Two-year Effect and Safety of Semaglutide 2.4 mg Once-weekly in Subjects With Overweight or Obesity
Phase: PHASE3
Conditions: Overweight, Obesity
Sponsor: Novo Nordisk A/S

Cover Page for Protocol 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03693430 
Sponsor trial ID: 
NN9536-4378 
Official title of study: 
Two-year effect and safety of semaglutide 2.4 mg once-weekly 
in subjects with overweight or obesity 
Document date*: 
29 June 2018 
 
*Document date refers to the date on which the document was most recently updated. 
Note: The date in the header from Page 2 is the date of compilation of the documents and not of an update to content. 

Pr ot oc ol
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2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
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Stat us:
Fi nal
Pa ge:
1 of 9 4
Pr ot oc ol
Pr ot oc ol title:
T w o - ye ar effect a n d s afet y of se m a gl uti de 2. 4 m g o nce -wee kl y i n s u b jects wit h o ver wei g ht or 
o besit y
S u bst a nce n a me: se m a gl uti de
U ni vers al Tri al N u m ber: U 1 1 1 1 - 1 2 0 2- 1 7 4 0
E u dr a C T N u m ber: 2 0 1 7 - 0 0 3 7 2 6- 3 2
Tri al p h ase: 3 b
  
  
  
  
  
  
 
  
  
 
  
   
 
  
  
   
  
   
  
  
  
  
  
 
  
 
 
  
  
  
  
  
  
  
  
   
  
  
 
  
   
 
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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. 
 
 
 
. 
 
 
T his c o nfi de ntial d oc u me nt is t he pr o pert y of N o v o N or dis k. N o u n p u blis he d i nf or mati o n c o ntai ne d herei n ma y be 
discl ose d w it h o ut pri or writte n a p pr o val fr o m N o v o N or dis k. Access t o t his d oc u me nt m ust be restricte d t o rele va nt 
parties.

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
2 of 9 4
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
Date
Versi o n
U p date d pr ot oc ol i ncl u di n g 
a me n d me nt 1
2 9 J u ne 2 0 1 8
3. 0
Ori gi nal pr ot oc ol
1 4 Ma y
2 0 1 8
2. 0
Pr ot oc ol  a me n d me nt n o. 1 ( 2 9 J u ne 2 0 1 8 versi on 2 . 0)
T his a me n d me nt is c o nsi dere d t o be n o n- s u bsta ntial base d o n t he criteria set f ort h i n Article 1 0(a) 
of  Di recti 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 o f t he E ur o pea n U ni o n 1
beca use it neit her si g nifica nt l y i m pacts t he safety n or p h ysical/ me ntal i nte grit y of  s u bjects n or t he 
scie ntific val ue of t he trial.
O ver all r ati o n ale f or a me n d me nt n o . 1:
T his pr ot oc ol a me n d me nt is pre pare d t o i ncl u de t he C o ntr ol of Eati n g Q uest i on naire ( C o E Q) at t he 
f oll owi n g t i me p oi nts: baseli ne ( wee k 0), wee k 2 0, wee k 5 2 a n d wee k 1 0 4. T he q uesti o n naire will 
be i m ple me nte d i n U S a n d Ca na da o nl y. 
Secti o n # a n d n a me
Descri pti o n of c h a n ge
R ati o n ale
Secti o n 1 0. 3. 3 E x pl orat or y e n d p oi nts
A d di n g t hat t he rati n g f or t he C o E Q 
will be s u m marise d usi n g descri pti ve 
statistics   
As t his is a n e x pl orat or y e n d p oi nt
Secti o n 9 Trial assess me nts a n d 
pr oce d ures a n d 9. 1. 3
A d di n g  patie nt re p orte d o utc o me 
q uesti o n naires a n d descri pti o n of h o w 
t he s u bjects s h o ul d c o m plete t he 
q uesti o n naire 
T o e x plai n h o w t he q uesti o n naire 
s h o ul d be c o m plete d
Secti o n 4. 2. 3 E x pl orat or y e n d p oi nts
A d di n g C o ntr ol of Eati n g 
Q uesti o n naire ( C o E Q): Sc ores fr o m 
t he 4 d o mai ns a n d 1 9 i n di vi d ual ite ms 
as a n e x pl orati ve e n d p oi nt
G L P -1 is a p h y si ol o gical re g ulat or of 
a p petite. T he C o E Q assesses t he 
i nte nsit y a n d t ype of f o o d cra vi n gs, as 
well as s u bjecti ve se nsati o ns of 
a p petite a n d m o o d.  I ncl u di n g t he 
C o E Q will pr o vi de val ua ble 
i nf or mati o n o n t he l o n g-ter m effect of 
se ma gl uti de 2. 4 m g o n a p petite a n d 
f o o d cra vi n g
Secti o n 4. 1 Pri mar y, sec o n dar y a n d 
e x pl orat or y o bjecti ve(s)
A d di n g c o ntr ol of eati n g  as a n 
e x pl orati ve o bjecti ve
Sa me as a b o ve
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Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
3 of 9 4
Ta ble of C o nte nts    
P a ge
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 .......................................................................................2
T a ble of C o nte nts ........................................................................................................................................3
1
S y n o psis ................................................................................................................................................6
2
Fl o wc h art .............................................................................................................................................9
3
I ntr o d ucti o n .......................................................................................................................................1 3
3. 1
Trial rati o nale ..........................................................................................................................1 3
3. 2
Bac k gr o u n d .............................................................................................................................1 4
3. 2. 1
Se ma gl ut i de...........................................................................................................1 4
3. 2. 2
Trial p o p ulati o n .....................................................................................................1 4
3. 3
Be nefit -ris k assess me nt ...........................................................................................................1 5
3. 3. 1
Be nefits .................................................................................................................1 5
3. 3. 2
Ris ks a n d preca uti o ns .............................................................................................1 5
3. 3. 3
C o ncl usi o n o n ris k -be nefit pr ofile ..........................................................................1 6
4
O bjecti ves a n d e n d p oi nts ...................................................................................................................1 7
4. 1
Pri mar y, sec o n dar y a n d e x pl orat or y o bjecti ve(s) ......................................................................1 7
4. 2
Pri mar y, sec o n dar y a n d e x pl orat or y e n d p oi nt(s) ......................................................................1 8
4. 2. 1
Pri mar y e n d p oi nt ...................................................................................................1 8
4. 2. 2
Sec o n dar y e n d p oi nts ..............................................................................................1 8
4. 2. 2. 1
C o nfir ma t or y sec o n dar y e n d p oi nts ...................................................1 8
4. 2. 2. 2
S u p p orti ve sec o n dar y e n d p oi nts .......................................................1 8
4. 2. 3
E x pl orat or y e n d p oi nts ............................................................................................1 9
5
Tri al desi g n ........................................................................................................................................2 0
5. 1
O verall desi g n .........................................................................................................................2 0
5. 2
S u bjec t a n d trial c o m pleti o n....................................................................................................2 1
5. 3
E n d of trial defi niti o n ..............................................................................................................2 1
5. 4
Scie ntific rati o nale f or trial desi g n ...........................................................................................2 1
5. 5
J ustificati o n f or d ose ...............................................................................................................2 1
6
Tri al p o p ul ati o n ................................................................................................................................. 2 2
6. 1
I ncl usi o n criteria .....................................................................................................................2 2
6. 2
E x cl usi o n criteria ....................................................................................................................2 2
6. 3
Ra n d o misati o n criteria ............................................................................................................2 4
6. 4
Lifest yle restricti o ns ................................................................................................................2 4
6. 4. 1
Meals a n d dietar y restricti o ns .................................................................................2 4
6. 4. 2
Caffei ne a n d t o bacc o ..............................................................................................2 4
6. 5
Scree n fail ures ........................................................................................................................2 4
7
Tre at me nts .........................................................................................................................................2 5
7. 1
Treat me nts a d mi nistere d .........................................................................................................2 5
7. 1. 1
Me dical de vices .....................................................................................................2 7
7. 1. 2
Diet a n d p h ysical acti vit y c o u nselli n g ....................................................................2 7
7. 2
D ose m o dificati o n ...................................................................................................................2 8
7. 3
Met h o d of treat me nt assi g n me nt ..............................................................................................2 8
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Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
4 of 9 4
7. 4
Bli n di n g ..................................................................................................................................2 8
7. 5
Pre parati o n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y ..........................................................................2 9
7. 6
Treat me nt c o m plia nce .............................................................................................................3 0
7. 7
C o nc o mita nt me dicati o n ..........................................................................................................3 0
7. 7. 1
Resc ue me dicati o n ................................................................................................. 3 0
7. 8
Treat me nt after t he e n d of t he trial ...........................................................................................3 0
8
Disc o nti n u ati o n/ Wit h dr a w al criteri a ................................................................................................3 1
8. 1
Disc o nti n uati o n of trial treat me nt ............................................................................................3 1
8. 1. 1
Te m p orar y disc o nti n uati o n of trial treat me nt ..........................................................3 2
8. 2
Wit h dra wal fr o m t he trial
........................................................................................................3 2
8. 2. 1
Re place me nt of s u bjects .........................................................................................3 2
8. 3
L ost t o f oll o w - u p.....................................................................................................................3 3
9
Tri al assess me nts a n d pr oce d ures .....................................................................................................3 3
9. 1
Efficac y assess me nts ...............................................................................................................3 4
9. 1. 1
B o d y meas ure me nts ...............................................................................................3 4
9. 1. 2
Cli nical efficac y la b orat or y assess me nts ................................................................. 3 5
9. 1. 3
Cli nical o utc o me assess me nt (a p plica ble f or U S a n d Ca na da o nl y) .........................3 5
9. 2
A d verse e ve nts ........................................................................................................................3 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 ........................3 5
9. 2. 1. 1
E ve nts f or a dj u dicati o n .....................................................................3 7
9. 2. 2
Met h o d of detecti n g A Es a n d S A Es
.......................................................................3 8
9. 2. 3
F oll o w -u p o n A Es a n d S A Es ..................................................................................3 8
9. 2. 4
Re g ulat or y re p orti n g re q uire me nts f or S A Es ..........................................................3 8
9. 2. 5
H y p o gl ycae mic, car di o vasc ular a n d deat h e ve nts ...................................................3 8
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 ...................................................................................................................3 8
9. 2. 7
Pre g na ncies a n d ass ociate d a d verse e ve nts .............................................................3 8
9. 2. 8
Me dical de vice i nci de nts (i ncl u di n g malf u ncti o ns) .................................................3 9
9. 2. 9
T e c h nical c o m plai nts .............................................................................................3 9
9. 3
Treat me nt of o ver d ose .............................................................................................................4 0
9. 4
Safet y assess me nts ..................................................................................................................4 0
9. 4. 1
Me ntal healt h assess me nt i nstr u me nts
....................................................................4 1
9. 4. 2
P h ysical e xa mi nati o ns ............................................................................................4 2
9. 4. 3
Vital si g ns ..............................................................................................................4 2
9. 4. 4
Electr ocar di o gra ms ................................................................................................4 2
9. 4. 5
Cli nical safet y la b orat or y assess me nts ....................................................................4 2
9. 5
P har mac o ki netics ....................................................................................................................4 3
9. 6
P har mac o d y na mics .................................................................................................................4 3
9. 7
Ge ne tics..................................................................................................................................4 3
9. 8
Bi o mar kers .............................................................................................................................4 3
9. 9
Se ver e h y perse nsiti vit y............................................................................................................4 3
1 0
St atistic al c o nsi der ati o ns ...................................................................................................................4 4
1 0. 1
S a m ple size deter mi nati o n .......................................................................................................4 4
1 0. 2
Defi niti o n of a nal ysis sets ........................................................................................................4 6
1 0. 3
Statistical a nal yses ..................................................................................................................4 7
1 0. 3. 1
Pri mar y e n d p oi nt ...................................................................................................4 7
1 0. 3 . 2
Sec o n dar y e n d p oi nts ..............................................................................................5 2
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Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
5 of 9 4
1 0. 3. 2. 1
C o nfir ma t or y sec o n dar y e n d p oi nts ...................................................5 2
1 0. 3. 2. 2
S u p p orti ve sec o n dar y e n d p oi nts .......................................................5 3
1 0. 3. 3
E x pl orat or y e n d p oi nt .............................................................................................5 5
1 0. 3. 4
E x pl orati ve statistical a nal ysis f or p har mac o ge netics a n d bi o mar kers .....................5 6
1 0. 3. 5
Ot her a nal yses .......................................................................................................5 6
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 .............................................................5 6
1 1
A p pe n dices .........................................................................................................................................5 7
A b bre vi ati o ns a n d Tr a de m ar ks .......................................................................................5 8
A p pe n di x 1
Cli nic al l a b or at or y tests ...................................................................................................6 1
A p pe n di x 2
Tri al g o ver n a nce c o nsi der ati o ns ......................................................................................6 4
A p pe n di x 3
A d verse e ve nts: defi niti o ns a n d pr oce d ures f or rec or di n g, e v al u ati o n, f oll o w -u p, 
A p pe n di x 4
a n d re p orti n g .....................................................................................................................................7 4
C o ntr ace pti ve g ui d a nce a n d c ollecti o n of pre g n a nc y i nf or m ati o n ................................. 8 0
A p pe n di x 5
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 -
A p pe n di x 6
u p a n d re p orti n g ................................................................................................................................8 3
M o nit ori n g of c alcit o ni n ...................................................................................................8 5
A p pe n di x 7
C o u ntr y -s pecific re q uire me nts ........................................................................................8 8
A p pe n di x 8
1 2
Refere nces ..........................................................................................................................................8 9
At tac h me nt I Glo bal  list of k e y staff a n d rele va nt de part me nts a n d s u p pliers
At tac h me nt II C o u ntr y list of key staff a n d rele va nt de part me nts
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Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
6 of 9 4
1
S y n o psis
R ati o n ale:
Lifest yle i nter ve nt i on i n t he f or m of di et a n d e xercise is first li ne treat me nt f or o besit y,  but m ost 
pe o pl e wit h o besit y str u g gle t o ac hie ve a n d mai ntai n t heir wei g ht l oss 2- 1 1. S ur gical treat me nts offer 
a n effecti ve alter nat i ve f or s o me pe o ple wit h se vere o besit y, b ut s ur ger y carries a ris k i n c o n necti o n 
wi t h t he pr oce d ure a n d is n ot wit h o ut c o mplicati o ns. F urt her m or e , s ur ger y re q uir es clos e f ol l ow- u p 
of  t he i n di vi d ual w hic h ca n be c u m bers o me a n d c ostly 2- 7, 1 2, 1 3. P har mac ot hera p y ma y t herefor e 
ser ve as a val ua ble a dj u nct t o lifestyle i nter ve nt i on f or i n di vi d uals wit h o besit y i n or der t o ac hie ve 
a n d s ustai n a cli nicall y rele va nt weig ht l oss, t o i m pr o ve c o m or bi d c o n di tio ns a n d t o facilitate a 
healt hier lifest yle. Fe w a nt i-o besit y me dicat i ons a re c urre ntl y a vaila ble a n d t here is a nee d f or m ore 
safe a n d effecti ve t hera pe ut ic o pti o ns f or treat me nt of o besity, es peciall y  tr e at me nts t hat als o tar get 
w ei g ht mai nte na nce, pre ve nt i on a n d treat me nt of c o m o r bidi ties 2- 6, 1 4, 1 5.
T he prese nt trial is desi g ne d t o c o m pare t he t w o -year effect a n d safet y of  s u bc uta ne o us (s.c.) 
se ma gl uti de 2. 4 m g o nce wee kl y vers us se ma gl ut i de place b o as a n a dj u nct t o a re d uce d-cal orie diet 
a n d i ncrease d p h ysical act i vity i n s u bjects wit h o ver wei g ht or o besity.  A t wo- ye ar perio d i s 
c o nsi dere d a n a p pr o priate p eri o d of  ti me f or e val uatio n of  lo n g- t er m treat me nt wit h s.c. se ma gl uti de 
2. 4 m g o nce wee kl y.
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 he t w o -year effe ct of se ma gl ut i de s.c. 2. 4 m g o nce wee kl y vers us se ma gl ut i de place b o 
as a n a dj u nct t o a re d uce d -calori e diet a n d i ncrease d p h ysical act i vity i n s u bjects wit h o ver weig ht or 
o besit y o n b o d y  wei g ht.
Sec o n d ar y o bjecti ve
T o c o m p are t he t w o -year effect of se ma gl ut i de s.c. 2. 4 m g o nce wee kl y vers us se ma gl ut i de place b o 
as a n a dj u nct t o a re d uce d -calori e diet a n d i ncrease d p h ysical act i vity i n s u bjects wit h o ver weig ht or 
o besit y o n:

Car di o vasc ular ri s k fact ors

Gl uc ose m eta b o lism
T o co m pare t he o ne -year effect of se ma gl uti de s.c. 2. 4 m g o nce wee kl y vers us se ma gl ut i de place b o 
as a n a dj u nct t o a re d uce d -calori e diet a n d i ncrease d p h ysical act i vity i n s u bjects wit h o ver weig ht or 
o besit y o n b o d y  wei g ht
T o c o m pare t he t w o -year safety a n d t ol era bilit y of se ma gl uti de s.c. 2. 4 m g o nce wee kl y vers us 
se ma gl uti de place b o as a n a dj u nct t o a re d uce d-cal orie diet a n d i ncrease d p h ysical act i vity i n 
s u bjects wit h o ver weig ht or o besit y
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C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
7 of 9 4
Pri m ar y est im a n d
T he est i ma n d will q ua ntif y t he a vera ge treat me nt effect of se ma gl uti de relati ve t o se ma gl uti de 
pl ace b o after 1 0 4 wee ks, as a n a dj u nct t o a re d uce d -calorie di et a n d i ncrease d p h ysical act i vity,  in 
all ra n d o mise d s u bjects re gar dless o f a d here nce t o treat me nt a n d re gar dless of starti n g resc ue 
i nter ve nt i ons ( w ei g ht m a na ge me nt dr u gs or bariatric s ur ger y) (“effecti ve ness”/“treat me nt p olic y” 
esti ma n d). T he est i ma n d will c o ver all effect-r elate d o bject i ves.
T he f o ll owi n g e x pa nsi o n of t he pri mar y  esti ma n d will c o ver o bjecti ves relate d t o wei g ht. T he 
esti ma n d will q ua nt if y t he a vera ge treat me nt effect of se ma gl uti de relati ve t o se ma gl uti de place b o 
after 5 2 wee ks, as a n a dj u nct t o a re d uce d-cal orie diet a n d i ncrease d p h ysical act i vity,  in all 
ra n d omise d s u bjects re gar dless of a d here nce t o treat me nt a n d re gar dless of s t artin g resc ue 
i nter ve nt i ons.
Pri m ar y e n d p oi nt
T he pri mar y  e n d p oi nts a d dressi n g t he pri mar y o bjecti ve:

C ha n ge fr o m baseli ne ( wee k 0) t o wee k 1 0 4 i n b o d y wei g ht ( %)

S u bjects w h o after 1 0 4 wee ks ac hie ve ( y es/ n o):

B o d y  wei g ht re d uctio n ≥ 5 % fr o m baseli ne ( wee k 0)
C o nfir m at or y s ec o n d ar y e n d p oi nt

S u bjects w h o after 1 0 4 wee ks ac hie ve ( y es/ n o):

B o d y  wei g ht re d uctio n ≥ 1 0 % fr o m baseli ne ( wee k 0)

B o d y  wei g ht re d uctio n ≥ 1 5 % fr o m baseli ne ( wee k 0)

C ha n ge fr o m baseli ne ( wee k 0) t o wee k 1 0 4 i n:

Waist circ u mfere nce (c m)

S y st olic blo o d press ure ( m m H g)
O ver all desi g n:
T his is a 1 0 4 -wee k, ra n d o mise d, d o u ble -bli n d, pl ace b o -c o ntr olle d, t w o -ar me d, parallel gr o u p, 
m ult i-ce ntre, mul tinat i ona l cli nical trial c o m par i n g se ma gl ut i de s.c. 2. 4 m g o nce wee kl y wit h 
se ma gl utid e pl ace b o i n s u bjects wit h o ver wei g ht or o besit y.
Eli gi ble s u bjects f ulfilli n g all ra n d o misat i on cri teria at visit 2 will be ra n d o mise d i n a 1: 1 ma n ner t o 
recei ve either se ma gl uti de s.c. 2. 4 m g o nce wee kl y or se ma gl ut i de place b o as a n a dj u nct t o a 
re d uce d-calori e diet a n d i ncrease d p h ysical act i vity.  
Ke y i ncl usi o n criteri a

Male or fe male, a ge ≥ 1 8 y ears at t he ti me of si g ni n g i nf or me d c o nse nt
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
7 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
8 of 9 4

B o d y  mass i n de x ( B MI) ≥ 3 0 k g/ m 2 or ≥ 2 7 k g/ m 2 wi t h t he prese nce of at least o ne of t he 
f oll owi n g wei g ht -relate d c o mor bi di ties (treate d or u ntreate d): h yperte nsi o n, d ysli pi dae mia, 
o bstr ucti ve slee p a p n oea or car di o vasc ular disease 

Hi st or y of at least o ne self-re p orte d u ns uccessf ul dietar y eff ort t o lose b o d y  wei g ht
K e y e xcl usi o n criteri a

H b A 1 c  ≥ 4 8 m m o l/ m ol ( 6. 5 %) as meas ure d b y t he ce ntral la b orat or y at scree ni n g 

A self -re p orte d c ha n ge i n b o d y wei g ht > 5 k g ( 1 1 l bs) wit hi n 9 0 da ys bef ore scree ni n g 
irres pecti ve of me dical rec or ds
N u m ber of s u bjects:
A p pr o xi matel y  3 5 3 s u bjects will be scree ne d t o ac hie ve 3 0 0 s u bjects ra n d o ml y assi g ne d t o trial 
pr o d uct. 
Tre at me nt gr o u ps a n d d ur ati o n:
Eli gi ble s u bjects f ulfilli n g all ra n d o misat i on cri teria at visit 2 will be ra n d o mise d i n a 1: 1 ma n ner t o 
recei ve either s.c. se ma gl ut i de 2. 4 m g o nce wee kl y or se ma gl uti de place b o as a n a dj u nct t o a 
re d uce d-calori e diet a n d i ncrease d p h ysical act i vity.
T he t otal trial d urati o n f or t he i n di vi d ual s u bject will be a p pr o xi matel y 1 1 2 wee ks. T he trial 
i ncl u des a scree ni n g p eri o d o f a p pr o xi matel y 1 wee k wit h a visit t o assess t he s u bject’s eli gi bilit y . 
S u bjects will i n t he first 1 6 wee ks be d ose escalate d fr o m 0. 2 5 m g o nce -wee kl y  u ntil tar get d ose 
wi t h visi ts/ p h o ne c o ntacts e ver y 2n d wee k d uri n g d ose escalat i on. Fr o m wee k 2 0, visits / p h o ne 
c o ntacts will ta ke place e ver y 4t h wee k f or t he re mai ni n g mai nte na nce peri o d u nt il e n d of treat me nt 
( wee k 1 0 4). A f oll o w-u p visi t (‘ E n d of trial’) f or safet y assess me nts is sc he d ule d 7 wee ks after e n d 
of  treat me nt t o acc o u nt f or t he e x p os ure a n d t o t he lo n g half -life of se ma gl uti de.
T he f o ll owi n g tri al pr o d ucts will be s u p plie d b y N o v o N or dis k A/ S f or t he d urati o n of t he trial:

S e m a gl ut i de B 1. 0 m g / m L P D S 2 9 0 a n d se ma glut i de place b o, s oluti o n f or i njecti o n, 3 m L 
P D S 2 9 0 pre -fille d pe n-i nject or

S e m a gl ut i de B 3. 0 m g / m L P D S 2 9 0 a n d se ma glut i de place b o, s oluti o n f or i njecti o n, 3 m L 
P D S 2 9 0 pre -fille d pe n-i nject or
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
8 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
1 3 of 9 4
3
I ntr o d ucti o n
3. 1
Tri al r ati o n ale
T he pre vale nce of o besit y has reac he d e pi de mic pr o p orti o ns i n m ost c o u ntries ar o u n d t he w orl d a n d 
t he pre vale nce is st ill i ncreasi n g at a n alar mi n g rate1 6 -2 2. T he m e dical a n d s ociet al i m pacts are 
c o nsi dera ble a n d o besit y is o ne of t he m ost si g nifica nt p u blic healt h c halle n ges w orl d wi de1 6 -2 2.
O besit y is ass ociate d wit h i ncrease d ris k of a variet y of c o mor bi di ties i ncl u di n g h y per gl ycae mia, 
t ype 2 di a betes ( T 2 D ), h y perte nsi on, d y sli pi dae mia, o bstr ucti ve slee p a p n oea, at her oscler osis, 
os te oart hritis, uri nar y inc o nt i ne nce, n o n- alc o h o lic steat o he patitis, car dio vasc ular di seases, certai n 
t yp es of  ca ncer, a n d ris k of earl y d e at h2 3 -3 7. M ore o ver, o besit y a d versel y affects p h ysical a n d me ntal 
healt h a n d re d uces healt h rel at ed q ualit y of  life3 8, 3 9. O besit y is als o ass ociate d wit h decrease d 
car dior es pi rat or y fitness, w hic h als o i ncreases t he ris k of car dio v ascular di seases a n d all-ca use 
m o rtality 4 0.
T he ri s k of o besity- relate d c o mplicati o ns a n d c o m or bi di ties i ncreases wi t h increasi n g B MI, a n d a 
w ei g ht l oss of 5 −1 0 % has si g nifica nt healt h be nefits i n ter ms of slo wi n g pr o gressi o n t o T 2 D 4 1 -4 4.
F urt her m ore, a wei g ht l oss of 5 −1 0 % i m pr o ves ma n y  ot her o besit y relate d c o mor bi di ties as well as 
p h ysic al s ym pt o ms a n d q ualit y of  life4 5 -5 2. Fi nall y, st u dies s u g gest a be neficial i m pact of weig ht 
l oss o n car dio vasc ular ris k a n d mortali t y in b ot h p e o ple wit h dia betes a n d o besit y 5 3 -5 5.
Lifest yle i nter ve nt i on i n t he f or m of di et a n d e xercise is first li ne treat me nt f or o besit y,  but m ost 
pe o pl e wit h o besit y str u g gle t o ac hie v e a n d mai ntai n t heir wei g ht l oss 2- 1 1. S ur gical treat me nts offer 
a n effecti ve alter nat i ve f or s o me pe o ple wit h se vere o besit y, b ut s ur ger y carries a ris k i n c o n necti o n 
wi t h t he pr oce d ure an d i s n ot wit ho ut c o m plicati o ns. F urt her m ore, s ur ger y  re q uir es clos e f ol l ow- u p 
of  t he i n di vi d ual w hic h ca n be c u m bers o me a n d c ostl y 2- 7, 1 2, 1 3. P ha r mac ot hera p y ma y t heref ore 
ser ve as a val ua ble a dj u nct t o lifestyle i nter ve nt i on f or i n di vi d uals wit h o besit y i n or der t o ac hie ve 
a n d s ustai n a cli nicall y rele va nt weig ht l oss, t o i m pr o ve c o m or bi d c o n di tio ns a n d t o facilitate a 
healt hier lifest yle. Fe w a nt i-o besit y me dicat i ons are c urre ntl y a vaila ble a n d t here is a nee d f or m ore 
safe a n d effecti ve t hera pe ut ic o pti o ns f or treat me nt of o besity, es peciall y  tr e at me nts t hat als o tar get 
w ei g ht mai nte na nce, pre ve nt i on a n d treat me nt of c o -m o r bidi ties 2- 6, 1 4, 1 5.
T he prese nt trial is desi g ne d t o c o m pare t he t w o -year effect a n d sa fety of  s u bc uta ne o us (s.c.) 
se ma gl uti de 2. 4 m g o nce wee kl y vers us se ma gl ut i de place b o as a n a dj u nct t o a re d uce d-cal orie diet 
a n d i ncrease d p h ysical act i vity i n s u bjects wit h o ver wei g ht or o besity.  A t w o-ye ar perio d i s 
c o nsi dere d an a p pr o priate p eri o d of  ti me f or e val uatio n of  lo n g- t er m treat me nt wit h s.c. se ma gl utid e 
2. 4 m g o nce wee kl y.
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
1 3 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
1 4 of 9 4
3. 2
B ac k gr o u n d
3. 2. 1
Se m a gl uti de
S e m a gl ut i de is t he ne xt ge nerati o n gl uca g o n li ke pe pti de -1 ( G L P - 1) rece pt or a g o nist (R A )
c urre ntl y u n der de vel o p me nt b y N o v o N or dis k f or t he treat ment  of w eig ht ma na ge me nt ( N N 9 5 3 6). 
S e m a gl ut i de has bee n o pti mise d res ulti n g i n a l o n ger half-life of a p pr o xi matel y 1 6 0 h o urs, ma ki n g 
it s uita ble f or o nce -wee kl y d osi n g 5 6. G L P-1 is a p h ysi o l ogical re g ulat o r of a p petite a n d G L P- 1 
rece pt ors are prese nt i n se veral areas of t he brai n i n v o l ve d i n a p petite re g ulati o n 5 7.
A 5 2 -wee k p hase 2 d ose -fi n di n g trial withi n wei g ht m a n age me nt ( N N 9 5 3 6 -4 1 5 3) has rece nt l y bee n 
c o mplete d. A t otal  of 9 5 7 ra n d o mise d s u bjects wit h o besity ( wit ho ut di a betes) were e x p ose d t o 
se ma gl uti de ( n = 7 1 8), lira gl ut i de 3. 0 m g ( n = 1 0 3) or place b o ( n = 1 3 6). I n t his trial, a n o verall 
m o n ot o ne d ose- de pe n de nt wei g h t loss was o bser ve d acr oss t he 5 se ma gl uti de d oses teste d ( 0. 0 5 t o 
0. 4 m g o nce -dail y). T he est i mate d wei g ht l oss at wee k 5 2 was 1 3. 8 % at t he hi g hest d ose teste d 
( 0. 4 m g o nce -dail y) c o mpare d t o t he wei g ht l oss of 2. 3 % ac hie ve d b y diet, e xercise a n d place b o 
alo ne 5 8.
C li nical5 9 -6 3 a n d n o n-cli nical data 6 4 i n dicate t hat t he b o d y wei g ht- re d uci n g effect of se ma gl uti de is 
mai nl y  me diate d b y a re d uce d e ner g y  int a k e. N o u ne x pecte d safet y fi n di n gs were i de nt ifie d a n d t he 
t olera bilit y a n d safet y pr ofile was o verall c o nsiste nt wit h pre vi o us fi n di n gs i n t he T 2 D de vel o p me nt 
pr o gra m me a n d the G L P -1 R A class i n ge neral .
A c o m pre he nsi ve re vie w of res ults fr o m t he n o n-cli nical a n d cli nical st u dies of  se ma gl uti de ca n be 
f ou n d i n t he c urre nt e dit i on of t he i n vesti gat or’s br oc h ure (I B)5 8 a n d a n y u p dates here o f.
3. 2. 2
Tri al p o p ul ati o n 
T he tri al p o p ulat i on wi ll c o nsist of s u bjects wit h o besity ( B MI ≥ 3 0 k g/ m 2) or wi t h o ver weig ht
( B MI ≥2 7 k g/ m 2) a n d wei g ht -r elate d c o mor bi di ties. T hese s u bjects re prese nt a cli nicall y rele va nt 
p o p ul at i on f or p har mac ot hera pe utic wei g ht ma n a g e me nt as t he y are at sig nifica nt ri s k f or wei g ht-
r elate d mor bi di ties a n d mortali t y, a n d are li kel y t o be nefit fr o m wei g ht re d ucti on. I nf or mat i on a b o ut 
w ei g ht- relate d c o m or bi dities, i ncl u di n g h y perte nsi o n, d ysli pi dae mia, o bstr ucti ve slee p a p n oea or 
car dio vasc ular di sease, will be c ollecte d s yst e mat icall y at scree ni n g b y t he i n vest i gat ors as part of 
t he me dical hist or y.
S u bjects wit h T 2 D are e xcl u de d fr o m t he trial. Su bjects wit h o ver wei g ht or o besi t y a n d T 2 D will  be 
a d dresse d i n a de dicate d trial.
Fi rst li ne treat me nt i n wei g ht ma na ge me nt s h o ul d al wa ys be lifestyle m o dificat i on t hr o u g h a 
re d uce d cal orie diet a n d i ncrease d p h ysical ac tivit y. T h us o nl y s u bjects w h o ha ve trie d b ut faile d a 
di et ar y w eig ht l oss i nter ve nt i on will be i ncl u de d i n acc or da nce wit h re g ulat or y g ui deli nes 6 5 , 6 6.
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
1 4 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
1 5 of 9 4
3. 3
Be nefit -ris k assess me nt
3. 3. 1
Be nefits
S u bjects will be treate d wit h a re gi me n a nt ici pate d t o be better t ha n or e q ual t o t he wei g ht 
ma na ge me nt t he y  recei ve at t he ti me of e ntr y int o t he trial. Res ults fr o m t he p hase 2 trial 
( N N 9 5 3 6-4 1 5 3) de m o nstrate d t hat se ma gl ut i de o nce -dail y  as a n a dju nct t o a re d uce d -cal orie diet 
a n d i ncrease d p h ysical act i vity was effecti ve f or wei g ht l oss i n s u bjects wit h o besit y,  w hile 
di s pla yi n g a satisfact or y t olera bilit y pr ofile. O verall, a mo n ot o ne d ose -de pe n de nt wei g ht l oss was 
o bser ve d acr oss all teste d d oses of se ma gl ut i de ( 0. 0 5 t o 0. 4 m g o nce-dail y). T he wei g ht l oss was 
1 1. 5 5 perce nta ge p oi nt s lar ger f or t he 0. 4 m g gr o u p c o m pare d wit h place b o . Wei g ht l oss was 
acc o m pa nie d b y a c o nsiste nt i m pr o ve me nt i n t he wei g ht -relate d c o m or bi dities, i n dicate d b y 
car dio vasc ular ris k fact ors, li pi d pr ofile a n d gl ycae mic fact ors, as well as i n cli nical o utc o m e 
assess me nts.
I n a d diti on, i t is e x pecte d t hat all s u bjects will be nefit fr o m partici pati o n t hr ou g h cl ose c o ntact wit h 
t he trial site a n d c o u nselli n g b y a di et icia n or a si milar q ualifie d healt hcare pr ofessi o nal , all of 
w hic h will m ost li kel y  res ult in i nte nsifie d wei g ht ma na ge me nt. 
3. 3. 2
Ris ks a n d prec a uti o ns
T he sect i ons bel o w descri be i de ntifie d a n d p ote ntial ris ks ass ociate d wit h se ma gl ut i de treat me nt.
F or cl assificat i on a n d f urt her details of t he ris ks, please refer t o t he c urre nt versi o n o f t he I B or a n y 
u p dates here of. T he i de nt ifie d/ p ote ntial ris ks are base d o n fi n di n gs i n n o n-cli nical st u dies a n d 
cli nical trials wit h se ma gl ut i de as well as ot her G L P-1 R As. F or eac h of t hese ris ks, mit i gati n g 
actio ns ha ve bee n i m ple me nte d t o mi ni mise t he ris ks f or s u bjects e nr olle d i n t his trial.

