Effect of Semaglutide Once-weekly Versus Insulin Aspart Three Times Daily, Both as Add on to Metformin and Optimised Insulin Glargine (U100) in Subjects With Type 2 Diabetes A 52-week, Multi-centre, Multinational, Open-label, Active-controlled, Two Armed, Parallel-group, Randomised Trial in Subjects With Type 2 Diabetes
Phase: PHASE3
Conditions: Diabetes Mellitus, Type 2
Sponsor: Novo Nordisk A/S

C o ver P a ge  f or Pr ot oc ol  
 
S p o ns or na me:  
N o v o N or dis k A/ S  
N C T n u m ber  
N C T 0 3 6 8 9 3 7 4  
S p o ns or t rial I D: 
N N 9 5 3 5 -4 3 8 6   
Official title of st u d y:  
Effect of se ma gl uti de o nce -wee kl y vers us i ns uli n as part t hree 
ti mes dail y, b ot h as a d d o n t o metf or mi n a n d o pti mise d i ns uli n 
glar gi ne ( U 1 0 0) i n s u bjects wit h t y pe 2 dia betes   
A 5 2 -wee k, m ulti -ce ntre, m ulti nati o nal, o pe n -la bel, acti ve-
c o ntr olle d, t w o ar me d, parallel -gr o u p,  ra n d o mise d trial i n 
s u bjects wit h t y pe 2 dia betes 
D oc u me nt date * : 
0 8 J ul y 2 0 2 0  
  * 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 nt e nt. 

Li n k
Li n k
Li n k
Li n k
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Li n k
List of c o nte nts
Pr ot oc ol ...............................................................................................................................................
Att ac h me nt I a n d II ............................................................................................................................
L o g of Pr ot oc ols ...................................................................................................................................
A me n d me nt 1 - D E .............................................................................................................................
A me n d me nt 2 - R O .............................................................................................................................
L o g of Pr ot oc ol A me n d me nts ............................................................................................................
Me m o o n C o vi d - 1 9.............................................................................................................................
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:
Se ma gl uti de s.c.
Trial I D: N N 9 5 3 5- 4 3 8 6
Cli nical Trial Re p ort
A p pe n di x 1 6. 1. 1
1 7 J u ne 2 0 2 1
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  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
1  of 1 0 5  
 
Pr ot oc ol  
 
Pr ot oc ol titl e:  
S U S T AI N 1 1  
Effect of se ma gl uti de o n ce -w ee kl y vers us i ns uli n as part t hree ti mes dail y, b ot h as a d d o n t o 
metf or mi n a n d o pti mise d i ns uli n glar gi ne ( U 1 0 0) i n s u bjects wit h t y pe 2 dia betes 
A 5 2 -wee k, m ulti -ce ntre, m ulti nati o nal, o pe n -la bel, acti ve-c o ntr olle d, t w o ar me d, parallel -gr o u p, 
ra n d o mise d trial i n s u bjects wit h t y pe 2 dia betes 
 
  
S u bst a nce: Se ma gl uti de  
U ni vers al Tri al N u m ber: U 1 1 1 1 -1 2 0 0 -0 1 6 4  
E U dr a C T N u m ber:  2 0 1 7 -0 0 3 2 1 9 -2 0  
Tri al p h ase:  3 b  
I n t he f oll o wi n g, N o v o N or dis k A/ S a n d its affiliates will be state d as “ N o v o N or dis k”. 
T his c o nfi de ntial d oc u me nt is t he pr o pert y of N o v o N or dis k. N o u n p u blis he d i nf or mati o n c o ntai ne d herei n ma y be 
discl ose d wit h o ut pri or writte n a p pr o val fr o m N o v o N or dis k. Access t o t his d oc u me nt m ust be restricte d t o rele va nt 
parties.  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
1 of 1 0 5
C O N FI D E N TI A L
T his c o nfi de ntial d oc u me nt is t he pr o pert y of N o v o N or dis k. N o u n p u blis he d i nf or mati o n c o ntai ne d herei n ma y be 
discl ose d w it h o ut pri or writte n a p pr o val fr o m N o v o N or dis k. Access t o t his d oc u me nt m ust be restricte d t o rele va nt 
parties.

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
2  of 1 0 5  
 
Pr ot oc ol a me n d me nt s u m m ar y of c h a n ges t a ble  
 
D O C U M E N T HI S T O R Y  
D oc u me nt versi o n  
Date  
A p plica ble i n c o u ntr y(ies) a n d/ or 
site(s) 
Pr ot oc ol versi o n 3. 0  
0 8 J ul 2 0 2 0  
Ger ma n y  
Pr ot oc ol versi o n 2. 0  
0 9 Ma y 2 0 1 8  
All c o u ntries  
Ori gi nal pr ot oc ol versi o n 1. 0  
0 9 J a n 2 0 1 8  
All c o u ntries  
 
Pr ot oc ol ve rsi o n 3 ( 0 8 -J ul -2 0 2 0)  
T his a me n d me nt is c o nsi dere d t o be s u bsta ntial base d o n t he criteri a set 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 3 8. 
O ver all r ati o n ale f or pre p ari n g pr ot oc ol, versi o n 3:  
Is t o a cc o m m o date t h e re q uire me nts pr o vi de d b y t he Ger ma n h ealt h a ut h orities of i m ple me nti n g t he 
preca uti o nar y meas ures s et o ut b y N o v o N or dis k t o e ns ure s u bject safet y, trial i nte grit y, a n d t he 
safet y of N o v o N or dis k a n d site staff d uri n g t he C O VI D-1 9 p a n de mic.  
T hese meas ures will e ns ure data v ali dit y a n d re g ulat or y re q uire m e nts b y alter nati ve met h o ds f or 
c ollecti o n of data f or pri mar y e n d p oi nt, patie nt safet y b y c o n versi o n of site visit t o p h o ne c o ntact, 
e ns uri n g alter nati ve trial pr o d uct dis pe nsi n g a n d e xte n di n g visit wi n d o w o n trial s pecific safet y 
assess me nts i.e. e ye e x a mi nati o n.  
 
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  
A p pe n di x 9, C o u ntr y s pecific 
re q uire me nts 
U p date d wit h safet y meas ures a n d 
ot her i nitiati ves t o pr otect s u bjects 
fr o m i m me diate hazar d d ue t o t he 
C O VI D -1 9 P a n de mic.  
As a res p o nse t o t he C O VI D -1 9 
pa n de mic, S p o ns or has pr o vi de d t he 
i n v ol ve d Ger ma n sites wit h a set of 
g ui deli nes i n or der t o s u p p ort t he sites 
i n ha n dli n g patie nt safet y a n d trial 
i nte grit y d uri n g t he pa n de mic. T he 
g ui deli nes are t o assist t he site i n 
ma na g i n g trial s u p plies t o patie nts a n d 
c ollecti o n of e n d p oi nt relate d data. 
T he miti gati n g acti o ns s h o ul d o nl y be 
use d d uri n g t he pa n de mic a n d if 
n or mal trial pr oce d ures ca n n ot be 
f oll o we d d ue t o e pi de mi ol o gic al 
restricti o ns.  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
2 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
3  of 1 0 5  
 
Ta ble of C o nte nts    
 
P a ge  
P r ot oc ol a me n d me nt s u m m ar y of c h a n ges t a ble  ........................................................................................... 2  
T a ble of C o nte nts .............................................................................................................................................. 3  
1  
S y n o psis  ...................................................................................................................................................... 6  
2  
Fl o wc h art  ................................................................................................................................................. 1 0  
3  
I ntr o d ucti o n ............................................................................................................................................. 1 6  
3. 1  
Trial rati o nale  ............................................................................................................................... 1 6  
3. 2  
Bac k gr o u n d  .................................................................................................................................. 1 6  
3. 3  
Be nefit -ris k assess me nt ................................................................................................................ 1 7  
3. 3. 1  
Ris ks relate d t o se ma gl uti de  ...................................................................................... 1 7  
3. 3. 2  
Ris ks relate d t o i ns uli n  ............................................................................................... 2 0  
3. 3. 3  
Be nefits  ...................................................................................................................... 2 1  
4  
O bjecti ves a n d e n d p oi nts ........................................................................................................................ 2 2  
4. 1  
Pri mar y o bj ecti ve  ......................................................................................................................... 2 2  
4. 2  
Sec o n dar y o bj ecti ves  ................................................................................................................... 2 2  
4. 3  
Esti ma n d  ...................................................................................................................................... 2 2  
4. 4  
E n d p oi nts  ..................................................................................................................................... 2 2  
4. 4. 1  
Pri mar y e n d p oi nt  ........................................................................................................ 2 2  
4. 4. 2  
Sec o n dar y e n d p oi nts  .................................................................................................. 2 3  
4. 4. 2. 1  
C o nfir mat or y sec o n dar y e n d p oi nts  ..................................................... 2 3  
4. 4. 2. 2  
S u p p orti ve sec o n dar y e n d p oi nts  .......................................................... 2 3  
4. 4. 2. 3  
E x pl orat or y e n d p oi nts  ......................................................................... 2 4  
5  
Tri al desi g n  .............................................................................................................................................. 2 6  
5. 1  
O verall desi g n  .............................................................................................................................. 2 6  
5. 2  
S u bj ect a n d trial c o m pleti o n  ........................................................................................................ 2 7  
5. 3  
E n d of trial defi niti o n  ................................................................................................................... 2 7  
5. 4  
Scie ntific rati o nale f or trial desi g n  ............................................................................................... 2 7  
5. 5  
J ustificati o n f or d ose .................................................................................................................... 2 8  
6  
Tri a l p o p ul ati o n ....................................................................................................................................... 2 9  
6. 1  
I ncl usi o n criteria .......................................................................................................................... 2 9  
6. 2  
E xcl usi o n criteria  ......................................................................................................................... 2 9  
6. 3  
Lifest yle restricti o ns  .................................................................................................................... 3 0  
6. 4  
R u n -i n e xcl usi o n criteria .............................................................................................................. 3 0  
6. 5  
Ra n d o misati o n criteria  ................................................................................................................. 3 1  
6. 6  
Sc ree n fail ures .............................................................................................................................. 3 1  
6. 7  
R u n -i n fail ures ............................................................................................................................. 3 2  
7  
Tre at me nts  ............................................................................................................................................... 3 3  
7. 1  
Treat me nts a d mi nistere d  .............................................................................................................. 3 3  
7. 1. 1  
I n vesti gati o nal me dici nal pr o d ucts ............................................................................ 3 3  
7. 1. 2  
N o n -i n vesti gati o nal me dici nal pr o d ucts .................................................................... 3 3  
7. 1. 3  
A u xiliar y s u p plies  ...................................................................................................... 3 4  
7. 2  
D ose m o dificati o n  ........................................................................................................................ 3 4  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
3 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
4  of 1 0 5  
 
7. 3  
Met h o d of treat me nt assi g n me nt  .................................................................................................. 3 4  
7. 4  
Bli n di n g  ....................................................................................................................................... 3 4  
7. 5  
Pre parati o n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y  ............................................................................. 3 5  
7. 6  
Treat me nt c o m plia nce  .................................................................................................................. 3 6  
7. 7  
C o nc o mita nt me dicati o n  .............................................................................................................. 3 6  
7. 8  
Resc ue me dicati o n  ....................................................................................................................... 3 6  
7. 9  
Treat me nt after t he e n d of t he trial  .............................................................................................. 3 7  
8  
Disc o nti n u ati o n/ Wit h dr a w al criteri a  .................................................................................................... 3 8  
8. 1  
Disc o nti n uati o n of trial treat me nt  ................................................................................................ 3 8  
8. 1. 1  
Treat me nt disc o nti n uati o n i n case of ra n d o misati o n i n vi olati o n of t he 
eli gi bilit y criteria ........................................................................................................ 3 9  
8. 1. 2  
T e m p orar y disc o nti n uati o n of trial treat me nt  ............................................................ 3 9  
8. 2  
Resc ue criteria  .............................................................................................................................. 3 9  
8. 3  
Wit h dra wal fr o m t he trial ............................................................................................................. 4 0  
8. 3. 1  
Re place me nt of s u bjects  ............................................................................................ 4 0  
8. 4  
L ost t o f oll o w -u p  ......................................................................................................................... 4 0  
9  
Tri al assess me nts a n d pr oce d ures  ......................................................................................................... 4 2  
9. 1  
Efficac y assess me nts  .................................................................................................................... 4 2  
9. 1. 1  
Self -meas ure d plas ma gl uc ose  ................................................................................... 4 3  
9. 1. 2  
Cli nical efficac y la b orat or y assess me nts  ................................................................... 4 4  
9. 1. 3  
Patie nt re p orte d o utc o mes  .......................................................................................... 4 4  
9. 1. 4  
B o d y meas ure me nts  ................................................................................................... 4 5  
9. 2  
A d verse e ve nts  ............................................................................................................................. 4 5  
9. 2. 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  
9. 2. 1. 1  
E ve nts f or a dj u dicati o n  ........................................................................ 4 8  
9. 2. 2  
Met h o d of detecti n g A Es a n d S A Es  .......................................................................... 4 9  
9. 2. 3  
F oll o w -u p o n A Es a n d S A Es  ..................................................................................... 4 9  
9. 2. 4  
Re g ulat or y re p orti n g re q uire me nts f or S A Es ............................................................. 4 9  
9. 2. 5  
Car di o vasc ular a n d deat h e ve nts  ................................................................................ 5 0  
9. 2. 6  
Disease -relate d e ve nts a n 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 ........................................................................................................................ 5 0  
9. 2. 7  
Pre g na ncies a n d ass ociate d a d verse e ve nts  ................................................................ 5 0  
9. 2. 8  
Me dical de vice i nci de nts (i ncl u di n g malf u ncti o ns)  ................................................... 5 1  
9. 2. 9  
T ec h nical c o m plai nts  ................................................................................................. 5 1  
9. 3  
Treat me nt of o ver d ose  ................................................................................................................. 5 1  
9. 4  
Safet y assess me nts  ....................................................................................................................... 5 2  
9. 4. 1  
P h ys ical e xa mi nati o ns ................................................................................................ 5 2  
9. 4. 2  
Vital si g ns  .................................................................................................................. 5 2  
9. 4. 3  
Cli nical safet y la b orat or y assess me nts  ....................................................................... 5 3  
9. 4. 4  
E ye e xa mi nati o n  ........................................................................................................ 5 3  
9. 5  
P har mac o ki netics  ......................................................................................................................... 5 4  
9. 6  
P har mac o d y na mics  ...................................................................................................................... 5 4  
9. 7  
Ge netics  ....................................................................................................................................... 5 4  
9. 8  
Bi o mar kers  ................................................................................................................................... 5 4  
1 0  St atistic al c o nsi der ati o ns  ........................................................................................................................ 5 5  
1 0. 1  
Sa m ple size deter mi nati o n  ........................................................................................................... 5 5  
1 0. 2  
Defi niti o n of a nal ysis sets  ............................................................................................................ 5 9  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
4 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
5  of 1 0 5  
 
1 0. 3  
Statistical a nal yses  ....................................................................................................................... 6 1  
1 0. 3. 1  
Pri mar y e n d p oi nt  ........................................................................................................ 6 2  
1 0. 3. 2  
Sec o n dar y e n d p oi nts  .................................................................................................. 6 4  
1 0. 3. 2. 1  
C o nfir mat or y sec o n dar y e n d p oi nts  ..................................................... 6 4  
1 0. 3. 2. 2  
S u p p orti ve sec o n dar y e n d p oi nts  .......................................................... 6 5  
1 0. 3. 3  
E x pl orat or y e n d p oi nts  ................................................................................................ 6 7  
1 0. 3. 4  
Ot her a nal yses  ............................................................................................................ 6 8  
1 0. 4  
P har mac o ki netic a n d/ or p har mac o d y na mic m o delli n g  ................................................................ 6 9  
1 1  Ref ere nces  ................................................................................................................................................ 7 0  
1 2  A p pe n dices  ............................................................................................................................................... 7 3  
 
A b bre vi ati o ns a n d Tr a de m ar ks  .......................................................................................... 7 3  
 
Cli nic al l a b or at or y tests  ....................................................................................................... 7 6  
 
Tri al g o ver n a nce c o nsi der ati o ns  ......................................................................................... 7 7  
 
A d verse e ve nts: defi niti o ns a n d pr oce d ures f or rec or di n g, e v al u ati o n, f oll o w -u p, 
a n d re p orti n g  ........................................................................................................................................... 8 6  
 
C o ntr ace pti ve g ui d a nce a n d c oll ecti o n of pre g n a nc y i nf or m ati o n  ................................... 9 0  
 
Tec h nic al c o m pl ai nts: Defi niti o n a n d pr oce d ures f or rec or di n g, e v al u ati o n, f oll o w -
u p a n d re p orti n g  ...................................................................................................................................... 9 3  
 
H y p o gl yc ae mic e pis o des  ....................................................................................................... 9 4  
 
Titr ati o n g ui deli ne  ................................................................................................................ 9 9  
 
C o u ntr y -s pecific re q uire me nts .......................................................................................... 1 0 4  
Attac h me nt I Gl o bal list of ke y staff a n d rel e va nt de part me nts a n d s u p pliers  
Attac h me nt II C o u ntr y list of ke y st aff a n d rele va nt de part me nts  
 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
5 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
6  of 1 0 5  
 
1  
S y n o psis  
R ati o n ale:  
Se ma gl uti de ma y pr o vi d e a n efficaci o us, safe a n d si m ple alter nati ve t o b ol us i ns uli n f or a d va nci n g 
basal i ns uli n re gi me n i n patie nts wit h late sta ge t y pe 2 dia betes, wit h l o wer ris k of h y p o gl ycae mia 
a n d wei g ht  gai n. T he p ur p ose of t he c urre nt trial is t o c o m pare t he effect o n gl ycae mic c o ntr ol, 
b o d y w ei g ht, s afet y ( h y p o gl ycae mia) a n d healt h -relate d q ualit y of life of se ma gl uti de vers us i ns uli n 
as part, b ot h as a d d -o n t o metf or mi n a n d o pti mise d i ns uli n glar gi ne ( U 1 0 0) treat me nt i n s u bjects 
wit h i na de q uatel y c o ntr olle d t y pe 2 di a betes.  
O bjecti ves a n d e n d p oi nts  
Pri m ar y o bjecti ve  
T o c o m pare t h e effect of se ma gl uti de o nce -wee kl y o n gl ycae mic c o ntr ol v ers us i ns uli n as part t hree 
ti mes dail y, b ot h as a d d o n t o metf or mi n a n d o pti mise d i ns uli n glar gi ne ( U 1 0 0) i n s u bjects wit h 
t y pe 2 dia b etes. 
Sec o n d ar y o bjecti ves  
T o de m o nstrate t hat se m a gl uti de o n ce -wee kl y l o wers t he ris k of s e vere h y p o gl ycae mic e pis o des 
c o m pare d t o i ns uli n as part t hree ti mes dail y, b ot h as a d d o n t o metf or mi n a n d o pti mise d i ns uli n 
glar gi n e ( U 1 0 0) i n s u bjects wit h t y pe 2 dia betes.  
T o c o m pare t h e effect of se ma gl uti de o nce -wee kl y vers us i ns uli n as part t hree ti mes dail y, b ot h as 
a d d o n t o metf or mi n a n d o pti mise d i ns uli n glar gi n e ( U 1 0 0) i n s u bjects wit h t y pe 2 dia betes wit h 
re gar ds t o: 
•  b o d y w ei g ht  
•  li pi ds 
•  bl o o d press ure  
•  healt h -rel ate d q ualit y of life 
•  safet y 
 
Pri m ar y e n d p oi nt  
C ha n ge fr o m bas eli ne t o wee k 5 2 i n H b A 1c ( %-p oi nt)  
Ke y sec o n d ar y e n d p oi nts  
C o nfir mat or y s ec o n dar y e n d p oi nts  
•  Ti me t o first e ve nt a dj u dicati o n  c o m mittee c o nfir me d se vere h y p o gl ycae mic e pis o de 
( A meric a n Dia bet es Ass ociati o n) fr o m ra n d o misati o n u p t o wee k 5 2 ( da ys) 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
6 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
7  of 1 0 5  
 
•  Ti me t o first e ve nt a dj u dicati o n c o m mittee  c o nfir me d se vere h y p o gl ycae mic e pis o de 
( A meric a n Dia bet es Ass ociati o n) re q uiri n g h os pit alisati o n, d oc u me nte d me dical hel p, or 
is life t hreate ni n g fr o m ra n d o misati o n u p t o wee k 5 2 ( da ys) 
•  C ha n ge fr o m bas eli ne t o wee k 5 2 i n b o d y wei g ht ( k g)  
 
Esti m a n d  
T he pri mar y esti ma n d is t he treat me nt differe n ce bet wee n se m a gl uti de a n d i ns uli n as part at wee k 5 2  
f or all ra n d o mise d s u bjects if all s u bjects re mai ne d o n ra n d o mise d treat me nt t hr o u g h o ut t he trial 
O verall desi g n:  
T his is a 5 2 -wee k, m ulti -ce ntre, m ulti nati o nal, o pe n -la bel, acti ve c o ntr olle d, t w o ar me d, parallel, 
ra n d o mise d trial wit h a 1 2-wee k r u n -i n peri o d i n s u bjects wit h t y pe 2 dia betes t o sec ure a direct 
c o m paris o n bet wee n se m a gl uti de o n ce -wee kl y a n d i ns uli n as part t hree ti mes dail y.  
At r u n -i n, eli gi ble s u bjects will disc o nti n ue pre-trial basal i ns uli n a n d t he a d diti o nal oral 
a nti dia betic dr u g (if a p plica ble, i ncl u di n g c o n v ersi o n fr o m fi x e d dr u g c o m bi nati o n me dicati o ns wit h 
metf or mi n t o metf or mi n o nl y) a n d start treat me nt wit h i ns uli n glar gi ne U 1 0 0.  
S u bjects treate d wit h metf or mi n a n d i ns uli n glar gi ne U 1 0 0, w h o are n ot i n gl ycae mic c o ntr ol 
( defi ne d as H b A1c of > 7. 5 % t o ≤ 1 0 % [ > 5 8 m m ol/ m ol t o ≤ 8 6 m m ol/ m ol]) after r u n -i n, will be 
ra n d o mise d i n a 1: 1 ma n ner t o recei ve a d d-o n treat me nt wit h f oll o wi n g treat me nts:  
•  se ma gl uti de o n ce-wee kl y  
•  i ns uli n as part t hree ti mes dail y   
 
Ke y i ncl usi o n criteri a  
•  Male or  fe m ale, a ge ≥ 1 8 years at t he ti me of si g ni n g i nf or m e d c o nse nt. 
•  Dia g n os e d wit h t y p e 2 dia betes ≥ 1 8 0 da ys pri or t o t he da y of scree ni n g.  
•  Treate d wit h basal i ns uli n o nce dail y or t wice dail y  f or ≥ 9 0 da ys pri or t o t he da y of 
scree ni n g. 
•  Sta ble dail y d ose f or 9 0 da ys pri or t o t he da y of scree ni n g of t he f oll o wi n g a nti-dia betic 
dr u gs or c o m bi nati o n re gi me ns: A n y metf or mi n f or m ulati o ns ( ≥ 1 5 0 0 m g t o ≤ 3 0 0 0 m g 
or ma xi m u m t olerate d or effecti ve d ose d oc u m e nte d i n s u bject's me dical rec or d), al o ne 
or i n c o m bi nati o n (i ncl u di n g fi x e d -d ose dr u g c o m bi nati o n) wit h u p t o o ne a d diti o nal of 
t he f oll o wi n g oral a nti dia betic dr u gs: s ulf o n yl ur eas, me gliti ni des, di pe pti d yl pe pti dase-
4i n hi bit ors or al p ha -gl uc osi dase i n hi bit ors.  
•  H b A 1c of > 7. 5 % t o ≤ 1 0. 0 % ( > 5 8 m m ol/ m ol t o ≤ 8 6 m m ol/ m ol).  
Ke y e xcl usi o n criteri a  
•  Hist or y or prese n ce of pa ncreatitis (ac ute or c hr o nic).  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
7 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
8  of 1 0 5  
 
•  A n y of t he f oll o wi n g: m y ocar dial i nfarcti o n, str o ke, h os pitalizati o n f or u nsta ble a n gi na 
or tra nsie nt isc hae mic attac k wit hi n t he past 1 8 0 d a ys pri or t o t he da y of scr ee ni n g.  
•  S u bjects prese ntl y classifie d as bei n g i n Ne w Y or k Heart Ass o ciati o n Class I V.  
•  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 k n o w n o n t he da y of 
scree ni n g. 
•  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 o t h er t ha n state d 
i n t he i ncl usi o n criteria wit hi n t he past 9 0 da ys pri or t o t he da y of scree ni n g. H o we ver, 
s h ort ter m b ol us i ns uli n treat me nt f or a ma xi m u m of 1 4 da ys pri or t o t he da y of 
scree ni n g is all o we d. 
•  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 p har mac ol o gi call y p u pil -dilate d f u n d us 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 e q uall y q ualifi e d healt h care pr o vi der (e. g. o pt o metrist) wit hi n t he past 9 0 da ys 
pri or t o r u n -i n. 
R a n d o mis ati o n criteri a  
T o be ra n d o mise d, all ra n d o misati o n criteria m ust be a ns were d " yes".  
•  H b A 1c of > 7. 5 % t o ≤1 0. 0 % ( > 5 8 m m ol/ m ol t o ≤8 6 m m ol/ m ol) meas ure d at V 7.  
•  Treate d wit h i ns uli n glar gi ne U 1 0 0 a n d metf or mi n ( ≥ 1 5 0 0 m g t o ≤ 3 0 0 0 m g or 
ma xi m u m t olerate d d ose d oc u me nte d i n s u bje ct's me dical rec or d) at ra n d o misati o n 
( V 8). 
•  T he nee d a n d willi n g ness t o u n der g o treat me nt i nt e nsificati o n wit h t he treat me nts 
i n vesti gate d i n t his trial wit h t he ai m t o reac h a n H b A1c of 6. 5 % t o 7. 5 % ( 4 8 m m ol/ m ol 
t o 5 8 m m ol/ m ol) ( b ot h i ncl usi ve), as ass esse d b y t he i n vesti gat or at ra n d o misati o n ( V 8).  
•  A bse nce of u nc o ntr olle d a n d p ote ntiall y u nsta ble dia betic reti n o pat h y or m ac ul o pat h y. 
Verifie d b y a p har mac ol o gicall y p u pil -dilate d f u n d us 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 e q uall y q ualifie d h ea lt h care pr o vi der (e. g. o pt o metrist) wit hi n 3 0 
da ys pri or t o ra n d o misati o n.  
 
N u m ber of s u bjects:  
•  N u m ber of s u bjects pla n ne d t o be scree ne d: 3 1 4 4  
•  N u m ber of s u bjects pla n ne d t o e nter -r u n-i n peri o d: 2 0 4 3 
•  N u m ber of s u bjects pla n ne d t o be ra n d o mise d: 1 7 3 6  
 
Tre a t me nt gr o u p a n d d ur ati o n: 
T he t otal d urati o n of t he trial will be a p pr o xi matel y 7 1 wee ks: 2 wee ks f or scree ni n g, a 1 2 -w ee k 
r u n-i n peri o d, a 5 2-wee k treat me nt peri o d a n d a f oll o w -u p peri o d of 5 wee ks.   
 
 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
8 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
9  of 1 0 5  
 
Tri al pr o d ucts:  
I n v esti gati o nal me dici nal pr o d ucts: 
•  I ns uli n glar gi ne ( La nt us ®) 1 0 0 U/ m L, 3 m L pre-fille d pe n-i nject or ( S ol o Star ®). 
•  Test pr o d uct:  
o  Se ma gl uti de 1. 3 4 m g/ ml, 1. 5 m L P D S 2 9 0 pre -fille d pe n-i nject or f or s.c. 
i njecti o n. 
•  Refere n ce t hera p y:  
o  I ns uli n as p art ( N o v o Ra pi d ®/ N o v o L o g ®) 1 0 0 U/ m L, 3 ml pre-fille d pe n – i nject or 
( Fle x Pe n ®). 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
9 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
Date:  
0 8 J ul y 2 0 2 0  
Stat us:  
Fi n al  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
P a ge:  
1 0  of 1 0 5  
2  
Fl o w c h art 
Scree ni n g  
R u n -i n 
R a n d o mis ati o n  
Tre at me nt  
E n d of tre at me nt  
Tre at me nt 
disc o nti n u ati o n  
F oll o w -u p  
Tre at me nt 
disc o nti n u ati o n 
F oll o w -u p 
Visit ( V)/ p h o ne c o ntact ( P)  
V 1  
V 2  P 3  V 4  P 5  
P 6  V 7  
V 8  
P 9  
P 1 0  
P 1 1  
V 1 2  P 1 3  V 1 4  P 1 5  
V 1 6  
P 1 7  V 1 8  P 1 9  
P 2 0  V 2 1  P 2 2 
P 2 3  V 2 4  P 2 5  
P 2 6  V 2 7  P 2 8  
P 2 9  V 3 0  P 3 1  
P 3 2  V 3 3  P 3 4  
P 3 5  
V 3 6  
V 3 6 A  
P 3 7  
P 3 7 A  
Ti mi n g of Visit ( wee ks)  
-1 4  
-1 2  
-
1 0  
-8
-6
-4
-2
0  
1  
2  
3  
4  
6  
8  
1 0  
1 2  
1 4  1 6  1 8  
2 0  2 2  2 4  
2 6  2 8  3 0  
3 2  3 4  3 6  
3 8  4 0  4 2  
4 4  4 6  
4 8  
5 0  
5 2  
5 7  
Visit Wi n d o w ( da ys)  
± 7  
± 3  ± 3  ± 3  ± 3  
± 3  
0  
± 3  
± 7  
± 3  
± 7  ± 3  
± 7  
± 3  ± 7  ± 3  ± 7  ± 3  ± 7  ± 3  ± 7  ± 3  ± 7  ± 3  ± 7  ± 3  
± 7  
+ 7  
S U BJ E C T R E L A T E D 
I N F O R M A TI O N A N D 
A S S E S S M E N T S  
I nf or m e d c o nse nt 
X  
I n/e xcl usi o n criteria 
X  
X  
R u n -i n e xcl usi o n criteria 
X  
X  
X  
X  
X  
Ra n d o misati o n  criteria 
X  
Ra n d o misati o n  
X  
Disc o nti n uati o n Criteria  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  X  X  X  X  
X  X  X  
X  
X  
Resc u e criteria  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  X  X  X  X  
X  X  X  
X  
X  
C o nc o mita nt ill ness  
X  
Me dical hist or y  
X  
Dia g n osis of dia betes  
X  
Dia betes hist or y a n d c o m plicati o ns  
X  
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 5 - 4 3 8 6
1 0 of 1 0 5

Pr ot o c ol  
Date:  
0 8 J ul y 2 0 2 0  
Stat us:  
Fi n al  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
P a ge:  
1 1  of 1 0 5  
Scree ni n g  
R u n -i n 
R a n d o mis ati o n  
Tre at me nt  
E n d of tre at me nt  
Tre at me nt 
disc o nti n u ati o n  
F oll o w -u p  
Tre at me nt 
disc o nti n u ati o n 
F oll o w -u p 
Visit ( V)/ p h o ne c o ntact ( P)  
V 1  
V 2  P 3  V 4  P 5  
P 6  V 7  
V 8  
P 9  
P 1 0  
P 1 1  
V 1 2  P 1 3  V 1 4  P 1 5  
V 1 6  
P 1 7  V 1 8  P 1 9  
P 2 0  V 2 1  P 2 2 
P 2 3  V 2 4  P 2 5  
P 2 6  V 2 7  P 2 8  
P 2 9  V 3 0  P 3 1  
P 3 2  V 3 3  P 3 4  
P 3 5  
V 3 6  
V 3 6 A  
P 3 7  
P 3 7 A  
Ti mi n g of Visit ( wee ks)  
-1 4  
-1 2  
-
1 0  
-8
-6
-4
-2
0  
1  
2  
3  
4  
6  
8  
1 0  
1 2  
1 4  1 6  1 8  
2 0  2 2  2 4  
2 6  2 8  3 0  
3 2  3 4  3 6  
3 8  4 0  4 2  
4 4  4 6  
4 8  
5 0  
5 2  
5 7  
Visit Wi n d o w ( da ys)  
± 7  
± 3  ± 3  ± 3  ± 3  
± 3  
0  
± 3  
± 7  
± 3  
± 7  ± 3  
± 7  
± 3  ± 7  ± 3  ± 7  ± 3  ± 7  ± 3  ± 7  ± 3  ± 7  ± 3  ± 7  ± 3  
± 7  
+ 7  
H y p o gl ycae mia u na ware ness a 
X  
X  
X  
C o nc o mita nt me dicati o n  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  X  X  X  X  
X  X  X  
X  
X  
X  
X  
X  
X  
T o bacc o use b 
X  
De m o gra p h y c 
X  
C hil d beari n g p ote ntial  
X  
E F FI C A C Y  
Se lf-meas ure d plas ma gl uc ose d 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  X  X  X  X  
X  X  X  
X  
X  
X  
X  
Gl uc ose meta b olis m  
H b A 1c 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Fasti n g plas ma gl uc ose  
X  
X  
X  
X  
X  
X  
X  
X  
X  
a I nf or mati o n o n h y p o gl ycae mia u na ware ness will be rec or de d at scree ni n g acc or di n g t o Clar ke’s q uesti o n naire, q uesti o n 8. 1.  
Clar ke W L, C o x DJ, G o n der -Fr e deric k L A, J ulia n D, Sc hl u n dt D, P ol o ns k y W. Re d uce d a war e n ess of h y p o gl yce mia i n a d ults wit h 
I D D M. A pr os pecti ve st u d y of h y p o gl yce mic fr e q ue n c y a n d ass ociate d s y m pt o ms. Dia betes Car e. 1 9 9 5; 1 8( 4): 5 1 7 -2 2. 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: “ Ha ve y o u e ver e x perie nce d a l o w bl o o d gl uc ose?” If a ns wer is “ Ye s” t he n f oll o wi n g 
q uesti o n s h o ul d be as ke d: “ T o w hat e xte nt ca n y o u tell b y y o ur s y m pt o m s t hat y o ur bl o o d gl uc ose is l o w?” S u bjects a ns weri n g ‘ ne ver, rarel y or s o meti mes’ are c o nsi dere d as ha vi n g i m paire d a ware nes s of h y p o gl ycae mia. 
b S m o ki n g 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  
c De m o gra p h y: date of birt h or year of birt h, se x, et h nicit y a n d race (acc or di n g t o l ocal re g ulati o n)
d Pre -brea kfast S M P G fr o m V 2 t o V 3 6/ V 3 6 A: All s u bjects.   Pre -l u nc h, pre-di n ner a n d pre -be dti me S M P G fr o m V 8 t o V 3 6/ V 3 6 A: 4 p oi nt S M P G pr ofile f or s u bjects ra n d o mise d t o I As p o nl y.  
-7 p oi nt S M P G pr ofile at V 8, V 2 4, V 3 6/ V 3 6 A: All s u bjects
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 5 - 4 3 8 6
1 1 of 1 0 5

Pr ot o c ol  
Date:  
0 8 J ul y 2 0 2 0  
Stat us:  
Fi n al  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
P a ge:  
1 2  of 1 0 5  
Scree ni n g  
R u n -i n 
R a n d o mis ati o n  
Tre at me nt  
E n d of tre at me nt  
Tre at me nt 
disc o nti n u ati o n  
F oll o w -u p  
Tre at me nt 
disc o nti n u ati o n 
F oll o w -u p 
Visit ( V)/ p h o ne c o ntact ( P)  
V 1  
V 2  P 3  V 4  P 5  
P 6  V 7  
V 8  
P 9  
P 1 0  
P 1 1  
V 1 2  P 1 3  V 1 4  P 1 5  
V 1 6  
P 1 7  V 1 8  P 1 9  
P 2 0  V 2 1  P 2 2 
P 2 3  V 2 4  P 2 5  
P 2 6  V 2 7  P 2 8  
P 2 9  V 3 0  P 3 1  
P 3 2  V 3 3  P 3 4  
P 3 5  
V 3 6  
V 3 6 A  
P 3 7  
P 3 7 A  
Ti mi n g of Visit ( wee ks)  
-1 4  
-1 2  
-
1 0  
-8
-6
-4
-2
0  
1  
2  
3  
4  
6  
8  
1 0  
1 2  
1 4  1 6  1 8  
2 0  2 2  2 4  
2 6  2 8  3 0  
3 2  3 4  3 6  
3 8  4 0  4 2  
4 4  4 6  
4 8  
5 0  
5 2  
5 7  
Visit Wi n d o w ( da ys)  
± 7  
± 3  ± 3  ± 3  ± 3  
± 3  
0  
± 3  
± 7  
± 3  
± 7  ± 3  
± 7  
± 3  ± 7  ± 3  ± 7  ± 3  ± 7  ± 3  ± 7  ± 3  ± 7  ± 3  ± 7  ± 3  
± 7  
+ 7  
Li pi ds  
X  
X  
X  
X  
Patie nt re p orte d o utc o mes  
S F -3 6 v 2 ™ 
X  
X  
X  
X  
D Q L C T Q -R  
X  
X  
X  
X  
T RI M -D  
X  
X  
X  
X  
B o d y meas ure me nts  
Hei g ht  
X  
B o d y  wei g ht  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Waist  Circ u mfere nce  
X  
X  
X  
X  
S A F E T Y  
A d verse e ve nts  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  X  X  X  X  
X  X  X  
X  
X  
X  
X  
X  
X  
H y p o gl ycae mic  e pis o des 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  X  X  X  X  
X  X  X  
X  
X  
X  
X  
X  
X  
Tec h nical C o m plai nts  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  X  X  X  X  
X  X  X  
X  
X  
X  
X  
P h ysical e xa mi nati o n  
X  
X  
X  
Vital si g ns  
X  
X  
X  
X  
X  
X  
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 5 - 4 3 8 6
1 2 of 1 0 5

Pr ot o c ol  
Date:  
0 8 J ul y 2 0 2 0  
Stat us:  
Fi n al  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
P a ge:  
1 3  of 1 0 5  
Scree ni n g  
R u n -i n 
R a n d o mis ati o n  
Tre at me nt  
E n d of tre at me nt  
Tre at me nt 
disc o nti n u ati o n  
F oll o w -u p  
Tre at me nt 
disc o nti n u ati o n 
F oll o w -u p 
Visit ( V)/ p h o ne c o ntact ( P)  
V 1  
V 2  P 3  V 4  P 5  
P 6  V 7  
V 8  
P 9  
P 1 0  
P 1 1  
V 1 2  P 1 3  V 1 4  P 1 5  
V 1 6  
P 1 7  V 1 8  P 1 9  
P 2 0  V 2 1  P 2 2 
P 2 3  V 2 4  P 2 5  
P 2 6  V 2 7  P 2 8  
P 2 9  V 3 0  P 3 1  
P 3 2  V 3 3  P 3 4  
P 3 5  
V 3 6  
V 3 6 A  
P 3 7  
P 3 7 A  
Ti mi n g of Visit ( wee ks)  
-1 4  
-1 2  
-
1 0  
-8
-6
-4
-2
0  
1  
2  
3  
4  
6  
8  
1 0  
1 2  
1 4  1 6  1 8  
2 0  2 2  2 4  
2 6  2 8  3 0  
3 2  3 4  3 6  
3 8  4 0  4 2  
4 4  4 6  
4 8  
5 0  
5 2  
5 7  
Visit Wi n d o w ( da ys)  
± 7  
± 3  ± 3  ± 3  ± 3  
± 3  
0  
± 3  
± 7  
± 3  
± 7  ± 3  
± 7  
± 3  ± 7  ± 3  ± 7  ± 3  ± 7  ± 3  ± 7  ± 3  ± 7  ± 3  ± 7  ± 3  
± 7  
+ 7  
Bi oc he mistr y  
X  
X  
X  
X  
X  
X  
Uri nal ysis e e 
X  
X  
X  
X  
X  
Calcit o ni n  
X  
Pre g na nc y test ff 
X  
X  
X  
X  
E ye e xa mi nati o n g g 
X  
X  
X  
X  
 T RI A L M A T E RI A L  
Dis pe nsi n g of trial pr o d uct  
I ns uli n as part 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
I ns uli n glar gi ne 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
ee Uri ne al b u mi n t o creati ni ne rati o  
ff O nl y a p plica ble f or w o me n of c hil d beari n g p ote ntial. At V 1, ser u m pre g na nc y test will be ta ke n. At V 8 a n d P 3 7/ P 3 7 A a n d i n cas e of a misse d peri o d, a uri ne pre g na nc y test  will be ta ke n.
g g
A n e ye e xa mi nati o n perf or me d wit hi n 9 0 da ys pri or t o r u n -i n is acce pta ble if a vaila ble at Visit 2. 
T he e ye e xa mi nati o n m ust be re peate d wit hi n 3 0 da ys pri or t o ra n d o misati o n a n d res ults m ust be a vaila ble f or e val uati o n at Vi sit 8. 
Res ults m ust be a vaila ble at V 3 6. A n e ye e xa mi nati o n perf or me d wit hi n 5 wee ks pri or t o Visit 3 6 is acce pta ble.
F or Visit 3 6 A t he assess me nts ca n be perf or m e d i n t he peri o d bet wee n Visit 3 6 A a n d P 3 7 A, if a vaila ble a n d re vie we d n o later t ha n at P 3 7 A  
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 5 - 4 3 8 6
1 3 of 1 0 5

Pr ot o c ol  
  
Date:  
0 8 J ul y 2 0 2 0  
Stat us:  
Fi n al  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
  
V ersi o n:  
3. 0  
P a ge:  
1 4  of 1 0 5  
 
 
Scree ni n g  
R u n -i n 
R a n d o mis ati o n  
 
 
Tre at me nt  
E n d of tre at me nt  
Tre at me nt 
disc o nti n u ati o n  
F oll o w -u p  
Tre at me nt 
disc o nti n u ati o n 
F oll o w -u p  
Visit ( V)/ p h o ne c o ntact ( P)  
V 1  
V 2  P 3  V 4  P 5  
P 6  V 7  
V 8  
P 9  
P 1 0  
P 1 1  
V 1 2  P 1 3  V 1 4  P 1 5  
V 1 6  
P 1 7  V 1 8  P 1 9  
P 2 0  V 2 1  P 2 2 
P 2 3  V 2 4  P 2 5  
P 2 6  V 2 7  P 2 8  
P 2 9  V 3 0  P 3 1  
P 3 2  V 3 3  P 3 4  
P 3 5  
V 3 6  
V 3 6 A  
P 3 7  
P 3 7 A  
Ti mi n g of Visit ( wee ks)  
-1 4  
-1 2  
-
1 0  
-8  
-6  
-4  
-2  
0  
1  
2  
3  
4  
6  
8  
1 0  
1 2  
1 4  1 6  
 
1 8  
2 0  
 
2 2  2 4  
2 6  2 8  
 
3 0  
3 2  
 
3 4  3 6  
3 8  4 0  
 
4 2  
4 4  
 
4 6  
4 8  
5 0  
5 2  
 
5 7  
 
Visit Wi n d o w ( da ys)  
± 7  
± 3  ± 3  ± 3  ± 3  
± 3  
0  
± 3  
± 7  
± 3  
± 7  ± 3  
± 7  
± 3  ± 7  ± 3  ± 7  ± 3  ± 7  ± 3  ± 7  ± 3  ± 7  ± 3  ± 7  ± 3  
± 7  
 
+ 7  
 
Se ma gl uti de  
 
 
 
 
 
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
 
 
 
 
Dr u g acc o u nta bilit y  
 
X   
 
X  
 
X  
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
X  
 
 
I WR S sessi o n  
X  
X  
 
X  
 
X  
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
X  
 
 
 R E MI N D E R S  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ha n d o ut I D car d  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ha n d o ut directi o ns f or use  
 
X  
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Trai ni n g i n pe n differe ntiati o n  
 
 
 
 
 
 
X  
 
X  
 
 
 
X  
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
Trai ni n g i n trial pr o d uct, pe n -ha n dli n g  
 
X  
 
X  
 
 
X  
 
X  
 
 
 
X  
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
Ha n d o ut a n d i nstr uct i n diar y  
 
X  
 
X  
 
X  
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
 
 
 
 
C ollect diar y  
 
 
 
X  
 
X  
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
X  
 
 
Ha n d o ut a n d i nstr uct i n B G -meter  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Atte n d visit fasti n g h 
 
 
 
 
 
 
X  
 
X  
 
X  
 
X  
 
X  
 
 
 
X  
 
 
 
X  
 
 
 
X  
X  
 
 
                                                 
h h Fasti n g is defi ne d as at least 8 h o urs pri or t o t he visit, wit h o ut f o o d or li q ui ds, e xce pt f or water. Trial pr o d uct a n d a n y m e dicati o n w hic h s h o ul d be ta ke n wit h or after a meal s h o ul d be wit h hel d o n t he da y of t he visit u ntil 
bl o o d sa m ples h a ve bee n o bta i ne d. If t he s u bject is n ot fasti n g as re q uire d, t he s u bject s h o ul d be calle d i n f or a ne w visit wit hi n t he visit wi n d o w t o ha ve t he fasti n g pr oce d ures d o ne.  
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 5 - 4 3 8 6
1 4 of 1 0 5

