Investigation of Efficacy and Safety of Semaglutide s.c. Once-weekly Versus Placebo in Subjects With Non-alcoholic Steatohepatitis and Compensated Liver Cirrhosis
Phase: PHASE2
Conditions: Non-alcoholic Steatohepatitis
Sponsor: Novo Nordisk A/S

C o ver P a ge  f or Pr ot oc ol  
 
S p o ns or na me:  
N o v o N or dis k A/ S  
N C T n u m ber  
N C T 0 3 9 8 7 4 5 1  
S p o ns or t rial I D: 
N N 9 9 3 1 -4 4 9 2  
Official title of st u d y:  
I n v esti gati o n of Efficac y a n d Safet y of Se ma gl uti d e s.c. O nce-
wee kl y  Vers us Place b o i n S u bjects Wit h N o n-alc o h olic 
Steat o he patitis a n d C o m pe nsate d Li ver Cirr h osis  
D oc u me nt date:  
2 1 Fe br u ar y 2 0 2 0  
* D oc u me nt date refers t o t he date o n w hic h t he d oc u me nt was m ost rece ntl y u p date d.  
N ote: T he date i n t he hea der of Pa ge 2 is t he date of c o m pilati o n of t he d oc u me nts a n d n ot of a n u p date t o c o nte nt. 
 

Li n k
Li n k
List of c o nte nts
Pr ot oc ol - versi o n 3 .............................................................................................................................
Gl o b al a n d c o u ntr y ke y N o v o N or dis k st aff .....................................................................................
Date:
N o v o N or di s k
Versi o n:
Stat us:
Se ma gl uti de s.c.
Trial I D: N N 9 9 3 1 4 4 9 2
Cli nical Trial Re p ort
A p pe n di x 1 6. 1. 1
1 2 Oct o ber 2 0 2 1
1. 0
Fi nal
1 6. 1. 1 Pr ot oc ol a n d pr ot oc ol a me n d me nts
C O N FI D E N TI A L
Re d acte d pr ot oc ol  
I ncl u des re d acti o n of pers o n al i de ntifi a ble i nf or m ati o n o nly. 
. 

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1- 4 4 9 2
Versi o n:
3. 0
Stat us:
Fi nal
Pa ge:
1 of 9 4
Pr ot oc ol
Pr ot oc ol title: I n vesti g ati o n of effic ac y a n d s afet y of se m a gl uti de s.c. o nce -wee kl y vers us 
pl ace b o i n s u bjects wit h n o n -alc o h olic ste at o he p atitis a n d c o m pe ns ate d li ver 
cirr h osis
S u bst a nce: Se m a gl uti de
U ni vers al Tri al N u m ber: U 1 1 1 1 - 1 2 2 4- 4 0 6 2
E U dr a C T N u m ber: 2 0 1 8 -0 0 4 4 8 4- 3 1
Tri al p h ase: 2a
I n t he f oll o wi n g, N o v o N or dis k A/ S a n d its affiliates will be state d as “ N o v o N or dis k”.
 
  
   
 
   
  
  
  
  
  
  
  
 
 
  
  
  
  
  
  
  
  
   
  
  
 
  
   
 
  Pr ot oc ol  v 3 | 
N N 9 9 3 1 - 4 4 9 2
1 of 9 4
C O N FI D E N TI A L
T his c o nfi de ntial d oc u me nt is t he pr o pert y of N o v o N or dis k. N o u n p u blis he d i nf or mati o n c o ntai ne d herei n ma y be 
discl ose d w it h o ut pri or writte n a p pr o val fr o m N o v o N or dis k. Access t o t his d oc u me nt m ust be restricte d t o rele va nt 
parties.

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1- 4 4 9 2
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
Pr ot oc ol 
2 1 Fe br uar y 2 0 2 0
3. 0
Ori gi nal Pr ot oc ol 
1 1 Ja n uar y 2 0 1 9
2. 0
Pr ot oc ol Versi o n 3. 0, 2 1 Fe br u ar y 2 0 2 0
T he c ha n ges t o Pr ot oc ol Versi o n 2. 0 are c o nsi dere d t o be s u bsta ntial base d o n t he criteria set f ort h 
i n Art icle 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 of t he 
E ur o pea n U ni o n 1. O verall r atio nal e for pre pari n g Pr ot oc ol Versi o n 3. 0 i ncl u di n g a s u m mar y  of 
c ha n ges ta ble
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 S y n o psis , Secti o n 4 
O bjecti ves a n d e n d p oi nts
T he f or mer sec o n dar y e n d p oi nt is 
c ha n ge d t o t he pri mar y e n d p oi nt: “ At 
least o n e sta ge of li ver fi br osis 
i m pr o ve me nt wit h n o w orse ni n g of 
N A S H after 4 8 wee ks ( yes/ n o) 
( w orse ni n g defi ne d as a n i ncrease of 
at least o ne sta ge of eit her l o b ular 
i nfla m mati o n, he pat oc yte ball o o ni n g 
or  steat osis acc or di n g t o t he N A S H 
C R N criteria).”
T he f or mer pri mar y e n d p oi nt is 
c ha n ge d t o t he sec o n dar y e n d p oi nt: 
" Relati ve c ha n ge fr o m baseli ne 
( wee k 0) t o wee k 4 8 i n li ver stiff ness 
meas ure d b y M R E." 
T he rati o nale f or t he pr ot oc ol 
a me n d me nt is t o ali g n wit h 
re q uire me nts as per re g ulat or y 
g ui da nce re g ar di n g pri mar y e n d p oi nt 
i n N A S H trials.
Secti o n 2 Fl o wc hart, Secti o n 8. 1 
Disc o nti n uati o n of trial pr o d uct, 
Secti o n 9. 1. 2 Li ver bi o ps y, 
A p pe n di x 7 Rete nti o n of h u ma n 
bi osa m ples, 
Li ver bi o psies nee de d at wee k 4 8 f or 
s u bjects w h o disc o nti n ue treat me nt 
d uri n g t he trial ( V 1 2 A)
T o e ns ure c o m plete f oll o w -u p of 
pri mar y  e n d p oi nt assess me nt.
Secti o n 1 S y n o psis , Secti o n 4 
O bjecti ves a n d e n d p oi nts, Secti o n 1 0 
Statistical c o nsi derati o ns
C ha n ge t o pri mar y esti ma n d
T o refl ect t he c ha n ge i n pri mar y 
e n d p oi nt
  Pr ot oc ol  v 3 | 
N N 9 9 3 1 - 4 4 9 2
2 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1- 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
3 of 9 4
U p date of statistical c o nsi derati o ns 
secti o n  
Secti o n 2 Fl o wc hart, Secti o n 6. 3. 1 
Meals a n d dietar y restricti o ns, 
Secti o n 8. 1 Disc o nti n uati o n of trial 
treat me nt, Secti o n 9. 1. 1 Ma g netic 
Res o na nce I ma gi n g, Secti o n 9. 1. 3 
C hil d -P u g h sc ore
Delete calcit o ni n fr o m fasti n g 
pr oce d ures.
N o M RI -P D F F a n d M R elast o gra p h y
nee de d at V 1 2 f or trial pr o d uct 
treat me nt disc o nti n ue d s u bjects.
Delete visceral a di p ose tiss ue a n d 
a b d o mi nal s u bc uta ne o us a di p ose 
tiss ue fr o m M RI assess me nts.
All assess me nts i ncl u de d i n t he 
C hil d -P u g h sc ore s h o ul d be 
perf or me d wit hi n t he visit wi n d o w. 
E nce p hal o pat h y was u p date d t o 
he patic e nce p hal o pat h y
Clarificati o n i n t he pr ot oc ol
  Pr ot oc ol  v 3 | 
N N 9 9 3 1 - 4 4 9 2
3 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1- 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
4 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 ........................................................................................................................................4
1
S y n o psis ................................................................................................................................................7
2
Fl o wc h art ...........................................................................................................................................1 1
3
I ntr o d ucti o n .......................................................................................................................................1 7
3. 1
Trial rati o nale ..........................................................................................................................1 7
3. 2
Bac k gr o u n d .............................................................................................................................1 7
3. 2. 1
Se ma gl uti de ...........................................................................................................1 7
3. 3
Be nefit -ris k assess me nt ...........................................................................................................1 8
3. 3. 1
Ris ks a n d preca uti o ns .............................................................................................1 9
3. 3. 2
C o ncl usi o n o n be nefit -ris k pr ofile ..........................................................................2 0
4
O bjecti ves a n d e n d p oi nts ...................................................................................................................2 2
4. 1
Pri mar y, sec o n dar y a n d e x pl orat or y o bjecti ves ........................................................................2 2
4. 1. 1
Pri mar y o bjecti ve ...................................................................................................2 2
4. 1. 2
Sec o n dar y efficac y o bjecti ves ................................................................................2 2
4. 1. 3
Sec o n dar y safet y o bjec ti ve.....................................................................................2 2
4. 2
Pri mar y a n d sec o n dar y e n d p oi nts ............................................................................................2 2
5
Tri al desi g n ........................................................................................................................................2 4
5. 1
O verall desi g n .........................................................................................................................2 4
5. 2
S u bject a n d trial c o m pleti o n ....................................................................................................2 4
5. 3
E n d of trial defi niti o n ..............................................................................................................2 5
5. 4
S c ie ntific rati o nale f or trial desi g n...........................................................................................2 5
5. 5
J ustificati o n f or d ose ...............................................................................................................2 6
6
Tri al p o p ul ati o n ................................................................................................................................. 2 7
6. 1
I ncl usi o n criteria .....................................................................................................................2 7
6. 2
E xcl us i o n criteria ....................................................................................................................2 7
6. 3
Lifest yle restricti o ns ................................................................................................................3 0
6. 3. 1
Meals a n d dietar y restricti o ns .................................................................................3 0
6. 4
Scree n fail ures ........................................................................................................................3 1
7
Tre at me nts .........................................................................................................................................3 2
7. 1
Treat me nts a d mi nistere d .........................................................................................................3 2
7. 1. 1
Me dical de vices .....................................................................................................3 4
7. 2
D ose m o dificati o n ...................................................................................................................3 4
7. 3
Met h o d o f treat me nt assi g n me nt..............................................................................................3 4
7. 4
Bli n di n g ..................................................................................................................................3 4
7. 5
Pre parati o n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y ..........................................................................3 5
7. 6
Treat me nt c o m plia nce .............................................................................................................3 6
7. 7
C o nc o mita nt me dicati o n ..........................................................................................................3 6
7. 7. 1
S u bjects treate d wit h i ns uli n ...................................................................................3 7
7. 7. 2
S u bjects treate d wit h S U ........................................................................................3 7
7. 7. 3
S u bjects de vel o pi n g t y pe 2 dia betes .......................................................................3 7
  Pr ot oc ol  v 3 | 
N N 9 9 3 1 - 4 4 9 2
4 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1- 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
5 of 9 4
7. 8
Treat me nt after t he e n d of t he trial ...........................................................................................3 7
8
Disc o nti n u ati o n/ Wit h dr a w al criteri a ................................................................................................3 8
8. 1
Disc o nti n uati o n of trial treat me nt ............................................................................................3 8
8. 1. 1
Te m p orar y disc o nti n uati o n of trial treat me nt ..........................................................3 9
8. 2
Wit h dra wal fr o m t he trial
........................................................................................................3 9
8. 2. 1
Re place me nt of s u bjects .........................................................................................4 0
8. 3
L ost t o f oll o w - u p.....................................................................................................................4 0
9
Tri al assess me nts a n d pr oce d ures .....................................................................................................4 1
9. 1
Efficac y assess me nts ...............................................................................................................4 1
9. 1. 1
Ma g netic Res o na nce I ma gi n g
................................................................................4 1
9. 1. 2
Li ver bi o ps y ...........................................................................................................4 2
9. 1. 2. 1
Ce ntral pat h ol o g y e val uati o n ............................................................4 3
9. 1. 3
C hil d -P u g h sc ore ...................................................................................................4 3
9. 1. 4
B o d y meas ure me nts ...............................................................................................4 4
9. 1. 4. 1
Hei g ht ..............................................................................................4 4
9. 1. 4. 2
B o d y wei g h t.....................................................................................4 4
9. 1. 4. 3
B o d y mass i n de x ( B MI) ...................................................................4 4
9. 1. 4. 4
Waist circ u mfere nce .........................................................................4 4
9. 1. 5
E x pl orat or y bi o mar kers ..........................................................................................4 4
9. 1. 6
Cli nical efficac y la b orat or y assess me nts ................................................................. 4 4
9. 2
A d verse e ve nts ........................................................................................................................4 5
9. 2. 1
Ti me peri o d a n d fre q ue nc y f or c ollecti n g A E a n d S A E i nf or mati o n ........................4 5
9. 2. 2
Met h o d of detecti n g A Es a n d S A Es
.......................................................................4 7
9. 2. 3
F oll o w -u p o n A Es a n d S A Es ..................................................................................4 7
9. 2. 4
Re g ulat or y re p orti n g re q uire me nts f or S A Es ..........................................................4 7
9. 2. 5
Car di o vasc ular a n d deat h e ve nts .............................................................................4 7
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 ...................................................................................................................4 7
9. 2. 7
Pre g na ncies a n d ass ociate d a d verse e ve nts .............................................................4 7
9. 2. 8
Me dical de vice i nc i de nts (i ncl u di n g malf u ncti o ns) .................................................4 8
9. 2. 9
T e c h nical c o m plai nts .............................................................................................4 8
9. 2. 1 0
H y p o gl ycae mic e pis o des ........................................................................................4 9
9. 3
Treat me nt of o ver d ose .............................................................................................................4 9
9. 4
Safet y assess me nts ..................................................................................................................5 0
9. 4. 1
P h ysical e xa mi nati o ns ............................................................................................5 0
9. 4. 2
Vital si g ns ..............................................................................................................5 0
9. 4. 3
T o bacc o use ...........................................................................................................5 1
9. 4. 4
Electr ocar di o gra ms ................................................................................................5 1
9. 4. 5
E y e e xa mi nati o n ....................................................................................................5 1
9. 4. 6
Cli nical safet y la b orat or y assess me nts ....................................................................5 2
9. 5
P har mac o ki netics ....................................................................................................................5 2
9. 6
P har mac o d y na mics .................................................................................................................5 2
9. 7
Ge netics ..................................................................................................................................5 2
9. 8
Bi o mar kers .............................................................................................................................5 2
1 0
St atistic al c o nsi der ati o ns ...................................................................................................................5 3
1 0. 1
S a m ple size deter mi nati o n .......................................................................................................5 3
1 0. 2
Defi niti o n of a nal ysis sets ........................................................................................................5 4
  Pr ot oc ol  v 3 | 
N N 9 9 3 1 - 4 4 9 2
5 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1- 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
6 of 9 4
1 0. 3
Statistical a nal yses ..................................................................................................................5 5
1 0. 3. 1
Pri mar y e n d p oi nt ...................................................................................................5 5
1 0. 3. 2
Sec o n dar y e n d p oi nts ..............................................................................................5 6
1 0. 3. 2. 1
S u p p orti ve sec o n dar y e n d p oi nts .......................................................5 6
1 0. 3. 3
E x pl orat or y e n d p oi nts ............................................................................................5 6
1 0. 3. 4
I nteri m re p orti n g....................................................................................................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 7
1 1
Refere nces ..........................................................................................................................................5 8
1 2
A p pe n dices .........................................................................................................................................6 2
A b bre vi ati o ns a n d Tr a de m ar ks .......................................................................................6 2
Cli nic al l a b or at or y tests ...................................................................................................6 6
Tri al g o ver n a nce c o nsi der ati o ns ......................................................................................6 9
A d verse e ve nts: defi niti o ns a n d pr oce d ures f or rec or di n g, e v al u ati o n, f oll o w -u p, 
a n d re p orti n g .....................................................................................................................................7 8
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 3
Tec h nic al c o m pl ai nts: Defi niti o n a n d pr oce d ures f or rec or di n g, e v al u ati o n, f oll o w -
u p a n d re p orti n g ................................................................................................................................8 6
Rete nti o n of h u m a n bi os a m ples .......................................................................................8 8
H y p o gl yc ae mic e pis o des ...................................................................................................8 9
C o u ntr y -s pecific re q uire me nts ........................................................................................9 4
At tac h me nt I Gl o bal list of ke y staff a n d rele va nt de part me nts a n d s u p pliers
At tac h me nt II C o u ntr y list of ke y staff a n d rele va nt de part me nts.
  Pr ot oc ol  v 3 | 
N N 9 9 3 1 - 4 4 9 2
6 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
7 of 9 4
1
S y n o psis
R ati o n ale:
N o n -alc o h o lic fatt y li ver disease ( N A F L D) re prese nts a s pectr u m of li ver da ma ges ra n gi n g fr o m
si m ple steat osis ( n o n-alc o h o lic fatt y li ver), n o n-alc o h olic steat o he patit is ( N A S H) wit h or wit h o ut 
fi br osis t hr o u g h t o cirr h osis. Li ver cirr h osis is defi ne d b y t he N A S H Cli nical Researc h Net w or k 
( C R N) as fi br osis sta ge 4 ( F 4)2, 3. N A S H is re p orte d i n 3-5 % of  t he Wester n p o p ulati on 4 a n d ar o u n d 
1 0 % of patie nts wit h N A S H de vel o p cirr h osis 5. N A S H li ver cirr h osis is t o da y t he t hir d most 
c o m m o n ca use o f li ver tra ns pla ntati o n i n t he U S A a n d is e x pecte d t o be t he pri mar y ca use i n 2 0 2 06-
8. T he pat h o p h ysiol o g y of  t he pr o gressio n t o li ver ci rr h osis i n N A S H is n ot well u n derst o o d, b ut 
o ver wei g ht a n d o besit y,  ins uli n resista nce, t y pe 2 dia betes ( T 2 D) a n d h y perte nsi o n  are rec o g nise d 
as ke y pre dis p osi n g fact ors 9. 
P ati e nts wit h N A S H a n d li ver cirr h osis ha ve t he hi g hest all ca use a n d li ver relate d m ortality 
c o mpare d t o pati e nts wit h less se vere li ver fi br osis1 0. T he i ncrease i n li ver relate d m ortality is 
ass o ciat e d wit h t he tra nsiti on fr o m t he c om pe nsate d t o dec o m pe nsate d sta ge, w hic h occ urs at a rate 
of  a p pr o xi matel y 5-7 % per year 1 1. Cirr hosis is n ot irre versi ble, as li ver fi br osis i n t he cirr h otic ra n ge 
i n ot her c hr o nic li ver diseases re gresses wit h effecti ve t hera p y, s uc h as a nti viral treat me nt f or 
c hr o nic he pat itis B or C1 2, 1 3 a n d ster oi ds f or a ut oi m m u ne he pat itis1 4.
C urre nt l y, first-li ne treat me nt of N A S H i n patient s wit h c om pe nsate d li ver cirr h osis a n d o ver wei g ht 
is lifestyle i nter ve nt i ons t o pr o vi de wei g ht l oss 1 5 a n d t o treat c o m or bi dit ies (e. g. h yperli pi dae mia, 
h y perte nsi o n a n d di a betes) as n o s pecific p har mace utical t hera pies are a p pr o ve d. I n t he case of 
pr o gress i on t o e n d -sta ge li ver disease, li ver tra ns pla ntati o n is t he o nl y treat me nt o pti o n 1 6.
Acc or di n gl y , t here is a s u bsta ntial u n met me dical nee d f or effecti ve treat me nt i n pat ient s wit h 
N A S H a n d c o m pe nsate d li ver cirr h osis.
O bjecti ves a n d e n d p oi nts :
Pri m ar y o bjecti ve
T o i n vesti gate t he effect of se ma gl uti de s u bc uta ne o us (s.c.) 2. 4 m g o nce -wee kl y o n li ver fi br osis 
c o mpare d wi t h place b o i n s u bjects wit h N A S H a n d c o m pe nsate d fi br osis sta ge 42, 3.
Pri m ar y esti m a n d
I n s u bjects wit h N A S H a n d c o m pe nsate d fi br osis sta ge 4, t he esti ma n d a d dressi n g t he pri mar y 
o bj ect i ve is t he pr o p orti o n of s u bjects wit h li ver fi br osis i m pr o ve me nt wit h n o w orse ni n g of N A S H 
c o mpare d bet wee n se ma gl ut ide s.c. 2. 4 m g o nce -wee kl y a n d place b o at 4 8 wee ks if all ra n d o mise d 
s u bjects ha d a d here d t o treat me nt. Ge neralisati on of t his esti ma n d de pe n ds a m o n g ot her t hi n gs o n 
t he e xte nt t o w hic h treat me nt a d here nce i n t his trial reflects cli nical practice. 
  Pr ot oc ol  v 3 | 
N N 9 9 3 1 - 4 4 9 2
7 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
8 of 9 4
Sec o n d ar y effic ac y o bjecti ves
T o i n vesti gate t he effect of se ma gl uti de s.c. 2. 4 m g o nce -wee kl y  o n N A S H c o mpare d wi t h place b o
i n s u bjects wit h N A S H a n d c o mpe nsate d fi br osis sta ge 4 .
Sec o n d ar y s afet y o bjecti ve
T o e val uate t he safet y a n d t olera bilit y of se ma gl uti de s.c. 2. 4 m g o nce-wee kl y  c o mpare d wi t h 
pl ace b o i n s u bjects wit h N A S H a n d c om pe nsate d fi br osis sta ge 4 .
Pri m ar y a n d sec o n d ar y e n d p oi nts
E n d p oi nt title
Ti me fr a me
U nit
Pri m ar y e n d p oi nt :
At  least o ne sta ge of li ver 
fi br osis i m pr o ve me nt wit h n o 
w orse ni n g of  N A S H after 4 8 
wee ks ( y es/ n o) ( w orse ni n g 
defi ne d as a n i ncrease of at 
least o ne sta ge of eit her 
l ob ular i nfla m mat i on , 
he pat oc y te ballo o ni n g or 
steat osis acc or di n g t o t he 
N A S H C R N criteria )2, 3.
Fr o m  baseli ne ( wee k 0) t o 
visit 1 2 ( wee k 4 8)
Yes / n o
Sec o n d ar y e n d p oi nts :
Relati ve c ha n ge fr o m 
baseli ne ( wee k 0) t o wee k 4 8 
i n li ver fat c o nte nt ( %) 
meas ure d b y M RI -P D F F.
Fr o m  baseli ne ( wee k 0) t o 
visit 1 2 ( wee k 4 8)
Rati o t o baseli ne
Relati ve c ha n ge fr o m 
baseli ne ( wee k 0) t o wee k 4 8 
i n li ver stiff ness meas ure d b y 
M R E . 
Fr o m  baseli ne ( wee k 0) t o 
visit 1 2 ( wee k 4 8)
Rati o t o baseli ne
N A S H res o l uti on after 4 8 
wee ks ( y es/ n o) ( defi ne d b y 
t he N A S H C R N as l ob ular 
i nfla m mati on 0 – 1 a n d 
ball o o ni n g 0) 2, 3.
Fr o m  baseli ne ( wee k 0) t o 
visit 1 2 ( wee k 4 8)
Yes / n o
  Pr ot oc ol  v 3 | 
N N 9 9 3 1 - 4 4 9 2
8 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
9 of 9 4
C ha n ge fr o m baseli ne i n 
Sta ge of fi br osis acc or di n g t o 
t he N A S H C R N fi br osis 
sc ore.
Fr o m  baseli ne ( wee k 0) t o 
visit 1 2 ( wee k 4 8)
Scal e ( 0-4) *
C ha n ge fr o m baseli ne i n 
N A F L D acti vit y sc ore ( N A S) 
acc or di n g t o t he N A S H C R N 
criteria.
Fr o m  baseli ne ( wee k 0) t o 
visit 1 2 ( wee k 4 8)
Scal e ( 0-8) *
N u m ber of treat me nt -
e mer ge nt a d verse e ve nts .
Fr o m  baseli ne ( wee k 0) t o 
visit 1 2 ( wee k 4 8)
C o u nt
* ra n ge of val ues o n a bs ol ute scale at o ne ti me-p oi nt
O ver all desi g n:
T his is a 4 8 -wee k ra n d o mise d, d o u ble -bli n d, pl ace b o -c o ntr olle d, parallel gr o u p, m ult i-ce ntre trial 
wi t h 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 o nce wee kl y i n s u bjects wit h 
N A S H a n d c o m pe nsate d fi br osis sta ge 4.
Ke y i ncl usi o n criteri a:

Male or fe male, a ge d 1 8 - 7 5 years ( b ot h i ncl usi ve) at t he ti me of si g ni n g i nf or me d c o nse nt.

Hi st olo gi c e vi de nce of N A S H a n d fi br osis sta ge 4 acc or di n g t o t he N A S H C R N 
classificat i on base d o n ce ntral pat h o l ogist e val uati o n of a li ver bi o ps y o btai ne d wit hi n 3 6 0
da ys pri or t o scree ni n g. I n s u bjects w h o ha ve ne ver ha d a li ver bi o ps y  s ho wi n g N A S H a n d 
F 4, li ver stiff ness > 1 4 k Pa b y  Fi br o Sca n® at scree ni n g m ust be d oc u me nte d bef ore s u bjects 
ca n ha ve a tri al-r elate d li ver bi o ps y

A hist ol o gi cal N A F L D acti vity sc ore ( N A S) ≥3 wit h a sc ore of 1 or m ore i n l o b ular 
i nfla m mati on a n d he pat oc y te ballo o ni n g base d o n ce ntral  pat h olo gist e val u ati o n

B o d y  mass i n de x ≥2 7 k g/ m 2
Ke y e xcl usi o n criteri a:

Prese nce or hist or y  of he pat ic dec om pe nsat i on (e. g. ascites, variceal blee di n g, he pat ic 
e nce p hal o pat h y or s p o nta ne o us bacterial perit onit is) or li ver tra ns pla ntati o n

Pres e nce or hist or y of gastr oes o p ha geal varices wit hi n t he past 3 6 0 da ys prior t o scree ni n g . 
F or s u bjects wit h n o k n o w n hist or y  of gastr oes o p ha geal varices a n d with a Fi br osca n ® ≥ 2 0 
k Pa a n d t hr o m b oc yt es ≤ 1 5 0, 0 0 0 1 7, a es o p ha g o gastr o d u o de n osc o p y m ust be perf or me d t o 
e val uate prese nce of gastr oes o p ha geal varices

Prese nce or hist or y  of he pat ocell ular carci n o ma

Treat me nt wit h vita mi n E (at d oses ≥8 0 0 I U/ da y ) or pio gli taz o ne w hic h has n ot bee n at a 
sta ble d ose i n t he o pi ni on of t he i n vesti gat or i n t he peri o d fr om 9 0 da ys pri or t o scree ni n g
  Pr ot oc ol  v 3 | 
N N 9 9 3 1 - 4 4 9 2
9 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
1 0 of 9 4

Treat me nt wit h gl uca g o n -li ke pe pti de-1 rece pt or a g o nists ( G L P -1 R As) i n t h e perio d fr om 
9 0 da y s prior t o scree ni n g

Treat me nt wit h ot her gl uc ose l o weri n g a ge nt(s) (a part fr o m w hat is liste d i n t he e xclusi o n  
crit erio n a b o ve) or w eig ht l oss m e dicatio n n ot sta ble i n t he o pi ni o n of t he i n vest i gat or i n t he 
p eri o d f r o m 2 8 da ys prior t o scree ni n g
N u m ber of s u bjects:
A p pr o xi matel y  2 4 0 s u bjects will be scree ne d t o ac hie ve 6 9 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:
T he t otal trial d urati o n f or t he i n di vi d ual s u bject is a p pr o xi matel y 6 1 wee ks. T his i ncl u des a 
scree ni n g peri o d of a p pr o xi matel y 6 wee ks f o ll owe d b y  ra n d o misati on, a 4 8 wee ks treat me nt peri o d 
a n d a 7 wee ks f o ll ow- u p peri o d after e n d of treat me nt. 
D ose esc alat i on of se ma gl ut i de/se ma gl uti de place b o will ta ke place e ver y 4 wee ks d uri n g t he first 
1 6 wee ks after ra n d o misat i on. All s u bjects m ust ai m at reac hi n g t he rec o m me n de d tar get d ose of 
se ma gl uti de s.c. 2. 4 m g o nce-wee kl y  or t he c orres p o n di n g v ol u me of place b o. 
Eli gi ble s u bjects f ulfilli n g all i n - a n d e xcl usi o n cri t eria at visit 2 will be ra n d o mise d i n a 2: 1 rati o t o 
recei ve either: 

S e m a gl ut i de s.c. 2. 4 m g o nce wee kl y

S e m a gl ut i de  place b o s.c. o nce wee kl y
Ra n d o misat i on will be stratifie d base d o n T 2 D ( wit h T 2 D or wit h o ut T 2 D). D uri n g t he trial all 
s u bjects will recei ve n utriti onal a n d p h ysical acti vit y c o u nselli n g i n acc or da nce wit h site practice. 
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 f or t he d urati o n of t he trial:

S e m a gl ut i de B 3. 0 m g/ m L, s o l uti on f or i njecti on, P D S 2 9 0 pre -fille d pe n-i nject or a n d 
se ma gl uti de place b o, s ol ut i on f or i njecti on, P D S 2 9 0 pre -fille d p e n -i nject or
  Pr ot oc ol  v 3 | 
N N 9 9 3 1 - 4 4 9 2
1 0 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
     
Date:
2 1 Fe br uar y 2 0 2 0
Stat us:
Fi nal
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
     
Versi o n:
3. 0
Pa ge:
1 6 of 9 4
f)
F or s u bjects disc o nti n ui n g tri al pr o d uct tre at me nt d uri n g t he tri al n o li ver bi o ps y s a m ple, M RI -P D F F a n d M R el ast o gr a p h y will be o bt ai ne d at e n d of tre at me nt visit 
( V 1 2). A li ver bi o ps y, M RI -P D F F a n d M R el ast o gr a p h y will b e o bt ai ne d at V 1 2 A. If e n d of tre at me nt is at t he s a me ti me p oi nt a s V 1 0, t he n M RI-P D F F a n d M R 
el ast o gr a p h y s h o ul d be o bt ai ne d
g)
A rece nt li ver bi o ps y o bt ai ne d wit hi n 3 6 0 d a ys pri or t o scree ni n g is acce pt a ble. F or s u bjects wit h n o rece nt li ver bi o ps y, t his m ust be perf or me d d uri n g t he scree ni n g 
peri o d after c o nfir m ati o n of li ver stiff ness ˃ 1 4 k P A b y Fi br osc a n ®
h)
All assess me nts i ncl u de d i n t he C hil d -P u g h sc ore s h o ul d be perf or me d wit hi n t he visit wi n d o w
i)
H b A 1c o nl y
j)
O nl y a p plic a ble f or fe m ale s u bjects. A uri ne pre g n a nc y test will be perf or me d at site visits wit h o ut bl o o d s a m pli n g ( V 4, V 6, V 9, V 1 1 a n d V 1 3). F or w o me n of 
c hil d be ari n g p ote nti al: uri ne pre g n a nc y test s h o ul d be perf or me d at a n y ti me d uri n g t he tri al if a me nstr u al peri o d is misse d
k)
O nl y bl o o d s a m pli n g, n o li ver tiss ue s a m pli n g
l)
O nl y if nee de d t o e v al u ate i ncl usi on criteri a 3 a n d / or e xcl usi o n criteri a 3
m)
O nl y a p plic a ble f or s u bjects wit h t y pe 2 di a betes
  Pr ot oc ol  v 3 | 
N N 9 9 3 1 - 4 4 9 2
1 6 of 9 4

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
1 7 of 9 4
3
I ntr o d ucti o n
3. 1
Tri al r ati o n ale
N o n -alc o h o lic fatt y li ver disease ( N A F L D) re prese nts a s pectr u m of li ver da ma ges ra n gi n g fr o m 
si m ple steat osis ( n o n-alc o h o lic fatt y li ver), n o n- alc o h olic steat o he patit is ( N A S H) wit h or wit h o ut 
fi br osis t hr o u g h t o cirr h osis. Li ver cirr h osis is defi ne d b y t he N A S H Cli nical Researc h Net w or k
( C R N) as fi br osis sta ge 4 ( F 4) 2, 3. N A S H is re p orte d i n 3 -5 % of  t he Wester n p o p ulati on 4 a n d ar o u n d 
1 0 % of patie nts wit h N A S H de vel o p cirr h osis 5. N A S H li ver cirr h osis is t o da y t he t hir d most 
c o m m o n ca use o f li ver tra ns pla ntati o n i n t he U S A a n d is e x pecte d t o be t he pri mar y ca use i n 2 0 2 0.6-
8 T he pat h o p h ysi o l og y  of t he pr o gressio n t o li ver cirr h osis i n N A S H is n ot well u n derst o o d, b ut 
o ver wei g ht a n d o besit y,  ins uli n resista nce, t y pe 2 dia betes ( T 2 D) a n d h y perte nsi o n  are rec o g nise d 
as ke y pre dis p osi n g fact ors9. 
P ati e nts wit h N A S H a n d li ver cirr h osis ha ve t he hi g hest all ca use a n d li ver relate d m ortality 
c o mpare d t o pati e nts wit h less se vere li ver fi br osis 1 0. T he i ncrease i n li ver relate d m ortality is 
ass ociate d wi t h t he tra nsiti on fr o m t he c om pe nsate d t o dec o m pe nsate d sta ge, w hic h occ urs at a rate 
of  a p pr o xi matel y 5-7 % per year 1 1. Cirr h osis is n ot irre versi ble, as li ver fi br osis i n t he cirr h otic ra n ge 
i n ot her c hr o nic li ver diseases re gresses wit h effecti ve t hera p y, s uc h as a nti viral treat me nt f or 
c hr o nic he pat itis B or C1 2, 1 3 a n d ster oi ds f or a ut oi m m u ne he pat itis1 4.
C urre nt l y, first-li ne treat me nt  of N A S H i n patient s wit h c om pe nsate d li ver cirr h osis a n d o ver wei g ht 
is lifestyle i nter ve nt i ons t o pr o vi de wei g ht l oss 1 5 a n d t o treat c o m or bi dit ies (e. g. h yperli pi dae mia, 
h y perte nsi o n a n d di a betes) as n o s pecific p har mace utical t hera pies are a p pr o ve d. I n t he case of 
pr o gressi o n t o e n d -sta ge li ver disease, li ver tra nspla ntati o n is t he o nl y  tr e at me nt o ptio n 1 6.
Acc or di n gl y , t here is a s u bsta nt ial u n met me dical nee d f or effecti ve treat me nt i n pat ient s wit h 
N A S H a n d c o m pe nsate d li ver cirr h osis.
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 a p ote nt h u ma n G L P-1 R A c urre nt l y i n de vel o p me nt b y N o v o N or dis k A/ S f or 
w ei g ht ma na ge me nt ( N N 9 5 3 6) a n d f or N A S H ( N N 9 9 3 1). Se ma gl uti de s.c. is a p pr o ve d i n se veral 
c o u ntries f or treat me nt of a d ults wi t h T 2 D u n der t he tra de na me Oze m pic® .
S e m a gl ut i de has bee n o pt i mise d fr o m nati ve G L P-1 res ul ti n g i n a lo n ger half -life of a p pr o xi matel y 
1 6 0 h o urs, m a ki n g it s uita ble f or o nce-wee kl y d osi n g 1 8. G L P-1 i s a p h ysi ol ogical  re g ulat or 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 ulat i on 1 9. B ot h h u ma n a n d a ni mal st u dies ha ve s h o w n a be neficial effect of G L P-1 R As o n li ver 
li pi d meta b o lis m a n d re d uctio n i n pr o gressi o n  of fatt y li ver t o N A S H2 0 -2 3. T he m ec ha nis m b y w hic h 
G L P -1 R As affect N A S H is n ot clear a n d neit her m uri ne n or h u ma n he pat oc y tes see m t o ha ve a n y 
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
1 7 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
1 8 of 9 4
G L P -1 rece pt o r e x pressi o n 2 1, 2 4. Se ma gl ut i de effecti vel y l o wers b o d y wei g ht a n d i n directl y i ncrease 
i ns uli n se nsiti vity 2 3, 2 5, 2 6. A d dit i onall y, se ma gl ut i de i ncreases i ns uli n a n d l o wers gl uca g o n le vels, all 
of  w hic h ma y be be neficial i n patient s wit h N A S H. Ot her mec ha nis ms of actio ns base d o n t he G L P -
1 bi ol o g y  are a nt i-i nfla m mat or y a n d li pi d lo weri n g effects 2 1. Ma r kete d G L P-1 R As are n ot k n o w n 
t o be he pat ot o xic2 7 -2 9. I n trial N N 9 5 3 5-3 6 5 1, t he e x p os ure of se ma gl uti de after a si n gle s.c. d ose of 
0. 5 m g was n ot affecte d b y  he pat ic i m pair me nt a n d t he P K pr o perties of  se ma gl uti de were si milar 
f or s u bjects wit h mil d, m o derate or se vere he patic i m pair me nt c o m pare d t o s u bjects wit h n or mal 
he pat ic f uncti o n 3 0.
T he i n vesti gat or s p o ns ore d st u d y Lira gl uti de Efficac y a n d Acti on i n N A S H ( L E A N), e nr olle d 5 2 
o ver wei g ht s u bjects wi t h a n d wit ho ut T 2 D, wi t h bi o ps y-c o nfir me d N A S H a n d fi br osis sta ge 0 -4  t o 
recei ve 1. 8 m g lira gl uti de s.c. or place b o o nce dail y . After 4 8 wee ks of treat me nt, 9 o ut of 2 3 ( 3 9 %) 
s u bjects treate d wit h lira gl uti de c o m pare d t o 2 o ut of 2 2 ( 9 %) s u bjects treate d wit h place b o ha d 
res olut i on of N A S H wit h n o w orse ni n g of fi br osis (rela ti ve ris k 4. 3 [ 1. 0– 1 7. 7] 9 5 % CI). 
F urt her m ore, si g nifica nt l y fe wer patient s treate d with lira gl uti de ha d w orse ni n g of fi br osis 
c o mpare d t o place b o 2 6.
As se ma gl uti de is str uct urall y  si milar t o lira gl uti de wit h si milar mec ha nis m of act i on a n d wit h a 
p ote nti al for m ore pr o n o u nce d effect o n gl ycae m ic c o ntr ol a n d b o d y wei g ht, se ma glut i de has bee n 
selecte d as a de vel o p me nt ca n di date f or t he treat me nt of N A S H ( N N 9 9 3 1).
3. 3
Be nefit -ris k assess me nt
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 treat me nt t he y 
recei ve at t he ti me of e ntr y int o t he tri al. 
T he L E A N st u d y  in dicate d a be neficial effect of lira gl ut i de o n N A S H2 6. F urt her m ore, t he p hase 2 
trial in wei g ht m a na ge me nt ( N N 9 5 3 6 -4 1 5 3) s h o we d t hat se ma gl uti de 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 was effecti ve f or wei g ht l oss i n s u bjects wit h o besit y 
w hile dis pla yi n g a satisfact or y  t olera bilit y pr ofile. I n N N 9 5 3 6 -4 1 5 3, a 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 uti 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 % 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 osses were 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 v asc ular ris k 
fact ors, li pi d pr ofile a n d gl ycae mic fact ors, as well as i m pr o ve me nts i n cli nical o utc o me 
assess me nts 3 1. Fi nall y, in a cli nical trial i n vest i gati n g t he effect of wei g ht l oss t hr o u g h lifestyle 
m o dificati o n i n hist ol o gi c f eat ures of  N A S H, a 1 0 % weig ht l oss si g nifica nt l y re d uce d t he fi br osis 
sc ore b y at least 1 p oi nt i n 1 3 of 1 6 ( 8 1 %) patie nts wit h fi br osis at baseli ne 3 2.
T h us, i n a d dit i on t o t hese a nt ici pate d effects of se ma gl uti de, it is e x pecte d t hat all s u bjects will 
be nefit fr o m part ici pati on i n t he trial t hr o u g h a cl ose c o ntact wit h t he trial site i ncl u di n g cl ose 
f oll ow- u p of  t h eir N A S H a n d ge neral meta b olic state, caref ul me dical e xa mi nati on a n d als o 
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
1 8 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
1 9 of 9 4
n utri tio nal a n d p h ysical act i vity c o u nselli n g. All of w hic h will m o st li kel y res ult i n i nte nsifie d 
N A S H ma na ge me nt.
3. 3. 1
Ris ks a n d prec a uti o ns
T he sect i ons be l ow 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. 
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 uti de as well as ot her G L P-1 R As. F or eac h of t hese ris ks, mit i gatin g acti o 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
o
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 uti d e were gastr oi ntest i nal A Es. A 
l ow st arti 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
o
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 h ase 2 weig ht m a na ge me nt trial ( 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 dj u dicati on c o m mittee c o nfir me d ac ute pa ncreat itis. 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 i s t o be 
i nitiate d at t he i n vest i gat or’s discreti o n.

H y p o gl ycae mia (i n c o m bi nat i on wi t h S U a n d/ or i ns uli n) (i de ntifie d f or T 2 D patie nts)
o
T here i s a lo w ri s k of h y p o gl ycae mic e pis o des w he n se ma gl ut i de is use d as 
m o n ot hera p y . S u bjects treate d wit h se ma gl uti de i n c o m bi nati o n with a S U or i ns uli n 
ha ve a n i ncrease d ris k of h y p o gl ycae mia. T he ris k of h y p o gl ycae mia ca n be l o were d 
b y re d uci n g t he d ose of S U or i ns uli n w he n i nit iati n g treat me nt wit h se ma gl uti de.

Di a bet ic reti n o pat h y c om p licati on (i de nt ifie d f or T 2 D patie nts)
o
T he car di o vasc ular o utc o m e trial i n t he se ma gl ut i de T 2 D de vel o p me nt pr o gra m me 
( N N 9 5 3 5-3 7 4 4) s h o we d a n i ncrease d ris k of e ve nts relate d t o dia bet ic reti n o pat h y 
c o mplicat i ons i n s u bjects treate d wit h se ma gl ut i de c o mpare d t o pl ace b o, al beit t he 
pr o p orti o n of  s u bjects wit h a n e ve nt of dia bet ic reti n o pat h y c om p licati o ns was l o w. 
T he i m bala nce was dri ve n b y  s u bjects wit h a hist or y of dia betic reti n o pat h y at 
baseli ne. As a preca ut i on, s u bjects wit h a hist or y of u nc o ntr olle d a n d p ote ntiall y  
u nsta ble dia bet ic reti n o pat h y or mac ulo pat h y will  be e xcl u de d fr o m t he trial, a n d 
f u n d us p h ot o gra p h y or slit-la m p bi omicr osc o p y  e xa mi nati on wi t h p har mac olo gi call y 
dilate d p u pils will be pe rfor m e d acc or di n g t o fl o wc hart a n d Secti o n 9. 4. 5 .

Ac ute pa ncreat itis
o
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 n ot be e nr olle d i n t he trial. I n a d dit i on, tri al pr o d uct s h o ul d be disc o nti n ue d i n 
case of s us pici o n of ac ute pa ncreatit is i n acc or da nce t o Secti o n 8. 1 .
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
1 9 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
2 0 of 9 4

Me d ullar y t h y r oid ca ncer ( M T C) ( base d o n n o n -cli nical data)
o
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 y per 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 trials wit h se ma gl ut i de, t here 
ha ve bee n n o re p orts of M T C or cli nicall y  rele va nt c ha n ges i n calcit o ni n le vels. T he 
C- cell c ha n ges i n r o de nts are me diate d b y t he G LP- 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 oid. Acc or di n gl y , t h e ris k of G L P-1 rece pt or -
me diate d C -cell c ha n ges i n h u ma ns is c o nsi dere d t o be l o w. H o we ver, as a 
preca uti o n, e xcl usi o n  criteria relate d t o me dical hist or y of mul tiple e n d ocri ne 
ne o pl asia t ype 2 ( M E N 2) or M T C a n d ele vate d plas ma le vels of 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
o
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 ket i 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 ncreat ic ca ncer has bee n classifie d as a p ote ntial class ris k of G L P-1 R As b y  
E ur o pea n Me dici nes A ge nc y. As a preca uti o n, s u bjects wit h a hist or y  of mali g na nt 
ne o pl as ms wit hi n t he past 5 year s prior t o scree ni n g will be e xcl u de d fr o m t he trial.

Aller gic reacti o ns
o
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 vel o pi n g i m m u n o ge nic a n d aller gic reacti ons. As a 
preca uti o n, s u bjects wi t h kn o w n or s us pecte d h y perse nsi tivit y t o se m a gl utide or 
r elate 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)
o
St u di es i n a ni mals ha ve s h o w n re pr o d ucti ve t o xicit y.  T here are li mite d data fr o m t he 
use of se ma gl uti de i n pre g na nt w o me n. T heref ore, se ma gl uti de s h o ul d n ot be use d 
d uri n g pre g na nc y. E xcl usi o n a n d disc o nt i n uati on cri t eria 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. 2
C o ncl usi o n o n be nefit -ris k 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 t o 
mi ni mise t he ris ks a n d i nc o n ve nie nces of partici pati o n. T he safet y pr ofile f or se m a gl ut i de ge nerate d 
fr om t he n o n-cli nical a n d cli nical de vel o p me nt pr o gra m me has n ot re veale d a n y  s af et y iss ues t hat 
w o ul d pr o hi bi t a d mi nistratio n of  se ma gl uti de i n patie nts wit h N A S H a n d c om pe nsate d F 4. T he 
res ults of t he L E A N st u d y2 6 a n d t he p hase 2 trial wit h se ma gl uti de i n wei g ht ma na ge me nt 
( N N 9 5 3 6-4 1 5 3) s u g gest t hat se ma gl ut i de ma y pr o vi de cli nicall y  mea ni n gf ul tr e at me nt effects f or 
pati e nts wit h N A S H a n d c o mpe nsate d F 4 .
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
2 0 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
2 1 of 9 4
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 nefit s a n d ris ks a n d reas o na bl y e x pecte d 
ad verse e ve nts of se ma gl ut i de s.c ma y be f o u n d i n t he c urre nt versi o n of t he i n vesti gat or’s br oc h ure 
a n d a n y u p dates here of 3 3.
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
2 1 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
2 2 of 9 4
4
O bjecti ves a n d e n d p oi nts
4. 1
Pri m ar y, sec o n d ar y a n d e x pl or at or y o bjecti ves
4. 1. 1
Pri m ar y o bjecti ve
T o i n vesti gate t he effect of se ma gl uti de s.c. 2. 4 m g o nce -wee kl y  o n li ver fi br osis c o m pare d wit h 
pl ace b o i n s u bjects wit h N A S H a n d c o m pe nsate d fi br osis sta ge 4 2, 3.
Pri m ar y esti m a n d
I n s u bjects wit h N A S H a n d c o m pe nsate d fi br osis sta ge 4, t he esti ma n d a d dressi n g t he pri mar y 
o bj ect i ve is t he pr o p orti o n of s u bjects wit h li ver fi br osis i m pr o ve me nt wit h n o w orse ni n g of N A S H 
c o mpar e d bet wee n se ma gl ut i de s.c. 2. 4 m g o nce-wee kl y a n d place b o at 4 8 wee ks if all ra n d o mise d 
s u bjects ha d a d here d t o treat me nt. Ge neralisati on of t his esti ma n d de pe n ds a m o n g ot her t hi n gs o n 
t he e xte nt t o w hic h treat me nt a d here nce i n t his trial reflects cli nica l practice.
4. 1. 2
Sec o n d ar y effic ac y o bjecti ves
T o i n vesti gate t he effect of se ma gl uti de s.c. 2. 4 m g o nce -wee kl y  o n N A S H c o mpare d wi t h place b o
i n s u bjects wit h N A S H a n d c o mpe nsate d fi br osis sta ge 4 .
4. 1. 3
Sec o n d ar y s afet y o bjecti ve
T o e val uate t he safet y a n d t olera bil ity of  se ma gl uti de s.c. 2. 4 m g o nce-wee kl y  c o mpare d wi t h 
pl ace b o i n s u bjects wit h N A S H a n d c om pe nsate d fi br osis sta ge 4 .
4. 2
Pri m ar y a n d sec o n d ar y e n d p oi nts
Pri mar y a n d sec o n dar y e nd p oi nts are liste d i n Ta ble 4- 1 .
T a ble 4 - 1
List of pri m ar y a n d sec o n d ar y e n d p oi nts
E n d p oi nt title
Ti me fr a me
U nit
Pri m ar y e n d p oi nt :
At  least o ne sta ge of li ver 
fi br osis i m pr o ve me nt wit h n o 
w orse ni n g of N A S H after 4 8 
wee ks ( y es/ n o) ( w orse ni n g 
defi ne d as a n i ncrease of at 
least o ne sta ge of eit her 
l ob ular i nfla m mat i on , 
he pat oc y te ballo o ni n g or 
Fr o m  baseli ne ( wee k 0) t o 
visit 1 2 ( wee k 4 8)
Yes / n o
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
2 2 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
2 3 of 9 4
steat osis acc or di n g t o t he 
N A S H C R N criteria )2, 3.
Sec o n d ar y e n d p oi nts :
Relati ve c ha n ge fr o m 
baseli ne ( wee k 0) t o wee k 4 8 
i n li ver fat c o nte nt ( %) 
meas ure d b y M RI -P D F F.
Fr o m  baseli ne ( wee k 0) t o 
visit 1 2 ( wee k 4 8)
Rati o t o baseli ne
Relati ve c ha n ge fr o m 
baseli ne ( wee k 0) t o wee k 4 8 
i n li ver stiff ness meas ure d b y 
M R E .
Fr o m  baseli ne ( wee k 0) t o 
visit 1 2 ( wee k 4 8)
Rati o t o baseli ne
N A S H res o l uti on after 4 8 
wee ks ( y es/ n o) ( defi ne d b y 
t he N A S H C R N as l ob ular 
i nfla m mati on 0 – 1 a n d 
ball o o ni n g 0) 2, 3.
Fr o m baseli ne ( wee k 0) t o 
visit 1 2 ( wee k 4 8)
Yes / n o
C ha n ge fr o m baseli ne i n 
Sta ge of fi br osis acc or di n g t o 
t he N A S H C R N fi br osis 
sc ore
Fr o m  baseli ne ( wee k 0) t o 
visit 1 2 ( wee k 4 8)
Scal e ( 0-4) *
C ha n ge fr o m baseli ne i n 
N A F L D acti vit y sc ore ( N A S) 
acc or di n g t o t he N A S H C R N 
criteria
Fr o m  baseli ne ( wee k 0) t o 
visit 1 2 ( wee k 4 8)
Scal e ( 0-8) *
N u m ber of treat me nt -
e mer ge nt a d verse e ve nts
Fr o m  baseli ne ( wee k 0) t o 
visit 1 2 ( wee k 4 8)
C o u nt
* ra n ge of val ues o n a bs ol ute scale at o ne ti me-p oi nt
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
2 3 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
2 4 of 9 4
5
Tr i al desi g n
5. 1
O ver all desi g n

T his is a 4 8- wee k ra n d o mise d, d o u ble -bli n d, pl ace b o -c o ntr olle d, par allel gr o u p, m ult i-ce ntre 
trial

T here i s a 6 wee ks scree ni n g peri o d f oll owe d b y  a ra n d o misati on visit a n d a 4 8 -wee k treat m e nt 
p eri o d. T he treat m e nt perio d is di vi de d i nt o a d ose esca lati on peri o d of  1 6 wee ks a n d a 
mai nte na nce peri o d of 3 2 wee ks. T he f o ll ow- u p peri o d i s 7 wee ks. T otal trial d urat i on is 
a p pr o xi matel y 6 1 wee ks

S u bjects will be ra n d o mise d i n a 2: 1 rati o t o recei ve eit her: 

S e m a gl ut i de s.c. 2. 4 m g o nce-wee kl y

S e m a gl ut i de pl ace b o s.c. o nce-wee kl y

D uri n g t he trial all s u bjects will recei ve n utrit i onal a n d p h ysical acti vit y c o u nselli n g i n 
acc or da nce wit h site practice at t he vis its s pecifie d i n t he fl o wc hart

T he tri al p o p ulat i on is s u bjects wit h N A S H a n d c o m pe nsate d F 4, wit h n o pre vi o us e ve nts of 
dec o m pe nsat i on, a n d n o ca uses of c hr o nic li ver disease ot her t ha n N A F L D. T he p o p ulat i on will 
s uffer fr o m o ver wei g ht or o besity,  a n d ma y ha ve T 2 D
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 t he 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. 
5. 2
S u bject a n d tri al c o m pleti o n
A p pr o xi matel y  2 4 0 s u bjects will be scree ne d t o ac hie ve 6 9 s u bjects ra n d o ml y assi g ne d t o trial 
pr o d uct.
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
2 4 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
2 5 of 9 4
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 ( F U visit ( visit 1 2 A f or d isc o nti n ue d s u bjects d uri n g tri al)) acc or di n g t o t he 
flo 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 p eri 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 recei ve d t he re q uire d 
treat me nt, a n d atte n de d t he 'e n d of treat me nt' visit ( visit 1 2) 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 h e last visit of t h e last s u bject i n t he trial. 
5. 4
Scie ntific r ati o n ale f or tri al desi g n
A ra n d o mise d, d o u ble -bli n d, place b o -c o ntr olle d, parallel gr o u p, m ulti-ce ntre trial is c h ose n t o 
mi ni mise bias i n t he assess me nt of t he effect a n d safet y of  se ma gl uti de s.c. 2. 4 m g. 
T he tri al incl u des 4 8 -wee ks of treat me nt w hic h is i n li ne wit h rece nt p hase 2 b a n d 3 trials i n 
s u bjects wit h N A S H a n d c o m pe nsate d cirr h osis ( B M S’ pe g-F G 2 1 cli ncaltrial. g o v N C T 0 3 4 8 6 9 1 2; 
Gilea d’s sel o nserti b cli nicaltrial. g o v N C T 0 3 0 5 3 0 6 3). T he 4 8 wee ks are c o nsi dere d s ufficie nt t o 
esta blis h if se ma gl ut i de has t he effects o n fi br osis a n d li ver steat osis i n s u bjects wi t h c o mpe nsate d 
F 4. T he 7 wee ks off treat me nt f o ll ow- u p peri o d i s i ncl u de d t o mo ni t or s afet y u ntil c o m p lete was h-
o ut of se ma gl ut i de. 
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 sec o n d wee k d uri n g t he first 1 2 wee ks of t he d ose escalati on peri o d. Fr o m  wee k 1 2 
u nt il e n d of treat me nt ( wee k 4 8) t here are 4 visits sc he d ule d wit h increasi n g ti me i nter val fr o m 4 t o 
1 2 wee ks bet wee n t he visits. T he n u m ber a n d fre q ue nc y o f visit s/ p h o ne c o ntacts are bala nce d 
bet wee n a de q uate efficac y a n d safet y e valu ati o n a n d t he ti me re q uire d b y t he s u bject t o partici pate. 
D ue t o t he lac k of  p har mac olo gi cal tr e at me nts for c o m pe nsate d F 4, pl ace b o is c h ose n as 
c o mparat or. T he trial has a 2: 1 ra n d o misat i on sc he me w hic h will i ncrease t he a m o u nt of 
se ma gl uti de e x p os ure data i n t he i ncl u de d p o p ulat i o n. 
S u bject s wit h T 2 D will be i ncl u de d i n t he trial p o p ulati on si nce t he pre vale nce of T 2 D is hi g h i n 
pati e nts wit h N A S H a n d li ver cirr h osis (a p pr o xi matel y 6 5 %)3 4 a n d patie nts wit h T 2 D ma y be nefit 
fr om treat me nt wit h se ma gl uti de. S u bjects will be stratifie d at ra n d o misati on base d o n T 2 D t o 
e ns ure e q ual all ocat i on t o eac h treat me nt ar m. 
T he pri mar y  a n d sec o n dar y e n d p oi nts are base d o n M R i ma gi n g a n d li ver hist ol o g y, w hic h is i n li ne 
wi t h t he c urre nt rec o m me n dat i ons fr om Li ver F or u m 3 5.
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
2 5 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
2 6 of 9 4
5. 5
J ustific ati o n f or d ose
T he rece nt l y c om p lete d p hase 2 d ose fi n di n g trial i n wei g ht ma na ge me nt ( N N 9 5 3 6-4 1 5 3) a n d t he 2 
o n g oi n g N A S H trials ( N N 9 9 3 1 -4 2 9 6 a n d N N 9 9 3 1 -4 3 8 1) ha ve se ma gl ut i de s.c. 0. 4 m g o nce-dail y 
as ma xi m u m d ose (ra n ge 0. 0 5 t o 0. 4 m g o nce-dail y). 
T he res ults fr o m N N 9 5 3 6- 4 1 5 3 s h o we d t hat t he se ma gl ut i de s.c. 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 bility pr ofile. Usi n g p o p ulate d 
p har mac o ki net ic m o delli n g, i t was esti mate d t hat a o nce-wee kl y  mai nte na nce d ose of s.c. 2. 4 mg 
res ulte d i n si milar Cma x at stea d y-state as t hat o btai ne d b y t he 0. 4 mg o nce -dail y d ose.
T he tar get d ose i n t he o n g oi n g p hase 3 pr o gra m me i n wei g ht ma na ge me nt ( N N 9 5 3 6) was c h ose n t o 
be se ma gl ut i de s.c. 2. 4 m g o nce-wee kl y . A mai nte na nce d ose of se ma gl ut i de s.c. 2. 4 m g o nce-
wee kl y is als o c h ose n as tar get d ose i n t his trial, as it is a nt ici pate d t o ease t he b ur de n of dr u g 
a d mi nistrati o n c o m pare d t o o nce-dail y i nject i ons i n cli nical practice. 
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. A fi xe d-d ose escalat i on re gi me n si milar t o t he re gi me n use d i n t he p hase 3 
pr o gra m me i n wei g ht ma na ge me nt ( N N 9 5 3 6) is a p plie d. S u bjects will be i nit iate d at a o nce-wee kl y  
d ose of 0. 2 4 m g a n d f o ll ow a fi xe d -d ose escalati o n re gi me n, wit h d ose i ncrease 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.
Pl ease refer t o Secti o n 7. 1 f or more details o n treat me nt d oses. 
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
2 6 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
2 7 of 9 4
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 mitted. 
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 o f t he f o ll 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 acti vities t o deter mi ne s uita bilit y f or 
t he trial.
2.
Male or fe male, a ge d 1 8 - 7 5 years ( b ot h i ncl usi ve) at t he ti me of si g ni n g i nf or me d c o nse nt.
3.
Hi st olo gi c e vi de nce of N A S H a n d fi br osis sta ge 4 acc or di n g t o t he N A S H C R N classificat i on 
ba se d o n ce ntral pat h ol o gist e val uat i on of a li ver bi o ps y o btai ne d wit hi n 3 6 0 da ys pri or t o 
scree ni n g. I n s u bjects w h o ha ve ne ver ha d a li ver bi o ps y s h o wi n g N A S H a n d F 4, li ver stiff ness 
> 1 4 k Pa b y  Fi br o Sca n® at scree ni n g m ust be d oc u me nte d bef ore s u bjects ca n ha ve a trial -
r elate d li ver bi o ps y. 
4.
A hist ol o gical N A F L D acti vit y sc ore ( N A S) ≥3 wi t h a sc ore of 1 or more i n l o b ular 
i nfla m mati on a n d he pat oc y te ballo o ni n g base d o n ce ntral  pat h olo gist e val u ati o n
5.
B o d y mass i n de x ≥2 7 k g/ m 2
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:
Li ver -rel ate d:
1.
Prese nce or hist or y  of c hr o nic li ver disease ot her t ha n N A F L D
2.
Prese nce or hist or y  of he pat ic dec om pe nsat i on (e. g. ascites, variceal blee di n g, he pat ic 
e nce p hal o pat h y or s p o nta ne o us bacterial perit o nitis) or li ver tra ns pla ntati on
3.
Prese nce or h ist or y of gastr oes o p ha geal varices wit hi n t he past 3 6 0 da ys prior t o scree ni n g . F or 
s u bjects wit h n o k n o w n hist or y of gastr oes o p ha geal varices a n d wi t h a Fi br osca n ® ≥2 0 k Pa a n d 
t hr o mb oc y t es ≤1 5 0, 0 0 0 1 7, a es o p ha g o gastr o d u o de n osc o p y must be perf or m e d t o e valuate 
prese nce of gastr oes o p ha geal varices
4.
K n o w n or s us pecte d a b use of alc o h o l ( > 1 2 g/ da y for w o m e n or > 2 4 g/ da y for m e n) or alc o h ol 
de pe n de nce assesse d b y t he Al c o h ol Use Dis or ders I de nt ificatio n Test ( A U DI T q uesti o n naire)
5.
Prese nce or hist or y  of he pat ocell ular carci n o ma
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
2 7 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
2 8 of 9 4
6.
Treat me nt wit h vita mi n E (at d oses ≥8 0 0 I U/ da y ) or pio gli taz o ne w hic h has n ot bee n at a sta ble 
d ose i n t he o pi ni o n of t he i n vesti gat or i n t he peri o d fr om 9 0 da y s prior t o scree ni n g
7.
Treat me nt wit h me dicati o ns (f or m ore t ha n 1 4 c o nsec ut i ve da ys) wit h k n o w n effect o n li ver 
steat osis (e. g. treat me nt wit h C ortic oster oids (t o pi c al a n d i n hale d are all o we d), Met h otre xate, 
T a m o xife n, Val pr o ic aci d, A mi o dar o ne or Tetrac ycli ne) w hic h has n ot bee n sta ble i n t he 
o pi ni o n of t he i n vest i gat or i n t he peri o d fr om 2 8 da ys pri or t o scree ni n g
8.
Ala ni ne a mi n otra nsferase ( A L T) > 5 ti mes u p per n or mal li mit ( U N L)
9.
As partate a mi n otra nsferase ( A S T) > 5 ti mes U N L
1 0. T ot al  bilir u bi n > 1. 5 m g/ d L. T otal  bilir u bi n le vel > 1. 5 m g/ d L is all o we d if c o nj u gate d bilir u bi n 
is < 1. 5 × U N L
1 1. I nter nati o nal n or malize d rati o (I N R) of pr ot hr o m bi n ti me > 1. 4
1 2. T hr o m b oc y t es < 1 0 0 ,0 0 0 per μl
1 3. M o d el  F or E n d-Sta ge Li ver Disease ( M E L D) sc ore ≥ 1 2 p oi nts
1 4. C hil d -P u g h Sc ore ≥ 7 p oi nts
1 5. Al b u mi n < 3. 4 g/ dl
1 6. P osi tive res ult t o test f or he patit is B s urface a nti ge n ( H Bs A g) or he patitis C a nti b o dies. I n case 
scree ni n g test f or he patit is C is p ositi ve, t he c o nfir mati ve test is decisi ve
1 7. Di a g n ostic test res ults p osit i ve f or HI V -1 or HI V -2 i nfect i on
Gl yc ae mi a -rel ate d:
1 8. Prese nc e or hist or y of t ype 1 di a betes
1 9. Gl yc os ylate d hae m o gl o bi n A 1c ( H b A 1c) > 9. 5 %
2 0. Treat me nt wit h gl uca g o n -li ke pe pti de-1 rece pt or a g o nists ( G L P -1 R As) i n t he peri o d fr om 9 0 
da ys pri or t o scree ni n g
2 1. Treat me nt wit h ot her gl uc ose l o weri n g a ge nt(s) (a part fr o m w hat is liste d i n e xcl usi o n cri t erio n 
2 0 ) or wei g ht l oss me dicati on n ot sta ble i n t he o pi ni o n of t he i n vesti gat or i n t he peri o d fr om 2 8 
da ys pri or t o scree ni n g
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
2 8 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
2 9 of 9 4
O besit y -rel ate d:
2 2. Pre vi o us or pla n ne d ( d uri n g t he trial perio d) o besi t 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 
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 rem o ve d > 1 y ear bef ore 
scree ni n g
Ge ner al s afet y:
2 3. Prese nce or hist or y  wit hi n t he past 5 years prior t o t he d a y of scree ni n g of mali g na nt ne o plas ms 
ot her t ha n descri be d i n e xcl usi o n cri t erio n 5. 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 we d
2 4. P rese nce of ac ute pa ncreatitis wit hi n t he past 1 8 0 da ys pri or t o t he da y of scree ni n g 
2 5. H istor y  or prese nce of c hr o nic pa ncreat itis 
2 6. F or s u bjects wit h t y pe 2 dia betes o nl y: U nc o ntr olle d a n d p ote ntiall y  u nsta ble dia betic 
reti n o pat h y or ma c ulo p at h y . Verifie d b y a fu n d us e xa mi nat i on perf or m e d wit hi n t he past 9 0 
da ys pri or t o scree ni n g or i n t he peri o d bet wee n scree ni n g a n d ra n d o misat i on. P har mac o l ogi cal 
p u pil -dilat i on is a re q uire me nt u nless usi n g a di gital fu n d us p h ot o gra p h y  ca mera s pecifi e d for 
n o n- dilate d e xa mi nat i on
2 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 yp e 2 or m e d ullar y 
t h yr oid carci n o ma
2 8. A n y of t he f o ll owi n g: m y ocar dial  infarct i on, str o ke, h os pitalizat i on f or u nsta ble a n gi na pect oris 
or tra nsie nt isc hae mic attac k wit hi n t he past 9 0 da ys pri or t o t he da y  of scree ni n g a n d bet wee n 
scree ni n g a n d ra n d o misat i on
2 9. Pre se ntl y classificati o n of heart fail ure Ne w Y or k Heart Ass ociat i on ( N Y H A) Class I V
3 0. Prese nce or hist or y  of s ufferi n g fr o m cla ustr o p h o bia precl udi n g ma g net ic res o na nce i ma gi n g
3 1. Prese nce of metallic i m pla nts, pace ma ker, defi brillat or, artificial val ves i n heart , i nter nal 
ele ctrical de vices (e. g., c oc hlear i m pla nt, ner ve st i m ulat or, brai n sti m ulat or, gastric pace ma ker, 
bla d der st i m ulat or etc.), a ne ur ys m cli ps, per ma ne nt ma ke u p or tatt o os precl udi n g m a g netic 
res o na nce i ma gi n g
3 2. U nsta ble b o d y  wei g ht defi ne d as m ore tha n 5 % self -re p orte d c ha n ge i n b o d y w eig ht i n t he 
p eri o d fr o m 2 8 da ys pri or t o scree ni n g
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
2 9 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
3 0 of 9 4
3 3. A n y c o n dit i on w hic h, i n t he i n vesti gat or's o pi ni o n mi g ht je o par dise s u bject's safet y or 
c o mplia nce wi t h t he pr ot oc ol
3 4. Me ntal  inca pacit y,  la n g ua ge barriers or u n willi n g n ess t o c o m pl y wit h t he re q uire me nts of t he 
pr ot oc ol , w hic h ma y precl u de a de q uate u n dersta n di n g or c o -o perati o n d uri n g t he tri a l as ju d ge d 
b y t he i n vesti gat or
3 5. S ur ger y  sc he d ule d f or t he trial d urati o n peri o d, e xce pt f or mi n or s ur gical pr oce d ures, i n t he 
o pi n i on of t he i n vest i gat or
3 6. K n o w n or s us pecte d h y perse nsi tivit y t o tri al pr o d uct or relate d pr o d ucts
3 7. Pre vi o us partici pat i on i n t his trial. Partici pati on is defi ne d as ra n d omisat i on
3 8. P arti cip ati o n i n a n ot her i nter ve nti o nal cli nical trial w ithi n 6 0 da ys bef ore sc ree ni n g
3 9. 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 ( hi g hl y effecti ve c o ntrace pti ve 
meas ures as re q uire d b y l ocal re g ulat i on or practice)
4 0. Calcit o ni n ≥ 1 0 0 n g/ L
4 1. Esti mate d Gl o mer ular Filtrati o n Rate (e G F R) < 3 0 m L/ mi n/ 1. 7 3 m 2 as defi ne d b y acc or di n g t o 
C K D E PI creati ni ne e q uat i on as defi ne d b y K DI G O 2 0 1 2 3 6
6. 3
Lifest yle restricti o ns
6. 3. 1
Me als a n d diet ar y restricti o ns

S u bjects m ust atte n d s o m e 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 ei g ht h o urs 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 dicatio n w hic h s h o ul d be ta ke n wi t h or after a meal s h o uld be wi t hhel d o n t he da y  of 
t he visit u nt il t he fasti n g pr oce d ure i.e. M R I, fi br osca n® a n d blo o d s a m ples ha ve bee n o btai ne d. 

Fast i n g pr oce d ures i ncl u de M R sca ns, b o d y w eig ht, Fi br osca n ® meas ure me nts a n d bl o o d 
sa m pli n g ( F P G, C- pe pti de , li pi ds (t otal ch o lester ol, free fatt y aci ds, H D L c h olester ol, L D L 
c h o lester ol, trigl yceri des, V L D L c h o lester ol) a n d se ma gl ut i de plas ma c o nce ntrati o n). 

O nl y f o ur h o urs fast i n g is re q uire d pri or t o M R sca n ni n g a n d i nta ke of water or li q ui d s h o ul d be 
a v o i de d or li mite d t w o h o urs bef ore M R sca n ni n g. 

O nl y t w o h o urs fast i n g is re q uire d pri or t o Fi br osca n® meas ure me nts.

If t he s u bject is n ot fasti n g as re q uire d, t he s u bject m ust be calle d i n f or a ne w visit wit hi n t he 
visit wi n d o w t o ha ve t he fasti n g pr oce d ures d o ne. 
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
3 0 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
3 1 of 9 4
6. 4
Scree n f ail ures
Scree n fail ures are defi ne d as s u bjects w h o c o nse nt t o partici pate i n t he cli nical trial b ut are n ot 
eli gi ble f or partici pat i on acc or di n g t o i n/e xcl usi o n cri teria. A mi ni mal set of scree n fail ure 
i nf or mat i on 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 om re g ulat or y a ut h orities. Mi ni mal i nf or mati on i ncl u des de m o gra p h y, scree n fail ure 
details, eli gi bilit y crit eria, a n d a n y S A E. A scree n fail ure sessi on m u st be ma de i n t he 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 be re -scree ne d o nce 
wi t hi n t he li mits of t he recr uit me nt p erio d. I n t he e ve nt of re -scree ni n g, a ne w i nf or me d c o nse nt 
m ust be o btai ne d a n d a ne w s u bject n u m ber m ust be all ocate d. 
Re -sa m pli n g of lab para meters is all o we d o nce, wit hi n t he scree ni n g visit wi n d o w, pr o vi de d t he 
me dical s pecialist res p o nsi ble f or t he trial a grees t o t he i n di vi d ual case. I n case o f tec h nical iss ues 
(e. g. hae m ol yse d or l ost), re-sa mpli n g is all o we d f or t he affecte d para meters wit h o ut as ki n g f or 
per missi o n fr o m t he me dical s pecialist at N o v o N or dis k. 
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
3 1 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
3 2 of 9 4
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 gatio nal  me dici nal pr o d ucts (I M P)

Tri al pr o d uct must o nl y be use d, if it a p pears clear a n d c ol ourl ess

All baseli ne assess me nts m ust be d o ne pri or t o a d mi nistrati o n of t he first d ose of trial pr o d uct.
T a ble 7- 1
Tri al pr o d ucts pr o vi de d b y N o v o N or dis k A/ S
Tri al pr o d uct n a me:
Se ma gl uti de B 3. 0 m g/ m L 
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

D ose escalat i on of se ma gl ut i de/se ma gl uti de pl ace b o s h o uld ta ke pl ace 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 . Se ma glut i de or se ma gl uti de place b o will be 
i nitiate d wit h a starti n g val ue of 8 ( 0. 2 4 mg) f or t he first 4 wee ks, a n d s u bse q ue ntl y t he val ue 
will be i ncrease d e ver y  4 wee ks as i n dicate d i n Ta ble 7- 2 . All s u bjects m ust ai m at reac hi n g t he 
rec o m me n de d tar get d ose of se ma gl uti de s.c. 2. 4 m g o nce-wee kl y  or t he c orres p o n di n g v ol u me 
of  place b o.
T a ble 7- 2  
D ose esc al ati o n a n d m ai nte n a nce d ose of se m a gl uti de s.c. 2. 4 m g/se m a gl uti de 
pl ace b o o nce -wee kl y
I M P
D ose 
V ol u me 
Val ue s h o w n 
i n t he d ose 
c o u nter
D urati o n
S e m a gl ut i de B 3. 0 m g/ m L 
P D S 2 9 0 or se ma gl ut i de place b o
0. 2 4 m g
8 0 µl
8
4 wee ks
S e m a gl ut i de B 3. 0 m g/ m L 
P D S 2 9 0 or se ma gl ut i de place b o
0. 5 m g
1 7 0 µl
1 7
4 wee ks
S e m a gl ut i de B 3. 0 m g/ m L 
P D S 2 9 0 or se ma gl ut i de place b o
1. 0 m g
3 4 0 µl
3 4
4 wee ks
S e m a gl ut i de B 3. 0 m g/ m L 
P D S 2 9 0 or se ma gl ut i de place b o
1. 7 m g
5 7 0 µl
5 7
4 wee ks
S e m a gl ut i de B 3. 0 m g/ m L 
P D S 2 9 0 or se ma gl ut i de place b o
2. 4 m g
8 0 0 µl
8 0
3 2 wee ks 
( mai nte na nce d ose)
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
3 2 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
3 3 of 9 4

If a s u bject d oes n ot t olerate t he pla n ne d 4-wee k d ose -escalat i on re gi me n d ue t o GI A Es or f or 
ot her reas o ns as j u d ge d b y t he i n vest i gat or, t he s u bject is all owe d t o sta y  lo n ger at t he i n di vi d ual 
d ose ste ps. T he I n vesti gat or m ust ai m f or ma xi m u m 1 e xtra wee k o n eac h d ose le vel. If t he 
pl a n ne d d ose escalat i on re gi me n is n ot a d here d t o, t he In vest i gat or s h o ul d e val uate wee kl y if t he 
d ose ca n be esca late d t o t he ne xt pla n ne d le vel.

If a s u bject d oes n ot t olerate t he rec o m me n de d tar get d ose of s.c. 2. 4 m g o nce -wee kl y , t he 
s u bject ma y sta y at t he lo wer d ose l e v el. T his is o nl y all owe d if t he s u bject w o ul d ot her wise 
di sc o nti 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 trial pr o d uct, 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 s u bject ma kes at least o ne atte m pt t o 
escalate t o t he rec o m me n de d tar get d ose of s.c. 2. 4 m g o nce - wee kl y, as per t he i n vesti gat or’s 
di scretio n.

It is rec o m me n de d t hat t he i n vesti gat or c o ntact t he m o nit or i n case of persiste nt de viati o ns fr om 
t he pla n ne d escalat i on.

S u bjects s h o ul d be i nstr ucte d t o i nject se ma gl uti de/se ma gl ut i de place b o o nce-wee kl y at t he 
sa me da y of t he wee k t hr o u g h o ut t he trial. 

I njecti ons ma y be a d mi nistere d i n t he t hi g h, a b d o me n or u p per ar m, at a n y t i me of day 
irres pecti ve of meals. S u bjects s h o ul d be e nc o ura ge d t o i nject i n t he sa me area t hr o u g h o ut t he 
trial, b ut c ha n gi n g bet wee n left a n d ri g ht si de is all o we d.

If a si n gle d ose of trial pr o d uct is misse d, it s h o ul d be a d mi nistere d as s o o n as n otice d, pr o vi de d
t he ti me t o t he ne xt sc he d ule d d ose is at least 4 8 h o urs. If a d ose is misse d a n d t he ne xt 
sc he d ule d d ose is less t ha n 4 8 h o urs a wa y, t he s u bject s h o ul d n ot a d mi nister a d ose u ntil t he 
ne xt sc he d ule d d ose. A misse d d ose s h o ul d n ot affect t he sc he d ule d d os i n g da y of t he wee k. 

If ≥ 2 c o nsec ut i ve d oses of trial pr o d uct are misse d, t he s u bject s h o ul d be e nc o ura ge d t o 
rec o m me nce t he treat me nt if c o nsi dere d safe as per t he i n vesti gat or’s discreti o n a n d if t he 
s u bject d oes n ot meet a n y of t he disc o nti n uati on cri teria (sectio n 8. 1 ). T he trial pr o d uct s h o uld 
be c o nt i n ue d as earl y as t he sit uati o n all o ws. T he misse d d oses s h o ul d n ot affect t he sc he d ule d 
d osi n g da y of t he wee k. T he start d ose f or re -i nitiatio n of  trial pr o d uct is at t he in vest i gat or’s 
di scretio n. I n case of q uesti o ns relate d t o re -i nitiati o n of trial pr o d uct, t he i n vesti gat or s h o ul d 
c o ns ult N o v o N or dis k gl o bal me dical e x perts. 

A u xiliar y  s u p plies will be pr o vi de d i n acc or da nce wit h t he trial materials ma n ual ( T M M).
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 P D S 2 9 0 pre -fille d pe n -i nject or. 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. Nee dles l o n ger t ha n 6 m m s h o ul d n ot be use d.
Directi o n f or use ( D F U) 
D F U f or 3 m L P D S 2 9 0 pre-fille d pe n-i nject or
B G -meters ( A b b ott 
Precisi o n Ne o or Precisi o n 
de pe n di n g o n c o u ntr y 
a p pr o val)
T he B G -meters use test stri ps cali brate d t o plas ma val ues. All meas ure me nts 
perf or me d wit h ca pillar y bl o o d are a ut o maticall y cali brate d t o plas ma 
e q ui vale nt gl uc ose val ues, w h ic h will be s h o w n o n t he dis pla y.
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
3 3 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
3 4 of 9 4
At  t he ra n d omisat i on visit ( visit 2) s u bjects wit h T 2 D will be pr o vi de d wit h a B G -met er i ncl u di n g 
a u xiliaries as well as i nstr ucti o ns f or use. I n case a s u bject is dia g n ose d wit h T 2 D d uri n g trial 
parti ci pat i on t he s u bject will be pr o vi de d wit h a B G -met er. T he s u bjects will be i nstr ucte d i n h o w t o 
use t he de vice. T he B G -meter pr o vi de d b y N o v o N or dis k s h o ul d be use d t o meas ure t he bl o o d 
gl uc ose i n c o n nect i on wi t h s y m pt o ms of h y p o gl ycae mia.
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 are f o u n d i n t he I B a n d a n y u p dates here of3 3. 
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 B 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 vest i gat or m ust d oc u me nt t hat D F U are gi ve n t o t he su bject orall y a n d i n writ i n g at t he first 
di s pe nsi n g visit (as s pecifie d i n t he fl o wc hart). T he s u bjects m ust be trai ne d acc or di n g t o t he 
di recti on f or use i n h o w t o ha n dle t he me dical de vice P D S 2 9 0 pre -fille d pe n-i nject or w he n ha n de d 
o ut t he first ti me. T rai ni n g m ust be re peate d, d uri n g t he trial i n acc or da nce with t he fl o wc hart i n 
or der t o e ns ure c orrect use of t he P D S 2 9 0 pre -filled pe n -i nject or. T he D F U s h o uld be ha n de d o ut at 
s u bse q ue nt visits if nee de d. T he P D S 2 9 0 pre-fille d pe n-i nject or will dis pla y a v al ue a n d n ot m g a n d 
s u bjects m ust be i nstr ucte d t o a d mi nister t he val ue s h o w n i n t he dis pla y. Trai ni n g i n P D S 2 9 0 pre -
fille d pe n-i nject or a n d i nject i on tec h ni q ue are t he res p o nsi bilit y of  t he i n vesti gat or or a dele gate. 
7. 2
D ose m o dific ati o n
N ot a p plica ble f or t hi s trial. Please refer t o Sectio n 7. 1 f or descripti o n of  misse d d ose(s).
7. 3
Met h o d of tre at me nt assi g n me nt

All eli gi ble s u bjects will be ce ntrall y ra n d o mise d usi n g a n I W R S a n d assi g ne d t o t he ne xt 
a vaila ble treat me nt acc or di n g t o r a n d o misat i on sc he d ule. Trial pr o d uct will be dis pe nse d at t he 
trial visits s u m marise d i n t he fl o wc hart.

Ra n d o misat i on will be stratifie d base d o n T 2 D (wit h T 2 D or wit h o ut T 2 D ). 
7. 4
Bli n di n g

T he acti ve dr u g a n d place b o are pac ke d bli n de d a n d are vis uall y i de nt ical. 
T he I W R S is use d f or bli n d -brea ki n g i nstr ucti o ns. T he bli n d ma y  be br o ke n i n a me dical e mer ge nc y 
if k n o wi n g t he act ual treat me nt w o ul d i nfl ue nce t he treat me nt of t he s u bject. N o v o N or dis k will be 
n otifie d i m me diatel y after brea ki n g t he bli n d. T he da te w he n a n d reas o n w h y t he bli n d was br o ke n 
m ust be rec or de d i n t he s u bject’s me dical rec or ds.
W he ne ver t he bli n d is br o ke n, t he pers o n brea ki n g t he bli n d m ust pri nt t he "c o de brea k 
c o nfir mat i on" n otificat i on ge nerate d b y t he I W R S a n d si g n a n d date t he d oc u me nt. 
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
3 4 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
3 5 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 liste d 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. 

St ora ge c o n dit i ons, i n -use c o n di tio ns a n d i n -us e ti mes ca n be f o u n d i n t he T M M.

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 scree ni n g 
a n d ra n d o misat i on.

T he i n ves tigat or m ust c o nfir m t hat a p pr o priate te m perat ure c o n 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 a n d a n y discre pa ncies are re p orte d a n d res ol 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 onit ore d ( m a n u al or a ut o mate d) 
area i n acc or da nce w ith t he l a 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).

T h e trial pr o d ucts will be dis pe nse d t o eac h s u bject as re q uire d acc or di n g t o treat me nt gr o u p. 
Eac h dis pe nsi n g u nit is u ni q uel y n u m bere d wit h a Di s pe nsi n g U nit N u m ber ( D U N). T he c orrect 
D U N(s) m ust be dis pe nse d t o t he s u bject. 

Dr u g acc o u nta bilit y is perf or me d usi n g t he I W R S dr u g acc o u nta bilit y m o d ule. T he tri al 
pr o d ucts m ust be acc o u nte d f or at pe n le vel a n d eit her rec or de d as use d/ partl y use d, u n use d or 
l ost. Ret ur ne d pe ns m ust be se nt f or destr ucti o n, t h us ma y n ot be re-all ocate d t o ne w s u bjects. 

T he s u bj ect must 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 d uri n g t he trial as i nstr ucte d b y t he i n vesti gat or.  

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 ucts m ust be d oc u me nte d i n t he I W R S. 

All ret ur ne d, e x pire d or da ma ge d trial pr o d ucts (f or tec h nical c o m p lai nt sa m ples see A p pe n di x 
6 ) must be st ore d se paratel 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.
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
3 5 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
3 6 of 9 4

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 l atest 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 nstr 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 will be assesse d b y  as ki n g s u bject a b o ut misse d d oses a n d m o nit ori n g t he 
di ar y. I nf or matio n 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 ds.
7. 7
C o nc o mit a nt me dic ati o n
T he f o ll owi n g m e dicat i ons m ust be sta bl e as descri be d i n e xcl usi o n cri teria 6, 7, 2 1 :

Vi ta mi n E a n d pio gli tz o ne

Me dicat i ons wit h k n o w n effect o n li ver steat osis

Gl uc ose -l oweri n g a n d wei g ht -l oss me dicatio ns 
T hr o u g h o ut t he trial s u bjects ca n n ot i nit iate treat me nt wit h:

G L P - 1 R As ( ot her t ha n trial pr o d uct) or S G L T-2 i n hi bit ors

Vi ta mi n E or pio glitaz o ne

Dr u gs wi t h p ote ntial effect o n steat osis (c ortic oster oids (t o pi c al, i n hale d a n d s h ort ter m s yste mic 
use ( ≤ 1 4 da ys) are all o we d), met h otre xate, ta m o xife n, val pr oic aci d, a mi o dar o ne or 
t etrac ycli ne)

Dr u gs t hat c o ul d pr o m ote wei g ht l oss ( orlistat, z o nisa mi de, t o pira mate, p he nter mi ne, l orcaseri n, 
b u pr o p i on a n d naltre x o ne al o ne or i n c o m bi nati o n wit h a n y ot her me dicati o n t hat c o uld pr o m ote 
w ei g ht l oss)
N ei t her ca n t he s u bjects partici pate i n a n y or ga nise d wei g ht re d ucti o n pr o gra m me t hr o u g h o ut t he 
trial. 
F or s u bjects treate d wit h vita mi n E or pi o glitaz o ne acc or di n g t o e xcl usi o n cri t erio n 6 , t hese 
me dicat i ons m ust be ke pt at a sta ble d ose t hr o u g h o ut t he trial. 
A n y me dicat i on or vacci ne (i ncl u di n g o ver -t he-c o u nter or prescri pt i on me dici nes, vita mi ns, a n d/ or 
her bal s u p ple me nts) 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 visit 1 or 
recei ves d uri n g t he trial m ust be rec or de d al o n g wit h:

Tra de na me or ge neric na me

Dates of a d mi nistrati o n i ncl u di n g start a n d st o p dates

F or vi ta mi n E a n d pi o glitaz o ne t he daily d ose m ust be rec or de d as well
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
3 6 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
3 7 of 9 4
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 Secti o n 9. 2 .
7. 7. 1
S u bjects tre ate d wit h i ns uli n
T hr o u g h o ut t he trial, i ns uli n d ose s h o ul d be t itrate d at t he discreti on of t he i n vesti gat or. F or t he 
i n di vi d ual s u bject, i ncreasi n g t he i ns uli n d ose bef ore t w o wee ks after t he e n d of t he fi nal d ose 
escalat i on s h o ul d be a v o i de d, u nless re q uire d t o c o ntr ol ac ute h y per gl ycae mia a n d ac ute dia betic 
c o mplicat i ons.
S u bjects tre ate d wit h i ns uli n a n d H b A 1c ≤ 8. 0 % at scree ni n g
S u bjects treate d wit h se ma gl ut i de i n c om bi na tio n wi t h ins uli n ma y ha ve a n i ncrease d ris k of 
h y p o gl ycae mia. T he ris k of h y p o gl ycae mia ca n be l o were d b y  re d uci n g t he d ose of i ns uli n, a n d a 
d ose re d ucti o n at ra n d o misat i on a n d t hr o u g h o ut t he trial s h o ul d be c o nsi dere d at t he discret i on of 
t he i n vest i gator.
7. 7. 2
S u bjects tre ate d wit h S U
S u bjects treate d wit h se ma gl ut i de i n c o m bi nati on wi t h a s ulf on yl urea ma y  ha ve a n i ncrease d ris k of 
h y p o gl ycae mia. T he ris k of h y p o gl ycae mia ca n be l o were d b y  re d uci n g t he d ose of s ulf on yl urea ,
a n d a d ose re d ucti o n at ra n d o misa tio n a n d t hr o u g h o ut t he trial s h o ul d be c o nsi dere d at t he 
di scretio n of  t he i n vesti gat or.
7. 7. 3
S u bjects de vel o pi n g t y pe 2 di a betes
S u bjects w h o are dia g n ose d wit h T 2 D as a res ult of a scree ni n g pr oce d ure or are dia g n ose d wit h 
T 2 D d uri n g t he trial s h o ul d recei ve di a betes treat me nt wit hi n t he restricti on of t he pr ot oc ol a n d at 
t he discret i on of t he i n vest i gat or. G L P -1 R As ( ot her t ha n trial pr o d uct) a n d S G L T -2 i n hi bit ors m ust 
n ot be use d. T he a nt i dia betic me dicat i on prescri be d b y t he i n vest i gat or will n ot be pr o vide d n or 
rei m b urse d b y N o v o N or dis k.
7. 8
Tre at me nt after t he e n d of t he tri al
After t he e n d of trial t he s u bject s h o ul d be treate d at t he discreti o n of t he i n vest i gat or. N o v o 
N or di s k will n ot pr o vi de trial pr o d ucts f oll owi n g t he e n d of t he trial.
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
3 7 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
3 8 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. 
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 pr o d uct treat m e nt ca n be deci de d b y bot h  t he i n vesti gat or a n d 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 ul d c o nti n ue wit h t he sc he d ule d visits a n d assess me nts 
a n d 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. 

If a s u bject disc o nti n ues trial pr o d uct treat me nt, t he i n vesti gat or m ust u n derta ke pr oce d ures 
si milar t o t h ose f or visit 1 2 (e n d of treat me nt) as s o o n as p ossi ble a n d t he f o ll ow- u p visit ( visit 
1 3) m ust be p erfor m e d 7 wee ks later. N o  li ver bi opsies , M RI-P D F F a n d M R elast o gra p h y  will  
be ta ke n at V 1 2 f or trial pr o d uct treat me nt di sc o nti n ue d s u bjects. If t he s u bject disc o nti n ues trial 
pr o d uct treat me nt at t he sa me ti me p oi nt as visit 1 0 ( 2 4 wee ks after ra n d o misat i on) , t he n a M RI -
P D F F a n d M R elast o gra p h y m ust be i ncl u de d i n visit 1 2 (e n d of treat me nt) as per ori gi nal visit 
sc he d ule. See t he fl o wc hart f or data t o be c ollecte d. 

F o ll owi n g visit 1 3, s u bjects s h o ul d c o nti n ue wit h t he ori gi nall y sc he d ule d site visits/c o nt acts u p 
t o a n d i ncl u di n g visit 1 2 A. Visit 1 2 A m ust ta ke place 4 8 wee ks ( ± 7 da ys) after t he 
ra n d omisat i on date . A l i ver bi o ps y, M RI -P D F F a n d M R elast o gra p h y  will be o btai ne d at V 1 2 A 
(see fl o wc hart f or a d dit i onal data t o be c ollecte d). H o we ver t he f oll o wi n g s h o ul d n ot be d o ne 
aft er visit 1 3 for s u bjects disc o nti n ui n g trial pr o d uct: Se ma glut i de plas ma c o nce ntrati o n, h y p o 
re p orti n g a n d ha n di n g o ut s u bject diaries.

S u bjects w h o disc o nt i n ue trial pr o d uct treat me nt will c o nti n ue t o recei ve n utriti onal a n d 
p h ysi c al e xercise c o u nselli n g t hr o u g h o ut t heir trial partici pati on.

Eff orts m ust be ma de t o ha ve s u bjects atte n d a n d c o m plete all sc he d ule d visit pr oce d ures. 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 visits eff orts s h o ul d be ma de t o ha ve t he 
v isits c o n verte d t o p h o ne c o ntacts a n d all eff orts s h o ul d be ma de t o ha ve t he s u bject t o atte n d at 
least visit 1 2 A ( 4 8 wee ks p ost-ra n d o misati on), t o c ollect t he re q uire d data f or t he a nal ysis of t he 
pri mar y  e n d p oi nt. 
T he s u bject m ust be disc o nt i n ue d fr om trial pr o d uct, if t he f oll o wi n g a p plies:
1.
Pre g na nc y
2.
I nte nti o n of bec o mi n g pre g na nt
3.
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 n al  pr o d uct
4.
Di a g n osis of ac ute pa ncreat itis
5.
Di a g n osis of me d ullar y t h yr oid carci n o ma
6.
S ur gical treat me nt f or o besit y
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
3 8 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
3 9 of 9 4
7.
Treat me nt wit h ot her G L P -1 rece pt or a g o nists or S G L T -2 i n hi bit ors
8.
A b n or m al li ver bl o o d para meters i n dicati n g dr u g i n d uce d li ver i nj ur y ( DI LI)
9.
E ve nts of he pat ic dec om pe nsati o n (e. g. ascites, variceal blee di n g , he patic e nce p hal o pat h y or 
s p o nta ne o us bacterial perit o nitis)
1 0. S af et y c o ncer ns as j u d ge d b y t he i n vesti gat or
S u bjects m eet i n g disc o nti n uati on of tri al tr e at me nt crit erio n n o. 3, 4, 5, 6, a n d 9 are n ot all o we d t o 
res u me trial pr o d uct if t he criteria is met .
S u bjects m eet i n g disc o nti n uati on of tri al tr e at me nt crit erio n n o. 1, 2, 7, 8, a n d 1 0 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.
F or di sc o nti n uati on of tri al treat me nt crit erio n n o. 8 : If a n alter nat i ve eti ol og y  is n ot defi niti vel y 
defi ne d a n d/ or li ver bl o o d para meters ha ve n ot ret ur ne d t o pre -e ve nt le vels, DI LI ca n n ot be 
e xcl u de d a n d trial pr o d uct m ust be per ma ne nt l y disc o nti n ue d. See A p pe n di x 2 f or more details.
See t he fl o wc hart f or data t o be c ollecte d at t he ti me of treat me nt disc o nti n uati o n a n d f o ll ow- u p a n d 
f or a n y furt her e val uat i ons t hat nee d t o be c o m plete d.
T he pri mar y  reas o n f or disc o nti n uati on of tri al pr o d uct m ust be s pecifie d i n t he e n d -of -tr e at me nt -
f or m in t he C R F, a n d fi nal dr u g acc o u nta bilit y m ust be perf or me d. A ‘tr e at me nt stat us’ sessi on 
m ust be ma de i n t he I W R S.
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 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 
i nstr uctio n f or misse d d oses i n sect i on 7. 1 . Si milarl y, a s u bject w h o disc o nti n ues trial pr o d uct o n 
t heir o w n i nitiat i ve s h o ul d be e nc o ura ge d t o res u me t he trial pr o d uct. 
Misse d d oses s h o ul d be rec or de d i n t he C R F. If a ‘treat me nt sta t 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 nt i n uati on of trial pr o d uct, a ne w ‘treat m e nt stat us’ sessi o n 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  tim e at his/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 visit 1 2 ( n o li ver bi o ps y a n d M R sca n if t he 
s u bject wit h dra ws c o nse nt bef ore visit 1 2 acc or di n g t o ori gi nal sc he d ule). 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. 
A ‘tr e at me nt stat us’ sessi on t o re gi ster disc o nti nu ati o n of  treat me nt must be m a de i n t he I W R S.
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
3 9 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
4 0 of 9 4
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 or d.
If t he s u bject wit h dra ws c o nse nt, N o v o Nor dis k ma y  retai n an d c o nt i 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 eff 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 wit h dra w fr om trial will n ot be replace d.
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 m ai 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 wi s hes t o a n d/ or s h o ul d c o nti n ue i n t he trial.

Bef ore a s u 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). T hese 
c o ntact atte m pts s h o ul d be d oc u me nte d i n t he s u bject's s o urce d oc u me nt.

S h o ul d t he s u bject c o nti n ue t o be u nreac ha ble, he/s he will be c o nsi dere d t o ha ve wit h dra w n 
fr om t he trial wi t h a pri mar y reas o n of lost t o 'f oll o w- u p'. 
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
4 0 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
4 1 of 9 4
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 hat 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 ui re 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. 

Fre q ue nc y of alc o h o l c o ns u m pt i on a n d scree n f or alc o h o l-relate d pr o ble ms a n d de pe n de nce 
s y m pt o ms s h o ul d be e val uate d by i nter vie wi n g s u bjects usi n g t he A U DI T q uesti o n naire 

T he es o p ha g o gastr o d u o de n osc o p y  s h o uld be perf or m e d bef ore o btai ni n g a li ver bi o ps y, if 
nee de d acc or di n g t o e xcl usi o n cri teria 3.

S u bjects w h o ha ve ne ver ha d a li ver bi o ps y  s ho wi n g N A S H a n d F 4 m ust ha ve a Fi br o Sca n ® n ot 
ol der t ha n 1 2 wee ks s h o wi n g li ver stiff ness > 1 4 k Pa bef ore t he s u bjects pr ocee d t o ha ve a li ver 
bi o ps y at scree ni n g. 

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 dere d s o urce data 
i ncl u des, b ut is n ot li mite d t o la b orat or y re p orts, E C G a n d diar y rec or di n gs.

S u bjects will be i nstr ucte d i n h o w t o c o m plete t he diar y

O nl y t he s u bject ca n ma ke e ntries a b o ut trial pr o d uct d ose ( date, ti me, d ose, i nject i on site) a n d 
h y p o gl ycae mic e pis o des i n t he diar y. 

T he i n vest i gat or m ust re vie w t he s u bject diar y at eac h cli nic visit after ra n d o misati on.

Re vie w of c o m plete d diaries, E C G, l a 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 m e nts or i n t he s u bject's s o urce d oc u me nts. If clarificati o n of e ntries or discre pa ncies i n t he 
di ar y is nee de d, t he s u bject m ust be q uesti o ne d a n d a c o ncl usi on ma d e i n t he s u bject's s o urce 
d oc u m e nts. Care must be ta ke n n ot t o bias t he s u bject.
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 fl o wc hart. 
9. 1. 1
M a g netic Res o n a nce I m a gi n g
M RI
m ust be d o ne acc or di n g t o t he i ma gi n g ma n ual pr o vi de d b y t he ce ntral i ma gi n g s u p plier.
I ma ges will be a nal yse d b y a ce ntral i ma gi n g s u p plier. F or sta n dar disat i on p ur p oses t he ce ntral 
i ma gi n g la b s u p plier will trai n t he trial s pecific M RI cli nics, as a p plica ble, a n d t he ce ntral i ma gi n g 
s u p plier will d o ce ntralise d bli n de d ( bli n de d t o treat me nt all o catio n) i ma ge a nal ysis/i nter pretati o n. 
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
4 1 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
4 2 of 9 4
M a g netic res o n a nce el ast o gr a p h y
Li ver stiff ness is meas ure d b y  M RI
usi n g a M R E tec h ni q ue. A res ult meas ure d i n k Pa will be
o btai ne d a n d data will be tra nsferre d electr o nicall y fr o m t he ce ntral ima gi n g la b s u p plier t o N o v o 
N or di s k. Data will be pr o vi de d t o t he i n vesti gat or after t he s u bject has c o m p lete d t he trial.
M a g netic res o n a nce i m a gi n g -esti m ate d pr ot o n de nsit y f at fr acti o n
Li ver steat osis will be assesse d via M RI -P D F F tec h ni q ue. A res ult meas ure d i n % will be o btai ne d 
a n d data will be tra nsferre d electr o nicall y fr o m t he ce ntral i ma gi n g la b s u p plier t o N o v o N or dis k.
Li ver fat v ol u me will be calc ulate d base d o n assess me nt o f li ver steat osis via M RI-P D F F a n d li ver 
v o l ume assesse d via M RI. A res ult meas ure d i n L will be o btai ne d a n d data will be tra nsferre d 
ele ctr o nicall y fr o m ce ntral ima gi n g l a b s u p plier t o N o v o N or dis k.
Li ver v o l ume will be assesse d via M RI. Res ults meas ure d i n L will be o btai ne d a n d data will be 
tra nsferre d electr o nicall y fr om t he ce ntral ima gi n g la b s u p plier t o N o v o N or dis k.
Data assesse d b y M RI -P D F F will be pr o vi de d t o t he i n vest i gat or after t he s u bject has c o m plete d t he 
trial.
9. 1. 2
Li ver bi o ps y
Li ver bi o ps y m u st be perf or me d acc or di n g t o site sta n dar d pr oce d ures.
I n case t he li ver bi o ps y o btai ne d d uri n g t he scree ni n g peri o d or u p t o 3 6 0 da ys pri or t o scree ni n g 
ca n n ot be use d t o e val uate eli gi bilit y o f t he s u bject d ue t o tec h nical iss ues wit h t he bi o ps y sa m ple, 
t he s u bject s h o ul d be as ke d t o ha ve a n ot her li ver bi o ps y perf or me d. If t he s u bject d oes n ot a gree t o 
t hat, t he s u bject is a scree n fail ure. 
All ra n d o mise d s u bjects c o m plet i n g 4 8 wee ks of trial pr o d uct treat me nt or di sc o nti n ui n g trial 
pr o d uct treat me nt d uri n g t he trial, s h o uld ha ve a li ver bi o ps y  p erfor m e d 4 8 wee ks after t he 
ra n d omisat i on ( visit 1 2 / 1 2 A). I n case c o ncl usi ve e val uati on of t his bi o ps y  is n ot p ossi ble d ue t o 
tec h nical iss ues with t he bi o ps y sa m ple, t he s u bject s h o ul d be as ke d t o ha ve a n ot her li ver bi o ps y 
perf or m e d. 
Ha n dli n g of hist ol o g y  sa m ples will be d o ne b y a ce ntral la b orat or y. Descript i ons o f lab orat or y  
s u p plies, pr oce d ures f or pre parati o n of tiss ue sa m ples, ha n dli n g, st ora ge, s hi p me nts a n d ret ur n of 
tiss ue sa m ples, will be gi ve n i n t he trial-s pecific la b orat or y ma n ual pr o vi de d b y t he ce ntral 
la b orat or y. 
Hi st olo g y  res ults will be ma de a vaila ble t o t he i n vesti gat or. 
O nl y t iss ue sa m ples re q ueste d i n t he pr ot oc ol m ust be se nt t o t he ce ntral la b orat or y. 
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
4 2 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
4 3 of 9 4
9. 1. 2. 1
Ce ntr al p at h ol o g y e v al u ati o n
T he hist o l ogi c e vi de nce of N A S H a n d hist ol o g y base d sc ores will be ce ntrall y assesse d b y a n 
i n de pe n de nt pat h ol o gist wit h e x pertise a n d e x perie nce i n N A S H. T he ce ntral pat h ol o gy e val uat i on 
will i ncl u de t he f o ll owi n g:

Prese nce or a bse nce of N A S H 

Sta ge of fi br osis (acc or di n g t o N A S H C R N criteria)

L o b ular i nfla m mat i on, he pat oc y te ball o o ni n g a n d steat osis ( N A S H C R N criteria) 

N A F L D Act i vity Sc ore ( N A S) (acc or di n g t o N A S H C R N criteria)

Is ha k Fi br osis sc ore (re p orte d t o N o v o N or dis k o nl y)

He pati c c olla ge n c o nte nt assesse d via m or p h o met r y (c olla ge n pr o p ortio nate area) (re p orte d t o 
N o v o N or dis k o nl y)
T he N A F D L act i vity s c or e is t he s u m of t he sc ori n g of l ob ular i nfla m mat i on, he pat oc y te ball o o ni n g 
a n d steat osis. T he pat h ol o gist will be bli n de d t o t he s u bject a n d treat me nt. 
9. 1. 3
C hil d -P u g h sc ore
C hil d -P u g h Sc ore is calc ulate d base d o n ce ntral la b orat or y  t ot al bilir u bi n, al b u mi n a n d I N R, 
c o m bi ne d wit h cli nical sc ori n g b y site staff o f ascit es (assesse d b y ultras o u n d) a n d he pat ic 
e nce p hal o pat h y (assesse d b y q u estio n nai r e). Fi g ur e 9- 1 s h o ws t he C hil d-P u g h classificat i on a n d 
h o w cal c ulat i on of C hil d -P u g h will be d o ne i n t his tri al 3 7. T he sc ore of ascites a n d he pat ic 
e nce p hal o pat h y t o get her wit h t he t otal sc ore s h o ul d be rec or de d in t he C R F.
T a ble 9- 1
C hil d -P u g h cl assific ati o n
C alc ul ati o n of C hil d -P u g h Sc ore
E nce p hal o pat h y
N o ne
1 p oi nt
Gra de 1/ 2
2 p oi nt s
Gra de 3/ 4
3 p oi nt s
Ascites
A bse nt
1 p oi nt
Sli g ht
2 p oi nts
M o derate/lar ge
3 p oi nts
Bilir u bi n le vel
< 2 m g/ d L
1 p oi nt
2- 3 m g/ d L
2 p oi nts
> 3 m g/ d L
3 p oi nts
Al b u mi n le vel
> 3. 5 g/ d L
1 p oi nt
2. 8 -3. 5 g/ d L
2 p oi nts
< 2. 8 g/ d L
3 p oi nts
I nter nati o nal N or ma lize d Rati o
< 1. 7
1 p oi nt
1. 7 -2. 3
2 p oi nts
> 2. 3
3 p oi nts
Assi g n me nt of C hil d -P u g h Cl assific ati o n Fr o m C hil d -P u g h Sc ore
5- 6 p oi nts
C hil d class A
7 -9 p oi nts
C hil d class B
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
4 3 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
4 4 of 9 4
1 0 -1 5 p oi nts
C hil d class C
9. 1. 4
B o d y me as ure me nts
9. 1. 4. 1
Hei g ht
H ei g ht is m eas ure d wit ho ut s h oes i n ce nt i metres or i nc hes. 
9. 1. 4. 2
B o d y wei g ht
T he b o d y  wei g ht s h o uld be meas ure d wit h a n e m pt y bla d der, wit h o ut s h oes a n d o nl y weari n g li g ht 
clot 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 acc or di n g t o t he 
di recti ons f or use.
9. 1. 4. 3
B o d y m ass i n de x ( B MI)
B MI will be calc ulate d b y t he C R F fr o m scree ni n g data.
9. 1. 4. 4
W aist circ u mfere nce
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 o wer 
rib mar 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 wit h a n o n -stretc ha ble meas uri n g ta pe an 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 m press s oft tiss ue a n d t wists i n t he ta pe 
s h o uld 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 uld prefera bl y 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 di s k t o e ns ure sta n dar disati on. 
9. 1. 5
E x pl or at or y 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 efficac y o bject i ves. 
T he f o ll owi n g bl o o d sa mples are re q ui re d a n d will be c ollecte d fr o m all s u bjects i n t his trial as 
s pecifie d i n t he fl owc hart ( See als o A p pe n di x 2 ):

Pr o -C 3 (c olla ge n mar ker)

E L F

A d i p o necti n

Hi g h se nsitivit y C reacti ve pr otei n ( hs C R P)
9. 1. 6
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 p e n di x 2, must be c o n d ucte d i n 
acc or da nce wit h t he fl o wc hart a n d t he la b orat or y  ma n ual.
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
4 4 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
4 5 of 9 4
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 din g a n d f o ll 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 t he fol l ow- u p visi t (visit 1 2 A f or s u bjects disc o nti n ui n g trial pr o d uct d uri n g trial ), 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 wi t 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 must 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 in 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 di s k.
T he m et h o d of rec or di n g, e val uat i n g a n d assessi n g ca usality of A E a n d S A E a n d t he pr oce d ures f or 
c o mplet i n g a n d tra ns mitti n g S A E re p orts are pr o vi de d i n A p pe n di x 4 .
Ti meli nes f or re p orti n g o f A Es, are liste d i n Fi g ure 9 - 1.
S o m e A Es re q uire a d dit i onal data c ollecti o n via a s pecific e ve nt f or m. T his i ncl u des me dicati o n 
err ors o bser ve d d uri n g t he trial. T he rele va nt s pecific e ve nts are liste d i n Ta ble 9- 2 a n d t he 
re p orti n g ti meli nes i n Fi g ure 9 - 1.
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
4 5 of 9 4
C O N FI D E N TI A L

C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
4 7 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/ or S A Es. O pe n-e n de d a n d 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 fol l ow eac h s u bject at 
s u bse q ue nt visits/c o ntacts. All S A Es, will be f o ll 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 oll 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 U S A Rs acc or di n g t o l ocal re g ulat or y re 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 n vesti gat or's br oc h ure a n d will n otif y t he I R B/I E C, if a p pr o priate acc or di n g t o l ocal 
re q uire me nts.
9. 2. 5
C ar di o v asc ul ar a n d de at h e ve nts
Car di o vasc ular a n d deat h e ve nts will be ha n dle d a n d re p orte d acc or di n g t o A E / S A Es descri pti on i n 
Secti o n 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 alif yi n g as a n A E or 
S A E
N ot a p plica ble f or t his tr ial. 
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 fol l ow- u p visi t ( visit 1 2 A f or s u bjects w h o disc o nti n ue 
trial pr o d uct d uri n g trial ).
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
4 7 of 9 4
C O N FI D E N TI A L

C O N FI D E N TI A L

C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
5 0 of 9 4
Acci de ntal  o ver d ose must be re p orte d as a me dicati o n err or ( A p pe n di x 4 ). Refer t o Sectio n 9. 2. 1 f or 
f urt her details. I nte nti onal o ver d ose s h o ul d be re p orte d as A E.
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 utid e 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 n vesti gat or' s br oc h ure 
a n d a n y u p dates here of3 3.
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.
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 ( visit 1) or f o u n d as a 
res ult of a scree ni n g pr oce d ure or ot her trial pr oce d ures perf or me d bef ore e x p os ure t o trial pr o d uct. 
Me dic al hist or y is a me dical e ve nt t hat t he s u bject has e x perie nce d i n t he past. O nl y rele va nt 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. S pecific me dical 
hist or y  of gall bla d der disease s h o uld o nl y be e ntere d o n t he s pecific f or m. T he i nf or mat i on 
c ollecte d f or c o nc o mita nt ill ness a n d me dical hist or y  s h o uld i ncl u de dia g n osi s, date of o nset a n d 
date of res ol ut i on or c o nti n uati o n, as a p plica ble.
I n case of a n a b n or mal a n d cli nicall y si g nifica nt fi n di n g, t he i n vesti gat or m ust rec or d t he fi n di n g o n 
t he Me dical Hist or y/ C o nc 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 uri n g t he trial a n d a n y cli nicall y si g nifica nt 
w orse ni n g fr o m baseli ne m ust be re p orte d as a n A E (see Secti o n 9. 2 ).
9. 4. 1
P h ysic al e x a mi n ati o ns

A p h ysical e xa mi nat i on will i ncl u de assess me nts of t he ge neral a p peara nce, s ki n, t h yr o i d gla n d, 
l y m p h n o de pal pati on, hea d, ears, e y es, n ose, t hr oat a n d nec k as well as t he car di o vasc ular, 
res pir at or y, gastr oi ntesti nal i ncl u di n g m o ut h, m usc ul os keletal, ce ntr al a n d perip h er al  s yste ms. 
T he o utc o me will be re p orte d i n t he C R F.

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. 2
V it al si g ns

P ul se rate as well as diast olic a n d s yst olic bl o o d press ure will be assesse d.

Bl o o d press ure a n d p ulse meas ure me nts assess me nt s h o ul d be prece de d b y  at least 5 mi n utes of 
rest f or t he s u bject i n a q uiet setti n g wit h o ut distracti o ns (e. g. tele visi on, cell p h o nes).
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
5 0 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
5 1 of 9 4

Bl o o d press ure at scree ni n g will c o nsist of 3 diast olic a n d s yst o lic bl o o d press ure meas ure me nts 
wi t h int er vals o f at least 1 mi n ute i n bet wee n. All t hree rea di n gs m ust be e ntere d i n t he C R F a n d 
t he a vera ge of t he 3 bl o o d press ure rea d i n gs will be calc ulate d i n t he C R F. At  s u bse q ue nt visits, 
t he bl o o d press ure s h o ul d o n l y be meas ure d o nce.

Bl o o d press ure a n d p ulse meas ure me nts s h o ul d be assesse d i n a sitti n g p ositi on wi t h a 
c o mpletel y a ut o m ate 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.

T he sa me ar m a n d a n a p pr o priate c uff size s h o uld be use d f or bl o o d press ure meas ure me nt at all 
visit s.
9. 4. 3
T o b acc o use
T he i n vest i gat or m ust d oc u me nt t he s m o ki n g stat us a n d e ntere d i n t he C R F as:

Ne ver s m o ke d

Pre vi o us s m o ker

C urre nt s m o ker
9. 4. 4
Electr oc ar di o gr a ms
A 1 2 -lea d E C G will be perf or me d o n l o c al  mac hi nes as per lo c al  g uideli nes a n d rec or d e d i n t he 
C R F as:

n or m al

a b n or mal
9. 4. 5
E ye e x a mi n ati o n
O nl y a p plica ble f or s u bjects wit h T 2 D:
S u bjects wit h u nc o ntr olle d a n d p ote ntiall y u nsta ble dia bet ic reti n o pat h y or mac ul o pat h y are n ot 
eli gi ble as t his i n dicates reti n o pat h y t hat has rece ntl y pr o gresse d t o a le vel t hat re q uires i nter ve nti on 
or i s a p pr oac hi n g i nter ve nti on, b ut has yet t o be br o u g ht u n der c o ntr ol. 
Res ults of a n e ye e xa mi nat i on perf or me d b y a n o p ht hal m o l ogist or a n ot her s uita bl y q ualifie d healt h 
care pr o vi der (e. g. o pt o metrist) m ust be a vaila ble a n d e val uate d b y t he i n vest i gat or bef ore 
ra n d omisat i on t o assess eli gi bilit y.  T he e ye e xa mi nati o n s h o ul d be perf or me d as a f u n d us 
p h ot o gra p h y  (e. g. 2-fiel d 6 0 de gree or better, c ol o ur or re d-free) or b y slit-la m p bi omicr osc o p y  
e xa mi nat i on (e. g. usi n g a pre- c or neal or c or neal c o ntact le ns e xa mi nati on). P har mac o l ogi cal p u pil-
dilat i on is a re quire me nt u nless usi n g a di gital f u n d us p h ot o gra p h y ca mera s pecifie d f or n o n -dilate d 
e xa mi nat i on.
If t he s u bject ha d s uc h a n e ye e xa mi nati on perf or me d wit hi n 9 0 da ys pri or t o scree ni n g, t he 
i n vesti gat or ma y base his/ her e val uat i on u p o n t he res ults of t hat e xa mi nat i on. T he e xa mi nat i on m ust 
be re peate d bef ore ra n d o misat i on if t he s u bject has e x perie nce d w orse ni n g of vis ual f u nct i on si nce 
t he last e xa mi nat i on. If t he a p plica ble e ye e xa mi nati o n was perf or me d bef ore t he s u bject si g ne d t he 
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
5 1 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
5 2 of 9 4
i nf or me d c o nse nt f or m, it must be d oc u m e nte d t hat t he reas o n f or perf or mi n g t he e xa mi nat i on was 
n ot rel ate d t o t his trial. G er m a n y: Fo r c o u ntr y s pecific re q uire me nts see A p pe n di x 9 .
Rele va nt fi n di n gs pri or t o ra n d o misat i on m ust be rec or de d as c o nc o mita nt ill ness/ me dical hist or y. 
W hile rele va nt fi n di n gs occ urri n g after ra n d o misati o n s h o ul d be re p orte d as a n A E, if a p plica ble 
acc or di n g t o Secti o n 9. 2 a n d A p pe n di x 4 .
9. 4. 6
Cli nic al s afet y l a b or at or y assess me nts
All pr ot oc ol -re q uire d la b orator 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 la b orat or y ma n ual a n d t he fl o wc hart i n Sect i on 2 .
9. 5
P h ar m ac o ki netics

A si n gle bl o o d sa m ple f or meas ure me nt of plas ma se ma gl uti de c o nce ntrati o n will be dra w n f or 
b ot h se m a gl ut i de a n d se ma gl uti de place b o s u bjects at t he visits s pecifie d i n t he fl o wc hart. 

S u bjects m ust be i nstr ucte d t o wit h h o l d t heir trial pr o d uct d ose i n t he m or ni n g u ntil bl o o d 
sa m pli n g is perf or me d at t he visit. I n a d diti on s u bjects m ust be i nstr ucte d t o c o m plete t heir diar y 
a n d bri ng i t t o t he visits.

T he P K d osi n g i nf or mati o n i n t he diar y  s ho ul d be tra nscri be d i nt o t he C R F f or t he last t wo
d oses of trial pr o d uct pri or t o t he visits wit h P K assess me nt. 

T he e xact ti mi n g of o btai ni n g t he P K sa m ple m ust be rec or de d o n t he la b orat or y  fo r m. 

T he p ur p ose of meas uri n g plas ma se ma gl uti de le vels is t o perf or m p o p ulat i on P K a nal yses 
( P o p-P K). Ha vi n g P o p -P K i n t his trial will f urt her s u p p ort bri d gi n g of P o p -P K fr o m trials 
c o n d ucte d i n ot her p o p ulati o ns. 
See al s o A p pe n di x 2 .
T he sa m pli n g m ust be c o n d ucte d i n acc or da nce wit h t he la b orat or y  ma n ual. 
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 ke rs
See secti o n 9. 1. 5 f or e x plorat or y  bio m ar kers a n d A p pe n di x 7 f or bios a m pl es f or f ut ure a nal ysis.
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
5 2 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
5 3 of 9 4
1 0
St atistic al c o nsi der ati o ns 
1 0. 1
S a m ple size deter mi n ati o n 
T he sa m ple size calc ulat i on was ori gi nall y base d o n a n ai m t o detect a differe nce i n t he treat me nt 
r atio f or M R E bet wee n se ma gl ut i de a n d place b o at a 5 % si g nifica nce le v el usi n g t he ass u m pti on of 
a t-test f or 2 i n de pe n de nt gr o u ps a n d a l o g-n or m al distri b ute d o utc o me with a 2: 1 ra n d o misati o n. 
T he p o wer wa s set t o 9 0 %.
I n Pr ot oc ol Versio n 3. 0, t he pri mar y e n d p oi nt was c ha n ge d fr o m relati ve c ha n ge fr o m baseli ne 
( wee k 0) t o wee k 4 8 i n li ver stiff ness meas ure d b y M R E t o t he bi nar y e n d p oi nt of at least o ne sta ge 
of  li ver fi br osis i m pr o ve me nt wit h n o w orse ni n g of N A S H after 4 8 wee ks. T his secti on of t he 
pr ot oc ol  is t heref ore s u p ple me nte d wit h p o wer calc ulat i on f or t his e n d p oi nt w hic h has bee n i nserte d 
after t he origi nal sa m ple size calc ulat i on f or M R E.
Stati stics i n relat i on t o effect of se ma gl ut i de o n M R E are n ot prese nt. He nce t he bel o w ass u m pti ons 
are base d o n statist ics c ollecte d fr o m scie ntific p u blicati ons wit h ot her treat me nt effects o n M R E 9 ,3 8 , 
3 9.
T a ble 1 0 - 1
N u m ber of r a n d o mise d s u bjects nee de d ass u mi n g al l s u bjects c o m pleti n g t he 
tri al o n tre at me nt a n d a p o wer of 9 0 % f or rejecti n g t he n ull h y p ot hesis 
(tre at me nt r ati o = 1) at t he 5 % si g nific a nce le vel i n a 2: 1 r a n d o mis ati o n sc he me. 
Tre at me ntr ati o 
C oefficie nt of v ari ati o n
0. 1 6 
0. 1 7 
0. 1 8 
0. 1 9
0. 8 7
6 6 
7 2 
8 1 
9 0
0. 8 6
5 7 
6 3 
6 9 
7 8
0. 8 5
4 8
5 4
6 0 
6 6
0. 8 4
4 2 
4 8 
5 4 
6 0
0. 8 3
3 9 
4 2 
4 8 
5 1
Ass u mi n g a 2: 1 ra n d o misati o n sc he me, a treat me nt rati o of 0. 8 5 a n d a c oefficie nt of variat i on of 
0. 1 7, 5 4 s u bjects nee d t o c o m plete t he 4 8 wee ks of treat me nt. He nce, ass u mi n g 2 0 % 
wi t hdra wal/ pre mat urel y trial pr o d uct disc o nti n uat i o n i n b ot h ar ms, a t otal sam ple size of 6 8 s u bjects 
is nee de d. T o ha ve a n u m ber t hat is di visi ble wit h 3, a t otal  n u m ber of 6 9 s u bjects is nee de d ( 4 6 
s u bjects ra n d o mise d t o se ma gl ut i de a n d 2 3 ra n d o mise d t o place b o).
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
5 3 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
5 4 of 9 4
It is a ntici pate d t hat t he res p o n der rate f or li ver fi br osis i m pr o ve me nt wit h n o w orse ni n g of N A S H 
will be u p t o 1 0 % f or s u bjects ra n d o mise d t o place b o. T he n u m ber of place b o res p o n ders was 1 5 
( 1 0. 4 %) of 1 4 4 s u bjects i n C E N T A U R 4 0 a n d 3 7 ( 1 1. 9 %) of 3 1 1 s u bjects i n R E G E N E R A T E 4 1.   
T here i s c urre ntl y n o g ui da nce o n mi ni m u m treat me nt effect o n hist ol o gical e n dp oi nts t hat w o ul d be 
c o nsi dere d cli nicall y rele va nt. 
s h o ws t he se nsiti vity i n p o wer f
or differe nt res p o n der pr o p orti o ns, ass u mi n g 6 9 s u bjects c o m plete t he 4 8 wee ks of treat me nt .
T a ble - 1 0- 2
P o wer f or rejecti n g t he n ull h y p ot hesis of n o differe nce i n t he pr o p orti o n 
bet wee n se m a gl uti de s.c. 2. 4 m g o nce -wee kl y a n d pl ace b o at 5 % si g nific a nce 
le vel i n a 2: 1 r a n d o mis ati o n sc he me wit h t ot al n u m ber of s u bjects e q u al t o 6 9.
Se m a gl uti de res p o n der 
pr o p o rti o n
Pl ace b o res p o n der pr o p orti o n
7. 5 %
1 0. 0 % 
1 2. 5 %
2 5. 0 %
3 9. 7 % 
2 8. 7 % 
2 0. 3 %
3 5. 0 %
7 3. 5 % 
6 2. 0 % 
5 0. 6 %
4 5. 0 %
9 3. 7 % 
8 8. 2 % 
8 0. 8 %
F or e xa m ple, ass u mi n g a se ma gl ut i de res p o n der pr o p ortio n of  3 5 % a n d a place b o res p o n der 
pr o p orti o n of  1 0 % res ults i n a p o wer of 6 2 % f or t he bi nar y hist olo g y  e n d p oi nt.
1 0. 2
Defi niti o n of a n al ysis sets
T he f ull a nal ysis set ( F A S) will be use d i n t he a nal ysis o f t he efficac y e nd p oi nts w hereas t he s afet y 
a nal ysis set ( S A S) will be use d f or t he safet y e n d p oi nts. 
T he F A S i ncl u des all ra n d o mise d s u bjects. S u bjects i n t he F A S will c o ntri b ute t o t he e val uat i on “as 
ra n d omise d”. T he S A S i ncl u des all s u bjects recei vi n g at least o ne d ose of ra n d o mise d treat m e nt. 
S u bjects i n t he S A S will c o ntri b ute t o t he e val uat i o n “as treate d”.
O bser v ati o n peri o ds

