A Phase 3, Single-arm, Open-label, Multicentre Study to Assess the Efficacy and Safety of Deep Subcutaneous Injections of Lanreotide Autogel® 120 mg Administered Every 28 Days in Chinese Participants With Unresectable, Locally Advanced or Metastatic Grade 1 or 2 Gastroenteropancreatic Neuroendocrine Tumours (GEP-NETs)
Phase: PHASE3
Conditions: Gastroenteropancreatic Neuroendocrine Tumor
Sponsor: Ipsen



 
D -C N -5 2 0 3 0 -4 1 1  
 
C O N FI D E N TI A L  
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7  M A Y  2 0 2 1  
P A G E 1 /9 9  
 
I pse n Pr ot oc ol te m plat e Versi o n 7. 0 
 
Pr ot oc ol Title:   
A P h ase 3, si n gl e -ar m, o pe n -la bel, m ultice ntre st u d y t o assess t he efficac y a n d safet y of dee p 
s u bc uta ne o us i njecti o ns of la nre oti de A ut o gel ® 1 2 0 m g a d mi nistere d e v er y 2 8 da ys i n C hi nese 
partici pa nts 
wit h 
u nresecta ble, l ocall y 
a d v a nce d 
or 
metastatic 
Gra de 
1 
or 
2 
gastr oe nter o pa ncreati c n e ur oe n d ocri ne t u m o urs ( G E P -N E Ts)  
 
Pr ot oc ol N u m ber: D -C N -5 2 0 3 0 -4 1 1  
 
C o m p o u n d: la nre oti de A ut o gel®  [la nre oti de (IN N) acetate ] (I P N 5 2 0 3 0) 
 
Brief Title: A n o pe n -la b el p hase 3 st u d y t o assess t he efficac y a n d s afet y of la nre oti de A ut o gel®  
i n C hi nese partici pa nts wit h G E P-N E Ts  
 
St u d y P h as e: 3  
 
Acr o n y m : P A L A C E  
 
S p o ns or N a me: I pse n P h ar m a  
 
Le gal Re gistere d A d dress:  
6 5, Q u ai Ge or ges G orse  
9 2 1 0 0 B o ul o g ne Billa nc o urt, Fra n ce  
Tel: 
 
 
 
D ate: 1 7  M a y  2 0 2 1  
Versi o n n u m ber:  2. 0  
A me n d me nt n u m ber:  1  
 
 
 
 
 
Pers o ns s u p plie d wit h t his i nf or m ati o n m ust u n derst a n d t h at it is strictly c o nfi de nti al.  
I nf or m ati o n c o nt ai ne d herei n c a n n ot be discl os e d, s u b mitte d f or p u bli c ati o n or use d f or a ny 
a ut h oris ati o n.  

I P S E N G R O U P  
D -C N -5 2 0 3 0 -4 1 1  
 
C O N FI D E N TI A L  
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7  M A Y 2 0 2 1  
P A G E 2 /9 9  
 
 
 
S p o ns or Si g n at or y:  
 
 
 
 
 
 
 
D ate 
 
 
 
 
 
 
 
 
Me dic al M o nit or N a me a n d C o nt act I nf or m ati o n:  
 
I pse n ( S h a n g h ai) P h a r m a ce utic al Scie nce a n d De vel o p me nt C o m p a n y, Lt d. 
N o. 2 3 0 6 I nter n ati o n al C a pit al Pl az a  
N o. 1 3 1 8 N ort h Sic h u a n R o a d  
S h a n g h ai 2 0 0 0 8 0, C hi n a  
Tel: 
 

I P S E N G R O U P  
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 3/ 9 9 
 
 
 
Pri nci p al I n vesti g at or Si g n at ure P a ge 
 
I ha v e rea d a n d a gree t o Pr ot oc ol D- C N- 5 2 0 3 0- 4 1 1 
p has e 3, si n gle- ar m, o p e n-la b el, 
m ultice ntre st u d y t o assess t he efficac y a n d s afet y of dee p s u bc uta ne o us i njecti o ns of la nre oti de 
A ut o gel ®  1 2 0 m g a d mi nistere d e v er y 2 8 da ys i n C hi nese partici p a nts wit h u nresect a ble, l oc all y 
a d va nce d or 
met astatic 
Gra d e 1 or 2 gastr o e nter o pa n creatic ne ur oe n d ocri ne t u m o urs 
( G E P-
wit h A me n d me nt 1. I a m a ware of m y res p o nsi bilities as a n i n vesti gat or u n d er 
t he g ui deli nes of G o o d Cli nical Practice ( G C P), l ocal re g ul ati o ns (as a p plica ble) a n d t he st u d y 
pr ot oc ol. I a gree t o c o n d uct t he st u d y a cc or di n g t o t hese g ui deli nes a n d t o a p pr o priatel y direct 
a n d assist t he staff u n der m y c o ntr ol, w h o will be i n v ol ve d i n t he st u d y. 
 
N A M E:  
[ ] 
TI T L E: 
P RI N CI P A L 
SI G N A T U R E: 
 
I N V E S TI G A T O R 
 
D A T E: 
 
O F FI C E: 
[ ] 
 
[ ] 
 
[ ] 
 
[ ] 
 
[ ] 
 

I P S E N G R O U P  
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 4/ 9 9 
 
 
 
P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S 
 
D O C U M E N T HI S T O R Y 
D o c u me nt 
D ate 
A me n d me nt 1 
 Pr ot o c ol Versi o n 2. 0 
1 7 M a y 2 0 2 1 
Ori gi nal Pr ot o c ol Versi o n 1. 0 
0 2 Oct o ber 2 0 2 0 
 
A me n d me nt 1 ( Pr ot oc ol Versi o n 2. 0, 1 7 M a y 2 0 2 1) 
O ver all R ati o n ale f or t he A me n d me nt: T h e mai n reas o n f or t his pr ot o c ol a m e n d m e nt is t o 
a d dress c o m me nts fr o m Ce nter f or Dr u g E val uati o n ( C D E) a n d i ncl u d e clarificati o ns.  
 
S u m m ar y C h a n ge T a ble fr o m Pre vi o us Versi o n of t he Pr ot oc ol 
C ha n ges relate d t o t he sa m e t o pi c are prese nte d t o get h er w here p ossi ble. Ne w or a me n de d te xt 
i n t he pr ot oc ol is i n di cat e d i n b ol d. Del eti o ns are mar ke d i n stri ke o ut te xt. Mi n or f or matti n g 
a n d e diti n g are n ot i ncl u d e d. 

I P S E N G R O U P  
D- C N- 5 2 0 3 0- 4 1 1 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 1 8/ 9 9 
 

I P S E N G R O U P  
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 1 9/ 9 9 
 
 
 
T A B L E O F C O N T E N T S 
P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S ............................................... 4  
LI S T O F A B B R E VI A TI O N S ................................................................................................ 2 4  
LI S T O F D E FI NI TI O N S ....................................................................................................... 2 7  
1  
P R O T O C O L S U M M A R Y ........................................................................................... 2 8  
1. 1  
S y n o psis .......................................................................................................................... 2 8  
1. 2  
Sc he m a ........................................................................................................................... 3 3  
1. 3  
Sc he d ule of Acti vities ( S o A) ......................................................................................... 3 4  
1. 4  
Brief S u m m a r y .............................................................................................................. 3 8  
2  
I N T R O D U C TI O N ........................................................................................................ 3 9 
2. 1  
St u d y R ati o n ale ............................................................................................................. 3 9  
2. 2  
B ac k gr o u n d ................................................................................................................... 3 9  
2. 3  
Be nefit/ Ris k Assess me nt ............................................................................................... 4 0  
2. 3. 1  
Ris k Assess me nt .......................................................................................... 4 0  
2. 3. 2  
Be nefit Assess me nt ...................................................................................... 4 1  
2. 3. 3  
Over all Be n efit/ Ris k C o ncl usi o n ................................................................ 4 1  
3  
O B J E C TI V E S A N D E N D P OI N T S ............................................................................. 4 2  
4  
S T U D Y D E SI G N ........................................................................................................... 4 4  
4. 1  
O ver all Desi g n ............................................................................................................... 4 4  
4. 2  
Scie ntific R ati o n ale f or St u d y Desi g n .......................................................................... 4 5  
4. 3  
J ustific ati o n f or D ose .................................................................................................... 4 6  
4. 4  
E n d of St u d y Defi niti o n ................................................................................................ 4 6  
5  
S T U D Y P O P U L A TI O N ............................................................................................... 4 8  
5. 1  
I ncl usi o n Criteri a .......................................................................................................... 4 8 
5. 2  
E xcl usi o n Criteri a ......................................................................................................... 4 9  
5. 3  
Lifest yle C o nsi der ati o ns ............................................................................................... 5 0  
5. 4  
Scree n F ail ures .............................................................................................................. 5 0  
5. 5  
Criteri a 
f or 
T e m p or aril y 
Del a yi n g 
E nr ol me nt/ St u d y 
I nter ve nti o n 
A d mi nistr ati o n .............................................................................................................. 5 1  
6  
S T U D Y I N T E R V E N TI O N A N D C O N C O MI T A N T T H E R A P Y ............................ 5 2  
6. 1  
St u d y I nter v e nti o n A d mi nistere d ................................................................................ 5 2  
6. 2  
Pre p ar ati o n, H a n dli n g, St or a ge a n d Acc o u nt a bilit y ................................................. 5 3  
6. 3  
Me as ures t o Mi ni mize Bi as: R a n d o mis ati o n a n d Bli n di n g ....................................... 5 3  
6. 3. 1  
R a n d o mis ati o n ............................................................................................ 5 3  
6. 3. 2  
M ai nte n a nce of Bli n di n g ............................................................................ 5 3  
6. 4  
St u d y I nter v e nti o n C o m pli a nce ................................................................................... 5 4  
6. 4. 1  
M ai n I nterve nti o n Peri o d ........................................................................... 5 4  
6. 4. 2  
I n de pe n de nt I njecti o n Peri o d ..................................................................... 5 4 
6. 5  
D os e M o dific ati o n ......................................................................................................... 5 4  
6. 6  
C o nti n ue d Access t o l a n re oti de A ut o gel 1 2 0 m g after t he E n d of t he St u d y .......... 5 4  

I P S E N G R O U P  
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 2 0/ 9 9 
 
 
 
6. 7  
Tre at me nt of O ver d ose ................................................................................................. 5 4  
6. 8  
C o n c o mit a nt T her a p y ................................................................................................... 5 5  
6. 8. 1  
Pr o hi bite d C o nc o mit a nt Me dic ati o ns, T her a pies a n d Pr oce d ures ........... 5 5  
6. 8. 2  
Resc ue Me dic ati o n ...................................................................................... 5 5  
7  
DI S C O N TI N U A TI O N O F S T U D Y I N T E R V E N TI O N A N D P A R TI CI P A N T 
DI S C O N TI N U A TI O N/ WI T H D R A W A L ................................................................... 5 6  
7. 1  
Disc o nti n u ati o n of St u d y I nter ve nti o n ........................................................................ 5 6  
7. 1. 1  
Liver C he mistry St o p pi n g Criteri a ............................................................. 5 6  
7. 1. 2  
Q Tc St o p pi n g Criteri a ................................................................................. 5 8  
7. 1. 3  
Criteri a f or Te m p or ary Disc o nti n u ati o n .................................................... 5 9  
7. 1. 4  
Rest art/ Rec h alle n ge .................................................................................... 5 9  
7. 1. 4. 1  
St u dy I nterve nti o n R est art or Rec h all e n ge after Liver St o p pi n g Crit eri a 
Met ............................................................................................................... 5 9  
7. 1. 4. 2  
St u dy I nterve nti o n Rest art of Rec h alle n ge aft er ot her Criteri a f or 
Te m p or ary Disc o nti n u ati o n Met .................................................................. 5 9  
7. 2  
P artici p a nt Dis c o nti n u ati o n/ Wit h dr a w al fr o m t he St u d y ........................................ 5 9  
7. 3  
L ost t o F oll o w- u p .......................................................................................................... 6 0  
8  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S ....................................................... 6 1  
8. 1  
Effic ac y Assess me nts .................................................................................................... 6 2  
8. 1. 1  
T u m o ur Assess m e nt .................................................................................... 6 2  
8. 1. 2  
Cli nic al Pr o gressi o n .................................................................................... 6 3  
8. 1. 3  
Ne ur oe n d ocri ne T u m o ur Cli nic al Sy m pt o ms ............................................ 6 3  
8. 1. 4  
Circ ul ati n g Bi o m ar kers .............................................................................. 6 3  
8. 1. 5  
Q u ality of Life ............................................................................................. 6 3  
8. 1. 6  
S urviv al St at us ............................................................................................. 6 3  
8. 1. 7  
He alt hc are Pr ofessi o n al vers us I n de pe n de nt i njecti o n ............................. 6 4  
8. 2  
S afet y Assess me nts ........................................................................................................ 6 4  
8. 2. 1  
P hysic al E x a mi n ati o ns ............................................................................... 6 4  
8. 2. 2  
Vit al Si g ns ................................................................................................... 6 4  
8. 2. 3  
G all bl a d der Ec h o gr a p h y ............................................................................. 6 4  
8. 2. 4  
Electr oc ar di o gr a ms ..................................................................................... 6 5  
8. 2. 5  
Cli nic al S af ety L a b or at ory Assess m e nts .................................................... 6 5  
8. 2. 6  
Pre g n a ncy Testi n g ....................................................................................... 6 5  
8. 3  
A d verse E ve nts ( A Es) a n d Seri o us A d verse E ve nts ( S A Es), a n d Ot her S afet y 
Re p orti n g ....................................................................................................................... 6 6  
8. 3. 1  
Ti m e Peri o d a n d Fre q ue ncy f or C ollecti n g A E a n d S A E I nf or m ati o n .... 6 6  
8. 3. 2  
Met h o d of Detecti n g A Es a n d S A Es ........................................................... 6 6  
8. 3. 3  
Rec or di n g a n d Re p orti n g A Es a n d S A Es................................................... 6 6  
8. 3. 4  
F oll o w- u p of A Es a n d S A Es ....................................................................... 6 6  
8. 3. 5  
Re g ul at ory Re p orti n g Re q uire m e nts f or S A Es .......................................... 6 6  
8. 3. 6  
Pre g n a ncy .................................................................................................... 6 7  

I P S E N G R O U P  
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 2 1/ 9 9 
 
 
 
8. 3. 7  
Dise ase- Rel at e d 
Eve nts 
a n d/ or 
Dis e as e- R el at e d 
O ut c o m es 
N ot 
Q u alifyi n g as A Es or S A Es ......................................................................... 6 7  
8. 3. 8  
A dverse Eve nts of S peci al I nter est ............................................................. 6 8  
8. 3. 9  
Re p orti n g of St u dy I nter ve nti o n Err ors i ncl u di n g Mis use/ A b use ............ 6 8  
8. 4  
P h ar m a c o ki n etics .......................................................................................................... 6 8  
8. 5  
Ge neti cs a n d/ or P h ar m ac o ge n o mics ........................................................................... 6 8  
8. 6  
Bi o m ar kers .................................................................................................................... 6 8  
8. 7  
I m m u n o ge nicit y Ass ess me nts ...................................................................................... 6 9 
8. 8  
He alt h Ec o n o mics or Me dic al Res o urce Utilis ati o n a n d H e alt h Ec o n o mics ........... 6 9  
9  
S T A TI S TI C A L C O N SI D E R A TI O N S ........................................................................ 7 0  
9. 1  
St atistic al H y p ot heses ................................................................................................... 7 0  
9. 2  
S a m ple Size Deter mi n ati o n .......................................................................................... 7 0  
9. 3  
A n al ysis Sets .................................................................................................................. 7 0  
9. 4  
St atistic al A n al yses ....................................................................................................... 7 1  
9. 4. 1  
Ge ner al C o nsi der ati o ns .............................................................................. 7 1  
9. 4. 1. 1  
A n alysis Sets ................................................................................................. 7 1  
9. 4. 1. 2  
P artici p a nt All oc ati o n a n d R e as o ns f or E xcl usi o n fr o m t he A n al yses ........ 7 1  
9. 4. 1. 3  
A dj ust me nt of M ulti plicity ............................................................................ 7 1  
9. 4. 1. 4  
Si g nific a nce T esti n g a n d Esti m ati o ns .......................................................... 7 1  
9. 4. 1. 5  
St atistic al/ A n alytic al Met h o ds ..................................................................... 7 2  
9. 4. 2  
A n alysis of Pri m ary E n d p oi nt .................................................................... 7 2  
9. 4. 3  
A n alysis of Sec o n d ary Effic acy E n d p oi nts ................................................ 7 2  
9. 4. 4  
A n alysis of E x pl or at ory Effic acy E n d p oi nts .............................................. 7 3  
9. 4. 5  
S afety A n alyses ............................................................................................ 7 3  
9. 4. 6  
S u b gr o u ps A n alyse(s) ................................................................................. 7 4  
9. 5  
I nteri m A n al yses ........................................................................................................... 7 4 
1 0  
S U P P O R TI N G 
D O C U M E N T A TI O N 
A N D 
O P E R A TI O N A L 
C O N SI D E R A TI O N S .................................................................................................... 7 5  
1 0. 1  A p pe n di x 1: Re g ul at or y, Et hic al, a n d St u d y O versi g ht C o nsi der ati o ns ................. 7 5  
1 0. 1. 1  
Re g ul at ory a n d Et hic al C o nsi der ati o ns ..................................................... 7 5  
1 0. 1. 2  
Fi n a nci al Discl os ure ................................................................................... 7 5  
1 0. 1. 3  
I nf or m e d C o nse nt Pr ocess .......................................................................... 7 5 
1 0. 1. 4  
D at a Pr otecti o n ........................................................................................... 7 6  
1 0. 1. 5  
C o m mittees Str uct ure .................................................................................. 7 6  
1 0. 1. 6  
Disse mi n ati o n of Cli nic al St u dy D at a ........................................................ 7 6  
1 0. 1. 7  
D at a Q u alit y Ass ur a nce .............................................................................. 7 7  
1 0. 1. 8  
S o urce D oc u m e nts ...................................................................................... 7 7  
1 0. 1. 9  
St u d y a n d Sit e St art a n d Cl os ure ................................................................ 7 8  
1 0. 1. 9. 1  
First Act of R ecr uit me nt ............................................................................... 7 8  
1 0. 1. 9. 2  
St u dy/ Site Ter mi n ati o n ................................................................................. 7 8  
1 0. 1. 1 0  
P u blic ati o n P olicy ....................................................................................... 7 8  

I P S E N G R O U P  
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 2 2/ 9 9 
 
 
 
1 0. 2  A p pe n di x 2: Cli nic al L a b or at or y S afet y Tests ........................................................... 8 0  
1 0. 3  A p pe n di x 3: 
A Es a n d S A Es: 
Defi niti o ns a n d Pr oce d ures f or 
Rec or di n g, 
E v al u ati n g, F oll o w- u p, a n d Re p orti n g ........................................................................ 8 1  
1 0. 3. 1  
Defi niti o n of A E .......................................................................................... 8 1  
1 0. 3. 2  
Defi niti o n of S A E ........................................................................................ 8 2  
1 0. 3. 3  
Rec or di n g a n d F oll o w- U p of A E a n d/ or S A E ........................................... 8 3  
1 0. 3. 4  
Re p orti n g of S A Es ....................................................................................... 8 4  
1 0. 4  A p pe n di x 4: C o ntr ace pti ve a n d B arri er G ui d a nce ................................................... 8 5  
1 0. 4. 1  
Defi niti o ns ................................................................................................... 8 5  
1 0. 4. 2  
C o ntr ace pti o n G ui d a nce ............................................................................. 8 6  
1 0. 5  A p pe n di x 5: Li ver S afet y: S u g geste d Acti o ns, F oll o w- u p Assess me nts a n d St u d y 
I nter ve nti o n Rec h alle n ge G ui deli nes .......................................................................... 8 7 
1 0. 5. 1  
St o p pi n g Criteri a a n d F oll o w- u p Assess m e nts .......................................... 8 7  
1 0. 5. 2  
Criteri a f or I ncre ase d M o nit ori n g wit h O n g oi n g St u dy I nter ve nti o n ...... 8 9  
1 0. 6  A p pe n di x 6: 
W or k Pr o d ucti vit y a n d Acti vit y/ Ge ner al H e alt h Q u alit y of Life 
Q uesti o n n aires ............................................................................................................... 9 0  
1 0. 7  A p pe n di x 7: I m p act of Tre at me nt A d mi nistr ati o n Setti n g o n C osts ....................... 9 4  
1 0. 8  A p pe n di x 8: T h e I m p act of S witc h i n A d mi nistr ati o n Setti n g o n O ver all A bilit y 
t o W or k .......................................................................................................................... 9 6 
1 0. 9  A p pe n di x 9: E aster n C o o per ati ve O nc ol o g y Gr o u p ( E C O G) Perf or m a nce St at us
 ........................................................................................................................................ 9 7 
1 1  
R E F E R E N C E S .............................................................................................................. 9 8  
 

I P S E N G R O U P  
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 2 3/ 9 9 
 
 
 
LI S T O F T A B L E S 
T a ble 1  
Sc he d ule of Acti vities .......................................................................................... 3 4  
T a ble 2  
O bjecti ves a n d E n d p oi nts ................................................................................... 4 2  
T a ble 3  
St u d y I nter v e nti o n A d mi nistere d d uri n g t he St u d y ........................................ 5 2  
T a ble 4  
Q Tc St u d y I nter ve nti o n Disc o nti n u ati o n Criteri a f or P artici p a nts wit h 
U n derl yi n g B u n dle Br a nc h Bl oc k ...................................................................... 5 8  
T a ble 5  
A n al ysis Set Defi niti o ns ....................................................................................... 7 0  
T a ble 6  
Ce ns ori n g R ules f or P F S a n d T T P E n d p oi nts .................................................. 7 2  
T a ble 7  
Pr ot oc ol- Re q uire d Cli nic al S afet y L a b or at or y Tests ....................................... 8 0  
T a ble 8  
Li ver C he mistr y St o p pi n g Criteri a a n d F oll o w- u p Assess me nts .................... 8 7  
T a ble 9  
Li ver C he mist r y I ncre ase d 
M o nit ori n g Criteri a wit h C o nti n ue d St u d y 
I nter ve nti o n .......................................................................................................... 8 9 
T a ble 1 0  E aster n C o o per ati ve O nc ol o g y Gr o u p ( E C O G) Perf or m a n ce St at us ............ 9 7  
 
LI S T O F FI G U R E S 
Fi g ure 1  
St u d y Sc he m a ....................................................................................................... 3 3  
Fi g ure 2  
Li ver C he mistr y St o p pi n g Criteri a a n d I ncre as e d M o nit ori n g Al g orit h m ... 5 7  
Fi g ure 3  
Li ver C he mistr y I ncre ase d M o nit o ri n g Al g o rit h m wit h C o nti n ue d St u d y 
 ........ 5 8 
 

I P S E N G R O U P  
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 2 4/ 9 9 
 
 
 
LI S T O F A B B R E VI A TI O N S 
A B B R E VI A TI O N 
W or di n g Defi niti o n   
A E 
A d verse e ve nt 
A L T 
Ala ni ne tra nsa mi nase 
A S T 
As p artate tra nsa mi nase 
BI C R 
Bli n de d i n de pe n d e nt ce ntral re vie w 
E C G 
Electr ocar di o gra m 
C B R 
Cli nical be nefit rate 
C g A 
C hr o m o gra ni n A 
CI 
C o nfi de nce i nter v al 
CI O M S 
C o u ncil f or I nter nati o nal Or ga nisati o ns of M e dic al Scie nces 
C O N S O R T 
C o ns oli date d Sta n dar ds of Re p orti n g Trials 
C R F 
Case re p ort f or m 
C S R 
Cli nical st u d y re p ort 
C T 
C o m p ute d t o m o gra p h y 
D C R 
Disease c o ntr ol rate 
DI LI 
Dr u g-i n d uce d li ver i nj ur y 
D 
Da y 
D N A 
De o x yri b o n ucleic aci d 
D R E 
Disease relate d e v e nt 
E C O G 
Easter n C o o perati ve O nc ol o g y Gr o u p 
E C G 
Electr ocar di o gra m 
E C L A 
Electr o C he mi L u mi nesce nt Assa y  
E E A 
E ur o pea n E c o n o mic Area 
E M A 
E ur o pea n Me dici nes A ge nc y 
E N E T S 
E ur o pea n Ne ur oe n d ocri n e T u m or S ociet y 
E O R T C Q L Q- C 3 0 
E ur o pea n Or ga nisati o n f or Researc h a n d Treat me nt of Ca ncer 
Q ualit y of Life Q uesti o n naire f or C a ncer Patie nts  
E O SI 
E n d of st u d y i nter v e nti o n 
F A S 
F ull a nal ysis set 
F D G- P E T  
Fl u or o de o x y gl uc ose- p ositr o n e missi o n t o m o gra p h y  
F S H 
F ollicle sti m ulati n g h or m o n e 
G C P 
G o o d cli nical pra cti ce 
G E P- N E C 
Gastr oe nter o p a ncreatic n e ur oe n d ocri ne carci n o ma 

I P S E N G R O U P  
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 2 5/ 9 9 
 
 
 
A B B R E VI A TI O N 
W or di n g Defi niti o n   
G E P- N E N 
Gastr oe nter o p a ncreatic n e ur oe n d ocri ne ne o plas m 
G E P- N E T 
Gastr oe nter o p a ncreatic n e ur oe n d ocri ne t u m o urs 
G H 
Gr o wt h h or m o ne 
GI- N E Ts 
Ne ur oe n d o cri ne t u m o urs ori gi nati n g i n t he gastr oi ntesti nal tract 
h C G 
H u ma n c h ori o nic g o na d otr o p hi n 
H C P 
Healt hcare pr ofessi o nal 
5- HI A A 
5- h y dr o x yi n d ol eacetic a ci d 
H R T 
H or m o ne re place m e nt t hera p y 
I C F 
I nf or me d c o ns e nt f or m 
I C H 
I nter nati o nal C o u ncil o n Har m o nisati o n 
I E C 
I n d e pe n de nt et hics c o m mittee 
I M P 
I n v esti gati o nal me dici nal pr o d uct 
I R B 
I nstit uti o nal re vie w b o ar d 
I T T 
I nte nti o n-t o-treat 
I V R S/I W R S 
I nteracti ve v oice/ we b res p o nse s yste m 
L A R 
L o n g-acti n g rel eas e 
Me d D R A 
Me dical Dicti o nar y f or Re g ul at or y Acti vities 
mI T T 
M o difie d i nt e nti o n-t o-tre at 
M RI 
Ma g n etic res o n a nce i ma gi n g 
m T O R 
Ma m malia n tar get of ra p a m yci n 
M T K 
M ulti-tar get t yr osi ne ki n ase 
N CI C T C A E 
Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteria f or 
A d verse E v e nts 
N C T 
I d e ntificati o n n u m b er f or Cli nical Trials. g o v 
N E T 
Ne ur oe n d o cri ne t u m o ur 
O R R 
O verall res p o nse rate 
O S 
O verall s ur vi val 
P a n- N E Ts 
Ne ur oe n d o cri ne t u m o urs ori gi nati n g i n t h e pa n creas 
P F S 
Pr o gressi o n free s ur vi val 
P P S 
Per- pr ot oc ol set 
P R 
Pr ol o n ge d releas e 
P R R T 
Pe pti de rece pt or ra di o n u cle oti de t hera p y 
P S U R 
Peri o dic safet y u p dat e re p ort 

I P S E N G R O U P  
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 2 6/ 9 9 
 
 
 
A B B R E VI A TI O N 
W or di n g Defi niti o n   
Q o L 
Q ualit y of life 
Q Tc B 
 
Q Tc F 
 
Q T L 
Q ualit y t olera nce li mit 
R E CI S T 
Res p o nse E val uati o n Criteria i n S oli d T u m o urs 
S A E 
Seri o us a d verse e ve nt 
S A P 
Statistical a nal ysis pla n 
S A S ®  
Statistical A nal ysis S yste m ®  
S o A 
Sc he d ule of acti vities 
S S T Rs 
S o mat ostati n rece pt ors 
S U S A R 
S us pecte d u ne x pecte d seri o us a d vers e reacti o n 
T A C E 
Tra nscat h eter arteri al c he m oe m b olis ati o n 
T A E 
Tra nscat h eter arteri al e m b olisati o n 
T E A E 
Treat me nt e mer ge nt a d v ers e e ve nt 
T T P 
Ti me t o pr o gressi o n 
U L N 
U p per li mit of n or mal 
U S( A) 
U nite d States ( of A merica) 
W 
Wee k 
W H O 
W orl d Healt h Or ga nisati o n 
W O C B P 
W o ma n of c hil d beari n g p ote ntial 
W P AI: G H 
W or k Pr o d ucti vit y a n d Acti vit y I m pair me nt Q u esti o n naire: 
Ge neral Healt h 
 

I P S E N G R O U P  
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 2 7/ 9 9 
 
 
 
LI S T O F D E FI NI TI O N S 
T E R M 
Defi niti o n  
Cli nic al be nefit r ate 
( C B R) 
T he pr o p orti o n of partici pa nts wit h a best o verall res p o ns e of 
c o nfir me d C R , c o nfir me d P R or c o nti n ue d S D u ntil t he ti me of 
assess me nt 
Dise ase c o ntr ol r ate 
( D C R) 
T he pr o p orti o n of partici pa nts wit h a best o verall res p o ns e of 
c o nfir me d C R, c o nfir me d P R or S D 
M ai n i nter ve nti o n 
peri o d 
Partici pa nts will rec ei ve dee p s u bc uta ne o us i njecti o n of la nre oti de 
A ut o gel 1 2 0 
m g e ver y 2 8 da ys (i.e. 4 
wee ks; a t otal of 
1 2 i njecti o ns). Visits f or st u d y assess me nts will be perf or me d o ne 
scree ni n g visit, 1 3 visits o ne, e ver y 4 wee ks ( Da y 1, W 4 t o W 4 8); 
wit h e n d of st u d y assess me nts at W 4 8 ( E O SI).  
I n de pe n de nt 
i njecti o n 
peri o d/c o h ort 
O nl y f or i n de pe n d e nt i njecti o n peri o d: partici pa nts will recei v e 
dee p s u bc uta n e o us i njecti o n of la nre oti de A ut o gel 1 2 0 m g e v er y 
2 8 da ys b y i n de pe n de nt (self/ part ner) i nj ecti o n. F or t his peri o d 
t here will b e u p t o si x a d diti o nal visits fr o m W 5 2 t o W 6 8 a n d W 7 2 
( E O SI) 
P ost-i nter ve nti o n 
s ur vi v al f oll o w- u p 
F oll o w u p of t he p arti ci pa nts s ur vi val stat us (ali ve or n ot) wit hi n 4 
wee ks after t he last partici pa nt e nr olle d i n t he mai n s t u d y reac h es 
W 4 8 or u ntil t he da y of disc o nti n uati o n. 
I n t he i n de pe n d e nt i njecti o n peri o d: f oll o w u p o n partici pa nts 
s ur vi val stat us (ali ve or n ot) wit hi n 4 wee ks u ntil t h e last 
partici pa nt e nr olle d i n t his c o h ort reac h es W 7 2 or u ntil t he da y of 
disc o nti n uati o n.  
 

