Conditions: Diabetes Mellitus, Type 2
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 92
Healthy volunteers: no

Brief summary:
This study looks at how well a new medicine called cagrilintide works together with semaglutide on blood sugar levels in people with type 2 diabetes compared to cagrilintide alone or semaglutide alone.

Before a new medicine can be prescribed to people it needs to be tested to see if it is safe and effective.

Participants will either get cagrilintide and semaglutide together or cagrilintide and a dummy medicine or semaglutide and a dummy medicine. Which treatment participants get is decided by chance.

A dummy medicine (placebo) looks like the study medicine but does not contain any active medicine. The dummy medicine is in the study to see if the study medicine works as expected.

Participants will get 2 injections per week on the same day. Participants will take the study medicine with a pen. A pen is a medical tool with a needle used for injections under the skin. The study doctor or staff will show how.

The study will last for about 39 weeks. Participants will have 12 visits at the clinic and 5 phone calls with the study doctor.

At 6 of the clinic visits participants must not eat and drink for 8 hours before the visit (water is allowed).

Women who can become pregnant cannot take part in this study. Only women that are surgically sterilised or post-menopausal are allowed to participate in this study Women cannot take part if pregnant, breast-feeding or plan to get pregnant during the study period

Detailed description:

Arms:
arm 1: Participants will receive cagrilintide and semaglutide once a week as injections for 32 weeks. arm 2: Participants will receive cagrilintide and placebo (semaglutide) once a week as injections for 32 weeks arm 3: Participants will receive semaglutide and placebo (cagrilintide) once a week as injections for 32 weeks

Interventions: intervention 1: Semaglutide 2.4 mg intervention 2: Cagrilintide 2.4 mg intervention 3: Placebo (semaglutide) intervention 4: Placebo (cagrilintide)
Intervention descriptions: intervention 1: Semaglutide administered s.c. (subcutaneously, under the skin) once weekly. Participants will gradually increase the dose until they reach the target dose, and will continue on the this dose once weekly up to 32 weeks intervention 2: Cagrilintide administered s.c. (subcutaneously, under the skin) once weekly. Participants will gradually increase the dose until they reach the target dose, and will continue on the this dose once weekly up to 32 weeks intervention 3: Placebo (semaglutide) administered s.c. (subcutaneously, under the skin) once weekly.

Participants will gradually increase the dose until they reach the target dose, and will continue on the this dose once weekly up to 32 weeks intervention 4: Placebo (cagrilintide) administered s.c. (subcutaneously, under the skin) once weekly.

Participants will gradually increase the dose until they reach the target dose, and will continue on the this dose once weekly up to 32 weeks

Protocol document:
Prot_000.pdf: 
C o v e r  P a g e  f o r P r ot o c ol  
 
S p o ns or  n a m e:  
N o v o  N or dis k  A/ S  
N C T  n u m b er  
N C T 0 4 9 8 2 5 7 5  
S p o ns or t ri al I D: 
N N 9 8 3 8 -4 8 6 2  
Offi ci al titl e  of st u d y:   
Effi c a c y  a n d s af et y  of  c o -a d mi nistr ati o n  of  c a grili nti d e s. c.  2. 4  
m g  a n d s e m a gl uti d e s. c.  2. 4  m g  o n c e  w e e kl y i n s u bj e cts  wit h 
t y p e  2  di a b et es 
D o c u m e nt  d at e *  
1 6  J u n e 2 0 2 1  
*  D o c u m e nt  d at e r ef ers t o t h e  d at e  o n  w hi c h t h e  d o c u m e nt  w as  m ost r e c e ntl y  u p d at e d.  
   N ot e:  T h e  d at e i n t h e  h e a d er  of  P a g e  2 is t h e  d at e  of  c o m pil ati o n  of t h e  d o c u m e nts  a n d  n ot  of  a n  u p d at e t o  c o nt e nt.  


Li n k
Li n k
List of c o nte nts
Pr ot oc ol ...............................................................................................................................................
1 6. 1. 0 1 St ate me nt Att ac h me nt I a n d II ............................................................................................
Date:
N o v o N or di s k
Versi o n:
Stat us:
Ca gri Se ma
Trial I D: N N 9 8 3 8 4 8 6 2
Cli nical Trial Re p ort
A p pe n di x 1 6. 1. 1
0 1 N o ve m ber 2 0 2 2
1. 0
Fi nal
1 6. 1. 1 Pr ot oc ol a n d pr ot oc ol a me n d me nts
C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
Stat us:  
Fi n al  
P a ge:  
1  of 7 4  
Pr ot oc ol
Pr ot oc ol titl e:  Effic ac y a n d s afet y of c o -a d mi nistr ati o n of c a grili nti de s.c. 2. 4 m g a n d 
se m a gl uti de s.c. 2. 4 m g o nce wee kl y i n s u bjects wit h t y pe 2 di a betes  
S u bst a nce n a me: c a grili nti de, se m a gl uti de  
I N D N u m ber: 1 5 5 7 9 6 
U ni vers al Tri al N u m b er: U 1 1 1 1 -1 2 6 6 -2 9 3 1 
Tri al 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”. 
   
   
   
   
    
  
  
   
   
   
   
   
 
 
   
   
   
   
   
   
   
   
    
   
   
 
   
    
 
 
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
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V V- T M F- 4 5 3 5 0 0 0
7 4
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C O N FI D E N TI A L
T his c o nfi de ntial d oc u me nt is t he pr o pert y of N o v o N or dis k. N o u n p u blis he d i nf or mati o n c o ntai ne d herei n ma y be 
discl ose d w it h o ut pri or writte n a p pr o val fr o m N o v o N or dis k. Access t o t his d oc u me nt m ust be restricte d t o rele va nt 
parties.


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
2  of 7 4  
 
Ta ble of C o nte nts    
 
P a ge  
T a ble of C o nte nts .............................................................................................................................................. 2  
1  Pr ot oc ol s u m m ar y  ....................................................................................................................................... 5  
1. 1  
S y n o psis  .............................................................................................................................................. 5  
1. 2  
Fl o wc hart  ............................................................................................................................................ 8  
2  I ntr o d ucti o n ............................................................................................................................................... 1 0  
2. 1  
Trial rati o nale  .................................................................................................................................... 1 0  
2. 2  
Bac k gr o u n d  ....................................................................................................................................... 1 1  
2. 3  
Be nefit -ris k assess me nt ..................................................................................................................... 1 2  
2. 3. 1   
Ris k assess me nt  ................................................................................................................. 1 3  
2. 3. 2   
Be nefit assess me nt  ............................................................................................................. 1 6  
2. 3. 3   
O v erall be nefit -ris k c o ncl usi o n ......................................................................................... 1 6  
3  O bjecti ves a n d e n d p oi nts  .......................................................................................................................... 1 6  
3. 1  
Pri mar y, sec o n dar y a n d e x pl orat or y o bj ecti ve(s) a n d esti ma n d(s)  ................................................... 1 6  
3. 1. 1   
Pri mar y o bj ecti ves  ............................................................................................................. 1 6  
3. 1. 2   
Sec o n dar y o bj ecti ves  ......................................................................................................... 1 7  
3. 1. 3   
Esti ma n ds  .......................................................................................................................... 1 7  
3. 2  
Pri mar y, sec o n dar y a n d e x pl orat or y e n d p oi nt(s)  .............................................................................. 1 8  
3. 2. 1   
Pri mar y e n d p oi nt  ............................................................................................................... 1 8  
3. 2. 2   
Sec o n dar y e n d p oi nts  .......................................................................................................... 1 8  
3. 2. 2. 1   
C o nfir mat or y sec o n dar y e n d p oi nts  ................................................................ 1 8  
3. 2. 2. 2   
S u p p orti ve sec o n dar y e n d p oi nts  .................................................................... 1 8  
4  Tri al desi g n  ................................................................................................................................................ 1 9  
4. 1  
O verall desi g n  ................................................................................................................................... 1 9  
4. 2  
Scie ntific  rati o nale f or trial desi g n .................................................................................................... 1 9  
4. 3  
J ustificati o n f or d ose ......................................................................................................................... 2 0  
4. 4  
E n d of trial defi niti o n  ........................................................................................................................ 2 1  
5  Tri al p o p ul ati o n  ......................................................................................................................................... 2 1  
5. 1  
I ncl usi o n criteria ............................................................................................................................... 2 1  
5. 2  
E xcl us i o n criteria .............................................................................................................................. 2 1  
5. 3  
Lifest yle c o nsi derati o ns  .................................................................................................................... 2 2  
5. 3. 1   
Meals a n d dietar y restricti o ns  ............................................................................................ 2 3  
5. 3. 2   
Caffei ne, alc o h ol a n d t o bacc o  ........................................................................................... 2 3  
5. 4  
Scree n fail ures  ................................................................................................................................... 2 3  
5. 5  
R u n -i n criteria a n d/ or ra n d o misati o n criteria .................................................................................... 2 3  
6  Tre at me nts  ................................................................................................................................................. 2 3  
6. 1  
Treat me nts a d mi nistere d  ................................................................................................................... 2 3  
6. 1. 1   
Me dical de vices  ................................................................................................................. 2 6  
6. 2  
Pre parati o n/ ha n dli n g/st ora ge/acc o u nta bilit y  ..................................................................................... 2 6  
6. 2. 1   
S hi p me nt of trial pr o d uct t o s u bject’s h o me  ...................................................................... 2 7  
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 ................................................................. 2 7  
6. 4  
Treat me nt c o m plia nce  ....................................................................................................................... 2 8  
6. 5  
C o nc o mita nt me dicati o n  ................................................................................................................... 2 8  
6. 5. 1   
Resc ue me dicati o n  ............................................................................................................. 2 9  
6. 6  
D ose m o dificati o n  ............................................................................................................................. 2 9  
6. 7  
Treat me n t after e n d of trial ............................................................................................................... 3 0  
7  Disc o nti n u ati o n of tri al tre at me nt a n d s u bject  disc o nti n u ati o n/ wit h dr a w al  ....................................... 3 0  
7. 1  
Disc o nti n uati o n of trial treat me nt  ..................................................................................................... 3 0  
7. 1. 1   
T e m p orar y disc o nti n uati o n of trial treat me nt  .................................................................... 3 1  
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
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V V- T M F- 4 5 3 5 0 0 0
7 4
 of
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1
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C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3  of 7 4  
 
7. 1. 2   
Resc ue criteria  ................................................................................................................... 3 1  
7. 2  
S u bj ect wit h dra wal fr o m t he trial ...................................................................................................... 3 1  
7. 2. 1   
Re place me nt of s u bjects  .................................................................................................... 3 2  
7. 3  
L ost t o f oll o w -u p ............................................................................................................................... 3 2  
8  Tri al assess me nts a n d pr oce d ures ............................................................................................................ 3 2  
8. 1  
Efficac y assess me nts  ......................................................................................................................... 3 3  
8. 1. 1   
B o d y meas ure me nts  ........................................................................................................... 3 3  
8. 1. 2   
C o nti n u o us gl uc ose m o nit ori n g  ......................................................................................... 3 3  
8. 1. 3   
Cli nical efficac y la b orat or y assess me nts  ........................................................................... 3 4  
8. 2  
Safet y assess me nts  ............................................................................................................................ 3 4  
8. 2. 1   
P h ysical e xa mi nati o ns  ....................................................................................................... 3 5  
8. 2. 2   
Vital si g ns  .......................................................................................................................... 3 5  
8. 2. 3   
Electr ocar di o gra ms  ............................................................................................................ 3 5  
8. 2. 4   
E ye e xa mi nati o n  ................................................................................................................ 3 5  
8. 2. 5   
Cli nic al safet y la b orat or y assess me nts  .............................................................................. 3 6  
8. 3  
A d verse e ve nts a n d seri o us a d verse e ve nts  ....................................................................................... 3 6  
8. 3. 1   
Ti me peri o d a n d fre q ue nc y f or c ollecti n g A E a n d S A E i nf or mati o n  ................................ 3 7  
8. 3. 2   
Met h o d of detecti n g A Es a n d S A Es  .................................................................................. 3 7  
8. 3. 3   
F oll o w -u p of A Es a n d S A Es  ............................................................................................. 3 7  
8. 3. 4   
Re g ulat or y re p orti n g re q uire me nts f or S A Es  .................................................................... 3 8  
8. 3. 5   
Pre g na nc y  .......................................................................................................................... 3 8  
8. 3. 6   
Car di o vasc ular a n d deat h e ve nts  ....................................................................................... 3 8  
8. 3. 7   
H y perse nsiti vit y  ................................................................................................................. 3 8  
8. 3. 8   
T ec h nical c o m plai nts  ......................................................................................................... 3 8  
8. 4  
Treat me nt of o ver d ose  ...................................................................................................................... 3 9  
8. 5  
P har mac o ki netics  .............................................................................................................................. 3 9  
8. 6  
P har mac o d y na mics  ........................................................................................................................... 3 9  
8. 7  
Ge netics  ............................................................................................................................................ 4 0  
8. 8  
Bi o mar kers  ........................................................................................................................................ 4 0  
8. 9  
I m m u n o ge nicit y assess me nts ............................................................................................................ 4 0  
8. 1 0  Healt h ec o n o mics  .............................................................................................................................. 4 0  
9  St atistic al c o nsi der ati o ns  .......................................................................................................................... 4 0  
9. 1  
Statistical h y p ot heses  ........................................................................................................................ 4 0  
9. 2  
Sa m ple size deter mi nati o n  ................................................................................................................ 4 0  
9. 3  
P o p ulati o ns f or a nal yses  ................................................................................................................... 4 1  
9. 4  
Statistical a nal yses  ............................................................................................................................ 4 2  
9. 4. 1   
Ge neral c o nsi derati o ns  ...................................................................................................... 4 2  
9. 4. 2   
Pri mar y e n d p oi nt  ............................................................................................................... 4 2  
9. 4. 3   
Sec o n dar y e n d p oi nt(s)  ....................................................................................................... 4 3  
9. 4. 3. 1   
C o nfir mat or y sec o n dar y e n d p oi nt(s)  .............................................................. 4 3  
9. 4. 3. 2   
S u p p orti ve sec o n dar y e n d p oi nts  .................................................................... 4 3  
9. 4. 4   
E x pl orat or y e n d p oi nts ........................................................................................................ 4 3  
9. 4. 5   
Ot her safet y a nal yses  ......................................................................................................... 4 3  
9. 4. 6   
Ot her a nal yses  ................................................................................................................... 4 3  
9. 4. 6. 1   
P har mac o ki netic m o delli n g  ............................................................................ 4 3  
9. 5  
I nteri m a nal yses ................................................................................................................................ 4 4  
9. 6  
Data m o nit ori n g c o m mittee  .............................................................................................................. 4 4  
9. 7  
Re p orti n g of t he mai n part of t he trial  ............................................................................................... 4 4  
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 .................................................................. 4 5  
1 0. 1  A p pe n di x 1: Re g ulat or y, et hical, a n d trial o versi g ht c o nsi derati o ns  ................................................ 4 5  
1 0. 1. 1  
Re g ulat or y a n d et hical c o nsi derati o ns  ............................................................................... 4 5  
1 0. 1. 2  
Fi na ncial discl os ure  ........................................................................................................... 4 5  
1 0. 1. 3  
I nf or me d c o nse nt pr ocess .................................................................................................. 4 5  
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
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Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4  of 7 4  
 
1 0. 1. 4  
I nf or mati o n t o s u bj ects d uri n g trial ................................................................................... 4 6  
1 0. 1. 5  
Data pr otecti o n  .................................................................................................................. 4 6  
1 0. 1. 6  
C o m mittees str uct ure  ......................................................................................................... 4 7  
1 0. 1. 6 . 1  
N o v o N or dis k safet y c o m mittee ..................................................................... 4 7  
1 0. 1. 6. 2   
Trial safet y gr o u p  ........................................................................................... 4 7  
1 0. 1. 6. 3   
Data m o nit ori n g c o m mittee ............................................................................ 4 7  
1 0. 1. 6. 4   
E ve nt a dj u dicati o n c o m mittee  ........................................................................ 4 7  
1 0. 1. 7  
Disse mi nati o n of cli nical trial data  .................................................................................... 4 7  
1 0. 1. 8  
Data q ualit y ass ura nce  ....................................................................................................... 4 7  
1 0. 1. 8. 1   
Case re p ort f or ms  ........................................................................................... 4 7  
1 0. 1. 8 . 2  
M o nit ori n g  ..................................................................................................... 4 8  
1 0. 1. 8. 3   
Pr ot oc ol c o m plia nce  ....................................................................................... 4 8  
1 0. 1. 9  
S o urce d oc u me nts  .............................................................................................................. 4 9  
1 0. 1. 1 0  Re te nti o n of cli nical trial d oc u me ntati o n .......................................................................... 4 9  
1 0. 1. 1 1  Trial a n d site cl os ure .......................................................................................................... 4 9  
1 0. 1. 1 2  Res p o nsi bilities  .................................................................................................................. 5 0  
1 0. 1. 1 3  I n de m nit y state me nt .......................................................................................................... 5 1  
1 0. 1. 1 4  P u blicati o n p olic y  .............................................................................................................. 5 1  
1 0. 1. 1 4. 1  
C o m m u nicati o n of res ults  .............................................................................. 5 1  
1 0. 1. 1 4. 2  
A ut h ors hi p  ...................................................................................................... 5 2  
1 0. 1. 1 4. 3  
Si te-s pecific p u blicati o n(s) b y i n vesti gat or(s)................................................ 5 2  
1 0. 1. 1 4. 4  
I n vesti gat or access t o data a n d re vie w of res ults ........................................... 5 2  
1 0. 2  A p pe n di x 2: Cli nical la b orat or y tests ................................................................................................ 5 3  
1 0. 3  A p pe n di x 3: A d verse e ve nts: Defi niti o ns a n d pr oce d ures f or rec or di n g, e val uati o n, f oll o w -u p, 
a n d re p orti n g ..................................................................................................................................... 5 6  
1 0. 3. 1  
Defi niti o n of A E  ................................................................................................................ 5 6  
1 0. 3. 2  
Defi niti o n of a n S A E  ......................................................................................................... 5 6  
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  ................................................... 5 7  
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  ..................................................................... 5 8  
1 0. 3. 5  
Re p orti n g of S A Es  ............................................................................................................. 6 0  
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  ............................... 6 2  
1 0. 4. 1  
Defi niti o ns  ......................................................................................................................... 6 2  
1 0. 4. 2  
C o ntrace pti o n g ui da nce  ..................................................................................................... 6 2  
1 0. 4 . 3 
C ollecti o n of pre g na nc y i nf or mati o n  ................................................................................. 6 3  
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  .................................................................................................................... 6 5  
1 0. 5. 1  
Defi niti o n of tec h nical c o m plai nt  ...................................................................................... 6 5  
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  ............................................................. 6 5  
1 0. 5. 3  
Re p orti n g of tec h nical c o m plai nts  ..................................................................................... 6 6  
1 0. 6  A p pe n di x 6: Rete nti o n of h u ma n bi osa m ples  ................................................................................... 6 7  
1 0. 7  A p pe n di x 7: H y p o gl ycae mic e pis o des  .............................................................................................. 6 8  
1 0. 8  A p pe n di x 8: A b bre viati o ns  ............................................................................................................... 7 0  
1 1  Ref ere nces  .................................................................................................................................................. 7 2  
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.  
 
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
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Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5  of 7 4  
 
1  Pr ot oc ol s u m m ar y  
1. 1   
S y n o psis  
R ati o n ale:  
Wei g ht l oss is rec o m me n de d f or t y pe 2 dia betes ( T 2 D) ma na ge me nt, as it re d uces fat acc u m ulati o n 
i n li ver a n d pa ncreas, le a di n g t o i m pr o ve d i ns uli n secreti o n a n d i ns uli n se nsiti vit y. Wei g ht l oss i n 
patie nts wit h T 2 D wit h o ver wei g ht or o besit y is ass ociate d wit h a decrease i n H b A 1c. C o m bi ne d 
a d mi nistrati o n of t he l o n g -acti n g a m yli n a nal o g ue ca grili nti de a n d t he gl uca g o n -li ke pe pti de-1 
( G L P-1) rece pt or a g o nist se ma gl uti de was i n vesti gat e d i n a p hase 1 trial ( N N 9 8 3 8 -4 3 9 5) a n d 
ass ociate d wit h a s u bsta ntial wei g ht l oss c o m pare d t o se ma gl uti de al o n e i n i n di vi d uals wit h 
o ver wei g ht a n d o besit y wit h o ut T 2 D. Treat me nt wit h se ma gl uti de is well -esta blis he d i n T 2 D t o 
sec ure g o o d gl ycae mic c o ntr ol a n d is a p pr o ve d w orl d wi de u n der t his i n dicati o n. O ne s h ort -acti n g 
a m yli n a g o nist is c urre ntl y a p pr o ve d f or treat me nt of  t ype 1 dia betes ( T 1 D ) a n d T 2 D. A 
c o m bi nati o n of a l o n g -acti n g a m yli n a g o nist a n d s e ma gl uti de c o ul d lea d t o n ot o nl y s u bsta ntial 
wei g ht l oss b ut p ote ntiall y als o a n i m pr o ve d gl ycae mic c o ntr ol i n s u bjects wit h T 2 D. C o nse q ue ntl y, 
it is rele va nt t o i n vesti gat e w het her a greater i m pr o ve me nt i n gl ycae mic c o ntr ol as meas ure d b y a 
decrease i n H b A 1c is o bser ve d after c o m bi ne d a d mi nistrati o n of ca grili nti de a n d se ma gl uti de 
c o m pare d t o se m a gl uti de or ca grili nti de al o ne.  
O bjecti ves a n d e n d p oi nts:  
Pri m ar y o bjecti ves  
T o c o m pare t h e effect of c o -a d mi nistere d s e ma gl uti de a n d ca grili nti de vers us se ma gl uti de i n 
s u bjects wit h T 2 D i na de q uatel y c o ntr olle d o n metf or mi n wit h or wit h o ut S G L T 2 i n hi bit or o n:  
•  c ha n ge fr o m baseli ne ( wee k 0) t o wee k 3 2 i n H b A 1c ( %-p oi nt)  
Sec o n d ar y o bjecti ves  
T o c o m pare t h e effect of c o -a d mi nistere d s e ma gl ut i de a n d ca grili nti de vers us se ma gl uti de i n 
s u bjects wit h T 2 D i na de q uatel y c o ntr olle d o n metf or mi n wit h or wit h o ut S G L T 2 i n hi bit or o n:  
•  ot her para meters f or gl ycae mic c o ntr ol  
•  b o d y wei g ht  
T o c o m pare t h e effect of c o -a d mi nistere d s e ma gl uti de a n d ca grili nti de v ers us ca grili nti de i n 
s u bjects wit h T 2 D i na de q uatel y c o ntr olle d o n metf or mi n wit h or wit h o ut S G L T 2 i n hi bit or o n:  
•  H b A 1c 
•  ot her para meters f or gl ycae mic c o ntr ol  
•  b o d y wei g ht  
T o c o m pare t h e effect of c o -a d mi nistere d s e ma gl uti de a n d ca grili nti de, se m a gl uti de a n d  ca grili nti de 
i n s u bjects wit h T 2 D i na de q uatel y c o ntr olle d o n metf or mi n wit h or wit h o ut S G L T 2 i n hi bit or o n: 
•  safet y a n d t olera bilit y 
•  h y p o gl ycae mia  
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
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V V- T M F- 4 5 3 5 0 0 0
7 4
 of
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C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6  of 7 4  
 
Pri m ar y e n d p oi nt  
E n d p oi nt title  
Ti me fr a me  
U nit  
C ha n ge i n H b A 1c  
Fr o m baseli ne ( wee k 0) t o we e k 3 2  
% -p oi nt  
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 effect of c o -a d mi nistere d 
se ma gl uti de a n d ca grili nti de vers us se ma gl uti de o n H b A 1c ( %-p oi nts) fr o m baseli ne t o wee k 3 2 i n 
s u bjects wit h T 2 D i na de q uatel y c o ntr olle d on metf or mi n wit h or wit h o ut S G L T 2 i n hi bit or, ha d all 
s u bjects re mai ne d o n tri al treat me nt wit h o ut use of resc u e me dicati o n (a nti -dia betic). A h y p ot h etical 
strate g y is a p plie d f or b ot h i nterc urre nt e ve nt of pre mat ure treat me nt disc o nti n uati o n a n d i nitiati o n  
of resc u e me dicati o n. T h e p o p ulati o n le vel s u m mar y is differe nce i n mea ns.  
T he pri mar y esti ma n d esti mates t he ac hie va ble treat me nt effect wit h o ut t he c o nf o u n di n g of 
treat me nt disc o nti n uati o n a n d i nitiati o n of resc ue i nter ve nti o n. T his a p pr oac h is c o nsi dere d rele va nt 
f or e val u ati n g a mec ha nistic effect.  
O ver all desi g n:  
T his is a 3 2 -wee k, ra n d o mise d, d o u ble -bli n d, acti ve -c o ntr olle d, t hree -ar m, parallel gr o u p, 
m ultice ntre cli nical trial. T he trial will c o m pare t h e effi cac y a n d safet y of c o -a d mi nistrati o n of 
ca grili nti de s u bc uta ne us (s.c.) 2. 4 m g a n d se m a gl uti de s.c. 2. 4 m g vers us s e ma gl uti de s.c. 2. 4 m g 
m o n ot hera p y a n d vers us ca grili nti de s.c. 2. 4 m g m o n ot hera p y i n s u bjects wit h T 2 D.  
S u bjects will be ra n d o mise d t o 1 of t he 3 treat me nt ar ms i n a rati o of 1: 1: 1 .  
Ra n d o misati o n will be stratifie d acc or di n g t o t he S G L T 2 i n hi bit or treat me nt ( Yes/ N o).  
Ke y i ncl usi o n criteri a:  
•  F e male of n o n -c hil d beari n g p ote ntial  or mal e  
•  A ge a b o ve or e q u al t o 1 8 years at t he ti me of si g ni n g i nf or m e d c o nse nt  
•  B o d y mass i n de x ( B MI) ≥ 2 7. 0 k g/ m 2 
•  Dia g n os e d wit h t y p e 2 dia betes mellit us ≥ 1 8 0 da ys bef ore s cree ni n g  
•  H b A 1c of 7. 5 -1 0. 0 % ( 5 8 -8 6 m m ol/ m ol) ( b ot h i ncl usi ve) as assess e d b y ce ntral la b orat or y at 
scree ni n g 
•  Sta ble dail y d ose(s) ≥ 9 0 da ys b ef ore scree ni n g of t he f oll o wi n g a nti dia betic  dr u g(s) or 
c o m bi nati o n re gi me n(s) at ma xi m u m t olerate d or effecti ve d ose as j u d ge d b y t he 
i n vesti gat or: metf or mi n wit h or wit h o ut S G L T 2 i n hi bit or 
Ke y e xcl usi o n criteri a:  
•  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 a n d pri or i ns uli n treat me nt f or gestati o nal dia b etes are all o we d 
•  Re nal i m pair me nt wit h esti mate d Gl o mer ular Filtrati o n Rate (e G F R) < 6 0 ml/ mi n/ 1. 7 3 m 2 b y 
ce ntral la b orat or y at scree ni n g  
•  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 9 0 da ys b ef ore scree ni n g or i n t he peri o d bet wee n 
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
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V V- T M F- 4 5 3 5 0 0 0
7 4
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1
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C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
7  of 7 4  
 
scree ni n g a n d ra n d o misati o n. P har mac ol o gi cal p u pil-dilati o n is a re q uire me nt u nless usi n g a 
di gital f u n d us p h ot o gra p h y ca mera s pecifi e d f or n o n -dilate d e x a mi nati o n  
N u m ber of s u bjects:  
A p pr o xi matel y 9 0 s u bj ects will be ra n d o ml y assi g ne d t o trial pr o d uct.   
Tre at me nt gr o u ps a n d d ur ati o n:  
T he trial i ncl u des a mi ni m u m 1 0 -da y s cree ni n g p eri o d t o assess t he s u bject’s eli gi bilit y, a 3 2 -wee k 
treat me nt peri o d a n d a 5-wee k f oll o w u p peri o d. T he 3 2 -wee k treat me nt peri o d c o nsists of a 
1 6 -wee k d os e escalati o n peri o d a n d a 1 6 -wee k mai nte na nce p eri o d. T he pla n ne d t otal trial d urati o n 
f or t he i n di vi d ual s u bject is a p pr o xi matel y 3 9 wee ks. 
T he f oll o wi n g tri al pr o d u cts will be s u p plie d b y N o v o N or dis k A/ S f or t he d urati o n of t he trial:  
•  Se ma gl uti de B 3. 0 m g/ m L P D S 2 9 0  pre -fille d pe n -i nject or a n d se ma gl uti de place b o, s ol uti o n 
f or i njecti o n, 3 m L P D S 2 9 0 pre-fille d pe n-i nject or 
•  Ca grili nti de A 1 0 m g/ m L a n d ca grili nti de place b o, s ol uti o n f or i njecti o n, 3 m L u n der -fille d 
cartri d ge, 1 ml s ol uti o n f or i njecti o n t o be use d wit h N o v o Pe n Ec h o ®  
D at a m o nit ori n g c o m m ittee:  
N ot a p plica ble f or t his st u d y . 
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
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V V- T M F- 4 5 3 5 0 0 0
7 4
 of
7
 
