An Open Label, Phase III Efficacy and Safety Study of L-PZQ ODT in Schistosoma Infected Children 3 Months to 6 Years of Age, Including a 2:1 Randomized, Controlled Cohort of Schistosoma Mansoni Infected Children 4 to 6 Years of Age Treated With L PZQ ODT or Commercial PZQ (Biltricide®)
Phase: PHASE3
Conditions: Schistosomiasis
Sponsor: Merck KGaA, Darmstadt, Germany

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h t he L- P Z Q O D T s
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O
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Cli nic al St u d y Pr ot oc ol
Title P a ge
Cli nic al St u d y Pr ot oc ol Title:
A n o pe n- la bel, P hase III efficac y an d safety st u d y 
of L- prazi q ua ntel or o dis persi ble ta blets ( L-P Z Q 
O D T) i n Sc hist os o ma -i nfecte d c hil dre n 3 m o nt hs 
t o 6 years of a ge, i ncl u di n g a 2: 1 ra n d o mize d, 
c o ntr olle d 
c o h ort 
of 
Sc hist os o ma
ma ns o ni -i nfecte d c hil dre n 4 t o 6 years of a ge
treate d wit h L- P Z Q O D T or c o m mercial P Z Q 
( Biltrici de®)
St u d y N u m ber:
M S 2 0 0 6 6 1 - 0 0 0 3
A m e n d me nt N u m ber
2
Merc k C o m p o u n d N u m ber:
M S C 2 4 9 9 5 5 0 A
S h ort Title:
P hase III pe diatric st u d y wit h t he L -P Z Q O D Ts
C o or di n ati n g Pri nci p al I n vesti g at or 
(I v or y C o ast):
L oc al Pri nci p al I n vesti g at or a n d 
Me dic al R es p o nsi ble (I v or y C o ast):
Pri nci p al I n vesti g at or ( Ke n y a): 
 
 
 
S p o ns or N a me a n d Le g al Re gistere d 
A d dress:
Merc k K Ga A
Fra n kf urter Strasse 2 5 0
6 4 2 9 3 Dar msta dt, Ger ma n y
Me dical Res p o nsi ble:
Na me :
A d dress : Fra n kf urter Strasse 2 5 0
6 4 2 9 3 Dar msta dt, Ger ma n y
P h o ne :
E -mail :
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
P P D
P P D
P P D
P P D
P P D
P P D
C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h t he L- P Z Q O D T s
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O
2/ 9 3
Re g ul at or y A ge nc y I de ntif yi n g 
N u m bers:
P A C T R 2 0 1 8 1 0 6 3 4 0 3 4 5 4 3
Cli nical Trials. g o v : N C T 0 3 8 4 5 1 4 0
Pr ot oc ol Versi o n:
1. 2
Re pl aces Versi o n:
1. 1 / 2 0 Fe b r uar y 2 0 1 9 ( Ke n ya)
1. 1 / 1 9 Marc h
2 0 1 9 (I v or y C oast)
A p pr o v al D ate:
1 1 A u g ust 2 0 2 0
Me dic al M o nit or N a me a n d C o nt act 
I nf or m ati o n:
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
P P D
C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h t he L- P Z Q O D T s
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O
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Pr ot oc ol A me n d me nt S u m m ar y of C h a n ges
Pr ot oc ol Hist or y
Versi o n N u m ber
T y pe
Versi o n D ate
1. 0
Ori gi nal Pr ot oc ol
2 4 O ct 2 0 1 8
1. 1 Ke n ya
1. 1 I v or y C oast
A me n de d Pr ot oc ol
A me n de d Pr ot oc ol
2 0 Fe b 2 0 1 9
1 9 Marc h 2 0 1 9
1. 2
A me n de d Pr ot oc ol
1 1 A u g ust 2 0 2 0
Pr ot oc ol Versi o n 1. 2 ( 1 1 A u g ust 2 0 2 0 )
T his a me n d me nt is s u bsta ntial base d o n t he criteria i n Article 1 0(a) of Directi ve 2 0 0 1/ 2 0/ E C of 
t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n.
O ver all R ati o n ale f or t he A me n d me nt
T he rati o nale f or t he pr ot oc ol a me n d me nt is as f oll o ws: 

T o i ncl u de a n a d diti o nal f oll o w -u p visit

T o u p date t he S p o ns or me dical res p o nsi ble 

T o assess t he ser u m c o nce ntrati o n of u p t o 1 5 s u bjects i n C o h ort 1 b a n d u p t o 1 5 
a d diti o nal s u bjects i n C o h ort 4

T o clarif y t he e x pl orati o n of meta b olites i n plas ma sa m ples

T o u p date t he uri ne sa m pli n g all o wi n g f or a d diti o nal sa m pli n g at Wee k 5 p ost d ose f or 
C o h ort 4 s u bjects t o be treate d at 6 0 m g/ k g
Secti o n # a n d 
N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
Title Pa ge
U p date t he na me a n d c o ntact 
details of t he S p o ns or m e dical 
res p o nsi ble a n d a d diti o n of 
b ot h Pri nci pal I n vesti gat or s
( PIs) details f or I v or y  C oast 
T he me dical res p o nsi ble was 
c ha n ge d i n t he st u d y a n d t o me nti o n 
b ot h PI s as re q ueste d by Et hics 
c o m mittee i n Iv or y  C oast
Secti o n 1. 1 
S y n o psis :
O bjecti ves a n d 
E n d p oi nts Ta ble
- Sec o n dar y  
O bjecti ves 
T he d efi niti o n f or cli nical cure 
was u p date d. T e xt was a d de d 
re gar di n g a d diti o nal u ri ne 
sa m ples f or testi n g, a n d 
a d diti o nal E xte n de d 
F oll o w -u p visits
Te xt was a d de d t o t he cli nical c ure 
rate t o i ncl u de t he E xte n de d 
F oll o w -u p visits t o i de ntif y  c ure 
rates be yo n d Wee k 3.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h t he L- P Z Q O D T s
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
4/ 9 3
Secti o n # a n d 
N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
Secti o n 1. 3 
Sc he d ule of 
Acti vities
A d diti o n of a n E xte n de d 
F oll o w -u p visit ( Da y  3 5 t o 4 0) 
T he ta ble was u p date d t o all o w f or 
t he E xte n de d F oll o w -u p visit. 
Secti o n 3 T a ble 1
O bjecti ves a n d 
E n d p oi nts -
Sec o n dar y  
O bjecti ves
A d diti o n of E xte n de d 
F oll o w -u p visit i nf or mati o n 
a n d clarificati o n of cli nical 
c ure defi niti o n 
Te xt was a d de d t o t he cli nical c ure 
rate t o i ncl u de t he E xte n de d 
F oll o w -u p visits t o i de ntif y  c ure 
rates be yo n d Wee k 3. 
Secti o n 4. 1 
O verall D esi g n 
A d diti o n of t he D a y 3 5 t o 4 0 
E xte n de d F oll o w -u p visit
T o ali g n pr ot oc ol te xt wit h a d diti o n 
of t he E xte n de d F oll o w -u p visit 
( Da y 3 5 t o 4 0)
Secti o n 4. 2. 5 
E n d p oi nts 
A d diti o n of t he D a y 3 5 t o 4 0 
E xte n de d F oll o w -u p visit , a n d 
t he a d diti o n of P K sa m pli n g i n 
t he Biltrici de c o ntr ol ar m
Ali g n me nt of te xt relate d t o t he 
a d diti o n of t he E xte n de d F oll o w - u p 
visit ( Da y 3 5 t o 4 0), a n d i ncl usi o n 
of P K sa m pli n g i n t he Biltrici de 
c o ntr ol ar m
Secti o n 4. 4 E n d 
of St u d y  
Defi niti o n
E n d of st u d y  defi niti o n was 
u p date d t o i ncl u de t he 
E xte n de d F oll o w -u p visit
Ali g n me nt of te xt re gar di n g e n d of 
st u d y d ue t o a d diti o n of t he
E xte n de d F oll o w -u p visit f or 
C o h ort 4 
Secti o n 5. 2 
E xcl usi o n 
Criteria
Ali g n me nt of e xcl usi o n 
criteria bet wee n t he Ke n ya 
a n d I v or y C oast pr ot oc ols b y 
re m o vi n g t he f oll o wi n g 
e xcl usi o n criteria liste d i n t he 
I v ory C oast pr ot oc ol:

Mar ke d i ncreases of t he 
li ver e nz ymes: ala ni ne 
a mi n otra nsferase a n d/ or 
as partate a mi n otra nsferase 
a b o ve 3 ti mes t he u p per 
li mit of n or mal ( U LN); 
t otal bilir u bi n le vel a b o ve 
1. 5 ti mes t he U L N

Partici pa nts wit h 
he pat os ple nic 
sc hist os o miasis
Har m o nizati o n of t he Ke n ya a n d 
I v or y C oast pr ot oc ols
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D:
C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h t he L- P Z Q O D T s
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O
5/ 9 3
Secti o n # a n d 
N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
Secti o n 5. 4 
Scree n F ail ures
C larificati o n of t he ha n dli n g 
of partici pa nt s n ot eli gi ble f or 
e nr oll me nt d ue t o a te m p orar y  
e xcl usi o n criteri o n.
A d diti o n of te xt re gar di n g 
bl o o d sa m pli n g v ol u me 
restrictio ns
T he te xt was a d de d d ue t o a re q uest 
fr o m t he P har mac y a n d P ois o ns 
B oar d of Ke n ya .
Secti o n 6. 5. 1 
Resc ue Me dici ne
T he w or d “sc hist os o miasis” 
was a d de d t o e x plicit ly state 
t he i nfecti o n t yp e
Te xt a d de d f or clarificati o n
Secti o n 8 St u d y  
Assess me nt a n d 
Pr oce d ures, 
F oll o w -u p visits
A d diti o n of t he E xte n de d 
F oll o w - u p visit ( D a y 3 5 t o 4 0 )
T he Ra pi d Dia g n ostic Test 
( R D T) m a y  n o w be perf or me d 
at t he discreti o n of t he 
I n vesti gat or f or I v ory C oast 
sites.
Ali g n me nt of te xt re gar di n g e n d of 
st u d y d ue t o a d diti o n of t he 
E xte n de d F oll o w -u p visit .
Har m o nizati o n of t he Ke n ya a n d 
I v or y C oast pr ot oc ols
Secti o n 8. 5 
P har mac o ki netics
U p date t he n u m ber of s u bjects 
wit h P K sa m pl i n g t o a t otal of 
3 0 f or t he hae mat o bi u m ar m 
( C o h ort 4)
I ncl u de P K sa m pli n g f or u p t o 
1 5 s u bjects i n Gr o u p 1 b
( Biltrici de).
T he te xt was m o difie d t o a d dress 
t he P K sa m pli n g after a d ose 
i ncrease t o 6 0 m g/ k g f or t he 
Hae mat o bi u m ar m.
T he te xt was m o difie d d ue t o t he 
i ncl usi o n of P K sa m pli n g i n t he 
Biltrici de c o ntr ol ar m
Secti o n 9. 4. 4  
A d diti o n of a n i nteri m 
a nal ys is wit h o ut pa usi n g t he 
st u d y was t o be perf or me d 
after 3 0 partici pa nts i n C o h ort 
4 we re treate d at 6 0 m g/ k g.
T he p ur p ose is t o i nf or m ot her 
st u dies wit h i n t he S p o ns or’s cli nical 
pr o gra m. 
A p pe n di x 4 
A d diti o n of E xte n de d 
F oll o w- u p visit sa m pli n g 
re q uire me nts
T o d oc u me nt t he st u d y sa m pli n g 
re q uire me nts at t he E xte n de d 
F oll o w -u p visit
A p pe n di x 5 
T a ble 7 Cli nical 
La b orat or y  tests 
Deleti o n of t he fasti n g g l uc ose 
test
O nl y  n or mal n o n-fasti n g gl uc ose 
testi n g will be perf or me d 
- C o nfi d e nti al –
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h t he L- P Z Q O D T s
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O
6/ 9 3
T hi s d o c u m e nt i s t h e pr o p ert y of M er c k K G a A, D ar m st a dt, G er m a n y, or o n e of it s s u b si di ari e s. It i s i nt e n d e d f or 
r e stri ct e d u s e o nl y a n d m a y n ot – i n f ull or p art – b e p a s s e d o n, r e pr o d u c e d, p u bli s h e d or u s e d wit h o ut e x pr e s s 
p er mi s si o n of M e r c k K G a A, D ar m st a dt, G er m a n y, or it s s u b si di ar y. C o p yri g ht © 2 02 0 b y M er c k K G a A, D ar m st a dt, 
G er m a n y, or it s s u b si di ar y. All ri g ht s r e s er v e d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h t he L- P Z Q O D T s
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O
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T a ble of C o nte nts
Title Pa ge
.............................................................................................................. 1
Ta ble of C o nte nts
.............................................................................................................. 7
1
Pr ot oc ol S u m mar y .............................................................................. 1 1
1. 1
S y n o psis ..............................................................................................1 1
1. 2
Sc he ma ................................................................................................ 1 8
1. 3
Sc he d ule of Acti vi ties......................................................................... 1 9
2
I ntr o d ucti o n......................................................................................... 2 1
2. 1
St u d y  Rati o nale................................................................................... 2 1
2. 2
Bac k gr o u n d ......................................................................................... 2 1
2. 3
Be nefit/ Ris k Assess me nt .................................................................... 2 3
3
O bjecti ves a n d E n d p oi nts ................................................................... 2 5
4
St u d y Desi g n ....................................................................................... 2 9
4. 1
O verall Desi g n .................................................................................... 2 9
4. 2
Scie ntific Rati o nale f or St u d y  Desi g n ................................................ 2 9
4. 2. 1
Mai n Fi n di n gs of t he P hase I St u dies wit h t he Ne w P Z Q O D Ts 
( M S 2 0 0 5 8 5- 0 0 1 a n d M S 2 0 0 6 6 1- 0 0 1)................................................ 3 1
4. 2. 2
Mai n Fi n di n gs of t he P hase I L -P Z Q O D T Palata bilit y  St u d y 
( E M R 2 0 0 6 6 1- 0 0 2).............................................................................. 3 1
4. 2. 3
Mai n Fi n di n gs of t he P hase II
D ose -fi n di n g St u dy i n Iv or y  C oast 
( M S 2 0 0 6 6 1- 0 0 0 5)............................................................................... 3 1
4. 2. 4
Rati o nale f or St u d y  P o p ulati o n........................................................... 3 2
4. 2. 5
E n d p oi nts ............................................................................................ 3 4
4. 2. 6
Stratificati o n ....................................................................................... 3 5
4. 3
J ustificati o n f or D ose ..........................................................................3 5
4. 4
E n d of St u d y  Defi niti o n...................................................................... 3 6
5
St u d y  P o p ulati o n.................................................................................3 6
5. 1
I ncl usi o n Criteria................................................................................ 3 7
5. 2
E xcl usi o n Criteria ............................................................................... 3 8
5. 3
Lifest y le C o nsi derati o ns.....................................................................3 9
5. 3. 1
Meals a n d Dietar y  Restricti o ns...........................................................3 9
5. 3. 2
Caffei ne Alc o h ol, a n d T o bacc o .......................................................... 3 9
5. 3. 3
Acti vit y ...............................................................................................3 9
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D:
C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h t he L- P Z Q O D T s
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O
8/ 9 3
5. 4
Scree n Fail ure s....................................................................................3 9
6
St u d y  Inter ve nti o n(s) .......................................................................... 4 0
6. 1
St u d y  Inter ve nti o n(s) A d mi nistrati o n ................................................. 4 1
6. 2
St u d y  Inter ve nti o n(s) Pre parati o n, Ha n dli n g, St ora ge, a n d 
Acc o u nta bilit y ..................................................................................... 4 2
6. 3
Meas ures t o Mi ni mize Bias: St u d y  Inter ve nti o n Assi g n me nt a n d 
Bli n di n g ..............................................................................................4 3
6. 3. 1
St u d y  Inter ve nti o n Assi g n me nt .......................................................... 4 3
6. 3. 2
Bli n di n g ..............................................................................................4 4
6. 3. 3
E mer ge nc y  U n bli n di n g....................................................................... 4 4
6. 4
St u d y  Inter ve nti o n C o m plia nce .......................................................... 4 4
6. 5
C o nc o mita nt T hera p y ......................................................................... 4 5
6. 5. 1
Resc ue Me dici ne ................................................................................. 4 5
6. 5. 2
Per mitte d Me dici nes ........................................................................... 4 5
6. 5. 3
Pr o hi bite d Me dici nes .......................................................................... 4 5
6. 5. 4
Ot her I nter ve nti o ns ............................................................................. 4 6
6. 6
D ose Selecti o n a n d M o dificati o n ........................................................ 4 7
6. 7
Treat me nt I nter ve nti o n after t he E n d of t he St u d y............................. 4 7
6. 8
S pecial Preca uti o ns ............................................................................. 4 7
6. 9
Ma na ge me nt of A d verse E ve nts of I nterest ........................................ 4 7
7
Disc o nti n uati o n of St u d y I nter ve nti o n a n d Partici pa nt 
Disc o nti n uati o n/ Wit h dra wal ...............................................................4 8
7. 1
Disc o nti n uati o n of St u d y I nter ve nti o n ................................................ 4 8
7. 2
Partici pa nt Disc o nti n uati o n/ Wit h dra wal fr o m t he St u d y ................... 4 8
7. 3
L ost t o F oll o w -U p ............................................................................... 4 9
8
St u d y  Assess me nts a n d Pr oce d ures.................................................... 4 9
8. 1
Efficac y  Assess me nts a n d Pr oce d ures................................................5 4
8. 1. 1
Assess me nt of Pri mar y  Efficac y E n d p oi nt......................................... 5 4
8. 1. 2
Assess me nt of Sec o n dar y  Efficac y E n d p oi nts ...................................5 4
8. 1. 3
S urr o gate E n d p oi nts ............................................................................5 5
8. 2
Safet y  Assess me nts a n d Pr oce d ures...................................................5 5
8. 2. 1
P ost Mar keti n g A d verse E ve nt Re p orts f or P Z Q ............................... 5 5
8. 2. 2
P h y sical E xa mi nati o ns ........................................................................ 5 8
8. 2. 3
Vital Si g ns .......................................................................................... 5 8
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D:
C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h t he L- P Z Q O D T s
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O
9/ 9 3
8. 2. 4
Cli nical Safet y  La b orat or y Assess me nts............................................5 8
8. 2. 5
C o nc o mita nt Me dicati o ns................................................................... 5 9
8. 3
A d verse E ve nts a n d Seri o us A d verse E ve nts ..................................... 5 9
8. 3. 1
Ti me Peri o d a n d Fre q ue nc y  f or C ollecti n g A d verse E ve nt a n d 
Seri o us A d verse E ve nt I nf or mati o n .................................................... 5 9
8. 3. 2
Met h o d of Detecti n g A d verse E ve nts a n d Seri o us A d verse E ve nts ...5 9
8. 3. 3
F oll o w -u p of A d verse E ve nts a n d Seri o us A d verse E ve nts ............... 5 9
8. 3. 4
Re g ulat or y  Re p orti n g Re q uire me nts f or Seri o us A d verse E ve nts ..... 6 0
8. 3. 5
Pre g na nc y ........................................................................................... 6 0
8. 4
Treat me nt of O ver d ose ....................................................................... 6 0
8. 5
P har mac o ki netics ................................................................................ 6 1
8. 6
P har mac o d y na mics ............................................................................. 6 2
8. 7
Ge netics ..............................................................................................6 2
8. 8
Bi o mar kers .......................................................................................... 6 2
8. 9
Healt h Ec o n o mics ............................................................................... 6 2
8. 1 0
I m m u n o ge nicity Assess me nts ............................................................ 6 2
9
Statistical C o nsi derati o ns .................................................................... 6 3
9. 1
Statistical H y p ot heses ......................................................................... 6 3
9. 2
Sa m ple Size Deter mi nati o n ................................................................ 6 3
9. 3
P o p ulati o ns f or A nal y ses .................................................................... 6 6
9. 4
Statistical A nal y ses ............................................................................. 6 6
9. 4. 1
Efficac y  A nalys es ............................................................................... 6 7
9. 4. 2
Safet y  A nalys es .................................................................................. 6 8
9. 4. 3
Ot her A nal ys es .................................................................................... 6 9
9. 4. 4
Se q ue nce of A nal ys es .........................................................................6 9
1 0
Refere nces ...........................................................................................7 0
1 1
A p pe n dices .........................................................................................7 1
1 2
A p pe n di x 1 A b bre viati o ns.................................................................. 7 2
A p pe n di x 2
St u d y  G o ver na nce...............................................................................7 4
A p pe n di x 3
A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, 
E val uati n g, F oll o w -u p, a n d Re p orti n g ................................................ 8 2
A p pe n di x 4
V ol u me of bi ol o gical fl ui d c ollecte d d uri n g t he st u d y ....................... 8 6
A p pe n di x 5
Cli nical L a b orat or y Tests ..................................................................8 8
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h t he L- P Z Q O D T s
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O
1 0 /9 3
A p pe n di x 6
P har mac o ki netic Bl o o d Sa m pli n g................................ ......................8 9
A p pe n di x 7
S p o ns or Si g nat ure Pa ge...................................................................... 9 0
A p pe n di x 8
C o or di nati n g Pri nci pal I n vesti gat or Si g nat ure Pa ge ........................... 9 1
A p pe n di x 8
L ocal Pri nci pal I n vesti gat o r Si g nat ure Pa ge I v or y C oast................... 9 2
A p pe n di x 9
Pri nci pal I n vesti gat or Si g nat ure Pa ge Ke n y a ..................................... 9 3
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D:
C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h t he L- P Z Q O D T s
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O
1 1 /9 3
1
Pr ot oc ol S u m m ar y
1. 1
S y n o psis
Pr ot oc ol Title: 
O pe n -la bel, P hase III efficac y an d safet y st u d y of L- prazi q ua ntel or o dis persi ble ta blets ( L-P Z Q 
O D T) i n Sc hist os o ma -i nfecte d c hil dre n 3 m o nt hs t o 6 years of a ge, i ncl u di n g a 2: 1 ra n d o mize d, 
c o ntr olle d c o h ort of Sc hist os o ma ma ns o ni -i nfecte d c hil dre n 4 t o 6 years of a ge treate d wit h 
L- P Z Q O D T or c o m mercial P Z Q ( Biltrici de ®)
S h ort Title:
P hase III pe diatric st u d y wit h L -P Z Q O D Ts
R ati o n ale: 
T his is a P hase III safet y/efficac y st u d y in Sc hist os o ma -i nfecte d Africa n c hil dre n 3 m o nt hs t o 
6
ye ars of a ge a n d it is part of t he P Z Q O D T cli nical de vel o p me nt pr o gra m, w hic h ai ms t o 
re gister a si n gle d ose of t he ne w O D Ts i n t he tar gete d pe diatric a ge gr o u p ( 3 m o nt hs t o 6 years
of a ge ).
T he rati o nale f or t his st u d y is base d o n data gat here d fr o m pre vi o usl y  co n d ucte d P hase I a n d 
P hase II cli nical st u dies wit h t he ne w P Z Q O D Ts.
O bjecti ves a n d E n d p oi nts: 
O bjecti ves
E n d p oi nts ( O utc o me Me a s ures)
E n d p oi nts 
( O utc o me 
Me as ures) 
Ti mefr a me
Pri m ar y
T o assess t he efficac y  of a si n gle 
d ose ( 5 0 m g/ k g) of L -P Z Q O D T as 
assesse d b y c ure rate 1 7 t o 2 1 da ys 
after treat me nt, i n c hil dre n 4 t o 6 
ye ars of a ge i nfecte d wit h S. 
ma ns o ni ( Treat me nt gr o u p 1a). T he 
efficac y of a si n gle d ose ( 4 0 
m g/ k g) of c o m mercial P Z Q ta blets 
(Biltrici de ) i n t he sa me patie nt 
p o p ulati o n ( Treat me nt gr o u p 1 b)
will be c o nsi dere d as a n i nter nal 
c o ntr ol.
Cli nical c ure is defi ne d as n o parasite 
e g gs i n t he st o ol 17 t o 2 1 da ys after 
treat me nt.
E g g c o u nts will be deter mi ne d b y  t he 
Kat o -Katz met h o d: O ne st o ol sa m ple 
will be c ollecte d d uri n g t he 
pre scree ni n g peri o d ( Da y -2 8 t o 
Da y  -1) a n d t he sec o n d o ne wit hi n a 
ma xi m u m of 5 da y s t hereafter as 
baseli ne. T w o a d diti o nal st o ol
sa m ples will be c ollecte d bet wee n 
Da y  1 7 t o 2 1 after d osi n g t o 
deter mi ne efficac y : t he first o ne will 
be c ollecte d wit hi n t he 1 7 t o 2 1- d a y
wi n d o w a n d t he sec o n d o ne wit hi n a 
ma xi m u m of 5 da y s f oll o wi n g 
E n d - of-St u d y  
visit ( 1 7 t o 2 1 
da y s after 
treat me nt)
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D:
C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h t he L- P Z Q O D T s
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O
1 2 /9 3
O bjecti ves
E n d p oi nts ( O utc o me Me a s ures)
E n d p oi nts 
( O utc o me 
Me as ures) 
Ti mefr a me
c ollecti o n of t he 1 st sa m ple. T hree 
Kat o -Katz t hic k s mears ( 4 1. 7 m g) 
will be pre pare d fr o m eac h st o ol 
sa m ple.
Sec o n d ar y
T o assess t he safet y of a si n gle 
d ose ( 5 0 m g/ k g) of L -P Z Q O D T i n 
c hil dre n 4 t o 6 years of a ge 
i nfecte d wit h S. ma ns o ni
( Treat me nt gr o u p 1a)
Safet y  a n d t olera bilit y assess me nts:
-
Occ urre nce, nat ure, se verit y  a n d 
o utc o me of a d verse e ve nts 
(A Es ),
-
Occ urre nce of treat me nt-relate d 
A Es
-
C ha n ges i n la b orat or y  safet y 
para meters ( he mat ol o g y , 
bi oc he mistr y , uri nal ysis) a n d 
vital si g ns ( b o d y te m perat ure, 
bl o o d press ure a n d p ulse rate)
First treat me nt t o 
pla n ne d 
E n d - of-St u d y  
visit
T o assess t he efficac y  of a si n gle 
d ose ( 5 0 m g/ k g) of L -P Z Q O D T as 
assesse d b y c ure rate 1 7 t o 2 1 da ys 
after treat me nt, i n c hil dre n 2 t o 3 
ye ars of a ge a n d i n i nfa nts/t o d dlers 
3 t o < 2 4 m o nt hs of a ge i nfecte d 
wit h S. ma ns o ni ( C o h orts 2 a n d 3, 
res pecti vely)
Sa me as C o h ort 1.
E n d - of-St u d y  
visit
T o assess t he safet y of a si n gle 
d ose ( 5 0 m g/ k g) of L -P Z Q O D T i n 
c hil dre n 2 t o 3 years of a ge a n d i n 
i nfa nts/t o ddlers 3 m o nt hs t o < 2 4 
m o nt hs of a ge i nfecte d wit h S. 
ma ns o ni ( C o h ort 2 a n d 3, 
res pecti vely)
Sa me as C o h ort 1.
First treat me nt t o 
pla n ne d 
E n d - of-St u d y  
visit
T o assess t he efficac y  of a si n gle 
d ose ( 5 0 m g/ k g, 6 0 m g / k g base d o n 
I D M C) of L-P Z Q O D T as assesse d 
b y  c ure rates 1 7 t o 2 1 da ys a n d 3 5
t o 4 0 da y s after treat me nt, i n 
c hil dre n 3 m o nt hs t o 6 years of a ge 
i nfecte d wit h S. hae mat o bi u m
Cli nical c ure is defi ne d as n o parasite 
e g gs i n t he uri ne sa m ples at 
f oll o w-u p.
E g g c o u nts will be deter mi ne d b y  
uri ne e xa mi nati o n usi n g t he uri ne 
filtrati o n tec h ni q ue: T he first sa m ple 
E n d - of-St u d y  
visit a n d 
E xte n de d 
F oll o w - u p visit
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D:
C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h t he L- P Z Q O D T s
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O
1 3 /9 3
O bjecti ves
E n d p oi nts ( O utc o me Me a s ures)
E n d p oi nts 
( O utc o me 
Me as ures) 
Ti mefr a me
( C o h ort 4)
will be c ollecte d d uri n g t he pre 
scree ni n g peri o d ( Da y -2 8 t o Da y  -1) 
a n d t he sec o n d a n d t he t hir d o ne 
wit hi n a ma xi m u m of 5 da y s 
t hereafter as baseline. At t he 
E n d - of-St u d y  visit ( bet wee n Da ys 1 7 
a n d 2 1) C o h ort 4 partici pa nts will be 
as ke d t o pr o vi de t hree uri ne sa m ples 
(a b o ut 1 0 m L eac h): t he first o ne will 
be c ollecte d wit hi n t he 1 7 t o 2 1 -d a y  
wi n d o w a n d t he ot her t w o wit hi n a 
ma xi m u m of 5 da y s f oll o wi n g 
c ollecti o n of t he 1 st sa m ple, f or 
a nal ys is b y t he filtrati o n met h o d. 
Si milarl y , at t he E xte n de d F oll o w - u p 
visit, C o h ort 4 partici pa nts will be 
as ke d t o pr o vi de t hree a d diti o nal 
uri ne sa m ples (a b o ut 1 0 m L  eac h) o n 
differe nt da ys bet wee n Da y  3 5 a n d 
Da y  4 0, f or efficac y assess me nt b y  
t he filtrati o n met h o d. T he uri ne 
sa m ples will be filtere d t hr o u g h a 
filter mes h. T his mes h is t he n 
e xa mi ne d u n der t he micr osc o pe f or 
S. hae mat o bi u m e g g c o u nt.
T o assess t he safet y of a si n gle 
d ose ( 5 0 m g/ k g , 6 0 m g/ k g base d o n 
I D M C) of L-P Z Q O D T i n c hil dre n 
3 m o nt hs t o 6 y ears of a ge i nfecte d 
wit h S. hae mat o bi u m ( C o h ort 4)
Sa me as C o h ort 1
First treat me nt t o 
pla n ne d 
E n d - of-St u d y  
visit
T o assess t he efficac y  of a si n gle 
d ose ( 5 0 m g/ k g) of t he L -P Z Q 
O D T as assesse d b y e g g re d ucti o n 
rate ( E R R) 17 t o 2 1 da ys after 
treat me nt, i n c hil dre n 4 t o 6 years 
of a ge i nfecte d wit h S. ma ns o ni
( Treat me nt gr o u p 1a). T he efficac y 
( E R R) of a si n gle d ose ( 40 m g/ k g) 
of c o m mercial P Z Q ta blets 
( Biltrici de) i n t he sa me patie nt 
p o p ulati o n ( Treat me nt gr o u p 1 b ) 
E R R fr o m pretreat me nt t o 17 t o 2 1 
da y s after treat me nt, usi n g parasite 
e g g c o u nts as deter mi ne d b y  t he 
Kat o -Katz met h o d f or C o h ort 1.
Pre scree ni n g 
visit t o 
E n d - of-St u d y  
visit 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h t he L- P Z Q O D T s
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O
1 4 /9 3
O bjecti ves
E n d p oi nts ( O utc o me Me a s ures)
E n d p oi nts 
( O utc o me 
Me as ures) 
Ti mefr a me
will be c o nsi dere d as a n i nter nal 
c o ntr ol.
T o assess t he efficac y  of a si n gle 
d ose ( 5 0 m g/ k g) of L -P Z Q O D T as 
deter mi ne d b y E R R i n c hil dre n 2 t o 
3 y ears of a ge a n d i n i nfa nts a n d 
t o d dlers 3 m o nt hs t o < 2 4 m o nt hs 
of a ge i nfecte d wit h S. ma ns o ni
( C o h orts 2 a n d 3, res pecti vel y). 
A n d i n c hil dre n 3 m o nt hs t o 6 
ye ars of a ge i nfecte d wit h S. 
hae mat o bi u m ( C o h ort 4; 5 0 m g/ k g, 
6 0 m g/ k g base d o n I D M C)  
E R R fr o m pre -treat me nt t o 17 t o 2 1 
da y s after treat me nt, usi n g parasite 
e g g c o u nts as deter mi ne d b y  t he 
Kat o -Katz met h o d f or C o h orts 2 a n d 
3 a n d t he uri ne filtrati o n met h o d f or 
C o h ort 4 . A d diti o nall y, E R R fr o m 
pretreat me nt t o 3 5 t o 4 0 da y s after 
treat me nt, usi n g parasite e g g c o u nts 
as deter mi ne d by t he uri ne filtrati o n 
met h o d f or C o h ort 4 partici pa nts.
Pre scree ni n g 
visit t o
E n d - of-St u d y
visit a n d 
E xte n de d F oll o w -
u p visit
T o assess t he c ure rate as 
de m o nstrate d wit h use of t he 
c o m merciall y a vaila ble 
p oi nt - of-care circ ulati n g cat h o dic 
a nti ge n ( P O C -C C A ® ) test 
(C o h orts 1, 2, a n d 3).
O ne uri ne sa m ple will be c ollecte d 
1 7 t o 2 1 da ys after treat me nt. C ure is 
defi ne d as a bse nce of test li ne i n t he 
P O C -C C A ® test cassette (i.e., n o 
Sc hist os o ma a nti ge ns detecte d). 
E n d - of-St u d y  
visit
T o assess acce pta bilit y  i n ter ms of 
ease of a d mi nistrati o n of t he 
selecte d O D T ( Treat me nt gr o u p 1a, 
C o h orts 2, 3, a n d 4) a n d 
c o m mercial P Z Q ta blet ( Treat me nt 
gr o u p 1 b)
Reacti o n t o St u d y  Inter ve nti o n
a d mi nistrati o n ( e. g., s pitti n g, cr yi n g) 
t o descri be t olera bilit y as assesse d by 
n urse/site staff f or all c hil dre n 
e nr olle d i n t he st u d y.
Palata bilit y  assess me nt usi n g a 
h u ma n g ustat or y  se nsati o n test 
( 1 0 0-m m vis ual a nal o g ue scale 
[ V A S]) sc ori n g m o difie d b y t he 
i nc or p orati o n of a 3 -p oi nt facial 
he d o nic scale f or all c hil dre n 5 a n d 6 
ye ars of a ge e nr olle d i n t he st u d y.
At St u d y  
I nter ve nti o n
a d mi nistrati o n 
T o assess t he c o nce ntrati o n -ti me 
pr ofile of t he L- P Z Q O D T 
f or m ulati o n a n d Biltrici de 
f or m ulati o n i n a s u bset of c hil dre n
C o nce ntrati o ns of R-(-)- P Z Q a n d
rac-P Z Q, a n d if a p pr o priate,
p har mac o ki netics ( P K ) para meters 
(e. g., Cma x , tma x , A U C0-t)
Pre d ose t o 1 2 
h o urs after war ds
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D:
C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h t he L- P Z Q O D T s
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O
1 5 /9 3
O ver all Desi g n: 
T his is a m ultice nter o pe n -la bel P hase III st u d y in w hic h partici pa nts assi g ne d t o 1 of 4 c o h orts 
base d o n a ge (i nfa nts a n d c hil dre n 3 m o nt hs t o 6 ye ars of a ge) a n d Sc hist os o ma s pecies of 
i nfecti o n will recei ve at D a y  1 a si n gle treat me nt d ose of L- P Z Q O D T 5 0 m g/ k g (see Secti o n  1. 3
Sc he d ule of Acti vities). T he st u d y incl u des 2: 1 ra n d o mizati o n of c hil dre n 4 t o 6 ye ars of a ge
i nfecte d wit h S. ma ns o ni ( C o h ort 1, n = 1 5 0) t o t he P Z Q O D T treat me nt ( Treat me nt gr o u p 1a) or 
t he c o ntr ol treat me nt ( 4 0 m g/ k g race mic P Z Q [rac-P Z Q] cr us he d ta blets, Treat me nt gr o u p 1 b). 
S. ma ns o ni -i nfecte d c hil dre n 2 t o 3 ye ars of a ge ( C o h ort 2 , n= 3 0 ), S. ma ns o ni-i nfecte d c hil dre n 3 t o 
< 2 4 m o nt hs
of a ge ( C o h ort 3 , n = 2 5 t o 6 5 ) a n d S. hae mat o bi u m -i nfecte d c hil dre n 3 m o nt hs t o 
6 ye ars of a ge ( C o h ort 4 , n = 6 0 t o 9 0 ) will be treate d wit h a si n gle d ose of 5 0 m g/ k g of L- P Z Q 
O D T. U p o n rec o m me n dati o n of t he I n de pe n de nt Data M o nit ori n g C o m mittee (I DM C ), t he d ose 
a d mi nistere d t o partici pa nts i n C o h ort 4 m a y  be i ncrease d t o 6 0 m g / k ga. N o ra n d o mizati o n is 
f oresee n i n C o h orts 2, 3, a n d 4.
N u m ber of P artici p a nts: 
T he pri mar y  en d p oi nt will be t he c ure rate c o m p ute d b y  treat me nt gr o u p o n t he m o difie d 
i nte nti o n-t o-treat (mI T T ) p o p ulati o n of 4 t o 6 ye ars of a ge c hil dre n i nfecte d wit h S. ma ns o ni 
( Co h ort 1). A t otal of 1 5 0 partici pa nts will be ra n d o mize d 2: 1 i nt o t he L- P Z Q O D T treat me nt 
gr o u p or t he c o m mercial rac-P Z Q ( Biltrici de) treat me nt gr o u p a n d a nal yz e d si milarl y; h o we ver, 
t he efficac y of t he t w o treat me nts will n ot be c o m pare d statistically. T he c o m mercial rac-P Z Q 
treat me nt ar m as a n acti ve c o ntr ol ar m will be c o nsi dere d a n i nter nal be nc h mar k. T he sa m ple 
size of n = 1 5 0 f or C o h ort 1 was c h ose n base d o n t he precisi o n of t he esti mate of t he tr ue c ure 
rate.
F or a fi xe d sa m ple size, t he precisi o n of t he esti mate of t he tr ue c ure rate is de pe n de nt o n t he 
o bser ve d c ure rate. I n Part 1 of t he P hase II st u d y, M S 2 0 0 6 6 1 -0 0 0 5, t he o bser ve d c ure rate i n t he 
mI T T p o p ulati o n f or L- P Z Q O D T 4 5 m g / kg a m o n g c hil dre n 4 t o 6 years of a ge was 8 3. 7 % 
( 3 6/ 4 3 c ure d; 9 5 % c o nfi de nce i nter val [CI ]: 6 9. 3 -9 3. 2). Wit h 
9 5 partici pa nts i n t he P hase III
mI T T A nal ys is Set recei vi n g L-P Z Q O D T i n Treat me nt gr o u p 1a, t he l o wer b o u n d of a 
t w o-si de d 9 5 % CI  for a si n gle pr o p orti o n usi n g t he Cl o p per -Pears o n e xact met h o d will e xte n d 
1 0. 0 % fr o m t he o bser ve d pr o p orti o n f or a n e x pecte d c ure rate of 7 3. 7 %.
Ass u mi n g 5 % of partici pa nts will nee d a nti-malarial
treat me nts after P Z Q treat me nt a n d a 2 0 % 
n o n- e val ua ble rate, a t otal of 1 5 0 partici pa nts will be ra n d o mize d i n C o h ort 1, acc or di n g t o a 2: 1 
rati o, t o ac hie ve 9 5 mI T T partici pa nts a n d 8 0 per -pr ot oc ol (P P ) partici pa nts e x p ose d t o t he 
L- P Z Q O D T a n d 4 7 mI T T a n d 4 0 P P partici p a nts e x p ose d t o c o m mercial rac-P Z Q ta blets 
(Biltrici de ). T he mI T T p o p ulati o n will be use d t o a nal yz e t he pri mar y e n d p oi nt.
I n C o h ort 2, a t otal of 3 0 partici pa nts 2 t o 3 years of a ge i nfecte d wit h S. ma ns o ni
will be 
e nr olle d t o assess c o nsiste nc y of t he treat me nt effect wit h t hat i n t he ol der a ge gr o u p. T he size of 
C o h ort 2 is 3 0 % of t hat of Treat me nt gr o u p 1a, t o be r o u g hly c o nsiste nt wit h t he distri b uti o n of 
                                                
a A n I n de pe n de nt Data M o nit ori n g C o m mittee (I D M C) meeti n g was hel d o n t he 0 9 Marc h 2 0 2 0 a n d a decisi o n was 
ma de t o i ncrease t he d ose i n C o h ort 4 t o 6 0 m g/ k g.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h t he L- P Z Q O D T s
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O
1 6 /9 3
c hil dre n 2 t o 3 years of a ge ( 2 7 %) a n d 4 t o 6 years of a ge ( 7 3 %) e nr olle d i n t he P hase II st u d y, i n 
w hic h n o differe nces i n c ure rate b y a ge were o bser ve d.
I n C o h ort 3 overall, a t otal of 6 5 partici pa nts 3 t o 2 4 m o nt hs of a ge i nfecte d wit h S. ma ns o ni will 
be e nr olle d i n t he P hase II a n d P hase III st u dies. T he sa m ple size i n eit her st u d y al o ne is t o o 
s mall t o ha ve a de q uate precisi o n o n t he c ure rate, t h us t he res ults i n t his P hase III st u d y (C o h ort 
3) will be p o ole d wit h C o h orts 8 a n d 9 of t he o n g oi n g P hase II st u d y (M S 2 0 0 6 6 1 -0 0 0 5). Pla n ne d 
e nr oll me nt i n S t u d y M S 2 0 0 6 6 1-0 0 0 5 is u p t o 3 0 partici pa nts 1 3 t o 2 4 m o nt hs of a ge a n d u p t o 1 0 
partici pa nts 3 t o 1 2 m o nt hs of a ge. I n C o h ort 3 of t his P hase III st u d y, at least 2 5 partici pa nts
3 t o 2 4 m o nt hs of a ge i nfecte d wit h S. ma ns o ni (i.e., ~ 2 0 % of t he t otal n u m ber of partici pa nts 2 
t o 6 ye ars of a ge recei vi n g L- P Z Q O D T) will be e nr olle d. If t he e nr oll me nt of t his a ge gr o u p 
fr o m P hase II is l o wer t ha n pla n ne d, t he n m ore t ha n 2 5 partici pa nts will be e nr olle d i n P hase III
C o h ort 3 t o ac hie ve a t otal of 6 5 partici pa nts i n t his a ge gr o u p. T his p o ole d sa m ple will all o w a 
ge neral c o m paris o n t o assess w het her t he treat me nt effect is si milar acr oss a ge gr o u ps.
A ma xi m u m of 9 0 c hil dre n will be e nr olle d i n C o h ort 4. A t otal of 6 0 c hil dre n i n C o h ort 4, 
3 m o nt hs t o 6 y ears of a ge i nfecte d wit h S. hae mat o bi u m , will be treate d wit h L-P Z Q O D T at t he 
fi nal d ose , eit her 5 0 m g/ k g or 6 0 m g/ k g. Sa m ple size is base d o n t he n u m ber of partici pa nts 
nee de d t o pr o vi de a mea ni n gf ul 
esti mate of c ure rate i n t he S. hae mat o bi u m -i nfecte d 
partici pa nts.
I n s u m mar y, a t otal of 2 6 5 t o 3 3 5 c hil dre n will be e nr olle d a n d all ocate d t o 4 c o h orts as f oll o ws:

C o h ort 1: 1 5 0 c hil dre n ( 4 t o 6 years of a ge) i nfecte d wit h S. ma ns o ni, ra n d o mize d 2: 1 i nt o 
Treat me nt 1a a n d Treat me nt 1 b. 

