An Open-label, Multicentre, Single Arm Study to Assess the Efficacy and Safety of Triptorelin 3-month Formulation in Chinese Children With Central Precocious Puberty
Phase: PHASE3
Conditions: Central Precocious Puberty
Sponsor: Ipsen

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 1/ 8 6 
 
A N O P E N- L A B E L, M U L TI C E N T R E, SI N G L E- A R M S T U D Y T O A S S E S S T H E 
E F FI C A C Y A N D S A F E T Y O F T RI P T O R E LI N 3- M O N T H F O R M U L A TI O N I N 
C HI N E S E C HI L D R E N WI T H C E N T R A L P R E C O CI O U S P U B E R T Y  
 
S T U D Y P R O T O C O L 
S T U D Y N U M B E R: D- C N- 5 2 0 1 4- 2 4 3 
 
Tri pt oreli n Pa m oate 1 5 m g f or i njecti o n ( 3- m o nt h f or m ul ati o n)  
 
Versi o n 1. 0: 2 7 J ul y 2 0 2 0 
Versi o n 2. 0 i ncl u di n g Gl o bal A me n d me nt 1: 2 8 Oct o ber 2 0 2 0  
Versi o n 3. 0 i ncl u di n g Gl o bal A me n d me nt 2: 1 6 M arc h 2 0 2 1 
Versi o n 4. 0 i ncl u di n g Gl o bal A me n d me nt 3: 0 9 J ul y 2 0 2 1  
St u d y S p o ns or: 
I ps e n P har ma 
6 5, Q uai Ge or ges G orse 
9 2 1 0 0 B o ul o g ne Billa nc o urt, Fra n ce 
Tel: 
 
 
St u d y P h ase: III 
 
S p o ns or Si g n at or y:  
 
I ps e n ( S ha n g hai) P har mace utical Scie nce a n d De v el o p m e nt C o m pa n y, Lt d. 
N o. 2 3 0 6 I nter nati o nal C a pital Plaza 
N o. 1 3 1 8 N ort h Sic h ua n R oa d 
S ha n g hai 2 0 0 0 8 0, C hi na 
Tel
 
 
F or s eri o us a d verse e ve nt ( S A E) a n d f or p re g n a n c y re p orti n g: 
E- mail: 
  
If e mail re p orti n g is n ot p ossi ble: 
Fa x: 
 
 
P ers 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 n e d 
herei n c a n n ot be discl ose d, s u b mitte d f or p u blic ati o n or use d f or a n y p ur p ose ot her t h a n t h at c o nt e m pl ate d 
 
P P D
P P D
P P D
P P D
C CI

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 2/ 8 6 
 
 
I n vesti g at or A gree me nt a n d Si g n at ure: 
- La b el, M ultice ntre, Si n gle- Ar m St u d y t o 
Assess t he Efficac y a n d Safet y of Tri pt oreli n 3- M o nt h F or m ulati o n i n C hi nese C hil dre n wit h 
- C N- 5 2 0 1 4- 2 4 3) wit h A me n d me nt # 3. I a m a ware of m y 
res p o nsi bilities as a n I n v esti gat or u n der t he g ui deli nes of G o o d Cli nical Practi ce ( G C P), G o o d 
P har mac o vi gila nce Practices ( G V P), l o cal re g ulati 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 h ese g ui d eli 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: 
 
 
 
 
 
 
 
N A M E: 
TI T L E: 
SI G N A T U R E: 
 
D A T E: 
O F FI C E: 
 
 
 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 4/ 8 6 
 
S Y N O P SI S 
N a me of S p o ns or/c o m p a n y : I pse n P har ma 
N a me of fi nis he d pr o d uct : Tri pt oreli n pa m oate 1 5 m g f or i njecti o n  
N a me of acti ve i n gre die nt(s) : Tri pt oreli n pa m oate ( he nc ef ort h referre d t o as tri pt oreli n) 
Title of st u d y : A n o pe n-la bel, m ultice ntre, si n gle-ar m st u d y t o ass ess t h e efficac y a n d 
safet y of tri pt oreli n 3- m o nt h f or m ul ati o n i n C hi n ese c hil dre n wit h ce ntral prec o ci o us  
p u bert y  
St u d y n u m ber : D- C N- 5 2 0 1 4- 2 4 3 
N u m ber of pl a n ne d ce ntres : T he st u d y will be c o n d ucte d i n a p pr o xi m atel y 5 t o 1 0 sites 
i n C hi na 
Pl a n ne d st u d y peri o d : 
Q 1 2 0 2 1 t o Q 1 2 0 2 2 
E xte nsi o n: Q 3 2 0 2 1 t o Q 3 2 0 2 2  
P h ase of de vel o p me nt : 
P hase III 
 
St u d y t y pe: A pr os p ecti ve, o pe n-la bel, m ultice ntre, si n gl e- ar m, i nt er v e nti o nal st u d y  
O bjecti ves of t he M ai n st u d y :  
Pri mar y O bj ecti ve: 
T he pri mar y o bjecti ve of t he st u d y is t o assess t he efficac y of t he tri pt oreli n 
3- m o nt h pr ol o n ge d rel ease ( P R) f or m ulati o n i n s u p pressi n g l ut ei nisi n g h or m o ne ( L H) 
le vels t o pre- p u bertal le vels ( defi ne d as a pea k L H 
 I U/ L after i ntra ve n o us (i. v.) 
g o na d otr o pi n-releasi n g h or m o ne ( G n R H) sti m ulati o n) at M o nt h 3 i n C hi nese c hil dre n wit h 
ce ntral prec o ci o us p u bert y ( C P P).  
Sec o n dar y O bj ecti ves: 
 
T o assess t he efficac y i n s u p presse d L H res p o ns e t o G n R H test at M o nt h 6 
 
T o assess f ollicle-sti m ul ati n g h or m o n e ( F S H) res p o nse t o G n R H test at M o nt h 3 a n d 
M o nt h 6 
 
T o assess L H a n d F S H le vels at M o nt h 3 a n d M o nt h 6 
 
T o assess s e x h or m o ne ser u m c o n ce ntrati o ns ( oestra di ol f or girls a n d test oster o ne 
f or b o ys) at M o nt h 3 a n d M o nt h 6 
 
T o assess s e x ual mat urati o n ( p u bertal st a ge as per T a n ner met h o d) at M o nt h 6 
 
T o assess a u x ol o gical p ara meters i ncl u di n g hei g ht, gr o wt h v el ocit y, wei g ht a n d 
b o d y mass i n d e x ( B MI) at M o nt h 3 a n d M o nt h 6 
 
T o assess b o ne a ge ( B A), t he differe nce bet wee n B A a n d c hr o n ol o gical a ge ( C A) at 
M o nt h 6 
 
T o assess g o na d al de vel o p me nt as deter mi ne d b y uteri ne le n gt h i n girls a n d 
testic ular v ol u me i n b o ys at M o nt h 6 
 
T o assess t he s afet y pr ofile. 
E x pl orat or y O bjecti ve: 
 
T o assess plas m a tri pt oreli n le vels at Da y 1, M o nt h 3 a n d M o nt h 6. 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 6/ 8 6 
 
t he y atte n d t he E n d of E xte nsi o n P h ase ( E O E P) visit at M o nt h 1 2. T his E xte nsi o n p hase is 
o pti o nal. 
Eac h parti ci pa nt ma y be treate d wit h t he st u d y dr u g f or u p t o 1 2 m o nt hs. 
N u m ber of p artici p a nts pl a n ne d :  
A p pr o xi matel y 3 2 p artici pa nts, i ncl u di n g t hree b o ys, will be e nr olle d i n t he st u d y. 
Di a g n osis a n d criteri a f or i ncl usi o n :  
M ai n st u dy p h ase: 
I n cl usi o n criteria: 
Partici pa nts m ust f ulfil all t he f oll o wi n g criteri a t o be i ncl u de d i n t he st u d y: 
( 1) 
Pr o visi o n of writte n i nf or me d c o ns e nt pri or t o a n y st u d y- rel ate d pr oce d ures. 
C o nse nt s h o ul d be pr o vi de d b y t he pare nt(s)/le gal g uar dia n. If deter mi ne d b y l oc al 
re q uire me nts, a si g n e d asse nt m ust be o bt ai ne d fr o m t h e pae diatric partici pa nt 
( 2) 
E vi de nce of C P P d oc u me nte d b y: 
- 
O ns et of de vel o p m e nt of sec o n dar y s e x c hara ct eristics ( breast de vel o p me nt 
i n girls or testic ular e nlar ge me nt i n b o ys acc or di n g t o t he T a n ner m et h o d: 
Sta ge II) bef ore t h e a ge of 8 years i n girls a n d 9 ye ars i n b o ys 
- 
P u bertal res p o nse of L H t o 
G n R H sti m ulati o n test (sti m ulat e d pea k 
L H 
 I U/ L) i n b ot h se x es 
- 
Differe nce b et we e n B A a n d C A > 1 year 
- 
uteri ne le n gt h a n d se v eral f ollicles wit h dia meter > 4 m m i n t he o var y 
o bser ve d b y p el vic t y p e B ultras o u n d at t he S cree ni n g visit; b o ys w h o ha ve 
 m L o bs er ve d b y t estic ular t y p e B ultras o u n d at t he 
Scree ni n g visit 
( 3) 
A ge less t h a n 9 years ol d f or girls a n d l ess t ha n 1 0 years ol d f or b o ys at i niti ati o n of 
tri pt oreli n treat me nt 
( 4) 
Wei g ht at least 2 0 k g 
( 5) 
Girls w h o ha ve alrea d y h a d m e n o p ha nia/ me n arc h e m ust ha ve a ne gati ve pre g na nc y 
test pri or t o t he start of st u d y treat me nt a n d s h o ul d n ot be at ris k of pre g na nc y 
t hr o u g h o ut t he st u d y peri o d. 
E x cl usi o n criteria: 
Partici pa nts will be i neli gi ble f or st u d y p artici pati o n if t he y meet a n y of t he f oll o wi n g 
criteria:  
( 1) 
G o na d otr o pi n- i n de pe n d e nt ( peri p heral) prec o ci o us p u bert y: e xtra pit uitar y s ecreti o n 
of g o na d otr o pi ns or g o na d otr o pi n- i n de pe n d e nt g o na d al or a dre nal se x ster oi d 
secreti o n 
( 2) 
N o n- pr o gressi n g is ol ate d pre mat ure t h el arc he 
( 3) 
Prese nce of a n u nsta ble i ntracra ni al t u m o ur or a n i ntracra nial t u m o ur re q uiri n g 
ne ur os ur ger y or cere bral irra diati o n. Partici pa nts wit h ha mart o mas n ot re q uiri n g 
s ur ger y are eli gi ble 
( 4) 
E vi de nce of r e nal (creati ni ne > 1. 5 x u p per li mit of n or mal ( U L N)) or he patic 
i m pair me nt ( bilir u bi n > 1. 5 x U L N or ala ni ne a mi n otra nsferas e ( A L T)/ as partate 
tra nsa mi nase ( A S T) > 3 x U L N) 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 7/ 8 6 
 
( 5) 
A n y ot her c o n diti o n or c hr o nic ill ness or tr eat me nt p ossi bl y i nt erferi n g wit h gr o wt h 
or ot h er st u d y e n d p oi nts (e. g. c hr o nic ster oi d use e x ce pt t o pical ster oi ds, r e nal 
fail ure, dia b etes, m o derate t o s e vere sc oli osis) 
( 6) 
Pri or or c urre nt t h era p y wit h a G n R H a g o nist ( G n R Ha), me dr o x y pr o gester o ne 
acetat e, gr o wt h h or m o ne or i ns uli n-li ke gr o wt h fact or- 1 (I G F- 1) 
( 7) 
Dia g n osis of s h ort stat ure, i.e. > 2. 2 5 sta n dar d de viati o n ( S D) b el o w t he mea n hei g ht 
f or a ge 
( 8) 
Maj or me dical or ps yc hiatric ill n ess t hat c o ul d i nterfere wit h st u d y visits 
( 9) 
K n o w n h y p erse nsiti vit y t o a n y of t he test materials or rel ate d c o m p o u n ds  
( 1 0) Use of a ntic o a g ula nts ( h e pari n a n d c o u mari n deri vati ves) wit hi n t he 2 wee ks p ri or 
t o t he Scree ni n g visit. 
E xte nsi o n p h ase: 
( 1 1) S u bjects will q ualif y f or t he e xte nsi o n p hase if t he y si g n t he c orres p o n di n g s pecific 
c o nse nt f or m, are still be nefiti n g fr o m treat me nt at t he e n d t he pri mar y st u d y a n d 
ha ve n ot e x perie nce d a n y u nacce pta ble s af et y iss ues. 
Test pr o d uct, d os e, m o d e of a d mi nistr ati o n : 
T he test pr o d uct is tri pt oreli n pa m oate 1 5 m g f or i njecti o n ( ma n ufact ure d b y I pse n P har ma 
Bi otec h), w hic h was create d t o g uara ntee t he release of 1 1. 2 5 m g of tri pt oreli n. It is 
prese nte d as a sli g htl y yell o w freez e- dri e d ca ke or p o w der i n a gl ass vial. T he s ol ve nt 
pr o vi de d f or i nj ecti o n is a 2 m L a m p o ule of ma n nit ol a n d water f or i nje cti o n.  
T he tri pt oreli n 3- m o nt h f or m ulati o n is t o be a d mi nist ere d b y i. m. r o ute o nl y. T he p o w d er 
is rec o nstit ute d wit h t he s ol v e nt f or s us pe nsi o n a n d s h o ul d be i nj ecte d i m me diatel y after 
pre parati o n.  
D ur ati o n of tre at me nt :  
M ai n st u dy p h ase: 
6 m o nt hs (i.e. t w o i njecti o ns) 
E xte nsi o n p h ase: 
A n a d diti o nal 6 m o nt hs will be gi ve n (i. e. t w o i njecti o ns) 
Refere nce t her a p y, d ose a n d m o de of a d mi nist r ati o n :  
N ot a p pli ca bl e.  
Criteri a f or e v al u ati o n (e n d p oi nts): 
M ai n st u dy p h ase: 
Effic ac y : 
Pri m ary E n d p oi nt a n d Ev al u ati o n: 
T he pri mar y e n d p oi nt i n t his st u d y is t he pr o p orti o n of c hil dre n wit h L H s u p pressi o n 
defi ne d as sti m ul ate d pea k L H 
 I U/ L aft er G n R H sti m ulati o n at M o nt h 3. T he G n R H 
sti m ul ati o n t est is perf or me d b y usi n g a n i. v. i njecti o n of g o na d oreli n (s y nt hetic G n R H) t o 
sti m ul ate g o na d otr o p hi n release a n d bl o o d sa m ples will be c ollecte d pri or t o a n d 3 0, 6 0 
a n d 9 0 mi n utes ( ± 5 mi n utes at eac h ti me p oi nt) aft er t he g o na d oreli n i njecti o n f or ce ntral 
assess me nt of ser u m L H le vels. 
Sec o n d ar y E n d p oi nts a n d E v al u ati o ns:  
 
C ha n ge i n bas al ser u m L H a n d F S H le vels at M o nt h 3 a n d M o nt h 6 c o m pare d t o 
baseli ne 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 8/ 8 6 
 
 
after G n R H sti m ulati o n at M o nt h 6 
 
C ha n ge i n pea k L H le v el after t he G n R H sti m ul ati o n test at M o nt h 3 a n d M o nt h 6 
c o m pare d t o baseli ne 
 
C ha n ge i n pea k F S H l e vel after t he G n R H sti m ulati o n test at M o nt h 3 a n d M o nt h 6 
c o m pare d t o baseli ne 
 
Pr o p orti o n of c hil dre n wit h pre- p u bertal le v els of se x ster oi ds ( defi ne d as oestra di ol 
 
 n g/ m L i n b o ys) at M o nt h 3 a n d M o nt h 6  
 
C ha n ge i n oestra di ol le v els i n girls a n d test oster o ne le vels i n b o ys at M o nt h 3 a n d 
M o nt h 6 c o m pare d t o bas eli n e 
 
C ha n ge i n p u bertal sta ge usi n g t he Ta n ner met h o d ( ge nital sta ge i n b o ys, breast sta ge 
i n girls a n d p u bic h air sta ge i n b ot h s e x es) at M o nt h 6 c o m pare d t o bas eli n e 
 
Pr o p orti o n of c hil dre n wit h sta bilise d p u bertal sta ge c o m pare d t o baseli ne sta ge 
usi n g t he Ta n n er met h o d at M o nt h 6 
 
C ha n ge i n a u x ol o gical p ara meters i ncl u di n g hei g ht, gr o wt h vel o cit y, wei g ht a n d 
B MI at M o nt h 3 a n d M o nt h 6 c o m pare d t o bas eli n e 
 
C ha n ge i n B A, differe nce bet we e n B A a n d C A at M o nt h 6 c o m pare d t o bas eli n e 
 
C ha n ge i n uteri ne le n gt h i n girls a n d testic ular v ol u me i n b o ys at M o nt h 6 c o m pare d 
t o baseli ne. 
S afet y : 
 
I n ci de nce of treat m e nt-e mer ge nt a d vers e e v e nts ( T E A Es) t hr o u g h o ut t he st u d y, 
i ncl u di n g l ocal t ol era bilit y 
 
C ha n ge i n cli nical safet y la b orat or y ( bl o o d bi oc he mistr y, hae mat ol o g y a n d 
uri n al ysis) para met ers at M o nt h 3 a n d 6 
 
C ha n ge i n p h ysi cal e x a mi nati o n a n d vital si g ns ( bl o o d press ure a n d heart rate) 
meas ure me nts at eac h visit. 
P h ar m a c o ki n etics: 
Ex pl or at ory E n d p oi nt: 
 
T o assess s pars e pl as ma tri pt oreli n c o nce ntr ati o ns at Da y 1, M o nt h 3 a n d M o nt h 6. 
E xte nsi o n p h ase: 
F or s u bjects p arti ci pati n g i nt o t he e xte nsi o n st u d y f oll o wi n g e n d p oi nts will be a nal yse d: 
Effic ac y : 
 
Pr o p orti o n of c hil dre n wit h L H s u p pressi o n ( defi n e d as L H 
 I U/ L) at M o nt h 1 2  
 
C ha n ge i n b asal ser u m L H a n d F S H le v els at M o nt h 9 a n d M o nt h 1 2  
 
Pr o p orti o n of c hil dre n wit h pre- p u bertal le v els of se x ster oi ds ( defi ne d as oestra di ol 
 
 n g/ m L i n b o ys) at M o nt h 9 a n d M o nt h 1 2  
 
C ha n ge i n oestra di ol le v els i n girls a n d test ost er o ne le vels i n b o ys at M o nt h 9 a n d 
M o nt h 1 2  
 
C ha n ge i n p u bertal sta ge usi n g t he T a n ner m et h o d ( ge nital sta ge i n b o ys, breast sta ge 
i n girls a n d p u bic h air sta ge i n b ot h s e x es) at M o nt h 1 2  
 
Pr o p orti o n of c hil dre n wit h sta bilise d p u bertal sta ge c o m pare d t o baseli ne sta ge 
usi n g t he Ta n n er met h o d at M o nt h 1 2 
 
C ha n ge i n a u x ol o gical p ara meters i ncl u di n g hei g ht, gr o wt h vel o cit y, wei g ht a n d 
B MI at M o nt h 9 a n d M o nt h 1 2 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 1 0/ 8 6 
 
t o o bs er ve t he effica c y of t he tri pt oreli n 3- m o nt h f or m ulati o n i n t he pr o p orti o n of c hil dre n 
wit h a s u p presse d L H res p o nse t o t he G n R H sti m ulati o n test at M o nt h 3.  
E xte nsi o n p h ase:  
A s e pa rate a n al ysis o n effi cac y a n d safet y e n d p oi nts will be perf or me d c o nsi deri n g t he 
e xte nsi o n p hase d urati o n, a peri o d of a n a d diti o nal 6 m o nt hs, lasti n g u ntil t he E n d of 
E xte nsi o n P hase visit at M o nt h 1 2. 
As t his is a n e xte nsi o n p hase f oll o wi n g t he mai n st u d y p h ase, t he efficac y a n d s afet y 
e n d p oi nts i n t he e xte nsi o n p hase will be s u m marise d des cri pti vel y. N o f or mal statistical 
h y p ot hes es testi n g will b e p erf or me d. 
Statistical a nal yses will i ncl u de t he f oll o wi n g: 
 
F or t he c o nti n u o us e n d p oi nts, t he descri pti ve s u m m ar y st atisti cs ( n u m ber of 
partici pa nts ( n), me a n, S D, me dia n, mi ni m u m, ma xi m u m) will be calc ulate d 
 
F or t he cate g orical e n d p oi nts, t he s u m mar y statisti cs of n u m ber a n d p erce nta g e of 
partici pa nts a n d t he e x act t w o-si de d 9 0 % c o nfi de n ce i nter val ( CI) will be calc ulat e d  
T he a n al ysis sets f or t he efficac y e n d p oi nts will be t he I nte nti o n- T o- Treat set (I T T) a n d t he 
per pr ot oc ol ( P P) set. A n al yses a n d s u m m ar y ta bles f or t he safet y e n d p oi nts will be base d 
u p o n t he Safet y p o p ulati o n. 
Sa m ple size calc ulati o n: T he n u m ber of partici pa nts i ncl u de d i n t he e xt e nsi o n st u d y will 
be de p e n de nt o n t h e n u m ber of partici p a nts fr o m st u d y D- C N- 5 2 0 1 4- 2 4 3 w h o gi v e c o ns e nt 
t o c o nti n ue i nt o t he e xte nsi o n st u d y. A ma xi m u m of 3 2 partici pa nts will be e x pecte d t o be 
e nr olle d i n t he e xte nsi o n p has e. 
 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 1 3/ 8 6 
 
Secti o n  
W A S  
( Versi o n 3. 0, 1 6 M a rc h 2 0 2 1) 
I S  
( V ersi o n 4. 0, 0 9 J ul y 2 0 2 1) 
R ati o n ale 
u nre ac h a bl e, he/s he 
will 
be c o nsi dere d t o 
h a v e 
wit h dr a w n 
fr o m 
t he 
st u d y.  
4. 7 / Scree n 
Fail ures 
 
A scree n f ail ure occ urs w he n 
a p a rtici p a nt w h o c o nse nts t o 
p a rtici p ate i n t he 
cli ni c al 
st u d y is 
n ot s u bse q u e ntl y 
e ntere d i n t h e 
st u d y. 
A 
mi ni m al set of scree n f ail u re 
i nf o r m ati o n is re q uire d t o 
e ns u re tr a ns p are nt re p o rti n g 
of scree n f ail ure p arti ci p a nts 
t o 
meet t he 
C o ns oli d ate d 
St a n d ar ds 
of 
Re p o rti n g 
Tri als 
( 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 ul at or y 
a ut h o rities. 
Mi ni m al 
i nf or m ati o n 
i ncl u des 
d ate of i nf o r me d 
c o nse nt, de m o g r a p h y, re as o n 
f o r scree n f ail ure, eli gi bilit y 
criteri a a n d a n y S A E. 
 
5. 1 / St u d y 
Sc he d ule 
T a ble 1: 
F o ot n ote (f): G n R H test 
sa m ples f or L H a n d F S H 
c o nce ntrati o ns will be c ollecte d 
at 3 0, 6 0 a n d 9 0 mi n ut es aft er 
t he G n R H t est. T he L H a n d 
F S H sa m ples will all be ta ke n 
bef ore i njecti o n of tri pt or eli n, if 
a p plica ble ( e. g. M o nt h 3 visit). 
 
 
T a ble 2: 
F o ot n ote ( b): G n R H t est 
sa m ples f or L H a n d F S H 
c o nce ntrati o ns will be c ollecte d 
at 3 0, 6 0 a n d 9 0 mi n ut es aft er 
t he G n R H t est. T he L H a n d 
F S H sa m ples will all be ta ke n 
bef ore i njecti o n of tri pt or eli n, if 
a p plica ble (e. g. M o nt h 3 visit). 
T a ble 1: 
F o ot n ote (f): G n R H test 
sa m ples f or L H a n d F S H 
c o nce ntrati o ns will be 
c ollecte d at 3 0, 6 0 a n d 
9 0 mi n utes ( ± 5 mi n utes at 
e ac h ti me p oi nt ) after t he 
G n R H test. T he L H a n d F S H 
sa m ples will all b e t a ke n 
bef ore i njecti o n of tri pt or eli n, 
if a p plica ble (e. g. M o nt h 3 
visit). 
 
T a ble 2: 
F o ot n ote ( b): G n R H t est 
sa m ples f or L H a n d F S H 
c o nce ntrati o ns will be 
c ollecte d at 3 0, 6 0 a n d 
9 0 mi n utes ( ± 5 mi n utes at 
e ac h ti me p oi nt ) after t he 
G n R H test. T he L H a n d F S H 
sa m ples will all b e t a ke n 
bef ore i njecti o n of tri pt or eli n, 
if a p plica ble. 
M ore feasi ble t o 
ha ve a ti me 
wi n d o w f or bl o o d 
c ollecti o n. 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 1 4/ 8 6 
 
Secti o n  
W A S  
( Versi o n 3. 0, 1 6 M a rc h 2 0 2 1) 
I S  
( V ersi o n 4. 0, 0 9 J ul y 2 0 2 1) 
R ati o n ale 
6. 3 / C o nc o mita nt 
Me dicati o n/ T hera p y  
T he 
f oll o wi n g 
c o nc o mita nt 
me dicati o ns ar e n ot per mitte d 
d uri n g t his st u d y: 
 
A n y 
treat me nt 
or 
pr oce d ure wit h a n effect 
o n t he 
meta b olis m or 
secreti o n 
of 
g o na d otr o pi ns ( L H or 
F S H) or se x ster oi ds 
( o estra di ol 
a n d/ or 
test oster o ne) 
will 
b e 
c o nsi dere d as a pr ot oc ol 
vi olati o n;  
 
All dr u gs m e nti o ne d 
as 
pr o hi bite d i n t he 
e xcl usi o n criteria r e mai n 
pr o hi bite d 
d uri n g t he 
st u d y 
p eri o d: 
G n R H 
a nal o g ues ( ot her t ha n 
tri pt oreli n 
3- m o nt h f or m ulati o n), 
me dr o x y pr o gester o ne 
acet ate, gr o wt h h or m o ne 
or I G F- 1, s yste mic or 
i n hale d ster oi ds ( mil d 
t o pical 
st er oids 
are 
per mitte d),  
a ntic o a g ula nts ( he pari n 
a n d 
c o u mari ne 
deri vati ves). 
T he 
f oll o wi n g 
c o nc o mita nt 
me dicati o ns / pr oce d ures 
are 
n ot p er mitte d d uri n g t his st u d y:  
 
A n y 
treat me nt 
or 
pr oce d ure 
wit h  
a 
defi niti ve or p ote nti al 
effect  
o n 
t he 
meta b olis m or secreti o n 
of g o na d otr o pi ns ( L H 
or F S H) or se x ster oi ds 
( o estra di ol 
a n d/ or 
test oster o ne) 
will 
b e 
c o nsi dere d 
as 
a 
pr ot oc ol vi ol ati o n;  
 
All dr u gs me nti o ne d as 
pr o hi bite d 
i n 
t he 
e xcl usi o n 
criteri a 
re mai n 
pr o hi bite d 
d uri n g t he st u d y peri o d: 
G n R H a nal o g ues ( ot her 
t ha n 
tri pt oreli n 
3- m o nt h f or m ulati o n), 
me dr o x y pr o gester o ne 
acet ate, 
gr o wt h 
h or m o ne 
or 
I G F- 1, 
s yste mic 
or 
i n hale d 
st er oi ds ( mil d t o pi cal 
st er oi ds are p er mitte d), 
a ntic o a g ula nts ( he pari n 
a n d 
c o u mari ne 
deri vati ves). 
 