Gastr oi ntesti nal a d verse e ve nts

C o nsiste nt wit h fi n di n gs wit h ot her G L P -1 R As, t he m ost fre q ue nt l y re p orte d a d verse 
e ve nts ( A E) i n cli nical trials wit h se ma gl ut i de were gastr oi ntesti nal A Es. A l o w starti n g 
d ose a n d d ose escalat i on ste ps will be i m ple me nte d i n t he trial t o mit i gate t he ris k of 
gastr oi ntesti nal A Es.

C h o lelithiasis

E ve nts of c h o lelithiasis were t he m ost fre q ue ntl y re p orte d gall bla d der e ve nts i n t he p hase 2 
w ei g ht ma na ge me nt tri al ( N N 9 5 3 6- 4 1 5 3) a n d were i n a fe w i nsta nces c o-re p orte d wit h t he 
e ve nt a dju dicat i on c o m mittee ( E A C) c o nfir me d ac ute pa ncreatit is. As a preca uti o n, if 
c h o lelithiasis is s us pecte d, a p pr o priate cli nical f o ll o w-u p is t o be i nit iate d at t he 
i n vesti gat or’s discreti on.

Ac ute pa ncreat itis

Ac ute pa ncreat itis has bee n o bser ve d wit h t he use of G L P - 1 R A dr u g class. As a 
preca uti o n, s u bjects wi t h a hist or y of c hr o nic pa ncreatitis or rece nt ac ute pa ncreatitis will 
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
1 5 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
1 6 of 9 4
n ot be e nr o lle d i n t he trial. I n a d diti on tri al pr o d uct s h o uld be di sc o nti n ue d i n case of 
s us pici on of ac ute pa ncreat itis i n acc or da nce t o secti o n 8. 1 . 

Me d ullar y t h y r oid ca ncer ( M T C) ( base d o n n o n -cli nical data)

E x pecte d pr oliferati ve t h y r oid C -cell c ha n ges were see n i n t he m o use a n d rat 
carci n o ge nicit y st u di es after dail y e x p os ure t o se ma gl ut i de f or 2 years. N o h yper plasia was 
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 1 3 -f ol d a b o ve t he cli nical plas ma 
e x p os ure at 2. 4 m g/ wee k. I n cli nical trial wi t h se ma glut i de, t here ha ve bee n n o cli nicall y 
r ele va nt c ha n ges i n calcit o ni n le vels. T h e C-cell c ha n ges i n r o de nts are me diate d b y t he 
G L P -1 rece pt or, w hic h is n ot e x presse d i n t he n or mal h u ma n t h yr oi d. Acc or di n gl y, t he ris k 
of  G L P-1 rece pt or -me d iate 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. H o we ver, as 
a preca utio n, e xcl usi o n a n d d isc o nti n uati on cri t eria r elate d t o me dical hist or y of mul tiple 
e n d ocri ne ne o plasia t y pe 2 ( M E N 2) or M T C ele vate d plas ma le vels o f calcit o ni n 
( bio m ar ker f or M T C) ha ve bee n i m ple me nte d i n t he trial. 

Pa ncreat ic ca ncer 

T here i s c urre ntl y n o s u p p ort fr o m n o n-cli nical st u dies, cli nical trials or p ost -mar keti n g data 
t hat G L P -1 R A -base d t hera pies i ncrease t he ris k of pa ncreat ic ca ncer, b ut pa ncreatic ca ncer 
has bee n classifie d as a p ote ntial class ris k of G L P -1 R As b y  Eur o pea n M e dici nes A ge nc y
( E M A). As a preca uti on, s u bjects wit h a hist or y  of mali g na nt ne o plas ms withi n t he past 5 
years pri or t o scree ni n g will be e xcl u de d fr o m t he trial. 

Aller gic reacti o ns

As i s t he case with all pr otei n - base d p har mace uticals, s u bjects treate d wit h se ma gl uti de are 
at ris k of de ve l opi n g i m m u n o ge nic a n d aller gic reacti o ns. As a preca uti o n, s u bjects wit h 
k n o w n or s us pecte d h y perse nsit i vity t o se ma glut i de or relate d pr o d ucts will n ot be e nr olle d 
i n t his trial.

Pre g na nc y a n d fertilit y ( base d o n n o n- cli nical data)

St u di es i n a ni mals ha ve s h o w n re pr o d uctive t o xi cit 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 nc y. E xcl usi o n a n d disc o nt i n uati on cri teria relate d t o pre g na nc y ha ve bee n 
i m ple me nte d i n t he trial.
3. 3. 3
C o ncl usi o n o n ris k -be nefit pr ofile
Necessar y  preca uti ons ha ve bee n i m ple me nte d i n t he desi g n a n d pla n ne d c o n d uct of t he trial i n 
or der t o mi ni mise t he ris ks a n d i nc o n ve nie nces of partici pat i on i n t he trial. T he safety pr ofile f or 
se ma gl uti de ge nerate d fr om t he cli nical a n d n o n- cli nical de vel o p me nt pr o gra m me has n ot re veale d 
a n y safet y iss ues t hat w o ul d pr o hi bit a d mi nistrati o n of se ma gl uti de 2. 4 m g o nce-wee kl y. T he res ults 
of  t he p hase 2 trial ( N N 9 5 3 6-4 1 5 3) i n dicate t hat se ma gl uti de will pr o vi de a cli nicall y mea ni n gf ul 
w ei g ht l oss.
I n c o ncl usi on, t he p ote ntial ris k t o t he s u bjects i n t his trial is c o nsi dere d l o w a n d o ut wei g he d b y t he 
a nt ici pate d be nefits t hat se ma gl uti de w o ul d pr o vi de s u bjects wit h o ver wei g ht or o besity.
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
1 6 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
1 7 of 9 4
M ore detaile d i nf or mat i on 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 na bl y 
e x pecte d A Es of se ma gl ut i de s.c. ma y be f o u n d i n t he I B5 8 a n d a n y u p dates here o f.
4
O bjecti ves a n d e n d p oi nts
4. 1
P r i m ar y, sec o n d ar y a n d e x pl or at or y o bjecti ve(s)
Pri m ar y o bjecti ve
T o c o m p are t he t w o -year effect of se ma gl ut i de s.c. 2. 4 m g o nce wee kl y vers us se ma gl ut i de place b o 
as a n a dj u nct t o a re d uce d -calori e diet a n d i ncrease d p h ysical act i vity i n s u bjects wit h o ver weig ht or 
o besit y o n b o d y  wei g ht.
Sec o n d ar y o bjecti ves
T o c o m p are t he t w o -year effect of se ma gl ut i de s.c. 2. 4 m g o nce wee kl y vers us se ma gl ut i de place b o 
as a n a dj u nct t o a re d uce d -calori e diet a n d i ncrease d p h ysical act i vity i n s u bjects wit h o ver weig ht or 
o besit y o n:

Car di o vasc ular ri s k fact ors 

Gl uc ose m eta b o lism
T o c o m p are t he o ne-year effect of se ma gl uti de s.c. 2. 4 m g o nce wee kl y vers us se ma gl ut i de place b o 
as a n a dj u nct t o a re d uce d -calori e diet a n d i ncrease d p h ysical act i vity i n s u bjects wit h o ver weig ht or 
o besit y o n b o d y  wei g ht.
T o c o m pare t he t w o -year safety a n d t olera bilit y of se ma gl uti de s.c. 2. 4 m g o nce wee kl y vers us 
se ma gl uti de place b o as a n a dj u nct t o a re d uce d-cal orie diet a n d i ncrease d p h ysical act i vity i n 
s u bjects wit h o ver weig ht or o besit y.
E x pl or at or y o bjecti ves
T o c o m p are t he t w o -year effect of se ma gl ut i de s.c. 2. 4 m g o nce wee kl y ver s us se ma gl uti de place b o 
as a n a dj u nct t o a re d uce d -calori e diet a n d i ncrease d p h ysical act i vity i n s u bjects wit h o ver weig ht or 
o besit y o n:

Gl ycae mic stat us

Use of me dicat i on f or h yperte nsi o n a n d d ysli pi dae mia .

Treat me nt disc o nt i n uati on

C o ntr ol  of eati n g (a p plica ble f or U S a n d Ca na da o nl y) 
Pri m ar y esti m a n d
T he est i ma n d will q ua ntif y t he a vera ge treat me nt effect of se ma gl uti de relati ve t o se ma gl uti de 
pl ace b o after 1 0 4 wee ks, as a n a dj u nct t o a re d uce d -calorie di et a n d i ncrease d p h ysical a ct i vity,  in 
all ra n d o mise d s u bjects re gar dless o f a d here nce t o treat me nt a n d re gar dless of starti n g resc ue 
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
1 7 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
1 8 of 9 4
i nter ve nt i ons ( wei g ht ma na ge me nt dr u gs or bariatric s ur ger y) (“effect i ve ness”/“treat me nt p olic y” 
esti ma n d). T he est i ma n d will c o ver all effect-r elat ed o bject i ves.
T he f o ll owi n g e x pa nsi o n of t he pri mar y  esti ma n d will c o ver o bjecti ves relate d t o wei g ht. T he 
esti ma n d will q ua nt if y t he a vera ge treat me nt effect of se ma gl uti de relati ve t o se ma gl uti de place b o 
after 5 2 wee ks, as a n a dj u nct t o a re d uce d-cal orie di et a n d i ncrease d p h ysical act i vity,  in all 
ra n d omise d s u bjects re gar dless of a d here nce t o treat me nt a n d re gar dless of starti n g resc ue 
i nter ve nt i ons.
Sec o n d ar y esti m a n d
T he est i ma n d will q ua ntif y t he a vera ge treat me nt effect of se ma gl uti de relati ve t o sema g l uti de 
pl ace b o after 1 0 4 wee ks, as a n a dj u nct t o a re d uce d -calorie di et a n d i ncrease d p h ysical act i vity,  in 
all ra n d o mise d s u bjects ha d t he y re mai ne d o n t heir ra n d o mise d treat me nt f or t he e nt ire pla n ne d 
d urati o n of  t he trial a n d n ot starte d a n y resc ue int er ve nt i on ( wei g ht m a na ge me nt dr u gs or bariatric 
s ur gery)  (“efficac y”/ “h y p ot heti cal” esti ma n d). T he esti ma n d will c o ver t he pri mar y o bjecti ve.
4. 2
Pri m ar y, sec o n d a r y a n d e x pl or at or y e n d p oi nt(s)
4. 2. 1
Pri m ar y e n d p oi nt
T he pri mar y  e n d p oi nts a d dressi n g t he pri mar y o bjecti ve:

C ha n ge fr o m baseli ne ( wee k 0) t o wee k 1 0 4 i n b o d y wei g ht ( %)

S u bjects w h o after 1 0 4 wee ks ac hie ve ( y es/ n o): 

B o d y  wei g ht re d uctio n ≥ 5 % fr o m baseli ne ( wee k 0)
4. 2. 2
S ec o n d ar y e n d p oi nts
T he c o nfir mat or y  a n d s u p p orti ve sec o n dar y e n d p oi nts a d dressi n g t he pri mar y a n d sec o n dar y 
o bj ect i ves are liste d i n secti on 4. 2. 2. 1 a n d 4. 2. 2. 2
4. 2. 2. 1
C o nfir m at or y sec o n d ar y e n d p oi nts

S u bjects w h o after 1 0 4 wee ks ac hie ve ( y es/ n o): 

B o d y  wei g ht re d uctio n ≥ 1 0 % fr o m baseli ne ( wee k 0)

B o d y  wei g ht re d uctio n ≥ 1 5 % fr o m baseli ne ( wee k 0)

C ha n ge fr o m baseli ne ( wee k 0) t o wee k 1 0 4 i n:

Waist circ u mfere nce (c m)

S y st olic blo o d press ure ( m m H g)
4. 2. 2. 2
S u p p orti ve sec o n d ar y e n d p oi nts
E ffect e n d p oi nts:

C ha n ge fr o m baseli ne ( wee k 0) t o wee k 1 0 4 i n:

B o d y  wei g ht ( k g)
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
1 8 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
1 9 of 9 4

B MI ( k g/ m 2)

H b A 1 c ( %, m m ol / mol )

F P G ( m g/ d L)

Fast i n g ser u m i ns uli n ( mI U/L)

Di ast olic blo o d press ure ( m m H g)

Li pi ds ( m g/ d L)

T ot al  c h olester ol

Hi g h de nsi t 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

V er y  lo w de nsi t y li p o pr otei n ( V L D L) c h olester ol

Free fatt y  aci ds ( F F A)

Tri gl yceri des

Hi g h se nsi tivit y C- React i ve Pr otei n ( hs C R P) ( mg/ L)

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)

B MI ( k g/ m 2)

Waist circ u mfere nce (c m)

S u bjects w h o after 5 2 wee ks ac hie ve ( y es/ n o): 

B o d y  wei g ht re d uctio n ≥ 5 % fr o m baseli ne ( wee k 0)

B o d y  wei g ht re d uctio n ≥1 0 % fr o m baseli ne ( wee k 0)

B o d y  wei g ht re d uctio n ≥ 1 5 % fr o m baseli ne ( wee k 0)
S afety e n d p oi nts:

N u m ber of treat me nt e mer ge nt a d verse e ve nts ( T E A Es) fr o m baseli ne ( wee k 0) t o wee k 1 1 1

N u m ber of seri o us a d verse e ve nts ( S A Es) fr o m baseli ne ( wee k 0) t o wee k 11 1

C ha n ge fr o m baseli ne ( wee k 0) t o wee k 1 0 4 i n:

P ul se ( b p m)

A m ylase ( U/ L)

Li pase ( U/ L)

Calcit o ni n ( n g/ L)
4. 2. 3
E x pl or at or y e n d p oi nts
T he e x pl orat or y  e n d p oi nts a d dressi n g t he e x pl orat i ve o bjecti ves:

C ha n ge fr o m baseli ne ( wee k 0) t o wee k 1 0 4 i n:

Gl ycae mic cate g or y ( n or mo- gl ycae mia, pre -dia betes, T 2 D)

A nt i h y perte nsi ve me dicat i on ( decrease, n o c ha n ge, i ncrease)

L i pi d-l oweri n g m e dicat i on ( decrease, n o c ha n ge, i ncrease)
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
1 9 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
2 0 of 9 4

S u bjects w h o fr o m ra n d omisat i on t o wee k 1 0 4 ha ve per ma ne nt l y disc o nti n ue d ra n d omise d trial
p r o d uct ( yes/ n o)

Ti me t o per ma ne nt disc o nt i n uati on of ra n d o mise d trial pr o d uct ( wee ks)

C o ntr ol  of Eati n g Q uesti on naire ( C o E Q): Sc ores fr o m t he 4 d o mai ns a n d 1 9 i n di vi d ual ite ms
(a p plica ble f or U S a n d Ca na da o nl y)
5
Tr i al desi g n
5. 1
O ver all desi g n
T his is a 1 0 4 -we e k, ra n d o mise d, d o u ble-bli n d, pl ace b o -c o ntr olle d, t w o -ar me d, parallel gr o u p, 
m ult i-ce ntre, mul tinat i ona l cli nical trial c o m par i n g se ma gl ut i de 2. 4 m g o nce wee kl y with 
se ma gl uti de place b o i n s u bjects wit h o ver wei g ht or o besit y.
T he tri al incl u des a scree ni n g visit t o assess t he s u bject’s eli gi bilit y f oll owe d b y  visits/ p h o ne 
c o ntacts e ver y 2n d wee k d uri n g d ose escalat i on. Fr o m wee k 2 0, visits/ p h o ne c o ntacts will ta ke place 
e ver y 4 t h wee k f or t he re m ai ni n g mai nte na nce peri o d u ntil e n d of treat me nt ( wee k 1 0 4). A f oll ow-
u p visit (‘ E n d of trial’) f or safet y assess me nts is sc he d ule d 7 wee ks after e n d of treat me nt t o 
acc o u nt f or t he e x p os ure t o t he l on g half -life of se ma gl uti de.
T he tri al desi g n is o utli ne d i n Fi g ure 5- 1
Fi g ure 5 - 1
A sc he m atic di a gr a m of t he tri al desi g n wit h d ur ati o n of t he tri al peri o ds 
i ncl u di n g f oll o w-u p peri o d. 
Eli gi ble s u bjects f ulfilli n g all  ra n d o misati on cri teria at visit 2 will be ra n d o mise d i n a 1: 1 ma n ner t o 
recei ve either se ma gl uti de 2. 4 m g o nce wee kl y or se ma gl utid e pl ace b o as a n a dju nct t o a re d uce d -
calori e diet a n d i ncrease d p h ysical act i vity.  A pla n ne d t otal of 3 0 0 s u bjects wil l be ra n d o mise d
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
2 0 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
2 1 of 9 4
5. 2
S u bject a n d tri al c o m pleti o n
A p pr o xi matel y  3 5 3 s u bjects will be scree ne d t o ac hie ve 3 0 0 s u bjects ra n d oml y assi g ne d t o trial 
pr o d uct.
Tri al peri o d c o m pleti o n f or a s u bject:
Tri al perio d c o m plet i on is defi ne d as w he n t he ra n d o mise d s u bject 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).
' Date of trial c o mplet i on' is t he date t he s u bject c o m plete 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 plet i on is defi ne d as w he n t he ra n d o mise d s u bject has atte n de d t he 'e n d of 
treat me nt' visit acc or di n g t o t he fl o wc hart.
5. 3
E n d of tri al defi niti o n
T he e n d o f t he trial is defi ne d as t he date of t he last visit of t he last s u bject i n t he tri al. 
5. 4
Scie ntific r ati o n ale f or tri al desi g n
T he treat me nt d urati o n of t he trial is 1 0 4 wee ks wit h a n a d dit i onal 7 wee ks f o ll ow- u p ( wi t ho ut 
treat me nt ). T he 7 wee ks f oll ow- u p peri o d is i ncl u de d t o acc o u nt f or t he e x p os ure a n d l on g half -life 
of  se ma gl uti de. A 1 0 4- wee k treat me nt d uratio n (i ncl u di n g 8 8 wee ks o n tar get d ose) is c o nsi dere d 
s ufficie nt t o assess l on g -t er m w ei g ht l oss, safet y a n d t olera bilit y i n t he p hase 3 wei g ht ma na ge me nt 
de vel o p me nt pr o gra m me i n acc or da nce wit h re g ulat or y  g uideli nes 6 5 , 6 6.
A ra n d o mise d, d o u ble -bli n de d , place b o-c o ntr olle d, m ult i-ce ntre trial desi g n is c h ose n t o mi ni mise 
bias i n t he assess m e nt of t he effect a n d safety of  se ma gl uti de 2. 4 m g o nce -wee kl y vers us
se ma gl uti de pl ace b o, as a n a dj u nct t o a re d uce d cal orie diet a n d i ncrease d p h y sical act i vity.
5. 5
J ustific ati o n f or d ose
Res ults fr o m t he p hase 2 d ose -fi n di n g trial ( N N 9 5 3 6-4 1 5 3) s h o we d t hat t he se ma gl uti de 0. 4 m g 
o nce -dail y  d ose was most effect i ve i n ter ms of wei g ht l oss w hile dis pla yi n g a n acce pta ble 
t olera bilit y pr ofile. Usi n g p o p ulat i on p har mac o ki netic m o delli n g, it was esti mate d t hat a o nce -
wee kl y mai nte na nce d ose of 2. 4 m g se ma gl ut i de will res ult i n si milar Cma x at stea d y-state as t hat 
o btai ne d b y  t he o nce-dail y  0. 4 mg se ma gl ut i de d ose i n trial N N 9 5 3 6- 4 1 5 3.
A mai nte na nce d ose of 2. 4 m g se ma gl ut i de o nce -wee kl y has bee n c h ose n f or t he p hase 3 wei g ht 
m a na ge me nt de vel o p me nt pr o gra m me. T he o nce wee kl y d osi n g is a ntici pate d t o ease t he b ur de n of 
dr u g a d mi nistrati o n i n cli nical pract ice. S u bjects will be i nitiate d at a o nce-wee kl y  d ose of 0. 2 5 mg 
a n d f o ll ow a fi xe d -d ose escalat i on re gi me n, wit h d ose i ncreases e ver y 4 wee ks (t o d oses of 0. 5, 1. 0,
1. 7 a n d 2. 4 m g/ wee k), u ntil t he tar get d ose is reac he d after 1 6 wee ks.
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
2 1 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
2 2 of 9 4
It is well k n o w n t hat t o mitigate GI si de effects wi t h G L P-1 R A treat m e nt, d ose escalat i on t o t he 
tar get d ose is re q uire d. Base d o n e x perie nce fr om t he se ma gl ut i de T 2 D de vel o p me nt pr o gra m me, a 
si milar fi xe d-d ose escalat i on re gi me n was selecte d, wit h d ose escalati o n e ver y 4 wee ks u nt il t he 
tar get d ose of 2. 4 m g is reac he d after 1 6 wee ks.
Pl ease refer t o S ecti o n 7. 1 f or more details o n treat me nt d oses.
6
Tr i al p o p ul ati o n
Pr os pecti ve a p pr o val o f pr ot oc ol  de viatio ns t o recr ui t me nt a n d e nr o l me nt criteria, als o k n o w n as 
pr ot oc ol  wai vers or e xe m pti ons, i s n ot per mitte d. 
6. 1
I ncl usi o n criteri a
S u bjects are eli gi ble t o be i ncl u de d i n t he trial o nl y if all of  t he f oll owi n g cri t eria a p pl y:
1.
I nf or me d c o nse nt o btai ne d bef ore a n y trial-relate d acti vities. Trial-relate d acti vities are a n y 
pr oce d ures t hat are carrie d o ut as part of t he trial, i ncl u di n g act i vities t o deter mi ne s uita bilit y f or 
t he trial
2.
Male or fe male, a ge ≥ 1 8 y ears at t he ti me of si g ni n g i nf or me d c o nse nt
3.
B o d y  mass i n de x ( B MI) ≥ 3 0 k g/ m 2 or ≥ 2 7 k g/ m 2 wi t h t he prese nce of at least o ne of t he 
f oll owi n g wei g ht -relate d c o m or bi dities (treate d or u ntreate d): h yperte nsi o n, d ysli pi dae mia, 
o bstr ucti ve slee p a p n oea or car di o vasc ular disease 
4.
Hi st or y of at least o ne self-re p orte d u ns uccessf ul dietar y eff ort t o lose b o d y  wei g ht
T he cri t eria will be assesse d at t he i n vest i gat or’s discreti o n u nless ot her wise state d.
F or c o u n tr y s pecific re q uire me nts see A p pe n di x 8
6. 2
E xcl usi o n criteri a 
S u bjects are e xcl u de d fr o m t he trial if a n y of  t h e foll o wi n g cri t eria a p pl y:
Gl yc ae mi a -rel ate d:
1.
H b A 1 c ≥ 4 8 m m o l/ m ol ( 6. 5 %) as meas ure d b y t he ce ntral la b orat or y at scree ni n g 
2.
Hi st or y of t ype 1 or t y pe 2 di a betes mellit us 
3.
Treat me nt wit h gl uc ose -l oweri n g a ge nt(s) wit hi n 9 0 da y s bef ore scree ni n g
O besit y – rel ate d:
4.
A self -re p orte d c ha n ge i n b o d y wei g ht > 5 k g ( 1 1 l bs) wit hi n 9 0 da ys bef ore scree ni n g 
irres pecti ve of me dical rec or ds
5.
Treat me nt wit h a n y me dicat i on f or t he i n dicati on of o besit y wi t hi n t he past 9 0 da ys bef ore 
scree ni n g
6.
Pre vi o us or pla n ne d ( d uri n g t he trial peri o d) o besit y tr e at me nt wit h s ur ger y or a weig ht l oss 
de vice. H o we ver, t he f o ll owi n g are all o we d: ( 1) li p os ucti o n a n d/ or a b d o mi n o plast y , if 
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
2 2 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
2 3 of 9 4
perf or m e d > 1 year bef ore scree ni n g, ( 2) la p ba n di n g, if t he ba n d has bee n re m o ve d > 1 year 
bef ore scree ni n g , ( 3) i ntra gastric ball o o n, if t he ball o o n has bee n re m o ve d > 1 year bef ore 
scree ni n g or ( 4) d u o de nal-jej u nal b y pass slee ve, if t he slee ve has bee n re m o ve d > 1 y ear bef ore 
scree ni n g
7.
U nc o ntr olle d t h y r oid disease, defi ne d as T S H > 6. 0 mI U/ L or < 0. 4 mI U/ L as meas ure d b y  t he 
ce ntral la b orat or y at scree ni n g
Me nt al he alt h:
8.
Hi st or y of major de pressi ve dis or der wi t hi n 2 years bef ore scree ni n g 
9.
Di a g n osis of ot her se vere ps yc hiatric dis or der (e. g., sc hiz o p hre nia, bi p o lar dis or der)
1 0. A Patie nt Healt h Q uest i on naire -9 ( P H Q -9) sc ore of  ≥ 1 5 at scree ni n g 
1 1. A lifeti me hist or y  of a s uicidal atte m pt
1 2. S ui ci dal b e h a vio ur wi t hi n 3 0 da ys bef ore scree ni n g 
1 3. S ui ci dal id e ati o n c orres p o n di n g t o t y pe 4 or 5 o n t he C o l um bia -S ui ci de Se verit y Rati n g Scale 
( C-S S R S) wi t hi n t he past 3 0 da ys bef ore scree ni n g
Ge ner al s afet y:
1 4. Prese nce of ac ute pa ncreatit is wit hi n t he past 1 8 0 da ys pri or t o t he da y of scree ni n g
1 5. Hi st or y or prese nce of c hr o nic pa ncreat itis
1 6. Calcit o ni n ≥ 1 0 0 n g/ L as meas ure d b y t he ce ntral la b orat or y  at scree ni n g
1 7. Pers o nal or first de gree relat i ve(s) hist or y of mul ti ple e n d ocri ne ne o plasia t ype 2 or me d ullar y 
t h yr oid carci n o ma
1 8. R e nal i m pair me nt meas ure d as est i mate d Gl omer ular Filtrati o n Rate (e G F R) val ue o f e G F R <
1 5 ml/ mi n/ 1. 7 3 m 2 as defi ne d b y K DI G O 2 0 1 2 6 7 b y t he ce ntral la b orat or y at scree ni n g
1 9. Hi st or y of mali g na nt ne o plas ms wit hi n t he past 5 years prior t o scree ni n g. Basal a n d s q ua m o us 
cell s ki n ca ncer a n d a n y carci n o ma i n-sit u are allo w e d
2 0. A n y of t he f o ll owi n g: m y ocar dial  infarct i on, str o ke, h os pitalisat i on f or u nsta ble a n gi na or 
tra nsie nt ischae mic attac k wit hi n t he past 6 0 da ys pri or t o scree ni n g
2 1. S u bject prese nt l y classifie d as bei n g i n Ne w Y or k Heart Ass ociati on ( N Y H A) Class I V
2 2. S ur ger y  sc he d ule d f or t he d urati o n of t he trial, e xce pt f or mi n or s ur gical pr oce d ures, i n t he 
o pi ni o n of t he i n vest i gat or 
2 3. K n o w n or s us pect e d a b use of alc o h o l or recreati o n al  dr u gs
2 4. K n o w n or s us pecte d h y perse nsi tivit y t o trial pr o d uct(s) or relate d pr o d ucts
2 5. Pre vi o us partici pat i on i n t his trial. Partici pati on is defi ne d as si g ne d i nf or me d c o nse nt 
2 6. P arti cip ati o n i n a n ot her cli nical trial wit hi n 9 0 da ys bef ore scree ni n g 
2 7. Ot her s u bject(s) fr o m t he sa me h o use h o l d partici pati n g i n a n y se ma gl uti de trial
2 8. Fe male w h o is pre g na nt, breast -fee di n g or i nte n ds t o bec ome pre g na nt or is of c hil d -beari n g 
p ote nti al a nd n ot usi n g a hi g hl y effecti ve c o ntrace pti ve met h o d
2 9. A n y dis or der, u n willi n g ness or i na bilit y,  n ot c o vere d b y a n y of t he ot her e xcl usi on cri t eria, 
w hic h i n t he i n vest i gat or’s o pi ni on, mi g ht je o par dise t he s u bject’s safet y or c o m plia nce wi t h t he 
pr ot oc ol
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
2 3 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
2 4 of 9 4
T he cri t eria will be assesse d at t he i n vesti gat or’s discreti o n u nless ot her wise state d.
F or c o u ntr y  s pecific re q uire me nts please see A p pe n di x 8
6. 3
R a n d o mis ati o n criteri a
S u bjects are eli gi ble t o be ra n d omise d i n t he trial, o nl y if all ra n d o misati on cri t eria a p pl y:
1.
Ha ve ke pt a f o o d diar y sat isf yi n gl y in t he peri o d bet wee n scree ni n g a n d r a n d o misat i on. T his is 
defi ne d as at least o ne e ntr y  per da y. H o we ver, misse d e ntries f or a ma xi m u m of t w o da ys are 
all o we d
2.
A P H Q -9 sc ore of < 1 5 at ra n d o misat i on 
3.
N o s ui ci dal be ha vi o ur i n t he peri o d bet wee n scree ni n g a n d ra n d o misat i on
4.
N o s ui ci dal id e ati o n c orres p o n di n g t o t y pe 4 or 5 o n t he C -S S R S i n t he peri o d bet wee n 
scree ni n g a n d ra n d o misat i on
Re -scree ni n g is n ot all o we d. S u bjects n ot f ulfilli n g t he ra n d o misat i on cri t eria will be c o nsi dere d 
scree n fail ure, see sect i on 6. 5 .
6. 4
Lifest yle restricti o ns
T o e ns ure ali g n me nt i n re gar ds t o perf or ma nce o f assess me nts acr oss s u bjects a n d trial sites, t he 
bel o w restricti o ns a p pl y.
6. 4. 1
Me als a n d diet ar y restricti o ns

S u bjects m ust atte n d t he visits fasti n g acc or di n g t o t he fl o wc hart.

