A 26-week Trial Comparing the Effect and Safety of Once Weekly Insulin Icodec and Once Daily Insulin Glargine 100 Units/mL, Both in Combination With Bolus Insulin With or Without Non-insulin Anti-diabetic Drugs, in Subjects With Type 2 Diabetes on a Basal-bolus Regimen
Phase: PHASE3
Conditions: Diabetes Mellitus, Type 2
Sponsor: Novo Nordisk A/S

C o ver P a ge  f or Pr ot oc ol  
 
S p o ns or na me:  
N o v o N or dis k A/ S  
N C T n u m ber  
N C T 0 4 8 8 0 8 5 0  
S p o ns or t rial I D: 
N N 1 4 3 6 -4 4 8 0  
Official title of st u d y:  
A 2 6 -wee k trial c o m pari n g t he effect a n d safet y of o nce 
wee kl y i ns uli n ic o dec a n d o nce dail y i ns uli n glar gi ne 1 0 0 
u nits/ m L, b ot h i n c o m bi nati o n wit h b ol us i ns uli n wit h or 
wit h o ut n o n-i ns uli n a nti- dia betic dr u gs, i n s u bjects wit h t y pe 2 
dia betes o n a bas al -b ol us re gi me n.  
D oc u me nt date: *  
1 4 A pril , 2 0 21  
    
   * D oc u me nt date refers t o t he date o n w hic h t he d oc u me nt was m ost rece ntl y u p date d.  
   N ote: T he date i n t he hea der of Pa ge 2 is t he date of c o m pilati o n of t he d oc u me nts, a n d n ot of a n u p date t o c o nte nt.  

Li n k
Li n k
List of c o nte nts
Pr ot oc ol ...............................................................................................................................................
Pr ot oc ol att ac h me nt ...........................................................................................................................
Date:
N o v o N or di s k
Versi o n:
Stat us:
I ns uli n ic o dec
Trial I D: N N 1 4 3 6 4 4 8 0 O N W A R D S 4
Cli nical Trial Re p ort
A p pe n di x 1 6. 1. 1
0 8 A u g ust 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
 
 
 
 
 
Re d acte d pr ot oc ol  
I ncl u des re d acti o n of pers o n al i de ntifi a ble i nf or m ati o n o nly. 
 
 
 
. 
 
 

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
1  of 1 0 2  
Pr ot oc ol
Pr ot oc ol titl e:  A 2 6 -w ee k tri al c o m p ari n g t he effect a n d s afet y of o nce wee kl y i ns uli n ic o dec 
a n d o nce d ail y i ns uli n gl ar gi ne 1 0 0 u nits/ m L, b ot h i n c o m bi n ati o n wit h b ol us 
i ns uli n wit h or wit h o ut n o n-i ns uli n a nti-di a betic dr u gs, i n s u bjects wit h t y pe 2 
di a betes o n a b as al -b ol us re gi me n.  
O N W A R D S 4  
S u bst a nce: I ns uli n ic o dec  
U ni vers al Tri al N u m ber:  U 1 1 1 1 -1 2 4 7 -5 2 6 9  
E u dr a C T N u m ber: 2 0 2 0 -0 0 0 4 7 4 -1 6 
I N D N u m ber: 1 3 7 4 0 6  
Tri al p h ase:  3a  
  
  
   
  
   
  
  
  
  
  
  
  
 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
1
 
-
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6
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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 o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
2  of 1 0 2  
P r ot oc ol a me n d me nt  s u m m ar y of c h a n ges t a ble 
D O C U M E N T HI S T O R Y  
D oc u me nt versi o n  
D ate  
A p plic a ble i n c o u ntr y( -ies) a n d/ or 
site(s)  
Pr ot oc ol versi o n 4. 0  
1 4  A pril 2 0 2 1  
All c o u ntries  
Pr ot oc ol versi o n 3 . 0 
3 0 N o ve m ber 2 0 2 0  
All c o u ntries  
Ori gi nal pr ot oc ol versi o n 2 . 0 
0 5 A u g ust 2 0 2 0  
All c o u ntries  
Pr ot oc ol ve rsi o n 4 . 0 (1 4  A pril 2 0 2 1 ) 
T his a me n d me nt is c o nsi dere d t o be n o n -s u bsta ntial base d o n t he criteria s et f ort h i n Article 1 0(a) of 
Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n 1, beca use 
it neit her si g nifica ntl y i m pacts t he safet y n or p h ysical/ me ntal i nte grit y of s u bjects n or t he scie ntific 
val ue of t he trial.  
O ver all r ati o n ale f or pre p ari n g pr ot oc ol, versi o n 4 . 0: 
T he pr ot oc ol has bee n a me n de d t o  c orrect t y p os a n d  e x cl u de J a pa n f r o m c o-partici pat i o n i n cli nical 
trials e val uati n g me dici n al pr o d ucts f or pre ve nti o n or treat me nt of C O VI D-1 9 disease or 
p osti nfecti o us c o n diti o ns  as per l ocal healt h a ut h orit y re q uest.  
Secti o n # a n d n a me  
Descri pti o n of c h a n ge  
Brief r ati o n ale  
8. 2. 2  P h ysical e xa mi nati o ns  
“t he B MI will be calc ulate d i n t he 
e C R F” is c orrecte d t o “ t he B MI 
s h o ul d be  calc ulate d a n d  rec or de d i n 
s u bj ect’s me dical rec or ds” 
C orrecti o n  
1 0. 6 A p pe n di x 6: Rete nti o n of h u ma n 
bi osa m ples  
“I n case of a s yste matic 
h y perse nsiti vit y reacti o n” is c orrecte d 
t o “I n case of a s yste mic 
h y perse nsiti vit y reacti o n ”  
C orrecti o n of t y p o  
1 0. 8 A p pe n di x 8 Titrati o n g ui deli ne  
T a ble f or V 2 a n d V 3 wee kl y d ose:  
F or “ T otal dail y d ose bef ore 
ra n d o misati o n ( U): 8 2 “ 
“V 2 i ns uli n ic o dec d ose ( U) ”: 9 6 0 is 
correcte d t o 8 6 0  
C orrecti o n of t y p o  
1 0. 9 A p pe n di x 9: C o u ntr y/ Re gi o n -
s pecific re q uire me nts 
F o ot n otes relate d t o c o -partici pati o n 
i n cli nical trial f or C O VI D-1 9 i n 
e xcl usi o n criteria 4 a n d 
disc o nti n uati o n criteria 4 are n ot 
a p plica ble f or J a pa n.  
T o meet l ocal J a pa nese Healt h 
A ut h orit y ( P M D A) re q uest.  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
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V V- T M F- 6 1 0 0 2
1 0 2
 of
2
 
-
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6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
3  of 1 0 2  
Secti o n # a n d n a me  
Descri pti o n of c h a n ge  
Brief r ati o n ale  
1 0. 1 1 A p pe n di x 1 1 Pr ot oc ol 
a me n d me nt hist or y  
A me n d me nt hist or y is u p date d b y 
m o vi n g pr ot oc ol v 3 . 0 hist or y t o 
a p pe n di x 1 1  
D ue t o t he ne w pr ot oc ol v 4 . 0 
1 1 Refere nces  
Refere nce  3 6  t o C T F G g ui da nce is 
a d de d i n A p pe n di x 4. 
Refere nce 8  is u p date d t o t he l atest 
versi o n 2. 0  
Refere nce u p dates  
. 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
3
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4  of 1 0 2  
 
Ta ble of C o nte nts    
 
P a ge  
P r ot oc ol ame n d me nt  s u m m ar y of c h a n ges t a ble ........................................................................................... 2  
T a ble of C o nte nts .............................................................................................................................................. 4  
1  
P r ot oc ol s u m m ar y  ..................................................................................................................................... 8  
1. 1  
S y n o psis  ........................................................................................................................................... 8  
1. 2  
Fl o wc hart  ....................................................................................................................................... 1 1  
1. 3  
Fl o wc hart –  p h o ne c o ntacts  ........................................................................................................... 1 4  
2  
I ntr o d ucti o n ............................................................................................................................................. 1 5  
2. 1  
Trial rati o nale  ................................................................................................................................. 1 5  
2. 2  
Bac k gr o u n d  .................................................................................................................................... 1 6  
2. 3  
Be nefit -ris k assess me nt .................................................................................................................. 1 7  
2. 3. 1  
Ris k assess me nt  ............................................................................................................... 1 7  
2. 3. 2  
Be nefit assess me nt  ........................................................................................................... 2 0  
2. 3. 3  
O verall be nefit -ris k c o ncl usi o n ....................................................................................... 2 1  
3  
O bjecti ves a n d e n d p oi nts  ........................................................................................................................ 2 1  
3. 1  
Pri mar y, sec o n dar y a n d e x pl orat or y o bj ecti ve a n d esti ma n d ......................................................... 2 1  
3. 1. 1  
Pri mar y o bj ecti ve  ............................................................................................................. 2 1  
3. 1. 2  
Sec o n dar y o bj ecti ve  ......................................................................................................... 2 2  
3. 1. 3  
Esti ma n d  .......................................................................................................................... 2 2  
3. 2  
Pri mar y, sec o n dar y a n d e x pl orat or y e n d p oi nts  .............................................................................. 2 2  
3. 2. 1  
Pri mar y e n d p oi nt  ............................................................................................................. 2 2  
3. 2. 2  
Sec o n dar y e n d p oi nts  ........................................................................................................ 2 2  
3. 2. 2. 1  
C o nfir mat or y sec o n dar y e n d p oi nts  ................................................................. 2 2  
3. 2. 2. 2  
S u p p orti ve sec o n dar y e n d p oi nts  ..................................................................... 2 2  
3. 2. 3  
E x pl orat or y e n d p oi nts  ..................................................................................................... 2 3  
4  
Tri a l desi g n .............................................................................................................................................. 2 3  
4. 1  
O verall desi g n  ................................................................................................................................ 2 3  
4. 2  
Scie ntific rati o nale f or trial desi g n  ................................................................................................. 2 4  
4. 2. 1  
S u bj ect i n p ut i nt o desi g n  ................................................................................................. 2 5  
4. 3  
J ustificati o n f or d ose ...................................................................................................................... 2 6  
4. 4  
E n d of trial defi niti o n  ..................................................................................................................... 2 6  
5  
Tri al p o p ul ati o n  ....................................................................................................................................... 2 6  
5. 1  
I ncl usi o n criteria ............................................................................................................................ 2 7  
5. 2  
E xcl usi o n criteria  ........................................................................................................................... 2 7  
5. 3  
Lifest yle c o nsi derati o ns  ................................................................................................................. 2 8  
5. 3. 1  
Meals a n d dietar y restricti o ns  .......................................................................................... 2 8  
5. 3. 2  
Caffei ne, alc o h ol a n d t o bacc o  ......................................................................................... 2 9  
5. 3. 3  
P h ysical acti vit y ............................................................................................................... 2 9  
5. 4  
Scree n fail ures  ................................................................................................................................ 2 9  
5. 5  
R u n -i n criteria, ra n d o misati o n criteria a n d d osi n g da y criteria ...................................................... 2 9  
6  
Tre at me nts  ............................................................................................................................................... 2 9  
6. 1  
Treat me nts a d mi nistere d  ................................................................................................................ 2 9  
6. 1. 1  
Me dical de vices  ............................................................................................................... 3 1  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
4
 
-
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6
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C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5  of 1 0 2  
 
6. 1. 1. 1  
I n vesti gati o nal me dical de vice ........................................................................ 3 1  
6. 1. 1. 2  
N o n -i n vesti gati o nal me dical de vices .............................................................. 3 2  
6. 2  
Pre parati o n/ ha n dli n g/st ora ge/acc o u nta bilit y  .................................................................................. 3 2  
6. 3  
Meas ures t o mi ni mise bias: Ra n d o misati o n a n d bli n di n g  ............................................................. 3 3  
6. 4  
Treat me nt c o m plia nce  .................................................................................................................... 3 3  
6. 5  
C o nc o mita nt me dicati o n  ................................................................................................................ 3 3  
6. 5. 1  
Resc ue me dicati o n or Resc ue t hera p y  ............................................................................. 3 4  
6. 6  
D ose m o dificati o n  .......................................................................................................................... 3 4  
6. 6. 1  
D ose e scalati o n trials ....................................................................................................... 3 4  
6. 7  
Treat me nt after e n d of trial  ............................................................................................................ 3 4  
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 4  
7. 1  
Disc o nti n uati o n of trial treat me nt  .................................................................................................. 3 5  
7. 1. 1  
T e m p orar y disc o nti n uati o n of trial treat me nt .................................................................. 3 6  
7. 1. 2  
Resc ue criteria  ................................................................................................................. 3 6  
7. 2  
S u bj ect disc o nti n uati o n/ wit h dra wal fr o m t he trial  ......................................................................... 3 6  
7. 2. 1  
Re place me nt of s u bjects  .................................................................................................. 3 7  
7. 3  
L ost t o f oll o w -u p  ........................................................................................................................... 3 7  
8  
Tri al assess me nts a n d pr oce d ures  ......................................................................................................... 3 7  
8. 1  
Efficac y assess me nts  ...................................................................................................................... 3 8  
8. 1. 1  
Self -meas ure d plas ma gl uc ose ( S M P G)  .......................................................................... 3 9  
8. 1. 2  
C o nti n u o us gl uc ose m o nit ori n g  ....................................................................................... 3 9  
8. 1. 3  
Cli nical efficac y la b orat or y assess me nts  ......................................................................... 4 0  
8. 2  
Safet y assess me nts  ......................................................................................................................... 4 0  
8. 2. 1  
I ns uli n d ose ...................................................................................................................... 4 1  
8. 2. 2  
P h ysical e xa mi nati o ns  ..................................................................................................... 4 1  
8. 2. 3  
Vital si g ns  ........................................................................................................................ 4 2  
8. 2. 4  
Electr ocar di o gra ms  .......................................................................................................... 4 2  
8. 2. 5  
E ye e xa mi nati o n  .............................................................................................................. 4 3  
8. 2. 6  
Cli nic al safet y la b orat or y assess me nts  ............................................................................ 4 3  
8. 3  
A d verse e ve nts a n d seri o us a d verse e ve nts  .................................................................................... 4 4  
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  .............................. 4 5  
8. 3. 2  
Met h o d of detecti n g A Es a n d S A Es  ................................................................................ 4 6  
8. 3. 3  
F oll o w -u p of A Es a n d S A Es  ........................................................................................... 4 6  
8. 3. 4  
Re g ulat or y re p orti n g re q uire me nts f or S A Es  .................................................................. 4 6  
8. 3. 5  
Pre g na nc y  ........................................................................................................................ 4 7  
8. 3. 6  
Car di o vasc ular a n d deat h e ve nts  ..................................................................................... 4 7  
8. 3. 7  
Disease -relate d e ve nts an d/ or disease -relate d o utc o mes n ot q ualif yi n g as a n A E or 
S A E  ................................................................................................................................. 4 7  
8. 3. 8  
A d verse e ve nt of s pecial i nterest a .................................................................................... 4 7  
8. 3. 9  
T ec h nical c o m plai nts  ....................................................................................................... 4 7  
8. 4  
Treat me nt of o ver d ose  ................................................................................................................... 4 7  
8. 5  
P har mac o ki netics  ........................................................................................................................... 4 8  
8. 6  
P har mac o d y na mics  ........................................................................................................................ 4 8  
8. 7  
Ge netics  ......................................................................................................................................... 4 9  
8. 8  
Bi o mar kers  ..................................................................................................................................... 4 9  
8. 9  
I m m u n o ge nicit y assess me nts ......................................................................................................... 4 9  
8. 9. 1  
A nti -dr u g a nti b o dies  ........................................................................................................ 4 9  
8. 9. 2  
H y perse nsiti vit y  ............................................................................................................... 4 9  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
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V V- T M F- 6 1 0 0 2
1 0 2
 of
5
 
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6
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C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6  of 1 0 2  
 
8. 1 0  Healt h ec o n o mics  ........................................................................................................................... 5 0  
9  
St atistic al c o nsi der ati o ns  ........................................................................................................................ 5 0  
9. 1  
Statistical h y p ot heses  ..................................................................................................................... 5 0  
9. 2  
Sa m ple size deter mi nati o n  ............................................................................................................. 5 1  
9. 3  
P o p ulati o ns f or a nal yses ................................................................................................................ 5 2  
9. 4  
Statistical a nal yses  ......................................................................................................................... 5 3  
9. 4. 1  
Ge neral c o nsi derati o ns  .................................................................................................... 5 3  
9. 4. 2  
Pri mar y e n d p oi nt  ............................................................................................................. 5 4  
9. 4. 3  
Sec o n dar y e n d p oi nts  ........................................................................................................ 5 5  
9. 4. 3. 1  
C o nfir mat or y sec o n dar y e n d p oi nt  ................................................................... 5 5  
9. 4. 3. 2  
S u p p orti ve sec o n dar y e n d p oi nts  ..................................................................... 5 5  
9. 4. 4  
E x pl orat or y e n d p oi nts  ..................................................................................................... 5 7  
9. 4. 5  
Ot her safet y a nal yses  ....................................................................................................... 5 7  
9. 4. 6  
Ot her a nal yses  ................................................................................................................. 5 7  
9. 4. 6. 1  
P har mac o ki netic m o delli n g  ............................................................................. 5 7  
9. 5  
I nteri m a nal yses ............................................................................................................................. 5 8  
9. 6  
Data m o nit ori n g c o m mittee  ........................................................................................................... 5 8  
9. 7  
Re p orti n g of t he mai n part of t he trial ............................................................................................ 5 8  
1 0  S u p p orti n g d oc u me nt ati o n a n d o per ati o n al c o nsi der ati o ns  ............................................................... 5 9  
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  ............................................. 5 9  
1 0. 1. 1  
Re g ulat or y a n d et hical c o nsi derati o ns  ............................................................................. 5 9  
1 0. 1. 2  
Fi na ncial discl os ure  ......................................................................................................... 5 9  
1 0. 1. 3  
I nf or me d c o nse nt pr ocess ................................................................................................ 6 0  
1 0. 1. 4  
I nf or mati o n t o s u bj ects d uri n g trial ................................................................................. 6 0  
1 0. 1. 5  
Data pr otecti o n  ................................................................................................................ 6 0  
1 0. 1. 6  
C o m mittees str uct ure  ....................................................................................................... 6 1  
1 0. 1. 6 . 1 N o v o N or dis k safet y c o m mittee ...................................................................... 6 1  
1 0. 1. 6. 2  Trial safet y gr o u p  ............................................................................................ 6 1  
1 0. 1. 6. 3  Data m o nit ori n g c o m mittee ............................................................................. 6 1  
1 0. 1. 6. 4  E ve nt a dj u dicati o n c o m mittee  ......................................................................... 6 1  
1 0. 1. 7  
Disse mi nati o n of cli nical trial data  .................................................................................. 6 1  
1 0. 1. 8  
Data q ualit y ass ura nce  ..................................................................................................... 6 2  
1 0. 1. 8. 1  Case re p ort f or ms  ............................................................................................ 6 2  
1 0. 1. 8. 2  M o nit ori n g  ...................................................................................................... 6 2  
1 0. 1. 8. 3  Pr ot oc ol c o m plia nce  ........................................................................................ 6 3  
1 0. 1 . 9 
S o urce d oc u me nts  ............................................................................................................ 6 3  
1 0. 1. 1 0  Rete nti o n of cli nical trial d oc u me ntati o n  ........................................................................ 6 4  
1 0. 1. 1 1  Trial a n d site cl os ure  ....................................................................................................... 6 4  
1 0 . 1. 1 2 Res p o nsi bilities ................................................................................................................ 6 5  
1 0. 1. 1 3  I n de m nit y state me nt ........................................................................................................ 6 5  
1 0. 1. 1 4  P u blicati o n p olic y  ............................................................................................................ 6 6  
1 0. 1. 1 4. 1  C o m m u nicati o n of res ults  ............................................................................... 6 6  
1 0. 1. 1 4. 2  A ut h ors hi p  ....................................................................................................... 6 7  
1 0. 1. 1 4. 3  Sit e -s pecific p u blicati o n(s) b y i n vesti gat or(s)................................................. 6 7  
1 0. 1. 1 4. 4  I n vesti gat or access t o data a n d re vie w of res ults ............................................ 6 7  
1 0. 2  A p pe n di x 2: Cli nical la b orat or y tests  ............................................................................................ 6 8  
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  ............................................................................................................................ 7 0  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
6
 
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6
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C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
7  of 1 0 2  
1 0. 3. 1  
Defi niti o n of A E  .............................................................................................................. 7 0  
1 0. 3. 2  
Defi niti o n of a n S A E  ....................................................................................................... 7 1  
1 0. 3. 3  
Descri pti o n of e ve nt(s) f or a dj u dicati o n a n d A Es re q uiri n g a d diti o nal data 
c ollecti o n ......................................................................................................................... 7 2  
1 0. 3. 4  
Rec or di n g a n d f oll o w -u p of A E a n d/ or S A E  ................................................................... 7 4  
1 0. 3. 5  
Re p orti n g of S A Es  ........................................................................................................... 7 6  
1 0. 4  A p pe n di x 4: C o ntrace pti ve g ui da nce a n d c ollecti o n of pre g na nc y i nf or mati o n  ............................ 7 8  
1 0. 5  A p pe n di x 5: Tec h nical c o m plai nts: Defi niti o n a n d pr oce d ures f or rec or di n g, e val uati o n, 
f oll o w-u p a n d re p orti n g  ................................................................................................................. 8 1  
1 0. 5. 1  
Defi niti o n of tec h nical c o m plai nt  .................................................................................... 8 1  
1 0. 5. 2  
Rec or di n g a n d f oll o w -u p of tec h nical c o m plai nts  ........................................................... 8 1  
1 0. 5. 3  
Re p orti n g of tec h nical c o m plai nts  ................................................................................... 8 2  
1 0. 6  A p pe n di x 6: Rete nti o n of h u ma n bi osa m ples  ................................................................................ 8 3  
1 0. 7  A p pe n di x 7: H y p o gl ycae mic e pis o des  ........................................................................................... 8 4  
1 0. 8  A p pe n di x 8: Titrati o n g ui deli ne  ..................................................................................................... 8 6  
1 0. 9  A p pe n di x 9: C o u ntr y -s pecific re q uire me nts .................................................................................. 9 1  
1 0. 1 0  A p pe n di x 1 0: A b bre viati o ns  .......................................................................................................... 9 5  
1 0. 1 1  A p pe n di x 1 1: Pr ot oc ol a me n d me nt hist or y  ................................................................................... 9 7  
1 1  Ref ere nces  .............................................................................................................................................. 1 0 0  
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  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
7
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
8  of 1 0 2  
1  
Pr ot oc ol s u m m ar y  
1. 1  
S y n o psis  
R ati o n ale:  
I ns uli n ic o dec is a n o vel l o n g-acti n g i ns uli n a nal o g ue w hic h is de vel o pe d t o safel y c o v er t he bas al 
i ns uli n re q uire me nts f or a f ull wee k wit h a si n gle s u bc uta ne o us i njecti o n. 
T he prese nt tri al is a 2 6 -wee k trial desi g n e d t o i n vesti gate effect a n d s afet y of o nce wee kl y i ns uli n 
ic o dec i n c o m paris o n t o o nce dail y i ns uli n glar gi ne  1 0 0 u nits/ m L (referre d t o as i ns uli n glar gi ne i n 
t his d oc u me nt), b ot h i n c o m bi nati o n wit h a b ol us i ns uli n, wit h or wit h o ut n o n-i ns uli n a nti-dia betic 
dr u gs , i n s u bjects wit h t y pe 2 dia betes ( T 2 D) o n a basal -b ol us re gi me n . 
O bjecti ves a n d e n d p oi nts:  
Pri m ar y o bjecti ve  
T he o bjecti ve of t his trial is t o de m o nstrate t he effect o n gl ycae mic c o ntr ol of o nce wee kl y i ns uli n 
ic o dec i n c o m bi nati o n wit h i ns uli n as part, wit h or wit h o ut n o n -i ns uli n a nti-dia betic dr u gs, i n 
s u bjects wit h T 2 D o n a b asal-b ol us re gi me n. T his i ncl u des c o m pari n g t he differe n ce i n c ha n ge fr o m 
baseli ne i n H b A 1c bet wee n i ns uli n ic o dec a n d i ns uli n glar gi ne after 2 6 wee ks of treat me nt t o a n o n -
i nferi orit y li mit of 0. 3 %. 
E sti m a n d 
T he esti ma n d is t he ‘treat me nt p olic y esti ma n d’ d efi ne d as t he treat me nt differe n ce b et wee n i ns uli n 
ic o dec a n d i ns uli n glar gi ne of t he c h a n ge i n H b A 1 c fr o m baseli ne t o wee k 2 6  f or all ra n d o mise d 
s u bjects, irres pecti ve of a d here nce t o ra n d o mise d treat me nt a n d c ha n ges t o a nti -dia betic bac k gr o u n d 
me dicati o n. T he f oll o wi n g i nterc urre nt e ve nts will be ha n dle d b y t he treat m e nt p olic y str ate g y:  
disc o nti n uati o n of ra n d o mise d i ns uli n tr eat me nt, a n d wit h dra wal fr o m t he trial ( meas ure me nts 
c ollecte d after t hes e i nterc urre nt e ve nts are use d i n t he pri mar y a n al ysis).  
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 ( V 2) t o wee k 2 6 ( V 2 8)  
% -p oi nt  
O ver all desi g n:  
T his is a 2 6 -wee k ra n d o mise d, o pe n la bel, acti ve -c o ntr olle d, parallel -gr o u p, m ultice ntre, 
m ulti nati o nal, treat -t o-tar get trial wit h t w o tr eat me nt ar ms.  
S u bjects will be ra n d o mise d ( 1: 1) t o recei ve o nce wee kl y i ns uli n ic o dec or o nce dail y i ns uli n 
glar gi n e , b ot h i n c o m bi nati o n wit h 2 -4 ti mes dail y i njecti o ns of i ns uli n as part.  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
8
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
9  of 1 0 2  
Ke y i ncl usi o n criteri a : 
1.
M ale or fe m ale a ge d a b o ve or e q ual t o 1 8 years at t he ti me of si g ni n g i nf or me d c o nse nt.
2.
Dia g n os e d wit h T 2 D ≥ 1 8 0 da ys pri or t o t he da y of scree ni n g.
3.
H b A 1 c fr o m 7. 0-1 0. 0 % ( 5 3. 0 -8 5. 8  m m ol/ m ol) b ot h i ncl usi ve at scree ni n g c o nfir me d b y ce ntr al
la b orat or y a n al ysis.
4.
Treate d wit h o nce dail y b asal i ns uli n ( n e utral p r ota mi ne h a ge d or n i ns uli n, i ns uli n de gl u dec,
i ns uli n dete mir, i ns uli n glar gi n e 1 0 0 u nits/ m L, or i ns uli n glar gi ne 3 0 0 u nits/ m L) a n d 2-4 dail y
i njecti o ns of b ol us i ns uli n a nal o g (i ns uli n as part, faster acti n g i ns uli n as part, i ns uli n lis pr o,
i ns uli n gl ulisi ne) ≥ 9 0 da y s pri or t o t he d a y of scree ni n g wit h or wit h o ut a n y of t he f oll o wi n g
a nti-dia betic dr u gs/r e gi me ns wit h sta ble d oses ≥ 9 0 da ys pri or t o scree ni n g:
• Metf or mi n
• S ulf o n yl ureas
• Me gliti ni des ( gli ni des)
• D P P -4 i n hi bit ors
• S G L T 2 i n hi bit ors
• T hiaz oli di ne di o nes
• Al p ha -gl u c osi dase i n hi bit ors
• Oral c o m bi nati o n pr o d ucts (f or t he all o we d i n di vi d ual o ral anti -dia betic
d r u gs)
• Oral or i nject a ble G L P -1 -rece pt or a g o nists
5.
B o d y mass i n de x ( B MI) ≤ 4 0. 0 k g/ m 2.
Ke y e xcl usi o n criteri a : 
1.
A n y e pis o des a of dia betic ket oaci d osis wit hi n 9 0 da ys  pri or t o t he da y of scree ni n g.
2.
M y ocar dial i nfarcti o n, str o ke, h os pitalisati o n f or u nsta ble a n gi na pect oris or tra nsie nt isc hae mic
attac k wit hi n 1 8 0 da ys pri or t o t he da y of scree ni n g.
3.
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  Class I V at scree ni n g.
4.
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).
5.
U nc o ntr olle d a n d p ote nti all y u nsta ble dia b etic reti n o pat h y or mac ul o pat h y. Verifie d b y a f u n d us
e x a mi nati o n perf or me d wit hi n t he past 9 0 da ys pri or t o scree ni n g or i n t he peri o d bet wee n
scree ni n g a n d ra n d o misati o n. P har mac ol o 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.
a as declare d b y t he s u bj ect or i n t he me dical rec or ds. 
N u m ber of s u bjects:  
A p pr o xi matel y 7 7 4  s u bj ects will be scree n e d t o ac hie ve 5 8 0  s u bjects ra n d o ml y assi g ne d t o trial 
pr o d uct.  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
9
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
1 0  of 1 0 2  
Tre at me nt gr o u ps a n d d ur ati o n:  
T he trial d urati o n is a p pr o xi matel y 3 3  wee ks, c o nsisti n g of a 2 -wee k s cree ni n g peri o d, f oll o we d b y 
a 2 6 -wee k ra n d o mise d tr eat me nt peri o d a n d a 5 -wee k f oll o w -u p p eri o d. All s u bject  will be ce ntr all y 
ra n d o mise d i n a 1: 1 ma n ner a n d assi g n e d t o recei ve o nce wee kl y i ns uli n ic o dec or o nce dail y 
i ns uli n glar gi ne, b ot h i n c o m bi nati o n wit h 2 -4 ti mes dail y i njecti o ns of i ns uli n as part t hr o u g h o ut t he 
2 6 -wee k tr eat me nt peri o d. After e n d of tre at me nt, s u bjects will be tra nsferre d t o a mar ket e d pr o d uct
at t he discreti o n of t he i n vesti gat or.
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 f or t he d urati o n of t he trial:  
• I ns uli n ic o dec 7 0 0 u nits/ m L, s u bc uta ne o us, 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
• I ns uli n glar gi ne 1 0 0 u nits/ m L, s u bc uta ne o us, s ol uti o n f or i njecti o n, 3 m L S ol o S T A R pre -fille d
pe n -i nject or
• I ns uli n as p art 1 0 0 u nits/ m L, s u bc uta ne o us, s ol uti o n f or i njecti o n, 3  m L pre -fille d Fl e x pe n
D at a m o nit o ri n g c o m mittee: N o  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
1 0
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
1 5  of 1 0 2  
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. T he c hr o nic h y p er gl ycae mia of dia betes mellit us 
is ass ociate d wit h si g nifi ca 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, ner ves, heart a n d bl o o d vess els.2 Dia betes is 
ge n erall y cl assifie d acc or di n g t o aeti ol o gical f act ors, w here t y p e 1 dia betes ( T 1 D) a n d t y p e 2 
dia betes ( T 2 D) c o nstit ute t he vast m aj orit y of cas es. I n t he l atest e diti o n of t he I nter n ati o nal 
Dia betes Fe derati o n’s Di a betes Atlas ( 2 0 1 9), t he esti mate d w orl d wi de dia b etes pre v ale 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. 3  
I ns uli n ic o dec ( pr o p os e d I N N) is a n o v el l o n g-acti n g i ns uli n a nal o g ue w hi c h is de vel o pe d t o saf el y 
c o ver t he b asal i ns uli n re q uire me nts f or a f ull wee k wit h a si n gle s u bc ut a ne o us i njecti o n. I ns uli n 
ic o dec has a ter mi nal eli mi nati o n half-life of a p pr o xi matel y 1 9 6 h o urs. F or s u bjects wit h dia betes 
t here is still a n u n met me dical nee d f or pr o d ucts wit h t he p ote ntial t o i m pr o ve cli nical o utc o mes 
t hr o u g h re d uce d treat me nt b ur de n a n d i ncrease d treat me nt a d here n ce a n d persiste nce4 c o m pare d t o 
o nce or t wice dail y basal i ns uli n a d mi nistrati o n. T he ai m of t he de v el o p me nt pr o gra m me f or i ns uli n 
ic o dec is t o i m pr o ve cli nical o utc o mes f or s u bj ects wit h dia betes b y li miti n g t he b ur de n ass o ciate d 
wit h i ns uli n treat me nt.  
2. 1  
Tri al r ati o n ale  
T he prese nt tri al is a 2 6 -wee k trial desi g n e d t o i n vesti gate effect a n d s afet y of o nce wee kl y i ns uli n 
ic o dec i n c o m paris o n t o o nce dail y i ns uli n glar gi ne 1 0 0 u nits/ m L (referre d t o as i ns uli n glar gi ne i n 
t his d oc u me nt), b ot h i n c o m bi nati o n wit h a b ol us i ns uli n, wit h or wit h o ut n o n-i ns uli n a nti-dia betic 
dr u gs , i n s u bje cts wit h t y pe 2 dia betes ( T 2 D) o n a basal-b ol us re gi me n .  
T he  l o n g-acti n g bas al i ns uli n pr o d ucts c urre ntl y a p pr o ve d f or tr eat me nt of dia betes are a d mi nistere d 
o nce or t wice dail y. S u bjects i n nee d of a basal i ns uli n treat me nt i n c o m bi nati o n wit h b ol us i ns uli n 
ha ve t o a d here t o a c o m plicate d treat me nt r e gi me n wit h m u lti ple dail y i njecti o ns. T he o nce wee kl y 
treat me nt re gi me n f or i ns uli n ic o dec w o ul d bec o m e a m ore c o n ve nie nt bas al i ns uli n, wit h 
si g nifica ntl y fe wer i njecti o ns o ver ti me, w hic h c o ul d i m pr o ve treat me nt a d here nce 4 as c o m pare d t o 
o nce dail y or t wic e dail y basal i ns uli n f or s u bjects wit h T 2 D.  
T he res ults of t he prese nt trial will be i m p orta nt f or e val uati n g t he effect a n d safet y para meters i n a 
pr o gresse d T 2 D p o p ulati o n s pecificall y o n t he c o m bi ne d use of i ns uli n ic o dec a n d b ol us i ns uli n a n d 
will be use d t o s u p p ort t he mar keti n g a ut h orisati o n a p pr o val of i ns uli n ic o dec. T he trial will als o 
ge n erat e data f or g ui da nce o n tra nsfer fr o m o n ce d ail y bas al i ns uli n t o o nce wee kl y i ns uli n ic o dec, 
a n d data o n d osi n g fle xi bilit y.  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
1 5
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
1 6  of 1 0 2  
 