A n y 
c o nc urre nt 
i n vesti g ati o n al 
a g e nt 
or pr oce d ure. 
I n vesti gati o nal 
a ge nts, ot her t ha n 
t h ose pla n ne d f or 
t his st u d y, ma y 
i m pact efficac y 
a n d s afet y d ata 
a n d s h o ul d n ot b e 
all o we d d uri n g 
st u d y 
parti ci p ati o n. 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 1 6/ 8 6 
 
Secti o n  
W A S  
( Versi o n 3. 0, 1 6 M a rc h 2 0 2 1) 
I S  
( V ersi o n 4. 0, 0 9 J ul y 2 0 2 1) 
R ati o n ale 
na usea, c hest p ai n), si g ns (e. g. 
tac h ycar dia, e nlar ge d li ver) or 
t he a b n or mal r es ults of a n 
i n vesti gati o n (e. g. la b orat or y 
fi n di n gs). I n cli nical st u dies a n 
A E ca n i ncl u de a n u n desira ble 
me dical c o n diti o n occ urri n g at 
a n y ti me, i ncl u di n g r u n i n or 
was h o ut p eri o ds, e ve n if n o 
tri pt oreli n has bee n 
a d mi nistere d.  
T his defi niti o n i ncl u d es e ve nts 
occ urri n g fr o m t he ti me t he 
parti ci p a nt gi ves i nf or me d 
c o nse nt u ntil t he e n d of t he 
st u d y (as defi ne d i n Secti o n 
3. 8). 
te m p o r all y 
ass oci at e d 
wit h t h e 
use of st u d y 
i nter ve nti o n, w het her o r 
n ot c o nsi d ere d rel ate d t o 
t h e st u d y i nter ve nti o n. 
N O T E: A n A E c a n t heref o re 
be a n y u nf a v o ur a ble a n d 
u ni nte n de d si g n (i ncl u di n g 
a n a b n o r m al l a b or at o r y 
fi n di n g), s y m pt o m, or dise as e 
( n e w o r e x acer b ate d) 
te m p o r all y ass oci ate d wit h 
t h e use of st u d y i nter ve nti o n. 
E ve nts 
M eeti n g 
t he 
A E 
Defi niti o n: 
 
A n y a b n or m al l a b or at or y 
test res ults ( h ae m at ol o g y, 
cli nic al 
c he mistr y, 
o r 
uri n al ysis) o r ot her s afet y 
assess me nts ( e. g. 
E C G, 
r a di ol o gic al sc a ns, vit al 
si g ns 
me as ure me nts), 
i ncl u di n g 
t h ose 
t h at 
w o rs e n 
fr o m 
b aseli ne,  
c o nsi dere d 
cli nic all y 
si g nifi c a nt i n t he me dic al 
a n d scie ntific j u d g me nt of 
t h e i n vesti g at or (i.e. n ot 
rel ate d t o pr o gressi o n of 
u n d erl yi n g dise ase). 
 
E x a cer b ati o n of a  c hr o nic 
or 
i nter mitte nt 
p re-
e xisti n g 
c o n diti o n 
i ncl u di n g 
eit her 
a n 
i ncre ase 
i n 
f re q ue n c y 
a n d/ or i nte nsit y of t he 
c o n diti o n. 
 
Ne w c o n diti o n detecte d o r 
di a g n ose d 
aft er 
st u d y 
i nter ve nti o n 
a d mi nis tr ati o n 
e ve n 
t h o u g h it m a y h a v e bee n 
prese nt bef o re t h e st a rt of 
t h e st u d y. 
 
Si g ns, s y m pt o ms, or t he 
cli nic al 
se q uel a e 
of 
a 
s us p ecte d 
i nter v e nti o n- 
i nter ve nti o n i nter a cti o n. 
 
Si g ns, s y m pt o ms, or t he 
cli nic al se q uel ae 
of 
a 
s us p ecte d 
o v er d ose 
of 
eit her st u d y i nter v e nti o n 
or 
a 
c o nc o mit a nt 
me di c ati o n. O ver d ose per 
se will n ot be re p ort e d as 
a n A E/ S A E u nless it is a n 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 1 7/ 8 6 
 
Secti o n  
W A S  
( Versi o n 3. 0, 1 6 M a rc h 2 0 2 1) 
I S  
( V ersi o n 4. 0, 0 9 J ul y 2 0 2 1) 
R ati o n ale 
i nte nti o n al 
o v er d ose 
t a ke n 
wit h 
p ossi ble 
s uici d al/self- h a r mi n g 
i nte nt. 
S uc h 
o ver d oses 
s h o ul d 
be 
re p orte d 
re g ar dless of se q uel ae. 
 
r 
per se will n ot be re p orte d 
as a n A E or S A E. S uc h 
i nst a nces will b e c a pt ure d 
i n 
t h e 
effic a c y 
assess me nts. 
H o w e ver, 
t h e 
si g ns, 
s y m pt o ms, 
a n d/ or  cli nic al se q uel ae 
res ulti n g fr o m l ac k of 
effic ac y will be re p orte d  
as A E or S A E if t he y f ulfil  
t h e defi niti o n of a n A E or 
S A E. 
E ve nt N O T 
M eeti n g t he A E 
Defi niti o n: 
 A n y cli ni c all y si g nific a nt 
a b n or m al  
l a b o r at o r y 
fi n di n gs 
or 
ot her 
a b n or m al  
s afet y 
assess me nts 
t h at 
are 
ass oci ate d 
wit h 
t he 
u n d erl yi n g dise ase, u nless 
j u d ge d b y t h e i n v esti g at or 
t o be 
m ore se v ere t h a n 
e x pecte d 
f or 
t he 
p a rtici p a nt's c o n diti o n.  
 
T he 
dise ase/ dis or der 
bei n g st u die d or e x pecte d 
pr o g ressi o n, 
si g ns 
or 
s y m pt o ms 
of 
t he 
dise ase/ dis or der 
bei n g 
st u di e d, 
u nless 
m ore 
se vere t h a n e x pect e d f o r 
t h e 
p artici p a nt's 
c o n diti o n. 
 
M e dic al 
or 
s ur gic al 
pr oce d ure 
(e. g. 
e n d osc o p y, 
a p pe n dect o m y): 
t he 
c o n diti o n t h at le a ds t o t h e 
pr oce d ure is t he A E. 
Sit u ati o ns i n 
w hic h a n 
u nt o w a r d 
me dic al 
occ urre nce di d n ot occ ur 
(s o ci al 
a n d/ or 
c o n ve nie nce a d missi o n t o 
a h os pit al). 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 2 0/ 8 6 
 
Secti o n  
W A S  
( Versi o n 3. 0, 1 6 M a rc h 2 0 2 1) 
I S  
( V ersi o n 4. 0, 0 9 J ul y 2 0 2 1) 
R ati o n ale 
c o nse nt m ust be o btai ne d pri or 
t o t he p artici pa nt e nteri n g t he 
st u d y ( b ef ore i nitiati o n of a n y 
st u d y relate d pr oce d ure a n d 
a d mi nistrati o n of tri pt oreli n). 
S ufficie nt ti me will be all o we d 
t o disc uss a n y q uesti o ns r aise d 
b y t he p artici pa nt. 
T he S p o ns or will pr o vi de a 
sa m ple i nf or me d c o nse nt f or m. 
T he fi nal versi o n c o ntr olle d 
f or m m ust be a gree d t o b y t he 
S p o ns or a n d t he I E C/I R B a n d 
m ust c o ntai n all ele me nts 
i ncl u de d i n t he sa m ple f or m, i n 
la n g ua ge rea dil y u n d erst o o d b y 
t he partici pa nt. Eac h 
f or m, pers o nall y si g ne d a n d 
date d b y t he p artici p a nt or b y 
t he partic
acce pta ble re prese nt ati ve a n d b y 
t he pers o n w h o c o n d ucte d t he 
i nf or me d c o nse nt disc ussi o n, 
will be ret ai ne d b y t he 
I n vesti gat or. T he I n vesti gat or 
will s u p pl y p arti ci p a nts wit h a 
c o p y of t heir si g ne d i nf or me d 
c o nse nt f or m. 
T he i nf or me d c o nse nt f or m ma y 
nee d t o be re vise d d uri n g t he 
st u d y s h o ul d i m p ort a nt ne w 
i nf or mati o n bec o me a vaila ble 
t hat ma y b e r ele va nt t o t he 
safet y of t he partici pa nt or as a 
res ult of pr ot oc ol a me n d me nts. 
I n t his i nsta nce, a p pr o val s h o ul d 
al wa ys be gi ve n b y t he 
I E C/I R B. 
res p o nsi bilit y t o e ns ure t hat all 
parti ci p a nts s u bs e q ue ntl y 
e ntere d i nt o t he st u d y a n d t h ose 
c urre ntl y i n t he st u d y si g n t he 
a me n d e d f or m. T his is 
d o c u me nte d i n t he sa me wa y as 
descri be d a b o ve. Partici pa nts 
w h o ha ve c o m plete d t he st u d y 
s h o ul d b e i nf or me d of a n y ne w 
i nf or mati o n t hat ma y i m pact 
t heir welfare/ well bei n g. 
T he I n vesti gat or s h o ul d, wit h 
t he c o ns e nt of t he p artici p a nt, 
p h ysi cia n a b o ut t heir 
parti ci p ati o n i n t he cli nical 
st u d y. 
be a p pr o v e d pri or t o use 
as 
descri be d 
i n 
Secti o n 1 4. 1 . 
 
T he 
i n v esti g at or 
o r 
his/ her 
a ut h o rise d 
re pres e nt ati v e 
will 
e x pl ai n t o t he p artici p a nt 
a n d 
t heir 
le g all y 
a ut h o rise d re prese nt ati ve 
t h e n at ure a n d o bjecti ves 
of t he st u d y a n d p ossi bl e 
ris ks 
a n d 
be nefits 
ass oci ate d 
wit h 
t he 
p a rtici p ati o n. 
T he y 
will 
a ns w er 
all 
q uesti o ns 
re g ar di n g t he st u d y. 
 
P artici p a nts 
a n d 
t h ei r 
le g all y 
a ut h orise d 
re pres e nt ati v e 
m ust 
be 
i nf o r me d 
t h at 
t heir 
p a rtici p ati o n is v ol u nt a r y.  
 
T he 
i n v e sti g at or 
or 
his/ her 
a ut h o rise d 
re pres e nt ati v e will o bt ai n 
w ritte n 
i nf or me d 
c o nse nt/ asse nt f r o m e a c h 
p a rtici p a nt 
a n d 
t he 
le g all y 
a ut h orise d 
re pres e nt ati v e bef ore a n y 
st u d y-s p ecific 
pr o ce d ure 
is 
perf o r me d. 
T he 
i n vesti g at o r 
will 
ret ai n 
t h e 
o ri gi n al 
of 
e a c h 
p a
 
si g ne d 
i nf o r me d 
c o nse nt/ asse nt 
f o r m. 
 
A c o p y 
of t h e si g ne d 
i nf o r me d c o nse nt m ust be 
pr o vi de d 
t o 
t he 
p a rtici p a nt 
a n d 
t heir 
le g all y 
a ut h orise d 
re pres e nt ati v e.  
 
T he me dic al rec or d m ust 
i ncl u de a st ate me nt t h at 
w ritte n i nf o r me d c o nse nt 
w as o bt ai ne d b ef ore t h e 
p a rtici p a nt w as e nr olle d 
i n t h e st u d y a n d t he d ate 
t h e w ritte n c o nse nt w as 
o bt ai ne d. T he a ut h orise d 
pers o n 
o bt ai ni n g 
t he 
i nf o r me d c o nse nt 
m ust 
als o si g n t he i nf o r me d 
c o nse nt f or m. 
 
P artici p a nts m ust be re-
c o nse nte d t o t he 
m ost 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 2 1/ 8 6 
 
Secti o n  
W A S  
( Versi o n 3. 0, 1 6 M a rc h 2 0 2 1) 
I S  
( V ersi o n 4. 0, 0 9 J ul y 2 0 2 1) 
R ati o n ale 
c urre nt 
versi o n of t he 
i nf o r me d c o nse nt f or m 
d uri n g t heir p arti ci p ati o n 
i n t he st u d y. If c h a n ges t o 
t h e i nf or me d c o nse nt d o 
n ot 
a p pl y 
t o 
all 
p a rtici p a nts, t his will be 
c o m m u nic ate d 
t o 
t he 
I R B/I E C wit h a r ati o n ale. 
I R B/I E C a p pr o v al 
m ust 
be 
recei ve d 
bef ore 
i m ple me nt ati o n 
as 
re quire d 
b y 
l oc al 
re g ul ati o ns. 
P artici p a nts will be t ol d t h at 
t h e y a re free t o ref use t o 
p a rtici p ate 
a n d 
m a y 
wit h dr a w t heir c o nse nt at a n y 
ti me 
a n d f or 
a n y re as o n 
d uri n g t he st u d y.  
Ot her d oc u me nts i m p acte d 
I nf or me d c o ns e nt f or m  
Yes 
 N o  
 
 
Case re p ort f or m ( C R F)  
Yes 
 N o  
 
 
Statistical a nal ysis pla n ( S A P)  
Yes 
 N o  
 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 2 2/ 8 6 
 
T A B L E O F C O N T E N T S 
M E N T ...................................................................................... 2  
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 T A B L E ............................... 1 1  
LI S T O F A B B R E VI A TI O N S ................................................................................................ 2 7  
1  
B A C K G R O U N D I N F O R M A TI O N ............................................................................ 2 9  
1. 1  
I ntr o d ucti o n ................................................................................................................... 2 9 
1. 2  
P o p ul ati o n t o Be St u die d .............................................................................................. 3 0  
1. 3  
C o m pli a nce St ate me nt .................................................................................................. 3 0  
2  
P U R P O S E O F T H E S T U D Y A N D S T U D Y O B J E C TI V E S ..................................... 3 2  
2. 1  
P ur p ose of t he St u d y ..................................................................................................... 3 2  
2. 2  
St u d y O bjecti ves ........................................................................................................... 3 2  
2. 3  
St u d y H y p ot hesis ........................................................................................................... 3 3  
3  
S T U D Y D E SI G N ........................................................................................................... 3 4  
3. 1  
Ge ner al Desi g n a n d St u d y Sc he m a ............................................................................. 3 4  
3. 2  
Pri m ar y a n d Sec o n d ar y E n d p oi nts a n d E v al u ati o ns ................................................ 3 5  
3. 2. 1  
Pri m ary Effic acy E n d p oi nt a n d Ev al u ati o n .............................................. 3 5  
3. 2. 2  
Sec o n d ary Effic acy E n d p oi nts a n d Ev al u ati o ns ........................................ 3 5  
3. 2. 3  
S afety E n d p oi nts a n d Ev al u ati o ns ............................................................. 3 5  
3. 3  
E xte nsi o n P h ase Effic ac y a n d S afet y E n d p oi nts a n d E v al u ati o ns ........................... 3 5  
3. 3. 1  
E xte nsi o n P h as e Effic acy E n d p oi nts a n d Ev al u ati o ns ............................. 3 5  
3. 3. 2  
E xte nsi o n P h as e S afety E n d p oi nts a n d Ev al u ati o ns ................................. 3 6  
3. 4  
E x pl or at or y P h ar m ac o ki netics E n d p oi nt ................................................................... 3 6  
3. 5  
R a n d o mis ati o n a n d Bli n di n g ....................................................................................... 3 6  
3. 6  
M ai nte n a nce of R a n d o mis ati o n a n d Bli n di n g ............................................................ 3 6  
3. 7  
St u d y T re at me nts a n d D os a ge ..................................................................................... 3 6  
3. 8  
St u d y D ur ati o n .............................................................................................................. 3 7  
3. 9  
S o urce D at a Rec or d e d o n t he C ase Re p ort F o r m ...................................................... 3 8  
4  
S E L E C TI O N A N D WI T H D R A W A L O F P A R TI CI P A N T S ................................... 3 9  
4. 1  
I ncl usi o n Criteri a .......................................................................................................... 3 9 
4. 2  
E xcl usi o n Criteri a ......................................................................................................... 3 9  
4. 3  
E xte nsi o n p h ase I n cl usi o n Criteri a ............................................................................. 4 0  
4. 4  
St o p pi n g R ules, Disc o nti n u ati o n a n d Wit h d r a w al Criteri a a n d P r oce d ures .......... 4 0  
4. 5  
Te m p or a r y Disc o nti n u ati o n ......................................................................................... 4 1  
4. 6  
L ost t o F oll o w- u p .......................................................................................................... 4 1  
4. 7  
Scree n F ail ures .............................................................................................................. 4 1  
5  
S T U D Y P R O C E D U R E S .............................................................................................. 4 2  
5. 1  
St u d y S c h e d ule .............................................................................................................. 4 2  
5. 2  
St u d y Visits .................................................................................................................... 4 4  
5. 2. 1  
Pr oce d ures f or t he Scree ni n g Visit ( D ay - 2 8 t o D ay - 1 Pri or t o 
Tre at m e nt) a n d E nr ol me nt ......................................................................... 4 4  

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 2 3/ 8 6 
 
5. 2. 2  
Pr oce d ures D uri n g t he Tre at me nt P h ase of St u dy ( D ay 1 a n d M o nt h 3) 4 5  
5. 2. 3  
Pr oce d ures F oll o wi n g St u dy Tre at m e nt ( M o nt h 6, E n d of M ai n St u dy or 
E arly Wit h dr a w al Visit) .............................................................................. 4 5  
5. 2. 4  
Pr oce d ures D uri n g t he E xte nsi o n P h ase ( M o nt h 6, M o nt h 9 a n d E n d of 
E xte nsi o n P h as e Visit) ................................................................................ 4 5  
5. 3  
L a b or at or y Assess me nts ............................................................................................... 4 6  
6  
T R E A T M E N T O F P A R TI CI P A N T S ......................................................................... 4 7  
6. 1  
I n vesti g ati o n al 
Me dici n al 
Pr o d uct 
Pre p ar ati o n, 
St or a ge, 
Sec urit y 
a n d 
Acc o u nt a bilit y ............................................................................................................... 4 7  
6. 1. 1  
I nvesti g ati o n al Me dici n al Pr o d uct St or a ge a n d Sec urity .......................... 4 7  
6. 1. 2  
I nvesti g ati o n al Me dici n al Pr o d uct Pre p ar ati o n ........................................ 4 7  
6. 1. 3  
I nvesti g ati o n al Me dici n al Pr o d uct Acc o u nt a bility .................................... 4 7  
6. 2  
St u d y Dr u gs A d mi nistere d ........................................................................................... 4 8  
6. 2. 1  
Tri pt oreli n 3- M o nt h F or m ul ati o n .............................................................. 4 8  
6. 3  
C o nc o mit a nt Me dic ati o n/ T her a p y .............................................................................. 4 8  
6. 4  
Lifest yle Restricti o ns/ Rec o m me n d ati o ns .................................................................... 4 9  
6. 5  
Pr o ce d ures f o r M o nit ori n g P artici p a nt C o m pli a nce ................................................. 4 9  
7  
A S S E S S M E N T O F E F FI C A C Y .................................................................................. 5 0  
7. 1  
Pri m ar y Effic ac y E n d p oi nt a n d E v al u ati o n ............................................................... 5 0  
7. 2  
Sec o n d ar y Effic ac y E n d p oi nts a n d E v al u ati o ns ........................................................ 5 0  
7. 3  
E xte nsi o n P h ase E n d p oi nts a n d E v al u ati o ns ............................................................. 5 1  
7. 4  
Met h o ds a n d Ti mi n g of Assessi n g, Rec or di n g a n d A n al ysi n g Effic ac y D at a .......... 5 2  
7. 4. 1  
C h a n ge i n L utei nisi n g H or m o ne a n d F ollicle-sti m ul ati n g H or m o n e 
Ser u m C o nce ntr ati o ns ................................................................................ 5 2  
7. 4. 2  
G o n a d otr o pi n-rele asi n g H or m o ne Sti m ul ati o n Test ................................. 5 2  
7. 4. 3  
C h a n ge i n 
Se x 
Ster oi ds ( Oestr a di ol 
a n d 
Test oster o ne 
Ser u m 
C o nce ntr ati o ns) ........................................................................................... 5 2  
7. 4. 4  
C h a n ge i n P u b ert al St a ge Usi n g t he T a n ner Met h o d ............................... 5 2  
7. 4. 5  
A u x ol o gic al 
P ar a meters, 
B o ne 
A ge 
a n d 
C hr o n ol o gic al 
A ge 
Me as ure m e nts a n d G o n a d Devel o p m e nt ................................................... 5 2  
8  
A S S E S S M E N T O F S A F E T Y ....................................................................................... 5 3  
8. 1  
A d verse E ve nts .............................................................................................................. 5 3  
8. 1. 1  
Defi niti o n of a n A dverse Eve nt .................................................................. 5 3  
8. 1. 2  
C ate g oris ati o n of A dverse Eve nts ............................................................... 5 4  
8. 1. 2. 1  
I nte nsity Cl assific ati o n ................................................................................. 5 4 
8. 1. 2. 2  
C a us ality Cl assific ati o n ............................................................................... 5 4  
8. 1. 2. 3  
Assess me nt of E x pecte d ness ......................................................................... 5 4  
8. 1. 2. 4  
L a b or at ory Test A b n or m alities .................................................................... 5 4  
8. 1. 2. 5  
A b n or m al P hysic al Ex a mi n ati o n Fi n di n gs .................................................. 5 5  
8. 1. 2. 6  
L oc al T ol er a bility A b n or m alities ................................................................. 5 5  
8. 1. 2. 7  
Ot her I nvesti g ati o n A b n or m al Fi n di n gs ...................................................... 5 5  
8. 1. 3  
A dverse Eve nts of S peci al I nter est ............................................................. 5 5  

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 2 4/ 8 6 
 
8. 1. 4  
Rec or di n g a n d F oll o w- u p of A dvers e Eve nts ............................................. 5 5  
8. 1. 5  
Re p orti n g of Seri o us A dverse Eve nts ......................................................... 5 5  
8. 1. 6  
Pre g n a ncy .................................................................................................... 5 7  
8. 1. 7  
De at hs .......................................................................................................... 5 8  
8. 1. 8  
Disc o nti n u ati o n/ Wit h dr a w al d ue t o A dverse Eve nts/ Seri o us A dvers e 
Eve nts .......................................................................................................... 5 8  
8. 1. 9  
Re p orti n g 
t o 
C o m pete nt 
A ut h orities/I n de pe n de nt 
Et hics 
C o m mittees/I nstit uti o n al Revie w B o ar ds/ Ot her I nvesti g at ors .................. 5 8  
8. 2  
Cli nic al L a b or at or y Tests ............................................................................................ 5 8  
8. 2. 1  
H ae m at ol o gy ................................................................................................ 5 8  
8. 2. 2  
Bl o o d C he mistr y .......................................................................................... 5 8  
8. 2. 3  
Uri n alysis ..................................................................................................... 5 9  
8. 2. 4  
Pre g n a ncy Test ............................................................................................ 5 9  
8. 2. 5  
Ot her Cli nic al L a b or at ory T ests ................................................................. 5 9  
8. 3  
P h ysic al E x a mi n ati o n ................................................................................................... 5 9  
8. 4  
L oc al T oler a bilit y .......................................................................................................... 5 9  
8. 5  
Vit al Si g ns ...................................................................................................................... 6 0  
9  
A S S E S S M E N T S O F P H A R M A C O KI N E TI C S/ P H A R M A C O D Y N A MI C S .......... 6 1  
9. 1  
P h ar m a c o ki n etics .......................................................................................................... 6 1  
9. 1. 1  
S a m ple C ollecti o n ....................................................................................... 6 1  
9. 1. 2  
A n alytic al Pr oce d ures ................................................................................. 6 1  
9. 1. 3  
D at a A n alysis ............................................................................................... 6 1  
9. 2  
P h ar m a c o d y n a mi cs ....................................................................................................... 6 1  
1 0  
E X P L O R A T O R Y BI O M A R K E R S A N D BI O B A N KI N G ....................................... 6 2  
1 1  
S T A TI S TI C S ................................................................................................................. 6 3  
1 1. 1  A n al ysis P o p ul ati o ns ..................................................................................................... 6 3  
1 1. 1. 1  
P o p ul ati o ns A n alyse d .................................................................................. 6 3  
1 1. 1. 2  
Re as o ns f or E xcl usi o n fr o m t he A n alyses ................................................. 6 3  
1 1. 2  S a m ple Size Deter mi n ati o n .......................................................................................... 6 3  
1 1. 3  Si g nific a nce Testi n g a n d Esti m ati o ns ......................................................................... 6 4  
1 1. 4  St atistic al/ A n al ytic al Met h o ds ..................................................................................... 6 4  
1 1. 4. 1  
De m o gr a p hic a n d Ot her B aseli n e C h ar acteristics .................................... 6 5  
1 1. 4. 2  
P artici p a nt Dis p ositi o n a n d Wit h dr a w als .................................................. 6 5  
1 1. 4. 3  
P h ar m ac o ki netic D at a ................................................................................ 6 5  
1 1. 4. 4  
Effic acy Ev al u ati o n ( M ai n P h ase) ............................................................. 6 5  
1 1. 4. 4. 1  
Pri m ary Effic acy E n d p oi nt .......................................................................... 6 5  
1 1. 4. 4. 2  
Sec o n d ar y Effi c acy E n d p oi nt ....................................................................... 6 5  
1 1. 4. 4. 3  
Ex pl or at ory P h ar m ac oki neti cs E n d p oi nt ..................................................... 6 6  
1 1. 4. 5  
A dj ust m e nt f or C o u ntry/ Ce ntr e Effect ....................................................... 6 6  
1 1. 4. 6  
S afety Ev al u ati o n ( M ai n P h ase) ................................................................. 6 6  
1 1. 4. 7  
Effic acy a n d S afety Ev al u ati o ns ( E xte nsi o n P h ase) ................................. 6 7  

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 2 5/ 8 6 
 
1 1. 4. 7. 1  
Effic acy E n d p oi nt ......................................................................................... 6 7  
1 1. 4. 7. 2  
S afety E n d p oi nts ........................................................................................... 6 7  
1 1. 5  S u b gr o u p A n al ys es ....................................................................................................... 6 7  
1 1. 6  I nteri m A n al yses ........................................................................................................... 6 7 
1 2  
DI R E C T A C C E S S T O S O U R C E D A T A A N D D O C U M E N T S ............................... 6 9  
1 3  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E .......................................... 7 0  
1 3. 1  Pr ot oc ol A me n d me nts a n d Pr ot oc ol De vi ati o ns ........................................................ 7 0  
1 3. 1. 1  
Pr ot oc ol A me n d m e nts ................................................................................. 7 0  
1 3. 1. 2  
Pr ot oc ol Devi ati o ns a n d E xce pti o ns........................................................... 7 0  
1 3. 2  I nf or m ati o n t o St u d y P ers o n nel .................................................................................. 7 1 
1 3. 3  St u d y M o nit ori n g .......................................................................................................... 7 1  
1 3. 4  I n vesti
 ........................................................................ 7 2 
1 3. 5  A u dit a n d I ns p ecti o n .................................................................................................... 7 2  
1 3. 6  D at a Q u alit y Ass ur a nce ................................................................................................ 7 2  
1 4  
E T HI C S ......................................................................................................................... 7 3  
1 4. 1  C o m pli a nce wit h G o o d Cli nic al Pr actice a n d Et hic al C o nsi d er ati o ns .................... 7 3  
1 4. 2  I nf or me d C o ns e nt f or P artici p ati o n i n t h e St u d y ...................................................... 7 3  
1 4. 3  He alt h A ut h orities a n d I n de pe n de nt Et hics C o m mittees/I nstit uti o n al Re vie w 
B o ar ds ............................................................................................................................ 7 4  
1 4. 4  C o nfi d e nti alit y Re g ar di n g St u d y P artici p a nts ........................................................... 7 4  
1 5  
D A T A H A N D LI N G A N D R E C O R D K E E PI N G ....................................................... 7 5  
1 5. 1  Rec o r di n g of St u d y D at a .............................................................................................. 7 5  
1 5. 2  D at a M a n a ge me nt ......................................................................................................... 7 5  
1 5. 3  Rec o r d Arc hi vi n g a n d Rete nti o n ................................................................................. 7 6  
1 6  
FI N A N CI N G A N D I N S U R A N C E ............................................................................... 7 7  
1 6. 1  C o ntr act u al a n d Fi n a nci al Det ails ............................................................................... 7 7  
1 6. 2  I ns ur a nce, I n de m nit y a n d C o m pe ns ati o n .................................................................. 7 7  
1 7  
R E P O R TI N G A N D P U B LI C A TI O N O F R E S U L T S ................................................ 7 8  
1 7. 1  P u blic ati o n P olic y ......................................................................................................... 7 8  
1 7. 2  Cli nic al St u d y Re p ort ................................................................................................... 7 9  
1 8  
R E F E R E N C E S .............................................................................................................. 8 0  
1 9  
LI S T O F A P P E N DI C E S .............................................................................................. 8 1  
 
LI S T O F T A B L E S 
T a ble 1  
Sc he d ule of Assess me nts ..................................................................................... 4 2  
T a ble 2  
Sc he d ule of Assess me nts i n E xte nsi o n P h ase .................................................... 4 4  
T a ble 3  
C o m p ositi o n of Tri pt oreli n P a m o ate 3- M o nt h F or m ul ati o n .......................... 4 8  
T a ble 4  
C o m p ositi o n of t he S ol ve nt f or S us pe nsi o n ....................................................... 4 8  
T a ble 5  
Sec o n d ar y Effic ac y E n d p oi nts a n d E v al u ati o ns ............................................... 5 0  
T a ble 6  
Effic ac y E n d p oi nts a n d E v al u ati o ns i n t he E xte nsi o n P h as e .......................... 5 1  

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 2 6/ 8 6 
 
 
LI S T O F FI G U R E S 
Fi g ure 1 M ai n St u d y Desi g n .................................................................................................. 3 4  
Fi g ure 2 E xte nsi o n P h ase Desi g n .......................................................................................... 3 4  
 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 2 7/ 8 6 
 
