Clinical trial NCT03693430
Conditions: Overweight Obesity
Sponsor: Novo Nordisk A/S
Start date: 2018-10-05; Completion date: 2021-03-23
Enrollment: 304 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will look at the change in body weight from the start to the end of the study. Researchers will compare the weight loss in people taking semaglutide (a new medicine) to people taking "dummy" medicine. In addition to taking the medicine, participants will also have talks with study staff about healthy food choices, how the participant can be more physically active and what participants can do to lose weight. Participants will either get semaglutide or "dummy" medicine - which treatment the participant gets is decided by chance. Participants will need to take 1 injection once a week. The study medicine is injected with a thin needle in a skin fold in the stomach, thigh or upper arm. The study will last for about 2 years. The participants will have 19 clinic visits and 15 phone calls with the study doctor.

Detailed description:

Arms: arm 1: Participants will receive semaglutide 2.4 mg during 104-week treatment period in addition to a reduced-calorie diet and increased physical activity. arm 2: Participants will receive placebo (semaglutide) during 104-week treatment period in addition to a reduced-calorie diet and increased physical activity.
Interventions: intervention 1: Semaglutide intervention 2: Placebo (Semaglutide)
Intervention descriptions: intervention 1: Subcutaneous (s.c., under the skin) injections of semaglutide once weekly at escalating doses (0.25 mg/week, 0.5 mg/week, 1.0 mg/week, 1.7 mg/week, 2.4 mg/week). The dose will be escalated to next level every 4 weeks intervention 2: S.c. injections of placebo once weekly at a similar dose escalation manner as semaglutide (placebo matched to semaglutide 0.25 mg/week, 0.5 mg/week, 1.0 mg/week, 1.7 mg/week, 2.4 mg/week). The dose will be escalated to next level every 4 weeks

Protocol documents:
Prot_000.pdf: 
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
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 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
  
  
  
  
  
  
 
  
  
 
  
   
 
  
  
   
  
   
  
  
  
  
  
 
  
 
 
  
  
  
  
  
  
  
  
   
  
  
 
  
   
 
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
1 of 9 4
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
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 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:
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
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 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:
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
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 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:
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
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 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:
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
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 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:
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.
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
3 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:
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.
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
3 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:
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. 
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
3 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:
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
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 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
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
3 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:
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.
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
4 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:
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 
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
4 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:
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.
  Pr ot oc ol  v 3. 0 | 
N N 9 5 3 6 - 4 3 7 8
4 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:
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  

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan 
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*: 
12 April 2021 
 
*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. 


Link
List of contents
Statistical analysis plan......................................................................................................................
Date:
Novo Nordisk
Version:
Status:
Semaglutide s.c. 2.4 mg once weekly
Trial ID: NN9536 4378
Clinical Trial Report
Appendix 16.1.9
11 May 2021
1.0
Final
16.1.9 Documentation of statistical methods
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
12 April 2021 Novo Nordisk 
Trial ID: NN9536-4378 
Version: 
1.0 
UTN:U1111-1202-1740 
Status: 
Final 
EudraCT No.:2017-003726-32 
Page: 
1 of 25 
 
Statistical Analysis Plan 
Trial ID: NN9536-4378 
 
STEP 5 
 
Two-year effect and safety of semaglutide 2.4 mg once-
weekly in subjects with overweight or obesity 
 
Author 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  SAP  NN9536-4378 | 
NN9536 -4378
1 of 25
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
Redacted statistical analysis plan 
Includes redaction of personal identifiable information only. 
. 


Statistical Analysis Plan 
 
Date: 
12 April 2021 Novo Nordisk 
Trial ID: NN9536-4378 
Version: 
1.0 
UTN:U1111-1202-1740 
Status: 
Final 
EudraCT No.:2017-003726-32 
Page: 
2 of 25 
 
Table of contents    
 
Page 
Table of contents ............................................................................................................................................... 2 
List of abbreviations ......................................................................................................................................... 3 
1 
Introduction ............................................................................................................................................... 4 
1.1 
Trial information ............................................................................................................................ 4 
1.1.1 
Objective(s) .................................................................................................................. 4 
1.1.1.1 
Primary objective .................................................................................. 4 
1.1.1.2 
Secondary objectives ............................................................................. 4 
1.1.2 
Estimands ..................................................................................................................... 4 
1.1.2.1 
Primary estimand ................................................................................... 4 
1.1.2.2 
Secondary estimand ............................................................................... 4 
1.1.3 
Endpoints ..................................................................................................................... 5 
1.1.3.1 
Primary endpoint ................................................................................... 5 
1.1.3.2 
Secondary endpoints ............................................................................. 5 
1.1.4 
Type of trial ................................................................................................................. 6 
1.2 
Scope of the statistical analysis plan .............................................................................................. 7 
2 
Statistical considerations .......................................................................................................................... 7 
2.1 
Sample size determination ............................................................................................................. 7 
2.2 
Definition of analysis sets .............................................................................................................. 9 
2.3 
Statistical analyses ......................................................................................................................... 9 
2.3.1 
Primary endpoint ........................................................................................................ 10 
2.3.2 
Secondary endpoints .................................................................................................. 15 
2.3.2.1 
Confirmatory secondary endpoints ..................................................... 15 
2.3.2.2 
Supportive secondary endpoints .......................................................... 16 
2.3.3 
Exploratory endpoints ................................................................................................ 18 
2.3.3.1 
Control of Eating Questionnaire (CoEQ) ............................................ 18 
2.3.4 
Explorative statistical analysis for pharmacogenetics and biomarkers ...................... 21 
2.3.5 
Other analyses ............................................................................................................ 21 
2.4 
Pharmacokinetic and/or pharmacodynamic modelling ................................................................ 21 
3 
Changes to the statistical analyses planned in the protocol ................................................................. 21 
3.1 
Trial-specific changes .................................................................................................................. 21 
3.2 
Changes applied across STEP trials ............................................................................................. 22 
4 
Change log................................................................................................................................................ 24 
5 
References ................................................................................................................................................ 25 
 
  SAP  NN9536-4378 | 
NN9536 -4378
2 of 25
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
12 April 2021 
Novo Nordisk 
Trial ID: NN9536-4378 
Version: 
1.0 
UTN:U1111-1202-1740 
Status: 
Final 
EudraCT No.:2017-003726-32 
Page: 
3 of 25 
 
List of abbreviations 
AD 
 
available but discontinued 
AE 
 
adverse event 
ANCOVA 
 
analysis of covariance 
AT 
 
available on randomised treatment 
BMI 
 
body mass index 
CI 
 
confidence interval 
dBP 
 
diastolic blood pressure 
FAS 
 
full analysis set 
FFA 
 
free fatty acid 
FPG 
 
fasting plasma glucose 
HbA1c 
 
glycated haemoglobin 
HDL 
 
high density lipoprotein 
hsCRP 
 
high-sensitivity C-Reactive Protein 
LAO-OT 
 
last available observation during the on-treatment period 
LDL 
 
low-density lipoprotein 
MD 
 
missing and discontinued 
MedDRA 
 
Medical Dictionary for Regulatory Activities 
MMRM 
 
mixed model for repeated measurements 
MT 
 
missing on randomised treatment 
OR 
 
odds ratio 
PYE 
 
patient years of exposure 
PYO 
 
patient years of observation 
RD-MI 
 
multiple imputation using retrieved subjects 
SAE 
 
serious adverse event 
SAP 
 
statistical analysis plan 
SAS 
 
safety analysis set 
sBP 
 
systolic blood pressure 
s.c. 
 
