Clinical trial NCT04852679
Conditions: Gastroenteropancreatic Neuroendocrine Tumor
Sponsor: Ipsen
Start date: 2021-05-24; Completion date: 2023-01-13
Enrollment: 43 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will be conducted to support the registration of the lanreotide Autogel 120 mg formulation in China for the treatment of GEP-NETs and treatment of clinical symptoms of NETs.

The study will include a screening period of up to 4 weeks followed by a 48-week intervention period. After completion of the main study period, five participants will continue in a self/partner injection cohort with lanreotide Autogel 120 mg every 28 days for 24 weeks.

Detailed description:

Arms: arm 1: Subjects will be treated with lanreotide Autogel® 120mg, every 28 days (+/- 3 days).
Interventions: intervention 1: Lanreotide autogel
Intervention descriptions: intervention 1: Administered as deep subcutaneous (SC) injections

Protocol documents:
Prot_000.pdf: 


 
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.  


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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: 
 


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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: 
[ ] 
 
[ ] 
 
[ ] 
 
[ ] 
 
[ ] 
 


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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. 




























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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  


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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  


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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  


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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  
 


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C O N FI D E N TI A L 
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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 w a 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-
 

SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN 
 
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) 
[D-CN-52030-411] 
 
 
This statistical analysis plan is based on: 
PROTOCOL VERSION AND DATE: 2.0  17 MAY 2021 
 
 
 
SAP Version 
Date 
Draft Version 0.1 
12MARCH2021 
Draft Version 0.2 
31MARCH2021 
Draft Version 0.3 
20APRIL2021 
Draft Version 0.4 
19MAY2021 
Draft Version 0.5 
21MAY2021 
Final Version 1.0 
21MAY2021 
Final Version 1.1 
30MAY2022 
Final Version 1.2 
17JUN2022 
Final Version 2.0 
01AUG2022 
Final Version 2.1 
05JAN2023 
Final Version 2.2 
14FEB2023 
Final Version 3.0 
17FEB2023 






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TABLE OF CONTENTS 
APPROVAL PAGE .................................................................................................................. 2 
HISTORY OF CHANGES ...................................................................................................... 3 
TABLE OF CONTENTS ......................................................................................................... 4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................... 6 
1 
INTRODUCTION .......................................................................................................... 8 
2 
PROTOCOL OVERVIEW ............................................................................................ 8 
2.1 
Study Objectives and Hypotheses ................................................................................. 8 
2.1.1 
Primary objective ........................................................................................... 8 
2.1.2 
Secondary Objectives .................................................................................... 8 
2.1.3 
Exploratory Objective ................................................................................... 8 
2.1.4 
Statistical Hypotheses ................................................................................... 8 
2.2 
Overall Study Design and Investigational Plan ........................................................... 8 
2.3 
Sample Size Determination and Power ....................................................................... 10 
2.4 
Randomisation and Blinding (if applicable) ............................................................... 10 
2.5 
Schedule of Assessments ............................................................................................... 10 
2.6 
Change from Statistical Section of the Protocol ........................................................ 11 
3 
PLANNED ANALYSES ............................................................................................... 11 
3.1 
Data Monitoring ............................................................................................................ 11 
3.2 
Interim Analysis / Primary Analysis ........................................................................... 11 
3.3 
Final Analysis ................................................................................................................ 11 
4 
ANALYSIS SETS ......................................................................................................... 11 
5 
STATISTICAL METHODS/ANALYSES .................................................................. 12 
5.1 
General Considerations ................................................................................................ 12 
5.1.1 
Outputs Presentation ................................................................................... 12 
5.1.1.1 
Tables Header .............................................................................................. 12 
5.1.1.2 
Presentation of Treatment Group ................................................................ 12 
5.1.1.3 
Presentation of Visits / Timepoints .............................................................. 12 
5.1.2 
Descriptive Statistics ................................................................................... 13 
5.1.3 
Baseline value ............................................................................................. 13 
5.1.4 
Reference Start Date and Study Day .......................................................... 13 
5.2 
Disposition and Analysis Sets ....................................................................................... 13 
5.3 
Protocol Deviations ....................................................................................................... 14 
5.4 
Demography and Other baseline characteristics ....................................................... 14 
5.5 
Medical history, non-drug therapies, medications and surgical procedures .......... 15 
5.6 
Compliance .................................................................................................................... 16 
5.7 
Efficacy .......................................................................................................................... 17 
5.7.1 
General Considerations .............................................................................. 17 
5.7.1.1 
Significance Testing and Estimations .......................................................... 17 


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5.7.1.2 
Handling of Dropouts and missing data ...................................................... 17 
5.7.1.3 
Statistical/analytical issues .......................................................................... 17 
5.7.2 
Analysis of Primary Efficacy Endpoint ...................................................... 17 
5.7.2.1 
Endpoint and Treatment Effect Definition ................................................... 17 
5.7.2.2 
Primary Analysis .......................................................................................... 18 
5.7.2.3 
Sensitivity Analysis ....................................................................................... 18 
5.7.2.4 
Supplementary Analysis ............................................................................... 18 
5.7.2.5 
Subgroup Analysis ....................................................................................... 18 
5.7.3 
Analysis of Key Secondary Efficacy Endpoints ......................................... 18 
5.7.3.1 
Endpoint and Treatment Effect Definition ................................................... 18 
5.7.3.2 
Main Secondary Analysis ............................................................................. 19 
5.7.3.3 
Subgroup Analysis ....................................................................................... 21 
5.7.4 
Analysis of Exploratory Endpoints ............................................................. 21 
5.7.5 
Analysis of COVID-19 impacts on efficacy endpoints .............................. 21 
5.8 
Safety .............................................................................................................................. 22 
5.8.1 
General Consideration ................................................................................ 22 
5.8.2 
Extent of exposure ...................................................................................... 22 
5.8.3 
Adverse Event .............................................................................................. 22 
5.8.4 
Laboratory Data .......................................................................................... 24 
5.8.5 
Vital Signs ................................................................................................... 25 
5.8.6 
Electrocardiogram (ECG)........................................................................... 26 
5.8.7 
Physical Examination ................................................................................. 26 
5.8.8 
Other (if applicable) .................................................................................... 26 
5.9 
PK (if applicable) .......................................................................................................... 26 
5.10 Anti-drug Antibodies (if applicable) ........................................................................... 26 
6 
DATA HANDLING ...................................................................................................... 27 
6.1 
Visit window .................................................................................................................. 27 
6.2 
Unscheduled Visits, Retest, Withdrawal Visit, ........................................................... 28 
6.3 
Laboratory Values or Concentration Data ................................................................ 28 
7 
DERIVED DATA (IF APPLICABLE) ....................................................................... 28 
8 
REFERENCES .............................................................................................................. 29 
9 
APPENDICES ............................................................................................................... 31 
A1. SAS code ........................................................................................................................ 31 
A2. Partial/Missing Date Convention ................................................................................ 32 
A3. Programming Convention for Outputs ....................................................................... 34 
A4. Listings conventions ...................................................................................................... 34 
A5. EudraCT categories for age ......................................................................................... 35 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ABBREVIATION 
Wording Definition 
ADA 
Anti-Drug Antibodies 
ADaM 
Analysis Dataset Model 
AE 
Adverse Event 
ATC 
Anatomic Therapeutic Class 
BICR 
Blinded independent central review 
C 
Concomitant  
CBR 
Clinical benefit rate 
CgA 
Chromogranin A 
CI 
Confidence interval 
eCRF 
Electronic Case Report Form 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOSI 
End of Study Intervention 
EMA 
European Medicines Agency 
EORTC QLQ-C30 
European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire for Cancer Patients 
FDA 
Food and Drug Administration 
GEP-NET 
Gastroenteropancreatic neuroendocrine tumours 
ICE 
Intercurrent Event 
ICH 
International Conference on Harmonisation  
IMP 
Investigational Medicinal Product 
ITT 
Intention-To-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intention to Treat 
MTK 
Multi-target tyrosine kinase 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria 
for Adverse Events 
ORR 
Overall response rate 
OS 
Overall survival 