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(s) 
A d verse E v e nt(s) 
A L P 
Al kali ne P h os p hatase 
A L T 
Ala ni ne A mi n otra nsferas e 
A S T 
As p artate Tra nsa mi nase 
B A 
B o ne A ge 
B MI 
B o d y Mass I n de x 
C A 
C hr o n ol o gical A ge 
C B C 
C o m plete Bl o o d C o u nt 
C E 
C o nf or mité E ur o pée n n e 
C R F 
C o de of Fe deral Re g ul ati o ns ( U S) 
CI 
C o nfi de nce I nter val 
C P P 
Ce ntral Prec oci o us P u bert y 
C R O 
C o ntract Researc h Or ga nis ati o n 
C S R 
Cli nical St u d y Re p ort 
E C 
Et hics C o m mittee 
e C R F 
Electr o nic Case Re p ort F or m 
E D C 
Electr o nic Data Ca pt ure 
E O S 
E n d of St u d y 
F S H 
F ollicle-sti m ulati n g H or m o ne 
G C P 
G o o d Cli nical Practice 
G L P 
G o o d La b orat or y Practice 
G M P 
G o o d Ma n ufact uri n g Practi ce 
G n R H 
G o na d otr o pi n-releasi n g H or m o ne 
G n R H a(s) 
G n R H A g o nist(s) 
I B 
 
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n of Tec h nical 
Re q uire me nts f or P har m ace uticals f or H u ma n Use 
I E C 
I n d e pe n de nt Et hics C o m mittee 
I G F- 1 
I ns uli n-li ke Gr o wt h Fact or 1 
i. m. 
I ntra m usc ular 
I N N 
I nter nati o nal N o n- pr o pri etar y Na me 
I R B 
I nstit uti o nal R e vie w B oar d 
I T T 
I nte nti o n-t o-treat 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 2 8/ 8 6 
 
A B B R E VI A TI O N 
W or di n g Defi niti o n  
I U 
I nter nati o nal U nits 
i. v. 
I ntra ve n o us 
I W R S 
I nteracti ve We b Res p o nse S yste m 
L H 
L utei nisi n g h or m o ne 
L H R H 
L utei nisi n g H or m o ne-rel easi n g H or m o ne 
M A H 
Mar keti n g A ut h orisati o n H ol der 
M D S S 
Material Data Safet y S heets 
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 
N 
N u m ber of Partici pa nts 
N CI- C T C A E 
Nati o nal Ca ncer I nstit ute 
 C o m m o n T er mi n ol o g y Criteria f or 
A d verse E v e nts 
P A S S 
P o wer A nal ysis a n d Sa m ple Size 
PI L 
Patie nt I nf or mati o n Leaflet 
P K 
P har mac o ki netic 
P P 
Per Pr ot oc ol 
P R 
Pr ol o n ge d Release 
P T 
Preferre d Ter m 
S A E 
Seri o us A d vers e E v e nt 
S A P 
Statistical A nal ysis Pla n 
S A S ®  
Statistical A nal ysis S yste m ®  
S D(s) 
Sta n dar d De viati o n(s) 
S M P 
Safet y M a na ge me nt Pla n 
S O C 
S yste m Or ga n Class 
S O P 
Sta n dar d O perati n g Pr oce d ure 
S U S A R(s) 
S us pecte d U ne x pecte d Seri o us A d vers e Reacti o n(s) 
t ½ 
Plas ma Half-life 
T E A E(s) 
Treat me nt-e m er ge nt A d v erse E ve nt(s) 
U L N 
U p per Li mit of N or m al 
W H O- D D 
W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 2 9/ 8 6 
 
1  
B A C K G R O U N D I N F O R M A TI O N 
1. 1  
I ntr o d ucti o n 
Prec oci o us p u bert y is a c o n diti o n t hat ca us es earl y se x u al de vel o p me nt i n girls a n d b o ys. W hile 
t he c hr o n ol o gic al a ge ( C A) li mit f or t he o ns et of p u bert y is 8 years i n girls a n d 9 years i n b o ys 
f or c hil dre n i n N ort h A merica a n d Wester n E ur o pea n c o u ntries [ Carel 2 0 0 8], c hil dre n wit h 
prec oci o us p u bert y e x hi bit prec oci o us p u bertal de vel o p me nt t hat ca n be 2. 5 t o 3 sta n d ar d 
de viati o ns ( S Ds) earlier t ha n t he c urre nt esti mate d a vera ge. T he pre val e nce of prec oci o us 
p u bert y is 1 0 ti mes hi g her i n girls t ha n i n b o ys [ Carel 2 0 0 8]. 
I n a mi n orit y of c hil dre n, prec o ci o us p u bert y ca n occ ur d ue t o a n or ga nic lesi o n (cere bral 
t u m o ur); i n 
m ost 
c hil dre n, t his 
c o n diti o n is 
ca use d 
b y t he 
earl y release 
of 
g o na d otr o pi n-releasi n g h or m o ne ( G n R H, als o k n o w n as l utei nisi n g h or m o ne-rel easi n g 
h or m o ne; L H R H) b y t he h y p ot hala m us. I n healt h y c hil dre n, G n R H sti m ul ates t he rel ease of 
pit uitar y g o na d otr o pi ns f ollicle-sti m ul ati n g h or m o ne ( F S H) a n d l utei nisi n g h or m o ne ( L H), 
w hic h is t he n f oll o we d b y pr ol o n ge d s u p pressi o n of t hese h or m o nes, c o ntri b uti n g t o n or mal 
p u bertal de vel o p me nt. T he f or m of prec oci o us p u bert y c a us e d b y earl y G n R H sti m ulati o n is 
ter me d ce ntral prec oci o us p u b ert y ( C P P). I n c hil dre n wit h C P P, earl y G n R H rel ease lea ds t o 
t he prec o ci o us secreti o n of L H a n d F S H w hi c h, i n t ur n, acti vate t he earl y s ecreti o n of g o na d al 
h or m o nes b y t h e o varies or test es.  
a n d be h a vi o ur. B o ys d e v el o p facial hair a n d t heir pe nis l e n gt he ns a n d girls de vel o p breasts a n d 
ma y ha v e me nstr ual peri o ds. I n c hil dre n wit h C P P, t hese si g ns pre mat urel y a p pear b ef ore t he 
a ge of 8 a n d 9 i n girls a n d b o ys, res pecti vel y. F urt h er m ore, gr o wt h vel o cit y accelerates, i nitiall y 
i n d uci n g a ra pi d hei g ht i ncreas e, w hic h st o ps at a n earl y a ge. Accelerate d b o ne mat urati o n lea ds 
t o pre m at ure e pi p h yseal cl os ure a n d a fi nal hei g ht bel o w t he tar get h ei g ht t hat was ot her wise 
i n c hil dre n wit h C P P.  
T here is c urre ntl y n o n ati o n wi de e pi de mi ol o g y st u d y of C P P data i n C hi na. O nl y t w o st u di es 
ha ve bee n p u blis he d a b o ut t he i nci de nce of prec o ci o us p u bert y i n t w o citi es: Ji u Jia n g (st u d y 
wit h 3, 3 1 2 c hil dre n i n vesti gat e d a n d a n i nci de n ce of 0. 6 8 %, 1. 2 5 % i n girls a n d 0. 1 1 % i n b o ys) 
[ H u 2 0 1 2] a n d Z he n gz h o u (st u d y wit h 8, 7 5 0 c hil dre n i n vesti gate d a n d a n i nci d e nce of 0. 7 4 %, 
1. 3 7 % i n girls a n d 0. 2 6 % i n b o ys) [ Wei 2 0 1 0]. I n c oastal areas of C hi na, prec o ci o us p u bert y 
has a n i nci de nce rate of 0. 3 8 %; t he i nci de nce i n girls is hi g her at 0. 6 7 %. T he pre vale n ce of 
prec oci o us p u bert y i n S ha n g h ai is 1 0 0/ 1 0, 0 0 0 [ Li n 2 0 0 4]. T hese data refer t o prec oci o us 
p u bert y wit h o ut G n R H- de pe n de nt sti m ul ati o n, w hic h is n ot s pecifi c f or C P P a n d are pr o ba bl y 
l o wer t ha n n u m bers d escri be d a b o ve. 
As re p orte d b y C arel a n d Lé ger [ Carel 2 0 0 8], t he assess me nt of g o na d otr o pi n le vels ( b as e d o n 
ultrase nsiti ve assa ys) is ce ntral t o t he dia g n osis of C P P. T he g ol d sta n dar d f or e val u ati o n is t he 
meas ure me nt of g o n a d otr o pi n le vels after sti m ulati o n wit h G n R H or a G n R H a g o nist ( G n R Ha). 
Pea k L H le v els of 5 t o 8 I U/ L s u g gest pr o gressi ve C P P b ut t here is a n o verla p b et we e n 
pre p u bert al a n d earl y p u bertal val ues [ Carel 2 0 0 8, Res e n d e 2 0 0 7]. Ca uti o n s h o ul d be ta ke n 
w he n i nt er preti n g g o n a d otr o pi n le vels i n c hil dre n y o u n ger t ha n 2 t o 3 years ol d as g o na d otr o pi n 
le vels are n or mall y hi g h i n t his a ge gr o u p [ Carel 2 0 0 8]. 
I n C P P (i.e. wit h n o ot h er i d e ntifie d ca us e s uc h as a cere bral t u m o ur), t here is n o s ur gical 
t hera p y a v aila ble a n d n o effecti ve alter nati ve t hera pe utic o pti o n ot her t h a n ta ki n g a pr ol o n ge d 
release ( P R) f or m ulati o n of s y nt hetic G n R H. I n se vere cases, u ntre ate d C P P ca uses p h ysical 
a n d ps yc h ol o gical pr o bl e ms f or t he c hil d.  
Treat me nt wit h G n R H a n al o g ues, w hic h act b y d o w nre g ul ati n g pit uitar y G n R H rece pt ors  
[ Carel 2 0 0 9, C o mite 1 9 8 1 Cr o wle y 1 9 8 1, Bertell o ni 2 0 1 3], re prese nt t he sta n d ar d of care f or 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 3 0/ 8 6 
 
t he treat me nt of C P P [ Carel 2 0 0 9]. T heir efficac y t o st o p prec oci o us d e v el o p me nt has bee n 
de m o nstrate d a n d t heir us e i n v ol ves o nl y mi n or a d verse e ve nts ( A Es). A re vie w of C P P 
treat me nt b y Kris h na et al c o nfir m e d t hat treat m e nt wit h P R f or m ul ati o ns of G n R Has is safe, 
wit h relati vel y mi n or si d e effects, a n d s u p p orte d t hat t he o utc o me i n ter ms of fi nal hei g ht is 
fa v o ura bl e i n m ost p ati e nts [ Kris h na 2 0 1 9].  
Di p hereli ne ®  (i nter nati o nal n o n- pr o prietar y na m e (I N N): tri pt oreli n) is a s y nt hetic G n R H 
a nal o g ue t hat is mai nl y c haract erise d b y t he re place me nt of t he L- gl yci ne i n t he 6 t h p ositi o n b y 
a D-tr y pt o p ha n. T his str uct ural m o dificati o n i ncreas es b ot h t he resista nce t o e nz y matic 
de gra dati o n a n d t he affi nit y t o t he pit uitar y rec e pt or, t h us pr ol o n gi n g t he pl as ma half-life (t 1/ 2) 
a n d i ncreasi n g t h e p ote nc y of t he dr u g.  
I n C hi na, Di p hereli ne® is a vail a ble as a 1- m o nt h f or m ul ati o n, w hic h is a p pr o ve d f or use i n 
patie nts wit h pr ostate ca n cer, C P P, e n d o m etri osis, fi br o m y o m as a n d fe m ale i nfertilit y, a n d a 3-
m o nt h f or m ul ati o n (c o ntai ni n g 1 5 m g of tri pt oreli n pa m oate t o e ns ure t he release of 1 1. 2 5 m g 
of pr o d uct), w hi c h is a p pr o ve d f or pr ostate ca ncer. 
Se veral st u dies ha ve assesse d t he efficac y a n d safet y of tri pt oreli n 3- m o nt h P R release 
f or m ulati o n, i ncl u di n g t hree I pse n-s p o ns ore d p h ase III st u di es a n d t w o i n de pe n de nt st u di es 
[ Carel 2 0 0 6, Marti nez- A g ua y o 2 0 0 6, Ze nat y 2 0 1 6]. I n 2 0 1 7, D ura n d et al. [ D ura n d 2 0 1 7] 
perf or me d a meta- a nal ysis t o assess t he data a v ail a ble fr o m a t otal of 1 5 3 c hil dre n wit h C P P 
( 1 3 b o ys a n d 1 4 0 girls) t hat ha d partici p ate d i n t he cli nical st u dies a n d recei ve d treat me nt wit h 
t his tri pt oreli n f or m ulati o n. Acr oss all st u dies, t he pri mar y o utc o me was t he pr o p orti o n of 
 I U/ L) t o t he G n R H test 3 m o nt hs after 
tri pt oreli n i nj ecti o n. Sec o n dar y o utc o mes i ncl u de d t he pr o p orti o n of c hil dre n wit h s u p presse d 
pea k L H res p o ns e at 6 m o nt hs, a n d t he pr o p orti o n of c hil dre n wit h s u p press e d pea k F S H 
 
 p m ol/ L) a n d pr o p orti o n 
 n g/ d L) at 3 m o nt hs [ D ura n d 2 0 1 7]. T he a ut h ors 
c o ncl u de d t h at t he 3- m o nt h f or m ulati o n of tri pt oreli n was efficaci o us i n s u p pressi n g L H p ea k 
a n d ot her g o na d al h or m o nes a n d i n sl o wi n g t he pr o gressi o n of C P P i n c hil dre n. 
T he w orl d wi de mar keti n g st at us of all tri pt oreli n f or m ulati o ns of w hic h I pse n is t he mar k eti n g 
F urt her 
details/a d diti o nal i nf or mati o n re gar di n g ris ks a n d be nefits t o parti ci pa nts ma y als o be f o u n d i n 
t he I B. 
A m ore detaile d d escri pti o n of t he pr o d uct is pr o vi de d i n Secti o n 3. 7  a n d Secti o n 6 . F urt her 
details o n a d mi nistrati o n pr oce d ures a n d d osa ge are pr o vi de d i n Secti o n 6. 2 . 
1. 2  
P o p ul ati o n t o Be St u die d 
T his st u d y will e nr ol C hi nes e parti ci p a nts wit h C P P less t ha n 9 years ol d f or girls a n d l ess t ha n 
1 0 years ol d f or b o ys at i nitiati o n of tri pt oreli n treat m e nt.  
1. 3  
C o m pli a nce St ate me nt 
T he st u d y will a d here t o all l ocal re g ul at or y re q uire me nts a n d rele va nt c o m pa n y p olicies. T h e 
S p o ns or will e ns ure t hat t he c o u ntries w h ere data are tra nsferre d t o are a ble t o pr o vi de a n 
a de q uate le vel of dat a pr otecti o n. 
Bef ore i niti ati n g t he st u d y, t he I n v esti gat or/i nstit uti o n 
will o btai n 
writte n a n d date d 
a p pr o val/fa v o ura ble o pi ni o n fr o m t he I n d e pe n de nt Et hi cs C o m mitt ee (I E C)/I nstit uti o nal 
Re vie w B oar d (I R B) f or t he st u d y pr ot oc ol/a me n d m e nt(s), writte n i nf or me d c o nse nt f or m fr o m 
t he partici pa nts, a n y c o nse nt f or m u p d ates, p artici pa nt e m er ge n c y st u d y c o ntact car ds, 
partici pa nt recr uit me nt pr oce d ures (e. g. a d vertis e me nts), a n y 
writt e n i nf or mati o n t o be 
pr o vi de d t o partici pa nts a n d a st at e me nt fr o m t he I E C/I R B t hat t he y c o m pl y wit h G o o d Cli nical 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 3 1/ 8 6 
 
Practice ( G C P) re q uire m e nts. T he I E C/I R B a p pr o val m ust i de ntif y t h e pr ot oc ol versi o n as well 
as t he d oc u me nts re vi e we d. 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 3 2/ 8 6 
 
2  
P U R P O S E O F T H E S T U D Y A N D S T U D Y O B J E C TI V E S 
2. 1  
P ur p ose of t he St u d y 
Tri pt oreli n pa m oate 1 5 m g ( 3- m o nt h f or m ul ati o n) f or i nj ecti o n is re gist ere d i n C hi na as 
Di p hereli ne ®  1 5 m g f or t he treat me nt of pr ostate ca ncer.  
C urre ntl y, t here h a ve bee n n o cli nical st u di es wit h t he 3- m o nt h f or m ul ati o n of tri pt oreli n f or 
C P P i n C hi na. F or t his reas o n, I pse n is s p o ns ori n g t his st u d y, w hic h is i nte n de d t o pr o vi d e data 
o n t he effi cac y a n d safet y of tri pt oreli n pa m oate 3- m o nt h f or m ul ati o n i n C hi nese c hil dre n wit h 
C P P.  
He ncef ort h i n t his pr ot oc ol, tri pt oreli n pa m oate 1 5 
 
2. 2  
St u d y O bjecti ves 
M ai n st u d y o bjecti ves 
T he pri mar y o bjecti ve of t he st u d y is t o assess t he efficac y of t he tri pt oreli n 3- m o nt h P R 
f or m ulati o n i n s u p pressi n g L H l e vels t o pre- p u b ertal le vels ( defi ne d as a pea k L H 
 I U/ L) 
after i ntra v e n o us (i. v.) G n R H sti m ulati o n at M o nt h 3 i n C hi nes e c hil dre n wit h C P P.  
T he sec o n d ar y o bjecti ves of t he st u d y are as f oll o ws: 
 
T o assess t he effica c y i n s u p press e d L H res p o ns e t o G n R H test at M o nt h 6 
 
T o assess f ollicle-sti m ul ati n g h or m o ne ( F S H) res p o nse t o G n R H test at M o nt h 3 a n d 
M o nt h 6 
 
T o assess L H a n d F S H le vels at M o nt h 3 a n d M o nt h 6 
 
T o assess se x h or m o ne ser u m c o nce ntrati o ns ( o estra di ol f or girls a n d test oster o ne f or 
b o ys) at M o nt h 3 a n d M o nt h 6 
 
T o assess s e x ual mat urati o n ( p u bertal st a ge as per T a n ner met h o d) at M o nt h 6 
 
T o assess a u x ol o gical p ara meters i ncl u di n g h ei g ht, gr o wt h v el ocit y, wei g ht a n d b o d y 
mass i n de x ( B MI) at M o nt h 3 a n d M o nt h 6 
 
T o assess b o ne a ge ( B A), t he differe nce bet wee n B A a n d c hr o n ol o gic al a g e ( C A) at 
M o nt h 6 
 
T o assess g o na d al de vel o p me nt as deter mi n e d b y uteri ne le n gt h i n girls a n d testic ular 
v ol u me i n b o ys at M o nt h 6 
 
T o assess t he safet y pr ofile. 
T he p har mac o ki netic ( P K) e x pl orat or y o bjecti ve is: 
 
T o assess plas m a tri pt oreli n le vels at Da y 1, M o nt h 3 a n d M o nt h 6. 
O bjecti ves of t he E xte nsi o n P h as e  
T o descri b e t he l o n g-ter m effi cac y a n d s afet y of Tri pt oreli n 3- m o nt h pr ol o n ge d rel ease 
f or m ulati o n t hr o u g h f oll o wi n g o bj ecti ves: 
 
T o assess t he perce nta ge of s u bjects wit h s u p press e d L H h or m o nes at m o nt h 1 2 
 
T o assess L H a n d F S H le vels at M o nt h 9 a n d 1 2 
 
T o assess se x h or m o ne ser u m c o nce ntrati o ns ( oestra di ol f or girls a n d test oster o ne f or 
b o ys) at M o nt h 9 a n d 1 2 
 
T o assess s e x ual mat urati o n ( p u bertal st a ge as per T a n ner met h o d) at M o nt h 1 2 
 
T o assess a u x ol o gical p ara meters i ncl u di n g h ei g ht, gr o wt h v el ocit y, wei g ht a n d b o d y 
mass i n de x ( B MI) at M o nt h 9 a n d M o nt h 1 2 
 
T o assess b o ne a ge ( B A), t he differe nce bet wee n B A a n d c hr o n ol o gical a ge ( C A) at 
M o nt h 1 2 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 3 3/ 8 6 
 
 
T o assess g o na d al de vel o p me nt as deter mi n e d b y uteri ne le n gt h i n girls a n d testic ular 
v ol u me i n b o ys at M o nt h 1 2 
 
T o assess t he safet y pr ofile. 
2. 3  
St u d y H y p ot hesis 
T he st u d y h y p ot hesis is t hat t he effecti ve ness of tri pt oreli n 3- m o nt h f or m ulati o n i n C hi nese 
p o p ulati o n of C P P c hil dre n has t he sa me or si mil ar tre n d wit h t hat i n o vers eas C P P p o p ulati o n. 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 3 5/ 8 6 
 
3. 2  
Pri m ar y a n d Sec o n d ar y E n d p oi nts a n d E v al u ati o ns 
3. 2. 1  
Pri m ary Effic acy E n d p oi nt a n d Ev al u ati o n 
T he pri mar y e n d p oi nt is t he pr o p orti o n of c hil dre n wit h L H s u p pressi o n d efi ne d as sti m ul ate d 
pea k L H 
 I U/ L after G n R H sti m ulati o n at M o nt h 3. T he G n R H sti m ulati o n test is perf or me d 
b y usi n g a n i. v. i nje cti o n of g o n a d oreli n (s y nt h eti c G n R H) t o sti m ul ate g o na d otr o p hi n release 
a n d bl o o d sa m ples will be c ollecte d pri or t o a n d 3 0, 6 0 a n d 9 0 mi n utes after t he g o na d oreli n 
i njecti o n f or ce ntral assess me nt of s er u m L H le vels. 
3. 2. 2  
Sec o n d ary Effic acy E n d p oi nts a n d Ev al u ati o ns 
 
C ha n ge i n b asal L H a n d F S H l e vels at M o nt h 3 a n d M o nt h 6 c o m pare d t o baseli n e; 
 
Pr o p orti o n of c hil dre n w
G n R H sti m ul ati o n at M o nt h 6 
 
C ha n ge i n pea k L H le vel after t h e G n R H sti m ulati o n test at M o nt h 3 a n d M o nt h 6 
c o m pare d t o baseli ne 
 
C ha n ge i n pea k F S H le vel aft er t he G n R H sti m ulati o n test at M o nt h 3 a n d M o nt h 6 
c o m pare d t o baseli ne 
 
Pr o p orti o n of c hil dre n 
wit h pre- p u bertal l e vels of s e x ster oi ds ( defi ne d as 
oestra di ol 
 p g/ m L i n girls or test oster o ne 
 n g/ m L i n b o ys) at 
M o nt h 3 a n d 
M o nt h 6 
 
C ha n ge i n o estra di ol le vels i n girls or test oster o ne le vels i n b o ys at M o nt h 3 a n d M o nt h 6 
c o m pare d t o baseli ne 
 
C ha n ge i n p u bertal sta ge usi n g t he Ta n ner met h o d ( ge nit al sta ge i n b o ys, breast sta ge i n 
girls a n d p u bic h air sta ge i n b ot h s e x es) at M o nt h 6 c o m pare d t o bas eli n e 
 
Pr o p orti o n of c hil dre n wit h sta bilis e d p u bertal sta ge usi n g t he Ta n ner met h o d at M o nt h 6 
c o m pare d t o baseli ne  
 
C ha n ge i n a u x ol o gical p ara meters i n cl u di n g hei g ht, gr o wt h v el ocit y, wei g ht, B MI at 
M o nt h 3 a n d M o nt h 6 c o m pare d t o baseli ne 
 
C ha n ge i n B A, differe nce bet wee n B A a n d C A at M o nt h 6 c o m pare d t o bas eli ne 
 
C ha n ge i n uteri ne l e n gt h i n girls or testic ular v ol u m e i n b o ys at M o nt h 6 c o m pare d t o 
baseli ne. 
3. 2. 3  
S afety E n d p oi nts a n d Ev al u ati o ns 
Safet y a n d t olera bilit y will be assesse d t hr o u g h o ut t he st u d y b y e val uati n g treat me nt-e m er ge nt 
a d vers e e v e nts ( T E A Es), i ncl u di n g l ocal t olera bilit y a n d i nj ecti o n site-rel ate d reacti o ns), 
cli nical la b orat or y test res ults, vital si g ns meas ure me nts, p h ysic al e x a mi nati o n res ults a n d 
c ha n ges fr o m b aseli ne i n c o nc o mita nt me dicati o n usa ge. Safet y p ara m eters will be m o nit ore d 
at vari o us ti me p oi nts fr o m t he ti me t he partici pa nt pr o vi des i nf or m e d c o ns e nt t o t he e n d of t he 
st u d y, as f oll o ws: 
 
I n ci de nce of T E A Es t hr o u g h o ut t he st u d y, i ncl u di n g l ocal t olera bilit y 
 
C ha n ge i n cli nical safet y la b orat or y ( bl o o d bi oc he mistr y, hae mat ol o g y a n d uri nal ysis) 
para meters at M o nt h 3 a n d 6 
 
C ha n ge i n p h ysi cal e x a mi nati o n a n d vital si g ns ( bl o o d press ure a n d heart rate) 
meas ure me nts at eac h visit.  
3. 3  
E xte nsi o n P h ase Effic ac y a n d S afet y E n d p oi nts a n d E v al u ati o ns 
3. 3. 1  
E xte nsi o n P h as e Effic acy E n d p oi nts a n d Ev al u ati o ns 
 
Pr o p orti o n of c hil dre n wit h L H s u p pressi o n ( defi n e d as L H 
 I U/ L) at M o nt h 1 2.  

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 3 6/ 8 6 
 
 
C ha n ge i n b asal ser u m L H a n d F S H le v els at M o nt h 9 a n d M o nt h 1 2  
 
Pr o p orti o n of c hil dre n wit h pre- p u b ertal le v els of s e x ster oi ds ( defi ne d as oestra di ol 
 p g/ m L 
 n g/ m L i n b o ys) at M o nt h 9 a n d M o nt h 1 2  
 
C ha n ge i n oestra di ol l e vels i n girls a n d test oster o ne le v els i n b o ys at M o nt h 9 a n d 
M o nt h 1 2  
 
C ha n ge i n p u bertal sta ge usi n g t he Ta n ner met h o d ( ge nit al sta ge i n b o ys, breast sta ge i n 
girls a n d p u bic h air sta ge i n b ot h s e x es) at M o nt h 1 2  
 
Pr o p orti o n of c hil dre n wit h sta bilise d p u bertal st a ge c o m pare d t o baseli ne st a ge usi n g t he 
Ta n ner met h o d at M o nt h 1 2 
 
C ha n ge i n a u x ol o gical para meters i ncl u di n g hei g ht, gr o wt h vel ocit y, wei g ht a n d B MI at 
M o nt h 9 a n d M o nt h 1 2 
 
C ha n ge i n B A, differe nce bet wee n B A a n d C A at M o nt h 1 2 
 
C ha n ge i n ut eri ne le n gt h i n girls a n d t estic ular v ol u me i n b o ys at M o nt h 1 2 
3. 3. 2  
E xte nsi o n P h as e S afety E n d p oi nts a n d Ev al u ati o ns 
 
I n ci de nce of treat me nt-e mer ge nt a d verse e ve nts ( T E A Es) t hr o u g h o ut t he st u d y, 
i ncl u di n g l ocal t ol era bilit y 
 
C ha n ge i n cli nical safet y la b orat or y ( bl o o d bi oc he mistr y, hae mat ol o g y a n d uri nal ysis) 
para meters at M o nt hs 9 a n d 1 2 
 
C ha n ge i n p h ysi cal e x a mi nati o n a n d vital si g ns ( bl o o d press ure a n d heart rate) 
meas ure me nts at eac h visit. 
3. 4  
E x pl or at or y P h ar m ac o ki netics E n d p oi nt  
 
T o assess s pars e plas ma tri pt oreli n c o nce ntrati o ns at Da y 1, M o nt h 3 a n d M o nt h 6. 
3. 5  
R a n d o mis ati o n a n d Bli n di n g 
T his is a n o n-ra n d o mise d, o pe n-la bel st u d y.  
3. 6  
M ai nte n a nce of R a n d o mis ati o n a n d Bli n di n g 
N ot a p pli ca ble. 
3. 7  
St u d y Tre at me nts a n d D os a ge 
T he i n vesti gati o nal me dici nal pr o d uct is t he tri pt oreli n 3- m o nt h f or m ul ati o n, w hic h will be 
a d mi nistere d b y a n i. m. i njecti o n o n Da y 1 a n d M o nt h 3, f or a t otal of t w o i nj ecti o ns d uri n g t he 
st u d y. A m ore d etaile d d escri pti o n of a d mi nistrati o n pr oce d ures is gi v e n i n S ecti o n 6. 2. 1 . 
Tri pt oreli n is prese nte d i n a vial seale d wit h a n hal o ge n o b ut yl elast o mer st o p per a n d a n 
al u mi ni u m cri m p o n w hic h a p ol y pr o p yle ne b utt o n is att ac he d. T he st o p p ere d vial is cli p pe d o n 
a blister pac k, w hi c h is t he n i ntr o d uce d i n a cart o n b o x. 
A c o m plete cart o n b o x of t he dr u g pr o d uct c o ntai ns: 
 
O ne t y pe I cle ar glass 4 m L vial c o ntai ni n g t he st erile l y o p hilisate of micr o parti cles wit h 
a hal o ge n o b ut yl elast o m er st o p per a n d al u mi ni u m/ p ol y pr o p yle n e cri m p 
 
O ne glass 2 m L a m p o ule of 2 m L sterile s ol ve nt 
 
O ne sterile blister pac k 
T he vial a n d t he a m p o ul e are cli p pe d o n t he b ac k of t he blister w hi c h is i nserte d i n a pre pri nte d 
pa per b oar d cart o n b o x. T he sterile heat f or m e d blister pac k has o btai n e d t he C o nf or mité 
 
T he blist er pac k c o ntai ns: 
 
A h y p o d er mic s yri n ge 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 3 7/ 8 6 
 
 
T w o h y p o d er mic, si n gle- us e nee dl es: 
- 
O ne use d f or tra nsferri n g t h e s us pe nsi o n ve hi cle 
- 
O ne use d f or t he i. m. i nj ecti o n. 
be use d i n t he st u d y, m aterial data s af et y s heets ( M D S S) f or tri pt oreli n a n d a pac ka gi n g or d er 
t hat reflects t he pr o d uct rel ease stat e me nt. 
T he c ore la bel te xts f or all pac ka gi n g u nits will be writte n i n C hi nese a n d/ or a dj uste d t o be i n 
c o m plia nce wit h a p plic a ble re g ulat or y re q uire m e nts (e. g. G o o d Ma n ufact uri n g Practice ( G M P) 
g ui deli nes ( V ol u me 4 A n ne x 1 3)), nati o nal la ws i n f orce a n d i n acc or da nce wit h t he l ocal 
la n g u a ges. It will i ncl u de:  
 
 
 
 
 
Na me, a d dress a n d tele p h o ne n u m ber of t he S p o ns or 
 
St ora ge c o n diti o ns 
 
E x pir y d at e 
 
Treat me nt n u m ber 
 
Batc h n u m ber. 
T he I n vesti gat or or d esi g nee will o nl y dis pe nse tri pt oreli n t o st u d y p artici pa nts. T he dis pe nsi n g 
f or eac h partici p a nt will be d oc u me nte d i n t he ele ctr o nic cas e re p ort f or m (e C R F). 
At eac h tri pt oreli n dis p e nsati o n, a treat me nt n u m ber will be assi g n e d b y a n I nteracti ve W e b 
Res p o nse S yste m (I W R S). T he I W R S will als o ma na ge all l o gistical as pects of t h e st u d y 
treat me nt (e. g. re place me nt, dr u g s u p plies a n d e x pir y d at es) a n d t h e rec or di n g of dr u g 
acc o u nta bilit y/ d estr ucti o n. 
T his ser vice pr o vi des t he I n vesti gat or, i n vesti gati o nal site 
c o or di nat ors a n d pr oject 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 ma y be f o u n d i n t he I W R S refere nce ma n ual pr o vi de d t o eac h 
i n vesti gati o nal site. I n case of tec h nical or dis pe nsati o n q ueries, a 2 4- h o ur hel pli ne is a vail a ble 
(see s u p p orti n g i nf or mati o n i n t he I n vesti gati o nal Site Fil e). If a p artici p a nt dis c o nti n ues t he 
st u d y b ef ore a n y i nta ke of st u d y treat m e nt, his/ her assi g ne d tre at m e nt 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 mati o n pr o vi de d i n t he I W R S, dr u g acc o u nta bilit y p a per rec or ds will be 
mai ntai ne d b y t h e I n vesti gat or. 
3. 8  
St u d y D ur ati o n 
T his st u d y i ncl u des a Scree ni n g peri o d ( u p t o 2 8 d a ys pri or t o Da y 1) a n d a 6 M o nt h o pe n-la bel 
d osi n g peri o d wit h effica c y a n d safet y ass ess me nts occ urri n g at M o nt h 3 a n d/ or M o nt h 6 visits, 
as i n dicate d i n T a ble 1 . F or t his reas o n, t h e o verall d urati o n of t he m ai n st u d y is pla n ne d t o be 
a ma xi m u m of 7 m o nt hs. 
Eac h p artici pa nt is e x pecte d t o be e nr olle d i n t his st u d y f or a mi ni m u m of 6 m o nt hs a n d u p t o 
7 m o nt hs (i ncl u di n g Scree ni n g peri o d) f or t he m ai n st u d y. Partici pati o n i n t h e st u d y will be 
c o nsi dere d t o ha v e e n d e d at t he ti me of t he last visit ( E O S visit).  
T he st u d y will be c o nsi dere d t o ha ve start e d w he n t he first partici pa nt has pr o vi de d si g ne d 
i nf or me d c o ns e nt. T he e n d of t he mai n st u d y will be w h e n t he last partici pa nt has c o m pl ete d 
t he l ast f oll o w- u p visit i n t he st u d y ( M o nt h 6). 
Partici pa nts w h o c o m pl et e t he M o nt h 6 st u d y visit after c o nfir m ati o n of eli gi bilit y will be a ble 
t o j oi n a n e xte nsi o n st u d y t o recei v e tri pt oreli n f or at least a n a d diti o n al 6 m o nt hs, f or a t otal 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 3 8/ 8 6 
 
st u d y d urati o n of 1 2 m o nt hs ( 1 3 m o nt hs i ncl u di n g Scree ni n g Peri o d), or as j u d ge d cli nicall y 
be neficial b y t he i n v esti gat or.  
T he e n d of t he e xte nsi o n st u d y will be w he n t he last partici pa nt has c o m plete d t he last f oll o w- u p 
visit i n t he st u d y ( M o nt h 1 2). 
3. 9  
S o urce D at a Rec or d e d o n t he C ase Re p ort F o r m 
Data will be c ollecte d i n t he e C R F i n c o m pli a n ce wit h t h e F o o d a n d Dr u g A d mi nistrati o n 
( F D A) 2 1 C o de of Fe deral Re g ul ati o ns ( C F R) Part 1 1. As re q uire d b y G C P g ui deli nes, t he 
S p o ns or-assi g n e d m o nit or will verif y, b y direct refere nce t o t he s o urce d oc u me nts, t hat t he data 
re q uire d b y t he pr ot oc ol are acc uratel y rec or d e d o n t he e C R F.  
T he s o urce d oc u me nts m ust, as a mi ni m u m, c o ntai n a st ate me nt t hat t he parti ci pa nt is i n cl u de d 
i n a cli nical st u d y, t he date t hat i nf or me d c o nse nt was o btai ne d pri or t o partici pati o n i n t he 
st u d y, t he i de ntit y of t h e st u d y, t hat dia g n osis a n d eli gi bilit y criteria were met, visit dates, d at e 
a n d ti me of tri pt oreli n a d mi nistrati o n a n d a n y A Es a n d ass ociate d c o nc o mita nt m e dicati o n. 
As re q uire d b y t he I nter nati o nal C o u ncil f or Har m o nisati o n of Tec h nical Re q uire me nts f or 
P har mace uticals f or H u ma n Use (I C H)- E 6, Secti o n 6. 4. 9, if s o me ite ms are rec or de d dire ctl y 
i n t he e C R F a n d are c o nsi dere d s o urce dat a, t he i de ntificati o n of t hes e d ata m ust be d oc u m e nte d 
a n d a gree d u p o n bet wee n t he I n v esti gat or a n d t he S p o ns or. 
Defi niti o n f or s o urc e dat a a n d s o urce d oc u m e nts are gi ve n b el o w: 
 
S o urce d at a:  All ori gi n al rec or ds a n d certifie d c o pies of ori gi n al rec or ds of cli nical 
fi n di n gs, o bser v ati o ns, or ot h er acti vities necessar y f or t he rec o nstr ucti o n a n d e val uati o n 
of t he st u d y. S o urce data are c o ntai ne d i n s o urce d oc u m e nts ( ori gi nal rec or ds or certifie d 
c o pies). 
 
S o urce d oc u me nts:  Ori gi nal d oc u me nts, data a n d rec or ds (e. g. h os pital rec or ds, cli nical 
a n d office 
c hec klists, p har mac y dis pe nsi n g rec or ds, rec or de d data fr o m a ut o mat e d i nstr u me nts, 
c o pies or tra nscri pti o ns certifi e d after verificati o n as bei n g acc urat e c o pies, mi cr ofic hes, 
p h ot o gra p hic ne gati ves, mi cr ofil m or ma g netic me dia, X-ra ys, parti ci p a nt files a n d 
rec or ds ke pt at t he p har mac y, at t he la b orat ori es a n d at me dic otec h ni cal d e part me nts 
i n v ol ve d i n t he cli nical st u d y). 
T he partici pa nt m ust ha v e c o nse nte d t o t heir me dical rec or ds 
a ut h orise d pers o n n el a n d b y l ocal a n d p ossi bl y f orei g n, c o m pet e nt a ut h orities. T his i nf or mati o n 
is i ncl u de d i n t he i nf or m e d c o nse nt. 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 3 9/ 8 6 
 
4  
S E L E C TI O N A N D WI T H D R A W A L O F P A R TI CI P A N T S 
4. 1  
I ncl usi o n Criteri a 
Partici pa nts m ust f ulfil all t he f oll o wi n g criteria t o be i ncl u de d i n t he st u d y: 
( 1) 
Pr o visi o n of writte n i nf or me d c o nse nt pri or t o a n y st u d y-relate d pr oce d ures. C o nse nt 
s h o ul d be pr o vi de d b y t h e pare nt(s)/le g al g u ar di a n. If det er mi ne d b y l ocal re q uire m e nts, 
a si g ne d asse nt m ust be o bt ai ne d fr o m t he p ae diatric partici pa nt 
( 2) 
E vi de nce of C P P d oc u me nte d b y: 
- 
O ns et of de vel o p me nt of sec o n dar y se x c haracteristics ( breast de v el o p me nt i n girls 
or testic ular e nl ar ge me nt i n b o ys a cc or di n g t o t he Ta n ner met h o d: Sta ge II) bef ore 
t he a ge of 8 years i n girls a n d 9 years i n b o ys 
- 
P u bertal res p o nse of L H t o G n R H sti m ulati o n test (sti m ulate d pea k L H 
 I U/ L) 
i n b ot h se x es 
- 
Differe nce b et wee n B A a n d C A > 1 year 
- 
uteri ne le n gt h a n d se v eral f ollicles wit h dia meter > 4 m m i n t he o var y o bser ve d b y 
pel vic t y pe B ultras o u n d at t he Scree ni n g visit; b o ys w h o ha ve testi c ul ar v ol u m e 
 m L o bs er ve d b y testic ular t y pe B ultras o u n d at t he Scree ni n g visit 
( 3) 
A ge less t ha n 9 years ol d f or girls a n d less t ha n 1 0 years ol d f or b o ys at i nitiati o n of 
tri pt oreli n treat me nt 
( 4) 
Wei g ht at least 2 0 k g 
( 5) 
Girls w h o h a ve alrea d y h a d me n o p ha nia/ m e narc h e m ust ha ve a ne gati ve pre g na nc y test 
pri or t o t he start of st u d y treat me nt a n d s h o ul d n ot be at ris k of pre g na nc y t hr o u g h o ut t he 
st u d y peri o d. 
4. 2  
E xcl usi o n Criteri a 
Partici pa nts will be i neli gi ble f or st u d y p artici pati o n if t he y meet a n y of t h e f oll o wi n g criteria:  
( 1) 
G o na d otr o pi n-i n de pe n d e nt ( peri p heral) prec oci o us p u bert y: e xtra pit uit ar y secreti o n of 
g o na d otr o pi ns or g o na d otr o pi n-i n de pe n de nt g o n a dal or a dre nal s e x ster oi d secreti o n 
( 2) 
N o n- pr o gressi n g is olate d pre mat ure t h el arc he 
( 3) 
Prese nce of a n u nst a ble i ntracr a nial t u m o ur or a n i ntracra ni al t u m o ur re q uiri n g 
ne ur os ur ger y or cere bral irra diati o n. P artici pa nts wit h ha mart o mas n ot re q uiri n g s ur ger y 
are eli gi bl e 
( 4) 
E vi de nce of re nal (creati ni ne > 1. 5 x u p per li mit of n or mal ( U L N)) or he p ati c i m pair m e nt 
( bilir u bi n > 1. 5 x U L N or ala ni ne a mi n otra nsferase ( A L T)/as partate tra ns a mi nas e 
( A S T) > 3 x U L N) 
( 5) 
A n y ot her c o n diti o n or c hr o nic ill ness or treat me nt p ossi bl y i nt erferi n g wit h gr o wt h or 
ot her st u d y e n d p oi nts (e. g. c hr o nic st er oi d use e x ce pt t o pical ster oi ds, re nal fail ure, 
dia betes, m o derate t o se v ere s c oli osis) 
( 6) 
Pri or or c urre nt t hera p y wit h a G n R H a g o nist ( G n R Ha), me dr o x y pr o gester o ne ac et ate, 
gr o wt h h or m o ne or i ns uli n-li ke gr o wt h fact or- 1 (I G F- 1) 
( 7) 
Dia g n osis of s h ort st at ure, i.e. > 2. 2 5 S D bel o w t h e mea n hei g ht f or a ge 
( 8) 
Maj or me dical or ps yc hiatric ill n ess t hat c o ul d i nterfere wit h st u d y visits 
( 9) 
K n o w n h y p erse nsiti vit y t o a n y of t he test materi als or relate d c o m p o u n ds  
( 1 0) Use of a ntic oa g ula nts ( h e pari n a n d c o u mari n deri v ati ves) wit hi n t he 2 wee ks pri or t o t he 
Scree ni n g visit. 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 4 0/ 8 6 
 
4. 3  
E xte nsi o n p h ase I ncl usi o n Criteri a 
( 1 1) S u bjects will q ualif y f or t h e e xte nsi o n p hase if t he y si g n t he c orres p o n di n g s pecific 
c o nse nt f or m, are still be nefiti n g fr o m treat m e nt at t h e e n d t he pri mar y st u d y a n d h a ve 
n ot e x perie nce d a n y u nacce pta ble safet y iss ues. 
4. 4  
St o p pi n g R ules, Disc o nti n u ati o n a n d Wit h d r a w al Criteri a a n d P r oce d ures 
T here are n o f or mal r ul es f or earl y ter mi nati o n of t his st u d y. D uri n g t he c o n d uct of t he st u d y, 
seri o us a d vers e e v e nts ( S A Es) will be re vie we d (s ee Secti o n 8. 1. 5 ) as t he y are re p orte d fr o m 
t he st u d y ce ntres t o i de ntif y safet y c o ncer ns. A s pecific cli nic al sit e or a gi ve n c o h ort ca n be 
disc o nti n ue d or t he e ntire st u d y m a y b e t er mi nate d at a n y ti me if t he S p o ns or j u d ges it necessar y 
f or a n y reas o n. I n s uc h case, all sc h e d ule d pr o ce d ures a n d assess me nts f or p artici pa nts w h o are 
still i n t he st u d y will be perf or me d. S o me p ossi bl e reas o ns f or t h e cl os ure of a st u d y sit e ma y 
i ncl u de: 
 
Fail ure of t he I n vesti gat or staff t o c o m pl y wit h t he pr ot oc ol or wit h t he G C P g ui deli nes 
 
Safet y c o n cer ns 
 
I n a de q uat e partici pa nt recr uit me nt. 
I n case of pre mat ure dis c o nti n uati o n of a cli nical sit e or t he c o m plete st u d y, d e pe n di n g o n t he 
reas o n(s) f or t he disc o nti n uati o n, t he S p o ns or will i nf or m t he I n v esti gat or(s) affecte d i n writi n g 
as t o 
w het her t he o n g oi n g partici p a nts s h o ul d recei v e t h e re m ai ni n g tri pt oreli n d ose 
a d mi nistrati o n(s). 
A p artici pa nt or t he p are nt(s)/le gal g uar di a n of t he partici pa nt m a y pre mat urel y disc o nti n ue 
partici pati o n i n t he st u d y at a n y ti me a n d f or a n y reas o n, i ncl u di n g: 
 
Dr u g-relate d A E 
 
N o n- dr u g relate d A E 
 
N o n- dr u g relate d reas o n, e. g. p artici pa nt rel o cat es 
 
Lac k of efficac y 
 
 
T he I n vesti gat or a n d/ or S p o ns or ca n wit h dra w a partici pa nt fr o m t he st u d y at a n y ti me f or a n y 
reas o n (e. g. pr ot oc ol vi olati o n or de viati o n as defi ne d i n Secti o n 1 3. 1. 2 , n o n-c o m plia nce wit h 
t he pr ot oc ol c o n diti o ns, A Es, partici pa nt d oes n ot rec ei ve a n y of t he tri pt oreli n i njecti o ns 
pla n ne d i n t he pr ot oc ol, partici pa nt l ost t o f oll o w- u p). All cases of disc o nti n uati o n will be 
disc usse d bet wee n t he I n vesti gat or a n d t h e S p o ns or.  
If a partici p a nt deci des t o wit h dra w fr o m t he st u d y after a d mi nistrati o n of tri pt oreli n, or s h o ul d 
t he I n v esti gat or deci de t o wit h dra w t he partici pa nt, all eff orts will be ma de t o c o m plete a n d 
re p ort t he o bs er vati o ns u p t o t he ti m e of wit h dra wal as t h or o u g hl y as p ossi ble. A c o m plet e fi nal 
 (see Secti o n 5. 2. 3  a n d 
Ta ble 1 , f or partici pa nts e ntere d i n t he e xte nsi o n p hase s h o ul d refer t o Ta ble 2 ) a n d a n 
e x pla nati o n gi ve n as t o w h y t he partici pa nt is wit h dra wi n g or bei n g wit h dra w n fr o m t he st u d y.  
T he r eas o n f or wit h dra wal a n d d ate of wit h dra wal fr o m t h e st u d y m ust be rec or de d o n t he 
e C R F. If a partici pa nt wit h dra ws c o nse nt, e v er y atte m pt will be ma de t o d eter mi ne t he reas o n. 
If t he reas o n f or wit h dra wal is a n A E or a cli nicall y si g nifi ca nt la b orat or y test a b n or malit y, 
m o nit ori n g will c o nti n ue u ntil t he e v e nt has res ol ve d or sta bilise d, u ntil t he parti ci pa nt is 
referre d t o t he care of a l ocal healt h care pr ofessi o nal, or u ntil a deter mi nati o n of a ca use 
u nrelat e d t o tri pt oreli n or st u d y pr oce d ure is ma d e. T he s p ecific A E or test res ult(s) m ust be 
rec or d e d o n t he e C R F. All e val uati o ns s h o ul d be perf or me d, acc or di n g t o t he pr ot oc ol, at t he 
E O S visit. If t he E O S visit is c o n d uct e d o utsi de t he wi n d o w aft er t h e fi nal tri pt oreli n d ose 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 4 1/ 8 6 
 
(Ta ble 1 , refer t o T a ble 2  f or t he e xte nsi o n p hase), all safet y e val u ati o ns will be perf or me d b ut 
efficac y e v al uati o ns will n ot be ma de. 
4. 5  
Te m p or a r y Disc o nti n u ati o n 
I n case of s us pecte 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, t he i nter ve nti o n 
prese ntati o n. I n s o me cases, t he i n vesti gat or ma y re q uest a partici pa nt be retest e d bef ore t he 
i nter ve nti o n a d mi nistrati o n is res u me d. 
4. 6  
L ost t o F oll o w- u p 
A partici pa nt will b e 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 bl e t o be c o ntacte 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 parti ci p a nt o n t he i m p ort a nce of mai ntai ni n g t he 
assi g ne d visit s c h e d ule a n d ascertai n w het her t h e partici pa nt wis h es 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 s u bject ( w here p ossi ble, t hree tele p h o ne calls a n d, 
e q ui val e nt met h o ds). T hese c o nt act atte m pts s h o ul d be d oc u me n
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 h a 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.  
4. 7  
Scree n F ail ures 
A scree n fail ure o cc urs w he n a partici p a nt w h o c o nse nts t o partici pate i n t he cli nical st u d y is 
n ot s u bse q ue ntl y e nt ere d i n t he st u d y. A mi ni mal s et of s cree 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 S A E. 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 4 3/ 8 6 
 
d 
P K S a m ples  o n Da y 1 t o be ta ke n pre d ose a n d at 4 h o urs p ost-i njecti o n ( ± 2- h o ur wi n d o w); P K sa m ple at M o nt h 3 visit 
t o b e ta ke n pre d ose; P K sa m ple at t he M o nt h 6 E O S/ earl y wit h dra wal visit.  
e 
B as al L H a n d F S H  sa m ples t o be dra w n bef ore G n R H test. Bl o o d s a m pli n g s h o ul d b e ta ke n at a p pr o xi mat el y t h e sa me 
ti me of d a y d uri n g eac h visit. 
f 
G n R H test  sa m ples f or L H a n d F S H c o nce ntrati o ns will be c ollecte d at 3 0, 6 0 a n d 9 0 mi n utes ( ± 5 mi n utes at eac h 
ti me p oi nt) after t h e G n R H test. T h e L H a n d F S H sa m ples will all be ta ke n b ef ore i nj ecti o n of tri pt oreli n, if a p pli ca ble 
(e. g. M o nt h 3 visit). 
g 
Oestr a di ol a n d Test oster o ne  sa m ples f or girls a n d b o ys, res p ecti vel y. 
h 
T a n ner p u bert al st a g e  as d efi n e d i n A p pe n di x  1 . 
i 
A u x ol o gic al p ar a meters  i ncl u di n g hei g ht, gr o wt h vel o cit y, wei g ht, B MI will be assesse d. 
j 
B o ne A g e  b y Gre ulic h a n d P yl e met h o d.  
k 
G o n a d de vel o p me nt  uteri ne le n gt h i n girls or testic ul ar v ol u me i n b o ys assess e d b y t y p e B ultras o u n d. 
l 
B o d y w ei g ht  
g o n i n cl usi o n i n t h e st u d y. 
m 
A d v ers e e ve nts  will be c oll ecte d u p t o a n d i ncl u di n g t h e M o nt h 6 visit (i. e. Da y 1 8 2 ± 3 d a ys)   
n 
Pre g n a nc y test  f or fe male partici p a nts o nl y. Girls w h o ha ve e ntere d me narc he m ust h a ve a ne gati v e pre g n a nc y test pri or 
t o t h e st art of st u d y treat me nt a n d s h o ul d n ot b e at ris k of pre g n a nc y t hr o u g h o ut t he st u d y peri o d. L ocal uri ne testi n g will 
b e sta n d ar d f or t h e pr ot o c ol u nless ser u m testi n g is re q uire d b y l o cal re g ulati o n or I R B/I E C b ef ore dr u g treat me nt f or all 
fe male partici p a nts of c hil d b eari n g p ote ntial a n d if cli nicall y i n dicate d t hereafter. 
o 
Cli nic al l a b or at or y  tests i n cl u di n g c he mistr y, h ae mat ol o g y a n d uri nal ysis. I n case of a b n or mal bl o o d gl uc os e as p er 
 b ef ore t h e first i njecti o n. 
p 
P h ysic al e x a mi n ati o n a n d vit al si g ns  bl o o d press ure a n d heart rate.  
q 
Pri or a n d c o nc o mit a nt me dic ati o ns  assesse d at e ver y visit 
r 
St u d y dr u g a d mi nistr ati o n  f oll o wi n g all ot h er assess me nts, a p art fr o m P K sa m ples o n Da y 1. 
s 
L oc al t oler a bilit y  
Meas ure d b y te n der n ess, re d n ess, br uisi n g, er yt h e ma, s welli n g, ras h, pai n, itc hi n g, i n d urati o n, 
h ae mat o ma, ulc erati o n or necr osis. T o b e assesse d at i njecti o n a n d 2 h o urs p ost i njecti o n.  
t 
E O S/ E arl y Wit h dr a w al  F or partici p a nts w h o d o n ot h a ve a fi nal visit wit hi n 3 m o nt hs (i.e. u p t o Da y 1 8 2 ± 3 da ys) after 
t heir last tri pt oreli n d ose, efficac y e val uati o ns (i ncl u di n g P K sa m pli n g) will n ot be perf or me d. Dat a fr o m a n y effi cac y 
e val u ati o ns p erf or me d after t his ti me will n ot be c ollect e d o n t h e e C R F.  
 
E xte nsi o n p h ase 
T he s c he d ule of pr o ce d ures a n d ass ess me nts t o b e perf or me d d uri n g t h e e xt e nsi o n st u d y is 
s u m marise d i n Ta ble 2 .  
 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 4 5/ 8 6 
 
mai ntai n a list of partici pa nt n u m bers a n d na mes t o e na ble rec or ds t o be f o u n d at a later dat e if 
re q uire d. E ac h I n vesti gat or will als o mai ntai n a rec or d of all partici pa nts scree ne d i n t he st u d y 
(i.e. w h o si g n e d t he i nf or me d c o nse nt f or m).  
U n der n o circ u mst a nces will partici pa nts b e scree ne d m ore t ha n o nce.  
F oll o wi n g c o nfir mati o n of eli gi bilit y f or t he st u d y, partici pa nts will be gi ve n a treat me nt 
n u m ber. 
i ncl usi o n a n d e x cl usi o n criteria prese nte d i n Se cti o n 4. 1  a n d Se cti o n 4. 2 , res pecti vel y) a n d t he 
assess me nts descri b e d i n Ta ble 1  will be perf or m e d. 
5. 2. 2  
Pr oce d ures D uri n g t he Tre at me nt P h ase of St u dy ( D ay 1 a n d M o nt h 3) 
I n cl usi o n a n d E x cl usi o n criteria prese nte d i n Secti o n 4. 1  a n d 4. 2 , res pecti v el y) b ef ore t he ot her 
assess me nts liste d i n Ta ble 1 .  
Partici pa nts will be a d mitte d at t he cli nical sit e o n t he m or ni n g of Da y 1 a n d t he M o nt h 3 visit 
a n d t he assess me nts d es cri be d i n Ta ble 1  will be perf or me d. St u d y dr u g a d mi nistrati o n will 
f oll o w after t he ot h er ass ess m e nts, a part fr o m a n y p ost- d os e P K sa m ples a n d l ocal t olera bilit y. 
5. 2. 3  
Pr oce d ures F oll o wi n g St u dy Tre at m e nt ( M o nt h 6, E n d of M ai n St u dy or E arly 
Wit h dr a w al Visit) 
Partici pa nts w h o c o m pl ete t he mai n st u d y will perf or m fi nal pr oce d ures a n d assess me nts at t he 
fi nal visit ( M o nt h 6). Partici pa nts w h o wit h dra w fr o m t he st u d y bef ore t he c o m pleti o n of t he 
e val uati o n peri o d will be i n vite d t o atte n d a n E arl y 
Wit h dra wal visit t o perf or m earl y 
disc o nti n uati o n pr oce d ures a n d ass ess me nts (as i n Ta ble 1 ). 
F or partici pa nts w h o d o n ot ha ve a fi nal visit wit hi n 3 m o nt hs (i.e. u p t o Da y 1 8 2 ± 3 da ys as i n 
Ta ble 1 ) aft er t heir l ast tri pt oreli n d ose, effi cac y e val uati o ns s h o ul d n ot b e perf or me d. Data 
fr o m a n y effi cac y e v al uati o ns perf or me d aft er t his ti me will n ot be c oll ecte d o n t he e C R F.  
Partici pa nts wit h o n g oi n g A Es or cli nicall y si g nifica nt la b orat or y test a b n or maliti es (as 
deter mi ne d b y t he I n v esti gat or) 
will be 
m o nit ore d as descri be d i n Secti o n 8. 1. 4  a n d 
Secti o n 8. 1. 2. 4 , res pe cti v el y. T h e A Es will be c oll ecte d u p t o 3 m o nt hs after t he date of t he last 
i njecti o n. 
5. 2. 4  
Pr oce d ures D uri n g t he E xt e nsi o n P h as e ( M o nt h 6, M o nt h 9 a n d E n d of E xte nsi o n 
P h ase Visit) 
At t he e n d of t he mai n st u d y, partici pa nts w h o are still be nefiti n g fr o m treat me nt (i. e. n ot 
pr o gressi n g) a n d w h o ha ve n ot e x perie nce d a n y u nacce pta bl e safet y iss ues, will ha ve t he o pti o n 
t o c o nti n ue t o recei v e tri pt oreli n e ver y 3 m o nt hs i n t he 6- m o nt h e xt e nsi o n p has e. 
visit ( M o nt h 6) ( base d o n t he I ncl usi o n criteria prese nte d i n Secti o n 4. 3 , res pecti vel y). T h e 
E xte nsi o n P hase Da y 1 visit will c orres p o n d t o t he E n d of mai n St u d y Visit.  
Partici pa nts will be a d mitte d at t he cli nical site o n t he m or ni n g of M o nt h 6, M o nt h 9 a n d 
M o nt h 1 2 visit a n d t he assess me nts des cri be d i n 
Ta ble 2  will be perf or me d. St u d y dr u g 
a d mi nistrati o n will f oll o w after t he ot her assess m e nts o n t he M o nt h 6 a n d M o nt h 9 visits, a part 
fr o m a n y p ost- d os e P K sa m ples a n d l ocal t olera bilit y. 
F or partici pa nts w h o d o n ot ha ve a fi nal visit wit hi n 3 m o nt hs (i.e. u p t o Da y 3 6 5 ± 3 da ys as i n 
Ta ble 2 ) aft er t heir l ast tri pt oreli n d ose, effi cac y e val uati o ns s h o ul d n ot b e perf or m e d. Dat a 
fr o m a n y effi cac y e v al uati o ns perf or me d aft er t his ti me will n ot be c oll ecte d o n t he e C R F.  

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 4 6/ 8 6 
 
5. 3  
L a b or at or y Assess me nts 
All efficac y para meters list e d bel o w (i.e. L H, F S H, test oster o ne a n d oestra di ol), a n d sa m ples 
f or tri pt oreli n P K, will be a n al ys e d ce ntrall y. T he pre parati o n a n d st ora ge of sa m ples are 
descri be d se paratel y i n t he La b orat or y Ma n ual. La b orat or y s afet y tests will be c o n d ucte d 
l ocall y. 
At Da y 
ti o n of 
t his test will be perf or me d bef ore t h e first tri pt oreli n i njecti o n.  
T he f oll o wi n g la b or at or y para meters will be a n al yse d fr o m sa m ples c ollecte d at ti me p oi nts 
descri be d i n Ta bl e 1 : 
( 1) 
L H a n d F S H c o nce ntrati o ns at bas eli ne a n d aft er G n R H sti m ul ati o n (t his a nal ysis will be 
c o n d ucte d as d es cri be d i n t he La b orat or y M a n ual); 
( 2) 
Oestra di ol a n d test oster o ne le v els; 
( 3) 
Pre g n a nc y test ( o nl y i n fe mal e p arti ci p a nts wit h c hil d beari n g p ot e ntial), Secti o n 8. 1. 6 ; 
( 4) 
Hae mat ol o g y (c o m plet e bl o o d c o u nt ( C B C)), S ecti o n 8. 2. 1 ; 
( 5) 
Bl o o d c he mistr y s uc h as creati ni ne a n d gl uc ose, Secti o n 8. 2. 2 ; 
( 6) 
Li ver f u ncti o n t ests, i ncl u di n g A L T, A S T, al kali ne p h os p hatase ( A L P) a n d bilir u bi n, 
Secti o n 8. 2. 2 ; 
( 7) 
Uri nal ysis ( p H, pr otei n, k et o nes, bilir u bi n, bl o o d, ur o bili n o ge n, nitrit es, le u k oc yt es, 
gl uc os e a n d s pecific gra vit y b y di pstic k), S ecti o n 8. 2. 3 ; 
( 8) 
P har mac o ki netic c o n ce ntrati o ns, Secti o n 9. 1 . 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 4 7/ 8 6 
 
6  
T R E A T M E N T O F P A R TI CI P A N T S 
6. 1  
I n vesti g ati o n al 
Me dici n al 
Pr o d uct 
Pre p ar ati o n, 
St or a ge, 
Sec urit y 
a n d 
Acc o u nt a bilit y 
6. 1. 1  
I nvesti g ati o n al Me dici n al Pr o d uct St or a ge a n d Sec urity 
T he I n vesti gat or or a n a p pr o ve d re prese ntati ve (e. g. p har m acist) will e ns ure t hat all tri pt oreli n 
a n d a n y ot her st u d y-rel ate d m aterial are st ore d i n a sec ure d area, u n der rec o m me n de d 
te m perat ure- m o nit ore d st ora ge c o n diti o ns, i n acc or d a nce 
wit h a p plica ble re g ul at or y 
re q uire m e nts. 
Tri pt oreli n m ust be st ore d i n t he o uter cart o n at a te m perat ure bel o w 2 5° C, pr otecte d fr o m 
freezi n g. 
At t he cli nical site(s), tri pt oreli n m ust o nl y be dis pe nse d b y t he I n v esti gat or or b y a me m ber of 
staff s pecificall y a ut h orise d b y t he I n vesti gat or a n d trai ne d f or tri pt oreli n rec o nstit uti o n a n d 
a d mi nistrati o n. 
Batc h a n d kit n u m ber of eac h a d mi nistere d tri pt oreli n kit will be rec or de d i n t he e C R F. 
6. 1. 2  
I nvesti g ati o n al Me dici n al Pr o d uct Pre p ar ati o n 
T he I n v esti gat or or a n a p pr o ve d re prese ntati ve (e. g. p har m acist) will e ns ure t hat tri pt oreli n is 
rec o nstit ute d a n d dis pe nse d b y a me m b er of staff s pecificall y a ut h orise d b y t he I n v esti gat or a n d 
trai ne d f or tri pt oreli n rec o nstit uti o n a n d a d mi nistrati o n. 
T he s us pe nsi o n f or i njecti o n m ust be rec o nstit ute d usi n g a n as e pti c tec h ni q ue a n d usi n g t he 
a m p o ule of s ol ve nt s u p plie d f or i njecti o n. 
T he i nstr ucti o ns f or rec o nstit uti o n hereafter a n d i n t he I M P Ha n dli n g M a n ual m ust be strictl y 
f oll o we d. 
T he s ol ve nt s h o ul d be dra w n i nt o t he s yri n ge pr o vi de d usi n g t he rec o nstit uti o n nee dle ( 2 0 G, 
wit h o ut safet y d e vice) a n d tra nsferre d t o t he vi al c o nt ai ni n g t he p o w der. T h e s us pe nsi o n s h o ul d 
be rec o nstit ute d b y s wirli n g t he vial i n a ge ntl e circ ular m oti o n u ntil a h o m o ge n e o us, mil k y 
s us pe nsi o n is f or me d. D o n ot i n vert t he vial. 
It is i m p orta nt t o c hec k t here is n o u ns us pe n de d p o w der i n t he vi al. T h e s us pe nsi o n o btai ne d 
s h o ul d t he n be dra w n bac k i nt o t he s yri n ge, wit h o ut i n verti n g t he vial. T h e rec o nstit uti o n nee dle 
s h o ul d t he n be c ha n ge d a n d t he i njecti o n ne e dle ( 2 0 G, wit h s afet y d e vice) us e d t o a d mi nister 
t he pr o d uct. 
As t he pr o d uct is a s us pe nsi o n, t he i njecti o n s h o ul d be a d mi nist ere d f or a si n gle use 
i m me di atel y aft er rec o nstit uti o n t o pre ve nt preci pitati o n. 
6. 1. 3  
I nvesti g ati o n al Me dici n al Pr o d uct Acc o u nt a bility 
Tri pt oreli n s u p plies a n d a n y ot h er st u d y-relate d materi al are t o be acc o u nt e d f or o n t he 
tri pt oreli n acc o u nta bilit y l o g pr o vi de d b y t he S p o ns or. It is ess e ntial t hat all use d a n d u n use d 
I n v esti gat or s h o ul d e ns ure a de q uat e rec or ds ar e mai ntai ne d i n t he tri pt oreli n acc o u nta bilit y l o g. 
U n us e d tri pt oreli n or st u d y-relate d mat erial m ust n ot be discar de d or use d f or a n y p ur p ose ot her 
t ha n t he prese nt st u d y. T hr o u g h o ut t he st u d y, t he 
m o nit or will c oll ect t he tri pt oreli n 
acc o u nta bilit y f or ms al o n g wit h a n y u n us e d tri pt oreli n s u p plies a n d e m pt y vi als, i n t heir ori gi nal 
pac ks. 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 4 9/ 8 6 
 
T he f oll o wi n g c o nc o mita nt m e dicati o ns/ pr o ce d ures are n ot per mitte d d uri n g t his st u d y: 
 
A n y treat me nt or pr oce d ur e wit h a defi niti ve or p ote ntial effect o n t he meta b olis m or 
secreti o n of g o na d otr o pi ns ( L H or F S H) or se x ster oi ds ( oestra di ol a n d/ or test oster o ne) 
will be c o nsi dere d as a pr ot oc ol vi olati o n;  
 
All dr u gs me nti o ne d as pr o hi bit e d i n t he e x cl usi o n crit eri a re m ai n pr o hi bite d d uri n g t he 
st u d y 
p eri o d: 
G n R H 
a nal o g ues ( ot h er t h a n tri pt oreli n 
3- m o nt h f or m ul ati o n), 
me dr o x y pr o gester o ne acetate, gr o wt h h or m o ne or I G F- 1, s yste mic or i n h ale d ster oi ds 
( mil d t o pical ster oi ds are per mitt e d), a nti c o a g ula nts ( he pari n a n d c o u mari ne deri vati ves). 
 
A n y c o nc urre nt i n vesti gati o nal a ge nt or pr oce d ure. 
6. 4  
Lifest yle Restricti o ns/ Rec o m me n d ati o ns 
I n a d diti o n t o t he r estricti o ns alre a d y prese nte d i n t he e xcl usi o n criteri a (s ee Secti o n 4. 2 ), fr o m 
4 8 h o urs pri or t o Da y 1 a n d u ntil t he E O S visit partici pa nts will als o be r e q u est e d t o a v oi d t he 
f oll o wi n g: 
 
Stre n u o us p h ysic al acti vit y; 
 
P o p p y-s ee d c o ns u m pti o n. 
6. 5  
Pr o ce d ures f o r M o nit ori n g P artici p a nt C o m pli a nce 
T he I n vesti gat or will be res p o nsi ble f or m o nit ori n g partici pa nt c o m plia nce. Partici pa nts ma y 
be wit h dra w n fr o m t he st u d y at a n y ti me if t he I n v esti gat or or t he S p o ns or deter mi nes t hat t he 
partici pa nt is n ot i n c o m pli a nce wit h t he st u d y pr ot oc ol (see Secti o n 4. 4  f or details). 
W he n partici pa nts are d ose d at t he site, t he y will recei ve tri pt oreli n directl y fr o m t he 
i n vesti gat or or desi g nee, u n der 
me dical s u per visi o n. T he date a n d ti me of eac h d ose 
a d mi nistere d i n t he site will be rec or de d i n t he s o urce d oc u me nts a n d i n t he C R F. T he d ose of 
tri pt oreli n a n d st u d y parti ci 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 
me m ber of t he st u d y sit e staff ot her t ha n t h e pers o n a d mi nisteri n g t he i njecti o n. 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 5 2/ 8 6 
 
M e as ure 
Ti me p oi nt 
V a ri a ble 
E n d p oi nt 
Uteri ne le n gt h or testis 
v ol u me 
B aseli ne, M o nt h 1 2 
( E O E P) 
G o na d d e vel o p me nt 
C ha n ge i n uteri ne le n gt h i n girls 
a n d testic ular v ol u me i n b o ys 
c o m p are d t o baseli ne  
B A = B o ne a ge; B MI = B o d y mass i n d e x; C A = C hr o n ol o gical a ge; E O E P = E n d of E xte nsi o n P h ase; F S H = F ollicle-
sti m ulati n g h or m o n e; G n R H = G o n a d otr o pi n-releasi n g h or m o ne; L H = L utei nisi n g h or m o ne; E 2 = Oestra di ol. 
 
7. 4  
Met h o ds a n d Ti mi n g of Assessi n g, Rec or di n g a n d A n al ysi n g Effic ac y D at a 
La b orat or y tests f or effic ac y will be perf or me d ce ntrall y. T he la b orat or y met h o ds f or assessi n g 
efficac y data are liste d i n Secti o n 5. 3.  T he ti mi n g of effic ac y ass ess m e nts is s u m marise d i n 
Ta ble 1 . Pr o ce d ures f or rec or di n g efficac y data are disc usse d i n S ecti o n 1 5. 1  a n d met h o ds of 
a nal ys es are disc usse d i n Secti o n 1 1. 4. 4 .  
7. 4. 1  
C h a n ge i n L utei nisi n g 
H or m o ne a n d F ollicle-sti m ul ati n g 
H or m o ne S er u m 
C o nce ntr ati o ns 
T hese para meters will be a nal ys e d ce ntrall y, as i n dicate d i n Secti o n 5. 3 . T he pre parati o n a n d 
st ora ge of s a m pl es are d escri be d s e paratel y i n t he La b orat or y M a n ual. 
7. 4. 2  
G o n a d otr o pi n-rele asi n g H or m o ne Sti m ul ati o n Test 
G o na d oreli n, a s y nt hetic G n R H ( ma n ufact urer t o be defi ne d), will be us e d f or g o na d otr o p hi n 
sti m ul ati o n. G o n a d oreli n use d f or G n R H sti m ul ati o n test will be pre pare d b y t he i n v esti gat or 
sites. 
Bl o o d sa m ples will be c ollecte d pri or t o g o na d oreli n i njecti o n (ti me p oi nt T 0) a n d at 3 0 mi n utes 
( T 3 0), 6 0 mi n utes ( T 6 0) a n d 9 0 mi n utes ( T 9 0) ( ± 5 mi n utes at eac h ti me p oi nt) after a si n gle i. v. 
i njecti o n of g o n a d oreli n wit h 2. 5 
 
 
 I U/ L a m o n g t he 
f o ur ti me p oi nts ( T 0, T 3 0, T 6 0 a n d T 9 0). 
T he F S H res p o ns e t o G n R H sti m ulati o n will be t he pea k F S H le v el a m o n g t he f o ur ti me p oi nts 
( T 0, T 3 0, T 6 0 a n d T 9 0).
7. 4. 3  
C h a n ge i n Se x Ster oi ds ( Oestr a di ol a n d Test oster o ne S er u m C o nce ntr ati o ns) 
T hese para meters will be a nal ys e d ce ntrall y, as i n dicate d i n S ecti o n 5. 3 . T he pre parati o n a n d 
st ora ge of s a m pl es are d escri be d s e paratel y i n t he La b orat or y M a n ual. 
7. 4. 4  
C h a n ge i n P u b ert al St a ge Usi n g t he T a n ner Met h o d 
See P u bertal Sta ges Acc or di n g t o t he Ta n ner Met h o d ( A p pe n di x 1 ) f or details. 
7. 4. 5  
A u x ol o gic al P ar a m eters, B o ne A ge a n d C hr o n ol o gi c al A ge Me as ure me nts a n d 
G o n a d Devel o p m e nt 
B o ne a ge d eter mi nati o n (i n years a n d m o nt hs) will be perf or me d b y X-ra ys of t he ha n d a n d 
wrist a n d esti mate d b y t he Gre uli c h a n d P yle m et h o d [ Gre ulic h 1 9 5 9 ].  
G o na d de vel o p me nt ( ut eri ne l e n gt h or t estis v ol u me) will be deter mi ne d b y t y pe B ultras o u n d. 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 5 3/ 8 6 
 
8  
A S S E S S M E N T O F S A F E T Y 
8. 1  
A d verse E ve nts 
All A Es will be m o nit ore d fr o m t he ti me t he partici pa nt gi ves i nf or m e d c o nse nt u ntil t he E O S 
visit, or E O E P visit f or t h ose e nr olle d i n t he e xte nsi o n p hase, (see Secti o n 3. 8  f or defi niti o n of 
t he st u d y d urati o n) a n d will be elicite d b y direct, n o n-lea di n g q uesti o ni n g. F urt her details a b o ut 
A E re p orti n g c a n be f o u n d i n Secti o n 8. 1. 2 . 
8. 1. 1  
Defi niti o n of a n A dverse Eve nt 
T hese defi niti o ns i ncl u de e ve nts occ urri n g fr o m t he ti me t he partici p a nt gi ves i nf or m e d c o nse nt 
u ntil t he e n d of t he st u d y (as defi ne d i n S ecti o n 3. 8 ). 
A E Defi niti o n:  
 
A n A E is a n y u nt o war d me dical occ urre nce i n a cli nical st u d y partici p a nt, te m p orall y 
ass oci ate d wit h t he use of st u d y i nt er v e nti o n, w het her or n ot c o nsi dere d relate d t o t he 
st u d y i nter ve nti o n. 
 
N O T E: A n A E ca n t heref ore b e a n y u nfa v o ura ble a n d u ni nt e n de d si g n (i ncl u di n g a n 
a b n or mal la b orat or y fi n di n g), s y m pt o m, or dis e ase ( ne w or e x acer bate d) te m p orall y 
ass ociate d wit h t he use of st u d y i nter v e nti o n. 
E ve nts Meeti n g t he A E Defi niti o n: 
 
A n y a b n or mal l a b orat or y test res ults ( hae mat ol o g y, cli nical c h e mistr y, or uri nal ysis) or 
ot her safet y ass ess m e nts (e. g. E C G, ra di ol o gi cal sca ns, vital si g ns meas ure me nts), 
i ncl u di n g t h os e t hat w orse n fr o m bas eli ne, c o nsi dere d cli nicall y si g nifi ca nt i n t he 
me dical a n d s cie ntific j u d g me nt of t he i n vesti gat or (i.e. n ot relate d t o pr o gressi o n of 
u n derl yi n g dise ase). 
 
E x acer bati o n of a c hr o nic or i nter mitte nt pre-e xisti n g c o n diti o n i ncl u di n g eit her a n 
i ncrease i n fre q u e nc y a n d/ or i nte nsit y of t he c o n diti o n. 
 
Ne w c o n diti o n detect e d or dia g n os e d aft er st u d y i nter ve nti o n a d mi nistrati o n e ve n t h o u g h 
it ma y ha v e bee n prese nt bef ore t h e start of t he st u d y. 
 
Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d i nter ve nti o n- i nt er ve nti o n 
i nteracti o n. 
 
Si g ns, s y m pt o ms, or t h e cli nical se q uel ae of a s us pecte d o ver d ose of eit her st u d y 
i nter ve nti o n or a c o nc o mita nt me dicati o n. O ver d os e per se will n ot be re p orte d as a n 
A E/ S A E u nless it is a n i nte nti o nal o ver d ose ta ke n wit h p ossi bl e s uici dal/self- har mi n g 
i nte nt. S uc h o ver d oses s h o ul d be re p orte d re gar dless of se q uelae. 
 
re p orte d as a n A E or S A E. S uc h i nst a nces will be ca pt ure d i n t he effic ac y assess me nts. 
H o we ver, t he si g ns, s y m pt o ms, a n d/ or cli nical se q uelae res ulti n g fr o m lac k of effi cac y 
will be re p orte d as A E or S A E if t he y f ulfil t he d efi niti o n of a n A E or S A E. 
E ve nt N O T Meeti n g t h e A E Defi niti o n: 
 
A n y cli nicall y si g nifi ca nt a b n or mal la b orat or y fi n di n gs or ot her a b n or mal safet y 
assess me nts t hat are ass ociate d wit h t he u n d erl yi n g diseas e, u nless j u d ge d b y t he 
i n vesti gat or t o be m or e s e vere t h a n e x pecte d f or t he partici pa nt's c o n diti o n. 
 
T he disease/ dis or der bei n g st u di e d or e x pecte d pr o gressi o n, si g ns or s y m pt o ms of t he 
disease/ dis or der b ei n g st u die d, u nless m ore se vere t ha n e x pecte d f or t he partici pa nt's 
c o n diti o n. 
 
Me dical or s ur gical pr oce d ure (e. g. e n d osc o p y, a p pe n dect o m y): t he c o n diti o n t hat lea ds 
t o t he pr oce d ure is t he A E. 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 5 4/ 8 6 
 
 
Sit uati o ns i n w hic h a n u nt o war d me dical occ urre nce di d n ot occ ur (s ocial a n d/ or 
c o n ve nie nce a d missi o n t o a h os pital). 
 
A ntici pate d da y-t o- da y fl uct uati o ns of pre-e xisti n g disease(s) or c o n diti o n(s) prese nt or 
detecte d at t he start of t h e st u d y t hat d o n ot w ors e n. 
8. 1. 2  
C ate g oris ati o n of A dverse Eve nts 
8. 1. 2. 1  
I nte nsity Cl assific ati o n 
All A Es will be rec or de d a n d gra d e d acc or di n g t o t he c urre nt versi o n of t he Nati o n al 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 ( N CI- C T C A E) Versi o n 5. 0. I n 
vie w of meta-a nal yses a n d f or c o n versi o n p ur p oses, t he f oll o wi n g c o n versi o n ma p pi n g will 
a p pl y if t he N CI- C T C A E scale is n ot a vaila ble f or a gi v e n A E: 
 
N CI- C T C A E Gra d e 1 c orres p o n ds t o mil d; 
 
N CI- C T C A E Gra d e 2 c orres p o n ds t o m o derate; 
 
N CI- C T C A E Gra d e 3 c orres p o n ds t o se ver e; 
 
N CI- C T C A E Gra d e 4 c orres p o n ds t o life t hreat e ni n g/ disa bli n g; 
 
N CI- C T C A E Gra d e 5 c orres p o n ds t o deat h (relat e d t o A E). 
W here:  
 
Mil d
 
 
M o der ate : s y m pt o ms pr o d uce s o me de gree of i m pair m e nt t o f u n cti o n b ut are n ot 
hazar d o us, u nc o mf orta bl e or e m barrassi n g t o t he partici pa nt; 
 
Se vere : s y m pt o ms defi nitel y h azar d o us t o well bei n g or ca usi n g si g nifica nt i m pair me nt 
of f u ncti o n or i nca p acitati o n; 
 
Life-t h re ate ni n g : a n y e ve nt t hat places t he partici pa nt at i m me diate ris k of deat h fr o m 
t he e v e nt as it occ urre d, i.e. it d oes n ot i ncl u de a reacti o n t hat, ha d it occ urre d i n a m ore 
se vere f or m, mi g ht h a ve ca use d deat h (als o s ee S ecti o n 8. 1. 5 ). 
8. 1. 2. 2  
C a us ality Cl assific ati o n 
T he relati o ns hi p of a n A E t o tri pt oreli n a d mi nistrati o n will be classifie d acc or di n g t o t h e 
f oll o wi n g: 
 
Rel ate d : re p orts i ncl u di n g g o o d reas o n a n d s ufficie nt i nf or mati o n (e. g. pla usi ble ti me 
se q ue nce, d os e res p o ns e relati o ns hi p, p har m ac ol o g y, p ositi ve dec hall e n ge a n d/ or 
rec halle n ge) t o ass u me a ca usal relati o ns hi p wit h tri pt oreli n a d mi nistrati o n i n t he se nse 
t hat it is pla usi ble, c o ncei va ble or li kel y; 
 
N ot rel ate d : re p orts i ncl u di n g g o o d reas o n a n d s uffi ci e nt i nf or mati o n (e. g. i m pla usi ble 
ti me se q ue nce a n d/ or attri b uta ble t o c o n c urre nt dis ease or ot her dr u gs) t o r ule o ut a c a usal 
relati o ns hi p wit h tri pt oreli n a d mi nistrati o n. 
8. 1. 2. 3  
Assess me nt of E x pecte d ness 
T he refere nce d oc u me nt f or assessi n g e x p ecte d n ess of A Es i n t his st u d y will be t he c urre nt I B.  
8. 1. 2. 4  
L a b or at ory Test A b n or m alities 
A b n or malities i n la b orat or y test val ues s h o ul d o nl y b e re p ort e d as A Es if a n y of t he f oll o wi n g 
a p pl y:  
 
T he y res ult i n a c h a n ge i n t he s c he d ul e of tri pt oreli n a d mi nistrati o n (c ha n ge i n d osa ge, 
dela y i n a d mi nistrati o n, st u d y dr u g disc o nti n uati o n); 
 
T he y re q uire i nter ve nti o n or a dia g n ostic e v al uati o n t o ass ess t he ris k t o t he partici pa nt; 
 
T he y are c o nsi dere d cli ni call y si g nifica nt b y t he I n vesti gat or; 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 5 5/ 8 6 
 
 
T he y are seri o us.  
8. 1. 2. 5  
A b n or m al P hysic al Ex a mi n ati o n Fi n di n gs 
Cli nicall y si g nifica nt c h a n ges, i n t he j u d ge me nt of t he I n v esti gat or, i n p h ysi cal e x a mi nati o n 
fi n di n gs (a b n or malities) will be rec or d e d as A Es.  
8. 1. 2. 6  
L oc al T ol er a bility A b n or m alities 
D uri n g l ocal t olera bilit y assess me nt after eac h tri pt oreli n i njecti o n, a n y ne w or w orse ni n g l oc al 
reacti o ns dee me d cli nic all y si g nific a nt  b y t he I n vesti g at or  m ust be re p orte d as a n A E i n t he 
A E pa ge of t he e C R F, i ncl u di n g st art a n d st o p dates, i nte nsit y, s eri o us n ess a n d acti o n ta ke n 
wit h st u d y treat me nt. 
8. 1. 2. 7  
Ot her I nvesti g ati o n A b n or m al Fi n di n gs 
A b n or mal test fi n di n gs j u d ge d b y t he I n v esti gat or as cli nicall y si g nific a nt t hat res ult i n a c ha n ge 
i n st u d y dr u g d osa ge or a d mi nistrati o n sc he d ul e, or i n disc o nti n uati o n of t he st u d y dr u g, or 
re q uire i nter ve nti o n or dia g n ostic e val uati o n t o assess t he ris k t o t he partici pa nt, s h o ul d be 
rec or d e d as A Es.  
8. 1. 3  
A dverse Eve nts of S peci al I nter est  
N ot a p pli ca ble. 
8. 1. 4  
Rec or di n g a n d F oll o w- u p of A dvers e Eve nts 
At eac h visit, t he parti ci pa nt s h o ul d be as ke d a n o n-
 
All o bser ve d or v ol u nteere d A Es, re gar dless of treat m e nt gr o u p or s us pecte d ca usal r elati o ns hi p 
t o tri pt oreli n, will be rec or de d i n t he A E pa ge(s) of t he e C R F. E ve nts i n v ol vi n g dr u g a n d/ or 
l ocal t ol era bilit y reacti o ns, acci de nts, ill nesses wit h o nset d uri n g t he treat me nt p hase of t he 
st u d y, or e x acer bati o ns of pre-e xisti n g ill nesses will be rec or d e d as A Es.  
A n y A Es alrea d y rec or de d a n d desi g nate d 
s u bse q ue nt assess me nt. 
F or all A Es, t he I n vesti gat or m ust p urs ue a n d o bt ai n a de q u ate i nf or m ati o n b ot h t o deter mi ne 
t he o utc o me of t he A E a n d t o ass ess w h et her it meets t he criteria f or classificati o n as a n S A E 
re q uiri n g i m m e di ate n otificati o n t o t he S p o ns or or its desi g nate d re pr ese nt ati v e. F or all A Es, 
s ufficie nt i nf or mati o n s h o ul d be o btai ne d b y t he I n vesti gat or t o d eter mi ne t he ca usalit y of t he 
A E (i.e. tri pt or eli n or ot her reas o n). T he I n vesti gat or is re q uire d t o assess ca usalit y a n d rec or d 
t hat assess me nt o n t he e C R F. F oll o w- u p of t he A E, after t he date of tri pt oreli n disc o nti n uati o n, 
is re q uire d if t he A E or its se q uel ae persist. F oll o w- u p is re q uire d u ntil t he e ve nt or its s e q uel ae 
or 
or his/ her desi g nate d re prese ntati ve.  
8. 1. 5  
Re p orti n g of Seri o us A dverse Eve nts 
All S A Es (as defi ne d bel o w), re gar dless of tre at m e nt gr o u p or s us pecte d relati o ns hi p t o 
 of 
t he e ve nt) usi n g t he S A E re p ort f or m via t he e mail a d dress or t he fa x n u m ber s pecifie d at t he 
be gi n ni n g of t his pr ot oc ol as well as rec or di n g t he m i n t he e C R F.  
A n S A E  is defi ne d as a n y u nt o war d me dic al occ urre nce t hat, at a n y d ose, meets o ne or m ore of 
t he criteria liste d: 
( 1) 
Res ults i n d eat h 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 5 6/ 8 6 
 
( 2) 
-
e ve nt i n w hic h t he partici pa nt was at ris k of d eat h at t he ti me of t he e ve nt. It d o es n ot 
refer t o a n e v e nt, w hic h h y p ot hetic all y mi g ht ha ve ca use d de at h, if it were m ore s e vere 
( 3) 
Re q uires i n- patie nt h os pit alisati o n or pr ol o n gati o n of e xisti n g h os pitalisati o n. 
I n ge neral, h os pitalisati o n si g nifies t hat t h e partici pa nt has bee n a d mitte d ( us uall y 
i n v ol vi n g at least a n o v er ni g ht st a y) at t he h os pital or e m er ge nc y war d f or o bs er vati o n 
o ut patie nt setti n g. C o m plicati o ns t hat occ ur d uri n g h os pitalisati o n are A Es. If a 
c o m plicati o n pr ol o n gs h os pitalisati o n or f ulfils a n y ot her seri o us criteria, t he e ve nt is 
A E s h o ul d be c o nsi dere d seri o us. 
H os pitalisati o n f or electi ve treat me nt of a pre-e xisti n g c o n diti o n t hat di d n ot w ors e n fr o m 
baseli ne is n ot c o nsi dere d a n A E  
( 4) 
Res ults i n a p ersiste nt or si g nific a nt disa bilit y/i nca pacit y. T he ter m disa bilit y mea ns a 
 
T his defi niti o n is n ot i nte n de d t o i ncl u d e e x perie nces of rel ati vel y mi n or me dical 
si g nifica nce s u c h as u nc o m plicate d hea d ac h e, na usea, v o miti n g, diarr h o ea, i nfl ue nza a n d 
acci de nt al tra u ma (e. g. s prai ne d a n kle) t hat ma y i nterfere wit h or pre ve nt e ver y da y lif e 
f u ncti o ns b ut d o n ot c o nstit ute a s u bsta nti al disr u pti o n. 
( 5) 
Res ults i n c o n ge nital a n o mal y/ birt h d efect i n t he offs pri n g of a partici p a nt w h o recei ve d 
t he tri pt oreli n 
( 6) 
Is a n i m p orta nt me dical e ve nt t hat ma y n ot res ult i n deat h, be life t hreate ni n g, or re q uire 
h os pitalisati o n b ut, base d u p o n a p pr o priate me dical j u d ge me nt, ma y je o par dise t he 
partici pa nt a n d m a y re q uire me dical or s ur gic al i nter ve nti o n t o pre v e nt o n e of t h e 
o utc o mes liste d i n t his defi niti o n. E x a m ples of s uc h me dical e ve nts i ncl u de aller gi c 
br o nc h os pas m re q uiri n g i nte nsi ve treat me nt i n a n e mer ge n c y r o o m or at h o me, bl o o d 
d yscrasias or c o n v ulsi o ns t hat d o n ot res ult i n i n- patie nt h os pitalisati o n, or t he 
de vel o p me nt of dr u g d e p e n de nc y or dr u g a b us e. 
Me dical or scie ntific j u d g me nt s h o ul d be e x ercise d b y t he I n v esti gat or i n deci di n g w het her S A E 
re p orti n g is a p pr o pri ate i n ot her sit uati o ns s uc h as si g nifica nt me dical e ve nts t hat ma y 
je o par dise t he partici p a nt or ma y re q uir e m e di cal or s ur gical i nt er ve nti o n t o pre ve nt o n e of t he 
ot her o utc o mes liste d i n t he a b o v e d efi niti o n. T hese e ve nts s h o ul d us u all y be c o nsi dere d 
seri o us. 
E x a m ples of s uc h e ve nts i ncl u de i n vasi ve or mali g na nt ca nc ers, i nte nsi ve treat m e nt f or all er gi c 
br o nc h os pas m, bl o o d d yscrasi as, c o n v ulsi o ns or de vel o p me nt of i nter ve nti o n de pe n de nc y or 
i nter ve nti o n a b use. 
A s us pecte d or c o nfir me d c or o na vir us C O VI D- 1 9 ( S A R S- C o V- 2) i nfecti o n m ust be re p orte d 
criteria are prese nt (e. g. h os pitalisati o n). 
 
