Conditions: Diabetes Mellitus, Type 2
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 582
Healthy volunteers: no

Brief summary:
This study compares insulin icodec (a new insulin taken once a week) to insulin glargine (an insulin taken once daily which is already available on the market) in people with type 2 diabetes.

The study will look at how well insulin icodec taken weekly controls blood sugar compared to insulin glargine taken daily.

Participants will either get insulin icodec that participants will have to inject once a week on the same day of the week or insulin glargine that participants will have to inject once a day at the same time every day. Which treatment participants will get is decided by chance. Participants will also get a mealtime insulin.The insulin is injected with a needle in a skin fold in the thigh, upper arm or stomach.

The study will last for about 8 months. participants will have 17 clinic visits and 13 phone calls with the study doctor.At 8 clinic visits participants will have blood samples taken. At 4 clinic visits participants cannot eat or drink (except for water) for 8 hours before the visit. Participants will be asked to wear a sensor that measures their blood sugar all the time in 3 periods for a total of 13 weeks (about 3 months) during the study.

Women cannot take part if pregnant, breast-feeding or plan to become pregnant during the study period.

Detailed description:

Arms:
arm 1: Participants will get once weekly injections in combination with 2-4 times daily injections of insulin aspart arm 2: Participants will get once daily injections in combination with 2-4 times daily injections of insulin aspart

Interventions: intervention 1: Insulin icodec intervention 2: Insulin glargine intervention 3: Insulin aspart
Intervention descriptions: intervention 1: Participants will receive subcutaneous (s.c.) injections of insulin icodec once weekly for 26 weeks intervention 2: Participants will receive subcutaneous (s.c.) injections of insulin glargine once daily for 26 weeks intervention 3: Participants will receive subcutaneous (s.c.) injections of insulin aspart 2-4 times daily for 26 weeks

Protocol document:
Prot_000.pdf: 
C o ver P a ge  f or Pr ot oc ol  
 
S p o ns or na me:  
N o v o N or dis k A/ S  
N C T n u m ber  
N C T 0 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
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V V- T M F- 6 1 0 0 2
1 0 2
 of
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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
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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:  
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
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V V- T M F- 6 1 0 0 2
1 0 2
 of
3
 
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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  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
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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
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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
 
-
 |
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  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
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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
 
-
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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 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
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
9 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:  
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
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
9 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 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
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
9 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 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
 
-
 |
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 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
 |
V V- T M F- 6 1 0 0 2
1 0 2
 of
1 0 2
 
-
 |
6
 |
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

SAP_001.pdf: