Conditions: Diabetes Mellitus, Type 2
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2274
Healthy volunteers: no

Brief summary:
This study will compare the effect of semaglutide once weekly to insulin aspart 3 times daily as add on to metformin and insulin glargine in people with type 2 diabetes. Participants will either get insulin glargine and semaglutide or insulin glargine and insulin aspart - which treatment the participant get is decided by chance. Insulin glargine is taken once a day and semaglutide once a week. Insulin aspart is taken three times per day before a meal. All three medicines come in pre-filled pens for injection under the skin. The study will last for about 71 weeks. If participant's blood sugar gets under or over certain values participant will only participate in 14 weeks. The study doctor will inform the participant about this. The participant will have 15 clinic visits and 22 phone calls with the study doctor.

Detailed description:

Arms:
arm 1: Run-in period (12 weeks): subjects will be treated with metformin and insulin glargine (IGlar) U100.

Treatment period: Participants who are not in glycaemic control (defined as HbA1c of more than or equal to 7.5% to less than or equal to 10%) after run-in will receive semaglutide for 52 weeks in addition to metformin and IGlar U100.

Metformin will be considered as background therapy during the trial. arm 2: Run-in period (12 weeks): subjects will be treated with metformin and insulin IGlar U100.

Treatment period: Participants who are not in glycaemic control (defined as HbA1c of more than or equal to 7.5% to less than or equal to 10%) after run-in receive insulin aspart for 52 weeks in addition to metformin and IGlar U100.

Metformin will be considered as background therapy during the trial.

Interventions: intervention 1: Semaglutide intervention 2: Insulin aspart intervention 3: Insulin glargine U100
Intervention descriptions: intervention 1: Subjects will receive subcutaneous (s.c., under the skin) injections of semaglutide once weekly (OW) with a dose of 0.25 mg. The dose should be increased after four weeks to 0.5 mg semaglutide. After 4 more weeks the dose can be increased to 1.0 mg semaglutide if the study doctor decides and further dose adjusted throughout the study. intervention 2: Subjects should initiate treatment with 4U of Insulin aspart (s.c. injections) before each main meal, three times daily (TID). The dose will be adjusted individually based on pre-prandial and bedtime self measured plasma glucose (SMPG) from the preceding 3 days intervention 3: Run-in period: Subjects will receive s.c. injections of IGlar U100 OD in accordance with the approved local label of IGlar U100. The dose will be adjusted based on the mean of three pre-breakfast SMPG values (target SMPG: 4.0-6.9 mmol/L)

Protocol document:
Prot_000.pdf: 
C o ver P a ge  f or Pr ot oc ol  
 
S p o ns or na me:  
N o v o N or dis k A/ S  
N C T n u m ber  
N C T 0 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
Li n k
Li n k
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  
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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  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  
 
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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  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.  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
1 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:  
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.  
  Pr ot oc ol  v 3. 0 |
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1 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:  
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. 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
2 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:  
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 ® . 
 
 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
2 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:  
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)  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
2 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:  
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)  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
2 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:  
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 |
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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 
  Pr ot oc ol  v 3. 0 |
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4 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:  
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.  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
4 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:  
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  
 
 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
4 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:  
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  
 
 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
4 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:  
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 
  Pr ot oc ol  v 3. 0 |
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4 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:  
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 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
4 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:  
5 0  of 1 0 5  
 
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 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
5 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:  
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 |
N N 9 5 3 5 - 4 3 8 6
5 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:  
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 |
N N 9 5 3 5 - 4 3 8 6
5 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:  
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 |
N N 9 5 3 5 - 4 3 8 6
5 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:  
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  
 
 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
5 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 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 |
N N 9 5 3 5 - 4 3 8 6
5 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:  
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
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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 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.  
 
 
  Pr ot oc ol  v 3. 0 |
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6 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:  
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 |
N N 9 5 3 5 - 4 3 8 6
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 |
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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 |
N N 9 5 3 5 - 4 3 8 6
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 |
N N 9 5 3 5 - 4 3 8 6
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 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)  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
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:  
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)  
 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
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:  
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 |
N N 9 5 3 5 - 4 3 8 6
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 |
N N 9 5 3 5 - 4 3 8 6
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 |
N N 9 5 3 5 - 4 3 8 6
8 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:  
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 |
N N 9 5 3 5 - 4 3 8 6
8 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:  
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.  
 
 
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
8 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:  
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  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
8 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:  
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.  
  Pr ot oc ol  v 3. 0 |
N N 9 5 3 5 - 4 3 8 6
8 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 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

SAP_001.pdf: 
C o ver P a ge  f or St atistic a l A n al ysis Pl a n  
 
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 * : 
2 5 Ja n uar y 2 0 2 1  
  * 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
List of c o nte nts
St atistic al a n al ysis pl a n ......................................................................................................................
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. 9
2 1 Ma y 2 0 2 1
1. 0
Fi nal
1 6. 1. 9 D oc u me nt ati o n of st atistic al met h o ds
.
C O N FI D E N TI A L
Re d acte d st atistic al a n alysis pl a n  
I ncl u des re d acti o n of pers o n al i de ntifi a ble inf or m ati o n o nly.  
. 


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
2 5 Ja n uar y 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 2 8  
 
  
N N 9 5 3 5 -4 3 8 6  
 
St atistic al A n al ysis Pl a n  
 
 
 
 
 
 
 
  S A P  4 3 8 6-statistical-a nal ysis- pla n | 
N N 9 5 3 5 - 4 3 8 6
1 of 2 8
.
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
2 5 Ja n uar y 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:  
2  of 2 8  
 