I P S E N G R O U P  
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 3 0/ 9 9 
 
 
 
O ver all Desi g n: 
T his is a pr os pecti ve, m ultice ntre, si n gl e-ar m, n o nra n d o mise d, o pe n-l a bel, i nter v e nti o nal, 
p hase 3 st u d y i n C hi nese a d ult p artici pa nts wit h u nresecta ble, well differe ntiate d l ocall y 
a d va nce d or 
met astatic G E P- N E Ts ( gastric, pa ncreas, 
mi d g ut, hi n d g ut), Gra de 1 or 2, 
n o nf u ncti o ni n g a n d f u ncti o ni n g. 
T he mai n st u d y will i ncl u de a scree ni n g peri o d of u p t o 4 wee ks f oll o we d b y a 4 8- w ee k 
i nter ve nti o n peri o d. 
D uri n g t he i nter ve nti o n p eri o d, 4 3 partici pa nts 
will recei ve dee p 
s u bc uta ne o us i nj ecti o n of la nre oti de A ut o gel 1 2 0 m g e ver y 2 8 d a ys (i.e. 4 wee ks; a t otal of 
1 2 i nj ecti o ns). T he mai n st u d y will i ncl u de 1 4 visits ( o ne scree ni n g visit, 1 3 visits, o ne e ver y 
4 wee ks ( Da y 1, W 4 t o W 4 8 ( E O SI)) d uri n g t he 4 8- wee k i nter ve nti o n peri o d.  
After c o m pleti o n of t he mai n st u d y peri o d, a p pr o xi m atel y fi ve parti ci pa nts (ass u mi n g 1 0 t o 
2 5 % eli gi ble partici p a nts after 4 8 wee ks of i nt er ve nti o n) will c o nti n ue i n a n i n de pe n de nt 
i njecti o n peri o d wit h l a nre oti de A ut o gel 1 2 0 m g e ver y 2 8 da ys f or 2 4 w ee ks (a t ot al of si x 
i n de pe n de nt i njecti o ns). T o be eli gi ble, t he p artici pa nt m ust pr o vi de a d diti o nal i nf or m e d 
c o nse nt t o c o nti n ue, h a v e a p ositi ve b e nefit/ris k rati o of c o nti n ui n g st u d y i nt er ve nti o n ( n o 
disease pr o gressi o n at W 4 8 a n d g o o d t olera bilit y d uri n g t he mai n st u d y peri o d) a n d be a s uita ble 
ca n di date f or i n de pe n de nt i nj ecti o n (c o nsi dere d a ble t o i n de pe n d e ntl y a d mi nister la nre oti de 
f oll o wi n g trai ni n g a n d li kel y t o b e n efit fr o m i n de pe n de nt a d mi nistrati o n e. g. re d u ci n g t h e 
b ur de n of fre q u e nt h os pital visits), i n t he o pi ni o n of t he i n vesti gat or. F or t he i n de pe n de nt 
i njecti o n peri o d t here will be u p t o si x a d diti o nal visits ( W 5 2 t o W 6 8 ( o pti o nal) a n d W 7 2 
( E O SI)). Visits f or st u d y assess me nts will be p erf or me d at W 4 8, W 5 2 ( o pti o nal) a n d W 5 6 
( o pti o nal); wit h e n d of st u d y i nter v e nti o n assess me nts at W 7 2. At t he 
W 4 8 visit, t he first 
i njecti o n will be perf or me d b y t he partici pa nt or t heir part n er at t he st u d y sit e ( u n der me di cal 
s u per visi o n) f or trai ni n g p ur p oses. At W 5 2 a n d W 5 6, t he sec o n d a n d t hir d i njecti o ns ma y als o 
be perf or m e d at t he st u d y site f or trai ni n g p ur p os es or ma y be p erf or me d at h o me if n o f urt her 
trai ni n g is nee d e d, i n t he o pi ni o n of t he i n vesti gat or. At W 6 0, W 6 4 a n d W 6 8, t he f o urt h, fift h 
a n d si xt h i nj ecti o ns will be perf or m e d at h o me or at t he st u d y site. Partici p a nts will be c o ntacte d 
b y t ele p h o ne at W 5 2, W 5 6, W 6 0, W 6 4 a n d W 6 8 (if n o st u d y sit e visit is perf or me d) f or s afet y 
p ur p oses. 
T he pri mar y efficac y e n d p oi nt is cli nical b e nefit rate ( C B R) of t u m o ur res p o nse assess e d usi n g 
Res p o nse E val uati o n Criteria i n S oli d T u m o urs ( R E CI S T) V ersi o n 1. 1 a n d c o nfir me d b y 
bli n de d i n de pe n de nt ce ntral re vie w ( BI C R) aft er 2 4 wee ks of st u d y i nt er ve nti o n. S ec o n dar y 
efficac y e n d p oi nts will b e assess e d d uri n g t h e i nt er ve nti o n peri o d, i ncl u di n g pr o gressi o n free 
s ur vi val ( P F S), o verall s ur vi val ( O S), ti me t o pr o gressi o n ( T T P), pr o p orti o n of p arti ci pa nts 
ali ve a n d wit h o ut pr o gressi ve t u m o ur, C B R after 4 8 wee ks of i nt er ve nti o n, o verall res p o nse 
rate ( O R R), diseas e c o ntr ol rate ( D C R), 
N E T-relat e d cli nical s y m pt o ms, circ ulati n g 
c hr o m o gra ni n A ( C g A), 5- h y dr o x yi n d oleacetic aci d ( 5- HI A A) a n d ot h er bi o mar kers a n d 
q ualit y of life ( Q o L). Safet y d ata i ncl u di n g a d verse e ve nts ( A Es), cli nical safet y l a b orat or y 
tests, electr ocar di o gra ms ( E C G), p h ysi cal e x a mi nati o n, vit al si g ns a n d gall bla d der ec h o gra p h y 
will als o be e val uate d. E x pl orat or y e n d p oi nts will be assesse d i n t he fi ve parti ci pa nts c o nti n ui n g 
i n t he i n de pe n d e nt i njecti o n peri o d ( pr o p orti o n of parti ci pa nts preferri n g i n de pe n de nt i njecti o n 
o ver H C P i njecti o ns, partici pa nt-re p orte d i n direct c osts a n d w or k pr o d ucti vit y, pl us t u m o ur 
res p o nse, N E T-rel ate d cli nical s y m pt o ms, Q o L, bi o mar kers a n d s afet y). 
T he p ost-i nt er ve nti o n s ur vi val f oll o w- u p will be perf or me d f or all partici pa nts ( n ot e nteri n g 
i n de pe n de nt i njecti o n peri o d) wit hi n 4 wee ks aft er t he last parti ci pa nt e nr olle d i n t he st u d y 
reac h es W 4 8 or u ntil t he da y of disc o nti n uati o n. W he n t he last partici pa nt W 4 8/ E O SI/ E D visit 
has occ urre d, all f urt her p ost-i nt er ve nti o n s ur vi val f oll o w- u p will st o p f or t hes e partici pa nts. 
T his p ost-i nt er ve nti o n s ur vi val f oll o w- u p will be perf or me d als o f or all partici pa nts i n t he 

I P S E N G R O U P  
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 3 1/ 9 9 
 
 
 
i n de pe n de nt i njecti o n peri o d wit hi n 4 wee ks after t he last p arti ci pa nt e nr olle d i n t he 
i n de pe n de nt i njecti o n st u d y reac hes W 7 2 or u ntil t he da y of disc o nti n uati o n. W he n t he last 
partici pa nt W 7 2/ E O SI/ E D visit has occ urre d, all f urt her p ost-i nter v e nti o n s ur vi val f oll o w- u p 
will st o p f or t hes e parti ci pa nts 
 
C o n diti o n/ Dise ase:  G E P- N E Ts 
 
St u d y H y p ot hesis:  
T he st u d y h y p ot hesis is t hat la nre oti de A ut o gel 1 2 0 m g is effic aci o us i n C hi nese partici pa nts 
wit h u nresecta ble, w ell differe nti at e d, l ocall y a d v a nce d or metastatic Gra d e 1 or 2 G E P- N E Ts 
at W 2 4. 
 
St u d y D ur ati o n: 
T he ma xi m u m d urati o n of t he st u d y is a p pr o xi m atel y 2 4 m o nt hs ( mai n st u d y: a p pr o xi m atel y 
1 8 m o nt hs). 
T he ma xi m u m d urati o n of t he st u d y per partici p a nt: 
 
Scree ni n g peri o d: u p t o 4 wee ks  
 
Mai n st u d y peri o d: 4 8 wee ks 
 
I n d e pe n de nt i njecti o n p eri o d f or i n d e pe n de nt i nje cti o n c o h ort o nl y: a d diti o nal 2 4 wee ks  
 
Visit Fre q ue nc y:  
 
Mai n st u d y: 1 4 visits ( o ne scree ni n g visit, 1 3 visits, o ne e ver y 4 w ee ks ( Da y 1, 
Wee k ( W) 4 t o W 4 8) d uri n g t he 4 8- wee k i nt er ve nti o n peri o d 
 
I n d e pe n de nt i njecti o n peri o d ( o nl y f or i n de pe n d e nt i nj ecti o n c o h ort): U p t o si x a d diti o nal 
o n-site visits ( W 5 2 t o W 6 8 ( o pti o n al), W 7 2).  
 
N u m ber of P artici p a nts: 
A p pr o xi matel y 5 1 partici pa nts will be e nr oll e d t o ac hie ve 4 3 recei vi n g  st u d y i nt er ve nti o n a n d 
3 6 partici pa nts e val ua ble f or C B R at W 2 4. A p pr o xi matel y fi ve p artici pa nts are e x pecte d t o be 
e nr olle d i n t he i n de pe n d e nt i njecti o n peri o d.  
N ote: " E nr oll e d" mea ns a partici p a nt's, or t heir 
t o parti ci pate i n a cli nic al st u d y f oll o wi n g c o m pl eti o n of t he i nf or m e d c o ns e nt pr ocess.  
 
I nter ve nti o n Gr o u ps a n d D ur ati o n: 
T he m ai n st u d y will i ncl u de a scree ni n g peri o d of u p t o 4 wee ks f oll o we d b y a fi xe d- d ose 
i nter ve nti o n peri o d of 4 8 wee ks wit h dee p s u bc ut a ne o us i njecti o ns of la nre oti de A ut o gel ®  
1 2 0 m g e v er y 2 8 da ys i n t he b utt oc ks ( 1 2 i njecti o ns i n t otal). I n a d diti o n, partici pa nts w h o ha d 
cli nical be nefit (c o m plete res p o ns e, parti al res p o nse or sta ble dis ease) at t he e n d of t h e 4 8- wee k 
i nter ve nti o n peri o d i n t he mai n st u d y will be i ncl u de d i n t he i n de pe n de nt i njecti o n peri o d at t he 
will be ma xi m u m 2 4 wee ks (t otal si x i nj ecti o ns). 
 

I P S E N G R O U P  
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 3 2/ 9 9 
 
 
 
D at a M o nit ori n g/ Ot her C o m mittee:  
N ot a p pli ca ble. T here will be n o o versi g ht c o m mitt ees i n t he st u d y. 
 
St atistic al Met h o ds: 
Sa m ple siz e calc ulati o n was base d o n t h e pri m ar y e n d p oi nt. T he e x pecte d C B R at W 2 4 was s et 
t o 6 4 % referri n g t o t he res ults of J a pa nese St u d y I T M- 0 1 4 N- 0 0 1 a n d gl o bal pi v otal 
St u d y 2- 5 5- 5 2 0 3 0- 7 2 6 ( C L A RI N E T; N C T 0 0 3 5 3 4 9 6). T he t hres h ol d C B R at W 2 4 was defi ne d 
as 4 0 % base d o n J a pa n ese st u d y I T M- 0 1 4 N-
statistical test was perf or me d f or a n ull h y p ot h esis wit h o ne si de d t y pe I err or of 2. 5 %, a 
mi ni m u m sa m pl e si ze re q uire d t o yiel d a p o wer of at least 8 0 % w o ul d be 3 6 partici pa nts. 
C o nsi deri n g 1 5 % dr o p- off rate, 4 3 p artici p a nts w o ul d be necessar y f or t h e pri m ar y effi cac y 
e val uati o n C B R at W 2 4. 
P oi nt esti m ates a n d e x act 9 5 % CIs base d o n t h e Cl o p per- Pears o n met h o d will be calc ulat e d f or 
a C B R at W 2 4, a n d ot her s ec o n dar y e n d p oi nts, if a p plica ble. 
Ti me- de pe n d e nt para m eters ( P F S, T T P a n d O S), Ka pla n- Mei er c ur ves a n d life ta bles will be 
ge n erat e d, a n d m e dia n wit h 9 5 % CIs will be calc ulate d. Ot her d ata will be a n al ys e d usi n g 
descri pti ve statisti cs a n d fre q ue n c y ta bles. 
 

I P S E N G R O U P  
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 3 3/ 9 9 
 
 
 
1. 2  
Sc he m a 
T he st u d y s c he ma is s h o w n i n Fi g ure 1 . 
Fi g ure 1 
St u d y Sc he m a 
                   M ai n St u d y 
 
Scree ni n g 
Peri o d 
 
Mai n I nter ve nti o n P eri o d 
(l a nre oti de A ut o gel 1 2 0 m g, d ee p s.c. Q 4 W, 1 2 i nj ecti o ns, 
4 8 wee ks) 
 
I n de pe n de nt I njecti o n Peri o d 
(l a nre oti de A ut o gel 1 2 0 m g, 
dee p s.c. Q 4 W, si x i njecti o ns, 
2 4 wee ks) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A b bre viati o ns: 
D = da y; 
E D =earl y 
dis c o nti n u ati o n; 
E O SI =e n d 
of 
st u d y i nter ve nti o n; 
Q 4 W =e ver y 
2 8 
d a ys; 
s.c. =s u b c uta ne o us(l y); w = wee k 
 
N ote: W 4 8/ E O SI =e n d of mai n st u d y (aft er 4 8 wee ks of i nter ve nti o n p eri o d) f or all partici p a nts; W 7 2/ E O SI =e n d of i n de pe n de nt 
i nj ecti o n p eri o d o nl y f or i n d e p e n de nt i njecti o n peri o d 
After fi nis hi n g t h e i nter ve nti o n i n t he mai n st u d y peri o d or t h e i n d e pe n de nt i njecti o n p eri o d, t h e i n vesti gat or will rec or d o verall 
s ur vi val stat us wit hi n 4 wee ks after t he l ast parti ci p a nt last visit i n eit h er p eri o d reac h es W 4 8 or W 7 2, res pecti vel y, or t h e da y 
of disc o nti n uati o n, irres p ecti ve of s u bse q ue nt t hera p y
A d mi nistrati o n  1         2         3        4         5          6         7         8        9        1 0        1 1       1 2        1 3       1 4       1 5        1 6      1 7      1 8         
Wee k            D 1         4 w      8 w      1 2 w    1 6 w     2 0 w    2 4 w    2 8 w   3 2 w     3 6 w    4 0 w     4 4 w   4 8 w     5 2 w    5 6 w     6 0 w    6 4 w    6 8 w   7 2 w 
 
 
Scree ni n g        Baseli ne                                     Pri mar y e n d p oi nt                                   W 4 8/ E O SI/ E D                       W 7 2/ E O SI/ E D  

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 3 8/ 9 9 
 
 
 
1. 4  
Brief S u m m a r y 
T he p ur p ose of t his st u d y is t o deter mi ne t he effic ac y a n d safet y of la nre oti de A ut o gel  1 2 0 m g 
a d mi nistere d b y dee p s u bc ut a ne o us i njecti o n i n C hi nese partici pa nts wit h u nresecta ble, well 
differe ntiat e d, l o call y a d va nce d or 
metastatic 
Gra d e 1 or 2 gastr oe nter o pa n creatic 
ne ur oe n d ocri ne t u m o urs ( G E P- N E Ts). St u d y details i ncl u de: 
St u d y d urati o n: A p pr o xi matel y 2 4 m o nt hs ( mai n st u d y: a p pr o xi matel y 1 8 m o nt hs) 
Treat me nt d urati o n: E ver y 2 8 da ys f or 4 8 wee ks ( mai n i nter ve nti o n peri o d) a n d a n a d diti o nal 
2 4 wee ks (i n de p e n de nt i njecti o n peri o d o nl y) 
Visit fre q ue nc y: E ver y 4 wee ks ( mai n i nter v e nti o n a n d i n de pe n de nt i njecti o n p eri o ds), f or a 
ma xi m u m of 4 8 wee ks ( mai n i nt er ve nti o n peri o d) a n d f or a n a d diti o nal 2 4 wee ks (i n de p e n de nt 
i njecti o n peri o d) 
H y p ot hesis: T h e st u d y h y p ot hesis is t hat l a nre oti de A ut o gel 1 2 0 m g is efficaci o us i n C hi nese 
partici pa nts wit h u nres ecta ble, well differe ntiate d, l ocall y a d v a nce d or met astatic Gra d e 1 or 2 
G E P- N E Ts at Wee k 2 4. 
Mai n o bser vati o n: T he pr o p orti o n of partici p a nts wit h a t u m o ur res p o nse o n i ma gi n g 
assess me nt acc or di n g t o t he Res p o nse E val uati o n Criteria i n S oli d T u m o urs ( R E CI S T) 
Versi o n 1. 1  

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 3 9/ 9 9 
 
 
 
2  
I N T R O D U C TI O N 
2. 1  
St u d y R ati o n ale 
T his bri d gi n g st u d y will be c o n d ucte d t o s u p p ort t h e re gistrati o n of t he la nre oti de A ut o gel 
1 2 0 m g f or m ulati o n i n C hi na f or t he treat me nt of G E P- N E Ts a n d treat m e nt of cli nical 
s y m pt o ms of N E Ts.  
Ne ur oe n d o cri ne t u m o urs are a heter o ge ne o us gr o u p of sl o w gr o wi n g ne o plas ms t hat arise fr o m 
diff use ne ur o e n d o cri ne cells. I n C hi na, t he i nci de n ce is ar o u n d 2. 0 3 per 1 0 0 0 0 0 pers o ns/ ye ar. 
S o mat ostati n a nal o g ues are t he tr eat m e nt of c h oice f or h or m o ne-rel at e d s y n dr o mes a n d 
la nre oti de is a well-esta blis he d pe pti de a nal o g ue of t he nat ural h or m o ne s o mat ostati n, i n w hic h 
t he bi oc he mical st a bilit y of t he pe pti de has b ee n i n creas e d b y i nc or p orati o n of m o difie d a mi n o 
aci ds. 
La nre oti de A ut o gel ®  f or m ulati o n ( 6 0, 9 0 a n d 1 2 0 m g) h as bee n a p pr o ve d i n m ore t ha n 
7 0 c o u ntries w orl d wi de f or t he treat me nt of acr o me gal y a n d f or t he treat me nt of s y m pt o ms of 
ne ur oe n d ocri ne t u m o urs ( N E Ts) si nce 2 0 0 1. I n a d diti o n, si nce 2 0 1 4, la nre oti de A ut o gel 1 2 0 m g 
has bee n a p pr o ve d f or c o ntr olli n g t u m o ur gr o wt h i n patie nts affecte d b y gastr oe nter o pa n creatic 
ne ur oe n d ocri ne t u m o urs ( G E P- N E Ts). I n Dece m ber 2 0 1 9, la nre oti de A ut o gel 6 0, 9 0 a n d 
1 2 0 m g w as a p pr o ve d i n C hi na f or t he treat me nt of a cr o me gal y. A pre vi o us l a nre oti de 
f or m ulati o n (l a nre oti de pr ol o n ge d rel eas e ( P R)) h as bee n re gist ere d i n C hi na (si nce 2 0 0 2) a n d 
m ore t ha n 1 5 ot her c o u ntries f or t he treat m e nt of cli nical s y m pt o ms of N E Ts a n d f or t he 
treat me nt of acr o me gal y.  
T he efficac y of la nre oti de 
A ut o gel 1 2 0 m g i n treati n g t he s y m pt o ms ass ociate d 
wit h 
- N E Ts has bee n de m o nstrate d i n St u d y 2- 5 5- 5 2 0 3 0- 7 3 0 ( E L E C T) a n d t he 
- N E Ts 
i n 
St u d y 2- 5 5- 5 2 0 3 0- 7 2 6 
( C L A RI N E T). Res ults fr o m St u d y I T M- 0 1 4 N- 0 0 1 a n d e xte nsi o n st u d y s u p p ort t he efficac y of 
la nre oti de A ut o gel i n Ja p a nese p artici pa nts wit h N E Ts. I n a d diti o n, p u blis he d literat ure 
[It o 2 0 1 7, Ka n g 2 0 1 9] s u g gests t hat Asia n p atie nts r es p o n d well t o S S A treat m e nt wit h n o 
s pecific safet y si g n als det ecte d, a n d t he res ults r e p orte d wit h la nre oti de A ut o gel 1 2 0 m g were 
c o nsiste nt wit h t h ose i n t he pi v otal St u d y 7 2 6. T he s p o ns or will c o n d uct a bri d gi n g st u d y i n 
partici pa nts wit h G E P- N E Ts f or f urt her c o nfir mati o n i n C hi na. S ci e ntifi c rati o nal of st u d y 
desi g n is pr o vi de d i n Secti o n 4. 2.  
La nre oti de A ut o gel is prese nte d as rea d y t o use, prefille d s yri n ges, wit h a rec o m me n d e d d ose 
of 1 2 0 m g a d mi nistere d e ver y 2 8 da ys f or t he treat me nt of G E P- N E Ts a n d treat m e nt of cli nical 
s y m pt o ms ass ociate d wit h N E Ts. I n t he c o u ntries w here la nre oti de A ut o gel is a p pr o v e d, t his 
prese ntati o n e na bles pati e nts or t heir care gi vers t o i n de pe n de ntl y a d mi nister la nre oti de A ut o gel 
i njecti o ns i n a place a n d at a ti m e of t heir c h o osi n g, after a p pr o priat e trai ni n g fr o m a healt hcare 
pr ofessi o nal ( H C P), rat her t ha n ha vi n g t o tra vel t o healt hcar e pr actiti o ners, wit h n o n ota bl e l oss 
of efficac y. T his c o ul d p ote ntiall y lea d t o a n i m pr o ve me
q ualit y of life ( Q o L) a n d be less of a b ur de n o n t he m fi na nci all y a n d o n t he healt h ser vice i n 
C hi na. T he d osi n g re gi me n of o n e d ee p s. c. i njecti o n e ver y 2 8 da ys is als o m ore c o n ve nie nt a n d 
ma y r es ult i n fe wer i njecti o n site reacti o ns c o m pare d t o t he e xisti n g la nre oti de f or m ulati o n 
(a d mi nistere d i. m. e v er y 1 0 or 1 4 da ys f or t h e treat me nt of cli nical s y m pt o ms of N E Ts 
ass oci ate d wit h carci n oi d t u m o urs).  
2. 2  
B ac k gr o u n d 
Ne ur oe n d o cri ne t u m o urs are a heter o ge ne o us gr o u p of sl o w gr o wi n g ne o plas ms t hat arise fr o m 
diff use ne ur o e n d ocri ne cells. T he maj orit y of N E Ts ori gi n at e i n t he gastr oi nt esti nal tract 
( GI- N E Ts) a n d i n t he pa ncreas ( pa n- N E Ts) a n d are t heref ore c ollecti vel y referre d t o as 
G E P- N E Ts. I n C hi na, t h e i nci de nce is ar o u n d 2. 0 3 per 1 0 0, 0 0 0/ year [ G u o 2 0 1 6 ].  

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 4 0/ 9 9 
 
 
 
T he ter m gastr o e nter o pa ncreatic n e ur o e n d ocri ne ne o plas ms ( G E P- N E Ns) e nc o m passes t w o 
mai n s u bt y pes; 
G E P- N E Ts 
w hic h ar e 
well- differe nti ate d a n d gastr oe nter o pa n creatic 
ne ur oe n d ocri ne carci n o mas ( G E P- N E Cs) w hic h are p o orl y differe ntiat e d. I n a h os pital- bas e d, 
nati o n wi de m ultice ntre 1 0- year ( 2 0 0 1 t o 2 0 1 0) retr os p ecti ve st u d y w hic h c ollecte d 2 0 1 0 
G E P-
f or G E P- N E Ns were t he pa ncreas ( 3 1. 5 %) a n d rect u m ( 2 9. 6 %), f oll o we d b y t he gastric b o d y 
( 1 5. 4 %) a n d gastric car dia ( 1 1. 6 %) of t he st o mac h. S mall i ntesti nal ( 5. 6 %) a n d c ol o nic ( 3. 0 %) 
N E Ns t o o k u p a relati vel y s mall pr o p orti o n of all patie nts [ Fa n 2 0 1 7 ].  
Base d o n t he a bilit y t o s ecrete bi oacti ve s u bsta nces, a n d w het her t hese s u bsta nces res ult i n a 
cli nical s y n dr o me (s y m pt o ms ass ociate d wit h h or m o nal h y p ersecreti o n of N E Ts) or n ot, 
G E P-
 
I nitial treat me nt c o nsists of s ur gical re m o val of t he t u m o ur ( w he n p ossi ble) a n d treat me nt of 
h or m o nal s y n dr o me ( w h e n pres e nt). O nce t he t u m o ur e nters i n a pr o gressi ve p hase, treat me nt 
us uall y i ncl u des h e pati c arter y e m b olisati o n, c he m ot hera p y, ra di ola b ell e d s o m at ost ati n 
a nal o g ues a n d/ or i nt erfer o n. T he r es p o nse rate of t hese treat me nts de pe n ds o n t u m o ur t y p e a n d 
are ofte n ass o ciate d wit h fre q ue nt a n d se v ere si de effects. I n t he E ur o p ea n Ne ur oe n d o cri ne 
T u m or S ociet y ( E N E T S) c o ns e ns us g ui deli nes [ E N E T S 2 0 2 0 ], S S A is rec o m m e n de d f or t he 
i n hi biti o n of t u m o ur gr o wt h i n b ot h i ntesti nal a n d pa n creatic N E T a n d t he treat m e nt of cli ni cal 
s y m pt o ms of N E Ts. 
Nat ural s o mat ost ati n i n hi bits t he s ecreti o n of a br oa d ra n ge of h or m o nes a n d acts b y bi n di n g t o 
me m bra ne b o u n d s o m at ostati n rece pt ors ( S S T Rs) (c o m prisi n g S S T Rs 1 t o 5) e x presse d o n m ost 
N E Ts. A p pr o xi matel y 8 0 t o 9 0 % of N E Ts e x press s o mat ostati n rece pt ors o n t heir cell s urface 
t hat bi n d wit h hi g h affi nit y t o la nre oti de. La nre oti de is a well-esta blis he d octa pe pti de a nal o g ue 
of t he nat ural h or m o ne s o mat ostati n i n w hi c h t he bi oc he mical sta bilit y of t he pe pti de has bee n 
i ncrease d b y i nc or p orati o n of m o difie d a mi n o aci ds. It bi n ds wit h hi g h er affi nit y t o S S R T 2 a n d 
S S T R 5 a n d o nce b o u n d, la nre oti de i n hi bits t he si g nal tra ns missi o n pat h wa ys me diate d b y 
s o mat ostati n rece pt ors, c a usi n g a re d u cti o n i n h or m o ne a n d bi o ge nic a mi n e secreti o n t hat ma y 
i m pr o ve t u m o ur relate d s y m pt o ms a n d sta bilise t u m o ur gr o wt h. [M o dli n 2 0 1 0 ].  
La nre oti de 
A ut o gel ( S o mat uli ne ®  
A ut o gel® ) f or m ulati o n is a d mi nistere d via a d ee p 
s u bc uta ne o us i nj ecti o n i nt o t he e xter nal q ua dra nt of t he b utt oc k b y a healt hcare pr ofessi o nal 
( H C P). Alter nati vel y, i n E ur o pe, a n d i n m ost ot her c o u ntries w here t he pr o d uct is re gist ere d, 
a n d i n t he case of i n de pe n de nt i nj ecti o n t h e s ol uti o n is a d mi nistere d b y dee p s u b c uta ne o us 
i njecti o n i nt o t he u p per o uter t hi g h. 
2. 3  
Be nefit/ Ris k Assess me nt 
M ore detaile d i nf or m ati o n a b o ut t he k n o w n a n d e x pecte d be nefits a n d ris ks a n d reas o n a bl y 
Br oc h ure. 
2. 3. 1  
Ris k Assess me nt 
T he s p o ns or belie ves t hat t he o verall ris k of differe nces i n t he safet y a n d effic ac y pr ofil e of 
la nre oti de A ut o gel d u e t o et h nicit y differe nces is l o w a n d race will li kel y n ot be a fact or 
si g nifica ntl y affecti n g e x p os ure a n d tr o u g h c o nce ntrati o n.  
I m p orta nt i de ntifi e d ris ks wit h la nre oti de i ncl u de gastr oi ntesti nal effects, c h ol elit hiasis, 
pa ncreatitis, effects o n gl yc ore g ulati o n, effects o n t h yr oi d f u ncti o n, bra d ycar dia, i nj ecti o n site 
reacti o ns a n d aller gic reacti o ns. Partici pa nts 
wit h c h olelit hiasis 
ma y re q uire peri o dic 
m o nit ori n g. 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 4 1/ 9 9 
 
 
 
I m p orta nt p ote ntial ris ks wit h la nre oti de i ncl u d e effects o n bi oa v aila bilit y of c o nc o mita nt 
me dicati o ns a n d he patic d ysf u ncti o n. 
F urt her i nf or mati o n o n t hese ris ks ca n b e f o u n d i n S ecti o n 6 (s u m m ar y of data a n d g ui da nce 
f or t he i n v esti gat or) of t h e I n v
be a p pr o priate m o nit ori n g of t he p artici pa nt, e x cl usi o n criteria a n d criteria f or te m p orar y a n d/ or 
per ma ne nt disc o nti n u ati o n of st u d y i nt er v e nti o n.  
T here are p ote ntial ris ks ass o ciate d wit h t u m o ur ass ess me nts. Partici pa nts w h o recei v e 
c o m p ute d t o m o gra p h y ( C T) sca ns will rec ei ve a n i ntra ve n o us i njecti o n of a n i o di ne- bas e d d ye 
(c o ntrast me dia) w hic h ma y ca us e all er gic reacti o ns. Ma g netic res o na nce i ma gi n g ( M RI) s ca ns 
are ge nerall y n ot a d vise d f or p artici pa nts wit h e pile ps y. I n vesti gat ors/site staff are re q uire d t o 
cr oss c h ec k t he p artici pa nt's m e dical hist or y pri or t o t he assess m e nt t o deter mi ne t heir 
s uita bilit y f or eit her pr oce d ure. 
2. 3. 2  Be nefit Assess me nt 
Cli nical st u di es a n d p u blis he d e x perie n ce s u p p ort t he efficac y of la nr e oti de. T he mai n p ote nti al 
be nefit f or partici pa nts is recei pt of treat me nt t hat has bee n de m o nstrate d t o pr ol o n g pr o gressi o n 
free s ur vi val ( P F S) a n d c o ntr ol t u m o ur gr o wt h. La nre oti de is als o ass oci at e d wit h a re d ucti o n 
of b ot hers o m e N E T-rel ate d s y m pt o ms (e. g. diarr h o ea a n d fl us hi n g) a n d i m pr o ve me nt i n q ualit y 
of life ( Q o L) (s ee Secti o n 4. 2 ).  
T he la nre oti de A ut o gel f or m ul ati o n offers f urt h er be nefits i n ter ms of c o n ve nie nce f or t he 
partici pa nt a n d H C P. T h e c urre ntl y a p pr o ve d la nre oti de P R f or m ulati o n is a d mi nist ere d b y 
i ntra m usc ular i njecti o n. La nre oti de A ut o gel f or m ulati o n will be a d mi nistere d b y a dee p 
s u bc uta ne o us i njecti o n, all o wi n g t h e p ote ntial f or i n de pe n de nt i njecti o n. As t his f or m ulati o n is 
ass oci ate d wit h a m ore s ust ai ne d releas e, t he fr e q ue nc y of i njecti o ns ca n b e decrease d t o e ver y 
2 8 da ys, c o m pare d t o e ver y 1 0 or 1 4 da ys wit h la nre oti de P R i ntra m usc ular i nj ecti o n a n d 
p ossi ble ass ociate d l oc al i njecti o n sit e reacti o ns c o ul d p ote ntiall y be re d u ce d. T his c o ul d res ult 
are n o ot her i n de p e n de ntl y a d mi nistere d t hera pi es a vail a ble i n C hi na i n dicate d t o treat patie nts 
wit h G E P- N E Ts, t he strai n o n t he healt h ser vice i n C hi na c o ul d als o be re d uce d. 
2. 3. 3  Over all Be nefit/ Ris k C o ncl usi o n 
Base d o n t he m ost rece nt peri o dic safet y u p date re p ort ( P S U R) f or la nre oti de ( dat a l o c k p oi nt 
Ma y 2 0 1 9), re vie w of t h e a vail a bl e safet y data ( pri maril y fr o m p ost mar k eti n g e x perie n ce b ut 
als o fr o m cli nical st u dies) has n ot c ha n ge d t he be n efit/ris k pr ofile of la nre oti de, w hic h re mai ns 
fa v o ura bl e w he n use d i n its a p pr o ve d i n dicati o ns a n d i n acc or da n ce wit h t h e a p pr o ve d 
prescri bi n g i nf or mati o n. I n a d diti o n, a c u m ulati ve re vie w of t he s p o nt a ne o us i n di vi d ual case 
safet y re p orts ori gi n ati n g fr o m C hi n a a n d Tai wa n c o m bi ne d ( usi n g t he sa m e data l oc k p oi nt as 
t he P S U R) has s h o w n t h at t he patt er n of a d vers e reacti o ns gr o u pe d b y M e dical Dicti o nar y f or 
Re g ulat or y Acti vities ( Me d D R A) s yst e m or ga n class is ge nerall y c o nsiste nt wit h t he re p orts 
fr o m t he rest of t he w orl d.  
Ta ki n g i nt o acc o u nt t he 
meas ures o utli ne d i n Secti o n 2. 3. 1  t o 
mi ni mis e ris k t o st u d y 
partici pa nts, t he p ote ntial ris ks i de ntifie d i n ass ociati o n wit h la nre oti de A ut o gel  are j ustifie d b y 
t he a ntici pate d be n efits t h at ma y b e aff or de d t o p artici pa nts wit h G E P- N E Ts. 
T he o verall be nefit/ris k pr ofile of la nre oti de A ut o gel t heref ore re mai ns fa v o ura ble wit h n o 
si g nal or i n dicati o n t hat C hi nese or Asia n pati e nts t ol erate t h e t hera p y a n y differe ntl y t o a n y 
Wester n or Ca ucasia n p o p ulati o ns.  

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 4 4/ 9 9 
 
 
 
4  
S T U D Y D E SI G N 
4. 1  
O ver all Desi g n 
T his is a pr os pecti ve, m ultice ntre, si n gl e-ar m, n o nra n d o mise d, o pe n-l a bel, i nter v e nti o nal, 
p hase 3 st u d y i n C hi nese a d ult p artici pa nts wit h u nresecta ble, well differe ntiate d l ocall y 
a d va nce d or 
met astatic G E P- N E Ts ( gastric, pa ncreas, mi d g ut, hi n d g ut), Gra de 1 or 2, 
n o nf u ncti o ni n g a n d f u ncti o ni n g. T he st u d y desi g n is ill ustrate d i n Fi g ure 1 . 
T he mai n st u d y will i ncl u de a s cree ni n g peri o d of u p t o 4 wee ks f oll o we d b y a 4 8- wee k 
i nter ve nti o n peri o d. 
D uri n g t he i nter ve nti o n p eri o d, 4 3 partici pa nts 
will recei ve dee p 
s u bc uta ne o us i njecti o n of la nre oti de A ut o gel 1 2 0 m g e ver y 2 8 d a ys (i.e. 4 wee ks; a t otal of 
1 2 i nj ecti o ns). T he mai n st u d y will i ncl u de 1 4 visits ( o ne scree ni n g visit, 1 3 visits, o ne e ver y 
4 wee ks ( Da y 1, W 4 t o W 4 8 ( E O SI)) d uri n g t he 4 8- wee k i nter ve nti o n peri o d.  
After c o m pleti o n of t he m ai n st u d y peri o d, a p pr o xi mat el y fi ve partici pa nts (ass u mi n g 1 0 t o 
2 5 % eli gi ble p artici pa nts after 4 8 wee ks of i nt er ve nti o n i n t he mai n st u d y) will e nter a n 
i n de pe n de nt i njecti o n peri o d wit h la nre oti de A ut o gel 1 2 0 m g e ver y 2 8 d a ys f or 2 4 wee ks (a 
t otal of si x i n de pe n de nt i njecti o ns). T o be eli gi bl e, t he partici pa nt m ust pr o vi de a d diti o nal 
i nf or me d c o nse nt t o c o nti n ue, ha ve a p ositi ve be nefit/ris k rati o of c o nti n ui n g st u d y i nter ve nti o n 
( n o dis ease pr o gressi o n at W 4 8 a n d g o o d t olera bilit y d uri n g t he m ai n st u d y p eri o d) a n d be a 
s uita ble ca n di date f or i n de pe n de nt i njecti o n (c o nsi dere d a ble t o i n de pe n de ntl y a d mi nister 
la nre oti de f oll o wi n g trai ni n g a n d li kel y t o be nefit fr o m i n de p e n d e nt a d mi nistrati o n 
e. g. re d uci n g t he b ur de n of fre q ue nt h os pit al visits) i n t he o pi ni o n of t he i n vesti gat or. F or t he 
i n de pe n de nt i nj ecti o n p eri o d t here will be u p t o si x a d diti o nal visits ( W 5 2 t o W 6 8 ( o pti o nal) 
a n d W 7 2 ( E O SI)). Visits f or st u d y ass ess me nts will be perf or me d at W 4 8, W 5 2 ( o pti o nal) a n d 
W 5 6 ( o pti o nal); wit h E O SI ass ess m e nts at W 7 2. At t he W 4 8 visit, t he first i njecti o n will be 
perf or me d i n de pe n d e ntl y at t he st u d y site ( u n d er m e dical s u per visi o n) f or trai ni n g p ur p oses. At 
W 5 2 a n d W 5 6, t he sec o n d a n d t hir d i njecti o ns ma y als o be p erf or me d at t he st u d y sit e f or 
trai ni n g p ur p os es or ma y be perf or me d at h o me if n o f urt her trai ni n g is n ee de d, i n t he o pi ni o n 
of t he i n vesti gat or. At 
W 6 0, 
W 6 4 a n d 
W 6 8, t he f o urt h, fift h a n d si xt h i njecti o ns will be 
perf or me d at h o me or at t he st u d y site. Partici pa nts will be c o ntacte d b y tele p h o n e at W 5 2, 
W 5 6, W 6 0, W 6 4 a n d W 6 8 (if n o st u d y sit e visit is perf or m e d) f or s afet y p ur p oses. 
T he pri mar y efficac y e n d p oi nt is cli nical b e nefit rate ( C B R) of t u m o ur res p o nse assess e d usi n g 
Res p o nse E val uati o n Criteria i n S oli d T u m o urs R E CI S T Versi o n 1. 1 [ Eise n ha uer 2 0 0 9 ] a n d 
c o nfir me d b y bli n de d i n d e pe n de nt ce ntral re vie w ( BI C R) after 2 4 wee ks of st u d y i nter ve nti o n. 
Sec o n dar y effic ac y e n d p oi nts will be ass esse d d uri n g t he i nter ve nti o n peri o d, i ncl u di n g P F S, 
o verall s ur vi v al ( O S), ti me t o pr o gressi o n ( T T P), pr o p orti o n of partici pa nts ali ve a n d wit h o ut 
pr o gressi ve t u m o ur, C B R after 4 8 w ee ks of i nter ve nti o n, o verall res p o nse rate ( O R R), disease 
c o ntr ol rate ( D C R), N E T-relate d cli nical s y m pt o ms, circ ulati n g c hr o m o gra ni n A ( C g A), 
5- h y dr o x yi n d ol eacetic aci d ( 5- HI A A) a n d ot her bi o mar kers a n d Q o L. Safet y data i n cl u di n g 
A Es, cli nical safet y la b orat or y tests, electr oc ar di o gr a ms ( E C G), p h ysical e x a mi nati o n, vital 
si g ns a n d gall bla d d er ec h o gra p h y will als o be e val uate d. E x pl orat or y e n d p oi nts will be assesse d 
i n t he fi ve partici pa nts c o nti n ui n g i n t he i n de p e n de nt i nj ecti o n peri o d ( pr o p orti o n of partici p a nts 
preferri n g i n de pe n de nt i njecti o n o ver H C P i njecti o ns, partici pa nt-re p ort e d i n direct c osts a n d 
w or k pr o d ucti vit y, pl us t u m o ur res p o ns e, N E T-rel ate d cli nical s y m pt o ms, Q o L, bi o mar k ers a n d 
safet y).  
T he ma xi m u m d urati o n of t he st u d y is a p pr o xi m atel y 2 4 m o nt hs ( mai n st u d y: a p pr o xi matel y 
1 8 m o nt hs). 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 4 5/ 9 9 
 
 
 
Ma xi m u m d urati o n of t he st u d y per partici pa nt: 
 
Scree ni n g peri o d: u p t o 4 wee ks  
 
Mai n st u d y peri o d: 4 8 wee ks 
 
I n d e pe n de nt i nj ecti o n peri o d f or t he i n de pe n de nt i njecti o n c o h ort o nl y: a d diti o nal 
2 4 wee ks  
After t he e n d of st u d y assess me nts, partici pa nts will e nter a re m ote p ost-i nter ve nti o n s ur vi val 
f oll o w- u p peri o d a n d a tel e p h o ne call will be us e d t o c ollect s ur vi v al stat us a n d s u bse q ue nt 
t hera pies. T his f oll o w- u p will be perf or me d f or all partici pa nts (irres pecti ve of w het h er t he y 
partici pat e i n t he i n de pe n de nt i njecti o n peri o d or n ot) wit hi n 4 wee ks after t he last partici pa nt 
e nr olle d i n t he st u d y reac hes W 4 8 or W 7 2 (f or i n de pe n de nt i njecti o n peri o d o nl y) or u ntil t he 
da y of disc o nti n uati o n. 
4. 2  
Scie ntific R ati o n ale f or St u d y Desi g n 
T he mai n effects of la nre oti de are re d uci n g s y m pt o ms of N E Ts a n d/ or t u m o ur sta bilisati o n: 
 
A gl o bal pi v ot al p has e 3, ra n d o mise d place b o- c o ntr olle d st u d y i n p arti ci pa nts wit h 
e nter o pa ncreatic 
e n d o cri ne 
t u m o urs 
( St u d y 
2- 5 5- 5 2 0 3 0- 7 2 6 
( C L A RI N E T; 
N C T 0 0 3 5 3 4 9 6)) de m o nstrate d t hat treat me nt wit h la nre oti de A ut o gel 1 2 0 m g e v er y 
2 8 da ys f or 9 6 wee ks re d uce d t he ris k of pr o gr essi o n or deat h b y 5 3 % ( h az ar d rati o = 0. 4 7, 
9 5 % c o nfi de n ce i nt er v al ( CI): 0. 3 0, 0. 7 3) [ Ca pli n 2 0 1 4 ]. 
 
A si n gle-ar m, o pe n-la b el p hase 2 st u d y i n J a pa nes e partici pa nts wit h u nresect a ble, 
metastatic or l ocall y a d va nce d 
N E Ts ( St u d y I T M- 0 1 4 N- 0 0 1) de m o nstrate d t hat 
la nre oti de A ut o gel 1 2 0 m g e v er y 2 8 da ys f or 1 2 m o nt hs was ass ociate d wit h a C B R 
( defi ne d as t he pr o p orti o n of parti ci pa nts wit h a c o m plet e res p o nse, partial res p o ns e or 
sta ble disease i n acc or da nce wit h R E CI S T Versi o n 1. 1) at 2 4 wee ks of 6 4. 3 % ( 9 5 % CI, 
4 4. 1- 8 1. 4) [ It o 2 0 1 7].  
 
A p hase 3, ra n d o mise d place b o-c o ntr olle d st u d y i n p artici pa nts wit h a hist or y of 
carci n oi d s y n dr o me ( St u d y 2- 5 5- 5 2 0 3 0- 7 3 0 ( E L E C T; N C T 0 0 7 7 4 9 3 0)) de m o nstrate d t h e 
efficac y of treat m e nt wit h la nre oti de A ut o gel 1 2 0 m g e ver y 2 8 da ys f or 1 6 wee ks i n 
c o ntr olli n g s y m pt o ms of N E Ts. T here was a statisticall y si g nifica nt differe nce i n t he 
n u m ber of da ys i n w hic h s u bc ut a ne o us o ctre oti de was use d as resc u e me dicati o n bet we e n 
t he la nre oti de a n d pl ace b o gr o u ps, re pres e nti n g a differe n ce of 1 4. 8 % ( 9 5 % CI: 2 6. 8, 
2. 8; p = 0. 0 1 7)
i n W 1 2 t o W 1 5) was si g nifi ca ntl y great er wit h la nre oti de t ha n place b o ( 2. 4; 9 5 % CI: 1. 1, 
5. 3; p = 0. 0 3 6) [ Vi ni k 2 0 1 6 ]. 
T he prese nt st u d y t o d e m o nstrate t he effic ac y a n d safet y of la nre oti de A ut o gel 1 2 0 m g i n 
C hi nese partici pa nts 
wit h 
N E Ts 
will be c o n d ucte d 
wit h a 
m ultice ntre, si n gle-ar m, 
n o nra n d o mise d, o pe n-la b el desi g n f or t he f oll o wi n g reas o ns: 
 
T his st u d y d esi g n is si milar t o St u d y I T M- 0 1 4 N- 0 0 1 i n J a pa nese partici pa nts [ It o 2 0 1 7] 
t o facilitat e t he c ollecti o n of bri d gi n g data. Disease e pi de mi ol o g y i n t he C hi nese 
p o p ulati o n is si milar t o t hat of t he J a pa nese p o p ulati o n a n d n o et h nic differe nces are 
e x pecte d i n C hi nese vers us J a pa nese partici pa nts. 
 
As N E Ts are a rare, a si n gle ar m st u d y all o ws c ollecti o n of as m uc h dat a as p ossi bl e o n 
a d mi nistrati o n of t he acti ve treat m e nt. 
 
Si nce N E Ts are a seri o us disease t hat c o ul d pr o gress wit h a hi g h m ortalit y rat e d e pe n di n g 
o n pri mar y l ocati o n a n d m et astases, t he us e of a si n gle ar m desi g n is c o nsi dere d et hical 
d ue t o tre at m e nt bei n g a vaila ble f or G E P- N E Ts i n C hi na. Place b o a d mi nistrati o n f or t he 
sa ke of partici pati o n i n t he st u d y is ass u me d t o be diffic ult. 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 4 6/ 9 9 
 
 
 
T he pri mar y e n d p oi nt is t o assess t he C B R at W 2 4: 
 
C B R is a c o nfir me d o bje cti ve effic ac y e n d p oi nt f or a ntit u m o ur effect o n t he basis of t he 
p har mac ol o gic al acti o ns of s o mat ostati n a nal o g ues a n d t he res ults of o v erseas cli ni cal 
st u dies.  
 
T he sa me pri m ar y e n d p oi nt was use d i n St u d y I T M- 0 1 4 N- 0 0 1 i n J a pa nese partici pa nts 
[It o 2 0 1 7]. As t he pri m ar y a ntit u m o ur effect of l a nre oti de A ut o gel is ass u m e d t o be 
sta bilisati o n of t u m o urs, C B R ( w hic h i ncl u des c o m plete res p o nse, parti al res p o nse or 
c o nti n ue d sta ble disease) was c o nsi dere d as a n i n dicat or w hic h e na bl es e val uati o n of 
partici pa nts c o nfir me d as ha vi n g persiste nt sta ble disease. Partiall y b eca use t his st u d y is 
a si n gle ar m-st u d y, C B R at W 2 4 has bee n select e d as t he pri mar y e n d p oi nt w hic h e na bles 
e x a mi nati o n of a ntit u m o ur effects. 
T he ke y sec o n dar y e n d p oi nts i n t his st u d y are t o assess efficac y a n d safet y i n partici pa nts wit h 
G E P N E Ts at W 4 8: 
 
Gra de 1 or 2 G E P- N E Ts acc or di n g t o 
W orl d Healt h Or ga nis ati o n ( W H O) 2 0 1 9 
classificati o n [ Na gte gaal 2 0 1 9 ] are us uall y sl o w- gr o wi n g t u m o urs ass ociate d wit h a 
relati vel y l o n g s ur vi val. T he para meter C B R will t heref or e be als o ass esse d at t he W 4 8 
ti me p oi nt. 
 
S y m pt o m e pis o des, P F S a n d c ha n ges i n circ ul ati n g bi o mar kers.  
 
Sta n dar d safet y p ara m eters w hi c h are ge nerall y rec o g nise d as relia ble, acc urate a n d 
rele va nt. 
T he sa m ple size j ustificati o n is pr o vi de d i n Secti o n 9. 1 .  
4. 3  
J ustific ati o n f or D ose 
I n a p hase 1 st u d y ( St u d y E- 2 8- 5 2 0 3 0- 7 1 7) i n vesti gati n g t he effect of race a n d et h ni cit y, a n 
o verla y of t he 9 0 % pre dicti o n i nter val of t h e p har mac o ki netic ti me c o urse of t he Ca ucasia n 
p o p ulati o n m o del wit h t he o bser ve d c o n ce ntrati o ns fr o m t he 1 1 a vail a ble Asia n partici pa nts 
was perf or m e d. M ost of t he ser u m la nre oti de c o n ce ntrati o ns i n t hese Asia n partici pa nts lai d 
wit hi n t he 9 0 % pre di cti o n i nter val. T heref ore, n o si g nific a nt effect of race o n t he 
p har mac o ki netics of l a nre oti de A ut o gel ®  was o bser ve d i n partici pa nts wit h G E P- N E Ts. 
O verall, n o si g nifi ca nt effect of race o n t he e x p os ure a n d C tr o u g h of la nre oti de is e x pecte d. T his 
is c o nsiste nt wit h w hat has bee n de m o nstr at e d f or la nre oti de A ut o gel i n partici pa nts wit h 
 
La nre oti de A ut o gel 1 2 0 m g was a d mi nistere d b y s u bc uta ne o us i njecti o n e ver y 2 8 da ys as a 
d o u ble- bli n d treat m e nt f or 9 6 wee ks i n St u d y 2- 5 5- 5 2 0 3 0- 7 2 6 ( C L A RI N E T) ( wit h c o nti n ui n g 
o pe n-la bel treat m e nt i n a n e xte nsi o n st u d y u p t o ~ 8 years), as a n o p e n-la bel tre at me nt f or 
1 2 m o nt hs i n St u d y I T M- 0 1 4 N- 0 0 1 a n d as a d o u bl e- bli n d treat me nt f or 1 6 
wee ks i n 
St u d y 2- 5 5- 5 2 0 3 0- 7 3 0 ( E L E C T) ( wit h f urt her o pe n la bel tre at me nt f or a n i nitial 3 2 wee ks a n d 
t he n i n a n e xt e nsi o n st u d y f or at least 2 years) (see Secti o n 4. 2 ). 
T he sa me d os e a n d d ose fre q ue nc y will t heref ore b e i n vesti gate d i n t his st u d y t o o btai n effic ac y 
a n d safet y bri d gi n g dat a i n C hi nese partici pa nts wit h G E P- N E Ts. 
4. 4  
E n d of St u d y Defi niti o n 
T he e n d of t he st u d y is d efi ne d as t he date of t he l ast visit of t he last parti ci pa nt i n t he st u d y.  
F or eac h i n di vi d ual partici pa nt, t heir partici pati o n i n t he mai n st u d y i nt er ve nti o n peri o d is 
c o nsi dere d t o be c o m pl ete d if t he y fi nis h 4 8 w ee ks of st u d y i nter ve nti o n. After fi nis hi n g t he 
i nter ve nti o n i n t he mai n st u d y peri o d, t he i n v esti gat or will rec or d o verall s ur vi val stat us wit hi n 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 4 7/ 9 9 
 
 
 
4 wee ks aft er t he last p artici pa nt last visit i n t h e mai n st u d y reac hes 
W 4 8 or t he da y of 
disc o nti n uati o n, irres pecti ve of s u bs e q ue nt t hera p y.  
A partici pa nt w h o c o nti n ues i nt o t he i n de pe n de nt i njecti o n peri o d will be c o nsi dere d t o ha v e 
c o m plete d t he st u d y if he/s he fi nis hes t he a d diti o nal 2 4 wee ks of st u d y i nt er ve nti o n i n t he 
i n de pe n de nt i njecti o n peri o d. 
After fi nis hi n g t he i nt er v e nti o n i n t his i n de pe n de nt i njecti o n peri o d, t he i n vesti gat or will rec or d 
o verall s ur vi val stat us wit hi n 4 wee ks after t he last parti ci pa nt last visit i n t he i n de pe n de nt 
i njecti o n peri o d rea c hes W 7 2 or t he da y of disc o nti n uati o n, irres pecti ve of s u bse q u e nt t hera p y. 
Criteria f or st u d y i nter ve nti o n disc o nti n uati o n a n d partici pa nt disc o nti n uati o n/ wit h dra wal fr o m 
t he st u d y are d escri be d i n Secti o n 7. 1  a n d Secti o n 7. 2 , res pecti vel y. L ost t o f oll o w- u p is 
descri be d i n Secti o n 7. 3 . 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 4 8/ 9 9 
 
 
 
5  
S T U D Y P O P U L A TI O N 
Pr os pecti ve a p pr o v al of pr ot oc ol de viati o ns t o recr uit m e nt a n d e nr ol me nt criteria, als o k n o w n 
as pr ot oc ol wai vers or e x e m pti o ns, is n ot per mitte d. 
5. 1  
I ncl usi o n Criteri a 
Partici pa nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if all of t he f oll o wi n g criteria a p pl y: 
( 1) 
Ca pa ble of gi vi n g si g ne d i nf or m e d c o nse nt as des cri be d i n A p pe n di x 1 0. 1. 3  w hic h 
i ncl u des c o m plia nce wit h t he re q uire me nts a n d restricti o ns liste d i n t he i nf or me d c o nse nt 
f or m (I C F) a n d i n t his pr ot oc ol. 
( 2) 
Male or fe m ale of 1 8 years of a ge or ol der w h e n i nf or me d c o ns e nt is o bt ai ne d. 
( 3) 
Has a hist ol o gicall y pr o ve n Gra de 1 or 2 G E P- N E T acc or di n g t o W H O classificati o n 
[Na gte gaal 2 0 1 9 ]. 
( 4) 
Has a n u nresect a ble ( or if t he partici pa nt ref us es s ur ger y) metastatic or l oc all y a d va n ce d 
N E T. 
( 5) 
Has a meas ura ble t u m o ur acc or di n g t o R E CI S T V ersi o n 1. 1. 
( 6) 
Has a n o nf u ncti o ni n g or f u ncti o ni n g G E P- N E T of a k n o w n pri mar y l o calisati o n ( gastric, 
pa ncreas, mi d g ut, hi n d g ut). 
( 7) 
Has a n E aster n C o o perati ve O nc ol o g y Gr o u p ( E C O G) perf or ma n ce stat us l o wer or e q ual 
t o 2 ( A p pe n di x 1 0. 9 ) 
( 8) 
A fe male p arti ci pa nt is eli gi bl e t o partici pate if s h e is n ot pre g na nt or breastfee di n g, a n d 
o ne of t he f oll o wi n g c o n diti o ns a p pli es: 
 
Is a w o ma n of n o n c hil d beari n g p ote nti al (see A p pe n di x 1 0. 4. 1 ), or 
 
Is a w o ma n of c hil d b eari n g p ote ntial ( W O C B P) a n d usi n g a n acce pta ble 
c o ntrace pti ve met h o d (see A p pe n di x 1 0. 4. 1  a n d A p pe n di x 1 0. 4. 2 ) d uri n g t he 
st u d y i nter ve nti o n peri o d (at a mi ni m u m u ntil 9 0 da ys after t he last d os e of st u d y 
i nter ve nti o n). T he i n vesti gat or s h o ul d e v al uate t he p ot e ntial f or c o ntrace pti v e 
met h o d fail ure (e. g. n o n c o m plia nce, rece ntl y i nitiate d) i n relati o ns hi p t o t he first 
d ose of st u d y i nter ve nti o n. 
 
A W O C B P m ust ha ve a ne gati ve hi g hl y se nsiti ve pre g n a n c y test ( uri ne or ser u m 
as r e q uire d b y l oc al re g ul ati o ns; se nsiti ve t o 2 5 
- h u ma n c h ori o nic 
g o na d otr o pi n ( h C G)) wit hi n 4 wee ks bef ore t h e first d ose of st u d y i nter ve nti o n, if 
a uri ne test ca n n ot be c o nfir me d as ne gati ve (e. g. a n a m bi g u o us res ult), a ser u m 
pre g na nc y t est is re q uire d. I n s u c h cas es, t he partici pa nt m ust be e x cl u de d fr o m 
partici pati o n if t he ser u m pre g na nc y res ult is p ositi ve. 
 
T he i n vesti gat or is res p o nsi bl e f or re vie w of me dical hist or y, me nstr ual hist or y, 
a n d rece nt se x ual acti vit y t o decreas e t he ris k f or i ncl usi o n of a w o ma n wit h a n 
earl y u n detecte d pre g na n c y. 
( 9) 
Male partici pa nts m ust a gree t hat, if t h eir part ner is at ris k of bec o mi n g pre g na nt, t he y 
will us e a n effecti ve met h o d of c o ntrace pti o n. T he partici pa nts m ust a gree t o use t he 
c o ntrace pti o n d uri n g t h e w h ole peri o d of t he st u d y a n d f or 9 0 da ys aft er t h e last d ose of 
st u d y i nter ve nti o n. 
( 1 0) F or t he i n de pe n de nt i njecti o n peri o d e nr ol me nt, t he partici pa nt: 
 
M ust pr o vi de a d diti o nal writte n i nf or me d c o nse nt pri or t o st u d y relate d pr o ce d ures 
i n t he i n de pe n de nt i njecti o n peri o d 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 4 9/ 9 9 
 
 
 
 
T he partici pa nt has b ee n recei vi n g t he i nt er ve nti o n wit h l a nre oti de A ut o gel at a 
sta ble d ose a n d fre q u e nc y f or 4 4 wee ks, s h o ws n o disease pr o gressi o n at W 4 8 a n d 
g o o d t olera bilit y d uri n g t he mai n st u d y peri o d 
 
M ust b e c o nsi dere d a s uita ble ca n di d ate f or i n de pe n de nt i njecti o n (c o nsi dere d a ble 
t o i n de pe n de ntl y a d mi nister la nre oti de f oll o wi n g trai ni n g a n d li kel y t o b e nefit 
fr o m a n i n de pe n d e nt a d mi nistrati o n) i n t he o pi ni o n of t he i n vesti gat or. 
 
T he s uita ble ca n di date s h o ul d be c o nsi dere d a ble t o u n dersta n d t h e i njecti o n 
tec h ni q ue, as j u d ge d b y t he i n vesti gat or 
5. 2  
E xcl usi o n Criteri a  
Partici pa nts are e x cl u de d fr o m t he st u d y if a n y of t he f oll o wi n g criteria a p pl y: 
( 1) 
Partici pa nts wit h p o orl y differe nti at e d G E P- N E C, hi g h- gra de G E P- N E C a n d g o blet cell 
carci n oi d. 
( 2) 
Has bee n treate d wit h o ctre oti de a cet ate l o n g-acti n g rele as e ( L A R) or la nre oti d e acetat e 
A ut o gel f or m ulati o n wit hi n 8 wee ks pri or t o scree ni n g tests or la nre oti de P R 4 0 m g 
wit hi n 4 wee ks pri or t o s cree ni n g tests. 
( 3) 
Has bee n treate d wit h s u bc uta ne o us or i ntra ve n o us octre oti de acetate wit hi n 1 wee k pri or 
t o scree ni n g tests. 
( 4) 
Has b ee n treat e d wit h m a m malia n tar get of ra pa m yci n ( m T O R) i n hi bit ors or m ulti-tar get 
t yr osi ne ki nas e ( M T K) i n hi bit ors wit hi n 4 wee ks pri or t o scree ni n g t ests. 
( 5) 
Has bee n treat e d wit h pe pti de rec e pt or ra di o n u cle oti de t hera p y ( P R R T) at a n y ti me pri or 
t o scree ni n g tests. 
( 6) 
Has b ee n treate d wit h ra di ot hera p y wit hi n 4 wee ks pri or t o scree ni n g t ests. 
( 7) 
Has bee n treate d wit h c he m ot hera p y, ra di ofre q u e nc y a blati o n or cr y oa bl ati o n wit hi n 
8 wee ks pri or t o s cree ni n g tests. 
( 8) 
Has bee n treate d 
wit h i nterfer o n, tra nscat h eter arteri al e m b olis ati o n ( T A E) or 
tra nscat het er arterial c h e m oe m b olisati o n ( T A C E) wit hi n 2 4 wee ks pri or t o scree ni n g 
tests. 
( 9) 
Has ha d a maj or s ur ger y relate d t o ne ur oe n d o cri ne t u m o urs wit hi n 1 2 wee ks pri or t o 
scree ni n g tests. 
( 1 0) Has bee n tr eate d wit h ot her i n vesti gati o nal dr u gs or u nlice nse d dr u gs wit hi n 8 wee ks 
pri or t o scree ni n g tests. 
( 1 1a) Has ot her c o n c urre nt mali g n a n c y t ha n ne ur oe n d ocri ne t u m o urs. 
( 1 2) Ca ncer hist or y of a n y mali g n a n cies, ot her t ha n a ne ur oe n d ocri n e t u m o ur (e x ce pt f or 
bas ocell ular carci n o ma of t he s ki n or i n-sit u carci n o ma of t he cer vi x), u nless t he 
c urati ve ca ncer treat me nt. 
( 1 3) Partici pa nts wit h me dical hist or y of h y p erse nsiti vit y t o s o mat ostati n a nal o g ues. 
( 1 4) Partici pa nts wit h s y m pt o matic c h olelit hiasis. 
( 1 5) Ala ni ne tra nsa mi nase ( A L T) ( or as partat e tra ns a mi nase ( A S T) > 2 × u p per li mit of n or mal 
 
( 1 6) T otal bilir u bi n > 1. 5 × U L N (is ol at e d bilir u bi n > 1. 5 × U L N is acce pta ble if t ot al bilir u bi n is 
fracti o nat e d a n d dire ct bilir u bi n < 3 5 %). 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 5 0/ 9 9 
 
 
 
( 1 7) C urre nt u nsta ble li ver or biliar y disease p er i n v esti gat or assess me nt defi ne d b y t he 
prese nce of as cites, e n ce p hal o pat h y, c o a g ul o pat h y, h y p o al b u mi ne mia, oes o p ha geal or 
gastric varices, persiste nt ja u n dice, or cirr h osis.  
gallst o nes, a n d c hr o nic sta ble he p atitis B) is acce pta ble if t he p artici p a nt ot h er wise m eets 
e ntr y criteri a.  
( 1 8) Partici pa nts wit h sec o n d de gree or hi g h er atri o ve ntric ular bl oc k, arr h yt h mia t hat re q uires 
treat me nt, or ot her se vere heart disease. 
( 1 9) Q Tc > 4 5 0 msec f or male parti ci pa nts or Q Tc > 4 7 0 msec f or fe male parti ci pa nts or 
Q Tc > 4 8 0 msec i n partici pa nts wit h b u n dle bra nc h bl oc k.  
-rea d 
or ma n uall y o v er-rea d.  
N ote B: T he s pecific f or m ul a use d t o deter mi ne eli gi bilit y a n d disc o nti n uati o n f or a n 
i n di vi d ual partici pa nt s h o ul d be deter mi ne d pri or t o i nitiati o n of t he st u d y. I n ot her 
w or ds, se veral differe nt f or m ulas ca n n ot be us e d t o calc ulate t he Q Tc f or a n i n di vi d ual 
partici pa nt a n d t he n t he l o west Q T c val ue use d t o i ncl u de or disc o nti n ue t he partici pa nt 
fr o m t he st u d y. 
( 2 0) Partici pa nts w h o ha ve t o recei v e pr o hi bite d dr u gs or t hera pies sti p ulate d b y t he st u d y 
pr ot oc ol fr o m t he date t hat i nf or me d c o nse nt was o btai ne d t o t he o bs er vati o n f or 
4 8 wee ks after t he first a d mi nistrati o n ( or wit h dra wal). 
( 2 1) Partici pa nts s ufferi n g fr o m alc o h olis m or dr u g a b use, or partici pa nts w h o ha ve a hist or y 
of it. 
( 2 2) A n y ot her me dical c o n diti o n t hat c o ul d je o par dis e t he safet y of t he partici pa nt or t he 
assess me nt of efficac y d uri n g t he st u d y, as assess e d b y t he i n vesti gat ors or 
s u b-i n vesti gat ors. 
5. 3  
Lifest yle C o nsi der ati o ns 
D ue t o t h e p ote ntial i nterfere n ce wit h t he assa y f or 5- HI A A, partici pa nts will be i nstr ucte d n ot 
t o eat b a na nas, pi nea p ple, pl u ms, wal n uts, e g g pla nt, t o mat oes, c h o c olate or a v oca d o d uri n g t he 
uri n e c oll ecti o n peri o d a n d t he 7 2 h o urs pri or t o uri ne c ollecti o n at Da y 1, W 1 2, W 2 4, W 3 6, 
W 4 8 (a n d 
W 7 2 f or partici pa nts c o nti n ui n g i n t he i n de pe n de nt i njecti o n peri o d) (see 
Secti o n 8. 6 ). 
Partici pa nts will be re q uire d t o fast f or at least 6 h o urs bef ore all cli nical la b orat or y safet y tests. 
5. 4  
Scree n F ail ures 
Scree n fail ures are d efi ne d as partici p a nts w h o c o nse nt t o parti ci pate i n t he cli nical st u d y b ut 
are n ot s u bse q ue ntl y e nt ere d i n t he st u d y. A mi ni m al set of scree n f ail ure i nf or mati o n is re q uire d 
t o e ns ure tra ns pare nt re p orti n g of s cree n fail ure parti ci pa nts t o meet t he C o ns oli date d Sta n dar ds 
of Re p orti n g Trials ( C O N S O R T) p u blis hi n g re q uire me nts a n d t o res p o n d t o q ueries fr o m 
re g ulat or y a ut h orities. Mi ni mal i nf or mati o n i ncl u des date of i nf or me d c o ns e nt, de m o gra p h y, 
reas o n f or scree n fail ure, eli gi bilit y criteria a n d a n y seri o us a d verse e v e nt ( S A E). 
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 st u d y (s cree n fail ure) ma y n ot 
be r escree ne d; t he e x ce pti o n bei n g if t he y h a v e s y m pt o matic c h olelit hiasis (acc or di n g t o 
e x cl usi o n criteri o n ( 1 4) t hat has bee n s uccessf ull y o p erat e d o n after scree ni n g. Rescree ne d 
partici pa nts s h o ul d b e assi g ne d a ne w partici pa nt n u m ber. A partici pa nt w h o is rescree ne d is 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 5 1/ 9 9 
 
