Clinical trial NCT03845140
Conditions: Schistosomiasis
Keywords: Schistosomiasis Children L-praziquantel Biltricide®
Sponsor: Merck KGaA, Darmstadt, Germany
Start date: 2019-09-02; Completion date: 2021-10-11
Enrollment: 288 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study would evaluate the safety and efficacy of L-praziquantel orodispersible (L-PZQ ODT) tablets in Schistosoma infected children aged 3 months to 6 years.

Detailed description:

Arms: arm 1: Participants aged 4 to 6 years infected with Schistosoma (S.) mansoni received Levorotatory enantiomer of praziquantel (L-PZQ) orodispersible tablets (ODT) (150 milligrams \[mg\]) orally at a dose of 50 milligram per kilogram (mg/Kg) as a single oral dose after food-intake on Day 1. arm 2: Participants aged 4 to 6 years infected with S. mansoni received Racemate Praziquantel tablets (Biltricide®) (600 mg) orally at a dose of 40 mg/kg as a single oral dose after food-intake on Day 1. arm 3: Participants aged 2 to 3 years infected with S. mansoni received L-PZQ ODT (150 mg) tablet orally at a dose of 50 mg/kg as a single oral dose after food-intake on Day 1. arm 4: Participants aged 3 to 24 months infected with S. mansoni received L-PZQ ODT (150 mg) tablet orally at a dose of 50 mg/kg as a single oral dose after food-intake on Day 1. arm 5: Participants aged 3 months to 6 years infected with S. haematobium received L-PZQ ODT (150 mg) tablet orally at a dose of 50 mg/kg as a single oral dose after food-intake on Day 1. arm 6: Participants aged 3 months to 6 years infected with S. haematobium received L-PZQ ODT (150 mg) tablet orally at a dose of 60 mg/kg as a single oral dose after food-intake on Day 1.
Interventions: intervention 1: L-PZQ ODT 50 mg/kg intervention 2: Biltricide® intervention 3: L-PZQ ODT 60 mg/kg
Intervention descriptions: intervention 1: Participants received single oral dose of L-PZQ ODT 50 mg/Kg on Day 1. intervention 2: Participants received single oral dose of Biltricide® 40 mg/kg on Day 1. intervention 3: Participant received single oral dose of L-PZQ ODT 60 mg/kg on Day 1.

Protocol documents:
Prot_000.pdf: 
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
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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
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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
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M S C 2 4 9 9 5 5 0 A
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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


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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
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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
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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
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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


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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


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M S 2 0 0 6 6 1- 0 0 0 3
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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

SAP_001.pdf: 
M S C 2 4 9 9 5 5 0 A  
P hase III p e diatric 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  
  
  
  
V ersi o n 3. 0  
 
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I N F O R M A T I O N 
1/ 3 6  
 
 
 
I nte g r ate d A n al ysis Pl a n 
Cli ni c al St u d y Pr ot oc ol 
I de ntific ati o n N o. 
M S 2 0 0 6 6 1- 0 0 0 3 
Title 
A n o pe 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 mi ze 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 d e ® ) 
St u d y P h ase 
III 
I n v esti g ati o n al Me dici n al 
Pr o d uct(s) 
M S C 2 4 9 9 5 5 0 A ( L- P Z Q) 
Cli ni c al St u d y Pr ot oc ol 
Versi o n 
1 9- Mar-
 
2 0 -Fe b -2 0 1 9 / V 1. 1 Ke n ya  
I nte gr ate d A n al ysis Pl a n 
A ut h or 
 
I nte gr ate d A n al ysis Pl a n 
D ate a n d Versi o n 
1 6- A u g- 2 0 2 1/ Versi o n 3. 0 
I nte gr ate d A n al ysis Pl a n 
Re vi e wers 
Merc k: 
, 
  
, 
 
, Me dical Res p o nsi ble 
, S afet y Re pr ese nt ati ve 
,  
 
, P har mac o ki neticist 
, 
 
 
 
 
, Bi ostatisticia n  
 
C o nfi de nti al  
T his d o c u me nt is t h e pr o p ert y of M erc k Healt h care K Ga A, Dar msta dt, Ger ma n y, or o n e of its affiliate d c o m p a nies. It is 
i nte n d e d f or restricte d use o nl y a n d ma y n ot - i n f ull or part - b e passe d o n, re pr o d uce d, p u blis h e d or use d wit h o ut e x press 
p er missi o n of M erc k K Ga A, Dar msta dt, Ger ma n y or its affiliate. C o p yri g ht © 2 0 1 9  b y Merc k Healt h care K Ga A, 
Dar msta dt, Ger ma n y or its affiliat e. All ri g hts res er ve d . 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
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P P D
P P D
P P D
P P D
P
P
D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P
D
P P D
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MSC2499550A 
Phase III pediatric study with L-PZQ ODT 
MS200661-0003 
 
 
 
Version 3.0 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
3/36
 
1 
Table of Contents 
1 
Table of Contents ..................................................................................3 
2 
List of Abbreviations and Definition of Terms ....................................5 
3 
Modification History ............................................................................7 
4 
Purpose of the Integrated Analysis Plan ...............................................8 
5 
Objectives and Endpoints .....................................................................9 
6 
Overview of Planned Analyses ...........................................................11 
6.1 
Study Design and Sample Size ...........................................................11 
6.2 
Interim Efficacy and Safety Analysis .................................................12 
6.3 
Final Analysis .....................................................................................13 
7 
Changes to the Planned Analyses in the Clinical Study Protocol ......13 
8 
Protocol Deviations and Analysis Populations ...................................13 
8.1 
Definition of Protocol Deviations and Analysis Populations .............13 
8.2 
Definition of Analysis Populations and Subgroups ............................14 
9 
General Specifications for Data Analyses ..........................................16 
10 
Study Participants ...............................................................................18 
10.1 
Disposition of Participants and Discontinuations ...............................18 
10.2 
Protocol Deviations ............................................................................19 
10.2.1 
Important Protocol Deviations ............................................................19 
10.2.2 
Reasons Leading to the Exclusion from an Analysis Population .......19 
11 
Demographics and Other Baseline Characteristics .............................19 
11.1 
Demographics .....................................................................................19 
11.2 
Medical History ..................................................................................20 
12 
Previous or Concomitant Medications/Procedures .............................21 
13 
Treatment Compliance and Exposure .................................................22 
14 
Efficacy Analyses ...............................................................................23 
14.1 
Primary Endpoint Analyses ................................................................23 
14.1.1 
Primary Analyses of Clinical Cure Rate .............................................23 
14.2 
Secondary Endpoint Analyses ............................................................23 
14.2.1 
Pooled analysis of 3 to 24-month-old participants: ............................27 
14.3 
Supportive Subgroup Analyses for Efficacy Analysis .......................27 
15 
Safety Analyses ..................................................................................28 


MSC2499550A 
Phase III pediatric study with L-PZQ ODT 
MS200661-0003 
 
 
 
Version 3.0 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
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15.1 
Adverse Events ...................................................................................28 
15.1.1 
All Adverse Events .............................................................................29 
15.1.2 
Adverse Events Leading to Study Intervention Discontinuation .......30 
15.2 
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events ...................................................................................30 
15.2.1 
Deaths .................................................................................................30 
15.2.2 
Serious Adverse Events ......................................................................30 
15.3 
Clinical Laboratory Evaluation ...........................................................31 
15.4 
Vital Signs ..........................................................................................31 
15.5 
Physical Examination .........................................................................32 
15.6 
Tolerability Evaluations ......................................................................32 
16 
Analyses of Other Endpoints ..............................................................32 
16.1 
Pharmacokinetics ................................................................................32 
16.1.1 
Presentation of PK Concentration and PK Parameter Data ................34 
16.1.1.1 
Listings and Tables .............................................................................34 
16.1.1.2 
Graphical Summaries and Individual plots (PK Analysis 
Population) ..........................................................................................35 
17 
References ...........................................................................................36 
18 
Appendices .........................................................................................36 
18.1 
Appendix A:  Planned analyses for IDMC meetings ..........................36 
18.2 
Appendix B:  Prohibited concomitant medications ............................36 
 


MSC2499550A 
Phase III pediatric study with L-PZQ ODT 
MS200661-0003 
 
 
 
Version 3.0 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
5/36
 
2 
List of Abbreviations and Definition of Terms 
ADaM  
Analysis Data Model  
AE  
Adverse Event  
ATC 
Anatomical Therapeutic Chemical (ATC) Classification System 
AUC0-t 
Area Under the Plasma Concentration-Time Curve from Dosing to 
Timepoint t
BP 
Blood pressure 
Cmax
Maximum Observed Plasma Concentration
CCA  
Circulating Cathodic Antigen  
CI  
Confidence Interval  
CRF  
Case Report Form  
CRO  
Contract Research Organization  
CSR 
Clinical Study Report 
CV%
Percentage coefficient of variation
eCRF 
Electronic Case Report Form 
EDC
Electronic Data Capture
ERR  
Egg Reduction Rate  
GM/GeoMean 
Geometric Mean 
ICH 
International Council for Harmonization 
IDMC 
Independent data monitoring committee 
iERR
Individual Egg Reduction Rate
IMP
Investigational Medicinal Product
L-PZQ 
Levorotatory enantiomer of praziquantel 
LOCF
Last Observation Carried Forward
LCI 
Lower Limit of the Confidence Interval 
LLOQ 
Lower Limit of Quantitation 
mg
Milligram
Kg
Kilogram
MedDRA
Medical Dictionary for Regulatory Activities
mITT 
Modified Intention-to-Treat 
ODT 
Orodispersible Tablet 
PK 
Pharmacokinetics 


MSC2499550A 
Phase III pediatric study with L-PZQ ODT 
MS200661-0003 
 
 
 