Ta ble of c o nte nts  
 
P a ge  
T a ble of c o nte nts  ............................................................................................................................................... 2  
T a ble of fi g ures  ................................................................................................................................................. 3  
T a ble of t a bles  ................................................................................................................................................... 3  
0  Versi o n hist or y ............................................................................................................................................. 4  
1  I ntr o d ucti o n ................................................................................................................................................. 5  
1. 1  
O bjecti ves a n d e n d p oi nts  .................................................................................................................... 5  
1. 1. 1  
O bjecti ves  ............................................................................................................................ 5  
1. 1. 1. 1  
Pri mar y o bj ecti ve  ............................................................................................. 5  
1. 1. 1. 2  
Sec o n dar y o bj ecti ves  ........................................................................................ 5  
1. 1. 2  
Esti ma n d  .............................................................................................................................. 5  
1. 1. 3  
E n d p oi nts  ............................................................................................................................. 6  
1. 1. 3. 1  
Pri mar y e n d p oi nt  .............................................................................................. 7  
1. 1. 3. 2  
Sec o n dar y e n d p oi nts  ........................................................................................ 7  
1. 1. 3. 2. 1  
C o nfir mat or y sec o n dar y e n d p oi nts  .......................................................... 7  
1. 1. 3. 2. 2  
S u p p orti ve sec o n dar y e n d p oi nts  .............................................................. 7  
1. 1. 3. 2. 3  
E x pl orat or y e n d p oi nts  .............................................................................. 8  
1. 2  
Trial desi g n  ....................................................................................................................................... 1 0  
2  St atistic al h y p ot heses  ................................................................................................................................ 1 1  
3  S a m ple  size deter mi n ati o n ........................................................................................................................ 1 2  
4  A n al ysis sets  ............................................................................................................................................... 1 3  
5  St atistic al a n al yses  ..................................................................................................................................... 1 5  
5. 1  
Ge nera l c o nsi derati o ns ...................................................................................................................... 1 5  
5. 2  
S u bj ect dis p ositi o n  ............................................................................................................................ 1 5  
5. 3  
Pri mar y e n d p oi nt a nal ysis  ................................................................................................................. 1 5  
5. 3. 1  
Defi niti o n of e n d p oi nt  ....................................................................................................... 1 5  
5. 3. 2  
Mai n a nal ytical a p pr oac h ................................................................................................... 1 5  
5. 3. 3  
Se nsiti vit y a nal yses  ........................................................................................................... 1 6  
5. 4  
Se c o n dar y e n d p oi nts a nal yses  ........................................................................................................... 1 7  
5. 4. 1  
C o nfir mat or y sec o n dar y e n d p oi nts  .................................................................................... 1 7  
5. 4. 1. 1  
Defi niti o n of e n d p oi nts  .................................................................................. 1 7  
5. 4. 1. 2  
Mai n a nal ytical a p pr oac h  ............................................................................... 1 7  
5. 4. 1. 3  
Se nsiti vit y a nal yses  ........................................................................................ 1 7  
5. 4. 2  
S u p p orti ve sec o n dar y e n d p oi nts  ........................................................................................ 1 8  
5. 5  
E x pl orat or y e n d p oi nts a nal yses  ........................................................................................................ 2 0  
5. 6  
Ot her safet y a nal yses  ........................................................................................................................ 2 2  
5. 7  
Ot her a nal yses  ................................................................................................................................... 2 2  
5. 7. 1  
Ot her de ri vati o ns a n d assess me nts .................................................................................... 2 2  
5. 8  
I nteri m a nal yses ................................................................................................................................ 2 2  
6  S u p p orti n g d oc u me nt ati o n  ....................................................................................................................... 2 3  
6. 1  
A p pe n di x 1: List of a b bre viati o ns  ..................................................................................................... 2 3  
6. 2  
A p pe n di x 2: C ha n ges t o pr ot oc ol -pla n ne d a nal yses  ......................................................................... 2 4  
6. 3  
A p pe n di x 3: Defi niti o n a n d calc ulati o n of e n d p oi nts, assess me nts a n d deri vati o ns  ........................ 2 5  
7  Ref ere nces  .................................................................................................................................................. 2 8  
  S A P  4 3 8 6-statistical-a nal ysis- pla n | 
N N 9 5 3 5 - 4 3 8 6
2 of 2 8
.
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
2 5 Ja n uar y 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:  
3  of 2 8  
 
Ta ble of fi g ures  
 
P a ge  
Fi g ure  1 -1  
Trial desi g n  ................................................................................................................................ 1 0  
 
Ta ble of t a bles  
 
P a ge  
T a ble  0 -1  
S A P Versi o n Hist or y S u m mar y  ................................................................................................... 4  
T a ble  1 -1  
O ver vie w of t he pla n ne d esti ma n d  .............................................................................................. 5  
T a ble  4 -1  
S u bj ect a nal ysis sets  .................................................................................................................. 1 3  
T a ble  4 -2  
A nal ysis data sets  ....................................................................................................................... 1 3  
  S A P  4 3 8 6-statistical-a nal ysis- pla n | 
N N 9 5 3 5 - 4 3 8 6
3 of 2 8
.
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
2 5 Ja n uar y 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:  
4  of 2 8  
 
0  Versi o n hist or y  
T h e Statistical A nal ysis Pla n ( S A P) f or trial N N 9 5 3 5 -4 3 8 6 is base d o n t he pr ot oc ol versi o n 3  date d 
0 8J U L 2 0 2 0 .  
T a ble  0 -1  
S A P V ersi o n Hist or y S u m m a r y  
S A P 
Versi o n  
A p pr o v al 
D ate  
C h a n ge  
R ati o n ale  
1  
 
N ot A p plica ble  
Ori gi nal v ersi o n  
 
 
 
  S A P  4 3 8 6-statistical-a nal ysis- pla n | 
N N 9 5 3 5 - 4 3 8 6
4 of 2 8
.
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
2 5 Ja n uar y 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:  
5  of 2 8  
 
1  I ntr o d ucti o n 
1. 1  
O bjecti ves a n d e n d p oi nts  
1. 1. 1  
O bjecti ves  
1. 1. 1. 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.  
1. 1. 1. 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 m a 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 
1. 1. 2  
Esti m a n d  
F or all o bjecti ves t h e pri 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. 
T a ble  1 -1  
O ver vie w of t he pl a n ne d esti m a n d  
O bjecti ve  
Esti m a n d 
c ate g or y 
Esti m a n d  
Tre at -me nt 
c o n diti o n  
V ari a ble/  
E n d p oi nt  
P o p ul a -
ti o n of 
i nterest 
I nterc ur-re nt  
e ve nt 
str ate g y 
P o p ul ati o n -
Le vel 
S u m m ar y 
M e as ure  
Pri m ar y o bjecti ve  
T o c o m pare t he 
effect of 
se ma gl uti de o nce-
wee kl y o n 
gl ycae mic c o ntr ol 
vers us i ns uli n 
Pri mar y  
Se ma -
gl uti de O W 
vs I As p 
TI D.  
C ha n ge fr o m 
baseli ne t o wee k 
5 2 i n H b A 1c   ( %-
p oi nt)  
All 
ra n d o mi-
se d 
S u bj ects l ost 
t o f oll o w-u p, 
w h o  ha ve  
w it h dra w n 
c o nse nt, or  
w h o 
disc o nti n ue 
Mea n 
treat me nt 
differe nce . 
  S A P  4 3 8 6-statistical-a nal ysis- pla n | 
N N 9 5 3 5 - 4 3 8 6
5 of 2 8
.
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
2 5 Ja n uar y 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:  
6  of 2 8  
 
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 bj ects 
wit h T 2 D.  
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 ha ve li ke 
s u bj ects t hat 
re mai n i n t he 
trial a n d are 
treate d wit h 
trial dr u g 
( h y p ot hetical 
strate g y). 
Sec o n d ar y 
o bjecti ve  
T o de m o nstrate 
t hat se ma gl uti de 
o nce -wee kl y has a 
l o wer ris k of se 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 ne 
( U 1 0 0) i n s u bj ects 
wit h T 2 D.  
 