 
 
re q uire d t o si g n a n ot h er I C F if t he rescree ni n g occ urs m ore t ha n 4 wee ks fr o m t he pre vi o us I C F 
si g nat ure date. T h e i nf or m e d c o ns e nt pr ocess is descri be d i n A p pe n di x 1 0. 1. 3 .  
5. 5  
Criteri a 
f or 
Te m p or aril y 
Del a yi n g 
E nr ol me nt/ St u d y 
I nter ve nti o n 
A d mi nistr ati o n  
N ot a p plica ble. T here are n o criteria f or te m p oraril y dela yi n g e nr ol me nt or st u d y i nter ve nti o n 
a d mi nistrati o n. 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 5 2/ 9 9 
 
 
 
6  
S T U D Y I N T E R V E N TI O N A N D C O N C O MI T A N T T H E R A P Y 
St u d y i nter ve nti o n is defi ne d as a n y i n vesti gati o nal i nter ve nti o n(s), m ar kete d pr o d uct(s), 
place b o, or me dical de vi ce(s) i nte n de d t o b e a d mi nist ere d t o a st u d y p arti ci pa nt ac c or di n g t o 
t he st u d y pr ot oc ol. 
6. 1  
St u d y I nter v e nti o n A d mi nistere d 
All partici pa nts will recei ve a fi x e d d ose of la nre oti de A ut o gel 1 2 0 m g b y dee p s u bc uta ne o us 
i njecti o n e ver y 2 8 d a ys d uri n g t he st u d y. T here is a n all o we d wi n d o w of ± 3 da ys f or eac h 
i njecti o n. Details of st u d y i nt er v e nti o n are pr o vi de d i n Ta ble 3 . 
T a ble 3 
St u d y I nter v e nti o n A d mi nistere d d uri n g t he St u d y 
I nter v e nti o n n a me 
La nre oti de A ut o gel 
T y pe  
Dr u g  
Descri pti o n 
W hite t o yell o wis h w hit e se mi s oli d ( gel)  
D ose f or m ul ati o n 
S ustai ne d -release i njecti o n  
U nit d ose stre n gt h 
1 2 0 m g  la nre oti de (e q ui vale nt t o 0. 2 4 6 m g/ m g of la nre oti d e c o nce ntrati o n) 
D os a g e le vel 
1 2 0 m g e ver y 2 8 d a ys  
R o ute of a d mi nistr ati o n 
Dee p s u bc uta ne o us i nj ecti o n  
Us e 
E x p eri me ntal  
I M P a n d A M P/ NI M P 
I M P  
S o urci n g 
Pr o vi de d ce ntrall y b y t he s p o ns or (I pse n P har m Scie nces, 1 7- 2 0 r ue Et he Virt o n, 
2 8 1 0 0 Dre u x, Fra nce). 
P ac k a gi n g a n d l a belli n g 
St u d y i nter ve nti o n will b e pr o vi de d i n a prefille d s yri n ge pr o d uct wit h nee dle i n 
a la mi nate d p ac ka ge. Eac h p ac ka ge will b e la belle d f or cli nical st u d y use as 
s p ecifi e d i n t he p har mac y ma n ual. T he la b el will i ncl u de, at a mi ni m u m: a 
u ni q ue i de ntifier (st u d y i nter v e nti o n n u m ber), l ot n u m ber, c o nte nt, d ose, st ora ge 
c o n diti o ns a n d na me & a d dress of s p o ns or.  
St o r a g e re q uire me nts 
i di n g t ha wi n g. 
T he la mi nate d p ac ka ge s h o ul d b e ta ke n o ut fr o m t he refri gerat or a p pr o xi matel y 
3 0 mi n ut es bef ore a d mi nistr ati o n. It m ust n ot b e o pe ne d u ntil i m me diatel y b ef ore 
a d mi nistrati o n.  
A b bre viati o ns: A M P =a u xiliar y me dici nal pr o d uct; I M P =i n v esti gati o nal me dici nal pr o d uct; 
NI M P = n o ni n vesti gati o nal me dici nal pr o d uct  
 
I n t he mai n st u d y peri o d, partici pa nts will recei v e 4 8 w ee ks of i nter v e nti o n wit h la nre oti de 
A ut o gel ( 1 2 i njecti o ns; Da y 1 t o W 4 4). I nje cti o ns will be ma de i n t he s u peri or e xt er nal q ua dra nt 
of t he b utt o c ks b y t h e i n vesti gat or or desi g nee.  
A p pr o xi matel y fi ve partici pa nts will c o nti n ue i n t he i n de pe n de nt i njecti o n peri o d. A f urt her 
2 4 wee ks of i nter ve nti o n wit h la nre oti de A ut o gel (si x i njecti o ns) will be i n de pe n d e ntl y 
a d mi nistere d. T he first i njecti o n at W 4 8 will be perf or me d at t he st u d y sit e ( u n der me dical 
s u per visi o n) f or trai ni n g p ur p oses. At W 5 2 a n d W 5 6, t he sec o n d a n d t hir d i njecti o ns ma y als o 
be perf or me d at t he st u d y site f or trai ni n g p ur p oses or ma y b e perf or m e d at h o me, if n o f urt her 
trai ni n g is nee de d i n t he o pi ni o n of t he i n vesti gat or. At W 6 0, W 6 4 a n d W 6 8, t he f o urt h, fift h 
a n d si xt h i njecti o ns will b e perf or me d at h o me or at t he st u d y sit e. I n de pe n de nt i nj ecti o ns will 
be ma de i n t he u p per o uter t hi g h.  
T he i njecti o n site s h o ul d be alt er n ate d bet wee n t h e ri g ht a n d l eft si de b et wee n i njecti o ns. T h e 
i njecti o n sit e s h o ul d be caref ull y e x a mi ne d t o a v oi d re peate d i njecti o n at t he sa me site. 
I m me diat el y bef ore a d mi nistrati o n, t he prefille d s yri n ge s h o ul d b e ta ke n o ut fr o m t he l a mi nate d 
pac ka ge. T he prefille d s yri n ge s h o ul d be re m o ve d fr o m its tra y, t he ca p of t he nee dle re m o ve d, 
a n d st u d y i nter ve nti o n i nj ecte d.  

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 5 3/ 9 9 
 
 
 
T he s yri n ge a n d la mi nate d pac ka ge of t he use d st u d y i nter ve nti o n s h o ul d be discar de d 
 
6. 2  
Pre p ar ati o n, H a n dli n g, St or a ge a n d Acc o u nt a bilit y 
F urt her g ui da nce a n d i nf or m ati o n f or t he recei pt, pre parati o n, ma na ge me nt a n d dis p os al/ret ur n 
 
 
T he i n vesti gat or or d esi g nee m ust c o nfir m a p pr o priate te m perat ure c o n diti o ns ha ve bee n 
mai ntai ne d d uri n g tra nsit f or all st u d y i nter ve nti o n recei ve d a n d a n y dis cre pa ncies are 
re p orte d a n d res ol ve d b ef ore us e of t he st u d y i nt er ve nti o n. 
 
O nl y partici p a nts scree n e d i n t he st u d y a n d w h o m eet t he eli gi bilit y crit eria ma y recei v e 
st u d y i nter ve nti o n 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 st u d y 
i nter ve nti o n. All st u d y i nt er ve nti o n 
m ust be st ore d i n a sec ure, e n vir o n me ntall y 
c o ntr olle d a n d m o nit ore d ( ma n ual or a ut o mat e d) area i n acc or da nc e wit h t he la b elle d 
st ora ge c o n diti o ns wit h access li mit e d t o t he i n vesti gat or a n d a ut h orise d sit e staff. 
 
T he i n vesti gat or, i nstit uti o n or t he h ea d of t he me dical i nstit uti o n ( w here a p pli ca bl e) is 
res p o nsi ble f or st u d y i nter ve nti o n acc o u nta bilit y, rec o n ciliati o n, dis p os al a n d rec or d 
mai nte na nce (i.e. recei pt, rec o nciliati o n a n d fi nal dis p ositi o n rec or ds). 
 
At eac h dis pe ns ati o n (at sc he d ul e d a n d u nsc he d ule d visits, if a p plica ble), st u d y 
i nter ve nti o n n u m ber(s) will be assi g ne d b y t he I nt eracti ve V oice/ W e b Res p o nse S yste m 
(I V R S/I W R S). T he I V R S/I W R S will als o m a na ge all l o gistical as pe cts of t he st u d y 
i nter ve nti o n (e. g. re place me nt, dr u g s u p plies a n d e x pir y d ates) a n d t he rec or di n g of dr u g 
acc o u nta bilit y/ d estr ucti o n. T his s er vice pr o vi des t he i n vesti gat or, st u d y site c o or di nat ors 
a n d pr oj ect tea m me m bers wit h a ser vice t hat is a vaila ble 2 4 h o urs a da y, 7 da ys a wee k. 
A d diti o nal details m a y b e f o u n d i n t he I V R S/I W R S refere n ce ma n ual pr o vi de d t o eac h 
st u d y sit e. I n cas e of tec h ni cal or dis pe nsati o n q ueries, a 2 4- h o ur h el pli ne is a vaila ble. If 
a partici pa nt disc o nti n ues t he st u d y b ef or e a n y i nta ke of st u d y i nt er ve nti o n, his/ her 
assi g ne d st u d y i nter ve nti o n n u m ber(s) will n ot be re use d. 
 
I n a d diti o n t o t he i nf or m ati o n pr o vi de d i n t he I V R S/I W R S, st u d y i nter ve nti o n 
acc o u nta bilit y pa per rec or ds will be mai ntai ne d b y t he i n vesti gat or. 
 
T he s p o ns or will pr o vi de g ui d a nce o n t he d estr u cti o n of u n use d st u d y i nter ve nti o n. If 
destr ucti o n is a ut h orise d t o ta ke place at t he i n vesti gati o nal sit e, t h e i n vesti gat or m ust 
e ns ure t hat t he materials are destr o ye d i n c o m plia nce wit h a p plica ble e n vir o n me ntal 
re g ulati o ns, i nstit uti o nal p olic y a n d a n y s pecial i nstr ucti o ns pr o vi de d b y t h e s p o ns or. All 
destr ucti o n m ust be a de q uatel y d o c u me nte d. 
6. 3  
Me as ures t o Mi ni mize Bi as: R a n d o mis ati o n a n d Bli n di n g 
6. 3. 1  
R a n d o mis ati o n 
T his is a n o nra n d o mise d st u d y. All p artici pa nts w h o f ulfil t he i ncl usi o n/e x cl usi o n criteria will 
recei v e la nre oti de A ut o gel 1 2 0 m g. 
6. 3. 2  
M ai nte n a nce of Bli n di n g 
T his is a n o pe n-la b el st u d y t heref ore n o pr oce d ures f or bli n di n g are a p plica ble. All partici pa nts 
will recei ve t he s a me st u d y i nter v e nti o n. N ot e: o nl y t he i n de pe n de nt ce ntral re vie wers ma ki n g 
t u m o ur assess me nts will be bli n de d t o cert ai n partici pa nt baseli ne a n d res p o nse i nf or mati o n 
(see Secti o n 8. 1. 1 ). 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 5 4/ 9 9 
 
 
 
6. 4  
St u d y I nter v e nti o n C o m pli a nce 
6. 4. 1  
M ai n I nterve nti o n Peri o d 
I n t h e mai n st u d y p eri o d, parti ci pa nts will recei ve all d oses of st u d y i nt er v e nti o n at t he st u d y 
site directl y fr o m t he i n vesti gat or or desi g nee. T h e date a n d ti me of eac h d ose a n d t he i njecti o n 
site (ri g ht/left) will be rec or de d i n t he s o urce d oc u me nts a n d cas e re p ort f or m ( C R F). T h e d ose 
of st u d y i nter ve nti o n a n d st u d y partici pa nt i de ntifi cati o n will be c o nfir me d at t he ti me of d osi n g 
b y a m e m ber of t h e st u d y site staff ot her t h a n t he p ers o n a d mi nisteri n g t he st u d y i nter ve nti o n.  
6. 4. 2  
I n de pe n de nt I njecti o n Peri o d 
Partici pa nts c o nti n ui n g i nt o t he i n de pe n de nt i nj ecti o n peri o d will recei ve a f urt her si x d oses of 
st u d y i nter ve nti o n. T he first will be i n de pe n de ntl y a d mi nistere d at t he st u d y site u n der me dical 
s u per visi o n. T he sec o n d a n d t hir d d oses will eit h er be i n de pe n de ntl y a d mi nistere d at t he st u d y 
site u n der m e dical s u p er visi o n or at h o me. T he re mai ni n g t hree d os es will be i n de p e n de ntl y 
a d mi nist ere d at h o me. I n de pe n de nt a d mi nistrati o n ma y be perf or me d b y t he partici pa nt or t heir 
part ner.  
 
F or i njecti o ns perf or me d at t he st u d y site, t he d ate a n d ti me of eac h d ose a n d t he i njecti o n 
site (ri g ht/left) will be re c or de d i n t he s o urce d oc u me nts a n d C R F. T he d ose of st u d y 
i nter ve nti o n a n d st u d y p artici pa nt i de ntificati o n will be c o nfir me d at t he ti me of d osi n g 
b y a m e m ber of t h e st u d y site staff. 
 
F or i njecti o ns perf or me d at h o me, t he d at e a n d ti me of eac h d ose a n d t h e i njecti o n sit e 
(ri g ht/left) will be rec or d e d i n t he partici pa nt diar y. C o m plia nce wit h st u d y i nter v e nti o n 
i n de pe n de nt a d mi nistrati o n will be assesse d at W 7 2/ E O SI b y re vi e w of t he diar y a n d 
direct q uesti o ni n g a n d d oc u me nte d i n t he s o urce d oc u me nts a n d C R F. 
A rec or d of t he q u a ntit y of la nre oti de A ut o gel prefille d s yri n ges dis p e ns e d a n d a d mi nistere d b y 
eac h partici pa nt m ust be mai ntai ne d a n d rec o ncil e d wit h st u d y i nt er v e nti o n a n d c o m plia nce 
rec or ds. I nter v e nti o n start a n d st o p dates a n d a n y d e viati o n(s) fr o m t he prescri be d d osa ge 
re gi me n s h o ul d be rec or de d i n t he C R F. 
6. 5  
D os e M o dific ati o n 
N ot a p pli ca ble. N o d ose m o dificati o ns are t o be p erf or me d i n t he st u d y. 
6. 6  
C o nti n ue d Access t o l a n re oti de A ut o gel 1 2 0 m g after t he E n d of t he St u d y 
T he p arti ci pa nts will n ot rec ei ve a n y a d diti o nal st u d y i nter ve nti o n f oll o wi n g t he e n d of t he 
st u d y. Bas e d o n G E P- N E T cli nical ma na ge m e nt g ui deli ne, t here are s u bse q ue nt t hera p y o pti o ns 
f or G E P-
j u d g me nt. 
6. 7  
Tre at me nt of O ver d ose 
F or t his st u d y, a n y d os e of st u d y i nter v e nti o n greater t ha n t hat s pecifie d i n t he pr ot oc ol ( 1 2 0 m g 
per dee p s u b c uta ne o us i njecti o n) will be c o nsi dere d a n o ver d ose. 
T he s p o ns or d oes n ot rec o m me n d s pecific treat m e nt f or a n o ver d os e. A p pr o priate treat m e nt of 
o ver d ose of st u d y i nt er ve nti o n will be deter mi ne d b y t h e i n v esti gat or acc or di n g t o t he 
c haracteristics of t he e v e nts a n d will be rec or de d i n t he C R F. A n e ve nt res ulti n g fr o m a n 
o ver d ose of t he st u d y i nter ve nti o n is n ot c o nsi dere d as seri o us u nless it meets t he defi niti o n of 
a n S A E.  
I n t he e ve nt of a n o ver d ose, t he i n vesti gat or/treati n g p h ysicia n s h o ul d: 
 
C o ntact t he me dical m o nit or i m me diat el y. 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 5 5/ 9 9 
 
 
 
 
E val uate t he partici pa nt t o deter mi ne, i n c o ns ultati o n wit h t he me dical m o nit or, w het her 
st u d y i nter ve nti o n s h o ul d be dis c o nti n ue d. 
 
Cl osel y m o nit or t he parti ci pa nt f or a n y A E/ S A E a n d l a b orat or y a b n or malities u ntil 
la nre oti de ca n n o l o n ger be detect e d s yst e micall y (at least 2 8 da ys). 
 
D oc u me nt t he q ua ntit y of t he e xcess d ose as well as t he d urati o n of t he o ver d ose. See 
A p pe n di x 1 0. 3. 1 f or re p orti n g re q uire me nts c o n cer ni n g o ver d os e. 
6. 8  
C o nc o mit a nt T her a p y 
A n y me di cati o n or vacci ne (i ncl u di n g o ver-t he-c o u nter or prescri pti o n me dici nes, recreati o nal 
dr u gs, vit a mi ns, a n d/ or her bal s u p ple m e nts), t h era p y or pr oce d ure t h at t he partici pa nt is 
recei vi n g at t he ti me of e nr ol me nt or recei ves d uri n g t he st u d y m ust be rec or de d al o n g wit h: 
 
Reas o n f or use 
 
Dates of a d mi nistrati o n i ncl u di n g start a n d e n d dates 
 
D os a ge i nf or m ati o n i ncl u di n g d os e a n d fre q ue nc y 
T he me dical m o nit or s h o ul d be c o ntacte d if t here are a n y q u esti o ns re gar di n g c o nc o mita nt or 
pri or t hera p y.  
6. 8. 1  
Pr o hi bite d C o nc o mit a nt Me dic ati o ns, T her a pies a n d Pr oce d ures 
See Secti o n 5. 2  f or me di cati o ns w hic h w o ul d res ult i n e x cl usi o n fr o m t he st u d y. 
T he c o nc o mita nt me dicati o ns, t h era pies or pr o ce d ures w hic h are n ot per mitte d d uri n g t his st u d y 
are:  
 
I nterfer o n, ra di o n ucli de ( ot her t ha n t hat use d f or i ma gi n g or S S T R sci nti gra p h y), 
c he m ot hera p y or c h e m oe m b olisati o n, ra di ofre q ue nc y a blati o n or cr y oa blati o n 
 
A n y s o mat ost ati n a n al o g ues ot her t ha n st u d y i nt er ve nti o n 
 
G H a nta g o nist 
 
C ycl os p ori n 
 
m T O R i n hi bit or, M T K i n hi bit ors 
 
T u m o ur resecti o n 
6. 8. 2  
Resc ue Me dic ati o n 
N o resc u e me di cati o ns are s pecifie d f or t h e st u d y. 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 5 6/ 9 9 
 
 
 
7  
DI S C O N TI N U A TI O N O F S T U D Y I N T E R V E N TI O N A N D P A R TI CI P A N T 
DI S C O N TI N U A TI O N/ WI T H D R A W A L 
7. 1  
Disc o nti n u ati o n of St u d y I nter ve nti o n 
I n rare i nsta nces, it ma y be necessar y f or a p arti ci pa nt t o per ma ne ntl y disc o nti n ue st u d y 
i nter ve nti o n. A n earl y disc o nti n uati o n visit ( W 4 8/ E O SI/ E D or W 7 2/ E O SI/ E D de pe n di n g o n 
w het her t he st u d y i nter ve nti o n disc o nti n uati o n occ urs i n t he mai n i nter ve nti o n peri o d or 
i n de pe n de nt i njecti o n p eri o d) s h o ul d b e c o n d u cte d if st u d y i nter ve nti o n is per ma n e ntl y 
disc o nti n ue d (see t h e S o A ( Ta ble 1 ) f or data t o b e c ollecte d at t he ti me of st u d y i nter ve nti o n 
disc o nti n uati o n). 
Partici pa nts w h o disc o nti n ue st u d y i nter ve nti o n b ut ha ve n ot wit h dra w n fr o m t h e st u d y m ust 
be f oll o we d f or s ur vi val data (acc or di n g t o t he p ost-i nter ve nti o n s ur vi val f oll o w- u p sc he d ule i n 
Ta ble 1 ) u ntil deat h or wit hi n 4 wee ks after t he last W 4 8 visit of t he last partici pa nt i n t he mai n 
i nter ve nti o n peri o d or wit hi n 4 wee ks after t he last W 7 2 visit of t he last partici pa nt i n t he 
i n de pe n de nt i njecti o n peri o d ( u nless t he partici pa nt has s pecificall y wit h dra w n c o nse nt f or a n y 
f urt her c o nt act).  
If partici p a nts are l ost t o f oll o w- u p, p u bli cl y a vail a ble i nf or mati o n s h o ul d be use d t o deter mi ne 
vital st at us o nl y as a p pr o priatel y directe d i n acc or da nce wit h l ocal la w. 
Partici pa nts meeti n g a n y of t h e f oll o wi n g crit eria s h o ul d per ma n e ntl y disc o nti n ue st u d y 
i nter ve nti o n: 
 
Deat h. 
 
Disease pr o gressi o n. 
 
U nacce pta ble t o xicit y, i n cl u di n g li ver i nj ur y me eti n g t he crit eri a i n S ecti o n 7. 1. 1  ( u nl ess 
rec halle n ge is c o nsi dere d a p pr o priat e, see Secti o n 7. 1. 4 ) a n d car diac c h a n ges meeti n g 
t he st o p pi n g criteria i n Secti o n 7. 1. 2 .  
 
C ha n ges i n t he c o n diti o n or i nterc urre nt ill ness ma ki n g c o nti n uati o n of st u d y i nter ve nti o n 
 
 
Recei pt of a n alter nati ve a ntica ncer t hera p y f or t h e st u d y i n dicati o n. 
 
Si g nifica nt pr ot oc ol d e viati o n or maj or n o nc o m plia nce wit h st u d y pr oce d ures ma ki n g 
t he partici pa nt u ns uit a ble f or f urt her st u d y i nter ve nti o n a d mi nistrati o n. 
 
Is retr os pecti vel y f o u n d n ot t o ha ve met all eli gi bilit y criteria (see Secti o n 5. 1  a n d 
Secti o n 5. 2 ) a n d t he i n vesti gat or c o nsi ders t he parti ci pa nt w o ul d n ot deri ve be nefit d ue 
t o t his. 
 
Pre g n a nc y (see Secti o n 8. 3. 6 ). 
 
Wit h dra wal of c o nse nt f or st u d y i nter ve nti o n b ut still pr o vi di n g c o nse nt f or f oll o w- u p.  
7. 1. 1  
Liver C he mistry St o p pi n g Criteri a 
Disc o nti n uati o n of st u d y i nter ve nti o n f or a b n or m al li ver tests is re q uire d b y t he i n v esti gat or 
w he n a partici pa nt meets o ne of t he st o p pi n g criteria c o n diti o ns o utli ne d i n t he al g orit h m i n 
Fi g ure 2  or i n t he prese nce of a b n or m al li ver c he mistries n ot meeti n g pr ot oc ol-s pecifie d 
st o p pi n g r ules if t he i n vesti gat or belie ves t hat it is i n t he best i nt er est of t he partici pa nt. T he 
re q uire d f oll o w- u p assess me nts are pr o vi de d i n f ull i n A p pe n di x 1 0. 5. 1 . 
If i ncrease d li ver c he mistr y m o nit ori n g is re q uire d w hilst c o nti n ui n g st u d y i nt er v e nti o n 
acc or di n g t o Fi g ure 2 , t h e n t he al g orit h m i n Fi g ure 3  s h o ul d be f oll o we d. T he re q uire d 
f oll o w- u p assess me nts are pr o vi de d i n f ull i n A p p e n di x 1 0. 5. 2 . 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 5 7/ 9 9 
 
 
 
Fi g ure 2 
Li v er C he mistr y St o p pi n g C rit eri a a n d I ncre ase d M o nit o ri n g Al g o rit h m 
 
A b bre viati o ns: A L T =al a ni ne tr a nsa mi nase; A S T =as partat e tra nsa mi nase, I N R =i nter nati o nal n or malis e d r ati o; 
T bili = T otal bilir u bi n; U L N = u p per li mit of n or mal 
Li ver Safet y: S u g geste d Acti o ns a n d F oll o w- u p Assess me nts ca n be f o u n d i n A p p e n di x 1 0. 5. 1  

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 5 8/ 9 9 
 
 
 
Fi g ure 3 
Li v er C h e mistr y I ncre ase d M o nit ori n g Al g orit h m wit h C o nti n u e d St u d y I nter v e nti o n f or 
 
 
A b bre viati o ns: A L T =al a ni ne tr a nsa mi nase; A S T =as partat e tra nsa mi nase, I N R =i nter nati o nal n or malise d rati o; 
T bili = T otal bilir u bi n; U L N = u p per li mit of n or mal 
Li ver Safet y: S u g geste d Acti o ns a n d F oll o w- u p Assess me nts ca n be f o u n d i n A p p e n di x 1 0. 5. 2  
7. 1. 2  
Q Tc St o p pi n g Criteri a 
If a cli nicall y si g nifica nt fi n di n g is i de ntifie d (i ncl u di n g, b ut n ot li mite d t o c ha n ges fr o m 
baseli ne i n Q Tc B or Q T c F (as d eter mi ne d pri or t o i niti ati o n of t he st u d y)) after e nr ol me nt, t he 
i n vesti gat or or q ualifie d desi g nee will det er mi ne if t he partici p a nt ca n c o nti n ue i n t he st u d y a n d 
if a n y c ha n ge i n p artici p a nt ma na ge me nt is nee d e d. Re vie w of t h e E C G pri nte d at t he ti me of 
c ollecti o n m ust be d oc u me nte d. A n y ne w cli nicall y rele v a nt fi n di n g s h o ul d be re p ort e d as a n 
A E. 
A partici pa nt wit h o ut u n derl yi n g b u n dl e bra nc h bl oc k w h o meets eit her of t he f oll o wi n g will 
be wit h dra w n fr o m st u d y i nter ve nti o n: 
 
Q Tc > 5 0 0 msec  
 
C ha n ge fr o m baseli ne of Q T c > 6 0 ms ec  
Disc o nti n uati o n criteria f or partici pa nts wit h u n derl yi n g b u n dle bra nc h bl oc k are pr o vi de d i n 
Ta ble 4 . 
T a ble 4 
Q Tc St u d y I nter ve nti o n Dis c o nti n u ati o n C riteri a f or P artici p a nts wit h U n derl yi n g B u n dle 
B r a nc h Bl o c k 
B aseli n e Q Tc wit h B u n dle B r a nc h Bl o c k 
Disc o nti n u ati o n Q Tc T hres h ol d wit h B u n dle 
B r a nc h Bl o c k 
< 4 5 0 ms ec 
> 5 0 0 msec 
4 5 0 t o 4 8 0 msec 
 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 5 9/ 9 9 
 
 
 
7. 1. 3  
Criteri a f or Te m p or ary Disc o nti n u ati o n 
I n case of s us p ecte d or c o nfir me d C O VI D- 1 9 ( S A R S- C o V- 2) i nfecti o n, st u d y i nter v e nti o n 
a d mi nistrati o n 
ma y be te m p oraril y dis c o nti n ue d de p e n di n g o n t h e parti ci pa nt cli nical 
prese ntati o n. I n s o m e cases, t he i n vesti gat or m a y re q uest t hat a parti ci pa nt be reteste d bef ore 
t he i nter ve nti o n a d mi nistrati o n is res u m e d.  
St u d y i nter ve nti o n s h o ul d als o be te m p oraril y dis c o nti n ue d i n case of: 
 
Se vere u nre mitti n g gastr oi ntesti nal i nt olera nce: Nati o nal Ca ncer I nstit ute C o m m o n 
i ncrease i n ost o m y o ut p ut c o m pare d t o bas eli ne; li miti n g  s elf-care acti viti es of dail y 
 h o urs; t u be fee di n g, t otal 
pare nteral n utriti o n or h os pitalisati o n i n dicate d) des pite o pti mal a nti diarr heal or 
a ntie metic treat me nt. 
 
P o orl y c o ntr olle d dia bet es mellit us: N CI C T C A
a nti dia betic treat me nt. 
 
 a m ylase ( > 2 × U L N) or li pas e ( > 2 × U L N) wit h 
s y m pt o ms, or f or > 7 c o nsec uti ve da ys wit h o ut s y m pt o ms. 
 
A n y ot her A E or lesser se verit y of t he A Es liste d a b o ve t hat, i n t h e o pi ni o n of t he 
i n vesti gat or, c o ul d je o par dise t he partici pa nt's safet y. 
7. 1. 4  
Rest art/ Rec h alle n g e 
7. 1. 4. 1  
St u dy I nterve nti o n Rest art or Rec h alle n ge aft er Liver St o p pi n g Crit eri a Met 
A partici pa nt w h o meets li ver c he mistr y st o p pi n g crit eria c a n n ot restart st u d y i nter ve nti o n. T he 
partici pa nt m ust per m a ne ntl y disc o nti n ue st u d y i nt er ve nti o n a n d m a y c o nti n u e i n t he st u d y f or 
pr ot oc ol-s pecifi e d assess me nts. 
7. 1. 4. 2  
St u dy I nter ve nti o n Rest art of R ec h alle n g e after ot her Crit eri a f or T e m p or ary 
Disc o nti n u ati o n Met 
If a n y of t he criteria f or t e m p orar y dis c o nti n uati o n of st u d y i nter v e nti o n o utli ne d i n 
Secti o n 7. 1. 3  are met, t h e i n vesti gat or s h o ul d ass ess w het her restart/rec h alle n ge is a p pr o priate 
i n t he e ve nt of rec o ver y, c o nsi deri n g t he ass ess m e nt of t he relati o ns hi p t o st u d y i nter ve nti o n, 
u n derl yi n g disease, i nterc urre nt ill ness or c o nc o mita nt m e dicati o ns a n d t he o verall be n efit/ris k 
f or t he p artici pa nt. If rest art/rec h alle n ge is n ot ass esse d t o be a p pr o priat e, st u d y i nt er v e nti o n 
s h o ul d be p er ma ne ntl y disc o nti n ue d. 
7. 2  
P artici p a nt Dis c o nti n u ati o n/ Wit h dr a w al f r o m t he St u d y 
 
A partici pa nt m a y wit h dra w fr o m t he st u d y at a n y ti me at his/ her o w n re q uest or ma y be 
wit h dra w n at a n y ti me at t he dis creti o n of t h e i n v esti gat or f or s afet y, b e ha vi o ural or 
c o m plia nce reas o ns.  
 
At t he ti me of disc o nti n ui n g fr o m t he st u d y, if p ossi ble, a n earl y disc o nti n uati o n visit 
( W 4 8/ E O SI/ E D or 
W 7 2/ E O SI/ E D as a p plica ble) s h o ul d be c o n d ucte d. See t he S o A 
(Ta ble 1 ) f or data t o be c ollecte d at t he ti me of st u d y dis c o nti n uati o n. 
 
T he reas o n f or disc o nti n uati o n will b e rec or de d i n t he C R F. 
 
If t he partici pa nt wit h dra ws c o ns e nt f or discl os ure of f ut ure i nf or mati o n, t he s p o ns or ma y 
retai n a n d c o nti n ue t o use a n y data c oll ect e d b ef ore s uc h wit h dra wal of c o nse nt. 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 6 0/ 9 9 
 
 
 
 
If t he p artici pa nt wit h dra ws c o nse nt, it s h o ul d be e x plai ne d i n detail i n t he me dical 
rec or ds b y t he i n v esti gat or as t o w het her t he wit h dra wal is o nl y fr o m f urt h er recei pt of 
st u d y i nter ve nti o n or als o fr o m f oll o w- u p. Partici pa nt data a n d bi ol o gical sa m ples 
c ollecte d u p t o t he date of c o ns e nt wit h dra wal will be i ncl u de d i n t he a n al ys es. 
 