subcutaneus 
SD 
 
standard deviation 
TEAE 
 
treatment-emergent adverse event 
VLDL 
 
very low density lipoprotein 
WC 
 
waist circumference 
  SAP  NN9536-4378 | 
NN9536 -4378
3 of 25
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
12 April 2021 
Novo Nordisk 
Trial ID: NN9536-4378 
Version: 
1.0 
UTN:U1111-1202-1740 
Status: 
Final 
EudraCT No.:2017-003726-32 
Page: 
4 of 25 
 
1 
Introduction 
1.1 
Trial information 
1.1.1 
Objective(s) 
1.1.1.1 
Primary objective 
To compare the two-year effect of semaglutide s.c. 2.4 mg once weekly versus semaglutide placebo 
as an adjunct to a reduced-calorie diet and increased physical activity in subjects with overweight or 
obesity on body weight. 
1.1.1.2 
Secondary objectives 
To compare the two-year effect of semaglutide s.c. 2.4 mg once weekly versus semaglutide placebo 
as an adjunct to a reduced-calorie diet and increased physical activity in subjects with overweight or 
obesity on: 
• Cardiovascular risk factors  
• Glucose metabolism 
To compare the one-year effect of semaglutide s.c. 2.4 mg once weekly versus semaglutide placebo 
as an adjunct to a reduced-calorie diet and increased physical activity in subjects with overweight or 
obesity on body weight. 
To compare the two-year safety and tolerability of semaglutide s.c. 2.4 mg once weekly versus 
semaglutide placebo as an adjunct to a reduced-calorie diet and increased physical activity in 
subjects with overweight or obesity. 
1.1.2 
Estimands 
1.1.2.1 
Primary estimand 
The estimand will quantify the average treatment effect of semaglutide relative to semaglutide 
placebo after 104 weeks, as an adjunct to a reduced-calorie diet and increased physical activity, in 
all randomised subjects regardless of adherence to treatment and regardless of initiation of other 
anti-obesity therapies (i.e. weight management drugs or bariatric surgery) (“treatment policy” 
estimand). The estimand will cover all effect-related objectives. 
The following expansion of the primary estimand will cover the supportive secondary objectives 
related to body weight. The estimand will quantify the average treatment effect of semaglutide 
relative to semaglutide placebo after 52 weeks, as an adjunct to a reduced-calorie diet and increased 
physical activity, in all randomised subjects regardless of adherence to treatment and regardless of 
initiation of other anti-obesity therapies. 
1.1.2.2 
Secondary estimand 
The estimand will quantify the average treatment effect of semaglutide relative to semaglutide 
placebo after 104 weeks, as an adjunct to a reduced-calorie diet and increased physical activity, in 
all randomised subjects had they remained on their randomised treatment for the entire planned 
duration of the trial and not initiated any other anti-obesity therapies (i.e. weight management drugs 
  SAP  NN9536-4378 | 
NN9536 -4378
4 of 25
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
12 April 2021 
Novo Nordisk 
Trial ID: NN9536-4378 
Version: 
1.0 
UTN:U1111-1202-1740 
Status: 
Final 
EudraCT No.:2017-003726-32 
Page: 
5 of 25 
 
or bariatric surgery) (“hypothetical” estimand). The estimand will cover all effect-related 
objectives. 
1.1.3 
Endpoints 
1.1.3.1 
Primary endpoint 
The primary endpoints addressing the primary objective: 
• Change from baseline (week 0) to week 104 in body weight (%) 
• Subjects who after 104 weeks achieve (yes/no):  
• 
Body weight reduction ≥ 5% from baseline (week 0) 
1.1.3.2 
Secondary endpoints 
The confirmatory and supportive secondary endpoints addressing the primary and secondary 
objectives are listed below. 
Confirmatory secondary endpoints 
• Subjects who after 104 weeks achieve (yes/no):  
• 
Body weight reduction ≥ 10% from baseline (week 0) 
• 
Body weight reduction ≥ 15% from baseline (week 0) 
• Change from baseline (week 0) to week 104 in: 
• 
Waist circumference (cm) 
• 
Systolic blood pressure (mmHg) 
 
Supportive secondary endpoints 
Effect endpoints: 
• Change from baseline (week 0) to week 104 in: 
• 
Body weight reduction ≥ 20% from baseline (week 0) 
• 
Body weight (kg) 
• 
BMI (kg/m2) 
• 
HbA1c (%, mmol/mol) 
• 
FPG (mg/dL, mmol/L) 
• 
Fasting serum insulin (mIU/L, pmol/L) 
• 
Diastolic blood pressure (mmHg) 
• Lipids (mg/dL, mmol/L) 
• Total cholesterol 
• High density lipoprotein (HDL) cholesterol 
• Low density lipoprotein (LDL) cholesterol 
• Very low density lipoprotein (VLDL) cholesterol 
• Free fatty acids (FFA) 
• Triglycerides 
• 
High sensitivity C-Reactive Protein (hsCRP) (mg/L) 
• Change from baseline (week 0) to week 52 in: 
• 
Body weight (%, kg) 
  SAP  NN9536-4378 | 
NN9536 -4378
5 of 25
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
12 April 2021 
Novo Nordisk 
Trial ID: NN9536-4378 
Version: 
1.0 
UTN:U1111-1202-1740 
Status: 
Final 
EudraCT No.:2017-003726-32 
Page: 
6 of 25 
 
• 
BMI (kg/m2) 
• 
Waist circumference (cm) 
• Subjects who after 52 weeks achieve (yes/no):  
• 
Body weight reduction ≥ 5% from baseline (week 0) 
• 
Body weight reduction ≥ 10% from baseline (week 0) 
• 
Body weight reduction ≥ 15% from baseline (week 0) 
• 
Body weight reduction ≥ 20% from baseline (week 0) 
Safety endpoints: 
• Number of treatment emergent adverse events (TEAEs) from baseline (week 0) to week 111 
• Number of serious adverse events (SAEs) from baseline (week 0) to week 111 
• Change from baseline (week 0) to week 104 in: 
• 
Pulse (bpm) 
• 
Amylase (U/L) 
• 
Lipase (U/L) 
• 
Calcitonin (ng/L) 
 
Exploratory endpoints 
The exploratory endpoints addressing the exploratory objectives: 
• Change from baseline (week 0) to week 104 in: 
• 
Glycaemic category (normo-glycaemia, pre-diabetes, T2D) 
• 
Antihypertensive medication (decrease, no change, increase) 
• 
Lipid-lowering medication (decrease, no change, increase) 
• Subjects who from randomisation to week 104 have permanently discontinued randomised trial 
product (yes/no) 
• Time to permanent discontinuation of randomised trial product (weeks) 
• Control of Eating Questionnaire (CoEQ): Scores from the 4 domains and 19 individual items 
(applicable for US and Canada only) 
 
1.1.4 
Type of trial 
This is a 104-week, randomised, double-blind, placebo-controlled, two-armed, parallel group, 
multi-centre, multinational clinical trial comparing semaglutide 2.4 mg once weekly with 
semaglutide placebo, as an adjunct to a reduced-calorie diet and increased physical activity, in 
subjects with overweight or obesity. 
 
The trial includes a screening visit to assess the subject’s eligibility followed by visits/phone 
contacts every 2nd week during dose escalation. From week 20, visits/phone contacts will take place 
every 4th week for the remaining maintenance period until end of treatment (week 104). A follow-
up visit (‘End of trial’) for safety assessments is scheduled 7 weeks after end of treatment to 
account for the exposure to the long half-life of semaglutide. 
 