2. 2  
B ac k gr o u n d  
Di a betes mellit us  
T 2 D is c haracterise d b y i ns uli n resista nce, i m paire d i ns uli n secreti o n, i ncrease d he patic gl u c ose 
o ut p ut d ue t o gl uca g o n d ysre g ulati o n res ulti n g i n c hr o nic h y per gl yca e mia. 5 T he pat h o ge nesis is n ot 
f ull y u n derst o o d b ut see ms t o be heter o ge n e o us, i n v ol vi n g e n vir o n me ntal, lifest yle, a n d ge netic 
fact ors le a di n g t o c hr o nic h y per gl ycae mia ca us e d b y peri p heral tiss ue i ns uli n resista nce, i m pair e d 
i ns uli n secreti o n d ue t o a b n or mal beta-cell f u ncti o n a n d a b n or ma l gl uc os e meta b olis m i n t he li ver.6 
T he c urre nt treat me nt cas ca de f oll o ws a ste p wise a p pr oac h c o m prisi n g lifest yl e c ha n ges i n 
c o m bi nati o n wit h p har mac ol o gical i nter v e nti o n. I n ma n y c o u ntries, metf or mi n is rec o m me n de d as 
i nitial p har mac ol o gi cal t hera p y, f oll o w e d b y c o m bi nati o n t hera p y wit h ot her oral a nti-dia betic 
dr u gs, gl uc a g o n -li ke pe pti de 1 rece pt or a g o nists ( G L P-1  R A ) a n d/ or i ns uli n as t he disease 
pr o gresses. 7 O n a v era ge, after fail ure of di et a n d e x ercise al o ne, s u bjects re q uire a ne w i nter ve nti o n 
wit h gl uc ose -l o weri n g a ge nts e ver y 3-4 years i n or der t o o btai n/retai n g o o d gl ycae mic c o ntr ol. 8 
Cli nical i nertia, ofte n res ulti n g fr o m a resista nce t o i ns uli n i nitiati o n a n d i nte nsificati o n, is a maj or 
c o ntri b uti n g fact or t o s u bjects wit h T 2 D w h o are n ot ac hie vi n g rec o m me n d e d gl ycae mic tar gets. 9, 1 0 
I n crease d c o n v e nie nce is belie ve d t o s u p p ort ti mel y i ns uli n i nitiati o n i n t he treat me nt f or T 2 D a n d 
t here b y o verc o mi n g t he cli nical i nertia ass ociate d wit h i ns uli n i nitiati o n. 
I ns uli n ic o dec  
I ns uli n ic o dec is a n o vel l o n g-acti n g i ns uli n a nal o g ue w hic h is de vel o pe d t o safel y c o v er t he bas al 
i ns uli n re q uire me nts f or a f ull wee k wit h a si n gle s u bc uta ne o us i njecti o n. I ns uli n ic o dec has a 
ter mi nal eli mi nati o n half-life of a p pr o xi matel y 1 9 6 h o urs. The m olec ule c o nsists of a pe pti de 
bac k b o ne a n d a fatt y aci d -c o ntai ni n g si d e -c h ai n. T he pe pti de bac k b o ne is m ore resista nt t o war ds 
pr ote ol ytical de gra dati o n c o m pare d t o h u ma n i ns uli n a n d t he si de c hai n gi v es a str o n g bi n di n g t o 
al b u mi n. B ot h feat ur es c o ntri b ute t o t he l o n g acti o n of i ns uli n ic o dec.  
T he de vel o p me nt pr o gra m me f or i ns uli n ic o dec is c urre ntl y o n g oi n g. T hree cli nical p har mac ol o g y 
trials, N N 1 4 3 6-4 3 1 4 [ T 2 D], N N 1 4 3 6 -4 2 2 6 [re nal i m paire d] a n d N N 1 4 3 6 -4 4 2 2 [ T 1 D] ha ve bee n 
c o m plete d. N o u ne x pecte d  safety c o n cer ns were i de ntifie d. T w o cli nical p h ar mac ol o g y trials 
( N N 1 4 3 6-4 4 6 2 [ T 2 D] a n d N N 1 4 3 6 -4 2 2 5 [ T 1 D]) are o n g oi n g.  
T hree p h ase 2 trials i n s u bjects wit h T 2 D ha ve rece ntl y bee n c o m plete d ( N N 1 4 3 6 -4 4 6 5, N N 1 4 3 6 -
4 3 8 3 a n d N N 1 4 3 6 -4 4 6 6). O nce w ee kl y i ns uli n ic o de c was s h o w n t o pr o vi de c o m para ble gl uc ose 
l o weri n g effects a n d si milar safet y pr ofile t o i ns uli n glar gi n e i n s u bjects wit h T 2 D. Res ults fr o m 
t hese trials were use d i n t he de vel o p me nt of t he i ns uli n ic o dec titrati o n g ui deli ne, see A p pe n di x 8 
( Secti o n 1 0. 8 ). 
A c o m pre he nsi v e re vie w of res ults fr o m t he n o n -cli nical a n d cli nical st u dies of i ns uli n ic o dec 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 1 1 a n d a n y u p d ates here of.  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
1 6
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
1 7  of 1 0 2  
I ns uli n gl ar gi ne 
F or f urt her det ails o n i ns uli n glar gi ne, please refer t o t he c urre nt E M A s u m mar y of pr o d u ct 
c haracteristics f or i ns uli n glar gi n e ( La nt us ® )1 2, t he U S p rescri bi n g inf or mati o n  f or i ns uli n glar gi ne 
( La nt us® )1 3, or a n y l ocall y a p pr o ve d la bel. 
I ns uli n as p art 
F or f urt her det ails o n i ns uli n as part, please refer t o t he c urre nt i ns uli n as part in vesti gat or’s 
b r oc h ure1 4, t he c urre nt E M A s u m mar y of pr o d uct c haracteristics f or i ns uli n as part ( N o v o Ra pi d® )1 5, 
t he U S prescri bi n g i nf or mati o n  f or i ns uli n as part ( N o v o L o g® )1 6, or a n y l ocall y a p pr o ve d la bel. 
Tri al p o p ul a ti o n 
T he trial p o p ulati o n will c o nsist of s u bjects wit h T 2 D o n a basal-b ol us re gi me n.  
S u bjects i ncl u de d i n t he trial will alrea d y b e o n basal i ns uli n a nal o g ue tr eat me nt wit h b ol us i ns uli n 
wit h or wit h o ut n o n -i ns uli n a nti-dia betic dr u gs e ns uri n g a trial p o p ulati o n re prese ntati ve of a 
pr o gresse d i ns uli n e x perie nce d T 2 D p o p ulati o n.  
S u bjects wit h T 1 D are e x cl u de d fr o m t his trial. S u bjects wit h T 1 D will be a d dresse d i n a d e dicate d 
trial. 
F or m ore i nf or mati o n o n t he trial p o p ulati o n, see Secti o n 4. 2 , or t he i ncl usi o n a n d e x cl usi o n criteria, 
S ecti o ns 5. 1  a n d 5. 2 , res pecti vel y. 
2. 3  
Be nefit -ris k assess me nt  
2. 3. 1  
Ris k assess me nt  
I d e ntifie d ris ks f or i ns uli n ic o dec i n t his secti o n are descri b e d as u n desir a ble cli nical o utc o mes f or 
w hic h t here is s ufficie nt e vi de nce t h at t he y are ca use d b y i ns uli n ic o dec. P ote ntial ris ks i n t his 
secti o n descri be u n d esira ble cli nical o utc o mes f or w hic h t here is scie ntifi c e vi de nce t o s us pect t he 
p ossi bilit y of a ca us al rel ati o ns h i p wit h i ns uli n ic o dec, b ut w here t here is c urre ntl y i ns ufficie nt 
e vi de nce t o c o ncl u de t hat t his ass ociati o n is ca usal.  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
1 7
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
1 9  of 1 0 2  
P ote nti al ris k:  
H y perse nsiti vit y 
Se vere s yste mic 
h y perse nsiti vit y reacti o ns 
ma y p ote ntiall y occ ur 
f oll o wi n g i nj ecti o n of 
t hera p e utic pr otei ns. N o 
s yste mic h y perse nsiti vit y 
reacti o ns were o bser ve d i n 
trials N N 1 4 3 6-4 3 1 4, 
N N 1 4 3 6 -4 3 8 3, N N 1 4 3 6 -
4 4 6 5, N N 1 4 3 6 -4 4 6 6, 
N N 1 4 3 6 -4 2 2 6 a n d N N 1 4 3 6 -
4 4 2 2.  
K n o w n or s us pecte d h y perse nsiti vit y t o trial 
pr o d uct(s) or relate d pr o d ucts is a n e xcl usi o n 
criteri o n i n t he cli nical trial.  
S u bj ects a n d i n vesti gat ors will be i nstr ucte d i n 
si g ns a n d s y m pt o ms of h y pers e nsiti vit y reacti o ns 
a n d s u bj ects will be i nstr ucte d t o c o ntact t he site 
i m me diatel y i n case of si g ns of s yste mic 
h y perse nsiti vit y.  
Bl o o d sa m pli n g f or assess me nt of a nti b o dies 
a gai nst i ns uli n ic o dec, as well as ot her 
assess me nts will be c o n d ucte d i n t he case of 
s yste mic h y perse nsiti vit y reacti o n. C o nfir me d 
a nti-i ns uli n ic o dec a nti b o d y p ositi ve sa m ples will 
ha ve a n a nti b o d y titer val ue deter mi ne d a n d will 
be f urt her teste d f or cr oss -reacti vit y t o 
e n d o ge n o us i ns uli n.  
T he ris k of h y perse nsiti vit y reacti o ns is descri be d 
i n t he I B1 1  a n d SI -I C.
F or f urt her i nf or mati o n o n h y perse nsiti vit y 
reacti o ns, please refer t o S ecti o n 8. 9. 2  a n d 
A p pe n di x 3 ( Secti o n 1 0. 3. 3 ). 
P ote nti al ris ks:  
A nti b o d y f or mati o n lea di n g t o 
c ha n ges i n cli nical effect  
A nti b o dies t o e x o ge n o usl y 
deli vere d i ns uli n are 
c o m m o n wit h i ns uli n 
treat me nt b ut are n ot ofte n 
cli nicall y si g nifica nt. 
I n trial N N 1 4 3 6 -4 3 8 3, t he 
pr o p orti o n of s u bj ects wit h 
a nti -i ns uli n a nti b o dies was 
hi g her wit h i ns uli n ic o dec 
( 8 2. 1 %) t ha n i ns uli n 
glar gi ne ( 3 5. 0 %).  
Ma xi m u m le vel of a nti b o d y 
res p o nse was hi g her a gai nst 
i ns uli n ic o dec t ha n i ns uli n 
glar gi ne.  
N o  a p pare nt relati o ns hi p 
bet wee n a nti b o d y titres a n d 
c ha n ge i n H b A 1c or wee kl y 
i ns uli n d ose was o bser ve d. 
Bl o o d sa m ples will be ta ke n f or a nal ysis of ser u m 
a nti b o dies a gai nst i ns uli n ic o d ec at pre -first d ose 
ti me p oi nt. T he n at a p pr o priate ti me p oi nts d uri n g 
t he trial a n d at t he e n d of trial  visit. C o nfir me d 
a nti -i ns uli n ic o dec a nti b o d y p ositi ve sa m ples will 
ha ve a n a nti b o d y titer val ue deter mi ne d a n d will 
be f urt her teste d f or cr oss -reacti vit y t o 
e n d o ge n o us i ns uli n. T here will be a cl ose 
m o nit ori n g of t he gl yce mic c o ntr ol o n s u bj ect 
le vel d uri n g t he trial. I n case l ac k of cli nical 
effect is o bser ve d, resc ue me dicati o n will be 
pr o vi de d if dee me d necessar y.  
I n t he case of s yste mic h y pers e nsiti vit y reacti o n 
bl o o d sa m pli n g f or assess me nt of a nti b o dies 
a gai nst i ns uli n ic o dec, as well as ot her 
assess me nts will be c o n d ucte d. F or m ore 
i nf or mati o n, please refer t o S ecti o n 8. 9. 2  a n d 
A p pe n di x 3 ( Secti o n 1 0. 3. 3 ). 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
1 9
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
2 1  of 1 0 2  
a d here n ce a n d q ualit y of life are e x pecte d t o i ncrease b y i ntr o d uci n g a o n ce wee kl y basal i ns uli n 
treat me nt.  
T he trial p o p ulati o n will c o nsist of s u bjects wit h T 2 D o n a basal-b ol us re gi me n. F or all s u bjects 
partici pati n g i n t his 2 6 -w ee k trial, t he a ntici p ate d be nefits i ncl u de i m pr o ve d gl ycae mic c o ntr ol. T h e 
titrati o n al g orit h m i n A p pe n di x  8  ( Secti o n 1 0. 8 ), w hic h s pecifies rec o m me n de d a dj ust me nts of 
basal i ns uli n d ose a n d b ol us i ns uli n d ose at differe nt plas ma gl uc os e le vels, will be use d t o e ns ure 
t hat s u bjects recei ve o pti mal treat me nt. S u bjects will recei ve i nte ns e me dical care b y mea ns of 
c o ntact wit h t he sites wee kl y.  
2. 3. 3  
O ver all be nefit -ris k c o ncl usi o n  
I ns uli n ic o dec is effi caci o us at cli nicall y rele va nt d oses. Titrati o n g ui da nce f or p hase 3 a trials ai ms 
t o ac hie ve g o o d gl ycae mic c o ntr ol wit h o ut i ncreasi n g t he ris k of h y p o gl ycae mic e ve nts.  
N o ne w si g nifica nt safet y i nf or m ati o n t hat c ha n ges t he c urre nt be nefit – ris k pr ofile of i ns uli n ic o dec 
e mer ge d fr o m t he o n g oi n g a n d c o m plete d cli nical trials. T he  safet y pr ofile of i ns uli n ic o dec re mai ns 
i n li ne wit h t he c u m ulati ve e x perie nce. 
As a n o verall assess me nt, N o v o N or dis k e val uat es t hat t he be nefit – ris k bala nce of i ns uli n ic o dec 
re mai ns fa v o ura ble.  
C o nsi deri n g t he meas ures ta ke n t o mi ni mise ris k t o s u bje cts partici pati n g i n t his trial, t he p ote ntial 
ris ks i de ntifie d i n ass ociati o n wit h i ns uli n ic o dec are j ustifie d b y t h e a ntici p ate d be nefits t hat ma y 
be aff or de d t o s u bjects wit h dia betes mellit us . 
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 k of i ns uli n ic o dec ca n b e 
f o u n d i n t he i n vesti gat or’s br oc h ure1 1 a n d a n y u p d ates here of.  
3  
O bjecti ves a n d e n d p oi nts  
3. 1  
Pri m ar y, sec o n d ar y a n d e x pl or at or y o bjecti ve a n d esti m a n d  
3. 1. 1  
Pri m ar y o bjecti ve  
T o de m o nstrate t he effect o n gl ycae mic c o ntr ol of o nce wee kl y i ns uli n ic o dec i n c o m bi nati o n wit h 
i ns uli n as part, wit h or wit h o ut n o n-i ns uli n a nti-dia betic dr u gs, i n s u bjects wit h T 2 D o n a basal -b ol us 
re gi me n. T his i ncl u des c o m pari n g t he differe nce i n c ha n ge fr o m baseli ne i n H b A 1c bet wee n i ns uli n 
ic o dec a n d i ns uli n glar gi ne after 2 6 wee ks of treat me nt t o a n o n-i nferi orit y li mit of 0. 3 %. 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
2 1
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
2 2  of 1 0 2  
 
3. 1. 2  
Sec o n d ar y o bjecti ve  
T o c o m pare s afet y wit h o nce wee kl y i ns uli n ic o dec vers us o nce dail y i ns uli n glar gi n e , b ot h i n 
c o m bi nati o n wit h i ns uli n as part, wit h or wit h o ut n o n -i ns uli n a nti-dia betic dr u g s, i n s u bjects wit h 
T 2 D o n a basal -b ol us re gi me n.  
3. 1. 3  
Esti m a n d  
T he esti ma n d is t he ‘treat me nt p olic y esti ma n d’ d efi ne d as t he treat me nt differe n ce b et wee n i ns uli n 
ic o dec a n d i ns uli n glar gi ne of t he c ha n ge i n H b A 1 c fr o m baseli ne t o wee k 2 6  f or all ra n d o mise d 
s u bjects, irres pecti ve of a d here nce t o ra n d o mise d treat me nt a n d c ha n ges t o a nti -dia betic bac k gr o u n d 
me dicati o n. T he f oll o wi n g i nterc urre nt e ve nts will be ha n dle d b y t he treat m e nt p olic y str ate g y:  
disc o nti n uati o n of ra n d o mise d i ns uli n tr eat me nt, a n d wit h dra wal fr o m t he trial ( meas ure me nts 
c ollecte d after t hes e i nterc urre nt e ve nts are use d i n t he pri mar y a n al ysis).  
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 nts  
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 ( V 2) t o wee k 2 6 ( V 2 8)  % -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  
Sec o n d ar y effic ac 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 ( V 2) t o wee k 2 6 ( V 2 8)  m m ol/ L  
Ti me i n tar get -ra n ge 3. 9– 1 0. 0  
m m ol/ L ( 7 0 -1 8 0 m g/ d L) *  
Fr o m wee k 2 2 ( V 2 4) t o wee k 2 6 ( V 2 8)  
% of rea di n gs  
* usi n g c o nti n u o us gl uc ose m o nit ori n g ( C G M) s yste m, De xc o m G 6  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
2 2
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
2 3  of 1 0 2  
Sec o n d ar y s af et y e n d p oi nts  
E n d p oi nt title 
Ti me fr a me  
U nit  
N u m ber of se vere h y p o gl ycae mic 
e pis o des (le vel 3)  
Fr o m  baseli ne  wee k 0 ( V 2) t o wee k 3 1 ( V 3 0)  N u m ber of e pis o des  
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)   
Fr o m baseli ne  wee k 0 ( V 2) t o wee k 3 1 ( V 3 0)  N u m ber of e pis o des  
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 ycae mic e pis o des (le vel 3)  
Fr o m baseli ne  wee k 0 ( V 2) t o wee k 3 1  ( V 3 0) N u m ber of e pis o des  
Ti me s pe nt < 3. 0 m m ol/ L 
( 5 4 m g/ d L) *  
Fr o m wee k 2 2 ( V 2 4) t o wee k 2 6 ( V 2 8)  
% of rea di n gs  
Ti me s pe nt > 1 0 m m ol/ L 
( 1 8 0 m g/ d L) *  
Fr o m wee k 2 2 ( V 2 4) t o wee k 2 6  ( V 2 8) 
% of rea di n gs  
Mea n wee kl y i ns uli n d ose  
Fr o m wee k 2 4 ( V 2 6) t o wee k 2 6 ( V 2 8) 
U  
C ha n ge i n b o d y wei g ht  
Fr o m baseli ne  wee k 0 ( V 2) t o wee k 2 6 ( V 2 8)  k g  
* usi n g c o nti n u o us gl uc ose m o nit ori n g ( C G M) s yste m, De xc o m G 6
3. 2. 3  
E x pl or at or y e n d p oi nts  
E n d p oi nt title  
Ti me fr a me  
U nit  
N u m ber of se vere h y p o gl ycae mic  
e pis o des (le vel 3)  
Fr o m baseli ne wee k 0 ( V 2) t o wee k 2 6 ( V 2 8)  N u m ber of e pis o des  
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)  
Fr o m baseli ne wee k 0 ( V 2) t o wee k 2 6 ( V 2 8)  N u m ber of e pis o des  
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 ycae mic e pis o des (le vel 3)  
Fr o m baseli ne wee k 0 ( V 2) t o wee k 2 6 ( V 2 8)  N u m ber of e pis o des  
4  
Tri al desi g n  
4. 1  
O ver all desi g n  
T his is a 2 6 -wee k ra n d o mise d,  o pe n la bel, acti ve -c o ntr olle d, parallel -gr o u p, m ultice ntre, 
m ulti nati o nal, treat -t o-tar get trial wit h t w o tr eat me nt ar ms i n vesti gati n g t he effect o n gl ycae mic 
c o ntr ol a n d safet y of treat me nt wit h o nce wee kl y i ns uli n ic o dec c o m pare d t o o nce dail y i ns uli n 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
2 3
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
2 4  of 1 0 2  
 
g lar gi n e, b ot h i n c o m bi nati o n wit h i ns uli n as part wit h or wit h o ut n o n-i ns uli n a nti-dia betic dr u gs, i n 
s u bjects wit h T 2 D. 
T he trial d urati o n is a p pr o xi matel y 3 3  wee ks, c o nsisti n g of a 2 -wee k s cree ni n g peri o d, f oll o we d b y 
a 2 6 -wee k ra n d o mise d tr eat me nt peri o d  a n d a 5 -wee k f oll o w -u p p eri o d. T he  o verall trial desi g n a n d 
visit sc he d ule are o utli ne d i n Fi g ure  4 -1  a n d trial fl o wc hart (see Secti o n  1. 2 ), res pecti vel y. 
 
