Conditions: Phenylketonuria
Keywords: Phenylketonuria PKU Kuvan Phenoptin Biopten Neurocognitive Function Phenylalanine
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 95
Healthy volunteers: no

Brief summary:
This multicenter, open label study is designed to evaluate the safety of Kuvan® and its effect on neurocognitive function, blood Phe concentration, and growth in children with PKU who are 0-6 years old.

Detailed description:
Rigorous control of diet is typically advocated in children 4 years and under with PKU because brain sensitivity to high Phe concentrations is expected to be greatest during these years of rapid neurocognitive development.

Prolonged high blood Phe concentrations are neurotoxic and lead to impairment of intelligence and other brain functions (such as attentiveness). Reduction of blood Phe concentrations through dietary control is an important determinant of long-term neurologic outcome in PKU patients, and reduction of blood Phe concentrations in patients with PKU has been shown to decrease the long term risk of neurologic injury.

It is difficult for many patients to maintain reduced blood Phe, and many patients with PKU experience some degree of neurological impairment despite efforts to maintain dietary Phe control.

The strongest determinant of intelligence quotient (IQ) and cognitive function is compliance with blood Phe control. Several clinical studies with Kuvan have already demonstrated efficacy in reducing blood Phe in subjects older than 4 years. This study will examine whether addition of Kuvan to the standard of care at an early age in children with well controlled diets can lower blood Phe levels (ie, reach and maintain a goal of ≤ 240 micromole/L) and preserve neurocognitive functioning. In addition, this study will provide data on Kuvan exposure, rate of uptake, half life, and clearance in young children.

Arms:
arm 1: A dose of 20 mg/kg will be administered dissolved in water or apple juice, based on subject's age and ability, and taken orally once daily with food.

Interventions: intervention 1: sapropterin dihydrochloride
Intervention descriptions: intervention 1: A dose of 20 mg/kg will be administered dissolved in water or apple juice, based on subject's age and ability, and taken orally once daily with food.

Protocol document:
Prot_000.pdf: 
 
 
 
 
    
 
 
 
 
 
 
Offici al Title : A P hase 3 b O pe n -La b el St u d y t o E val uate t he Effect of  K u v a n ® o n Ne ur o c o g niti ve 
F u ncti o n, Mai nte na n ce of Bl o o d P he n ylala ni ne C o nce ntrati o ns, Safet y, a n d 
P o p ulati o n P har mac o ki netics i n Y o u n g C hil dre n wit h P he n yl ket o n uria 
 
N C T N u m ber : N C T 0 0 8 3 8 4 3 5 
 
A p plic a nt/ M A H:  Bi o Mari n  P har mace utical I nc.  
 
Versi o n D ate : 3 0 N o ve m ber 2 0 1 0   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Pr o prietar y a n d C o nfi de ntial  
3 0 N o ve m ber 2 0 1 0 
C LI NI C A L S T U D Y P R O T O C O L 
St u d y Title: 
A P hase 3 b O pe n- La bel St u d y t o E val uate t he Effect of 
K u va n ®  o n Ne ur oc o g niti ve F u ncti o n, Mai nte na nce of Bl o o d 
P he n ylala ni ne C o nce ntrati o ns, Safet y, a n d P o p ulati o n 
P har mac o ki netics i n Y o u n g C hil dre n wit h P he n yl ket o n uria 
Pr ot oc ol N u m ber: 
P K U- 0 1 5 
I n vesti g ati o n al Pr o d uct: 
K u va n ®  (sa pr o pteri n di h y dr oc hl ori de; 6 R- B H 4) 
I N D/ E U D R A C T 
N u m ber: 
0 6 9 7 0 8 
I n dic ati o n: 
P he n yl ket o n uria ( P K U) 
S p o ns or: 
Bi o Mari n P har mace utical I nc. 
1 0 5 Di gital Dri ve 
N o vat o, C A 9 4 9 4 9 
De vel o p me nt P h ase: 
P hase 3 b 
S p o ns or's Res p o nsi ble 
Me dic al Officer: 
, M D  
Bi o Mari n P har mace utical I nc. 
1 0 5 Di gital Dri ve 
N o vat o, C A 9 4 9 4 9 
D ur ati o n: 
7 years 
D ose: 
2 0 m g/ k g/ da y  
P atie nt P o p ul ati o n: 
C hil dre n a ge 0 t o 6 years 
D ate of Ori gi n al 
Pr ot oc ol:  
2 1 Ma y 0 8 
D ate of A me n d me nt 1 
2 5 N o v 0 8 
D ate of A me n d me nt 2  
3 0 N o v 1 0 
 
Pr o pert y of Bi o M ari n 
C O N FI D E N TI A L 
 
M a y n ot be di v ul ge d, p u blis he d, or ot her wise discl ose d t o ot hers wit h o ut pri or writte n a p pr o v al 
fr o m Bi o M ari n. 
 
T his st u d y will be c o n d ucte d acc or di n g t o t he pri n ci ples of G o o d Cli nic al Pr actice as descri be d 
i n t he U. S. C o de of Fe der al Re g ul ati o ns a n d t he I nter n ati o n al C o nfere nce o n H ar m o nis ati o n 
G ui deli nes, i ncl u di n g t he arc hi vi n g of esse nti al d oc u me nts. 
 
Bi o Mari n is a re gistere d tra de mar k of Bi o Mari n P har mace utical I nc. 


 
P K U- 0 1 5
 Pa ge
 
2
 
 
Pr o prietar y a n d C o nfi de ntial 
3 0 N o ve m ber 2 0 1 0 
 
C LI NI C A L S T U D Y P R O T O C O L A M E N D M E N T S U M M A R Y  
 
A me n d me nt:  2 
D ate:  3 0 N o ve m ber 2 0 1 0 
 
 
R A TI O N A L E A N D S U M M A R Y O F C H A N G E S  
T he f oll o wi n g c ha n ge was ma de i n acc or da n ce wit h a rec o m me n dati o n b y re g ulat or y 
a ut h orities: 
1.  E xcl usi o n Criteria will i ncl u de a n y use of a p h os p h o diesterase t y pe 5 i n hi bit or ( P D E 5 
i n hi bit or) b y a n y st u d y s u bject. 
T he f oll o wi n g c ha n ges were ma de i n t he pr ot oc ol f or c o nsiste nc y a n d clarificati o n bet wee n 
pr ot oc ol secti o ns a n d trai ni n g d oc u me n ts pr o vi de d t o t he st u d y sites.  
2.  Clarificati o ns f or t he a d mi nistrati o n of ne ur oc o g niti ve testi n g a ge ra n ges a n d fre q ue nc y 
of a d mi nistrati o n were c ha n ge d wit hi n t he pr ot oc ol t o matc h t he trai ni n g ma n ual.  
3.  Dietar y c ha n ges f or bl o o d P he res ults < 1 2 0 μ m ol/ L a n d > 2 4 0 μ m ol/ L are clarifie d. 
4.  T he “ St u d y Sc he matic” was m o difie d t o reflec t t hat S u bst u d y 1 is fr o m Wee k 0 t h o u g h 
M o nt h 6 of t he 7- year st u d y. 
5.  “ Wei g ht” was se parate d fr o m t he gr o wt h asse ss me nts a n d was a d de d t o all st u d y visits, 
i ncl u di n g Wee k 0. Hei g ht a n d hea d circ u mfere nce were re m o ve d fr o m Wee k 0 w he n t he 
Wee k 0 visit is
 ≤7 da ys fr o m t he scree ni n g visit.  
6.  A ges were m o difie d f or t he p o p ulati o n P K sa m ples t o ta ke i nt o acc o u nt cl osi n g of t he 
0 t o 1 year ol d a ge gr o u p d ue t o a hi g her t h a n e x pecte d res p o n der rate. T he n u m ber of 
s u bjects u n der g oi n g P K sa m pli n g was decreased fr o m 3 0 s u bjects t o 1 0 s u bjects i n t he 
0 t o 1 year a ge gr o u p a n d i ncrease d fr o m t he fi rst 5 0 s u bjects t o t he first 7 0 s u bjects i n 
t he >  1 t o 6 year a ge gr o u p.  
7.  Bl o o d sa m pli n g ti mi n g was clarifie d. 
8.  A d mi nistrati o n, d ose r o u n di n g, a n d dail y d os i n g of i n vesti gati o nal pr o d uct (I P) was 
clarifie d.  
9.  T he S u m mar y of Ris ks secti o n was u p date d t o  c orres p o n d t o t he ris ks i n I n vesti gat or 
Br oc h ure ( versi o n 5). 
1 0.  T he Me dical M o nit or was u p da te d t o Dr 
, M D. 


 
P K U- 0 1 5
 Pa ge
 
3
 
 
Pr o prietar y a n d C o nfi de ntial 
3 0 N o ve m ber 2 0 1 0 
 
1 1.  T he Pr o d uct C haracteristics a n d La beli n g sec ti o n was m o difie d t o reflect t he c ol or 
c ha n ge d ue t o a c ha n ge i n c o m pacti o n pr ocess. 
1 2.  Cli nical la b orat or y clarificati o ns i ncl u de t he a d diti o n of c hl ori de as pa rt of t he electr ol yte 
e val uati o n i n t he c he mistr y pa nel. Uri nal ysis ma y be perf or me d i n t he cli nical la b or via 
“ di pstic k” i n c hil dre n t o o y o u n g t o pr o vi de a uri ne sa m ple. 
1 3.  E m p hasis was a d de d t hat e ver y s u bject s h o ul d c o m plete a ter mi nati o n visit, w hic h 
s h o ul d occ ur o n t he date t hat t he s u bject wit h dra ws fr o m or c o m pletes t his st u d y. 
1 4.  I nstr ucti o ns f or t he 3- M o nt h I nteri m p h o ne co ntact perf or me d bet wee n t he cli nic visits 
t hat occ ur after M o nt h 6 m o nt h a n d t hro u g h M o nt h 8 4 were clarifie d.  Assess me nts 
i ncl u de wei g ht, a d verse e ve nts/seri o us a d verse e ve nts a n d c o nc o mita nt me dicati o ns, a n d 
dis pe nsi n g of st u d y dr u g. 
1 5.  Clarificati o n was ma de t o st u d y pr oce d ur es re gar di n g pr oce d ure ti me p oi nts. 
1 6.  A b bre viati o ns u p date d t o matc h use i n pr ot oc ol. 
 


 
P K U- 0 1 5
 Pa ge 4
 
Pr o prietar y a n d C o nfi de ntial 
 
3 0 N o ve m ber 2 0 1 0 
 
P R O T O C O L A M E N D M E N T T E X T R E VI SI O N S 
T he f oll o wi n g ta ble s u m marizes t he re visi o ns ma de t o t he pr ot oc ol a n d relates t he c ha n ges t o t he a p pr o priate  rati o nale. Te xt t hat has 
bee n a d de d or i nserte d is i n dicate d b y u n derli ne d f o nt, a n d delete d te xt is i n dicate d b y stri ket hr o u g h f o nt.  
Secti o n N o./ Title  
Re visi o n 
C o m me nts 
Rel ates t o 
C h a n ge N o. 
1/ Title Pa ge 
S p o ns or's Res p o nsi ble Me dic al Officer: 
, M D 
, Cli nical Affairs 
, M D 
Bi o Mari n P har mace utical I nc. 
1 0 5 Di gital Dri ve 
N o vat o, C A 9 4 9 4 9  
Dr 
 has 
re place d  Dr.  
 
 as t he 
S p o ns or’s 
Res p o nsi ble Me dical 
Officer 
1 0 
2/ S y n o psis: St u d y 
Desi g n a n d Pla n 
… H o we ver, if a s u bject’s bl o o d P he c o nce ntrati o n dr o ps bel o w 1 2 0 μ m ol/ L, at t he 
discreti o n of t he i n vesti gat or, a gra d ual i ncrease of a p pr o xi matel y 5 t o 2 0 m g/ k g  of 
dail y dietar y P he i nta ke ma y be a d de d t o t h e diet. It is i m p orta nt t o a v oi d u nsta ble 
s wi n gs i n t he bl o o d P he val ues i ncrease d b y 5 m g/ k g i nitiall y a n d ma y be 
i ncrease d f urt her at t he discreti o n of t he I n vesti gat or if t he s u bject’s bl o o d P he 
c o nce ntrati o n re mai ns bel o w 1 2 0  μ m ol/ L . …... 
Dietar y c ha n ges 
clarifie d 
3 


 
P K U- 0 1 5
 Pa ge 5
 
Pr o prietar y a n d C o nfi de ntial 
 
3 0 N o ve m ber 2 0 1 0 
Secti o n N o./ Title  
Re visi o n 
C o m me nts 
Rel ates t o 
C h a n ge N o. 
2/ S y n o psis: St u d y 
Desi g n a n d Pla n 
Part 2: Ne ur oc o g niti ve St u d y 
Ne ur oc o g niti ve Assess me nts  
A ge 
Gr o u p  
I nf a nc y Presc h o ol
 Sc h o ol- A ge
 
Assess me nt  Ba yle y-III
 W P P SI-III
 W P P SI-III
WI S C-I V  
A ge  0
 
m o nt hs
 
t hr o u g h 
 < 3 0 m o nt hs
≥ 3 0 m o nt hs 
t hr o u g h < 4 years
≥ 4 y ears 
t hr o u g h 
 < 7 y ears 
≥ 7 y ears a n d 
ol der  
Fre q ue nc y  E ver y
 
6
 
m o nt hs  ± 2 
wee ks  
O nce a y ear 
 ± 2 wee ks 
O nce a 
y ear 
 ± 2 wee ks 
E ver y 
2 y ears ± 2 wee ks
 
Ne ur oc o g niti ve meas ure me nts i n s u bjects 0 -2 y ears ol d will be ma de e ver y si x 
m o nt hs usi n g t he Ba yle y -III u ntil s u bjects reac h a ge 3 0 m o nt hs.  After a ge 3 0 
m o nt hs, W P P SI -III will be a d mi nistere d u ntil s u bjects reac h a ge 6 years. S u bject > 
6 y ears ol d will be teste d usi n g WI S C -I V.  Ne ur oc o g niti ve testi n g will be 
c o n d ucte d usi n g W P P SI -III a n d WI S C-I V e ver y 1 2 m o nt hs u ntil t he s u bject 
reac hes a ge 7, t he n e ver y 2 y ears t hr o u g h t he e n d of t he st u d y. 
T he Ba yle y-III will be a d mi nistere d t o s u bjects w h o are fr o m 0 m o nt hs t o less t ha n 
3 0 m o nt hs of a ge a n d will be a d mi nistere d e ver y 6 m o nt hs ± 2 wee ks. At 3 0 
m o nt hs ol d or ol der, t he s u bjects will be a d mi nistere d t he W P P SI-III. T he W P P SI-
III has t w o f or ms. T he y o u n ger c hil dre n will be a d mi nistere d t he first f or m f or a g es 
Ta ble a d de d a n d 
re w or de d f or clarit y 
2 


 
P K U- 0 1 5
 Pa ge 6
 
Pr o prietar y a n d C o nfi de ntial 
 
3 0 N o ve m ber 2 0 1 0 
Secti o n N o./ Title  
Re visi o n 
C o m me nts 
Rel ates t o 
C h a n ge N o. 
3 0 m o nt hs t o less t ha n 4 y ears ol d. T he sec o n d f or m will be use d f or s u bjects 4 
y ears of a ge t o less t ha n 7 y ears ol d. T he W P P SI-III will be a d mi nistere d 
y earl y ± 2 wee ks. Be gi n ni n g at 7 y ears ol d, st u d y s u bjects will be a d mi nistere d t he 
WI S C-I V e ver y 2 y ears ± 2 wee ks.  
Gr o wt h, bl o o d P he c o nce ntrati o n, a n d sa fet y will be m o nit ore d. T hese a n d t he 
ne ur oc o g niti ve assess me nts ,,,  
2/ S y n o psis: St u d y 
Desi g n a n d Pla n  
S u bst u d y 2: P o p ul ati o n P h ar m ac o ki netics ( P K) i n S u bjects 0- 6 Ye ars Ol d 
F or t he p o p ulati o n P K e val uati o n, plas ma sa m ples fr o m t he first  3 0  1 0 s u bjects 
e nr olle d i n Part 1 w h o are 0- 1 y ears ol d a n d t he first  5 0  7 0 s u bjects w h o i n t he 
> 1- 6 y ears a ge gr o u p  ( 3 sa m ples eac h fr o m s u bjects ≤ 1 y ear ol d; 4 sa m ples eac h 
fr o m s u bjects > 1 y ears ol d) will be c ollecte d … 
Beca use of greater 
t ha n e x pecte d 
res p o nse rate i n t he 
u n der 1 y ear a ge 
gr o u p t he 
de m o gra p hics were 
c ha n ge d   
6 
2/ S y n o psis: 
Dia g n osis a n d All 
Criteria f or 
I ncl usi o n a n d 
E xcl usi o n 
•  Use of p h os p h o diesterase t y pe 5 i n hi bit or,  ofte n s h orte ne d t o P D E 5 i n hi bit or 
(e g.sil de nafil citrate, var de nafil, ta dalafil, a va nafil, l o de nafil, mir o de nafil, 
u de nafil)  
A d de d t o E xcl usi o n 
criteria per 
rec o m me n dati o n b y 
re g ulat or y a ut h orities 
1 
2/ S y n o psis: 
I n vesti gati o nal 
Pr o d uct(s), D ose, 
R o ute, a n d 
Re gi me n 
K u va n is pr o vi de d i n ta blets of 1 0 0 m g of sa pr o pteri n di h y dr oc hl ori de. A d ose of 
2 0 m g/ k g will be a d mi nistere d diss ol ve d i n water,  or a p ple j uice, or s oft f o o ds, 
base d o n s u bject’s a ge a n d a bilit y, a n d ta ke n orall y o nce dail y wit h f o o d. 
S oft f o o ds a d de d f or 
ease of a d mi nistrati o n. 
8 


 
P K U- 0 1 5
 Pa ge 7
 
Pr o prietar y a n d C o nfi de ntial 
 
3 0 N o ve m ber 2 0 1 0 
Secti o n N o./ Title  
Re visi o n 
C o m me nts 
Rel ates t o 
C h a n ge N o. 
S u bst u d y 1: 
S afet y a n d 
Effic ac y i n 
S u bjects 0-
6 Ye ars Ol d 
 
… K u va n d ose ma y als o be re d uce d after wee k 5 a n d  after c o ns ultati o n wit h t he 
Me dical M o nit or if t he s u bject d oes n ot t olerate t he 2 0 m g/ k g/ da y d ose … 
 
Clarificati o n of d ose 
c ha n ges after Wee k 5 
8 
2/ S y n o psis: 
Criteria f or 
E val uati o n 
Effic ac y:  
Ne ur oc o g niti ve de vel o p me nt will be e val uate d base d o n I Q meas ure d b y t he a ge-
a p pr o priate tests liste d bel o w:  
•  Ba yle y-III i n a ges 0 t o  <  3 0 m o nt hs 
•  W P P SI-III i n a ges ≥ 3 0 m o nt hs t o  < 7 years  ≤ 6 y ears  
•  WI S C-I V i n a ges  ≥ 7  y ears  > 6 y ears 
Clarificati o n of a ges  
2 


 
P K U- 0 1 5
 Pa ge 8
 
Pr o prietar y a n d C o nfi de ntial 
 
3 0 N o ve m ber 2 0 1 0 
Secti o n N o./ Title  
Re visi o n 
C o m me nts 
Rel ates t o 
C h a n ge N o. 
2. 1/ Sc he d ule of 
E ve nts 
T a ble 2. 1: Sc he d ule of E ve nt, All S u bjects  
P art 2: L o n g -ter m Assess me nt of 
Ne ur oc o g niti ve A bilit y a n d S afet y b  
 
P art 1: E v al u ati o n 
of K u v a n 
Res p o nsi ve n ess a S u bst u d y 1:  6 -
M o nt h S afet y 
a n d Effic ac y c 
 
F oll o w -
u p/ E T V d
 
Fr o m A me n d me nt 1: 
Sc he d ule of E ve nt, 
Hea di n g of Ta ble 2. 1 
c ha n ge d.  
1 5 
2. 1/ Sc he d ule of 
E ve nts 
T a ble 2. 1: Sc he d ule of E ve nt, All S u bjects  
 
P art 1: 
E v al u ati o n of 
K u v a n 
Res p o nsi ve n ess 
(i ncl u des 
S u bst u d y 2) a 
P art 2: L o n g-ter m Assess me nt of 
Ne ur oc o g niti ve A bilit y a n d S afet y b  
 
S u bst u d y 1:  6- M o nt h S afet y 
a n d Effic ac y 
 
F oll o w-
u p/ E T V d
 
 
Fr o m A me n d me nt 2: 
S u bst u d y 1: C ha n ge d 
fr o m M o nt hs 1 t o 6 
( A me n d me nt 1) t o 
Wee k 0 t o M o nt h 6 
( A me n d me nt 2)  
1 5 


 
P K U- 0 1 5
 Pa ge 9
 
Pr o prietar y a n d C o nfi de ntial 
 
3 0 N o ve m ber 2 0 1 0 
Secti o n N o./ Title  
Re visi o n 
C o m me nts 
Rel ates t o 
C h a n ge N o. 
2. 1/ Sc he d ule of 
E ve nts 
Hei g ht, wei g ht , 
hea d 
circ u mfere nce
X  X  
X  X  
X
X
X
X
X
X
X
X 
X 
X  ( X i)
 
Wei g ht delete d fr o m 
hei g ht, wei g ht a n d 
hea d circ u mfere nce 
5 
2. 1/ Sc he d ule of 
E ve nts 
Wei g ht  
X X X X X X X X X X
X
X
X
X
X
X
X
X  X X ( X i)
 
Wei g ht a d de d t o e ver y 
visit as a se parate r o w. 
5 
2. 1/ Sc he d ule of 
E ve nts 
Ba yle y-III q  
 (a ges 0 t o < 3 0 m o nt hs) 
 
W P P SI-III
r 
  (>  3 0 m o nt hs t o 
   < 7 y ears) ≤ 6  y ears ) 
 
  WI S C-I Vs 
  (≥ 7 y ears) ( > 6 y ears)  
 
Clarificati o n of a ge 
ra n ges f or assess me nts
2 
2. 1/ Sc he d ule of 
E ve nts 
c M o nt hl y visits s h o ul d occ ur wit hi n 5 da ys of sc he d ule d ti me p oi nt (ie, ±  5 da ys) 
f or M 2, M 3, M 4, M 5 a n d M 6. All visits will occ ur at t he cli nic. 
d F oll o w -u p will be perf or me d f or all s u bjects, e ve n if t he y wit h dra w earl y fr o m t he 
st u d y. S u bjects will be c o ntacte d b y tele p h o ne 4 wee ks ( 2 8  ±  3 da ys) after t he last 
d ose of st u d y dr u g, u nless re q uire d  t o ret ur n f or a cli nic visit (see f o ot n otes i, q, r, 
s, a n d t).  
Clarificati o n
 2, 3, 5, 6, 1 2, 1 4,
 
1 5 


 
P K U- 0 1 5
 Pa ge 1 0
 
Pr o prietar y a n d C o nfi de ntial 
 
3 0 N o ve m ber 2 0 1 0 
Secti o n N o./ Title  
Re visi o n 
C o m me nts 
Rel ates t o 
C h a n ge N o. 
d E ver y s u bject s h o ul d c o m plete a F oll o w- u p or Ter mi nati o n visit t o e n d t heir 
partici pati o n i n t he st u d y. F oll o w- u p vis it is perf or me d f or s u bjects w h o c o m plete 
o nl y Part 1 of t he st u d y, or w h o are e nr olle d i nt o Part 2 a n d c o m plete Part 2.  T he 
Ter mi nati o n visit is c o m plete d b y s u bjects w h o wit h dra w or are disc o nti n ue d fr o m 
t he st u d y.  S u bjects will be c o ntacte d b y tele p h o ne 4 wee ks ( 2 8 ±  3 da ys) after t he 
last d ose of st u d y dr u g, u nless re q uire d t o ret ur n f or a cli nic visit (see f o ot n otes i, 
q, r, s, a n d t).  
e All st u d y pr oce d ures f or t he W 0 visit m ust occ ur bef ore t he first d ose of st u d y 
dr u g is ta ke n d uri n g t hat visit. S u bjects w ill recei ve t heir first d ose of st u d y dr u g 
u n der o bser vati o n after all ot her pr oce d ures ha ve bee n perf or me d. P h ysical 
e xa mi nati o n, cli nical la b orat or y tests, hei g ht, wei g ht,  a n d hea d circ u mfere nce 
meas ure me nts will be re peate d o nl y if t he W 0 visit is > 7 da ys after t he 
Scree ni n g visit. 
e S u perscri pt “e” a d de d t o W O a n d re m o ve d fr o m hei g ht a n d hea d circ u mfere nce, 
p h ysical e xa mi nati o n, a n d la b orat or y te st assess me nts i n t he Wee k O c o m u m n.  
i  S u perscri pt “i” re m o ve d fr o m ne ur oc o g niti ve assess me nts at F oll o w – u p/ E T V 
j Cli nical la b orat or y tests i ncl u de he mat ol o g y, c he mistr y, a n d uri nal ysis. Uri nal ysis 
ma y be  perf or me d i n t he cli nical la b or via “ di pstic k” i n c hil dre n t o o y o u n g t o 
pr o vi de a uri ne sa m ple.  
o If a s u bject’s bl o o d P he c o nce ntrati o n dr o ps bel o w 1 2 0 μ m ol/ L, at t he discreti o n 
of t he i n vesti gat or , t he s u bject’s dietar y P he restricti o n will ma y be m o difie d t o 
all o w a gra d ual  i ncrease d i nta ke of a p pr o xi matel y 5- 2 0 m g/ k g of P he per da y, 
a v oi di n g u nsta ble s wi n gs i n t he bl o o d P he val ue s..  


