nti o n peri o d 
a n d a 9-w ee k  f oll o w-u p peri o d. T he i nterv e nti o n peri o d i ncl u de s 1 2 -2 4 wee ks d ose escalati o n 
f oll o we d b y 1 6-2 8 wee ks o n mai nte na nce d os e.  
St u d y i nter ve nti o n gr o u ps a n d d ur ati o n:  
F or eac h partici pa nt, t he ma xi m u m i nter ve nti o n a n d st u d y d urati o n is 4 0 wee ks a n d 5 2 wee ks, 
res pecti vel y. 
T he f oll o wi n g  i n v esti gati o nal me dici nal pr o d ucts (I M P) are us e d i n t he st u d y: 
 Se ma gl uti de 
 m g/ m L  
 Se ma gl uti de  
place b o  
T he I M Ps will be a d mi nistere d s u bc uta ne o usl y wit h N o v o Pe n ® 4 ( me dical de vice use d o utsi de 
a p pr o val).  
F oll o wi n g t he s cree ni n g peri o d, eli gi ble p artici pa nts will be ra n d o mise d i n a 3: 1: 3: 1: 3: 1 rati o t o 
recei v e se ma gl uti de s.c. ( 2 m g, 8  m g, 1 6 m g) or m atc hi n g pl ace b o.  Ra n d o misati o n will be stratifie d 
acc or di n g t o H b A 1c at scree ni n g ( < 8. 5 %/ ≥8. 5 % ). 
N u m ber of p artici p a nts:  
2 4 0 partici pa nts will be as si g ne d t o r a n d o mise d treat me nt. 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
8
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
9  of 1 0 0  
 
P artici p a nt c h ar acteristics:  
Ke y i ncl usi o n criteria:  
 Male or fe m ale.  
 A ge d 1 8 -6 4  years ( b ot h i ncl usi ve)  at t he ti me of si g ni n g i nf or me d c o nse nt.  
 Dia g n os e d wit h t y p e 2 dia betes mellit us ≥ 1 8 0 da ys pri or t o t he da y of scree ni n g. 
 H b A 1 c of 7. 0 –  1 0. 5 % ( 5 3 –  9 1 m m ol/ m ol)  ( b ot h i ncl usi ve). 
 B MI ≥ 2 7. 0 k g/ m 2. 
 Sta ble dail y d ose(s) ≥ 9 0 da ys pri or t o t he da y of scree ni n g of a n y metf or mi n f or m ulati o ns.  
Ke y e x cl usi o n criteria:  
 Treat me nt wit h a n y me di cati o n f or t he i n dicati o n of d ia betes or o b esit y ot h er t ha n state d i n t he 
i ncl usi o n criteria wit hi n 9 0 da ys b ef ore scree ni n g. H o we ver, s h ort ter m i ns uli n treat me nt f or a 
ma xi m u m of 1 4 da ys pri or t o t he da y of scree ni n g is all o we d, as is pri or i ns uli n treat me nt f or 
gestati o nal dia b etes.   
 U nc o ntr olle d a n d p ote nti all y u nsta ble dia b etic reti n o pat h y or mac ul o pat h y. Verifie d b y a f u n d us 
e x a mi nati o n perf or me d wit hi n t he past 9 0 da ys pri or t o da y of scree ni n g or i n t he peri o d 
bet wee n scree ni n g a n d ra n d o misati o n. P har mac ol o gical p u pil -dilati o n i s a re q uire me nt u nless 
usi n g a di gital f u n d us p h ot o gra p h y ca mera s pecifi e d f or n o n -dilate d e x a mi nati o n.  
 Re nal i m pair me nt meas ure d as esti mate d gl o mer ular filtrati o n rate (e G F R) val ue of 
< 3 0  m L/ mi n/ 1. 7 3 m 2 at scree ni n g.  
Efficac y a n d safet y data will be c oll ecte d at r e g ul ar i nter vals t hr o u g h o ut t h e st u d y.  
D at a m o nit ori n g c o m mittee: N o  
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
9
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
      
Date:  
0 3 Fe br uar y 2 0 2 3  
Stat us:  
Fi n al  
N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
      
V ersi o n:  
3. 0  
P a ge:  
1 0  of 1 0 0  
 
1. 2  
Fl o w c h art  
 
Scree ni n g  R a n d o mis ati o n  
Tre at me nt peri o d  
E n d of tre at me nt  
F oll o w -u p peri o d  
 
E n d of st u d y  
Visit  
V 1  
V 2  
V 3  V 4  V 5  V 6  P 7  V 8  P 9  V 1 0  P 1 1  V 1 2  V 1 3  V 1 4  
V 1 5  
P 1 6  
V 1 7  
Ti mi n g of Visit ( Wee ks)  
-2  
0  
4  
8  1 2  1 6  1 7  2 0  2 1  2 4  
2 5  
2 8  
3 2  
3 6  
4 0  
4 5  
4 9  
Visit Wi n d o w ( Da ys)  
± 7  
0  
± 3  ± 3  ± 3  ± 3  ± 3  ± 3  ± 3  ± 3  ± 3  ± 3  
± 3  
± 3  
± 3  
0/ 7  
0/ 7  
I nf or m e d C o nse nt a n d De m o gra p h y  a (1 0. 1. 3 ) 
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C hil d beari n g P ote ntial (1 0. 4 ) 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T o bacc o Use (5. 3. 2 ) 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eli gi bilit y Criteria (5. 1 ,5. 2 ) 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ra n d o misati o n a n d Ra n d o misati o n Criteria  (5. 5 )  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C o nc o mita nt Me dicati o n 6. 8 ) 
X  
X  
X  X  X  X  X  X  X  
X  
X  
X  
X  
X  
X  
X  
X  
Disc o nti n uati o n Criteria (7. 1 ) 
 
X  
X  X  X  X  X  X  X  
X  
X  
X  
X  
X   
 
 
Me dical Hist or y/ C o nc o mita nt Ill ness (8. 2 ) 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre g na nc y Test (8. 2. 7 ,8. 3. 5 ,1 0. 4 ) 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
X  
B o d y Wei g ht (8. 1. 1 ) 
X  
X  
X  X  X  X   
X   
X   
X  
X  
X  
X  
 
 
Hei g ht (8. 2. 1 ) 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Waist Circ u mfere nce (8. 1. 2 ) 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
Vital Si g ns (8. 2. 2 ) 
X  
X  
X  X  X  X   
X   
X   
X  
X  
X  
X  
 
X  
Electr ocar di o gra m ( 8. 2. 4 ) 
 
X  
 
 
 
 
 
 
 
X   
X   
 
X  
 
 
E ye E xa mi nati o n  b (8. 2. 3 ) 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
P h ysical E xa mi nati o n (8. 2. 1 ) 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
A d verse E ve nt (8. 3 ,1 0. 3 ) 
 
 
X  X  X  X  X  X  X  
X  
X  
X  
X  
X  
X  
X  
X  
H y p o gl ycae mic E pis o des (1 0. 8 ) 
 
 
X  X  X  X  X  X  X  
X  
X  
X  
X  
X  
X  
X  
X  
Tec h nical C o m plai nt (8. 3. 6 ,1 0. 5 ) 
X  
X  
X  X  X  X  X  X  X  
X  
X  
X  
X  
X  
X  
X  
X  
Atte n d Visit Fasti n g (5. 3. 1 ) 
 
X  
X  X  X  X   
X   
X   
 
 
 
X  
 
X c  
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
 .
-
 |
1
V V- T M F- 5 9 0 1 0 6 5
  Pr ot oc ol  4 9 8 4 v 3. 0
 |
1 0
 of
1 0 0

Pr ot o c ol  
      
Date:  
0 3 Fe br uar y 2 0 2 3  
Stat us:  
Fi n al  
N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
      
V ersi o n:  
3. 0  
P a ge:  
1 1  of 1 0 0  
 
 
Scree ni n g  R a n d o mis ati o n  
Tre at me nt peri o d  
E n d of tre at me nt  
F oll o w -u p peri o d  
 
E n d of st u d y  
Visit  
V 1  
V 2  
V 3  V 4  V 5  V 6  P 7  V 8  P 9  V 1 0  P 1 1  V 1 2  V 1 3  V 1 4  
V 1 5  
P 1 6  
V 1 7  
Ti mi n g of Visit ( Wee ks)  
-2  
0  
4  
8  1 2  1 6  1 7  2 0  2 1  2 4  
2 5  
2 8  
3 2  
3 6  
4 0  
4 5  
4 9  
Visit Wi n d o w ( Da ys)  
± 7  
0  
± 3  ± 3  ± 3  ± 3  ± 3  ± 3  ± 3  ± 3  ± 3  ± 3  
± 3  
± 3  
± 3  
0/ 7  
0/ 7  
P K Sa m pli n g (8. 4. 1  1 0. 2 ) 
 
 
X  X   
X   
X   
X  
 
X  
 
X  
X  
 
X  
La b orat or y Assess m e nts (8. 6 , 1 0. 2 ) 
X  
X  
X  X  X  X   
X   
X   
X  
X  
X  
X  
 
X  
A nti b o d y sa m pli n g  (8. 7 , 1 0 . 2) 
 
X  
X  X  
 
X   
 
 
X   
 
 
 
X  
 
X  
Bi osa m ples f or F ut ure A nal ysis (1 0. 2 , 1 0. 7 ) 
 
X  
X  X  X  X   
X   
X   
X   
 
X  
 
 
S pir o metr y  d (8. 1. 3 ) 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
Dr u g Dis pe nsi n g (6. 2 ) 
 
X  
 
X   
X   
 
 
X   
 
 
 
 
 
 
Trai ni n g i n Trial Pr o d uct, Pe n -ha n dli n g (6. 1 ) 
 
X  
 
 
 
X   
 
 
X   
 
 
 
 
 
 
C ollect, re vie w a n d tra nscri be diaries  
 
 
X  
X  
X  
X  
 
X  
 
X  
 
X  
X  
X  
X  
 
X  
a: De m o gra p h y c o nsists of dat e of birt h, se x, et h nicit y a n d race (acc or di n g t o l ocal re g ulati o n). Race a n d et h nicit y m ust b e self -re p orte d b y t he partici pa nt. 
b: I ntra oc ular press ure is part of t he e ye e xa mi nati o n a n d ca n o nl y be e xcl u de d if n ot feasi ble f or t he cli nical site. 
c: Fasti n g is defi ne d as at least 2 h o urs pri or t o t he visit wit h o ut f o o d or li q ui d, e xce pt f or water (see Secti o n 5. 3. 1 ). 
d: S pir o metr y ca n o nl y be e xcl u de d  if t he cli nical site d oes n ot ha ve t he ca pa bilit y t o perf or m t he assess me nt.  
 
 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
 .
-
 |
1
V V- T M F- 5 9 0 1 0 6 5
  Pr ot oc ol  4 9 8 4 v 3. 0
 |
1 1
 of
1 0 0

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
1 2  of 1 0 0  
 
2  I ntr o d ucti o n 
Se ma gl uti de is a p ote nt gl uca g o n -li ke pe pti de-1 rece pt or a g o nist ( G L P -1 R A) wit h a hi g h de gree of 
h o m ol o g y t o h u ma n G L P -1. G L P -1 R As are rec o m me n de d f or t he treat me nt of patie nts wit h t y pe 2 
dia betes ( T 2 D) wit h i na d e q uate gl ycae mic c o ntr ol. F urt her m ore, patie nts o n G L P -1 R As ca n be n efit 
fr o m wei g ht l oss.2 G ui deli nes ha ve rece ntl y bee n u p date d t o rec o m me n d  G L P -1 R As f or patie nts 
wit h T 2 D a n d hi g h car di o vasc ular ( C V) ris k, esta blis he d C V  disease, or c hr o nic ki d ne y disease 
( C K D).2 
Se ma gl uti de s.c. is a p pr o ve d gl o b all y ( Oze m pic ®  0. 5 m g a n d 1 m g, N N 9 5 3 5, base d o n t he gl o bal 
cli nical pr o gra m me S U S T AI N) f or o nce -wee kl y a d mi nistrati o n as a n a dj u nct t o diet a n d e x ercise t o 
i m pr o ve gl ycae mic c o ntr ol i n a d ults wit h T 2 D. I n a d diti o n, a hi g her mai nte na nce d ose of Oze m pic ®  
2 m g is a p pr o v e d i n U S, E U, Ca na da a n d S witzerla n d base d o n a p hase 3 b st u d y ( S U S T AI N 
F O R T E, N N 9 5 3 5 -4 5 0 6) c o m pari n g o nce -wee kl y se ma gl uti de s. c. 2  m g a n d 1  m g i n patie nts wit h 
T 2 D.  
Se ma g l uti de s.c. h as als o rece ntl y bee n a p pr o ve d i n U S, E U, a n d U K f or o nce-wee kl y 
a d mi nistrati o n f or c hr o ni c wei g ht ma na ge me nt ( We g o v y ®  2. 4 m g, N N 9 5 3 6, base d o n t he gl o bal 
cli nical pr o gra m me S T E P) i n pe o ple wit h o besit y or o ver wei g ht a n d wit h at least o ne wei g ht -relate d 
c o m or bi d c o n diti o n (e. g. h y perte nsi o n, T 2 D , or d ysli pi dae mia).  
F urt her m ore, se ma gl uti d e is a p pr o ve d f or o nce -dail y oral a d mi nistrati o n ( R y b els us ® 3, 7 a n d 1 4 m g, 
N N 9 9 2 4, base d o n t he gl o bal cli nical pr o gra m me PI O N E E R) i n m ulti ple re gi o ns as a n a dj u nct t o 
diet a n d e x ercise t o i m pr o ve gl ycae mic c o ntr ol i n a d ults wit h T 2 D.  
2. 1  
St u d y r ati o n ale  
A d diti o nal H b A 1c re d ucti o n a n d b o d y wei g ht l oss ha ve bee n de m o nstrate d f or se ma gl uti de s.c. 
d oses e x cee di n g t he hi g h est o nce -w ee kl y d ose i n v esti gate d i n t he ori gi nal d ose -fi n di n g st u d y 
( N N 9 5 3 5-1 8 2 1). 3 F urt her m ore, se veral p hase 3 st u dies ha ve de m o nstrat e d t hat i m ple me nti n g a 
pr ol o n ge d d ose es calati o n peri o d ca n miti gate t olera bilit y iss ues  i n d oses u p t o 2 m g a n d 2. 4 m g f or 
t he i n dicati o n of T 2 D a n d c hr o nic wei g ht ma n a ge me nt, res pecti vel y.  
I n brief, av aila ble dat a ( prese nte d i n secti o n 2. 2 ) s u g gests t hat patie nts c a n ac hie ve a d diti o nal 
effic ac y of hi g her d oses  of  o nce -wee kl y  se m a gl uti de s.c. wit h o ut a si g nifica nt i m pact o n 
t olera bilit y. T his ne w i nf or mati o n , a n d t he acc u m ulati o n of e x perie nce wit h se ma gl uti de s. c., 
j ustifies c haracterisati o n of t he d ose -res p o nse c ur ve, i ncl u di n g hi g her d oses t ha n t h ose pre vi o usl y 
i n vesti gate d. 
T his cli nical st u d y is desi g ne d t o c haracterise t he d ose -res p o ns e c ur ve of o n ce -wee kl y se ma gl uti de 
s.c. u p t o 1 6  m g f or c ha n ge i n H b A 1c fr o m baseli ne t o wee k 4 0 i n patie nts  wit h T 2 D a n d a B MI 
≥2 7  k g/ m 2 as a n a d d -o n t o a sta ble d ose of metf or mi n.  
2. 2  
B ac k gr o u n d  
Dail y d os es of se ma gl uti de s.c. c orres p o n di n g t o wee kl y e q ui val e nts of 0. 3 5 m g –  2. 1 m g ha ve 
de m o nstrat e d d ose-d e pe n de nt i m pr o ve me nts i n b ot h gl ycae mic c o ntr ol a n d b o d y wei g ht l oss f or t h e 
i n dicati o n of T 2 D.4 T he hi g hes t d oses i n vesti gate d were ge nerall y well-t olerate d as reflecte d b y t he 
l o w pr o p orti o n of partici pa nts ( < 5 %) dis c o nti n ui n g treat me nt. F urt her, i n S U S T AI N F O R T E, a 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
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1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
1 2
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
1 3  of 1 0 0  
 
p hase 3 b st u d y, a d diti o nal re d ucti o n of H b A 1c a n d b o d y wei g ht l oss a n d si milar safet y pr ofile were 
c o nfir me d f or se ma gl uti de s.c. 2 m g as c o m pare d t o se ma gl uti de s. c. 1 m g. 5 Se ma gl uti de s.c. 2  m g 
was c o m para ble t o 1  m g wit h res pect t o re p orte d s eri o us a d verse e v e nts ( S A E), a n d, i n li ne wit h t he 
safet y a n d t olera bilit y pr ofile of t he G L P-1 R A dr u g cl ass.  
I n S T E P 2, a p h ase 3a st u d y of s e ma gl uti de s.c. f or t he i n dicati o n of c hr o nic wei g ht ma na ge m e nt 
a d diti o nal gl ycae mic c o ntr ol a n d b o d y wei g ht l oss i n a d ults wit h o ver wei g ht or o besit y, a n d  T 2 D 
was de m o nstrate d wit h se ma gl uti de s.c. 2. 4 m g c o m pare d t o 1 m g. T he re p orte d rate of 
gastr oi ntesti nal a d v erse e ve nts was sli g htl y hi g her i n t he  se ma gl uti de 2. 4  m g gr o u p ( 4. 2 %) vers us 
1  m g gr o u p ( 3. 5 %), b ut disc o nti n uati o ns d ue t o a d verse e v e nts were l o w a n d si milar i n b ot h 
gr o u ps. 6  
T o e ns ure t hat b ot h b o d y wei g ht ma n a ge me nt a n d i nte nsifie d gl ycae mic c o ntr ol is i n dicate d , t he 
st u d y p o p ulati o n will c o nsist  of patie nts  wit h i na de q uatel y c o ntr olle d T 2 D o n  a sta ble d ose of 
metf or mi n a n d B MI ≥ 2 7  k g/ m 2. 
2. 3  
Be nefit -ris k assess me nt  
T he mai n be nefits a n d ris ks relate d t o partici p ati o n i n t he st u d y are descri be d i n t he bel o w secti o ns. 
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 nefi ts a n d ris ks a n d reas o n a bl y 
e x pecte d a d vers e e v e nts of se ma gl uti de s.c. a n d N o v o Pe n ® 4 ma y be f o u n d i n t he i n vesti gat or’s 
br oc h ures 7, 8 (a n d a n y u p dates here of), t he S u m mar y of Pr o d uct C haracteristics 9 a n d prescri bi n g 
i nf or mati o n1 0 f or Oze m pic® . 
2. 3. 1  
Ris k assess me nt  
T a ble  2 -1  
Ris k assess me nt  
P ote nti al ris k of cli nic al 
si g nific a nce 
S u m m ar y of d at a/r ati o n ale f or 
ris k 
 
Miti g ati o n str ate g y  
St u d y i nter ve nti o n ( se m a gl uti de) 
Gastr oi ntesti nal dis or ders  
C o nsiste nt wit h ot her G L P -1 R As, 
t he m ost fre q ue nt a d verse e ve nts 
( A Es) wit h se ma gl uti de are 
gastr oi ntesti nal (s uc h as na use a, 
v o miti n g a n d diarr h oea). I n ge neral, 
t hese reacti o ns are mil d or m o derate 
i n se verit y, of s h ort d urati o n, a n d 
d ose de pe n de nt.   
 
I n partici pa nts  treate d wit h G L P-1 
R As, na usea, v o miti n g a n d diarr h oea 
ma y lea d t o si g nifica nt de h y dr ati o n. 
T his s h o ul d be c o nsi dere d w he n 
treati n g partici pa nts  wit h i m paire d 
re nal f u ncti o n as it ma y ca use a 
deteri orati o n of re nal f u ncti o n.  
Cli nical st u dies ha ve s h o w n t hat a 
l o w starti n g d ose a n d gra d ual d ose 
escalati o n miti gates t he ris k of 
de vel o pi n g gastr oi ntesti nal 
s y m pt o ms.  
 
P artici pa nts  wit h GI s y m pt o ms are 
rec o m me n de d t o dri n k ple nt y of 
fl ui ds t o a v oi d v ol u me de pleti o n. 
H y p o gl yce 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. P artici pa nts  treate d 
wit h se ma gl uti de i n c o m bi nati o n 
wit h s ulf o n yl urea or i ns uli n ma y 
ha ve a n i ncrease d ris k of 
h y p o gl ycae mia.  
T he ris k of h y p o gl ycae mia ca n be 
l o were d b y re d uci n g t he d ose of 
s ulf o n yl urea or i ns uli n (if use d as 
resc ue me dicati o n) w he n i niti ati n g 
treat me nt wit h se ma gl uti de. 
 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
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V V- T M F- 5 9 0 1 0 6 5
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-
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1
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 of
  Pr ot oc ol  4 9 8 4 v 3. 0
1 3
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
1 4  of 1 0 0  
 
P ote nti al ris k of cli nic al 
si g nific a nce 
S u m m ar y of d at a/r ati o n ale f or 
ris k 
 
Miti g ati o n str ate g y  
Dia b etic reti n o pat h y c o m plicati o ns  
 
I n a 2-year cli nical st u d y wit h s.c. 
se ma gl uti de ( N N 9 5 3 5-3 7 4 4) 
i n v ol vi n g 3, 2 9 7 partici pa nts  wit h 
T 2 D,  hi g h car di o vasc ular  ris k, l o n g 
d urati o n of dia betes a n d p o orl y 
c o ntr olle d bl o o d gl uc ose, E A C -
c o nfir me d e ve nts of dia betic 
reti n o pat h y c o m plicati o ns occ urre d 
i n m ore partici pa nts  treate d wit h s.c. 
se ma gl uti de ( 3. 0 %) c o m pare d t o 
place b o ( 1. 8 %). T h e a bs ol ute ris k 
i ncrease f or dia betic reti n o pat h y 
c o m plicati o ns was lar ger a m o n g 
partici pa nts  wit h a hist or y of dia betic 
reti n o pat h y at baseli ne. I n t he 
partici pa nts  w h o di d n ot ha ve a 
d oc u me nte d hist or y of dia beti c 
reti n o pat h y t he n u m ber of e ve nts 
were si milar f or s.c. se ma gl uti de a n d 
place b o. I n t he ot her cli nical st u dies 
u p t o 1 year i n v ol vi n g 4, 8 0 7 
partici pa nts wit h T 2 D, A Es relate d 
t o dia betic reti n o pat h y were re p orte d 
i n si milar pr o p orti o ns of partici pa nt s 
treate d wit h s.c. se ma gl uti de ( 1. 7 %) 
a n d c o m p arat ors ( 2. 0 %).  
Ra pi d i m pr o ve me nt i n gl uc os e 
c o ntr ol has bee n ass ociate d wit h a 
te m p orar y w orse 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 xcl u de d. L o n g -ter m 
gl ycae mic c o ntr ol decreases t he ris k 
of dia betic reti n o pat h y. T hese 
partici pa nts  s h o ul d be m o nit ore d 
cl osel y a n d treate d acc or di n g t o 
cli nical g ui deli nes.  
 
Aller gic reacti o ns  
As wit h all pr otei n -base d 
p har mace uticals, treat me nt wit h 
se ma gl uti de ma y e v o ke aller gi c 
reacti o ns, i ncl u di n g seri o us all er gic 
reacti o ns s uc h as a n gi oe de ma a n d 
a na p h ylactic reacti o ns.  
As a preca uti o n, partici pa nts wit h 
k n o w n or s us pecte d h y perse nsiti vit y 
t o se ma gl uti de or relate d pr o d ucts 
will n ot be e nr olle d i n t his st u d y. I n 
a d diti o n, partici pa nts will be 
i nstr ucte d t o c o ntact t he site st aff as 
s o o n as p ossi ble f or f urt her g ui da nce 
if s us pici o n of a h y perse nsiti vit y 
reacti o n t o t he st u d y pr o d uct occ urs.  
Ac ute pa ncreatitis  
Ac ute pa ncreatitis has bee n o bser ve d 
wit h t he use of G L P -1 R As. I n t he 
c o m plete d p hase 3 st u dies wit h 
se ma gl uti de s.c. a n d oral 
se ma gl uti de, b ot h t he e ve nt rate a n d 
t he pr o p orti o n of partici pa nts 
e x perie nci n g c o nfir me d pa ncr eatitis 
were si milar wit h se ma gl uti de a n d 
c o m parat or. Fe w e ve nts were 
c o nfir me d; t he e ve nts occ urre d 
t hr o u g h o ut t he st u d y peri o ds a n d t he 
o verall rates were si milar t o t he rates 
re p orte d i n bac k gr o u n d p o p ulati o ns. 
P artici pa nts s h o ul d be i nf or me d of 
t he c haracteristic s y m pt o ms of ac ute 
pa ncreatitis a n d if pa ncreatitis is 
s us pecte d, se ma gl uti de s h o ul d be 
disc o nti n ue d. If c o nfi r me d, 
se ma gl uti de s h o ul d n ot be rest arte d. 
Ne o plas ms ( mali g na nt a n d n o n -
mali g na nt)  
P atie nts wit h T 2 D, as well as 
patie nts wit h o ver wei g ht or o besit y, 
ha ve a n i ncrease d ris k of certai n 
t y pes of ca ncer. T here is n o e vi de nce 
fr o m cli nical st u dies t hat G L P-1 -
base d t hera pies i ncrease t he ris k of 
ne o plas ms. H o we ver, i n t he 
se ma gl uti de s.c. as well as oral 
se ma gl uti de p hase 3a st u dies, t he 
P artici pa nts wit h prese nce or hist or y 
of mali g na nt ne o plas m wit hi n 
5  years pri or t o t he da y of scre e ni n g 
will n ot be e nr olle d i n t his st u d y. 
Basal a n d s q ua m o us cell s ki n ca ncer, 
i n sit u carci n o mas of t he cer vi x, or i n 
sit u pr ostate ca ncer is all o we d. 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
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V V- T M F- 5 9 0 1 0 6 5
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1
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 of
  Pr ot oc ol  4 9 8 4 v 3. 0
1 4
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
1 5  of 1 0 0  
 
P ote nti al ris k of cli nic al 
si g nific a nce 
S u m m ar y of d at a/r ati o n ale f or 
ris k 
 
Miti g ati o n str ate g y  
pr o p orti o n of partici pa nts wit h 
ne o plas ms ( mali g na nt a n d n o n -
mali g na nt) were sli g htl y hi g her wit h 
se ma gl uti de t ha n wit h c o m par at or. 
T he n u m ber of partici pa nts e x p ose d 
t o se ma gl uti de s.c. or oral 
se ma gl uti de f or a l o n ger peri o d is 
c o nsi dere d i ns ufficie nt f or a 
t h or o u g h assess me nt of t he ris k of 
ne o plas ms.  
P a ncreatic ca ncer  
P atie nts 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. T here is 
c urre ntl y n o s u p p ort fr o m n o n -
cli nical st u dies, cli nical st u dies or 
p ost -mar keti n g data t hat G L P -1 
base d t hera pies i ncrease t he ris k of 
pa ncreatic ca ncer. H o we ver, 
pa ncreatic ca ncer has bee n classifie d 
as a p ote nt ial class ris k f or all 
mar kete d G L P -1 R As b y re g ul at or y 
a ge ncies. T here is n o i n dicati o n of 
a n i ncrease d relati ve ris k i n t he 
se ma gl uti de treat me nt gr o u ps vs. 
c o m parat or, i ncl u di n g place b o. T he 
rates of E A C-c o nfir me d e ve nts of 
pa ncreatic ca ncer were c o nsis t e ntl y 
l o w acr oss st u dies. 
P artici pa nts  wit h prese nce or hist or y 
of mali g na nt ne o plas m wit hi n 
5  years pri or t o t he da y of scre e ni n g 
will n ot be e nr olle d i n t his st u d y. 
Me d ullar y t h yr oi d ca ncer  
T h yr oi d C -cell t u m o urs were s ee n i n 
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. T he r o de nt 
C -cell t u m o urs are ca use d b y a n o n -
ge n ot o xic, s pecific G L P -1 rec e pt or 
me diate d mec ha nis m t o w hic h 
r o de nts are partic ularl y se nsiti ve. N o 
C -cell t u m o urs were o bser ve d i n 
m o n ke ys after 5 2 wee ks e x p os ure u p 
t o 5 2-f ol d a b o ve t he cli nical plas ma 
e x p os ure at 1 4 m g/ da y. T he G L P -1 
rece pt or is n ot e x presse d i n t he 
n or mal h u ma n t h yr oi d, a n d t heref ore 
t he cli nical rele va nce of t he fi n di n gs 
is c o nsi dere d t o be l o w. 
T o miti gate t his ris k , partici pa nts 
wit h a fa mil y or pers o nal hist or y of 
me d ullar y t h yr oi d carci n o ma or 
m ulti ple e n d ocri ne ne o plasia t y pe 2 
are e xcl u de d fr o m cli nical st u dies 
wit h se ma gl uti de.  
St u d y pr oce d ures  
Disc o mf ort relate d t o i n vasi ve st u d y 
pr oce d ure  
Disc o mf ort ma y occ ur ar o u n d t he 
site of bl o o d sa m pli n g. 
E x perie nce d a n d pr o perl y trai ne d site 
pers o n nel will e ns ure mi ni mis ati o n 
of disc o mf ort ca use d b y st u d y 
pr oce d ures.  
Ris k of C O VI D -1 9 i nfecti o n i n 
relati o n t o partici pati o n i n t he st u d y 
P artici pa nts ma y be e x p ose d t o  t he 
ris k of C O VI D-1 9 tra ns missi o n a n d 
i nfecti o n i n relati o n t o site visits if 
a n o ut brea k is o n g oi n g i n t he 
c o u ntr y at t he ti me of st u d y c o n d uct.  
T he ris k of C O VI D -1 9 tra ns missi o n 
i n relati o n t o site visits is o ver all 
c o nsi dere d t o be l o w, h o we ver t his 
ma y var y bet wee n ge o gra p hic al 
areas. T o mi ni mise t he ris k as m uc h  
as p ossi ble, t he f oll o wi n g meas ures 
ha ve bee n ta ke n:  
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
1 5
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
1 6  of 1 0 0  
 
P ote nti al ris k of cli nic al 
si g nific a nce 
S u m m ar y of d at a/r ati o n ale f or 
ris k 
 
Miti g ati o n str ate g y  
 Ca uti o us partici pa nt recr uit me nt 
pla n ni n g e ns ures c o ntr olle d 
partici pa nts e nr ol me nt i n 
c o u ntries w here t he C O VI D -1 9 
pa n de mic is e val uate d t o be 
s ufficie ntl y u n der c o ntr ol, a n d at 
sites w here healt h care res o urc es 
are e val uate d t o be a de q uate.  
 O n -site visits will be well-
pre pare d a n d as s h ort as p ossi ble. 
P h ysical c o ntact bet wee n 
partici pa nts a n d site staff will be 
li mite d t o t he e xte nt p ossible, a n d 
pr otecti ve meas ures will b e 
i m ple me nte d (e. g. use of mas ks, 
sa nitizers, n o aer os ol-ge nerati n g 
pr oce d ures etc. acc or di n g t o t he 
l ocal practice). 
 A p pe n di x 9 ( Secti o n 1 0. 9 ) 
incl u des miti gati o ns t hat ca n b e 
i m ple me nte d t o e ns ure partici pa nt 
safet y a n d data i nte grit y i n cas e a 
maj or e mer ge nc y ( C O VI D -1 9 
o ut brea k) lea ds t o l oc k -d o w n of 
sites w hic h affects t he a bility t o 
perf or m st u d y -relate d pr oce d ures.  
 
Ot her  
Pre g na nc y a n d fertilit y  
St u dies i n a ni mals ha ve s h o w n 
re pr o d ucti ve t o xicit y. T here 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. 
Se ma gl uti de s h o ul d n ot be use d 
d uri n g pre g na nc y. W o me n of 
c hil d beari n g p ote ntial are re q uire d t o 
use hi g hl y effecti ve c o ntrace pti ve 
met h o ds w he n partici pati n g i n t his 
st u d y ( A p pe n di x 4, T a ble  1 0 -6 ). If a 
partici pa nt  wis hes t o bec o me 
pre g na nt, or pre g na nc y occ urs, 
se ma gl uti de s h o ul d be disc o nti n ue d 
( please refer t o S ecti o n 8. 3. 5  f or 
f urt her g ui da nce). T he effect of 
se ma gl uti de o n fertilit y i n h u ma ns is 
u n k n o w n.  
 
Ris k assess me nt has bee n c o n d ucte d f or N o v o Pe n ® 4 f or s e ma gl uti de s.c. i n acc or da nce wit h I S O 
1 4 9 7 1: 2 0 1 9. A st u d y -s pecific de vic e ris k assess m e nt has bee n p erf or me d t o e ns ure safe a n d 
acc urate ha n dli n g a n d d osi n g of se m a gl uti de w he n usi n g N o v o Pe n ® 4 i n patie nts wit h  T 2 D  a n d 
o ver wei g ht.  
N o a d diti o nal ris ks ha ve bee n  ass oci ate d wit h usi n g N o v o Pe n ® 4 acc or di n g t o t he cli nical 
pr oce d ures s pecifi e d i n t his pr ot oc ol, c o m pare d wit h usi n g N o v o Pe n ® 4 wit hi n its a p pr o ve d i nte n de d 
use a n d i n dicati o n f or us e. 8 T he use of  N o v o Pe n ® 4 i n t his st u d y is t heref ore c o nsi dere d t o be of 
n o n -si g nifica nt ris k. 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
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V V- T M F- 5 9 0 1 0 6 5
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1
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 of
  Pr ot oc ol  4 9 8 4 v 3. 0
1 6
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
1 7  of 1 0 0  
 
2. 3. 2  
Be nefit assess me nt  
All partici pa nts will recei ve t h or o u g h me dical atte nti o n a n d e ver y ra n d o mise d partici pa nt is 
e x pecte d t o  be nefit fr o m i nte nsifie d gl ycae mic c o ntr ol as meas ure d b y H b A 1c, a n d i n acc or da n ce 
wit h i nter nati o nal g ui deli nes o n T 2 D ma na ge me nt, se ma gl uti de s. c. will be gi ve n as a n a d d -o n t o 
metf or mi n. Resc ue me di cati o n will be prescri be d f or partici pa nts n ot ac hie vi n g s uffi cie nt gl ycae mic 
c o ntr ol re gar dless of ra n d o mise d treat me nt. 
 