H os pit alis ati o n  is defi ne d as a n y i n- patie nt a d missi o n (e ve n if l ess t ha n 2 4 h o urs). F or 
c hr o nic or l o n g-ter m i n- patie nts, i n- patie nt a d missi o n als o i ncl u des tra nsfer wit hi n t he 
h os pital t o a n ac ute/i nte nsi ve care i n- patie nt u nit 
 
Pr ol o n g ati o n of h os pit alis ati o n  is defi ne d as a n y e xt e nsi o n of a n i n- patie nt 
h os pitalisati o n be y o n d t he sta y a ntici p ate d/re q uire d f or t he reas o n f or t he i nitial 
a d missi o n, as 
deter mi ne d 
b y t he I n vesti g at or or tre ati n g 
p h ysici a n . 
F or 
pr ot oc ol-s pecifi e d h os pitalisati o n i n cli nical st u dies, pr ol o n gati o n is defi ne d as a n y 
e xte nsi o n be y o n d t h e le n gt h of sta y d es cri be d i n t h e pr ot oc ol. Pr ol o n gati o n i n t he a bse nce 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 5 7/ 8 6 
 
of a preci pitati n g, T E A Es (i.e. n ot ass ociate d wit h t he de vel o p me nt of a ne w A E or 
w orse ni n g of a pre-e xisti n g c o n diti o n) ma y meet t he criteri a f or "s eri o us ness" b ut is n ot 
a n a d vers e e x p erie nce a n d t h us is n ot s u bject t o i m me diate re p orti n g t o t he S p o ns or 
 
Pre pl a n ne d  or electi ve tre at me nts/s u r gic al pr oce d ures  s h o ul d be n ote d i n t he 
pla n ne d or electi ve 
treat me nt/s ur gical pr oce d ure s h o ul d n ot be re p orte d as a n S A E u nl ess t here are 
c o m plicati o ns or se q uela e t hat meet t he criteria f or seri o us ness des cri be d a b o ve. 
A n y S A E m ust be re p ort e d i m me diatel y ( wit hi n 2 4 h o urs), usi n g t he S A E re p ort f or m via t he 
e mail a d dress or t he fa x n u m ber s pecifie d at t he be gi n ni n g of t his pr ot oc ol as well as rec or di n g 
t he m i n t he e C R F, i n de pe n de nt of t he circ u msta n ces or s us pect e d c a use, if it occ urs or c o mes 
t o t he atte nti o n of t he I n v esti gat or at a n y ti me d uri n g t he st u d y peri o d. 
A n y A E/ S A E wit h a s us pect e d ca usal relati o ns hi p t o tri pt oreli n a d mi nistrati o n occ urri n g at a n y 
ot her ti me after c o m pleti o n of t he st u d y m ust be re p orte d pr o m ptl y, wit hi n 2 4 h o urs. 
T he f oll o wi n g i nf or m ati o n is t he mi ni m u m t hat m ust be pr o vi de d t o t he S p o ns or wit hi n 
2 4 h o urs f or eac h S A E: 
 
St u d y n u m b er 
 
Ce ntre n u m ber 
 
Partici pa nt n u m ber 
 
A E 
 
 
T he a d diti o nal i nf or m ati o n i ncl u de d i n t he S A E f or m m ust be pr o vi de d t o t he S p o ns or or 
re pres e ntati ve as s o o n as it is a vaila ble. T he I n vesti gat or s h o ul d al wa ys pr o vi de a n ass ess m e nt 
of ca us alit y f or ea c h e v e nt re p orte d t o t he S p o ns or. U p o n recei pt of t h e i nitial re p ort, t he 
S p o ns or will as k f or t he I n vesti gat or's ca usalit y ass ess me nt if it was n ot pr o vi de d wit h t h e i nitial 
re p ort. 
T he I n vesti gat or s h o ul d re p ort a dia g n osis or a s y n dr o me rat her t h a n i n di vi d ual si g ns or 
s y m pt o ms. T he I n vesti gat or s h o ul d als o tr y t o se p arate a pri mar y A E c o nsi dere d t he f ore m ost 
u nt o war d m e dical o cc urre nce fr o m sec o n d ar y A Es t hat occ urre d as c o m pli cati o ns. 
8. 1. 6  
Pre g n a ncy 
I nf or mati o n re gar di n g pre g n a ncies m ust be c ollecte d as a n S A E o n t he A E pa ge of t he e C R F 
a n d re p orte d t o t he S p o ns or wit hi n 2 4 h o urs as des cri be d i n Secti o n 8. 1. 5 . 
If pre g n a nc y o cc urs d uri n g t he st u d y, t he o ut c o me of t he pre g na nc y will be c ollecte d f oll o wi n g 
c o m pleti o n of t he st u d y. T he S p o ns or will re q uest f urt her i nf or mati o n fr o m t he I n vesti gat or as 
t o t he c o urse a n d o utc o m e of t he pre g na nc y usi n g t he Sta n dar d Dr u g E x p os ure f or Pre g na nc y 
F or m. 
T he 
I n v esti gat or 
m ust i nstr uct 
all fe male 
partici pa nts 
w h o 
h a ve 
alrea d y 
ha d 
me n o p ha nia/ m e narc he t o i nf or m t he m i m m e di atel y s h o ul d t he y b ec o me pre g na nt d uri n g t he 
st u d y. T he I n vesti gat or s h o ul d c o u nsel t he partici pa nt, disc uss t he ris ks of c o nti n ui n g wit h t he 
pre g na nc y a n d t he p ossi ble effects o n t he f oet us. M o nit ori n g of t he partici pa nt s h o ul d c o nti n ue 
u ntil c o ncl usi o n of t he pre g n a nc y, w hic h ma y i n v ol ve f oll o w- u p after t he partic
i n v ol ve me nt i n t he st u d y has e n de d.  
me dicati o n m ust als o be re p orte d t o t he I n vesti gat or f or o n war d re p orti n g t o t he S p o ns or. 
If t he I n vesti gat or b ec o m es a ware of a pre g n a n c y o cc urri n g i n t he part ner of a p artici pa nt 
partici pati n g i n t he st u d y, t his s h o ul d be re p orte d t o t he S p o ns or as des cri be d a b o ve. 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 5 8/ 8 6 
 
st u d y me di cati o n s h o ul d be re p orte d aft er t he part ner h as gi ve n writte n c o nse nt a n d t h e p art ner 
s h o ul d be c o u nsell e d a n d f oll o we d as descri be d a b o ve. M o nit ori n g of t he part ner s h o ul d 
c o nti n ue u ntil c o ncl usi o n of t he pre g n a nc y. 
8. 1. 7  
De at hs 
All A Es res ulti n g i n deat h d uri n g t he st u d y p eri o d (fr o m first i nj ecti o n u ntil 3 m o nt hs after t he 
date of t h e last st u d y dr u g a d mi nistrati o n), m ust be re p orte d as a n S A E wit hi n 2 4 h o urs of t h e 
. 
T he c o n ve nti o n f or rec or di n g de at h is as f oll o ws:  
 
A E ter m: l ea d ca use of deat h (e. g. m ulti pl e or ga n fail ure, p n e u m o nia, m y o car di al 
i nfarcti o n) 
 
O utc o me: fatal. 
T he o nl y e xce pti o n  is if t he ca us e of d eat h is u n k n o w n (i.e. s u d de n or u ne x plai ne d deat h), i n 
 
8. 1. 8  
Disc o nti n u ati o n/ Wit h dr a w al d ue t o A dverse Eve nts/ Seri o us A d verse Eve nts 
Disc o nti n uati o n/ wit h dra wal d ue t o 
A Es s h o ul d be disti n g uis he d fr o m disc o nti n uati o n/ 
wit h dra wal d ue t o i ns uffici e nt res p o nse t o tri pt oreli n (see Secti o n 4. 4 ). 
desi g nat e d re prese nt ati ve (s ee Secti o n 8. 1. 5 ). 
I n all cas es, t he I n vesti gat or m ust e ns ure t hat t he partici pa nt recei ves a p pr o priate me di cal 
f oll o w- u p (see Secti o n 8. 1. 4 ). 
8. 1. 9  
Re p orti n g t o C o m pete nt A ut h orities/I n de pe n de nt Et hics C o m mittees/I nstit uti o n al 
Revie w B o ar ds/ Ot her I nvesti g at ors 
T he S p o ns or will e ns ure t hat pr ocesses are i n place f or t he s u b missi o n of re p orts of s us pecte d 
u ne x pecte d seri o us a d v ers e reacti o ns ( S U S A Rs) occ urri n g d uri n g t h e st u d y t o t he c o m pete nt 
a ut h orities, I E Cs a n d ot her I n vesti gat ors i n v ol ve d wit h tri pt oreli n. Re p orti n g will b e i n 
acc or da n ce wit h t he a p pli ca ble re g ul at or y re q uire me nts. 
8. 2  
Cli nic al L a b or at or y Tests 
Bl o o d a n d uri ne sa m pl es will be c ollecte d as per Ta ble 1  a n d T a ble 2  f or t he e val uati o n of 
hae mat ol o g y, ser u m c he mistr y a n d uri nal ysis. 
T he I n vesti gat or will re vie w t he safet y la b orat or y t est res ults, d oc u me nt t he re vie w a n d rec or d 
a n y cli nicall y rele va nt c h a n g es o cc urri n g or o bser ve d d uri n g t he st u d y i n t he A E secti o n of t he 
e C R F (see Secti o n 8. 1. 2. 4  f or a b n or mal la b orat or y t ests t hat s h o ul d be rec or de d as A Es). 
All cli nicall y rele v a nt a b n or mal la b orat or y tests occ urri n g d uri n g t h e st u d y will be re peate d at 
a p pr o priate i nter vals u ntil t he y ret ur n t o baseli n e or t o a le vel dee me d acce pta bl e b y t he 
desi g nate d r e prese nt ati ve) or u ntil 
t he a b n or malit y is e x plai ne d b y a n a p pr o pri ate di a g n osis.  
8. 2. 1  
H ae m at ol o gy 
Bl o o d sa m ples ( v ol u me t o be c ollecte d as p er l oc al la b orat or y ma n ual) will be c oll ect e d i n a 
p otassi u m et h yle ne di a mi net etraacetic aci d t u be t o assess C B C.  
8. 2. 2  
Bl o o d C he mistr y 
Bl o o d sa m ples ( v ol u me c ollecte d as per l ocal cli ni cal practi ce) will be c ollecte d i n a n acti vat or 
gel t u be t o assess t he f oll o wi n g para met ers: 
 
Creati ni n e 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 5 9/ 8 6 
 
 
Gl uc ose 
 
A L T 
 
A S T 
 
A L P 
 
Bilir u bi n. 
I n t h e case of a b n or mal bl o o d gl uc os e as per I n v
will be perf or me d b ef ore t he first tri pt oreli n i njecti o n.  
8. 2. 3  
Uri n alysis  
Fres h uri ne sa m ples (at l east 1 0 m L) will be c ollecte d t o ass ess t he f oll o wi n g v aria bles: p H, 
pr ot ei n, ket o nes, bilir u bi n, bl o o d, ur o bili n o ge n, nitrites, le u k oc ytes, gl uc os e a n d s pecific 
gra vit y b y di pstic k.  
Micr osc o p y will be perf or me d, if i n di cate d, b ut res ults will n ot be c oll ecte d i n t he e C R F. If i n 
t he o pi ni o n of t he I n vesti gat or t here are a n y cli nicall y si g nifi ca nt a b n or malities i n mi cr os c o p y, 
t he y will be rec or de d as a n A E i n t he e C R F. 
8. 2. 4  
Pre g n a ncy Test 
L ocal uri ne 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 re q uire d b y l ocal 
re g ulati o n or I R B/I E C b ef ore dr u g treat me nt f or all fe male partici p a nts of c hil d beari n g p ote ntial 
a n d if cli nicall y i n dicate d t here after. A n y partici p a nt bec o mi n g pre g na nt d uri n g t he st u d y will 
be wit h dra w n. All pre g n a ncies t hat o cc ur d uri n g t he st u d y ar e t o be re p ort e d as descri be d i n 
Secti o n 8. 1. 6 . 
8. 2. 5  
Ot her Cli nic al L a b or at ory T ests 
Ot her cli nical l a b orat or y tests will be p erf or me d t o e ns ure t h e safet y of t h e p arti ci pa nts b ut will 
n ot be a n assess me nt of t he safet y of t h e st u d y dr u g. 
8. 3  
P h ysic al E x a mi n ati o n 
P h ysical e x a mi nati o ns, i ncl u di n g b o d y wei g ht, will be c o n d ucte d at ti me p oi nts descri be d i n 
Ta ble 1  a n d T a ble 2 . B o d y wei g ht will be meas ure d i n u n der wear a n d wit h o ut s h oes. 
A n y cli nicall y si g nifica nt p h ysi cal e x a mi nati o n fi n di n gs (a b n or m aliti es) o bser ve d d uri n g t he 
st u d y will be r e p orte d as A Es. A n y p h ysical e x a mi nati o n fi n di n gs ( a b n or malities) persisti n g at 
t he e n d of t he st u d y will be f oll o we d b y t he I n vesti gat or u ntil res ol uti o n or u ntil rea c hi n g a 
cli nicall y sta ble e n d p oi nt. 
8. 4  
L oc al T oler a bilit y 
Assess me nt of l ocal t olera bilit y will be c o n d ucte d as prese nte d i n t he sc he d ule of assess me nts 
(Ta ble 1  a n d T a ble 2 ) a n d as descri be d i n t his secti o n. 
After eac h tri pt oreli n i njecti o n, t he i njecti o n sit e will be e x a mi ne d, at i nj ecti o n a n d 2 h o urs p ost 
i njecti o n, b y a p h ysi ci a n or me dical researc h ass o ciate a n d assesse d f or c h aract eristics s uc h as 
b ut n ot li mit e d t o te n d er ness, re d ness, br uisi n g, er yt he ma, s welli n g, ras h, pai n, itc hi n g, 
i n d urati o n, hae mat o ma, ulcerati o n or n ecr osis. If pres e nt, t he e xte nt of er yt he m a, hae m at o ma, 
ras h, ulcerati o n or necr osis will be des cri be d a n d assesse d q ua ntitati vel y; t his will at least 
i ncl u de meas ure me nt of ma xi m u m l e n gt h a n d ma xi m u m wi dt h.  
A n y reacti o n dee me d cli nicall y si g nifica nt b y t he I n v esti gat or meets t he defi niti o n of a T E A E, 
t h us it n ee ds t o b e re p ort e d i n t he e C R F as s uc h, as i n dicate d i n Secti o n 8. 1. 2. 6 . 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 6 0/ 8 6 
 
8. 5  
Vit al Si g ns 
Bl o o d press ure a n d heart rate will be assesse d at ti me p oi nts descri be d i n Ta ble 1  a n d Ta ble 2  
wit h a n a ut o m ate d de vice s o t hat meas ure m e nts are i n de pe n de nt of t he o bser ver. Bl o o d press ur e 
a n d heart rate will be rec or de d i n sitti n g p ositi o n after 5 mi n utes of r est (seate d). A bs ol ute 
val ues a n d c h a n ge fr o m bas eli ne will be a nal yse d. 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 6 1/ 8 6 
 
9  
A S S E S S M E N T S O F P H A R M A C O KI N E TI C S/ P H A R M A C O D Y N A MI C S 
9. 1  
P h ar m a c o ki n etics 
S parse P K sa m ples (tri pt oreli n), will be ta ke n i n all partici pa nts as des cri be d i n Ta ble 1 . 
9. 1. 1  
S a m ple C ollecti o n 
Bl o o d sa m ples f or t h e ass a y of tri pt oreli n will be c ollecte d i n Vac utai ner t u bes at t he ti me p oi nts 
i n dicate d i n Ta ble 1 . F ull details of s a m ple c ollecti o n, pr ocessi n g, r e q uire d la belli n g, st ora ge 
a n d t he s hi p m e nt pr ocess f or t hese s a m ples will be d oc u me nte d i n t he St u d y Ma n ual. 
O n pre deter mi ne d dates, sa m pl es will be s hi p pe d t o t he bi oa nal ytical C R O u n der fr oze n 
c o n diti o ns. F or sec urit y reas o ns, ali q u ots of ea c h sa m ple will be s hi p pe d se paratel y. T h e bat c h 
c o ntai ni n g t h e sec o n d ali q u ot will n ot be s hi p pe d u ntil t he first o ne h as arri ve d. U p o n recei pt at 
t he bi oa nal yti cal C R O, sa m ples will be c hec k e d a n d st ore d u ntil a nal ysis. 
9. 1. 2  
A n alytic al Pr oce d ures 
T he c o nce ntrati o n of tri pt oreli n will be a nal yse d usi n g a v ali date d s pecific a n d s e nsiti ve 
met h o d, a n d i n acc or da nce wit h G o o d La b or at or y Practice ( G L P). All details of sa m pl e 
c ollecti o n, ha n dli n g, s hi p me nt, m et h o d ol o g y a n d refere nce ra n ges will be pr o vi de d i n t he St u d y 
Ma n ual a n d arc hi ve d i n t he Trial M aster Fil e. 
9. 1. 3  
D at a A n alysis 
I n di vi d ual listi n gs a n d s u m mar y statistics will be prese nt e d f or P K c o nc e ntrati o ns. 
9. 2  
P h ar m a c o d y n a mi cs 
N ot a p pli ca ble. 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 6 2/ 8 6 
 
1 0  
E X P L O R A T O R Y BI O M A R K E R S A N D BI O B A N KI N G 
T here are n o e x pl orat or y bi o mar kers or bi o ba n ki n g pla n n e d f or t his st u d y.  
N ote t hat a des cri pti o n of pri mar y a n d sec o n d ar y efficac y bi o mar kers ca n be f o u n d i n 
Secti o n 3. 2 . 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 6 3/ 8 6 
 
1 1  
S T A TI S TI C S 
Detaile d met h o d ol o g y f or s u m m ar y a n d st atistical a nal ys es of t he dat a c ollecte d i n t his st u d y 
will be d oc u m e nt e d i n a statisti cal a nal ysis pla n ( S A P), t o be a p pr o ve d bef ore t he first 
partici pa nt e nters t he st u d y. T h e S A P ma y i ncl u d e c ha n ges t o t he pla ns o utli ne d i n t his pr ot oc ol; 
h o we ver, a n y maj or m o dificati o ns of t he pri mar y e n d p oi nt a n d/ or its a nal ysis will als o be 
reflecte d i n a pr ot oc ol a me n d me nt. 
Statistical e val uati o n will be perf or me d usi n g Statistical A nal ysis S yst e m ( S A S ® ) Versi o n 9. 4 
( or hi g h er if a vaila ble). 
1 1. 1  
A n al ysis P o p ul ati o ns 
T he f oll o wi n g p o p ulati o ns will be use d d uri n g statistical a nal ys es: 
 
Scree ne d p o p ul ati o n : All partici pa nts scree ne d (i.e. w h o si g n e d t he i nf or me d c o nse nt) 
 
S afet y p o p ul ati o n : All partici pa nts w h o recei ve d at least o ne d os e of st u d y me dicati o n 
a n d ha ve at least o ne p ost- baseli ne safet y ass ess m e nt 
 
I nte nti o n- T o- Tre at p o p ul ati o n (I T T): All partici pa nts w h o recei ve d at least o ne d ose 
of st u d y me dic ati o n 
 
M o difie d I nte nti o n- T o- Tre at p o p ul ati o n ( mI T T):  All treate d partici pa nts ha vi n g at 
least o ne baseli ne a n d at M o nt h 3 p ost- baseli ne assess me nt of t he pri mar y efficac y 
e n d p oi nt 
 
Per pr ot oc ol ( P P) s et : All partici pa nts i n t he mI T T after e xcl usi o n of t he partici pa nts 
w h o ha d maj or pr ot o c ol de viati o ns t hat c o ul d p ote ntiall y affect t he pri mar y efficac y 
e n d p oi nt o utc o me f or t he partici pa nts 
 
P K set:  All partici pa nts w h o recei ve d at least o n e d ose of st u d y me dicati o n a n d ha v e at 
least o ne vali d a n d q ua ntifi a ble c o nce ntrati o n. 
1 1. 1. 1  
P o p ul ati o ns A n alyse d 
M ai n p h ase 
T he pri mar y efficac y a nal ysis will be perf or me d o n t he mI T T p o p ulati o n. S u p p orti ve a nal ysis 
of t he pri m ar y efficac y e n d p oi nts will be base d o n t he I T T a n d t he P P p o p ulati o ns. 
T he sec o n d ar y effi cac y a nal ys es will be b ase d o n t he mI T T p o p ulati o n. S u p p orti ve a nal ysis of 
t he sec o n dar y a nal yses m a y b e perf or me d o n t he P P p o p ulati o n. 
T he a nal yses of safet y d ata will be perf or me d base d o n t he S afet y p o p ulati o n. 
T he a nal yses of P K dat a will be perf or m e d b ase d o n t he P K p o p ulati o n. 
E xte nsi o n p h ase  
T he a nal ysis s ets f or t he efficac y e n d p oi nts will be t he I T T set a n d t he P P set. A nal yses a n d 
s u m mar y ta bl es f or t he safet y e n d p oi nts will be b ase d u p o n t he Safet y p o p ulati o n. 
1 1. 1. 2  
Re as o ns f or E xcl usi o n fr o m t he A n alyses 
A n y m aj or pr ot oc ol de vi ati o n (see Secti o n 1 3. 1. 2  f or d efi niti o n) will be d escri be d a n d liste d 
a n d its i m pact o n t he i n cl usi o n of a n y p arti ci pa nt i n eac h a nal ysis p o p ulati o n will be s pecifi e d. 
T he fi nal list of pr ot oc ol de viati o ns i m pacti n g eac h a nal ysis p o p ulati o n will be re vie we d pri or 
t o dat a base l oc k. T h e list ma y b e u p d ate d, u p t o t he p oi nt of data bas e l o c k, t o i ncl u de a n y 
a d diti o nal pr ot oc ol de viati o ns w hic h ma y i m pact t he a nal ysis of eac h p o p ulati o n. 
1 1. 2  
S a m ple Size Deter mi n ati o n 
M ai n p h ase 
T he p ur p os e of t his st u d y is t o o bser ve w het h er t he effecti ve ness of tri pt oreli n 3- m o nt h 
f or m ulati o n i n C hi nese p o p ul ati o n of C P P c hil dre n has t he s a me or si milar tre n d wit h t hat i n 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 6 4/ 8 6 
 
o verseas C P P p o p ulati o n, mai nl y usi n g d escri pti ve statistical a nal ysis. Alt h o u g h n o f or mal 
statistical testi n g will be carrie d o ut, t he f oll o wi n g ass u m pti o ns were ma de, base d o n gl o bal 
Ze nat y 2 0 1 6 ], f or t he sa m pl e size t o e na ble a n e val uati o n of t he 
tre n d of effecti ve ness: 
 
E x pecte d o utc o me f or t he pr o p orti o n of c hil dre n wit h a s u p presse d L H res p o nse t o t he 
G n R H sti m
 I U/ L) at M o nt h 3 is 9 0 % 
 
N ull pr o p orti o n is 7 0 % 
 
A n e x act bi n o mial test of a pr o p orti o n wit h a o n e-si de d n o mi nal si g nific a nce le vel of 
0. 0 5 a n d p o wer = 8 5 % 
 
E x pecte d c o m m o n dr o p o ut rat e = 1 0 %.  
U n der t hese ass u m pti o ns, a p pr o xi mat el y 3 2 ( 2 8 wit h a d diti o n al 1 0 % dr o p o uts) partici pa nts 
( P o wer A nal ysis a n d Sa m ple Siz e ( P A S S) s oft ware) i ncl u di n g t hree b o ys are pla n ne d t o be 
e nr olle d i nt o t he st u d y i n or der t o o bser ve t he effi cac y of t he tri pt oreli n 3- m o nt h f or m ulati o n i n 
t he pr o p orti o n of c hil dre n wit h a s u p press e d L H res p o nse t o t he G n R H sti m ulati o n test at 
M o nt h 3. 
E xte nsi o n p h ase 
T he n u m ber of partici pa nts i ncl u de d i n t he e xte nsi o n st u d y will be de pe n de nt o n t he n u m ber of 
partici pa nts fr o m st u d y D- C N- 5 2 0 1 4- 2 4 3 w h o gi ve c o nse nt t o c o nti n ue i nt o t he e xte nsi o n 
st u d y. A ma xi m u m of 3 2 partici pa nts will be e x pecte d t o be e nr olle d i n t he e xte nsi o n p hase. 
1 1. 3  
Si g nific a nce Testi n g a n d Esti m ati o ns 
9 3. 8 %). Wit h N = 2 8, t here is 9 0 % pr o ba bilit y t hat t he o bser ve d res p o ns e rate will be wit hi n 
1 6 perce nt a ge p oi nts of t he tr ue res p o ns e rate bas e d o n a si m ulati o n. D ue t o t he s mall sa m ple 
size a n d p ote ntial wi der precisi o n of t he esti mat or, t he pri m ar y e n d p oi nt will be s u m m arise d 
descri pti vel y. N o f or mal h y p ot hesis test will be perf or me d
F or t h e pri mar y effic ac y e n d p oi nt, t he s u m m ar y st atistics of n u m ber a n d perce nta ge of 
partici pa nts a n d t he e x act t w o-si de d 9 0 % c o nfi de nce i nter v al ( CI) f or a bi n o mial pr o p orti o n 
will be c o m p ute d b y S A S ®  usi n g t he e x act bi n o mi al distri b uti o ns o n t he mI T T ( pri mar y 
p o p ulati o n of a nal ysis), I T T a n d P P. 
F or sec o n d ar y efficac y e n d p oi nts relate d t o a c ha n ge at M o nt h 3 a n d M o nt h 6 c o m pare d t o 
baseli ne, t he descri pti ve s u m mar y st atistics ( n, m ea n, S D, me dia n, mi ni m u m, ma xi m u m) will 
be calc ulate d o n t he mI T T. I n a d diti o n, s ec o n d ar y efficac y e n d p oi nts ma y be perf or me d o n t h e 
P P. E xact t w o-si de d 9 0 % CIs will als o b e c o nstr u cte d f or all s ec o n dar y e n d p oi nts e x press e d as 
perce nt a ges. 
F or e xte nsi o n p hase efficac y e n d p oi nts relate d t o a c ha n ge at M o nt h 9 a n d M o nt h 1 2 c o m pare d 
t o baseli ne, t he descri pti v e s u m mar y statisti cs ( n, mea n, S D, me dia n, mi ni m u m, ma xi m u m) will 
be calc ulate d o n t he I T T a n d P P. E x act t w o-si de d 9 0 % CIs will als o be c o nstr ucte d f or all 
e xte nsi o n p has e effic ac y e n d p oi nts e x presse d as perce nt a ges. 
T he a nal ysis res ults b ase d o n t he st atistical met h o ds a b o ve will pr o vi de t he refere n ce f or 
w het her t he efficac y of treat me nt of C P P i n c hil dre n i n C hi na h as s a me or si milar tre n d wit h 
t hat i n o verseas C P P p o p ulati o n.  
1 1. 4  
St atistic al/ A n al ytic al Met h o ds 
de part me nt. 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 6 5/ 8 6 
 