  SAP  NN9536-4378 | 
NN9536 -4378
6 of 25
CONFIDENTIAL




Statistical Analysis Plan 
 
Date: 
12 April 2021 
Novo Nordisk 
Trial ID: NN9536-4378 
Version: 
1.0 
UTN:U1111-1202-1740 
Status: 
Final 
EudraCT No.:2017-003726-32 
Page: 
8 of 25 
 
significant superiority of semaglutide 2.4 mg vs. semaglutide placebo must be demonstrated for 
each of the primary endpoints. 
In the analysis approach addressing the primary estimand, week 104 assessments from retrieved 
subjects (AD) are used. These data are also used to impute missing measurements at week 104 for 
non-retrieved subjects (MD). The imputation is done separately within each treatment arm (see 
description below). However, for the power calculations missing values (MT and MD), regardless 
of treatment arm, are assumed to be similar to semaglutide placebo subjects. These assumptions are 
likely conservative with respect to the power, and correspond to the jump to reference sensitivity 
analysis planned below. 
Assumptions 
The common assumptions for the power calculations are 
• The significance level is 5% 
• The randomisation ratio is 1:1  
• For continuous endpoints the t-test on the mean difference assuming equal variances is used 
• For binary endpoints the Pearson chi-square test for two independent proportions is used  
• 40% of subjects discontinue permanently and 50% of these are retrieved (AD) at week 104 
• All subjects in the semaglutide placebo arm are assumed to have same effect as subjects who 
complete the trial on semaglutide placebo (AT) 
• Retrieved subjects (AD) in the semaglutide 2.4 mg arm are assumed to have an effect 
corresponding to 25% of the treatment difference (compared to semaglutide placebo) of subjects 
who complete the trial on semaglutide 2.4 mg (AT) 
• Non-retrieved subjects (MD) in the semaglutide 2.4 mg arm are assumed to have an effect 
corresponding to semaglutide placebo  
Further assumptions made to calculate the power for each of the primary and confirmatory 
secondary endpoints are based on findings from other projects conducted by Novo Nordisk 
(NN8022 (SCALE), NN9535 (SUSTAIN), NN9924 (PIONEER)), and trial NN9536-4153 and are 
presented in Table 2-2. For weight, waist circumference and systolic blood pressure a 2 year 
completer was assumed to have 90% the effect of a 1 year completer. 
Given these assumptions, the sample size of 300 subjects (150 in each arm), gives an effective 
power (marginal powers multiplied) of 43%. As sample size is primarily driven by the two primary 
endpoints, additional scenarios for assumptions are not included due to the high power for these 
endpoints. 
  SAP  NN9536-4378 | 
NN9536 -4378
8 of 25
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
12 April 2021 
Novo Nordisk 
Trial ID: NN9536-4378 
Version: 
1.0 
UTN:U1111-1202-1740 
Status: 
Final 
EudraCT No.:2017-003726-32 
Page: 
9 of 25 
 
Table 2-2 
Assumptions, marginal power and effective power for each endpoint in the 
hierarchical testing procedure given an anticipated number of 300 randomised 
subjects  
Order 
Endpoint 
Assumed mean (±SD) or 
proportion for completers 
Expected mean 
(±SD) or 
proportion 
Expected 
difference or 
proportion 
ratio 
Marginal 
power 
(%) 
Effective 
power 
(%) 
Semaglutide 
2.4 mg 
Semaglutide 
placebo 
Semaglutide 
2.4 mg 
1 
% weight change # 
12.6 (±11) 
3.0 (±11) 
9.2 (±12) 
6.2%-points 
> 99 
> 99 
2 
5% responders 
76% 
43% 
64% 
1.5 
96 
96 
3 
10% responders 
59% 
26% 
48% 
1.8 
97 
93 
4 
15% responders 
41% 
14% 
31% 
2.2 
96 
89 
5 
WC change (cm) # 
9.3 (±11) 
4 (±11) 
7.4 (±12) 
3.4 cm 
69 
62 
6 
sBP change (mmHg) # 
7.6 (±13) 
1.5 (±13) 
5.5 (±14) 
4 mmHg 
69 
43 
SD = standard deviation; WC = waist circumference; sBP = systolic blood pressure; # shown as a positive number 
All tests in the hierarchy are based on the primary estimand 
2.2 
Definition of analysis sets 
Two analysis sets are defined: 
• The full analysis set (FAS) includes all randomised subjects according to the intention-to-treat 
principle. Subjects in the FAS will contribute to evaluation “as randomised”. 
• The safety analysis set (SAS) includes all randomised subjects exposed to at least one dose of 
randomised treatment. Subjects in the SAS will contribute to evaluation “as treated”. 
Any observation excluded from the analysis will be documented before database lock with the 
reason for exclusion provided. 
Two observation periods are defined for each subject: 
• In-trial: The in-trial period is defined as the uninterrupted time interval from date of 
randomisation to date of last contact with trial site. 
• On-treatment (with trial product): A time-point is considered as ‘on-treatment’ if any dose of 
trial product has been administered within the prior 2 weeks (14 days). The on-treatment period 
is defined as all times which are considered on-treatment. 
• In general, the on-treatment period will therefore be from the date of first trial product 
administration to date of last trial product administration (±14 days) excluding potential off-
treatment time intervals triggered by at least two consecutive missed doses. 
• For the evaluation of adverse events, the lag time for each on-treatment time interval is 7 
weeks (49 days). 
The in-trial and on-treatment periods define the patient years of observation (PYO) and patient 
years of exposure (PYE), respectively, as the total time duration in the periods. 
2.3 
Statistical analyses 
If necessary, a statistical analysis plan (SAP) may be written in addition to the protocol, including a 
more technical and detailed elaboration of the statistical analyses. The SAP will be finalised before 
database lock. 
  SAP  NN9536-4378 | 
NN9536 -4378
9 of 25
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
12 April 2021 
Novo Nordisk 
Trial ID: NN9536-4378 
Version: 
1.0 
UTN:U1111-1202-1740 
Status: 
Final 
EudraCT No.:2017-003726-32 
Page: 
10 of 25 
 
Effect endpoints will be analysed using the FAS; safety endpoints will be analysed using the SAS.  
Results from statistical analyses will generally be accompanied by two-sided 95% confidence 
intervals and corresponding p-values. Superiority will be claimed if p-values are less than 5% and 
the estimated treatment contrasts favours semaglutide 2.4 mg.  
Handling of missing baseline data 
The last available and eligible observation at or before randomisation, is used as the baseline value. 
If no assessments are available, the mean value at randomisation across all subjects is used as the 
baseline value. 
2.3.1 
Primary endpoint 
Definition of primary endpoint: % weight change 
Change from baseline (week 0) to week 104 in body weight (%) is defined as 
% weight change = (body weight at week 104 – body weight at baseline)
body weight at baseline
 ×100. 
Definition of primary endpoint: 5% responders 
A body weight reduction of at least 5% from baseline (week 0) to week 104 is defined as  
5% responder = {1 if  % weight change ≤ – 5%
0 if  % weight change > – 5%. 
Analyses addressing the primary estimand 
The following statistical analyses and imputation methods are designed to address the primary 
estimand, i.e. to assess the effectiveness of semaglutide 2.4 mg.  
The analysis model for % weight change is a linear regression (ANCOVA) of % weight change 
with randomised treatment as a factor and baseline body weight (kg) as covariate. The estimated 
treatment difference between semaglutide 2.4 mg and semaglutide placebo will be reported together 
with the associated two-sided 95% CI and corresponding p-value. 
The analysis model for the 5% responder endpoint is a logistic regression using randomised 
treatment as a factor and baseline body weight (kg) as covariate. The estimated odds ratio (OR) 
between semaglutide 2.4 mg and semaglutide placebo will be reported together with the associated 
two-sided 95% CI and corresponding p-value. 
The superiority tests of semaglutide 2.4 mg vs. semaglutide placebo will be carried out as follows 
for the two analysis models. 
Let μsemaglutide and μsemaglutide placebo denote the true mean of % weight change for semaglutide 2.4 mg 
and semaglutide placebo group, respectively. The null and alternative hypotheses tested are 
𝐻: 𝜇𝑠𝑒𝑚𝑎𝑔𝑙𝑢𝑡𝑖𝑑𝑒≥𝜇𝑠𝑒𝑚𝑎𝑔𝑙𝑢𝑡𝑖𝑑𝑒 𝑝𝑙𝑎𝑐𝑒𝑏𝑜 𝑣𝑠
𝐻𝐴: 𝜇𝑠𝑒𝑚𝑎𝑔𝑙𝑢𝑡𝑖𝑑𝑒< 𝜇𝑠𝑒𝑚𝑎𝑔𝑙𝑢𝑡𝑖𝑑𝑒 𝑝𝑙𝑎𝑐𝑒𝑏𝑜.  
  SAP  NN9536-4378 | 
NN9536 -4378
10 of 25
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
12 April 2021 
Novo Nordisk 
Trial ID: NN9536-4378 
Version: 
1.0 
UTN:U1111-1202-1740 
Status: 
Final 
EudraCT No.:2017-003726-32 
Page: 
11 of 25 
 