 
P K U- 0 1 5
 Pa ge 1 1
 
Pr o prietar y a n d C o nfi de ntial 
 
3 0 N o ve m ber 2 0 1 0 
Secti o n N o./ Title  
Re visi o n 
C o m me nts 
Rel ates t o 
C h a n ge N o. 
q Ba yle y-III, perf or me d wit hi n 6 wee ks of deter mi nati o n of K u va n res p o nsi ve ness 
i n K u va n-res p o nsi ve s u bjects a n d at e ver y 6 m o nt hs i nter vals t hereafter u ntil t he 
s u bject is ≥ 3 0 m o nt hs ol d. At t hat ti me, t he s u bject will be assesse d usi n g t he 
W P P SI-III test. If a s u bject lea ves t he st u d y bet wee n 4 t o 6 m o nt hs after t he 
prece di n g Ba yle y-III assess me nt, t his test, or t he W P P SI-III test if t he s u bject is 
ol der t ha n  ≥3 0 m o nt hs at dr o p o ut, will be d o ne at f oll o w- u p.  
r W P P SI-III, perf or me d wit hi n 6 wee ks of deter mi nati o n of K u va n res p o nsi ve ness 
i n K u va n-res p o nsi ve s u bjects, t he n y earl y t hereafter u ntil t he s u bject is ≥7 y ears 
ol d >  6  y ears ol d . At t hat ti me, t he s u bject will be assesse d usi n g t he WI S C-I V 
test. If a s u bject lea ves t he st u d y bet wee n 9 m o nt hs a n d 1 y ear after t he prece di n g 
W P P SI-III assess me nt, t his, or t he WI S C-I V test if t he s u bject is ol der t ha n 
7 y ears at dr o p o ut, will be d o ne at f oll o w- u p. 
s T he W P P SI-III has t w o f or ms. T he y o u n ger c hil dre n will be a d mi nistere d t he first 
f or m f or a ges 3 0 m o nt hs u p t o 4 y ears ol d. T he sec o n d f or m will be use d f or 
s u bjects 4 y ears of a ge u p t o 7 y ears ol d. 
ts WI S C-I V, perf or me d wit hi n 6 wee ks of deter mi nati o n of K u va n res p o nsi ve ness 
i n K u va n-res p o nsi ve s u bjects a n d e ver y 2 y ears  y earl y t hereafter. If a s u bject 
lea ves t he st u d y bet wee n 9 m o nt hs a n d 1 y ear after t he prece di n g WI S C- VI 
assess me nt, t his test will be d o ne at f oll o w- u p. 
u T he W P P SI-III or WI S C-I V will c o nti n ue t o  be a d mi nistere d o n a n a n n ual or bi-
a n n ual basis, de pe n de nt o n s u bject’s  a ge, at m o nt hs, 6 0, 7 2 a n d 8 4.  
u S u perscri pt “ u” a d de d t o WI S C-I V ne ur oc o g niti ve assess me nt i n t he M 6 0/ M 8 4 
c ol u m n.  


 
P K U- 0 1 5
 Pa ge 1 2
 
Pr o prietar y a n d C o nfi de ntial 
 
3 0 N o ve m ber 2 0 1 0 
Secti o n N o./ Title  
Re visi o n 
C o m me nts 
Rel ates t o 
C h a n ge N o. 
v 3- M o nt h i nteri m p h o ne c o ntact s h o ul d occ ur wit hi n 1 wee k of sc he d ule d 
ti me p oi nt (ie, ±  1 wee k). P h o ne calls will be perf or me d bet wee n cli nic visits t hat 
occ ur after m o nt h 6 a n d t hr o u g h M o nt h 8 4.  S u bjects will be c o ntacte d b y 
tele p h o ne t o d oc u me nt t he s u bject's wei g ht, st u d y dr u g s u p pl y, A Es, a n d C o n 
Me ds.   
v S u perscri pt “ v” re m o ve d fr o m Hei g ht, hea d circ u mfere nce  a n d a d de d t o t he Part 
2: L o n g-ter m Assess me nt of Ne ur oc o g niti ve A bilit y a n d Safet y.  
w t T he p o p ulati o n P K st u d y will be perf or me d usi n g 8 0 s u bjects, wit h at least 3 0  
1 0  s u bjects 0- 1 y ears ol d, a n d 5 0 7 0 s u bjects > 1- 6 y ears ol d w h o e nr oll i n Part 1 
of t he st u d y. See Secti o n 1 2. 3 f or details. 
4/ List of 
A b bre viati o ns a n d 
Defi niti o ns of 
Ter ms 
P D E 5  P h os p h o diesterase t y pe 5 i n hi bit or  
 
A b bre viati o ns u p date d 
t o matc h use i n 
pr ot oc ol 
1 6 
7. 4. 1/ S u m mar y of 
Ris ks 
T he m ost seri o us a d verse reacti o ns d ur i n g K u va n a d mi nistrati o n (re gar dless of 
relati o ns hi p t o treat me nt) were gastritis, s pi nal c or d i nj ur y, stre pt oc occal i nfecti o n, 
testic ular carci n o ma, a n d urinar y tract i nfecti o n. Mil d t o m o derate ne utr o pe nia was 
n ote d d uri n g K u va n a d mi nistrati o n i n 2 4 of 5 7 9  s u bjects ( 4 %). T he m ost c o m m o n 
(≥4 % of s u bjects treate d wit h K u va n) acr oss all st u dies ( n  =  5 7 9) were hea dac he, 
diarr hea, a b d o mi nal pai n, u p per res pirat or y tract i nfecti o n, p har y n g olar y n geal pai n, 
v o miti n g, a n d na usea.  
A d verse reacti o ns ha ve us ua ll y bee n mil d a n d tra nsie nt. T he i nte grate d safet y 
data base c o nsists of 5 7 9 patie nts i n K u va n cli nical trials. T hese patie nts were 
treate d at dail y d oses of 5 m g/ k g, 1 0 m g/ k g, or 2 0 m g/ k g, fr o m 8 da ys t o o ver 
C ha n ge d a d verse 
reacti o n para gra p h 
fr o m te xt i n t he 
pac ka ge i nsert t o te xt 
fr o m t he 
I n vesti gat or’s 
Br oc h ure 
9 


 
P K U- 0 1 5
 Pa ge 1 3
 
Pr o prietar y a n d C o nfi de ntial 
 
3 0 N o ve m ber 2 0 1 0 
Secti o n N o./ Title  
Re visi o n 
C o m me nts 
Rel ates t o 
C h a n ge N o. 
6 m o nt hs.  N o d ose-relate d or e xte nt of e x p os ure-relate d c ha n ge i n fre q ue nc y of 
A Es was o bser ve d. Si x seri o us a d verse e ve nts  occ urre d i n cli nical trials, n o ne were 
c o nsi dere d t o be st u d y dr u g relate d. O ne s u bject wit h dre w fr o m a cli nical trial d ue 
t o a n A E of pre g na nc y. T he m ost fre q ue nt A Es t h o u g ht t o be relate d t o K u va n i n 
place b o-c o ntr olle d trials were p har y n g olar y n geal pai n, a n d r hi n orr h oea. T he m ost 
fre q ue ntl y re p orte d a d verse reacti o ns i n all cli nical trials ( > 4 %), re gar dless of 
relati o ns hi p t o st u d y dr u g, were hea dac he, diarr hea, a b d o mi nal pai n, u p per 
res pirat or y tract i nfecti o n, p har y n g olar y n geal pai n, v o miti n g, a n d na usea.  Mil d t o 
m o derate ne utr o pe nia was n ote d d uri n g K u va n a d mi nistrati o n i n 2 4 of 5 7 9 s u bjects 
( 4 %) a n d i n 3 of 5 9 s u bjects recei vi n g place b o ( 5 %). 
9. 1/ O verall St u d y 
Desi g n a n d Pla n 
Fi g ure 9. 1. 1  
Pe diatric Safet y a n d 
Efficac y clarifie d 
4 
9. 1/ O verall St u d y 
Desi g n a n d Pla n 
Part 1: E val uati o n of K u va n Res p o nsi ve ness 
 
Be gi n ni n g at Wee k 0 … H o we ver, if a s u bject’s bl o o d P he c o nce ntrati o n dr o ps 
bel o w 1 2 0 μ m ol/ L, at t he discreti o n of t he i n vesti gat or, a gra d ual i ncrease of 
a p pr o xi matel y 5 t o 2 0 m g/ k g of  dail y dietar y P he i nta ke ma y be a d de d t o t he diet. 
It is i m p orta nt t o a v oi d u nsta ble s wi n gs i n t he bl o o d P he val ues i ncrease d b y 
5  m g/ k g i nitiall y a n d ma y be i ncrease d f urt he r at t he discreti o n of t he I n vesti gat or 
if t he s u bject’s bl o o d P he c o nce ntrati o n re mai ns bel o w 1 2 0  μ m ol/ L . …. 
Dietar y c ha n ges 
clarifie d 
3 


 
P K U- 0 1 5
 Pa ge 1 4
 
Pr o prietar y a n d C o nfi de ntial 
 
3 0 N o ve m ber 2 0 1 0 
Secti o n N o./ Title  
Re visi o n 
C o m me nts 
Rel ates t o 
C h a n ge N o. 
9. 1/ O verall St u d y 
Desi g n a n d Pla n 
Part 2: Ne ur oc o g niti ve St u d y 
S u bjects w h o are res p o nsi ve t o K u va n (see t he defi niti o n of res p o nsi ve ness i n 
I ncl usi o n a n d E xcl usi o n Eli gi bilit y Criteri o n) will … T he t y pes of ne ur oc o g niti ve 
tests use d (ie, Ba yle y Scale of I nfa nt a n d T o d dler De vel o p me nt ® T hir d E diti o n 
[ Ba yle y-III], Wec hsler Presc h o ol a n d Pri mar y Scale of I ntelli ge nce ™ T hir d 
E diti o n [ W P P SI III], a n d/ or Wec hsler I n telli ge nce Scale f or C hil dre n ® F o urt h 
E diti o n [ WI S C I V]), will be t h ose c o nsi dere d a p pr o priate f or t he s u bject’s a ge. 
Ne ur oc o g niti ve meas ure me nts i n s u bjects 0 -2 y ears ol d will be ma de e ver y si x 
m o nt hs usi n g t he Ba yle y -III u ntil s u bjects reac h a ge 3 0 m o nt hs. After a ge 3 0 
m o nt hs, W P P SI I II will be a d mi nistere d u ntil s u bjects reac h a ge 7  6 y ears. S u bjects 
≥ 7 y ears ol d  >  6 y ears ol d will be teste d usi n g WI S C I V. Ne ur oc o g niti ve testi n g 
will be c o n d ucte d usi n g W P P SI III a n d WI S C -I V e ver y 1 2 m o nt hs u ntil t he s u bject 
reac hes a ge 7, t he n t he WI S C-I V e ver y 2 y ears  y earl y t hr o u g h t he e n d of t he st u d y. 
Ne ur oc o g nit i ve meas ure me nts i n s u bjects 0-2  y ears ol d will be ma de e ver y 
6  m o nt hs usi n g t he Ba yle y -III u ntil s u bjects reac h a g e 3 0  m o nt hs. After 
a ge 3 0  m o nt hs, W P P SI -III will be a d mi nistere d u ntil s u bjects reac h a ge 7  y ears. 
S u bjects ≥ 7 y ears ol d will be teste d usi ng WI S C -I V. Ne ur oc o g niti ve testi n g will 
be c o n d ucte d usi n g W P P SI -III e ver y 1 2 m o nt hs u ntil t he s u bject reac hes a ge  7, 
t he n t he WI S C-I V e ver y 2 y ears t hr o u g h t he e n d of t he st u d y. Gr o wt h, bl o o d P he 
c o nce ntrati o n, a n d safet y will be m o nit ore d. T hese assess me n ts will be perf or me d 
e ver y 6 t o 2 4 m o nt hs, de pe n di n g o n t he t y pe of  assess me nt, u ntil t he e n d of t he 
st u d y. Refer t o Ta ble 2. 1  f or details. 
 
Clarificati o n of a ge 
ra n ges f or assess me nts
2 


 
P K U- 0 1 5
 Pa ge 1 5
 
Pr o prietar y a n d C o nfi de ntial 
 
3 0 N o ve m ber 2 0 1 0 
Secti o n N o./ Title  
Re visi o n 
C o m me nts 
Rel ates t o 
C h a n ge N o. 
T a ble 9. 1. 1 Ne ur oc o g niti ve Assess me nts  
A ge 
Gr o u p 
I nf a nc y
 Presc h o ol
  Sc h o ol- A ge
 
Assess me nt
 Ba yle y-III
  
W P P SI-III
  
W P P SI-III  
WI S C-I V
 
A ge
 0
 
m o nt hs
 
t hr o u g h 
 < 3 0 m o nt hs
≥ 3 0 m o nt hs 
t hr o u g h < 4 years
≥ 4 y ears 
t hr o u g h 
 < 7 y ears 
≥ 7 y ears a n d 
ol der 
Fre q ue nc y
 E ver y
 
6
 
m o nt hs  ± 2 
wee ks 
O nce a y ear 
 ± 2 wee ks 
O nce a 
y ear 
 ± 2 wee ks 
E ver y 
2 y ears ± 2 wee ks
 
T he Ba yle y-III will be a d mi nistere d t o s u bjects w h o are fr o m 0 m o nt hs t o 3 0 
m o nt hs of a ge a n d will be a d mi nistere d e ver y 6 m o nt hs ± 2 wee ks. At 3 0 m o nt hs 
ol d or ol der, t he s u bjects will be a d mi nistere d t he W P P SI-III. T he W P P SI-III has 
t w o f or ms. T he y o u n ger c hil dre n will be a dmi nistere d t he first f or m f or a ges 3 0 
m o nt hs t o 4 years ol d. T he sec o n d f or m will be use d f or s u bjects 4 y ears of a ge t o 
7 y ears ol d. T he W P P SI-III will be a d mi nistere d y earl y ± 2 wee ks. Be gi n ni n g at 7 
y ears ol d st u d y, s u bjects will be a d mi nistere d t he WI S C I V e ver y 2 y ears ± 2 
wee ks.  
Gr o wt h, bl o o d P he c o nce ntrati o n, a n d safe t y will be m o nit ore d. T hese assess me nts 
will be perf or me d e ver y 6 t o 2 4 m o nt hs, de pe n di n g o n t he t y pe of assess me nt, u ntil 
t he e n d of t he st u d y. Refer t o Ta ble 2. 1 f or details. 