C o h ort 2: 3 0 partici pa nts, 2 t o 3 y ears of a ge , i nfecte d wit h S. ma ns o ni.

C o h ort 3: 2 5 t o 6 5 partici pa nts (t he tar get is t o ha ve a t otal of 6 5 c hil dre n i n t he p o ole d 
a nal ys is wit h P hase II, M S 2 0 0 6 6 1 - 0 0 0 5, C o h orts 8 a n d 9), 3 m o nt hs
t o 2 4 m o nt hs
of a ge, 
i nfecte d wit h S. ma ns o ni. 

C o h ort 4: 6 0 t o 9 0 c hil dre n, 3 m o nt hs t o 6 y ears of a ge , i nfecte d wit h S. hae mat o bi u m. A t otal 
of 6 0 c hil dre n i n C o h ort 4, 3 m o nt hs t o 6 years of a ge i nfecte d wit h S. hae mat o bi u m , will be 
treate d wit h L- P Z Q O D T at t he fi nal d ose eit her 5 0 m g/ k g or 6 0 m g/ k g. T he fi nal d ose will 
de pe n d o n t he efficac y res ults of t he i nitially selecte d 5 0 m g /k g d ose, base d o n a n i nteri m 
assess me nt of 3 0 partici pa nts . 
St u d y I nter ve nti o n Gr o u ps a n d D ur ati o n: 
A ma xi m u m 2 8 -da y  pre scree ni n g a n d scree ni n g peri o d, f oll o we d b y a si n gle treat me nt o n Da y 1 
a n d 17 t o 2 1 da ys of f oll o w-u p are f oresee n f or eac h partici pa nt, wit h a t otal st u d y  d urati o n of u p 
t o 7 wee ks f or a gi ve n partici pa nt. I n C o h ort 4 s u bjects treate d wit h 6 0 m g/ k g , a n a d diti o nal 
uri ne c ollecti o n is pla n ne d at D a y s 3 5 t o 4 0, lea di n g t o a st u d y durati o n of 9 wee ks. D urati o n of 
t he St u d y  Inter ve nti o n peri o d is f oresee n t o be u p t o 6 m o nt hs.
I n v ol ve me nt of S peci al C o m mittee(s): 
A n I n de pe n de nt Data M o nit ori n g C o m mittee (I DM C)
will be i n c har ge of re vie wi n g t he safety 
data
of t he P hase III. T he I D M C will 
als o e val uate t he efficac y data of C o h ort 
4 
( S. hae mat o bi u m -i nfecte d c hil dre n 3 m o nt hs t o 6 years of a ge) after 3 0 c hil dre n ha ve bee n 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h t he L- P Z Q O D T s
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
1 7 /9 3
treate d wit h L- P Z Q O D T 5 0 m g/ k g a n d will
deci de if a d ose i ncrease t o 6 0 m g/ k g is nee de d 
(see I D M C c harter f or a d diti o nal details). T he I DM C will c o nsist of a Pe diatricia n s pecializi n g i n 
Sc hist os o miasis a n d dee me d a gl o bal e x pert, a me dical d oct or i n a n e n de mic c o u ntr y an d a 
bi ostatisticia n. 
T he Safet y  Mo nit ori n g C o m mittee (S M C) has revie we d t he safety a n d efficac y data a vaila ble o n 
t he first 1 0 partici pa nts fr o m C o h ort 8 e nr olle d i n Part 2 of P hase II st u d y, M S 2 0 0 6 6 1 - 0 0 0 5 a n d 
dee me d t he m satisfact or y. As t his was a prere q uisite f or t he e nr oll me nt of C o h ort 3 i n t he 
P hase III st u d y, M S 2 0 0 6 1-0 0 0 3, t he e nr oll me nt of t his c o h ort will ta ke place as pla n ne d. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h t he L- P Z Q O D T s
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
1 8 /9 3
1. 2
Sc he m a
T he pr o p ose d P h ase III st u dy c o nsists of 4 c o h orts, t o be e nr olle d i n p ar allel, as s h o w n i n Fi g ure 1 . 
Fi g ure 1
Desi g n Di a gr a m
b
                                                
a Le v o -Prazi q ua ntel Or o dis persi ble Ta blet
b 6 5 partici pa nts are re q ueste d i n p o ole d a nal ysis wit h P hase 2, M S 2 0 0 6 6 1 -0 0 0 5, C o h orts 8 a n d 9. If t he tar get 
n u m ber is n ot reac he d i n t h ose t w o c o h orts, a d diti o nal patie nts will be e nr olle d i n C o h ort 3 
c After 3 0 patie nts i n C o h ort 4 are treate d, t he efficac y data will be e val uate d b y t he I D M C t o deci de w het her a n 
i ncrease of t he d ose t o 6 0 m g/ k g is nee de d, i n w hic h case 3 0 a d diti o nal patie nts will be a d de d t o t his c o h ort a n d 
treate d wit h t he 6 0 m g/ k g d ose
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h t he L -P Z Q O D Ts
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
1 9 /9 3
1. 3
Sc he d ule of Acti vities
Assess me nts & Pr oce d ures
Pre 
S cree ni ng 1
Scree ni n g
Tre a t ment
E n d of 
C o nfi ne me nt 
visit
F oll o w- u p
E n d -of
St u d y visit
E xte n de d 
F oll o w -u p 9
D a y/ Ti me of t he Assess me nt
D a y -2 8 t o
D a y - 1
D a y -7 t o 
D a y 1
D a y 1
H o ur s 1 22 t o 
2 4
D a y 3 t o 
D a y 4 3
D a y 1 7 t o 
D a y 2 1
D a y 3 5 t o 
D a y 4 0
Ti m e of t he Assess me nt
Pr e d ose
H 0
H 0. 5
H 1  
H 2  
H 3  
H 4  
H 6  
H 8
H 1 2
Pr e scree ni n g I nf or me d C o nse nt F or m (I C F)
si g nat ure
X
I C F si g nat ure2 0
X
Uri ne P O C- C C A ® test4
X 5
X 5
St o ol e xa mi nati o n b y Kat o- Katz
X 6
X 7
Uri ne filtrati o n
X 8
X 9
X
Malaria ra pi d dia g n ostic test
( X)1 0
X
Safet y la b orat or y tests ( hae mat ol o g y, 
bi oc he mistr y, uri nal ysis)
X
X
De m o gra p hics
X
De m o gra p hics, me dical hist or y a n d hist or y 
of me dicati o n
X
Vital si g ns ( B P, P ulse Rate, Te m perat ure)
X 1 1
X
X
X
P h ysical e xa mi nati o n (i ncl hei g ht & wei g ht)
X
X 1 2
X
I ncl usi o n/e xcl usi o n criteria
X
C o h ort all ocati o n
X
C o nfi ne me n t1 3
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
F o o d a d mi nistrati o n
X 1 4
X 1 5
X 1 5
A d mi nistrati o n of St u d y I nter ve nti o n
X
Reacti o n t o St u d y I nter ve nti o n
X  
X  
X  
X  
X  
X  
X  
X  
X
Palata bilit y 1 6
X
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h t he L -P Z Q O D Ts
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
2 0 /9 3
P har mac o ki netics ( P K) sa m pli n g (s u bset of 
partici pa nts o nl y) 1 7
X 1 8
X 1 9
X 1 9
X 1 9
X 1 9
X 1 9
X 1 9
X 1 9
X 1 9
A E a n d c o nc o mita nt me dicati o n
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
1
Pr e scree ni n g will be c o n d ucte d i n t he villa ges. F or C o h orts 1 t hr o u g h 3, o nl y c hil dre n w h o are p ositi ve f or S. ma ns o ni
a n d ne gati ve f or S. hae mat o bi u m will be 
tra nsferre d t o t he h os pital f or f urt her scree ni n g. F o r C o h ort 4, o nl y c hil dre n w h o are p ositi ve f or S. hae mat o bi u m a n d ne gati ve f or S. ma ns o ni will be tra nsferre d t o t he 
h os pital f or f urt her scree ni n g.
2 If t he partici pa nt, f or l o gistical or s ocial reas o ns, has t o re mai n i n h os pital a n a d diti o nal ni g ht, t he c o nfi ne me nt ma y e n d u p t o 2 4 h o urs after d osi n g . At e n d of c o nfi ne me nt, 
v ital si g ns will be rec or de d a n d a p h ysical e xa mi nati o n perf or me d.
3
F oll o w- u p of A d ve rse E ve nt (A E ), if re q uire d.
4
P O C- C C A cassettes will be classifie d as eit her p ositi ve or ne gati ve, acc o rdi n g t o t he ma n ufact urer's i nstr ucti o ns, wit h f urt her stratificati o n de pe n di n g o n t he stre n gt h of  
t he c ol or reacti o n. T h us, p ositi ve cassettes will be classifie d as + 1 ( w he n res ult li ne is eas y t o see b ut still wea k), + 2 ( w he n res ult li ne is dar k, b ut lig hter t ha n t he 
c o ntr ol li ne) or + 3 ( w he n res ult li ne is as dar k as or dar ker t ha n t he c o ntr ol li ne).
5
F or C o h orts 1 t hr o u g h 3 o nl y
6
C o h ort 1 t o 3: t w o st o ol sa m ples c ollecte d wit hi n 5 da ys d uri n g t he pre scree ni n g peri o d. T hree Kat o- Katz s mears will be pre pare d fr o m eac h of the st o ol sa m ples t o 
deter mi ne S. ma ns o ni e g g c o u nts. F or C o h ort 4: a st o ol sa m ple wi ll be c ollecte d d uri n g t he pre scree ni n g peri o d . T w o Kat o Katz s mears will be pre pare d fr o m t he 
sa m ple t o e val uate t he prese nce of S. ma ns o ni e g gs.
7
F or C o h orts 1 t hr o u g h 3 o nl y . Ast o ol sa m ple will be c ollecte d bet wee n Da y 1 7 t o 2 1 da ys after d osi n g a n d a n ot her o ne wit hi n 5 da ys t hereafter. 
8
F or C o h orts 1- 3, o ne uri ne sa m ple (a b o ut 1 0 m L) will be filtere d t hr o u g h a filter mes h a n d t he me s h e xa mi ne d u n der t he micr osc o pe t o e xcl u de t he prese nce of S.
hae mat o bi u m e g gs. F or C o h ort 4: t hree uri ne sa m ples (a b o ut 1 0 m L eac h ), c ollecte d wit hi n 5 da ys , will be filtere d t hr o u g h a filter mes h a n d t he mes h will be s u bse q ue ntl y 
e xa mi ne d u n der t he m icr osc o pe f or S. hae mat o bi u m e g g c o u nt .
9 C o h ort 4 o nl y i n case treate d wit h 6 0 m g/k g L -P Z Q O D T . 
1 0 Malaria Ra pi d Dia g n ostic Test ca n be d o ne at discreti o n of i n vesti gat or d uri n g pre scree ni n g.
1 1 Bef ore P K sa m ples are ta ke n .
1 2 Hei g ht o nl y at scree ni n g 
1 3 C o nfi ne me nt fr o m t he m or ni n g of t he d osi n g u ntil at least 1 2 h o urs after t he St u d y I nter ve nti o n a d mi nistrati o n . 
1 4 Wit hi n o ne h o ur bef ore d osi n g
1 5 Partici pa nts s h o ul d fast f or 4 h o urs after d osi n g if t he y are i n t he P K s u bset. F or all ot her st u d y partici pa nts, f o o d ca n be gi ve n at t he discreti o n of t he I n vesti gat or
1 6 Palata bilit y assess me nt will be d o ne usi n g a h u m a n g ustat or y se nsati o n test ( 1 0 0- m m V A S) sc ori n g m o difie d b y t he i nc or p orati o n of a 3- p oi nt facial he d o nic scale (f or 
c hil dre n 5 a n d 6 years of  a ge o nl y ).
1 7 F or c hil dre n wit h b o d y wei g ht of less t ha n 1 0 k g, please see S ecti o n 8. 5 f or details.  
1 8 J ust bef ore d osi n g
1 9 T he all o we d de viati o n fr o m t he pre -s pecifie d assess me nt will be ± 1 0 % (i n mi n utes) of t he sc he d ule d ti me p oi nt. I n case se veral assess me nts are pla n ne d at t he sa me ti me 
p oi nt, t he P K sa m ples will be ta ke n at t he pre -defi ne d ti me p oi nt.
2 0 If scree ni n g pr oce d ures are re peate d (e. g d ue t o te m p oral e xcl usi o n of partici pa nt f or m ore t ha n 7 da ys) t he I nf or me d c o nse nt f or m d oes n ot nee d t o be resi g ne d 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
2 1 /9 3
2
I ntr o d ucti o n
Prazi q ua ntel (P Z Q ), the c urre nt sta n dar d treat me nt a gai nst sc hist os o miasis ( or bil harzia), is a 
race mic mi xt ure c o m p ose d of t he R-(-)- P Z Q a n d S- ( +)-P Z Q e na nti o mers i n a 1: 1 rati o. T he ci dal
acti vit y resi des i n t he R-(-)- P Z Q e na nti o mer (as s h o w n i n vitr o a n d i n a ni mal e x peri me nts [ 6]) 
w hereas t he S- ( +)-P Z Q e na nti o mer was s u g geste d t o be lar gely res p o nsi ble f or t he bitter ness of 
t he c o m mercial f or m ulati o n.
T he ne w L- P Z Q f or m ulati o n has n o w be e n ma n ufact ure d as a s oli d oral d osa ge f or m w hic h ca n 
be a d mi nistere d as a n or o dis persi ble ta blet or dis persi ble ta blet (f or si m plicit y, t he f or m ulati o n 
will be referre d t o as “O D T ” t hr o u g h o ut t his d oc u me nt) a n d has s h o w n better palata bilit y  as 
c o m pare d wi t h t he rac-P Z Q 6 0 0 m g c o m mercial pr o d uct (st u d y EM R 2 0 0 6 6 1 -0 0 2). I n t his st u d y,
Sc hist os o ma -i nfecte d Africa n c hil dre n 3 m o nt hs t o 6 years of a ge will recei ve a si n gle d ose of 
5 0 m g/ k g (as deter mi ne d b y  the data fr o m Part 1 of t he P hase II st u d y, M S 2 0 0 6 6 1 - 0 0 0 5). F or 
C o h ort 4 ( S. hae mat o bi u m -i nfecte d c hil dre n) o nl y , t he I D M C m a y
deci de t o i ncrease t he 
pr o p ose d d osa ge t o 6 0 m g/ k g after re vie w of efficac y a n d safety data f or t he first 3 0 e nr olle d 
partici pa nts .
C o m plete i nf or mati o n o n t he c he mistr y, p har mac ol o g y,  efficac y, a n d safet y of t he L- P Z Q O D T 
f or m ulati o n is i n t he I nvesti gat or’s Br oc h ure (I B) versi o n 4. St u d y R ati o n ale
T his is a P hase III safet y/efficac y st u d y in Sc hist os o ma -i nfecte d Africa n c hil dre n 3 m o nt hs t o 
6 ye ars of a ge a n d it is part of t he P Z Q O D T cli nical de vel o p me nt pr o gra m, w hic h ai ms t o 
re gister a si n gle d ose of t he ne w O D Ts i n t he tar gete d pe diatric a ge gr o u p ( 3 m o nt hs t o 6 years
of a ge ).
T he 
pr o gra m 
has 
bee n 
desi g ne d 
i n li ne wit h 
e x isti n g I nter nati o nal C o u ncil 
f or
Har m o nisati o n/ E ur o pea n U n i o n/ U nite d States F o o d a n d Dr u g A d mi nistrati o n (I C H/ E U/ F D A) 
pe diatric de vel o p me nt g ui da nce d oc u me nts a n d rec o m me n dati o ns, i ncl u di n g t he I CH E 1 1 
G ui deli ne, t he E ur o pea n Me dici nes A ge nc y  ( E M A) Reflecti o n Pa per o n e xtra p olati o n of efficac y 
a n d safety i n pe dia tric me dici ne 
de vel o p me nt, t he F D A g ui da nce of 2 0 1 4 f or pe diatric 
de vel o p me nt , as well as ot her a p plica ble E U a n d F D A g ui da nce f or t he de vel o p me nt of c hiral 
dr u gs, i ncl u di n g t he E U G ui deli ne o n t he I n vesti gati o n of C hiral Acti ve S u bsta nces ( A pril 1 9 9 4).
T he rati o nale f or t his st u d y is base d o n d ata gat here d fr o m pre vi o usl y  co n d ucte d P hase I a n d 
P hase II cli nical st u dies wit h t he ne w P Z Q O D Ts ( s u m marize d i n S ecti o n 4. 2 ).
2. 2
B ac k gr o u n d
Sc hist os o miasis, als o calle d bil harzia, is o ne of t he m ost i m p orta nt of t he ne glecte d tr o pical 
diseases ca use d b y  flat w or ms a n d re mai ns o ne of t he m ost pre vale nt parasitic diseases i n 
de vel o pi n g c o u ntries. I n ter ms of i m pact, t his disease is sec o n d o nl y t o malaria as t he m ost 
de vastati n g parasitic disease, wit h 
si g nifica nt ec o n o mic
a n d p u blic healt h c o nse q ue nces .
Sc hist os o miasis is a se vere c hr o nic i nfla m mat or y disease t hat is e n de mic i n a b o ut 7 8 de vel o pi n g 
c o u ntries. M ore t ha n 2 5 8 milli o n pe o ple are i nfecte d, wit h m ore t ha n 9 0 % of t he m li vi n g i n 
Africa, partic ularl y  i n r ural a gric ult ural a n d peri-ur ba n areas. M ore t ha n 7 0 0 milli o n pe o ple are at 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
2 2 /9 3
ris k. I n ma n y areas, sc hist os o miasis i nfects a lar ge pr o p orti o n of c hil dre n u n der t he a ge of 1 4 
ye ars, i ncl u di n g a n esti mate d 2 8 milli o n presc h o ol -a ge c hil dre n ( P S A C). I n t hese v er y  yo u n g 
c hil dre n, l ocal pre vale nce of i nfecti o n ma y e xcee d 6 0 % ( Re p ort of a meeti n g t o re vie w t he 
res ults of st u dies o n t he treat me nt of sc hist os o miasis i n presc h o ol -a ge c hil dre n, W H O, Ge ne va, 
S witzerla n d, 1 3 – 1 4 Se pte m ber 2 0 1 0).
T here are t w o maj or f or ms of sc hist os o miasis— i ntesti nal a n d ur o ge nital — ca use d b y  fi ve mai n 
s pecies of bl o o d fl u ke. T he m ost pre vale nt s pecies i n S u b -Sa hara n Afric a ( S S A) are S . ma ns o ni 
(i ntesti nal sc hist os o miasis) a n d S.
hae mat o bi u m ( ur o ge nital sc hist os o miasis). Ur o ge nital 
sc hist os o miasis is als o c o nsi dere d t o be a ris k fact or f or h u ma n i m m u n o deficie nc y vir us ( HI V) 
i nfecti o n, es peciall y i n w o me n.
T he W orl d Healt h Or ga nizati o n ( W H O)-rec o m me n de d strate g y to c o ntr ol m or bi dit y  ca use d b y  
sc hist os o miasis is base d o n pre ve nti ve c he m ot hera p y inter ve nti o ns tar geti n g t he maj orit y of t he 
at-ris k p o p ulati o n. T he c urre nt g ol d sta n dar d treat me nt e m pl o ys a n a n n ual, si n gle oral d o se 
( 4 0 m g/ k g ) of P Z Q ta blets. P Z Q was j oi ntl y de vel o pe d b y  Ba yer A G a n d Merc k K Ga A i n t he
1 9 7 0’ s a n d c o m mercialize d i n 1 9 8 0 as Biltrici de ( Ba yer A G), Ces ol ® / C ystici de® / Cistici d®
( Merc k K Ga A) f or h u ma n use, a n d s u bse q ue ntl y as ot her ge neric pr o d ucts. P Z Q has bee n use d 
o ver t he s u bse q ue nt ye ars t o c o ntr ol sc hist os o miasis i n ma n y  co u ntries. I n 2 0 1 2 m ore t ha n 
3 5 milli o n pe o ple, 8 3 % of t he m i n S S A, were treate d f or sc hist os o miasis. O ver all t hese ye ars of 
treat me nt, P Z Q ta blets ha ve s h o w n a g o o d safet y a n d t olera bilit y pr ofile in pre vi o us st u dies, i n 
t he rece ntly p u blis he d meta -a nal ys is i n c hil dre n 1 a n d acc or di n g t o t he m ost rece nt Peri o dic 
Be nefit - Ris k E val uati o n Re p ort ( P B R E R).
At t he W orl d 
Healt h Asse m bl y  in 2 0 0 1, Res ol uti o n A 5 4. 1 9 was p ut f or war d, “ w hic h ur ge d 
e n de mic c o u ntries t o start seri o usl y tac kli n g w or ms, 
s pecificall y sc hist os o miasis a n d 
s oil- tra ns mitte d hel mi nt hs ( S T H)”, wit h a gl o bal tar get t o treat at least 7 5 % of all sc h o ol-a ge 
c hildre n w h o are at ris k of m or bi dit y  fr o m sc hist os o miasis a n d S T H b y  the ye ar 2 0 1 0. I n 2 0 1 3, 
t he W orl d Healt h Asse m bl y passe d Res ol uti o n 6 6. 2 0, i n w hic h t he Me m ber States esse ntiall y 
c o nfir me d t heir c o m mit me nt t o f ulfill t he W H O 2 0 2 0 R oa d ma p f or t he eli mi natio n of ne glecte d 
tr o pical disease s (i ncl u di n g sc hist os o miasis) or re d ucti o ns i n t heir i m pact t o le vels at w hic h t he y 
are n o l o n ger c o nsi dere d p u blic-healt h pr o ble ms. P S A C, w h o are a hi g h -ris k gr o u p f or 
sc hist os o me i nfecti o ns, are c urre ntl y n ot i ncl u de d i n t he W H O sc hist os o miasis c o ntr ol pr o gra ms. 
I n 20 1 2, t he W H O 
f or mall y rec o g nise d t hat i nfa nts a n d P S A C are at si g nifica nt ris k of 
sc hist os o miasis a n d q ualif y f or treat me nt wit h P Z Q.
I n or der t o tac kle t his i m p orta nt p u blic healt h pr o ble m, a pe diatric sc hist oso miasis c o ns orti u m 
was f or me d i n J ul y 20 1 2 u n der t he lea ders hi p of Merc k K Ga A, wit h t he g oal of de vel o pi n g a n d 
re gisteri n g a s uita ble pe diatric f or m ulati o n of P Z Q f or use i n P S A C. T he c o ns orti u m c urre ntl y 
c o nsists of 8 part ners: Merc k K Ga A ( Ger ma ny), L y gat ure ( Net herla n ds), Astellas P har ma I nc. 
(Ja pa n), S wiss Tr o pical a n d P u blic Healt h I nstit ute ( S witzerla n d), Far ma n g ui n h os Fi ocr uz 
F o u n dati o n 
(Brazil), 
t he Sc hist os o miasis 
C o ntr ol 
I nitiati ve ( U K), 
U ni versité 
Féli x 
H o u p h o uët -B oi g n y (Iv or y  Coast) a n d t he Ke n ya Me dical Researc h I nstit ute (Ke n ya ). Si m C y p 
( U K) e xite d t he C o ns orti u m i n A u g ust 2 0 1 7, after c o m pleti o n of t heir m o deli n g a n d si m ulati o n 
acti vities.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
2 3 /9 3
2. 3
Be nefit/ Ris k  Assess me nt
O ver t he past 4 0 ye ars, rac-P Z Q ta blets ha ve s h o w n a g o o d safety a n d t olera bilit y pr ofile i n 
pre vi o us trials, i n t he rece ntl y pu blis he d meta -a nal ysis i n c hil dre n (Z wa n g J, et al. 2 0 1 4 )1 a n d 
acc or di n g t o t he rece ntl y pre pare d Peri o dic Be nefit -Ris k E val uat i o n Re p ort (P B R E R ). I n t he 
meta -a nal ys is, 2 7 3 st u dies were i de ntifie d; t here of, 5 5 st u dies were dee me d eli gi ble ( 1 9, 4 9 9 
partici pa nts treate d wit h P Z Q, c o ntr ol treat me nt or place b o). M ost st u dies i n v ol ve d sc h o ol- a ge 
c hil dre n ( 6 4 %) i nfecte d wit h S. ma ns o ni ( 5 8 %) a n d treate d wit h a 4 0 m g/ k g d ose ( 5 6 %); 6 8 % of 
partici pa nts were i n Africa. T olera bilit y  was assesse d i n 4 0 st u dies ( 1 2, 4 3 5 partici pa nts) as 
A d verse E ve nt (A E ) i nci de nce. O n a vera ge, 5 6. 9 % ( 9 5 % CI : 4 7. 4, 6 7. 9) of t he partici pa nts 
recei vi n g P Z Q 4 0 m g / k g e x perie nce d a n A E. T he i nci de nce of A Es ra n ge d fr o m 2. 3 % f or 
urticaria t o 3 1. 1 % f or a b d o mi nal pai n. 
T he data fr o m t he P Z Q O D T P hase I st u d y (E M R 2 0 0 6 6 1 -0 0 1) was c o nsiste nt wit h t he alrea d y 
well -esta blis he d safety pr ofile f or t he rac-P Z Q ta blets a n d also de m o nstrate d g o o d safety a n d 
t olera bilit y for L- P Z Q O D Ts i n a d ults. At si milar e x p os ure le vels, fe wer treat me nt-e mer ge nt 
a d verse e ve nts (T E A Es ) were o bser ve d wit h L- P Z Q O D T
t ha n wit h rac-P Z Q , alt h o u g h t he 
n u m ber of e nr olle d s u bjects w as s mall. T he m ost co m m o n A Es after a d mi nistrati o n of P Z Q are 
gastr oi ntesti nal effects: diarr hea, na usea, v o miti n g a n d a b d o mi nal pai n, as well as tra nsie nt 
ne ur ol o gical effects ( hea dac he a n d dizzi ness), alt h o u g h dizzi ness was n ot o bser ve d after L- P Z Q
O D T a d mi nistrati o n i n t he P hase I st u d y. Re gar di n g ge neral dis or ders, t he f oll o wi n g A Es ha ve 
bee n re p orte d i n p ost mar keti n g setti n gs: wea k ness, fati g ue a n d i ncrease d b o d y  te m perat ure. All 
of t hese s ym pt o ms were us uall y  tra nsie nt, a n d t he y res ol ve d s p o nta ne o usl y. A d verse reacti o ns, 
i ncl u di n g h y perse nsiti vit y  reacti o ns , w hic h m a y  partl y re prese nt e n d o ge n o us reacti o ns t o t he 
killi n g of t he parasites b y  PZ Q, were n ot o bser ve d i n t he P hase I st u d y wit h L- P Z Q
O D T
i n 
healt h y  vol u nteers. F or patie nts s ufferi n g fr o m sc hist os o miasis, t his u n derl yi n g parasit osis c o ul d 
als o mas k t he A Es of P Z Q treat me nt, e. g., Kata y a ma s yn dr o me, w hic h is a n earl y cli nical 
ma nifestati o n of sc hist os o miasis occ urri n g se veral wee ks p ost i nfecti o n wit h Sc hist os o ma s p p 
(tre mat o de) w or ms. T he di sease o nset a p pears t o be relate d t o mi grati n g sc hist os o m ula a n d e g g 
de p ositi o n , wit h i n di vi d uals t y picall y  prese nti n g wit h n oct ur nal fe ver, c o u g h, m y al gia, hea dac he, 
a n d a b d o mi nal te n der ness ( R oss et al., 2 0 0 7)2
A n acce pta ble safet y pr ofile f or t he P Z Q O D Ts was als o o bser ve d i n Part 1 of t he P hase II st u d y 
( M S 2 0 0 6 6 1-0 0 0 5) i n c hil dre n 2 t o 6 ye ars of a ge i nfecte d wit h S ma ns o ni. T he safety s u m mar y 
data fr o m Part 1 of t his stu d y  di d n ot s h o w a n y T E A Es lea di n g t o deat h a n d n o wit h dra wals d ue 
t o A Es. A m o n g
a t otal of 4 2 0 partici pa nts ra n d o mize d, 6 4 ( 1 5. 2 %) partici pa nts re p orte d 6 8 
dr u g -relate d T E A Es. T he dr u g -relate d T E A Es were m ostl y mil d ( 4 2) a n d m o derate ( 2 5) i n 
i nte nsit y, wit h o nl y  one se vere T E A E i n C o h ort 3 (rac- P Z Q O D T 4 0 m g/ k g), w hic h c o ul d be 
e x plai ne d alter nati vel y (u n derl y i n g malaria, a n d he patic fi br osis d ue t o c hr o nic he pat os ple nic 
sc hist os o miasis). T w o u nliste d T E A Es assesse d b y  the I n vesti gat or as dr u g -relate d h a ve ne ver 
bee n re p orte d bef ore wit h P Z Q. T hese T E A Es were re p orte d i n C o h ort 4 (rac-P Z Q
O D T 
6 0 m g/ k g ): gastr oe nteritis (i n 3 partici pa nts) a n d t hr o m b oc yt o pe nia (i n 1 partici pa nt). T hese 
T E A Es c o ul d n ot be e x plai ne d b y t he mec ha nis m of acti o n of P Z Q. 
O nl y  TE A Es re p orte d i n t he S y ste m Or ga n Class (S O C ) Gastr oi ntesti nal dis or ders occ urre d i n 
> 1 0 % 
of 
partici pa nts: 
a b d o mi nal pai n 
( 2 5), v o miti n g 
( 1 1), diarr h oea 
( 1 0)/ diarr h oea 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
2 4 /9 3
hae m orr ha gic ( 1), a n d na usea ( 2). C o h ort 6 ( L-P Z Q O D T 4 5 m g / k g) ha d t he l o west n u m ber o f 
partici pa nts wit h st u d y inter ve nti o n -relate d T E A Es ( 2) a n d C o h ort 4 (rac- P Z Q O D T 6 0 m g / k g) 
ha d t he hi g hest n u m ber ( 1 6), wit h t he ot her c o h orts i n bet wee n ( C o h ort 3, 4 0 m g/ k g rac-P Z Q 
O D T – 6 T E A Es; C o h ort 5, 3 0 m g/ k g L- P Z Q O D T – 8 T E A Es; C o h ort 1, Biltric i de 3 x 2 0 m g/ k g
– 9 T E A Es; C o h ort 2, Biltrici de 4 0 m g/ k g – 1 1 T E A Es, a n d C o h ort 7, 6 0 m g/ k g L- P Z Q O D T –
1 2 T E A Es). M ost T E A Es were tra nsie nt a n d res ol ve d s p o nta ne o usl y , ge nerall y  n ot re q uiri n g a n y 
s pecial treat me nt. 
P ost treat me nt c o m plai nts, w het her re p orte d b y  patie nts or healt h care pr o vi ders, ca n be ca use d 
directl y  b y PZ Q (I, direct relati o ns hi p), ca n be re gar de d as a n e n d o ge n o us reacti o n t o t he killi n g 
of t he parasites b y  PZ Q (II, i n direct relati o ns hi p) or else, ca n re prese nt si g ns a n d s ym pt o ms of 
t he parasitic i nfecti o n (III, n o relati o ns hi p). It is ofte n diffic ult t o relia bl y differe ntiate bet wee n 
p ossi bilities I , II a n d III. 
P Z Q is c o ntrai n dicate d i n i n di vi d uals wit h a hist or y  of pr o ve n h y perse nsiti vit y  to P Z Q or an y  of 
t he e xci pie nts; i n i ntra oc ular c ysticerc osis; a n d i n c o m bi nati o n wit h rifa m pici n. Ca uti o n is 
warra nte d 
i n dec o m pe nsate d 
he patic 
i ns ufficie nc y 
or i n patie nts 
wit h 
he pat os ple nic 
sc hist os o miasis. T h ose wit h car diac arr h yt h mias s h o ul d be m o nit ore d d uri n g t hera py.  The sa me 
a p plies t o patie nts wit h heart fail ure re q uiri n g di gitalis t hera py,  si nce a di gitalis -a nta g o nistic 
effect has bee n de m o nstrate d i n a ni mal st u dies.
T he c u m ulati ve p ost a ut h orizati o n e x p os ure t o P Z Q si nce Ja n uar y  2 0 0 9 t o Ma y 2 0 1 7 is esti mate d 
t o be a b o ut 9 7 2, 5 3 5 patie nts ( De vel o p me nt Safet y U p date Re p ort, re p orti n g peri o d 2 6 Ma y  2 0 1 6 
t o 2 5 Ma y 2 0 1 7).
M ore 
detaile d i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be nefits a n d ris ks a n d reas o na bly 
e x pecte d A Es
f oll o wi n g a d mi nistrati o n of t he L- P Z Q
O D T
m a y  be f o u n d i n Secti o n 4. 2
( Scie ntific Rati o nale f or St u d y  Desi g n) a n d t he I B. Base d o n t he a vaila ble n o ncli nical a n d 
cli nical data t o date, t he c o n d uct of t he st u d y, as s pecifie d i n t his pr ot oc ol, is c o nsi dere d 
j ustifia ble.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
2 5 /9 3
3
O bjecti ves a n d E n d p oi nts
T a ble 1
O bjecti ves a n d E n d p oi nts
O bjecti ves
E n d p oi nts ( O utc o me Me as ures)
E n d p oi nts 
( O utc o me 
Me as ures) 
Ti mefr a me
Pri m ar y
T o assess t he efficac y of a si n gle 
d ose ( 5 0 m g/ k g) of L -P Z Q O D T as 
assesse d b y c ure rate 1 7 t o 2 1 da y s 
after treat me nt, i n c hil dre n 4 t o 6 
ye ars of a ge i nfecte d wit h S. 
ma ns o ni ( Treat me nt gr o u p 1a). T he 
efficac y of a si n gle d ose ( 4 0 
m g/ k g) of c o m mercial P Z Q ta blets 
( Biltrici de) i n t he sa me patie nt 
p o p ulati o n ( Treat me nt gr o u p 1 b)
will be c o nsi dere d as a n i nter nal 
c o ntr ol.
Cli nical c ure is defi ne d as n o parasite 
e g gs i n t he st o ol 1 7 t o 2 1 da y s after 
treat me nt.
E g g c o u nts will be deter mi ne d b y  t he 
Kat o -Katz met h o d: O ne st o o l sa m ple 
will be c ollecte d d uri n g t he pre 
scree ni n g peri o d ( Da y -2 8 t o Da y  -1) 
a n d t he sec o n d o ne wit hi n a 
ma xi m u m of 5 da y s t hereafter as 
baseli ne. T w o a d diti o nal st o ol 
sa m ples will be c ollecte d bet wee n 
Da y  1 7 t o 2 1 after d osi n g t o 
deter mi ne efficac y : t he first o ne will 
be c ollecte d wit hi n t he 1 7 t o 2 1 da y  
wi n d o w a n d t he sec o n d o ne wit hi n a 
ma xi m u m of 5 da y s f oll o wi n g 
c ollecti o n of t he 1 st sa m ple. T hree 
Kat o -Katz t hic k s mears ( 4 1. 7 m g) 
will be pre pare d fr o m eac h st o ol 
sa m ple.
E n d - of-St u d y  
visit ( 1 7 t o 2 1 
da y s after 
treat me nt)
Sec o n d ar y
T o assess t he safet y of a si n gle 
d ose ( 5 0 m g/ k g) of L -P Z Q O D T i n 
c hil dre n 4 t o 6 years of a ge 
i nfecte d wit h S. ma ns o ni
( Treat me nt gr o u p 1a)
Safet y  a n d t olera bilit y assess me nts:
-
Occ urre nce, nat ure, se verit y  a n d 
o utc o me of a d verse e ve nts 
( A Es),
-
Occ urre nce of treat me nt -relate d 
A Es
-
C ha n ges i n la b orat or y  safet y 
para meters ( he mat ol o g y , 
bi oc he mistr y , uri nal ysis) a n d 
vital si g ns ( b o d y te m perat ure, 
bl o o d press ure a n d p ulse rate)
First treat me nt t o 
E n d - of-St u d y  
visit
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
2 6 /9 3
O bjecti ves
E n d p oi nts ( O utc o me Me as ures)
E n d p oi nts 
( O utc o me 
Me as ures) 
Ti mefr a me
T o asse ss t he efficac y of a si n gle 
d ose ( 5 0 m g/ k g) of L -P Z Q O D T as 
assesse d b y c ure rate 1 7 t o 2 1 da y s 
after treat me nt, i n c hil dre n 2 t o 3 
ye ars of a ge a n d i n i nfa nts/t o d dlers 
3 t o < 2 4 m o nt hs of a ge i nfecte d 
wit h S. ma ns o ni ( C o h orts 2 a n d 3, 
res pecti vely)
Sa me as C o h ort 1.
E n d - of-St u d y  
visit
T o assess t he safet y of a si n gle 
d ose ( 5 0 m g/ k g) of L -P Z Q O D T i n 
c hil dre n 2 t o 3 years of a ge a n d i n 
i nfa nts/t o d dlers 3 m o nt hs t o < 2 4 
m o nt hs of a ge i nfecte d wit h S. 
ma ns o ni ( C o h ort 2 a n d 3, 
res pecti vely)
Sa me as C o h ort 1.
First treat me nt t o 
E n d - of-St u d y  
visit
T o assess t he efficac y  of a si n gle 
d ose ( 5 0 m g/ k g, 6 0 m g / k g base d o n 
I D M C) of L-P Z Q O D T as assesse d 
b y  c ure rate 1 7 t o 2 1 da ys a n d 3 5 t o 
4 0 da y s after treat me nt, i n c hil dre n 
3 m o nt hs t o 6 y ears of a ge i nfecte d 
wit h S. hae mat o bi u m ( C o h ort 4)
Cli nical c ure is defi ne d as n o parasite 
e g gs i n t he uri ne sa m ples at f oll o w-
u p.
E g g c o u nts will be deter mi ne d b y  
uri ne e xa mi nati o n usi n g t he uri ne 
filtrati o n tec h ni q ue: T he first sa m ple 
will be c ollecte d d uri n g t he 
pre scree ni n g peri o d ( Da y  -2 8 t o 
Da y  -1) a n d t he sec o n d a n d t he t hir d 
o ne wit hi n a ma xi m u m of 5 da y s 
t hereafter as baseli ne. At t he 
E n d - of-St u d y  visit ( bet wee n Da ys 1 7 
a n d 2 1) C o h ort 4 partici pa nts will be 
as ke d t o pr o vi de t hree uri ne sa m ples 
(a b o ut 1 0 m L eac h): t he first o ne will 
be c ollecte d wit hi n t he 1 7 t o 2 1-d a y  
wi n d o w a n d t he ot her t w o wit hi n a 
ma xi m u m of 5 da y s f oll o wi n g 
c ollecti o n of t he 1 st sa m ple, f or 
a nal ys is b y t he filtrati o n met h o d. 
Si milarl y , at t he E xte n de d F oll o w -u p 
visit, C o h ort 4 partici pa nts will be
as ke d t o pr o vi de t hree a d diti o nal 
uri ne sa m ples (a b o ut 1 0 m L  eac h) o n 
E n d - of-St u d y  
visit a n d 
E xte n de d 
F oll o w -u p visit
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
2 7 /9 3
O bjecti ves
E n d p oi nts ( O utc o me Me as ures)
E n d p oi nts 
( O utc o me 
Me as ures) 
Ti mefr a me
differe nt da ys bet wee n Da y  3 5 a n d 
Da y  4 0, f or efficac y assess me nt b y 
t he filtrati o n met h o d. T he uri ne 
sa m ples will be filtere d t hr o u g h a 
filter mes h. T his mes h is t he n 
e xa mi ne d u n der t h e micr osc o pe f or 
S. hae mat o bi u m e g g c o u nt.
T o assess t he safet y of a si n gle 
d ose ( 5 0 m g/ k g , 6 0 m g/ k g base d o n 
I D M C) of L-P Z Q O D T i n c hil dre n 
3 m o nt hs t o 6 y ears of a ge i nfecte d 
wit h S. hae mat o bi u m ( C o h ort 4)
Sa me as C o h ort 1.
First treat me nt t o 
pla n ne d 
E n d - of-St u d y  
visit
T o assess t he efficac y  of a si n gle 
d ose ( 5 0 m g/ k g) of t he L -P Z Q 
O D T as assesse d b y e g g re d ucti o n 
rate ( E R R) 1 7 t o 2 1 da ys after 
treat me nt, i n c hil dre n 4 t o 6 years 
of a ge i nfecte d wit h S. ma ns o ni
( Treat me nt gr o u p 1a). T he efficac y 
( E R R) of a si n gle d ose ( 4 0 m g/k g) 
of c o m mercial P Z Q ta blets 
( Biltrici de) i n t he sa me patie nt 
p o p ulati o n ( Treat me nt gr o u p 1 b ) 
will be c o nsi dere d as a n i nter nal 
c o ntr ol.
E R R fr o m pretreat me nt t o 1 7 t o 2 1 
da y s after treat me nt, usi n g parasite 
e g g c o u nts as deter mi ne d b y  t he 
Kat o -Katz met h o d f or C o h ort 1.
Pre scree ni n g
visit t o 
E n d - of-St u d y  
visit
T o assess t he efficac y  of a si n gle 
d ose ( 5 0 m g/ k g) of L -P Z Q O D T as 
deter mi ne d b y E R R i n c hil dre n 2 t o 
3 y ears of a ge a n d i n i nfa nts a n d 
t o d dlers 3 m o nt hs t o < 2 4 m o nt hs 
of a ge i nfecte d wit h S. ma ns o ni
( C o h orts 2 a n d 3, res pecti vel y).
A n d i n c hil dre n 3 m o nt hs t o 6 
ye ars of a ge i nfecte d wit h S. 
hae mat o bi u m ( C o h ort 4; 5 0 m g/ k g, 
6 0 m g/ k g base d o n I D M C).
E R R fr o m pretreat me nt t o 1 7 t o 2 1 
da y s after treat me nt, usi n g parasite 
e g g c o u nts as deter mi ne d b y  t he 
Kat o -Katz met h o d f or C o h orts 2 a n d 
3 a n d t he uri ne filtrati o n met h o d f or 
C o h ort 4. A d diti o nall y , E R R fr o m 
pretreat me nt t o 3 5 t o 4 0 da y s after 
treat me nt, usi n g parasite e g g c o u nts 
as deter mi ne d b y t he uri ne filtrati o n 
met h o d f or C o h ort 4 partici pa nts.
Pre scree ni n g
visit t o 
E n d - of-St u d y  
visit a n d 
E xte n de d 
F oll o w - u p visit
T o assess t he c ure rate as 
de m o nstrate d wit h use of t he 
c o m merciall y a vaila ble 
O ne uri ne sa m ple will be c ollecte d 
1 7 t o 2 1 da y s after treat me nt. C ure is 
defi ne d as a bse nce of test li ne i n t he 
E n d - of-St u d y  
visit
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
2 8 /9 3
O bjecti ves
E n d p oi nts ( O utc o me Me as ures)
E n d p oi nts 
( O utc o me 
Me as ures) 
Ti mefr a me
p oi nt - of-care circ ulati n g cat h o dic 
a nti ge n ( P O C -C C A ®) test 
(C o h orts 1, 2, a n d 3).
P O C -C C A ® test cassette ( i.e., n o 
Sc hist os o ma a nti ge ns detecte d). 
T o assess acce pta bilit y  i n ter ms of 
ease of a d mi nistrati o n of t he 
selecte d O D T ( Treat me nt gr o u p 1a, 
C o h orts 2, 3, a n d 4 ) a n d 
c o m mercial P Z Q ta blet ( Treat me nt 
gr o u p 1 b )
Reacti o n t o St u d y  Inter ve nti o n
a d mi nistrati o n ( e. g., s pitti n g, cr yi ng) 
t o descri be t olera bilit y as assesse d by 
n urse/site staff f or all c hil dre n 
e nr olle d i n t he st u d y.
Palata bilit y  assess me nt usi n g a 
h u ma n g ustat or y  se nsati o n test 
( 1 0 0-m m vis ual a nal o g ue scale 
[ V A S]) sc ori n g m o difie d b y t he 
i nc or p orati o n of a 3-p oi nt facial 
he d o nic scale f or all c hil dre n 5 a n d 6 
ye ars of a ge e nr olle d i n t he st u d y.
At St u d y  
I nter ve nti o n
a d mi nistrati o n 
T o assess t he c o nce ntrati o n- ti me 
pr ofile of t he L -P Z Q O D T 
f or m ulati o n a n d Biltrici de 
f or m ulati o n i n a s u bset of c hil dre n
C o nce ntrati o ns of R-(-)- P Z Q a n d 
rac-P Z Q a n d, if a p pr o priate, 
p har mac o ki netics ( P K ) para meters 
(e. g., Cma x , tma x , A U C0 -t)
Pre -d ose t o 1 2 
h o urs after war ds
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
2 9 /9 3
4
St u d y Desi g n
4. 1
O ver all Desi g n
T his is a m ultice nter o pe n -la bel P hase III st u d y in w hic h partici pa nts assi g ne d t o 1 of 4 c o h orts 
base d o n a ge (i nfa nts a n d c hil dre n 3 m o nt hs t o 6 ye ars of a ge) a n d Sc hist os o ma s pecies of 
i nfecti o n will recei ve at D a y  1 a si n gle treat me nt d ose of L- P Z Q O D T 5 0 m g/ k g (see Secti o n  1. 3
Sc he d ule of Acti vities). T he st u d y incl u des 2: 1 ra n d o mizati o n of c hil dre n 4 t o 6 ye ars of a ge
i nfecte d wit h S. ma ns o ni t o t he P Z Q O D T treat me nt (Treat me nt gr o u p 1a) ( n = 1 0 0) or t he c o ntr ol 
treat me nt ( 4 0 m g/ k g
race mic P Z Q 
cr us he d ta blets, Treat me nt 
gr o u p
1 b)
( n = 5 0) . S. 
ma ns o ni -i nfecte d c hil dre n 2 t o 3 ye ars of a ge ( n= 3 0) (C o h ort 2), S. ma ns o ni -i nfecte d c hil dre n 3 t o
< 2 4 m o nt hs
of a ge ( n= 2 5 t o 6 5 ) ( Co h ort 3 ) a n d S. hae mat o bi u m -i nfecte d c hil dre n 3 m o nt hs t o 
6 ye ars of a ge ( n= 6 0) ( Co h ort 4) will be treate d wit h a si n gle d ose of 5 0 m g/ k g of L- P Z Q O D T.
U p o n rec o m me n dati o n of t he I D M C, t he d ose a d mi nistere d t o partici pa nts i n C o h ort 4 ma y  be 
i ncrease d t o 6 0 m g/k g. 3 N o ra n d o mizati o n is f oresee n i n C o h orts 2, 3, a n d 4.
A ma xi m u m 2 8 -da y  pre scree ni n g a n d scree ni n g peri o d, f oll o we d b y  a si n gle treat me nt o n Da y 1 
a n d 1 7 t o 2 1 da y s of f oll o w-u p or 3 5 t o 4 0 da ys ( C o h ort 4) (see Secti o n 1. 3 Sc he d ule of 
Acti vities) are f oresee n f or eac h partici pa nt , wit h a t otal st u d y d urati o n of u p t o 7 or 1 0 wee ks f or 
a gi ve n partici pa nt . D urati o n of t he St u d y  Inter ve nti o n peri o d is f oresee n t o be u p t o 6 m o nt hs.
T he partici pa nts i n C o h ort 1 will be stratifie d acc or di n g t o t heir i nfecti o n i nte nsit y, wit h tar get 
e nr ol lme nt of 4 0 % m o derate/ hea v y i nfecti o ns a n d 6 0 % of li g ht i nfecti o ns. N o stratificati o n will 
be i m ple me nte d f or C o h orts 2 , 3, a n d 4 , or per se x or c o u ntr y. F or C o h ort 3, t he tar get is t o ha ve 
a t otal of 6 5 partici pa nts i n a p o ole d a nal ysis wit h P hase II st u d y (M S 2 0 0 6 6 1 -0 0 0 5) C o h orts 8 
a n d 9. M ore t ha n 2 5 partici pa nts ma y  be e nr olle d i n C o h ort 3 if < 4 0 partici pa nts are e nr olle d i n 
t he P hase II st u d y in t his a ge gr o u p. After t he treat me nt of t he first 3 0 partici pa nts i n C o h ort 4,
t he efficac y a n d safety data will be e val uate d b y  the I DM C t o deci de w het her a n i ncrease of t he 
d ose t o 6 0 m g/ k g is nee de d; i n s uc h a case, 3 0 a d diti o nal partici pa nts will be e nr olle d, i. e. t ot al 
s a m pl e si z e of 9 0 f or C o h ort 4, n= 6 0 r e c ei vi n g t h e fi n al d os e .
4. 2
Scie ntific R ati o n ale f or St u d y Desi g n
T his is a n o pe n -la bel st u d y in w hic h partici pa nts i n 4 c o h orts base d o n a ge a n d Sc hist os o ma
s pecies of i nfectio n will recei ve a si n gle treat me nt d ose of t he ne w L- P Z Q O D T at Da y  1. T he 
st u d y incl u des 2: 1 ra n d o mizati o n of c hil dre n 4 t o 6 years of a ge i nfecte d wit h S. ma ns o ni t o t he 
P Z Q O D T treat me nt (Treat me nt gr o u p 1a) or t he c o ntr ol treat me nt ( 4 0 m g/ k g race mic P Z Q 
cr us he d ta blets, Treat me nt gr o u p 1 b). T he c o ntr ol ar m i ncl u des o nl y chil dre n 4 t o 6 ye ars of a ge , 
si nce t here is n o a p pr o ve d a ge nt t o treat sc hist os o miasis f or c hil dre n < 4 years of a ge. T he st u d y 
is n ot p o were d f or h yp ot hesis testi n g, si nce t he ai m of Treat me nt gr o u p 1 b is t o act as a n i nter nal 
c o ntr ol, pr o vi di n g a be nc h mar k f or i nter pretati o n of t he res ults o bs er ve d i n t he L- P Z Q O D T 
c o h orts .
                                                