The hypothesis will be rejected and superiority claimed, if the upper limit of the estimated two-
sided 95% CI is below 0. 
Let ORsemaglutide/semaglutide placebo denote the true odds ratio between semaglutide 2.4 mg and 
semaglutide placebo. The null and alternative hypotheses tested are 
𝐻: 𝑂𝑅𝑠𝑒𝑚𝑎𝑔𝑙𝑢𝑡𝑖𝑑𝑒/𝑠𝑒𝑚𝑎𝑔𝑙𝑢𝑡𝑖𝑑𝑒 𝑝𝑙𝑎𝑐𝑒𝑏𝑜≤1 𝑣𝑠
𝐻𝐴: 𝑂𝑅𝑠𝑒𝑚𝑎𝑔𝑙𝑢𝑡𝑖𝑑𝑒/𝑠𝑒𝑚𝑎𝑔𝑙𝑢𝑡𝑖𝑑𝑒 𝑝𝑙𝑎𝑐𝑒𝑏𝑜> 1.  
The hypothesis will be rejected and superiority claimed, if the lower limit of the estimated two-
sided 95% CI is above 1. 
Handling of missing week 104 values for the primary estimand 
All available data at week 104 (AT and AD) are used and missing values (MT and MD) at week 
104 will be imputed and the endpoints will be derived from the imputed values. Several approaches 
for imputation will be applied. First, a description of the primary imputation approach to address the 
primary estimand for the primary endpoints is given followed by a description of the sensitivity 
analyses used to assess the robustness of the primary analysis results. The sensitivity analyses 
investigate how assumptions on body weight development after discontinuation of randomised 
treatment impact the estimated treatment contrasts between semaglutide 2.4 mg and semaglutide 
placebo. An illustration of all imputation approaches for the primary estimand is given in Figure 1. 
Primary imputation approach for the primary estimand 
Multiple imputation approach using retrieved subjects (RD-MI): The primary imputation approach 
for the primary estimand is a multiple imputation similar to the one described by McEvoy1. Missing 
body weight measurement at week 104 for non-retrieved subjects (MD) are imputed using 
assessments from retrieved subjects (AD) in each randomised treatment arm. This will be done 
according to the timing of last available observation on-treatment (LAO-OT) of body weight prior 
to week 104. Missing body weight measurements at week 104 for subjects on randomised treatment 
(MT) are imputed in a similar way by sampling from available measurements at week 104 from 
subjects on randomised treatment (AT) in the relevant randomised treatment arm. The multiple 
imputation approach is done in three steps: 
1. Imputation: Defines an imputation model using retrieved subjects (AD) from FAS and done 
within groups defined by randomised treatment and the timing of the LAO-OT of body weight. 
The model will be a linear regression of body weight (kg) at week 104 with gender 
(male/female), baseline BMI (kg/m2) (in categories -<35, 35-<40, ≥40) and timing of the LAO-
OT of body weight as factors and baseline body weight (kg) and LAO-OT of body weight (kg) 
as covariates. No interactions will be included. The grouping of timing will be done by quarters 
(intervals of 26 weeks for endpoints evaluating the change after 104 weeks, intervals of 13 
weeks for endpoints evaluating the change after 52 weeks). If timing by quarters is too 
restrictive, halves (intervals of 52 weeks for endpoints evaluating the change after 104 weeks, 
intervals of 26 weeks for endpoints evaluating the change after 52 weeks) or excluding timing 
will be used. The timing by quarters or halves is defined as too restrictive if the imputation 
model cannot be fit due to inadequate numbers of retrieved subjects in 1 or more groups. If the 
imputation model still cannot be fit after excluding timing then the model will be further reduced 
  SAP  NN9536-4378 | 
NN9536 -4378
11 of 25
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
12 April 2021 
Novo Nordisk 
Trial ID: NN9536-4378 
Version: 
1.0 
UTN:U1111-1202-1740 
Status: 
Final 
EudraCT No.:2017-003726-32 
Page: 
12 of 25 
 
until the model can be fit. Reduction will be done in a fixed order by first removing gender, then 
collapsing the two highest baseline BMI groups into one (≥35) and finally removing baseline 
BMI group. If no LAO-OT exists post-baseline then LAO-OT will be the baseline body weight 
and the timing will be the first interval. If any subjects are MT, an imputation model for missing 
body weight measurements at week 104 for MT subjects will also be defined using AT subjects 
in a similar way. The estimated posterior distribution for the parameters (regression coefficients 
and variances) in the imputation models are then used to impute missing week 104 body weight 
values for each randomised treatment arm. This will be done 1,000 times and results in 1,000 
complete data sets. 
2. Analysis: Analysis of each of the 1,000 complete data sets, using the analysis models 
(ANCOVA and logistic regression) results in 1,000 times 2 estimations. 
3. Pooling: Integrates the 1,000 times 2 estimation results into two final results using Rubin’s 
formula. 
Based on NN9536-4153 phase 2 results 1,000 copies should be sufficient to establish stable results. 
If 1,000 copies are insufficient, 10,000 copies will be used. The multiple imputations will be 
generated using Novo Nordisk trial number 95364378 as seed number. In addition to the seed 
number, it is specified that the dataset is sorted by subject ID. 
Sensitivity analyses 
Jump to reference multiple imputation approach (J2R-MI): Missing values of body weight at week 
104 (MT and MD) for both the semaglutide 2.4 mg and semaglutide placebo group are imputed by 
sampling among all available assessments at week 104 in the semaglutide placebo group (AT and 
AD). This approach makes the assumption that subjects instantly after discontinuation lose any 
effect of randomised treatment beyond what can be expected from semaglutide placebo treatment as 
adjunct to reduced-calorie diet and increased physical activity2. The multiple imputation approach 
is done as above with the first step replaced by: 
1. Imputation: Defines an imputation model using semaglutide placebo subjects from FAS with a 
week 104 measurement (AT and AD). The model will be a linear regression of body weight (kg) 
at week 104 with gender (male/female), BMI (kg/m2) (in categories -<35, 35-<40, ≥40) as 
factors and baseline body weight (kg) as covariate. No interactions will be included. If the 
imputation model cannot be fit due to inadequate numbers of retrieved subjects in one or more 
groups, then the imputation model will be reduced until the model can be fit. Reduction will be 
done in a fixed order by first removing gender, then collapsing the two highest baseline BMI 
groups into one (≥35) and finally removing baseline BMI group. The estimated posterior 
distribution for the parameters (regression coefficients and variances) in the imputation models 
are then used to impute missing week 104 body weight values for each randomised treatment 
arm. This will be done 1,000 times and results in 1,000 complete data sets. 
 
