Clinical trial NCT03987451
Conditions: Non-alcoholic Steatohepatitis
Sponsor: Novo Nordisk A/S
Start date: 2019-06-18; Completion date: 2021-06-10
Enrollment: 71 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Semaglutide is a medicine studied in patients with non-alcoholic steatohepatitis (NASH), as it may improve liver damage. Participants will either get semaglutide or placebo (a dummy medicine) - which treatment participants get is decided by chance. The study will last for about 61 weeks in total. Participants will have 10 clinic visits and 3 phone calls with the study doctor or staff during the study. Some of the clinic visits may be spread over more days. Participants will need to inject themselves with medicine under the skin. Participants will have to do this once a week for 48 weeks. The study includes magnetic resonance imaging (MRI) scans of the liver, 1 or 2 liver tissue samples, ultrasound scans of the stomach and a possible examination of the food pipe. For some tests participants may need to remove some items of clothing. Participants will stop in the study if the doctor thinks that there are any risks for their health. The information collected from participants during the study may help them and other patients with NASH in the future. Women cannot take part if pregnant, breast-feeding or planning to become pregnant during the study period.

Detailed description:

Arms: arm 1: Dose escalation to 2.4 mg of semaglutide once-weekly arm 2: Semaglutide placebo once-weekly
Interventions: intervention 1: Semaglutide intervention 2: Placebo (semaglutide)
Intervention descriptions: intervention 1: Semaglutide given subcutaneously (s.c., under the skin) once-weekly for 48 weeks intervention 2: Semaglutide placebo s.c. given once-weekly for 48 weeks

Protocol documents:
Prot_000.pdf: 
C o ver P a ge  f or Pr ot oc ol  
 
S p o ns or na me:  
N o v o N or dis k A/ S  
N C T n u m ber  
N C T 0 3 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
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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 | 
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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  

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03987451 
Sponsor trial ID: 
NN9931-4492 
Official title of study: 
Investigation of Efficacy and Safety of Semaglutide s.c. Once-
weekly Versus Placebo in Subjects With Non-alcoholic 
Steatohepatitis and Compensated Liver Cirrhosis 
Document date* 
17 June 2021 
*Document date refers to the date on which the document was most recently updated. 
Note: The date in the header of Page 2 is the date of compilation of the documents and not of an update to content. 


Link
List of contents
Statistical analysis plan......................................................................................................................
Date:
Novo Nordisk
Version:
Status:
Semaglutide s.c.
Trial ID: NN9931 4492
Clinical Trial Report
Appendix 16.1.9
11 October 2021
1.0
Final
16.1.9 Documentation of statistical methods
CONFIDENTIAL
Redacted statistical analysis plan 
Includes redaction of personal identifiable information only. 
. 


Statistical Analysis Plan 
 
Date: 
17 June 2021 Novo Nordisk 
Study ID: NN9931-4492 
Version: 
1.1 
UTN: U111-1224-4062 
Status: 
Final 
EudraCT No.: 2018-004484-31 
Page: 
1 of 22 
Statistical Analysis Plan
Investigation of efficacy and safety of semaglutide s.c. once-
weekly versus placebo in subjects with non-alcoholic 
steatohepatitis and compensated liver cirrhosis 
Substance: Semaglutide 
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CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
17 June 2021 Novo Nordisk 
Study ID: NN9931-4492 
Version: 
1.1 
UTN: U111-1224-4062 
Status: 
Final 
EudraCT No.: 2018-004484-31 
Page: 
2 of 22 
Table of contents 
Page 
Table of contents ............................................................................................................................................... 2 
Table of figures ................................................................................................................................................. 3 
Table of tables ................................................................................................................................................... 4 
Version History ................................................................................................................................................. 5 
1 Introduction ................................................................................................................................................. 6 
1.1 
Objectives, Endpoints, and Estimands ................................................................................................ 6 
1.1.1 
Objectives ............................................................................................................................ 6 
1.1.2 
Endpoints ............................................................................................................................. 6 
1.1.3 
Estimands ............................................................................................................................ 6 
1.2 
Study Design ....................................................................................................................................... 6 
2 Statistical Hypotheses ................................................................................................................................. 8 
2.1 
Multiplicity Adjustment ...................................................................................................................... 8 
3 Analysis Sets ................................................................................................................................................ 9 
4 Statistical Analyses .................................................................................................................................... 10 
4.1 
General Considerations ..................................................................................................................... 10 
4.2 
Primary Endpoint/Estimand Analysis ............................................................................................... 10 
4.2.1 
Definition of Endpoint ....................................................................................................... 10 
4.2.2 
Main Analytical Approach ................................................................................................ 10 
4.2.3 
Sensitivity Analysis ........................................................................................................... 11 
4.2.4 
Supplementary Analyses ................................................................................................... 12 
4.3 
Secondary Endpoint Analysis ........................................................................................................... 12 
4.3.1 
Supportive Secondary Endpoints ....................................................................................... 12 
4.3.2 
Efficacy endpoints ............................................................................................................. 12 
4.3.2.1 
Histology ........................................................................................................ 12 
4.3.2.2 
Biomarkers of NASH disease ........................................................................ 14 
4.3.2.2.1 
Weight-related parameters ..................................................................... 16 
4.3.2.2.2 
Glucose metabolism related parameters ................................................ 16 
4.3.2.2.3 
Cardiovascular risk factors .................................................................... 17 
4.3.2.3 
Safety endpoints ............................................................................................. 17 
4.3.2.3.1 
Adverse events ....................................................................................... 17 
4.3.2.3.2 
Hypoglycaemic episodes ....................................................................... 17 
4.3.2.3.3 
Pulse ....................................................................................................... 18 
4.4 
Exploratory Endpoints/Estimand Analysis ....................................................................................... 18 
4.5 
Other Safety Analysis ....................................................................................................................... 18 
4.6 
Other Analyses .................................................................................................................................. 18 
4.6.1 
Other Variables and/or Parameters .................................................................................... 18 
4.6.2 
Subgroup Analyses ............................................................................................................ 18 
4.7 
Interim Analyses ............................................................................................................................... 18 
4.8 
Changes to Protocol-planned Analyses ............................................................................................. 18 
5 Sample size determination ........................................................................................................................ 19 
6 Supporting Documentation ...................................................................................................................... 20 
6.1 
Appendix 1: List of abbreviations ..................................................................................................... 20 
6.2 
Appendix 2: Definition and calculation of endpoints, assessments and derivations ........................ 21 
7 References .................................................................................................................................................. 22 
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Statistical Analysis Plan 
 
Date: 
17 June 2021 Novo Nordisk 
Study ID: NN9931-4492 
Version: 
1.1 
UTN: U111-1224-4062 
Status: 
Final 
EudraCT No.: 2018-004484-31 
Page: 
3 of 22 
 
Table of figures 
 
Page 
Figure 1 A schematic diagram of the trial design, with the duration of the trial periods including follow-
up period. ..................................................................................................................................... 7 
 
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Statistical Analysis Plan 
 
Date: 
17 June 2021 Novo Nordisk 
Study ID: NN9931-4492 
Version: 
1.1 
UTN: U111-1224-4062 
Status: 
Final 
EudraCT No.: 2018-004484-31 
Page: 
4 of 22 
 
Table of tables 
 
Page 
Table 1 
SAP version history summary ..................................................................................................... 5 
 
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Statistical Analysis Plan 
 
Date: 
17 June 2021 Novo Nordisk 
Study ID: NN9931-4492 
Version: 
1.1 
UTN: U111-1224-4062 
Status: 
Final 
EudraCT No.: 2018-004484-31 
Page: 
5 of 22 
 
 
Version History 
This Statistical Analysis Plan (SAP) for study NN9931-4492 is based on the protocol version 3.0 
dated 21-FEB-2020. 
Table 1 
SAP version history summary 
SAP Version 
Date 
Change 
Rationale 
1.0 
17-JUN-2019 
Not Applicable 
Original version 
2.0 
17-JUN-2021 
Clarification of primary analysis. 
Specification of secondary supportive analyses not 
described in protocol. 
Updated to reflect 
protocol amendment. 
 
 
 
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Statistical Analysis Plan 
 
Date: 
17 June 2021 Novo Nordisk 
Study ID: NN9931-4492 
Version: 
1.1 
UTN: U111-1224-4062 
Status: 
Final 
EudraCT No.: 2018-004484-31 
Page: 
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1 
Introduction 
This SAP elaborates on the statistical analyses described in the protocol section 10. Additional 
analyses for supportive secondary endpoints are specified, see section 4. 
1.1 
Objectives, Endpoints, and Estimands 
1.1.1 
Objectives 
Primary objective 
To investigate the effect of semaglutide s.c. 2.4 mg once-weekly on liver fibrosis compared with 
placebo in subjects with NASH and compensated fibrosis stage 4. 
Secondary efficacy objective  
To investigate the effect of semaglutide s.c. 2.4 mg once-weekly on NASH compared with placebo 
in subjects with NASH and compensated fibrosis stage 4. 
Secondary safety objective 
To evaluate the safety and tolerability of semaglutide s.c. 2.4 mg once-weekly compared with 
placebo in subjects with NASH and compensated fibrosis stage 4. 
1.1.2 
Endpoints 
Primary and secondary endpoints 
See protocol table 4-1. or 6.2 
1.1.3 
Estimands 
In subjects with NASH and compensated fibrosis stage 4, the estimand addressing the primary 
objective is the proportion of subjects with liver fibrosis improvement with no worsening of NASH 
compared between semaglutide s.c. 2.4 mg once-weekly and placebo at 48 weeks regardless of 
adherence to treatment. The treatment policy strategy is applied for the intercurrent event of 
premature discontinuation of randomised treatment. 
Results based on this estimand are expected to mirror the clinical practice scenario because the 
estimand considers both the efficacy and tolerability of subcutaneously administered semaglutide. 
1.2 
Study Design 
This is a 48 week, randomised, double-blind, placebo-controlled, two-armed, parallel group, multi-
centre, multi-national trial comparing once-weekly administration of 2.4 mg semaglutide s.c. with 
placebo in subjects with NASH and fibrosis stage 4. 
A total of 71 subjects were randomised in a 2:1 ratio. 
The trial has a 6-week screening period followed by a randomisation visit and a 48-week treatment 
period. The treatment period id divided into a dose escalation period of 16 weeks and a maintenance 
period of 32 weeks. The follow up period is 7 weeks. The total trial duration is approximately 61 
weeks (see Figure 1). For further trial detail see protocol section 5. 
 
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Statistical Analysis Plan 
 
Date: 
17 June 2021 Novo Nordisk 
Study ID: NN9931-4492 
Version: 
1.1 
UTN: U111-1224-4062 
Status: 
Final 
EudraCT No.: 2018-004484-31 
Page: 
7 of 22 
 
 
 
 
Figure 1 A schematic diagram of the trial design, with the duration of the trial periods 
including follow-up period.  
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Statistical Analysis Plan 
 
Date: 
17 June 2021 Novo Nordisk 
Study ID: NN9931-4492 
Version: 
1.1 
UTN: U111-1224-4062 
Status: 
Final 
EudraCT No.: 2018-004484-31 
Page: 
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2 
Statistical Hypotheses 
For the primary endpoint, at least one stage of liver fibrosis improvement with no worsening of 
NASH after 48 weeks, a confirmatory test comparing semaglutide 2.4 mg OW with placebo is 
planned. The comparison will test for superiority of semaglutide versus placebo using a one-sided 
significance level of 2.5% corresponding to a two-sided level of 5%. For remaining analyses, a two-
sided 5% significance level will be used. For more detail see section 4.2.2. 
2.1 
Multiplicity Adjustment 
Not applicable as only one confirmatory endpoint is stated. 
 
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Statistical Analysis Plan 
 
Date: 
17 June 2021 Novo Nordisk 
Study ID: NN9931-4492 
Version: 
1.1 
UTN: U111-1224-4062 
Status: 
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3 
Analysis Sets 
Population sets 
The following population analysis sets are defined in accordance with ICH-E9 guidance1 
Participant Analysis Set 
Description 
Full analysis set (FAS) 
Includes all randomised subjects. Subjects in the FAS will contribute to the 
evaluation “as randomised”. 
Safety analysis set (SAS) 
Includes all subjects receiving at least one dose of randomised treatment. Subjects 
in the SAS will contribute to the evaluation “as treated”. 
 
Observation periods 
Data will be evaluated based on different observation periods which will be derived individually for 
each subject. The following two observation periods are defined: 
• In-trial: This period starts on the date of the randomisation visit and ends on the first of the 
following dates (both inclusive): 
a) follow-up visit (end-of-trial visit) 
b) withdrawal of consent 
c) last contact with subject (for subjects lost to follow-up) 
d) death 
• On-treatment: For evaluation of adverse events (AEs), electrocardiogram (ECG) and 
hypoglycaemic episodes, this period starts on the date of first administration of trial product and 
ends on the date of whatever comes first of: a) last dose of trial product + 49 days (7 half-lives 
of semaglutide) or b) end of the in-trial period.  
For evaluation of MR scans and histology data the period ends at the date of the last dose of trial 
product +42 days. 
For evaluation of all other data, the period ends at the date of the last dose of trial product +7 
days.  
Data collected after the observation period in question will be excluded from any summary or 
analysis based on that observation period. 
 
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Statistical Analysis Plan 
 
Date: 
17 June 2021 Novo Nordisk 
Study ID: NN9931-4492 
Version: 
1.1 
UTN: U111-1224-4062 
Status: 
Final 
EudraCT No.: 2018-004484-31 
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4 
Statistical Analyses 
4.1 
General Considerations 
The statistical analyses will in general consist of the pairwise treatment comparison between: 
 
Semaglutide s.c. 2.4 mg OW versus Placebo 
The results of the comparisons will be presented as estimated treatment contrasts together with two-
sided 95% confidence intervals and p-values corresponding to two-sided alternative tests of the null 
hypothesis of no difference. In addition, for the primary analysis i.e. confirmatory test of 
superiority, the one-sided p-value will be reported additionally to the two-sided p-value, see section 
4.2.2 for details.  
The statistical analyses of the efficacy endpoints will primarily be based on the in-trial period. The 
on-treatment period is used for some supportive efficacy analyses and all statistical analyses of 
safety endpoints. Summary statistics will in general be presented for both observation periods at the 
end of treatment visit (visit 12/12A). 
The baseline measurement is defined as the latest available measurement at or prior to the 
randomisation visit. An exception is made for identifying abnormal laboratory findings (including 
ALT, AST, GGT, bilirubin and INR) in which case the baseline value is defined as the mean of the 
available measurements at the screening and randomisation visits. 
Laboratory values below the lower limit of quantification (LLOQ) will be set to ½LLOQ while 
values above upper limit of quantification (ULOQ) will be set to ULOQ. 
The stratification variable given by type 2 diabetes (T2D) status (yes/no) at baseline will be 
included in the models as a factor. 
When using body weight measurements, body weight will be used without consideration to fasting 
status.  
For continuous endpoints the change from baseline of the response will be given by either absolute 
change from baseline, logarithm of the ratio to baseline or percental change from baseline. 
4.2 
Primary Endpoint/Estimand Analysis 
4.2.1 
Definition of Endpoint 
The primary endpoint is the binary outcome defined as: At least one stage of liver fibrosis 
improvement with no worsening of NASH. Improvement in fibrosis is defined by a decrease from 
baseline to week 48 of at least one stage according to the Kleiner fibrosis classification. Worsening 
of NASH is defined as an increase of at least one stage of either lobular inflammation, hepatocyte 
ballooning or steatosis as defined by the NASH Clinical research network (CRN). 
4.2.2 
Main Analytical Approach 
 
The primary analysis will be based on the Cochran-Mantel-Haenszel (CMH) test. The common 
odds ratio between semaglutide and placebo adjusting for baseline diabetes will be estimated along 
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Statistical Analysis Plan 
 
Date: 
17 June 2021 Novo Nordisk 
Study ID: NN9931-4492 
Version: 
1.1 
UTN: U111-1224-4062 
Status: 
Final 
EudraCT No.: 2018-004484-31 
Page: 
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with exact 95% confidence interval based on conditioning on the marginal 2×2 tables. 
The exact one-sided p-value will be calculated for testing superiority as the sum of probabilities of 
outcomes being equal to or more in favour of semaglutide under the null hypothesis conditioning on 
the marginal 2×2 tables. 
The two-sided p-value will be calculated as the sum of probabilities of outcomes having equal or 
lower probability than the observed outcome. 
The primary analysis is based on FAS in-trial. Response data will consist of histological readings of 
the week 48 biopsies including biopsies taken after premature discontinuation of trial product. 
Missing or non-eligible data will be imputed as non-responders. 
4.2.3 
Sensitivity Analysis 
To investigate the sensitivity of the result of the primary analysis with regard to the handling of 
missing data, the following sensitivity analysis will be performed: 
An analysis where missing data will be handled by reference-based multiple imputation (MI) that is 
informed by data from placebo subjects. It is assumed that subjects in either treatment group 
without an observed outcome have the same chances of meeting the endpoint as subjects in the 
placebo group with an observed outcome. Subjects dying before week 48 visit will be handled as 
non-responders, i.e. these subjects will not be considered to have met the endpoint regardless of 
imputation. 
Technically, the analysis will be performed in the following steps: 
1. 500 replicates of the non-missing data in the placebo group are generated using a non-
parametric resampling scheme with replacement within the two strata given by diabetes 
status (with or without T2D). For each replicated data set and each stratum the responder 
proportion (i.e. probability of meeting the endpoint) is estimated by the observed sample 
proportion.  
2. The observed data including missing outcomes is replicated 500 times.  
For each replicate both treatment groups’ missing outcomes are imputed by independent 
draws from a Bernoulli distribution using the corresponding estimated responder proportion 
as parameter within strata. 
3. For each of the 500 complete data sets, the log common odds ratio adjusting for stratum is 
estimated using the Mantel-Haenszel estimator together with Robins, Breslow, and 
Greenland2 estimate of the standard error of the log common odds ratio. The estimated log 
common odds ratio and standard errors for the 500 complete data sets are then pooled using 
Rubin’s rule3: 
𝑚𝑀𝐼= 1
𝑁∑𝑚𝑖
𝑁
𝑖=1
,
𝑆𝐸𝑀𝐼= √1
𝑁∑𝑆𝐸𝑖
2
𝑁
𝑖=1
+ (1 + 1
𝑁) (
1
𝑁−1) ∑(𝑚𝑖−𝑚𝑀𝐼)2
𝑁
𝑖=1
, 
where mi and SEi are the estimated log odds ratios and corresponding standard errors for the 
N = 500 data sets, and mMI  and SEMI are the pooled estimates. From mMI and SEMI, the 95% 
confidence intervals for the odds ratios and associated p-values are calculated. 
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Statistical Analysis Plan 
 
Date: 
17 June 2021 Novo Nordisk 
Study ID: NN9931-4492 
Version: 
1.1 
UTN: U111-1224-4062 
Status: 
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EudraCT No.: 2018-004484-31 
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In step 3, zero counts in cells may not allow for calculation of the Mantel-Haenszel estimator, 
consequently all sample proportions will be equal to zero yielding with in-between variation of 
zero. In this case the above analysis will not be carried out. 
4.2.4 
Supplementary Analyses 
The following two supplementary analyses will be made for the primary endpoint 
1. A complete case on-treatment analysis: The same as the primary analysis but where subjects 
with missing week 48 data or for whom the data were collected after the on-treatment period 
are excluded from the analysis. 
2. An analysis excluding subjects whose primary endpoint is missing due to COVID-19. 
Subjects have been identifies through protocol deviations (PD) where it has been deemed 
that attainment of primary endpoint has not been possible primarily due to COVID-19. The 
analysis-excludes subjects N = 3, listed by unique subject id: 
NN9931-4492/
, NN9931-4492/
, NN9931-4492/
. 
4.3 
Secondary Endpoint Analysis 
Not applicable 
 
4.3.1 
Supportive Secondary Endpoints 
4.3.2 
Efficacy endpoints 
4.3.2.1 
Histology 
Histology scores 
Analyses will be performed for the change from baseline in the following histological features, all 
of which are ordinal scores except hepatic collagen which is a proportion: 
• Fibrosis stage according the Kleiner fibrosis classification: (0-4) 
• Hepatocyte ballooning, CRN score: (0-2) 
• Lobular inflammation CRN score: (0-3) 
• Steatosis CRN score: (0-3) 
• Total CRN NAS: (0-8) 
• Activity component of SAF: (0-4) 
• Ishak fibrosis score: (0-7) 
• Hepatic collagen, proportionate area: (0-100).  
The activity component of the SAF score is defined as the unweighted sum of hepatocyte 
ballooning and lobular inflammation. The definition of the lobular inflammation score is modified 
in this calculation so that the scores 2 and 3 on the original scale are merged to a score of 2. The 
possible range of the sum is thus 0 to 4. For all scores, a higher value indicates a more severe state 
of disease.  
 
Ordinal histological feature scores (i.e. excluding hepatic collagen) will be analysed by ordered 
logistic regression (also known as proportional odds model) with the histological scores at week 48 
as response, treatment, baseline diabetes status as factor; and baseline body weight and 
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Statistical Analysis Plan 
 
Date: 
17 June 2021 Novo Nordisk 
Study ID: NN9931-4492 
Version: 
1.1 
UTN: U111-1224-4062 
Status: 
Final 
EudraCT No.: 2018-004484-31 
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corresponding histological score at baseline as covariate. 
The results will be presented as the estimated cumulative odds ratio between semaglutide and 
placebo. The analyses will be based on FAS in-trial population and missing week 48 data will be 
imputed as no change from baseline in agreement with the analyses of the binary histological 
endpoints. 
Change in hepatic collagen from baseline to week 48 will be analysed using ANCOVA and 
MMRM. See section 4.3.2.2 for description of ANCOVA and MMRM analyses. 
Histology, derived binary endpoints 
The binary endpoint based on histology NASH resolution after 48 weeks (yes/no) defined by NASH 
CRN value of hepatocyte ballooning of 0 and lobular inflammation score 0-1 will be analysed as the 
primary endpoint (see section 4.2.2) including the complete case on-treatment supplementary 
analyses as for the primary endpoint and the multiple imputation sensitivity analysis (see section 
4.2.3). 
The composite binary endpoint based on histology defined by NASH Resolution and improvement 
in fibrosis will be analysed following the same approach as for the primary analysis. 
Further, binary histological endpoints defined as improvement in histological score from baseline to 
week 48 (Yes/No) will be derived and analysed. Improvement is defined as at least one stage 
decrease from baseline to week 48 in corresponding histological score:  
• Improvement in Fibrosis stage according the Kleiner fibrosis classification (Yes/No) 
• Improvement in Hepatocyte ballooning, CRN score (Yes/No) 
• Improvement in Lobular inflammation CRN score (Yes/No) 
• Improvement in Steatosis CRN score (Yes/No) 
• Improvement in Total CRN NAS (Yes/No) 
• Improvement in Activity component of SAF (Yes/No) 
• Improvement in Ishak fibrosis score (Yes/No) 
The derived binary endpoints will be analysed using a CMH test following the same approach as for 
the primary analysis (see section 4.2.2). 
 
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Statistical Analysis Plan 
 
Date: 
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Version: 
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4.3.2.2 
Biomarkers of NASH disease 
Analyses will be performed for the change from baseline to week 48 in the following biomarkers 
for NASH disease: 
• Algorithms 
o Fibrosis-4 (Fib-4) score. 
o NAFLD Fibrosis Score (NFS) 
• Blood samples 
o Portal hypertension  
▪ Thrombocytes 
o Liver enzymes  
▪ Alanine aminotransferase (ALT) 
▪ Aspartate aminotransferase (AST) 
▪ Gamma glutamyl transferase (GGT) 
o Liver synthesis function 
▪ Albumin  
▪ International normalized ratio (INR) 
▪ Total Bilirubin 
▪ Direct Bilirubin 
o Exploratory biomarkers 
▪ Adiponectin 
▪ Released N-Terminal Pro-Peptide C3 (Pro-C3) 
▪ Enhanced liver fibrosis (ELF), including subcomponents: 
• Tissue inhibitor of metalloproteinase 1 (TIMP1) 
• Hyaluronic acid (HA)  
• Procollagen III Amino Terminal Peptidecollagen (PIIINP) 
• Imaging 
o Liver stiffness (MRE) (kPa) 
o Liver fat content, steatosis (MRI-PDFF) (%) 
o Liver fat volume (MRI) (L) 
o Total liver volume (MRI) (L) 
 
All above parameters except NFS and ELF will be logarithmically transformed in the statistical 
analysis. The estimated treatment differences will subsequently be back-transformed to the original 
scale as the estimated treatment ratios. 
 Fib-4 score will be derived according to the formula4:  
Fib-4 =
Age (years) × AST (U/L)
Thrombocyte count (109/L) × √ALT (U/L)
 
The derivation will be performed at each visit where ALT, AST and thrombocyte count have been 
assessed. If any of the three laboratory parameters is missing at a specific visit, the Fib-4 score will 
be considered missing as well. 
The NAFLD Fibrosis Score will be derived according to the linear regression formula5: 
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Statistical Analysis Plan 
 
Date: 
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Study ID: NN9931-4492 
Version: 
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UTN: U111-1224-4062 
Status: 
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NFS = −1.675 + 0.037 × Age (years) + 0.094 × BMI (kg/m2)
+ 1.13 × Hyperglycaemia (yes/no) + 0.99 × AST/ALT
−0.013 × Thrombocyte count (109/L) −0.66 × Albumin (g/dL) 
Hyperglycaemia (yes/no) is a binary variable defined as 1 if FPG ≥ 6.1 mmol/L (110 mg/dL) at the 
corresponding visit of assessment or the subject has been diagnosed with T2D at screening; 
otherwise, the variable is defined as 0. NFS will be derived at each visit where body weight, FPG, 
ALT, AST, thrombocyte count and albumin have been assessed. If any of the elements are missing, 
NFS will be considered missing as well. 
The ELF discriminant score will be derived as a log-linear combination of the markers hyaluronic 
acid (HA), amino-terminal propeptide of type III collagen (PIIINP) and tissue inhibitor of 
metalloproteinase 1 (TIMP1). The derivation will be performed at the central laboratory according 
to the instructions of the equipment manufacturer. 
The main analysis of each of the biomarkers will based on FAS in-trial using analysis of covariance 
(ANCOVA) with missing outcomes handled by unconditional reference-based imputation.  
 
This will be done following the steps: 
1. An ANCOVA model with baseline diabetes status as factor and baseline body weight and 
baseline value of the corresponding biomarker as covariates is fitted to the change from 
baseline to week 48 for the placebo group only. 
2. Using the fitted model 500 sets of values of the model parameters (regression coefficients 
and residual variance) are drawn from the posterior distribution of the estimators. 
For each draw of parameter values, missing week 48 outcomes across treatment groups are 
imputed as predicted values from the linear combination of drawn model parameters and 
data. Subjects with missing covariates e.g. baseline measurement will not be included. 
3. For each of the 500 complete data set, the treatment effect on change from baseline to week 
48 is estimated using an ANCOVA model with treatment and baseline diabetes status as 
factors, and baseline body weight and baseline biomarker as covariates. 
4. The 500 estimated treatment differences and standard errors are pooled using Rubin’s rule. 
From the pooled estimates and standard errors the 95% confidence interval for treatment 
difference and associated two-sided p-value is calculated. 
A supportive analysis based on FAS on-treatment using a mixed model for repeated measurements 
(MMRM) will be performed for each of the biomarkers. In this model, all scheduled post-baseline 
measurements taken during the individual subject’s on-treatment period will enter as response; 
planned treatment and baseline diabetes status will be included as factors; and baseline body weight 
and baseline value of the corresponding biomarker will be included as covariates. All factors and 
covariates will be nested within visit and an unstructured covariance matrix for within subject 
residual errors will be employed. There will be no explicit imputation of missing values. As for the 
main analysis, the estimated treatment differences at week 48 with associated 95% confidence 
intervals and two-sided p-values will be presented. 
Whereas the main analysis attempts to estimate the de-facto treatment effect (in agreement with the 
chosen estimand for the primary objective), the supportive analysis aims to estimate the de-jure 
effect that would have been observed if all subjects had remained on treatment and completed all 
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Statistical Analysis Plan 
 
Date: 
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Study ID: NN9931-4492 
Version: 
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UTN: U111-1224-4062 
Status: 
Final 
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visits. The latter analysis relies on the assumption that data are missing at random, which means that 
given the observed data, the events that lead to data being missing are independent of the 
unobserved data. 
4.3.2.2.1 
Weight-related parameters 
The endpoints related to weight are defined as change from baseline to week 48 in: 
• Body weight (% and kg) 
• Waist circumference (cm) 
• Body mass index (BMI) 
These endpoints will be analysed separately based on FAS in-trial using the same type of 
ANCOVA with MI as for the biomarkers with treatment, baseline diabetes status and corresponding 
baseline value as a single covariate. Supportive FAS on-treatment analyses will be performed based 
on MMRM in the same way as for the biomarkers with factors and covariates specified as in the 
ANCOVA model. 
Weight-derived binary endpoints 
In addition to the continuous endpoints, the following binary endpoints related to weight will be 
analysed separately: 
• Weight loss of ≥ 5% of baseline body weight at 48 weeks (yes/no) 
• Weight loss of ≥ 10% of baseline body weight at 48 weeks (yes/no) 
The binary endpoints will be compared between treatment arms using an MI approach similar to the 
continuous endpoints but based on logistic regression: 
The 500 data sets with imputed values generated in the ANCOVA for percent change in body 
weight will be reused to derive an equal number of complete data sets for the binary outcomes. For 
each data set, the binary outcomes will be analysed using a logistic regression model which includes 
treatment, diabetes status as factors and baseline body weight as a covariate. The estimated log odds 
ratios and standard errors for the 500 complete data sets are then pooled using Rubin’s rule. From 
the pooled estimates and standard errors, the 95% confidence intervals for the odds ratios and 
associated p-values are calculated. 
4.3.2.2.2 
Glucose metabolism related parameters 
The secondary endpoints related to glucose metabolism are defined as change from baseline to 48 
weeks in: 
• Glycosylated haemoglobin A1c (HbA1c) 
• Fasting plasma glucose (FPG) 
• Fasting C-peptide 
Before analysis fasting C-peptide will be logarithmically transformed. The endpoints will be 
analysed using the same type of MMRM and ANCOVA with MI as for the biomarkers. Only 
subjects with type 2 diabetes at screening will be included consequently diabetes statues will not be 
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Statistical Analysis Plan 
 
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included as a factor in the models. The model will include treatment as factor; and baseline 
bodyweight and corresponding baseline value as  covariates. 
4.3.2.2.3 
Cardiovascular risk factors 
The secondary endpoints related to cardiovascular risk factors are defined as change from baseline 
to 48 weeks in:  
• Systolic and diastolic blood pressure 
• Lipids (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein 
cholesterol, very low-density lipoprotein cholesterol, triglycerides, free fatty acids) 
• High-sensitivity C-reactive protein (hsCRP) 
These endpoints will be analysed separately using the same type of MMRM and ANCOVA with MI 
as for the biomarkers The lipids and hsCRP will be logarithmically transformed before analysis. 
The model will include treatment and diabetes status as factors; and baseline body weight and 
corresponding baseline value covariates. 
 
4.3.2.3 
Safety endpoints 
Specifications of safety tables, figures and listings (TFL) and other specifications not included in 
this SAP will be described in the mock TFL. 
The following secondary endpoints are used to support the safety objectives.  
• Number of treatment-emergent adverse events during the trial 
• Number of treatment-emergent hypoglycaemic episodes during the trial 
• Change from baseline to 48 weeks in pulse 
 
4.3.2.3.1 
Adverse events 
AEs will be coded using version 24.0 of the Medical Dictionary for regulatory Activities 
(MedDRA) coding. A treatment emergent adverse event (TEAE) is defined as an event that has 
onset date during the on-treatment period (see section 3).  
AE data will be displayed in terms of the number of subjects with at least one event, the percentage 
of subjects with at least one event, the number of events and the event rate per 100 patient years of 
exposure. The main AE summaries will only contain TEAEs. Non-treatment emergent AEs will be 
included in listings and overview summaries. 
Additional summaries will be made for select AEs based on predefined MedDRA searches. A list of 
MedDRA search terms will be specified and documented before database lock. 
4.3.2.3.2 
Hypoglycaemic episodes 
For subjects with type 2 diabetes at randomisation, the severe or BG confirmed symptomatic 
hypoglycaemic episodes will be analysed as a binary outcome using Fisher's exact test for the 
comparison between semaglutide and placebo. The results will be presented as estimated odds ratio 
with two-sided p-value.  
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Statistical Analysis Plan 
 