Version 3.0 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
6/36
 
PKP 
Pharmacokinetic Analysis Population 
POC-CCA  
Point-of-Care Circulating Cathodic Antigen  
PP  
Per Protocol  
PR 
Pulse Rate 
PZQ  
Praziquantel  
PT 
Preferred Term 
SAE 
Serious Adverse Event 
Q1
First Quartile
Q3 
Third Quartile 
SAF 
Safety Analysis Population 
SCR 
Screening Analysis Population 
SD 
Standard deviation 
SDTM 
Standard Data Tabulation Model 
SOC
System Organ Class
TEAEs 
Treatment-Emergent Adverse Events 
TESAEs 
Treatment-Emergent Serious Adverse Events 
tmax 
Time when Cmax is Observed 
tlag 
Time Prior to the First Measurable Plasma Concentration 
UCI
Upper Limit of the Confidence Interval
VAS
Visual Analogue Scale
WHO 
World Health Organization 
 
 


M S C 2 4 9 9 5 5 0 A  
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3  
M o dific ati o n Hist or y 
U ni q u e 
I de ntifier f or 
Versi o n 
D ate of 
I A P V ersi o n 
A ut h or 
C h a n g es fr o m t he Pre vi o us 
Versi o n 
1. 0  
0 8- N o v- 2 0 1 9 
 
I nitial d oc u me nt 
2. 0  
1 8- N o v- 2 0 2 0 
 
 U p date d 
n a me 
of 
S p o ns or 
me dical res p o nsi ble i n re vie wer 
list.  
 Te xt was a d de d re gar di n g t h e  
a d diti o nal 
assess me nt 
visit 
( E xte n de d F oll o w- u p visit, Da y 
3 5 t o 4 0) f or c o h ort 4, a n d 
re gar di n g  
a d diti o nal 
P K 
sa m pli n g i n c o h ort 1 b ( Biltrici de 
ar m) a n d i n c o h ort 4 tr eate d wit h 
6 0 m g/ k g i n t he O bjecti ves a n d 
t he 
E n d p oi nts 
Ta ble 
a n d 
w here v er a p plica ble. 
 A d diti o n of a n i nteri m a nal ysis 
wit h o ut pa usi n g t h e st u d y t o be 
perf or me d after 3 0 partici pa nts i n 
C o h ort 4 
w ere treate d at 6 0 
m g/ k g i n I nteri m 
effi c ac y a n d 
safet y a nal ysis se cti o n 6. 2. 
 N ote a d de d f or classifica ti o n a n d 
prese ntati o n of S. h ae mat o bi u m 
i nfecti o n i n defi niti o n of anal ysis 
p o p ulati o ns 
a n d 
s u b gr o u ps  
secti o n  
8. 2. 
S pecificall y, 
partici pa nts i n c o h ort 4 treate d 
wit h 
L- P Z Q 
5 0 
m g/ k g 
was 
na me d as treat m e nt gr o u p 4 a, a n d 
t h ose treate d wit h 6 0 m g/ k g was 
na me d as treat me nt gr o u p 4 b 
 A d de d n ote f or deci m al place 
prese ntati o n 
a n d 
baseli ne 
defi niti o n 
u p date i n 
g e n eral 
s pecificati o ns f or data a nal ys es 
secti o n 9. 
 U p date d date prese ntati o n i n 
s u m mar y  
ta bles  
i n 
De m o gra p hics s ecti o n 1 1. 1. 
P P D
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U ni q u e 
I de ntifier f or 
Versi o n 
D ate of 
I A P V ersi o n 
A ut h or 
C h a n g es fr o m t he Pre vi o us 
Versi o n 
 E R R Deri vati o n met h o d u p date d 
i n efficac y a n al ysis secti o n 1 4 
 A d de d t he n u m ber of a d diti o nal 
s u bjects wit h P K sa m pli n g: u p t o 
1 5 i n t he h ae mat o bi u m ar m 
treate d at 6 0 m g/ k g ( 4 b) a n d u p 
t o 1 5 s u bjects i n Biltrici de ar m 
( 1 b) i n P har mac o ki netics secti o n 
1 6. 
 I m p utati o n strate g y re vise d f or 
i nc o m plete dates f or 
m e dical 
hist or y, 
A d verse 
e ve nt 
a n d 
pre vi o us  
or  
c o nc o mita nt 
me dicati o n secti o n 1 1. 2, 1 2 , 1 5 
res pecti vel y. 
3. 0  
1 6 A U G 2 0 2 1 
 
 U p date d t he deter mi n ati o n of  
s yste mic c o n ce ntrati o ns of R-
Prazi q ua ntel, S- Prazi q ua ntel, R-
4- O H- Tra ns Prazi q ua ntel a n d S-
4- O H- Tra ns Prazi q ua ntel R-(-)-
P Z Q  aft er treat me nt i n S ecti o n 
1 6. 
4  
P ur p ose of t he I nte gr ate d A n al ysis Pl a n 
T he p ur p ose of t his I A P is t o d oc u m e nt tec h nical a n d d etaile d s pecificati o ns f or t he fi nal a nal ysis 
of data c oll ecte d f or pr ot oc ol M S 2 0 0 6 6 1- 0 0 0 3. O ut p ut re q uire d b y t he trial i n de pe n de nt data 
m o nit ori n g c o m mittee (I D M C) f or re vie wi n g t he safet y a n d effi cac y data of t he P hase III. Res ults 
of t he a nal ys es des cri b e d i n t his I A P will be i ncl u de d i n t he Cli nical St u d y Re p ort ( C S R). 
A d diti o nall y, t h e pla n ne d a nal yses i de ntifie d i n t his I A P will be i ncl u de d i n re g ul at or y s u b missi o ns 
or f ut ure ma n uscri pts. A n y p ost- h oc, or u n pla n ne d a nal yses perf or me d t o pr o vi de res ults f or 
i ncl usi o n i n t he C S R b ut n ot i de ntifie d i n t his pr os pecti v e I A P will b e clearl y i de ntifie d i n t he C S R. 
T he I A P is base d u p o n Secti o n 9 ( Statistical C o nsi derati o ns) of t he st u d y pr ot oc ol a n d pr ot oc ol 
a me n d me nts a n d is pre p are d i n c o m plia nce wit h I C H E 9.  
 
 
 
 
P P D


MSC2499550A 
Phase III pediatric study with L-PZQ ODT 
MS200661-0003 
 
 
 
Version 3.0 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
9/36
 
 
5 
Objectives and Endpoints 
Objectives 
Endpoints (Outcome Measures) 
Endpoints 
(Outcome 
Measures) 
Timeframe 
IAP 
section
Primary 
To assess the efficacy of a single dose 
(50 mg/Kg) of L-PZQ ODT as assessed 
by cure rate 17 to 21 days after 
treatment, in children 4 to 6 years of age 
infected with S. mansoni (Treatment 
group 1a). The efficacy of a single dose 
(40 mg/kg) of commercial PZQ tablets 
(Biltricide®) in the same patient 
population (Treatment group 1b) will be 
considered as an internal control. 
Clinical cure is defined as no parasite eggs 
in the stool 17 to 21 days after treatment.  
Egg counts will be determined by the Kato-
Katz method: One stool sample will be 
collected during the pre screening period 
(Day -28 to Day -1) and the second one 
within a maximum of 5 days thereafter as 
baseline. Two additional stool samples will 
be collected between Day 17 to 21 after 
dosing to determine efficacy: the first one 
will be collected within the 17 to 21 day 
window and the second one within a 
maximum of 5 days following collection of 
the 1st sample. Three Kato-Katz thick 
smears (41.7 mg) will be prepared from 
each stool sample. 
End-of-Study 
visit (17 to 21 
days after 
treatment). 
14.1 
Secondary 
To assess the safety of a single dose (50 
mg/Kg) of L-PZQ ODT in children 4 to 6 
years of age infected with S. mansoni 
(Treatment group 1a)  
Safety and tolerability assessments:  
- Occurrence, nature, severity and outcome 
of adverse events (AEs),  
- Occurrence of treatment-related AEs  
- Changes in laboratory safety parameters 
(hematology, biochemistry, urinalysis) and 
vital signs (body temperature, blood 
pressure and pulse rate)  
First 
treatment to 
planned End-
of-Study visit  
15 
To assess the efficacy of a single dose 
(50 mg/Kg) of L-PZQ ODT as assessed 
by cure rate 17 to 21 days after 
treatment, in children 2 to 3 years of age 
and in infants/toddlers 3 to <24 months of 
age infected with S. mansoni (Cohorts 2 
and 3, respectively)  
Same as Cohort 1.  
End-of-Study 
visit  
14.2 
To assess the safety of a single dose (50 
mg/Kg) of L-PZQ ODT in children 2 to 3 
years of age and in infants/toddlers 3 
months to < 24 months of age infected 
with S. mansoni (Cohort 2 and 3, 
respectively)  
Same as Cohort 1.  
First 
treatment to 
planned End-
of-Study visit  
15 


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Objectives 
Endpoints (Outcome Measures) 
Endpoints 
(Outcome 
Measures) 
Timeframe 
IAP 
section
To assess the efficacy of a single dose 
(50 mg/kg, 60 mg/kg based on 
IDMC) of L-PZQ ODT as assessed by 
cure rate 17 to 21 days and 35 to 40 
days after treatment, in children 3 months 
to 6 years of age infected with S. 
haematobium (Cohort 4) 
At each assessment visit after treatment 
clinical cure is defined as no parasite eggs 
in the urine samples.  
Egg counts will be determined by urine 
examination using the urine filtration 
technique: The first sample will be collected 
during the pre screening period (Day -28 to 
Day -1) and the second and the third one 
within a maximum of 5 days thereafter as 
baseline. At the End-of-Study visit (between 
Day 17 and 21) Cohort 4 participants will be 
asked to provide three urine samples (about 
10 mL each: the first one will be collected 
within the 17 to 21-day window and the 
other two within a maximum of 5 days 
following collection of the 1st sample, for 
analysis by the filtration method. Similarly, 
at the Extended Follow-up visit, Cohort 4 
participants will be asked to provide three 
additional urine samples (about 10 mL 
each) on different days between Day 35 and
Day 40, for efficacy assessment by the 
filtration method. The urine samples will be 
filtered through a filter mesh. This mesh is 
then examined under the microscope for S. 
haematobium egg count. 
End-of-Study 
visit and 
Extended 
Follow-up 
visit  
14.2 
To assess the safety of a single dose (50 
mg/Kg,60 mg/kg based on IDMC) of L-
PZQ ODT in children 3 months to 6 years 
of age infected with S. haematobium 
(Cohort 4)  
Same as Cohort 1.  
First 
treatment to 
planned End-
of-Study visit  
15 
To assess the efficacy of a single dose 
(50 mg/Kg) of the L-PZQ ODT as 
assessed by egg reduction rate (ERR) 17 
to 21 days after treatment, in children 4 to 
6 years of age infected with S. mansoni 
(Treatment group 1a). The efficacy (ERR) 
of a single dose (40 mg/Kg) of 
commercial PZQ tablets (Biltricide®) in 
the same patient population (Treatment 
group 1b) will be considered as an 
internal control.   
ERR from pre treatment to 17 to 21 days 
after treatment, using parasite egg counts 
as determined by the Kato-Katz method for 
Cohort 1.  
 