Pr ot o c ol  
Date:  
0 8 J ul y 2 0 2 0  
Stat us:  
Fi n al  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
P a ge:  
1 5  of 1 0 5  
Scree ni n g  
R u n -i n 
R a n d o mis ati o n  
Tre at me nt  
E n d of tre at me nt  
Tre at me nt 
disc o nti n u ati o n  
F oll o w -u p  
Tre at me nt 
disc o nti n u ati o n 
F oll o w -u p 
Visit ( V)/ p h o ne c o ntact ( P)  
V 1  
V 2  P 3  V 4  P 5  
P 6  V 7  
V 8  
P 9  
P 1 0  
P 1 1  
V 1 2  P 1 3  V 1 4  P 1 5  
V 1 6  
P 1 7  V 1 8  P 1 9  
P 2 0  V 2 1  P 2 2 
P 2 3  V 2 4  P 2 5  
P 2 6  V 2 7  P 2 8  
P 2 9  V 3 0  P 3 1  
P 3 2  V 3 3  P 3 4  
P 3 5  
V 3 6  
V 3 6 A  
P 3 7  
P 3 7 A  
Ti mi n g of Visit ( wee ks)  
-1 4  
-1 2  
-
1 0  
-8
-6
-4
-2
0  
1  
2  
3  
4  
6  
8  
1 0  
1 2  
1 4  1 6  1 8  
2 0  2 2  2 4  
2 6  2 8  3 0  
3 2  3 4  3 6  
3 8  4 0  4 2  
4 4  4 6  
4 8  
5 0  
5 2  
5 7  
Visit Wi n d o w ( da ys)  
± 7  
± 3  ± 3  ± 3  ± 3  
± 3  
0  
± 3  
± 7  
± 3  
± 7  ± 3  
± 7  
± 3  ± 7  ± 3  ± 7  ± 3  ± 7  ± 3  ± 7  ± 3  ± 7  ± 3  ± 7  ± 3  
± 7  
+ 7  
E n d of Treat me nt i 
X  
X  
E n d of Trial i 
X  
i If a s u bject c o m pletes b ot h t he treat me nt a n d t he trial at sc he d ule d ti me, t he E n d of Treat me nt f or m m ust be fille d i n at V 3 6 a n d E n d of Trial f or m m ust be fille d i n at P 3 7. If disc o nti n uati o n of trial pr o d uct bef ore t he e n d of 
treat me nt ( V 3 6), E n d of Treat me nt f or m m ust be fille d-i n w he n t he disc o nti n uati o n ha p pe ns a n d E n d of Trial f or m at sc he d uled visit P 3 7. I n case of s u bject wit h dra wal, b ot h E n d of Treat me nt f or m a n d E n d of Trial f or m m ust 
be fille d i n at t he ti me of wit h dra wal fr o m t he trial.  
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 5 - 4 3 8 6
1 5 of 1 0 5

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
1 6  of 1 0 5  
 
3  
I ntr o d ucti o n  
3. 1  
Tri al r ati o n ale  
Acc or di n g t o t he A merica n Dia betes Ass o ciati o n ( A D A) a n d E ur o pea n Ass ociati o n f or St u d y of 
Dia betes ( E A S D), treat me nt i nte nsificati o n s h o ul d be c o nsi dere d f or p atie nts wit h t y pe 2 dia bet es 
( T 2 D) w h o d o n ot reac h A D A/ E A S D rec o m me n d e d gl ycate d hae m o gl o bi n ( H b A 1c) g oal wit hi n 3-6 
m o nt hs of treat me nt wit h basal i ns uli n i n c o m bi nati o n wit h oral a n ti dia betic dr u gs ( O A Ds). 
A d va nci n g t o a c o m bi ne d i njecta ble treat me nt ca n be ac hie ve d wit h t he a d diti o n of a gl uca g o n -li ke 
pe pti de -1 rece pt or a g o nist ( G L P -1 R A), or b ol us i ns uli n t o t he treat me nt wit h basal i ns uli n. Dr u g 
c h oice s h o ul d be i n di vi d ualise d a n d  base d o n l o cal g ui deli nes a n d p atie nt prefere nces, as w ell as 
vari o us patie nt, disease, a n d dr u g c haracteristics, wit h t he g oal of i m pr o vi n g bl o o d gl uc ose ( B G) 
le vels w hile mi ni mizi n g si de effects, es peciall y h y p o gl ycae mia.2, 3  
Se vere h y p o gl ycae mia i m pacts hea vil y o n t he well -bei n g, pr o d u cti vit y, healt h -relate d q u alit y a n d 
me ntal f u ncti o ni n g of life of pe o ple wit h T 2 D. Se vere h y p o gl ycae mia re pr ese nts a s u bsta ntial c ost 
b ur de n, as it ma y i n v ol ve c osts relate d t o a m b ula nces, para me dics, a n d h os pitalisati o n. 4 
It is rec o m me n de d t hat t h e H b A1c g oals s h o ul d be  i n di vi d ualise d a n d wit hi n t he ra n ge of 6. 5 % t o 
7. 5 % ( 4 8 m m ol/ m ol t o 5 8 m m ol/ m ol) f or t he maj orit y of a d ult patie nts wit h T 2 D. 2, 3, 5 Less 
stri n ge nt H b A1c g o als ma y be a p p r o pri ate f or patie nts wit h a hist or y of se v ere h y p o gl ycae mia, 
li mite d life e x pecta nc y, a d va nce d micr o- or macr o vasc ular c o m plicati o ns, e xte nsi ve c o m or bi d 
c o n diti o ns, or l o n g-sta n di n g dia bet es i n w h o m t he g oal is diffic ult t o ac hie ve des pite dia betes s elf -
m a na ge me nt e d u cati o n, a p pr o priate gl uc ose m o nit ori n g a n d effecti ve d os es of m ulti ple gl uc ose -
l o weri n g a ge nts, i ncl u di n g i ns uli n.2, 3 
T he p ur p ose of t h e c urre nt tria l is t o c o m pare t he effect o n gl ycae mic c o ntr ol, b o d y wei g ht, safet y 
a n d healt h -relate d q ualit y of life of se ma gl uti de vers us i ns uli n as part (I As p), b ot h as a d d-o n t o 
metf or mi n a n d o pti mise d i ns uli n glar gi ne (I Glar U 1 0 0) treat me nt i n s u bjects wit h i na de q ua tel y 
c o ntr olle d T 2 D.  
Se ma gl uti de ma y pr o vi d e a n efficaci o us a n d si m ple alter nati ve t o b ol us i ns uli n f or a d va nci n g b asal 
i ns uli n re gi me n i n patie nts wit h late sta ge T 2 D, wit h l o wer ris k of h y p o gl ycae mia a n d wei g ht gai n.  
3. 2  
B ac k gr o u n d  
Se ma gl uti de is a n o vel G L P -1 ( Gl uca g o n -li ke p e pti de-1) a nal o g u e wit h a half -life ar o u n d 1 wee k 
( 1 4 9 t o 1 6 5 h o urs), s uita ble f or o nce-wee kl y ( O W) s u bc uta ne o us (s.c.) a d mi nistrati o n. 6 I n t he 
S U S T AI N cli nical de vel o p me nt pr o gra m me, se m a gl uti de de m o nstrate d cli nicall y rele va nt a n d 
s u peri or re d u cti o ns i n H b A 1c a n d b o d y wei g ht vers us place b o ( m o n ot hera p y a n d a d d -o n t o bas al 
i ns uli n) a n d acti ve c o m p arat ors (e x e nati de, d ula gl uti de, sita gli pti n a n d I Glar). T he car di o vas c ular 
( C V) safet y of se ma gl uti de has bee n esta blis he d i n a 2 -year C V o utc o mes trial ( S U S T AI N 6) t hat 
s h o we d cli nicall y rel e va nt C V ris k re d ucti o n wit h se ma gl uti de c o m pare d t o place b o.7 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
1 6 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
1 7  of 1 0 5  
 
Se ma gl uti de a d d e d o n t o basal i ns uli n i n patie nts wit h i na de q uatel y c o ntr olle d T 2 D de m o nstrate d 
s u peri or effects o n gl ycae mic c o ntr ol, wei g ht l oss, treat me nt satisfacti o n  a n d re d ucti o n i n basal 
i ns uli n d ose c o m pare d t o place b o.8 
Basal -b ol us t hera p y, i n v ol vi n g t he a d diti o n of ra pi d acti n g i ns uli n at mealti me t o o n g oi n g basal 
i ns uli n, is a n effecti ve tr eat me nt f or l o weri n g gl uc ose le vels b ut ca n b e ass ociate d wit h a ris k of 
h y p o gl ycae mia a n d wei g ht gai n. 2, 3 T he a d here nce t o basal -b ol us re gi me ns ma y b e percei ve d as 
c o m plicate d f or t h e patie nt, a n d it ma y affect t he patie nt’s q ualit y of life. S pecificall y, bas al -b ol us 
treat me nt wit h I Glar a n d I As p is a wi del y pres cri b e d a n d acce pt e d T 2 D treat me nt re gi me n 
w orl d wi de.  
Rece nt trials e val u ati n g t he use of G L P -1 R As wit h basal i ns uli n, de m o nstrate d e q ual or s u p eri or 
effic ac y o n gl ycae mic c o ntr ol c o m pare d t o b ol us i ns uli n, wit h great er wei g ht l oss a n d less 
h y p o gl ycae mia. 9 -1 1 Li mite d i nf or mati o n is a vaila ble o n c o m paris o n of o nce -wee kl y G L P -1 R As t o 
b ol us i ns uli n, c o nfir mi n g t he se fi n di n gs.1 2  
Patie nts wit h i na de q uatel y c o ntr olle d T 2 D wit h  basal i ns uli n, sta ble d ose of metf or mi n wit h or 
wit h o ut a n a d diti o nal O A D, are t he t ar get p o p ulati o n f or i ncl usi o n i n t his trial. As a c o nse q u e nce, 
t hese s u bjects will alrea d y ha v e e x ha uste d t he o pti o n of treat me nt wit h diet a n d e x ercise i n 
c o m bi nati o n wi t h O A Ds a n d basal i ns uli n a n d q ualif y f or f urt her treat me nt i nte nsificati o n. U p o n 
trial e ntr y, all s u bjects will be tra nsferre d fr o m t heir pre-trial b asal i ns uli n treat me nt t o I Glar U 1 0 0, 
pr o vi de d b y N o v o N or dis k A/ S as t he i n vesti gati o nal me dici nal pr o d uc t (I M P).  
S u bjects treate d wit h metf or mi n a n d o pti mise d I Glar U 1 0 0 w h o ha ve n ot reac he d a de q uat e 
gl ycae mic c o ntr ol after 1 2 wee k r u n -i n will ha ve t heir treat me nt i nte nsifie d wit h eit her se ma gl uti de 
O W or I As p TI D.  
T he select e d acti ve c o m parat or i n t his tri al is I As p. I As p ( N o v o Ra pi d ®  a n d N o v o L o g ® ) is a ra pi d-
acti n g i ns uli n a nal o g u e i n dicate d f or t h e treat me nt of dia betes mellit us pr o vi di n g p ost pra n dial 
gl ycae mic c o ntr ol b y me a ns of l o weri n g t otal gl uc ose e x c ursi o n f oll o wi n g a meal b ot h i n s u bjects 
wit h t y pe 1 dia b etes a n d T 2 D. I n or der t o refl ect us ual cli nical practice, t he i n vesti gat or ca n c h a n ge 
b ol us i ns uli n d uri n g t he trial.  
All s u bjects i ncl u de d i n t he trial will be treate d wit h I Glar U 1 0 0 as t h e basal i ns uli n. I Glar U 1 0 0 
( La nt us® ) is a l o n g-acti n g i ns uli n a nal o g ue, i n dicate d f or treat me nt o f dia b etes mellit us i n 
c o m bi nati o n wit h oral a nti dia betic a ge nts a n d as p art of a b asal -b ol us i ns uli n re gi me n.  
3. 3  
Be nefit -ris k assess me nt  
3. 3. 1  
Ris ks rel ate d t o se m a gl uti de  
Base d o n t h e cli nical de v el o p me nt pr o gra m me a ca usal relati o ns hi p wit h se ma gl uti de was s u g g este d 
f or t he f oll o wi n g ris ks (i de ntifie d ris ks): 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
1 7 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
1 8  of 1 0 5  
 
G astr oi ntesti n al dis or ders  
F or se ma gl uti de as f or ot her G L P -1 R As, t he m ost fre q ue ntl y re p orte d a d verse reacti o ns i n cli nical 
trials were gastr oi ntesti nal dis or ders, i ncl u di n g na usea, diarr h oea a n d v o miti n g. I n ge n eral, t hes e 
reacti o ns w ere mil d or m o derate i n se v erit y a n d of s h ort d urati o n. A d ose d e pe n de n c y has bee n 
o bser ve d f or m ost of t he gastr oi ntesti nal dis or ders. Cli nical trials ha ve s h o w n t hat a l o w starti n g 
d ose a n d gra d u al d ose es calati o n miti gates  t he ris k of gastr oi ntesti nal A Es.  
I n p atie nts treate d wit h G L P-1 R As, na us ea, v o miti n g a n d diarr h oea ma y lea d t o si g nifica nt 
de h y drati o n. T his s h o ul d be c o nsi dere d w he n tr eati n g patie nts wit h i m paire d re nal f u n cti o n as it 
ma y ca use a deteri orati o n of re n al f u n cti o n. S u bjects wit h GI ( Gastr oi ntesti nal) A Es are 
rec o m me n de d t o dri n k ple nt y of fl ui ds t o a v oi d v ol u me de pleti o n.  
H y p o gl yc ae mi a  
S u bjects treate d wit h se ma gl uti de i n c o m bi nati o n wit h a s ulf o n yl ur ea or i ns uli n ha ve a n i ncrease d 
ris k of h y p o gl ycae mia. T he ris k of h y p o gl ycae mia ca n be l o w ere d b y re d uci n g t he d ose of 
s ulf o n yl ur ea or i ns uli n w he n i nitiati n g treat me nt wit h se ma gl uti de.  
Di a betic reti n o p at h y c o m plic ati o ns  
I n a 2-year cli nic al trial i n v ol vi n g 3, 2 9 7 s u bjects wit h t y pe 2 dia betes a n d hi g h car di o vasc ul ar ris k, 
l o n g d urati o n of di a betes a n d p o orl y c o ntr olle d bl o o d gl uc os e, a dj u dicate d e ve nts of dia betic 
reti n o pat h y c o m plicati o ns occ urre d i n m ore patie nts treate d wit h se ma gl uti de ( 3. 0 %) c o m pare d t o 
place b o ( 1. 8 %). Dia b etic reti n o pat h y  c o m plicati o ns were a c o m p osite of: nee d f or reti nal 
p h ot oc oa g ulati o n, nee d f or treat me nt wit h i ntra vitreal a ge nts, vitre o us hae m orr ha ge a n d o nset of 
dia betes -relate d bli n d ness. T he a bs ol ute ris k i ncrease f or dia betic reti n o pat h y c o m plicati o ns was 
lar ger am o n g p atie nts wit h a hist or y of dia betic reti n o pat h y at b aseli ne. I n t he patie nts t hat di d n ot 
ha ve a d o c u me nte d hist or y of dia betic reti n o pat h y t he n u m ber of e v e nts were si milar f or 
se ma gl uti de a n d place b o.  
I n ot her cli nical trials u p t o 1 year i n v ol vi n g 4, 8 0 7 patie nts wit h t y pe 2 dia betes patie nts, a d verse 
e ve nts relat e d t o dia betic reti n o pat h y were re p orte d i n si milar pr o p orti o ns of s u bjects treat e d wit h 
se ma gl uti de ( 1. 7 %) a n d c o m parat ors ( 2. 0 %). 
Ra pi d i m pr o ve me nt i n gl uc ose c o ntr ol has bee n ass ociate d wit h a te m p or ar y w orse ni n g of dia b etic 
reti n o pat h y. L o n g-ter m gl ycae mic c o ntr ol d ecreas es t he ris k of dia betic reti n o pat h y. S u bjects wit h a 
hist or y of dia b etic reti n o pat h y s h o ul d be m o nit ore d f or w orse ni n g a n d treate d acc or di n g t o cli nical 
g ui deli nes.  
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C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
1 9  of 1 0 5  
 
Ot h er ris ks  
Patie nts treate d wit h se m a gl uti de ma y als o e x perie nce c h olelit hiasis, decrease d a p petite, dizzi ness, 
d ys ge usia, fati g ue, i ncrease d heart rate, i ncreas e d li pase a n d a m ylas e, i njecti o n site reacti o ns a n d 
wei g ht d ecrease.  
 
I n a d diti o n, f or t he ris ks bel o w, t here is s o me basis f or s us pici o n of a n ass o ciati o n wit h se ma gl uti de, 
h o we ver, t he relati o ns hi p has n ot bee n c o nfir me d ( p ote ntial ris ks).  
Aller gic re acti o ns  
As i n t he case wit h all pr otei n -base d p har mace uticals, treat me nt wit h se ma gl uti de ma y e v o k e 
aller gic reacti o ns, i ncl u di n g seri o us aller gic reacti o ns s uc h as a na p h yl actic reacti o ns.  
Ac ute p a ncre atitis  
Ac ute pa n creatitis has bee n o bser ve d wit h t he use of G L P -1 R As. Patie nts s h o ul d be i nf or me d of 
t he c haracteristic s y m pt o ms of ac ute pa n creatitis a n d if pa ncreatitis is s us pecte d, se ma gl uti de 
s h o ul d be disc o nti n ue d. If c o nfir me d, s e ma gl uti de s h o ul d n ot be restarte d.  
M ali g n a nt ne o pl as ms  
T here is n o i n dicati o n of a ca usal relati o ns hi p bet wee n se ma gl uti de a n d mali g na nt n e o plas m base d 
o n t he a vaila ble d ata . H o we ver, it is n ot p ossi ble t o dra w a n y fir m c o ncl usi o ns d ue t o ver y l o w 
n u m bers.  
•  P a ncre atic c a ncer  
Patie nts wit h T 2 D ha ve a n i ncreas e d ris k of certai n t y pes of ca n cer s uc h as pa ncreatic 
ca ncer. I n t he d e vel o p me nt pr o gra m me, rat es of pa ncreatic ca ncer wa s l o w a n d d o n ot 
s u p p ort a ca us al ass ociati o n wit h se ma gl uti de, a n d n o safet y c o n cer ns relate d t o t he pa ncreas 
were i de ntifi e d i n t he n o ncli nical pr o gra m me wit h se ma gl uti de. H o we ver, pa ncreatic ca ncer 
has bee n cl assifie d as a p ote ntial class ris k f or all m ar kete d G L P -1 rece pt or a g o nists b y 
re g ulat or y a ge ncies.  
•  Me d ull ary t hyr oi d c a ncer  
T h yr oi d C -cell t u m o urs were s ee n i n mice a n d rat carci n o ge nicit y st u dies after dail y 
e x p os ure t o se ma gl uti de f or 2 years. T he r o de nt C -cell t u m o urs are ca us e d b y a n o n -
ge n ot o xic, s pecific G L P -1 rece pt or me diate d mec ha nis m t o w hic h r o de nts are partic ularl y 
se nsiti ve.  N o C-cell t u m o urs were o bser ve d i n m o n ke ys after 5 2 wee ks e x p os ure u p t o 2 7 -
f ol d a b o ve t he cli nic al plas ma e x p os ure at 1. 0 m g/ wee k. 
T he G L P -1 rece pt or is n ot e x pr esse d i n t he n or mal h u ma n t h yr oi d a n d t h e ris k of G L P -1 
rece pt or-me diate d C -cell c ha n ges i n h u ma ns is c o nsi dere d t o be l o w.  
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Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
2 0  of 1 0 5  
 
Ot her s af et y c o nsi der ati o ns  
  
Dr u g i nter acti o ns  
Se ma gl uti de del a ys gastric e m pt yi n g a n d h as t he p ote ntial t o i m pact t he rate of a bs o r pti o n of 
c o nc o mita ntl y a d mi nistere d oral me dici nal pr o d ucts. T he p ote ntial effect of se ma gl uti de o n t he 
a bs or pti o n of c o -a d mi nistere d oral me dicati o ns w as st u die d i n trials at se ma gl uti de 1 m g/ wee k 
stea d y st ate e x p os ure. N o cli nicall y rele va nt dr u g-dr u g i nteracti o ns wit h se ma gl uti de were o bs er ve d 
base d o n t he e v al uate d m e dicati o ns.  
Se ma gl uti de di d n ot c ha n ge t h e o verall p har mac o d y n a mics of warfari n as meas ure d b y t h e 
i nter nati o nal n or malise d rati o (I N R). H o we ver, u p o n i nitiati o n of se ma gl uti de treat me nt in patie nts 
o n warfari n a n d/ or c o u mari n deri vati ves, fre q u e nt m o nit ori n g of I N R is rec o m me n de d.  
Pre g n a nc y, l act ati o n a n d fertilit y  
St u dies i n a ni mals ha ve s h o w n re pr o d ucti ve t o xicit y. T here are li mite d data fr o m t he use of 
se ma gl uti de i n pre g na nt w o me n. T heref ore, se ma gl uti de s h o ul d n ot be use d d uri n g pre g na n c y. If a 
patie nt wis hes t o bec o me pre g na nt, or pre g na n c y occ urs, se ma gl uti de s h o ul d be disc o nti n ue d. 
Se ma gl uti de s h o ul d be disc o nti n ue d at least 2 m o nt hs bef ore a pl a n ne d pre g na nc y d ue t o t he l o n g 
hal f-life. I n l actati n g rats, se ma gl uti de was e x crete d i n mil k. As a ris k t o a breast-fe d c hil d ca n n ot 
be e x cl u de d, se ma gl uti de s h o ul d n ot be use d d uri n g breast -fee di n g 
T he effect of s e ma gl uti de o n fertilit y i n h u ma ns is u n k n o w n. Se ma gl uti de di d n ot affect ma l e 
fertilit y i n rats. I n fe male rats, a n i ncrease i n o estr o us le n gt h a n d a s mall re d ucti o n i n n u m ber of 
o v ulati o ns were o bser ve d at d oses ass ociate d wit h mater nal b o d y wei g ht l oss.  
3. 3. 2  
Ris ks rel ate d t o i ns uli n  
H y p o gl yc ae mi a  
T he m ost fre q ue ntl y re p orte d a d verse  reacti o n of i ns uli n t hera p y is h y p o gl ycae mia. It ma y o cc ur if 
t he i ns uli n d ose is t o o hi g h i n rel ati o n t o t he i ns uli n re q uire me nt. Patie nts, w h ose bl o o d gl u c ose 
c o ntr ol is greatl y i m pr o ve d, e. g. b y i nte nsifie d i ns uli n t hera p y, m a y e x perie nce a c ha n ge i n t heir 
us ual war ni n g s y m pt o ms of h y p o gl ycae mia, a n d s h o ul d be a d vise d acc or di n gl y. Us ual w ar ni n g 
s y m pt o ms ma y disa p pear i n patie nts wit h l o n gsta n di n g dia bet es. 
Ot her  
Ot her e ve nts i ncl u d e i njecti o n site reacti o ns, li p o d ystr o p h y at i njecti o n site, aller gic re acti o ns, 
oe de ma a n d m e dicati o n err ors f or d ual i ns uli n t hera p y  
I nte nsifi cati o n of i ns uli n t hera p y wit h a br u pt i m pr o ve me nt i n gl ycae mic c o ntr ol ma y be ass ociate d 
wit h te m p orar y w ors e ni n g of dia b etic reti n o pat h y.  
F or I Gl ar: fast i m pr o ve m e nt i n B G c o ntr ol ma y  b e ass ociate d wit h ac ute pai nf ul ne ur o pat h y, w hic h 
is us uall y re v ersi ble. 
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Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
2 1  of 1 0 5  
 
3. 3. 3  
Be nefits  
I n cli nical trials se ma gl uti de has pr o vi de d s u peri or gl ycae mic c o ntr ol i n T 2 D a n d cli nicall y rel e va nt 
re d ucti o ns i n b o d y wei g ht as c o m pare d t o c o m m o nl y use d mar kete d pr o d u cts a n d place b o. T he C V 
safet y of se m a gl uti de has bee n esta blis he d i n a C V o utc o me trial ( S U S T AI N 6) a n d t he trial 
s u g geste d a cli nicall y rele va nt C V ris k re d u cti o n wit h se ma gl uti de c o m p are d t o place b o.  
I As p is wi d el y prescri be d a n d acce pte d b ol us i ns uli n use d i n patie nts wit h T 2 D w orl d wi de, wit h 
well c haracterise d cli nical pr ofile.  
D uri n g t his trial it is e x pecte d t hat all patie nts will be nefit fr o m partici pati o n t hr o u g h i nte nsifie d 
treat me nt re gi me n i n b ot h gr o u ps w hi c h i ncl u des fre q ue nt c o ntact wit h t he trial site, w here p atie nts 
are m o nit ore d a n d treat e d f oll o wi n g caref ul me dical e xa mi nati o ns.  
T o e ns ure all patie nts h a ve a n a d e q uate gl ycae mi c c o ntr ol, i n vesti gat ors are e nc o ura ge d t o o pti mise 
gl ycae mic c o ntr ol t hr o u g h o ut t he trial i n acc or da n ce wit h t he i n di vi d ualise d gl ycae mic g oal a n d t he 
titrati o n g ui deli nes.  
Ris k a n d be nefit c o ncl usi o n  
T he ai m of t his trial is t o c o m pare t he effect of s e ma gl uti de t o t hat of I As p. I n cl usi o n a n d e x cl usi o n 
criteria h a ve bee n c h ose n t o e ns ure t hat s u bjects e nr olli n g i n t he trial ha ve T 2 D at a sta ge w here 
treat me nt i nte nsificati o n wit h eit her G L P-1 R As or pra n dial i ns uli n is rec o m me n de d b y T 2 D 
treat me nt g ui deli nes. Ra n d o mise d s u bjects s h o ul d be nefit fr o m treat me nt i nte nsificati o n wit h eit her 
se ma gl uti de or I As p. It is t heref ore c o n cl u de d t hat t he p ote ntial be nefits fr o m t he trial will o ut wei g h 
t he p ote ntial ris ks f or t he se ma gl uti de as well as t he I As p treate d patie nts. 
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 nefits a n d ris ks a n d reas o n a bl y 
e x pecte d a d vers e e v e nts of se ma gl uti de ma y 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.  
Detaile d i nf or mati o n a b o ut I As p is a v aila ble i n t he c urre nt versi o n of t he l ocal la bel.  
Detaile d i nf or mati o n a b o ut I Glar is a vaila ble i n t h e c urre nt versi o n of t he l ocal la bel f or La nt us ® . 
 
 
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C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
2 2  of 1 0 5  
 
4  
O bjecti ves a n d e n d p oi nts  
4. 1  
Pri m ar y o bjecti ve  
T o c o m pare t h e effect of se ma gl uti de o nce -wee kl y o n gl ycae mic c o ntr ol v ers us i ns uli n as part t hree 
ti mes dail y ( TI D), b ot h as a d d o n t o metf or mi n a n d o pti mise d i ns uli n glar gi ne ( U 1 0 0) i n s u bjects 
wit h T 2 D.  
4. 2  
Sec o n d ar y o bjecti ves  
T o de m o nstrate t hat se m a gl uti de o n ce -wee kl y has a l o wer ris k of s e vere h y p o gl ycae mic e pis o des 
c o m pare d t o I As p TI D, b ot h as a d d o n t o metf or mi n a n d o pti mise d i ns uli n glar gi n e ( U 1 0 0) i n 
s u bjects wit h T 2 D. 
T o c o m pare t h e effect of se ma gl uti de O W vers us I As p TI D, b ot h as a d d o n t o metf or mi n a n d 
o pti mise d i ns uli n glar gi n e ( U 1 0 0) i n s u bjects wit h T 2 D wit h re gar ds t o:  
•  b o d y w ei g ht  
•  li pi ds 
•  bl o o d press ure  
•  healt h -rel ate d q ualit y of life 
•  safet y 
4. 3  
Esti m a n d  
F or all o bjecti ves t h e pr i mar y esti ma n d is t he treat me nt differe n ce bet w ee n se ma gl uti de O W a n d 
I As p TI D f or all ra n d o mise d s u bjects if all s u bjects i nitiate d a n d re mai ne d o n ra n d o mise d treat me nt 
t hr o u g h o ut t he trial. 
Patie nts w h o are l ost t o f oll o w -u p, w h o ha ve wit h dra w n c o ns e nt, or w h o disc o nti n ue trial dr u g are 
ass u me d, i n t he ti me f oll o wi n g t his e ve nt, t o be h a ve li ke patie nts t hat re mai n i n t he trial a n d are 
treate d wit h trial dr u g. 
4. 4  
E n d p oi nts  
Defi niti o n of b aseli ne  
F or eac h ass ess me nt, t he baseli ne assess me nt is defi ne d as t he m eas ure me nt at t he ra n d o misati o n 
visit ( V 8). H o we ver, if a visit 8 assess me nt is missi n g t he n t he assess me nt fr o m visit 7, if a vaila ble, 
will be use d as t he baseli ne assess me nt.  
4. 4. 1  
Pri m ar y e n d p oi nt  
•  C ha n ge fr o m bas eli ne t o wee k 5 2 i n H b A 1c ( %-p oi nt)  
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C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
2 3  of 1 0 5  
 
4. 4. 2  
Sec o n d ar y e n d p oi nts 
4. 4. 2. 1  
C o nfir m at or y s ec o n d ar y e n d p oi nts  
•  Ti me t o first e ve nt a dj u dicati o n c o m mittee ( E A C) c o nfir me d se v ere h y p o gl ycae mic 
e pis o de ( A D A) fr o m ra n d o misati o n u p t o wee k 5 2 ( da ys)  
•  Ti me t o first E A C c o nfir me d se vere h y p o gl ycae mic e pis o de ( A D A) re q uiri n g 
h os pit alisati o n, d oc u me nte d me dical hel p, or is lif e t hreate ni n g fr o m ra n d o misati o n u p 
t o wee k 5 2 ( d a ys) 
•  C ha n ge fr o m bas eli ne t o wee k 5 2 i n b o d y wei g ht ( k g)  
4. 4. 2. 2  
S u p p orti ve sec o n d ar y e n d p oi nts  
•  C ha n ge fr o m bas eli ne t o wee k 5 2 i n:  
o  Fasti n g plas ma gl uc ose ( F P G) ( m m ol/ L)  
o  7 -p oi nt self -meas ur e d plas ma gl uc os e pr ofile  
▪ Mea n 7 -p oi nt pr ofile ( m m ol/ L)  
▪ Mea n p ost -pra n di al i ncre me nt ( o ver all meals) ( m m ol/ L)  
o  S yst olic a n d diast olic bl o o d press ure ( m m H g)  
o  Fasti n g bl o o d li pi ds (t otal c h olester ol, l o w -de nsit y li p o pr otei n ( L D L) 
c h olesterol, hi g h -de nsit y li p o pr otei n ( H D L) c h ol ester ol, tri gl yceri des) ( m m ol/ L)  
o  B o d y mass i n de x ( B MI) ( k g/ m 2)  
o  Waist circ u mfere n ce (c m)  
o  B o d y wei g ht ( %)  
o  P ulse ( b p m)  
•  N u m ber of E A C c o nfir m e d se vere h y p o gl ycae mic e pis o des ( A D A) fr o m ra n d o misati o n  
t o wee k 5 2 
•  N u m ber of E A C c o nfir m e d se vere ( A D A) or bl o o d gl uc ose c o nfir me d, s y m pt o matic 
h y p o gl ycae mic e pis o des ( P G < 3. 1 m m ol/ L ( 5 6 m g/ d L)) fr o m r a n d o misati o n t o wee k 5 2  
•  N u m ber of E A C c o nfir m e d se vere ( A D A) or bl o o d gl uc ose c o nfir me d, s y m pt o matic  
h y p o gl ycae mic e pis o des ( P G ≤ 3. 9 m m ol/ L ( 7 0 m g/ d L)) fr o m r a n d o misati o n t o wee k 5 2  
•  N u m ber of E A C c o nfir m e d se vere h y p o gl ycae mic e pis o des ( A D A) re q uiri n g 
h os pitalisati o n, d oc u me nte d me dical hel p, or is lif e t hreate ni n g fr o m ra n d o misati o n t o 
wee k 5 2  
 
S u p p orti ve sec o n d ar y H R Q o L e n d p oi nts  
C ha n ge fr o m bas eli ne t o wee k 5 2 i n t he f oll o wi n g sc ores f or t he selecte d patie nt -re p ort e d o utc o mes 
( P R O): 
•  3 6 -ite m S h ort F or m Healt h S ur ve y v ersi o n 2 ( S F-3 6 v 2 ™  )  
o  P h ysical C o m p o ne nt S u m mar y ( P C S) sc ore (ra n ge: 7. 3 2 -7 0. 1 4)  
o  Me ntal C o m p o ne nt S u m mar y ( M C S) sc o re (ra n ge: 5. 7 9-6 9. 9 1)  
o  P h ysical F u ncti o ni n g ( P F) d o mai n sc ore (ra n ge: 1 9. 2 6 -5 7. 5 4)  
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C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
2 4  of 1 0 5  
 
o  R ole -P h ysical ( R P) d o mai n sc ore (ra n ge: 2 1. 2 3 -5 7. 1 6)  
o  B o dil y Pai n ( B P) d o mai n sc ore (ra n ge: 2 1. 6 8 -6 2. 0 0)  
o  Ge neral Healt h ( G H) d o mai n sc ore (ra n ge: 1 8. 9 5 -6 6. 5 0)  
o  Vitalit y ( V T) d o m ai n sc ore (ra n ge: 2 2. 8 9 -7 0. 4 2)  
o  S ocial F u ncti o ni n g ( S F) d o mai n sc ore (ra n ge: 1 7. 2 3 -5 7. 3 4)  
o  R ole -E m oti o nal ( R E) d o mai n sc ore (ra n ge: 1 4. 3 9 -5 6. 1 7)  
o  Me ntal Healt h ( M H) d o mai n sc ore (ra n ge: 1 1. 6 3 -6 3. 9 5)  
 
T he te n sc ores relat e d t o S F -3 6 v 2 ™ are meas ure d o n a scale fr o m 5. 7 9 -7 0. 4 2, a n d 
calc ulate d usi n g t he 2 0 0 9 Ge neral U. S. P o p ulati o n.  
Hi g her sc ores are i n dicati ve of a better healt h stat e.  
 
•  Dia betes Q ualit y Of Life Cli nical Trial Q uesti o n naire ( D Q L C T Q -R)  
o  P h ysical f u n cti o ni n g d o mai n sc ore  
o  E ner g y / fati g ue d o mai n sc ore  
o  Healt h distress d o mai n sc ore  
o  Me ntal healt h d o mai n sc ore  
o  Satisfacti o n d o mai n sc ore  
o  Treat me nt satisfacti o n d o mai n sc ore  
o  Treat me nt fle xi bilit y d o mai n sc ore  
o  Fre q u e nc y of s y m pt o ms d o mai n sc ore  
 
T he e i g ht sc ores relate d t o D Q L C T Q-R are meas ure d o n a scale fr o m 0 -1 0 0.  
Hi g her sc ores are i n dicati ve of better healt h state.  
4. 4. 2. 3  
E x pl or at or y e n d p oi nts  
E x pl or at or y res p o n der e n d p oi nts  
•  H b A 1c ≤ 7. 5 % ( 5 8 m m ol/ m ol) at wee k 5 2 ( Y/ N)  
•  H b A 1c < 7. 0 % ( 5 3 m m ol/ m ol) at wee k 5 2 ( Y/ N) ( A D A)  
•  H b A 1c ≤ 6. 5 % ( 4 8 m m ol/ m ol) at wee k 5 2 ( Y/ N) ( A A C E)  
•  H b A 1c ≤ 7. 5 % ( 5 8 m m ol/ m ol) at wee k 5 2 wit h o ut a n E A C c o nfir me d s e vere 
h y p o gl ycae mic e pis o de ( A D A) fr o m ra n d o misati o n t o wee k 5 2 ( Y/ N)  
•  H b A 1c ≤ 7. 5 % ( 5 8 m m ol/ m ol)  at wee k 5 2 wit h o ut a n E A C c o nfir me d s e vere 
h y p o gl ycae mic e pis o de ( A D A) re q uiri n g h os pitalisati o n, d oc u me nte d me di cal hel p, or 
is life t hreate ni n g fr o m ra n d o misati o n t o wee k 5 2 ( Y/ N) 
•  Wei g ht l oss ≥ 5 % at wee k 5 2 ( Y/ N)  
•  Wei g ht l oss ≥ 1 0 % at wee k 5 2 ( Y/ N)  
 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
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C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
2 5  of 1 0 5  
 
E x p l or at or y P R O e n d p oi nts 
C ha n ge fr o m bas eli ne t o wee k 5 2 i n t he sc ores f or t he Treat me nt Relat e d I m pact Meas ure f or 
Dia betes ( T RI M -D):  
•  T RI M -D T otal Sc ore  
•  Treat me nt B ur de n D o mai n Sc ore  
•  Dail y Lif e D o mai n Sc ore  
•  Dia betes Ma n a ge me nt D o mai n Sc ore  
•  C o m plia nce D o mai n  Sc ore  
•  Ps yc h ol o gical H ealt h D o mai n Sc ore  
 
T he si x sc ores relate d t o T RI M -D are meas ure d o n a scale fr o m 0 -1 0 0.  
Hi g her sc ores are i n dicati ve of better healt h state (less ne gati ve i m pact).  
 
 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
2 5 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
2 6  of 1 0 5  
 
 
5  
Tri al desi g n  
5. 1  
O ver all desi g n  
T his is a 5 2 -wee k, m ulti -ce ntre, m ulti nati o nal, o pe n -la bel, acti ve c o ntr olle d, t w o ar me d, parallel, 
ra n d o mise d trial wit h a 1 2-wee k r u n -i n peri o d i n s u bjects wit h T 2 D. T he t otal d urati o n of t he trial 
will be a p pr o xi matel y 7 1 wee ks: 2 wee ks f or s cree ni n g, a 1 2 -wee k r u n -i n peri o d, a 5 2-wee k  
treat me nt peri o d a n d a f oll o w-u p peri o d of 5 wee ks.  
At r u n -i n, eli gi ble s u bjects will disc o nti n ue pre-trial basal i ns uli n a n d t he a d diti o nal O A D (if 
a p plica ble, i ncl u di n g c o n versi o n fr o m fi x e d dr u g c o m bi nati o n me dicati o ns wit h metf or mi n a n d 
D P P -4i ( Di pe pt i d yl pe pti dase-4 i n hi bit or) t o metf or mi n o nl y) a n d start treat me nt wit h I Glar U 1 0 0.  
D uri n g r u n -i n, s u bjects will be treate d wit h metf or mi n a n d I Glar U 1 0 0. D uri n g r u n-i n metf or mi n 
ca n be o pti mise d wit hi n t he d ose ra n ge of ≥ 1 5 0 0 m g t o ≤ 3 0 0 0 m g. T h e I Glar U 1 0 0 d ose will be 
o pti mise d as descri be d i n t he A p pe n di x 8 . 
S u bjects treate d wit h metf or mi n a n d I Glar U 1 0 0 w h o are n ot i n gl ycae mic c o ntr ol ( defi ne d  as 
H b A 1 c of > 7. 5 % t o ≤ 1 0 % [ > 5 8 m m ol/ m ol t o ≤ 8 6 m m ol/ m ol]) after r u n -i n, will be ra n d o mise d 1: 1 
t o recei ve a d d-o n tr eat me nt wit h se ma gl uti de O W or I As p TI D. F or details of t he d osi n g of I Glar, 
I As p a n d se ma gl uti de, refer t o A p pe n di x 8 . A sc h e matic o ver vie w of t he trial desi g n is s h o w n 
bel o w.
 
Fi g ure 5 -1  Tri al desi g n  
T he trial i ncl u des a s cree ni n g vi sit t o assess t he s u bject’s eli gi bilit y, a d diti o nal visits a n d p h o ne 
c o ntacts d uri n g r u n -i n a n d treat me nt peri o d, a n d a f oll o w-u p p h o ne c o ntact at wee k 5 7 t o e ns ure t he 
ca pt ure of a d verse e v e nts ( A Es) d uri n g was h -o ut of se ma gl uti de O W. T he visit sc he d ule d escri be d 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
2 6 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
2 7  of 1 0 5  
 
i n Secti o n 2  is c h ose n t o sec ure a n o pti mal i ns uli n titrati o n a n d se ma gl uti de O W d ose a dj ust me nt 
acc or di n g t o a pre d efi ne d treat me nt al g orit h m.  
5. 2  
S u bject a n d tri al c o m pl eti o n  
A p pr o xi matel y 3 1 4 4 s u bj ects wi ll be scree ne d t o ac hie ve 1 7 3 6 s u bjects r a n d o ml y assi g ne d t o trial 
pr o d ucts. A p pr o xi matel y 2 0 4 3 s u bjects are pla n ne d t o be i ncl u de d i n t he r u n -i n peri o d. 
 
Tri al peri o d c o m pleti o n f or a s u bject  
Trial peri o d c o m pleti o n is defi ne d as w h e n t he ra n d o mise d s u bje ct has c o m plete d t he fi nal 
sc he d ule d visit ('e n d of trial' acc or di n g t o t he fl o wc hart, Secti o n 2 ).' Date of trial c o m pleti o n' is t he 
date t he s u bject  c o m plet e d t he fi nal sc he d ule d visit.  
 
Tre at me nt peri o d c o m pleti o n f or a s u bject  
Treat me nt peri o d c o m pleti o n is defi ne d as w he n t he ra n d o mise d s u bject h as recei v e d t he re q uire d 
treat me nt, a n d atte n d e d t he 'e n d of tr eat me nt' visit ( V 3 6) acc or di n g t o t he fl o wc hart, Secti o n 2 . 
5. 3  
E n d of tri al defi niti o n  
T he e n d of t he tri al is defi ne d as t he date of t he last visit of t he last s u bject i n t he trial.  
5. 4  
Scie n tific r ati o n ale f or tri al desi g n 
T he trial has bee n desi g n e d as a parallel -gr o u p, t w o -ar me d, o p e n -la bel, ra n d o mise d trial t o sec ure a 
direct c o m paris o n bet wee n se ma gl uti de O W a n d I As p TI D.  
A 1 2 -wee k r u n -i n peri o d is i ncl u de d i n or der t o e ns ure t he d ose o pti misati o n of I Glar after t h e 
tra nsfer of all s u bjects fr o m t heir pre-trial b asal i ns uli n t o I Glar a n d aft er t h e disc o nti n uati o n of t he 
a d diti o nal O A D t o metf or mi n (if a p plica ble). O nl y s u bjects wit h i na de q uat e gl ycae mic c o ntr ol at 
ra n d o misati o n ( per ce ntr al la b orat or y H b A1c val ue o btai ne d at t he last visit d uri n g r u n -i n, V 7) will 
be i nitiate d o nt o t he a d d -o n treat me nt wit h se ma gl uti de or I As p.  
T he trial is o pe n -la b el d ue t o t he differe nt re q uir e me nts i n n u m ber a n d ti mi n g of t he i njecti o ns, B G 
self-m o nit ori n g a n d t he d ose escal ati o n/titrati o n al g orit h ms f or s e ma gl uti de a n d I As p.  
Ra n d o mise d treat me nt d urati o n will be 5 2 wee ks t o e ns ure a d e q uate ti me t o c o m pare t he f ull effect 
a n d safet y of ra n d o mise d treat me nts. R o b ust assess me nt of effect o n gl ycae mic c o ntr ol , b o d y 
wei g ht, s afet y a n d Healt h Relate d Q ualit y of Life ( H R Q o L) e n d p oi nts is e ns ure d wit h t he treat me nt 
d urati o n of 5 2 wee ks.  
Titrati o n al g orit h ms f or i ns uli ns a n d d ose a dj ust me nt g ui da nce f or se ma gl uti de, i ncl u di n g 
i n di vi d ualise d gl ycae mic g oals as well as resc ue criteria are i n place t o e ns ure o pti mal gl ycae mic 
c o ntr ol f or all s u bjects i n cl u de d i n t he trial. T o e ns ure u nif or mit y b et wee n t he sites, as well as t o 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
2 7 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
2 8  of 1 0 5  
 
e ns ure t hat t he s u bjects r ecei ve a n o pti mal treat m e nt, titrati o n al g orit h ms h a ve bee n de vel o p e d 
s pecif yi n g rec o m me n de d d ose a dj ust me nts at differe nt self-meas ure d pl as ma gl u c ose ( S M P G) a n d 
H b A 1 c le vels. T o o pti mise a n d mai ntai n gl ycae mic c o ntr ol t he i n vesti gat or s h o ul d t hr o u g h o ut t he 
trial be i n bi m o nt hl y c o nt act wit h t he s u bjects t o e ns ure a de q u ate treat me nt. F or f urt her det ails, 
please see A p pe n di x 8 . 
T he f oll o w -u p peri o d is 5 wee ks t o e ns ure safet y d ata c ollecti o n d uri n g was h -o ut of se ma gl uti de 
d ue t o its l o n g half -life. 
5. 5  
J ustific ati o n f or d ose  
F or t he d etails o n t he r o ute of a d mi nistrati o n, i nitiati o n a n d d ose a dj ust me nts of I M Ps (I Gl ar U 1 0 0, 
se ma gl uti de a n d I As p) pl ease refer t o Secti o n 7. 1  a n d A p pe n di x 8 . 
 