I n v esti gati o nal me dici nal pr o d ucts (I M Ps) a n d a u xiliar y s u p plies, i ncl u di n g n o n -i n vesti gati o nal 
me dical de vice us e d  o utsi de a p pr o val,  will be pr o vi de d b y N o v o N or dis k A/ S  ( please see 
Sect i o n 6. 1  f or m ore det ails). 
2. 3. 3  
O ver all be nefit -ris k c o ncl usi o n  
Preca uti o ns ha ve b ee n i m ple me nte d i n t he desi g n a n d pla n ne d c o n d u ct of t he st u d y t o mi ni mise t he 
ris ks a n d i nc o nve nie nces of partici pati o n i n  t he st u d y. T he s afet y pr ofile f or se ma gl uti de ge nerate d 
fr o m t he cli nical a n d n o n-cli nical de vel o p me nt pr o gra m me s has n ot re v eal e d a n y safet y iss ues t hat 
w o ul d pr o hi bit i n vesti gati o n of u p t o 1 6 m g  se ma gl uti de s.c. o nce-wee kl y .  
I n c o ncl usi o n, t he p ote ntial ris ks i de ntifie d i n ass ociati o n wit h se ma gl uti de s.c. are c o nsi dere d 
acce pta ble i n vie w of t h e a ntici pate d be nefits t hat ma y b e aff or de d t o patie nts  wit h T 2 D . 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
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V V- T M F- 5 9 0 1 0 6 5
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-
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1
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 of
  Pr ot oc ol  4 9 8 4 v 3. 0
1 7
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
1 8  of 1 0 0  
 
3  O bjecti ves, e n d p oi nts a n d esti m a n ds  
3. 1  
O bjecti ves a n d e n d p oi nts  
T he o bjecti ves a n d e n d p oi nts are pres e nte d i n Ta ble  3 -1 . 
T a ble  3 -1  
O bjecti ves a n d e n d p oi nts  
O bjecti ves  
E n d p oi nts  
Pri mar y  
Title  
Ti me fra me  
U nit  
T o c haracterise t he d ose -res p o nse 
c ur ve of o nce -wee kl y se ma gl uti de s.c. 
f or c ha n ge i n H b A1c fr o m bas eli ne t o 
wee k 4 0 i n patie nts wit h T 2 D a n d B MI 
≥ 2 7 k g/ m 2 as a n a d d -o n t o a sta ble 
d ose of metf or mi n  
Pri mar y  
C ha n ge i n H b A 1c 
Fr o m baseli ne 
( wee k 0) t o e n d 
of treat me nt 
( wee k 4 0) 
% -p oi nt  
Sec o n dar y  
Title  
Ti me fra me  
U nit  
T o c haracterise t he d ose -res p o nse 
c ur ve of o nce -wee kl y se ma gl uti de s.c. 
f or c ha n ge i n b o d y wei g ht fr o m 
baseli ne t o wee k 4 0 i n patie nts wit h 
T 2 D a n d B MI ≥ 2 7 k g/ m 2 as a n a d d -o n 
t o a sta ble d ose of metf or mi n 
C o nfir mat or y  
C ha n ge i n b o d y wei g ht  
Fr o m baseli ne 
( wee k 0) t o e n d 
of treat me nt 
( wee k 4 0) 
k g  
T o c haracterise t he d ose -res p o nse 
c ur ve of o nce -wee kl y se ma gl uti de s.c. 
f or safet y a n d t olera bilit y fr o m 
baseli ne t o wee k 4 9 i n patie nts wit h 
T 2 D a n d B MI ≥ 2 7 k g/ m 2 as a n a d d -o n 
t o a sta ble d ose of metf or mi n 
S u p p orti ve  
N u m ber of treat me nt -e mer ge nt a d verse 
e ve nts ( T E A Es)  
Fr o m baseli ne 
( wee k 0) t o e n d 
of st u d y ( wee k 
4 9)  
C o u nt of e ve nts  
N u m ber of treat m e nt -e mer ge nt se vere 
h y p o gl ycae mic e pis o des  
Fr o m baseli ne 
( wee k 0) t o e n d 
of st u d y ( wee k 
4 9)  
C o u nt of e ve nts  
 
3. 2  
Esti m a n ds  
T he esti ma n ds a n d t heir rati o nale are descri be d i n detail f or eac h of t he t w o pri mar y a n d sec o n dar y  
o bjecti ves i n Secti o ns 3. 2. 1  a n d 3. 2. 2 . T w o i nterc urre nt e ve nts were i de ntifie d: 
 Pre mat ure disc o nti n uati o n of ra n d o mise d treat me nt  
 I nitiati o n of resc ue m e dicati o n (see Secti o n 6. 8. 1 ) 
3. 2. 1  
A d dressi n g t he pri m ar y o bjecti ve  
3. 2. 1. 1  
Pri m ar y esti m a n d  
T he pri mar y esti ma n d a d dresses t he mai n q uesti o n of i nterest:  W hat is t he d ose -res p o ns e c ur ve of 
o nce -w ee kl y se ma gl uti de s.c/p o ole d place b o  f or c han ge i n H b A 1c ( %-p oi nt) fr o m baseli ne t o w ee k 
4 0 i n patie nts wit h T 2 D a n d B MI ≥ 2 7  k g/ m 2, as a n a d d-o n t o a sta ble d ose of metf or mi n re gar dless 
of pre mat ure disc o nti n uati o n of ra n d o mise d treat me nt a n d i nitiati o n of rec use me dicati o n?  N ota bl y, 
i n t he treat me nt re gi me n e val uate d, p artici pa nts w h o ca n n ot t olerate t h e recei ve d d ose will ha ve 
treat me nt disc o nti n ue d. 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
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V V- T M F- 5 9 0 1 0 6 5
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1
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 of
  Pr ot oc ol  4 9 8 4 v 3. 0
1 8
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
1 9  of 1 0 0  
 
T he pri mar y esti ma n d is defi ne d b y t he f oll o wi n g fi ve attri b utes:  
 P o p ulati o n: Patie nts wit h T 2 D a n d B MI ≥ 2 7 k g/ m 2. 
 E n d p oi nt:  C ha n ge fr o m baseli ne t o wee k 4 0 i n H b A 1c ( %-p oi nt).  
 Treat me nt c o n diti o n: Ra n d o mise d treat me nt as a d d -o n t o a sta ble d ose of metf or mi n, wit h or 
wit h o ut pre mat ure disc o nti n uati o n of treat me nt a n d i nitiati o n of resc ue me dicati o n.    
 Re mai ni n g i nterc urre nt e ve nts: N o f urt her i nterc urre nt e ve nts are i de ntifie d. T he t w o 
i nterc urre nt e ve nts des cri be d as part of t h e treat me nt c o n diti o n will all be ha n dle d b y a 
treat me nt p olic y strate g y. 
 P o p ulati o n -le vel s u m mar y: Differe n ce i n mea n c h a n ges fr o m bas eli ne. 
Rati o nale f or esti ma n d: T his esti ma n d q ua ntifies t he differe nce i n treat me nt effects bet wee n t h e 
differe nt treat me nt r e gi me ns t hat ca n be e x pecte d i n cli nical practice. It reflects t he cli nical pr actice, 
u n der w hic h t he tr eat me nt re gi me ns are t o b e a p pli e d.  
3. 2. 1. 2  
A d diti o n a l esti m a n d 
T he a d diti o nal esti ma n d a d dresses a n a d diti o nal q uesti o n of i nterest: W hat is t he d ose -res p o nse 
c ur ve of o n ce -wee kl y s e ma gl uti de s.c/p o ole d place b o  f or c ha n ge i n H b A 1c ( %-p oi nt) fr o m baseli ne 
t o wee k 4 0 i n patie nts wit h T 2 D a n d B MI ≥ 2 7 k g/ m 2, as a n a d d-o n t o a sta ble d ose of metf or mi n, if 
all partici pa nts ha d re mai ne d o n ra n d o mise d treat me nt wit h o ut i nitiati o n of resc u e me dicati o n?  
N ota bl y, i n t he tr eat me nt re gi me n e val u ate d, partici pa nts w h o ca n n ot t olerate t he recei ve d d os e will 
ha ve treat me nt  disc o nti n ue d.    
T he esti ma n d attri b utes: p o p ulati o n, e n d p oi nt, a n d p o p ulati o n -le vel s u m mar y are t h e sa me as f or t he 
pri mar y esti ma n d. T he re mai ni n g attri b utes are:  
 Treat me nt c o n diti o n: Ra n d o mise d treat me nt as a d d -o n t o a sta ble d ose of metf or mi n, wit h o ut 
pre mat ure disc o nti n uati o n of treat me nt a n d i nitiati o n of resc u e me dicati o n.   
 Re mai ni n g i nterc urre nt e ve nts: N o f urt her i nterc urre nt e ve nts are i de ntifie d. T he t w o 
i nterc urre nt e ve nts des cri be d as part of t h e treat me nt c o n diti o n will all be ha n dle d b y a 
h y p ot hetic al strate g y.  
Rati o nale f or esti ma n d: T his esti ma n d q ua ntifies t he ac hie va ble differe n ce i n treat me nt effects 
bet wee n t he differe nt treat me nt re gi me ns. It r eflects t he dr u g efficac y.  
3. 2. 2  
A d dressi n g t he sec o n d ar y o bjecti v e  
T he rele v a nt e n d p oi nt is t he sec o n dar y c o nfir mat or y e n d p oi nt “c ha n ge fr o m baseli ne t o wee k 4 0 i n 
b o d y w ei g ht ( k g)”.  
C h a n ge i n b o d y w ei g ht - pri m a r y esti m a n d  
T he mai n cli nical q uesti o n of i nterest f or t his sec o n dar y c o nfir m at or y o bjecti ve is si milar t o t he 
pri mar y esti ma n d f or t he pri mar y  o bjecti ve . 
T he esti ma n d attri b utes: p o p ulati o n, treat me nt c o n diti o n, re mai ni n g i nterc urre nt e ve nts, a n d 
p o p ulati o n -le vel s u m mar y are t he s a me as f or t he pri mar y esti ma n d f or t he pri mar y o bjecti ve. T h e 
re mai ni n g esti ma n d attri b ute is: 
 E n d p oi nt: C ha n ge fr o m  baseli ne t o wee k 4 0 i n b o d y wei g ht ( k g).  
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
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V V- T M F- 5 9 0 1 0 6 5
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-
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1
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 of
  Pr ot oc ol  4 9 8 4 v 3. 0
1 9
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
2 0  of 1 0 0  
 
Rati o nale f or esti ma n d: T he rati o nale is t he s a me as f or t he pri mar y esti ma n d f or t he pri mar y 
o bjecti ve.  
C h a n ge i n b o d y w ei g ht –  a d diti o n al esti m a n d  
T he a d diti o nal cli nical q uesti o n of i nterest f or t his sec o n dar y c o nfir mat or y o bjecti ve is si milar t o t he 
a d diti o nal esti ma n d f or t he pri mar y o bjecti ve.  
T he esti ma n d attri b utes: p o p ulati o n, treat me nt c o n diti o n, re mai ni n g i nterc urre nt e ve nts, a n d 
p o p ulati o n -le vel s u m mar y are t he s a me as f or t he a d diti o nal esti ma n d f or t he pri mar y o bjecti ve. T h e 
re mai ni n g esti ma n d attri b ute is: 
 E n d p oi nt: C ha n ge fr o m baseli ne t o wee k 4 0 i n b o d y wei g ht ( k g).  
Rati o nale f or esti ma n d: T he rati o nale is t he s a me as f or t he a d diti o nal esti ma n d f or t he pri mar y 
o bjecti ve . 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
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V V- T M F- 5 9 0 1 0 6 5
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1
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 of
  Pr ot oc ol  4 9 8 4 v 3. 0
2 0
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
2 1  of 1 0 0  
 
4  St u d y desi g n  
4. 1  
O ver all desi g n  
T his is a n i nter ve nti o nal, m ulti -ce ntre, parallel -gr o u p, ra n d o mise d, place b o -c o ntr olle d, partici pa nt - 
a n d i n vesti gat or -bli n de d wit hi n d ose le vel, s p o ns or o pe n-la bel, d ose -res p o nse st u d y of o n ce -wee kl y 
s u bc uta ne o usl y a d mi nistere d se m a gl uti de i n patie nts  wit h T 2 D a n d o ver wei g ht wit h a baseli ne 
H b A 1 c of 7. 0 – 1 0. 5 % a n d as a n a d d -o n t o a sta ble d ose of metf or mi n ( Fi g ure  4 -1 ). 
A t otal of 2 4 0 partici pa nts will be ra n d o mise d i n a 3: 1: 3: 1: 3: 1 rati o t o recei ve se ma gl uti de s.c. 
( 2 m g, 8 m g, 1 6 m g) or matc hi n g pla ce b o. All partici pa nts are t o es calate t o t he ra n d o mise d tar get 
mai nte na nce d os e acc or di n g t o t he d ose es calati o n o utli ne d i n Ta ble  6 -2 . 
Ra n d o misati o n will be stratifie d acc or di n g t o H b A 1c at scree ni n g ( < 8. 5 %/ ≥8. 5 % ). 
Fi g ure  4 -1  
St u d y desi g n  
 
T he st u d y c o nsists of:  
 a n u p t o 3 -wee k scree ni n g peri o d  
 a d ose escalati o n peri o d of 1 2 -2 4 wee ks (see Ta bl e  6 -2 ) 
 a mai nte na nce peri o d of 1 6 -2 8 wee ks (see T a ble  6 -2 ) 
 a 9-wee k f oll o w -u p p eri o d  
F or eac h partici pa nt, t he ma xi m u m i nter ve nti o n a n d st u d y d urati o n is 4 0 wee ks a n d 5 2  wee ks, 
res pecti vel y. 
T he n u m ber of i njecti o ns, a n d i njecti o n v ol u me, ra n ges fr o m o ne i njecti o n of 2 1 0 µl t o 3 i njecti o ns 
of 5 6 0 µl bet wee n t he tar get d ose of t he t hree d ose le vels (see T a ble  6 -2 ). F or eac h d os e le vel, t he 
acti ve treat me nt ar m a n d t he c orres p o n di n g v ol u m e -matc he d pl ace b o ar m will be bli n de d t o war ds 
eac h ot her. T o mi ni mise t he b ur de n of st u d y acti vit y ( b y li miti n g t he n u m ber of i njecti o ns) d o u ble -
bli n di n g will be a p plie d bet wee n pla ce b o a n d se ma gl uti de wit hi n eac h d ose le vel, b ut n ot bet wee n 
t he t hree d ose l e vels. 
I n S T E P 81 1 a differe ntial c ha n ge fr o m baseli ne was o bser ve d f or wei g ht l oss b et wee n place b o o nce 
dail y a n d pl ace b o o n ce -wee kl y. H o we ver, t h ere is n o a vaila ble data s u g gesti n g t hat o nce-wee kl y  
a d mi nistrati o n wit h a varia ble n u m ber of i njecti o ns  (i.e., 1  f or place b o 2 m g, 2 f or place b o 8  m g a n d 
3 f or place b o 1 6  m g ) w o ul d dri ve a differe ntia te d place b o res p o nse.  
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
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V V- T M F- 5 9 0 1 0 6 5
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-
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1
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 of
  Pr ot oc ol  4 9 8 4 v 3. 0
2 1
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
2 2  of 1 0 0  
 
4. 2  
Scie ntific r ati o n ale f or st u d y desi g n  
T his cli nical st u d y is desi g ne d t o c haracterise t he d ose -res p o ns e c ur ve f or o nce -wee kl y se ma gl uti de 
s.c. i ncl u di n g d oses b e y o n d w hat has pre vi o usl y b ee n i n vesti gate d. T h e  4 0 -wee k st u d y  d urati o n is 
c o nsi dere d s ufficie nt t o e val uate t olera bilit y, safet y, a n d e na ble differe ntiati o n bet wee n gr o u ps o n 
effic ac y me as ure d b y t he pri mar y  e n d p oi nt, c ha n ge i n H b A 1 c. 
 
T he s p o ns or o pe n -l a bel d esi g n per mits  access t o o n g oi n g  c o m parati ve safet y dat a to e ns ure 
c o nti n u o us m o nit ori n g  as a n a d diti o nal preca uti o n . P artici pa nt- a n d i n vesti gat or -bli n di n g wit hi n 
d ose le vel , i n a d diti o n t o ra n d o misati o n a n d place b o -c o ntr ol, is i m ple me nte d t o mi ni mise bias . T his 
a p pr oac h  is c o nsi dere d j ustifie d stri ki n g t he bala nce bet wee n  partici pa nt  s afet y a n d data i nte grit y 
f or t he o bjec ti ve pri mar y e n d p oi nt.   
 
T he u n bala nce d ( 3: 1) ra n d o misati o n e ns ures r elati ve m ore o bser vati o ns  o n acti ve treat me nt  t o 
i nf or m t he d ose-res p o nse c ur ve. T h e place b o gr o u p will e na ble differe ntiati o n of res p o nse relate d t o 
se ma gl uti de s. c. fr o m r es p o nse d ue t o ot her fact ors s uc h as st u d y p artici pati o n  a n d i nte nsifie d 
me dical atte nti o n . 
T he d ose of se m a gl uti de s.c. ( or v ol u me -mat c he d place b o  wit hi n d ose le vels ) will be d o u ble d e ver y 
f o urt h wee k i n li ne wit h t he a p pr o ve d p os ol o g y f or Oze m pic®  u ntil t he hi g hest d ose e val uat e d 
( 1 6 m g) is i nitiate d at w ee k  2 4 (see T a ble  6 -2 ).  
T he  9 -wee k f oll o w -u p p eri o d (c orres p o n di n g t o r o u g hl y 9 ti mes t 1/ 2 1 0) is i m ple me nte d t o all o w 
was h -o ut of 1 6 m g se ma gl uti de bef ore p ost -tr eat me nt safet y e v al uati o n a n d t o a v oi d dr u g 
i nterfere nce i n t he a nti-dr u g a nti b o d y ass a ys.  
4. 3  
J ustific ati o n f or d ose  
T he starti n g d os e i n t his st u d y will be 0. 2 9 m g as t his is t he d ose cl osest t o t he a p pr o ve d  starti n g 
d ose of se ma gl uti de s.c. f or t he i n dicati o n of T 2 D of 0. 2 5 m g w hi c h ca n b e i njecte d usi n g t he 
N o v o Pe n ® 4 f or a d mi nistrati o n of se ma gl uti de 
m g/ m L (see Ta ble  6 -2 ). Alt h o u g h t he a p pr o ve d  
starti n g d ose of se ma gl uti de s.c. is 0. 2 5 m g, a si n gle d ose of 0. 5 m g has bee n a d mi nistrate d i n 
pre vi o us cli nical st u dies wit h acce pt a ble t olera bilit y.   
T he se ma gl uti de s.c. d os es of 2 m g, 8 m g, a n d 1 6 m g is c h ose n t o all o w differe ntiati o n of efficac y 
a n d safet y i ncl u di n g t olera bilit y bet wee n d oses. U si n g a n esta blis he d p h ar m ac o ki netic ( P K)  m o d el  
f or se ma gl uti de s.c. a n d ass u mi n g d ose-pr o p orti o nalit y , t he pre dicte d C a v g f or 8 m g a n d 1 6 m g are 
2 1 7 n m ol/ L ( 9 0 % ra n ge: 1 5 7 –  2 9 3 n m ol/ L) a n d 4 3 4 n m ol/ L ( 9 0 % ra n ge: 3 1 3 –  5 8 7 n m ol/ L) , 
res pecti vel y.  
T he pre dict e d  plas ma e x p os ure at 1 6 m g/ wee k is a p pr o xi matel y 2 -f ol d l o w er t ha n e x p os ures  at t he 
n o o bser ve d a d v erse effect le vels ( N O A E L) i n c hr o nic t o xicit y st u d y  i n rats ( Ca v g: 7 5 4  n m ol/ L). I n  
m o n ke ys , the N O A E L i n t he c hr o nic t o xicit y st u d y was deter mi ne d b y a n E C G a b n or malit y of t he 
heart (left b u n dle bra n c h bl oc k li ke rec or di n g; L B B B) o bser ve d at t he hi g h est d ose ( 0. 3 6 m g/ k g 
t wice wee kl y; Ca v g: 7 6 0 n m ol/ L ) i n o ne o ut of ei g ht fe male m o n ke ys. Car diac hist o pat h ol o g y was 
n or mal i n t he a ni mal . O v erall, b ase d o n t h e n o ncli nical data a n d t he l ar ge a m o u nt of a vaila ble 
cli nical safet y dat a f or s e ma gl uti de, i ncl u di n g t h or o u g h e v al uati o ns i n t he car di o vasc ular o utc o mes 
st u d y ( S U S T AI N 6, N N 9 5 3 5-3 7 4 4) , t he L B B B o bser vati o n i n o ne m o n ke y is n ot c o nsi dere d t o 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
2 2
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
2 3  of 1 0 0  
 
affect t he safet y pr ofile of se ma gl uti de  a n d has t heref ore bee n disr e gar de d i n t he prese nt safet y 
assess me nt. Acc or di n gl y, t he rele va nt a ni mal t o h u ma n e x p os ure rati o at 1 6 m g/ wee k is 
7 5 4  n m ol/ L / 4 3 4 n m ol/ L = 1. 7; i.e., t he pre dict e d h u ma n e x p os ure at 1 6 m g is a p pr o xi matel y 2-f ol d 
l o wer t ha n t he n o ncli nic al e x p os ures. 
I n a P K st u d y of dif fere nt f or m ulati o ns of oral se ma gl uti de ( N N 9 9 2 4-4 6 3 3) , 4 9 partici pa nts 
ac hie ve d e x p os ure le vels hi g her t h a n t he 2 1 7 n m ol/ L pre di cte d C a v g f or t he 8 m g se ma gl uti de s.c. 
d ose a n d 8  partici p a nts a c hie ve d  e x p os ure le vels hi g her t h a n  t he 4 3 4 n m ol/ L pre dicte d C a v g f or t he 
1 6  m g se ma gl uti de s.c.  d ose . T he A E pr ofile of t h e 5 7 partici pa nts was si milar t o t he e x pecte d 
safet y pr ofile f or G L P-1 R As , a n d t here was n o c orrelati o n bet wee n e x p os ure le vels a n d A E 
re p orti n g ( data o n file). T he pr o p orti o n of partici pa nts disc o nti n ui n g trial pr o d uct d ue t o A Es w as 
a p pr o xi matel y 1 7 % . I n t his c urre nt st u d y, d ose es calati o n d urati o n is d o u bled  t o miti gate GI A Es.  
I n brief, n o n-cli nical a n d cli nical data s u g gests t hat i n vesti gati o n of u p t o 1 6 m g se ma gl uti de s.c. is 
b ot h t olera ble a n d safe  a n d ma y pr o vi de a d diti o nal be nefit f or p atie nts wit h T 2 D  a n d o ver wei g ht . 
4. 4  
E n d of st u d y defi niti o n  
T he e n d of t he st u d y is d efi ne d as t he d ate of t he l ast visit of t he last partici pa nt i n t he st u d y 
gl o ball y.  
A partici pa nt is c o nsi dere d t o ha ve c o m plet e d t he st u d y if he/s he h as c o m plete d all peri o ds of t he 
st u d y i ncl u di n g t h e last visit.  
T he pri mar y e n d p oi nt is e val uate d at visit 1 5 ( wee k 4 0). T he pri mar y c o m pleti o n date ( P C D) is 
defi ne d  as t he d ate of visit 1 5 ( wee k 4 0) o n w hi c h t he last partici pa nt i n t he cli nical st u d y has a n 
assess me nt f or t he pri mar y e n d p oi nt. If t he last partici pa nt is wit h dra w n earl y, t he P C D is 
c o nsi dere d t he d ate w h e n t he last partici pa nt w o ul d ha ve c o m plete d vis it 1 5.  
 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
2 3
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
2 4  of 1 0 0  
 
5  St u d y p o p ul ati o n  
Pr os pecti ve a p pr o val of pr ot oc ol de viati o ns t o recr uit me nt a n d e nr ol me nt criteria, als o k n o w n as 
pr ot oc ol wai vers or e x e m pti o ns, is n ot per mitte d.  
Pre -scree ni n g is defi ne d as re vie w of t he patie nt me dical rec or ds, i ncl u di n g ha n di n g o ut partici pa nt 
i nf or mati o n, as well as d ata base re vie w. A n y pre-scree ni n g acti vities m ust be d oc u me nte d o n site 
b y t he i n vesti gat or.  
5. 1  
I ncl usi o n criteri a 
Partici pa nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if all t he f oll o w i 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 st u d y-relate d acti vities. St u d y-rel ate d acti vities are a n y 
pr oce d ures t hat are carrie d o ut as part of t he st u d y, i ncl u di n g acti vities t o deter mi ne s uita bilit y 
f or t he st u d y. 
2.  Male or fe m ale.  
3.  A ge d 1 8 -6 4  years ( b ot h i ncl usi ve)  at t he ti me of si g ni n g i nf or me d c o nse nt.  
4.  Dia g n os e d wit h t y p e 2 dia betes mellit us ≥ 1 8 0 da ys pri or t o t he da y of scree ni n g.  
5.  H b A 1 c of 7. 0 –  1 0. 5 % ( 5 3 –  9 1 m m ol/ m ol ) ( b ot h i ncl usi ve). 
6.  B MI ≥ 2 7. 0 k g/ m 2. 
7.  Sta ble dail y d ose(s) ≥ 9 0 da ys pri or t o t he da y of scree ni n g of a n y metf or mi n f or m ulati o ns.  
H u n gar y: Please s ee A p p e n di x 1 0 ( Secti o n 1 0. 1 0 ) f or c o u ntr y-s p ecific re q uire me nts. 
5. 2  
E x cl usi o n criteri a  
Partici pa nts are e x cl u de d fr o m t he st u d y if a n y of t he f oll o wi n g criteria a p pl y:  
1.  Treat me nt wit h a n y me di cati o n f or t he i n dicati o n of dia betes or o b esit y ot h er t ha n state d i n t he 
i ncl usi o n criteria wit hi n 9 0 da ys b ef ore scree ni n g. H o we ver, s h ort ter m i ns uli n treat me nt f or a 
ma xi m u m of 1 4 da ys pri or t o t he da y of scree ni n g is all o we d, as  is pri or i ns uli n treat me nt f or 
gestati o nal dia b etes.  
2.  A ntici pate d i nitiati o n or c ha n ge i n c o nc o mita nt me dicati o ns (f or m ore t ha n 1 4 c o nsec uti ve da ys) 
k n o w n t o affect wei g ht or gl uc os e meta b olis m (e. g. treat me nt wit h orlistat, t h yr oi d h or m o nes, or 
c ortic oster oi ds). 
3.  Use of a n y me di cati o n wit h u n k n o w n or u ns pecifi e d c o nte nt wit hi n 9 0 da ys bef ore s cree ni n g.  
4.  U nc o ntr olle d a n d p ote nti all y u nsta ble dia b etic reti n o pat h y or mac ul o pat h y. Verifie d b y a f u n d us 
e x a mi nati o n perf or me d wit hi n t he past 9 0 da ys pri or t o da y of scree ni n g or i n t he peri o d 
bet wee n scree ni n g a n d ra n d o misati o n. P har mac ol o gical p u pil -dilati o n is a re q uire me nt u nless 
usi n g a di gital f u n d us p h ot o gra p h y ca mera s pecifi e d f or n o n -dilate d e x a mi nati o n.  
5.  Re nal i m pair me nt meas ure d as esti mate d gl o mer ular fil trati o n rate (e G F R) val ue of 
< 3 0  m L/ mi n/ 1. 7 3 m 2 at scree ni n g.  
6.  M y ocar dial i nfarcti o n, str o ke, h os pitalizati o n f or u nsta ble a n gi na pect oris or tra nsie nt isc hae mic 
attac k wit hi n 1 8 0 da ys bef ore scree ni n g.  
7.  C hr o nic heart fail ure cl assifie d as bei n g i n Ne w Y or k Heart Ass ociati o n ( N Y H A) Class I V at 
scree ni n g. 
8.  Pla n ne d c or o nar y, car oti d or peri p heral art er y re v asc ularisati o n.  
9.  Prese nce or hist or y of pa ncreatitis (ac ute or c hr o nic).  
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
2 4
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
2 5  of 1 0 0  
 
1 0.  Prese nce or hist or y of mali g na nt ne o plas m ( ot h er t ha n basal or s q u a m o us cell s ki n ca nc er, i n-
sit u carci n o mas of t he cer vi x, or i n sit u pr ostate ca ncer) wit hi n 5 years bef ore scree ni n g.  
1 1.  Pers o nal or first -d e gree relati ve(s) hist or y of m ulti ple e n d ocri ne n e o plasia t y p e 2 or me d ullar y 
t h yr oi d carci n o ma*.  
1 2.  K n o w n or s us pect e d h y p erse nsiti vit y t o st u d y i nter ve nti o n(s) or relate d pr o d ucts. 
1 3.  Pre vi o us partici pati o n i n t his st u d y. Partici pati o n is defi ne d as si g ne d i nf or me d c o nse nt.  
1 4.  Fe male w h o is pre g na nt, breast -fee di n g or i nte n ds t o bec o me pre g n a nt or is of c hil d beari n g 
p ote ntial a n d n ot usi n g hi g hl y effecti ve c o ntrace pti ve met h o d, as defi n e d i n A p pe n di x  4 
( Secti o n 1 0. 4 ). 
1 5.  Partici pati o n (i.e., si g n e d i nf or me d c o nse nt) i n a n y i nter ve nti o nal, cli nical st u d y wit hi n 9 0 da ys 
bef ore s cree ni n g.     
1 6.  Recei pt of a n a p pr o ve d C O VI D -1 9 v acci n e wit hi n 1 4 da ys pri or t o scree ni n g or pla n ne d  
C O VI D -1 9 vacci nati o n b et wee n scree ni n g a n d ra n d o mis ati o n. 
1 7.  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 
partici pa nt’s safet y or c o m plia nce wit h t he pr ot oc ol.  
1 8.  A ntici pate d c ha n ge i n lifest yle (e. g., eati n g, e x ercise or slee pi n g patter n) d uri n g t he st u d y.  
 
*As declare d b y t he p arti ci pa nt or i n t he me dical r ec or ds.  
5. 3  
Lif est yle c o nsi der ati o ns  
5. 3. 1  
Me als a n d diet ar y rest ricti o ns  
T o e ns ure ali g n me nt re gar di n g perf or m a nce of ass ess me nts acr oss partici pa nts a n d st u d y sites, t he 
bel o w restricti o ns a p pl y.  
Partici pa nts m ust att e n d visits fasti n g acc or di n g t o t he fl o wc hart ( Secti o n 1. 2 ).  
 Fasti n g is defi ne d as n o f o o d or li q ui d, e xce pt f or water, f or at least 6 h o urs pri or t o t he visit.  
 F or t he e n d of st u d y visit ( visit 1 7) fasti n g is defi n e d as at least 2 h o urs pri or t o t he visit wit h o ut 
f o o d or li q ui d, e x ce pt f or water.  
 A n y me di cati o n w hic h s h o ul d be ta ke n wit h or after a meal s h o ul d be wit h hel d o n t he da y of t he 
visit u nt il bl o o d sa m ples ha ve bee n o btai ne d. 
 Assess me nts re q uiri n g partici pa nts t o fast are liste d i n A p pe n di x 2 ( Secti o n 1 0. 2 ) 
 
If a partici pa nt is n ot fasti n g as r e q uire d, t he partici pa nt s h o ul d be calle d i n f or a ne w visit wit hi n 
t he visit wi n d o w t o ha ve t he fasti n g pr oce d ures perf or me d. 
5. 3. 2  
C affei ne, alc o h ol a n d t o b acc o  
Partici pa nts s h o ul d a v oi d caffei ne a n d t o b acc o us e f or at least 3 0 mi n utes pri or t o mea s ure me nt of 
vital si g ns ( Secti o n  8. 2. 2 ). 
T o bacc o us e is defi ne d as s m o ki n g at least o ne ci garette or e q ui vale nt dail y.  
5. 3. 3  
Acti vit y  
Partici pa nts s h o ul d a v oi d p h ysical acti vit y f or at least 3 0 mi n utes pri or t o meas ure m e nt of vital 
si g ns ( Secti o n 8. 2. 2 ). 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
2 5
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
2 6  of 1 0 0  
 
5. 4  
Scree n f ail ures  
A scree n fail ure occ urs w he n a partici p a nt w h o c o nse nts t o partici pate i n t he cli nical st u d y is n ot 
s u bse q ue ntl y eli gi ble f or partici pati o n acc or di n g t o t he i ncl usi o n/e xcl usi o n criteria. A mi ni mal set 
of scree n fail ure i nf or mati o n is re q uire d t o e ns ure tra ns pare nt re p orti n g of scree n fail ure p artici pa nts 
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 i nf or me d c o ns e nt 
date, 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 m ust be ma de i n t he s yst em ( R a n d o misati o n a n d T rial S u p plies M a na ge me nt 
syste m ( R T S M) /Interacti ve W e b R es p o nse S yste m ( I W R S). 
I n di vi d uals w h o d o n ot meet t he criteri a f or p arti ci pati o n i n t his st u d y ma y n ot be rescree n e d.  If t h e 
partici pa nt has f aile d o ne of t he i ncl usi o n criteria or f ulfille d o ne of t he e x cl usi o n criteria relat e d t o 
la b orat or y para meters, re-sa m pli n g is n ot all o we d. H o we ver, i n case of tec h nical iss ues (e. g., 
hae m ol ys e d or l ost), re -s a m pli n g is all o we d f or t he affecte d para m eter(s). 
5. 5  
R a n d o mis ati o n criteri a  
T o be ra n d o mise d, all ra n d o misati o n criteria m ust be a ns were d " yes".  
1.  N o recei pt of a n a p pr o ve d C O VI D -1 9 vacci ne bet wee n scree ni n g a n d ra n d o misati o n.  
 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
2 6
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
2 7  of 1 0 0  
 
6  St u d y i nter ve nti o n(s) a n d c o nc o mit a nt t her a p y  
St u d y i nter ve nti o n is defi ne d as a n y i n vesti gati o nal i nter ve nti o n(s), mar ket e d pr o d uct(s), place b o, or 
me dical de vice(s) i nte n d e d t o be a d mi nistere d t o a st u d y p artici pa nt acc or di n g t o t he st u d y pr ot oc ol.  
Trial pr o d uct c o m prise i n vesti gati o nal me dici n al pr o d ucts (I M Ps), i ncl u di n g place b o a n d 
c o m parat ors, n o n -i n vesti gati o nal me di ci nal pr o d u cts ( NI M Ps) a n d/ or i n vesti gati o nal me dical 
de vices.  
6. 1  
St u d y i nter ve nti o n(s) a d mi nistere d  
Ta ble  6 -1  pr o vi des a n o v er vie w of t h e I M Ps i n t he st u d y. T he d os es a n d i njecti o n v ol u mes of t he 
I M Ps t o be a d mi nistere d i n eac h st u d y ar m d uri n g d ose escal ati o n ste ps a n d t he mai nte na nce peri o d 
are prese nte d i n T a ble  6 -2 .   
T a ble  6 -1  
I n vesti g ati o n al me dicin al pr o d ucts  
I nter v e nti o n ar m 
Se m a gl uti de  
Se m a gl uti de pl ace b o  
I nter v e nti o n n a me 
Se ma gl uti de 
 
Se ma gl uti de  place b o  
I nter v e nti o n t y pe 
I M P, test pr o d uct 
I M P, refere nce t hera p y 
P h ar m ace utic al f or m  
S ol uti o n f or i nj ecti o n  
S ol uti o n f or i nj ecti o n  
R o ute of 
a d mi nistr ati o n  
S u bc uta ne o us  
S u bc uta ne o us  
M e dic al de vice  
 
T he trial pr o d uct will be a d mi nistere d wit h 
N o v o P e n ® 4 ( me dical de vice use d o utsi de 
a p pr o val 1). 
P artici pa nts will be pr o vi de d wit h D F U 
ver ball y a n d i n writi n g.  
T he trial pr o d uct will be a d mi nistere d wit h 
N o v o P e n ® 4 ( me dical de vice use d o utsi de 
a p pr o val 1). 
P artici pa nts will be pr o vi de d wit h D F U 
ver ball y a n d i n  writi n g.  
Tri al pr o d uct stre n gt h  
 m g/ m L 
N ot a p plica ble  
D ose a n d d ose 
fre q ue nc y 
O nce -wee kl y  
F or d oses refer t o  T a ble  6 -2  
O nce -wee kl y  
F or d oses refer t o T a ble  6 -2  
D osi n g i nstr ucti o ns 
a n d a d mi nistr ati o n  
D ose t o  be a d mi nistere d wit h t he 
N o v o P e n ® 4 i n acc or da nce wit h t he D F U.  
D ose t o be a d mi nistere d wit h t he 
N o v o P e n ® 4 i n acc or da nce wit h t he D F U.  
S o urci n g  
Ma n ufact ure d a n d s u p plie d b y N o v o 
N or dis k A/ S  
Ma n ufact ure d a n d s u p plie d b y N o v o 
N or dis k A/ S  
P ac k a gi n g a n d 
l a belli n g 
 
 
La b elle d a n d pac ka ge d b y N o v o 
N or dis k A/ S  
 
La b elle d i n acc or da nce wit h A n ne x 
1 3, 1 2 l ocal re g ulati o ns a n d st u d y 
re q uire me nts 
 
Trial pr o d uct will be pr o vi de d i n 3 m L 
cartri d ge  
 
La belle d a n d pac ka ge d b y N o v o 
N or dis k A/ S  
 
La belle d i n acc or da nce wit h A n ne x 
1 3, 1 2 l ocal re g ulati o ns a n d st u d y 
re q uire me nts 
 
Trial pr o d uct will be pr o vi de d i n 3 m L 
cartri d ge  
A b bre vi ati o ns : I M P = I n vesti gati o nal Me dici nal Pr o d uct, D F U = Directi o ns f or use. 
1T he me dical de vice N o v o P e n ® 4 is use d o utsi de its a p pr o ve d i nte n de d use a n d/ or i n dicati o n f or use b ut is n ot bei n g 
assesse d f or de vice a p pr o val pr oce d ure (acc or di n g t o Article 8 2 of E U M D R 2). Safet y data c ollecti o n a n d safet y 
re p orti n g are re q uire d f or t he me dical de vice. Please see Se cti o n 8. 3  f or details o n a d vers e e ve nts a n d ot her safet y 
re p orti n g, a n d Secti o n 2. 3. 1  f or i nf or mati o n o n st u d y-s pecifi c de vice ris k assess me nt. 
I n vesti g ati on al me dici n al pr o d ucts (I M P)  
T he I M Ps are liste d i n Ta ble  6 -1 . 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
2 7
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
2 8  of 1 0 0  
 
Directi o ns f or use  
T he i n vesti gat or m ust d oc u me nt t hat directi o ns f or use was gi ve n t o t h e p artici pa nt ver ball y a n d i n 
writi n g as a directi o ns f or use ( D F U) d o c u me nt at t he first dis pe nsi n g visit, a n d as s pecifi e d i n t he 
fl o wc hart ( Secti o n 1. 2 ). T he i n vesti gat or s h o ul d ha n d o ut d ose re mi n der car ds t o t he partici pa nts at 
all cli nic visits as a p plica ble per treat me nt ar m. 
D osi n g i nstr ucti o ns  
Partici pa nts will be i nstr ucte d t o a d mi nister se ma gl uti de/se ma gl uti de place b o b y s u b c uta ne o us 
i njecti o n i n t he a b d o me n, u p per ar m, or t hi g h o nce-wee kl y o n t he s a me da y of t he wee k t hr o u g h o ut 
t he st u d y at a ti me t hat is c o n ve nie nt f or t h e partici pa nt. If t he d osi n g d a y c oi nci des wit h a cli nic 
visit t he d ose m ust  be a d mi nistere d after bl o o d sa m ples ha ve bee n o bt ai ne d  –  t his is n ot re q uire d f or 
V 5 a n d V 1 3 . 
A d mi nistrati o n of 2 m g, 8 m g a n d 1 6 m g se ma gl uti de/se ma gl uti de place b o d oses re q uires 1, 2 a n d 3 
i njecti o ns, res pecti vel y. T he 2n d a n d 3 r d i njecti o n s h o ul d be a d mi nistere d i m me diatel y after t he 1st 
injecti o n usi n g a differe nt site of i njecti o n, eit her wit hi n t he sa me or a ne w b o d y re gi o n , b ut at least 
5  c m fr o m t he first i njecti o n site. 
T he re q uir e d d ose v ol u m e (c orres p o n di n g t o a n u m ber of i ncre me nts o n t he pe n  as o utli ne d i n 
Ta ble  6 -2 ) f or d oses u p t o 4 m g m ust be a d mi nistere d fr o m o ne cartri d ge a n d ca n n ot be s plit acr oss 
cartri d ges. It is o nl y all o we d t o s plit t he 8 m g a n d 1 6 m g d oses  acr oss cartri d ges, as t h ese t w o d oses 
re q uire m or e t ha n o ne i nj ecti o n. Eac h i njecti o n , of 4 2 a n d 5 6 i ncre me nts f or t he 8 m g a n d 1 6 m g 
d ose, res pecti vel y, m ust be a d mi nistere d fr o m t he sa me cartri d ge . If t h e re q uire d i ncre m e nts ca n n ot 
be a d mi nis tere d wit h a p artl y us e d cartri d ge, a n e w a n d u n use d cartri d ge m ust be use d f or 
a d mi nistrati o n.  
D ose esc al ati o n  
D ose escalati o n of se ma gl uti de s h o ul d ta ke place d uri n g t he first 1 2, 2 0 a n d 2 4 wee ks after 
ra n d o misati o n f or se ma gl uti de s.c. 2 m g, 8 m g, a n d 1 6 m g, res pecti vel y as ill ustrate d i n Ta ble  6 -2 .  
D ose m o dificati o n is n ot all o we d. Partici pa nts s h o ul d reac h t he ra n d o mise d tar get mai nte na n ce d ose 
f oll o wi n g t he s pecifie d d ose-escalati o n. If t he p artici pa nt ca n n ot t olerat e t he recei ve d d ose (e. g. 
persiste nt se vere  na usea, v o miti n g or diarr h o ea e v e nts) t he y will be disc o nti n ue d fr o m ra n d o mise d 
treat me nt. 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
2 8
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
2 9  of 1 0 0  
 