Pre screening 
visit to  
End-of-Study 
visit  
 
14.2 
To assess the efficacy of a single dose 
(50 mg/Kg) of L-PZQ ODT as determined 
by ERR in children 2 to 3 years of age 
and in infants and toddlers 3 months to < 
24 months of age infected with 
S.mansoni (Cohorts 2 and 3, 
respectively) and in children 3 months to 
6 years of age infected with S. 
haematobium (Cohort 4).  
ERR from pre treatment to 17 to 21 days 
after treatment, using parasite egg counts 
as determined by the Kato-Katz method for 
Cohorts 2 and 3 and the urine filtration 
method for Cohort 4. Additionally, for Cohort 
4 participants treated with 60 mg/kg, ERR 
from baseline to 35 to 40 days after 
treatment, using parasite egg counts as 
determined by the urine filtration method. 
Pre screening 
visit to End-
of-Study visit 
and 
Extended 
Follow-up 
visit 
14.2 


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Objectives 
Endpoints (Outcome Measures) 
Endpoints 
(Outcome 
Measures) 
Timeframe 
IAP 
section
To assess the cure rate as demonstrated 
with use of the commercially available 
point-of-care circulating cathodic antigen 
(POC-CCA®) test (Cohorts 1, 2, and 3).  
One urine sample will be collected 17 to 21 
days after treatment. Cure is defined as 
absence of test line in the POC-CCA® test 
cassette (i.e., no Schistosoma antigens 
detected).  
End-of-Study 
visit  
14.2 
To assess acceptability in terms of ease 
of administration of the selected ODT 
(Treatment group 1a, Cohorts 2, 3, and 
4) and commercial PZQ tablet (Treatment 
group 1b)  
Reaction to Study Intervention 
administration (e.g., spitting, crying) to 
describe tolerability as assessed by 
nurse/site staff for all children enrolled in the 
study.  
Palatability assessment using a human 
gustatory sensation test (100-mm visual 
analogue scale [VAS]) scoring modified by 
the incorporation of a 3-point facial hedonic 
scale for all children 5 and 6 years of age 
enrolled in the study.  
At Study 
Intervention 
administration 
15.6 
To assess the concentration-time profile 
of the L-PZQ ODT and Biltricide 
formulation in a subset of children  
Concentrations of R-(-)-PZQ and rac-PZQ 
and, if appropriate, pharmacokinetics (PK) 
parameters (eg, Cmax, tmax, AUC0-t)  
Pre dose to 
12 hours 
afterwards 
16.1 
 
6 
 Overview of Planned Analyses 
6.1 
Study Design and Sample Size 
This is an open-label study in which participants in 4 cohorts based on age and Schistosoma species 
of infection will receive a single treatment dose of the new L-PZQ ODT at Day 1. The study 
includes 2:1 randomization of children 4 to 6 years of age infected with S. mansoni to the PZQ 
ODT treatment (Treatment group 1a) or the control treatment (40 mg/Kg racemic PZQ crushed 
tablets, Treatment group 1b). Specifically, 
 Cohort 1: S. mansoni-infected children 4 to 6 years of age (n=150) will be randomized in 
a 2:1 ratio. Treatment group 1a, n=100, will be treated with a single dose of 50 mg/Kg of 
L-PZQ ODT (as the test treatment); Treatment group 1b, n=50, will be treated with the 
reference PZQ commercial product (Biltricide® 600 mg) crushed tablets at a single dose 
of 40 mg/Kg (as the internal control treatment). 
 Cohort 2: S. mansoni-infected children 2 to 3 years of age (n=30) will be treated with a 
single dose of 50 mg/Kg of L-PZQ ODT. The primary aim of the descriptive efficacy 
analysis in this cohort is to explore whether the treatment effect is consistent with the 
treatment effect in older children (not an independent proof of efficacy in this subgroup). 
 Cohort 3: S. mansoni-infected infants and toddlers 3 to 24 months of age (n=25 to 65) will 
be treated with a single dose of 50 mg/Kg of L-PZQ ODT. The primary aim of the 
descriptive efficacy analysis in this cohort is to explore whether the treatment effect is 


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consistent with the treatment effect in older children (not an independent proof of efficacy 
in this subgroup). 
 Cohort 4: S. haematobium-infected children 3 months to 6 years of age (n=60) will be 
treated with a single dose of 50 mg/Kg of L-PZQ ODT, to assess the safety and efficacy 
in this group (not an independent proof of efficacy in this subgroup). After 30 children are 
enrolled and treated in Cohort 4, the efficacy and safety data will be summarized and 
evaluated by the IDMC to decide whether there is a need to increase the dose to 60 mg/Kg. 
1 If a dose increase is needed, 30 additional patients will be added to this cohort (i.e., total 
sample size of 90 for Cohort 4, n=60 receiving the final dose) and treated with the 60 
mg/Kg dose of L-PZQ ODT. 
 
1 An Independent Data Monitoring Committee (IDMC) meeting was held on the 09 March 
2020 and a decision was made to increase the dose in Cohort 4 to 60 mg/kg. 
6.2 
Interim Efficacy and Safety Analysis 
Independent Data Monitoring Committee (IDMC): 
Cut-off for analysis: 30 participants are enrolled, treated, completed follow-up visit (17 to 21 
days after treatment) and their data entered to the database, in Cohort 4. 
Responsible party: Triclinium Clinical Development, Merck Healthcare KGaA. 
An IDMC will evaluate the interim efficacy and safety results after 30 participants are enrolled 
and treated in Cohort 4, in order to determine whether there is a need to increase the dose of L-
PZQ ODT to 60 mg/Kg in this Cohort. The IDMC will also review the safety data for all patients 
who have been treated with L-PZQ ODTs that are available at that time. The evaluation will be 
based on an extract from the on-going database as clean as possible. No database lock or soft lock 
is planned for this purpose.   
Analysis results will be shared with the IDMC. 
Interim Analysis: 
Cut-off for analysis: The first 30 subjects in Cohort 4 treated with 60 mg/kg of L-PZQ ODT have 
completed all assessments. 
Responsible party: Triclinium Clinical Development, Merck Healthcare KGaA. 
An interim analysis for efficacy based on ongoing database without pausing the study is planned 
when the first 30 subjects in Cohort 4 treated with 60 mg/kg of L-PZQ ODT have completed all 
assessments. The results will be available only to the internal clinical team to inform other studies 
in the PZQ clinical program, e.g. whether another clinical trial is necessary to evaluate the efficacy 
of L-PZQ ODT on S. haematobium infected children. No action to this ongoing study is planned 
subsequent to the interim analysis. The evaluation will be based on an extract from the on-going 
database as clean as possible. No database lock or soft lock is planned for this purpose.   


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No hypothesis testing is planned, so no Type I error control is necessary. 
 
6.3 
Final Analysis 
Cut-off for analysis: Final database lock. 
Responsible party: Triclinium Clinical Development, Merck Healthcare KGaA. 
Following completion of the trial, the final trial analyses identified in this IAP will be performed 
only after the last subject has completed the scheduled assessments of the trial with all trial data 
in-house, all data queries resolved, and the database locked. 
All primary, secondary endpoints and safety endpoints will be analysed.  
A data review meeting will be held prior to database lock. In addition, no database can be locked 
until this IAP has been approved. 
7 
Changes to the Planned Analyses in the Clinical Study 
Protocol 
The statistical methods as described in the protocol and protocol amendments were adopted. There 
are no changes to the planned analyses. 
Impact of COVID-19 considerations:  
This is a single dose study with lean design. Efficacy assessments are taken at home based follow 
up visits. The impact of COVID-19 on efficacy assessment was deemed low. Missing data and 
increase in protocol deviations due to COVID-19 are not anticipated, hence no sample size re-
estimation is planned, and no change in this IAP is made for COVID-19.  
If in rare scenarios COVID-19 is diagnosed for any subjects, the occurrence of this disease will be 
summarized in the AE tables. If protocol deviation was determined with COVID-19 as the reason, 
the scenario will be also summarized in protocol deviation table(s).    
8 
Protocol Deviations and Analysis Populations 
8.1 
Definition of Protocol Deviations and Analysis Populations 
Important protocol deviations are protocol deviations that might significantly affect the 
completeness, accuracy, and/or reliability of the study data or that might significantly affect a 
participant's rights, safety, or well-being. 
Important protocol deviations include: 
 Participants that are dosed on the study despite not satisfying the inclusion or meeting the 
exclusion criteria, i.e. any inclusion/exclusion criteria violations 


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 Participants that develop withdrawal criteria whilst on the study but are not withdrawn 
 Participants that receive the wrong study intervention or an incorrect dose 
 Deviation from Good Clinical Practice 
The following deviations will be identified and confirmed prior to or at the Data Review Meeting 
at the latest: 
 Subjects that receive any prohibited medications/foods/fluids as outlined in sections 5.3.1, 
5.3.2, 6.5.2 and 6.5.3 of the protocol (see Appendix B for further guidance). 
 Any missed doses of Investigational Medicinal Product (IMP) 
 Vomiting within the first hour of IMP administration 
 Any medical condition that may modify the pharmacokinetic profile of the IMP or compromise 
the natural immunity of the subject 
 Stool and urine samples required for assessing any of the study endpoint are missing or collected 
out-of-window. Some of these important protocol deviations are clinically important, if leading 
to the exclusion of a participant from an analysis population (see Section 10.2) 
Important protocol deviations should be documented in the SDTM DV dataset whether identified 
through sites monitoring, medical review or programming. A clinically-important protocol 
deviations need to be in listings and described in an appendix of the CSR. 
8.2 
Definition of Analysis Populations and Subgroups 
Screening Analysis Population (SCR) 
The Screening analysis population includes all participants who signed the informed consent. 
Intention-to-Treat (ITT) 
For the purposes of this trial the ITT analysis set described in the protocol and the safety analysis 
set described below are considered equivalent. For this reason, the safety analysis set will be 
utilized for ITT and safety analysis purposes.  
Modified ITT Analysis Population (mITT)  
The modified ITT (mITT) analysis population will includes all enrolled participants who receive 
one dose of treatment and have baseline measurement. Children who require malaria treatment 
after enrollment in the study will not be included in the mITT population. The primary analysis of 
this study will be performed on the mITT population. 
Per Protocol Analysis Population (PP) 
Per-protocol (PP) Analysis population includes all participants who are in the mITT population 
and have one post baseline measurement for Cohorts 1, 2, 3 and 4a, and two post baseline 
measurements for Cohort 4b, without any clinically important protocol deviations. Details of the 


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criteria for exclusion from the PP population are provided below. An additional determination will 
be made prior to database lock, based on a review of data accrued during the conduct of the study. 
Participants who meet any one of the following criteria will be excluded from the PP: 
 Inclusion/exclusion violations 
 Subjects that develop withdrawal criteria whilst on the study, but are not withdrawn 
 Subjects that receive the incorrect treatment 
 Subjects that receive any prohibited medications/foods/fluids as outlined in Sections 5.3, 6.5.2 
and 6.5.3 of the protocol; 
 Any missed doses of IMP 
 Any medical condition that may modify the pharmacokinetic profile of the IMP or compromise 
the natural immunity of the subject  
 End-of-study stool (C1-C3) samples or urine samples (C4) required for assessing the primary 
endpoint are missing or collected out-of-window 
Safety Analysis Population (SAF) 
The Safety analysis population will include all participants who receive a dose of study treatment. 
Participants will be analyzed according to the actual treatment they receive. 
Pharmacokinetic Analysis Population (PKP) 
The PK Analysis Population is a subset of the SAF population and will consist of all participants 
who receive at least one dose of active IMP and provide at least one measurable post-dose 
concentration. A measurement below lower limit of quantification (BLQ) is considered a valid 
measurement. Participants will be analyzed according to the actual treatment they received. 
Subjects in this analysis population may not have taken prohibited medications/foods/fluids, and 
may not have experienced any diarrhea or vomiting after IMP administration. 
Additional Subgroup Analysis Populations 
Subgroup analyses will be performed on subgroups as defined below.  
The final parameterization will be updated and fixed at the Data Review Meeting at the latest and 
documented in an amendment to this IAP if different from the following definition.  
The following subgroups will be defined: 
 Age 
 
4 to 6 years of age (Cohorts 1 and 4)  
 
2 to 3 years of age (Cohorts 2 and 4)  
 
3 to < 24 months of age (Cohorts 3 and 4)  
 Gender 


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 Male  
 Fe male 
 
 Se verit y of i nfecti o n (as assesse d at Pre-scree ni n g [ D- 2 8 t o D- 1]) 
 S. m a ns o ni i nfecti o n 
o  Li g ht i nfecti o n: 1 - 9 9 e g gs per gra m of faeces  
o  
faeces 
 S. h ae m at o bi u m i nfecti o n 
o  Li g ht i nfecti o n: < 
  
o  Hea v y i nfecti o n: 
 
 
N ote: I n s u m mar y ta bles, S. hae mat o bi u m h ea v y i nfecti o n will be classifie d as M o derate 
/ Hea v y w he n b ei n g pres e nt e d si de-t o-si de wit h ot her c o h orts. 
 Trial ce nter/c o u ntr y 
 
  
 
  
9  
Ge ner al S pecific ati o ns f or D at a A n al yses 
St u d y i nter ve nti o n gr o u ps 
St u d y i nter ve nti o n gr o u ps are defi ne d a n d la b elle d as Biltrici de ®  a n d L- P Z Q O D T. 
U nless ot her wise i n di cate d all a nal yses will be prese nt e d se paratel y f or treat m e nt gr o u ps . 
S pecificall y, C o h orts 1a a n d 1 b will be prese nte d se paratel y i n all ta bles. I n ge neral, i n t his I A P 
 
f or C o h orts 1 a, 1 b, 2, 3, 4a a n d 4 b wit h 4a a n d 4 b re prese nti n g C o h ort 4 partici pa nts treate d wit h 
5 0 m g/ k g a n d 6 0 m g/ k g, res p ecti vel y. 
D at a h a n dli n g after c ut- off d ate 
Data ( ot h er t h a n t he d ate of deat h a n d t he d ate last k n o w n t o be ali ve) o btai ne d after t he c ut- off 
will n ot be dis pla ye d i n a n y listi n gs or use d f or s u m mar y statistics, e. g. la b orat or y v al ues of 
sa m ples ta ke n aft er data c ut- off, A Es wit h o nset d ate after data c ut off, etc. will n ot be i n cl u d e d i n 
a n y a nal ysis or listi n g. 
Si g nific a nc e le vel 
N o f or mal c o m paris o ns w ere pl a n ne d f or t he pri mar y o bjecti ve. 
 
 
 
 
Prese nt ati o n of c o nti n u o us a n d q u alit ati v e v ari a bles 
C o nti n u o us varia bles will be s u m marize d usi n g descri pti ve statistics, i.e. 
P P D
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 number of participants, number of participants with missing values, 
 mean, standard deviation, 
 median, 25th percentile, 75th percentile (Q1, Q3), 
 minimum and maximum. 
Qualitative variables will be summarized by counts and percentages. 
Unless otherwise stated, the calculation of proportions will be based on the number of participants 
of the analysis population of interest. Therefore, counts of missing observations will be included 
in the denominator and presented as a separate category. 
The following conventions are applied for reporting descriptive statistics of all continuous: 
Statistic 
Reporting convention 
Mean 
Observed + 1 decimal place 
SD, SEM 
Observed + 2 decimal place 
Minimum  
Observed 
Median 
Observed + 1 decimal place 
Maximum 
Observed 
CV%  
Up to 1 decimal place 
Point Estimate 
Observed + 1 decimal place 
95% CI  
Observed + 1 decimal place 
Q1 
Observed + 1 decimal place 
Q3 
Observed + 1 decimal place 
Note: At rare situations, there might be deviations from the above convention. 
Definition of baseline 
In general, the last non-missing measurement prior to the study intervention administration will 
serve as the baseline measurement.  
Definition of change from baseline 
Change from baseline = visit value  baseline value 
Percent Change from Baseline = 100 * (visit value  baseline value) / baseline value 
Note: If baseline observation is missing then respective subject summary will not be calculated 
for Change from Baseline or Percent Change from Baseline. 
Definition of pre-treatment value 


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In general, the last non-missing measurement prior to the first study intervention will be used as 
the pre-treatment baseline measurement. 
Definition of duration 
If required, duration in days will be calculated by the difference of start and stop date + 1 (if not 
otherwise specified). 
The time since an event will be calculated as reference date minus date of event. 
Conversion factors 
The following conversion factors will be used to convert days into months or years: 1 month = 
30.4375 days, 1 year = 365.25 days. 
Handling of missing data 
Unless otherwise specified (Sections 13, 15, 16 and 17), missing data will not be imputed. 
In all participant data listings, imputed values will be presented. In all listings imputed information 
will be flagged.
ND  For example, 
ND . 
Time window 
Day 1 is the day of the study intervention, the day before is Day -1 (no Day 0 is defined). 
Study day is defined relative to Day 1. 
Software(s) 
The statistical software SAS® (windows version 9.1 or higher) may be used to perform statistical 
analyses, produce tables, listings and figures and calculate summary statistics of PK Parameters if 
appropriate. WinNonlin (version 6.4 or higher) will be used for estimating PK parameters. 
10 
Study Participants 
This section includes specifications for reporting participant disposition and study 
intervention/study discontinuations. Additionally, procedures for reporting protocol deviations are 
provided. 
10.1 
Disposition of Participants and Discontinuations 
 Total number of participants screened (i.e. participants who gave informed consent) 
 Number of subjects who excluded from the trial prior to randomisation / enrolment, overall and 
grouped by the main reason (e.g. did not meet eligibility criteria, withdrawal of consent, etc.).  