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ABBREVIATION 
Wording Definition 
P 
Prior 
PD 
Progressive Disease 
PFS 
Progression free survival 
PK 
Pharmacokinetic 
PN 
Preferred Name 
PP 
Per Protocol  
PR interval 
Prolonged Release Interval 
PRRT 
Peptide Receptor Radionuclide Therapy 
Confirmed PR 
Confirmed Partial Response 
PT 
Preferred Term 
QoL 
Quality of life 
QRS 
Time interval for ventricular depolarization 
QT 
Time interval for ventricular depolarisation and 
repolarisation 
QTc 
Corrected QT interval 
QTcB 
 
QTcF 
formula 
RR 
Time between QRS complexes 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
SE 
Standard Error 
SI 
International System of Units 
SOC 
System Organic Class 
TEAE 
Treatment Emergent Adverse Event 
TFLs 
Tables, Figures and Listings 
TTP 
Time to progression 
ULN 
Upper Limit of Normal 
 


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1 
INTRODUCTION 
The purpose of this SAP is to outline the planned analyses to be completed to support the 
completion of the Clinical Study Report (CSR) for protocol D-CN-52030-411. It describes the 
rules and conventions to be used in the analysis and presentation of data, the data to be 
summarised and analysed, including specificities of the statistical analyses to be performed.  
Exploratory analyses not necessarily identified in this SAP may be performed to support the 
clinical development program. Any post-hoc, or unplanned, analyses not identified in this SAP 
performed will be clearly identified in the respective CSR. 
The SAP is to be finalised before first participant in.  A separate shell will be provided for 
tables, figures and listings.  
Any deviations from the SAP after database lock will be documented in the CSR (section 9.8 
hanges in the conduct of the study or planned analyses  as per International Conference on 
Harmonisation (ICH) E3).  
This analysis plan does not cover pharmacokinetics (PK) and biomarker analysis which will be 
described in a separate document. 
 
2 
PROTOCOL OVERVIEW 
2.1 
Study Objectives and Hypotheses 
2.1.1 
Primary objective 
The primary objective of the study is to evaluate the efficacy of repeated deep s.c. injection of 
lanreotide Autogel 120 mg every 28 days for 24 weeks in Chinese participants with 
unresectable, locally advanced or metastatic GEP-NETs. 
2.1.2 
Secondary Objectives 
The secondary objectives of the study are as follows: 
 To evaluate the efficacy of lanreotide Autogel 120 mg administered every 28 days for 48 
weeks. 
 To evaluate the safety of lanreotide Autogel 120 mg administered every 28 days for 48 
weeks. 
2.1.3 
Exploratory Objective 
 To evaluate independent injection of lanreotide Autogel 120 mg administered every 28 days 
for 24 weeks during the independent injection period (independent injection cohort). 
2.1.4 
Statistical Hypotheses 
The null hypothesis H0: P
40% versus the alternative hypothesis H1: P>40%, where P is the 
CBR at the end of 24 weeks of study intervention. The threshold CBR at W24 was defined as 
40%. 
2.2 
Overall Study Design and Investigational Plan 
This is a prospective, multicentre, single-arm, nonrandomised, open-label, interventional, phase 
3 study in Chinese adult participants with unresectable, well differentiated locally advanced or 
metastatic GEP-NETs (gastric, pancreas, midgut, hindgut), Grade 1 or 2, nonfunctioning and 
functioning. The study design is illustrated in Figure 1.  
The main study will include a screening period of up to 4 weeks followed by a 48-week 
intervention period. During the intervention period, 43 participants will receive deep 
subcutaneous injection of lanreotide Autogel 120 mg every 28 days (i.e. 4 weeks; a total of 12 


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injections). The main study will include 14 visits (one screening visit, 13 visits, one every 4 
weeks (Day 1, W4 to W48 (EOSI)) during the 48-week intervention period. 
After completion of the main study period, approximately five participants (assuming 10 to 
25% eligible participants after 48 weeks of intervention in the main study) will enter an 
independent (self/partner) injection period with lanreotide Autogel 120 mg every 28 days for 
24 weeks (a total of six independent injections). To be eligible, the participant must provide 
additional informed consent to continue, have a positive benefit/risk ratio of continuing study 
intervention (no disease progression at W48 and good tolerability during the main study period) 
and be a suitable candidate for independent injection (considered able to independently 
administer lanreotide following training and likely to benefit from independent administration 
e.g. reducing the burden of frequent hospital visits) in the opinion of the investigator. For the 
independent injection period there will be up to six additional visits (W52 to W68 (optional) 
and W72 (EOSI)). Visits for study assessments will be performed at W48, W52 (optional) and 
W56 (optional); with EOSI assessments at W72. At the W48 visit, the first injection will be 
performed independently at the study site (under medical supervision) for training purposes. At 
W52 and W56, the second and third injections may also be performed at the study site for 
training purposes or may be performed at home if no further training is needed, in the opinion 
of the investigator. At W60, W64 and W68, the fourth, fifth and sixth injections will be 
performed at home or at the study site. Participants will be contacted by telephone at W52, 
W56, W60, W64 and W68 (if no study site visit is performed) for safety purposes. 
The primary efficacy endpoint is clinical benefit rate (CBR) of tumour response assessed using 
Response Evaluation Criteria in Solid Tumours RECIST Version 1.1 [Eisenhauer 2009] and 
confirmed by blinded independent central review (BICR) after 24 weeks of study intervention. 
Secondary efficacy endpoints will be assessed during the intervention period, including PFS, 
overall survival (OS), time to progression (TTP), proportion of participants alive and without 
progressive tumour, CBR after 48 weeks of intervention, overall response rate (ORR), disease 
control rate (DCR), NET-related clinical symptoms, circulating chromogranin A (CgA), 5-
hydroxyindoleacetic acid (5-HIAA) and other biomarkers and QoL. Safety data including AEs, 
clinical safety laboratory tests, electrocardiograms (ECG), physical examination, vital signs and 
gallbladder echography will also be evaluated. Exploratory endpoints will be assessed in the 
five participants continuing in the independent injection period (proportion of participants 
preferring independent injection over HCP injections, participant-reported indirect costs and 
work productivity, plus tumour response, NET-related clinical symptoms, QoL, biomarkers and 
safety). 
The maximum duration of the study is approximately 24 months (main study: approximately 
18 months). 
Maximum duration of the study per participant: 
  Screening period: up to 4 weeks 
  Main study period: 48 weeks 
  Independent injection period for the independent injection cohort only: additional 24 weeks 
After the end of study assessments, participants will enter a remote post-intervention survival 
follow-up period and a telephone call will be used to collect survival status and subsequent 
therapies. This follow-up will be performed for all participants (irrespective of whether they 
participate in the independent injection period or not) within 4 weeks after the last participant 
enrolled in the study reaches W48 or W72(for independent injection period only) or until the 
day of discontinuation. 
 


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Figure 1 Study Schema 
 
Note: W48/EOSI=end of main study (after 48 weeks of intervention period) for all participants; W72/EOSI=end of independent injection period only 
for independent injection period 
After finishing the intervention in the main study period or the independent injection period, the investigator will record overall survival status within 
4 weeks after the last participant last visit in either period reaches W48 or W72, respectively, or the day of discontinuation, irrespective of subsequent 
therapy  
2.3 
Sample Size Determination and Power 
Approximately 51 participants will be enrolled to achieve 43 receiving study intervention in the 
main study period and 36 participants evaluable for CBR at W24. Based on Chinese 
epidemiology, it is expected to have the relevant representation of all types of GEP-NETs in 
the Chinese population, including Pan-NET and GI-NET. 
 
to participate in a clinical study following completion of the informed consent process. 
The expected CBR at W24 was set to 64% based on the results from Japanese Study ITM-
014N-001 and global pivotal Study 2-55-52030-726 (CLARINET; NCT00353496). The 
threshold CBR at W24 was defined as 40% based on Japanese Study ITM-014N-001 and 
 one-
sided type I error of 2.5%, a minimum sample size required to yield a power of at least 80% 
would be 36 participants. Considering a 15% drop-off rate, 43 participants would be necessary 
for the primary efficacy evaluation of CBR at W24. 
To provide clinical experience of independent injection in Chinese participants, approximately 
five qualified participants (having a positive benefit/risk ratio) will have independent injection 
of lanreotide Autogel during the 24 weeks of the independent injection period (assuming 10 to 
25% eligible participants after 48 weeks of intervention in the main study will continue to 
receive independent injection). The aim is to achieve five participants that have been trained to 
perform independent injections and are considered able to independently administer lanreotide 
from the investigator. 
2.4 
Randomisation and Blinding (if applicable) 
This is a non-randomised, open-label study. 
2.5 
Schedule of Assessments 
Schedule of assessments is presented in section 1.3 from the protocol. 