The jump to reference approach is the basis for the sample size calculations.  
A single imputation approach as done by Sacks3 (S1-SI and S2-SI): Missing weight measurements 
at week 104 for non-retrieved subjects (MD) are imputed using a weight regain rate of 0.3 kg/month 
after LAO but truncated at no change from baseline whenever the extrapolation would lead to a 
positive weight gain relative to baseline. If a subject's weight at drug discontinuation represented a 
  SAP  NN9536-4378 | 
NN9536 -4378
12 of 25
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
12 April 2021 
Novo Nordisk 
Trial ID: NN9536-4378 
Version: 
1.0 
UTN:U1111-1202-1740 
Status: 
Final 
EudraCT No.:2017-003726-32 
Page: 
13 of 25 
 
gain in weight relative to baseline, no additional gain will be imputed, and the unfavourable gain is 
carried forward to week 104. The weight regain imputation will be done for both randomised arms 
(S1-SI). Additionally, a version where only the semaglutide 2.4 mg arm uses the regain rate while 
the semaglutide placebo arm uses last available observation (corresponding to a weight regain rate 
of 0 kg/month) will be performed (S2-SI). For both versions, missing weight measurements at week 
104 for subjects on randomised treatment (MT) are imputed by using LAO.  
Tipping-point multiple imputation analysis (TP-MI): First, missing data are imputed according to 
the primary multiple imputation approach. Then, a penalty is added to the imputed values at week 
104. The approach is to explore a range of penalties for both treatment groups, and the impact these 
would have on the study conclusions. The 2-dimensional space of penalties covering the range from 
-30% to 30% will be explored for both treatment groups. This sensitivity analysis evaluates the 
robustness of the superiority conclusions to departures from the observed change in body weight in 
both treatment groups. 
Mixed model for repeated measurements (MMRM): This ‘MMRM for effectiveness’ will use all 
assessments regardless of adherence to randomised treatment, including assessments at week 104 
for retrieved drop-outs (AD). The MMRM for effectiveness will be fitted using the same factor and 
covariate as for the primary analyses all nested within visit. An unstructured covariance matrix for 
measurements within the same subject will be employed, assuming that measurements for different 
subjects are independent. For the 5% responder analysis, the same MMRM will be applied except 
that body weight (kg) will be used as response variable in the model. Individual missing values for 
body weight at week 104 will be predicted from the MMRM and used to classify each subject as 
5% responder or not. This classification will then be analysed using the same logistic regression 
model as in the primary analysis of the primary estimand. 
Subjects with missing week 104 assessment as non-responders: For the 5% responder analysis an 
analysis using subjects with missing week 104 assessment as non-responders in the logistic 
regressions will be done. 
  SAP  NN9536-4378 | 
NN9536 -4378
13 of 25
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
12 April 2021 
Novo Nordisk 
Trial ID: NN9536-4378 
Version: 
1.0 
UTN:U1111-1202-1740 
Status: 
Final 
EudraCT No.:2017-003726-32 
Page: 
14 of 25 
 
 
Figure 1 
Illustration of imputation approaches for the primary estimand 
Analysis addressing the secondary estimand 
The secondary estimand for % weight change addresses the efficacy of semaglutide 2.4 mg and will 
be assessed using a ‘MMRM for efficacy’. Week 104 assessments for retrieved drop-outs (AD) are 
not used in this analysis. The MMRM for efficacy will use assessments only from subjects who are 
taking the randomised treatment until end of treatment or until first discontinuing of randomised 
treatment. The derived date of the second consecutive missed dose will be used as the latest date for 
using assessments in this MMRM. The assessment closest in time and before the derived date of the 
  SAP  NN9536-4378 | 
NN9536 -4378
14 of 25
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
12 April 2021 
Novo Nordisk 
Trial ID: NN9536-4378 
Version: 
1.0 
UTN:U1111-1202-1740 
Status: 
Final 
EudraCT No.:2017-003726-32 
Page: 
15 of 25 
 
second consecutive missed dose will be used as last assessment on randomised treatment. For 
subjects who initiate other anti-obesity therapies before completion or first discontinuing of 
randomised treatment, the date of starting weight management drugs or undergoing bariatric 
surgery will be used as latest date for using assessments in this MMRM. Similarly, the assessment 
closest in time and before the date of starting weight management drugs or undergoing bariatric 
surgery will be used as last assessment on randomised treatment. The MMRM for efficacy will be 
fitted using % weight change and the same factor and covariate as for the primary analyses all 
nested within visit. An unstructured covariance matrix for measurements within the same subject 
will be employed, assuming that measurements for different subjects are independent.  
The secondary estimand for 5% responders will be assessed using the same MMRM for efficacy 
except that body weight (kg) will be used as response variable in the model. For subjects with 
missing body weight at week 104, individual values for body weight will be predicted from the 
MMRM and used to classify each subject as 5% responder or not. This classification will then be 
analysed using a logistic regression model with treatment as the only factor. 
An overview of all analysis and imputation methods to address the primary and secondary 
estimands for the primary endpoints is given in Table 2-3. 
2.3.2 
Secondary endpoints 
2.3.2.1 
Confirmatory secondary endpoints 
Confirmatory secondary endpoints are listed in section 4.2.2.1 of the study protocol and are all 
included in the fixed-sequence statistical strategy, see above. All tests are tests of superiority of 
semaglutide 2.4 mg to semaglutide placebo.  
Analyses addressing the primary estimand 
All confirmatory secondary endpoints will be analysed using the same imputation approach as used 
for the primary endpoints and to address the primary estimand. The imputation model is the same as 
for the primary endpoints with body weight replaced by assessments of the endpoint to be analysed. 
The statistical model for continuous endpoints will be ANCOVA with factor and covariate as for 
the primary endpoint % weight change with baseline body weight replaced by the baseline 
assessment of the endpoint to be analysed. The statistical model for body weight responder 
endpoints will be logistic regression with factors and covariate as for the primary endpoint 5% 
responders.  
Analyses addressing the secondary estimand 
The confirmatory secondary endpoints which relate to the primary objective for week 104 will be 
analysed to address the secondary estimand using the same MMRM for efficacy described for the 
primary endpoints. 
Sensitivity analyses for confirmatory secondary endpoints 
For all continuous confirmatory secondary endpoints a sensitivity analysis using jump to reference 
as imputation approach will be carried out. For all binary confirmatory secondary endpoints a 
sensitivity analysis using non-retrieved subjects as non-responders will be carried out. 
  SAP  NN9536-4378 | 
NN9536 -4378
15 of 25
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
12 April 2021 
Novo Nordisk 
Trial ID: NN9536-4378 
Version: 
1.0 
UTN:U1111-1202-1740 
Status: 
Final 
EudraCT No.:2017-003726-32 
Page: 
16 of 25 
 