T o c o m pare t he 
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 ne ( U 1 0 0) i n 
s u bj ects wit h T 2 D 
wit h re gar ds t o:  
• b o d y wei g ht 
• li pi ds 
• bl o o d press ure 
• healt h-relate d 
q ualit y of life  
• safet y 
Sec o n dar y  
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 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 u p 
t o wee k 5 2 ( da ys) 
H azar d rati o . 
Sec o n dar y  
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 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 u p 
t o wee k 5 2 ( da ys) 
H azar d rati o . 
Sec o n dar y  
C ha n ge fr o m 
baseli ne t o wee k 
5 2 i n b o d y 
wei g ht ( k g)  
Mea n 
treat me nt 
differe nce . 
 
 
1. 1. 3  
 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 meas 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.   
  S A P  4 3 8 6-statistical-a nal ysis- pla n | 
N N 9 5 3 5 - 4 3 8 6
6 of 2 8
.
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
2 5 Ja n uar y 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:  
7  of 2 8  
 
1. 1. 3. 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)  
1. 1. 3. 2  
Sec o n d ar y  e n d p oi nts 
1. 1. 3. 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 ( d a 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 pi talisati 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)  
1. 1. 3. 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 olester ol, 
hi g h -de nsit y li p o pr otei n ( H D L) c h olest er ol, tri gl yc eri 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 life t hreate ni n g 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  cli nicall y si g nifica nt h y p o gl ycae mic e pis o des 
( P G < 3. 0 m m ol/ L ( 5 4 m g/ d L)) fr o m r a n d o misati o n t o wee k 5 2 
 
•  I ns uli n d ose  
o  Dail y  b asal i ns uli n d ose at wee k 5 2 ( U)  
o  T otal dail y  i ns uli n d ose at wee k 5 2 ( U) 
S u p p orti ve sec o n d ar y H R Q o L e n d p oi nts  
  S A P  4 3 8 6-statistical-a nal ysis- pla n | 
N N 9 5 3 5 - 4 3 8 6
7 of 2 8
.
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
2 5 Ja n uar y 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:  
8  of 2 8  
 
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 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 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 T M  are meas ure d o n a scale fr o m 5. 7 9 -7 0. 4 2, a n d calc ul ate 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 ei g ht sc ores relate d t o D Q L C T Q -R are m eas 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.  
1. 1. 3. 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) 
•  H b A 1c < 7 . 0% ( 5 3 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 ( A D A) or 
cli nical l y si g nifica nt h y p o gl ycae mic e pis o de ( P G < 3. 0 m m ol/ L ( 5 4 m g/ d L)) ( Y/ N) 
  S A P  4 3 8 6-statistical-a nal ysis- pla n | 
N N 9 5 3 5 - 4 3 8 6
8 of 2 8
.
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
2 5 Ja n uar y 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:  
9  of 2 8  
 
•  H b A 1c < 7. 0 % ( 5 3 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 ( A D A) or 
cli nical l y si g nifica nt h y p o gl ycae mic e pis o de ( P G < 3. 0 m m ol/ L ( 5 4 m g/ d L)) a n d n o wei g ht 
gai n 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)  
•  T otal  dail y  i ns uli n d ose  ≤ 1 0 U at wee k 5 2 ( Y/ N)  
•  T otal dail y i ns uli n d ose ≤ 2 0 U at wee k 5 2 ( Y/ N)   
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 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 h er sc ores are i n dicati ve of better healt h state (less ne gati ve i m pact).  
  S A P  4 3 8 6-statistical-a nal ysis- pla n | 
N N 9 5 3 5 - 4 3 8 6
9 of 2 8
.
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
2 5 Ja n uar y 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 0  of 2 8  
 
1. 2  
Tri al 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 p hase 3 b 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 scree ni n g, a 
1 2 -wee k r u n -i n peri o d, a 5 2-wee k  tr eat me nt peri o d a n d a f oll o w-u p p eri 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 pti 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 he I Glar 
U 1 0 0 d ose will be  o pti mise d as descri be d i n  pr ot o c ol  ap 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 1c 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 v e 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 m a gl uti de, refer pr ot oc ol  ap p e n di x 8 .  
A sc he matic o ver vie w of t he trial desi g n is s h o w n  i n Fi g ure  1 -1 . 
Fi g ure  1 -1  
Tri al desi g n  
 
T he trial i ncl u des a s cree ni n g visit 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 descri be d  
i n pr ot oc ol  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 defi ne d treat me nt al g orit h m.  
  S A P  4 3 8 6-statistical-a nal ysis- pla n | 
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C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
2 5 Ja n uar y 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 1  of 2 8  
 
2  St atistic al h y p ot heses  
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. 
1.  H b A 1c n o n -i nf eri 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 p is 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 hreate ni 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 orit y 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 n e 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. I n t his trial FI As p s h o we d a n H b A 1c 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 vels3. He nce, base 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 effect c o m pare d t o  
place b o g reater 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 wit 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. 
  S A P  4 3 8 6-statistical-a nal ysis- pla n | 
N N 9 5 3 5 - 4 3 8 6
1 1 of 2 8
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C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
2 5 Ja n uar y 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 2  of 2 8  
 
3  S a m ple size deter mi n ati o n  
Please refer t o t he pr ot o c ol secti o n 1 0. 1 . 
 
 
  S A P  4 3 8 6-statistical-a nal ysis- pla n | 
N N 9 5 3 5 - 4 3 8 6
1 2 of 2 8
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C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
2 5 Ja n uar y 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 3  of 2 8  
 
4  A n al ysis sets  
F or t he p ur p os es of a n al ysis, t he f oll o wi n g a nal ysis sets are defi ne d . 
T a ble  4 -1  
S u bject a n al ysis sets  
S u bject A n al ysis Set  
Descri pti o n  
F ull A nal ysis 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. 
Safet y A nal ysis 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 yse d acc or di n g t o t he trial pr o d uct recei ve d f or t he maj orit y of 
t he peri o d t he y were o n treat me nt. 
Per pr ot oc ol ( P P) 
a nal ysis s et  
In cl u des all s u bjects i n t h e F A S w h o f ulfil t he f oll o wi n g crite ria: 
•  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 h e 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  
 