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 N u m ber of ra n d o mise d / e nr olle d s u bjects, o v erall a n d gr o u p e d b y i nf ecti o n se verit y (i. e. li g ht, 
m o derate/ hea v y), c o h ort as w ell as a n al ysis set.  
 N u m ber of ra n d o mise d / e nr olle d s u bjects w h o disc o nti n ue d t he trial after ra n d o misati o n / 
e nr ol m e nt, o verall a n d gr o u pe d b y c o h ort as w ell as mai n reas o n f or dis c o nti n uati o n (e. g. 
a d verse e ve nt, l ost t o f oll o w- u p, etc.).  
 N u m ber of ra n d o mise d / e nr oll e d s u bjects w h o c o m plete d t he trial, o verall a n d gr o u pe d b y 
c o h ort. O nl y t h ose s u bj ects wit h E n d of St u dy visits, n ot d ue t o earl y wit h dra wal, will be 
c o nsi dere d as c o m pl ete d t he trial.  
 N u m ber of s u bjects i n t he mI T T, P P, S C R, S A F a nal ysis p o p ulati o ns 
T he n u m ber a n d perce nt a ge of p arti ci pa nts i n eac h of t h e a b o ve dis p ositi o n cate g ories will be 
prese nte d b y gr o u p (c o h ort/treat me nt) a n d o v erall. Perce nta ges will be prese nte d wit h res p ect t o 
t he n u m ber of e nr olle d/ra n d o mize d partici pa nts. 
1 0. 2  
Pr ot oc ol De vi ati o ns 
1 0. 2. 1  
I m p ort a nt Pr ot o c ol De vi ati o ns 
T he f oll o wi n g s u m mar y ta bles a n d listi n gs of i m p orta nt pr ot oc ol de viati o ns will be pr o vi de d: 
 Fre q u e nc y ta ble p er reas o n of i m p orta nt pr ot oc ol de viati o ns b y treat me nt gr o u p. 
 Listi n g of i m p orta nt pr ot oc ol de viati o ns 
1 0. 2. 2  
Re as o ns 
Le a di n g t o t he 
E xcl usi o n fr o m 
a n 
A n al ysis 
P o p ul ati o n 
F or partici pa nts e xcl u de d fr o m t h e mI T T a n d P P, t he reas o ns f or e x cl usi o n will be s u m m arize d 
a n d liste d: 
 Fre q u e nc y t a ble of de vi ati o ns fr o m eac h c o h ort, gr o u pe d b y reas o n of i m p orta nt pr ot oc ol 
de viati o ns, i ncl u di n g C O VI D- 1 9 as a reas o n, if a p pli ca ble 
 Listi n g of reas o ns of e x cl usi o n 
 
1 1  
De m o g r a p hics a n d Ot her B aseli ne C h ar acteristi cs 
If n ot state d ot her wis e, s u m maries will be prese nte d o n t he S A F a n d o n t he mI T T a nal ysis 
p o p ulati o n, b y treat me nt gr o u p a n d o verall. 
1 1. 1  
De m o g r a p hics 
De m o gra p hic c har acteristi cs will be s u m marize d usi n g t he f oll o wi n g i nf or mati o n fr o m t he 
Scree ni n g/ Baseli ne Visit C R F pa ges. 
 De m o gra p hic c haracteristics  
C
C
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 Gender: male, female  
  Race/Ethnic: Black or African American, Asian, Native Hawaiian or other Pacific Islander, 
American Indian or Alaska Native, White, other, not collected at site. 
  Age (months and years): summary statistics 
  Age categories: 
o 4 to 6 years of age   
o 2 to 3 years of age  
o 3 to < 24 months of age 
 Height in cm at Baseline: summary statistics 
 Weight in kg at Baseline: summary statistics 
 Body-mass index (kg/m2) at Baseline: summary statistics 
Specifications for computation: 
 Age [months and years]:  
 Age [in years] will be calculated as follows: 
(date of given informed consent - date of birth + 1) / 365.25 
 Age [in months] will be calculated as follows: 
(date of given informed consent - date of birth + 1) / 30.4375 
 In case of missing day for at least one date, but month and year available for both dates:  
Missing day will default to the first day of the month, i.e. 01 
 In case of missing month for at least one date, but year available for both dates:  
Missing month will default to the first month of the year, i.e. January or 01 
In all tables, age will be summarized in years. 
11.2 
Medical History 
version 22.0 (or above), preferred term as event category and system organ class (SOC) body term 
as Body System category. 
Medical conditions will be summarized by SOC and preferred term, providing the number and 
percentage of subjects with the condition, as well as the number and percentage of conditions. 
Summaries will be presented two-fold, ordered alphabetically for SOC, and PT within SOC. 
If required for an analysis, incomplete date fields will be imputed as follows: 
 Missing start day and month will default to the first day of the month and first month of the 
year, subject to the following exceptions:  
 Missing start day and month for medical history stopped prior to IMP administration will 
not be imputed. 
 Missing stop day and month will default to the last day of the month and last month of the 
year, subject to the following exceptions:  


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 If stop day is missing for a known medical history, then the stop day will default to 1 day 
prior the IMP start day. 
 If stop day and month is missing for a known medical history, then the stop month and day 
will default to 1 day prior to IMP start date. 
 Missing years will not be imputed. 
12 
Previous or Concomitant Medications/Procedures 
Previous medications are medications, other than trial medications and pre-medications for trial 
drug, which are taken within four weeks prior to first IMP administration and for which the end 
  
Anatomical Therapeutic Chemical (ATC) term 2nd level and preferred term will be tabulated as 
given from the WHODrug Global Version is March 2019 (or above) and format is B3. In case 
-2nd level will be used for reporting.  
Concomitant treatments are medications, other than trial medications, which are taken by 
subjects any time on-trial (
that is ongoing with a start date  
).  
-2nd 
level and preferred term will be tabulated as given from WHODrug Global Version is March 2019 
(or above) and format is B3. In case multiple 
-2nd level will 
be used for reporting.  
Prohibited medications are medications, other than trial medications, listed in section 6.5.3 of the 
trial protocol that are taken by subjects at any time.  
 Prohibited prior medic
ATC level 2 and preferred term will be tabulated as given from the WHODrug Global Version 
is March 2019 (or above) and format is B3. 
ATC-2nd level will be used for reporting.  
 Prohibited concomitant medications, which includes medications that were started prior to 
dosing but were not stopped prior to dosing, will be summarised and listed separately. 
Prohibited concomitant medications will be identified from the 
eCRF page, using Appendix B as guide. ATC level 2 and preferred term will be tabulated as 
given from the WHODrug Global Version is March 2019 (or above) and format is B3. In case 
o a drug, all ATC-2nd level will be used for reporting. 
All Concomitant Procedures, which were undertaken any time on trial, will be listed according 
 
 Concurrent procedures will be listed by verbatim term. 
If required for an analysis, incomplete date fields will be imputed as follows: 
 Missing start day and month will default to the first day of the month and first month of the 
year, subject to the following exceptions:  


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o If concomitant medication start day is missing and month and year is the same as the month 
and year of IMP administration, then the start day will default to the IMP start day. If the 
month or year are different, the start day will default to the first day of the month. 
o If start day and month is missing and year is the same as the year of IMP administration 
and stop date is not missing stop date, then the start day and month will default to the IMP 
start day and month. If the year is different, then the start day=01 and month=Jan. 
 
 Missing stop dates will default to the last day of the month and last month of the year, subject 
to the following exceptions: 
o If stop day is missing for a known previous medication, then the stop day will default to 1 
day prior the IMP start day. 
o If stop day and month is missing for a known prior medication, then the stop month and 
day will default to 1 day prior to IMP start date. 
o If the stop day and month for a concomitant medication is missing, it will default to the day 
and month of last contact with the participant. 
 Missing years will not be imputed. 
Note: ATC coding will not be indication/other differentiators (namely route) based, but all ATC 
available for a drug in the dictionary will be provided. 
13 
Treatment Compliance and Exposure 
Compliance and exposure will be reported for the SAF, mITT and PP analysis sets. 
Dosing Preparation
 
Compliance will be derived as follows: 
 100 × {Actual number of doses administered / expected number of doses that were to be 
administered}, rounded to the nearest integer using the ROUND() function. 
Compliance will be categorised as: 
o Compliance = 0% 
 
{0 dose administered in C1-C4} 
o Compliance = 100%  
{1 dose administered in C1-C4} 
Compliance will be summarised by cohort and compliance level, as well as listed by cohort and 
subject. 
Exposure, in terms of dosing, will be derived as follows: 
 Exposure: 
{Actual Dose [mg]} 
If Actual Dose is missing, exposure will be kept as missing. 
 Exposure with respect to baseline weight: 
{Actual Dose [mg]} / weight [kg], as calculated using the weight measurement at baseline 
If Actual Dose is missing, exposure will be kept as missing.


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14 
Efficacy Analyses 
14.1 
Primary Endpoint Analyses 
14.1.1 
Primary Analyses of Clinical Cure Rate 
 
Analysis 
(Analysis 
Populatio
n) 
Derivation 
Statistical Analysis Methods 
Missing data 
handling 
Primary endpoint: Cure rate 17 to 21 days after treatment, in children 4 to 6 years of age infected with S. 
mansoni (Treatment group 1a and 1b) 
Primary 
(mITT) 
 
Clinical cure is defined 
as no parasite eggs in 
the stool 17 to 21 days 
after treatment. 
Egg counts will be 
determined by the 
Kato-Katz method: One 
stool sample will be 
collected during the pre 
screening period (Day -
28 to Day -1) and the 
second one within a 
maximum of 5 days 
thereafter as baseline. 
Two additional stool 
samples will be 
collected between Day 
17 to 21 after dosing to 
determine efficacy: the 
first one will be 
collected within the 17 
to 21 day window and 
the second one within a 
maximum of 5 days 
following collection of 
the 1st sample. Three 
Kato-Katz thick smears 
(41.7 mg) will be 
prepared from each 
stool sample 
No hypothesis testing will be performed. Point 
estimates and corresponding two-sided 95% CIs 
will be determined. 
Subjects cured of infection during the trial will be 
defined as subjects with no parasite eggs (as 
determined by Kato-Katz method) in the End of 
Study stool samples, 17 to 21 days after 
End of 
Study (Day 17 to Day 21)
onders and 
non-responders will be coded as follows: 
 For responders, response = 1  
 For non-responders, response = 0  
The proportion of responders in each cohort will 
be determined based on a binomial distribution. 
Exact 95% CIs will be calculated based on the 
Clopper-Pearson method. The PROC FREQ 
procedure in SAS will be used with the 
BINOMIAL and EXACT option for point 
estimates and corresponding 95% CIs. 
Point estimates and corresponding 95% CIs will 
be presented for cure rate, in terms of proportion 
of responders, by cohort. Response will be listed 
by cohort and subject. Estimates of cure rate will 
be presented graphically in the form of forest 
plots presenting point estimates and 95% CIs. 
For mITT analysis tables will be presented with 
imputation and without imputation. 
Results will be presented for each analysis set.  
If the End of Study 
Kato-Katz egg count 
is missing, it will be 
imputed using the 
Last Observation 
Carried Forward 
(LOCF) approach. 
Subjects with missing 
data will be 
considered non-
responders. 
Sensitive 
   (PP) 
No imputation will be 
done 
Sensitive 
   (SAF) 
No imputation will be 
done 
14.2 
Secondary Endpoint Analyses 
 
Analysis 
(Analysis 
Population) 
Derivation 
Statistical Analysis Methods 
Missing data handling 


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Secondary endpoint: Cure rate 17 to 21 days after treatment, in children 2 to 3 years of age and in 
infants/toddlers 3 to < 24 months of age infected with S. mansoni (Cohorts 2 and 3, respectively) 
Primary 
(mITT) 
See 14.2.1 
for details 
about 
analysis for 
participant 3 
to 24 months 
of age 
(Cohort 3). 
Same as Cohort 1 
(primary analysis).  
 
Same as Cohort 1 (primary analysis).  
 
If the End of Study Kato-
Katz egg count is 
missing, it will be imputed 
using the Last 
Observation Carried 
Forward (LOCF) 
approach. Subjects with 
missing data will be 
considered non-
responders. 
Primary 
(PP) 
No Imputation will be 
done. 
Secondary endpoint: Cure rate 17 to 21 days and 35 to 40 days after treatment, in children 3 months to 6 
years of age infected with S. haematobium (Cohort 4) 
Primary 
(mITT) 
 
At each assessment 
visit after treatment, 
clinical cure is defined 
as no parasite eggs in 
the urine samples.  
Egg counts will be 
determined by urine 
examination using the 
urine filtration 
technique: The first 
sample will be collected 
during the pre 
screening period (Day -
28 to Day -1) and the 
second and the third 
one within a maximum 
of 5 days thereafter as 
baseline. At the End-of-
Study visit (between 
Day 17 and 21) Cohort 
4 participants will be 
asked to provide three 
urine samples (about 
10 mL each): the first 
one will be collected 
within the 17 to 21-day 
window and the other 
two within a maximum 
of 5 days following 
collection of the 1st 
sample, for analysis by 
the filtration method. 
Similarly, at the 
Extended Follow-up 
No hypothesis testing will be performed. 
Point estimates and corresponding two-
sided 95% CIs will be determined. 
Subjects cured of infection during the trial 
At each of 
the End of Study visit (17 to 21 days after 
treatment, according to 
End 
of Study (Day 17 to Day 21) ) and the 
Extended Follow-up visit (35 to 40 days after 
treatment, according to the eCRF page 
Extended Follow-up (Day 35 to Day 40) ), 
responders will be defined as subjects with 
no parasite eggs urine samples, (as 
determined by urine filtration method) 
Responders and non-responders will be 
coded as follows: 
 For responders, response = 1  
 For non-responders, response = 0  
The proportion of responders in each cohort 
will be determined based on a binomial 
distribution. 
Exact 
95% 
CIs 
will 
be 
calculated based on the Clopper-Pearson 
method. The PROC FREQ procedure in 
SAS will be used with the appropriate 
BINOMIAL and EXACT statements for point 
estimates and corresponding 95% CIs. 
Point estimates and corresponding 95% CIs 
will be presented for cure rate, in terms of 
proportion 
of 
responders, 
by 
cohort. 
Response will be listed by cohort and 
subject. Estimates of cure rate will be 
presented graphically in the form of forest 
plots presenting point estimates and 95% 
CIs.  
Results will be presented for each analysis 
set. 
If the End of Study or 
Extended Follow-up visit 
egg count is missing, 
carried forward for 
imputation. According to 
this rule subjects with 
missing egg count data 
at post-treatment 
assessment will be 
considered as non-
responders at the End-of 
-study visit. For cohort 
4b, if the assessment at 
Extended Follow-up visit 
is missing, the 
assessment result at 
End-of-study visit will be 
carried forward.  


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visit, Cohort 4 
participants will be 
asked to provide three 
additional urine 
samples (about 10 mL 
each) on different days 
between Day 35 and 
Day 40. Each urine 
samples will be filtered 
through a filter mesh. 
This mesh is then 
examined under the 
microscope for S. 
haematobium egg 
count. 
Secondary endpoint: Egg Reduction Rate (ERR) 17 to 21 days after treatment, in children 4 to 6 years of 
age infected with S. mansoni (Treatment group 1a and 1b) 
Primary 
(mITT) 
 
ERR from pre 
treatment to 17 to 21 
days after treatment, 
using parasite egg 
counts as determined 
by the Kato-Katz 
method for Cohort 1.  
 
The group/collective egg reduction rate will 
be determined for cohort 1a and 1b as 
follows: 
Step 1: Calculate the arithmetic group mean 
and geometric group mean egg counts 
(egp) at each visit. The geometric mean is 
defined as:   
 
Where 
 is the egg count for subject i. 
Step 2: Calculate group ERR for each 
treatment group and individual ERR 
 ERRA 
(%) 
= 
relative 
difference 
expressed in percent between the post-
treatment mean egg count and the pre-
treatment 
mean 
egg 
count 
((pre-
treatment mean egg count - post-
treatment mean egg count) / pre-
treatment egg count). 
 ERRG 
(%) 
= 
relative 
difference 
expressed in percent between the 
geometric mean post-treatment egg 
count 
and 
geometric 
mean 
pre-
treatment egg count ((geometric mean
pre-treatment 
egg 
count 
- 
log-
transformed post-treatment egg count) / 
geometric mean pre-treatment egg 
count).  
 
In addition: individual ERR (iERR) will be 
calculated for each patient:  
 iERR 
(%) 
= 
relative 
difference 
expressed in percent between the post-
treatment egg count and the pre-
treatment egg count ((pre-treatment egg 
count - post-treatment egg count) / pre-
treatment egg count). 
All raw egg counts will be multiplied by 4 in 
background of EDC system generating egg 
counts 
as 
eggs/gram 
(mansoni) 
and 
eggs/10ml (haematobium) respectively.  
If the End of Study Kato-
Katz egg count is 
missing, it will be imputed 
using the Last 
Observation Carried 
Forward (LOCF) 
approach. Subjects with 
missing data will be 
considered non-
responders. 
Primary 
(PP) 
No Imputation will be 
done. 


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Point and interval estimates of ERRA, ERRG
and 
proportion 
of 
individuals 
with 
iERR 90% will be presented by treatment 
group. 95% CIs of these 3 parameters will 
be calculated by bootstrapping (using SAS 
procedure SURVEYSELECT). Mean Kato-
Katz egg counts will be listed by cohort and 
subject and time point. Estimates of ERRA, 
ERRG 
and 
iERR 
will 
be 
presented 
graphically in the form of boxplots, by 
cohort.  
Results will be presented for each analysis 
set. 
Secondary endpoint: Egg Reduction Rate (ERR) in children 2 to 3 years of age and in infants and toddlers 
3 months to < 24 months of age infected with S. mansoni (Cohorts 2 and 3, respectively) and in children 3 
months to 6 years of age infected with S. haematobium (Cohort 4). 
Primary 
(mITT) 
See 14.1.2 
for details 
about 
analysis for 
participant 3 
to 24 months 
of age 
(Cohort 3). 
ERR from pre 
treatment to 17 to 21 
days after treatment, 
using parasite egg 
counts as determined 
by the Kato-Katz 
method for Cohorts 2 
and 3 and the urine 
filtration method for 
Cohort 4. Additionally, 
for Cohort 4b 
participants ERR from 
baseline to 35 to 40 
days after treatment, 
using parasite egg 
counts as determined 
by the urine filtration 
method, 
Same as Cohort 1 (Secondary analysis).  
 
If the End of Study egg 
count is missing, it will be 
imputed using the Last 
Observation Carried 
Forward (LOCF) 
approach. Subjects with 
all post-baseline egg 
counts missing will be 
considered non-
responders. 
For cohort 4b, if egg 
counts is missing only at 
Extended Follow-up visit, 
it will be imputed by 
taking the value from 
End-of-study visit. 
Secondary endpoint: cure rate as demonstrated with use of the commercially available point-of-care 
circulating cathodic antigen (POC-CCA®) test (Cohorts 1, 2, and 3). 
Primary 
(mITT) 
See 14.2.1 
for details 
about 
analysis for 
participant 3 
to 24 months 
of age 
(Cohort 3). 
One urine sample will 
be collected 17 to 21 
days after treatment. 
Cure is defined as 
absence of test line in 
the POC-CCA® test 
cassette (i.e., no 
Schistosoma antigens 
detected).  
 
Cure rate by POC-CCA® (Cohorts 1, 2, and 
3) will be analyzed in the same manner as 
the primary endpoint, with proportion cured 
and its 95% CI.  
In addition, estimates of cure rate will be 
presented graphically in the form of forest 
plots presenting point estimates and 95% 
CIs of treatment groups and proportion of 
patients with each POC-CCA response 
(negative, positive 1+, positive 2+ and 
positive 3+) for the following time points:  
 
D-28 to D-1 
 
D17 to D21 
The proportion of CCA negative, 1+, 2+ 
and 3+ participants (colour-coded for 
category) will be plotted over time, for each 
of the cohorts. The same will be plotted for 
treatment types (Biltricide® and L-PZQ), 
instead of cohorts. 
If the End of by POC-
CCA egg count is 
missing, it will be imputed 
using the Last 
Observation Carried 
Forward (LOCF) 
approach. Subjects with 
missing data will be 
considered non-
responders. 
Primary 
(PP) 
No Imputation will be 
done. 
Note:  
 
Pooled analysis of Cohort 3 mITT population from this study and the mITT population for participants 3 to 
24 months of age in the Phase II study MS200661-0005 (Cohorts 8 and 9) is detailed in Section 14.2.1. 


