Conditions: Central Precocious Puberty
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 32
Healthy volunteers: no

Brief summary:
The purpose of this research was to confirm the effectiveness and safety of the study drug, Triptorelin pamoate 15mg 3-month formulation, in a Chinese population of Central Precocious Puberty (CPP) children.

Detailed description:

Arms:
arm 1: Triptorelin was injected at day 1 and month 3.

If participants were willing to enter the extension phase, two additional Triptorelin injections were given at month 6 and month 9.

Interventions: intervention 1: Triptorelin pamoate 15mg
Intervention descriptions: intervention 1: Intramuscular injection (IM)

Protocol document:
Prot_000.pdf: 
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 
Z he n gz h o u Re gi o n. J A p pl Cli n Pe diatr 2 0 1 0; 2 5: 1 5 6 8- 7 0. 
1 5  
Ze n at y D, Bl u m ber g J, Li ya n a ge N et al. A 6- M o nt h Tri al of t he Efficac y a n d S afet y of 
Tri pt oreli n Pa m oate ( 1 1. 2 5 m g) E ver y 3 M o nt hs i n C hil dre n wit h Prec oci o us P u b ert y: A 
Retr os pecti ve C o m paris o n wit h Tri pt oreli n Acetate. H or m Res Pae di atr 2 0 1 6; 8 6: 1 8 8- 9 5. 

SAP_001.pdf: 






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TABLE OF CONTENTS 
1 
INTRODUCTION ........................................................................................................... 8 
2 
PROTOCOL OVERVIEW ............................................................................................ 8 
2.1 
Study Objectives and Hypotheses .................................................................................. 8 
2.1.1 
Objectives of the Main study phase ............................................................... 8 
2.1.1.1 
Primary objective ........................................................................................... 8 
2.1.1.2 
Secondary Objectives ..................................................................................... 8 
2.1.1.3 
Exploratory Objective ...................................................................................... 8 
2.1.2 
Objectives of the Extension Phase ................................................................ 9 
2.1.3 
Study Hypothesis ........................................................................................... 9 
2.2 
Overall Study Design and Investigational Plan ............................................................ 9 
2.3 
Sample Size Determination and Power........................................................................ 10 
2.4 
Randomization and Blinding (if applicable) ............................................................... 11 
2.5 
Schedule of Assessments ............................................................................................... 11 
2.6 
Change from Statistical Section of the Protocol ......................................................... 11 
3 
PLANNED ANALYSES ................................................................................................ 11 
3.1 
Data Monitoring ............................................................................................................ 11 
3.2 
Interim Analysis / Other Analyses ................................................................................ 11 
3.3 
Final Analysis ................................................................................................................ 11 
4 
ANALYSIS POPULATIONS (SETS) ......................................................................... 11 
4.1 
Populations Analysed ..................................................................................................... 12 
5 
STATISTICAL METHODS/ANALYSES .................................................................. 12 
5.1 
General Considerations ................................................................................................ 12 
5.1.1 
Outputs Presentation ................................................................................... 12 
5.1.1.1 
Tables Header .............................................................................................. 12 
5.1.1.2 
Presentation of Gender Group ..................................................................... 12 
5.1.1.3 
Presentation of Visits / Timepoints ............................................................... 13 
5.1.2 
Descriptive Statistics .................................................................................... 13 
5.1.3 
Baseline Value .............................................................................................. 13 
5.1.4 
Reference Start Date and Study Day .......................................................... 13 
5.2 
Disposition and Population ............................................................................................ 13 
5.3 
Protocol Deviations ........................................................................................................ 14 
5.4 
Demography and Other baseline characteristics ........................................................ 14 
5.5 
Medical history, non-drug therapies, medications and surgical procedures ........... 15 
5.6 
Compliance .................................................................................................................... 16 
5.7 
Efficacy (Main Study Phase) ........................................................................................ 16 
5.7.1 
General Considerations ............................................................................... 16 
5.7.1.1 
Significance Testing and Estimations ........................................................... 16 
5.7.1.2 
Statistical/analytical issues ........................................................................... 16 


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5.7.2 
Analysis of Primary Efficacy Endpoint ...................................................... 17 
5.7.2.1 
Endpoint ....................................................................................................... 17 
5.7.2.2 
Primary Analysis .......................................................................................... 17 
5.7.2.3 
Sensitivity Analysis ....................................................................................... 17 
5.7.2.4 
Supplementary Analysis ............................................................................... 17 
5.7.2.5 
Subgroup Analysis ........................................................................................ 17 
5.7.3 
Analysis of Secondary Efficacy Endpoints ................................................. 17 
5.7.3.1 
Endpoint, Treatment Effect and Estimand Definition ................................... 17 
5.7.3.2 
Secondary Analysis ....................................................................................... 19 
5.7.3.3 
Sensitivity Analysis ....................................................................................... 19 
5.7.3.4 
Subgroup Analysis ........................................................................................ 19 
5.8 
Safety (Main Phase) ....................................................................................................... 19 
5.8.1 
General Consideration ................................................................................ 19 
5.8.2 
Extent of exposure ....................................................................................... 19 
5.8.3 
Adverse Event .............................................................................................. 20 
5.8.4 
Laboratory Data ........................................................................................... 22 
5.8.5 
Vital Signs .................................................................................................... 22 
5.8.6 
Electrocardiogram (ECG) ........................................................................... 22 
5.8.7 
Physical Examination................................................................................... 22 
5.8.8 
Other (if applicable) .................................................................................... 22 
5.9 
Efficacy and Safety Evaluations (Extension Phase) .................................................... 23 
5.9.1 
Efficacy Endpoint for Extension Phase ..................................................... 23 
5.9.2 
Safety Endpoint for Extension Phase ......................................................... 24 
5.10 Pharmacokinetics .......................................................................................................... 24 
5.11 Anti-drug Antibodies (if applicable) ............................................................................ 25 
5.12 Pharmacodynamics (if applicable) ............................................................................... 25 
6 
DATA HANDLING ....................................................................................................... 25 
6.1 
Visit window .................................................................................................................. 25 
6.2 
Unscheduled Visits, Retest, Withdrawal Visit, ........................................................... 25 
7 
DERIVED DATA (IF APPLICABLE) ........................................................................ 25 
8 
REFERENCES .............................................................................................................. 26 
9 
APPENDICES ............................................................................................................... 28 
A1. SAS code ......................................................................................................................... 28 
A2. Partial/Missing Date Convention ................................................................................. 29 
Algorithm for Prior/ Concomitant ................................................................................. 29 
Algorithm for TEAE ....................................................................................................... 29 
A3. Programming Convention for Outputs ....................................................................... 31 
A4. Listings conventions ...................................................................................................... 31 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 