I n-trial: T his peri o d starts o n t he date of t he ra n d o misat i on visit a n d e n ds o n t he date of t he last 
trial-relate d pr oce d ure/assess me nt

O n -tr e at me nt: F or e val uat i on of A Es a n d h y p o gl ycae mic e pis o des, t his peri o d starts o n t he date 
of  first a d mi nistrati o n of trial pr o d uct a n d e n ds o n t he date of w hate ver c o mes first of: a) last 
d ose of tri al pr o d uct + 4 9 da ys ( 7 half-li ves of se ma gl uti de), b) f o ll ow- u p visi t ( visit 1 3), or c) 
e n d of t he i n-tri al p erio d.
T he stati stical a nal yses of t he efficac y e n d p oi nts will pri maril y be base d o n t he i n-trial p erio d. T he 
o n -treat me nt peri o d will be use d f or a nal yses of safety e n d p o i nts. 
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
5 4 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
5 5 of 9 4
Missi n g d at a
Wit h re s pect t o t he pri mar y a nal ysis of t he pri mar y e n d p oi nt, missi n g wee k 4 8 data will be i m p ute d 
as n o i m pr o ve me nt i n li ver fi br osis.
1 0. 3
St atistic al a n al yses
A stati stical a nal ysis pla n ( S A P) will be writte n i n a d diti on t o t he pr ot oc ol, i ncl u di n g a m ore 
tec h nical a n d detaile d ela b orati o n of t he statistical a nal yses. T he S A P will be fi nalise d bef ore first 
s u bject, first visit ( FS F V). I n case, t hat a n i nteri m re p orti n g (see sect i on 1 0. 3. 4 ) is deci de d t he n a 
desi g nate d S A P will be pr o d uce d a n d fi nalise d bef ore t he data base l oc k i n relat i on t o t he i nteri m. 
T h e est i ma n d a d dressi n g t he pri mar y o bjecti ve is t he pr o p orti o n of s u bjects wit h li ver fi br osis 
i m pr o ve me nt wit h n o w orse ni n g of N A S H c om pare d bet wee n treat me nt gr o u ps at 4 8 wee ks i n 
s u bjects wit h N A S H a n d c o m pe nsate d fi br osis sta ge 4 re gar dless of a d here nce t o treat me nt.
Ge neralisat i on of t his esti ma n d de pe n ds a m o n g ot her t hi n gs o n t he e xte nt t o w hic h treat me nt 
a d here nce i n t his trial reflects cli nical pract ice.
T he stati stical a nal yses will i n ge neral c o nsist of t he f oll owi n g treat m e nt c o mparis o n:

se ma gl utide s.c. 2. 4 m g o nce -wee kl y  vers us place b o
T he res ults of t he c o m paris o ns will be prese nte d as esti mate d treat me nt c o ntrasts t o get her wit h t w o -
side d 9 5 % c o nfi de nce i nter vals a n d p -val ues c orres p o n di n g t o t w o -si de d tests of n o differe nce.
1 0. 3. 1
Pri m ar y e n d p oi nt
T h e pri mar y e n d p oi nt is t he bi nar y o ut c o me of at least o ne sta ge of li ver fi br osis i m pr o ve me nt wit h 
n o w orse ni n g of N A S H at 4 8 wee ks ( y es/ n o). T he a nal ysis will be base d o n t he C oc hra n -M a nt el -
Hae nszel ( C M H) test. T he test will a dj ust f or baseli ne dia betes st at us ( wit h T 2 D or wit h o ut T 2 D).
T he res p o nse data will c o nsist of t he o utc o mes of t he wee k 4 8 bi o ps y i ncl u di n g assess me nts ta ke n 
after pre mat ure disc o nti n uati o n o f trial pr o d uct. Missi n g res p o nse data will be i m p ute d as n o n-
res p o n ders. T his a p pr oac h d oes not rel y  o n a n ass u m pti on of missi n g at ra n d o m a n d s h o ul d be 
c o nsi dere d c o nser vati ve f or esti mati n g t he treat me nt effect.
Se nsiti vit y a n al ysis
A nal ysis usi n g i m p utati o n base d o n u nc o n dit i onal refere nce: A n a nal ysis base d o n t he sa me t y pe of 
n o n- para metri c met h o d as f or t he pri mar y a nal ysis b ut wit h missi n g data ha n dle d b y a n MI met h o d 
w hic h ass u mes t hat t he u n o bser ve d o utc o mes are well descri be d b y t he o bser ve d o utc o mes fr o m 
s u bjects i n t he place b o ar m a n d wit h si milar baseli ne c haracteristics. T he i m p utati on will be d o ne 
b y ra n d o m sa m pli n g of o bser ve d o utc o mes fr om s u bjects wit h t he sa me baseli ne dia betes stat us a n d 
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
5 5 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
5 6 of 9 4
baseli ne fi br osis sta ge. 5 0 0 re plicates of a c o m plete data set will be ge nerate d t hat will t he n be 
a nal yse d a n d t he res ults c o m bi ne d usi n g R u bi n ’s r ule t o dra w i nfere nce.
M ore details will be s pecifie d i n t he S A P.
1 0. 3. 2
Sec o n d ar y e n d p oi nts
1 0. 3. 2. 1
S u p p orti ve sec o n d ar y e n d p oi nts
T he c ha n ge i n M R E fr o m baseli ne t o 4 8 wee k’s meas ure me nts will be a nal yse d usi n g a M M R M 
wi t h t h e lo g tra nsf or m e d valu e of  M R E ( k Pa) as t he e n d p o i nt a n d wit h treat me nt (se ma gl utid e 
vers us place b o), T 2 D ( wit h T 2 D or wit h o ut T 2 D), b o d y  wei g ht ( k g) a n d t he l o g tra nsf or me d 
baseli ne M R E ( k Pa) as c o variates, all neste d wit hi n wee ks ( visits) as a fact or. T 2 D ( wit h T 2 D or 
wi t ho ut T 2 D) i s i ncl u de d as t his is t he stratificati o n varia ble i n t he ra n d o misat i on sc he me. A n 
u nstr uct ure d c o varia nce matri x will be use d t o descri be t he varia bilit y f or t he re peate d 
meas ure me nts f or a s u bject. Fr o m t his M M R M m o del t he treat me nt rati o at wee k 4 8 will be 
esti mated f or se ma gl ut i de vers us place b o a n d t he c orres p o n di n g 9 5 % c o nfi de nce i nter val a n d t he 2 -
side d p -val ue will be calc ulate d t o get her wit h t he esti mate d ge o metric mea ns. All meas ure me nts 
fr om t he sc he d ule d visits (fr o m baseli ne t o wee k 4 8) will be i ncl u de d i n t he M M R M.
S u bjects wit h o ut a n y  p ost-ra n d omisat i on data f or t he e n d p o i nt will n ot be i ncl u de d i n t he a nal ysis.
1 0. 3. 3
E x pl or at or y e n d p oi nts
Will be descri be d i n S A P.
1 0. 3. 4
I nteri m re p orti n g
A n i nteri m a nal ysis o f t he M R sca ns ma y b e p erfor me d at wee k 2 4 i n or der t o s u p p ort i nter nal 
b usi ness decisi o ns i n relati on t o e. g. i nit iati on of a p hase 3 pr o gra m me. 
T his i nteri m a nal ysis will n ot affect t he c o nti n uat i on of t he trial a n d he nce n o al p ha -spe n di n g is 
c o nsi dere d. 
I n case t he i nteri m a nal ysis is perf or me d, s p o ns or is u n bli n de d after t he i nteri m, w hereas 
i n vesti gat or a n d s u bjects re mai n bli n de d f or t he rest of t he trial. No v o N or di s k pers o n nel w h o will 
ha ve access t o data after t he i nteri m wil l be descri be d i n a n i nteri m data access pla n w hic h, will be 
fi nalise d bef ore FS F V. N o p u blic discl os ure of t he i nteri m res ults will be ma de.
T he sa me M M R M m o del as use d i n t he pri mar y  a nal ysis will be use d f or a nal ysis of t he c ha n ge i n 
M R -M R E fr o m  baseli ne t o 2 4 wee ks. T his m o del is e q ui vale nt t o a n A N O V A m o del wit h c ha n ge i n 
M R -M R E fr o m  baseli ne f or t he c o mpleters after 2 4 wee ks. 
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
5 6 of 9 4
C O N FI D E N TI A L

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

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
5 8 of 9 4
1 1
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 ment atio 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. 2 0 0 1.
2.  
Klei ner D E, Br u nt E M, Va n Natta M, Be hli n g C, C o nt os MJ, C u m mi n gs O W, et al. Desi g n 
a n d vali dat i on of a hist ol o gical sc ori n g s yste m f or n o nalc o h olic fatt y  li ver disease. 
He pat ol o g y . 2 0 0 5; 4 1( 6): 1 3 1 3- 2 1.
3.
Br u nt E M, Ti nia k os D G. Hist o pat h ol o g y  of no nalc o h olic fatt y  li ver disease. W orl d J 
Gastr oe nter ol. 2 0 1 0; 1 6( 4 2): 5 2 8 6 - 9 6.
4.
Ver n o n G, Bara n o va A, Y o u n ossi Z M. S y st e mat ic re vie w: t he e pi de mi ol og y  a n d nat ural 
hist or y  of no n -alc o h o lic fatt y li ver disease a n d n o n-alc o h o lic steat o he patitis i n a d ults. 
Ali me nt P har mac o l T her. 2 0 1 1; 3 4( 3): 2 7 4 - 8 5.
5.
A da ms L A, L y m p J F, St Sa u ver J, Sa n ders o n S O, Li n d or K D, Fel dstei n A, et al. T he nat ural 
hist or y  of no nalc o h ol ic fatt y li ver disease: a p o p ulati o n-base d c o h ort st u d y . 
Gastr oe nter ol o g y . 2 0 0 5; 1 2 9( 1): 1 1 3- 2 1.
6.
S ha ker M, Ta b baa A, Al bel da wi M, Al k h o uri N. Li ver tra ns pla ntati o n f or n o nalc o h o lic fatt y 
li ver disease: ne w c halle n ges a n d ne w o p p ort u nit ies. W orld J Gastr oe nter ol . 
2 0 1 4; 2 0( 1 8): 5 3 2 0 - 3 0.
7.
C harl t o n M R, B ur ns J M, Pe derse n R A, Watt K D, Hei m bac h J K, Dier k hisi n g R A. Fre q ue nc y 
a n d o utc o mes of li ver tra ns pla ntati o n f or n o nalc o h olic steat o he patit is i n t he U nite d States. 
Gastr oe nter ol o g y . 2 0 1 1; 1 4 1( 4): 1 2 4 9- 5 3.
8.
Mer ol a J, Lia pa kis A, M ulli ga n D C, Y o o P S. N o n -alc o h o lic fatt y li ver disease f oll owi n g 
li ver tra ns pla ntati o n: a cli nical re vie w. Cli n Tra ns pla nt. 2 0 1 5; 2 9( 9): 7 2 8-3 7.
9.
Si n g h S, Alle n A M, Wa n g Z, Pr o k o p LJ, M ura d M H, L o o m ba R. Fi br osis pr o gressi o n i n 
n o nalc o h o lic fatt y li ver vs n o nalc o h olic steat o he patitis: a s yste matic re vie w a n d meta-
a nal ysis of paire d -bi o ps y  st u dies. Cli n Gastr oe nter ol He pat ol. 2 0 1 5; 1 3( 4): 6 4 3-5 4.e 1 -9; q uiz 
e 3 9- 4 0.
1 0.
D ul ai P S, Si n g h S, Patel J, S o ni M, Pr o k o p LJ, Y o u n ossi Z, et al. I ncrease d ri s k of mortali t y 
b y fi br osis sta ge i n n o nalc o h olic fatt y li ver disease: S yste matic re vie w a n d meta-a nal ysis. 
He pat ol o g y . 2 0 1 7; 6 5( 5): 1 5 5 7- 6 5.
1 1.
D' A mic o G, Garcia -Tsa o G, Pa gliar o L. Nat ural hist or y  a n d pr o g n ostic i n dicat ors of s ur vi val 
i n cirr h osis: a s yste matic re vie w of 1 1 8 st u dies. J He pat ol. 2 0 0 6; 4 4( 1): 2 1 7- 3 1.
1 2.  
Marcelli n P, Ga ne E, B uti M, Af d hal N, Sie vert W, Jac o bs o n I M, et al. Re gressi o n of 
cirr h osis d uri n g treat me nt wit h te n of o vir dis o pr o xil f u marate f or c hr o nic he patitis B: a 5-
year o pe n -lab el  fol l ow- u p st u d y . La ncet. 2 0 1 3; 3 8 1( 9 8 6 5): 4 6 8 -7 5.
1 3.
M or ga n T R, G ha n y M G, Ki m H Y, S n o w K K, S hiff ma n M L, De Sa nt o J L, et al. O utc o m e of 
sustai ne d vir o l ogi cal res p o n ders wit h hist ol o gicall y a d va nce d c hr o nic he patit is C. 
He pat ol o g y . 2 0 1 0; 5 2( 3): 8 3 3- 4 4.
1 4.
D uf o ur J F, De Lellis R, Ka pla n M M. Re versi bilit y of  he patic fi br osis i n a ut oi m m u ne 
he pat itis. A n n I nter n Me d. 1 9 9 7; 1 2 7( 1 1): 9 8 1- 5.
1 5.
easl o ffice @easl office.e u E Aft S ot L Ea, Li ver E Aft S ot. E A S L Cli nical Practice G ui deli nes o n 
n utri tio n i n c hr o nic li ver disease. J He pat ol. 2 0 1 8.
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
5 8 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
5 9 of 9 4
1 6.
C halasa ni N, Y o u n ossi Z, La vi ne J E, Die hl A M, Br u nt E M, C usi K, et al. T he dia g n osis a n d 
ma na ge me nt of n o n -alc o h o lic fatt y li ver disease: practice G ui deli ne b y t he A merica n 
Ass oci at i on f or t he St u d y of Li ver Diseases, A merica n C olle ge of Gastr oe nter ol o g y, a n d t he 
A merica n Gastr oe nter ol o gical Ass ociati o n. He pat ol o g y . 2 0 1 2; 5 5( 6): 2 0 0 5- 2 3.
1 7.
de Fra nc his R, Fac ult y B V. E x p a n di n g c o nse ns us i n p ortal h y perte nsi o n: Re p ort of t he 
Ba ve n o VI C o nse ns us W or ks h o p: Stratif yi n g ris k a n d i n di vi d ualizi n g care f or p ortal 
h y perte nsi o n. J He pat ol. 2 0 1 5; 6 3( 3): 7 4 3- 5 2.
1 8.
La u J, Bl oc h P, Sc häffer L, Petterss o n I, S petzler J, K of oe d J, et al. Di sc 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.
1 9.
G utz willer J P, Dre we J, G o ke B, Sc h mi dt H, R o hrer B, Larei da J, e t al. Gluca g o n -li ke 
pe pti de- 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.
2 0.
Lee J, H o n g S W, R hee EJ, Lee W Y. G L P -1 Rece pt or A g o nist a n d N o n -Alc o h o lic Fatt y  
Li ver Di sease. Dia betes Meta b J. 2 0 1 2; 3 6( 4): 2 6 2 - 7.
2 1.
Pa nj wa ni N, M ul vi hill E E, L o n g uet C, Y usta B, Ca m p bell J E, Br o w n TJ, et al. G L P - 1 
rece pt or activati o n i n di rectl y re d uces he patic li pi d acc u m ulati on b ut d oes n ot atte n uate 
de vel o p me nt of at her oscler osis i n dia bet ic male A p o E( -/-) mice. E n d ocri n ol og y . 
2 0 1 3; 1 5 4( 1): 1 2 7 - 3 9.
2 2.
Ga o H, Ze n g Z, Z ha n g H, Z h o u X, G ua n L, De n g W, et al. T he Gl uca g o n -Li ke Pe pti de- 1 
A nal o g ue Lira gl ut i de I n hi bits O xi dati ve Stress a n d I nfla m mat or y Res p o nse i n t he Li ver of 
Rats wit h Diet -I n d uce d N o n-alc o h o lic Fatt y Li ver Disease. Bi ol P h ar m B ull. 
2 0 1 5; 3 8( 5): 6 9 4 - 7 0 2.
2 3.
Mells J E, F u P P, S har ma S, Ols o n D, C he n g L, Ha n d y J A, et al. Gl p -1 a nal o g, lira gl uti de, 
a meliorates he pat ic steat osis a n d car diac h y pertr o p h y i n C 5 7 B L/ 6J mice fe d a Wester n diet. 
A m J Ph ys i ol Gastr oi ntest Li ver P h ysi o l. 2 0 1 2; 3 0 2( 2): G 2 2 5-G 3 5.
2 4.
P y ke C, Heller R S, Kir k R K, Ørs k o v C, Ree dtz -R u n ge S, Kaastr u p P, et al. G L P - 1 Rece pt or 
L ocalizat i on i n M o n ke y a n d H u ma n Tiss ue: N o vel Distri b uti on Re veale d Wit h E xte nsi vel y  
Vali date d M o n ocl o nal A nt i b o d y. E n d ocri n ol og y . 2 0 1 4; 1 5 5( 4): 1 2 8 0- 9 0.
2 5.
Ar mstr o n g MJ, H ull D, G u o K, Bart o n D, Hazle h urst J M, Gat herc ole L L, et al. Gl uca g o n -
Li k e P e pti de 1 Decreases Li p ot o xicit y i n N o n-Alc o h olic Steat o p he pat itis. J He pat ol. 
2 0 1 6; 6 4: 3 9 9 - 4 0 8.
2 6.
Ar mstr o n g MJ, Ga u nt P, Ait hal G P, Bart o n D, H ull D, Par ker R, et al. Lira gl uti de safet y a n d 
efficac y in pat ient s wit h n o n-alc o h o lic steat o he patitis ( L E A N): a m ultice ntre, d o u ble-bli n d, 
ra n d omise d, place b o -c o ntr olle d p hase 2 st u d y. La ncet. 2 0 1 6; 3 8 7( 1 0 0 1 9): 6 7 9-9 0.
2 7.
N o v o N or dis k A/ S. Vict oza ® (lira gl uti de), E U S u m mar y of Pr o d uct C haracterist ics ( S m P C). 
2 2 Se p 2 0 1 6.
2 8.
N o v o N or dis k A/ S. Vict oza ® (lira gl uti de), U S Prescri bi n g I nf or mati on ( PI). 2 2 A pr 2 0 1 6.
2 9.
Faillie J L Y O, Yi n H, Hillaire -B u ys D, Bar k u n A, Az o ula y L. Ass o ciatio n of  Bile D uct a n d 
Gall bla d der Diseases Wit h t he Use of I ncret i n-Base d Dr u gs i n Pat ient s With T y pe 
2 Dia betes Mellit us. J A M A I nter n Me d. 2 0 1 6; 1 7 6( 1 0): 1 4 7 4- 8 1.
3 0.
Je nse n L, K u pc o va V, Ar ol d G, Petterss o n J, Hjer pste d J B. P har mac o ki net ics a n d 
t olera bility of se ma gl uti de i n pe o ple wit h he pat ic i m pair me nt. Dia betes O bes Meta b. 
2 0 1 8; 2 0( 4): 9 9 8 - 1 0 0 5.
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
5 9 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
6 1 of 9 4
4 6.
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.
4 7.
U. S. De part me nt of Healt h a n d H u ma n Ser vices , F o o d a n d Dr u g A d mi nistrati o n. F o o d a n d 
Dr u g A d mi nistrati o n A me n d me nts Act of 2 0 0 7 as a me n de d b y t he Fi nal R ule " Cli nical 
Tri als Re gistratio 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.
4 8.
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.
4 9.
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 of 3 1 Marc h 2 0 0 4 la yi n g d o w n 
C o m m u nit y pr oce d ures f or t he a ut h 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.
5 0.
Sc h wartz N S, Cl utt er W E, S ha h S D, Cr yer P E. Gl yce mic t hres h ol ds f or acti vat i on of 
gl uc ose c o u nterre g ulat or y  s yste ms are hi g her t ha n t he t hres h ol d f or s y m pt o ms. J Cli n I n vest. 
1 9 8 7; 7 9( 3): 7 7 7 - 8 1.
5 1.
Sea q uist E R, A n ders o n J, C hil ds B, Cr y er P, Da g o g o -Jac k S, Fis h L, et al. H yp o gl yce mia 
a n d dia betes: a re p ort of a w or k gr o u p of t he A merica n Dia betes Ass ociati o n a n d t he 
E n d ocri ne S ociet y.  Dia betes Care. 2 0 1 3; 3 6( 5): 1 3 8 4 - 9 5.
5 2.
U. S. De part me nt of Healt h a n d H u ma n Ser vices, F o o d a n d Dr u g A d mi nistrati o n. G ui da nce 
f or I n d ustr y. P atie nt -Re p orte d O utc o me Meas ures: Use i n Me dical Pr o d uct De vel o p me nt t o 
S u p p ort La beli n g Clai ms. A valia ble fr o m: 
ht t p:// w w w.f da. g o v/ d o w nl oa ds/ Dr u gs/ G ui da nces/ U C M 1 9 3 2 8 2. p df. 2 0 0 9.
5 3.
St ull D E, Lei d y N K, Paras ura ma n B, C hassa n y  O. O pti mal recall perio ds f or pat ient -
re p orte d o utc o mes: c halle n ges a n d p ote ntial s ol uti o ns. C urr Me d Res O pi n. 2 0 0 9; 2 5( 4): 9 2 9-
4 2.
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
6 1 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
6 2 of 9 4
1 2
A p pe n dices
A b bre vi ati o ns a n d Tr a de m ar k s
A D A
A merica n Dia betes Ass ociati o n
A E
a d verse e ve nt
A L T
ala ni ne a mi n otra nsferase
A N O V A
a nal ysis of varia nce
A S T
as partate a mi n otra nsferase
A U DI T
Alc o h ol Use Dis or ders I de ntificati o n Test
B G
bl o o d gl uc ose
B MI
b o d y mass i n de x
B M S
Br ist ol-M yers S q ui b b
B U N
b l o o d urea nitr o ge n 
C K D E PI
C hr o nic Ki d ne y Disease E pi de mi ol o g y C olla b orati o n 
CI
c o nfi de nce i nter val
C ma x
ma xi m u m c o nce ntrati o n 
C R F
case re p ort f or m
C R N
Cli nical Researc h Net w or k 
C T R
cli nical trial re p ort
D F U
directi o n f or use
DI LI
dr u g i n d uce d li ver i nj ur y 
D N A
de o x yri b o n ucleic aci d
D U N
dis pe nsi n g u nit n u m ber
E C G
electr ocar di o gra m
e C R F
electr o nic case re p ort f or m
E G D
es o p ha g o gastr o d u o de n osc o p y
e G F R
esti mate d gl o mer ular filtrati o n rate
E L F
e n ha nce d li ver fi br osis
E O T
e n d of treat me nt
F 4
fi br osis sta ge 4
F A S
f ull a nal ysis set
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
6 2 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
6 3 of 9 4
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 F V
first s u bject first visit
F S H
f ollicle-sti m ulati n g h or m o ne 
F U
f oll o w- u p
G C P
G o o d Cli nical Practice
G G T
g a m ma- gl uta m yl tra nsferase 
GI
gastr oi ntesti nal
G L P - 1
gl uca g o n -li ke-pe pti de - 1
G L P -1 R A
gl uca g o n -li ke-pe pti de - 1-rece pt or a g o nist 
H b A 1c
gl ycate d hae m o gl o bi n
H Bs A g
h e patitis B s urface a nti ge n 
h C G
h u ma n c h ori o nic g o na d otr o pi n
H D L
h i g h de nsit y li p o pr otei n 
HI V
h u ma n i m m u n o deficie nc y vir us
H O M A -I R
h o me ostatic m o del assess me nt – i ns uli n resista nce
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 vit y C-reacti ve pr otei n
I B
in 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 C MJ E
I nter nati o nal C o m mittee of Me dical J o ur nal E dit ors 
I E C
i n de pe n de nt et hics c o m mittee
I M P
i n vesti gati o nal me dici nal pr o d uct
I N R
int e r nati onal n o r malize d rati o
I R B
i nstit uti o nal re vie w b oar d
I U
I nter nati o nal U nit
I W R S
i nteracti ve we b res p o nse s yste m
K DI G O
Ki d ne y  Disease I m pr o vi n g Gl o bal O utc o mes ( or ga nisati o n)
L D L
l o w-de nsit y  li p o pr otei n
M E L D
m o del f or e n d -sta ge li ver disease
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
6 3 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
6 4 of 9 4
M M R M
mi xe d m o del f or re peate d meas ures 
M R
ma g netic res o na nce
M R E
ma g netic res o na nce elast o gra p h y
M R -M R E
m a g netic res o na nce – ma g netic res o na nce elast o gra p h y
M RI
ma g netic res o na nce i ma gi n g
M RI -P D F F
m a g netic res o na nce i ma gi n g - Pr ot o n de nsit y fat fracti o n
M T C
m e d ullar y t h yr oi d ca ncer 
Na
s o di u m
N A F L D
n o n -alc o h olic fatt y li ver disease
N A S
N A F L D acti vit y sc ore
N A S H
n o n -alc o h olic steat o he patitis
P
p h o ne visit
P C D
pri mar y  c o m pleti o n date
P G
plas ma gl uc ose
P K
p har mac o ki netic
P P
per pr ot oc ol
Pr o -C 3
t ype III c olla ge n f or mati o n
R N A
ri b o n ucleic aci d
S A E
seri o us a d verse e ve nt
S A P
statistical a nal ysis pla n
S A S
safet y a nal ysis set
s.c.
s u bc uta ne o us
S G L T - 2 
so di u m - gl uc ose c o tra ns p ort er 2
SI F
safet y i nf or mati o n f or m
S M P G
self-meas ure d plas ma gl uc ose
S U
s ul p h o n yl urea
S U S A R
s us pecte d u ne x pecte d seri o us a d verse reacti o n
T 2 D
t ype 2 dia betes
T M M
trial materials ma n ual
V
visit
U N L
u p per n or mal li mit
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
6 4 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
6 5 of 9 4
U T N
u ni versal trial n u m ber
V L D L
v er y l o w de nsit y  li p o pr otei n
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 |
N N 9 9 3 1 - 4 4 9 2
6 5 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
6 6 of 9 4
Cli nic al l a b or at or y tests

T he tests detai le d i n Ta ble 1 2- 1 a n d Ta ble 1 2- 2 will be perf or m e d b y t he ce ntral la b orat or y or 
la b orat or y s u b-c o ntracted b y  ce ntral la b orat or y.