 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
2 8 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
2 9  of 1 0 5  
 
6  
Tri al p o p ul ati o n   
Pr os pecti ve a p pr o val of pr ot oc ol de viati o ns t o recr uit me nt a n d e nr ol me nt criteria, als o k n o w n as 
pr ot oc ol wai vers or e x e m pti o ns, is n ot per mitte d.  
6. 1  
I ncl usi o n criteri a  
S u bjects are eli gi ble t o b e i ncl u de d i n t he trial o nl y if all of t h e f oll o wi n g criteria a p pl y:  
1.  I nf or me d c o ns e nt o btai ne d bef ore a n y trial-relate d acti vities. Trial-rel ate d acti vities are a n y 
pr oce d ures t hat are carrie d o ut as part of t h e 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, a ge ≥ 1 8 years at t he ti me of si g ni n g i nf or m e d c o nse nt.  
3.  Dia g n os e d wit h t y p e 2 dia betes ≥ 1 8 0 da ys pri or t o t he da y of scree ni n g.  
4.  Treate d wit h basal i ns uli n o nce dail y ( O D ) or t wi ce dail y ( BI D) f or ≥ 9 0 d a ys pri or t o t he 
da y of scree ni n g.  
5.  Sta ble dail y d ose f or 9 0 da ys pri or t o t he da y of scree ni n g of t he f oll o wi n g a nti -dia betic 
dr u gs or c o m bi nati o n re gi me ns: A n y metf or mi n f or m ulati o ns ( ≥ 1 5 0 0 m g t o ≤ 3 0 0 0 m g or 
ma xi m u m t ole rate d or effecti ve d ose d o c u me nte d i n s u bject's me dical rec or d), al o ne or i n 
c o m bi nati o n (i ncl u di n g fi x e d -d ose dr u g c o m bi nati o n) wit h u p t o o ne a d diti o nal of t he 
f oll o wi n g O A Ds: s ulf o n yl ureas, me gliti ni des, D P P-4 i n hi bit ors or al p ha -gl u c osi dase 
i n hi bit ors. 
6.  H b A 1c of > 7. 5 % t o ≤ 1 0. 0 % ( > 5 8 m m ol/ m ol t o ≤ 8 6 m m ol/ m ol)  
7.  T he nee d a n d willi n g ness t o u n der g o treat me nt i nt e nsificati o n wit h t he treat me nts 
i n vesti gate d i n t his trial wit h t he ai m t o reac h a n H b A1c of 6. 5 % t o 7. 5 % ( 4 8 m m ol/ m ol t o 
5 8 m m ol/ m ol) ( b ot h i ncl u si ve), as assess e d b y t he i n vesti gat or. 
8.  A bilit y a n d willi n g n ess t o a d here t o t he pr ot oc ol i ncl u di n g perf or ma n ce of S M P G pr ofiles 
acc or di n g t o t he pr ot oc ol.  
9.  A bilit y a n d willi n g n ess t o eat at least 3 meals ( brea kfast, l u nc h a n d di n n er) e ver y da y d uri n g 
t he trial. 
6. 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 n f 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 t o bec o me pre g n a nt or is of c hil d-beari n g 
p ote ntial a n d n ot usi n g hi g hl y effecti ve c o ntrace pti ve met h o ds as re q uir e d b y l ocal 
re g ulati o n or practice. 
4.  Recei pt of a n y i n vesti gati o nal me dici nal  pr o d uct wit hi n 3 0 da ys bef ore s cree ni n g e x ce pt 
fr o m I Glar. 
5.  A n y dis or d er w hic h i n t h e i n vesti gat or ’s o pi ni o n mi g ht je o par dise t h e s u bject’s safet y or 
c o m plia nce wit h t he pr ot oc ol.  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
2 9 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
3 0  of 1 0 5  
 
6.  Pers o nal or first de gree relati ve(s) hist or y of m ulti ple e n d ocri ne n e o plasia  t y p e 2 or 
me d ullar y t h yr oi d carci n o ma.  
7.  Hist or y or prese n ce of pa ncreatitis (ac ute or c hr o nic).  
8.  A n y of t he f oll o wi n g: m y ocar dial i nfarcti o n, str o ke, h os pitalizati o n f or u nsta ble a n gi na or 
tra nsie nt isc hae mic attac k wit hi n t he past 1 8 0 da ys pri or t o t he da y of scree ni n g.  
9.  S u bjects prese ntl y classifie d as bei n g i n Ne w Y or k Heart Ass o ciati o n Class I V.  
1 0.  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 k n o w n o n t he da y of 
scree ni n g. 
1 1.  Re nal i m pair me nt meas ure d as esti mate d Gl o mer ular Filtrati o n Rate (e G F R) < 3 0 
ml/ mi n/ 1. 7 3 m 2 as defi ne d b y K DI G O 2 0 1 2. 1 3 
1 2.  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 t he past 9 0 da ys pri or t o t he da y of scree ni n g. H o we ver, s h ort 
ter m b ol us i ns uli n treat me nt f or a ma xi m u m of 1 4 da ys pri or t o t he da y of scree ni n g is 
all o we d.  
1 3.  U nc o ntr olle d a n d p ote nti all y u nsta ble dia b etic reti n o pat h y or mac ul o pat h y. Verifie d b y a 
p har mac ol o gic all y p u pil -dilate d f u n d us e x a mi nati o n perf or me d b y a n o p ht h al m ol o gist or a n 
e q uall y q u alifie d healt h care pr o vi d er (e. g. o pt o metrist) wit hi n t he past 9 0 da ys pri or t o r u n -
i n. 
1 4.  Prese nce or hist or y of mali g na nt ne o plas ms wit hi n t he past 5 years pri or t o t he da y of 
scree ni n g. Bas al a n d s q u a m o us cell s ki n ca ncer a n d a n y carci n o ma i n -sit u are all o we d. 
6. 3  
Lif est yle restricti o ns  
N ot a p plica ble  
6. 4  
R u n -i n e xcl usi o n criteri a 
T he s u bject m ust be e x cl u de d fr o m t he trial d uri n g t he r u n -i n peri o d, if t he f oll o wi n g a p plies after 
scree ni n g a n d bef ore or at ra n d o misati o n: 
1.  I n cl u de d i n t he trial i n vi olati o n of t he i ncl usi o n a n d/ or e x cl usi o n criteria 
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 partici pati o n i n a n ot her 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 
5.  A n y dis or d er w hic h i n t h e i n vesti ga t or’s o pi ni o n mi g ht je o par dise s u bject’s safet y 
6.  Pa ncreatitis (ac ute or c hr o nic)  
7.  A n y of t he f oll o wi n g: m y ocar dial i nfarcti o n, str o ke or h os pitalizati o n f or u nsta ble a n gi na or 
tra nsie nt isc hae mic attac k 
8.  Ne w Y or k Heart Ass ociati o n ( N Y H A) Class I V  
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  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
3 0 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
3 1  of 1 0 5  
 
1 0.  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 e x ce pt metf or mi n 
a n d I Glar U 1 0 0. H o we v er, s h ort -ter m b ol us i ns uli n treat me nt f or a ma xi m u m of 1 4 da ys is 
all o we d.  
1 1.  Pre -brea kfast S M P G val ues ta ke n o n t hree c o nsec uti ve da ys or a n y of t he F P G sa m ples 
a nal ys e d b y t he ce ntral la b orat or y e x cee d t h e li mit of 1 5. 0 m m ol/ L ( 2 7 0 m g/ d L), fr o m 
scree ni n g t o r a n d o misati o n a n d: 
•  n o treata ble i nterc urre nt ca use f or t he h y per gl ycae mia (e. g. n o n -c o m pliance) is 
i de ntifie d,  
a n d 
•  c o nfir mat or y F P G o btai ne d a n d a n al ys e d b y t he ce ntral la b orat or y e x cee ds t he li mit of 
1 5. 0 m m ol/ L ( 2 7 0 m g/ d L).  
6. 5  
R a n d o mis ati o n criteri a  
T o be ra n d o mise d, all ra n d o misati o n criteria m ust be a ns were d " yes".  
1.  H b A 1c of > 7. 5 % t o ≤1 0. 0 % ( > 5 8 m m ol/ m ol t o ≤8 6 m m ol/ m ol) meas ure d at V 7.  
2.  Treate d wit h I Glar U 1 0 0 a n d metf or mi n ( ≥ 1 5 0 0 m g t o ≤ 3 0 0 0 m g or ma xi m u m t olerate d 
d ose d oc u me nte d i n s u bj ect's me dical r ec or d) d uri n g t he r u n -i n a n d at r a n d o misati o n ( V 8). 
3.  T he nee d a n d willi n g ness t o u n der g o treat me nt i nt e nsificati o n wit h t he treat me nts 
i n vesti gate d i n t his trial wit h t he ai m t o reac h a n H b A1c of 6. 5 % t o 7. 5 % ( 4 8 m m ol/ m ol t o 
5 8 m m ol/ m ol) ( b ot h i ncl usi ve), as assess e d b y t he i n vesti gat or at ra n d o mis ati o n ( V 8).  
4.  A bse nce of u nc o ntr olle d a n d p ote ntiall y u nsta ble dia betic reti n o pat h y or m ac ul o pat h y. 
Verifie d b y a p har mac ol o gic all y p u pil -dilate d f u n d us 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 e q uall y q ualifie d h ealt h care pr o vi der (e. g. o pt o metrist) wit hi n 3 0 
da ys pri or t o ra n d o misati o n . 
  
Re -sa m pli n g is n ot all o w e d if t he s u bject has faile d t he ra n d o misati o n criteria relat e d t o H b A 1c. 
6. 6  
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 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 or mati o n i ncl u des de m o gra p h y, date of 
i nf or me d c o nse nt, scree n fail ure det ails, eli gi bilit y criteria, a n d a n y S A E. A scree n fail ure s essi o n 
m ust be ma de i n t he I W R S (I nteracti ve We b Res p o nse S yste m).  
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. Re-
sa m pli n g is n ot all o we d if t he s u bject has faile d o ne of t he i ncl usi o n criteria or f ulfille d o ne of t he 
e x cl usi o n criteria relate d t o la b orat or y para meters. 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 meters.  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
3 1 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
3 2  of 1 0 5  
 
6. 7  
R u n -i n f ail ures 
R u n -i n fail ures are defi n e d as s u bjects w h o are n ot eli gi ble t o be ra n d o mise d (i.e. has met o ne of t h e 
r u n-i n e x cl usi o n criteria or has n ot met all of t he ra n d o misati o n criteria). C o nse q ue ntl y, t he r u n-i n 
fail ure m ust be re gistere d in t he I W R S a n d a r u n -i n fail ure f or m m ust be c o m plete d i n t he electr o nic 
case re p ort f or m (e C R F) t o get her wit h t he reas o n f or n ot c o nti n ui n g i n t he trial. T he last date of trial 
pr o d uct m ust be ca pt ur e d i n t he e C R F. N o f oll o w -u p visit s h o ul d ta ke place a n d  n o a d diti o nal 
assess me nts are n ee d e d. S A Es a n d n o n -seri o us A Es fr o m r u n-i n f ail ures m ust be rec or de d b y t he 
i n vesti gat or i n t he e C R F. F oll o w-u p of A Es m ust be carrie d o ut acc or di n g t o A p pe n di x 4 . 
 
 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
3 2 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
3 3  of 1 0 5  
 
7  
Tre at me nts  
7. 1  
Tre at me nts a d mi nistere d  
7. 1. 1  
I n vesti g ati o n al me dici n al pr o d ucts 
•  All trial pr o d ucts liste d i n Ta ble  7 -1  are c o nsi d ere d I M P.  
•  Trial pr o d uct m ust o nl y b e use d, if it a p pears clear a n d c ol o urless.  
T a ble  7 -1  
Tri al pr o d ucts pr o vi de d b y N o v o N or dis k A/ S  
Tri al pr o d uct n a me:  
 
I ns uli n glar gi ne 
( La nt us® ) 1 0 0 U/ m L 
(I M P) 
Se ma gl uti de 1. 3 4 
m g/ ml  
(I M P, test pr o d uct) 
I ns uli n as part 
( N o v o Ra pi d ®/ N o v o L o g ®
) 1 0 0 U/ m L 
(I M P, refere nce t hera p y) 
D os a 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 
s ol uti o n f or i nj ecti o n 
 
R o ute of a d mi nistr ati o n :  
 
S u bc uta ne o us  
S u bc uta ne o us  
S u bc uta ne o us  
D osi n g i nstr ucti o ns:  
O nce dail y  
 
F or details,  
see A p pe n di x 8  
O nce -wee kl y  
 
F or details,  
see A p pe n di x 8  
T hree ti mes dail y  
 
F or details,  
see A p pe n di x 8  
P ac k a gi n g  
 
3 m L pre -fille d pe n-
i nj ect or ( S ol o Star® ) 
1. 5 ml pre -fille d 
P D S 2 9 0  pe n -i nj ect or 
3 ml pre -fille d pe n –
i nj ect or ( Fle x P e n® ) 
 
•  S u bjects m ust be trai ne d i n ha n dli n g t he pe n -i nject ors w he n dis pe nse d t he first ti me a n d 
trai ni n g m ust be re peat e d d uri n g t he tri al as i n dicate d per fl o w c hart Secti o n 2 . T he 
i n vesti gat or ma y c h o ose t o o bser ve t he s u bject w h e n a d mi nisteri n g t h e first d ose.  
•  T he i n vesti gat or m ust d oc u me nt t hat directi o ns f or use ( D F U) are gi v e n ver ball y a n d i n 
writi n g t he first ti me trial pr o d uct is dis pe nse d a n d a gai n d uri n g t he trial as nee de d.  
•  T he s u bject s h o ul d be a d vise d t o discar d t he i njecti o n nee dle aft er eac h i njecti o n a n d 
st ore t he pe n wit h o ut a n i njecti o n nee dle attac he d. Nee dles t o be us e d wit h t he trial 
pr o d uct s h o ul d be pr o vi d e d t hr o u g h o ut t he trial as nee de d.  
•  If alter nati ve b ol us i ns uli n is re q uire d per i n vesti gat or’s discreti o n it will be rei m b urse d 
b y N o v o N or dis k A/ S.  
7. 1. 2  
N o n -i n vesti g ati o n al me dici n al pr o d ucts 
After si g ni n g t he i nf or me d c o nse nt, s u bjects s h o ul d c o nti n ue metf or mi n treat me nt. D uri n g r u n -i n 
o p ti misati o n of metf or mi n wit hi n t he d ose ra n ge of ≥ 1 5 0 0 m g t o ≤ 3 0 0 0 m g or ma xi m u m t olerate d 
d ose is all o we d. Fr o m ra n d o misati o n ( V 8) a n d t hr o u g h o ut t he e ntire trial t he d ose of metf or mi n 
s h o ul d be mai ntai ne d at t he sa me le vel a n d wit h sa me fre q ue nc y u nl ess safet y c o ncer n rel ate d t o t he 
bac k gr o u n d me dicati o n arises. F or s u bjects usi n g fi x e d dr u g c o m bi nati o n tr eat me nt wit h metf or mi n 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
3 3 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
3 4  of 1 0 5  
 
pre -trial, tra nsfer t o metf or mi n-o nl y f or m ulati o n s h o ul d be perf or me d at r u n -i n. All l ocall y a v aila ble 
metf or mi n f or m ulati o ns a re all o w e d. 
I n a d diti o n, metf or mi n: 
•  is c o nsi dere d a n o n-i n vesti gati o nal me dici nal pr o d uct ( NI M P) 
•  will n ot be s u p plie d or rei m b urse d b y N o v o N or dis k A/ S, u nless re q uire d acc or di n g t o 
l ocal re g ulati o ns. 
•  s h o ul d be use d i n acc or da nce wit h t he c urre nt a p pr o ve d la bel i n t he i n di vi d ual c o u ntr y.  
•  t he d ose m ust n ot e x cee d t he ma xi m u m a p pr o ve d d ose i n t he i n di vi d ual c o u ntr y. 
7. 1. 3  
A u xili ar y s u p plies  
•   T he f oll o wi n g a u xiliar y s u p plies will be pr o vi de d b y N o v o N or dis k:  
o  Ne e dles f or t he pe n -i nject ors 
o  D F U f or t he pe n -i nject ors  
o  B G meter a n d relate d a u xiliaries  
•  S u bjects will be i nstr ucte d i n h o w t o use t he B G -meter a n d t he i nstr ucti o ns will be 
re peat e d d uri n g t he trial as nee de d.  
•  O nl y nee dles pr o vi de 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.  
 
 
7. 2  
D ose m o dific ati o n  
D ose m o dificati o n of I M Ps is perf or me d i n relati o n t o i n di vi d ualise d S M P G, o verall H b A 1c g o als, 
l ocal g ui d eli nes a n d i n acc or da nce wit h t he trial r e q uire me nts liste d i n A p pe n di x 8 . S u bjects 
ra n d o mise d t o se ma gl uti de s h o ul d f oll o w t he rec o m me n de d d ose escalati o n re gi me n i n or der t o 
l o wer t he ris k of gastr oi ntesti nal A Es. Please see f urt her details i n A p pe n di x 8 . 
7. 3  
Met h o d of tre at me nt assi g n me nt  
All s u bjects will be ce ntr all y ra n d o mise d usi n g a n I W R S a n d assi g n e d t o t he ne xt a vaila ble 
treat me nt acc or di n g t o ra n d o misati o n sc he d ule. Trial pr o d uct will be dis pe nse d at t he trial visits 
s u m marise d i n t he fl o wc hart.  
At scree ni n g, eac h s u bject will be assi g ne d a u ni q ue 6 -di git s u bject n u m ber w hic h will re mai n t he 
sa me t hr o u g h o ut t he trial. Eac h site is assi g n e d a 3-di git n u m ber a n d all s u bject n u m bers will start 
wit h t he site n u m ber.  
7. 4  
Bli n di n g  
T his is a n o pe n -la bel trial.  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
3 4 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
3 5  of 1 0 5  
 
7. 5  
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 e nr olle d i n t he trial ma y recei ve trial pr o d uct a n d o nl y a ut h orise d site staff ma y 
s u p pl y or ad mi nister trial pr o d uct.   
T a ble  7 -2  
Tri al pr o d uct st or a ge c o n diti o ns  
Tri al pr o d uct n a me  
St o r a ge c o n diti o ns  
( n ot-i n-use)  
I n-use c o n diti o ns  
I n-use ti me a 
Se ma gl uti de 1. 3 4 m g/ ml  
St ore i n refri gerat or 
( 2° C-8° C)  
 
D o n ot freeze  
 
Pr otect fr o m li g ht  
I n-use c o n diti o ns will be 
a vaila ble o n t he trial pr o d uct 
la bel. 
I n-use c o n diti o ns will be 
a vaila ble o n t he trial 
pr o d uct la bel.  
I ns uli n as part 1 0 0 U/ ml 
I ns uli n glar gi ne 1 0 0 U/ ml 
 
a F or se ma gl uti de, i n -use ti me starts w he n t he pr o d uct is ta ke n o ut of t he refri gerat or i n t he s u bject’s 
h o me. F or I As p a n d I Gl ar, i n -use ti me starts w he n t he pr o d uct is ta ke n o ut of t he refri gerat or i n t he 
s u bject’s h o me f or start of use or f or carr yi n g as a s pare.  
•  Eac h trial site will be s u p plie d wit h s ufficie nt trial pr o d ucts f or t he trial o n a n o n -g oi n g 
basis c o ntr olle d b y t h e I W R S. Trial pr o d uct will be distri b ute d t o t he trial sites 
acc or di n g t o scree ni n g, r u n -i n a n d ra n d o misati o n n u m bers. 
•  T he i n vesti g at or m ust c o nfir m t hat a p pr o priat e 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 a n y discre pa n cies are 
re p orte d a n d res ol ve d b ef ore use of t he trial pr o d u cts. 
•  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 a cc or da nce wit h t he la belle d st ora ge c o n diti o ns wit h access li mite d 
t o t he i n vesti gat or a n d a ut h orise 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 
store d o utsi de s pecifie d c o n diti o ns. A d diti o nal details re gar di n g ha n dli n g of te m perat ur e 
de viati o ns ca n be f o u n d i n t he trial materials ma n u al ( T M M).  
•  Trial pr o d uct t hat has b ee n st ore d i m pr o perl y m ust n ot be dis pe nse d t o a n y s u bject 
bef ore it has b ee n e v al uat e d a n d a p pr o ve d f or f urt h er use b y N o v o N or dis k.  
•  S u bjects m ust ret ur n all use d, partl y use d a n d u n us e d trial pr o d ucts as i nstr u cte d b y t he 
i n vesti gat or.  
•  T he i n vesti gat or is res p o nsi ble f or dr u g acc o u nta bilit y a n d rec or d mai nte na nce (i.e. 
recei pt, acc o unta bilit y a n d fi nal dis p ositi o n rec or ds).  
•  Dr u g acc o u nta bilit y s h o ul d be perf or m e d i n t he I W R S b y re gisteri n g p e n -i nject ors as 
ret ur ne d eit her as use d/ p artl y us e d, u n use d or as l ost.  
•  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 wi ll be d o ne 
acc or di n g t o l ocal pr oce d ures after acc o u nta bilit y is fi nalise d b y t he site a n d rec o ncile d 
b y t he m o nit or.  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
3 5 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
3 6  of 1 0 5  
 
•  Destr ucti o n of trial pr o d u cts m ust be d oc u me nte d i n t he I W R S.  
•  All ret ur ne d, e x pire d or da ma ge d trial pr o d u cts (f or tec h nical c o m plai nt s a m ples see 
A p pe n di x 6 ) m ust be st ore d se paratel y fr o m n o n-all ocate d trial pr o d ucts. N o 
te m 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 tri al site.  
7. 6  
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 ns ur e s u bject c o m plia nce. T h e i n vesti gat or will at eac h c o ntact ( visit or p h o ne 
c o ntact) ass ess t he s u bject’s c o m plia nce b y e v al uati n g t he gl ycae mic c o ntr ol a n d a d here nce t o t he 
visit sc he d ule a n d c o m pl eti o n of t he s u bject’s diar y, i ncl u di n g t he S M P G pr of iles, d ose a n d 
h y p o gl ycae mia re p orti n g. I n a d diti o n, s u bject c o m plia nce will be assess e d b y m o nit ori n g of dr u g 
acc o u nta bilit y. If a s u bject is f o u n d t o be n o n -c o m plia nt, t he i n vesti gat or will re mi n d t he s u bject of 
t he i m p orta nce of f oll o wi n g t he i nstr ucti ons gi ve n i ncl u di n g ta ki n g t he trial pr o d ucts as pres cri be d.  
7. 7  
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(s) t hat t he s u bject is recei vi n g at t he ti me of scree ni n g  
or recei ves d uri n g t he tri al m ust be rec or de d al o n g wit h:  
•  Tra de n a me o r ge n eric 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 dates or c o nti n uati o n  
•  O nl y a p plica ble f or a nti -dia betic me dicati o n: start date of c urre nt d ose a n d t otal dail y 
d ose  
 
C ha n ges i n c o nc o mita nt me dicati o n m ust be rec or de d at eac h visi t. If a c h a n ge is d u e t o a n 
A E/ S A E , t he n t his m ust be re p ort e d acc or di n g t o Secti o n 9. 2 .   
At t he r u n -i n visit ( Visit 2), pre-tri al basal i ns uli n a n d O A D tr eat me nt (e x ce pt f or metf or mi n) m ust 
be disc o nti n ue d a n d a st o p date rec or de d i n t he e C R F.  
7. 8  
Resc ue me dic ati o n  
It is i m p orta nt f or tri al i nte grit y t hat o nl y s u bjects w h o act uall y nee d treat m e nt i nte nsificati o n 
acc or di n g t o Secti o n 8. 2  are start e d o n res c ue me dicati o n. Resc ue me dicati o n s h o ul d be prescri b e d 
at t he i n vesti gat or’s discreti o n  as a d d-o n t o ra n d o mise d treat me nt a n d acc or di n g t o A D A/ E A S D 
treat me nt g ui deli nes.3, 1 4 
 
S u bjects w h o are starte d o n resc ue m e dicati o n s h o ul d c o nti n ue t o f oll o w t he pr ot oc ol -s pecifie d visit 
sc he d ule.  
 
  Pr ot oc ol  v 3. 0 |
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3 6 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
3 7  of 1 0 5  
 
Resc ue me dicati o n (i nitiati o n of ne w a nti dia betic me dicati o n) a n d a n y c ha n ges h eret o m ust be 
rec or de d o n t he c o n c o mita nt me dicati o n f or m i n t he e C R F.  
C h oice of res c ue me dicati o n, at t he discreti o n of t he i n vesti gat or, c o ul d i ncl u de t he a d diti o n of 
t hiaz oli di ne di o nes, s o di u m– gl uc ose c otra ns p ort er i n hi bit ors, me gliti ni des, or al p ha -gl uc osi das e 
i n hi bit ors. A d diti o n of s ulf o n yl ur eas, ot her i n creti n-base d t hera pies (e. g. G L P -1 R A or D D P -4 
i n hi bit ors) or pra n dial i ns uli n are pr o hi bite d. 
Resc ue me dicati o n is c o nsi dere d NI M P a n d will n ot be pr o vi de d b y N o v o N or dis k A/ S.  
7. 9  
Tre at me nt after t he e n d of t he 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 tra nsferre d t o a s uita ble mar kete d pr o d uct 
at t he discreti o n of t he i n vesti gat or. T h e l o n g half -life of se ma gl uti de m ust be ta ke n i nt o 
c o nsi derati o n w he n s electi n g a n ti-dia betic tr eat me nt after disc o nti n uati o n of trial pr o d uct.  
 
 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
3 7 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
3 8  of 1 0 5  
 
8  
Disc o nti n u ati o n/ Wit h dr a w al criteri a  
All eff orts s h o ul d be ma d e t o kee p s u bjects o n trial pr o d ucts.  
T he s u bject ma y be disc o nti n ue d at a n y ti me d uri n g t he trial at t he discreti o n of t he i n ves ti gat or f or 
safet y, be h a vi o ural, c o m plia nce or a d mi nistrati ve reas o ns.  
Eff orts m ust be ma de t o ha ve t he ra n d o mise d s u bjects, w h o disc o nti n ue trial pr o d uct, atte n d visit 
3 6 A as s o o n as p ossi ble ( prefera bl y t he sa m e da y)  t o u n derta ke pr oce d ures, w hic h are si milar t o 
t h ose at visit 3 6. P h o ne c o ntact 3 7 A s h o ul d be sc h e d ule d 5 wee ks after t he last date o n trial pr o d uct.  
If disc o nti n uati o n of trial pr o d uct is deci de d d uri n g a s c he d ule d visit after ra n d o misati o n, t he visit 
will be c o n verte d i nt o a Visit 3 6 A a n d trial pr oce d ures m ust be perf or me d acc or di n gl y. Ra n d o mise d 
su bjects s h o ul d c o nti n ue wit h t he ori gi nall y sc h e d ule d site c o ntacts aft er P h o ne c o ntact 3 7 A a n d u p 
t o a n d i ncl u di n g P h o ne c o ntact 3 7. If necessar y, i n or der t o ret ai n t he s u bject i n t he trial, site visits 
ca n be re place d b y p h o ne c o ntacts aft er P h o ne c o ntact 3 7 A. H o we v er, all atte m pts s h o ul d be ma de 
t o e ns ure t hat Visit 3 6 is perf or me d as a site visit a n d i ncl u des all pla n ne d assess me nts. 
Ra n d o mise d s u bjects s h o ul d sta y i n t he trial irres p ecti ve of  lac k of a d h ere n ce t o ra n d o mise d 
treat me nt, lac k of a d here nce t o visit sc he d ule, missi n g assess me nts or disc o nti n uati o n of trial 
pr o d uct f or a n y reas o n.  
S u bjects m ust be e d ucate d a b o ut t he c o nti n ue d sci e ntific i m p orta nce of t heir data, e v e n if t he y 
disc o n ti n ue trial pr o d uct. 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.  
8. 1  
Disc o nti n u ati o n of tri al tre at me nt  
 T he s u bject m ust be disc o nti n ue d fr o m trial pr o d u ct, if t he f oll o wi n g a p plies:  
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 partici pati o n i n a n ot her 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. 
5.  C o nfir mati o n of ac ute p a ncreatitis ( o nl y a p plica bl e f or s u bje cts treate d wit h se ma gl uti de)  
 
See t he fl o wc h art Secti o n 2  f or data t o be c ollecte d at t he ti me of treat me nt disc o nti n uati o n a n d 
f oll o w-u p a n d f or a n y f urt her e val uati o ns t hat nee d t o be c o m plete d.  
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 C R F, an d fi n al dr u g acc o u nta bilit y m ust be perf or m e d.  A treat me nt disc o nti n uati o n 
sessi o n m ust be ma de i n t he I W R S. 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
3 8 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
3 9  of 1 0 5  
 
U p o n disc o nti n uati o n of trial pr o d uct(s), t he ra n d o mise d s u bject s h o ul d be s witc he d t o a s uita ble 
mar kete d pr o d u ct at t he discreti o n of t he i n vest i gat or, w hile ta ki n g i nt o c o nsi derati o n t he l o n g h alf-
life of se ma gl uti de. It is t he i n vesti gat or’s res p o nsi bilit y t o e ns ure o pti mal gl ycae mic c o ntr ol f or t he 
s u bjects w h o disc o nti n ue trial pr o d uct. 
8. 1. 1  
Tre at me nt disc o nti n u ati o n i n c ase of r a n d o mis ati o n i n vi o l ati o n of t he eli gi bilit y 
criteri a  
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/r u n -i n e x cl usi o n/ra n d o misati 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 a 
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 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 uire me nts. If t here is n o safet y c o ncer ns, trial treat me nt ma y be c o nti n ue d or res u me d at 
t he discreti o n of t he i n vesti gat or after a gree me nt wit h t he s p o ns or's gl o bal me dical e x pert. 
8. 1. 2  
Te m p or a r y disc o nti n u ati o n of tri al tre at me nt  
If ac ut e pa ncreatitis is s us pecte d, te m p or ar y treat me nt disc o nti n uati o n of se ma gl uti de s h o ul d 
pr o m ptl y be i nitiate d at t he discreti o n of t he i n vesti gat or. If ac ut e pa ncreatitis is c o nfir me d, trial 
pr o d uct s h o ul d n ot be restarte d.  
8. 2  
Resc ue criteri a   
S u bjects wit h persiste nt a n d u nacce pta ble h y per gl ycae mia s h o ul d be offere d treat me nt 
i nte nsificati o n. T o all o w ti me f or d ose escalati o n t o ma xi m u m d ose a n d t o o bser ve t he e x pecte d 
effect of treat me nt o n gl ycae mic p ara met ers, res c u e criteri a will be a p plie d at wee k 8 a n d o n war ds.  
6.  Pre -brea kfast S M P G val ues ta ke n o n t hree c o nsec uti ve da ys or if a n y of t h e F P G s a m ples 
a nal ys e d b y t he ce ntral la b orat or y e x cee d t h e li mit of:  
•  1 5. 0 m m ol/ L ( 2 7 0 m g/ d L) wee k 8 t o e n d of wee k 1 2  
•  1 3. 3 m m ol/ L ( 2 4 0 m g/ d L) fr o m wee k 1 3 t o e n d of treat me nt,  
a n d  
•  if n o treata ble i nterc urre nt ca use f or t h e h y per gl yc ae mia (e. g. n o n-c o m plia nce) has b ee n 
i de ntifie d.  
I n s u c h cas e, t he s u bject m ust be calle d f or a c o nfir mat or y F P G meas ure me nt as s o o n as 
p ossi ble. A c o nfir mat or y F P G m ust be o btai ne d a n d a nal ys e d b y t he c e ntral la b orat or y. If 
t his F P G e x cee ds t he li mits descri be d a b o ve s u bj ect f ulfils t he resc u e criteri o n. 
7.  H b A 1c (at ce ntral la b orat or y) > 8. 5 % ( > 6 9. 4 m m ol/ m ol), fr o m wee k 2 6 t o e n d of treat me nt. 
 
I n case o n e of t he criteria a b o ve is f ulfille d, i ncrease i n the d ose of t he I M P(s) (I Gl ar U 1 0 0 a n d/ or 
I As p/s e ma gl uti de) s h o ul d be c o nsi dere d as t he first c h oice i n acc or da n ce wit h A p pe n di x 8  a n d will 
n ot be c o nsi dere d as res c ue me dicati o n.  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
3 9 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
4 0  of 1 0 5  
 
I n case f urt her d os e i ncrease of t he I M P(s) is n ot p ossi ble d ue t o safet y c o n cer n or u n acce pta ble 
i nt olera bilit y, s u bject s h o ul d be starte d o n res c ue me dicati o n. Please refer t o Secti o n 7. 8  f or f urt her 
details.  
8. 3  
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 nse nt, t he i n vesti gat or m ust as k t he s u bject if he/she is willi n g, as s o o n as 
p ossi ble, t o ha ve assess m e nt perf or m e d acc or di n g t o  visit 3 6 A. See t he fl o wc hart f or data t o be 
c ollecte d.  
If a s u bject h as alrea d y pre mat urel y disc o nti n ue d fr o m trial pr o d uct a n d pre vi o usl y atte n d e d V 3 6 A 
a n d P 3 7 A, n o f urt her vis its s h o ul d be atte n de d. 
Fi nal dr u g acc o u nta bilit y m ust be perf or me d e ve n if t he s u bject is n ot a ble t o c o me t o t he trial site.  
A treat me nt disc o nti n uati o n sessi o n m ust be ma de i n t he I W R S.  
If a s u bject wit h dra ws fr o m t he trial, he/s he ma y re q uest destr ucti o n of a n y sa m ples ta ke n a n d n ot 
teste d, a n d t he i n vesti gat or m ust d oc u me nt t his i n t he me dical rec or d. 
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.  
Alt h o u g h a s u bjec t 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 C R F. 
8. 3. 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.  
8. 4  
L ost t o f oll o w -u p  
A s u bject will be c o nsi dere d l ost t o f oll o w -u p if he or s he re peat e dl y fails t o ret ur n f or sc he d ule d 
visits a n d is u na ble t o be c o ntacte d b y t he tri al 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 trial site f or a re q uire d visit:  
•  T he site m ust atte m pt t o c o ntact t he s u bject a n d resc he d ule t he misse d visit as s o o n as 
p ossi ble a n d c o u nsel t he s u bject o n t he i m p orta nce of mai ntai ni n g t h e assi g ne d visit 
sc he d ule a n d ascertai n w het her or n ot t he s u bject wis hes t o a n d/ or s h o ul d c o nti n ue i n 
t he trial. 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
4 0 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
4 1  of 1 0 5  
 
•  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 m ust ma ke e ver y eff ort t o 
re gai n c o ntact wit h t he s u bject ( w here p ossi ble, at least t hree tele p h o ne calls a n d, if 
necessar y, a certifie d lett er t o t he s u bject's last k n o w n maili n g a d dress or l ocal 
e q ui vale nt met h o ds). If atte m pts ha ve faile d, fa mil y me m bers or ot her c o ntacts 
c o nse nte d b y t he s u bject ca n be c o ntacte d f or alter nati ve c o ntact det ails. T hese c o ntact 
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 be u nreac ha bl e, he/s he will be c o nsi dere d t o ha ve 
wit h dra w n fr o m t he tri al wit h a pri mar y reas o n of l ost t o 'f oll o w -u p'.  
 
 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
4 1 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
4 2  of 1 0 5  
 
9  
Tri al assess me nts a n d pr oce d ures  
•  Trial pr oce d ures a n d t h eir ti mi n g are s u m marise d i n t he fl o wc hart, Secti o n 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 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 eli gi bilit y 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 b jects scree ne d 
a n d t o c o nfir m eli gi bilit y or rec or d reas o n f or s cree n fail ure, as a p plica bl e.  
•  At scree ni n g, s u bjects will be pr o vi de d wit h a car d stati n g t hat t he y are partici pati n g i n a 
trial a n d gi vi n g c o nt act d etails of rele va nt trial site staff.  
•  A d her e 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.  
•  T he i n vesti gat or s h o ul d i nf or m t he s u bjects’ pri m ar y p h ysicia n a b o ut t he p atie nts’ 
partici pati o n i n t he trial if t he s u bject ha s a pri mar y p h ysicia n a n d if t he s u bject a grees 
t o t he pri mar y p h ysi cia n bei n g i nf or me d.  
•  S u bjects s h o ul d be as ke d t o pr o vi de c o ntact i nf or mati o n f or pers o ns, e. g. relati ves, 
pri mar y care pr o vi d er etc., w h o m i n vesti gat or ca n c o ntact i n cas e of iss ues w he n tr yi n g 
t o c o ntact t he s u bject d uri n g t he trial.  
•  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 patie nt o n t he i m p orta nce of mai ntai ni n g t he assi g ne d visit 
sc he d ule. 
•  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 C R F m ust be 
a vaila ble a n d will us uall y be t h e s u bject’s me dical rec or ds. A d diti o nal rec or di n g t o be 
c o nsi dere d s o ur ce d ata i n cl u des, b ut is n ot li mite d t o la b orat or y re p orts, diar y rec or di n gs 
a n d P R O q uesti o n naires .  
•  Re vie w of c o m plete d di aries, P R O q uesti o n naires, la b orat or y re p orts, e ye a n d p h ysic al 
e x a mi nati o ns etc. m ust be d oc u me nte d eit her o n t he d oc u me nts or i n t he s u bject's 
me dical rec or ds. If clarifi cati o n of e ntries or discre pa ncies i n t he diar y or P R O 
q ues ti o n naires is nee d e d, t he s u bject m ust be q uesti o ne d a n d a c o n cl usi o n ma de i n t he 
s u bject's s o ur ce d o c u me nts. Care m ust be ta ke n n ot t o bias t he s u bject.  
•  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 pe n di x 2  f or f urt her 
details o n la b orat or y sa m ples.  
9. 1  
Effic ac y assess me nts  
Pla n ne d ti me p oi nts f or all efficac y assess me nts are pr o vi de d i n t he fl o w c hart Secti o n 2    
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
4 2 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
4 3  of 1 0 5  
 
9. 1. 1  
Self -me as ure d pl as m a gl uc ose  
At Visit 2, s u bjects will be pr o vi de d wit h a B G meter i ncl u di n g  a u xiliaries as well as i nstr ucti o ns 
f or use, if nee de d. T h e s u bjects will be i nstr ucte d i n h o w t o use t he de vice a n d t he i nstr ucti o n 
s h o ul d be re peate d as necessar y d uri n g t he trial. 
T he B G m eters use test stri ps cali brate d t o plas ma val ues. T heref ore, all meas ure me nts perf or me d 
wit h ca pillar y bl o o d are a ut o maticall y cali brate d t o plas ma e q ui vale nt gl uc ose val ues, w hic h will be 
s h o w n o n t he dis pla y.  
T he B G m eter pr o vi d e d b y N o v o N or di s k s h o ul d be use d f or t h e meas ure me nts re q uire d i n t he 
pr ot oc ol, as descri be d i n Secti o n 2  a n d A p pe n di x 8 . 
S u bjects s h o ul d be i nstr ucte d i n h o w t o rec or d t he res ults of t he S M P G val ues i n t he diaries. T he 
rec or d of eac h S M P G val ue s h o ul d i ncl u de date a n d val ue. Rele va nt dat a fr o m t he diar y as specifie d 
i n A p pe n di x 8  m ust be tra nscri be d i nt o t he C R F d uri n g or f oll o wi n g t he c o ntact. If o btai ne d vi a 
p h o ne a n d a discre pa n c y is later detecte d, t h e val u es i n t he C R F m ust be c orrect e d. 
Occasi o nal re vie w b y t h e i n vesti gat or of t h e B G meter val ues st or e d i n t he me m or y of t he B G meter 
a n d c orrect r e p orti n g of t hese i n t he diar y is a d vis e d i n or der t o e ns ure a d e q uac y of t he d ata re p orte d 
i n t he trial data base.  
O nce d ail y pre -bre a kf ast S M P G  
All s u bjects i n t he trial s h o ul d perf or m pre -brea kfast S M P G e ver y da y fr o m Visit 2 t o Visit 3 6. 
S M P G val ues meas ure d bef ore brea kfast s h o ul d b e perf or me d i n a fasti n g c o n diti o n.  
 
4 -p oi nt S M P G pr ofile  
S u bjects ra n d o m ise d t o I As p s h o ul d perf or m 4-p oi nt pr ofiles e ver y d a y aft er ra n d o misati o n. T he 
meas ure me nts s h o ul d be perf or me d at t he f oll o wi n g ti me p oi nts:  
•  Bef ore brea kfast  
•  Bef ore l u nc h  
•  Bef ore mai n e v e ni n g me al ( di n ner)  
•  At be dti me  
S M P G val ues meas ure d bef ore brea kfast , l u nc h, mai n e ve ni n g meal, a n d at be dti me s h o ul d be 
perf or me d b ef ore a n y i nj ecti o n of b ol us i ns uli n a n d j ust bef ore t he start of t he meal ( brea kfast, 
l u nc h or mai n e ve ni n g m eal). S M P G val ues meas ure d bef ore brea kfast s h o ul d be perf or m e d i n a 
fasti n g c o n diti o n. T he 4-p oi nt pr ofile is part of t he 7 -p oi nt pr ofiles w hic h are meas ure d pri or t o 
selecte d site visits. 
 