T a ble  6 -2  
O ver vie w of d ose esc al ati o n a n d m ai nte n a nce d ose  
R a n d o mise d tre at me nt  
 
D ose esc al ati o n/ m ai nte n a nce  
M ai nte n a nce  
4 wee ks  4 wee ks  4 wee ks  4 wee ks  4 wee ks  4 wee ks  1 6 wee ks  
Se ma gl uti de 2 m g  
D ose  
I ncre me nts 
o n pe n  
0. 2 9 m g  
3  
0. 5 8  m g  
6  
1. 0 6  m g  
1 1  
2. 0 2  m g  
2 1  
Se ma gl uti de 8 m g  
D ose  
I ncre me nts 
o n pe n  
0. 2 9 m g  
3  
0. 5 8  m g  
6  
1. 0 6  m g  
1 1  
2. 0 2  m g  
2 1  
4. 0 3  m g  
4 2  
8. 0 6  m g  
2 x 4 2  
Se ma gl uti de 1 6 m g  
D ose  
I ncre me nts 
o n pe n  
0. 2 9 m g  
3  
0. 5 8  m g  
6  
1. 0 6  m g  
1 1  
2. 0 2  m g  
2 1  
4. 0 3  m g  
4 2  
8. 0 6  m g  
2 x 4 2  
1 6. 1 3  m g  
3 x 5 6  
Eac h i ncre me nt o n t he N o v o P e n ® 4 c orres p o n ds t o 1 0 µl, e. g., 3 i ncre me nts are 3 0 µl. Wit h t he c o nce ntrati o n of t he I M P 
a n d i nj ecti o n v ol u mes t hat ca n be deli vere d wit h t he N o v o P e n® 4 f or se ma gl uti de 
 m g/ m L, t he tar get d oses 
a d mi nistere d are 2. 0 2 m g, 8. 0 6 m g a n d 1 6. 1 3  m g; h o we ver,  t he d ose ar ms are referre d t o as 2 m g, 8 m g a n d 1 6 m g 
t hr o u g h o ut t he pr ot oc ol. 
Misse d d oses  
If a si n gle d ose of ra n d o mise d treatme nt  is misse d, it s h o ul d be a d mi nistere d as s o o n as n otice d, if 
t he ti me u ntil t he ne xt sc he d ule d d ose is at least 2 da ys ( 4 8 h o urs). If a d ose is misse d a n d t he ne xt 
sc he d ule d d ose is less t ha n 2 da ys ( 4 8 h o urs) a wa y, t he partici pa nt s h o ul d n ot a d mi nister a d ose 
u ntil t he ne xt sc he d ule d d ose. A misse d d ose s h o ul d n ot affect t he s c he d ul e d d osi n g d a y of t he 
wee k.  
N o n -i n vesti g ati o n al me dici n al pr o d ucts ( NI M P) 
A nti -dia betic bac k gr o u n d me dicati o n ( metf or mi n) a n d res c ue me dicati o n are c o nsi dere d NI M Ps a n d 
will n ot be s u p plie d b y N o v o N or dis k.  
A u xili ar y s u p plies i ncl u di n g n o n -i n vesti g ati o n al me dic al de vice 
T he a u xiliar y s u p plies o utli ne d i n Ta ble  6 -3  will be pr o vi de d b y N o v o N or dis k.  
T a ble  6 -3  
A u xili ar y s u p plies i ncl u di n g n o n -i n vesti g ati o n al me dic al de vice 
Ite m 
Det ails  
Directi o ns f or use ( D F U)  
D F U f or N o v o P e n ® 4 will be ha n de d o ut se paratel y.  
Bl o o d gl uc ose ( B G) meter a n d relate d 
a u xiliaries  
A Precisi o n Xtra B G meter will be ha n de d o ut at t he ra n d o misati o n visit 
( V 2). P artici pa nts will be i nstr ucte d i n h o w t o use t he B G meter a n d t he 
i nstr ucti o ns will be re peate d d uri n g t he st u d y as nee de d. 
N o v o P e n ® 4 a 
N o v o P e n ® 4 f or s.c. a d mi nistrati o n of se ma gl uti de a n d se ma gl uti de place b o. 
N o v o P e n ® 4 has bee n pac ke d a n d la belle d s pecificall y f or t he prese nt st u d y.  
Nee dles  
Nee dles f or N o v o P e n ® 4.  
Details will be pr o vi de d i n t he Trial Materials Ma n ual ( T M M). O nl y nee dles 
pr o vi de d b y N o v o  N or dis k a n d wit h a ma xi m u m le n gt h of 6 m m m ust b e 
use d f or a d mi nistrati o n of I M P. 
a N o v o P e n ® 4  is use d o utsi de a p pr o val. 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
2 9
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 0  of 1 0 0  
 
6. 2  
Pre p ar ati o n, h a n dli n g, st or a ge a n d acc o u nt a bilit y  
O nl y partici pa nts e nr olle d i n t he st u d y ma y use I M P a n d o nl y dele gate d site staff ma y s u p pl y I M P. 
Eac h site will be s u p plie d wit h s ufficie nt I M P f or t he st u d y o n a n o n g oi n g basis acc or di n g t o 
recr uit me nt a n d ra n d o misati o n. 
T he i n vesti gat or or desi g nee m ust c o nfir m t hat a p pr o priate 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 I M P recei ve d, a n d t hat a n y discre p a ncies are re p orte d a n d res ol ve d 
bef ore us e of t he I M P. 
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 
dele gate d site staff.  
T he i n vesti gat or m ust i nf or m N o v o N or dis k i m me diatel y if a n y I M P has bee n st or e d o utsi de 
s pecifie d c o n diti o ns. T he I M P m ust n ot be dis pe ns e d t o a n y partici pa nt b ef ore it has bee n e val 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. A d diti o nal details re gar di n g ha n dli n g of te m p erat ur e 
de viati o ns ca n be f o u n d i n t he Trial Materi als  Ma n ual ( T M M).  
T he i n vesti gat or or desi g nee is res p o nsi ble f or I M P acc o u nta bilit y a n d rec or d mai nte na nce (i.e., 
recei pt, acc o u nta bilit y a n d fi nal dis p ositi o n rec or ds). A cc o u nta bilit y m ust be perf or me d at visit V 4, 
V 6,  V 1 0 a n d V 1 5  at cartri d ge le v el ret ur n e d eit her as use d/ partl y use d, u n use d or l ost a n d rec or de d 
i n t he R T S M/I W R S. T he me dical de vice  m ust be ret ur ne d at t he e n d of tr eat me nt visit ( V 1 5)  
T he i n vesti gat or or desi g nee m ust i nstr uct t he partici pa nt i n w hat t o ret ur n at ne xt visit.  
T he i n vesti gat or  or desi g nee m ust i nstr uct t he partici pa nt o n h o w t o ma na ge t he i n -use ti me of t he 
dis pe nse d I M Ps. 
Destr ucti o n of I M P ca n b e perf 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 aft er acc o u nt a bilit y is fi nalise d b y t he site a n d rec o n cile d b y t he m o nit or , if n ot 
ot her wise a gree d at t he site selecti o n .  
All ret ur ne d ( us e d or u n-use d),  e x pire d or da ma ge d I M Ps a n d medi cal de vi ce  (f or tec h nical 
c o m plai nt sa m ples, see A p pe n di x  5 [ Secti o n 1 0. 5 ]) m ust be st ore d se paratel y fr o m n o n-all ocat e d 
I M Ps an d me di cal de vices . N o te m perat ur e m o nit ori n g is re q uire d. 
N o n -all ocate d I M Ps, i ncl u di n g e x pire d or da m a ge d pr o d ucts, m ust be acc o u nte d f or b y t he  site 
a n d/ or rec o ncile d b y t he m o nit or , at t he latest at cl os ure of t he site. 
6. 3  
Me as ures t o mi ni mise bi as: R a n d o mis ati o n a n d bli n di n g  
All partici pa nts will be scree n e d a n d ce ntr all y ra n d o mise d usi n g R T S M /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 t he ra n d o misati o n sc he d ule. Ra n d o mise d treat me nt  will be 
all ocate d b y t he R T S M /I W R S a n d dis pe nse d b y t he i n vesti gat or at t he st u d y visits s u m marise d i n 
t he fl o wc hart. 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
3 0
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 1  of 1 0 0  
 
At scree ni n g, eac h p artici pa nt  will be assi g n e d a u ni q ue 6 -di git S u bject I D  w hic h will re mai n t he 
sa me t hr o u g h o ut t he st u d y. Eac h site will be assi g ne d a 3-di git n u m ber a n d all S u bject I D  will start 
wit h t he site n u m ber.  
Eli gi ble partici pa nts will be ra n d o mise d i n a 3: 1: 3: 1: 3: 1 rati o to recei ve s e ma gl uti de s.c. ( 2  m g, 
8  m g, 1 6 m g) or mat c hi n g pla ce b o . 
Ra n d o misati o n will be stratifie d acc or di n g t o H b A 1c at scree ni n g ( < 8. 5 %/ ≥8. 5 % ). 
T he st u d y is o pe n t o s p o ns or a n d bli n de d wit hi n d ose le vel t o  partici pa nt a n d i n vesti gat o r. 
Partici pa nts a n d  i n vesti gat ors are bli n de d t o all ocati o n  of ra n d o mise d treat me nt . N o v o N or dis k 
pers o n nel will ha ve access t o t he all ocati o n of ra n d o mise d treat me nt t hr o u g h o ut  t he st u d y.  
T he R T S M/ I W R S is use d f or bli n d-brea ki n g. I n case of a n e mer ge nc y, t he i n vesti gat or h as t he s ole 
res p o nsi bilit y f or det er mi ni n g if u n bli n di n g of a partici pa nt’s ra n d o mise d tr eat me nt is warra nte d. 
Partici pa nt safet y m ust al wa ys be t he first c o nsi derati o n i n ma ki n g s uc h a d eter mi nati o n.  
If t he i n vesti gat or deci des t hat u n bli n di n g is warra nte d, t he i n vesti gat or s h o ul d ma ke e ver y eff ort t o 
c o ntact N o v o N or dis k pri or t o u n bli n di n g a partici pa nt’s ra n d o mise d treat me nt u nless t his c o ul d 
dela y e mer ge nc y tr eat me nt of t he par tici pa nt. 
If a partici pa nt’s ra n d o mise d treat me nt is u n bli n de d, N o v o N or dis k ( Gl o bal Safet y d e part me nt) 
m ust be n otifie d wit hi n 2 4 h o urs after brea ki n g t h e bli n d. T he date a n d reas o n t hat 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. T he pers o n brea ki n g t he bli n d m ust pri nt t he 
bli n d brea k c o nfir m ati o n n otificati o n ge n erate d b y t he R T S M/ I W R S, si g n a n d date t he d oc u me nt. If 
R T S M/ I W R S is n ot accessi ble at t he ti me of bli n d brea k, t he R T S M/ I W R S hel p des k s h o ul d be 
c o ntacte d. C o ntact d etails  are liste d i n Attac h me nt I . 
Partici pa nt will c o nti n ue ra n d o mise d treat me nt aft er u n bli n di n g, if t here are n o safet y c o n cern s as 
j u d ge d b y t he i n v esti gat or. 
T he la b orat or y res p o nsi ble f or P K a n d a nti b o d y a nal ysis will ha ve access t o t he all ocati o n  of 
ra n d omise d treat me nt.  
6. 4  
St u d y i nter ve nti o n c o m pli a nce  
Dr u g tre at me nt c o m pli a nce  
T hr o u g h o ut t he st u d y, t h e i n vesti gat or will re mi n d t he partici pa nts t o f oll o w t he st u d y pr oce d ures 
a n d re q uir e me nts t o e nc o ura ge partici pa nt c o m plia nce.  
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
3 1
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 2  of 1 0 0  
 
W he n partici pa nts self -a d mi nister ra n d o mise d treat me nt at h o me, c o m plia nce wit h a d mi nistrati o n 
of ra n d o mise d treat me nt will be assesse d, a n d t he assess me nt d oc u me nte d i n s o urce d oc u m e nts at 
eac h visit w here i nf or mati o n is a vaila ble. If a n y s us pici o n of n o n -c o m plia nce arises, t he site m ust 
e nter i nt o a dial o g ue wit h t he partici pa nt, re -e m p h asizi n g t he i m p orta nce of c o m plia nce a n d 
u nc o ver barriers t o c o m plia nce. T his dial o g ue m ust be d oc u me nte d. C o m plia nce will be ass esse d b y 
cr oss c hec ki n g t he f oll o wi n g s o ur ces a n d c o m pari n g t hese t o t he e x pecte d use:  
 Acc o u nta bilit y i nf or mati o n; c o u nti n g ret ur ne d I M P 
 Re vie w of d osi n g diaries  
 C ollecti o n of i nf or mati o n f or a d mi nistrati o n of ra n d o mise d treat me nt: 
o  Date of d ose  
o  Ti me of d ose  
o  Act ual d ose ( i ncre me nt v al ue s h o w n i n d ose c o u nt er)  
o  I nje cti o n site 
S tart a n d st o p dates f or ra n d o mise d treat me nt will be rec or de d i n t he eC R F.  
6. 5  
D ose m o dific ati o n  
D ose m o dificati o n is n ot all o we d. Please refer t o Secti o n 6. 1  f or des cri pti o n of d ose escalati o n a n d 
misse d d oses.  
6. 6  
C o nti n ue d access t o st u d y i nter ve nti o n after e n d of st u d y  
W he n disc o nti n ui n g st u d y i nter ve nti o n, t he partici pa nt s h o ul d be tra nsferre d t o a s uita ble mar kete d 
pr o d uct at t he discreti o n of t he i n vesti gat or. 
T he l o n g h alf -life of se m a gl uti de m ust be ta ke n i nt o c o nsi derati o n w he n sel ecti n g a nti-dia betic 
treat me nt after disc o nti n uati o n of ra n d o mise d treat me nt. 
6. 7  
Tre at me nt of o ver d ose  
T here is n o s pecific a nti d ote t o se ma gl uti de  i n t he e ve nt of a n o v er d ose.  
A n y d os e of se ma gl uti de greater t ha n t he pla n ne d d ose acc or di n g t o Ta ble  6 -2  a n d w hic h d e viate 
fr o m t he i nte n de d d ose t o a n e xte nt w here cli nical c o nse q ue nces f or t h e st u d y partici pa nts are li kel y 
t o ha p pe n, as j u d ge d b y t he i n vesti gat or, will be c o nsi dere d a n o v er d ose. 
Acci de ntal o v er d ose m ust be re p orte d as a me dicati o n err or. I nte nti o nal o v er d ose m ust be re p orte d 
as mis use a n d a b use, ple ase refer t o Secti o n  8. 3  a n d A p pe n di x  3 ( Secti o n  1 0. 3 ) f or f urt her det ails. 
I n t he e ve nt of a n o ver d ose, t he i n vesti gat or s h o ul d cl osel y m o nit or t he p artici pa nt f or o ver d ose -
relate d A Es/ S A Es a n d la b orat or y a b n or malities. A p pr o priate treat me nt s h o ul d be i nitiate d 
acc or di n g t o t he p artici pa nts’ cli nical si g ns a n d s y m pt o ms. A pr ol o n ge d peri o d of o bser vati o n 
a n d/ or treat me nt f or s y m pt o ms ma y be necessar y, c o nsi deri n g t he l o n g half-life of se ma gl uti de of 
a p pr o xi matel y o ne w ee 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 base d o n 
t he cli nical e val uati o n of t he partici pa nt. 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
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V V- T M F- 5 9 0 1 0 6 5
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1
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 of
  Pr ot oc ol  4 9 8 4 v 3. 0
3 2
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 3  of 1 0 0  
 
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 N N 9 5 3 5 i n vesti gat or’s 
br oc h ure (I B).  
6. 8  
C o nc o mit a nt t her a p y 
A n y me di cati o n or vacci ne (i ncl u di n g o v er -t h e-c o u nter or pres cri pti o n me dici nes, recreati o nal 
dr u gs, vita mi ns, a n d/ or h er bal s u p ple me nts) t hat t he partici pa nt is recei vi n g at t he ti me of t h e first 
visit ( V 1)  or recei ves u ntil t he e n d of st u d y m ust b e rec or de d al o n g wit h:  
 Tra de n a me or ge n eric n a me  
 Pri mar y i n dicati o n   
 Dates of a d mi nistrati o n i ncl u di n g start a n d st o p dates   
 D ose ( o nl y a p plica bl e f or a nti-dia betic me dicati o n)  
 Fre q u e nc y ( o nl y a p plica ble f or a nti -dia betic me dicati o n)  
A p pr o ve d C O VI D -1 9 vacci nes t hat t he partici pa nt recei ve d wit hi n 6 m o nt hs pri or t o scree ni n g 
s h o ul d be rec or de d i n t he e C R F at t he scree ni n g visit ( V 1). 
C ha n ges i n c o nc o mita nt me dicati o n  m ust be rec or de d at eac h visit.  If a c h a n ge is d u e t o a n A E, t he n 
t his m ust be re p orte d acc or di n g t o Secti o n 8. 3 . 
Afte r si g ni n g t he i nf or me d c o nse nt, partici pa nts m ust c o nti n ue t heir a nti-dia betic bac k gr o u n d 
me dicati o n ( metf or mi n) t hr o u g h o ut t he e ntire st u d y a n d t h e bac k gr o u n d me dicati o n d ose s h o ul d 
re mai n at t he sa m e d ose l e vel a n d wit h t he sa me fre q ue nc y d uri n g t he e ntire st u d y i nter ve nti o n 
peri o d u nless gl ycae mic resc ue m e dicati o n is nee de d (as des cri be d i n Secti o n 6. 8. 1 ) or a safet y 
c o ncer n relat e d t o t he use of a nti -dia betic b ac k gr o u n d me dicati o n arises.  
6. 8. 1  
Resc ue me dici ne  
G l ycae mic resc u e me dicati o n, i.e. i nte nsificati o n of a nti-dia betic bac k gr o u n d me dicati o n a n d/ or 
i nitiati o n of ne w a nti-dia betic treat me nt , s h o ul d b e i m ple me nte d  at t he discreti o n of t he i n vesti gat or 
i n case of persiste nt h y p er gl ycae mia. Pleas e see S ecti o n 7. 1. 2  fo r resc ue criteria. 
Resc ue me dicati o n s h o ul d be selecte d acc or di n g t o A D A/ E A S D g ui deli ne 2 (e x cl u di n g G L P-1 R As, 
di pe pti d yl pe pti dase -4 ( D P P -4) i n hi bit ors a n d a m yli n a nal o g u es) . 
Partici pa nts  t hat are starte d o n resc u e me dicati o n s h o ul d c o nti n ue t o f oll o w t he pr ot oc ol-s pecifie d 
visit sc he d ule a n d sta y o n ra n d o mise d treat me nt u nless t he i n vesti ga t or j u d ges t hat it will je o par dise 
partici pa nt’s  safet y. 
Resc ue me dicati o n s h o ul d be d oc u me nte d i n me di cal rec or ds a n d re p orte d o n t he c o nc o mita nt 
me dicati o n f or m i n t he e C R F. 
Resc ue me dicati o n will n ot be s u p plie d b y N o v o N or dis k b ut rei m b urse d , if re q uire d acc or di n g t o 
l ocal re g ulati o ns, as l o n g as t he partici pa nt is i n t he st u d y. 
 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
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V V- T M F- 5 9 0 1 0 6 5
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1
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 of
  Pr ot oc ol  4 9 8 4 v 3. 0
3 3
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 4  of 1 0 0  
 
7  Disc o nti n u ati o n of st u d y i nter ve nti o n a n d p artici p a nt 
disc o nti n u ati o n/ wit h dr a w al  
Disc o nti n uati o n of s pecific sites or of t he st u d y as a w h ole is detaile d i n A p pe n di x  1 
( Secti o n 1 0. 1. 1 1 ). 
7. 1  
Disc o nti n u ati o n of st u d y i nter ve nti o n  
Ra n d o mise d treat me nt  ma y b e disc o nti n ue d at a n y ti me d uri n g t he st u d y at t he discreti o n of t he 
partici pa nt or 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 ra n d o mise d tr eat me nt m ust be disc o nti n ue d, if a n y of t he f oll o wi n g a p plies f or t he partici p a nt:  
1.  Pre g n a nc y  
2.  I nte nti o n of b ec o mi n g pre g n a nt 
3.  Si m ulta ne o us use 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 i n a n ot her 
cli nical st u d y 
4.  Safet y c o ncer n as j u d ge d b y t he i n vesti gat or  
5.  C o nfir mati o n of ac ute p a ncreatitis  
T he partici pa nts s h o ul d c o nti n ue wit h t he re mai ni n g sc h e d ule d visits a n d assess me nts u ntil t he ti me 
of t he ori gi nall y s c he d ule d e n d of treat me nt visit ( V 1 5) a n d f oll o w -u p visit ( V 1 7).  
Eff orts m ust be ma de t o ha ve partici p a nts atte n d a n d c o m ple te all sc he d ule d visit pr oce d ures t o 
c ollect t he re q uir e d data f or t he a nal ysis of t he pri mar y a n d c o nfir mat or y s ec o n dar y e n d p oi nt s. O nl y 
partici pa nts w h o wit h dra w c o nse nt will be c o nsi d ere d as wit h dra w n fr o m t he st u d y. Partici p a nts 
m ust be i nf or me d a b o ut t he c o nti n ue d scie ntific i m p orta nce of t h eir data, e ve n if t he y disc o nti n ue 
ra n d o mise d treat me nt. 
T he pri mar y reas o n f or disc o nti n uati o n of ra n d o mise d treat me nt m ust be s p ecifie d i n t he eC R F, a n d 
fi nal I M P acc o u nta bilit y m ust be perf or me d. D isc o nti n uati o n of ra n d o mise d treat me nt  m ust be 
ma de i n t he R T S M /I W R S. 
7. 1. 1  
Te m p or a r y disc o nti n u ati o n of st u d y i nter ve nti o n  
I n case of s us pici o n of ac ute pa ncreatitis, t he ra n d o mise d treat me nt s h o ul d pr o m ptl y be i nterr u pte d 
( disc o nti n uati o n of ra n d o mise d treat me nt s h o ul d n ot be ma de i n R T S M /I W R S bef ore dia g n osis of 
ac ute pa n creatitis is c o nfir me d). A p pr o priate acti o ns s h o ul d be i nitiate d, i ncl u di n g l ocal 
meas ure me nt of a m yl ase a n d li pase (see A p pe n di x 3, Secti o n 1 0. 3  f or re p orti n g of A E). If ac ute 
pa ncreatitis is c o nfir me d, ra n d o mise d treat me nt s h o ul d n ot be restarte d, a n d disc o nti n uati o n of 
ra n d o mise d treat me nt m ust  be ma de  i n R T S M /I W R S. If t he Atla nta criteri a1 3 are n ot f ulfille d a n d 
t h us, t he s us pici o n of ac ute pa ncreatitis is n ot c o nfir me d, ra n d o mise d treat me nt ma y b e res u me d. 
If a partici pa nt has disc o nti n ue d ra n d o mise d treat me nt d ue t o te m p orar y safet y c o ncer n n ot rel ate d 
t o t he ra n d o mise d treat m e nt, ra n d o mise d treat me nt ca n be res u med . Si milarl y, a p artici pa nt w h o 
disc o nti n ues ra n d o mise d treat me nt 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 
ra n d o mise d treat me nt. 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
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V V- T M F- 5 9 0 1 0 6 5
 .
-
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1
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 of
  Pr ot oc ol  4 9 8 4 v 3. 0
3 4
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 5  of 1 0 0  
 
If a partici pa nt has misse d a si n gle d os e , t he misse d d ose g ui d a nce i n Secti o n 6. 1  m ust  be f oll o we d. 
If m ore t ha n o n e d ose is misse d, t he i n vesti gat or s h o ul d c o ns ult N o v o N or dis k gl o bal me dical 
e x perts f or g ui d a nce re gar di n g  c o nti n uati o n of ra n d o mise d treat me nt. 
7. 1. 2  
Resc ue crite ri a 
Partici pa nts  wit h persiste nt a n d u nacce pta ble h y p er gl ycae mia s h o ul d be offere d tr eat me nt 
i nte nsificati o n at t he discreti o n of t he i n vesti gat or a n d i n acc or da nce wit h t he A D A/ E A S D 
g ui deli nes e x cl u di n g G L P -1 R As, D P P -4 i n hi bit ors a n d a m yli n a n al o g ues.  
T o  all o w ti me f or d ose es calati o n a n d t o o bser v e t he e x pecte d effect of ra n d o mise d treat me nt o n 
gl ycae mic para meters, resc ue criteria will be a p pli e d fr o m wee k 1 2 a n d o n war ds. If a n y of t he 
H b A 1 c val ues e x cee ds t he li mit o utli ne d bel o w a n d n o i nterc urre nt ca us e of t he h y p er gl ycae mia ca n 
be i de ntifie d, a c o nfir mat or y H b A 1c in t he ce ntral la b orat or y s h o ul d be o btai ne d wit hi n 3 0 da ys. If 
t he c o nfir mat or y H b A 1c e x cee ds t he val ue des cri be d bel o w t he n t he partici p a nt  s h o ul d be offere d 
treat me nt i nte nsificati o n (resc u e me dicati o n)  at t he discreti o n of t he i n vesti gat or, a n d i n acc or da nce 
wit h t he g ui deli nes i n Secti o n 6. 8. 1 . 
Resc ue me dicati o n s h o ul d be offere d fr o m wee k 1 2  ( V 5) t o wee k 4 0 ( V 1 5) t o:  
 Partici pa nts wit h persiste nt H b A 1c val ue a b o ve 8. 5 % ( 6 9 m m ol/ m ol) t hat is c o nfir me d wit hi n 
3 0  da ys b y t h e ce ntr al la b orat or y a n d  c o nsi dere d u nacce pta bl y hi g h acc or di n g t o i n vesti gat or ’s 
assess me nt.  
7. 2  
P artici p a nt disc o nti n u ati o n/ wit h dr a w al f r o m t he st u d y  
A partici pa nt ma y wit h dr a w c o nse nt at a n y ti me at his/ her o w n re q u est.  
If a partici pa nt wit h dra ws c o nse nt or is wit h dra w n b y t he i n vesti gat or pri or t o ra n d o misati o n, t he 
partici pa nt  will n ot be as ke d t o ha ve a n y f oll o w -u p assess me nts perf or me d. T he f oll o wi n g d ata 
m ust be c ollecte d: De m o gra p h y, eli gi bilit y criteria, date of i nf or me d c o ns e nt, date of scree ni n g a n d 
t he date w he n p artici pa nt’s partici pati o n e n de d . T he e n d of st u d y f or m m ust be c o m plete d. 
If a partici pa nt wit h dra ws c o nse nt after ra n d o misati o n, t he i n vesti gat or m ust as k t he partici pa nt if 
he/s he is  willi n g, as s o o n as p ossi ble, t o ha ve assess me nts perf or me d acc o r di n g t o visit 1 5 . See t he 
fl o wc hart f or data t o b e c ollecte d. 
Fi nal I M P acc o u nta bilit y m ust be perf or me d e ve n if t he partici pa nt is n ot a ble t o c o me t o t he site.  
Disc o nti n uati o n of ra n d o mise d treat me nt  m ust be ma de i n t he R T S M /I W R S. 
If t he partici p a nt wit h dra ws c o nse nt, N o v o N or dis k ma y retai n a n d c o nti n ue t o use a n y data 
c ollecte d bef ore s u c h a wit h dra wal of c o ns e nt f or t he p ur p ose of t h e st u d y or scie ntific researc h.  
If a partici pa nt wit h dra ws fr o m t he st u d y, h e/s he ma y  re q uest destr u cti 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 m e nt t his i n t he me dical rec or d.  
Alt h o u g h a p artici pa nt is n ot o bli ge d t o gi ve his/ her reas o n (s) f or wit h dra wi n g, t he i n vesti gat or 
m ust ma ke a reas o na ble eff ort t o as certai n t he reas o n(s), w hile f ull y  res p ecti n g t he partici p a nt’s 
ri g hts. W here t he reas o ns are o btai ne d, t h e pri mar y reas o n f or wit h dra wal m ust be s pecifie d i n t he 
eC R F.  
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
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V V- T M F- 5 9 0 1 0 6 5
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1
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3 5
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 6  of 1 0 0  
 
7. 2. 1  
Re pl ace me nt of p artici p a nts  
If a partici pa nt disc o nti n ues ra n d o mise d treat me nt, wit h dra ws c o nse nt or is wit h dra w n b y t he 
i n vesti gat or, h e/s he will n ot be re place d. 
7. 3  
L ost t o f oll o w -u p  
A partici pa nt will be c o nsi dere d l ost t o f oll o w -u p if he/s he re p eate 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 site.  
T he f oll o wi n g acti o ns m ust be ta ke n if a p a rtici pa nt fails t o ret ur n t o t he site f or a re q uir e d visit: 
 T he site m ust atte m pt t o c o ntact t he partici pa nt 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 partici pa nt o n t he i m p orta nce of m ai 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 partici pa nt wis hes t o a n d/ or s h o ul d c o nti n ue i n t he st u d y.  
 Bef ore a p artici pa nt is dee me d l ost t o f oll o w -u p, t he i n vesti gat or or desi g n ee m ust ma ke e v er y 
eff ort t o r e gai n c o ntact wit h t he partici pa nt ( w here p ossi ble, at least t hree tele p h o ne calls a n d, if 
necessar y, a certifie d lett er t o t he partici pa nt’s last k n o w n maili n g a d dress or l ocal e q ui vale nt 
met h o ds). T hese c o nt act atte m pts s h o ul d be d oc u me nte d i n t he partici pa nt’s s o urce d o c u me nt.  
 S h o ul d t he partici pa nt c o nti n ue t o be u nreac ha ble  b y t he e n d of st u d y , he/s he will be c o nsi dere d 
t o ha ve wit h dra w n fr o m t he st u d y wit h a pri mar y reas o n of ‘l ost t o f oll o w-u p’.  
 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
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V V- T M F- 5 9 0 1 0 6 5
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1
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 of
  Pr ot oc ol  4 9 8 4 v 3. 0
3 6
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 7  of 1 0 0  
 
8  St u d y assess me nts a n d pr oce d ures  
T he f oll o wi n g s ecti o ns d escri be t he assess me nts a n d pr oce d ures, w hile t heir ti mi n g is s u m mar ise d 
i n t he fl o wc hart ( Secti o n 1. 2 ). 
I nf or me d c o ns e nt m ust be o btai ne d bef ore a n y st u d y-relate d acti vit y, s ee A p pe n di x 1 
( Secti o n 1 0. 1. 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 partici pa nts 
meet all i ncl usi o n criteria a n d n o ne of t he e x cl usi o n criteria.  
T he i n vesti gat or will mai ntai n a scree ni n g l o g t o r ec or d det ails of all partici pa nts scree n e d a n d t o 
c o nfir m eli gi bilit y or rec or d reas o n f or scree n fail ure, as a p plica ble.  
At scree ni n g, p artici pa nts will be pr o vi de d wit h a car d stati n g t hat t he y are partici pati n g i n a st u d y 
a n d gi vi n g c o nt act details of rele va nt site staff t hat ca n be c o nt acte d i n case of e mer ge nc y.   
A d here n ce t o t he st u d y d esi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he fl o wc hart, is esse ntial 
a n d re q uir e d f or st u d y c o n d uct.  
T he i n vesti gat or m ust e ns ure t o kee p re g ular c o nt act wit h eac h partici pa nt t hr o u g h o ut t he e ntire 
st u d y, a n d al wa ys ha v e u p date d c o nta ct 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 resc he d ule, e ver y eff ort m ust be ma de t o ha ve all partici pa nts f oll o we d f or t he pri mar y e n d p oi nt 
a n d A Es.  
It is t he res p o nsi bilit y of t he i n vesti gat or t o sc he d ule t he visits a n d p h o ne c o ntacts as per t he 
pr ot oc ol fl o wc hart ( Secti o n 1. 2 ) a n d t o e ns ure t he y ta ke place. See secti o n 6. 4  f or st u d y i nter ve nti o n 
c o m plia nce.  
S u g geste d or d er of assess me nts:  
 E C G a n d vital si g ns  
 Bl o o d sa m ples  
 Ot her assess me nts  
 Diaries will i ncl u de t he f oll o wi n g i n relati o n t o t he visit t he y s u p p ort: 
 I nstr u cti o n o n h o w t o use t he diar y 
 Re mi n ders:  
o  t o atte n d visit fasti n g (see Secti o n 5. 3  a n d fl o wc h art i n Sectio n 1. 2 ) 
o  t o ret ur n I M P at visit  V 4, V 6, V 1 0 a n d V 1 5  
o  t o ret ur n diar y at n e xt site visit 
 I nf or mati o n t o be c ollecte d: 
o  d etaile d d osi n g i nf or mati o n  (see Secti o n  6. 4 ) f or all d oses a d mi nistere d 
o  h y p o gl ycae mic e v e nts (acc or di n g t o A p pe n di x 8 ( Secti o n 1 0. 8 )) 
o  healt h iss ues ( A Es, S A Es, c o nc o mita nt me dicati o n)  
Visit -s pecific diaries m ust be ha n de d o ut  at t he ra n d o misati o n visit ( V2 ) a n d at all f oll o wi n g site 
visits. Partici pa nts  m ust be i nstr ucte d i n h o w t o use t he diar y.  
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
3 7
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 8  of 1 0 0  
 
I nf or mati o n fr o m t he diaries m ust be tra nscri b e d b y t he i n vesti gat or or desi g nee t o t he a p pr o priate 
secti o ns of t he e C R F after a me dical re vie w of t he data b y t he i n vesti gat or t o e ns ure t hat A Es a n d 
S A Es, i ncl u di n g a n y o verall c ha n ge i n h ealt h a n d c o nc o mita nt me dicati o n are re p orte d. If 
ap plica ble, a d diti o n of missi n g i nf or mati o n after i nter vie wi n g t he partici pa nt s h o ul d be rec or de d i n 
t he s o urce d o c u me nts a n d tra nsferre d t o t he e C R F as rele va nt. 
Re vie w of diaries, E C G, la b orat or y re p orts, etc., m ust be d oc u me nte d i n t he s o urce d o c u me nts or 
t he partici pa nt’s me dical rec or d. If cl arificati o n of e ntries or discre pa nci es i n t he diar y is nee d e d, 
t he partici pa nt m ust be q uesti o ne d, a n d a c o n cl usi o n ma de i n t he partici pa nt’s s o urce d oc u m e nts. 
Care m ust be ta ke n n ot t o bias t he partici pa nt.  
Re peat  sa m ples ma y be t a ke n f or t ec h nical iss ues a n d u nsc he d ule d s a m ples or assess me nts ma y be 
ta ke n f or safet y reas o ns. Please refer t o A p p e n di x 2 ( Secti o n  1 0. 2 ) f or f urt h er details o n la b orat or y 
sa m ples. 
8. 1  
Effic ac y assess me nts  
Pla n ne d ti me p oi nts f or all efficac y assess me nts are pr o vi de d i n t he fl o w c hart ( Secti o n 1. 2 ). 
8. 1. 1  
B o d y w ei g ht  
B o d y wei g ht s h o ul d be meas ure d a n d rec or de d as s pecifie d i n t he fl o wc hart ( Secti o n 1. 2 ). B o d y 
wei g ht s h o ul d be meas ur e d o n a di gital scale, prefera bl y usi n g t he sa me s cale t hr o u g h o ut t he st u d y. 
T he scale m ust be cali brate d yearl y as a mi ni m u m, u nless t he ma n ufact urer or l ocal re q uir e me nts 
certifies t hat cali brati o n of t he sca le is vali d f or t he d urati o n of t he st u d y. 
Meas ure me nt m ust be p erf or me 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 a n d rec or de d i n t he 
e C R F i n kil o gra m [ k g] or p o u n d [l b] wit h a precisi o n of 1/ 1 0 u nit (e. g. 8 0 .3  k g / 1 7 7. 0  l b). 
B MI will be calc ulate d i n t he e C R F base d o n b o d y wei g ht a n d hei g ht meas ure me nts at scree ni n g . 
8. 1. 2  
W aist circ u mfere nce  
Waist circ u mfere n ce is d efi ne d as t he mi ni mal a b d o mi nal circ u mfere nce l ocate d mi d wa y b et wee n 
t he l o wer ri b mar gi n a n d t he iliac crest a n d will be meas ure d usi n g a n o n-stretc ha ble m eas uri n g ta pe 
at visits o utli ne d i n t he fl o wc hart ( Secti o n 1. 2 ). T he meas ure me nt of waist circ u mfere nce s h o ul d be 
perf or me d a n d rec or de d i n t he e C R F t o t he nearest ½ c m or ¼ i nc h.  
T he waist circ u mfere nce s h o ul d be meas ure d i n  a sta n di n g p ositi o n wit h a n e m pt y bla d der a n d 
weari n g li g ht cl ot hi n g wit h accessi ble waist. T he partici pa nt s h o ul d be sta n di n g wit h ar ms d o w n 
t heir si de a n d feet t o get h er. T he me as uri n g 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. 
T he partici p a nt s h o ul d be as ke d t o breat he n or mall y, a n d t h e meas ure me nt s h o ul d be ta ke n w he n 
t he partici pa nt is breat hi n g o ut ge ntl y. 
8. 1. 3  
S pir o metr y  
At cli nical sites wit h ca p a bilit y, s pir o metr y s h o ul d be perf or me d as o utli ne d i n t he fl o wc hart 
( Secti o n 1. 2 ).  
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
3 8
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 9  of 1 0 0  
 