3 A n I n de pe n de nt Data M o nit ori n g C o m mittee (I D M C) meeti n g was hel d o n t he 0 9 Marc h 2 0 2 0 a n d a decisi o n w as 
ma de t o i ncrease t he d ose i n C o h ort 4 t o 6 0 m g/ k g.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
3 0 /9 3
A n o pe n -la bel desi g n is c o nsi dere d a p pr o priate, as t he pri mar y  en d p oi nt (c ure rate) is assesse d 
o n t he basis of o bjecti ve assess me nt of e g g c o u nts. T he st u d y  will be bli n de d f or t h ose la b orat or y 
pers o n nel directl y  i n v ol ve d i n t he assess me nt of t he Kat o-Katz sc ore.  
T he st u d y  desi g n i ncl u des a n o pe n-la bel, ra n d o mize d all ocati o n of p artici pa nts t o L-P Z Q O D T or 
Biltri ci de i n C o h ort 1, f or w h o m mar kete d P Z Q is a p pr o ve d b y  healt h a ut h orities f or t he 
treat me nt of sc histos o miasis i n c hil dre n ≥4 years of a ge. Sc hist os o miasis c ure rates re p orte d i n 
t he literat ure are heter o ge ne o us acr oss st u dies. I ncl usi o n of t he c o ntr ol gr o u p ( Treat me nt gr o u p
1 b) as a be nc h mar k will hel p wit h i nter pretati o n of t he P hase III st u d y res ults, s h o ul d t he y differ 
mar ke dl y fr o m t he P hase II st u d y res ults.
C o h ort all oc ati o n

C o h ort 1: S. ma ns o ni -i nfecte d c hil dre n 4 t o 6 years of a ge ( n= 1 5 0) will be ra n d o mize d i n a 
2: 1 rati o. Treat me nt gr o u p 1a, n = 1 0 0, will be treate d wit h
a si n gle d ose of 5 0 m g /k g of 
L -P Z Q O D T (as t he test treat me nt); Treat me nt gr o u p 1 b, n = 5 0, will be treate d wit h t he 
refere nce P Z Q c o m mercial pr o d uct ( Biltrici de 6 0 0 m g) cr us he d ta blets at a si n gle d ose of 
4 0 m g/ k g (as t he i nter nal c o ntr ol treat me nt).

C o h ort 2: S. ma ns o ni -i nfecte d c hil dre n 2 t o 3 years of a ge ( n= 3 0) will be treate d wit h a si n gle 
d ose of 5 0 m g/ k g of L- P Z Q O D T. T he pri mar y  ai m of t he descri pti ve efficac y anal y sis i n t his 
c o h ort is t o e x pl ore w het her t he treat me nt effect is c o nsiste nt wit h t he treat me nt effect i n ol der 
c hil dre n ( n ot a n i n de pe n de nt pr o of of efficac y  i n t his s u b gr o u p).

C o h ort 3: S. ma ns o ni -i nfecte d i nfa nts a n d t o d dlers 3 t o< 2 4 m o nt hs of a ge ( n= 2 5 t o 6 5 ) will 
be treate d wit h a si n gle d ose of 5 0 m g/ k g of L -P Z Q O D T. T he pri mar y  ai m of t he descri pti ve 
efficac y anal ys is i n t his c o h ort is t o e x pl ore w het her t he treat me nt effect is c o nsiste nt wit h t he 
treat me nt effect i n ol der c hildre n ( n ot a n i n de pe n de nt pr o of of efficac y  i n t his s u b gr o u p).

C o h ort 4: S. hae mat o bi u m -i nfecte d c hil dre n 3 m o nt hs t o 6 years of a ge ( n= 6 0) will be treate d 
wit h a si n gle d ose of 5 0 m g/ k g of L- P Z Q O D T, t o assess t he safet y an d efficac y in t his gr o u p 
( n ot a n i n de pe n de nt pr o of of efficac y in t his s u b gr o u p). Aft er 3 0 c hil dr e n ar e e nr oll e d a n d 
tr e at e d i n C o h ort 4, t h e effi c a c y a n d s af et y d at a will b e s u m m ari z e d a n d e v al u at e d b y  th e 
I D M C t o d e ci d e w h et h er t h er e is a n e e d t o i n cr e as e t h e d os e t o 6 0 m g/ k g. 4 If a dos e 
i n cr e as e is n e e d e d, 3 0 a d diti o n al p ati e nts will b e a d d e d t o t his c o h ort (i. e., t ot al s a m pl e 
si z e of 9 0 f or C o h ort 4, n= 6 0 r e c ei vi n g t h e fi n al d os e) a n d tr e at e d wit h t h e 6 0 m g/ k g d os e 
of L -P Z Q O D T.
T his st u dy is p ar t o f t he P Z Q O D T cli nical de ve l o p me nt pr o gram , w hic h ai ms t o re gister a si n gle 
d ose of L -P Z Q O D Ts i n t he tar gete d pe diatric a ge gr o u p ( 3 m o nt hs to 6 ye ars of a ge). T he 
rati o nale f or t he desi g n o f t his st u dy is als o base d o n t he i nf or mati o n a n d data gat here d fr o m
pre vi o usl y  co n d ucte d P hase I a n d P h as e II st u di es wit h
t he P Z Q O D Ts
(s u m marize d bel o w)
a n d ta kes i nt o acc o u nt fee d bac k recei ve d fr o m healt h a ut h orities.
                                                
4 A n I n de pe n de nt Data M o nit ori n g C o m mittee (I D M C) meeti n g was hel d o n t he 0 9 Marc h 2 0 2 0 a n d a decisi o n w as 
ma de t o i ncrease t he d ose i n C o h ort 4 t o 6 0 m g/ k g.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
3 1 /9 3
4. 2. 1
M ai n 
F i n di n gs of t he P h ase I St u dies wit h t he N e w  PZ Q 
O D Ts ( M S 2 0 0 5 8 5 -0 0 1 a n d M S 2 0 0 6 6 1 -0 0 1)
T he L- P Z Q O D T f or m ulati o n was assesse d i n a P hase I relati ve bi oa vaila bilit y  (B A) st u d y in 
a d ult healt h y  
male v ol u nteers ( E M R 2 0 0 6 6 1-0 0 1), wit h 
t he c o m mercial rac-P Z Q 
ta blet 
( Cistici d® 5 0 0 m g ) as a refere nce. T he res ults s h o we d a l o wer B A of t he L- P Z Q O D T ( 4 0 % of 
t he refere nce). T he B A o f t he rac-P Z Q O D T f or m ulati o n was als o assesse d wit h
t he sa me 
refere nce i n st u d y EM R 2 0 0 5 8 5 - 0 0 1, s h o wi n g c o m para ble B A. T he res ults pertai ni n g t o t he 
L- P Z Q O D T f or m ulati o n are s u m marize d i n t he I B v 3.
4. 2. 2
M ai n F i n di n gs of t he P h ase I L- P Z Q O D T P al at a bilit y St u d y 
( E M R 2 0 0 6 6 1-0 0 2)
T he o verall palata bilit y  of t he L- P Z Q O D T a n d t he rac-P Z Q O D T was teste d i n a taste st u d y in 
Ta nza nia n chil dre n 6 t o 1 1 y ears of a ge . B ot h f or m ulati o ns were f o u n d t o ha ve better palata bilit y 
t ha n t he a vaila ble P Z Q pr o d uct ( Ces ol 6 0 0 m g ta blets) as assesse d b y  m ea ns of h u ma n g ustat or y 
se nsati o n tests ( 1 0 0-m m vis ual a nal o g ue scale ( V A S ) sc ori n g, m o difie d b y t he i nc or p orati o n of a 
5- p oi nt facial he d o nic scale). N o si g nifica nt differe nce i n V A S sc ore was o bser ve d bet wee n t he 
L- P Z Q O D T a n d t he rac -P Z Q O D T.
Dis persi o n of t he L- P Z Q f or m ulati o n i n t he m o ut h
ta kes a bit m ore
t ha n 3 0 sec o n ds. T h us, t he
pr o p ose d f or m ulati o n ma y
n ot meet
a f or mal defi niti o n of “ O D T” i n all re gi o ns. Alt h o u g h
a
m ore precise na mi n g mi g ht b e “ O DT- li ke”, t he f or m ulati o n will be referre d t o as “ O D T” i n t his
d oc u me nt .
4. 2. 3
M ai n 
F i n di n gs of t he P h ase II D ose -fi n di n g S t u d y i n I v or y 
C o ast ( M S 2 0 0 6 6 1 - 0 0 0 5)
Data fr o m Part 1 of t he P hase II st u d y, M S 2 0 0 6 6 1 - 0 0 0 5, rece ntly c o m plete d i n Africa n c hil dre n 
2 t o 6 ye ars of a ge i nfecte d wit h S. ma ns o ni ( usi n g differe nt d oses of rac -P Z Q O D Ts a n d L- P Z Q 
O D Ts as well as refere nce c o m mercial rac-P Z Q ar ms) s h o we d t hat L- P Z Q 6 0 m g / kg a n d 
L- P Z Q 4 5 m g/ k g ha d t he hi g hest efficac y, wit h c ure rates of 9 0 % ( 9 5 % CI : 7 9 %, 9 6 %) a n d 8 6 % 
( 9 5 % CI: 7 4 %, 9 4 %), res pecti vely, i n t he mI T T p o p ulati o n .
Part II of t his st u d y is c o m plete d a n d has e nr olle d 2 0 S. ma ns o ni -i nfecte d c hil dre n 1 3 t o 2 4 
m o nt hs of a ge i n C o h ort 8 a n d 4 S. ma ns o ni -i nfecte d c hil dre n 3 t o 1 2 m o nt hs of a ge i n C o h ort 9.
Detaile d o utc o mes of t he t hree st u dies are descri be d i n t he I B.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
3 2 /9 3
4. 2. 4
R ati o n al e f or S t u d y P o p ul ati o n
C o h ort 1
T he pri mar y  ai m of C o h ort 1 is t o assess t he efficac y an d safety of a si n gle d ose of t he ne w 
L- P Z Q O D T a n d a si n gle d ose of c o m mercial P Z Q ta blets ( Biltrici de) i n c hil dre n 4 t o 6 years of 
a ge i nfecte d wit h S. ma ns o ni . 
C hil dre n wit h li g ht ( 1 t o 9 9 e g gs per gra m of feces) or m o derate/ hea v y ( ≥1 0 0 e g gs per gra m of 
feces) S. ma ns o ni
i nfecti o n will be recr uite d, wit h a tar get e nr oll me nt of 4 0 % of st u d y 
partici pa nts wit h m o derate/ hea v y i nfecti o ns a n d 6 0 % wit h li g ht i nfecti o ns, c o nsiste nt wit h t he 
distri b uti o n i n t he P hase II st u d y. 
Treat me nt gr o u p 1a: T he efficac y an d safet y of a si n gle d ose of L- P Z Q O D T 5 0 m g / k g,
a d mi nistere d after f o o d i nta ke, will be assesse d i n 1 0 0 c hil dre n 4 t o 6 ye ars of a ge i nfecte d wit h 
S. ma ns o ni . 
Treat me nt gr o u p 1 b: T he efficac y an d safety of a si n gle d ose ( 4 0 m g / k g) of c o m mercial P Z Q 
ta blets ( Biltrici de 6 0 0 m g), a d mi nistere d after f o o d i nta ke, will be assesse d i n t his p o p ulati o n 
(c o ntr ol ar m) of 5 0 c hil dre n 4 t o 6 years of a ge i nfecte d wit h S. ma ns o ni . A si n gle d ose of 
4 0 m g/ k g b o d y wei g ht will be use d, w hic h is t he d ose rec o m me n de d b y  WH O t o treat a d ults a n d
sc h o ol-a ge c hil dre n a n d is wi del y  use d f or W H O mass dr u g a d mi nistrati o n pr o gra ms f or P Z Q i n 
S S A. I n a rece nt c o m me ntar y pa per b y t he W H O De part me nt of C o ntr ol of Ne glecte d Tr o pical 
Diseases ( M o ntres or a n d Gar b a, 2 0 1 7 )3 a n d base d o n a rece nt P Z Q cli nical st u d y in P S A C, t he 
a ut h ors als o rec o m me n d t hat i n t he a bse nce of treat me nt alter nati ves, a si n gle d ose of P Z Q 
4 0 m g/ k g ca n be e n d orse d f or P S A C ( C o uli bal y et al., 2 0 1 7 )4 i n pre ve nti ve c he m ot hera p y 
pr o gra ms . T he efficac y res ults fr o m t his treat me nt gr o u p will ser ve as a n i nter nal c o ntr ol ar m, 
pr o vi di n g a be nc h mar k f or t he test re gi me n ( Tre at me nt gr o u p 1a).  
C o h ort 2
T he efficac y an d safet y of a si n gle d ose of L- P Z Q O D T 5 0 m g/ k g, a d mi nistere d after f o o d 
i nta ke, will be assesse d i n t his c o h ort of 3 0 c hil dre n 2 t o 3 ye ars of a ge i nfecte d wit h S. ma ns o ni . 
T he n u m ber of c hil dre n i n t his c o h ort is 3 0 % of t he n u m ber of c hil dre n 4 t o 6 years of a ge i n 
Treat me nt gr o u p 1a ( n= 1 0 0), reflecti n g t he de m o gra p hic data a vaila ble fr o m Part 1 of t he P hase 
II st u d y i n Iv or y  C oast, i n w hic h, a m o n g t he i nfecte d c hil dre n e nr olle d, 2 7 % were 2 t o 3 ye ars of 
a ge a nd 7 3 % were 4 t o 6 ye ars of a ge. C ure rates i n t he P hase II st u d y were ge nerall y  si milar 
acr oss t hese a ge c o h orts. 
C hil dre n wit h li g ht ( 1 t o 9 9 e g gs per gra m of faeces) or m o derate/ hea v y  (≥1 0 0 e g gs per gra m of 
faeces) i nfecti o n will be recr uite d, wit h o ut
stratificati o n f or i nte nsity. T he pri mar y  ai m of t he 
descri pti ve a nal ys is i n p artici pa nts 2 t o 3 years of a ge is t o e x pl ore w het her t he treat me nt effect 
( % c ure d) is ge nerally si milar t o t hat i n ol der c hil dre n ( C o h ort 1).
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
3 3 /9 3
C o h ort 3
I n C o h ort 3, S. ma ns o ni -i nfecte d i nfa nts a n d t o d dlers, 3 t o< 2 4 m o nt hs
of a ge, will be treate d 
wit h t he L- P Z Q O D T at a d ose of 5 0 m g / k g, a d mi nistere d after f o o d i nta ke. E nr oll me nt will 
be gi n o nl y  after t he P hase II st u d y’s Safet y M o nit ori n g C o m mittee (S M C ) has re vie we d t he
safety/ efficac y d ata a vaila ble o n 1 0 partici pa nts fr o m C o h ort 8 e nr olle d i n Part 2 of t hat P hase II
st u d y, M S 2 0 0 6 6 1 - 0 0 0 5, a n d f o u n d t hese data t o be satisfact or y .
T he o verall n u m ber of partici pa nts i n C o h ort 3 is 2 5 or m ore, t o ac hie ve 6 5 patie nts i n p o o le d 
a nal ys is wit h C o h orts 8 a n d 9 of t he P hase II st u d y. 
T he pri mar y  ai m of t he descri pti ve a nal ysis i n p artici pa nts 3 t o 2 4 m o nt hs of a ge is t o e x pl ore 
w het her t he treat me nt effect ( % c ure d) is ge nerall y  si milar t o t hat i n ol der c hil dre n ( n ot a n 
i n de pe n de nt pr o of of efficac y i n t his s u b gr o u p). Si nce t he n u m ber of partici pa nts i n t his c o h ort is 
li mite d i n t his st u d y, t he efficac y res ults will be p o ole d wit h t h ose fr o m C o h orts 8 a n d 9 of t he 
P hase II st u d y (u p t o 3 0 partici pa nts i n t he 1 3 t o 2 4 m o nt h s of a ge c o h ort a n d u p t o 1 0 
partici pa nts i n t he 3 t o 1 2 m o nt h s of a ge c o h ort) t o assess if treat me nt effect is ge nerall y si milar 
acr oss a ge gr o u ps.
C o h ort 4
T he efficac y an d safet y of a si n gle d ose of L- P Z Q O D T 5 0 m g/ k g, a d mi nistere d after f o o d 
i nta ke, will be assesse d i n 6 0 c hil dre n 3 m o nt hs t o 6 ye ars of a ge i nfecte d wit h S. hae mat o bi u m . 
C hil dre n wit h li g ht ( < 5 0 e g gs/ 1 0  mL of uri ne) or hea v y  (≥5 0 e g gs/ 1 0  mL of uri ne) i nfecti o n 
will be recr uite d. After 3 0 p artici pa nts i n C o h ort 4 are treate d, t he efficac y a n d safety data will 
be e val uate d b y  the I D M C t o deci de w het her t here is a nee d t o i ncrease t he d ose t o 6 0 m g/ k g. If 
a d ose i ncrease is nee de d, 3 0 a d diti o nal p artici pa nts will be a d de d t o t his c o h ort (i.e., t otal 
sa m ple size of 9 0 f or C o h ort 4, n= 6 0 t otal o n t he fi nal d ose) a n d treate d wit h t he 6 0 m g/ k g d ose.
T he pri mar y  ai m of t he descri pti ve a nal ys is i n t his c o h ort is t o s u m marize safety a n d efficac y of 
t he P Z Q O D T i n c hil dre n 3 m o nt hs t o 6 ye ars of a ge i nfecte d wit h S. hae mat o bi u m ( n ot as a n 
i n de pe n de nt pr o of of efficac y i n t his s u b gr o u p).
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
3 4 /9 3
4. 2. 5
E n d p oi nts
T he pri mar y  a n d sec o n dar y efficac y e n d p oi nts are t he sa me as t h ose use d i n t he P hase II st u d y. A 
palata bilit y  o utc o me is a d de d i n t his st u d y.
Pri m ar y effic ac y o utc o me: c ure r ate
Cli nical c ure is defi ne d as n o parasite e g gs i n t he st o ol (S. ma ns o ni ) or uri ne (S. hae mat o bi u m )
sa m ples at a f oll o w- u p visit .
S afet y o utc o me
T o assess t he safet y of a si n gle d ose of P Z Q (all c o h orts), t he f oll o wi n g will be c ollecte d:

Occ urre nce, nat ure, se verit y  a n d o utc o me of A Es,

Occ urre nce of treat me nt-relate d A Es,

C ha n ges i n la b orat or y safet y para meters ( hae mat ol o g y, bi oc he mistr y , uri nal y sis) a n d vital 
si g ns ( b o dy te m perat ure, bl o o d press ure [ BP ] a n d p ulse rate).
Sec o n d ar y effic ac y o utc o me: E g g re d ucti o n r ate ( E R R)
T he W H O 
g ui deli ne f or m or bi dit y  co ntr ol of sc hist os o miasis ( Assessi n g t he efficac y of
a nti hel mi nt hic dr u gs a gai nst sc hist os o miasis a n d s oil-tra ns mitte d hel mi nt hiases, W H O, Ge ne ve, 
S witzerla n d, 2 0 1 3) rec o m me n ds meas ure me nt of gr o u p -base d E R R 2 t o 3 w ee ks after P Z Q dr u g 
a d mi nistrati o n, as a n a p pr o priate parasit ol o gical i n dicat or f or m or bi dit y c o ntr ol. T h us, i n t his 
st u d y, E R Rs usi n g gr o u p -base d mea ns will be calc ulate d f or eac h of t he c o h orts. T he i n di vi d ual 
E R R will als o be calc ulated b y  meas uri n g t he perce nt re d ucti o n of e g g c o u nts f or eac h 
i n di vi d ual.
Sec o n d ar y effic ac y o utc o me: C ure r ate b y P O C -C C A ®
C ure rate b y  PO C -C C A ®, 
defi ne d as n o parasite a nti ge ns i n uri ne as assesse d b y  the 
c o m merciall y a vaila ble P O C -C C A ® assa y f or S. ma ns o ni .
Sec o n d ar y o utc o me: Acce pt a bilit y of t he St u d y I nter ve nti o n
Reacti o n t o St u d y  Inter ve nti o n a d mi nistrati o n (e. g., s pitti n g, cr yi n g) will be rec or de d, t o descri be 
t olera bilit y as assesse d b y n urse/site staff f or all c hil dre n e nr olle d i n t he st u d y.
T h e p alata bilit y assess me nt will us e a h u ma n g ustat or y se nsati o n test ( 1 0 0-m m V A S) sc ori n g 
m o difie d b y  the i nc or p orati o n of a 3 -p oi nt facial he d o nic scale f or all c hil dre n 5 a n d 6 ye ars of 
a ge e nr olle d i n t he st u d y.
Sec o n d ar y o utc o me: P h ar m ac o ki netics
Assess me nt of t he c o nce ntrati o n ti me pr ofile of t he L P Z Q O D T a n d Biltrici de f or m ulati o n i n a 
s u bset of c hil dre n a n d, if a p pr o priate, p har mac o ki netics ( P K) para meters (e. g.,
Cma x , tma x , 
A U C 0-t) of - (-)-P Z Q a n d rac -P Z Q.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
3 5 /9 3
4. 2. 6
Str atific ati o n
N o stratificati o n f or male or fe male c hil dre n will be d o ne. It is e x pecte d t hat t he n u m ber of 
c hil dre n wit h a hea v y  S. ma ns o ni
i nfecti o n will be l o w i n t he areas w here t he st u d y will be 
c o n d ucte d. F or t he m o deratel y- i nfecte d c hil dre n, we e x pect a n o verall pre vale nce of 3 2 % i n 
I v or y Coast a n d 2 4 % i n Ke n ya ( Davis et al., 2 0 1 5 )5. T he partici pa nts i n C o h ort 1 will be 
stratifie d, wit h tar get e nr oll me nt of 4 0 % m o derate/ hea vy i nfec ti o ns a n d 6 0 % li g ht i nfecti o n. 
F or C o h orts 2, 3, a n d 4, n o stratificati o n will be i m ple me nte d. I nfa nts a n d t o d dlers i n C o h ort 3 
are o nl y e x pecte d t o carr y li g ht i nfecti o ns.
N o stratificati o n f or c o u ntr y will be i m ple me nte d. Eac h c o u ntr y is e x pecte d t o c o ntri b ute at least 
1 0 % t o t he fi nal p artici pa nt n u m bers t o be i ncl u de d i n t he fi nal efficac y  a nal ysis.
4. 3
J ustific ati o n f or D ose
T he d ose of L -P Z Q O D T (si n gle d ose of 5 0 m g / k g) t o be use d f or C o h ort 1 ( Treat me nt 1 a), 2, 3 
a n d 4, has bee n selecte d base d o n pre defi ne d decisi o n criteria, w hic h c o m bi ne d pri mar y  an d 
sec o n dar y efficac y an d safety e n d p oi nts, fr o m t he o utc o me of P hase II ( Part 1) st u d y
M S 2 0 0 6 6 1 - 0 0 0 5, t hat was rece ntly c o m plete d i n Africa n c hil dre n 2 t o 6 ye ars of a ge i nfecte d 
wit h S. ma ns o ni ( usi n g differe nt d oses of rac-P Z Q O D Ts a n d L- P Z Q O D Ts , as well as refere nce 
c o m mercial rac-P Z Q ar ms). I n the P hase II st u d y, the 4 5 m g / k g d ose of L- P Z Q O D T was f o u n d 
t o be t he d ose wit h t he o pti mal be nefit /ris k pr ofile f or efficac y an d safet y. F or ease of d ose 
calc ulati o n a n d i m ple me ntati o n d uri n g p u blic healt h pr o gra ms (c o nsi deri n g t hat t he O D T ta blets 
ha ve a 1 5 0 m g stre n gt h), L-P Z Q O D T at 5 0 m g/ k g was selecte d f or f urt her de vel o p me nt. 
T he si n gle d ose of 4 0 m g/ k g b o d y wei g ht f or Treat me nt gr o u p 1 b (c o m mercial P Z Q c o ntr ol ar m) 
is 
t he 
rec o m me n de d 
d ose 
b y  
WH O 
t o 
treat 
a d ults 
a n d 
sc h o ol-a ge 
c hil dre n 
( htt p:// w w w. w h o.i nt/sc hist os o miasis/strate g y/e n/) a n d is wi del y  use d f or W H O 
mass 
dr u g 
a d mi nistrati o n P Z Q pr o gra ms i n S S A. It has als o bee n rec o m me n de d b y  the W H O De part me nt 
of C o ntr ol of Ne glecte d Tr o pical Diseases f or use i n P S A C as necessar y  in pre ve nti ve 
c he m ot hera p y pr o gra ms .
T he d ose of L- P Z Q O D T f or C o h ort 4 will be t he sa me as f or Treat me nt gr o u p 1a ( 5 0 m g / k g). 
Data 
fr o m t he meta -a nal ysis b y  
Zwa n g , et al. ( 2 0 1 4)1
i n dicate d t hat c ure rates f or 
S. hae mat o bi u m were hi g her or at w orst 2 % l o wer t ha n c ure rates f or S. ma ns o ni
at eac h d ose 
re p orte d. T heref ore, usi n g t he sa me d ose of L- P Z Q O D T f or S. hae mat o bi u m as f or S. ma ns o ni
is a p pr o priate. H o we ver, 
si nce L- P Z Q O D T 
has n ot yet bee n i n vesti gate d a gai nst S. 
ha e mat o bi u m, t he efficac y data will be e val uate d b y t he I D M C after 3 0 partici pa nts are treate d i n 
C o h ort 4. I n case of s u b-o pti mal efficac y (criteria will be defi ne d pr os pecti vel y, bef ore st u d y 
start, i n t he I D M C c harter), t he I D M C c o ul d deci de t o i ncrease t he d ose t o 6 0 m g/ k g, i n w hic h 
case 3 0 a d diti o nal partici pa nts will be a d de d t o t his c o h ort (i.e., t otal sa m ple size of 9 0 f or 
C o h ort 4, n = 6 0 t otal o n fi nal d ose) a n d treate d wit h t he 6 0 m g/ k g d ose.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
3 6 /9 3
4. 4
E n d of St u d y Defi niti o n
A partici pa nt has c o m plete d t he st u d y if he/s he has c o m plete d all st u d y parts, i ncl u di n g st o ol
( C o h orts 1 , 2, a n d 3) or uri ne ( C o h ort 4) sa m pli n g at t he sc he d ule d f oll o w-u p visit s. 
T he e n d of t he st u d y is defi ne d as t he date of t he E n d- of- st u d y visit (or E xte n de d F oll o w -u p visit 
uri ne c ollecti o n at W ee k 5 f or C o h ort 4) of t he last partici pa nt. 
5
St u d y P o p ul ati o n
C hil dre n a n d i nfa nts 3 m o nt hs t o 6 ye ars of a ge wit h sc hist os o miasis will be i ncl u de d i n t his 
st u d y. As pre vi o usl y  note d, P S A C are a hi g h -ris k gr o u p f or sc hist os o me i nfecti o ns a n d yet t he y
are c urre ntl y n ot treate d i n sc hist os o miasis c o ntr ol pr o gra ms , as t he c urre nt f or m ulati o n is n ot 
s uita ble f or a d mi nistrati o n t o yo u n g c hil dre n.
C hil dre n are vie we d as v ul nera ble i n di vi d uals, wit h w h o m ris k s h o ul d be ke pt t o a mi ni m u m 
d uri n g t he c o n d uct of cli nical researc h. I n t his st u d y, n o si g nifica nt ris k is a ntici pate d t o st u d y 
partici pa nts at t he L- P Z Q O D T teste d d osa ges of 5 0 m g / kg. Biltrici de is a p pr o ve d f or treat me nt 
of sc hist os o miasis i n c hil dre n ≥4 ye ars of a ge, b ut it ca n be use d t o treat c hil dre n bel o w t his a ge 
u n der me dical s u per visi o n. Part ici pa nts will re mai n i n t he facilit y for 1 2 t o 2 4 h o urs after d osi n g 
a n d will be cl osel y m o nit ore d. La b orat or y  safet y tests are i ncl u de d t o s h o w t hat c hil dre n 
partici pati n g i n t he st u d y are n ot bei n g a d versel y affecte d b y  the st u d y treat me nt; these tests w ill 
be re peate d at t he e n d of h os pitalizati o n.
T he criteria i n Secti o ns 5. 1 (I ncl usi o n Criteria)
a n d 5. 2 ( E xcl usi o n Criteria ), are desi g ne d t o 
e nr oll o nl y  partici pa nts w h o are a p pr o priate f or t he st u d y, t here b y ens uri n g t he st u d y fulfills its 
o bjecti ves. All rele va nt me dical a n d n o n me dical c o nditi o ns s h o ul d be ta ke n i nt o c o nsi derati o n 
w he n deci di n g w het her a partici pa nt is s uita ble f or t his st u d y .
Pr os pecti ve a p pr o val of pr ot oc ol de viati o ns t o i ncl usi o n a n d e xcl usi o n criteria, als o k n o w n as 
pr ot oc ol wai vers or e xe m pti o ns, is n ot per mitte d.
Part ici pa nts will 
re q uire t he writte n 
i nf or me d c o nse nt of o ne of t heir pare nts or t heir 
g uar dia n/ le gall y aut h orize d re prese ntati ve. W he ne ver 
p ossi ble, a n d acc or di n g t o l ocal E t hical 
C o m mittee re q uire me nts, a partici pati n g c hil d’s asse nt s h o ul d be als o pr o vi de d. Acc or di n g t o t he 
E U g ui da nce f or cli nical st u dies o n pe diatric p o p ulati o ns, it is n ot p ossi ble t o o btai n asse nt i n 
c hil dre n 3 m o nt hs t o 3 years of a ge . 
O nl y  chil dre n meeti n g all i ncl usi o n criteria a n d n o e xcl usi o n criteria ma y  be e nr olle d i nt o t he 
st u d y as partici pa nts . Bef ore perf or mi n g a n y st u d y assess me nts t hat are n ot part of t he 
partici pa nt’s r o uti ne me dical care, t he I n vesti gat or will c o nfir m t hat t he partici pa nt , or t he 
partici pa nt’s pare nts or g uar dia n/ le gall y aut h orize d re prese ntati ve has pr o vi d e d writte n i nf or me d 
c o nse nt, as i n dicate d i n A p pe n di x 2 .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
3 7 /9 3
5. 1
I ncl usi o n Criteri a
Partici pa nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if all t he f oll o wi n g criteria a p pl y:
A ge
1. Are 
•
4 t o 6 y ears of a ge ( C o h orts 1 a n d 4) 
•
2 t o 3 y ears of a ge ( C o h orts 2 a n d 4)
•
3 t o < 2 4 m o nt hs of a ge ( C o h orts 3 a n d 4)
T y pe of P artici p a nt a n d Dise ase C h ar acteristics
2. Are
•
S. ma ns o ni -p ositi ve ( C o h orts 1, 2, a n d 3) ; dia g n osis defi ne d as p ositi ve e g g c o u nts i n 
st o ol ≥1 e g g/ 1 occasi o n) acc or di n g t o W H O classificati o n [ 1]: li g ht ( 1 t o 9 9 e g gs per 
gra m of feces), m o derate ( 1 0 0 t o 3 9 9 e g gs per gra m of feces) a n d hea v y ( ≥4 0 0 e g gs 
per gra m of feces) i nfecti o ns
•
S. hae mat o bi u m -p ositi v e ( C o h ort 4) ; dia g n osis defi ne d as p ositi ve e g g c o u nts i n uri ne 
( ≥1 e g g/ 1 0 m L
uri ne) acc or di n g t o W H O 
classificati o n ( Pre ve nti o n a n d C o ntr ol of 
Sc hist os o miasis a n d S oil Tra ns mitte d Hel mi nt hiasis. W H O 
Tec h nical Re p ort Series 
N o. 9 1 2. W H O, Ge ne va, 
S witzerla n d, 2 0 0 2). : li g ht ( < 5 0 e g gs/ 1 0  mL of uri ne) a n d 
hea v y ( ≥5 0 e g gs/ 1 0   mL of uri ne) i nfecti o ns
Wei g ht
3. Ha ve a mi ni m u m b o d y  wei g ht of 8. 0 k g i n 2 t o 6 ye ars of a ge c hil dre n a n d 5 . 0 k g i n 3
m o nt hs t o< 2 4 m o nt h s of a ge i nfa nts a n d t o d dlers
Se x
4. Are male or fe male.
I nf or me d C o nse nt
5. Pare nt or g uar dia n /le gall y aut h orize d re prese ntati ve ca n gi ve si g ne d i nf or me d c o nse nt ,
as i n dicate d i n A p pe n di x 2 , w hic h i ncl u des c o m plia nce wit h t he re q uire me nts a n d 
restricti o ns liste d i n t he Inf or me d C o nse nt F or m (I C F) a n d t his pr ot oc ol
6. Pare nt’s or g uar dia n/ le gall y a ut h orize d re prese ntati ve’s a bilit y to c o m m u nicate well 
wit h t he I n vesti gat or a n d his/ her dele gate, t o u n dersta n d t he pr ot oc ol re q uire me nts a n d 
restricti o ns, a n d t o be willi n g t o ha ve t heir c hil dre n c o m pl y wit h t he re q uire me nts of 
t he e ntire st u d y, i.e.:

T o be e xa mi ne d b y  a st u d y ph y sicia n at scree ni n g, at E n d of C o nfi ne me nt Visit a n d 
1 7 t o 2 1 da ys after treat me nt

T o pr o vi de st o ol sa m ples at scree ni n g (a n d 1 7 t o 2 1 d a y s after treat ment f or 
C o h orts 1 , 2 a n d 3)
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
3 8 /9 3

T o pr o vi de uri ne sa m ples at scree ni n g, 1 2 h after treat me nt a n d 1 7 t o 2 1 d a y s a n d 3 5 
t o 4 0 da y s after treat me nt

T o pr o vi de ve n o us bl o o d sa m ples f or la b orat or y  assess me nts

T o be h o use d i n t he cli nic f or 1 2 t o 2 4 h o urs

T o pr o vi de ve n o us bl o o d sa m ples f or p har mac o ki netics (P K ) assess me nts (f or 
partici pa nts i n t he P K s u bset )
A d diti o n al i ncl usi o n criteri a f or P K s u b st u d y p artici p a nts
7.
Ha ve a mi ni m u m he m o gl o bi n le vel of 1 0 g/ dl
5. 2
E xcl usi o n Criteri a
Partici pa nts are e xcl u de d f r o m t he st u d y if a n y of t he f oll o wi n g criteria a p pl y:
Me dic al C o n diti o ns
1.
Fi n di n gs i n t he cli nical e xa mi nati o n a n d/ or la b orat or y safet y exa mi nati o n o n t he 
treat me nt d a y , t hat i n t he o pi ni o n of t he I n vesti gat or c o nstit ute a ris k or a 
c o ntrai n dicati o n f or t he c hil d’s partici pati o n i n t he st u d y or that c o ul d i nterfere wit h t he 
st u d y o bjecti ves, c o n d uct or e val uati o n. T his i ncl u des b ut is n ot restricte d t o bacterial or 
viral i nfecti o ns, s uc h as d yse nter y, gastr oe nteritis, ascites, ja u n dice, etc
2.
Partici pa nts wit h
seiz ures a n d/ or me dical hist or y  of seiz ures a n d/ or ot her si g ns of 
p ote ntial ce ntral ner v o us s y ste m i n v ol ve me nt
3.
Partici pa nts wit h k n o w n c ysticerc osis, or wit h si g ns or s ym pt o ms (e. g., s u bc uta ne o us 
n o d ules) s u g gesti ve of c ysticerc osis
4.
Partici pa nts wit h a n ac ute i nfecti o n or ot her ac ute ill ness wit hi n t he 7 da y s pri or t o 
st u d y scree ni n g
5.
De bilitati n g ill ness s uc h as t u berc ul osis, mal n utriti o n, etc
Pri or/ C o nc o mit a nt T her a p y
6.
Treat me nt wit h P Z Q wit hi n t he 4 wee ks pri or t o t he st u d y  scree ni n g
7.
C o nc o mita nt treat me nt ( wit hi n 2 wee ks pri or t o e nr oll me nt) wit h me dicati o n t hat mi g ht 
affect t he meta b olis m of P Z Q, s uc h as certai n a nti e pile ptics (e. g., car ba maze pi ne or 
p he n y t oi n), gl uc oc ortic oster oi ds (e. g., de xa met has o ne), c hl or o q ui ne, rifa m pici n or 
ci meti di ne (see Biltrici de ® S u m mar y  of Pr o d uct C haracteristics [S m P C])
8.
Treat me nt wit hi n 
t he 2 wee ks 
pri or t o t he st u d y scree ni n g wit h 
a nti malarial 
me dicati o ns
9.
F or i nfa nts a n d t o d dlers bei n g breast -fe d, treat me nt of t he m ot hers/ wet n urses wit h P Z Q 
i n t he 3 da y s pri or t o P Z Q O D T a d mi nistrati o n
Pri or/ C o nc urre nt Cli nic al St u d y E x perie nce
1 0. Partici pati o n i n a n y cli nical st u d y wit hi n 4 wee ks pri or t o a d mi nistrati o n of P Z Q O D T, 
or a ntici pate d at a n y ti me u ntil c o m pleti o n of t he E n d - of- St u d y visit
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
3 9 /9 3
Di a g n ostic Assess me nts
1 1. Fe ver, defi ne d as te m perat ure a b o ve 3 7. 5 ° C a xillar y or oral
1 2.
Mi xe d S. hae mat o bi u m a n d S. ma ns o ni i nfecti o ns
Ot her E xcl usi o ns
1 3. Hist or y  of hy p erse nsiti vit y t o P Z Q or a n y of t he e xci pie nts
5. 3
Lifest yle C o nsi der ati o ns
5. 3. 1
Me als a n d Diet ar y Restricti o ns
C o ns u m pti o n o f gra pefr uit m a y lead t o i ncreased P Z Q le vels, t heref ore gra pefr uit a n d gra pefr uit 
j uice pr o d ucts will n ot be all o we d fr o m 2 4 h o urs bef ore t he ti me of St u d y  Inter ve nti o n
a d mi nistrati o n u ntil 2 4 h o urs after St u d y  Inter ve nti o n a d mi nistrati o n. D uri n g t he s ame peri o d, 
Se ville ora n ge a n d Se ville ora n ge j uice will n ot be all o we d.
5. 3. 2
C affei ne Alc o h ol, a n d T o b acc o
Partici pa nts will a bstai n fr o m i n gesti n g caffei ne- or xa nt hi ne -c o ntai ni n g pr o d ucts (e. g., c offee, 
tea, c ola dri n ks, a n d c h oc olate) f or 2 4 h o urs bef ore t he start of d osi n g u ntil 2 4 h o urs after St u d y 
I nter ve nti o n a d mi nistrati o n . Use of alc o h ol or t o bacc o is n ot a p plica ble as partici pa nts are 
3 m o nt hs t o 6 y ears of a ge.
5. 3. 3
Acti vit y
N ot a p plica ble; partici pa nts i n t his st u d y  are 3 m o nt hs t o 6 years of a ge .
5. 4
Scree n F ail ures
T his st u d y incl u des b ot h a pre scree ni n g visit bet wee n D a y  - 2 8 a n d D a y  - 1, a n d a scree ni n g visit 
bet wee n Da y  -7 a n d Da y  - 1. 
Partici pa nts w h o fail at t he pre scree ni n g visit ma y be pre scree ne d a gai n; t he y will be assi g ne d a 
ne w partici pa nt n u m be r at t he ti me of t he sec o n d pre scree ni n g visit.
I n di vi d uals w h o pass pre scree ni n g b ut at t he ti me of t he pla n ne d scree ni n g visit:
1.
Ha ve c o ns u me d gra pefr uit or gra pefr uit j uice 2 4 h o urs pri or t o e nr oll me nt
2.
Ha ve bee n breast- fe d b y  mot hers/ wet n urses treate d wit h P Z Q i n t he 3 d a y s pri or t o 
e nr oll me nt
3.
Ha ve a n y ot her c o n diti o n t hat ca n be n or malize d wit hi n t he scree ni n g wi n d o w 
ca n be e nr olle d as s o o n as t he te m p oral e xcl usi o n criteri o n d oes n ot a p pl y an y m ore, a n d as l o n g 
as t he scree ni n g wi n d o w is res pe cte d, wit h o ut a n y nee d of bei n g rescree ne d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
4 0 /9 3
I n di vi d uals w h o pass pre scree ni n g b ut at t he ti me of t he pla n ne d scree ni n g visit: 
4.
Ha ve bee n treate d wit hi n 2 wee ks pri or t o e nr oll me nt wit h a nti-malarial
me dicati o n or 
dr u gs t hat mi g ht affect t he meta b olis m of P Z Q 
5.
Are i n nee d of a nti -malarial me dicati o ns 
6.
Ha ve a n y ot her c o n diti o n t hat ca n be n or malize d wit hi n t he pre scree ni n g wi n d o w of 2 8 
da y s
ma y  be rescree ne d at I nvesti gat or’s discreti o n as s o o n as t he te m p oral e xcl usi o n criteri o n d oes 
n ot a p pl y an y m ore, a nd as l o n g as t he 2 8- d a y  wi n d o w bet wee n pre scree ni n g a n d e nr oll me nt is 
res pecte d.
If t he sec o n d scree ni n g visit is n ot p ossi ble t o be perf or me d wit hi n t he ori gi nal scree ni n g visit 
wi n d o w ( Da y - 7 t o D a y 1) t he n all pr oce d ures of t he S cree ni n g V isit (e xce pt f or t he si g nat ure of 
a n ot her scree ni n g c o nse nt ) m ust be re peate d usi n g t he sa me parti ci pa nt scree ni n g n u m ber. N ote 
t hat tests re q uiri n g a d diti o nal bl o o d ma y  be re peate d as l o n g as t he o verall bl o o d v ol u me dra w n 
wit hi n 4- wee k peri o d d oes n ot e xcee d 3 % of the t otal bl o o d v ol u me. T heref ore, per st u d y 
pr ot oc ol n o a d diti o nal bl o o d dra wi n gs are all o we d i n c hil dre n bel o w 7 k g wit hi n t he 4 -wee k 
peri o d.
I n t his case, t he sa me partici pa nt scree ni n g n u m ber ca n be ke pt. If t he i nter val t o t he pr o p ose d 
St u d y  Inter ve n ti o n d osi n g w o ul d fall o utsi de of t he 2 8- d a y  wi n d o w, t he n b ot h pre scree ni n g a n d 
scree ni n g acti vities ha ve t o be re peate d, a n d a ne w partici pa nt n u m ber has t o be assi g ne d. 
6
St u d y I nter ve nti o n(s)
St u d y  Inter ve nti o n is a n y i n vesti gati o nal i nter ve nti o n ( L-P Z Q ) or mar kete d pr o d uct (Biltrici de ) 
i nte n de d t o be a d mi nistere d t o a st u d y partici pa nt per t he st u d y pr ot oc ol.
M S C 2 4 9 9 5 5 0 A (referre d t o as L- P Z Q)
C he mical Na me: ( 1 1 b R)- 2-( Cycl o he x yl car b o n yl )- 1, 2, 3, 6, 7, 1 1 b-he xa h y dr o -4 H- p y razi n o [ 2, 1-a] 
is o q ui n oli n- 4- o ne
Rec o m me n de d I nter nati o nal N o n pr o prietar y  na me (rI N N):
R -(-)-Prazi q ua ntel
C o m pa n y  or La b orat or y C o de:
M S C 2 4 9 9 5 5 0 A
M olec ular F or m ula:
C 1 9 H 2 4 N 2 O 2
Relati ve M olec ular Mass:
3 1 2. 4 g/ m ol
W hite or al m ost w hite, cr ystalli ne p o w der.
M S C 2 4 9 9 5 5 0 A is prese nte d as 1 5 0 m g stre n gt h.
T he ta blet c o nsists of M S C 2 4 9 9 5 5 0 A 
c o m bi ne d wit h t he f oll o wi n g p har mace utical gra de 
e xci pie nts: 
 
 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
4 1 /9 3
Pr azi q u a ntel ( Biltrici de 6 0 0 m g)
C he mical Na me: ( 1 1 b R S)- 2-(c ycl o he x ylcar b o n yl)- 1, 2, 3, 6, 7, 1 1 b-he xa h y dr o -4 H- p y razi n o [ 2, 1-a] 
is o q ui n oli n- 4- o ne
Rec o m me n de d I nter nati o nal N o n pr o prietar y  na me (rI N N): 
( R S)-Prazi q ua ntel
M olec ular F or m ula:
C 1 9 H 2 4 N 2 O 2
Relati ve M olec ular Mass:
3 1 2. 4 g/ m ol
Biltrici de is s u p plie d as a w hite, fil m- c oate d, o bl o n g ta blet wit h t hree di vi di n g sc ores.
I n b ot h c o u ntries , t he Ger ma n c o m mercial pr o d uct will be use d. T he ta blet c o ntai ns 6 0 0 m g of 
P Z Q a n d t he f oll o wi n g i nacti ve i n gre die nts: 
 
 
6. 1
St u d y I nter ve nti o n(s) A d mi nistr ati o n
T h e act ual d ose t o be a d mi nistere d will be base d o n meas ure d b o d y  wei g ht. A ta ble will be 
i ncl u de d i n t he P har mac y Ma n ual .
Tre at me nt gr o u p 1 a : S. 
ma ns o ni -i nfecte d c hil dre n, 4 t o 6 years 
of a ge.
C o h ort 2 : S. ma ns o ni-i nfecte d 
c hil dre n, 2 t o 3 years of a ge.
C o h ort 3 : S. ma ns o ni-i nfecte d 
c hil dre n, 3 t o< 2 4 m o nt hs of a ge.
C o h ort 4 : S. hae mat o bi u m-i nfecte d 
c hil dre n, 3 m o nt hs t o 6 years of a ge.
Tre at me nt gr o u p 1 b : S. 
ma ns o ni -i nfecte d c hil dre n, 4 t o 6 
ye ars of a ge
St u d y 
I nter ve nti o n 
N a me:
L- P Z Q O D T 
C o m mercial P Z Q ( Biltrici de ® )  
D ose 
F or m ul ati o n:
1 5 0 m g ta blet 
6 0 0 m g ta blet
U nit D ose 
Stre n gt h(s)/
D os a ge Le vel(s):
L- P Z Q O D T at 5 0 m g/ k g 
F or C o h ort 4, t he d ose mi g ht be 
i ncrease d t o 6 0 m g/k g after I D M C 
re vie w
Biltrici de at 4 0 m g/ k g
R o ute of 
A d mi nistr ati o n:
Oral
Oral
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
4 2 /9 3
D osi n g 
I nstr ucti o ns:
Si n gle d ose of L -P Z Q O D T, dis perse d 
i n water, after f o o d i nta ke (see 
Secti o n 6. 6 , D ose Selecti o n a n d 
M o dificati o n )
Si n gle d ose of c o m mercial P Z Q 
( Biltrici de). 
T he Bil trici de ta blets will be di vi de d 
i nt o 1 5 0 m g parts, cr us he d, 
s us pe n de d i n water, a n d 
a d mi nist ere d after f o o d i nta ke.
S u p plier/
M a n uf act urer:
Far ma n g ui n h os Fi ocr uz, Brazil
Merc k K Ga A (c o m mercial pr o d uct 
s o urce d fr o m B a y er Ger ma n y)
P ac k a gi n g a n d 
L a beli n g :
L- P Z Q O D T ta blets will be s u p plie d 
b y  t he s p o ns or i n
 
. Eac h  
 
c o ntai ns 1 5 0 ta blets. 
Eac h  
 will be pac ka ge d a n d 
la bele d per all a p plica ble re g ulat or y 
re q uire me nts a n d G o o d Ma n ufact uri n g 
Practice G ui deli nes.
Biltrici de c o mes i n a  
 
 wit h w hite cl os ure, c o ntai ni n g 
6 ta blets.
 
 
Eac h  
 will be pac ka g e d a n d 
la bele d per all a p plica ble re g ulat or y 
re q uire me nts a n d G o o d 
Ma n ufact uri n g Practice G ui deli nes.
6. 2
St u d y I nter ve nti o n(s) Pre p ar ati o n, H a n dli n g, St or a ge, a n d 
Acc o u nt a bilit y
T he 
I n vesti gat or
a n d/ or desi g nee
is res p o nsi ble f or St u d y  Inter ve nti o n
acc o u nta b ilit y, 
rec o nciliati o n, a n d rec or d mai nte na nce 
(i.e., recei pt, rec o nciliati o n, a n d fi nal dis p ositi o n 
rec or ds).

U p o n recei pt of t he St u d y  Inter ve nti o n (s), t he In vesti gat or or desi g nee m ust 
c o nfir m 
a p pr o priate te m perat ure c o n diti o ns ha ve bee n mai ntai ne d d uri n g tra nsit a n d a n y discre pa ncies 
are re p orte d a n d res ol ve d bef ore use. Als o, t he res p o nsi ble pers o n will c hec k f or acc urate 
deli ver y  an d ac k n o wle d ge recei pt b y si g ni n g or i nitiali n g a n d dati n g t he a p pr o priate d oc u me nt 
a n d ret ur ni n g it t o t he l ocati o n s pecifie d. A c o p y will be arc hi ve d f or t he I n vesti gat or Site 
File.

O nl y  p artici pa nts e nr olle d i n t he st u d y ma y recei ve St u d y  Inter ve nti o n (s) a n d o nl y  aut h orize d 
site staff m a y  su p pl y or a d mi nister it. All St u d y I nter ve nti o n(s) m ust be st ore d i n a sec ure 
e n vir o n me ntall y-c o ntr olle d, a n d m o nit ore d ( ma n ual or a ut o mate d) area, i n acc or da nce wit h 
t he la bele d st ora ge c o n diti o ns ( L-P Z Q O D T :
, a n d wit h access li mite d t o t he In vesti gat or a n d a ut h orize d site staff. 

T he i n vesti gat or a n d/ or desi g nee is res p o nsi ble f or e ns uri n g t hat t he te m perat ure at w hic h t he 
St u d y  Inter ve nti o n is t o be st ore d is m o nit ore d t hr o u g h o ut t he d urati o n of t he st u d y an d t hat 
te m perat ure rec or ds are mai ntai ne d. T he te m perat ure will be rec or de d c o nti n u o usl y a n d 
m o nit ore d ma n uall y  t wice a da y. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
4 3 /9 3

Dis pe nsi n g will be rec or de d o n t he a p pr o priate acc o u nta bilit y f or ms s o t hat acc urate rec or ds 
will be a vaila ble f or verificati o n at eac h m o nit ori n g visit. 

T he pre parati o n of t he n u m ber of ta blets f or t he i n di vi d ual s u bject i n eac h c o h ort will be d o ne 
b y  a phar macist a n d p har macist assista nt u n der t he res p o nsi bilit y of t he I n vesti gat or. T he 
p har mac y  will pre pare t he St u d y  Inter ve nti o n f or all partici pa nts per c o h ort acc or di n g t o t he 
treat me nt ra n d o mizati o n list w he n a p plica ble (Treat me nt gr o u ps 1a a n d 1 b) a n d t he meas ure d 
b o d y  wei g ht i n acc or da nce wit h sta n dar d pr oce dures.

Biltrici de ta blets will be di vi de d i nt o 1 5 0 m g parts, cr us he d a n d s us pe n de d i n water. L- P Z Q
O D T ta blets will be dis perse d i n water. St u d y  Inter ve nti o n s will be a d mi nistere d wit hi n o ne 
h o ur after f o o d ( details descri be d i n t he c orres p o n di n g i nf or me d co nse nt f or ms) i nta ke. 
Detaile d pr oce d ures are descri be d i n t he P har mac y  Ma n ual. 

St u d y  Inter ve nti o n(s) acc o u nta bilit y  rec or ds at t he st u d y site will i ncl u de t he f oll o wi n g:
o
C o nfir mati o n of recei pt, i n g o o d c o n diti o n a n d i n t he defi ne d te m perat ure ra n ge.
o
T he i n ve nt or y pr o vi de d f or t he cli nical st u d y a n d pre pare d at site.
o
T he d ose(s) eac h partici pa nt use d d uri n g t he st u d y.
o
T he dis p ositi o n (i ncl u di n g ret ur n, if a p plica ble) of a n y  u n use d St u d y  Inter ve nti o n (s).
o
Dates, q ua ntities, batc h n u m bers, vial n u m bers, e x pir y dates, f or m ulati o n (f or St u d y  
I nter ve nti o ns pre pare d at t he site), a n d t he partici pa nt n u m bers.

T he I n vesti gat or site will mai ntai n rec or ds, w hic h a de q uatel y doc u me nts t hat partici pa nts 
were pr o vi de d t he d oses s pecifie d i n t his pr ot oc ol, a n d all St u d y  Inter ve nti o n (s) pr o vi de d were 
f ull y rec o ncile d.

U n use d St u d y  Inter ve nti o n (s) 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. N o St u d y  Inter ve nti o n t hat is dis pe nse d t o a partici pa nt ma y be re dis pe nse d t o 
a differe nt partici pa nt.

A St u d y  M o nit or will peri o dicall y c ollect t he St u d y  Inter ve nti o n (s) acc o u nta bilit y f or ms.

F urt her g ui da nce a n d i nf or mati o n f or t he fi nal dis p ositi o n of u n use d St u d y  Inter ve nti o n (s) are 
pr o vi de d i n t he P har mac y  Ma n ual.
6. 3
Me as ures t o Mi ni mize Bi as: St u d y I nter ve nti o n Assi g n me nt 
a n d Bli n di n g
6. 3. 1
St u d y I nter ve nti o n Assi g n me nt
T he st u d y co nsists of 4 c o h orts , w hic h will
be e nr olle d i n parallel. C o h ort 1 i ncl u des a 2: 1 
ra n d o mizati o n of c hil dre n 4 t o 6 ye ars of a ge i nfecte d wit h S. ma ns o ni t o a si n gle d ose of t he 
L- P Z Q O D T 5 0 m g / k g (test ar m; Treat me nt gr o u p 1a) or a si n gle d ose of t he P Z Q sta n dar d of 
care (rac-P Z Q cr us he d ta blets 4 0 m g/ k g ; Treat me nt gr o u p 1 b). N o ra n d o mizati o n is f oresee n f or 
C o h orts 2, 3, a n d 4. 
T he partici pa nts i n C o h ort 1 will be stratifie d acc or di n g t o t heir i nfecti o n i nte nsit y, wit h tar get 
e nr oll me nt of 4 0 % m o derate/ hea v y i nfecti o ns a n d 6 0 % li g ht i nfecti o ns. N o stratificati o n will be 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
4 4 /9 3
i m ple me nte d f or C o h orts 2, 3 , a n d 4. N o stratificati o n will be i m ple me nte d per se x or per 
c o u ntr y.
I n Treat m e nt Gr o u ps 1a a n d 1 b o nl y , after c o nfir mati o n of partici pa nt’s eli gi bilit y an d at t he last 
practical m o me nt 
pri or t o st u d y inter ve nti o n a d mi nistrati o n, partici pa nts will be ce ntrall y 
all ocate d t o eit her L- P Z Q
O D T
or Biltrici de i n a 2: 1 rati o usi n g a c o m p uter-ge nerate d 
ra n d o mizati o n list i nte grate d i n t he electr o nic data ca pt uri n g s yste m. Ra n d o mizati o n will n ot be 
use d t o all ocate partici pa nts i n a n y of t he ot her c o h orts.
Bef ore t he st u d y  is i nitiate d, t he l o gi n i nf or mati o n a n d directi o ns f or t he electr o nic data ca pt uri n g 
s yste m will be pr o vi de d t o eac h site. T he site will ca pt ure t he partici pa nt’s data i n t he electr o nic 
data ca pt uri n g s yste m a n d b y  co m pleti n g t he c orres p o n di n g f or ms recei ve t he st u d y inter ve nti o n 
gr o u p f or partici pa nts of C o h ort 1 .
6. 3. 2
Bli n di n g
Bli n di n g Met h o d
T his is a n o pe n -la bel st u d y in w hic h partici pa nts will recei ve a si n gle treat me nt d ose of t he 
L- P Z Q O D T f or m ulati o n (Treat me nt gr o u p 1a, C o h orts 2, 3, a n d 4) or t he c o m mercial P Z Q 
f or m ulati o n ( Treat me nt gr o u p 1 b) at Da y  1. 
Bli n di n g of site pers o n nel a n d partici pa nts/ pare nts is n ot warra nte d i n t his st u d y, si nce t he 
pri mar y  efficac y assess me nt of e g g c o u nt usi n g t he Kat o -Katz met h o d is a n o bjecti ve la b orat or y 
meas ure. La b orat or y  pers o n nel will re mai n bli n de d t o a partici pa nt’s treat me nt gr o u p a n d 
scree ni n g or baseli ne val ues. T o mi ni mize bias re gar di n g t he p o p ulati o n of partici pa nts i ncl u de d 
f or a nal ysis of t he pri mar y  efficac y outc o me, t he list of reas o ns f or pr ot oc ol vi olati o ns will be 
fi nalize d bef ore fi nal a nal ysis of p ost treat me nt e g g co u nts .
6. 3. 3
E mer ge nc y U n bli n di n g
N ot a p plica ble .
6. 4
St u d y I nter ve nti o n C o m pli a nce
All st u d y inter ve nti o ns will be a d mi nistere d as dis persi ble ta blets dis perse d i n water ( or 
dis perse d i n water after cr us hi n g of Biltrici de
ta blets f or Treat me nt gr o u p 1 b ) u n der t he 
s u per visi o n of t he I n vesti gat or or desi g nee. T he st u d y inter ve nti o n a d mi nistrati o n will be 
rec or de d i n t he electr o nic case re p ort f or m ( eC R F ).
St u d y  i nter ve nti o n a d mi nistrati o n rec or ds will be use d t o assess c o m plia nce.
T he I n vesti gat or is res p o nsi ble f or t he c o ntr ol of st u d y inter ve nti o ns ; a de q uate rec or d of recei pt 
(e. g., Dr u g Recei pt Rec or d) a n d dis p ositi o n ( e. g., Dr u g Acc o u nta bilit y Rec or d, Dr u g Destr ucti o n 
Rec or d) of t he st u d y inter ve nti o n i ncl u di n g dates, q ua ntities a n d use b y t he st u d y partici pa nt
m ust be mai ntai ne d.
All rec or ds a n d st u d y inter ve nti o n s u p plies m ust be a vaila ble f or i ns pecti o n at e ver y mo nit ori n g 
visit. W he n t he st u d y is ter mi nate d a n d st u d y inter ve nti o n acc o u nta bilit y has bee n satisfact oril y 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
4 5 /9 3
c o m plete d b y  the p har macist/I n ves ti gat or or st u d y dr u g pre parer ( or desi g nee), t he use d a n d 
u n use d st u d y dr u g (i.e. e m pt y, partiall y  use d a n d u n use d c o ntai ners) s h o ul d be destr o y e d at t he 
cli nical st u d y site after writte n a p pr o val b y t he S p o ns or. T he c o m plete d Dr u g Acc o u nta bilit y  an d 
Dr u g Destr ucti o n Rec or ds will be se nt t o t he m o nit or or its desi g nee.
T he site p har macist or p har macist assista nt m ust mai ntai n rec or ds of t he st u d y inter ve nti o n
deli ver y  to t he st u d y site, t he i n ve nt or y at t he site, t he use b y  eac h partici pa nt a n d its destr ucti o n 
or ret ur ni n g after st u d y i nter ve nti o n acc o u nta bilit y has bee n perf or me d b y  the res p o nsi ble 
m o nit or. 
T he dr u g -dis pe nsi n g l o g m ust 
be ke pt u p date d, listi n g t he i de ntificati o n of t he 
partici pa nt w h o recei ve d dr u g al o n g wit h t he date a n d q ua ntit y of dr u g dis pe nse d; it m ust be 
a vaila ble f or m o nit ori n g. Te m perat ure of t he st ora ge l ocati o n will be m o nit ore d a n d d oc u me nte d.
T he I n vesti gat or will e ns ure t hat t he st u d y inter ve nti o n s u p pl y is n ot use d f or a n y p ur p ose ot her 
t ha n t his st u d y.
6. 5
C o nc o mit a nt T her a p y
All
c o nc o mita nt t hera pies (e. g., me dici nes 
or n o n dr u g i nterve n ti o ns) use d fr o m t he ti me 
partici pa nt ’s pare nt or g uar dia n /le gally a ut h orize d re prese ntati ve si g ns t he I CF u ntil c o m pleti o n 
of t he st u d y, i ncl u di n g a n y cha n ges , will be rec or de d i n t he a p pr o priate e C R F. F or prescri pti o n 
a n d o ver-t he-c o u nter me dici nes, vacci nes, vita mi ns, a n d her bal s u p ple me nts, t he na me, reas o n 
f or use, dates a d mi nistere d, a n d d osi n g i nf or mati o n will 
be rec or de d. A ll c o nc o mita nt 
me dicati o ns ( wit hi n 7 da y s of partici pa nt’s st u d y treat me nt) recei ve d b y  nursi n g m ot hers of 
e nr olle d partici pa nts will be rec or de d o n t he a p pr o priate e C R F.
C o ntact t he Me dical M o nit or f or a n y q uesti o ns o n c o nc o mita nt or pri or t hera p y.
6. 5. 1
Resc ue Me dici ne
Biltrici de m a y  be a d mi nistere d t o a d dress i neffecti ve Sc his t os o miasis treat me nt. Ot her resc ue 
me dicati o ns ma y  be a d mi nistere d t o treat a ntici pate d a d verse reacti o ns or a ntici pate d e mer ge nc y 
reacti o ns.
6. 5. 2
Per mitte d Me dici nes
A n y  me dici nes t hat are c o nsi dere d necessar y  to pr otect t he partici pa nt’s welfare i n e mer ge nci es
ma y  be gi ve n at t he I n vesti gat or’s discreti o n, re gar dless if it res ults i n a pr ot oc ol de viati o n.
6. 5. 3
Pr o hi bite d Me dici nes
As referre d t o i n t he e xcl usi o n criteria ( Secti o n 5. 2 ), a d mi nistrati o n of P Z Q or use of a n y
i n vesti gati o nal de vic e wit hi n 4 wee ks pri or t o a d mi nistrati o n of t he st u d y inter ve nti o n (P Z Q 
O D T or Biltrici de) a n d d uri n g t he e ntire cli nical st u d y is not per mitte d.
If t he a d mi nistrati o n of a n o n- per mitte d c o nc o mita nt dr u g bec o mes necessar y  duri n g t he st u d y,
e.g., beca use of A Es, t he partici pa nt s h o ul d be disc o nti n ue d fr o m t he st u d y b ut o nl y  after 
c o ns ultati o n wit h t he S p o ns or. C hil dre n w h o re q uire malaria treat me nt after recei vi n g st u d y
treat me nt will n ot be wit h dra w n fr o m t he st u d y, b ut beca use s o me a nti-malarial
a ge nts (e. g.,
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
4 6 /9 3
arte misi ni n deri vati ves) ha ve acti vit y agai nst Sc hist os o ma s p p. ( Li u et al, 2 0 1 1 )6, t he y will be 
e xcl u de d fr o m t he pri mar y efficac y  a nalys is.
F or c hil dre n bei n g breastfe d, a d mi nistrati o n of P Z Q t o n ursi n g m ot hers is n ot all o we d i n t he 3 
da y s pri or t o P Z Q O D T a d mi nistrati o n (see S ecti o n 6. 5 ).
T he c o nc o mita nt a d mi nistrati o n of a ge nts t hat i n d uce t he dr u g -meta b olisi n g
e nz y m e s yste m i n 
t he li ver ( c yt oc hr o me P 4 5 0), s uc h as certai n a ntie pile ptics (e. g., car ba maze pi ne or p he n y t oi n), 
gl uc oc ortic oster oi ds ( e. g., de xa met has o ne) or c hl or o q ui ne, m a y  lea d t o re d uce d plas ma le vels of 
P Z Q a n d will n ot be all o we d. T he c o nc o mita nt ad mi nistrati o n of rifa m pici n, w hic h is a str o n g 
i n d ucer of c yt oc hr o me P 4 5 0, or of ot her c yt oc hr o me P 4 5 0 i n d ucers, is c o ntrai n dicate d as n o 
t hera pe uticall y effecti ve plas ma le vels of P Z Q ca n be e x pecte d i n t hat setti n g. 
Si milarl y , t he c o nc o mita nt a d mi nistrati o n of a ge nts t hat i n hi bit t he c yt oc hr o me P 4 5 0 s yste m, 
e. g., ci meti di ne, m a y  lea d t o i ncrease d plas ma le vels a n d a pr ol o n ge d rete nti o n peri o d of P Z Q 
a n d will n ot be all o we d. 
As c o ns u m pti o n of gra pefr uit ma y  lea d t o i ncrease d P Z Q le vels, gra pefr uits a n d g ra pefr uit j uice 
pr o d ucts will n ot be all o we d d uri n g c o nfi ne me nt . I n case a partici pa nt ma y  ha ve bee n e nr olle d 
a n d d ose d after gra pefr uit c o ns u m pti o n , a pr ot oc ol de viati o n will be iss ue d, h o we ver partici pa nts
will n ot be disc o nti n u e d fr o m t he st u d y an d data w o n’t be e xcl u de d fr o m t he a nal ys is. T he 
I n vesti gat or will nee d t o e n q uire t he e ve nt ual c o ns u m pti o n of gra pefr uit i n t he 2 4 h o urs bef ore 
e nr ol me nt a n d ens ure t hat t he c hil d eats o nl y t he sta n dar d meals d uri n g c o nfi ne me nt . At 
disc har ge, he will e x plai n t he pare nt/ g uar dia n/le gall y  a ut h orize d re prese ntati ve t he i m p orta nce of 
a bstai ni n g fr o m gra pefr uit 
c o ns u m pti o n u ntil 
2 4 
h o urs 
after t he st u d y inter ve nti o n 
a d mi nistrati o n.
Als o, a n y me dicati o n fr o m scree ni n g u ntil t he E n d- of- S t u d y visit is n ot all o we d wit h o ut pri or 
a p pr o val fr o m t he I n vesti gat or (e xce pt f or occasi o nal use of paraceta m ol or i b u pr ofe n). All 
me dicati o ns t hat are a d mi nistere d fr o m scree ni n g t hr o u g h t he E n d- of- S t u d y visit will be rec or de d 
o n t he a p pr o priate eC R F.
6. 5. 4
Ot her I nter ve nti o ns
A n y  un pla n ne d dia g n ostic, t hera pe utic, or s ur gical pr oce d ure perf or me d fr o m scree ni n g t hr o u g h 
t he E n d - of- St u d y visit or E xte n de d f oll o w- u p visits (f or patie nts i n C o h ort 4 wit h a 6 0 m g/ k g 
d ose) m ust be rec or de d i n t he c o nc o mita nt pr oce d ur e secti o n i n t he eC R F, i ncl u di n g t he date, 
i n dicati o n a n d descri pti o n of t he pr oce d ure(s) a n d o utc o me. 
A n y  ot her s pecial c o nsi derati o ns, e. g., c o ncer ni n g f o o d, caffei ne a n d p h y sical e xercise, s h o ul d be
n ote d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
4 7 /9 3
6. 6
D ose Selecti o n a n d M o dific ati o n
T his is a n o pe n -la bel st u d y in w hic h partici pa nts will recei ve a si n gle treat me nt d ose of t he ne w 
L- P Z Q O D T (Treat me nt gr o u p
1 a, C o h ort s 2, 3, a n d 4) or t h e c o m m er ci al P Z Q 
f or m ul ati o n (Treat me nt gr o u p 1 b) at D a y 1 . Theref ore , n o d ose m o dificati o n is a p plica ble.
If t he partici pa nt v o mits or s pits t he L- P Z Q/ Biltrici de after d osi n g, he/s he will n ot recei ve a ne w 
d ose of L- P Z Q/ Biltrici de. If v o miti n g occ urs, water 
a n d/ or f o o d ma y  be gi ve n at t he 
I n vesti gat or’s discreti o n a n d t his will be d oc u me nte d i n t he C R F. S u bjects wi ll n ot be e xcl u de d 
fr o m t he a nal ys is.
A n I D M C will e val uate t he i nteri m safet y a n d efficac y data after 3 0 partici pa nts are e nr olle d a n d 
treate d i n C o h ort 4. T he data will be s u m marize d a n d e val uate d t o deci de w het her t here is a nee d 
t o i ncrease t he d ose t o 6 0 m g/ k g i n C o h ort 4 ( see S ecti o n 9. 4. 4 ).5
6. 7
Tre at me nt I nter ve nti o n after t he E n d of t he St u d y
Partici pa nts w h o were p ositi ve f or S. ma ns o ni
or S. hae mat o bi u m b ut were n ot e nr olle d i n t he 
st u d y, or e nr olle d patie nts w h o were n ot f o u n d t o be c ure d at t he E n d -of - St u d y visit, m a y  be 
offere d treat me nt wit h 
t he l ocall y availa ble P Z Q 6 0 0 m g
ta blets base d o n nati o nal
rec o m me n dati o ns.
6. 8
S peci al Prec a uti o ns
T he me dicati o n a d mi nistrati o n part of t he st u d y will be c o n d ucte d i n a setti n g wit h access t o 
basic e mer ge nc y facilities. E q ui p me nt a n d ot her a ge nts (e pi ne p hri ne, pre d nis ol o ne e q ui vale nts, 
etc.) will be ma de a vaila ble at t he st u d y site i n case of se vere aller gic reacti o ns.
Partici pa nts will be o bser ve d w he n recei vi n g t he st u d y inter ve nti o n. T he y  will re mai n i n t he 
facilit y f or at least 1 2 h o urs after d osi n g a n d will be cl osely m o nit ore d.
6. 9
M a n a ge me nt of A d verse E ve nts of I nterest
N o cli nicall y si gnifica nt ris k is a ntici pate d t o partici pa nts at t he teste d d ose. Partici pa nts will 
re mai n i n t he facilit y f or at least 1 2 h o urs after d osi n g a n d will be cl osely o bser ve d. A partici pa nt 
ma y  be c o nfi ne d f or u p t o 2 4 h o urs i n t he e ve nt of a n y A E re q uiri n g pr ol o n ge d o bser vati o n. 
Base d o n t he P K pr o perties of P Z Q, dr u g -relate d A Es ( me nti o ne d i n Secti o n 8. 2 ) are e x pecte d t o 
occ ur wit hi n a p pr o xi matel y 12 h o urs after d osi n g. I n t he e ve nt t hat a partici pa nt sta ys i n t he 
cli nic d ue t o reas o ns ot her t ha n a n A E or seri o us a d verse e ve nt (S A E ), t he disc har ge ti me will be 
i n li ne wit h at least 1 2 h o urs a n d t he a d ditio nal sta y will n ot be re p orte d as a n A E. I n a d diti o n, 
f oll o w- u p of A Es 
will 
be perf or me d, if re q uire d, d uri n g t he first wee k 
after d osi n g 
(see Secti o n 1. 3 , Sc he d ule of Acti vities) b ut n ot necessaril y i n t he facilit y.
                                                
5 A n I n de pe n de nt Data M o nit ori n g C o m mittee (I D M C) meeti n g was hel d o n t he 0 9 Marc h 2 0 2 0 a n d a decisi o n w as 
ma de t o i ncrease t he d ose i n C o h ort 4 t o 6 0 m g/ k g.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
4 8 /9 3
A Es will be ma na ge d i n t he partici pati n g healt h facilit y  by st u d y me dical d oct ors w h o will 
re mai n i n t he facilit y d uri n g t he st u d y.
7
Disc o nti n u ati o n 
of 
St u d y 
I nter ve nti o n a n d 
P artici p a nt 
D isc o nti n u ati o n/ Wit h dr a w al
7. 1
Disc o nti n u ati o n of St u d y I nter ve nti o n
N ot a p plica ble.
7. 2
P artici p a nt Disc o nti n u ati o n/ Wit h dr a w al fr o m t he St u d y
T his is a si n gle-d ose treat me nt st u d y. If a partici pa nt wit h dra ws pri or t o a d mi nistrati o n of t he 
st u d y treat me nt, t he E n d- of- St u d y visit will be perf or me d a n d n o atte m pts will be ma de t o c ollect 
a d diti o nal data. N o f urt her e val uati o ns will be perf or me d, e xce pt f or safet y pur p ose w he n 
a p plica ble.