Fast i n g is defi ne d as at least 8 h o urs o ver ni g ht bef ore 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 me dicat i on w hic h s h o ul d be ta ke n wi t h or after a meal s ho 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 ha ve bee n o btai 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 fast i n g pr oced ures d o ne. Pr oce d ures re q uiri n g s u bject t o fast i ncl u de 
bl o o d sa m pli n g of fasti n g plas ma gl uc ose (F P G ), fasti n g s er u m i ns uli n a n d free fatt y acids .
6. 4. 2
C affei ne a n d t o b acc o

S u bject s h o ul d a v o i d caffei ne a n d s m o ki n g at least 3 0 mi n utes pri or t o meas uri n g t he bl oo d 
press ure.
6. 5
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 pat i on acc or di n g t o i n/e xcl usi o n cri teria or ra n d o misati on cri t eria. 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 pare 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 date of i nf or me d 
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
2 4 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
2 5 of 9 4
c o nse nt, date of visit, de m o gra p h y, scree n fail ure details, eli gi bility crit eria, a n d a n y s erio us a d verse 
e ve nt ( S A E). A scree n fail ure sessi on m ust be ma de i n t he i nteracti ve we b res p o nse s yste m (I W R S). 
I n di vi d uals w h o d o n ot meet t he criteria f or partici pati o n i n t his trial ma y not be rescree ne 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 cri t eria or f ulfille d o ne of t he 
e xcl usi o n cri teria 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 o l yse d or l ost), re-sa m pli n g is all o we d f or t he affecte d para meters. 
7
Tr e at me nts
7. 1
Tre at me nts a d mi nistere d

All tri al pr o d ucts liste d i n Ta ble 7- 1 are c o nsi dere d i n vest i gati onal me dici nal pr o d ucts (I M P).

Tri al pr o d uct m ust o nl y be use d, if it a p pears clear a n d c o l ourl ess.
T a ble 7- 1
Tri al pr o d ucts pr o vi de d b y N o v o N o r dis k A/ S
Tri al pr o d uct n a me:
Se ma gl uti de B 1. 0 m g/ m L P D S 2 9 0 or
se ma gl uti de place b o *
Se ma gl uti de B 3. 0 m g/ m L P D S 2 9 0 or  
se ma gl uti de place b o
D os a ge f or m:
S ol uti o n f or i njecti o n
S ol uti o n f or i njecti 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
D osi n g i nstr ucti o ns:
O nce -wee kl y
O nce -wee kl y
Deli ver y de vice
3 m L P D S 2 9 0 pre -fille d pe n-i nject or
3 m L P D S 2 9 0 pre -fille d pe n-i nject or
* Se ma gl uti de B 1. 0 m g P D S 2 9 0 / m L/se ma gl uti de place b o will o nl y be dis pe nse d at t he first dis pe nsi n g visit.

D ose escalat i on of se ma gl ut i de/se ma gl uti de place b o s h o uld ta ke place d uri n g t he first 1 6 wee ks
after ra n d o misati on as descri be d i n Ta ble 7- 2 . All s u bjects s h o ul d ai m at reac hi n g t he
rec o m me n de d tar get d ose of 2. 4 m g se ma gl uti de o nce -wee kl y or t he c orres p o n di n g v o l ume of
pl ace b o.

If a s u bject d oes n ot t olerate t he rec o m men de d tar g et d ose of 2. 4 m g o nce-wee kl y , t he s u bject
ma y sta y  at t he l ower d ose le vel of  1. 7 mg o nce wee kl y . T his s h o uld o nl y be all o we d if t he
s u bject w o ul d ot her wise disc o nt i n ue trial pr o d uct c o m pletel y a n d if c o nsi dere d safe t o c o nti n ue
o n tri al pr o d uct, as per the i n vest i gat or’s discreti on. It i s rec o m me n de d t hat t he s u bject ma kes at
least o ne atte m pt t o re-escalate t o t he rec o m me n de d tar get d ose of 2. 4 m g o nce-wee kl y , as per
t he i n vest i gat or’s discreti o n.

It is rec o m me n de d t hat t he i n vesti gat or c o ns ults N o v o N ordis k i n case o f persiste nt de viat i ons
fr om t he pla n ne d escalat i on re gi me n.

A d ose re mi n der car d will be ha n de d o ut t o t he s u bjects at eac h site visit d uri n g t he escalat i on
p eri o d. T his i s t o re mi n d t he s u bjects of t he d ose t o be ta ke n u nt il ne xt si te visit a n d pr o vi de a
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
2 5 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
2 7 of 9 4
T a ble 7 - 3  
A u xili ar y s u p plies pr o vi de d b y N o v o N or dis k A/ S
A u xili ar y s u p pl y
Det ails
Nee dles
Nee dles f or pre -fille d pe n s yste m. Details pr o vi de d i n t he T M M.
O nl y nee dles pr o vi de d a n d a p pr o ve d b y N o v o N or dis k m ust be use d f or a d mi nistrati o n 
of trial pr o d uct. 
Directi o n f or use ( D F U)
D F U f or 3 ml P D S 2 9 0 pre -fille d pe n-i nject or
N ot i ncl u de d i n t he dis pe n si n g u nit a n d t o be ha n de d o ut se paratel y 
7. 1. 1
Me dic al de vices
I nf or mat i on a b o ut t he P D S 2 9 0 pre -fille d pe n-i nject or ma y be f o u n d i n t he I B a n d a n y u p dates 
here o f5 8.
I nf or mat i on a b o ut t he use of t he P D S 2 9 0 pre -fille d pe n-i nject or f or se ma gl uti de 1. 0 m g/ m L, 
se ma gl uti de 3. 0 m g/ m L, a n d se ma gl uti de place b o ca n be f o u n d i n t he D F U.
Tr ai ni n g i n t he P D S 2 9 0 pre -fille d pe n-i nject or
T he i n vesti gat or m ust d oc u me nt t hat trai ni n g i n D F U has bee n gi ve n t o t he s u bjects orall y a n d i n 
wri ti n g at t he first dis pe nsi n g visit . Trai ni n g must be re peate d d uri n g t he trial at re g ular i nter vals i n 
or der t o e ns ure c orrect use of t he me dical de vice. Trai ni n g is t he res p o nsi bilit y of t he i n vest i gat or or 
a d el e gate.
7. 1. 2
D iet a n d p h ysic al acti vit y c o u nselli n g
All su bjects i n b ot h  treat me nt ar ms will recei ve c o u nselli n g wit h re gar ds t o diet ( 5 0 0 kcal deficit per 
d a y  relati ve t o t he esti mate d t otal e ner g y e x pe n dit ure ( T E E) calc ulate d o nce at ra n d o misati o n) a n d 
p h ysical act i vity ( 1 5 0 mi n o f p h ysical acti vit y per wee k i s e nc o ura ge d e. g. walki n g or , use t he 
stairs). C o u nselli n g s h o ul d be d o ne b y a dieticia n or a si milar q ualifie d healt hcare pr ofessi o nal 
e ver y 4 t h wee k via visits/ p h o ne c o ntacts. 
S u bjects will be as ke d t o rec or d t heir f o o d i nta ke a n d p h ysical act i vity at least 3 da ys pri or t o t he 
p h o ne c o ntact a n d c li nic visits acc or di n g t o t he fl owc hart t o assist t heir lifestyle i nter ve nt i on . 
H o we ver, t he s u bjects s h o ul d be e nc o ura ge d t o kee p diar y of  t heir f oo d i nta ke a n d p h ysical act i vity 
o n a dail y basis . After ra n d o misat i on t he s u bjects ca n use a t o ol of t heir o w n c h o ice 
( pa per/a p p/ ot her t o ol) f or rec or di n g, e ns uri n g it ca n be re vie we d d uri n g diet a n d p h ysical acti vit y 
c o u nselli n g. S u bjects m ust recei ve i nstr ucti o ns i n h o w t o ca pt ure t heir p h ysical a ct i vity a n d f o o d 
i nta ke.
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
2 7 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
2 9 of 9 4
W he n t he bli n d is br o ke n, t he treat me nt all ocati o n will be accessi ble t o t he i n vesti gat or a n d t he 
N o v o N or dis k Gl o bal Safet y  de partme nt . If I W R S is n ot accessi ble at t he ti me of bli n d brea k, t he 
I W R S hel p des k s h o ul d be c o ntacte d. C o ntact details are listed i n Attac h me nt I.
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 o lle 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 a d mi nister trial pr o d uct. 
T a ble 7- 5 
T ri 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 or 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 B 1. 0 m g/ m L 
P D S 2 9 0 
St ore i n refri gerat or 
( 2° C-8° C/ 3 6° F -4 6° F)
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 ti me will be a vaila ble 
o n t he trial pr o d uct la bel
Se ma gl uti de place b o
Se ma gl uti de B 3. 0 m g/ m L 
P D S 2 9 0 
St ore i n refri gerat or 
( 2° C-8° C/ 3 6° F -4 6° F)
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 ti me will be a vaila ble 
o n t he trial pr o d uct la bel
Se ma gl uti de place b o
aI 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. 

Eac h tri al 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 he 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 n u m ber 
of  s u bjects scree ne d a n d ra n d o mise d.

T he i n vest i gat or m ust c o nfir m t hat a p pr o priate te m perat ure c on dit i ons ha ve bee n mai ntai ne d 
d uri n g tra nsit f or all trial pr o d ucts recei ve d (see Ta ble 7 - 5) a n d a n y discre pa ncies are re p orte d 
a n d res o l ve d bef ore use of t he trial pr o d ucts.

All tri al pr o d ucts must be st ore d i n a sec ure, c o ntr olle d, a n d m o nit ore d ( m a n u al or a ut o mate d) 
area i n acc or da nce wit h t he la belle d st ora ge c o n diti o ns wit h access li mite d t o t he i n vest i gat or 
a n d a ut h orise d site staff.

T he i n vest i gat or m ust i nf or m N o v o N or dis k i m me diatel y if a n y trial pr o d uct has bee n st ore d 
o utsi de s pecifie d c o n dit i ons. A d dit i onal details re gar di n g ha n dli n g of te m perat ure de viat i ons 
ca n be f o u n d i n t he T M M. 

Tri al pr o d uct t hat has bee 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 
bee n e val uate d a n d a p pr o ve d f or f urt her use b y  N o v o N or dis k.

T he i n vest i gat or is res p o nsi ble f or dr u g acc o u nta bility a n d rec or d mai nte na nce (i.e. receipt, 
acc o u nta bilit y a n d fi nal dis p osit i on rec or ds).

Dr u g acc o u nta bilit y s h o uld be perf or me d o n a pe n le vel a n d m ust be d oc u me nte d i n t he I W R S .

T he s u bject m ust ret ur n all use d, partl y  use d a n d u n use d trial pr o d uct i ncl u di n g e m pty 
pac ka gi n g material s d uri n g t he tri a l as i nstr ucte d b y t he i n vesti gat or.
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
2 9 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
3 0 of 9 4

Destr ucti o n of trial pr o d ucts ca n be perf or me d o n a n o n g o i n g basis a n d will be d o ne acc or di n g 
t o lo c al  pr oce d ures after acc o u nta bility is fi nalise d b y t he site a n d rec o ncile d b y t he m o nit or. 

Destr ucti o n of trial pr o d uc ts must be d oc u m e nte d i n t he I W R S. 

All ret ur ne d, e x pire d or da m a ge d trial pr o d ucts (f or tec h nical c o m plai nt sa m ples, see A p pe n di x 
6 ) must be st ore d separatel y fr o m n o n- allocate d trial  pr o d ucts. N o te m perat ure m o nit ori n g is 
re q uire d.

N o n -all ocate d trial pr o d ucts i ncl u di n g e x pire d or da ma ge d pr o d ucts m ust be acc o u nte d as 
u n use d, at t he latest at cl os ure of t he trial site. 
7. 6
Tre at me nt c o m pli a nce
T hr o u g h o ut  t he trial, 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 ure s u bject c o m plia nce. If a s u bject is f o u n d t o be n o n-c o mplia 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 owi n g t he i nst r ucti o ns gi ve n, i ncl u di n g 
ta ki n g t he trial pr o d ucts as prescri be d.
Treat me nt c o m plia nce of  tri al pr o d uct will be assesse d b y as ki n g s u bject a b o ut misse d d oses.
I nf or mat i on a b o ut c o m plia nce a n d misse d d oses s h o ul d be descri be d i n t he s u bject’s me dical 
rec or d, als o see secti on 8. 1. 1 .
7. 7
C o nc o mit a nt me dic ati o n
A n y me dicat i on (i ncl u di n g o ver -t he- c o unt er or prescri pt i on me dici nes ) ot her t ha n t he trial pr o d uct 
t hat t he s u bject is recei vi n g at t he ti me o f t he first visit or recei ves d uri n g t he trial m ust be rec or de d 
alo n g wi t h:

Tra de na me or ge neric na me

I n dicati on

D ates of a d mi nistrati o n i ncl u di n g start a n d st o p dates

D ose ( o nl y t o be rec or de d f or a nti-h y perte nsi ve a n d li pi d-lo weri n g me d icati on)
D uri n g t he trial s u bjects s h o ul d n ot i nit iate a n y a nti-o besit y tr e at me nt (e. g. me dicat i on) w hic h is n ot 
part of t he trial p r oce d ures. If s uc h a nti-o besit y treat me nt is i nit iate d, t he s u bject s h o ul d be 
i nstr ucte d t o st o p t he a nti-o b esi t y tr e at me nt.
C ha n ges i n c o nc o mit a nt me dicat i on m u st be rec or de d at eac h visit. If a c ha n ge is d ue t o a n A E , t he n 
t his m ust be re p orte d acc or di n g t o Sectio n 9. 2 .
7. 7. 1
Resc ue me dic ati o n
T his sect i on is n ot a p plica ble f or t his trial.
7. 8
Tre at me nt after t he e n d of t he tri al
After t he e n d of t he trial t he s u bject s h o ul d be treate d at t he discret i on of t he i n vesti gat or. 
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
3 0 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
3 1 of 9 4
8
Disc o nti n u ati o n/ Wit h dr a w al criteri a 
T he s u bject ma y be disc o nt i 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 vesti gat or f or 
safety,  be ha vio ur al , c o mplia nce or a d mi nistrati ve reas o ns. 
Eff orts m ust be ma de t o ha ve t he s u bjects, w h o disc o nti n ue trial pr o d uct, t o c o nt i n ue i n t he trial.
S u bjects m ust be e d ucate d a b o ut t he c o nti n ue d scie nt ific i m p orta nce of t heir data, e ve n if t he y 
di sc o nti n ue trial pr o d uct. O nl y s u bjects w h o wit h dra w c o nse nt will be c o nsi dere d as wit h dra w n 
fr om t he trial.
8. 1
Disc o nti n u ati o n of tri al tre at me nt

Di sc o nti n uatio n of  trial tr e at me nt ca n be deci de d b y eit her t he i n vest i gat or or t he s u bject.

S u bjects w h o disc o nt i n ue trial pr o d uct s h o uld c o nti n ue wi t h t he sc he d uled visi ts a n d 
assess me nts t o e ns ure c o nti n ue d c o u nselli n g a n d data c ollect i on.

If t he s u bject d oes n ot wis h t o atte n d t he sc he d ule d cli nic visit s eff orts s h o ul d be ma de t o 
ha ve t he visits c o n verte d t o p h o ne c o ntacts. H o we ver all eff orts s h o ul d be ma de t o atte n d at 
least t he ‘e n d of treat me nt ’ cli nic visit c o ntai ni n g t he fi nal data c ollect i on of pri mar y  a n d 
c o nfir mat or y sec o n dar y efficac y e n d p oi nts, a n d t he ‘e n d of trial’ visit.

T he ‘e n d of trial’ visi t is sc he d ule d a p pr o xi matel y 7 wee ks after t he fi nal data c ollect i on, t o 
e ns ure t he safet y of  t he s u bject.

If t he s u bject ref uses t o atte n d t he ‘e n d of treat me nt’ a n d/ or ‘e n d of trial’ visit, inf or mat i on 
a b o ut t he atte m pts t o f o ll ow u p wi t h t he s u bject m ust be d oc u me nte d i n t he s u bject’s 
me dical rec or d .
T he s u bject m ust be disc o nt i n ue d fr om trial pr o d uct, if a n y of t he fol l owi n g a p plies:
1.
S af et y c o ncer n as j u d ge d b y t he i n vesti gat or
2.
Calcit o ni n ≥ 1 0 0 n g/ L (see A p pe n di x 7 )
3.
S us pi cio n  of pa ncreatitis
4.
Pre g na nc y
5.
I nte nti o n of bec o mi n g pre g na nt
6.
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 onal me dici nal pr o d uct.
If ac ute pa ncreat itis is s us pecte d a p pr o priate ma na ge me nt s h o ul d be i nitiate d, i ncl u di n g l ocal 
meas ure me nt of a m ylase a n d li pase (see A p pe n di x 4 f or re porti n g )
S u bjects m eet i n g disc o nti n uati on of tri al pr o d uct cri t erio n n o. 3 are all o we d t o res u me trial pr o d uct 
if t he Atla nta criteria 6 9 are n ot f ulfille d a n d t h us, t he s us pici o n of ac ute pa ncreatit is is n ot 
c o nfir me d. Trial pr o d uct ma y be re s u me d f or s u bjects wit h a gallst o ne-i n d uce d pa ncreatitis i n case 
of  c h olec ystect o m y.
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Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
3 2 of 9 4
S u bjects m eet i n g disc o nti n uati on of  trial pr o d uct crit eria n o. 1, 4 a n d 5 are all o we d t o res u me trial 
pr o d uct, if t he criteria are n o l o n ger met (see Secti o n 8. 1. 1 ).
T he pri mar y  reas o n f or disc o nti n uati on of tri al pr o d uct must be s pecifie d i n t he s o urce data at t he 
ti me of disc o nti n uati on, a n d s u bject s h o ul d c o nti n ue t o f o ll ow t he visit a n d assess me nt sc he d ule. A 
c ha n ge i n ‘treat me nt stat us’ m ust be ma de i n I W R S t o disc o nt i n ue trial pr o d uct. If su bject is n ot 
all o we d t o res u me tri al pr o d uct, t he n t he reas o n f or disc o nt i n uati on will be rec or de d i n t he ‘e n d of
treat me nt ’ f or m i n t he case re p ort f or m ( C R F ), a n d fi nal dr u g acc o u nta bility m ust be perf or me d. 
8. 1. 1
Te m p or ar y disc o nti n u ati o n of tri al tre at me nt
If a s u bject has disc o nti n ue d trial pr o d uct due t o t em p orar y s afet y c o ncer n n ot rel ate d t o trial 
pr o d uct a n d is all o we d t o res u me, t he s u bject s h o ul d f oll ow t he g ui d e f or misse d d os es ( S ectio n 
7. 1 ). Si milarl y, a s u bject w h o disc o nti n ue trial pr o d uct o n t heir o w n i nit iati ve s h o ul d be e nc o ura ge d 
t o res u me trial pr o d uct ( Secti o n 7. 1 ). 
Eac h misse d d ose s h o ul d be rec or de d i n t he case re p ort f or m ( C R F ), as per s u bject’s rec ollecti on. If 
a ‘treat me nt stat us’ sessi on pre vi o usl y  has bee n ma de i n I W R S t o i n dicate disc o nti n uati on of tri al 
pr o d uct, a ne w ‘treat me nt stat us’ sessi on m ust be ma de t o res u me trial pr o d uct.
8. 2
Wit h dr a w al fr o m t he tri al
A s u bject m a y wit hdra w c o nse nt at a n y  time at hi s/ her o w n re q uest.
If a s u bject wit h dra ws c o nse nt, t he i n vesti gat or m ust as k t he s u bject if he/s he is willi n g, as s o o n as 
p ossi ble, t o ha ve assess me nt perf or me d acc or di n g t o t he ‘e n d of treat me nt ’ visi t. See t he fl o wc hart 
f or data t o be c ollecte d. 
Fi nal dr u g acc o u nta bilit y m ust be perf or me d e ve n if t he s u bject is n ot a ble t o c o me t o t he trial site. 
T he i n vest i gat or m ust ma ke a ‘treat me nt stat us’ sessi on in I W R S t o disc o nt i n ue trial pr o d uct. 
If a s u bject wit h dra ws fr om t he trial, he/s he ma y re q uest destr uctio 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 ord.
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 uc h a wit h dra wal o f c o nse nt.
Alt h o u g h a s u bject is n ot o bli ge d t o gi ve his/ her reas o n(s) f or wit h dra wi n g, t he i n vest i gat or m ust 
ma ke a reas o na ble ef f ort t o ascertai n t he reas o n(s), w hile f ull y res pecti n g t he s u bject's ri g hts. W here 
t he reas o ns are o btai ne d, t he pri mar y reas o n f or wit h dra wal must be s pecifie d i n t he ‘ e n d of trial’
f or m in t he C R F.
8. 2. 1
Re pl ace me nt of s u bjects
S u bjects w h o disc o nt i n ue trial pr o d uct or wi t hdra w fr o m  trial will n ot be re place d.
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Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
3 3 of 9 4
8. 3
L ost t o f oll o w -u p
A s u bject will be c o nsi dere d l ost t o f oll o w -u p if he or s he re peate dl y  fails t o ret ur n f or sc he d ule d 
visit s a n d is u na ble t o be c o ntacte d b y t he trial sit e. 
T he f o ll owi n g acti o ns m ust be ta ke n if a s u bject fails t o ret ur n t o t he 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 nt ai ni n g t he 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 nt i n ue i n t he trial.

Bef ore a s u bject is dee me d l ost t o f o ll ow- 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 letter 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 mpts ha ve faile d , famil 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 nat i ve c o ntact details. T hese c o ntact atte mpts s h o ul d be d oc u m e nte d i n t he 
s u bject's s o urce d oc u me nt.

S h o ul d t he s u bject c o nti n ue t o be u nreac ha ble at ‘e n d of’ treat me nt ’ visit , he/s he will be 
c o nsi dere d t o ha ve wit h dra w n fr o m t he trial wit h a pri mar y reas o n of ‘lost t o f oll ow- u p'. 
9
Tr i al assess me nts a n d pr oce d ures

Tri al pr oce d ures a n d t heir ti mi n g are s u m marise d i n t he fl o wc hart. 

I nf or me d c o nse nt must 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 val uati ons m u st be c o mplete d a n d re vie we d t o c o nfir m t h at p ote ntial s u bjects 
meet all eli gi bilit y criteria. 

T he i n vest i gat or will mai ntai n a scree ni n g l o g t o rec or d details of all s u bjects scree ne d a n d t o 
c o nfir m eli gi bilit y or rec or d reas o n f or scree n fail ure, as a p plica ble.

At  scree ni n g, s u bjects will be pr o vi de d with a car d stati n g t hat t he y  are partici pat i n g i n a trial 
a n d gi vi n g c o ntact details of rele va nt trial site staf f. 

A d here nce t o t he trial desi 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 nt ial a n d re q uire d f or trial c o n d uct. 

Assess me nts s h o ul d be carrie d o ut acc or di n g t o t he cli nic’s sta n dar d of practice u nless 
ot her wi se s pecifie d i n t he c urre nt sectio n. Eff orts s h o ul d be m a de t o li mit t he bias bet wee n 
assess me nts. T he s u g geste d or der of  t he assess me nts:
1.
E lectr ocar di o gra m (E C Gs) a n d vit al si g ns
2.
B l oo d sa m ples
3.
P ati e nt re p orte d o utc o me q uesti o n naires (see sect i o n 9. 1. 3 ) (a p plica ble f or U S a n d Ca na da 
o nl y) a n d me nt al healt h assess me nt i nstr u me nts (see Secti o n 9. 4. 1 )
4.
O t her assess me nts

S o urce data of cli nical assess me nts perf or me 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 he 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 d ere d s o urce data 
i ncl u des, b ut is n ot li mite d t o la b orat or y re p orts, E C G, diar y a n d rec or di n gs.
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
3 3 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
3 4 of 9 4

S u bject m ust recei ve i nstr uctio ns i n h o w t o ca pt ure t heir dail y  f oo d i nta ke i n t he ha n de d o ut 
f oo d di ar y fr o m scree ni n g t o ra n d o misati o n. E ntries must be e val ua te d i n acc or da nce wit h t he 
ra n d omisat i on cri t eria.

O nl y t he s u bject ca n ma ke e ntries a n d c orrectio ns i n t he diaries, u nless t he sect i on is s pecifie d 
f or site staff.

T he barriers a n d m oti vat i on i nter vie w i de ntifies barriers t o a n d m oti vat i on f or lifestyle c ha n ge 
a n d c o m p lia nce with t he pr ot oc ol. T he i nter vie w m ust be c o n d ucte d at scree ni n g t o assist i n 
i de ntif yi n g s u bjects w h o are u na ble or u n willi n g t o c o m pl y with pr ot oc ol pr oce d ures as per t he 
e xcl usi o n cri teria. I n a d ditio n, t he i nter vie w will e ns ure t ha t a n y mi n or barriers are a d dresse d 
d uri n g lifest yle c o u nselli n g.

T he res ults of t he i nter vie w will n ot be e ntere d i nt o t he C R F. It will be at t he i n vesti gat or’s 
di scretio n t o e val uate t he m oti vat i on of t he s u bject a n d relate d eli gi bilit y.

S u bject’s wei g ht hist or y  must be rec or de d i n t he s u bject’s me dical rec or d.

Re vie w of me nt al healt h assess me nt i nstr u me nts, E C G, la b orat or y re p orts must be d oc u m e 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 d . If clarificati o n of e ntries or 
di scre pa ncies is nee de d, t he s u bject m ust be q uest i o ne d a n d a c o ncl usi on ma de i n t he s u bject's 
s o urce d oc u me nts. Care m ust be ta ke n n ot t o bias t he s u bject.

Re peat lab orat or y  sa m ples ma y be ta ke n f or tec h nical iss ues a n d u nsc he d ule d sa m ples or 
assess me nts ma y be ta ke n f or safety reas o ns. Please refer t o A p pe n di x 2 f or furt her details o n 
la b orat or y s a mples.

F or s u bjects recei vi n g a nt i h y perte nsi ve or li pi d-l oweri n g treat me nt, t he i n vest i gat or s h o ul d 
e val uate c ha n ges i n t he s u bjects’ treat me nt i nte nsit y wi t hi n eac h t hera pe utic area. T he 
e val uat i on s h o ul d be base d o n w het her a n o verall c ha n ge fr o m ra n d o misat i on u nt il t he ti me of 
t he e val uat i on has occ urre d (i.e., eit he r i ncrease, decrease or n o c ha n ge) after re vie wi n g all 
a vaila ble rele va nt i nf or mati o n e. g., c ha n ges i n dr u g d ose, dr u g class, n u m ber of dr u gs or a 
c o m bi nat i on of t hese.
9. 1
Effic ac y assess me nts 
Pl a n ne d ti me p o i nts f or all efficac y assess me nts are pr o vi de d i n t he flo w c h art.
9. 1. 1
B o d y me as ure me nts

B o d y  wei g ht s h o uld be meas ure d at all sit e visits wit h o ut s h oes, o n a n e m pt y  bla d der a n d o nl y 
weari n g li g ht cl ot hi n g. It s h o ul d be meas ure d o n a di gital scale a n d rec or de d i n kil o gra ms or 
p o u n ds ( o ne deci mal) usi n g t he sa me scale t hr o u g h o ut t he trial. T he scale m ust be cali brate d 
yearl y  as a mi ni m u m.