If a partici pa nt wit h dra ws fr o m t he st u d y, he/s he ma y re q uest destr ucti o n of a n y s a 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 site st u d y rec or ds. 
7. 3  
L ost t o F oll o w- u p 
A partici pa nt will be c o nsi dere d l ost t o f oll o w- u p if he/s he re p eate dl y fails t o ret ur n f or 
sc he d ule d visits a n d is u na ble t o be c o nta cte d b y t he st u d y sit e. 
T he f oll o wi n g acti o ns m ust be ta ke n if a partici pa nt fails t o ret ur n t o t he cli nic f or a re q uire d 
st u d y visit: 
 
T he site m ust atte m pt t o c o ntact t he partici pa nt a n d resc he d ule t he misse d visit as s o o n 
as p ossi ble. T he site s h o ul d c o u nsel t he partici p a nt o n t he i m p orta n ce 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 partici pa nt wis hes t o a n d/ or 
s h o ul d c o nti n ue i n t he st u d y. 
 
Bef ore a partici pa nt is dee me d l ost t o f oll o w- u p, t h e i n vesti gat or or desi g n ee m ust ma ke 
e ver y eff ort t o re gai n c o ntact wit h t he partici pa nt ( w h ere p ossi ble, t hree t ele p h o ne calls 
me dical rec or d. 
 
S h o ul d t he partici pa nt c o nti n ue t o be u nreac ha ble, he/s he will be c o nsi dere d t o h a ve 
wit h dra w n fr o m t he st u d y. 
 
St u d y sit e p ers o n nel, or a n i n de pe n de nt t hir d part y, will atte m pt t o c ollect t he vit al stat us 
of t he partici pa nt wit hi n le gal a n d et hical b o u n dari es f or all p arti ci pa nts w h o recei ve d 
st u d y i nt er ve nti o n. P u blic s o urces m a y b e searc h e d f or vital st at us i nf or mati o n. If vit al 
stat us is deter mi ne d as decease d, t his will be d o c u me nte d, a n d t h e partici pa nt will n ot be 
c o nsi dere d l ost t o f oll o w- u p. S p o ns or pers o n nel will n ot be i n v ol ve d i n a n y atte m pts t o 
c ollect vital stat us i nf or mati o n. 
Disc o nti n uati o n of s pecific sit es or of t he st u d y as a 
w h ole is ha n dle d as part of 
A p pe n di x 1 0. 1. 9 . 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 6 1/ 9 9 
 
 
 
8  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S 
St u d y pr oce d ures a n d t heir ti mi n g are s u m m arise d i n t he S o A (s ee T a ble 1 ). Pr ot oc ol wai vers 
a n d e x e m pti o ns are n ot all o we d. A d diti o nal u nsc he d ule d visits or pr oce d ures ma y b e perf or me d 
at t h e discreti o n of t he i n vesti gat or (e. g. f or safet y p ur p os es). 
I m me diat e safet y c o ncer ns s h o ul d be disc uss e d wit h t he s p o ns or i m me diatel y u p o n o cc urre n ce 
or a ware ness t o det er mi ne if t he partici pa nt s h o ul d c o nti n ue or dis c o nti n ue st u d y i nt er ve nti o n. 
A d here nce t o t he st u d y d esi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he S o A ( Ta ble 1 ), is 
esse ntial a n d re q uire d f or st u d y c o n d u ct. 
Scree ni n g will be perf or me d i n t he 4 wee ks pri or t o t he first d ose of st u d y i nter v e nti o n. N o 
st u d y r elate d pr oce d ures will be perf or me d u ntil t he partici pa nt has pr o vi d e d writte n i nf or me d 
c o nse nt b y si g ni n g t he I C F (s ee A p pe n di x 1 0. 1. 3 ). 
 
T he f oll o wi n g will be rec or de d at scree ni n g: 
- 
De m o gra p hic i nf or mati o n. 
- 
Disease hist or y ( d at e of di a g n osis, pri mar y N E T site, N E T gra d e ( Ki 6 7 i n de x or 
mit otic c o u nts per 1 0 H P F ( Hi g h P o wer Fiel d; 4 0 0 × Micr osc o p e Ma g nificati o n per 
fiel d f or N E T), prese n ce or a bse n ce of S S T R, prese nce or a bs e nce of N E T-relate d 
s y m pt o ms a n d t u m o ur classificati o n, N E T size a n d prese nce or a bse n ce of 
pr o gressi o n. 
- 
Hist or y of pre vi o us treat me nt of N E T. 
- 
C o m plete 
me dical 
hist or y, i ncl u di n g 
e v al uati o n f or 
p ast 
a n d 
prese nt 
car di o vasc ular, res pirat or y, 
gastr oi ntesti nal, re nal, 
he p atic, 
ne ur ol o gic al, 
e n d ocri ne, 
l y m p h atic, 
hae mat ol o gical, 
i m m u n ol o gical, 
d er mat ol o gic al, 
o p ht hal m ol o gical, ps yc hiatric, ge nit o uri n ar y, a n d s ur gic al hist or y a n d a n y ot her 
diseases or dis or ders. 
- 
E C O G perf or ma nce stat us.  
- 
Ot her pri or ( wit hi n 3 m o nt hs bef ore scree ni n g) a n d c o nc o mita nt me dicati o ns (see 
Secti o n 6. 8 ). 
 
T he f oll o wi n g will be perf or me d at scree ni n g: 
- 
C T/ M RI sca n a n d t u m o ur assess m e nt (s ee Secti o n 8. 1. 1 ). 
- 
Safet y assess me nts: p h ysical e xa mi nati o n, vital si g ns, 1 2-lea d E C G, gall bla d der 
ec h o gra p h y a n d cli nical s afet y la b orat or y tests (s ee Secti o n 8. 2. 1  t o Secti o n 8. 2. 5 ). 
- 
Pre g n a nc y test f or W O C B P (see Secti o n 8. 2. 6 ). 
- 
F ollicle sti m ulati n g h or m o ne ( F S H) t est (if re q uire d t o deter mi ne p ost m e n o pa usal 
stat us; see A p pe n di x 1 0. 4. 1 ). 
 
(e. g. bl o o d 
c o u nt) a n d o btai ne d bef ore si g ni n g of t he I C F ma y b e utilise d f or scree ni n g or baseli ne 
p ur p oses pr o vi de d t he pr oce d ures m et t he pr ot oc ol-s pecifie d criteria a n d w ere perf or m e d 
wit hi n t he ti mefra me defi ne d i n t he S o A (s ee T a ble 1 ). 
 
All scree ni n g e val u ati o ns m ust be c o m plete d a n d re vi e we d t o c o nfir m t hat p ote ntial 
partici pa nts meet all eli gi bilit y criteria. T he i n vesti gat or will m ai nt ai n a scree ni n g l o g t o 
rec or d d etails of all partici p a nts scree ne d a n d t o c o nfir m eli gi bilit y or rec or d reas o ns f or 
scree ni n g fail ure, as a p plica ble. 
T he pr oce d ures a n d assess me nts t o be perf or me d i n t he i nter ve nti o n peri o d a n d i n de pe n d e nt 
i njecti o n peri o d are descri be d i n Secti o n 8. 1  (efficac y), Secti o n 8. 2  a n d S ecti o n 8. 3  (safet y), 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 6 2/ 9 9 
 
 
 
Secti o n 8. 6  ( bi o mar kers) a n d Secti o n 8. 7  (i m m u n o ge nicit y). All assess me nts s h o ul d be 
perf or me d b ef ore st u d y i nter ve nti o n a d mi nistrati o n o n st u d y visit da ys. 
 
T he ma xi m u m a m o u nt of bl o o d c ollecte d fr o m ea c h partici pa nt o ver t he d urati o n of t h e 
st u d y, i ncl u di n g a n y e xtra assess me nts t hat ma y b e re q uire d, will n ot e x cee d 2 1 0 m L f or 
t he mai n st u d y ( or 2 6 0 m L f or p artici pa nts c o nti n ui n g i n t he i n de pe n de nt i njecti o n 
peri o d). 
 
Re peat or u ns c he d ule d s a m ples ma y be ta k e n f or s afet y r eas o ns or i n case of tec h nical 
iss ues wit h t he sa m ples. 
 
Earl y disc o nti n uati o n visit pr oce d ures s h o ul d be perf or m e d ( W 4 8/ E O SI/ E D or 
W 7 2/ E O SI/ E D as a p plica ble) f or partici pa nts w h o disc o nti n ue t h e st u d y. 
8. 1  
Effic ac y Ass ess me nts 
8. 1. 1  
T u m o ur Assess m e nt 
Dia g n ostic i ma gi n g will be perf or me d at s cree ni n g ( b aseli ne), W 1 2, W 2 4, W 3 6 a n d 
W 4 8. 
A f urt her sca n will be perf or me d at W 7 2 f or p artici pa nts c o nti n ui n g i n t he i n de pe n de nt i nje cti o n 
peri o d. 
A C T sca n is t h e preferre d met h o d of t u m o ur meas ure me nt a n d will be use d w he ne ver p ossi ble. 
Ma g n etic res o n a nce i ma gi n g ma y b e use d b ut s h o ul d be c o nsi dere d as a n alter nati ve met h o d. 
I n or d er t o e ns ure c o m p ara bilit y bet wee n t u m o ur assess m e nts, t he s a m e met h o d of t u m o ur 
meas ure me nt m ust be use d t hr o u g h o ut t he st u d y f or eac h p artici pa nt, w h ere ver p ossi bl e. 
At scree ni n g ( baseli ne), t he f oll o wi n g s h o ul d be p erf or me d: 
 
C T or M RI of t he nec k, c hest, a b d o me n a n d pel vis i n t he 4 wee ks bef ore t he start of st u d y 
i nter ve nti o n. 
 
C T or M RI of t he hea d, b o ne s ci nti gra p h y or fl u or o de o x y gl u c ose- p ositr o n e missi o n 
t o m o gra p h y ( F D G- P E T), C T or M RI of b o ne l esi o ns bef ore t he first d ose of st u d y 
i nter ve nti o n. 
At W 1 2, W 2 4, W 3 6 a n d W 4 8 (a n d W 7 2, if a p plica ble) t he f oll o wi n g s h o ul d be perf or me d: 
 
Dia g n ostic i ma gi n g test ( C T or M RI) of t he he a d. 
If t he scree ni n g test re v eals a lesi o n i n t h e brai n or pit uit ar y gla n d or if cli nic all y i n dicate d, 
t he sa me dia g n ostic i ma gi n g t est s h o ul d be re peate d. 
 
Dia g n ostic i ma gi n g test ( C T or M RI) of t he nec k, c hest, a b d o me n a n d p el vis. 
 
Dia g n ostic i ma gi n g test of b o ne lesi o ns ( b o ne s ci nti gra p h y or F D G- P E T, C T or M RI). 
If t h e scree ni n g test re veale d a b o ne lesi o n or if cli nicall y i n dicate d, assess me nt s h o ul d 
be perf or me d usi n g t he sa me met h o d. 
T u m o ur res p o nse will be ass esse d acc or di n g t o R E CI S T Versi o n 1. 1 [ Eise n ha uer 2 0 0 9 ]. 
Data will be re vi e we d l ocall y b y t he l o cal ra di ol o gist/i n vesti gat or at t he st u d y site a n d als o 
sa ve d i n di gital f or m at a n d s e nt f or BI C R a cc or di n g t o i nstr ucti o ns i n t he I ma gi n g M a n ual. I n 
or der t o pre ve nt t he dis cl os ur e of p ers o nal d etails, partici pa nt i nf or m ati o n s h o ul d be 
a n o n y mise d i n a ma n ner t hat i n di vi d uals ca n n ot be i de ntifie d w h e n s u b mitti n g i ma ge d ata. T h e 
BI C R will be perf or me d as s pecifie d i n t he I n de pe n de nt R e vie w C harter. 
T he l ocal assess me nt will be use d f or t he cli nical ma na ge me nt of t he st u d y p artici pa nt 
(e. g. w het her t o disc o nti n ue d u e t o dis ease pr o gressi o n). partici pa nt ma n a ge me nt will be at t he 
i n vesti gat or's discreti o n. 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 6 3/ 9 9 
 
 
 
8. 1. 2  
Cli nic al Pr o gressi o n 
T he i n vesti gat or will rec or d a n y cli nical/ bi ol o gical si g ns of t u m o ur pr o gressi o n a n d, w here 
a p plica ble, a d diti o nal t u m o ur assess m e nts s h o ul d be perf or m e d t o deter mi ne ra di ol o gi cal 
pr o gressi o n f oll o wi n g t he pr oce d ure i n Secti o n 8. 1. 1 . 
8. 1. 3  
Ne ur oe n d ocri ne T u m o ur Cli nic al Sy m pt o ms 
T he pres e nce or a bse nce of e n d ocri ne s y m pt o ms of N E Ts (e. g. fl us hi n g, di arr h oea, a b d o mi nal 
pai n, wea k ness, heart b ur n, na us ea, v o mit, s weati n g, tre m or, pal pitati o n, or er yt h e ma) will be 
assess e d b y t he i n vesti gat or at scree ni n g.  
I n partici pa nts wit h s y m pt o ms of N E Ts at scree ni n g, a baseli ne assess me nt of t he s y m pt o ms 
e x perie nce d i n t he last 4 wee ks will be perf or me d b y q u esti o ni n g bef ore st u d y i nter v e nti o n 
a d mi nistrati o n at Da y 1. T hese s y m pt o ms will be rec or d e d i n t he C R F. 
F or partici pa nts wit h diarr h oea a n d/ or fl us hi n g at baseli ne, a diar y will be dis pe ns e d at Da y 1 
a n d t he partici pa nts will be i nstr ucte d t o rec or d t he n u m b er of diarr h oea a n d/ or fl us hi n g 
e pis o des per da y a n d a n y m e dicati o ns t a ke n t o treat t hese s y m pt o ms d uri n g t he i nt er ve nti o n 
peri o d (a n d t he i n de p e n de nt i njecti o n peri o d, if a p plica ble). At eac h visit, t he diar y will be 
re vie we d a n d c ollecte d b y t h e i n vesti gat or, a n d a ne w diar y will be dis pe nse d. T he i n vesti gat or 
will e nter i nf or mati o n of diarr h oea a n d/ or fl us hi n g deter mi ne d t o be ass ociate d wit h N E Ts i n 
t he C R F (t he fre q ue nc y of diarr h o ea a n d/ or fl us hi n g, t he s e verit y gra de d u p o n C T C A E 5. 0 a n d 
t he use of a n y resc u e me dicati o n). 
F or partici pa nts wit h ot her s y m pt o ms at baseli ne, t hese s y m pt o ms will be assesse d b y t he 
i n vesti gat or b y q u esti o ni n g at eac h visit d uri n g t he i nt er ve nti o n peri o d (a n d t he i n de pe n de nt 
i njecti o n peri o d, if a p pli ca ble). T he i n vesti gat or will e nter t h e i nf or mati o n of t he s y m pt o ms 
deter mi ne d t o be ass o ci ate d wit h N E Ts i n t he C R F ( dis a p peare d, rea p peare d, i m pr o ve d, 
a g gra vat e d or n o c ha n ge, se verit y gra d e d u p o n C T C A E 5. 0 a n d t he use of a n y resc ue 
me dicati o n). 
8. 1. 4  
Circ ul ati n g Bi o m ar kers  
Bi o mar ker assess me nts are descri be d i n S ecti o n 8. 6 . 
8. 1. 5  
Q u ality of Life 
Partici pa nt re p ort e d o utc o mes will be assesse d usi n g t he E ur o pea n Or ga nisati o n f or Researc h 
a n d Treat m e nt of Ca ncer Q ualit y of Life Q u esti o n naire f or C a ncer P atie nts ( E O R T C Q L Q-
C 3 0) at baseli ne ( Da y 1), W 1 2, W 2 4, W 3 6 a n d W 4 8 (see A p pe n di x 1 0. 6 ). A f urt her assess me nt 
will be perf or me d at W 7 2 f or partici pa nts c o nti n ui n g i n t he i n de pe n de nt i njecti o n peri o d. T he 
u n der t he sa m e c o n diti o ns t hr o u g h o ut t he st u d y, w here ver p ossi ble. 
T he q uesti o n naire f or m s h o ul d be c o m plete d bef ore a n y assess me nts or pr oce d ures, i ncl u di n g 
st u d y i nter ve nti o n a d mi nistrati o n o n t he visit da y a n d bef ore a n y c o ns ultati o n wit h t he 
i n vesti gat or i n relati o n t o diseas e stat us. 
C o m plete d q uesti o n naires will be re vie we d b y t he i n vesti gat or or desi g nate d st u d y sit e 
pers o n nel. I n v esti gat ors m ust n ot e nc o ura ge t he partici pa nts t o c ha n ge a n y res p o ns es. 
8. 1. 6  
S urviv al St at us 
T he date of deat h or last k n o w n t o be ali ve d ate will be rec or d e d t o deter mi ne O S. W het her t he 
deat h was rel ate d t o N E T (if k n o w n) will als o b e rec or de d. F or partici pa nts t hat are l ost t o 
f oll o w- u p or wit h dra w c o nse nt, atte m pts t o deter mi ne s ur vi val stat us s h o ul d be ma de b y access 
t o p u blic rec or ds, as p er mitte d b y l ocal l a w. 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 6 4/ 9 9 
 
 
 
After t h e e n d of st u d y ass ess me nts, a tel e p h o ne call will be use d t o c ollect s ur vi val stat us ( dat e 
of c o ntact, ali ve/ de a d, d ate of d eat h, w het her deat h is rel at e d t o N E T if k n o w n) a n d s u bse q ue nt 
t hera pies ( d os e, u nit, fre q ue nc y, start a n d st o p date) starte d si nce t h e pre vi o us c o ntact.  
T he data will be c oll ecte d wit hi n 4 w ee ks after t he last partici pa nt i n t he mai n st u d y reac h es 
W 4 8 or t he da y of disc o nti n uati o n.  
T he data will be als o c ollecte d wit hi n 4 wee ks aft er t he last partici pa nt e nr olle d i n t he 
i n de pe n de nt i njecti o n peri o d reac h es W 7 2 or t he da y of disc o nti n uati o n. 
8. 1. 7  
He alt hc are Pr ofessi o n al vers us I n de pe n de nt i njecti o n 
Partici pa nts c o nti n ui n g i n t he i n de pe n de nt i nj ecti o n peri o d will be as k e d if t he y prefer 
i n de pe n de nt i njecti o n or H C P i njecti o ns at t he e n d of t he i n de p e n de nt i njecti o n peri o d ( W 7 2). 
8. 2  
S afet y Assess me nts 
A d verse e ve nt re c or di n g a n d re p orti n g is det ail e d i n S ecti o n 8. 3 . 
Pla n ne d ti me p oi nts f or all s afet y assess me nts are pr o vi de d i n t he S o A ( Ta ble 1 ). 
8. 2. 1  
P hysic al E x a mi n ati o ns 
A c o m plete p h ysical e xa mi nati o n will be carrie d o ut b y t he i n vesti gat or or me dicall y q u alifie d 
desi g n ee at scree ni n g, b aseli ne ( Da y 1) a n d s u bse q ue nt visits t o t he st u d y sit e i n t he i nter ve nti o n 
peri o d (a n d i n de p e n de nt i njecti o n peri o d if a p plic a ble) as p er Ta bl e 1 . 
A c o m plete p h ysical e x a mi nati o n 
will i n cl u de, at a 
mi ni m u m, assess me nts of t he 
car di o vasc ular, res pirat or y, gastr oi ntesti nal a n d ne ur ol o gical s yste ms. 
Wei g ht will als o be 
meas ure d a n d rec or de d. 
I n v esti gat ors s h o ul d pa y s pecial atte nti o n t o cli ni cal si g ns relat e d t o pre vi o us s eri o us ill nesses. 
A n y cli nic all y si g nifica nt a b n or malities/c ha n ges fr o m baseli ne i n acc or d a nce wit h t he N CI 
C T C A E Versi o n 5 [ N CI C T C A E 2 0 1 7 ] s h o ul d be rec or de d as a n A E at t he discreti o n of t he 
i n vesti gat or.  
8. 2. 2  
Vit al Si g ns 
Vital si g ns will be meas ure d at scree ni n g, bas eli ne ( Da y 1) a n d s u bse q ue nt visits t o t he st u d y 
site i n t he i nt er ve nti o n peri o d (a n d i n de pe n d e nt i njecti o n peri o d if a p plica ble) as p er Ta ble 1 . 
 
Te m perat ure, p uls e rat e, res pirat or y rate, a n d bl o o d press ure will be assess e d. 
 
Bl o o d press ure a n d p ulse meas ure me nts will be assesse d i n a se mi-s u pi ne p ositi o n wit h 
a c o m pletel y a ut o mate d de vice. M a n ual tec h ni q u es will be use d o nl y if a n a ut o mat e d 
de vice is n ot a vaila ble. 
- 
Bl o o d press ure a n d p ulse meas ure me nts s h o ul d be prece d e d b y at least 5 mi n utes 
of rest f or t he p artici pa nt i n a q uiet setti n g wit h o ut distracti o ns (e. g. tel e visi o n, cell 
p h o nes). 
 
Vital si g ns are t o be ta ke n bef ore bl o o d c ollecti o n if perf or m e d t he sa me d a y. 
 
A n y cli nicall y si g nifica nt a b n or malities/c h a n ges fr o m baseli ne i n t he o pi ni o n of t he 
i n vesti gat or i n a cc or da nce wit h N CI C T C A E Versi o n 5 [N CI C T C A E 2 0 1 7 ] s h o ul d be 
rec or d e d as a n A E at t he discreti o n of t he i n vesti gat or.  
8. 2. 3  
G all bl a d der Ec h o gr a p h y 
Gall bla d der ec h o gra p h y will be perf or me d i n all partici pa nts u nless t he y ha ve a d oc u me nte d 
c h olec ystect o m y. A gall bl a d der ec h o gra p h y will b e carrie d o ut b y t he i n v esti gat or or me dicall y 
q ualifie d desi g nee at scree ni n g, W 2 4 a n d W 4 8 ( pl us W 7 2 f or partici p a nts c o nti n ui n g i n t he 
i n de pe n de nt i njecti o n peri o d). 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 6 5/ 9 9 
 
 
 
T he prese n ce of lit hi asis a n d sl u d ge will be ass ess e d a n d rec or de d ( Yes/ N o) i n t he C R F. 
U ns c he d ule d ass ess me nts s h o ul d be perf or me d at a n y ti me if s y m pt o ms are t h o u g ht t o be 
relate d t o gall bla d der lit hiasis. 
A b n or mal test fi n di n gs t hat res ult i n st u d y i nter ve nti o n disc o nti n uati o n or re q uire i nter ve nti o n 
or dia g n ostic e val uati o n t o ass ess t he ris k t o t he partici pa nt, s h o ul d be rec or de d as A Es. 
8. 2. 4  
Electr oc ar di o gr a ms 
 
Si n gle 1 2-lea d E C G will be o btai ne d at scree ni n g, 
W 2 4 a n d 
W 4 8 ( pl us 
W 7 2 f or 
partici pa nts c o nti n ui n g i n t he i n de pe n de nt i njecti o n peri o d) acc or di n g t o st u d y site 
sta n dar d pr o ce d ures. A n E C G mac hi ne t hat a ut o maticall y cal c ulates t h e heart rat e a n d 
meas ures P R, Q R S, Q T a n d Q Tc B or Q T c F i nt er v als s h o ul d be use d. St u d y i nter ve nti o n 
disc o nti n uati o n criteria f or Q T c a n d a n y a d diti o nal rea di n gs t hat ma y be necessar y are 
s pecifie d i n S ecti o n 7. 1. 2 . 
 
A n y cli nicall y si g nifica nt a b n or malities/c h a n ges fr o m baseli ne i n t he o pi ni o n of t he 
N CI C T C A E 2 0 1 7 ] s h o ul d be 
rec or d e d as a n A E at t he discreti o n of t he i n vesti gat or. 
8. 2. 5  
Cli nic al S af ety L a b or at ory Assess m e nts 
Cli nical la b orat or y s afet y tests t o be perf or m e d will be perf or me d at scree ni n g, b aseli ne ( Da y 1) 
a n d W 2 4 a n d W 4 8 ( pl us W 7 2 f or partici pa nts c o nti n ui n g t he i n de pe n d e nt i njecti o n peri o d). 
 
T he list of pr ot oc ol-re q uire d cli nical s afet y l a b orat or y tests t o be p erf or me d is pr o vi de d 
i n Ta ble 7 . All pr ot oc ol-re q uire d la b orat or y tests m ust be c o n d ucte d i n acc or da nce wit h 
t he La b orat or y M a n ual a n d t he S o A (Ta ble 1 ). 
 
T he i n vesti gat or m ust re vie w t he la b orat or y re p ort, d oc u me nt t his re vie w, a n d rec or d a n y 
cli nicall y si g nific a nt c ha n ges o cc urri n g d uri n g t he st u d y as a n A E. T h e la b orat or y re p orts 
m ust be file d wit h t he s o urce d oc u me nts.  
 
A b n or mal la b orat or y fi n di n gs ass oci ate d wit h t he u n d erl yi n g disease are n ot c o nsi dere d 
cli nicall y si g nifica nt u nless j u d ge d b y t he i n vesti gat or t o be m ore se vere t ha n e x pecte d 
f or t he partici p a nt's c o n diti o n. 
 
All la b orat or y t ests wit h val ues c o nsi dere d cli nicall y si g nifi ca ntl y a b n or mal d uri n g 
partici pati o n i n t he st u d y or peri o d of ti me after t he last d ose of st u d y i nter ve nti o n j u d ge d 
reas o na bl e b y t he i n vesti gat or s h o ul d b e r e p eat e d u ntil t he val ues ret ur n t o n or mal or 
baseli ne or are n o l o n ger c o nsi dere d cli nicall y si g nifica nt b y t he i n vesti gat or or me dical 
m o nit or. 
 
If cli nicall y si g nifica nt v al ues d o n ot ret ur n t o n or mal/ baseli ne wit hi n a peri o d of ti me 
j u d ge d reas o na bl e b y t he i n vesti gat or, t he aeti ol o g y s h o ul d be i de ntifie d, a n d t he s p o ns or 
n otifie d. 
 
If la b orat or y val u es fr o m n o n pr ot oc ol s pecifi e d la b orat or y tests perf or m e d at t he st u d y 
cli nicall y si g nifi ca nt b y t he i n vesti gat or (e. g. S A E or A E or d ose m o dificati o n), t he n t he 
res ults m ust be rec or de d i n t he C R F. 
8. 2. 6  
Pre g n a ncy Testi n g 
Refer t o I ncl usi o n Criteri o n ( 7) i n Secti o n 5. 1  f or pre g na nc y testi n g e ntr y criteria a n d Ta bl e 1 . 
A d diti o nal ser u m or uri ne pre g na n c y tests ma y be perf or me d, as det er mi n e d necess ar y b y t he 
i n vesti gat or or r e q uire d b y l o cal re g ul ati o n, t o est a blis h t h e a bs e nce of pre g n a nc y i n a 
partici pa nt at a n y ti me d uri n g t he st u d y. 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 6 6/ 9 9 
 
 
 
8. 3  
A d verse E ve nts ( A Es) a n d Seri o us A d verse E ve nts ( S A Es), a n d Ot h er S afet y 
Re p orti n g 
T he defi niti o ns of A Es a n d S A Es ca n b e f o u n d i n A p pe n di x 1 0. 3. 1  a n d A p pe n di x 1 0. 3. 2 , 
res pecti v el y. 
A d verse e ve nts (i ncl u di n g i njecti o n sit e-relat e d reacti o ns) will be re p orte d b y t h e partici pa nt 
( or, w he n a p pr o priate, b y a care gi v er, s urr o gate, or t he partici pa nt's le gall y a ut h oris e d 
re pres e ntati ve). 
T he i n vesti gat or a n d a n y q ualifie d desi g nees ar e res p o nsi ble f or d etecti n g, d oc u me nti n g, a n d 
rec or di n g e ve nts t h at meet t he defi niti o n of a n A E or S A E a n d re m ai n res p o nsi ble f or f oll o wi n g 
u p all A Es (see Secti o n 7 ). 
8. 3. 1  
Ti m e Peri o d a n d Fre q ue ncy 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 olle cte d c o nti n u o usl y fr o m o bt ai ni n g i nf or me d c o nse nt u ntil t he E O SI visit 
( 2 8 da ys after t he last d ose of st u d y i nt er v e nti o n) as s pecifie d i n t he S o A (Ta ble 1 ). T his 
i ncl u des me dical oc c urre nces t hat be gi n bef ore t h e start of st u d y i nter ve nti o n. 
I n v esti gat ors are n ot o bli gat e d t o acti vel y see k i nf or mati o n o n A Es or S A Es after c o n cl usi o n of 
t he st u d y partici pati o n. H o we ver, if t he i n vesti gat or lear ns of a n y S A E, i ncl u di n g a d eat h, at 
a n y ti me after a p artici pa nt has bee n disc har ge d fr o m t he st u d y, a n d he/s he c o nsi ders t he e ve nt 
t o b e reas o na bl y relate d t o t he st u d y i nter ve nti o n or st u d y partici pati o n, t he i n vesti gat or m ust 
pr o m ptl y n otif y t he s p o ns or. 
8. 3. 2  
Met h o d of Detecti n g A Es a n d S A Es 
Care will 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 nlea di n g ver bal q uesti o ni n g of t he partici pa nt is t he preferre d met h o d t o i n q uire a b o ut 
A E occ urre nces. 
8. 3. 3  
Rec or di n g a n d Re p orti n g A Es a n d S A Es 
T he met h o d of rec or di n g, e val uati n g, a n d assessi n g ca usalit y of A Es a n d S A Es a n d t he 
pr oce d ures f or c o m pleti n g a n d tra ns mitti n g S A E re p orts is pr o vi de d i n A p p e n di x 1 0. 3. 3 . 
All S A Es will be rec or de d a n d re p ort e d t o t he s p o ns or or desi g n ee i m me di atel y a n d u n der n o 
circ u mst a nc e s h o ul d t his e x cee d 2 4 h o urs of a ware ness of t he e v e nt, as i n dic ate d i n 
A p pe n di x 1 0. 3. 4 . T he i n vesti gat or will s u b mit a n y u p d ate d S A E d ata t o t he s p o ns or wit hi n 
2 4 h o urs of it bei n g a vail a ble. 
8. 3. 4  
F oll o w- u p of A Es a n d S A Es 
After t he i nitial A E/ S A E re p ort, t he i n vesti gat or is re q uire d t o pr oacti vel y f oll o w eac h 
partici pa nt at s u bse q ue nt visits/c o ntacts. 
All S A Es 
will be f oll o we d u ntil res ol uti o n, 
sta bilisati o n, t he e ve nt is ot her wise e x plai ne d, or t he partici pa nt is l ost t o f oll o w- u p (as defi ne d 
i n Secti o n 7. 3 ). F urt her i nf or mati o n o n f oll o w- u p pr oce d ures is pr o vi de d i n A p pe n di x 1 0. 3. 3 . 
8. 3. 5  
Re g ul at ory Re p orti n g Re q uire m e nts f or S A Es 
 
Pr o m pt n otificati o n b y t h e i n vesti gat or t o t he s p o ns or of a n S A E is ess e ntial s o t hat le gal 
o bli gati o ns a n d et hical res p o nsi biliti es t o war ds t he safet y of partici pa nts a n d t he safet y 
of a st u d y i nter ve nti o n u n der cli nical i n vesti gati o n are met. 
 
T he s p o ns or has a le gal res p o nsi bilit y t o n otif y b ot h t he l ocal r e g ulat or y a ut h orit y a n d 
ot her re g ulat or y a ge n cies a b o ut t he safet y of a st u d y i nter v e nti o n u n der cli nical 
i n vesti gati o n. T he s p o ns or will c o m pl y wit h c o u ntr y-s p ecific re g ulat or y re q uire m e nts 
relati n g t o s afet y re p orti n g t o t he re g ulat or y a ut h orit y, I R B/I E C a n d i n vesti gat ors. 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 6 7/ 9 9 
 
 
 
 
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 n S A E or ot her 
s pecific safet y i nf or m ati o n (e. g. s u m mar y or listi n g of S A Es) fr o m t he s p o ns or will 
re vie w a n d t he n file it al o n g wit h t he I
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. 
 
I n v esti gat or safet y re p orts m ust be pre pare d f or s us pect e d u ne x pecte d seri o us a d verse 
reacti o ns ( S U S A R) acc or di n g t o l ocal re g ul at or y re q uire me nts a n d s p o ns or p olic y a n d 
f or war de d t o i n vesti gat ors as necess ar y. 
8. 3. 6  
Pre g n a ncy 
 
Details of all pre g na ncies i n fe m ale p artici pa nts a n d, if i n dicat e d, fe male part ners of male 
partici pa nts will be c ollecte d fr o m t he si g ni n g of t he I C F a n d u ntil 9 0 da ys after t he last 
d ose of st u d y i nter ve nti o n. 
 
