Clinical trial NCT05486065
Conditions: Diabetes Mellitus, Type 2
Sponsor: Novo Nordisk A/S
Start date: 2022-08-08; Completion date: 2023-12-13
Enrollment: 245 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study compares how three doses of semaglutide work in participants with type 2 diabetes (T2D) and overweight who are taking metformin. The study will look mainly at how well participant's blood sugar and participant's body weight are controlled when they are taking the study medicine at different doses. Participants will either get semaglutide \[2 milligrams (mg), 8 mg, or 16 mg\] or semaglutide placebo (a dummy medicine). Participants will take the study medicine with an injection pen called NovoPen®4. The injection pen is a medical tool with a needle used to inject the study medicine under the skin. The study will last for about 52 weeks. Participants will have 13 clinic visits and 4 phone calls.

Detailed description:

Arms: arm 1: Participants will receive once-weekly semaglutide 2 mg subcutaneous (s.c.) injection. arm 2: Participants will receive once-weekly semaglutide placebo 2 mg s.c. injection. arm 3: Participants will receive once-weekly semaglutide 8 mg s.c. injection. arm 4: Participants will receive once-weekly semaglutide placebo 8 mg s.c. injection. arm 5: Participants will receive once-weekly semaglutide 16 mg s.c. injection. arm 6: Participants will receive once-weekly semaglutide placebo 16 mg s.c. injection.
Interventions: intervention 1: Semaglutide intervention 2: Placebo
Intervention descriptions: intervention 1: Semaglutide s.c. injection once-weekly for 40 weeks. Dose gradually increased over 24 weeks, followed by a 16 week maintenance period. intervention 2: Semaglutide placebo s.c. injection once-weekly for 40 weeks. Dose gradually increased over 24 weeks, followed by a 16 week maintenance period.

Protocol documents:
Prot_000.pdf: 
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
 |
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
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
 |
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
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
 |
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 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
 |
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 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
 .
-
 |
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
 |
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 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
 |
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 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
 |
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 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
 |
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 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
 |
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 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
 |
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 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
 |
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 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
 |
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 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
 |
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 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
 |
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 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
 |
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 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
 |
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 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
 |
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 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
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 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:  
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
 |
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 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 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
 |
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 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:  
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
 |
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 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
 |
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 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
 .
-
 |
1
 |
 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
 .
-
 |
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
 |
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 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
 |
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 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
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 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:  
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
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
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 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
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 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
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 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:  
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
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 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
 .
-
 |
1
 |
 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
 .
-
 |
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
 |
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 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
 |
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 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
 .
-
 |
1
 |
 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. 
 
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 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:  
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.  
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 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:  
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.  
 
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 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:  
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
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 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:  
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
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 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:  
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
 |
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 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
 |
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 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
 |
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 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
 |
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 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
 |
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 0 0
1 0 0
C O N FI D E N TI A L

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT05486065 
Sponsor trial ID: 
NN9535-4984 
Official title of study: 
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
Document date: 
04 August 2022 


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
04 August 2022 Novo Nordisk 
Study ID: NN9535-4984 
Version: 
1.0 
Status: 
Final 
Page: 
1 of 23 
Statistical Analysis Plan 
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 
Substance: Semaglutide
Author 
 
CDS-GBS Biostatistics 
NN9535-4984
NN9535
0
 |
VV-TMF-5378386
 .
-
 |
1
 |
 of
 SAP  NN9535-4984 Statistical analysis plan
1
23
CONFIDENTIAL
Redacted statistical analysis plan 
Includes redaction of personal identifiable information only. 
. 