H ei g ht is m eas ure d wi t ho ut s h oes i n ce nt i metres or i nc hes ( o ne deci mal). B MI will be 
calc ulate d b y t he C R F fr o m scree ni n g data a n d m ust be i n a gree me nt wit h i ncl usi o n cri t erio n 
n o. 3 .

Waist circ u mfere nce is defi ne d as t he a b d o mi nal circ u mfere nce l ocate d mi d wa y bet wee n t he 
l ower ri b m ar gi n a n d t he iliac crest. Meas ures m ust be o btai ne d i n sta n di n g p osit i on wi t h a n o n-
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
3 4 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
3 5 of 9 4
stretc ha ble meas uri n g ta pe a n d t o t he nearest c m or i nc h. T he ta pe s h o ul d t o uc h t he s ki n b ut n ot 
c o mpress s oft ti ss ue a n d t wists i n t he ta pe s h o ul d be a v oi de d. T he s u bject s h o ul d be as ke d t o 
breat he n or mall y. T he sa me meas uri n g ta pe s h o ul d be use d t hr o u g h o ut t he trial. T he meas uri n g 
ta pe will be pr o vi de d b y N o v o N or dis k t o e ns ure sta n dar disati o n.
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 uire d la b orat or y assess me nts, as defi ne d i n A p pe n di x 2 , must b e c o n d ucte d i n 
acc or da nce wit h t he fl owc hart a n d t he la borat or y  ma n ual.
9. 1. 3
Cli nic al o utc o me assess me nt ( a p plic a ble f or U S a n d C a n a d a o nl y)
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 mplete t he q uesti o n nai re b y t he msel ves wit ho ut 
i nterr u ptio n. T he q uest i on naire ta kes a p pr o xi matel y 1 0 mi n utes t o c o m plete.
T he f o ll owi n g pati e nt re p orte d o utc o me q uest i on nai re will be use d:

C o ntr ol  of Eati n g Q uesti on naire ( C o E Q) is desi g ne d t o assess t he i nte nsit y a n d t y pe of f o o d 
cra vi n gs, as well as s u bject i ve se nsatio ns of  a p petite a n d m o o d. F or t his trial a 1 9 ite ms 
versi o n will be use d. T he 1 9 i n di vi d ual ite ms i n t he q uesti o n naire are gr o u pe d i nt o 4 
d o m ai ns: Cra vi n g C o ntr ol, P osit i ve M o o d, Car vi n g f or S weet, a n d Cra vi n g f or Sa v o ur y. T he 
q uesti o n naire will be a vaila b le i n a li n g uisticall y vali date d tra nslate d versi o n 7 0.
9. 2
A d verse e ve nts
T he defi nit i ons 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 vest i 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 owi n g u p o n e ve nts 
t hat meet t he defi nit i on 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 o llecte d fr om t he first trial-relate d acti vity after o btai ni n g i nf or me d c o nse nt a n d 
u nt il ‘e n d of trial’ visi t, at t he ti me p oi nts s pecifie d i n t he fl o wc hart. 
All S A Es will be rec or de d a n d re p orte d t o N o v o N or dis k or desi g nee wit hi n 2 4 h o urs, 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 i t bei n g a vaila ble.
I n vesti gat ors are n ot o bli gate 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 ver, if 
t he i n vest i gat or lear ns of a n y S A E, i ncl u di n g a deat h, at a n y time after a s u bject has bee n 
di sc o nti n ue d fr om/c o m p lete d t he trial, a n d t he i n vesti gat or c o nsi ders t he e ve nt t o be 
p ossi bl y/ pr o ba bl y relate d t o t he i n vest i gati o nal trial pr o d uct or trial partici pati o n, t he i n vesti gat or 
m ust pr o m pt l y n otif y N o v o N or dis k.
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
3 5 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
3 7 of 9 4
      C or o nar y arter y re vasc ularisati o n
X
Ac ute p a ncreatitis
X
X
Ac ute g all bla d der disease
X
Mali g na nt ne o plas ms
X
He patic e ve nt 
X
* A d diti o nal data f or Mis use or a b use of trial pr o d uct is re p orte d o n t he me dicati o n err or e ve nt f or m.
9. 2. 1. 1
E ve nt s f or a dj u dic ati o n
E ve nt a dj u dicat i on will be perf or me d f or a d verse e ve nts i n ra n d omise d s u bjects. T hese e ve nts are 
re vie we d b y 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) i n a bli n de d ma n ner, 
refer t o A p pe n di x 3 f or furt her details.
T here are f our wa y s t o ide nt if y e ve nts rele va nt f or a dj u dicati on as descri be d bel o w :

I n vesti gat or-re p orte d e ve nts f or a dj u dicati on: W he n re p orti n g A Es, t he i n vesti gat or m ust select 
t he a p pr o priate A E cate g or y base d o n pre-defi ne d criteria (see Ta ble 9- 1 a n d A p pe n di x 4 )

Deat h

A E Searc h (sta n dar dis e d scree ni n g): All A Es n ot direct l y re p orte d b y t he i n vesti gat or as 
re q uirin g a dj u dicat i on, will u n der g o scree ni n g t o i de ntif y p ote ntial e ve nts f or a dj u dicati on. T he 
i n vesti gat or ca n be q uerie d t o pr o vi de a d diti onal i nf or mat i on relate d t o t he re p orte d A E, e. g. 
alter nati ve aeti ol og y, u n derl yi n g ca use(s) a n d/ or cli nical details.

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 ve nt f or 
a dju dicat i on, t he E A C ca n i de nt if y a d diti onal e ve 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 vestigat or. I n t hese i nsta nces, t he i n vest i gat or will be n otifie d of t he 
ne wl y i de nt ifie d e ve 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 he i n vesti gat or deci des t o re p ort t he e ve nt, it will u n der g o a dj u dicat i on. Occasi o nall y, 
E A C -i de 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 ocu me 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 ve nt a dj u dicati o n s yste m ( E AS) .
Wit h t he e xce pti o n o f E A C -i de ntifie d e ve nts, a n e ve nt-s pecific a dj u dicati on f or m for t he e ve nt 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 wl e d ge of t he e ve nt. 
C o pi es of c ollecte d s o urce d oc u me nts s h o ul d be la belle d with trial I D, s u bject a n d A E n u m ber, 
re dacte d (a n o n y mise d of pers o nal i de ntifiers) a n d u pl oa de d t o t he e ve nt a dju dicat i on s yste m wi t hi n 
4 wee ks acc or di n g t o i nstr uctio ns o utli ne d i n t he e ve nt a dj u dicat i on 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 on s u p plier, t he i n vesti gat or ca n be 
as ke d t o c o m plete a cli nical narrati ve t o be u plo a d e d t o t he E A S. 
If ne w i nf or mat i on bec o mes a vaila ble f or a n e ve nt se nt f or a dj u dicat i on, it is t he res p o nsi bility of 
t he i n vest i gat or t o e ns ure t he ne w i nf or mati on is u pl oa de d t o t he E A S. 
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3 7 of 9 4
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Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
3 8 of 9 4
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 detecti n g A Es a n d/ o r S A Es. O pe n-e n de d a nd n o n -
lea di n g ver bal q uesti o ni n g of t he s u bject 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 nit ial A E/ S A E re p ort, t he i n vesti gat or is re q uire d t o pr oacti vel y f oll ow eac h s u bject at 
s u bse q ue nt visits/c o ntacts. All S A Es will be f oll owe d u nt il res ol uti on, sta bilizat i on, 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 dit i on) or t he s u bject is l ost t o f oll o w -u p (as defi ne d i n 
Secti o n 8. 3 ). F urt her i nf or mati o n o n f o ll ow- 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 otificat i on b y t he i n vest i 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 gat i ons a n d et hical res p o nsi bilit ies t o war ds t he safety of s u bjects a n d t he safety 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 lo c al 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 safety of a trial pr o d uct u n der cli nical i n vesti gati on. N o v o N or dis k 
will c o m p l 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 ortin 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 vesti gat or safety re p orts m ust be pre pare d f or s us pecte d u ne x pecte d seri o us a d ver se reacti ons
(S U S A Rs ) acc or din g t o lo c al re g ulat or y r e q uire me nts a n d N o v o N or dis k p o lic y a n d f or war de d t o 
i n vesti gat ors as necessar 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 pecific safet y 
i nf or mat i on (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 
alo n g wi t h t he I B 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
H y p o gl yc ae mic , car di o v asc ul ar a n d de at h e ve nts
H y p o gl ycae mic, c ar dio 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 pt i on i n Secti on 9. 2. 1 .
9. 2. 6
Dise ase -rel ate d e ve nts a n d/ or dise ase -rel ate d o utc o mes n ot q u a lif yi n g as a n A E or 
S A E
N ot a p plica ble f or t his trial. 
9. 2. 7
Pre g n a ncies a n d ass oci ate d a d verse e ve nts
Details o f pre g na ncies i n fe male s u bjects will be c ollecte d after t he first -trial-relate d acti vity after 
o btai ni n g i nf or me d c o nse nt a n d u nt il t he ‘e n d of trial’ visit .
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
3 8 of 9 4
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Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
3 9 of 9 4
If a pre g na nc y is re 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 nc y a n d s h o uld fol l ow 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 na nc y o utc o me s h o ul d be d oc u me nte d i n t he s u bject's me dical rec or d. A b n or mal pre g na nc y 
o utc o me (e. g. s p o nta ne o us a b orti o n, f oetal deat h, still birt h, c o n ge nital a n o ma lies a n d ect o pic 
pre g na nc y) is c o nsi dere d a n S A E.
M a t ern al f or m 1 b
≤1 4 c al e n d ar d a ys aft er birt h
M at er n al f or m 1 a
≤1 4 c al e n d ar d a ys
Aft er birt h /
t er mi n ati o n 
of pr eg n a n c y
N o a d diti o n al 
ac tio n
N or m a l o utc o m e 
M at er n al f or m 2 ≤1 4 c al e n d ar d a ys
P at er n al f or m * 1 ≤1 4 c al e n d ar d a ys
A b n or m al  o utc o m e 
Pr eg n a ncy 
v erifi e d
* 1 F urt h er i nf or m ati o n c oll ect ed o n P at er n al f or m f or m al e p art n ers of 
f e m al e su bj ects r e q uir e s si g ni n g of s p ecific i nf or m e d c o ns e nt.
A E /S A Es i n c o n n ecti 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  to 
birt h or  
pr e g n a nc y 
t er mi n atio 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 is n ot a p plica ble f or t his trial. Refer t o tec h nical c o m plai nts i n Sect i on 9. 2. 9
9. 2. 9
Tec h nic al c o m pl ai nts
T he i n vest i 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 nit i ons a n d re p orti n g pr ocess f or tec h ni c al c o mplai nts ca n be f o u n d i n A p pe n di x 6 .
Ti meli nes f or re p orti n g tec h nical c o m p lai nts are liste d i n Fi g ure 9- 3
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Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
4 0 of 9 4
T e c h ni c al c o m pl ai nt  f o r m: ≤ 2 4 h o ur s 
A E  fo r m : ≤ 2 4 h o ur s 
S I F: ≤ 5 c al e n d ar d a y s
Is it rel at e d t o a n S A E ?
T ec h n ical c o m pl ai nt 
i d e ntifi e d
I s it rel a t e d t o an 
A E ?
Y es
N o
T e c h ni c a l c o m p l ain t  f o r m
≤ 5 c al e n d ar d a y s
T e c h ni c al c o m pl ai nt  f o r m: 
≤ 5 c al e n d ar d a y s
A E  fo r m : ≤ 5 c al e n d ar d a ys
N o
Y es
A E : A d v ers e Ev e nt , S A E : S e ri ous  Adv er s e Ev e nt ,  SIF : S af et y I nf or m ati o n F or m
Fi g ure 9- 3
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 tec h nic al c o m pl ai nts.
9. 3
Tre at me nt of o ver d ose
O ver d oses of u p t o 4 m g i n a si n gle d ose, a n d u p t o 4 m g i n a wee k ha ve bee n re p orte d i n cli nical 
trials. T he most c o m m o nl y re porte d A E was na usea. All s u bject s rec o vere d wit h o ut c o m plicat i ons.
T here i s n o s pecific a nti d ote f or o ver d ose wit h se ma gl ut i de. I n t he e ve nt of a n o ver d ose, a p pr o priate 
s u p p orti ve treat me nt s h o ul d be i nitiate d acc or di n g t o s u bject’s cli nical si g ns a n d s y m pt o ms.
T he o ver d ose m ust be re p orte d as a me dicat i on err or (A p pe n di x 4 ) a n d for re p orti n g t i mes see
Secti o n 9. 2. 1 a n d Fi g ure 9- 1 .
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 . A pr olo n ge d peri o d of  o bser vati on a n d treat me nt ma y  be 
necessar y, ta ki n g i nt o acc o u nt t he lo n g half -life of se ma gl uti de of a p pr o xi matel y o ne wee k.
Decisi o ns re gar di n g d ose i nterr u pti o ns or m o dificati o ns will be ma de b y t he i n vest i gat or base d o n 
t he cli nical e val uati o n o f t he s u bject.
F or m ore i nf or m at i on o n o ver d ose, als o c o ns ult t he c urre nt versi o n of t he I B5 8 an d a n y u p dates 
here o f.
9. 4
S afet y assess me nts 
Pl a n ne d ti me p o i nts f or all safety assess me nts are pr o vi de d i n t he fl o wc hart.
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N N 9 5 3 6 - 4 3 7 8
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Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
4 1 of 9 4
A c o nc o mit a nt ill ness is a n y ill ness t hat is prese nt at t he start of t he trial (i.e. at t he first visit) or 
f ou 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 bj ect has e x perie nce d i n t he past. O nl y rele va nt a n d 
sig nifica nt me dical hist or y  as j u d ge d b y t he i n vesti gat or s h o ul d be rec or de d. Fi n di n gs of s pecific 
me dical hist or y  s h o uld de descri be d i n desi g nate d f or ms.
As part of t he me dical hist or y  inf or m at i on relate d t o hist or y  of gall bla d der disease, breast ne o plas m, 
c olo n ne o plas m , s ki n ca ncer a n d ps yc hiatric dis or der will be rec or de d. F oll o w -u p q uesti o ns will be 
as ke d at t he e n d of trial relate d t o t he breast ne o plas m a n d c o l on ne o plas m.
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 vest i 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 omit a nt Ill ness f or m if it is prese nt at scree ni n g. A n y ne w fi n di n g 
f ulfilli n g t he A E defi niti on (see A p pe n di x 4 ) d urin g t he tri al a n d a n y cli nicall y si g nifica nt 
w orse ni n g fr o m baseli ne m ust be re p orte d as a n A E (see Secti o n 9. 2 ).
9. 4. 1
Me nt al he alt h assess me nt i nstr u me nts

P H Q - 97 1 is a 9-ite m de pressi on m o d ule of t he patie nt health q uest i on naire, w hic h is a self -
a d mi nistere d dia g n ostic t o ol use d f or assess me nt of me nt al dis or ders. T he q uesti on naire wil l be 
a vaila ble i n a li n g uisticall y vali date d tra nslate d vers i on . 

C- S S R S 7 2 is a detaile d q uesti on naire assessi n g b ot h s uici dal be ha vi o ur a n d s uici dal i deat i on . 
T he q uest i on naire will be a d mi nistere d as a n i nter vie w b y t he i n vest i gat or or a q ualifie d 
d ele gate. T he q uesti o n naire ( C-S S R S Baseli ne a n d C -S S R S Si nce Last Vi sit) will b e a vaila ble 
i n a li n g uist icall y vali date d tra nslate d versi o n .

Pri or t o a d mi nisteri n g t he C -S S R S q uesti o n naire, t he i n vesti gat or or q ualifie d dele gate m ust 
c o mplete s ufficie nt trai ni n g.
If a s u bject has a P H Q-9 sc ore of 1 0 -1 4 b ot h i ncl usi ve t he s u bject s h o ul d be referre d t o a me ntal 
healt h pr ofessi o nal ( M H P) if j u d ge d rele va nt b y t he i n ves tigat or. If referral is n ot dee me d rele va nt 
t his, alo n g wi t h t he reas o n w h y, m ust be d oc u me nte d i n t he s u bject’s me dical rec or ds.
A s u bject m ust be referre d t o a M H P if:

t he s u bject has a P H Q -9 sc ore ≥1 5 or

t he s u bject has a n y s uici dal be ha vi o ur or

t he s u b ject has a n y s uici dal i deati on of t ype 4 or t y pe 5 o n a n y  C-S S R S assess me nt or

i n t he o pi ni on of t he i n vest i gat or, it is necessar y f or t he safety of t he s u bject
If o ne or more of t he referral criteria are met, t he i n vesti gat or s h o ul d e x plai n t o t he s u bject w h y t he 
referral a n d ps yc hiatric e val uati on b y a M H P is nee de d. If t he s u bject ref uses t o be referre d t o a 
M H P, t he s u bject’s decisi o n s h o ul d be d oc u m e nte d i n s u bject’s me dical rec or d a n d t he i n vest i gat or 
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4 1 of 9 4
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Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
4 2 of 9 4
m ust assess if it is safe f or t he s u bject t o c o n tin ue i n t he tri al or if t he s u bject s h o ul d be disc o nti n ue d 
fr om trial pr o d uct.
If a s u bject’s ps yc hiatric dis or der ca n be a de q uatel y treate d wit h ps yc h ot hera p y a n d/ or 
p har mac ot hera pe utic treat me nt, t he n t he s u bject, at t he discreti o n of t he i n vest i gat or (a nd i n 
a gree me nt wit h t he M H P), ma y c o nti n ue i n t he trial. Ot her wise, t he s u bject m ust be disc o nti n ue d 
fr om trial pr o d uct d ue t o safet y c o ncer n as j u d ge d b y t he i n vestig at or.
9. 4. 2
P h ysic al e x a mi n ati o ns

A p h ysical e xa mi nat i on will i ncl u de assess me nts of t he ge nera l a p peara nce, t h yr oid gla n d,
breast (fe males), a n d a b d o me n, as well as t he c ar di o vasc ular a n d res pirat or y s yste ms. 

I n vesti gat ors s h o ul d pa y s pecial atte nti o n t o cli nical si g ns relate d t o pre vi o us seri o us ill nesses.
9. 4. 3
Vit al si g ns

T he m et h o d f or meas uri n g s yst olic a n d diast olic bl o o d press ure nee ds t o f oll ow t he sta n dar d 
cli nical practice at site.

Bl o o d press ure ( diast olic a n d s yst olic) a n d p ulse meas ure me nts s h o uld be prece de d b y  at least 5
mi n utes of rest f or t he s u bject i n a q uiet setti n g wit h o ut distracti o ns (e. g. tele visi o n, cell
p h o nes).

Bl o o d press ure a n d p ulse meas ure me nts will be assesse d i n a sitti n g p ositi on wi t h a c o mpletel y 
a ut o mate d de vice. Ma n ual tec h ni q ues will be use d o nl y  if a n a ut o mate d de vice is n ot a vaila ble.
9. 4. 4
Electr oc ar di o gr a ms

1 2- lea d E C G will be o btai ne d as o utli ne d i n t he fl owc hart usi n g a l ocal E C G mac hi ne t hat 
a ut o mat icall y calc ulates t he heart rate a n d meas ures P R, Q R S a n d Q T i nter vals .
9. 4. 5
Cli nic al s afet y l a b or at or y ass ess me nts
All pr ot oc ol -re q uire d la b orat or y assess me nts, as defi ne d i n A p pe n di x 2 , must be c o n d ucte d i n 
acc or da nce wit h t he fl owc hart a n d t he la b orat ory ma n ual.

If t he la b orat or y fi n di n g base d o n t he res ults fr o m ce ntral la b orat or y me ets t he criteria f or 
la borat or y o utli ners, a la b orat or y o utli ner f or m  in t he C R F s h o ul d be c o m plete d. Please refer t o 
A p pe n di x 2 f or t he criteria f or t he la borat or y o utli ners.

Uri ne pre g na nc y  tests pr o vide d b y c e ntr al la b orat or y must be perf or m e d for w o me n of 
c hil d beari n g p ote ntial at scree ni n g a n d as s pecifie d i n t he fl ow c hart. Uri ne pre g na nc y t est must 
be re peate d at a n y  time d uri n g t he trial if pre g na nc y is s us pecte d. F urt her i nstr ucti o ns ca n be 
f ou n d i n t he la b orat or y ma n ual.
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4 2 of 9 4
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Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
4 3 of 9 4
9. 5
P h ar m ac o ki netics
N ot a p plica ble f or t his trial.
9. 6
P h ar m ac o d y n a mics
N ot a p plica ble f or t his trial.
9. 7
Ge netics
N ot a p plica ble f or t his trial.
9. 8
Bi o m ar kers
C ollect i on of sa m ples f or bi o mar ker researc h is part of t his trial t o s u p p ort t he effect o bjecti ves. T he 
f oll owi n g sa m ples m u st 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 flo wc hart:
Bi o mar kers li n ke d t o car dio vasc ular ris k

Hi g h se nsi tive C -reacti ve pr otei n ( hs C R P)
9. 9
Se vere h y perse nsiti vit y
I n t he e ve nt of a se vere i m me diate h y perse nsiti vity reactio n t o trial pr o d uct, blo o d sa m pli n g f or 
assess me nt of a nt i-se ma gl uti de I g E a n d bi n di n g a nti b o dies s h o uld be c o n d ucte d aft er 1– 2 wee ks 
a n d 7 wee ks of trial pr o d uct was h -o ut (i. e. after t he s u bject ha d t he last d ose of t he trial pr o d uct). 
I n t hese cases, it is als o rec o m me n de d t o test f or tr y ptase (t otal a n d/ or mat ure tr y ptase) wit hi n 3 
h o urs of t he h yperse nsi tivit y reacti on. I n case a tr y ptase sa m ple was c o llecte d wit hi n 3 h o urs of t he 
e ve nt of h y perse nsit i vity react i on, a baseli ne tr y ptase sa m ple s h o ul d be ta ke n at t he sa me t i me as 
t he I g E sa mple is o b tai ne d (after 1-2 wee ks of trial pr o d uct wa s h-o ut). Tr y ptase c o nce ntrati o ns (if 
meas ure d) as well as res ults of a nt i-se ma gl uti de a nti b o d y a n d I g E is ot ype a nti -se ma gl uti de 
a nt i b o dies will be c o llecte d b y N o v o N or dis k a n d t he res ults will be re p orte d i n t he C T R .
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
4 3 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
4 4 of 9 4
1 0
St atistic al c o nsi der ati o ns
T a x o n o m y of wee k 1 0 4 assess me nts
F or eac h s u bject a gi ve n assess me nt at wee k 1 0 4 ma y be a vaila ble or missi n g a n d Ta ble 1 0- 1
descri bes t he ta x o n o m y f or t his. N ote, t his is d o ne per assess me nt a n d per s u bject; s u bjects ma y  be 
a differe nt t yp e for differe nt assess me nts (a s u bject ma y  ha ve “a vaila ble o n ra n d o mise d treat me nt 
( A T)” f or b o d y wei g ht b ut “ missi n g o n ra n d o mise d treat me nt ( M T)” f or waist circ u mference). 
T a ble 1 0- 1
T a x o n o m y f or s u bjects b ase d o n wee k 1 0 4 assess me nts
Assess me nt
at wee k 1 0 4
S u bjects o n 
r a n d o mise d 
tre at me nt at 
wee k 1 0 4 
T y pe descri pti o n
T y pe
A b bre vi ati o n
A vaila ble
Y es
A v ail a ble o n r a n d o mise d tre at me nt :
S u bjects w h o c o m plete t he trial o n ra n d o mise d treat me nt wit h a n assess me nt at wee k 
1 0 4: I ncl u des t h ose t hat st o p a n d restart trial pr o d uct.
A T
N o
A v ail a ble b ut disc o nti n ue d
S u bjects w h o disc o nti n ue d ra n d o mise d treat me nt pre mat urel y b ut ret ur ne d t o ha ve a n 
assess me nt at wee k 1 0 4. T hese are als o calle d retrie ve d s u bjects
A D
Missi n g
Y es
Missi n g o n r a n d o mise d tre at me nt :
S u bjects w h o c o m plete t he trial o n ra n d o mise d treat me nt wit h o ut a n assess me nt at wee k 
1 0 4: I ncl u des t h ose t hat st o p a n d restart trial pr o d uct.
M T
N o
Missi n g a n d disc o nti n ue d :
S u bjects w h o disc o nti n ue d ra n d o mise d treat me nt pre mat urel y a n d di d n ot ret ur n t o ha ve 
a n assess me nt at wee k 1 0 4. T hese are als o calle d n o n -retrie ve d s u bjects
M D
1 0. 1
S a m ple size deter mi n ati o n 
T he sa m ple size was pri maril y defi ne d t o e ns ure s ufficie nt p o wer f or t he t w o pri mar y e n d p oi nts. 
Gi ve n t he trial sa m ple size, t he p o wer of statist ical tests f or all c o nfir mat or y e n d p oi nts is descri be d 
bel o w.
T he tests of s u peri orit y of se ma gl utid e 2. 4 mg t o se m a gl ut i de place b o f or t he pri mar y a n d 
c o nfir mat or y sec o n dar y e n d p oi nts are perf or me d usi n g t he fi xe d-se q ue nce statistical strate g y. T his 
strate g y tests t he e n d p oi nts usi n g a pre defi ne d hierarc hical or der, all at t he si g nifica nce le vel of 5 %, 
m o vi n g t o test t he ne xt e n d p o i nt o nl y after a statisticall y si g nifica nt s u peri ority res ult ( p-
val ue < 5 %) o n t he pre vi o us e n d p o i nt. T he test hierarc h y is gi ve n i n Ta ble 1 0- 2 wit h u n derl yi n g 
ass u m pt i ons, mar gi nal p o wer a n d effecti ve p o wer. T he effecti ve p o wer is calc ulate d u n der t he 
ass u m pt i on of i n de pe n de nce of e n d p o i nts b y multi pl yi n g t he res pecti ve mar gi nal p o wers 
s uccessi vel y. As t he t w o pri mar y  e n d p oi nts are i ncl u de d i n t he statistical testi n g hierarc h y, 
sig nifica nt s u peri orit y of se ma gl uti de 2. 4 m g vs. se ma gl uti de place b o m ust be de m o nstrate d f or 
eac h of t he pri mar y e n d p o i nts.
I n t he a nal ysis a p pr oac h a d dressi n g t he pri mar y esti ma n d, wee k 1 0 4 assess me nts fr om r etrie ve d 
s u bjects ( A D) are use d. T hese data are als o use d t o i m p ute missi n g meas ure me nts at wee k 1 0 4 f or 
n o n- r etrie ve d s u bjects ( M D). T he i m p utati o n is d o ne se paratel y wit hi n eac h treat me nt ar m (see 
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
4 4 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
4 5 of 9 4
descri pt i on bel o w). H o we ver, f or t he p o wer calc ulati o ns missi n g val ues ( M T a n d M D), re gar dless 
of treat me nt ar m, are ass u me d t o be si milar t o se ma gl uti de place b o s u bjects. T hese ass u m pti ons are 
li kel y c o nser vati ve wit h res pect t o t he p o wer, a n d c orres p o n d t o t he j u m p t o refere nce se nsiti vity 
a nal ysis pla n ne d belo w.
Ass u m pti o ns
T he c o m m o n ass u m pti o ns f or t he p o wer calc ulati o ns are

T he si g nifica nce le vel is 5 %

T he ra n d o misat i on ratio is 1: 1 

F or c o nti n u o us e n d p o i nts t he t -test o n t he mea n differe nce ass u mi n g e q ual varia nces is use d

F or bi nar y  e n d p oi nts t he Pears o n c hi-s q uare test f or t w o i n de pe n de nt pr o p orti o ns is use d 

4 0 % of s u bjects disc o nt i n ue per ma ne ntl y a n d 5 0 % of t hese are retrie ve d ( A D) at wee k 1 0 4

All s u bjects i n t he se ma gl uti de place b o ar m are ass u me d t o ha ve sa me effect as s u bjects w h o 
c o mplete t he tri al o n se ma glut i de place b o ( A T)

Retri e ve d s u bjects ( A D) i n t he se ma gl ut i de 2. 4 m g ar m are ass u me d t o ha ve a n effect 
c orres p o n di n g t o 2 5 % of t he treat me nt differe nce (c o m pare d t o se ma gl uti de place b o) of s u bjects 
w h o c o m plete t he trial o n se ma gl ut i de 2. 4 m g (A T)

N o n -retrie ve d s u bjects ( M D) i n t he se ma gl ut i de 2. 4 m g ar m are ass u me d t o ha ve a n effect 
c orres p o n di n g t o se ma gl ut i de place b o 
F urt her ass u m pti o ns ma de t o calc ulate t he p o wer f or eac h of t he pri mar y a n d c o nfir mat or y 
sec o n dar y e n d p oi nts are base d o n fi n di n gs fr om ot her pr oj ects c o n d ucte d b y N o v o N or dis k 
( N N 8 0 2 2 ( S C A L E), N N 9 5 3 5 ( S U S T AI N), N N 9 9 2 4 ( PI O N E E R)), a n d trial N N 9 5 3 6 -4 1 5 3 a n d are 
prese nte d i n Ta ble 1 0- 2 . F or wei g ht, waist circ u mfere nce a n d s yst olic bl o o d press ure a 2 year 
c o mpleter was ass u me d t o ha ve 9 0 % t he effect of a 1 y ear c o mpleter.
Gi ve n t hese ass u m pt i ons, t he sa m ple size o f 3 0 0 s u bje cts ( 1 5 0 i n eac h ar m), gi ves a n effecti ve 
p o wer ( m ar gi nal p o wers multiplie d) of 4 3 %. As sa m ple size is pri maril y dri ve n b y t he t w o pri mar y 
e n d p o i nts, a d diti onal sce nari os f or ass u m pt i ons are n ot i ncl u de d d ue t o t he hi g h p o wer f or t hese 
e n d p o i nts.
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
4 5 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
4 6 of 9 4
T a ble 1 0- 2
Ass u m pti o ns, m ar gi n al p o wer a n d effecti ve p o wer f or e ac h e n d p oi nt i n t he 
hier arc hic al testi n g pr oce d ure gi ve n a n a ntici p ate d n u m ber of 3 0 0 r a n d o mise d 
s u bjects 
Or der
E n d p oi nt
Ass u me d me a n ( ± S D) or 
pr o p orti o n f or c o m pleters
E x pecte d me a n 
( ± S D) or 
pr o p orti o n
E x pecte d 
differe nce or 
pr o p orti o n 
r ati o
M ar gi n al 
p o wer 
( %)
Effecti ve 
p o wer 
( %)
Se m a gl uti de
2. 4 m g
Se m a gl uti de 
pl ace b o
Se m a gl uti de
2. 4 m g
1
% wei g ht c ha n ge #
1 2. 6 ( ± 1 1)
3. 0 ( ± 1 1) 
9. 2 ( ± 1 2)
6. 2 % -p oi nts
> 9 9 
> 9 9
2
5 % res p o n ders
7 6 %
4 3 %
6 4 %
1. 5
9 6 
9 6
3
1 0 % res p o n ders
5 9 %
2 6 %
4 8 %
1. 8
9 7 
9 3
4
1 5 % res p o n ders
4 1 %
1 4 %
3 1 %
2. 2
9 6 
8 9
5
W C c ha n ge (c m) #
9. 3 ( ± 1 1)
4 ( ± 1 1)
7. 4 ( ± 1 2)
3. 4 c m
6 9 
6 2
6
s B P c ha n ge ( m m H g) #
7. 6 ( ± 1 3) 
1. 5 ( ± 1 3) 
5. 5 ( ± 1 4)
4 m m H g
6 9 
4 3
S D = sta n dar d de viati o n; W C = waist circ u mfere nce; s B P = s yst olic bl o o d press ure; # s h o w n as a p ositi ve n u m ber
1 0. 2
Defi niti o n of a n al ysis sets
T w o a nal ysis sets are defi ne d:

T he f ull a n alysis set ( F A S) i ncl u des all ra n d omise d s u bjects acc or di n g t o t he i nte nti o n -t o-treat 
pri nci ple.