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2.6 
Change from Statistical Section of the Protocol 
There is no change in SAP from statistical section of the protocol. 
3 
PLANNED ANALYSES 
3.1 
Data Monitoring  
No independent DMC will be used in this study. 
3.2 
Interim Analysis / Primary Analysis 
No interim analysis will be performed. Two analyses will be performed according to the 
following data cut-offs in the main study period. 
The first analysis will be performed when all participants complete the first 24 weeks of the 
main study period. The cut-off date considered for this analysis is the date of the last W24 visit 
for the last participant. All available data at the time of this data cut-off date will be included in 
this analysis. The purpose of this analysis is the final analysis of the primary efficacy endpoint, 
as well as efficacy and safety analyses of the first 24 weeks of the main study period. This 
analysis will not be considered as an interim analysis because the first 24 weeks of main study 
period is of primary interest. 
The second analysis will be performed when all participants have had the opportunity to 
complete the main study (W48). The reporting database will include all main study data for all 
participants enrolled into the study. 
3.3 
Final Analysis 
The third and final analysis will be performed when the last participant completes the 
independent injection period. The reporting database will include all independent injection 
period study data. 
4 
ANALYSIS SETS 
Enrolled Set 
The enrolled set will contain all participants who sign the ICF.  
 
Safety Set 
The safety set will contain all participants who receive at least one dose of study intervention. 
If there is any doubt whether a participant was treated or not, they will be assumed treated for 
the purposes of analysis.  
 
Intention-To-Treat (ITT) Set 
The ITT set will contain all participants who receive at least one dose of study intervention.  
 
Modified Intention-To-Treat (mITT) Set 
The mITT set will contain all participants in the ITT having at least W24 data recorded for the 
primary efficacy endpoint.  
 
Per Protocol Set 
The per-protocol set (PP) will contain all participants in the mITT who did not experience any 
major protocol deviations that may interfere with the efficacy evaluation. Please refer to section 
5.3 for details regarding the management of deviations. 
 


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Immunogenicity Set 
The immunogenicity set will contain all participants in the ITT who have baseline and at least 
one postbaseline anti-lanreotide antibody result. 
 
Independent Injection Set 
The independent injection set will contain all participants who receive the study intervention 
by independent injection. 
5 
STATISTICAL METHODS/ANALYSES 
The statistical analyses will be performed in accordance with ICH E9 guideline and guidelines 
presented in section 8. 
TigerMed will perform the statistical analysis of this study under the supervision of the data 
management/statistical department of IPSEN. 
5.1 
General Considerations 
The precision of the measurement for each continuous variable will be used to determine the 
number of decimal places to present in tables, figures, and derived listings. Unless otherwise 
specified, min and max values will be reported with the same decimal as the units of measure; 
the mean, median and SD will be reported to 1 greater decimal place, all of them will not be 
greater than 4 decimal places. Any values that require transformation to standard units (metric 
or International System [SI]) will be converted with the appropriate corresponding precision. 
Percentages of categorical variables will be presented to 1 decimal place unless otherwise 
specified.  
All statistical analyses will be performed using the SAS® software version 9.4. 
5.1.1 
Outputs Presentation 
5.1.1.1 
Tables Header 
Since this is a single-arm study, all summary tables will be presented by treatment group. 
5.1.1.2 
Presentation of Treatment Group 
Tables, Figures and Listings (TFLs) will be displayed using the following treatment group 
labels:  
Lanreotide Autogel 120mg 
5.1.1.3 
Presentation of Visits / Timepoints 
Summaries by visit will be presented using visit number as collected in the Electronic Case 
Report Form (eCRF). 
Visits in the TFLs will be presented as follows and in the following order: 
 
Long Visit Name  
Short Name
Screening (Visit 1) 
Scr 
Baseline (Visit XX)
Bsl 
Week 4 (Visit 3) 
W4 
Week 8 (Visit 4) 
W8 
Week 12 (Visit 5)
W12
Week 16 (Visit 6)
W16
Week 20 (Visit 7)
W20
Week 24 (Visit 8)
W24


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Week 28 (Visit 9)
W28
Week 32 (Visit 10) 
W32
Week 36 (Visit 11) 
W36
Week 40 (Visit 12) 
W40
Week 44 (Visit 13) 
W44
Week 52 (Visit 15) 
W52
Week 56 (Visit 16) 
W56
Week 60 (Visit 17) 
W60 
Week 64 (Visit 18) 
W64 
Week 68 (Visit 19) 
W68
End of Study Intervention in Main Intervention Period
EOSIM
End of Study Intervention in Independent Injection Period
EOSII 
Early Discontinuation in Main Intervention Period 
EDM
Early Discontinuation in Independent Injection Period
EDI 
Remote Follow-up
FU 
the listings the 
baseline flag may correspond to values from Visit 1, Visit 2 or sometimes unscheduled visit. 
5.1.2 
Descriptive Statistics 
All raw and derived variables will be listed and described using summary statistics. For 
categorical variables, summary statistics will be displayed using descriptive statistics by 
frequency count and percentages by category. The missing category will be presented if there 
is at least one missing category for at least one treatment group. Except otherwise specified, 
participants with missing data will be included in the calculation of percentages. For 
quantitative variables, summary statistics will be displayed using descriptive statistics by 
number of observations, mean, standard deviation (SD), first quartile, median, third quartile, 
minimum and maximum. Frequency and proportion of missing data will be displayed.  
5.1.3 
Baseline value 
Unless otherwise specified, baseline is defined as the last non-missing measurement taken prior 
to first Investigational Medicinal Product (IMP) administration (including unscheduled 
assessments). If the assessment time and/or IMP administration time is not collected, the 
assessment performed on the same day as the first IMP administration will be considered as 
baseline. 
5.1.4 
Reference Start Date and Study Day 
Reference start date is defined as the day of the first IMP administration.  
The day of the first IMP administration will be Day 1. Study day will be calculated as: 
- The difference between the event date and the reference date plus one day, if the event is on 
or after the reference date. 
- The difference between the event date and the reference date, if the date of event is prior to 
the reference date.  
Study day will appear in any listings where an assessment date or event date appears. 
In case of partial or missing event date, study day will appear missing while any associated 
durations will be presented based on the imputations described in appendix A2. 
 
5.2 
Disposition and Analysis Sets 
Following disposition summaries and listings will be provided: 


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- 
Summary table with the number and percentages of treated participants per site on the 
ITT set, 
- 
Summary table with the number and percentage of participants screened, screen failed, 
reason for screen failures, treated, completed, withdrawn and reason for withdrawal on 
the enrolled set, 
- 
Summary table on duration of participant participation in the study. The definition of the 
duration of participant participation is from date of consent to the last study visit on the 
ITT set, 
- 
Summary of the number and percentage of participants with treatment discontinuation or 
study withdrawal due to COVID-19, 
- 
Summary of the number and percentage of participants with study disruption due to 
COVID-19, 
- 
Listing of dates of visit including duration of participant participation on the ITT set, 
- 
Listing of screen failure participants on the enrolled set, 
- 
Listing of withdrawal participants on the ITT set, 
- 
Listing of participants impacted by COVID-19, 
- 
Listing of participants with study disruption, including missed tumour assessment and 
dose delay due to COVID-19. 
 