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
04 August 2022 Novo Nordisk 
Study ID: NN9535-4984 
Version: 
1.0 
Status: 
Final 
Page: 
2 of 23 
Table of contents 
Page 
Table of contents ............................................................................................................................................... 2
Table of figures ................................................................................................................................................. 3
Table of tables ................................................................................................................................................... 4
Version History ................................................................................................................................................. 5
List of abbreviations ......................................................................................................................................... 6
1 Introduction ................................................................................................................................................. 7
1.1 
Objectives, Endpoints, and Estimands ................................................................................................ 7
1.1.1 
Estimands ............................................................................................................................ 8
1.1.2 
Addressing the primary objective ........................................................................................ 8
1.1.2.1
Primary estimand ............................................................................................. 8
1.1.2.2
Additional estimand ......................................................................................... 8
1.1.3 
Addressing the secondary objective .................................................................................... 9
1.2
Study Design ....................................................................................................................................... 9
2 Statistical Hypothesis ................................................................................................................................ 11
2.1
Multiplicity Adjustment .................................................................................................................... 11
3 Analysis Sets .............................................................................................................................................. 12
4 Statistical Analyses .................................................................................................................................... 14
4.1
Dose-response modelling .................................................................................................................. 14
4.2
General Considerations ..................................................................................................................... 15
4.3
Primary Endpoint Analysis ............................................................................................................... 15
4.3.1 
Definition of Endpoint ....................................................................................................... 15
4.3.2 
Main Analytical Approach ................................................................................................ 16
4.3.2.1
Analysis addressing the primary estimand ..................................................... 16
4.3.3 
Supplementary Analysis .................................................................................................... 16
4.4
Secondary Endpoint Analysis ........................................................................................................... 17
4.4.1.1 
Primary estimand ........................................................................................... 17
4.4.1.2 
Supplementary analysis .................................................................................. 17
4.5
Exploratory Endpoints Analysis ....................................................................................................... 17
4.6
Safety Analysis ................................................................................................................................. 17
4.6.1
Adverse Events .................................................................................................................. 17
4.6.2
Additional Safety Assessments ......................................................................................... 17
4.7
Other Analyses .................................................................................................................................. 18
4.7.1
Other Parameters ............................................................................................................... 18
4.7.2
Subgroup Analysis ............................................................................................................. 19
4.8
Interim Analysis ................................................................................................................................ 19
4.9
Changes to Protocol-planned Analysis ............................................................................................. 19
5 Sample size determination ........................................................................................................................ 21
6 Supporting Documentation ...................................................................................................................... 22
7 References .................................................................................................................................................. 23
NN9535-4984
NN9535
0
 |
VV-TMF-5378386
 .
-
 |
1
 |
 of
  SAP  NN9535-4984 Statistical analysis plan
2
23
CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
04 August 2022 Novo Nordisk 
Study ID: NN9535-4984 
Version: 
1.0 
Status: 
Final 
Page: 
3 of 23 
Table of figures 
Page 
Figure 1
Study design ............................................................................................................................... 10
NN9535-4984
NN9535
0
 |
VV-TMF-5378386
 .
-
 |
1
 |
 of
  SAP  NN9535-4984 Statistical analysis plan
3
23
CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
04 August 2022 Novo Nordisk 
Study ID: NN9535-4984 
Version: 
1.0 
Status: 
Final 
Page: 
4 of 23 
Table of tables 
Page 
Table 1
Objectives and Endpoints ............................................................................................................ 7
Table 2
Participant analysis sets ............................................................................................................. 12
Table 3
Data points sets .......................................................................................................................... 12
Table 4
Dose-response candidate models ............................................................................................... 14
NN9535-4984
NN9535
0
 |
VV-TMF-5378386
 .
-
 |
1
 |
 of
  SAP  NN9535-4984 Statistical analysis plan
4
23
CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
04 August 2022 Novo Nordisk 
Study ID: NN9535-4984 
Version: 
1.0 
Status: 
Final 
Page: 
5 of 23 
Version History 
This Statistical Analysis Plan (SAP) for study NN9535-4984 is based on the protocol version 2.0 
dated 16JUN2022. 
SAP Version 
Date 
Change 
Rationale 
1.0 
04 August 
2022 
Not Applicable 
Original version 
NN9535-4984
NN9535
0
 |
VV-TMF-5378386
 .
-
 |
1
 |
 of
  SAP  NN9535-4984 Statistical analysis plan
5
23
CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
04 August 2022 Novo Nordisk 
Study ID: NN9535-4984 
Version: 
1.0 
Status: 
Final 
Page: 
6 of 23 
List of abbreviations 
AE 
adverse event 
ANCOVA 
analysis of covariance 
BMI 
body mass index 
CI 
confidence interval 
DMC 
data monitoring committee 
EMA 
European Medicines Agency 
FDA 
US Food and Drug Administration 
ICH 
International Council on Harmonization 
LLoQ 
lower limit of quantification 
MedDRA 
medical dictionary for regulatory activities 
SAP 
Statistical Analysis Plan 
SMQs 
standardized MedDRA queries 
TFL 
tables, figures and listings 
NN9535-4984
NN9535
0
 |
VV-TMF-5378386
 .
-
 |
1
 |
 of
  SAP  NN9535-4984 Statistical analysis plan
6
23
CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
04 August 2022 Novo Nordisk 
Study ID: NN9535-4984 
Version: 
1.0 
Status: 
Final 
Page: 
7 of 23 
1 
Introduction 
There are no changes to the analyses described in the protocol. 
Specifications of tables, figures and listings (TFL) and other specifications not included in this SAP 
will be described in the mock TFL. 
1.1 
Objectives, Endpoints, and Estimands 
Table 1 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
Title 
Time Frame 
Unit 
To characterise the 
dose-response curve 
of once-weekly 
semaglutide s.c. for 
change in HbA1c 
from baseline to week 
40 in patients with 
T2D and BMI ≥ 27 
kg/m2 as an add-on to 
a stable dose of 
metformin 
Change in HbA1c 
From baseline (week 
0) to end of treatment
(week 40)
%-point 
Secondary 
Title 
Time Frame 
Unit 
To characterise the 
dose-response curve 
of once-weekly 
semaglutide s.c. for 
change in body weight 
from baseline to week 
40 in patients with 
T2D and BMI ≥ 27 
kg/m2 as an add-on to 
a stable dose of 
metformin 
Confirmatory 
Change in body 
weight 
From baseline (week 
0) to end of treatment
(week 40)
kg 
To characterise the 
dose-response curve 
of once-weekly 
semaglutide s.c. for 
safety and tolerability 
from baseline to week 
49 in patients with 
T2D and BMI ≥ 27 
kg/m2 as an add-on to 
Supportive 
Number of treatment-
emergent adverse 
events (TEAEs) 
From baseline (week 
0) to end of study
(week 49)
Count of events 
Number of treatment 
emergent severe 
hypoglycaemic 
episodes 
From baseline (week 
0) to end of study
(week 49)
Count of events 
NN9535-4984
NN9535
0
 |
VV-TMF-5378386
 .
-
 |
1
 |
 of
  SAP  NN9535-4984 Statistical analysis plan
7
23
CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
04 August 2022 Novo Nordisk 
Study ID: NN9535-4984 
Version: 
1.0 
Status: 
Final 
Page: 
8 of 23 
a stable dose of 
metformin 
1.1.1 
Estimands 
The estimands and their rationale are described in detail for each of the two primary and secondary 
objectives. Two intercurrent events were identified: 