Date: 
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Study ID: NN9931-4492 
Version: 
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UTN: U111-1224-4062 
Status: 
Final 
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For details on the classification of hypoglycaemia, see protocol section 9.2.10. 
4.3.2.3.3 
Pulse 
Pulse will be summarised by descriptive statistics and analysed using the same type of MMRM as 
for the on-treatment analyses of the biomarkers with actual treatment, baseline diabetes status as 
factors; baseline bodyweight and baseline pulse as covariates. 
4.4 
Exploratory Endpoints/Estimand Analysis 
Exploratory analysis to evaluate the performance of the biomarkers as predictors of NASH, fibrosis 
and/or NAS components are not included since they do not concern the trail objectives. 
4.5 
Other Safety Analysis 
Not applicable 
4.6 
Other Analyses 
4.6.1 
Other Variables and/or Parameters 
Not applicable 
4.6.2 
Subgroup Analyses 
Not applicable 
4.7 
Interim Analyses 
No interim analyses or other analyses of unblinded data will be performed before the database lock. 
4.8 
Changes to Protocol-planned Analyses 
Estimand 
The estimand stated in the protocol is updated in the SAP (see section 1.1.3) to align with the 
specified primary analysis approach in the protocol. 
 
Primary endpoint 
An  additional analysis of the primary endpoint has been added that excludes subjects from primary 
analysis if endpoint is missing mainly due to COVID-19 (see section 4.2.4) 
Supportive secondary endpoints 
Addition of new binary endpoints given as improvement in the different histological ordinal 
outcomes that are analysed separately using the method of primary endpoint (see section 4.3.2.1). 
 
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Statistical Analysis Plan 
 
Date: 
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5 
Sample size determination 
Refer to protocol section 10.1 for sample size considerations. 
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Statistical Analysis Plan 
 
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6 
Supporting Documentation 
6.1 
Appendix 1: List of abbreviations 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
BG 
blood glucose 
BMI 
body mass index 
CAP 
controlled attenuation parameter 
CK-18 
cytokeratin 18 
CMH 
Cochran-Mantel-Haenszel 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ELF 
enhanced liver fibrosis 
FAS 
full analysis set 
FGF-21 
fibroblast growth factor 21 
Fib-4 
fibrosis-4 score 
FPG 
fasting plasma glucose 
GGT 
gamma glutamyltransferase 
HbA1c 
glycosylated haemoglobin A1c 
HOMA-IR homeostatic model assessment - insulin resistance  
hsCRP 
high-sensitivity C-reactive protein 
ICH 
International Council on Harmonization 
IL-1R 
interleukin-1 receptor  
INR 
international normalized ratio  
LLOQ 
lower limit of quantification 
MCP-1 
monocyte chemoattractant protein 1 
MedDRA 
medical dictionary for regulatory activities 
MI 
multiple imputation 
miR-122 
microRNA 122 
MMRM 
mixed model for repeated measurements 
NAFLD 
non-alcoholic fatty liver disease 
NAS 
NAFLD activity score  
NASH 
non-alcoholic steatohepatitis 
NFS 
NAFLD fibrosis score  
SAP 
statistical analysis plan 
SAS 
safety analysis set 
s.c. 
subcutaneous 
T2D 
type 2 diabetes 
TEAE 
treatment emergent adverse event 
 
 
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Statistical Analysis Plan 
 
Date: 
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Study ID: NN9931-4492 
Version: 
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6.2 
Appendix 2: Definition and calculation of endpoints, assessments and derivations 
Refer to protocol section 4.2 Table 4-1. 
Endpoints analysed but not specified in protocol are: 
• Improvement in Fibrosis stage according the Kleiner fibrosis classification 
• Improvement in Hepatocyte ballooning, CRN score 
• Improvement in Lobular inflammation CRN score 
• Improvement in Steatosis CRN score 
• Improvement in Total CRN NAS 
• Improvement in Activity component of SAF 
• Improvement in Ishak fibrosis score 
• Resolution of NASH and improvement in fibrosis 
Where improvement is defined as at least one stage decrease from baseline to week 48. Resolution 
of NASH and improvement in fibrosis is as defined in section 4.3.2.1. 
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Statistical Analysis Plan 
 
Date: 
17 June 2021 Novo Nordisk 
Study ID: NN9931-4492 
Version: 
1.1 
UTN: U111-1224-4062 
Status: 
Final 
EudraCT No.: 2018-004484-31 
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7 
References 
1. 
ICH E9 Expert Working Group. Statistical principles for Clinical Trials: ICH Harmonised 
Tripartite Guideline. Statistics in Medicine. 1999. p. 1905-42. 
2. 
A A. Categorical Data Analysis. 2nd ed. New York ed: John Wiley & Sons; 2002. 
3. 
Little R, Rubin D. Statistical analysis with missing data. Sons. JW, editor. New York.: John 
Wiley & Sons. 1987. 
4. 
Sterling RK, Lissen E, Clumeck N, Sola R, Correa MC, Montaner J, et al. Development of a 
simple noninvasive index to predict significant fibrosis in patients with HIV/HCV 
coinfection. Hepatology. 2006;43(6):1317-25. 
5. 
Angulo P. Long-term mortality in nonalcoholic fatty liver disease: is liver histology of any 
prognostic significance? Hepatology. 2010;51(2):373-5. 
 
 
 
 
 
 
 
 
 
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