 
P K U- 0 1 5
 Pa ge 1 6
 
Pr o prietar y a n d C o nfi de ntial 
 
3 0 N o ve m ber 2 0 1 0 
Secti o n N o./ Title  
Re visi o n 
C o m me nts 
Rel ates t o 
C h a n ge N o. 
T he st u d y will be c o nsi dere d c o m plete w h e n a p pr o xi matel y 4 5 s u bjects ha ve bee n 
f oll o we d f or 7 y ears a n d ha ve at least 2 p ost-treat me nt W P P SI III a n d/ or WI S C I V 
tests a d mi nistere d 2 y ears a part. 
After st u d y c o m pleti o n, s u bjects will be gi ve n t he o p p ort u nit y t o partici pate i n a 
re gistr y st u d y t hat will f oll o w l o n ger ter m o utc o mes. 
S u bst u d y 1:  
S afet y a n d 
Effic ac y i n 
S u bjects 0- 6 
Ye ars Ol d 
K u va n d ose ma y als o be re d uce d after wee k 5 a n d  after c o ns ultati o n wit h t he 
Me dical M o nit or if t he s u bject d oes n ot t olerate t he a p pr o xi matel y 5- 2 0 m g/ k g/ da y 
d ose. 
Clarificati o n of w he n 
t he d ose ma y be 
c ha n ge d. 
8 
9. 1/ O verall St u d y 
Desi g n a n d Pla n 
F or t he p o p ulati o n P K e val uati o n, t he first 3 0  1 0 s u bjects i n t he 0- 1 y ear a ge gr o u p 
a n d t he first 5 0  7 0 s u bjects i n t he > 1- 6 year a ge gr o u p …. 
Beca use of greater 
t ha n e x pecte d 
res p o nse rate i n t he 
u n der 1 y ear a ge 
gr o u p t he 
de m o gra p hics were 
c ha n ge d   
6 
9. 2/ Disc ussi o n of 
St u d y Desi g n, 
I ncl u di n g C h oice 
of C o ntr ol Gr o u p 
 
… D uri n g S u bst u d y 1 ( M o nt hs 2 –  6), safet y a n d efficac y assess me nts will be 
c o n d ucte d wee kl y d uri n g Wee k 0 t o Wee k 4, t he n  m o nt hl y f or M o nt hs 2 t hr o u g h 
M o nt h 6.  
Clarificati o n of 
pr oce d ures 
1 5 


 
P K U- 0 1 5
 Pa ge 1 7
 
Pr o prietar y a n d C o nfi de ntial 
 
3 0 N o ve m ber 2 0 1 0 
Secti o n N o./ Title  
Re visi o n 
C o m me nts 
Rel ates t o 
C h a n ge N o. 
9. 3. 2/ E xcl usi o n 
Criteria 
•  Use of p h os p h o diesterase t y pe 5 i n hi bit or,  ofte n s h orte ne d t o P D E 5 i n hi bit or 
(e g.sil de nafil citrate, var de nafil, ta dalafil, a va nafil, l o de nafil, mir o de nafil, 
u de nafil)  
A d de d t o E xcl usi o n 
criteria per 
rec o m me n dati o n b y 
re g ulat or y a ut h orities 
1 
9. 4. 1/ Treat me nts 
A d mi nistere d 
I n Part 1, be gi n ni n g at Wee k 0, su bjects will recei ve K u va n at a d ose of 2 0 
m g/ k g/ da y orall y, pr o vi de d i n ta blets t hat eac h c o ntai n 1 0 0 m g of sa pr o pteri n, f or a 
t otal of 4 wee ks. All st u d y dr u g will be take n i n t he diss ol ve d f or m t hr o u g h o ut t he 
st u d y. F or ease i n a d mi nistrati o n a n d i nstr uctio n t o t he fa milies, t he d ose ca n als o 
be r o u n de d u p or d o w n:  
F or c hil dre n w h o are ol der a n d ca n ta ke t heir me dicati o n fr o m a c u p or glass, 
r o u n di n g of t he d ose t o t he nearest w h ole ta blet is acce pta ble. F or e xa m ple, a c hil d 
wei g hi n g 1 1 k g w o ul d ha ve a d ose of 2 2 0 m g  of K u va n w hic h t hat ma y be r o u n de d 
d o w n t o 2 0 0 m g ( 2 ta blets). A c hil d wei g hi n g 1 4 k g w o ul d ha ve a d ose of 2 8 0 m g 
t hat ma y be r o u n de d u p t o 3 0 0 m g ( 3 ta blets). 
W het her t he d ose is deter mi ne d usi n g Ta ble 9. 4. 4. 1 or b y r o u n di n g t he d osa ge u p 
or d o w n, be c o nsiste nt wit h t he met h o d. T his is es peciall y i m p orta nt t hr o u g h Wee k 
4 w he n res p o nsi ve ness is bei n g deter mi n e d.  
T he first d ose i n Part 1 will be ta ke n at  t he Wee k 0 visit u n der o bser vati o n, after 
t he c o m pleti o n of all ot her st u d y pr oce d ures. T he re mai ni n g d oses i n Part 1 will be 
ta ke n dail y at t he sa me ti me wit h t he m or ni n g meal wit h f o o d t o i ncrease 
a bs or pti o n, prefera bl y at t he sa me ti me eac h da y. T he K u va n d ose ca n n ot be 
a dj uste d d uri n g Part 1 wit h o ut c o ns ultati o n wit h t he Me dical M o nit or. S u bjects 
w h o are e nr olle d i nt o Part 2 will i nitiall y c o nti n ue t o ta ke 2 0 m g/ k g/ da y K u va n 
wit h t he m or ni n g meal  at t he sa me ti me eac h da y wit h a meal. Aft er wee k 5, at t he 
discreti o n of t he I n vesti gat or a n d after c o ns ultati o n wit h t he Me dical M o nit or, a 
D ose a d mi nistrati o n 
a n d r o u n di n g clarifie d 
8 


 
P K U- 0 1 5
 Pa ge 1 8
 
Pr o prietar y a n d C o nfi de ntial 
 
3 0 N o ve m ber 2 0 1 0 
Secti o n N o./ Title  
Re visi o n 
C o m me nts 
Rel ates t o 
C h a n ge N o. 
s u bject’s K u va n d ose ma y be l o were d if t he s u bject d oes n ot t olerate t he 2 0 
m g/ k g/ da y d ose. 
9. 4. 2. 1/ Pr o d uct 
C h ar acteristics 
a n d L a beli n g 
… Ta blets are r o u n d, ra n gi n g fr o m  off w hite t o li g ht yell o w, li g ht ora n ge/ pi n k, 
bei ge, or m ottle d (s pec kle d) a p peara nce , a n d de b osse d wit h “ 1 7 7”. 
Ta blet c ol or clarifie d  
1 1 
9. 4. 4/ Directi o ns 
f or A d mi nistrati o n 
K u va n (sa pr o pteri n di h y dr oc hl ori de) ta blets s h o ul d be a d mi nistere d orall y at t he 
m or ni n g meal  wit h f o o d t o i ncrease a bs or pti o n, prefera bl y at t he sa me ti me eac h 
da y wit h a meal. K u va n ta blets ca n  s h o ul d be diss ol ve d i n 4 t o 8 oz. ( 1 2 0 t o 2 4 0 
m L) of water or a p ple j uice … all of t he me dici ne is ta ke n. A d mi nistrati o n of 
cr us he d K u va n ta blets ma y als o be stirre d i n s oft f o o ds s uc h as a p ple sa uce or 
le m o n p u d di n g. A misse d d ose … 
At t he discreti o n of t he I n vesti gat or, ta blets ma y be diss ol ve d i n as little as 5 m L 
water or a p ple j uice per ta blet , base d o n t he s u bject’s size a n d ca pa bilit y. F or 
i nfa nts wei g hi n g < 5 k g, a si n gle K u va n ta blet … of t his K u va n s ol uti o n. A d osi n g 
ta ble f or s u bjects wei g hi n g 2 0 1 0 k g a n d less is s h o w n bel o w ( Ta ble 9. 4. 4. 1). 
S oft f o o ds a d de d f or 
ease of a d mi nistrati o n. 
8 


 
P K U- 0 1 5
 Pa ge 1 9
 
Pr o prietar y a n d C o nfi de ntial 
 
3 0 N o ve m ber 2 0 1 0 
Secti o n N o./ Title  
Re visi o n 
C o m me nts 
Rel ates t o 
C h a n ge N o. 
9. 4. 4/ Directi o ns 
f or A d mi nistrati o n 
Ta ble 9. 4. 4. 1:  K u va n D osi n g Ta ble f or Y o u n g C hil dre n 
C hil d’s 
Wei g ht 
( k g) 
D ose Gi ve n 
( Milli gr a ms) 
m L of 
S ol uti o n 
N o. of 1 0 0 
m g T a blets 
Diss ol ve d 
m L 
A d mi nistere d t o 
S u bject 
1
 2 0
  5
  1
  
1
 
2
 4 0
  5
  1
  
2
 
3
 6 0
  5
  1
  
3
 
4
 8 0
  5
  1
  
4
 
5
 1 0 0
  5
  1
  
5
 
6
 1 2 0
 1 0
  2
  
6
 
7
 1 4 0
 1 0
  2
  
7
 
8
 1 6 0
 1 0
  2
  
8
 
9
 1 8 0
 1 0
  2
  
9
 
1 0
 2 0 0
  1 0
  2
  
1 0
 
1 1  2 2 0
 1 5
 
3 1 1
 
1 2  2 4 0
 1 5
 
3 1 2
 
D ose a d mi nistrati o n 
clarificati o n 
8 


 
P K U- 0 1 5
 Pa ge 2 0
 
Pr o prietar y a n d C o nfi de ntial 
 
3 0 N o ve m ber 2 0 1 0 
Secti o n N o./ Title  
Re visi o n 
C o m me nts 
Rel ates t o 
C h a n ge N o. 
1 3  2 6 0
 1 5
 
3 1 3
 
1 4  2 8 0
 1 5
 
3 1 4
 
1 5  3 0 0
 1 5
 
3 1 5
 
1 6  3 2 0
 2 0
 
4 1 6
 
1 7  3 4 0
 2 0
 
4 1 7
 
1 8  3 6 0
 2 0
 
4 1 8
 
1 9  3 8 0
 2 0
 
4 1 9
 
2 0  4 0 0
 2 0
 
4 2 0
 
 
9. 4. 6. 1/ Selecti o n 
of Ti mi n g of D ose 
f or Eac h S u bject 
Ta ki n g t he dail y d ose i n t he m or ni n g  at t he sa me ti me of da y wit h a meal ma y hel p 
t o facilitate treat me nt c o m plia nce. 
D ose a d mi nistrati o n 
clarificati o n 
8 


 
P K U- 0 1 5
 Pa ge 2 1
 
Pr o prietar y a n d C o nfi de ntial 
 
3 0 N o ve m ber 2 0 1 0 
Secti o n N o./ Title  
Re visi o n 
C o m me nts 
Rel ates t o 
C h a n ge N o. 
9. 6/ Dietar y or 
Ot her Pr ot oc ol 
Restricti o ns 
S u bjects a n d t heir pare nt(s) or g uar dia n(s)  m ust be willi n g t o a d here t o a prescri be d 
P he restricte d diet i n or der t o mai ntai n bl o o d P he c o nce ntrati o ns wit hi n t he 
rec o m me n de d ra n ges esta blis he d at t he s u bject’s st u d y site. T he g oal f or bl o o d P he 
c o nce ntrati o n d uri n g t he st u d y is ≤ 2 4 0 µ m ol/ L. F oll o wi n g sta n dar d of care, all 
s u bjects a n d t heir pare nt(s) or g uar dia n(s) will meet wit h a st u d y dieticia n 
n utriti o nist  at eac h visit t o re vie w dietar y P he i nta ke. A 3 da y dietar y rec or d … 
Clarificati o n
 3
 
9. 6/ Dietar y or 
Ot her Pr ot oc ol 
Restricti o ns 
If bl o o d P he le vels fall bel o w 1 2 0 µ m ol/ L, dietar y P he ma y be a d de d … be 
m o nit ore d cl osel y. I ncreases i n P he s u p p le me nt will be base d o n bl o o d P he le vel, 
a ge, a n d i deal b o d y wei g ht f or a s u bject’s ge n der, wei g ht, a n d hei g ht. 
•  
If a s u bject’s bl o o d P he falls bel o w 1 2 0 μ m ol/ L, at t he discreti o n of t he 
i n vesti gat or, a gra d ual i ncrease of a p pr o xi matel y 5- 2 0 m g/ k g of P he 
s u p ple me nt ma y be a d de d t o t he diet. It is i m p orta nt t o a v oi d u nsta ble 
s wi n gs i n t he bl o o d P he val ues 
•  
If a s u bject’s bl o o d P he le vel g oes a b o ve 2 4 0 μ m ol/ L, dietar y P he will  ma y 
be decrease d b y a p pr o xi matel y 5 t o 2 0 m g/ k g or defi ne d b y t he sta n dar d 
use d at eac h treat me nt ce nter, at t he discreti o n of t he i n vesti gat or. 
Dietar y c ha n ges 
clarifie d 
3 
9. 7. 1. 2/ P h ysical 
E xa mi nati o n 
Fi n di n gs 
C o m plete p h ysical e xa mi n ati o ns will i n cl u de t he e val uati o n of all maj or b o d y 
s yste ms, hei g ht, wei g ht, a n d hea d circu mfere nce. Ot her b o d y s yste ms ma y be 
e xa mi ne d. Da y 1  Wee k 1 of Part 1 res ults will be t he baseli ne val ues, a n d cli nicall y 
si g nifica nt c ha n ges fr o m baseli ne will b e rec or de d as a n A E. 
 