An overview of all analysis and imputation methods to address the primary and secondary 
estimands for confirmatory secondary endpoints is given in Table 2-3. 
Table 2-3 
Analysis and imputation methods to address the primary and secondary 
estimands for the primary and confirmatory secondary endpoints in the 
statistical testing hierarchy 
Objective 
Endpoint 
Test 
order 
Endpoint 
type 
Estimand 
Analysis 
set 
Statistical 
model 
Imputation 
approach 
Sensitivity 
analyses 
Primary endpoints 
Primary 
% weight change 
1 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
J2R-MI 
S1-SI 
S2-SI 
TP-MI 
MMRM 
Secondary 
FAS 
MMRM 
- 
- 
Primary 
5% responders 
2 
Binary 
Primary 
FAS 
LR 
RD-MI 
J2R-MI 
S1-SI 
S2-SI 
TP-MI 
MMRM 
Non-
responder 
Secondary 
FAS 
LR 
MMRM 
- 
Confirmatory secondary endpoints 
Primary 
10% responders 
3 
Binary 
Primary 
FAS 
LR 
RD-MI 
Non-
responders 
Secondary 
FAS 
LR 
MMRM 
- 
Primary 
15% responders 
4 
Binary 
Primary 
FAS 
LR 
RD-MI 
Non-
responders 
Secondary 
FAS 
LR 
MMRM 
- 
Primary 
WC change (cm) 
5 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
J2R-MI 
Secondary 
FAS 
MMRM 
- 
- 
Secondary 
sBP change (mmHg) 
6 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
J2R-MI 
Secondary 
FAS 
MMRM 
- 
- 
FAS = full analysis set; ANCOVA = analysis of covariance; RD-MI = multiple imputation using retrieved subjects; 
J2R-MI = jump to reference multiple imputation; S1-SI and S2-SI = single imputation as done by Sacks; TP-MI = 
tipping point multiple imputation; MMRM = mixed model for repeated measurements; LR = logistic regression; WC = 
waist circumference; sBP = systolic blood pressure 
Test order refers to the order of the endpoint in the statistical test hierarchy outlined in Table 2-3. 
2.3.2.2 
Supportive secondary endpoints 
Supportive secondary endpoints are listed in section 4.2.2.2 of the study protocol. All tests are tests 
of superiority of semaglutide 2.4 mg to semaglutide placebo.  
Analyses addressing the primary estimand 
The effect-related supportive secondary endpoints will be analysed using the same imputation 
approach as used for the primary endpoints and to address the primary estimand. The imputation 
model is the same as for the primary endpoints with body weight replaced by assessments of the 
endpoint to be analysed. The statistical model for continuous endpoints will be ANCOVA with 
factor and covariate as for the primary endpoint % weight change with baseline body weight 
replaced by the baseline assessment of the endpoint to be analysed.  
 
For lipids, fasting serum insulin and hsCRP a multiplicative model will be used, i.e. the ratio 
between post randomisation measurements and baseline will be calculated instead of differences, 
and both the dependent variable and covariate will be log-transformed. 
  SAP  NN9536-4378 | 
NN9536 -4378
16 of 25
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
12 April 2021 
Novo Nordisk 
Trial ID: NN9536-4378 
Version: 
1.0 
UTN:U1111-1202-1740 
Status: 
Final 
EudraCT No.:2017-003726-32 
Page: 
17 of 25 
 
Analyses addressing the secondary estimand 
The supportive secondary endpoints which relate to the primary objective will be analysed to 
address the secondary estimand using the same MMRM for efficacy described for the primary 
endpoints. 
Additional considerations for statistical analyses 
Supportive secondary endpoints evaluating the one-year effect of semaglutide 2.4 mg will be 
analysed using the same imputation approach as used for the primary endpoints and to address the 
primary estimand. The imputation model is the same as for the primary endpoints. The statistical 
model for continuous endpoints will be ANCOVA with factor and covariate as for the primary 
endpoint % weight change. The statistical model for body weight responder endpoints will be 
logistic regression with factor and covariate as for the primary endpoint 5% responders.  
The supportive secondary endpoint “Change from baseline to week 52 in body weight (%)” will be 
compared to the primary endpoint “Change from baseline to week 104 in body weight (%)”.  
Sensitivity analyses for supportive secondary endpoints 
For supportive secondary endpoints no sensitivity analysis will be carried out. 
Analysis of safety endpoints 
The safety endpoint pulse will be analysed using an MMRM for efficacy as described in section 
2.3.1. For amylase, lipase and calcitonin descriptive statistics will be provided. The analysis of 
calcitonin will be stratified by gender. Amylase, lipase and calcitonin will be log-transformed.  
Adverse events will be defined as “treatment-emergent” (TEAE), if the onset of the event occurs in 
the on-treatment period (see definition in section 2.2). TEAEs and SAEs will be summarised by 
descriptive statistics, such as frequencies and rates. No formal statistical inference will be carried 
out based on the number of TEAEs and SAEs. All AEs will be coded using the most recent version 
of the Medical Dictionary for Regulatory Activities (MedDRA). 
An overview of all analysis and imputation methods to address the primary and secondary 
estimands for supportive secondary endpoints is given in Table 2-4. 
Table 2-4 
Analysis and imputation methods to address the primary and secondary 
estimands for supportive secondary endpoints 
Objective 
Endpoint 
Endpoint 
type 
Estimand 
Analysis 
set 
Statistical 
model 
Imputation 
approach 
Sensitivity 
analyses 
Supportive secondary endpoints (effect related) 
From baseline to week 104 
Primary 
20% responders 
Binary 
Primary 
FAS 
LR 
RD-MI 
- 
Secondary 
FAS 
LR 
MMRM 
- 
Primary 
Weight change (kg) 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Primary 
BMI change (kg/m2) 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Secondary 
HbA1c change (%, mmol/mol) 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Secondary 
FPG change (mg/dL, mmol/L) 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Secondary 
Fasting serum insulin change 
(mIU/L, pmol/L) 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
  SAP  NN9536-4378 | 
NN9536 -4378
17 of 25
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
12 April 2021 
Novo Nordisk 
Trial ID: NN9536-4378 
Version: 
1.0 
UTN:U1111-1202-1740 
Status: 
Final 
EudraCT No.:2017-003726-32 
Page: 
18 of 25 
 
Secondary 
dBP change (mmHg) 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Secondary 
Total cholesterol change (mg/dL, 
mmol/L) 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Secondary 
HDL change (mg/dL, mmol/L) 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Secondary 
LDL change (mg/dL, mmol/L) 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Secondary 
VLDL change (mg/dL, mmol/L) 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Secondary 
FFA change (mg/dL, mmol/L) 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Secondary 
Triglycerides change (mg/dL, 
mmol/L) 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Secondary 
hsCRP change (mg/L) 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
From baseline to week 52 
Secondary 
Weight change (%, kg) 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Secondary 
BMI change (kg/m2) 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Secondary 
WC change (cm) 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Secondary 
5% responders 
Binary 
Primary 
FAS 
LR 
RD-MI 
- 
Secondary 
FAS 
LR 
MMRM 
- 
Secondary 
10% responders 
Binary 
Primary 
FAS 
LR 
RD-MI 
- 
Secondary 
FAS 
LR 
MMRM 
- 
Secondary 
15% responders 
Binary 
Primary 
FAS 
LR 
RD-MI 
- 
Secondary 
FAS 
LR 
MMRM 
- 
Secondary 
20% responders 
Binary 
Primary 
FAS 
LR 
RD-MI 
- 
Secondary 
FAS 
LR 
MMRM 
- 
Supportive secondary endpoints (safety related) 
Secondary 
Number of TEAEs 
Continuous 
- 
SAS 
- 
- 
- 
Secondary 
Number of SAEs 
Continuous 
- 
SAS 
- 
- 
- 
Secondary 
Pulse change (bpm) 
Continuous 
- 
SAS 
MMRM 
- 
- 
Secondary 
Amylase change (U/L) 
Continuous 
- 
SAS 
Descriptive 
statistics 
- 
- 
Secondary 
Lipase change (U/L) 
Continuous 
- 
SAS 
Descriptive 
statistics 
- 
- 
Secondary 
Calcitonin change (ng/L) 
Continuous 
- 
SAS 
Descriptive 
statistics 
- 
- 
FAS = full analysis set; ANCOVA = analysis of covariance; RD-MI = multiple imputation using retrieved subjects; 
MMRM = mixed model for repeated measurements; BMI = body mass index; HbA1c = Hemoglobin A1c; FPG = fasting 
plasma glucose; dBP = diastolic blood pressure; HDL = high density lipoprotein; LDL = low density lipoprotein; VLDL 
= very low density lipoprotein; FFA = free fatty acids; hsCRP = high sensitivity C-Reactive Protein; WC = waist 
circumference; LR = logistic regression; TEAEs = treatment emergent adverse events; SAEs = serious adverse events 
2.3.3 
Exploratory endpoints 
Exploratory endpoints are listed in 4.2.3 of the study protocol. Observed data for exploratory 
endpoints will be summarised by the descriptive statistics. 
2.3.3.1 
Control of Eating Questionnaire (CoEQ) 
The CoEQ comprises 21-items designed to assess the intensity and type of food craving, as well as 
subjective sensations of appetite and mood4. In STEP5 a version with 19 items has been used (see 
Table 2-5). One of the two excluded items is open-ended and addresses specific foods, and the other 
excluded item concerns how difficult it has been to resist this specific food; and the items are 
therefore not part of any of the four domains. 
  SAP  NN9536-4378 | 
NN9536 -4378
18 of 25
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
12 April 2021 
Novo Nordisk 
Trial ID: NN9536-4378 
Version: 
1.0 
UTN:U1111-1202-1740 
Status: 
Final 
EudraCT No.:2017-003726-32 
Page: 
19 of 25 
 