T he test pr oce d ure f or s pi r ometers t hat meas ure i ns pirati o n a n d e x pirati o n i ncl u des 1) ma xi mal 
i ns pirati o n, 2) a ‘ blast’ of e x pirati o n, 3) c o nti n ue d c o m plete e x pirati o n f or a ma xi m u m of 
1 5  sec o n ds, a n d 4) i ns pirati o n at ma xi mal fl o w bac k t o ma xi m u m l u n g v ol u me. 
T he pr oce d ure s h o ul d be perf or me d acc or di n g t o t he i nter nati o nal g ui deli ne s1 4: 
1.  Ha ve partici pa nt  ass u me t he c orrect p ost ure  wit h h ea d sli g htl y ele vate d  
2.  Attac h n ose cli p , place m o ut h piece i n m o ut h, a n d cl ose li ps ar o u n d t he m o ut h piece 
3.  Breat he n or mall y  
4.  I ns pire c o m pletel y a n d ra pi dl y wit h a pa use of ≤2 s at t otal l u n g ca p acit y 
5.  E x pire wit h ma xi mal eff ort u ntil n o m ore air ca n be e x pelle d w hile mai ntai ni n g a n u pri g ht 
p ost ure  
6.  I ns pire wit h ma xi mal eff ort u ntil c o m pletel y f ull 
7.  Re peat i nstr ucti o ns as necessar y, c oac hi n g vi g or o usl y  
8.  Re peat f or a mi ni m u m of t hree ma n oe u vres , (us u all y n o m ore t ha n ei g ht ) 
9.  C hec k t he f orce d e x pirat or y v ol u me i n 1 sec o n d ( F E V1) a n d f orce d vital ca pacit y ( F V C) 
re peat a bilit y a n d p erf or m m ore ma n oe u vres  as necessar y 
F or ex pirati o n -o nl y d e vic es , i ns pirati o n t hr o u g h t h e m o ut h piece d oes n ot a p pl y .  
T he F E V 1 a n d F V C  meas ure me nt  of t he m ost re prese ntati ve ma n oe u vre , as per i n vesti gat or’s 
discreti o n, m ust be rec or de d i n t he e C R F i n t he u nit litres. 
8. 1. 4  
Cli nic al effic ac y l a b or at or y assess me nts  
All pr ot oc ol -re q uir e d la b orat or y assess me nts, as defi ne d i n A p pe n di x 2 ( Secti o n  1 0. 2 ), m ust be 
c o n d ucte d i n acc or da nce wit h t he fl o wc hart a n d t he la b orat or y m a n ual.  
8. 2  
S afet y assess me nts  
Pla n ne d ti me p oi nts f or all safet y assess me nts are pr o vi de d i n t he fl o wc h art  ( Secti o n 1. 2 ).  
Me dic al hist or y is a me dical e ve nt t hat t he partici pa nt e x perie nce d pri or t o t he ti me p oi nt fr o m 
w hic h A Es are c ollect e d. O nl y rele va nt me dical hist or y  i ncl u di n g C O VI D-1 9 , as j u d ge d b y t he 
i n vesti gat or, s h o ul d be re p orte d i n t he e C R F.  Fi n di n gs of s pecific me dical hist or y liste d bel o w 
s h o ul d de descri be d i n desi g nate d f or ms: 
 Dia betes  
 E ye dis ease  
 Ki d ne y dis ease  
 Ne ur o pat h y  
 Car di o vasc ular dise ase  
 Pa ncreatic dis ease  
 Gall bla d de r disease 
 D ysli pi dae mia  
 Ot her  
A c o nc o mit a nt ill ness  is a n y ill ness t hat is alr ea d y prese nt at t he ti me p oi nt fr o m w hic h A Es are 
c ollecte d or f o u n d as a res ult of a scree ni n g pr oce d ure or ot her st u d y pr oce d ures perf or me d bef ore 
e x p os ure t o st u d y i nter ve nti o n u n der cli nical i n vesti gati o n.  
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
3 9
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 0  of 1 0 0  
 
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 f ulfilli n g t he defi niti o n of me dical hist or y 
or c o nc o mita nt ill ness, t he i n vesti gat or m ust rec or d t he fi n di n g o n t he me di cal hist or y/ c o nc o mita nt 
ill ness f or m. 
8. 2. 1  
P h ysic a l e x a mi n ati o ns 
A p h ysic al e x a mi nati o n will i ncl u de assess me nts of : 
 ge n eral a p peara n ce  
 s ki n 
 t h yr oi d gla n d 
 res pirat or y s yste m 
 car di o vas c ular  s yste m 
 gastr oi ntesti nal  s yste m i n cl u di n g m o ut h 
 ce ntral a n d p eri p heral ner v o us s yste m  
A n y a b n or mal, cli nicall y si g nifica nt fi n di n gs bef ore first a d mi nistrati o n of ra n d o mise d treat me nt 
m ust be rec or de d as c o n c o mita nt ill ness. A n y n e w a b n or mal, cli nicall y si g nifica nt fi n di n gs or 
cli nicall y si g nifica nt w orse ni n g fr o m ti me of first a d mi nistrati o n of ra n d o mise d treat me nt m ust be 
re p orte d as a n A E ( Secti o n 8. 3  a n d A p pe n di x 3 ( Secti o n 1 0. 3 )). 
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. 
Hei g ht m ust  be me as ure d at scree ni n g  a n d rec or de d i n t he e C R F . Meas ure me nt m ust be perf or me d 
wit h o ut s h oes  a n d rec or de d t o nearest ½ c m or  ¼ i nc h.  
8. 2. 2  
Vit al si g ns  
P ulse rate, s yst olic a n d diast olic bl o o d press ure will be assesse d at visits o utli ne d i n t he fl o wc hart 
( Secti o n 1. 2 ). Please see secti o ns 5. 3. 2  a n d 5. 3. 3  f or restricti o ns pri or t o vital si g ns assess me nt. 
Bl o o d press ur e a n d p ulse rate 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 he 
partici pa nt i n a q uiet setti n g wit h o ut distracti o ns (e. g., n o use of tele visi o n, cell p h o nes).  
Bl o o d press ur e a n d p ulse rate meas ure me nts will be assesse d sitti n g 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 m ust be use d o nl y if a n a ut o mate d de vice is n ot a vaila ble.  
Bl o o d press ur e will  c o nsist of 3 s yst olic a n d diast olic bl o o d press ure meas ure me nts wit h i nter vals 
of at least 1 -2 mi n utes. A n a d diti o nal f o urt h bl o o d press ure meas ure m e nt m ust be perf or m e d if t he 
first t w o rea di n gs o n s yst olic or diast olic bl o o d press ure differ b y > 1 0 m m H g. N o m ore t ha n f o ur 
meas ure me nts s h o ul d be perf or me d.  
 T he last 2 s yst olic a n d l ast 2 diast olic bl o o d press ure meas ure me nts s h o ul d be rec or de d i n t he 
eC R F. T he eC R F will calc ulate t he mea n of t he last 2  meas ure me nts.  
 
P ulse rate will be meas ur e d i n c o n necti o n t o t he bl o o d press ure meas ure m e nts.  
 T he p ulse rate f or t he last 2 meas ure me nts s h o ul d be rec or de d i n t he eC R F. T he eC R F will 
calc ulate t he m ea n of t h e last 2  meas ure me nts.  
 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
4 0
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 1  of 1 0 0  
 
8. 2. 3  
E ye e x a mi n ati o n  
Partici pa nts wit h u nc o ntr olle d a n d p ote ntiall y u nst a ble dia betic reti n o pat h y or mac ul o pat h y are n ot 
eli gi ble as t his i n dicates reti n o pat h y t hat h as rece ntl y pr o gresse d t o a le vel t hat re q uires i nter ve nti o n 
or is a p pr oac hi n g i nter ve nti o n b ut has yet t o be br o u g ht u n der c o ntr ol.  
Res ults of a n e ye e x a mi nati o n perf or me d b y a n o p ht hal m ol o gist or a n ot her s uita bl y q ualifie d h ealt h 
care pr o vi der (e. g., o pt o metrist) m ust be a vaila ble a n d e v al uate d b y t he i n vesti gat or b ef ore 
ra n d o misati o n t o assess eli gi bilit y. T he e ye e x a mi nati o n m ust  be perf or me d as a f u n d us 
p h ot o gra p h y (e. g., 2 -fiel d 6 0 de gree or better, c ol o ur or re d-free) or b y slit-la m p bi o micr osc o p y 
e x a mi nati o n (e. g., usi n g a pre -c or neal or c or neal c o ntact le ns e x a mi nati o n). P har mac ol o gical p u pil -
dilati o n is a re q uire me nt u nless usi n g a di gital f u n d us p h ot o gra p h y ca mera s pec ifie d f or n o n-dilate d 
e x a mi nati o n. 
If t he partici p a nt ha d s uc h a n e ye e x a mi nati o n perf or me d wit hi n 9 0 da ys pri or t o scree ni n g, t he 
i n vesti gat or ma y b ase his/ her e val uati o n u p o n t he res ults of t hat e xa mi nati o n. T he e x a mi nati o n m ust 
be re peate d bef ore ra n d o m isati o n if t he partici pa nt has e x perie nce d w orse ni n g of vis ual f u n cti o n 
si nce t he last e x a mi nati o n. If t he a p plica ble e ye e x a mi nati o n was perf or me d bef ore t h e partici pa nt 
si g ne d t he i nf or me d c o ns e nt f or m, it m ust be d oc u me nte d t hat t he reas o n f or perf or mi n g t he 
e x a mi nati o n was n ot relate d t o t his st u d y.  
After ra n d o misati o n a n e ye e x a mi nati o n m ust be perf or me d acc or di n g t o a b o ve as per pr ot oc ol 
fl o wc hart ( Secti o n 1. 2 ). Res ults m ust be a vaila ble at V 1 5 (e n d of treat me nt visit). A n e ye 
e x a mi nati o n perf or me d wit hi n 3 wee ks pri or t o V 1 5 is acce pt a ble, pr o vi d e d n o cli nical s y m pt o ms 
s u g gesti ve of e ye dise ase ha ve occ urre d i n t he mea nti me. 
T he e ye e x a mi nati o n s ho ul d i ncl u de meas ure m e nt of i ntra oc ular press ur e (I O P) of b ot h e yes . T h e 
I O P s h o ul d be rec or de d i n t he e C R F i n t he u nit m m H g.  If t he meas ure is a vaila ble, t he I O P s h o ul d 
be ca pt ur e d i n t he e C R F w he n a pre vi o us  e ye e x a mi nati o n is use d f or scree ni n g. I n cas e I O P ca n n ot 
be c ollecte d, or i nf or mati o n is n ot a vaila ble fr o m pre vi o us e ye e x a mi nati o n t he n t his meas ure ca n 
be o mitte d,  a n d a ne w e ye e x a mi nati o n is n ot re q uire d.  
T he i n vesti gat or s h o ul d i n dicate t he o utc o me of eac h e ye e x a mi nati o n. Rele va nt fi n d i n gs pri or t o 
ra n d o misati o n m ust be rec or de d as c o nc o mita nt ill ness/ me dical hist or y. Rel e va nt fi n di n gs o cc urri n g 
after ra n d o misati o n s h o ul d be re p ort e d as a n A E ( please refer t o  Secti o n 8. 3 ). 
8. 2. 4  
Electr oc a r di o gr a ms  
1 2 -lea d E C G will be o btai ne d as o utli ne d i n t he fl o wc hart usi n g a n E C G mac hi ne t hat a ut o maticall y 
calc ulates t he h eart rate a n d meas ures P R, Q R S, Q T a n d Q Tc i nter vals. 
T he  i n vesti gat or m ust perf or m re vi e w of t he E C G f or cli nicall y si g nifica nt a b n or mal fi n di n gs. 
E C G m ust be perf or me d acc or di n g t o t he ma n ual fr o m t he s u p plier.  
8. 2. 5  
Cli nic al s af et y l a b or at or y assess me nts  
All pr ot oc ol -re q uir e d la b orat or y assess me nts, as defi ne d i n Ap pe n di x  2 ( Secti o n  1 0. 2 ), m ust be 
c o n d ucte d i n acc or da nce wit h t he la b orat or y ma n ual a n d t he pr ot oc ol fl o w c hart.  
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
4 1
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 2  of 1 0 0  
 
8. 2. 6  
Pl as m a gl uc ose me as ure me nts  
Plas ma gl uc ose ( P G) s h o ul d al wa ys be meas ure d usi n g a B G meter a n d rec or de d i n t he diar y a n d 
e C R F w he n a h y p o gl ycae mic e pis o de is s us pecte d. See A p pe n di x 8 ( Secti o n 1 0. 8 ) f or m ore 
i nf or mati o n o n re p orti n g of h y p o gl ycae mic e pis o des.  
W he n usi n g B G m eters, t he meas ur e me nt is perf or me d wit h ca pillar y bl o o d cali brate d t o plas ma 
e q ui vale nt gl uc ose val u es, i.e., t he meas ure m e nt is perf or me d o n bl o o d w hile t he  val ue is re p ort e d 
as plas ma; t heref ore ‘ P G’ is t he ter m t o use as des cri pt or f or t he v al ue.  
T he B G m eters use test stri ps cali brate d t o plas ma val ues. T heref ore, all meas ure me nts perf or me d 
wit h ca pillar y bl o o d are a ut o maticall y cali brate d t o plas ma e q ui va le nt gl uc ose val ues, w hic h will be 
s h o w n o n t he dis pla y. 
T he B G m eter pr o vi d e d b y N o v o N or dis k s h o ul d be use d f or t h e meas ure me nts re q uire d i n t he 
pr ot oc ol (see a u xiliar y s u p plies i n Secti o n 6. 1 ). 
Partici pa nts s h o ul d be i nstr ucte d i n h o w t o rec or d t he res ults of t he P G val ues i n t he diaries. T he 
rec or d of eac h P G val ue s h o ul d i ncl u de date, ti me a n d val ue. All data fr o m t he diar y m ust be 
tra nscri be d i nto t he e C R F d uri n g or f oll o wi n g t he c o ntact. If o bt ai ne d via p h o ne, a n d a discre pa n c y 
is later detecte d, t h e val u es i n t he e C R F m ust be c orrect e d. Occasi o nal re vie w b y t he i n vesti gat or of 
t he val ues st ore d i n t he me m or y of t he B G meter a n d c orrect r e p orti n g of t hese i n t he diar y is 
a d vise d t o e ns ure a de q uac y of t he data re p ort e d i n t he st u d y data base.  
8. 2. 7  
Pre g n a nc y testi n g  
W o ma n of c hil d beari n g p ote ntial ( W O C B P) s h o ul d o nl y be i ncl u de d after a ne gati ve, hi g hl y 
se nsiti ve uri ne pre g n a nc y test (refer t o A p pe n di x 2 , Secti o n 1 0. 2 ). 
Pre g n a nc y testi n g s h o ul d be perf or me d acc or di n g t o t he fl o wc hart ( Secti o n 1. 2 ) a n d w he n e ver a 
me nstr uati o n is misse d or w he n pre g na nc y is ot her wise s us pecte d. Pr e g na n c y t esti n g is a d vise d 
9  wee ks after pre mat ure disc o nti n uati o n of ra n d o mise d treat me nt.  
A d diti o nal pre g n a nc y testi n g s h o ul d be perf or me d d uri n g t he treat me nt peri o d, if re q uire d l ocall y, 
refer t o A p pe n di x 1 0 ( Secti o n 1 0. 1 0 ). 
8. 3  
A d verse e v e nts a n d ot her s af et y re p orti n g  
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 e ve nts 
t hat meet t he defi niti o n of a n A E or S A E. 
T he defi niti o n of A Es a n d S A Es ca n be f o u n d i n A p pe n di x  3 ( Secti o n  1 0. 3 ), al o n g wit h a 
descri pti o n of A Es re q uiri n g a d diti o nal data c ollecti o n.  
T he defi niti o ns of A Es, S A Es, a d vers e de vice effects ( A D Es), seri o us a d verse de vice effects 
( S A D Es), u na ntici pate d s eri o us a d vers e de vice effects ( U S A D Es) a n d de vi ce defi cie ncies 
pertai ni n g t o t he m e dical de vice use d o utsi de a p pr o val ca n be f o u n d i n A p p e n di x 6 ( Secti o n 1 0. 6 ). 
Tec h nical c o m plai nts are c o vere d i n s ecti o n 8. 3. 6 . 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
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4 2
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Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 3  of 1 0 0  
 
S o me A Es re q uire a d diti o nal data c ollecti o n  o n a s pecific e v e nt f or m. T he rele va nt e ve nt(s) are 
liste d bel o w i n Ta ble  8 -1 , t o get her wit h ot h er e v e nts re q uiri n g c ollecti o n of a d diti o nal i nf or mati o n.  
T a ble  8 -1  
A Es re q uiri n g a d diti o n al d at a c ollecti o n, a n d ot her e ve nts  re q uiri n g a d diti o n al 
d at a c ollecti o n  
E ve nt t y pe   
A E re q uiri n g 
a d diti o n al d at a 
c ollecti o n  
Ot her e ve nt re q uiri n g 
c ollecti o n of a d diti o n al 
i nf or m ati o n 
Ac ute ki d ne y i nj ur y  
X  
 
Dia b etic reti n o pat h y  
X  
 
Gall bla d der disease  
X  
 
He p atic e ve nt  
X  
 
H y perse nsiti vit y  reacti o n 
X  
 
Ne o plas ms ( mali g na nt a n d n o n -mali g na nt)  
X  
 
Ac ute p a ncreatitis  
X  
 
Me dicati o n err or  
X  
 
Mis use a n d a b use  
X  
 
H y p o gl ycae mic e pis o des  
 
X  
 
Defi niti o ns a n d re p orti n g ti meli nes f or t he e ve nts me nti o ne d i n t he a b o ve t a ble ca n b e f o u n d i n 
A p pe n di x  3 ( Secti o n  1 0. 3 ) a n d A p pe n di x 8 ( Secti o n 1 0. 8 ) f or h y p o gl ycae mic e pis o des. 
8. 3. 1  
Ti me peri o d a n d fre q ue nc y f or c ollecti n g A E i nf or m ati o n  
All A Es a n d S A Es m ust be c ollecte d fr o m first a d mi nistrati o n of I M P u n der cli nical i n vesti gati o n 
a n d u ntil t he e n d of st u d y visit i n acc or da nce wit h t he fl o wc hart ( Secti o n  1. 2 ) or w he n e ver, wit hi n 
t he a b o ve ti me peri o d, t h e site bec o mes a ware of a n A E or S A E.  
C o n diti o ns prese nt pri or t o t he ti me p oi nt fr o m w hic h A Es are c ollecte d a n d a ntici pate d da y -t o-da y 
fl uct uati o ns of t hese 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 d uri n g ot h er st u d y-
relate d pr oce d ures perf or me d bef ore e x p os ure t o I M P u n der cli nical i n vesti gati o n, will be rec or de d 
as me dical hist or y/ c o nc o mita nt ill ness.  
A E a n d S A E re p orti n g ti meli nes ca n be f o u n d i n A p pe n di x  3 ( Secti o n   1 0. 3 ) a n d A p pe n di x  6 
( Secti o n 1 0. 6 ). All S A Es m ust be rec or de d a n d re p orte d t o N o v o N or dis k wit hi n 2 4 h o urs, a n d t he 
i n vesti gat or m ust s u b mit a n y u p d ate d S A E data t o N o v o N or dis k wit hi n 2 4 h o urs of it bei n g 
a vaila ble.  
I n v esti gat ors are n ot o bli gat e d t o acti vel y see k f or A E or S A E i n f or mer st u d y partici pa nts. 
H o we ver, if t he i n vesti gat or lear ns of a n y S A E, i ncl u di n g a d eat h, at a n y ti me after a par tici p a nt has 
bee n disc o nti n ue d fr o m/c o m plete d t he st u d y, a n d t he i n vesti gat or c o nsi ders t he e ve nt t o be relate d 
t o t he I M P a n d/ or me di cal de vice use d o utsi de a p pr o val or rel ate d t o st u d y partici pati 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. 
8. 3. 2  
Me t h o d of detecti n g A Es  
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 tr a ns mitti n g S A E re p orts are pr o vi de d i n A p pe n di x  3 ( Secti o n  1 0. 3 ) a n d 
A p pe n di x  6 ( Secti o n 1 0. 6 ). 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
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V V- T M F- 5 9 0 1 0 6 5
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4 3
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Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 4  of 1 0 0  
 
Care s h o ul d be ta ke n n ot t o i ntr o d uce bias w he n d etect i n g A Es a n d/ or S A Es. O pe n-e n d e d a n d n o n -
lea di n g v er bal q u esti o ni n g of t he p artici pa nt is t he preferre d m et h o d t o i n q uire a b o ut e ve nts. 
8. 3. 3  
F oll o w -u p of A Es  
After t he i nitial A E/ S A E re p ort, t he i n vesti gat or is re q uire d t o pr o acti vel y f oll o w eac h partici pa nt at  
s u bse q ue nt visits/c o ntacts. All S A Es s h o ul d be f oll o we d u ntil fi nal o utc o me of t he e v e nt or u ntil t he 
partici pa nt is l ost t o f oll o w -u p as des cri be d i n Secti o n  7. 3 . F urt her i nf or mati o n o n f oll o w-u p a n d 
fi nal o utc o me of e v e nts is gi ve n i n A p pe n di x 3 ( Secti o n  1 0. 3 ) a n d A p pe n di x 6 ( Secti o n  1 0. 6 ). 
8. 3. 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 n S A E is esse ntial s o t hat le gal 
o bli ga ti o ns a n d et hical res p o nsi bilities t o war ds t he safet y of partici pa nts a n d t he safet y of a st u d y 
i nter ve nti o n u n der cli nic al 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 st u d y i nt er ve nti o n 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 ul at 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. T his als o i ncl u des s u s pecte d u ne x pecte d 
seri o us a d vers e reacti o ns ( S U S A R) a n d u na ntici p ate d seri o us a d v erse d e vice effect ( U S A D E) . 
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 n 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 otif y t he I R B/I E C, if a p pr o priate acc or di n g t o 
l ocal re q uir e me nts. 
8. 3. 5  
Pre g n a nc y  
Details of pre g n a ncies i n fe male partici pa nts  will be c ollecte d after first e x p os ure t o I M P a n d u ntil 
Visit 1 7 . F or details re gar di n g c ollecti o n a n d re p orti n g of pre g na n c y i nf or mati o n, please refer t o 
A p pe n di x  4 ( Secti o n  1 0. 4 ). 
8. 3. 6  
Tec h nic al c o m pl ai nts  
Tec h nical c o m plai nts will be c ollecte d f or all pr o d ucts liste d o n t he tec h nical c o m plai nt f or m.  
I nstr u cti o ns f or re p orti n g tec h nical c o m plai nts ca n be f o u n d i n A p pe n di x 5 ( Secti o n 1 0. 5 ). 
I n or der f or N o v o N or dis k t o perf or m a c o m plete i n vesti gati o n of re p orte d S A Es, N o v o N or dis k 
mi g ht as k t he i n vesti gat or t o c o m plete a tec h nica l c o m plai nt f or m. 
8. 4  
P h ar m a c o ki netics a n d p h ar m ac o d y n a mics  
8. 4. 1  
P h ar m a c o ki netics  
Plas ma s a m ples will be use d t o e val uate t he p har m ac o ki netics of se m a gl uti de a n d will be c ollecte d 
acc or di n g t o t he fl o wc hart ( Secti o n 1. 2 ) a n d T a ble  1 0 -3  i n A p pe n di x 2 ( Secti o n 1 0. 2 ). All sa m ples 
m ust be dra w n pri or t o a d mi nistrati o n of ra n d o mise d treat me nt if a d mi nistrati o n is pla n ne d o n t he 
sa m pli n g da y –  ple ase see d osi n g i nstr ucti o ns i n Secti o n  6. 1 .  
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
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V V- T M F- 5 9 0 1 0 6 5
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4 4
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Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 5  of 1 0 0  
 
Pr oce d ures f or sa m pli n g, ha n dli n g, la b elli n g, st ora ge, a n d s hi p me nt m ust be perf or me d i n 
acc or da nce wit h t he la b orat or y ma n ual.  
Resi d ual P K sa m ples ma y be us e d f or e x pl orat or y meta b olite a na l ysis. P ote ntial meta b olite a nal ysis 
will be re p orte d se p aratel y fr o m t he C S R.  
Ge netic a n al ys es will n ot be perf or me d o n t hese pl as ma sa m ples.  
Bi oa nal ysis of t he plas m a sa m ples f or s e ma gl uti de will be perf or me d at a s pecial la b orat or y usi n g a 
vali date d a ssa y. T h e P K bi oa nal ysis is o utli ne d i n t he S pecial la b orat or y st u d y pla n. Ass a y 
descri pti o ns will be pr o vi de d i n a bi oa nal ytical r e p ort pre pare d b y t he la b orat ories, a n d t he 
bi oa nal ytical re p ort will be pr o vi de d bef ore fi nalisati o n of t he C S R. Q ualit y c o n tr olle d d ata m ust be 
a vaila ble f or re vie w b y N o n Cli nical a n d Cli nical Assa y Sci e nces, N o v o N or dis k, pri or t o i nteri m 
a nal ys es or dat a base  l o c k. After fi nal re p orti n g, st u d y sa m ples will be d estr o ye d ( u p o n a p pr o val b y 
N o v o N or dis k), a n d c o nfir mati o n of des tr ucti o n m ust be se nt t o N o v o N or dis k.  
Bi oa nal ysis will be perf or me d o n sa m ples fr o m partici pa nts ra n d o mise d t o t he t hree acti ve 
treat me nt ar ms. Sa m ples fr o m partici pa nts recei vi n g place b o will n ot be a n al yse d. 
8. 4. 2  
P h ar m a c o d y n a mi cs  
N ot a p plica ble f or t his st u d y.  
8. 5  
Ge neti cs  
N ot a p plica ble f or t his st u d y.  
8. 6  
Bi o m ar kers  
C ollecti o n of sa m ples f or bi o mar ker researc h is part of t his st u d y. Bl o o d  sa m ples will be c ollecte d 
fr o m all partici pa nts acc or di n g t o Ta bl e  1 0 -5  i n A p pe n di x 2 ( Secti o n  1 0. 2 ). T he  p ur p ose of t h e  
bi o mar ker  researc h is t o f urt her de v el o p t he u n dersta n di n g of t he bi ol o g y f oll o wi n g se ma gl uti de 
treat me nt w hic h ma y b e n efit f ut ure de v el o p me nt pr o gra m mes a n d ulti matel y t he p atie nts recei vi n g 
treat me nt. T he bi o mar ker researc h will i ncl u de t he f oll o wi n g e x pl orat or y bi o mar kers:  
 B rai n n atri uretic p e pti de ( B N P ) 
 C -ter mi nal cr ossli n ke d tel o pe pti de t y pe I c olla ge n ( C T XI) 
 Gl uc ose -de p e n de nt i ns uli n otr o pic p ol y pe pti de ( GI P)  
 Pr oc olla ge n -1 N -ter mi nal pe pti de (P 1 N P ) 
 Le pti n  
 S ol u ble le pti n rece pt or  
T hese pre d efi ne d bi o mar kers will be a nal yse d pri or  t o D B L a n d re p orte d i n t he C S R 
I n a d diti o n, ser u m b i osa m ples are c ollecte d f or f ut ure researc h o n bi o mar kers, pr ote o mes a n d 
meta b olites  a m o n g ot hers . Refer t o Secti o n 8. 8  f or f urt her details a n d A p pe n di x  7  ( Secti o n 1 0. 7 ( f or 
rete nti o n. 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
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V V- T M F- 5 9 0 1 0 6 5
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1
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4 5
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 6  of 1 0 0  
 
8. 7  
I m m u n o ge nicit y assess me nts 
8. 7. 1  
A nti -se m a gl uti de a nti b o dies 
A nti b o d y bl o o d  sa m ples will be c ollecte d acc or di n g t o t he fl o wc hart ( Secti o n 1. 2 ) a n d Ta ble  1 0 -4  i n 
A p pe n di x 2 ( Secti o n 1 0. 2 ). All sa m ples m ust be dra w n pri or t o a d mi nistrati o n of ra n d o mise d 
treat me nt if a d mi nistrati o n is pla n ne d o n t he sa m pli n g da y –  please see d osi n g i nstr ucti o ns i n 
Secti o n  6. 1 . Please see S ecti o n 5. 3. 1  re gar di n g fasti n g re q uir e me nts pri or t o a nti b o d y sa m pli n g. 
Pr oce d ures f or sa m pli n g, ha n dli n g, st ora ge, la belli n g a n d s hi p me nt of s a m ples m ust be perf or me d i n 
acc or da nce wit h t he la b orat or y ma n ual. 
Sa m ples fr o m partici pa nts ra n d o mise d t o se ma gl uti de will be a nal yse d f or a nti-se ma gl uti de 
a nti b o dies f oll o wi n g a tiere d a p pr oac h. Sa m ples p ositi ve f or a nti -se ma gl uti de a nti b o dies will be 
titrate d. I n a d diti o n, c o nfir me d a nti b o d y-p ositi ve sa m ples will be f urt her c h aract erise d f or 
cr oss-reacti vit y i n n ati ve G L P-1 . C o nfir m e d a nti b o d y p ositi ve f oll o w u p sa m ples ( Visit 1 7) will be 
a nal ys e d f or i n vitr o ne utralisi n g effect t o war ds se ma gl uti de. F oll o w -u p sa m ples ( Visit 1 7) 
c o nfir me d p ositi ve f or cr oss -reacti vit y will be a n al yse d f or i n vitr o ne utralisi n g effect t o war ds 
nati ve G L P -1.  
A n ti-se ma gl uti de a nti b o d y a n al ysis i ncl u di n g cr oss-reacti vit y t o nati ve G L P -1  will be perf or me d b y 
a s pecialise d la b a p p oi nte d b y N o v o N or dis k . T he i n vitr o ne utralisi n g a n ti b o d y a n al ysis t o war ds 
se ma gl uti de a n d nati ve G L P-1 will be perf or me d b y N o v o N or dis k.  
T he i n vesti gat or will n ot be a ble t o re vi e w t he res ults of a nti b o d y meas ure me nts i n relati o n t o A Es  
as t he data will u n bli n d t he i n vesti gat or a n d  as a nti b o d y sa m ples ma y n ot b e a nal yse d u ntil aft er last 
partici pa nt last visit.  
Refer t o A p pe n di x 7 ( Secti o n 1 0. 7 ) f or details o n rete nti o n of a nti b o d y s a m ples. 
8. 7. 2  
H y perse nsiti vit y  
If s us pici o n of a h y p erse nsiti vit y reacti o n occ urs t he partici pa nts s h o ul d be i nstr ucte d t o c o ntact t he 
site staff as s o o n as p ossi ble f or f urt h er g ui da nce. 
 
H y p erse nsiti vit y reacti o ns m ust be re p orte d as A Es acc or di n g t o Secti o n 8. 3  a n d a d diti o nal data 
c ollecti o n will be perf or me d f or t hese e ve nts.  
I n t he e ve nt of a s yste mi c h y p erse nsiti vit y reacti o n,  j u d ged  b y t he i n v esti gat or as p ossi bl y or 
pr o ba bl y relat e d t o ra n d o mise d treat me nt , a d diti o nal bl o o d sa m pli n g s h o ul d be  perf or me d. If 
p ossi ble, a bl o o d sa m ple s h o ul d be ta ke n as s o o n as p ossi ble a n d n o later t h a n 1 -2 wee ks after t he 
reacti o n. A s ec o n d sa m pl e s h o ul d be ta ke n 3-4  wee ks after t h e reacti o n.  
 
T he a d diti o nal bl o o d sa m ples will  be a nal ysed f or  t he f oll o wi n g para met ers: 
 Tr y pt ase ( o nl y if retrie ve d wit hi n 0. 5 –  2 h o urs p ost t he h y perse nsiti vit y reacti o n)  
 A nti -se ma gl uti de I g E a nti b o dies 
 A nti -se ma gl uti de bi n di n g a nti b o dies 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
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V V- T M F- 5 9 0 1 0 6 5
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1
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 of
  Pr ot oc ol  4 9 8 4 v 3. 0
4 6
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 7  of 1 0 0  
 
I n a d diti o n, t he baseli ne a nti b o d y sa m ple fr o m t he sa me partici pa nt will als o be assesse d o n t he 
a b o ve-me nti o ne d assa ys t o c o m pare a nti b o d y le vels a n d aller g y mar k ers o n sa m ples dra w n pri or t o 
first a d mi nistrati o n of ra n d o mise d treat me nt. Dat a o btai ne d i n t hese cases will n ot be a vaila ble f or 
t he i n vesti gat ors u ntil aft er t he e n d of t he st u d y a n d ca n n ot be use d f or a n y dia g n ostic p ur p os es. 
T he a nal yses will be perf or me d b y N o v o N or dis k.  
8. 8  
H u m a n bi os a m ples f or f ut ure rese arc h  
C ollecti o n of bi osa m ples f or f ut ur e a nal ysis is a c o m p o ne nt of t his st u d y. T he sa m ples will be 
st ore d i n a bi o ba n k a n d all o w f or f ut ure a nal yses w he n ne w k n o wl e d ge or i m pr o ve d testi n g 
tec h n ol o gi es ma y ha ve b ec o me a v aila ble d uri n g or after t h e st u d y. Partici pati o n is o pti o nal, a n d 
partici pa nts m ust si g n a s e parat e i nf or me d c o nse nt t o i n dicate t heir partici p ati o n i n t he bi o ba n k 
c o m p o ne nt(s) of t he st u d y. Partici pa nts w h o d o n ot wis h t o partici pate i n t he bi o ba n k c o m p o ne nt(s) 
ma y still partici pate i n t h e st u d y.  
Bl o o d sa m ples will be c ollecte d at visits descri be d i n A p pe n di x 2 ( Ta ble  1 0 -2 ) a n d acc or di n g 
A p pe n di x  7  ( Secti o n 1 0. 7 ) a n d st ore d f or f ut ur e use. 
A nal ys es of cir c ulati n g bi o mar kers will meas ure h or m o nes, meta b olites or ot her n o n -ge n etic ser u m 
e ntit y wit h t he p ur p ose of u n dersta n di n g a n d pre dicti n g res p o ns e t o  se ma gl uti de s.c. as well as 
u n dersta n di n g t y p e 2 dia betes, o ver wei g ht or ot her relate d c o n diti o ns.  
T he sa m ples ma y be a nal ys e d as part of a m ulti -st u d y ass ess me nt. Res ults will n ot be re p orte d t o 
t he i n vesti gat or f or ass ess me nts of A Es n or will t he y b e part of t he cli nical st u d y re p ort. T he 
pri mar y o bjecti ve of t h e a nal ysis is t o i n vesti gate o n a p o p ulati o n le vel a n d res ults are v er y u nli kel y 
t o ha ve cli nical utilit y o n a n i n di vi d ual le vel. F urt her m ore, t he a nal yses will be d o ne o n 
pse u d o n y mise d d ata. T her ef ore, a n y o utc o me of t h e a nal yses will n ot be re p orte d directl y t o 
partici pa nts or sites. T he res ult ma y b e re p orte d i n p u blicati o ns, at scie ntific c o nfere n ces or t o 
a ut h orities. 
T he h u ma n bi osa m ples f or f ut ure researc h will be st ore d f or u p t o 1 5 years a fter e n d of st u d y at a 
ce ntral la b orat or y or a p pr o priate st ora ge facilit y (see A p pe n di x  7  [ Secti o n 1 0. 7 ]). 
8. 9  
He alt h ec o n o mics  
N ot a p plica ble f or t his st u d y. 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
4 7
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 8  of 1 0 0  
 
9  St atistic al c o nsi der ati o ns  
T he statistical a nal ysis pla n ( S A P) will be fi nalise d pri or t o first patie nt first visit ( F P F V), a n d it 
will i ncl u de a m ore tec h nical a n d detaile d descri pti o n of t he statistical a nal ys es d escri be d i n t his 
secti o n. T his secti o n is a s u m mar y of t he pla n ne d statistical a nal ys es of t he m ost i m p orta nt 
e n d p oi nts i ncl u di n g pri m ar y a n d sec o n dar y c o nfir mat or y esti ma n ds.  
9. 1  
St atistic al h y p ot heses  
N ot a p plica ble  
9. 1. 1  
M ulti plicit y a dj ust me nt  
N ot a p plica ble  
9. 2  
A n al ysis sets  
T w o partici pa nt a n al y sis sets are defi ne d: 
P artici p a nt a n al ysis set  
Descri pti o n  
F ull a nal ysis set  
All ra n d o mise d partici pa nts. P artici pa nts will be i ncl u de d i n t he a nal ys es 
acc or di n g t o t he pla n ne d ra n d o mise d treat me nt.  
Safet y a nal ysis set  
All partici pa nts w h o are e x p ose d t o ra n d o mise d treat me nt. P artici pa nts will be 
i ncl u de d i n t he a nal yses acc or di n g t o t he treat me nt t he y act uall y recei ve d. 
 