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 ma j orit y of t he p eri o d t he y 
were o n tr eat me nt.  
T a ble  4 -2  
A n al ysis d at a sets  
Defi ne d A n al ysis 
D at a Sets  
Descri pti o n  
I n-trial 
T his o bser vati o n peri o d is defi ne d as t he p eri 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 ntact f or s u bjects l ost t o f oll o w -u p  
O n -treat me nt 
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 prese 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 
  S A P  4 3 8 6-statistical-a nal ysis- pla n | 
N N 9 5 3 5 - 4 3 8 6
1 3 of 2 8
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C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
2 5 Ja n uar y 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 4  of 2 8  
 
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)  
•  Date of last d ose of trial pr o d uct  + 4 2 da ys  
•  T he e n d -d a te 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 oll o 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 date o n tri al pr o d uct wit h a v isit 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 haract eristics of differe nt b ol u s 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 ollec te 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.  
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 place. Neit her s u bjects 
n or o bser v ati 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 ons 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. 
Defi niti o n of tre at me nt disc o nti n u ati o n  
A “treat me nt disc o nti n uer” is defi ne d as a s u bject w h o disc o nti n ues ra n d o mise d treat me nt. If a 
s u bject disc o nti n ues treat me nt d uri n g t he r u n-i n peri o d, t he s u bject will n ot f ulfil t he ra n d o misati o n 
criteria a n d t heref ore b e defi ne d as a r u n -i n f ail ure.  
Defi niti o n of st u d y disc o nti n u ati o n  
A “st u d y disc o nti n uer” is defi ne d as a s u bject w h o disc o nti n ues t he st u d y at a n y ti me after si g ni n g 
i nf or me d c o nse nt.  
  S A P  4 3 8 6-statistical-a nal ysis- pla n | 
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1 4 of 2 8
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C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
2 5 Ja n uar y 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 5  of 2 8  
 
5  St atistic al a n al yses  
5. 1  
Ge ner al c o nsi der ati o ns  
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 is  
l oc ke d. 
T he c o m paris o n prese nte d fr o m a statistica l 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 treat 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.  
5. 2  
S u bject dis p ositi o n  
See m oc k T F Ls.  
5. 3  
Pri m ar y e n d p oi nt a n al ys is 
5. 3. 1  
Defi niti o n of 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).  
5. 3. 2  
M ai n a n al ytic al a p pr o ac h  
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 data 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 mati o 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:  
•  
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 MC) 
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 utati 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 m issi 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 first visit aft er baseli ne a n d 
  S A P  4 3 8 6-statistical-a nal ysis- pla n | 
N N 9 5 3 5 - 4 3 8 6
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C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
2 5 Ja n uar y 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 6  of 2 8  
 
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 us e 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 variates. T he res ulti n g 5 0 0 c o m plete 
datasets will f urt her m or e be use d f or t h e s u bse q ue nt ti p pi n g  a nal ysis t o e val uate t he 
r o b ust ness of t he pri mar y a nal 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 ul e 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 . 
5. 3. 3  
Se nsiti vit y a n al ys es 
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 oncl 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 m a 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 ult 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 lo n ger si g nifica nt.  
Ti p pi n g p oi nt n o n -i nferi orit y or  s u p eri orit y s e nsiti vit y a nal ysis is o nl y  d o n e if t he c orres p o n di n g 
pri mar y n o n -i nferi orit y or  s u peri orit y a nal ysis i n dicates statistical si g nifi ca n ce.    
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 ned n ot o nl y b y 
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. 
  S A P  4 3 8 6-statistical-a nal ysis- pla n | 
N N 9 5 3 5 - 4 3 8 6
1 6 of 2 8
.
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
2 5 Ja n uar y 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 7  of 2 8  
 
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.  
5. 4  
Sec o n d ar y e n d p oi nts a n al ys es 
5. 4. 1  
C o nfir m at or y s ec o n d ar y e n d p oi nts  
5. 4. 1. 1  
Defi niti o n of 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 o s pitalizati 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.  
5. 4. 1. 2  
M ai n a n al ytic al a p pr o ac h  
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 2 . 
T he statistical a nal ysis of t i 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 n g 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.  
B o d y wei g ht will be a n al ys e d usi n g a si milar a p pr oac h as des cri be d i n Secti o n 5. 3. 2 . B o d y wei g ht 
will be teste d f or s u peri orit y 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 2 . Baseli ne a n d p ost-baseli ne b o d y wei g ht will be use d as c o vari ates i nstea d of H b A 1c. 
5. 4. 1. 3  
Se nsiti vit y a n al ys es 
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 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 hi n t he ‘i n -trial’ 
  S A P  4 3 8 6-statistical-a nal ysis- pla n | 
N N 9 5 3 5 - 4 3 8 6
1 7 of 2 8
.
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
2 5 Ja n uar y 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 8  of 2 8  
 
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 ysi s 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.  T he ti p pi n g p oi nt se nsiti vit y a nal ysis is o nl y 
d o ne if t he c orres p o n di n g c o nfir mat or y s u peri orit y a n al ysis of b o d y wei g ht  i n dicates statistical 
si g nifica n ce.  I n a d diti o n, t he retrie v e d dr o p o ut se nsiti vit y a n al ysis will als o be perf or me d f or b o d y 
wei g ht.  
5. 4. 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 nsit 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 A 1c 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. 
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:  
  S A P  4 3 8 6-statistical-a nal ysis- pla n | 
N N 9 5 3 5 - 4 3 8 6
1 8 of 2 8
.
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
2 5 Ja n uar y 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 9  of 2 8  
 
•  
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  
•  
N u m ber of E A C c o nfir m e d se vere ( A D A) or cli nical l y si g nifica nt h y p o gl ycae mic 
e pis o des ( P G < 3. 0 m m ol/ L ( 5 4 m g/ d L)) fr o m r a n d o misati o n t o wee k 5 2  
T he n u m ber of h y p o gl ycae mic e pis o des of t h e a b o ve 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 h e ti me peri o d c o vere d b y 
t he s u 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 n cl u de treat me nt as a 
fi x e d fact or a n d bas eli ne H b A1c as a c o variat e. T his a nal ysis will be bas e d o n t he F A S usi n g t h e 
‘ o n-treat me nt’ o bser vati o n peri o d. T he res ults will be descri b e d b y t he rat e rati o bet wee n treat me nts 
a n d t he ass ociat e d 9 5 % CI a n d p -val ue f or n o treat me nt differe nce.  
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. 
If a ne gati ve bi n o mial re gressi o n a nal ysis fails t o c o n v er ge, a P oiss o n re gressi o n a nal ysis will be 
use d  acr oss all t he s u p p orti ve sec o n dar y safet y e n d p oi nts relate d t o h y p o gl ycae mic e pis o des  
i nstea d.  
I ns uli n d ose 
D ail y b asal i ns uli n d ose ( U) at wee k 5 2 a n d t otal d ail y i ns uli n d ose ( U) at w ee k 5 2  will be  l o g-
tra nsf or me d a n d a nal yse d usi n g a n a nal ysis si milar t o t he pri mar y a nal ysis of t he pri mar y e n d p oi nt  
descri be d i n Secti o n 5. 3. 2 , wit h t he ass ociat e d l o g-tra nsf or me d baseli ne v al ue as a c o v ariat e i nstea d. 
T he a nal yses will be base d o n m ulti ple i m p ute d datasets  of i ns uli n d oses lea di n g u p t o  site visits 
o nl y . T he tr eat me nt differe nces a n d ass oci ate d 9 5 % CIs  will be b ac k -tr a nsf or me d t o t he ori gi nal 
scale, i m pl yi n g t hat l o g-treat me nt-differe nces are re p orte d as treat me nt r ati os.  T he a nal yses will be 
base d o n t he S A S usi n g t he ‘ o n -treat me nt’ 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)  
  S A P  4 3 8 6-statistical-a nal ysis- pla n | 
N N 9 5 3 5 - 4 3 8 6
1 9 of 2 8
.
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
2 5 Ja n uar y 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:  
2 0  of 2 8  
 