Fi g ure  4 -1  
Tri al desi g n  
S u bjects will be ra n d o mise d ( 1: 1) t o recei ve o nce wee kl y i ns uli n ic o dec  or o nce dail y  i ns uli n 
glar gi n e, b ot h i n c o m bi nati o n wit h 2 -4 ti mes dail y i njecti o ns of i ns uli n as part.  T he d ose a n d d osi n g 
fre q ue n c y of a n y pre-trial n o n-i ns uli n a nti-dia betic treat me nt s h o ul d n ot be c ha n ge d d uri n g t he trial 
u nless d ue t o safet y c o n cer ns;  e x ce pt f or treat me nt wit h s ulf o n yl ureas a n d gli ni des t hat m ust be 
disc o nti n ue d at ra n d o misati o n. D uri n g t he 2 6 -wee k treat me nt peri o d, s u bjects will ha ve c o ntact 
wit h t he site wee kl y eit her at site visits or b y p h o n e. T he e n d of treat me nt visit ( V 2 8 ) will be o ne 
wee k after t he l ast d ose of i ns uli n ic o dec a n d o n t h e da y of or t h e da y after t he last d ose of i ns uli n  
glar gi n e. T w o f oll o w -u p visits ( V 2 9  a n d V 3 0 ) will be perf or me d 2 a n d 5 wee ks, res pecti vel y, after 
t he e n d of treat me nt visit. T his will all o w f or a p pr o priate was h -o ut of trial dr u g, f oll o wi n g at least 5 
half -li ves of i ns uli n ic o dec. After t he e n d of treat me nt s u bjects will be tra nsferre d t o a mar kete d 
pr o d uct at t he discreti o n of t he i n vesti gat or.  
T o e val uate t he effect o n gl ycae mic c o ntr ol, s u bjects will ha ve c o nti n u o us gl uc ose m o nit ori n g  
(C G M ) pr ofiles c ollecte d, as s pecifie d i n t he fl o wc hart (see Secti o n 1. 2 ). T h e C G M data will be 
bli n de d f or b ot h s u bjects a n d i n vesti gat ors.  
E ve nt a dj u dicati o n will be perf or me d f or ac ute c or o nar y s y n dr o me e ve nts ( ac ute m y ocar dial 
i nfarcti o n or u nsta ble a n gi na p ect oris re q uiri n g h os pitalisati o n), cere br o vasc ular e v e nts (str o ke or 
tra nsie nt isc he mic attac k), heart fail ure (re q uiri n g h os pitalisati o n or ur ge nt heart fail ure visit) a n d 
all-ca use d eat h.  
4. 2  
Scie ntific r ati o n ale f or tri al desi g n  
T he trial is desi g n e d t o i n vesti gate t h e effect o n gl ycae mic c o ntr ol a n d saf et y of o nce wee kl y i ns uli n 
ic o dec vers us o nce d ail y i ns uli n glar gi ne i n c o m bi nati o n wit h 2-4 dail y i njecti o ns of i ns uli n as part 
d uri n g 2 6 w ee ks of treat me nt.  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
2 4
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
2 5  of 1 0 2  
C urre ntl y, b asal i ns uli ns are d ose d o n ce or t wice d ail y. I n or der t o c o m p are t o well esta blis he d a n d 
wi del y us e d basal i ns uli n a nal o g ues wit h o nce d ail y d osi n g, i ns uli n  glar gi n e has bee n c h os e n as 
c o m parat or.  
T he treat me nt ar ms will be o pe n la bel d u e t o safet y c o n cer ns. It was n ot c o nsi dere d feasi ble t o bli n d 
t he t w o treat me nts d ue t o t he ris k of pe n-m i x-u p i n a d o u ble -bli n d, d o u ble -d u m m y trial usi n g t hr ee 
differe nt p e ns (t w o bas al a n d o ne b ol us pe n).  
T he treat me nt d ur ati o n of 2 6 wee ks is e v al uate d t o be a de q u ate ti me f or assessi n g effect o n 
gl ycae mic c o ntr ol a n d safet y. T his d urati o n will als o all o w f or u p -titrati n g t he basal i ns uli n. T he 
treat-t o-tar get a p pr o ac h h as bee n c h os e n i n or der t o e ns ure o pti mal titrati o n of i ns uli n base d o n self-
meas ure d plas ma gl u c ose ( S M P G) val ues wit h t he ai m of i m pr o vi n g H b A1c i n t he peri o d. 
Titrati o n of i ns uli n ic o dec a n d i ns uli n glar gi ne will be base d o n pre -brea kfast S M P G val ues a n d 
f oll o w t he pri nci ples o utli ne d i n t he titrati o n g ui deli ne, see A p pe n di x 8 ( Secti o n 1 0. 8 ). Sai d 
g ui deli ne f urt her i ncl u d es t he titrati o n pri nci ples of i ns uli n as part, w hic h is base d o n pre -pra n di al 
a n d be dti me S M P G val ues. C G M val ues w ill be use d d uri n g t h e re p orti n g p hase t o ge nerate pr ofiles 
f or e val u ati n g t he effect o n gl ycae mic c o ntr ol d uri n g i nitiati o n of trial pr o d uct, stea d y state a n d 
f oll o w-u p. T o a v oi d i nfl u e nce o n titrati o n a n d t he gl ycae mic c o ntr ol t he C G M data will be bli n de d 
f or b ot h st u d y s u bjects a n d i n vesti gat or. 
S u bjects i ncl u de d i n t he trial will alrea d y b e o n basal i ns uli n a nal o g ue tr eat me nt  wit h b ol us i ns uli n 
wit h or wit h o ut n o n -i ns uli n a nti-dia betic dr u gs e ns uri n g a trial p o p ulati o n re prese ntati ve of a  
pr o gresse d i ns uli n e x perie nce d T 2 D p o p ulati o n. T o mi ni mise t he ris k of h y p o gl ycae mia 
s ulf o n yl ur eas a n d gli ni des m ust be disc o nti n ue d at ra n d o misati o n. 
T o safe g uar d s u bjects, t h e i ncl usi o n a n d e x cl usi o n criteria d efi ne d i n t his trial will li mit t he trial 
p o p ulati o n t o s u bjects n ot s ufferi n g fr o m a d va nce d u n derl yi n g dise ases ot h er t ha n T 2 D a n d relat e d 
diseases. T his is t o a v oi d c o m pr o misi n g t he safet y of t he s u bjects partici p ati n g i n t he trial a n d t o 
stre n gt h e n c o ncl usi o ns re gar di n g t h e effect a n d safet y of o n ce wee kl y i ns uli n ic o dec.  
D uri n g t h e 2 6 wee ks l o n g treat me nt peri o d, t he s u bjects will ha ve wee kl y c o ntact wit h t he site, 
eit her as site visits or p h o ne c o ntacts. T h e e n d of trial  visit is pla n ne d si x wee ks after t h e last wee kl y 
d ose of i ns uli n ic o dec, a ll o wi n g e n o u g h ti me f or was h-o ut of trial dr u g, f oll o wi n g at least fi v e half -
li ves of i ns uli n ic o dec. 
A s ufficie nt ass a y -se nsiti vit y f or t he n o n-i nferi orit y e v al uati o n will be e ns ure d b y t he treat-t o-tar get 
trial desi g n, t he a p plie d titrati o n tar get/al g orit h m t o get h er wit h cl ose titrati o n s ur veilla nce a n d b y 
ha vi n g f oc us o n a d h ere n ce a n d disc o nti n uati o n.  
4. 2. 1  
S u bject i n p ut i nt o desi g n  
N ot a p plica ble f or t his trial.  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
2 5
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
2 6  of 1 0 2  
4. 3  
J ustific ati o n f or d ose  
I ns uli n glar gi ne will be s witc he d fr o m t he pre-trial basal i ns uli n a nal o g ues acc or di n g t o l ocal la bel 
a n d i ns uli n ic o dec will be i nitiate d acc or di n g t o t h e pri nci ples o utli ne d i n t he titrati o n g ui deli ne i n 
A p pe n di x 8 ( Secti o n 1 0. 8 ). A 5 0 % l oa di n g d ose will be a p plie d t o a v oi d gl ycae mic sli p d uri n g t he 
first fe w wee ks of treat m e nt. N o safet y c o ncer ns ha ve bee n i de ntifie d i n s u bjects wit h T 2 D, 
i ncl u di n g v ul nera ble s u bj ects, usi n g a l oa di n g d ose w he n i nitiati n g i ns uli n ic o dec (trial N N 1 4 3 6-
4 4 6 6 ). 
O ne u nit of i ns uli n ic o dec has si milar gl u c ose l o w eri n g effect t o o ne u nit of i ns uli n glar gi ne, a n d 
t heref ore o nce wee kl y d osi n g c orres p o n ds t o se ve n ti mes t he dail y d ose of t he o nce dail y 
c o m parat or.  
T he P K / P D pr o perties of i ns uli n ic o dec f oll o wi n g fi ve wee ks of o nce wee kl y d osi n g i n s u bjects 
wit h T 2 D (trial N N 1 4 3 6 -4 3 1 4) s h o we d t hat i ns uli n ic o dec e x p os ure was w ell distri b ute d acr oss t he 
d osi n g i nter val, wit h a P K pr ofile s uita ble  f or o n ce wee kl y d osi n g. I ns uli n ic o dec was well t olerat e d 
i n s u bjects wit h T 2 D a n d n o u ne x pecte d  safet y c o ncer ns were i de ntifi e d aft er m ulti ple o nce wee kl y 
d osi n g i n t he d ose ra n ge of 1 2 −2 4 n m ol/ k g ( 2 -4 u nits/ k g).  
After ra n d o misati o n, s u bjects s h o ul d star t o nce dail y i ns uli n glar gi n e or o nce wee kl y i ns uli n ic o dec 
i njecti o ns o n t he sa me da y. D u e t o t he l o n ger half-life of i ns uli n ic o dec, the last d ose of i ns uli n 
ic o dec will be a d mi nistere d 2 5 wee ks after ra n d o misati o n, w hile t he last d ose of o nce d ail y i ns uli n 
glar gi n e will be a d mi nistere d  2 6 w ee ks after ra n d o misati o n.  T he f oll o w-u p peri o d  f or b ot h i ns uli n 
ic o dec a n d i ns uli n g lar gi ne will be  t he 5 wee ks fr o m  e n d of treat me nt ( V 2 8 ) u ntil e n d of trial ( V3 0 ). 
I ns uli n as p art s h o ul d be ta ke n 2-4 ti mes dail y wit h meals t hr o u g h o ut t he 2 6 wee ks treat me nt 
d urati o n. S witc h fr o m ot her s h ort -acti n g i ns uli n a nal o g u es s h o ul d be d o ne u nit -t o-u nit.  
F urt her d etails o n d ose a dj ust me nt ca n be f o u n d i n t he titrati o n g ui deli ne i n 
A p pe n di x  8  ( Secti o n 1 0. 8 ). 
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. 
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 gl o ball y. 
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 o t per mitte d. 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
2 6
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
2 7  of 1 0 2  
F or c o u ntr y -s pecific re q uire me nt t o t he i ncl usi o n a n d e x cl usi o n criteria, please refer t o A p pe n di x 9  
(Secti o n 1 0. 9 ) f or f urt her i nf or mati o n. 
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 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 activities. 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.
Male or fe m ale.
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.
Dia g n os e d wi t h T 2 D ≥ 1 8 0 da ys pri or t o t he da y of scree ni n g.
5.
H b A 1c fr o m 7. 0-1 0. 0 % ( 5 3. 0 -8 5. 8  m m ol/ m ol) b ot h i ncl usi ve at scree ni n g c o nfir me d b y
ce ntral la b orat or y a n al ysis.
6.
Treate d wit h o nce dail y  b asal i ns uli n ( n e utral p r ota mi ne h a ge d or n i ns uli n, i ns uli n de gl u dec,
i ns uli n dete mir, i ns uli n glar gi n e 1 0 0 u nits/ m L, or i ns uli n glar gi ne 3 0 0 u nits/ m L) a n d 2 -4
dail y i njecti o ns of b ol us i ns uli n a nal o g (i ns uli n as part, faster acti n g i ns uli n as part, i ns uli n
lis pr o, faster acti n g i ns uli n lis pro, i ns uli n gl ulisi ne) ≥ 9 0 da ys pri or t o t he d a y of scree ni n g
wit h or wit h o ut a n y of t h e f oll o wi n g a nti -dia betic dr u gs/r e gi me ns wit h sta ble d oses ≥ 9 0
da ys pri or t o scree ni n g:
• Metf or mi n
• S ulf o n yl ureas
• Me gliti ni des ( gli ni des)
• D P P -4 i n hi bit ors
• S G L T 2 i n hi bit or s
• T hiaz oli di ne di o nes
• Al p ha -gl uc osi dase i n hi bit ors
• Oral c o m bi nati o n pr o d ucts (f or t he all o we d i n di vi d ual o ral anti -dia betic
d r u gs)
• Oral or i nject a ble G L P -1  R As
7.
B o d y mass i n de x ( B MI) ≤ 4 0. 0 k g/ m 2.
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.
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.
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.
3.
Fe male w h o is pre g na nt, breast -fee di n g or i nte n ds to bec o me pre g n a nt or is of c hil d -beari n g
p ote ntial a n d n ot usi n g a n a de q uate c o ntrace pti ve met h o d (a de q uat e c o ntr ace pti ve meas ures
as re q uire d b y l o cal r e g ulati o n or practice).
4.
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 a.
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
2 7
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
2 8  of 1 0 2  
 
5.  A n y dis or d er, e x ce pt f or c o n diti o ns ass ociate d wit h T 2 D , 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.  
6.  A n y e pis o des b of dia betic ket oaci d osis wit hi n 9 0 da ys pri or t o t he da y of scree ni n g.  
7.  M y ocar dial i nfarcti o n, str o ke, h os pitalisati o n f or u nsta ble a n gi na pect oris or tra nsie nt 
isc hae mic attac k wit hi n 1 8 0 da ys pri or t o t he da y of scree ni n g. 
8.  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 Class I V at 
scree ni n g.  
9.  Pla n ne d c or o nar y, car oti d or peri p heral art er y re v asc ularisati o n.  
1 0.  Re nal i m pair me nt wit h esti mate d g l o mer ular filtrati o n rate val ue of < 3 0  ml/ mi n/ 1. 7 3 m 2 at 
scree ni n g1 9 b y ce ntral la b orat or y a n al ysis.  
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 ≥ 2. 5 ti mes or Bilir u bi n >1. 5 
ti mes u p per n or mal li mit at scree ni n g b y ce ntr al la b orat or y a n al ysis. 
1 2.  K n o w n h y p o gl ycae mic  u na ware ness as i n dicate d b y t he in vesti gat or acc or di n g t o Clar ke’s 
q uesti o n naire q uesti o n 8 1 7 ( Secti o n 8. 2 ). 
1 3.  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 in vesti gat or.  
1 4.  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 5.  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 pri or to t he da y of scree ni n g.  
1 6.  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 w ei g ht or gl uc ose m eta 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).  
1 7.  U nc o ntr olle d a n d p ote nti all y u nsta ble dia b etic reti n o pat h y or mac ul o pat h y. Verifie d b y a 
f u n d us e x a mi nati o n perf or me d wit hi n t he past 9 0 da ys pri or t o scree ni n g or i n t he peri o d 
bet wee n scree ni n g a n d ra n d o misati o n. P har mac ol o gical p u pil -dilati o n is a re q uire me nt 
u nless usi n g a  di gital f u n d us p h ot o gra p h y ca mera s pecifie d f or n o n -dilate d e x a mi nati o n.  
1 8.  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 pri or t o t he da y of 
scree ni n g. 
1 9.  A ntici pate d c ha n ge i n lifest yle affecti n g gl uc ose c o ntr ol.  
a Si m ulta ne o us partici pati o n i n a trial wit h t he pri mar y o bj ecti ve of e val uati n g a n a p pr o ve d or n o n -a p pr o ve d 
i n vesti gati o nal me dici nal pr o d uct f or pre ve nti o n or treat me nt of C O VI D-1 9 disease or p osti nfecti o us c o n diti o ns is 
all o we d if t he last d ose of t he i n vesti gati o nal me dici nal pr o d uct has bee n recei ve d m ore t ha n 3 0 da ys bef ore scree ni n g.  
b  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  
5. 3. 1  
Me als a n d diet ar y rest ricti o ns  
T he s u bjects s h o ul d be fasti n g w he n atte n di n g s o me of t h e visits, see fl o wc hart ( Secti o n 1. 2 ). 
Fasti n g is defi ne d as at least 8 h o urs wit h o ut f o o d a n d dri n k i nta ke, e x ce pt f or water a n d ot her 
prescri be d m e dicati o n. Trial pr o d uct a n d ot her gl uc ose l o weri n g a ge nts s h o ul d be wit h hel d o n t he 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
2 8
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
2 9  of 1 0 2  
 
da y of t he fasti n g visit u ntil bl o o d sa m pli n g ha ve b ee n perf or me d. A n y ot her prescri be d me dicati o n 
s h o ul d be ta ke n as us ual. If t he s u bject atte n ds a fasti n g visit i n a n o n-fasti n g state, t he bl o o d 
sa m pli n g pr oce d ures s h o ul d be re-sc h e d ule d. 
5. 3. 2  
C affei ne, alc o h ol a n d t o b acc o  
T o bacc o us e is defi ne d as s m o ki n g at least o ne ci garette or e q ui vale nt dail y.  
5. 3. 3  
P h ysic al acti vit y  
N ot a p plica ble f or t his trial . 
5. 4  
Scree n f ail ures  
Scree n fail ures are defi ne d as s u bjects w h o c o nse nt t o partici pate i n t he cli nical trial b ut are n ot 
eli gi ble f or partici pati o n acc or di n g t o i ncl usi o n/e xcl usi o n criteria. A mi ni mal set of scree n fail ure 
i nf or mati o n is re q uire d t o e ns ure tra ns p are nt re p orti n g of scree n fail ure s u bjects t o meet 
re q uire me nts fr o m re g ulat or y a ut h orities. Mi ni mal i nf ormati o n i ncl u des i nf or me d c o nse nt dat e,  
de m o gra p h y, scree n fail ure details, a n d eli gi bilit y criteria.  
A scree n fail ure sessi o n m ust be ma de i n t he i nteracti ve we b res p o nse s yst e m (I W R S).  
I n di vi d uals w h o d o n ot meet t he criteri a f or p arti ci pati o n i n t his trial ma y n ot be rescree n e d. If t he 
s u bject has faile d o n e of t he i ncl usi o n criteria or f ulfille d o ne of t he e x cl usi o n criteria relate d t o 
la b orat or y para meters, re-sa m pli n g is n ot all o we d. H o we ver, i n case of tec h nical iss ues (e. g. 
hae m ol ys e d or l ost), re -s a m pli n g is all o we d f or t he affecte d para m eters. 
5. 5  
R u n -i n criteri a, r a n d o mis ati o n criteri a a n d  d osi n g d a y criteri a  
N ot a p plica ble f or t his trial.  
6  
Tre at me nts  
6. 1  
Tre at me nts a d mi nistere d  
I n vesti g ati o n al me dici n al pr o d ucts (I M P) 
All i n vesti gati o nal me dic al pr o d uct s (I M Ps) are liste d i n Ta ble  6 -1 . 
T a ble  6 -1  
I n vesti g ati o n al me dici n al pr o d uct pr o vi de d b y N o v o N or dis k  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
2 9
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
3 0  of 1 0 2  
Tri al pr o d uct n a me:  
I ns uli n ic o dec 7 0 0 u nits/ m L  
(I M P, test pr o d uct) 
I ns uli n gl ar gi ne 1 0 0 u nits/ m L 
(I M P, refere nce t her a py) 
D osa ge f or m  
S ol uti o n f or i nj ecti o n  
S ol uti o n f or i nj ecti o n  
R o ute of a d mi nistrati o n 
S u bc uta ne o us  (i nt o t he t hi g h, u p per ar m 
or a b d o me n)  
S u bc uta ne o us (i nt o t he t hi g h, u p per ar m 
or a b d o me n)  
Rec o m me n de d i nitial d ose  
Please refer t o A p pe n di x 8 , Se cti o n 1 0. 8  
Please refer t o A p pe n di x 8, Se cti o n 1 0. 8  
D osi n g i nstr ucti o ns  
A d mi nister i ns uli n ic o dec o nce wee kl y, 
o n t he sa me da y eac h wee k, at a n y ti me 
of t he da y.  T he da y of wee kl y 
a d mi nistrati o n ca n be c ha n ge d if 
necessar y, b y u p t o 3 da ys. A mi ni m u m 
of 4 da ys bet wee n i nj ecti o ns s h o ul d 
al wa ys be e ns ure d.  
R otati o n of i nj ecti o n site is 
rec o m me n de d. 
A d mi nister i ns uli n glar gi ne o nce dail y, at 
a n y ti me of t he da y b ut at t he sa me ti me 
e ver y da y t hr o u g h o ut t he trial. R otati o n of 
i nj ecti o n site is rec o m me n de d. 
P ac ka gi n g  
3 m L P D S 2 9 0 pre -fille d pe n-i nj ect or 
3 m L S ol o S T A R  pre -fille d pe n-i nj ect or 
• At ra n d o misati o n visit ( V 2) s u bjects s h o ul d a d mi nister trial dr u g at site
• S u bjects s h o ul d be i nstr ucte d t o discar d t he n ee dle after eac h i njecti o n a n d st ore t he
pe n -i nject or wit h o ut a n ee dle attac h e d.
N o n -i n vesti g ati o n al me dici n al pr o d ucts ( NI M P) 
T a ble  6 -2  
N o n -i n vesti g ati o n al me dici n al pr o d ucts 
Tri al pr o d uct n a me:  
I ns uli n as p art 1 0 0 u nits/ m L  
( NI M P, a u xili ary t her a py) 
D osa ge f or m  
S ol uti o n f or i nj ecti o n  
R o ute of a d mi nistrati o n 
S u bc uta ne o us (i nt o t he t hi g h,  u p per ar m or a b d o me n)  
Rec o m me n de d i nitial d ose  
Please refer t o A p pe n di x 8, Se cti o n 1 0. 8  
D osi n g i nstr ucti o ns  
I ns uli n as part s h o ul d be a d mi nistere d wit h meals 2 -4 ti mes dail y. 
R otati o n of i nj ecti o n site is rec o m me n de d  
P ac ka gi n g  
3 m L pre -fille d Fle x pe n 
Pr o vi der  
N o v o N or dis k  
N o n -i ns uli n b ac k gr o u n d m e dic ati o n 
After ra n d o misati o n s u bjects s h o ul d c o nti n ue t heir pre -tri al n o n-i ns uli n a nti-dia betic bac k gr o u n d 
me dicati o n t hr o u g h o ut t h e e ntire trial e xce pt fr o m s ulf o n yl ur eas a n d gli ni des, w hic h m ust be 
disc o nti n ue d at ra n d o misati o n. T he  bac k gr o u n d me dicati o n s h o ul d b e mai ntai ne d at t he sta ble, pre -
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
3 0
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 1  of 1 0 2  
 
trial d ose a n d at t he sa m e fre q ue n c y d uri n g t he e ntire treat me nt peri o d u nless d ue t o safet y 
c o ncer ns.  
I n a d diti o n, t he bac k gr o u n d me dicati o n: 
•  is c o nsi dere d t o be n o n-i n vesti gati o nal me dici n al pr o d uct ( NI M P) 
•  will n ot be pr o vi de d b y N o v o N or dis k a n d s h o ul d be p urc has e d or ot her wise deli vere d t o 
s u bjects i n acc or 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 i n di vi d ual c o u ntr y at 
t he discreti o n of t he i n vesti gat or.  
A u xil i ar y s u p plies 
A u xiliar y s u p plies c o m prise s u p plies ot her t ha n trial pr o d ucts. A u xiliar y s u p plies will be pr o vi de d 
i n acc or da nce wit h t he trial materials ma n ual, please see Ta bl e  6 -3 . 
T a ble  6 -3  
A u xili ar y s u p plies  
A u xili ar y s u p pl y  
Det ails  
Nee dles  
Nee dles f or pre -fille d pe n i nj ect ors.   
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  
At ra n d o misati o n ( V 2) s u bj ects m ust be i nstr ucte d i n h o w t o use t he B G meter a n d t he 
B G meter s h o ul d be li n ke d t o t he e Diar y as descri be d i n t he e Diar y site g ui de.  
Pl ease refer t o t he 
ma n ufact urer’s g ui de .  
C o nti n u o us g l uc ose 
m o nit ori n g  ( C G M) 
s yste m 
At ra n d o misati o n ( V 2) s u bj ects m ust be i nstr ucte d i n ha n dli n g of t he C G M.  
Please refer t o t he De xc o m G 6 ®  ma n ufact urer’s g ui de pr o vi de d.  
e Diar y 
S u bj ect M o bile A p p, H C P We b P ortal, & Cl o u d Ser vice . 
Please refer t o t he e Diar y site g ui de.  
•  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 a n d pre -fille d Fle x Pe n  ca n be f o u n d i n t he 
directi o ns f or use pr o vi de d i n t he e Diar y.  
•  I nf or mati o n a b o ut t he S ol o S T A R pre -fille d pe n -i nject or ca n b e f o u n d i n t he s u m mar y of 
pr o d uct c haract eristics . 
•  A pe n differe ntiati o n g ui de will be pr o vi de d . 
•  Trai ni n g i n t he p e n -i nject ors is t he res p o nsi bilit y of t he i n vesti gat or or a d el e gate a n d m ust be 
re peat e d d uri n g t he trial at re g ular i nter vals, as s p ecifie d i n t he fl o wc hart (see Secti o n 1. 2 ) i n 
or der t o e ns ur e c orrect use of t he pe n -i nject or.  
6. 1. 1  
Me dic al de vices  
6. 1. 1. 1  
I n vesti g ati o n al me dic al de vice  
N ot a p plica ble f or t his trial . 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
3 1
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 2  of 1 0 2  
 
6. 1. 1. 2  
N o n -i n vesti g ati o n al me dic al de vices 
N o n -i n vesti gati o nal me dical de vices are liste d as a u xiliar y s u p plie s (T a ble  6 -3 ). 
F or t he c o u ntries w here B G meter a n d C G M are n ot a p pr o ve d, pleas e refer t o t he A p pe n di x 9 
( Secti o n 1 0. 9 ) c o u ntr y-s p ecific re q uire me nts f or f urt her i nf or mati o n. 
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. 
•  Acce pt a ble te m perat ure ra n ges a n d c o n diti o ns f or st ora ge a n d h a n dli n g of eac h trial pr o d u ct 
w he n n ot i n use a n d w h e n i n use are d escri be d i n t he trial m aterial m a n u al a n d trial pr o d uct 
la bel. 
•  Eac h site will be s u p plie d wit h s ufficie nt trial pr o d uct f or t he trial o n a n o n g oi n g basis. Trial 
pr o d uct 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 r ecei ve d, a n d t hat a n y discre pa ncies 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 n ce wit h t he la bel le 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 gat e 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 m at erial m a n ual. 
•  T he i n vesti gat or or desi g nee is res p o nsi ble f or dr u g acc o u nta bili t 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 . 
•  Eac h si n gle pe n s h o ul d b e acc o u nte d.  
•  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 ncil e d b y t h e 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  
A p pe n di x 5  (S ecti o n 1 0. 5 )) m ust be st ore d se p aratel y fr o m n o n -all ocat e d trial pr o d ucts. N o 
te m perat ur e 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. 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  
•  T his is a n o pe n  la bel trial; h o we ver, t he s p ecific tr eat me nt f or a s u bject will be assi g n e d usi n g 
a n I W R S. T he site will access t he I W R S bef ore t he start of trial pr o d u ct a d mi nistrati o n f or 
eac h s u bject. P ote ntial bias will be re d uce d b y ce ntral ra n d o misati o n a n d a dj u dicati o n.  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
3 2
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
3 3  of 1 0 2  
• 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 mis ati o n sc he d ule. Trial pr o d u ct 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 (see Secti o n 1. 2 ). 
6. 4  
Tre at me nt c o m pli a nce  
Dr u g tre at me nt c o m pli a nce  
T hr o u g h o ut t he tri al, t he i n vesti gat or will re mi n d t he s u bjects t o f oll o w t he trial pr oce d ures a n d 
re q uire me nts t o e n c o ura ge s u bject c o m plia nce. 
W he n s u bjects self -a d mi nister trial pr o d uct at h o me, c o m plia nce wit h trial pr o d uct a d mi nistrati o n 
will be assesse d b y cr oss c hec ki n g t he f oll o wi n g s o urces a n d c o m pari n g t h ese t o t he e x pecte d use:  
• Dr u g acc o u nta bilit y i nf or mati o n
• Re vie w of e Di aries i ncl u di n g S M P G pr ofiles, i ns uli n d ose a n d h y p o gl ycae mia re p orti n g
• E val uati n g gl ycae mic c o ntr o l a n d a d here nce t o t he visit sc he d ule
• If a n y s us pici o n of n o n-c o m plia nce arises t he site m ust e nter i nt o a dial o g u e wit h t he s u bject,
re-e m p h asizi n g t he i m p orta nce of c o m plia nce a n d u nc o ver barriers t o c o m plia nce. T his
dial o g ue m ust be d o c u me nte d i n t he me dical r ec or d. 
6. 5  
C o nc o mit a nt me dic ati o n  
A n y me di cati o n ot her t ha n t he trial pr o d uct a n d a nti-dia betic me dicati o n  t hat t he s u bject recei ves 
fr o m scree ni n g ( V 1) u ntil e n d of trial  visit  (V 3 0 ) m ust be rec or de d al o n g wit h:  
• Ge neric n a me or tr a de n a me
• I n dic ati o n
• Dates of a d mi nistrati o n i ncl u di n g start a n d st o p date .
C o nc o mit a nt me dic ati o n ( di a betes)  
A n y a nti -dia betic me dicati o n ot her t ha n t he trial pr o d uct t hat t he s u bject r ecei ves fr o m s cree ni n g 
( V 1) u ntil e n d of trial visit ( V 3 0 ) m ust  be rec or de d i n a se parate c o n c o mita nt me dicati o n ( dia betes) 
f or m i n t he electr o ni c cas e re p ort f or m  (e C R F ).  
T he f oll o wi n g i nf or mati o n m ust be rec or de d f or oral a nti -dia betic dr u gs, G L P -1 R As, i ns uli n 
pr o d ucts i ncl u di n g pre -tri al i ns uli n a n d p ost -treat me nt i ns uli n i n t he f oll o w-u p peri o d:  
• Ge neric n a me or tr a de n a me (f or i ns uli n pr o d ucts: o nl y tra d e na me) .
• Dates of a d mi nistrati o n i ncl u di n g start a n d st o p date.
• D oses a n d fre q ue n c y (e. g. o nce dail y, t wice d ail y).
U ntil e n d of treat me nt ( V 2 8 ) o nl y ra n d o mise d treat me nt (trial pr o d ucts a nd pre -trial n o n-i ns uli n 
a nti-dia betic bac k gr o u n d me dicati o n  e x ce pt f or s ulf o n yl ur eas a n d gli ni des w hic h m ust be 
disc o nti n ue d at ra n d o misati o n) are all o we d, u nless d ue t o safet y reas o ns at t he discreti o n of t he 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
3 3
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 4  of 1 0 2  
 
i n vesti gat or. If t he i n vesti gat or c h o oses t o initiate a nti -dia betic me dicati o n or c ha n ge d os e of pre -
trial a nti-dia betic bac k gr o u n d me dicati o n pri or t o e n d of treat me nt ( V 2 8 ), t his s h o ul d be re gistere d 
i n t he e C R F as c ha n ge i n c o nc o mita nt me dicati o n ( dia betes). 
C ha n ges i n c o nc o mita nt me dicati o n i ncl u d i n g a nti-dia betic me dicati o n  a n d ot her i n dicati o ns m ust 
be rec or de d at eac h visit. If a c h a n ge is d ue t o a n a d verse e v e nt , t he n t his m ust be re p orte d 
acc or di n g t o Secti o n 8. 3 . 
F or i nf or m ati o n re gar di n g c o n c o mita nt me dicati o n c ollecti o n i ncl u di n g a nti -dia betic me dicati o n 
a n d ot her i n dicati o ns f or s u bjects w h o disc o nti n ue trial pr o d uct see Secti o n 7 . 
6. 5. 1  
Resc ue me dic ati o n or R esc ue t her a p y  
N ot a p plica ble f or t his trial . 
6. 6  
D ose m o dific ati o n  
D oses are a dj uste d acc or di n g t o bl o o d/ plas ma gl u c ose val ues as descri be d i n 
A p pe n di x  8  ( Secti o n 1 0. 8 ). 
6. 6. 1  
D ose esc al ati o n tri als  
N ot a p plica ble f or t his trial.  
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 ucts, t he s u bject s h o ul d be t ra 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 . If t he s witc h t o p ost-trial treat me nt i ncl u des a ne w i ns uli n 
treat me nt, please refer t o t he titrati o n g ui deli ne i n A p pe n di x 8 ( Secti o n 1 0. 8 ).  
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 gator  f or safet y, be ha vi o ural, c o m plia nce or a d mi nistrati ve reas o ns. 
Eff orts m ust be ma de t o ha ve t he s u bjects w h o dis c o nti n ue trial pr o d uct att e n d t he e n d of tr eat me nt 
visit  ( V2 8 ) as s o o n as p ossi ble t o c ollect t he re q uire d data f or t he a n al ysis of t he pri mar y e n d p oi nt. 
T w o f oll o w -u p visits, V 2 9  a n d V 3 0 , m ust be perf or me d after disc o nti n uati o n of t he trial pr o d uct. 
Visits V 2 9  a n d V 3 0  m ust be c o n d ucte d 3 a n d 6 wee ks res pecti vel y after disc o nti n uati o n of o nce 
wee kl y i ns uli n ic o dec a n d 2 a n d 5 wee ks res pecti vel y  after disc o nti n uati o n of o nce dail y i ns uli n 
glar gi n e. It is stresse d t hat t he visit wi n d o w is pl us  3 da ys f or b ot h  visits  V 2 9  a n d V 3 0 . 
F urt her, it is i m p orta nt t hat disc o nti n ue d s u bjects c o me i n f or disc o nti n uati o n f oll o w -u p visit V 2 8 A, 
2 6 wee ks after t he  ra n d o misati o n visit. V 2 8 A will be t he last visit f or disc o nti n ue d s u bjects. 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
3 4
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 5  of 1 0 2  
 