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For mITT analysis tables will be presented with imputation and without imputation. 
14.2.1 
Pooled analysis of 3 to 24-month-old participants: 
A total of 65 participants 3 to 24 months of age infected with S. mansoni is planned for analysis. 
Since the sample size in either the Phase II or Phase III study alone is too small to have adequate 
precision on the cure rate, the results in this Phase III study (MS200661-0003, Cohort 3) will be 
pooled with Cohorts 8 and 9 of the Phase II study (MS200661-0005, Cohorts 8 and 9). Data that 
will be pooled for analysis purposes comprises efficacy data, as well as demographics, other 
baseline characteristics and compliance & drug accountability . R
the subject-level (ADSL) and efficacy ADaM datasets of the Phase II study (ADLBPARA) will 
be pooled with the applicable ADaM datasets from the Phase III study (to be prepared). Derived 
variables will be pooled, directly given that the relevant derivation rules are the same across the 
two studies. Imputations will be handled in the same way. Efficacy endpoint data that will be 
pooled from the ADLBPARA dataset from MS200661-0005 include the following: 
 Infection intensity data 
 Egg counts  
 POC-CCA data 
For presentation purposes, results from the MS200661-0003 trial will be presented in one table, 
and then additional tables will be prepared, specifically for participants aged 3 to 24 months, i.e. 
Cohort 3 from MS200661-0003, and Cohort 8 and 9 from MS200661-0005. These additional 
tables will be prepared for demographics, other relevant baseline characteristics and all primary 
and secondary efficacy results. 
To align the data from MS200661-0003 the following visits from MS200661-0005 will be used in 
efficacy analyses: 
 Baseline: DAYS -28 TO -1 
 FOLLOW UP DAYS 14 to 21 (for analysis purposes this visit will be considered the same 
DAYS 17 to 21
-0003) 
The definitions of analysis sets including SAF, mITT and PP are the same across the two studies, 
so the flag for them will not be redrived for the MS200661-0005 participants. The pooled analysis 
will only apply at the final analysis of the trial data.  
14.3 
Supportive Subgroup Analyses for Efficacy Analysis 
Analysis set(s): 
 Supportive analyses of the primary endpoint will be based on the mITT and PP analysis 
sets. 
Clinical cure rate by subgroup: 
If the End of Study Kato-Katz egg count is missing, it will be imputed using the LOCF 
approach. Subgroup analyses the study will be performed, by the following subgroups: 
 Age category (Cohort 4 only) 


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 Gender 
 Severity of infection 
 Country  
Descriptive statistics of cure rates for each subgroup will be estimated for each cohort. 
Cure rate, in terms of proportion of responders, will be summarised by cohort and by infection 
severity, gender and country and listed by cohort and subject. Estimates of cure rate will be 
presented graphically in the form of a forest plots presenting point estimates and 95% CIs, by 
treatment group and subgroup. Forest plot by age group is needed for Cohort 4 only. Cure rates 
will be presented as percentages, not proportions, i.e. 
.  
For mITT analysis tables will be presented with imputation and without imputation. 
15 
Safety Analyses 
 
Safety and tolerability assessments: 
 Occurrence, nature, severity and outcome of adverse events (AEs), 
 Occurrence of treatment-related AEs 
 Changes in laboratory safety parameters (hematology, biochemistry, urinalysis) and 
vital signs (body temperature, blood pressure and pulse rate) 
Analysis set(s): 
 
SAF analysis set. 
Safety analyses will be done on the SAF analysis set and according to the as-treated principle. 
This section includes specifications for summarizing safety endpoints that are common across 
clinical trials such as AEs, laboratory tests, reactions to the IMP and vital signs. 
15.1 
Adverse Events 
Detail
-emergent 
adverse events (TEAEs) will be defined as those events with onset dates/time occurring after 
first IMP administration or events that worsen after first IMP administration. 
All analyses described in Section 15.1 will be based on TEAEs if not otherwise specified. 
If required for an analysis, incomplete date or date/time fields will be imputed as follows: 
 Missing start dates will default to the first day of the month and first month of the year, 
subject to the following exceptions:  
o If an AE start day is missing and month and year is the same as the month and year 
of IMP administration, then the start day will default to the IMP start day. If the 
month or year is different, the start day will default to the first day of the month. 
o If start day and month are missing and year is equal to IMP administration year, 
then the start day and month will be the minimum of IMP administration start date 
and AE resolution date (AE end date). 


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 Missing stop dates imputation:  
o If only the day is missing then the last day of the month is used if this does not 
result in a date after the subject's death in which case the death date will be used; 
o  In all other cases the AE end date will not be imputed. 
 Unknown times will default to 00:00, subject to the following exceptions: 
o If an AE start time is missing and day and month is the same as the date of IMP 
administration, then the start time will default to the IMP start time. If the day or 
month is different, the start time will default to 00:00. 
o If start time, date and month is missing and stop date is not before IMP 
administration, then the start date/time will default to the IMP start date/time. 
o If start time, date and month and stop date is missing, then the start date/time will 
default to the IMP start date/time. 
 Missing years will not be imputed. 
Further information after cut-off (like fatal outcome) might be taken from Safety data base and 
included separately into CSR. 
15.1.1 
All Adverse Events 
Adverse events will be summarized by worst severity per subject, using MedDRA version 22.0 
(or above) preferred term as event category and MedDRA 22.0 (or above) primary system organ 
class (SOC) body term as Body System category.  
Adverse events summaries will be ordered alphabetically for SOC, and PT within SOC unless 
otherwise specified. 
With respect to TEAEs by severity, subjects will be counted only once for multiple events in 
the same SOC, by worst severity experienced. If a subject experiences more than one TEAE 
within a PT, he/she will be counted only once in the PT for the greatest severity he/she 
experienced. If severity is missing for an event, the greatest severity will be assumed. 
With respect to TEAEs by relationship to IMP, subjects will be counted only once for multiple 
events in the same SOC, by strongest/closest relationship with IP. If a subject experiences more 
than one TEAE within a PT, he/she will be counted only once in the PT for the strongest 
relationship to IP he/she experienced. If relationship to study treatment is missing for an event, 
the strongest relationship will be assumed. 
Adverse events related to trial treatment are those events with relationship missing, unknown 
or yes.
In case a subject had events with missing and non-missing grades, the maximum of the non-
missing grades will be displayed. 
Treatment refers to the following trial treatments administered: Biltricide® or L-PZQ ODT; and 
includes the overall/total group. The following overall frequency tables will be prepared. In 
addition, the tables will be provided by PT and primary SOC in alphabetical order, unless 
otherwise specified: 


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 TEAEs by treatment group 
 TEAEs by treatment group and severity 
 Related TEAEs by treatment group 
 Related TEAEs by treatment group and severity 
 TESAEs by treatment group  
 TESAEs by treatment group and severity  
 Related TESAEs by treatment group 
 Related TESAEs by treatment group and severity 
 Most commonly reported AEs by PT, sorted by overall frequency 
The following listings will be also be prepared: 
 TEAEs leading to subject withdrawal 
 TEAEs leading to death 
Clinical trial.gov and EudraCT -requirements 
The following summary tables for non-serious adverse events (excluding SAEs) applying 
frequency threshold of 5% will be provided. 
 TEAEs by treatment group 
 Related TEAEs by treatment group 
In all adverse events tables Treatment groups 1a and 1b will be presented as separate columns. 
15.1.2 
Adverse 
Events 
Leading 
to 
Study 
Intervention 
Discontinuation 
All AEs leading to treatment discontinuation will be listed by SOC and PT. 
15.2 
Deaths, Other Serious Adverse Events, and Other 
Significant Adverse Events 
15.2.1 
Deaths 
End of Study
ecorded on the 
FATAL
Date and cause of death will be provided in individual subject 
data listing together with all dosing information, by cohort.  
15.2.2 
Serious Adverse Events 
Tables will be provided by PT and primary SOC in alphabetical order: 
 TESAEs by treatment group 
 TESAEs by treatment group and severity 
 Related TESAEs by treatment group  
 Related TESAEs by treatment group and severity 


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In addition, listings will be provided of all SAEs. 
15.3 
Clinical Laboratory Evaluation 
Laboratory values (including corresponding normal ranges) will be used for summary statistics 
and shift tables. 
Quantitative data will be examined for trends using descriptive statistics (mean, SD, median, 
Q1, Q3, minimum, and maximum) of actual values and changes from baseline to each visit over 
time. The changes computed will be the differences from baseline (Day -7 to Day 1 
samples(screening)) to end-of-treatment (Day 1 12hrs sample / early withdrawal). Qualitative 
data based on reference ranges will be described according to the categories (i.e. Low, Normal, 
 will be flagged. The number of subjects with 
clinical laboratory values below, within, or above normal ranges will be tabulated for each test 
by treatment group. Shift tables of baseline versus end-of-treatment will be presented. 
Laboratory values that are outside the normal range will also be flagged in the data listings, 
along with corresponding normal ranges. Any out-of-range values that are identified by the 
investigator as being clinically significant will be shown in a data listing.  
Baseline (Day -7 to Day 1 samples(screening)) is the last measurement prior to the dose of any 
trial treatment. 
Subjects without post baseline laboratory samples will be excluded from analyses with respect 
to change from baseline summaries. 
Data will also be presented for absolute and change from baseline results using boxplots, by 
time point/visit. 
Note: In order for summarization, quantitative clinical 
i.e. below limit of quantitation, will be converted to X/2, i.e. half value of the lower limit of quantitation; 
quantitative clinical 
quantification, will be converted by as 1.5X, i.e. 1.5 folds of upper limit of quantification. 
15.4 
Vital Signs 
Vital signs including blood pressure (BP), pulse rate (PR) and body temperature will be assessed 
according to the trial schedule. Vital signs will be considered abnormal as follows: 
 
Parameter 
Age  
Low  
Normal  
High  
Systolic blood pressure  
[mmHg]s  
3 - <12-months 
<72 
72  104 
>104 
12 - <24-months 
<86 
86  106 
>106 
2 - 6 years 
<89 
89  115 
>115 
Diastolic blood pressure  
[mmHg] 
3 - <12-month 
<37 
37 - 56  
>56 
12 - <24-months 
<42 
42  63 
>63 
2 - 6 years 
<46 
46 - 76 
>76 