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 state.  
•  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 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 di n 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 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. 
Sc ori n g of D Q L C T Q -R  
B y usi n g re v erse sc ori n g f or s o me q uesti o ns i n t he D Q L C T Q -R, a ll q uesti o ns  are sc ore d  s uc h t h at 
hi g her s c ores are i n dicati ve of a better healt h state. T he ei g ht d o mai n sc ores relate d t o D Q L C T Q -R 
are re pres e nte d o n a s cal e fr o m 0 -1 0 0 usi n g t he c o n versi o n -met h o d descri be d i n K otsa n os et a l5. 
5. 5  
E x pl or at or y e n d p oi n ts a n al ys es 
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 w ee k 5 2 ( Y/ N) 
  S A P  4 3 8 6-statistical-a nal ysis- pla n | 
N N 9 5 3 5 - 4 3 8 6
2 0 of 2 8
.
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
2 5 Ja n uar y 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:  
2 1  of 2 8  
 
•  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)  
•  H b A 1c < 7. 0 % ( 5 3 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 ( A D A) or 
cli nical l y si g nifica nt h y p o gl ycae mic e pis o de ( P G < 3. 0 m m ol/ L ( 5 4 m g/ d L)) ( Y/ N) 
•  H b A 1c < 7. 0 % ( 5 3 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 ( A D A) or 
cli nical l y si g nifica nt h y p o gl ycae mic e pis o de ( P G < 3. 0 m m ol/ L ( 5 4 m g/ d L)) a n d n o wei g ht 
gai n 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)  
•  T otal dail y i ns uli n d os e ≤ 1 0 U at wee k 5 2 ( Y/ N)  
•  T otal dail y i ns uli n d ose ≤ 2 0 U at wee k 5 2 ( Y/ N)  
T he a b o ve bi nar y e n d p oi nts will be a nal ys e 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 effect a n d b aseli ne res p o nse as c o vari ate (i.e. baseli ne H b A1c 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, e x ce pt t he a nal yses re gar di n g t otal dail y  i ns uli n d ose  w hic h will be 
base d o n t he S A S a n d t h e ‘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 he 
a nal ysis will be ma d e usi n g a s e q ue ntial m ulti ple i m p utati o n a p pr oac h as d escri be d b el 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  as well as t he s u p p orti ve 
a nal ys es of i ns uli n d oses . 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 mic e pis o des, 
t he n u m ber of h y p o gl ycae mic e pis o des f or t h e re mai ni n g u n o bser ve d part of t he 
o bser vati o n peri o d will b e 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 P oiss o n  l o g-li n k m o del 
wit h treat me nt as a fi x e d fact or a n d baseli ne H b A 1c as a c o vari ate, a n d t he l o garit h m of 
t he ti me peri o d c o vered b y t he s u bject’s ‘ o n -tr eat me nt’ o bser vati o n peri o d as offset.  
•  
Eac h of t he c o m plete dat a set s 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 ul e 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 Relate 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  
  S A P  4 3 8 6-statistical-a nal ysis- pla n | 
N N 9 5 3 5 - 4 3 8 6
2 1 of 2 8
.
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
2 5 Ja n uar y 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:  
2 2  of 2 8  
 
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 (le ss 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 5. 4. 2 . 
5. 6  
Ot her s af et y a n al yses  
N ot a p plica ble.   
5. 7  
Ot her a n al yses  
5. 7. 1  
Ot her deri v ati o ns a n d assess me nts  
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:  
•  
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 on 5. 4. 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 data c ollecte d i n t he ‘i n -trial’ o bser vati o n peri o d. 
5. 8  
I nteri m 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 is 
l oc ke d. 
 
  S A P  4 3 8 6-statistical-a nal ysis- pla n | 
N N 9 5 3 5 - 4 3 8 6
2 2 of 2 8
.
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
2 5 Ja n uar y 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:  
2 3  of 2 8  
 
 
6  S u p p orti n g d oc u me nt ati o n  
6. 1  
A p pe n di x 1 : List of a b bre vi ati o ns  
A A C E  
A merica n Ass o ciati o n of Cli nical E n d ocri n ol o gists  
A D A  
A merica n Di a betes Ass o ciati o n  
A E  
a d verse e ve nt  
A N C O V A  
a nal ysis of c o varia nce  
B MI  
b o d y mass i n de x  
CI  
c o nfi de nce i nter val  
D P P -4i  
di pe pti d yl pe pti dase -4 i n hi bit or  
D Q L C T Q -R  Dia betes Q ualit y Of Life Cli nical Trial Q uesti o n naire –  Re vise d  
E A C  
e ve nt a dj u dicati o n c o m mittee  
F A S  
f ull a nal ysis set 
F P G  
fasti n g plas ma gl u c ose  
H D L  
hi g h de nsit y li p o pr otei n  
H R  
hazar d rati o  
H R Q o L  
healt h -rel ate d q ualit y of life 
I C H 
I nter nati o nal C o u ncil o n Har m o nizati o n  
L D L  
l o w de nsit y li p o pr otei n  
L L O Q  
l o wer li mit of q ua ntificati o n 
M A R  
missi n g at ra n d o m  
M C M C  
Mar k o v C hai n M o nte Carl o  
O A D  
oral a nti -dia betic  dr u g  
O W  
o nce -w ee kl y  
P G  
plas ma gl uc os e  
P P  
per pr ot oc ol a n al ysis set  
P R O  
patie nt re p orte d o ut c o mes  
  S A P  4 3 8 6-statistical-a nal ysis- pla n | 
N N 9 5 3 5 - 4 3 8 6
2 3 of 2 8
.
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
2 5 Ja n uar y 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:  
2 4  of 2 8  
 
 
S A P  
statistical anal ysis p la n 
S A S  
safet y a n al ysis set 
S M P G  
self meas ur e d plas ma gl u c ose  
TI D  
t hree ti mes dail y  
T F L  
ta bles, fi g ures a n d listi n gs 
T RI M -D  
Treat me nt Relate d I m p act Meas ure F or Dia betes  
T 2 D  
t y pe 2 dia b etes  
U L O Q  
u p per li mit of q ua ntificati o n  
 
6. 2  
A p pe n di x 2: C h a n ges t o pr ot oc ol -pl a n ne d a n al yses  
T he Ba yes ne gati ve bi n o mial l o g -li n k m o del use d f or i m p utati o n of h y p o gl ycae mic e pis o des i n 
c o n necti o n wit h t he c o m p osite e n d p oi nts  has bee n c ha n ge d t o Ba yes P oiss o n l o g -li n k m o del i n 
or der t o miti gat e c o m p utati o nal iss ues d ue t o fe w E A C c o nfir me d se v ere h y p o gl ycae mic e pis o des 
re p orte d i n t his trial, see Secti o n 5. 5 .  
F or t he sa m e reas o n, a P oiss o n re gressi o n a nal ysis will be use d t o a nal ys e all t he s u p p orti ve 
sec o n dar y s afet y e n d p oi nts relate d t o h y p o gl ycae mic e pis o des if o ne of  t h e ne gati ve bi n o mial 
re gressi o n a n al ysis fails t o c o n ver ge, s ee Secti o n 5. 4. 2 . 
 
S u p ple me ntar y st atistical a nal ys es of i ns uli n d oses ha ve bee n i ncl u de d t o f urt her c o m pare t he 
cli nical pr ofiles of t he tr eat me nt ar ms , see Secti o ns 1. 1. 3. 2. 2  a n d 1. 1. 3. 2. 3 : 
•  S u p p orti ve sec o n dar y e n d p oi nts  
o  I ns uli n d ose  
▪ Dail y b asal i ns uli n d ose at wee k 5 2 ( U)  
▪ T otal dail y i ns uli n d ose at wee k 5 2 ( U)  
•  E x pl orat or y res p o n d er e n d p oi nts  
o  T otal dail y i ns uli n d ose ≤ 1 0 U at wee k 5 2 ( Y/ N)  
o  T otal dail y i ns uli n d ose ≤ 2 0 U at wee k 5 2 ( Y/ N)  
 
F urt her m ore, t he f oll o wi n g e n d p oi nts are a d d e d t o  f urt her el a b orat e o n t he pri mar y a n d sec o n dar y 
c o nfir mat or y e n d p oi nts , see Secti o ns 1. 1. 3. 2. 2  a n d 1. 1. 3. 2. 3 : 
•  S u p p orti ve sec o n dar y e n d p oi nts  
o  N u m ber of E A C c o nfir m e d se vere ( A D A) or cli nicall y si g nifica nt h y p o gl ycae mic 
e pis o des ( P G < 3. 0 m m ol/ L ( 5 4 m g/ d L)) fr o m r a n d o misati o n t o wee k 5 2  
•  E x pl orat or y res p o n d er e n d p oi nts  
o  H b A 1c < 7. 0 % ( 5 3 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 ( A D A) 
or cli nicall y si g nifica nt h y p o gl ycae mic e pis o de ( P G < 3. 0 m m ol/ L ( 5 4 m g/ d L)) 
( Y/ N) 
  S A P  4 3 8 6-statistical-a nal ysis- pla n | 
N N 9 5 3 5 - 4 3 8 6
2 4 of 2 8
.
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
2 5 Ja n uar y 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:  
2 5  of 2 8  
 
 
o  H b A 1c < 7. 0 % ( 5 3 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 ( A D A) 
or cli nicall y si g nifica nt h y p o gl ycae mic e pis o de ( P G < 3. 0 m m ol/ L ( 5 4 m g/ d L)) a n d 
n o wei g ht gai n fr o m ra n d o misati o n t o wee k 5 2 ( Y/ N)  
A sc he matic o ver vie w of t he esti ma n d has bee n pr o vi de d, see Ta bl e  1 -1 .  
 
6. 3  
A p pe n di x 3: Defi niti o n a n d c alc ul ati o n of e n d p oi nts, assess me nts a n d deri v ati o ns   
T y pe  
Title  
Ti me fr a me  
U nit  
Det ails  
Pri mar y 
e n d p oi nt  
C ha n ge fr o m baseli ne ( wee k 0) t o 
wee k 5 2 i n H b A 1c ( % -p oi nt)  
Fr o m w ee k 0 t o wee k 5 2 
i n H b A 1c  ( %-p oi nt)  
% -p oi nt  
 
C o nfir mat or y 
sec o n dar y 
e n d p oi nt  
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 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 ( wee k 0) u p t o wee k 
5 2 ( da ys)  
Fr o m r a n d o misati o n 
( wee k 0) t o wee k 5 2 
( da ys) 
Da ys  
 
C o nfir mat or y 
sec o n dar y 
e n d p oi nt  
Ti me t o first 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 dical hel p, or is life 
threate ni n g fr o m ra n d o misati o n u p t o 
wee k 5 2 ( da ys)  
Fr o m r a n d o misati o n 
( wee k 0) t o wee k 5 2 
( da ys) 
Da ys  
 
C o nfir mat or y 
sec o n dar y 
e n d p oi nt  
C ha n ge fr o m baseli ne ( wee k 0) t o 
wee k 5 2 i n b o d y wei g ht ( k g)  
Fr o m w ee k 0 t o wee k 5 2 
i n b o d y wei g ht ( k g) 
K g  
 
S u p p orti ve 
sec o n dar y 
e n d p oi nt  
C ha n ge fr o m baseli ne ( wee k 0) t o 
wee k 5 2 i n fasti n g plas ma gl uc ose 
( m m ol/ L) 
Fr o m w ee k 0 t o wee k 5 2 
i n fasti n g plas ma gl uc ose 
( m m ol/ L) 
m m ol/ L  
 
S u p p orti ve 
sec o n dar y 
e n d p oi nt  
C ha n ge fr o m baseli ne ( wee k 0) t o 
wee k 5 2 i n mea n 7 -p oi nt pr ofile  
( m m ol/ L) 
Fr o m w ee k 0 t o wee k 5 2 
i n mea n 7-p oi nt pr ofile 
( m m ol/ L) 
m m ol/ L  
 
S u p p orti ve 
sec o n dar y 
e n d p oi nt  
C ha n ge fr o m baseli ne ( wee k 0) t o 
wee k 5 2 i n mea n p ost -pra n dial 
i ncre me nt ( o ver all meals) ( m m ol/ L) 
Fr o m w ee k 0 t o wee k 5 2 
i n mea n p ost-pra n dial 
i ncre ment ( m m ol/ L)  
m m ol/ L  
 
S u p p orti ve 
sec o n dar y 
e n d p oi nt  
C ha n ge fr o m baseli ne ( wee k 0) t o 
wee k 5 2 i n s yst olic bl o o d press ure 
( m m H g) 
Fr o m w ee k 0 t o wee k 5 2 
i n s yst olic bl o o d press ure 
( m m H g) 
m m H g  
 
S u p p orti ve 
sec o n dar y 
e n d p oi nt  
C ha n ge fr o m baseli ne ( wee k 0) t o 
wee k 5 2 i n diast olic bl o o d press ure 
( m m H g) 
Fr o m w ee k 0 t o wee k 5 2 
i n diast olic bl o o d 
press ure ( m m H g)  
m m H g  
 
S u p p orti ve 
sec o n dar y 
e n d p oi nt  
C ha n ge fr o m baseli ne ( wee k 0) t o 
wee k 5 2 i n t otal c h olester ol 
( m m ol/ L) 
Fr o m w ee k 0 t o wee k 5 2 
i n t otal c h olester ol 
( m m ol/ L) 
m m ol/ L  
 
S u p p orti ve 
sec o n dar y 
e n d p oi nt  
C ha n ge fr o m baseli ne ( wee k 0) t o 
wee k 5 2 i n l o w -de nsit y li p o pr otei n 
( m m ol/ L) 
Fr o m w ee k 0 t o wee k 5 2 
i n l o w-de nsit y 
li p o pr otei n ( m m ol/ L) 
m m ol/ L  
 
S u p p orti ve 
sec o n dar y 
e n d p oi nt  
C ha n ge fr o m baseli ne ( wee k 0) t o 
wee k 5 2 i n hi g h -de nsit y li p o pr otei n 
( m m ol/ L) 
Fr o m w ee k 0 t o wee k 5 2 
i n hi g h-de nsit y 
li p o pr otei n ( m m ol/ L) 
m m ol/ L  
 
S u p p orti ve 
sec o n dar y 
e n d p oi nt  
C ha n ge fr o m baseli ne ( wee k 0) t o 
wee k 5 2 i n tri gl yceri des ( m m ol/ L)  
Fr o m w ee k 0 t o wee k 5 2 
i n tri gl yceri des ( m m ol/ L) 
m m ol/ L  
 
S u p p orti ve 
sec o n dar y 
e n d p oi nt  
C ha n ge fr o m baseli ne ( wee k 0) t o 
wee k 5 2 i n b o d y mass i n de x ( k g/ m 2)  
Fr o m w ee k 0 t o wee k 5 2 
i n b o d y mass i n de x 
( k g/ m 2) 
k g/ m 2  
 
  S A P  4 3 8 6-statistical-a nal ysis- pla n | 
N N 9 5 3 5 - 4 3 8 6
2 5 of 2 8
.
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
2 5 Ja n uar y 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:  
2 6  of 2 8  
 
 
S u p p orti ve 
sec o n dar y 
e n d p oi nt  
C ha n ge fr o m baseli ne ( wee k 0) t o 
wee k 5 2 i n waist circ u mfere nc e (c m)  
Fr o m w ee k 0 t o wee k 5 2 
i n waist circ u mfere nce 
(c m) 
c m 
 
S u p p orti ve 
sec o n dar y 
e n d p oi nt  
C ha n ge fr o m baseli ne ( wee k 0) t o 
wee k 5 2 i n b o d y wei g ht ( %)  
Fr o m w ee k 0 t o wee k 5 2 
i n b o d y wei g ht ( %) 
%  
 
S u p p orti ve 
sec o n dar y 
e n d p oi nt  
C ha n ge fr o m baseli ne ( wee k 0) t o 
wee k 5 2 i n p ulse ( b p m)  
Fr o m w ee k 0 t o wee k 5 2 
i n p ulse ( b p m) 
b p m  
 
S u p p orti ve 
sec o n dar y 
e n d p oi nt  
N u m ber of E A C c o nfir me 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 
Fr o m r a n d o misati o n 
( wee k 0) t o wee k 5 2 
C o u nt  
 
S u p p orti ve 
sec o n dar y 
e n d p oi nt  
N u m ber of E A C c o nfir me 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 ra n d o misati o n t o wee k 
5 2  
Fr o m r a n d o misati o n 
( wee k 0) t o wee k 5 2 
C o u nt  
 
S u p p orti ve 
sec o n dar y 
e n d p oi nt  
N u m ber of E A C c o nfir me 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 ra n d o misati o n t o wee k 
5 2  
Fr o m r a n d o misati o n 
( wee k 0) t o wee k 5 2 
C o u nt  
 
S u p p orti ve 
sec o n dar y 
e n d p oi nt  
N u m ber of 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 fr o m ra n d o misati o n t o 
wee k 5 2  
Fr o m r a n d o misati o n 
( wee k 0) t o wee k 5 2 
C o u nt  
 
S u p p orti ve 
sec o n dar y 
e n d p oi nt  
N u m ber of E A C c o nfir me d se vere 
( A D A) or cli nicall y si g nifica nt 
h y p o gl ycae mic e pis o des ( P G < 3. 0 
m m ol/ L ( 5 4 m g/ d L)) fr o m 
ra n d o misati o n t o wee k 5 2 
Fr o m ra n d o misati o n 
( wee k 0) t o wee k 5 2 
C o u nt  
 
S u p p orti ve 
sec o n dar y 
e n d p oi nt  
Dail y  basal i ns uli n d ose at we e k 5 2 
( U) 
At wee k 5 2  ( U) 
U  
 
S u p p orti ve 
sec o n dar y 
e n d p oi nt  
T otal dail y i ns uli n d ose at wee k 5 2 
( U) 
At wee k 5 2 ( U)  
U  
 
S u p p orti ve 
sec o n dar y 
e n d p oi nt  
C ha n ge fr o m baseli ne ( wee k 0) t o 
wee k 5 2 i n S F -3 6 d o mai n sc or es  
Fr o m wee k 0 t o wee k  5 2 
i n S F-3 6 d o mai n sc ores  
Sc ore 
( 5. 7 9-
7 0. 4 2)  
 
S u p p orti ve 
sec o n dar y 
e n d p oi nt  
C ha n ge fr o m baseli ne ( wee k 0) t o 
wee k 5 2 i n D Q L C T Q -R d o mai n 
sc ores 
Fr o m wee k 0 t o wee k 5 2 
i n D Q L C T Q-R d o mai n 
sc ores 
Sc ore ( 0 -
1 0 0)  
 
E x pl orat or y 
e n d p oi nt  
H b A 1c ≤ 7. 5 % ( 5 8 m m ol/ m ol ) at 
wee k 5 2 ( Y/ N)  
At wee k 5 2 ( Y/ N)  
Y/ N  
 
E x pl orat or y 
e n d p oi nt  
H b A 1c < 7. 0 % ( 5 3 m m ol/ m ol) at 
wee k 5 2 ( Y/ N) ( A D A)  
At wee k 5 2 ( Y/ N)  
Y/ N  
 
E x pl orat or y 
e n d p oi nt  
H b A 1c ≤ 6. 5 % ( 4 8 m m ol/ m ol) at 
wee k 5 2 ( Y/ N) ( A A C E)  
At wee k 5 2 ( Y/ N)  
Y/ N  
 
E x pl orat or y 
e n d p oi nt  
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 
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)  
Fr o m ra n d o misati o n 
( wee k 0) t o wee k 5 2 
( Y/ N) 
Y/ N  
 
  S A P  4 3 8 6-statistical-a nal ysis- pla n | 
N N 9 5 3 5 - 4 3 8 6
2 6 of 2 8
.
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
2 5 Ja n uar y 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:  
2 7  of 2 8  
 
 
E x pl orat or y 
e n d p oi nt  
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 
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)  
Fr o m ra n d o misati o n 
( wee k 0) t o wee k 5 2 
( Y/ N) 
Y/ N  
 
E x pl orat or y 
e n d p oi nt  
H b A 1c < 7. 0 % ( 5 3 m m ol/ m ol ) at 
wee k 5 2 wit h o ut a n E A C c o nfir me d 
se vere ( A D A) or cli nicall y 
si g nifica nt h y p o gl ycae mic e pis o de 
( P G < 3. 0 m m ol/ L ( 5 4 m g/ d L)) 
( Y/ N) 
Fr o m ra n d o misati o n 
( wee k 0) t o wee k 5 2 
( Y/ N) 
Y/ N  
 
E x pl orat or y 
e n d p oi nt  
H b A 1c < 7. 0 % ( 5 3 m m ol/ m ol) at 
wee k 5 2 wit h o ut a n E A C c o nfir me d 
se vere ( A D A) or cli nicall y 
si g nifica nt h y p o gl ycae mic e pis o de 
( P G < 3. 0 m m ol/ L ( 5 4 m g/ d L)) a n d 
n o wei g ht gai n fr o m ra n d o misati o n 
t o wee k 5 2 ( Y/ N) 
Fr o m ra n d o misati o n 
( wee k 0) t o wee k 5 2 
( Y/ N) 
Y/ N  
 
E x pl orat or y 
e n d p oi nt  
W ei g ht l oss ≥ 5 % at wee k 5 2 ( Y/ N)  
At wee k 5 2 ( Y/ N)  
Y/ N  
 
E x pl orat or y 
e n d p oi nt  
W ei g ht l oss ≥ 1 0 % at wee k 5 2 ( Y/ N)  
At wee k 5 2 ( Y/ N)  
Y/ N  
 
E x pl orat or y 
e n d p oi nt  
T otal dail y i ns uli n d ose ≤ 1 0 U at 
wee k 5 2 ( Y/ N)  
At wee k 5 2 ( Y/ N)  
Y/ N  
 
E x pl orat or y 
e n d p oi nt  
T otal dail y i ns uli n d ose ≤ 2 0 U at 
wee k 5 2 ( Y/ N)  
At wee k 5 2 ( Y/ N)  
Y/ N  
 
E x pl orat or y 
e n d p oi nt  
C ha n ge fr o m baseli ne ( wee k 0) t o 
wee k 5 2 i n T RI M -D d o mai n s c ores  
Fr o m wee k 0 t o wee k 5 2 
i n T RI M-D d o mai n 
sc ores 
Sc ore ( 0 -
1 0 0)  
 
Assess me nt  
C ha n ge fr o m baseli ne ( wee k 0) t o 
wee k 5 2 i n p h ysical e xa mi nati o n  
Fr o m wee k 0 t o wee k 5 2 
i n p h ysical e xa mi nati o n 
Cate g orical  S hift fr o m 
baseli ne le vel 
( N or mal, 
A b n or mal n ot  
cli nicall y 
si g nifica nt, 
A b n or mal 
cli nicall y  
si g nifica nt) t o 
le vel at wee k 5 2 
Assess me nt  
C ha n ge fr o m base li ne ( wee k 0) t o 
wee k 5 2 i n e ye e xa mi nati o n  
Fr o m wee k 0 t o wee k 5 2 
i n e ye e xa mi nati o n 
Cate g orical  S hift fr o m 
baseli ne le vel 
( N or mal, 
A b n or mal n ot  
cli nicall y 
si g nifica nt, 
A b n or mal 
cli nicall y  
si g nifica nt) t o 
le vel at wee k 5 2 
Assess me nt  
C ha n ge fr o m baseli ne  ( wee k 0) t o 
wee k 5 2 i n bi oc he mistr y  
Fr o m wee k 0 t o wee k 5 2 
i n bi oc he mistr y 
M ulti ple 
u nits  
 
Assess me nt  
C ha n ge fr o m baseli ne ( wee k 0) t o 
wee k 5 2 i n uri ne al b u mi n t o 
creati ni ne rati o  
Fr o m wee k 0 t o wee k 5 2 
i n uri ne al b u mi n t o 
creati ni ne rati o  
m g/ m m ol  
 
 
  S A P  4 3 8 6-statistical-a nal ysis- pla n | 
N N 9 5 3 5 - 4 3 8 6
2 7 of 2 8
.
C O N FI D E N TI A L


Statistical A nal ysis Pla n  
C O N FI D E N TI A L  
Date:  
2 5 Ja n uar y 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:  
2 8  of 2 8  
 
 
7  Refere nces  
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 pt i o n b y C H M P. 1 4 Ma y 2 0 1 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.  
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 h e 
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).  
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 Me d. 2 0 0 9; 2 8( 4): 5 8 6 -6 0 4.  
5.  
K otsa n os J G, Vi g nati L, H uster W, A n drej asic h C, B o g gs M B, J ac o bs o n A M, et al. Healt h -
relate d q ualit y-of -life res ults fr o m m ulti nati o nal cli nical trials of i ns uli n lis pr o. Assessi n g 
be nefits of a n e w dia bet es t hera p y. Dia b etes Care. 1 9 9 7; 2 0( 6): 9 4 8 -5 8.  
 
  S A P  4 3 8 6-statistical-a nal ysis- pla n | 
N N 9 5 3 5 - 4 3 8 6
2 8 of 2 8
.
C O N FI D E N TI A L