 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
4 3 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
4 4  of 1 0 5  
 
7 -p oi nt S M P G pr ofile  
All s u bjects will be i nstr ucte d t o perf or m 7 -p oi nt S M P G pr ofiles i n t he wee k pri or t o V 8, V 2 4 a n d 
V 3 6 acc or di n g t o t he ti me p oi nts liste d bel o w:  
•  Bef ore brea kfast  
•  9 0 mi n utes  after t he start of brea kfast  
•  Bef ore l u nc h  
•  9 0 mi n utes after t he start of l u nc h  
•  Bef ore mai n e v e ni n g me al ( di n ner)  
•  9 0 mi n utes after t he start of mai n e ve ni n g meal ( di n ner)  
•  At be dti me  
S M P G val ues meas ure d bef o re brea kfast, l u nc h, mai n e ve ni n g meal a n d at be dti me s h o ul d be 
perf or me d b ef ore a n y i ns uli n i njecti o n a n d j ust bef ore t he start of t h e meal ( brea kfast, l u nc h or mai n 
e ve ni n g meal). S M P G val ues meas ure d b ef ore brea kfast s h o ul d be perf or m e d i n a fasti n g c o n diti o n. 
T he meas ur e me nts will be use d t o e val uat e t he gl u c ose pr ofile.  
9. 1. 2  
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 , m ust be c o n d ucte d i n 
acc or da nce wit h t he fl o wc hart a n d t he l a b orat or y ma n ual.  
9. 1. 3  
P ati e nt re p orte d o utc o mes  
T he f oll o wi n g P R O q uesti o n naires will be use d i n t he trial:  
•  3 6 -ite m S h ort F or m Healt h S ur ve y v ersi o n 2 ( S F -3 6 v 2 ™)  
•  Treat me nt r elate d i m pact meas ure f or dia bet es ( T RI M -D)  
•  Dia betes Q ualit y of Lif e Cli nical Trial Q uesti o n naire ( D Q L C T Q -R)  
T he q uesti o n naires s h o ul d be c o m plete d b y t he s u bject as s pecifi e d i n t he fl o wc hart (see Secti o n 2 ). 
It ta k es a p pr o xi matel y 2 0 mi n utes t o c o m plete t he q uesti o n naires. S u bjects s h o ul d be gi ve n t he 
o p p ort u nit y t o c o m plete t he q uesti o n naires b y t he msel ves wit h o ut i nterr u pti o n. All res ults fr o m t he 
P R Os m ust be tra nsferre d i nt o t he e C R F.  
S F -3 6 v 2 ™ 
T he S F -3 6 v 2 ™ q uesti o n naire (sta n d ar d versi o n) will be use d t o assess s u bjects o verall H R Q o L a n d 
ca n als o be us e d t o esti mate q ualit y a dj uste d life years w hic h is us e d i n c ost effecti ve ness 
calc ulati o ns. T his q uesti o n naire c o ntai ns 3 6 ite ms a n d meas ures t he i n di vi d ual o verall H R Q o L o n 8 
d o mai ns; p h ysical f u n cti o ni n g, r ole f u ncti o ni n g, b o d y pai n, ge neral healt h, vitalit y, s o cial 
f u ncti o ni n g, r ol e e m oti o nal a n d me ntal healt h.  
T RI M -D  
T he T RI M -D q uesti o n naire will be use d t o assess t he treat me nt i m pact a n d b ur de n f or s u bjects. T he 
q uesti o n naire c o ntai ns 2 8 ite ms a n d pr o vi des a n o verall sc ore ( T RI M -D sc ore) as well as a s c ore of 
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C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
4 5  of 1 0 5  
 
eac h of t h e 5 d o mai ns; Treat me nt b ur d e n, Dail y life, Dia bet es ma na ge me nt, C o m plia nce a n d 
Ps yc h ol o gical he alt h.  
D Q L C T Q -R  
T he D Q L C T Q -R q uesti o n naire will be use d t o ass ess s u bjects’ H R Q o L. T h e q uesti o n naire c o ntai ns 
5 7 ite ms a n d meas ures a n d pr o vi de sc ores f or eac h of t he 8 i ncl u de d d o mai ns; P h ysic al F u ncti o n, 
E ner g y/ Fati g u e, Healt h Distress, Me ntal Healt h, Satisfacti o n, Treat me nt S atisfacti o n, Treat me nt 
Fle xi bilit y a n d Fre q u e nc y of S y m pt o ms.  
9. 1. 4  
B o d y me as ure me nts  
•  Hei g ht is meas ure d wit h o ut s h oes i n ce nti metres or i nc hes a n d rec or de d t o nearest ½ c m 
or ¼i nc h . 
•  B o d y wei g ht s h o ul d be meas ure d wit h o ut s h oes a n d o nl y weari n g li g ht cl ot hi n g a n d 
rec or de d i n t he e C R F i n kil o gra m or p o u n d [ k g/l b], wit h a precisi o n of 1/ 1 0 u nit, (e. g. 
4 5. 2 k g / 1 3 7. 2 l b).  B MI will be calc ulate d i n t he e C R F.  
•  T he waist circ u mfere nce is defi ne d as t he mi ni mal a b d o mi nal circ u mf ere n ce l ocate d 
mi d wa y b et wee n t h e l o w er ri b mar gi n a n d t h e iliac crest a n d will be meas ure d usi n g a 
n o n -stretc ha ble m eas uri n g ta pe. T he meas ure me nt of waist circ u mf ere n ce s h o ul d be 
perf or me d a n d rec or de d i n t he e C R F t o t he nearest ½ c m or ¼i nc h usi n g t h e sa me 
meas uri n g ta pe t hr o u g h o ut t he trial. T he waist cir c u mfere nce s h o ul d be m eas ure d i n a 
sta n di n g p ositi o n wit h a n e m pt y bla d der a n d weari n g li g ht cl ot hi n g wit h accessi ble 
waist. T he s u bject s h o ul d be sta n di n g wit h a r ms d o w n t heir si de a n d feet t o get h er. T he 
ta pe s h o ul d t o uc h t he s ki n b ut n ot c o m press s oft tiss ue. T he s u bject s h o ul d be as ke d t o 
breat he n or mall y a n d t he meas ure me nt s h o ul d be t a ke n w he n t h e s u bject is breat hi n g 
o ut ge ntl y.  
9. 2  
A d verse e v e nts  
T he defi niti o n s of A Es a n d S A Es ca n be f o u n d i n A p pe n di x 4 . 
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.  
9. 2. 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 will be c ollecte d fr o m after r u n -i n ( V 2) a n d u ntil t he f oll o w-u p visit, at t he ti me p oi nts 
s pecifie d i n t he fl o wc hart ( Secti o n 2 ). Me dical o cc urre nces wit h o nset bet wee n i nf or me d c o nse nt 
a n d da y of r u n -i n or c o n diti o ns detecte d as part of scree ni n g pr oce d ures nee d t o be rec or de d, if 
a p plica ble, o n t he me dical hist or y/ c o nc o mita nt ill ness f or m i n t he C R F ( n ot t he A E C R F).  
All S A Es will be rec or de d a n d re p ort e d t o N o v o N or dis k or desi g nee wit hi n 2 4 h o urs, as i n dicate d 
i n A p pe n di x 4 . T he i n vesti gat or m ust s u b mit a n y u p date d S A E data t o N o v o N or dis k wit hi n 2 4 
h o urs of it bei n g a vaila bl e.  
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C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
4 6  of 1 0 5  
 
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 i n vesti gati o nal trial pr o d uct  or trial partici p ati 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.  
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 4 . 
Ti meli nes f or re p orti n g of A Es,  are liste d i n Fi g ure  9 -1 . 
S o me A Es re q uire a d diti o nal data c ollecti o n via a s pecific e v e nt f or m. T his i ncl u des me dicati o n 
err ors o bs er ve d d uri n g t h e trial. T he rele va nt s pe cific e ve nts are liste d i n Ta ble  9 -1  a n d t he 
re p orti n g ti meli nes i n Fi g ure  9 -1 . 
A E i d e ntifi e d
Is t h e e v e nt t o b e 
a dj u dic at e d ?
A E f or m  ≤  2 4 h o urs
SIF ≤ 5 c al e n d ar d a ys
Si g n off  ≤ 7 c al e n d ar d a ys
Is t h e A E s eri o us or 
n o n-s eri o us ?
A E f or m
Is t h e A E list e d as 
r e q uiri n g a S p ecific E v e nt 
F or m t o b e c o m plet e d ?
A dj u dic ati o n f or m
 ≤ 1 4 c al e n d ar d a ys
S o urc e d at a  ≤  4 w e e ks
N o n-s eri o us
S eri o us
Y es
N o a d diti o n al acti o n
N o
S p ecific e ve nt f or m
F or S A E:
 ≤ 1 4 c al e n d ar d a ys
Y es
Ti m eli n es  ar e fr o m t h e a war e n ess of a n A E.
Q u eri es a n d f oll o w- u p  r e q u ests t o b e r es ol v e d ≤ 1 4 c al e n d ar d a ys.
A E : A dv ers e E v e nts , S AE : S eri o us A d v ers e E v e nts , SI F: S af et y I nf or mati o n F or m
N o a d diti o n al acti o n
N o
 
Fi g ure  9 -1  
Decisi o n tree f or deter mi ni n g t he e ve nt t y pe a n d t he res pecti ve f or ms t o 
c o m plete wit h ass oci ate d ti meli nes  
 
 
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Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
4 7  of 1 0 5  
 
T a ble  9 -1  
A Es re q uiri n g a d diti o n al d at a c ollecti o n ( vi a s pecific e ve nt f or m) a n d e ve nts f or 
a dj u dic ati o n  
E ve nt t y pe   
Descri pti o n  
A E 
re q uiri n g 
a d diti o n al 
e ve nt f or m 
E ve nt f or 
a dj u dic ati o n  
(9. 2. 1. 1 ) 
A dj u dic ati o n 
o utc o me  
Ac ute 
gall bla d der 
disease  
E ve nts of s y m pt o matic ac ute gall bla d der 
disease (i ncl u di n g gallst o nes a n d 
c h olec ystitis)  
X  
 
 
Deat h  
All -ca use deat h  
 
X  
•  
Deat h 
ass ociate d 
wit h se vere 
h y p o gl ycae mic 
e pis o de 
( A D A),  
•  
Deat h 
ass ociate d 
wit h ac ute 
pa ncreatitis  
•  
Deat h n ot 
ass ociate d 
wit h se vere 
h y p o gl ycae mia 
or ac ute 
pa ncreatitis  
Se vere 
h y p o gl ycae mic 
e pis o de ( A D A)  
A n e pis o de re q uiri n g assista nc e of a n ot her 
pers o n t o acti vel y a d mi nister c ar b o h y drate, 
gl uca g o n, or ta ke ot her c orrecti ve acti o ns. 
Plas ma gl uc ose ( P G) c o nce ntr at i o ns ma y n ot 
be a vaila ble d uri n g a n e ve nt, b ut ne ur ol o gical 
rec o ver y f oll o wi n g t he ret ur n of plas ma 
gl uc ose t o n or mal is c o nsi dere d s ufficie nt 
e vi de nce t hat t he e ve nt was i n d uce d b y a l o w 
plas ma gl uc ose c o nce ntrati o n  
 
X  
Se vere 
h y p o gl ycae mic 
e pis o de ( A D A)  
Mali g na nt 
ne o plas m  
Mali g na nt ne o plas m b y hist o p at h ol o g y or 
ot her  
s u bsta ntial cli nical e vi de nce 
X  
 
 
Ac ute 
pa ncreatitis  
Dia g n osis re q uires at least t w o of t he 
f oll o wi n g: 
 1) a b d o mi nal pai n c o nsiste nt wit h ac ute 
pa ncreatitis (ac ute o nset of a p ersiste nt, 
se vere, e pi gastric pai n ofte n ra diati n g t o t he 
bac k)  
 2) ser u m li pase (a n d/ or a m ylase) at least 
t hree ti mes greater t ha n t he u p per li mit of 
n or mal  
 3) c haracteristic fi n di n gs of ac ute 
pa ncreatitis o n i ma gi n g.  
X  
X  
Ac ute pa ncreatitis  
(acc or di n g t o 
Atla nta 
classificati o n 1 5) 
Dia b etic 
reti n o pat h y 
Ne w o nset or w orse ni n g of dia betic 
reti n o pat h y 
X  
 
 
Me dicati o n 
err or 
A d mi nistrati o n of wr o n g dr u g.  
X  
 
 
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C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
4 8  of 1 0 5  
 
Wr o n g r o ute, s uc h as i ntra m us c ular i nstea d 
of  
s.c. or acci de ntal 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 w here cli nical 
c o nse q ue nces f or t he patie nt were li kel y t o 
ha p pe n, alt h o u g h t he y di d n ot necessaril y 
occ ur.  I nte nti o nal dr u g err ors relate d t o trial 
pr o d uct are mis use/a b use a n d s h o ul d be 
re p orte d as A Es a n d n ot as me dicati o n err ors. 
9. 2. 1. 1  
E ve nts f or a dj u dic ati o n  
T o i ncreas e t he vali dit y of t he e n d p oi nts a n d e ns ure a sta n dar dise d a n d u nif or m assess me nt of 
se vere h y p o gl ycae mic e pis o des, ac ute pa n creatitis a n d all deat hs, t hese e ve nts will u n der g o 
a dj u dicati o n. Ta ble  9 -1  lists t he A Es t hat are s u bject t o e ve nt a dj u dicati o n i ncl u di n g a n ela b orate 
defi niti o n of t he e ve nt t y pes. T he re p orti n g ti meli nes are liste d i n Fi g ure  9 -2 . 
E ve nt a dj u dicati o n will be perf or me d f or e ve nts i n ra n d o mise d s u bjects i ncl u di n g e v e nts wit h a n 
o nset date o n t he da y of ra n d o misati o n a n d  o n war ds.  
T hese e v e nts are re vie we d b y a n i n d e pe n de nt e xter nal e ve nt a dj u dicati o n c o m mittee i n a bli n de d 
ma n ner; refer t o A p p e n di x 3  f or f urt her details. 
E ve nts rele va nt f or a dj u dicati o n are i de ntifie d as d escri be d b el o w:  
1.  I n v esti gat or-re p orte d e ve nts f or a dj u dicati o n: Se vere h y p o gl ycae mic e pis o de or 
h y p o gl ycae mic e pis o de re p orte d as S A E as well as Ac ute Pa ncreatitis  
2.  Deat hs ( A Es re p ort e d wit h fatal o utc o me)  
3.  P T Searc h (sta n d ar dize d scree ni n g): All A Es n ot directl y re p ort e d b y t he i n vesti gat or as 
re q uiri n g a dj u dicati o n, will u n der g o scree ni n g a n d e val uati o n t o i de ntif y p ote ntial e ve nts f or 
a dj u dicati o n. T he i n vesti gat or ca n b e q ueri e d t o pr o vi de a d diti o nal i nf or mati o n relate d t o t he 
re p orte d A E, e. g. alter nati ve aeti ol o g y, u n d erl yi n g ca use(s) a n d/ or cli nical details. 
4.  E A C -i de ntifie d e ve nts: W he n re vie wi n g 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, t he E A C ca n i de ntif y a d d iti o nal e v e nts i n sc o pe f or a dj u dicati o n t hat were n ot 
i nitiall y re p orte d b y t he i n vesti gat or. I n t hese i nsta nces, t he i n vesti gat or will be n otifie d of 
t he ne wl y i de ntifie d e v e nt a n d has t he o pti o n t o re p ort t he E A C-i de ntifie d e ve nt. Re gar dless 
of w het her t h e i n vesti gat or deci des t o re p ort t he e ve nt or n ot, it will u n der g o a dj u dicati o n. 
Occasi o nall y, E A C -i d e ntifie d e ve nts ma y re q uire t he i n vesti gat or t o c ollect a d diti o nal 
s o urce d oc u m e nts, w hic h s h o ul d be pr o vi de d b y u pl oa di n g t o t he e v e nt a dj u dicati o n s yst e m 
( E A S). 
 
Wit h t he e x ce pti o n of E A C -i de ntifie d e ve nts, a n a dj u dicati o n f or m f or t h e s pecific e v e nt t y p es i n 
q uesti o n s h o ul d be c o m plete d i n t he C R F wit hi n 1 4 cale n dar da ys of t he i n vesti gat or's first 
k n o wle d ge of t he e ve nt. C o pies of c ollecte d s o urce d oc u me nts s h o ul d be la belle d wit h trial I D, 
s u bject a n d A E n u m ber, re dact e d (a n o n y mise d of pers o nal i de ntifiers, tri al dr u g, d os e, r o ute of 
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C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
4 9  of 1 0 5  
 
a d mi nistrati o n, n u m ber of dr u g a d mi nistrati o ns etc.) a n d u pl oa de d t o t he E A S wit hi n 4 wee ks 
acc or di n g t o i nstr ucti o ns o u tli ne d i n t he e ve nt a dj u dicati o n site ma n ual. If n o, or i ns ufficie 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 b e as ke d t o c o m plete a 
cli nical narrati ve t o ser ve as s u p p orti n g d o c u me ntati o n a n d u pl oa d t his 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 as t h e ne w i nf or m ati o n ma y 
res ult i n re-a dj u dicati o n of t he e ve nt.  
A site ma n ual will be pr o vi de d t o eac h site det aili n g h o w t o pr o vi d e t he rel e va nt d oc u me ntati o n t o 
t he a dj u dicati o n ve n d or. I n a d diti o n, t he a n o n y mi zati o n re q uire me nts will als o be descri b e d i n t he 
site ma n ual.  
9. 2. 2  
Met h o d of detecti n g A Es a n d S A Es  
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. 
9. 2. 3  
F oll o w -u p o n 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 will be f oll o we d u ntil res ol uti o n, sta bilizati o n, or if t he e ve nt 
is ot her wise e x plai ne d (e. g. c hr o nic c o n diti o n) or t he s u bject is l ost t o f oll o w-u p (as d efi ne d i n 
Secti o n 8. 4 ). U nres ol ve d n o n-seri o us A Es s h o ul d be f oll o we d u ntil e n d of trial. F urt her i nf or mati o n 
o n f oll o w -u p pr oce d ures is gi ve n i n A p pe n di x 4 . 
9. 2. 4  
Re g ul at or y re p orti n g re q uire me nts f or S A Es  
Pr o m pt n otificati o n b y t he i n vesti gat or t o N o v o N or dis k of a 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. 
I n v esti gat or safet y re p orts m ust be pre pare d f or s us pecte d u ne x pecte d s eri o us a d verse reacti o ns 
( S U S A Rs) acc or di n g t o l ocal re g ulat or y re q uir e m e nts a n d N o v o N or dis k p olic y a n d f or war de d t o 
i n vesti gat ors as n ecessar y. 
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 peci fic 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 
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C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
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al o n g wit h t he i n vesti gat or's br oc h ure a n d will n otif y t he I R B/I E C, if a p pr o priate acc or di n g t o l ocal 
re q uire me nts. 
9. 2. 5  
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 A E/ S A Es descri pti o n i n 
Secti o n 9. 2. 1 . 
9. 2. 6  
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 alif yi n g as a n A E or 
S A E  
T he f oll o wi n g Disease -Relate d E ve nts ( D R Es) are c o m m o n i n s u bjects wit h t y pe 2 dia betes a n d ca n 
be seri o us/life t hreate ni n g:  
•  H y p o gl ycae mic e pis o des  
Defi niti o ns, classificati o n a n d re p orti n g re q uire m e nts are d escri be d i n A p pe n di x 7    
All e ve nts of h y p o gl ycae mia m ust be re p orte d o n t he h y p o gl ycae m ic e pis o de f or m. Please refer t o 
A p pe n di x 7  f or details. 
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, a n A E 
f or m, a safet y i nf or mati o n f or m ( SI F) a n d a n a dj u dicati o n f or m m ust als o be fille d i n. O ne A E f or m 
a n d SI F ca n be relate d t o se veral h y p o gl ycae mic e pis o de f o r ms, if t he s u bject has n ot rec o v ere d 
bet wee n t he e pis o des. I n a d diti o n, o ne h y p o gl ycae mic e pis o de ca n b e rel ate d t o se veral A Es.  
9. 2. 7  
Pre g n a ncies a n d ass oci ate d a d verse e v e nts  
Details of pre g n a ncies i n fe male s u bjects will be c ollecte d after t he first -tri al-relat e d acti vit y after 
o btai ni n g i nf or me d c o nse nt a n d u ntil pre g n a nc y o utc o me.  
If a pre g na nc y is r e p orte d i n fe male s u bjects, t he i n vesti gat or s h o ul d i nf or m N o v o N or dis k wit hi n 
1 4 cale n dar da ys of lear ni n g of t he pre g na n c 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 
Fi g ure  9 -2  a n d A p pe n di x 5 .  
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 di cal rec or d. A b n or mal pre g n a nc y 
o utc o me (e. g. s p o nta n e o us a b orti o n, f oetal deat h, still birt h, c o n ge nital a n o malies a n d ect o pic 
pre g na nc y) is c o nsi dere d a n S A E. T he i n vesti gat or will re p ort i nf or mat i o n o n t he patie nt a n d t he 
pre g na nc y o ut c o me u ntil t he ne w b or n i nf a nt is o ne m o nt h of a ge i n acc or da nce wit h E ur o pea n 
Me dici nes A ge n c y ( E M A) a n d C o m mittee f or M e dici nal Pr o d ucts f or H u ma n Use ( C H M P).
1 6 
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Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
5 1  of 1 0 5  
 
M at er n al f or m 1 b  
≤ 1 4 c al e n d ar d ays aft er birt h
M at er n al f or m 1 a
≤ 1 4 c al e n d ar d ays
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 c al e n d ar d ays
P at er n al f or m * 1 ≤ 1 4 c al e n d ar d ays
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 A Es i n c o n n e cti o n wit h t h e pr e g n a nc y 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 9. 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  9 -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.  
9. 2. 8  
Me dic al de vice i nci de nts (i ncl u di n g m alf u ncti o ns)  
Secti o n n ot a p plica ble f or t his trial. Refer t o tec h nical c o m plai nts i n Secti o n 9. 2. 9 . 
9. 2. 9  
Tec h nic al c o m pl ai nts  
T he i n vesti gat or m ust assess w het her a tec h nical c o m plai nt is relate d  t o a n A E. T he defi niti o ns a n d 
re p orti n g pr ocess f or te c h nical c o m plai nts ca n be f o u n d i n A p pe n di x 6 . 
9. 3  
Tre at me nt of o ver d ose  
T he acci de ntal o ver d os e m ust be re p orte d as a me dicati o n err or. R efer t o Secti o n 9. 2. 1  f or f urt her 
details.  
I n t he e ve nt of a n o ver d ose, t he i n vesti gat or s h o ul d cl osel y m o nit or t he s u bject f or o ver d ose-relate d 
A E/ S A E a n d la b orat or y a b n or malities.  
Decisi o ns re g ar 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.  
I ns uli n 
A s pecific o v er d ose f or i ns uli n ca n n ot be defi ne d; h o we ver, h y p o gl ycae mi a ma y de vel o p o v er 
se q ue ntial sta ges if t o o hi g h doses relati ve t o t he patie nt’s re q uir e me nt are a d mi nistere d. Mil d 
e pis o des of h y p o gl ycae mia ca n us uall y be tr eate d wit h oral car b o h y drates. A dj ust me nts i n d ose of 
t he me dici nal pr o d uct, m eal patter ns, or p h ysi cal acti vit y ma y be n ee de d. M ore se vere e pis o d es 
wit h c o ma, seiz ure, or ne ur ol o gic i m pair m e nt ma y be treate d wit h i ntra m usc ular/s.c. gl uca g o n or 
c o nce ntr ate d i ntra ve n o us gl uc ose. S ustai ne d car b o h y drate i nta ke a n d o bser vati o n ma y b e necessar y 
beca use h y p o gl ycae mia ma y rec ur after a p p are nt cli nical rec o v er y.  
  Pr ot oc ol  v 3. 0 |
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Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
5 2  of 1 0 5  
 
Se m a gl uti de  
O ver d oses of u p t o 4 m g of se ma gl uti de i n a si n gl e d ose/i n o ne wee k ha ve bee n re p orte d i n cli nical 
trials. T he m ost c o m m o nl y re p orte d a d v erse reacti o n was na usea. All patie nts rec o vere d wit h o ut 
c o m plicati o ns. I n t h e e ve nt of o ver d ose, a p pr o priate s u p p orti ve treat me nt s h o ul d be i nitiate d 
acc or di n g t o t he p atie nts’ cli nical si g ns a n d s y m pt o ms. A pr ol o n ge d p eri o d of o bser vati o n a n d 
treat me nt f or t hes e s y m pt o ms ma y be n ecess ar y, ta ki n g i nt o acc o u nt t he l o n g half-life of 
se ma gl uti de of a p pr o xi matel y o n e wee k.  
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 s e ma gl uti de  i n vesti gat or's 
br oc h ure a n d t he c urre nt versi o n of t he l ocal la b el f or La nt us ®  a n d N o v o Ra pi d ® / N o v o L o g® .  
9. 4  
S afet y assess me nts  
Pla n ne d ti me p oi nts f or all sa fet y assess me nts are pr o vi de d i n t he fl o wc h art Secti o n 2 . 
A c o nc o mit a nt ill ness  is a n y ill ness t hat is pres e nt at t he start of t he trial (i. e. at t he first visit) 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 has e x perie nce d i n t he past . O nl y rele va nt 
c o nc o mita nt ill ness a n d me dical hist or y as j u d ge d b y t he i n vesti gat or s h o ul d be re p orte d. Dia betes 
hist or y a n d relate d c o m plicati o ns s h o ul d be re p ort e d se paratel y i n t he dia betes hist or y/c o m plicati o n 
f or m.  
T he i nf or mati o n c ollect e d f or c o nc o mita nt ill ness a n d me dical hist or y s h o ul d i ncl u de dia g n osis, 
date of o nset a n d d ate of res ol uti o n or c o nti n uati o n, as a p plica ble.  
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, 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 if it is prese nt at scree ni n g. A n y n e w fi n di n g 
f ulfilli n g t he A E defi niti o n (see A p p e n di x 4 ) d uri n g t he trial a n d a n y cli nicall y si g nifica nt 
w orse ni n g fr o m r u n -i n ( Visit 2) m ust be re p orte d as a n A E (see Secti o n 9. 2 ). 
9. 4. 1  
P h ysic al e x a mi n ati o ns  
•  A p h ys ic al e x a mi nati o n will i ncl u de assess me nts of t he ge neral a p peara nce, t h yr oi d 
gla n d a n d t he Car di o vas c ular, Res pirat or y, Gastr oi ntesti nal, M usc ul os keletal a n d 
Ne ur ol o gical s yste ms.  
•  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 previ o us seri o us 
ill nesses. 
9. 4. 2  
Vit al si g ns  
•  P ulse rate, as w ell as diast olic a n d s yst olic bl o o d press ure will be assesse d.  
•  Bl o o d press ur e a n d p ulse meas ure me nts  s h o ul d be prece d e 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. tele visi o n, cell p h o nes).  
  Pr ot oc ol  v 3. 0 |
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Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
5 3  of 1 0 5  
 
•  Bl o o d press ur e at scree ni n g  will c o nsist of 3 diast olic a n d s yst olic bl o o d press ure 
meas ure me nts wit h i nter vals of at least 1 mi n ute.  
•  P ulse at scree ni n g will als o c o nsist of 3 meas ure m e nts.  
•  All bl o o d press ure a n d p ulse rea di n gs m ust be e nt ere d i n t he C R F a n d t h e a vera ge of t he 
3 bl o o d press ure rea di n gs will be calc ulate d i n  t he C R F.  
•  At t he s u bse q ue nt visits, t he bl o o d press ure a n d p ulse s h o ul d o nl y be meas ure d o nce.  
•  Bl o o d press ur e a n d p ulse meas ure me nts will be  assesse d w hile t he s u bject is i n a sitti n g 
p ositi o n  wit h a c o m pletel y a ut o mat e d de vice. Ma n ual tec h ni q ues will be us e d o nl y if a n 
a ut o mate d de vice is n ot a vaila ble.  
9. 4. 3  
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 , m ust be c o n d ucte d i n 
acc or da nce wit h t he la b orat or y ma n ual a n d t he fl o wc hart i n Secti o n 2 . 
9. 4. 4  
E ye e x a mi n ati o n  
S u bjects wit h u nc o ntr olle d a n d p 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.  
Res ults of a n e ye e x a mi nati o n perf or me d as per fl o w c hart (s ee Secti o n 2 ) b y a n o p ht h al m ol o gist, or 
a n ot her s uita ble q ualifie d certifie d h ealt h care pr o vi der m ust be a vaila ble a n d e val uate d b y t he 
i n vesti gat or at Visit 2 at t he latest 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 pre-c or neal or c or neal 
c o ntact le ns e x a mi nati o n) a n d perf or me d wit h p har mac ol o gicall y dilate d p u pils.  
If t he s ubject 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 r u n -i n ( Visit 2), 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 o rse ni n g of vis ual f u ncti o n si nce 
t he last e x a mi nati o n. If t he a p plica ble e ye e x a mi nati o n was perf or me d bef ore t he s u bject si g ne d t he 
i nf or me d c o nse nt f or m, it m ust be d oc u me nte d t hat t he reas 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.  
T he e x a mi nati o n m ust be re peat e d wit hi n 3 0 da ys pri or t o ra n d o misati o n a n d res ults m ust be 
a vaila ble f or e val uati o n at Visit 8.  
After ra n d o misati o n a n e ye e x a mi nati o n perf or me d acc or di n g t o a b o ve m ust be perf or m e d a t Visit 
3 6 or wit hi n 5 wee ks pri or t o t his. T he i n vesti gat or s h o ul d i n dicate t he o ut c 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 r a n d o misati o n m ust be rec or de d as c o nc o mita nt 
ill ness/ me dical hist or y. W hile rele va nt fi n di n gs o cc urri n g after ra n d o misati o n s h o ul d be re p orte d as 
  Pr ot oc ol  v 3. 0 |
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C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
5 4  of 1 0 5  
 
a n A E, if a p plica ble acc or di n g t o Secti o n 9. 2 .  Res ults m ust be a vaila ble a n d e val uate d b y t he 
i n vesti gat or at Visit 3 6.  F or s u bjects w h o disc o nti n ue trial treat me nt, t he e ye e x a mi nati o n s h o ul d be 
perf or me d b ot h at V 3 6 A a n d V 3 6. At V 3 6 A t he assess me nt ca n be p erf or me d i n t he peri o d bet w ee n 
V 3 6 A a n d P 3 7 A, b ut t he res ults s h o ul d be a vaila bl e a n d re vi e we d n o lat er t ha n at P 3 7 A.  
9. 5  
P h ar m a c o ki netics  
N ot a p plica bl e  
9. 6  
P h ar m a c o d y n a mi cs  
N ot a p plica ble  
9. 7  
Ge neti cs  
N ot a p plica ble  
9. 8  
Bi o m ar kers  
N ot a p plica ble  
 
 
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C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
5 5  of 1 0 5  
 
1 0  St atistic al c o nsi der ati o ns  
1 0. 1  
S a m ple size deter mi n ati o n  
T he pri mar y e n d p oi nt is c ha n ge fr o m baseli ne t o wee k 5 2 i n H b A 1c, a n d b ot h n o n-i nferi orit y a n d 
s u bse q ue ntl y s u p eri orit y are pla n n e d t o be teste d. T he c o nfir mat or y sec o n d ar y e n d p oi nts are ti me t o 
first E A C c o nfir me d se v ere h y p o gl ycae mic e pis o de ( A D A) fr o m ra n d o misati o n u p t o wee k 5 2, ti me 
t o first E A C c o nfir me d s e vere hy p o gl ycae mic e pis o de re q uiri n g h os pitalisati o n, d oc u me nte d 
me dical hel p, or is life t hreate ni n g fr o m ra n d o mis ati o n u p t o wee k 5 2, a n d c ha n ge fr o m baseli ne t o 
wee k 5 2 i n b o d y wei g ht. F or t hese e n d p oi nts s u peri orit y will be teste d. T h e t y pe -I err or rate will be 
c o ntr olle d i n t he str o n g s e nse acr oss t he pri mar y a n d t he c o nfir mat or y s ec o n dar y h y p ot heses at a n 
o verall al p ha (t w o -si de d) of 0. 0 5. M ulti plicit y c o ntr ol a n d criteria f or c o nfir mi n g h y p ot heses is 
descri be d i n Secti o n 1 0. 3  bel o w.  
T he trial is desi g n e d t o h a ve 8 5 % p o w er t o j oi ntl y esta blis h n o n -i nferi orit y, wit h res pect t o 
gl ycae mic c o ntr ol, a n d t o c o nfir m s u peri orit y o n E A C c o nfir me d se v ere h y p o gl ycae mic e pis o des 
( A D A), a n d t o c o nfir m s u peri orit y o n E A C c o nfir me d se vere h y p o gl ycae mic e pis o des ( A D A) 
re q uiri n g h os pitalisati o n, d oc u me nte d me dical hel p, or is life t hreate ni n g, of se ma gl uti de c o m pare d 
t o I As p. T h e s u peri orit y h y p ot hes es f or b ot h se v ere h y p o gl ycae mic e n d p oi nts are t he det er mi ni n g 
fact or f or t he sa m ple siz e. T his mea ns t hat t he p o wer f or H b A1c n o n -i nferi orit y is i n directl y 
o btai ne d wit h t he n u m ber of s u bjects ne e de d t o c o nfir m s u peri orit y o n b ot h se vere h y p o gl ycae mic 
e n d p oi nts.  
Pri m ar y e n d p oi nt  
Wit h 1 7 3 6 s u bjects ra n d o mise d t o e ns ure s uffici e nt j oi nt p o wer ( 8 5 %) f or t he h y p ot hes es f or t he 
c o nfir mat or y se v ere h y p o gl ycae mic e n d p oi nts, t h ere is > 9 9. 9 % p o wer f or c o nfir mi n g t h at 
se ma gl uti de is n o n-i nf eri or t o I As p o n c ha n ge fr o m baseli ne t o week 5 2 i n H b A 1c. T his is base d o n 
a 1: 1 ra n d o misati o n, a t w o -si de d si g nifica nce le vel of 0. 0 5, a t-test, a n ass u m pti o n of n o treat me nt 
differe n ce, a n o n -i nferi orit y mar gi n of 0. 3 %-p oi nt, a n d a sta n dar d de viati o n ( S D) of 1. 1 % -p oi nt. 
B ot h se ma gl uti de a n d I As p ha ve a lar ge effect o n gl ycae mic c o ntr ol, t h us a c o nser vati ve a p pr oac h 
m oti vates t he ass u me d tr eat me nt differe nce of 0. 0 % -p oi nt, a n d t he ass u me d S D is base d o n t he 
S U S T AI N pr o gra m. Wit h t he a b o ve ass u m pti o ns, t he mar gi nal p o wer f or esta blis hi n g s u peri orit y  of 
se ma gl uti de v ers us I As p o n c ha n ge fr o m baseli ne t o wee k 5 2 i n H b A 1c c orres p o n ds t o t he t y pe -I 
err or.    
C o nfir m at or y s ec o n d ar y e n d p oi nts  
Ti me t o first E A C c o nfir me d severe hy p o gl yc ae mic e pis o de ( A D A) fr o m r a n d o mis ati o n u p t o week 
5 2  
T he p o wer calc ul ati o n f or t he s u peri orit y h y p ot hesis f or t his e n d p oi nt is base d o n t he f oll o wi n g 
ass u m pti o ns  
  Pr ot oc ol  v 3. 0 |
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C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
5 6  of 1 0 5  
 
•  First E A C c o nfir me d s e v ere h y p o gl ycae mic e pis o de ( A D A) occ ur at a n i n ci de nce rate of 
4. 0 per 1 0 0 patie nt years of ris k ti me ( P Y R) i n t he I As p gr o u p  
•  First E A C  c o nfir me d s e v ere h y p o gl ycae mic e pis o de ( A D A) occ ur at a n i n ci de nce rate of 
1. 0 per 1 0 0 P Y R i n t he se ma gl uti de gr o u p, c orres p o n di n g t o a hazar d rati o of 0. 2 5  
•  1 0 % of t he s u bjects r a n d o mise d t o I As p will pre m at urel y disc o nti n ue trial me dicati o n 
u nif or ml y d ur i n g t he 5 2 wee ks of treat me nt  
•  1 5 % of t he s u bjects r a n d o mise d t o se ma gl uti de will pre mat urel y disc o nti n ue trial 
me dicati o n u nif or ml y d uri n g t he 5 2 wee ks of treat me nt  
 
T he ass u m pti o ns f or t he i nci de nce rate of se vere h y p o gl ycae mia are bas e d o n t he pre vi o usl y 
c o n d ucte d cli nical tri als wit h si milar p o p ulati o n, titrati o n a n d d urati o n: D U A L VII ( N N 9 0 6 8 -
4 1 8 5) 1 7, B E GI N Basal-B ol us T 2 D ( N N 1 2 5 0 -3 5 8 2) 1 8, A W A R D-4 1 9, D E V O T E ( E X 1 2 5 0-4 0 8 0) 2 0 
a n d S U S T AI N 5 ( N N 9 5 3 5 -3 6 2 7) 8. I n t hes e trials, t he f oll o wi n g i nci d e nce rates of or pr o p orti o n of 
s u bjects e x perie nci n g se v ere h y p o gl ycae mic e pis o des were o bser ve d f or I As p a n d se ma gl uti de 
res pecti vel y: 
I As p 
•  D U A L VII  ( 2 6 wee ks, N N I De g Lir a titrati o n al g orit h m): 2 5 3 s u bjects treat e d wit h I Glar a n d 
I As p 2-4 x/ da y w h ere of 4 s u bjects e x perie nce d a s e vere h y p o gl ycae mic e pis o de ( A D A). 
Wit h a t otal e x p os ure of 1 1 9. 3 years t his gi ves a n i nci de nce rate of 3. 4 p er 1 0 0 P Y R.  
•  B E GI N  B A S A L B O L U S  T 2 D ( 5 2 wee ks, N N i ns uli n titrati o n al g orit h m): 2 5 1 s u bjects treate d 
wit h I Glar a n d I As p TI D w here of 1 1 s u bjects e x perie nce d a se vere h y p o gl ycae mic e pis o de 
( A D A). Wit h a t otal e x p os ure of 2 2 8. 8 years t his gi ves a n i n ci de nce rate of 4. 8 per 1 0 0 
P Y R.  
•  A W A R D -4  ( 5 2 wee ks, titrati o n al g orit h m a d a pte d base d o n Ri d dle a n d Ber ge nsta hl): 2 9 6 
s u bjects treate d wit h I Gl ar a n d Lis pr o TI D w here of 1 5 s u bjects e x perie nce d a se vere 
h y p o gl ycae mic e pis o de (i n vesti gat or’s cli nical j u d ge m e nt). T his gi v es a pr o p orti o n of 5. 1 %.  
•  D E V O T E  ( 2 years, N N i ns uli n titrati o n al g orit h m a n d i n di vi d ualise d titrati o n) 1 7 5 5 s u bjects 
wit h a pre -ra n d o misati o n treat me nt of bas al-b ol us i ns uli n (i ncl u di n g b ol us o nl y a n d pre -
mi x) w here treate d wit h I Glar w here of 1 5 1 s u bjects e x perie nce d a n E A C c o nfir me d se vere 
h y p o gl ycae mic e pis o de ( A D A). Wit h a mea n o bser vati o n ti me of 1. 9 8 years t his gi ves a n 
i nci de nce rate of 4. 3 p er 1 0 0 P Y R. 
 
Se m a gl uti de  
•  S U S T AI N 5  ( 3 0 wee ks, n o e nf orce d titrati o n): 1 3 2 s u bjects treate d wit h bas al i ns uli n a n d 
se ma gl uti de O W 0. 5 m g w hereof 0 s u bjects e x perie nce d a s e vere h y p o gl ycae mic e pis o de 
( A D A). 1 3 1 s u bjects treate d wit h basal i ns uli n a n d se ma gl uti de O W 1. 0 m g w here of 2 
s u bjects e x perie nce d a se vere h y p o gl ycae mic e pis o de ( A D A). Wit h a t otal e x p os ure acr oss 
treat me nts of 1 1 6. 1 years t his gi ves a n i nci de n ce rate of 1. 2 per 1 0 0 P Y R  acr oss treat me nt 
gr o u ps.  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
5 6 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
5 7  of 1 0 5  
 
Base d o n t h ese res ults a n d usi n g a c o nser vati ve a p pr oac h t o acc o m m o date t he u ncert ai nt y i n t he 
i nci de nce rates, a n i nci d e nce rat e of 4. 0 per 1 0 0 P Y R i n t he I As p gr o u p, mai nl y bas e d o n t he E A C 
c o nfir me d se v ere h y p o gl ycae mic e pis o des i n D E V O T E, a n d a n i n ci de nce rate of 1. 0 p er 1 0 0 P Y R 
i n t he se ma gl uti de gr o u p are ass u me d. Wit h 1 7 3 6 ra n d o mise d s u bjects, a 1: 1 ra n d o misati o n, a t w o-
si de d si g nifica n ce le v el of 0. 0 5, a n d a l o g-ra n k test, t his yiel ds a mar gi nal p o wer of 9 6. 8 %.  
Ti me t o first E A C c o nfir me d severe hy p o gl yc ae mic e pis o de ( A D A) re q uiri n g h os pit alis ati o n, 
d oc u me nte d me dic al hel p, or is life t hre ate ni n g fr o m r a n d o mis ati o n u p t o week 5 2  
Base d o n t h e o bser vati o ns fr o m t he D E V O T E trial, a  t otal of 9 5 s u bjects e x perie nce d a n E A C 
c o nfir me d se v ere h y p o gl ycae mic e pis o de (acc or di n g t o A D A) t hat f ulfille d t he a d diti o nal 
re q uire me nt t hat t hes e e v e nts were eit her S A Es (c o veri n g e ve nts r e q uiri n g h os pitalisati o n or life 
t hreate ni n g e v e nts), or t h e su bject e x perie nci n g t his e ve nt was u nc o ns ci o us, i n c o ma or ha d a 
seiz ure, or re q uir e d me di cal assista nce or was tr eate d wit h I. V. gl uc ose or gl uca g o n. T his 
c orres p o n ds t o a n o bs er ve d i nci de nce rate of 2. 7 p er 1 0 0 P Y R. T he ass u m pti o n of u nif or m l oss 
f u ncti ons of 1 5 % f or t h e se ma gl uti de ar m a n d 1 0 % f or t he I As p ar m, as well as t he rati o of 1: 4 
bet wee n t he s e ma gl uti de a n d t he I As p ass u me d i n ci de nce rates, use d f or p o wer calc ulati o ns f or t he 
first E A C c o nfir me d se v ere h y p o gl ycae mic e pis o de ( A D A), are mai ntai ne d f or t his e n d p oi nt. Base d 
o n t hese ass u m pti o ns, t he p o wer calc ulati o n f or t his e n d p oi nt is base d o n a n ass u me d i nci de nce rate 
of 0. 6 7 5 per 1 0 0 P Y R f or se ma gl uti de a n d 2. 7 per 1 0 0 P Y R f or I As p. Wit h 1 7 3 6 ra n d o mise d 
s u bjects, a 1: 1 ra n d o misati o n, a t w o-si de d si g nifica nce le vel of 0. 0 5, a n d a l o g-ra n k test, t his yiel ds 
a mar gi nal p o wer of 8 7. 9 %.  
C h a n ge fr o m b aseli ne t o week 5 2 i n b o dy wei g ht  
Wit h 1 7 3 6 s u bjects ra n d o mise d t o e ns ure s uffici e nt j oi nt p o wer ( 8 5 %) f or t he c o nfir mat or y s e vere 
h y p o gl ycae mic e n d p oi nt s, t here is > 9 9. 9 % mar gi nal p o wer f or c o nfir mi n g t hat se ma gl uti de is 
s u peri or t o I As p o n c h a n ge fr o m baseli ne t o w ee k 5 2 i n b o d y wei g ht. T his is base d o n a 1: 1 
ra n d o misati o n, a t w o-si d e d si g nifica nce le vel of 0. 0 5, a t-test, a n ass u me d treat me nt differe n ce of 
2. 0 k g, a n d a S D of 4. 0 k g. T he ass u me d treat me nt differe n ce a n d t h e S D is base d o n t he S U S T AI N 
pr o gra m.  
T he j oi nt (effecti ve) p o wer is calc ul ate d u n der t h e ass u m pti o n of i n de pe n de nce of e n d p oi nts b y 
m ulti pl yi n g t he res pecti v e mar gi nal p o wers s uccessi v el y. Si nce s o me of t h ese e n d p oi nts/tests are 
p ositi vel y c orrelate d, t he ass u m pti o n of i n de pe n de nce is vie we d as c o nser vati ve. Wit h t he a b o ve 
ass u m pti o ns, a j oi nt p o wer of 8 5 % f or c o nfir mi n g n o n -i nferi orit y i n H b A1c, a n d s u peri orit y o n b ot h 
se vere h y p o gl ycae mic e n d p oi nts will re q uire a t otal of 1 7 3 6 ra n d o mise d s u bjects, i.e. 8 6 8 s u bjects 
ra n d o mise d i n eac h ar m, w he n c o m pari n g s e ma gl uti de t o I As p. T a ble  1 0 -1 s u m marises t he 
ass u m pti o ns t hat t he sa m ple siz e calc ulati o n is base d o n as well as pr o vi di n g a n o v er vie w of t he 
mar gi n al a n d j oi nt p o wer f or eac h h y p ot hesis.   
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
5 7 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
5 8  of 1 0 5  
 
T a ble  1 0 -1  
 
H y p ot hesis  
Ass u m pti o ns  
R a n d o mise d 
s u bjects 
M ar gi n al 
p o w er  
J oi nt 
p o w er  
H b A 1c,  
n o n -i nferi orit y 
Treat me nt differe nce: 0. 0 % -p oi nt  
Sta n dar d de viati o n: 1. 1 % -p oi nt  
N o n -i nferi orit y mar gi n: 0. 3 %-p oi nt  
1 7 3 6  
> 9 9. 9 %  
> 9 9. 9 %  
E A C c o nfir me d se v ere 
h y p o gl yc a e mic e pis o des 
( A D A),  
s u peri orit y 
Hazar d rati o: 0. 2 5  
I nci de nce rate f or se ma gl uti de: 1. 0 per 1 0 0 
P Y R  
I nci de nce rate f or I As p: 4. 0 per 1 0 0 P Y R 
1 0 % u nif or m l oss f or I As p  
1 5 % u nif or m l oss f or se ma gl uti de  
1 7 3 6  
9 6. 8 %  
9 6. 8 %  
E A C c o nfir me d se v ere 
h y p o gl yc a e mic e pis o des 
( A D A) re q uiri n g 
h os pit alis ati o n, 
d oc u me nte d me dic al hel p, 
or is life t hre ate ni n g ,  
s u peri orit y  
Hazar d rati o: 0. 2 5  
I nci de nce rate f or se ma gl uti de: 0. 6 7 5 per 1 0 0 
P Y R  
I nci de nce rate f or I As p: 2. 7 per 1 0 0 P Y R 
1 0 % u nif or m l oss f or I As p 
1 5 % u nif or m l oss f or se ma gl uti de  
1 7 3 6  
8 7. 9 %  
8 5. 0 %  
B o d y w ei g ht,  
s u peri orit y 
Treat me nt differe nce: 2. 0 k g  
Sta n dar d de viati o n: 4. 0 k g  
1 7 3 6  
> 9 9. 9 %  
8 5. 0 %  
H b A 1c,  
s u peri orit y 
Treat me nt differe nce: 0. 0 % -p oi nt  
Sta n dar d de viati o n: 1. 1 % -p oi nt  
1 7 3 6  
Less t ha n or e q ual 
t o T y pe I err or per 
ass u m pti o n  
T he sa m ple siz e calc ulati o ns a b o ve are se nsiti ve t o t he ass u m pti o ns ma de f or t he i nci de nce rates 
a n d tr ue hazar d rati os f or t he se vere h y p o gl ycae mic e n d p oi nts. Ta ble  1 0 -2 ill ustrates t his wit h ei g ht 
alter nati ve set of ass u m pti o ns.   
T a ble  1 0 -2  
P o w er wit h differe nt i nci de nce r ates f or se vere h y p o gl yc ae mic e pis o des f or t he 
I As p tre at me nt gr o u p 
Sce nari os  
Sce nari o 1  
Sce nari o 2  
Sce nari o 3  
Sce nari o 4  
B ase c ase  
Sce nari o 5  
Sce nari o 6  
Sce nari o 7  
Sce nari o 
8  
Ti me t o first E A C c o nfir me d se vere h y p o gl yca e mic e pis o de ( A D A)  
I nci d e nce rate 
per 1 0 0 P Y R:  
se ma gl uti de  
1. 0  
1. 0  
1. 0  
1. 0  
1. 0  
1. 0  
1. 0  
1. 0  
1. 0  
I nci d e nce rate 
per 1 0 0 P Y R:  
I As p 
3. 5  
3. 7 5  
4. 2 5  
4. 5  
4. 0  
4. 0  
4. 0  
4. 0  
4. 0  
H R  
0. 2 9  
0. 2 7  
0. 2 4  
0. 2 2  
0. 2 5  
0. 2 5  
0. 2 5  
0. 2 5  
0. 2 5  
Mar gi n al 
p o wer  
9 1. 7 %  
9 4. 7 %  
9 8. 0 %  
9 8. 8 %  
9 6. 8 %  
9 6. 8 %  
9 6. 8 %  
9 6. 8 %  
9 6. 8 %  
E x pecte d 
n u m ber of first 
e ve nts: 
se ma gl uti de  
9  
9  
9  
9  
9  
9  
9  
9  
9  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
5 8 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
5 9  of 1 0 5  
 
E x pecte d 
n u m ber of first 
e ve nts: I As p  
3 0  
3 2  
3 7  
3 9  
3 5  
3 5  
3 5  
3 5  
3 5  
Ti me t o first E A C c o nfir me d se vere h y p o gl yca e mic e pis o de ( A D A) re q uiri n g h os pitalisati o n, d oc u me nte d me dical hel p, or is life 
t hreate ni n g 
I nci d e nce rate 
per 1 0 0 P Y R:  
se ma gl uti de  
0. 6 7 5  
0. 6 7 5  
0. 6 7 5  
0. 6 7 5  
0. 6 7 5  
0. 6 7 5  
0. 6 7 5  
0. 6 7 5  
0. 6 7 5  
I nci d e nce rate 
per 1 0 0 P Y R:  
I As p 
2. 7  
2. 7  
2. 7  
2. 7  
2. 7  
2. 1  
2. 4  
3. 0  
3. 3  
H R  
0. 2 5  
0. 2 5  
0. 2 5  
0. 2 5  
0. 2 5  
0. 3 2  
0. 2 8  
0. 2 5  
0. 2 0  
Mar gi n al 
p o wer  
8 7. 9 %  
8 7. 9 %  
8 7. 9 %  
8 7. 9 %  
8 7. 9 %  
6 8. 1 %  
7 9. 8 %  
9 3. 1 %  
9 6. 2 %  
E x pecte d 
n u m ber of first 
e ve nts: 
se ma gl uti de  
6  
6  
6  
6  
6  
6  
6  
6  
6  
E x pecte d 
n u m ber of first 
e ve nts: I As p  
2 4  
2 4  
2 4  
2 4  
2 4  
1 9  
2 1  
2 6  
2 9  
Ra n d o mise d 
s u bjects 
1 7 3 6  
1 7 3 6  
1 7 3 6  
1 7 3 6  
1 7 3 6  
1 7 3 6  
1 7 3 6  
1 7 3 6  
1 7 3 6  
J oi nt p o wer  
8 0. 6 %  
8 3. 3 %  
8 6. 2 %  
8 6. 9 %  
8 5. 0 %  
6 5. 9 %  
7 7. 2 %  
9 0. 1 %  
9 3. 1 %  
1 0. 2  
Defi niti o n of a n al ysis sets  
Data sele cti o n f or statistical a nal yses will be a t w o -ste p pr ocess, first selecti n g s u bjects base d o n t h e 
a nal ysis p o p ulati o n a n d s u bse q ue ntl y e ve nts/ data f or t h ose s u bjects base d o n t he o bser vati o n peri o d.  
F ull a n alysis set ( F A S): All ra n d o mise d s u bjects . S u bjects will be a nal ys e d acc or di n g t o t he 
treat me nt t o w hic h t he y were assi g n e d at r a n d o misati o n. 
S afety a n alysis set ( S A S): All s u bjects e x p ose d t o at least o ne d ose of trial pr o d uct. S u bjects will be 
a nal ys e d acc or di n g t o t he trial pr o d uct recei ve d f o r t he maj orit y of t h e peri o d t he y were o n 
treat me nt. 
Per pr ot oc ol ( P P) a n alysis set:  i ncl u des all s u bjects i n t he F A S w h o f ulfil t he f oll o wi n g criteria: 
•  Ha ve n ot vi olate d a n y i n cl usi o n criteria  
•  Ha ve n ot f ulfille d a n y e x cl usi o n criteria  
•  Ha ve n ot f ulfille d a n y r u n -i n e xcl usi o n criteria 
•  Ha ve n ot vi olate d a n y ra n d o misati o n criteria  
•  Ha ve a v ali d H b A 1c meas ure me nt at t he ra n d o misati o n visit ( V 8) a n d/ or t he last r u n -i n 
visit ( V 7)  
Is o n trial pr o d uct at visit 2 1 a n d ha ve at least o ne vali d H b A1c meas ure me nt at or after 
visit 2 1  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
5 9 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
6 0  of 1 0 5  
 
 
S u bjects will be a nal ys e d acc or di n g t o t he tri al pr o d uct recei ve d f or t h e maj orit y of t he p eri o d t he y 
were o n tr eat me nt.  
‘I n-tri al’ o bserv ati o n peri o d: T his o bser vati o n peri o d is defi ne d as t he peri o d fr o m date of 
ra n d o misati o n t o t he first date of a n y of t he f oll o wi n g, b ot h i ncl usi ve:  
•  date of e n d -of -trial f oll o w-u p visit  
•  date of deat h  
•  date w he n s u bject wit h dre w c o nse nt  
•  date of last c o nta ct f or s u bjects l ost t o f oll o w -u p  
 
‘ O n-tre at me nt’ o bs erv ati o n peri o d: T his o bser vati o n peri o d is a s u b -set of t he ‘i n -trial’ o bser vati o n 
peri o d a n d re pres e nts t he ti me peri o d w here s u bjects are c o nsi dere d e x p ose d t o trial pr o d uct. T he 
o bser vati o n peri o d starts at t he date of first d ose of trial pr o d uct a n d e n ds at a n e n d p oi nt -s pecifi c 
e n d-date acc or di n g t o t he  fl o w c hart. F or a d verse e ve nts, (e x cl u di n g h y p o gl ycae mic e ve nts), t he 
o bser vati o n peri o d e n ds at t he first date of a n y of t he f oll o wi n g:  
•  T he f oll o w -u p visit ( P 3 7)  
•  T he pre mat ure disc o nti n uati o n f oll o w -u p visit ( P 3 7 A)  
•  T he last date o n ra n d o mise d treat me nt r e gi me n + 4 2 da ys  
•  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 f oll o w -u p visit is sc he d ule d t o ta ke place 5 wee ks after t h e last date o n trial pr o d uct 
c orres p o n di n g t o a p pr o xi matel y fi v e half -li ves of se ma gl uti de O W. T he visit wi n d o w f or t he 
f ollo w -u p visit is + 7 da ys, a t otal of 4 2 da ys.  
F or efficac y a n d ot her safet y assess me nts ( h y p o gl ycae mic e pis o des, la b orat or y ass ess me nts, b o d y 
meas ure me nts, S M P G, P R O q uesti o n naires, a n d vital si g ns) t he ‘ o n -treat m e nt’ o bser vati o n peri o d 
e n ds at t he last dat e o n tri al pr o d uct wit h a visit wi n d o w of + 7 da ys i n a cc or da nce t o t he trial fl o w 
c hart. He n ce, f or t hese assess me nts, t he ‘ o n -treat me nt’ o bser vati o n peri o d reflects t he p eri o d i n 
w hic h s u bjects are treate d.  
D ue t o i n here ntl y si milar p har mac ol o gical c harac t eristics of differe nt b ol us i ns uli ns, s u bjects 
ra n d o mise d t o I As p w h o ha ve c h a n ge d t o a differe nt b ol us i ns uli n will be c o nsi dere d as b ei n g o n 
ra n d o mise d treat me nt. I n t his case t he last date o n ra n d o mise d trial re gi me n will be t he last date o n 
a n y b ol us i ns uli n.  
 