A partici pa nt ma y  wit h dra w fr o m t he st u d y at a n y ti me, u p o n re q uest of par tici pa nt’s pare nt or 
g uar dia n/ le gall y aut h orize d
re prese ntati ve (i.e., wit h dra wal 
of c o nse nt) or if t he c hil d 
c o m m u nicates ( ver bally or o p p osi n g resista nce) t hat he/s he is u n willi n g t o c o nti n ue, a n d 
wit h o ut gi vi n g a reas o n. H o we ver, t he reas o n s h o ul d be o b tai ne d w he n it is p ossi ble t o d o s o, 
a n d t he n t he reas o n s h o ul d be re p orte d i n t he a p pr o priate Case Re p ort F or m .

T he partici pa nt m a y  be wit h dra w n b y  the I n vesti gat or d ue t o partici pati o n i n a n ot her cli nical 
st u d y.

T he partici pa nt m a y  be wit h dra w n at a n y time at t he discreti o n of t he I nvesti gat or f or safety,  
be ha vi oral, c o m plia nce, or a d mi nistrati ve reas o ns.

T he partici pa nt ma y  be wit h dra w n if l ost t o f oll o w- u p.

If a partici pa nt wit h dra ws fr o m t he st u d y, n o f urt her e val uati o ns s h o ul d be perf or me d, a n d n o 
atte m pts s h o ul d be ma de t o c ollect a d diti o nal data, wit h t he e x ce pti o n of safety data, w hic h 
s h o ul d still be c ollecte d if p ossi ble, b ut n ot ca pt ure d i n t he data base .

If a partici pa nt is wit h dra w n fr o m t he st u d y beca use of a treat me nt-li miti n g A E , t h or o u g h 
efforts s h o ul d be ma de t o clearl y d oc u me nt t he o utc o me.

Data o btai ne d pri or t o a partici pa nt’s wit h dra wal will still be i ncl u de d i n t he efficac y an d 
safety a nal ysis .

Partici pa nts wit h dra w n fr o m t he st u d y  will n ot be re place d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
4 9 /9 3
7. 3
L ost t o F oll o w -U p
A partici pa nt will be c o nsi dere d l ost t o f oll o w-u p if he or s he fails t o ret ur n f or sc he d ule d visits 
a n d is u na ble t o be c o ntacte d b y t he st u d y site.
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, c o u nsel t he partici pa nt o n t he i m p orta nce of mai ntai ni n g t he assi g ne d visit sc he d ule, 
a n d ascertai n if t he partici pa nt wa nts t o or s h o ul d c o nti n ue i n t he st u d y. E v er y eff ort will be 
ma de t o u n derta ke a fi nal e xa mi nati o n visit as s o o n as p ossi ble a n d perf or m all pr oce d ures of 
t he E n d- of-St u d y  visit.

Bef ore a partici pa nt is dee me d “l ost t o f oll o w-u p”, t he I n vesti gat or or desi g nee m ust ma ke 
e ver y eff ort t o re gai n c o ntact wit h t he partici pa nt . Co ntact atte m pts s h o ul d be d oc u me nte d i n 
t he partici pa nt’s me dical rec or d.

S h o ul d t he partici pa nt c o nti n ue t o be u nreac ha ble, he/s he will be c o nsi dere d t o ha ve 
wit h dra w n fr o m t he st u d y.
8
St u d y Assess me nts a n d Pr oce d ures
St u d y  assessme nts a n d pr oce d ures a n d t heir ti mi n g are s u m marize d i n t he Sc he d ule of A cti vities 
( Secti o n 1. 3 ). Details are gi ve n i n t he f oll o wi n g para gra p hs. 
A d here nce t o t he st u d y desi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he S c he d ule o f 
Acti vities , is esse ntial a n d re q uire d f or st u dy c o n d uct.
N o pr ot oc ol wai vers or e xe m pti o ns are all o we d.
I m me diate safety c o ncer ns s h o ul d be disc usse d wit h t he S p o ns or i m me diatel y up o n occ urre nce 
or a ware ness t o deter mi ne if t he partici pa nt s h o ul d c o nti n ue or disc o nti n ue st u d y  i nter ve nti o n.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
5 0 /9 3
Pre -scree ni n g
St u d y  partici pa nts will be selecte d fr o m c o m m u nities li vi n g i n t he re gi o ns of de part me nts of 
Bia n k o u ma n a n d Ma n
i n t he T o n k pi re gi o n, as well as Fac o bl y a n d K o ui bl y  in t he G ué m o n 
re gi o n, Ma n , I v ory C oast a n d ar o u n d t he s h ores of La ke Vict oria ar o u n d H o ma B a y a n d M bita i n 
H o ma ba y  Co u nt y , Ke n ya. Pri or t o st u d y onset, a list of all c hil dre n 3 m o nt hs
t o 6 years of a ge
li vi n g i n t he selecte d areas will be pre pare d usi n g rec or ds o btai ne d fr o m t he latest ce ns us. At 
st u d y be gi n ni n g, t he h o use h ol ds i n t he villa ges will be i nf or me d a b o ut t he st u d y t hr o u g h 
c o m m u nit y meeti n gs . Pri or t o perf or mi n g a n y st u d y assess me nts t hat are n ot part of r o uti ne 
me dical care, t he I n vesti gat or or a n a p pr o priate desi g nee (if l ocal re g ulati o ns per mit) will o btai n 
writte n pre scree ni n g c o nse nt fr o m o ne of t he pare nts or t he g uar dia n/ le gall y aut h orize d 
re prese ntati ve of t he p ot e ntial partici pa nt t o all o w t he dia g n os tic acti vities a n d t he i de ntificati o n 
of sc hist os o miasis i nfecte d c hil dre n, as descri be d i n A p pe n di x 2 . 
Pare nts or g uar dia ns/ le gall y aut h orize d re prese ntati ves of partici pa nts will be pr o vi de d wit h 
plastic c o ntai ners la bele d wit h 
u ni q ue i de ntificati o n n u m bers (IDs) 
at t he first d a y  of 
pre scree ni n g. 
Pare nts
or 
g uar dia ns/ le gall y 
a ut h orize d 
re prese ntati ves
of 
c hil dre n 
3 t o < 2 4 m o nt hs
of a ge will be pr o vi de d wit h uri ne c ollecti n g ba gs s pecifically desi g ne d f or 
ba bies . T he y  will be i nstr ucte d t o c ollect st o ol a n d uri ne sa m ples of t he c hil d, eac h i n o ne of t he 
t w o se parate c o ntai ners. St o ol a n d uri ne sa m ples ma y  n ot be pr ocesse d o n t he sa me da y .
Pre scree ni n g dia g n osis of S. ma ns o ni i nfecte d partici pa nts ( C o h orts 1 t o 3) 
Pre scree ni n g dia g n osis of S. ma ns o ni i nfecti o n will be d o ne usi n g a si n gle P O C -C C A uri ne 
cassette test. P O C C C A cassettes will be classifie d as eit her p ositi ve or ne gati ve, acc or di n g t o t he 
ma n ufact urer's i nstr ucti o ns, wit h f urt her stratificati o n de pe n di n g o n t he stre n gt h of t he c ol or 
reacti o n. T h us, p ositi ve cassettes will be classifie d as + 1 ( w he n res ult li ne is eas y to see b ut still 
wea k) , + 2 ( w he n res ult li ne is dar k, b ut li g hter t ha n t he c o ntr ol li ne) or + 3 ( w he n res ult li ne is 
as dar k as or dar ker t ha n t he c o ntr ol li ne). Partici pa nts w h o are p ositi ve i n t he P O C -C C A test 
will be f urt her scree ne d wit h t he ai m of : 

Assessi n g S. hae mat o bi u m c o-i nfecti o n usi n g t he uri ne filtrati o n tec h ni q ue. A uri ne sa m ple 
(a b o ut 1 0 m L ) will be filtere d t hr o u g h a filter mes h, a n d t he mes h will t he n be e xa mi ne d 
u n der t he micr osc o pe f or S. hae mat o bi u m e g g c o u nt. A dia g n osis of S. hae mat o bi u m is 
defi ne d as p ositi ve e g g c o u nt of S. hae mat o bi u m i n uri ne ( > 1 e g g/ 1 0 m L  of uri ne) acc or di n g 
t o W H O classificati o n ( W H O, Ge ne ve, S witzerla n d, 2 0 0 2) li g ht ( < 5 0 e g gs/ 1 0  m L of uri ne) 
a n d hea v y ( ≥5 0 e g gs/ 1 0  m L of uri ne) i nfecti o ns. Per Secti o n  5. 2 ( E xcl usi o n Criteria), a c hil d 
i nfecte d wit h b ot h S. ma ns o ni a n d S. hae mat o bi u m ca n n ot partici pate i n t his st u d y.  

Assessi n g i nfecti o n i nte nsit y at baseli ne usi n g t he Kat o -Katz met h o d: O ne st o ol sa m ple will 
be c ollecte d d uri n g t he pre scree ni n g peri o d ( Da y - 2 8 t o Da y  -1) a n d t he sec o n d o ne wit hi n a 
ma xi m u m of 5 da y s t hereafter as baseli ne. I n case t he st o ol c ollecti o n will n ot be p ossi ble 
wit hi n a ma xi m u m of 5 da y s bet wee n t he sa m ples, 2 ot her st o ol sa m ples c o ul d be c ollecte d 
a gai n ( ma xi m u m 3 ti mes o ver 2 8 da y s). T hree Kat o -Katz t hic k s mears ( 4 1. 7 m g) will be 
pre pare d fr o m eac h of t he st o ol sa m ples. I nfecti o n i nte nsit y (e x presse d as e g g c o u nt per gra m 
of st o ol [e p g]) will be calc ulate d f or eac h i n di vi d ual. A dia g n osis of S. ma ns o ni is defi ne d as 
p ositi ve e g g c o u nts of S. ma ns o ni i n st o ol ( > 1 e g g/ 1 occasi o n) acc or di n g t o t he W H O 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
5 1 /9 3
classificati o n: li g ht ( 1 t o 9 9 e g gs per gra m of feces), m o derate ( 1 0 0 t o 3 9 9 e g gs per gra m of 
feces) a n d hea vy ( ≥4 0 0 e g gs per gra m of feces) i nfecti o ns.
Pre scree ni n g dia g n osis of S. hae mat o bi u m i nfecte d partici pa nt ( C o h ort 4)
T he pre scree ni n g dia g n osis f or S. hae mat o bi u m i nfecte d partici pa nts will ta ke place i n a 
ge o gra p hical area w here t he pre vale nce of t his pa rasite is e x pecte d t o be hi g h a n d t he pre vale nce 
of S. ma ns o ni l o w. As S. hae mat o bi u m a n d S. ma ns o ni c o-i nfecte d c hil dre n will n ot be i ncl u de d 
i n t his st u d y (see a b o ve), c hil dre n will pr o vi de:

A st o ol sa m ple fr o m w hic h t w o Kat o -Katz t hic k s mears ( 4 1. 7 m g ) will be pre pare d a n d 
o bser ve d u n der a micr osc o pe t o assess S. ma ns o ni i nfecti o n, defi ne d as p ositi ve e g g c o u nts of 
S. ma ns o ni i n st o ol ( > 1 e g g/ 1 occasi o n). 

T hree uri ne sa m ples t o asses S. hae mat o bi u m i nfecti o n wit h t he uri ne f iltrati o n tec h ni q ue. T he 
first sa m ple will be c ollecte d d uri n g t he pre scree ni n g peri o d ( Da y - 2 8 t o Da y  -1) a n d t he 
sec o n d a n d t he t hir d o ne wit hi n a ma xi m u m of 5 da y s t hereafter as baseli ne. I n case t he uri ne 
c ollecti o n will n ot be p ossi ble wit hi n a ma xi m u m of 5 da y s a m o n g t he sa m ples, 3 ot her uri ne 
sa m ples c o ul d be c ollecte d a gai n ( ma xi m u m 3 ti mes o ver 2 8 da ys). Eac h uri ne sa m ples (a b o ut 
1 0 m L ) will be filtere d t hr o u g h a filter mes h, a n d t he mes h will t he n be e xa mi ne d u n der t he 
micr osc o pe f or S. hae mat o bi u m e g g c o u nt (see a b o ve f or i nfecti o n classificati o n). O ne 
p ositi ve sa m ple o ut of t hree is s ufficie nt f or a p ositi ve dia g n osis.
At t he pre scree ni n g visit, a Ra pi d Dia g n ostic Test ( R D T) t o detect malaria i nfecti o n ( o ne bl o o d 
sa m ple c ollecte d b y  fi n ger p u nct ure) ca n be perf or me d at i n vesti gat or’s discreti o n. Treat me nt of 
malar ia will be u n derta ke n acc or di n g t o nati o nal g ui deli nes.
At t he pre scree ni n g visit, t he f oll o wi n g data will be c ollecte d: date of birt h, date of pre scree ni n g 
c o nse nt si g nat ure, ge n der a n d race. 
Scree ni n g
C hil dre n w h o ha ve teste d p ositi ve f or S. hae mat o bi u m (o nl y ) a n d c hil dre n w h o ha ve teste d 
p ositi ve f or S. ma ns o ni (o nl y ), t o get her wit h o ne of t heir pare nts or g uar dia ns/ le gall y aut h orize d
re prese ntati ves, will be i n vite d t o t he st u d y  h os pital. 
Pri or t o perf or mi n g a n y st u d y assess me nts t hat are n ot part of r o uti ne me dical care, t he 
I n vesti gat or or a n a p pr o priate desi g nee (if l ocal re g ulati o ns per mit) will o btai n writte n i nf or me d 
c o nse nt as s pecifie d i n A p pe n di x 2 t o all o w partici pati o n i n t he st u d y an d t he c o m pleti o n of t he 
st u d y pr oce d ures, fr o m o ne of t he pare nts or a g uar dia n/ le gall y aut h orize d re prese ntati ve of t he 
partici pa nt.
Pr oce d ures c o n d ucte d as part of t he partici pa nt’s r o uti ne me dic al care (e. g., bl o o d c o u nt) a n d 
o btai ne d bef ore si g ni n g of t he I CF m a y  b e use d f or scree ni n g or baseli ne p ur p oses , pr o vi de d t he 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
5 2 /9 3
pr oce d ures met t he pr ot oc ol -s pecifie d criteria a n d were perf or me d wit hi n t he ti me fra me defi ne d 
i n t he Sc he d ule o f A cti vities (see Secti o n 1. 3) .
D uri n g t he scree ni n g peri o d, t he f oll o wi n g tests/i nf or mati o n-gat heri n g will be perf or me d wit hi n 
a ma xi m u m of o ne wee k pri or t o treat me nt i nitiati o n:

Cli nical safet y  la b orat or y eval uati o ns: hae mat ol o g y , bi oc he mistr y  an d uri nal y sis. All 
bi ol o gical assess me nts will be perf or me d i n a faste d c o n diti o n, if p ossi ble , e xce pt f or 
breast -fe d ba bies.

A Ra pi d Dia g n ostic Test ( R D T) t o detect malaria i nfecti o n ( o ne bl o o d sa m ple c ollecte d b y  
fi n ger p u nct ure). T his pr oce d ure mi g ht be perf or me d eit her i n t he h os pital or i n t he villa ge ,
f or o perati o nal p ur p oses.

De m o gra p hic data, c o nsisti n g of date of birt h, ge n der a n d hei g ht

Me dical 
hist or y , i ncl u di n g occ urre nce of seiz ures, a n d c o nsisti n g of all pre vi o us diseases 
c o nsi dere d rele va nt (rele va nt is defi ne d as nee di n g me dical treat me nt f or at least 1 wee k) b y  
t he In vesti gat or .

All pre vi o us me dicati o ns recei ve d wit hi n t he last 6 m o nt hs as c o nsi dere d rele va nt b y  the 
I n vesti gat or (rele va nt is defi ne d as pre scri be d t o treat a rele va nt disease as descri be d a b o ve)

C o m plete p h y sical e xa mi nati o n (see S ecti o n 8. 2. 2) i ncl u di n g b o dy wei g ht

Vital si g ns i n s u pi ne p ositi o n (see S ecti o n 8. 2. 3) i ncl u di n g:
o
B P (sys t olic a n d diast olic) – t o be assesse d at least 5 mi n utes after resti n g
o
P ulse rate – t o be assesse d at least 5 mi n utes after resti n g
o
B o d y te m perat ure. T his pr oce d ure mi g ht be perf or me d eit her i n t he h os pital or i n t he 
villa ge f or o perati o nal p ur p oses.
All o bser ve d A Es a n d C o nc o mita nt Me dicati o ns will be re p orte d i n t he C R F.
F o o d will be pr o vi de d wit hi n o ne h o ur fr o m d osi n g.
All scree ni n g e val uati o ns m ust be c o m plete d a n d re vie we d t o c o nfir m t hat p ote ntial partici pa nts 
meet all eli gi bilit y criteria. T he I n vesti gat or will mai ntai n a scree ni n g l o g t o rec or d details of all 
partici pa nts scree ne d, t o c o nfir m eli gi bilit y, a n d if a p plica ble, rec or d reas o ns f or scree ni n g 
fail ure.
Tre at me nt peri o d 
Partici pa nts will be h os pitalize d fr o m t he m or ni n g of d osi n g u ntil at least 1 2 h o urs after St u d y  
I nter ve nti o n a d mi nistrati o n. D uri n g t his ti me, partici pa nts will be m o nit ore d f or A Es b y  st u d y 
site staff.
I n case se veral assess me nts are pla n ne d at t he sa me ti me p oi nt, t he P K sa m ples will be ta ke n at 
t he pre -defi ne d ti me p oi nt. Vital si g ns will be rec or de d bef ore P K sa m ples.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
5 3 /9 3
Pre d ose assess me nts
Partici pa nts will u n der g o p h y sical e xa mi nati o n, vital si g ns assess me nt a n d re c hec k of eli gi bilit y 
criteria. If assess me nts ha ve bee n d o ne o n t he sa me d a y  th e y  do n ot nee d t o be re peate d. P K 
sa m ples will be ta ke n i m me diatel y pri or t o d osi n g.
P ost d ose assess me nts
P K sa m ples will be ta ke n acc or di n g t o t he sa m pli n g sc he me (see Secti o n s 1. 3 a n d 8. 5 ). T he 
all o we d de viati o n fr o m t he pre -s pecifie d assess me nt will be ± 1 0 % (i n mi n utes) of t he sc he d ule d 
ti me p oi nt. I n case se veral assess me nts are pla n ne d at t he sa me ti me p oi nt, t he P K sa m ples will 
be ta ke n at t he pre -defi ne d ti me p oi nt.
Vital si g ns will be rec or de d 8 h o urs after first d osi n g a n d a gai n at t he e n d of c o nfi ne me nt 
( 12 t o 2 4 h o urs after d osi n g), w he n a p h ys ical e xa mi nati o n will als o be perf or me d.
Cli nical 
safety 
la b orat or y eval uati o ns (i.e.,
he mat ol o g y , bi oc he mistr y  an d 
uri nal ys is) 
(S ecti o n 8. 2. 4 ) will be c o n d ucte d 1 2 h o urs after d osi n g. All bi ol o gical assess me nts will be 
perf or me d i n a faste d c o n diti o n if p ossi ble, e xce pt f or t h ose i n breast-fe d i nfa nts.
T he ma xi m u m a m o u nt of bl o o d c ollecte d fr o m eac h partici pa nt o ver t he d urati o n of t he st u d y, 
i ncl u di n g a n y e xtra assess me nts t hat m a y  be re q uire d, will n ot e xcee d 1 7 m L
(see A p pe n di x 6
P har mac o ki netic Bl o o d Sa m pli n g ). Re peat or u nsc he d ule d sa m ples ma y  be ta ke n f or safet y 
reas o ns or f or tec h nical iss ues wit h t he sa m ples.
I n case t he partici pa nt, d ue t o l o gistical or s ocial reas o ns, will ha ve t o s pe n d a n ad diti o nal ni g ht 
i n t he h os pital, t he e n d of c o nfi ne me nt will be d oc u me nte d a n d t he a d diti o nal ni g ht will n ot be 
c o nsi dere d as part of c o nfi ne me nt. As s uc h, it will n ot q ualif y  as a n S A E, as descri be d i n 
A p pe n di x 3.  
F oll o w -u p visit s
D uri n g t he 3 d a y s f oll o wi n g t heir release fr o m t he h os pital, partici pa nts will be m o nit ore d b y  t he 
n urses i n t he healt h areas a n d/ or b y  the c o m m u nit y age nts of t he differe n t l ocalities f or p ote ntial 
A E s. If a n A E is o bser ve d, t he n urse/c o m m u nit y a ge nt will nee d t o i nf or m t he me dical tea m i n 
c har ge of t he st u d y f or t he necessar y f oll o w - u p.
At t he E n d - of-St u d y  visit ( bet wee n D a ys 1 7 a n d 2 1), partici pa nts fr o m C o h orts 1, 2, a n d 3 will 
be as ke d t o pr o vi de t w o st o ol sa m ples (t he first o ne will be c ollecte d wit hi n t he 1 7 t o 2 1 da y 
wi n d o w a n d t he sec o n d o ne wit hi n a ma xi m u m of 5 da y s f oll o wi n g c ollecti o n of t he 1st sa m ple) 
a n d o ne uri ne sa m ple (a b o ut 1 0 m L ) f or a nal ysis usi n g t he Kat o -Katz a n d P O C -C C A tests
res pecti vely. 
C o h ort 4 partici pa nt s will be as ke d t o pr o vi de t hree uri ne sa m ples (a b o ut 1 0 m L  eac h), wit hi n 5 
da y s, f or a nal ys is b y  t he filtrati o n met h o d at t he E n d of St u d y  Visit bet wee n Da y s 1 7 a n d 2 1, as 
well as t he E xte n de d F oll o w - u p Visit ( bet wee n Da y  3 5 a n d 4 0). 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
5 4 /9 3
T he f oll o wi n g tests a n d i nf or mati o n gat heri n g will be als o perf or me d:

Vital si g ns i n s u pi ne p ositi o n (see S ecti o n 8. 2. 3 )