Table 2-5 Overview of items in CoEQ 
Item 
No. 
Item text 
Response scale  
1 
How hungry have you felt? 
10 = Extremely hungry, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0 = Not at all hungry 
2 
How full have you felt? 
10 = Extremely full, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0 = Not at all full 
3 
How strong was your desire to eat sweet 
foods? 
10 = Extremely strong, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0 = Not at all strong 
4 
How strong was your desire to eat salty and 
spicy foods (french fries, potato chips, 
burgers, pizza, etc.)? 
10 = Extremely strong, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0 = Not at all strong 
5 
How happy have you felt? 
10 = Extremely happy, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0 = Not at all happy 
6 
How anxious have you felt? 
10 = Extremely anxious, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0 = Not at all anxious 
7 
How alert have you felt? 
10 = Extremely alert, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0 = Not at all alert 
8 
How contented have you felt? 
10 = Extremely contended, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0 = Not at all contended 
9 
During the last 7 days how often have you 
had food cravings? 
10 = Very often, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0 = Not at all  
10 
How strong have any food cravings been? 
10 = Extremely strong, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0 = Not at all strong 
11 
How difficult has it been to resist any food 
cravings? 
10 = Extremely difficult, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0 = Not at all difficult 
12 
How often have you eaten in response to 
food cravings? 
10 = After every one, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0 = Not at all 
13 
How often have you had cravings for 
chocolate and chocolate flavoured foods? 
10 = Extremely often, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0 = Not at all 
14 
How often have you had cravings for other 
sweet foods (cakes, pastries, biscuits, etc)? 
10 = Extremely often, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0 = Not at all 
15 
How often have you had cravings for fruit 
or fruit juice? 
10 = Extremely often, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0 = Not at all 
16 
How often have you had cravings for dairy 
foods (cheese, yoghurt, milk, etc.)? 
10 = Extremely often, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0 = Not at all 
17 
How often have you had cravings for 
starchy foods (bread, rice, pasta, etc.)? 
10 = Extremely often, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0 = Not at all 
18 
How often have you had cravings for salty 
and spicy foods (french fries, potato chips, 
burgers, pizza, etc.)? 
10 = Extremely often, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0 = Not at all 
19 
Generally, how difficult has it been to 
control your eating? 
10 = Extremely difficult, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0 = Not at all difficult 
 
Item scores 
The CoEQ item are scores on an 11-point graded response scale ranging from 10 to 0. No reversal 
of item scores will be done. 
Domain scores 
The sum of the items in each domain is calculated, and divided by the number of items in the 
domain in order to obtain a domain score. Items 1 and 2 are not included in any domain score. 
Details are given in Table 2-6. 
 
Table 2-6 Overview of domains for CoEQ 
Domain 
Items included in domain 
Comment 
Craving Control 
Question 9, 10, 11, 12 and 19 
The domain score is reversed such that a greater score 
represents a greater level of Craving Control (i.e. 10 to 0, 9 to 
1, …, 0 to 10) 
Positive Mood 
Question 5, 6, 7 and 8 
Scores from item 6 are reversed (i.e. 10 to 0, 9 to 1, …, 0 to 10) 
  SAP  NN9536-4378 | 
NN9536 -4378
19 of 25
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
12 April 2021 
Novo Nordisk 
Trial ID: NN9536-4378 
Version: 
1.0 
UTN:U1111-1202-1740 
Status: 
Final 
EudraCT No.:2017-003726-32 
Page: 
20 of 25 
 
Craving for Savoury 
Question 4, 16, 17 and 18 
 
Craving for Sweet 
Question 3, 13, 14, and 15 
 
 
Missing data at instrument level will be handled in the following way. To score a domain it is 
required that a least 50% of the items need to be answered. Then, the domain is scored based on the 
average of the items answered. If less than 50% of the items of a domain are answered no score will 
be derived. 
Table 2-7 Analysis and imputation methods to address the primary and secondary estimands 
for exploratory endpoints 
Objective 
Endpoint 
Endpoint 
type 
Estimand 
Analysis 
set 
Statistical 
model 
Imputation 
approach 
Sensitivity 
analyses 
Exploratory endpoints 
From baseline to week 104 
Exploratory 
CoEQ q1 score change 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Exploratory 
CoEQ q2 score change 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Exploratory 
CoEQ q3 score change 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Exploratory 
CoEQ q4 score change 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Exploratory 
CoEQ q5 score change 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Exploratory 
CoEQ q6 score change 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Exploratory 
CoEQ q7 score change 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Exploratory 
CoEQ q8 score change 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Exploratory 
CoEQ q9 score change 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Exploratory 
CoEQ q10 score change 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Exploratory 
CoEQ q11 score change 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Exploratory 
CoEQ q12 score change 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Exploratory 
CoEQ q13 score change 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Exploratory 
CoEQ q14 score change 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Exploratory 
CoEQ q15 score change 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Exploratory 
CoEQ q16 score change 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Exploratory 
CoEQ q17 score change 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Exploratory 
CoEQ q18 score change 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Exploratory 
CoEQ q19 score change 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Exploratory 
Craving Control score change 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Exploratory 
Positive Mood score change 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Exploratory 
Craving for Savoury score 
change 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
Exploratory 
Craving for Sweet score change 
Continuous 
Primary 
FAS 
ANCOVA 
RD-MI 
- 
Secondary 
FAS 
MMRM 
- 
- 
 
  SAP  NN9536-4378 | 
NN9536 -4378
20 of 25
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
12 April 2021 
Novo Nordisk 
Trial ID: NN9536-4378 
Version: 
1.0 
UTN:U1111-1202-1740 
Status: 
Final 
EudraCT No.:2017-003726-32 
Page: 
21 of 25 
 
Analyses addressing the primary estimand 
The exploratory endpoints regarding the CoEQ will be analysed using the same imputation 
approach as used for the primary endpoints and to address the primary estimand. The imputation 
model is the same as for the primary endpoints with body weight replaced by assessments of the 
endpoint to be analysed. The statistical model for continuous endpoints will be ANCOVA with 
factor and covariate as for the primary endpoint % weight change with baseline body weight 
replaced by the baseline assessment of the endpoint to be analysed.  
Handling of missing week 104 values for the primary estimand 
The imputation method RD-MI will be modified for the CoEQ item scores as follows: 
1. Imputed values will be rounded to whole numbers. 
2. Imputed values outside the 0-10 scale will be truncated to the nearest extreme value. 
 