S u bjects w h o pre mat urel y disc o nti n ue trial pr o d u ct s h o ul d kee p a n d use t h e e Diar y , a n d ret ur n it at 
t he f oll o w-u p 2  visit ( V 3 0).  
T he i n vesti gat or s h o ul d c ha n ge s u bject stat us i n t he healt hcare pr ofessi o nal  (H C P ) we b p ortal t o 
' F oll o w-u p' at t he e n d of treat me nt visit t o e ns ure t hat t he s u bject s h o ul d n o l o n ger re p ort i ns uli n 
d ose.  
C o nti n ue t o c ollect, rec or d a n d re p ort A Es as descri be d i n Secti o n 8. 3 . A Es  a n d a nti-dia betic 
me dicati o n s h o ul d be c ollecte d a n d rec or de d i n t h e e C R F u ntil t he disc o nti n uati o n f oll o w-u p visit 
( V 2 8 A) f or disc o nti n ue d s u bjects, n o ot her c o nc o mita nt me dicati o n will be c ollecte d. Pleas e, refer 
t o Secti o n 6. 7  f or treat me nt after e n d of trial. 
I n case of a n y u ncertai nt y re gar di n g t he s c he d uli n g of t he visits aft er disc o nti n uati o n or q uesti o ns t o 
sai d visits, t he i n vesti gat or s h o ul d c o ns ult N o v o N or dis k f or f urt h er g ui da nce.  
O nl y s u bjects w h o wit h dra w c o ns e nt will be c o nsi dere d as wit h dra w n fr o m t he trial. S u bjects m ust 
be e d ucate d a b o ut t he c o nti n ue d scie ntific i m p orta nce of t h eir data, e ve n if t he y disc o nti n ue tri al 
pr o d uct. F urt h er, t he site s h o ul d sta y i n c o ntact wit h disc o nti n ue d s u bjects b y p h o ne a n d/ or site 
visits t o m oti vate s u bjects t o at te n d t he visits u ntil t he disc o nti n uati o n f oll o w-u p visit ( V 2 8 A). Site 
c o ntact wit h disc o nti n ue d s u bjects s h o ul d be d oc u me nte d i n t he me dical r ec or d.  
7. 1  
Disc o nti n u ati o n of tri al tre at me nt  
T he trial pr o d uct m ust be disc o nti n ue d, if a n y of t he f oll o wi n g a p plies  f or t he s u bject: 
1.  Safet y c o ncer n relate d t o trial pr o d uct or u nacce pt a ble i nt olera bilit y  
2.  Pre g n a nc y  
3.  I nte nti o n of b ec o mi n g pre g n a nt 
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 a 
5.  Lac k of effic ac y,  d efi ne d as f ulfil me nt of A L L  4 criteria bel o w:  
a. N o re d ucti o n i n H b A 1c meas ure d b y ce ntr al la b orat or y fr o m ra n d o misati o n ( V 2) t o 
V 1 2 , or t o V 2 0 , A N D  
b.  the pre -brea kfast S M P G rea di n gs o n 3 c o ns ec uti ve da ys hi g her t ha n 2 4 0 m g/ d L 
( 1 3. 3 m m ol/ L) wit hi n t he last t w o wee ks peri o d des pite a p pr o priate d os e 
a dj ust me nts , A N D  
c. a c o nfir mat or y fasti n g plas ma gl u c ose e x cee di n g 2 4 0 m g/ d L ( 1 3. 3 m m ol/ L) 
meas ure d b y ce ntral la b orat or y. T he s u bject s h o ul d c o me i n f or a n u ns c he d ule d visit 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
3 5
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 6  of 1 0 2  
 
as s o o n as p ossi ble ( wit hi n o ne wee k) , the ne xt sc he d ule d visit s h o ul d n ot be 
a waite d , A N D  
d.  n o treata ble i nterc urre nt ca use (e. g. n o n -c o m plia nce) f or t he h y per gl ycae mia at t he 
i n vesti gat or’s j u d g me nt. 
a Si m ulta ne o us partici pati o n i n a trial wit h t he pri mar y o bj ecti ve of e val uati n g a n a p pr o ve d or  n o n -a p pr o ve d 
i n vesti gati o nal me dici nal pr o d uct f or pre ve nti o n or treat me nt of C O VI D-1 9 disease or p osti nfecti o us c o n diti o ns is 
all o we d at t he i n vesti gat or dis creti o n wit h o ut disc o nti n ui n g trial pr o d uct.  
T he pri mar y reas o n f or disc o nti n uati o n of trial pr o d uct m ust be s pecifie d i n t he e n d  of  treat me nt 
f or m i n t he e C R F, a n d fi nal dr u g acc o u nta 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.  
A s u bject, w h o d oes n ot f ulfil t he eli gi bilit y (i ncl usi o n/e x cl usi o n) criteria, m ust n ot be  ra n d o mise d. 
Ra n d o misati o n i n vi olati o n of a n y of t he eli gi bilit y criteria is g o o d cli nical p ractice ( G C P) n o n-
c o m plia nce a n d m ust be re p orte d t o t he s p o ns or wit h o ut dela y. T his will be ha n dle d as a n i m p orta nt 
pr ot oc ol de viati o n, a n d t he i n de pe n de nt et hics  c o m mittee/i nstit uti o nal re vie w b oar d (I E C/I R B) a n d 
re g ulat or y a ut h orities m ust be n otifie d acc or di n g t o l ocal re q uir e me nts.  
S u bjects t hat are ra n d o mise d i n vi olati o n of i ncl usi o n a n d e x cl usi o n criteria ca n be all o we d t o 
c o nti n ue i n t he trial a n d recei ve tri al pr o d uct if t here are n o safet y c o ncer ns as e val uate d b y t h e 
i n vesti gat or a n d N o v o N or dis k me dical s pecialist. 
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  
T he s u bject s h o ul d a d here t o t he treat me nt t o t he e xte nt p ossi ble, wit h t he e x ce pti o n of a n y a d v erse 
e ve nts s uc h as h os pitalisati o n or safet y c o n cer ns, at t he discreti o n of t he i n vesti gat or. S u bjects w h o 
ha ve te m p oraril y disc o nti n ue d trial pr o d uct are all o we d t o restart tri al pr o d uct, u nless a n y of t he 
disc o nti n uati o n criteria s pecifie d i n Secti o n  7. 1  a p plies.  
7. 1. 2  
Resc ue criteri a  
N ot a p plica ble f or t his tri al. 
7. 2  
S u bject disc o nti n u ati o n/ wit h dr a w al fr o m t he tri al  
A s u bject ma y wit h dra w c o nse nt at a n y ti me at his/ her o w n re q u est. If a s u bject wit h dra ws c o ns e 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 me nt 
perf or me d acc or di n g t o  t he e n d of tr eat me nt visit ( V2 8 ). See t he fl o wc h art ( 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 p erf 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 stat us sessi o n m ust be ma de i n t he I W R S. 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
3 6
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
3 7  of 1 0 2  
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.  
If a s ubject 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 n e d, t he pri mar y reas o n f or wit h dra wal m ust be s pecifie d i n t he e n d of trial 
f or m i n t he e 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 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 /s he re p eate dl y fails t o ret ur n f or sc h e d ule d visits 
a n d is u na ble t o be c o nta cte 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 f ails t o ret ur n t o t he site f or a re q uir e d visit: 
• T he site m ust atte m pt t o c o ntact t he 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 m ai ntai ni n g t he ass i g ne d visit sc he d ule a n d
ascert ai 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 r e gai n c o ntact wit h t he s u bject ( w here p ossi bl e, 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 s o urce d oc u m e nt.  
• S h o ul d t he s u bject c o nti n ue t o b e 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 (s ee Secti o n 1. 2 ). 
• I nf or me d c o ns e nt m ust be o btai ne d bef ore a n y trial relate d acti vit y, see
A p pe n di x  1  ( Secti o n 1 0. 1. 3 ).
• All scree ni n g e v al uati o ns m ust be c o m plete d a n d re vie we d t o c o nfir m t hat p ote ntial 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 r ec or d det ails of all s u bjects sc ree 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 details of rele va nt site staff t hat ca n be c o nt acte d  i n case of e mer ge nc y.
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
3 7
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 8  of 1 0 2  
 
•  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 s pecifie d 
i n t he c urre nt se cti o n. Eff orts s h o ul d be ma de t o li mit t he bias bet wee n t he assess me nts. T he 
s u g geste d or der of t he assess me nts at ra n d o misati o n visit ( V 2) is as f oll o ws:  
o  Bl o o d sa m ple c ollecti o n  
o  O t her assess me nts t o c o nfir m eli gi bilit y 
o  R a n d o misati o n i n IW R S  
o  C o nti n u o us gl uc ose m o nit ori n g  fitti n g a n d trai ni n g 
o  T he in vesti gat or s h o ul d create a s u bject pr ofile a n d rec or d a d mi nistrati ve 
i nf or mati o n (e. g. s u bject I D, year of birt h a n d ge n der a n d tr eat me nt ar m i n t he H C P 
we b p ortal  
o  S u bjects s h o ul d be pr o vi de d wi t h a n e Diar y a n d i nstr ucte d i n h o w t o use it.  
o  T he B G m eter s h o ul d be c o n necte d wit h t he e Diar y  
o  A fasti n g S M P G s h o ul d be meas ure d usi n g t he B G meter  
o  D osi n g of tri al pr o d uct . 
•  F or i nf or m ati o n re gar di n g t he e Diar y a n d H C P we b p ortal pleas e refer t o t he site g ui de.  
•  Please refer t o Secti o n 6. 4  f or dr u g treat me nt c o m plia nce. 
•  All data e ntere d i n t he e Diar y is c o nsi dere d s o urce data. T he i n v esti gat or s h o ul d re vie w all t he 
data f or t he s u bjects t hr o u g h t he H C P we b p ortal, bef ore or d uri n g eac h visit/ p h o ne c o ntact.  
•  Re vie w of e Di ar y, E C G, la b orat or y re p orts, e ye - a n d p h ysic al e xa mi nati o ns m ust be 
d oc u me nte d eit her o n t h e d oc u me nts or i n t he s u bject's s o urce d oc u me nts. If clarificati o n of 
e ntries or discre pa nci es i n t he e Diar y is ne e de d, t h e 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 s o urce d o c u me nts, t he e Diar y s h o ul d be u p date d 
retr os pecti vel y if a p plica ble. Care m ust be ta ke n n ot t o bias t he s u bject. 
•  S o urce data of cli nical assess me nts perf or m e d a n d rec or de d i n t he e C R F m ust be a vaila ble a n d 
will us uall y b e i n t he s u bject’s me dical r ec or ds. A d diti o nal rec or di n g t o be c o nsi dere d s o urce 
data i ncl u des, b ut is n ot li mite d t o;  la b orat or y re p orts, B G meter, C G M, pict ures a n d E C G 
rec or di n gs.  
•  Re peat sa m ples ma y be t a ke n f or t ec h nical iss ues a n d u nsc he d ule d s a m ples or assess me nts ma y 
be ta ke n f or safet y reas o ns. Please refer t o A p p e n di x 2 ( Secti o n 1 0. 2 ) f or f urt 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 ( see Secti o n 1. 2 ). 
8. 1. 1  
Self -me as ure d pl as m a gl uc ose ( S M P G)  
S u bjects will be pr o vi de d wit h a bl o o d gl uc ose m eter i ncl u di n g a u xiliaries. T he B G m eters use test 
stri ps cali brate d t o plas m a val ues. T heref ore, all m eas ure m e nts perf or me d wit h ca pillar y bl o o d are 
a ut o maticall y cali brate d t o plas ma e q ui vale nt gl uc ose val ues, w hic h will be s h o w n o n t he dis pla y .  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
3 8
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
3 9  of 1 0 2  
 
T he B G m eter pr o vi d e d b y N o v o N or dis k s h o ul d be use d f or t h e plas ma gl uc ose meas ure me nts 
re q uire d i n t he pr ot o c ol, as descri be d i n t he fl o wc hart (see Secti o n 1. 2 ). 
A baseli ne S M P G val ue, i n fasti n g c o n diti o n, s h o ul d be c ollecte d usi n g t he B G meter at V 2.  
4 -p oi nt d ail y S M P G  
S u bjects s h o ul d be i nstr ucte d t o meas ure t heir pre -pra n dial a n d be dti me S M P Gs dail y fr o m w ee k 0 
( V 2) t o e n d of tri al ( V 3 0) at t he f oll o wi n g ti me p oi nts: pre -brea kfast, pr e -l u nc h, pre-di n n er, a n d at 
be dti me. T he s u bject s hall tra nsfer t he m eas ure d S M P G val ues i nt o t he e Diar y.  
Selecte d titrati o n data (e. g. certai n S M P Gs a n d d ose data) fr o m t he e Di ar y will be use d d uri n g t h e 
trial f or ce ntral titratio n s ur veilla nce, t o e ns ure c o m plia nce wit h t he titrati o n g ui deli ne i n 
A p pe n di x  8 ( Secti o n  1 0. 8 ) a n d will n ot be re p ort e d i n t he cli nical trial re p ort. All data will be st ore d 
b y N o v o N or dis k (see A p pe n di x 1, Secti o n  1 0. 1 ). 
8. 1. 2  
C o nti n u o us gl uc ose m o nit ori n g  
S u bjects will be e q ui p pe d wit h a C G M de vice d uri n g t he treat me nt peri o ds fr o m wee k 0  ( V 2) t o 
wee k 4  ( V 6), a n d fr o m w ee k 2 2 ( V 2 4) t o wee k 2 6 ( V 2 8) a n d d uri n g t he f oll o w-u p peri o d fr o m 
wee k 2 6  ( V 2 8) t o wee k 3 1 ( V 3 0). 
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 ® . 
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 
i ns uli n d ose titrati o n 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 o n fitti n g  of t he se ns or a n d tr a ns mitter o n t he s u bject 
d uri n g t he site visits. Trai ni n g i n t he C G M is t he res p o nsi bilit y of t h e i n vesti gat or or site staff at t he 
rele va nt visits. F or i nf or mati o n o n fitti n g, a n d c h a n gi n g of t he C G M parts, please refer t o t he 
ma n ufac t ur er’s ma n u al a n d s u bject g ui de pr o vi de d. 
C G M Se ns or C hec k  
T he site staff s h o ul d e ns ure t hat t he s u bject h as fitte d t he se ns or c orrectl y a n d t hat t he C G M 
recei v er is w or ki n g. T his will be d o ne i n pers o n d uri n g t he cli nic visit, as s pecifie d i n t he fl o wc hart 
(see Secti o n  1. 2 ). At t he e n d of treat me nt visit ( V 2 8), t he site s h o ul d e ns ure t he s u bject ca n c ha n ge 
t he se ns or at h o me w ee kl y d uri n g t he f oll o w-u p peri o d.   
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
3 9
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
4 0  of 1 0 2  
C G M U pl o a d  
Data st ore d o n t he C G M recei v er m ust be u pl oa de d at t he site b y t he site st aff 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 nt e d b y t h e s yst e m 
directl y.  
T he serial n u m ber of t he C G M r ecei ver m ust be rec or de d i n t he e C R F at t he start of eac h C G M 
peri o d. I n case t he C G M recei v er is bei n g re place d, t he 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  (see S ecti on 1. 2 ) a n d t he la b orat or y ma 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  (see Secti o n 1. 2 ). 
A c o nc o mit a nt ill ness  is a n y ill ness t hat is alr ea d y prese nt at t he ti me p oi nt fr o m w hic h A Es are 
c ollecte d or f o u n d as a res ult of a scree ni n g pr oce d ure or ot her trial pr oce d ures perf or me d bef ore 
e x p os ure t o trial pr o d uct.   
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 me dical hist or y as j u d ge d b y t he i n vesti gat or will be rec or de d i n 
t he e C R F. 
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. 
Wit h re gar d t o e x cl usi o n criteria 1 2 ( Secti o n 5. 2 ), i nf or mati o n o n h y p o gl ycae mia u na ware n ess will 
be rec or de d acc or di n g t o Clar ke's q uesti o n naire, q uesti o n 8 1 7. T he i n vesti gat or m ust as k t he s u bject 
i n t he f oll o wi n g wa y: " T o w hat e xte nt ca n y o u tell b y y o ur s y m pt o ms t hat y o ur bl o o d gl uc os e is 
l o w?" S u bjects a ns weri n g 'ne v er, rarel y or s o meti mes' are c o nsi dere d t o h a ve i m paire d a ware ness of 
h y p o gl ycae mia, w h ereas t h ose a ns weri n g “ ofte n or al wa ys” are n ot .  
8. 2. 1  
I ns uli n d ose 
T he prescri be d  i ns uli n d oses will be deter mi ne d  b y t he i n vesti gat or i n acc or da nce wit h t he titrati o n 
g ui deli ne  (see A p p e n di x 8, Secti o n 1 0. 8 ). 
D uri n g t h e trial, starti n g at ra n d o misati o n ( V 2), s u bjects m ust be i nstr ucte d t o re p ort date , d ose a n d 
ti me of o nce wee kl y i ns uli n or o nce dail y i ns uli n, a n d of b ol us i ns uli n i n t he e Diar y. I n t he f oll o w-
u p peri o d if t he s u bject s witc hes t o a ne w basal i ns uli n  a n d a ne w b ol us i ns uli n , t he s u bject s h o ul d 
als o re p ort date, d os e a n d ti me of t he ne w bas al  a n d b ol us  i ns uli n i n t he e Diar y. 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
4 0
 
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6
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C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 1  of 1 0 2  
 
Please refer t o A p p e n di x 8 ( Secti o n 1 0. 8 ) f or m or e i nf or mati o n. 
T he i n vesti gat or m ust rec or d t he f oll o wi n g i n t he e C R F  
•  
First a n d last date o n tri al pr o d uct  
•  
First a n d last d ose of tri al pr o d uct  
F or d osi n g of a nti -dia b etic me dicati o n pres cri be d i n t he f oll o w -u p peri o d pl ease see S ecti o n 6. 5  
8. 2. 2  
P h ysic al e x a mi n ati o ns  
A p h ysic al e x a mi nati o n will i ncl u de assess me nts of:  
•  
Hea d, ears, e yes, n ose, t hr oat, nec k  
•  
Car di o vasc ular s yste m  
•  
Res pirat or y s yst e m  
•  
Gastr oi ntesti nal s yste m  
•  
Ce ntral a n d Peri p heral N er v o us S yste m  
•  
M usc ul os keletal s yste m  
•  
S ki n.  
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.  
T he p h ysi cal e x a mi nati o n will be rec or de d i n t he e C R F as eit her ‘ n or mal’ or ‘a b n or mal’. If 
‘a b n or mal’, a c o m me nt m ust be gi ve n t o get her wit h a n assess me nt of cli nical si g nifi ca nce ( yes/ n o).  
A b n or mal, cli nicall y si g nifica nt fi n di n gs at scree ni n g s h o ul d be rec or de d as c o nc o mita nt ill ness i n 
t he e C R F. At t he f oll o wi n g visits, a n y ne w a b n or mal, cli nicall y si g nifica nt fi n di n gs or cli nicall y 
si g nifica nt d eteri or ati o ns fr o m baseli ne s h o ul d be re p orte d as a n a d verse e v e nt  (see 
A p pe n di x  3 , Secti o n  1 0. 3 ). 
B o d y meas ure me nts ( hei g ht a n d wei g ht) will als o be meas ure d a n d rec or de d . Hei g ht will be 
meas ure d  a n d rec or de d  at scree ni n g visit ( V 1) . Wei g ht will be meas ure d a n d rec or de d t hr o u g h o ut 
t he trial as s pecifi e d i n t he fl o wc hart ( Secti o n 1. 2 ). 
o  B o d y wei g ht s h o ul d be meas ure d i n kil o gra m ( k g) or p o u n ds (l b) wit h o ut c oat a n d 
s h oes weari n g o nl y li g ht cl ot hi n g. B o d y wei g ht will be rec or de d t o o ne deci mal.  
o  B o d y wei g ht s h o ul d be assesse d wit h t he sa me e q ui p me nt t hr o u g h o ut t he trial, if 
p ossi ble.  
o  Hei g ht s h o ul d be meas ure d i n ce nti metres (c m) or i nc hes (i n) wi t h o ut s h oes. Hei g ht 
will be rec or de d t o t he nearest w h ole n u m ber.  
o  Fr o m t he b o d y w ei g ht a n d hei g ht, t he B MI s h o ul d be calc ul ate d a n d rec or de d i n t he 
s u bject’s me dical r ec or ds.  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
4 1
 
-
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6
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C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
4 2  of 1 0 2  
8. 2. 3  
Vit al si g ns  
• P ulse rate, as w ell as s yst olic a n d diast olic bl o o d press ure will be  assesse d .
• 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 tele visi o n, m o bil e p h o nes).
• Bl o o d press ur e a n d p ulse rate meas ure me nts will be as sesse d sitti n g wit h a c o m pletel y
a ut o mate d de vice. Ma n u al tec h ni q 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 a n d p ulse rate at scree ni n g ( V 1), V 1 6 a n d e n d of tr eat me nt ( V 2 8) will c o nsist of
3 s yst olic a n d diast olic bl o o d p ress ure meas ure m e nts wit h i nter vals of at least 1-2 mi n utes. A n
a d diti o nal f o urt h bl o o d press ure meas ure m e nt m ust be perf or m e d if t he first t w o rea di n gs o n 
s yst olic or diast olic bl o o d press ure differ b y > 1 0 m m H g. S yst olic bl o o d press ure will be 
calc ulate d as t he mea n of t he last 2 s yst olic bl o o d press ure rea di n gs, a n d di ast olic bl o o d 
press ure as t he mea n of t he last 2 diast olic bl o o d press ure rea di n gs. O nl y t he last 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.  
• P ulse  rate will be meas ur e d i n c o n necti o n t o t he bl o o d press ure meas ure m e nts. Rec or d t he p ulse
rate f or t h e last 2 bl o o d press ure meas ure m e nts i n t he e C R F. T he p ulse rate will be calc ulate d
as t he mea n of t h e last 2 meas ure me nts.  
8. 2. 4  
Electr oc a r di o gr a ms  
• A 1 2 -lea d E C G m ust be perf or me d b y t h e i n vesti gat or or dele gate d staff as o utli ne d i n t he
fl o wc hart ( Secti o n 1. 2 ).
• T he E C G s h o ul d be prece de d b y at l east 5 mi n utes of rest f or t he s u bj ect i n a s u pi ne/sitti n g
p ositi o n i n a q uiet setti n g wit h o ut distracti o ns (e. g. n o use of tele visi o n, m o bile  p h o nes).
• T he E C G m ust be i nter prete d, si g n e d a n d dat e d b y t he i n vesti gat or t o v erif y t hat t he data has
bee n re vi e we d .
• T he E C G re q uir e d at scree ni n g ca n be o bt ai ne d wit hi n 2 wee ks pri or t o V 2 b ut at t he latest at
V 2. T he res ults m ust be i nter prete d b y t h e i n vesti gat or pri or t o ra n d o misati o n i n or der t o
deter mi ne t he eli gi bilit y of t he s u bject.  
• T he E C G re q uir e d at t he e n d of treat me nt visit ca n be o btai ne d wit hi n 2 wee ks pri or t o t he e n d
of treat me nt visit. T he res ults m ust be a vaila ble f or e val uati o n at t he e n d of treat me nt visit.
• A b n or mal, cli nicall y si g nifica nt fi n di n gs at scree ni n g s h o ul d be rec or de d as c o nc o mita nt ill ness
i n t he e C R F. At t he f oll o wi n g visits, a n y ne w a b n or mal, cli nicall y si g nifica nt fi n di n gs or
cli nicall y si g nifica nt d eteri orati o ns fr o m baseli ne s h o ul d be re p orte d as a n a d verse e v e nt  (see 
A p pe n di x  3 , Secti o n  1 0. 3 ). 
8. 2. 5  
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 ote 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.  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
4 2
 
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6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 3  of 1 0 2  
 
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 m e d as a f u n d us 
p h ot o gra p h y (e. g. 2 -fiel d 6 0 de gree or better, c ol o ur or re d-free) or b y slit-la m p bi o micr osc o p y 
e x a mi nati o n (e. g. usi n g a pr e-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. E ye e x a mi nati o ns perf or me d pri or t o ra n d o misati o n visit ( V 2) are acce pta ble 
if res ults are a vaila ble f or e val uati o n bef ore ra n d o misati o n. If t he a p plica bl e e ye e x a mi nati o n was 
perf or me d b ef ore t he s u bject si g ne d t h e 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 o n f or perf or mi n g t he e x a mi nati o n was n ot relate d t o t his trial.  
E ye e x a mi nati o ns re q uire d at t he e n d of tr eat me nt ( V 2 8) visit ca n be p erf or me d wit hi n 2 wee ks 
pri or t o t he visit, if res ults are a v aila ble f or e val uati o n at t he visit. F or disc o nti n ue d s u b jects, e ye 
e x a mi nati o n ca n be perf or me d u p t o 2 wee ks after t he e n d of treat me nt visit. T he i n vesti gat or 
s h o ul d i n dicate t he o utc o me of eac h e ye e x a mi nati o n. Rele va nt fi n 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. W hile rele va nt fi n di n gs occ 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 d v erse e v e nt , please refer t o Secti o n 8. 3 . 
8. 2. 6  
Cli nic al s af et y l a b or at or y assess me nts  
All pr ot oc ol -re q uir e d la b orat or y assess me nts, as defi ne d i n 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 (see S ecti o n 1. 2 ) a n d la b orat or y ma n ual . 
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 defi niti o n of a n A E or S A E. 
T he defi niti o n of A Es a n d S A Es ca n be f o u n d i n A p pen di x 3 ( Secti o n 1 0. 3 ), al o n g wit h a 
descri pti o n of e ve nts f or a dj u dicati o n a n d  A Es re q uiri n g a d diti o nal data c ollecti o n.  
S o me A Es re q uire a d diti o nal data c ollecti o n o n a s pecific e v e nt f or m. T his al wa ys i ncl u des 
me dicati o n, mis use a n d a b use of I M P. T he rele va nt e ve nts are liste d i n Ta bl e  8 -1 , t o get her wit h 
e ve nts f or a dj u dicati o n.  
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 d ata c ollecti o n o n a h y p o gl ycae mic e pis o de f or m i n t he e Di ar y. 
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 h e 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
4 3
 
-
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6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 4  of 1 0 2  
 
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 i nf or mati o n f or m m ust be fille d i n i n t he e C R F, 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 
( Secti o n 1 0. 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), a n d 
e ve nts f or a dj u dic ati o n   
E ve nt t y pe   
A E re q uiri n g a d diti o n al d at a 
c ollecti o n  
E ve nt f or a dj u dic ati o n  
 
Me dicati o n err or  
X  
 
Mis use a n d a b use  
X  
 
Ac ute c or o nar y s y n dr o me (ac ute m y ocar dial 
i nfarcti o n or u nsta ble a n gi na pect oris re q uiri n g 
h os pitalisati o n)  
 
X  
Cere br o vasc ular e ve nts a (str o ke or tra nsie nt 
isc he mic attac k) 
 
X  
Heart fail ure (re q uiri n g h os pit alisati o n or ur ge nt 
heart fail ure visit)  
 
X  
Deat h  
 
X  
H y perse nsiti vit y  
X  
 
I nj ecti o n Site Reacti o n 
X  
 
a All cere br o vasc ular e ve nts ar e t o be re p orte d a n d se nt f or a dj u dicati o n, h o we ver t he E A C will o nl y c o nfir m str o kes.  
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  ( Secti o n 1 0. 3. 3 ). 
E ve nts f or A dj u dic ati o n  
E ve nt a dj u dicati o n will be perf or me d i n ra n d o mis e d s u bjects a n d will be e val uate d b y a n 
i n de pe n de nt e xter nal E A C i n a bli n de d ma n ner, pl ease refer t o Secti o n 1 0. 1. 6. 4 . 
T here are f o ur wa ys t o i d e ntif y e ve nts rel e va nt f or a dj u dicati o n as descri be d bel o w:  
•  
I n v esti gat or-re p orte d e ve nts f or a dj u dicati o n: i n vesti gat or selects t he a p pr o priate A E 
cate g or y rele v a nt f or a dj u dicati o n ( A p pe n di x 3, Secti o n 1 0. 3. 3 ). 
•  
A Es re p orte d wit h fatal o utc o me .  
•  
A E searc h (sta n dar dise d scree ni n g): All A Es n ot re p orte d wit h a n A E cate g or y rele va nt f or 
a dj u dicati o n will u n der g o scree ni n g t o i de ntif y p ote ntial e ve nts f or a dj u dicati o n. 
I n v esti gat ors will be n otifie d of t hese e ve nts i n t he e C R F.  
•  
E A C -i de ntifie d e ve nts: U nre p orte d e ve nts rel e va nt f or a dj u dicati o n i de ntifie d b y t he E A C 
d uri n g re vie w of s o urce d oc u me nts pr o vi de d f or a n ot her e v e nt f or a dj u dicati o n.  
I n v esti gat ors will be n otifie d of t hese e ve nts i n t he e C R F a n d h as t he o pti o n t o re p ort t he 
E A C -i de ntifie d e ve nt.  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
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V V- T M F- 6 1 0 0 2
1 0 2
 of
4 4
 
-
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6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
4 5  of 1 0 2  
F or eac h e v e nt rel e va nt f or a dj u dicati o n a n e v e nt t y p e s p ecific a dj u dicati o n f or m s h o ul d be 
c o m plete d i n t he e C R F wit hi n 1 4 da ys.  
C o pies of s o urce d o c u me nts s h o ul d be u pl oa de d t o t he e ve nt a dj u dicati o n s yste m ( E A S) as s o o n as 
p ossi ble a n d prefera bl y w it hi n 4 wee ks. I n cases w here t he E A S is n ot accessi ble t he i n vesti gat or 
s h o ul d e ns ure t hat t he rele va nt s o urce d oc u me nts are c ollecte d a n d s a ve d l ocall y u ntil t he E A S is 
rea d y. If n o, or i ns uffi cie nt s o urce d oc u me nts are pr o vi de d t o t he a dj u dicati o n s u p plier, t he 
i n vesti gat or ca n be as ke d t o c o m plete a cli nical narrati ve t o be u pl oa d e d t o t he E A S.  
If ne w i nf or mati o n bec o mes a vaila ble f or a n e v e nt se nt f or a dj u dicati o n, it is t he res p o nsi bilit y of 
t he i n vesti gat or t o e ns ure t he ne w i nf or mati o n is u pl oa de d t o t he E A S. 
A n eve nt adj u dicati o n site m a n ual will be pr o vi de d t o eac h site detaili n g w hic h s o urce d o c u me nts 
are rele va nt a n d h o w t hes e s h o ul d be pr o vi de d t o t he a dj u dicati o n s u p plier. T he a n o n y mizati o n a n d 
la belli n g re q uire me nts are als o descri b e d i n t he e v e nt a dj u dicati o n site ma n ual.  
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 ra n d o misati o n visit a n d u ntil t he e n d of trial visit  as 
s pecifie d i n t he fl o wc hart (see Secti o n 1. 2 ). F or s u bjects disc o nti n ui n g trial pr o d uct pre mat urel y 
A Es m ust be c ollecte d u ntil t he d isc o nti n uati o n foll o w -u p visit  (V 2 8 A ). 
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 ( Secti o n 1 0. 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 wit hi n 2 4 h o urs, a n d t he i n vesti gat or m ust s u b mit a n y u p d ate d S A E data t o N o v o N or dis k 
wit hi n 2 4 h o urs of it bei n g a 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 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.  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
4 5
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 6  of 1 0 2  
 
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 o acti 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 ( Secti o n 1 0. 3 ). 
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 R).  
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 bjects will be c ollecte d  fr o m first e x p os ure t o trial pr o d uct a n d 
u ntil  t he ne w-b or n i nfa nt is o ne m o nt h of a ge.  
If a fe male 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 n a nc y a n d s h o ul d f oll o w t he pr oce d ures  o utli ne d i n 
A p pe n di x  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  
Dise ase -rel ate d e v e nts a n d/ or dise ase -rel ate d o utc o mes n ot q u ali f yi n g as a n A E or 
S A E  
N ot a p plica ble f or t his trial.  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
4 6
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 7  of 1 0 2  
 