If a pre g na nc y is re p ort e d, t h e i n vesti gat or will rec or d pre g na n c y i nf or mati o n o n t he 
a p pr o priate f or ms ( S A E f or m i n t he C R F a n d Dr u g E x p os ure F or m 
 pa p er f or m) a n d 
s u b mit t o t he s p o ns or wit hi n 2 4 h o urs of lear ni n g of t he pre g na n c y (fe m al e partici p a nt 
or fe m ale part ner of male partici pa nt (after o bt ai ni n g t he necessar y si g n e d i nf or me d 
c o nse nt fr o m t he fe m ale part ner)). 
 
A n y pre g n a nc y c o m plicati o n or electi ve ter mi nati o n of a pre g na n c y f or me dical reas o ns 
will be re p orte d as a n A E or S A E. 
 
A b n or mal pre g na nc y o utc o mes (e. g. s p o nt a ne o us a b orti o n, f o etal d eat h, still birt h, 
c o n ge nital a n o malies, ect o pic pre g na nc y) are c o nsi dere d S A Es a n d will b e re p orte d as 
s uc h. 
 
T he parti ci pa nt/ pre g n a nt fe mal e part n er will be f oll o we d t o deter mi ne t he o utc o me of t he 
pre g na nc y. 
T h e 
i n vesti gat or 
will 
c ollect 
f oll o w- u p 
i nf or m ati o n 
o n 
t he 
partici pa nt/ pre g na nt fe m ale part n er a n d t he ne o nate, a n d t he i nf or mati o n will be 
f or war de d t o t he s p o ns or. 
 
A n y p ost-st u d y pre g n a n c y-rel ate d S A E c o nsi dere d reas o na bl y relate d t o t he st u d y 
i nter ve nti o n b y t he i n vesti gat or will be re p ort e d t o t he s p o ns or as descri be d i n 
Secti o n 8. 3. 5 . W hil e t he i n v esti gat or is n ot o bli gate d t o acti vel y see k t his i nf or mati o n i n 
f or mer st u d y partici p a nts/ pre g na nt fe male part ner, he or s he ma y lear n of a n S A E t hr o u g h 
s p o nta ne o us re p orti n g. 
 
A n y fe male p artici pa nt w h o bec o mes pre g na nt w hile partici pati n g i n t he st u d y will be 
disc o nti n ue d fr o m st u d y i nter ve nti o n (s ee S ecti o n 7 ). 
8. 3. 7  
Dise ase- Rel at e d E ve nts a n d/ or Dis e ase- Rel ate d O utc o m es N ot Q u alifyi n g as A Es 
or S A Es 
Disease-rel ate d e ve nts ( D R Es) relate d t o N E T cli nical s y m pt o ms (i n partici pa nts wit h 
f u ncti o nal N E Ts) or dis ease pr o gressi o n (i ncl u di n g m etastas es) s h o ul d be rec or de d as part of 
t he efficac y e val uati o n (s ee S ecti o n 8. 1. 1  a n d Secti o n 8. 1. 3 ) a n d n ot as A Es/ S A Es: 
N O T E: H o we v er, if eit her of t he f oll o wi n g c o n diti o ns a p plies, t he n t he e v e nt m ust be rec or d e d 
a n d re p orte d as a n A E/ S A E (i nstea d of a D R E): 
 
t ha n e x pecte d f or t he i n di vi d ual partici pa nt. 
O R 
 
T he i n vesti gat or c o nsi ders t hat t here is a reas o na ble p ossi bilit y t hat t he e ve nt was relate d 
t o st u d y i nter ve nti o n. 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 6 8/ 9 9 
 
 
 
8. 3. 8  A dverse Eve nts of S peci al I nter est  
N ot a p pli ca ble. N o A Es of s pecial i nt erest ha ve b ee n defi n e d f or t his st u d y. 
8. 3. 9  Re p orti n g of St u dy I nter ve nti o n Err ors i ncl u di n g Mis us e/ A b us e 
 
Me dicati o n err ors are u ni nte nti o nal err ors i n t he prescri bi n g, dis pe nsi n g, a d mi nistrati o n 
or m o nit ori n g of a st u d y i nter ve nti o n ( me dici nal pr o d uct) w hile u n d er t he c o ntr ol of a 
healt hcare pr ofessi o nal, partici pa nt or c o ns u m er ( E ur o pea n M e dici n es A ge nc y ( E M A) 
defi niti o n). 
 
Mis use refers t o sit uati o ns 
w here t he st u d y i nter ve nti o n is i nte nti o nall y a n d 
i na p pr o priatel y use d n ot i n acc or d a nce wit h t he pr ot oc ol. 
 
A b us e c orres p o n ds t o t he persiste nt or s p ora dic, i nte nti o nal e x cessi ve use of a me dici nal 
pr o d uct, w hic h is acc o m pa nie d b y har mf ul p h ysic al or ps yc h ol o gical effects. 
 
St u d y i nter v e nti o n err ors a n d uses o utsi de of w hat is f oresee n i n t he pr ot oc ol will be 
rec or d e d i n t he C R F irres pecti ve of w het her ass o ciate d wit h a n A E/ S A E or n ot. It will 
als o be d o c u me nte d i n t he A E secti o n of t he C R F if ass oci ate d wit h a n A E. It will be 
re p orte d i n t he safet y dat a base o nl y if ass o ciate d wit h a n S A E.  
 
Mis use or a b use will be c ollecte d a n d re p orte d i n t he safet y dat a base, w het h er ass o ciate d 
or n ot wit h a n A E/ S A E, w
 
8. 4  
P h ar m a c o ki n etics 
N ot a p pli ca ble. P har mac o ki netics are n ot e v al uate d i n t his st u d y. 
8. 5  
Ge neti cs a n d/ or P h ar m ac o ge n o mics 
N ot a p pli ca ble. Ge netics are n ot e v al uat e d i n t his st u d y. 
8. 6  
Bi o m ar kers 
F ull details o n pr ocesses f or c oll ecti o n, st ora ge, s hi p m e nt t o t he ce ntral la b orat or y a n d 
destr ucti o n of sa m ples ca n be f o u n d i n t he La b orat or y M a n ual.  
Bl o o d a n d uri ne sa m ples will be c ollecte d at b aseli ne ( Da y 1), W 1 2, W 2 4, W 3 6 a n d W 4 8 ( pl us 
W 7 2 f or partici p a nts c o nti n ui n g i n t he i n de p e n d e nt i njecti o n peri o d) t o meas ure circ ulati n g 
C g A, 5- HI A A a n d ot her bi o mar kers.  
C hr o m o gra ni n A is e x presse d i n 8 0 t o 9 0 % of all G E P- N E Ts a n d he n ce i n partici pa nts i n t his 
st u d y. C hr o m o gra ni n A d eter mi nati o n is als o us ef ul f or sta gi n g, pr o g n osis a n d f oll o w u p, si nce 
t he ser u m c o nce ntrati o n c orrel ates t o t he t u m o ur mass. 5- h y dr o x yi n d oleacetic aci d, t he maj or 
meta b olite of s er ot o ni n, is of val ue f or dia g n osis of N E Ts a n d c orrelat es wit h s e verit y of 
carci n oi d s y n dr o m e. 
 
T he f oll o wi n g bl o o d sa m ples will be ta ke n, a n d sa m pli n g dates a n d ti mes will be 
rec or d e d i n t he C R F: 
- 
A 5 m L sa m ple will be ta ke n t o ass ess C g A. 
- 
A 5 m L s a m ple mi g ht be ta ke n t o assess ot her bi o mar k ers (e. g. gastri n, gl uca g o n 
a n d i ns uli n, if a p plica ble). 
 
A 2 4- h o ur uri ne c oll ecti o n at h o me pri or t o eac h sc he d ule d visit is re q uire d t o assess 
5- HI A A. Partici p a nts will be pr o vi de d wit h a rece ptacle b y t he st u d y sit e f or t his p ur p ose. 
T he c ollecti o n p eri o d will be gi n o n ce t he partici pa nt has e m ptie d his/ her bla d der ( n ot 
i nt o t he c oll ecti o n rece ptacle) aft er wa ki n g u p o n t he m or ni n g of t he da y pri or t o t he visit. 
T his ti m e s h o ul d be rec or de d o n t he rece ptacle. 
T he partici pa nt will be i nstr ucte d t o c oll ect all t heir uri ne i n t he rece pt acle f or a peri o d of 
2 4 h o urs a n d bri n g t he sa m pl e t o t he s c he d ule d visit. D u e t o t he p ote ntial i nterfere nce wit h t he 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 6 9/ 9 9 
 
 
 
assa y f or 5- HI A A, p artici pa nts will be i nstr ucte d n ot t o eat ba na nas, pi n ea p ple, pl u ms, wal n uts, 
e g g pla nt, t o mat oes, c h o c olate or a v oca d o d uri n g t he uri ne c ollecti o n peri o d a n d t he 7 2 h o urs 
pri or t o eac h c ollecti o n. At t he st u d y visits t he i n vesti gat or will q uesti o n t he p arti ci pa nt a b o ut 
his/ her diet o ver t he c oll ecti o n peri o d. At t he e n d of t he c ollecti o n peri o d t he partici pa nt s h o ul d 
e m pt y his/ her bla d d er as f ull y as p ossi bl e i nt o t he c ollecti o n rece ptacle a n d rec or d t he ti me. 
T he c oll ecte d uri ne will b e gi ve n t o t he i n vesti gat or ( or d esi g nee), w h o will m eas ure t he v ol u m e 
of uri ne c oll ecte d a n d rec or d t his, al o n g wit h t he start a n d st o p ti mes of t he c oll ecti o n peri o d, 
i n t he C R F. A s a m pl e of t he t otal uri ne will be ta k e n t o be se nt f or a nal ysis. 
I n a d diti o n, uri nar y creati ni ne will be a nal ys e d i n or der t o assess c o m pli a nce wit h t he 2 4- h o ur 
c ollecti o n peri o d. 
Sa m ples will be a nal ys e d usi n g vali date d met h o ds. 
8. 7  
I m m u n o ge nicit y Ass ess me nts 
P utati ve a nti b o dies t o la nre oti de will be e val uate d i n ser u m sa m pl es c ollecte d fr o m all 
partici pa nts at baseli ne ( Da y 1), W 2 4 a n d W 4 8. A d diti o nall y, ser u m s a m ples s h o ul d als o be 
c ollecte d at t he fi nal visit fr o m partici pa nts w h o disc o nti n ue d st u d y i nter ve nti o n or were 
wit h dra w n fr o m t he st u d y. T hes e sa m ples will be teste d b y t he s p o ns or or s p o ns or's d esi g nee. 
At eac h ti me p oi nt, 5 m L bl o o d s a m ples will be c ollecte d, a n d t h e sa m pli n g data a n d ti me 
rec or d e d i n t he C R F. F ull details o n pr ocess es f or c ollecti o n, st ora ge, s hi p m e nt t o t he ce ntral 
la b orat or y a n d d estr ucti o n of sa m ples ca n b e f o u n d i n t he La b orat or y M a n ual. 
T he deter mi nati o n of p utati ve a nti-la nre oti de a nti b o dies 
will be e val uate d usi n g a n 
Electr o C he mi L u mi nesce nt assa y ( E C L A) v ali date d m et h o d. 
8. 8  
He alt h Ec o n o mics or Me dic al Res o urce Utilis ati o n a n d H e alt h Ec o n o mics 
Healt h ec o n o mi cs will be e val uate d i n t he fi v e partici pa nts c o nti n ui n g i n t he i n de pe n de nt 
i njecti o n peri o d. Partici pa nts will be i nter vie we d at t he W 4 8 a n d W 7 2 visits a n d t he f oll o wi n g 
i nf or mati o n c ollecte d: 
 
I n direct c osts will be assesse d usi n g a bes p o ke q u esti o n naire (see A p pe n di x 1 0. 7 ): 
- 
Tra vel ti m e t o h os pital visits. 
- 
 
- 
M o de of tra ns p ort t o h os pit al/ cli nic visits (i.e. car, trai n b us, etc.) 
- 
C ost of tra vel t o a h os pital/cli nic visit f or treat me nt - partici p a nt a n d fri e n d/fa mil y 
me m ber, if a p pr o priate. 
- 
Ti me s pe nt at h os pital. 
- 
Mai n acti vities misse d d ue t o atte n di n g h os pit al a p p oi nt me nts f or treat me nt 
(i.e. pai d w or k, c hil dcare, v ol u nteeri n g). 
- 
I m pact of s witc h i n a d mi nistrati o n s etti n g o n mai n dail y acti vities. 
 
W or k-rel ate d pr o d ucti vit y ( w h ere rel e va nt) will be assess e d usi n g t he W or k Pr o d ucti vit y 
a n d Acti vit y Q uesti o n naire: Ge neral Healt h ( W P AI: G H) (s ee A p pe n di x 1 0. 6 ): 
- 
H o urs of w or k misse d d u e t o pr o ble ms ass ociate d wit h G E P- N E Ts. 
- 
I m pact of healt h o n w or k pr o d ucti vit y. 
- 
I m pact of healt h o n a bilit y t o carr y o ut e v er y da y acti vities ( ot her t ha n w or k). 
 
I n a d diti o n, t he i m pact of s witc h i n a d mi nistrati o n setti n g o n o verall a bilit y t o w or k will 
be assesse d usi n g a b es p o ke q u esti o n naire ( A p pe n di x 1 0. 8 ). 
 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 7 0/ 9 9 
 
 
 
9  
S T A TI S TI C A L C O N SI D E R A TI O N S 
9. 1  
St atistic al H y p ot heses 
C B R at t he e n d of 2 4 wee ks of st u d y i nter ve nti o n. T he t hres h ol d C B R at W 2 4 was defi ne d as 
4 0 %.  
9. 2  
S a m ple Size Deter mi n ati o n 
A p pr o xi m atel y 5 1 partici pa nts will be e nr olle d t o ac hie ve 4 3 recei vi n g  st u d y i nter ve nti o n i n t he 
mai n st u d y p eri o d a n d 3 6 partici pa nts e val ua ble f or C B R at 
W 2 4. Base d o n C hi nese 
e pi de mi ol o g y, it is e x pect e d t o h a ve t h e rel e va nt re prese ntati o n of all t y p es of G E P- N E Ts i n 
t he C hi nes e p o p ulati o n, i ncl u di n g P a n- N E T a n d GI- N E T. 
t o parti ci pate i n a cli nic al st u d y f oll o wi n g c o m pl eti o n of t he i nf or m e d c o ns e nt pr ocess. 
T he e x pect e d C B R at 
W 2 4 was set t o 6 4 % base d o n t he res ults fr o m J a pa n ese St u d y 
I T M- 0 1 4 N- 0 0 1 a n d gl o b al pi v ot al St u d y 2- 5 5- 5 2 0 3 0- 7 2 6 ( C L A RI N E T; N C T 0 0 3 5 3 4 9 6). T he 
t hres h ol d C B R at 
W 2 4 was defi ne d as 4 0 % b ase d o n Ja pa nes e St u d y I T M- 0 1 4 N- 0 0 1 a n d 
i o ns. W he n a st atistical test was perf or me d f or a n ull h y p ot h esis wit h 
o ne-si de d t y p e I err or of 2. 5 %, a mi ni m u m s a m ple size re q uire d t o yiel d a p o wer of at l east 
8 0 % w o ul d b e 3 6 partici pa nts. C o nsi deri n g a 1 5 % dr o p- off rate, 4 3 p artici pa nts w o ul d be 
necess ar y f or t he pri mar y effic ac y e v al uati o n of C B R at W 2 4.  
T o pr o vi de cli nical e x perie nce of i n de pe n de nt i nj ecti o n i n C hi nese partici pa nts, a p pr o xi mat el y 
fi ve q ualifi e d partici pa nts ( ha vi n g a p ositi ve be nefit/ris k rati o) will ha ve i n de pe n de nt i nj ecti o n 
of la nre oti de A ut o gel d uri n g t he 2 4 wee ks of t h e i n de pe n de nt i njecti o n peri o d (ass u mi n g 1 0 t o 
2 5 % eli gi ble partici pa nts after 4 8 w ee ks of i nter ve nti o n i n t he mai n st u d y will c o nti n ue t o 
recei v e i n de pe n de nt i njecti o n). T he ai m is t o ac hie ve fi ve partici p a nts t hat ha ve bee n trai ne d t o 
perf or m i n de p e n de nt i nje cti o ns a n d are c o nsi dere d a ble t o i n de pe n de ntl y a d mi nist er la nre oti de 
fr o m t he i n vesti gat or. 
9. 3  
A n al ysis Sets 
F or t he p ur p oses of a n al ysis, t he a nal ysis sets i n T a ble 5  are defi n e d: 
T a ble 5 
A n al ysis Set Defi niti o ns 
P artici p a nt A n al ysis S et 
Descri pti o n 
E nr olle d set  
All p artici pa nts w h o si g n t he I C F  
Safet y set 
All partici pa nts w h o recei ve at least o ne d ose of st u d y i nter v e nti o n. If t here is 
a n y d o u bt w het her a partici pa nt was treate d or n ot, t he y will be ass u me d 
treate d f or t he p ur p os es of a nal ysis 
I T T 
All p artici pa nts w h o recei ve at l east o ne d ose of st u d y i nt er ve nti o n 
mI T T 
All p artici pa nts i n t he I T T ha vi n g at least W 2 4 data rec or d e d f or t he pri mar y 
efficac y e n d p oi nt 
P P S 
All p artici pa nts i n t he mI T T w h o di d n ot e x p erie nce a n y maj or pr ot o c ol 
de viati o ns t hat ma y i nterfere wit h t he effi cac y e val uati o n 
I m m u n o ge nicit y set 
All partici p a nts i n t he I T T w h o ha ve baseli ne a n d at least o ne p ost b as eli ne 
a nti -la nre oti de a nti b o d y res ult 
I n de pe n de nt i nj ecti o n set 
All partici p a nts w h o recei ve t h e st u d y i nter ve nti o n b y i n d e pe n d e nt i njecti o n 
A b bre viati o ns: I C F =i nf or me d c o nse nt f or m; I T T =i nte nti o n-t o-treat; 
mI T T = m o difi e d i nte nti o n-t o- treat; 
P P S = per -pr ot oc ol set; W = wee k  
 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 7 1/ 9 9 
 
 
 
9. 4  
St atistic al A n al ys es 
T he statistical a nal ysis pla n ( S A P) will be fi nalise d pri or t o dat a base l oc k a n d it will i ncl u de a 
m ore tec h nical a n d det ail e d descri pti o n of t he statistical a nal ys es descri be d i n t his s ecti o n. T his 
secti o n is a s u m mar y of t he pla n ne d statistical a nal yses of t he m ost i m p orta nt e n d p oi nts 
i ncl u di n g pri mar y a n d ke y sec o n dar y e n d p oi nts. 
Ot her e n d p oi nts as w ell as de m o gra p hic, b aseli ne c haract eristi cs a n d dis p ositi o n will be detaile d 
i n t he S A P. 
Statistical a nal yses will be perf or me d usi n g Statisti cal A nal ysis S yste m ®  ( S A S® ) s oft ware 
( Versi o n 9. 4 or hi g her). 
T hree a nal yses are pla n n e d acc or di n g t o t he f oll o wi n g dat a c ut- offs: 
( 1) 
T he first a nal ysis will be perf or m e d w he n all partici pa nts c o m plet e t he first 2 4 wee ks of 
t he mai n st u d y peri o d. T he c ut- off date c o nsi dere d f or t his a nal ysis is t he d ate of t he l ast 
W 2 4 visit f or t he last partici pa nt. All a vaila ble dat a at t he ti me of t his data c ut- off dat e 
will be i ncl u de d i n t his a nal ysis. T he p ur p os e of t his a nal ysis is t he fi nal a nal ysis of t h e 
pri mar y efficac y e n d p oi nt, as well as efficac y a n d safet y a n al yses of t h e first 2 4 wee ks 
of t he mai n st u d y p eri o d. T his a nal ysis will n ot be c o nsi dere d as a n i nt eri m a nal ysis 
beca use t h e first 2 4 wee ks of mai n st u d y peri o d is of pri mar y i nt erest. 
( 2) 
T he sec o n d a n al ysis will be perf or me d w he n all partici pa nts ha ve ha d t he o p p ort u nit y t o 
c o m plete t he m ai n st u d y ( W 4 8). T h e re p orti n g d ata base will i ncl u de all m ai n st u d y d ata 
f or all partici pa nts e nr olle d i nt o t he st u d y.  
( 3) 
T he t hir d a n d fi nal a nal ysis will be perf or me d w he n t he last partici pa nt c o m pletes t he 
i n de pe n de nt i njecti o n p eri o d. T he re p orti n g data b ase will i ncl u de all i n de pe n de nt 
i njecti o n peri o d st u d y data. 
9. 4. 1  Ge ner al C o nsi der ati o ns 
9. 4. 1. 1  
A n alysis Sets 
T he pri mar y effi cac y e val uati o n will be perf or me d o n t he i nte nti o n-t o-treat (I T T) set. 
S u p p orti ve a nal ysis of t he pri mar y efficac y e val uati o n will be base d o n t he 
m o difie d 
i nte nti o n-t o-treat ( mI T T) set a n d t he per pr ot o c ol s et ( P P S). S ec o n dar y a nal yses will be 
perf or me d o n t h e I T T set. S u p p orti ve a nal ysis of t he s ec o n dar y efficac y e val uati o n ma y be 
base d o n t he P P S. T he i m m u n o ge nicit y e val uati o n will be p erf or me d i n t he i m m u n o ge ni cit y 
set. Safet y a n al ys es will be perf or me d o n t h e safet y s et. E x pl orat or y a n al ys es will be perf or me d 
o n t he i n de pe n de nt i njecti o n set. 
9. 4. 1. 2  
P artici p a nt All oc ati o n a n d Re as o ns f or Excl usi o n fr o m t he A n alyses 
A n y maj or pr ot oc ol d e viati o n t y p es will be descri be d i n t he Pr ot oc ol De viati o n D oc u me nt a n d 
t heir i m pact o n i ncl usi o n i n eac h a nal ysis s et f or a n y partici p a nt will be s pecifie d. T he fi nal list 
of pr ot oc ol de viati o ns i m pacti n g eac h a n al ysis set will be re vie we d d uri n g t he data re vie w 
meeti n g h el d pri or t o data base l o c k.  
9. 4. 1. 3  
A dj ust me nt of M ulti pli city 
M ulti plicit y will n ot be a dj uste d. 
9. 4. 1. 4  
Si g nific a nce T esti n g a n d Esti m ati o ns 
T he 9 5 % e x act c o nfi de n ce i nter vals f or t h e pri m ar y e n d p oi nt will be cal c ulate d base d o n t he 
Cl o p per- P ears o n met h o d. 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 7 2/ 9 9 
 
 
 
9. 4. 1. 5  
St atistic al/ A n alytic al Met h o ds  
C o nti n u o us data will be s u m maris e d wit h t he f oll o wi n g ite ms: n u m ber of p artici pa nts, me dia n, 
ra n ge, 
mea n a n d sta n d ar d d e viati o n, if rele va nt. Cate g ori cal dat a will be prese nte d i n 
c o nti n ge nc y t a bles wit h fre q ue nci es a n d perce nta ges of eac h m o dalit y (i ncl u di n g missi n g data 
m o dalit y). T o descri be ti me- de pe n d e nt para m et ers ( P F S, T T P a n d O S), Ka pla n- Meier c ur ves 
a n d life ta bl es will be pr o vi de d. T he 9 5 % CI o n t h e me dia n will be gi ve n. 
9. 4. 2  
A n alysis of Pri m ary E n d p oi nt 
P oi nt esti m ates a n d e x act 9 5 % CIs base d o n t h e Cl o p per- Pears o n m et h o d will be calc ulat e d f or 
a C B R at W 2 4 (see T a ble 2 ). 
9. 4. 3  
A n alysis of Sec o n d ary Effic acy E n d p oi nts 
T he f oll o wi n g a nal yses will be perf or me d o n t h e s ec o n dar y efficac y e n d p oi nts (see Ta ble 2 ): 
 
F or ti me- d e pe n de nt p ara meters ( P F S, T T P a n d O S), Ka pla n- Mei er c ur ves a n d life t a bles 
will be ge nerat e d, a n d m e dia n wit h 9 5 % CIs will b e calc ulate d at W 2 4 a n d W 4 8. 
Ce ns ori n g r ul es f or t he P F S a n d T T P e n d p oi nts are s h o w n i n Ta ble 6 . 
T a ble 6 
Ce ns ori n g R ules f or P F S a n d T T P E n d p oi nts 
Sit u ati o n 
D ate of P r o g ressi o n o r C e ns ori n g 
O utc o me 
N o baseli ne ra di ol o gical assess me nts  
T he da y of first a d mi nistrati o n 
Ce ns ore d  
C o nfir me d ( d oc u me nte d) P D d uri n g t he st u d y 
Date of ra di ol o gical assess me nt 
s h o wi n g P D 
E ve nt 
N o deat h or c o nfir me d P D 
Date of last a d e q uate ra di ol o gical 
assess me nt 
Ce ns ore d 
St u d y i nter ve nti o n disc o nti n uati o n f or cli nical 
( u nc o nfir me d) pr o gressi o n 
Date of last a d e q uate ra di ol o gical 
assess me nt 
Ce ns ore d 
St u d y i nter ve nti o n disc o nti n uati o n f or t o xicit y 
or r eas o n ot her t ha n c o nfir me d P D, cli ni cal 
pr o gressi o n or d eat h  
Date of last a d e q uate ra di ol o gical 
assess me nt 
Ce ns ore d 
Ne w a ntica ncer treat me nt f or G E P- N E T st arte d 
wit h n o c o nfir me d P D bef ore ha n d 
Date of last a d e q uate ra di ol o gical 
assess me nt bef ore start of ne w 
treat me nt 
Ce ns ore d 
Deat h d uri n g t he st u d y bef ore c o nfir me d P D 
Date of deat h ( P F S)/ D ate of last 
a de q uate ra di ol o gical assess me nt ( T T P) 
E ve nt 
( P F S)/ Ce ns ore d 
( T T P) 
C o nfir me d P D after t w o or m ore misse d 
ra di ol o gical assess me nts 
Date of last a d e q uate ra di ol o gical 
assess me nt bef ore misse d assess me nts  
Ce ns ore d 
St u d y i nter ve nti o n disc o nti n uati o n f or ot her 
t ha n c o nfir me d P D or deat h, a n d n o p ost b as eli ne 
ra di ol o gical assess me nts 
T he da y of first a d mi nistr ati o n 
Ce ns ore d 
A b bre viati o ns: G E P- N E T = gastr oe nter o pa ncr eatic ne ur oe n d o cri ne t u m o urs; P D = pr o gressi ve dis ease; 
P F S = pr o gressi o n fr ee s ur vi val; T T P =ti me t o pr o gr essi o n  
 
T he O S will be ass esse d o nce t he data fr o m t he l ast partici pa nt c o m pleti n g t he m ai n st u d y are 
a vaila ble. O verall s ur vi val is defi ne d as t he ti me fr o m t he da y of first a d mi nistrati o n t o deat h 
d ue t o a n y ca use. P artici pa nts w h o are n ot k n o w n t o ha ve di e d at t he ti me of t he a n al ysis will 
be ce ns ore d. 
W here p ossi ble, p ost-i nt er ve nti o n s ur vi val stat us will be c o nfir me d f or all 
partici pa nts t hat are ali ve at t he last assess me nt. A n y partici pa nt w h o is c o nfir me d t o be ali ve 
will be ce ns ore d at t his ti me. A n y p arti ci pa nt w h o c o ul d n ot be c o ntacte d at t his ti me will be 
ce ns ore d at t he ti me t hat t he partici pa nt was l ast c o nfir me d t o be ali ve. 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 7 3/ 9 9 
 
 
 
 
Pr o p orti o n of partici p a nts w h o are ali ve a n d wit h o ut t u m o ur pr o gressi o n at W 2 4 a n d 
W 4 8 a n d t heir 9 5 % CI will be calc ulate d b y t he Ka pla n- M eier m et h o d 
 
P oi nt esti mates a n d e x act 9 5 % CIs b ase d o n t he Cl o p per- P ears o n met h o d will be 
calc ulate d f or t he f oll o wi n g: 
- 
C B R at W 4 8 
- 
O R R at W 2 4 a n d W 4 8 
- 
D C R at W 2 4 a n d W 4 8 
 
Descri pti ve statistics will be us e d t o s u m m arise: 
- 
C ha n ge fr o m baseli ne i n N E T-rel ate d cli nical s y m pt o ms at W 2 4 a n d W 4 8  
- 
C ha n ge fr o m b as eli ne i n Q o L ass ess me nt at e val uati o n p oi nts usi n g t he E O R T C 
Q L Q- C 3 0  
- 
C ha n ge fr o m baseli ne i n C g A a n d ot her bi o m ar k er(s) i n t he circ ulati o n at W 2 4 
a n d W 4 8.  
9. 4. 4  
A n alysis of E x pl or at ory Effic acy E n d p oi nts 
Descri pti ve statisti cs will be use d t o s u m m aris e t he e x pl orat or y effi cac y e n d p oi nts (see Ta ble 2 ) 
f or partici pa nts c o nti n ui n g i n t he i n de p e n de nt i nje cti o n peri o d: 
 
Pr o p orti o n of parti ci pa nts preferri n g i n de pe n d e nt i nj ecti o n o ver H C P i njecti o ns at W 7 2 
 
Partici pa nt-re p orte d i n direct c osts (e. g. tr a ns p ort c osts) at W 4 8 a n d W 7 2 
 
Partici pa nt-re p orte d w or k pr o d ucti vit y at W 4 8 a n d W 7 2 
 
T he a ntit u m o ur effect (assess e d b y i ma gi n g) at W 7 2 
 
C ha n ge fr o m baseli ne i n N E T-rel ate d s y m pt o ms c o ntr ol at W 7 2 (if a p pli ca bl e) 
 
C ha n ge fr o m baseli ne i n C g A a n d ot h er bi o mar kers i n t he circ ulati o n at W 7 2  
 
C ha n ge fr o m baseli ne i n Q o L at W 7 2. 
9. 4. 5  
S afety A n alyses 
A d verse e ve nts re p ort e d b y i n v esti gat ors usi n g t he N CI C T C A E classificati o n ( Versi o n 5) will 
be c o de d usi n g Me d D R A (lat est versi o n). 
A Treat me nt E mer ge nt A d verse E ve nt ( T E A E) is defi ne d as a n y A E t hat occ urs d uri n g t he 
acti ve p hase of t he st u d y if:  
 
It was n ot prese nt pri or t o recei vi n g t he first d ose of st u d y i nter v e nti o n, or  
 
It was prese nt pri or t o recei vi n g t he first d ose of st u d y i nt er ve nti o n b ut t he i nt e nsit y 
i ncrease d d uri n g t he acti ve p hase of t h e st u d y. 
S u m mar y i nci d e nce ta bles of all T E A Es will be pr o vi de d b y Me d D R A s yst e m or ga n class a n d 
preferre d ter m. I n a d diti o n, s u m mar y t a bl es will b e f urt her prese nte d b y w orst ass ociate d N CI 
C T C A E Gra de a n d relati o ns hi p t o st u d y i nter ve nti o n. Listi n gs of S A Es a n d T E A Es lea di n g t o 
wit h dra wal will be pr o vi de d. 
S u m mar y statisti cs ( m ea n, me di a n, st a n dar d de viati o n a n d ra n ge as a p pr o priate) will be 
prese nte d f or vital si g ns, E C G varia bles a n d cli nical safet y la b orat or y tests at eac h assess m e nt, 
wit h c ha n ge fr o m baseli ne. F or la b orat or y dat a, a b n or mal val u es will be fla g ge d i n t h e dat a 
listi n gs a n d a list of cli nicall y si g nifica nt a b n or mal val ues will b e prese nte d. S hift ta bles will be 
prese nte d f or t he n u m ber a n d perce nta ge of partici pa nts wit h l o w, n or mal or hi g h val ues a n d 
n or m al or a b n or mal res ults. 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 7 4/ 9 9 
 
 
 
Hae mat ol o gical a n d bi o c he mical t o xiciti es will be gra de d acc or di n g t o t he N CI C T C A E 
criteria, w h ere a vaila ble. T h e N CI C T C A E Gra de 3 a n d 4 hae mat ol o g y a n d bi oc he mistr y 
varia bles b y partici pa nt a n d b y c ycle will be list e d. F or w hit e bl o o d cells, n e utr o p hils, platelets 
a n d hae m o gl o bi n, wit h ass oci ate d Gra d e 3 or 4 t o xicities, na dir a n d da y t o na dir will be 
calc ulate d.  
9. 4. 6  
S u b gr o u ps A n alyse(s)  
Descri pti ve s u b gr o u p a n al yses of t he pri mar y efficac y vari a bl e will be p erf or me d o n t he 
pri mar y t u m o ur t y p e. 
F urt her d etails will be pr o vi de d i n t he S A P. 
9. 5  
I nteri m A n al yses  
N o i nteri m a n al yses are pla n ne d f or t his st u d y. If a n u n pl a n ne d i nteri m a n al ysis is dee m e d 
necessar y, t he a p pr o priate s p o ns or m e dical direct or, or d esi g n ee, will be c o ns ulte d t o deter mi ne 
w het her it is necess ar y t o a me n d t he pr ot oc ol.  