Data p oi nts c ollecte d o utsi de a n o bser vati o n peri o d will be treate d as missi n g i n t he a n al ysis. 
Baseli ne d ata will al wa ys be i ncl u de d i n a n o bser vati o n peri o d.  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
6 0 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
6 1  of 1 0 5  
 
Bef ore dat a are l oc ke d f or statistical a nal ysis, a re vie w of all data will ta ke plac e. Neit her s u bjects 
n or o bser vati o ns s h o ul d be e x cl u de d fr o m data. If s u bjects or o bser vati o ns are e x cl u de d, t he reas o ns 
f or t heir e x cl usi o n m ust be d oc u me nte d b ef ore data base l oc k a n d d escri b e d i n t he cli nical trial 
re p ort. A n y decisi o n t o e x cl u de eit her a s u bject or si n gle o bser vati o ns fr o m t he statistical a nal ysis is 
t he j oi nt res p o nsi bilit y of t he me m bers of t he N o v o N or dis k st u d y gr o u p. 
1 0. 3  
St atistic al a n al yses  
N o i nteri m a nal yses or ot her a nal ys es of u n -bli n de d data will be perf or me d bef ore t h e data base i s 
l oc ke d. 
If necessar y, a statistical a nal ysis pla n ( S A P) ma y be writte n i n a d diti o n t o t he pr ot oc ol, i ncl u di n g a 
m ore tec h nical a n d detail e d ela b orati o n of t he statistical a nal yses. T he S A P will be fi nalise d bef ore 
data base l oc k.  
T he c o m paris o n prese nte d fr o m a statistical a nal ysis will be se ma gl uti de vers us I As p. 
If n o statistical a nal ysis is s pecifie d, data will be prese nte d usi n g rele va nt s u m mar y statistics. 
Acc or di n gl y, a d v erse e ve nts will be s u m marise d descri pti vel y. Data c ollect e d bef ore ra n d o misati o n 
( V 8) will o nl y b e s u m marise d descri pti vel y. 
D at a tr a nsf or m ati o ns  
S o me of t he c o nti n u o us para meters will be l o g -tra nsf or me d pri or t o statistical a nal ysis. T he o ut p ut 
ta bles a n d fi g ures will s h o w t he res ults of t he a n al ysis bac k-tra nsf or me d t o t he ori gi nal s cale, 
i m pl yi n g t hat l o g-tr eat me nt-differe nces are re p ort e d as tre at me nt r ati os.  
 
La b orat or y v al ues bel o w t he l o wer li mit of q ua ntificati o n ( L L O Q) will be set t o ½ L L O Q. 
La b orat or y v al ues a b o v e t he u p per li mit of q ua ntificati o n ( U L O Q) will be set t o U L O Q.  
 
M ulti plicit y c o ntr ol a n d criteri a f or c o nfir mi n g h y p ot heses  
I n or der t o preser ve t he o verall t y p e-I err or t he c o ncl usi o n of n o n-i nferi orit y a n d s u p eri orit y of 
se ma gl uti de v ers us I As p will be e val uate d hierarc hicall y acc or di n g t o t he s e q ue nce bel o w, a n d 
starti n g wit h t he first h y p ot hesis. I n t his testi n g s e q ue nce it is necessar y t o f ulfil t he test criteria, 
w hic h is t o reject t he c orres p o n di n g n ull h y p ot hesis i n or der t o g o t o t he ne xt ste p. If t he 
c orres p o n di n g n ull h y p ot hesis is n ot rejecte d, t he t esti n g will st o p a n d n o f urt her c o n cl usi o ns will be 
dra w n. T he tr eat me nt  differe n ce is defi ne d as μ = (se ma gl uti de mi n us I As p). T he hazar d rati o ( H R) 
is f or t he c o m paris o n of s e ma gl uti de vs. I As p.  
 
 
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Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
6 2  of 1 0 5  
 
1. H b A 1 c n o n -i nferi orit y of se ma gl uti de  vs. I As p 
•  H 0: μ ≥ 0. 3 %-p oi nt a gai nst H a: μ < 0. 3 %-p oi nt  
2. S u peri orit y of s e ma gl uti de vs . I As p o n E A C c o nfir me d se vere h y p o gl ycae mic e pis o des ( A D A) 
•  H 0: H R ≥ 1. 0 a gai nst Ha: H R < 1. 0 
3. S u peri orit y of s e ma gl uti de vs. I As p o n E A C c o nfir me d se vere h y p o gl ycae mic e pis o des ( A D A) 
re q uiri n g h os pitalisati o n, d oc u me nte d me dical hel p, or is life t hreateni n g  
•  H 0: H R ≥ 1. 0 a gai nst Ha: H R < 1. 0 
4. S u peri orit y of s e ma gl uti de vs. I As p o n b o d y wei g ht  
•  H 0: μ ≥ 0. 0 k g a gai nst Ha: μ < 0. 0 k g 
5.  S u peri orit y of s e ma gl uti de vs. I As p o n H b A 1c 
•  H 0: μ ≥ 0. 0 %-p oi nt a gai nst H a: μ < 0. 0 %-p oi nt  
N o n -i nferi orit y a n d s u p eri ority of se ma gl uti de vers us I As p will be c o nsi dere d c o nfir me d if t h e 
ass ociate d H 0 is reject e d. 
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 E M A g ui deli ne 2 1  a n d t he effect of 
faster-acti n g i ns uli n as part ( FI As p) o n gl ycae mic effect see n i n a si milar tri al ( N N 1 2 1 8 -4 0 4 9) 
w here FI As p was use d i n a basal-b ol us re gi me n vers us basal i ns uli n t hera p y, b ot h i n c o m bi nati o n 
wit h metf or mi n. 2 2  I n t his trial FI As p s h o we d a n H b A1c treat me nt differe n ce t o place b o of -0. 9 4 % -
p oi nt. FI As p is n o n -i nferi or t o I As p i n ter ms of l o weri n g H b A1c le vels.2 3 He nce, b ase d o n t his trial, 
t he c h ose n mar gi n of 0. 3 %-p oi nt pr o vi des ass ur a n ce t hat se ma gl uti de has a n eff ect c o m pare d t o 
place b o greater t ha n 0 wit h a cli nicall y rele va nt size. Wit h re gar ds t o t he c o nsta nc y ass u m pti o n, 
c o ntr olle d cli nical trials ha ve c o nsiste ntl y esta blis he d t hat I As p is a n effecti ve a nti -dia betic dr u g. 
T heref ore, la c k of trial se nsiti vit y wi t h I As p as c o m parat or is n ot a ntici pate d t o be a n iss ue i n t his 
trial. 
1 0. 3. 1  
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 fr o m baseli ne t o wee k 5 2 i n H b A 1c ( %-p oi nt).  
Pri m ar y a n al ysis  
Acc or di n g t o t he pri mar y esti ma n d, t he pri mar y a n al ysis will be esti mate d b ase d o n t he F A S usi n g 
p ost -baseli ne meas ur e me nts u p t o a n d i ncl u di n g wee k 5 2 fr o m t he ’ o n -treat me nt’ o bser vati o n 
peri o d. I m p utati o n of missi n g data will be ha n dle d usi n g m ulti ple i m p utati o n ass u mi n g t hat missi n g 
data is missi n g at ra n d o m ( M A R). Missi n g da ta will be i m p ute d usi n g o bser ve d data wit hi n eac h of 
t he t w o gr o u ps defi ne d b y t he ra n d o mise d treat me nt (se ma gl uti de/I As p). It is here b y ass u me d t hat 
t he li kel y val u es of w hat t he missi n g data w o ul d h a ve bee n, if a vaila bl e, are best descri be d b y 
i nf or matio n fr o m s u bjects w h o recei ve t he sa me treat me nt.  
Tec h nicall y, missi n g v al ues will be i m p ute d as f oll o ws:  
  Pr ot oc ol  v 3. 0 |
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6 2 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
6 3  of 1 0 5  
 
•  I nter mitte nt missi n g val ues are i m p ute d usi n g a M ar k o v C hai n M o nte Carl o ( M C M C) 
met h o d, i n or der t o o btai n a m o n ot o ne missi n g data patter n. T his i m p uta ti o n is d o ne f or 
eac h of t h e treat me nt gr o u ps se paratel y a n d 5 0 0 c o pies of t he dataset will be ge nerate d.  
•  A se q ue ntial c o n diti o nal li near re gressi o n a p pr oac h f or i m p uti n g m o n ot o ne missi n g 
val ues at pla n ne d visits will be i m ple me nte d starti n g wit h t he firs t visit aft er baseli ne 
a n d se q ue ntiall y c o nti n ui n g t o t he last pla n ne d visit at wee k 5 2. A m o del use d t o i m p ute 
missi n g val ues at e ac h pl a n ne d visit will be fitte d f or eac h of t he ra n d o mise d treat me nt 
gr o u ps usi n g o bser ve d data. T he m o del will i ncl u de t he baseli ne a n d p ost -b aseli ne 
H b A 1c val ues o bser ve d pri or t o t he visit i n q uesti o n as c o vari ates. T he res ulti n g 5 0 0 
c o m plete datasets will f urt her m ore b e use d f or t he s u bse q ue nt ti p pi n g a n al ysis t o 
e val uate t he r o b ust ness of t he pri mar y a n al ysis.  
•  A n a nal ysis of c o v aria nce ( A N C O V A) wit h treat me nt as cate g orical effect a n d baseli ne 
H b A 1c as a c o variate will be use d t o a nal yse H b A 1c val ues at wee k 5 2 f or eac h of t he 
5 0 0 c o m plete data sets. R u bi n’s r ule 2 4 will be use d t o c o m bi ne t he a nal ysis res ults i n 
or der t o dra w i nfere nce.  
 
Fr o m t his a nal ysis, t he esti mate d treat me nt differe nce bet w ee n se ma gl uti de a n d I As p at w ee k 5 2 
will be  prese nte d t o get h er wit h t he ass ociate d t w o -si de d 9 5 % c o nfi d e nce i nter val ( CI) a n d t w o-
si de d p-val ue.  
Se nsiti vit y a n al yses  
T he ai m of t he bel o w pre -s pecifie d s e nsiti vit y a nal ysis is t o i n vesti gate t h e r o b ust ness of t he 
c o ncl usi o ns fr o m t he pri mar y a nal ysis  a n d t o stress test t he missi n g at ra n d o m ass u m pti o n.  
Ti p pi n g p oi nt a n alysis  
T he ti p pi n g p oi nt a nal ysis is base d o n t he F A S usi n g t he ’o n -treat me nt’ o bs er vati o n peri o d. I n t his 
a nal ysis, s u bjects fr o m t h e se ma gl uti de gr o u p wit h missi n g o bser vati o ns will be gi ve n a pe n alt y, 
i.e., it is ass u me d t hat s u bjects wit h missi n g o bser vati o ns w h o are ra n d o mise d t o se ma gl uti de will 
recei v e a tr eat me nt t hat is less be neficial t ha n s u bj ects wit h o bser ve d v al ues w h o are ra n d o mise d t o 
se ma gl uti de. T h e 5 0 0 c o m plete datasets create d f or t he pri mar y a n al ysis will be re -use d f or t he 
ti p pi n g-p oi nt a nal ysis. F or eac h of t hese d atasets, pe nalt y v al ues are a d d e d ste p wise t o t he i m p ute d 
c ha n ge fr o m baseli ne at wee k 5 2 f or s u bjects r a n d o mise d t o se ma gl uti de, f oll o we d b y perf or mi n g 
a n A N C O V A. T he a d diti o n of t he pe nalt y val ues a n d s u bse q ue nt a nal ysis ste ps s h o ul d be re peate d 
wit h i ncreasi n g pe n alt y v al ues u ntil a si g nifica nt r es u lt i n t he c orres p o n di n g s u peri orit y a n d n o n-
i nferi orit y a nal yses are n o l o n ger si g nifica nt.  
Retrieve d dr o p o ut a n alysis  
T he retrie v e d dr o p o ut a n al ysis will be base d o n t h e F A S usi n g t he ‘i n -trial’ o bser vati o n peri o d. 
Missi n g data will be i m p ute d usi n g t he sa m e a p pr oac h as des cri be d f or t he pri mar y a nal ysis of t he 
pri mar y esti ma n d. H o we ver t he i m p utati o n will be d o ne wit hi n t he sa me gr o u p defi ne d n ot o nl y b y 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
6 3 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
6 4  of 1 0 5  
 
t he ra n d o mise d treat me nt (se ma gl uti de/ I As p) b ut als o b y t he treat me nt stat us (still o n ra n d o mise d 
treat me nt at wee k 5 2 yes/ n o) ( 4 gr o u ps i n t otal). It is here b y ass u me d t hat t h e li kel y v al ues of w hat 
t he missi n g data w o ul d h a ve bee n if a vaila bl e are best descri be d b y i nf or mati o n fr o m s u bjects w h o 
at wee k 5 2 are si milar i n ter ms of ra n d o mise d tr eat me nt a n d treat me nt stat us. T his a nal ysis will be 
perf or me d f or b ot h n o n -i nferi orit y a n d s u peri orit y testi n g. 
Per pr ot oc ol a n alysis  
T he per pr ot o c ol a nal ysis is base d o n t he P P a nal ysis set usi n g t he ‘ o n -tr eat me nt ’ o bser vati o n 
peri o d. T his a nal ysis will be carrie d o ut f or n o n -i nferi orit y testi n g o nl y. T h e statistical a nal ysis will 
be t he sa me as t h e pri mar y a n al ysis f or t he pri mar y esti ma n d.  
1 0. 3. 2  
Sec o n d ar y e n d p oi nts  
1 0. 3. 2. 1  
C o nfir m at or y s ec o n d ar y e n d p oi nts  
T he c o nfir mat or y sec o n d ar y e n d p oi nts are ti me t o first E A C c o nfir me d se v ere h y p o gl ycae mic 
e pis o de ( A D A), ti me t o first E A C c o nfir me d se vere h y p o gl ycae mic e pis o d e ( A D A) re q uiri n g 
h os pitaliz ati o n, d oc u me nte d me dical hel p, or is lif e t hreate ni n g a n d c ha n ge fr o m baseli ne t o wee k 
5 2 i n b o d y wei g ht.  
C o nfir m at or y a n al yses  
T he statistical a nal ysis of ti me t o first E A C c o nfir me d se vere h y p o gl ycae mic e pis o de ( A D A) will 
be base d o n t he F A S usi n g t he ‘ o n -treat me nt’ o bser vati o n peri o d. T he h azar d rati o c o m pari n g 
se ma gl uti de v ers us I As p will be esti mate d fr o m a C o x pr o p orti o nal hazar ds m o del wit h treat me nt 
gr o u p (se ma gl uti de, I As p) as fi x e d fact or t o get h er wit h t he t w o -si de d 9 5 % CI a n d t h e t w o-si de d p-
val ue. S u bjects w h o ha ve n ot e x perie nce d a n E A C c o nfir me d se v ere h y p o gl ycae mic e pis o de ( A D A) 
wit hi n t he ‘ o n -treat me nt’ o bser vati o n peri o d will be c o nsi dere d ce ns ore d wit h t he ce ns ori n g date 
gi ve n b y t he e n d -dat e of t he ‘ o n -treat me nt’ o bser vati o n peri o d. S u peri orit y will be teste d acc or di n g 
t o t he statistical a nal ysis a p pr oac h t o m ulti plicit y descri be d i n Secti o n 1 0. 3 . 
T he statistical a nal ysis of ti me t o first E A C c o nfir me d se vere h y p o gl ycae mic e pis o de ( A D A) 
re q uiri n g h os pitaliz ati o n, d oc u me nte d me dical hel p, or is life t hreate ni ng will be a nal ys e d i n t he 
sa me ma n ner as t he c o nfir mat or y e n d p oi nt ti me t o first E A C c o nfir me d se v ere h y p o gl ycae mic 
e pis o de ( A D A) as des cri be d a b o ve. T his a nal ysis will be base d o n t he F A S a n d t he ‘ o n -tr eat me nt’ 
o bser vati o n peri o d.  
F or eac h ti me -t o-e ve nt e n d p oi nt, a Ka pla n -Mei er pl ot wit h n u m bers of s u bjects at ris k at s pecifi c  
ti me p oi nts f or eac h tr eat me nt gr o u p will be prese nte d. 
 
Acc or di n g t o t he pri mar y esti ma n d, b o d y wei g ht will be a nal ys e d usi n g t he sa me a p pr oac h as 
descri be d i n Secti o n 1 0. 3. 1 . B o d y wei g ht will be t este d f or s u peri orit y acc or di n g t o t he statistical 
  Pr ot oc ol  v 3. 0 |
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6 4 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
6 5  of 1 0 5  
 
a nal ysis a p pr oac h t o m ulti plicit y d escri be d i n Secti o n 1 0. 3 . Baseli ne a n d p ost-baseli ne b o d y wei g ht 
will be use d as c o variates i nstea d of H b A 1c. 
Se nsiti vit y a n al yses  
A n i n -trial se nsiti vit y a nal ysis will be perf or me d t o e val uate t he r o b ust ness of t he c o ncl usi o ns fr o m 
t he statistical a nal ysis of ti me t o first E A C c o nfir me d se vere h y p o gl ycae mic e pis o de ( A D A). T his 
i n-trial a nal ysis is base d o n t he F A S usi n g t h e ‘i n-trial’ o bser vati o n peri o d. S u bjects w h o ha ve n ot 
e x perie nced a n E A C c o nfir me d se vere h y p o gl ycae mic e pis o de ( A D A) wit hi n t he ‘i n -trial’ 
o bser vati o n peri o d will b e c o nsi dere d ce ns ore d wit h t he ce ns ori n g date gi v e n b y t h e i n -trial e n d-
date. T he statistical a n al ysis will be t he sa me as t he statistical a nal ysis f or t he  pri mar y esti ma n d.  
M ore o ver, t he ti me t o first E A C c o nfir me d se vere h y p o gl ycae mic e pis o de ( A D A) re q uiri n g 
h os pitaliz ati o n, d oc u me nte d me dical hel p, or is lif e t hreate ni n g will be a nal ys e d usi n g t he s a me 
m o del as descri be d a b o v e b ut usi n g all data c ollecte d  i n t he ‘i n-trial’ o bser vati o n peri o d i nstea d.   
T he ti p pi n g p oi nt se nsiti vit y a nal ysis pre -s pecifie d t o e val uate t he r o b ust n ess of t he c o n cl usi o ns 
fr o m t he pri mar y a nal ysis of H b A1c will als o be perf or me d t o e val uate t h e r o b ust ness of t he  
c o ncl usi o ns fr o m  t he b o d y w ei g ht s u p eri orit y t est. I n a d diti o n, t he retrie v e d dr o p o ut se nsiti vit y 
a nal ysis will als o be p erf or me d f or b o d y wei g ht.  
1 0. 3. 2. 2  
S u p p orti ve sec o n d ar y e n d p oi nts  
T he f oll o wi n g c o nti n u o us s u p p orti ve sec o n dar y e n d p oi nts are c o nsi dere d. C ha n ge fr o m bas eli ne t o 
wee k 5 2 i n:  
•  Fasti n g plas ma gl uc ose ( m m ol/ L)  
•  Mea n 7 -p oi nt self -me as ure d plas ma gl uc ose pr ofil e ( m m ol/ L)  
•  Mea n p ost -pra n di al i ncre me nt ( o ver all meals) ( m m ol/ L)  
•  S yst olic a n d diast olic bl o o d press ure ( m m H g)  
•  Fasti n g bl o o d li pi ds (t otal c h olester ol, l o w -de nsi t y li p o pr otei n ( L D L) c h olester ol, hi g h-
de nsit y li p o pr otei n ( H D L) c h olester ol, tri gl yceri des) ( m m ol/ L)  
•  B o d y mass i n de x ( B MI) ( k g/ m 2) 
•  Waist circ u mfere n ce (c m)  
•  B o d y wei g ht ( %)  
 
T he a b o ve c o nti n u o us e n d p oi nts will be a nal yse d se parat el y usi n g a si milar m o del a p pr oac h as f or 
t he pri mar y e n d p oi nt wit h t he ass ociate d baseli ne val ue as c o v ariate i nstea d of H b A1c f or t heir 
res pecti ve a nal yses. T h es e a nal yses will be b ase d o n t he F A S a n d t he ‘ o n-treat me nt’ o bser vati o n 
peri o d.  
Fasti n g bl o o d li pi d e n d p oi nts will be l o g -tra nsf or me d pri or t o a nal ysis wit h t he ass ociate d l o g-
tra nsf or me d b aseli ne val ue as a c o v ariat e. 
  Pr ot oc ol  v 3. 0 |
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Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
6 6  of 1 0 5  
 
P ulse r ate  
C ha n ge fr o m bas eli ne t o wee k 5 2 i n p ulse rate ( b p m) will be a nal yse d usi n g a n a nal ysis si milar t o 
t he pri mar y a n al ysis of t h e pri mar y e n d p oi nt b ut wit h t he baseli ne p ulse rate val ue as c o v ariate 
i nstea d of H b A1c. T his a nal ysis will be base d o n t h e S A S usi n g t he ‘ o n-tr eat me nt’ o bser vati o n 
peri o d.  
Hy p o glyc a e mic e pis o des  
T he s u p p orti ve sec o n d ar y safet y e n d p oi nts rel ate d t o h y p o gl ycae mic e pis o des are:  
•  N u m ber of E A C c o nfir m e d se vere h y p o gl ycae mic e pis o des ( A D A) fr o m ra n d o misati o n 
t o wee k 5 2 
•  N u m ber of E A C c o nfir m e d se vere ( A D A) or bl o o d gl uc ose c o nfir me d, s y m pt o matic 
h y p o gl ycae mic e pis o des ( P G < 3. 1 m m ol/ L ( 5 6 m g/ d L)) fr o m r a n d o misati o n t o wee k 5 2  
•  N u m ber  of E A C c o nfir m e d se vere ( A D A) or bl o o d gl uc ose c o nfir me d, s y m pt o matic 
h y p o gl ycae mic e pis o des ( P G ≤ 3. 9 m m ol/ L ( 7 0 m g/ d L)) fr o m r a n d o misati o n t o wee k 5 2  
•  N u m ber of E A C c o nfir m e d se vere h y p o gl ycae mic e pis o des ( A D A) re q uiri n g 
h os pitalisati o n, d oc u me nte d me di cal hel p, or is lif e t hreate ni n g fr o m ra n d o misati o n t o 
wee k 5 2  
 
T he n u m ber h y p o gl ycae mic e pis o des of t he a b o v e t y p es will be a nal yse d usi n g a n e gati ve bi n o mial 
re gressi o n m o del wit h a l o g-li n k f u n cti o n a n d t he l o garit h m of t he ti me peri o d c o vere d b y t h e 
su bject’s ‘ o n -tr eat me nt’ o bser vati o n peri o d as offset. T he m o del will i ncl u de treat me nt as a fi x e d 
fact or a n d baseli ne H b A1c as a c o vari ate. T his a nal ysis will be base d o n t he F A S usi n g t he ‘ o n -
treat me nt’ o bser vati o n peri o d. T he res ults will be descri be d b y t he rate rati o bet wee n tr eat me nts a n d 
t he ass ociate d 9 5 % CI a n d p-val ue f or n o treat me nt differe n ce.  
M ore o ver, t he a b o ve t y p es of n u m ber of h y p o gl ycae mic e pis o des will als o be a nal yse d b ase d o n t he 
‘i n-trial’ o bser vati o n peri o d, still usi n g t he a b o ve me nti o ne d m o del, h o we v er usi n g all data 
c ollecte d i n t he ‘i n -tri al’ o bser vati o n peri o d. 
S u p p orti ve sec o n d ar y H R Q o L e n d p oi nts  
C ha n ge fr o m bas eli ne t o wee k 5 2 i n t he f oll o wi n g sc ores f or t he selecte d P R Os:  
•  3 6 -ite m S h ort F or m Healt h S ur ve y v ersi o n 2 ( S F-3 6 v 2 ™  )  
o  P h ysical C o m p o ne nt S u m mar y ( P C S) sc ore (ra n ge: 7. 3 2 -7 0. 1 4)  
o  Me ntal C o m p o ne nt S u m mar y ( M C S) sc ore (ra n ge: 5. 7 9 -6 9. 9 1)  
o  P h ysical F u ncti o ni n g ( P F) d o mai n sc ore (ra n ge: 1 9. 2 6 -5 7. 5 4)  
o  R ole -P h ysical ( R P) d o mai n sc ore (ra n ge: 2 1. 2 3 -5 7. 1 6)  
o  B o dil y Pai n ( B P) d o mai n sc o re (ra n ge: 2 1. 6 8-6 2. 0 0)  
o  Ge neral Healt h ( G H) d o mai n sc ore (ra n ge: 1 8. 9 5 -6 6. 5 0)  
o  Vitalit y ( V T) d o m ai n sc ore (ra n ge: 2 2. 8 9 -7 0. 4 2)  
o  S ocial F u ncti o ni n g ( S F) d o mai n sc ore (ra n ge: 1 7. 2 3 -5 7. 3 4)  
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C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
6 7  of 1 0 5  
 
o  R ole -E m oti o nal ( R E) d o mai n sc ore (ra n ge: 1 4. 3 9 -5 6. 1 7)  
o  Me ntal Healt h ( M H)  d o mai n sc ore (ra n ge: 1 1. 6 3 -6 3. 9 5)  
 
T he te n sc ores relat e d t o S F -3 6 v 2 ™   are meas ure d o n a scale fr o m 5. 7 9 -7 0. 4 2, a n d 
calc ulate d usi n g t he 2 0 0 9 Ge neral U. S. P o p ulati o n. Hi g her sc ores are i n dicati ve of a 
better healt h state.  
 
•  Dia betes Q ualit y Of Life Cli nic al Trial Q uesti o n naire ( D Q L C T Q -R)  
o  P h ysical f u n cti o ni n g d o mai n sc ore  
o  E ner g y / fati g ue d o mai n sc ore  
o  Healt h distress d o mai n sc ore  
o  Me ntal healt h d o mai n sc ore  
o  Satisfacti o n d o mai n sc ore  
o  Treat me nt satisfacti o n d o mai n sc ore  
o  Treat me nt fle xi bilit y d o mai n sc ore  
o  Fr e q u e nc y of s y m pt o ms d o mai n sc ore  
 
T he ei g ht sc ores relate d t o D Q L C T Q -R are meas ure d o n a scale fr o m 0 -1 0 0.  
Hi g her sc ores are i n dicati ve of a better healt h stat e.  
 
T he P R O q uesti o n naires, S F -3 6 v 2 ™ a n d D Q L C T Q -R, will be use d t o e val uate t he o bjecti ve 
re gar din g Q u alit y of Life. Eac h of t he P R O e n d p oi nts will be a nal ys e d se paratel y as t he ot her 
c o nti n u o us s u p p orti ve sec o n dar y e n d p oi nts usi n g a si milar m o del a p pr oac h as f or t he pri mar y 
e n d p oi nt wit h t he ass ociate d baseli ne val ue as c o v ariates. T hes e a n al ys es wil l be base d o n t he F A S 
a n d t he ‘ o n -tr eat me nt’ o bser vati o n peri o d. 
1 0. 3. 3  
E x pl or at or y e n d p oi nts  
E x pl or at or y res p o n der e n d p oi nts  
•  H b A 1c ≤ 7. 5 % at wee k 5 2 ( Y/ N)  
•  H b A 1c < 7. 0 % ( 5 3 m m ol/ m ol) at wee k 5 2 ( Y/ N) ( A D A)  
•  H b A 1c ≤ 6. 5 % ( 4 8 m m ol/ m ol) at wee k 5 2 ( Y/ N) ( A A C E)  
•  H b A 1c ≤ 7. 5 % at wee k 5 2 wit h o ut a n E A C c o nfir me d se vere h y p o gl ycae mic e pis o de 
( A D A) fr o m ra n d o misati o n t o wee k 5 2 ( Y/ N) 
•  H b A 1c ≤ 7. 5 % at wee k 5 2 wit h o ut a n E A C c o nfir me d se vere h y p o gl ycae mic e pis o de 
( A D A) re q uiri n g h os pitalisati o n, d oc u me nte d me dical hel p, or is life t hreate ni n g fr o m 
ra n d o misati o n t o wee k 5 2 ( Y/ N) 
•  Wei g ht l oss ≥ 5 % at wee k 5 2 ( Y/ N)  
•  Wei g ht l oss ≥ 1 0 % at wee k 5 2 ( Y/ N)  
 
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C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
6 8  of 1 0 5  
 
T he a b o ve s e ve n bi nar y e n d p oi nts will be a nal yse d usi n g a l o gistic re gressi o n m o del wit h treat me nt 
as fi x e d effects a n d baseli ne res p o nse as c o variate (i.e. baseli ne H b A 1c f or bi nar y H b A1c e n d p oi nts, 
baseli ne wei g ht f or wei g ht e n d p oi nts). T hese a n al ys es will be b ase d o n t he F A S a n d t he ‘ o n -
treat me nt’ o bser vati o n peri o d. T o acc o u nt f or missi n g data, t h e a nal ysis will be ma de usi n g a 
se que ntial m ulti ple i m p utati o n a p pr oac h as descri b e d bel o w:  
•  T he bi nar y e n d p oi nts will be deri ve d bas e d o n t he 5 0 0 i m p ute d datasets fr o m t he 
pri mar y a nal ysis of H b A 1c a n d c o nfir mat or y a nal ysis of b o d y wei g ht. F or t he res p o n der 
e n d p oi nts relate d t o h y p o gl ycae mi c e pis o des, t h e n u m ber of h y p o gl ycae mic e pis o des 
f or t he re m ai ni n g u n o bs er ve d part of t h e o bser vati o n peri o d will be i m p ute d a n d 
s u bse q ue ntl y t he t otal n u m ber of h y p o gl ycae mic e pis o des will be dic h ot o mise d. T his 
will be d o ne usi n g a Ba yes ne gati ve bi n o mial  l o g-li n k m o del wit h baseli ne H b A1c as 
c o variate, a n d t he l o garit h m of t he ti me peri o d c o vere d b y t he s u bject’s ‘ o n -treat me nt’ 
o bser vati o n peri o d as offset.  
•  Eac h of t he c o m plete dat a set will be a nal yse d wit h t he descri be d l o gistic re gressi o n 
m o del. Esti mate d o d ds rati os will be l o g tra nsf or m e d a n d i nfere nce will be dra w n usi n g 
R u bi n’s r ule 2 4. 
 
T he res ults will be bac k -tra nsf or me d a n d des cri be d b y t he o d ds rati o bet wee n treat me nts a n d t h e 
ass ociate d 9 5 % CI a n d p -val ue f or n o tr eat me nt differe n ce.  
E x pl or at or y P R O e n d p oi nts  
C ha n ge fr o m bas eli ne t o wee k 5 2 i n t he f oll o wi n g sc ores f or t he f oll o wi n g P R O:  
•  Treat me nt Relat e d I m p act Meas ure F or Dia betes ( T RI M -D)  
o  T RI M -D T otal Sc ore  
o  Treat me nt B ur de n D o mai n Sc ore  
o  Dail y Lif e D o mai n Sc ore  
o  Dia betes Ma n a ge me nt D o mai n Sc ore  
o  C o m plia nce D o mai n Sc ore  
o  Ps yc h ol o gical H ealt h D o mai n Sc ore  
 
T he si x sc ores relate d t o T RI M -D are meas ure d o n a scale fr o m 0 -1 0 0.  
Hi g her sc ores are i n dicati ve of better healt h state (less ne gati ve i m pact).  
 
T he P R O q uesti o n naire, T RI M -D, will be a nal yse d as t he ot her P R O q uesti o n naires descri be d i n 
Secti o n 1 0. 3. 2. 2 . 
1 0. 3. 4  
Ot her a n al yses  
A t otal of f o ur a d diti o nal a nal ys es re gar di n g h y p o gl ycae mic e pis o des will be perf or me d. T hes e 
c o nsi der:  
  Pr ot oc ol  v 3. 0 |
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6 8 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
6 9  of 1 0 5  
 
•  Ti me t o first E A C c o nfir me d  se vere ( A D A) or bl o o d gl uc os e c o nfir me d, s y m pt o matic 
h y p o gl ycae mic e pis o de ( P G < 3. 1 m m ol/ L ( 5 6 m g/ d L)) fr o m r a n d o misati o n u p t o wee k 
5 2 ( da ys)  
•  Ti me t o first E A C c o nfir me d se vere ( A D A) or bl o o d gl uc os e c o nfir me d, s y m pt o matic 
h y p o gl ycae mic e pis o de ( P G ≤ 3. 9 m m ol/ L ( 7 0 m g/ d L)) fr o m r a n d o misati o n u p t o wee k 
5 2 ( da ys)  
 
T hese a n al ys es will be perf or me d i n t he sa m e ma n ner as t he c o nfir mat or y a nal ysis of t he e n d p oi nt 
ti me t o first E A C c o nfir me d se vere h y p o gl ycae mic e pis o de ( A D A) as d escri be d i n Secti o n 1 0. 3. 2. 1 . 
T hese a n al ys es will be base d o n F A S a n d t he ‘ o n -treat me nt’ o bser vati o n peri o d. M ore o ver, t h ese 
a nal ys es will als o be perf or me d usi n g F A S a n d all dat a c ollecte d i n t he ‘i n -trial’ o bser vati o n peri o d. 
1 0. 4  
P h ar m a c o ki netic a n d/ or p h ar m a c o d y n a mic m o delli n g  
N ot a p plica ble f or t his trial.  
  Pr ot oc ol  v 3. 0 |
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6 9 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
7 0  of 1 0 5  
 
1 1  Refere nces  
1.  
Clar ke W L, C o x DJ, G o n der -Fre d eric k L A, J ulia n D, Sc hl u n dt D, P ol o ns k y W. Re d uce d 
a ware ness of h y p o gl yce mia i n a d ults wit h I D D M. A pr os pecti ve st u d y of h y p o gl yce mic 
fre q ue n c y a n d ass ociate d s y m pt o ms. Dia betes Care. 1 9 9 5; 1 8( 4): 5 1 7-2 2.  
2.  
A merica n Di a betes Ass o ciati o n. Sta n dar ds of me dical care i n dia betes - 2 0 1 7. Dia betes 
Care. 2 0 1 7; 4 0( S u p pl 1): S 1 -1 3 5.  
3.  
I nz ucc hi SE, 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.  
4.  
Leese G P, W a n g J, Br o o m hall J, Kell y P, Mars de n A, M orris o n W, et al. Fre q ue nc y of 
se vere h y p o gl yce mia re q uiri n g e mer ge n c y treat m e nt i n t y pe 1 a n d t y p e 2 dia betes: a 
p o p ulati o n -base d st u d y of healt h se r vice res o urce use. Dia betes Care. 2 0 0 3; 2 6( 4): 1 1 7 6 -8 0.  
5.  
B u n desärzte ka m mer ( B Ä K), Kasse närztlic he B u n des verei ni g u n g ( K B V), 
Ar beits ge mei nsc haft der Wisse nsc haftlic he n Me di zi nisc he n Fac h ges ellsc hafte n ( A W M F). 
Nati o nale Vers or g u n gs Leitli nie T hera pie des T y p -2 -Dia bet es. La n gfass u n g.  U R L: 
htt p:// w w w.a w mf. or g/ u pl oa ds/t x _szleitli nie n/ n vl -0 0 1 gl _ S 3 _ T y p -2 -Di a betes -
T hera pie _ 2 0 1 4 -1 1. p df. 2 0 1 4.  
6.  
Ka pitza C, N ose k L, J e ns e n L, Hart vi g H, J e nse n C B, Fli nt A. Se ma gl uti de, a o nce -wee kl y 
h u ma n G L P -1 a nal o g, d o es n ot r e d uce t he bi oa vail a bilit y of t he c o m bi ne d oral 
c o ntrace pti ve, et hi n yl estr a di ol/le v o n or gestrel. J Cli n P har mac ol. 2 0 1 5; 5 5( 5): 4 9 7-5 0 4.  
7.  
Mars o S P, Bai n S C, C o ns oli A, Eliasc he witz F G, J ó dar E, Leiter L A, et al. Se ma gl uti de a n d 
Car di o vasc ular O utc o mes i n Pat ie nts wit h T y p e 2 Dia betes. N E n gl J Me d. 2 0 1 6; 3 7 5: 1 8 3 4 -
4 4.  
8.  
R o d bar d H, Li n g va y I, R ee d J, de la R osa R, R ose L, S u gi m ot o D, et al. Efficac y a n d s afet y 
of se ma gl uti de o nce -wee kl y vs place b o as a d d -o n t o basal i ns uli n al o ne  or i n c o m bi nati o n 
wit h metf or mi n i n s u bjects wit h t y p e 2 dia betes ( S U S T AI N 5) [a bstract]. Dia bet ol o gia. 
2 0 1 6; 5 9( S u p pl 1): 3 6 4 -5.  
9.  
E n g C, Kra mer C K, Zi n ma n B, Ret na kara n R. Gl uca g o n -li ke pe pti de-1 rece pt or a g o nist a n d 
basal i ns uli n c o m bi nati o n treat me nt f or t he m a na ge m e nt of t y p e 2 dia b et es: a s yste matic 
re vie w a n d m eta-a nal ysis. La n cet. 2 0 1 4; 3 8 4( 9 9 6 1): 2 2 2 8 -3 4.  
1 0.  
Dia ma nt M, Na uc k M A, S ha gi nia n R, Mal o ne J K, Cleall S, Rea ne y M, et al. Gl uca g o n -li ke 
pe pti de 1 rece pt or a g o nist or b ol us i ns uli n wit h o pti mize d basal i ns uli n i n t y p e 2 di a bet es. 
Dia betes Care. 2 0 1 4; 3 7( 1 0): 2 7 6 3 -7 3.  
1 1.  
Bale n a R, He nsle y I E, Miller S, Bar nett A H. C o m bi nati o n t hera p y wit h G L P -1 rece pt or 
a g o nists a n d b asal i ns uli n: a s yste matic re vie w of t he literat ure. Dia betes O bes Meta b. 
2 0 1 3; 1 5( 6): 4 8 5 -5 0 2.  
1 2.  
R ose nst oc k J, F o nseca V A, Gr oss J L, Rat ner R E, A hré n B, C h o w F C, et al. A d va nci n g bas al 
i ns uli n re place me nt i n t y pe 2 dia betes i na d e q uatel y c o ntr olle d wit h i ns uli n glar gi n e pl us oral 
a ge nts: a c o m paris o n of a d di n g al bi gl uti de, a wee kl y G L P -1 rece pt or a g o nist, vers us t hric e-
dail y pra n dial i ns uli n lis pr o. Dia betes Care. 2 0 1 4; 3 7( 8): 2 3 1 7 -2 5.  
1 3.  
Ki d ne y Disease: I m pr o vi n g Gl o bal O ut c o mes ( K DI G O) C K D W or k Gr o u p. K DI G O 2 0 1 2 
Cli nical Practice G ui deli ne f or t he E v al uati o n a n d Ma na ge me nt of C hr o ni c Ki d ne y Disease. 
Ki d ne y I nt S u p pl. 2 0 1 3; 3( 1): 1 -1 5 0.  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
7 0 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
7 1  of 1 0 5  
 