C o m plete p h y sical e xa mi nati o n (see S ecti o n 8. 2. 2)
If a partici pa nt wit h dra ws pre mat urel y fr o m t he st u d y, e ver y eff ort will be ma de t o u n derta ke a 
fi nal e xa mi nati o n visit as s o o n as p ossi ble a n d perf or m all pr oce d ures ass ociate d wit h
t he 
E n d - of-St u d y  visit.
A n y  o n g oi n g me dicall y rele va nt a b n or mal fi n di n gs at t he E n d - of-St u d y  visit, will be f oll o we d u p 
u ntil res ol uti o n or sta bilizati o n (acc or di n g t o A p pe n di x 3 )
8. 1
Effic ac y Assess me nts a n d Pr oce d ures
8. 1. 1
Assess me nt of P ri m ar y E ffic ac y E n d p oi nt
T he pri mar y  en d p oi nt of t his st u d y is cli nical c ure rate base d o n o bjecti ve assess me nt of e g g 
c o u nts i n C o h ort 1. T o assess cli nical c ure i n t he 4 t o 6 year s of a ge c hil dre n i nfecte d wit h S. 
ma ns o ni
( C o h ort 1, Treat me nt Gr o u p s 1a a n d 1 b ), e p g will be q ua ntifie d 1 7 t o 2 1 d a y s after 
treat me nt, as deter mi ne d b y  the Kat o -Katz t hic k s mear met h o d descri be d b y  WH O ( 2 0 1 3). T h e 
met h o d will be i de ntical t o t he o ne use d i n t he P hase II st u d y. T w o st o ol sa m ples will be 
c ollecte d wit hi n a ma xi m u m of 5 d a y s d uri n g t he pre scree ni n g peri o d ( Da y - 2 8 t o D a y  -1) as 
baseli ne . T w o a d diti o nal st o ol sa m ple will be c ollecte d at t he E n d- of- S t u d y visit, o ne bet wee n 
1 7 a n d 2 1 d a y s after d osi n g , a n d an ot her o ne wit hi n a ma xi m u m of 5 da ys later t o deter mi ne 
efficac y. T hree Kat o-Katz t hic k s mears will be pre pare d fr o m eac h of t he st o ol sa m ples a n d rea d 
u n der t he micr osc o pe. T o meet t he pri mar y  efficac y en d p oi nt, a p artici pa nt m ust ha ve n o 
S. ma ns o ni e g gs i n a n y of t he Kat o -Katz s mears c ollecte d after t he d osi n g .
8. 1. 2
Assess me nt of S ec o n d ar y E ffic ac y E n d p oi nts
T he e p g will be deter mi ne d 1 7 t o 2 1 da y s after treat me nt b y  the Kat o -Katz met h o d as descri be d 
a b o ve a n d E R R (i n %) usi n g gr o u p -base d mea ns will be calc ulate d f or eac h of t he c o h orts. T he 
i n di vi d ual E R R will als o be calc ulate d b y meas uri n g t he perce nt re d ucti o n of e g g c o u nts f or eac h 
i n di vi d ual.
T he assess me nt of cli nical c ure i n C o h orts 2 a n d 3 wil l be d o ne as descri be d a b o ve usi n g t he 
Kat o -Katz met h o d. 
Cli nical c ure i n C o h orts 1, 2, a n d 3 will als o be assesse d usi n g t he p oi nt - of-care P O C -C C A ®
test, f oll o wi n g t he ma n ufact urer’s i nstr ucti o ns. O ne uri ne sa m ple will be c ollecte d 1 7 t o 2 1 da y s 
after treat me nt. After a p pl yi n g t he uri ne, a n y C C A a nti ge n t hat m a y  be prese nt i n t he sa m ple 
bi n ds t o t he la bele d m o n ocl o nal a nti b o d y im m o bilize d o n t he sa m ple me m bra ne. T he s ol uti o n 
t he n r u ns o ver t he stri p, w here t he a nti ge n -a nti b o d y co m ple x attac hes t o a n ot her m o n ocl o nal 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
5 5 /9 3
a nti b o d y im m o bilize d at t he test li ne. A pi n k -c ol ore d li ne de vel o ps. T he i nte nsit y of t he li ne is 
q ualitati vel y  relate d t o t he i nte nsit y of t he i nfecti o n. T he a bse nce of a li ne i n dicates t hat n o 
Sc hist os o ma a nti ge ns are detecte d a n d is i n dicati v e of cli nical c ure.
C ure rate as assesse d b y  the P O C -C C A ® assa y will be e val uate d f or c orrelati o n wit h c ure rate 
a n d E R R usi n g t he Kat o -Katz met h o d.
F or C o h ort 4, t he c ure rate will be deter mi ne d usi n g t he uri ne filtrati o n met h o d as descri be d i n 
t he St u d y  Pr oce d ure 
Ma n ual.
T o 
be c o nsi dere d c ure d, a partici pa nt m ust 
ha ve n o 
S. hae mat o bi u m e g gs i n t he uri ne sa m ple s c ollecte d at a f oll o w- u p. 
8. 1. 3
S urr o g ate E n d p oi nts
N ot a p plica ble
8. 2
S afet y Assess me nts a n d Pr oce d ures
T he safet y profile of t he st u d y inter ve nti o n will be assesse d t hr o u g h t he rec or di n g, re p orti n g a n d 
a nal ys is of baseli ne me dical c o n diti o ns, A Es, p h y sical e xa mi nati o n fi n di n gs, vital si g ns an d 
la b orat or y tests.
C o m pre he nsi ve assess me nt of a n y pote ntial t o xicit y ex perie nce d b y  eac h partici pa nt will be 
c o n d ucte d starti n g w he n t he partici pa nts gi ve i nf or me d c o nse nt a n d t hr o u g h o ut t he st u d y. T he 
I n vesti gat or will re p ort a n y A Es, w het her o bser ve d b y  the I n vesti gat or or re p orte d b y  th e 
partici pa nt; t he re p orti n g peri o d is s pecifie d i n Secti o n 8. 3. 1 ( Ti me Peri o d a n d Fre q ue nc y  for 
C ollecti n g A d verse E ve nt a n d Seri o us A d verse E ve nt I nf or mati o n).
T he u n desira ble effects after a d mi nistrati o n of P Z Q de pe n d o n d osa ge a n d d urati o n of t he 
t hera py a n d of ki n d, e xte nt a n d l ocalizati o n of parasitic i nfestati o n, as well as d urati o n of 
i nfecti o n. T hese are m ostl y  tra nsie nt c o m plai nts, n ot ge nerall y  re q uiri n g a n y special treat me nt. 
A d verse reacti o ns ma y  partl y re prese nt e n d o ge n o us reacti ons t o t he killi n g of t he parasites b y  
P Z Q . T he f oll o wi n g si de effects of Biltrici de
were o bser ve d ge nerall y, i n or der of se verity:  
malaise, hea dac he, dizzi ness, a b d o mi nal disc o mf ort wit h or wit h o ut na usea, rise i n te m perat ure 
a n d urticaria. S uc h si de effects m a y  be m ore fre q ue nt a n d/ or seri o us i n patie nts wit h a hea v y 
w or m b ur de n.
8. 2. 1
P ost M ar k eti n g A d verse E ve nt Re p orts f or P Z Q 
A d diti o nal A E s re porte d fr o m w orl d wi de p ost -mar keti n g e x perie nce a n d fr o m p u blicati o ns wit h 
P Z Q i ncl u de: a b d o mi nal pai n, aller gic reacti o n ( ge neralize d h y perse nsiti vit y , i ncl u di n g 
p ol y ser ositis), a n ore xia, arr h yt h mia (i ncl u di n g bra d yc ar dia, ect o pic r h yt h ms, ve ntric ular 
fi brillati o n, atri o ve ntric ular bl oc ks), ast he nia, bl o o d y  diarr hea, c o n v ulsi o n, e osi n o p hilia, fati g ue, 
m y al gia, pr urit us , ras h, s o m n ole nce, verti g o a n d v o miti n g. F or f urt her details refer t o t he 
Biltrici de ® S u m mar y  of Pr o d uct C haracteristics (S m P C ).
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
5 6 /9 3
T a ble  2
K n o w n A d verse Re acti o ns t o P Z Q
Or g a n cl ass 
C o m m o n
≥1/ 1 0 0 t o < 1/ 1 0
Ver y r are
< 1/ 1 0, 0 0 0
N ot k n o w n
Car diac dis or ders
U ns pecific arr h y t h mia
Gastr oi ntesti nal 
dis or ders
A b d o mi nal pai n
Na usea
E mesis
Ge neral dis or ders a n d 
a d mi nistrati o n 
c o n diti o ns
Wea k ness 
Fati g ue 
I ncrease d b od y
te m perat ure
He pat o biliar y dis or ders
He patic c o ma 
( de pe n di n g o n t he
t ype of parasite i n 
a d va nce d disease 
sta ges)
Meta b olis m a n d 
n utriti o n dis or ders
Lac k of a p petit e
Ner v o us s yste m 
dis or ders 
Hea dac he
Dizzi ness
Li g ht hea de d ness
C o n v ulsi o ns 
( After t he i nta ke of P Z Q 
f or treati n g ta pe w or m 
i nfecti o n, c o n v ulsi o ns 
ha ve occ urre d i n rare 
i n di vi d ual cases; t hese 
ha ve pr o ve n t o be a 
reacti o n t o c o-e xisti n g 
ne ur oc ysticerc osis. S uc h 
cases, w hic h ma y occ ur 
es peciall y i n e n de mic 
re gi o ns of Tae nia s oli u m 
(C ysticerc us cell ul osae), 
s h o ul d be clarifie d as 
q uic kl y as p ossi ble.
S ki n a n d s u bc uta ne o us 
tiss ue dis or ders
Urticari a
T he c o m plete d P hase I st u dies ( M S 2 0 0 5 8 5- 0 0 1 a n d M S 2 0 0 6 6 1 -0 0 1) c o nfir me d t he esta blis he d 
g o o d safet y pr ofile f or t he P Z Q O D Ts i n healt h y v ol u nteers. N o S A Es were re p orte d, a n d n o 
ne w t ypes of treat me nt relate d A Es were o bser ve d. T he f oll o wi n g T E A Es occ urre d: a b d o mi nal 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
5 7 /9 3
disc o mf ort, dizzi ness, fati g ue, hea dac he, na usea a n d ras h (liste d i n t he Refere nce Safet y 
I nf or mati o n, see rac-P Z Q O D T a n d L- P Z Q O D T I Bs). T E A Es were mil d t o m o derate i n 
se verity, a n d ge nerall y res ol ve d s p o nta ne o usl y wit hi n a fe w h o urs. T he rece ntl y  c o m plete d Part 1 
of t he P hase 
II st u d y in 2 t o 6
year s of a ge
c hil dre n i nfecte d wit h 
S. ma ns o ni
( St u d y M S 2 0 0 6 6 1 -0 0 0 5) als o c o nfir med t he well -esta blis he d fa v ora ble safety pr ofile of t he 
rac-P Z Q a n d L -P Z Q O D Ts .
Ne wl y re p orte d P Z Q-relate d A Es are n ot a ntici pate d i n t his P hase III st u d y, b ut t he y ma y occ ur.
I n partic ular, gi ve n t he size of Treat me nt gr o u p 1a a n d t he 2: 1 ra n d o mizati o n be t wee n Treat me nt 
gr o u p s 1a a n d 1 b, A Es ma y  be see n i n Treat me nt gr o u p 1a t hat are n ot see n i n ot her c o h orts; 
t hese ma y b e s e e n b y c ha nce al o ne a n d d o n ot reflect a real differe nce i n t he safet y  pr ofile i n t his 
c o h ort.  
Partici pa nts will re mai n i n t he facilit y for at least 1 2 h o urs after d osi n g a n d will be cl osel y 
o bser ve d. Base d o n t he P K pr o perties of P Z Q, a n y dr u g -relate d a d verse reacti o ns are e x pecte d t o 
occ ur wit hi n a p pr o xi matel y 12 h o urs after d osi n g. I n a d diti o n, f oll o w - u p of A Es will be 
perf or me d, if re q uire d, d uri n g t he first wee k after d osi n g (see Secti o n 1. 3 ). La b orat or y  safet y 
testi n g is i ncl u de d at baseli ne a n d 1 2 h o urs after dr u g a d mi nistrati o n . As per t he L- P Z Q O D T I B 
a n d literat ure re vie w, n o s pecific safety la b orat or y para meter a b n or malities are f o u n d after 
a d mi nistrati o n of P Z Q; o nl y  n o n s pecific i nfla m mat or y para meters ha ve bee n re p orte d, w hic h 
c o ul d be d ue t o t he u n derl yi n g i nfecti o n.
At eac h st u d y visit, t he pare nt or g uar dia n /le gall y aut h orize d re prese ntati ve (a n d t he c hil dre n, if 
t he y are a ble) will be q uerie d o n c ha n ges i n t he p artici pa nt’s c o n diti o n. D uri n g t he re p orti n g 
peri o d, a n y unfa v ora ble c ha n ges i n t he p artici pa nt’s c o n diti o n will be rec or de d as A Es, w het her 
re p orte d b y  the p artici pa nt’s pare nt or g uar dia n /le gall y aut h orize d represe ntati ve or o bser ve d b y 
t he In vesti gat or.
C o m plete, acc urate a n d c o nsiste nt data o n all A Es e x perie nce d f or t he d urati o n of t he re p orti n g 
peri o d will be re p orte d o n a n o n g oi n g basis i n t he a p pr o priate secti o n of t he eC R Fs. All S A Es 
m ust be a d diti o nall y d oc u me nte d a n d re p orte d usi n g t he a p pr o priate Seri o us A d verse E ve nt 
Re p ort F or m.
Eac h A E re p ort will i ncl u de a descri pti o n of t he e ve nt, its d urati o n ( o nset a n d res ol uti o n dates 
a n d ti mes), its se verity, its ca usal relati o ns hi p (as assesse d b y  the I n vestigat or) wit h t he st u d y
treat me nt, a n y ot her p ote ntial ca usal fact ors, a n y treat me nt gi ve n, or ot her acti o n ta ke n, a n d its 
o utc o me. I n a d diti o n, seri o us cases will be i de ntifie d, a n d t he a p pr o priate seri o us ness criteria 
d oc u me nte d.
S pecific g ui da nce will be pr o vi de d i n t he Case Re p ort F or m C o m pleti o n a n d M o nit ori n g 
C o n ve nti o ns pr o vi de d b y t he S p o ns or or b y  t he C R O.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
5 8 /9 3
8. 2. 2
P h ysic al E x a mi n ati o ns
P h y sical e xa mi nati o n will be d o ne acc or di n g t o l ocal pr oce d ures. Refer t o t he S c he d ule o f 
Acti vities ( Secti o n 1. 3 ) f or t he ti me p oi nts.
A c o m plete p h y sical e xa mi nati o n will i ncl u de, at a mi ni m u m, 
assess me nts of t he S ki n, 
Car di o v asc ular, Res pirat or y, M usc ular, Gastr oi ntesti nal a n d Ne ur ol o gical s yste ms.
Hei g ht a n d wei g ht will be meas ure d a n d rec or de d at scree ni n g ( bef ore d osi n g) ; wei g ht will be 
meas ure d a gai n at t he e n d of c o nfi ne me nt ( 1 2 t o 2 4 h o urs after d osi n g ). I nvesti gat ors s h o ul d pa y 
s pecial atte nti o n t o cli nical si g ns relate d t o pre vi o us seri o us ill nesses.
8. 2. 3
Vit al Si g ns
A xillar y  te m perat ure, p ulse rate, res pirat or y rate, a n d bl o o d press ure will be assesse d acc or di n g 
t o t he st u d y sc he d ule i n t he Sc he d ule of Acti vities ( Secti o n 1. 3).
B P a n d p ulse meas ure me nts s h o ul d be prece de d b y  at least 5 mi n utes of rest f or t he partici pa nt i n 
a q uiet setti n g wit h o ut distracti o ns (e.g., tele visi o n, cell p h o nes).
B P a n d p ulse rate meas ure me nts s h o ul d be o btai ne d wit h t he partici pa nt 's ar m u nc o nstrai ne d b y  
cl ot hi n g or ot her material. T he meas ure me nts will be o btai ne d wit h t he a p pr o priate c uff size, 
usi n g t he o p p osite ar m fr o m t hat use d f or bl o o d sa m pli n g, w here p oss i ble.
A xillar y  bo d y  te m perat ure will be meas ure d usi n g a di gital t her m o meter. B o d y te m perat ure will 
be ta ke n t o get her wit h meas ure me nts of B P a n d p ulse rate.
8. 2. 4
Cli nic al S afet y L a b or at or y Assess me nts
Bl o o d a n d uri ne sa m ples will be c ollecte d f or t he cli nical la b orat or y  tests liste d i n A p pe n di x 5 , at 
t he ti me p oi nts liste d i n t he Sc he d ule of Acti vities ( Secti o n 1. 3) . All sa m ples s h o ul d be clearl y 
i de ntifie d. 
A d diti o nal tests ma y  be perf or me d at a n y ti me d uri n g t he st u d y, as deter mi ne d necessar y  by t he 
In vesti gat or or re q uire d b y  l ocal re g ulati o ns.
T he tests will be pe rf or me d b y t he l ocal la b orat or y.
Sa m ples f or t he uri ne, hae mat ol o g y  an d bi oc he mistr y  tests will be c ollecte d i n a faste d c o n diti o n 
if p ossi ble (e xce pt f or breast -fe d i nfa nts), a n d perf or me d b y  the l ocal la b orat or y. Detaile d 
i nf or mati o n is gi ve n i n t he St u d y  Pr oce d ure Ma n ual. 
T he S p o ns or m ust recei ve a list of t he l ocal la b orat or y nor mal ra n ges bef ore s hi p me nt of st u d y 
i nter ve nti o n(s). A n y c ha n ges t o t he ra n ges d uri n g t he st u d y m ust be f or war de d t o t he S p o ns or .
T he In vesti gat or m ust re vie w eac h la b orator y  re p ort, d oc u me nt t heir re vie w, a n d rec or d a n y 
cli nicall y rele va nt c ha n ges occ urri n g d uri n g t he st u d y in t he A E secti o n of t he eC R F.
T he 
la b orat or y re p orts m ust be file d wit h t he s o urce d oc u me nts.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
5 9 /9 3
8. 2. 5
C o nc o mit a nt Me dic ati o ns
E ve nt ual c o nc o mita nt me dicati o ns will be e val uate d fr o m Scree ni n g u ntil t he E n d - of- St u d y visit, 
at t he ti me p oi nts liste d i n t he Sc he d ule of Acti vities ( Secti o n  1. 3).
8. 3
A d verse E ve nts a n d Seri o us A d verse E ve nts
T he defi niti o ns of a n A E a n d an S A E are i n A p pe n di x 3 .
8. 3. 1
Ti me Peri o d a n d Fre q ue nc y f or C ollecti n g A d verse E ve n t 
a n d Seri o us A d verse E ve nt I nf or m ati o n
T he A E re p orti n g peri o d f or safety s ur veilla nce be gi ns w he n t he partici pa nt is i nitiall y incl u de d 
i n t he st u d y (date of si g nat ure of i nf or me d c o nse nt) a n d c o nti n ues t hr o u g ho ut t he st u d y’s 
p ost -treat me nt f oll o w-u p per i o d, u ntil t he E n d - of- St u d y v isit. A E s will be ca pt ure d i n t he 
data base fr o m t he Scree ni n g visit u p t o t he E n d- of- St u d y  visit.
A n y S A E assesse d as relate d t o st u d y  i nter ve nti o n m ust be rec or de d a n d re p orte d, as i n dicate d i n 
A p pe n di x 3,  w he ne ver it occ urs, irres pecti ve of t he ti me ela pse d si nce t he last a d mi nistrati o n of 
st u d y i nter ve nti o n.
T he met h o d of rec or di n g, e val uati n g, a n d assessi n g ca usalit y of A Es (i ncl u di n g S A Es) a n d t he 
pr oce d ures f or c o m pleti n g a n d tra ns mitti n g S A E re p orts are i n  A p pe n di x 3.
8. 3. 2
Met h o d 
of Detecti n g A d verse E ve nts a n d Seri o us A d verse 
E ve nts
At eac h st u d y visit, t he partici pa nt will be q uerie d o n c ha n ges i n his or her c o n diti o n . D uri n g t he 
re p orti n g peri o d, a n y u nfa v ora ble c ha n ges i n t he partici pa nt’s c o n diti o n will be rec or de d as A Es, 
re gar dless of w het her re p orte d b y t he partici pa nt or o bser ve d b y t he In vesti gat or.
C o m plete, acc urate a n d c o nsiste nt data o n all A Es e x perie nce d f or t he d urati o n of t he re p orti n g 
peri o d ( defi ne d bel o w) will be re p orte d o n a n o n g oi n g basis i n t he a p pr o priate secti o n of t he 
e C R F. All S A Es m ust be a d diti o nall y doc u me nte d a n d re p orte d usi n g t he a p pr o priate Re p ort 
F or m as s pecifie d i n  A p pe n di x 3.
8. 3. 3
F oll o w -u p of A d verse E ve nts a n d Seri o us A d verse E ve nts
A Es are rec or de d a n d assesse d c o nti n u o usl y thr o u g h o ut t he st u d y, as s pecifie d i n Secti o n 8. 3. 1
( Ti me Peri o d a n d Fre q ue nc y  for C ollecti n g A d verse 
E ve nt a n d Seri o us A d verse 
E ve nt 
I nf or mati o n) a n d are assesse d f or t heir o utc o me at t he E n d - of-St u d y  visit. All S A Es o n g oi n g at 
t he E n d - of-St u d y  visit m ust be m o nit ore d a n d f oll o we d u p b y  the I n vesti gat or u ntil sta bilizati o n 
or u ntil t he o utc o me is k n o w n, u nless t he partici pa nt is d oc u me nte d as “l ost t o f oll o w-u p”. 
Reas o na ble atte m pts t o o btai n t his i nf or mati o n m ust be ma de a n d d oc u me nte d. It is als o t he 
res p o nsi bilit y of t he I n vesti gat or t o e ns ure t hat a n y necessar y ad diti o nal t hera pe utic meas ures 
a n d f oll o w-u p pr oce d ures are perf or me d. F urt her i nf or mati o n o n f oll o w- u p pr oce d ures is gi ve n 
i n A p pe n di x 3 .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
6 0 /9 3
8. 3. 4
Re g ul at or y Re p orti n g 
Re q uire me nts 
f or Seri o us A d verse 
E ve nts
T he S p o ns or will se n d a p pr o priate safety n otificati o ns t o Healt h A ut h orities i n acc or da nce wit h 
a p plica ble la ws a n d re g ulati o ns.
T he I n vesti gat or m ust c o m pl y wit h a n y a p plica ble c o u ntr y-s pecific re quire me nts relate d t o t he 
re p orti n g of S A Es ( partic ularly deat hs) i n v ol vi n g st u d y partici pa nts t o t he I n de pe n de nt Et hics 
C o m mittee/I nstit uti o nal Re vie w B oar d ( I E C/IR B ) t hat a p pr o ve d t he st u dy.
I n acc or da nce wit h I CH G o o d Cli nical Practices (G C P ), t he S p o ns o r/ desi g nee will i nf or m t he 
I n vesti gat or of fi n di n gs t hat c o ul d a d versel y affect t he safety of partici pa nts, affect t he c o n d uct 
of t he st u d y or alter t he I EC’s/I R B’s a p pr o val/fa v ora ble o pi ni o n t o c o nti n ue t he st u d y. I n li ne 
wit h res pecti ve re g ulati o ns, t he S p o ns or/ desi g nee will i nf or m t he I nvesti gat or of A Es t hat are 
b ot h seri o us a n d u ne x pecte d a n d c o nsi dere d t o be relate d t o t he a d mi nistere d pr o d uct (“s us pecte d 
u ne x pecte d seri o us a d verse reacti o ns,” or S U S A Rs). T he I n vesti gat or s h o ul d place c o pies of 
Safet y
Re p orts i n t he I n vesti gat or Site File. Nati o nal re g ulati o ns re gar di n g Safet y  Re p ort 
n otificati o ns t o I n vesti gat ors will be c o nsi dere d.
W he n 
s pecificall y re q uire d b y  re g ulati o ns a n d g ui deli nes, t he S p o ns or/ desi g nee will pr o vi de 
a p pr o priate Safet y Re p orts directl y  to t he c o ncer ne d lea d I E C/IR B a n d will mai ntai n rec or ds of 
t hese n otificati o ns. W he n 
direct re p orti n g is n ot clearl y defi ne d b y  nati o nal or site-s pecific 
re g ulati o ns, t he I n vesti gat or will be res p o nsi ble f or pr o m ptl y n otif yi n g t he c o ncer ne d I E C/IR B of 
a n y Safet y Re p orts pr o vi de d b y  the S p o ns or/ desi g nee a n d of fili n g c o pies of all relate d 
c orres p o n de nce i n t he I nvesti gat or Site File.
All safet y re p orti n g will be descri be d i n Safet y M a na ge me nt Pla n .
8. 3. 5
Pre g n a nc y
N ot a p plica ble ; partici pa nts i n t his st u dy are 3 m o nt hs t o 6 years of a ge.
8. 4
Tre at me nt of O ver d ose
F or t his st u d y , a n y d ose of L- P Z Q O D T or Biltrici de greater t ha n t he hi g hest d ose pla n ne d i n t he 
P har mac y  Ma n ual f or a n i n di vi d ual partici pa nt e nr olle d i n t he st u d y t hat is i n geste d wit hi n
a 
2 4- h o ur ti me peri o d will be c o nsi dere d a n o ver d ose.
T he S p o ns or d oes n ot rec o m me n d s pecific treat me nt f or a n o ver d ose . As n o a nti d ote or n o n dr u g 
t hera py is a vaila ble, t he I n vesti gat or s h o ul d use his/ her cli nical j u d ge me nt w he n treati n g a n 
o ver d ose of a n i n vesti ga ti o nal dr u g.
E ve n if it is n ot ass ociate d wit h a n A E or a S A E, a n y o ver d ose is rec or de d i n t he eC R F a n d 
re p orte d t o Gl o bal Patie nt S afet y in a n e x pe dite d ma n ner. O ver d oses are re p orte d o n a S A E 
Re p ort F or m, f oll o wi n g t he pr oce d ure i n A p pe n di x 3 , secti o n o n Re p orti n g Seri o us A d verse 
E ve nts a n d A d verse E ve nts of S pecial I nterest a n d D ose L i miti n g T o xicities.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
6 1 /9 3
8. 5
P h ar m ac o k i netics
T o get i nf or mati o n o n s yste mic plas ma c o nce ntrati o ns after a d mi nistrati o n of t he fi nal L- P Z Q 
O D T f or m ulati o n i n t he tar gete d pe diatric a ge gr o u ps, a s u b gr o u p of u p t o 2 0 partici pa nts 4 t o 6 
ye ars of a ge (Treat me nt gr o u p 1a), u p t o 1 5 partici pa nts 2 t o 3 ye ars of a ge ( C o h ort 2), bet wee n 5 
a n d 1 0 partici pa nts 3 t o < 2 4 m o nt hs of a ge ( C o h ort 3) are nee de d t o s u p pl y bl o o d sa m ples  for 
deter mi nati o ns of s yste mic c o nce ntrati o ns of R-(-)- P Z Q (a n d if a p plica ble its meta b olites). P K 
sa m pli n g fr o m u p t o 1 5 partici pa nts i n Treat me nt Gr o u p 1 b will pr o vi de i nf or mati o n o n t he 
s yste mic plas ma c o nce ntrati o ns o bser ve d after Biltrici de a d mi nistrati o n. F or C o h ort 4, 1 5 
partici pa nts i nfecte d wit h S. ha e mat o bi u m ( C o h ort 4) are nee de d t o s u p pl y bl o o d sa m ples f or 
deter mi nati o n of s yste mic c o nce ntrati o ns of R -(-)-P Z Q (a n d if a p plica ble its meta b olites). P K 
sa m pli n g fr o m a n a d diti o nal 1 5 partici pa nts will be c ollecte d f or t he 6 0 m g/ k g d ose gr o u p i n 
C o h ort 4. A se parate writte n i nf or me d c o nse nt will be o btai ne d f or P K sa m pli n g. O nl y 
partici pa nts w it h mi ni m u m
he m o gl o bi n of 1 0 g/ d L will be as ke d t o ta ke part i n t he P K 
s u b-st u d y.
B l o o d sa m ples of a p pr o xi matel y 1
mL per ti me p oi nt will be c ollecte d f or meas ure me nt of 
plas ma
c o nce ntrati o ns of R-(-)- P Z Q
( or rac-P Z Q) a n d, if a p plica ble, of its meta b olites , 
i m me diatel y pri or t o d osi n g (pre d ose) a n d t hereafter ( p ost-d ose) , u p t o 1 2 h o urs after d osi n g , as 
s pecifie d i n t he S c he d ule o f A cti vities ( Secti o n 1. 3 ). I nstr ucti o ns f or t he c ollecti o n a n d ha n dli n g 
of bi ol o gical sa m ples will be pr o vi de d b y  the S p o ns or. T he act ual date a n d ti me ( 2 4-h o ur cl oc k 
ti me) of dr u g a d mi nistrati o n a n d eac h sa m ple will be rec or de d i n t he e C R F.
As t he k n o w n varia bilit y of s yste mic P Z Q c o nce ntrati o ns a n d P K para meters is hi g h i n a d ults, 
t he n u m ber of partici pa nts i n eac h P K s u b gr o u p is n ot base d o n statistical c o nsi derati o ns b ut o n 
feasi bilit y assess me nts. C hil dre n wei g hi n g 5 k g t o less t ha n 7 k g will ha ve 4 P K sa m ples ta ke n, 
c hil dre n wei g hi n g 7 k g t o less t ha n 1 0 k g will ha ve 7 P K sa m ples ta ke n, a n d c hil dre n wei g hi n g 
1 0 k g a n d a b o ve will ha ve t he f ull P K sa m pli n g sc he me wit h 9 P K sa m ples ta ke n. F or 
bac k gr o u n d i nf or mati o n please see “A p pe n di x 6
P har mac o ki netic 
Bl o o d 
Sa m pli n g ”. 
Partici pa nts assi g ne d t o t he P K s u b st u d y  s h o ul d fast bet wee n t he d osi n g a n d 4 h p ost d osi n g.
T a ble 3
P K s a m pli n g ti mes per b o d y wei g ht gr o u p
B o d y 
wei g ht 
ra n ge 
( k g)
Sa m pli n g ti mes ( h o urs)
Pre d ose 
P ost d ose
5 t o < 7
N o
0. 5 
1 
2 
3 
- 
- 
- 
-
7 t o < 1 0
N o
0. 5 
1 
2 
3 
4 
6 
8 
-
1 0 
a n d 
a b o ve
Yes
0. 5 
1 
2 
3 
4 
6 
8 
1 2
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
6 2 /9 3
Plas ma c o nce ntrati o ns will 
be ta b ulate d a n d s u m marize d usi n g descri pti ve statistics. P K 
para meters will be calc ulate d if p ossi ble as a p pr o priate f or t he res pecti ve sa m pli n g sc he mes. All 
P K para meters will be calc ulate d usi n g sta n dar d n o n c o m part me ntal met h o ds a n d t he act ual 
a d mi nistere d d ose. Calc ulati o ns 
will 
be perf or me d usi n g t he vali date d s oft ware t o ol 
P h oe ni x ® / Wi n N o nli n 6. 3 ®
( or later) b y  the P har mac o ki netics/ P har mac o d y na mics pr ocessi n g 
gr o u p of Q ua ntitati ve P har mac ol o g y , Merc k 
Bi o p har ma, Dar msta dt, Ge r ma ny, or will be 
o uts o urce d u n der t he s u per visi o n of t he S p o ns or.
T he f oll o wi n g P K para meters will be calc ulate d, w he n a p pr o priate:
T a ble  4
P K p ar a meters
S y m b ol
Defi niti o n
C ma x
Ma xi m u m o bser ve d c o nce ntrati o n i n plas ma
A U C 0 -t
Area u n der t he plas ma c o nce ntrati o n -ti me c ur ve ( A U C) fr o m ti me zer o t o 
t he last sa m pli n g ti me at w hic h t he c o nce ntrati o n is at or a b o ve t he l o wer
li mit of q ua ntificati o n
tma x
Ti m e t o reac h t he ma xi m u m plas ma c o nce ntrati o n
tla g
Ti m e pri or t o t he first mea s ura ble (n o n zer o) c o nce ntrati o n
P K para meters will 
be e val uate d a n d liste d f or all partici pa nts
w h o 
pr o vi de s ufficie nt 
c o nce ntrati o n ti me data.
8. 6
P h ar m ac o d y n a mics
N ot a p plica ble
8. 7
Ge netics
N ot A p plica ble
8. 8
Bi o m ar k ers
N ot a p plica ble
8. 9
He alt h Ec o n o mics
N ot a p plica ble
8. 1 0
I m m u n o ge nicit y Assess me nts
N ot a p plica ble
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
6 3 /9 3
9
St atistic al C o nsi der ati o ns
9. 1
St atistic al H y p ot hes es
N o f or mal h y p ot hesis testi n g is pla n ne d. P oi nt esti mates of t he c ure rate a n d t w o- si de d 9 5 % CI  
will be calc ulate d f or all c o h orts.
9. 2
S a m ple Size Deter mi n a ti o n
T he pri mar y  en d p oi nt will be t he c ure rate c o m p ute d b y  treat me nt gr o u p o n t he mI T T p o p ulati o n 
of 4 t o 6 year s of a ge c hil dre n i nfecte d wit h S. ma ns o ni
(C o h ort 1). A t otal of 1 5 0 p artici pa nts 
will be ra n d o mize d 2: 1 i nt o t he L -P Z Q O D T treat me nt gr o u p or t he c o m mercial rac-P Z Q 
( Biltrici de) treat me nt gr o u p a n d a nal yz e d si milarl y; h o we ver, t he efficac y of t he t w o treat me nts 
will n ot be c o m pare d statisticall y. T he c o m mercial rac-P Z Q treat me nt ar m as a n acti ve c o ntr ol 
ar m will be c o nsi dere d a n i nter nal be nc h m ar k. T he sa m ple size of n = 1 5 0 f or C o h ort 1 was 
c h ose n base d o n t he precisi o n of t he esti mate of t he tr ue c ure rate.
F or a fi xe d sa m ple size, t he precisi o n of t he esti mate of t he tr ue c ure rate is de pe n de nt o n t he 
o bser ve d c ure rate. I n Part 1 of t he P hase II st u d y, M S 2 0 0 6 6 1 - 0 0 0 5, t he o bser ve d c ure rate i n t he 
mI T T p o p ulati o n f or L- P Z Q O D T 4 5 m g / kg a m o n g c hil dre n 4 t o 6 years of a ge was 8 3. 7 % 
( 3 6/ 4 3 c ure d; 9 5 % CI : 6 9. 3 -9 3. 2). Wit h 
9 5 partici pa nts i n t he P hase III mI T T A nal y sis Set 
recei vi n g L- P Z Q O D T i n Tre at me nt gr o u p 1a, t he l o wer b o u n d of a t w o-si de d 9 5 % CI  for a 
si n gle pr o p orti o n usi n g t he Cl o p per -Pears o n e xact met h o d will e xte n d 1 0. 0 % fr o m t he o bser ve d 
pr o p orti o n f or a n e x pecte d c ure rate of 7 3. 7 %. Ta ble 5 (as f oll o ws) s h o ws a ra n ge of l o wer 
b o u n ds of the t w o-si de d 9 5 % CI  if t he o bser ve d P hase II res ults were hi g her t ha n t he tr ue c ure 
rate a n d a l o wer c ure rate is o bser ve d i n t his P hase III st u d y.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
6 4 /9 3
T a ble 5
Precisi o n of esti m ate f or a r a n ge of p ossi ble c ure r ates o bser ve d i n 
P h ase III
Tre at me nt 
Gr o u p,
N e nr olle d
A n al ysis 
P o p ul ati o n, n 
e x pecte d
E x pecte d 
C ure R ate
O bser ve d i n 
P h ase III
(c ure d/t ot al)
L o wer B o u n d of 
t w o-si de d 9 5 % CIa
Precisi o n b
L- P Z Q 
O D T 
5 0 
m g/ k g 
( 1a), N= 1 0 0 
mI T T c, n = 9 5 
8 6. 3 % ( 8 2/ 9 5)
7 7. 7 %
8. 6 %
8 0. 0 % ( 7 6/ 9 5)
7 0. 5 %
9. 5 %
7 3. 7 % ( 7 0/ 9 5)
6 3. 6 %
1 0. 0 %
Biltrici de
4 0 
m g/ k g 
( 1 b), 
N = 5 0 
mI T T c, n = 4 7 
8 7. 2 % ( 4 1/ 4 7)
7 4. 2 %
1 3. 0 %
7 8. 7 % ( 3 7/ 4 7)
6 4. 3 %
1 4. 4 %
7 0. 2 % ( 3 3/ 4 7)
5 5. 1 %
1 5. 1 %
L- P Z Q O D T 
5 0 m g/ k g 
( 1a), N= 1 0 0 
P P d, n = 8 0 
8 6. 3 % ( 6 9/ 8 0)
7 6. 7 %
9. 5 %
8 0. 0 % ( 6 4/ 8 0)
6 9. 6 %
1 0. 4 %
7 3. 8 % ( 5 9/ 8 0)
6 2. 7 %
1 1. 0 %
Biltrici de 4 0 
m g/ k g ( 1 b), 
N = 5 0 
P P d, n = 4 0 
8 7. 5 % ( 3 5/ 4 0)
7 3. 2 %
1 4. 3 %
8 0. 0 % ( 3 2/ 4 0)
6 4. 4 %
1 5. 6 %
7 2. 5 % ( 2 9/ 4 0)
5 6. 1 %
1 6. 4 %
aUsi n g t he Cl o p per -Pears o n e xact met h o d
bDefi ne d as dista nce fr o m o bser ve d c ure rate t o l o w er b o u n d of 9 5 % C o nfi de nce I nter val ( CI )
cAss u mi n g 5 % of partici pa nts will re q uire a nti -malarial treat me nts (as wit h P hase II e x perie nce) 
dP P = Per -pr ot oc ol, all o w i n g f or 2 0 % of partici pa nts e xcl u de d fr o m the per -pr ot oc ol a nal ysis
Ass u mi n g 5 % of partici pa nts will nee d a nti-malarial
treat me nts after P Z Q treat me nt a n d a 2 0 % 
n o n- e val ua ble rate, a t otal of 1 5 0 partici pa nts will be ra n d o mize d i n C o h ort 1, acc or di n g t o a 2: 1 
rati o, t o ac hie ve 9 5 mI T T partici pa nts a n d 8 0 P P partici pa nts e x p ose d t o t he L -P Z Q O D T, a n d 4 7 
mI T T partici pa nts a n d 4 0 P P partici pa nts e x p ose d t o c o m mercial rac-P Z Q ta blets (Biltrici de ). 
T he mI T T p o p ulati o n will be use d t o a nal yze t he pri mar y  en d p oi nt. S ee Secti o n 9. 3 f or 
defi niti o ns of t he mI T T a n d P P p o p ulati o ns.
I n C o h ort 2, a t otal of 3 0 partici pa nts 2 t o 3 years of a ge i nfecte d wit h S. ma ns o ni
will be 
e nr olle d t o assess c o nsiste nc y of t he treat me nt effect wit h t hat i n t he ol der a ge gr o u p. As 
descri be d i n Secti o n 4. 2. 4 , t he size of C o h ort 2 is 3 0 % of t hat of Treat me nt gr o u p 1a, t o be 
r o u g hly c o nsiste nt wit h t he distri b uti o n of c hil dre n 2 t o 3 years of a ge ( 2 7 %) a n d 4 t o 6 ye ars of 
a ge ( 7 3 %) e nr olle d i n t he P hase II st u d y, i n w hic h n o differe nces i n c ure rate b y  age were 
o bser ve d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
6 5 /9 3
I n C o h ort 3, o verall a t otal of u p t o 6 5 partici pa nts 3 t o 2 4 m o nt hs
of a ge i nfecte d wit h 
S. ma n s o ni will be e nr olle d i n t he P hase II a n d P hase III st u dies. T he sa m ple size i n eit her st u d y 
al o ne is t o o s mall t o ha ve a de q uate precisi o n o n t he c ure rate, t h us t he res ults i n t his P ha se III
st u d y (C o h ort 3) will be p o ole d wit h C o h orts 8 a n d 9 of t he o n g oi n g P hase II st u d y 
( M S 2 0 0 6 6 1-0 0 0 5). I n t he P hase II St u d y  MS 2 0 0 6 6 1 - 0 0 0 5, 2 0 o ut of 3 0 pla n ne d partici pa nts 
1 3 t o 2 4 m o nt hs of a ge a n d 4 o ut of 1 0 pla n ne d partici pa nts 3 t o 1 2 m o nt hs of a ge were e nr olle d 
i n t he st u d y. I n C o h ort 3 of t his P hase III st u d y, at least 2 5 partici pa nts 3 t o 2 4 m o nt hs
of a ge
i nfecte d wit h S. ma ns o ni (i.e., ~ 2 0 % of t he t otal n u m ber of partici pa nts 2 t o 6 ye ars of a ge 
recei vi n g L- P Z Q O D T) will be e nr olle d. Si nce t he e nr oll me nt of t his a ge gr o u p fr o m P hase II
was
l o wer t ha n pla n ne d, m ore t ha n 2 5 partici pa nts will be e nr olle d i n P hase III C o h ort 3 t o 
ac hie ve a t otal of 6 5 partici pa nts i n t his a ge gr o u p . T his p o ole d sa m ple will all o w a g e neral 
c o m paris o n t o assess w het her t he treat me nt effect is si milar acr oss a ge gr o u ps.
A ma xi m u m of 9 0 c hil dre n will be e nr olle d i n C o h ort 4. A t otal of 6 0 c hil dre n i n C o h ort 4,
3 m o nt hs t o 6 y ears of a ge i nfecte d wit h S. hae mat o bi u m, will be treate d wit h L -P Z Q O D T at t he 
fi nal d ose , eit her 5 0 m g/ k g or 6 0 m g/ k g. Sa m ple size is base d o n t he n u m ber of partici pa nts 
nee de d t o pr o vi de a mea ni n gf ul 
esti mate of c ure rate i n t he S. hae mat o bi u m -i nfecte d 
partici pa nts. Ass u mi n g 
5 % of partici pa nts will 
nee d a nti-malarial
treat me nts after P Z Q 
treat me nt, t he 6 0 e nr olle d partici pa nts are e x pecte d t o yi el d at least 5 7 mI T T partici pa nts. Wit h 
at least 5 7 mI T T partici pa nts a n d a n e x pecte d c ure rate of 7 5 %, t he t w o-si de d 9 5 % CI  will ha ve 
1 3. 2 % precisi o n fr o m t he o bs er ve d c ure rate. Ass u mi n g a n o n- e val ua ble rate of 2 0 %, t he 6 0 
e nr olle d partici pa nts are e x pecte d t o yi el d at least 4 8 P P partici pa nts. Wit h 
at least 4 8 P P
partici pa nts a n d a n e x pecte d c ure rate of 7 5 %, t he t w o-si de d 9 5 % CI  will ha ve 1 4. 6 % precisi o n 
fr o m t he o bser ve d c ure rate.
Calc ulati o ns are base d o n a 2- si de d 9 5 % CI  for pr o p orti o ns usi n g t he e xact ( Cl o p per-Pears o n) 
met h o d ( R S oft ware, versi o n 3. 4. 2, Vie n na, A ustria).
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
6 6 /9 3
9. 3
P o p ul ati o ns f or A n al yses
T he a nal ys is p o p ulati o ns are s pecifie d bel o w, i n Ta ble 6. T he fi nal decisi o n t o e xcl u de 
partici pa nts fr o m a n y a nal ysis p o p ulati o n will be ma de d uri n g a bli n de d data re vie w meeti n g 
pri or t o data base l oc k .
T a ble  6
A n al ysis p o p ul ati o ns
P o p ul ati o n
Descri pti o n
E nr olle d
All partici pa nts w h o si g n i nf or me d c o nse nt.
I nte nti o n-t o-tre at
T he I nte nti on-t o- Treat (I T T) A nal ys is Set will i ncl u de all partici pa nts
e nr olled.
M o difie d
I nte nti o n- T o- Tr
e at
M o difie d
i nte nti on-t o- treat ( mI TT ) An al y sis Set i ncl u des all e nr olle d
partici pa nts w h o recei ve o ne d ose of treat me nt a n d w h o ha ve baseli ne
meas ure me nt.
C hil dre n w h o re q uire malaria treat me nt after e nr oll me nt
i n t he st u d y will n ot be i ncl u de d i n t he mI T T A nal y sis Set. T he
pri mar y a nal ys is of t his st u d y w ill be perf or me d o n t he mI T T A nal y sis
Set.
Pe r- Pr ot oc ol
Per -pr ot oc ol ( P P) A nal ys is Set i ncl u des all partici pa nts w h o are i n
t he mI T T p o p ulati o n a n d ha ve o ne p ost baseli ne meas ure me nt
wit h o ut a n y cli nicall y i mp orta nt pr ot oc ol de viati o ns. Details of t he
criteria f or e xcl usi o n fr o m t he P P p o p ulati o n will be pr o vi de d i n t he
Statistical A nal y sis P la n pla n ne d t o be fi nalize d bef ore first
partici pa nt bei n g d ose d. A n a d diti o nal deter mi nati o n will be ma de 
pri or t o data base l oc k, base d o n a re vie w of data ( wit h o ut k n o wle d ge 
of treat me nt assi g n me nt f or C o h ort 1) accr ue d d uri n g t he c o n d uct of 
t he st u d y.
S afet y
T he Safet y A nal ys is Set will i ncl u de all partici pa nts w h o recei ve a 
d ose of st u d y treat me nt. Partici pa nts will be a nal yze d acc or di n g t o
t he act ual treat me nt t he y recei ve.
9. 4
St atistic al A n al yses
All e n d p oi nts will be a nal y ze d descri pti vel y. Gra p hs will be pr o d uce d as a p pr o priate. Descri pti ve 
statistics f or cate g orical e n d p oi nts will i ncl u de fre q ue nc y  co u nts a n d perce nta ges. F or pr o p orti o n 
e n d p oi nts, t he calc ulati o n of 9 5 % CIs will be base d o n t he Cl o p per -Pears o n (e xact) met h o d. 
Descri pti ve statistics f or c o nti n u o us e n d p oi nts will i ncl u de: n u m ber of a vaila ble o bser vati o ns, 
mea n, sta n dar d de viati o n, me dia n, l o wer q uartile, u p per q uartile, mi ni m u m, a n d ma xi m u m. F or 
c o nti n u o us e n d p oi nts, t he 9 5 % CI ar o u n d t he mea n will be calc ulate d w here a p plica ble.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
6 7 /9 3
9. 4. 1
Effic ac y A n al yses
T he pri mar y  efficac y anal y sis will be perf or me d o n t he mI T T p o p ulati o n of C o h ort 1. T he 
pri mar y  en d p oi nt of c ure rate will be calc ulate d as t he perce nta ge of e g g-p ositi ve partici pa nts at 
baseli ne w h o bec o me e g g-ne gati ve after treat me nt (as assesse d b y  the Kat o -Katz met h o d). T he 
e xact 9 5 % CI  will be calc ulate d base d o n t he Cl o p per -Pears o n met h o d. C o h orts 2, 3, a n d 4 will 
be a nal yz e d si milarl y.
T he sec o n dar y  e n d p oi nt of c ure rate b y P O C-C C A ® ( C o h orts 1, 2, a n d 3) will be a nal y ze d i n t he 
sa me ma n ner as t he pri mar y e n d p oi nt, wit h pr o p orti o n c ure d a n d its 9 5 % CI.
T he sec o n dar y en d p oi nt of E R R will be a nal yze d f or eac h of t he c o h orts a n d treat me nt gr o u p 
( C o h ort 1) as gr o u p -base d E R R (arit h metic a n d ge o metric) a n d as i n di vi d ual E R R (arit h metic 
a n d ge o metric). 
S u b gr o u p a nal yses will als o be c o n d ucte d b y  se verit y of i nfecti o n (li g ht vs. m o derate/ hea v y 
i nfecti o n stratificati o n fact or), c o u ntr y a n d ge n der. I n C o h ort 4, s u b gr o u p a nal ys es will als o be 
d o ne b y  specif ic a ge gr o u ps (e. g., 3 m o nt hs t o 2 4 m o nt hs
of a ge, 2 t o < 4 ye ars of a ge, 
4 t o 6 ye ars of a ge).
Se nsiti vit y  anal ys es ma y  be perf or me d o n t he I T T p o p ulati o n of C o h ort 1, t o deter mi ne t he 
i m pact of partici pa nts re q uiri n g malaria treat me nt, a n d o n t he P P p o p ulati o n of C o h ort 1, t o 
assess t he i m pact of a n y pr ot oc ol de viati o ns (s uc h as c o m pleti n g st u d y as sess me nts o utsi de t he 
D a y  1 7 t o 2 1 wi n d o w).
A nal y sis of C o h ort 3 will be a p o ole d a nal ys is, i ncl u di n g t he mI T T p o p ulati o n fr o m t his st u d y 
a n d t he mI T T p o p ulati o n f or partici pa nts 3 t o 2 4 m o nt hs 
of a ge i n t he P hase II st u d y 
M S 2 0 0 6 6 1 - 0 0 0 5 ( C o h orts 8 a n d 9). A l o gistic re gressi o n m o del wit h a dj ust me nt f or st u d y an d 
site varia bilit y will be use d t o esti mate c ure rate.
A nal y sis of C o h ort 4 will be perf or me d o nl y o n t he mI T T p o p ulati o n a n d usi n g t he sa me 
met h o ds as f or C o h ort 1.
I m p utati o n will be nee de d f or part ici pa nts i n t he mI T T A nal ys is Set b ut n ot i n t he P P A nal ys is 
Set. F or c o nti n u o us e n d p oi nts, t he i m p utati o n met h o d of last o bser vati o n carrie d f or war d will be 
use d f or missi n g data at t he p ost baseli ne meas ure me nt. F or bi nar y  en d p oi nts, t he i m p utati o n 
met h o d of w orst case will be use d f or missi n g data at t he p ost baseli ne meas ure me nt. T he 
baseli ne e g g c o u nt f or partici pa nts wit h missi n g f oll o w- u p e g g c o u nt will be carrie d f or war d f or 
b ot h E R R a n d c ure rate calc ulati o ns, s uc h t hat t hese partici pa nts will be c o nsi dere d “ n o c ha n ge” 
a n d “ n ot c ure d”, res pecti vel y, f or p ur p oses of t he efficac y anal y sis. T his is e q ui vale nt t o t he 
“ missi n g = n o n-res p o n der ” a p pr oac h. F or t he 6 0 m g/ k g d ose gr o u p i n C o h ort 4, if e g g c o u nt at 
E xte n de d F oll o w -u p is missi n g, e g g c o u nt fr om E n d of St u d y  visit will be carrie d f or war d f or 
c ure rate a n d E R R calc ulati o n i n t he a nalys es wit h i m p utati o n .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
6 8 /9 3
Se nsiti vit y  anal ys es will be perf or me d t o u n dersta n d t he i m pact of missi n g data o n t he pri mar y 
a n d sec o n dar y e n d p oi nts.
Effic ac y E n d p oi nt
St ati stic al A n al ysis Met h o ds
Pri mar y
C ure rate as assesse d b y t he Kat o -Katz met h o d f or C o h ort 1
Sec o n dar y
C ure rate as assesse d b y t he Kat o -Katz met h o d f or C o h orts 2 a n d 3.
C ure rate as assesse d b y t he P O C - C C A met h o d f or C o h orts 1, 2, a n d 3. 
C ure rate as deter mi ne d b y  uri ne filtrati o n tec h ni q ue f or C o h ort 4. 
E R R fr o m pretreat me nt t o 17 t o 2 1 da y s after treat me nt usi n g 
Kat o -Katz met h o d f or C o h orts 1, 2 , a n d 3.
E R R s fr o m pretreat me nt t o 17 t o 2 1 da y s a n d 3 5 t o 4 0 da y s after 
treat me nt usi n g uri ne filtrati o n tec h ni q ue f or C o h ort 4.
9. 4. 2
S afet y A n al yses
All safet y anal ys es will be perf or me d o n t he Safet y  Anal ys is Set, w hic h will i ncl u de all 
partici pa nts w h o recei ve a d ose of st u d y treat me nt. Partici pa nts will be a nal yze d acc or di n g t o t he 
act ual treat me nt t he y recei ve.
Val ues f or all safety varia bles will be liste d b y  su bject a n d ti me p oi nt. Safet y varia bles will be 
s u m marize d usi n g descri pti ve statistics b y c o h ort a n d b y  treat me nt gr o u p (f or C o h ort 1).
A Es will be c o de d b y  the Me dical Dicti o nar y  for Re g ulat or y  Acti vities ( Me d D R A) preferre d 
ter ms, a n d all s u m mar y ta bles f or A Es will be or ga nize d b y  these cate g ories. Fre q ue nc y  co u nts 
a n d perce nta ges will be prese nte d f or s u bjects wit h at least 1 T E A E wit hi n eac h S y ste m Or ga n 
Class (S O C ) a n d preferre d ter m, se parate d b y  treat me nt gr o u p a n d c o h ort. T E A Es will als o be 
s u m marize d b y  relati o ns hi p t o treat me nt a n d b y  se verit y wit hi n eac h c o h ort a n d treat me nt gr o u p 
(f or C o h ort 1).
B y -patie nt listi n gs of cli nical la b orat or y data a n d vital si g ns will i ncl u de i n dicati o ns of val ues 
t hat are o utsi de t he refere nce ra n ges, a n d val ues t hat are cli nicall y si g nifica nt. Ta bles descri bi n g 
o ut- of- refere nce ra n ge s hifts will be pr o vi de d f or cli nical la b orat or y test res ults a n d vital si g ns as 
a p pr o priate a n d b y treat me nt ar m.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
6 9 /9 3
9. 4. 3
Ot her A n al yses
De m o gra p hic data i ncl u di n g a ge, ge n der, hei g ht, me dical hist or y  an d pre vi o us me dicati o n will 
be pr o vi de d i n b y- patie nt listi n gs a n d s u m marize d b y  c o h ort a n d treat me nt gr o u p (f or C o h ort 1).
P K p ara meters a n d calc ulati o ns ha ve bee n detaile d i n Secti o n 8. 5 . P K a nal ys is will als o be 
s pecifie d i n t he I nte grate d A nal ysis Pla n t hat will be fi nalize d bef ore data base l oc k.
Esti mati o n of I n di vi d ual P K Para meters:

P har mac o ki netic para meters will be calc ulate d b y  the P K/ P D Data Pr ocessi n g Gr o u p of Q P, 
Merc k, Dar msta dt, Ger ma n y , or b y  a C o ntract Researc h Or ga nizati o n (C R O ) selecte d b y  the 
S p o ns or, usi n g sta n dar d n o n- c om part me ntal met h o ds a n d t he act ual a d mi nistere d d ose. P K 
para meters will be calc ulate d usi n g t he act ual ela pse d ti me si nce d osi n g, gi ve n wit h a 
precisi o n of 1 4 si g nifica nt di gits or t he S A S f or mat Best 1 2.  W he n t he act ual sa m pli n g ti me is 
missi n g, calc ulat i o ns will be perf or me d usi n g t he sc he d ule d ti me. Ot her wise, t here will be n o 
f urt her i m p utati o n of missi n g data. T he act ual c ollecti o n i nter vals will be use d i n t he 
calc ulati o n of uri ne a n d fecal para meters. 