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ABBREVIATION 
Wording Definition 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Transaminase 
ATC 
Anatomic Therapeutic Class 
BA 
Bone Age 
BMI 
Body Mass Index 
CA 
Chronological Age 
CI 
Confidence Interval 
CRF 
Case Report Form 
CPP 
Central Precocious Puberty 
CRO 
Clinical Research Organisation 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee 
e 
Electronic 
EOS 
End of Study 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating Hormone 
GnRH 
Gonadotropin-releasing Hormone 
ICH 
International Conference on Harmonisation 
IMP 
Investigational Medicinal Product 
ITT 
Intention-To-Treat 
IU 
International Units 
i.v. 
Intravenous 
LH 
Luteinising Hormone 
LLN 
Lower Limit of Normal 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intention-To-Treat 
NCI-CTCAE 
National Cancer Institute – Common Terminology Criteria 
for Adverse Events 
NRI 
Non-responder imputation 
PASS 
Power Analysis and Sample Size 
PD 
Pharmacodynamics 


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ABBREVIATION
Wording Definition
PK 
Pharmacokinetic 
PN 
Preferred Name 
PPS 
Per protocol set 
PR 
Prolonged Release 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS® 
Statistical Analysis System® 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SE 
Standard Error 
SI 
Standard International 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TEAE 
Treatment Emergent Adverse Event 
TFLs 
Tables, Figures and Listings 
ULN 
Upper Limit of Normal 
WHO-DD 
World Health Organization – Drug dictionary 


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1 
INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to outline the planned analyses to be 
completed to support the completion of the Clinical Study Report (CSR) for protocol D-CN- 
52014-243. It describes the rules and conventions to be used in the analysis and presentation 
of data, the data to be summarised and analysed, including specificities of the statistical 
analyses to be performed. 
Exploratory analyses not necessarily identified in this SAP may be performed to support the 
clinical development program. Any post-hoc, or unplanned, analyses not identified in this 
SAP performed will be clearly identified in the respective CSR. 
The SAP is to be finalised before first participant in. A separate shell will be provided for 
tables, figures and listings. 
Any deviations from the SAP after database lock will be documented in the CSR (section 9.8 
“Changes in the conduct of the study or planned analyses” as per ICH E3). 
 
2 
PROTOCOL OVERVIEW 
2.1 
Study Objectives and Hypotheses 
2.1.1 
Objectives of the Main study phase 
2.1.1.1 
Primary objective 
The primary objective of the study is to assess the efficacy of the triptorelin 3-month 
prolonged release (PR) formulation in suppressing luteinising hormone (LH) levels to pre- 
i.v.) gonadotropin-releasing 
hormone (GnRH) stimulation) at Month 3 in Chinese children with central precocious puberty 
(CPP). 
2.1.1.2 
Secondary Objectives 
The secondary objectives of the study are as follows: 
• 
To assess the efficacy in suppressed LH response to GnRH test at Month 6 
• 
To assess follicle-stimulating hormone (FSH) response to GnRH test at Month 3 and 
Month 6 
• 
To assess LH and FSH levels at Month 3 and Month 6 
• 
To assess sex hormone serum concentrations (oestradiol for girls and testosterone for 
boys) at Month 3 and Month 6 
• 
To assess sexual maturation (pubertal stage as per Tanner method) at Month 6 
• 
To assess auxological parameters including height, growth velocity, weight and body 
mass index (BMI) at Month 3 and Month 6 
• 
To assess bone age (BA), the difference between BA and chronological age (CA) at 
Month 6 
• 
To assess gonadal development as determined by uterine length in girls and testicular 
volume in boys at Month 6 
• 
To assess the safety profile. 
2.1.1.3 
Exploratory Objective 
• 
To assess plasma triptorelin levels at Day 1, Month 3 and Month 6. 


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2.1.2 
Objectives of the Extension Phase 
To describe the long-term efficacy and safety of Triptorelin 3-month prolonged release 
formulation through following objectives: 
• 
To assess the percentage of subjects with suppressed LH hormones at Month 12 
• 
To assess LH and FSH levels at Month 9 and 12 
• 
To assess sex hormone serum concentrations (oestradiol for girls and testosterone for 
boys) at Month 9 and 12 
• 
To assess sexual maturation (pubertal stage as per Tanner method) at Month 12 
• 
To assess auxological parameters including height, growth velocity, weight and body 
mass index (BMI) at Month 9 and Month 12 
• 
To assess bone age (BA), the difference between BA and chronological age (CA) at 
Month 12 
• 
To assess gonadal development as determined by uterine length in girls and testicular 
volume in boys at Month 12 
• 
To assess the safety profile. 
2.1.3 
Study Hypothesis 
The effectiveness of triptorelin 3-month formulation in Chinese population of CPP children 
has the same or similar trend with that in overseas CPP population. 
2.2 
Overall Study Design and Investigational Plan 
The study is a prospective, open-label, multicentre, single-arm, interventional study intended 
to evaluate the efficacy and safety of triptorelin 3-month formulation in Chinese children with 
CPP. 
Main study phase: 
A total of 32 participants, including three boys, will be enrolled in the study and treated with 
an intramuscular (i.m.) injection of triptorelin on Day 1 of the study and at Month 3 (3 months 
after the first injection). Triptorelin injections do not have to be adapted based on body weight 
but the participant should have a minimum weight of 20 kg. 
The study consists of a Screening period (the Screening visit will take place up to 28 days 
before enrolment), during which participants with CPP will be screened for eligibility before 
receiving the first triptorelin injection (Day 1 of the study) and will visit the study centre at 
Month 3 and Month 6 for efficacy and safety assessments (Figure 1). Participants will receive 
a total of two injections during the study period before they attend the End of Study (EOS) 
visit at Month 6. 
Each participant is expected to be enrolled in this study for a minimum of 6 months and up to 
7 months (including Screening period). 
Participants who complete the study will perform final procedures and assessments at the final 
visit (Month 6). Participants who withdraw from the study before the completion of the 
evaluation period will be invited to attend an Early Withdrawal visit to perform early 
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enrolled into the study in order to observe the efficacy of the triptorelin 3-month formulation 
in the proportion of children with a suppressed LH response to the GnRH stimulation test at 
Month 3. 
Extension phase: 
The number of participants included in the extension study will be dependent on the number 
of participants from study D-CN-52014-243 who give consent to continue into the extension 
study. A maximum of 32 participants will be expected to be enrolled in the extension phase. 
2.4 
Randomization and Blinding (if applicable) 
This is a non-randomised, open-label study. 
2.5 
Schedule of Assessments 
Schedule of assessments is presented in section 5.1 from the protocol. 
2.6 
Change from Statistical Section of the Protocol 
There is no change in SAP from statistical section of the protocol. 
3 
PLANNED ANALYSES 
3.1 
Data Monitoring 
No independent DMC will be used in this study. 
3.2 
Interim Analysis / Other Analyses 
No interim analysis will be performed. Three analyses are planned according to the following 
data cut-offs if applicable: 
(1) The first analysis will be performed when all participants have completed the first 3 
months of the study period. The cut-off date considered for this analysis will be the date of the 
last Month 3 visit for the last participant. All available data at the time of this data cut-off date 
will be included in this analysis. The purpose of this analysis will be the final analysis of the 
primary efficacy endpoint, as well as the secondary efficacy and safety analyses of the first 3 
months of the study period. This analysis will not be considered as an interim analysis 
because the first 3 months of the study period is of primary interest. 
(2) The second analysis will be performed when all participants have had the opportunity to 
complete the main study (Month 6). This reporting database will include all main study data 
for all participants enrolled into the study. 
3.3 
Final Analysis 
Final analysis will be done when all participants complete the extension phase and after 
database lock. 
4 
ANALYSIS POPULATIONS (SETS) 
The following populations will be used during statistical analyses: 
• 
Screened population: All participants screened (i.e. who signed the informed consent) 
• 
Safety population: All participants who received at least one dose of study medication 
and have at least one post-baseline safety assessment 
• 
Intention-To-Treat population (ITT): All participants who received at least one dose 
of study medication 
• 
Modified Intention-To-Treat population (mITT): All treated participants having at 
least one baseline and at Month 3 post-baseline assessment of the primary efficacy 
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• 
Per protocol set (PPS): All participants in the mITT after exclusion of the participants 
who had major protocol deviations that could potentially affect the primary efficacy 
endpoint outcome for the participants 
• 
PK set (PKS): All participants who received at least one dose of study medication and 
have at least one valid and quantifiable concentration in main study phase. 
4.1 
Populations Analysed 
Main study phase 
The primary efficacy analysis will be performed on the mITT population. Supportive analysis 
of the primary efficacy endpoints will be based on the ITT and the PP populations. 
The secondary efficacy analyses will be based on the mITT population. Supportive analysis of 
the secondary analyses may be performed on the PP population. 
The analyses of safety data will be performed based on the Safety population. 
The analyses of PK data will be performed based on the PK population. 
Extension phase 
The analysis sets for the efficacy endpoints will be the ITT set and the PP set. Analyses and 
summary tables for the safety endpoints will be based upon the Safety population. 
5 
STATISTICAL METHODS/ANALYSES 
The statistical analyses will be performed in accordance with ICH E9 guideline and guidelines 
presented in section 8. 
TigerMed will perform the statistical analysis of this study under the supervision of the 
Biometry department of IPSEN. 
5.1 
General Considerations 
The precision of the measurement for each continuous variable will be used to determine the 
number of decimal places to present in tables, figures, and derived listings. Unless otherwise 
specified, min and max values will be reported with the same decimal as the units of measure; 
the mean, median and SD will be reported to 1 greater decimal place, all of them will not be 
greater than 4 decimal places. Any values that require transformation to standard units (metric 
or International System [SI]) will be converted with the appropriate corresponding precision. 
Percentages of categorical variables will be presented to 1 decimal place unless otherwise 
specified. 
For laboratory values data below the lower limit of quantification (LLOQ) like “<xxx” or 
“<=xxx”, or above the upper limit of quantification (ULOQ) like “>xxx” or “>=xxx”, LLOQ 
or ULOQ (xxx) will be used for calculation of descriptive statistics. The original laboratory 
values (“<xxx”, “<=xxx”, “>xxx” or “>=xxx”) are presented in the listings. 
All statistical analyses will be performed using the SAS® software version 9.4 or above 
version. 
5.1.1 
Outputs Presentation 
5.1.1.1 
Tables Header 
Since this is a single-arm study, all summary tables will be presented by Female, Male and 
Overall. 
5.1.1.2 
Presentation of Gender Group 
TFLs will be displayed using the following gender group label: Female, Male, Overall. 




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phase, withdrawn the main study and reason for withdrawal and extension phase with 
the number and percentage of participants enrolled, treated, completed the extension 
phase, withdrawn the extension phase and reason for withdrawal, on the screened 
population, 
- 
Summary table on duration of participant participation in the study. The definition of 
the duration of participant participation is from date of consent to the last study visit on 
the ITT population separately in main study phase and extension phase, 
- 
Listing of dates of visit including duration of participant participation for the treated 
participants on the ITT population, 
- 
Listing of screen failure participants on screened population, 
- 
Listing of withdrawal participants on the ITT population. 
 
Following population summaries and listings will be provided on the ITT population: 
- 
Listing of participants violated inclusion criteria, 
- 
Listing of participants fulfilled exclusion criteria, 
- 
Summary of the number and percentage of participants in each analysis population by 
gender group, based on all treated participants with reasons for exclusion from each 
analysis population, 
- 
Listing including flag for each analysis population and reason for exclusion from each 
population. 
5.3 
Protocol Deviations 
An exhaustive list of major protocol deviations that may occur during the course of the study 
and any action to be taken regarding exclusion of participants from the PPS population is 
defined in Protocol Deviation Assessment Plan. Major protocol deviations will be determined 
before database lock of the study, finalised during the data review meeting and documented in 
a separate document. 
Following protocol deviation summary and listing will be provided on the ITT population: 
- 
Number and percentage of participants with protocol deviations by deviation category 
separately in main study phase and extension phase (see DV section of Standard 
SDTM+ user guide), 
- 
All protocol deviations will be listed with flags indicating if deviations are major or 
minor PDs separately in main study phase and extension phase, 
- 
A separate listing for major protocol deviations will be displayed separately in main 
study phase and extension phase, 
5.4 
Demography and Other baseline characteristics 
All demographic and baseline characteristics summaries and listings will be provided for ITT, 
mITT, PPS and safety population. 
Following summaries will be provided on: 
- 
Demographic variables (age, ethnicity, sex) 
- 
Other baseline characteristics (height, weight, BMI, pubertal stage, growth velocity, 
bone age, chronological age, the difference between bone age and chronological age), 


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- 
Baseline Disease characteristics (Time from initial diagnosis of CPP, GnRH-stimulated 
LH peak, GnRH-stimulated FSH peak, Basal LH, FSH, oestradiol levels and uterine 
length for girls, testosterone levels and testicular volume for boys). 
Listings will also be provided for all the summaries listed above separately in main study 
phase and extension phase. 
5.5 
Medical history, non-drug therapies, medications and surgical procedures 
Medical and surgical history, non-drug therapies and surgical procedures will be coded using 
the latest version of MedDRA in effect within IPSEN at the time of database lock. 
Medications will be coded using the latest version of WHO-Drug dictionary in effect within 
IPSEN at the time of database lock. 
Medication, non-drug therapies and surgical procedures start and stop dates will be compared 
to the date of the first IMP administration to allow classification as either Prior only, Prior and 
Concomitant, or Concomitant only: 
 
 
Prior (P) 
Start and stop dates prior to the date of the first IMP 
administration. 
Prior and 
Concomitant (PC) 
Start date before the date of the first IMP administration and 
stop date on or after the date of the first IMP administration. 
Concomitant (C) 
Start date on or after the date of first IMP administration.
 
-
only, summary tables on concomitant 
-drug 
 procedures will 
include “C” and “PC”. 
 
See detailed rules in appendix A2 
- 
 
 
The therapeutic class will correspond to the second level of ATC code, that is, corresponding 
to the first 3 figures. 
 
Following summaries, presenting count and percentages of participants will be provided on 
the ITT population: 
- 
Medical and surgical history by primary system organ class (SOC) and preferred term 
(PT), 
- 
Prior medications (P) for the study indication by ATC class (ATC level 2) and 
preferred Name PN, 
- 
Concomitant medications (PC, C) for the study indication by ATC class (ATC level 2) 
and preferred Name PN, 
- 
Prior non-drug therapies (P) by primary SOC and PT, 
- 
Concomitant non-drug therapies (PC, C) by primary SOC and PT, 
- 
Prior surgical procedures (P) by primary SOC and PT, 
- 
Concomitant surgical procedures (PC, C) by primary SOC and PT, 


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Listings will be provided for all the summaries listed above. These listings should include a 
flag indicating the category (P, PC, C) as described in the table above. 
A prohibited medication listing be provided including the following drug: 
Oestradiol, Testosterone, GnRH analogues (other than triptorelin 3-month formulation), 
medroxyprogesterone acetate, growth hormone or IGF-1, systemic or inhaled steroids 
(mild topical steroids are permitted), anticoagulants (heparin and coumarine derivatives). 
5.6 
Compliance 
Compliance will be present separately in main study phase and extension phase, 
Compliance with study treatment will be presented as the number and proportion of patients 
who received the two IMP injections. A listing of treatment compliance will be provided. 
5.7 
Efficacy (Main Study Phase) 
5.7.1 
General Considerations 
The analysis sets for the primary and secondary efficacy endpoints will be the mITT 
population. 
Supportive analysis of the primary efficacy endpoints will be based on the ITT and the PPS 
populations. Supportive analysis of the secondary analyses may be performed on the PPS 
population. 
A listing of all efficacy data (raw and derived) should be provided (see listing detail 
conventions in Appendix A4). Descriptive statistics will be provided for all endpoints. 
5.7.1.1 
Significance Testing and Estimations 
The statistical analysis of efficacy is only descriptive therefore no formal statistical 
significance testing will be performed. 
5.7.1.2 
Statistical/analytical issues 
Adjustments for 
 Effect 
Descriptive analysis will be carried out to evaluate any possible centre effect. 
 