T he s afety a n alysis set ( S A S) i ncl u des all ra n d o mise d s u bjects e x p ose d t o at least o ne d ose of 
ra n d omise d treat me nt.
A n y o bser vat i on e xcl u de d fr o m t he a nal ysis will be d oc u me nte d bef ore data base l oc k wit h t he 
reas o n f or e xcl usi on pr o vide d.
T w o o bser vati o n peri o ds are defi ne d f or eac h s u bject:

I n-trial: T he i n-tri al peri o d is defi ne d as t he u ni nterr u pte d ti me i nter val fr om date of 
ra n d omisat i on t o date of last c o ntact wit h trial site.

O n -tr e at me nt ( wit h trial pr o d uct): A ti me-p oi nt is c o nsidere d as ‘ o n -treat me nt’ if a n y d ose of 
trial pr o d uct has bee n a d mi nistere d wit hi n t he pri or 2 wee ks ( 1 4 da ys). T he o n- tre at me nt peri o d
is defi ne d as all ti mes w hic h are c o nsi dere d o n-tr eat me nt.

I n ge neral, t he o n-treat me nt perio d will t heref ore be fr o m t he date of first trial pr o d uct 
a d mi nistrati o n t o date of last trial pr o d uct a d mi nistrati o n e xcl u di n g p ote ntial o ff-tr e at me nt 
ti me i nter vals tri g gere d b y at least t w o c o nsec uti ve misse d d oses.

F or t he e val uat i on of a d verse e ve nts t he la g t i me f or eac h o n-treat me nt ti me i nter val is 7 
wee ks ( 4 9 da y s)
T he i n -trial a n d o n -treat me nt perio ds defi ne t he patie nt years of o bser vat i on ( P Y O) a n d patie nt 
years o f e x p os ure ( P Y E), res pecti vel y, as t he t ot al ti me d urati o n i n t he peri o ds.
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
4 6 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
4 9 of 9 4
1. I m p ut ati o n: Defi nes a n i m p utati o n m o del usi n g retrie ve d s u bjects ( A D) fr om F A S a n d d o ne 
wi t hi n gr o u ps defi ne d b y ra n d o mise d treat me nt a n d t he ti mi n g of t he L A O of b o d y wei g ht. T he 
m o d el will be a li near re gressi on of b o d y wei g ht ( k g) at wee k 1 0 4 wit h ge n der ( male/fe male), 
baseli ne B MI ( k g/ m 2) (i n cate g ories 2 7 -< 3 5, 3 5- < 4 0, ≥4 0) as fact ors a n d baseli ne b o d y wei g ht 
( k g) a n d L A O of b o d y wei g ht ( kg) as c o variates. N o i nteracti o ns will be i ncl u de d. T he gr o u pi n g 
of ti mi n g will be d o ne b y q uarters (i nter vals o f 2 6 wee ks f or e n d p oi nts e val uati n g t he c ha n ge 
after 1 0 4 wee ks, i nter vals of 1 3 wee ks f or e n d p oi nts e val uat i n g t he c ha n ge after 5 2 wee ks). If 
timi n g b y q uarters is t o o restrict i ve, hal ves (i nter vals of 5 2 wee ks f or e n d p o i nts e val uati n g t he 
c ha n ge after 1 0 4 wee ks, i nter vals o f 2 6 wee ks f or e n d p o i nts e val uati n g t he c ha n ge after 5 2 
wee ks ) or e xclu di n g t i mi n g will be use d. If a n y s u bjects are M T, a n im p utati o n mo d el for 
missi n g b o d y  wei g ht meas ure me nts at wee k 1 0 4 f or M T s u bjects will als o be defi ne d usi n g A T 
s u bjects i n a si milar wa y. T he esti mate d p osteri or distri b uti on f or t he para meters (re gressi o n 
c oefficie nts a n d varia nces) i n t he i m p utati o n m o de ls are t he n use d t o i m p ute missi n g wee k 1 0 4 
b o d y wei g ht valu es f or eac h ra n d o mise d treat me nt ar m. T his will be d o ne 1, 0 0 0 ti mes a n d res ults 
i n 1, 0 0 0 c o m plete data sets.
2. A n al ysis : A nal ysis of eac h of t he 1, 0 0 0 c o m plete data sets, usi n g t he a nal ysis m o dels 
(A N C O V A a n d l o gist ic re gressi on) res ults i n 1, 0 0 0 ti mes 2 esti mat i ons.
3. P o oli n g : I nte grates t he 1, 0 0 0 ti mes 2 esti mati on res ults i nt o t w o fi nal res ults usi n g R u bi n’s 
f or mula.
Base d o n N N 9 5 3 6 -4 1 5 3 p hase 2 res ults 1, 0 0 0 c o pies s h o ul d be s ufficie nt t o esta blis h sta ble res ults. 
If 1, 0 0 0 c o pies are i ns ufficie nt, 1 0, 0 0 0 c o pies will be use d. T he m ult i ple i m p utati o ns will be 
ge nerate d usi n g N o v o N or dis k trial n u m ber 9 5 3 6 4 3 7 8 as see d n u m ber.
Se nsitivity a n alyses
J u m p t o refere nce m ulti ple i m p ut ati o n a p pr o ac h (J 2 R- MI): Mi ssi n g val ues of b o d y wei g ht at wee k 
1 0 4 ( M T a n d M D) f or b ot h t he se ma gl ut i de 2. 4 m g a n d se ma gl uti de place b o gr o u p are i m p ute d b y 
sa m pli n g a m on g all a vaila ble assess me nts at wee k 1 0 4 i n t he se ma gl ut i de place b o gr o u p ( A T a n d 
A D). T his a p pr oac h ma kes t he a ss u m pti o n t hat s u bjects i nsta ntl y after disc o nt i n uati on l ose a n y 
effect of ra n d o mise d treat me nt be y o n d w hat ca n be e x pecte d fr o m se ma gl uti de place b o treat me nt as 
a dju nct t o re d uce d -cal orie diet a n d i ncrease d p h ysical act i vity 7 4. T he m ultiple i m p utati o n a p pr oac h 
is d o ne as a b o ve wit h t he first ste p re place d b y
1. I m p ut ati o n: Defi nes a n i m p utati o n m o del usi n g se ma gl uti de place b o s u bjects fr o m F A S wit h a 
wee k 1 0 4 meas ure me nt ( A T a n d A D). T he m o del will be a li near re gressi o n o f b o d y wei g ht ( k g) 
at wee k 1 0 4 wit h ge n der ( male/fe male), B MI ( k g/ m 2) (i n cate g ories 2 7-< 3 5, 3 5- < 4 0, ≥4 0) as 
fact ors a n d baseli ne b o d y wei g ht ( k g) as c o variate. N o i nteracti o ns will be i ncl u de d. T he 
esti mate d p osteri or distri b ut i on f or t he para meters (re gressi o n c oefficie nts a n d varia nces) i n t he 
i m p utatio n mo dels are t he n use d t o i m p ute missi n g wee k 1 0 4 b o d y  wei g ht valu es f or eac h 
ra n d omise d treat me nt ar m. T his will be d o ne 1, 0 0 0 ti mes a n d res ult s i n 1, 0 0 0 c o m plete data sets.
T he j u m p t o refere nce a p pr oac h is t he basis f or t he sa m ple size calc ulat i ons. 
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
4 9 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
5 0 of 9 4
A si n gle i m p ut ati o n a p pr o ac h as d o ne by S acks 7 5 ( S 1-SI a n d S 2 -SI) : Missi n g wei g ht meas ure me nts 
at wee k 1 0 4 f or n o n -retrie ve d s u bjects ( M D) are i m p ute d usi n g a wei g ht re gai n rate of 0. 3 k g/ m o nt h 
after L A O b ut tr u ncate d at n o c ha n ge fr o m baseli ne w he ne ver t he e xtra p olati on w o ul d lea d t o a 
p ositive wei g ht gai n relat i ve t o baseli ne. If a s u bject's wei g ht at dr u g disc o nt i n uati on re prese nte d a 
gai n i n wei g ht relat i ve t o baseli ne, n o a d diti o nal gai n will be i m p ute d, a n d t he u nfa v o ura ble gai n is 
carrie d for war d t o wee k 1 0 4 . T he wei g ht re gai n i m p utati o n will be d o ne f or b ot h ra n do mise d ar ms 
( S 1-SI). A d dit i onall y, a versio n  w here o nl y t he se ma gl uti de 2. 4 m g ar m uses t he re gai n rate w hile 
t he se ma gl ut i de place b o ar m uses last a vaila ble o bser vati on (c orres p o n di n g t o a wei g ht re gai n rate 
of 0 k g/ mo nt h) will be perf or me d ( S 2 -SI). F or b ot h versi o ns, missi n g wei g ht meas ure me nts at wee k 
1 0 4 f or s u bjects o n ra n d o mise d treat me nt ( M T) are i m p ute d b y usi n g L A O. 
Ti p pi n g -p oi nt m ulti ple i m p ut ati o n a n alysis ( T P -MI) : First, missi n g data are i m p ute d acc or di n g t o 
t he pri mar y multiple i m p utati o n a p pr oac h. Sec o n d, f or t he se ma gl ut i de 2. 4 m g treat me nt ar m a 
pe nalt y will be a d de d t o t he i m p ute d val ues at wee k 1 0 4 . T he a p pr oac h is t o gra d uall y i ncrease t his 
pe nalt y u ntil all c o nfir me d c o ncl usi o ns fr om t he pri mar y a nal ysis are re verse d. F or eac h h y p ot hesis
teste d t he s pecific val ue of t he pe nalty t hat re verses t he c o ncl usi o n will be use d t o e val uate t he 
r o b ust ness of t he pri mar y a nal ysis res ults. T his se nsitivit y a nal ysis e val uates t he r o b ust ness of t he 
s u periorit y c o nclusio n s.
Mixe d m o del f or re pe ate d me as ure me nts ( M M R M) : T his ‘ M M R M f or effecti ve ness’ will use all 
assess me nts re gar dless of a d here nce t o ra n d o mise d treat me nt, i ncl u di n g assess me nts at wee k 1 0 4 
f or retrie ve d dr o p -o uts ( A D). T he M M R M f or effecti ve ness will be fitte d usi n g t he sa me fact or a n d 
c o variate as f or t he pri mar y a nal yses all neste d wit hi n visit. A n u nstr uct ure d c o varia nce matri x f or 
meas ure me nts wit hi n t he sa me s u bject will be e m pl o ye d, ass u mi n g t hat meas ure me nts f or differe nt 
s u bjects are i n de pe n de nt.
N o n -retrieve d s u bjects as n o n-res p o nders : F or t he 5 % res p o n der a nal ysis a n a nal ysis usi n g n o n-
retrie ve d s u bjects as n o n -res p o n ders i n t he l o gistic re gressi o ns will be d o ne.
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
5 0 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
5 1 of 9 4
Fi g ure 1 0- 1
Ill ustr ati o n of i m p ut ati o n a p pr o ac hes f or t he effecti ve ness esti m a n d
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
5 1 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
5 2 of 9 4
A n al ysis a d dressi n g t he sec o n d ar y esti m a n d
T he sec o n dar y  esti ma n d f or % weig ht c ha n ge a d dresses t he efficac y  of se ma gl uti de 2. 4 m g a n d will 
be assesse d usi n g a ‘ M M R M f or efficac y’. Wee k 1 0 4 assess me nts f or retrie ve d dr o p -o uts ( A D) ar e 
n ot use d i n t his a nal ysis. T he M M R M f or efficac y will use assess me nts o nl y fr o m s u bjects w h o are 
ta ki n g t he ra n d omise d treat me nt u ntil e n d o f treat me nt or u ntil first disc o nti n ui n g of ra n d omise d 
treat me nt. T he deri ve d date of t he sec o n d c o nsec uti ve misse d d ose will  be use d as t he latest date f or 
usi n g assess me nts i n t his M M R M. T he assess me nt cl osest i n ti me a n d bef ore t he deri ve d date of t he 
sec o n d c o nsec uti ve misse d d ose will be use d as last assess me nt o n ra n d o mise d treat me nt. F or 
s u bjects w h o i nitiate resc ue i nter ve nt i ons bef ore c o m plet i on or first disc o nt i n ui n g of ra n d omise d 
treat me nt, t he date of starti n g wei g ht ma na ge me nt dr u gs or u n der g oi n g bariatric s ur ger y  will be 
use d as latest date f or usi n g assess me nts i n t his M M R M. Si milarl y, t he assess me nt cl o sest i n ti me 
a n d bef ore t he date of starti n g wei g ht ma na ge me nt dr u gs or u n der g oi n g bariatric s ur ger y  will be 
use d as last assess me nt o n ra n d o mise d treat me nt. T he M M R M f or efficac y will be fitte d usi n g % 
w ei g ht c ha n ge a n d t he sa me fact or a n d c o variate as f o r t he pri mar y a nal yses all neste d wit hi n visit. 
A n u nstr uct ure d c o varia nce matri x f or meas ure me nts wit hi n t he sa me s u bject will be e m pl o ye d, 
ass u mi n g t hat meas ure me nts f or differe nt s u bjects are i n de pe n de nt. 
T he sec o n dar y  esti ma n d f or 5 % res p o n ders will be assesse d usi n g t he sa me M M R M f or efficac y . 
Fr o m  t he M M R M i n di vi d uall y pre dicte d val ues f or % wei g ht c ha n ge at wee k 1 0 4 will be use d t o 
classif y eac h s u bject as 5 % res p o n der or n ot. T his classificati on will t he n be a nal yse d usi n g a 
l ogist ic re gressi on m o d el wit h treat me nt as t he o nl y fa ct or.
A n o ver vie w of all a nal ysis a n d i m p utati o n met h o ds t o a d dress t he effect i ve ness a n d efficac y 
esti ma n ds f or t he pri mar y e n d p o i nts is gi ve n i n Ta ble 1 0- 3
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 sec o n d ar y e n d p oi nts
C o nfir mat or y  sec o n dar y e n d p oi nts are liste d i n secti o n 4 a n d are all i ncl u de d i n t he fi xe d -se q ue nce 
statistical strate g y, see a b o ve. All tests are tests of s u peri ority of se ma gl uti de 2. 4 m g t o se ma gl uti de 
place b o. 
A n al yses a d dressi n g t he pri m ar y e sti m a n d
All c o nfir mat or y sec o n dar y e n d p oi nts will be a nal yse d usi n g t he sa me i m p utati o n a p pr oac h as use d 
f or t he pri mar y e n d p oi nts a n d t o a d dress t he pri mar y esti ma n d. T he i m p utati o n m o del is t he sa me as 
f or t he pri mar y e n d p oi nts wit h b o d y wei g ht re plac e d b y assess me nts of t he e n d p o i nt t o be a nal yse d. 
T he stati stical m o d el for c o nti n u o us e n d p oi nts will be A N C O V A wit h fact or a n d c o variate as f or 
t he pri mar y e nd p oi nt % wei g ht c ha n ge wi t h baseli ne b o d y w eig ht re place d b y  t he baseli ne 
assess me nt of t he e n d p oi nt t o be a nal yse d. T he statistical mo d el for b o d y  wei g ht res p o n der 
e n d p o i nts will be l o gistic re gressi on wit h fact ors a n d c o variate as f or t he pri mar y e nd p oi nt 5 % 
res p o n ders. 
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
5 2 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
5 3 of 9 4
A n al yses a d dressi n g t he sec o n d ar y esti m a n d
T he c o nfir mat or y  sec o n dar y e n d p oi nts w hic h relate t o t he pri mar y o bjecti ve will be a nal yse d t o 
a d dress t he sec o n dar y esti ma n d usi n g t he sa me M M R M f or efficac y descri be d f or t he pri mar y 
e n d p o i nts.
Se nsitivity a n alyses f or c o nfir m at ory sec o n d ary e n d p oi nts
F or all c o nti n u o us c o nfir mat or y  sec o n dar y e n d p oi nts a se nsiti vity a nal ysis usi n g j u m p t o refere nce 
as i m p utati o n a p pr oac h will be carrie d o ut. F or all bi nar y c o nfir mat or y sec o n dar y e n d p o i nts a 
se nsiti vity a nal ysis usi n g n o n -retrie ve d s u bjects as n o n-res p o n ders will be carrie d o ut.
A n o ver vie w of all a nal ysis a n d i m p utati o n met h o ds t o a d dress t he effecti ve ness a n d efficac y 
esti ma n ds f or c o nfir mat or y sec o n dar y e n d p oi nts is gi ve n i n Ta ble 1 0- 3 .
T a ble 1 0- 3
A n al ysis a n d i m p ut ati o n met h o ds t o a d dress t he effecti ve ness a n d effic ac y 
esti m a n ds f or t he pri m ar y a n d c o nfir m at or y sec o n d ar y e n d p oi nts i n t he 
st atistic al testi n g hier arc h y
O bjecti ve
E n d p oi nt
Test 
or der
E n d p oi nt 
t y pe
Esti m a n d
A n al ysis 
s et
St atistic al 
m o del
I m p ut ati o n 
a p pr o ac h
Se nsiti vit y 
a n al yses
Pri m ar y e n d p oi nts
Pri mar y
% wei g ht c ha n ge
1
C o nti n u o us
Pri mar y
F A S
A N C O V A
R D -MI
J 2 R-MI
S 1 -SI
S 2 -SI
T P -MI
M M R M
Sec o n dar y
F A S
M M R M
-
-
Pri mar y
5 % res p o n ders
2
Bi nar y
Pri mar y
F A S
L R
R D -MI
J 2 R-MI
S 1 -SI
S 2 -SI
T P -MI
M M R M
N o n -
res p o n der
Sec o n dar y
F A S
L R
M M R M
-
C o nfir m at or y sec o n d ar y e n d p oi nts
Pri mar y
1 0 % res p o n ders
3
Bi nar y
Pri mar y
F A S
L R
R D -MI
N o n -
res p o n ders
Sec o n dar y
F A S
L R
M M R M
-
Pri mar y
1 5 % res p o n ders
4
Bi nar y
Pri mar y
F A S
L R
R D -MI
N o n -
res p o n ders
Sec o n dar y
F A S
L R
M M R M
-
Pri mar y
W C c ha n ge (c m)
5
C o nti n u o us
Pri mar y
F A S
A N C O V A
R D -MI
J 2 R-MI
Sec o n dar y
F A S
M M R M
-
-
Sec o n dar y
s B P c ha n ge ( m m H g)
6
C o nti n u o us
Pri mar y
F A S
A N C O V A
R D -MI
J 2 R-MI
F A S = f ull a nal ysis set; A N C O V A = a nal ysis of c o varia nce; R D -MI = m ulti ple i m p utati o n usi n g retrie ve d s u bjects; 
J 2 R-MI = j u m p t o refere nce m ulti ple i m p utati o n; S 1 -SI a n d S 2 -SI = si n gle i m p utati o n as d o ne b y Sac ks; T P -MI = 
ti p pi n g p oi nt m ulti ple i m p utati o n; M M R M = mi xe d m o del f or re peate d meas ure me nts; L R = l o gistic re gressi o n; W C = 
waist circ u mfere nce; s B P = s yst olic bl o o d press ure
1 0. 3. 2. 2
S u p p orti ve sec o n d ar y e n d p oi nts
S u p p orti ve sec o n dar y e n d p oi nts are liste d i n secti on 4 . All tests are tests of s u periorit y of 
se ma gl uti de 2. 4 m g t o se ma gl uti de place b o. 
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
5 3 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
5 4 of 9 4
A n al yses a d dressi n g t he pri m ar y esti m a n d
T he effect -relate d s u p porti ve sec o n dar y  e n d p oi nts will be a nal yse d usi n g t he sa me i m p utati o n 
a p pr oac h as use d f or t he pri mar y e n d p oi nts a n d t o a d dress t he pri mar y esti ma n d. T he i m p utati o n 
m o d el is t he sa me as f or t he pri mar y e nd p oi nts wi t h b o d y wei g ht re place d b y assess me nts of t he 
e n d p o i nt t o be a nal yse d. T he statistical mo d el for c o nti n u o us e n d p oi nts will be A N C O V A wit h 
fact or a n d c o variate as f or t he pri mar y e n d p oi nt % wei g ht c ha n ge wit h baseli ne b o d y wei g ht 
r e place d b y t he baseli ne assess me nt of t he e n d p oi nt t o be a nal yse d. 
F or li pi ds a n d hs C R P a m ult i plicati ve m o d el will be use d, i.e. t he ratio bet wee n p ost ra n d o misati o n 
meas ure me nts a n d baseli ne will be calc ulate d i nstea d of differe nces, a n d b ot h t he de pe n de nt 
varia ble a n d c o variate will be l o g -tra nsf or me d.
A n al yses a d dress i n g t he sec o n d ar y esti m a n d
T he s u p p orti ve sec o n dar y  e n d p oi nts w hic h relate t o t he pri mar y o bjecti ve will be a nal yse d t o 
a d dress t he sec o n dar y esti ma n d usi n g t he sa me M M R M f or efficac y descri be d f or t he pri mar y 
e n d p o i nts.
A d diti o n al c o nsi der ati o ns f or st ati stic al a n al yses
S u p p orti ve sec o n dar y  e n d p oi nts e val uati n g t he o ne-year effect of se ma gl ut i de 2. 4 m g will be 
a nal yse d usi n g t he sa me i m p utati o n a p pr oac h as use d f or t he pri mar y e n d p o i nts a n d t o a d dress t he 
pri mar y  esti ma n d. T he i m p utati o n m o del is t he sa me as f or t he pri mar y e n d p oi nts. T he statistical 
m o d el for c o nti n u o us e n d p oi nts will be A N C O V A wit h fact or a n d c o variate as f or t he pri mar y  
e n d p o i nt % weig ht c ha n ge. T he statistical m o del f or b o d y  wei g ht res p o n der e n d p oi nts will be 
l ogist ic re gressi on wit h fa ct or a n d c o variate as f or t he pri mar y e nd p oi nt 5 % res p o n ders. 
T he 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 t o wee k 5 2 i n b o d y w eig ht ( %)” will be 
c o mpare d t o t he pri mar y e n d p oi nt “ C ha n ge fr o m baseli ne t o wee k 1 0 4 i n b o d y  w eig ht ( %)”. T he 
c o mparis o n will  be d o ne usi n g t he pri mar y est i ma n d at wee k 5 2 a n d wee k 1 0 4.
Se nsitivity a n alyses f or s u p p ortive sec o n d ary e n d p oi nts
F or s u p p orti ve sec o n dar y  e n d p oi nts n o se nsiti vity a nal ysis will be carrie d o ut.
A n al ysis of s afet y e n d p oi nts
T he safet y e n d p oi nt  p ulse will be a nal yse d usi n g a n M M R M f or efficac y as descri be d i n secti on 
1 0. 3. 1 . F or a m ylase, li pase a n d calcit o ni n descri pti ve statistics will be pr o vi de d. T he a nal ysis of 
calcit o ni n will be stratifie d b y ge n der.
A d verse e ve nts will be defi ne d as “treat me nt -e mer ge nt” ( T E A E), if t he o nset of t he e ve nt occ urs i n 
t he o n-treat me nt perio d (see defi niti on i n sect i on 1 0. 2 ). T E A Es a n d S A Es will be s u m marise d b y 
descri pt i ve statistics, s uc h as fre q ue ncies a n d rates. N o f or mal statistical i nfere nce will be carrie d 
o ut base d o n t he n u m ber of T E A Es a n d S A Es.
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
5 4 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
5 5 of 9 4
A n o ver vie w of all a nal ysis a n d i m p utati o n met h o ds t o a d dress t he effect i ve ness a n d efficac y 
esti ma n ds f or s u p p orti ve sec o n dar y e n d p oi nts is gi ve n i n Ta ble 1 0- 4 .
T a ble 1 0- 4
A n al ysis a n d i m p ut ati o n met h o ds t o a d dress t he effecti ve ness a n d effic ac y 
esti m a n ds f or s u p p orti ve sec o n d ar y e n d p oi nts
O bjecti ve
E n d p oi nt
E n d p oi nt 
t y pe
Esti m a n d
A n al ysis 
s et
St atistic al 
m o del
I m p ut ati o n 
a p pr o ac h
Se nsiti vit y 
a n al yses
S u p p orti ve sec o n d ar y e n d p oi nts (effect rel ate d)
Fr o m b aseli ne t o week 1 0 4
Pri mar y
Wei g ht c ha n ge ( k g)
C o nti n u o us
Pri mar y
F A S
A N C O V A
R D -MI
-
Sec o n dar y
F A S
M M R M
-
-
Pri mar y
B MI c ha n ge ( k g/ m 2)
C o nti n u o us
Pri mar y
F A S
A N C O V A
R D -MI
-
Sec o n dar y
F A S
M M R M
-
-
Sec o n dar y
H b A 1 c c ha n ge ( %, m m ol/ m ol)
C o nti n u o us
Pri mar y
F A S
A N C O V A
R D -MI
-
Sec o n dar y
F P G c ha n ge ( m g/ d L)
C o nti n u o us
Pri mar y
F A S
A N C O V A
R D -MI
-
Sec o n dar y
Fasti n g ser u m i ns uli n c ha n ge 
( mI U/L)
C o nti n u o us
Pri mar y
F A S
A N C O V A
R D -MI
-
Sec o n dar y
d B P c ha n ge ( m m H g)
C o nti n u o us
Pri mar y
F A S
A N C O V A
R D -MI
-
Sec o n dar y
T otal c h olester ol c ha n ge ( m g/ d L)
C o nti n u o us
Pri mar y
F A S
A N C O V A
R D -MI
-
Sec o n dar y
H D L c ha n ge ( m g/ d L)
C o nti n u o us
Pri mar y
F A S
A N C O V A
R D -MI
-
Sec o n dar y
L D L c ha n ge ( m g/ d L)
C o nti n u o us
Pri mar y
F A S
A N C O V A
R D -MI
-
Sec o n dar y
V L D L c ha n ge ( m g/ d L)
C o nti n u o us
Pri mar y
F A S
A N C O V A
R D -MI
-
Sec o n dar y
F F A c ha n ge ( m g/ d L)
C o nti n u o us
Pri mar y
F A S
A N C O V A
R D -MI
-
Sec o n dar y
Tri gl yceri des c ha n ge ( m g/ d L)
C o nti n u o us
Pri mar y
F A S
A N C O V A
R D -MI
-
Sec o n dar y
hs C R P c ha n ge ( m g/ L)
C o nti n u o us
Pri mar y
F A S
A N C O V A
R D -MI
-
Fr o m b aseli ne t o week 5 2
Sec o n dar y
Wei g ht c ha n ge ( %, k g)
C o nti n u o us
Pri mar y
F A S
A N C O V A
R D -MI
-
Sec o n dar y
B MI c ha n ge ( k g/ m 2)
C o nti n u o us
Pri mar y
F A S
A N C O V A
R D -MI
-
Sec o n dar y
W C c ha n ge (c m)
C o nti n u o us
Pri mar y
F A S
A N C O V A
R D -MI
-
Sec o n dar y
5 % res p o n ders
Bi nar y
Pri mar y
F A S
L R
R D -MI
-
Sec o n dar y
1 0 % res p o n ders
Bi nar y
Pri mar y
F A S
L R
R D -MI
-
Sec o n dar y
1 5 % res p o n ders
Bi nar y
Pri mar y
F A S
L R
R D -MI
-
S u p p orti ve sec o n d ar y e n d p oi nts (s afet y rel ate d)
Sec o n dar y
N u m ber of T E A Es
C o nti n u o us
-
S A S
-
-
-
Sec o n dar y
N u m ber of S A Es
C o nti n u o us
-
S A S
-
-
-
Sec o n dar y
P ulse c ha n ge ( b p m)
C o nti n u o us
-
S A S
M M R M
-
-
Sec o n dar y
A m ylase c ha n ge ( U/ L)
C o nti n u o us
-
S A S
Descri pti ve 
statistics
-
-
Sec o n dar y
Li pase c ha n ge ( U/ L)
C o nti n u o us
-
S A S
Descri pti ve 
statistics
-
-
Sec o n dar y
Calcit o ni n c ha n ge ( n g/ L)
C o nti n u o us
-
S A S
Descri pti ve 
statistics
-
-
F A S = f ull a nal ysis set; A N C O V A = a nal ysis of c o varia nce; R D-MI = m ulti ple i m p utati o n usi n g retrie ve d s u bjects; 
M M R M = mi xe d m o del f or re peate d meas ure me nts; B MI = b o d y mass i n de x; H b A
1 c = He m o gl o bi n A 1c; F P G = fasti n g 
plas ma gl uc ose; d B P = diast olic bl o o d press ure; H D L = hi g h de nsit y li p o pr otei n; L D L = l o w de nsit y li p o pr otei n; V L D L 
= ver y  l o w de nsit y li p o pr otei n; F F A = free fatt y aci ds; hs C R P = hi g h se nsiti vit y C-Reacti ve Pr otei n; W C = waist 
circ u mfere nce; L R = l o gistic re gressi o n; T E A Es = treat me nt e mer ge nt a d verse e ve nts; S A Es = seri o us a d verse e ve nts
1 0. 3. 3
E x pl or at or y e n d p oi nt
E x pl or at or y e n d p o int s are liste d i n secti on 4 . O bser ve d data f or e x pl orat or y e n d p o i nts will be 
s u m marise d b y descri pti ve st atistics. 
F o o d cra vi n gs will be assesse d b y t he C o E Q at baseli ne ( wee k 0), wee k 2 0, wee k 5 2 a n d wee k 1 0 4, 
wi t h eac h of t he 1 9 ite ms rate d o n a 1 0 p oi nts scale. T he rati n g f or eac h q uest i on will be 
s u m marise d usi n g descri pti ve statistics (a p plica ble f or U S a n d Ca na da o nl y).
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
5 5 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
5 6 of 9 4
1 0. 3. 4
E x pl or ati ve st atistic al a n al ysis f or p h ar m ac o ge netics a n d bi o m ar kers
T he stati stical a nal ysis of bi o mar ker e n d p o i nts is descri be d u n der secti on 1 0. 3. 2. 2 .
1 0. 3. 5
Ot her a n al yses
All c ollecte d data t hat were n ot defi ne d as e n d p o i nts will be s u m marise d b y descri pt i ve statistics.
1 0. 4
P h ar m ac o ki netic a n d/ or p h ar m ac 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 6 - 4 3 7 8
5 6 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
5 7 of 9 4
1 1
A p pe n dices
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
5 7 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
5 8 of 9 4
A b bre vi ati o ns a n d Tr a de m ar k s
A p pe n di x 1
A D
a vaila ble b ut disc o nti n ue d 
A E
a d verse e ve nt
A L T
ala ni ne a mi n otra nsferase
A N C O V A
a nal ysis of c o varia nce
A S T
as partate a mi n otra nsferase
A T
a vaila ble o n ra n d o mise d treat me nt 
B MI
b o d y mass i n de x
C L A E
cli nical la b orat or y a d verse e ve nt
C o E Q
co ntr ol of eati n g q uesti o n naire 
C R F
case re p ort f or m
D F U
d irecti o n f or use 
D U N
dis pe nsi n g u nit n u m ber
E A C
e ve nt a dj u dicati o n c o m mittee 
E A S
e ve nt a dj u dicati o n s yste m
E C G
electr ocar di o gra m
e G F R
esti mate d gl o mer ular filtrati o n r ate 
F A S
f ull a nal ysis set
F D A
U. S. F o o d a n d Dr u g A d mi nistrati o n
F D A A A
F D A A me n d me nts Act
F P G
fasti n g plas ma gl uc ose
F S H
f ollicle-sti m ulati n g h or m o ne 
G C P
G o o d Cli nical Practice
G L P -1 R A
g l uca g o n-li ke pe pti de-1 rece pt or a g o nist
H b A 1 c
gl ycate d hae m o gl o bi n
H R T
h or m o ne re place me nt t hera p y
hs C R P
hi g h se nsiti ve C -reacti ve pr otei n 
I B
i n vesti gat or’s br oc h ure
I C H
I nter nati o nal C o u ncil f or Har m o nisati o n
I E C
i n de pe n de nt et hics c o m mittee
I M P
i n vesti gati onal me dici nal pr o d uct
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
5 8 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
5 9 of 9 4
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 me
L A O
last a vaila ble o bser vati o n 
L C D 
l o w-cal orie diet 
L D L
l o w-d e nsit y li p o pr otei n
L P L V
last patie nt last visit
L R
l o gistic re gressi o n
M E N 2
m ulti ple e n d ocri ne ne o plasia t y pe 2
M D
missi n g a n d disc o nti n ue d
M M R M
mi xe d m o del f or re peate d meas ure me nts 
M T
missi n g o n ra n d o mise d treat me nt 
M T C
m e d ullar y t h yr oi d ca ncer 
O A D
or al a nti dia betic dr u g
O R
o d ds rati o 
P AI -1
plas mi n o ge n acti vat or i n hi bit or -1 
P C D
pri mar y c o m pleti o n date
R D -MI
m ulti ple i m p utati o n usi n g retrie ve d s u bjects
S A S
safet y a n al ysis set
S A E
seri o us a d verse e ve nt
S A P
statistical a nal ysis pla n
s B P
syst olic bl o o d press ure
s.c.
s u bc uta ne us
S D
sta n dar d de viati o n
S U S A R
s us pecte d u ne x pecte d seri o us a d verse reacti o ns 
T 2 D
t ype 2 dia betes 
T E A E
treat me nt e mer ge nt a d verse e ve nt
T E E
t otal e ner g y e x pe n dit ure 
T M M
trial materials ma n ual
T S H
t h yr oi d sti m ulati n g h or m one 
W C
waist circ u mfere nce
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
5 9 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
6 0 of 9 4
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 6 - 4 3 7 8
6 0 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
6 1 of 9 4
Cli nic al l a b or at or y tests
A p pe n di x 2