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1
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C O N FI D E N TI A L






Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
1 0  of 7 4  
 
2  
I ntr o d ucti o n 
Dia betes mellit us is a meta b olic dis or der c h aracterise d b y t he prese n ce of h y p er gl ycae mia d ue t o 
defecti ve i ns uli n secreti o n, i ns uli n acti o n or b ot h. C hr o nic h y p er gl ycae mia of dia betes mellit us is 
ass ociate d wit h si g nifica nt l o n g -ter m c o m plicati o ns, partic ularl y da ma ge, d ysf u ncti o n a n d fail ure of 
vari o us tiss ues  –  es peciall y t he ki d ne y, e ye a n d n er ves. 1 Dia betes is ge nerall y classifie d acc or di n g 
t o aeti ol o gical fact ors, w here T 1 D a n d T 2 D c o nstit ute t he vast maj orit y of cases. I n t he 
I nter nati o nal Dia betes Fe derati o n’s Dia betes Atlas ( 2 0 1 9), t he esti mate d w orl d wi de dia betes 
pre vale nce was 4 6 3 milli o n, wit h a pre dicti o n t hat b y 2 0 4 5, t he n u m ber of pe o ple wit h dia betes will 
ha ve i ncrease d t o 7 0 0 milli o n. 2 
T he p ur p ose of t h e pres e nt trial is t o i n vesti gate t he effi cac y a n d safet y of t he c o m bi nati o n of t he 
G L P -1 rece pt or a g o nist  ( G L P-1 R A) , s e ma gl uti de a n d a m yli n a nal o g ue, ca grili nti de (i nter nati o nal 
n o n pr o prietar y n a me), b ot h a d mi nistere d o nce  wee kl y.  
G L P -1 is a n i n creti n h or m o ne releas e d fr o m i ntesti nal L -cells wit h a gl uc ose -de pe n d e nt sti m ulat or y 
effect o n i ns uli n a n d i n hi bit or y effect o n gl u ca g o n secreti o n fr o m t he pa ncreatic islets. 3 G L P -1 is a 
p h ysi ol o gical r e g ulat or of a p petite a n d G L P -1 rece pt ors are prese nt  i n se veral areas of t he brai n 
i n v ol ve d i n a p petite re g ulati o n.4 Treat me nt wit h G L P -1 rece pt or a g o nists l o wers b o d y wei g ht a n d 
re d uces H b A1c.4 Se ma gl uti de s.c. is a o nce -wee kl y G L P -1 r ece pt or a g o nist a p pr o ve d f or t he 
treat me nt of a d ults wit h T 2 D at d oses of 0. 5 a n d 1. 0 m g ( Oze m pic
® ). O n ce-wee kl y s e ma gl uti de s.c. 
has rece ntl y b ee n s u b mitte d f or re g ulat or y re vie w at d ose of 2. 0 m g f or a d diti o nal gl ycae mic c o ntr ol 
f or a d ults wit h T 2 D, a n d at d ose of 2. 4 m g f or wei g ht ma na ge me nt i n a d ults.  
E n d o ge n o us a m yli n is a ne ur oe n d ocri ne pe pti de h or m o ne t hat is c o -secrete d wit h i ns uli n fr o m 
pa ncreatic beta -cells i n r es p o nse t o f o o d i nta ke. St u dies i n dicate t hat e n d o ge n o us a m yli n is i n v ol ve d 
i n t he ce ntral r e g ulati o n of f o o d i nta ke a n d b o d y wei g ht. 5 Pra mli nti de ( S y mli n ® ) is a s h ort-acti n g 
am yli n a n al o g u e w hic h was a p pr o ve d i n 2 0 0 5 i n t he U nite d States ( U S) as a mealti me a dj u nct 
treat me nt t o i ns uli n i n patie nts wit h T 1 D a n d T 2 D t o c o ntr ol bl o o d gl uc ose.6 Pra mli nti de has bee n 
s h o w n t o sl o w gastric e m pt yi n g a n d t o s u p press p ost-pra n dial gl uca g o n release. 7 Ca grili nti de is a 
l o n g-acti n g a m yli n a nal o g ue wit h a g o nistic effects o n a m yli n rece pt ors. T he wei g ht l oss p ote ntial of 
ca grili nti de has bee n i n ve sti gate d i n a p hase 2 tri al a n d t he c o m bi nati o n wit h se ma gl uti de has bee n 
i n vesti gate d i n a p h ase 1 trial. T he res ults c ollecti v el y i n dicate d t hat t he c o m bi nati o n has t he 
p ote ntial t o offer s u bsta ntiall y greater wei g ht l oss t ha n eit her m o n ot hera p y.  
2. 1   
Tri al r ati o n ale  
Wei g ht l oss is rec o m me n de d i n cli nical practice g ui deli nes f or T 2 D ma n a ge me nt,
8, 9 as it re d uces 
fat acc u m ulati o n i n li ver a n d pa ncreas, lea di n g t o i m pr o ve d i ns uli n secreti o n a n d i ns uli n 
se nsiti vit y. 1 0 Wei g ht l oss i n patie nts wit h T 2 D wit h o ver wei g ht or o besit y is ass ociate d wit h a 
decrease i n H b A 1c.1 1  
Base d o n t h e wei g ht -l o w eri n g effect of c o m bi ni n g ca grili nti de a n d se ma gl uti de, t he esta blish e d 
effect of se ma gl uti de o n gl ycae mic c o ntr ol as well as t he p ote ntial i n v ol ve me nt of a m yli n a g o nists 
i n gl uc ose met a b olis m, it is rele va nt t o i n vesti gate w het her a greater i m pr o ve me nt i n gl ycae mic 
c o ntr ol as meas ure d b y a decrease i n H b A 1c is o bser ve d after c o m bi ne d a d mi nistrati o n of 
ca grili n ti de a n d se ma gl uti de c o m pare d t o s e ma gl uti de or ca grili nti de al o ne.  
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
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V V- T M F- 4 5 3 5 0 0 0
7 4
 of
1 0
 
-
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1
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C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
1 1  of 7 4  
 
2. 2   
B ac k gr o u n d  
Se m a gl uti de  
Se ma gl uti de s.c. is a o n ce -wee kl y G L P -1 rece pt or a g o nist a p pr o ve d f or t he treat me nt of a d ults wit h 
T 2 D at d oses of 0. 5 a n d 1. 0  m g ( Oze m pic ® ). O n ce-wee kl y s e ma gl uti d e s.c. has rece ntl y b ee n 
s u b mitte d f or re g ulat or y re vie w at d os e of 2. 0 m g f or a d diti o nal gl ycae mic c o ntr ol f or a d ults wit h 
T 2 D, a n d at d ose of 2. 4 m g f or wei g ht ma na ge me nt. Se ma gl uti de has a half -life of a p pr o xi matel y 
1 6 0 h o urs, ma ki n g it s uita ble f or o n c e-wee kl y d osi n g. 1 2  
I n t he p hase 3 d e vel o p me nt pr o gra m me f or s e ma gl uti de s.c. 0. 5 a n d 1. 0 m g (t he S U S T AI N 
pr o gra m me), se ma gl uti de pr o vi de d s u peri or l o n g -ter m gl ycae mic c o ntr ol a n d b o d y wei g ht 
re d ucti o n as c o m p are d t o c o m m o nl y use d mar kete d pr o d ucts acr oss t he s pectr u m of patie nts wit h 
T 2 D, ra n gi n g fr o m treat me nt -naï ve t o i ns uli n -treate d. T he safet y pr ofile of se ma gl uti de is well-
d oc u me nte d base d o n d at a fr o m  t he n o ncli nical a n d cli nical de vel o p me nt pr o gra m mes, a n d is 
c o nsiste nt wit h t he safet y pr ofile of ot her dr u gs wit hi n t he G L P -1 R A dr u g class. 1 3, 1 4  
T he S U S T AI N F O R T E trial ( N N 9 5 3 5 -4 5 0 6) i ncl u de d 9 6 1 pe o ple wit h T 2 D. I n t he trial, pe o ple 
treate d wit h se ma gl uti de 2. 0 m g ac hie ve d a s u peri or re d ucti o n i n H b A1c c o m pare d t o se ma gl uti de 
1. 0 m g. B ot h d oses of se ma gl uti de a p p eare d t o ha ve safe a n d well -t olerate d pr ofiles. T he m ost 
c o m m o n a d verse e ve nts were gastr oi ntesti nal, t he vast maj orit y were mil d t o m o derate a n d 
di mi nis he d o ver ti me a n d were c o nsiste nt wit h t he G L P -1 rece pt or a g o nist class. C o m pare d t o 
se ma gl uti de 1. 0 m g, t he gastr oi ntesti nal a d verse e ve nts were si milar f or se ma gl uti de 2. 0 m g.
1 5 
A gl o bal p h ase 3a cli nical de vel o p me nt pr o gra m m e wit h se ma gl uti de s.c. 2. 4 m g o nce  wee kl y h as 
bee n c o m plete d i n p e o ple wit h o ver wei g ht or o besit y ( S T E P pr o gra m me). T he lar gest trial 
( N N 9 5 3 6-4 3 7 3; S T E P 1) i ncl u de d 1, 9 6 1 a d ults wit h o besit y or o ver wei g ht wit h c o m or bi dities. 
S u bjects treate d wit h se ma gl uti de s.c. 2. 4 m g o n ce  wee kl y ac hi e ve d si g nifica ntl y greater wei g ht 
l oss ( 1 4. 9 %) after 6 8 wee ks c o m pare d t o place b o ( 2. 4 %), b ot h i n c o nj u ncti o n wit h lifest yle 
i nter ve nti o n.1 6 I n a trial wit h 1, 2 1 0 a d ults wit h B MI ≥2 7 k g/ m2 a n d T 2 D ( N N 9 5 3 6 -4 3 7 4; S T E P 2) a 
si g nifica ntl y greater wei g ht l oss was ac hie ve d wit h se ma gl uti de s.c. 2. 4 m g o nce  wee kl y ( 9. 6 %) vs . 
se ma gl uti de s. c. 1. 0 m g ( 7. 0 %) a n d vs. place b o ( 3. 4 %); all i n c o nj u ncti o n wit h lifest yl e 
i nter ve nti o n.1 7 T he safet y pr of ile of se ma gl uti de s.c. 2. 4 m g o n ce wee kl y was c o nsiste nt wit h t hat 
see n pre vi o usl y wit h se m a gl uti de o nce wee kl y i n t y p e 2 di a betes, 1 8 a n d wit h t he esta blis he d pr ofile 
of t he G L P -1 rece pt or a g o nist class. 1 9, 2 0 T he m ost c o m m o n a d verse e ve nts a m o n g p e o ple treate d 
wit h se ma gl uti de 2. 4 m g o nce  wee kl y were gastr oi ntesti nal e ve nts. 1 6, 1 7 
A c o m pre he nsi v e re vie w of res ults fr o m t he n o ncli nical a n d cli nical st u dies of se ma gl uti de s.c. 
2. 4  m g o nce  wee kl y ca n be f o u n d i n t he c urre nt e diti o n of t he i n vesti gat or’s br oc h ure (I B)
2 1 a n d a n y 
u p dates here of.  
C a grili nti de  
Ca grili nti de is a l o n g -acti n g a m yli n a g o nist u n der i n vesti gati o n f or t he treat me nt of s u bjects wit h 
o ver wei g ht a n d o besit y, as well as s u bjects wit h T 2 D. T he half -life of ca grili nti de  is a p pr o xi matel y 
1 8 0 h o urs i n dicati ve of a p har mac o ki netics ( P K) pr ofile s uita ble f or a o nce -wee kl y d osi n g re gi me n.  
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
1 1
 
-
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1
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C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
1 2  of 7 4  
 
A p hase 2 d ose -fi n di n g trial has bee n c o m plet e d f or ca grili nti de ( N N 9 8 3 8-4 4 3 3). T he 2 6 -wee k 
bli n de d p hase 2 m o n ot hera p y trial wit h ca grili nti de s.c. i n vesti gate d safet y, t olera bilit y a n d efficac y 
f or wei g ht ma na ge me nt i n 7 0 6 a d ults wit h o besit y or o ver wei g ht wit h at least o ne wei g ht-relate d 
c o m or bi dit y. T he s u bjects were ra n d o mise d e q u all y t o o nce -wee kl y treat me nt wit h fi ve differe nt 
d oses o f ca grili nti de s.c. ( 0. 3 m g, 0. 6 m g, 1. 2 m g, 2. 4 m g, 4. 5 m g), place b o o nce  wee kl y or 
lira gl uti de 3. 0 m g o nce d ail y, i n c o nj u ncti o n wit h lifest yle i nter v e nti o n. Base d o n t he pri mar y 
e n d p oi nt, t he wei g ht l oss o bser ve d f or all ca grili nti de d oses was si g nifica ntl y greater  t h a n f or 
place b o. Fr o m a bas eli ne wei g ht of a p pr o xi matel y 1 0 0 k g, treat me nt wit h 2. 4 m g a n d 4. 5 m g s.c. 
ca grili nti de res ulte d i n a wei g ht l oss of 9. 7 % a n d 1 0. 8 % at wee k 2 6, res p ecti vel y, c o m pare d t o a 
wei g ht l oss of 3. 0 % wit h place b o. Ca grili n ti de ha d a safe a n d well-t olerate d pr ofile wit h t he m ost 
fre q ue ntl y re p orte d a d verse e ve nts bei n g gastr oi nt esti nal ( n o n-seri o us a n d mil d t o m o derate i n 
se verit y) a n d i njecti o n site reacti o ns (all n o n-seri o us a n d mil d t o m o derate i n se verit y). 
A c o m pre he nsi v e re vie w of res ults fr o m t he n o ncli nical a n d cli nical st u dies of ca grili nti de ca n be 
f o u n d i n t he c urre nt e diti o n of t he I B2 2 a n d a n y u p dates here of.  
C o m bi n ati o n tri al  
Res ults are a vaila bl e fr o m a m ulti ple -asce n di n g d ose trial i n vesti gati n g t he saf et y, t olera bilit y a n d 
P K pr o perties of 6 ca grili nti de d oses ( 0. 1 6 m g u p t o 4. 5 m g per wee k) a d mi nistere d i n c o m bi nati o n 
wit h t he sa me se ma gl uti de d ose ( 2. 4 m g per wee k) as se parate s.c. i njecti o ns ( N N 9 8 3 8 -4 3 9 5). A 
2 0 -wee k tr eat me nt peri o d was a p plie d i ncl u di n g a  1 6 -wee k d os e -es calati o n peri o d f oll o we d b y 
4  wee ks at t he tar get d os e. T he res ults de m o nstrate d t hat ca grili nti de was well -t olerate d i n 
c o m bi nati o n wit h se ma gl uti de 2. 4 m g wit h t he m ost fre q ue nt a d verse e ve nts relate d t o 
gastr oi ntesti nal i nt olera n ce a n d i njecti o n site reacti o ns. N o ne w safet y c o ncer ns were i de ntifie d f or 
t he c o m bi nati o n c o m pare d t o t he safet y pr ofile of t he m o n o-c o m p o ne nts. After 2 0 wee ks of 
treat me nt, s u bjects r ecei vi n g 2. 4 m g ca grili nti de i n c o m bi nati o n wit h 2. 4 m g se ma gl uti de l ost a n 
a vera ge of 1 7. 1 % of b o d y wei g ht w hile a wei g ht l oss of 9. 8 % was o bser ve d f or se ma gl uti de 2. 4 m g 
m o n ot hera p y. He n ce, a n a d diti o nal wei g ht l oss was o bser ve d w he n c o m bi ni n g 2. 4 m g ca grili nti de 
a n d 2. 4 m g s e ma gl uti de treat me nt.  
A c o m pre he nsi v e re v ie w of res ults fr o m t he n o ncli nical a n d cli nical st u dies of ca grili nti de i n 
c o m bi nati o n wit h se ma gl uti de ca n be f o u n d i n t he c urre nt e diti o n of t he ca grili nti de I B 2 2 a n d a n y 
u p dates here of.  
2. 3   
Be nefit -ris k assess me nt  
Mai n be nefits a n d ris ks are descri b e 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 n efits a n d ris ks a n d reas o n a bl y e x pecte d a d verse e v e nts of ca grili nti de or 
se ma gl uti de ma y b e f o u n d i n t he I Bs 2 1, 2 2 a n d a n y u p dates t here of.  
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
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V V- T M F- 4 5 3 5 0 0 0
7 4
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C O N FI D E N TI A L




Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
1 4  of 7 4  
 
Acti vati o n of t he 
R e ni n -A n gi ote nsi n -
Al d oster o n  S yste m  
ca grili nti de  
Treat me nt wit h ca grili nti de has bee n 
ass ociate d wit h i ncrease d mea n le vels of 
al d oster o ne a n d re ni n, wit hi n n or mal 
ra n ge. N o sti m ulat or y effect o n bl o o d 
press ure, heart rate or c ha n ges i n 
electr ol ytes has bee n o bser ve d. 2 1 
Plas ma re ni n acti vit y, al d oster o ne le vels, 
electr ol ytes a n d bl o o d press ure will be 
m o nit o re d ( A p pe n di x 2, Secti o n 1 0. 2 ). 
De vel o p me nt of a nti -
ca grili nti de 
a nti b o dies  
ca grili nti de  
Ca grili nti de has a hi g h h o m ol o g y t o nati ve 
a m yli n. I n t he p hase 2 trial ( N N 9 8 3 8 -
4 4 3 3), u p t o 7 3 % of s u bj ects de vel o pe d 
a nti -ca grili nti de a nti b o dies i n a d ose -
de pe n de nt ma n ner. A n i ncrease d ris k of 
i nj ecti o n site reacti o ns was o bser ve d i n 
s u bj ects wit h a nti b o dies. 
N o miti gati n g acti o ns are i m pl e me nte d. 
Sa m pli n g f o r i n vesti gati o n of prese nce of 
a nti b o dies (a nti -ca grili nti de I g E a n d a nti -
se ma gl uti de I g E) will be perf or me d i n case of 
s yste mic h y perse nsiti vit y reacti o ns (see 
S ecti o n 8. 3. 7 ). 
Ac ute pa ncreatitis  
se ma gl uti de 
Ac ute pa ncreatitis has bee n o bser ve d wit h 
t he use of G L P-1 R As .2 1, 2 2   
T he fre q ue nc y of a dj u dicati o n -c o nfir me d 
ac ute pa ncreatitis re p orte d i n S T E P 
cli nical de vel o p me n t pr o gra m me was 
0. 2 % f or se ma gl uti de 2. 4 m g a n d < 0. 1 % 
f or place b o, res pecti vel y. O verall, 
se ma gl uti de was n ot ass ociate d wit h a n 
i ncrease d ris k of ac ute pa ncreatitis vs 
c o m parat or.  
S u bj ects wit h a hist or y of c hr o nic or rece nt 
ac ute pa ncreatitis will n ot be e nr olle d (see 
Secti o n 5. 2 ).  
S u bj ects 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, trial pr o d uct 
s h o ul d be disc o nti n ue d. If c o nfir me d, trial 
pr o d uct s h o ul d n ot be restarte d i n acc or da nce 
wit h Secti o n 7 . 
M T C ( base d o n n o n -
cli nical data)  
se ma gl uti de 
T h yr oi d C -cell t u m o urs ha ve bee n 
o bser ve d i n carci n o ge nicit y st u dies of 
se ma gl uti de i n r o de nts, b ut n ot i n 
m o n ke ys. 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 p ecific G L P -1 
rece 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. 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.2 2  
S u bj ects wit h a fa mil y or pers o nal hist or y of 
m ulti ple e n d ocri ne ne o plasia t y pe 2 ( M E N 2) 
or me d ullar y t h yr oi d ca ncer will be e xcl u de d 
fr o m t he trial (see Secti o n 5. 2 ). 
 
Ne o plas ms 
( mali g na nt a n d n o n-
mali g na nt)  
se ma gl uti de 
P atie nts wit h o ver wei g ht or o besit y as well 
as patie nts wit h T 2 D, 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. N o i m bala nce was o bser ve d i n 
t he se ma gl uti de 2. 4 m g f or wei g ht 
ma na ge me nt p hase 3a trials wit h re gar ds t o 
t he pr o p orti o ns of s u bj ects wit h ne o plas ms 
( mali g na nt a n d n on -mali g na nt). 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 f or T 2 D, t he 
pr o p orti o n of s u bj ects 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 parat or. T he n u m ber of s u bj ects 
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.  
S u bj ects wit h a hist or y of mali g na nt 
ne o plas ms wit hi n t he past 5 years pri or t o 
scree ni n g will n ot be e nr olled i n t his trial. 
Basal a n d s q ua m o us cell s ki n ca ncer a n d a n y 
carci n o ma i n -sit u is all o we d (see Secti o n 5. 2 ). 
 
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
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V V- T M F- 4 5 3 5 0 0 0
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Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
1 7  of 7 4  
 
3. 1. 2   
Sec o n d ar y o bjecti ves  
T o c o m pare t h e effect of c o -a d mi nistere d s e ma gl uti de a n d ca grili nti de vers us se m a gl uti de i n 
s u bjects wit h T 2 D i na de q uatel y c o ntr olle d o n metf or mi n wit h or wit h o ut S G L T 2 i n hi bit or o n:  
•  ot her para meters f or gl ycae mic c o ntr ol  
•  b o d y wei g ht  
T o c o m pare t h e effect of c o -a d mi nistere d s e ma gl uti de a n d ca grili nti de vers us ca grili nti de i n 
s u bjects wit h T 2 D i na de q uatel y c o ntr olle d o n metf or mi n wit h or wit h o ut S G L T 2 i n hi bit or o n:  
•  H b A 1c  
•  ot her para meters f or gl ycae mic c o ntr ol  
•  b o d y wei g ht  
T o c o m pare t h e effect of c o -a d mi nistere d s e ma gl uti de a n d ca grili nti de, se m a gl uti de a n d ca grili nti de 
i n s u bjects wit h T 2 D i na de q uatel y c o ntr olle d o n metf or mi n wit h or wit h o ut S G L T 2 i n hi bit or o n:  
•  safet y a n d t olera bilit y 
•  h y p o gl ycae mia  
3. 1. 3   
Esti m a n ds  
A pri mar y a n d a n a d diti o nal esti ma n d is defi ne d f or t he pri mar y o bjecti ve. T w o i nterc urre nt e ve nts 
are i de ntifie d: treat me nt disc o nti n uati o n a n d i nitiati o n of a nti-dia betic res c ue i nter ve nti o n. T he 
attri b utes f or t he esti ma n ds are s u m marise d i n Ta ble  3 -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 effect of c o -a d mi nistere d 
se ma gl uti de a n d ca grili nti de vers us se ma gl uti de o n c ha n ge i n H b A 1c ( %-p oi nts) fr o m baseli ne t o 
wee k 3 2 i n s u bjects wit h T 2 D i na de q uatel y c o ntr olle d o n m etf or mi n wit h or wit h o ut S G L T 2 
i n hi bit or, ha d all s u bjects re mai ne d o n trial treat m e nt wit h o ut use of resc u e me dicati o n (a nti-
dia betic). A h y p ot hetical strate g y is a p plie d f or b ot h i nterc urre nt e ve nt of pre mat ure treat me nt 
disc o nti n uati o n a n d i nitiati o n of  resc ue me di cati o n. T he p o p ulati o n le vel s u m mar y is differe n ce i n 
mea ns.  
T he pri mar y esti ma n d esti mates t he ac hie va ble treat me nt effect wit h o ut t he c o nf o u n di n g of 
treat me nt disc o nti n uati o n a n d i nitiati o n of resc ue i nter ve nti o n. T his a p pr oac h is c o nsi dere d rele va nt 
f or e val u ati n g a mec ha nistic effect.  
A d diti o n al esti m a n d f or t he pri m a r y o bjecti ve  
T he a d diti o nal esti ma n d a d dresses a differe nt q uesti o n of i nterest: W hat is t he effect of  
c o-a d mi nistere d s e ma gl uti de a n d ca grili nti de vers us se ma gl uti de o n H b A 1c ( %-p oi nts) fr o m 
baseli ne t o wee k 3 2 i n s u bjects wit h T 2 D i na de q u atel y c o ntr olle d wit h metf or mi n wit h or wit h o ut 
S G L T 2 i n hi bit or, re gar dl ess of pre mat ure treat me nt disc o nti n uati o n or i nitiati o n of resc u e 
me dicati o n (a nti -dia betic).  
F or t he a d diti o nal esti m a n d, t he treat me nt p olic y strate g y is a p plie d f or b ot h t he i nterc urre nt e ve nt 
of i nitiati o n of pre mat ure treat me nt disc o nti n uati o n or resc u e me dicati o n. T he p o p ulati o n -le vel 
s u m mar y is differe n ce i n mea ns. Res ults base d o n t he a d diti o nal esti ma n d are e x pec te d t o mirr or t he 
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
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V V- T M F- 4 5 3 5 0 0 0
7 4
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C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
1 8  of 7 4  
 
cli nical practice sce n ari o beca use t h e esti ma n d c o nsi ders b ot h t he efficac y a n d t olera bilit y of 
treat me nts. 
T a ble  3 -1  Attri b utes f or t he esti m a n ds  
Esti m a n d 
c ate g or y 
Tre at me nt c o n diti o n   
V ari a ble/
E n d p oi nt  
P o p ul ati o n 
of i nterest  
I nterc urre nt e ve nt 
str ate g y 
P o p ul ati o n -le vel 
s u m m ar y me as ure 
Pri mar y   
T he effect of c o -
a d mi nistere d se ma gl uti de 
a n d ca grili nti de vers us 
se ma gl uti de o n H b A 1c, 
b ot h as a d d -o n t o 
metf or mi n wit h or wit h o ut 
S G L T 2 i n hi bit or a n d 
wit h o ut resc ue me dicati o n  
C ha n ge i n 
H b A 1c 
( %-p oi nt) 
fr o m 
baseli ne t o 
wee k 3 2  
S u bj ects 
wit h T 2 D 
i na de q uatel y 
c o ntr olle d o n 
metf or mi n 
wit h or 
wit h o ut 
S G L T 2 
i n hi bit or 
H y p ot hetical 
strate g y f or 
•
 I nitiati o n of a n y 
resc ue me dicati o n 
• 
Treat me nt 
disc o nti n uati o n  
Differe nce i n 
mea ns  
A d diti o nal   
T he effect of c o -
a d mi nistere d se ma gl uti de 
a n d ca grili nti de vers us 
se ma gl uti de o n H b A 1c, 
b ot h as a d d -o n t o 
metf or mi n wit h or wit h o ut 
S G L T 2 i n hi bit or  
Treat me nt p olic y 
strate g y f or 
•
 I nitiati o n of a n y 
resc ue me dicati o n  
•
Treat me nt 
disc o nti n uati o n  
3. 2   
Pri m ar y, sec o n d ar y a n d e x pl or at or y e n d p oi nt(s)  
3. 2. 1   
Pri m ar y e n d p oi nt  
E n d p oi nt title  
Ti me fr a me  
U nit  
C ha n ge i n H b A 1c  
Fr o m baseli ne ( wee k 0) t o we e k 3 2  
% -p oi nt  
3. 2. 2   
Sec o n d ar y e n d p oi nts  
3. 2. 2. 1   
C o nfir m at or y s ec o n d ar y e n d p oi nts  
N ot a p plica ble f or t his trial.  
3. 2. 2. 2   
S u p p orti ve sec o n d ar y e n d p oi nts  
E n d p oi nt title  
Ti me fr a me  
U nit  
C ha n ge i n fasti n g plas ma gl uc ose ( F P G)   
Fr o m baseli ne ( wee k 0) t o we e k 3 2  
m m ol/ L a n d m g/ d L  
C G M: C ha n ge i n mea n gl uc os e  
Fr o m baseli ne ( wee k 0) t o we e k 3 2  
m m ol/ L a n d m g/ d L  
C G M: T i me a b o ve ra n ge ( T A R) > 1 0. 0 
m m ol/ L  ( > 1 8 0 m g/ d L) 
At wee k 3 2  
% of rea di n gs  
C G M: T i me i n ra n ge ( TI R) 3. 9 – 1 0. 0 
m m ol/ L  ( 7 0– 1 8 0 m g/ d L)  
At wee k 3 2  
% of rea di n gs  
C ha n ge i n b o d y wei g ht  
Fr o m baseli ne ( wee k 0) t o we e k 3 2  
%  
C ha n ge i n b o d y wei g ht  
Fr o m baseli ne ( wee k 0) t o we e k 3 2  
K g  
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 we e k 3 7  
C o u nt  
N u m ber of cli nicall y si g nifica nt 
h y p o gl ycae mic e pis o des (le vel 2) 
( < 3. 0 m m ol/ L ( 5 4 m g/ d L), c o nfir me d b y 
B G meter) or se vere h y p o gl yc ae mic 
e pis o des (le vel 3)  
Fr o m baseli ne ( wee k 0) t o we e k 3 7   
C o u nt of e pis o des  
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
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V V- T M F- 4 5 3 5 0 0 0
7 4
 of
1 8
 