Handling of Dropouts or Missing Data 
A NRI method will be used for missing LH response and FSH response at month 3 or month 
6. For any missing value of LH response and FSH response at month 3 or month 6, a Non- 
response value will be imputed. 
 
Interim Analyses and Data Monitoring 
No interim analysis will be performed. 
 
Multicentre Studies 
No by-centre displays or adjustments for centre are planned for this study. 
 
Multiple 
 
Since no formal hypothesis test will be performed in this study, no multiple testing will be 
performed in this study 


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Use of an "Efficacy Subset" of Participants 
No Efficacy subset is planned in this study. 
 
Examination of Subgroups 
No subgroup analysis is planned. 
5.7.2 
Analysis of Primary Efficacy Endpoint 
5.7.2.1 
Endpoint 
LH Response: defined as a peak LH 
 
 after intravenous (i.v.) gonadotropin-releasing 
hormone (GnRH) stimulation) in Chinese children with central precocious puberty (CPP). 
5.7.2.2 
Primary Analysis 
For the primary efficacy endpoint, the summary statistics of number and percentage of 
participants and the exact two-
nfidence interval (CI) for a binomial proportion 
will be computed by SAS® using the exact binomial distributions on the mITT. 
The SAS code to be used could be presented in Appendix A1. 
A listing will be provided including all participants with missing values for the primary 
endpoint. For these participants, the listing will provide all observed data related to the 
primary endpoint i.e. all measurements recorded prior to the missing value, any measurements 
recorded after the missing value, important baseline characteristics, the reason for study 
discontinuation and the timing of study discontinuation. The listing will also provide the 
imputed value(s) (if applicable) used in the primary analysis and any sensitivity analyses. 
5.7.2.3 
Sensitivity Analysis 
Sensitivity analyses will be conducted to further explore the primary efficacy endpoint with 
the same statistical method using NRI method on the ITT set. 
A PPS population will also be used to explore the primary efficacy endpoint with the same 
statistical method. 
5.7.2.4 
Supplementary Analysis 
No supplementary analyses will be performed. 
5.7.2.5 
Subgroup Analysis 
No subgroup analyses will be performed. 
5.7.3 
Analysis of Secondary Efficacy Endpoints 
5.7.3.1 
Endpoint, Treatment Effect and Estimand Definition 
Secondary efficacy endpoints and evaluations are summarised in following table: 
 
 
Table 1 Secondary Efficacy Endpoints and Evaluations 
 
Measure 
Timepoint 
Variable 
Endpoint 
Basal LH and FSH 
Baseline, 
Month 3 and 
Month 6 (EOS)
LH and FSH 
concentration 
Change in basal serum LH and 
FSH levels at Month 3 and Month 
6 compared to baseline 
Peak LH after 
GnRH 
Baseline, 
Month 3 and 
Peak LH levels 
after 
Change in peak LH levels after 
GnRH stimulation test at 




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5.7.3.2 
Secondary Analysis 
For secondary efficacy endpoints related to a change at Month 3, 6 compared to baseline, the 
descriptive summary statistics (number of participants (n), mean, SD, median, quartiles, 
minimum, maximum) will be calculated on the mITT. 
Exact two-sided 
 CI will also be constructed for all secondary endpoints expressed as 
proportions. 
Testicular Volume over time will be graphically presented via individual observed values 
(scatter) as well as mean and standard deviation of the observed values (Baseline, Month 3, 
and Month 6). 
5.7.3.3 
Sensitivity Analysis 
Secondary efficacy endpoints will be performed on the PPS using the same statistical method 
as mITT. 
5.7.3.4 
Subgroup Analysis 
No subgroup analyses will be performed. 
5.8 
Safety (Main Phase) 
5.8.1 
General Consideration 
All safety summaries and analyses will be based upon the Safety population. All safety data 
will be included in participant data listings (see listing detail conventions in Appendix A4). 
There will be no statistical comparison between the gender groups for safety data, unless 
otherwise specified within the relevant section. 
If conversion factors are used, they should be presented either in the relevant section or a link 
to section 7 should be added. 
All AEs will be recorded and graded according to the current version of the National Cancer 
Institute – Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0. 
5.8.2 
Extent of exposure 
Duration of exposure will be defined in days as: 
Days of exposure = Date of Last Study Visit – First dose date + 1. 
The following extent of exposure summaries will be presented: 
• 
Summary of the duration of exposure to treatment, by gender. Provide the mean, 
median, and the count and percentage of participants exposed for specified periods of 
time choosing appropriate time intervals. 
• 
Summary of the actual dose by gender. Provide the mean, median, sum and the count 
and percentage of participants exposed to specified dose levels choosing appropriate 
dose intervals. 
• 
Summary of number of injections, 
• 
Summary of total exposure, 
• 
Listing of exposure data. 