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Parameter 
Age  
Low  
Normal  
High  
Heart rate  
[beats/min] 
3 - <12-months 
<100 
100 - 180 
>180 
12 - <24-months 
<90 
90 - 160 
>160 
2 - 6 years 
<80 
80  140 
>140 
Oral Temperature  
[°C] 
3-month - 6 years
<35.5 
35.5 - 37.5 
>37.5 
Quantitative data will be summarized using descriptive statistics (mean, SD, median, Q1, Q3, 
minimum, and maximum) of actual values and changes from baseline to each visit over time. 
Subjects data will be listed by cohort, subject and time point. An additional subject data listing 
will present all changes from baseline reported. Data will also be presented for absolute and 
change from baseline results using boxplots, by time point/visit. 
15.5 
Physical Examination 
Physical examination will be done according to local procedures. Body weight will be recorded 
during the physical examination, i.e. at screening (before dosing) and 24 hours after dosing. Any 
abnormal physical examination findings will be presented as adverse events. 
15.6 
Tolerability Evaluations 
The reaction to IMP administration (e.g. spitting, crying), tolerability, will be captured on the 
cross-tabulation with reaction category. 
The palatability assessment will use a human gustatory sensation test (100-mm VAS) scoring 
modified by the incorporation of a 3-point facial hedonic scale for all children 5 and 6 years of age 
enrolled in the study. 
Quantitative data will be summarized using descriptive statistics (mean, SD, median, Q1, Q3, 
minimum, and maximum, frequency and percentage) of palatability assessment. 
Relevant data listings will be presented. 
16 
Analyses of Other Endpoints 
16.1 
Pharmacokinetics 
To get information on systemic plasma concentrations after administration of L-PZQ ODT 
formulation in the targeted pediatric age groups, a subgroup of 20 participants 4 to 6 years of 
age (Treatment group 1a), 15 participants 2 to 3 years of age (Cohort 2), between 5 and 10 
participants 3 to <24 months of age (Cohort 3), and 15 participants infected with S. 
haematobium (Cohort 4) are planned to supply blood samples for determination of systemic 
concentrations of R-Praziquantel, S-Praziquantel, R-4-OH-Trans Praziquantel and S-4-OH-
Trans Praziquantel  after treatment of L-PZQ 50 mg/kg. PK sampling from up to 15 participants 
in Treatment Group 1b will provide information on the systemic plasma concentrations 


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observed after Biltricide administration. An additional up to 15 participants will be collected 
for the 60 mg/kg dose group in Cohort 4b to study the systemic concentration of R-Praziquantel, 
S-Praziquantel, R-4-OH-Trans Praziquantel and S-4-OH-Trans Praziquantel after treatment of 
L-PZQ 60 mg/kg. A separate written informed consent will be obtained for PK sampling. Only 
participants with minimum hemoglobin of 10 g/dL will be asked to take part in the PK sub-
study. 
Blood samples of approximately 1 mL per time point will be collected for measurement of 
plasma concentrations of R-Praziquantel, S-Praziquantel, R-4-OH-Trans Praziquantel and S-4-
OH-Trans Praziquantel, immediately prior to dosing (pre dose) and thereafter (post-dose), 
multiple times till 12 hours after dosing, as specified in the Schedule of Activities (Section 1.3 
in protocol) and below. Instructions for the collection and handling of biological samples will 
be provided by the Sponsor. The actual date and time (24-hour clock time) of drug 
administration and each sample will be recorded in the eCRF. 
Note: Analyses that took place prior to 01-Mar-2021 will only include R-Praziquantel and S-
Praziquantel. All analyses taking place from 01-Mar-2021 will include 4 analytes R-
Praziquantel, S-Praziquantel, R-4-OH-Trans Praziquantel and S-4-OH-Trans Praziquantel. 
As the known variability of systemic PZQ concentrations and PK parameters is high in adults, 
the number of participants in each PK subgroup is not based on statistical considerations but on 
feasibility assessments. Children weighing 5 kg to less than 7 kg will have 4 PK samples taken, 
children weighing 7 kg to less than 10 kg will have 7 PK samples taken, and children weighing 
10 kg and above will have the full PK sampling scheme with 9 PK samples taken. For 
 (in protocol) Pharmacokinetic Blood 
dosing and 4h 
post dosing. 
Table 1 
 PK sampling times per body weight group 
Body weight range (kg)   
Sampling times (hours)  
 
 
 
  
Pre dose  
Post dose  
 
 
 
 
5 to < 7  
No  
0.5  
1  
2  
3  
-  
-  
-  
-  
7 to < 10  
No  
0.5  
1  
2  
3  
4  
6  
8  
-  
10 and above  
Yes  
0.5  
1  
2  
3  
4  
6  
8  
12  
Note: the tolerance window of  ±10% for the collections of timepoints. 
Plasma concentrations will be tabulated and summarized using descriptive statistics. PK 
parameters will be calculated if possible as appropriate for the respective sampling schemes. 
All PK parameters will be calculated using standard non compartmental methods and the actual 
administered dose. Calculations will be performed using a validated software tool as described 
below. 
The following PK parameters will be calculated, when appropriate: 
Table 2 PK parameters 


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Symbol  
Definition  
Cmax  
Maximum observed concentration in plasma  
AUC0-t  
Area under the plasma concentration-time curve (AUC) from time zero to the 
last sampling time at which the concentration is at or above the lower limit of 
quantification. Calculated using the mixed log linear trapezoidal rule (linear up, 
log down).  
tmax  
Time to reach the maximum plasma concentration  
tlag  
Time prior to the first measurable (non-zero) concentration  
PK parameters will be evaluated and listed for all participants who provide sufficient 
concentration time data. 
Estimation of Individual PK Parameters:  
 Pharmacokinetic parameters will be calculated by the Clinical PK/PD Group of 
Translational Medicine, Merck, Darmstadt, Germany, or by a Contract Research 
Organization (CRO) selected by the Sponsor, using standard non-compartmental methods 
and the actual administered dose. PK parameters will be calculated using the actual elapsed 
time since dosing, given with a precision of 14 significant digits or the SAS format Best12.  
When the actual sampling time is missing, calculations will be performed using the 
scheduled time. Otherwise, there will be no further imputation of missing data.  
 Non-compartmental computation of pharmacokinetic parameters will be performed using 
the computer program Phoenix® WinNonlin® version 6.3, or higher (Certara, L.P., 1699 
S Hanley Road, St Louis, MO 63144, USA). 
 The statistical software SAS® (Statistical Analysis System, SAS-Institute, Cary NC, USA, 
windows version 9.1 or higher) may be used to produce tables, listings and figures, if 
appropriate (see below). No other analyses are planned.  
16.1.1 Presentation of PK Concentration and PK Parameter Data  
16.1.1.1 Listings and Tables (PK Analysis Population) 
Statistical analyses and descriptive summaries of pharmacokinetic data will be performed on the 
PK Analysis Population (PKP, as defined in Section 8.2). The following PK tables and listings 
will be produced: 
a) Descriptive Statistics of PK Concentration Data: 
 PK measurements will be descriptively summarized using: number of non-missing 
observations (N), arithmetic mean (Mean), standard deviation (SD), coefficient of variation 
(CV%), minimum (Min), median (Median) and maximum (Max).   
 Descriptive statistics will only be calculated for N>2 in which a measurement of <LLOQ 
represents a valid measurement 


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 Descriptive statistics of PK concentration data will be calculated using values with the 
same precision as the source data and rounded for reporting purposes only.   
 The following conventions will be applied when reporting descriptive statistics of PK 
concentration data:  
o Mean, Min, Median, Max:  
3 significant digits  
o SD 
 
 
 
4 significant digits  
o CV%:  
 
 
1 decimal place   
b) Descriptive Statistics of PK Parameter Data 
 PK parameter data will be descriptively summarized using: number of non-missing 
observations (as N), arithmetic mean, standard deviation (SD), coefficient of variation 
(CV%), minimum, median, maximum, geometric mean (GeoMean), the geometric 
coefficient of variation (GeoCV) and the 95% confidence interval for the GeoMean (LCI 
95% GM, UCI 95% GM). For time to reach maximum observed concentration (tmax), only 
n, minimum, median, and maximum will be reported.   
 Descriptive statistics will only be calculated for a PK parameter when N>2.   
 PK parameters read directly from the measurements (i.e. Cmax) will be reported with the 
same precision as the source data. All other PK parameters will be reported to 3 significant 
figures. In export datasets, as well as in the SDTM PP domain, PK parameters will be 
provided with full precision and will not be rounded. Descriptive statistics of PK parameter 
data will be calculated using full precision values and rounded for reporting purposes only.  
 The following conventions will be applied when reporting descriptive statistics of PK 
parameter data:  
o Mean, Min, Median, Max, GeoMean, 95% CI:  
3 significant digits  
o SD: 
 
 
 
 
 
 
4 significant digits  
o CV%, GeoCV%: 
 
 
 
 
1 decimal place   
16.1.1.2 Graphical Summaries and Individual plots (PK Analysis Population) 
 Individual concentration versus time plots; linear and semi-log; using the actual time points 
by participants, day, analyte, matrix and group; if any post-dose concentrations is <LLOQ 
the line representing LLOQ will be added to the semi-log plots. 
 Overlaid individual concentration versus time plots; linear and semi-log; by analyte, matrix 
and group; if any post-dose concentrations is <LLOQ the line representing LLOQ will be 
added to the semi-log plots. 
 Mean concentration time plots; linear with standard deviation and semi-log; using 
scheduled (nominal) time points by day, analyte, matrix and group; if any post-dose 


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concentration is <LLOQ the line representing LLOQ will be added to the semi-log plots. 
Error bars should be included only in the linear plots. 
17 
References 
Clinical protocol number MS200661-0003 
 
20 Feb 2019 /V1.1 Kenya, 
11 August 2020/V1.2 
18 
Appendices 
18.1 
Appendix A: 
 
Planned 
analyses 
for 
IDMC 
meetings 
Refer to the IDMC Charter. 
18.2 
Appendix B: 
 
Prohibited concomitant medications 
Prohibited medications, by WHO Drug Dictionary ATC classification: 
Specific prohibited medications, listed by preferred term: 
 Cimetidine 
Prohibited medications 
ATC Code 
ATC level
Praziquantel and other antihelminthics 
P02 
2 
Antimalarials, including chloroquine 
P01B 
3 
Antiepileptics 
N03 
2 
Glucorcorticosteroids (systemic) 
H02 
2 
Anti-infectives for systemic use 
J 
1 
Xanthine-containing drugs 
C03BD 
4 
N06BC 
4 
R03DA 
4 
R03DB 
4 
Anti-retrovirals 
J05AB 
4 
J05AE 
4 
J05AF 
4 
J05AG 
4 
J05AR 
4 
J05AX 
4