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1
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C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
1 9  of 7 4  
 
4  
Tri al desi g n  
4. 1   
O ver all desi g n  
T his is a 3 2 -wee k, ra n d o mise d, d o u ble -bli n d, acti ve -c o ntr olle d, t hree -ar m, parallel gr o u p, 
m ultice ntre cli nical trial. T he trial will c o m pare t h e  effi cac y a n d safet y of c o -a d mi nistrati o n of 
ca grili nti de s.c. 2. 4 m g o nce  wee kl y a n d se ma gl uti de s.c. 2. 4 m g o n ce  wee kl y vers us s e ma gl uti de 
s.c. 2. 4 m g o n ce wee kl y m o n ot hera p y vers us ca grili nti de s.c. 2. 4 m g o nce  wee kl y m o n ot hera p y i n 
s u bjects wit h T 2 D.  
A p pr o xi matel y 9 0 eli gi bl e s u bjects will be ra n d o mise d t o 1 of t he 3 treat me nt ar ms i n a rati o of 
1: 1: 1. Ra n d o misati o n will be stratifie d acc or di n g t o t he S G L T 2 i n hi bit or treat me nt ( Yes/ N o).  
T he trial i ncl u des a mi ni m u m 1 0 -da y s cree ni n g p eri o d t o assess s u bject eli gi bilit y, a 3 2 -wee k 
treat me nt peri o d a n d a 5-wee k f oll o w u p peri o d. T he 3 2 -wee k treat me nt peri o d c o nsists of a 
1 6 -wee k d os e escalati o n peri o d a n d a 1 6 -wee k mai nte na nce p eri o d. T he pla n ne d t otal trial d urati o n 
f or t he i n di vi d ual s u bject is a p pr o xi matel y 3 9 wee ks.  
T o e val uate t he effect o n gl ycae mic c o ntr ol, s u bjects will ha ve C G M pr ofiles c ollecte d, as s pecifi e d 
i n t he fl o wc hart (s ee Secti o n 1. 2 ). T his will i ncl u de C G M pr ofili n g d uri n g t he 1 0-da y scree ni n g 
peri o d re prese nti n g baseli ne C G M e val uati o n. T he C G M will be bli n de d f or b ot h s u bjects a n d 
i n vesti gat ors a n d n ot us e d f or d ose a dj ust me nts. 
T he trial desi g n is ill ustrate d i n Fi g ure  4 -1 . 
Fi g ure  4 -1  
Sc he m atic di a gr a m of t he tri al desi g n  
 
4. 2   
Scie ntific r ati o n ale f or tri al desi g n  
A ra n d o mise d, d o u ble -bli n de d trial desi g n h as bee n c h ose n t o i ncrease t he vali dit y of t he trial a n d t o 
a v oi d bias. Ca grili nti de s.c. 2. 4 m g o n ce  wee kl y a n d se ma gl uti de s.c. 2. 4 m g o nce  wee kl y are 
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
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V V- T M F- 4 5 3 5 0 0 0
7 4
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1 9
 
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1
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C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
2 0  of 7 4  
 
c h ose n as acti ve c o m parat ors. T he pri mar y o bjecti ve is t o c o m pare t he effect of c o -a d mi nistrati o n 
of ca grili nti de  s.c. 2. 4 m g o nce  wee kl y a n d se ma gl uti de s.c. 2. 4 m g o nce  wee kl y vers us s e ma gl uti de 
s.c. 2. 4 m g o n ce wee kl y o n gl ycae mic c o ntr ol. B ot h efficac y a n d safet y of c o -a d mi nistrati o n of 
ca grili nti de s.c. 2. 4 m g o nce  wee kl y a n d se ma gl uti de s.c. 2. 4 m g o n ce  wee kl y c o m pare d t o eac h 
i n di vi d ual c o m p o ne nt will be i n vesti gate d. Se ma gl uti de is k n o w n t o ha ve a gl uc ose l o weri n g effect 
a n d is a p pr o ve d f or treat me nt of T 2 D i n l o wer d oses t ha n i n vesti gat e d i n t his trial. N o cli nical data 
o n t he effect of treat me nt wit h ca grili nti de o n gl ycae mic c o ntr ol i n s u bjects wit h T 2 D are c urre ntl y 
a vaila ble a n d t heref ore a ca grili nti de s.c. 2. 4 m g o nce  wee kl y treat me nt ar m has bee n i ncl u de d i n 
t his trial. 
T he pla n ne d tr eat me nt d urati o n is 3 2 wee ks. T he treat me nt d urati o n i ncl u d es a 1 6 -wee k d ose 
escalati o n peri o d a n d a 1 6 -wee k mai nte na nce peri o d. T he d ose of trial pr o d uct will be escalat e d 
e ver y 4 wee ks t o miti gat e t he ris ks of gastr oi ntesti nal si de effects. T he t otal treat me nt d urati o n of 3 2 
wee ks is e x pecte d t o e ns ure a de q u ate ti me f or c o m pari n g t he effect o n H b A
1c i n acc or da nce wit h 
t he pri mar y o bjecti ve of t he trial. A 1 0-da y s cree ni n g peri o d is i ncl u de d t o e ns ure eli gi bilit y of 
s u bjects a n d t o c ollect C G M pr ofiles bef ore t he i nitiati o n of treat me nt wit h trial pr o d uct s. 
F urt her m ore, a 1 0 -da y C G M data c ollecti o n will be c o n d ucte d after t he d ose escal ati o n peri o d a n d 
at t he e n d of t he mai nte n a nce p eri o d. A f oll o w -u p visit is pla n ne d t o c ollect data o n safet y 5 wee ks 
after e n d of treat me nt t o acc o u nt f or t he l o n g half -life of trial pr o d ucts. 
T he ra n d o misati o n rati o is 1: 1: 1 t o e ns ure a bala nce d c o m paris o n bet w ee n gr o u ps. T o a v oi d a 
pr o n o u nce d differe nce i n S G L T 2 i n hi bit or use bet wee n t he treat me nt ar ms at baseli ne, 
ra n d o misati o n will be stratifie d acc or di n g t o t he S G L T 2 i n hi bit or treat me nt ( Yes/ N o).  
T he relati vel y h o m o ge n e o us trial p o p ulati o n of s u bjects wit h T 2 D w h o are i n i na de q uate gl ycae mic 
c o ntr ol usi n g metf or mi n wit h or wit h o ut S G L T 2 i n hi bit or ha ve bee n c h ose n t o li mit t he varia bilit y. 
I n cl u di n g s u bjects wit h H b A1c of 7. 5 % -1 0. 0 % all o w s f or a n e val uati o n of gl uc ose p ara meters. O nl y 
s u bjects wit h B MI ≥ 2 7. 0 k g/ m 2 are i ncl u de d t o miti gate t he n ee d f or re d u cti o n i n d ose i n case t he 
c o-a d mi nistrati o n of ca grili nti de a n d se ma gl uti de l ea ds t o pr o n o u nce d wei g ht re d ucti o n i n s u bjects 
wit h T 2 D.  
4. 3   
J ustific ati o n f or d ose  
Se ma gl uti de s.c. h as bee n a p pr o ve d f or treat me nt of T 2 D i n t he d oses of 0. 5 m g a n d 1. 0 m g a n d a 
d ose of 2. 0 m g is c urre ntl y u n der re g ul at or y re vi e w. Wit hi n t he wei g ht ma na ge me nt i n dicati o n, a 
gl o bal p has e 3a cli nical de vel o p me nt pr o g ra m me wit h se ma gl uti de s.c. 2. 4 m g o nce wee kl y is u n der 
re g ulat or y re vie w. O ne of t he trials c o m plete d wit hi n t he p hase 3a wei g ht ma na ge me nt pr o gra m me 
( N N 9 5 3 6-4 3 7 4) i n cl u de d 1 2 1 0 s u bjects wit h o ver wei g ht or o besit y a n d T 2 D. Se ma gl uti de s.c. 
2. 4  m g o nce  wee kl y a p peare d t o ha ve a safe a n d well t olerate d pr ofile i n li n e wit h w hat has 
pre vi o usl y b ee n o bser ve d f or se ma gl uti de 2 3. 
Base d o n t h e res ults fr o m cli nical trials (see Secti o n  2. 1 ) a ca grili nti de d ose of 2. 4 m g a d mi nistere d 
i n c o m bi nati o n wit h se ma gl uti de s.c. 2. 4 m g is c o nsi dere d t o pr o vi de ma xi m u m effect o n b o d y 
wei g ht w hile e ns uri n g safet y a n d t olera bilit y. T he o nce wee kl y c o m bi nati o n of ca grili nti de 2. 4 m g 
a n d se ma gl uti de 2. 4 m g is bei n g i n vesti gate d wit hi n t he i n dicati o n of wei g ht ma na ge me nt. Si nce 
wei g ht l oss is ass ociate d wit h i m pr o ve me nts i n gl ycae mic p ara met ers (see Secti o n 2. 1 ) d oses of 
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
2 0
 
-
 |
1
 |
C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
2 1  of 7 4  
 
2. 4  m g f or b ot h ca grili nti de a n d se ma gl uti de will be use d t o i n vesti gate w h et her ca grili nti de a d ds t o 
t he gl uc os e l o weri n g effect of se ma gl uti de i n s u bjects wit h T 2 D. 
Escalat i o n of t he ca grili nti de a n d se ma gl uti de d oses will be d o ne e ver y 4 wee ks, u ntil t he 
mai nte na nce d os e is reac he d after 1 6 wee ks, i n or der t o miti gate t he well -k n o w n gastr oi ntesti nal 
si de effects o bser ve d wit h b ot h ca grili nti de a n d se ma gl uti de treat me nts.  
4. 4   
E n d of tri al defi niti o n  
A s u bject is c o nsi dere d t o ha ve c o m plete d t h e trial if he/s he has c o m plete d all p hases of t he trial 
i ncl u di n g t he last visit s h o w n i n t he fl o wc hart.  
T he e n d of t he tri al is defi ne d as t he date of t he last visit of t he last s u bject i n t he trial. 
5  
Tri al p o p ul ati o n  
Pr os pecti ve a p pr o val of pr ot oc ol de viati o ns t o recr uit me nt a n d e nr ol me nt 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.  
5. 1   
I ncl usi o n criteri a 
S u bjects are eli gi ble t o b e i ncl u de d i n t he trial o nl y if all of t he f oll o wi n g criteria a p pl y:  
1.  I nf or me d c o ns e nt o btai ne d bef ore a n y trial-relate d acti vities. Trial-rel ate d acti vities are a n y 
pr oce d ures t hat are carrie d o ut as part of t he trial, i ncl u di n g acti vities t o deter mi ne s uita bilit y f or 
t he trial 
2.  F e male of  n o n -c hil d beari n g p ote ntial (s ee defi niti o n i n A p pe n di x 4, Secti o n 1 0. 4 ) or male  
3.  A ge a b o ve or e q u al t o 1 8 years at t he ti me of si g ni n g i nf or m e d c o nse nt  
4.  B MI ≥ 2 7. 0 k g/ m 2 
5.  Dia g n os e d wit h t y p e 2 dia betes mellit us ≥ 1 8 0 da ys bef ore s cree ni n g  
6.  H b A 1c of 7. 5 -1 0. 0 % ( 5 8 -8 6 m m ol/ m ol) ( b ot h i ncl usi ve) as assess e d b y ce ntral la b orat or y at 
scree ni n g 
7.  Sta ble dail y d ose(s) ≥ 9 0 da ys b ef ore scree ni n g of t he f oll o wi n g a nti dia betic dr u g(s) or 
c o m bi nati o n re gi me n(s) at ma xi m u m t olerate d or effecti ve d ose as j u d ge d b y t he i n vesti gat or: 
metf or mi n wit h or wit h o ut S G L T 2 i n hi bit or  
8.  A ble a n d willi n g t o a d here t o t he pr ot oc ol i ncl u di n g weari n g pr o visi o ne d c o nti n u o us gl uc ose 
m o nit ori n g ( C G M) de vice base d o n t he I n vesti gat or’s j u d ge me nt  
5. 2   
E xcl usi o n criteri a   
S u bjects are e x cl u de d fr o m t he trial if a n y of t he f oll o wi n g criteria a p pl y:  
1.  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 a n d pri or i ns uli n treat me nt  f or gestati o nal dia betes are all o we d 
2.  Pre vi o us or pla n ne d ( d uri n g t he trial p eri o d) o besit y treat me nt wit h s ur ger y o r a wei g ht l oss 
de vice. H o we ver, t h e f oll o wi n g are all o we d: ( 1) li p os ucti o n a n d/ or a b d o mi n o plast y, if 
perf or me d > 1 year bef ore scree ni n g, ( 2) la p ba n di n g, if t he b a n d has bee n re m o ve d > 1 year 
bef ore s cree ni n g, ( 3) i ntr a gastric ball o o n, if t he b all o o n has  bee n re m o v e d > 1 year bef ore 
scree ni n g or ( 4) d u o d e nal-je n u nal b y p ass slee v e, if t he slee ve h as bee n re m o ve d > 1 year bef ore 
scree ni n g 
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
2 1
 
-
 |
1
 |
C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
2 2  of 7 4  
 
3.  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)  
4.  Prese nce or hist or y of c hr o nic pa ncreatitis a 
5.  Prese nce or hist or y of ac ute pa ncreatitis wit hi n 1 8 0 da ys b ef ore scree ni n g a 
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 ularisa ti o n 
9.  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 maa 
1 0.  Re nal i m pair me nt wit h esti mate d Gl o mer ular Filtrati o n Rate (e G F R) < 6 0 ml/ mi n/ 1. 7 3 m 2 b y 
ce ntral la b orat or y at scree ni n g  
1 1.  I m paire d li ver f u ncti o n, defi ne d as Al a ni ne A mi n otra nsferase ( A L T) ≥ 2. 5 ti mes or Bilir u bi n 
> 1. 5 ti mes u p per n or mal li mit ( U N L) b y ce ntral la b orat or y at scree ni n g  
1 2.  Hist or y or prese n ce of a disease, ca usi n g i m paire d calci u m h o me ostasis as j u d ge d b y t he 
i n vesti gat or 
1 3.  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 9 0 da ys bef ore s cree 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 pecifie d f or n o n -dilate d e x a mi nati o n  
1 4.  A n y e pis o des a of dia betic ket oaci d osis wit hi n 9 0 da ys b ef ore scree ni n g  
1 5.  Rec urre nt s e vere h y p o gl ycae mic e pis o des wit hi n t he last year as j u d ge d b y t he I n v esti gat or  
1 6.  I n a de q uat el y treate d bl o o d press ure d efi ne d as S yst olic ≥1 8 0 m m H g or diast olic ≥1 1 0 m m H g at 
scree ni n g 
1 7.  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 ncer, 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 or e scree ni n g  
1 8.  S ur ger y sc he d ul e d f or t h e d urati o n of t he trial, e x pect f or mi n or s ur gical pr oce d ures, i n t he 
o pi ni o n of t he I n v esti gat or  
1 9.  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.  
2 0.  K n o w n or s us pect e d h y p erse nsiti vit y t o trial pr o d uct(s) or relate d pr o d u cts  
2 1.  Pre vi o us partici pati o n i n t his trial. Partici pati o n is defi ne d as si g ne d i nf or me d c o nse nt  
2 2.  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  
2 3.  Partici pati o n i n a n y cli nical trial of a n a p pr o ve d or n o n -a p pr o ve d i n vesti gati o nal me dici nal 
pr o d uct wit hi n 9 0 da ys b ef ore s cree ni n g  
2 4.  A n y dis or d er, w hic h i n t he i n vesti gat or’s o pi ni o n  mi g ht je o par dise s u bject’s safet y or 
c o m plia nce wit h t he pr ot oc ol  
a: As declare d b y t he s u bj ect or i n t he me dical rec or ds  
5. 3   
Lif est yle c o nsi der ati 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 s u bjects a n d trial sites, t he bel o w 
restricti o ns a p pl y. 
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
2 2
 
-
 |
1
 |
C O N FI D E N TI A L








Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
2 6  of 7 4  
 
A u xili ar y s u p plies  
A u xiliar y s u p plies will b e pr o vi de d i n acc or da nce wit h t he trial materials ma n ual ( T M M) a n d 
Ta ble  6 -4 . 
T a ble  6 -4   
A u xili ar y s u p plies  
A u xili ar y s u p pl y  
Det ails  
Nee dles  
O nl y nee dles pr o vi de d a n d a p pr o ve d b y N o v o N or dis k m ust be use d f or 
a d mi nistrati o n of trial pr o d uct.  
Bl o o d gl uc ose ( B G) meter   
S u bj ects m ust be i nstr ucte d i n h o w t o use t he B G meter as s p ecifie d i n A p pe n di x 7, 
Secti o n 1 0. 7 . Please refer t o t he ma n ufact urer’s g ui de. 
C o nti n u o us  gl uc ose  
m o nit ori n g ( C G M)  
S u bj ects m ust be i nstr ucte d i n ha n dli n g of t he C G M as s pecifie d i n t he fl o wc hart , 
Secti o n 1. 2 . Please refer t o t he C G M S u bj ect G ui de pr o vi de d. 
Directi o n  f or use ( D F U)  
D F U f or P D S 2 9 0 pre -fille d pe n-i nj ect or a n d N o v o P e n Ec h o ®  
N ot i ncl u de d i n t he dis pe nsi n g u nit a n d t o be ha n de d o ut se p aratel y  
 
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 if t he s u bject e x perie nces a 
h y p o gl ycae mic e pis o de , see A p pe n di x 7 ( Secti o n 1 0. 7 ). 
Trai ni n g i n t he p e n -i nject or a n d d ura bl e de vice is t he res p o nsi bilit y of t he i n vesti gat or or a del e gate 
a n d m ust be re peate d d uri n g t he trial at re g ular i nt er vals, as s pecifie d i n t he fl o wc hart 
(see Secti o n  1. 2 ) i n or d er t o e ns ure c orrect use of t he pe n-i nject or.  
6. 1. 1   
Me dic al de vices  
I nf or mati o n a b o ut t he P D S 2 9 0 pre-fille d pe n-i nject or f or s e ma gl uti de/ place b o a n d N o v o Pe n Ec h o ®  
d ura ble de vice f or ca grili nti de/ place b o ca n be f o u n d i n t he D F U.  
6. 2   
Pre p ar ati o n/ h a n dli n g/st or a ge/ acc o u nt a bilit y  
O nl y s u bjects ra n d o mise d t o treat me nt ma y use trial pr o d uct a n d o nl y dele gat e d site staff ma y 
s u p pl y trial pr o d uct. 
•  Eac h site will be s u p plie d wit h s ufficie nt trial pr o d ucts f or t he trial o n a n o n g oi n g basis. 
Trial pr o d ucts will be distri b ute d t o t he sites acc or di n g t o scree ni n g 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 trial pr o d ucts recei v e d, a n d t hat a n y discre pa n cies are 
re p orte d a n d res ol ve d b ef ore use of t he trial pr o d ucts. 
•  All trial pr o d ucts m ust be st ore d i n a sec ure, c o ntr olle d, a n d m o nit ore d ( ma n ual or 
a ut o mate d) area i n acc or da nce wit h t he la belle d st ora ge c o n diti o ns wit h access li mite d t o t he 
i n vesti gat or a n d 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 trial pr o d uct has bee n st ore d 
o utsi de s pecifie d c o n diti o ns. T he trial pr o d uct m ust n ot be dis pe nse d t o a n y s u bject b ef ore it 
has bee n e v al uate d a n d a p pr o ve d f or f urt her us e b y N o v o N or dis k. A d diti o nal details 
re gar di n g h a n dli n g of t e m perat ure d e viati o ns ca n be f o u n d i n t he trial mat erials ma n ual 
( T M M). 
•  T he i n v esti gat or or desi g nee is res p o nsi ble f or dr u g acc o u nta bilit y a n d rec or d mai nte na nce 
(i.e. recei pt, acc o u nta bilit y a n d fi nal dis p ositi o n rec or ds). 
•  T he i n vesti gat or or desi g nee m ust i nstr uct t he s u bject i n w hat t o ret ur n at ne xt visit.  
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
2 6
 
-
 |
1
 |
C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
2 7  of 7 4  
 
•  Dr u g acc o u nta bilit y s h o ul d be perf or me d at pe n le vel.  
•  Destr ucti o n of trial pr o d u cts ca n be p erf or me d o n a n o n g oi n g b asis a n d will be d o ne 
acc or di n g t o l ocal pr oce d ures after acc o u nta bilit y is fi nalise d b y t he site a n d rec o ncile d b y 
t he m o nit or. 
•  All ret ur ne d, u n -us e d , e x pire d or da ma ge d trial pr o d ucts (f or tec h nical c o m plai nt sa m ples, 
see Secti o n 1 0. 5 ) m ust be st ore d se paratel y fr o m n o n-all ocate d trial pr o d ucts. N o 
te m perature m o nit ori n g is re q uire d.  
•  N o n -all ocate d trial pr o d u cts i ncl u di n g e x pire d or da ma ge d pr o d u cts m ust be acc o u nte d as 
u n use d, at t he latest at cl os ure of t he site.  
6. 2. 1   
S hi p me nt of tri al pr o d uct t o s u bject’s h o me  
If per mitte d b y l ocal re g ulati o ns, t he i n vesti gat or ma y offer t o s e n d trial pr o d ucts a n d a u xiliaries 
fr o m t he trial site or p har mac y t o t he s u bject’s h o me b y c o urier ser vice.  
T he pr ocess f or se n di n g trial pr o d uct fr o m t he tri al site or p har mac y t o a s u bject’s h o me is 
descri be d i n t he “ Trial site/ p har mac y  i nstr ucti o n f or s hi p me nt of trial pr o d uct t o s u bjects’ h o mes” 
d oc u me nt. T his d oc u me nt c o ntai ns detaile d i nstr ucti o ns f or pre p ari n g pac k a gi n g a n d setti n g u p t he 
pic k -u p of trial pr o d u ct s, ha n d o ver of tri al pr o d ucts fr o m t he trial site or p h ar mac y staff t o t he 
c o urier, re q uire d t e m perat ure m o nit ori n g of tri al pr o d uct s, deli ver y t o a n d recei pt of trial pr o d u cst 
b y t he s u bject. T he pr ocess f or ret ur ni n g trial pr o d uct t o t he trial site or p har mac y b y c o urier is als o 
des cri be d i n t his d oc u me nt.  
I n v esti gat ors, trial site staff a n d s u bjects w h o will be i n v ol ve d i n s hi p me nt of trial pr o d uct t o t he 
s u bject’s h o me will be a d e q uatel y trai ne d i n t his pr ocess. 
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 s u bjects will be ce ntr all y scree n e d a n d ra n d o mise d usi n g a n I W R S a n d assi g ne d t o t he n e xt 
a vaila ble treat me nt acc or di n g t o ra n d o misati o n sc he d ule. Trial pr o d ucts  will be dis pe nse d/all ocate d 
at t he trial visits s u m marise d i n t he fl o wc hart.  
Ra n d o misati o n  will be stratifie d acc or di n g t o treat me nt wit h S G L T 2 i n hi bit or at scree ni n g ( yes/ n o).  
At scree ni n g, eac h s u bject will be assi g ne d a u ni q ue 6 -di git S u bjects I D, w hic h will re mai n t he 
sa me t hr o u g h o ut t he trial. Eac h site is assi g n e d a 3-di git n u m ber a n d S u b ject I Ds start wit h t he site 
n u m ber.  
T he I W R S is use d f or bli n d -brea ki n g. I n cas e of a n e mer ge n c y, t he i n vesti gat or has 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 s u bjects’ treat me nt is warra nte d. S u bject safet y 
m ust al wa ys b e t he first c o n si derati o n i n ma ki n g s uc h a deter mi nati o n. If t he i n vesti gat or deci d es 
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 s u bj ects’ treat me nt u nless t his c o ul d dela y e mer ge nc y treat me nt of t he s u bject. 
If a s u bject’s treat me nt is u n bli n de d, N o v o N or dis k ( Gl o bal Safet y de p art m e nt) m ust be n otifie d 
wit hi n 2 4 h o urs after brea ki n g t he bli n d. T he d ate a n d reas o n t h at t he bli n d was br o ke n m ust be 
rec or de d i n t he me dical rec or ds. T he p ers o n brea ki ng t he bli n d m ust pri nt t he “c o d e brea k 
c o nfir mati o n” n otificati o n ge n erat e d b y t he I W R S, si g n a n d d ate t he d oc u m e nt. If I W R S is n ot 
accessi ble at t he ti me of bli n d brea k, t he I W R S hel p des k s h o ul d be c o ntact e d. C o ntact details are 
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
2 7
 
-
 |
1
 |
C O N FI D E N TI A L




Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
2 9  of 7 4  
 
•  will n ot be pr o vi de d b y N o v o N or dis k u nless re q uire d b y l o cal la w a n d s h o ul d be p urc has e d 
or ot her wise d eli vere d t o s u bjects i n acc o r da nce wit h l ocal healt h pla ns  
•  S h o ul d be use d i n acc or da nce wit h sta n dar d of care or l ocal la b el i n t he c o u ntr y  
I n v esti gat ors ca n s witc h oral a nti -dia betic ( O A D ) treat me nt wit hi n t he sa me dr u g c lass, e. g. i n case 
s pecific dr u gs b ec o me u na vaila ble. C ha n ges  i n c o nc o mita nt me dicati o n, i ncl u di n g s witc h of O A D 
treat me nt wit hi n t he sa me dr u g class m ust be rec or de d at eac h visit / p h o ne c o ntact. If a c ha n ge is 
d ue 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 . 
6. 5. 1   
Resc ue me dic ati o n  
Gl ycae mic resc u e me dicati o n, i.e. i nte nsificati o n of bac k gr o u n d oral a nti -dia betic ( O A D) 
me dicati o n a n d/ or i nitiati o n of ne w a nti -dia betic me dicati o n, s h o ul d be 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 per gl ycae mia. Please s ee Secti o n 7. 1. 2 . 
Resc ue me dicati o n s h o ul d be selecte d acc or di n g t o t he A D A/ E A S D g ui deli ne 2 4, 2 5 (e x cl u di n g 
G L P -1 R As, di pe pti d yl p e pti dase -4 ( D P P -4) i n hi bit ors a n d a m yli n a n al o g u es).  
S u bjects t hat are start e d o n resc ue m e 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 gat or j u d ge t hat it je o par dises s u bject’s 
safet y. 
Resc ue me dicati o n (i nte nsificati o n of e xisti n g bac k gr o u n d m e dicati o n a n d/ or i nitiati o n of ne w 
me dicati o n)  a n d a n y c ha n ges t o t his s h o ul d be d oc u me nte d i n me dical rec or ds a n d re p orte d o n t he 
c onc 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.  
6. 6   
D ose m o dific ati o n  
C o nsi der dela yi n g d os e escalati o n or re d u ci n g t he d ose d uri n g d os e escalati o n if:  
•  T he c urre nt d ose is n ot t olerate d b y t he s u bject. T his s h o ul d  o nl y b e all o we d if t he s u bject 
w o ul d ot her wise disc o nti n ue trial pr o d uct s c o m pletel y a n d o nl y  if c o nsi dere d safe t o 
c o nti n ue o n a n y trial pr o d ucts d ose, as per i n vesti gat or’s discreti o n  
C o nsi der re d uci n g t he m ai nte na nce d ose if:  
•  T he mai nte na nce d ose is n ot t olerate d b y t he s u bject. T he s u bject ma y sta y at a l o wer d ose 
le vel b ut o nl y if t he s u bject w o ul d ot her wise disc o nti n ue trial pr o d ucts c o m pletel y a n d o nl y 
if c o nsi dere d s afe t o c o nti n ue o n a n y trial pr o d ucts d ose, as per i n vesti gat or’s discreti o n.  
•  T he  s u bject ac hie ves a B MI of < 2 2. 5 k g/ m 2 a n d c o nti n ues l osi n g wei g ht, p er i n vesti gat or’s 
discreti o n  
 