Uri ne pre g na nc y  tests will be s u p plie d b y t he ce ntral la b orat or y. T he test will be perf or me d at 
t he sit e.

La b orat or y  sa m ples s pecifie d i n t he pr ot oc ol m ust be se nt t o t he ce ntral la b orat or y for a nal ysis. 
S e m a gl ut i de plas ma c o nce ntratio n a n d s o me e x pl o rati ve bi omar kers will be a nal yse d at a 
s pecialise d la b orat or y. 

A d dit i onal tests ma y be perf or me d at a n y  time 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 ulati o ns . O nl y la b orat or y s a mples s pecif ie d i n t he pr ot oc ol 
s h o uld be se nt t o t he ce ntral la b orat or y  for a nal ysis; if a d di tio nal la b orat or y  sa m pli n g is nee de d, 
e. g. t o f o ll ow u p o n A Es a n d meas ure me nt of a m ylase a n d li pase i n s us pici o n o f ac ute 
pa ncreat itis, t his m ust be d o ne at a l ocal la b orat or y.

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 yses acc or di n g t o s pecificat i 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 o mita 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.

H u m a n biosa m ples f or f ut ure a nal ysis will be st ore d as descri be d i n A p pe n di x 7 .
T a ble 1 2- 1
Pr ot oc ol -re q uire d effic ac y l a b or at or y assess me nts
L a b or at or y assess me nts
P ar a meters
E x pl o rat o y bi o mar kers

Pr o -C 3 (c olla ge n mar ker)

E L F

A di p o necti n

hs C R P
Ot her tests

Bi osa m ples f or f ut ure a nal ysis

Se ma gl uti de plas ma c o nce ntrati o n
T a ble 1 2- 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

Er y t hr oc yt es

Hae mat ocrit

Hae m o gl o bi n

Le uc oc ytes

T hr o m b oc ytes
Bi oc he mistr y 1

Ala ni ne A mi n otra nsferase ( A L T) 

Al b u mi n

Al kali ne p h os p hatase
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
6 6 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
6 7 of 9 4

A m ylase

As partate A mi n otra nsferase ( A S T)

Calci u m

Creati ni ne

Creati ni ne ki nase

Ga m ma -Gl uta m yl Tra nsferase ( G G T)

H O M A -I R

Li pase

M E L D - Na-sc ore

M E L D -sc ore

P otassi u m

S o di u m

T otal bilir u bi n ( + direct bilir u bi n)

Ur ea/ B U N
C oa g ulati o n para meter

I N R
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

Ver y -l o w de nsit y li p o pr otei n ( V L D L) c h olester ol

Tri gl yceri des

Free fatt y aci d
H or m o nes

Calcit o ni n at scree ni n g o nl y
Ser ol o g y 

HI V 1 a nti b o d y at scree ni n g o nl y

HI V 2 a nti b o d y at scree ni n g o nl y

HI V a nti ge n at scree ni n g o nl y

He patitis B s urface a nti ge n ( H Bs A g) at scree ni n g o nl y

He patitis C vir us a nti b o d y at scree ni n g o nl y
Pre g na nc y Testi n g f or 
w o me n of c hil d beari n g 
p ote nt ial

Ser u m h u ma n c h ori o nic g o na d otr o pi n ( h C G) pre g na nc y test at V 1, V 2, V 8, V 1 0, 
V 1 2. Uri ne h C G pre g na nc y test at V 4, V 6, V 9, V 1 1 a n d V 1 3 f or w o me n of 
c hil d beari ng p ote ntial
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
Gl uc ose meta b olis m 

H b A 1c

Fasti n g Plas ma Gl uc ose ( F P G) 2

C- pe pti de
N otes :
1 Details 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 bel o w, i n A p pe n di x 4 ( p ote ntial H y’s La w) a n d Secti o n 8. 1 .
2A F P G res ult ≤ 3. 9 m m ol/ L ( 7 0 m g/ d L) i n relati o n t o pla n ne d fasti n g visits s h o ul d n ot be re p orte d as a 
h y p o gl ycae mic e pis o de b ut as a n A E at t he discreti o n of t he i n vesti gat or ( A p pe n di x 4 ). A F P G res ult > 1 6. 7 m m ol/ L 
( 3 0 0 m g/ d L) s h o ul d be re p orte d as a n A E at t he discreti o n of t he i n vesti gat or ( A p pe n di x 4 ).
T he res ults of plas ma c o nce ntrati o ns of se ma gl ut i de will n ot be pr o vi de d t o t he i n vesti gat or, as 
t hese res ults will n ot be use d f or a n y cli nical e val uati o n d uri n g t he trial a n d w o ul d p ote ntiall y 
u n bli n d t he treat me nt.
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
6 7 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
6 8 of 9 4
E x pl or at or y  bio m ar ker res ults a n d H O M A-I R will n ot be pr o vi de d t o t he i n vesti gat or, as t hese 
res ults will not be use d f or a n y  cli nical e val uati on d uri n g t he trial. 
Assess me nts i n c ase of i ncre ase d le vels of li ver bl o o d p ar a meters
T e m p orar y  disc o nt i n uati on of tri al dr u g s h o uld be c o nsi dere d i n case a n y of t he bel o w criteria is 
met:

A L T or A S T > 8 x U N L

T ot al  bilir u bi n > 2. 0 m g/ dl 

I N R > 1. 6
Tri al pr o d uct must be te m p oraril y disc o nti n ue d i n case a n y  of t he bel o w criteria is met: 

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 here n o alter nat i ve aeti ol og y  e xists 
( P ote ntial H y’s La w) (see A p pe n di x 4 ).

A L T or A S T i ncrease t o > 5 x baseli n e val ue i n s u bjects w here t he baseli ne A L T or A S T 
were < 2 x U N L. 

A L T or A S T i ncrease t o > 3 x baseli ne val ue or > 3 0 0 U/ L, w hic he ver occ urs first, i n 
s u bjects w here t he baseli ne val ues were ≥ 2 x U N L b ut < 5 x U N L.

Bilir u bi n i ncrease acc o m pa nie d b y si g ns a n d s y m pt o m(s) c o mpat i ble with dr u g i n d uce d 
li ver i nj ur y ( DI LI) s uc h as ras h, e osi n o p hilia, na usea, v o miti n g, or rig ht u p per q ua dra nt pai n, 
re gar dless of t he tra nsa mi nase c o nce ntrati o ns. 
E ve nt m ust be re p orte d acc or di n g t o A p pe n di x 4 .
F or all s uc h e ve nts re peat testi n g m ust occ ur wit hi n 4 8 t o 7 2 h o urs a n d w or k u p f or c o m pet i n g 
etiol o gi es m ust be perf or me d 4 2 i ncl u di n g: 

C o m plete li ver pr ofile i ncl u di n g A L T, A S T, al kali ne p h os p hatase, t otal bilir u bi n a n d I N R. 
Hereafter, re peat testi n g s h o ul d be d o ne 2 t o 3 ti mes wee kl y . If clos e m o ni t orin g is n ot 
p ossi ble t he trial dr u g s h o ul d be disc o nt i n ue d. T he fre q ue nc y of retesti n g ca n decrease t o 
o nce a wee k or less if a b n or malit ies sta bilise a n d t he s u bject is as y m pt o matic.

A detaile d hist or y  of s y m pt o ms a n d prior or c o nc urre nt di seases. 

Hi st or y of c o nc o mita nt dr u g use (i ncl u di n g n o n-prescri pt i on me dicat i ons a n d her bal a n d 
di et ar y s u p ple me nt pre parati o ns), alc o h ol use, recreati o nal dr u g use, a n d s pecial diets.

R uli n g o ut ac ute viral he pat itis; a ut oi m m u ne or alc o h olic he patitis; h y p o xic/isc he mic 
he pat o pat h y; a n d biliar y tract disease.

O btai ni n g a hi st or y of e x p os ure t o e n vir o n me ntal c he mical a ge nts.
Tri al dr u g ca n be restarte d if a n alter nati ve eti ol o g y  is defi nitivel y  ide nt ifie d a n d li ver bl o o d 
para m eters ha ve ret ur ne d t o pre -e ve nt le vels.
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
6 8 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
6 9 of 9 4
Tri al g o ver n a nce c o nsi der ati o ns
1) Re g ul at or y a n d et hic al c o nsi der ati o ns

T his tri al 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:

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 4 3 a n d a p plica ble I C H G o o d Cli nical Pract ice ( G C P) G ui deli ne4 4

A p plica ble la ws a n d re g ulatio ns

T he pr ot oc ol, i nf or me d c o nse nt f or m, i n vest i gat or’s br oc h ure (as a p plica ble) a n d ot her rele va nt 
d oc u m e nts (e. g. a d vertise me nts), m ust be s u b mitte d t o a n I R B/I E C a n d re vie we d a n d a p pr o ve d 
b y t he I R B/I E C bef ore t he trial is i 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 safety 
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:

pr o vi di n g wri tte n s u m maries of t he stat us of t he trial a n n uall y or mor e f re 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

n otif yi n g t he I R B/I E C of S A Es or ot her sig 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

pr o vi di 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 ulati ons

e ns uri n g s u b missi o n of t he cli nical trial re p ort ( C T R) s y n o psis t o t he I R B/I E C.
2) Fi n a nci al discl os ure
I n 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 n a ncial 
certificati o n or discl os ure state me nts t o t he a p pr o priate 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: verificati on u n der di sclos ures per C o de of Fe deral Re g ulat i ons ( C F R) of 
Fi na ncial C o nflict of I nterest.
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.
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
6 9 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
7 0 of 9 4

T he i n vest i gat or m ust e ns ure t he s u bject a m ple t i me t o c o me t o a decisi o n w het her or n ot t o 
parti ci 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 .

T he s u bject will be prese nte d wit h t w o i nf or me d c o nse nt f or ms – a mai n ma n dat or y inf or m  
c o nse nt f or m t o c o nse nt t o t he trial a n d a n o pti o nal i nf or m c o nse nt f or m f or bi osa m ples f or 
f ut ure a nal ysis. 

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 4 4 , Declarati o n of Helsi n ki4 3 a n d t he I R B/I E C 
or tri al sit e.

T he m e dical rec or d must i ncl u de a state me 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 m e d c o nse nt must 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 bje ct.
4) I nf or m ati o n t o s u bjects d uri n g tri al
Si tes will be offere d a c o m m u nicati 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 o r distri b utio 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. 
I nitiati ves f or s u bject rete nti o n will be i nst itut e d f or t his trial. T hese ma y i ncl u de rete nti o n 
acti vit ies, materials a n d ite ms, 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 pati on i n t he trial a n d / or t heir disease. 
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 on 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.
5) D at a pr otecti o n

S u bjects will be assi g ne d a 6 -di gi t 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 ntifier 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 be i de ntifie d b y s u bject 
n u m ber, vi sit n u m ber a n d trial I D. A p pr o priat e meas ures s uc h as e ncr y pti o n or lea vi n g o ut 
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
7 0 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
7 1 of 9 4
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 pe rs 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.
U nite d Ki n g d o m : F or c ou ntr y s pecific re q uire me nts see A p pe n di x 9 .
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 dis k will c o nst itute a n i nter nal se ma gl ut i de safety c o m mit tee t o perf or m o n g oi n g safety 
s ur veilla nce. T he se ma gl uti de 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 f urt 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.
7) P u blic ati o n p olic y
T he i nf or 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 ntial, a n d ma y be 
use d b y or o n be half of N o v o N or dis k f or re g ulat or y p ur p oses as 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 wi t h t his 
trial s hall re mai n t he s ole pro 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 mati 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 certai n c o n dit i ons are f ulfille d, N o v o N or dis k ma y gr a 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 
di sease 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 nical t rial re p ort f or t his trial.
O ne ( or t w o) i n vest i gat or(s) will be a p p oi nte d b y N o v o N or dis k t o re vie w a n d si g n t he cli nical trial 
re p ort (si g nat or y in vesti gat or(s)) 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 nted 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 4 5.
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
7 1 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
7 2 of 9 4
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 m e. 
Di s clos ure i ncl u des p u blicati o n of a ma n uscri pt i n a pee r-re vie we d scie ntific j our nal, a bstract 
s u b missi on wi t 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 g ht 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 o n of t he stre n gt hs a n d li mitati o ns. I n t h e e ve nt of a n y disa gree me nt o n t he 
c o nte nt of a n y p u blicati o n, b ot h t he i n 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 will w or k wit h o ne or m ore 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 m ore 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 wit h t he Rec o m me n dat i ons f or t he C o n d uct, 
Re p or ti n g, E diti 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 ors 4 5.
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 val uate t he pla n ne d p u blicat i on. 
W here re q uire d b y  t h e jo ur n al , t he i n vesti gat or fr o m eac h trial site will be na me d i n a n 
ac k n o wle d ge me nt or i n t he s u p ple me ntar y mat 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 ul tice ntre cli nical trial, a nal yses base d o n si n gle-site data us uall y ha ve si g nifica nt statist ical 
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 dis k. 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 blicat i 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 uscr i pt of t he trial.
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
7 2 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
7 3 of 9 4
I n vesti g at or access t o d at a a n d re vie w of res ults
As o w ner of t 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 researc h s u bjects' data, a n d will be pr o vi de d wi t h 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) 4 6, 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) 4 7, E ur o pea n C o m missi on Re q uire me nts 4 8, 4 9 a n d ot her rele 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 he i n vesti ga t 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.
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 oi nt, a n d i s for t hi s 
trial Last S u bje ct First Treat me nt ( L S F T) + 4 8 wee ks c orres p o n di n g t o visit 1 2. If t he last s u bject is 
wi t hdra w n earl y, t he P C D is c o nsi dere d t he date w he n t he last s u bject w o ul d ha ve c o m plete d visit 
1 2. T he P C D deter mi nes t he dea dl i ne f or res ults discl os ure at cli nicaltrials. g o v acc or di n g t o 
F D A A A.
9) D at a q u alit y ass ur a nce
C ase Re p ort F or ms ( C R Fs)

N o v o N or dis k or desi g nee i s 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 uality 
c hec ki n g o f t he data.

All s u bject data relat i 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 
ele ctr 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 onicall 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 Fs are use d.

T he f o ll owi n g will be pr o vi de d as pa per C R Fs: 

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 C R F is re v o ke d or 
t he C R F is te m p oraril y u na vaila ble:

A E f or ms 

S af et y i nf or mati on f or ms 
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
7 3 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
7 4 of 9 4

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 orrectio ns are ma de b y t he i n vesti gat or’s dele 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, pr ef era 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 ni t 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 ncl 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 
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 rel e va nt trial site staff s h o uld be a vaila ble f or 
di sc ussi ons at m o ni t ori ng visi ts a n d bet wee n mo ni t orin g visit s (e. g. b y t ele p h o ne). 

Tri al mo ni t 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 m e 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 gr ee me nts, 
I C H G C P, a n d all a p plica ble re g ulat or y re 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 
pl a 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 t o 
e ns ure c o nsiste nc y a n d/ or i de nt if y omissi o ns c o m pare d t o t he C R F. 
Pr ot oc ol c o m pli a nce
De 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 h e i n vest i gat or m ust 
i nf or m t h e mo ni t or a n d t he i m plicati ons of t he de viat i on m u st be re vie we d a n d disc usse d.
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
7 4 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
7 5 of 9 4
De vi at i ons m ust 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 rea s 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 list i 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 n al  of t he c o mplete d di aries must n ot be re m o ve d fr o m  t he trial site, u nless t he y for m  
part of t he C R F a n d a c o p y  is ke pt at t he sit e.

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 o n t he pa per C R F or e ntere d i n t he electr o nic C R F t hat are tra nscri be d fr o m 
s o urce d oc u me nts m ust be c o nsiste nt wit h t he s o urce d oc u me nts or t he discre pa ncies m ust be 
e x plai ne d. T he i n vest i gat or ma y nee d t o 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 in s o urce d oc u me nts s uc h as s u bject’s 
me dical rec or d. 

T he i n vest i gat or m ust d oc u me nt a n y att e mpt t o o b tai 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 utes 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 site. 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 ituti o 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 y e d d uri n g t he rete nti o n peri o d wit h o ut t he writte n a p pr o val of N o v o N or dis k. N o rec or ds 
ma y be tra nsferre d t o a n ot her l oc atio n or part y  wit ho ut wri tte 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 wi t ho ut i n v ol vi n g N o v o N or dis k 
i n a n y w a y. If a p plica ble, electr o nic C R F 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 s u p plie d 
b y N o v o N or di s k. Sit e-s pecific C R Fs a n d ot her s u bject data (i n a n electro ni c 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 vi d e d el ectr o nic data (e. g. 
t he C D-R O M) i s n ot rea da ble d uri n g t he e nt ire st ora ge perio d, t he i n vest i 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 nstituti o n or pri vate practi ce
S pai n: F or c o u ntr y  s pecific re q uire me nts see A p pe n di x 9 .
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
7 5 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
7 6 of 9 4
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 ter mi nate t he trial at a n y t i me f or a n y 
reas o n at t he s ole discreti o n of N o v o N or dis k. If t he trial is sus 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 m ptl y i nf or m t he re g ulat or y a ut h orities a n d 
I R Bs/I E Cs a n d pr o vi de a detaile d writte n e x pla nat i 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 m e nts a n d trial s u p plies ha ve bee n c ollecte d a n d a trial site cl os ure visit has bee n perf or me d.
T he i n 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.
Reas o ns f or t he earl y cl os ure of a trial site b y  N ov o N or dis k or i n vest i 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

di sc o nti n uati on of f u rt her trial pr o d uct de velo p m e 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 site. If a n y tas ks are dele gate d, t he i n vest i gat or 
m ust m ai ntai n a l o g of a p pr o pria t el 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 bi 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 of a trial a n d t he q ualit y 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 vest i 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 vesti gat or 
m ust be a ble t o pr o vi de t he necessar y  inf or m at i on or ot her wise de m o n strate t o N o v o N or dis k t hat 
s uc h tec h nical a n d or ga nisat i onal safety me as ures ha ve bee n ta ke n.
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
7 6 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
7 7 of 9 4
D uri n g a n y peri o d of u na vaila bilit y, t he i n vest i gat or m ust dele gate res p o nsi bility 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 readil 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 retires) a 
ne w i n vest i gat or will be a p p oi nte d i n c o ns ultati on wi t 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 f or 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 clinical tri als 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. 
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 bilit y 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 sai d site or i n vestig at or a re 
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. 
N o v o N or dis k acce pts lia bilit y i n acc or da nce wit h:
Fra nce: F or c o u n tr y s pecific i n de m nity state m e nts see A p pe n di x 9 .
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
7 7 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
7 8 of 9 4
A d verse e ve nts: defi niti o ns a n d pr oce d ures f or 
rec or di n g, e v al u ati o n, f oll o w -u p, a n d re p orti n g
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 ormal 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 b use: Persiste nt or s p ora dic, i nte nti o nal e xcessi ve use of me dical pr o d uct, w hic h is acc o m pa nie d b y har mf ul 
p h y sical 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).

Mis use: Sit uati o n w here t he me dici nal pr o d uct is i nte nti o nall y a n d a p pr o priatel y use d n ot i n acc or da nce wit h t he 
pr ot oc ol or t he te r ms of t he mar keti n g a ut h orizati o n.

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.
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 pre-e xisti n g c o n diti o ns, i ncl u di n g t h ose i de ntifie d 
d uri n g scree ni n g or ot her trial pr oce d ures perf or me d bef ore e x p os ure t o trial pr o d uct. 
N ote: pre -e xisti n g c o n diti o ns s h o ul d be rec or de d as me dical hist or y/c o nc o mita nt ill ness.

Pr e -pla n ne d pr oce d ures, u nless t he c o n diti o n f or w hic h t he pr oce d ure was pla n ne d has w orse ne d fr o m t he first 
trial relate d acti vit y after t he s u 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 pitalisati o n” 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 baseli ne is n ot 
c o nsi dered a n A E.
N ote:
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
7 8 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
7 9 of 9 4

H os pitalisati o ns f or a d mi nistrati ve, trial relate d a n d s ocial p ur p oses d o n ot c o nstit ute A Es a n d s h o ul d 
t heref ore n ot be re p orte d as A Es or S A Es.

H os pital a d missi o ns f or s ur gical pr oce d ures, pla n ne d bef ore trial i ncl usi o n, are n ot c o nsi dere d A Es or S A Es.

Res ults i n persiste nt dis a bilit y/i nc a p acit y
T he ter m disa bilit y mea ns a s u bsta ntial disr u pti o n of a pers o n’s a bilit y t o c o n d uct n or mal life f u ncti o ns.
T his defi niti o n is n ot i nte n de d t o i ncl u de e x perie nce of relati vel y mi n or me dical si g nif ica nce s uc h as 
u nc o m plicate d hea dac he, na usea, v o miti n g, diarr h oea, i nfl ue nza, a n d acci de ntal tra u ma (e. g. s prai ne d a n kle), 
w h ic h ma y i nterfere wit h or pre ve nt e ver y da y life f u ncti o ns b ut d o n ot c o nstit ute a s u bsta ntial disr u pti o n.

Is a c o n ge nit al a n o m al y/ birt h defect

I m p ort a nt me dic al e ve nt:

Me dical or scie ntific j u d g me nt s h o ul d be e xercise d i n deci di n g w het her S A E re p orti n g is a p pr o priate i n ot her 
sit uati ons. T his i ncl u des i m p orta nt me dical e ve nts t hat ma y n ot be i m me diatel y life -t hreate ni n g or res ult in 
deat h o r h os pitalisati o n, b ut ma y je o par dise t he s u bject or ma y re q uire me dical or s ur gical i nter ve nti o n t o 
pre ve nt o ne of t he ot her o utc o mes liste d i n t he a b o ve defi niti o n. T hese e ve nts s h o ul d us uall y be c o nsi dere d 
seri o us a n d re p orte d as S A Es usi n g t he i m p orta nt me dical e ve nt criteri o n.