1 4.  
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 yce mia i n t y p e 2 dia betes: a patie nt -ce ntere d a p pr oac h: p ositi o n 
state me nt of t he A meri ca n Dia betes Ass oci ati o n ( A D A) a n d t h e E ur o pea n Ass ociati o n f or 
t he St u d y of Dia b etes ( E A S D). Dia betes Care. 2 0 1 2; 3 5( 6): 1 3 6 4-7 9.  
1 5.  
Ba n ks P A, B olle n T L, D er ve nis C, G o osze n H G, J o h ns o n C D, Sarr M G, et al. Classificati o n 
of ac ute p a ncreatitis -2 0 1 2: re visi o n of t he Atla nta classificati o n a n d defi niti o ns b y 
i nter nati o nal c o nse ns us. G ut. 2 0 1 3; 6 2( 1): 1 0 2-1 1.  
1 6.  
G ui deli ne o n t he e x p os ure t o me dici nal pr o d ucts d uri n g pre g na n c y: Nee d f or p ost -
a ut h orisati o n data ( E M E A/ C H M P/ 3 1 3 6 6 6/ 2 0 0 5). 2 0 0 5.  
1 7.  
Billi n gs L, D os hi, A, G o uet, D, O vie d o, A, R o d bar d, H, Te nt ol o uris,  N, Gr ø n, R, Halla di n, 
N, J o dar, E. Efficac y a n d Safet y of I ns uli n De gl u d ec/ Lira gl uti de (I De g Lir a) vs. Basal -B ol us 
( B B) T hera p y i n Patie nts wit h T y pe 2 Dia betes ( T 2 D): D U A L VII Trial. Di a betes 1 0  J u ne 
2 0 1 7 2 0 1 7.  
1 8.  
Gar ber AJ, Ki n g A B, Del Prat o S, Sree na n  S, Balci M K, M u n oz -T orres M, et al. I ns uli n 
de gl u d ec, a n ultra -l o n gacti n g basal i ns uli n, vers us i ns uli n glar gi ne i n basal-b ol us treat me nt 
wit h mealti me i ns uli n as part i n t y pe 2 di a betes ( B E GI N Basal -B ol us T y pe 2): a p hase 3, 
ra n d o mise d, o pe n-la b el, treat-t o-tar get n o n-i nf eri orit y trial. La n cet. 2 0 1 2; 3 7 9( 9 8 2 5): 1 4 9 8-
5 0 7.  
1 9.  
Bl o n de L, J e n dle J, Gr oss J, W o o V, Jia n g H, Fa hr bac h J L, et al. O nce -wee kl y d ula gl uti de 
vers us be dti me i ns uli n gl ar gi ne, b ot h i n c o m bi nati o n wit h pra n dial i ns uli n lis pr o, i n patie nts 
wi t h t y pe 2 dia b etes ( A W A R D-4): a ra n d o mise d, o pe n -la bel, p has e 3, n o n-i nferi orit y st u d y. 
La n cet. 2 0 1 5; 3 8 5( 9 9 8 2): 2 0 5 7 -6 6.  
2 0.  
N o v o N or dis k A/ S. Cli nical Trial Re p ort ( E X 1 2 5 0 -4 0 8 0).  A trial c o m pari n g car di o vas c ular 
safet y of i ns uli n de gl u de c vers us i ns uli n glar gi ne i n s u bjects wit h t y pe 2 di a betes at hi g h ris k 
of car di o v asc ular e ve nts. 2 4 Mar 2 0 1 7.  
2 1.  
E ur o pea n Me dici nes A ge nc y, C o m mittee f or M e di ci nal Pr o d ucts f or H u ma n Use ( C H M P). 
G ui deli ne o n cli nical i n vesti gati o n of me di ci 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. 1). A d o pti o n b y C H M P. 1 4 Ma y 2 0 1 2.  
2 2.  
R o d bar d H W, Tri pat h y D, Vi dri o Veláz q uez M, De missie M, Ta mer S C, Piletič M. A d di n g 
fast-acti n g i ns uli n as part t o basal i ns uli n si g nifica ntl y i m pr o ve d gl ycae mic c o ntr ol i n 
patie nts wit h t y pe 2 dia b etes: A ra n d o mize d, 1 8 -wee k, o pe n -la bel, p has e 3 trial ( o nset 3). 
Dia betes O bes M eta b. 2 0 1 7; 1 9( 1 0): 1 3 8 9 -9 6.  
2 3.  
B o weri n g K C C, Har ve y J, et al,. Faster -acti n g i ns uli n as part vs i ns uli n as part as part of 
basal -b ol us t hera p y i m pr o ves p ost pra n dial  gl yce mic c o ntr ol i n u nc o ntr olle d T 2 D i n t he 
d o u ble bli n de d o nset 2 trial. Ca n J Dia betes. 2 0 1 6; 4 0( 5)( S u p pl).  
2 4.  
Bretz F, M a urer W, Bra n nat h W, P osc h M. A gra p hical a p pr oac h t o se q ue ntiall y rej ecti ve 
m ulti ple test pr oce d ures. Stat M e d. 2 0 0 9; 2 8( 4): 5 8 6 -6 0 4.  
2 5.  
Little RJ A, R u bi n D B. Statistical a nal ysis wit h missi n g data. Ne w Y or k: Wile y. 1 9 8 7. xi v, 
2 7 8 p. p.  
2 6.  
W orl d Me dical Ass ociati o n. Declarati o n of Helsi n ki - Et hical Pri nci ples f or Me dical 
Researc h I n v ol vi n g H u ma n S u bjects. Last a me n de d b y t he 6 4t h W M A Ge n eral Asse m bl y, 
F ortaleza, Brazil. 1 Oct 2 0 1 3.  
2 7.  
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), C urre nt 
Ste p 4 versi o n. 0 9 N o v 2 0 1 6.  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
7 1 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
7 2  of 1 0 5  
 
2 8.  
I nter nati o nal Or ga niz ati o n f or Sta n dar dizati o n. I S O 1 4 1 55: 2 0 1 1, Cli nical i n vesti gati o n of 
me dical de vices f or h u m a n s u bjects - G o o d cli nical practice. 0 1 Fe b 2 0 1 1.  
2 9.  
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 d ical J o ur nals; c urre nt versi o n 
a vaila ble at w w w.ic mje. or g.  
3 0.  
De A n gelis C, Draze n J M, Frizelle F A, Ha u g C, H oe y J, H ort o n R, et 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.  
3 1.  
U. S. F o o d a n d Dr u g A d mi nistrati o n. F o o d a n d Dr u g A d mi nistrati o n A me n d me nts Act of 
2 0 0 7 as a me n de d b y t he Fi nal R ule " Cli nical Trials Re gistrati o n a n d Res ults I nf or mati o n 
S u b missi o n". 2 1 Se pte m ber 2 0 1 6.  
3 2.  
T he E ur o pea n Parlia me nt a n d t he  C o u ncil of t he E ur o pea n C o u ncil. Directi ve 2 0 0 1/ 2 0/ E C 
of t he E ur o pea n Parlia me nt a n d of t he C o u ncil of 4 A pril 2 0 0 1 o n t he a p pr o xi mati o n of t he 
la ws, re g ulati o ns a n d a d mi nistrati ve pr o visi o ns of t he Me m ber States relati n g t o t he 
i m ple me ntati o n of g o o d clinical 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, article 1 1. Official J o ur nal of t he E ur o pea n C o m m u nities. 0 1 Ma y 
2 0 0 1.  
3 3.  
T he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n C o u ncil. Re g ulati o n ( E C) N o 
7 2 6/ 2 0 0 4 of  t he E ur o pea n Parlia me nt a n d of t he C o u ncil of 3 1 Marc h 2 0 0 4 la yi n g d o w n 
C o m m u nit y pr oce d ures f or t he a ut h orisati o n a n d s u per visi o n of me dici nal pr o d ucts f or 
h u ma n a n d veteri n ar y us e a n d esta blis hi n g a E ur o pea n Me dici nes A ge nc y, article 5 7. 3 0 
A pril 2 0 0 4.  
3 4.  
Sc h wartz N S, Cl utter W E, S ha h S D, Cr yer P E. Gl yce mic t hres h ol ds f or acti vati o n of 
gl uc ose c o u nterre g ulat or y s yste ms are hi g her t ha n t he t hres h ol d f or s y m pt o ms. J Cli n I n v est. 
1 9 8 7; 7 9( 3): 7 7 7 -8 1.  
3 5.  
Sea q uist E R, A n ders o n J, C hil ds B, Cr yer P, Da g o g o -J ack S, Fis h L, et al. H y p o gl yce mia 
a n d dia betes: a re p ort of a w or k gr o u p of t he A merica n Dia bet es Ass ociati o n a n d t he 
E n d ocri ne S ociet y. Dia b etes Care. 2 0 1 3; 3 6( 5): 1 3 8 4 -9 5.  
3 6.  
U S F o o d a n d Dr u g A d mi nistrati o n. G ui da nce f or I n d ustr y. Patie nt -Re p ort e d O utc o me 
M eas ures: Us e i n Me dical Pr o d uct De vel o p me nt t o S u p p ort La b eli n g Clai ms. Dece m ber 
2 0 0 9.  
3 7.  
St ull D E, Lei d y N K, Paras ura ma n B, C hassa n y O. O pti mal recall peri o ds f or patie nt -
re p orte d o utc o m es: c hall e n ges a n d p ote ntial s ol uti o ns. C urr Me d Res O pi n. 2 0 0 9; 2 5( 4): 9 2 9-
4 2.  
3 8.  
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.  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
7 2 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
7 3  of 1 0 5  
 
1 2  A p pe n dic es  
 
A b bre vi ati o ns a n d Tr a de m a r ks  
A D A  
A merica n Dia b etes Ass ociati o n  
A E  
A d verse  e ve nt  
B G  
Bl o o d  gl uc ose  
BI D  
T wice  dail y   
B MI  
B o d y mass  i n de x 
CI  
C o nfi de nce  i nter val 
C L A E  
Cli nical  la b orat or y a d verse  e ve nt  
C V  
Car di o vasc ular  
D P P -4i  
Di pe pti d yl p e pti dase -4 i n hi bit or  
D F U  
Directi o ns  f or use   
D Q L C T Q -R  
Dia b etes Q ualit y Of Life Cli ni cal Trial Q uesti o n naire -re vise d  
D R E  
Disease -Relate d E ve nt  
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 A S D  
E ur o pea n Ass ociati o n f or St u d y of Dia betes  
(e) C R F 
( Electr o nic) case re p ort f or m 
e G F R  
esti mate d  gl o mer ular  filtrati o n rate 
E M A  
E ur o pea n Me dici nes  A ge nc y  
F A S  
F ull  a nal ysis set 
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  
Gl uca g o n -li ke pe pti de-1  
G L P -1 R A  
Gl uca g o n -li ke pe pti de-1 rece pt or a g o nist  
H b A 1c 
Gl ycate d  hae m o gl o bi n  
h C G  
H u ma n c h ori o nic g o na d otr o pi n  
H D L  
Hi g h -de nsit y  li p o pr otei n  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
7 3 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
7 4  of 1 0 5  
 
H R Q o L  
Healt h relate d q ualit y of life  
I As p 
I ns uli n as part  
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 Glar 
I ns uli n glar gi ne  
I M P 
I n vesti gati o nal me dici nal pr o d uct  
I N R 
I nter nati o nal N or malise d Rati o 
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 
K DI G O  
Ki d ne y Disease: I m pr o vi n g Gl o bal O utc o mes  
L D L  
L o w -de nsit y  li p o pr otei n 
Me d D R A  
Me dical Dicti o nar y f or Re g ul at or y Acti vities  
NI M P  
N o n -i n vesti gati o nal me dici nal pr o d uct 
N Y H A  
Ne w Y or k Heart Ass ociati o n  
O A D  
Oral a nti dia betic dr u gs  
O D  
O nce  dail y   
O W  
O nce -wee kl y  
P C D  
Pri mar y  c o m pleti o n date  
P G  
Plas ma gl uc ose  
P P  
P er pr ot oc ol  
P R O  
P atie nt re p orte d o utc o me  
s.c. 
S u bc uta ne o us  
S A E  
Seri o us  a d verse  e ve nt  
S A P  
Statistical  a nal ysis pla n  
S F -3 6 v 2 ™   
3 6 -ite m S h ort F or m Healt h S ur ve y versi o n 2  
SI F  
Safet y i nf or mati o n f or m  
S M P G  
Self -meas ure d  plas ma gl uc ose  
S U S A R  
S us pecte d u ne x pecte d seri o us a d verse reacti o n 
T 2 D  
T y pe 2 dia betes  
TI D  
T hree  ti mes dail y  
T M M  
Trial  materials  ma n ual  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
7 4 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
7 5  of 1 0 5  
 
T RI M -D  
Treat me nt Relate d I m pact Me as ure F or Dia betes  
W O C B P  
W o ma n of c hil d beari n g p ote ntial  
 
 
 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
7 5 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
7 6  of 1 0 5  
 
 
Cli nic al l a b or at or y tests  
•  Bl o o d sa m ples ha ve t o b e o btai ne d, a n d se nt t o t h e ce ntr al la b orat or y, w here t he tests 
detaile d i n  Ta ble  1 2 -1  a n d Ta ble  1 2 -2  will be perf or me d.  
•  A d diti o nal tests ma y be p erf or me d at a n y ti me d uri n g t he trial as deter mi ne d necessar y 
b y t he i n vesti gat or or re q uire d b y l o cal r e 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 nal ysis; if a d diti o nal la b orat or y 
sa m pli n g is nee d e d, e. g. t o f oll o w u p o n A Es, t his m ust be d o ne at a l ocal la b orat or y. 
•  T he 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 o n a n o n g oi n g basis a n d n o l ater t ha n at 
fi nalisati o n of t he cli nical trial re p ort.  
T a ble  1 2 -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   
•  
F P G 1 
•  
H b A 1c 
Li pi ds   
•  
T otal 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  
N O T E S :  
1 A F P G res ult ≤3. 9 m m ol/ L ( 7 0 m g/ d L) i n relati o n t o pla n ne d fasti n g visits s h o ul d n ot be re p orte d as a 
h y p o gl ycae mic e pis o de b ut as a cli nical la b orat or y a d verse e ve nt ( C L A E) at t he discreti o n of t he i n vesti gat or 
(A p pe n di x 4 ). 
 
T a ble  1 2 -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  
Bi oc he mistr y  
•  
Creati ni ne  
•  
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  
 
Uri nal ysis  
•  
Uri ne al b u mi n t o creati ni ne rati o  
H or m o nes  
•  
Calcit o ni n ( o nl y f or scree ni n g p ur p oses)  
Pre g na nc y T esti n g  
•  
Ser u m or 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 (f or 
W O C B P)  
All trial -re q uire d l a b orat or y assess me nts will be p erf or me d b y a ce ntral la b orat or y, wit h t he 
e x ce pti o n of uri ne pre g n a nc y testi n g, w hic h will be perf or me d l ocall y.  
 
 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
7 6 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
7 7  of 1 0 5  
 
 
Tri al g o ver n a nce c o nsi der ati o ns  
1) Re g ul at or y a n d et hic al c o nsi der ati o ns  
•  T his trial will be c o n d ucte d i n acc or da nce wit h t he pr ot o c 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 Practice ( G C P) G ui deli ne 2 6 
•  I S O 1 4 1 5 52 7 
•  A p plica ble l a 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 m e nts (e. g. a d vertise me nts), m ust be s u b mitte d t o a n I R B/I E C a n d 
re vie we d a n d a p pr o ve d b y t he I R B/I E C bef ore t he trial is i nitiate d. 
•  Re g ulat or y a ut h orities will recei ve t he cli nical 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 
of c ha n ges m a de t o t he trial desi g n, e x ce pt f or c ha n ges n ecess ar y t o eli mi nate a n 
i m me diate safet y hazar d t o trial s u bjects. 
•  Bef ore a trial site is all o we 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 w ill be res p o nsi ble f or: 
•  pr o vi di n g writte n s u m maries of t he stat us of t he 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  
•  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 
•  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 r e q uire me nts 
of  I C H g ui deli nes, t he I R B/I E C, a n d all ot her a p plica ble l ocal r e g ulati o ns  
•  kee pi n g a l o g of st aff a n d dele gati o n of tas ks.  
•  e ns uri n g s u b missi o n of t he cli nical trial re p ort ( C T R) s y n o psis t o t he I R B/I E C.  
2) Fi n a nci al discl os ure  
I n v esti gat ors a n d s u bi n vesti gat ors will pr o vi de N o v o N or dis k wit h s ufficie nt, acc urate fi na n cial 
i nf or mati o n as re q u este d to all o w N o v o N or dis k t o s u b mit c o m plete a n d acc urate fi na ncial 
certificati o n or discl os ure state me nts t o t he a p pr o priate re g ul at or y a ut h orities. I n v esti gat ors are 
res p o nsi ble f or pr o vi di n g i nf or mati o n o n fi na ncial i nterests d uri n g t h e c o urse of t he trial an d o n e 
year after c o m pleti o n of t he trial.  
F or U S trial sites: verific ati o n u n der discl os ures p er C o de of Fe d eral Re g ul ati o ns ( C F R) of 
Fi na ncial C o nflict of I nterest.  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
7 7 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
7 8  of 1 0 5  
 
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 n at ure of t h e trial t o t he 
s u bject a n d a ns w er all q u esti o ns re gar di n g t he trial. 
•  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 will be re q uire d t o si g n a n d date a state m e nt of i nf or me d c o ns e nt t hat meets t he 
re q uire me nts of l o cal re g ulati o ns, I C H g ui deli nes2 6, Declarati o n of Helsi n ki2 5 a n d t he 
I R B/I E C or trial site. 
•  T he me dical r ec or d m ust i ncl u de a state me nt t hat writte n i nf or me d c o ns e nt was o btai ne d 
bef ore a n y trial r elate d acti vit y a n d t he date w he n t he writte n c o nse nt w as o btai ne d. T he 
a ut h orise d pers o n o btai ni n g t he i nf or me d c o nse nt m ust als o si g n a n d date t he i nf or me d 
c o nse nt f or m bef ore a n y trial relate d acti vit y.  
•  T he res p o nsi bili t y of s ee ki n g i nf or me d c o nse nt m ust re mai n wit h t he i n vesti gat or, b ut 
t he i n vesti gat or m a y dele gat e t he tas k of i nf or mi n g t o a me di call 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 arti ci 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.  
 
4) I nf or m ati o n t o s u bjects d uri n g tri al  
T he site will be offere d a c o m m u nicati o n pac ka ge f or t he s u bject d uri n g t h e c o n d uct of t he trial. 
T he pac k a ge c o nt e nt is iss ue d b y N o v o N or dis k. T he c o m m u nicati o n pac k a ge will c o ntai n writte n 
i nf or mati o n i nte n de d f or distri b uti o n t o t he s u bjects. T he writte n i nf or mati o n will be tra nslate d a n d 
a dj uste d t o l ocal re q uir e me nts a n d distri b ute d t o t he s u bject at t he discreti o n of t he i n vesti gat or. T he 
s u bject ma y recei ve a “ w elc o me t o t he trial letter” a n d a “t ha n k y o u f or y o ur partici pati o n letter” 
after c o m pleti o n of t he trial. F urt her t h e s u bject m a y recei ve ot her writte n i nf or mati o n d uri n g t h e 
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. 
5) D at a pr otecti o n  
•  S u bjects will be assi g ne d a 6 -di git u ni q ue i de ntifier, a s u bject n u m ber. A n y s u bject 
rec or ds or datasets t hat are tra nsferre d t o N o v o N or dis k will c o ntai n t he i de ntifier o nl y; 
s u bject na mes or a n y i nf or mati o n w hic h w o ul d ma ke t he s u bject i de ntifia ble will n ot be 
tra nsferre d. 
•  T he s u bject a n d a n y bi ol o gical material o btai ne d fr o m t he s u bject will be i de ntifie d b y 
s u bject n u m ber, visit n u m ber a n d trial I D. A p pr o priate meas ures s uc h as e ncr y pti o n or 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
7 8 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
7 9  of 1 0 5  
 
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 oc al, re gi o n al a n d nati o nal re q uire me nts.  
•  T he s u bject m ust be i nf or me d 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 dat a pr otecti o n la w. T he discl os ure of t he data 
m ust als o be e x plai ne d t o t he s u bj ect.  
•  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 p ers o n nel a p p oi nte d b y N o v o N or dis k, b y a p pr o priat e I R B/I E C 
me m bers, a n d b y i ns pect ors fr o m re g ul at or y a ut h orities.  
6) C o m mittee str uct ure  
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 c o nstit ute a n i nter nal  safet y c o m mittee t o perf or m o n g oi n g safet y s ur veilla nce.  
 
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 ve nt a dj u dicati o n c o m mittee ( 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 s electe d t y pes of e ve nts a n d deat hs (see Ta ble  9 -1  a n d A p pe n di x 4 ). T he 
E A C will e val uate e v e nts se nt f or a dj u dicati o n usi n g pre -defi ne d defi niti o ns a n d g ui d eli nes i n 
acc or da nce wit h t he E A C C harter. T he e v al uati o n is base d o n re vie w of pre -defi ne d cli nical d ata 
c ollecte d b y t he i n vesti gati o nal sites.  
 
T he E A C is c o m p ose d of per ma ne nt me m bers c o v eri n g all re q uir e d me dical 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 orisati o ns t o i m pact o n trial c o n d uct, trial pr ot oc ol or 
a me n d me nts.  
 
T he assess me nt ma de b y t he E A C will be i ncl u de d i n t he cl i nical trial re p ort as well as assess me nts 
ma de b y t he i n vesti gat or. H o we ver, t he a dj u dicati o n ma de b y t he E A C, gi v e n its i n de pe n de nt 
a nal ysis of eac h e ve nt, will be attri b ute d wit h greater i m p orta nce of t he t w o.  
 
T he A Es f or a dj u dicati o n are liste d i n Se cti o n 9. 2 . 
A dj u dicati o n of se vere h y p o gl ycae mic e v e nts is perf or me d t o e ns ure a sta n dar dise d a n d u nif or m 
assess me nt here b y i ncreasi n g t he vali dit y of t hese i m p orta nt e n d p oi nts . A dj u dicati o n of ac ute 
pa ncreatitis is perf or me d d ue t o t he fact t hat treat me nt wit h G L P -1 a g o nists has bee n ass o ciate d 
wit h ac ute pa n creatitis, t h us N o v o N or dis k m o nit ors t his e ve nt t y pe cl osel y.  
7) 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 be half of N o v o N or dis k f or re g ulat or y p ur p oses as w ell as f or t he ge neral 
de vel o p me nt of t he trial pr o d uct. All i nf or mati o n s u p plie d b y N o v o N or dis k i n c o n necti o n wit h t his 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
7 9 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
8 0  of 1 0 5  
 
trial s hall re mai n t he s ole pr o pert y of N o v o N or dis k a n d is t o be c o nsi dere d c o nfi de ntial 
i nf or mati o n. 
N o c o nfi de ntial i nf or mati o n s hall be discl ose d t o ot hers wit h o ut pri or writte n c o nse nt fr o m N o v o 
N or dis k. S uc h i nf or mati o n s hall n ot be use d e x ce pt i n t he perf or ma n ce of t his 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 u ct st u die d i n t his trial.  
N o v o N or dis k ma y p u blis h o n its cli nical trials we bsite a re dacte d cli nical trial re p ort f or t his trial.  
 
O ne i n vesti gat or will be a p p oi nte d b y N o v o N or dis k t o re vie w a n d si g n t he cli nical trial re p ort 
(si g nat or y i n v esti gat or) o n be half of all partici pati n g i n vesti gat ors.  
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. 
A t 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 p ert y.  
I n all cases t he trial res ults will be re p orte d i n a n o bjecti ve, acc urat e, bala nce d a n d c o m plete 
ma n ner, wit h a disc ussi o n of t he stre n gt hs a n d li mitati o ns. I n t he e v e nt of a n y disa gree me nt o n t he 
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. 
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.  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
8 0 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
8 1  of 1 0 5  
 
A ut h ors hi p of p u blicati o ns s h o ul d be i n acc or da n ce wit h t he Rec o m me n d ati o ns f or t he C o n d uct, 
Re p orti n g, E diti n g a n d P u blicati o n of Sc h olarl y W or k i n Me dical J o ur nals b y t he I nt er nati o nal  
C o m mittee of Me dical J o ur nal E dit ors 2 8. 
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 trial 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.  
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.  
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' data, a n d will be pr o vi de d wit h t he 
ra n d o misati o n c o de after res ults are a vaila ble. 
8) Di sse 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 h e I nter n ati o nal 
C o m mittee of Me dical J o u r nal E dit ors (I C MJ E)2 9, t he 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 D A A A) 3 0, E ur o pea n C o m missi o n Re q uire me nts3 1, 3 2  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 uests 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 u bject. As a res ult of i ncreasi n g re q uire me nts f or tra ns p are n c y, s o me c o u ntries 
re q uire p u blic discl os ur e of i n vesti gat or n a mes a n d t heir affiliati o ns. 
T he Pri mar y C o m pleti o n Date ( P C D) is t he last assess 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 Tr eat me nt ( V 2) + 6 4 wee ks c orres p o n di n g t o ‘ e n d of treat me nt’ visi t ( V 3 6). 
If t he last s u bject is wit h dra w n earl y, t he P C D is c o nsi dere d t he date w h e n t he last s u bject w o ul d 
ha ve c o m plete d ‘e n d of treat me nt’ visit ( V 3 6). T h e P C D deter mi nes t he dea dli ne f or res ults 
discl os ure at cli nicaltrials. g o v acc or di n g t o F D A A A.  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
8 1 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
8 2  of 1 0 5  
 
9) D at a q u alit y ass ur a nce  
C ase Re p ort F or ms ( C R Fs)  
•  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 h ec ki n g of t he d ata.  
•  All s u bject data rel ati n g t o t he trial will be rec or de d o n electr o nic  C R Fs  u nl ess 
tra ns mitte d electr o nicall y t o N o v o N or dis k or desi g nee (e. g. l a b orat or y d ata). T he 
i n vesti gat or is r es p o nsi ble f or verif yi n g t hat data e ntries are acc urate a n d c orrect b y 
p h ysicall y or electr o ni call y si g ni n g t he C R F a n d f or e ns uri n g t hat all rel e va n t q uesti o ns 
are a ns were d, a n d t hat n o e m pt y dat a fiel d e xists.  
•  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 C R F is re v o ke d 
or t he C R F is te m p oraril y u na v aila ble:  
o  A E f or ms  
o  SI Fs  
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 t hat are n ot 
s u bject relate d, e. g. disc o vere d at tri al site bef ore all ocati o n)  
•  C orrecti o ns t o t he C R F d ata ma y be ma de b y t he i n vesti gat or or t he i n vesti gat or’s 
dele gate d staff.  A n a u dit trail will be mai ntai ne d i n t 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 h e data, dat e 
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 he 
i n vesti gator’s d ele gat e d staff aft er t he d ate w he n t he i n vesti gat or si g n e d t he C R F, t he 
C R F m ust be si g ne d a n d date d a gai n b y t he i n v esti 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 data 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 verificati o n a n d vali dati o n p ur p oses.  
 
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 ovi de direct access t o s o urce data d oc u me nts 
( ori gi n al d oc u me nts, data a n d rec or ds). Direct access i ncl u des per missi o n t o e x a mi ne, 
a nal ys e, verif y a n d re pr o d uce a n y rec or d(s) a n d re p ort(s) t hat are i m p orta nt t o t he 
e val uati o n of t he trial. If t he electr o nic  m e dical r ec or d d oes n ot ha v e a visi ble a u dit trail, 
t he i n vesti gat or m ust pr o vi de t he m o nit or wit h si g ne d a n d date d pri nt o uts. I n a d diti o n 
t he rele va nt trial 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).  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
8 2 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
8 3  of 1 0 5  
 
•  Trial m o nit ors will perf or m o n g oi n g s o urce data verificati o n t o c o nfir m t hat data e ntere d 
i nt o t he C R F b y a ut h oris e d site pers o n nel are acc urate, c o m plete a n d verifia ble fr o m 
s o urce d oc u m e nts; t hat t he safet y a n d ri g hts of s u bjects are b ei n g pr otect e d, t o m o nit or 
dr u g acc o u nt a bilit y a n d c ollect c o m plete d pa per C R F pa ges, if a p plica ble, a n d t hat t he 
trial is bei n g c o n d u cte 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 her trial a gree me nts, I C H G C P, a n d all a p plica bl e re g ulat or y re q uir e me nts.  
•  M o nit ori n g will be c o n d ucte d usi n g a ris k base 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 trial sites.  
•  M o nit ors will re vie w t he s u bject’s m e dical r ec or ds a n d ot her s o urce data  e. g. t he diaries 
a n d P R Os, t o e ns ure c o nsiste nc y a n d/ or i de ntif y o missi o ns c o m pare d t o t he C R F.  
 
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 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 os si ble, ca n be 
ac k n o wle d ge d a n d c o nfir me d via e dit c hec ks i n t he C R F or via listi n gs fr o m t he trial data base.   
1 0) S o urce d oc u me nts  
•  All data e ntere d i n t he C R F m ust be verifia ble i n s o urce d oc u m e ntati o n ot her t ha n t he 
C R F.  
•  T he ori gi nal of t he c o m pl ete d diaries a n d/ or P R Os m ust n ot be re m o ve d fr o m t he trial 
site, u nless t he y f or m part of t he C R F a n d a c o p y is ke pt at t he site. 
•  S o urce d oc u me nts pr o vi d e e vi de nce f or t h e e xiste nce of t he s u bject a n d s u bsta ntiate t he 
i nte grit y of t he d ata c ollecte d. S o urce d oc u me nts are file d at t he tri al site.  
•  Data re p orte d o n t he p a p er C R F or e nt ere d i n t he electr o nic C R F t hat are tr a nscri be d 
fr o m s o urce d o c u me nts m ust be c o nsiste nt wit h t he s o urce d o c u me nts or t he 
discre pa n cies m ust be e x plai ne d. T he i n vesti gat or ma y n ee d t o re q u est pre vi o us me dical 
rec or ds or tra nsf er rec or ds. Als o, c urre nt me dical r ec or ds m ust be a v aila 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 r ec or d.   
•  T he i n vesti gat or m ust d oc u me nt a n y att e m pt t o o btai n e xter nal me dical i nf or mati o n b y 
n oti n g t he date(s) w he n i nf or mati o n was re q ueste d a n d w h o was c o ntacte d.  
•  Defi niti o n of w hat c o nstit utes s o urce data ca n b e f o u n d i n a s o urce d o c u me nt a gree me nt 
at eac h tri al 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 
data ele me nt.  
  Pr ot oc ol  v 3. 0 |
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C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
8 4  of 1 0 5  
 
1 1) 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 uct of t his trial m ust be retai ne d b y t h e i n vesti gat or f or 1 5 years afte r 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 rete nti o n p eri o d. N o 
rec or ds ma y b e 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 be tra nsferre d t o a n ot her l ocati o n or part y wit h o ut 
writte n n otificati o n t o N o v o N or dis k.  
•  T he i n vesti gat or m ust be a ble t o access his/ her trial d oc u me nts wit h o ut i n v ol vi n g N o v o 
N or dis k i n a n y wa y. If a p plica ble, electr o nic C R F a n d ot her s u bject d ata will be 
pr o vi de d i n a n ele ctr o nic rea da bl e f or mat t o t he i n vesti gat or b ef ore access is re v o ke 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 her s u bject data (i n a n 
electr o nic rea d a ble f or m at or as pa per c o pies or pri nts) m ust be retai ne d b y t he trial site. 
If t he pr o vi de d electr o ni c data (e. g. t he C D-R O M) is n ot rea da ble d uri n g t h e e ntire 
st ora ge peri o d, t he i n v esti gat or ca n re q uest a n e w c o p y. 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 pit al, i nstit uti o n or pri vate practice  
1 2) 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 trial 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 dis creti o n of N o v o N or dis k. If t h e trial is s us pe n de d or ter mi nate d, t he 
i nvesti 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 h era p y a n d f oll o w -u p. T h e 
i n vesti gat or a n d/ or N o v o N or dis k m ust als o pr o m ptl y i nf or m t he re g ulat or y a ut h orities a n d 
I R Bs/I E Cs a n d pr o vi de a detaile d writte n e x pla nati o n. 
Trial sites will be cl ose d u p o n trial c o m pleti o n. A trial site is c o nsi dere d cl ose d w he n all re q uire d 
d oc u me nts a n d trial s u p plies ha ve bee n c ollecte d a n d a trial site cl os ure visit has bee n perf or me d.  
T he i n vesti gat or ma y i nitiate trial 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 tri al site b y N o v o N or dis k or i n vesti gat or ma y i ncl u d e b ut are n ot 
li mite d t o: 
•  fail ure of t he i n v esti gat or t o c o m pl y wit h t he pr ot o c ol, t he re q uir e me nts of t he I R B/I E C 
or l ocal healt h a ut h orities, N o v o N or dis k pr oce d ures or G C P g ui deli nes  
•  i na de q uate recr uit me nt of s u bjects b y t he i n vesti gat or 
•  disc o nti n uati o n of f urt her trial pr o d uct de vel o p me nt.  
1 3) Res p o nsi bilities  
T he i n vesti gat or is acc o u nta ble f or t he c o n d uct of t he trial at his/ her site a n d m ust e ns ure a de q u ate 
s u per visi o n of t he c o n d u ct of t he trial at t he trial site. If a n y tas ks are del e 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 ualifie d p ers o ns t o w h o m he/s he has dele gate d s pecifie d trial -
  Pr ot oc ol  v 3. 0 |
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C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
8 5  of 1 0 5  
 
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 bi n vesti gat or f or t he tri al, m ust be res p o nsi ble 
f or all trial-relate d me dical decisi o ns.  
T he i n vesti gat or is res p o nsi ble f o r 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 ntificat i 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 oss 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 hat 
suc 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 bjects d u ri 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 be a p p oi nte d i n c o ns ultati o n wit h N o v o N or dis k.  
T he i n vesti gat or a n d ot her site pers o n nel m ust ha v e s ufficie nt E n glis h s kills acc or di n g t o t heir 
assi g ne d t as k(s).  
1 4) 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 co 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.  
 
 
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C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
8 6  of 1 0 5  
 
 
A d verse e ve nts: d efi niti o ns a n d pr o ce d ures f or 
rec or di n g, e v al u ati o n, f oll o w -u p, a n d re p orti n g  
A E defi niti o n  
•  A n A E is a n y u nt o war d me dical occ urre nce i n a cli nical trial s u bj ect t hat is te m p orall y ass ociate d wit h t he use of a 
me dici nal pr o d uct, w het her or n ot c o nsi dere d relate d t o t he me dici nal pr o d uct.  
•  A n A E ca n be a n y u nfa v o ura ble a n d u ni nte n de d si g n, i ncl u di n g a n a b n or mal la b orat or y fi n di n g, s y m pt o m or 
disease ( ne w or e xacer bate d) te m p orall y ass ociate d wit h t he use of a me dici nal pr o d uct.  
 
E ve nts meeti n g  t he A E defi niti o n 
•  A n y a b n or mal la b orat or y test res ults or safet y assess me nts, i ncl u di n g t h ose t hat w orse n fr o m baseli ne, c o nsi dere d 
cli nicall y si g nifica nt i n t he me dical a n d scie ntific j u d g me nt of t he i n vesti gat or.  
•  A C L A E: a cli nical a b n or mal la b orat or y fi n di n g w hic h is cli nicall y si g nifica nt, i.e. a n a b n or malit y t hat s u g gests a 
disease a n d/ or or ga n t o xicit y a n d is of a se verit y t hat re q uires acti ve ma na ge me nt. Acti ve ma na ge me nt i ncl u des 
acti ve treat me nt or f urt her i n vesti gati o ns, f or e xa m ple c ha n ge of me dici ne d ose or m ore fre q ue nt f oll o w -u p d ue t o 
t he a b n or malit y. 
•  E xacer bati o n of a c hr o nic or i nter mitte nt pre -e xisti n g c o n diti o n i ncl u di n g eit her a n i ncreas e i n fre q ue nc y a n d/ or 
i nte nsit y of t he c o n diti o n. 
•  Si g ns, s y m pt o ms or t he cli nic al se q uelae  of a s us pecte d dr u g -dr u g i nteracti o n.  
•  Si g ns, s y m pt o ms or t he cli nic al se q uelae of a s us pecte d o ver d ose of trial pr o d uct re gar dless of i nte nt.  
•  A "lac k of efficac y" or "fail ur e of e x pecte d p har mac ol o gical acti o n" c o nstit utes a n A E or S A E. Als o, t he si g ns, 
sy m pt o ms a n d/ or cli nical se q uelae res ulti n g fr o m lac k of effi cac y will be re p orte d as A E or S A E if t he y f ulfil t he 
defi niti o n.  
E ve nts N O T  meeti n g t he A E defi niti o n  
•  Pre -e xisti n g c o n diti o ns, a ntici pate d da y -t o-da y fl uct uati o ns of pre -e xisti n g c o n diti o ns, i ncl u di n g t h ose i de ntifie d 
d uri n g scree ni n g or 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.  
N ote: pre -e xisti n g c o n diti o ns s h o ul d be rec or de d as me dical hist or y/c o nc o mita nt ill ness.  
•  Pre -pla n ne d pr oce d ures, u nless t he c o n diti o n f or w hic h t he pr oce d ure was pla n ne d has w orse ne d fr o m t he first 
trial relate d acti vit y after t he s u bj ect has si g ne d t he i nf or me d c o nse nt. 
 
Defi niti o n of a n S A E  
A n S A E is a n A E t h at f ulfils at le ast o ne of t he f oll o wi n g criteri a:  
•  Res ults i n de at h  
•  Is life-t hre ate ni n g 
T he ter m 'life -t hreate ni n g' i n t he defi niti o n of 'seri o us' refers t o a n e ve nt i n w hic h t he s u bj ect was at ris k of deat h 
at t he ti me of t he e ve nt. It d oes n ot refer t o a n e ve nt w hic h h y p ot heticall y mi g ht ha ve ca us e d deat h, if it were m ore 
se vere.  
•  Re q uires i n p atie nt h os pit alis ati o n or pr ol o n g ati o n of e xisti n g h os pit alis ati o n  
•  H os pitalisati o n si g nifies t hat t he s u bj ect has bee n detai ne d at t he h os pital or e mer ge nc y war d f or o bser vati o n 
a n d/ or treat me nt t hat w o ul d n ot ha ve bee n a p pr o priate i n t he p h ysicia n’s office or o ut patie nt setti n g. 
C o m plicati o ns t hat occ ur d uri n g h os pitalisati o n are A Es. If a c o m plicati o n pr ol o n gs h os pitalisati o n or f ulfils a n y 
ot her seri o us criteria, t he e ve nt is seri o us. W he n i n d o u bt as t o w het her “ h os pitalisati o n” o cc u rre d or was 
necessar y, t he A E s h o ul d be c o nsi dere d seri o us.  
•  H os pitalisati o n f or electi ve treat me nt of a pre -e xisti n g c o n diti o n t hat di d n ot w orse n fr o m b aseli ne is n ot 
c o nsi dere d a n A E.  
N ote:  
▪ H os pitalisati o ns f or a d mi nistr ati ve, trial relate d a n d s ocial p ur p oses d o n ot c o nstit ute A Es a n d s h o ul d 
t heref ore n ot b e re p orte d as A Es or S A Es.  
▪ H os pital a d missi o ns f or s ur gic al pr oce d ures, pla n ne d bef ore trial i ncl usi o n, are n ot c o nsi dere d A Es or S A Es.   
•  Res ults i n persiste nt dis a bilit y/i nc a p acit y  
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C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
8 7  of 1 0 5  
 
•  T he ter m disa bil it y mea ns a s u bsta ntial disr u pti o n of a pers o n’s a bilit y t o c o n d uct n or mal life f u ncti o ns. 
•  T his defi niti o n is n ot i nte n de d t o i ncl u de e x perie nce of relati vel y mi n or me dical si g nifica n ce s uc h as 
u nc o m plicate d hea dac he, na us ea, v o miti n g, diarr h oea, i nfl ue nza , a n d acci de ntal tra u ma (e. g. s prai ne d a n kle), 
w hic h ma y i nterfere wit h or pre ve nt e ver y da y life f u ncti o ns b ut d o n ot c o nstit ute a s u bsta ntial disr u pti o n.  
•  Is a c o n ge nit al a n o m al y/ birt h defect 
•  I m p ort a nt me dic al e ve nt: 
•  Me dical or scie ntific j u d g me nt s h o ul d  be e xercise d i n deci di n g w het her S A E re p orti n g is a p pr o priate i n ot her 
sit uati o ns. T his i ncl u des i m p orta nt me dical e ve nts t hat ma y n ot be i m me diatel y life -t hreat e ni n g or res ult i n deat h 
or h os pitalisati o n, b ut ma y j e o par dise t he s u bj ect or ma y re q uire me d ical or s ur gical i nter ve nti o n t o pre ve nt o ne of 
t he ot her o utc o mes liste d i n t he a b o ve defi niti o n. T hese e ve nts s h o ul d us uall y be c o nsi dere d seri o us a n d re p orte d 
as S A Es usi n g t he i m p orta nt me dical e ve nt criteri o n.  
•  T he f oll o wi n g a d verse e ve nts m ust al wa ys be re p orte d as S A Es usi n g t he i m p orta nt me di cal e ve nt criteri o n, if n o 
ot her seri o us ness criteria are a p plica ble:  
▪ s us pici o n of tra ns missi o n of i nfecti o us a ge nts via t he trial pr o d uct.  
▪ ris k of li ver i nj ur y defi ne d as ala ni ne a mi n otra nsferase ( A L T) or as partate a mi n otra nsferase ( A S T) > 3 x 
U N L a n d t otal bilir u bi n > 2 x U N L, w here n o alter nati ve aeti ol o g y e xists ( H y's la w).  
 
Descri pti o n of A Es re q uiri n g a d diti o n al d at a c ollecti o n ( vi a s pecific e ve nt f or m) a n d e ve nts f or a dj u dic ati o n.  
A Es re q uiri n g a d diti o nal data c ollecti o n a n d e ve nts f or a dj u dicati o n are descri be d i n Secti o n  9. 2  
M e dic ati o n err or:  
A me dicati o n err or c o ncer ni n g trial pr o d ucts is defi ne d 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 nless it res ults i n a c o nfir me d 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.c.  
Acci de ntal 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 h ere cli nical c o nse q ue nces f or t he trial s u bj ect were li kel y t o ha p pe n as j u d ge d b y t he 
i n vesti gat or, alt h o u g h t he y di d n ot necessaril y occ ur. 
 
A E a n d S A E rec o r di n g  
•  T he i n vesti gat or will rec or d all rele va nt A E/ S A E i nf or mati o n i n t he C R F.  
•  T he i n vesti gat or will atte m pt t o esta blis h a dia g n osis of t he e ve nt base d o n si g ns, s y m pt o ms, a n d/ or ot her cli nical 
i nf or mati o n. I n s uc h cases, t he dia g n osis ( n ot t he i n di vi d ual si g ns/s y m pt o ms) will be d oc u me nte d as t he A E/ S A E. 
•  W he n a n A E/ S A E occ urs, it is t he res p o nsi bilit y of t he i n vesti gat or t o re vie w all d oc u me nt ati o n (e. g. h os pital 
pr o gress n otes, la b orat or y a n d dia g n ostics re p orts) relate d t o t he e ve nt.  
•  F or all n o n -seri o us A Es t he a p plica ble f or ms s h o ul d be si g ne d w he n t he e ve nt is res ol ve d or at t he e n d of t he trial 
at t he latest. F or si g n -off of S A E relate d f or ms refer t o “ S A E re p orti n g via pa per C R F” later i n t his secti o n.  
•  N o v o N or dis k pr o d ucts use d as c o nc o mita nt me dicati o n: if a n A E is c o nsi dere d t o ha ve a ca usal relati o ns hi p wit h 
a N o v o N or dis k mar kete d pr o d uct use d as c o nc o mita nt me dicati o n i n t he trial, it is i m p ort a nt t hat t he s us pecte d 
relati o ns hi p is re p orte d t o N o v o N or dis k, e. g. i n t he alter nati ve aeti ol o g y secti o n o n t he safet y i nf or mati o n f or m. 
N o v o N or dis k ma y nee d t o re p ort t his a d verse e ve nt t o rele va nt re g ulat or y a ut h orities.  
 
 
Assess me nt of se v erit y  
T he i n vesti gat or will assess i nte nsit y f or eac h e ve nt re p orte d d uri n g t he trial a n d assi g n it t o o ne of t he f oll o wi n g 
cate g ories:  
•  Mil d : A n e ve nt t hat is easil y t olerate d b y t he s u bj ect, ca usi n g mi ni mal disc o mf ort a n d n ot i nterferi n g wit h 
e ver y da y acti vities.  
•  M o der ate : A n e ve nt t hat ca us es s ufficie nt disc o mf ort a n d i nterferes wit h n or mal e very da y acti vities.  
•  Se vere : A n e ve nt t hat pre ve nts n or mal e ver y da y acti vities.  
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Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
8 8  of 1 0 5  
 
N ote: Se vere is a cate g or y use d f or rati n g t he i nte nsit y of a n e ve nt; a n d b ot h a n A E a n d S A E ca n be assesse d as 
se vere. A n e ve nt is defi ne d as ‘seri o us’ w he n it meets at least o ne  of t he o utc o mes descri be d i n t he defi niti o n of a n 
S A E a n d n ot w he n it is rate d as se vere.  
 
 
Assess me nt of c a us alit y  
T he i n vesti gat or is o bli gate d t o assess t he relati o ns hi p bet we e n trial pr o d uct a n d t he occ urr e nce of eac h A E/ S A E.  
Relati o ns hi p bet wee n a n  A E/ S A E a n d t he rele va nt trial pr o d uct (s) s h o ul d be assesse d as:  
•  Pr o ba ble - G o o d reas o n a n d s ufficie nt d oc u me ntati o n t o ass u me a ca usal relati o ns hi p.  
•  P ossi ble - A ca usal relati o ns hi p is c o ncei va ble a n d ca n n ot be dis misse d.  
•  U nli kel y - T he e ve nt is m ost li k el y relate d t o aeti ol o g y ot her t ha n t he trial pr o d uct.  
 