F o ur  data p oi nts sets are defi ne d:  
D at a p oi nts set ( D P S)  
Descri pti o n  
D P S 1 –  i n-st u d y 
All o bser ve d data p oi nts fr o m ra n d o misati o n u ntil t he first d ate of:  
 e n d of st u d y visit ( V 1 7)  
 deat h  
 wit h dra wal of i nf or me d c o nse nt  
 last c o ntact as defi ne d b y i n vesti gat or f or partici pa nts t hat ar e l ost t o f oll o w u p 
D P S 2 –  o n -treat me nt 
All o bser ve d data p oi nts fr o m first dr u g date u ntil t he first date of: 
 e n d of D P S 1  
 last a d mi nistrati o n of ra n d o mise d treat me nt + 6 3 da ys 
D P S 2 - m o difie d  
All o bser ve d data p oi nts wit h ac ute o nset (la b orat or y assess me nts, a n d p h ysical 
e xa mi nati o n) fr o m first dr u g d ate u ntil t he first date of:  
 e n d of D P S 1  
 last a d mi nistrati o n of ra n d o mise d treat me nt + 7 da ys 
D P S 3 –  o n -treat me nt wit h o ut 
resc ue 
All o bser ve d data p oi nts fr o m first dr u g date u ntil t he first date of:  
 i nitiati o n of resc ue me dicati o n 
 last a d mi nistrati o n of ra n d o mise d treat me nt + 7 da ys  
 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
4 8
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 9  of 1 0 0  
 
T he f ull a nal ysis set ( F A S) will be use d w he n a n al ysi n g effi cac y e n d p oi nts a n d assess me nts, a n d t he 
safet y a n al ysis set ( S A S) will be use d w he n a n al ysi n g safet y e n d p oi nts a n d assess me nts.  
T he F A S a n d D P S 1 are use d t o esti mate t he pri mar y esti ma n d  f or t he pri mar y e n d p oi nt a n d t he 
sec o n dar y esti ma n d f or t he c o nfir mat or y s ec o n d ar y e n d p oi nt.  
T he F A S a n d D P S 3 are use d t o esti mate t he a d diti o nal esti ma n ds f or t he pri mar y a n d c o nfir mat or y 
sec o n dar y e n d p oi nt. 
T he S A S a n d D P S 2 are use d as t he pri mar y d ata p oi nts set t o e val uate safet y dat a ( A Es, e ye 
e x a mi nati o n, vital si g ns a n d h y p o gl ycae mic e pis o d es). T he pri mar y e val u ati o n of a nti b o dies will be 
base d o n t he safet y a nal ysis set a n d D P S 2.  
T he S A S a n d a m o difie d D P S 2 are use d t o pres e nt safet y data wit h a n a c ut e o nset (la b orat or y 
assess me nts, a n d p h ysical e x a mi nati o n).  
9. 3  
St atistic al a n al yses  
D ose -res p o nse m o delli n g  
T o c haracteris e t he d ose -res p o nse relati o ns hi p f or c ha n ge i n H b A 1c ( %-p oi nt) a n d c ha n ge i n b o d y 
wei g ht ( k g) at w ee k 4 0 f or t he pri mar y a n d a d diti o n al esti ma n d, t he f oll o wi n g d ose -res p o nse 
ca n di date m o dels i n Ta bl e  9 -1  will be fit se paratel y. T he v aria bl e d is t he n o mi nal d ose le vel, a n d 
t he ot her vari a bles are m o del para met ers t o be esti mate d.    
T a ble  9 -1  
D ose -res p o nse c a n di d ate m o dels  
M o del  
F u ncti o n al f or m f( d,θ ) 
E m ax  
𝐸0 + 𝐸𝑚𝑎𝑥
𝑑
𝐸𝐷5 0 + 𝑑 
Si g m oi d al E m ax  
𝐸0 + 𝐸𝑚𝑎𝑥
𝑑𝜆
𝐸𝐷5 0
𝜆+ 𝑑𝜆 
Li ne ar  
𝐸0 + 𝛽𝑑 
Li ne ar l o g -d ose  
𝐸0 + 𝛽l o g(𝑑+ 1 ) 
E 0: t he e x pecte d effect o n H b A 1c / B o d y wei g ht w he n treate d wit h se ma gl uti de s.c./p o ole d place b o, E D 5 0: T he d ose, 
w hic h pr o d uces half of E ma x , Ema x : Ma xi m u m effect attri b ut a ble t o t he dr u g. 
 
T he ca n di dat e m o dels will be fit t o t he mea n esti mate d e n d p oi nt c ha n ges at wee k 4 0 f or t he 
e val uate d se m a gl uti de  s.c. d oses a n d p o ole d place b o deri ve d fr o m t he a nal ys es m o dels d escri be d 
a b o ve acc or di n g t o t he esti ma n d e val uate d. W he n fitti n g t he m o dels, t he mea n esti mate d e n d p oi nt 
c ha n ge will be w ei g hte d b y t heir i n verse esti mate d varia nces.  
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
4 9
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 0  of 1 0 0  
 
T he m o del ulti matel y use d t o e val uate d ose -res p o nse will be selecte d a m o n g t he ca n di date m o d els 
base d o n t he best fit t o data. T he best fit will be e v al uate d base d o n c o n ver ge nce, m o del c o m ple xit y, 
A kai ke i nf or mati o n criteri o n ( AI C) val ue, a n d vis ual e val uati o n.   
9. 3. 1  
Ge ner al c o nsi der ati o n s 
Fr o m t he statistical a nal yses t he p oi nt esti mate, t w o -si de d 9 5 % CIs, a n d t he ass ociate d t w o-si de d 
p -val ues will be pres e nte d f or t he f oll o wi n g c o m p aris o n:  
 Se ma gl uti de 2 m g vs p o ole d place b o  
 Se ma gl uti de 8 m g vs p o ole d place b o  
 Se ma gl uti de 1 6  m g  vs p o ole d place b o  
 Se ma gl uti de 8 m g vs Se ma gl uti de 2 m g  
 Se ma gl uti de 1 6 m g vs Se ma gl uti de 8 m g  
 Se ma gl uti de 1 6 m g vs Se ma gl uti de 2 m g  
F or all a n al ys es a n d re p orti n g, t he t hree place b o ar ms will be p o ole d i nt o o ne place b o gr o u p. 
F urt her m ore, t o i n vesti gate t he p o oli n g o f place b o descri pti ve statistics will be pr o vi de d of c ha n ge 
i n H b A 1 c at wee k 4 0 a n d c ha n ge i n b o d y wei g ht ( k g) at wee k 4 0 will be d o ne wit h o ut p o oli n g t he 
place b o.  
If a n ass ess me nt has bee n ma de b ot h at scree ni n g a n d ra n d o misati o n, t he val ue fr o m t he 
ra n d omisati o n visit will be use d as t he b aseli ne v al ue. If t he v al ue meas ure d at t he ra n d o misati o n 
visit is missi n g, a n d t he assess me nt was ma de at scree ni n g, t he s cree ni n g v al ue will be use d as t he 
baseli ne val ue. T h e parti ci pa nts wit h missi n g bas eli ne val ues will n ot c o ntri b ute t o a n y a nal ysis t hat 
a dj ust f or t he gi ve n bas eli ne.  
T he stratificati o n fact or i n t he statistical a nal ysis will be base d o n o bser ve d baseli ne val ue of 
H b A 1 c ≥ 8. 5 % ( Y/ N).  
9. 3. 2  
Pri m ar y e n d p oi nt a n al ysis  
T he pri mar y e n d p oi nt is c ha n ge fr o m bas eli ne t o wee k 4 0 i n H b A 1c ( %-p oi nt).  
9. 3. 2. 1  
Pri m ar y esti m a n d  
T he pri mar y esti ma n d, prese nte d i n Secti o n 3. 2. 1. 1 , will be esti mate d base d o n t he F A S usi n g t h e 
i n-st u d y data p oi nts set ( D P S 1). 
T he pri mar y a n al ysis f or t his esti ma n d is a n a nal ysis of c o varia n ce ( A N C O V A) wit h ra n d o mise d 
treat me nt a n d stratificati o n fact or as fi x e d effects a n d baseli ne H b A1c as a c o variate.  
H a n dli n g of missi n g d at a  
J u m p t o refere nce: Missi n g wee k 4 0 data will be i m p ute d usi n g m ulti ple i m p utati o n ass u mi n g t hat 
missi n g data are missi n g n ot at ra n d o m. T he i m p utati o n will be perf or me d b y sa m pli n g a m o n g all 
a vaila ble ass ess me nts at wee k 4 0 i n t he p o ole d pl ace b o gr o u p. A patter n mi xt ure m o del a p pr oac h is 
a p plie d w here wit h dra w n partici pa nts wit h o ut a f oll o w -u p visit are ass u me d t o res p o n d as if treate d 
wit h place b o f or t h e e ntire st u d y. T his a p pr oac h is als o k n o w n as “j u m p t o r efere nce” a n d m a kes t he 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
5 0
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 1  of 1 0 0  
 
ass u m pti o n t hat partici pa nts i nsta ntl y after disc o nti n uati o n l ose a n y effect of ra n d o mise d treat me nt 
be y o n d w hat c a n be e x pecte d fr o m t he p o ole d pl ace b o gr o u p.  
M ulti ple c o pies ( 5 0 0 c o pie s) of t he f ull datas et will be ge nerate d b y i m p uti n g missi n g v al ues base d 
o n esti mate d para m eters f or t he p o ole d place b o gr o u p. T his will be d o ne as f oll o ws:  
 5 0 0 c o pies of t he dat aset will be ge n erat e d.  
 A n e nric he d A N C O V A m o del wit h stratificati o n fact or a n d se x as fi x e d effects a n d b aseli ne 
H b A 1 c as c o variate will b e fitte d t o t he c ha n ge fr o m baseli ne t o wee k 4 0 i n H b A 1c f or t he 
c o m pleters i n t he p o ole d place b o gr o u p o nl y.  
 F or eac h of t h e 5 0 0 c o pies of t he dataset, t he esti mate d para meters a n d t heir varia nces fr o m t his 
m o del will be use d t o i m p ute missi n g wee k 4 0 v al ues f or partici pa nts i n all treat me nt ar ms, 
base d o n t heir fact or le v el a n d t he val ues of t he c o variate.  
 F or eac h of t h e 5 0 0 c o m plete datasets, t he c ha n ge fr o m baseli ne t o wee k 4 0 i n H b A 1c will be 
a nal ys e d re peati n g t he A N C O V A descri be d a b o v e. T he esti mate s a n d st a n dar d err ors ( S Es) f or 
t he 5 0 0 data sets are p o ol e d t o o ne esti mate a n d ass ociate d SE  usi n g R u bi n’s r ule. 1 5 
9. 3. 2. 2  
S u p ple me nt ar y a n al ysis  
A d diti o n al esti m a n d a n al ysis  
T he a d diti o nal esti ma n d, prese nte d i n Secti o n 3. 2. 1. 2 , will be esti mate d bas e d o n t he F A S usi n g 
p ost -baseli ne data c ollect e d u p t o a n d i ncl u di n g wee k 4 0 fr o m t he ‘ o n -treat me nt wit h o ut resc ue’ 
o bser vati o n peri o d ( D P S 3).  
I m p utati o n of missi n g d ata will be ha n dle d b y MI ass u mi n g t hat missi n g data are M A R. T h e 
i m p utati o n will be perf or me d se paratel y wit hi n eac h treat me nt gr o u p d efi n e d b y ra n d o mise d 
treat me nt. First, i nter mitte nt missi n g val ues are i m p ute d usi n g a M ar k o v C h ai n M o nte Carl o 
met h o d t o o btai n a m o n ot o ne missi n g data patter n,  ge n erati n g 5 0 0 c o m plet e data sets. Sec o n dl y, a 
se q ue ntial c o n diti o nal li near re gressi o n a p pr oac h f or i m p uti n g m o n ot o ne missi n g val ues will be 
i m ple me nte d starti n g wit h t he first visit after baseli ne a n d se q ue ntiall y c o nti n ui n g t o t he last 
pla n ne d visit at  wee k 4 0. T he m o del use d f or i m p utati o n will i ncl u de stratificati o n fact or a n d se x as 
fi x e d effects a n d b aseli ne a n d p ost-baseli ne H b A 1c val ues o bser ve d pri or t o t he visit i n q uesti o n as 
c o variates.  
T he 5 0 0 c o m plete dat asets will be a nal ys e d usi n g a n A N C O V A wit h stratificati o n fact or a n d 
ra n d o mise d treat me nt as fi x e d effects a n d b aseli ne H b A1c as a c o variat e. R u bi n’s r ule will be 
a p plie d t o c o m bi ne t he esti mates a n d dra w i nfere n ce.  
9. 3. 3  
Sec o n d ar y e n d p oi nts a n al ysis  
9. 3. 3. 1  
Pri m ar y esti m a n d  
F or t he e n d p oi nt “c ha n ge fr o m baseli ne t o wee k 4 0 i n b o d y wei g ht ( k g)” a si milar a nal ysis as 
descri be d i n Secti o n 9. 3. 2. 1  will be perf or me d, b ut wit h val ues of b o d y wei g ht i nstea d of H b A 1c. 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
5 1
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 2  of 1 0 0  
 
9. 3. 3. 2  
S u p ple me nt ar y a n al ysis  
A d diti o n al esti m a n d  
A si milar a nal ysis as des cri be d i n Secti o n 9. 3. 2. 2  will be perf or me d, b ut wit h val ues of b o d y wei g ht 
i nstea d of H b A1c. 
9. 3. 3. 3  
S u p p orti ve  
F or details o n a n al ys es of s u p p orti ve sec o n dar y e n d p oi nts, please refer t o t h e S A P.  
9. 3. 4  
E x pl or at or y e n d p oi nts a n al ysis  
N ot a p plica ble, as t here are n o e x pl orat or y e n d p oi nts i n t he st u d y.  
9. 3. 5  
S afet y a n al yses  
All safet y a nal yses will  be ma de o n t he safet y a n al ysis set. T he sta n d ar d safet y assess me nts ( A Es, 
la b orat or y para meters, vital si g ns, etc.) will be re p orte d descri pti vel y bas e d o n t he D P S 2 a n d 
m o difie d D P S 2; i ncl u di n g a n y n ot a ble c h a n ges of cli nical i nterest i n la b orat or y p ara m e ters. T he 
pri mar y e val u ati o n of a nti b o dies will be base d o n t he safet y a nal ysis set a n d D P S 2.  
9. 3. 6  
Ot her a n al yses  
P o p ulati o n p har mac o ki netic ( P K) a n d e x p os ure -res p o nse a nal ys es is descri be d bel o w. F or ot her 
a nal ys es, pleas e refer t o t he S A P.  
P h ar m a c o ki netic a n d / or p h ar m a c o d y n a mic m o delli n g 
P o p ulati o n P K a n d e x p os ure -res p o nse a n al ys es will be use d t o c haracterize t he e x p os ure-res p o nse 
c ur ve of s e ma gl uti de s.c., a n d t o s u p p ort selecti o n of a d ose f or p ote ntial f ut ure i n vesti gati o n i n 
patie nt s wit h T 2 D . 
A m o delli n g a n al ysis pla n will be pre pare d bef ore data base l oc k, or pri or t o i nteri m a nal ys es, 
o utli ni n g details of t he a n al yses. T he m o delli n g w ill be perf or me d b y Q ua ntitati ve Cli nical 
P har mac ol o g y at N o v o N or dis k a n d will be re p ort e d se paratel y fr o m t he  C S R.  
9. 4  
I nteri m a n al ysis 
A  ma xi m u m of t w o i nteri m a nal ys es ma y be c o n d ucte d t o ma ke treat me nt gr o u p c o m paris o ns 
d uri n g t he st u d y  t o s u p p ort i nter nal decisi o ns a n d pla n ni n g. T he first ma y, at t he earliest, oc c ur 
w he n at least o ne t hir d of t he partici pa nts fr o m t he acti ve 8 m g ar m ha v e c o m plete d visit 1 2, a n d t he 
sec o n d ma y, at t he earliest, occ ur w he n at least o n e t hir d of t he partici p a nts fr o m t he acti ve 1 6 m g 
ar m ha ve c o m plete d visit 1 3, c orres p o n di n g t o ei g ht wee ks o n mai nte na n ce d ose , res pecti vel y i n 
eac h ar m. T hese i nteri m a nal ys es will i ncl u de a v aila ble safet y, efficac y,  a n d P K data.  
A mi ni m u m gr o u p of N o v o N or dis k staff, i.e. , t he i nteri m c harter gr o u p, w o ul d perf or m t he i nteri m 
a nal ys es. T he me m b ers of t he i nteri m c hart er gr o u p will be s pecifie d i n a n i nteri m c harter . N o 
c ha n ge i n t he st u d y desi g n a n d c o n d uct ca n occ ur base d o n t he i nteri m a n al ys es . Detaile d 
i nf or mati o n o n t he i nteri m a nal ys es  will be s pecifie d i n a n i nteri m c harter. It is n ot c o nsi dere d a 
pr ot oc ol de viati o n if n o i nteri m a nal ys is is perf or me d. 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
5 2
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 3  of 1 0 0  
 
9. 5  
S a m ple size deter mi n ati o n  
T hree d oses of se ma gl uti de s.c. ( 2 m g, 8 m g, a n d 1 6 m g) are c o nsi dere d a d e q uate t o c h aracter ise t he 
s ha pe of t he c ur ve f or t he d ose-res p o ns e relati o ns hi p. T he sa m ple siz e f or eac h d ose is deter mi ne d 
t o ac hie ve a s ufficie nt precisi o n o n t he d ose-res p o nse relati o ns hi p. F urt h er m ore, sa m ple siz e 
calc ulati o n is d o ne f or a n al yses a d dressi n g t he pri mar y  esti ma n d wit h pri mar y a n d c o nfir mat or y 
sec o n dar y e n d p oi nt.  
Hist orical data c o nsi dere d f or l o wer d oses of se m a gl uti de s.c. i n t he s a m ple siz e calc ulati o n are as 
o utli ne d i n Ta ble  9 -2  a n d Ta ble  9 -3 . 
T a ble  9 -2  
Hist oric al d at a f or c h a n ge i n H b A 1c fr o m b aseli ne t o t ar get wee k 
 
S T E P 2  
S U S T AI N F O R T E  
S U S T AI N 2  
N  
4 0 4  
4 3 3  
3 4 4  
Se m a gl uti de s.c. d ose  2. 4 m g  
2 m g  
1 m g  
Tre at me nt peri o d  
I n-st u d y 
O n -treat me nt 
O n -treat me nt 
T ar g et w ee k  
W ee k 4 4  
Wee k 4 0  
Wee k 4 0  
M e a n  
-1. 8 % -p oi nts  
-2. 2 % -p oi nts  
-1. 7 2 % -p oi nts  
St a n d ar d de vi ati o n  
1. 1 % -p oi nts  
1. 0 % -p oi nts  
1. 0 2 % -p oi nts  
S T E P 2: N N 9 5 3 6 -4 3 7 4; S U S T AI N F O R T E: N N 9 5 3 5 -4 5 0 6; S U S T AI N 2: N N 9 5 3 5 -3 6 2 6.  
T a ble  9 -3  
Hist oric al d at a f or c h a n ge i n B o d y wei g ht fr o m b aseli ne t o t ar get wee k  
 
S T E P 2  
S U S T AI N F O R T E  
S U S T AI N 2  
N  
3 8 3, 3 8 1  
4 3 4  
3 4 6  
Se m a gl uti de s.c. d ose  2. 4 m g  
2. 0 m g  
1. 0 m g  
Tre at me nt peri o d  
I n-st u d y 
O n -treat me nt 
O n -treat me nt 
T ar g et w ee k  
W ee k 3 6, Wee k 4 4  
Wee k 4 0  
Wee k 4 0  
M e a n  
-9. 3 k g, -9. 7 k g  
-7. 0 k g  
-5. 9 4 k g  
St a n d ar d de vi ati o n  
7. 3 k g  a vera ge of wee k 3 6, 4 4  
5. 8 k g  
5. 1 3 k g  
S T E P 2: N N 9 5 3 6 -4 3 7 4; S U S T AI N F O R T E: N N 9 5 3 5 -4 5 0 6; S U S T AI N 2: N N 9 5 3 5 -3 6 2 6.  
Si nce t here are n o a vaila ble hist orical data f or t he hi g her d oses of se m a gl uti de s.c., a ra n ge of 
per -gr o u p S Ds has b ee n i n vesti gate d i n Fi g ure  9 -1  f or H b A 1c ( %) a n d Fi g ure  9 -2  f or B o d y wei g ht 
( k g) u n der t he ass u m pti o n of 6 0 partici pa nts i n eac h acti ve tr eat me nt/ p o ole d place b o gr o u p.  
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
5 3
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 4  of 1 0 0  
 
Fi g ure  9 -1  
Se nsiti vit y of precisi o n  ( 9 5 % CI h alf-wi dt h) f or v ari o us S Ds –  H b A 1c( %-p oi nt)  
 
Wit h 6 0 partici pa nts i n eac h acti ve treat me nt/ p o ol e d place b o gr o u p a n d f or vari o us S Ds bet wee n 
0. 9 a n d 1. 2 % -p oi nts, t here is at least 8 0 % pr o b a bilit y t hat t he 9 5 % CI will b e c o ntai ne d wit hi n 
± 0. 3 4 a n d  ± 0. 4 6 % -p oi nts of t he esti mate. T his is c o nsi dere d a s ufficie nt ra n ge of precisi o n t o 
c haracterise t h e d ose -res p o nse relati o ns hi p of se ma gl uti de s.c. 
0 .3 5 0
0 .3 7 5
0 .4 0 0
0 .4 2 5
0 .4 5 0
H alf -Wi dt h
0 .0
0 .2
0 .4
0 .6
0 .8
1 .0
Pr o b (Wi dt h )
1 .2
1 .1
1 .0
0 .9
S D %- p oi nt s
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
5 4
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 5  of 1 0 0  
 
Fi g ure  9 -2  
Se nsiti vit y of precisi o n ( 9 5 % CI h alf -wi dt h) f or v ari o us S Ds –  B o d y wei g ht ( k g)  
 
Wit h 6 0 partici pa nts i n eac h acti ve treat me nt/ p o ol e d place b o gr o u p a n d f or vari o us S Ds bet wee n 
5. 0  a n d 7. 5 k g , t h ere is at least 8 0 % pr o ba bilit y t h at t he 9 5 % CI will be c o ntai ne d wit hi n ±2. 0  a n d 
± 3. 0 k g  of t he esti mate. T his is c o nsi dere d a s ufficie nt ra n ge of precisi o n t o c haracterise t h e 
d ose -res p o ns e relati o ns hi p of se ma gl uti de s.c. 
U n der t he ass u m pti o n of 6 0 partici pa nts i n eac h acti ve treat me nt/ p o ole d place b o gr o u p, t he s a me 
ra n ge of S Ds a n d t heir c orres p o n di n g mea n differe nces pr o vi di n g a p o wer of 8 0 % ha ve b ee n 
e val uate d i n Fi g ure  9 -3  f or H b A 1c ( %) a n d Fi g ure  9 -4  f or B o d y wei g ht ( k g). Treat me nt differe n ces 
bet wee n 0. 4 6 a n d 0. 6 2 % -p oi nts a n d 2. 6 a n d 3. 9 k g  ha ve 8 0 % p o wer w h e n ma ki n g a n y pair wise 
c o m paris o n of H b A 1c a n d B o d y wei g ht  c h a n ge fr o m baseli ne t o wee k 4 0 b et wee n gr o u ps i n t his 
st u d y. 
I n c o ncl usi o n, t he t otal sa m ple size will be 2 4 0 partici pa nts. 
2 .0
2 .2
2 .4
2 .6
2 .8
3 .0
H alf -Wi dt h
0 .0
0 .2
0 .4
0 .6
0 .8
1 .0
Pr o b (Wi dt h )
7 .5
7 .0
6 .5
6 .0
5 .5
5 .0
S D K g
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
5 5
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 6  of 1 0 0  
 
Fi g ure  9 -3  
Tre at me nt differe nces wit h 8 0 % p o wer f or v ari o us S Ds  –  H b A 1c( %) 
 
M e a n diff er e n c e
4 5
.
0
5 0
.
0
5 5
.
0
6 0
.
0
6 5
.
0
St a n d ar d d e vi ati o n
0 .9
1 .0
1 .1
1 .2
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
5 6
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 7  of 1 0 0  
 
Fi g ure  9 -4  
Tre at me nt differe nce wit h 8 0 % p o wer f or v ari o us S Ds  –  B o d y wei g ht ( k g)  
 
M e a n diff er e n c e
0.
2
5.
2
0.
3
5.
3
0.
4
5.
4
0.
5
St a n d ar d d e vi ati o n
5 .0
5 .5
6 .0
6 .5
7 .0
7 .5
8 .0
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
5 7
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 8  of 1 0 0  
 
1 0  S u p p orti n g d oc u me nt ati o n a n d o p er ati o n al c o nsi de r ati o ns  
1 0. 1  A p pe n di x  1: Re g ul at or y, et hic al, a n d st u d y o versi g ht c o nsi der ati o ns  
1 0. 1. 1  
Re g ul at or y a n d et hic al c o nsi der ati o ns  
T his st u d y will be c o n d u cte d i n acc or da n ce wit h t he pr ot oc ol a n d wit h t he f oll o wi n g:  
 C o nse ns us et hical pri nci ples deri ve d fr o m i nter nati o nal g ui deli nes i ncl u di n g t he Declarati o n of 
Helsi n ki 1 6 a n d a p plica ble I C H G o o d Cli nical Practice ( G C P) G ui deli ne 1 7 
 A p plica ble la ws a n d re g ulati o ns  
T he pr ot oc ol, i nf or me d c o nse nt f or m, i n vesti gat or’s br oc h ure (as a p plica bl e) a n d ot her rele va nt 
d oc u me nts (e. g., a d v ertis e 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 a p pr o ve d b y 
t he I R B/I E C bef ore t he st u d y 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 C S R acc or di n g t o nati o nal re q uire me 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 st u d y d esi g n, e x ce pt f or c ha n ges necessar y t o eli mi nate a n i m me diate safet y hazar d t o 
st u d y partici p a nts. 
Bef ore a site is all o w e d t o start scree ni n g p artici p a nts, 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 st u d y a n n u all 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 o t her si g nifi ca nt safet y fi n di n gs as re q uir e d b y I R B/I E C 
pr oce d ures  
 pr o vi di n g o versi g ht of t h e c o n d uct of t he st u d y 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 all 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 C S R s y n o psis t o t he I R B/I E C  
 re p orti n g a n y p ote ntial seri o us breac h es t o t he s p o ns or i m me diatel y after disc o ver y 
U nite d states: Please see A p pe n di x 1 0 ( Secti o n 1 0. 1 0 ) f or c o u ntr y-s pecific re q uire me nts. 
1 0. 1. 2  
Fi n a nci al discl os ure  
I n v esti gat ors a n d s u b-i n v esti gat ors will pr o vi de N o v o N or dis k wit h s uffici e nt, acc urate fi na ncial 
i nf or mati o n as re q u este d t o all o w N o vo N or dis k t o s u b mit c o m plete a n d acc urate fi na ncial 
certificati o n or discl os ure state me nts t o t he a p pr o priate re g ul at or y a ut h orities. I n v esti gat ors are 
res p o nsi ble f or pr o vi di n g i nf or mati o n o n fi na ncial i nterests d uri n g t h e c o urse of t he st u d y a n d o ne 
year  after c o m pleti o n of t he st u d y.  
F or U S sites: Verifi cati o n u n der discl os ures p er C o de of Fe deral Re g ulati o ns ( C F R) of Fi n a ncial 
C o nflict of I nt erest.  
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
5 8
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 9  of 1 0 0  
 
1 0. 1. 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 h e st u d y, i ncl u di n g t he ris ks 
a n d be nefits, t o t he partici pa nt a n d a ns wer all q uesti o ns re gar di n g t he st u d y. T his i ncl u des t he use of 
a n i m partial wit ness w here re q uir e d acc or di n g t o l ocal re q uir e me nts . 
T he i n vesti gat or m ust e ns ure t he partici p a nt a m ple ti me t o c o me  t o a decisi o n w het her or n ot t o 
partici pate i n t he st u d y.  
Partici pa nts m ust be i nf or me d t hat t heir partici p ati o n is v ol u ntar y. Partici pa nts will be re q uire d t o 
si g n a n d d ate a state m e nt of i nf or me d c o ns e nt t hat meets t he re q uir e me nts of l ocal re g ul ati o ns,  I C H 
G C P 1 7 g ui deli nes, Declarati o n of Helsi n ki, 1 6 pri vac y a n d data pr otecti o n re q uire me nts, w here 
a p plica ble, a n d t h e I R B/I E C or site.  
T he me dical r ec or d m ust i ncl u de a state me nt t hat writte n i nf or me d c o ns e nt was o btai ne d bef ore a n y 
st u d y-relate d acti vit y a n d t he date w he n t h e 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 m e 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 ns e nt f or m bef ore a n y 
st u d y-relate d acti vit y. 
T he res p o nsi bilit y of s ee ki n g i nf or me d c o nse nt m ust re mai n wit h t he i n vesti gat or, b ut t he 
i n vesti gat or ma y d ele gat e t he tas k 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. 
Partici pa nts m ust be re -c o nse nte d t o t he m ost c urre nt versi o n of t he i nf or m e d c o nse nt f or m (s) 
d uri n g t heir p artici pati o n i n t he st u d y.  
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 partici pa nt.  
A se parate i nf or me d c o nse nt f or m i nte n de d f or c ollecti o n of a d diti o nal bl o o d sa m ples f or f ut ur e 
researc h is a v aila ble f or t his st u d y (see Secti o n 8. 8 ). 
A se parate i nf or me d c o nse nt f or m i nte n de d f or a male  part ner of a female partici pa nt i n case of a n 
a b n or mal pre g n a nc y or c hil d b or n wit h healt h pr o ble m  is a vaila ble f or t his st u d y ( A p p e n di x 4, 
Secti o n 1 0. 4 ). 
1 0. 1. 4  
 I nf or m ati o n t o p artici p a nts d uri n g t he st u d y 
T he site will be offere d a c o m m u nicati o n pac ka ge f or t he partici p a nt d uri n g t he c o n d uct of t he 
st u d y. T he p ac ka ge c o nte nt is iss ue d b y N o v o N or dis k. T he c o m m u nicati o n pac ka ge will c o 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 partici pa nts. T he writte n i nf or mati o n will be 
tra nslate d a n d a dj uste d t o l ocal re q uir e me nts a n d distri b ute d t o t he partici pa nt at t he discreti o n of 
t he i n vesti gat or. T h e partici pa nt ma y recei ve a “t h a n k y o u f or y o ur partici p ati o n letter” aft er 
c o m pleti o n of t he st u d y. F urt her, t h e partici pa nt m a y recei ve ot her writte n i nf or mati o n d uri n g t h e 
st u dy.  
All writte n i nf or mati o n t o partici pa nts m ust be se nt t o I R B/I E C f or a p pr o val/fa v o ura bl e o pi ni o n a n d 
t o re g ul at 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 ul ati o ns. 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
5 9
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6 0  of 1 0 0  
 
1 0. 1. 5  
D at a pr otecti o n  
Partici pa nts will be assi g ne d a 6 -di git u ni q ue i de ntifier, a s u bject I D. A n y partici pa nt rec or ds or 
datasets t hat are tra nsf erre d t o N o v o N or dis k will c o ntai n t he i de ntifier o nl y. N o direct i de ntifiers 
fr o m t he partici pa nt are tra nsferre d t o N o v o N or dis k. 
T he partici pa nt a n d a n y bi ol o gical material o bt ai ne d fr o m t he partici pa nt will be i de ntifie d b y 
s u bject I D, visit n u m ber a n d st u d y I D. A p pr o pri ate 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 partici pa nts as re q uire d b y l ocal, 
re gi o nal a n d nati o nal re q uire me nts.  
T he partici pa nt m ust be i nf or me d a b o ut his/ her pri vac y ri g hts, i ncl u di n g t h at his/ her pers o nal st u d y -
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 la w. T he 
discl os ure of t he dat a m ust als o be e x pla i ne d t o t he partici pa nt. 
T he partici pa nt m ust be i nf or me d t hat his/ her me dical rec or ds ma y be e x a mi ne d b y a u dit ors or ot her 
a ut h orise d pers o n n el a p p oi nte d b y N o v o N or dis k, b y a p pr o priate I R B/I E C me m bers, a n d b y 
i ns pect ors fr o m re g ulat or y a ut h orities. 
Pers o nal data ma y b e c ollecte d fr o m p artici pa nts d ue t o pr ocess r e q uire me nts fr o m N o v o N or dis k’s 
s u p pliers. T his data is nee de d t o e ns ure t hat t he rele va nt data a n al ysis f or t he st u d y ca n be 
perf or me d, b ut will n ot be part of t he data tra nsferre d t o N o v o N or dis k, t he assess me nt of t he st u d y 
e n d p oi nts or t he cli nical st u d y re p ort. A list of a n y s uc h d ata val ues m ust be ke pt as part of t he 
st u d y d oc u me ntati o n al o n g wit h a n e x pla nati o n of w h y it was re q uir e d.  
1 0. 1. 6  
C o m mittees st r uct ure  
1 0. 1. 6. 1  
N o v o N or dis k s af et y c o m mittee  
N o v o N or dis k will perf or m o n g oi n g safet y s ur veilla nce. If ne w s afet y si g nals are i de ntifie d, t hes e 
will be e val uate d b y a n i nter nal safet y c o m mittee.  
1 0. 1. 7  
Disse mi n ati o n of cli nic al st u d y d at a  
St u d y i nf or mati o n 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 a n d, if 
a p plica ble, als o o n ot her nati o nal or re gi o nal st u d y re gistries. It will be discl ose d acc or di n g t o 
a p plica ble re q uire me nts, rele va nt r ec o m me n dati o ns or re g ulati o ns, s uc h as t he Decl arati o n of 
Helsi n ki, 1 6 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),1 8 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), 1 9 E ur o pea n C o m missi o n Re q uire me nts ,1, 2 0, 2 1 E U 
M D R
2 2 a n d i n acc or da nce wit h N o v o N or dis k c o m mit me nt t o cli nical tra ns pare nc y. If a p artici pa nt 
re q uests t o be i ncl u de d i n t he st u d y via t he N o v o N or dis k e-mail c o ntact at t hese we b sit es, N o v o 
N or dis k ma y dis cl ose t he i n vesti gat or’s c o ntact d etails t o t he partici pa nt. 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 ntri es re q uire p u blic discl os ure of i n vesti gat or n a mes a n d 
t heir affiliati o ns. 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
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1
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 of
  Pr ot oc ol  4 9 8 4 v 3. 0
6 0
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6 1  of 1 0 0  
 
1 0. 1. 8  
D at a q u alit y ass ur a nce  
1 0. 1. 8. 1  
C ase  re p ort f or ms  
N o v o N or dis k or desi g nee is res p o nsi ble f or t he d ata ma na ge me nt of t his st u d y i ncl u di n g q ualit y 
c hec ki n g of t he d ata.  
T o de m o nstrate his/ her o versi g ht of t he c ollect e d data, t he i n vesti gat or s h o ul d si g n t he C R F o n a 
re g ular b asis d uri n g t he co n d uct of t he st u d y as well as at t he e n d of t he st u d y, as d escri b e d i n t he 
C R F c o m pleti o n g ui deli n e.  
All partici pa nt data relati n g t o t he st u d y will be rec or de d o n C R Fs  u nless tr a 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 d ata). T he i n vesti gat or is res p o nsi ble f or verif yi n g 
t hat data e ntries are acc urate a n d c orrect b y p h ysi call y or electr o nicall y si g ni n g t he eC R F.  
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  
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 eC R F is re v o k e d or t h e 
eC R F is te m p oraril y u na vaila ble:  
 A E f or ms   
 Safet y i nf or mati o n f or ms  
 Tec h nical c o m plai nt f or ms (als o t o be use d t o re p ort c o m pl ai nts o n st u d y i nter ve nti o n n ot yet 
all ocate d t o a partici pa nt)  
 De vice d eficie n c y t hat c o ul d ha ve le d t o a n S A E f or m  
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 h e C R F a p plicati o n c o ntai ni n g as a mi ni m u m: t he ol d a n d t he  
ne w data, i de ntificati o n of t he pers o n e nteri n g t he data, date a n d ti me of t he e ntr y a n d reas o n f or t he 
c orrecti o n. If c orrecti o ns are ma d e b y t he i n vesti gat or’s dele gate d st aff after t he date w he n  t h e 
i n vesti gat or si g ne d t he C R F, t he C R F m ust be si g ne d a n d date d a gai n b y t he i n vesti gat or. 
T he i n vesti gat or m ust e ns ure t hat data is rec or de d i n t he C R F as s o o n as p ossi ble, prefera bl y wit hi n 
5 w or ki n g d a ys aft er t he visit. O nce data has b ee n e ntere d, it will be a v aila ble t o N o v o N or dis k f or 
data verifi cati o n a n d vali dati o n p ur p oses.  
1 0. 1. 8. 2  
M o nit ori n g  
T he i n vesti gat or m ust per mit st u d y -rel ate d m o nit ori n g, a u dits, I R B/I E C re vie w, a n d re g ul at or y 
a ge nc y i ns pe cti o ns a n d pr o vi de direct access t o s o urce dat a d oc u me nts ( ori gi nal d oc u m e nts, data 
a n d rec or ds). Direct a ccess i ncl u des per missi o n t o e x a mi ne, a nal ys e, verif y a n d re pr o d uce a n y 
rec or d(s) a n d re p ort(s) t hat are i m p orta nt t o t he e v al uati o n of t he st u d y. If t he electr o ni c s o urce data 
d oes n ot ha ve a visi b le 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 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).  
St u d y m o nit ors will  perf or m o n g oi n g s o urce data verificati o n of critical dat a p oi nts 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 orise d site pers o n nel are acc urate, c o m plete a n d verifia ble fr o m 
s o urce d oc u m e nts. St u d y m o nit ors will perf or m o n g oi n g s o urce data re vie w t o e ns ure t hat t he st u d y 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
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1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
6 1
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6 2  of 1 0 0  
 
is bei n g c o n d u cte d i n acc or da nce wit h t he c urre nt a p pr o ve d pr ot o c ol a n d a n y ot her st u d y 
a gree m e nts,  I C H G C P1 7, a n d all a p plica ble re g ulat or y re q uire m e nts, e val uati n g t he a d e q uac y of 
critical pr ocesses at site f or t he e x ec uti o n of t he pr ot oc ol, c ollecti o n of st u d y dat a, t o e ns ure t h at t he 
safet y a n d ri g hts of p artici pa nts are bei n g pr otecte d. 
M o nit ori n g will be c o n d ucte d usi n g a ris k -bas e 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 ass ess me nt of data b y N o v o N or dis k) a n d visits t o sites.  
Q ualit y t olera nce li mits ( Q T Ls) will be pre d efi ne d i n t he r ele va nt m o nit ori n g pla n t o i de ntif y 
s yste matic iss ues t hat ca n i m pact partici pa nt safet y a n d/ or relia bilit y of st u d y res ults. T hese 
pre defi n e d para meters will be m o nit ore d d uri n g t h e st u d y, a n d i m p orta nt de viati o ns fr o m t he Q T Ls 
a n d re me dial acti o ns ta ke n will be s u m marise d i n t he cli nical st u d y re p ort.  
1 0. 1. 8. 3  
Pr ot oc ol c o m pli a nce  
De viati o ns fr o m t he pr ot oc ol s h o ul d be a v oi de d. If de viati o ns d o occ ur, t h e i n vesti gat or m ust 
i nf or m t he m o nit or wit h o ut dela y a n d t he i m plicati o ns of t he de viati o n m ust be re vie we d a n d 
d isc 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 eC R F or vi a listi n gs fr o m t he st u d y data base.  
1 0. 1. 9  
S o urce d oc u me nts  
All data e ntere d i n t he e 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 eC R F .  
If s o urce data is e ntere d directl y i n a pa per C R F, eac h d ata e ntr y or clear series of dat a e ntries m ust 
be si g ne d a n d date d s e paratel y b y t he st u d y staff ma ki n g t he e ntr y.  
T he ori gi nal of t he c o m pl ete d diaries m ust n ot be re m o ve d fr o m t he site, u nless t he y f or m part of 
t he eC R F a n d a c o p y is ke pt at t he site.  
S o urce d oc u me nts pr o vi d e e vi de nce f or t h e e xiste nce of t he p artici pa nt a n d s u bsta ntiate t he 
i nte grit y of t he d ata c ollecte d. S o urce d o c u me nts are file d at t he site. A n y s o urce dat a ge nerate d b y 
i n vesti gat or’s s u b c o ntract ors m ust be arc hi ve d a n d accessi ble b y t h e site. 
Data t hat is tra nscri be d i nt o t he eC R F fr o m s o urce d oc u me nts m ust be c o nsiste nt wit h t he s o urce 
d oc u me nts, or t he discre pa ncies m ust be e x plai ne d. T he i n vesti gat or ma y nee d t o re q u est pre vi o us 
me dical rec or ds or tr a nsf er rec or ds. Als o, c urre nt me dical rec or ds m ust be a vaila ble.  
It m ust be p ossible t o verif y partici pa nt’s me dical hist or y i n s o urce d oc u me nts, s uc h as partici pa nt’s 
me dical rec or d.  
T he i n vesti gat or m ust d oc u me nt a n y atte m pt t o o btai n e xter nal me dical i nf or mati o n b y n oti n g t he 
date(s) w h e n i nf or mati o n was re q u este d, a n d w h o was c o nta ct e d.  
Defi niti o n of w hat c o nstit utes s o urce data ca n b e f o u n d i n a s o urce d o c u me nt a gree me nt at eac h 
site. T here will o nl y b e o ne s o urce d o c u me nt defi ne d at a n y ti me f or a n y d ata ele me nt.  
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
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V V- T M F- 5 9 0 1 0 6 5
 .
-
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1
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 of
  Pr ot oc ol  4 9 8 4 v 3. 0
6 2
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6 3  of 1 0 0  
 