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5.8.3 
Adverse Event 
All adverse events (AEs) recorded in the eCRF will be coded using the latest version of 
MedDRA dictionary in effect within IPSEN at the time of the database lock. AEs will be 
classified as treatment-emergent AEs (TEAEs) according to the rules below: 
• 
Events with start date on or after the date of first IMP administration and up to 
the EOS or 185 days after first dose days which comes first. 
• 
Events whose CTCAE grade worsens on or after the date of first IMP 
administration, 
• 
Events whose causality changes to “Related” on or after the date of first IMP 
administration, 
• 
Refer to appendixP
 A2 for handling of partial 
date. In the case where it is not possible to define an AE as treatment emergent 
or not, the AE will be classified by the worst case; i.e. treatment emergent. 
Tabular summaries will be presented by gender. Summaries will include the number and 
percentage of participants and classified by primary system organ class and preferred term. 
The following summaries will be reported for AEs, TEAE regardless of drug relationship, 
TEAE related to study drug, TEAE grade 3 and above regardless of drug relationship, TEAE 
grade 3 and above related to study drug, serious AEs (SAEs), AE leading to study drug 
discontinuation, and AE leading to death: 
• 
An overview table summarizing the number and percentage of participants with 
at least one of the following AEs: any AE; any TEAE; SAE, treatment emergent 
SAE, treatment-related TEAE, treatment emergent-related SAE, Non-serious 
TEAEs, TEAE leading to treatment discontinuation; TEAE leading to 
discontinuation from the study, CTCAE Grade >=3 TEAE, Death, TEAE leading 
to death, 
• 
A summary of the number and percentage of participants reporting a TEAE by 
gender, SOC and PT, 
• 
A summary of the number and percentage of participants reporting a SAE by 
gender group and PT, 
• 
A summary of the number and percentage of participants reporting a Serious 
TEAE by gender group and PT, 
• 
A summary of the number and percentage of participants reporting a treatment- 
related Serious TEAE by gender group and PT, 
• 
A summary of the number and percentage of participants reporting a TEAE 
leading to treatment discontinuation by gender group and PT, 
• 
A summary of non-serious TEAE by gender group, SOC and PT, 
• 
A summary of TEAE by gender group and PT, 
• 
A summary of the number and percentage of participants reporting a TEAE by 
gender group, CTCAE grade, SOC and PT, 
• 
A summary of the number and percentage of participants reporting a drug-related 
TEAE by gender group, CTCAE grade, SOC and PT, 
• 
A summary of the number and percentage of participants reporting a TEAE by 
gender group, causality, SOC and PT, 
• 
A summary of 
by gender group, SOC and 
PT. 


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AEs summaries will be ordered in term of decreasing frequency for SOC and PT within SOC 
in the gender, and then alphabetically for SOC and PT within SOC. 
 
AEs will be counted as follows: 
• 
Participants with more than one AE within a particular SOC are counted only once for 
that SOC. Similarly, participants with more than one AE within a particular PT are 
counted only once for that PT; 
• 
Participants reporting a TEAE more than once within that 
 the TEAE with the 
worst case CTCAE grade will be used in the corresponding CTCAE grade summaries; 
• 
Participants reporting a TEAE more than once 
 TEAE with the 
worst case relationship to study medication will be used in the corresponding 
relationship summaries; 
• 
If the CTCAE grade is missing for a TEAE, it will be considered as missing in the 
summary tables; 
• 
If the causality is missing for a TEAE, it will be considered related in the summary 
tables; 
• 
The non-serious TEAEs table should include a specific row “any non-serious TEAE 
; 
• 
A TEAE is counted only in the study where it started (if there is a change in the 
CTCAE grade an additional AE should have been collected in the eCRF). 
 
In addition, a listing with all AEs data will be listed by gender group including non-TEAEs, 
Treatment-emergence status will be flagged in the listing. Listing of Drug-related AEs will 
also be added. 
 
The following listing will also be provided: 
• 
A listing of all deaths that occurred during the study, 
• 
A listing of all serious adverse events, 
• 
A listing of all adverse events leading to discontinuation of study treatment. 
 
Local tolerability Abnormalities 
 
The following summary tables will be provided: 
• 
A summary of the number and percentage of participants reporting a local tolerability 
reaction, by gender, SOC and PT, 
 
The following listing will be provided: 
• 
A listing of all local tolerability reactions that occurred during the study. 
 
5.8.4 
Laboratory Data 
All laboratory data will be presented in the units of International System of Units (SI). 


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Describe the summaries that are to be provided. These may include the following summaries: 
• 
A summary of the actual and change from baseline in each laboratory parameter by 
gender group and timepoint, 
• 
A summary of the number and percentage of participants experiencing treatment- 
emergent clinically significant laboratory abnormalities, by gender group and 
laboratory parameter, 
• 
A shift from baseline to worst post-dose (i.e. highest grade) in CTCAE Grade of 
laboratory results. 
 
For shift tables, the denominator should be the number of participants with both a baseline 
and a post-baseline assessment at a given timepoint. 
 