Following summaries and listings will be provided on the ITT set: 
- 
Listing of participants not meeting at least one inclusion criteria,  
- 
Listing of participants fulfilling at least one exclusion criteria,  
- 
Summary of the number and percentage of participants in each analysis set by treatment 
group, based on all treated participants with reasons for exclusion from each analysis set, 
- 
Listing including flag for each analysis set and reason for exclusion from each set. 
5.3 
Protocol Deviations 
An exhaustive list of major protocol deviations that may occur during the course of the study 
and any action to be taken regarding exclusion of participants from the PP set is defined in 
protocol deviation log. Major protocol deviations will be determined before database lock of 
the study, finalised during the blind data review and documented in a separate document. 
Following protocol deviation summary and listing will be provided on the ITT set: 
- 
Number and percentage of participants with major protocol deviations by deviation 
category (see DV section of Standard Study Data Tabulation Model (SDTM) user 
guide).  
- 
Number and percentage of participants with major protocol deviations related to 
COVID-19 by deviation category 
- 
A Listing of major protocol deviations.  
- 
A listing of all protocol deviations by deviation class (e.g. minor/major)  
- 
A listing of protocol deviations related to COVID-19 by deviation class (e.g. 
minor/major)  
5.4 
Demography and Other baseline characteristics 
All demographic and baseline characteristics summaries and listings will be provided for the 
ITT set and mITT set. 


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Following summaries will be provided on: 
- 
Demographic variables (age, age categories (from 18 to 64 years/from 65 to 84 years/85 
years and over), sex, ethnicity, race, height), 
- 
Other baseline characteristics (weight, BMI, tobacco use, alcohol use), 
- 
Disease characteristics: 
type of GEP-NET (functioning/non-functioning); 
NET grade; 
mitotic count; 
proliferation index Ki67;  
time since initial diagnosis; 
primary NET site; 
menopausal (yes/no); 
has the assessment of Somatostatin receptor been performed (yes, no, unknown); 
the outcome of Somatostatin receptor (Positive, Negative) 
the method of performing Somatostatin receptor (Imaging, Immunohistochemistry) 
presence or absence of NET-related symptoms; 
sum of diameters for target lesions; 
presence or absence of progression; 
follicle stimulating hormone result; 
ECOG performance score. 
Listings will also be provided for all the summaries listed above.  
5.5 
Medical history, non-drug therapies, medications and surgical procedures 
Medical and surgical history, non-drug therapies, surgical procedures and clinical symptoms 
will be coded using the latest version of Medical Dictionary for Regulatory Activities 
(MedDRA) in effect within IPSEN at the time of database lock. Medications will be coded 
using the latest version of World Health Organization-Drug dictionary in effect within IPSEN 
at the time of database lock. 
 
Medication, non-drug therapies and surgical procedures start and stop dates will be compared 
to the date of the first IMP administration and the last IMP administration to allow classification 
as either Prior only, Prior and Concomitant, Concomitant only, or Subsequent only: 
 
Prior (P)  
Start and stop dates prior to the date of the first IMP 
administration.  
Prior 
and 
Concomitant (PC)  
Start date before the date of the first IMP administration and stop 
date on or after the date of the first IMP administration.  
Concomitant (C) 
Start date on or after the date of first IMP administration.
Subsequent 
Start date after the date of last IMP administration. 
 
Summary tables on prior medications/non-
summary tables on concomitant medications/non-drug therapies/surgical procedures will include 
 
 


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See detailed rules in appendix A2 for classification of prior and concomitant medication/non-
drug therapies, surgical procedures in case of partial/missing date. 
 
The therapeutic class will correspond to the second level of Anatomic Therapeutic Class (ATC) 
code, that is, corresponding to the first 3 figures. 
 
Following summaries, presenting count and percentages of participants will be provided on the 
ITT set: 
- 
Medical and surgical history by primary system organ class (SOC) and preferred term 
(PT), 
- 
Prior medications (P) for the study indication by ATC class (ATC level 2) and preferred 
Name PN, 
- 
Concomitant medications (PC, C) for the study indication by ATC class (ATC level 2) 
and Preferred Name PN, 
- 
Prior non-drug therapies (P) by primary SOC and PT, 
- 
Concomitant non-drug therapies (PC, C) by primary SOC and PT, 
- 
Prior surgical procedures (P) by primary SOC and PT, 
- 
Concomitant surgical procedures (PC, P) by primary SOC and PT, 
- 
Prior radiotherapies (P) by primary SOC and PT, 
- 
Concomitant radiotherapies (PC, C) by primary SOC and PT, 
- 
Subsequent medications for the study indication by ATC class (ATC level 2) and 
preferred Name PN, 
- 
Subsequent surgical procedures by primary SOC and PT, 
- 
Subsequent radiotherapies by primary SOC and PT. 
 
Listings will be provided for all the summaries listed above. These listings should include a 
flag indicating the category (P, PC, C) as described in the table above.  
A prohibited medication or therapy or procedure listing be provided including the following 
drugs and procedures: 
 Interferon, PRRT (other than that used for imaging or SSTR scintigraphy), 
chemotherapy or chemoembolisation, radiofrequency ablation or cryoablation 
 Any somatostatin analogues other than study intervention 
 GH antagonist 
 Cyclosporin 
 mTOR inhibitor, MTK inhibitors 
 Tumour resection 
5.6 
Compliance 
Compliance will be calculated by period as: number of actual injections/number of planned 
injections in main intervention period or in independent injection period.  
Following summary and listing will be provided on the safety set: 
 - Descriptive statistics of compliance including number of percentage of participants by class 
of compliance and period (e.g. <80%, >=80%).  


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- A listing of treatment compliance including whether each subject is affected by COVID-19.  
5.7 
Efficacy  
5.7.1 
General Considerations 
The primary efficacy evaluation will be performed on the intention-to-treat (ITT) set. 
Sensitivity analysis of the primary efficacy evaluation will be based on the modified intention-
to-treat (mITT) set and the per protocol set (PP). Secondary analyses will be performed on the 
ITT set.  
 
A listing of all efficacy data (raw and derived) should be provided (see listing detail conventions 
in Appendix A4). Descriptive statistics will be provided for all endpoints. 
 
5.7.1.1 
Significance Testing and Estimations 
All statistical tests will be two-sided at the 5% level of significance. Confidence intervals will 
be 95%, unless otherwise specified in the description of the analyses. 
 
5.7.1.2 
Handling of Dropouts and missing data  
The imputation of missing single item values in the quality-of-life questionnaires (EORTC 
QLQ-C30 and QLQ-GI.NET21) within one visit will be made following the recommendations 
for these questionnaires [Fayers PM, 2021]. If for a patient at least half of the items from the 
respective scale have been answered, the missing items will be imputed with the average value 
of those items which are present. For all other variables, no adjustments will be made for 
missing data in the analysis. 
5.7.1.3 
Statistical/analytical issues  
Adjustments for Covariates  
No covariate adjustment analysis is planned in this study. 
 
Interim Analyses and Data Monitoring 
No interim analysis will be performed. Please refer to section 3. 
 
Multicentre Studies 
No by-centre displays or adjustments for centre are planned for this study. 
 
Multiple Comparisons/Multiplicity  
Multiplicity will not be adjusted. 
 
5.7.2 
Analysis of Primary Efficacy Endpoint 
5.7.2.1 
Endpoint and Treatment Effect Definition 
The primary efficacy endpoint is CBR of tumour response assessed using RECIST (Version 
1.1) and confirmed by BICR at W24. 
CBR is defined as the proportion of participants with a best overall response of confirmed CR, 
confirmed PR, or continued SD until the time of assessment.  