1 0. 1. 1 0  Rete nti o n of cli nic al st u d y d oc u me nt ati o n  
Rec or ds a n d d o c u me nts, i nc l u di n g si g n e d i nf or me d c o nse nt f or ms, pertai ni n g t o t he c o n d u ct of t his 
st u d y m ust be retai n e d b y t he i n vesti gat or f or 2 5 years after e n d of st u d y u nless l ocal re g ulati o ns or 
i nstit uti o nal p olicies re q uire a l o n ger rete nti o n peri o d. N o rec or ds ma y be d estro ye d d uri n g t he 
rete nti o n peri o d wit h o ut t he writte n a p pr o val of N o v o N or dis k. N o rec or ds ma y b e tra nsferre d t o 
a n ot her l ocati o n or p art y wit h o ut writte n n otificati o n t o N o v o N or dis k.  
T he i n vesti gat or m ust be a ble t o access his/ her st u d y d oc u m e 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 bl e, el ectr o nic C R F (e C R F) a n d ot her partici pa nt d ata will be pr o vi de d i n a n 
electr o nic rea d a ble f or m at t o t he i n vesti gat or bef ore access is re v o k e 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 nd ot her p artici pa nt data (i n a n el ectr o ni c rea d a ble f or mat or as 
pa per c o pi es or pri nts) m ust be retai ne d b y t he site. A c o p y of all data will be st ore d b y N o v o 
N or dis k.  
Partici pa nt’s me dical r ec 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 h e h os pital, 
i nstit uti o n or pri vate practice. 
1 0. 1. 1 1  St u d y 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 site or ter mi nate t he st u d y at a n y ti me f or a n y reas o n at 
t he s ole discreti o n of N o v o N or dis k. If t he st u d y 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 partici pa nts pr o m ptl y a n d e ns ure a p pr o priate t hera 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.  
Sites will be cl ose d u p o n st u d y c o m pleti o n. A site is c o nsi dere d cl ose d w he n all re q uire d d o c u me nts 
a n d st u d y s u p plies ha v e bee n c ollecte d a n d a site cl os ure visit has bee n p erf or me d.  
T he i n vesti gat or ma y i nitiate site cl os ure at a n y ti me, pr o vi de d t here is reas o na ble c a 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 site b y N o v o N or dis k or i n vesti gat or m a 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 o c ol, t he re q uir e me nts of t he I R B/I E C or l ocal 
healt h a ut h orities, N o v o N or dis k pr oce d ures or G C P g ui deli nes  
 i na de q uate recr uit me nt of partici pa nts b y t he i n vesti gat or 
 disc o nti n uati o n of f urt her st u d y i nter ve nti o n de v el o p me nt.  
1 0. 1. 1 2  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 st u d y at his/ her site a n d m ust e ns ure a de q u ate 
s u per visi o n of t he c o n d u ct of t he st u d y at t he site. If a n y tas ks are d ele gate d, t he i n vesti gat or m ust 
mai ntai n a l o g of a p pr o priatel y q u alifie d pers o ns t o w h o m he/s he has dele gate d s peci fi e d st u d y-
relate d d uties. T he i n v esti gat or m ust e ns ure t hat t h ere is a d e q uate a n d d oc u me nte d trai ni n g f or all 
staff partici p ati n g i n t he c o n d uct of t he st u d y. It is t he i n vesti gat or’s res p o nsi bilit y t o s u per vise t h e 
c o n d uct of t he st u d y a n d t o pr otect t he  ri g hts, safet y, a n d well-bei n g of t h e partici pa nts.  
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
6 3
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6 4  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 st u d y, m ust be res p o nsi ble 
f or all st u d y-relat e d me di cal 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 o c 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 st u d y a n d t he q ualit y of t he d ata 
pr o d uce d) i n t he i n v esti gat or trial master file. T h e d oc u me nts, i ncl u di n g t he partici pa nt 
i de ntificati o n c o de list m ust be ke pt i n a sec ure l o c ke d facilit y s o t hat n o u na ut h orise d pers o ns ca n 
get access t o t he data.  
T he i n vesti gat or will ta ke all necessar y tec h nical a n d or ga nisati o nal safet y meas ures t o pre ve nt 
acci de nt al or wr o n gf ul d estr ucti o n, l oss or deteri orati o n of dat a. T h e i n vesti gat or will pr e ve nt a n y 
u na ut h orise d access t o data or a n y ot her pr ocessi n g of data a gai nst a p plica ble la w. T his als o 
i ncl u des e ns uri n g t hat n o i n direct s hari n g of user cre de ntials f or I T s yste ms use d i n t his st u d y ta kes 
place (e. g., b y n ot s h ari n g I T e q ui p me nt wit h ot hers i n a wa y w here us er cre de ntials ha ve t he 
p ossi bilit y of bei n g s h are d). T he i n vesti gat or m ust be a ble t o pr o vi de t he n ecessar y i nf or mati o n or 
ot her wise de m o nstrat e 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 v e 
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 
partici pa nts t o a s pecific q ualifie d p h ysi cia n w h o will be rea dil y a vaila bl e t o partici pa nts d uri n g t hat 
ti me. 
If t he i n vesti gat or is n o l o n ger a ble t o f ulfil t he r ole as i n vesti gat or (e. g., if he/s he m o ves or retires), 
a ne w i n vesti gat or will b e 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 v e s ufficie nt E n glis h s kills acc or di n g t o t heir 
assi g ne d t as k(s).  
1 0. 1. 1 3  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 st u dies 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 v e nt of ne gli ge n ce or a n y ot her li a bilit y of t he sites or 
i n vesti gat ors c o n d u cti n g t he st u d y or b y p ers o ns f or w h o m t he sai d site or i n vesti gat or are 
res p o nsi ble. 
N o v o N or dis k carries  lia bilit y i n a cc or da nce wit h c o u ntr y-s pecific re q uire me nts of P ola n d. Please 
refer t o A p pe n di x 1 0  ( Secti o n 1 0. 1 0 ).  
1 0. 1. 1 4  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 st u d y 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 w ell as f or t he ge neral 
de vel o p me nt of t he st u d y i nter ve nti o n. All i nf or mati o n s u p plie d b y N o v o N or dis k i n c o n necti o n 
wit h t his st u d y 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 N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
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V V- T M F- 5 9 0 1 0 6 5
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1
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 of
  Pr ot oc ol  4 9 8 4 v 3. 0
6 4
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6 5  of 1 0 0  
 
N o c o nfi de ntial i nf or mati o n s hall be discl ose d t o ot hers wit h o ut pri or writte n c o nse nt fr o m N o v o 
N or dis k. S uc h i nf or mati o n s hall n ot be  use d e x ce pt i n t he perf or ma n ce of t his st u d y.  
T he i nf or mati o n o btai ne d d uri n g t his st u d y 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 st u dies wit h t he st u d y i nter ve nti o n, if dee me d necessar 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 st u d y t o res earc hers w h o re q uire access f or researc h pr ojects st u d yi n g t he s a me 
or relate d dise ases a n d/ or st u d y i nter ve nti o n st u die d i n t his st u d y.  
N o v o N or dis k ma y p u blis h o n its cli nical st u dies we bsite a re dact e d C S R f or t his st u d y.  
O ne i n vesti gat or 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 C S R (si g nat or y 
i n vesti gat or) o n b e half of all partici pati n g i n v esti gat ors. 
1 0. 1. 1 4. 1  
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 st u dies re gar dless of o utc o me. 
Discl os ure i ncl u des p u bli cati o n of a ma n us cri pt i n a peer -re vi e we d s cie ntific j o ur nal, a bstract 
s u b missi o n wit h a p oster or oral pres e ntati o n at a s cie ntific meeti n g or discl os ure b y ot her mea ns.   
T he res ults of t his st u d y will be s u bject t o p u blic discl os ure o n e xter nal we b sites acc or di n g t o 
i nter nati o nal a n d nati o nal re g ulati o ns. N o v o N or dis k reser ves t he ri g ht t o defer t h e release of data 
u ntil s pecifie d milest o ne s are reac he d, f or e x a m ple w he n t he C S R is a vaila ble. T his i ncl u des t he 
ri g ht n ot t o rele ase t he res ults of i nteri m a nal yses, beca use t h e rel ease of s uc h i nf or mati o n ma y 
i nfl ue nce t he res ults of t he e ntire st u d y. 
At t he e n d of t he st u d y, o ne or m ore sci e nt ific p u blicati o ns ma y be pre p are d c olla b orati vel y b y t he 
i n vesti gat or(s) a n d N o v o N or dis k. N o v o N or dis k reser ves t he ri g ht t o p ost p o ne p u blicati o n a n d/ or 
c o m m u nicati o n f or u p t o 6 0 da ys t o pr ot ect i ntellect ual pr o pert y.  
I n all cases, t he st u d y res ults will be re p orte d i n a n o bjecti ve, acc urat e, bal a nce d a n d c o m plete 
ma n ner, wit h a disc ussi o n of t he stre n gt hs a n d li mitati o ns. I n t he e v e nt of a n y disa gree me nt o n t he 
c o nte nt of a n y p u blicati o n, b ot h t he i n vesti gat ors’ a n d N o v o N or dis k o pi ni o ns will be fairl y a n d 
s ufficie ntl y re prese nte d i n t he p u blicati o n. 
1 0. 1. 1 4. 2  
A ut h ors hi p  
N o v o N or dis k will w or k wit h o ne or m ore i n vesti gat or(s) a n d ot h er e x perts w h o ha ve c o ntri b ute d t o 
t he st u d y c o n ce pt or d esi g n, ac q uisiti o n, a nal ysis or i nter pretati o n of d ata t o re p ort t he res ults i n o ne 
or m ore p u blicati o ns.  
A ut h ors hi p of p u blicati o ns s h o ul d be i n acc or da n ce wit h t he Rec o m me n d ati o ns f or t he C o n d uct, 
Re p orti n g, E diti n g a n d P u blicati o n of Sc h olarl y W or k i n Me dical J o ur nals b y t he I nt er nati o nal 
C o m mittee of Me dical J o ur nal E dit ors. 2 3 
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 d e d t o 
e val uate t he pla n n e d p u blicati o n.  
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
6 5
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6 6  of 1 0 0  
 
W here re q uir e d b y t he j o ur nal, t he i n vesti gat or fr o m eac h site will be na me d i n a n 
ac k n o wle d ge me nt or i n t he s u p ple me ntar y mat eri al, as s pecifie d b y t h e j o ur nal.   
1 0. 1. 1 4. 3  
Site -s pecific p u blic ati o n(s) b y i n vesti g at or(s) 
F or a m ultice ntr e cli nical st u d y, a n al ys es base d o n si n gle -site dat a us uall y h a 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 d e mea ni n gf ul i nf or mati o n f or healt hcare 
pr o fessi o nals or partici pa nts, a n d t heref ore ma y n ot be s u p p orte d b y N o v o N or dis k. T h us, N o v o 
N or dis k ma y d e n y a re q u est or as k f or d efer 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 pt e d f or p u blicati o n. I n li ne wit h G o o d P u blicati o n Practice, s u c h 
i n di vi d ual re p orts s h o ul d n ot prece d e t he pri mar y ma n uscri pt a n d s h o ul d al wa ys refere nce t h e 
pri mar y ma n uscri pt of t h e st u d y.  
1 0. 1. 1 4. 4  
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 st u d y d ata base, N o v o N or dis k has  t he discreti o n t o deter mi ne 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 researc h partici p a nts’ data a n d will be pr o vi de d wit h 
t he ra n d o misati o n c o de after res ults are a v aila ble. 
 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
6 6
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6 7  of 1 0 0  
 
1 0. 2  A p pe n di x  2: Cli nic al l a b or at or y tests 
T he tests detaile d i n Ta bl e  1 0 -1  t o Ta ble  1 0 -5  will be perf or me d b y  t he ce ntral la b orat or y u nl ess 
ot her wise n ote d.  
A d diti o nal tests ma y be p erf or me d at a n y ti me d uri n g t he st u d y as d eter mi ne d necessar y b y t he 
i n vesti gat or or re q uir e d b y l ocal re g ulati o ns. 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 n al 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 ce ntr al la b will c o m m u nicate t o t he i n vesti gat or a b n or mal val ues of para meters n ot re q ueste d i n 
t he pr ot oc ol b ut i de ntifie d b y t he la b orat or y e q ui p me nt a n d/ or t heir pr ocess es acc or di n g t o t heir 
la b orat or y S O Ps. T hese d ata will n ot be tra nsferre d t o t he st u d y data base. T he i n vesti gat or s h o ul d 
re vie w s uc h v al ues f or A Es a n d re p ort t hese acc or di n g t o t his pr ot oc ol. 
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.  
T he i n vesti gat or m ust kee p a n o ver vi e w, e. g. a l o g, of la b orat or y s a m ples n ot  ha n dle d acc or di n g t o 
t he la b orat or y ma n u al. I n a d diti o n, t he i n vesti gat or m ust kee p a n o ver vi e w, e. g. a l o g, of la b orat or y 
sa m ples st ore d at site. 
La b orat or y s a m ples will be destr o ye d n o lat er t ha n at e n d of st u d y or n o later t ha n at fi nalisati o n of 
t he CS R.  
H u ma n bi osa m ples f or f ut ure researc h  a n d resi d ual a nti b o d y sa m ples  will b e st ore d as des cri be d i n 
A p pe n di x  7 ( Secti o n  1 0. 7 ). 
U S: F or c o u ntr y -s p ecific re q uire me nts; pleas e see A p pe n di x 1 0 ( Secti o n 1 0. 1 0 ). 
T a ble  1 0 -1  
Pr ot oc ol -req 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  
Visits  
Gl uc ose meta b olis m  
  
 H b A 1c  
V 1, V 2, V 3, V 4, V 5, V 6, V 8, V 1 0, 
V 1 2, V 1 3, V 1 4, V 1 5  
 Fasti n g plas ma gl uc ose a, b 
V 2, V 3, V 4, V 5, V 6, V 8, V 1 0, V 1 5  
 
 Fasti n g i ns uli n b 
 Fasti n g gl uca g o n b 
 Fasti n g C -pe pti de b 
 H O M A B  
 H O M A I R  
 B eta -h y dr o x y b ut yrate  
N otes:  
a A n F P G res ult < 3. 9 m m ol/ L ( 7 0 m g/ d L) i n relati o n t o pla n ne d fasti n g visits s h o ul d n ot b e re p orte d as a 
h y p o gl ycae mic e pis o de b ut as a n A E at t he discreti o n of t he i n vesti gat or ( A p pe n di x 3, Secti o n  1 0. 3 ). 
b Assess me nt t o be d o ne i n fasti n g state (see Secti o n 5. 3. 1 ). 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
6 7
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6 8  of 1 0 0  
 
T a ble  1 0 -2  
Pr ot oc ol -re q uire d s af et 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  
Visits  
Hae mat ol o g y  
 B as o p hils  
 E osi n o p hils  
 Er yt hr oc ytes  
 Hae m o gl o bi n  
 Le uc o c ytes  
 L y m p h oc ytes  
 Mea n c or p usc ular v ol u me  
 M o n oc ytes  
 Ne utr o p hils  
 T hr o m b oc ytes  
V 1, V 1 0, V 1 5  
Bi oc he mistr y a 
 
 Ala ni ne A mi n otra nsferase ( A L T)  
 Al kali ne p h os p hatase  
 A m ylase  
 As partate A mi n otra nsferase ( A S T)  
 Bilir u bi n  
 Calci u m  
 Creati ni ne  
 Li pase  
 P h os p hate  
 P otassi u m  
 S o di u m  
V 1, V 6, V 8, V 1 0, V 1 2, V 1 5  
Li pi ds b 
  
 Free fatt y aci ds  
 Hi g h de nsit y li p o pr otei n c h olester ol  
 L o w de nsit y li p o pr otei n c h olester ol  
 T otal c h olester ol  
 Tri gl yceri des  
 Ver y l o w de nsit y li p o pr otei n c h olester ol  
V 2, V 3, V 4,  V 5, V 6, V 8, V 1 0, V 1 5  
Pre g na nc y T esti n g c  
 Hi g hl y se nsiti ve 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  
V 1, V 2, V 1 5, V 1 7  
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  
V 1, V 6, V 8, V 1 0, V 1 2, V 1 5  
 Uric aci d  
V 2, V 3, V 4, V 5, V 6, V 8, V 1 0, V 1 5  
 hs -C R P  
V 2, V 3, V 4, V 5, V 6, V 8, V 1 0, V 1 5  
 Bi osa m ples f or f ut ure researc h  
V 2, V 3, V 4, V 5, V 6, V 8, V 1 0, 
V 1 2, V 1 5  
N otes:  
a Details 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 are gi ve n i n A p pe n di x  3 
( Secti o n 1 0. 3 ) ( H y’s La w).  
b Assess me nt t o be d o ne i n fasti n g state (see Secti o n 5. 3. 1 ). 
c F or w o me n of c hil d beari n g p ote ntial, as nee de d, l ocal uri ne testi n g will be sta n dar d u nless ser u m testi n g is re q uire d 
b y l ocal re g ulati o n or  I R B/I E C, see A p pe n di x 4 ( Secti o n  1 0. 4 ). 
 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
6 8
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6 9  of 1 0 0  
 
T a ble  1 0 -3  
Pr ot oc ol -re q uire d P K assess me nts  
L a b or at or y assess me nts  
P ar a meters  
Visits  
P har mac o ki netics a, b 
 Se ma gl uti de plas ma c o nce ntrati o n  
V 3, V 4, V 6, V 8, V 1 0, V 1 2, V 1 4, 
V 1 5, V 1 7  
N otes:  
a A nal ysis will be perf or me d b y a s pecial la b orat or y c o ntract e d b y N o v o N or dis k.  
b Res ults will n ot b e pr o vi de d t o t he i n vesti gat or . T hese res ults will n ot be use d f or a n y cli nical e val uati o n d uri n g t he 
st u d y u nless  it is deci de d t o c o n d uct i nteri m a nal yse s. 
 
T a ble  1 0 -4  
Pr ot oc ol -re q uire d a nti b o d y assess me nts  
L a b or at or y assess me nts  
P ar a meters  
Visits  
A nti b o dies a, b 
 
 
 A nti -Se ma gl uti de A nti b o d y C o nfir mati o n 
( P ositi ve/ Ne gati ve) 
 A nti -se ma gl uti de A nti b o dies le vel ( Titer)  
 A nti b o dies cr oss reacti n g wit h nati ve G L P -1 
( P ositi ve/ Ne gati ve) 
V 2, V 3, V 4, V 6, V 1 0, V 1 5, V 1 7  
 Se ma gl uti de A B ( ne utralisi n g effect) 
( P ositi ve/ Ne gati ve)  
V 1 7  
 A nti b o dies ne utralisi n g nati ve G L P -1 
( P ositi ve/ Ne gati ve) 
V 1 7  
N otes:  
a A nal yses will be perf or me d b y a s pecial la b orat or y c o ntracte d b y N o v o N or dis k, wit h t he e xce pti o n of ne utralisi n g 
a nti b o dies assess me nt, w hic h will b e perf or me d b y N o v o N or dis k la b orat or y.  
b Res ults will n ot b e pr o vi de d t o t he i n vesti gat or, as t hese res ults will n ot be use d f or a n y cli nical e val uati o n d uri n g t he 
st u d y. 
 
T a ble  1 0 -5  
Pr ot oc ol -re q uire d bi o m ar kers  
L a b or at or y assess me nts  
P ar a meters  
Visits  
Bi o mar kers a  
 B N P  
V 2, V 1 5  
 C T XI b 
V 2, V 1 5  
 GI P  
V 2, V 3, V 4, V 5, V 6, V 8, V 1 0, V 1 5  
 P 1 N P b 
V 2, V 1 5  
 Le pti n b , c 
V 2, V 1 0, V 1 5  
 S ol u ble le pti n rece pt or b , c 
V 2, V 1 0, V 1 5  
N otes:  
a Res ults will n ot b e pr o vi de d t o t he i n vesti gat or, as t hese res ults will n ot be use d f or a n y cli nical e val uati o n d uri n g t he 
st u d y. 
b Assess me nt t o be d o ne i n fasti n g state (see Secti o n 5. 3. 1 ). 
c A nal ysis will be perf or me d b y a s pecial la b orat o r y c o ntract e d b y N o v o N or dis k . 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
6 9
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
7 0  of 1 0 0  
 
1 0. 3  A p pe n di x  3: A d verse E ve nts a n d Seri o us A d verse E ve nts: Defi niti o ns a n d pr oce d ures 
f or rec or di n g, e v al u ati n g, f oll o w-u p, a n d re p orti n g  
F or defi niti o ns a n d pr oce d ure f or rec or di n g, e val u ati o n, f oll o w -u p a n d re p orti n g c o n cer ni n g t he 
me dical de vice us e d o utsi de a p pr o val, please als o refer t o A p pe n di x  6 ( Secti o n  1 0. 6 ). 
1 0. 3. 1  
Defi niti o n of A E  
A n A E is a n y u nt o war d me dical occ urre n ce i n a cli nical st u d y partici pa nt t hat is te m p orall y 
ass ociate d wit h t he use of I M P, w het her or n ot c o nsi dere d rel ate d t o t he I M P. A n A E ca n t heref ore 
be a n y u nfa v o ura ble a n d u ni nte n de d si g n (i n cl u di n g a n a b n or m al la b orat or y fi n di n g), s y m pt o m or 
disease ( ne w or e x acer bate d) te m p orall y ass oci ate d wit h t he use of a I M P.  
E ve nts t o be re p orte d as A Es:  
 A n y a b n or mal la b orat or y test res ults or safet y ass ess me nts c o nsi dere d cli nicall y si g nifica nt i n 
t he me dical a n d sci e ntific j u d g me nt of t h e i n vesti gat or, i n cl u di n g e ve nts t h at ha ve w ors e ne d 
fr o m pri or t o t he ti me p oi nt fr o m w hic h A Es are c ollecte d 
 C o n diti o ns detecte d or dia g n os e d aft er I M P a d mi nistrati o n e ve n t h o u g h it ma y h a ve bee n 
prese nt pri or t o t he ti me p oi nt fr o m w h ic h A Es are c ollecte d 
 E x acer bati o n/ w orse ni n g of a c hr o ni c or i nter mitte nt c o n diti o n i ncl u di n g eit her a n i ncreas e i n 
fre q ue n c 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 nical se q uelae of a s us p ecte d dr u g -dr u g i nteracti o n  
 Si g ns, s y m pt o ms or  t he cli nical se q uelae of a s us p ecte d o ver d ose of I M P re gar dless of i nte nt 
A ‘lac k of effi cac y’ or ‘fail ure of e x pecte d p har m ac 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 ur e d i n t he efficac y ass ess me nts. H o we ve r, 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 t o be re p orte d as A Es:  
 C o n diti o ns prese nt pri or t o t he ti me p oi nt fr o m w hic h A Es are c ollecte d a n d a ntic i pate d da y-t o-
da y fl uct uati o ns of t hese c o n diti o ns. T his i ncl u des t h ose c o n diti o ns i de ntifie d d uri n g scree ni n g 
or i de ntifie d d uri n g ot her st u d y pr oce d ures perf or me d bef ore e x p os ure t o I M P.  
N ote: C o n diti o ns prese nt or occ urri n g pri or t o t he ti me p oi nt fr o m  w hic h A Es are c ollecte d 
s h o ul d be rec or de d as c o nc o mita nt ill ness/ me dical hist or y. 
 Me dical or s ur gic al pr oce d ures ( e. g., e n d osc o p y, a p pe n dect o m y). T he c o n diti o n t hat lea ds t o t he 
pr oce d ure is t he A E.  
 Me dical or s ur gic al pr oce d ures n ot prece d e d b y a n A E or  w orse ni n g of a k n o w n c o n diti o n.  
1 0. 3. 2  
Defi niti o n of a n S A E  
A n S A E is a n y u nt o w ar d me dical occ urre n ce t hat f ulfils at least o ne of t he f oll o wi n g criteria:  
 Res ults i n de at h  
 Is lif e-t hre ate ni n g 
 T he ter m ‘life -t hreat e ni n g’ refers t o a n e v e nt i n w hic h t he partici pa nt w as 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 hi c h h y p ot h eticall y mi g ht ha ve ca use d deat h, if 
it were m ore s e 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  
N N 9 5 3 5- 4 9 8 4
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C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
7 1  of 1 0 0  
 
 H os pitalisati o n si g nifies t h at t he partici pa nt has b ee n a d mitte 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 pri ate i n t he p h ysici a n’s 
office or o ut p atie 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 s eri o us ness 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 necessar 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 ( e. g., e lecti ve me dical or s ur gi cal pr o ce d ures) of a 
c o n diti o n t hat was prese nt pri or t o t he ti me p oi nt fr o m w hic h A Es are c ollecte d, a n d t hat di d n ot 
w orse 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 nistrati ve, st u d y -relate d, s ocial a n d c o n ve nie nce reas o ns 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 me dical or s ur gical pr oce d ures, pla n ne d bef ore st u d y i ncl usi o n, are n ot c o nsi dere d A Es 
or S A Es  
 Res ults i n persiste nt or si g nific a 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 rel ati vel y mi n or me dical 
si g nifica n ce, s uc h as u nc o m plicate d hea dac he, n a usea, v o miti n g, diarr h oea, i nfl ue nza, a n d 
acci de nt al tra u ma (e. g., s prai ne d a n kle), t hat ma y i nterfere wit h or pre v e nt e ver y da y life 
f u ncti o ns b ut d o n ot c o nstit ute a s u bsta ntial disr u pti o n. 
 Is a c o n ge nit al a n o m al y/ birt h defect 
 I m p ort a nt me dic al e v e nt: 
 Me dical or sci e ntifi c j u d g me nt s h o ul d be e x ercise d b y t he i n vesti gat or i n d eci di n g w het her S A E 
re p orti n g is a p pr o priat e 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 je o par dise t he 
partici pa nt or ma y re q uir e me dical or s ur gi cal 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 s eri 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 criter i o n. 
 T he f oll o wi n g m ust be re p orte d as a n S A E usi n g t he i m p orta nt me dical e ve nt criteri o n if n o 
ot her seri o us ness criteria are a p plica ble:  
o  
S us pici o n of tra ns missi o n of i nfecti o us a ge nts via I M P  
o  
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 parate 
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)  
1 0. 3. 3  
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 a n d ot her e ve nts re q uiri n g 
c ollecti o n of a d diti o n al i nf or m ati o n   
A d verse e v e nts  re q uiri n g a d diti o n al d at a c ollecti o n  
A n A E re q uiri n g a d diti o nal data c ollecti o n is a n A E w here N o v o N or dis k has e val uate d t h at 
a d diti o nal data is nee de d i n t he e val uati o n of safet y.  
Ac ute ki d ney i nj ury  
E ve nts of a n a br u pt or ra pi d decli ne i n re nal filtrat i o n f u ncti o n. T his c o n diti o n is us uall y mar ke d b y 
a rise i n ser u m creati ni ne c o nce ntr ati o n or b y az ote mia (a rise i n bl o o d urea nitr o ge n [ B U N] 
c o nce ntr ati o n) . 
N N 9 5 3 5- 4 9 8 4
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Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
7 2  of 1 0 0  
 
Di a betic reti n o p at hy  
Ne w o nset or w orse ni n g of dia betic reti n o pat h y . 
G all bl a d der dise ase  
E ve nts of s y m pt o matic ac ute gall bla d der dis ease (i ncl u di n g gallst o nes a n d c h olec ystitis).  
He p atic eve nt  
He patic e v e nt defi ne d as:  
 Dis or ders of t he li ver i ncl u di n g c h olestatic c o n diti o ns a n d li ver relat e d si g ns a n d s y m pt o ms  
 A L T or A S T > 3 x U N L a n d t otal bilir u bi n > 2 x U N L *  
 A L T or A S T > 3 x U N L wit h t he a p peara nce of fati g ue, na us ea, v o miti n g, ri g ht u p per q u a dra nt 
pai n or te n der ness, fe v er, ras h, a n d/ or e osi n o p hilia ( > 5 %)  
* Please n ote t hat i n cas e of a he patic e ve nt defi ne d as A L T or 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), t his m ust be re p orte d as a n S A E usi n g t h e 
i m p orta nt me dical e ve nt criteri o n if n o ot her seri o us ness criteria are a p plica ble. 
Hy perse nsitivity re acti o ns  
All e ve nts of h y pers e nsiti vit y reacti o ns ( p o ssi bl y ca use d b y aller gic reacti o ns, i m m u ne c o m ple x 
disease a n d a nti -se ma gl uti de a nti b o d y f or mati o n). 
Ne o pl as ms ( m ali g n a nt a n d n o n -m ali g n a nt)  
All e ve nts of ne o plas ms . 
Ac ute p a ncre atitis  
T he dia g n osis of ac ut e pa ncreatitis re q uir es t w o of t he f oll o wi n g t hr e e feat ur es:  
 a b d o mi nal pai n c o nsiste nt wit h ac ute pa ncreatitis (ac ute o nset of a persiste nt, se vere, e pi gastric 
pai n ofte n ra di ati n g t o t h e bac k)  
 ser u m li pase acti vit y (a n d/ or a m ylas e acti vit y) at l east t hree ti mes greater t ha n t he u p per li mit of 
n or mal  
 c haracteristic fi n di n gs of ac ute pa n creatitis o n i ma gi n g 
 
Me dic ati o n err or:  
A me dicati o n err or is a n u ni nte n de d fail ure i n t he I M P treat me nt pr ocess t hat lea ds t o, or has t he 
p ote ntial t o lea d t o, har m t o t he partici pa nt, s uc h as:  
 a d mi nistrati o n of wr o n g dr u g  a n d/ or use of wr o n g de vice  
N ote: Use of wr o n g D U N is n ot c o nsi dere d a me dicati o n err or u nl ess it res ults i n a d mi nistrati o n 
of wr o n g dr u g.  
 wr o n g r o ute of a d mi nistrati o n, s uc h as i ntra m usc ular i nstea d of s u bc ut a ne o us  
 acci de nt al a d mi nistrati o n of a  hi g h er d o s e t ha n i nte n de d. T he a d mi nistere d d ose m ust de viate 
fr o m t he i nte n de d d ose t o a n e xte nt w here cli nical c o nse q ue nces f or t h e st u d y partici pa nt were 
li kel y t o ha p pe n as j u d ge d b y t he i n vesti gat or, alt h o u g h t he y di d n ot necess aril y o cc ur. 
N N 9 5 3 5- 4 9 8 4
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7 2
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
7 3  of 1 0 0  
 
Mis use a n d a b use:  
 Sit uati o ns w here t he I M P is i nte nti o nall y a n d i na p pr o priatel y use d n ot i n acc or da nce wit h t he 
pr ot oc ol (e. g., o ver d ose t o ma xi mise effect)  
 Persiste nt or s p ora dic, i nt e nti o nal e xcessi ve use of a n I M P w hic h is acc o m pa nie d b y har mf ul 
p h ysical or ps yc h ol o gical  effects (e. g., o v er d ose wit h t he i nte nti o n t o ca use har m)  
N ote: Me dicati o n err or, mis use a n d a b use m ust al wa ys be re p orte d o n a n A E f or m a n d a s pecific 
e ve nt f or m m ust be c o m plete d. T he A E dia g n osis o n t he A E f or m m ust refl ect w hat occ urre d (e. g., 
acci de nt al o ver d ose, i nte nti o nal o ver d ose or ot her). If t he me dicati o n err or a n d/ or mis use a n d a b use 
res ulte d i n a cli nical c o ns e q ue nce, t his m ust be re p orte d o n a n a d diti o nal A E f or m. 
Ot her eve nts re q uiri n g c ollecti o n of a d diti o n al i nf or m ati o n  
H y p o gl ycae mic e pis o des : 
All h y p o gl ycae mic e pis o des m ust be rec or de d o n a h y p o gl ycae mic e pis o de f or m. If t he 
h y p o gl ycae mic e pis o de f ulfills t he criteria f or a n S A E, t he n i n a d diti o n t o t he h y p o gl ycae mic 
e pis o de f or m, a n A E f or m a n d a safet y i nf or mati o n f or m m ust be fille d i n . O ne A E f or m a n d safet y 
i nf or mati o n f or m ca n c o ver se veral h y p o gl ycae mic e pis o de f or ms, if t he p artici pa nt has n ot 
rec o vere d b et wee n t h e e pis o des. 
1 0. 3. 4  
Rec or di n g a n d f oll o w -u p of A E a n d/ or S A E  
1 0. 3. 4. 1  
A E a n d S A E rec or di n g  
T he i n vesti gat or will rec or d all rele v a nt A E/ S A E i nf or mati o n i n t he eC R F.  
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 u c h cas es, t he dia g n osis ( n ot t he i n di vi d ual si g ns/s y m pt o ms) will be 
d oc u me nte d as t he A E/ S A E.  
W he n a n A E/ S A E occ urs, it is t he res p o nsi bilit y of t he i n vesti gat or t o re vie w all d oc u me ntati o n 
(e. g., h os pital pr o gress n otes, la b orat or y a n d di a g n ostics re p orts) relate d t o t he e ve nt. 
T here ma y b e i nsta nces w he n c o pies of s o urce d o c u me nts (e. g., me dical rec or ds) f or certai n cas es 
are re q ueste d b y N o v o N or dis k. I n s u c h cas es, all partici pa nt i de ntifiers, wit h t he e x ce pti o n of t he 
s u bject I D, m ust be re d acte d o n t he c o pies of t he s o urce d oc u m e nts bef ore s u b missi o n t o N o v o 
N or dis k.  
F or all n o n -s eri o us A Es, the 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 st u d y at t he lat est. F or si g n -off of S A E -relate d f or ms, refer t o “ A E a n d 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 di cati o n: if a n A E is c o nsi d ere 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 st u d y, 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 s ecti o n o n t he s afet 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 v a nt re g ulat or y a ut h orities . 
N N 9 5 3 5- 4 9 8 4
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C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
7 4  of 1 0 0  
 
1 0. 3. 4. 2  
Assess me nt of se verit y  
T he i n vesti gat or will assess se verit y f or eac h e ve nt re p orte d d uri n g t he st u d y a n d assi g n it t o o ne of 
t he f oll o wi n g cate g ori es: 
 Mil d : A n e ve nt t hat is easil y t olerate d b y t h e parti ci pa nt, ca usi n g mi ni mal disc o mf ort a n d n ot 
i nterferi n g wit h e v er 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 d a y 
acti vities. 
 Se vere : A n e ve nt t hat pr e ve nts n or mal e ver y da y acti vities.  
N ote: A n A E t hat is assesse d as se vere s h o ul d n ot be c o nf use d wit h a n S A E. B ot h A Es a n d 
S A Es ca n be ass esse d as se vere.  
1 0. 3. 4. 3  
Assess me nt of c a us alit y  
T he i n vesti gat or is o bli gate d t o assess t he relati o n s hi p bet wee n I M P a n d t he occ urre nce of eac h 
A E/ S A E. T he i n vesti gat or will use cli nical j u d g me nt t o deter mi ne t he relati o ns hi p.  
Relati o ns hi p bet wee n a n A E/ S A E a n d t he rele va nt I M P s h o ul d be ass esse d as:  
 Pr o b a ble  - G o o d reas o n a n d s ufficie nt d oc u m e ntati o n t o ass u me a ca usal r elati o ns hi p. 
 P ossi ble  - A ca usal r elati 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 h e I M P.  
Alter nati ve aeti ol o g y, s u c h as u n derl yi n g diseas e(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 or al relati o ns hi p of t he e ve nt t o I M P a d mi nistrati o n, s h o ul d be c o nsi dere d a n d 
i n vesti gate d. 
T he i n vesti gat or s h o ul d  use t he i n vesti gat or’s br oc h ure a n d/ or pr o d uct i nf or mati o n, f or mar kete d 
pr o d ucts, 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 h e/s he has r e 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 us alit y. 
T here ma y b e sit uati o ns i n w hic h a n S A E has occ urre d, a n d t h e i n vesti gat or has mi ni ma l 
i nf or mati o n t o i ncl u de i n t he i nitial re p ort. H o we v er, it is i m p ort a nt t h at t he i n vesti g at or al w a ys 
m a kes a n assess me nt of c a us alit y f or e ver y e ve nt bef ore t he i niti al tr a ns missi o n of t he S A E 
d at a . 
T he i n vesti gat or ma y c h a 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 eC R F.  
T he ca us alit y ass ess 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 
1 0. 3. 4. 4  
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 h e partici pa nt has f ull y rec o vere d, or b y m e 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 w he n first d oc u me nte d 
 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 h e partici pa nt is e x pecte d to rec o ver 
fr o m t he e ve nt.  T his ter m ma y als o be a p plica ble f or A Es o n g oi n g at t he ti me of deat h ( w here 
deat h was d ue t o a n ot her A E).  
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
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V V- T M F- 5 9 0 1 0 6 5
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7 4
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
7 5  of 1 0 0  
 
N ote: F or S A Es, t his ter m is o nl y a p plica ble if t h e partici pa nt has c o m plete d t he f oll o w -u p 
peri o d a n d is e x pecte d t o rec o ver.  
 Rec o vere d/res ol ve d wit h se q uel ae : T he partici pa nt has rec o vere d fr o m t h e c o n diti o n b ut wit h 
lasti n g effect d u e t o a dis ease, i nj ur y, treat me nt or pr oce d ure. If a se q uel a 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 o l ve d: T he c o n diti o n of t he partici pa nt has n ot i m pr o ve d, a n d t he 
s y m pt o ms are u n c ha n ge d, or t he o utc o me is n ot k n o w n. T his ter m ma y b e a p plica ble i n cases of 
c hr o nic c o n diti o ns, ca n cer or A Es o n g oi n g at ti me of deat h ( w h ere d eat h is d ue t o a n ot her A E).  
 F at al : T his ter m is o nl y a p plica ble if t he partici pa nt die d fr o m a c o n diti o n relate d t o t he 
re p orte d A E. O utc o mes of ot her re p orte d A Es i n a partici pa nt bef ore he/s h e die d s h o ul d be 
assesse d as ‘rec o vere d/res ol ve d’, ‘rec o veri n g/r es ol vi n g’, ‘rec o v ere d/r es ol v e d  wit h se q uelae’ or 
‘ n ot rec o v ere 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 partici pa nt is l ost t o f oll o w-u p  
1 0. 3. 4. 5  
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 g e f or t he c o n d u ct of s u p ple me ntal meas ure me nts 
a n d/ or e val uati o ns as me dicall y i n dicat e 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 ur e 
a n d/ or ca us alit y of t he A E or S A E as f ull y as p ossi ble (e. g., se vere h y perse nsiti vit y reacti o ns, H y’s 
la w). T his ma y i ncl u de a d diti o nal la b orat or y tests 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.  
If a partici pa nt dies d uri n g partici pati o n i n t he st u d y or d uri n g a rec o g nise d f oll o w-u p peri o d, t he 
i n vesti gat or s h o ul d, u p o n re q uest, pr o vi de N o v o N or dis k wit h a c o p y of t he a ut o ps y re p ort 
i ncl u di n g hist o pat h ol o g y, if a vaila ble.  
Ne w or u p d ate d i nf or mati o n s h o ul d be rec or de d i n t he eC R F.  
1 0. 3. 5  
Re p orti n g of S A Es  
A E a n d S A E re p orti n g vi a C R F  
Rele va nt f or ms m ust be c o m plete d i n t he eC R F.  
F or S A Es, 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 h e nee d f or 
t he i n vesti gat or t o c o m plete t he A E a n d s afet y i nf or mati o n f or ms wit hi n t he desi g n ate d re p orti n g 
ti meli nes (see F i g ure 1 0 -1 ): 
 A E f or m wit hi n 2 4  h o urs  
 Safet y i nf or mati o n f or m wit hi n 5  cale n dar da ys  
 B ot h f or ms m ust be si g n e d wit hi n 7  cale n dar da ys after first k n o wle d ge b y t he i n vesti gat or. 
 S pecific e ve nt f or m wit hi n 1 4  cale n dar da ys.  
If t he e C R F is u na v aila ble f or m ore t h a n 2 4 h o urs, t he n t he sites will use t he pa per A E f or m, a n d if 
t he e C R F is u na vaila ble f or m ore t ha n 5 cale n dar da ys, t he n t he site will use t he pa per safet y 
i nf or mati o n f or m. T he sit e s h o ul d e nter t he S A E d ata i n t he e C R F as s o o n as it bec o mes a vaila ble. 
T he rele v a nt C R F f or ms ( A E a n d safet y i nf or mati o n f or ms) m ust be f or war de d t o N o v o N or dis k i n 
acc or da nce wit h Secti o n  1 0. 1. 5 . 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
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1
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 of
  Pr ot oc ol  4 9 8 4 v 3. 0
7 5
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
7 6  of 1 0 0  
 
After t he st u d y is c o m plete d, t he st u d y dat a base will be l oc ke d, a n d t he eC 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 v e s a 
re p ort of a n e w S A E fr o m a partici pa nt or recei ves u p date d i nf or mati o n o n a pre vi o usl y re p orte d 
S A E after eC R F dec o m missi o 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 bel o w) or t o N o v o N or dis k b y tele p h o n e. 
 