8. 3. 8  
A d verse e v e nt of s peci al i nterest a 
N ot a p plica ble f or t his trial.  
a A d verse e ve nts of s pecial i nt erest are, as per N o v o N or dis k defi niti o ns a n d pr ocesses, re q uire d t o ha ve e x pe dite d 
re p orti n g b y t he i n vesti gat ors. O nl y a d verse e ve nts f ulfilli n g t he seri o us ness criteria are c o nsi dere d f or e x pe dite d 
re p orti n g i n t his trial. 
8. 3. 9  
Tec h nic al c o m pl ai nts  
Tec h nical c o m plai nts will be c ollecte d f or all pr o d ucts liste d o n t he tec h nical c o m plai nt f or m.  
I nstr u cti o ns f or re p orti n g tec h nical c o m plai nts ca n be f o u n d i n A p pe n di x 5 ( Secti o n 1 0. 5 ). 
I n or der f or N o v o N or dis k t o perf or m a c o m plete i n vesti gati o n of re p orte d S A Es, N o v o N or dis k 
mi g ht as k t he i n vesti gat or t o c o m plete a tec h nical c o m plai nt f or m.  
8. 4  
Tre at me nt of o ver d ose  
Acci de ntal o v er d ose m ust be re p orte d as a me dicati o n err or. I nte nti o nal o v er d ose m ust be re p orte d 
as mis use a n d a b use, ple ase refer t o Sect i o n 8. 3  a n d A p pe n di x 3 ( Secti o n  1 0. 3. 3 ) f or f urt her det ails. 
I n t he e ve nt of a n o ver d ose, t he i n vesti gat or s h o ul d cl osel y m o nit or t he 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 u ntil t he bl o o d gl uc os e is n or malise d a n d ( or) 
si g ns/s y m pt o ms ha ve b ee n relie ve d. 
A s pecific o v er d ose f or i ns uli n ic o dec ca n n ot be defi ne d; h o we v er, h y p o gl ycae mia ma y d e vel o p 
o ver se q ue ntial sta ges if t he d oses a d mi nistere d are t o o hi g h relati ve t o t he s u bject’s re q uir e me nts.  
•  
Mil d h y p o gl ycae mia ca n be treate d b y oral a d mi nistrati o n of gl uc os e or s u gar y pr o d ucts.  
•  
Se vere h y p o gl ycae mia, w here t he s u bj ect is n ot a ble t o treat hi m/ herself, ca n be treate d b y 
gl uc a g o n ( 0. 5 t o 1 m g) gi ve n i ntra m usc ularl y or s u bc uta ne o usl y b y a tr ai ne d pers o n, or b y 
gl uc ose gi v e n i ntra ve n o usl y b y a me dical pr of essi o nal. Gl uc ose m ust als o be gi v e n 
i ntra ve n o usl y, if t h e s u bject d ose n ot res p o n d t o gl uca g o n wit hi n 1 0 -1 5 mi n utes. If t he 
s u bject has bee n u n c o nsci o us, a d mi nistrati o n of oral car b o h y drates is rec o m me n de d f or t he 
s u bject u p o n re gai ni n g c o nsci o us ness, i n or der t o pre ve nt a rela pse.  
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 i ns uli n ic o dec  
in vesti gat or’s br oc h ure 1 1 or  t he i ns uli n glar gi ne E M A s u m mar y of pr o d uct c haracteristics 1 2, U S 
prescri bi n g i nf or mati o n 1 3, or a n y l ocall y a p pr o ve d la bel; or i ns uli n as part i n vesti gat or’s br oc h ure1 4. 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
4 7
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 8  of 1 0 2  
 
8. 5  
P h ar m a c o ki netics  
Bl o o d sa m ples will be us e d t o e val uate t he p har m ac o ki netics ( P K) of i ns uli n ic o dec. P K sa m ples 
will be c ollecte d at t he visits o utli ne d i n t he fl o wc hart ( Secti o n 1. 2 ) f or s u bjects ra n d o mise d t o 
i ns uli n ic o dec. T he date a n d e x act cl oc k ti me f or bl o o d sa m pli n g m ust be rec or de d . 
Bi oa nal ysis of i ns uli n ic o dec sa m ples will be perf or me d at a s pecial la b orat or y u si n g a v ali date d 
lu mi nesce nt o x y ge n cha n nelli n g im m u n oassa y. T h e e x act met h o d will be descri be d i n a 
bi oa nal ytical re p ort.  
Resi d ual P K sa m ples ma y be us e d f or e x pl orat or y meta b olite a nal ysis. P ote ntial meta b olite a nal ysis 
will be re p orte d se p aratel y fr o m t he cli nical trial r e p ort .  
Ge netic a n al ys es will n ot be perf or me d o n t hese pl as ma/ser u m/ w h ole bl o o d sa m ples. S u bject 
c o nfi de ntialit y will be m ai ntai ne d.  
Pr oce d ures f or sa m pli n g, ha n dli n g, st ora ge, la belli n g a n d s hi p me nts of t he s peci me ns m ust be 
perf or me d  i n acc or da n ce wit h t he la b orat or y ma n ual. A ra n d o misati o n list will be pr o vi de d t o t he 
s pecial la b orat or y. Sa m ples fr o m ra n d o mise d s u bj ects will be a nal yse d f or i ns uli n ic o dec 
c o nce ntr ati o n.  
S u bjects s h o ul d be i nstr ucte d t o re p ort d osi n g i nf or mati o n i n t h e e Diar y as per Secti o n 8. 2. 1 . 
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. 
8. 7  
Ge neti cs  
N ot a p plica ble f or t his trial. 
8. 8  
Bi o m ar kers  
N ot a p plica ble f or t his trial. 
8. 9  
I m m u n o ge nicit y assess me nts 
8. 9. 1  
A nti -dr u g a nti b o dies  
A nti -dr u g a nti b o d y s a m ples will be c ollecte d acc or di n g t o t he fl o wc hart ( Secti o n 1. 2 ) f or s u bjects 
ra n d o mise d t o i ns uli n ic o dec. All sa m ples m ust be dra w n pri or t o trial pr o d uct a d mi nistrati o n if trial 
pr o d uct a d mi nistrati o n is pla n ne d o n t he sa m pli n g da y. Assess me nt of a nti b o dies a gai nst i ns uli n 
ic o dec (a nti-dr u g a nti b o dies) i n ser u m will be perf or me d at a N o v o N or dis k a p p oi nte d la b orat or y. 
F or details o n bl o o d sa m pli n g, ser u m pre parati o n a n d st ora ge, please refer t o t he la b orat or y ma n ual.  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
4 8
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
4 9  of 1 0 2  
 
A nal ysis f or a nti-dr u g a nti b o d y  will be d o ne as liste d i n fl o wc hart wit h a bi n di n g a nti -dr u g a nti b o d y  
assa y. P ositi ve sa m ples will be f urt her c h aracterise d f or titre, a n d cr oss -reacti vit y t o e n d o ge n o us 
h u ma n i ns uli n.  
Detaile d descri pti o n of t he assa y met h o ds will be i ncl u de d i n a n a n al ytical r e p ort. A nti b o d y assa ys 
will be vali date d acc or di n g t o i nter nati o na l g ui deli nes a n d rec o m me n dati o ns.  
At t he e n d of t he trial, t h e f oll o wi n g d ata will be electr o nicall y tra nsferre d t o t he N o v o N or dis k 
data base: A nti -i ns uli n ic o dec bi n di n g a nti b o dies ( p os/ ne g) a n d titre of a nti-dr u g a nti b o d y  p ositi ve 
sa m ples, a n d a nti-i ns uli n ic o dec bi n di n g a nti b o dies cr oss-reacti n g wit h e n d o ge n o us h u m a n i ns uli n 
stat us ( p os/ ne g). 
T he i n vesti gat or will n ot be a ble t o re vi e w t he res ults of a nti b o d y meas ure me nts i n relati o n t o A Es 
as t he sa m ples are ofte n a nal ys e d after last s u bject last visit . Res ults fr o m t he bi n di n g a nti-dr u g 
a nti b o d y a n al ys es fr o m visit s ra n d o misati o n ( V 2), V 4, V 8, V 1 2, V 2 0, e n d of treat me nt ( V 2 8) a n d 
e n d of trial  ( V 3 0) will be a vaila ble after t he c o m pleti o n of t he trial . 
8. 9. 2  
H y perse nsiti vit y  
S u bjects a n d i n vesti gat ors will be i nstr ucte d t o detect si g ns a n d s y m pt o ms of s yste mic 
h y perse nsiti vit y.  
F or s u bjects r a n d o mise d t o i ns uli n ic o dec: I n t he e ve nt of a s yste mic h y perse nsiti vit y ( n ot l ocall y at 
t he i njecti o n site), 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 pt ase ( o pti mal 0. 5 -2 h o urs p ost t he h y p erse nsiti vit y reacti o n)  
•  
T otal i m m u n o gl o b uli n E (I g E) a nti b o dies  
•  
A nti -i ns uli n ic o dec I g E a nti b o dies 
•  
A nti -i ns uli n ic o dec bi n di n g a nti b o dies 
•  
A nti -h u ma n i ns uli n 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 tests s h o ul d als o be perf or me d o n sa m ples dra w n pri or t o first 
a d mi nistrati o n of trial dr u g.  
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.  
A nal ysis will be perf or m e d b y N o v o N or dis k or a N o v o N or dis k a p p oi nte d s pecial la b orat or y 
( please refer t o Atta c h me nt I). T h e res ults will be re p orte d i n a se p arat e re p ort a n d attac h e d t o t he 
cli nical trial re p ort . 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
4 9
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 0  of 1 0 2  
 
If t he reacti o n is classifie d as a S A E, t he res ults fr o m t he h y perse nsiti vit y t ests will als o be re p orte d 
t o N o v o N or dis k Safet y O perati o ns f or i n cl usi on i n t he A R G U S data base a n d i ncl u de d i n t he 
narrati ves of t he cli nical trial re p ort . 
F or rete nti o n of resi d ual h y perse nsiti vit y sa m ples, please refer t o Secti o n 1 0. 6 . 
Di git al pict ures  
T he i n vesti gat or or t he s u bject m ust ta ke di gital pi ct ures of t he affecte d area at ti me of 
i de ntificati o n, usi n g a n y de vice a v aila ble ( m o bile p h o ne, ca mera et c.) a n d t hereafter as ofte n as 
j u d ge d n ecess ar y b y t he i n vesti gat or. T he pict ures s h o ul d i ncl u de s u bject i de ntificati o n n u m ber, 
date a n d ti me, ti me after d osi n g a n d a r uler f or scali n g. All pict ures m ust be st ore d as part of s o urce 
d oc u me ntati o n at site.  
8. 1 0  
He alt h ec o n o mics  
N ot a p plica ble f or t his trial.  
9  
St atist ic al c o nsi der ati o ns  
9. 1  
St atistic al h y p ot heses  
T he pri mar y h y p ot hesis t o be teste d is t hat i ns uli n ic o dec is n o n -i nferi or t o i ns uli n glar gi ne i n ter ms 
of c ha n ge fr o m bas eli ne t o wee k  2 6  i n H b A1c. 
F or mall y, let D be t he treat me nt differe nce ‘i ns uli n ic o dec’ mi n us ‘i ns uli n glar gi n e ’ of t he c ha n ge i n 
H b A 1 c fr o m baseli ne t o wee k 2 6 . T he n ull -h y p ot hesis will be teste d a gai nst t he alter nati ve 
h y p ot hesis of n o n -i nferi orit y as gi ve n b y  
H 0: D ≥0. 3 0 % a gai nst H A: D < 0. 3 0 %  
T he n o n -i nferi orit y mar gi n of 0. 3 %-p oi nt is c h ose n base d o n t he rec o m me n dati o n i n t he F D A 
g ui da n ce f or i n d ustr y o n de vel o pi n g dr u gs f or tr eat me nt of dia betes. 2 0 Als o, t his ma r gi n is 
c o nsi dere d t o pr o vi de s ufficie nt assa y se nsiti vit y b ase d o n t he bel o w c o nsi derati o ns:  
•  
T he mar gi n d oes n ot r e prese nt a n u nacce pt a ble l oss of efficac y wit h i ns uli n ic o dec relati ve 
t o treat me nt wit h a basal i ns uli n a nal o g ue. 
•  
It r e pres e nts less t ha n 5 0% of a s uita bl y c o nser vati ve esti mate of i ns uli n gl ar gi ne´s 
treat me nt effect o n H b A1c i n a place b o-c o ntr olle d trial i n a basal -b ol us i ns uli n treate d 
p o p ulati o n; T he treat me nt effect of glar gi ne vers us place b o i n a basal -b ol us i ns uli n treate d 
p o p ulati o n is  u n k n o w n b ut glar gi ne was s h o w n t o be s u peri or t o place b o i n i ns uli n naï ve 
s u bjects (esti mate d treat me nt differe n ce : -0. 8 5 % -p oi nt [ -1. 0 4; -0. 6 6] 9 5 % CI).2 1 I n a m or e 
pr o gresse d T 2 D p o p ulati o n of s u bjects alrea d y treate d  wit h lira gl uti de, de gl u dec was s h o w n 
t o be s u peri or t o place b o (esti mate d treat me nt differe nce : -0. 9 2 % -p oi nt [ -1. 0 0; -0. 7 5] 9 5 % CI) 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
5 0
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 1  of 1 0 2  
 
a n d ot her bas al i ns uli ns ha ve pre vi o usl y bee n s h o w n t o yiel d si milar re d u cti o ns i n H b A 1c 
c o m pare d t o i ns uli n gl ar gi ne. 2 2 
9. 2  
S a m ple size deter mi n ati o n  
T he sa m ple siz e is  deter mi ne d i n or der t o ha ve 9 0 % p o wer f or declari n g n o n -i nferi orit y wit h a  n o n -
i nferi orit y m ar gi n of 0. 3 % -p oi nt wit h res pect t o c ha n ge i n H b A 1c f or t he s pecifie d esti ma n d a n d t he 
f ull a nal ysis set ( pri mar y a nal ysis s et).  
Base d o n a rece nt st u d y wit h basa l-b ol us treat me nt ( N N 9 0 6 8 -4 1 8 5) t he perce nt e x perie n ci n g a n 
i nterc urre nt e ve nt as s p ecifie d a b o ve is e x pecte d t o be 1 0 % per 6 m o nt hs i n a basal-b ol us st u d y i n 
s u bjects wit h T 2 D.  
It is ass u me d t hat t here is n o differe n ce i n H b A1c bet wee n t he treat me nt ar ms  f or s u bjects 
c o m pleti n g ra n d o mise d treat me nt a n d a treat me nt differe n ce of 0. 3 % -p oi nt i n fa v o ur of t he 
c o m parat or f or s u bjects eit her disc o nti n ui n g treat me nt pre mat urel y or wit h dra wi n g fr o m trial. T h us, 
wit h 1 0 % e x pecte d t o e x perie nce a n y of t h e s pecifie d  i nterc urre nt e ve nts bef ore wee k 2 6, t his lea ds 
t o a n ass u m pti o n of a me a n treat me nt differe n ce of 0. 0 3 %-p oi nt f or t he s p ecifie d esti ma n d i n t he 
o verall p o p ulati o n.   
T he S D is ass u me d t o be 1. 0 % -p oi nt base d o n res ults fr o m st u dies wit h i ns uli n glar gi ne 1 0 0 
u nits/ m L  i n s u bjects treat e d wit h basal i ns uli n ( N N 1 2 5 0-3 5 8 2).   
Fr o m t he a b o v e ass u m pti o ns a n d re q uir e me nts, 5 8 0 s u bjects will be ra n d o mise d trial pr o d uct.  T his 
will e ns ure s ufficie nt p o wer ( 9 0 %) of c o nfir mi n g n o n -i nferi orit y.  
Wit h a n e x pecte d scree ni n g fail ure rate of 2 5 %, a p pr o xi matel y 7 7 4 s u bjects will be scree n e d t o 
ac hie ve 5 8 0 s u bjects ra n d o ml y assi g ne d t o trial pr o d uct.  
T his sa m ple siz e a p pears t o be reas o n a ble als o u n d er de viati o ns fr o m t he ass u me d treat me nt 
differe n ce as ill ustrate d i n Ta ble  9 -1  dis pla yi n g p o wer f or vari o us alter nati ve treat me nt differe n ces 
a n d S D s. 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
5 1
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 2  of 1 0 2  
 
T a ble  9 -1  
P o w er f or v ari o us tre at me nt differe nces a n d st a n d ar d de vi ati o ns.  
S D  
( %-p oi nt)  
 
 
 
0. 0 1 5  
Tre at me nt differe nce  
( %-p oi nt)  
 
0. 0 3  
 
 
 
0. 0 4 5  
0. 9  
9 7 %  
9 5 %  
9 3 %  
1. 0  
9 3 %  
9 0 %  
8 7 %  
1. 1  
8 8 %  
8 4 %  
8 0 %  
  S D : P o wer is c o m p ute d f or 1: 1 ra n d o misati o n a n d 5 8 0 s u bjects ra n d o mise 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  
Ra n d o mise d  
All s u bj ects ra n d o mise d  
F ull a nal ysis set  
F ull a nal ysis set: All s u bj ects ra n d o mise d. S u bj ects will be a nal yse d acc or di n g t o 
t he ra n d o mise d treat me nt.  
Safet y  a nal ysis set  
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. S u bj ects are a nal yse d acc or di n g t o t he treat me nt t he y act uall y 
recei ve d.  
I n e x ce pti o nal cases, s u bj ects or o bser vati o ns ma y be eli mi nate d fr o m t he f ull a nal ysis set. I n s uc h 
case t he reas o ns f or t heir e x cl usi o n will be d oc u me nte d bef ore u n bli n di n g. T he s u bjects a n d 
o bser vati o ns e x cl u de d fr o m a nal ysis sets, a n d t h e reas o n f or t his, will be descri be d i n t he cli nical 
trial re p ort. 
T he f oll o wi n g p eri o ds will be c o nsi dere d f or t he d ata c ollecte d:  
I n-tri al peri o d 
T he i n -trial peri o d starts at ra n d o misati o n a n d e n ds at t he date of: 
•  T he last direct s u bject -site c o ntact. 
•  Wit h dra wal f or s u bjects w h o wit h dra w t heir i nf or me d c o nse nt . 
•  T he last s u bject -i n vesti gat or c o ntact as d efi ne d b y t he i n vesti gat or f or s u bjects w h o are l ost t o 
f oll o w-u p (i.e. p ossi bl y a n u nsc he d ule d p h o ne visit) . 
•  Deat h f or s u bj ects w h o die bef ore a n y of t he a b o v e . 
F or s u bjects n ot ra n d o mise d b ut e x p ose d t o trial pr o d uct t he i n -trial peri o d starts at t he date of first 
d ose of trial pr o d uct. T h e e n d date is as defi ne d as a b o ve.  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
5 2
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 3  of 1 0 2  
 
O n -tre at me nt peri o d 
T he o n -treat me nt peri o d starts at t he date of first d ose of trial pr o d uct as rec or de d o n t he e C R F, a n d 
e n ds at t he first date of a n y of t he f oll o wi n g:  
•  T he e n d of trial visit ( V 3 0 ). 
•  T he last date o n trial pr o d uct + 5 wee ks f or o n ce dail y i ns uli n a n d + 6 wee ks f or o nce wee kl y 
i ns uli n (c orres p o n di n g t o 5 wee ks after t he e n d of t he d osi n g i nter val f or b ot h treat me nt ar ms). 
•  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 re pres e nts t he ti me peri o d i n w hic h a s u bject is c o nsi dere d e x p ose d t o trial 
pr o d uct.  
All efficac y e n d p oi nts will be s u m marise d a n d a nal yse d usi n g t he f ull a n al ysis set a n d t he ‘i n -trial’ 
peri o d. Safet y e n d p oi nts will be e val uate d usi n g t he o n-treat me nt peri o d wit h descri pti ve statistics 
bei n g b ase d o n t he safet y a nal ysis s et ( S A S) a n d stat istical a nal yses bei n g b ase d o n t he f ull a n al ysis 
set u nless ot her wise s pecifie d.  
9. 4  
St atistic 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 first s u bject first visit, a n d it will 
i ncl u de a m ore te c 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 a n d sec o n dar y e n d p oi nts. 
9. 4. 1  
Ge ner al c o nsi der ati o ns  
Prese ntati o n of res ults fr o m a statistical  a nal ysis will i ncl u de t he esti mate d mea n treat me nt 
differe n ce ( or rati o) pres e nte d t o get her wit h t he t w o -si de d 9 5 % c o nfi de nce i nter val a n d t he 
c orres p o n di n g t w o -si d e d p-val ue.  
I n t he st atistical m o dels, e x pla nat or y fact ors will be c o de d as f oll o ws: 
•  Treat m e nt: O nce wee kl y i ns uli n ic o dec, i ns uli n glar gi ne . 
•  Re gi o n: Asia, E ur o p e, N ort h A merica, S o ut h A m erica .  
T he re gi o ns will be defi ne d as f oll o ws:  
•  Asia: I n di a, J a pa n . 
•  E ur o pe: Bel gi u m, N et herla n ds, It al y, R o ma nia, R ussia . 
•  N ort h A meric a: U nite d States . 
•  S o ut h A merica: Me xic o . 
T he last a vaila ble assess me nt ma de pri or t o t he first d ose will be use d as t he baseli ne val u e.  
All e n d p oi nts base d o n C G M meas ure m e nts will be deri ve d t he f oll o wi n g wa y. T he perce nta ge of 
ti me s pe nt i n a gi ve n gl ycae mic 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 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
5 3
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 4  of 1 0 2  
 
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. 
F oll o wi n g i nter nati o nal c o nse ns us criteria it wi ll be re q uir e d t hat at least 7 0 % of t he pla n ne d C G M 
meas ure me nts d uri n g t he last f o ur wee ks of treat me nt are a vaila ble f or e n d p oi nt data t o be i ncl u de d 
i n t he a nal ysis.2 3 
9. 4. 2  
Pri m ar y e n d p oi nt  
T he pri mar y e n d p oi nt is c ha n ge i n H b A 1c fr o m baseli ne t o wee k 2 6.  
T he ‘treat me nt p olic y’ esti ma n d, wil l be esti mate d base d o n t he full an al ysis set usi n g all H b A 1c 
meas ure me nts o btai ne d at t he wee k 2 6 visit, es peciall y i ncl u di n g meas ure me nts fr o m s u bjects 
disc o nti n ui n g t heir ra n d o mise d treat me nt. Missi n g H b A 1c at t he wee k 2 6 visit (re gar dless of 
treat me nt c o m pleti o n stat us) will be i m p ute d fr o m trial partici pa nts, w h o ha ve disc o nti n ue d t heir 
ra n d o mise d treat me nt pri or t o t he wee k 2 6 visit a n d ha ve a meas ure m e nt at t he wee k 2 6 visit i n t he 
f oll o wi n g w a y: 
•  First, o ne t h o usa n d ( 1 0 0 0) c o pies of t he dataset will be ge n erat e d f or H b A 1c. 
•  Sec o n d, f or s u bjects w h o disc o nti n ue d t heir ra n d o mise d treat me nt pri or t o t he wee k 2 6 visit a n d 
ha ve a n H b A 1c visit meas ure me nt at t he wee k 2 6 visit, t he c ha n ge i n H b A 1c fr o m last a vaila ble 
pla n ne d o n -treat me nt ( L A O T) val ue t o t he wee k 2 6 visit will be a nal yse d f or eac h datas et c o p y 
usi n g a n a nal ysis of c o varia nce ( A N C O V A) m o del wit h ra n d o mise d treat m e nt as fi x e d fact or 
a n d L A O T val u e a n d t he ti me p oi nt (st u d y d a y) of t his assess me nt as c o vari ates. T he esti mate d 
para meters, a n d t heir  v ari a nces, fr o m t he m o del will be use d t o i m p ute missi n g H b A 1c val ues 
f or t he c h a n ge fr o m L A O T t o t he wee k 2 6 visit a n d s u bse q ue ntl y t he missi n g H b A 1c val ue at 
t he wee k 2 6 visit.  
•  F or eac h of t h e c o m plete data sets, t he pri mar y e n d p oi nt will be a nal yse d u si n g a n A N C O V A 
m o del wit h re gi o n a n d ra n d o mise d treat me nt as fi x e d fact ors, a n d bas eli ne H b A
1c as a 
c o variate. T he esti mates a n d S D s f or t he 1 0 0 0 dat a sets will be p o ole d t o o ne esti mate a n d 
ass ociate d S D  usi n g R u bi n’s r ule. 2 4 
T his a nal ysis has t he u n d erl yi n g ass u m pti o n t hat s u bjects wit h missi n g data be ha ve si milarl y as 
s u bjects t hat disc o nti n ue ra n d o mise d treat me nt.  
T he f oll o wi n g s e nsiti vit y a nal ysis e val uati n g  t he r o b ust ness of t he ass u m pti o ns a b o ut t he missi n g 
data will be carrie d o ut:  
F or t he pri mar y e n d p oi nt, a t w o -di me nsi o nal ti p pi n g p oi nt a nal ysis will be perf or me d w here 
s u bjects ha vi n g i m p ute d H b A 1c meas ure me nt at t he wee k 2 6 visit are ass u me d t o ha ve a w orse 
o utc o me i n t he i ns uli n ic o dec ar m a n d a better o ut c o me i n t he i ns uli n glar gi ne ar m c o m pare d t o 
w hat was i m p ute d i n t he pri mar y a nal ysis. T his is d o ne b y a d di n g or s u btracti n g val u es Δi t o t he 
i m p ute d H b A1c val ues bef ore a n al ysi n g t he data. T he val ue o f Δi will be varie d i n de pe n de ntl y i n t he 
t w o treat me nt ar ms. T h e n o n -i nferi orit y mar gi n of 0. 3 % will be a m o n g t h e Δi val ues i n vesti gate d. 
T he pla usi bilit y of t he val ues of Δi w here t he c o n cl usi o n of t he pri mar y a nal ysis c ha n ge will be 
e val uate d t o ass ess t he r o b ust ness of t he pri mar y a nal ysis res ult.   
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
5 4
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 5  of 1 0 2  
 
9. 4. 3  
Sec o n d ar y e n d p oi nts  
9. 4. 3. 1  
C o nfir m at or y s ec o n d ar y e n d p oi nt  
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  
S u p p orti ve sec o n dar y e n d p oi nts will be e val uate d i n t he fra me w or k of t he pri mar y esti ma n d.  
Effi c ac y e n d p oi nts 
C h a n ge i n f asti n g pl as m a gl uc ose ( F P G) fr o m b aseli ne  wee k 0 ( V 2) t o wee k 2 6 ( V 2 8)  
Missi n g F P G val ues at t he wee k 2 6 visit (re gar dl ess of treat me nt c o m pleti o n stat us)  will be i m p ute d 
fr o m trial partici pa nts w h o are fr o m t he i ns uli n glar gi ne gr o u p, a n d w h o ha ve c o m plete d a n d 
a d here d t o  t heir ra n d o mise d i ns uli n treat me nt - i.e., data will be i m p ute d base d o n t he ass u m pti o n 
t hat s u bjects wit h missi n g e n d p oi nt dat a will be ha ve li ke s u bjects c o m pleti n g  t he i ns uli n gl ar gi ne 
treat me nt. S pecificall y, t he i m p utati o ns a n d a nal yses will be carrie d o ut as f oll o ws: 
•  First, o ne t h o usa n d ( 1 0 0 0) c o pies of t he dataset will be ge n erat e d f or F P G . 
•  Sec o n d, f or eac h d ataset c o p y, a n a n al ysis of  c ovaria nce ( A N C O V A) m o del wit h a baseli ne 
val ue as a c o vari ate will be fitte d t o F P G val ues f or s u bjects w h o c o m plete d t heir ra n d o mise d 
treat me nt i n t he i ns uli n glar gi n e gr o u p. T he esti mate d  mea n, a n d varia n ces, fr o m t he m o del 
will be use d t o i m p ute missi n g val ues i n b ot h  treat me nt gr o ups.  
•  F or eac h of t h e c o m plete data sets, t he e n d p oi nt will be a nal ys e d usi n g a n A N C O V A  m o del 
wit h re gi o n a n d ra n d o mise d treat me nt as fi x e d fact ors, a n d a bas eli ne val ue as a c o variate. T h e 
esti mates a n d S D s f or t he 1 0 0 0 data sets will be p o ole d t o o ne esti mate a n d ass ociate d S D  
usi n g  R u bi n’s r ule. 2 4 
Ti m e i n t ar get r a n ge 3. 9 -1 0. 0 m m ol/ L ( 7 0 -1 8 0 m g/ d L) fr o m wee k 2 2 ( V 2 4) t o wee k 2 6 ( V 2 8)  
Ti me i n tar get ra n ge 3. 9 -1 0. 0 m m ol/ L ( 7 0 -1 8 0 m g/ d L) fr o m wee k 2 2 t o wee k 2 6 will be a nal yse d 
usi n g t he sa me m o d el as s pecifie d f or c ha n ge i n F P G, b ut wit h o ut usi n g t he baseli ne val u e as a 
c o variate.  
S afet y e n d p oi nts  
Hy p o glyc ae mic e pis o des  
T he f oll o wi n g h y p o gl ycae mic e n d p oi nts will be a nal yse d s e paratel y usi n g t h e met h o d descri be d 
bel o w:  
•  N u m ber of se v ere h y p o gl ycae mic e pis o des (le vel 3) fr o m baseli ne wee k 0 ( V 2) t o wee k 3 1 
( V 3 0). 
•  N u m ber of cli nic all 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) fr o m baseli ne wee k 0 ( V 2) t o wee k 3 1 ( V 3 0) . 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
5 5
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 6  of 1 0 2  
 
•  N u m ber of cli nic all 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 ycae mic e pis o des (le vel 3) fr o m baseli ne wee k 0 
( V 2) t o wee k 3 1 ( V 3 0). 
F or s u bjects w h o disc o nti n ue d t he ir ra n d o mise d tr eat me nt t he n u m ber of e pis o des i n t he missi n g 
peri o d (ti me of f oll o w-u p 2  visit  ( V 3 0) t o pla n ne d e n d of t he o n-tr eat me nt p eri o d) will be i m p ute d 
usi n g a m ulti ple i m p utati o n tec h ni q ue, ass u mi n g t hat t he e ve nt r ate pre f oll o w-u p 2  visit  ( V 3 0) 
f oll o ws t he res pecti ve treat me nt gr o u ps rate w hilst p ost f oll o w-u p 2  visit  ( V 3 0) e ve nt r ate is t he rat e 
of t he i ns uli n glar gi ne gr o u p. T he i m p utati o n will be d o ne as f oll o ws:  
•  First, a Ba yes n e gati ve bi n o mial m o del wit h l o g -li n k f u ncti o n will be fitte d t o t he e ve nt rate 
data t o o btai n t he p osteri or distri b uti o n of m o del para meters. T he m o del will i ncl u de re gi o n 
a n d ra n d o mise d treat me nt as fi x e d fact ors a n d t he l o garit h m of t he o n -treat me nt peri o d as 
offset.  
•  Sec o n d, base d o n t he esti mate d para m eters f or t he i ns uli n glar gi ne gr o u p i n t his m o del, t he 
n u m ber of e pis o des i n t h e missi n g peri o d will be i m p ute d f or s u bjects w h o disc o nti n ue d t heir 
ra n d o mise d treat me nt. M ulti ple c o pies ( 1 0 0 0 c o pi es) of a c o m plete data s et will be ge n erat e d 
b y sa m pli n g fr o m t he esti mat e d distri b uti o n.  
•  F or eac h of t h e c o m plete data sets, t he n u m ber of e pis o des will be a nal ys e d usi n g a n e gati ve 
bi n o mial m o del wit h l o g -li n k, fi x e d fact ors a n d offset as descri b e d i n ste p 1. T he esti mates a n d 
S D s f or t he 1 0 0 0 data sets will be p o ole d t o o ne esti mate a n d ass ociate d S D  usi n g R u bi n’s 
r ule.2 4 
 