D ose m o dificati o ns m ust  be a p plie d t o b ot h trial pr o d ucts. I n cas e of de viati o ns fr o m t he pla n ne d 
d ose escal ati o n re gi me n, it is rec o m me n de d t hat t he s u bject  ma kes at least o ne atte m pt t o re -es calat e 
t o t he mai nte na nce d os e, as per t he i n vesti gat or’s discreti o n. It is rec o m me n de d t hat t he i n vesti gat or 
c o ns ults N o v o N or dis k i n case of persiste nt de viati o ns fr o m t he pla n ne d es calati o n re gi me n . 
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
2 9
 
-
 |
1
 |
C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 0  of 7 4  
 
6. 7   
Tre at me nt after e n d of tri al  
W he n disc o nti n ui n g trial pr o d uct s at t he ‘e n d -of -treat me nt’ visit, t he s u bject 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. C o nsi deri n g t he l o n g half-life of 
se ma gl uti de a n d ca grili nti de a n d t o a v oid o ver -e x p os ure t o G L P -1 R As a n d i nterfere nce wit h safet y 
data c ollecti o n, i nitiati n g G L P -1 R A , D P P -4i or a m yli n a nal o g u es s h o ul d be a v oi de d bet wee n t he 
e n d-of -tr eat me nt visit ( V 1 6) a n d t he e n d -of -trial visit ( V 1 7). 
7  
Disc o nti n u ati o n of tri al tre at me nt a n d s u bject 
disc o nti n u ati o n/ wit h dr a w al  
Treat me nt of a s u bject m a y b e disc o nti n ue d at a n y ti me d uri n g t he trial at t h e discreti o n of t he 
i n vesti gat or f or safet y, be ha vi o ural, c o m plia nce or a d mi nistrati ve reas o ns. 
7. 1   
Disc o nti n u ati o n of tri al tre at me nt  
Trial pr o d uct s ma y be dis c o nti n ue d at a n y ti me d uri n g t he trial at t he discreti o n of t he s u bject or at 
t he discreti o n of t he i n vesti gat or f or safet y, b e ha vi o ural, c o m plia nce or a d mi nistrati ve reas o ns. 
T he trial pr o d uct s m ust be disc o nti n ue d, if a n y of t he f oll o wi n g a p p lies f or t he s u bject: 
1.  Safet y c o ncer n as j u d ge d b y t he i n vesti gat or  
2.  S us pici o n of ac ute pa n creatitis  
3.  Pre g n a nc y  
4.  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 trial  
S u bjects  meeti n g disc o nti n uati o n of tre at me nt crit eria n o. 1, 2  or  3  ca n res u me trial pr o d ucts if t he 
criteria is n o l o n ger m et.  
F or disc o nti n uati o n of treat me nt criteri o n n o. 2:  
If ac ut e pa ncreatitis is s us pecte 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 ). 
S u bjects ca n res u me trial pr o d ucts if t he Atla nta criteri o n2 6 is n ot f ulfille d a n d t h us t he s us pici o n of 
ac ute pa n creatitis is n ot c o nfir me d. Trial pr o d u cts  ma y b e res u me d f or s u bj ects wit h a gallst o ne -
i n d uce d pa ncreatitis i n case of c h olec yst ecto m y.  
T he pri mar y reas o n f or disc o nti n uati o n of trial pr o d ucts m ust be s pecifie d i n t he s u bject’s me dical 
rec or ds a n d t he e n d-of -tr eat me nt f or m i n t he e C R F, a n d fi nal dr u g acc o u nt a bilit y m ust be 
perf or me d. A ‘treat me nt stat us sessi o n’ m ust be ma de i n t he I W R S t o disc o nti n ue trial pr o d uct s. 
If a s u bject h as disc o nti n ue d trial pr o d ucts, eff orts m ust be ma de t o ha ve s u bjects atte n d a n d 
c o m plete all re mai ni n g s c he d ule d visit pr oce d ures. All eff orts s h o ul d be ma de t o ha ve t he s u bject 
atte n d at least visit V 1 2 , t he ‘e n d of  tr eat me nt’ visit ( V 1 6) a n d t he ‘e n d of  trial’ visit ( V 1 7).  If t he 
s u bjects d o n ot wis h t o atte n d t he sc he d ule d cli nic visits, eff orts s h o ul d be ma de t o ha ve t he 
re mai ni n g cli nic visits c o n verte d t o p h o ne call visits. If a s u bject is u n willi n g t o atte n d t he 
re mai ni n g visits, i nf or mati o n a b o ut t he atte m pts t o f oll o w u p wit h t he s u bject m ust be d oc u me nte d 
i n t he s u bject’s me dical r ec or ds . 
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
3 0
 
-
 |
1
 |
C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 1  of 7 4  
 
T he ‘e n d of  trial’ visit ( V 1 7) is sc he d ule d a p pr o xi matel y 5 wee ks after e n d of treat me nt t o e ns ure 
t he safet y of t he s u bj ect. If t he s u bject has disc o nti n ue d trial pr o d ucts > 5 wee ks pri or t o t he ‘e n d of  
treat me nt’ visit  ( V 1 6), a n d t he re q uire m e nts f or t h e f oll o w-u p peri o d pri or t o t he ‘e n d of  trial’ visit 
( V 1 7) are f ulfille d, t he n t he ‘e n d of  tri al’ visit  ( V 1 7) ca n be o mitte d.  
7. 1. 1   
Te m p or a r y disc o nti n u ati o n of tri al tre at me nt  
If a s u bject h as disc o nti n ue d trial pr o d ucts d ue t o te m p orar y safet y c o n cer n n ot relate d t o trial 
pr o d ucts a n d ca n res u me treat me nt, t he s u bject s h o ul d f oll o w t he g ui de f or misse d d oses Ta ble  6 -3 . 
Si milarl y, a s u bject w h o disc o nti n ues trial pr o d uct s 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 trial pr o d u cts ( Secti o n 6. 1 ). A ‘treat me nt stat us sessi o n’ m ust be ma de i n t he I W R S w he n a 
s u bject pa uses treat me nt or res u mes treat me nt. 
I n case of s us pici o n of ac ute pa ncreatitis, t he trial pr o d ucts m ust pr o m ptl y be di sc o nti n ue d; 
h o we ver, ‘treat me nt stat us sessi o n’ s h o ul d n ot be ma de i n I W R S bef ore dia g n osis of ac ute 
pa ncreatitis is c o nfir me d. If ac ut e pa ncreatitis is c o nfir me d, treat me nt wit h trial pr o d uct s m ust n ot 
be restart e d, a n d a ‘treat me nt stat us sessi o n’ s h o ul d  be ma de i n I W R S.  
7. 1. 2   
Resc ue criteri a  
If a n y of t he F P G val u es e x cee d t he li mits o utli ne d bel o w a n d n o i nterc urre nt ca use of t he 
h y per gl ycae mia ca n b e i de ntifie d, t he s u bject s h o ul d be offere d resc ue me dicati o n, see 
Secti o n  6. 5. 1 ). 
Resc ue me dicati o n s h o ul d be offere d if F P G val ues e x cee ds:  
•  
1 5. 0 m m ol/ L ( 2 7 0 m g/ d L) fr o m ra n d o misati o n t o e n d of wee k 8  
•  
1 3. 3 m m ol/ L ( 2 4 0 m g/ d L) fr o m wee k 9 t o e n d of wee k 2 0  
•  
1 1. 1 m m ol/ L ( 2 0 0 m g/ d L) fr o m wee k 2 1 t o e n d of treat me nt  
A c o nfir mat or y F P G s h o ul d be o btai ne d b y t he ce ntral la b orat or y. If t he c o nfir mat or y F P G e x cee ds 
t he val ues descri be d a b o ve, t he s u bject s h o ul d be offere d res c ue me dicati o n at t he discreti o n of t he 
i n vesti gat or a n d in acc or da nce wit h t he A D A/ E A S D g ui deli ne 2 4, 2 7 (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 nal o g ues). R esc ue me di cati o n s h o ul d be prescri be d as a d d-o n t o ra n d o mise d 
treat me nt a n d s u bjects 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. 
7. 2   
S u bject wit h dr a w al f r o m t he tri al  
A s u bject ma y wit h dra w c o nse nt at a n y ti me at his/ her o w n re q u est  
If a s u bject wit h dra ws c o nse nt, t he i n vesti gat or m ust as k t he s u bject if he/s he is willi n g, as s o o n as 
p ossi ble, t o ha ve assess m e nt perf or m e d acc or di n g t o  ‘e n d of treat me nt ’ visit ( V 1 6). See t he 
fl o wc hart ( Secti o n 1. 2 ) f or data t o be c ollecte d. 
Fi nal dr u g acc o u nta bilit y m ust be perf or me d e ve n if t he s u bject is n ot a ble t o c o me t o t he site. A 
‘treat me nt status  sessi o n’ m ust be ma de i n t he I W R S.  
If t he s u bject wit h dra ws c o nse nt, N o v o N or dis k ma y retai n a n d c o nti n ue t o use a n y data c ollecte d 
bef ore  s u c h a wit h dr a wal of c o nse nt. 
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
3 1
 
-
 |
1
 |
C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 2  of 7 4  
 
If a s u bject wit h dra ws fr o m t he trial, he/s he ma y re q uest destr ucti o n of a n y sa m ples ta ke n a n d n ot 
teste d, a n d t he i n vesti gat or m ust d oc u me nt t his i n t he me dical rec or d. 
Alt h o u g h a s u bject is n ot o bli ge d t o gi ve his/ her reas o n(s) f or wit h dra wi n g, t he i n vesti gat or m ust 
ma ke a reas o na bl e eff ort t o ascertai n t he reas o n(s), w hile f ull y res pecti n g t h e s u bject’s ri g hts. 
W here t he reas o ns are o btai ne d, t he pri mar y reas o n f or wit h dra wal m ust be s pecifie d i n t he e n d of 
trial f or m i n t he e C R F. 
7. 2. 1   
Re pl ace me nt of s u bjects  
S u bjects w h o disc o nti n ue trial pr o d uct s or wit h dra w fr o m trial will n ot be re place d.  
7. 3   
L ost t o f oll o w -u p  
A s u bject will be c o nsi dere d l ost t o f oll o w -u p if he or s he re peat e dl y fails t o ret ur n f or sc he d ule d 
visits a n d is u na ble t o be c o ntacte d b y t he site.  
T he f oll o wi n g acti o ns m ust be ta ke n if a s u bject fails t o ret ur n t o t he site f or a re q uire d visit:  
•  T he site m ust atte m pt t o c o ntact t he s u bject a n d resc he d ule t he misse d visit as s o o n as 
p ossi ble a n d c o u nsel t he s u bject o n t he i m p orta nce of mai ntai ni n g t h e assi g ne d visit 
sc he d ule a n d ascertai n w het her or n ot t he s u bject wis hes t o a n d/ or s h o ul d c o nti n ue i n t he 
trial. 
•  Bef ore a s u bj ect is dee m e d l ost t o f oll o w -u p, t he i n vesti gat or or desi g nee m ust ma ke e ver y 
eff ort t o re gai n c o ntact wit h t he s u bject ( 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 s u bject’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 s u bject’s me dical re c or ds.  
•  S h o ul d t he s u bject c o nti n ue t o be u nreac ha bl e, he/s he will be c o nsi dere d t o ha ve wit h dra w n 
fr o m t he trial wit h a pri m ar y reas o n of `l ost t o f oll o w-u p’.  
8  
Tri al 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 marise d 
i n t he fl o wc hart. 
•  I nf or me d c o ns e nt m ust be o btai ne d bef ore a n y trial relate d acti vit y, see 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 s u bjects 
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 rec or d det ails of all s u bjects scree ne d a n d 
t o c o nfir m eli gi bilit y or rec or d reas o n f or scree n fail ure, as a p plica ble.  
•  At scree ni n g, s u bjects will be pr o vi de d wit h a car d stati n g t hat t he y are partici pati n g i n a 
trial a n d gi vi n g c o nt act d etails of rele va nt site staff t hat ca n be c o ntact e d i n case of 
e mer ge n c y.  
•  A d here n ce t o t he trial d esi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he fl o wc hart, is 
esse ntial a n d re q uire d f or trial c o n d uct.   
•  Assess me nts s h o ul d be carrie d o ut acc or di n g t o t h e cli nic’s sta n dar d of practice u nless 
ot her wise s pecifie d i n t he c urr e nt secti o n. Eff orts s h o ul d be ma de t o li mit t he bias bet wee n 
assess me nts. T he s u g gest e d or der of t he ass ess me nts:  
o  Bl o o d sa m ples  
o  B o d y meas ure me nts (see Secti o n 8. 1. 1 ) 
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
3 2
 
-
 |
1
 |
C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 3  of 7 4  
 
o  Vital si g ns (see Secti o n 8. 2. 2 ) 
o  E C G  
•  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:  
o  Re mi n ders:  
▪ t o atte n d visit fasti n g (see fl o wc hart i n Secti o n 1. 2 ) 
▪ t o ret ur n trial pr o d ucts at ne xt site visit 
▪ t o ret ur n diar y at n e xt site visit 
▪ t o re mi n d o nl y t o use eac h ca grili nti de cartri d ge t w o ti mes 
o  I nstr u cti o n o n h o w t o use t he diar y 
o  I nf or mati o n t o be c ollecte d:  
▪ d ose, date a n d site of i njecti o n of trial pr o d ucts  
▪ d ose, date, site a n d ti me of last 2 d oses pri or t o P K sa m ples 
▪ h y p o gl ycae mic e v e nts (acc or di n g t o A p pe n di x 6, Secti o n 1 0. 6 ) 
▪ healt h iss ues  
•  Re vie w of diaries, E C G, la b orat or y re p orts a n d e ye e x a mi nati o ns m ust be d oc u me nte d eit her 
o n t he d oc u me nts or i n t he s u bject’s me dical rec or ds. If clarifi cati o n of e ntries or 
discre pa n cies i n t he diari es is nee de d, t he s u bject m ust be q uesti o ne d, a n d a c o ncl usi o n 
ma de i n t he s u bject’s me dical rec or ds. Care m ust be ta ke n n ot t o bias t he s u bject.  
•  Res ults of pre g na nc y testi n g m ust be d oc u me nte d i n t he s u bject’s me dical rec or ds.  
•  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 sa m ples or assess me nts 
ma y b e ta ke n f or safet y reas o ns. Please refer t o A p pe n di x 2 , S ecti o n 1 0. 2  f or f urt her 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  (S ecti o n 1. 2 ) a n d 
A p pe n di x 2, Ta ble  1 0 -1 . 
8. 1. 1   
B o d y me as ure me nts  
•  B o d y wei g ht  s h o ul d be meas ure d wit h o ut s h oes, o n a n e m pt y bl a d der 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 ms [ k g] or p o u n ds [l b], wit h precisi o n of 
1/ 1 0 u nit (e. g. 7 5. 3 k g / 1 6 6. 0 l b). T he b o d y wei g ht s h o ul d be assesse d o n t he sa me 
cali brate d wei g hi n g s cale t hr o u g h o ut t he trial. T h e cali brati o n sta n dar d s h o ul d prefera bl y be 
o nce yearl y or reflect t he c o u ntr y re q uire me nts, u nless t he ma n ufact urer cert ifies t hat 
cali brati o n of t he wei g hi n g scale is vali d f or t he lifeti me of t he scale.  
•  Hei g ht  is meas ure d wit h o ut s h oes i n ce nti metres or i nc hes ( o ne deci mal). B MI will be 
calc ulate d i n t he e C R F fr o m scree ni n g dat a.  
8. 1. 2   
C o nti n u o us gl uc ose m o nit ori n g  
S u bjects wil l be e q ui p pe d wit h a C G M de vice at t he site visits ( V 1 , V 1 1, V 15 ). F or eac h of t he 
C G M assess me nt peri o ds t he se ns or m ust be w or n f or 1 0 f ull da ys a n d b e re m o ve d at t he visits or as 
cl ose t o t he visits as p ossi ble at t he site visits (V 2, V 1 2, V 1 6 ). T his nee ds t o be c o nsi dere d w he n 
pla n ni n g t he visits w here t he se ns or is t o be fitte d a n d re m o ve d.  
T he C G M s yste m use d i n t his trial will be t he De xc o m G 6 ® . 
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
3 3
 
-
 |
1
 |
C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 4  of 7 4  
 
T he C G M rea di n gs will be bli n de d t o b ot h t he s u bject a n d i n vesti gat or a n d will n ot be use d f or a n y 
d ose a dj ust me nts or h y p o gl ycae mic e pis o de re p orti n g.  
If a s u bject wit h dra ws c o nse nt d uri n g t he tri al, a site visit s h o ul d be sc he d ule d i n or der t o re m o ve 
t he C G M se ns or a n d u pl oa d t he data fr o m t he recei ver. 
C G M fitti n g a n d tr ai ni n g  
T he site staff will cl osel y s u per vise a n d assist wit h fitti n g of t he se ns or a n d tra ns mitter o n t he 
s u bject d uri n g t h e site visits. Trai ni n g i n t he C G M is t he res p o nsi bilit y of t he i n vesti gat or or site 
staff at t he rele va nt visits. T he site s h o ul d e ns ure t he s u bject is trai ne d i n c h a n gi n g t he se ns or at 
h o me i n case t he C G M s e ns or nee ds t o b e c ha n ge d after fitti n g at site i n case it falls off. All 
s u bjects will be pr o vi de d wit h a n e xtra se ns or t o bri n g h o me i n case t he y n ee d t o re -fit t he se ns or. 
F or i nf or m ati o n o n fitti n g, a n d c ha n gi n g  of t he C G M parts, please refer t o t he I n v esti gat ors C G M 
ma n ual a n d S u bject g ui d e pr o vi de d.  
C G M u pl o a d  
T he s u bject will ret ur n t h e recei ver t o site staff at visit ( V 2, V 1 2,  V 1 6) f or data u pl oa d. Dat a st ore d 
o n t he C G M recei ver m ust be u pl oa de d at t he site  b y t he site staff t o t he C G M s oft ware f oll o wi n g 
t he i nstr ucti o n pr o vi de d t o t he sites. T he u pl oa d will be d oc u me nte d b y t he s yste m directl y. 
T he serial n u m ber of t he C G M recei ver m ust be rec or de d a n d c o nfir me d i n t he e C R F at t he start of 
eac h C G M peri o d. I n cas e t he C G M recei ver is bei n g re pl ace d, t h e serial n u m ber s h o ul d be 
u p date d.  
8. 1. 3   
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 ). 
A c o nc o mit a nt ill ness  is a n y ill ness t hat is alrea 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 trial pr oce d ures perf or me d bef ore 
e x p os ure t o trial pr o d uct s.  
Me dic al hist or y is a me dical e ve nt t hat t he s u bject 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 ollecte d . O nl y rele va nt a n d si g nifica nt me dical hist or y 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 eC R F  at t he scree ni n g visit. Fi n di n gs of s pecific me dical hist or y (dia betes 
hist or y, c o m or bi dities a n d hist or y of car di o vas c ular disease)  s h o ul d be des cri be d i n t he desi g nat e d 
f or ms. 
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 a c o nc o mita nt 
ill ness or me dical hist or y, t he i n vesti gat or m ust rec or d t he fi n di n g o n t he Me dical Hist or y/ 
C o nc o mita nt Ill ness f or m.   
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
3 4
 
-
 |
1
 |
C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 5  of 7 4  
 
8. 2. 1   
P h ysic al e x a mi n ati o ns  
A p h ysic al e xa mi nati o n will i ncl u de assess me nts of:  
•  Ge neral a p peara n ce  
•  Hea d, ears, e yes, n ose, m o ut h, t hr oat, nec k  
•  Res pirat or y s yst e m  
•  Car di o vasc ular s yste m  
•  A b d o me n  
•  M usc u l os keletal s yste m 
•  Ce ntral a n d peri p h eral n er v o us s yste m  
•  S ki n  
•  T h yr oi d gla n d  
•  L y m p h n o de p al pati o n  
•  Breast (fe m ales o nl y ). 
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. 
8. 2. 2   
Vit al si g ns  
•  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 s u bject i n a q uiet setti n g wit h o ut distracti o ns (e. g. n o use of tel e 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 omate d de vice. Ma n u al tec h ni q ues 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 u re me nt m ust be 
perf or me 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. O nl y t he l ast 2 s yst olic a n d last 2 diast olic bl o o d press ure rea di n gs m ust be 
rec or de d i n t he e C R F. T h e e C R F will t he n cal c ulate t he mea n f or s yst olic a n d diast olic 
bl o o d press ure.  
•  P ulse rate will be meas ure d i n c o n necti o n t o t he bl o o d press ure meas ure m e nts. Rec or d t he 
p ulse rate f or t he last 2 bl o o d press ure meas ure m e nts i n t he e C R F. T he e C R F will calc ulate 
t he mea n p ulse rate val ues base d o n the last 2 meas ure me nts.  
8. 2. 3   
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 ulat es t he heart rate a n d meas ures P R, Q R S a n d Q T -i nter vals. 
8. 2. 4   
E ye e x a mi n ati o n  
S u bjects wit h u nc o ntr olle d a n d p ot e ntiall y u nsta bl e dia betic reti n o pat h y or mac ul o pat h y are n ot 
eli gi ble as t his i n dicates reti n o pat h y t hat h as rece ntl y pr o gresse d t o a le vel t hat re q uires i nter ve nti o n 
or is a p pr oac hi n g i nter ve nti o n b ut has yet t o be br o u g ht u n der c o ntr ol.   
Res ults of a n e ye e x a mi nati o n perf or me d b y a n o p ht hal m ol o gist or a n ot her s uita bl y q ualifie d h ealt h 
care pr o vi der (e. g. o pt o m etrist) m ust be a vaila ble a n d e val uat e d b y t he i n vesti gat or bef ore 
ra n d o misati o n t o assess eli gi bilit y. T he e ye e x a mi nati o n s h o ul d be perf or me d as a f u n d us 
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
3 5
 
-
 |
1
 |
C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 6  of 7 4  
 
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 pecifie d f or n o n -dilate d 
e x a mi nati o n. 
If t he s u bject ha d s u c h a n e ye e x a mi nati o n perf or me d wit hi n 9 0 da ys pri or t o scree ni n g, t he 
i n vesti gat or ma y b ase his/ her e val uati o n u p o n t he res ults of t hat e xa mi nati o n. T he e x a mi nati o n m ust 
be  re peate d bef ore ra n d o misati o n if t he s u bject has e x perie nce d w ors e ni n g of vis ual f u ncti 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 he s u bject si g ne d t he 
i nf or me d c o nse nt f or m, it m ust be d oc u me nte d t hat t he reas on f or perf or mi n g t he e x a mi nati o n was 
n ot relate d t o t his trial.  
After ra n d o misati o n a n e ye e x a mi nati o n perf or me d acc or di n g t o a b o ve m ust be perf or me d as per 
pr ot oc ol fl o wc hart  (Secti o n 1. 2 ). A n e ye e x a mi nati o n perf or me d wit hi n 2 wee ks pri or t o t he 
a p plica ble visits is acce pt a ble, pr o vi de d t hat n o cli nical s y m pt o ms s u g gesti ve of e ye dis ease h a ve 
occ urre d i n t he mea nti me i n case o f w hi c h a ne w e x a mi nati o n m ust be c o m plete 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 i n t he e C R F.  
T he f u n d us p h ot o gra p h y or slit -la m p bi o micr osc o p y e x a mi nati o n s h o ul d be use d f or e val uati o n of 
reti n o pat h y or mac ul o p at h y. A d diti o nal e x a mi nati o ns (e. g., o ptical c o here n ce t o m o gra p h y a n d/ or 
best c orrecte d vis ual ac uit y) ca n be p erf or me d as a s u p ple me nt f or f urt her e val uati o n. H o we ver, i n 
t his trial, a d diti o nal e ye e x a mi nati o ns i ncl u di n g t he o ptical c o here nce t o m o gra p h y a n d/ or best 
c orrecte d vis ual ac uit y, ca n n ot re place t he f u n d us p h ot o gra p h y or slit -la m p bi o micr osc o p y 
e x a mi nati o n. 
Rele va nt fi n di n gs pri or t o ra n d o misati o n m ust be rec or de d as c o n c o mita nt ill ness/ me dical hist or y. 
R ele va nt fi n di n gs o cc urri n g after ra n d o misati o n s h o ul d be re p orte d as a n A E, please refer t o 
Secti o n  8. 3 . 
8. 2. 5   
Cli nic al s afet 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, 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 wc hart.  
8. 3   
A d verse e v e nts a n d seri o us a d verse e ve nts  
T he i n vesti gat or is res p o nsi ble f or detecti n g, d oc u me nti n g, rec or di n g a n d f oll o wi n g u p o n e ve nts 
t hat meet t he definiti 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, 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, please refer t o Ta ble  8 -1 . 
H y p o gl yc ae mic e pis o des  
H y p o gl ycae mic e pis o des re q uire a d diti o nal data c ollecti o n o n a h y p o gl ycae mic e pis o de f or m. As 
o p p ose d t o A Es re q uiri n g a d diti o nal dat a c ollecti o n ( Ta ble  8 -1 ), n o n-seri o us h y p o gl ycae mic 
e pis o des d o n ot re q uire a n A E f or m t o be fille d i n. If t he h y p o gl ycae mic e pis o de f ulfils 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 des f or m, a n A E f or m a n d a safet y 
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
3 6
 