 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
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1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
7 6
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
7 7  of 1 0 0  
 
F i g ure 1 0 -1  Decisi o n tree f or deter mi ni n g t he e ve nt t y pe a n d t he res pecti ve f or ms t o 
c o m plete wit h ass oci ate d ti meli nes  
 
 
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 tri al master file. 
 
 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
7 7
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
7 8  of 1 0 0  
 
1 0. 4  A p pe n di x  4: 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  
1 0. 4. 1  
Defi niti o ns  
W o m a n of c hil d be ari n g p ote nti al ( W O C B P)  
A w o ma n is c o nsi dere d fertile f oll o wi n g m e narc h e a n d u ntil bec o mi n g p ost me n o pa usal u nless 
per ma ne ntl y  sterile. 
If fertilit y is u nclear (e. g., a me n orr hea i n a d oles ce nts or at hletes), a n d a me nstr ual c ycle ca n n ot be 
c o nfir me d bef ore first d ose of st u d y i nter ve nti o n, a d diti o nal e val uati o n s h o ul d be c o nsi dere d.  
Fe m ales i n t he f oll o wi n g c ate g ories are n ot c o ns i dere d W O C B P 
1.  Pre me narc heal  
2.  Fe males wit h o ne or m or e of t he f oll o wi n g:  
 
D oc u me nte d t otal 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  
F or fe males wit h per m a n e nt i nfertilit y d ue t o a n alter nate me dical ca us e ot her t ha n t he  a b o v e 
(e. g., M ülleria n a ge nesis, a n dr o ge n i nse nsiti vit y), i n vesti gat or discreti o n s h o ul d be a p plie d i n 
deter mi ni n g st u d y e nr ol me nt.  
3.  P ost me n o pa usal fe male:  
 A p ost me n o pa usal state is defi ne d as a m e n orr h o ea f or at least 1 2 m o nt hs wit h o ut a n alter nati ve 
me dic al ca us e i n a fe m ale >  4 5  years of a ge.  Alter nati ve me dical ca uses f or a me n orr h oea 
i ncl u de, b ut are n ot li mite d t o, h or m o nal c o ntrace pti o n or h or m o nal re place me nt t hera p y.  
 Fe males ≥ 6 0 years of a ge ca n b e c o nsi dere d p ost me n o pa usal.  
Fe males o n H R T a n d w h o se me n o pa usal stat us is i n d o u bt are c o nsi dere d of c hil d beari n g p ote ntial  
a n d will be re q uir e d t o use o ne of t he hi g hl y effecti ve c o ntrace pti o n met h o ds.  
N ote: D oc u me ntati o n re gar di n g cate g ories 1 -3 ca n c o me fr o m t he site staff’s re vie w of partici pa nt’s 
me dical rec or ds, me dic al e x a mi nati o n or me dical hist or y i nter vie w.  
1 0. 4. 2  
C o ntr ace pti ve g ui d a nce  
M ale p artici p a nts  
N o c o ntrace pti o n meas ur es are n ee d e d f or mal e partici pa nts , as t he ris k of 
terat o ge nicit y/fet ot o xicit y ca use d b y tr a nsfer of se ma gl uti de s.c. i n se mi nal fl ui d is u nli kel y. 
Fe m ale p artici p a nts  
Fe male p artici pa nts of c hil d beari n g p ot e ntial are eli gi ble t o partici pate if t h e y a gree t o use met h o ds 
of c o ntrace pti o n c o nsiste ntl y a n d c orrectl y. T a ble  1 0 -6  lists t he hi g hl y effecti ve met h o ds of 
c o ntrace pti o n all o we d. L ocal re g ulati o ns ma y a p pl y, see A p pe n di x  1 0  ( Secti o n 1 0. 1 0 ). 
Hi g hl y effecti ve c o ntrace pti o n s h o ul d be utilise d f or a least 6 3  da ys after l ast d ose of I M P 
(c orres p o n di n g t o ti me d uri n g tr eat me nt a n d u ntil t he e n d of rele va nt s yste mic e x p os ure). 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
7 8
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
7 9  of 1 0 0  
 
T a ble  1 0 -6  
Hi g hl y effecti ve c o ntr ace pti ve met h o ds all o w e d 2 4 
Hi g hl y effecti ve met h o ds a ( F ail ure r ate of < 1 % per ye ar w he n use d c o nsiste ntl y a n d c orrectl y): 
 C o m bi ne d (estr 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 b 
 oral  
 i ntra va gi nal 
 tra ns der mal 
 Pr o gest o ge n -o nl y h or m o ne 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 
 i m pla nta ble 
 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 mize d part ner  
Vasect o mize d part ner is a hi g hl y effecti ve c o ntrace pti ve met h o d pr o vi de d t hat t he part ner is t he s ole se x ual part ner  
of t he w o ma n of c hil d beari n g p ote ntial, 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. S per mat o ge nesis c ycle is a p pr o xi matel y 9 0 da ys.  
 Se x ual a bsti ne nce  
Se x ual a bsti ne nce is c o ns i 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 st u d y i nter ve nti o n. T he relia bilit y of se x ual 
a bsti ne nce nee ds t o be e val uat e d i n relati o n t o t he d urati o n of t he st u d y a n d t he preferre d a n d us ual lifest yle of t he 
partici pa nt.  
N O T E S  
a. C o ntrace pti ve use b y me n or w o me n s h o ul d c o m pl y wit h l o cal re g ulati o ns re gar di n g t he use of c o ntrace pti ve 
met h o ds f or t h ose partici pati n g i n cli nical st u dies.  
b.  If l ocall y re q uire d, i n acc or da nce wit h Cli nical Trial Facilitati o n Gr o u p ( C T F G) g ui deli nes, acce pta ble 
c o ntrace pti ve met h o ds are li mite d t o t h ose w hic h i n hi bit o v ulati o n as t he pri mar y m o de of acti o n.  
T he f oll o wi n g m et h o ds are n ot acce pta ble m et h o ds of c o ntrace pti o n: Peri o di c a bsti ne nce (cale n dar, 
s y m pt ot her mal, p ost-o v ulati o n met h o ds), wit h dra wal (c oit us i nterr u pt us), s per mici des o nl y, a n d 
lactati o nal a me n orr h oea met h o d ( L A M). 
Greece: Please s ee A p p e n di x 1 0 ( Secti o n 1 0. 1 0 ) f or c o u ntr y-s pecific re q uir e me nts. 
1 0. 4. 3  
C ollecti o n of pre g n a nc y i nf or m ati o n  
Fe male p artici pa nts w h o bec o me pre g na nt  
I n v esti gat or will c ollect pre g na nc y i nf or mati o n o n a n y fe male p artici pa nt w h o bec o mes pre gna nt 
w hile partici pati n g i n t his st u d y.  
I nf or mati o n will be rec or de d o n t he a p pr o priate f or m a n d s u b mitte d t o N o v o N or dis k wit hi n 
1 4  cale n dar da ys of lear ni n g of a p artici pa nt’s pre g na n c y (see Fi g ure  1 0 -2 ). 
T he partici pa nt will be f oll o we d t o deter mi ne t he o utc o me of t he pre g na nc y. T he i n vesti gat or will 
c ollect f oll o w -u p i nf or m ati o n o n partici pa nt a n d n e o nate w hic h will be f or war de d t o N o v o N or dis k 
wit hi n 1 4 cale n dar da ys. 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 he deli ver y date. 
A n y ter mi nati o n of pre g n a nc y will be re p orte d, re gar dless of f o etal stat us ( prese nce or a bs e nce of 
a n o malies) or i n dicati o n f or pr oce d ure.  
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
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V V- T M F- 5 9 0 1 0 6 5
 .
-
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1
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 of
  Pr ot oc ol  4 9 8 4 v 3. 0
7 9
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
8 0  of 1 0 0  
 
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 a d v erse e ve nt i n c o n necti o n wit h 
pre g na nc y or ele cti ve ter mi nati o n of a pre g na n c y f or me dical r eas o ns will be re p ort e d as a n A E or 
S A E. If rele v a nt, c o nsi der a d di n g ‘ gestati o nal’, ‘ pre g n a nc y-relat e d’ or a si milar ter m w he n 
re p orti n g t he A E/ S A E. 
Pre g n a nc y o utc o me s h o ul d be d oc u me nte d i n t he partici pa nt’s me dical rec or d. A b n or mal pr e 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 n S A E. I n cas e of a b n or mal pre g na n c y o utc o me, pater nal i nf or m ati o n 
s h o ul d be rec or de d i n t he a p pr o priate f or m aft er o btai ni n g t he necessar y si g ne d p ater n al i nf or me d 
c o nse nt.  
If t he i n vesti gat or lear ns of a n S A E occ urri n g as a res ult of a p ost -st u d y pre g na n c y w hic h is 
c o nsi dere d relate d t o t he I M P b y t he i n vesti gat or, t he S A E s h o ul d be re p ort e d t o N o v o N or dis k as 
descri be d i n A p p e n di x  3 ( Secti o n  1 0. 3 ). 
Fi g ure  1 0 -2  Decisi o n tree f or deter mi ni n g t he f or ms t o c o m plete f or c ollecti o n of pre g n a nc y 
i nf or m ati o n a n d ti meli nes f or re p orti n g –  F or fe m ale p artici p a nts  
 
A n y fe male p artici pa nt w h o bec o mes pre g na nt w hile partici pati n g i n t he st u d y will disc o nti n ue 
st u d y i nter ve nti o n.  
 
 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
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V V- T M F- 5 9 0 1 0 6 5
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-
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1
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 of
  Pr ot oc ol  4 9 8 4 v 3. 0
8 0
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
8 1  of 1 0 0  
 
1 0. 5  A p pe n di x  5: 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  
1 0. 5. 1  
Defi niti o n of tec h nic al c o m pl ai nt 
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 pl ai nt ma y b e ass ociat e d wit h a n A E b ut d oes n ot 
c o ncer n t h e A E itself. Tec h nical c o m plai nts i ncl u de t he defi niti o n of de vice deficie nc y, pleas e refer 
t o A p pe n di x 6 ( Secti o n  1 0. 6 ). 
E x a m ples of tec h nical c o m plai nts:  
 Pr o ble ms wit h t he p h ysic al or c he mical a p peara n ce of st u d y i nter ve nti o ns (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 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 h e 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 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 d efi ne d o n t he tec h nical c o m plai nt 
f or m. 
1 0. 5. 2  
Rec or di n g a n d f oll o w -u p of tec h nic al c o m pl ai nts  
Re p orti n g of tec h nic al c o m pl ai nts t o  N o v o N o r dis k  
F or c o nta ct details f or C ust o mer C o m plai nt Ce nter, please refer t o Attac h m e nt I . 
Tec h nical c o m plai nts o n pr o d ucts all ocate d t o a partici pa nt m ust be re p orte d o n a se parate tec h nical 
c o m plai nt f or m:  
1.  F or pr o d u cts wit h D U N: 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.  F or pr o d u cts wit h o ut D U N: 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 b atc h, 
c o de or l ot n u m ber.  
F or me dic al de vice us e d o utsi de a p pr o val, e val uat e o n t he tec h nical c o m plai nt f or m if t he tec h nica l 
c o m plai nt c o ul d ha ve le d t o a n S A E.  
If t he tec h ni cal c o m plai nt o n a me dical de vice use d o utsi de a p pr o val c o ul d ha ve le d t o a n S A E, a 
de vice deficie nc y t h at c o ul d ha ve le d t o S A E f or m m ust be c o m plete d as descri be d i n A p p e n di x  6 
( Secti o n 1 0. 6 ). 
Ti meli nes f or re p orti n g 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 plete t he tec h nical c o m plai nt f or m i n t he e C R F wit hi n:  
 2 4  h o urs if c o ul d ha ve le d t o a n S A E  
 2 4 h o urs if relate d t o a n S A E 
 5 cale n dar da ys f or all ot her tec h nical c o m plai nts  
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
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1
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 of
  Pr ot oc ol  4 9 8 4 v 3. 0
8 1
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
8 2  of 1 0 0  
 
If t he eC R F is u na v aila ble, or w he n re p orti n g a tec h nical c o m plai nt o n a pr o d uct t hat is n ot yet 
all ocate d t o a partici pa nt, t he i nf or mati o n m ust be pr o vi de d o n a pa p er f or m t o C ust o mer C o m plai nt 
Ce nter, N o v o N or dis k, wit hi n t he sa me ti meli nes as state d a b o ve. W he n t he eC R F bec o mes 
a vaila ble a gai n, t he i n vesti gat or m ust e nter t h e 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 
eC 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 n e 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 par ts 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 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 t ec 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 v aila 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 shi 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 te c h nical c o m plai nt sa m ple m ust be d o ne i n acc or da nce wit h t he c o n diti o ns 
prescri be d f or t he st u d y i nter ve nti o n.  
1 0. 5. 3  
Re p orti n g of tec h nic al c o m pl ai nts f o r pr o d ucts n ot i ncl u de d i n t he tec h nic al 
c o m pl ai nt f or m  
Tec h nical c o m plai nts o n 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 ma n ufact uri n g h ol der. 
 
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Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
8 3  of 1 0 0  
 
1 0. 6  A p pe n di x  6: A Es, A D Es, S A Es, S A D Es, U S A D Es a n d de vice deficie ncies: Defi niti o ns 
a n d pr oce d ures f or rec or di n g, e v al u ati n g, f oll o w -u p, a n d re p orti n g i n Me dic al de vice 
st u dies 
1 0. 6. 1  
Defi niti o n of A E a n d a d verse de vice effects  
A n A E is a n y u nt o war d me dical occ urre n ce, u ni nte n de d disease or i nj ur y, or u nt o war d cli nic al si g ns 
(i ncl u di n g a b n or mal la b orat or y fi n di n g) i n st u d y p artici pa nts, users, or ot h er pers o ns, w het h er or n ot 
relate d t o t he me dical de vice use d o utsi de a p pr o val a nd w het her a ntici pate d or u na ntici pate d. T his 
defi niti o n i ncl u des e ve nts relate d t o t he me dical de vice use d o utsi de a p pr o val or c o m parat or a n d 
e ve nts relat e d t o t he pr oce d ures i n v ol ve d. F or users or ot her pers o ns, t his defi niti o n is restricte d t o 
e ve nts rel at e d t o t he me dical de vice us e d o utsi de a p pr o val or c o m parat ors.  
A n a d vers e de vic e effect ( A D E) is a n A E relat e d t o t he use of a me di cal de vice use d o utsi de 
a p pr o val. T his defi niti o n i ncl u des a n y A Es res ulti n g fr o m i ns ufficie nt or i n a de q uate i nstr ucti o ns f or 
use, de pl o y m e nt, i m pla ntati o n, i nstallati o n, or o perati o n, or a n y malf u n cti o n of t he me dical de vi ce 
use d o utsi de a p pr o val as well as a n y e v e nt res ulti n g fr o m use err or or fr o m i nte nti o nal mis use of t he 
me dical de vice us e d o utsi de a p pr o val or c o m parat or  if t he c o m parat or is a me dical de vice. S ee t he 
I B f or t he me dic al de vice use d o utsi de a p pr o val f or t he a ntici pate d A D Es 
1 0. 6. 2  
Defi niti o n of S A E, seri o us a d verse de vice effect a n d u n a ntici p ate d seri o us a d verse 
de vice effect  
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:  
1.  Res ults i n deat h  
2.  Lea ds t o seri o us deteri orati o n i n t he healt h of t he partici pa nt, user or ot her pers o n t hat eit her 
res ults i n: 
a)  A life -t hreate ni n g ill ness or i nj ur y. T h e ter m ‘lif e-t hreate ni n g’ refers t o a n e ve nt i n w hic h 
t he partici pa nt was at ris k of deat h at t he ti me of t he e ve nt. It d oes n ot refer t o a n e ve nt 
w hic h h y p ot h eticall y mi g ht ha ve ca us e d deat h, if it were m or e se vere.  
b)  Persiste nt or si g nifica nt disa bilit y/i nca pacit y: A per ma ne nt i m pair me nt of a b o d y str uct ure 
or a  b o d y f u ncti o n i ncl u di n g c hr o ni c diseases.  
c)  I n-patie nt or pr ol o n ge d h os pitalisati o n . Pla n ne d h os pitalisati o n f or a pre-e xisti n g c o n diti o n, 
or a pr oce d ure re q uir e d b y t he pr ot o c ol, wit h o ut seri o us deteri orati o n i n healt h, is n ot 
c o nsi dere d a n S A E.  
d)  I m p ort a nt me dical e v e nt: Me dical or s ur gical i nter ve nti o n t o pre ve nt life -t hreate ni n g ill ness 
or i nj ur y or per ma n e nt i m pair me nt t o a b o d y str u ct ure or a b o d y f u ncti o n.  
3.  C o n ge nital a n o mal y/ birt h defect: Res ults i n f oetal distress, f oetal deat h or a c o n ge nital 
a b n or mal it y or birt h defect i ncl u di n g p h ysical or me ntal i m pair me nt 
Seri o us a d verse de vice effect  
A seri o us a d verse de vi ce effect ( S A D E) is a n a d verse de vice effect t hat has res ulte d i n a n y of t he 
c o nse q ue nces c h aracteristic of a n S A E.  
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C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
8 4  of 1 0 0  
 
U n a ntici p ate d seri o us a d vers e de vice effect  
A n  u na ntici pate d seri o us a d verse d e vice effect ( U S A D E) is a seri o us a d v erse de vice effect w hic h 
b y its nat ure, i n ci de nce, se verit y or o utc o me h as n ot bee n i de ntifie d i n t he c urre nt ris k assess me nt 
a nal ysis re p ort (s ee Secti o n  2. 3 ). 
A ntici pate d seri o us a d v erse de vice effect is a n effect w hic h b y its nat ure, i n ci de nce, s e verit y or 
o utc o me has bee n i d e ntifie d i n t he ris k assess me nt  
1 0. 6. 3  
Defi niti o n of seri o us he alt h t hre at  
A seri o us healt h t hreat is a si g nal fr o m a n y a d v erse e ve nt or d e vice d eficie nc y t h at i n dicates a n 
i m mi ne nt ris k of deat h or a seri o us deteri orati o n i n t he healt h i n st u d y partici pa nts, users or ot her 
pers o ns, a n d t hat re q uires pr o m pt re me dial acti o n f or ot her partici p a nts, users or ot her pers o ns. T his 
w o ul d i ncl u de e ve nts t hat are of si g nifica nt a n d u ne x pecte d nat ure s u c h t hat t he y b ec o me alar mi n g 
as a p ote ntial seri o us healt h hazar d or p ossi bilit y of m ulti ple deat hs occ urri n g at s h ort i nter vals. 
1 0. 6. 4  
Defi niti o n of de vice deficie nc y  
A de vice d eficie n c y is a n i na de q uac y of a me dical de vice wit h res p ect t o its i de ntit y, q ualit y, 
d ura bilit y, relia bilit y, usa bilit y, safet y, or perf or ma nce. De vice d eficie ncies i ncl u de malf u ncti o ns, 
use err or s, a n d t he i na d e q uac y of t he i nf or mati o n s u p plie d b y t he ma n ufact urer, i ncl u di n g la belli n g. 
T his defi niti o n i ncl u des de vice deficie nci es relat e d t o t he me dical de vice use d o utsi de a p pr o val.  
De vice d eficie n c y is part of tec h nical c o m plai nt defi niti o n, please refer t o A p pe n di x  5 
( Secti o n 1 0. 5 ). 
1 0. 6. 5  
Defi niti o n of use err or  
A use err or is a user acti o n or lac k of us er acti o n w hile usi n g t he me dical de vice  t hat lea d t o a 
differe nt res ult t ha n t hat i nte n de d b y t he ma n ufact urer or e x pecte d b y t he user.  
Use err or i ncl u des t he i n a bilit y of t he user t o c o m plete a tas k.  
Use err ors ca n res ult fr o m a mis matc h bet wee n t h e c haracteristics of t he us er, user i nterface,  tas k or 
use e n vir o n me nt.  
Users mi g ht b e a w are or u na ware t hat a use err or has occ urre d.  
N ote : A n u ne x pecte d p h ysi ol o gical r es p o nse of t he partici pa nt  is n ot b y itself c o nsi dere d a use 
err or.  
N ote : A malf u n cti o n of a me dical de vice t h at ca us es a n u ne x pecte d res ult is n ot c o nsi dere d a us e 
err or.  
 
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Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
8 5  of 1 0 0  
 
1 0. 6. 6  
Rec or di n g a n d f oll o w -u p of A E a n d/ or S A E a n d de vice deficie ncies  
1 0. 6. 6. 1  
A E, S A E a n d de vice deficie nc y rec or di n g  
W he n a n A E/ S A E/ de vice deficie nc y o cc urs, it is t he res p o nsi bilit y of t he i n vesti gat or t o re vie w all 
d oc u me ntati o n (e. g., h os pital pr o gress n otes, la b orat or y re p orts, a n d dia g n ostics re p orts) relate d t o 
t he e ve nt. 
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.  
T here ma y b e i nsta nces w he n c o pies of s o urce d o c u me nts (e. g., me dical rec or ds) f or certai n cas es 
are re q ueste d b y N o v o N or dis k. I n s u c h cas es, all partici pa nt i de ntifiers, wit h t he e x ce pti o n of t he 
s u bject I D, will be re d act e d o n t he c o pies of t h e s o urce d oc u m e nts bef or e s u b missi o n t o N o v o 
N or dis k.  
F or all n o n -s eri 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 st u d y at t he lat est. F or si g n -off of S A E -relate d f or ms, refer t o Secti o n 1 0. 6. 2 . 
T he i n vesti gat or will rec or d all rele v a nt A E/ S A E/ de vice deficie nc y i nf or m ati o n i n t he partici pa nt’s 
me dical rec or ds, i n acc or da nce wit h t he i n vesti gat or’s n or mal cli nical pr actice a n d  o n t he 
a p pr o priate f or m of t he C R F.  
F or de vic e deficie ncies, it is ver y i m p orta nt t hat t h e i n vesti gat or descri bes a n y c orrecti ve acti o ns 
ta ke n t o pre ve nt rec urre n ce of t he e ve nt. 
1 0. 6. 6. 2  
Assess me nt of se verit y  
T he i n vesti gat or will ma ke a n assess me nt of se verit y  f or eac h A E/ S A E/ de vice defici e nc y re p orte d 
d uri n g t he st u d y 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 h e parti ci pa nt, ca usi n g mi ni mal disc o mf ort a n d n ot 
i nterferi n g wit h e v er y da y acti vities. 
 M o der ate:  A n  e v e 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 d a y 
acti vities. 
 Se vere : A n e ve nt t hat pr e ve nts n or mal e ver y da y acti vities.  
N ote: A n A E t hat is assesse d as se vere s h o ul d n ot be c o nf use d wit h a n S A E. Se vere is a 
cate g or y utilise d f o r rati n g t he i nte nsit y of a n e ve nt; a n d b ot h A Es a n d S A Es ca n be ass esse d as 
se vere. 
A n e ve nt is defi ne d as ‘s eri o us’ w he n it meets at least o ne of t he criteria descri be d i n t he defi niti o n 
of a n S A E, N O T w h e n it is rate d as se vere.  
1 0. 6. 6. 3  
Assess me nt of c a us alit y  
T he i n vesti gat or is o bli gate d t o assess t he relati o ns hi p bet wee n t he me di cal de vice use d o utsi de 
a p pr o val, t he pr oce d ure a n d eac h o cc urre nce of eac h A E/ S A E.  T he i n vesti gat or will use cli nical 
j u d g me nt t o deter mi ne relati o ns hi p. 
N N 9 5 3 5- 4 9 8 4
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C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
8 6  of 1 0 0  
 
Relati o ns hi p bet wee n a n A E/ S A E a n d t he me dical de vice use d o utsi de a p pr o val a n d t he pr oce d ure 
s h o ul d be assesse d as: 
 Ca usal: w he n relati o ns hi p is be y o n d a n y d o u bt  
 Pr o ba ble: w he n relati o ns hi p see ms rele va nt a n d/ or t he e ve nt ca n n ot be e x plai ne d b y a n ot her 
ca use  
 P ossi ble: w he n relati o ns hi p is wea k b ut ca n n ot be r ule d o ut  
 N ot relate d: w he n relati o ns hi p ca n be e x cl u de d  
Alter nati ve ca uses, s uc h as u n derl yi n g disease(s), c o nc o mita nt t hera p y, a n d ot her ris k fact ors, as 
well as t he te m p oral r elati o ns hi p of t he e ve nt t o  t he use of t he me di cal de vi ce u n der i n v esti gati o n, 
will be c o nsi dere d a n d i n vesti gate d.  
T he i n vesti gat or will als o c o ns ult t he i n vesti gat or’s br oc h ure i n his/ her 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 h e 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 f or A E or S A E. 
T here ma y b e sit uati o ns i n w hic h a n A E/ S A E has occ urre d, a n d t he i n v esti gat or h as mi ni mal 
i nf or mati o n t o i ncl u de i n t he i nitial re p ort t o N o v o N or dis k. H o we ver, it is ver y i m p orta nt t hat t he 
i n vesti gat or al wa ys ma kes a n assess me nt of ca usalit y f or e ver y e ve nt bef ore t he i nitial tra ns missi o n 
of t he S A E data.  
T he i n vesti gat or ma y c h a 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 se n d 
a n A E/ S A E f oll o w -u p re p ort wit h t he u p date d ca usalit y assess me nt.  
T he ca us alit y ass ess 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. 
1 0. 6. 6. 4  
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 h e partici pa nt has f ull y rec o vere d, or b y m e 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 w he n first d oc u me nte d. 
 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 h e partici pa nt is e x pecte d t o rec o ver 
fr o m t he e ve nt. T his ter m may b e a p plica bl e i n cas e of c hr o ni c c o n diti o ns, ca ncer of A Es 
o n g oi n g at ti me of deat h ( w here deat h is d ue t o a n ot her A E).  
N ote: f or S A Es, t his ter m is o nl y a p plica ble if t he partici pa nt has c o m plete d t he f oll o w -u p 
peri o d a n d is e x pecte d t o rec o ver.  
 Rec o ver e d/res ol ve d wit h se q uel ae : t he partici pa nt has rec o v ere d fr o m t he c o n diti o n b ut wit h 
lasti n g effect d u e t o disease, i nj ur y, tr eat me nt or pr oce d ure. If a s e q uela m eets a n S A E criteri o n, 
t he A E m ust be re p ort e 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 partici pa nt has n ot i m pr o ve d, a n d t he 
s y m pt o ms are u n c ha n ge d, or t he o utc o me is n o k n o w n. 
N ote: t his ter m ma y b e a p plica ble i n case of c hr o nic c o n diti o ns, ca ncer or A Es o n g oi n g at ti me 
of deat h ( w h ere d eat h is d ue t o a n ot her A E).  
 F at al : T his ter m is o nl y a p plica ble if t he partici pa nt die d fr o m a c o n diti o n relate d t o t he 
re p orte d A E. O utc o me of ot her re p ort e d A Es i n a partici pa nt bef ore he/s h e die d s h o ul d be 
N N 9 5 3 5- 4 9 8 4
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8 6
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C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
8 7  of 1 0 0  
 
assesse d as ‘rec o vere d/res ol ve d’, ‘rec o veri n g/r es ol vi n g’, ‘rec o v ere d/r es ol v e d wit h se q ue lae’ or 
‘ n ot rec o v ere 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 partici pa nt is l ost t o f oll o w-u p.  
1 0. 6. 6. 5  
F oll o w -u p of A E/ S A E/ de vice deficie nc y  
T he i n vesti gat or is o bli gate d t o perf or m or ar ra n ge f or t he c o n d u ct of s u p ple me ntal meas ure me nts 
a n d/ or e val uati o ns as me dicall y i n dicat e 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 ur e 
a n d/ or ca us alit y of t he A E/ S A E/ de vice defici e nc y as f ull y as p ossi ble. T his ma y i ncl u d e a d diti o nal 
la b orat or y tests or i n vesti gati o ns, hist o pat h ol o gi cal 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 d ate d i nf or mati o n will be rec or de d i n t he ori gi n all y c o m plete d C R F.  
T he i n vesti gat or will s u b mit a n y u p date d S A E d ata t o N o v o N or dis k  wit hi n 2 4 h o urs of recei pt of 
t he i nf or mati o n. 
1 0. 6. 7  
Re p orti n g of S A Es, Seri o us De vice Deficie nc y t h at c o ul d h a ve le d t o a n S A E a n d 
seri o us he alt h t hre ats 
Rele va nt C R F f or ms ( A E a n d safet y i nf or mati o n f or ms, de vice deficie nc y t hat c o ul d ha ve le d t o a n 
S A E f or m)  m ust be f or w ar de d t o N o v o N or dis k i n acc or da nce wit h Secti o n  1 0. 1. 9 . 
I nitial n otificati o n via tel e p h o ne is acce pta ble, alt h o u g h it d oes n ot re pl ace t he nee d f or t he 
i n vesti gat or t o c o m plete t he A E, de vice defi cie nc y t hat c o ul d ha ve le d t o a n d S A E a n d safet y 
i nf or mati o n f or m wit hi n t he desi g n ate d re p orti n g ti me fra mes: 
 A E a n d de vic e defi cie nc y t hat c o ul d h a ve le d t o a n S A E f or m wit hi n 2 4  h o urs  
 Safet y i nf or mati o n f or m wit hi n 5  cale n dar da ys  
 All f or ms m ust be si g ne d wit hi n 7  cale n dar da ys after first k n o wle d ge b y t he i n vesti gat or.  
A s us pici o n of a seri o us healt h t hreat m ust be i n dicate d i n t he S A E f or m or i n t he de vice deficie nc y 
t hat c o ul d ha ve le d t o a n S A E f or m.  
F or de vic e deficie nc y t h at c o ul d ha ve le d t o a n S A E, a tec h nical c o m plai nt f or m m ust als o be 
c o m plete d, refer t o A p p e n di x 5  ( Secti o n 1 0. 5 ). 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
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V V- T M F- 5 9 0 1 0 6 5
 .
-
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1
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 of
  Pr ot oc ol  4 9 8 4 v 3. 0
8 7
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
8 8  of 1 0 0  
 
1 0. 7  A p pe n di x  7: Rete nti o n of h u m a n bi os a m ples  
I n c o u ntries w h ere a p plica ble, t he st u d y will i n v ol ve c ollecti o n of h u ma n bi osa m ples f or f ut ure 
researc h t o be st or e d i n a ce ntral la b orat or y facilit y. 
H u ma n bi osa m ples (als o i n s o me cases k n o w n as h u ma n bi os peci me n or h u ma n bi ol o gical 
materials) are sa m ples t h at ha ve bee n ta ke n fr o m t he h u ma n b o d y d uri n g life or aft er deat h. It 
i ncl u des:  
 Pri mar y cells, tiss ues, or ga ns or cell c o nt ai ni n g fl ui ds of h u ma n ori gi n (f or e x a m ple, w h ole 
bl o o d, uri ne, sali va, s y n o vial fl ui d)  
 Cell free fl ui ds of pri mar y h u ma n ori gi n (f or e x a m ple, ser u m a n d plas ma)  
 E xtracts or deri vati ves of t he a b o ve, w he n deri ve d  b y p urifi cati o n (f or e x a m ple, D N A, R N A, 
pr otei ns, me m bra nes, mi cr os o mes a n d ot her cell ular s u bstr uct ures).  
Ser u m sa m ples will be c ollecte d acc or di n g t o t he fl o wc hart ( Secti o n 1. 2 ) a n d Ta ble  1 0 -2  i n 
A p pe n di x 2 ( Secti o n 1 0. 2 ). O ne ser u m sa m ple will be c ollecte d per ti me p oi nt  a n d di vi de d i n t w o 
ali q u ots  f or st ora ge. 
T he bi osa m ples will be st ore d at a ce ntr al la b orat or y, at a ce ntral st ora ge facilit y or a n a nal ysi n g  
la b orat or y c o ntr acte d b y N o v o N or dis k f or u p t o 1 5 years after e n d of st u d y. O nl y rele va nt N o v o 
N or dis k, c o ns ulta nts, a u dit ors, researc h or ga nisati o ns or la b orat ories w or ki n g f or or c olla b orati n g 
wit h N o v o N or dis k as well as st ora ge facilit y e m pl o yees wil l be a ble t o access t he st ore d 
bi osa m ples a n d ass ociate d data. T he bi osa m ples ma y b e tra nsferre d t o ot her c o u ntries f or a n al ysis 
a n d will be destr o ye d at t he latest 1 5 years after e n d of st u d y.  
T he a nal yses of t he bi osa m ples f or f ut ure researc h are n ot i nt e n de d t o i de ntif y partici pa nt -s pecific 
fi n di n gs, b ut t o u n dersta n d a n d pre dict res p o nse t o se ma gl uti de as well  as u n dersta n di n g T 2 D a n d 
relate d c o n diti o ns o n a p o p ulati o n le vel. 
A nal ysis will be d o ne o n t he bi osa m ples a n d ass ociate d data ( d ata rel ati n g t o t he test res ults or 
res ults fr o m t he mai n st u d y). 
N o v o N or dis k will e ns ur e t hat t hir d part y c olla b orat ors li ve u p t he re g ulati o ns o n data pr otecti o n, 
see A p pe n di x 1 ( Secti o n   1 0. 1. 5 ). 
T he partici pa nt ma y re q u est t he st ore d bi osa m ples f or f ut ure researc h t o b e destr o ye d b y 
wit h dra wi n g t he desi g nat e d i nf or me d c o ns e nt at a n y ti me p oi nt d uri n g a n d after t he st u d y. F or 
sa m ples t hat ha ve alr ea d y bee n a n al ys e d, t he res ults ca n still be use d f or scie ntific researc h a n d will 
n ot be re m o ve d fr o m t he datafile.  
Resi d ual a nti b o d y sa m pl es ma y b e retai ne d f or lat er a nal ysis f or f urt her c h aract erisati o n of a nti b o d y 
res p o nses t o war ds dr u g, if re q uire d b y healt h a ut h orities or f or safet y reas o ns. T he sa m ples will be 
st ore d at N o v o N or dis k, or a s peci alise d la b assi g ne d b y N o v o N or dis k,  after e n d of st u d y a n d u ntil 
mar keti n g a ut h orisati o n a p pr o val or 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 st u d y after w hi c h t he y will be destr o ye d . 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
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V V- T M F- 5 9 0 1 0 6 5
 .
-
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1
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 of
  Pr ot oc ol  4 9 8 4 v 3. 0
8 8
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
8 9  of 1 0 0  
 