F or t he d efi niti o n a n d classificati o n of h y p o gl ycae mic e pis o des refer t o A p pe n di x 7 ( Secti o n 1 0. 7 ). 
Ti m e s pe nt < 3. 0 m m ol/ L ( 5 4 m g/ d L) a n d ti m e s pe nt > 1 0 m m ol/ L ( 1 8 0 m g/ d L) fr o m wee k 2 2 
( V 2 4) t o we e k 2 6 ( V 2 8) 
Ti me s pe nt < 3. 0 m m ol/ L ( 5 4 m g/ d L) ( bel o w ra n ge) a n d ti me s pe nt > 1 0 m m ol/ L ( 1 8 0  m g/ d L) 
(a b o ve ra n ge) fr o m wee k 2 2 t o wee k 2 6 will be a n al yse d s e paratel y usi n g t he sa me m o del as 
s pecifie d f or c ha n ge i n F P G, b ut wit h o ut usi n g t he baseli ne val u e as a c o v ariate.  T his m o del will be 
use d if dee me d a p pr o pri ate, i.e. if data ca n be c o nsi dered n or mall y distri b ute d. H o we v er, if a l ar ge 
n u m ber  of s u bjects ha v e 0 % ti me s pe nt, t he n a n alter nati ve a n al ysis will be perf or me d eit her 
c o nsi deri n g t he e n d p oi nt as a dic h ot o m o us e n d p oi nt or b y a p pl yi n g a ce ns ore d a nal ysis of t he l o g -
tra nsf or me d v al ues. F urt her details will be pr o vi d e d i n t he S A P. 
Me a n wee kly i ns uli n d ose fr o m wee k 2 4 ( V 2 6) t o wee k 2 6 ( V 2 8)  
Mea n wee kl y i ns uli n d os e d uri n g t h e last 2 wee ks of treat me nt (fr o m wee k 2 4 t o wee k  2 6) , d efi ne d 
as t he s u m of t he mea n w ee kl y basal a n d t h e mea n wee kl y  b ol us d ose,  will be l o g -tra nsf or me d a n d 
a nal ys e d usi n g t he sa me m o del as s pecifie d f or c h a n ge i n F P G, b ut wit h usi n g t he l o g -tr a nsf or me d 
wee kl y i ns uli n d ose at scree ni n g as a c o variate.  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
5 6
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 7  of 1 0 2  
 
C h a n ge i n b o dy wei g ht fr o m b aseli ne wee k 0 ( V 2) t o wee k 2 6 ( V 2 8)  
C ha n ge i n b o d y wei g ht fr o m wee k 0 t o wee k 2 6 will be a nal ys e d usi n g t h e sa me statistical m o del as 
s pecifie d f or t he pri mar y e n d p oi nt, b ut wit h t he c orres p o n di n g baseli ne v al ue as a c o v ariat e.  
F or details o n a n al ys es of a d diti o nal s u p p orti ve sec o n dar y e n d p o i nts, please refer t o t he S A P. 
9. 4. 4  
E x pl or at or y e n d p oi nts  
F or details o n a n al ys es of e x pl orat or y e n d p oi nts, please refer t o t he S A P.  
9. 4. 5  
Ot her s af et y a n al yses  
All safet y a nal yses will be ma de o n t he safet y a n al ysis set. T he sta n d ar d safet y assess me nts ( S A Es , 
A Es, s afet y la b orat or y para meters, vital si g ns, etc.) will be re p orte d d escri pti vel y base d o n t h e 
o n -treat me nt peri o d; 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 met ers. I n 
a d diti o n, S A Es will be re p orte d descri pti vel y bas e d o n t he i n -trial peri o d. 
9. 4. 6  
Ot her a n al yses   
F or ot her a nal yses,  ple as 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  
I ns uli n ic o dec ser u m c o n ce ntrati o n data will be use d f or p o p ulati o n P K a nal ysis. T he o bjecti ve of 
t he p o p ulati o n P K a nal ysis is t o e val uate t he effects of pre -s p ecifie d c o variates o n ser u m 
c o nce ntr ati o ns of i ns uli n ic o dec.  
T he p o p ulati o n P K a nal ysis will be perf or me d b y Q ua ntitati ve Cli nical P har mac ol o g y, N o v o 
N or dis k. A m ore te c h nic al a n d detaile d el a b orati o n of t he p o p ulati o n P K a nal ysis will be gi ve n i n a  
m o delli n g a nal ysis pla n, w hic h will be pre pare d b ef ore d ata bas e l oc k . I n brief, a pre vi o usl y 
de vel o pe d P K m o del f or i ns uli n ic o dec will be a p plie d. T he a bs or pti o n rat e c o nsta nt ( Ka) i n t he 
m o del will be fi x e d, a n d t he a p pare nt cleara nce ( C L/ F) a n d t he a p p are nt v ol u me of distri b uti o n 
( V/ F) will be re-esti mate d. T he c o variates of i nterest will be i nc or p orate d i nt o t he P K m o del usi n g 
criteria w hi c h will be s pecifie d i n t he m o delli n g a nal ysis pla n . 
T he p o p ulati o n P K a nal ysis will be re p orte d i n a s e parat e m o de lli n g re p ort, w hic h will n ot be part 
of t he cli nical trial r e p ort. T he i n di vi d ual i ns uli n ic o dec ser u m c o nce ntrati o n data will be ta b ulate d 
i n t he bi oa nal ytical re p ort. 
9. 5  
I nteri m a n al yses  
N ot  a p plica ble f or t his trial. 
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.  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
5 7
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 8  of 1 0 2  
 
9. 7  
Re p orti n g of t he m ai n p art of t he tri al  
N ot a p plica ble f or t his trial.  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
5 8
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
5 9  of 1 0 2  
 
1 0  S u p p orti n g d oc u me nt ati o n a n d o p er ati o n al c o nsi de r ati o ns  
1 0. 1  
A p pe n di x 1: Re g ul at or y, et hic al, a n d 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 d er 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 5 a n d a p plica ble I C H g o o d cli nical p ractice ( G C P) G ui deli ne2 6. 
•  A p plica ble la ws a n d re g ulati o ns. 
•  T he pr ot oc ol, i nf or me d c o nse nt f or m, i n vesti gat or’s br oc h ure (as a p plica bl e) a n d ot her rele va nt 
d oc u me nts (e. g. a d v ertise me nts) m ust be s u b mitte d t o a n I R B/I E C a n d re vi e we d a n d a p pr o ve d 
b y t he I R B/I E C bef ore t h e trial is i nitiate d.  
•  Re g ulat or y a ut h orities will recei ve t he cli nical trial a p plicati o n, pr ot oc ol a m e n d me nts, re p orts 
o n S A Es, a n d t he cli nical trial re p ort  acc or di n g t o nati o nal re q uire m e nts.  
•  A n y a me n d me nts t o t he pr ot oc ol will re q uire I R B/I E C a p pr o val bef ore i m ple me ntati o n o f 
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 ve 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 he 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 uir e 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 cli nical trial re p ort  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 nfor 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 he c o urse of t he trial a n d o ne 
year after c o m pleti o n of t he trial.  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
5 9
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6 0  of 1 0 2  
 
1 0. 1. 3  
I nf or me d c o nse nt pr ocess 
•  T he i n vesti gat or or his/ her re prese nt ati ve will e x plai n t he nat ure of t h e trial t o t he s u bject a n d 
a ns wer all q uesti o ns re gar di n g t he tri al.   
•  T 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 da te 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 nes2 6, Declarati o n of Helsi n ki 2 5 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 tri al relate d acti vit y a n d t he date w he n t h e writte n c o nse nt was o btai n e d. T he a ut h orise d 
pers o n o btai ni n g t h e i nf or me d c o nse nt m ust als o si g n a n d d ate t he i nf or m e d c o nse nt f or m 
bef ore a n y trial r elate d acti vit y.  
•  T he res p o nsi bilit y of s ee ki n g i nf or me d c o nse nt m ust re mai n wit h t he i n vest i 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 pati o n i n t he trial.  
•  A c o p y of t he i nf or me d c o nse nt f or m (s) m ust be pr o vi de d t o t he s u bject.  
1 0. 1. 4  
I nf or m ati o n t o s u bjects d uri n g tri al 
N o v o N or dis k offers a c o m m u nicati o n pac ka ge f or t he s u bject d uri n g t he c o n d uct of t he trial. T he 
c o m m u nicati o n pac ka ge c o ntai ns writte n i nf or mati o n w hic h will be tra nslat e d a n d a dj uste d t o l ocal 
re q uire 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 vesti gat or. T he s u bject ma y 
recei v e a “ welc o me t o t h e trial letter” a n d a “t h a n k y o u f or y o ur partici pati o n letter” after 
c o m pleti o n of t h e 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 bjects m ust be se nt t o I R B/I E C f or a p pr o val/fa v o ura ble o pi ni o n a n d t o 
re g ulat or y a ut h orities f or a p pr o val or n otificati o n acc or di n g t o l ocal re g ulati o ns. 
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 nsf erre d t o N o v o N or dis k will c o ntai n t he i de ntifier o nl y. N o direct 
i de ntifiers fr o m t he s u bject are tr a 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 gic al material o btai ne d fr o m t he s u bject will be i de ntifie d b y s u bj ect 
n u m ber, visit n u m ber a n d trial I D. A p pr o pri ate m eas ures s u c h as e n cr 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 o cal, 
re gi o nal a n d nati o nal re q uire me nts.  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
6 0
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6 1  of 1 0 2  
 
•  T he s u bject m ust be i nf or me d a b o ut his/ her pri vac y ri g hts, i ncl u di n g t 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 protecti o n la w. T he 
discl os ure of t he dat 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 n el a p p oi nte d b y N o v o N or dis k, b y a p pr o priate I R B/I E C me m bers, a n d 
b y i ns pect ors fr o m re g ulat or y a ut h orities.  
1 0. 1. 6  
C o m mittees st r uct ure  
1 0. 1. 6. 1  
N o v o N or dis k s af et y c o m mittee  
N o v o N or dis k will perf or m o n g oi n g safet y s ur veilla nce. If ne w s afet y si g nals are i de ntifie d, t hes e 
will be e val uate d b y a n i nter nal safet y c o m mittee.  
1 0. 1. 6. 2  
Tri al s af et 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  
A n i n de pe n de nt e xter nal E A C is esta blis he d t o perf or m o n g oi n g bli n de d a dj u dicati o n of select e d 
A Es a n d deat hs (s ee  T a ble  8 -1 ). 
T he E A C will e val uate e ve nts se nt f or a dj u dicati o n usi n g pre -defi n e d defi niti o ns a n d g ui deli nes i n 
acc or da nce wit h t he E A C c harter. T h e e v al uati o n is base d o n re vie w of pre -defi n e d cli nical data 
c ollecte d b y t he sites. T h e E A C is c o m p ose d of per ma ne nt me m b ers c o veri n g all re q uire d me di cal 
s pecialities. E A C me m bers m ust discl ose a n y p ote ntial c o nflicts of i nterest a n d m ust be i n de pe n de nt 
of N o v o N or dis k. T he E A C will ha ve n o a ut h orit y t o i m pact trial c o n d uct, trial pr ot oc ol or 
a me n d me nts. T he ass ess me nts ma d e b y b ot h t he e ve nt a dj u dicati o n c o m mittee a n d t he i n vesti gat or 
will be e val uate d a n d i ncl u de d i n t he cli nical trial re p ort .  
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 uir e 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 2 7, 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)2 8, E ur o pea n C o m missi o n Re q uire me nts1, 2 9, 3 0 a n d ot her rele va nt rec o m me n dati o ns or 
re g ulati o ns. If a s u bject 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 or dis k e-mail c o ntact at 
t hese we b sites, N o v o N or dis k ma y discl ose t h e i n vesti gat or’s c o ntact details t o t he s ubject. 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 uir e p u blic discl os ure of 
i n vesti gat or n a mes a n d t heir affiliati o ns. 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
6 1
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6 2  of 1 0 2  
 
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 +  2 6  wee ks  c orres p o n di n g t o visit V 2 8 . If t h e 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 
V 2 8 . T he P C D deter mi nes t he dea dli ne f or res ults discl os ure at cli nic altrials. 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 or t he d ata ma na ge me nt of t his trial i ncl u di n g q ualit y 
c hec ki n g of t he d ata.  
•  All s u bject data rel ati n g t o t he trial will be rec or de d o n electr o nic C R Fs (e C R Fs)  u nless 
tra ns mitte d electr o nicall y t o N o v o N or dis k (e. g. la b orat or y a n d e Diar y d ata) or w he n 
a p plica ble o n pa p er C R F. T he i n vesti gat or is res p o nsi ble f or verif yi n g t hat d ata e ntries are 
acc urate a n d c orrect b y p h ysicall y or electr o ni call y si g ni n g t he C R F.  
•  T he f oll o wi n g will be pr o vi de d as pa per C R Fs:  
o  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 e C R F is re v o k e d 
or t he e C R F is te m p oraril y u na v aila ble:  
o  A d verse e ve nt  f or ms  
o  Safet y i nf or mati o n  f or ms 
o  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)  
•  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 t he C R F a p plicati o n c o ntai ni n g as a mi ni m u m: t he 
ol d a n d t he ne w 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 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 h e i n vesti gat or’s d ele gate d staff after 
t he date whe n t h e i n vesti gat or si g n e d t he C R F, t h e 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 data v erific ati o n a n d vali dati o n p ur p oses.   
1 0. 1. 8. 2  
M o nit ori n g  
•  T he i n vesti gat or m ust per mit 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 dat a d oc u me nts ( ori gi nal d oc u m e nts, 
data a n d rec or ds). Direct access i ncl u des per missi o n t o e xa mi ne, a nal yse, v erif y a n d re pr o d uce 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
6 2
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6 3  of 1 0 2  
 
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 h e e val uati o n of t he trial. If t he electr o nic 
me dical rec or d d oes n ot ha ve a visi bl e 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 d ate 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 ne).   
•  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 e C R F b y a ut h orise d site pers o n nel are acc urate, c o m plete a n d verifia ble fr o m s o urce 
d oc u me nts; t hat t he safet y a n d ri g hts of s u bjects are bei n g pr otecte d, t o m o nit or dr u g 
acc o u nta bilit y a n d c ollect c o m plete d pa per C R F 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 oc ol a n d a n y ot h er trial a gree me nts, 
I C H G C P, a n d all a p plica ble re g ulat or y re q uir e 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 r ec or ds a n d ot her s o urce data t o e ns ure co 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 e 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 viati o ns, f or w hic h c orrecti o ns are n ot p ossi ble, ca n be 
ac k n o wle d ge d a n d c o nfir me d via e dit c hec ks i n t he  e C R F or via listi n gs fr o m t he trial data base.  
1 0. 1. 9  
S o urce d oc u me nts  
All data e ntere d i n t he e C R F m ust be verifia ble i n s o urce d oc u m e ntati o n, e xce pt f or t he f oll o wi n g 
data t hat has bee n tra nsf erre d directl y i nt o t he data base a n d will be c o nsi d ere d s o urc e d ata:  
•  F or e. g. e Diar y, d ata i n t he ser vice pr o vi ders’ dat a base is c o nsi dere d s o urce data.  
•  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 ort e d o n t he p a 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 or ma y n ee d t o r e q uest pr e vi o us me dical rec or ds or tra nsfer rec or ds. 
A ls o, c urre nt me dic al 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 me nt a n y atte m pt t o o btai n e xter nal me dical i nf or mati o n b y n oti n g 
t he date(s) w h e n i nf or mati o n was re q ueste d, a n d w h o was c o ntacte d.  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
6 3
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6 4  of 1 0 2  
 
•  Defi niti o n of w hat c o nstit utes s o urce data ca n b e f o u n d i n a s o urce d o c u me nt a gree me nt at eac h 
site. T here will o nl y b e o ne s o urce d o c u me nt defi ne d at a n y ti me f or a n y d ata ele me nt.  
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 he i n vesti gat or f or 1 5 years after e n d of trial 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 p art y wit h o ut writte n n otificati o n t o N o v o 
N or dis k.   
•  T he i n vesti ga t 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 w a y. If a p plica ble, electr o nic C R F (e C R F) a n d ot her s u bject d ata will be pr o vi de d i n a n 
electr o nic rea d a ble f or m at t o t he i n vesti gat or bef ore access is re v o k e d t o t he s yste ms s u p plie d 
b y N o v o N or dis k. Site -s pecific C R Fs a n d ot h er s u bject data (i n a n electr o ni c rea d a ble f or mat 
or as pa per c o pies or pri nts) m ust be retai ne d b y t h e 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 
detai le 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 ollecte d a n d a site cl os ure visit has bee n perf or me d.  
T he i n vesti gat or ma y i nitiate site cl os ure at a n y ti me, pr o vi de d t here is reas o na ble 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: 
•  F ail ure of t he i n vesti gat or t o c o m pl y wit h t he pr ot oc ol, t he re q uir e me nts of t he I R B/I E C or 
l ocal healt h a ut h orities, N o v o N or dis k pr oce d ures or G C P g ui deli nes 
•  i na de q uate recr uit me nt of 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.  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
6 4
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6 5  of 1 0 2  
 
1 0. 1. 1 2  
Res p o nsi bilities  
T h e 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 d e q uate a n d d oc u me nte d trai ni n g f or all 
staff partici p ati n g i n t he c o n d uct of t he 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 h e 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 bl e 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 h e data 
pr o d uce d) i n t he i n v esti gat or trial master file. T h e d oc u me nts, i ncl u di n g t he s u bject i de ntif icati o n 
c o de list m ust be ke pt i n a sec ure l oc ke d facilit y s o t hat n o u na ut h orize d pers o ns ca n get access t o 
t he data.  
T he i n vesti gat or will ta ke all necessar y tec h nical a n d or ga nisati o nal safet y meas ures t o pre ve nt 
acci de nt al or wr o n gf ul d estr ucti o n, l os s or deteri orati o n of data. T he i n vesti gat or will pr e ve nt a n y 
u na ut h orise d access t o data or a n y ot her pr ocessi n g of data a gai nst a p plica ble la w. T he i n vesti gat or 
m ust be a ble t o pr o vi de t he necessar y i nf or m ati o n or ot her wise d e m o nstrate t o N o v o N or dis k t h at 
s uc h tec h nical a n d or ga nisati o nal safet y meas ures ha ve bee n ta ke n.  
D uri n g a n y peri o d of u na vaila bilit y, t he i n vesti gat or m ust dele gate res p o nsi bilit y f or me dical care of 
s u bjects t o a s pecific q u alifie d p h ysicia n w h o will be rea dil y a v aila ble t o s u bject s 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 v e s uf ficie nt E n glis h s kills acc or di n g t o t heir 
assi g ne d t as k(s).  
1 0. 1. 1 3  
I n de m nit y st ate me nt  
N o v o N or dis k carries pr o d uct lia bilit y f or its pr o d ucts, a n d lia bilit y as ass u me d u n der t he s pecial 
la ws, acts a n d/ or g ui deli n es f or c o n d u cti n g cli nical 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.  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
6 5
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6 6  of 1 0 2  
 
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 ov 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 ose d t o ot hers wit h o ut pri or writte n c o nse nt fr o m N o v o 
N or dis k. S uc h i nf or ma ti 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 nical trials wit h t he trial pr o d uct, if dee me d necess ar y b y N o v o N or dis k. 
Pr o vi de d t hat certai n c o n diti o ns are f ulfille d, N o v o N or dis k ma y gra nt access t o i nf or mati o n 
o btai ne d d uri n g t his trial t o researc hers w h o re q uire access f or researc h pr oj ects st u d yi n g t he sa m e 
disease a n d/ or tri al pr o d uct st u die d i n t his trial.  
N o v o N or dis k  ma y p u blis h o n its cli nical trials we bsite a re dacte d cli nical trial re p ort  f or t his trial. 
O ne or t w o i n vesti gat ors will be a p p oi nte d b y N o v o N or dis k t o re vie w a n d si g n t he cli nical trial 
re p ort (si g nat or y i n vesti gat or) o n be h alf of all partici pati n g i n vesti 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 us cri pt i n a peer -re vi e we d s cie ntific j o ur nal, a bstract 
s u b missi o n wit h a p oster or oral pres e ntati o n at a s cie ntific meeti n g or discl os ure b y ot her mea ns.  
T he res ults of t his 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 h e 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 cli nical trial r e p ort  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 ys es, beca use t he release of s uc h 
i nf or mati o n ma y i nfl u e 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 ot ect 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 d isa gree me nt o n t he 
c o nte nt of a n y p u blicati o n, b ot h t he i n vesti gat ors’ a n d N o v o N or dis k o pi ni o ns will be fairl y a n d 
s ufficie ntl y re prese nte d i n t he p u blicati o n. 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
6 6
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6 7  of 1 0 2  
 
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 q uisiti 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 ur nals b y t he I nt er nati o nal 
C o m mittee of Me dical J o ur nal E dit ors. 3 1 
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 uir e d b y t he j o ur nal, t he i n vesti gat or fr o m eac h site will be na me d i n a n 
ac k n o wle d ge me nt or i n t he s u p ple me ntar y mat eri al, as s pecifie d b y t h e j o ur nal.   
1 0. 1. 1 4. 3  
Site -s pecific p u blic ati o n(s) b y i n vesti g at or(s) 
F or a m ultice ntr e cli nical 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 pri mar y ma n uscri pt 
is acce pte d f or p u blicati o n. I n li ne wit h G o o d P u blicati o n Practice, s u c h i n di vi d ual re p orts s h o ul d 
n ot prece d e t he pri mar y ma n uscri pt a n d s h o ul d al wa ys refere nce t h e pri mar y ma n us cri 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  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
6 7
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6 8  of 1 0 2  
 
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 T a ble  1 0 -2  will be perf or me d b y t h e ce ntral la b orat or y.  
•  A d diti o nal tests ma y be p erf o r 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 oc al re g ulati o ns. O nl y la b orat or y sa m ples s pecifie d i n t he pr ot oc ol 
s h o ul d be se nt t o t he ce ntral la b orat or y f or a n al ysis; if a d diti o nal la b orat or y sa m pli n g is 
ne e de d, e. g. t o f oll o w -u p o n A Es, t his m ust be d o ne at a l ocal la b orat or y.  
•  T he ce ntr al la b will c o m m u nicate t o t he i n vesti gat or a b n or mal val ues of para meters n ot 
re q ueste d i n t he pr ot o c ol b ut i de ntifie d b y t he la b orat or y e q ui p me nt a n d/ or t heir pr ocesses 
acc or di n g t o t heir l a b S O Ps. T hese data will n ot be tra nsferre d t o t he trial d ata base. T h e 
i n vesti gat or s h o ul d r e vie w s uc h val 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.  
•  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 cli nical trial re p ort , 
e x ce pt t he f oll o wi n g:  
•  
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.  
•  
H u ma n bi osa m ples f or rete nti o n will be st ore d as descri be d i n A p p e n di x  6 ( Secti 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  
Gl uc ose meta b olis m  
( V 2, V 1 2, V 2 0, V 2 8) 
•  Fasti n g  plas ma gl uc ose  ( F P G)1 
•  H b A 1c (als o at V 1 a n d V 2 8 A) 
N O T E:  
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 b e re p orte d as a 
h y p o gl ycae mic  e pis o de b ut as a n a d verse e ve nt  at t he discreti o n of t he i n vesti gat or ( A p pe n di x 3, Secti o n 1 0. 3 ). 
A F P G res ult > 1 6. 7 m m ol/ L ( 3 0 0 m g/ d L) s h o ul d n ot be re p orte d as a h y per gl ycae mic e pis o de b ut as a n A E at t he 
discreti o n of t he i n vesti gat or ( A p pe n di x 3, Secti o n 1 0. 3 ). 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
6 8
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
6 9  of 1 0 2  
 
T a ble  1 0 -2  
Pr ot oc ol -re q uire d s af et y l a b or at or y assess me nts  
L a b or at or y  
 assess me nts  
P ar a meters  
Hae mat ol o g y  
( V 1, V 1 2, V 2 8) 
•  Er yt hr oc ytes  
•  Hae mat ocrit  
•  Hae m o gl o bi n  
•  Le uc o c ytes  
•  T hr o m b oc ytes  
•  B as 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  
Bi oc he mistr y 1 
( V 1, V 1 2, V 2 8)  
•  Ala ni ne A mi n otr a nsferase  
•  Al b u mi n  
•  Al kali ne p h os p hatase  
•  As partate A mi n otra nsferase  
•  Creati ni ne  
•  P otassi u m  
•  S o di u m  
•  T otal bilir u bi n  
Li pi ds  
( V 2, V 1 2, V 2 8) 
•  C h olester ol  
•  Hi g h de nsit y li p o pr otei n ( H D L) c h olester ol  
•  L o w de nsit y li p o pr otei n ( L D L) c h olester ol  
•  Tri gl yceri des  
•  Free fatt y aci ds  
Pre g na nc y T esti n g  
( V2 , V 2 8, V 3 0) 
•  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 (as 
nee de d f or w o me n of c hil d beari n g p ote ntial) 2 
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, e G F R is f or scree ni n g p ur p oses o nl y.  
•  I n case of s yste mic h y perse nsiti vit y ( Secti o n 8. 9. 2 ): Tr y ptas e ( o pti mal 0. 5 -2 h o urs 
p ost t he h y perse nsiti vit y reacti o n), t otal I g E a nti b o dies, a nti -i ns uli n ic o dec I g E 
a nti b o dies, a nti -i ns uli n ic o dec bi n di n g a nti b o dies, a nti-h u ma n i ns uli n I g E a n ti b o dies. 
•  A nti -i ns uli n ic o dec a nti b o dies ( V 2, V 4, V 8, V 1 2, V 2 0, V 2 8, V 3 0 ). 
•  Ins uli n -ic o dec ser u m c o nce ntr ati o n ( V 4, V 8, V 1 2, V 2 0, V 2 8, V 3 0). 
N otes:  
1Details of re q uire d acti o ns f or i ncrease d li ver para meters  ar e gi ve n i n Secti o n 1 0. 3. 2  ( H y’s La w). 
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.  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
6 9
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
7 3  of 1 0 2  
 
A na p h yl a xis is a n ac ute, p ote ntiall y let hal, m ultis yst e m s y n dr o me res ulti n g fr o m t he s u d de n 
releas e of mast c ell- a n d bas o p hil -deri ve d me diat ors i nt o t he circ ulati o n 3 2. It m ost ofte n res ults 
fr o m i m m u n ol o gic reacti o ns t o f o o ds, me dicati o ns, a n d i nsect sti n gs, alt h o u g h it ca n als o be 
i n d uce d t hr o u g h n o ni m m u n ol o gic mec ha nis ms b y a n y a ge nt ca pa ble of pr o d uci n g a s u d de n, 
s yste mic de gra n ulati o n of mast cells or bas o p hils 3 3. C haracteristic s y mpt o ms a n d si g ns, occ urri n g 
mi n utes t o a fe w h o urs after e x p os ure t o p ote ntial tri g geri n g a ge nts or e ve nts ma y i ncl u de: 
fl us hi n g, urticaria, a n gi o e de ma, h oarse ness, t hr oat ti g ht ness, stri d or, w heezi n g, c o u g hi n g, 
s h ort ness of breat h, a b d o mi nal pai n, v o miti n g, a n d/ or h y p ote nsi o n, diz zi ness or c olla pse. 
L ocal h y pers e nsiti vit y reacti o ns, i ncl u di n g ras h, re d ness, pr urit us a n d o e de ma, ma y o cc ur at t he 
site of i n vesti gati o nal dr u g i njecti o n. 
Dr u g h y pers e nsiti vit y reacti o ns ( D H Rs) are t he a d verse effects of p har m ace utical f or m ulati o ns 
(i ncl u di n g acti ve dr u gs a n d e x ci pie nts) t hat cli nicall y rese m ble aller g y3 4. T he y ca n b e aller gic a n d 
n o n -aller gic.  
If a h y perse nsiti vit y e v e nt is s us pecte d, t he s u bjects m ust c o ntact t he site staff as so o n as p ossi ble 
f or f urt her g ui da nce. All e ve nts m ust be re p ort e d, a n d i n case of s yst e mic h y p erse nsiti vit y, 
a d diti o nal i nf or mati o n m ust be pr o vi de d  o n a se p arate  f or m. 
Me dic ati o n err o r  
A me dicati o n err or is a n u ni nte n de d fail ure i n t he I M P treat me nt pr ocess t hat lea ds t o, or has t he 
p ote ntial t o lea d t o, har m t o t he s u bject, s uc h as:   
•  a d mi nistrati o n of wr o n g dr u g.   
N ote: Use of wr o n g D U N is n ot c o nsi dere d a me dicati o n err or u nl ess it res ults i n 
a d mi nistrati o n of wr o n g dr u g.  
•  wr o n g r o ute of a d mi nistrati o n, s uc h as i ntra m usc ular i nstea d of s u bc ut a ne o us  
•  acci de nt al a d mi nistrati o n of a l o wer or hi g her d ose t ha n i nte n de d. T he a d mi nistere d d ose 
m ust de viate fr o m t he i nte n de d d ose t o a n e xte nt w here cli nical c o nse q u e n ces f or t he tria l 
s u bject were li kel y t o h a p pe n as j u d ge d b y t he i n vesti gat or, alt h o u g h t h e y di d n ot 
necessaril y o cc ur.  
•  misse d d oses or dr u g pa uses are n ot t o be re p orte d as a me dicati o n err or.  
Mis use a n d a b use   
•  Sit uati o ns w here t he I M P is i nte nti o nall y a n d i na p pr o priatel y use d n ot i n acc or da nce wit h t he 
pr ot oc ol (e. g. o ver d ose t o ma xi mise effect ) 
•  Persiste nt or s p ora dic, i nt e nti o nal e xcessi ve use of a n I M P w hic h is acc o m pa nie d b y har mf ul 
p h ysical or ps yc h ol o gical effects (e. g. o v er d ose wit h t he i nte nti o n t o ca use har m)  
Me d icati o n err or, mis use a n d a b use m ust al wa ys b e re p ort e d as a n A E (e. g. acci de nt al o ver d ose, 
i nte nti o nal o ver d ose or ot her) o n a se p arate A E f or m, a n d a me dicati o n err or, mis use a n d a b use 
f or m m ust be c o m plete d. I n case of a me dicati o n err or a n d/ or mis use an d a b use res ulti n g i n a 
cli nical c o nse q ue n ce, t his m ust be re p orte d o n a n a d diti o nal A E f or m.  
 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
7 3
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
7 8  of 1 0 2  
 