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Unconfirmed PR or CR preceding SD or following SD are treated as SD. Thus, in the data 
analysis this situation will be regarded as continued SD. 
5.7.2.2 
Primary Analysis 
For the primary efficacy endpoint CBR at W24, the summary statistics of number and 
percentage of participants and point estimates and exact 95% CIs based on the Clopper-Pearson 
method will be calculated based on ITT. 
The SAS code to be used could be presented in Appendix A1. 
A listing will be provided including all participants with missing values for the primary 
endpoint.  For these participants, the listing will provide all observed data related to the primary 
endpoint i.e. all measurements recorded prior to the missing value, any measurements recorded 
after the missing value, important baseline characteristics, the reason and timing for study 
discontinuation. The listing will also provide the imputed value(s) (if applicable) used in the 
primary analysis and any sensitivity analyses. 
5.7.2.3 
Sensitivity Analysis 
Sensitivity analyses will be conducted to further explore the primary efficacy endpoint with 
the same statistical method on the mITT set. 
A PP set will also be used to explore the primary efficacy endpoint with the same statistical 
method. 
5.7.2.4 
Supplementary Analysis 
No supplementary analyses will be performed. 
5.7.2.5 
Subgroup Analysis 
Descriptive subgroup analyses of the primary efficacy variable will be performed on the 
following factors. The subgroups include: 
 
Age: 
65 years or >65 years  
 
Sex: Male or Female 
 
Progression at baseline: Yes or No  
 
Previous treatment for NET (drug or other treatment method): Yes or No 
 
Progression at baseline, Previous treatment for NET (drug or other treatment method): 
(Yes, Yes) or (Yes, No) or (No, Yes) or (No, No) 
 
Classification of site of primary tumour: gastric, pancreas, midgut, hindgut, other 
 
GEP-NET Grading: 1, 2 
 
Somatostatin receptors: (Yes or No or Unknown)  
 
COVID-19 impact on treatment or not: (Yes or No) 
5.7.3 
Analysis of Key Secondary Efficacy Endpoints 
5.7.3.1 
Endpoint and Treatment Effect Definition 
Secondary efficacy endpoints and evaluations are summarised in table 1. 
Table 1 Secondary Endpoints and the related definition 
Endpoint 
Variable 
Definition  
PFS within 24 and 48 weeks 
after the first administration of 
study intervention 
PFS 
Time from the first administration of study
intervention to the date of the first 
documented PD measured using RECIST 
(Version 1.1) and confirmed by BICR, or 


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death from any cause, whichever comes 
first. 
OS at the end of the main study  OS 
The time from the first administration of 
study intervention to the date of death from 
any cause 
TTP within 48 weeks after the 
first administration of study 
intervention 
TTP 
The time from the first administration of 
study intervention to the date of the first 
documented PD, or clinical progression 
confirmed by the investigator 
Proportion 
of 
participants 
alive and without tumour
progressive at W24 and W48 
Proportion of 
participants 
alive 
and 
without 
tumour 
progressive 
The number and proportion of participants 
alive and without progressive disease  at 
W24 and W48 
CBR at W48 
CBR 
The proportion of participants with a best 
overall 
response 
of 
confirmed 
CR, 
confirmed PR, or confirmed SD until the 
time of assessment 
ORR at W24 and W48 
ORR 
The proportion of participants with a best 
a best overall response of confirmed CR, 
confirmed PR  
DCR at W24 and W48 
DCR 
The proportion of participants with a best 
overall 
response 
of 
confirmed 
CR, 
confirmed PR or SD 
Change from baseline in NET-
related clinical symptoms at 
W24 and W48 
Change from 
baseline 
in 
NET-related 
clinical 
symptoms 
NET-related clinical symptoms (eg: 
flushing, diarrhea, abdominal pain, 
weakness, heartburn, nausea, vomit, 
sweating, tremor, palpitation, or 
erythema) 
Change 
from baseline 
in 
plasma CgA, 5-HIAA and 
other 
biomarkers 
in 
the 
circulation at W12, W24, W36 
and W48 
Change from 
baseline 
in 
plasma CgA, 
5-HIAA 
and 
other 
biomarkers 
Other biomarkers include: Gastrin, 
Glucagon and Insulin. 
Change from baseline in QoL 
assessment at each visit 
Change from 
baseline 
in 
QoL 
assessment 
See section 7 
5.7.3.2 
Main Secondary Analysis 
For time-to-event endpoints (PFS, TTP and OS), the survival curve will be estimated by the 
Kaplan-Meier estimate, the proportion of subjects with event or censored and the median 
survival and its 95% CI, and Kaplan-Meier estimated probabilities with corresponding 95% CIs 


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at W24 and W48 will be provided based on ITT. The listing of PFS, TTP and OS will also be 
provided. 
Censoring rules for the PFS and TTP endpoints are shown in table 2. 
Table 2 Censoring Rules for PFS and TTP Endpoints 
The OS will be assessed once the data from the last participant completing the main study are 
available. Participants who are not known to have died at the time of the analysis will be 
censored. Where possible, post-intervention survival status will be confirmed for all 
participants that are alive at the last assessment. Any participant who is confirmed to be alive 
will be censored at this time. Any participant who could not be contacted at this time will be 
censored at the time that the participant was last confirmed to be alive. 
The below secondary endpoint will be assessed by Kaplan-Meier method based on ITT. 
 
A summary of number and percentage of participants who are alive and without tumour 
progression at W24 and W48 and their 95% CI will be calculated by the Kaplan-Meier 
method. 
The below secondary endpoints will be assessed by the same statistical method as the primary 
efficacy endpoint based on ITT. 
Situation  
Date of Progression or Censoring Outcome 
No baseline radiological assessments  
The day of first administration 
Censored 
Confirmed (documented) PD during 
the study 
Date of radiological assessment 
showing PD 
Event 
No death or confirmed PD 
Date of last adequate radiological
assessment 
Censored 
Study intervention discontinuation for 
clinical (unconfirmed) progression 
Date of last adequate radiological
assessment 
Censored 
Study intervention discontinuation for 
toxicity or reason other than confirmed 
PD, clinical progression or death 
Date of last adequate radiological
assessment 
Censored 
New anticancer treatment for GEP-
NET started with no confirmed PD 
beforehand 
Date of last adequate radiological
assessment before start of new 
treatment 
Censored 
Death 
during 
the 
study 
before 
confirmed PD 
Date of death (PFS)/Date of last 
adequate radiological assessment 
(TTP) 
Event 
(PFS)/Censored
(TTP) 
Confirmed PD after two or more 
missed radiological assessments 
Date of last adequate radiological
assessment 
before 
missed 
assessments 
 
Censored 
Study intervention discontinuation for 
other than confirmed PD or death, and 
no 
postbaseline 
radiological 
assessments 
The day of first administration 
Censored 


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A summary of number and percentage of participants with CBR at W48 
 
A summary of number and percentage of participants with ORR at W24 and W48 
 
A summary of number and percentage of participants with DCR at W24 and W48 
The below secondary endpoints will be assessed by the descriptive statistics based on ITT: 
 
A summary of change from baseline in NET-related clinical symptoms at W24 and W48 
 
A summary of change from baseline in QoL assessment at W12/W24/W36/W48 using 
the EORTC QLQ-C30 
 
A summary of change from baseline in CgA, 5-HIAA and other biomarker(s) in the 
circulation at W24 and W48. 
5.7.3.3 
Subgroup Analysis 
No subgroup analysis for main secondary efficacy endpoints. 
5.7.4 
Analysis of Exploratory Endpoints 
Descriptive statistics will be used to summarise the exploratory efficacy endpoints on 
independent injection set: 
 
A summary of proportion of participants preferring independent injection over HCP 
injections at W72 
 
A summary of participant-reported indirect costs (e.g. transport costs) at W48 and W72 
 
A summary of participant-reported work productivity at W48 and W72 
 
The antitumour effect CBR (assessed by imaging) at W72 
 
A summary of change from baseline in NET-related symptoms control at W72 (if 
applicable) 
 