Premature discontinuation of randomised treatment

Initiation of rescue medication (refer protocol Section 6.8.1)
1.1.2 
Addressing the primary objective 
1.1.2.1 
Primary estimand 
The primary estimand addresses the main question of interest: What is the dose-response curve of 
once-weekly semaglutide s.c/pooled placebo for change in HbA1c (%-point) from baseline to week 
40 in patients with T2D and BMI ≥ 27 kg/m2, as an add-on to a stable dose of metformin regardless 
of premature discontinuation of randomised treatment and initiation of recuse medication? Notably, 
in the treatment regimen evaluated, participants who cannot tolerate the received dose will have 
treatment discontinued. 
The primary estimand is defined by the following five attributes: 

Population: Patients with T2D and BMI ≥ 27 kg/m2.

Endpoint: Change from baseline to week 40 in HbA1c (%-point).

Treatment condition: Randomised treatment as add-on to a stable dose of metformin, with or
without premature discontinuation of treatment and initiation of rescue medication.

Remaining intercurrent events: No further intercurrent events are identified. The two
intercurrent events described as part of the treatment condition will all be handled by a
treatment policy strategy.

Population-level summary: Difference in mean changes from baseline.
Rationale for estimand: This estimand quantifies the difference in treatment effects between the 
different treatment regimens that can be expected in clinical practice. It reflects the clinical practice, 
under which the treatment regimens are to be applied. 
1.1.2.2 
Additional estimand 
The additional estimand addresses an additional question of interest: What is the dose-response 
curve of once-weekly semaglutide s.c/pooled placebo for change in HbA1c (%-point) from baseline 
to week 40 in patients with T2D and BMI ≥ 27 kg/m2, as an add-on to a stable dose of metformin, 
if all participants had remained on randomised treatment without initiation of rescue medication? 
Notably, in the treatment regimen evaluated, participants who cannot tolerate the received dose will 
have treatment discontinued. 
NN9535-4984
NN9535
0
 |
VV-TMF-5378386
 .
-
 |
1
 |
 of
  SAP  NN9535-4984 Statistical analysis plan
8
23
CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
04 August 2022 Novo Nordisk 
Study ID: NN9535-4984 
Version: 
1.0 
Status: 
Final 
Page: 
9 of 23 
The estimand attributes: population, endpoint, and population-level summary are the same as for the 
primary estimand. The remaining attributes are: 

Treatment condition: Randomised treatment as add-on to a stable dose of metformin,
without premature discontinuation of treatment and initiation of rescue medication.