T he f oll o wi n g a d verse e ve nts m ust al wa ys be re p orte d as S A Es usi n g t he i m p orta nt me dical e ve nt criteri o n, if 
n o ot her seri o us ness criteria are a p plica ble:

s us pici o n of tra ns missi o n of i nfecti o us a ge nts via t he trial pr o d uct. 

ris k of li ver i nj ur y defi ne d as ala ni ne a mi n otra nsferase ( A L T) or as partate a mi n otra nsferase ( A S T) > 3 x 
U N L a n d t otal bilir u bi n > 2 x U N L, w here n o alter nati ve aeti ol o g y e xists ( p ote ntia l H y's la w).
Descri pti o n of A Es re q uiri n g a d diti o n al d at a c ollecti o n ( vi a s pecific e ve nt f or m) 
A Es re q uiri n g a d diti o nal data c ollecti o n are A Es, w here t he a d diti o nal data will be nefit t he e val uati o n of t he safet y of 
t he trial pr o d uct (Ta ble 9- 1 ). T he selecti o n of t hese e ve nts is base d o n t he n o n-cli nical a n d cli nical data wit h 
se ma gl uti de, k n o wle d ge fr o m t he G L P-R A dr u g class as well as re g ulat or y re q uire me nts. 
E ve nt t y pe
Descri pti o n
Ac ute gall bla d der disease
E ve nts of s y m pt o matic ac ute gall bla d der disease 
(i ncl u di n g gallst o nes a n d, c h olec ystitis)
He patic e ve nt

A L T or A S T > 8 x U N L

T otal bilir u bi n > 2. 0 m g/ dl 

I N R > 1. 6

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 here n o alter nati ve aeti ol o g y 
e xists ( p ote ntial H y’s La w)

A L T or A S T i ncrease t o > 5 x baseli ne 
val ue i n s u bjects were t he baseli ne A L T or 
A S T were < 2 x U N L

A L T or A S T i ncrease t o > 3 x baseli ne 
val ue or > 3 0 0 U/ L, whi c he ver occ urs 
first, i n s u bjects were t he baseli ne val ues 
were ≥ 2 x U N L b ut < 5 x U N L.

Bilir u bi n i ncrease acc o m pa nie d b y si g ns 
a n d s ym pt o m(s) c o m pati ble wit h dr u g 
i n d uce d li ver i nj ur y ( DI LI) s uc h as ras h, 
e osi n o p hilia, na usea, v o miti n g, or ri g ht 
u p per q ua dra nt pai n, re gar dless of t he 
tra nsa mi nase c o nce ntrati o ns.
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
7 9 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
8 0 of 9 4

M o del F or E n d -Sta ge Li ver Disease 
( M E L D) sc ore ≥ 1 5 or M E L D -Na ≥ 1 2

Li ver tra ns pla nt 

Ascites re q uiri n g me dical i nter ve nti o n

Gastr oes o p ha geal variceal blee di n g

He patic e nce p hal o pat h y

S p o nt a ne o us bacterial perit o nitis

He patic e ve nts lea di n g t o trial pr o d uct 
disc o nti n uati o n
Mali g na nt ne o plas ms
Mali g na nt ne o plas m, i ncl u di n g he pat ocell ular 
carci n o ma, b y hist o pat h ol o g y or ot her s u bsta ntial 
cli nical e vi de nce
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 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.
Dia betic reti n o pat h y
Ne w o nset or w orse ni n g of dia betic reti n o pat h y
Me dicati o n err or
A me dicati o n err or is a n u ni nte n de d fail ure i n t he trial 
dr u g treat me nt pr ocess t hat lea ds t o, or has t he p ote ntial 
t o lea d t o, har m t o t he s u bject, s uc h as: 

A d mi nistrati o n of wr o n g dr u g .
N ote: Use of wr o n g 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 c o nfir me d a d mi nistrati o n of wr o n g dr u g. 

Wr o n g r o ute of a d mi nistrati o n, s uc h as i ntra m usc ular 
i nstea d of s u bc uta ne o us. 

Acci de ntal a d mi nistrati o n of hi g her d ose t ha n 
i nte n de d. H o we ver, t he a d mi nister e 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.
Dr u g pa uses will n ot t o be re p orte d as a me dicati o n 
err or.
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 ntati 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 h e e ve nt.
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
8 0 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
8 1 of 9 4

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 uct s 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 ons hi p is re p orte d t o N o v o N or dis k, e. g. i n t he alter nati ve aeti ol o g y secti o n o n t he safet y i nf or mati o n f or m. 
N o v o N or dis k ma y nee d t o re p ort t his a d verse e ve nt t o rele va nt re g ulat or y a ut h orities.
Assess me nt of se 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 ormal 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 nsit y of a n e ve nt; a n d b ot h a n A E a n d S A E ca n be assesse d as 
se vere. A n e ve nt is defi ne d as ‘seri o us’ w he n it meets at least o ne of t he o utc o mes descri be d i n t he defi niti o n of a n 
S A E a n d n ot w he n it is rate d as se vere.
Assess me nt of c a us alit y
T he i n vesti gat or is o bli gate d t o assess t he relati o ns hi p bet 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 be t 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.
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 co nsi dere d a n d i n vesti gate d.
T he i n vesti gat or s h o ul d use t he i n vesti gat or’s br oc h ure, if 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 p ort a nt t h at t he i n vesti g at or al w a ys m a kes a n assess me nt of c a us alit y f or e 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.
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
8 1 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
8 2 of 9 4

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 h e 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 gat or s h o ul d 
pr o vi de N o v o N or dis k wit h a c o p y of a ut o ps y re p ort i ncl u di n g hist o pat h ol o g y, if a vaila ble.
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 mati o n f or m) m ust be c o m plete d i n t he C R F. 

F or re p orti n g a n d si g n -off ti meli nes, see b o x bel o w. 

If t he C R F is u na vaila ble f or m ore t ha n 2 4 h o urs, t he n t he site will use t he pa per A E f or m a n d if t he C R F is 
u na vaila ble f or m ore t ha n 5 cale n dar da ys t he n t he site will use t h e 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 9. 2. 1 .

After t he trial is c o m plete d at a gi ve n site, t he C R F will be dec o m missi o ne d t o pre ve nt t he e ntr y of ne w data or 
c ha n ges t o e xisti n g data. If a site recei ves a re p ort of a ne w S A E fr o m a s u 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 mi ssi 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 i n a n e ncr y pte d 
ma n ner b y e -mail or fa x/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 il l 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 |
N N 9 9 3 1 - 4 4 9 2
8 2 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
8 3 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 
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 nt ial. 
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 m a 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 no pa usal  state i n w o me n n ot usi n g h or mo 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 ui re d t o use o ne of t he 
n o n- h or m o nal hi g hl y effect 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 di sc o nti n ue H R T t o all o w c o nfir mat i on of 
p ost m e 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 uire d f or male s u bjects, as t he ris k of terat o ge nicit y/ fet ot o xicity 
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 pti o 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 |
N N 9 9 3 1 - 4 4 9 2
8 3 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
8 4 of 9 4
T a ble 1 2 - 3
Hi g hl y effecti ve c o ntr ace pti ve met h o ds
Hi g hl y effecti ve c o ntr ace pti ve met h o ds t h at are user de pe n de nt a a n d b
Fail ure rate of < 1 % per year w he n use d c o nsiste ntl y a n d c orrectl y.
C o m bi ne d ( oestr o ge n a n d pr o gest o ge n c o ntai ni n g) h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n b

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 b

I ntra uteri ne De vice (I U D)

I ntra uteri ne h or m o ne-releasi n g S yste m (I U S)

Bilateral t u bal occl usi o n
V asect o mise d p art ner 
A vasect o mise d part ner is a hi g hl y effecti ve c o ntrace pti o n met h o d pr o vi de d t hat t he part ner is t he s ole male se x ual 
part ner of t he W O C B P a n d t he a bse nce of s per m has bee n c o nfir me d. If n ot, a n a d diti o nal hi g hl y effecti ve met h o d of 
c o ntrace pti o n s h o ul d be use d.
Se x u al a bsti ne nce b
Se x ual a bsti ne nce is c o nsi dere d a hi g hl y effecti ve met h o d o nl y if defi ne d as refrai ni n g fr o m heter ose x ual i nte rc 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 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 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 tre at me nt peri o d a n d f or at least 4 9 da ys after t he last d ose of trial 
pr o d uct.
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 gati ve hi g hl y se nsiti ve ser u m pre g na nc y t est.

Pre g na nc y testi n g s h o ul d be perf or me d at e ver y  sit e visit d uri n g t he treat me nt perio d acc or di n g 
t o t he fl o wc hart a n d A p pe n di x 2 . 

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 9 ).

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.

W O C B P nee ds t he last uri ne pre g na nc y  test at F U visit. If t he F U visit is a p h o ne c o ntact, t he 
s u bjects ca n ta ke t he uri ne test at h o me a n d i nf or m t he i n vesti gat or of t he res ult.
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
8 4 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
8 5 of 9 4
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 fe male s u bject, w h o bec o mes pr e 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 he 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 na tio n 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 ordis k as descri be d i n 
A p pe n di x 4 . W hile t he i nvest i 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 |
N N 9 9 3 1 - 4 4 9 2
8 5 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
8 6 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 
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. disc o l or atio n, parti cles 
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, 
p us h 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 d efi 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
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
8 6 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
8 7 of 9 4
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 ociat e 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 orm. If se veral sa m ples are s hi p pe d i n o ne s hi p me nt, t he sa m ple a n d t he c orres p o n di n g 
tec h nical c o m plai nt f or m s h o ul d be ke pt t o get her.
St ora ge of t he tec h nical c o m plai nt sa m 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.
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
8 7 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1- 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
8 8 of 9 4
Rete nti o n of h u m a n bi os a m ples
Bi os a m ples f or f ut ure a n al ysis

T he tri al will in v o l ve c ollecti on of h u ma n bi o sa m ples t o be st ore d i n a ce ntral arc hi ve. S u bjects 
w h o d o n ot wis h t o c o ntri b ute wit h bi o sa m ples f or st ora ge ma y still partici pate i n t he trial.

S u bjects m ust si g n a n d date a se parate i nf or me d c o nse nt f or m bef ore bi osa m ples are c ollecte d t o 
be st ore d f or f ut ure a nal ysis.  

T he m at erial t o be c ollecte d is bl o o d a n d li ver tiss ue. 

Bl o o d will be c ollecte d at scree ni n g ( visit 1 ), wee k 2 4 ( visit 1 0), a n d wee k 4 8 ( visit 1 2/ 1 2 A).
Li ver ti ss ue will be c ollecte d at scree ni n g ( visit 1 ) a n d wee k 4 8 ( visit 1 2/ 1 2 A). T he li ver tiss ue 
will be ta ke n fr o m t he li ver bi o ps y o btai ne d f or t he mai n tri al, n o a d ditio nal  li ver bi o ps y will be 
o btai ne d.   

Bi osa m ples will  be use d t o i m pr o ve t he u n dersta n di n g of N A S H, mec ha nis m of act i on a n d 
di sease aeti ol og y . Biosa m ples ma y  als o be use d t o i de ntif y disease s u b-p o p ul at i ons s uc h as 
hi g h -res p o n ders or s u bjects pr o ne t o a d verse e ve nts. T he a nal ysis o f bi o sa m ples ma y incl u de 
D N A a n d R N A se q ue nci n g, e pi ge net ic a nal ysis a n d ot her met h o ds i n ' omics' use d t o 
c haracterise t he disease. As ne w k n o wle d ge ma y arise relate d t o N A S H a n d se ma gl ut i de d uri n g 
t he c o n d uct of t he trial, t he a nal yses of t he st ore d bi osa m ples ma y incl u de bi o m ar kers prese ntl y 
n ot k n o w n, w hic h ha ve n ot bee n i ncl u de d u p -fr o nt i n t he scie ntific h y p ot heses of t his trial.

T he bi o sa m ples will be st ore d at a ce ntral la b orat or y for u p t o 1 5 y ears after e n d of trial. O nl y 
N o v o N or dis k staff a n d pers o n nel fr o m t he ce ntral la b orat or y will ha ve access t o t he st ore d 
s peci me ns. T he bi osa m ples ma y be tra nsferre d t o ot her c o u ntries f or a nal ysis a n d will be 
destr o y e d at t he latest 1 5 years after e n d of trial. 

S u bject’ s id e nti t y will re mai n c o nfi de ntial a n d t he sa m ples will be i de ntifie d o nl y b y s u bject 
n u m ber, visit n u m ber a n d trial i de nt ificati on n u m ber. N o direct i de nt ificati on of t he s u bject will 
be st ore d t o get her wit h t he sa m ples. 

T he s u bject ma y re q uest t he st or e d bi osa m ples t o be destr o ye d b y wit hdra wi n g t he desi g nate d 
i nf or me d c o nse nt. T he res ults o btai ne d fr o m a n y alrea d y p erfor m e d a nal yses of t he sa m ples will 
still be use d. 

I n t he e ve nt t hat t he c ollecte d bi osa m ples (ser u m, plas ma, li ver bi o ps y sa m ples) will be use d i n 
t he f ut ure, t he i n vest i gat or will bec ome direct l y i nf or me d b y N o v o N or dis k a b o ut t he res ults, if 
t he fi n di n gs are dee me d cli nicall y rele va nt a n d a nal yt icall y vali d a n d q ua ntifia ble. I n s uc h case, 
a writte n s u m mar y of t he fi n di n gs, i ncl u di n g listin gs of s u bject s pecific val ues, will be pr o vi de d 
o nce a fir m c o ncl usi o n fr o m t he res ults has bee n dra w n b y N o v o N or dis k. P ote nti all y, 
o bser vat i ons of ne o plast ic diseases, seri o us here ditar y diseases, ot her u n-treata ble diseases or 
a n y ot her a b n or mal fi n d i n gs c o uld be part of t he o bser vat i ons. S u bjects ca n c o ntact t he 
i n vesti gat or if t he y wis h t o be i nf or me d a b o ut res ults deri ve d fr o m st ore d bi osa m ples o btai ne d 
fr om t heir o w n b o d y.
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
8 8 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
8 9 of 9 4
H y p o gl yc ae mic e pis o des
N o v o N or dis k cl assific ati o n of h y p o gl yc ae mi a
I n n or mal p h ysiol o g y , s y m pt o ms of h y p o gl ycae mia occ ur bel o w a P G le vel of 3. 1 m m ol/L ( 5 6 
m g/ d L) 5 0. T heref ore, N o v o N o r dis k has i ncl u de d h y p o gl ycae mia with P G l e vels bel o w t his c ut -off 
p oi nt i n t he defi nit i on of B G c o nfir me d h y p o gl ycae mia.
N o v o N or dis k uses t he f o ll owi n g classificat i on ( Fi g ure 1 2- 1 ) i n a d diti on t o t he A D A 
classificat i on 5 1:
1.
Se vere h y p o gl ycae mia acc or di n g t o t he A D A classificat i on 5 1.
2.
S y m pt o m atic B G c o nfir me d h y p o gl ycae mia: A n e pis o de t hat is B G c o nfir me d b y P G val ue 
< 3. 1 m m o l/ L ( 5 6 mg/ d L) wit h s y m pt o ms c o nsiste nt with h y p o gl ycae mia.
3.
As y m pt o mat ic B G c o nfir me d h y p o gl ycae mia: A n e pis o de t hat is B G c o nfir me d b y P G val ue 
< 3. 1 m m o l/ L ( 5 6 mg/ d L) wit h o ut s y m pto m s c o nsiste nt wit h h y p o gl ycae mia.
4.
B G c o nfir me d h y p o gl ycae mia: T he u ni o n of 2. a n d 3.
5.
Se vere or B G c o nfir me d s y m pt o mat ic h y p o gl ycae mia: T he u ni o n of 1. a n d 2.
6.
Se vere or B G c o nfir me d h y p o gl ycae mia: T he u ni o n of 1., 2. a n d 3.
F or h y p o gl ycae mic e pis o des re p orte d wit h missi n g i nf or mat i on rel ate d t o t he classificat i on, t he 
f oll owi n g a p plies w he n classif yi n g t he e pis o d e acc or di n g t o t he N o v o N or dis k classificat i on:

A h y p o gl ycae mic e pis o de wit h missi n g i nf or mat i on o n s y m pt o ms will be classifie d as wit h o ut 
s y m pt o ms. 

A h y p o gl ycae mic e pis o de wit h missi n g i nf or mat i on o n bei n g a ble t o self -treat will be re gar de d 
as a n e pis o d e w here t he s u bject was a ble t o self- treat a n d classifie d i n acc or da nce wit h t he a ble 
t o self-tr e at classificat i ons.
E pis o des t hat ca n n ot be classifie d acc or di n g t o t he a b o ve, are i ncl u de d i n o ne of t he f o ll owi n g 
cate g ories:

‘ N o v o N or dis k u nclassifia ble’ incl u des e pis o des w here s u bjects were a ble t o self -treat a n d wit h 
P G ≥3. 1 m m o l/ L ( 5 6 mg/ d L) a n d h y p o gl ycae mic e pis o des f or a s u bject a ble t o self -treat wit h 
missi n g P G as it is t o be treate d as a n e pis o de wit h P G > 3. 9 m m o l/L ( 7 0 m g/ d L).

‘ N ot a ble t o self-tr e at – u nclassifia ble’ i ncl u des e pis o des w here t he s u bjects were n ot a ble t o 
self-treat b ut neit her of t he f oll owi n g c o n di tio ns were re p orte d: P G ≤3. 9 m m o l/L ( 7 0 m g/ d L), 
alle viat i on of s y m pt o ms, seiz ure, u nc o nsci o us/c o mat ose or fatal.
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
8 9 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
9 2 of 9 4
≤3. 9 m m o l/ L ( 7 0 mg/ d L) or 
> 3. 9 m m o l/ L ( 7 0 mg/ d L) occ urri n g i n c o nj u nct i on wi t h h y p o gl ycae mic s y m pt o ms s ho ul d be 
re p orte d as a h yp o gl ycae mic e pis o de acc or di n g t o t he fl o wc hart a n d i nstr ucti o ns bel o w. W he n a 
s u bject e x perie nces a h y p o gl ycae mic e pis o de, s u bject s h o ul d rec or d t he ge neral i nf or mat i on i n 
r elat i on t o t he h y p o gl ycae mia (ti mi n g, P G meas ure me nts, s y m p t o ms etc. as descri be d i n t he diar y).
I n case a s u bject is n ot a ble t o fill i n t he diar y (e. g. i n case of h os pitalisati on), t he n i n vest i gat or 
s h o uld re p ort t he h y p o gl ycae mic e pis o de direct l y i n t he C R F. 
U p o n o nset of a h y p o gl ycae mic e pis o de t he s u bject is rec o m me n de d t o meas ure P G e ver y 1 5 
mi n utes u nt il t he S M P G val ue is > 3. 9 m m ol/ L ( 7 0 m g/ d L) a n d/ or s y m pt o ms ha ve bee n res ol ve d i n 
acc or da nce wit h c urre nt g ui deli nes 5 1.
Re peate d S M P G meas ure me nts a n d/ or s y m pt o ms will b y defa ult be c o nsi dere d as o ne 
h y p o gl ycae mic e pis o de u nt il a s uccee di n g S M P G val ue is > 3.9 m m ol / L ( 7 0 mg/ d L) a n d/ or 
s y m pt o ms ha ve bee n res ol ve d. O ne h y p o gl ycae mic e pis o de f or m is t o c o ver t hese meas ure me nts 
a n d/ or s y m pt o ms. 
I n case of se veral l o w S M P G val ues wit hi n t he h y p o gl ycae mic e pis o de, t he l o west val ue is t he o ne 
t hat will be re p orte d a s t he S M P G val ue f or t he h y p o gl ycae mic e pis o de b ut t he start ti me of t he 
e pis o de will re mai n as t he ti me f or t he first l o w S M P G val ue a n d/ or s y m pt o m.
T he l o west val ue meas ure d d uri n g t he h y p o gl ycae mic e pis o de will be re p orte d as t he P G val ue f or 
t he e pis ode. T he re mai ni n g val ues will be ke pt as s o urce data i n t he diar y.
A h y p o gl ycae mic e pis o de starti n g wit h o ut s y m pt o ms s h o ul d be u p date d t o s y m pt o mat ic if t he 
s u bject e x perie nces s y m pt o ms later d uri n g t he e pis o de.
If t he se verity of  a h y p o gl ycae mic e pis o de worse ns, o nl y o ne h y p o gl ycae mic e pis o de s h o ul d be 
re p orte d, reflecti n g t he m ost se vere de gree of h y p o gl ycae mia.
I n vesti gat or m ust i nstr uct s u bjects t hat t he a ns wer t o t he q uesti o n: " Was t he s u bject a ble t o treat 
hi m/ herself?" m ust be a ns were d " N o" f or a n e p is o de re q uiri n g assista nce of a n ot her pers o n t o 
acti vel y a d mi nister car b o h ydrate, gl uca g o n, or ta ke ot her c orrecti ve acti o ns. P G c o nce ntrati o ns ma y 
n ot be a vaila ble d uri n g a n e ve nt, b ut ne ur ol o gical rec o ver y  fol l owi n g t he ret ur n of P G t o n or mal is 
c o nsi der e d s ufficie nt e vi de nce t hat t he e ve nt was i n d uce d b y a l o w P G c o nce ntrati o n 5 1.
A d dit i onal i nf or mati o n (e. g. descri pti o n of s y m pt o ms, alle viati on of s y m pt o ms, seiz ure, c o ma, 
fatal) i n relat i on t o t hese se vere h y p o gl ycae mic e pis o des m ust be rec or de d.
Or al  car b o h y drates m ust n ot be gi ve n if t he s u bject is u nc o nsci o us. 
F or l o w S M P G val u es f or h y p o gl ycae mic e pis o des w here t he s u bject was a ble t o self -treat: If a 
h y p o gl ycae mic e pis o de f or m is n ot c o m plete d wit hi n 7 cale n dar da y s of t he S M P G meas ure me nt, 
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
9 2 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
9 3 of 9 4
the e pis o de s h o ul d be re p orte d o n a h y p o gl ycae mic e pis o de f or m wit h as m uc h i nf or mat i on as 
p ossi ble. N o v o N or dis k will n ot q uer y  for a d di tio n al  data e xce pt f or t he start date, S M P G val ue a n d 
w het her t he s u bject was a ble t o self -treat d ue t o decrease d vali dit y of s uc h data5 2, 5 3.
T he s u bject m ust be re -trai ne d i n h o w t o re p ort h y p o gl ycae mic e pis o des if t he i n vesti gat or i de ntifies 
l ow S M P G val ues n ot re p orte d as h y p o gl ycae mic e pis o des.
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
9 3 of 9 4
C O N FI D E N TI A L

Pr ot oc ol
Date:
2 1 Fe br uar y 2 0 2 0
N o v o N or di s k
Trial I D: N N 9 9 3 1 - 4 4 9 2
Versi o n:
3. 0
     
Stat us:
Fi nal
     
Pa ge:
9 4 of 9 4
C o u ntr y -s pecific re q uire me nts 
Secti o n 2 Fl o wc h art

F or Ger m a n y: S u bject's f ull Date of Birt h is n ot all o we d t o be c ollecte d a n d m ust be 
s h orte ne d t o Year of Birt h.

F or Fr a nce: C ollect i on of race ( Blac k/ ot her) a n d a ge is nee de d f or t he calc ulati o n o f e G F R 
( C K D-E PI) 3 6. F or Fra nce t he race will n ot be c ollecte d i n t he C R F.
Secti o n 9. 4. 6 E ye e x a mi n ati o n

F or Ger m a n y: I n Ger ma n y t he e ye e xa mi nat i on m ust be perf or me d b y a n o p ht hal m o l ogist.
A p pe n di x 3, 5 D at a pr otecti o n

F or U nite d Ki n g d o m : T he I R B/I E C d o n ot ha ve access t o t he patie nts’ me dical rec or ds.
A p pe n di x 3, secti o n 1 1 Rete nti o n of cli nic al tri al d oc u me nt ati o n

F or S p ai 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 2 5 y ears after e n d of trial. 
A p pe n di x 3, secti o n 1 4 I n de m nit y st ate me nt

F or Fr a nce: T he s p o ns or is res p o nsi bl e for i de nt ificati on of t he har mf ul c o nse q ue nces of 
t he bi o me dical t he researc h f or t he pers o n le n di n g hi mself t heret o a n d f or i n de m nificat i on of 
his be neficiaries, e xce pt i n case of pr o of, i nc u m be nt o n it, t hat t he prej u dice is n ot 
attri b uta ble t o his fa u lt or of t he fa ult of a n y int er ve ni n g part y, wit ho ut t he s p o ns or's bei n g 
e nt itle d t o call o n acts b y a t hir d part y or t he v ol u ntar y wit h dra wal of t he pers o n w h o ha d 
i nitiall y c o nse nte d t o c o o perati n g i n t he researc h (acc or di n g t o T he Fre nc h P u blic Health 
C o de arti cle L 1 1 2 1 -1 0 (l a w n° 2 0 0 4 -8 0 6 of 9 A u g ust 2 0 0 4 art. 8 8 I,I X, J o ur nal Officiel o f 
1 1 A u g ust 2 0 0 4).
  Pr ot oc ol  v 3 |
N N 9 9 3 1 - 4 4 9 2
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