A summary of change from baseline in CgA, 5-HIAA and other biomarkers in the 
circulation at W72 
 
A summary of change from baseline in QoL at W72. 
5.7.5 
Analysis of COVID-19 impacts on efficacy endpoints 
Primary Efficacy Endpoint 
For the primary efficacy endpoint CBR at W24, the summary statistics of number and 
percentage of participants and point estimates and exact 95% CIs based on the Clopper-Pearson 
method will be calculated based on ITT without missed or delayed study intervention due to 
the COVID-19 up to W24. 
Further analyses will be conducted to explore the primary efficacy endpoint with the same 
statistical method on the subsets of ITT. The subsets of ITT include: 
 
ITT with dose delayed due to COVID-19 up to W24, 
 
ITT with 1 dose missing due to COVID-19 up to W24, 
 
ITT with 2 or more doses missing due to COVID-19 up to W24. 
Secondary Efficacy Endpoints  
For the secondary efficacy endpoints (OS and PFS), the survival curve will be estimated by the 
Kaplan-Meier estimate, the proportion of subjects with event or censored and the median 
survival and its 95% CI, and Kaplan-Meier estimated probabilities with corresponding 95% CIs 
at W48 will be provided based on ITT without missed or delayed study intervention due to the 
COVID-19 up to W48. 
Note: Due to the possible impact of COVID-19, the evaluation for the primary efficacy endpoint 
at scheduled visits after the first dose may be delayed. After performing the remapping step (see 


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the note in visit window section), if the tumour evaluation at a scheduled visit after the first 
dose is delayed and there is no record of unscheduled visit before the next scheduled visit, the 
missing tumour evaluation results at scheduled visits will be imputed by the results of delayed 
evaluation at the next scheduled visit. 
5.8 
Safety 
5.8.1 
General Consideration 
All safety summaries and analyses will be based upon the safety set. All safety data will be 
included in participant data listings (see listing detail conventions in Appendix A4).  
Baseline value definition is given in section 5.1.3. Rules to handle multiple observations of the 
same parameter that occurred for the same visit/timepoint are explained in section 5.1.1.3. If 
conversion factors are used, they should be presented either in the relevant section or a link to 
section 7 should be added. 
All AEs will be recorded and graded according to the current version of the National Cancer 
Institute  Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0. 
5.8.2 
Extent of exposure  
Duration of exposure will be defined in weeks as: 
Weeks of exposure = (Date of last study drug administration  Date of first study drug 
administration + 28)/7.  
The following extent of exposure summaries will be presented in each period:  
 
Summary of the duration of exposure to treatment, by treatment group. Provide the mean, 
median, and the count and percentage of participants exposed for specified periods.   
 
Summary of the actual dose by treatment group.  Provide the mean, median, sum and the 
count and percentage of participants. 
 
Summary of number of injections, 
 
Summary of dose intensity (dose intensity = cumulative dose/planned total dose 
*100%.), 
 
Listing of exposure data. 
 
5.8.3 
Adverse Event 
All adverse events (AEs) recorded in the eCRF will be coded using the latest version of 
MedDRA dictionary in effect within IPSEN at the time of the database lock. AEs will be 
classified as treatment-emergent AEs (TEAEs) during main intervention period and TEAEs 
during independent injection period according to the rules below: 
 
Within each period, events with start date on or after the date of first IMP 
administration and up to EOS or 4 weeks after date of last dose of treatment, 
 
Within each period, events whose CTCAE grade worsens on or after the date of 
first IMP administration, 
 
Refer to appendix Partial/Missing Date Convention for handling of partial date.  
 
In the case where it is not possible to define an AE as treatment emergent or not, 
the AE will be classified by the most conservative case; i.e. treatment emergent. 
The following summaries will be presented by treatment group and by period: 
 
An overview table summarizing the  


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- number and percentage of participants with at least one of the following AEs: any 
AE, any TEAE, Serious Adverse Event (SAE), serious TEAE, drug-related TEAE, 
drug-related serious TEAE, non-serious TEAE, TEAE leading to treatment 
discontinuation, TEAE leading to discontinuation from the study, CTCAE Grade 
>=3 TEAE, TEAE leading to death, serious TEAE leading to death, drug-related 
serious TEAE Leading to Death, serious TEAE leading to treatment 
discontinuation, serious TEAE leading to discontinuation from the study, 
- corresponding number of events for each of the AE categories listed above 
(these should be distinguished from counts and rates of participants e.g. marked 
by square brackets []) 
 
A summary of the number and percentage of participants reporting an AE by 
treatment group, SOC and PT, 
 
A summary of the number and percentage of participants reporting a TEAE by 
treatment group, SOC and PT, 
 
A summary of the number and percentage of participants reporting a TEAE by 
treatment group and PT,  
 
A summary of the number and percentage of participants reporting a TEAE by 
treatment group, CTCAE grade, SOC and PT, 
 
A summary of the number and percentage of participants reporting a TEAE by 
treatment group, causality, SOC and PT, 
 
A summary of the number and percentage of participants reporting a drug-related 
TEAE by treatment group, CTCAE grade, SOC and PT, 
 
A summary of non-serious TEAE by treatment group, SOC and PT, 
 
A summary of the number and percentage of participants reporting a serious TEAE 
related to COVID-19 by treatment group, SOC and PT. 
 
AEs summaries will be ordered in term of decreasing frequency for SOC and PT within SOC, 
and then alphabetically for SOC and PT within SOC. AEs summaries by PT will be ordered in 
term of decreasing frequency of PT, and then alphabetically for PT. 
 
AEs will be counted as follows: 
 
Participants with more than one AE within a particular SOC are counted only once for 
that SOC. Similarly, participants with more than one AE within a particular PT are 
counted only once for that PT; 
 
Participants reporting a TEAE more than once within that SOC/ PT, the TEAE with the 
worst-case CTCAE grade (grade order: 5>4>3>2>1>missing) will be used in the 
corresponding CTCAE grade summaries; 
 
Participants reporting a TEAE more than once within that SOC/ PT, the TEAE with the 
worst-case relationship to study medication (order: related > not related > missing) will 
be used in the corresponding relationship summaries; 
 
If the CTCAE grade is missing for a TEAE, it will be considered as missing in the 
summary tables; 
 
Summary by CTCAE grade will be presented (in the same order as above); 
 
If the causality is missing for a TEAE, it will be considered related in the summary tables; 


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The non-serious TEAEs table 
non-serious TEAE 
above 10%; 
 
In addition, a listing with all AEs data will be listed by treatment group and period including 
non-TEAEs, Treatment-emergence status will be flagged in the listing.  
 
The following listing will be provided by period:  
 
A listing of all deaths that occurred during the study, 
 
A listing of all SAEs, 
 
A listing of all adverse events leading to discontinuation of study treatment, 
 
A listing of participants reporting a serious TEAE related to COVID-19 
 
Deaths, SAEs, and Other Significant Adverse Events (AE) 
  
The following summary tables will be provided by period:  
 
A summary of the number and percentage of on-treatment deaths (including SAEs with 
fatal outcome and deaths as PT), by treatment group, 
 
A summary of the number and percentage of deaths (including SAEs with fatal outcome 
and deaths as PT), by treatment group, 
 
A summary of the number and percentage of subjects reporting a serious TEAE, by 
treatment group, SOC and PT, 
 
A summary of the number and percentage of subjects with AEs leading to 
discontinuation of study treatment, by treatment group, SOC and PT. 
 
Injection site related reactions  
 
The following summary tables will be provided by period:  
 
A summary of the number and percentage of participants reporting an injection site 
related reaction, by treatment group, SOC and PT,  
 
The following listing will be provided by period:  
 
A listing of all injection site related reactions that occurred during the study.  
 