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  
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 ncle ar 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.  Pre me narc heal  
2.  Fe males wit h o ne or m or e of t he f oll o wi n g:  
•  
D oc u me nte d t otal h ysterect o m y  
•  
D oc u me nte d bilateral sal pi n gect o m y  
•  
D oc u me nte d bilateral o o p h orect o m y  
Fe males wit h per m a 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 dr o ge n i nse nsiti vit y), i n vesti gat or discreti o n s h o ul d be a p plie d i n deter mi ni n g 
trial e nr ol me nt. 
3.  P ost me n o pa usal fe male:  
•  A p ost me n o pa usal state is defi ne d a s 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 use.  
•  Fe males  ≥ 5 0 years of a ge ca n b e c o nsi dere d p ost me n o pa usal (irres pecti ve of treat me nt wit h a 
h or m o nal c o ntrace pti o n or h or m o ne re place m e nt t hera p y ( H R T)) if t he y h a ve b ot h:  
o  A me n orr h oea a n d  
o  D oc u me ntati o n of 2 hi g h f ollicle sti m ulati n g h or m o ne ( F S H) m eas ure me nts i n t he 
p ost me n o pa usal ra n ge a n d o ne of t hese was o bser ve d ≥1 year pri or t o scree ni n g.  
•  Fe males ≥ 6 0 years of a ge ca n b e c o nsi dere d p ost me n o pa usal.  
Fe males o n H R T a n d w h ose me n o pa usal st at us is i n d o u bt are c o nsi dere d of c hil d beari n g p ote ntial 
a n d will be re q uir e d t o use at least a n acce pta ble effecti ve c o ntrace pti o n met h o ds as descri be d i n 
Ta ble  1 0 -3 . 
N ote: D oc u me ntati o n re gar di n g cate g ories 1 -3 ca n c o me fr o m t he site staff’s re vie w of s u bject’s 
me dical rec or ds, me dic al e x a mi nati o n or me dical hist or y i nter vie w . 
C o ntr ace pti o n g ui d a nce  
Male s u bjects   
N o c o ntrace pti o n meas ur es are re q uir e d as t he ris k of terat o ge ni cit y/f et ot o xicit y ca use d b y tr a nsfer 
of i ns uli n ic o dec or i ns uli n glar gi n e  or i ns uli n as part i n se mi nal fl ui d is u nli kel y 3 5. 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
7 8
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
8 0  of 1 0 2  
 
C ollecti o n of pre g n a nc y i nf or m ati o n   
Fe m ale s u bjects w h o bec o me pre g n a nt  
•  I n v esti gat or will c ollect pre g na nc y i nf or mati o n o n a n y fe male s u bj ect w h o bec o mes pre g na nt 
w hile partici pati n g i n t his  trial. 
•  I nf or mati o n will be rec or de d o n t he a p pr o priate f or m a n d s u b mitte d t o N o v o N or dis k wit hi n 1 4 
cale n dar da ys of lear ni n g of s u bject ’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 ors 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 d ar da ys. G e nerall y, f oll o w -u p will n ot b e 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 d eli 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 t he f oetal stat us ( prese n ce or 
a bse nce of a n o malies) or i n dicati o n f or pr oce d ure.  
•  W hile pre g na n c y itself is n ot c o nsi dere d t o be a n A E  or S A E, a n y a d v erse e ve nt i n c o n necti o n 
wit h pre g na nc y or ele cti ve ter mi nati o n of a pre g na nc y f or me dical reas o ns will be re p orte d as 
a n A E or S A E. If rele v a nt, c o nsi der a d di n g “ gestati o nal”, “ pre g n a nc y relate d” or 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 r ec 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.  
•  A n y S A E o cc urri n g as a res ult of a p o st-trial pr e g na nc y w hic h is c o nsi dere d p ossi ble/ pr o ba bl y 
relate d t o t he I M P b y t he i n vesti gat or will be re p orte d t o N o v o N or dis k as d escri be d i n 
A p pe n di x 3 ( Secti o n 1 0. 3 ) . W hile t he i n vesti gat or is n ot o bli gate d t o acti vel y see k t his 
i nf or mati o n i n f or mer s u bjects, he/s he ma y lear n of a n S A E t hr o u g h s p o nta ne o us re p orti n g.  
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
 
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.  
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  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
8 0
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
8 3  of 1 0 2  
 
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  
H y perse nsiti vit y re acti o n s a m ples  
I n case of a s yste mic h y p erse nsiti vit y reacti o n, t he a d diti o nal bl o o d sa m ples ta ke n i n relati o n t o t he 
reacti o n (Secti o n  8. 9. 2 ) ma y b e retai n e d t o f oll o w-u p o n t he h y perse 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 tests ma y be p erf or me d, e. g. hista mi ne release 
( bas o p hil acti vati o n). If meas ure d, s uc h data will be re p ort e d i n a se parate re p ort. 
T he sa m ples will be st ore d at N o v o N or dis k or a N o v o N or dis k desi g n ate d referral ce ntral bi o -
re p osit or y. T he sa m ples mi g ht be transferre d t o ot her c o u ntries, if n ot pr o hi bite d b y l ocal 
re g ulati o ns. O nl y N o v o N or dis k staff a n d bi o-re p osit or y pers o n nel will ha ve access t o t he st ore d 
sa m ples. T he sa m ples ma y be s hi p p e d t o a c o ntr act researc h or ga nisati o n ( C R O) f or a nal ysis.  
T he sa m ples  will be a n o n y mise d (i de ntifie d o nl y b y a u ni q u e 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 date). C o nfi de ntialit y a n d p ers o nal dat a pr otecti o n will be 
e ns ure d d uri 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 a n d t heir 
relati ves. S u bjects ca n c o ntact t he i n vesti gat or if t he y wis h t o be i nf or me d a b o ut res ults deri ve d 
fr o m st ore d a nti b o d y sa m ples o btai ne d fr o m t heir o w n b o d y. 
T he sa m ples will be st ore d after e n d of trial a n d u ntil mar keti n g a ut h orisati o n a p pr o val or u ntil t he 
researc h pr oj ect ter mi nat es, b ut n o l o n ger t ha n 1 5 years fr o m e n d of trial after w hic h t he y will be 
destr o ye d.  
A nti b o d y s a m ples  
A nti b o d y sa m ples ma y b e retai ne d  f or f urt her c haracterisati o n of a nti b o d y res p o nses t o war ds dr u g, 
if re q uire d b y h ealt h a ut h orities or f or safet y reas o ns. T he sa m ples ma y als o be use d f or f urt her 
de vel o p me nt of a nti -i ns uli n a nti b o d y assa ys, or f or e x pl orat or y i n vesti gati o n of a nti b o dies.  
T he a nti b o d y s a m ples will be st ore d after e n d of trial a n d u ntil mar keti n g a ut h orisati o n a p pr o val or 
u ntil t he researc h pr oje ct ter mi nates, b ut n o l o n ger t ha n 1 5 years fr o m e n d of trial after  w hic h t he y 
will be destr o ye d.  
M et a b olis m s a m ples ( P K s a m ples)  
Sa m ples f or meta b olis m a nal ysis ma y b e ret ai ne d f or later a nal ysis of meta b olites if nee de d. If 
sa m ples are s electe d f or meta b olite a nal ysis, t he y will be st ore d at N o v o N or dis k after e n d of tr ial 
a n d u ntil mar keti n g a ut h orisati o n a p pr o val or u ntil t he researc h pr oj ect ter mi nates, b ut n o l o n ger 
t ha n 1 5 years fr o m e n d of trial after w hic h t he y will be destr o ye d. 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
8 3
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
8 5  of 1 0 2  
If t he h y p o gl ycae mic e pis o de f ulfils t he criteri a f or a n S A E t he n i n a d diti o n t o t he a b o ve patie nt 
re p orte d d ata, a n e C R F A E f or m an d a safet y i nf or mati o n f or m m ust als o be fille d i n. O ne A E f or m 
a n d safet y i nf or mati o n f or m ca n c o v er se v eral h y p o gl ycae mic val ues , if t he s u bject has n ot 
rec o vere d b et wee n t h em a n d has re p orte d t he m as o ne  e pis o de i n t he e Di ar y. 
U p o n o nset of a h y p o gl yca e 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 h a 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 l o w P G meas ure me nts ca n be re p ort e d b y t he s u bject as o ne h y p o gl ycae mic e pis o de u ntil 
a s uccee di n g P G val ue is ≥ 3. 9 m m ol/ L ( 7 0 m g/ d L). I n cas e of se v eral 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 n e t hat will be re p ort e 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. T he re mai ni n g val ues will be ke pt as s o urce data.  
If t he se verit y of a h y p o gl ycae mic e pis o de c ha n ges, o nl y o ne h y p 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 bjects 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 f oll o wi n g t he ret ur n of P G t o n or mal is c o nsi dere d s 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 n4 1. 
e Di ar y re vie w  
At eac h c o ntact t he i n ve sti gat or s h o ul d re vi e w t he e Diar y dat a f or c orrect r e 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 cas e of i nc o m plet e or i nc orrect dat a i n t he e Diar y, t he s u bject m ust 
be q uesti o ne d w het her t h ere ha v e bee n a n y se v ere h y p o gl ycae mic e pis o des si nce t he last visit. T he 
s u bject s hall u p date t he re p orte d data i n t he e Diar y acc or di n gl y.  
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 piso 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 s o ur ce d o c u me nts. 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
8 5
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
8 6  of 1 0 2  
 
1 0. 8  
A p pe n di x 8: Titr ati o n g ui deli ne  
I ntr o d ucti o n 
Titrati o n g ui deli nes ha v e bee n de v el o pe d, pr o vi di n g rec o m me n de d d os e a dj ust me nts at differe nt P G 
le vels t o e ns ure t hat s u bj ects recei ve a n o pti mal treat me nt. H o we v er, it is rec o g nise d t hat i ns uli n 
treat me nt s h o ul d be i n di vi d ualise d, a n d t he s pecifi c titrati o n al g orit h ms ma y n ot be a p plica ble i n 
certai n cli nical sit uati o ns. He nce, it is i m p orta nt t hat ot her i nf or mati o n, s uc h as s y m pt o ms of 
h y p o -/ h y p er gl ycae mia, pre vi o us res p o nse t o d ose a dj ust me nts, ot her gl uc os e meas ure me nts a n d 
ot her i n dicat ors of t he s u bject’s le vel of gl ycae mi c c o ntr ol, is ta ke n i nt o c o nsi derati o n w he n 
decisi o ns o n d osi n g are ma de. T he i n vesti gat or is res p o nsi ble f or t he tr eat me nt of t he s u bjects a n d 
ca n t heref ore o verr ule t h e g ui d eli nes t o a v oi d safet y hazar ds.  
I niti ati o n of tri al pr o d ucts 
At ra n d o misati o n eli gi ble s u bjects will be ra n d o mise d t o recei ve i ns uli n ic o dec or i ns uli n gl a r gi ne. 
B ot h i n c o m bi nati o n wit h b ol us i ns uli n as part.  
•  I ns uli n ic o dec s h o ul d be ta ke n o nce wee kl y o n t he sa me da y of t he wee k. All patie nts 
s h o ul d recei ve a l oa di n g d ose at ra n d o misati o n ( V 2), w hic h c o nsist of t otal dail y bas al 
i ns uli n d ose bef ore ra n d o misati o n x 7  +  5 0 % of t heir t otal dail y b asal i ns uli n d ose  x  7. T he 
f oll o wi n g w ee kl y d ose ( V 3) s h o ul d be t he t otal d ail y d ose x  7. I n t he f oll o wi n g ta ble t h e 
wee kl y V 2 a n d V 3 d oses f or patie nts recei vi n g fr o m 1 0 U t o 1 0 0 U per da y h a ve bee n 
calc ulate d. Pleas e, n ote t hat t he dis pla ye d val ues are r o u n d off t o t he nearest d ose di vi da ble 
b y 1 0.  
T ot al d ail y d os e 
bef ore r a n d o mis ati o n 
( U) 
V 2 i ns uli n ic o dec d os e 
( U) 
V 3 i ns uli n ic o dec d os e 
( U) 
T ot al d ail y d os e 
bef ore r a n d o mis ati o n 
( U) 
V 2 i ns uli n ic o dec d os e 
( U) 
V 3 i ns uli n  ic o dec d os e 
( U) 
1 0  
1 1 0  
7 0  
5 6  
5 9 0  
3 9 0  
1 1  
1 2 0  
8 0  
5 7  
6 0 0  
4 0 0  
1 2  
1 3 0  
8 0  
5 8  
6 1 0  
4 1 0  
1 3  
1 4 0  
9 0  
5 9  
6 2 0  
4 1 0  
1 4  
1 5 0  
1 0 0  
6 0  
6 3 0  
4 2 0  
1 5  
1 6 0  
1 1 0  
6 1  
6 4 0  
4 3 0  
1 6  
1 7 0  
1 1 0  
6 2  
6 5 0  
4 3 0  
1 7  
1 8 0  
1 2 0  
6 3  
6 6 0  
4 4 0  
1 8  
1 9 0  
1 3 0  
6 4  
6 7 0  
4 5 0  
1 9  
2 0 0  
1 3 0  
6 5  
6 8 2  
4 6 0  
2 0  
2 1 0  
1 4 0  
6 6  
6 9 0  
4 6 0  
2 1  
2 2 0  
1 5 0  
6 7  
7 0 0  
4 7 0  
2 2  
2 3 0  
1 5 0  
6 8  
7 1 0  
4 8 0  
2 3  
2 4 0  
1 6 0  
6 9  
7 2 0  
4 8 0  
2 4  
2 5 0  
1 7 0  
7 0  
7 4 0  
4 9 0  
2 5  
2 6 0  
1 8 0  
7 1  
7 5 0  
5 0 0  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
8 6
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
8 7  of 1 0 2  
 
2 6  
2 7 0  
1 8 0  
7 2  
7 6 0  
5 0 0  
2 7  
2 8 0  
1 9 0  
7 3  
7 7 0  
5 1 0  
2 8  
2 9 0  
2 0 0  
7 4  
7 8 0  
5 2 0  
2 9  
3 0 0  
2 0 0  
7 5  
7 9 0  
5 3 0  
3 0  
3 2 0  
2 1 0  
7 6  
8 0 0  
5 3 0  
3 1  
3 3 0  
2 2 0  
7 7  
8 1 0  
5 4 0  
3 2  
3 4 0  
2 2 0  
7 8  
8 2 0  
5 5 0  
3 3  
3 5 0  
2 3 0  
7 9  
8 3 0  
5 5 0  
3 4  
3 6 0  
2 4 0  
8 0  
8 4 0  
5 6 0  
3 5  
3 7 0  
2 5 0  
8 1  
8 5 0  
5 7 0  
3 6  
3 8 0  
2 5 0  
8 2  
8 6 0  
5 7 0  
3 7  
3 9 0  
2 6 0  
8 3  
8 7 0  
5 8 0  
3 8  
4 0 0  
2 7 0  
8 4  
8 8 0  
5 9 0  
3 9  
4 1 0  
2 7 0  
8 5  
8 9 0  
6 0 0  
4 0  
4 2 0  
2 8 0  
8 6  
9 0 0  
6 0 0  
4 1  
4 3 0  
2 9 0  
8 7  
9 1 0  
6 1 0  
4 2  
4 4 0  
2 9 0  
8 8  
9 2 0  
6 2 0  
4 3  
4 5 0  
3 0 0  
8 9  
9 3 0  
6 2 0  
4 4  
4 6 0  
3 1 0  
9 0  
9 5 0  
6 3 0  
4 5  
4 7 0  
3 2 0  
9 1  
9 6 0  
6 4 0  
4 6  
4 8 0  
3 2 0  
9 2  
9 7 0  
6 4 0  
4 7  
4 9 0  
3 3 0  
9 3  
9 8 0  
6 5 0  
4 8  
5 0 0  
3 4 0  
9 4  
9 9 0  
6 6 0  
4 9  
5 1 0  
3 4 0  
9 5  
1 0 0 0  
6 7 0  
5 0  
5 3 0  
3 5 0  
9 6  
1 0 1 0  
6 7 0  
5 1  
5 4 0  
3 6 0  
9 7  
1 0 2 0  
6 8 0  
5 2  
5 5 0  
3 6 0  
9 8  
1 0 3 0  
6 9 0  
5 3  
5 6 0  
3 7 0  
9 9  
1 0 4 0  
6 9 0  
5 4  
5 7 0  
3 8 0  
1 0 0  
1 0 5 0  
7 0 0  
5 5  
5 8 0  
3 9 0  
 
 
 
 
•  I ns uli n gl ar gi ne s h o ul d be ta ke n o nce dail y, at a n yti me of t he d a y b ut at t he sa me ti me 
e ver y da y. S witc hi n g fr o m pre vi o us basal i ns uli n s h o ul d be i n acc or da nce wit h l ocal la bel.  
•  I ns uli n as p art s h o ul d be ta ke n wit h mai n meals 2-4 ti mes per da y. S witc h fr o m pre vi o us 
b ol us i ns uli n s h o ul d be d o ne u nit -t o-u nit per meal.  
•  T he treat -t o-tar get a p pr oac h will be a p plie d t o b ot h treat me nt ar ms t o o pti mise gl ycae mic 
c o ntr ol t hr o u g h o ut t he tri al.  
•  T here are n o ma xi m u m or mi ni m u m i ns uli n d oses.  
D ose a dj ust me nt of tri al pr o d ucts d uri n g t he tri al  
After ra n d o misati o n t he i n vesti gat or s h o ul d a dj ust t he trial pr o d ucts o nce wee kl y i n c o n necti o n wit h 
t he sc he d ule d visits/ p h o ne c o ntacts as d escri b e d b el o w: 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
8 7
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
8 8  of 1 0 2  
 
•  T he d ose a dj ust me nt will be base d o n t he t hree pre -brea kfast S M P G val ues meas ure d o n t w o 
da ys pri or t o titrati o n a n d o n t he da y of t he c o nt act.  
•  If o ne or m ore pre-brea kfast S M P G val ues are missi n g, t he d ose a dj ust me nt s h o ul d be 
perf or me d o n t h e re m ai ni n g S M P G val ue(s).  
•  T he prescri be d d ose s h o ul d be deter mi ne d b y t he i n vesti gat or a n d rec or de d i n t he H C P we b 
p ortal.  
Titr ati o n of i ns uli n gl ar gi ne  
A dj ust me nt of i ns uli n glar gi ne will be d o ne i n acc or da nce wit h  Ta ble  1 0 -5 . 
T a ble  1 0 -5  
I ns uli n gl ar gi ne 
Pre -bre a kf ast S M P G  
D ose a dj ust me nt  
Val ue t o use  
m m ol/ L  
m g/ d L  
U  
L o west of t he S M P G 
val ues  
< 4. 4  
< 8 0  
– 3  
Mea n of t he S M P G 
val ues  
4. 4 – 7. 2  
8 0 – 1 3 0  
0  
> 7. 2  
> 1 3 0  
+ 3  
Titr ati o n of i ns uli n ic o dec  
A dj ust me nt of i ns uli n ic o dec will be d o ne i n acc or da nce wit h  Ta bl e  1 0 -6 . 
T a ble  1 0 -6  
I ns uli n ic o dec 
Pre -bre a kf ast S M P G  
D ose a dj ust me nt  
Val ue t o use  
m m ol/ L  
m g/ d L  
U  
L o west of t he S M P G 
val ues  
< 4. 4  
< 8 0  
– 2 0  
Mea n of t he S M P G 
val ues  
4. 4 – 7. 2  
8 0 – 1 3 0  
0  
> 7. 2  
> 1 3 0  
+ 2 0  
Titr ati o n of i ns uli n as p art  
I n t he first 8 w ee ks after r a n d o mis ati o n i ns uli n as p art s h o ul d o nl y be a dj uste d f or s afet y 
re as o ns.  T hereafter t he d oses s h o ul d be c o nsi dere d a dj uste d t wice wee kl y at i nter vals of 3 -4 d a ys, 
eit her as self -titrati o n or assiste d b y t he i n vesti gat or. 
D ose a dj ust me nt will be base d o n t he pre -pra n dial or be dti me S M P G val ues meas ure d o n t he t hree 
da ys pri or t o titrati o n i n acc or da n ce wit h  T a ble  1 0 -7 . 
•  
Brea kfast d os e will be a dj uste d base d o n t he pre -l u nc h S M P G val ues. 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
8 8
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
8 9  of 1 0 2  
 
•  
L u nc h d os e will be a dj uste d base d o n t he pre -di n n er S M P G val ues . 
•  
Di n ner d ose will be a dj uste d base d o n t he be dti me S M P G val ues.  
If t he patie nt e ats m ore t ha n f o ur ti mes a da y t h e f o urt h d ose will be a dj uste d i n a gree me nt wit h t he 
i n vesti gat or. 
T a ble  1 0 -7  
I ns uli n as p art 
T ar g et pre -pr a n di al a n d be dti me 
S M P G  
R ule  
D ose a dj ust me nt  
m m ol/ L  
m g/ d L  
 
U  
4. 4 -7. 2  
8 0 -1 3 0  
≥1 S M P G bel o w tar get  
-1  
N o S M P G bel o w tar get  
0 -1 S M P G a b o ve tar get  
0  
N o S M P G bel o w tar get  
≥2 S M P Gs a b o ve tar get  
+ 1  
 
De vi ati o ns f r o m t he al g orit h m  
It is rec o m me n de d t hat t h e al g orit h m is f oll o we d. H o we ver, it is als o i m p orta nt t hat t he decisi o n t o 
a dj ust i ns uli n d oses is base d o n all rele va nt i nf or mati o n. A reas o n f or de viati n g fr o m t he al g orit h m 
s h o ul d be e ntere d t h e i nt o t he H C P we b p ortal b y t he i n vesti gat or as a p plica ble.  
Missi n g i ns uli n ic o dec d ose g ui d a nce  
If a n i ns uli n ic o dec d os e is misse d f or ≤ 3 da ys aft er t he pla n ne d d osi n g d a y, s u bjects s h o ul d i nject 
t he pla n ne d d ose as s o o n as p ossi ble a n d perf or m c o ntr ol S M P G meas ure me nt. If t h e missi n g d ose 
is misse d f or > 3 da ys, t h e s u bject s h o ul d a wait t h e ne xt pla n ne d  da y -of -i nj ecti o n. 
D ose rec o m me n d ati o n fr o m e n d of tre at me nt a n d d uri n g f oll o w u p (i ns uli n ic o dec)  
If it is deci de d t hat t he i n di vi d ual s u bject s h o ul d c o nti n ue basal i ns uli n after e n d of treat me nt, it is 
rec o m me n de d t h at t he s u bject is s witc he d fr o m i ns ulin ic o dec t o a n y a vaila ble basal i ns uli n at t he 
discreti o n of t he i n vesti gat or. T he i n vesti gat or s h o ul d i nstr uct t he s u bject i n h o w t o s witc h at t he  
e n d of treat me nt visit ( V 2 8).  
Re gar di n g t he s witc h fr o m i ns uli n ic o dec t o p ost -trial basal i ns uli n t he f oll o wi n g s h o ul d be 
c o nsi dere d:  
•  
Calc ulate t he ne w d ail y b asal i ns uli n d ose di vi di n g t he latest i ns uli n ic o dec d ose b y 7 . 
•  
I nitiate t he n e w dail y bas al i ns uli n t w o wee ks after t he last i njecti o n of i ns uli n ic o dec . 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
8 9
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
9 0  of 1 0 2  
 
•  
C o nti n ue t o meas ure pre -brea kfast S M P G dail y  i n t he f oll o w u p peri o d. If pre-brea kfast 
S M P G e x cee ds 1 0. 0 m m ol/ L ( 1 8 0 m g/ d L), it s h o ul d be c o nsi dere d t o i nitiate t he dail y basal 
i ns uli n d ose earlier t ha n t w o wee ks after t h e last d ose of i ns uli n ic o dec. 
•  
C o nsi der titrati n g t he bas al i ns uli n o nce or t wi ce wee kl y acc or di n g t o t he pre -brea kfast 
S M P G val ues a n d t he l ocal la bel of t he c h os e n i ns uli n.  
D at a c ollecti o n  
T he s u bject s h o ul d be i nstr ucte d t o re p ort t he f oll o wi n g i n t he e Diar y:  
•  
Date, d ose a n d ti me of i ns uli n as part a n d i ns uli n glar gi n e or i ns uli n ic o dec i njecti o ns . 
•  
E ns ure tra nsf er of S M P G val ues wit h a n i n dicati o n of “ pre -brea kfast ”, “ pre -l u nc h”, “ pre-
di n ner ”, “b e dti me ” or “ot her ” (s ee S ecti o n 8. 1. 1 ). 
•  
H y p o gl ycae mic e pis o des as descri be d i n A p pe n di x 7 ( Secti o n 1 0. 7 ). 
W hile usi n g t he H C P we b p ortal f or titrati o n t he f oll o wi n g will be e ntere d b y i n vesti gat or:  
•  
I ns uli n glar gi ne or i ns uli n ic o dec a n d i ns uli n as part d oses prescri be d at t his c o ntact. 
•  
Reas o ns f o r de vi ati o n fr o m t he i ns uli n glar gi ne or i ns uli n ic o dec titrati o n al g orit h ms, if 
a p plica ble.  
D at a s ur veill a nce  
S ur veilla nce of titrati o n data will be perf or me d ce ntrall y b y N o v o N or dis k i n a n u n biase d or, if 
p ossi ble, a bli n de d ma n ner. T he d ata will be re v i e we d a n d si g nifica nt d e viati o ns fr o m t he titrati o n 
al g orit h m will be f oll o we d u p.  
It is i m p orta nt t hat data re gar di n g d ose titrati o n is e ntere d i nt o t he e Diar y a n d t he H C P we b p ortal. 
Ti mel y re gistrati o n is cr ucial i n or der t o ta k e a p pr o priate acti o ns be f ore t h e s u bject’s ne xt site 
visit/ p h o ne c o ntact. T he ai m is t o re d uce t he ti me peri o ds i n w hic h a s u bject ma y recei v e 
s u b o pti mal treat me nt. 
T he titrati o n data s h o ul d be re vie we d b y N o v o N or dis k wit hi n 2 4 h o urs ( o n w or k da ys). T he 
re vie wer ma y c o nt act t he i n vesti gat or b y e-mail or p h o ne t o clarif y reas o ns f or de viati o n or t o 
re q uest e ntr y of missi n g data. W he n t he i n vesti gat or recei ves a n i n q uir y, a res p o nse s h o ul d be 
recei v e d at N o v o N or dis k wit hi n 2 4 h o urs ( o n w or k da ys). 
I n a d diti o n, N o v o N or dis k will m o nit or c ha n ges i n H b A1c. N o v o N or dis k ma y visit or p h o ne sites t o 
disc uss pr o gress i n gl ycae mic c o ntr ol a n d titrati o n of i n di vi d ual s u bjects.  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
9 0
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o  N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
9 1  of 1 0 2  
 
1 0. 9  
A p pe n di x 9: C o u ntr y -s pecific re q uire me nts 
F or B el gi u m:  
•  C o ntr ace pti ve g ui d a nce : Hi g hl y effecti ve m et h o ds of birt h c o ntr ol are d efi ne d as t h ose, 
al o ne or i n c o m bi nati o n, t hat res ult i n a l o w fail ure rate (i.e., less t ha n 1 % per year) w he n 
use d c o nsiste ntl y a n d c orrectl y; s u c h as i m pla nts, i njecta bles, c o m bi ne d oral c o ntrace pti ves, 
s o me i ntra uteri ne de vi ces, tr ue se x ual a bsti ne nce (i.e. refrai ni n g fr o m het er ose x ual 
i nterc o urse d uri n g t h e e ntire peri o d of ris k ass o ciate d wit h t he st u d y treat me nts) or 
vasect o mise d part n er.  
•  I n de m nit y st ate me nt: " La w c o ncer ni n g e x peri m e nts o n t he h u ma n pers o n of 0 7 Ma y 2 0 0 4 
- Article 2 9: § 1. E ve n if wit h o ut fa ult, t he s p o ns or is lia ble f or t he da ma ge w hic h t he s u bject 
a n d/ or his ri g htf ul clai ma nts s ustai n a n d w hic h s h o ws eit her a dir ect or a n i n direct 
c o n necti o n wit h t he trial.  
F or It al y:  
•  A d diti o n al e xcl usi o n criteri a:  2 0 . K n o w n se vere dia betic a ut o n o mic ne ur o pat h y as j u d ge d 
b y t he i n vesti gat or .  
F or J a p a n:  
•  I ncl usi o n criteri a 3: a ge ≥ 2 0 years at t he ti me of si g ni n g i nf or me d c o ns e nt 
•  Pre parati o n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y: T he hea d of t he tri al site or t he trial pr o d uct 
st ora ge ma na ger assi g ne d b y t he hea d of t he trial site (a p har macist i n pri nci ple) is 
res p o nsi ble f or c o ntr ol a n d acc o u nta bilit y of t he trial pr o d ucts. 
•  Tri al g o ver n a nce c o nsi der ati o n : A seal is acce pte d as si g n at ure.  
•  E xcl usi o n criteri a  4: t he f o ot n ote, “Si m ulta ne o us partici pati o n i n a trial wit h t he pri mar y 
o bjecti ve of e v al uati n g a n a p pr o ve d or n o n -a p pr o ve d i n vesti gati o nal me di ci nal pr o d uct f or 
pre ve nti o n or treat me nt of C O VI D -1 9 disease or p osti nfecti o us c o n diti o ns is all o we d if t he 
last d ose of t he i n vesti gati o nal me dici nal pr o d uct has bee n recei ve d m ore t ha n 3 0 da ys 
bef ore s cree ni n g ”, is n ot a p plic a ble f or J a p a n. 
•  Disc o nti n u ati o n  criteri a  4, Secti o n  7. 1 : t he f o ot n ote, “Si m ulta ne o us partici pati o n i n a trial 
wit h t he pri mar y o bjecti v e of e val u ati n g a n a p pr o ve d or n o n -a p pr o ve d i n vesti gati o nal 
me dici nal pr o d uct f or pre ve nti o n or treat me nt of C O VI D -1 9 disease or p osti nfecti o us 
c o n diti o ns is all o we d at t he i n vesti gat or discreti o n wit h o ut disc o nti n ui n g trial pr o d uct”, is 
n ot a p plic a ble f or J a p a n.  
 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
9 1
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o  N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
      