Remaining intercurrent events: No further intercurrent events are identified. The two
intercurrent events described as part of the treatment condition will all be handled by a
hypothetical strategy.
Rationale for estimand: This estimand quantifies the achievable difference in treatment effects 
between the different treatment regimens. It reflects the drug efficacy. 
1.1.3 
Addressing the secondary objective 
The relevant endpoint is the secondary confirmatory endpoint “change from baseline to week 40 in 
body weight (kg)”. 
Change in body weight - primary estimand 
The main clinical question of interest for this secondary confirmatory objective is similar to the 
primary estimand for the primary objective. 
The estimand attributes: population, treatment condition, remaining intercurrent events, and 
population-level summary are the same as for the primary estimand for the primary objective. The 
remaining estimand attribute is: 

Endpoint: Change from baseline to week 40 in body weight (kg).
Rationale for estimand: The rationale is the same as for the primary estimand for the primary 
objective. 
Change in body weight – additional estimand 
The additional clinical question of interest for this secondary confirmatory objective is similar to the 
additional estimand for the primary objective. 
The estimand attributes: population, treatment condition, remaining intercurrent events, and 
population-level summary are the same as for the additional estimand for the primary objective. The 
remaining estimand attribute is:  

Endpoint: Change from baseline to week 40 in body weight (kg).
Rationale for estimand: The rationale is the same as for the additional estimand for the primary 
objective. 
1.2 
Study Design 
This is an interventional, 40-week, multi-centre, parallel-group, randomised, placebo-controlled, 
participant and investigator-blinded within dose level, sponsor open-label, dose-response study of 
NN9535-4984
NN9535
0
 |
VV-TMF-5378386
 .
-
 |
1
 |
 of
  SAP  NN9535-4984 Statistical analysis plan
9
23
CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
04 August 2022 Novo Nordisk 
Study ID: NN9535-4984 
Version: 
1.0 
     
Status: 
Final 
     
Page: 
10 of 23 
 
 
once-weekly subcutaneously administered semaglutide in patients with T2D and overweight with a 
baseline HbA1c of 7.0–10.5% and as an add-on to a stable dose of metformin (Figure 1). 
A total of 240 participants will be randomised in a 3:1:3:1:3:1 ratio to receive semaglutide s.c. (2 
mg, 8 mg, 16 mg) or matching placebo. All participants are to escalate to the randomised target 
maintenance dose according to the dose escalation outlined in Table 6-2.  
Randomisation will be stratified according to HbA1c at screening (<8.5%/≥8.5%). 
Figure 1 
Study design 
 
The study consists of: 
 an up to 3-week screening period 
 a dose escalation period of 12-24 weeks (see Table 6-2) 
 a maintenance period of 16-28 weeks (see Table 6-2) 
 a 9-week follow-up period 
 
For each participant, the maximum intervention and study duration is 40 weeks and 52 weeks, 
respectively. 
For further study design information, refer the protocol section 4.1. 
NN9535-4984
NN9535
0
 |
VV-TMF-5378386
 .
-
 |
1
 |
 of
  SAP  NN9535-4984 Statistical analysis plan
10
23
CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
04 August 2022 Novo Nordisk 
Study ID: NN9535-4984 
Version: 
1.0 
Status: 
Final 
Page: 
11 of 23 
2 
Statistical Hypothesis 
Not applicable 
2.1 
Multiplicity Adjustment 
Not applicable 
NN9535-4984
NN9535
0
 |
VV-TMF-5378386
 .
-
 |
1
 |
 of
  SAP  NN9535-4984 Statistical analysis plan
11
23
CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
04 August 2022 Novo Nordisk 
Study ID: NN9535-4984 
Version: 
1.0 
     
Status: 
Final 
     
Page: 
12 of 23 
 
 
3 
Analysis Sets 
Two participant analysis sets are defined, see Table 2: 
Table 2 
Participant analysis sets 
Participant analysis set 
Description 
Full analysis set 
All randomised participants. Participants will be included in the 
analyses according to the planned randomised treatment. 
Safety analysis set 
All participants who are exposed to randomised treatment. 
Participants will be included in the analyses according to the 
treatment they actually received. 
 