1 1. 4. 1  
De m o gr a p hic a n d Ot her B aseli n e C h ar acteristics 
Descri pti ve s u m m ar y statistics ( n, m ea n, S D, m e dia n, mi ni m u m, ma xi m u m) a n d fre q u e nc y 
c o u nts of de m o gra p hi c a n d baseli ne data ( m e dical hist or y, c o n c o mita nt disease, pre d osi n g A Es 
a n d o n g oi n g m e dical hist or y, pri or a n d c o n c o mita nt me dicati o ns a n d t hera pies) will be 
prese nte d f or t he I T T, mI T T a n d P P, as well as t he Safet y p o p ulati o n. 
1 1. 4. 2  
P artici p a nt Dis p ositi o n a n d Wit h dr a w als 
T he n u m bers a n d perce nta ges of partici p a nts scree ne d a n d i ncl u de d i n e ac h of t he a n al ysis 
p o p ulati o ns will be t a b ul ate d o verall a n d b y ce ntre. T he reas o ns f or p artici p a nt e x cl usi o ns fr o m 
eac h of t he p o p ulati o ns a n d pri m ar y reas o ns f or st u d y disc o nti n uati o n will be ta b ulate d.  
1 1. 4. 3  
P h ar m ac o ki netic D at a 
S u m mar y st atistics will be prese nte d f or tri pt oreli n plas ma c o nce ntrati o ns. C o nce ntrati o ns will 
be c o m pare d t o t he hist orical data usi n g a m o d el pre vi o usl y de v el o pe d. If re q uire d a n d 
warra nte d b y t he data, a n att e m pt t o b uil d a m o del t o c haracterize t he P K i n t he p o p ulati o n will 
be ma de.  
1 1. 4. 4  
Effic acy Ev al u ati o n ( M ai n P h ase) 
1 1. 4. 4. 1  Pri m ary Effic acy E n d p oi nt 
As i n dicate d i n S ecti o n 7. 1 , t he pri mar y effi cac y e n d p oi nt is t he pr o p orti o n of c hil dre n wit h L H 
s u p pressi o n defi ne d as sti m ulate d pea k L H 
 I U/ L after G n R H sti m ul ati o n at M o nt h 3. T he 
G n R H sti m ul ati o n test is perf or me d b y usi n g i. v. i njecti o n of g o na d oreli n (s y nt heti c G n R H) t o 
sti m ul ate g o na d otr o p hi n release, a n d bl o o d s a m pl es will be c ollecte d pri or t o a n d 3 0, 6 0, 
9 0 mi n utes ( ± 5 mi n utes at eac h ti me p oi nt) after t he g o na d oreli n i njecti o n f or ce ntral assess m e nt 
of ser u m L H le v els. 
1 1. 4. 4. 2  Sec o n d ar y Effic acy E n d p oi nt 
As i n di cate d i n Secti o n 7. 2 , t he sec o n dar y efficac y e n d p oi nts are t he f oll o wi n g: 
 
C ha n ge i n b asal ser u m L H a n d F S H le v els at M o nt h 3 a n d M o nt h 6 c o m pare d t o baseli ne 
 
G n R H sti m ul ati o n at M o nt h 6 
 
C ha n ge i n pea k L H le v el aft er t he G n R H sti m ulati o n test at M o nt h 3 a n d M o nt h 6 
c o m pare d t o baseli ne 
 
C ha n ge i n pea k F S H le vel after t he G n R H sti m ulati o n test at M o nt h 3 a n d M o nt h 6 
c o m pare d t o baseli ne 
 
Pr o p orti o n of c hil dre n wit h pre- p u b ertal le v els of s e x ster oi ds ( defi ne d as oestra di ol 
 
 n g/ m L i n b o ys) at M o nt h 3 a n d M o nt h 6 
 
C ha n ge i n oestra di ol l e vels i n girls a n d test oster o ne le v els i n b o ys at M o nt h 3 a n d 
M o nt h 6 c o m pare d t o bas eli n e 
 
C ha n ge i n p u bertal sta ge usi n g t he Ta n ner m et h o d ( ge nit al sta ge i n b o ys, breast sta ge i n 
girls a n d p u bic h air sta ge i n b ot h s e x es) at M o nt h 6 c o m pare d t o bas eli n e 
 
Pr o p orti o n of c hil dre n wit h sta bilise d p u bertal st a ge c o m pare d t o baseli ne st a ge usi n g t he 
Ta n ner met h o d at M o nt h 6 
 
C ha n ge i n a u x ol o gical para meters i ncl u di n g hei g ht, gr o wt h vel ocit y, wei g ht a n d B MI at 
M o nt h 3 a n d M o nt h 6 c o m pare d t o baseli ne 
 
C ha n ge i n B A, differe nce bet wee n B A a n d C A at M o nt h 6 c o m pare d t o bas eli n e 
 
C ha n ge i n uteri ne le n gt h i n girls a n d testic ular v ol u me i n b o ys at M o nt h 6 c o m pare d t o 
baseli ne. 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 6 6/ 8 6 
 
1 1. 4. 4. 3  Ex pl or at ory P h ar m ac oki neti cs E n d p oi nt  
 
T o assess s pars e plas ma tri pt oreli n c o nce ntrati o ns at Da y 1, M o nt h 3 a n d M o nt h 6. 
1 1. 4. 5  
A dj ust m e nt f or C o u ntry/ Ce ntr e Effect 
Descri pti ve a n al ysis will be carrie d o ut t o e val u ate a n y p ossi ble ce ntre effect. 
1 1. 4. 6  
S afety Ev al u ati o n ( M ai n P h ase) 
Safet y e n d p oi nts are i n di cate d i n Secti o n 3. 2. 3 . 
All s afet y data will be i ncl u de d i n t he partici pa nt data listi n gs. A nal yses a n d s u m mar y t a bles 
will be base d o n t he Safet y p o p ulati o n. 
All A Es will be c o d e d acc or di n g t o t he 
Me dical Di cti o n ar y f or Re g ulat or y Acti vities 
( Me d D R A) versi o n ( versi o n i n use bef ore data b as e l oc k) a n d will be classifie d b y Me d D R A 
preferre d ter m ( P T) a n d s yste m or ga n class ( S O C). All A E listi n gs will be prese nte d b y 
partici pa nt a n d b y S O C a n d P T. 
T he i nci de nce of all re p orte d T E A Es, T E A Es ass o ciate d wit h earl y wit h dra wal a n d S A Es will 
be ta b ulate d o ver all. I n a d diti o n, s u m mar y ta bles will be pres e nte d b y ma xi m u m i nte nsit y a n d 
dr u g relati o ns hi p.  
A 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 ( bet wee n t he 
start date of t he treat me nt a n d t he e n d of st u d y treat me nt) if:  
 
It was n ot prese nt pri or t o recei vi n g t he first d os e of tri pt oreli n, or 
 
It was pres e nt pri or t o recei vi n g t he first d ose of tri pt oreli n b ut t he gra de i ncreas e d or 
beca me seri o us d uri n g t h e acti ve p h ase of t he st u d y, or 
 
It was prese nt pri or t o recei vi n g t h e first d ose of tri pt oreli n, t he gra d e/s eri o us n ess is t he 
 
All T E A Es will be fla g ge d i n t he A E listi n gs.  
S u m mar y i nci de n ce t a bles will be pr o vi de d, classifie d b y S O C, P T a n d ass ociate d N CI- C T C A E 
w orst gra de. I n t he e v e nt of m ulti ple occ urre nces of t he sa m e A Es bei n g re p orte d f or t he s a me 
partici pa nt, t he ma xi m u m i nte nsit y ( Gra d e 5 > Gra de 4 > Gra de 3 > Gra de 2 > Gra d e 1 > missi n g 
> n ot a p plica ble) will be c h ose n. All A Es will be c oll ect e d u p t o t he E O S visit (see Ta bl e 1  f or 
sc he d ule), or E O E P visit f or t h ose e nr olle d i n t he e xte nsi o n p hase. 
C o nc o mita nt me dicati o n will b e c o de d b y usi n g W orl d Healt h Or ga niz ati o n Dr u g Dicti o n ar y 
( W H O- D D) v ersi o n (c urre nt versi o n i n use at t he start of t he st u d y) a n d will be s u m m arise d 
wit h t he n u m ber a n d perce nta ge of partici pa nts recei vi n g c o nc o mita nt me di cati o n b y dr u g cl ass 
a n d preferre d dr u g na m e. 
Hae mat ol o gical a n d bi o c he mical t o xicities will be rec or d e d a n d gra de d acc or di n g t o t he 
N CI- C T C A E criteria, w here a vail a ble. T he N CI- C T C A E Gra d es 3 a n d 4 hae mat ol o g y a n d 
bi oc he mistr y v aria bles will be liste d b y p artici pa nt a n d b y visit. 
Act ual val u es a n d c ha n ges fr o m Baseli ne i n cli nic al la b orat or y t ests, p h ysical e xa mi nati o ns a n d 
vital si g ns will be s u m marise d usi n g des cri pti ve statisti cs at eac h visit. F or la b orat or y data, 
a b n or mal val ues will be fla g ge d i n t he 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 be prese nte d. S hift ta bles usi n g t h e w orst o n-treat m e nt gra d e will be prese nt e d f or 
t he n u m ber a n d perce nta ge of parti ci p a nts wit h N CI- C T C A E gra des. 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 6 7/ 8 6 
 
1 1. 4. 7  
Effic acy a n d S afety Ev al u ati o ns ( E xte nsi o n P h ase) 
A se parate a nal ysis o n efficac y a n d s afet y e n d p oi nts will be perf or me d c o nsi deri n g t he 
e xte nsi o n p hase d urati o n, a peri o d of a n a d diti o nal 6 m o nt hs, lasti n g u ntil t he E n d of E xte nsi o n 
P hase Visit at M o nt h 1 2. 
As t his is a n e xte nsi o n p hase f oll o wi n g t he mai n st u d y p h ase, t he efficac y a n d safet y e n d p oi nts 
i n t he e xte nsi o n p hase will be s u m marise d descri pti vel y. N o f or mal st atisti cal h y p ot heses 
testi n g will be perf or me d. 
Statistical a nal yses will i ncl u de t he f oll o wi n g: 
 
F or t he c o nti n u o us e n d p oi nts, t he descri pti v e s u m m ar y st atisti cs ( n u m ber of partici pa nts 
( n), mea n, S D, me di a n, mi ni m u m, ma xi m u m) will be calc ul ate d 
 
F or t he cate g orical e n d p oi nts, t he s u m m ar y statisti cs of n u m ber a n d perce nt a ge of 
partici pa nts a n d t he e x act t w o-si de d 9 0 % c o nfi de n ce i nter val ( CI) will be calc ulate d. 
1 1. 4. 7. 1  Effic acy E n d p oi nt 
As i n di cate d i n Secti o n 3. 3. 1 , t he e xte nsi o n p hase effi cac y e n d p oi nts are t h e f oll o wi n g: 
 
Pr o p orti o n of c hil dre n wit h L H s u p pressi o n ( defi n e d as L H 
 I U/ L) at M o nt h 1 2  
 
C ha n ge i n b asal ser u m L H a n d F S H le v els at M o nt h 9 a n d M o nt h 1 2  
 
Pr o p orti o n of c hil dre n wit h pre- p u b ertal le v els of s e x ster oi ds ( defi ne d as oestra di ol 
 
 n g/ m L i n b o ys) at M o nt h 9 a n d M o nt h 1 2  
 
C ha n ge i n oestra di ol l e vels i n girls a n d test oster o ne le v els i n b o ys at M o nt h 9 a n d 
M o nt h 1 2  
 
C ha n ge i n p u bertal sta ge usi n g t he Ta n ner met h o d ( ge nit al sta ge i n b o ys, breast sta ge i n 
girls a n d p u bic h air sta ge i n b ot h s e x es) at M o nt h 1 2  
 
Pr o p orti o n of c hil dre n wit h sta bilise d p u bertal sta ge c o m pare d t o baseli ne st a ge usi n g t he 
Ta n ner met h o d at M o nt h 1 2 
 
C ha n ge i n a u x ol o gical para meters i ncl u di n g hei g ht, gr o wt h vel ocit y, wei g ht a n d B MI at 
M o nt h 9 a n d M o nt h 1 2 
 
C ha n ge i n B A, differe nce bet wee n B A a n d C A at M o nt h 1 2 
 
C ha n ge i n ut eri ne le n gt h i n girls a n d t estic ular v ol u me i n b o ys at M o nt h 1 2 
1 1. 4. 7. 2  S afety E n d p oi nts 
As i n di cate d i n Secti o n 3. 3. 2 , t he e xte nsi o n p hase safet y e n d p oi nts are t he f oll o wi n g: 
 
I n ci de nce of treat me nt-e mer ge nt a d verse e ve nts ( T E A Es) t hr o u g h o ut t he st u d y, 
i ncl u di n g l ocal t ol era bilit y 
 
C ha n ge i n cli nical safet y la b orat or y ( bl o o d bi oc he mistr y, hae mat ol o g y a n d uri nal ysis) 
para meters at M o nt hs 9 a n d 1 2 
 
C ha n ge i n p h ysic al e x a mi nati o n a n d vital si g ns ( bl o o d press ure a n d heart rate) 
meas ure me nts at eac h visit 
1 1. 5  
S u b gr o u p A n al yses 
N o s u b gr o u p a nal ysis will be perf or m e d. 
1 1. 6  
I nteri m A n al yses 
N o i nteri m a nal ysis will be perf or me d. If a n u n pla n ne d i nt eri m a nal ysis is dee me d necessar y, 
t he a p pr o priat e s p o ns or me dical direct or, or desi g nee, will be c o ns ulte d t o deter mi ne w het her 
it is necessar y t o a me n d t he pr ot oc ol. 
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 if a p plica ble: 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 6 8/ 8 6 
 
( 1) 
T he first a nal ysis will be perf or me d w he n all partici pa nts ha v e c o m pl ete d t he first 
3 m o nt hs of t h e st u d y peri o d. T he c ut- off d ate c o nsi dere d f or t his a nal ysis will be t he 
date of t h e last M o nt h 3 visit f or t he last partici pa nt. All a vaila bl e data at t he ti m e of t his 
data c ut- off d ate will b e i ncl u de d i n t his a n al ysis. T he p ur p ose of t his a nal ysis will be t he 
fi nal a nal ysis of t he pri mar y efficac y e n d p oi nt, as well as t he sec o n dar y efficac y a n d 
safet y a nal yses of t he first 3 m o nt hs of t he 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 nteri m a nal ysis beca use t he first 3 m o nt hs of t he st u d y peri o d is of 
pri mar y i nterest. 
( 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 mai n st u d y ( M o nt h 6). T his re p orti n g d ata base will i ncl u de all mai n st u d y 
data 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 
e xte nsi o n p has e. T he re p orti n g data b ase will i ncl u de all e xte nsi o n p hase dat a. 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 6 9/ 8 6 
 
1 2  
DI R E C T A C C E S S T O S O U R C E D A T A A N D D O C U M E N T S 
A ut h orise d pers o n nel fr o m e xter nal c o m pete nt a ut h orities a n d S p o ns or-a ut h oris e d q ualit y 
ass ura nce pers o n nel ma y carr y o ut i ns pecti o ns a n d a u dits. T he p ur p ose of a n a u dit is t o e ns ure 
t hat et hical, r e g ulat or y a n d q ualit y re q uire me nts are f ulfille d i n all st u dies perf or me d b y t he 
S p o ns or. 
A u dit ors a n d i ns pect ors m ust ha ve direct access t o st u d y d o c u me nts a n d site f acilities as 
s pecifie d i n Secti o n 1 3. 4 a n d t o a n y ot her l ocati o ns us e d f or t he p ur p os e of t he st u d y i n q uesti o n 
(e. g. la b orat ories). 
I n t h e e ve nt of t he site bei n g n otifie d directl y of a re g ulat or y i ns pe cti o n, t he I n v esti gat or m ust 
i ns pecti o n. 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 7 0/ 8 6 
 
1 3  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E 
1 3. 1  
Pr ot oc ol A me n d me nts a n d Pr ot oc ol De vi ati o ns 
1 3. 1. 1  
Pr ot oc ol A m e n d m e nts 
N o c ha n ges fr o m t he fi nal a p pr o ve d (si g ne d) pr ot oc ol will be i nitiate d wit h o ut t he pri or writte n 
a p pr o val or fa v o ura ble o pi ni o n of t he I E C/I R B, e xce pt w he n necessar y t o eli mi nate i m me diate 
safet y c o ncer ns t o t he p artici pa nts or w h e n t he c ha n ge o nl y i n v ol ves l o gistics or a d mi nistrati o n.  
I n t he e ve nt t h at a n a me n d me nt t o t his pr ot oc ol is re q uire d, it will be classifi e d i nt o o ne of t he 
f oll o wi n g t hree cate g ories: 
 
N o n-s u bst a nti al a me n d m e nts  
(e. g. a d mi nistrati ve c ha n ges) a n d as s uc h o nl y nee d t o be n otifi e d t o t he I E Cs or 
re g ulat or y a ut h orities f or i nf or mati o n p ur p os es. 
 
S u bst a nti al a m e n d m e nts  
st u d y w h ere t he y are li kel y t o ha ve a si g nifica nt i m pact o n: 
- 
T he safet y or p h ysical or me ntal i nte grit y of t he p artici pa nts 
- 
T he scie ntific val u e of t he st u d y 
- 
T he c o n d uct or ma na ge m e nt of t he st u d y, or 
- 
T he q ualit y or safet y of t he st u d y dr u g use d i n t he st u d y. 
S u bsta ntial a me n d me nts m ust be s u b mitte d t o a n d a p pr o ve d b y t h e I E Cs a n d rele va nt 
re g ulat or y a ut h orities, acc or di n g t o l oc al re g ul ati o ns, pri or t o i m ple me nti n g c ha n ges. 
 
Ur g e nt a m e n d me nts  are t h os e t hat re q uire ur ge nt safet y meas ures t o pr otect t he st u d y 
partici pa nts fr o m i m me diate hazar d a n d as s uc h ma y be i m ple me nte d i m m e diatel y b y 
t he S p o ns or wit h s u bse q ue nt I E Cs a n d re g ulat or y a ut h orit y n otificati o n, f ort h wit h. 
T he Pri nci pal I n vesti gat or a n d t he S p o ns or will si g n all pr ot oc ol a me n d me nts. 
1 3. 1. 2  
Pr ot oc ol Devi ati o ns a n d E xce pti o ns 
s 
re pres e ntati ve. I m p orta nt pr ot oc ol de viati o ns are a s u bset of pr ot oc ol de viati o ns t hat ma y 
si g nifica ntl y i m pact t he c o m pl ete ness, acc urac y, a n d/ or relia bilit y of ke y st u d y data or t hat ma y 
- bei n g. 
A maj or pr ot oc ol de viati o n is a n y si g nifica nt di ver ge nce fr o m t he pr ot o c ol, i. e. n o n-a d here nce 
o n t he part of t he p artici pa nt, t he I n v esti gat or, or t h e S p o ns or t o pr ot oc ol-s pecific 
i ncl usi o n/e x cl usi o n criteria, pri mar y o bjecti ve e val uati o n criteria a n d/ or G C P g ui deli nes. 
Ge nerall y, a pr ot oc ol de viati o n q ualifi es as maj or if: 
( 1) 
T he de viati o n has har m e d or p ose d a si g nifica nt or s u bsta nti ve ris k of har m t o t he 
researc h partici pa nt 
( 2) 
T he de viati o n c o m pr o mis es t he scie ntific i nte grit y of t he d ata c oll ect e d f or t he st u d y 
( 3) 
T he de viati o n is a wilf ul or k n o wi n g breac h of partici pa nt pr otecti o n re g ulati o ns, 
p olicies, or pr oce d ures o n t he part of t he I n v esti gat or(s) 
( 4) 
T he de viati o n i n v ol ves a s eri o us or c o nti n ui n g n o n-c o m plia nce wit h a n y a p plica ble 
partici pa nt pr otecti o n re g ulati o ns, p oli cies, or pr oc e d ures 
( 5) 
pri n ci ples. 
See als o S ecti o n 1 1. 1. 2  f or details o n t he i m pact of maj or pr ot oc ol de viati o ns o n t he i ncl usi o n 
of partici pa nts i n eac h a n al ysis p o p ulati o n. 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 7 1/ 8 6 
 
A mi n or pr ot oc ol de viati o n is a n y si g nific a nt di ver ge nce fr o m t he pr ot oc ol t hat d oes n ot i m pact 
t he st u d y res ults. 
As a matter of p oli c y, t he S p o ns or will n ot gra nt e xce pti o ns t o pr ot oc ol-s pecific e ntr y criteria 
t o all o w p artici pa nts t o e nter t he st u d y. If u n der e xtra or di nar y circ u mst a nces s uc h acti o n is 
c o nsi dere d et hicall y, me dicall y a n d scie ntificall y j ustifie d f or a p arti c ular partici p a nt, pri or 
a p pr o val fr o m t he S p o ns or a n d t he res p o nsi ble I R B/I E C, i n acc or da nce wit h t he sta n dar d 
o perati n g pr o ce d ure ( S O P), is re q uire d b ef ore t he partici pa nt will be all o we d t o e nt er t he st u d y. 
If i n vesti gati ve ce ntre pers o n nel lear n t h at a parti ci pa nt w h o di d n ot meet pr ot oc ol eli gi bilit y 
criteria was e ntere d i n t he st u d y (a pr ot oc ol vi ol ati o n), t he y m ust i m m e diatel y i nf or m t he 
S p o ns or. S uc h partici pa nts will be disc o nti n ue d fr o m t h e st u d y, barri n g e x ce pti o nal i nst a nces 
f oll o wi n g re vie w a n d writt e n a p pr o val b y t he S p o ns or a n d t h e I R B/I E C, acc or di n g t o t he 
a p plica ble S O P. Rete nti o n of t hes e partici pa nts i n t he st u d y will be disc usse d bet wee n S p o ns or 
a n d I n vesti gat or, ta ki n g i nt o acc o u nt partici pa nt s afet y a n d d ata relia bilit y. T he I R B/I E C will 
be i nf or me d if partici pa nt safet y/ pr otecti o n is i g n ora ntl y i m pacte d. 
1 3. 2  
I nf or m ati o n t o St u d y P ers o n nel 
T o e ns ure acc urate, c o m plete a n d relia ble data, t h e S p o ns or or its re prese ntati ves will pr o vi de 
i nstr ucti o nal material t o t h e st u d y sites, as a p pr o pri ate. A st u d y i nitiati o n visit will be c o n d ucte d 
pri or t o Scree ni n g start t o i nstr uct t he I n v esti gat ors a n d st u d y c o or di nat ors. T his sessi o n will 
gi ve i nstr ucti o n o n t he pr ot oc ol, t he c o m pleti o n of t he e C R F a n d all st u d y pr oce d ures. T he 
I n v esti gat or is res p o nsi ble f or gi vi n g i nf or mati o n a b o ut t he st u d y t o all staff m e m bers i n v ol ve d 
i n t he st u d y or i n a n y ele me nt of partici p a nt ma na ge me nt, b ot h bef ore st arti n g a n y st u d y 
pr oce d ures a n d d uri n g t he c o urse of t he st u d y (e. g. w he n ne w st aff b ec o m e i n v ol ve d). T he 
I n v esti gat or m ust ass ure t hat all st u d y st aff m e m bers are q u alifie d b y e d uc ati o n, e x perie nce a n d 
trai ni n g t o perf or m t heir s pecific res p o nsi bilities. T hese st u d y staff me m bers m ust be liste d o n 
t he st u d y c e ntr e a ut h orisati o n f or m, w hic h i ncl u des a clear descri pti o n o
res p o nsi bilities. T his list m ust be u p date d t hr o u g h o ut t he st u d y, as ne cessar y. 
T he st u d y m o nit or is r es p o nsi ble f or e x plai ni n g t he pr ot oc ol t o all st u d y staff, i ncl u di n g t he 
I n v esti gat or a n d f or e ns uri n g t heir c o m plia nce wit h t he pr ot oc ol. A d diti o nal i nf or mati o n will 
be ma de a vaila bl e d uri n g t he st u d y w he n ne w staff bec o me i n v ol ve d i n t he st u d y a n d as 
ot her wise a gree d u p o n wit h eit her t h e I n vesti gat or or t he st u d y m o nit or. 
1 3. 3  
St u d y M o nit ori n g 
T he I n vesti gat or is res p o nsi ble f or t he vali dit y of all data c oll ecte d at t he site. 
T he S p o ns or is res p o nsi ble f or m o nit ori n g t hese d at a t o verif y t hat t he ri g hts a n d well bei n g of 
partici pa nts are pr ot ecte d, t hat st u d y d ata are acc urate (c o m pl ete a n d verifi a ble t o s o urce dat a) 
a n d t hat t he st u d y is c o n d ucte d i n c o m plia nce wit h t he pr ot oc ol, G C P g ui deli nes a n d re g ul at or y 
re q uire me nts. 
S p o ns or-assi g n e d m o nit ors will c o n d uct re g ul ar site visits. T he I n v esti gat or will all o w direct 
access t o all rele va nt files (f or all partici pa nts) a n d cli nical st u d y s u p pli es ( dis pe nsi n g a n d 
st ora ge areas) f or t he p ur p ose of v erif yi n g e ntries ma de i n t he e C R F a n d will assist wit h t he 
a vaila ble b y t he I n v esti gat or. 
T he site m ust c o m plete t he e C R Fs o n a n o n g oi n g basis t o all o w re g ular re vi e w b y t he st u d y 
m o nit or, b ot h re m otel y b y i nter net a n d d uri n g sit e visits.  T he ce ntral st u d y m o nit or at t he 
S p o ns or will use f u ncti o ns of t he electr o nic dat a ca pt ure ( E D C) s yste m t o a d dress a n y q ueries 
raise d w hile re vie wi n g t h e data e nt ere d b y t h e st u d y site pers o n nel i n a ti mel y ma n ner. 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 7 2/ 8 6 
 
(e. g. la b orat or y pri nt o uts), t he na m e m ust b e re dact e d b y t he sit e pers o n nel, lea vi n g t he i nitials 
visi ble, a n d a n n otat e d wit h t he partici pa nt n u m ber as i de ntificati o n. 
1 3. 4  
 
All cli nical w or k u n der t his pr ot oc ol will be c o n d ucte d acc or di n g t o I C H G C P g ui deli n es a n d 
a p plica ble l ocal re g ul ati o ns. T h e I n v esti gat or m ust b e a w are t hat t he st u d y ma y be a u dite d at 
a n y ti me b y a q ualit y ass ura nce pers o n nel desi g nate d b y t h e S p o ns or or i ns p ecte d b y re g ulat or y 
b o dies. T he I n v esti gat or m ust a d here t o I C H G C P g ui deli nes i n a d diti o n t o a n y a p plica ble l ocal 
re g ulati o ns. 
If re q uest e d, t he I n vesti gat or will pr o vi de t he S p o ns or, a p pli ca bl e re g ul at or y a ge nci es a n d 
a p plica ble Et hics C o m mittees ( E Cs) wit h direct a ccess t o a n y ori gi nal s o urce d oc u me nts. 
T he I n vesti gat or(s) s h o ul d de m o nstrate d ue dili ge nce i n recr uit m e nt a n d s cree ni n g of p ot e nti al 
st u d y p artici pa nts. T he e nr ol me nt rate s h o ul d be s ufficie nt t o c o m plete t he st u d y as a gree d u p o n 
wit h t he S p o ns or. T h e S p o ns or s h o ul d be n otifie d of a n y pr oj ecte d dela ys t hat ma y i m pact t he 
c o m pleti o n of t he st u d y. 
T his cli nical trial will be c o n d ucte d i n c o m pli a nce wit h all i nter nati o nal l a ws a n d re g ulati o ns 
a n d nati o nal l a ws a n d re g ulati o ns of t he c o u ntr y(i es) i n w hic h t he cli nical tri al is perf or me d, as 
well as a n y a p plica ble g ui deli nes. 
1 3. 5  
A u dit a n d I ns p ecti o n 
A ut h orise d pers o n nel fr o
Ass ura nce pers o n n el ma y carr y o ut i ns pecti o ns a n d a u dits (see Secti o n 1 2 ). 
1 3. 6  
D at a Q u alit y Ass ur a nce 
M o nit ore d e C R Fs tr a nsf erre d fr o m t he i n v esti gati o nal site t o t he assi g n e d data ma na ge me nt 
gr o u p will be re vie we d (sec o n dar y m o nit ori n g) f or c o m pl ete ness, c o nsiste nc y, le gi bilit y a n d 
pr ot oc ol c o m plia n ce. 
Reas o ns s h o ul d be gi ve n o n t he rele v a nt e C R F f or a n y missi n g dat a a n d ot her pr ot oc ol 
de viati o ns. A n y el ectr o ni c q ueries a n d ite ms n ot a de q uatel y e x plai ne d will re q uire a d diti o nal 
electr o nic 
m a n ual 
q u eries t o 
be raise d t o t he I n vesti gat or 
b y t he 
m o nit or f or 
clarificati o n/c orrecti o n. T he I n vesti gat or m ust e ns ure t hat q ueries are d ealt wit h pr o m ptl y. All 
data c ha n ges a n d cl arificati o ns ca n be vie we d i n t he a u dit trail f u ncti o n of t he e C R F. 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 7 3/ 8 6 
 
1 4  
E T HI C S 
1 4. 1  
C o m pli a nce wit h G o o d Cli ni c al Pr acti ce a n d Et hic al C o nsi d er ati o ns 
T his st u d y will be c o n d ucte d i n c o m plia nce wit h I E Cs/I R Bs, i nf or m e d c o ns e nt re g ulati o ns, t he 
Declarati o n of Helsi n ki a n d I C H G C P g ui deli nes ( S ecti o n 1. 3 ). 
I n a d diti o n, t his st u d y will a d here t o all l ocal re g ulat or y re q uire m e nts.  
Bef ore i nitiati n g t he st u d y, t he I n vesti gat or/i nstit uti o n 
m ust ha ve 
writte n a n d d at e d 
a p pr o val/fa v o ura ble o pi ni o n fr o m t he I E C/I R B f or t he st u d y pr ot oc ol/ a me n d me nt(s), writte n 
i nf or me d c o ns e nt f or m, a n y c o ns e nt f or m u p dates, partici pa nt e mer ge n c y st u d y c o ntact car ds, 
partici pa nt recr uit me nt pr oce d ures (e. g. a d vertis e m e nts), a n y writte n i nf or mati o n t o be pr o vi de d 
t o partici pa nts a n d a st ate m e nt fr o m t he I E C/I R B t hat t he y c o m pl y wit h G C P re q uire me nts. T he 
I E C/I R B a p pr o v al m ust i de ntif y t he pr ot oc ol versi o n as well as t he d oc u m e nts re vie we d. 
After I E C/I R B a p pr o val, c ha n ges will re q uire a f or mal a me n d me nt. O nce t h e st u d y h as starte d, 
a me n d m e nts s h o ul d be ma de o nl y i n e x ce pti o nal circ u msta nces. C ha n ges t hat d o n ot affect 
partici pa nt safet y or data i nte grit y are classifie d as a d mi nistrati ve c ha n ges a n d ge nerall y d o n ot 
re q uire et hical a p pr o val. If et hicall y rele v a nt as pects are c o nc er ne d, t h e I E C/I R B m ust be 
i nf or me d a n d, if n ecess ar y, a p pr o v al s o u g ht pri or t o i m ple m e ntati o n. Et hi cal a p pr o val o n 
a d mi nistrati ve c ha n ges will be o btai ne d if re q uire d b y l ocal/site I E C/I R B. 
1 4. 2  
I nf or me d C o ns e nt f or P artici p ati o n i n t h e St u d y 
 
T he i nf or me d c o nse nt f or m a n d a n y partici pa nt/asse nt recr 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 ulat 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 pli ca bl e pri vac y la ws. T he y m ust b e a p pr o ve d pri or t o us e as des cri be d i n 
Secti o n 1 4. 1 . 
 