5.8.4 
Laboratory Data 
All laboratory data will be presented in the units of International System of Units (SI).  The 
tests detailed in table 3 will be performed by the local laboratory. 
Table 3 Protocol-Required Clinical Safety Laboratory Tests 
Test 
Parameters Assessed 
Pregnancy testing 
Highly sensitive serum or urine hCG pregnancy test 
(as needed for women of childbearing potential) 
Other screening tests 
FSH (as needed in women of non-childbearing 
potential only) 
Haematology 
Red blood cell count, hemoglobin, hematocrit, 
platelet count, white blood cell 


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count, and differential white blood count (neutrophil, 
eosinophil basophil, monocyte and lymphocyte) 
Biochemistry 
Liver function 
Total protein, albumin, total 
and direct bilirubin, ALP, 
ALT, AST, GGT
Renal function 
Blood urea nitrogen, 
creatinine 
Pancreatic function 
Amylase, lipase 
Lipid profile 
LDL cholesterol, HDL 
cholesterol, triglyceride
Electrolytes
Sodium, potassium, chloride
Minerals
Calcium, inorganic phosphate,
Miscellaneous 
Fasting glucose, HbA1c, 
lactate dehydrogenase 
Endocrinology 
FT3, FT4, TSH, and prolactin 
Coagulation
aPTT, PT, INR
Urinalysis
Protein, glucose, urobilinogen and occult blood
 
Describe the summaries that are to be provided.  These may include the following summaries: 
 
A summary of the actual and change from baseline in each laboratory parameter by 
treatment group and timepoint,   
 
A shift from baseline of the number and percentage of participants experiencing 
Abnormalities. 
 
A summary of the number and percentage of participants experiencing treatment-
emergent clinically significant laboratory abnormalities, by laboratory parameter and 
treatment group,  
 
A shift from baseline to worst post-dose (i.e. highest grade) in CTCAE Grade of 
laboratory results. 
 
For shift tables, the denominator should be the number of participants with both a baseline and 
a post-baseline assessment at a given timepoint. 
 
In addition, the following listings are to be provided: 
 
A listing of all laboratory data. Out-of-reference-range values will be flagged as high (H) 
or low (L), 
 
Laboratory reference ranges, 
 
A listing of Abnormalities. All data for a laboratory parameter will be displayed for a 
participant having at least one post-baseline Abnormality(with flag indicating 
Abnormality), 
 
A listing of CTCAE grade 3 and higher values.  All data for a laboratory parameter will 
be displayed for a participant who has any post-baseline value with CTCAE grade greater 
than or equal to 3 for the parameter. 
5.8.5 
Vital Signs 
Weight, temperature, pulse rate, respiratory rate, and systolic/diastolic blood pressure will be 
assessed. Describe the summaries that are to be provided.  These may include: 
 
A summary of the actual and change from baseline in each vital sign parameter by 
treatment group and timepoint, 
The following listing are to be provided: 


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A listing of vital sign data by treatment group, with abnormal value highlighted.  
5.8.6 
Electrocardiogram (ECG) 
The following quantitative ECG measurements will be taken during the study: 
- 
Normal Sinus Rhythm (yes/no), 
- 
heart rate (bpm), 
- 
PR interval (msec), 
- 
QRS duration (msec), 
- 
QT interval (msec), 
Bazett corrected QT (QTcB) interval (msec) = QT/
;  
Fridericia corrected QT (QTcF) interval (msec) = QT/
);  
- 
Corrected QT Interval (msec). 
 
 
 
The following summaries of ECG data will be provided:  
 
A summary of the actual and change from baseline in each ECG parameter by treatment 
group and timepoint,  
 
A Shift from baseline (normal vs. abnormal, not clinically significant vs. abnormal, 
clinically significant) to each post-baseline visit. 
 
The following listing are to be provided: 
 
A listing of ECG data by treatment group, with abnormal value highlighted.  
5.8.7 
Physical Examination 
The following summary and listings will be provided: 
 
A shift from baseline (normal vs abnormal) to each post-baseline visit  
 
A listing of physical examination data, 
 
A listing with any participants with at least one physical examination abnormality. 
5.8.8 
Other (if applicable) 
Pregnancy data will be shown in a data listing.  
For gallbladder ultrasonography data, a shift from baseline (normal vs abnormal) to each post-
baseline visit is needed and also the related listing should be provided. 
5.9 
PK (if applicable) 
Not applicable. 
5.10 
Anti-drug Antibodies (if applicable) 
Serum lanreotide levels and antidrug antibodies (ADA) assessments will be performed by a 
bioanalytical CRO (LabCorp
validated method. The analysis for ADA will be based on immunogenicity set. 
A listing of antibodies sampling times and any deviations from the scheduled times will be 
provided. 
Concerning ADA sample results, the following definitions will be considered: 


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- 
Seroconverters are subjects with negative ADA at baseline and positive ADA post-
treatment. 
- 
Seroreverters are subjects with positive ADA at baseline and negative ADA post-
treatment. 
- 
Incidence is defined as the proportion of seroconverters. 
The following conventions will be considered: 
 Percentage of seroconverters and incidence should be calculated using the number of 
subjects with a baseline assessment and at least one ADA assessment posttreatment. 
 Percentages of seroreverters should be calculated using the number of subjects with 
positive ADA at baseline and at least one ADA assessment posttreatment. 
The following summaries of ADA data will be provided: 
 An overall summary of ADA status with: 
- 
Number and percentage of positive baseline results; 
- 
Number and percentage of seroconverters; 
- 
Number and percentage of seroreverters. 
 A listing of individual antibodies results will also be provided as well as two tables 
including: 
- 
The percentage of subjects developing anti-lanreotide antibodies at each ADA time 
point; and 
- 
Descriptive statistics on anti-lanreotide antibodies titer. 
6 
DATA HANDLING 
6.1 
Visit window 
All data will be organized and analysed according to the scheduled visits outlined in the 
protocol. As defined by the protocol, screening has to be performed within 4 weeks before fist 
treatment. And all participants will receive a fixed dose of lanreotide Autogel 120 mg by deep 
subcutaneous injection every 28 days during the study. There is an allowed window of ±3 days 
for each injection. 
Participants who discontinue study intervention but have not withdrawn from the study must 
be followed for survival data until death or within 4 weeks after the last W48 visit of the last 
participant in the main intervention period or within 4 weeks after the last W72 visit of the last 
participant in the independent injection period (unless the participant has specifically 
withdrawn consent for any further contact). 
Note: Due to the possible impact of COVID-19, the tumour evaluation at scheduled visits after 
the first dose may be delayed. If the tumour evaluation at a scheduled visit after the first dose 
is delayed and there is a valid evaluation record at unscheduled visit before the next scheduled 
visit, the missing tumour evaluation results at scheduled visits will be remapped by the results 
of delayed evaluation at unscheduled visit before the next scheduled visit. If there are more than 
two consecutive scheduled visits delayed and there is a valid evaluation record at unscheduled 
visit before the next scheduled visit, the last missing tumour evaluation result at scheduled visits 
will be not remapped by the results of delayed evaluation at unscheduled visit before the next 
scheduled visit. 
If the tumour evaluation at a scheduled visit after the first dose is delayed and there is no record 
of unscheduled visit before the next scheduled visit, the missing tumour evaluation results at 
scheduled visits will be not remapped. 


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6.2 
Unscheduled Visits, Retest, Withdrawal Visit,  
All listings will include retests and unscheduled visits, while for the description by visit in the 
tables, only the scheduled visits according to the protocol will be described.  
Unscheduled visit and retest measurements will be used to provide a measurement for a baseline 
data or endpoint value (e.g. worst value), if appropriate according to their definition. These 
measurements will also be used to determine abnormal laboratory, vital signs values or ECG. 
If a value requires a retest (for laboratory values, vital signs and ECG) the closest non-missing 
reliable value to the scheduled visit will be used in the summary tables. 
Participants who have withdrawn early from the study have their last assessment entered as visit 
90 in the eCRF.  
6.3 
Laboratory Values or Concentration Data 
For laboratory values or concentration data below the lower limit of quantification (LLOQ) like 
LLOQ or ULOQ (xxx) will be used for calculation of descriptive statistics. The original 
labo
in the listing. 
7 
DERIVED DATA (IF APPLICABLE) 
When applicable, below derivation rules should be followed: 
 
Change from baseline 
Change from baseline at a given visit will be calculated as a difference from baseline.  
 