T he tests detaile d i n Ta ble 1 1- 1 a n d Ta ble 1 1- 2 will be perf or m e d b y t he ce ntral la b orat or 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 for 
a nal ysis.

A d dit i onal tests ma y be perf or me d at l ocal la b or at or y a n y t i 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 local re g ul at i ons. 

T he l a b orat or y e q uip m e nt m a y pr o vi de a nal yses n ot re q ueste d i n t he pr ot oc ol b ut pr o d uce d 
a ut o mat icall y i n c o n necti o n with t he re q ueste d a nal yse s acc or di n g t o s pecificati ons i n t he 
la b orat or y sta n dar d o perati n g pr oce d ures. S uc h data will n ot be tra nsferre d t o t he trial data base, 
b ut a b n or mal val ues will be re p orte d t o t he i n vest i gat or. 

T he i n vest i gat or m ust re vie w all la b orat or y res ults f or c o nc omit a nt ill nesses a n d A Es.

La b orat or y  sa m ples will be destr o ye d n o later t ha n at fi nalisat i on of t he cli nical trial re p ort. 

F or hae mat ol o g y  sa m ples ( differe ntial c o u nt) w here t he test res ult is n ot n or mal, t he n a part of 
t he sa mple ma y be ke pt f or u p t o t wo years or acc or di n g t o l ocal re g ulat i ons.
T a ble 1 1- 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 

Fasti n g plas ma gl uc ose 1

H b A 1 c

Fasti n g ser u m i ns uli n
Li pi ds

C h olester ol

Hi g h de nsit y li p o pr otei n ( H D L) c h olester ol

L o w de nsit y li p o pr otei n ( L D L) c h olester ol

Tri gl yceri des

Ver y -l o w-de nsit y li p o pr otei n ( V L D L) c h olester ol

Free fatt y aci ds
Bi o mar kers

Ser u m hs C R P
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 yp o gl ycae mic e pis o de b ut as a 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
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
6 1 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
6 2 of 9 4
T a ble 1 1- 2
Pr ot oc ol -re q uire d s afet y l a b or at or y assess me nts
L a b or at or y assess me nts
P ar a meters
Hae mat ol o g y

Bas o p hils

E osi n o p hils

Er y t hr oc yt es

Hae mat ocrit

Hae m o gl o bi n

Le uc oc ytes

L y m p h oc y t es

M o n oc ytes

Ne utr o p hils

T hr o m b oc ytes
Bi oc he mistr y 1

Ala ni ne A mi n otra nsferase ( A L T) 2

Al b u mi n e

Al b u mi ne c orrecte d calci u m

Al kali ne p h os p hatase

A m ylase 3

As partate A mi n otra nsferase ( A S T) 2

Calcit o ni n 3

Creati ne ki nase

Creati ni ne

Li pase 3

P otassi u m

S o di u m

T h y r oi d sti m ulati n g h or m o ne ( T S H) 4

T otal bilir u bi n

Ur ea
Pre g na nc y Testi n g

U ri ne h u ma n c h ori onic g ona d otr o pi n ( h C G) pre g na nc y test (as nee de d f or w o me n of 
c hil d beari n g p ote ntial 5
Ot her tests

e G F R calc ulate d b y t he ce ntral la b orat or y base d o n t he creati ni ne val ue usi n g t he C K D 
E PI e q uati o n as defi ne d b y K DI G O 2 0 1 2 6 7

( Tr yptase i n case of se vere h y perse nsiti vit y, see Secti o n 9. 9 )
N otes :
1Details of re q uire d acti o ns a n d f oll o w -u p assess me nts f or i ncrease d li ver para meters i ncl u di n g a n y disc o nti n uati o n 
criteria are gi ve n i n A p pe n di x 4 ( H y’s La w) a n d Secti o n 8. 1 .
2If A L T or A S T > 3 u p per n or mal li mit ( U N L), a d diti o nal bl o o d sa m ples s h o ul d be ta ke n fr o m t he s u bject t o a nal yse 
i nter nati onal n or malise d rati o (I N R) b y ce ntral la b orat or y (e xce pt at scree ni n g visit). Re peat testi n g of t he a b n or mal la b 
assess me nts s h o ul d be perf or me d f or t he s u bject u ntil a b n or malities ret ur n t o n or mal or baseli ne state. 
3N ot c ollecte d at wee k 8 4 .
4If T S H le vel is o ut of n or mal ra n ge, a d diti o nal testi n g will be perf or me d b y ce ntral la b: t otal a n d free T 3 a n d T 4 e xce pt 
at scree ni n g visit .
5L ocal uri ne testi n g will be sta n dar d u nless ser u m testi n g is re q uire d b y l ocal re g ulati o n or I R B/I E C.

La b orat or y  o utlier: If t he f oll owi n g la b orat or y  para meters are a b o ve/ bel o w t he c ut-off -val ues i n 
Ta ble 1 1- 3 t he y are c o nsi dere d t o be lab orat or y o utliers a n d s h o ul d be re p orte d b y c o mplet i n g a 
la b orat or y o utlier f or m in t he C R F :
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
6 2 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
6 3 of 9 4
T a ble 1 1- 3
Criteri a f or l a b or at or y o utliers
C ut -off
H ae m at ol o g y
Le uc oc ytes
< 1 × 1 0 9/ L
L y m p h oc y t es
< 0. 2 × 1 0 9/ L
T hr o m b oc ytes
< 2 5 × 1 0 9/ L
Bi oc he mistr y
Al b u mi n c orrecte d calci u m
< 1. 5 0 m m ol/ L or > 3. 4 m m ol/ L
Al kali ne p h os p hatase
> 2 0 × U L N
Calcit o ni n
> 1 0 0 n g/ L
Creati ni ne
> 6 × U L N
Creati ne ki nase
> 1 0 × U L N
P otassi u m
< 2. 5 0 m m ol/ L or > 7. 0 m m ol/ L
S o di u m
< 1 2 0 m m ol/ L or > 1 6 0 m m ol/ L
He pati c la b orat or y o utlier: if t he f o ll owi n g he patic la b orat or y para meters are a b o ve t he c ut -offs
val ues i n Ta ble 1 1- 4 , it is c o nsi dere d t o be a he pat ic lab orat or y o utlier a n d s h o uld be re p orte d b y  
c o mplet i n g a he patic e ve nt f or m i n t he C R F. It is at t he i n vestigat or’s discret i on t o deter mi ne 
w het her it s h o ul d als o be re p orte d as a n a d verse e ve nt ( A p pe n di x 4 ).
T a ble 1 1- 4
Criteri a f or he p atic l a b or at or y o utliers
C ut -off
Al kali ne p h os p hatase
> 2 0 x U N L
A L T
> 5 x U N L
A S T
> 5 x U N L
T ot al  bilir u bi n
> 1 0 x U N L
Please n ote t hat i n case of a he patic e ve nt defi ne d as A L T or A S T > 3 x U N L a n d t otal bilir u bi n > 2 x U N L, w h ere n o 
alter nati ve aeti ol o g y e xists ( H y's la w), t his m ust be re p orte d as a n S A E usi n g t he i m p orta nt me dical e ve nt criteri o n if n o 
ot her seri o us ness criteria are a p plica ble
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
6 3 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
6 4 of 9 4
Tri al g o ver n a nce c o nsi der ati o ns
A p pe n di x 3
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 with t he pr ot oc ol a n d wit h t he f o ll owi n g:
1.
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
7 6a n d a p plica ble I C H G o o d Cli nical Pract ice ( G C P) 
G ui deli ne 7 7
2.
A p plica ble la ws a n d re g ulati o ns

T he pr ot oc ol, i nf or me d c o nse nt f or m, I B (as a p plica ble) a n d ot her rele va nt d oc u me nts (e. g. 
a d vert ise 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 nit iate d.

Re g ulat or y  a ut h orities will recei ve t he cli nical trial a p plicat i on, pr ot oc ol a me 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 nat i onal re q uire me nts.

A n y a me n d me nts t o t he pr ot oc ol will re q uire I R B/I E C a p pr o val bef ore i m ple me ntati o n of 
c ha n ges ma de t o t he trial desi g n, e xce pt f or c ha n ges necessar 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 tri al sit e is allo 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 vest i gat or will be res p o nsi ble f or:
1.
pr o vidi n g wri tte n s u m maries of t he stat us of t he trial a n n uall y or m ore fre q ue 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
2.
n otif yi n g t he I R B/I E C of S A Es or ot her si g nifica nt safet y fi n di n gs as re q uire d b y 
I R B/I E C pr oce d ures
3.
pr o vidi n g o versi g ht of t he c o n d uct of t he trial at t he site a n d a d here nce t o 
re q uire me nts of  I C H g ui deli nes, t he I R B/I E C, a n d all ot her a p plica ble l ocal 
re g ulat i ons
4.
e ns uri n g s u b missi o n of t he cli nical trial re p ort s y n o psis t o t he I R B/I E C.
2) Fi n a nc i al discl os ure
I n vesti 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 ncial 
i nf or mat i on as re q ueste d t o all o w N o v o N or dis k t o s u b mit c o m plete a n d acc urate fi na ncial 
certificati o n or discl os ure state me nts t o t he a p pr o pria te re g ulat or y a ut h orities. I n vestigat ors are 
res p o nsi ble f or pr o vi di n g i nf or mati on o n fi na ncial i nterests d uri n g t he c o urse of t he trial a n d o ne 
year after c o m plet i on of t he trial.
F or U S tri al sites: verific ati o n u n der discl os ures per C o de of Fe der al Re g u l ati o ns ( C F R) of 
Fi n a nci al C o nflict of I nterest.
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
6 4 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
6 5 of 9 4
3) I nf or me d c o nse nt pr ocess

T he i n vest i gat or or his/ her re prese ntati ve will e x plai n t he nat ure of t he trial t o t he s u bject a n d 
a ns wer all q uest i ons re gar di n g t he trial.

T he i n vest i gat or m ust e ns ure t he s u bje ct a mple t i 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 me nt of i nf or me d c o nse nt t hat meets t he 
re q uire me nts of l ocal re g ulati ons, I C H g ui deli nes 7 7, Decl aratio n of  Helsi n ki 7 6 a n d t he I R B/I E C 
or trial sit e.

T he m e dical rec or d must i ncl u de a state m e nt t hat writte n i nf or me d c o nse nt was o btai ne d bef ore 
a n y trial relate d acti vit y a n d t he date w he n t he writte n c o nse nt was o btai ne d. T he a ut h orise d 
pers o n o btai ni n g t he i nf or me d c o nse nt m ust als o si g n a n d date t he i nf or me d c o nse nt f or m bef ore 
a n y trial relate d acti vit y.

T he res p o nsi bilit y of see ki n g i nf or me d c o nse nt m ust re mai n with t he i n vesti gat or, b ut t he 
i n vesti gat or ma y dele gate t he tas k of i nf or mi n g t o a me dicall y q ualifie d pers o n, i n acc or da nce 
wi t h lo c al r e q uire me nts.

S u bjects m ust be re -c o nse 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 partici pat i on 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) must 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 nicat i on pac ka ge f or t he s u bject d uri n g t he c o n d uct of t he trial. 
T he pac ka ge c o nte nt is iss ue d b y N o v o N or dis k. T he c o m m u nicat i on pac ka ge will c o ntai n writte n 
i nf or mat i on 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 mat i on will be tra nslate d a n d 
a djuste d t o l o c al r e q uire me nts a n d distri b ute d t o t he s u bject at t he discreti on of t he i n vest i gat or. 
All writte n i nf or mat i on 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 on acc or di n g t o l ocal re g ulat i ons.
Differe nt i nit iati ves f or s u bject rete nti o n will be i m ple me nte d t hr o u g h o ut t his trial. Site rete nti o n 
acti vit ies ma y i ncl u de c o o ki n g classes, gr o u p m eeti n gs, a n d ot hers. Materials a n d it e ms will be 
s u p plie d if l ocall y acce pta ble. T he rete nti o n ite ms will be rele va nt f or t he s u bjects’ partici pat i on i n 
t he trial a n d/ or t heir o besit y a n d will n ot e xcee d l ocal fair mar ket val ue.
T he i nit iati ves f or s u bjects must 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 on acc or di n g t o l ocal re g ulat i ons.
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
6 5 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
6 6 of 9 4
5) D at a pr otecti o n

S u bjects will be assi g ne d a 6 -digit u ni q ue ide 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 nt ifier o nl y; s u bject na mes or 
a n y i nf or mat i on w hic h w o ul d ma ke t he s u bject i de nt ifia ble will n ot be tra nsferre d.

T he s u bject a n d a n y bi o l ogical mat erial o btai ne d fr o m t he s u bject will b e ide nt ifie 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 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 nt ity of s u bjects as re q uire d b y lo c al, 
r e gio nal a n d nati onal 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 data will be use d b y N o v o 
N or di s k i n acc or da nce wit h l ocal data pr otecti o n la w. T he discl os ure of t he data m ust als o be 
e x plai ne d t o t he s u bject. 

T he s u bject m ust be i nf or me d t hat his/ her me dical rec or ds ma y be e xa mi ne d b y a u dit ors or 
ot her a ut h orise d pers o n nel a p p o i nte d b y N o v o N or dis k, b y a p pr o priate I R B/I E C me m bers, a n d 
b y i ns pect ors fr o m re g ulat or y a ut h orities.
6) C o m mittee str uct ure
N o v o N or dis k s afet y c o m mittee
N o v o N or d is k will c o nstitute a n i nter nal S e ma gl ut i de s.c. safety c o m mittee t o perf or m o n g oi n g 
safety s ur veilla nce. T he Se ma gl uti d e s.c. safety c o m mittee ma y rec o m me n d u n bli n di n g of a n y data 
f or furt her a nal ysis, a n d i n t his case a n i n de pe n de nt a d h oc gr o u p will be esta blis he d i n or der t o 
mai ntai n t he bli n di n g of t he trial pers o n nel.
E ve nt a dj u dic ati o n c o m mittee
A n i n de pe n de nt e xter nal E A C is esta blis he d t o perf or m o n g oi n g bli n de d a dj u dicati on of selecte d 
t yp es 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 ve nts se nt f or 
a dju dicat i on usi n g pre- defi ne d defi nit i ons a n d g ui deli nes i n acc or da nce wit h t he E A C C harter. T he 
e val uat i on is base d o n re vie w o f pre -defi ne d cli nical data c ollecte d b y t he trial sites. 
T he E A C is c o m p ose d of per ma ne nt me m bers c o veri n g all re q uire d me dical s pecialit ies. E A C 
me m bers m u st 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 di s 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  b ot h t he E A C a n d t he i n vesti gat or will be prese nte d i n t he cli nical trial 
re p ort. 
I n t his trial, car dio vasc ular e ve nts will be a dj u dicate d i n or der t o a de q uatel y  c haracterize t he 
car dio vasc ular safet y pr ofile , si nce car dio vasc ular di sease is a n i m p orta nt a n d seri o us c o m or bi dity 
of o besit y7 8. I n a d diti on, e ve nts of ac ute pa ncreatit is will be a dj u dicate d beca use N o v o N or dis k 
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
6 6 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
6 7 of 9 4
m o nit ors t hese e ve nts cl osel y as treat me nt wit h G L P-1 R A s has bee n ass ociate d wit h ac ute 
pa ncreat itis. 
7) P u blic ati o n p olic y
T he i nf o r mat i on 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 nt ial, 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 well 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 mat i on s u p plie d b y N o v o N or dis k i n c o n nect i on wit h t his 
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 mat i on.
N o c o nfi de nt ial i nf or mati on 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 di s k. S uc h i nf or mati on s hall n ot be use d e xce pt i n t he perf or ma nce of t his trial.
T he i nf or mat i on 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 vest i gat ors w h o are 
c o n d ucti n g ot her cli nical trials wit h t he trial pr o d uct, if dee me d necessar y  b y N o v o N or dis k. 
Pr o vi de d t hat cer tai n c o n diti ons are f ulfille d, N o v o N or dis k ma y gra nt access t o i nf or mati o n 
o btai ne d d uri n g t his trial t o researc hers w h o re q uire access f or researc h pr ojects st u d yi n g t he sa me 
disease a n d/ or trial pr o d uct st u die d i n t his trial.
N o v o N or dis k ma y p u blis h o n its cli nical trials we bsite a re dacte d cli nic al tri al re p ort f or t his trial.
O ne ( or t w o) i n vesti gat or(s) will be a p p o i 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 in vesti gat or) o n be half o f all partici pat i n g i n vesti gat ors. T he si g nat or y 
i n vesti gat or(s) will be a p p oi nte d base d u p o n t he criteria defi ne d b y t he I nter nati onal C o m mittee of 
Me dical J o ur nal E dit ors f or researc h p u blicat i ons 7 9 .
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 o se res ults of trials re gar dless o f o utc o me. 
Di s clos ure i ncl u des p u blicati o n of a ma n uscri pt i n a peer -re vie we d scie ntific j our nal, a bstract 
s u b missi on wit h a p oster or oral prese ntatio n at a sci e nt ific 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 nat i onal a n d nat i onal re g ulat i ons. N o v o N or dis k reser ves t he ri g ht t o defer t he release of data 
u nt il s pecifie d milest o nes are reac he d, f or e xa m ple w he n t he cli nical trial re p ort is a vaila ble. T his 
i ncl u des t he ri ght  n ot t o release t he res ults of i nteri m a nal yses, beca use t he release of s uc h 
i nf or mat i on ma y i nfl ue nce t he res ults of t he e ntire trial.
At  t he e n d of t he trial, o ne or m ore scie ntific p u blicati o ns ma y be 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 nicat i on f or u p t o 6 0 da ys t o pr otect i ntellect ual pr o pert y.
I n all cases t he trial res ults will be re p orte d i n a n o bjecti ve, acc urate, bala nce d a n d c om p lete 
ma n ner, wit h a disc ussi on of t he stre n gt hs a n d li mitati o ns. I n t he e ve nt of a n y disa gree me nt o n t he 
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
6 7 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
6 8 of 9 4
c o nte nt of a n y p u blicati o n, b ot h t he i n vest i gat ors’ a n d N o v o N or dis k o pi ni ons will be fairl y a n d 
s ufficie ntl y re prese nte d i n t he p u blicati on.
A ut h ors hi p
N o v o N or dis k wi ll w or k wi t h o ne or more i n vesti gat or(s) a n d ot her 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 uisit i on, a nal ysis or i nter pretati o n of data t o re p ort t he res ults i n o ne 
or more p u blicati o ns.
A ut h ors hi p of p u blicat i ons s h o ul d be i n acc or da nce wi t h t he Rec o m me n dati ons f or t he C o n d uct, 
Re p orti n g, E dit i n g a n d P u blicati on of Sc h o larl y W or k i n Me dical J o ur nals b y t he I nter nati o nal 
C o m mittee of Me dical J o ur nal E dit or s 7 9.
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 de d t o 
e va l uate t he pla n ne d p u blicati on. 
W here re q uire d b y  t h e jo ur n al, t he i n vestig at or f r o m e ac 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 erial, as s pecifie d b y t h e jo 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 ultic e ntre cli nical trial, a nal yses base d o n si n gle -site data us uall y ha v e sig nifica nt stati stical 
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 mati o n f or healthcare pr ofessi o nals or 
s u bjects, a n d t heref ore ma y not be s u p p orte d b y  N o v o N or disk. T h us, N o v o N or dis k ma y  de n y a 
re q uest or as k f or defer me nt of t he p u blicati on of i n di vi d ual site res ults u nt il t he pri mar y ma n uscri pt 
is acce pte d f or p u blicati on. I n li ne wit h G o o d P u blicat i on Practice, s uc h i n di vi d ual re p orts s h o ul d 
n ot prece de t he pri mar y ma n uscri pt a n d s h o ul d al wa ys refere nce t he pri mar y  ma n uscript 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 he trial data base, N o v o N or dis k has t he discret i on t o deter mi ne 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 s u bjects' data, a n d will be pr o vi de d with t he 
ra n d omisat i on c o de after res ults are a vaila ble.
8) Disse mi n ati o n of cli nic al tri al d at a
I nf or mat i on of t he trial will be discl o se 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 o se d acc or di n g t o ot her a p plica ble re q uire me nts s uc h as t h ose of t he I nter nati o nal 
C o m mittee of Me dical J o ur nal E dit ors ( I C MJ E)8 0, t he F o o d a n d Dr u g A d mi nistrati o n A me n d me nt 
Act ( F D A A A) 8 1, E ur o pea n C o m missi o n Re q uire me nts 1, 8 2 a n d ot her rel e va nt rec o m me n dat i ons or 
re g ulat i ons. If a s u bject re 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 -ma il 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 increasi n g re q uire me nts f or tra ns pare nc y, s o me c o u ntries re q uire p u blic discl os ure of 
i n vesti gat or na mes a n d t heir affiliati ons.
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
6 8 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
6 9 of 9 4
T he Pri mar y  C o mplet i on Date ( P C D) is t he last assess me nt of t he pri mar y e n d p o i nt, a n d is f or t his 
trial Last S u bje ct First Treat me nt ( L S F T) + 1 0 4 wee ks c orres p o n di n g t o V 3 3 (‘e n d of treat m e nt ’
visit ). If t h e last s u bject is wit hdra w n earl y, t he P C D is c o ns i dere d t he date w he n t he last s u bject 
w o ul d ha ve c o m plete d V 3 3 ( ‘en d of treat m e nt ’ visit ). T he P C D deter mi nes t he dea dli ne f or res ults 
dis clos ure at cli nicaltrials. g o v acc or di n g t o F D A A A.
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 desig nee is res p o nsi ble f or t he data ma na ge me nt of t his trial i ncl u di n g q ualit y 
c hec ki n g o f t he data.

All s u bject data relati n g t o t he trial will be rec or de d o n electr o nic C R Fs u nless tra ns mitte d 
electr o nicall y t o N o v o N or dis k or desi g nee (e. g. la b orat or y data). T he i n vesti gat or is res p o nsi ble 
f or verif yi n g t hat data e ntries are acc urate a n d c orrect b y p h ysicall y or electr o nicall y si g ni n g t he 
C R F. 

F or s o me data b ot h electr o nic a n d pa per C R F s are use d .

T he f o ll owi n g will be pr o vi de d as pa per C R Fs:
1.
Pre g na nc y f or ms

T he f o ll owi 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 ele ctr o nic C R F is 
re v o ke d or te m p oraril y u na vaila ble: 
1.
A E f or ms 
2.
S af et y i nf or mati on f or ms
3.
Tec h nical c o m p lai 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
r elate d, e. g. disc o vere d at trial site bef ore all ocatio n)

C orrecti o ns t o t he C R F data ma y  be ma de b y t he i n vesti gat or or t he i n vest i 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 plicat i on c o ntai ni n g as a mi ni m u m: t he ol d 
a n d t he ne w data, i de nt ificati on of t he pers o n e nteri n g t he data, date a n d ti me of t he e ntr y  a n d 
reas o n f or t he c orrecti o n. If c orrecti o ns are ma de b y t he i n vestigat or’s del e gate d staff after t he 
date w he n t he i n vesti gat or si g ne d t he C R F, t he C R F m ust be si g ne d a n d date d a gai n b y  t he 
i n vesti gat or.

T he i n vest i 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 
wi t 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 di s k f or data verificati on a n d vali dat i on p ur p oses.
M o nit ori n g

T he i n vest i gat or m ust per mit trial-relate d mo nit ori n g, a u dits, I R B/I E C re vie w, a n d re g ulat or y 
a ge nc y ins pect i ons a n d pr o vi de direct access t o s o urce data d oc u me nts ( ori gi nal d oc u me nts, 
data a n d rec or ds). Direct access i n cl u des per missi o n t o e xa mi ne, a nal yse, verif y a n d re pr o d uce 
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
6 9 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
7 0 of 9 4
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 uat i on of t he trial. If t he electr o nic 
me dical rec or d d oes n ot ha ve a visi ble a u dit trail, t he i n vest i gat or m ust pr o vi de t he m o nit or wit h 
sig ne d a n d date d pri nt o uts. I n a d dit i on t he rele va nt trial site staff s h o uld be a vaila ble f or 
disc ussi ons at mo nit ori n g visits a n d bet wee n mo nit orin g visit s (e. g. b y t ele p h o ne). 

Tri al mo nit ors will p erfor 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 orise d site pers o n nel are acc urate, c o m plete a n d verifia ble fr o m s o urce 
d oc u me nts; t hat t he safet y a n d rig hts of  s u bjects are bei n g pr otecte d, t o m o nit or dr u g 
acc o u nta bilit y a n d c ollect c o m plete d pa per C R F pa ges, if a p plica ble, a n d t hat t he trial is bei n g 
c o n d ucte d i n acc or da nce wit h t he c urre nt l 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 ble re g ulat or y r e q uire me nts.

M o ni t 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 ncl u di n g ris k assess me nt, m o nit ori n g 
pla ns, ce ntralise 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 ni t ors will re vie w t he s u bject’s me dical rec or ds a n d ot her s o urce data e. g. t he diaries a n d 
me ntal  healt h assess me nt i nstr u me nts, t o ens ure c o nsiste nc y a n d/ or i de nt if y omissi o ns 
c o mpare d t o t he C R F. 
Pr ot oc ol c o m pli a nce
De viat i ons fr o m  t he pr ot oc ol s h o uld be a v o i de d. If de viati ons d o occ ur, t he i n vest i gat or m ust 
i nf or m t h e mo nit or wit h o ut dela y a n d t he i m plicat i o ns of t he de viati on m u st be re vie we d a n d 
disc usse d.
De viat i ons must be d oc u m e nte d a n d e x plai ne d i n a pr ot oc ol de viat i on b y stati n g t he reas o n, date, 
a n d t he acti o n(s) ta ke n. S o me de viat i ons, f or w hic h c orrecti o ns are n ot p ossi ble, ca n be 
ac k n o wle d ge d a n d c o nfir me d via e dit c hec ks i n t he C R F or via listi n gs fr om 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 me ntati o n ot her t ha n t he C R F.