-
 |
1
 |
C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 7  of 7 4  
 
i nf or mati o n f or m m ust be fille d i n, please refer t o A p pe n di x 3. F or m ore i nf or mati o n o n 
h y p o gl ycae mic e pis o des, please refer t o A p pe n di x 7 . 
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 (seri o us a n d n o n -seri o us A Es)  
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  
Me dicati o n err or  
X  
Mis use a n d a b use  
X  
Ac ute gall bla d der disease  
X  
Ac ute pa ncreatitis  
X  
Dia betic reti n o pat h y 
X  
H y perse nsiti vit y reacti o n  
X  
I nj ecti o n site reacti o n 
X  
I nf or mati o n o n mis use a n d a b use A Es are ca pt ure d o n t he me dicati o n err or f or m.  
A detaile d descri pti o n of t he e ve nts me nti o ne d i n t he a b o ve ta bl e ca n b e f o u n d i n A p pe n di x 3.  
8. 3. 1   
Ti me peri o d  a n d fre q ue nc y f or c ollecti n g A E a n d S A E i nf or m ati o n  
All A Es a n d S A Es m ust be c ollecte d fr o m t he scree ni n g visit a n d u ntil t he ‘e n d of trial ’ visit at t he 
ti me p oi nts s pecifie d i n t he fl o wc hart.  
Me dical occ urre n ces t hat ta ke place or ha v e o nset pri or t o t he ti me p oi nt fr o m w hic h A Es are 
c ollecte d will be rec or de d as c o nc o mita nt ill ness/ me dical hist or y. 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. 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 or desi g nee 
wit hi n 2 4 h o urs, a n d t he i n ves ti 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 or 
desi g nee wit hi n 2 4 h o urs of it bei n g a v aila ble.  
I n v esti gat ors are n ot o bli gat e d t o acti vel y see k f or A E or S A E i n f or mer trial s u bjects. H o we v er, if 
t he i n vesti gat or l ear ns of a n y S A E, i n cl u di n g a d eat h, at a n y ti me after a s u bject has bee n 
disc o nti n ue d fr o m/c o m plete d t he trial, a n d t he i n v esti gat or c o nsi ders t he e v e nt t o be 
p ossi bl y/ pr o ba bl y rel ate d t o t he trial pr o d uct s or relate d t o trial 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   
Met h o d of detecti n g A Es a n d S 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 ). 
Care s h o ul d be ta ke n n ot t o i ntr o d uce bias w he n d etecti n g A Es a n d/ or S A Es. O pe n -e n d e d a n d n o n -
lea di n g v er bal q u esti o ni n g of t he s u bj ect is t he preferre d met h o d t o i n q uire a b o ut e ve nts. 
8. 3. 3   
F oll o w -u p of A Es a n d S A Es  
After t he i nitial A E/ S A E re p ort, t he i n vesti gat or is re q uire d t o pr oacti vel y f oll o w eac h s u bject 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 t he 
s u bject is l ost t o f oll o w-u p as descri 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 ve nts is gi ve n i n A p pe n di x 3.   
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
3 7
 
-
 |
1
 |
C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 8  of 7 4  
 
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 or desi g n ee of a S A E is esse ntial s o t hat 
le gal o bli gati o ns a n d et hical res p o nsi bilities t o war ds t he safet y of s u bjects a n d t he safet y of a trial 
pr o d uct u n der cli nical i n vesti gati o n are met.   
N o v o N or dis k has a le gal res p o nsi bilit y t o n otif y b ot h t he l ocal re g ulat or y a ut h orit y a n d ot her 
re g ulat or y a ge ncies a b o ut t he safet y of a trial pr o d uct u n der cli nical i n vesti gati o n. N o v o N or dis k 
will c o m pl y wit h c o u ntr y -s pecific re g ulat or y re q uire me nts relati n g t o safet y re p orti n g t o t he 
re g ulat or y a ut h orit y, I R B/I E C, a n d i n vesti gat ors. T his als o i ncl u des s us pecte d u ne x pecte d seri o us 
a d verse reacti o ns ( S U S A Rs).  
A n i n vesti gat or w h o recei ves a n i n vesti gat or safet y re p ort descri bi n g a S A E or ot her s pecific safet y 
i nf or mati o n (e. g. s u m mar y or listi n g of S A Es) fr o m N o v o N or dis k will re vie w a n d t he n file it al o n g 
wit h t he i n vesti gat or’s br oc h ure a n d will n otif y t h e I R B/I E C, if a p pr o priate acc or di n g t o l ocal 
re q uire me nts. 
8. 3. 5   
Pre g n a nc y  
Details of pre g n a ncies i n fe male s u b jects will be c ollecte d after scree ni n g visit a n d u ntil  ‘e n d of 
trial’ visit ( V 1 7). If a fe m ale s u bject bec o mes pre g na nt, t he i n vesti gat or s h o ul d i nf or m N o v o 
N or dis k wit hi n 1 4 cale n dar da ys of lear ni n g of t he pre g na nc y a n d s h o ul d f oll o w t he pr oce d ures 
o utl i ne d i n A p pe n di x 4 ( Secti o n 1 0. 4 ). 
8. 3. 6   
C ar di o v asc ul ar a n d de at h e ve nts  
Car di o vasc ular a n d deat h e ve nts will be ha n dle d a n d re p orte d acc or di n g t o Secti o n 8. 3 . 
8. 3. 7   
H y perse nsiti vit y  
I n t he e ve nt of a s yste mic h y p erse nsiti vit y reacti o n t o trial pr o d ucts, t he s u bject s h o ul d be calle d i n 
as s o o n as p ossi ble t o ha ve a d diti o nal bl o o d sa m ples ta ke n i n or der t o a nal ys e t he f oll o wi n g 
para meters:  
•  tr y ptas e  
•  t otal i m m u n o gl o b uli n E (I g E) a nti b o dies 
•  a nti-ca grili nti de I g E a nti b o dies   
•  a nti-se ma gl uti de I g E a nti b o dies  
T he bl o o d sa m pli n g s h o ul d be re peate d 2 -4 wee ks f oll o wi n g o nset of t he s yste mic h y perse nsiti vit y 
reacti o n. If p ossi ble, t he a b o ve-me nti o ne d a nal yses s h o ul d als o be perf or me d o n t he P K sa m ple 
fr o m visit 4 ( wee k 4). 
F or details r elate d t o bl o o d sa m pli n g, plas ma pre parati o n a n d st ora ge, please refer t o t he l a b orat or y 
ma n ual.  
F or rete nti o n of resi d ual h y perse nsiti vit y sa m ples, please refer t o A p pe n di x 6, S ecti o n 1 0. 6 .  
8. 3. 8   
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.  
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
3 8
 
-
 |
1
 |
C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 9  of 7 4  
 
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, S ecti 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 gatio 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 nical c o m plai nt f or m.   
8. 4   
Tre at me nt of o ver d ose  
O ver d oses of u p t o 6. 0 m g has b ee n o bser ve d wit h ca grili nti de treat me nt i n t he p hase 2 cli nical trial 
( N N 9 8 3 8-4 4 3 3). T h e o ver d oses w ere relate d t o n o n -seri o us A Es, m ost c o m m o nl y GI A Es a n d 
dizzi ness.  
Se ma gl uti de o ver d oses of u p t o 4. 0 m g i n a si n gle d ose, a n d u p t o 4. 0 m g i n a wee k ( b y m ulti ple 
a d mi nistrati o ns) ha ve bee n re p ort e d i n cli nical trials ( S T E P -pr o gra m me). T he m ost c o m m o nl y 
re p orte d A E was na us ea. All s u bjects rec o vere d wit h o ut c o m plicati o ns. 
T here is n o s pecific a nti d ote f or o ver d ose wit h eit her se ma gl uti de or ca grili nti de. I n t he e ve nt of a n 
o ver d ose, a p pr o priate s u p p orti ve treat me nt s h o ul d be i nitiate d acc or di n g t o s u bject ’s cli nical si g ns 
a n d s y m pt o ms.  
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, please refer t o Secti o n 8. 3  a n d A p pe n di x 3 f or f urt her details.  
I n t he e ve nt of a n o ver d ose, t he i n vesti gat or s h o ul d cl osel y m o nit or t he s u bject f or o ver d ose-relate d 
A E/ S A E  a n d la b orat or y a b n or malities, c o nsi deri n g t he l o n g half -life of ca grili nti de a n d 
se ma gl uti de.  
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 s u bject. 
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  ca grili nti de a n d 
se ma gl uti de i n vesti gat or’s br oc h ure. 
8. 5   
P h ar m a c o ki netics  
Plas ma sa m ples t o be a nal yse d f or plas ma c o n ce ntrati o n of se ma gl uti de a n d ca grili nti de will be 
c ollecte d at ti me p oi nts as s pecifie d i n t he fl o w c hart (see Secti o n 1. 2  a n d 1 0. 2 ). Bl o o d sa m ples f or 
meas ure me nt of ca grili nti de a n d se ma gl uti de c o n ce ntrati o n m ust be dra w n bef ore d osi n g of trial 
pr o d uct ( C tr o u g h meas ure me nt).   
Se parate plas m a sa m ples will be c ollecte d f or  ca grili nti de a n d se ma gl uti de. Sa m pli n g a n d ha n dli n g 
will be perf or me d as detaile d i n t he la b orat or y ma n ual.  
Se ma gl uti de a n d ca grili nti de will be assa ye d i n pl as ma b y vali date d ass a ys. Details of t he 
bi oa nal ysis will be o utli ne d i n a bi oa nal ytical st u d y p la n. 
F or rete nti o n of resi d ual ca grili nti de P K sa m ples, please refer t o A p pe n di x 6, S ecti o n 1 0. 6 . 
8. 6   
P h ar m a c o d y n a mi cs  
N ot a p plica ble f or t his trial.  
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
3 9
 
-
 |
1
 |
C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 0  of 7 4  
 
8. 7   
Ge neti cs  
N ot a p plica ble f or t his trial.  
8. 8   
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 trial t o s u p p ort t he effi cac y o bj ecti ves. 
T he f oll o wi n g s a m ples m ust be c ollecte d a n d pr ocesse d i n acc or da n ce wit h t he la b orat or y ma n ual 
a n d A p p e n di x 2, S ecti o n 1 0. 2  : 
Bi o mar kers li n ke d t o car di o vasc ular ris k a n d i nfl a m mati o n:  
•  Hi g h se nsiti ve C -reacti ve pr otei n ( hs C R P) 
Bi o mar kers li n ke d t o a p p etite re g ulati o n:  
•  Le pti n  
•  S ol u ble le pti n rece pt or  
8. 9   
I m m u n o ge nicit y assess me nts 
N ot a p plica ble f or t his trial.  
8. 1 0   
He alt h ec o n o mics   
N ot a p plica ble f or t his trial.  
9  
St atistic al c o nsi der ati o ns   
9. 1   
St atistic al h y p ot heses  
N o c o nfir mat or y statistical h y p ot hesis testi n g  will be d o ne i n t his trial. Treat me nt differe n ces will 
be re p ort e d wit h 2 -si de d 9 5 % c o nfi de n ce i nter vals. 
9. 2   
S a m ple size deter mi n ati o n   
As t he prese nt st u d y is e x pl orat or y t he sa m ple size calc ul ati o n is n ot base d o n c o nfir mat or y testi n g 
b ut ai ms at q ua ntif yi n g t he ma g nit u de of e x pecte d variati o n i n t he treat me nt differe n ce f or t he 
pri mar y e n d p oi nt s u p p orti n g t he pri mar y o bjecti ve. F or t he pri mar y esti ma n d a sta n dar d de viati o n 
of 0. 9 ( S T E P 2) or 1 is ass u me d f or H b A 1c c ha n ge fr o m baseli ne t o wee k 3 2. Wit h 3 0 r a n d o mise d 
s u bjects per treat me nt ar m a p pr o xi matel y 8 0 % pr o ba bilit y is ac hie ve d f or o btai ni n g a 9 5 % 
c o nfi de nce i nter val of t h e treat me nt differe n ce wit h half -wi dt h 0. 5 a n d 0. 5 6 % -p oi nts, res pecti vel y. 
T he ac hie va ble half -wi dt h ( wit h r o u g hl y 8 0 % pr o ba bilit y)  vers us sa m ple size is s h o w n i n   
Fi g ure  9 -1  f or differe nt c h oices of sa m ple size. Base d o n t his, a sa m ple size of 3 0 ra n d o mise d 
s u bjects per treat me nt ar m, i.e. a t otal of 9 0 ra n d o mise d s u bjects, is c o nsi dere d s ufficie nt.  
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
4 0
 
-
 |
1
 |
C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 1  of 7 4  
 
Fi g ure  9 -1 . H alf-wi dt h of 9 5 % CI f or tre at me nt differe nce o n H b A 1c c h a n ge o bt ai ne d wit h 
8 0 % p o wer vers us s a m ple size b y st a n d ar d de vi ati o n (st d).  
 
9. 3   
P o p ul ati o ns f or a n al yses   
T he f oll o wi n g p o p ul ati o n s are defi ne d : 
P o p ul ati o n  
Descri pti o n  
F ull a nal ysis set ( F A S)   
All s u bj ects ra n d o mise d.  
Safet y a nal ysis set ( S A S)   
All s u bj ects ra n d o ml y assi g ne d t o trial treat me nt a n d w h o ta ke at least 1 d ose of trial 
pr o d uct.  
T he s u bjects or o bser vati o ns t o be e x cl u de d fr o m t he a nal ysis sets a n d t he reas o ns f or t heir  
e x cl usi o n m ust be d oc u me nte d bef ore u n bli n di n g a n d will be descri be d i n t he C T R. Efficac y 
e n d p oi nts will be a nal ys e d usi n g t he F A S a n d safet y e n d p oi nts will be a nal ys e d usi n g t he S A S. F or 
b ot h t he pri mar y esti ma n d a n d t he a d diti o nal esti ma n d, s u bjects c o ntri b ute t o t he a nal ysis acc or di n g 
t o t he ra n d o mise d treat m e nt. 
T hree o bser vati o n peri o ds are defi ne d f or eac h s u bject:  
•  T he i n -trial peri o d is defi ne d as t he ti me i nter val fr o m date of ra n d o misati o n t o date of last 
c o ntact wit h trial site.  
•  T he o n -treat me nt peri o d is a s u bset of t he ‘i n-trial’ o bser vati o n peri o d a n d re pres e nts t he 
ti me peri o d w here s u bjects are c o nsi dere d e x p ose d t o trial pr o d uct. T he o bser vati o n peri o d 
starts at t he date of first d ose of trial pr o d uct a n d e n ds at t he first date of a n y of t he 
f oll o wi n g: 
o  T he date of l ast d ose of trial pr o d uct + 3 5 da ys f or A Es a n d h y p o gl ycae mic e pis o des/ 
+ 1 4 da ys f or ot h er e n d p oi nts  
o  T he e n d -d ate f or t h e ‘i n -trial’ o bser vati o n peri o d 
T he o n -treat me nt peri o d will be use d for re p orti n g A Es  a n d h y p o gl ycae mic e pis o des . 
T he o n -treat me nt wit h o ut resc ue m e dicati o n peri o d is a s u bset of t he ‘ o n-treat me nt’ o bser vati o n 
peri o d a n d re pres e nts t he ti me peri o d w here s u bjects are c o nsi dere d e x p ose d t o trial pr o d uct b ut  
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
4 1
 
-
 |
1
 |
C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 2  of 7 4  
 
ha ve n ot i nitiate d  a n y res c ue me dicati o ns. T he o bser vati o n peri o d starts at t he date of first d ose  of 
trial pr o d uct a n d e n ds at t he first date of a n y of t he f oll o wi n g: 
•  I nitiati o n of resc ue m e dicati o n 
•  T he last date of t he o n -tr eat me nt peri o d 
T he i n -trial a n d o n-tr eat me nt peri o ds defi ne t he patie nt years of o bs er vati o n ( P Y O) a n d patie nt 
years of e x p os ure ( P Y E), res pecti vel y, as t he t otal ti me d urati o n i n t he peri o ds.  
Data p oi nts c ollecte d o utsi de a n o bser vati o n peri o d will n ot be i ncl u de d i n t he a nal ysis. Bas eli ne 
data will al wa ys be i ncl u de d i n a n o bser vati o n peri o d.  
F or t he pri mar y esti ma n d, t he o n -treat me nt wit h o ut resc ue me di cati o n peri o d will be use d f or 
re p orti n g of efficac y e n d p oi nts. F or t he a d diti o nal esti ma n d, data fr o m t he i n-trial o bser vati o n 
peri o d is use d.  
9. 4   
St atist ic al a n al yses 
T he statistical a nal ysis pla n ( S A P) will be fi nalise d pri or t o t he first a d mi nistrati ve D B L a n d it will 
i ncl u de a m ore tec h nical a n d detaile d des cri pti o n of t he statistical a nal yses descri be d i n t his secti o n. 
T his secti o n is a s u m mar y of t he pl a 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 mar y e n d p oi nt. 
9. 4. 1   
Ge ner al c o nsi der ati o ns  
H a n dli n g of missi n g b aseli ne d at a  
T he latest a vaila ble m eas ure me nt at or pri or t o ra n d o misati o n is use d as t he baseli ne meas ure me nt.  
If n o meas ure me nts ha ve bee n o btai ne d at or pri or t o ra n d o misati o n, t he mea n val ue at 
ra n d o misati o n acr oss all s u bjects is use d as t he baseli ne val ue. 
9. 4. 2   
Pri m ar y e n d p oi nt  
A n al ysis a d dressi n g t he pri m ar y esti m a n d  
H b A 1c ( %-p oi nt) c ha n ge fr o m baseli ne will be a n al yse d  usi n g a mi x e d m o del f or re p eate d 
meas ure me nts ( M M R M). Wee k 3 2 assess me nts f or retrie v e d dr o p -o uts are n ot use d i n t his a nal ysis. 
T he M M R M will use assess me nts o nl y fr o m s u bjects w h o are t a ki n g t h e ra n d o mise d treat me nt u ntil 
e n d of treat me nt or u ntil first  disc o nti n uati o n of ra n d o mise d treat me nt defi n e d as 2 c o nsec uti ve 
misse d d oses. T he deri ve d date of t he sec o n d c o ns ec uti ve misse d d ose will be use d as t he lat est date 
f or usi n g assess me nts i n t his M M R M. F or s u bjects w h o i nitiate resc ue m e dicati o n bef ore 
c om pleti o n or first disc o nti n uati o n of ra n d o mise d treat me nt, t he date of starti n g resc ue me di cati o n 
will be use d as latest date f or usi n g assess me nts i n t his M M R M. T he M M R M will be fitte d usi n g 
H b A 1c c ha n ge wit h treat me nt a n d stratificati o n fact or as fact ors  a n d b aseli ne H b A 1c as c o variat e –  
all neste d wit hi n visit. A n u nstr uct ure d c o v aria n ce matri x f or meas ure me nts wit hi n t he sa me s u bject 
will be e m pl o ye d. If t his m o del is n ot feasi ble, t he m o del will be si m plifie d b y first e xcl u di n g t h e 
stratificati o n fact or fr o m t he m o del a n d, if necessar y, usi n g a c o m p o u n d s y m metr y c o v aria n ce 
matri x.  
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
4 2
 
-
 |
1
 |
C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 3  of 7 4  
 
T he prese nt A N C O V A -M M R M m o del will be use d t o deri ve esti mates of treat me nt differe nces 
wit h 9 5 % c o nfi de nce i nter vals f or ca grili nti de 2. 4 m g/se ma gl uti de 2. 4 m g vers us se ma gl uti de 
2. 4  m g ( pri mar y o bjecti v e) a n d vers us ca grili nti de 2. 4 m g (sec o n dar y o bjecti ve) t o get h er wit h p -
val ues f or t he 2 -si de d tests of n o treat me nt differe nces. 
A n al yses a d dressi n g t he a d diti o n al esti m a n d  
T he a nal ysis m o del f or c ha n ge i n H b A 1c ( %-p oi nt) is a n 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 fact ors a n d baseli ne H b A 1c as a c o variate. T he a d diti o nal esti ma n d will be 
base d o n t he F A S usi n g all a vaila ble wee k 3 2 meas ure me nts fr o m t he i n -tri al o bser vati o n peri o d. 
Missi n g wee k 3 2 d ata  will be i m p ute d fr o m retrie ve d s u bjects off treat me nt b y m ulti ple i m p utati o n 
( R D MI) usi n g a n A N C O V A m o del wit h t he sa me fact ors a n d c o variate as f or t he a n al ysis m o del. If 
necessar y f or feasi bilit y, t his m o del will be si m plifie d b y e x cl u di n g t he stratific ati o n fact or.  
T he prese nt A N C O V A -R D MI m o d el will be use d t o deri ve esti mates of treat me nt differe nces wit h 
9 5 % c o nfi de n ce i nter vals f or ca grili nti de 2. 4 m g/s e ma gl uti de 2. 4 m g v ers us se ma gl uti de 2. 4 m g 
( pri mar y o bjecti ve) a n d v ers us ca grili nti de 2. 4 m g (sec o n dar y o bjecti ve) t o get her wit h p -val u es f or 
t he 2-si de d tests of n o treat me nt differe nces. 
9. 4. 3   
Sec o n d ar y e n d p oi nt(s)  
9. 4. 3. 1   
C o nfir m at or y s ec o n d ar y e n d p oi nt(s)  
N ot a p plica ble f or t his trial.  
9. 4. 3. 2   
S u p p orti ve sec o n d ar y e n d p oi nts  
C G M e n d p oi nts 'ti me i n tar get r a n ge' a n d 'ti me a b o ve tar get ra n ge' will be calc ulate d as 1 0 0 ti mes 
t he n u m ber of rec or de d meas ure me nts i n t he gi ve n gl ycae mic ra n ge, di vi d e d b y t h e t otal n u m ber of 
rec or de d meas ure me nts.  
A nal ysis of ot h er sec o n d ar y e n d p oi nts are descri be d i n t he S A P.  
9. 4. 4   
E x pl or at or y e n d p oi nts 
A nal ys es of e x pl orat or y e n d p oi nts are des cri be d i n t he S A P.  
9. 4. 5   
Ot her 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 dar d safet y assess me nts ( A Es, 
safet y la b orat or y para met ers, vital si g ns, et c.) will be re p orte d descri pti vel y , i ncl u di n g a n y n ota bl e 
c ha n ges of cli nical i nterest i n la b orat or y p ara meters.  
9. 4. 6   
Ot her a n al yses   
F or ot her a nal yses, pleas e refer t o t he S A P.   
9. 4. 6. 1   
P h ar m a c o ki netic m o delli n g  
Data fr o m t he tri al ma y b e use d f or e x pl orat or y p h ar mac o ki netic a nal ysis as  nee de d.  
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
4 3
 
-
 |
1
 |
C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 4  of 7 4  
 
9. 5   
I nteri m a n al yses 
I n or der t o pre p o ne a p hase 3 st o p/ g o decisi o n a n d i nitiate p ote ntial p hase 3 pla n ni n g, i nteri m 
a nal ys es are pla n ne d at w ee k 2 0 f or t h e f oll o wi n g e n d p oi nts:  
•  C ha n ge fr o m bas eli ne t o wee k 2 0 i n H b A1c  
•  C ha n ge fr o m bas eli ne t o wee k 2 0 i n F P G 
•  C G M e n d p oi nts: Mea n gl uc ose c ha n ge fr o m baseli ne t o wee k 2 0, Ti me i n t ar get ra n ge at 
wee k 2 0 a n d ti me a b o ve tar get ra n ge at w ee k 2 0.  
•  C ha n ge fr o m bas eli ne t o wee k 2 0 i n b o d y wei g ht  
A n ot her i nteri m ma y be c o n d ucte d after last s u bject's last treat me n t i n case t he i nteri m at wee k 2 0 
was i nc o ncl usi ve.  
A mi ni m u m n u m ber of N o v o N or dis k pers o n nel will be u n bli n de d t o perf or m t he i nteri m 
e val uati o ns. After u n bli n di n g, t hese p e o ple ca n n ot be i n v ol ve d i n dail y trial acti vities  u ntil D B L . N o 
c ha n ge i n trial de si g n ca n occ ur a n d t h e trial will n ot be st o p pe d f or eit her p ositi ve efficac y or 
f utilit y at t he i nteri m e val uati o ns. It is n ot c o nsi dere d a pr ot oc ol de vi ati o n if a n i nteri m a nal ysis is 
n ot perf or me d. F urt her i nf or mati o n o n t he i nteri m e val uati o ns will be s pecifie d i n a n i nteri m c harter 
bef ore u n bli n di n g.  
9. 6   
D at a m o nit ori n g c o m mittee  
N ot a p plica ble f or t his trial.  
9. 7   
Re p orti n g of t he m ai n p art of t he tri al  
A D B L is pla n n e d s h ortl y after last s u bject last visit . T he trial will be re p orte d after t his D B L.  
 
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
4 4
 
-
 |
1
 |
C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 5  of 7 4  
 
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 der 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 tri al 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 trial will be c o n d ucte d i n acc or da nce wit h t he pr ot oc ol a n d wit h t he f oll o wi n g:  
•  C o nse ns us et hical pri nci ples deri ve d fr o m i nter nati o nal g ui deli nes i ncl u di n g t he Declarati o n 
of Helsi n ki 2 8 a n d a p plica ble I C H G o o d Cli nical Practice ( G C P) G ui deli ne 2 9 
•  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 n se nt f or m, i n vesti gat or’s br oc h ure (as a p plica bl e) a n d ot her 
rele va nt d oc u m e nts (e. g. a d vertise me nts) m ust be s u b mitte d t o a n I R B/I E C a n d re vie we d 
a n d a p pr o ve d b y t he I R B/I E C bef ore t he trial is i nitiate d.  
•  Re g ulat or y a ut h orities will recei ve t he cli nical t rial 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 T R acc or di n g t o nati o n al re q uire m e nts. 
•  A n y a me n d me nts t o t he pr ot oc ol will re q uire I R B/I E C a p pr o val bef ore i m ple me ntati o n of 
c ha n ges ma d e t o t he trial desi g n, e x ce pt f or c ha n ges necess ar y t o eli mi nate a n i m me diate 
safet y hazar d t o trial s u bj ects. 
•  Bef ore a site is all o w e d t o start scree ni n g s u bjects, writte n n otificati o n fr o m N o v o N or dis k 
m ust be recei v e d.  
•  T he i n vesti gat or will be res p o nsi ble f or:  
o  pr o vi di n g writte n s u m maries of t he stat us of t h e tri al a n n uall y or m ore fre q u e ntl y i n 
acc or da nce wit h t he re q uire me nts, p olicies, a n d pr oce d ures esta blis he d b y t he 
I R B/I E C a n d/ or re g ulat or y a ut h orities 
o  n otif yi n g t he I R B/I E C of S A Es or ot her si g nifi ca nt safet y fi n di n gs as re q uire d b y 
I R B/I E C pr oce d ures 
o  pr o vi di n g o versi g ht of t h e c o n d uct of t he trial at t he site a n d a d here n ce t o 
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 o cal 
re g ulati o ns 
o  e ns uri n g s u b missi o n of t he C T R s y n o psis t o t he I R B/I E C  
o  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  
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 v o N or dis k t o s u b mit c o m plete a n d acc urate fi na ncial 
certificati o n or discl os ure state me nts t o t he a p pr o priate re g ul at or y a ut h orities. I n v esti gat ors are 
res p o nsi ble f or pr o vi di n g i nf or mati o n o n fi na ncial i nterests d uri n g t h e c o urse of t he trial a n d o ne 
year after c o m pleti o n of t he trial.  
Verificati o n u n der d iscl os ures per C o de of Fe deral Re g ulati o ns ( C F R) of Fi na ncial C o nflict of 
I nterest. 
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 he trial t o t he s u bject 
a n d a ns wer all q uesti o ns re gar di n g t he tri al.   
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
4 5
 