Analysis addressing the secondary estimand 
The exploratory endpoint which relate to the exploratory objective regarding the CoEQ for week 
104 will be analysed to address the secondary estimand using the same MMRM for efficacy 
described for the primary endpoints. 
2.3.4 
Explorative statistical analysis for pharmacogenetics and biomarkers 
The statistical analysis of the biomarker endpoint is described under section 10.3.2.2 of the study 
protocol. 
2.3.5 
Other analyses 
All collected data that were not defined as endpoints will be summarised by descriptive statistics. 
2.4 
Pharmacokinetic and/or pharmacodynamic modelling 
Not applicable for this trial. 
 
3 
Changes to the statistical analyses planned in the protocol 
The main analyses were described in the protocol for the trial NN9536-4378. However, 
clarifications and more detailed descriptions of endpoints and analyses are provided in this SAP. 
The changes from the protocol of NN9536-4378 are summarised below: 
3.1 
Trial-specific changes 
• The CoEQ will be analysed statistically using both the primary estimand and the 
hypothetical estimand for the 19 items and 4 domains from baseline to week 104. 
• The supportive secondary endpoint “Body weight reduction ≥ 20% from baseline at week 0” 
was added both for week 52 and 104. 
• The statement “The comparison will be done using the primary estimand at week 52 and 
week 104” was deleted as the secondary estimand will cover all affect-related objectives. 
 
  SAP  NN9536-4378 | 
NN9536 -4378
21 of 25
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
12 April 2021 
Novo Nordisk 
Trial ID: NN9536-4378 
Version: 
1.0 
UTN:U1111-1202-1740 
Status: 
Final 
EudraCT No.:2017-003726-32 
Page: 
22 of 25 
 
3.2 
Changes applied across STEP trials 
• The text “rescue intervention” was replaced with “anti-obesity therapies” in the estimand 
definitions in order to avoid any potential confusion with diabetes rescue medication. 
• It has been corrected that the secondary estimand will cover all effect-related objectives. 
• It was clarified that subjects in the FAS/SAS will be evaluated “as randomised”/“as treated”. 
• In the text describing that “In general, the on-treatment period will therefore be from the 
date of first trial product administration to date of last trial product administration” the 
following has been added “(+14 days)” to emphasize that the lag-time after last trial product 
administration is included in the on-treatment period. 
• The text explaining how to handle missing baseline values has been changed to make it clear 
that if no eligible observation at or before randomisation is available then the mean of 
baseline values across all subjects is used as baseline value. 
• All AEs will be coded using the most recent version of the Medical Dictionary for 
Regulatory Activities (MedDRA) coding. 
• The BMI-grouping “27-<35” has been changed to “-<35”, since subjects may lose weight 
between the screening and the randomisation visit, and therefore have a BMI below 27 
kg/m2 at the time of randomisation. 
• It is clarified that RD-MI imputation is performed according to the timing of last available 
observation during the on-treatment period (LAO-OT). This is true for all endpoints. This is 
to clarify that the grouping of subjects according to timing is as in McEvoy1. Furthermore it 
is clarified that the LAO-OT must be prior to the landmark visit (week 104). 
• In grouping of retrieved subjects by timing of LAO-OT in the RD-MI procedure, it is 
clarified that timing by quarters or halves is defined as too restrictive if the imputation 
model cannot be fit due to inadequate numbers of retrieved subjects in 1 or more groups. 
Furthermore it is described how a model reduction will be performed if needed. 
• It is clarified that if no post-baseline LAO-OT exist, then the LAO-OT will be the baseline 
value and the timing of LAO-OT will be the first interval. 
• In all multiple imputation procedures, in addition to the seed number, it is specified that the 
dataset is sorted by subject ID. 
• The TP-MI procedure has been updated to be a 2-way tipping point analysis in which 
penalties are applied to both treatment groups (semaglutide 2.4 mg and placebo). 
o First, missing data are imputed according to the primary multiple imputation 
approach. Then, a penalty is added to the imputed value at week 104. The approach 
is to explore a range of penalties for both treatment groups, and the impact these 
have on the study conclusions. The 2-dimensional space of penalties covering the 
range from -30% to 30% will be explored for both treatment groups. This sensitivity 
analysis evaluates the robustness of the superiority conclusions to departures from 
the observed change in body weight in both treatment groups. 
o The rationale for the change in TP-MI is the following feedback from FDA: “To 
confirm the robustness of superiority conclusions using a tipping point analysis, we 
believe that a 2-way tipping point analysis represents the real-world situation for 
missing data from the both treatment arms (semaglutide and placebo). We would like 
to see departures from the treatment difference by varying both treatment arms 
rather than only adding a penalty to the active treatment arm (semaglutide). 
  SAP  NN9536-4378 | 
NN9536 -4378
22 of 25
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
12 April 2021 
Novo Nordisk 
Trial ID: NN9536-4378 
Version: 
1.0 
UTN:U1111-1202-1740 
Status: 
Final 
EudraCT No.:2017-003726-32 
Page: 
23 of 25 
 
Additionally, please include interpretations for the varying scenarios and how likely 
they would be seen in a real-world setting”. 
• A description has been included of the sensitivity analysis of the 5% responder endpoint 
(primary estimand) using MMRM. 
• It has been clarified that the non-responder analysis includes subjects with missing body 
weight assessment at week 104 as non-responders. 
• It has been clarified that the 5% responder analysis using MMRM for the secondary 
estimand will be predicting individual values for body weight only when body weight is 
missing at week 104. Furthermore, it is clarified that the logistic regression will include both 
randomised treatment as a factor and baseline body weight as covariate. 
• It is specified that fasting serum insulin will be log-transformed and analysed using a 
multiplicative model. 
• It is specified that lipids, FPG and fasting insulin will also be analysed in SI-units. 
 
 
 
  SAP  NN9536-4378 | 
NN9536 -4378
23 of 25
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
12 April 2021 
Novo Nordisk 
Trial ID: NN9536-4378 
Version: 
1.0 
UTN:U1111-1202-1740 
Status: 
Final 
EudraCT No.:2017-003726-32 
Page: 
24 of 25 
 
4 
Change log 
SAP change log 
  
Version 
Reason for change 
1.0 
New 
 
 
 
  SAP  NN9536-4378 | 
NN9536 -4378
24 of 25
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
12 April 2021 
Novo Nordisk 
Trial ID: NN9536-4378 
Version: 
1.0 
UTN:U1111-1202-1740 
Status: 
Final 
EudraCT No.:2017-003726-32 
Page: 
25 of 25 
 
5 
References 
1. McEvoy BW. Missing data in clinical trials for weight management. J Biopharm Stat. 
2016;26(1):30-6. 
2. Carpenter JR, Roger JH, Kenward MG. Analysis of longitudinal trials with protocol 
deviation: a framework for relevant, accessible assumptions, and inference via multiple 
imputation. J Biopharm Stat. 2013;23(6):1352-71. 
3. Sacks FM, Bray GA, Carey VJ, Smith SR, Ryan DH, Anton SD, et al. Comparison of 
weight-loss diets with different compositions of fat, protein, and carbohydrates. N Engl J 
Med. 2009;360(9):859-73 
4. Dalton, M., Finlayson, G., Hill, A., & Blundell, J. (2015). Preliminary validation and 
principal components analysis of the Control of Eating Questionnaire (CoEQ) for the 
experience of food craving. European Journal of Clinical Nutrition, Vol. 69, p. 1313-1317. 
 
  SAP  NN9536-4378 | 
NN9536 -4378
25 of 25
CONFIDENTIAL