T he ori gi nal of t he c o mplete d diaries must n ot be re m o ve d fr o m  t h e 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 sit e. F or f o o d a n d p h ysical acti vit y diar y , if t he s u bject 
uses a n a p p or a t o ol ot her t ha n t he pa per diaries, t he me dical rec or d or dieticia n’s n otes fr om 
t he diet a n d p h ysical act i vity c o u nselli n g ca n be use d as s o urce d oc u me nt.

S o urce d oc u me nts pr o vi de e vi de nce f or t he e xiste nce of t he s u bject a n d s u bsta nt iate t he 
i nte grit y of t he data c ollecte d. S o urce d oc u me nts are file d at t he trial site.

Data re p orte d in t he C R F t hat are tra nscri be d fr om s o urce d oc u me nts m ust be c o nsiste nt wit h 
t he s o urce d oc u me nts or t he discre pa ncies m ust be e x plai ne d. T he i n vesti gat or ma y nee d t o 
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
7 0 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
7 1 of 9 4
re q uest pre vi o us me dical rec or ds or tra nsfer rec or ds. Als o, c urre nt me dical rec or ds m ust be 
a vaila ble. 

It must be p ossi ble t o verif y  s u bject’s me dical hist or y i n t he s o urce d oc u me nts s uc h as s u bject’s 
me dical rec or d .

S u bjects c o m plet i n g electr o nic patient  re p orte d o utc o me i nstr u me nts are t he data ori gi nat ors. 
Data will be tra ns mitte d t o a tec h n ol o g y  ser vice pr o vider data base, t h us t he ser vice pr o vi der 
data base is t he s o urce.

T he i n vest i gat or m ust d oc u me nt a n y atte m pt t o o btai n e xter nal me dical i nf or mati on b y n oti n g 
t he date(s) w he n i nf or mat i on was re q ueste d a n d w h o was c o ntacte d.

Defi nit i on o f w hat c o nstit ut es s o urce data ca n be f o u n d i n a s o urce d oc u me nt  a gree me nt at eac h 
trial sit e. T here will o nl y be o ne s o urce d oc u me nt defi ne d at a n y ti me f or a n y data ele me nt.
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 oc u me nts, i ncl u di n g si g ne 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 he i n vesti gat or f or 1 5 years after e n d of trial u nless l ocal 
re g ulat i ons or i nst itutio nal p olicies re q uir e a lo n ger rete nti o n peri o d. N o rec or ds m a y be 
destr o ye d d uri n g t he rete nti o n perio d wit ho ut t he wri tte 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 ho ut writte n n otificati on t o N o v o N or dis k. 

T he i n vest i 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 data will be pr o vi de d i n a n 
ele ctr o nic rea da ble f or mat t o t he i n vesti gat or bef ore access is re v o ke d t o t he s yst e ms a n d/ or 
electr o nic de vices s u p plie d b y N o v o N or dis k. Sit e-s pecific C R Fs a n d ot her s u bject data (i n a n 
electr o nic rea da ble f or mat 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 vide d ele ctr o nic data (e. g. t he C D -R O M) is n ot rea da ble d uri n g t he e ntire st ora ge peri o d, t he 
i n vesti gat or ca n re q uest a ne 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 pital, 
i nstitutio 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 ose t he trial site or t er mi nate t he trial at a n y time f or a n y 
reas o n at t he s ole discreti o n of N o v o N or dis k. If t he trial is s us pe n de d or ter mi nate d, t he 
i n vesti gat or m ust i nf or m t he s u bjects pr o m ptl y a n d e ns ure a p pr o priate t hera p y a n d fol l ow- u p. T he 
i n vesti gat or a n d/ or N o v o N or dis k m ust als o pr o mptl y infor 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.
Tri al sites will be clos e d u p o n trial c o mplet i on. A tri al sit e is c o nsidere 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 o llecte d a n d a trial site cl os ure visit has bee n perf or me d.
T he i n vest i gat or ma y i nitiate trial sit e clos ure at a n y time, pr o vi de d t here i s reas o na ble ca use a n d 
s ufficie nt n otice is gi ve n i n a d va nce o f t he i nte n de d ter mi nat i on.
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
7 1 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
7 2 of 9 4
Reas o ns f or t he earl y cl o s ure of a trial sit e b y N o v o N or dis k or i n vesti gat or ma y i ncl u de b ut are n ot 
li mite d t o:

fail ure of t he i n vesti gat or t o c o m pl y with t he pr ot oc ol, t he re q uire me nts of t he I R B/I E C or l ocal 
healt h a ut h orit ies, 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 on 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 vest i 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 uate 
s u per visi on of t he c o n d uct of t he trial at t he trial sit e. If a n y tas ks are dele gate d, t he i n vesti gat or 
m ust m ai ntai n a l o g of a p pr o priatel y q ualifie d pers o ns t o w h o m he/s he has dele gate d s pecifie d trial-
r elate d d uties. T he i n vestig at or m ust e ns ure t hat t here is a de q uate a n d d oc u me nte d trai ni n g f or all 
staff partici pati 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 bility t o s u per vise t he 
c o n d uct of t he trial a n d t o pr otect t he ri g hts, safet y,  a n d well-bei n g of t he s u bjects. 
A q ualifie d p h ysicia n, w h o is a n i n vest i gat or or a s u b-i n vesti gat or f or t he trial, m ust be res p o nsi ble 
f or all trial -relate d me dical decisi o ns. 
T he i n vest i gat or is res p o nsi ble f or fili n g esse ntial d oc u me nts (i.e. t h ose d oc u me nts w hic h 
i n di vi d uall y a n d c ollecti vel y per mit e val uati on of t he c o n d uct o f a trial a n d t he q uality o f t he data 
pr o d uce d) i n t he i n vesti gat or trial master file. T he d oc u me nts, i ncl u di n g t he s u bject i de ntificat i on 
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 onal safety meas ures t o
pre ve nt 
accid e nt al or wr o n gf ul destr ucti o n, l oss or deteri orati o n of data. T he i n vesti gat or will pre ve nt a n y 
u na ut h ori se 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 vest i gat or 
m ust be a ble t o pr o vi de t he necessar y  infor mat i on or ot her wise de m o nstrate t o N o v o N or dis k t hat 
s uc h tec h nical a n d or ga nisati onal safety me as 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 in vest i 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 ualifie d p h ysicia n w h o will be rea dil y a vaila ble t o s u bjects d uri n g t hat 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 oves or retire s) a 
ne w i n vest i gat or will be a p p oi nte d i n c o ns ultati on wit h N o v o N or dis k. 
T he i n vest i gat or a n d ot her site pers o n nel m ust ha ve s ufficie nt E n glis h s kills acc or di n g t o t heir 
assi g ne d tas 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 for its pr o d ucts, a n d lia bility as ass u me d u n der t he s pecial 
la ws, acts a n d/ or g ui deli nes f or c o n d ucti n g cli nical trials i n a n y c o u ntr y, u nless ot hers ha ve s h o w n 
ne gli ge nce. 
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
7 2 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
7 3 of 9 4
N o v o N or dis k ass u mes n o lia bilit y i n t he e ve nt of ne gli ge nce or a n y ot her lia bility of t he sites or 
i n vesti gat ors c o n d ucti n g t he trial or b y pers o ns f or w h o m t he site or i n vestigat or are res p o nsi ble. 
N o v o N or dis k ma y pa y a d dit i onal c osts i nc urre d i n relat i on t o assess me nts rele va nt f or f o ll owi n g 
t he safet y of t he s u bject. I n vesti gat or m ust c o ntact N o v o N or dis k o n a case b y case basis f or 
w het her t he c osts will be c o vere d.
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
7 3 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
7 4 of 9 4
A d verse e ve nts: defi niti o ns a n d pr oce d ures f or 
A p pe n di x 4
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 bject 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 bn 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 ncrease 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 nical 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 nical 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 ure of e x pecte d p har mac ol o gical acti o n" per se will n ot be re p orte d as a n A E or S A E. 
S uc h i nsta nces will be ca pt ure d i n t he efficac y assess me n ts. H o we ver, t he si g ns, s y m pt o ms a n d/ or cli nical se q uelae 
res ulti n g fr o m lac k of efficac 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 

Pr e -e xisti n g c o n diti o ns, a ntici pate d da y-t o-d a y fl uct uati o ns of pr e-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.

Pr e -pla n ne d pr oce d ures, u nle ss 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 bject 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 bject 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 use 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 bject 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 pi talisati on” occ urre 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 ba seli 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 nistrati ve, trial relat e 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 
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
7 4 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
7 6 of 9 4
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), t his 
m ust be re p orte d as a n S A E usi n g t he i m p orta nt me dical e ve nt criteri o n if 
n o ot her seri o us ness criteria are a p plica ble.
Me dicati 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 dis pe nsi n g u nit n u m ber ( 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 us c ular i nstea d of 
s u bc uta ne o us. 

Acci de ntal a d mi nistrati o n of m ore t ha n 2. 4 m g/ wee k or a hi g her d ose 
t ha n i nte n de d d uri n g d ose escalati o n, h o we ver, t he a d mi nistere d d ose 
m ust de viate fr o m t he i nte n de d d ose t o a n e xte nt w here cli nical 
c o nse q ue nces f or t he trial s u bject 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.
Mis use or a b use of trial
pr o d uct *

Mis use is w he n t he trial pr o d uct is i nte nti o nall y a n d i na p pr o priatel y 
use d. A b use of  trial pr o d uct is persiste nt or s p ora dic, i nte nti o nal 
e xcessi ve use, w hic h is acc o m pa nie d b y har mf ul p h ysical or 
ps yc h ol o gical effects (e. g. o ver d ose wit h t he i nte nti o n t o ca use har m).
* A d diti o nal data f or Mis use or a b use of trial pr o d uct is re p orte d o n t he me dicati o n err or e ve nt f or m.
E ve nts f or a dj u dic ati o n
E ve nt t y pe
Descri pti o n
A dj u dic ati o n o utc o me
Deat h
All- ca use deat h

Car di o vasc ular deat h 
(i ncl u di n g u n deter mi ne d 
ca use of deat h)

N o n -Car di o vasc ular deat h
Ac ute C or o nar y S y n dr o me
Ac ute C or o nar y S y n dr o me c o n diti o ns 
i ncl u de all t y pes of ac ute m y ocar dial 
i nfarcti o n a n d h os pitalisati o n f or 
u nsta ble a n gi na pect oris

Ac ute m y ocar dial i nfarcti o n 
(i ncl u di n g s u b gr o u p 
classificati o ns)

H os pitalisati o n f or u nsta ble 
a n gi na pect oris
Cere br o vasc ular e ve nts
E pis o de of f ocal or gl o bal ne ur ol o gical 
d ysf u ncti o n t hat c o ul d be ca use d b y 
br ai n, s pi nal c or d, o r reti nal vasc ular 
i nj ur y as a res ult of hae m orr ha ge or 
i nfarcti o n

Isc hae mic str o ke

Hae m orr ha gic str o ke

U n deter mi ne d str o ke

Tra nsie nt Isc hae mic Attac k
C or o nar y arter y 
re vasc ularisati o n
C or o nar y re vasc ularisati o n p r oce d ure 
is a cat heter-base d (P CI) or a s ur gical 
pr oce d ure ( C A B G) desi g ne d t o 
i m pr o ve m y ocar dial bl o o d fl o w

C or o nar y  re vasc ularisati o n
pr oce d ure
Heart fail ure
Prese ntati o n of t he patie nt f or a n 
ur g e nt, u nsc he d ule d 
cli nic/ office/e mer ge nc y de part me nt
visit or h os pital a d missi o n, wit h a 
pri mar y dia g n osis of heart fail ure ( ne w 
e pis o de or w orseni n g of e xisti n g heart 
fail ure)

Heart fail ure h os pitalisati o n

Ur ge nt heart fail ure visit
Ac ute pa ncreatitis
T he dia g n osis of ac ute pa ncreatitis 
re q uires t w o of t he f oll o wi n g t hree 

Ac ute pa ncreatitis
Mil d
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
7 6 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
7 7 of 9 4
feat ures:
( 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 
persiste 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 acti vit y (a n d/ or 
a m ylase acti vit y) 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
M o deratel y se vere
Se vere
A E a n d S A E rec or 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.

T here ma y be i nsta nces w he n c o pies of s o urce d oc u me nts (e. g. me dical rec or ds) f or certai n cases are re q ueste d b y 
N o v o N or dis k. I n s uc h cases, all s u bject i de ntif iers, wit h t he e xce pti o n of t he s u bject n u m ber, will be re dacte d o n t he 
c o pies of t he s o urce d oc u me nts bef ore s u b missi o n t o N o v o N or dis k.

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 orta nt t hat t he s us pecte d 
relati onshi 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 E t o rele va nt re g ulat ory a ut h orities.
Assess me nt of se verit 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 bject, 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 uses s ufficie nt disc o mf ort a n d i nterferes wit h n or mal e ver y 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. 
N ote: Se vere is a cate g or y use d f or rati n g t he i nte n sit 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 wee n trial pr o d uct a n d t he occ urre 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 n li kel y - T he e ve nt is m ost li kel y relate d t o aeti ol o g y ot her t ha n t he trial pr o d uct.
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
7 7 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
7 8 of 9 4
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 B 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 he 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 port 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 ver y 
e ve 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.
Fi n al o utc o me
T he i n vesti gat or will select t he m ost a p pr o priate o utc o me:

Rec o vere d/res ol ve d: T he s u bject 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 bject 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 bject 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 bject 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 bject 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 bject 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 a l: T his ter m is o nl y a p plica ble if t he s u bject 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 bject bef 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 bject 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
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 usalit 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 bject dies d uri n g partici pati o n i n t he trial or d uri n g a rec o g nise d f oll o w-u p peri o d, t he i n vesti ga t or sh 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 be 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 ma ti 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 pa per 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 S ecti o n 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 
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
7 8 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
7 9 of 9 4
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 bject 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 Fi g ure 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 be 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 or trial master file.
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
7 9 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
8 0 of 9 4
C o ntr ace pti ve g ui d a nce a n d c ollecti o n of pre g n a nc y 
A p pe n di x 5
i nf or m ati o n
It must be rec or de d i n t he C R F w het her fe male 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 owi n g me narc he a n d u nt il bec o mi n g p ost me n o pa usal u nless 
p er ma ne nt l y sterile. 
W o me n i n t he f oll o wi n g c ate g ories are n ot c o nsi dere d W O C B P
1.
Pr e m e narc heal 
2.
Pr e m e n o pa usal fe male wit h o ne of t he f oll o wi n g:

D oc u m e nte d h ysterect o m y

D oc u m e nte d bilateral sal pi n gect o m y

D oc u m e 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 xa mi nat i on or me dical hist or y  int er vie w.
3.
P os t me n o pa usal fe male

A p ost m e n o pa usal state is defi ne d as n o me nses f or 1 2 m o nt hs wit h o ut a n alter nati ve 
me dical ca use. A hi g h F ollicle St i m ulati n g H or m o ne ( F S H) le vel i n t he p ost me n o pa usal 
ra n ge ma y be use d t o c o nfir m a p ost me n o pa usal state 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 nal Re place me nt T hera p y ( H R T). H o we ver, 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 mo nal hi g hl y effe ct i ve c o ntrace pti o n met 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 trial. Ot her wise, t he y  must disc o nti n ue H R T t o all o w c o nfir mat i on 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 ures are re q uir e d for male s u bjects as t he ris k of terat o ge nicity/ fet ot o xicit y 
ca use d b y tra nsfer of se ma 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 use met h o ds of 
c o ntrace ptio n c o nsiste ntl y a n d c orrectl y as descri be d i n ta ble(s) bel o w:
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
8 0 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
8 1 of 9 4
T a ble 1 1- 5  
H i 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 year whe 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

or al 

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

or al 

i njecta 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 ociate 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 h l 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 urati 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 bject.
N otes:
a T y pical use fail 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 d of c o ntrace pti ve met h o ds f or s u bjects 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 4 9 da ys after t he las t d ose of trial pr o d uct.
I n certai n cases, it is acce pte d t o use d o u ble barrier met h o ds (a c o n d o m c o m bi ne d with a n occl usi ve 
ca p (e. g. dia 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 males 
wi t h:
1) k n o w n i nt olera nce t o t he hi g hl y effect i ve met h o ds m e nt i one d i n Ta ble 1 1- 5 -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 u res are c o ntrai 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 nit iati n g treat me nt wit h a s pecific hi g hl y effecti ve met h o d o ut wei g hs t he be nefit f or 
t he fe male.
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
8 1 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
8 2 of 9 4
J ustificati o n f or acce pti n g d o u ble barrier met h o d s h o ul d be at t he discreti o n of t he i n vest i gat or 
ta ki n g i nt o c o nsi derati on his/ hers k n o wle d ge a b o ut t he fe male’s o besit y hist or y, c o nc o mit a nt 
ill ness, c o nc o mita nt me dicati o n a n d o bser ve d A Es. T he j ustificati on m ust be state d i n t he me dical 
rec or ds.
Pre g n a nc y testi n g

W O C B P s h o ul d o nl y be i ncl u de d after a ne gat i ve hi g hl y se nsiti ve uri ne pre g na nc y test.

Uri ne pre g na nc y  testi n g s h o uld be perf or me d at e ver y site visit (e ver y 4- 8 wee ks) d uri n g t he 
treat me nt perio d, at e n d of treat me nt a n d after t he 7 wee ks off -dr u g f ol l ow- u p peri o d acc or di n g 
t o t he fl o w c hart.

A d dit i onal uri ne pre g na nc y test i n g s h o ul d be perf or me d at m o nt hl y i nter vals d uri n g t he 
treat me nt perio d, if re q uire d l ocall y (A p pe n di x 5 ).

Pre g na nc y testi n g s h o ul d be perf or me d w he ne ver a me nstr ual c ycle 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 vesti gat or will c ollect pre g na nc y i nf or mati on o n a n y f e male s u bject, w h o bec o mes pre g na nt 
w hile partici pat i n g i n t his trial.

I nf or mat i on 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 bject's pre g na nc y.

S u bject will be f o ll owe d t o deter mi ne t h e o utc o me of t he pre g na nc y. T he i n vesti gat or will 
c ollect f o ll ow- 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 di s k. Ge nerall y, f oll ow- u p will n ot be re q uire d f or l o n ger t ha n 1 m o nt h be y o n d t he deli ver y  
date.

A n y ter mi nat i on of pre g na nc y  will be re p orte d, re gar dless of f oetal stat us ( prese nce or a bse nce 
of a n oma lies) or i n dicati on f or pr oce d ure.

W hile pre g na nc 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 nc y c o mplicat i on or 
elect i ve ter 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 occ urri n g as a res ult of a p ost -trial pre g na nc y w hic h is c o nsi dere d p ossi bl y/ pr o ba bl y 
r elate 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 be 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 mati on i n f or mer 
s u bjects, he or s he ma y lear n o f 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 pat i n g i n t he trial will disc o nti n ue trial 
pr o d uct. 
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
8 2 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
8 3 of 9 4
Tec h nic al c o m pl ai nts : Defi niti o n a n d pr oce d ures f or 
A p pe n di x 6
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 nical c o m plai nt ma y be ass ociate d wit h a n A E, b ut d oes n ot c o ncer n t he A E itself.
E xa m ples of tec h nical c o m p lai nts:

Pr o ble ms wit h t he p h ysical or c he mical a p peara nce of trial pr o d ucts (e. g. di sc ol or atio n, particles 
or c o nta mi nat i on).

Pr o ble ms wit h pac ka gi n g material i ncl u di n g la belli n g.

Pr o ble ms relate d t o me dical de vices (e. g. t o t he i njecti o n mec ha nis m, d ose setti n g mec ha nis m, 
d ose b utt o n or i nterface bet wee n t he pe n -i nject or a n d t he nee dle).
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 h ic 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 be 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
Tec h nical c o m plai nts m ust be re p orte d o n a se parate tec h nical c o m plai nt f or m:
1. O ne tec h nical c o m plai nt f or m m ust be 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 plete t he tec h nical c o m plai nt f or m i n t he C R F wit hi n t he ti meli nes s pecifie d i n Fi g ure 9 -3 . 
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 bject relate d, t he i nf or mati o n m ust be 
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 be 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 
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
8 3 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
8 4 of 9 4
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 ple 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.
Re p orti n g of tec h nic al c o m pl ai nts f or N o v o N or dis k pr o d ucts n ot i ncl u de d i n tec h nic al c o m pl ai nt f or m
Tec h nical c o m plai nts o n N o v o N or dis k pr o d ucts n ot i ncl u de d i n t he tec h nical c o m plai nt f or m s h o ul d be re p orte d t o 
l ocal N o v o N or dis k affiliate wit h a refere nce t o trial I D.
All tec h nical c o m p lai nts are ha n dle d b y C ust o mer C o m p lai nt Ce nter at N o v o N or dis k. O nl y 
tec h nical c o m p lai nts relate d t o a d verse e ve nts will be i ncl u de d i n t he CT R. 
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
8 4 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
8 5 of 9 4
M o nit ori n g of c alcit o ni n
A p pe n di x 7
B ac k gr o u n d
Treat me nt wit h G L P - 1 R As has bee n s h o w n t o be ass ociate d wit h t h y r oid C -cell c ha n ges i n r o de nts 
b ut n ot i n n o n -h u ma n pri mates. T he h u ma n rele va nce o f t his fi n di n g is u n k n o w n. H o we ver, base d 
o n t he fi n di n gs i n r o de nts, m o nit ori n g of ser u m calcit o ni n (a se nsit i ve bi omar ker f or C -cell 
acti vat i on) is c urre nt l y bei n g perf or me d i n cli nical trials wit h se ma gl ut i de.
W hile t here is ge neral a gree me nt o n t he cli nical i nt er pretatio n of  s u bsta ntiall y ele vate d calcit o ni n 
le vels ( > 1 0 0 n g/ L) as li kel y i n dicat i ve of C-cell n e o plasia, t he i nter pretati o n of val ues bet wee n 
u p per n or mal ra n ge ( 5. 0 a n d 8. 4 n g/ L f or w o me n a n d me n, res pecti vel y) a n d 1 0 0 n g/ L is less clear 
wi t h re gar ds t o i n dicati o n of disease.
T here are se veral k n o w n c o nf o u n di n g fact ors affecti n g calcit o ni n le vels, e. g.:

re nal d ysf u ncti o n

t o bacc o use

a ut oi m m u ne t h yr oiditis

se veral dr u g classes (e. g. pr ot o n p u m p i n hi bit ors, beta -bl oc kers, H 2-bl oc kers a n d 
gluc oc orti c o i ds)
P h ysi o l og y of  C-cell acti vatio n i n vario us cli nical c o n ditio ns a n d i n differe nt patie nt p o p ulat i ons 
(i.e. wit h vario us c o m o r bi dities) is p o orl y u n derst o o d. T here ma y be vari o us cli nical c o n dit i ons n ot 
i de ntifie d s o far w hic h mil dl y or m o deratel y affect calcit o ni n secreti on b y C -cells.
C alcit o ni n m o nit ori n g
A bl o o d sa m ple will be dra w n at pre -s pecifie d trial visits f or meas ure me nt of calcit o ni n.
I n case a s u bject has a calcit o ni n val ue ≥ 1 0 n g/ L, t he al g orit h m o utli ne d i n Fi g ure 1 1- 1 a n d 
descri be d bel o w s h o ul d be f o ll owe d. T he al g orit h m a p plies f or all calcit o ni n val ues i n t he trial.
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
8 5 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
8 6 of 9 4
E v al u a ti o n o f 
c al ci t o ni n r e s ul t s
C al cit o ni n < 1 0 n g / L
C al cit o ni n ≥ 1 0 n g / L a n d < 5 0 n g / L
C al cit o ni n ≥ 5 0  n g / L a n d < 1 0 0 n g / L
C al cit o ni n ≥ 1 0 0 n g / L 
C al cit o ni n ≥ 1 0 n g / L a n d l a st 
m e a s ur m et n i n t h e tri al
N o a cti o n

I nv e sti g at e p ot e nti al c o nf o u n d i ng 
f a ct or s

C o n ti n u e s a m pli n g of c al cit o ni n 
a c c or di n g t o pr ot o c ol

Di s c o nti n u e tri al pr o d u ct

R ef er t o  th y r oi d s p e ci alist

R ef er t o  th y r oi d s p e ci alist

R ef er t o  th y r oi d s p e ci alist
Fi g ure 1 1- 1
Fl o w of c alcit o ni n m o nit ori n g
C alcit o ni n ≥ 1 0 0 n g/ L
Acti o n: T he s u bject (e ve n if a scree n fail ure) m ust i m me diatel y be referre d t o a t h yr o i d s pecialist 
f or furt her e val uat i on a n d t he trial pr o d uct m u st be disc o nti n ue d (see Secti o n 8. 1 ). T he s u bject 
s h o uld re mai n i n t he tri al; h o we ver, all me dicat i ons s us pecte d t o relate t o t his c o n dit i on m ust be 
disc o nti n ue d u ntil dia g n osis has bee n esta blis he d.
B ac k gr o u n d: T hese val ues we re f o u n d i n 9 ( 0. 1 5 %) of a p o p ulati o n of 5 8 1 7 pati e nts wit h t h yr oid 
n o d ular disease 8 3 . All of t hese pat ient s were dia g n ose d wit h M T C, res ulti n g i n a positi ve 
pre dict i ve val ue of 1 0 0%.
Di a g n ostic e val uati o n s h o ul d i ncl u de:

t h yr oid ultras o u n d e xa mi nati on

fi ne nee dle as pirati o n of a n y n o d ules > 1 c m 

p ote nti all y, s ur ger y wit h nec k d issecti o n
I n case a s u bject is dia g n ose d wit h M T C, it is c o m m on cli nical pract ice t o e x pl ore t he fa mil y 
hist or y of M T C or M E N 2 a n d perf or m a ge netic test f or R E T pr ot o-o nc o ge ne m utati o n.
C alcit o ni n ≥ 5 0 a n d < 1 0 0 n g/ L
Acti o n: T he s u bject (e ve n if a scree n fail ure) s h o ul d be referre d t o a t h yr oid s pecialist f or f urt her 
e val uat i on. T he s u bject s h o ul d re mai n i n t he trial a n d ca n c o nti n ue o n trial pr o d uct.
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
8 6 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
8 7 of 9 4
B ac k gr o u n d: T hese val ues were f o u n d i n 8 ( 0. 1 4 %) of t he p o p ulati o n of 5 8 1 7 patie nts wit h t h yr o i d 
n o d ular disease 8 3. T w o of t hese s u bjects were dia g n ose d wit h M T C a n d t w o were dia g n ose d wit h C 
cell h y per plasia, res ult i n g i n a p ositi ve pre dicti ve v alue of a C -cell a n o mal y of 5 0 %.
Di a g n ostic e val uati o n s h o ul d i ncl u de: 

t h yr oid ultras o u n d e xa mi nati on 

if a vaila ble, a n d if t here are n o c o ntrai n dicati o ns, a pe nta gastri n sti m ulati on test s h o ul d be d o ne. 
F or s u bjects wit h p osit i ve pe nta gastri n sti m ulati o n test, s ur ger y s h o ul d be c o nsi dere d. 