In addition, the following listings are to be provided: 
• 
A listing of all laboratory data. Out-of-reference-range values will be flagged as high 
(H) or low (L), 
• 
A listing of CTCAE grade 3 and higher values. All data for a laboratory parameter will 
be displayed for a participant who has any post-baseline value with CTCAE grade 
greater than or equal to 3 for the parameter. 
5.8.5 
Vital Signs 
Describe the summaries that are to be provided. These include: 
• 
A summary of the actual and change from baseline in each vital sign parameter by 
gender group and timepoint, 
 
5.8.6 
Electrocardiogram (ECG) 
Not applicable. 
5.8.7 
Physical Examination 
Physical examinations, including body weight (kg) and body height (cm), will be conducted at 
Baseline (Visit 2), at Visit 3 and at Visit 4 if applicable. 
The following summary and listings will be provided: 
• 
A shift from baseline (normal vs abnormal) to each post-baseline visit 
• 
A change from baseline to each post-baseline visit 
• 
A listing of physical examination data, 
• 
A listing with any participants with at least one physical examination abnormality. 
5.8.8 
Other (if applicable) 
Participants are to be discontinued from the study if they become pregnant. Pregnancy data 
will be shown in a data listing if applicable. No special analysis will be performed on the 
pregnancy. 
5.9 
Efficacy and Safety Evaluations (Extension Phase) 
An additional analysis on efficacy and safety endpoints will be performed considering the 
extension phase duration, a period of an additional 6 months, lasting until the End of 
Extension Phase Visit at Month 12. 




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Auxological 
parameters (height, 
growth velocity, 
weight, BMI) 
Baseline, 
Month 9 and 
Month 12 
(EOEP) 
- 
Change in auxological 
parameters compared to 
baseline 
BA 
Baseline, 
Month 12 
(EOEP) 
- 
Change in BA, difference 
between BA and CA compared 
to baseline 
Uterine length or 
testis 
volume 
Baseline, 
Month 12 
(EOEP) 
Gonad 
development 
Change in uterine length in girls 
and testicular 
volume in boys compared to 
baseline 
BA = Bone age; BMI = Body mass index; CA = Chronological age; EOEP = End of Extension Phase; FSH = Follicle 
stimulating hormone; GnRH = Gonadotropin-releasing hormone; LH = Luteinising hormone; E2 = Oestradiol. 
 
Unless otherwise specified, all analysis of extension phase efficacy endpoints will be the same 
as main study phase. 
For extension phase efficacy endpoints related to a change at Month 9 and Month 12 
compared to baseline, the descriptive summary statistics (n, mean, SD, median, minimum, 
maximum) will be calculated on the ITT and PP. Exact two-
constructed for all extension phase efficacy endpoints expressed as percentages. 
5.9.2 
Safety Endpoint for Extension Phase 
The extension phase safety endpoints are the following; 
• 
Incidence of treatment-emergent adverse events (TEAEs) throughout the study, 
including local tolerability 
• 
Change in clinical safety laboratory (blood biochemistry, haematology and urinalysis) 
parameters at Months 9 and 12 
• 
Change in physical examination and vital signs (blood pressure and heart rate) 
measurements at each visit 
Unless otherwise specified, all the analysis of extension phase safety endpoints including AE, 
laboratory, physical examination and vital signs will be the same as main study phase. 
5.10 
Pharmacokinetics 
Pharmacokinetics analysis is only for main study phase. 
The individual plasma triptorelin concentration are measured in all subjects receiving study 
drug on Day 1 (to be taken predose and at 4 hours post-injection); at Month 3 visit (to be 
e 
summary statistics will be presented for triptorelin plasma concentrations. 
er Geomean CI) will be summarized by each scheduled visit, and by 
timepoint where applicable. To compute descriptive statistics, all BLQ values must be 
replaced by missing in the data set. BLQ values substituted by missing are excluded in the 
calculation of descriptive statistics. 
Triptorelin concentrations will be displayed with the same precision as the BLQ values. For 
the descriptive statistics, calculations derived from concentrations (mean, min, max, median, 
SD etc.) will follow the same rule as Min and Max, but coefficient of 
 will be 
displayed with one decimal digit only. 


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every 3 values) of the data are available and above the limit of quantification. Otherwise, only 
minimum and maximum are reported. Individual and mean plasma concentration time 
profiles, as well as spaghetti plots, on the PK Set will be generated. 
If required and warranted by the data, an attempt to build a model to characterize the PK in 
the population will be made. 
This will be described in a separate analysis plan and the outcomes summarised in a 
standalone report. 
5.11 
Anti-drug Antibodies (if applicable) 
Not applicable. 
5.12 
Pharmacodynamics (if applicable) 
Not applicable. 
6 
DATA HANDLING 
6.1 
Visit window 
All data will be organized and analysed according to the scheduled visits outlined in the 
protocol. As defined by the protocol, visit 1 (Screening visit) has to be performed within Day 
-28 to Day -1 prior to first treatment. Visit 2 (Baseline visit) will be the day of first treatment. 
Visit 3 will correspond to Day 88 to Day 94 and participants who complete the study will 
perform final procedures and assessments at the final visit (Month 6). 
Participants who withdraw from the study before the completion of the evaluation period will 
be invited to attend an Early Withdrawal visit to perform early discontinuation procedures and 
assessments. 
For participants who do not have a final visit within 3 months (i.e. up to Day 182±3 days as in 
Protocol Table 1) after their last triptorelin dose, efficacy evaluations should not be 
performed. Data from any efficacy evaluations performed after this time will not be collected 
on the eCRF. 
6.2 
Unscheduled Visits, Retest, Withdrawal Visit, 
All listings will include retests and unscheduled visits, while for the description by visit in the 
tables, only the scheduled visits according to the protocol will be described. 
Unscheduled visit and retest measurements will be used to provide a measurement for a 
baseline data or endpoint value (e.g. worst value), if appropriate according to their definition. 
These measurements will also be used to determine abnormal laboratory, vital signs values or 
ECG. 
If a value requires a retest (for laboratory values and vital signs) the closest non-missing 
reliable value to the scheduled visit will be used in the summary tables. 
Participants who have withdrawn early from the study have their last assessment entered as 
visit 90 in the electronic Case Report Form (eCRF). 
7 
DERIVED DATA (IF APPLICABLE) 
When applicable, below derivation rules should be followed: 
• 
Change from baseline 
Change from baseline at a given visit will be calculated as a difference from baseline. 
• 
Age 