-
 |
1
 |
C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 6  of 7 4  
 
•  T he i n vesti gat or m ust e ns ure t he s u bject a m ple ti me t o c o me t o a decisi o n w het her or n ot t o 
partici pate i n t he trial.   
•  S u bjects m ust be i nf or me d t hat t heir partici pati o n is v ol u ntar y.  
•  S u bjects m ust be i nf or me d a b o ut t heir pri vac y ri g hts.  
•  S u bjects will be re q uire d t o si g n a n d date a state m e nt of i nf or me d c o ns e nt t hat meets t he 
re q uire me nts of l o cal re g ulati o ns, I C H g ui deli nes 2 9, Declarati o n of Helsi n ki2 8 a n d t he 
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 trial r el ate d acti vit y a n d t he date w he n t he writte n c o nse nt w as o btai ne d. T he 
a ut h orise d pers o n o btai ni n g t he i nf or me d c o nse nt m ust als o si g n a n d date t he i nf or me d 
c o nse nt f or m bef ore a n y trial relate d acti vit y.  
•  T he res p o nsi bilit y of see ki n g i nf or me d c o nse nt m ust re mai n wit h t he i n vesti gat or, b ut t he 
i n vesti gat or ma y d ele gat e t he tas k t o a me dicall y q ualifie d pers o n, i n acc or da nce wit h l ocal 
re q uire me nts. 
•  S u bjects m ust be re -c o ns e nte d t o t he m ost c urre nt versi o n of t he i nf or me d c o nse nt f or m s 
d uri n g t heir p artici pat i o n i n t he trial. 
•  A c o p y of t he i nf or me d c o nse nt f or ms m ust be pr o vi de d t o t he s u bject.  
1 0. 1. 4   
I nf or m ati o n t o s u bjects d uri n g tri al 
T he site will be offere d a c o m m u nicati o n pac ka ge f or t he s u bject d uri n g t h e c o n d uct of t he trial. 
T he pac k a ge c o nt e nt is iss ue d b y  N o v o N or dis k. T he c o m m u nicati o n pac k a ge will c o ntai n writte n 
i nf or mati o n i nte n de d f or distri b uti o n t o t he s u bjects. T he writte n i nf or mati o n will be tra nslate d a n d 
a dj uste d t o l ocal re q uir e me nts a n d distri b ute d t o t he s u bject at t he discreti o n of t he i n ves ti gat or. T he 
s u bject ma y recei ve a “ welc o me t o t he trial letter” a n d a “t ha n k y o u f or y o ur partici pati o n letter” 
after c o m pleti o n of t he trial. F urt her, t he s u bject ma y recei ve ot her writte n i nf or mati o n d uri n g t he 
trial.  
All writte n i nf or mati o n t o s u bject s m ust be se nt t o I R B/I E C f or a p pr o val/fa v o ura ble o pi ni o n a n d t o 
re g ulat or y a ut h orities f or a p pr o val or n otificati o n acc or di n g t o l ocal re g ulati o ns. 
1 0. 1. 5   
 D at a pr otecti o n  
•  S u bjects will be assi g ne d a 6 -di git u ni q ue i de ntifier, a s u bject n u m ber. A n y s u bject rec or ds 
or datasets t hat are tra nsferre d t o N o v o N or dis k will c o ntai n t he i de ntifier o nl y. N o direct 
i de ntifiers fr o m t he s u bject are tra nsferre d t o N o v o N or dis k. 
•  T he s u bject a n d a n y bi ol o gical material o btai ne d fr o m t he s u bject will be i de ntifie d b y 
s u bject n um ber, visit n u m ber a n d trial I D. A p pr o priate meas ures s uc h as e ncr y pti o n or 
lea vi n g o ut certai n i de ntifiers will be e nf orce d t o pr otect t he i de ntit y of s u bjects as re q uire d 
b y l ocal, re gi o nal a n d n ati o nal re q uire me nts.   
•  T he s u bject m ust be i nf or me d a b o ut h is/ her pri vac y ri g hts, i ncl u di n g t hat his/ her pers o nal 
trial relate d dat a will be use d b y N o v o N or dis k i n acc or da nce wit h l ocal data pr otecti o n la w. 
T he discl os ure of t he d at a m ust als o be e x plai ne d t o t he s u bject.   
•  T he s u bject m ust be i nf or me d t hat his/ her me dical rec or ds ma y b e e x a mi ne d b y a u dit ors or 
ot her a ut h orise d pers o n nel a p p oi nte d b y N o v o N or dis k, b y a p pr o priate I R B/I E C me m bers, 
a n d b y i ns p ect ors fr o m re g ulat or y a ut h orities.  
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
4 6
 
-
 |
1
 |
C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 7  of 7 4  
 
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 afet 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 safet y si g nals are i de ntifie d, t hese 
will be e val uate d b y a n i nter nal safet y c o m mittee.  T he  safet y c o m mittee ma y rec o m me n d 
u n bli n di n g of a n y dat a f or f urt her a nal ysis, a n d i n t his case a n i nter nal trial i n de pe n d e nt a d h oc 
gr o u p will be esta blis he d i n or der t o mai ntai n t he bli n di n g of t he trial pers o n nel.  
1 0. 1. 6. 2   
Tri al s afet y gr o u p  
N ot a p plica ble f or t his trial.  
1 0. 1. 6. 3   
D at a m o nit ori n g c o m mittee  
N ot a p plica ble f or t his trial . 
1 0. 1. 6. 4   
E ve nt a dj u dic ati o n c o m mittee  
N ot a p plica ble f or t his t rial. 
1 0. 1. 7   
Disse mi n ati o n of cli nic al tri al d at a  
I nf or mati o n of t he trial will be discl ose d at cli nicaltrials. g o v a n d n o v o n or dis k-trials.c o m. It will als o 
be discl ose d acc or di n g t o ot her a p plica ble re q uire me nts, s uc h as t h ose of t he I nter n ati o nal 
C o m mittee of Me dical J o ur nal E dit ors (I C MJ E) 3 0, t he F o o d a n d Dr u g A d mi nistrati o n A me n d me nt 
Act ( F D A A A) 3 1, E ur o pea n C o m missi o n Re q uire me nts3 2 -3 4 a n d ot her rele va nt rec o m me n d ati o ns or 
re g ulati o ns. If a s u bject r e q uest t o be i ncl u de d i n t he trial via t he N o v o N ordis k e -mail c o ntact at 
t hese we b sites, N o v o N or dis k ma y discl ose t h e i n vesti gat or’s c o ntact details t o t he s u bject. As a 
res ult of i ncreasi n g re q uire me nts f or tr a ns pare nc y, s o me c o u ntries re q uire p u blic discl os ure of 
i n vesti gat or n a mes a n d t heir affiliatio ns.  
T he pri mar y c o m pleti o n date ( P C D) is t he last ass ess me nt of t he pri mar y e n d p oi nt a n d is f or t his 
trial last s u bject first treat me nt ( L S F T) + 3 2 wee ks c orres p o n di n g t o ‘e n d of treat me nt visit ( visit 
1 6). If t he last s u bject is wit h dra w n earl y, t he P C D is c o nsi dere d t he date w he n t he last s u bject 
w o ul d ha ve c o m plete d visit 1 6. T he P C D deter mi nes t he dea dli ne f or res ults discl os ure at 
cli nicaltrials. g o v acc or di n g t o F D A A A.  
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 o r t he d ata ma na ge me nt of t his trial i ncl u di n g 
q ualit y c h ec ki n g of t he d ata.  
•  All s u bject data rel ati n g t o t he trial will be rec or de d o n electr o nic  C R Fs  u nl ess tra ns mitte d 
electr o nicall y t o N o v o N or dis k or desi g n ee (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 C R F.  
•  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 b e mai ntai ne d i n the 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 dat a, 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 
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
4 7
 
-
 |
1
 |
C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 8  of 7 4  
 
e ntr y a n d reas o n f or t he c orrecti o n. If c orrecti o ns are ma de b y t he i n v esti gat or’s dele gat e d 
staff aft er t he dat e w hen t he i n vesti gat or si g n e 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 da ys after t he visit. O nce dat a has bee n e ntere d, it will be a vaila ble t o 
N o v o N or dis k f or dat a verificati o n a n d vali dati o n p ur p oses.  
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 C R F is re v o ke d or t he 
C R F is te m p oraril y u n a v aila ble: 
•  A E f or ms  
•  Safet y i nf or mati o n f or ms  
•  Tec h nical c o m plai nt f or ms (als o t o be use d t o re p ort c o m plai nts o n trial pr o d uct n ot yet 
all ocate d t o a s u bject)   
1 0. 1. 8. 2   
M o nit ori n g  
•  T he i n vesti gat or m ust per mit trial -relate d m o nit ori n g, a u dits, I R B/I E C re vi e w, a n d 
re g ulat or y a ge nc y i ns pe cti o ns a n d pr o vi de direct access t o s o urce data d oc u me nts ( ori gi nal 
d oc u me nts, data a n d rec or ds). Direct access i ncl u d es per missi o n t o e x a mi ne, a nal ys e, verif y 
a n d re pr o d uce a n y rec or d(s) a n d re p ort(s) t hat are i m p orta nt t o t he e val uati o n of t he trial. If 
t he electr o nic m e dical r ec or d d oes n ot ha v e a visi ble a u dit trail, t he i n vesti gat or m ust 
pr o vi de t he m o nit or wit h si g ne d a n d date d pri nt o uts. I n a d diti o n, t he rele va nt site staff 
s h o ul d be a vaila ble f or disc ussi o ns at m o nit ori n g visits a n d bet wee n m o nit ori n g visits (e. g. 
b y tele p h o n e).   
•  Trial m o nit ors will perf or m o n g oi n g s o urce data verificati o n t o c o nfir m t hat data e ntere d 
i nt o t he C R F b y a ut h oris e d site pers o n nel are acc urate, c o m plete a n d verifia ble fr o m s o urce 
d oc u me n ts; t hat t he safet y a n d ri g hts of s u bjects are bei n g pr otecte d, t o m o nit or dr u g 
acc o u nta bilit y a n d c ollect c o m plete d pa per C R F p a ges, if a p plica ble, a n d t h at t he trial is 
bei n g c o n d ucte d i n acc or da nce wit h t he c urre ntl y a p pr o ve d pr ot o c ol a n d a n y ot her tria l 
a gree m e nts, I C H G C P, a n d all a p plica ble re g ulat or y re q uire m e nts.  
•  M o nit ori n g will be c o n d ucte d usi n g a ris k -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 ntr alise d m o nit ori n g (re m ote assess me nt of data b y N o v o N or dis k) a n d 
visits t o sites.   
•  M o nit ors will re vie w t he s u bject’s me dical rec or ds a n d ot her s o urce data,  e. g. t he diaries  t o 
e ns ure c o nsiste n c y a n d/ or i de ntif y o missi o ns c o m pare d t o t he C R F.   
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 
disc usse d.  
De viati o ns m ust be d oc u me nte d a n d e x plai ne d i n a pr ot oc ol de viati o n b y st ati n g t he reas o n, d ate, 
a n d t he acti o n(s) t a ke n. S o me de via ti o ns, f or w hic h c orrecti o ns are n ot p ossi ble, ca n be 
ac k n o wle d ge d a n d c o nfir me d via e dit c hec ks i n t he C R F or via listi n gs fr o m t he trial data base.   
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
4 8
 
-
 |
1
 |
C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 9  of 7 4  
 
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 C R F . 
•  C G M data is c o nsi dere d i nter me diate dat a u ntil it has bee n tra nsferre d t o t h e ser vice 
pr o vi der’s dat a base. C G M data tra nsferre d t o t his data base will be c o nsi dere d s o urce data. 
After dat a base l oc k, site s pecific C G M data will be pr o vi de d t o sites f or sit e arc hi v al. 
•  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 C 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 s u bject a n d s u bsta ntiate t he 
i nte grit y of t he d ata c ollecte d. S o urce d o c u me nts are file d at t he site.  
•  Data re p orte d o n t he pa p er C R F or e nt ere d i n t he e C R F t hat are tra nscri be d 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 p a ncies m ust be 
e x plai ne d. T he i n vesti gat o r ma y n ee d t o re q uest pr e vi o us me dical rec or ds or tra nsfer 
rec or ds. Als o, c urre nt me dical rec or ds m ust be a vaila ble.  
•  It m ust be p ossi ble t o verif y s u bject’s me dical hist or y i n s o urce d o c u me nts, s uc h as s u bject’s 
me dical rec or d.  
•  T he i n vesti gat or m ust d oc u m e nt a n y atte m pt t o o btai n e xter nal me dical i nf or mati o n b y 
n oti n g t he date(s) w he n i nf or mati o n was re q ueste d, a n d w h o was c o ntacte d.  
•  Defi niti o n of w 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 be o ne s o urce d oc u me nt defi ne d at a n y ti me f or a n y dat a ele me nt. 
1 0. 1. 1 0   
Rete nti o n of cli nic al tri al d oc u me nt ati o n  
•  Rec or ds a n d d o c u me nts, i ncl u di n g si g n e d i nf or me d c o nse nt f or ms, pertai ni n g t o t he c o n d u ct 
of t his trial m ust be retai ne d b y t h e i n vesti gat or f or 1 5 years after e n d of tri al u nless l ocal 
re g ulati o ns or i nstit uti o nal p olicies re q uire a l o n ger ret e nti o n peri o d. N o rec or ds ma y be 
destr o ye d d uri n g t he rete nti o n peri o d wit h o ut t he writte n a p pr o val of N o v o N or dis k. N o 
rec or ds ma y b e tra nsferre d t o a n ot her l ocati o n or part y wit h o ut writte n n otificati o n t o N o v o 
N or dis k.   
•  T he i n vesti gat or m ust be a ble t o access his/ her trial d oc u me nts wit h o ut i n v ol vi n g N o v o 
N or dis k i n a n y wa y. If a p plica ble, electr o nic C R F (e C R F) a n d ot h er s u bject data will be 
pr o vi de d i n a n electr o ni c rea da bl e f or mat t o t he i n vesti gat or bef ore access is re v o ke d t o t he 
s yste ms a n d/ or electr o nic de vices s u p plie d b y N o v o N or dis k. Site-s pecific C R Fs a n d ot her 
s u bject data (i n a n electr o nic rea 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. 
•  S u bject’s me dical rec or ds m ust be ke pt f or t he ma xi m u m peri o d per mitte d b y t he h os pital, 
i nstit uti o n or pri vate practice. 
1 0. 1. 1 1   
Tri al a n d site cl os ure  
N o v o N or dis k reser ves t he ri g ht t o cl os e t he site or ter mi nate t he trial at a n y ti me f or a n y reas o n at 
t he s ole discreti o n of N o v o N or dis k. If t he trial is s us pe n de d or ter mi nat e d, t he i n vesti gat or m ust 
i nf or m t he s u bjects 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 trial c o m pleti o n. A site is c o nsi dere d cl os e d w he n all re q uire d d o c u me nts 
a n d trial s u p plies ha ve bee n c ollect e d a n d a site cl os ure visit has bee n perf or me d.  
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
4 9
 
-
 |
1
 |
C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 0  of 7 4  
 
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 ca us e a n d 
s ufficie nt n otice is gi ve n i n a d va nce of t he i nte n de d ter mi nati o n. 
Reas o ns f or t he earl y cl os ure of a 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 oc ol, t he re q uire me nts of t he I R B/I E C or 
l ocal healt h a ut h orities, N o v o N or dis k pr oce d ures or G C P g ui deli nes 
•  i na de q uate recr uit me nt of s u bjects b y t he i n vesti gat or  
•  disc o nti n uati o n of f urt her trial pr o d uct de vel o p me nt.  
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 trial at his/ her site a n d m ust e ns ure a de q u ate 
s u per visi o n of t he c o n d u ct of t he trial at t he site. If a n y tas ks are dele 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 pecifi e d trial -
relate d d uties. T he i n v esti gat or m ust e ns ure t hat t h ere is a de q uate a n d d oc u me nte d trai ni n g f or all 
staff partici p ati n g i n t he c o n d uct of t he trial. It is t he i n vesti gat or’s res p o nsi bilit y t o s u per vise t he 
c o n d uct of t he trial a n d t o pr otect t he ri g hts, safet y, a n d well -bei n g of t he s u bjects.   
A q ualifie d p h ysicia n, w h o is a n i n vesti gat or or a s u b i n vesti gat or f or t he trial , m ust be res p o nsi ble 
f or all trial-relate d me dical decisi o ns.  
T he i n vesti gat or is res p o nsi ble f or fili n g esse ntial d oc u me nts (i.e. t h ose d oc u me nts w hic h 
i n di vi d uall y a n d c ollecti v el y p er mit e val uati o n of t he c o n d uct of a trial a n d t he q ualit y of t he data 
pr o d uce d) i n t he i n v esti gat or trial master file. T he d oc u me nts, i ncl u di n g t he s u bject i de ntificati o n 
c o de list m ust be ke pt i n a sec ure l oc ke d facilit y s o t hat n o u na ut h orize d pers o ns ca n get access t o 
t he data.  
T he i n vesti gat or will ta ke all necessar y t ec 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 data. T he i n vesti gat or will pre ve nt a n y 
u na ut h orise d access t o data or a n y ot her pr ocessi n g of data a gai nst a p plica ble la w. T 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 hari 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 
s u bjects t o a s pecific q u alifie d p h ysicia n w h o will be rea dil y a v aila ble t o s u bjects d uri n g t h at ti me. 
If t he i n vesti gat or is n o l o n ger a ble t o f ulfil t he r ole as i n vesti gat or (e. g. if he/s he m o ves or retires), 
a ne w i n vesti gat or will 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 ve s ufficie nt E n glis h s kills acc or di n g t o t heir 
assi g ne d t as k(s).  
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
5 0
 
-
 |
1
 |
C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 1  of 7 4  
 
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 trials i n a n y c o u ntr y, u nless ot hers ha ve s h o w n 
ne gli ge n ce.   
N o v o N or dis k ass u mes n o lia bilit y i n t he e v e nt of ne gli ge n ce or a n y ot her li a bilit y of t he sites or 
i n vesti gat ors c o n d u cti n g t he trial or b y pers o ns f or w h o m t he sai d site or i n vesti gat or are 
res p o nsi ble.  
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 trial is c o nsi dere d c o nfi de ntial a n d ma y be use d 
b y or o n b e half of N o v o N or dis k f or re g ulat or y p ur p oses as well as f or t he ge n eral d e vel o p me nt of 
t he trial pr o d uct. All i nf or mati o n s u p plie d b y N o v o N or dis k i n c o n necti o n wit h t his trial s hall 
re mai n t he s ole pr o p ert y of N o v o N or dis k a n d is t o be c o nsi dere d c o nfi de ntial i nf or mati o n. 
N o c o nfi de ntial i nf or mati o n s hall be discl o se d t o ot hers wit h o ut pri or writte n c o nse nt fr o m N o v o 
N or dis k. S uc h i nf or mati o n s hall n ot be use d e x ce pt i n t he perf or ma n ce of t his trial.  
T he i nf or mati o n o btai ne d d uri n g t his trial ma y be ma de a vaila ble t o ot her i n vesti gat ors w h o are 
c o n d ucti n g ot h er cli n ical trials wit h t he trial pr o d uct, if dee me d necess ar y b y N o v o N or dis k. 
Pr o vi de d t hat certai n c o n diti o ns are f ulfille d, N o v o N or dis k ma y gra nt access t o i nf or mati o n 
o btai ne d d uri n g t his trial t o researc hers w h o re q uire access f or researc h pr ojects st u d yi n g t he sa m e 
disease a n d/ or tri al pr o d u ct st u die d i n t his trial.  
N o v o N or dis k ma y p u blis h o n its cli nical trials we bsite a re dacte d C T R f or t his trial.  
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 T 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 trials re gar dless of o utc o me. 
Discl os ure i ncl u des p u bli cati o n of a ma n uscri pt i n a peer -re vi e we d s cie ntific j o ur nal, a bstract 
s ub missi o n wit h a p oster or oral pres e ntati o n at a s cie ntific meeti n g or discl os ure b y ot her mea ns.   
T he res ults of t his trial will be s u bject t o p u blic discl os ure o n e xter nal we b sites acc or di n g t o 
i nter nati o nal a n d nati o nal re g ulati o ns. N o v o N or dis k reser ves t he ri g ht t o defer t he release of data 
u ntil s pecifie d milest o nes are reac he d, f or e x a m ple w he n t he C T R is a vaila ble. T his i ncl u des t he 
ri g ht n ot t o release t he res ults of i nteri m 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 trial. 
At t he e n d of t he trial, o n e or m ore sci e ntific p u blicati o ns ma y b e pre pare d c olla b orati vel y b y t he 
i n vesti gat or(s) a n d N o v o N or dis k. N o v o N or dis k reser ves t he ri g ht t o p ost p o ne p u blicati o n a n d/ or 
c o m m u nicati o n f or u p t o 6 0 da ys t o pr otect i ntellect ual pr o pert y.  
I n all cases, t he trial res ults will be re p orte d i n a n o bjecti ve, acc urat e, bala nce d a n d c o m plete 
ma n ner, wit h a disc ussi o n of t he stre n gt hs a n d li mitati o ns. I n t he e v e nt of a n y disa gree me nt o n t he 
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
5 1
 
-
 |
1
 |
C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 2  of 7 4  
 
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 trial c o nce pt or desi g n, ac quisiti o n, a nal ysis or i nter pretati o n of dat a 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 u r 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. 3 5 
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.   
W here re q uire d b y t he j o ur nal, t he i n vesti gat or fr o m eac h 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 erial, 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 trial, a nal yses bas e d o n si n gle -site d ata us uall y ha ve si g nifica nt statistical 
li mitati o ns a n d fre q ue ntl y d o n ot pr o vi de mea ni n gf ul i nf or m ati o n f or healt hcare pr ofessi o nals or 
s u bjects, a n d t heref ore m a y n ot b e s u p p orte d b y N o v o N or dis k. T h us, N o v o N or dis k ma y d e n y a 
re q uest or as k f or defer m e nt of t he p u blicati o n of i n di vi d ual site res ults u ntil t he primar y ma n uscri pt 
is acce pte d f or p u blicati o n. I n li ne wit h G o o d P u blicati o n Practice, s u c h i n di vi d ual re p orts s h o ul d 
n ot prece d e t he pri mar y ma n uscri pt a n d s h o ul d al wa ys refere nce t h e pri mar y ma n uscri pt of t he trial.  
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 trial data base, N o v o N or dis k h as t he discreti o n t o deter mi n e w h o will ha ve access 
t o t he data base. 
I n di vi d ual i n vesti gat ors will ha ve t heir o w n researc h s u bjects’ d ata a n d will be pr o vi de d wit h t he 
ra n d o misati o n c o de after res ults are a vaila ble.  
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
5 2
 
-
 |
1
 |
C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 3  of 7 4  
 
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  a n d Ta ble  1 0 -2  will be perf or me d b y t h e ce ntral or s pecial 
la b orat or y. 
•  A d diti o nal tests ma y be p erf or me d at a n y ti me d uri n g t he trial as deter mi ne d necessar y b y 
t he i n vesti gat or or re q uir e d b y l o cal re g ul ati o ns. O nl y la b orat or y sa m ples s pecifie d i n t he 
pr ot oc ol s h o ul d be se nt t o t he ce ntral la b orat or y f or a nal ysis; if a d diti o nal la b orat or y 
sam 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 orat or y will c o m m u nicate t o t he i n vesti gat or a b n or mal val u es of para met ers 
n ot re q ueste d i n t he pr ot o c ol b ut i de ntifie d b y t he l a b orat or y e q ui p me nt a n d/ or t heir 
pr ocesses acc or di n g t o t heir la b S O Ps. T hese data will n ot be tra nsferre d t o t he trial 
data base. T h e 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.  
•  F or hae mat ol o g y s a m ples ( differe ntial c o u nt) w here t he test res ult is n ot n or mal, t he n a part 
of t he sa m ple ma y be k e pt f or u p t o t w o years or acc or di n g t o l ocal re g ulati o ns.   
•  Res ult s of p har mac o ki netics , Le pti n a n d S ol u ble le p ti n rece pt or will n ot be s hare d  wit h site . 
•  O utc o me of h y perse nsiti vit y  tests will be c o m m u ni cate d t o site. Res ults of tr y ptase, t otal 
i m m u n o gl o b uli n E (I g E), a nti-ca grili nti de I g E a n d  a nti-se ma gl uti de I g E will n ot be s hare d  
wit h site .  
•  La b orat or y s a m ples will be destr o ye d n o lat er t ha n at fi nalisati o n of t he C T R e x ce pt f or 
sa m ples descri bed  i n S ecti o n 1 0. 6 .  
T a ble  1 0 -1  
Pr ot oc ol -re q uire d effic ac y l a b or at or y assess me nts  
L a b or at or y assess me nts   
P ar a meters  
Visits  
Gl uc ose meta b olis m  
•  H b A 1 c 
1, 2, 4, 6, 8, 1 2, 1 4, 1 6  
•  Fasti n g plas ma gl uc ose 1 
2, 4, 6, 8, 1 2, 1 6  
•  Fasti n g Ser u m I ns uli n  
•  C -P e pti de  
•  Pr oi ns uli n  
•  Gl uca g o n  
2, 6, 1 2, 1 6  
Li pi ds  
•  C h olester ol  
•  Hi g h de nsit y li p o pr otei n ( H D L) c h olester ol  
•  L o w de nsit y li p o pr otei n ( L D L) c h olester ol  
•  Ver y -l o w-de nsit y li p o pr otei n ( V L D L) 
c h olester ol  
•  Tri gl yceri des  
2, 6, 1 2, 1 6  
Bi o mar ker  
•  Hi g h se nsiti ve C -reacti ve pr otei n ( hs C R P)  
•  Le pti n  
•  S ol u ble le pti n rece pt or  
2, 6, 1 2, 1 6  
N O T E S:  
1A 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 be 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 ( Secti o n 1 0. 3 ). 
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
5 3
 
-
 |
1
 |
C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 4  of 7 4  
 
T a ble  1 0 -2  
Pr ot oc ol -re q uire d s afet y l a b or at or y assess me nts  
L a b or at or y  assess me nts   
P ar a meters  
Visits  
Hae mat ol o g y  
•  Hae m o gl o bi n  
•  Hae mat ocrit  
•  Er yt hr oc ytes  
•  T hr o m b oc ytes  
•  Le uc oc ytes  
•  Bas o p hils  
•  E osi n o p hils  
•  L y m p h oc ytes  
•  M o n oc ytes  
•  Ne utr o p hils  
1, 4, 6, 8, 1 2, 1 6  
Bi oc he mistr y 1  
•  Ala ni ne A mi n otr a nsferase ( A L T) 3 
•  Al b u mi n  
•  Al b u mi n c orrecte d calci u m  
•  Al kali ne p h os p hatase  
•  As partate A mi n otra nsferase ( A S T) 3 
•  Bilir u bi n  
•  Calci u m  
•  Creati ne ki nase  
•  Creati ni ne  
•  Ga m ma Gl uta m yl Tra nsferase ( G G T)  
•  Ma g nesi u m  
1, 4, 6, 8, 1 2, 1 6  
•  P otassi u m  
•  S o di u m  
1, 2, 4, 6, 8, 1 2, 1 6, 1 7  
H or m o nes  
•  Al d oster o ne   
•  Plas ma re ni n acti vit y  
•  Al d oster o ne -t o-re ni n acti vit y rati o 
1, 2, 4, 6, 8, 1 2, 1 6,  1 7  
•  T h yr oi d sti m ulati n g h or m o ne ( T S H)  
•  F ol licle-sti m ulati n g h or m o ne ( F S H) (fe male 
s u bj ects o nl y) 4 
1  
Pre g na nc y T esti n g  
•  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 (o nl y 
p ost me n o pa usal fe male s u bj ects w h o ha ve 
st o p pe d me nstr uati n g wit hi n t he last 5 years )2 
1, 2, 4, 6, 8, 1 0, 1 2, 1 4, 1 6, 1 7  
P har mac o ki netics  
•  Se ma gl uti de plas ma c o nce ntrati o n  
•  Ca grili nti de plas ma c o nce ntrati o n  
4, 6, 1 2, 1 6,  
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  
1, 4, 6, 8, 1 2, 1 6  
•  tr y ptase  
•  t otal i m m u n o gl o b uli n E (I g E) a nti b o dies 
•  a nti -ca grili nti de I g E a nti b o dies   
•  a nti -se ma gl uti de I g E a nti b o di es  
O nl y i n case of s yste mic 
h y perse nsiti vit y, see secti o n 8. 3. 7  
N otes:  
1Details of re q uire d acti o ns a n d f oll o w -u p assess me nts f or i ncrease d li ver para meters i ncl u di n g a n y disc o nti n uati o n 
criteria are gi ve n i n Secti o n 1 0. 3  ( H y’s La w) a n d Secti o n 7. 1  
2L ocal uri ne testi n g will be sta n dar d u nless ser u m testi n g  is r e q uire d b y l ocal re g ulati o n or I R B/I E C. A pre g na nc y 
test s h o ul d be perf or me d e ver y 4 wee ks a n d at t he E n d of tri al (after 5 wee ks off treat me nt) (refer t o fl o wc hart, 
Secti o n 1. 2  a n d A p pe n di x 4) . 
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
5 4
 
-
 |
1
 |
C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 5  of 7 4  
 
3If A L T or A S T > 3 u p per n or mal li mit ( U N L), a d diti o nal bl o o d sa m ple s h o ul d be ta ke n fr o m t he s u bj ect t o a nal yse 
i nter nati o nal n or malise d rati o (I N R) b y ce ntral la b orat or y (e xce pt at scree ni n g visit). Re pe at testi n g of t he a b n or mal 
la b orat or y assess me nts s h o ul d be perf or me d via ce ntral la b orat or y f or t he s u bj ect u ntil a b n or malities ret ur n t o n or mal 
or baseli ne state.  
 4A p plica ble f or p ost me n o pa usal w o me n o nl y t o c o nfir m p ost me n o pa usal stat us (see A p pe n di x 4, Secti o n 1 0. 4 )  
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
5 5
 
-
 |
1
 |
C O N FI D E N TI A L












Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6 1  of 7 4  
 
Fi 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 t i 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.  
 