if pe nta gastri n sti m ulati on test i s n ot a vaila ble, t h yr oi d ultras o u n d a n d fi ne nee dle as pirat i on 
bi o ps y ma y  a d d i m p orta nt cli nical i nf or mati on a b o ut t he nee d f or s ur ger y .
C alcit o ni n ≥ 1 0 a n d < 5 0 n g/ L
Acti o n: T he s u bject ca n c o nti n ue i n t he trial o n trial pr o d uct. C o nti n ue sa m pli n g o f calc ito ni n 
acc or di n g t o t he pr ot oc ol.
If t he s u bject is a scree n fail ure, or if t he valu e is fr o m t h e last sa mple ta ke n i n t he trial, t he s u bject 
s h o uld be referre d t o a t h y r oid s pecialist f or f urt her e val uati o n.
B ac k gr o u n d: Calcit o ni n val ues fr o m 2 0 – 5 0 n g/ L w ere f o u n d i n u p t o 1 % of s u bjects of t he 
p o p ulat i on of 5 8 1 7 patie nts wit h t h y r oid n o d ular disease 8 3. T he pre dicti ve val ue of a C -cell 
a n o ma l y f or t his calcit o ni n le vel was 8. 3 %. H o we ver, t he li keli h o o d of ha vi n g a me d ullar y 
carci n o ma > 1 c m wit h calcit o ni n i n t his ra n ge is e xtre mel y  lo w.
F or calcit o ni n val ues bet wee n 1 0 -2 0 n g/ L C os ta nte et al.8 3 i de ntifie d 2 1 6 ( 3. 7 %) patie nts. O ne 
patie nt o ut of t he 2 1 6 ha d a s u bse q ue nt basal ( u nst i m ulate d) calcit o ni n val ue of 3 3 n g/ L, a n d ha d C-
cell h y per plasia at s ur ger y. T w o ot her st u dies use d a c ut -off of calcit o ni n > 1 0 n g/ L t o scree n f or C -
cell disease, b ut t he y d o n ot pr o vide s ufficie nt i nf o r mat i on o n pati e nts wit h bas al C T > 1 0 a n d < 2 0 
n g/ L t o all o w c o ncl usi o ns 8 4, 8 5.
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
8 7 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
8 8 of 9 4
C o u ntr y -s pecific re q uire me nts
A p pe n di x 8
T he bel o w list is n ot a n e x ha uste d list of c o u ntr y  s pecific re q uire me nts. The list will o nl y be 
u p date d i n case of a gl o bal pr ot oc ol a me n d me nt.
F or S p ai n: D o u ble -b arrier c o ntrace pti ve met h o ds are n ot c o nsi dere d as ' hi g hl y  effecti ve' met h o ds 
acc or di n g t o t he E M A g ui deli ne. T heref ore d o u ble -barriers met h o ds c o uld n ot be c o nsi dere d as 
vali d i n S pai n t o assess e xcl usi o n crit erio n n u m ber 2 8.
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
8 8 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
8 9 of 9 4
1 2
Refere nces
1.
T he E ur o pea n Parlia me nt a n d t he C o u ncil o f t he E ur o pea n C o u ncil. Direct i 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 mat i on of t he 
la ws, re g ulati o ns a n d a d mi nistrati ve pr o visi ons of t he Me m ber States relat i 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 use, article 1 1. Official J o ur nal of t he E ur o pea n C o m m u nit ies. 0 1 Ma y 
2 0 0 1.
2.
T he A merica n S ociet y f or Meta b olic a n d Bariatric S ur ger y, T he O besity S ociet y , T he 
A merica n S ociet y of Bariatric P h ysicia ns a n d t he A merica n Ass ociat i on of Cli nical 
E n d ocri n o l ogists. O besit y is a Disease: Lea di n g O besity Gr o u ps A g ree (J oi nt Press 
Release). 1 9 J u ne 2 0 1 3.
3.
Mec ha nic k JI, Gar ber AJ, Ha n dels ma n Y, Gar ve y W T. A merica n Ass ociati o n of Cli nical 
E n d ocri n o l ogists' p ositio n state me nt o n o besit y a n d o besit y me dici ne. E n d ocr Pract. 
2 0 1 2; 1 8( 5): 6 4 2 - 8.
4.
T o pl a k H, W o o d war d E, Y u m u k V, O p pert J M, Half or d J C, Fr ü h bec k G. 2 0 1 4 E A S O 
P osi tio n State m e nt o n t he Use of A nt i-O besi t y Dr u gs. O bes Facts. 2 0 1 5; 8( 3): 1 6 6-7 4.
5.
Fr u h bec k G, T o pla k H, W o o d war d E, Y u m u k V, Maisl os M, O p pert J M, et al. O besit y: t he 
gate wa y t o ill health - a n E A S O p ositio n state me nt o n a risi n g p u blic healt h, cli nical a n d 
scie ntific c halle n ge i n E ur o pe. O bes Facts. 2 0 1 3; 6( 2): 1 1 7 - 2 0.
6.  
A p o via n C M, Ar o n ne LJ, Bessese n D H, Mc D o n nell M E, M ura d M H, Pa g ott o U, et al. 
P har mac o l ogical ma na ge me nt of o besit y: a n e n d ocri ne S oc iety cli nical pract ice g ui deli ne. J 
Cli n E n d ocri n o l Meta b. 2 0 1 5; 1 0 0( 2): 3 4 2 - 6 2.
7.
Fer g us o n C, Da vi d S, Di vi ne L, Ka ha n S, Galla g her C, G o o di n g M, et al. O besit y Dr u g 
O utc o m e Meas ures. A C o nse ns us Re p ort of C o nsi derati o ns Re gar di n g P har mac ol o gic 
I nter ve nti on. A valia ble fr o m: htt ps:// p u blic healt h. g w u.e d u/ p df/ o besit y dr u g meas ures. p df . 
2 0 1 2.
8.
S u mit hra n P, Pre n der gast L A, Del bri d ge E, P urcell K, S h ul kes A, Kri ket os A, et al. L o n g -
t er m persiste nce of h or m o nal a da ptati o ns t o wei g ht l oss. N E n gl J Me d. 2 0 1 1; 3 6 5( 1 7): 1 5 9 7-
6 0 4.
9.
Sc h wartz A, D o ucet E. Relati ve c ha n ges i n resti n g e ner g y e x pe n dit ure d uri n g wei g ht l oss: a 
s yste mat ic re vie w. O bes Re v. 2 0 1 0; 1 1( 7): 5 3 1- 4 7.
1 0.
Pas ma n WJ, Saris W H, Westerter p -Pl a nte n ga M S. Pre dict ors of wei g ht mai nte na nce. O bes 
Res. 1 9 9 9; 7( 1): 4 3 - 5 0.
1 1.
D o m br o ws ki S U, K nittle K, A ve nell A, Ara uj o -S oares V, S nie h otta F F. L o n g ter m 
mai nte na nce of wei g ht l oss wit h n o n -s ur gical i nter ve nt i ons i n o bese a d ults: s yste matic 
re vie w a n d meta -a nal yses of ra n d o mise d c o ntr olle d trials. B MJ. 2 0 1 4; 3 4 8: g 2 6 4 6.
1 2. 
Bret ha uer S A, C ha n d B, Sc ha uer P R. Ris ks a n d be nefits of bariatric s ur ger y: c urre nt 
e vi de nce. Cle ve Cli n J Me d. 2 0 0 6; 7 3( 1 1): 9 9 3- 1 0 0 7.
1 3.
Sc ha uer P R, I kra m u d di n S, G o uras h W, Ra ma nat ha n R, L u ket ich J. O utc o mes after 
la par osc o pic R o u x-e n-Y gastri c b y pass f or mor bid o besit y. A n n S ur g. 2 0 0 0; 2 3 2( 4): 5 1 5 -2 9.
1 4.
Y u m u k V, Tsi g os C, Fri e d M, Sc hi n dler K, B usett o L, Micic D, et al. E ur o pea n G ui deli nes 
f or O besit y Ma na ge me nt i n A d ults. O bes Facts. 2 0 1 5; 8( 6): 4 0 2 - 2 4.
1 5.
Hasla m D. Wei g ht ma na ge me nt i n o besit y - past a n d prese nt. I nt J Cli n Pract. 
2 0 1 6; 7 0( 3): 2 0 6 - 1 7.
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
8 9 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
9 0 of 9 4
1 6.
Kell y T, Ya n g W, C he n C S, Re y n o l ds K, He J. Gl o bal b ur de n o f o besit y i n 2 0 0 5 a n d 
pr oject i ons t o 2 0 3 0. I nt J O bes ( L o n d). 2 0 0 8; 3 2( 9): 1 4 3 1 - 7.
1 7.
O g de n C L, Carr oll M D, Kit B K, Fle gal K M. Pre vale nce o f c hil d h o o d a n d a d ult o besit y i n 
t he U nite d States, 2 0 1 1 -2 0 1 2. J A M A. 2 0 1 4; 3 1 1( 8): 8 0 6- 1 4.
1 8.
Ste ve ns G A, Si n g h G M, L u Y, Da naei G, Li n J K, Fi n uca ne M M, et al. Nati o n al, r e gio nal, 
a nd glo b al tre n ds i n a d ult o ver wei g ht a n d o besity pre vale nces. P o p ul Healt h Metr. 
2 0 1 2; 1 0( 1): 2 2.
1 9.
N C D Ris k Fact or C olla b orati o n. Tre n ds i n a d ult b o d y -mass i n de x i n 2 0 0 c o u ntries fr o m 
1 9 7 5 t o 2 0 1 4: a p o ole d a nal ysis o f 1 6 9 8 p o p ul at i on- base d meas ure me nt st u dies wit h 1 9· 2 
milli o n part ici pa nts. La ncet. 2 0 1 6; 3 8 7( 1 0 0 2 6): 1 3 7 7- 9 6.
2 0.
Fi n kelstei n E A, Di B o na ve nt ura M, B ur gess S M, Hale B C. T he c osts of o besit y i n t he 
w or k pl ace. J Occ u p E n vir o n Me d. 2 0 1 0; 5 2( 1 0): 9 7 1- 6.
2 1.
Va n N u ys K, Gl o be D, N g -Ma k D, C he u n g H, S ull i va n J, G ol d ma n D. T he ass ociati on 
bet wee n e m pl o yee o besit y a n d e m plo y er c osts: e vi de nce fr o m a pa nel o f U. S. e m plo y ers. 
A m J Health Pr o m ot. 2 0 1 4; 2 8( 5): 2 7 7 - 8 5.
2 2.
Wa n g Y C, Pa m pli n J, L o n g M W, War d ZJ, G ort ma ker S L, A n dre ye va T. Se vere O besit y I n 
A d ults C o st State Me dicai d Pr o gra ms Nearl y $ 8 Billio n  I n 2 0 1 3. Healt h Aff ( Mill w o o d). 
2 0 1 5; 3 4( 1 1): 1 9 2 3 - 3 1.
2 3.
C usi K. R o le of o besity a n d li p ot o xicit y in t he de vel o p me nt of n o nalc o h olic steat o he patitis: 
pat h o p h ysi o l og y a n d cli nical i m plicati ons. Gastr oe nter ol o g y . 2 0 1 2; 1 4 2( 4): 7 1 1 -2 5.e 6.
2 4.
G u h D P, Z ha n g W, Ba ns bac k N, A marsi Z, Bir mi n g ha m C L, A nis A H. T he i nci de nce of c o -
m o r bidities r elate d t o o besit y a n d o ver wei g ht: a s yste matic re vie w a n d meta -a nal ysis. B M C 
P u blic Healt h. 2 0 0 9; 9: 8 8.
2 5.
Pi sc h o n T, B oei n g H, H off ma n n K, Ber g ma n n M, Sc h ulze M B, O ver va d K, et al. Ge neral 
a n d a b d o mi nal a di p osit y a n d ris k of deat h i n E ur o pe. N E n gl J Me d. 2 0 0 8; 3 5 9( 2 0): 2 1 0 5 - 2 0.
2 6.
Ber g h o fer A, Pisc h o n T, Rei n h ol d T, A p o via n C M, S har ma A M, Willic h S N. O besity 
pre vale nce fr o m a E ur o pea n pers pecti ve: a s yste matic re vie w. B M C P u blic Healt h. 
2 0 0 8; 8: 2 0 0.
2 7.
Masters R K, Reit her E N, P o wers D A, Ya n g Y C, B ur ger A E, Li n k B G. T he i m pact of 
o besit y o n U S m ortalit y le vels: t he i m p orta nce of a ge a n d c o h ort fact ors i n p o p ulati o n 
esti mates. A m J P u blic Heal t h. 2 0 1 3; 1 0 3( 1 0): 1 8 9 5- 9 0 1.
2 8.
Ar n o l d M, Pa n de ya N, B yr nes G, Re ne ha n A G, Ste ve ns G A, Ezzati M, et al. Gl o bal b ur de n 
of ca ncer attri b uta ble t o hi g h b o d y-mass i n de x i n 2 0 1 2: a p o p ulat i on- base d st u d y. La ncet 
O nc o l. 2 0 1 5; 1 6( 1): 3 6- 4 6.
2 9.
W o rld Healt h Or ga nizat i on. O besit y:  Pre ve nti n g a n d Ma na gi n g t he Gl o bal E pi de mic. Re p ort 
of a W H O C o ns ultati o n. W orl d Health Or ga nisati o n Ge ne va, S witzerla n d. 2 0 0 0.
3 0.
T h o mse n M, N or dest gaar d B G. M y o c ar dial I nfarctio n  a n d Isc he mic Heart Disease i n 
O ver wei g ht a n d O besit y W ith a n d Wit h o ut Meta b olic S y n dr o me. J A M A i nter nal me dici ne. 
2 0 1 3; 1 7 4( 1): 1 5 - 2 2.
3 1.
Ec kel  R H, Ka h n S E, Ferra n ni ni E, G ol dfi ne A B, Nat ha n D M, Sc h wartz M W, et al. O besit y 
a n d t y pe 2 dia betes: w hat ca n be u nifie d a n d w hat nee ds t o be i n di vi d ualize d? J o ur nal of
cli nical e n d ocri n ol o g y a n d meta b olis m. 2 0 1 1; 9 6( 6): 1 6 5 4- 6 3.
3 2.
K ha o d hiar L, C u m mi n gs S, A p o via n C M. Treati n g dia betes a n d pre dia betes b y  foc usi n g o n 
o besit y ma na ge me nt. C urr Dia b Re p. 2 0 0 9; 9( 5): 3 4 8- 5 4.
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
9 0 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
9 1 of 9 4
3 3.
W heat o n A G, Perr y  G S, C ha p ma n D P, Cr oft J B. Slee p dis or dere d breat hi n g a n d de pressi o n 
a mo n g U. S. a d ul ts: Natio nal H e alt h a n d N utritio n E xa mi nat i on S ur ve y , 2 0 0 5 -2 0 0 8. Sl ee p. 
2 0 1 2; 3 5( 4): 4 6 1 - 7.
3 4.
Pr os pecti ve St u dies C o lla b orati o n, W hitl oc k G, Le wi n gt o n S, S herli ker P, Clar ke R, 
E m bers o n J, et al. B o d y -ma ss i n de x a n d ca use-s pecific mortalit y in 9 0 0 0 0 0 a d ults: 
c olla b orati ve a nal yses of 5 7 pr os pecti ve st u dies. La ncet. 2 0 0 9; 3 7 3( 9 6 6 9): 1 0 8 3 - 9 6.
3 5.
M ust A, S pa da n o J, C oa kle y E H, Fiel d A E, C ol dit z G, Dietz W H. T he disease b ur de n 
ass ociat e d wit h o ver weig ht a n d o b esit y. J A M A. 1 9 9 9; 2 8 2( 1 6): 1 5 2 3- 9.
3 6.
C h urc h T S, K u k J L, R oss R, Priest E L, Bilt o ft E, Bilt off E, et al. Ass ociati on of 
car dior es pirat or y fitness, b o d y  mass i n de x, a n d waist circ u mfere nce t o n o nalc o h o lic fatt y 
li ver disease. Gastr oe nter olo g y. 2 0 0 6; 1 3 0( 7): 20 2 3- 3 0.
3 7.
Bl a g o jevic M, Ji n ks C, Jeffer y  A, J or da n K P. Ris k fact ors f or o nset of oste oart hritis of t he 
k nee i n o l der a d ults: a s yste matic re vie w a n d meta-a nal ysis. Oste oart hri tis Cartila ge. 
2 0 1 0; 1 8( 1): 2 4 - 3 3.
3 8.
Gar ner R E, Fee n y D H, T h o m ps o n A, Ber nier J, Mc Farla n d B H, H u g uet N, et al. 
B o d y wei g ht, ge n der, a n d q ualit y of life: a p o p ulati o n-base d l o n git u di nal st u d y . Q u al Life 
Res. 2 0 1 2; 2 1( 5): 8 1 3 - 2 5.
3 9.
Kear ns B, Ara R, Y o u n g T, Relt o n C. Ass ociat i on bet wee n b o d y  ma ss i n de x a n d healt h-
r elate d q ualit y of life, a n d t he i m pact of self-re p orte d lo n g- t er m c o n ditio ns - cr oss-secti o nal 
st u d y fr o m t he s o ut h Y or ks hire c o h ort dataset. B M C P u blic Healt h. 2 0 1 3; 1 3: 1 0 0 9.
4 0.
Wei M, Ka m pert J B, Barl o w C E, Nic ha ma n M Z, Gi b b o ns L W, P affe n bar ger R S, et al. 
Relati o ns hi p bet wee n l o w car di ores pirat or y  fitness a n d m ortalit y i n n or mal -wei g ht, 
o ver weig ht, a n d o bese m e n. J A M A. 1 9 9 9; 2 8 2( 1 6): 1 5 4 7- 5 3.
4 1.
T u o mile ht o J, Li n dstr o m J, Eri kss o n J G, Valle T T, Ha malai ne n H, Ila n ne -P ari k ka P, et al . 
Pr e ve nt i on of t ype 2 dia betes mellit us b y c ha n ges i n lifest yle a m o n g s u bjects wit h i m paire d 
gluc ose t ol era nce. N E n gl J Me d. 2 0 0 1; 3 4 4( 1 8): 1 3 4 3 - 5 0.
4 2.
K n o wl er W C, Barrett -C o n n or E, F o wler S E, Ha m ma n R F, Lac hi n J M, Wal ker E A, et al. 
Re d ucti o n i n t he i nci de nce of t ype 2 dia betes wit h lifestyle i nter ve nt i on or m etfor m i n. N 
E n gl  J Me d. 2 0 0 2; 3 4 6( 6): 3 9 3- 4 0 3.
4 3.
Li  G, Z ha n g P, Wa n g J, Gre g g E W, Ya n g W, G o n g Q, et al. T he l o n g- t er m effect of lifest yle 
i nter ve nt i ons t o pre ve nt dia betes i n t he C hi na Da Qi n g Dia betes P re ve nti o n St u d y: a 2 0-year 
f oll ow- u p st u d y . La ncet. 2 0 0 8; 3 7 1( 9 6 2 6): 1 7 8 3-9.
4 4.
Di a betes Pre ve nt i on Pr o gra m  Researc h Gr o u p, K n o wler W C, F o wler S E, Ha m ma n R F, 
C hr ist o p hi C A, H off ma n HJ, et al. 1 0-year f oll ow- u p of dia betes i nci de nce a n d wei g ht l oss 
i n t he Dia betes Pre ve nt i on Pr o gra m  O utc o mes St u d y. La ncet. 2 0 0 9; 3 7 4( 9 7 0 2): 1 6 7 7 -8 6.
4 5.
F oster G D, B orra daile K E, Sa n ders M H, Mill ma n R, Za m mit G, Ne w ma n A B, et al. A 
Ra n d o mize d St u d y  o n t he Effect of Wei g ht L oss o n O bstr ucti ve Slee p A p nea A m on g O bese 
P ati e nts Wit h T y pe 2 Dia betes T he Slee p A H E A D St u d y. Arc hi ves of I nter nal Me dici ne. 
2 0 0 9; 1 6 9( 1 7): 1 6 1 9 - 2 6.
4 6.
Fels o n D T, Z ha n g Y, A nt h o n y  J M, Nai mar k A, A n ders o n JJ. Wei g ht l oss re d uces t he ris k 
f or s y m pt o mat ic k nee oste oart hritis i n w ome n. T he Fra mi n g ha m St u d y . A n n I nter n Me d. 
1 9 9 2; 1 1 6( 7): 5 3 5 - 9.
4 7.
De n g o A L, De n nis E A, Orr J S, Mari ni k E L, E hrlic h E, Da v y  B M, et al. Art erial destiffe ni n g 
wi t h wei g ht loss i n o ver wei g ht a n d o bese mi d dle- a ge d a n d older a d ul ts. H yperte nsi o n. 
2 0 1 0; 5 5( 4): 8 5 5 - 6 1.
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
9 1 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
9 2 of 9 4
4 8.
Dattil o A M, Kris -Et hert o n P M. Effects of wei g ht re d ucti o n o n bl o o d li pi ds a n d li p o pr otei ns: 
a met a -a nal ysis. A m J Cli n N utr. 1 9 9 2; 5 6( 2): 3 2 0-8.
4 9.
A n ders o n J W, K o nz E C. O besit y a n d disease ma na ge me nt: effects of wei g ht l oss o n 
c o mor bi d c o n di tio ns. O bes Res. 2 0 0 1; 9 S u p pl 4: 3 2 6 S -3 4 S.
5 0.
Gar ber AJ, A bra ha ms o n MJ, Barzila y JI, Bl o n de L, Bl o o m gar de n Z T, B us h M A, et al. 
A merica n Ass ociat i on of Cli nical E n d ocri n o l ogists' C o m pre he nsi ve Dia betes Ma na ge me nt 
Al g ori t h m 2 0 1 3 C o nse ns us State me nt - E xec uti ve S u m mar y . E n d ocri ne Practice. 
2 0 1 3; 1 9( 3 ): 5 3 6- 4 7.
5 1.
Merte ns I L, Va n Gaal L F. O ver wei g ht, o besit y,  a n d blo o d press ure: t he effects of m o dest 
w ei g ht re d ucti o n. O bes Res. 2 0 0 0; 8( 3): 2 7 0 - 8.
5 2.
D ei t el M, St o ne E, Kassa m H A, Wil k EJ, S ut herla n d DJ. G y nec ol o gic-o bstetri c c ha n ges 
aft er loss of massi ve e xcess weig ht f ol l owi n g bari atric s ur ger y. J A m C oll N utr. 
1 9 8 8; 7( 2): 1 4 7 - 5 3.
5 3.
Sj östr ö m L. Re vie w of t he ke y res ults fr o m t he S we dis h O bese S u bjects ( S O S) trial - a 
pr os pecti ve c o ntr olle d i nter ve nt i on st u d y of bariatric s ur ger y. J I nter n Me d. 
2 0 1 3; 2 7 3( 3 ): 2 1 9- 3 4.
5 4.
Gre g g E W, Ja kicic J M, Blac k b ur n G, Bl o o m q uist P, Bra y  G A, Clar k J M, et al. Ass ociat i on 
of t h e ma g nit u d e of wei g ht loss a n d c ha n ges i n p h ysical fit ness wit h l o n g -t er m 
car dio vasc ular disease o utc o m es i n o ver wei g ht or o bese pe o ple wit h t ype 2 di a betes: a p ost -
h oc a nal ysis o f t he L o o k A H E A D ra n d o mise d cli nical trial. La ncet Dia betes E n d ocri n o l. 
2 0 1 6; 4( 1 1): 9 1 3 - 2 1.
5 5.
Afs hi n A, F or o uza nfar M H, Reits ma M B, S ur P, Este p K, Lee A, et al. Healt h Effects of 
O ver wei g ht a n d O besit y i n 1 9 5 C o u ntries o ver 25 Years. N E n gl  J Me d. 2 0 1 7; 3 7 7( 1): 1 3- 2 7.
5 6.
La u J, Bl oc h P, Sc häffer L, Petterss o n I, S petzler J, K of oe d J, et al. Disc o ver y  of t he O nce-
Wee kl y Gl uca g o n -Li ke Pe pti de- 1 ( G L P -1) A nal o g ue Se ma gl uti de. J Me d C he m. 
2 0 1 5; 5 8( 1 8): 7 3 7 0 - 8 0.
5 7.
G utz willer J P, Dre w e J, G o ke B, Sc h mi dt H, R o hrer B, Larei da J, et al. Gl uca g o n -li ke 
pe ptide- 1 pr o m otes sati et y a n d re d uces f o o d i nta ke i n pat ient s wit h dia betes mellit us t ype 2. 
A m J P h ysiol. 1 9 9 9; 2 7 6( 5 Pt 2): R 1 5 4 1- 4.
5 8.
N o v o N or dis k A/ S. I n vest i gat or's Br oc h ure, Se ma gl utide s.c. 2. 4 m g, pr oject N N 9 5 3 6, 
( e ditio n 1). 2 8 N o v 2 0 1 7.
5 9.
S orli C, Haras hi ma SI, Ts o u kas G M, U n ger J, Kars b øl J D, Ha nse n T, et al. Efficac y a n d 
safety of o nce-wee kl y se ma gl ut i de m o n ot hera p y vers us place b o i n pat ient s wit h t ype 2 
dia betes ( S U S T AI N 1): a d o u ble -bli n d, ra n d o mise d, place b o -c o ntr olle d, parallel-gr o u p, 
m ult i nati onal, m ult ice ntre p hase 3a trial. La ncet Dia betes E n d ocri n ol. 2 0 1 7; 5( 4): 2 5 1- 6 0.
6 0.
Ar o da V R, Bai n S C, Cari o u B, Piletič M, R ose L, A xelse n M, et al. Efficac y  a n d safety of 
o nce -wee kl y se ma glut i de vers us o nce -dail y i ns uli n glar gi ne as a d d -o n t o metfor m i n ( with or 
wi t ho ut s ulf o n yl ureas) i n i ns uli n -nai ve pat ient s wit h t ype 2 dia betes ( S U S T AI N 4): a 
ra n d omise d, o pe n -label, parallel -gr o u p, m ultice ntre, multinat i onal, p hase 3a trial. La ncet 
Di a betes E n d ocri n ol. 2 0 1 7; 5( 5): 3 5 5- 6 6.
6 1.
A hré n B, Mas mi q uel L, K u mar H, Sar gi n M, Kars b øl J D, Jac o bse n S H, et al. Efficac y a n d 
safety of o nce-wee kl y se ma gl ut i de vers us o nce -dail y sita gli pti n as a n a d d-o n t o met f or mi n, 
t hiaz o li di ne di ones, or b ot h, i n pat ie nts wit h t ype 2 dia betes ( S U S T AI N 2): a 5 6 -wee k, 
d o u ble- bli n d, p hase 3a, ra n d o mise d trial. La ncet Dia betes E n d ocri n ol. 2 0 1 7; 5( 5): 3 4 1 - 5 4.
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
9 2 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
9 3 of 9 4
6 2.
A h ma n n A, Ca pe h or n M, C har pe nt ier G, D otta F, He n kel E, Li n g va y I, et al. Efficac y a n d 
safety of o nce-wee kl y se ma g l uti de vs e xe nat i de E R after 5 6 Wee ks i n s u bjects wit h t y pe 2 
dia betes ( S U S T AI N 3).  E ur o pea n Ass ociat i on f or t he St u d y of Dia betes, 5 2 n d meeti n g 
2 0 1 6, Oral  Prese ntatio n # 1 4 7 2 0 1 6.
6 3. 
R o d bar d H, Li n g va y I, Ree d J, de la R osa R, R ose L, S u gi m ot o D, et al. E fficac y a n d safety 
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 nat i on 
wi t h met f or mi n i n s u bjects wit h t ype 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.
6 4.
Bl u n dell J, Fi nla ys o n G, A xelse n M , Fli nt A, Gi b b o ns C, K vist T, et al. Effects of o nce-
wee kl y se ma gl ut i de o n a p petite, e ner g y int a ke, c o ntr ol of eati n g, f o o d prefere nce a n d b o d y 
w ei g ht i n s u bjects wit h o besit y.  Dia betes O bes Meta b. 2 0 1 7.
6 5.
E ur o pea n Me dici nes A ge nc y. E M A/ C H M P/ 3 1 1 8 0 5/ 2 0 1 4; G ui deli ne o n cli nical e val uat i on 
of me dici nal pr o d ucts use d i n wei g ht ma na ge me nt. 0 1 Ja n 2 0 1 7.
6 6.
F o o d a n d Dr u g A d mi nistrati o n. F D A G ui da nce f or I n d ustr y : De velo pi n g pr o d ucts f or 
w ei g ht ma na ge me nt. 2 0 0 7.
6 7.
Ki d ne y Disease: I m pr o vi n g Gl o bal O utc o m es ( 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 val uat i on a n d Ma na ge me nt of C hr o nic 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.
6 8.
F A O/ W H O/ U N U. H u ma n e ner g y  r e q uire me nts. Re p ort of a j oi nt F A O/ W H O/ U N U e x pert
c o ns ultati o n. F A O: f o o d a n d n utrit i on tec h nical re p ort series 1. R o me: 2 0 0 4 2 0 0 4.
6 9.
Ba n ks P A, B o lle n T L, Der ve nis C, G o osze n H G, J o h ns o n C D, Sarr M G, et al. Classificati o n 
of ac ute pa ncreatitis-2 0 1 2: re visi o n of t he At lant a classificat i on a n d defi nit i on s b y 
i nter nat i onal c o nse ns us. G ut. 2 0 1 3; 6 2( 1): 1 0 2 -1 1.
7 0.
D al t o n M, Fi nla ys o n G, Hill A, Bl u n dell J. Preli mi nar y vali dati on a n d pri nci pal c o m p o ne nts 
a nal ysis of t he C o ntr ol of Eati n g Q uest i on naire ( C o E Q) f or t he e x perie nce of f o o d cra vi n g. 
E ur J Cli n N utr. 2 0 1 5; 6 9( 1 2): 1 3 1 3 -7.
7 1.
Kr oe n ke K, S pitzer R L, Willia ms J B. T he P H Q - 9 - Vali dit y of a brief de pressi o n se verit y 
meas ure. J Ge n I nter n Me d. 2 0 0 1; 1 6( 9): 6 0 6- 1 3.
7 2.
P os ner K, O q ue n d o M A, G o ul d M, Sta nle y B, Da vies M. C ol u m bia Classificat i on 
Al g ori t h m of S uici de Assess me nt ( C-C A S A): classificat i on of s uici dal e ve nts i n t he F D A's 
pe diatric s uici dal ris k a nal ysis o f a nt i de pressa nts. A m J Ps yc hiatr y. 2 0 0 7; 1 6 4( 7): 1 0 3 5- 4 3.
7 3.
Mc E v o y B W. Missi n g data i n cli nical trials f or wei g ht ma na ge me nt. J Bi o p har m Stat. 
2 0 1 6; 2 6( 1): 3 0 - 6.
7 4.
Car pe nter J R, R o ger J H, Ke n war d M G. A nal ysis of l o n git u di nal trials wit h pr ot oc ol 
de viat i on: a fra me w or k f or rele va nt, accessi ble ass u m pt i ons, a n d i nfere nce via m ult i ple 
i m p utatio n. J Bio p har m Stat. 2 0 1 3; 2 3( 6): 1 3 5 2- 7 1.
7 5.
Sac ks F M, Bra y  G A, Care y  VJ, S mit h S R, R ya n D H, A nt o n S D, et al. C o m paris o n of 
w ei g ht- l oss diets wit h differe nt c o mp ositio ns of  fat, pr otei n, a n d car b o h y drates. N E n gl J 
Me d. 2 0 0 9; 3 6 0( 9): 8 5 9 - 7 3.
7 6.
W o rld Me dical Ass oci at i on. Declarat i on of Helsi n ki - Et hi cal Pri nci ples f or Me dical 
Researc h I n v o l 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 neral Asse m bl y, 
F ortaleza, Brazil. 1 Oct 2 0 1 3.
7 7.
I C H Har m o nise d Tri partite 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 6 - 4 3 7 8
9 3 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 9 J u ne 2 0 1 8
N o v o N or di s k
Trial I D: N N 9 5 3 6 - 4 3 7 8
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
9 4 of 9 4
7 8.
C o m mit tee f or Me dici nal Pr o d ucts f or H u ma n Use ( C H M P). G ui deli ne o n cli nical 
e val uat i on of me dici nal pr o d ucts use d i n wei g ht ma na ge me nt. E M A/ C H M P/ 3 1 1 8 0 5/ 2 0 1 4. 
2 0 1 6.
7 9.
I nter nati o nal C om mittee of Me dical J o ur nal E dit ors. Rec o m me n dat i ons f or t he C o n d uct, 
Re p orti n g, E ditin g a n d P u blicat i on of Sc h o larl y W or k i n Me dical J o ur nals; c urre nt versi o n 
a vaila ble at w w w.ic mje. or g .
8 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 
r e gistr atio n: a state m e 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.
8 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 m e 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 mat i on 
S u b missi o n". 2 1 Se pte m ber 2 0 1 6.
8 2.
T he E ur o pea n Parlia me nt a n d t he C o u ncil o f t he E ur o pea n C o u ncil. Re g ulat i on ( 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 o f 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 orisat i on 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 nar y use 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.
8 3.
C osta nte G, Meri n g o l o D, D ura nte C, Bia nc hi D, N ocera M, T u mi n o S, et al. Pre dict i ve 
val ue of ser u m calcit o ni n le vels f or pre o perati ve dia g n osis of me d ullar y t h yr o i d carci n oma 
i n a c o h ort of 5 8 1 7 c o nsec ut i ve patie nts wit h t h yr oi d n o d ules. J Cli n E n d ocri n ol  Meta b. 
2 0 0 7; 9 2( 2): 4 5 0 - 5.
8 4.
Sc he u ba C, Kaserer K, M oritz A, Dr oste n R, Vier ha p per H, Bie gl ma yer C, et al. S p ora dic 
h y percalcit o ni ne mia: cli nical a n d t hera pe ut ic c o nse q ue nces. E n d ocr Relat Ca ncer. 
2 0 0 9; 1 6( 1): 2 4 3 - 5 3.
8 5.
Ver ga U, Ferrer o S, Vice nt i ni L, Bra m billa T, Cirell o V, M uzza M, et al. Hist o pat h ol o gical 
a n d m o lec ular st u dies i n patient s wit h g oiter a n d h y percalcit o ni ne mia: reacti ve or ne o plastic 
C- cell h y per plasia? E n d ocr Relat Ca ncer. 2 0 0 7; 1 4( 2): 3 9 3 - 4 0 3.
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
9 4 of 9 4
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