Age 
Age (years) will be calculated as follows and truncated to the largest integer that is less than or 
equal to the calculated result: 
Age = (date of informed consent date - birth date)/365.25. 
 
BMI 
BMI (kg/m2) will be derived as Weight (kg)/[Height(cm)/100]**2 measured at each visit and 
rounded to the nearest decimal. 
 
Quality of Life Questionnaire EORTC QLQ-C30 (Version 3.0) 
The EORTC QLQ-C30 questionnaire contains 30 single items (Q1  Q30). Q1  Q28 range 
from 1 to 4 with 1 being the most favourable answer and 4 the worst case (1 = Not at all, 2 = A 
little, 3 = Quite a bit, 4 = Very much). Q29 and Q30 range from 1 (= Very poor) to 7 (= 
Excellent) with 1 being the worst case and 7 the most favourable answer. 
Subscores will be derived according to the rules contained within the EORTC Scoring Manual 
[12]. The subscores will include five functional scales, three symptom scales, a global health 
status / QoL scale, and six single items (see the below table). Each of the multi-item scales 
includes a different set of items - no item occurs in more than one scale. 
 
Table: EORTC QLQ-C30 definition of subscores 
EORTC QLQ-C30 
Subscores Single questions 
Subscores Single questions 
Global health status / QoL (QL) 
Q29, Q30
Physical functioning (PF)  
Q1, Q2, Q3, Q4, Q5
Role functioning (RF)  
Q6, Q7 
Emotional functioning (EF)  
Q21, Q22, Q23, Q24


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Cognitive functioning (CF) 
Q20, Q25
Social functioning (SF)  
Q26, Q27
Fatigue (FA)  
Q10, Q12, Q18
Nausea and vomiting (NV) 
Q14, Q15
Pain (PA)  
Q9, Q19
Dyspnoea (DY)  
Q8
Insomnia (SL) 
Q11
Appetite loss (AP)  
Q13 
Constipation (CO)  
Q16 
Diarrhoea (DI) 
Q17
Financial difficulties (FI)  
Q28
 
All of the subscores range in score from 0 to 100. A high scale score represents a higher 
response level. Thus a high score for a functional scale represents a high /healthy level of 
functioning; a high score for the global health status / QoL represents a high QoL, but a high 
score for a symptom scale / item represents a high level of symptomatology / problems. 
The principle for scoring these scales is the same in all cases: 
i) Estimate the average of the items (I1, I2, ..In) that contribute to the scale; this is the raw score. 
n) / n 
ii) Use a linear transformation to standardize the raw score, so that scores range from 0 to 100; 
a higher score represents a higher ("better") level of functioning, or a higher ("worse") level of 
symptoms. 
For functional scales: Score = {1  [(RS - 1) / range]} x 100 
For symptom scales and global health status / QOL: 
Score = {(RS - 1) / range} x 100 
where range is the difference between the maximum possible value of RS and the 
minimum possible value of RS. 
8 
REFERENCES 
Reference to ICH regulatory guidelines: 
- 
ICH E3: Structure and Content of Clinical Study Reports 
- 
ICH E6 (R2): Good Clinical Practice 
- 
ICH E9: Statistical Principles for Clinical Trials 
- 
ICH E9 (R1) Addendum: Estimands and Sensitivity Analysis in Clinical Trials 
 
Reference to NMPA regulatory guidelines: 
- 
Biostatistics Guidelines for Drug Clinical Trials 
- 
Good Clinical Practice 
- 
Guidelines for Principles of Structure and Content of Clinical Study Report of Drugs 
- 
Guidelines for Data Management and Statistical Analysis Plan and Report of Drug 
Clinical Trials 
 
Reference to EMA or point to consider guidelines: 
- 
Adjustment for baseline covariates in clinical trials 


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- 
Choice of a non-inferiority margin 
- 
Clinical trials in small populations 
- 
Data monitoring committees 
- 
Investigation of subgroups in confirmatory clinical trials 
- 
Missing data in confirmatory clinical trials 
- 
Application with Meta Analyses, One pivotal study 
- 
Multiplicity issues in clinical trials 
Switching between superiority and non-inferiority 
 
Reference to FDA guidelines: 
- 
Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics (December 
2018) 
 
Standard Ipsen SDTM user guide 
Standard ADaMs user guide 
 
Ipsen Global Style guide 
 
References for all statistical methods are listed below: 
- 
Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, on behalf 
of the EORTC Quality of Life Group. The EORTC QLQ-C30 Scoring Manual (3rd 
Edition). Published by European Organisation for Research and Treatment of Cancer, 
Brussels 2001. 
 


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9 
APPENDICES 
 
A1. SAS code 
The code to get exact 95% CIs based on the Clopper-Pearson:




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YYYY-MM = YYYY-MM of 
[First IMP admin.] 
Min ([First IMP 
admin.], AE end 
date) 
2002-08-XX 
Min (2002-08-
11, AE end 
date) 
YYYY-MM > YYYY-MM of 
[First IMP admin.] 
YYYY-MM-01 
2002-09-XX 
2002-09-01 
Day and month are missing 
YYYY < YYYY OF [First IMP 
admin.] 
YYYY-01-01 
2001-XX-XX 
2001-01-01 
YYYY = YYYY OF [First IMP 
admin.] 
Min ([First IMP 
admin.], AE end 
date)
2002-XX-XX 
Min (2002-08-
11, AE end 
date)
YYYY > YYYY OF [First IMP 
admin.] 
YYYY-01-01 
2003-XX-XX 
2003-01-01 
Day, month, and year are missing
XXXX-XX-XX 
Min ([First IMP 
admin.], AE end 
date)
 
Min (2002-08-
11, AE end 
date)
YYYY = non-missing year, MM = non-missing month, DD = non-missing day, XX = missing 
field. 
 
For studies with injection cycle: 
If an AE onset date is partial or missing, the event will be allocated to the first IMP 
administration where onset could have occurred (taking into account date and time stopped). 
 
If AE end date is partial, imputation could be done assuming the latest possible date (i.e. last 
day of month if day unknown, or 31st of December if day and month are unknown). 
 


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A3. Programming Convention for Outputs 
All text fields must be left justified and numeric or numeric with some text specification (e.g.: 
ified. 
 
The mean, median, lower quartile, upper quartile, SD and standard errors (SE) of the mean 95% 
confidence interval values will be reported to one decimal place greater than the raw data 
recorded in the database.   
The minimum and maximum values will be reported with the same number of decimal places 
as the raw data recorded in the database. 
In general, the maximum number of decimal places reported should be four for any summary 
statistic. 
 
Percentages will be presented to one decimal place. Percentages will not be presented for zero 
counts. Percentage will be calculated using n as denominator. The denominator n will be 
specified in a footnote for clarification if necessary. If sample sizes are small, the data displays 
will show the percentages, but in the CSR only frequency counts should be described.  
 
P-values will be reported to four decimal places (e.g.: p=0.0037), after rounding. P-values 
 
 
All values below or above a limit of detection (e.g. <0.1 or >100) will be listed as such.   
 
Dates will be presented in the format [ddmmmyyyy] and times in the format [hh:mm]. 
 
A4. Listings conventions 
Any listings will contain at least the following data: participant identifier, age and gender. When 
dates are presented, the associated study days should be included. They should be sorted by 
treatment group then participant identifier. For multicentre studies, listings should be broken 
down by centre and treatment group. 
Note: In this study (D-CN-52030-411), any listings will contain at least the following data: 
participant identifier, age and gender. All listings should be sorted by participant identifier. 


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A5. EudraCT categories for age 
For EudraCT results summaries, in addition to quantitative descriptive statistics of age, 
demographic tables should include presentation of age using the following EudraCT categories 
(as applicable): 
 
Adults (18-64 years)
From 65 to 84 years
85 years and over