N o n -c o m part me ntal c o m p utati o n of p har mac o ki neti c para meters will be perf or me d usi n g t he 
c o m p uter pr o gra m P h oe ni x ® Wi n N o nli n ® 
versi o n 6. 3, or hi g her ( Certara, L. P., 1 6 9 9 S 
Ha nle y  R oa d, St Lo uis, M O 6 3 1 4 4, U S A). 

T he statistical s oft ware S A S ® ( Statistical A nal ysis S y ste m, S A S -I nstit ute, Car y  NC, U S A, 
wi n d o ws versi o n 9. 1 or hi g her) m a y  be use d t o pr o d uce ta bles, listi n gs a n d fi g ures a n d i n t he 
calc ulati o n of P K para meters if a p pr o priate.
N o ot her a nal ys es are pla n ne d. 
9. 4. 4
Se q ue nce of A n al yses
A n I D M C will e val uate t he i nteri m efficac y an d safety res ults after 3 0 partici pa nts are e nr olle d 
a n d treate d i n C o h ort 4, i n or der t o deter mi ne w het her t here is a nee d t o i ncrease t he d ose of 
L -P Z Q O D T t o 6 0 m g / kg i n t his C o h ort. T he I D M C will als o re vie w t he safety data f or all 
patie nts w h o ha ve bee n treate d wit h L -P Z Q O D Ts t hat are a vaila ble at t hat ti me, a n d all efficac y 
a n d safet y data of all c o h orts at t he e n d of t he st u d y.
A n i nteri m a nal ys is f or efficac y wit h o ut pa usi n g t he st u d y is pla n ne d w he n t he first 3 0 s u bjects 
i n C o h ort 4 treate d wit h 6 0 m g/ k g of L- P Z Q O D T ha ve c o m plete d all assess me nts. T he res ults 
will be a vaila ble o nl y  to t he i nter nal cli nical tea m n ot directl y i n v ol ve d i n t he st u d y t o i nf or m 
ot her st u dies i n t he P Z Q cli nical pr o gra m, e. g. w het her a n ot her cli nical trial is necessar y t o 
e val uate t he effica c y of L- P Z Q
O D T
o n S. hae mat o bi u m i nfecte d c hil dre n. N o acti o n t o t his 
o n g oi n g st u d y is pla n ne d s u bse q ue nt t o t he i nteri m a nal ysis.
N o h y p ot hesis testi n g is pla n ne d, s o n o T y pe I err or c o ntr ol is necessar y . 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
7 0 /9 3
1 0
Refere nces 
1 Z wa n g J a n d Olliar o P L . Cli nical Efficac y  an d T olera bilit y  of Prazi q ua ntel f or I ntesti nal a n d 
Uri nar y  Sc hist os o miasis — A 
Meta -a nal ys is of C o m parati ve a n d N o n -c o m parati ve Cli nical 
Trials. P L o S Ne gl Tr o p Dis. 2 0 1 4; 8( 1 1):e 3 2 8 6. 
2 R oss A G, Vic kers D, Ol ds G R, et al. Kata y a m s yn d r o me. La ncet I nfect Dis. 2 0 0 7 ; 7: 2 1 8 - 2 4.
3 M o ntres or A a n d Gar ba A. Treat me nt of presc h o ol c hil dre n f or sc hist os o miasis. La n cet Gl o b 
Healt h. 2 0 1 7; 5: 6 4 0 - 4 1.
4
C o uli bal y
JT,
Pa nic
G,
Sil ué
K D,
et al . Efficac y
a n d
safet y of prazi q ua ntel
i n
presc h o ol -a ge d a n d sc h o ol-a ge d c hil dre n i nfecte d wit h
Sc hist os o ma ma ns o ni:
a ra n d o mise d 
c o ntr olle d, 
parallel- gr o u p ,  
d ose-ra n gi n g,  
P hase 
II
trial.
La n cet
Gl o b 
H e a l t h . 2 0 1 7; 5:e 6 8 8-e 9 8.
5 Da vis S M, Wie ga n d R., M ula ma F, et al. M or bi dit y  ass ociate d wit h sc hist os o miasis bef ore a n d 
after treat me nt i n yo u n g c hil dre n i n 8R usi n ga Isla n d, wester n Ke n ya. A m J Tr o p Me d H yg. 2 0 1 5: 
9 2 ( 5): 9 5 2 – 8.
6 Li u R, D o n g H F, G u o Y, et al. Efficac y of prazi q ua ntel a n d arte misi ni n deri vati ves f or t he 
treat me nt a n d pre ve nti o n of h u ma n sc hist os o miasis: a s yste matic re vie w a n d meta -a nal ysis. 
Parasit Vect ors. 2 0 1 1; 4: 2 0 1.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
7 1 /9 3
1 1
A p pe n dices
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
7 2 /9 3
1 2
A p pe n di x 1
A b bre vi ati o ns 
A E
A d verse E ve nt
B A
Bi oa vaila bilit y
B P
Bl o o d press ure
C C A
Circ ulati n g Cat h o dic A nti ge n
CI
C o nfi de nce I nter val
CI O M S
C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical Scie nces
C R F
Case Re p ort F or m
C R O
C o ntract Researc h Or ga nizati o n
D- P Z Q
De xtr or otat or y  e na nti o mer of prazi q ua ntel
D T
Dis persi ble ta blet
e C R F
Electr o nic Case Re p ort F or m
e p g
E g g c o u nt per gra m ( of st o ol)
E R R
E g g Re d ucti o n Rate
E U 
E ur o pea n U ni o n
F D A
F o o d a n d Dr u g A d mi nistrati o n
G C P
G o o d Cli nical Practice
I B
I n vesti gat or’s Br oc h ure
I CF 
I n f or me d C o nse nt F or m
I C H
I nter nati o nal C o u ncil f or Har m o nizati o n
I D M C
I n de pe n de nt data m o nit ori n g c o m mittee
I E C
I n de pe n de nt Et hics C o m mittee
I RB
I nstit uti o nal Re vie w B oar d
I T T
I nte nti o n-t o-Treat
K E M RI
Ke n ya Me dical Researc h I nstit ute
L- P Z Q
Le v or otat or y  e na nti o mer of prazi q ua ntel
mI T T
M o difie d I nte nti o n -t o-Treat
O D T
Or o dis persi ble Ta blet
P K
P har mac o ki netics
P O C -C C A
P oi nt - of-Care Circ ulati n g Cat h o dic A nti ge n
P P
Per Pr ot oc ol
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
7 3 /9 3
P S A C
Pre sc h o ol a ge c hil dre n
P Z Q
Prazi q ua ntel
Rac -P Z Q
Race m ic prazi q ua ntel
S A E
Seri o us A d verse E ve nt
S S A
S u b -Sa hara n Africa
S U S A R
S us pecte d U ne x pecte d Seri o us A d verse Reacti o ns
T E A Es
Treat me nt -E mer ge nt A d verse E ve nts
V A S
Vis ual A nal o g ue Scale
W H O
W orl d Healt h Or ga nizati o n
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
7 4 /9 3
A p pe n di x 2
St u d y G o ver n a nce
Fi n a nci al Discl os ure
A fi na ncial discl os ure f or m will be si g ne d b y  all i n vesti gat ors pri or t o st u d y start a n d o ne ye ar 
after c o m pleti o n of t he st u d y.
I nf or me d C o nse nt Pr ocess
Pre scree ni n g c o nse nt
Pri or t o perf or mi n g a n y st u d y assess me nts t hat are n ot part of r o uti ne me dical care f or t he 
partici pa nt, t he I n vesti gat or or a n a p pr o priate desi g nee (if l ocal re g ulati o ns per mit) will o btai n 
writte n 
pre scree ni n g c o nse nt fr o m o ne of t he pare nts or a g uar dia n/ le gall y aut h orize d
re presentati ve of t he partici pa nt t o all o w t he dia g n os tic acti vities a n d t he i de ntificati o n of 
i nfecte d c hil dre n, as descri be d i n Secti o n  8. Partici pa nts will be i nf or me d t hat t heir partici pati o n 
i n t he pre scree ni n g acti vities is v ol u ntar y.
I nf or me d c o nse nt
Sc hist os o me -p ositi ve partici pa nts after pre scree ni n g assess me nt, t o get her wit h o ne of t heir 
pare nts or g uar dia n /le gall y aut h orize d re prese ntati ves, will be i n vite d t o t he st u d y hos pital, f or 
t he c o m pleti o n of t he st u d y pr oce d ures.
A n u nc o n diti o nal prere q uisite f or eac h partici pa nt pri or t o partici pati o n i n t he st u d y is writte n 
i nf or me d c o nse nt, w hic h m ust be gi ve n bef ore a n y st u d y-relate d acti vities are carrie d o ut. 
Writte n i nf or me d c o nse nt will be pr o vi de d b y  eit her o ne of t he partici pa nt’s pare nts or o ne of 
his/ her g uar dia n/ le gall y aut h orize d re prese ntati ve. If per mitte d b y  nati o nal re g ulati o ns, a pers o n 
ot her t ha n t he I nvesti gat or ( desi gnee) m a y  inf or m t he partici pa nt’s pare nt or g uar dia n/ le gall y 
a ut h orize d re prese ntati ve a b o ut t he st u d y a n d si g n t he Inf or me d C o nse nt F or m, as a b o ve.
A partici pa nt i nf or mati o n s heet will be pre pare d i n t he l ocal la n g ua ges, Fre nc h, Kis wa hili a n d 
D h ol u o, i n acc or da nce wit h I CH G C P , a n d will be pr o vi de d b y  the S p o ns or f or t he p ur p ose of 
o btai ni n g pre scree ni n g c o nse nt a n d i nf or me d c o nse nt/asse nt. 

T he I n vesti gat or or his/ her re prese ntati ve will e x plai n t he nat ure of t he st u d y to t he 
partici pa nt a n d his/ her pare nt/ g uar dia n/ le gally a ut h orize d re prese ntati ve a n d a ns wer all 
q uesti o ns o n t he st u d y, usi n g la n g ua ge c h ose n s o t hat t he i nf or mati o n ca n be f ull y  a n d rea dily 
u n derst o o d b y  l a ypers o ns. 

T he partici pa nt’s pare nt (s) or g uar dia n/ le gall y aut h orize d
re prese ntati ve will be gi ve n 
s ufficie nt ti me t o rea d t he i nf or mati o n a n d t he o p p ort u nit y  to as k q uesti o ns a n d t o re q uest 
a d diti o nal i nf or mati o n a n d clarificati o n. 

Partici pa nts m ust be i nf or me d t hat t heir partici pati o n is v ol u ntar y

After t he i nf or mati o n is pr o vi de d b y  the I n vesti gat or or a n a p pr o priate desi g nee, o ne or b ot h 
(acc or di n g t o c o u ntr y specific et hic re q uire me nts) of t he partici pa nts’ pare nts or his/ her 
g uar dia n/ le gally- a ut h orize d re prese ntati ve will be re q uire d t o si g n a n d date a state me nt of 
i nf or me d c o nse nt t hat meets t he re q uire me nts of l ocal re g ulati o ns; I CH g ui deli nes a n d t he 
I RB/I E C.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
7 5 /9 3

T he me dical rec or d m ust i ncl u de a state me nt t hat writte n i nf or me d c o nse nt was o btai ne d 
bef ore t he partici 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 orize 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 C F. 

If t he partici pa nt’s pare nt (s) or his/ her g uar dia n/ le gall y aut h orize d re prese ntati ve is (are)
illiterate, a n i m partial wit ness m ust be prese nt d uri n g t he i nf or matio n sessi o n. T he wit ness 
will e x plai n t o t he pare nt or g uar dia n /le gall y aut h orize d re prese ntati ve t he i nf or mati o n 
c o ntai ne d i n t he writte n d oc u me nt a n d as k t o gi ve ver bal c o nse nt t o ha ve his/ her c hil d 
partici pati n g i n t he st u d y. C o nse nt of t he partici pa nt’s pare nt or g uar dia n /le gall y aut h orize d
re prese ntati ve will be c o nfir me d b y  his/ her fi n ger pri nt o n t he f or m; t he wit ness will si g n a n d 
date t he f or m.

F or c hil dre n u n der g oi n g P K a nal ys is, i nf or mati o n c o ncer ni n g t he necessit y  of f urt her bl o o d 
dra wi n g will be pr o vi de d b y  t he i n vesti gat or a n d a n a d diti o nal I CF will be si g ne d. 

T he ori gi nal si g ne d a n d date d declarati o n of i nf or me d c o nse nt will 
re mai n at t he 
I n vesti gat or’s site a n d m ust be safel y arc hi ve d s o t hat it ca n be retrie ve d at a n y ti me f or 
m o nit ori n g, a u diti n g a n d i ns pecti o n p ur p oses. 

A c o p y of t he si g ne d a n d date d i nf or mati o n a n d I CF(s) s h o ul d be pr o vi de d t o o ne of t he 
partici pa nt’s pare nts or his/ her
g uar dia n/ le gall y aut h orize d
re prese ntati ves pri or t o 
partici pati o n. 

If t he I CF is u p date d d uri n g t heir partici pati o n i n t he st u d y, partici pa nts m ust be re c o nse nte d 
t o t he m ost c urre nt, a p pr o ve d versi o n.
I n case a partici pa nt is n ot eli gi ble at t he pre scree ni n g acti vities (“pre scree ni n g fail ure”) a n d is
pre scree ne d a gai n later, S ecti o n 5. 4 descri bes t he pr oce d ures t o be re peate d.
I n case a Sc hist os o ma -p ositi ve c hil d is n ot eli gi ble at t he scree ni n g acti vities (“scree ni n g 
fail ure”), he/s he ca n be re assesse d, at i n vesti gat or discreti o n. If t he reassess me nt is perf or me d 
later t ha n 7 da y s after t he i nitial scree ni n g visit , a ne w I CF s h o ul d be o btai ne d . If t he i nter val 
fr o m t he i nitial pre scree ni n g c o nse nt t o t he pr o p ose d St u d y  inter ve nti o n d osi n g is greater t ha n
2 8 d a y s, t he n b ot h I CFs nee d t o be o btai ne d a gai n: b ot h pre scree ni n g a n d scree ni n g acti vities 
ha ve t o be re peate d, a n d a ne w partici pa nt n u m ber h as t o be assi g ne d .
D at a Pr otecti o n
T he o btai ne d data will be ha n dle d strictly c o nfi de ntiall y. F or eac h partici pa nt, ori gi nal me dical 
data will be accessi ble f or t he p ur p oses of s o urce data verificati o n b y  the M o nit or, a u dits a n d 
re g ulat or y ins pecti o ns, b ut patie nt c o nfi de ntialit y will be strictl y mai ntai ne d. Pers o nal data will 
be a n o n y m ize d f or data a nal ys is. N o na mes will be p u blis he d at a n y ti me a n d p u blis he d re p orts 
will n ot all o w f or i de ntificati o n of si n gle partici pa nts. A n o n y mize d bl o o d sa m ples will b e se nt t o 
 f or P K a nal ysis. 
. C o nfi de ntialit y  an d 
a n o n ymit y  will be e ns ure d t hr o u g h o ut t he e ntire researc h pr oject.
•
T he I nvesti gat or will assi g n a u ni q ue i de ntifier t o partici pa nts after o btai ni n g t heir 
i nf or me d c o nse nt. T his n u m ber will ser ve as t he partici pa nt’s i de ntifier i n t he st u d y as well as i n 
t he cli nical st u d y data base. All partici pa nt rec or ds or datasets tra nsferre d t o t he S p o ns or will 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI
P P D

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
7 6 /9 3
c o ntai n t he i de ntifier o nl y ; partici pa nt na mes or a n y i de ntifia ble i nf or mati o n will n ot be 
tra nsferre d.
O nl y  the I n vesti gat or or desi g nee will be a ble t o li n k st u d y data t o a n i n di vi d ual partici pa nt via 
a n i de ntificati o n list ke pt at t he site. 
Data pr otecti o n a n d pri vac y  re g ulati o ns will be o bser ve d i n ca pt uri n g, f or war di n g, pr ocessi n g, 
a n d st ori n g partici pa nt data. 
•
T he S p o ns or m ust i nf or m partici pa nts t hat t heir pers o nal st u d y -relate d data will be use d per 
l ocal data pr otect i o n a n d pri vac y  la ws. T he le vel of discl os ure m ust als o be e x plai ne d t o t he 
partici pa nt’s pare nt or his/ her g uar dia n/ le gall y aut h orize d re prese ntati ve, w h o will be re q ueste d 
t o gi ve c o nse nt o n data ha n dli n g pr oce d ures i n acc or da nce wit h nati o nal re g ulati o ns.
•
T he partici pa nt m ust be i nf or me d t hat his/ her me dical rec or ds m a y  be e xa mi ne d b y  
Cli nical Q ualit y  Ass ura nce a u dit ors or ot her S p o ns or -a p p oi nte d, a ut h orize d pers o n nel, b y  
a p pr o priate I RB/I E C me m bers, a n d b y  re g ulat or y aut h orit y i ns pect ors. All s uc h per s o ns will 
strictl y mai ntai n partici pa nts’ c o nfi de ntiality.
St u d y A d mi nistr ati ve
T he st u d y will be c o n d ucte d i n 2 ce nters: 

t he h os pital of Ma n, I v or y C oast

t he H o ma Ba y  H os pital, Ke n ya.
T he Pri nci pal I n vesti gat ors liste d o n t he title pa ge,
 
 
re prese nt all I n vesti gat ors f or decisi o ns a n d disc ussi o ns o n t his st u d y, 
per I C H G C P. T he Pri nci pal I n vesti gat ors will pr o vi de e x pert me dical i n p ut a n d a d vice o n t he 
st u d y desi g n a n d e xec uti o n a n d is res p o nsi ble f or t he re vie w a n d si g n-off of t he cli nical st u d y 
re p ort. 
T he st u d y will a p pear i n t he f oll o wi n g cli nical st u dies re gistries: cli nicaltrials. g o v a n d Pa n 
Africa n Cli nical Trials Re gistr y  ( P A C T R). 
T his cli nical st u d y will be s p o ns ore d b y:
Merc k K Ga A
Fra n kf urter Strasse 2 5 0
6 4 2 9 3 Dar msta dt, Ger ma n y .
T he S p o ns or will e nlist t he s u p p ort of t he f oll o wi n g C R O: 
Data Ma na ge me nt ser vice will be pr o vi de d b y
Tricli ni u m Cli nical De vel o p me nt ( Pt y ) Lt d
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
P P D
P P D
C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
7 7 /9 3
Details of str uct ures a n d ass ociate d pr oce d ures will be defi ne d i n a se parate Ma n ual 
of 
O perati o ns, w hic h will be pre pare d u n der t he s u p er visi o n of t he Cli nical Trial Lea der.
T he st u d y inter ve nti o ns a d mi nistere d i n t his st u d y ( L-P Z Q O D T a n d t he c o m mercial refere nce 
pr o d uct , Biltrici de) will be s u p plie d a n d distri b ute d b y  t he S p o ns or or desi g nee.
A n I D M C will be c har ge d wit h re vie wi n g efficac y an d safet y data of t he first 3 0 partici pa nts of 
C o h ort 4 a n d t he a vaila ble safet y data f or all patie nts w h o ha ve bee n treate d wit h L- P Z Q O D Ts 
u p t o t hat ti me. I n a d diti o n, it will re vie w safet y a n d efficac y data f or all c o h orts at t he e n d of t he 
st u d y. T he I DM C 
will be c haire d b y  a pers o n wit h e x perie nce i n cli nical st u d ys a n d wit h 
partici pati o n i n I D M Cs. I D M C me m bers hi p will c o m prise at least a cli nicia n wit h e x pertise i n 
sc hist os o miasis, a pe diatricia n a n d a bi ostatisticia n.
F urt her details o n t he I DM C c o m p ositi o n, pr ocesses a n d decisi o n criteria will be pr o vi de d i n t he 
I D M C c harter t hat will be a vaila ble bef ore t he start of e nr oll me nt.
T he S p o ns or’s Gl o bal Patie nt Safet y de part me nt, or its desi g nate d re prese ntati ves, will s u per vise 
dr u g safety a nd t he ti meli ne f or re p orti n g of A Es a n d S A Es t o all c o ncer ne d parties i n 
acc or da nce wit h t he a p plica ble g ui deli nes, la ws, a n d re g ulati o ns.
Re g ul at or y a n d Et hic al C o nsi der ati o ns

T his st u d y  will be c o n d ucte d i n acc or da nce wit h t he pr ot oc ol a n d t he f oll o wi n g:

C o nse ns us et hical pri nci ples deri ve d fr o m i nter nati o nal g ui deli nes, i ncl u di n g t he 
Declarati o n 
of Helsi n ki 
a n d C o u ncil f or I nter nati o nal Or ga nizati o ns 
of Me dical 
Scie nces ( CI O M S) I nter nati o nal Et hical G ui deli nes

A p plica ble I C H G o o d Cli nical Practice ( G C P) G ui deli nes

A p plica ble la ws a n d re g ulati o ns

T he I n vesti gat or m ust s u b mit t he pr ot oc ol, pr ot oc ol a me n d me nts (if a p plica ble), I C F, 
I n vesti gat or Br oc h ure, a n d ot her rele va nt d oc u me nts (e. g., a d vertise me nts) t o a n IR B/I E C 
a n d t he I R B/I E C m ust re vie w a n d a p pr o ve t he m bef ore t he st u d y  is i nitiate d.

A n y  pr ot oc ol a me n d me nts (i.e., c ha n ges t o t he pr ot oc ol) will be d oc u me nte d i n writi n g 
a n d re q uire I R B/I E C a p pr o val bef ore i m ple me ntati o n of c ha n ges, e xce pt f or c ha n ges 
necessar y  to eli mi nate a n i m me diate hazar d t o st u d y partici pa nts. W he n 
a p plica ble, 
a me n d me nts will be s u b mitte d t o t he a p pr o priate Healt h A ut h orities.

T he I n vesti gat or will be res p o nsi ble f or t he f oll o wi n g:

Pr o vi di n g writte n s u m maries of t he stat us of t he st u d y to t he I RB/I E C a n n uall y or m ore 
fre q ue ntly per t he I R B’s/I E C’s re q uire me nts, p olicies, a n d pr oce d ures.

N otif y i n g t he I R B/I E C of S A Es or ot her si g nifica nt safety fi n di n gs, as re q uire d b y  
I RB/I E C pr oce d ures

Pr o vi di n g o versi g ht of t he st u d y co n d uct at t he site a n d a d here nce t o re q uire me nts of 2 1 
C F R, I CH g ui deli nes, t he I RB/I E C, E ur o pea n re g ulati o n 5 3 6/ 2 0 1 4 f or cli nical st u dies 
(if a p plica ble), a n d all ot her a p plica ble l ocal re g ulati o ns
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
7 8 /9 3

T he pr ot oc ol a n d a n y a p plica ble d oc u me ntati o n wil l be s u b mitte d or n otifie d t o t he 
Healt h A ut h orities i n acc or da nce wit h all l ocal a n d nati o nal re g ulati o ns f or eac h site.
I nci de nt al fi n di n gs

T he pr oce d ure t o be f oll o we d i n case of a n y i nci de ntal fi n di n gs will be descri be d i n t he 
pr oject ma na ge me nt pla n.
E mer ge nc y Me dic al S u p p ort

T he S p o ns or or desi g nee will pr o vi de E mer ge nc y Me dical S u p p ort car ds t o partici pa nts 
f or use d uri n g t he st u d y. T hese pr o vi de t he mea ns f or partici pa nts t o i de ntif y the msel ves 
as partici pati n g i n a cli nical st u d y. Als o, t hese gi ve healt h care pr o vi ders access t o a n y 
i nf or mati o n a b o ut t his partici pati o n t hat m a y  be nee de d t o deter mi ne t he c o urse of 
me dical 
treat me nt f or t he partici pa nt. T he i nf or mati o n o n t he E mer ge nc y  
Me dical 
S u p p ort car d ma y  i ncl u de t he pr ocess f or e mer ge nc y u n bli ndi n g (if a p plica ble).

T he first p oi nt of c o ntact f or all e mer ge ncies will be t he cli nical st u d y In vesti gat or cari n g 
f or t he partici pa nt. C o nse q ue ntl y, t h e I n vesti gat or a grees t o pr o vi de his or her e mer ge nc y 
c o ntact i nf or mati o n o n t he car d. If t he I nvesti ga t or is a vaila ble w he n a n e ve nt occ urs, 
t he y will a ns wer a n y q uesti o ns. A n y  su bse q ue nt acti o n (e. g., u n bli n di n g) will f oll o w t he 
sta n dar d pr ocess esta blis he d f or I n vesti gat ors.

W he n t he I nvesti gat or is n ot a vaila ble, t he S p o ns or pr o vi des t he a p pr o priate mea ns t o 
c o ntact a S p o ns or p h y sicia n. T his i ncl u des pr o visi o n of a 2 4- h o ur c o ntact n u m ber at a 
call ce nter, w here b y t he healt h care pr o vi ders will be gi ve n access t o t he a p pr o priate 
S p o ns or p h y sicia n t o assist wit h t he me dical e mer ge nc y an d t o pr o vi de s u p port f or t he 
p ote ntial u n bli n di n g of t he partici pa nt c o ncer ne d.
Cli nic al St u d y I ns ur a nce a n d C o m pe ns ati o n t o P artici p a nts
I ns ura nce c o vera ge will be pr o vi de d f or eac h c o u ntr y partici pati n g i n t he st u d y. I ns ura nce 
c o n diti o ns s hall meet g o o d l ocal sta n dar ds, as a p plica ble.
O ne of t he pare nts or g uar dia n /le gall y aut h orize d re prese ntati ves of t he c hil dre n partici pati n g i n 
t he st u d y will be c o m pe nsate d. T he c o m pe nsati o n will i ncl u de rei m b urse me nt of tra ns p ort 
t o/fr o m t he h os pital, f o o d d uri n g t he h os pital visits a n d a m o netar y  co m pe nsati o n f or t he i nc o me 
l oss d ue t o t he visits t o t he h os pital. Pri or t o t heir i m ple me ntati o n, t he details of t he pr o p ose d 
c o m pe nsati o n will be re vie we d b y t he a p plica ble I E C/I R B.
Cli nic al St u d y Re p ort
After st u d y co m pleti o n, t he S p o ns or or dele gate will write a cli nical st u d y re p ort i n c o ns ultati o n 
wit h t he C o or di nati n g I n vesti gat ors f oll o wi n g t he g ui da nce i n I C H T o pic E 3.
P u blic ati o n
T he res ults of t his st u d y ma y b e pu blis he d or prese nte d at scie ntific meeti n gs. If t his is f oresee n, 
t he I n vesti gat or a grees t o s u b mit all ma n uscri pts or a bstracts t o t he S p o ns or bef ore s u b missi o n. 
T his all o ws Merc k t o pr otect pr o prietar y  i nf or mati o n a n d t o pr o vi de c o m me nts. 
T he S p o ns or will c o m pl y wit h t he re q uire me nts f or p u blicati o n of st u d y res ults. Per sta n dar d 
e dit orial a n d et hical practice, t he S p o ns or will ge nerall y s u p p ort p u blicati o n of m ultice nter 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
7 9 /9 3
st u dies o nl y  in t heir e ntiret y an d n ot as i n di vid ual site data. I n t his case, a c o or di nati n g 
I n vesti gat or will be desi g nate d by a gree me nt.
A ut h ors hi p will be deter mi ne d b y  agree me nt a n d i n li ne wit h I nter nati o nal C o m mittee of 
Me dical J o ur nal E dit ors a ut h ors hi p re q uire me nts.
T he first p u blicati o n will i ncl u de t he res ults of t he a nal ysis of t he pri mar y  en d p oi nt. T he 
I n vesti gat or will i nf or m t he S p o ns or i n a d va nce a b o ut a n y pla ns t o p u blis h or prese nt data fr o m 
t he st u d y. A n y  pu blicati o ns a n d prese ntati o ns of t he res ults (a bstracts i n j o ur nals or ne ws pa pers , 
oral prese ntati o ns, etc.), eit her i n w h ole or i n part, b y  In vesti gat ors or t heir re prese ntati ves will 
re q uire re vie w b y  the S p o ns or bef ore s u b missi o n. T he S p o ns or will n ot s u p press p u blicati o n b ut
mai ntai ns t he ri g ht t o dela y  p u blicati o n i n or der t o pr otect i ntellect ual pr o pert y ri g hts.
Disse mi n ati o n of Cli nic al St u d y D at a
T he st u d y res ults will be disse mi nate d acc or di n g t o Merc k’ s p olic y  a n d S O Ps . T he pr oce d ures 
f or p ubli cati o n pla n ni n g will als o f oll o w t he m ost rece nt rec o m me n dati o ns fr o m t he I nter nati onal 
C o m mittee of Me dical J o ur nal E dit ors . 
T he s pecific st u d y i nf or mati o n a n d data will als o be discl ose d b y  the S p o ns or p u blicl y  by
re gisteri n g cli nical st u dies o n p u blicl y  accessi ble we b platf or ms s uc h as w w w.cli nicaltrials. g o v 
pri or t o, d uri n g a n d after t he c o m pleti o n of t he cli nical st u d y i n ma n ners c o nsiste nt wit h 
a p plica ble la ws a n d r ules g o ver ni n g pr otecti o n of patie nt pri vac y  an d i ntellect ual pr o pert y . I n 
a d diti o n, t he st u d y res ults will be ma de p u blicl y  availa ble b y  mea ns of a Cli nical St u d y Re p or t 
s yn o psis i n acc or da nce wit h pri vac y  le gislati o n a n d r ules. Ot her researc hers ca n, b y  foll o wi n g 
t he a p pr o priate Merc k 
K Ga A pr ocesses, gai n access t o t he data f or a d diti o nal a nal ys is or 
i nf or mati o n as part of E F PI A/ P h R M A c o m mit me nt t o Res p o nsi ble Data S har i n g. Merc k K Ga A 
o bser ves stri n ge nt data pr otecti o n r ules a n d as s uc h has i m ple me nte d a strict pr ocess w here b y 
e xter nal researc hers ma y a p pl y for access t o t he data. All details c o ncer ni n g o btai ni n g access t o 
t he cli nical st u d y data are a vaila ble o n a de dic ate d we b pa ge o n t he Merc k K Ga A we bsite: 
htt p:// bi o p har ma. merc k gr o u p.c o m/e n/researc h _ de vel o p me nt/cli nical _trials/c o m mit me nt _t o _res p
o nsi ble _cli nical _trial _ data _s hari n g/c o m mit me nt _t o _res p o nsi ble _cli nical _trial _ data _ 
s hari n g. ht ml.
D at a Q u alit y Ass ur a nce

All p artici pa nt st u d y data will be rec or de d o n electr o nic C R Fs
or tra ns mitte d t o t he 
S p o ns or or desi g nee electr o nicall y (e. g., la b orat or y data). T he I n vesti gat or is res p o nsi ble 
f or verif y i n g t hat data e ntries are c o m plete, acc urate, le gi ble, a n d ti mely b y  ph y sicall y or 
electr o nicall y si gni n g t he C R F. Details f or ma na gi n g C R Fs are i n t he St u d y  P r oce d ure
Ma n ual.

T he I n vesti gat or m ust mai ntai n acc urate d oc u me ntati o n (s o urce data) t hat s u p p orts t he 
i nf or mati o n i n t he C R F.

T he I n vesti gat or m ust per mit st u d y-relate d m o nit ori n g, q ualit y ass ura nce a u dits, I RB/I E C 
re vie w, a n d re g ulat or y age nc y  ins pecti o ns a n d pr o vi de direct access t o t he st u d y file a n d 
s o urce data.

T he S p o ns or or desi g nee is res p o nsi ble f or data ma na ge me nt of t his st u d y, i ncl u di n g 
q ualit y  chec ki n g of t he data a n d mai ntai ni n g a vali date d data base. Data base l oc k will occ ur 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
8 0 /9 3
o nce q ualit y  co ntr ol a n d q ualit y  ass ura nce pr oce d ures ha ve bee n c o m plete d. P D F files of 
t he C R Fs will be pr o vi de d t o t he In vesti gat ors at st u d y  c o m pleti o n. 

St u d y  m o nit ors will perf or m o ng oi n g o n -site a n d off-site s o urce data verificati o n at re g ular 
i nter vals acc or di n g t o t he m o nit ori n g pla n, t o c o nfir m t hat data i n t he e C R F are acc urate, 
c o m plete, a n d verifia ble; t hat t he safety a n d ri g hts of partici pa nts are bei n g pr otecte d; a n d 
t hat t he st u d y is bei n g c o n d ucte d per t he c urre ntl y ap pr o ve d pr ot oc ol a n d a n y ot her st u d y 
a gree me nts, IC H G C P, a n d all a p plica ble re g ulat or y  re q uire me nts.

U p o n i nitiati o n of t he st u d y, t he I n vesti gat or or desi g nee will be pr o vi de d wit h a n 
I n vesti gat or Site File c o ntai ni n g all necessar y  st u d y d oc u me nts, w hic h will be c o m plete d 
t hr o u g h o ut t he st u d y a n d u p date d as necessar y.

Rec or ds a n d d oc u me nts, i ncl u di n g si g ne d I CFs, pertai ni n g t o t he c o n d uct of t his st u d y 
m ust be retai ne d b y  th e I n vesti gat or f or 1 5 ye ars after st ud y  co m pleti o n, u nless l ocal 
re g ulati o ns, i nstit uti o nal p olicies, or t he S p o ns or re q uires a l o n ger rete nti o n. N o rec or ds 
ma y  be destr o ye d d uri n g t he rete nti o n peri o d wit h o ut t he S p o ns or’s writte n a p pr o val. N o 
rec or ds m a y  be tra nsferre d t o a n ot her l ocati o n o r part y wit h o ut t he S p o ns or’s writte n 
n otificati o n.

T he cli nical st u d y pr ot oc ol, eac h ste p of t he data ca pt ure pr oce d ure a n d t he ha n dli n g of t he 
data, i ncl u di n g t he fi nal cli nical st u d y re p ort, will be s u bject t o Q ualit y  Ass ura nce 
acti vities. A u dits ma y  be c o n d ucte d at a n y ti me d uri n g or after t he st u d y t o e ns ure t he 
vali dit y  an d i nte grit y  of t h e st u d y data. Re prese ntati ves of t he Q ualit y  Ass ura nce u nit fr o m 
t he S p o ns or or a desi g nate d or ga nizati o n, as well as Healt h A ut h orities, m ust be per mitte d 
t o access all st u d y d oc u me nts a n d ot her materials at t he site, i ncl u di n g t he I n vesti gat or Site 
File, t he c o m plete d C R Fs, all St u d y  Inter ve nti o n a n d St u d y  Inter ve nti o n acc o u nta bilit y 
rec or ds, a n d t he ori gi nal me dical rec or ds or files f or eac h partici pa nt .
S o urce D oc u me nts

S o urce d oc u me nts pr o vi de e vi de nce f or t he e xiste nce of t he partici pa nt a n d s u bsta ntiate t he 
i nte grity of t he data c ollecte d.

T he I n vesti gat or m ust kee p a pa per or electr o nic file ( me dical file a n d ori gi nal me dical 
rec or ds) at t he site f or eac h stu d y  partici pa nt. T he file m ust i de ntif y eac h partici pa nt, 
c o ntai n t he f oll o wi n g de m o gra p hic a n d me dical i nf or mati o n f or t he partici pa nt, a n d s h o ul d 
be as c o m plete as p ossi ble:

Partici pa nt’s f ull na me, date of birt h, se x, hei g ht, a n d wei g ht

Me dical hist or y  a n d c o nc o mita nt diseases

Pri or a n d c o nc o mita nt t hera pies (i ncl u di n g c ha n ges d uri n g t he st u d y )

St u d y  i de ntifier ( Scree ni n g n u m ber) a n d partici pa nt’s st u d y n u m ber (e nr oll me nt n u m ber 
or Ra n d o mizati o n n u m ber).

Dates of e ntr y int o t he st u d y (si g nat ure date o n the pre scree ni n g c o nse nt a n d t he 
i nf or me d c o nse nt) a n d eac h visit t o t he site

A n y  me dical e xa mi nati o ns a n d cli nical fi n di n gs pre defi ne d i n t he pr ot oc ol
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
8 1 /9 3

All A Es

Date t hat t he partici pa nt left t he st u d y, i ncl u di n g a n y reas o n f or earl y wit h dra wal fr o m 
t he st ud y  or st u d y i nter ve nti o n, if a p plica ble.