Clarificati o n of 
pr oce d ures 
1 5 


 
P K U- 0 1 5
 Pa ge 2 2
 
Pr o prietar y a n d C o nfi de ntial 
 
3 0 N o ve m ber 2 0 1 0 
Secti o n N o./ Title  
Re visi o n 
C o m me nts 
Rel ates t o 
C h a n ge N o. 
9. 7. 1. 4/ Bl o o d P he 
C o ntr ol 
Sa m ples f or bl o o d P he c o nce ntrati o n s h o ul d be dra w n si m ulta ne o usl y wit h 
sa m ples dra w n f or P K o n da ys w he n b ot h t y pes of bl o o d dra w are re q uire d. Wit h 
t he e xce pti o n of Da y 1 t he P K sa m ples ( Part 1), bl o o d f or P he c o nce ntrati o n 
meas ure me nts …i n t he Sc he d ule of E ve nts ( Ta ble 2. 1).  
Clarificati o n
 7
 
9. 7. 2 / Pri mar y 
Efficac y Varia ble 
Ne ur oc o g niti ve testi n g will be perf or me d wit hi n 6 wee ks of deter mi nati o n of 
K u va n res p o nsi ve ness i n all K u va n-res p o nsi ve s u bjects. S u bse q ue nt 
ne ur oc o g niti ve meas ure me nts will be o btai ne d  e ver y 6 m o nt hs u ntil t he s u bject is  
> ≥ 3 0 m o nt hs ol d … 
Clarificati o n or a ge 
gr o u ps f or 
ne ur oc o g niti ve testi n g 
2 
9. 7. 3/ Sec o n dar y 
Efficac y Varia bles 
 
T he first  sec o n dar y efficac y e n d p oi nt is c ha n ge i n de vel o p me ntal gr o wt h fact ors, 
as meas ure d b y hei g ht, wei g ht,  a n d hea d circ u mfere n ce fr o m baseli ne. T hese 
meas ure me nts will be ma d e at Scree ni n g, Wee k 0, Wee k 4, M o nt h 3, M o nt h 6, a n d 
e ver y 6 m o nt hs t hereafter. , w hile t he wei g ht will be meas ure d at e ver y visit.  T he 
sec o n d sec o n dar y efficac y varia ble is t he baseli ne a n d 6- m o nt h f oll o w u p 
ne ur oc o g niti ve testi n g res ults us i n g Ba yle y-III i n c hil dre n a ge 0 t o less t h a n 
3 0 m o nt hs ol d.  
Wei g ht delete d fr o m 
hei g ht, wei g ht a n d 
hea d circ u mfere nce 
2, 5 
Ta ble 9. 7. 4. 1. 1:  
Cli nical 
La b orat or y Tests  
 
C hl ori de  
Uri nal ysis ma y be perf or me d i n t he cli ni cal la b or via “ di pstic k” i n c hil dre n t o o 
y o u n g t o pr o vi de a uri ne sa m ple  
C hl ori de was a d de d as 
part of t he electr ol yte 
e val uati o n i n t he 
c he mistr y pa nel. 
Uri ne testi n g was 
clarifie d.  
1 2 


 
P K U- 0 1 5
 Pa ge 2 3
 
Pr o prietar y a n d C o nfi de ntial 
 
3 0 N o ve m ber 2 0 1 0 
Secti o n N o./ Title  
Re visi o n 
C o m me nts 
Rel ates t o 
C h a n ge N o. 
1 1. 1 / 
Ne ur oc o g niti ve 
Assess me nts 
 
T he Ba yle y-III is a t o ol f or assessi n g all facets of de vel o p me nt i n i nfa nts wit hi n a n 
a ge ra n ge of 1 2 m o nt hs u p  t o 3 0 m o nt hs, wit h n or mati ve data …  
T he W P P SI-III is a t o ol f or assessi n g t he i n telli ge nce of c hil dre n 2 y ears 6 m o nt hs 
t hr o u g h ≥ 3 0 m o nt hs t hr o u g h <7 y ears 3 m o nt hs ol d. T he W P P SI-III is 
a d mi nistere d o n t w o f or ms as a ge a p pr o priate …. 
T he WI S C-I V assesses t he i n telli ge nce of c hil dre n 6 7 y ears 0 m o nt hs t hr o u g h 
1 6 y ears 1 1 m o nt hs ol d. … 
 
Clarificati o n of are 
gr o u ps f or assess me nt 
2 
1 2. 1. 2/ Scree ni n g 
Visit 
 
•  
… 
•  
Wei g ht  
•  
Hei g ht, wei g ht,  a n d hea d circ u mfere nce 
•  
… 
•  
Pre g na nc y test if, i n t he esti mati o n of t he i n vesti gat or, t he s u bject has 
reac he d c hil d- beari n g p ote ntial. ( A ser u m pre g na nc y test will be 
perf or me d i n t he e ve nt of a n y p ositi ve or e q ui v ocal uri ne pre g na nc y 
test res ult.) 
Wei g ht was se parate d 
fr o m hei g ht a n d hea d 
circ u mfere nce a n d 
a d de d t o e ver y visit 
5, 


 
P K U- 0 1 5
 Pa ge 2 4
 
Pr o prietar y a n d C o nfi de ntial 
 
3 0 N o ve m ber 2 0 1 0 
Secti o n N o./ Title  
Re visi o n 
C o m me nts 
Rel ates t o 
C h a n ge N o. 
1 2. 1. 3. 1/ Wee k 0  
Da y  1  Visit 
Wit hi n 2 8 da ys of c o m pleti n g scree ni n g asse ss me nts, t he f oll o wi n g st u d y acti vities 
will be perf or me d o n Da y  1  (Wee k 0)  of Part 1. Assess me nts will b e d o ne pre d ose 
u nless ot her wise s pecifie d: 
•  
Wei g ht  
•  
Hei g ht, wei g ht, a n d hea d circ u mfere nces  
•  
Dietar y re vie w wit h n utriti o nist  dieticia n 
•  
P h ysical e xa mi nati o n if >  7  da ys after Scree ni n g  
•  
Cli nical la b orat or y tests i f > 7  da ys after Scree ni n g 
•  
Bl o o d P he c o nce ntrati o n if  >  7 da ys after Scree ni n g  . … 
•  
Pre g na nc y test if, i n t he esti mati o n of t he i n vesti gat or, t he s u bject has 
reac he d c hil d- beari n g p ote ntial. ( A ser u m pre g na nc y test will be 
perf or me d i n t he e ve nt of a n y p ositi ve or e q ui v ocal uri ne pre g na nc y test 
res ult.) 
•  
P h ysical e xa mi nati o n, cli nical la b orat or y tests, hei g ht a n d hea d 
circ u mfere nce meas ure me nts will be re peate d o nl y if t he Wee k 0 visit is 
> 7 da ys after t he Scree ni n g visit  
•  
Dis pe nse St u d y Dr u g  
Wei g ht was se parate d 
fr o m hei g ht a n d hea d 
circ u mfere nce a n d 
a d de d t o e ver y visit 
a n d visit pr oce d ure 
clarificati o n 
5, 1 5 


 
P K U- 0 1 5
 Pa ge 2 5
 
Pr o prietar y a n d C o nfi de ntial 
 
3 0 N o ve m ber 2 0 1 0 
Secti o n N o./ Title  
Re visi o n 
C o m me nts 
Rel ates t o 
C h a n ge N o. 
1 2. 1. 3. 2/ Wee k 1 
t hr o u g h Wee k 4 
Visits ( ± 2 da ys) 
•  
Wei g ht  
•  
… 
•  
Dietar y re vie w wit h n utriti o nist P he m o dificati o n (if necessar y) wit h 
dieticia n 
Wei g ht a d de d dietar y 
re vie w clarifie d 
5, 1 5 
1 2. 1. 3. 4/ Wee k 4 
Visit O nl y 
( ± 2 da ys) 
Wee k 4 Visit o O nl y ( ±  2 da ys) 
 
•  
P h ysical e xa mi nati o n ( Wee k 4 o nl y)  
•  
Hei g ht, wei g ht , a n d hea d circ u mfere nce ( Wee k 4 o nl y) 
•  
Pre g na nc y test if, i n t he esti mati o n of t he i n vesti gat or, t he s u bject has 
reac he d c hil d- beari n g p ote ntial ( Wee k 4 o nl y) ( A ser u m pre g na nc y test 
will be perf or me d i n t he e ve nt of a n y p ositi ve or e q ui v ocal uri ne 
pre g na nc y test res ult)  
Title c ha n ge a n d 
clarificati o n of visits 
5, 1 5 


 
P K U- 0 1 5
 Pa ge 2 6
 
Pr o prietar y a n d C o nfi de ntial 
 
3 0 N o ve m ber 2 0 1 0 
Secti o n N o./ Title  
Re visi o n 
C o m me nts 
Rel ates t o 
C h a n ge N o. 
1 2. 1. 4. 1/ M o nt h 2 -
3  M o nt h 2- 5 ( ± 5 
d a ys)  
•  
Vital si g ns  
•  
Wei g ht  
•  
Cli nical la b orat or y tests  
•  
Bl o o d P he c o nce ntrati o n  
•  
C o nc o mita nt me dicati o ns  
•  
Assess me nt of A Es  
•  
Dietar y re vie w wit h P he m o dificati o n (if necessar y) wit h a dieticia n  
•  
Dis pe nse St u d y Dr u g  
Title c ha n ge d a n d 
pr oce d ures clarifie d 
1 5 
1 2. 1. 4. 1  / Mo nt h 2 -
3 (  ±  5 da ys), 
1 2. 1. 4. 2 M o nt h 
2/ Visit O nl y 
( ± 5 d a ys)  
•  
A d mi nistrati o n of a ge-a p pr o priate I Q test; t his test m ust be c o m plete d 
wit hi n 6 wee ks of deter mi nati o n of K u va n res p o nsi ve ness i n 
K u va n-res p o nsi ve s u bjects w h o c o nti n ue i nt o t he Ne ur oc o g niti ve St u d y 
 
C ha n ge d secti o n 
n u m ber a n d title 
1 5 
1 2. 1. 4. 2 M o nt h 3 
(±- 5 da ys) 
1 2. 1. 4. 3/ M o nt h 3 
a n d 6 Visits O nl y 
( ± 5 d a ys) 
•  
Hei g ht a n d hea d circ u mfere nce  
•  
P h ysical e xa mi nati o n  
C ha n ge d secti o n 
n u m ber a n d title a n d 
pr oce d ures clarifie d 
1 5 
1 2. 1. 4. 4/ M o nt h 6 
Visit O nl y 
( ± 5 d a ys) 
•  
Pre g na nc y test, if i n t he esti mati o n of t he i n vesti gat or, t he s u bject has 
reac he d c hil d- beari n g p ote ntial ( A ser u m pre g na nc y test will be 
perf or me d i n t he e ve nt of a n y p ositi ve or e q ui v ocal uri ne pre g na nc y 
Secti o n a d de d wit h 
Title a n d pr oce d ure 
clarificati o n 
1 5 


 
P K U- 0 1 5
 Pa ge 2 7
 
Pr o prietar y a n d C o nfi de ntial 
 
3 0 N o ve m ber 2 0 1 0 
Secti o n N o./ Title  
Re visi o n 
C o m me nts 
Rel ates t o 
C h a n ge N o. 
 
test res ult.)  
•  
6- m o nt h re peat testi n g wit h Ba yle y-III i n c hil dre n 0- 2 y ears ol d at 
e nr oll me nt 
 
1 2. 1. 4. 3/ 6 -M o nt h 
Visits, Starti n g at 
M o nt h 6 ( M o nt hs 
6, 1 2, 1 8, etc. +  2 
wee ks   
1 2. 1. 4. 5 
M o nt hs 6, 1 2, 1 8, 
2 4,  3 0, etc. ( 6 
m o nt h i nter v als 
± 2 wee ks)  
 