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
6 1
 
-
 |
1
 |
C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6 2  of 7 4  
 
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  
It m ust be rec or de d i n t he e C R F w het h er fe male s u bjects are of c hil d beari n g p ote ntial.  
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 trial treat me nt, 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 ori es are n ot c o nsi dere d W O C B P  
1.  Fe mal es 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  
Fe males wit h per ma ne nt i nfertilit y d ue t o a n alter nate me dical ca use ot her t ha n t he a b o ve (e. g. 
M ülleria n a ge n esis, a n d r 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 
trial e nr ol me nt. 
2.  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 1 2 m o nt hs wit h o ut a n alter nati ve 
me dical 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.  
A F S H meas ure me nt ma y be us e d t o c o nfir m p ost me n o pa usal stat u s (see A p pe n di x 2, 
Secti o n  1 0. 2 ).  
Fe males o n h or m o ne re pl ace me nt t hera p y ( H R T ) a n d w h ose 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 are n ot eli gi ble t o partici p ate  i n t his trial.  
N ote: D oc u me ntati o n re gar di n g cate g ories 1 -2  ca n c o me fr o m t he site staff’s re vie w of s u bject’s 
me dical rec or ds, me dical e xa mi nati o n or me dical hist or y i nter vie w.  
1 0. 4. 2   
C o ntr ace pti o n g ui d a nce  
M ale s u bjects  
N o c o ntrace pti o n meas ures are re q uir e d f or mal e s u bjects, 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 ca grili nti de i n se mi nal fl ui d is u nli kel y 2 2.  
Fe m ale s u bjects  
Fe male s u bjects of c hil d beari n g p ote ntial are n ot eli gi ble t o partici p ate . 
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
6 2
 
-
 |
1
 |
C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6 3  of 7 4  
 
Pre g n a nc y testi n g  
•  P ost me n o pa usal fe male s u bjects w h o ha ve st o p pe d me nstr uati n g wit hi n t h e last 5 years  m ust 
ha ve uri ne pre g na n c y tests perf or me d at cli nic visits as o utli ne d i n t he fl o wc hart ( Secti o n 
1. 2 ).  
•  Pre g n a nc y testi n g m ust be perf or me d at h o me  i n a d diti o n t o cli nic visits acc or di n g t o t he 
fl o wc hart a n d h o me-testi n g kits m ust be ha n de d o ut acc or di n g t o fl o wc hart 
(see Sect i o n 1. 2 ). 
•  Pre g n a nc y testi n g m ust be re peate d at a n y ti me d uri n g t he tri al if t he s u bject e x perie nces a 
late or misse d me nstr ual c ycle or if pre g na n c y is ot her wise s us pect e d. Trial pr o d ucts m ust 
be dis c o nti n ue d u ntil a pre g n a nc y test has b ee n c o nfir me d ne gati ve b y t h e i n vesti gat or.  
1 0. 4. 3   
C ollecti o n of pre g n a nc y i nf or m ati o n   
Fe m ale s u bjects w h o bec o me pre g n a nt   
•  I n v esti gat or will c ollect pre g na nc y i nf or mati o n o n a n y fe male s u bj ect w h o bec o mes 
pre g na nt w hile par tici pati n g i n t his trial. 
•  I nf or mati o n will be rec or de d o n t he a p pr o priate f or m a n d s u b mitte d t o N o v o N or dis k wit hi n 
1 4 cale n dar da ys of lear ni n g of a s u bj ect’s pre g na nc y (see Fi g ure  1 0 -2 ). 
•  S u bject will be f oll o we d t o deter mi ne t he o utc o me of t he pre g n a nc y. T he i n vesti gat or will 
c ollect f oll o w -u p i nf or m ati o n o n s u bject a n d ne o n ate 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 d ate.  
•  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 bse nce of a n o malies) or i n dicati o n f or pr oce d ure.  
•  W hile p re 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 n a n c y or electi ve ter mi nati o n of a pre g n a nc y f or me dical reas o ns will 
be re p ort e d as a n A E or S A E. If rele va nt, c o nsi der a d di n g ‘ gestati o nal’, ‘ pre g n a nc y relate 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 s u bject’s me dical rec or d. A b n or mal 
pre g na nc y o ut c o me (e. g. s p o nta ne 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 n c y) is c o nsi dere d a n S A E.  I n case of a b n or mal pre g na nc y o ut c 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 after o btai ni n g t he 
necessar y si g n e d pater nal 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 -trial pre gna nc 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 orte d t o N o v o 
N or dis k as descri be d i n A p pe n di x 3  (Secti o n 1 0. 3 ).  
 
 
 
 
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
6 3
 
-
 |
1
 |
C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6 4  of 7 4  
 
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 wit h ass oci ate d ti meli nes f or 
pre g n a nc y.  
M at er n al f or m 1 b  
  1 4 cal e n d ar d a ys aft er birt h
M at er n al f or m 1 a
  1 4 cal e n d ar d a ys
Aft er birt h/
t er mi n ati o n 
of pr eg n a nc y
N o a d diti o n al 
acti o n
N or m al o ut c o m e 
M at er n al f or m 2   1 4 cal e n d ar d a ys
P at er n al f or m * 1   1 4 cal e n d ar d a ys
A b n or m al o utc o m e 
Pr eg n a ncy 
v erifi e d
* 1 F urt h er i nf or m ati o n c oll ect e d o n P at er n al f or m f or m al e p art n ers of 
f e mal e s u bj ects r e q uir es si g ni n g of s p e cific i nf or m e d c o ns e nt.
A E/ S AEs i n c o n n ecti o n wit h t h e pr e g n a ncy a n d i n t h e f o et us/ n e w b or n 
s h o ul d f oll o w t h e ti m eli n es i n Fi g ur e 1 0. 1.
Pri or t o 
birt h or 
pr e g n a nc y 
t er mi n ati o n 
F or f e m al e s u bj ects
 
 
A n y fe male s u bject w h o bec o mes pre g na nt w hile partici pati n g i n t he tri al will disc o nti n ue I M P.  
 
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
6 4
 
-
 |
1
 |
C O N FI D E N TI A L






Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or d i s k 
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
Stat us:  
Fi n al  
P a ge:  
6 7  of 7 4  
1 0. 6   
A p pe n di x 6: Rete nti o n of h u m a n bi os a m ples  
T he sa m ples will be pse u d oa n o n y mise d (s o pers o nal  data ca n n o l o n ger be attri b ute d t o a s pecific 
data s u bject wit h o ut t he use of a d diti o nal i nf or mati o n s uc h as a u ni q ue sa m ple I D, visit n u m ber, 
trial i de ntificati o n n u m ber a n d sa m pli n g d ate). C o nfi de ntialit y a n d p ers o nal data pr otecti o n will be 
e ns ure d d u ri n g st or a ge after t he e n d of tri al a n d n o direct i de ntificati o n of t h e s u bject will be st ore d 
t o get her wit h t he sa m ples. 
P ote ntial f urt her a nal ys es of t he sa m ples will n ot ha ve a n y c o nse q ue n ces f or t he s u bject.  
T he bi osa m ples will be st ore d at a ce ntral la b orat or y, at a ce ntral st ora ge facilit y or N o v o N or dis k 
f or u p t o 1 5 years after e n d of trial. O nl y rele va nt N o v o N or dis k, c o ns ulta nts, researc h or ga nis ati 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 will 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 be 
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 
trial. 
T he f oll o w i n g h u m a n bi osa m ples ma y b e ret ai ne d u ntil mar keti n g a ut h orisati o n a p pr o val: 
Resi d u al ca grili nti de  P K s a m ples  
•
T he resi d ual P K sa m ples  ma y b e retai n e d f or lat er a nal ysis of meta b olites or assa y
vali dati o n p ur p oses  if nee de d.
•
T he resi d ual P K sa m ples ma y b e use d f or h y perse nsiti vit y reacti o n a n al ysis.
Resi d u al h y perse nsiti vit y s a m ples  
•
I n case of a s yste mic h y p erse nsiti vit y reacti o n, t he resi d ual h y perse nsiti vit y sa m ples ( please
refer t o Secti o n 8. 3. 7 ) ma y be retai ne d t o f oll o w-u p o n t he h y p erse nsiti vit y reacti o n. If
dee me d rele va nt b y N o v o N or dis k, rele va nt e x pl orat or y a n al ysis ma y b e perf or me d, e. g.,
hista mi ne release ( bas o p hil acti vati o n ), c o m ple me nt a nal ysis, pric k tests a n d/ or i ntra-der mal
tests.
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
6 7
 
-
 |
1
 |
C O N FI D E N TI A L




Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or d i s k 
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
Stat us:  
Fi n al  
P a ge:  
6 9  of 7 4  
U p o n o nset o f a h y p o gl ycae mic e pis o de t he s u bject 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. 4 1 
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 mi c 
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 ha t 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 piso de c ha n ges, o nl y o ne h y p o gl 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 s u bje cts t o a ns wer “ Yes”, if t he e pis o de was a n e v e nt 
t hat re q uire 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 gical 
rec o ver y foll o wi n g t he ret ur n of P G t o n or mal is c o nsi dere d s uffi cie nt e vi d e nce t hat t he e ve nt was 
i n d uce d b y a l o w P G c o n ce ntrati o n.4 1 
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 s u bject 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: 
•
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 s u bject wit hi n 7
cale n dar 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 me dical
rec or ds a n d re p orte 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 s u bject 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 dat e d ue t o recall bias .4 2, 4 3
Re -tr ai ni n g of s u bjects 
T he s u bject m ust be re -tr ai 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 ort e d as h y p o gl ycae mic e pis o des. T he 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 t he me dical rec or ds. 
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
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V V- T M F- 4 5 3 5 0 0 0
7 4
 of
6 9
 
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1
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C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
Stat us:  
Fi n al  
P a ge:  
7 0  of 7 4  
1 0. 8   
A p pe n di x 8: A b bre vi ati o ns  
A D A   
A merica n Dia betes Ass ociati o n  
A E  
a d verse e ve nt  
A L T  
ala ni ne a mi n otra nsferase  
A S T  
as partate a mi n otra nsferase  
B G  
bl o o d gl uc ose  
B MI  
b o d y mass i n de x  
C G M   
c o nti n u o us gl uc ose m o nit ori n g  
C R F  
case re p ort f or m  
C T R  
cli nical trial re p ort  
D B L  
data b ase l oc k 
D F U  
directi o ns f or use  
D U N   
dis pe nsi n g u nit n u m ber  
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 P G  
fasti n g plas ma gl uc ose 
F S H  
f ollicle-sti m ulati n g h or m o ne 
GI  
gastr oi ntesti nal  
G L P -1   
gl uca g o n -li ke pe pti de-1  
G C P  
G o o d Cli nical Practice  
H b A 1 c  
gl ycate d hae m o gl o bi n  
H R T  
h or m o ne re place me nt t hera p y  
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n 
I E C 
i n de pe n de nt et hics c o m mittee 
I B 
i n vesti gat or’s br oc h ure 
I M P 
i n vesti gati o nal me dici nal pr o d uct 
I R B 
i nstit uti o nal re vie w b oar d 
I W R S  
i nteracti ve we b res p o nse s yste m 
L D L  
l o w-de nsit y li p o pr otei n  
M M R M   
Mi xe d m o del f or re peate d me as ure me nts  
NI M P   
n o n -i n vesti gati o nal me dical pr o d uct 
O A D   
oral a nti -dia betic  
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
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V V- T M F- 4 5 3 5 0 0 0
7 4
 of
7 0
 
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1
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C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
Stat us:  
Fi n al  
P a ge:  
7 1  of 7 4  
P C D  
pri mar y c o m pleti o n date  
P G  
plas ma gl uc ose  
P K  
p har mac o ki netics  
s.c.
s u bc uta ne us 
S A E  
seri o us a d verse e ve nt 
S A P  
statistical a nal ysis pla n 
S G L T 2   
S o di u m -gl uc ose c o -tra ns p orter-2  
S U S A R   
s us pecte d u ne x pecte d seri o us a d verse reacti o n 
T 2 D  
t y pe 2 dia betes 
T M M   
trial materials ma n ual 
U N L  
u p per n or mal li mit  
W O C B P   
w o ma n of c hil d -beari n g p ote ntial  
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
7 1
 
-
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1
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C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
Stat us:  
Fi n al  
P a ge:  
7 2  of 7 4  
1 1  Refere nces  
1. 
A merica n Di a betes Ass o ciati o n. 2. Classificati o n a n d Dia g n osis of Dia betes:. Dia betes Care.
2 0 1 9; 4 2( S u p pl 1): S 1 3 -S 2 8.
2. 
I nter nati o nal Dia betes Fe derati o n. I D F Dia b etes Atlas, 9t h E diti o n. 2 0 1 9.
3. 
Kieffer TJ, Ha be ner J F. T he gl u ca g o n -li ke p e pti des. E n d ocr Re v. 1 9 9 9; 2 0( 6): 8 7 6-9 1 3.
4. 
M üller T D, Fi na n B, Bl o o m S R, D' Alessi o D, Dr uc ker DJ, Flatt P R , et al. Gl uca g o n -li ke
pe pti de 1 ( G L P -1). M ol Meta b. 2 0 1 9; 3 0: 7 2 -1 3 0.
5. 
B o yl e C N, L utz T A, Le F oll C. A m yli n - Its r ole i n t he h o me ostatic a n d he d o nic c o ntr ol of
eati n g a n d rece nt de vel o p me nts of a m yli n a n al o gs t o treat o besit y. M ol M eta b. 2 0 1 8; 8: 2 0 3 -
1 0.
6 . 
U S Prescri bi n g I nf or mati o n, 2 0 1 6 f or S y mli n ®, N D A 2 1 -3 3 2.
7. 
Y o u n g A, De nar o M. R oles of a m yli n i n dia betes a n d i n re g ulati o n of n utrie nt l oa d.
N utriti o n. 1 9 9 8; 1 4( 6): 5 2 4 -7.
8. 
Gar ber AJ, Ha n dels ma n Y, Gr u n ber ger G, Ei n h or n D, A bra h a ms o n MJ, Barzila y JI, et al.
C o nse ns us State me nt b y t he A merica n Ass ociati o n of Cli nical E n d ocri n ol o gists a n d
A merica n C olle ge of E n d ocri n ol o g y o n t he C o m pre he nsi ve T y p e 2 Dia betes Ma na ge me nt
Al g orit h m - 2 0 2 0 E x ec uti ve S u m mar y. E n d ocr Pract. 2 0 2 0; 2 6( 1): 1 0 7 -3 9.
9. 
C ose nti n o F, G ra nt PJ, A b o ya ns V, Baile y CJ, Ceriell o A, Del ga d o V, et al. 2 0 1 9 E S C
G ui deli nes o n dia betes, pre -dia betes, a n d car di o vasc ular diseas es de vel o pe d i n c olla b orati o n
wit h t he E A S D. E ur Heart J. 2 0 2 0; 4 1( 2): 2 5 5 -3 2 3.
1 0. 
Ta yl or R, Al -Mra b e h A, Sattar N. U n derst a n di n g t he mec ha nis ms of re versal of t y p e 2
dia betes. La n cet Dia bet es E n d ocri n ol. 2 0 1 9; 7( 9): 7 2 6 -3 6.
1 1. 
G u m mess o n A, N y m a n E, K n utss o n M, Kar pef ors M. Effect of wei g ht re d ucti o n o n
gl ycate d hae m o gl o bi n i n wei g ht l oss trials i n patie nts wit h t y p e 2 dia betes.  Dia betes O bes
Meta b. 2 0 1 7; 1 9( 9): 1 2 9 5 -3 0 5.
1 2. 
La u J, Bl oc h P, Sc häffer L, Petterss o n I, S petzler J, K of oe d J, et al. Disc o ver y of t he O nce -
Wee kl y Gl uca g o n -Li ke P e pti de -1 ( G L P -1) A nal o g ue Se ma gl uti de. J Me d C he m.
2 0 1 5; 5 8( 1 8): 7 3 7 0 -8 0.
1 3. 
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 haract eristics
( S m P C). 2 0 1 8.
1 4. 
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). Dec 2 0 1 7.
1 5. 
N o v o N or dis k A/ S. C o m pa n y A n n o u nce m e nt:  O nce -wee kl y se ma gl uti de 2. 0 m g
de m o nstrates s u peri or re d ucti o n i n H b A 1c vs o nce -wee kl y s e ma gl uti de 1. 0 m g i n pe o ple
wit h t y pe 2 dia betes i n t he S U S T AI N F O R T E trial 2 0 2 0 [cite d 2 0 2 0 1 7 N o ve m ber].
1 6. 
Wil di n g J P H, Batter ha m R L, Cala n na S, Da vies M, Va n Gaal L F, Li n g va y I, et al. O nce -
Wee kl y Se ma gl uti de i n A d ults wit h O ver wei g ht or O besit y. N E n gl J Me d. 2 0 2 1.
1 7. 
Da vies M, F ærc h L, J e 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 ou 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 n cet. 2 0 2 1; 3 9 7( 1 0 2 7 8): 9 7 1 -8 4.
1 8. 
Ar o da V, A h m a n n A, Cari o u B, C h o w F, Da vies M, J´ o dar E, et al. C o m parati ve efficac y,
safet y, a n d car di o vas c ular o utc o mes wit h o nce-wee kl y s u bc uta ne o us se ma gl uti de i n t he
treat me nt of t y pe 2 dia betes: I nsi g hts fr o m t he S U S T AI N 1– 7 trials. Dia bet es &
Meta b olis m. 2 0 1 8.
1 9. 
L ys e n g -Willia ms o n K A. Gl uca g o n -Li ke Pe pti de -1 Rece pt or A n al o g u es i n T y pe 2 Dia betes:
T heir Use a n d Differe nti al Feat ures. Cli n Dr u g I n ve sti g. 2 0 1 9; 3 9( 8): 8 0 5-1 9.
2 0. 
Na uc k M A, Mei er JJ. M A N A G E M E N T O F E N D O C RI N E DI S E A S E: Are all G L P -1
a g o nist e q u al i n t he treat me nt of t y pe 2 di a betes? E ur J E n d ocri n ol. 2 0 1 9.
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
7 2
 
-
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1
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C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
7 3  of 7 4  
 
 
2 1.   
N o v o N or dis k A/ S. I n v esti gat or's  Br oc h ure, Se ma gl uti de s.c. 2. 4 m g f or wei g ht 
ma n a ge me nt, pr ojects N N 9 5 3 6 a n d E X 9 5 3 6 (e diti o n 6). 0 3 Dec 2 0 2 0.  
2 2.   
N o v o N or dis k A/ S. I n v esti gat or Br oc h ure, N N C 0 1 7 4 -0 8 3 3/ Ca grili nti de/ Ca gri Se ma, pr oject 
N N 9 8 3 8 (e diti o n 6). 2 1 Dec 2 0 2 0.  
2 3.   
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 m ati o n ( PI). Ja n 2 0 2 0.  
2 4.   
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 b et es, 2 0 1 8. A C o nse ns us Re p ort b y t h e 
A merica n Di a betes Ass o ciati o n ( A D A) a n d t he E ur o pea n Ass o ciati o n f o r t he St u d y of 
Dia betes ( E A S D). Dia bet es Care. 2 0 2 0; 4 3( 2): 4 8 7 -9 3.  
2 5.   
Da vies MJ, D' Alessi o D A, Fra d ki n J, Ker na n W N, Mat hie u C, Mi n gr o ne G, et al. 
Ma na ge me nt of H y per gl yce mia i n T y pe 2 Dia b et es, 2 0 1 8. A C o nse ns us Re p ort b y t h e 
A merica n Di a betes Ass o ciati o n  ( A D A) a n d t he E ur o pea n Ass o ciati o n f or t he St u d y of 
Dia betes ( E A S D). Dia bet es Care. 2 0 1 8; 4 1( 1 2): 2 6 6 9 -7 0 1.  
2 6.   
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 class ificati 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.  
2 7.   
Da vies MJ, D’ Alessi o D A, Fra d ki n J, Ker na n W N, Mat hie u C, Mi n gr o ne G, et al. 
Ma na ge me nt of h y p er gl ycae 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 Di a bete s Ass o ciati o n ( A D A) a n d t he E ur o pea n Ass o ciati o n f or t he St u d y of 
Dia betes ( E A S D). Dia bet ol o gia. 2 0 1 8; 6 1( 1 2): 2 4 6 1 -9 8.  
2 8.   
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 n eral Asse m bl y, 
F ortaleza, Brazil. Oct o ber 2 0 1 3.  
2 9.   
I C H Har m o nise d Tri p artite G ui deli ne. G ui deli ne f or G o o d Cli nical Practice E 6( R 2), Ste p 4 
versi o n. 0 9 N o v 2 0 1 6.  
3 0.   
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 a l. Cli nical trial 
re gistrati o n: a state me nt fr o m t he I nter nati o nal C o m mittee of Me dical J o ur nal E dit ors. N 
E n gl J Me d. 2 0 0 4; 3 5 1( 1 2): 1 2 5 0 -1.  
3 1.   
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.  
3 2.   
T he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n C o u ncil. Directi ve 2 0 0 1/ 2 0/ E C 
of t he E ur o pea n Parlia me nt a n d of t he C o u ncil of 4 A pril 2 0 0 1 o n t he a p pr o xi mati o n of t he 
la ws, re g ulati o ns a n d a d mi nistrati ve pr o visi o ns of t he me m ber states relati n g t o t he 
i m ple me ntati o n of g o o d cli nical practice i n t he c o n d uct of cli nical trials o n me dici nal 
pr o d ucts f or h u ma n us e. 2 0 0 1 . 
3 3.   
T he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n C o u ncil. Re g ulati o n ( E C) N o 
7 2 6/ 2 0 0 4 of t he E ur o pea n Parlia me nt a n d of t he C o u ncil of 3 1 Marc h 2 0 0 4 la yi n g d o w n 
C o m m u nit y pr oce d ures f or t he a ut h orisati o n a n d s u per visi o n of me dici nal pr o d ucts f or 
h u ma n a n d veteri n ar y us e a n d esta blis hi n g a E ur o pea n Me dici nes A ge nc y, article 5 7. 3 0 
A pril 2 0 0 4.  
3 4.   
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 h e C o u ncil of 1 2 Dece m b er 2 0 0 6 o n 
me dici nal pr o d ucts f or p ae diatric 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.  
3 5.   
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 . 
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
0
 |
V V- T M F- 4 5 3 5 0 0 0
7 4
 of
7 3
 
-
 |
1
 |
C O N FI D E N TI A L


Pr ot oc ol  
 
Date:  
1 6 J u ne 2 0 2 1  N o v o N or di s k  
Trial I D: N N 9 8 3 8 -4 8 6 2  
V ersi o n:  
2. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
7 4  of 7 4  
 
 
3 6.   
I nter nati o nal H y p o gl ycae mia St u d y Gr o u p. Gl uc os e 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 ositi 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 Di a betes. 
Dia betes Care. 2 0 1 7; 4 0( 1): 1 5 5 -7.  
3 7.   
A merica n Di a betes Ass o c iati o n. 6. Gl yce mic Tar gets: Sta n dar ds of Me dical Care i n 
Dia betes -2 0 1 8. Di a betes Care. 2 0 1 8; 4 1( S u p pl 1): S 5 5 -S 6 4.  
3 8.   
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 m a 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 b etes. 2 0 1 8; 1 9 S u p pl 
2 7: 1 7 8 -9 2.  
3 9.   
A gi ostrati d o u G, A n h alt 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 1 c f or T y p e 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 o cri ne S ociet y, a n d t he T 1 D E x c ha n ge. Dia betes C are. 
2 0 1 7; 4 0( 1 2): 1 6 2 2 -3 0.  
4 0.   
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.  
4 1.   
Sea q uist E R, A n ders o n J, C hil ds B, Cr yer P, Da g o g o -J ac k S, Fis h L, et al. H y p o gl yce mia 
a n d dia betes: a re p ort of a w or k gr o u p of t he A merica n Dia bet es Ass ociati o n a n d t he 
E n d ocri ne S ociet y. Dia b etes Care. 2 0 1 3; 3 6( 5): 1 3 8 4 -9 5.  
4 2.   
U S 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 orte d O utc o me 
Meas ures: Us e i n Me dical Pr o d uct De vel o p me nt t o S u p p ort La b eli n g Clai ms. Dece m ber 
2 0 0 9.  
4 3.   
St ull D E, Lei d y N K, Paras ura ma n B, C hassa n y O. O pti mal reca ll peri o ds f or patie nt-
re p orte d o utc o m es: c hall e 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.  
 
  Pr ot oc ol  4 8 6 2 Pr ot oc ol V 2 0
N N 9 8 3 8- 4 8 6 2
N N 9 8 3 8
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1 6. 1. 0 1  
Pr ot oc ol  Att ac h me nt  
Pr ot oc ol A ttac h me nt I is l ocate d i n t he Trial Mast er File. 
If a p plica bl e, Pr ot oc ol Attac h me nt II is als o l ocate d i n t he Trial Master File. 
C o nte nt: Gl o bal ke y staff a n d C o u ntr y k e y staff.  
Date:
N o v o N or di s k
Versi o n:
Stat us:
Ca gri Se ma
Trial I D: N N 9 8 3 8 4 8 6 2
Cli nical Trial Re p ort
A p pe n di x 1 6. 1. 1
0 1 N o ve m ber 2 0 2 2
1. 0
Fi nal
C O N FI D E N TI A L

SAP_001.pdf: 
Cover Page for SAP 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT04982575 
Sponsor trial ID: 
NN9838-4862 
Official title of study: 
Efficacy and safety of co-administration of cagrilintide s.c. 2.4 
mg and semaglutide s.c. 2.4 mg once weekly in subjects with 
type 2 diabetes 
Document date* 
12 March 2022 
* Document date refers to the date on which the document was most recently updated.
Note: The date in the header of Page 2 is the date of compilation of the documents and not of an update to content.