Four data points sets are defined, see Table 3: 
Table 3 
Data points sets 
Data points set (DPS) 
Description 
DPS1 – in-study 
All observed data points from randomisation until the first date of: 
 end of study visit (V17) 
 death 
 withdrawal of informed consent 
 last contact as defined by investigator for participants that 
are lost to follow up 
DPS2 – on-treatment 
All observed data points from first drug date until the first date of: 
 end of DPS1 
 last administration of randomised treatment +63 days 
DPS2 - modified 
All observed data points with acute onset (laboratory assessments, 
and physical examination) from first drug date until the first date of: 
 end of DPS1 
 last administration of randomised treatment +7 days 
DPS3 – on-treatment 
without rescue 
All observed data points from first drug date until the first date of: 
 initiation of rescue medication 
 last administration of randomised treatment +7 days 
 
The full analysis set (FAS) will be used when analysing efficacy endpoints and assessments, and the 
safety analysis set (SAS) will be used when analysing safety endpoints and assessments. 
The FAS and DPS1 are used to estimate the primary estimand for the primary endpoint and the 
primary estimand for the confirmatory secondary endpoint. 
The FAS and DPS3 are used to estimate the additional estimands for the primary and confirmatory 
secondary endpoint. 
NN9535-4984
NN9535
0
 |
VV-TMF-5378386
 .
-
 |
1
 |
 of
  SAP  NN9535-4984 Statistical analysis plan
12
23
CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
04 August 2022 Novo Nordisk 
Study ID: NN9535-4984 
Version: 
1.0 
Status: 
Final 
Page: 
13 of 23 
The SAS and DPS2 are used as the primary data points set to evaluate safety data (AEs, eye 
examination, vital signs and hypoglycaemic episodes). The primary evaluation of antibodies will be 
based on the safety analysis set and DPS2. 
The SAS and a modified DPS2 are used to present safety data with an acute onset (laboratory 
assessments, and physical examination). 
NN9535-4984
NN9535
0
 |
VV-TMF-5378386
 .
-
 |
1
 |
 of
  SAP  NN9535-4984 Statistical analysis plan
13
23
CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
04 August 2022 Novo Nordisk 
Study ID: NN9535-4984 
Version: 
1.0 
Status: 
Final 
Page: 
14 of 23 
4 
Statistical Analyses 
4.1 
Dose-response modelling 
To characterise the dose-response relationship for change in HbA1c (%-point) and change in body 
weight (kg) at week 40 for the primary and additional estimand, the following dose-response 
candidate models in Table 4 will be fit separately. The variable d is the nominal dose level, and the 
other variables are model parameters to be estimated. 
Table 4 
Dose-response candidate models 
Model 
Functional form f(d,θ) 
Linear log-dose 
𝐸0 + 𝛽log(𝑑+ 1) 
Emax 
𝐸0 + 𝐸𝑚𝑎𝑥
𝑑
𝐸𝐷50 + 𝑑
Sigmoidal Emax 
𝐸0 + 𝐸𝑚𝑎𝑥
𝑑𝜆
𝐸𝐷50
𝜆+ 𝑑𝜆
Linear + Emax 
𝐸0 + 𝛽𝑑+ 𝐸𝑚𝑎𝑥
𝑑
𝐸𝐷50 + 𝑑
Emax: 
The Emax model, describes the concentration-effect relationship in terms of a baseline effect when 
no drug is present (E0), the maximum possible effect (Emax), and the drug concentration producing 
half-maximal effect (ED50) and the nominal dose level (d). 
Sigmoidal Emax: 
The Emax model including slope parameter (λ) is referred to as the sigmoidal Emax model. 
Linear log-dose: 
The linear log-dose model, describes the concentration-effect relationship in terms of a baseline 
effect when no drug is present (E0), with location-scale model which is expressed as log(d + c) 
where c = 1 and nominal dose level (d) and 𝛽 is slope associated with log(d + c) . 
Linear + Emax: 
The combination of linear and Emax model, where in the linear model describes the concentration-
effect relationship in terms of a baseline effect when no drug is present (E0), slope parameter (𝛽), 
the nominal dose level (d). Emax has been described as above.  
The candidate models will be fit to the mean estimated endpoint changes at week 40 for the 
evaluated semaglutide s.c. doses and pooled placebo derived from the analyses models described 
above according to the estimand evaluated. When fitting the models, the mean estimated endpoint 
change will be weighted by their inverse estimated variances. 
NN9535-4984
NN9535
0
 |
VV-TMF-5378386
 .
-
 |
1
 |
 of
  SAP  NN9535-4984 Statistical analysis plan
14
23
CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
04 August 2022 Novo Nordisk 
Study ID: NN9535-4984 
Version: 
1.0 
Status: 
Final 
Page: 
15 of 23 
The model ultimately used to evaluate dose-response will be selected among the candidate models 
based on the best fit to data. The best fit will be evaluated based on convergence and Akaike 
information criterion (AIC) value.  
4.2 
General Considerations 
From the statistical analyses the point estimate, two-sided 95% CIs, and the associated two-sided 
p-values will be presented for the following comparison:

Semaglutide 2 mg vs pooled placebo

Semaglutide 8 mg vs pooled placebo

Semaglutide 16 mg vs pooled placebo

Semaglutide 8 mg vs Semaglutide 2 mg

Semaglutide 16 mg vs Semaglutide 8 mg

Semaglutide 16 mg vs Semaglutide 2 mg
For all analyses and reporting, the three placebo arms will be pooled into one placebo group to have 
an unbiased analysis due to the differentiation of response to semaglutide s.c. from response due to 
other factors such as study participation and intensified medical attention. 
Furthermore, to investigate the pooling of placebo descriptive statistics will be provided of change 
in HbA1c at week 40 and change in body weight (kg) at week 40 will be done without pooling the 
placebo. 
If an assessment has been made both at screening and randomisation, the value from the 
randomisation visit will be used as the baseline value. If the value measured at the randomisation 
visit is missing, and the assessment was made at screening, the screening value will be used as the 
baseline value. The participants with missing baseline values will not contribute to any analysis that 
adjust for the given baseline. 
The stratification factor in the statistical analysis will be based on observed baseline value of 
HbA1c ≥ 8.5% (Y/N).
4.3 
Primary Endpoint Analysis 
4.3.1 
Definition of Endpoint 
Definition of primary endpoint: Change in HbA1c (%-point) 
Change from baseline (week 0) to week 40 in HbA1c is defined as: 
HbA1c change = HbA1c at week 40 − HbA1c at baseline 
NN9535-4984
NN9535
0
 |
VV-TMF-5378386
 .
-
 |
1
 |
 of
  SAP  NN9535-4984 Statistical analysis plan
15
23
CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
04 August 2022 Novo Nordisk 
Study ID: NN9535-4984 
Version: 
1.0 
     
Status: 
Final 
     
Page: 
16 of 23 
 
 
4.3.2 
Main Analytical Approach 
4.3.2.1 
Analysis addressing the primary estimand 
The primary estimand, presented in Section 1.1.1, will be estimated based on the FAS using the in-
study data points set (DPS1). 
The primary analysis for this estimand is an analysis of covariance (ANCOVA) with randomised 
treatment and stratification factor as fixed effects and baseline HbA1c as a covariate. 
Handling of missing data 
Jump to reference: Missing week 40 data will be imputed using multiple imputation assuming that 
missing data are missing not at random. The imputation will be performed by sampling among all 
available assessments at week 40 in the pooled placebo group. A pattern mixture model approach is 
applied where withdrawn participants without a follow-up visit are assumed to respond as if treated 
with placebo for the entire study. This approach is also known as “jump to reference” and makes the 
assumption that participants instantly after discontinuation lose any effect of randomised treatment 
beyond what can be expected from the pooled placebo group. 
Multiple copies (500 copies) of the full dataset will be generated by imputing missing values based 
on estimated parameters for the pooled placebo group. This will be done as follows: 
 500 copies of the dataset will be generated. 
 An enriched ANCOVA model with stratification factor and sex as fixed effects and baseline 
HbA1c as covariate will be fitted to the change from baseline to week 40 in HbA1c for the 
completers in the pooled placebo group only. 
 For each of the 500 copies of the dataset, the estimated parameters and their variances from 
this model will be used to impute missing week 40 values for participants in all treatment 
arms, based on their factor level and the values of the covariate. 
 For each of the 500 complete datasets, the change from baseline to week 40 in HbA1c will 
be analysed repeating the ANCOVA described above. The estimates and standard deviations 
(SDs) for the 500 data sets are pooled to one estimate and associated SD using Rubin’s rule. 
4.3.3 
Supplementary Analysis 
Additional estimand analysis 
The additional estimand, presented in section 1.1.2.2, will be estimated based on the FAS using 
post-baseline data collected up to and including week 40 from the ‘on-treatment without rescue’ 
observation period (DPS3). 
Imputation of missing data will be handled by MI assuming that missing data are MAR. The 
imputation will be performed separately within each treatment group defined by randomised 
treatment. First, intermittent missing values are imputed using a Markov Chain Monte Carlo 
method to obtain a monotone missing data pattern, generating 500 complete data sets. Secondly, a 
NN9535-4984
NN9535
0
 |
VV-TMF-5378386
 .
-
 |
1
 |
 of
  SAP  NN9535-4984 Statistical analysis plan
16
23
CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
04 August 2022 Novo Nordisk 
Study ID: NN9535-4984 
Version: 
1.0 
Status: 
Final 
Page: 
17 of 23 
sequential conditional linear regression approach for imputing monotone missing values will be 
implemented starting with the first visit after baseline and sequentially continuing to the last 
planned visit at week 40. The model used for imputation will include stratification factor and sex as 
fixed effects and baseline and post-baseline HbA1c values observed prior to the visit in question as 
covariates. 
The 500 complete datasets will be analysed using an ANCOVA with stratification factor and 
randomised treatment as fixed effects and baseline HbA1c as a covariate. Rubin’s rule will be 
applied to combine the estimates and draw inference. 
4.4 
Secondary Endpoint Analysis 
4.4.1.1 
Primary estimand 
For the endpoint “change from baseline to week 40 in body weight (kg)” a similar analysis as 
described in Section 4.3.2.1 will be performed, but with values of body weight instead of HbA1c. 
4.4.1.2 
Supplementary analysis 
Additional estimand 
A similar analysis as described in Section 4.3.3 will be performed, but with values of body weight 
instead of HbA1c. 
4.5 
Exploratory Endpoints Analysis 
Not applicable 
4.6 
Safety Analysis 
All safety analyses will be made on the safety analysis set. The standard safety assessments (AEs, 
laboratory parameters, vital signs, etc.) will be reported descriptively based on the DPS2 and 
modified DPS2; including any notable changes of clinical interest in laboratory parameters.  
The primary evaluation of antibodies will be based on the safety analysis set and DPS2. 
4.6.1 
Adverse Events 
Summaries of TEAEs are presented as an overview including all AEs, serious AEs, AEs leading to 
withdrawal, AEs by severity, AEs by relation to treatment and outcome of AEs. Furthermore, 
summary tables based on system organ class and preferred term is made for:  