•  
Wei g ht  
•  
Hei g ht, wei g ht,  a n d hea d circ u mfere nce 
•  
Dietar y re vie w wit h n utriti o nist  P he m o dificati o n (if necessar y) wit h a 
dieticia n …  
•  
Pre g na nc y test if, i n t he esti mati o n of t he i n vesti gat or, t he s u bject has 
reac he d c hil d- beari n g p ote ntial. ( A ser u m pre g na nc y test will be perf or me d 
i n t he e ve nt of a n y p ositi ve or e q ui v ocal uri ne pre g na nc y test res ult.) 
•  
Bl o o d tr y pt o p ha n a n d t yr osi ne M o nt h 6 a n d 1 2, t he n y earl y  (starti n g at 
M o nt h 1 2) 
•  
Ne ur oc o g niti ve tests wit h Ba yle y -III u ntil t he s u bject reac hes a ge 3 0 
m o nt hs  (see Secti o n 2. 1 S u m mar y of E ve nts a n d Secti o n 9 I n vesti gati o nal 
Pla n)  
C ha n ge d secti o n 
n u m ber a n d title a n d 
pr oce d ures clarifie d 
5, 1 5 
1 2. 1. 4. 4  Yearl y 
Visits ( M o nt hs 1 2, 
2 4, 3 6, 4 8, etc. +  2 
wee ks)   
•  
Vital si g ns  
•  
Bl o o d P he c o nce ntrati o n  
•  
Hei g ht, wei g ht, a n d hea d circ u mfere nce  
C ha n ge d secti o n 
n u m ber a n d title a n d 
visit pr oce d ures 
clarifie d 
1 5 


 
P K U- 0 1 5
 Pa ge 2 8
 
Pr o prietar y a n d C o nfi de ntial 
 
3 0 N o ve m ber 2 0 1 0 
Secti o n N o./ Title  
Re visi o n 
C o m me nts 
Rel ates t o 
C h a n ge N o. 
1 2. 1. 4. 6/ M o nt hs 
1 2, 2 4, 3 6, 4 8, 6 0, 
7 2 a n d 8 4 ( a n n u al 
i nter v als ± 2 
wee ks) 
•  
P h ysical e xa mi nati o n  
•  
Cli nical la b orat or y tests  
•  
Pre g na nc y test if, i n t he esti mati o n of t he i n vesti gat or, t he s u bject has 
reac he d c hil d-beari n g p ote ntial  
•  
C o nc o mita nt me dicati o ns  
•  
Dietar y re vie w wit h n utriti o nist  
•  
Assess me nt of A Es  
•  
Dis pe nse St u d y Dr u g  
•  
Bl o o d tr y pt o p ha n, a n d  t yr osi ne ( Starti n g at M o nt h 1 2) 
•  
Ne ur oc o g niti ve tests usi n g W P P SI III or WI S C I V (starti n g at M o nt h 1 2; 
perf or me d e ver y 1 2 m o nt hs u ntil t he s u bject reac hes a ge 7, t he n e ver y 2 
y ears t hr o u g h t he e n d of t he st u d y.)  
•  
 


 
P K U- 0 1 5
 Pa ge 2 9
 
Pr o prietar y a n d C o nfi de ntial 
 
3 0 N o ve m ber 2 0 1 0 
Secti o n N o./ Title  
Re visi o n 
C o m me nts 
Rel ates t o 
C h a n ge N o. 
1 2. 1. 4. 7 3- M o nt h 
I nteri m P h o ne 
C o ntact ( M o nt hs 
9, 1 5, 2 1, 2 7, etc, 
±  1 wee k)  
•  
Wei g ht  
•  
Assess me nt of A Es  
•  
C o nc o mita nt Me dicati o ns  
•  
Dis pe nsi n g St u d y Dr u g  
Secti o n a d de d.  
Clarificati o n of visit 
pr oce d ures 
5, 1 5 
1 2. 1. 5 Earl y 
Ter mi nati o n a n d 
F oll o w u p Visit(s) 
( wit hi n 2 8 +/- 3 
da ys of last d ose 
of st u d y dr u g) 
E ver y s u bject s h o ul d c o m plete  eit her a F oll o w- u p or T er mi nati o n Visit, t o e n d 
t heir partici pati o n i n t he st u d y.  T he F ollo w- u p Visit is c o m plete d b y a s u bject w h o 
c o m pletes o nl y Part 1 of t he st u d y, or w h o is e nr olle d i nt o Part 2 a n d c o m pletes 
Part 2.  T he Ter mi nati o n Visit is c o m p lete d b y a s u bject w h o wit h dra ws or is 
disc o nti n ue d fr o m t he st u d y.  T he F oll o w- u p or Ter mi nati o n Visit s h o ul d occ ur 2 8 
da ys after t he s u bject’s fi nal d ose of dr u g . E ver y reas o na ble eff ort will be ma de t o 
ha ve t he s u bject c o m plete a F oll o w- u p or Ter mi nati o n Visit.  If t he s u bject d oes 
n ot c o m plete a F oll o w- u p or Ter mi nati o n Vi sit i n t he cli nic, mi ni mall y a f oll o w- u p 
p h o ne call will be ma de.  
•  
Dietar y re vie w wit h n utriti o nist (if visit is re q uire d)  dieticia n 
•  
P h ysical e xa mi nati o n (if visit is re q uire d)   (if at a cli nic visit) 
•  
Vital si g ns (if visit is r e q uire d)  (if at a cli nic visit) 
•  
Wei g ht  
•  
Hei g ht, wei g ht a n d hea d circ u mfere nce (if visit is re q uire d)   (if at a cli nic 
visit)  
•  
Cli nical la b orat or y tests (if visit is re q uire d)   (if at a cli nic visit) 
Clarificati o n of visit 
pr oce d ures 
1 3, 1 5 


 
P K U- 0 1 5
 Pa ge 3 0
 
Pr o prietar y a n d C o nfi de ntial 
 
3 0 N o ve m ber 2 0 1 0 
Secti o n N o./ Title  
Re visi o n 
C o m me nts 
Rel ates t o 
C h a n ge N o. 
•  
Bl o o d tr y pt o p ha n a n d t yr osi ne (if visit is re q uire d)   (if at a cli nic visit) 
•  
Pre g na nc y test, if i n t he esti mati o n of t he i n vesti gat or, t he s u bject has 
reac he d c hil d- beari n g p ote ntial ( A ser u m pre g na nc y test will be perf or me d 
i n t he e ve nt of a n y p ositi ve or e q ui v ocal uri ne pre g na nc y test res ult. (if at a 
cli nic visit) 
•  
Ne ur oc o g niti ve test usi n g Ba yle y-III if t he f oll o w u p or earl y ter mi nati o n 
visit is 4- 6 m o nt hs after t he last assess me nt.  
•  
Ne ur oc o g niti ve tests usi n g W P P SI III or WI S C I V if t he f oll o w- u p or earl y 
ter mi nati o n visit is 9 m o nt hs or m ore after t he last assess me nt (if at a cli nic 
visit) …  
1 2. 2. 2  M o nt hl y  
Visits ( M o nt hs 2 -
6 ( ± 5 Da ys) 
 
•  
Wei g ht  
•  
Dietar y re vie w wit h n utriti o nist P he m o dificati o n (if necessar y) wit h a 
dieticia n   
Wei g ht a d de d a n d 
clarificati o n of visit 
pr oce d ures 
5, 1 5 
1 2. 2. 3  M o nt hs  3  
a n d 6 O nl y ( ± 5 
D a ys)  
•  
Hei g ht, wei g ht,  a n d hea d circ u mfere nce 
 
Title m o difie d a n d 
wei g ht re m o ve d fr o m 
Hei g ht, wei g ht, a n d 
hea d circ u mfere nce. 
1 5 
1 2. 2. 4  M o nt h  6  
O nl y ( + 3 0 da ys)  
( ± 2 wee ks) 
•  
Pre g na nc y test, if i n t he esti mati o n of t he i n vesti gat or, t he s u bject has 
reac he d c hil d- beari n g p ote ntial ( A ser u m pre g na nc y test will be perf or me d 
i n t he e ve nt of a n y p ositi ve or e q ui v ocal uri ne pre g na nc y test res ult.) 
Title m o difie d  a n d 
clarificati o n of visit 
pr oce d ures 
1 5 
1 2. 2. 5 Earl y 
Secti o n delete d 
Earl y Ter mi nati o n 
N A 


 
P K U- 0 1 5
 Pa ge 3 1
 
Pr o prietar y a n d C o nfi de ntial 
 
3 0 N o ve m ber 2 0 1 0 
Secti o n N o./ Title  
Re visi o n 
C o m me nts 
Rel ates t o 
C h a n ge N o. 
Ter mi nati o n fr o m 
S u bst u d y 1 ( wit hi n 
2 8 +/- 3 da ys of 
last d ose of st u d y 
dr u g) 
 
secti o n c o vere d i n 
Secti o n 1 2. 1. 5 
1 2. 3/ S u bst u d y 2: 
P o p ulati o n 
P har mac o ki netic 
St u d y i n S u bjects 
0 6 Years Ol d 
A p o p ulati o n P K st u d y will be c o m plete d i n a t otal of 8 0 s u bjects. Of t hese 8 0 
s u bjects, 1 0 3 0 will be a ges 0 t o ≤ 1 y ears a n d 7 0 5 0 will be > 1 t o 6 y ears ol d. 
S u bjects will ta ke t heir d ose i n t he m or ni n g at t he sa me ti me of da y wit h a meal, per 
site i nstr ucti o ns, t o o btai n sa m ples f or t he p o p ulati o n P K a nal ysis wit hi n t he 
s pecifie d ti me wi n d o ws (e g, bef ore d osi n g a n d 0. 2 2 t o 8 h o urs or 7 t o 4 8 0 mi n utes, 
after d osi n g). T he e xact ti mes of d osi n g will be rec or de d. Bl o o d sa m ples will still 
nee d t o  be c ollecte d a p pr o xi matel y 2. 5 t o 5 h o urs after brea kfast t he meal t o o btai n 
bl o o d P he c o nce ntrati o ns w hile i n P h ase 1 of t his st u d y ( Wee k 0- Wee k 6) ….  
Clarificati o n of P K 
a ge ra n ge a n d bl o o d 
sa m ple ti mi n g 
6, 7 


 
P K U- 0 1 5
 Pa ge
 
3 2
 
 
Pr o prietar y a n d C o nfi de ntial 
3 0 N o ve m ber 2 0 1 0 
2  
S Y N O P SI S 
N A M E O F C O M P A N Y 
Bi o Mari n P har mace utical I nc. 
1 0 5 Di gital Dri ve 
N o vat o, C A 9 4 9 4 9 
 
N A M E O F FI NI S H E D P R O D U C T: 
K u va n ®  
 
N A M E O F A C TI V E I N G R E DI E N T: 
sa pr o pteri n di h y dr oc hl ori de; 6 R- B H 4 
S U M M A R Y T A B L E 
Referri n g t o Part of t he 
D ossier: 
 
V ol u me:  
 
Pa ge:    
 
Refere n ce:  
F O R N A TI O N A L 
A U T H O RI T Y U S E 
O N L Y: 
TI T L E O F S T U D Y:  
A P hase 3 b O pe n- La bel St u d y t o E val uate t he Effect of K u va n ®  o n Ne ur oc o g niti ve F u ncti o n, 
Mai nte na nce of Bl o o d P he n ylala ni ne C o nce ntrati o ns, Safet y, a n d P o p ulati o n P har mac o ki netics i n 
Y o u n g C hil dre n wit h P he n yl ket o n uria 
P R O T O C O L N U M B E R : 
P K U- 0 1 5 
S T U D Y SI T E S: 
U p t o 4 0 sites 
P H A S E O F D E V E L O P M E N T: 
3 b 
S T U D Y R A TI O N A L E: 
Ri g or o us c o ntr ol of diet is t y picall y a d v ocate d i n c hil dre n 4 y ears a n d u n der wit h p he n yl ket o n uria 
( P K U) beca use brai n se nsiti vit y t o hi g h p he n ylala ni ne ( P he) c o nce ntrati o n is e x pecte d t o be greatest 
d uri n g t hese y ears of ra pi d ne ur oc o g niti ve de vel o p me nt. A m o n g P K U patie nts, t he str o n gest 
deter mi na nt of i ntelli ge nce q u otie nt (I Q) a n d c o g niti ve f u ncti o n is c o m plia nce wit h bl o o d P he c o ntr ol. 
Se veral cli nical st u dies wit h K u va n ha ve alrea d y de m o nstrate d efficac y i n re d uci n g bl o o d P he i n 
s u bjects ol der t ha n 4 y ears. T his st u d y will e xa mi ne w het her use of K u va n at a n earlier a ge preser ves 
ne ur oc o g niti ve f u ncti o n a n d n or mal gr o wt h, as well as pr o vi di n g l o n g-ter m safet y data a n d efficac y 
data f or c o ntr olli n g bl o o d P he c o nce ntrati o ns wit h i n acce pta ble ra n ges. I n a d diti o n, 2 s u bst u dies will 
be c o n d ucte d. S u bst u d y 1 will pr o vi de 6 m o nt hs of safet y, efficac y, a n d ne ur oc o g niti ve data i n 
s u bjects 0- 6 years ol d. S u bst u d y 2 will pr o vi de p h ar mac o ki netic data i n c hil dre n 0- 6 y ears ol d. 
O B J E C TI V E S:  
Pri mar y O bjecti ve  
•  
T o e val uate t he l o n g-ter m efficac y of K u va n i n preser vi n g ne ur oc o g niti ve f u ncti o n i n c hil dre n 
wit h P K U w he n treat me nt is i nitiate d at 0- 6 y ears  