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 7 5/ 9 9 
 
 
 
1 0  
S U P P O R TI N G 
D O C U M E N T A TI O N 
A N D 
O P E R A TI O N A L 
C O N SI D E R A TI O N S 
1 0. 1  
A p pe n di x 1: Re g ul at or y, Et hic al, a n d St u d y O versi g ht C o nsi der ati o ns 
1 0. 1. 1  
Re g ul at ory a n d Et hic al C o nsi der ati o ns 
 
T his st u d y will be c o n d u cte d i n acc or da n ce wit h t he pr ot oc ol a n d wit h t he f oll o wi n g: 
- 
C o nse ns us et hical pri nci ples deri ve d fr o m i nter nati o nal g ui deli nes i ncl u di n g t he 
Declarati o n of Helsi n ki a n d C o u ncil f or I nter n ati o nal Or ga nisati o ns of Me dical 
Scie nces ( CI O M S) I nter n ati o nal Et hical G ui deli nes. 
- 
A p plica ble I nter nati o nal C o u ncil o n Har m o nisati o n (I C H) G o o d Cli nical Practice 
( G C P) G ui deli nes. 
- 
A p plica ble la ws a n d re g ulati o ns. 
 
T he pr ot oc ol, pr ot oc ol a m e n d m e nts, I C F a n d a n y parti ci pa nt recr uit me nt materi als, 
se me nts) m ust be 
a p pr o ve d b y t he I R B/I E C bef ore t he st u d y is i nitiate d. 
 
A n y a me n d me nts t o t he pr ot oc ol will re q uir e I R B/I E C a p pr o val bef ore i m ple me nt ati o n 
of c ha n ges ma d e t o t he st u d y d esi g n, e x ce pt f or c ha n ges ne cessar y t o eli mi nate a n 
i m me diate hazar d t o st u d y partici pa nts. 
 
Pr ot oc ols a n d a n y s u bsta nti al a me n d me nts t o t he pr ot o c ol will re q uire healt h a ut h orit y 
a p pr o val pri or t o i nitiati o n e x ce pt f or c ha n ges necessar y t o eli mi nate a n i m m e diate 
hazar d t o st u d y partici pa nts. 
 
T he i n v esti gat or will be res p o nsi ble f or t he f oll o wi n g: 
- 
Pr o vi di n g writte n s u m maries of t he stat us of t he st u d y t o t he I R B/I E C a n n u all y or 
m ore fre q u e ntl y i n acc or da nce wit h t he re q uire me nts, p olicies, a n d pr o ce d ures 
esta blis he d b y t h e I R B/I E C. 
- 
N otif yi n g t h e I R B/I E C of S A Es or ot her si g nifica nt safet y fi n di n gs as re q uire d b y 
I R B/I E C pr oce d ures. 
- 
Pr o vi di n g o versi g ht of t he c o n d uct of t he st u d y at t he st u d y site a n d a d her e nce t o 
a p plica ble 
l ocal 
re g ulati o ns, 
I C H 
g ui deli nes 
a n d 
t he 
I R B/I E C 
re q uire me nts/ pr oce d ures. 
1 0. 1. 2  
Fi n a nci al Discl os ure 
I n v esti gat ors a n d s u b-i n v esti gat ors will pr o vi de t h e s p o ns or wit h s ufficie nt, acc urate fi na n cial 
i nf or mati o n as re q u este d t o all o w t he s p o ns or 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 priat e re g ulat or y a ut h orities. I n vesti gat ors are 
res p o nsi ble f or pr o vi di n g i nf or mati o n o n fi na n cial i nterests d uri n g t he c o urse of t he st u d y a n d 
f or o ne year after c o m pleti o n of t he st u d y. 
1 0. 1. 3  
I nf or m e d C o nse nt Pr ocess 
 
T he I C F(s) a n d a n y partici pa nt r ecr uit me nt materials m ust be i n c o m plia nce wit h I C H 
G C P, l ocal re g ul at or y re q uire me nts, a n d le gal re q uire me nts, i ncl u di n g a p plic a ble pri vac y 
la ws a n d a p pr o v e d pri or t o use as des cri be d i n A p pe n di x 1 0. 1. 1 . 
 
T he i n vesti gat or or his/ her a ut h oris e d re pres e ntati ve will e x plai n t o t he parti ci pa nt ( or 
t heir le gall y a ut h orise d re pres e nt ati ve) t he nat ure a n d o bjecti ves of t he st u d y a n d p ossi bl e 
ris ks ass ociate d wit h t h e partici pati o n. T he y will a ns wer all q uesti o ns re gar di n g t he 
st u d y. 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 7 6/ 9 9 
 
 
 
 
Partici pa nts ( or t heir le gall y a ut h orise d re pres e ntati ve, w he n a p plica bl e) 
m ust be 
i nf or me d t hat t heir partici pati o n is v ol u ntar y. 
 
T he i n vesti gat or or his/ her a ut h orise d re pres e nt ati ve will o btai n writt e n i nf or me d c o nse nt 
fr o m eac h partici pa nt ( or t heir le gall y a ut h orise d re pres e ntati ve, w he n a p pli ca ble) b ef ore 
a n y st u d y-s pecific pr oce d ure is perf or me d. T he i n vesti gat or will retai n t he ori gi nal of 
 
 
A c o p y of t he si g ne d I C F(s) m ust be pr o vi de d t o t he partici pa nt ( or t heir l e gall y 
a ut h orise d re prese ntati ve). 
 
T he me di cal rec or d m ust i ncl u de a st ate me nt t hat writte n i nf or me d c o nse nt was o btai ne d 
bef ore t he p artici pa nt was e nr olle d i n t he st u d y a n d t he date t he writte n c o nse nt was 
o btai ne d. T he a ut h oris e d pers o n o bt ai ni n g t h e i nf or me d c o nse nt m ust als o si g n t he I C F. 
 
All partici pa nts will pr o vi de writt e n i nf or me d c o nse nt f or t he mai n st u d y peri o d pri or t o 
scree ni n g pr oce d ures bei n g perf or me d. Partici pa nts c o nti n ui n g i nt o t he i n de pe n de nt 
i njecti o n peri o d will be re q uire d t o pr o vi de f urt her writte n i nf or me d c o nse nt f or t he 
a d diti o nal pr oce d ures bef ore e nteri n g t h e i n de pe n de nt i njecti o n peri o d. 
 
If a p pli ca ble, partici pa nts m ust be re-c o ns e nte d t o t he m ost c urre nt versi o n of t he I C F 
d uri n g t heir p arti ci pati o n i n t he st u d y. 
 
A partici p a nt w h o is res cree ne d is n ot re q uire d t o si g n a n ot her I C F if t he rescree ni n g 
occ urs wit hi n 4 wee ks fr o m t he pre vi o us I C F si g n at ure date. 
 
T he I C F will c o ntai n a se parat e s ecti o n t hat a d dresses t he use of all data f or o pti o nal 
f ut ure res earc h. T hese data ma y o nl y b e use d f or scie ntific healt h-rel ate d researc h t o fi n d 
ne w wa ys t o dete ct, tr eat, pre ve nt or c ure healt h pr o ble ms.  Partici pa nts will be t ol d t hat 
t he y ar e free t o ref use t o p arti ci pate a n d ma y wit h dra w t heir c o nse nt at a n y ti me a n d f or 
a n y reas o n d uri n g t h e st u d y. A s pecific c o nse nt will be re q uire d t o d oc u me nt a 
 f or f ut ure res earc h. 
 
A s pecific I C F f or pre g na nt p art ner m ust be use d bef ore c oll ecti n g details o n t he 
pre g na nc y a n d its o utc o me (see Secti o n 8. 3. 6 ). 
1 0. 1. 4  
D at a Pr otecti o n 
 
Partici pa nts will be assi g ne d a u ni q ue i de ntifier b y t h e s p o ns or. A n y partici pa nt rec or ds 
or datasets t hat are tra nsferre d t o t he s p o ns or will c o ntai n t he i de ntifier o nl y; p artici pa nt 
na mes or a n y i nf or m ati o n w hic h w o ul d ma k e t h e partici p a nt i de ntifia bl e will n ot be 
tra nsferre d. 
 
T he partici pa nt m ust be i nf or me d t hat his/ her p ers o nal st u d y-relate d data will be use d b y 
t he s p o ns or i n acc or da n ce wit h l ocal data pr otecti o n la w. T he l e vel of discl os ure m ust 
als o be e x plai ne d t o t he partici pa nt w h o will be re q uire d t o gi ve c o nse nt f or t heir data t o 
be use d as descri be d i n t he i nf or m e d c o ns e nt. 
 
T he partici pa nt 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 t h e 
ns or, 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 r e g ulat or y a ut h orities. 
1 0. 1. 5  
C o m mittees Str uct ure 
N ot a p pli ca ble. T here will be n o o versi g ht c o m mitt ees i n t he st u d y. 
1 0. 1. 6  
Disse mi n ati o n of Cli nic al St u dy D at a 
 
T he s p o ns or see ks t o p u blis h t he res ults of its cli nical tri als i n bi o me dical j o ur nals, 
w hate ver t he o utc o me. Cli nical tri al res ults m a y als o be pres e nte d at i nter nati o nal 
c o n gresses as p osters or oral pres e nt ati o ns. 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 7 7/ 9 9 
 
 
 
 
Pr ot oc ol a n d res ult s u m mar y will be ma de p u blicl y a v ail a ble o n t he U nite d States ( U S) 
Cli nical Trials Re gistr y ( Cli ni cal Trials. g o v). T he s p o ns or als o pr o vi des cli nical trial 
i nf or mati o n t o ot her nati o nal cli nical trial re gistries or d ata bas es acc or di n g t o l o cal 
re q uire me nts/le gislati o n (c hi na dr u gtri als. or g.c n). 
 
A cli nical st u d y re p ort ( C S R) will be pre pare d if at least o ne p artici pa nt has si g ne d 
i nf or me d c o nse nt a n d recei ve d st u d y i nter ve nti o n, re gar dless of w het her t he st u d y is 
c o m plete d or pre m at urel y ter mi nate d. T he C S R m a y be discl ose d acc or di n g t o re g ulat or y 
re q uire me nts. 
1 0. 1. 7  
D at a Q u alit y Ass ur a nce 
 
All partici pa nt data relati n g t o t he st u d y will be rec or de d i n a C R F u nless tra ns mitte d t o 
t he s p o ns or or d esi g n ee electr o nicall y (e. g. la b orat or y dat a). T h e i n vesti gat or is 
res p o nsi ble f or verif yi n g t hat data e ntries are acc urat e a n d c orrect b y p h ysicall y or 
electr o nicall y si g ni n g t he C R F. 
 
G ui da n ce o n c o m pleti o n of C R Fs will be pr o vi de d i n C R F c o m pleti o n g ui d eli nes. 
 
T he i n vesti gat or m ust per mit st u d y-relate d m o nit ori n g, a u dits, I R B/I E C re vi e w, a n d 
re g ulat or y a ut h orit y i ns p ecti o ns, ma ke all d oc u m e nts a vail a ble f or a u dit a n d i ns pecti o n 
a n d pr o vi de direct access t o s o urce data d o c u me nts. 
 
Q ualit y t olera n ce li mits ( Q T Ls) will be pre- d efi n e d i n t he i nte grat e d o versi g ht pla n t o 
i de ntif y s yste m atic iss ues t hat ca n i m pact partici pa nt safet y a n d/ or reli a bilit y of st u d y 
res ults. T hese pre- defi n e d para meters will be m o nit ore d d uri n g t he st u d y a n d i m p orta nt 
de viati o ns fr o m t he Q T Ls a n d re me dial acti o ns ta ke n will be s u m m aris e d i n t he C S R. 
 
M o nit ori n g details descri bi n g strate g y (e. g. ris k- bas e d i niti ati ves i n o perati o ns a n d 
q ualit y s uc h as Ris k Ma na ge me nt a n d Miti gati o n Strate gies a n d A n al ytical Ris k- Bas e d 
M o nit ori n g), 
met h o ds, res p o nsi bilities a n d re q uire m e nts, i ncl u di n g ha n dli n g of 
n o nc o m plia nce iss ues a n d m o nit ori n g tec h ni q ues (ce ntral, re m ote, or o n-site m o nit ori n g) 
are pr o vi d e d i n t he M o nit ori n g Pla n. 
 
T he s p o ns or or desi g nee is res p o nsi ble f or t he data ma n a ge me nt of t his st u d y i ncl u di n g 
q ualit y c h ec ki n g of t he data. 
 
T he s p o ns or ass u m es acc o u nta bilit y f or acti o ns dele gat e d t o ot h er i n di vi d uals 
(e. g. C o ntract R esearc h Or ga nis ati o ns). 
 
Rec or ds a n d d oc u me nts, i ncl u di n g si g ne d I C Fs, p ertai ni n g t o t he c o n d u ct of t his st u d y 
s h o ul d be retai ne d b y t he i n vesti gat or acc or di n g t o t he I C H G C P g ui deli nes, l ocal 
re g ulati o ns, or as s p ecifie d i n t he st u d y a gree me nt, w hic h e ver is l o n ger. N o rec or ds m a y 
be destr o ye d d uri n g t he rete nti o n peri o d wit h o ut t h e writte n a p pr o val of t h e s p o ns or. N o 
rec or ds m a y be tra nsferre d t o a n ot her l oc ati o n or p art y wit h o ut writte n n otificati o n t o t he 
s p o ns or. 
1 0. 1. 8  
S o urce D oc u m e nts 
 
S o urce d oc u me nts pr o vi de e vi de n ce f or t he e xiste nce of t he p artici pa nt a n d s u bsta ntiate 
t he i nte grit y of t he data c ollecte d. S o urce d o c u me nts are file d at t he st u d y site. 
 
Data e ntere d i n t he C R F or t hat are tra ns cri be d fr o m s o urce d oc u m e nts m ust b e c o nsiste nt 
wit h t he s o urce d oc u m e nts or t he discre pa n cies m ust be e x plai ne d. T he i n vesti gat or ma y 
nee d t o re q uest pre vi o us me dical rec or ds or tra nsfer rec or ds, d e pe n di n g o n t he st u d y. 
Als o, c urre nt me dical rec or ds m ust be a vaila bl e. 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 7 8/ 9 9 
 
 
 
 
T he i n vesti gat or m ust mai ntai n acc urate d oc u me ntati o n t hat s u p p orts t he i nf or mati o n 
e ntere d i n t he C R F. S o urce data m ust be attri b uta ble, le gi bl e, c o nte m p ora n e o us, ori gi n al, 
acc urate a n d c o m pl ete. 
 
St u d y m o nit ors will perf or m o n g oi n g s o urce dat a v erificati o n t o c o nfir m t h at data e ntere d 
i nt o t he C R F b y a ut h orise d st u d y site pers o n nel are ac c urat e, c o m pl ete, a n d verifia ble 
fr o m s o urce d oc u me nts; t hat t he safet y a n d ri g hts of partici pa nts are bei n g pr otecte d; a n d 
t hat t he st u d y is bei n g c o n d ucte d i n acc or da n ce wit h t he c urre ntl y a p pr o v e d pr ot o c ol a n d 
a n y ot h er st u d y a gree me nts, I C H G C P, a n d all a p pli ca ble re g ulat or y re q uir e me nts. 
1 0. 1. 9  
St u d y a n d Sit e St art a n d Cl os ure 
1 0. 1. 9. 1  First Act of R ecr uit me nt 
T he st u d y st art date is t he d ate o n w hic h t he cli nical st u d y will be o pe n f or recr uit me nt of 
partici pa nts. 
1 0. 1. 9. 2  St u dy/ Site Ter mi n ati o n 
T he s p o ns or or desi g n ee r eser v es t he ri g ht t o cl os e t he st u d y site or ter mi n ate t he st u d y at a n y 
ti me f or a n y reas o n at t h e s ole dis creti o n of t he s p o ns or. St u d y sites will be cl ose d u p o n st u d y 
c o m pleti o n. A st u d y site is c o nsi dere d cl ose d w he n all re q uire d d oc u m e nts a n d st u d y s u p plies 
ha ve bee n c oll ecte d a n d a st u d y-site cl os ure visit has bee n p erf or me d. 
T he i n vesti gat or ma y i nitiate st u d y sit e cl os ure at a n y ti me, pr o vi de d t h ere is reas o na bl e ca use 
a n d s ufficie nt n oti ce is gi ve n i n a d va nc e of t h e i nt e n de d ter mi nati o n. 
Reas o ns f or t he earl y cl os ure of a st u d y sit e b y t h e s p o ns or or i n vesti gat or ma y i n cl u de b ut are 
n ot li mite d t o: 
 
F or st u d y ter mi nati o n: 
- 
Disc o nti n uati o n of f urt her st u d y i nter v e nti o n de vel o p m e nt 
 
F or site ter mi nati o n: 
- 
Fail ure of t he i n vesti gat or t o c o m pl y wit h t he pr ot oc ol, t he re q uire me nts of t he 
I R B/I E C or l o cal he alt h a ut h orities, t he s p o ns or's pr oce d ur es, or I C H G C P 
g ui deli nes 
- 
I n a de q uat e or n o recr uit me nt (e val uat e d after a reas o na bl e a m o u nt of ti me) of 
partici pa nts b y t he i n vesti gat or 
- 
T otal n u m ber of partici pa nts i ncl u de d earlier t ha n e x pecte d 
If t he st u d y is pre mat urel y ter mi nate d or s us pe n de d, t he s p o ns or s hall pr o m ptl y i nf or m t he 
i n vesti gat ors, t he I R Bs/I E Cs, t he re g ulat or y a ut h orities, a n d a n y c o ntract researc h 
or ga nisati o n(s) use d i n t he st u d y of t he reas o n f or ter mi nati o n or s us pe nsi o n, as s pecifie d b y 
t he a p plica bl e re g ulat or y re q uire me nts. T he i n vesti gat or s h all pr o m ptl y i nf or m t he p arti ci pa nt 
a n d s h o ul d ass ure a p pr o priate partici pa nt t her a p y a n d/ or f oll o w- u p. 
1 0. 1. 1 0  P u blic ati o n P olicy 
 
T he res ults of t his st u d y m a y b e p u blis he d or pres e nt e d at s ci e ntific meeti n gs. If t his is 
f oresee n, t he i n vesti gat or a grees t o s u b mit all ma n uscri pts or a bstracts t o t he s p o ns or 
bef ore s u b missi o n. T his all o ws t he s p o ns or t o pr otect pr o pri et ar y i nf or m ati o n a n d t o 
pr o vi de c o m me nts. 
 
T he s p o ns or will c o m pl y wit h t he r e q uire me nts f or p u bli cati o n of st u d y res ults. I n 
acc or da n ce wit h sta n dar d e dit ori al a n d et hical practice, t he s p o ns or will ge n erall y s u p p ort 
p u blicati o n of m ultice ntr e st u dies o nl y i n t heir e ntiret y a n d n ot as i n di vi d ual site dat a. I n 
t his case, a c o or di nati n g i n vesti gat or will be desi g nate d b y m ut ual a gree me nt. 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 7 9/ 9 9 
 
 
 
 
A ut h ors hi p will be deter mi ne d b y m ut ual a gree m e nt a n d i n li ne wit h I nter nati o nal 
C o m mittee of Me dical J o ur nal E dit ors a ut h ors hi p re q uire me nts. 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 8 0/ 9 9 
 
 
 
1 0. 2  
A p pe n di x 2: Cli nic al L a b or at or y S afet y Tests 
 
T he tests detaile d i n Ta ble 7  will be perf or me d b y t he l ocal la b orat or y acc or di n g t o t he 
ti me p oi nts i n t he S o A (Ta ble 1 ). 
 
Pr ot oc ol-s pecific re q uire me nts f or i ncl usi o n or e xcl usi o n of partici pa nts are detaile d i n 
Secti o n 5 . 
 
A d diti o nal tests ma y be p erf or me d at a n y ti me d uri n g t he st u d y as d eter mi ne d necess ar y 
b y t he i n vesti gat or or re q uire d b y l o cal re g ulati o ns. 
T a ble 7 
P r ot o c ol- Re q uire d Cli nic al S afet y L a b or at or y Tests 
T est  
Para meters Assesse d  
Pre g na nc y testi n g 
 
Ot her scr ee ni n g tests 
 
Hae mat ol o g y 
 
Bi o c he mistr y 
 
T otal pr otei n, al b u mi n, t otal a n d direct bilir u bi n, A L P[ c], 
A L T, A S T, G G T  
 
Bl o o d urea nitr o ge n, creati ni ne  
 A m ylas e, li pas e  
 
L D L c h olester ol, H D L c h olest er ol, tri gl yceri de  
 
S o di u m, p otassi u m, c hl ori d e 
 
Calci u m, i n or ga nic p h os p hate, 
 
Fasti n g gl uc ose[ d], H b A 1c, lactate d e h y dr o ge nase 
E n d ocri n ol o g y 
F T 3, F T 4, T S H, a n d pr olacti n 
C oa g ulati o n  
a P T T, P T, I N R 
Uri nal ysis[ e] 
Pr otei n, gl uc ose, ur o bili n o ge n a n d o cc ult bl o o d  
A b bre viati o ns: 
A L P =al kali ne 
p h os p hat ase; 
A L T =ala ni ne 
a mi n otra nsferas e; 
a P T T = acti vat e d 
p artial 
t hr o m b o plasti n ti me; 
A S T =as partate a mi n otra nsferase; 
G G T = ga m ma gl uta m yl tra nsferase; F S H =f ollicle 
sti m ulati n g 
h or m o ne; 
F T 3 =free trii o d ot h yr o ni ne; 
F T 4 =fr ee t h yr o xi ne; 
H b A 1c = gl ycate d 
hae m o gl o bi n; 
h C G = h u ma n c h ori o nic g o na d otr o pi n; 
H D L = hi g h de nsit y li p o pr otei n; I N R =i nt er nati o nal n or malise d rati o; 
I R B/I E C =i nstit uti o nal 
r e vie w 
b o ar d/i n d e p e n d e nt 
et hics 
c o m mittee 
L D L =l o w 
de nsit y 
li p o pr otei n; 
P T = pr ot hr o m bi n ti me; T S H =t h yr oi d sti m ul ati n g h or m o ne; U L N = u p per li mit of n or mal 
a 
Uri ne testi n g will b e sta n d ar d f or t he pr ot oc ol u nless ser u m testi n g is r e q uire d b y l o cal re g ul ati o n or I R B/I E C  
b 
Details of li ver c he mistr y st o p pi n g criteri a a n d re q uire d acti o ns a n d f oll o w- u p ar e gi ve n i n Secti o n 7. 1. 1  a n d 
A p pe n di x 5 . All e ve nts of A L T or A S T 3 × U L N a n d t otal bilir u bi n 2 × U L N ( > 3 5 % direct bilir u bi n) or A L T 
or A S T 
La w), m ust b e re p ort e d t o s p o ns or i n a n e x p e dite d ma n ner 
c 
If al kali ne p h os p hatase is ele v ate d, c o nsi d er fracti o nati n g 
d 
T he partici p a nt m ust n ot ha ve eate n a n y f o o d f or at least 6 h o urs pri or t o bl o o d sa m pl e b ei n g ta ke n 
e 
L ocal uri ne di pstic k  testi n g will be sta n dar d f or t he pr ot o c ol u nless ser u m testi n g is r e q uire d b y l ocal 
re g ulati o n or t he I R B/I E C. 
I n v esti gat ors m ust d oc u me nt t heir re vie w of ea c h cli ni cal s afet y la b orat or y re p ort. 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 8 5/ 9 9 
 
 
 
1 0. 4  
A p pe n di x 4: C o ntr ace pti ve a n d B arri er G ui d a nce  
T he f oll o wi n g g ui d a nce is a da pte d fr o m t he Cli nic al Trials Facilitati o n Gr o u p [ C T F G 2 0 1 4 ]. 
1 0. 4. 1  
Defi niti o ns 
W o me n i n t he f oll o wi n g cate g ories are c o nsi dere d W O C B P (fertile): 
( 1) 
F oll o wi n g me n arc h e 
( 2) 
Fr o m t he ti m e of me narc he u ntil bec o mi n g p ost me n o pa us al u nless per ma n e ntl y steril e 
(see bel o w) 
 
A p ost me n o pa usal state is defi n e d as n o me ns es f or 1 2 m o nt hs wit h o ut a n 
alter nati ve me dical ca use: 
- 
A hi g h F S H le v el i n t he p ost me n o pa usal ra n ge m a y be use d t o c o nfir m a 
p ost me n o pa usal state i n w o me n n ot usi n g h or m o nal c o ntrace pti o n or 
h or m o nal re place me nt t hera p y ( H R T). 
H o we v er, i n t he a bse n ce of 
1 2 m o nt hs of a me n orr hea, c o nfir mati o n 
wit h 
m ore t ha n o n e F S H 
meas ure me nt [i nsert t hr es h ol d if re q uire d ( > 4 0 I U/ L or mI U/ m L) or re m o ve 
t o all o w f or fle xi bilit y 
wit h differe nt l ocal t hres h ol ds f or defi ni n g 
p ost me n o pa usal state] is re q uire d. 
- 
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 uir e d 
t o use o ne of t he n o n oestr o ge n h or m o nal hi g hl y effecti 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 st u d y. Ot her wise, 
t he y m ust dis c o nti n ue H R T t o all o w c o nfir mati o n of p ost me n o pa us al stat us 
bef ore st u d y e nr ol me nt. 
 
Per ma ne nt st erilisati o n met h o ds (f or t he p ur p ose of t his st u d y) i ncl u de: 
- 
D oc u me nte d h ysterect o m y. 
- 
D oc u me nte d bilateral sal pi n gect o m y. 
- 
D oc u me nte d bilateral o o p h orect o m y. 
- 
F or i n di vi d uals wit h per ma ne nt i nfertilit y d u e t o a n alter n ate m e dical ca us e 
ot her t ha n t he a b o ve, (e. g. 
M ulleria n a ge n esis, a n dr o ge n i nse nsiti vit y, 
g o na dal d ys ge nesis), i n vesti gat or discreti o n s h o ul d be a p pli e d t o deter mi ne 
eli gi bilit y f or st u d y e ntr y. 
partici pa n
 
 
If fertilit y is u n clear (e. g. a me n orr hea i n a d oles ce nts or at hlet es) a n d a me nstr ual 
c ycle c a n n ot be c o nfir me d bef ore first d ose of st u d y i nter ve nti o n, a d diti o nal 
e val uati o n s h o ul d be c o nsi dere d. 
 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 8 6/ 9 9 
 
 
 
1 0. 4. 2  
C o ntr ace pti o n G ui d a nce 
C O N T R A C E P TI V E S[ a] A L L O W E D D U RI N G T H E S T U D Y I N C L U D E:  
Hi g hl y Effecti ve M et h o ds[ b] T h at H a ve L o w Us er De pe n de nc y F ail ure r ate of < 1 % p er ye ar w he n 
us e d c o nsiste ntly a n d c orrectl y. 
 
I m pla nt a ble pr o gest o ge n- o nl y h or m o ne c o ntrace pti o n ass oci ate d wit h i n hi biti o n of o v ulati o n[ b]  
 
I ntr a ut eri ne d e vice  
 
I ntr a ut eri ne h or m o ne-releasi n g s yste m[ b]  
 
Bilateral t u bal o ccl usi o n 
 
Az o os p er mic p art ner ( vasect o mize d or d ue t o a me dical ca use) 
Az o os per mi a is a hi g hly effective c o ntr a ce ptive met h o d pr ovi de d t h at t h e p art ner is t h e s ole sex u al 
p art ner of t h e W O C B P a n d t he a bse nce of s per m h as bee n c o nfir me d. If n ot, a n a d diti o n al hi g hly 
effective met h o d of c o ntr a ce pti o n s h o ul d b e use d. S per m at o ge n esis cycl e is a p pr o xi m ately 9 0 d a ys.  
s re vie w 
) 
Hi g hl y Effecti ve M et h o ds[ b] T h at Are Us er De pe n de nt F ail ure r ate of < 1 % per ye ar w h e n use d 
c o nsiste ntly a n d c orr ectl 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 o ci ate d 
wit h 
i n hi biti o n of o v ulati o n[c] 
- 
Oral 
- 
I ntr a va gi nal 
- 
Tra ns der mal 
- 
I nj ecta ble 
 
Pr o gest o ge n- o nl y h or m o ne c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n[ c] 
- 
Oral 
- 
I nj ecta ble 
 
Se x ual a bsti ne nce 
Sex u al a bsti ne nce is c o nsi d er e d a hi g hly eff ecti ve met h o d o nly if defi ne d as refr ai ni n g fr o m 
heter osex u al i nter c o urse d uri n g t he e ntire peri o d of risk ass oci ate d wit h t he st u dy i nterve nti o n. T he 
reli a bility of sex u al a bsti ne n ce nee ds t o be ev al u ate d i n rel ati o n t o t h e d ur ati o n of t he st u dy a n d t he 
pr ef erre d a n d us u al lif estyle of t h e p arti ci p a nt.  
Effecti ve M et h o ds[ d] T h at Are N ot C o nsi dere d Hi g hl y Effecti ve 
us e d c o nsiste ntly a n d c orrectl y. 
 
Pr o gest o ge n- o nl y or al h or m o nal c o ntrace pti o n w her e i n hi biti o n of o v ulati o n is n ot t he pri mar y m o de 
of acti o n 
 
Mal e or fe male c o n d o m wit h or wit h o ut s p er mici de 
 
Cer vical ca p, dia p hra g m, or s p o n ge wit h s per mici de  
 
A c o m bi nati o n of male c o n d o m wit h eit her cer vical ca p, dia p hra g m, or s p o n ge wit h s per mici d e 
( d o u ble-barrier met h o ds)[ e] 
A b bre viati o ns: C T F G = Cli nical Tri als F acilitati o n Gr o u p  
a 
C o ntr ace pti ve use b y me n or w o me n s h o ul d b e 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 t h ose parti ci pati n g i n cli nical st u dies 
b 
Fail ure r ate of < 1 % per year w he n use d c o nsiste ntl y a n d c orrectl y. T y pical use fail ure rates differ 
fr o m t h ose w he n us e d c o nsiste ntl y a n d c orrectl y 
c 
Mal e c o n d o ms m ust be use d i n a d diti o n t o h or m o nal c o ntrace pti o n. If l ocall y re q uire d, i n 
acc or da nce wit h C T F G g ui d eli nes, acce pta ble c o ntrace pti ve met h o d s are li mite d t o t h os e w hic h 
i n hi bit o v ulati o n as t he pri mar y m o de of acti o n 
d 
C o nsi d ere d effecti ve, b ut n ot hi g hl y effecti ve - 
Peri o dic a bsti ne nce 
(cale n dar, s y m pt other mal, p ost o v ulati o n met h o ds), wit h dra wal ( c oit us i nterr u pt us), s per mici d es 
o nl y, a n d l actati o nal a me n orr hea met h o d are n ot acce pta ble met h o ds of c o ntrace pti o n 
e 
Male c o n d o m a n d fe m ale c o n d o m s h o ul d n ot b e use d t o get her ( d ue t o ris k of fail ure fr o m fri cti o n) 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 8 7/ 9 9 
 
 
 
1 0. 5  
A p pe n di x 5: Li ver S afet y: S u g geste d Acti o ns, F oll o w- u p Assess me nts a n d St u d y 
I nter ve nti o n Rec h alle n ge G ui deli nes 
1 0. 5. 1  
St o p pi n g Criteri a a n d F oll o w- u p Assess m e nts 
Li ver c he mistr y st o p pi n g criteria are desi g ne d t o ass ure p arti ci pa nt safet y a n d t o e val uate li ver 
e ve nt aeti ol o g y. T he st o p pi n g criteria, a cti o ns a n d f oll o w- u p ass ess me nts t o be perf or me d are 
s h o w n i n Ta ble 8 . 
T a ble 8 
Li v er C h e mistr y St o p pi n g C rit eri a a n d F oll o w- u p Assess me nts  
Li v er C he mistr y St o p pi n g C rit eri a 
A L T or A S T- a bs ol ute 
A L T or A S T 
8 × U L N  
A L T or A S T-i ncre ase 
A L T or A S T 
5 × U L N b ut < 8 × U L N p ersists f or 
2 wee ks 
A L T or A S T 
3 × U L N b ut < 5 × U L N p ersists f or 
4 wee ks 
Bilir u bi n[ a], [ b] 
A L T or A S T 
3 × U L N a n d  t otal bilir u bi n 2 × U L N ( > 3 5 % dir ect bilir u bi n)  
I N R 2  
A L T or A S T 
3 × U L N a n d  I N R > 1. 5 
C a n n ot M o nit or 
A L T or A S T 
5 × U L N b ut < 8 × U L N a n d ca n n ot b e m o nit ore d wee kl y f or 
2 wee ks  
A L T or A S T 
3 × U L N b ut < 5 x U L N a n d ca n n ot b e m o nit ore d wee kl y f or 
4 wee ks 
S y m pt o m atic[c] 
A L T or A S T 
3 × U L N ass oci ate d wit h s y m pt o ms ( ne w or w orse ni n g) beli e ve d t o 
be relate d t o li ver i nj ur y or h y perse nsiti vit y 
S u g geste d Acti o ns, M o nit o ri n g, a n d F oll o w u p Assess me nts 
Acti o ns 
F oll o w U p Assess me nts 
 
I m me di atel y disc o nti n ue st u d y i nter ve nti o n. 
 