1 0. 8  A p pe n di x  8: H y p o gl yc ae mic e pis o des  
T a ble  1 0 -7  
Cl assific ati o n of h y p o gl yc ae mi a  
Cl assific ati o n of h y p o gl yc ae mi a  
Le vel  
Gl ycae mic criteria  
Descri pti o n  
H y p o gl ycae mia alert val ue 
(le vel 1) 
< 3. 9 m m ol/ L ( 7 0 m g/ d L) a n d  
≥ 3. 0 m m ol/ L ( 5 4 m g/ d L)  
S ufficie ntl y l o w f or treat me nt wit h fast -acti n g 
car b o h y drate a n d d ose a dj ust me nt of gl uc ose -l o weri n g 
t hera p y 
Cli nicall y si g nifica nt 
h y p o gl ycae mia (le vel 2)  
< 3. 0 m m ol/ L ( 5 4 m g/ d L)  
S ufficie ntl y l o w t o i n dicate seri o us, cli nicall y i m p orta nt 
h y p o gl ycae mia  
Se vere h y p o gl ycae mia 
(le vel 3)1 
N o s pecific gl uc ose t hres h ol d  
1H y p o gl ycae mia ass ociate d wit h se vere c o g niti ve 
im pair me nt re q uiri n g e xter nal assista nce f or rec o ver y  
N otes: T he N o v o N or dis k ter ms are a d a pte d fr o m I H S G, 2 5 A D A, 2 6 I S P A D,2 7 t y pe 1 dia betes o utc o mes pr o gra m,2 8 
A T T D. 2 9  S e vere h y p o gl ycae mia as defi ne d b y Sea q uist 3 0 a n d I S P A D. 2 7 
 
Se vere h y p o gl yc ae mi a  
1Se vere h y p o gl ycae mia is a n e ve nt r e q uiri n g assista nce of a n ot her p ers o n t o acti vel y a d mi nister 
car b o h y drates,  gl uca g o n, or ta ke ot her c orrecti ve acti o ns. Plas ma gl uc os e c o nce ntrati o ns ma y n ot be 
a vaila ble d uri n g a n e ve nt, b ut ne ur ol o gical rec o ver y f oll o wi n g t he ret ur n of plas ma gl uc os e t o 
n or mal is c o nsi dere d s ufficie nt e vi de nce t h at t he e ve nt was i n d uce d b y a l o w plas ma gl uc ose 
c o nce ntr ati o n. 3 0 
N oct u r n al h y p o gl yc ae mi a  
N oct ur nal h y p o gl ycae mic e pis o des: e pis o des occ urri n g b et wee n 0 0: 0 1 a n d 0 5: 5 9 b ot h i ncl usi ve.  
Re p orti n g of h y p o gl yc ae mic e pis o des  
All h y p o gl ycae mic e pis o des m ust be rec or de d o n a h y p o gl ycae mic e pis o de f or m. If t he 
h y p o gl ycae mic e pis o de f u lfils t he criteria f or a n S A E, t he n i n a d diti o n t o t he h y p o gl ycae mic 
e pis o de f or m, a n A E f or m a n d a safet y i nf or mati o n f or m m ust be fille d i n. O ne A E f or m a n d safet y 
i nf or mati o n f or m ca n c o ver se veral h y p o gl ycae mic e pis o de f or ms, if t he p artici pa nt has n ot 
rec o vere d b et wee n t h e e pis o des. 
Re p orti n g of h y p o gl ycae mic e pis o des b y B G met ers:  
Plas ma gl uc ose ( P G) s h o ul d al wa ys be rec or de d i n t he diar y/ e C R F w he n a h y p o gl ycae mic e pis o de 
is s us pecte d. 
W he n a partici pa nt e x perie nces a h y p o gl ycae mic e pis o de, t he partic i p a nt s h o ul d rec or d t he ge neral 
i nf or mati o n i n relati o n t o t he h y p o gl ycae mia (ti mi n g, P G meas ure me nts, s y m pt o ms, etc.) as 
descri be d i n t he diar y. T he i n vesti gat or s h o ul d e ns ure c orrect r e p orti n g of t he h y p o gl ycae mic 
e pis o de a n d re p ort t he h y p o gl ycae mic e pi s o de t o t he eC R F. I n case a partici pa nt is n ot a ble t o fill i n 
t he diar y (e. g., i n case of h os pitalisati o n), t he i n vesti gat or s h o ul d still re p ort t he h y p o gl ycae mic 
e pis o de o n t he h y p o gl ycae mic e pis o des f or m.  
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
8 9
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
9 0  of 1 0 0  
 
U p o n o nset of a h y p o gl ycae mic e pis o de t he partici pa nt is rec o m me n de d t o meas ure P G e v er y 1 5 
mi n utes u ntil t he P G val ue is ≥3. 9 m m ol/ L ( 7 0 m g/ d L) a n d/ or s y m pt o ms ha ve bee n res ol ve d i n 
acc or da nce wit h c urre nt g ui deli nes. 3 0 
Re peate d P G meas ure me nts a n d/ or s y m pt o ms will b y defa ult be c o nsi d ere d as o ne h y p o gl ycae mic 
e pis o de u ntil a s uccee di n g P G val ue is ≥ 3. 9 m m ol/ L ( 7 0 m g/ d L) a n d/ or s y m pt o ms ha ve bee n 
res ol ve d a n d s h o ul d be re p orte d as o nl y o ne h y p o gl ycae mic e pis o de. I n case of se veral l o w P G 
val ues wit hi n t he h y p o gl ycae mic e pis o de, t he l o west val ue is t he o ne t hat will be re p orte d as t he P G 
val ue f or t he h y p o gl ycae mic e pis o de, b ut t he start ti me of t he e pis o de will re mai n as t he ti me f or t he 
first l o w P G val ue a n d/ or s y m pt o m. T he re m ai ni n g val u es will be ke pt as s o urce dat a. 
If t he se verit y of a h y p o gl ycae mic e pis o de c ha n ges, o nl y o ne h y p ogl ycae mic e pis o de will be 
re p orte d, reflecti n g t he m ost se vere de gree of h y p o gl ycae mia. 
Re gar di n g t he q uesti o n: “ T o feel better, di d y o u n ee d hel p t o get a s u gar y dri n k, f o o d, or 
me dici ne? ” t he i n vesti gat or m ust i nstr uct t he partici pa nts t o a ns wer “ Yes ”, i f t he e pis o de was a n 
e ve nt t hat re q uir e d assista nce of a n ot her p ers o n t o acti vel y a d mi nister car b o h y drate, gl uca g o n, or 
ta ke ot her c orrecti ve acti o ns. P G c o nce ntrati o ns ma y n ot be a vaila ble d uri n g a n e ve nt, b ut 
ne ur ol o gi cal r ec o ver y f oll o wi n g t he ret ur n of  P G t o n or mal is c o nsi dere d s ufficie nt e vi de n ce t hat 
t he e ve nt was i n d uce d b y a l o w P G c o nce ntrati o n.3 0 
A d diti o nal i nf or mati o n (e. g., d escri pti o n of s y m pt o ms, alle viati o n of s y m pt o ms, seiz ure or c o ma) i n 
relati o n t o se vere h y p o gl ycae mic e pis o des m ust be rec or de d i n t he h y p o gl ycae mic e pis o de (e)C R F.  
Di ar y re vie w  
At eac h c o ntact t he i n vesti gat or m ust re vie w t he diar y d ata f or c orrect re p orti n g of P G val u es a n d 
h y p o gl ycae mic e pis o des. I n case of i nc o m plete or i nc orrect data i n t he diar y, t he partici pa nt m ust be 
q uesti o ne d w het her t h ere ha ve bee n a n y se v ere h y p o gl ycae mic e pis o des si n ce t he last visit a n d 
re p ort acc or di n gl y. 
F or l o w P G val ues f or h y p o gl ycae mic e pis o des wit h i nc o m plete re p orti n g i nf or mati o n:  
1.  If a h y p o gl ycae mic e pis o de f or m i n t he diar y is n ot c o m plete d b y t h e partici pa nt wit hi n 7 
cale ndar da ys of t he P G meas ure me nt, t he e pis o de s h o ul d be descri be d i n t he s o urce d o c u me nts 
a n d re p ort e d b y t he i n vesti gat or o n a h y p o gl ycae mic e pis o de (e)C R F wit h as m uc h i nf or mati o n 
as p ossi ble. If t he partici pa nt di d n ot nee d hel p t o get a s u gar y dri n k, f o o d, or me dici ne, N o v o 
N or dis k will o nl y as k f or start date d ue t o r ecall bi as .3 1, 3 2 
Re -tr ai ni n g of p artici p a nts 
T he partici pa nt m ust be re -trai ne d i n h o w t o re p ort h y p o gl ycae mic e pis o des if t he i n vesti gat or 
i de ntifies l o w P G val ues n ot re p orte d as h y p o gl ycae mic e pis o des. T h e trai ni n g s h o ul d be 
d oc u me nte d b y t he i n vesti gat or i n  s o urce d oc u me nts. 
 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
9 0
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
9 1  of 1 0 0  
 
1 0. 9  A p pe n di x  9: Miti g ati o ns t o e ns ure p artici p a nt s afet y a n d d at a i nte grit y d uri n g a n 
e mer g e nc y sit u ati o n  
1 0. 9. 1  
Defi niti o n a n d sc o pe of a p pe n di x  
A maj or e mer ge nc y is defi ne d as a sit uati o n t hat ca uses s u bsta ntial restricti o ns t o st u d y sit e access 
f or partici pa nts a n d/ or s p o ns or re prese ntati ves. 
I n case l o cal restri cti o ns d ue t o C O VI D -1 9 o ut br ea k  lea d t o l oc k-d o w n of a site, t he site m ust 
c o ntact N o v o N or dis k t o all o w f or i m ple me ntati o n of miti gati o ns me nti o ne d i n t his a p pe n di x base d 
o n m ut ual a gree me nt.  
Acc or di n g t o l ocal re g ulati o n, healt h a ut h orities a n d i n de pe n de nt et hics c o m mittees s h o ul d be 
n otifie d i n case el e me nts of t he e mer ge nc y a p pe n di x are acti vate d.  
S ites s h o ul d al wa ys tr y t o f oll o w t he assess me nts o utli ne d i n t he ori gi nal fl o wc hart ( Secti o n 1. 2 ) t o 
t he e xte nt p ossi ble. I m ple me ntati o n of s pecifi c miti gati o ns s h o ul d be base d o n assess me nt of 
feasi bilit y at t he i n di vi d u al site. 
Sites s h o ul d c o m pl y wit h l ocal re g ulati o ns, re q uire me nts a n d/ or g ui d eli nes if t he y are iss ue d.  
1 0. 9. 2  
Visits  
Scree ni n g ( Visit 1) a n d ra n d o misati o n  ( Visit 2) s h o ul d al wa ys be perf or me d as o n-site visits. If a 
site is u na ble t o perf or m t hese visits o n-site, scree ni n g a n d ra n d o misati o n of ne w partici pa nts at t hat 
site s h o ul d be o n h ol d u ntil o n-site visits are p ossi ble. 
Visits  1, 2, 1 0 a n d 1 5 s h o ul d be perf or m e d as o n-site visits, if i n a n y wa y p ossi ble. If n ot, 
assess me nts ca n b e c o n d ucte d re m otel y ( vi d e o, p h o ne or si milar) or as off -site visits. 
O n -site visits ( Visits 3 -6, 8, a n d 1 2 -1 4  ) ca n be c o n verte d t o re m ote visits ( vi de o, p h o ne or si milar) 
or off -site visits. 
If t he e n d of treat me nt visit ca n n ot be perf or me d o n -site, usi n g re m ote ( vi de o, p h o ne or si milar) or 
off -site visits wit hi n t he gi ve n visit wi n d o w, t he visit wi n d o w f or t he assess me nt ca n be e xte n de d 
f or u p t o 1 wee k . 
If t he e n d of st u d y visit c a n n ot be perf or me d o n-site, usi n g re m ote ( vi de o, p h o ne or si milar) or off-
site visits wit hi n t he gi ve n visit wi n d o w, t he visit wi n d o w f or t he ass ess me nt ca n be e xte n de d f or u p 
t o 1  m o nt h .  
At eac h visit, t he i n vesti gat or m ust i n dicate i n t he eC R F h o w t he visit was perf or me d a n d s pecif y 
t he reas o n f or t he preferre d assess me nt met h o d. 
1 0. 9. 3  
Assess me nts  
Assess me nts use d f or safet y or t h e c o nfir m at or y e n d p oi nts (i.e., H b A 1c, b o d y wei g ht a n d A Es) 
s h o ul d be pri oritise d. T he preferre d or der f or t h e met h o d of assess me nt is: o n -site, off -site vi de o, 
p h o ne . S pecificati o ns r e gar di n g h o w t o perf or m t hese assess me nts usi n g re m ote visits or as off -site 
visits will be pr o vi de d b y N o v o N or dis k a n d will be base d o n o pti o ns a n d re q uire me nts at c o u ntr y 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
9 1
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
9 2  of 1 0 0  
 
le vel a n d if per mitte d b y l ocal re g ulati o ns. S pecifi cati o ns will i ncl u de trai ni n g f or raters perf or mi n g 
re m ote assess me nts a n d a d o pti o n of m o dificati o ns f or e q ui vale nt a d mi nistrati o n of assess me nts 
usi n g re m ote visits ( vi de o, p h o ne or si milar).  
L ocal la b orat ories or dia g n ostic facilities ca n be use d f or hae mat ol o g y, bi o c he mistr y a n d E C G at 
t he i n vesti gat or’s discreti o n if o n-site visits are n ot p ossi ble or i n case of te m p orar y l oc k d o w n of t he 
ce ntral la b orat or y. O nl y fi n di n gs meeti n g t he defi niti o n f or a n A E (refer t o A p pe n di x  3 
[ Secti o n 1 0. 3 ]) s h o ul d be re p orte d i n t he eC R F.  
If t he H b A 1 c, b o d y w ei g ht a n d A E assess me nts ca n n ot be perf or m e d as o n -site visits, re m ote visits 
or be a nal ys e d at a l ocal la b orat or y or di a g n ostic facilit y, t he y s h o ul d be p erf or me d at t he first 
p ossi ble ti me p oi nt f oll o wi n g t he ori gi nall y sc h e d ule d visit i n a gree me nt wit h N o v o N or dis k.  
1 0. 9. 4  
St u d y i nter ve nti o n  
Alter nati ve dis pe nsi n g met h o ds of I M P ma y b e i m ple me nte d, a n d det ails will be c o m m u nicate d a n d 
d oc u me nte d. T he dis pe nsi n g o pti o ns will be pr o vi de d b y N o v o N or dis k A/ S a n d will be base d o n 
o pti o ns a n d re q uire me nts at c o u ntr y le vel a n d if per mitte d b y l ocal re g ulati o ns. 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
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V V- T M F- 5 9 0 1 0 6 5
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1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
9 2
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
9 3  of 1 0 0  
 
1 0. 1 0  A p pe n di x  1 0: C o u ntr y -s pecific re q uire me nts 
Greece  
 A p pe n di x 4, Secti o n 1 0. 4 : 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:  
C o ntrace pti o n a n d pre g n a nc y testi n g s h o ul d b e i n acc or da nce wit h t he c urre nt E U 
rec o m me n dati o ns: Cli nical Trials Facilitati o n an d C o or di nati o n Gr o u p C T F G, 
Rec o m me n dati o ns relate d t o c o ntrace pti o n a n d pre g n a nc y testi n g i n cli nical trials.  
H u n g ar y  
 Secti o n  5. 1 : I ncl usi o n criteria:  
Par tici pa nt’s f ull Date of Birt h is n ot all o we d t o be c ollecte d a n d m ust be s h orte ne d t o Year 
of Birt h.  
P ol a n d  
 A p pe n di x 1 ( Secti o n  1 0. 1. 1 3 ): I n d e m nit y state m e nt: 
N o v o N or dis k carries lia bilit y i ns ur a nce f or t he Trial - Ter ms a n d C o n diti o ns c o m plia nt wit h 
t he Or di na nce of Mi nistr y of Fi na nce fr o m 1 8 Ma y 2 0 0 5 a m e n di n g t h e Or di na nce of 
Mi nistr y of Fi n a nce fr o m 3 0 A pril 2 0 0 4 o n C o m p uls or y Lia bili t y I ns ura n ce of Researc h er 
a n d S p o ns or.  
U nite d St ates  
 A p pe n di x 1 , Secti o n 1 0. 1. 1 : Re g ulat or y a n d et hical c o nsi derati o ns : 
F D A f or m 1 5 7 2:  
F or U S sites:  
o  I nte n d e d f or U S sites 
o  C o n d ucte d u n der t he I N D  
o  All U S i n vesti gat ors, as descri be d a b o ve, will si g n F D A F or m 1 5 7 2  
F or sites o utsi de t he U S:  
o  I nte n d e d f or p artici pati n g sites o utsi de of t he U S 
o  N ot c o n d ucte d u n der t he I N D  
o  All i n vesti gat ors o utsi de of t he U S will n ot si g n F D A f or m 1 5 7 2  
N o v o N or dis k will a nal yse a n d re p ort data fr o m all sites t o get her if m ore t ha n o ne site is 
i n v ol ve d i n t he stu d y . 
 A p pe n di x 2, Secti o n 1 0. 2 : Cli nical la b orat or y t ests:  
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, a part of 
t he sa m ple ma y be ke pt f or u p t o t w o years or acc or di n g t o l ocal re g ulati o ns. 
 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
9 3
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
9 4  of 1 0 0  
 
1 0. 1 1  A p pe n di x  1 1: A b bre vi ati o ns  
A D A  
A merica n Dia b etes Ass ociati o n  
A D E  
a d verse de vice effect  
A E  
a d verse e ve nt  
A L T  
ala ni ne a mi n otra nsferase  
A N C O V A  
a nal ysis of c o varia nce  
A S T  
as partate a mi n otra nsferase  
A T T D  
A d va nce d T ec h n ol o gies & Treat me nts f or Dia b etes  
B G  
bl o o d gl uc ose  
B MI  
b o d y mass i n de x  
B N P  
b rai n natri uretic pe pti de  
B U N  
bl o o d urea nitr o ge n  
C F R  
C o de of Fe deral Re g ulati o ns  
CI  
c o nfi de nce i nter val  
C K D  
c hr o nic ki d ne y disease  
C K D -E PI  
C hr o nic Ki d ne y Disease E pi de mi ol o g y C olla b orati o n  
C O VI D -1 9  
C or o na vir us disease 2 0 1 9  
C R F  
case re p ort f or m  
C S R  
cli nical st u d y re p ort  
C T F G  
cli nical trial facilitati o n gr o u p  
C T XI  
C -ter mi nal cr ossli n ke d tel o pe pti de t y pe I c olla ge n  
C V  
car di o vasc ular  
D B L  
data b ase l oc k  
D F U  
directi o ns f or use  
D P P -4  
di pe pti d yl p e pti dase -4  
D P S  
data p oi nts set  
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  
E A S D  
E ur o pea n Ass ociati o n f or t he St u d y of Dia betes  
E C G  
electr ocar di o gra m  
e C R F  
electr o nic case re p ort f or m  
e G F R  
esti mate d gl o mer ular filtrati o n rate  
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 E V 1 
force d e x pirat or y v ol u me  
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
9 4
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
9 5  of 1 0 0  
 
F P F V  
first partici pa nt first visit 
F P G  
fasti n g plas ma gl uc ose 
F V C  
F orce d vital ca p acit y  
G C P  
G o o d Cli nical Practice  
GI  
gastr oi ntesti nal  
GI P  
Gl uc ose -de p e n de nt i ns uli n otr o pic pe pti de  
G L P -1 R A  
gl uca g o n -li ke pe pti de-1 rece pt or a g o nist (  
H b A 1 c 
gl ycate d hae m o gl o bi n  
H O M A B  
h o me ostatic m o del assess me nt of beta -cell f u ncti o n  
H O M A I R  
h o me ostatic m o del assess me nt i ns uli n resista nce  
H R T  
h or m o ne re place me nt t hera p y  
hs -C R P  
h i g hl y se nsiti ve C-Reacti ve Pr otei n  
I B 
i n vesti gat or’s br oc h ure 
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n 
I C MJ E 
I nter nati o nal C o m mittee of M e dical J o ur nal E dit ors  
I E C 
i n de p e n de nt et hics c o m mittee 
I H S G 
T he I nter nati o nal H y p o gl ycae mia St u d y Gr o u p  
I M P 
i n vesti gati o nal me dici nal pr o d uct 
I N D 
i n vesti gati o nal ne w dr u g 
I O P 
i ntra o c ular press ure 
I R B 
i nstit uti o nal re vie w b oar d 
I S O 
I nter nati o nal Or ga nizati o n f or Har m o nizati o n 
I S P A D 
I nter nati o nal S ociet y f or P e diatric a n d A d olesce nt Dia betes 
I U D 
I ntra uteri ne de vice  
I U S 
I ntra uteri ne h or m o ne-releasi n g s yste m  
I W R S 
i nteracti ve we b res p o nse s yste m 
L A M  
lactati o nal a me n orr h oea met h o d  
L B B B  
left b u n dle bra nc h bl oc k li ke r ec or di n g 
L P L T  
last partici pa nt last treat me nt 
L P L V  
last partici p a nt last visit 
M D R  
Me dical De vice Re g ulati o n  
NI M P  
n o n -i n vesti gati o nal me dici nal pr o d uct 
N O A E L  
n o o bser ve d a d verse effect le vels  
N Y H A  
Ne w Y or k Heart Ass ociati o n  
P 1 N P  
Pr oc olla ge n 1 N -T er mi nal Pr o pe pti de  
P C D  
pri mar y c o m pleti o n date  
P G  
plas ma gl uc ose  
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
9 5
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
9 6  of 1 0 0  
 
P K  
p har mac o ki netic  
Q T L  
q ualit y t olera nce li mits  
R T S M  
R a n d o misati o n a n d T rial S u p plies M a na ge me nt  
S A D E  
seri o us a d verse de vice effect  
S A E  
seri o us a d verse e ve nt 
S A P  
Statistical A nal ysis Pla n  
S A S  
safet y a nal ysis set 
S D  
sta n dar d de viati o n 
S E  
Sta n dar d err or  
SI F  
Safet y i nf or mati o n f or m  
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 E A E  
treat me nt e mer ge nt a d verse e ve nt 
T M M  
Trial Materials Ma n ual  
U N L  
u p per n or mal li mit  
U S A D E  
U na ntici pate d seri o us a d verse de vice effect  
W O C B P  
w o ma n of c hil d beari n g p ote ntial  
 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
9 6
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
9 7  of 1 0 0  
 
1 0. 1 2  A p pe n di x  1 2: Pr ot oc ol a me n d me nt hist or y  
T he Pr ot oc ol a me n d me nt s u m mar y of c ha n ges ta ble f or t he c urre nt pr ot o c ol versi o n is l ocate d 
directl y b ef ore t he ta ble of c o nte nts.  
Pr ot oc ol ve rsi o n 2 . 0: (1 6 J u ne 2 0 2 2 ), gl o b al 
T his a me n d me nt is c o nsi dere d t o be n o n -s u bsta ntial base d o n t he criteria s et 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 h e E ur o pea n U ni o n 1, beca use 
it neit her si g nifica ntl y i m pacts t he safet y or p h ysic al/ me ntal i nte grit y of p artici pa nts n or t he 
scie ntific val ue of t h e st u d y. 
O ver all r ati o n ale f or pre p ari n g pr ot oc ol versi o n 2. 0  
Secti o n # a n d n a me  
Descri pti o n of c h a n ge  
Brief r ati o n ale  
Secti o n 5. 1 I ncl usi o n criteria  
C orrecti o n of u nit f or H b A 1c 
T o state t he ri g ht u nit  
Secti o n 6. 1 St u d y i nter ve nti o n(s) 
a d mi nistere d  
C orrecti o n of a n err or i n t he f o ot n ote 
of T a ble 6 -2  
T o ali g n t he f o ot n ote wit h T a ble 6 -2  
Secti o n 1 0. 2 A p pe n di x 2 Cli ni cal 
la b orat or y tests 
A d diti o n of f o ot n ote t o T a ble 1 0 -5  
T o ma ke it clear i n t he pr ot oc ol t hat 
a nal ysis of le pti n a n d s ol u ble l e pti n 
rece pt or will be perf or me d b y a s pecial 
la b orat or y c o ntracte d b y N o v o N or dis k 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
9 7
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
9 8  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. 2 0 0 1.  
2.  
B use J B, We xler DJ, Tsa pas A, R ossi n g P, Mi n gr o ne G, Mat hie u C, et al. 2 0 1 9 
U p date t o: Ma na ge me nt of H y per gl yce mia i n T y pe 2 Dia betes, 2 0 1 8. A 
C o nse ns us Re p ort b y t he A merica n Dia betes Ass ociati o n ( A D A) a n d t he 
E ur o pea n Ass ociati o n f or t he St u d y of Dia betes ( E A S D). Dia betes Care. 
2 0 2 0; 4 3( 2): 4 8 7 -9 3.  
3.  
Na uc k M A, Petrie J R, Sesti G, Ma n n ucci E, C o urrè ges J P, Li n de gaar d M L, et 
al. A P hase 2, Ra n d o mize d, D ose -Fi n di n g St u d y of t he N o vel O nce -Wee kl y 
H u ma n G L P -1 A nal o g, Se ma gl uti de , C o m pare d Wit h Place b o a n d O pe n-La bel 
Lira gl uti de i n Patie nts Wit h T y pe 2 Dia betes. Dia betes Care. 2 0 1 6; 3 9( 2): 2 3 1 -
4 1.  
4.  
Li n g va y I, Des o uza C V, Lalic K S, R ose L, Ha nse n T, Zac h o J, et al. A 2 6 -
Wee k Ra n d o mize d C o ntr olle d Trial of Se ma gl uti de O nce Dail y Ver s us 
Lira gl uti de a n d Place b o i n Patie nts Wit h T y pe 2 Dia betes S u b o pti mall y 
C o ntr olle d o n Diet a n d E xercise Wit h or Wit h o ut Metf or mi n. Dia betes Care. 
2 0 1 8; 4 1( 9): 1 9 2 6 -3 7.  
5.  
Frías J, A uer bac h P, Bajaj H, F u k us hi ma Y, Li n g va y I, Mac ura S, et al. 
Efficac y a n d s afet y of o nce -wee kl y se ma gl uti de 2· 0 m g   vers us 1· 0 m g i n 
patie nts wit h t y pe 2 dia betes ( S U S T AI N F O R T E): a d o u ble -bli n d, ra n d o mise d, 
p hase 3 B trial. La ncet Dia betes E n d ocri n ol o g y. 2 0 2 1; 2 1: 2 0 5 -9.  
6.  
Da vies M, F ærc h L, Je p pese n O K, Pa kseres ht A, Pe derse n S D,  Perrea ult L, et 
al. Se ma gl uti de 2· 4 m g o nce a wee k i n a d ults wit h o ver wei g ht or o besit y, a n d 
t y pe 2 dia betes ( S T E P 2): a ra n d o mise d, d o u ble-bli n d, d o u ble -d u m m y, 
place b o -c o ntr olle d, p hase 3 trial. La ncet. 2 0 2 1; 3 9 7( 1 0 2 7 8): 9 7 1 -8 4.  
7.  
N o v o N or dis k A/ S. A b bre v iate d i n vesti gat or's br oc h ure, se ma gl uti de s.c. f or 
T 2 D ( Oze m pic  ® ), pr oject N N 9 5 3 5 (e diti o n 1 8). 3 0 J ul y 2 0 2 1. 
8.  
N o v o N or dis k A/ S. I n vesti gat or's Br oc h ure, N o v o Pe n ®  4, pr oject M S 2 3 6, 
(e diti o n 2). 1 7 Ja n 2 0 2 2. 
9.  
N o v o N or dis k A/ S. Oze m pic ®  (se ma gl uti de), E U S u m mar y of pr o d uct 
c haracteristics ( S m P C). 2 2 Mar 2 0 2 1.  
1 0.  
N o v o N or dis k A/ S. Oze m pic  ® (se ma gl uti de), U S Prescri bi n g I nf or mati o n 
( PI). A pr 2 0 2 1. 
1 1.  
R u bi n o D M, Gree n wa y F L, K hali d U, O' Neil P M, R ose nst oc k J, S ørri g R, et 
al. Effect of Wee kl y S u bc uta ne o us Se ma gl uti de vs Dail y Lira gl uti de o n B o d y 
Wei g ht i n A d ults Wit h O ver wei g ht or O besit y Wit h o ut Dia betes: T he S T E P 8 
Ra n d o mize d Cli nical Trial. J A M A. 2 0 2 2; 3 2 7( 2): 1 3 8 -5 0.  
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
 |
V V- T M F- 5 9 0 1 0 6 5
 .
-
 |
1
 |
 of
  Pr ot oc ol  4 9 8 4 v 3. 0
9 8
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
9 9  of 1 0 0  
 
 
1 2.  
E ur o pea n C o m missi o n. T he R ules G o ver ni n g Me dici nal Pr o d ucts i n t he 
E ur o pea n U ni o n, V ol u me 4, A n ne x 1 3, I n vesti gati o nal Me dici nal Pr o d ucts  
( E N T R/ F/ 2/ A M/a n D( 2 0 1 0) 3 3 7 4). 0 3 Fe b 2 0 1 0. 
1 3.  
Ba n ks P A, B olle n T L, Der ve nis C, G o osze n H G, J o h ns o n C D, Sarr M G, et al. 
Classificati o n of ac ute pa ncreatitis -2 0 1 2: re visi o n of t he Atla nta classifi cati o n 
a n d defi niti o ns b y i nter nati o nal c o nse ns us. G ut. 2 0 1 3; 6 2( 1): 1 0 2 -1 1.  
1 4.  
Gra ha m B L, Stee n br u g ge n I, Miller M R, Barja ktare vic I Z, C o o per B G, Hall 
G L, et al. Sta n dar dizati o n of S pir o metr y 2 0 1 9 U p date. A n Official A merica n 
T h oracic S ociet y a n d E ur o pea n Res pirat or y S ociet y Tec h nical State me nt. A m J 
Res pir Crit Care Me d. 2 0 1 9; 2 0 0( 8):e 7 0 -e 8 8. 
1 5.  
Little RJ A, R u bi n D B. Statistical a nal ysis wit h missi n g data. Ne w Y or k: 
Wile y. 1 9 8 7. xi v, 2 7 8 p. p.  
1 6.  
W orl d Me dical Ass ociati o n. W M A Declarati o n of Helsi n ki - Et hical Pri nci ples 
f 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. Oct o ber 2 0 1 3.  
1 7.  
I C H Har m o nise d Tri partite G ui deli ne. G ui deli ne f or G o o d Cli nical Practice 
E 6( R 2),  C urre nt ste p 4 versi o n. 0 9  N o v 2 0 1 6.  
1 8.  
De A n gelis C, Draze n J M, Frizelle F A, Ha u g C, H oe y J, H ort o n R, et al. 
Cli nical trial re gistrati o n: a state me nt fr o m t he I nter nati o nal C o m mittee of 
Me dical J o ur nal E dit ors. N E n gl J Me d. 2 0 0 4; 3 5 1( 1 2): 1 2 5 0 -1.  
1 9.  
U. S. De part me nt of Healt h a n d  H u ma n Ser vices, F o o d a n d Dr u g 
A d mi nistrati o n. F o o d a n d Dr u g A d mi nistrati o n A me n d me nts Act of 2 0 0 7 as 
a me n de d b y t he Fi nal R ule " Cli nical Trials Re gistrati o n a n d Res ults 
I nf or mati o n S u b missi o n". 2 1 Se pte m ber 2 0 1 6. 
2 0.  
T he E ur o pea n Parlia me nt a n d t he C o u nci l 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 nar y use 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.  
2 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. Re g ulati o n 
( E C) N o 1 9 0 1/ 2 0 0 6 of t he E ur o pea n Parlia me nt a n d of t he C o u ncil of 1 2 
Dece m ber 2 0 0 6 o n me dici nal pr o d ucts f or pae diatri c use a n d a me n di n g 
Re g ulati o n ( E E C) N o 1 7 6 8/ 9 2, Directi ve 2 0 0 1/ 2 0/ E C, Directi ve 2 0 0 1/ 8 3/ E C 
a n d Re g ulati o n ( E C) N o 7 2 6/ 2 0 0 4, article 4 1. Official J o ur nal of t he E ur o pea n 
C o m m u nities. 2 7 Dec 2 0 0 6.  
2 2.  
T he E ur o pea n U ni o n. Re g ulati o n ( E U) 2 0 1 7/ 7 4 5 ( M D R)  of t he  E ur o pea n 
Parlia me nt a n d of t he C o u ncil of 5 A pril 2 0 1 7 o n me dical de vices, a me n di n g 
Directi ve 2 0 0 1/ 8 3/ E C, Re g ulati o n ( E C) N o 1 7 8/ 2 0 0 2 a n d Re g ulati o n ( E C) N o 
1 2 2 3/ 2 0 0 9 a n d re peali n g C o u ncil Directi ves 9 0/ 3 8 5/ E E C a n d 9 3/ 4 2/ E E C. 0 5 
Ma y 2 0 1 7.  
2 3.  
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 . 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
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V V- T M F- 5 9 0 1 0 6 5
 .
-
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1
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 of
  Pr ot oc ol  4 9 8 4 v 3. 0
9 9
1 0 0
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 3 Fe br uar y 2 0 2 3  N o v o N or di s k  
St u d y I D: N N 9 5 3 5 -4 9 8 4  
V ersi o n:  
3. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
1 0 0  of 1 0 0  
 
 
2 4.  
Cli nical Trial Facilitati o n Gr o u p ( C T F G), Hea ds of Me dici nes A ge nc y. 
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. 2 1 Se p 2 0 2 0. 
2 5.  
I nter nati o nal H y p o gl ycae mia St u d y Gr o u p. Gl uc ose C o nce ntrati o ns of Less 
T ha n 3. 0 m m ol/ L ( 5 4 m g/ d L) S h o ul d Be Re p orte d i n Cli nical Trials: A J oi nt 
P o siti o n State me nt of t he A merica n Dia betes Ass ociati o n a n d t he E ur o pea n 
Ass ociati o n f or t he St u d y of Dia betes. Dia betes Care. 2 0 1 7; 4 0( 1): 1 5 5 -7.  
2 6.  
A merica n Dia betes Ass ociati o n. 6. Gl yce mic Tar gets: Sta n dar ds of Me dical 
Care i n Dia betes -2 0 1 8. Dia betes Care . 2 0 1 8; 4 1( S u p pl 1): S 5 5-S 6 4.  
2 7.  
A bra ha m M B, J o nes T W, Nara nj o D, Kar ges B, O d u w ole A, Ta usc h ma n n M, 
et al. I S P A D Cli nical Practice C o nse ns us G ui deli nes 2 0 1 8: Assess me nt a n d 
ma na ge me nt of h y p o gl yce mia i n c hil dre n a n d a d olesce nts wit h dia betes. 
Pe diatr Dia be tes. 2 0 1 8; 1 9 S u p pl 2 7: 1 7 8-9 2.  
2 8.  
A gi ostrati d o u G, A n halt H, Ball D, Bl o n de L, G o ur gari E, Harri ma n K N, et al. 
Sta n dar dizi n g Cli nicall y Mea ni n gf ul O utc o me Meas ures Be y o n d H b A 1c f or 
T y pe 1 Dia betes: A C o nse ns us Re p ort of t he A merica n Ass ociati o n of Cli nical  
E n d ocri n ol o gists, t he A merica n Ass ociati o n of Dia betes E d ucat ors, t he 
A merica n Dia betes Ass ociati o n, t he E n d ocri ne S ociet y, J D R F I nter nati o nal, 
T he Le o na M. a n d Harr y B. Hel msle y C harita ble Tr ust, t he Pe diatric 
E n d ocri ne S ociet y, a n d t he T 1 D E xc ha n ge. Dia betes Care. 2 0 1 7; 4 0( 1 2): 1 6 2 2 -
3 0.  
2 9.  
Da n ne T, Ni mri R, Batteli n o T, Ber ge nstal R M, Cl ose K L, De Vries J H, et al. 
I nter nati o nal C o nse ns us o n Use of C o nti n u o us Gl uc ose M o nit ori n g. Dia betes 
Care. 2 0 1 7; 4 0( 1 2): 1 6 3 1 -4 0.  
3 0.  
Sea q uist E R, A n ders o n J, C hil ds B, Cr ye r P, Da g o g o-Jac k S, Fis h L, et al. 
H y p o gl yce mia a n d dia betes: a re p ort of a w or k gr o u p of t he A merica n Dia betes 
Ass ociati o n a n d t he E n d ocri ne S ociet y. Dia betes Care. 2 0 1 3; 3 6( 5): 1 3 8 4 -9 5.  
3 1.  
F o o d a n d Dr u g A d mi nistrati o n. G ui da nce f or I n d ustr y. Patie nt -Re p ort e d 
O utc o me Meas ures: Use i n Me dical Pr o d uct De vel o p me nt t o S u p p ort La beli n g 
Clai ms. Dece m ber 2 0 0 9.  
3 2.  
St ull D E, Lei d y N K, Paras ura ma n B, C hassa n y O. O pti mal recall peri o ds f or 
patie nt -re p orte d o utc o mes: c halle n ges a n d p ote ntial s ol uti o ns. C urr Me d Res 
O pi n. 2 0 0 9; 2 5( 4): 9 2 9 -4 2.  
 
N N 9 5 3 5- 4 9 8 4
N N 9 5 3 5
0
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V V- T M F- 5 9 0 1 0 6 5
 .
-
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1
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 of
  Pr ot oc ol  4 9 8 4 v 3. 0
1 0 0
1 0 0
C O N FI D E N TI A L