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Age (years) will be calculated as follows and truncated to the largest integer that is less than 
or equal to the calculated result: 
Age = (informed consent date of main study phase - birth date + 
 
• 
Chronological Age 
Chronological Age (years) will be calculated as follows and truncated to the largest integer 
that is less than or equal to the calculated result: 
Chronological Age = (Visit Date - birth date + 
 
• 
BMI 
BMI 
 will be derived as Weight 
 measured at each visit and 
rounded to the nearest decimal. 
• 
Bone Age 
For bone age recorded as 9+ or 10-, the original result will be listed in listing and update 9+ to 
9.25 and 10- to 9.75 in the summary analysis. 
 
8 
REFERENCES 
Zenaty D, Blumberg J, Liyanage N et al. A 6-Month Trial of the Efficacy and Safety of 
Triptorelin Pamoate (11.25 mg) Every 3 Months in Children with Precocious Puberty: A 
Retrospective Comparison with Triptorelin Acetate. Horm Res Paediatr 2016;86:188-95. 
 
Reference to ICH regulatory guidelines: 
- 
ICH E3: Structure and Content of Clinical Study Reports 
- 
ICH E6: Good Clinical Practice 
- 
ICH E9: Statistical Principles for Clinical Trials 
- 
ICH E9 (R1) Addendum: Estimands and Sensitivity Analysis in Clinical Trials 
 
Reference to EMA or point to consider guidelines: 
- 
Adjustment for baseline covariates in clinical trials 
- 
Choice of a non-inferiority margin 
- 
Clinical trials in small populations 
- 
Data monitoring committees 
- 
Investigation of subgroups in confirmatory clinical trials 
- 
Missing data in confirmatory clinical trials 
- 
Application with Meta Analyses, One pivotal study 
- 
Multiplicity issues in clinical trials 
Switching between superiority and non-inferiority 
 
Reference to FDA guidelines: 
- 
Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics 
Standard SDTM+ user guide 


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Ipsen Global Style guide 


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9 
APPENDICES 
 
CCI


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A2.Partial/Missing Date Convention 
In all listings, missing or incomplete dates should be left as they have been recorded. 
used: 
- 
The most conservative approach will be systematically considered (i.e. if the onset date 
during the study treatment phase (i.e. a TEAE for AEs) except if the partial onset date 
or the stop date indicates differently. 
- 
Where this is possible, the derivations based on a partial date will be presented as 
superior inequalities (i.e.: for an AE started in FEB2004 after the first IMP 
administration performed on 31JAN2004, the days 
similarly the duration of ongoing AEs or 
 according to the start 
and last visit dates). 
 
Algorithm for Prior/ Concomitant 
 
Medication, non-drug therapies and surgical procedures start and stop dates will be compared 
to the date of the first IMP administration to allow classification as either Prior only, Prior and 
Concomitant, or Concomitant only. 
-
imputation will be done to determine the classification: 
- 
If a partial start date, the first day of the month will be imputed for missing day and 
January for missing month, 
- 
If a partial stop date, the last day of the month will be imputed for missing days and 
December will be imputed for missing month. 
In case incomplete start or stop date does not allow the classification, will be classified as 
concomitant. 
 
If the start date of a medication is partial or missing, the medication will be assigned to the 
most recent treatment received on or before the medication start date (taking into account date 
stopped). 
 
Algorithm for TEAE 
For deriving the TEAE flag the following process of temporary date imputation is done (for 
AE start date only assuming no AE end date are missing). The date imputation algorithm for 
incomplete adverse event start dates is described in Table 1. Classification of adverse event 
according to its treatment-emergent status is then done using the imputed date. 
 
In the following table, all dates are presented using an YYYY-MM-DD format. As an 
example, suppose First IMP administration = 2002-08-11 and several AEs have incomplete 
start dates. 
 
Table 1: Data imputation algorithm for AE start date (AESTDT) 




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A3. Programming Convention for Outputs 
All text fields must be left justified and numeric or numeric with some text specification (e.g.: 
not done, unknown, <4.5, …) must be decimal justified. 
 
The mean, median, lower quartile, upper quartile, SD and standard errors of the mean (SE), 
 confidence interval values will be reported to one decimal place greater than the raw data 
recorded in the database. 
The minimum and maximum values will be reported with the same number of decimal places 
as the raw data recorded in the database. 
In general, the maximum number of decimal places reported should be four for any summary 
statistic. 
 
Percentages will be presented to one decimal place. Percentages will not be presented for zero 
counts. Percentage will be calculated using n as denominator. The denominator will be 
specified in a footnote for clarification if necessary. If sample sizes are small, the data 
displays will show the percentages, but in the CSR only frequencies should be described. 
 
P-values will be reported to four decimal places (e.g.: p=0.0037), after rounding. P-values 
which are less than 0.0001 will be presented as ‘<0.0001’. 
 
All values below or above a limit of detection (e.g. <0.1 or >100) will be listed as such. 
Dates will be presented in the format [ddmmmyyyy] and times in the format [hh:mm]. 
A4. Listings conventions 
Any listings will contain at least the following data: participant identifier, age and gender. 
When dates are presented, the associated study days should be included. They should be 
sorted by gender group then participant identifier. For multicentre studies, listings should be 
broken down by centre and gender group. 
 
Note: In this study (D-CN-52014-243), any listings will contain at least the following data: 
participant identifier, age and gender. All listings should be sorted by participant identifier.