Alter nati ve aeti ol o g y, s uc h as u n derl yi n g disease(s), c o nc o mita nt me dicati o n, a n d ot her ris k fact ors, as well as t he 
te m p oral relati o ns hi p of t he e ve nt t o trial pr o d uct a d mi nistrati o n will be c o nsi dere d a n d i n vesti gate d.  
T he i n vesti gat or s h o ul d use t he i n vesti gat or’s br oc h ure f or s e ma gl uti de a n d t he c urre nt versi o n of t he l ocal la bel f or 
I As p a n d I Glar f or t he assess me nt. F or eac h A E/ S A E, t he i n vesti gat or m ust d oc u me nt i n t he me dical rec or ds t hat 
he/s h e has re vie we d t he A E/ S A E a n d has pr o vi de d a n assess me nt of ca usalit y.  
T here ma y be sit uati o ns i n w hic h a n S A E has occ urre d a n d t he i n vesti gat or has mi ni mal i nf or mati o n t o i ncl u de i n t he 
i nitial re p ort. H o we ver, it is i m p ort a nt t h at t he i n vesti g at or al w a ys m a kes a n assess me nt of c a us alit y f or e v er y 
e v e nt bef ore t he i niti al tr a ns missi o n of t he S A E d at a . 
T he i n vesti gat or ma y c ha n ge his/ her o pi ni o n of ca usalit y i n li g ht of f oll o w -u p i nf or mati o n a n d se n d a f oll o w -u p 
re p ort wit h t he u p date d ca usalit y assess me nt. 
T he ca usalit y assess me nt is o ne of t he criteria use d w he n deter mi ni n g re g ulat or y re p orti n g re q uire me nts.  
 
If a n A E is c o nsi dere d t o ha ve a ca usal relati o ns hi p wit h a N o v o N or dis k mar kete d pr o d uct use d as c o nc o mita nt 
me dicati o n i n t he trial, it is i m p orta n t t hat t he s us pecte d relati o ns hi p is re p orte d t o N o v o N or dis k, e. g. i n t he 
alter nati ve aeti ol o g y secti o n o n t he SI F. N o v o N or dis k ma y nee d t o re p ort t his a d verse e ve nt t o rele va nt re g ulat or y 
a ut h orities.  
 
Fi n al o utc o me  
T he i n vesti gat or will select t he m o st a p pr o priate o utc o me: 
•  Rec o vere d/res ol ve d:  T he s u bj ect has f ull y rec o vere d, or b y me dical or s ur gical treat me nt t he c o n diti o n has 
ret ur ne d t o t he le vel o bser ve d at t he first trial-relate d acti vit y after t he s u bj ect si g ne d t he i nf or me d c o nse nt. 
•  Rec o veri n g/ res ol vi n g:  T he c o n diti o n is i m pr o vi n g a n d t he s u bj ect is e x pecte d t o rec o ver fr o m t he e ve nt. T his 
ter m is o nl y a p plica ble if t he s u bj ect has c o m plete d t he trial or has die d fr o m a n ot her A E. 
•  Rec o vere d/res ol ve d wit h se q uel ae:  T he s u bj ect has rec o vere d fr o m t he c o n diti o n, b ut wit h lasti n g effect d ue t o a 
disease, i nj ur y, treat me nt or pr oce d ure. If a se q uelae meets a n S A E criteri o n, t he A E m ust be re p orte d as a n S A E.  
•  N ot rec o vere d/ n ot res ol ve d:  T he c o n diti o n of t he s u bj ect has n ot i m pr o ve d a n d t he s y m pt o ms are u nc ha n ge d or 
t he o utc o me is n ot k n o w n. 
•  F at al:  T his ter m is o nl y a p plica ble if t he s u bj ect die d fr o m a c o n diti o n relate d t o t he re p orte d A E.  O utc o mes of 
ot her re p orte d A Es i n a s u bj ect b ef ore he/s he die d s h o ul d be assesse d as “rec o vere d/res ol ve d”, 
“rec o veri n g/res ol vi n g”, “rec o vere d/res ol ve d wit h se q uelae” or “ n ot rec o vere d/ n ot res ol ve d”. A n A E wit h a fatal 
o utc o me m ust be re p orte d as a n S A E.  
•  U n k n o w n:  T his ter m is o nl y a p plica ble if t he s u bj ect is l ost t o f oll o w -u p.  
 
F oll o w -u p of A E a n d S A E  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
8 8 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
8 9  of 1 0 5  
 
T he i n vesti gat or  is o bli gate d t o perf or m or arra n ge f or t he c o n d uct of s u p ple me ntal meas ure me nts a n d/ or e val uati o ns 
as me dicall y i n dicate d or as re q ueste d b y N o v o N or dis k t o el uci date t he nat ure a n d/ or ca us alit y of t he A E or S A E as 
f ull y as p ossi ble (e. g. se vere h y perse nsiti vit y reacti o ns). T his ma y i ncl u de a d diti o nal la b orat or y tests (e. g. s ki n pric k 
test) or i n vesti gati o ns, hist o pat h ol o gical e xa mi nati o ns, or c o ns ultati o n wit h ot her healt h care pr ofessi o nals. 
If a s u bj ect dies d uri n g partici pati o n i n t he trial or d uri n g a r ec o g nise d f oll o w-u p peri o d, t he i n vesti gat or s h o ul d 
pr o vi de N o v o N or dis k wit h a c o p y of a ut o ps y re p ort i ncl u di n g hist o pat h ol o g y.  
Ne w or u p date d i nf or mati o n will b e rec or de d i n t he C R F.  
 
S A E re p orti n g vi a electr o nic C R F  
•  Rele va nt f or ms ( A E a n d safet y i nf or mati o n f or m) m ust be c o m plete d i n t he C R F.  
•  F or re p orti n g a n d si g n -off ti meli nes, see b o x bel o w.  
•  If t he C R F is u na vaila ble f or m ore t ha n 2 4 h o urs, t he n t he site will use t he pa per A E f or m a n d if t he C R F is 
u na vaila ble f or m ore t ha n 5 cale n dar da ys t he n t he site will use t he safet y i nf or mati o n f or m (see b o x bel o w). 
•  T he site will e nter t he S A E data i nt o t he C R F as s o o n as it bec o mes a vaila ble, see 9. 2. 1.  
•  After t he trial is c o m plete d at a gi ve n site, t he C R F will be dec o m missi o ne d t o pre ve nt t he e ntr y of ne w data or 
c ha n ges t o e xisti n g data. If a site recei ves a re p ort of a ne w S A E fr o m a s u bj ect or recei ves u p date d data o n a 
pre vi o usl y re p orte d S A E after C R F dec o m missi o n, t he n t he site ca n re p ort t his i nf or mati o n o n a pa per A E a n d 
safet y i nf or mati o n f or m (see b o x bel o w) or t o N o v o N or dis k  b y tele p h o ne.  
 
S A E re p orti n g vi a p a per C R F  
•  Rele va nt C R F f or ms ( A E a n d safet y i nf or mati o n f or m) m ust be f or war de d t o N o v o N or dis k eit her b y fa x, e -mail 
or c o urier.  
•  I nitial n otificati o n via tele p h o ne is acce pta ble, alt h o u g h it d oes n ot re place t he nee d f or t he i n vesti gat or t o 
c o m plete t he A E a n d safet y i nf or mati o n f or m wit hi n t he desi g nate d re p orti n g ti me fra mes ( as ill ustrate d i n 
T a ble  9 -1 ): 
•  
A E f or m wit hi n 2 4 h o urs.  
•  
S afet y i nf or mati o n f or m  wit hi n 5 cale n dar da ys.  
•  
B ot h f or ms m ust b e si g ne d wit hi n 7 cale n dar da ys.  
C o ntact details f or S A E re p orti n g ca n be f o u n d i n t he i n vesti gat o r trial master file. 
 
 
 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
8 9 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
9 0  of 1 0 5  
 
 
C o ntr ace pti ve g ui d a nce a n d c ollecti o n of pre g n a nc y 
i nf or m ati o n  
It m ust be rec or de d i n t he C R F w het her fe mal e s u bjects are of c hil d beari n g p ote ntial.  
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.  
W o me n 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  
5.  Pre me narc heal  
6.  Pre me n o pa usal f e male wit h o ne of t he f oll o wi n g:  
•  D oc u me nte d 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  
N ote: D oc u me ntati o n ca n c o me fr o m t he site pers o n nel’s re vie w of s u bject’s me dical rec or ds, 
me dical e x a mi nati o n or me dical hist or y i nter vie w.  
7.  P ost me n o pa usal fe male  
•  A p ost me n o pa usal state is defi ne d as n o me ns es f or 1 2 m o nt hs wit h o ut a n alter nati ve 
me dical ca us e. A hi g h F ollicle Sti m ulati n g H or m o ne ( F S H) l e vel i n t he p ost me n o pa usal 
ra n ge ma y b e use d t o c o nfir m a p ost me n o pa usal st ate i n w o me n n ot usi n g h or m o nal 
c o ntrace pti o n or H or m o n al Re place me nt T h era p y ( H R T). H o we v er, i n t he a bse nce of 1 2 
m o nt hs of a me n orr hea, a si n gle F S H meas ure me nt is i ns ufficie nt.  
•  Fe males o n H R T a n d w h ose me n o pa usal stat us is i n d o u bt will be re q uire d t o use o ne of 
t he n o n-h or m o nal hi g hl y effecti ve c o ntr ace pti o n m et h o ds if t he y wis h t o c o nti n ue t heir 
H R T d uri n g t he tri al. Ot her wise, t he y m ust disc o nti n ue H R T t o all o w c o nfir mati o n of 
p ost me n o pa usal stat us bef ore trial e nr ol me nt.  
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 f or mal e s u bjects as t he ris k of terat o ge nicit y/fet ot o xicit y 
ca use d b y tr a nsfer of se m a gl uti de i n se mi nal fl ui d is u nli kel y.  
Fe male s u bjects  
Fe male s u bjects of c hil d beari n g p ote ntial are eli gi ble t o partici pate if t he y a gree t o us e met h o ds of 
c o ntrace pti o n c o nsiste ntl y a n d c orrectl y as des cri b e d i n ta ble(s) bel o w:  
 
 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
9 0 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
9 1  of 1 0 5  
 
T a ble  1 2 -3  
Hi g hl y effecti ve c o ntr ace pti ve met h o ds  
Hi g hl y effecti ve c o ntr ace pti ve met h o ds t h at are user de pe n de nt
 a  a n d b 
Fail ure rate of < 1 % per ye ar w he n use d c o nsiste ntl y a n d c orrectl y.   
C o m bi ne d ( oestr o ge n a n d pr o gest o ge n c o ntai ni n g) h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n   
•  oral  
•  i ntra va gi nal  
•  tra ns der mal  
Pr o gest o ge n o nl y h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n  of o v ulati o n  
•  oral  
•  i nj ecta ble  
Hi g hl y effecti ve met h o ds t h at are user i n de pe n de nt
 b   
•  I m pla nta ble pr o gest o ge n o nl y h or m o nal c o ntrace pti o n ass oci ate d wit h i n hi biti o n of o v ulati o n  
•  I ntra uteri ne De vice  
•  I ntra uteri ne h or m o ne-releasi n g S yste m  
•  Bilateral t u bal occl usi o n 
V asect o mise d p art ner  
A vasect o mise d part ner is a hi g hl y effecti ve c o ntrace pti o n met h o d pr o vi de d t hat t he part ner is t he s ole male se x ual 
part ner of t he W O C B P a n d t he a bse nce of s per m has bee n c o nfir me d. If n ot, a n a d diti o nal hi g hl y effecti ve met h o d of 
c o ntrace pti o n s h o ul d be use d.   
Se x u al a bsti ne nce b   
Se x ual a bsti ne nce is c o nsi dere d a hi g hl y effecti ve met h o d o nl y if defi ne d as refrai ni n g fr o m heter ose x ual i nterc o urse 
d uri n g t he e ntire peri o d of ris k ass ociate d wit h t he trial pr o d uct . T he relia bilit y of se x ual a bsti ne nce nee ds t o be 
e val uate d i n relati o n t o t he d ur ati o n of t he trial a n d t he preferre d a n d us ual lifest yle of t he s u bj ect.   
N otes:  
aFail ure rates ma y differ fr o m < 1 % per year, if n ot use d c o nsiste ntl y a n d c orrectl y. Use s h o ul d be c o nsiste nt wit h l ocal 
re g ulati o ns re gar di n g t he use of c o ntrace pti ve met h o ds f or s u bj ects partici pati n g i n cli nical trials.  
b C o ntrace pti o n s h o ul d be utilise d d uri n g t he treat me nt peri o d a n d f or at least 3 5 da ys after t he last d ose of trial pr o d uct.  
 
I n cert ai n cases, it is acce pte d t o use d o u ble barri er met h o ds (a c o n d o m c o m bi ne d wit h a n occl usi ve 
ca p (e. g. di a p hra g m) wit h/ wit h o ut t he use of s per mici de). T his s h o ul d o nl y be all o we d i n fe m ales 
wit h:  
1) k n o w n i nt olera nce t o t he hi g hl y effecti ve met h o ds me nti o ne d i n Ta ble  1 2 -3  or w here t he use of 
a n y of t he liste d hi g hl y effecti ve c o ntrace pti ve meas ures are c o ntr ai n dicate d i n t he i n di vi d ual 
s u bject, a n d/ or   
2) if t he ris k of i nitiati n g treat me nt wit h a s pecific hi g hl y effecti ve m et h o d o ut wei g hs t he b e nefit f or 
t he fe male. 
J ustificati o n f or acce pti n g d o u ble b arrier met h o d s h o ul d be at t he discreti o n of t he i n vesti gat or. T he 
j ustificati o n m ust be state d i n t he me dical r ec or ds. 
Pre g n a nc y testi n g  
•  W O C B P s h o ul d o nl y b e i ncl u de d after a n e gati ve hi g hl y se nsiti ve pre g n a nc y test.  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
9 1 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
9 2  of 1 0 5  
 
•  Uri ne pre g n a nc y testi n g s h o ul d be perf or m e d at f oll o w -u p visit acc or di n g t o t he 
fl o wc hart. 
•  A d diti o nal uri ne pre g na n c y t esti n g s h o ul d be p erf or me d d uri n g t he treat me nt peri o d, if 
re q uire d l oc all y (A p pe n di x 9 ). 
•  Pre g n a nc y testi n g s h o ul d be perf or me d w he ne ver a me nstr ual c ycl e is misse d or w he n 
pre g na nc y is ot her wise s us pecte d.  
 
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 a s u bje ct's pre g na nc y.  
•  S u bject will be f oll o we d t o deter mi ne t he o utc o me of t he pre g n a nc y. T he i n vesti gat or 
will c ollect f oll o w -u p i nf or mati o n o n s u bject a n d ne o nate, w hic h will be f or war de d t o 
N o v o N or dis k. Ge nerall y, f oll o w -u p will n ot be re q uire d f or l o n ger t h a n 1 m o nt h 
be y o n d t h e deli ver y d ate.  
•  A n y ter mi nati o n of pre g n a nc y will be re p orte d, re gar dless of f o etal stat us ( prese nce or 
a bse nce of a n o malies) or i n dicati o n f or pr oce d ure.  
•  W hile 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 pre g na n c y 
c o m pl icati o n or electi ve t er mi nati o n of a pre g na nc y will be re p orte d as a n A E or S A E.  
•  A s p o nta ne o us a b orti o n is al wa ys c o nsi dere d t o be a n S A E a n d will be re p orte d as s uc h.  
•  A n y S A E o cc urri n g as a res ult of a p ost -trial pr e g na nc y w hic h is c o nsi dere d 
p ossi bl y/ pr o ba bl y rel ate d t o t he trial pr o d uct 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 descri b e d i n A p pe n di x 4 . 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 m ati o n i n f or mer s u bjects, he or 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.  
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 trial 
pr o d uct.  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
9 2 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
9 3  of 1 0 5  
 
 
Tec h nic al c o m pl ai nts: D efi niti o n a n d pr oce d u res f or 
rec or di n g, e v al u ati o n, f oll o w -u p a n d re p orti n g  
Tec h nic al c o m pl ai nt defi niti o n  
•  
A tec h nical c o m plai nt is a n y writte n, electr o nic or oral c o m m u nicati o n t hat alle ges pr o d uct ( me dici ne 
or de vice) defects. T he tec h ni cal c o m plai nt ma y be ass ociat e d wit h a n A E, b ut d oes n ot c o ncer n t he A E 
itself. 
 
E x a m ples of tec h nical c o m plai nts:  
•  Pr o ble ms wit h t he p h ysic al or c he mical a p peara n ce of trial pr o d ucts ( e. g. disc ol orati o n, 
particles or c o nt a mi nati o n).  
•  Pr o ble ms wit h pac ka gi n g material i ncl u di n g l a belli n g. 
 
Ti me peri o d f or detecti n g tec h nic al c o m pl ai nts  
All tec h nical c o m plai nts , w hic h occ ur fr o m t he ti me of recei pt of t he pr o d uct at trial site u ntil t he ti me of t he last 
usa ge of t he pr o d uct, m ust b e c ollecte d f or pr o d ucts pre defi ne d o n  t he tec h nical c o m plai nt f or m.  
 
Re p orti n g of tec h nic al c o m pl ai nts t o N o v o N or dis k  
C o ntact details (fa x, e -mail a n d a d dress) f or C ust o mer C o m plai nt Ce nter –  refer t o Attac h me nt I 
T ec h nical c o m plai nts m ust b e re p orte d o n a se parate tec h nic al c o m plai nt f or m: 
1.  O ne tec h nical c o m plai nt f or m m ust b e c o m plete d f or eac h affecte d D U N  
2.  If D U N is n ot a vaila ble, a tec h nical c o m plai nt f or m f or eac h batc h, c o de or l ot n u m ber m ust be c o m plete d  
 
Ti meli nes f or re p orti n g of tec h nic al c o m pl ai nts t o N o v o N or dis k  
T he i n vesti gat or m ust c o m plet e t he tec h nical c o m plai nt f or m i n t he C R F wit hi n 2 4 h o urs if relate d t o a n S A E. All 
ot her tec h nical c o m plai nts wit hi n 5 da ys.  
If t he C R F is u na vaila ble or w he n re p orti n g a tec h nical c o m plai nt t hat is n ot s u bj ect relate d, t he inf or mati o n m ust b e 
pr o vi de d o n a pa per f or m b y fa x, e -mail or c o urier t o C ust o mer C o m plai nt Ce nter, N o v o N or dis k, wit hi n t he sa me 
ti meli nes as state d a b o ve. W he n t he C R F bec o mes a vaila ble a gai n, t he i n vesti gat or m ust e nter t he i nf or mati o n o n t he 
tec h nical c o m plai nt f or m i n t he C R F.  
 
F oll o w -u p of tec h nic al c o m pl ai nts  
T he i n vesti gat or is res p o nsi ble f or e ns uri n g t hat ne w or u p date d i nf or mati o n will be rec or de d o n t he ori gi nall y 
c o m plete d f or m.   
 
C ollecti o n, st or a ge a n d s hi p me nt of tec h nic al c o m pl ai nt s a m ples 
T he i n vesti gat or m ust c ollect t he tec h nical c o m plai nt sa m ple a n d all ass ociate d parts t hat were pac ke d i n t he sa me 
D U N a n d n otif y t he m o nit or wit hi n 5 cale n dar da ys of o btai ni n g t he sa m ple at trial site. T he sa m ple a n d all 
ass ociate d parts m ust b e  se nt as s o o n as p ossi ble t o C ust o mer C o m plai nt Ce nter, N o v o N or dis k, t o get her wit h a c o p y 
of t he c o m plete d tec h nical c o m plai nt f or m. T he tec h nical c o m plai nt sa m ple s h o ul d c o ntai n t he batc h, c o de or l ot 
n u m ber a n d, if a vaila ble, t he D U N. If t he tec h nical c o m plai nt sa m ple is u n o btai na ble, t he reas o n m ust be state d o n 
t he tec h nical c o m plai nt f or m. If se veral sa m ples are s hi p pe d i n o ne s hi p me nt, t he sa m ple a n d t he c orres p o n di n g 
tec h nical c o m plai nt f or m s h o ul d be ke pt t o get her. St ora ge of t he tec h nical c o m plai nt sa m pl e m ust be d o ne i n 
acc or da nce wit h t he c o n diti o ns prescri be d f or t he pr o d uct.  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
9 3 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
9 4  of 1 0 5  
 
 
H y p o gl yc ae mic e pis o des  
N o v o N or dis k cl assific ati o n of h y p o gl yc ae mi a  
I n n or mal p h ysi ol o g y, s y m pt o ms of h y p o gl ycae mia occ ur bel o w a P G le v el of 3. 1 m m ol/ L ( 5 6 
m g/ d L) 3 3. T heref ore, N o v o N or dis k has i ncl u de d h y p o gl ycae mia wit h P G le vels bel o w t his c ut-off 
p oi nt i n t he defi niti o n of B G c o nfir me d h y p o gl ycae mia.  
N o v o N or dis k uses t he f oll o wi n g classificati o n ( Ta ble  1 2 -1 ) i n a d diti o n t o t he A D A cl assificati o n3 4: 
8.  Se vere h y p o gl ycae mia acc or di n g t o t he A D A classificati o n 3 4. 
9.  S y m pt o matic B G c o nfir me d h y p o gl ycae mia: A n e pis o de t hat is B G c o nfir me d b y P G val u e 
< 3. 1 m m ol/ L ( 5 6 m g/ d L) wit h  s y m pt oms c o nsiste nt wit h h y p o gl ycae mia.  
1 0.  As y m pt o matic B G c o nfir me d h y p o gl ycae mia: A n e pis o de t hat is B G c o nfir me d b y P G val u e 
< 3. 1 m m ol/ L ( 5 6 m g/ d L) wit h o ut  s y m pt o ms c o nsiste nt wit h h y p o gl ycae mi a. 
1 1.  B G c o nfir me d h y p o gl ycae mia: T he u ni o n of 2. a n d 3.  
1 2.  Se vere or B G c o nfir me d s y m pt o matic h y p o gl ycae mia: T he u ni o n of 1. a n d 2.  
1 3.  Se vere or B G c o nfir me d h y p o gl ycae mia: T he u ni o n of 1, 2. a n d 3.  
F or h y p o gl ycae mic e pis o des re p orte d wit h missi n g i nf or m ati o n relate d t o t he classificati o n, t he 
f oll o wi n g a p plies w h e n classif yi n g t he e pis o d e acc or di n g t o t he N o v o N or dis k classificati o n:  
•  A h y p o gl ycae mic e pis o de wit h missi n g i nf or mati o n o n s y m pt o ms will be classifie d as 
wit h o ut s y m pt o ms.  
•  A h y p o gl ycae mic e pis o de wit h missi n g i nf or mati o n o n bei n g a ble t o self -treat will be 
re gar de d as a n e pis o de w here t he s u bject was a bl e t o self -treat a n d classifie d i n 
acc or da nce wit h t he a ble t o self -treat classificati o ns. 
E pis o des t hat ca n n ot be classifie d acc or di n g t o t he a b o ve, are i ncl u de d i n o ne of t he f oll o wi n g 
cate g ories:  
•  ‘ N o v o N or dis k u nclassifia ble’ i ncl u des e pis o des w here s u bjects were a ble t o self -treat 
a n d wit h P G ≥3. 1 m m ol/ L ( 5 6 m g/ d L) a n d h y p o gl ycae mic e pis o des f or a s u bject a ble t o 
self-treat wit h missi n g P G as it is t o be treate d as a n e pis o de wit h P G > 3. 9 m m ol/ L ( 7 0 
m g/ d L).  
•  ‘ N ot a ble t o self-tr eat –  u nclassifia ble’ i ncl u d es e pis o des w here t h e s u bjects were n ot 
a ble t o self -tr eat b ut neit her of t he f oll o wi n g c o n diti o ns were re p orte d: P G ≤3. 9 m m ol/ L 
( 7 0 m g/ d L), alle viati o n of s y m pt o ms, seiz ure, u nc o nsci o us,c o mat ose or fatal. 
 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
9 4 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
9 5  of 1 0 5  
 
H y p o gl y c a e mi c
e pi s o d e
P G ≤ 3. 9 m m ol / L 
( 7 0 m g / d L ) 
or 
All e vi ati o n of 
s y m pt o m s 
or
S ei z ur e , 
u n c o n s ci o u s /
c o m at o s e or f at al 
S M P G
m e a s ur e m e nt
P G < 3. 1 m m ol / L
( 5 6 m g / d L )
wi t h  s y m pt o m s
P G < 3. 1 m m ol / L
( 5 6 m g / d L )
wi t h o u t  
s y m pt o m s
2 . S y m pt o m ati c 
B G c o nfi r m e d 
h y p o gl y c a e mi a
3 . A s y m pt o m ati c 
B G c o nfi r m e d 
h y p o gl y c a e mi a
Y e s
N o
5 . S e v er e or 
B G c o nfi r m e d 
s y m pt o m ati c 
h y p o gl y c a e mi a
4 . B G c o nfi r m e d 
h y p o gl y c a e mi a
6 . S e v er e or 
B G c o nfi r m e d 
h y p o gl y c a e mi a
N ot e : Gl u c o s e m e a s ur e m e nt s ar e p erf or m e d wit h c a pill ar y bl o o d c ali br at e d t o pl a s m a e q ui v al e n t gl u c o s e v al u e s
B G : bl o o d gl u c o s e  P G : pl a s m a gl u c o s e  S M P G : S elf- m e a s ur e d pl a s m a gl u c o s e  
S u bj e ct 
a bl e t o 
tr e at hi m /
h er s elf
1. S e v er e 
h y p o gl y c a e mi a 
( A D A 2 0 1 3 )
 
Fi g ure  1 2 -1  N o v o N or dis k cl assific ati o n of h y p o gl yc ae mi a  
A D A cl assific ati o n 3 4 of h y p o gl yc ae mi a  
•  Se vere h y p o gl ycae mia: A n e pis o de re q uiri n g assista nce of a n ot her pers o n t o acti vel y a d mi nister 
car b o h y drate, gl uc a g o n or ta ke ot her c orrecti ve acti o ns. P G c o nce ntrat i 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 r ec o v er y f oll o wi n g t he ret ur n of P G t o n or mal is c o nsi dere d 
s ufficie nt e vi de n ce t hat t he e ve nt w as i n d uce d b y a l o w P G c o nce ntrati o n.  
•  As y m pt o matic h y p o gl ycae mia: A n e pis o de n ot acc o m pa nie d b y t y pi cal s y m pt o ms of 
h y p o gl ycae mia, b ut wit h a meas ur e d P G c o nce ntrati o n ≤3. 9 m m ol/ L ( 7 0 m g/ d L).  
•  D oc u me nte d s y m pt o matic h y p o gl ycae mia: A n e pis o de d uri n g w hic h t y pical s y m pt o ms of 
h y p o gl ycae mia are acc o m pa nie d b y a meas ure d P G c o nce ntrati o n ≤ 3. 9 m m ol/ L ( 7 0 m g/ d L).  
•  Pse u d o -h y p o gl ycae mia: A n e pis o de d uri n g w hic h t he pers o n wit h dia betes re p orts a n y of t h e 
t y pical s y m pt o ms of h y p o gl ycae mia wit h a meas ure d P G c o nce ntrati o n > 3. 9 m m ol/ L ( 7 0 
m g/ d L) b ut a p pr oac hi n g t hat le vel.  
•  Pr o ba ble s y m pt o matic h y p o gl ycae mia: A n e pis o de d uri n g w hi c h s y m pt o ms of h y p o gl ycae mia 
are n ot a cc o m pa nie d b y a P G deter mi nati o n b ut t hat was pres u m a bl y ca use d b y a P G 
c o nce ntr ati o n ≤ 3. 9 m m ol/ L ( 7 0 m g/ d L).  
F or h y p o gl ycae mic e pis o des re p orte d wit h missi n g i nf or m ati o n relate d t o t he classificati o n, t he 
f oll o wi n g a p plies w h e n classif yi n g t he e pis o d e acc or di n g t o t he A D A classificati o n: 
•  A h y p o gl ycae mic e pis o de wit h missi n g i nf or mati o n o n s y m pt o ms will be classifie d as wit h o ut 
s y m pt o ms.  
•  A h y p o gl ycae mic e pis o de wit h missi n g i nf or mati o n o n bei n g a ble t o self-treat will be re gar de d 
as a n e pis o de w h ere t he s u bject was a ble t o s elf -tr eat a n d cl assifie d i n acc or da nce wit h t he a ble 
t o self-treat classificati o ns 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
9 5 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
9 6  of 1 0 5  
 
E pis o des t hat ca n n ot be classifie d acc or di n g t o t he a b o ve, are i ncl u de d i n o ne of t he f oll o wi n g 
cate g ories  
•  ‘ A D A u ncl assifia ble’ i ncl u des e pis o des w here s u bjects were a ble t o self-treat a n d wit h P G > 3. 9 
m m ol/ L ( 7 0 m g/ d L) or missi n g P G, a n d wit h n o i nf or mati o n o n s y m pt o ms.  
•  ‘ N ot a ble t o self-tr eat –  u nclassifia ble’ i ncl u d es e pis o des w here t h e s u bjects were n ot 
a ble t o self -tr eat b ut neit her of t he f oll o wi n g c o n diti o ns were re p orte d: P G ≤3. 9 m m ol/ L 
( 7 0 m g/ d L), alle viati o n of s y m pt o ms, seiz ure, u nc o nsci o us,c o mat ose or fatal. 
H y p o gl y c a e mi c 
e pi s o d e 
P G ≤ 3. 9 m m ol/ L 
( 7 0 m g / d L ) 
or 
All e vi ati o n of 
s y m pt o m s 
or
S ei z ur e , 
u n c o n s ci o u s /
c o m at o s e  or f at al 
S M P G
m e a s ur e m e nt
A s y m pt o m ati c 
h y p o gl y c a e mi a
D o c u m e nt e d 
s y m pt o m ati c 
h y p o gl y c a e mi a
P s e u d o- 
h y p o gl y c a e mi a
Pr o b a bl e 
s y m pt o m ati c 
h y p o gl y c a e mi a
N o
Y e s
N o m e a s ur e m e nt 
wit h  s y m pt o m s
P G > 3. 9 m m ol/ L 
( 7 0 m g / d L )
wit h  s y m pt o m s
P G ≤ 3.9 m m ol/ L 
( 7 0 m g / d L )
wit h  s y m pt o m s
P G ≤ 3.9 m m ol/ L 
( 7 0 m g / d L )
wit h o ut  s y m pt o m s
N o
Y e s
N ot e : Gl u c o s e m e a s ur e m e nt s ar e p e rf or m e d wit h c a pill ar y bl o o d c ali br at e d t o pl a s m a e q ui v al e nt gl u c o s e v al u e s
P G : pl a s m a gl u c o s e  S M P G : S elf- m e a s ur e d pl a s m a gl u c o s e  
S u bj e ct 
a bl e t o 
tr e at hi m/
h e r s elf
S e v er e 
h y p o gl y c a e mi a 
( A D A 2 0 1 3)
 
Fi g ure  1 2 -2  A D A cl assific ati o n of h y p o gl yc ae mi a  
 
Treat me nt -e mer ge nt:  h y p o gl ycae mic e pis o des will be defi ne d as treat me nt -e mer ge nt, if t he o ns et of 
t he e pis o de occ urs i n t he o n-treat me nt peri o d (see defi niti o n i n Secti o n 1 0. 2 ). 
N oct ur nal h y p o gl ycae mic e pis o des:  e pis o des occ urri n g b et wee n 0 0: 0 1 a n d 0 5: 5 9 b ot h i ncl usi ve.  
H y p o gl ycae mic e pis o des are cl assifie d acc or di n g t o t he N o v o N or dis k classificati o n of 
h y p o gl yc ae mia a n d t h e A D A classificati o n of h y p o gl ycae mia 3 4. 
 
I n a d diti o n, a s u bset of t he e pis o des c o nf or mi n g A D A defi niti o n of se vere h y p o gl ycae mic e pis o des, 
i.e. e pis o des of se v ere h y p o gl ycae mia re q uiri n g h os pitalisati o n or d oc u me nte d me dical hel p (e. g. 
i ntra ve n o us a d mi nistrati o n of gl uc ose or a d mi nistrati o n of gl uca g o n), or e pis o des t hat are life 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
9 6 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
9 7  of 1 0 5  
 
t hreate ni n g3 1 will be a nal ys e d as a n e x pl orat or y e n d p oi nt.  Life t hr eate ni n g h y p o gl ycae mic e pis o des 
relates t o h y p o gl ycae mic e pis o des t hat are c o nsi dere d seri o us a d v erse e ve nts w hic h were life 
t hreate ni n g or h y p o gl ycae mic e pis o des w here t he s u bject e x perie nce d s eiz ure, or was u nc o nsci o us, 
or was i n c o ma. T his s u bset is referre d t o as ‘se vere h y p o gl ycae mia re q uiri n g h os pitalisati o n, 
d oc u me nte d me dical hel p, or is life t hreate ni n g’.  
 
Re p orti n g of h y p o gl yc ae mic e pis o des:  
P G s h o ul d al wa ys b e me as ure d a n d rec or de d w he n a h y p o gl ycae mic e pis o de is s us pecte d.  
All P G val ues:  
≤3. 9 m m ol/ L ( 7 0 m g/ d L) or  
> 3. 9 m m ol/ L ( 7 0 m g/ d L) occ urri n g i n c o nj u n cti o n wit h h y p o gl ycae mic s y m pt o ms s h o ul d be 
re p orte d as a h y p o gl ycae mic e pis o de acc or di n g t o t he fl o wc hart a n d i nstr ucti o ns bel o w.  W he n a 
s u bject e x perie nces a h y p o gl ycae mic e pis o de, s u bject s h o ul d rec or d t h e ge neral i nf or mati o n i n 
relati o n t o t he h y p o gl ycae mia (ti mi n g, P G meas ure me nts, s y m pt o ms etc. as descri be d i n t he diar y ). 
I n case a s u bject is n ot a ble t o fill i n t he diar y (e. g. i n case of h os pitalisati o n or at t he ‘f oll o w-u p 
p h o ne c o ntact’), t he n i n v esti gat or s h o ul d state i n t he me dical r ec or ds t hat t he s u bject was n ot a bl e t o 
fill i n t he diar y, i ncl u di n g t he reas o n, a n d s h o ul d re p ort t he h y p o gl ycae mic e pis o de i n C R F.  
U p o n o nset of a h y p o gl ycae mic e pis o de t he s u bject is rec o m me n de d t o meas ure P G e v er y 1 5 
mi n utes u ntil t he S M P G val ue is > 3. 9 m m ol/ L ( 7 0 m g/ d L) a n d/ or s y m pt o ms ha ve bee n res ol ve d i n 
acc or da nce wit h c urre nt g ui deli nes 3 4. 
Re peate d S M P G meas ur e me nts a n d/ or s y m pt o ms, occ urri n g wit hi n a p eri o d of 6 0 mi n utes after 
o nset of a h y p o gl ycae mi c e pis o de, will b y d efa ult be c o nsi dere d as o ne h y p o gl ycae mic e pis o de 
u ntil a s uccee di n g S M P G val ue is > 3. 9 m m ol/ L ( 7 0 m g/ d L) a n d/ or s y m pt o ms ha ve bee n res ol ve d 
a n d s h o ul d be re p orte d o n o ne h y p o gl ycae mic e pis o de f or m. S M P G meas ure me nts ≤3. 9 m m ol/ L 
( 7 0 m g/d L) or h y p o gl ycae mic s y m pt o ms after t he 6 0 mi n utes peri o d s hall tri g ger t h e re p orti n g of a 
ne w h y p o gl ycae mia e pis o de.  
I n case of se veral l o w S M P G val ues wit hi n t he 6 0 mi n utes i nter val, t he l o west val ue is t he o ne t hat 
will be re p orte d as t he S M 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 S M P G val ue a n d/ or s y m pt o m.  
T he l o west val ue me as ur e d d uri n g t he h y p o gl ycae mic e pis o de will be re p orte d as t he P G val ue f or 
t he e pis o de. T he re mai ni n g val u es will be ke pt as s o urce dat a i n t he diar y.  
A h y p o gl ycae mic e pis o de starti n g wit h o ut s y m pt o ms s h o ul d be u p date d t o s y m pt o matic if t he 
s u bject e x perie nces s y m pt o ms later d uri n g t he e pis o de. 
If t he se verit y of a h y p o gl ycae mic e pis o de w orse ns, o nl y o ne hy p o gl ycae mic e pis o de s h o ul d be 
re p orte d, reflecti n g t he m ost se vere de gree of h y p o gl ycae mia. 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
9 7 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
9 8  of 1 0 5  
 
I n v esti gat or m ust i nstr uct s u bjects t hat t he a ns wer t o t he q uesti o n: " Was t he s u bject a ble t o treat 
hi m/ herself?" m ust be a ns were d " N o" f or a n e pis o de re q uiri n g as sista nce of a n ot her pers o n t o 
acti vel y a d mi nister car b o h y drate, gl uca g o n, or ta k e ot her c orrecti ve acti o ns. P G c o nce ntr ati 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 ufficie nt e vi d e nce t hat t he e ve nt w as i n d uce d b y a l o w P G c o n ce ntrati o n 3 4. 
 
A d diti o nal i nf or mat i o n (e. g. d escri pti o n of s y m pt o ms, alle viati o n of s y m pt o ms, seiz ure, c o ma, 
fatal) i n rel ati o n t o t hese se vere h y p o gl ycae mic e pis o des m ust be rec or de d. 
 
Oral car b o h y drat es m ust n ot be gi ve n if t h e s u bject is u nc o nsci o us.  
T he i n vesti gat or m ust re vie w t he di ar y f or l o w S M P G val ues n ot re p orte d as h y p o gl ycae mic 
e pis o des. T he s u bject m ust be q uesti o ne d w het her a n y of t he l o w val ues were se vere, i.e. w h et her 
t he s u bject was a bl e t o self-treat or n ot. If t he s u bj ect was n ot a ble t o s elf-tr eat, it has t o be re p orte d 
as a se vere h y p o gl ycae mic e pis o de.  
 
F or l o w S M P G val ues f or h y p o gl ycae mic e pis o des w here t he s u bj ect was a ble t o self -treat: If a 
h y p o gl ycae mic e pis o de f or m is n ot c o m plete d wit hi n 7 cale n dar da ys of t h e S M P G meas ure me nt, 
t he e pis o de s h o ul d be re p orte d o n a h y p o gl ycae mic e pis o de f or m wit h as m uc h i nf or mati o n as 
p ossi ble. N o v o N or dis k will n ot q uer y f or a d diti o nal data e x ce pt f or t he st art date, S M P G val ue a n d 
w het her t he s u bject was a ble t o self -tr eat d ue t o d ecrease d v ali dit y of s uc h data3 5, 3 6. 
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 S M P G val ues n ot re p orte d as h y p o gl ycae mic e pis o des. 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
9 8 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
9 9  of 1 0 5  
 
 
Titr ati o n g ui deli n e  
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 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 cert ai 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 per gl ycae mia, pre vi o us res p o nse t o d ose a dj ust me nts, ot her gl uc ose 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 
de cisi 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.  
T o o pti mise a n d mai ntai n gl ycae mic c o ntr ol, t he i n vesti gat or s h o ul d t hr o u g h o ut t he trial be at least 
i n t wice m o nt hl y c o nta ct wit h t he s u bjects t o assist t he s u bjects i n a dj usti n g treat me nt a n d t o e ns ure 
t he s u bject’s welf are. 
1.  Treat me nt r e gi me ns  
All s u bjects i n t he trial will be treate d wit h I Glar U 1 0 0 a n d metf or mi n. At r u n -i n ( V 2), eli gi ble 
s u bjects will be tra nsferre d fr o m t heir pre vi o us basal i ns uli n d ose t o I Glar U 1 0 0 O D acc or di n g t o 
Secti o n 3. 1 , A p pe n di x 8.  
D uri n g t h e f oll o wi n g 1 2 wee ks t he i n vesti gat or will f oc us o n a dj usti n g t he I Glar U 1 0 0 d ose 
acc or di n g t o Secti o n 3. 2 , A p pe n di x 8. 
At ra n d o misati o n ( V 8), eli gi ble s u bjects will be ra n d o mise d 1: 1 i nt o t w o parallel treat me nt gr o u ps:  
1. metf or mi n + I Glar U 1 0 0 + se ma gl uti de O W  
2. metf or mi n + I Glar U 1 0 0 + mealti me I As p TI D  
D uri n g t h e f oll o wi n g 5 2 wee ks treat me nt peri o d t he i n vesti gat or will f oc us o n a dj usti n g ra n d o mise d 
treat me nt acc or di n g t o Secti o n 3. 3 , 3. 5  a n d 3. 7 , A p pe n di x 8. 
•  1 . 1 
I nje cti o n area 
•  I Gl ar U 1 0 0 s h o ul d be i nj ecte d s.c. i nt o t he a b d o m e n, t hi g h, or u p p er ar m. 
•  Se ma gl uti de  s h o ul d b e i njecte d s.c. i n t he a b d o m e n, t hi g h, or u p p er ar m  
•  I As p s h o ul d b e i njecte d s.c. i nt o t he a b d o me n, t hi g h, or u p per ar m. 
 
R otati o n of i njecti o n sites wit hi n a gi ve n re gi o n is rec o m me n de d.  
•  
1 . 2 Ti me of i njecti o n  
•  I Gl ar U 1 0 0 s h o ul d be a d mi nistere d O D at a n y ti me of t he da y, at t he sa me ti me e ver y 
da y.  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
9 9 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
1 0 0  of 1 0 5  
 
•  Se ma gl uti de s h o ul d be a d mi nistere d O W, at a n y ti me of t he da y irres pecti v e of meals, 
b ut o n t he sa me da y of t h e wee k. If a s e ma gl uti de d ose is misse d, it s h o ul d be 
a d mi nistere d as s o o n as n otice d, pr o vi de d t he ti me  t o t he ne xt sc he d ule d d ose is at least 
2 da ys ( 4 8 h o urs). If a d ose is misse d a n d t he ne xt sc he d ule d d ose is less t ha n 2 da ys ( 4 8 
h o urs) a w a y, t he s u bject s h o ul d n ot a d mi nister t he misse d d ose b ut rat her wait f or t he 
ne xt sc he d ule d d ose. A misse d d ose s h o ul d n ot affect t he s c he d ule d d osi n g da y of t he 
wee k.  
•  I As p s h o ul d b e a d mi nistere d TI D, wit h mai n meals i n acc or da nce wit h l ocal la bel. Mai n 
meals are d efi ne d as brea kfast, l u nc h a n d mai n e v e ni n g meal.  
 