C o m plete S A E C R F as a me di call y i m p orta nt 
e ve nt[ b] 
 
Re p ort t he e ve nt t o t he s p o ns or wit hi n  2 4 h o urs 
 
Perf or m f oll o w- u p assess me nts as descri be d i n 
t he F oll o w u p Assess me nt c ol u m n 
 
M o nit or t he partici p a nt u ntil li ver c he mistr y test 
a b n or maliti es res ol ve, sta bilis e, or ret ur n t o 
baseli ne 
M O NI T O RI N G: 
If A L T or A S T 3 × U L N A N D t ot al bilir u bi n 
2 × U L N or I N R > 1. 5:  
 
Re p eat li ver c he mistr y tests (i ncl u d e A L P, A L T, 
A S T, t ot al bilir u bi n a n d I N R) a n d p erf o r m li ver 
e ve nt f oll o w- u p ass ess me nts wit hi n 2 4 h o urs  
 
M o nit or p artici p a nt t wice wee kl y u ntil li ver 
c he mistr y test a b n or malities r es ol ve, sta bilise, or 
ret ur n t o b aseli ne 
 
A s p eci alist or he pat ol o g y c o ns ultati o n is 
rec o m me n de d 
 
Viral he patitis ser ol o g y[ d] 
 
O btai n ser u m C P K, L D H, G G T a n d G L D H, 
a n d s er u m al b u mi n 
 
Fracti o nate bilir u bi n, if t otal bilir u bi n 
2 × U L N 
 
O btai n c o m plet e bl o o d c o u nt wit h differe ntial 
t o assess e osi n o p hilia 
 
Rec or d t he a p peara nce or w orse ni n g of 
cli nical s y m pt o ms of li ver i nj ur y, or 
h y perse nsiti vit y 
 
Rec or d use of c o nc o mita nt me dicati o ns 
(i ncl u di n g aceta mi n o p he n, her bal re me dies, 
recreati o nal dr u gs, a n d ot her o ver-t he-c o u nter 
me dicati o ns) 
 
Rec or d alc o h ol use 
If A L T or A S T 3 × U L N A N D t ot al bilir u bi n 
2 × U L N o r I N R > 1. 5 o btai n t he f oll o wi n g i n 
a d diti o n t o t he assess me nts liste d a b o ve 
[E A S L  2 0 1 9 ]: 
 
A nti- n uclear a nti b o d y, a nti- s m o ot h 
m uscle 
a nti b o d y, T y p e 1 a nti -li ver ki d ne y micr os o mal 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 8 8/ 9 9 
 
 
 
If A L T or A S T 3 × U L N A N D t ot al bilir u bi n 
< 2 × U L N a n d I N R 
1. 5:  
 
Re p eat li ver c he mistr y tests (i ncl u d e A L P, A L T, 
A S T, t ot al bilir u bi n a n d I N R) a n d p erf or m li ver 
c he mistr y f oll o w- u p assess me nts wit hi n 2 4 t o 
7 2 h o urs  
 
M o nit or p artici p a nts wee kl y u ntil li ver c he mistr y 
a b n or maliti es res ol ve, sta bilises, or ret ur n t o 
baseli ne 
R E S T A R T/ R E C H A L L E N G E: 
 
D o n ot rest art/rec h all e n ge  partici p a nt wit h st u d y 
i nter ve nti o n u nl ess all o we d per pr ot oc ol a n d 
s p o ns or a p pr o val is gra nte d 
 
If r estart/rec halle n ge n ot all o we d per pr ot oc ol 
or n ot g r a nte d , p er ma ne ntl y disc o nti n ue st u d y 
i nter ve nti o n a n d c o nti n ue p artici pa nt i n t he st u d y 
f or a n y pr ot oc ol s p ecifie d f oll o w u p assess me nts 
a nti b o dies, a n d q ua ntitati ve t ot al I g G or ga m ma 
gl o b uli ns 
 
Ser u m aceta mi n o p he n a d d uct assa y, w h e n 
a vaila ble, t o assess p ote ntial a cet a mi n o p he n 
c o ntri b uti o n t o li ver i nj ur y i n partici pa nts wit h 
defi nit e or li kel y aceta mi n o p he n use i n t he 
pr ece di n g wee k [ J a mes 2 0 0 9] 
 
Li ver i ma gi n g ( ultras o u n d, ma g netic res o na nce 
or C T) t o e val uate li ver diseas e 
 
Li ver bi o ps y ma y b e c o nsi der e d a n d disc usse d 
wit h l ocal s pecialist if a vail a bl e, f or i nst a nce: 
- 
I n partici pa nts w he n ser ol o g y raises t he 
p ossi bilit y of a ut oi m m u ne he p atitis  
- 
I n p artici pa nts w h e n s us p ecte d dr u g 
i n d uce d li ver i nj ur y pr o gresses or fails t o 
res ol ve o n wit h dra wal of st u d y 
i nter ve nti o n 
- 
I n p artici pa nts wit h ac ute or c hr o nic 
at y pical pr ese ntati o n 
A b bre viati o ns: A L P =al kali ne p h os p hatas e; A L T =ala ni ne a mi n otra nsferase; A S T =as partate a mi n otra nsfer ase; 
C P K =creati ne p h os p h o ki nase; C R F =cas e re p ort f or m; C T =c o m p ute d t o m o gra p h y; D N A = d e o x yri b o n ucleic 
aci d; G G T = ga m ma gl uta m yl tra nsferase; G L D H = gl uta mate de h y dr o ge nase; H B c A b = he patitis B c or e a nti b o d y; 
H Bs A g = he p atitis B s urface a nti ge n; I g G =i m m u n o gl o b uli n G; I g M =i m m u n o gl o b uli n M; I N R =i nter nati o nal 
n or malise d ra ti o; 
L D H =l act ate d e h y dr o ge nas e; 
R N A =ri b o n ucleic aci d; 
S A E =seri o us a d verse e ve nt; 
U L N = u p per li mit of n or mal 
a 
Ser u m bilir u bi n fracti o nati o n s h o ul d b e p erf or me d if testi n g is a vaila ble. If ser u m bil ir u bi n fracti o nati o n 
is n ot i m me diatel y a vaila ble, disc o nti n ue st u d y i nter ve nti o n if A L T or A S T 3 × U L N a n d  t otal bilir u bi n 
2 × U L N. 
A d diti o nall y, if ser u m 
bilir u bi n fracti o nati o n testi n g is 
u na vaila ble, 
rec o r d t he 
a bse n ce/ prese nce of detect a bl e uri n ar y bili r u bi n o n di pstic k  w hic h is i n dicati ve of direct bilir u bi n 
ele vati o ns s u g gesti n g li ver i nj ur y 
b 
All e ve nts of A L T or A S T 3 × U L N a n d t otal bilir u bi n 2 × U L N ( > 3 5 % direct bilir u bi n) or A L T or A S T 
3 x U L N a n d  I N R > 1. 5 ma y i n dicate s e vere li ver i nj ur y 
he p atic i m p air me nt or cirr h osis) . T he I N R state d t hres h ol d val ue will n ot a p pl y t o partici pa nts r ecei vi n g 
a ntic o a g ula nts. 
c 
Ne w or w orse ni n g s y m pt o ms b eli e ve d t o b e relat e d t o li ver i nj ur y (s uc h as fati g ue, na usea, v o miti n g, ri g ht 
u p per q ua dra nt p ai n or te n der ness, or j a u n di ce) or h y pers e nsiti vit y (s uc h as fe ver, ras h or e osi n o p hilia). 
d 
I ncl u des: He patitis A I g M a nti b o d y; H Bs A g a n d H Bc A b; he p atitis C R N A; c yt o me gal o vir us I g M a nti b o d y; 
E pstei n- B arr viral ca psi d a nti ge n I g M a nti b o d y ( or if u na vaila ble, heter o p hile a nti b o d y or m o n os p ot 
testi n g); a n d he patitis E I g M a nti b o d y. I n t h os e wit h u n d erl yi n g c hr o ni c he p atitis B at st u d y e ntr y 
(i de ntifie d b y p ositi ve H Bs A g) q ua ntitati ve he p atitis B D N A a n d he patitis d elta a nti b o d y If he p atitis delta 
a nti b o d y assa y ca n n ot b e perf or me d, it ca n be re pl ace d wit h a p ol y merase c hai n reacti o n of he p atitis D 
R N A vir us ( w here nee de d) [ L e Gal 2 0 0 5 ] 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 8 9/ 9 9 
 
 
 
1 0. 5. 2  
Criteri a f or I ncre ase d M o nit ori n g wit h O n g oi n g St u dy I nter ve nti o n 
Criteria re q uiri n g i ncrease d m o nit ori n g, are s h o w n i n Ta ble 9 . St u d y i nt er ve nti o n m a y be 
c o nti n ue d.  
T a ble 9 
Li v er C he mistr y I n cre ase d M o nit ori n g C riteri a wit h C o nti n ue d St u d y I nter v e nti o n  
Criteri a 
Acti o ns 
A L T or A S T 
5 × U L N a n d  < 8 × U L N a n d  
t otal bilir u bi n < 2 × U L N or I N R < 1. 5 wit h o ut  
s y m pt o ms b elie ve d t o be relate d t o li ver 
i nj ur y or h y p erse nsiti vit y, a n d  w h o ca n be 
m o nit ore d wee kl y f or 2 wee ks. 
O R 
A L T or A S T
3 × U L N a n d < 5 × U L N a n d  
t otal bilir u bi n < 2 × U L N or I N R < 1. 5 wit h o ut  
s y m pt o ms b elie ve d t o be relate d t o li ver 
i nj ur y or h y p erse nsiti vit y, a n d  w hi c h ca n b e 
m o nit ore d wee kl y f or 4 wee ks. 
 
 
N otif y t he s p o ns or wit hi n 2 4 h o urs  of lear ni n g of t he 
a b n or malit y t o dis c uss p artici p a nt safet y 
Partici pa nt ca n c o nti n ue st u d y i nt er ve nti o n.  
 
Partici pa nt 
m ust ret ur n 
wee kl y f or re peat li ver 
c he mistr y tests ( A L P, A L T, A S T, t otal bilir u bi n) u ntil 
t he a b n or malities res ol ve, sta bilise, or ret ur n t o 
baseli ne. 
 
If at a n y ti me, t he partici p a nt meets li ver c he mistr y 
st o p pi n g criteria, pr o cee d as descri be d i n T a ble 8  
 
If A L T or A S T decreases fr o m A L T or A S T 5 × U L N 
a n d  
m o nit or li ver c he mistri es wee kl y 
 
If, after 4 wee ks of m o nit ori n g, A L T or A S T < 3 × U L N 
a n d t otal bilir u bi n < 2 × U L N, m o nit or p artici pa nts 
t wice m o nt hl y u ntil li ver c he mistr y tests res ol ve, 
st a bilise, or ret ur n t o baseli ne 
A b bre viati o ns: A b bre viati o ns: A L P =al kali ne p h os p hatase; A L T =ala ni ne a mi n otra nsferase; A S T =as partate 
a mi n otra nsferase; I N R =i nter n ati o nal n or malise d rati o; U L N = u p p er li mit of n or mal 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 9 0/ 9 9 
 
 
 
1 0. 6  
A p pe n di x 6: 
W o r k Pr o d u cti vit y a n d Acti vit y/ Ge ne r al He alt h Q u alit y of Life 
Q uesti o n n aires  
 
W or k Pr o d ucti vit y a n d Acti vit y I m p air me nt Q u esti o n n aire: 
Ge ner al He alt h V 2. 0 ( W P AI: G H) 
T he f oll o wi n g q uesti o ns as k a b o ut t he effect of y o ur healt h pr o bl e ms o n y o ur a bilit y t o w or k 
a n d perf or m re g ular acti vities. B y healt h pr o ble ms we mea n a n y p h ysi cal or e m oti o nal pr o bl e m 
or s y m pt o m. Ple ase fill i n t h e bl a nks or circle a n u m ber, as i n dic at e d. 
 
1. 
Are y o u c urre ntl y e m pl o ye d ( w or ki n g f or pa y)?  
_ _ _ _  N O 
_ _ _ _  Y E S 
 
 
T he ne xt q uesti o ns are a b o ut t he p ast s e ve n d a ys , n ot i ncl u di n g t o da y. 
 
2. 
D uri n g t he past se ve n d a ys, h o w m a n y h o urs di d y o u miss fr o m w or k b eca use of y o ur 
healt h pr o ble ms ? I ncl u de h o urs y o u misse d o n sic k d ays, ti mes y o u we nt i n l at e, left e arly, 
etc., bec a use of y o ur he alt h pr o bl e ms. D o n ot i n cl u de ti me y o u misse d t o p arti ci p at e i n t his 
st u dy. 
_ _ _ _ _ H O U R S 
 
3. 
D uri n g t he p ast se ve n da ys, h o w m a n y h o urs di d y o u miss fr o m w or k beca use of a n y ot her 
reas o n, s uc h as vacati o n, h oli da ys, ti me off t o partici pate i n t his st u d y? 
_ _ _ _ _ H O U R S 
 
4. 
D uri n g t h e past se ve n d a ys, h o w ma n y h o urs di d y o u act u all y w or k? 
_ _ _ _ _ H O U R S 
 
 
5.  D uri n g t h e past se v e n da ys, h o w m u c h di d y o ur h ealt h pr o ble ms affe ct y o ur pr o d ucti vit y 
w hile y o u were w or ki n g? 
 
T hi nk a b o ut d ays y o u were li mite d i n t he a m o u nt or ki n d of w or k y o u c o ul d d o, d ays y o u 
acc o m plis he d less t h a n y o u w o ul d li ke, or d ays y o u c o ul d n ot d o y o ur w ork as c aref ully as 
us u al. If he alt h pr o ble ms aff ect e d y o ur w ork o nl y a little, c h o ose a l o w n u m ber. C h o ose a 
hi g h n u m ber if he alt h pr o ble ms affecte d y o ur w or k a gre at de al.  
 
C o nsi der o nl y h o w m uc h healt h pr o ble ms affect e d  
pr o d ucti vit y w hile y o u were w or ki n g. 
Healt h pr o ble ms 
ha d n o effect o n 
m y w or k 
 
 
 
 
 
 
 
 
 
 
 
Healt h pr o ble ms 
c o m pletel y 
pre ve nte d m e 
fr o m w or ki n g 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
1 0 
CI R C L E A N U M B E R 
 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 9 1/ 9 9 
 
 
 
6. 
D uri n g t he p ast se ve n da ys, h o w m uc h di d y o ur h ealt h pr o ble ms affect y o ur a bilit y t o d o 
y o ur r e g ular d ail y acti viti es, ot her t ha n w or k at a j o b?  
 
By re g ul ar activities, we me a n t he us u al activities y o u d o, s uc h as w ork ar o u n d t he h o use, 
s h o p pi n g, c hil dc are, exercisi n g, st u dyi n g, etc. T hi nk a b o ut ti mes y o u wer e li mite d i n t he 
a m o u nt or ki n d of a ctivities y o u c o ul d d o a n d ti m es y o u ac c o m plis he d less t h a n y o u w o ul d 
like. If h e alt h pr o ble ms affecte d y o ur activities o nl y a little, c h o ose a l o w n u m ber. C h o os e 
a hi g h n u m ber if he alt h pr o bl e ms affecte d y o ur activities a gr e at de al.  
 
C o nsi der o nl y h o w m uc h healt h pr o ble ms affect e d y o ur a bilit y  
t o d o y o ur re g ular d ail y acti viti es, ot her t ha n w or k at a j o b. 
Healt h pr o ble ms 
ha d n o effect o n 
m y dail y 
acti vities 
 
 
 
 
 
 
 
 
 
 
 
Healt h pr o ble ms 
c o m pletel y 
pre ve nte d m e 
fr o m d oi n g m y 
dail y acti viti es 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
1 0 
CI R C L E A N U M B E R 
 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 9 2/ 9 9 
 
 
 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 9 3/ 9 9 
 
 
 
 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 9 4/ 9 9 
 
 
 
1 0. 7  
A p pe n di x 7: I m p act of Tre at me nt A d mi nistr ati o n Setti n g o n C osts 
T his secti o n of t he s ur ve y will as k y o u q uesti o ns a b o ut t he c osts, i ncl u di n g tra vel ti me a n d 
pers o nal ti me, ass ociate d wit h y o ur la nre oti de A ut o gel ®  tre at m e nt at h o me a n d i n h os pital. 
 
T hi nki n g a b o ut h os pit al visits y o u atte n de d t o receive y o ur l a nre oti de A ut o gel ®  i nj ecti o n i n 
h os pit al, pri or t o s wit c hi n g t o t he i n de pe n de nt i njecti o n: 
(at visit W 4 8) 
 
1. 
If y o u n or mall y tra velle d t o t he h os pit al, h o w ma n y kil o m eters di d y o u tra v el o ne- wa y 
fr o m y o ur h o use t o t he h os pital? Please writ e t h e esti mate d n u m ber of kil o meters as bel o w. If 
y o u d o n ot k n o w t he e x act n u m ber kil o m eters, pl ease pr o vi de y o ur best esti m ate. 
_ _ _ ( Esti mate d kil o meters) 
 
2. 
W he n y o u visite d t he h os pit al t o recei ve y o ur la nre oti de A ut o gel ®  i njecti o n, h o w di d 
y o u n or mall y tra v el ? Pl ease sel ect t he o pti o n t hat best des cri bes h o w y o u n or mall y tra v elle d 
fr o m y o ur h o me t o t he h os pital If y o u n or mall y use d m ore t ha n o ne f or m of tra ns p ort, please 
select t he f or m of tra ns p ort us e d f or t he m ai n (l o n gest i n t er ms of dista nce) p art of y o ur j o ur n e y. 
 
a. 
Car ( b y m ys elf) 
b. 
Car (acc o m pa nie d b y s o me o ne else) 
c. 
Trai n 
d. 
B us 
e. 
Ta xi 
f. 
Wal ki n g 
g. 
Bic ycle 
h. 
Ot her 
 
3. 
If y o u use d p u bli c tra ns p ort, a n d were acc o m pa nie d b y a frie n d or fa mil y me m ber, h o w 
m uc h di d t h e y s pe n d o n t he c ost of t h eir j o ur ne y? Pl ease write t h e esti mate d c ost as bel o w. P ut 
zer o if y o u di d n ot n or mall y pa y a fare.  
 
T otal c ost of ret ur n fare ( C N Y) _ _ _ ( Y ua n) 
 
4. 
If y o u n or mall y tra v elle d t o t he h os pital or cli nic b y p u blic tra ns p ort (i. e. b us or trai n), 
w hat was t he a p pr o xi m ate c ost of t he j o ur ne y (t here a n d bac k)? Please writ e t he esti m at e d c ost 
as b el o w. P ut zer o if y o u di d n ot n or mall y pa y a fare. 
 
T otal c ost of ret ur n fare ( C N Y) _ _ _ ( Y ua n) 
 
5. 
If y o u n or mall y tr a vell e d t o t he h os pital or cli nic b y ta xi w hat w as t he a p pr o xi m ate c ost 
of t he j o ur ne y (t here a n d bac k)? Pleas e writ e t he esti mate d c ost i n t he b o x bel o w. P ut zer o if 
y o u di d n ot n or mall y pa y a fare. 
 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 9 5/ 9 9 
 
 
 
T otal c ost of ret ur n fare ( C N Y) _ _ _ ( Y ua n) 
 
6. 
If y o u n or mall y tra v elle d t o t he h os pital b y car a n d ha d t o pa y p ar ki n g a n d/ or t oll fees, 
h o w m uc h di d t hese fees a m o u nt t o? Pleas e write t h e esti mate d c ost i n t he b o x bel o w. P ut zer o 
if y o u di d n ot n or mall y p a y a fee. 
 
Par ki n g/t oll fees ( C N Y) _ _ _ ( Y u a n) 
 
7. 
W he n y o u visite d t he h os pit al t o r ecei v e y o ur l a nre oti de A ut o gel ®  i nj ecti o n, h o w l o n g 
di d it n or mall y ta k e o ne- wa y t o tra vel t here fr o m y o ur h o me? Please writ e t he a p pr o xi mate 
n u m ber of h o urs a n d/ or mi n utes as bel o w. 
 
_ _- _ _ ( Hrs- Mi ns) 
 
8. 
W he n y o u visite d t he h os pit al t o r ecei v e y o ur l a nre oti de A ut o gel ®  i nj ecti o n, h o w l o n g 
di d y o u n or mall y s pe n d t here? Please write t he a p pr o xi mate n u m ber of h o urs a n d/ or mi n utes as 
bel o w. 
 
_ _- _ _ ( Hrs- Mi ns) 
 
9. 
W hat w o ul d y o u h a v e n or mall y bee n d oi n g as y o ur us u al dail y acti vities if y o u ha d n ot 
g o ne t o t he h os pital t o recei ve y o ur la nre oti de A ut o gel ®  i nj ecti o n? Please s elect t he o pti o n t hat 
best descri bes w h at y o u w o ul d n or m all y be d oi n g as y o ur mai n acti vit y. 
 
a. 
H o us e w or k 
b. 
C hil dcare 
c. 
Leis ure acti viti es 
d. 
Atte n di n g sc h o ol/ u ni versit y 
e. 
Pai d w or k 
f. 
V ol u nteeri n g 
g. 
O n sic k l ea ve 
h. 
See ki n g w or k 
i. 
Ot her 
 
T hi nki n g a b o ut I m p act of s witc h i n a d mi nistr ati o n s etti n g o n m ai n d ail y activities: 
(at visit W 7 2) 
1 0. 
H o w m uc h has y o ur a bilit y t o d o y o ur us u al dail y acti vities c ha n ge d si nce s witc hi n g 
fr o m h os pital t o t he i n de pe n de nt a d mi nistrati o n of la nre oti de A ut o gel® ? 
 
a. 
O verall a bilit y t o d o m y mai n acti vit y has i m pr o ve d 
b. 
O verall a bilit y t o d o m y mai n acti vit y has n ot c h a n ge d 
c. 
O verall a bilit y t o d o m y mai n acti vit y has w orse n e d 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 9 6/ 9 9 
 
 
 
1 0. 8  
A p pe n di x 8: T he I m p act of S witc h i n A d mi nistr ati o n Setti n g o n O ver all A bilit y 
t o W or k 
Q uesti o n: (at visit W 7 2) 
T hi nki n g a b o ut y o ur over all ex p erie nc e of s witc h i n l a nre oti de 
A ut o gel ®  i nj ecti o n 
a d mi nistr ati o n setti n g: 
( 2) 
D o y o u t hi n k s witc hi n g fr o m h os pital t o i n de pe n de nt a d mi nistrati o n of la nre oti de 
A ut o gel ®  i nj ecti o n has h a d a p ositi ve or ne gati ve effe ct o n y o ur o verall a bilit y t o w or k? 
( d) 
P ositi ve effect 
(e) 
N o effect 
(f) 
Ne gati ve effect 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 9 7/ 9 9 
 
 
 
1 0. 9  
A p pe n di x 9: E aster n C o o per ati ve O nc ol o g y Gr o u p ( E C O G) Perf or m a nce St at us 
T a ble 1 0 
E aster n C o o p er ati ve O nc ol o g y Gr o u p ( E C O G) Perf or m a nce St at us 
Gr a de 
Descri pti o n 
0 
F ull y acti ve, a ble t o carr y  o n all pre -disease perf or ma nce wit h o ut restricti o n  
1 
Restricte d i n p h ysicall y stre n u o us acti vit y b ut a m b ulat or y a n d a ble t o carr y o ut w or k of a 
li g ht or se d e ntar y nat ure, e. g., li g ht h o use w or k, office w or k 
2 
A m b ulat or y a n d ca p a ble of all s elfcare b ut u n a ble t o carr y o ut a n y w or k acti vities. U p a n d 
a b o ut m ore t ha n 5 0 % of wa ki n g h o urs  
3 
Ca pa ble of o nl y li mite d self-care, c o nfi ne d t o be d or c h air m ore t ha n 5 0 % of wa ki n g h o urs  
4 
C o m pletel y disa ble d. C a n n ot carr y o n a n y self -care. T otall y c o nfi ne d t o b e d or c hair  
5 
Dea d  
 
As p u blis he d b y [ O ke n 1 9 8 2 ]. East er n C o o p erati ve O nc ol o g y Gr o u p. 
 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 9 8/ 9 9 
 
 
 
1 1  
R E F E R E N C E S 
A n dra de RJ, R o bles M, L uce na MI. Rec hall e n ge i n dr u g-i n d uc e d li v er i nj ur y: t he attracti ve 
hazar d. E x pert O pi n Dr u g Saf. 2 0 0 9; 8: 7 0 9- 1 4. 
Ca pli n M E, Pa vel M, C wi kla J B et al. La nre oti de i n metastati c e nt er o p a ncreatic ne ur oe n d o cri ne 
T u m ors. N E n gl J M e d 2 0 1 4; 3 7 1: 2 2 4- 3 3. 
E ur o pea n Ass ociati o n f or t he St u d y of t he Li v er Cli nical Practice G ui deli nes: Dr u g-i n d uce d 
li ver i nj ur y. J o ur nal of He pat ol o g y 2 0 1 9; 7 0( 6): 1 2 2 2- 6 1. 
Eise n ha uer E A, T h erass e P, B o gaerts J et al. Ne w res p o nse e v al uati o n criteria i n s oli d t u m o urs: 
re vise d R E CI S T g ui deli n e ( versi o n 1. 1) E ur J Ca ncer 2 0 0 9 Ja n; 4 5( 2): 2 2 8- 4 7. 
Fa n J H, Z ha n g Y Q, S hi S S et al. A nati o n- wi de retr os pecti ve e pi d e mi ol o gical st u d y of 
gastr oe nter o pa ncreati c 
ne ur oe n d ocri ne 
ne o plas ms 
i n 
c hi na. 
O nc otar get, 
2 0 1 7; 8 
( 4 2): 7 1 6 9 9- 7 0 8. 
E ur o pea n Ne ur oe n d o cri ne T u m or S ociet y C o nse ns us G ui deli nes f or t he Dia g n osis a n d 
Treat me nt 
of 
Ne ur oe n d o cri ne 
T u m ors, 
2 0 1 2. 
[ A vaila ble 
at: 
htt ps:// w w w.e nets. or g/ e n ets _ g ui deli nes. ht ml accesse d at 2 8 S e pt e m b er 2 0 2 0] 
G u o L Wa n g C a n d Ta n g C. E pi de mi ol o gical feat ures of gastr oe nt er o pa n creati c ne ur oe n d ocri ne 
t u m ors i n C he n g d u cit y wit h a p o p ul ati o n of 1 4 milli o n base d o n data fr o m a si n gle i nstit uti o n. 
Asia Pac J Cli n O nc ol, 2 0 1 6; 1 2( 3): 2 8 4- 8 
Hea ds of Me dici nes A ge ncies, Cli nical Trials Facilitati o n Gr o u p ( C T F G). Rec o m m e n dati o ns 
relate d t o c o ntrace pti o n a n d pre g n a nc y testi n g i n cli nical trials. Fi nal Versi o n 2 0 1 4. [a vaila ble 
at: 
htt ps:// w w w. h ma. e u/filea d mi n/ dateie n/ H u ma n _ M e dici nes/ 0 1-
A b o ut _ H M A/ W or ki n g _ Gr o u ps/ C T F G/ 2 0 1 4 _ 0 9 _ H M A _ C T F G _ C o ntrace pti o n. p df, accesse d at 
2 8 Se pte m ber 2 0 2 0]  
H u nt, C M. Mit oc h o n drial a n d i m m u n oaller gic i nj ur y i n crease ris k of p ositi ve dr u g rec halle n ge 
after dr u g-i n d uce d li ver i nj ur y: A s yst e matic re vie w. He pat ol. 2 0 1 0; 5 2: 2 2 1 6- 2 2. 
It o T, H o n ma Y, Hiji o ka S et al. P has e II st u d y of l a nre oti de a ut o gel i n J a pa nes e pati e nts wit h 
u nresect a ble or metastatic well- differe ntiate d ne ur oe n d ocri n e t u m ors. I n vest Ne w Dr u gs. 
2 0 1 7; 3 5,  4 9 9 5 0 8.  
J a mes L P, Letzi g L, Si m ps o n P M et al. P har mac o ki netics of Aceta mi n o p he n- A d d uct i n A d ults 
wit h Aceta mi n o p he n O v er d ose a n d Ac ute Li ver Fail ure. Dr u g Meta b Dis p os. 2 0 0 9; 3 7: 1 7 7 9- 8 4. 
Ka n g J, Y o o C, H wa n g H S et al. Efficac y a n d s afet y of la nre oti de i n K orea n patie nts wit h 
metastatic, well- differe ntiate d gastr oe nt er o pa ncreatic- ne ur oe n d ocri ne t u m ors: a retr os pecti ve 
a nal ysis. 
 
Le Gal F, G or die n E, Aff ola bi D et al. Q ua ntificati o n of He patitis Delta Vir us R N A i n S er u m 
b y C o nse ns us Real- Ti me P C R I n dicates Differe nt P att er ns of Vir ol o gic al Res p o nse t o 
I nterfer o n T hera p y i n C hr o ni call y I nfecte d Patie nts. J Cli n Micr o bi ol. 2 0 0 5; 4 3( 5): 2 3 6 3 9. 
M o dli n I M, Pa v el 
M, 
Ki d d 
M et al. S o mat ost ati n 
A nal o g ues i n t he Treat me nt of 
Gastr oe nter o p a ncreati c Ne ur oe n d o cri ne (carci n oi d) T u m o urs. Ali m e nt P har mac ol T her. 2 0 1 0; 
3 1( 2): 1 6 9- 8 8. 
Na gte gaal I D, O dze R D, Kli mstra D et al. T he 2 0 1 9 W H O classificati o n of t u m o urs of t he 
di gesti ve s yste m. Hist o p at h ol o g y. 2 0 2 0; 7 6( 2): 1 8 2- 8.  
Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts Versi o n 5 
( p u blis he d 2 7 N o ve m ber 2 0 1 7). 
O ke n M, Creec h R, T or me y D et al. T o xicit y a n d res p o nse criteria of t he Easter n C o o perati ve 
O nc ol o g y Gr o u p. A m J Cli n O nc ol. 1 9 8 2; 5: 6 4 9- 5 5. 

I P S E N G R O U P 
D- C N- 5 2 0 3 0- 4 1 1 
 
C O N FI D E N TI A L 
P R O T O C O L: FI N A L V E R SI O N 2. 0 I N C L U DI N G A M E N D M E N T 1: 1 7 M A Y 2 0 2 1 
P A G E 9 9/ 9 9 
 
 
 
Pa pa y JI, Cli nes D, Rafi R et al. Dr u g-i n d uce d li ver i nj ur y f oll o wi n g p ositi ve dr u g rec h all e n ge. 
Re g ul T o x P har m. 2 0 0 9; 5 4: 8 4- 9 0. 
Vi ni k AI, W oli n E M, Li ya n a ge N et al. E val uati o n of la nre oti de d e p ot/ A ut o gel effic ac y a n d 
safet y as a carci n oi d s y n dr o me treat me nt ( E L E C T): a ra n d o mi ze d, 
d o u ble- bli n d, 
place b o-