T he i n vesti gat or or his/ h er a ut h orise d re prese nt ati ve will e x plai n t o t he partici pa nt a n d 
t heir le gall y a ut h orise d re prese ntati ve t he nat ure a n d o bjecti ves of t he st u d y a n d p ossi ble 
ris ks a n d be nefits ass ociate d wit h t he partici p ati 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. 
 
Partici pa nts a n d t heir le gall y a ut h orise d re pres e ntati ve 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/ h er a ut h orise d re prese ntati ve will o btai n writte n i nf or me d 
c o nse nt/asse nt fr o m eac h partici pa nt a n d t h e le gall y a ut h orise d re pres e ntati ve bef ore a n y 
st u d y-s pecific pr oce d ure is perf or m e d. T h e i n vesti gat or will retai n t he ori gi nal of eac h 
 
 
A c o p y of t he si g n e d i nf or me d c o nse nt m ust be pr o vi de d t o t he partici pa nt a n d t heir 
le 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 orise d pers o n o btai ni n g t he i nf or me d c o nse nt m ust als o si g n t he 
i nf or me d c o nse nt f or m. 
 
Partici pa nts m ust be re-c o nse nt e d t o t he m ost c urre nt versi o n of t he i nf or me d c o nse nt 
f or m d uri n g t heir partici pati o n i n t he st u d y. If c h a n ges t o t he i nf or me d c o nse nt d o n ot 
a p pl y t o all partici pa nts, t his will be c o m m u nicate d t o t he I R B/I E C wit h a rati o nale. 
I R B/I E C a p pr o val 
m ust be rec ei ve d b ef ore i m ple m e ntati o n as re q uire d b y l o cal 
re g ulati o ns. 
Partici pa nts will be t ol d t hat t he y are free t o ref use t o partici pate a n d ma y wit h dra w t h eir 
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 he st u d y. 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 7 4/ 8 6 
 
1 4. 3  
He alt h A ut h orities a n d I n de pe n de nt Et hics C o m mittees/I nstit uti o n al Re vie w 
B o ar ds 
re g ulat or y as pects are c o vere d a n d o btai n a p pr o v al of t he a p pr o priate re g ulat or y b o dies, pri or 
t o st u d y i nitiati o n i n re gi o ns w here a n a p pr o val is re q uire d. 
T he f oll o wi n g d oc u me nts s h o ul d be s u b mitte d t o t he rele v a nt E C/I R B f or re vie w a n d a p pr o v al 
t o c o n d uct t he st u d y (t his list ma y n ot b e e x ha usti ve): 
 
Pr ot oc ol/a me n d m e nt(s) a p pr o ve d b y t he S p o ns or 
 
C urre ntl y a p plica ble I B or pac ka g e la belli n g 
 
Rele v
 
 
Partici pa nt i nf or mati o n a n d i nf or m e d c o nse nt d oc u m e nt(s) a n d f or m(s) 
 
Partici pa nt e mer ge nc y st u d y c o nt act car ds 
 
Recr uit me nt pr oce d ures/ materials (a d v ertis e m e nts), if a n y. 
T he E C(s) will re vie w all s u b missi o n d oc u me nts as re q uire d a n d a writte n fa v o ura ble o pi ni o n 
f or t he c o n d uct of t he st u d y s h o ul d be ma de a vail a ble t o t he I n vesti gat or bef ore i nitiati n g t he 
st u d y. T his d oc u me nt m ust be date d a n d clearl y i de ntif y t he versi o n n u m b er(s) a n d date(s) of 
t he d oc u me nts s u b mitte d/re vie we d a n d s h o ul d i ncl u de a state me nt fr o m t he E C t hat t he y 
c o m pl y wit h G C P re q uire me nts. 
T he st u d y ma y be gi n at t he i n vesti gati o nal site(s) o nl y after recei vi n g t his dat e d a n d si g ne d 
d oc u me nt ati o n of t he E C a p pr o val or fa v o ura ble o pi ni o n. 
D uri n g t h e st u d y, a n y u p date t o t he f oll o wi n g d oc u m e nts will be s e nt t o t he E C, eit her f or 
i nf or mati o n, or f or re vie w a n d a p pr o v al, de p e n di n g o n h o w s u bsta ntial t h e m o dificati o ns are: 
( 1) I B; ( 2) re p orts of S A Es; ( 3) all pr ot oc ol a me n d me nts a n d re vise d i nf or me d c o ns e nt(s), if 
a n y. 
At t he e n d of t he st u d y, t he E C will be n otifie d a b o ut st u d y c o m pleti o n. 
1 4. 4  
C o nfi d e nti alit y Re g ar di n g St u d y P artici p a nts 
T he I n v esti gat or m ust ass ure t hat t he pri v ac y of t he partici pa nts, i ncl u di n g t heir pers o nal 
i de ntit y a n d all pers o nal me dical i nf or mati o n, will b e mai ntai ne d at all ti mes. I n e C R Fs a n d 
ot her d oc u me nts or i ma ge materi al s u b mitt e d t o t he S p o ns or, partici pa nts will be i de ntifie d n ot 
b y t heir n a mes b ut b y a n i de ntificati o n c o de (e. g. i nitials a n d i de ntificati o n n u m ber). 
Pers o nal me dical i nf or m ati o n ma y be re vie we d f or t he p ur p os e of verif yi n g data rec or de d o n 
t he e C R F. T his re vie w ma y be c o n d ucte d b y t h e st u d y m o nit or, pr o perl y a ut h orise d pers o ns o n 
be half of t he S p o ns or, t h e q ualit y ass ura nc e u nit, or re g ulat or y a ut h oriti es. P ers o nal me di cal 
i nf or mati o n will al wa ys b e treate d as c o nfi d e nti al. 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 7 5/ 8 6 
 
1 5  
D A T A H A N D LI N G A N D R E C O R D K E E PI N G 
1 5. 1  
Rec o r di n g of St u d y D at a 
I n c o m pli a nce wit h G C P g ui deli nes, t he me dical rec or ds/ me dic al n otes, etc., s h o ul d be clearl y 
mar ke d a n d per mit eas y i de ntificati o n of 
st u d y. 
T he I n vesti gat or m ust rec or d all data relati n g t o pr ot oc ol pr oce d ures, tri pt oreli n a d mi nistrati o n, 
la b orat or y d ata, safet y d ata a n d effi cac y r ati n gs o n t he e C R Fs pr o vi d e d f or t he st u d y. T he 
I n v esti gat or, b y c o m pleti n g t he si g n at ure l o g, ma y f or mall y desi g nate a ut h orit y t o c o m pl et e 
e C R Fs t o a p pr o priat el y q ualifie d staff ha vi n g certifie d user acc ess t o t he e C R F . P arti ci pa nt 
c o m plete d diaries a n d q u esti o n naires will be pri nt e d or electr o nic. 
T he I n v esti gat or m ust, as a mi ni m u m, pr o vi de a n electr o nic si g n at ure (e-si g n at ure) t o eac h case 
re p ort b o o k t o attest t o t he acc urac y a n d c o m pl ete ness of all t he data. If a n y c ha n ges ar e ma de 
t o t he e C R F after a f or m has bee n l o c ke d a n d electr o nicall y si g ne d, t h e I n v esti gat or will be 
re q uire d t o perf or m a n a d diti o nal e-si g nat ure a ut h orisi n g a gree me nt wit h a n y ne w i nf or mati o n 
or c ha n ges t o t he e C R F. 
All c orrecti o ns o n t he e C R F will be a ut o m ati call y trac ke d a n d a reas o n f or c ha n ge is al wa ys 
re q uire d. I n t he e C R F, t he a u dit trail f u n cti o n will all o w t he c h a n ges ma de t o b e vie we d o n eac h 
ite m e nt ere d. 
1 5. 2  
D at a M a n a ge me nt 
A n E D C s yst e m will be utilis e d f or c ollecti n g parti ci pa nt data. Eac h sit e is re q uire d t o ha ve a 
c o m p uter a n d i nter net c o n necti o n a vail a ble f or site e ntr y of cli nical data. All e ntries i n t he e C R F 
will be ma de u n der t he e-si g nat ure of t he pers o n perf or mi n g t he acti o n. T his electr o nic si g nat ure 
c o nsists of a n i n di vi d ual a n d c o nfi de ntial user na me a n d pass w or d c o m bi nati o n. It is declare d t o be 
t he le gall y bi n di n g e q ui vale nt of t he ha n d writte n si g nat ure. O nl y S p o ns or-a ut h orise d users will 
ha ve access t o t he e C R F as a p pr o priate t o t heir st u d y res p o nsi bilities. Users m ust ha ve s uccessf ull y 
u n der g o ne s oft ware a p plicati o n trai ni n g pri or t o e nteri n g data i nt o t he e C R F. 
de part m
bei n g recei ve d i n- h o use at t he assi g ne d C R O, t he y will be m o nit ore d at t he i n vesti gati o nal site (f or 
f urt her details see Secti o n 1 3. 3 ). T he e C R F a n d ot her data d oc u me ntati o n re m o ve d fr o m t he 
i n vesti gati o nal site(s) will be trac ke d b y t he C R O a n d t he m o nit or. 
T he S p o ns or will e ns ure t hat a n a p pr o priat e e C R F is de vel o p e d t o ca pt ure t he data a cc uratel y 
a n d s uita ble q ueries are raise d t o res ol ve a n y missi n g or i nc o nsiste nt  dat a. T he I n vesti gat or will 
recei v e t heir d ata, fr o m t he cli nical st u d y, i n a n el ectr o nic f or mat ( P D F files) w hi c h will be a n 
e x act c o p y of t he e C R F a n d will i ncl u de t he f ull a u dit trail, f or arc hi vi n g p ur p oses a n d f ut ure 
refere nce. 
A n y q ueri es ge n erate d d uri n g t he d ata ma n a ge m e nt pr ocess will als o be tra c ke d b y t he 
c o ntracte d dat a m a na ge me nt C R O/ will be rais e d wit hi n t he E D C s yste m. It is t he ce ntral st u d y 
 
T he S p o ns or will als o e ns ure t h at S A E d ata c ollecte d i n t he e C R F are c o nsiste nt wit h 
- versa).  
T he c o di n g of a n A E, m e dical hist or y, s ur gical pr oce d ures a n d c o nc o mita nt me dicati o n t er ms 
will be perf or m e d b y t h e c o ntracte d C R O directe d b y t he S p o ns or
re vie we d a n d a p pr o ve d b y t he S p o ns or. C o nc o mita nt me dicati o ns will be c o de d usi n g 
W H O- D D a n d A Es/ me di cal hist or y t er ms will be c o de d usi n g M e d D R A. 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 7 6/ 8 6 
 
O nl y data fr o m e nr olle d partici pa nts will be re p ort e d i n t he e C R Fs a n d c ollecte d i n t he 
 
F or scree n fail ure p artici pa nts, o nl y t he u ni q ue partici pa nt i de ntifier, t h e date of i nf or me d 
c o nse nt si g nat ure, t he reas o n w h y t he partici pa nt faile d scree ni n g a n d t he p ote ntial A Es w hic h 
occ urre d d uri n g t h e scree ni n g p has e will be re p orte d i n t he e C R Fs a n d c ollecte d i n t he 
 
1 5. 3  
Rec o r d Arc hi vi n g a n d Rete nti o n 
D uri n g t he pre-st u d y a n d i nitiati o n visits, t he m o nit or m ust e ns ure t hat t h e arc hi vi n g facilities 
are a de q uate a n d t hat t h e arc hi vi n g/rete nti o n res p o nsi bilities of t he I n vesti gat or ha ve bee n 
disc usse d.  
St u d y d o c u m e nts s h o ul d be retai ne d f or at least 2 years aft er t he l ast a p pr o val of a mar keti n g 
a p plicati o n i n a n I C H re gi o n a n d u ntil t here are n o pe n di n g or pla n n e d mar keti n g a p pli cati o ns 
i n a n I C H re gi o n (t hat is at least 1 5 years) or at l east 2 years ha v e ela pse d si nce t he f or mal 
disc o nti n uati o n of cli nical de vel o p me nt of t h e pr o d uct. H o we v er, t hese d oc u me nts s h o ul d be 
retai n e d f or a l o n ger p eri o d if re q uire d b y t h e a p plica ble re g ulat or y re q uire me nts or b y 
a gree m e nt wit h t he S p o ns or. T he I n vesti gat or s h o ul d ta ke meas ures t o pre ve nt acci de ntal or 
pre mat ure destr ucti o n of t hese d oc u me nts. T he fi nal arc hi vi n g arra n ge me nts will be c o nfir me d b y 
t he m o nit or w he n cl osi n g o ut t he site. T he S p o ns or will i nf or m t he I n v esti gat or, i n writi n g, as t o 
w he n t hese d o c u m e nts n o l o n ger nee d t o be retai n e d. 
If t he Pri nci pal I n v esti gat or rel oc ates or retires, or ot her wis e wit h dra ws his/ h er res p o nsi bilit y 
f or mai nte na n ce a n d r ete nti o n of st u d y d o c u m e nts, t he S p o ns or m ust be n otifie d ( prefera bl y i n 
writi n g) s o t hat a de q uate pr o visi o n ca n be ma de f or t heir f ut ure m ai nt e na nce a n d ret e nti o n. 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 7 7/ 8 6 
 
1 6  
FI N A N CI N G A N D I N S U R A N C E 
1 6. 1  
C o ntr act u al a n d Fi n a nci al Det ails 
T he I n vesti gat or (a n d/ or, as a p pr o pri ate, t he h os pital a d mi nistrati ve re prese ntati ve) a n d t he 
S p o ns or will si g n a cli nical st u d y a gree me nt pri or t o t he start of t he st u d y, o utli ni n g o verall 
S p o ns or a n d I n v esti gat or res p o nsi bilities i n relati o n t o t he st u d y. Fi na ncial re m u nerati o n will 
c o ver t h e c ost per i ncl u d e d partici pa nt, base d o n t he cal c ulate d c osts of perf or mi n g t he st u d y 
assess me nts i n acc or d a n ce wit h t he pr ot oc ol a n d t he s pecifie d ter ms of pa y m e nt will be 
descri be d i n t he c o ntract. T he c o ntract s h o ul d descri be w het h er c osts f or p h ar mac y, l a b orat or y 
a n d ot her pr ot oc ol re q uir e d ser vices are bei n g pai d directl y or i n directl y. 
1 6. 2  
I ns ur a nce, I n de m nit y a n d C o m pe ns ati o n 
T he S p o ns or will pr o vi de pr o d uct li a bilit y i ns ura n ce f or all parti ci pa nts i ncl u de d i n t he cli nical 
st u d y. W here re q uire d, a h os pital-s pecific i n de m nit y a gree me nt will be us e d. 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 7 8/ 8 6 
 
1 7  
R E P O R TI N G A N D P U B LI C A TI O N O F R E S U L T S 
1 7. 1  
P u blic ati o n P olic y 
T he S p o ns or is c o m mitte d t o discl osi n g i nf or m ati o n a b o ut t he cli nical trials it s p o ns ors. Res ults 
will be c o m m u nicate d at scie ntific meeti n gs a n d all reas o na ble eff orts m ust be ma de t o see k 
p u blicati o n i n a peer-re vi e we d scie ntific j o ur nal. S pecific p u blicati o n c o nce pts, i ncl u di n g data 
t o be c o vere d, tar get c o n gress/j o ur nal a n d pr o p ose d a ut h ors, s h o ul d be dis c usse d wit h t he 
a p pr o priate gl o bal p u bli cati o ns ma n a ger a n d i nc or p orat e d i n t he rele va nt p u blicati o n pla n 
bef ore i nitiati o n. A de dicate d p u blicati o ns c o m mittee, i n v ol vi n g i ntereste d me m bers of t he 
st u d y steeri n g c o m mittee as well as t he gl o b al p u blicati o ns ma na ger, ma y be esta blis he d t o pl a n 
s pecific p u blicati o ns. At a mi ni m u m, s u m mar y r es ults of t his st u d y s h o ul d be p oste d o n t he 
rele va nt cli nical trial re gistr y. W he n t he trial has bee n c o n d ucte d b y a lar ge m ulti ce ntre gr o u p, 
res p o nsi ble p h ysicia n s h o ul d disc uss a n d a gree u p o n t he s electi o n of a ut h ors f or pla n ne d 
p u blicati o ns i n a d va nce. T he y ma y deci de t o use a gr o u p na me a n d n o mi nate a ut h ors o n be half 
of t he st u d y gr o u p. All c o ntri b uti n g I n v esti gat ors will be liste d i n t he ac k n o wle d ge m e nts 
t o get her wit h a n y ot h ers w h o ma y ha v e c o ntri b ute d b ut n ot s ufficie ntl y t o q ualif y f or 
a ut h ors hi p. 
Selecti o n of a ut h ors f or s ci e ntific p u blicati o ns will f oll o w t he I nt er nati o nal C o m mittee of 
Me dical J o ur nal E dit ors g ui d eli nes  
(a vaila ble 
fr o m 
htt p:// w w w.ic mje. or g/rec o m me n d ati o ns/ br o wse/ m a n uscri pt-
pre parati o n/ pre pari n g-f or-s u b missi o n. ht ml). I n p artic ular, t h ose na me d as a ut h ors, w het her 
partici pat e d s uffi cie ntl y i n t he w or k t o ta ke p u blic res p o nsi bi
 
A ut h ors hi p cre dit s h o ul d be base d o n: 
 
S u bsta ntial c o ntri b uti o ns t o t he c o nce pti o n a n d d esi g n, or ac q uisiti o n of data, or a nal ysis 
a n d i nt er pret ati o n of data 
 
Drafti n g t h e article or re visi n g it criticall y f or i m p orta nt i ntellect ual c o nte nt 
 
Fi nal a p pr o v al of t he versi o n t o be p u blis h e d 
 
A gree me nt t o be acc o u nt a bl e f or all as pects f or t he w or k, t here b y e ns uri n g t hat q uesti o ns 
relate d t o t he acc urac y or i nte grit y of a n y part of t h e w or k were a p pr o priatel y i n vesti gate d 
a n d res ol ve d. 
All a ut h ors of a ma n us cri pt s h o ul d meet all f o ur criteria. Eac h a ut h or m ust a gree t o t heir 
i ncl usi o n i n t he list of a ut h ors. Use of pr ofessi o nal me dical writi n g s u p p ort ma y b e e m pl o ye d.  
Res ol uti o n of scie ntific differe n ces i n t he prese ntati o n or i nter pret ati o n of st u d y fi n di n gs will 
be c o n d ucte d al o n g pri n ci ples of h o nest scie ntific de bate. T he S p o ns or s hall be pr o m ptl y 
n otifie d of a n y a me n d me nts s u bse q ue ntl y r e q ueste d b y referees or j o ur nal e dit ors. 
All p u blicati o ns arisi n g fr o m t his st u d y will be re vi e we d b y rele va nt f u n cti o ns at t he S p o ns or, 
c o or di nate d b y t he gl o b al p u blicati o ns tea m. Re q uests a n d s u g gesti o ns f or c ha n ges will be 
disc usse d wit h all a ut h ors (a n d 
me dic al writer, if a p plica ble). Res ol uti o n of scie ntific 
differe n ces i n t he prese ntati o n or i nter pretati o n of st u d y fi n di n gs will be c o n d ucte d al o n g 
a fi nal versi o n f or s u b missi o n ca n be a p pr o ve d b y t he a ut h or tea m. 
If pate nt a bilit y w o ul d be a d versel y affect e d b y p u blicati o n, t his will be dela ye d u ntil (i) a p ate nt 
a p plicati o n is file d f or t h e c o nte nt of t he p u blicati o n i n acc or da nce wit h a p plica ble pr o visi o ns 
of t he cli nical trial a gree me nt c o ncer ne d, (ii) t h e S p o ns or c o nse nts t o t he p u blicati o n, or (iii) t he 
ti me peri o d as ma y be a gree d u p o n i n t he c o ntract ual arra n ge me nts, i ncl u di n g cli nical trial 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 7 9/ 8 6 
 
after recei pt of t he pr o p os e d p u blicati o n b y t he S p o ns or, w hic he ver of (i), (ii) or (iii) occ urs 
first.  
1 7. 2  
Cli nic al St u d y Re p ort 
A fi nal cli nical st u d y re p ort ( C S R) will be pre p are d acc or di n g t o t h e I C H a n d Nati o nal M e di cal 
Pr o d ucts A d mi nistrati o n g ui deli ne o n str uct ure a n d c o nte nts of C S Rs. A fi nal C S R will be 
pre pare d w here a n y p arti ci pa nt has si g ne d i nf or m e d c o nse nt, re gar dl ess of w het her t he st u d y is 
c o m plete d or pre mat urel y t er mi nat e d. 
W here a p pr o priate, a n a b bre viate d re p ort ma y be 
pre pare d. T he C S R will c o m pl y wit h a n y a p plic a ble re g ul at or y re q uire me nts, nati o nal l a ws i n 
f orce. 
If a p plica ble, a mai n C S R will be writte n t o re p ort t he pri mar y e n d p oi nt. If re q uire d, a C S R 
A d de n d u m will s u bse q ue ntl y be a d de d t o s u m marise t he re mai n der of t he data fr o m after t he 
pri mar y e n d p oi nt. 

I P S E N G R O U P 
D- C N- 5 2 0 1 4- 2 4 3 
 
C O N FI D E N TI A L 
FI N A L P R O T O C O L ( WI T H A M E N D M E N T # 3): V E R SI O N 4. 0, 0 9 J U L Y 2 0 2 1 
P A G E 8 0/ 8 6 
 
1 8  
R E F E R E N C E S 
1  
Bertell o ni S, Bar o ncelli G. C urre nt P har mac ot hera p y of C e ntral Prec oci o us P u bert y b y 
G n R H 
A nal o gs: 
Certai nties a n d 
U ncert ai nties. 
E x p ert 
O pi n 
P har mac ot hera p y 
2 0 1 3; 1 4: 1 6 2 7- 3 9. 
2  
Carel J- C, Bl u m ber g J, Se y m ore C et al. T hree- M o nt h S ustai ne d-release Tri pt oreli n 
( 1 1. 2 5 
m g) i n t he Treat me nt of Ce ntral Prec oci o us P u bert y. E ur J E n d ocri n ol 
2 0 0 6; 1 5 4: 1 1 9- 2 4. 
3  
Carel J- C, Le ger J. Prec oci o us P u bert y. N E n gl J Me d 2 0 0 8; 3 5 8( 2 2): 2 3 6 6- 7 7. 
4  
Carel, J- C, E u gst er E, R o g ol A et al. E S P E- L W P E S G n R H A nal o gs C o nse ns us 
C o nfere nce Gr o u p - C o nse ns us State me nt o n T he Use of G o n a d otr o pi n-rel easi n g 
H or m o ne A nal o gs I n C hil dre n. P e diatrics 2 0 0 9; 1 2 3( 4):e 7 5 2-e 7 6 2. 
5  
C o mite F, C utl er G B, Ri vier J et al. S h ort-ter m Treat me nt of I di o pat hi c Prec oci o us 
P u bert y wit h A L o n g-acti n g A nal o g u e of L utei ni zi n g H or m o ne-releasi n g H or m o ne: A 
Preli mi nar y Re p ort. N E n gl J Me d 1 9 8 1; 3 0 5. 2 6: 1 5 4 6- 5 0. 
6  
Cr o wle y W, C o mit e F, Vale W et al. T hera pe utic Use of Pit uitar y Oese nsitiz ati o n Wit h 
A L o n g- Acti n g L H R M A g o nist: A P ot e ntial Ne w Treat me nt f or I di o pat hic Prec oci o us 
P u bert y. J Cli n E n d ocri n ol Meta b ol 1 9 8 1; 5 2: 3 7 0- 2. 
7  
D ura n d A, Ta u ber M, Patel B et al. Meta-a n al ysis of Pae diatric Pati e nts wit h Ce ntral 
Prec oci o us 
P u bert y 
Treate d 
wit h 
I ntra m usc ular 
Tri pt oreli n 
1 1. 2 5 
m g 
3-
M o nt h Pr ol o n ge d-releas e F or m ulati o n. H or m Res Pae diatr 2 0 1 7; 8 7( 4): 2 2 4- 3 2. 
8  
Gre ulic h W, a n
- 5 1. 
9  
H u H Y C he n g H, 
Wa n g H L et al. E pi de mi ol o gical A nal ysis of S e x ual Prec ocit y of 
 Years Ol d i n Ji u Jia n g. C hi n J C hil d Healt h Care 2 0 1 2; 2 0: 9 8 5- 7. 
1 0  
Kris h na K, F u q u a J, R o g ol A et al. Us e of G o n a d otr o pi n-rel easi n g H or m o ne A nal o gs i n 
C hil dre n: U p date b y A n I nter nati o nal C o ns orti u m. H or m Res Pae diatr 2 0 1 9; 9 1: 3 5 7- 7 2. 
1 1  
Li n F, Z he n g C, Pa n L et al. I n v esti g ati o n a n d Res earc h A b o ut Prec oci o us P u bert y i n 
Easter n C oast of Z h ejia n g Pr o vi nc e. J A p pl Cli n Pe diatr 2 0 0 4; 1 9: 6 4 0- 2. 
1 2  
Martí nez- A g u a y o A, Her má n dez M, Beas F et al. Treat m e nt of Ce ntral Prec oci o us 
P u bert y wit h Tri pt oreli n 1 1. 2 5 m g De p ot F or m ulati o n. J Pe diatr E n d ocri n ol Meta b ol 
2 0 0 6; 1 9: 9 6 3- 7 0. 
1 3  
Rese n de E A, Lara B H, Reis J D et al. Assess me nt of Basal a n d G o n a d otr o pi n-rel easi n g 
H or m o ne-sti m ul ate d 
G o na d otr o pi ns 
b y 
I m m u n oc h e mil u mi n o metric 
a n d 
I m m u n ofl u or o metric 
Assa ys i n 
N or m al 
C hil dre n. J 
Cli n 
E n d ocri n ol 
Meta b ol 
2 0 0 7; 9 2( 4): 1 4 2 4- 9. 
1 4  
Wei H Y, C he n Y, Li C et al. St u d y o n Pre vale n ce of Prec oci o us P u bert y i n C hil dre n i n 
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