2.  I nitiati o n a n d titrati o n 
B ot h self -m o nit ori n g of plas m a gl uc os e ( S M P G) a n d H b A 1c s h o ul d g ui de t he i n vesti gat or i n t he 
decisi o n t o a dj ust treat me nts o ver t he c o urse of t h e trial. S u bjects are re q uire d t o perf or m S M P G as 
descri be d i n Secti o n 2  a n d Secti o n 9. 1. 1 . 
H b A 1 c g oal s h o ul d be i n di vi d ualise d f or eac h s u bject wit hi n t he H b A 1c ra n ge of 6. 5 % t o 7. 5 % ( 4 8 
m m ol/ m ol t o 5 8 m m ol/ m ol) ( b ot h i ncl usi ve). S M P G tar gets s h o ul d be i n di vi d ualise d at 
i n vesti gator's discreti o n wit hi n t he ra n ges s pecifie d i n Ta ble  1 2 -4  ,T a ble 1 2 -5  a n d Ta ble  1 2 -6  or i n 
acc or da nce wit h l ocal g ui deli nes.  
2 . 1 
I nitiati o n of I Gl ar U 1 0 0 at r u n-i n ( Visit 2) 
Eli gi ble s u bjects will disc o nti n ue pre -tri al basal i ns uli n a n d t he a d diti o nal O A D (if a p plica ble, 
i ncl u di n g c o n v ersi o n fr o m fi x e d dr u g c o m bi nati o n me dicati o ns wit h metf or mi n a n d D P P-4i t o 
metf or mi n o nl y).  
S u bjects will be tra nsferre d fr o m t heir pre -trial b asal i ns uli n treat me nt ( o nce or t wice d ail y) t o O D 
I Gl ar U 1 0 0, pr o vi de d b y N o v o N or dis k A/ S i n acc or da nce wit h t he a p pr o ve d l ocal la bel of I Gl ar 
U 1 0 0.  
2 . 2 
Titrati o n of I Glar U 1 0 0 d uri n g r u n -i n  
T he I Glar U 1 0 0 d ose ca n be a dj uste d i n t he r u n -i n peri o d i n c o n necti o n wit h t he site visits or 
tele p h o ne c o nta cts. I ncreases i n t he I Glar U 1 0 0 d ose s h o ul d be base d o n t he mea n of t hree pre-
brea kfast S M P G val ues o btai ne d o n t he da y of t he visit/tele p h o ne c o ntact a n d t w o da ys b ef ore t he 
c o ntact a cc or di n g t o Ta bl e  1 2 -4 . 
If o ne of t he S M P G val u es is bel o w tar get ( < 4. 0 m m ol/ L or < 7 1 m g/ d L), t he I Glar U 1 0 0 d ose 
s h o ul d be re d uce d i n acc or da nce wit h Ta ble 1 2 -5 . 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
1 0 0 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
1 0 1  of 1 0 5  
 
T a ble  1 2 -4  
I ncre ase of I Gl ar U 1 0 0 d ose 
M e a n pre -bre a kf ast S M P G v al ues  
I ncre ase of  d ose 
m m ol/ L  
m g/ d L  
U  
4. 0 -6. 9  
7 1 -1 2 5  
N o a dj ust me nt  
7. 0 -7. 8  
1 2 6 -1 4 0  
2  
7. 9 -8. 9  
1 4 1 -1 6 0  
4  
9. 0 -1 0. 0  
1 6 1 -1 8 0  
6  
> 1 0. 0  
> 1 8 0  
8  
 
 
T a ble 1 2 -5  
Re d ucti o n of I Gl ar U 1 0 0 d ose  
 
It is i m p orta nt t hat t he decisi o n of I Glar U 1 0 0 d os es is base d o n all a vaila bl e i nf or mati o n, s uc h as 
s y m pt o ms of h y p o- a n d/ or h y p er gl ycae mia, pre vi o us res p o nses t o d ose a dj ust me nts as well as 
S M P G meas ure me nts ot her t ha n t h ose re q uire d p er t he trial pr ot oc ol.  
2 . 3 
Titrati o n of I Glar U 1 0 0 fr o m ra n d o misati o n ( Visit 8)  
A re d ucti o n i n t he d ose of I Glar U 1 0 0 u p o n se ma gl uti de/I As p treat me nt i nitiati o n s h o ul d be 
c o nsi dere d i n a cc or da nce wit h t he a p pr o ve d l ocal la bel t o re d uce t he ris k of h y p o gl ycae mia. F urt her 
d os e re d ucti o ns ma y be n ee de d d uri n g t he trial a n d i n partic ular d uri n g d ose escalati o n of 
se ma gl uti de.  
D ose a dj ust me nts of I Glar U 1 0 0 ca n b e d o ne i n li ne wit h t he titrati o n al g orit h m descri be d i n 
Ta ble  1 2 -4  a n d T a ble 1 2 -5  a n d t he i n di vi d ualise d tar get acc or di n g t o i n vesti gat or's dis creti o n . 
H o we ver, fr o m ra n d o misati o n ( V 8), t he i n vesti gat or s h o ul d pri maril y f oc us o n a dj usti n g t he 
se ma gl uti de or I As p d ose.  
2 . 4 
I nitiati o n of se ma gl uti de at Visit 8 
S u bjects ra n d o mise d t o se ma gl uti de s h o ul d i nitiate treat me nt wit h a d os e of 0. 2 5 m g   
2 . 5 
D ose a dj ust me nt of se ma gl uti de fr o m ra n d o misati o n ( Visit 8)  
After 4 w ee ks of treat me nt wit h 0. 2 5 m g, t he d ose s h o ul d be i ncreas e d t o 0. 5 m g. Aft er at least 4 
wee ks wit h a d ose of 0. 5 m g O W, t he d ose of se ma gl uti de ca n be i n crease d t o 1 m g t o f urt her 
i m pr o ve gl ycae mic c o ntr ol, at t he i n vesti gat or’s discreti o n.  
L o w est pre -bre a kf ast S M P G v al ue  
Re d ucti o n of d ose  
m m ol/ L  
m g/ d L  
U  
< 3. 1  
< 5 6  
4  
3. 1 -3. 9  
5 6 -7 0  
2  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
1 0 1 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
1 0 2  of 1 0 5  
 
F urt her d os e a dj ust me nts i ncl u di n g d ose re d ucti o ns of se ma gl uti de are all o we d d uri n g t he trial. 
D ose re d u cti o n fr o m t he d ose of 1 m g t o t he d os e of 0. 5 m g of se ma gl uti de is all o we d i n case of 
safet y c o n cer n or u nacce pta ble i nt olera bilit y. Date a n d d ose nee d t o be rec or de d i n t he C R F w he n 
trial pr o d uct d ose is i nitiate d a n d c ha n ge d, i n acc or da nce wit h t he a p pr o ve d l ocal la bel. 
2 . 6 
I nitiati o n of I As p at Visit 8 
S u bjects ra n d o mise d t o t he I As p treat me nt ar m s h o ul d i nitiate treat me nt wit h 4 U of I As p bef ore 
eac h mai n me al, TI D.  
2 . 7 
Titrati o n of I As p fr o m ra n d o misati o n ( Visit 8)  
I As p d os e a dj ust me nts s h o ul d be c o nsi dere d t wi ce wee kl y. D ose a dj ust me nts s h o ul d be base d o n 
pre -pra n dial a n d be dti me S M P G fr o m t he prece di n g 3 da ys acc or di n g t o Ta ble  1 2 -6  a n d t he 
i n di vi d ualise d g oal a cc or di n g t o i n vesti gat or’s dis creti o n.   
•  Pre -brea kfast I As p d ose will be a dj uste d acc or di n g t o t he pre -l u nc h S M P G t he pre vi o us 
t hree da ys  
•  Pre -l u nc h I As p d os e will be a dj uste d acc or di n g t o t he pre -di n ner S M P G t he pre vi o us  
t hree da ys 
•  Pre -di n ner I As p will be a dj uste d acc or di n g t o t he be dti me S M P G t he pre vi o us  t hree 
da ys  
T a ble  1 2 -6  
D ose a dj ust me nt of I As p t wice wee kl y  
Pre pr a n di al o r be dti me S M P G  
D ose a dj ust me nt  
m m ol/ L  
m g/ d L  
 
U  
< 4. 0  
< 7 1  
O ne or m ore val ues < 7 1 
( 4. 0) 
-1  
4. 0 –  6. 9  
7 1 -1 2 5  
N o val ues < 7 1 ( 4. 0) a n d 
ma x o ne val ue > 1 2 5  
0  
> 6. 9  
> 1 2 5  
N o val ues < 7 1 ( 4. 0) a n d 
t w o or m ore val ues > 
1 2 5  
+ 1  
It is i m p orta nt t hat t he decisi o n of I As p d oses is b ase d o n all a vaila bl e i nf or mati o n, s uc h as 
s y m pt o ms of h y p o- a n d/ or h y p er gl ycae mia, pre vi o us res p o nses t o d ose a dj ust me nts as well as 
S M P G meas ure me nts ot her t ha n t h ose re q uire d p er t he trial pr ot oc ol.  
2 . 8 
De viati o ns fr o m t he al g orit h m/ d ose a dj ust me nt rec o m me n dati o n  
It is rec o m me n de d t hat t h e al g orit h m/ d ose a dj ust me nt rec o m me n d ati o ns are f oll o we d. H o we v er, 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/se ma gl uti de d oses is bas e 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/ d ose a dj ust me nt rec o m me n dati o ns s h o ul d 
be e ntere d i nt o t he C R F b y t he i n vesti gat or as a p plica ble.  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
1 0 2 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
1 0 3  of 1 0 5  
 
3.  Data s ur veilla n ce  
N o v o N or dis k A/ S will e ns ure m o nit ori n g of i ns uli n titrati o n a n d pr o vi de fee d -bac k t o  sites 
t hr o u g h o ut t he trial.  
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 diar y a n d  i nt o t he C R F. If dela ys 
occ ur, acti o n ca n n ot be t a ke n i n d ue ti me bef ore t he 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 m a y recei ve s u b o pti mal treat me nt. 
 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
1 0 3 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
1 0 4  of 1 0 5  
 
 
 
C o u ntr y -s pecific re q uire me nts  
P ol a n d:  
N o v o N or dis k carries lia bilit y f or t he Tri al e xcl usi vel y i n t he sc o p e defi n e d b y t he a p plica ble la ws 
a n d i n partic ular b y t h e Ci vil C o de a n d t he P har mace utical La w date d 6 Se pte m ber 2 0 0 1 ( u nif or m 
versi o n J o ur nal of La ws of 2 0 0 8 N o. 4 5 ite m 2 7 1 wit h a me n d me nts).  I n or der t o s u p p ort p ote ntial 
clai ms f or lia bilit y attri b uta ble t o t he Trial, N o v o N or dis k a n d I n vesti gat or are c o v ere d b y t he 
I ns ura nce P olic y iss ue d acc or di n g t o a p plica bl e P olis h la w. 
Ger m a n y:  
D uri n g t h e C O VI D -1 9 p a n de mic a set of miti gati n g acti o ns ha s bee n pre p are d as s u p p ort t o sites o n 
h o w t o ha n dle trial re q uir e me nts d uri n g t h e pa n de mic. A d here n ce t o t he pr ot oc ol s h o ul d be 
c o m plie d wit h t o t he e xte nt p ossi ble. T he o utli ne d acti o ns s h o ul d be re gar de d as te m p orar y a n d 
s h o ul d n ot be use d if n or mal pr ot oc ol pr oce d ure is p ossi ble.  
 
T he acti o ns are di vi de d i nt o t hree gr o u ps.  
 
Pri m ar y e n d p oi nt  
I n or der t o e ns ure trial v ali dit y wit h o ut c o m pr o misi n g s u bjects’ s afet y, pri m ar y e n d p oi nt data will 
be c ollecte d t o t he e xte nt p ossi ble b y e x pa n di n g t h e visit wi n d o w f or E n d of Treat me nt ( E o T). T h e 
visit wi n d o w of ± 7 da ys ma y b e e x pa n de d f or u p t o - 4 wee ks / + 1 2 wee ks. D uri n g t h e e xte n de d 
visit wi n d o w s u bjects will c o nti n ue t o recei v e trial pr o d uct u ntil t he y ha v e c o m plete d t he E o T visit.  
S u bjects’ self -meas u re d plas ma gl uc os e will c o nti n ue t o be s u per vise d b y t he titrati o n gr o u p 
me m bers o n a re g ular b asis a n d s u bjects will be i n c o ntact wit h site ( p h o n e c o ntact at least bi -
wee kl y).  
 
C h a n ges t o visit sc he d ule d uri n g tri al c o n d uct  
A d here n ce t o t he cli nic al tria l pr ot oc ol s h o ul d c o nti n ue t o t he e xte nt p ossi ble d uri n g t he o ut brea k. 
I n cases w here t his is n ot p ossi ble d ue t o e pi de mi ol o gical r estricti o ns, c ha n ges t o t he visit sc he d ule 
ma y b e i m ple me nte d. Pla n ne d p h ysi cal site visits ma y b e perf or me d o utsi d e pr ot oc ol -defi ne d visit 
wi n d o ws or ma y be c o n v erte d i nt o p h o ne c o ntacts, at t he i n vesti gat or’s discreti o n.  
F oll o wi n g s u bject s pecifi c ma n dat or y ass ess me nt ma y b e perf or me d o utsi d e of t he pr ot oc ol s pe cific 
re q uire me nts d uri n g t he C O VI D-1 9 o ut brea k:  
•  uri ne pre g n a nc y t ests s h o ul d be pr o vi de d t o get her wit h t he trial pr o d uct i n case a p h ysic al site 
visit is c o n verte d t o a p h o ne c o ntact  
•  e ye e x a mi nati o n at E o T ca n be p ost p o ne d u ntil t he f oll o w -u p visit  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
1 0 4 of 1 0 5
C O N FI D E N TI A L

Pr ot o c ol  
C O N FI D E N TI A L  
Date:  
0 8 J ul y 2 0 2 0  
N o v o N or di s k  
Trial I D: N N 9 5 3 5 -4 3 8 6  
V ersi o n:  
3. 0  
  
Stat us:  
Fi n al  
  
P a ge:  
1 0 5  of 1 0 5  
 
 
 
Alter n ati ve dis pe nsi n g of tri al pr o d uct, fr o m site t o s u bject  
I n case a site visit is c o n verte d t o a p h o ne c o ntact or a s u bject is hi n dere d i n recei vi n g trial pr o d u ct 
at site, alter nati ve dis pe nsi n g met h o ds ma y be p erf or me d. F oll o wi n g o pti o ns f or alter nati ve 
dis pe nsi n g met h o ds are all o we d if s u bject is u na ble t o c o me t o site : 
•  trial pr o d uct is c ollecte d at site b y a p p oi nte d s u bstit ute 
•  trial pr o d uct is deli vere d b y a site staff me m ber t o t he s u bject/s u bstit ute off-site 
 
 
 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
1 0 5 of 1 0 5
C O N FI D E N TI A L

 
 
Gl o b al a n d co u ntr y  ke y N o v o N or dis k st aff  
 
Attac h me nt s I a n d II (if a p plica ble) t o t he pr ot oc ol are 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:
Se ma gl uti de s.c.
Trial I D: N N 9 5 3 5- 4 3 8 6
Cli nical Trial Re p ort
A p pe n di x 1 6. 1. 1
1 7 J u ne 2 0 2 1
1. 0
Fi nal
C O N FI D E N TI A L

L o g of Pr ot oc ols  
C O N FI D E N TI A L  
Date:  
1 6 Marc h 2 0 2 1  
N o v o N or di s k  
Trial  I D: N N 9 5 3 5-4 3 8 6  
V ersi o n:  
1. 0  
U T N: U 1 1 1 1 -1 2 0 0 -0 1 6 4  
Stat us:  
Fi n al  
E U dra C T N o.: 2 0 1 7 -0 0 3 2 1 9 -2 0  
P a ge:  
1  of 1  
 
L o g of Pr ot oc ol s 
D ate  
 
Fi n al, v ersi o n  
Pr ot oc ol i ncl u des t he f oll o wi n g a me n d me nts  
0 9 -J A N-2 0 1 8  
1. 0  Fi nal  
4 3 8 6 -pr ot oc ol -versi o n -1. 0.  
 
N/ A  
First versi o n of t he pr ot oc ol.  
0 9 -M A Y -2 0 1 8  
2. 0 Fi nal  
4 3 8 6 -pr ot oc ol -versi o n -2. 0  
 
 
0 8 -j ul-2 0 2 0  
3. 0  Fi nal  
4 3 8 6 -pr ot oc ol -versi o n -3 . 0 
 
L ocal Ger ma n a me n d m e nt d ue t o C o vi d -1 9  
 
  Pr ot oc ol  l o g of s |
N N 9 5 3 5 - 4 3 8 6
1 of 1
C O N FI D E N TI A L

Pr o t oc ol A me n d me nt n o 1
C O N FI D E N TI A L
Date:
1 4 A u g ust 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 5 - 4 3 8 6
Versi o n:
1. 0
     
Stat us:
Fi nal
     
Pa ge:
1 of 3
Pr ot oc ol A me n d me nt
n o 1
t o Pr ot oc ol, versi o n 2. 0
d ate d 0 9 M a y 2 0 1 8
Tri al I D: N N 9 5 3 5 -4 3 8 6
Effect of se m a gl uti de o nce -wee kl y vers us i ns uli n as p art t hree ti mes d ail y, b ot h as a d d o n t o
metf or mi n a n d o pti mise d i ns uli n gl ar gi ne ( U 1 0 0) i n s u bjects wit h t y pe 2 di a betes
A 5 2 -wee k, m ulti -ce ntre, m ulti n ati o n al, o pe n -l a bel, acti ve-c o ntr olle d, t w o ar me d, p ar allel-
gr o u p, r a n d o mise d tri al i n s u bjects wit h t y pe 2 di a betes
Tri al p h ase: 3 b
A p plic a ble t o Ger m a n y
T his c o nfi de ntial d oc u me nt is t he pr o pert y of N o v o N or dis k. N o u n p u blis he d i nf or mati o n c o ntai ne d herei n ma y be 
discl ose d wit h o ut pri or writte n a p pr o val fr o m N o v o N or dis k. Access t o t his d oc u me nt m ust be restricte d t o rele va nt 
parties.
D E  Pr ot oc ol A me n d me nt  1 de | 
N N 9 5 3 5 - 4 3 8 6
1 of 3
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 o t oc ol A me n d me nt n o 1
C O N FI D E N TI A L
Date:
1 4 A u g ust 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 5 - 4 3 8 6
Versi o n:
1. 0
     
Stat us:
Fi nal
     
Pa ge:
2 of 3
T a ble of C o nte nts    
1
I ntr o d ucti o n i ncl u di n g r ati o n ale f or t he pr ot oc ol a me n d me nt ...........................................................3
2
C h a n ges t o A p pe n di x 9  C o u ntr y s pecific re q uire me nt ......................................................................3
D E  Pr ot oc ol A me n d me nt  1 de |
N N 9 5 3 5 - 4 3 8 6
2 of 3
C O N FI D E N TI A L

Pr ot oc ol A me n d me nt n o 1
C O N FI D E N TI A L
Date:
1 4 A u g ust 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 5 - 4 3 8 6
Versi o n:
1. 0
Stat us:
Fi nal
Pa ge:
3 of 3
1
I ntr o d ucti o n i ncl u di n g r ati o n ale f or t he pr ot oc ol a me n d me nt
C ha n ges are i ntr o d uce d t o fulfil  lo c al  re q uire me nts i n Ger ma n y.
I n t his pr ot oc ol a me n d me nt:

A n y ne w te xt is writte n i n it alics.

A n y te xt delete d fr o m t he pr ot oc ol is writte n usi n g stri ke t hr o u g h.
2
C h a n ges t o A p pe n di x 9 C o u ntr y s pecific re q uire me nt
Ger m a ny:
•
C o ntr ace ptive me as ures c o nsi dere d a de q u ate are o nly hi g hly effective c o ntr ace ptive
met h o ds as liste d i n T a ble 1 2 - 3 ‘ Hi g hly effective c o ntr ace ptive met h o ds’ i n A p pe n dix 5. T he o pti o n
t o use d o u ble -b arrier met h o ds i n fe m ales w it h k n o w n i nt oler a nce or c o ntr ai n dic ati o ns t o t he hi g hly
effective met h o ds or where t he risk of i niti ati n g tre at me nt w it h a s pecific hi g hly effective met h o d
o ut w ei g hs t he be nefit f or t he fe m ale is n ot a p plic a ble f or Ger m a ny .
D E  Pr ot oc ol A me n d me nt  1 de |
N N 9 5 3 5 - 4 3 8 6
3 of 3
C O N FI D E N TI A L

Pr o t oc ol A me n d me nt n o 2
C O N FI D E N TI A L
Date:
2 0 Ma y 2 0 1 9
N o v o N or di s k
Trial I D: N N 9 5 3 5 - 4 3 8 6
Versi o n:
0. 1
     
Stat us:
Draft
     
Pa ge:
1 of 4
Pr ot oc ol A me n d me nt
n o 2
t o Pr ot oc ol, versi o n 2. 0
d ate d 0 9 M a y 2 0 1 8
Tri al I D: N N 9 5 3 5 -4 3 8 6
Effect of se m a gl uti de o nce -wee kl y vers us i ns uli n as p art t hree ti mes d ail y, b ot h as a d d o n t o
metf or mi n a n d o pti mise d i ns uli n gl ar gi ne ( U 1 0 0) i n s u bjects wit h t y pe 2 di a betes
A 5 2 -wee k, m ulti -ce ntre, m ulti n ati o n al, o pe n -l a bel, acti ve-c o ntr olle d, t w o ar me d, p ar allel-
gr o u p, r a n d o mise d tri al i n s u bjects wit h t y pe 2 di a betes
Tri al p h ase: 3 b
A p plic a ble t o R o m a ni a
T his c o nfi de ntial d oc u me nt is t he pr o pert y of N o v o N or dis k. N o u n p u blis he d i nf or mati o n c o ntai ne d herei n ma y be 
discl ose d wit h o ut pri or writte n a p pr o val fr o m N o v o N or dis k. Access t o t his d oc u me nt m ust be restricte d t o rele va nt 
parties.
R O  Pr ot oc ol A me n d me nt  2 r o |
N N 9 5 3 5 - 4 3 8 6
1 of 4
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 o t oc ol A me n d me nt n o 2
C O N FI D E N TI A L
Date:
2 0 Ma y 2 0 1 9
N o v o N or di s k
Trial I D: N N 9 5 3 5 - 4 3 8 6
Versi o n:
0. 1
     
Stat us:
Draft
     
Pa ge:
2 of 4
T a ble of C o nte nts    
1
I ntr o d ucti o n i ncl u di n g r ati o n ale f or t he pr ot oc ol a me n d me nt ...........................................................3
2
C h a n ges t o A p pe n di x 9  C o u ntr y s pecific re q uire me nt ......................................................................3
R O  Pr ot oc ol A me n d me nt  2 r o | 
N N 9 5 3 5 - 4 3 8 6
2 of 4
C O N FI D E N TI A L

Pr ot oc ol A me n d me nt n o 2
C O N FI D E N TI A L
Date:
2 0 Ma y 2 0 1 9
N o v o N or di s k
Trial I D: N N 9 5 3 5 - 4 3 8 6
Versi o n:
0. 1
     
Stat us:
Draft
     
Pa ge:
3 of 4
1
I ntr o d ucti o n i ncl u di n g r ati o n ale f or t he pr ot oc ol a me n d me nt
C ha n ges are i ntr o d uce d t o fulfil  lo c al  re q uire me nts i n R o ma nia .
I n t his pr ot oc ol a me n d me nt:

A n y ne w te xt is writte n i n it alics.

A n y te xt delete d fr o m t he pr ot oc ol is writte n usi n g stri ke t hr o u g h.
2
C h a n ges t o A p pe n di x 9 C o u ntr y s pecific re q uire me nt
R o m a ni a :
•
C o ntr ace ptive me as ures c o nsi dere d a de q u ate are o nly hi g hly effective c o ntr ace ptive
met h o ds as liste d i n T a ble 1 2 - 3 ‘ Hi g hly effective c o ntr ace ptive met h o ds’ i n A p pe n dix 5. T he o pti o n 
t o use d o u ble -b arrier met h o ds i n fe m ales w it h k n o w n i nt oler a nce or c o ntr ai n dic ati o ns t o t he hi g hly 
effective met h o ds or where t he risk of i niti ati n g tre at me nt w it h a s pecific hi g hly effective met h o d
o ut w ei g hs t he be nefit f or t he fe m ale is n ot a p plic a ble f or R o m a ni a .
R O  Pr ot oc ol A me n d me nt  2 r o | 
N N 9 5 3 5 - 4 3 8 6
3 of 4
C O N FI D E N TI A L

Pr ot oc ol A me n d me nt n o 2
C O N FI D E N TI A L
Date:
2 0 Ma y 2 0 1 9
N o v o N or di s k
Trial I D: N N 9 5 3 5 - 4 3 8 6
Versi o n:
0. 1
     
Stat us:
Draft
     
Pa ge:
4 of 4
Date a n d Si g nat ure: 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
I nter nati o nal Trial Ma na ger
Date a n d Si g nat ure: 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
R O  Pr ot oc ol A me n d me nt  2 r o | 
N N 9 5 3 5 - 4 3 8 6
4 of 4
C O N FI D E N TI A L

L o g of Pr ot oc ol A me n d me nts  
U T N: U 1 1 1 1 -1 2 0 0 -0 1 6 4  
Date:  
2 5 Marc h 2 0 2 1  
Stat us:  
Fi n al  
N o v o N or di s k  
Trial I D: N N 9 5 3 5-4 3 8 6  
E u dra C T n o.: 2 0 1 7 -0 0 3 2 1 9 -2 0  
V ersi o n:  
1. 0  
P a ge:  
1  of 1  
 
L o g of Pr ot oc ol A me n d me nts  
P r ot oc ol  
a me n d me nt n o  
D ate  
( D D M o nt h Y Y Y Y) 
Fi n al,  
Versi o n  
C o u ntr y(ies) a n d/ or tri al 
site(s) affecte d 
Brief c o nte nt  
1  
1 4 -A u g -2 0 1 8  
1. 0  
Ger ma n y  
C ha n ges are i ntr o d uce d t o f ulfil l ocal 
re q uire me nts i n Ger ma n y. 
2  
2 0 -Ma y -2 0 1 9  
1. 0  
R o ma nia  
C ha n ges are i ntr o d uce d t o f ulfil l ocal 
re q uire me nts i n R o ma nia . 
 
  Pr ot oc ol A me n d me nt  l o g of s |
N N 9 5 3 5 - 4 3 8 6
1 of 1

 
 
N N 9 5 3 5 -4 3 8 6  
 
 
M e m o  
T o : 
I n v e s ti g a t o r s, S t u d y C o o r di n a t o r s, a n d Si t e S t aff i n v ol v e d i n 
N N 9 5 3 5 - 4 3 8 6 ( S U S T A I N 1 1 )  
 
 
F r o m : 
S U S T A I N 1 1 T ri al M a n a g e m e n t t e a m  
 
 
 
1 7  A pril 2 0 2 0  
 
 
 
N N 9 5 3 5 - 4 3 8 6 ( S U S T A I N 1 1 )   
 
D e a r I n v e s ti g a t o r s, S t u d y C o o r di n a t o r s, a n d Si t e S t aff,  
T h e C O VI D - 1 9 p a n d e mi c w e ar e c urr e ntl y f a ci n g i s u n pr e c e d e nt e d a n d it i s p utti n g 
s e v er e c o n str ai nt s o n b ot h w or k a n d f a mil y lif e all o v er t h e w orl d. W e ar e gr at ef ul f or 
y o ur  dili g e n c e a n d t h e diff er e n c e y o u m a k e f or y o ur s u bj e ct s . Y o ur f o c u s s h o ul d b e o n 
t h e s af et y of o ur s u bj e ct s.  
 
T h e p ur p o s e of t hi s M E M O i s t o  i nf or m y o u of t h e miti g ati o n s t o e n s ur e s u bj e ct  s af et y 
d uri n g t h e C O VI D - 1 9 p a n d e mi c a n d t o h el p m ai nt ai n t h e tri al v ali dit y b y c oll e cti n g crit -
i c al E n d of Tr e at m e nt d at a.  
 
T h e i m p o r t a n c e of S elf - M e a s u r e d P l a s m a G l u c o s e d u ri n g t h e 
C o vi d - 1 9 p a n d e mi c  
Pl e a s e r e mi n d t h e s u bj e ct s of t h e f oll o wi n g : All s u bj e ct s h o ul d d ail y m e a s ur e t h eir pr e -
br e a kf a st S M P G fr o m V 2 t o V 3 6. M or e o v er,  t h e s u bj e ct s tr e at e d wit h In s uli n A s p art  ar e 
t o m e a s ur e 4- p oi nt S M P G pr ofil e s e v er y d a y fr o m V 8 t o V 3 6. T h e s e ar e i m p ort a nt s af et y 
a s s e s s m e nt s i n a p eri o d wit h C o vi d - 1 9 p a n d e mi c t o e n s ur e s u bj e ct gl y c a e mi c c o ntr ol i s 
k e pt, a n d e s p e ci all y a s w e e x p e ct m or e sit e s vi sit s will b e tr a n sf err e d t o p h o n e vi sit s 
a n d t h er e will b e mi s si n g l a b or at or y v al u e s n or m all y u s e d b y t h e i n v e sti g at or s  a n d t h e 
titr ati o n t e a m t o o v er s e e t h e s u bj e ct ’s gl y c a e mi a  
 
E n s u r e c o m pl eti o n of E n d of T r e a t m e n t Vi si t ( V 3 6 )  
T h e sit u ati o n w e ar e c urr e ntl y f a ci n g i s u n pr e c e d e nt e d a n d d e m a n d s a l ot fr o m all of 
u s.  
  
  C o m m u nicati o n 1 7 A pr 2 0 2 0 Site Me m o Acti o ns C o vi d 1 9 | 
N N 9 5 3 5 - 4 3 8 6
1 of 7

 
 
N N 9 5 3 5 -4 3 8 6  
 
 
P a g e  2  of  7  
 
D uri n g t h e u p c o mi n g 
m o nt h s 
m a n y s u bj e ct s will att e n d t h e E n d of Tr e at m e nt Vi sit 
( E O T ; V 3 6 ). W e w o ul d li k e t o pr e s e nt o ur miti g ati o n str at e g y t o e n s ur e t h e c o m pl eti o n 
of E O T f or o ur s u bj e ct s a n d t hi s al s o off er s t h e p o s si bilit y f or y o u t o b e pr o - a cti v e a n d 
pl a n r el e v a nt i niti ati v e s. O v er all, w e h o p e t hi s will s u p p ort y o u a n d c o v er d o u bt s c o mi n g 
fr o m o ur s u bj e ct s.  
 
F or b ot h ar m s ( S e m a gl uti d e a n d I n s uli n A s p art ar m ) w e all o w t h e b el o w t o e n s ur e 
c o m pl eti o n of E O T :  
Pr ol o n g ati o n of t h e vi sit wi n d o w b et w e e n P 3 5 t o V 3 6. A s p er pr ot o c ol V 3 6 s h o ul d t a k e 
pl a c e 5 2 w e e k s aft er r a n d o mi z ati o n . C urr e ntl y t h e pr ot o c ol all o w s f or a 2 w e e k s vi sit 
i nt er v al ( + / -  7 d a y s ). W e all o w y o u t o pr ol o n g t hi s vi sit wi n d o w u p t o 4 w e e k s, ( wit h 
t h e p o s si bilit y f or a d diti o n al 8 w e e k s, s h o ul d t h e sit u ati o n r e q uir e), i n or d er t o e n s ur e 
t h e s af et y of t h e s u bj e ct s a n d t h e c oll e cti o n of V 3 6 d at a. T hi s will e vi d e ntl y m e a n t h at  
t h e s u bj e ct s wit h u p c o mi n g V 3 6 will b e o n tr e at m e nt wit h tri al pr o d u ct f or a l o n g er 
p eri o d. T hi s c a n b e all o w e d a s s u bj e ct s i n S U S T AI N 1 1 ar e o n tri al dr u g s t h at ar e m ar-
k et e d pr o d u ct s wit h a w ell - k n o w n s af et y pr ofil e. Gl y c a e mi c a n d cli ni c al p ar a m et er s 
s h o u l d b e st a bl e i n t h e l a st p art of t h e tri al, wit h li mit e d c h a n g e s ar o u n d t h e V 3 6, 
all o wi n g f or t hi s fl e xi bl e a p pr o a c h. Pl e a s e r e m e m b er u ntil o n - sit e V 3 6 a d diti o n al p h o n e 
c o nt a ct s h o ul d b e p erf or m e d e v er y 1 4 d a y s a n d d o c u m e nt e d i n t h e s u bj e ct s sit e 
fil e/m e di c al r e c or d s.  
N ot e n e w or u p d at e s t o a d v er s e e v e nt s, c o n c o mit a nt m e di c ati o n a n d h y p o gl y c a e mi c 
e pi s o d e s s h o ul d al w a y s b e r e p ort e d i n t h e E D C.   
 
W e al s o all o w y o u t o s h ort e n t h e vi sit 
int er v al  u p t o 3 - 4 w e e k s. T hi s m e a n s s u bj e ct s 
c a n att e n d V 3 6 3 - 4 w e e k s e arli er t h a n e x p e ct e d. If t hi s i s t h e c a s e t h e n P 3 5 c a n ’t t a k e 
pl a c e, t h e n t h e p h o n e c o nt a ct i n t h e E D C (I nf or m )  s h o ul d b e d o c u m e nt e d a s “ N ot 
D o n e ”.  
 
If t h e vi sit wi n d o w f or V 3 6 i s pr ol o n g e d, it will r e q uir e t h at t h e s u bj e ct h a v e a d diti o n al 
a p pr o v e d  di ar y p a g e s a v ail a bl e  f or w hi c h y o u s h o ul d a s k y o ur m o nit or f or g ui d a n c e.  
If t hi s i s n ot p o s si bl e, w e a d vi s e y o u t o fi n d a n alt er n ati v e  s ol uti o n. E. g. d o c u m e nt t h e 
a d diti o n al S M P G ’s o n a pi e c e of p a p er a n d pi n it wit h s u bj e ct di ar y (t h e s e p a g e s will 
h a v e s u bj e ct i d e ntifi er s ) a n d will b e r e vi e w e d b y PI/ C o - I/ sit e st aff. M o nit or will al s o 
u p d at e S o ur c e D at a A gr e e m e nt ( S D A ) a c c or di n gl y.  
 
If m or e tri al pr o d u ct n e e d s t o b e di s p e n s e d i n or d er t o m a k e u s e of t h e e xt e n d e d vi sit 
wi n d o w, alt er n ati v e di s p e n si n g 
m et h o d s c a n b e u s e d, pl e a s e di s c u s s t h i s wit h y o ur 
N o v o N or di s k m o nit or. Sit e st aff n e e d t o e n s ur e t h at s u bj e ct h a s e n o u g h tri al pr o d u ct 
a n d h a v e f ull c o ntr ol o v er t h e e x pir y m a n a g e m e nt. A d diti o n al di s p e n si n g vi a I W R S c a n 
b e d o n e a n d e xtr a tri al pr o d u ct t o t h e sit e will b e pr o vi d e d. If t h er e i s n ot s uffi ci e nt tri al 
pr o d u ct a v ail a bl e  i n or d er t o e n s ur e s u bj e ct i s o n tr e at m e nt t hr o u g h o ut t h e pr olo n g ati o n 
u ntil o n - sit e V 3 6 t a k e pl a c e, w e al s o all o w f or  t h e u s e of c o m m er ci all y a v ail a bl e pr o d -
u ct s ( S e m a gl uti d e, I n s uli n A s p art, a n d I n s uli n Gl ar gi n e) . Pl e a s e a s k y o ur N o v o N or di s k 
m o nit or if y o u n e e d f urt h er g ui d a n c e.   
 
If y o u ar e n ot a bl e t o s hi p l a b s a m pl e s c oll e ct e d at t hi s vi sit, pl e a s e n ot e t h at s er u m 
  C o m m u nicati o n 1 7 A pr 2 0 2 0 Site Me m o Acti o ns C o vi d 1 9 |
N N 9 5 3 5 - 4 3 8 6
2 of 7

 
 
N N 9 5 3 5 -4 3 8 6  
 
 
P a g e  3  of  7  
s a m pl e s f or c h e mi str y a n d H b A 1 c  s a m pl e s s h o ul d b e fr o z e n at - 8 0 ° C or - 2 0 ° C, if   - 8 0 ° C 
i s n ot a v ail a bl e. Pl e a s e r ef er t o t h e r el e v a nt m e m o di stri b ut e d b y 
.  
I n c a s e t h e pr ot o c ol r e q uir e m e nt f or e y e e x a mi n ati o n at V 3 6 c a n n ot b e m et, t h e e y e 
e x a mi n ati o n c a n b e  d o n e b et w e e n V 3 3 a n d P 3 7, w h er e P 3 7 i s u p t o 5 ( + 1 ) w e e k s aft er 
V 3 6.  
G ui d a n c e f o r vi si t s 8 u n til vi si t 3 6  
B y n o w all s u bj e ct s i n t h e tri al h a v e att e n d e d V 8. D u e t o C O VI D - 1 9 u p c o mi n g vi sit s 
b ef or e E O T m a y b e i m p a ct e d, pl e a s e n ot e t h e f oll o wi n g:  
•  
E n s ur e s u bj e ct  s af et y a n d w ell - b ei n g r e m ai n s t h e m o st i m p ort a nt pri orit y. C o n si d er 
t h e f oll o wi n g :  
o  
Pl a n / e st a bli s h w a y s t o c o n d u ct r e g ul ar c h e c k - i n p h o n e c all s wit h tri al s u b -
j e ct s, e n s uri n g t h at s u bj e ct s  c o nti n u e t o h a v e a dir e ct w a y t o c o m m u ni c at e 
wit h sit e st aff, i n cl u di n g m e di c al p er s o n n el s o t h at t h e y c a n r ai s e a n y q u e s -
ti o n s a n d / or c o n c er n s a n d a c c e ss r el e v a nt c ar e.  
o  
C o nti n u e t o e n s ur e t h e ti m el y r e p orti n g of a d v er s e e v e nt s a n d h y p o gl y c a e-
mi c e pi s o d e s vi a t h e c urr e nt pr o c e s s e s / s y st e m s p er t h e tri al pr ot o c ol  
 
•  
T h e vi sit s c a n t a k e pl a c e o ut si d e pr ot o c ol - d efi n e d vi sit wi n d o w s or c a n b e c o n v ert e d 
i nt o p h o n e or vi d e o c o nt a ct s, at t h e i n v e sti g at or ’s di s cr eti o n. Alt er n ati v e di s p e n si n g 
of t h e tri al pr o d u ct s h o ul d b e e n s ur e d i n c a s e a sit e vi sit i s c o n v ert e d t o a 
p h o n e/ vi d e o c o nt a ct, pl e a s e di s c u s s t hi s wit h y o ur N o v o N or di s k 
m o nit or. If sit e 
w a nt s t o c o n v er t a di s p e n si n g vi sit i nt o a p h o n e vi sit, sit e s h o ul d l o g a c a s e i n t h e 
C u st o m er P ort al a n d h a v e t h e m r e gi st er t h e vi sit wit h o ut a n yt hi n g di s p e n s e d. Sit e 
s h o ul d n ot d o a n yt hi n g t h e m s el v e s i n t h e I W R S. Sit e s c a n t h e n eit h er d o a d diti o n al 
di s p e n si n g or j u st d o t h e n e xt di s p e n si n g vi sit w h e n s u bj e ct c o m e s i n n e xt ti m e  
 
•  
S af et y l a b or at or y a s s e s s m e nt s c a n b e p erf or m e d i n a l o c al l a b at t h e i n v e sti g at or ’s 
di s cr eti o n .   
 
•  
Uri n e pr e g n a n c y t e st s s h o ul d b e pr o vi d e d t o g et h er wit h t h e tri al pr o d u ct i n c a s e a 
p h y si c al sit e  vi sit i s c o n v ert e d t o a p h o n e/ vi d e o c o nt a ct. If n e e d e d, c o m m er ci all y 
a v ail a bl e uri n e pr e g n a n c y t e st s c a n b e u s e d. A d at e d p h ot o of t h e t e st r e s ult c a n 
s er v e a s d o c u m e nt ati o n.  
 
•  
F or t h e r e g ul ar vi sit s a n d i n c a s e sit e s ar e cl o s e d or s u bj e ct r u n s o ut of tri al pr o d u ct 
a n d f urt h er di s p e n di n g c a n n ot  b e p erf or m e d, t h e u s e of c o m m er ci al pr o d u ct s 
( S e m a gl uti d e, I n s uli n A s p art, a n d I n s uli n Gl ar gi n e)  ar e al s o all o w e d. If o n e of t h e 
pr o d u ct s i s n ot c o m m er ci all y a v ali bl e, s u bj e ct e n d u p b ei n g “ Tr e at m e nt Di s c o nti n -
u e d ”.   
 
C o nti n u e t o c oll e ct all tri al - r el at e d i nf or m ati o n / d at a i n t h e s u bj e ct s ’ m e di c al r e c or d s 
a n d c o nti n u e t o u p d at e t h e r el e v a nt d at a c a pt u r e s y st e m s i n a ti m el y m a n n er ( e. g. 
E D C, I W R S ). E n s ur e g o o d d o c u m e nt ati o n i n t h e 
m e di c al r e c or d s a b o ut a cti o n s 
t a k e n / d e vi ati o n s fr o m pr ot o c ol d u e t o t h e C O VI D - 1 9 p a n d e mi c.  
  C o m m u nicati o n 1 7 A pr 2 0 2 0 Site Me m o Acti o ns C o vi d 1 9 | 
N N 9 5 3 5 - 4 3 8 6
3 of 7

 
 
N N 9 5 3 5 -4 3 8 6  
 
 
P a g e  4  of  7  
H o m e vi si t s  
B ef or e a n y h o m e vi sit s c a n b e d o n e, e n s ur e g ui d a n c e fr o m l o c al A ut h orit i e s ar e f oll o w e d 
i n t er m s of q u ar a nti n e  r e g ul ati o n s. I m p ort a ntl y it i s t o b e k e pt i n mi n d t h e ri s k of C or o n a 
tr a n s mi s si o n i n s u c h a sit u ati o n b et w e e n s u bj e ct s  a n d sit e st aff /i n v e sti g at or s, w hi c h 
c a n h a p p e n b ot h w a y s.  Al s o it i s i m p ort a nt t o k e e p i n mi n d t h at p e o pl e wit h di a b et e s 
i n cl u di n g T 2 D M, ar e p arti c ul ar v ul n er a bl e t o C O VI D- 1 9.  
 
H o m e vi sit s ar e all o w e d at t h e di s cr eti o n of t h e i n v e sti g at or, if t h e i n v e sti g at or fi n d it 
n e c e s s ar y d u e t o s af et y r e a s o n s. O ur f o c u s s h o ul d still b e o n t h e s af et y of o ur s u b j e ct s 
a n d sit e st aff .  
 
If t h e s u bj e ct c a n ’t att e n d a vi sit at sit e, alt er n ati v e h o m e m e a s ur e m e nt s  ( e. g. w ei g ht, 
pr e g n a n c y t e st, uri n e t e st s, H b A 1 c m e a s ur e m e nt s ) , s h o ul d o nl y b e c arri e d o ut if t h e 
I n v e sti g at or r e q uir e s it f or hi s or h er e v al u ati o n a n d t hi s i s all o w e d .  
If t h e alt er n ati v e m e a n s of m e a s ur e m e nt ar e c arri e d o ut, pl e a s e r e m e m b er t h at t h e s e 
d at a s h o ul d b e e nt er e d i nt o t h e  s u bj e ct sit e fil e/ m e di c al r e c or d .  
 
N ot e a n y  alt er n ati v e h o m e m e a s ur e m e nt s  p erf or m e d s h o ul d  n ot  b e e nt er e d i n E D C  or 
s e n d t o  
 f or a n al y si s , t h e s e r e s ult s s h o ul d o nl y b e  c a pt ur e d i n t h e s u bj e ct sit e 
fil e/m e di c al r e c or d s.   
 
P R O q u e s ti o n n ai r e s  
W e all o w sit e st aff t o fill i n a p a p er v er si o n of t h e P R O q u e sti o n n air e s d uri n g i nt er vi e w 
wit h t h e s u bj e ct d uri n g a p h o n e vi sit s, a n d t h e n tr a n sf er t h e r e s p o n s e s t o t h e E D C , 
w hi c h will e n s ur e w e h a v e a p a p er v er si o n a s s o ur c e d at a.  
Sit e st aff n e e d t o a d d o nt o t h e q u e sti o n n air e s a n ot e, t h at t hi s w a s fill e d i n d uri n g a n 
i nt er vi e w wit h t h e s u bj e ct o n t h e d at e of t h e p h o n e vi sit a n d s a v e t hi s i n t h e m e di c al 
r e c or d s. A n d t h e n t h e sit e st aff c a n tr a n sf er t h e d at a t o t h e E D C .  
 
D a t a e n t r y i n E D C ( I n F o r m )  
W e a c k n o wl e d g e t h at d e s pit e all y o ur eff ort s, it i s li k el y t h at w e will h a v e mi s si n g d at a 
i n t h e n e xt w e e k s/ m o nt h s d u e t o t he C O VI D - 1 9  p a n d e mi c . I n a d diti o n t o d o c u m e nti n g 
all a cti o n s i n t h e m e di c al r e c or d s, it i s i m p ort a nt t o al s o c a pt ur e r el e v a nt i nf or m ati o n i n  
E D C.  
  
B el o w pl e a s e s e e t h e i nf or m ati o n r e g ar di n g t h e pr ef err e d w a y of d at a e ntr y :  
If a vi sit i s c o n v ert e d i nt o a p h o n e vi sit O R i s p erf or m e d o ut of t h e pr ot o c ol - s p e cifi e d 
vi sit wi n d o w O R i s N ot D o n e d u e t o t h e C O VI D - 1 9 p a n d e mi c, t h e n sit e m u st r e c or d a 
F O R M L E V E L C O M M E N T o n t h e D A T E of VI SI T F O R M.  
 
 
  C o m m u nicati o n 1 7 A pr 2 0 2 0 Site Me m o Acti o ns C o vi d 1 9 | 
N N 9 5 3 5 - 4 3 8 6
4 of 7

 
 
N N 9 5 3 5 -4 3 8 6  
 
 
P a g e  5  of  7  
G ui d a n c e t o e n t e r F o r m l e v el c o m m e n t if a sit e vi sit i s O U T O F 
W I N D O
W o r  
V i sit i s c o n v e r t e d t o P H O N E V I S I T i n E D C  
 
St e p 1 : G o t o  t h e s p e cifi c vi sit “ D at e of Vi sit ” f or m a n d e nt er t h e d at e of vi sit a n d 
c o nt a ct t y p e . 
 
 
 
St e p 2 : Aft er s u b mitti n g t hi s d at a, cli c k o n t h e f or m l e v el c o m m e nt i c o n at t o p ri g ht 
h a n d si d e of t h e f or m, ( s e e t h e r e d b o x )  
 
 
St e p 3 : O n c e t h e b el o w s cr e e n a p p e ar s pl e a s e pr o vi d e t h e r e a s o n o n  t h e c o m m e nt 
b o x a s “ D U E T O C O VI D - 1 9 SI T U A TI O N ” a n d cli c k s u b mit  
 
 
  C o m m u nicati o n 1 7 A pr 2 0 2 0 Site Me m o Acti o ns C o vi d 1 9 | 
N N 9 5 3 5 - 4 3 8 6
5 of 7

 
 
N N 9 5 3 5 -4 3 8 6  
 
 
P a g e  6  of  7  
St e p 4 : O n c e t h e c o m m e nt i s u p d at e d t h e f or m a p p e ar s a s b el o w :  
 
G ui d a n c e t o e n t e r F o r m l e v el c o m m e n t if a vi sit i s N O T D O N E  
St e p 1 : G o t o “ D at e of vi sit ”  f or m a n d cli c k o n t h e f or m l e v el c o m m e nt i c o n at t o p 
ri g ht h a n d si d e of t h e f or m, ( s e e t h e r e d b o x )  
 
 
 
St e p 2 : O n c e t h e b el o w s cr e e n a p p e ar s pl e a s e pr o vi d e t h e r e a s o n o n t h e c o m m e nt 
b o x a s “ D U E T O C O VI D - 1 9 SI T U A TI O N ” a s w ell a s al s o e nt er R e a s o n i n c o m pl et e b o x  
a s ‘ N O T D O N E’ a n d cli c k s u b mit  
 
 
 
  C o m m u nicati o n 1 7 A pr 2 0 2 0 Site Me m o Acti o ns C o vi d 1 9 | 
N N 9 5 3 5 - 4 3 8 6
6 of 7

 
 
N N 9 5 3 5 -4 3 8 6  
 
 
P a g e  7  of  7  
 
S h o ul d y o u h a v e a n y q u e sti o n s or c o n c er n s, pl e a s e c o nt a ct y o ur N o v o N or di s k m o nit or.  
 
W e w o ul d o n c e a g ai n li k e t o t h a n k y o u all f or y o ur c o m mit m e nt a n d h ar d w or k! 
 
 
Ki n d r e g ar d s,  
T h e S U S T AI N 1 1  Tri al M a n a g e m e nt t e a m  
  C o m m u nicati o n 1 7 A pr 2 0 2 0 Site Me m o Acti o ns C o vi d 1 9 | 
N N 9 5 3 5 - 4 3 8 6
7 of 7