All s o urce data m ust be file d ( C T or M RI  sca n i ma ges, E C G rec or di n gs, a n d la b orat or y 
res ults a n d a n y ot her c o nc o mita nt pr oce d ure res ults c ollecte d d uri n g t he c o urse of t he 
st u d y an d f or t he f oll o w-u p of A Es). Eac h d oc u me nt m ust ha ve t he partici pa nt n u m ber a n d 
t he pr oce d ure date, i deall y, pri nte d b y  t he i nstr u me nt use d f or t he pr oce d ure. As necessar y, 
me dical e val uati o n of t hese rec or ds s h o ul d be perf or me d, d oc u me nte d, si g ne d a n d date d b y 
t he In vesti gat or. 

Data rec or de d o n pri nte d or electr o nic C R Fs t hat are tra nscri be d fr o m s o urce d oc u me nts 
m ust be c o nsiste nt wit h t he s o urce d oc u me nts or t he discre pa ncies m ust be e x plai ne d. T he 
I n vesti gat or m a y  nee d t o re q uest pre vi o us me dical rec or ds or tra nsfer rec or ds, de pe n di n g 
o n t he st u d y . Als o, c urre nt me dical rec or ds m ust be a vaila ble.

T he st u d y mo nit ors will use pri nt o uts of electr o nic files f or s o urce data verificati o n. T hese 
pri nt o uts m ust be si g ne d a n d date d b y  the I n vesti gat or or desi g nee a n d ke pt i n t he st u d y 
file.

S o urce d oc u me nts are st ore d at t he site f or t he l o n gest p ossi ble ti me per mitte d b y  the 
a p plica ble re g ulati o ns, a n d/ or as per I C H G C P g ui deli nes, w hic he ver is l o n ger. T he 
I n vesti gat or e ns ures t hat n o destr ucti o n of me dical rec or ds is perf or me d wit h o ut t he 
S p o ns or’s writte n a p pr o val.

Defi niti o n of w hat c o nstit utes s o urce data is f o u n d i n I C H G C P G ui deli ne E 6 C ha pter 1. 5 1.
St u d y a n d Site Cl os ure

T he S p o ns or reser ves t he ri g ht t o cl ose t he st u d y  site or ter mi nate t he st u d y at a n y ti me a n d 
f or a ny reas o n. St u d y sites will be cl ose d u p o n st u d y c o m pleti o n. A st u d y site is c o nsi dere d 
cl ose d w he n all re q uire d d oc u me nts a n d st u d y su p plies ha ve bee n c ollecte d a n d a site 
cl os ure visit has bee n c o m plete d.

T he I n vesti gat or m a y  initiate site cl os ure at a n y ti me, pr o vi de d t here is reas o na ble ca use 
a n d s ufficie nt n otice is gi ve n i n a d va nce of t he i nte n de d ter mi nati o n.

Reas o ns f or t he earl y cl os ure of a st u d y site b y t he S p o ns or or I n vesti gat or ma y  i ncl u de:

Fail ure of t he I n vesti gat or t o c o m pl y  wit h t he pr ot oc ol, t he re q uire me nts of t he IR B/I E C 
or l ocal healt h a ut h orities, t he S p o ns or's pr oce d ures, or G C P g ui deli nes

I na de q uate recr uit me nt of partici pa nts b y  t he I n vesti gat or

Disc o nti n uati o n of f urt her de vel o p me nt of t he S p o ns or’s c o m p o u n d
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
8 2 /9 3
A p pe n di x 3
A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, 
E v al u ati n g, F oll o w -u p, a n d Re p orti n g
Defi niti o ns
A d verse E ve nt
A n A E is a n y u nt o war d me dical occ urre nce i n a partici pa nt a d mi nistere d a p har mace utical 
pr o d uct, re gar dless of ca usal relati o ns hi p wit h t his treat me nt. T heref ore, a n A E ca n be a n y 
u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal la b orat or y fi n di n g), s ym pt o m, or 
disease te m p orally ass ociate d wit h t he use of a me dici nal 
pr o d uct, re gar dless if it is 
c o nsi dere d relate d t o t he me dici nal pr o d uct.
F or s ur gical or dia g n ostic pr oce d ures, t he c o n diti o n/ill ness lea di n g t o s uc h a pr oce d ure is 
c o nsi dere d as t he A E rat her t ha n t he pr oce d ure itself.
T he I n vesti gat or is re q uire d t o gra de t he se verit y or t o xicit y  of eac h A E.
I n vesti gat ors m ust assess t he se verit y of A Es per t he Q ualitati ve T o xicit y  Scale, as f oll o ws:
Mil d:
T he partici pa nt is a ware of t he e ve nt or s ym pt o m, b ut t he e ve nt or s ym pt o m is 
easil y t olerate d.
M o der ate:
T he partici pa nt e x perie nces s ufficie nt disc o mf ort t o i nterfere wit h or re d uce his 
or her us ual le vel of acti vit y .
Se vere:
Si g nifica nt i m pair me nt of f u ncti o ni n g: t he partici pa nt is u na ble t o carr y o ut his 
or her us ual acti vities.
E x pecte d si de effects f or t he differe nt researc h pr o d ucts are detaile d i n t he i n vesti gat or's 
br oc h ure a n d i n t he i nf or me d c o nse nt.
I n vesti gat ors m ust 
als o s yste matically assess t he ca usal relati o ns hi p of A Es 
t o st u dy 
i nter ve nti o n (i ncl u di n g a n y ot her n o n st u d y inter ve nti o ns, ra diati o n t hera p y, etc.) usi n g t he 
f oll o wi n g defi niti o ns. Decisi ve fact ors f or t he assess me nt of ca usal relati o ns hi p of a n A E t o 
t he st u d y inter ve nti o n i ncl u de, b ut ma y  not be li mite d t o, te m p oral relati o ns hi p bet wee n t he 
A E a n d t he st u d y inter ve nti o n, k n o w n si de effects of st u d y inter ve nti o n, me dical hist or y , 
c o nc o mita nt medicati o n, c o urse of t he u n derl yi n g disease, a n d st u d y  pr oce d ures.
U nrel ate d:
N ot reas o na bly relate d t o t he st u d y inter ve nti o n. A E c o ul d n ot me dicall y 
( p har mac ol o gically/ cli nicall y) be attri b ute d t o t he st u d y inter ve nti o n u n der 
st u d y in t his cli nical st u d y pr ot oc ol. A reas o na ble alter nati ve e x pla nati o n m ust 
be a vaila ble.
Rel ate d:
Reas o na bl y 
relate d t o t he st u d y inter ve nti o n. 
A E 
c o ul d 
me dicall y 
( p har mac ol o gically/ cli nicall y) be attri b ute d t o t he st u d y inter ve nti o n u n der 
st u d y i n t his cli nical st u d y pr ot oc ol. 
A b n or m al L a b or at or y Fi n di n gs a n d Ot her A b n or m al I n vesti g ati o n al Fi n di n gs
A b n or mal la b orat or y fi n di n gs a n d ot her a b n or mal i n vesti gati o nal fi n di n gs (e. g., o n a n E C G 
trace) s h o ul d n ot be re p orte d as A Es u nless t he y are ass ociate d wit h cli nical si g ns a n d 
s ym p t o ms, lea d t o st u d y i nter ve nti o n disc o nti n uati o n or are c o nsi dere d ot her wise me dicall y 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
8 3 /9 3
i m p orta nt b y  the I n vesti gat or. If a la b orat or y ab n or malit y  fulfills t hese criteria, t he i de ntifie d 
me dical c o n diti o n (e. g., a ne mia or i ncrease d A L T) m ust be re p orte d as t he A E rat her t ha n t he 
a b n or mal val ue itself.
Seri o us A d verse E ve nts
A n S A E is a n y  u nt o war d me dical occ urre nce t hat at a n y d ose:

Res ults i n deat h

Is life-t hreate ni n g. Life -t hreate ni n g refers t o a n e ve nt i n w hic h t he partici pa nt is at ris k of 
deat h at t he t i me of t he e ve nt, n ot a n e ve nt t hat h yp ot heticall y  mi g ht ha ve ca use d deat h if it 
was m ore se vere.

Re q uires i n patie nt h os pitalizati o n or pr ol o n gs a n e xisti n g h os pitalizati o n

Res ults i n persiste nt or si g nifica nt disa bilit y  or i nca pacity

Is a c o n ge nital a n o mal y or birt h defect

Is ot her wise c o nsi dere d t o be me dicall y  im p orta nt. I mp orta nt me dical e ve nts t hat ma y  not 
res ult i n deat h, be life-t hreate ni n g, or re q uire h os pitalizati o n ma y  be c o nsi dere d as S A Es 
w he n, base d u p o n a p pr o priate me dical j u d g me nt, t he y ma y je o par dize t he partici pa nt or 
ma y  re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d a b o ve. 
E xa m ples of s uc h e ve nts i ncl u de aller gic 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 nc y ro o m or at h o me, bl o o d d y scrasias or c o n v ulsi o ns t hat d o n ot res ult i n i n patie nt 
h os pitalizati o n, or t he de vel o p me nt of dr u g de pe n de nc y  or dr u g a b use.

F or t he p ur p oses of re p orti n g, a n y  s us pecte d tra ns missi o n of a n i nfecti o us a ge nt via a st u d y 
i nter ve nti o n is als o c o nsi dere d a n S A E, as s pecifie d bel o w f or re p orti n g S A Es.
E ve nts t h at D o N ot Meet t he Defi niti o n of a n S A E
Electi ve h os pitalizati o ns t o a d mi nister, or t o si m plif y st u d y inter ve nti o n or pr oce d ures 
(e. g., a n o ver ni g ht sta y to facilitate c he m ot hera p y a n d relate d h y drati o n t hera py a p plicati o n) 
are n ot c o nsi dere d S A Es. H o we ver, all e ve nts lea di n g t o u n pla n ne d h os pitalizati o ns or 
u n pla n ne d pr ol o n gati o n of a n electi ve h os pitalizati o n (i.e.,
u n desira ble effects of a n y 
a d mi nistere d treat me nt) m ust be d oc u me nte d a n d re p orte d as S A Es.
E ve nts N ot t o Be C o nsi dere d as A Es/ S A Es
Me dical 
c o n diti o ns prese nt at t he i nitial st u d y visit, t hat d o n ot w orse n i n se verit y or 
fre q ue nc y duri n g t he st u d y are defi ne d as Baseli ne Me dical C o n diti o ns a n d are n ot t o b e 
c o nsi dere d A Es. H o we ver, if a d verse si g ns or s ym p t o ms occ ur i n ass ociati o n wit h disease 
pr o gressi o n t he n t hese s h o ul d be rec or de d as A Es.
Pre -defi ne d A d verse E ve nts of S peci al I nterest f or S afet y M o nit ori n g
Healt h y p a rtici pa nts mi g ht 
e x perie nce diarr hea , na usea, v o miti n g, hea dac he, dizzi ness, 
i nfla m mati o n a n d a b d o mi nal pai n. T hese s ym pt o ms are al m ost al wa ys tra nsie nt a n d occ ur 
earl y d uri n g t hera p y initiati o n a n d s p o nta ne o usl y res ol ve i n m ost cases. If a n y of t hese A Es 
are o bser ve d, t heir se verit y sh o ul d be defi ne d base d o n cli nical j u d g me nt of t he I n vesti gat or 
a n d defi ne d acc or di n g t o t he Q ualitati ve T o xicit y  Scale as descri be d a b o ve.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
8 4 /9 3
Rec or di n g a n d F oll o w -U p of A E a n d/ or S A E
Fr o m scree ni n g visit t o E n d of St u d y , t he partici pa nt a n d t he pare nts or g uar dia n /le gally 
a ut h orize d re prese ntati ve will b e q uerie d o n c ha n ges i n his or her c o n diti o n. D uri n g t he 
re p orti n g peri o d, a n y u nfa v o ura ble c ha n ges i n t he partici pa nt’s c o n diti o n will be rec or de d as 
A Es, w het her re p orte d b y  t he partici pa nt or o bser ve d b y t he I n vesti gat or.
C o m plete, acc urate a n d c o nsistent data o n all A Es e x perie nce d f or t he d urati o n of t he 
re p orti n g peri o d ( defi ne d bel o w) will be re p orte d o n a n o n g oi n g basis i n t he a p pr o priate 
secti o n of t he C R F. All S A Es m ust be a d diti o nall y doc u me nte d a n d re p orte d usi n g t he 
a p pr o priate Seri o us A d verse E ve nt Re p ort F or m as descri be d i n t he f oll o wi n g secti o n.
It is i m p orta nt t hat eac h A E re p ort i ncl u de a descri pti o n of t he e ve nt, its d urati o n ( o nset a n d 
res ol uti o n dates a n d als o o nset a n d res ol uti o n ti mes, w he n it is i m p orta nt t o assess t he ti me of 
A E o ns et relati ve t o t he rec or de d st u d y inter ve nti o n a d mi nistrati o n ti me), its se verit y, its 
ca usal relati o ns hi p wit h t he st u d y inter ve nti o n, a n y ot her p ote ntial ca usal fact ors, a n y 
treat me nt gi ve n or ot her acti o n ta ke n, i ncl u di n g d ose m o dificati o n or disc o nti n u ati o n of t he 
st u d y inter ve nti o n, a n d its o utc o me. I n a d diti o n, seri o us cases s h o ul d be i de ntifie d, a n d t he 
a p pr o priate seri o us ness criteria d oc u me nte d. 
S pecific g ui da nce is i n t he C R F c o m pleti o n g ui deli ne pr o vi de d b y t he C R O.
A d verse E ve nt Re p orti n g Peri o d
T he A E re p orti n g peri o d f or safety s ur veilla nce be gi ns at scree ni n g visit, ( date of si g nat ure of 
i nf or me d c o nse nt) a n d c o nti n ues t hr o u g h t he st u d y’s p ost treat me nt f oll o w-u p peri o d u ntil t he 
E n d - of-St u d y v isit.
A n y  SA E assesse d as relate d t o a St u d y  Inte r ve nti o n m ust be re p orte d w he ne ver it occ urs, 
irres pecti ve of t he ti me ela pse d si nce t he last a d mi nistrati o n of t he St u d y  Inter ve nti o n .
Re p orti n g Seri o us A d verse E ve nts
I n t he e ve nt of a n y ne w S A E occ urri n g d uri n g t he re p orti n g peri o d, t he I nvesti gat or m us t 
i m me diatel y ( wit hi n a ma xi m u m of 2 4 H O U R S after bec o mi n g a ware of t he e ve nt) i nf or m t he 
S p o ns or or its desi g nee i n writi n g. All writte n re p orts s h o ul d be tra ns mitte d usi n g t he S A E 
Re p ort F or m, w hic h m ust be c o m plete d b y  the I n vesti gat or f oll o wi n g s pecific c o m pleti o n 
i nstr ucti o ns.
I n e xce pti o nal circ u msta nces, a n S A E ( or f oll o w- u p i nf or mati o n) ma y  be re p orte d b y  
tele p h o ne; i n t hese cases, a writte n re p ort m ust be se nt i m me diately t hereafter b y  fa x or 
e-mail. Na mes, a d dresses, a n d tele p h o ne a n d fa x n u m bers f or S A E re p orti n g will be i ncl u de d 
i n t he st u d y s pecific S A E Re p ort F or m. 
Rele va nt pa ges fr o m t he C R F ma y  be pr o vi de d i n parallel (e. g., me dical hist or y , c o nc o mita nt 
dr u gs). 
A d diti o nal 
d oc u me nts 
m a y  
be
pr o vi de d 
b y  the 
I n vesti gat or, if a vaila ble 
(e. g., la b orat or y res ults, h os pital re p ort, a ut o ps y re p ort). I n all cases, t he i nf or mati o n pr o vi de d 
o n t he S A E Re p ort F or m m ust be c o nsiste nt wit h t he data a b o ut t he e ve nt rec or de d i n t he 
C R F.
T he I n vesti gat or m u st res p o n d t o a n y re q uest f or f oll o w-u p i nf or mati o n (e. g., a d diti o nal 
i nf or mati o n, o utc o me, fi nal e val uati o n, ot her rec or ds w here nee de d) or t o a n y questi o n t he 
S p o ns or/ desi g nee m a y  ha ve o n t he A E wit hi n t he sa me ti meli nes as t h ose n ote d a b o ve f or 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
8 5 /9 3
i nitial re p orts. T his is necessar y  to e ns ure pr o m pt assess me nt of t he e ve nt b y  the S p o ns or or 
desi g nee a n d (as a p plica ble) t o all o w t he S p o ns or t o meet 
strict re g ulat or y ti meli nes 
ass ociate d wit h e x pe dite d safet y re p orti n g o bli gati o ns.
Re q uests f or f oll o w-u p will us uall y  be ma de via t he res p o nsi ble M o nit or, 
alt h o u g h i n 
e xce pti o nal circ u msta nces t he dr u g safety de part me nt ma y  co ntact t he I nvesti gat or directl y t o 
o btai n f urt her i nf or mati o n or t o disc uss t he e ve nt.
S afet y Re p orti n g t o He alt h A ut h orities, I n de pe n de nt Et hics C o m mittees/I n di pe n de nt
Re vie w B o ar ds a n d I n vesti g at ors
T he S p o ns or will se n d a p pr o priate safety n otificati o ns t o Healt h A ut h orities i n acc or da nce 
wit h a p plica ble la ws a n d re g ulati o ns.
T he I n vesti gat or m ust c o m pl y wit h a n y a p plica ble site-s pecific re quire me nts relate d t o t he 
re p orti n g of S A Es ( partic ularl y deat hs) i n v ol vi n g st u d y partici pa nts t o t he I E C/IR B t hat 
a p pr o ve d t he st u d y.
I n acc or da nce wit h I CH G C P, t he S p o ns or/ desi g nee will i nf or m t he I nvesti gat or of “fi n di n gs 
t hat c o ul d a d versely affect t he safety of partici pa nts or i m pact t he c o n d uct of t he st u d y or alter 
t he I EC’s/I R B’s a p pr o val/ fa v ora ble o pi ni o n t o c o nti n ue t he trial.” I n partic ular a n d i n li ne 
wit h res pecti ve re g ulati o ns, t he S p o ns or/ desi g nee will i nf or m t he I nvesti gat or of A Es t hat are 
b ot h seri o us a n d u ne x pecte d a n d are c o nsi dere d t o be relate d t o t he a d mi nistere d pr o d uct 
(“s us pecte d u ne x pecte d seri o us a d verse reacti o ns” or S U S A Rs). T he I n vesti gat or s h o ul d place 
c o pies of Safet y Re p orts i n t he I n vesti gat or Site File. Nati o nal re g ulati o ns wit h re gar d t o 
Safet y  Re p ort n otificati o ns t o In vesti gat ors will be ta ke n i nt o acc o u nt.
W he n s pecificall y re q uire d b y  re g ulati o ns a n d g ui deli nes, t he S p o ns or/ desi g nee will pr o vi de 
a p pr o priate Safet y  Re p orts directl y  to t he c o ncer ne d lea d I EC/I R B a n d will mai ntai n rec or ds 
of t hese n otificati o ns. W he n direct re p orti n g is n ot clearl y defi ne d b y  nati o nal or site-s pecific 
re g ulati o ns, t he I nvesti gat or will 
be res p o nsi ble f or pr o m ptl y  notif y i n g the c o ncer ne d 
I E C/I R B of a n y Safet y Re p orts pr o vi de d b y  the S p o ns or / desi g nee a n d of fili n g c o pies of all 
relate d c orres p o n de nce i n t he I n vesti gat or Site File. All details a b o ut t he c o u ntr y specific 
re p orti n g re q uire me nts f or I n di vi d ual Case Safety Re p orts (I C S Rs) a n d peri o dic safet y re p orts 
t o Healt h A ut h orities are descri be d i n t he latest versi o n of t he Dr u g Safety Ma n ual.
F or st u dies c o vere d b y  the E ur o pea n Directi ve 2 0 0 1/ 2 0/ E C, t he S p o ns or’s res p o nsi bilities 
re gar di n g t he re p orti n g of S A Es/ S U S A Rs/ Safet y Iss ues will be carrie d o ut i n acc or da nce wit h 
t hat Directi ve a n d wit h t he relate d Detaile d G ui da nce d oc u me nts.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
8 6 /9 3
A p pe n di x 4
V ol u me of bi ol o gic al fl ui d c ollecte d d uri n g t he st u d y
Pre Scree ni n g ( D a y -2 8 t o D a y - 1)
B o d y 
Fl ui d
T y pe of Test
S pecific Test
N u m ber 
of  
S a m pli n g
V ol u me/ wei g ht per 
S a m pli n g ( a p pr o x.)
T ot al 
V ol u me
( a p pr o x..)
C 1 - C 3
St o ol
Parasit ol o g y
Kat o -Katz
2
2 g
4 g
Uri ne *
Parasit ol o g y
P O C -C C A
1
1 0 0 μ L 
1 0 m L
Filtrati o n 
1 0 m L
Bl o o d
Parasit ol o g y
Malaria R D T * * 
1
2 0- 5 0 μ L
2 0- 5 0 μ L
C 4
St o ol
Parasit ol o g y
Kat o -Katz
1
2 g
2 g
Uri ne *
Parasit ol o g y
Filtrati o n
3
1 0 m L
3 0 m L
Bl o o d
Parasit ol o g y
Malaria R D T * * 
1
2 0- 5 0 μ L
2 0- 5 0 μ L
Scree ni n g ( D a y -7 t o D a y 1)
B o d y 
Fl ui d
T y pe of Test
S pecific Test
N u m ber of 
S a m pli n g
V ol u me per 
S a m pli n g ( a p pr o x.)
T ot al 
V ol u me
( a p pr o x.)
C 1 - C 4
Uri ne *
Uri nal ysis
N A
1
5- 1 0 m L
5- 1 0 m L
Bl o o d
Parasit ol o g y
Malaria R D T
1
2 0- 5 0 μ L
2 0- 5 0 μ L
Hae mat ol o g y
Bi oc he mistr y
N A
1
4 m L
4 m L
Treat me nt ( D a y 1) f or P K s u b-st u d y partici pa nts o nl y
B o d y 
Fl ui d
T y pe of Test
S pecific Test
N u m ber of 
S a m pli n g
V ol u me per 
S a m pli n g ( a p pr o x.)
T ot al 
V ol u me
( a p pr o x.,)
C 1 b, 
C 4
Bl o o d
P K
N A
4 - 9
(see S ecti o n 8. 5 )
1 m L
4 - 9 m L
1 2 h o urs after d osi n g ( D a y 1/ D a y 2)
B o d y 
Fl ui d
T y pe of Test
S pecific Test
N u m ber of 
S a m pli n g
V ol u me per 
S a m pli n g ( a p pr o x.)
T ot al 
V ol u me
C 1 - C 4
Uri ne
Uri nal ysis
N A
1
5- 1 0 m L
5- 1 0 m L
(a p pr o x..)
Bl o o d
Hae mat ol o g y
Bi oc he mistr y
N A
N A
1
4 m L
4 m L
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
8 7 /9 3
E n d - of-St u d y  Visit ( Da y 1 7 t o 2 1)
B o d y 
Fl ui d
T y pe of Test
S pecific Test
N u m ber of 
S a m pli n g
V ol u me per 
S a m pli n g ( a p pr o x.)
T ot al 
V ol u me
( a p pr o x..)
C 1 - C 3
St o ol
Parasit ol o g y
Kat o -Katz
2
2 g
4 g
Uri ne *
Parasit ol o g y
P O C -C C A 
1
1 0 0 μ L
1 0 m L
1 0 m L
C 4
Uri ne *
Parasit ol o g y
Filtrati o n
3
1 0 m L
3 0 m L
E xte n de d F oll o w - u p Visit ( D a y 3 5 t o 4 0)
B o d y 
Fl ui d
T y pe of Test
S pecific Test
N u m ber of 
S a m pli n g
V ol u me per 
S a m pli n g ( a p pr o x.)
T ot al 
V ol u me 
( a p pr o x..)
C 4, 6 0 
m g/ k g 
d ose 
gr o u p
Uri ne *
Parasit ol o g y
Filtrati o n
3
1 0 m L
3 0 m L
* T he sa me sa m ple mi g ht be use d f or a d diti o nal e x pl orat or y uri ne a nal ys es.
* * At i n vesti gat or’s discreti o n
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
8 8 /9 3
A p pe n di x 5
Cli nic al L a b or at or y Tests
T a ble  7
Pr ot oc ol -Re q uire d Cli nical La b orat or y  Assess me nts
L a b or at or y 
Assess me nts
P ar a m eters
H e m at ol o g y
Platelet C o u nt 
R B C I n dices :

M C V

M C H

M C R
W B C C o u nt wit h 
Differe ntial :

Ne utr o p hils

L y m p h oc ytes

Le uc oc ytes
R B C C o u nt
H e m o gl o bi n
H e m at ocrit
Cli nical 
C he mistr y
Creati ni ne
As partate A mi n otra nsferase ( A S T)/ Ser u m 
Gl uta mic- O xal oacetic Tra nsa mi nase 
( S G O T)
T otal Pr otei n
B U N
Bilir u bi n
Gl uc ose 
Ala ni ne A mi n otra nsferase ( A L T)/ Ser u m 
Gl uta mic- P y r u vic Tra nsa mi nase ( S G P T)
C R P
R o uti ne 
Uri nal ysis

p H, gl uc ose, pr otei n, bl o o d, ket o nes, bilir u bi n, ur o bili n o ge n, nitrite, le u k oc yte esterase b y 
di pstic k a n d gra vit y
Ot her Scree ni n g 
Tests

Malaria ra pi d dia g n osis test perf or me d o n a bl o o d fr o m fi n ger pric k

Kat o Katz met h o d o n st o ol

P O C -C C A test perf or me d o n uri ne

Filtrati o n met h o d perf or m o n uri ne
All st u d y -re q uire d la b orat or y assess me nts will be perf or me d b y t he l ocal la b orat or y.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
8 9 /9 3
A p pe n di x 6
P h ar m ac o k i netic Bl o o d S a m pli n g
T he E ur o pea n C o m missi o n E x pert Gr o u p 
( Et hical C o nsi derati o ns f or cli nical st u d ys o n 
me dici nal pr o d ucts c o n d ucte d wit h mi n ors, Re visi o n Se p 2 0 1 7), i n its rec o m me n dati o n f or bl o o d 
sa m pli n g i n pae diatrics, states t hat t he t otal bl o o d v ol u me i n pae diatrics is esti mate d at 
8 0 m L per k g of b o d y wei g ht. B l o o d l oss s h o ul d n ot e xcee d 3 % of t he t otal bl o o d v ol u me o ver 
4 wee ks , a n d s h o ul d n ot e xcee d 1 % at a n y si n gle ti me. Wit h t his rec o m me n dati o n i n mi n d, t he 
f oll o wi n g ta ble was create d, t o s u m marize a n d e ns ure t hat t he a m o u nt of bl o o d ta ke n fr o m t he 
c hil dre n e nr olle d i n t his st u d y  is n ot e xcessi ve, a n d is wit hi n t he rec o m me n de d ra n ge. 
B o d y  Wei g ht Ra n ge 
( k g)
A p pr o x . A ge
T otal bl o o d v ol u me @ 
8 0 ml/ k g 
3 % V ol u me ( m L) 
1 % V ol u me ( m L)
6 ± 1. 5 k g
3 m o nt hs 
4 8 0
1 4. 4
4. 8
9 ± 1. 5 k g
1 0 m o nt hs
7 2 0
2 1. 6
7. 2
1 2 ± 1. 5 k g
2 yrs 
9 6 0
2 8. 8
9. 6
1 5 ± 1. 5 k g
4 yrs
1 2 0 0
3 6
1 2
1 8 ± 1. 5 k g
5 yrs
1 4 4 0
4 3. 2
1 4. 4
2 1 ± 1. 5 k g
6 yrs
1 6 8 0
5 0. 4
1 6. 8
2 4 ± 1. 5 k g
8 yrs
1 9 2 0
5 7. 6
1 9. 2
T he K e n ya n healt h a ut h orit y KE M RI iss ue d a g ui da nce 2 0 0 8, stati n g t hat t he v ol u me dra w n f or 
researc h p ur p oses i n a d diti o n t o v ol u me nee de d f or r o uti ne care, s h o ul d n ot e xcee d 1 m L / k g, a n d 
t he ma xi m u m 
c u m ulati ve dra w v ol u me all o we d is 5 m L / k g wit hi n 
8 wee ks. 
S o u rce: 
htt p:// w w w. w h o.i nt/ b ulleti n/ v ol u mes/ 8 9/ 1/ B L T -1 0 - 0 8 0 0 1 0-ta ble-T 2. ht ml
T he prese nt st u d y i ncl u des t he f oll o wi n g sa m pli n g:
B o d y  Wei g ht 
Ra n ge ( k g)
Mi ni m u m T otal 
bl o o d v ol u me @ 
8 0 ml/ k g
3 % V ol u me 
( mL)
V ol u me R o uti ne 
Care
( mL)
V ol u me P K 
( mL)
V ol u me T otal
( mL)
N ot e xcee d 7
4 0 0
1 4. 4
8
4
1 2
7 t o < 1 0
5 6 0
1 6. 8
8
7
1 5
1 0 a n d a b o ve
6 4 0
1 9. 2
8
9
1 7
P K sa m pli n g was desi g ne d s o as n ot t o e xcee d t he all o wa ble a m o u nt of bl o o d t hat ca n be dra w n , 
b ot h acc or di n g t o E U a n d K E M RI g ui da nce . 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A 
P h ase III pe di atric st u d y wit h L- P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
9 0/ 9 3
A p pe n di x 7 
S p o ns or Si g n at ure P a ge
St u d y Title:
A n o p e n la bel, P hase III efficac y a n d safet y st u d y of L prazi q ua ntel 
or o dis persi ble ta blets ( L P Z Q 
O D T) i n Sc hist os o ma i nfecte d 
c hil dre n 3 m o nt hs t o 6 years of a ge, i ncl u di n g a 2: 1 ra n d o mize d, 
c o ntr olle d c o h ort of Sc hist os o ma ma ns o ni i nfecte d c hil dre n 4 t o 6 
years of a ge treate d 
wit h L P Z Q 
O D T or c o m mercial P Z Q 
( Biltrici de ®)
St u d y N u m ber:
M S 2 0 0 6 6 1- 0 0 0 3
Cli nic al St u d y Pr ot oc ol 
Versi o n / D ate:
1. 2 / 1 1 A u g ust 2 0 2 0
I a p pr o ve t he desi g n of t he cli nical st u d y:
_ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Si g nat ure
Date of Si g nat ure
N a me, ac a de mic de gree:
F u ncti o n/ Title:
Me dical Res p o nsi ble
I nstit uti o n:
Merc k K Ga A 
A d dress:
Fra n kf urter Strasse 2 5 0, 6 4 2 9 3 Dar msta dt, Ger ma n y
Tele p h o ne n u m ber:
E- m ail a d dress:
 
D oc u me nt N o. 
O bject N o. 
1 4. 0 8. 2 0 2 0
Gl o bal Versi o n I D: 
P P D
P P D
P P D
P P D
C CI
C CI
C CI

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
9 1 /9 3
A p pe n di x 8
C o or di n ati n g Pri nci p al I n vesti g at or Si g n at ure P a ge
St u d y Title:
A n o pe n la bel, P hase III efficac y an d safet y st u d y of L 
prazi q ua ntel or o dis persi ble
ta blets ( L P Z Q O D T) 
i n 
Sc hist os o ma i nfecte d c hil dre n 3 m o nt hs t o 6 years of a ge, 
i ncl u di n g a 2: 1 
ra n d o mize d, c o ntr olle d c o h ort of 
Sc hist os o ma ma ns o ni i nfecte d c hil dre n 4 t o 6 y ears of a ge 
treate d wit h 
L 
P Z Q 
O D T 
or 
c o m mercial 
P Z Q 
( Biltrici de ®)
St u d y N u m be r:
M S 2 0 0 6 6 1 - 0 0 0 3
Cli nic al St u d y Pr ot oc ol Versi o n / 
D ate :
1. 2 / 1 1 A u g ust 2 0 2 0
Site N u m ber:
1 0 0
I a m res p o nsi ble f or t he c o n d uct of t he st u d y at t his site, a n d u n dersta n d a n d will c o n d uct it per 
t he cli nical st u d y pr ot oc ol, a n y ap pr o ve d pr ot oc ol a me n d me nts, I nter nati o nal C o u ncil f or
Har m o nisati o n 
G o o d 
Cli nical 
Practice ( T o pic E 6) a n d all a p plica ble Healt h 
A ut h orit y 
re q uire me nts a n d nati o nal la ws.
I als o u n dersta n d t hat Healt h A ut h orities ma y  re q uire t he S p o ns ors of cli nical st u dies t o o btai n 
a n d s u p pl y details a b o ut o w ners hi p i nterests i n t he S p o ns or or I n vesti gati o nal Me dici nal Pr o d uct 
a n d a n y ot her fi na ncial ties wit h t he S p o ns or. T he S p o ns or will use a n y s uc h i nf or mati o n s olely 
f or c o m pl yi n g wit h t he re g ulat or y re q uire me nts. T heref ore, I a gree t o s u p pl y the S p o ns or wit h 
a n y necessar y inf or mati o n re gar di n g o w ners hi p i nterest a n d fi na ncial ties i ncl u di n g t h ose of m y  
s p o use a n d de pe n de nt c hil dre n, a n d t o pr o vi de u p dates as necessar y  to meet Healt h A ut h orit y 
re q uire me nts.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
  D ate of Si g nat ure
Pri nci pal I n vesti gat or
_ _ _ _ _ _ _ _ _
Si g nat ure
N a me, ac a de mic de gree:  
F u ncti o n/ Title:  
I nstit uti o n:
A d dress:
Tele p h o ne n u m ber:  
F a x n u m ber:
E- m a il a d dress:
N A
D oc u me nt N o. 
O bject N o. 
1 7 - a o û t - 2 0 2 0  |  0 4 : 0 5 : 1 7  P D T
Gl o bal Versi o n I D: 
P P D
P P D
P P D
C CI
C CI
C CI
P P D
P P D
P P D
P P D
P P D
P P D
SIGN

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
9 2 /9 3
A p pe n di x 8
L oc al Pri nci p al I n vesti g at or Si g n at ure P a ge I v or y C o ast
St u d y Title:
A n o pe n la bel, P hase III efficac y an d safet y st u d y of L 
prazi q ua ntel or o dis persi ble
ta blets ( L P Z Q O D T) 
i n 
Sc hist os o ma i nfecte d c hil dre n 3 m o nt hs t o 6 years of a ge, 
i ncl u di n g a 2: 1 
ra n d o mize d, c o ntr olle d c o h ort of 
Sc hist os o ma ma ns o ni i nfecte d c hil dre n 4 t o 6 y ears of a ge 
treate d wit h 
L 
P Z Q 
O D T 
or 
c o m mercial 
P Z Q 
( Biltrici de ®)
St u d y N u m be r:
M S 2 0 0 6 6 1 - 0 0 0 3
Cli nic al St u d y Pr ot oc ol Versi o n / 
D ate:
1. 2 / 1 1 A u g ust 2 0 2 0
Site N u m ber:
1 0 0
I a m res p o nsi ble f or t he c o n d uct of t he st u d y at t his site, a n d u n dersta n d a n d will c o n d uct it per 
t he cli nical st u d y pr ot oc ol, a n y ap pr o ve d pr ot oc ol a me n d me nts, I nter nati o nal C o u ncil f or 
Har m o nisati o n 
G o o d 
Cli nical 
Practice ( T o pic E 6) a n d all a p plica ble Healt h 
A ut h orit y 
re q uire me nts a n d nati o nal la ws.
I als o u n dersta n d t hat Healt h A ut h orities ma y  re q uire t he S p o ns ors of cli nical st u dies t o o btai n 
a n d s u p pl y details a b o ut o w ners hi p i nterests i n t he S p o ns or or I n vesti gati o nal Me dici nal Pr o d uct 
a n d a n y ot her fi na ncial ties wit h t he S p o ns or. T he S p o ns or will use a n y s uc h i nf or mati o n s olely 
f or c o m pl yi n g wit h t he re g ulat or y re q uire me nts. T heref ore, I a gree t o s u p pl y the S p o ns or wit h 
a n y necessar y inf or mati o n re gar di n g o w ners hi p i nterest a n d fi na ncial ties i ncl u di n g t h ose of m y  
s p o use a n d de pe n de nt c hil dre n, a n d t o pr o vi de u p dates as necessar y  to meet Healt h A ut h orit y 
re q uire me nts.
_ _ _ _ _ _ _ _ _ _ _ _ _
Si g nat ure
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Date of Si g nat ure
N a me, ac a de mic de gree:  
F u ncti o n/ Title:  
I nstit uti o n:
A d dress:
Tele p h o ne n u m ber:  F a x 
n u m ber:
E- m ail a d dress:
 Pri nci pal I n vesti gat or 
N A
D oc u me nt N o. 
O bject N o. 
1 4 - a o û t - 2 0 2 0  |  0 6 : 5 6 : 5 6  P D T
Gl o bal Versi o n I D: 
P P D
P P D
P P D
C CI
C CI
C CI
P P D
P P D
P P D
P P D
P P D
P P D
SIGN

M S C 2 4 9 9 5 5 0 A
P h ase III pe di atric st u d y wit h L -P Z Q O D T
M S 2 0 0 6 6 1- 0 0 0 3
C O N F I D E N T I A L
I N F O R M A T I O N
9 3 /9 3
A p pe n di x 9
Pri nci p al I n vesti g at or Si g n at ure P a ge Ke n y a
St u d y Title:
A n o pe n la bel, P hase III efficac y an d safet y st u d y of L 
prazi q ua ntel or o dis persi ble
ta blets ( L P Z Q O D T) 
i n 
Sc hist os o ma i nfecte d c hil dre n 3 m o nt hs t o 6 years of a ge, 
i ncl u di n g a 2: 1 
ra n d o mize d, c o ntr olle d c o h ort of 
Sc hist os o ma ma ns o ni i nfecte d c hil dre n 4 t o 6 y ears of a ge 
treate d wit h 
L 
P Z Q 
O D T 
or 
c o m mercial 
P Z Q 
( Biltrici de ®)
St u d y N u m be r:
M S 2 0 0 6 6 1 - 0 0 0 3
Cli nic al St u d y Pr ot oc ol Versi o n / 
D ate :
1. 2 / 1 1 A u g ust 2 0 2 0
Site N u m ber:
2 0 0
I a m res p o nsi ble f or t he c o n d uct of t he st u d y at t his site, a n d u n dersta n d a n d will c o n d uct it per 
t he cli nical st u d y pr ot oc ol, a n y ap pr o ve d pr ot oc ol a me n d me nts, I nter nati o nal C o u ncil f or 
Har m o nisati o n 
G o o d 
Cli nical 
Practice ( T o pic E 6) a n d all a p plica ble Healt h 
A ut h orit y 
re q uire me nts a n d nati o nal la ws.
I als o u n dersta n d t hat Healt h A ut h orities ma y  re q uire t he S p o ns ors of cli nical st u dies t o o btai n 
a n d s u p pl y details a b o ut o w ners hi p i nterests i n t he S p o ns or or I n vesti gati o nal Me dici nal Pr o d uct 
a n d a n y ot her fi na ncial ties wit h t he S p o ns or. T he S p o ns or will use a n y s uc h i nf or mati o n s olely 
f or c o m pl yi n g wit h t he re g ulat or y re q uire me nts. T heref ore, I a gree t o s u p pl y the S p o ns or wit h 
a n y necessar y inf or mati o n re gar di n g o w ners hi p i nterest a n d fi na ncial ties i ncl u di n g t h ose of m y  
s p o use a n d de pe n de nt c hil dre n, a n d t o pr o vi de u p dates as necessar y  to meet Healt h A ut h orit y 
re q uire me nts.
_ _ _ _ _ _ _ _ _ _ _ _ _ _
Si g nat ure
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Date of Si g nat ure
N a me, ac a de mic 
de gree:  F u ncti o n/ Title:  
I nstit uti o n:
A d dress:
Tele p h o ne n u m ber:  E-
m ail a d dress:
Pri nci pal I n vesti gat or 
D oc u me nt N o. 
O bject N o. 
1 3 - A u g - 2 0 2 0  |  0 7 : 0 4 : 1 6  E D T
Gl o bal Versi o n I D: 
P P D
P P D
C CI
C CI
C CI
P P D
P P D
P P D
P P D
SIGN