 
P K U- 0 1 5
 Pa ge
 
3 3
 
 
Pr o prietar y a n d C o nfi de ntial 
3 0 N o ve m ber 2 0 1 0 
N A M E O F C O M P A N Y 
Bi o Mari n P har mace utical I nc. 
1 0 5 Di gital Dri ve 
N o vat o, C A 9 4 9 4 9 
 
N A M E O F FI NI S H E D P R O D U C T: 
K u va n ®  
 
N A M E O F A C TI V E I N G R E DI E N T: 
sa pr o pteri n di h y dr oc hl ori de; 6 R- B H 4 
S U M M A R Y T A B L E 
Referri n g t o Part of t he 
D ossier: 
 
V ol u me:  
 
Pa ge:    
 
Refere n ce:  
F O R N A TI O N A L 
A U T H O RI T Y U S E 
O N L Y: 
Sec o n dar y O bjecti ves   
•  
T o e val uate t he l o n g-ter m safet y of K u va n i n t he st u d y p o p ulati o n   
•  
T o e val uate t he effect of K u va n o n gr o wt h para meters i n t he st u d y p o p ulati o n 
S u bst u d y 1: 6- M o nt h S afet y a n d Effic ac y i n C hil dre n 0- 6 Ye ars Ol d 
Pri mar y O bjecti ve  
•  
T o e val uate t he safet y of 6 m o nt hs of treat me nt wit h K u va n i n c hil dre n wit h P K U w h o are 
0- 6 y ears ol d.  
Sec o n dar y O bjecti ve   
•  
T o e val uate t he efficac y of 6 m o nt hs of tr eat me nt wit h K u va n i n c o ntr olli n g bl o o d P he 
c o nce ntrati o n  wit hi n acce pta ble ra n ges i n c hil dre n wit h P K U w h o are 0- 6 y ears ol d  
•  
T o e val uate baseli ne ne ur oc o g niti ve f u ncti o n f o r all K u va n-res p o nsi ve s u bjects a n d 6- m o nt h 
Ba yle y-III data f or s u bjects w h o are 0- 2 y ears ol d at e nr oll me nt 
S u bst u d y 2: P o p ul ati o n P h ar m ac o ki netics i n C hil dre n 0- 6 Ye ars Ol d 
Pri mar y O bjecti ve  
•  
T o e val uate t he p o p ulati o n p har mac o ki netics of K u va n i n y o u n g c hil dre n  
S T U D Y D E SI G N A N D P L A N:  
P art 1: E v al u ati o n of K u v a n Res p o nsi ve ness 
Be gi n ni n g at Wee k 0 a n d after all baseli ne assess me nts are c o m plete d, s u bjects e nr olle d i nt o t he st u d y 
will recei ve 2 0 m g/ k g K u va n dail y f or 4 wee ks. S u bj ects will ret ur n t o t he cli nic wee kl y f or safet y 
assess me nts a n d bl o o d P he c o nce ntrati o n meas ure me nt.  S u bjects s h o ul d c o nti n ue wit h t heir c urre nt 
le vel of dietar y P he i nta ke. H o we ver, if a su bject’s bl o o d P he c o nce ntrati o n dr o ps bel o w 1 2 0 μ m ol/ L, 
at t he discreti o n of t he i n vesti g at or, a gr a d u al i ncre ase of a p pr o xi m atel y 5 t o 2 0 m g/ k g of P he 
s u p ple me nt m a y be a d de d t o t he diet. It is i m p ort a nt t o a v oi d u nst a ble s wi n gs i n t he bl o o d P he 
v al ues.  N o d ose a dj ust me nts ca n be ma de d uri n g Part 1 wit h o ut c o ns ultati o n wit h t he Me dical 
M o nit or. 
 


 
P K U- 0 1 5
 Pa ge
 
3 4
 
 
Pr o prietar y a n d C o nfi de ntial 
3 0 N o ve m ber 2 0 1 0 
N A M E O F C O M P A N Y 
Bi o Mari n P har mace utical I nc. 
1 0 5 Di gital Dri ve 
N o vat o, C A 9 4 9 4 9 
 
N A M E O F FI NI S H E D P R O D U C T: 
K u va n ®  
 
N A M E O F A C TI V E I N G R E DI E N T: 
sa pr o pteri n di h y dr oc hl ori de; 6 R- B H 4 
S U M M A R Y T A B L E 
Referri n g t o Part of t he 
D ossier: 
 
V ol u me:  
 
Pa ge:    
 
Refere n ce:  
F O R N A TI O N A L 
A U T H O RI T Y U S E 
O N L Y: 
P art 2: Ne ur oc o g niti ve St u d y 
S u bjects w h o are res p o nsi ve t o K u va n (see t he defi niti o n of res p o nsi ve ness i n Eli gi bilit y Criteri o n) 
will c o nti n ue t o recei ve dail y si n gle d oses of 2 0 m g/ k g K u va n orall y. At t he discreti o n of t he 
I n vesti gat or, a gr a d u al i ncre ase of a p pr o xi m atel y 5 t o 2 0  m g/ k g of P he s u p ple me nt m a y be a d de d 
t o t he diet. It is i m p ort a nt t o a v oi d u nst a ble s wi n gs i n t he bl o o d P he v al ues. K u va n d ose ma y als o 
be re d uce d after Wee k 5 after c o ns ultati o n wit h t h e Me dical M o nit or, i n s u bjects w h o d o n ot t olerate 
t he 2 0 m g/ k g/ da y d ose. Ne ur oc o g niti ve testi n g will be perf or me d wit hi n 6 wee ks of deter mi nati o n of 
K u va n res p o nsi ve ness i n all K u va n-res p o nsi ve s u bject s. T he t y pes of ne ur oc o g niti ve tests use d (ie, 
Ba yle y Scales of I nfa nt a n d T o d dler De vel o p me nt ®- T hir d E diti o n [ Ba yle y-III ®], Wec hsl er Presc h o ol 
a n d Pri mar y Scale of I ntelli ge nce ™- T hir d E diti o n [ W P P SI™-III], a n d/ or Wec hsler I ntelli ge nce Scale 
f or C hil dre n ®- F o urt h E diti o n [ WI S C ®-I V]), will be t h ose c o nsi dere d a p pr o priate f or t he s u bject’s 
a ge.  
Ne ur oc o g niti ve Assess me nts 
 
A ge Gr o u p  I nf a nc y
 Presc h o ol
 Sc h o ol- A ge
 
Assess me nt  Ba yle y-III
 W P P SI-III
 W P P SI-III
 WI S C-I V
 
A ge   
0 m o nt hs t hr o u g h 
 < 3 0 m o nt hs 
≥ 3 0 m o nt hs 
t hr o u g h < 4 years 
≥ 4 y ears t hr o u g h 
 < 7 y ears 
≥ 7 y ears a n d 
ol der  
Fre q ue nc y  E ver y
 
6
 
m o nt hs
 
 ± 2 wee ks 
O nce a y ear 
 ± 2 wee ks 
O nce a y ear 
 ± 2 wee ks  
E ver y 
2 y ears ± 2 wee ks  
 
 
T he B a yle y-III will be a d mi nistere d t o s u bjects w h o are fr o m 0 m o nt hs t o less t h a n 3 0 m o nt hs of 
a ge a n d will be a d mi nistere d e ver y 6 m o nt hs ± 2 wee ks. At 3 0 m o nt hs ol d or ol der, t he s u bjects 
will be a d mi nistere d t he W P P SI-III. T he W P P SI-III h as t w o f or ms. T he y o u n ger c hil dre n will be 
a d mi nistere d t he first f or m f or a ges 3 0 m o nt hs t o  less t h a n 4 ye ars ol d. T he sec o n d f or m will be 
use d f or s u bjects 4 ye ars of a ge t o less t h a n 7 ye ars ol d. T he W P P SI-III will be a d mi nistere d 
ye arl y  ±  2 wee ks. Be gi n ni n g at 7 ye ars ol d, st u d y s u bjects will be a d mi nistere d t he WI S C-I V 
e ver y 2 ye ars  ±  2 wee ks.   


 
P K U- 0 1 5
 Pa ge
 
3 5
 
 
Pr o prietar y a n d C o nfi de ntial 
3 0 N o ve m ber 2 0 1 0 
N A M E O F C O M P A N Y 
Bi o Mari n P har mace utical I nc. 
1 0 5 Di gital Dri ve 
N o vat o, C A 9 4 9 4 9 
 
N A M E O F FI NI S H E D P R O D U C T: 
K u va n ®  
 
N A M E O F A C TI V E I N G R E DI E N T: 
sa pr o pteri n di h y dr oc hl ori de; 6 R- B H 4 
S U M M A R Y T A B L E 
Referri n g t o Part of t he 
D ossier: 
 
V ol u me:  
 
Pa ge:    
 
Refere n ce:  
F O R N A TI O N A L 
A U T H O RI T Y U S E 
O N L Y: 
Gr o wt h, bl o o d P he c o nce ntrati o n, a n d safet y will be m o nit ore d. T hese a n d t he ne ur oc o g niti ve  
assess me nts will be perf or me d e ver y 6 t o 2 4 m o nt hs, de pe n di n g o n t he t y pe of assess me nt, u ntil t he 
e n d of t he st u d y. Refer t o Ta ble 2. 1  f or details. 
T he st u d y will be c o nsi dere d c o m plete w he n a p pr o xi matel y 4 5 s u bjects ha ve bee n f oll o we d f or 7 y ears 
a n d ha ve at least 2 p ost-treat me nt W P P SI-III a n d/ or WI S C-I V tests a d mi nistere d 2 y ears a part. 
After st u d y c o m pleti o n, s u bjects will be gi ve n t he o p p o rt u nit y t o partici pate i n a re gistr y st u d y t hat 
will f oll o w l o n ger-ter m o utc o mes.  
S u bst u d y 1: S afet y a n d Effic ac y i n S u bjects 0- 6 Ye ars Ol d 
All K u va n-res p o nsi ve s u bjects will be  e nr olle d i n S u bst u d y 1 a n d will be assesse d m o nt hl y f or t he first 
6 m o nt hs of t he st u d y. Bl o o d P he c o nce ntrati o ns, vari o us meas ures of gr o wt h, a n d safet y data will be 
c ollecte d. T he s u bject’s dail y P he i nta ke will be i ncrease d o nl y if t he s u bject’s bl o o d P he le vels fall 
bel o w 1 2 0 μ m ol/ L. K u va n d ose ma y als o be re d uce d after wee k 5 a n d  after c o ns ultati o n wit h t he 
Me dical M o nit or if t he s u bject d oes n ot t olerate t he 2 0 m g/ k g/ da y d ose. Refer t o Ta ble 2. 1, Sc he d ule 
of E ve nts f or t he ti mi n g of assess me nts. 
S u bst u d y 2: P o p ul ati o n P h ar m ac o ki netics ( P K) i n S u bjects 0- 6 Ye ars Ol d 
F or t he p o p ulati o n P K e val uati o n, plas ma sa m ples fr o m t he first  1 0 s u bjects e nr olle d i n Part 1 w h o are 
0- 1 y ears ol d a n d t he first - 7 0 s u bjects i n t he > 1- 6 ye ars a ge gr o u p ( 3 sa m ples eac h fr o m s u bjects 
≤ 1 y ear ol d; 4 sa m ples eac h fr o m s u bjects > 1 years ol d) will be c ollecte d at t he Wee k 0 t hr o u g h 
Wee k 4 visits acc or di n g t o a pre deter mi n e d sc he d ule. See Secti o n 1 2. 3  a n d Ta ble 1 2. 3. 1  f or sa m pli n g 
wi n d o ws. I n a d diti o n, i n vesti gat ors will be as ke d t o c o llect a bl o o d sa m ple f or t otal bi o pteri n testi n g at 
t he ti me of a n S A E, w he n p ossi ble, if it is c o nsi dere d b y t he i n vesti gat or t o be pr o ba bl y or p ossi bl y 
relate d t o K u va n. 
N U M B E R O F S U B J E C T S P L A N N E D :  
T he st u d y is e x pecte d t o c o m prise a mi ni m u m of 6 0 K u va n-res p o nsi ve s u bjects. At least 2 0 s u bjects 
will be 0- 2 y ears ol d a n d at least 1 0 of t hese 2 0 s u bjects will be 0- 1 y ears ol d. At least 2 0 s u bjects will 
be 2- 4 y ears ol d a n d t he re mai ni n g s u bjects will be 4- 6 y ears ol d. I n or der t o o btai n a mi ni m u m of 
6 0 K u va n-res p o nsi ve s u bjects, we a ntici pate t hat m ore  t ha n 2 3 0 s u bjects will be e nr olle d i n Part 1, 
E val uati o n of K u va n Res p o nsi ve ness. 
DI A G N O SI S A N D A L L C RI T E RI A F O R I N C L U SI O N A N D E X C L U SI O N :  
I n di vi d uals eli gi ble t o partici pate i n Part 1, E val uati o n of K u va n Res p o nsi ve ness a n d S u bst u d y 2 
( p o p ulati o n P K) m ust meet all of t he f oll o wi n g criteria: 