All TEAEs

Serious TEAEs

AE Leading to premature treatment discontinuation
4.6.2 
Additional Safety Assessments 
Not applicable 
NN9535-4984
NN9535
0
 |
VV-TMF-5378386
 .
-
 |
1
 |
 of
  SAP  NN9535-4984 Statistical analysis plan
17
23
CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
04 August 2022 Novo Nordisk 
Study ID: NN9535-4984 
Version: 
1.0 
     
Status: 
Final 
     
Page: 
18 of 23 
 
 
4.7 
Other Analyses 
Pharmacokinetic and/or pharmacodynamic modelling 
Population PK and exposure-response analyses will be used to characterize the exposure response 
curve of semaglutide s.c., and to support selection of a dose for potential future investigation in 
patients with T2D. 
The population PK model will be implemented identical to that reported for NN9535-4506. A 
single pre-specified exposure-response analysis will be applied to investigate trends towards higher 
effect at higher exposure levels, based on the average semaglutide concentration estimated at the 
planned maintenance dose. These analyses will be based on the active arms (excluding placebo) 
conducted for change in HbA1c and change in body weight at end of treatment (Change.EOT), 
assessing exposure-response as if subjects were randomized at week 16. 
Change.EOT = E0+Slope*log(Cavg)+p*Change.Week.16 
Where E0, Slope and p, are parameters in the model. 
Additional exposure-response modelling will be considered exploratory and potentially conducted 
together with other semaglutide trials.  Modelling results will be reported separately from the CSR. 
Anti-Semaglutide antibodies 
Anti-Semaglutide antibodies will be summarised in terms of the number and percentage of subjects 
per visit that are antibody-positive, antibody-negative, cross-reacting and in vitro neutralising, 
respectively.  
4.7.1 
Other Parameters 
All collected continuous or categorical data that were not defined as endpoints will be summarised 
by descriptive statistics or by count and percentage respectively using FAS. 
Pulse 
For the endpoint “change from baseline to week 40 in pulse” a similar analysis as described in 
Section 4.3.2.1will be performed, but with values of pulse instead of HbA1c. 
Responder for HbA1c 
  HbA1c <7.0% at week 40 (yes/no) ,  
 ≤6.5% at week 40 (yes/no)  and 
 <5.7% at week 40 (yes/no)  
 