Link
Link
List of contents
Statistical analysis plan......................................................................................................................
MedDRA searches 4862.....................................................................................................................
Date:
Novo Nordisk
Version:
Status:
CagriSema
Trial ID: NN9838 4862
Clinical Trial Report
Appendix 16.1.9
01 November 2022
1.0
Final
16.1.9 Documentation of statistical methods
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Statistical Analysis Plan 
 
Date: 
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Study ID: NN9838-4862 
Version: 
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Status: 
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Page: 
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Statistical Analysis Plan 
Efficacy and safety of co-administration of cagrilintide s.c. 2.4 
mg and semaglutide s.c. 2.4 mg once weekly in subjects with 
type 2 diabetes 
Substance name/number: cagrilintide, semaglutide
Author: 
, Biostatistics Obesity and Nash 
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Includes redaction of personal identifiable information only. 
. 
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Statistical Analysis Plan 
 
Date: 
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Study ID: NN9838-4862 
Version: 
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Status: 
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Table of contents 
Page 
Table of contents ............................................................................................................................................... 2 
Table of figures ................................................................................................................................................. 3 
Table of tables ................................................................................................................................................... 4 
Version History ................................................................................................................................................. 5 
1 Introduction ................................................................................................................................................. 6 
1.1 
Objectives, Endpoints, and Estimands ................................................................................................ 6 
1.1.1 
Primary objectives ............................................................................................................. 6 
1.1.2 
Secondary objectives ......................................................................................................... 6 
1.1.3 
Estimands ........................................................................................................................... 6 
1.2 
Primary, secondary and exploratory endpoint(s) ................................................................................ 7 
1.2.1 
Primary endpoint ................................................................................................................. 7 
1.2.2 
Secondary endpoints ............................................................................................................ 8 
1.2.2.1 
Confirmatory secondary endpoints .................................................................. 8 
1.2.2.2 
Supportive secondary endpoints ...................................................................... 8 
1.3 
Study Design ....................................................................................................................................... 8 
2 Statistical considerations ............................................................................................................................ 9 
2.1 
Statistical hypotheses ........................................................................................................................ 9 
2.2 
Sample size determination ............................................................................................................... 9 
2.3 
Populations for analyses ................................................................................................................. 10 
2.4 
Statistical analyses .......................................................................................................................... 11 
2.4.1 
General considerations .................................................................................................... 11 
2.4.2 
Primary endpoint ............................................................................................................. 11 
2.4.3 
Secondary endpoint(s) ..................................................................................................... 12 
2.4.3.1 
Confirmatory secondary endpoint(s) ......................................................... 12 
2.4.3.2 
Supportive secondary endpoints ................................................................. 12 
2.4.4 
Other safety analyses ....................................................................................................... 12 
2.4.5 
Other analyses .................................................................................................................. 12 
2.4.5.1 
Pharmacokinetic modelling ......................................................................... 12 
2.5 
Interim analyses .............................................................................................................................. 13 
2.6 
Data monitoring committee............................................................................................................ 13 
2.7 
Reporting of the main part of the trial .......................................................................................... 13 
2.8 
Changes to Protocol-planned Analyses ............................................................................................. 13 
3 Supporting Documentation ...................................................................................................................... 15 
3.1 
Appendix 1: List of abbreviations ..................................................................................................... 15 
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Table of figures 
 
Page 
Figure 1-1 
Schematic diagram of the trial design .......................................................................................... 9 
Figure 1-2. Half-width of 95% CI for treatment difference on HbA1c change obtained with 80% 
power versus sample size by standard deviation (std). ......................................................... 10 
 
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Table of tables 
 
Page 
Table 1-1 Attributes for the estimands ............................................................................................................... 7 
 
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Statistical Analysis Plan 
 
Date: 
12 March 2022 Novo Nordisk 
Study ID: NN9838-4862 
Version: 
1.0 
IND Number: 155796 
Status: 
Final 
IND Number: Universal Trial Number: 
U1111-1266-2931  
Page: 
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Version History 
 
This Statistical Analysis Plan (SAP) for study NN9838-4862 is based on the protocol version 2.0 
dated 16 June 2021. 
SAP Version 
Date 
Change 
Rationale 
1.0 
12-Mar-2022 
Not Applicable 
Original version 
 
 
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Statistical Analysis Plan 
 
Date: 
12 March 2022 Novo Nordisk 
Study ID: NN9838-4862 
Version: 
1.0 
IND Number: 155796 
Status: 
Final 
IND Number: Universal Trial Number: 
U1111-1266-2931  
Page: 
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diabetic). A hypothetical strategy is applied for both intercurrent event of premature treatment 
discontinuation and initiation of rescue medication. The population level summary is difference in 
means. 
The primary estimand estimates the achievable treatment effect without the confounding of 
treatment discontinuation and initiation of rescue intervention. This approach is considered relevant 
for evaluating a mechanistic effect.  
Additional estimand for the primary objective 
The additional estimand addresses a different question of interest: What is the effect of 
co-administered semaglutide and cagrilintide versus semaglutide on HbA1c (%-points) from 
baseline to week 32 in subjects with T2D inadequately controlled with metformin with or without 
SGLT2 inhibitor, regardless of premature treatment discontinuation or initiation of rescue 
medication (anti-diabetic).  
For the additional estimand, the treatment policy strategy is applied for both the intercurrent event 
of initiation of premature treatment discontinuation and rescue medication. The population-level 
summary is difference in means. Results based on the additional estimand are expected to mirror the 
clinical practice for the population scenario because the estimand considers both the efficacy and 
tolerability of treatments.
Table 1-1 Attributes for the estimands 
Estimand 
category 
Treatment condition 
Variable/
Endpoint 
Population 
of interest 
Intercurrent event 
strategy 
Population-level 
summary measure 
Primary 
The effect of co-
administered semaglutide 
and cagrilintide versus 
semaglutide on HbA1c, 
both as add-on to 
metformin with or without 
SGLT2 inhibitor and 
without rescue medication 
Change in 
HbA1c 
(%-point) 
from 
baseline to 
week 32 
Subjects 
with T2D 
inadequately 
controlled on 
metformin 
with or 
without 
SGLT2 
inhibitor 
Hypothetical 
strategy for 
• Initiation of any
rescue medication
• Treatment
discontinuation
Difference in 
means 
Additional 
The effect of co-
administered semaglutide 
and cagrilintide versus 
semaglutide on HbA1c, 
both as add-on to 
metformin with or without 
SGLT2 inhibitor 
Treatment policy 
strategy for 
• Initiation of any
rescue medication
•Treatment
discontinuation
1.2 
Primary, secondary and exploratory endpoint(s) 
1.2.1 
Primary endpoint 
Endpoint title 
Time frame 
Unit 
Change in HbA1c  
From baseline (week 0) to week 32 
%-point 
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Statistical Analysis Plan 
 
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12 March 2022 Novo Nordisk 
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IND Number: 155796 
Status: 
Final 
IND Number: Universal Trial Number: 
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1.2.2 
Secondary endpoints 
1.2.2.1 
Confirmatory secondary endpoints 
Not applicable for this trial. 
1.2.2.2 
Supportive secondary endpoints 
Endpoint title 
Time frame 
Unit 
Efficacy 
Change in fasting plasma glucose (FPG) 
From baseline (week 0) to week 32 
mmol/L and mg/dL 
CGM: Change in mean glucose 
From baseline (week 0) to week 32 
mmol/L and mg/dL 
CGM: Time above range (TAR) >10.0 
mmol/L (>180 mg/dL) 
At week 32 
% of readings 
CGM: Time in range (TIR) 3.9–10.0 
mmol/L (70–180 mg/dL) 
At week 32 
% of readings 
Change in body weight 
From baseline (week 0) to week 32 
% 
Change in body weight 
From baseline (week 0) to week 32 
Kg 
Safety 
Number of treatment emergent adverse 
events (TEAEs) 
From baseline (week 0) to week 37 
Count 
Number of clinically significant 
hypoglycaemic episodes (level 2) 
(<3.0mmol/L (54mg/dL), confirmed by 
BG meter) or severe hypoglycaemic 
episodes (level 3) 
From baseline (week 0) to week 37 
Count of episodes 
For the secondary efficacy endpoints change in fasting plasma glucose (FPG), CGM: Change in 
mean glucose, and change in body weight the primary and additional estimands are modified by 
substituting the relevant assessment for HbA1c.  
1.3 
Study Design 
Approximately 90 eligible subjects with T2D will be randomised to 1 of the 3 treatment arms in a 
ratio of 1:1:1. Randomisation will be stratified according to the SGLT2 inhibitor treatment 
(Yes/No). The trial design is illustrated in Figure 1-1. An interim analysis is planned when last 
subject has concluded the week 20 visit 12. Further details are found in the study protocol.  
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Statistical Analysis Plan 
 
Date: 
12 March 2022 Novo Nordisk 
Study ID: NN9838-4862 
Version: 
1.0 
IND Number: 155796 
Status: 
Final 
IND Number: Universal Trial Number: 
U1111-1266-2931  
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Figure 1-1 
Schematic diagram of the trial design 
2 
Statistical considerations 
2.1 
Statistical hypotheses 
No confirmatory statistical hypothesis testing will be done in this trial. Treatment differences will 
be reported with 2-sided 95% confidence intervals. 
2.2 
Sample size determination 
As the present study is exploratory the sample size calculation is not based on confirmatory testing 
but aims at quantifying the magnitude of expected variation in the treatment difference for the 
primary endpoint supporting the primary objective. For the primary estimand a standard deviation 
of 0.9 (STEP 2) or 1 is assumed for HbA1c change from baseline to week 32. With 30 randomised 
subjects per treatment arm approximately 80% probability is achieved for obtaining a 95% 
confidence interval of the treatment difference with half-width 0.5 and 0.56 %-points, respectively. 
The achievable half-width (with roughly 80% probability) versus sample size is shown in  
Figure 1-2 for different choices of sample size. Based on this, a sample size of 30 randomised 
subjects per treatment arm, i.e. a total of 90 randomised subjects, is considered sufficient. 
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Statistical Analysis Plan 
 
Date: 
12 March 2022 Novo Nordisk 
Study ID: NN9838-4862 
Version: 
1.0 
IND Number: 155796 
Status: 
Final 
IND Number: Universal Trial Number: 
U1111-1266-2931  
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Figure 1-2. Half-width of 95% CI for treatment difference on HbA1c change obtained with 
80% power versus sample size by standard deviation (std). 
2.3 
Populations for analyses  
The following populations are defined: 
Population 
Description 
Full analysis set (FAS) 
All subjects randomised. 
Safety analysis set (SAS) 
All randomised subjects and who take at least 1 dose of trial product. 
The subjects or observations to be excluded from the analysis sets and the reasons for their 
exclusion must be documented before unblinding and will be described in the CTR. Efficacy 
endpoints will be analysed using the FAS and safety endpoints will be analysed using the SAS. For 
both the primary estimand and the additional estimand, subjects contribute to the analysis according 
to the randomised treatment. 
Three observation periods are defined for each subject: 
•
The in-trial period is defined as the time interval from date of randomisation to date of last
contact with trial site.
•
The on-treatment period is a subset of the ‘in-trial’ observation period and represents the
time period where subjects are considered exposed to trial product. The observation period
starts at the date of first dose of trial product and ends at the first date of any of the
following:
o
The date of last dose of trial product +35 days for AEs and hypoglycaemic episodes/
+ 14 days for other endpoints
o
The end-date for the ‘in-trial’ observation period
The on-treatment period will be used for reporting AEs and hypoglycaemic episodes. 
The on-treatment without rescue medication period is a subset of the ‘on-treatment’ observation 
period and represents the time period where subjects are considered exposed to trial product but 
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Statistical Analysis Plan 
 
Date: 
12 March 2022 Novo Nordisk 
Study ID: NN9838-4862 
Version: 
1.0 
IND Number: 155796 
Status: 
Final 
IND Number: Universal Trial Number: 
U1111-1266-2931  
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have not initiated any rescue medications. The observation period starts at the date of first dose of 
trial product and ends at the first date of any of the following: 
1) Initiation of rescue medication
2) The last date of the on-treatment period
The in-trial and on-treatment periods define the patient years of observation (PYO) and patient 
years of exposure (PYE), respectively, as the total time duration in the periods. 
Data points collected outside an observation period will not be included in the analysis. Baseline 
data will always be included in an observation period. 
For the primary estimand, the on-treatment without rescue medication period will be used for 
reporting of efficacy endpoints. For the additional estimand, data from the in-trial observation 
period is used. 
2.4 
Statistical analyses 
2.4.1 
General considerations 
Handling of missing baseline data 
The latest available measurement at or prior to randomisation is used as the baseline measurement. 
If no measurements have been obtained at or prior to randomisation, the mean value at 
randomisation across all subjects is used as the baseline value. 
2.4.2 
Primary endpoint 
Analysis addressing the primary estimand 
HbA1c (%-point) change from baseline will be analysed using a mixed model for repeated 
measurements (MMRM). Week 32 assessments for retrieved drop-outs are not used in this analysis. 
The MMRM will use assessments only from subjects who are taking the randomised treatment until 
end of treatment or until first discontinuation of randomised treatment defined as 2 consecutive 
missed doses. The derived date of the second consecutive missed dose will be used as the latest date 
for using assessments in this MMRM. For subjects who initiate rescue medication before 
completion or first discontinuation of randomised treatment, the date of starting rescue medication 
will be used as latest date for using assessments in this MMRM. The MMRM will be fitted using 
HbA1c change with treatment and stratification factor as factors and baseline HbA1c as covariate – 
all nested within visit. An unstructured covariance matrix for measurements within the same subject 
will be employed. If this model is not feasible, the model will be simplified by first excluding the 
stratification factor from the model and, if necessary, using a Toeplitz (second choice) or compound 
symmetry (third choice) covariance matrix.  
The present MMRM model will be used to derive estimates of treatment differences with 95% 
confidence intervals for cagrilintide 2.4 mg/semaglutide 2.4 mg versus semaglutide 2.4 mg (primary 
objective) and versus cagrilintide 2.4 mg (secondary objective) together with p-values for the 2-
sided tests of no treatment differences. 
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Statistical Analysis Plan 
 
Date: 
12 March 2022 Novo Nordisk 
Study ID: NN9838-4862 
Version: 
1.0 
IND Number: 155796 
Status: 
Final 
IND Number: Universal Trial Number: 
U1111-1266-2931  
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Analyses addressing the additional estimand 
The analysis model for change in HbA1c (%-point) is an ANCOVA with randomised treatment and 
stratification factor as factors and baseline HbA1c as a covariate. The additional estimand will be 
based on the FAS using all available week 32 measurements from the in-trial observation period. 
Missing week 32 data will be imputed from retrieved subjects off treatment by multiple imputation 
(RDMI) using an ANCOVA model with the same factors and covariate as for the analysis model. If 
necessary for feasibility, this model will be simplified by successively excluding the stratification 
factor and treatment factor until convergence is reached. If the reduced RDMI model is infeasible 
an MMRM model similar to the one used for the primary estimand but including all data regardless 
of treatment adherence or rescue medication will be used. 
The present model will be used to derive estimates of treatment differences with 95% confidence 
intervals for cagrilintide 2.4 mg/semaglutide 2.4 mg versus semaglutide 2.4 mg and versus 
cagrilintide 2.4 mg together with p-values for the 2-sided tests of no treatment differences. 
2.4.3 
Secondary endpoint(s) 
2.4.3.1 
Confirmatory secondary endpoint(s) 
Not applicable for this trial. 
2.4.3.2 
Supportive secondary endpoints 
CGM endpoints 'time in target range' and 'time above target range' will be calculated as 100 times 
the number of recorded measurements in the given glycaemic range, divided by the total number of 
recorded measurements. Prior to calculation of CGM endpoints extremely low values will be 
handled according to below rules. 
Extremely low CGM values: 
•
Values < 14 mg/dL will be set to missing
•
Values between 14 and 39 mg/dL will be set to 39
2.4.4 
Other safety analyses 
All safety analyses will be made on the safety analysis set. The standard safety assessments (AEs, 
safety laboratory parameters, vital signs, etc.) will be reported descriptively, including any notable 
changes of clinical interest in laboratory parameters. 
2.4.5 
Other analyses 
 Not applicable for this trial. 
2.4.5.1 
Pharmacokinetic modelling 
Data from the trial may be used for exploratory pharmacokinetic analysis as needed. 
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Statistical Analysis Plan 
 
Date: 
12 March 2022 Novo Nordisk 
Study ID: NN9838-4862 
Version: 
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IND Number: 155796 
Status: 
Final 
IND Number: Universal Trial Number: 
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2.5 
Interim analyses 
In order to inform early phase 3 stop/go decision and initiate potential phase 3 planning, interim 
analyses are planned at week 20 and may include the following endpoints: 
•
Change from baseline to week 20 in HbA1c
•
Change from baseline to week 20 in FPG
•
CGM endpoints
o
Mean glucose change from baseline to week 20
o
Time in target range at week 20
o
Time above target range at week 20.
•
Change from baseline to week 20 in body weight
•
Number of treatment emergent adverse events (TEAEs)
•
Number of clinically significant hypoglycaemic episodes (level 2) (<3.0mmol/L (54mg/dL),
confirmed by BG meter) or severe hypoglycaemic episodes (level 3)
In addition the following parameters may be assessed by descriptive statistics: 
•
Vital signs
o
Systolic blood pressure
o
Diastolic blood pressure
o
Pulse
Statistical analyses during the interim will be based on the primary estimand. The above lab 
parameters, vital signs, adverse events and hypoglycaemic episodes are summarised using 
descriptive statistics. 
A minimum number of Novo Nordisk personnel will be unblinded to perform the interim 
evaluations. After unblinding, these people cannot be involved in daily trial activities until DBL. No 
change in trial design can occur and the trial will not be stopped for either positive efficacy or 
futility at the interim evaluations. It is not considered a protocol deviation if an interim analysis is 
not performed. Further information on the interim evaluations will be specified in an interim charter 
before unblinding.  
2.6 
Data monitoring committee 
Not applicable for this trial. 
2.7 
Reporting of the main part of the trial 
A DBL is planned shortly after last subject last visit. The trial will be reported after this DBL. 
2.8 
Changes to Protocol-planned Analyses 
•
No interim is planned for visit week 32
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Statistical Analysis Plan 
 
Date: 
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Version: 
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IND Number: 155796 
Status: 
Final 
IND Number: Universal Trial Number: 
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•
The option of using a Toeplitz covariance matrix in the primary MMRM model in case the
model can not converge with an unstructured covariance matrix is added.
•
The imputation model for RDMI may be further reduced: If necessary for feasibility, this
model will be simplified by successively excluding the stratification factor and treatment
factor until convergence is reached. If the reduced RDMI model is infeasible an MMRM
model similar to the one used for the primary estimand but including all data regardless of
treatment adherence or rescue medication will be used.
•
A short description of estimands and statistical analyses of secondary efficacy endpoints is
added.
•
Minor editorial changes are made
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Statistical Analysis Plan 
 
Date: 
12 March 2022 Novo Nordisk 
Study ID: NN9838-4862 
Version: 
1.0 
IND Number: 155796 
Status: 
Final 
IND Number: Universal Trial Number: 
U1111-1266-2931  
Page: 
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3 
Supporting Documentation 
 
 
3.1 
Appendix 1: List of abbreviations 
 
AE 
adverse events 
ANCOVA 
analysis of covariance 
CI 
confidence interval 
DBL 
database lock 
FAS 
full analysis set 
MMRM 
mixed model for repeated measurements 
RDMI 
Retrieved drop-outs multiple imputation 
SAP 
statistical analysis plan 
SAS  
safety analysis set 
std 
standard deviation 
TEAE 
treatment emergent adverse events 
TFL  
tables, figures and listings 
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Signature Page for VV-TMF-5139062 v1.0
Signature Page for VV-TMF-5139062 v1.0
Reason for signing: Approved
Name:
Role: Author
Date of signature: 14-Mar-2022 13:12:01
GMT+0000
 SAP  NN9838-4862 Statistical Analysis Plan
NN9838-4862
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CONFIDENTIAL


Cagrilintide and semaglutide 
Date: 
01 November 2022 Novo Nordisk 
Trial ID: NN9838-4862 
Version: 
1.0 
Clinical Trial Report 
Status: 
Final 
MedDRA searches 
Page: 
1 of 7 
 
Clinical Trial Report
Trial ID: NN9838-4862 
MedDRA searches within safety focus areas 
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties. 
VV-CLIN-150308
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CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Cagrilintide and semaglutide 
 
Date: 
01 November 2022 Novo Nordisk 
Trial ID: NN9838-4862 
Version: 
1.0 
Clinical Trial Report 
Status: 
Final 
MedDRA searches 
Page: 
2 of 7 
 
Table of contents  
 
Page  
Table of contents ............................................................................................................................................... 2 
List of abbreviations and definitions of terms ............................................................................................... 3 
1 MedDRA searches for safety focus areas in study NN9838-4862 ........................................................... 4 
2 Abuse and misuse ........................................................................................................................................ 4 
3 Acute gallbladder disease ........................................................................................................................... 4 
4 Acute renal failure ....................................................................................................................................... 4 
5 Acute pancreatitis ........................................................................................................................................ 4 
6 Allergic reactions ......................................................................................................................................... 5 
7 Cardiovascular disorders ........................................................................................................................... 5 
8 COVID-19 .................................................................................................................................................... 5 
9 Gastrointestinal disorders .......................................................................................................................... 5 
10 Hepatic disorders......................................................................................................................................... 5 
11 Injection site reaction .................................................................................................................................. 6 
12 Medication error ......................................................................................................................................... 6 
13 Neoplasms .................................................................................................................................................... 6 
14 Rare events ................................................................................................................................................... 6 
15 Retinal disorders ......................................................................................................................................... 7 
16 Suspected transmission of infectious agent via trial product .................................................................. 7 
 
 
 
VV-CLIN-150308
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CONFIDENTIAL


Cagrilintide and semaglutide 
 
Date: 
01 November 2022 Novo Nordisk 
Trial ID: NN9838-4862 
Version: 
1.0 
Clinical Trial Report 
Status: 
Final 
MedDRA searches 
Page: 
3 of 7 
 
List of abbreviations and definitions of terms  
HLT 
high level term 
MedDRA 
Medical Dictionary for Regulatory Activities 
NEC 
not elsewhere classified 
NNMQ 
Novo Nordisk MedDRA query 
PT 
preferred term 
SMQ 
standardised MedDRA query 
SOC 
system organ class 
 
 
VV-CLIN-150308
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CONFIDENTIAL


Cagrilintide and semaglutide 
 
Date: 
01 November 2022 Novo Nordisk 
Trial ID: NN9838-4862 
Version: 
1.0 
Clinical Trial Report 
Status: 
Final 
MedDRA searches 
Page: 
4 of 7 
 
1 
MedDRA searches for safety focus areas in study NN9838-4862  
The MedDRA search strings in this document (ordered alphabetically) were used for the 
NN9838-4862 clinical trial report. The MedDRA version used was 25.0. 
 
2 
Abuse and misuse  
Custom query (NNMQ Abuse and Misuse): 
 SMQ Drug abuse and dependence (contains only narrow terms) 
 HLT Intentional product misuses 
 Additional PTs 
o Poisoning deliberate 
o Intentional dose omission 
o Performance enhancing product use 
o Completed suicide 
o Intentional self-injury 
o Suicide attempt 
o Assisted suicide 
o Suspected suicide attempt 
o Suspected suicide.   
 
3 
Acute gallbladder disease  
Custom query (NNMQ Gallbladder-related disorders) (narrow terms only): 
 SMQ Infectious biliary disorders 
 SMQ Functional, inflammatory and gallstone related biliary disorders including all sub-SMQs 
(Biliary tract disorders, Biliary system related investigations, signs and symptoms, Gallbladder 
related disorders and Gallstone related disorders) 
 
4 
Acute renal failure  
SMQ Acute renal failure (narrow terms only) 
 
 
5 
Acute pancreatitis  
Custom Query (NNMQ Acute pancreatitis): 
 SMQ Acute pancreatitis (narrow terms only) 
 HLT Acute and chronic pancreatitis (including primary and secondary terms not included in 
the SMQ Acute pancreatitis) 
VV-CLIN-150308
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CONFIDENTIAL


Cagrilintide and semaglutide 
 
Date: 
01 November 2022 Novo Nordisk 
Trial ID: NN9838-4862 
Version: 
1.0 
Clinical Trial Report 
Status: 
Final 
MedDRA searches 
Page: 
5 of 7 
 
6 
Allergic reactions  
Custom Query (NNMQ Allergic reactions) (narrow terms only): 
 SMQ Anaphylactic reaction  
 SMQ Anaphylactic/anaphylactoid shock conditions  
 SMQ Angioedema 
 SMQ Hypersensitivity  
 SMQ Severe cutaneous adverse reactions  
 
7 
Cardiovascular disorders  
Custom Query (NNMQ Cardiovascular disorders) (narrow and broad terms): 
 SMQ Central nervous system vascular disorders 
 SMQ Vasculitis  
 SMQ Ischaemic heart disease  
 SMQ Cardiac arrhythmias  
 SMQ Cardiac failure  
 SMQ Cardiomyopathy  
 SMQ Embolic and thrombotic events including sub-SMQs: Embolic and thrombotic events, 
arterial, Embolic and thrombotic events, venous, and Embolic and thrombotic events, vessel 
type unspecified and mixed arterial and venous 
 SMQ Shock including sub-SMQs: Anaphylactic/anaphylactoid shock conditions, 
Hypoglycaemic and neurogenic shock conditions, Hypovolaemic shock conditions, Shock-
associated circulatory or cardiac conditions (excl. torsade de pointes), Torsade de pointes, 
shock-associated conditions, and Toxic-septic shock conditions 
 SMQ Torsade de pointes/QT prolongation 
 
 
8 
COVID-19  
SMQ COVID-19 (narrow and broad terms) 
 
9 
Gastrointestinal disorders  
Custom query (NNMQ Gastrointestinal disorders SOC): 
 SOC Gastrointestinal disorders (primary terms only) 
 
10 Hepatic disorders  
SMQ Drug related hepatic disorders, comprehensive search (narrow and broad terms) 
 
VV-CLIN-150308
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CONFIDENTIAL


Cagrilintide and semaglutide 
 
Date: 
01 November 2022 Novo Nordisk 
Trial ID: NN9838-4862 
Version: 
1.0 
Clinical Trial Report 
Status: 
Final 
MedDRA searches 
Page: 
6 of 7 
 
11 Injection site reaction  
Custom Query (NNMQ Injection site reactions):   
 HLT Administration site reactions NEC (primary and secondary terms) 
 HLT Application and instillation site reactions (primary and secondary terms) 
 HLT Infusion site reactions (primary and secondary terms) 
 HLT Injection site reactions (primary and secondary terms) 
 
12 Medication error  
SMQ Medication errors (narrow and broad terms) 
 
13 Neoplasms  
Custom Query (NNMQ Neoplasm): 
 SMQ Biliary neoplasms (narrow and broad terms) 
 SMQ Breast neoplasms, malignant and unspecified (narrow and broad terms) 
 SMQ Liver neoplasms, benign (incl. cysts and polyps)(narrow and broad terms) 
 SMQ Liver neoplasms, malignant and unspecified (narrow and broad terms) 
 SMQ Malignancies (narrow and broad terms) 
 SMQ Malignant lymphomas (narrow and broad terms) 
 SMQ Oropharyngeal neoplasms (narrow and broad terms) 
 SMQ Ovarian neoplasms, malignant and unspecified (narrow and broad terms) 
 SMQ Premalignant disorders (narrow and broad terms) 
 SMQ Prostate neoplasms, malignant and unspecified (narrow and broad terms) 
 SMQ Skin neoplasms, malignant and unspecified (narrow and broad terms) 
 SMQ Uterine and fallopian tube neoplasms, malignant and unspecified (narrow and broad 
terms) 
 SOC Neoplasms benign, malignant and unspecified (incl. cysts and polyps) (primary and 
secondary terms)  
 
14 Rare events  
Custom Query (NNMQ Rare events), excluding PTs from other safety focus areas: 
 SMQ Agranulocytosis (narrow terms only) 
 SMQ Cholestasis and jaundice of hepatic origin (narrow and broad terms) 
 SMQ Guillain-Barre syndrome (narrow terms only) 
 SMQ Haematopoietic cytopenias affecting more than one type of blood cell (narrow and 
broad terms)  
 SMQ Haematopoietic leukopenia (narrow and broad terms)  
 SMQ Haematopoietic thrombocytopenia (narrow terms only)  
VV-CLIN-150308
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CONFIDENTIAL


Cagrilintide and semaglutide 
 
Date: 
01 November 2022 Novo Nordisk 
Trial ID: NN9838-4862 
Version: 
1.0 
Clinical Trial Report 
Status: 
Final 
MedDRA searches 
Page: 
7 of 7 
 
 SMQ Hepatic failure, fibrosis and cirrhosis and other liver damage-related conditions 
(narrow terms only)  
 SMQ Hepatitis, non-infectious (narrow and broad terms)  
 SMQ Interstitial lung disease (narrow terms only)  
 SMQ Neuroleptic malignant syndrome (narrow terms only)  
 SMQ Noninfectious myocarditis/pericarditis (narrow terms only)  
 SMQ Pseudomembranous colitis (narrow terms only)  
 SMQ Retroperitoneal fibrosis (narrow terms only)   
 SMQ Severe cutaneous adverse reactions (narrow terms only) 
 SOCs: Congenital, familial and genetic disorders (contains only primary terms) 
 HLTs: Angioedemas (primary and secondary terms), Glomerulonephritis and nephrotic 
syndrome (primary and secondary terms), Nephritis NEC (primary and secondary terms).  
 PTs: Disseminated intravascular coagulation, Multiple organ dysfunction syndrome and 
Hepatic lymphocytic infiltration 
 
15 Retinal disorders  
Custom Query (NNMQ Retinal disorders): 
 SMQ Retinal disorders (narrow terms only) 
 HLT Visual impairment and blindness (excluding colour blindness) (primary terms only) 
 
16 Suspected transmission of infectious agent via trial product  
 
Custom Query (NNMQ Transmission): 
 HLT Infectious disorders carrier (primary terms only) 
 HLT Infectious transmissions (primary terms only) 
 
 
 
 
 
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