Stat us:  
Fi n al  
      
P a ge:  
9 2  of 1 0 2  
 
F or Me xic o:  
•  Wit h dr a w al fr o m t he tri al:  s h o ul d t he s u bject, his/ her fa mil y m e m bers, pare nts or le gal 
re pres e ntati ve deci de t o wit h dra w t he c o ns e nt fr o m t he trial, t he s u bject will be e ntitle d t o 
recei v e a p pr o priate, free of c har ge me dical care a n d/ or trial dr u g d uri n g t he f oll o w-u p peri o d 
of t he pr ot oc ol w he n it will be esta blis he d wit h certai nt y t hat n o u nt o war d me dical 
c o nse q ue nces of t he s u bj ect´s partici p ati o n  i n t he researc h occ urre d. 
•  Tri al g o ver n a nce c o nsi der ati o ns : I n t he case of Me xic o, t he f oll o wi n g res p o nsi bilities will 
be i ncl u de d f or t h e hea d of t he I nstit uti o n/ Healt h Care Esta blis h me nt, Et hics, Researc h a n d, 
w he n a p plica bl e, Bi osafet y C o m mittees a n d s p o ns or wit hi n t heir sc o pe of res p o nsi bilit y: a) 
I n v esti gati o n f oll o w-u p; b) Da ma ges t o h ealt h arisi n g fr o m t he i n v esti gati o n de vel o p me nt; 
as well as t h ose arisi n g fr o m i nterr u pti o n or a d va n ce d s us pe nsi o n of treat me nt d ue t o n o n -
attri b uta ble reas o ns t o t h e S u bject; c) Ti mel y c o m plia nce of t he ter ms i n w hic h t he 
a ut h orizati o n of a researc h f or healt h i n h u ma n bei n gs ha d b ee n iss ue d; d) T o prese nt i n a 
ti mel y ma n ner t h e i nf or mati o n re q uire d b y t he Healt h A ut h orit y. 
•  I n de m nit y st ate me nt: a) 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 nes f or c o n d u cti n g cli nical 
trials i n a n y c o u ntr y, i ncl u di n g t h ose a p plica ble pr o visi o ns o n t he Me xica n U nite d States. If 
t he s u bject feels t hat s o met hin g g oes wr o n g d uri n g t he c o urse of t his trial, t he s u bject s h o ul d 
c o ntact t he trial staff i n t he first i nsta nce.  
•  b) If d uri n g t heir p artici p ati o n i n t he trial t he s u bject e x perie nces a disease or i nj ur y t hat, 
acc or di n g t o t he tri al d oct or a n d t he s p o ns or, is directl y ca use d b y t h e st u d y me dicati o n 
a n d/ or a st u d y pr oce d ure t hat ot her wise w o ul d n ot ha ve bee n part of his/ her re g ular me di cal 
care, t h e s u bject will recei ve fr o m t he i nstit uti o n or me dical care esta blis h me nt a n d free of 
c har ge, t h e a p pr o priate m e d ical treat me nt as re q uir e d. I n t his case, t he c osts res ulti n g fr o m 
s uc h treat me nt as well as t he c osts of a n y i n de m nificati o n esta blis he d b y la w will be c o vere d 
b y t he trial s p o ns or i n acc or da nce wit h t he ter ms pr o vi de d b y all a p plica bl e re g ulati o ns; 
e ve n if t he s u bject disc o nti n ues his/ her partici pati o n i n t he st u d y b y his o w n will or b y a 
decisi o n fr o m t he i n vesti gat or.  
•  c) B y si g ni n g t he i nf or m e d c o nse nt, t he s u bject will n ot re n o u nce t o a n y c o m pe nsati o n or 
i n de m nificati o n he/s he ma y b e e ntitle d t o b y la w, n or will he/s he will i nc ur a n y a d diti o nal 
e x pe nse as a res ult of his/ her partici pati o n i n t he trial; a n y a d diti o nal e x pe nse res ulti n g fr o m 
t he s u bject’s partici p ati o n i n t he trial will be c o vere d b y t he trial s p o ns or. 
F or R ussi a:  
•  Tri al g o ver n a nce c o nsi de r ati o ns:  T he trial s h o ul d be c o n d ucte d i n c o m plia nce wit h t he 
pr ot oc ol, Mi nistr y of Healt hcare of R ussia n Fe derati o n’ or der # 2 0 0 н fr o m A pril, 0 1, 2 0 1 6 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
9 2
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o  N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
9 3  of 1 0 2  
” A p pr o val of r ules of g o o d cli nical practice” a n d le gal re q uir e me nts of t he R ussia n 
Fe derati o n re g ul ati n g  cir c ulati o n of me dici nes.  
•
T he B G m eter a n d C G M are n ot a p pr o ve d at t he ti me of t he fi nal pr ot oc ol v ersi o n 1. 0,
t heref ore are re gar de d as i n vesti gati o nal de vices a n d will be la belle d t o i n dicate f or
i n vesti gati o nal use o nl y.
T he B G m eter has b ee n s electe d i n or d er t o ha v e a ut o matic tra nsfer of S M P G data t o t he
e Diar y a n d t h ere b y i n crease t he acc urac y of S M P G val ues. It is e x pecte d t hat t he better
acc urac y i n S M P G data will facilitate a n i m pr o ve me nt i n t he i ns uli n titrati o n eff orts d uri n g
t he trial.
Tec h nical c o m plai nts o n t he B G meter, stri ps, la ncets or c o ntr ol s ol uti o ns, i ncl u di n g
tec h nical c o m plai nts rel ate d t o A Es a n d S A Es, m ust be re p orte d t o 
 o n a s pecial
tec h nical c o m plai nt pa p er f or m.
T he C G M has bee n s electe d i n or der t o pr o vi de t h e b est data acc urac y a n d t o be c o nsiste nt
i n t he gl o bal cli nical pr o gra m me. Tec h nical c o m plai nts o n t he C G M m ust be re p ort e d t o
 o n a s pecial te c h nical c o m plai nt pa per f or m.
Ti meli nes f or re p orti n g, fr o m t he trial site o btai ni n g k n o wle d ge of t he tec h nical c o m plai nt:
o
Tec h nical c o m plai nt assesse d as relat e d t o a S A E wit hi n 2 4 h o urs
o
All ot her tec h nical c o m plai nts wit hi n 5 cale n dar da ys
A Es a n d S A Es relat e d t o t he tec h nical c o m plai nt m ust be re p orte d  b ot h  o n t he s pecial 
tec h nical c o m plai nt pa p er f or m a n d i n t he e C R F. I n a d diti o n t he y m ust be re p orte d i n 
acc or da nce wit h t he sta n dar d pr ot oc ol re q uire me nts f or A E a n d S A E re p orti n g as des cri be d 
i n Secti o n 8. 3 . 
At t he e n d of t he trial t he B G meter a n d C G M m ust be c ollecte d b y t he i n v esti gat or.  
If t he C G M or B G M is a p pr o ve d i n R ussia d uri n g t he trial c o n d uct, t he pr oce d ures a b o ve 
are n ot a p plic a ble a n y m ore a n d tec h nical c o m plai nts re p orti n g s h o ul d f oll o w t he sta n dar d 
vi gila nce pr oce d ures.  
F or U S A:  
•
Fi n a nci al discl os ure : Verificati o n u n der discl os ur es per C o de of Fe d eral Re g ul ati o ns ( C F R)
of Fi na nci al C o nflict of I nterest.
F or I n di a a n d Me xic o w here C G M is n ot a p pr o ve d at t he ti me of t he fi n al pr ot oc ol versi o n 
1. 0 : 
•
T he C G M is re gar de d as a n i n vesti gati o nal d e vice  a n d will be la belle d t o i n dicate f or
i n vesti gati o nal use o nl y.
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
9 3
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o  N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
9 4  of 1 0 2  
T he C G M has bee n s electe d i n or der t o pr o vi de t h e best data acc urac y a n d t o be c o nsiste nt 
i n t he gl o bal cli nical pr o gra m me. Tec h nical c o m plai nts o n t he C G M m ust be re p ort e d t o 
o n a s pecial te c h nical c o m plai nt pa per f or m.  
Ti meli nes f or re p orti n g, fr o m t he trial site o btai ni n g k n o wle d ge of t he tec h nical c o m plai nt:  
o
Tec h nical c o m plai nt assesse d as relat e d t o a S A E wit hi n 2 4 h o urs
o
All ot her tec h nical c o m plai nts wit hi n 5 cale n dar da ys
A Es a n d S A Es relat e d t o t he tec h nical c o m plai nt m ust be re p orte d  b ot h  o n t he s pecial 
tec h nical c o m plai nt pa p er f or m a n d i n t he e C R F . I n a d diti o n t he y m ust be re p orte d i n 
acc or da nce wit h t he sta n dar d pr ot oc ol re q uire me nts f or A E a n d S A E re p orti n g as des cri be d 
i n S ecti o n 8. 3 . 
At t h e e n d of t he trial C G M m ust be c ollecte d b y t he i n vesti gat or.  
If t he C G M is a p pr o ve d  i n a n y of t he c o u ntri es d uri n g t he tri al c o n d uct, t he pr oce d ures 
a b o ve are n ot a p plica bl e a n y m or e i n t he sai d c o u ntr y a n d t ec h nical c o m plai nts re p orti n g 
s h o ul d f oll o w t he sta n dar d vi gila nce pr oce d ures. 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
9 4
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
9 5  of 1 0 2  
1 0. 1 0  A p pe n di x 1 0: A b bre vi ati o ns 
A E  
a d verse e ve nt  
A N C O V A  
a nal ysis of c o varia nce 
B G  
bl o o d gl uc ose  
C G M  
c o nti n u o us gl uc ose m o nit ori n g 
CI  
c o nfi de nce i nter val 
C R F  
case re p ort f or m  
D P P -4  
di pe pti d yl p e pti dase -4  
D U N  
dis pe nsi n g u nit n u m ber  
E A C  
e ve nt a dj u dicati o n c o m mittee  
E A S  
e ve nt a dj u dicati o n s yste m  
E C G  
electr ocar di o gra m  
e C R F  
electr o nic case re p ort f or m  
E M A  
E ur o pea n Me dici nal A ge nc y  
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  
U. S. F o o d a n d Dr u g A d mi nistrati o n  A me n d me nts Act  
F P G  
fasti n g plas ma gl uc ose 
G C P  
G o o d Cli nical Practice  
G L P -1  R A  
gl uca g o n -li ke pe pti de 1 rece pt or a g o nists 
H b A 1c 
gl ycate d hae m o gl o bi n  
H C P  
healt hcare pr ofessi o nal  
H R T  
h or m o ne re place me nt t hera p y  
I B 
i n vesti gat or’s br oc h ure  
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n 
I E C 
i n de p e n de nt et hics c o m mittee 
I g E 
i m m u n o gl o b uli n E 
I M P 
i n vesti gati o nal me dici nal pr o d uct 
I N N 
i nter nati o nal n o n pr o prietar y na me 
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 A O T -W O B  
last a vaila ble pla n ne d o n-treat me nt wit h o ut i nitiati o n of m or e t ha n 2 wee ks b ol us i ns uli n tr eat me nt 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
9 5
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
9 6  of 1 0 2  
NI M P  
n o n -i n vesti gati o nal me dical pr o d uct 
P C D  
pri mar y c o m pleti o n date  
P D  
p har mac o d y na mic  
PI  
prescri bi n g i nf or mati o n  
P K  
p har mac o ki netics  
P G  
plas ma gl uc ose  
S A E  
seri o us a d verse e ve nt 
S A P  
statistical a nal ysis pla n 
S D  
sta n dar d de viati o n 
SI -I C 
su bj ect  i nf or mati o n-i nf or me d c o nse nt 
S m P C  
s u m mar y of pr o d uct c haracteristics 
S M P G  
self-meas ure d plas ma gl uc ose  
T 1 D  
t y pe 1 dia betes mellit us  
T 2 D  
t y pe 2 dia betes mellit us  
V  
visit  
W O C B P  
w o ma n of c hil d beari n g p ote ntial  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
9 6
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
9 7  of 1 0 2  
1 0. 1 1  A p pe n di x 1 1 : Pr ot oc ol a me n d me nt hist or y 
T he Pr ot oc ol a me n d me nt s u m mar y of c ha n ges ta ble f or t he c urre nt pr ot o c ol versi o n is l ocate d 
directl y b ef ore t he ta ble of c o nte nts.  
Pr ot oc ol ve rsi o n 3 . 0 (3 0 N o ve m ber 2 0 2 0 ) 
T his a me n d me nt is c o nsi dere d t o be n o n -s u bsta ntial base d o n t he criteria s et f ort h i n Article 1 0(a) of 
Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n 1, beca use 
it neit her si g nifica ntl y i m pacts t he safet y n or p h ysical/ me ntal i nte grit y of s u bjects n or t he scie ntific 
val ue of t he trial.  
O ver all r ati o n ale f or pre p ari n g pr ot oc ol, versi o n 3. 0:  
T he pr ot oc ol has bee n a me n de d t o all o w s u bjects t o c o -partici pate i n cli nical trials e val uati n g 
me dici nal pr o d ucts f or pre ve nti o n or treat me nt of C O VI D -1 9 diseas e or p osti nfecti o us c o n diti o ns.  
Secti o n # a n d n a me  
Descri pti o n  of c h a n ge  
Brief r ati o n ale  
Pr ot oc ol a me n d me nt s u m mar y of 
c ha n ges ta ble  
Ne w secti o n a d de d.  
Discl ose versi o n hist or y.  
1. 2 Fl o wc hart  
“(i ns uli n ic o dec ser u m 
c o nce ntrati o n) ” a n d “(a nti -i ns uli n 
ic o dec a nti b o dies)” ha ve bee n a d de d. 
T o ma ke it clear t hat P K a n d a nti b o d y 
testi n g are o nl y c o n d ucte d i n t he 
i ns uli n ic o dec ar m. 
1. 2 Fl o wc hart  
Delete d ra n d o misati o n visit ” X” f or 
h y p o -re p orti n g.  
C orrecti o n of err or ( h y p o -re p orti n g 
s h o ul d f oll o w A E re p orti n g). 
2. 3. 1 Ris k assess me nt  
A d de d a f urt her C O VI D -1 9 relate d 
miti gati o n strate g y . 
T o pr o vi de g ui da nce i n case of 
C O VI D -1 9 relate d l oc k d o w n of a site 
or c o u ntr y.  
5 Trial p o p ulati o n  
A d de d a refere nce t o A p pe n di x 9 
( Secti o n 1 0. 9 ). 
T o stress t hat c o u ntr y -s pecific 
re q uire me nts t o t he eli gi bilit y criteria 
are descri be d i n a p pe n di x 9. 
5. 2 E xcl usi o n criteria  
A clarif yi n g f o ot n ote has bee n a d de d 
t o e xcl usi o n criteria 4. 
T o all o w s u bj ects t o c o -partici pate i n 
cli nical trials e val uati n g me di ci nal 
pr o d ucts f or pre ve nti o n or treat me nt 
of C O VI D -1 9 disease or 
p osti nfecti o us c o n diti o ns.  
7. 1 Disc o nti n uati o n of trial treat me nt  
A clarif yi n g f o ot n ote has bee n a d de d 
t o disc o nti n uati o n criteria 4.  
T o all o w s u bj ects t o c o -partici pate i n 
cli nical trials e val uati n g me di ci nal 
pr o d ucts f or pre ve nti o n or treat me nt 
of C O VI D -1 9 disease or 
p osti nfecti o us c o n diti o ns wit h o ut 
disc o nti n ui n g trial pr o d uct.  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
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V V- T M F- 6 1 0 0 2
1 0 2
 of
9 7
 
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6
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C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
9 8  of 1 0 2  
Secti o n # a n d n a me  
Descri pti o n  of c h a n ge  
Brief r ati o n ale  
7. 1 Disc o nti n uati o n of trial treat me nt  
7. 2 S u bj ect 
disc o nti n uati o n/ wit h dra wal fr o m t he 
trial 
U p date d w or di n g t o “treat me nt stat us 
sessi o n”. 
C orrecti o n of err or.  
8. 2 Safet y assess me nts  
Delete d a se nte nce descri bi n g a 
disease s pecific f or m i n t he e C R F.  
T he e C R F f or me dical hist or y has 
c ha n ge d t o i ncl u de t he dia g n osis of 
dia betes, t h us t he i nf or mati o n is n ot 
a p plica ble a n y m ore.  
8. 2. 2  P h ysical e xa mi nati o ns  
C orrecti n g wr o n g cr oss -refere nce. 
C orr ecti o n of t y p o. 
8. 2. 4  Electr ocar di o gra ms  
C orrecti n g wr o n g cr oss -refere nce. 
C orrecti o n of t y p o. 
8. 3 A d verse e ve nts ( A Es) a n d seri o us 
a d verse e ve nts ( S A E)  
F o ot n ote t o ta ble 8 -1 i nserte d.  
T o clarif y t hat i n vesti gat ors s h o ul d 
c ollect all cere br o vasc ular e ve nts e ve n 
t h o u g h t he E A C will o nl y be 
c o nfir mi n g str o ke.  
8. 3. 1 Ti me peri o d a n d fre q ue n c y f or 
c ollecti n g A E a n d S A E i nf or mati o n  
Re p hrasi n g a se nte nce i n t he first 
para gra p h.  
C orrecti o n of a n err or  a n d 
clarificati o n.  
8. 3. 8 A d verse e ve nt of s pecial i nterest A clarif yi n g f o ot n ote has bee n a d de d . T o clarif y N o v o N or dis k defi niti o ns 
a n d pr ocesses a b o ut A E of s pe cial 
i nterest. 
8. 4  Treat me nt of o ver d ose  
C r oss-refere nce s pecifie d. 
I m pr o ve rea der-frie n dli ness. 
8. 5 P har mac o ki netics  
“f or s u bj ects ra n d o mise d t o i ns uli n 
ic o dec” has bee n a d de d. 
T o ma ke it clear t hat P K testi n g is 
o nl y c o n d ucte d i n t he i ns uli n i c o dec 
ar m.  
8. 5 P har mac o ki netics  
Re p hrasi n g t o: T he date a n d e xact 
cl oc k ti me f or bl o o d sa m pli n g m ust be 
rec or de d. 
T he date a n d e xact cl oc k ti me of t he 
sa m pli n g m ust be rec or de d i n t he la b 
re q uisiti o n f or m, n ot i n t he e C R F. 
8. 9. 1 A nti -dr u g a nti b o dies  
“f or s u bj ects ra n d o mise d t o i ns uli n 
ic o dec” has bee n a d de d. 
T o ma ke it clear t hat a nti -dr u g 
a nti b o dies testi n g is o nl y c o n d ucte d i n 
t he i ns uli n ic o dec ar m. 
8. 9. 2 H y perse nsiti vit y  
T he se nte nce “ F or t he s u bj ects 
ra n d o mise d t o i ns uli n ic o dec” has 
bee n a d de d i n t he first para gra p h.  
T o clarif y t hat t he a d diti o nal bl o o d 
sa m pli n g is o nl y ta ke n i n t he i ns uli n 
ic o dec ar m. 
9. 4. 3. 2 S u p p orti ve sec o n dar y 
e n d p oi nts: Me a n  weekly i ns uli n d ose 
fr o m week 2 4 ( V 2 6) t o week 2 6 ( V 2 8) 
A d de d t he se nte nce: “ defi ne d as t he 
s u m of t he wee kl y basal a n d wee kl y 
b ol us d ose”.  
T o clarif y h o w t he e n d p oi nt is 
defi ne d.  
1 0. 1. 8. 2 M o nit ori n g  
Delete d “ H C P we b p ortal” a n d 
“e Diaries”.  
M o nit ors are n ot re q ueste d t o perf or m 
s o urce data verificati o n i n t he H C P 
we b p ortal.  
1 0. 9 A p pe n di x 9: C o u ntr y/ Re gi o n -
s pecific re q uire me nts 
A d de d a n Italia n s pecific e xcl usi o n 
criteria.  
A d de d e xcl usi o n criteria as re q ueste d 
b y Italia n Healt h A ut h orit y i n 
O N W A R D S 1 trial. 
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
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V V- T M F- 6 1 0 0 2
1 0 2
 of
9 8
 
-
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6
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C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
9 9  of 1 0 2  
Secti o n # a n d n a me  
Descri pti o n  of c h a n ge  
Brief r ati o n ale  
1 0. 9 A p pe n di x 9: C o u ntr y/ Re gi o n -
s pecific re q uire me nts 
Delete d U S A s pecific e ye 
e xa mi nati o n re q uire me nt.  
U S A will f oll o w t he gl o bal 
re q uire me nts f or e ye e xa mi nati o n i n 
secti o n 8. 2. 5. 
1 0. 1 1  A p pe n di x 1 1: Pr ot oc ol 
a me n d me nt hist or y  
Ne w a p pe n di x a d de d.  
L o g a me n d me nts a n d versi o n hist or y.  
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
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V V- T M F- 6 1 0 0 2
1 0 2
 of
9 9
 
-
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6
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C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
1 0 0  of 1 0 2  
1 1  Refere nces  
1.
T he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n C o u ncil. Directi ve 2 0 0 1/ 2 0/ E C
of t he E ur o pea n Parlia me nt a n d of t he C o u ncil of 4 A pril 2 0 0 1 o n t he a p pr o xi mati o n of t he
la ws, re g ulati o ns a n d a d mi nistrati ve pr o visi o ns of t he me m ber states relati n g t o t he
i m ple me ntati o n of g o o d cli nical practice i n t he c o n d uct of cli nical trials o n me dici nal
pr o d ucts f or h u ma n us e. 2 0 0 1.
2.
A merica n Di a betes Ass o cia ti 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.
3.
I nter nati o nal Dia b etes Fe derati o n. I D F Dia b etes Atlas, 9t h E diti o n. 2 0 1 9.
4.
Alat orre C, Fer ná n dez La n d ó L, Y u M, Br o w n K, M o nteja n o L, J u nea u P, et al. Treat me nt
patter ns i n patie nts wit h t y p e 2 di a betes mellit us treate d wit h gl uca g o n -li ke pe pti de-1
rece pt or a g o nists: Hi g h er a d here n ce a n d persiste n ce wit h d ula gl uti de c o m p are d wit h o nce-
wee kl y e x e nati de a n d lira gl uti de. Di a betes O b es Meta b. 2 0 1 7; 1 9( 7): 9 5 3 -6 1.
5.
Lea h y J L. Pat h o ge nesis of t y pe 2 di a betes mellit us. Arc h Me d Res. 2 0 0 5; 3 6( 3): 1 9 7 -2 0 9.
6.
De Fr o nz o R A. Pat h o ge n esis of t y p e 2 dia betes m ellit us. Me d Cli n N ort h A m.
2 0 0 4; 8 8( 4): 7 8 7 -8 3 5, i x.
7.
I nz ucc hi S E, Ber ge nstal R M, B use J B, Dia ma nt M, Ferra n ni ni E, Na u c k M, 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 5: a patie nt -ce ntre d a p pr oac h.
U p date t o a p ositi o n state me nt of t he A merica n Di a betes Ass oci ati o n a n d t he E ur o pea n
Ass ociati o n f or t he St u d y of Dia betes. Di a bet ol o gia. 2 0 1 5; 5 8( 3): 4 2 9 -4 2.
8.
E ur o pea n Me dici nes A ge nc y. G ui deli ne o n cli nical i n vesti gati o n of me dici nal pr o d ucts i n
t he treat me nt or pre ve nti o n of dia betes mellit us ( C P M P/ E W P/ 1 0 8 0/ 0 0 Re v. 2). 2 9 J a n 2 0 1 8.
9.
Hali mi S, Bal ka u B. Bett er a nal yze t he deter mi na nts of t hera pe utic i ne rtia t o o verc o me it.
Dia betes Meta b. 2 0 1 2; 3 8 S u p pl 3: S 2 7 -8.
1 0.
K h u nti K, Millar -J o nes D. Cli nical i nertia t o i ns uli n i nitiati o n a n d i nte nsificati o n i n t he U K:
A f oc use d literat ure re vie w. Pri m Care Dia betes. 2 0 1 7; 1 1( 1): 3 -1 2.
1 1.
N o v o N or dis k A/ S. I n v esti g at or's Br oc h ure, i ns uli n ic o dec, pr oject N N 1 4 3 6, (e diti o n 6). 5
J u n 2 0 2 0.
1 2.
Sa n ofi -A ve ntis De utsc hl a n d G m b H. La nt us ®   (i ns uli n glar gi ne), E U S u m mar y of Pr o d uct
C haracteristics ( S m P C). 2 0 1 8.
1 3.
F o o d a n d Dr u g A d mi nistrati o n. La nt us - U. S. La b el i nf or mati o n. 2 0 1 5.
1 4.
N o v o N or dis k A/ S. A b bre viate d I n vesti gat or's Br oc h ure, i ns uli n as part ( N o v o Ra pi d  ® ),
E X 1 0 3 0 (e diti o n 9. 0). 0 7 Fe b 2 0 1 9.
1 5.
N o v o N or dis k A/ S. N o v o Ra pi d (i ns uli n as part), E U S u m mar y of pr o d uct c haract eristics
( S m P C). 2 3 A u g 2 0 1 9.
1 6.
N o v o N or d is k A/ S. N o v o L o g®   (i ns uli n as part), U. S. Prescri bi n g I nf or mati o n. Mar 2 0 1 7.
1 7.
Clar ke W, J o nes T, Re wers A, D u n ger D, Kli n ge ns mit h GJ. 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 betes. 2 0 0 9; 1 0 S u p pl
1 2 : 1 3 4-4 5.
1 8.
P ol o ns k y W H, Fis her L, Hessler D, Br u h n D, Best J H. Patie nt pers pecti ves o n o nce -wee kl y
me dicati o ns f or dia bet es. Dia betes O besit y & Met a b olis m. 2 0 1 1; 1 3( 2): 1 4 4 -9.
1 9.
K DI G O 2 0 1 2 Cli nical Practice G ui d eli ne f or t he E val uati o n a n d Ma na ge me nt of C hr o nic
Ki d ne y Disease. htt p:// w w w. ki d ne y -i nter nati o nal. or g. 2 0 1 3 2 0 1 3.
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
1 0 0
 
-
 |
6
 |
C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
1 0 1  of 1 0 2  
2 0.
F o o d a n d Dr u g A d mi nistrati o n, C D E R. G ui da nce f or I n d ustr y. Dia b etes M ellit us:
De vel o pi n g Dr u gs a n d T hera pe utic Bi ol o gics f or Treat me nt a n d Pr e ve nti o n, Draft G ui da nce.
Fe br uar y 2 0 0 8 .
2 1.
R ussell -J o nes D, Vaa g A, Sc h mitz O, Set hi B K, Lalic N, A ntic S, et al. Lir a gl uti de vs
i ns uli n glar gi ne a n d pl ace b o i n c o m bi nati o n wit h metf or mi n a n d s ulf o n yl urea t hera p y i n
t y pe 2 dia b etes mellit us ( L E A D-5 met + S U): a ra n d o mise d c o ntr olle d trial. Dia b et ol o gi a.
2 0 0 9; 5 2( 1 0): 2 0 4 6 -5 5.
2 2.
Ar o da V R, Baile y T S, Cari o u B, K u m ar S, Leiter L A, Ras ki n P, et al. Effect of a d di n g
i ns uli n de gl u dec t o treat me nt i n patie nts wit h t y p e 2 dia betes i na d e q uatel y c o ntr olle d wit h
metf or mi n a n d lira gl uti de: a d o u ble -bli n d ra n d o mize d c o ntr olle d trial ( B E GI N: A D D T O
G L P -1 St u d y). Dia b etes O bes Meta b. 2 0 1 6; 1 8( 7): 6 6 3 -7 0.
2 3.
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.
2 4.
Little R, R u bi n D. Statistical a nal ysis wit h missi n g dat a. S o ns. J W, e dit or. Ne w Y or k.: J o h n
Wile y & S o ns. 1 9 8 7.
2 5.
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 b jects. 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 6.
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.
2 7.
De A n gelis C, Draze n J M, Frizelle F A, Ha u g C, H oe y J, H ort o n R, et al. Cli nical trial
re gistrati o n: a state me nt fr o m t he I nter nati o nal C o m mittee of Me dical J o ur nal E dit ors. N
E n gl J Me d. 2 0 0 4; 3 5 1( 1 2): 1 2 5 0 -1.
2 8.
U. S. De part me nt of Healt h a n d H u ma n Ser vices , F o o d a n d Dr u g A d mi nistrati o n. F o o d a n d
Dr u g A d mi nistrati o n A me n d me nts Act of 2 0 0 7 as a me n de d b y t he Fi nal R ule " Cli nical
Trials Re gistrati o n a n d Res ults I nf or mati o n S u b missi o n". 2 1 Se pte m ber 2 0 1 6.
2 9.
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 pe a 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 d ici nes A ge nc y, article 5 7. 3 0
A pril 2 0 0 4.
3 0.
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 us e a n d a me n d i 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 1.
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 .
3 2.
Sa m ps o n H A, M u n oz -F url o n g A, Ca m p b ell R L, A d ki ns o n N F, Jr., B oc k S A, Bra n u m A, et
al. Sec o n d s y m p osi u m o n t he defi niti o n a n d ma na ge m e nt of a na p h yl a xis: s u m mar y re p ort --
Sec o n d Nati o nal I nstit ute of Aller g y a n d I nfecti o us Disease/ F o o d Aller g y a n d A na p h yl a xis
Net w or k s y m p osi u m. J Aller g y Cli n I m m u n ol. 2 0 0 6; 1 1 7( 2): 3 9 1 -7.
3 3.
Ke m p S F, L oc k e y R F. A na p h yl a xis: a re vie w of ca uses a n d mec ha nis ms. J Aller g y Cli n
I m m u n ol. 2 0 0 2; 1 1 0( 3): 3 4 1-8.
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
1 0 1
 
-
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6
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C O N FI D E N TI A L

Pr ot o c ol  
 
Date:  
1 4 A pril 2 0 2 1  
N o v o N or di s k  
Trial I D: N N 1 4 3 6 -4 4 8 0  
V ersi o n:  
4. 0  
Stat us:  
Fi n al  
P a ge:  
1 0 2  of 1 0 2  
3 4.
J o ha nss o n S G, Bie ber T, Da hl R, Frie d ma n n P S, La nier B Q, L oc k e y R F, et al. Re vise d
n o me nclat ure f or aller g y f or gl o bal use: Re p ort of t he N o me nclat ure Re vie w C o m mittee of
t he W orl d Aller g y Or ga nizati o n, Oct o ber 2 0 0 3. J Aller g y Cli n I m m u n ol. 2 0 0 4; 1 1 3( 5): 8 3 2 -6.
3 5.
Scialli A R, Baile y G, Be yer B K, B ø g h I B, Bresli n WJ, C he n C L, et al. P ote ntial se mi nal
tra ns p ort of p har mace uti cals t o t he c o nce pt us. Re pr o d T o xic ol. 2 0 1 5; 5 8: 2 1 3-2 1.
3 6.
Cli nical Trial Fa cilitati o n Gr o u p ( C T F G), Hea ds of Me dici nes A ge nc y. Rec o m me n dati o ns
relate d t o c o ntrace pti o n a n d pre g na nc y t esti n g i n cli nical trials. 2 1 Se p 2 0 2 0.
3 7.
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 8.
A merica n Di a betes Ass o ciati 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 9.
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 betes. 2 0 1 8; 1 9 S u p pl
2 7: 1 7 8 -9 2.
4 0.
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 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 oc ri ne S ociet y. Dia b etes Care. 2 0 1 3; 3 6( 5): 1 3 8 4-9 5.
  Pr ot oc ol  versi o n 4 0 Gl o bal
N N 1 4 3 6- 4 4 8 0
N N 1 4 3 6
0
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V V- T M F- 6 1 0 0 2
1 0 2
 of
1 0 2
 
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6
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C O N FI D E N TI A L

 
1 6. 1. 0 1  
Pr ot oc ol  Att ac h me nt  
Pr ot oc ol A ttac h me nt I is l ocate d i n t he Trial Mast er File. 
If a p plica bl e, Pr ot oc ol Attac h me nt II is als o l ocate d i n t he Trial Master File. 
C o nte nt: Gl o bal ke y staff a n d C o u ntr y k e y staff.  
C O N FI D E N TI A L
Date:
N o v o N or di s k
Versi o n:
Stat us:
I ns uli n ic o dec
Trial I D: N N 1 4 3 6 4 4 8 0 O N W A R D S 4
Cli nical Trial Re p ort
A p pe n di x 1 6. 1. 1
0 8 A u g ust 2 0 2 2
1. 0
Fi nal
C O N FI D E N TI A L