The endpoints will be analysed using the imputed data from primary endpoint as described in 
Section 4.3.2.1 
The statistical model for the responder endpoints relating to HbA1c will be analysed using logistic 
regression with factor and covariates used as for primary endpoint with baseline HbA1c.  
NN9535-4984
NN9535
0
 |
VV-TMF-5378386
 .
-
 |
1
 |
 of
  SAP  NN9535-4984 Statistical analysis plan
18
23
CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
04 August 2022 Novo Nordisk 
Study ID: NN9535-4984 
Version: 
1.0 
Status: 
Final 
Page: 
19 of 23 
Responder for Body weight 

Weight loss ≥ 5% at week 40 (yes/no),

Weight loss ≥ 10% at week 40 (yes/no).
The endpoints will be analysed using the imputed data from primary endpoint as described in 
Section 4.4.1.1 
The statistical model for the responder endpoints relating to body weight will be analysed using 
logistic regression with factor and covariates used as for primary endpoint with baseline body 
weight. 
4.7.2 
Subgroup Analysis 
Not applicable. 
4.8 
Interim Analysis 
Not applicable. 
4.9 
Changes to Protocol-planned Analysis 

Linear model has been removed from “Dose response modelling” instead Linear +Emax has
been included and the order of the model to be used has been changed in Table 4.

The following text in protocol:
“The FAS and DPS1 are used to estimate the primary estimand for the primary endpoint and the 
secondary estimand for the confirmatory secondary endpoint.” 
is replaced to: 
“The FAS and DPS1 are used to estimate the primary estimand for the primary endpoint and the 
primary estimand for the confirmatory secondary endpoint.” 

The following text in protocol:
“The best fit will be evaluated based on convergence, model complexity, Akaike information 
criterion (AIC) value, and visual evaluation. “ 
is replaced to: 
“The best fit will be evaluated based on convergence and Akaike information criterion (AIC) 
value.”  
NN9535-4984
NN9535
0
 |
VV-TMF-5378386
 .
-
 |
1
 |
 of
  SAP  NN9535-4984 Statistical analysis plan
19
23
CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
04 August 2022 Novo Nordisk 
Study ID: NN9535-4984 
Version: 
1.0 
     
Status: 
Final 
     
Page: 
20 of 23 
 
 
 The following text in protocol: 
“A modelling analysis plan will be prepared before database lock outlining details of the analyses. 
The modelling will be performed by Quantitative Clinical Pharmacology at Novo Nordisk and will 
be reported separately from the CSR.” 
is replaced to: 
“The population PK model will be implemented identical to that reported for NN9535-4506. A 
single pre-specified exposure-response analysis will be applied to investigate trends towards higher 
effect at higher exposure levels, based on the average semaglutide concentration estimated at the 
planned maintenance dose. These analyses will be based on the active arms (excluding placebo) 
conducted for change in HbA1c and change in body weight at end of treatment (Change.EOT), 
assessing exposure-response as if subjects were randomized at week 16. 
Change.EOT = E0+Slope*log(Cavg)+p*Change.Week.16 
Where E0, Slope and p, are parameters in the model. 
Additional exposure-response modelling will be considered exploratory and potentially conducted 
together with other semaglutide trials.  Modelling results will be reported separately from the CSR.” 
 
NN9535-4984
NN9535
0
 |
VV-TMF-5378386
 .
-
 |
1
 |
 of
  SAP  NN9535-4984 Statistical analysis plan
20
23
CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
04 August 2022 Novo Nordisk 
Study ID: NN9535-4984 
Version: 
1.0 
Status: 
Final 
Page: 
21 of 23 
5 
Sample size determination 
See the protocol section 9.5. 
NN9535-4984
NN9535
0
 |
VV-TMF-5378386
 .
-
 |
1
 |
 of
  SAP  NN9535-4984 Statistical analysis plan
21
23
CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
04 August 2022 Novo Nordisk 
Study ID: NN9535-4984 
Version: 
1.0 
Status: 
Final 
Page: 
22 of 23 
6 
Supporting Documentation 
Not applicable 
NN9535-4984
NN9535
0
 |
VV-TMF-5378386
 .
-
 |
1
 |
 of
  SAP  NN9535-4984 Statistical analysis plan
22
23
CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
04 August 2022 Novo Nordisk 
Study ID: NN9535-4984 
Version: 
1.0 
Status: 
Final 
Page: 
23 of 23 
7 
References 
Not applicable 
NN9535-4984
NN9535
0
 |
VV-TMF-5378386
 .
-
 |
1
 |
 of
  SAP  NN9535-4984 Statistical analysis plan
23
23
CONFIDENTIAL