 
P K U- 0 1 5
 Pa ge
 
3 6
 
 
Pr o prietar y a n d C o nfi de ntial 
3 0 N o ve m ber 2 0 1 0 
N A M E O F C O M P A N Y 
Bi o Mari n P har mace utical I nc. 
1 0 5 Di gital Dri ve 
N o vat o, C A 9 4 9 4 9 
 
N A M E O F FI NI S H E D P R O D U C T: 
K u va n ®  
 
N A M E O F A C TI V E I N G R E DI E N T: 
sa pr o pteri n di h y dr oc hl ori de; 6 R- B H 4 
S U M M A R Y T A B L E 
Referri n g t o Part of t he 
D ossier: 
 
V ol u me:  
 
Pa ge:    
 
Refere n ce:  
F O R N A TI O N A L 
A U T H O RI T Y U S E 
O N L Y: 
•  Esta blis he d dia g n osis of P K U wit h h y per p he n ylala ni ne mia ( H P A) d oc u me nte d i n t he 
me dical rec or d b y at least 2 bl o o d P he c o nce ntrati o ns ≥ 3 6 0 μ m ol/ L ( 6 m g/ d L) ta ke n 
at least 3 da ys a part 
•  
D oc u me nte d bl o o d P he c o ntr ol ( defi ne d b y t he st a n dar d use d at eac h treat me nt ce nter) pri or t o 
st u d y e nr oll me nt, if a p plica ble (e g, t he s u bject is ol d e n o u g h f or t hese data t o be c ollecte d); 
bl o o d P he c o nce ntrati o ns f or s u bjects < 6 m o nt hs ol d at Scree ni n g m ust be c o nsi dere d 
c o ntr olle d a n d sta ble b y t he I n vesti gat or  
•  
Willi n g t o a d here t o a prescri be d P he-restrict e d diet i n or der t o mai ntai n bl o o d P he 
c o nce ntrati o ns wit hi n t he rec o m me n de d ra n ges esta blis he d at t he s u bject’s st u d y site 
•  
A ge 0 t o 6 y ears ol d, i ncl usi ve, at Scree ni n g 
•  
Pare nt(s) or g uar dia n(s) willi n g a n d a ble t o pr o vi de writte n, si g ne d i nf or me d c o nse nt after t he 
nat ure of t he st u d y has bee n e x plai ne d, a n d pri or t o a n y researc h-relate d pr oce d ures 
•  
Pare nt(s) or g uar dia n(s) willi n g a n d a ble  t o c o m pl y wit h all st u d y pr oce d ures 
•  
Fe mal e s u bjects of c hil d beari n g p ote ntial (as deter mi n e d b y t he i n vesti gat or) a n d se x uall y 
mat ure male s u bjects willi n g t o use a me dica ll y acce pte d met h o d of c o ntrace pti o n t hr o u g h o ut 
t he st u d y. Fe male s u bjects of c hil d beari n g p ote ntial willi n g t o u n der g o peri o dic pre g na nc y 
tests d uri n g t he c o urse of t he st u d y 
I n di vi d uals eli gi ble t o partici pate i n Part 2: Ne uroc o g niti ve St u d y a n d S u bst u d y 1 m ust meet all of t he 
f oll o wi n g criteria: 
•  
C o m pleti o n of Wee k 4 visit i n Part 1  
•  
Res p o nsi ve t o K u va n d uri n g Part 1, defi ne d as a ≥ 3 0 % a vera ge re d ucti o n i n bl o o d P he 
c o nce ntrati o n calc ulate d as t he mea n of t he w ee kl y perce nt c ha n ge fr o m baseli ne i n bl o o d P he 
c o nce ntrati o n at Wee ks 1, 2, 3, a n d 4 
•  
Ba yle y-III or I Q test sc ore ≥ 8 0 wit hi n 6 wee ks of deter mi nati o n of K u va n res p o nsi ve ness   
I n di vi d uals w h o meet a n y of t he f oll o wi n g e xcl usi o n criteria will n ot be eli gi ble t o partici pate i n t he 
st u d y: 
•  
Esta blis he d dia g n osis of pri mar y te tra h y dr o bi o pteri n ( B H 4) deficie nc y  
•  
K n o w n h y perse nsiti vit y t o K u va n or its e xci pie nts  


 
P K U- 0 1 5
 Pa ge
 
3 7
 
 
Pr o prietar y a n d C o nfi de ntial 
3 0 N o ve m ber 2 0 1 0 
N A M E O F C O M P A N Y 
Bi o Mari n P har mace utical I nc. 
1 0 5 Di gital Dri ve 
N o vat o, C A 9 4 9 4 9 
 
N A M E O F FI NI S H E D P R O D U C T: 
K u va n ®  
 
N A M E O F A C TI V E I N G R E DI E N T: 
sa pr o pteri n di h y dr oc hl ori de; 6 R- B H 4 
S U M M A R Y T A B L E 
Referri n g t o Part of t he 
D ossier: 
 
V ol u me:  
 
Pa ge:    
 
Refere n ce:  
F O R N A TI O N A L 
A U T H O RI T Y U S E 
O N L Y: 
•  
Hist or y of or ga n tra ns pla ntati o n 
•  
Percei ve d t o be u nrelia ble or u na vaila ble f or st u d y partici pati o n or t o ha ve pare nts or le gal 
g uar dia ns w h o are percei v e d t o be u nrelia ble or u na vaila ble 
•  
Use of met h otre xate or ot her me dicati o ns t hat i n hi bit f olate meta b olis m 
•  
Seri o us ne ur o ps y c hiatric ill ness (e g, maj or de pressi o n) n ot c urre ntl y u n der me dical c o ntr ol  
•  
Use of K u va n or a n y i n vesti gati o nal a ge nt w it hi n 3 0 da ys pri or t o Scree ni n g, or k n o w n 
re q uire me nt f or a n y i n vesti gati o nal a ge nt pri or t o c o m pleti o n of all sc he d ule d st u d y 
assess me nts 
•  
C o nc urre nt disease or c o n diti o n t hat w o ul d i nterfe re wit h st u d y partici pati o n or safet y (e g, 
seiz ure dis or der, oral ster oi d- de pe n de nt ast h ma or ot her c o n diti o n re q uiri n g oral or pare nteral 
c ortic oster oi d a d mi nistrati o n, i ns uli n- de pe n de nt dia betes 
•  
Use of p h os p h o diester ase t y pe 5 i n hi bit or, ofte n s h orte ne d t o P D E 5 i n hi bit or (e g. 
sil de n afil citr ate, v ar de n afil, t a d al afil, a v a n afil, l o de n afil, mir o de n afil, u de n afil)  
•  
A n y c o n diti o n t hat, i n t he vie w of t he Pri nci pa l I n vesti gat or ( PI), re n ders t he s u bject at hi g h 
ris k f or fail ure t o c o m pl y wit h treat me nt or t o c o m plete t he st u d y 
I N V E S TI G A TI O N A L P R O D U C T( S), D O S E, R O U T E A N D R E GI M E N:  
K u va n is pr o vi de d i n ta blets of 1 0 0 m g of sa pr o pteri n di h y dr oc hl ori de. A d ose of 2 0 m g/ k g will be 
a d mi nistere d diss ol ve d i n water, a p ple j uice, or s oft f o o ds, base d o n s u bject’s a ge a n d a bilit y, a n d 
ta ke n orall y o nce dail y wit h f o o d. 
D U R A TI O N O F T R E A T M E N T :  
E val uati o n of K u va n Res p o nsi ve ness: 4 wee ks 
Ne ur oc o g niti ve St u d y: 7 years 
S u bst u d y 1: 6 m o nt hs 
S u bst u d y 2: 4 wee ks 


 
P K U- 0 1 5
 Pa ge
 
3 8
 
 
Pr o prietar y a n d C o nfi de ntial 
3 0 N o ve m ber 2 0 1 0 
N A M E O F C O M P A N Y 
Bi o Mari n P har mace utical I nc. 
1 0 5 Di gital Dri ve 
N o vat o, C A 9 4 9 4 9 
 
N A M E O F FI NI S H E D P R O D U C T: 
K u va n ®  
 
N A M E O F A C TI V E I N G R E DI E N T: 
sa pr o pteri n di h y dr oc hl ori de; 6 R- B H 4 
S U M M A R Y T A B L E 
Referri n g t o Part of t he 
D ossier: 
 
V ol u me:  
 
Pa ge:    
 
Refere n ce:  
F O R N A TI O N A L 
A U T H O RI T Y U S E 
O N L Y: 
R E F E R E N C E T H E R A P Y(I E S), D O S E, R O U T E A N D R E GI M E N :  
N ot a p plica ble  
C RI T E RI A F O R E V A L U A TI O N: 
Effic ac y:  
Ne ur oc o g niti ve de vel o p me n t will be e val uate d base d o n I Q meas ure d b y t he a ge-a p pr o priate tests 
liste d bel o w:  
•  
Ba yle y-III i n a ges 0 t o  < 3 0 m o nt hs 
•  
W P P SI-III i n a ges ≥ 3 0 m o nt hs t o < 7 ye ars 
•  
WI S C-I V i n a ges  ≥ 7 y ears  
T he l o n g-ter m be nefit of K u va n treat me nt will be e val uate d b y de m o nstrati n g t hat ne ur oc o g niti ve 
de vel o p me nt is n ot w orse t ha n t he e x pect e d de vel o p me nt f or s u bjects wit h P K U o n a 
P he-restricte d diet. 
Gr o wt h will be assesse d usi n g t he f oll o wi n g meas ure me nts: 
•  
Hei g ht, wei g ht, a n d hea d circ u mfere nce 
S afet y: 
Safet y assess me nts will i ncl u de me dical hist or y, a d verse e ve nts ( A Es), vital si g ns, p h ysical 
e xa mi nati o ns i ncl u di n g hei g ht, wei g ht, a n d hea d  circ u mfere nce, a n d cli nical la b orat or y tests 
(c he mistr y, he mat ol o g y, a n d uri nal ysis). 
S u bst u d y 1: S afet y a n d Effic ac y i n C hil dre n A ge 0- 6 Ye ars 
Effic ac y: 
T he be nefit of K u va n treat me nt will be e val uate d b y deter mi ni n g w het her K u va n ca n c o ntr ol bl o o d 
P he c o nce ntrati o ns wit hi n acce pta bl e ra n ges f or a ge a n d base d o n t he criteria use d at eac h treat me nt 
ce nter. T he assess me nt will be ma de usi n g t he pr o p orti o n of s u bjects w h ose bl o o d P he c o nce ntrati o n is 
wit hi n eac h s u bject’s acce pta ble ra n ge a n d t he mea n  c ha n ge i n bl o o d P he c o nce ntrati o n fr o m baseli ne 
at eac h ti me p oi nt.  
S afet y: 
Safet y assess me nts will i ncl u de me dical hist or y, A E s, vital si g ns, p h ysical e xa mi nati o ns i ncl u di n g 
hei g ht, wei g ht, a n d hea d circ u mfere nce, bl o o d tr y pt o p h a n a n d t yr osi ne c o nce ntrati o n, sta n dar d cli nical 


 
P K U- 0 1 5
 Pa ge
 
3 9
 
 
Pr o prietar y a n d C o nfi de ntial 
3 0 N o ve m ber 2 0 1 0 
N A M E O F C O M P A N Y 
Bi o Mari n P har mace utical I nc. 
1 0 5 Di gital Dri ve 
N o vat o, C A 9 4 9 4 9 
 
N A M E O F FI NI S H E D P R O D U C T: 
K u va n ®  
 
N A M E O F A C TI V E I N G R E DI E N T: 
sa pr o pteri n di h y dr oc hl ori de; 6 R- B H 4 
S U M M A R Y T A B L E 
Referri n g t o Part of t he 
D ossier: 
 
V ol u me:  
 
Pa ge:    
 
Refere n ce:  
F O R N A TI O N A L 
A U T H O RI T Y U S E 
O N L Y: 
la b orat or y tests (c he mistr y, he mat ol o g y, a n d uri nal ysis), a n d a n E C G (electr ocar di o gra m), if re q uire d.  
S u bst u d y 2: P o p ul ati o n P K St u d y i n C hil dre n A g e 0- 6 Ye ars 
T he p har mac o ki netics of K u va n will be assesse d t hr o u g h  meas ure me nt of t otal bi o pteri n c o nce ntrati o n 
i n plas ma sa m ples o btai ne d d uri n g t he Wee k 0 t hr o u g h Wee k 4 visits usi n g a p o p ulati o n 
p har mac o ki netics a p pr oac h.  
S T A TI S TI C A L M E T H O D S:  
S a m ple Si ze 
T he calc ulati o n of sa m ple size ass u m es t hat eac h c hil d will ha ve 2 p ost-treat me nt test res ults fr o m t he 
W P P SI-III a n d/ or WI S C-I V tests at least 2 y ears a part. T he g oal is t o e xcl u de a mea n 2. 5- p oi nt l oss 
per y ear i n sc ore. Gi ve n a 2-si de d T y pe I err or rate of 0. 0 5, if t he mea n I Q sc ore at baseli ne is 1 0 0, t he 
sta n dar d de viati o n is 1 5, a n d t he c orrelati o n bet wee n t he 2 test res ults is 0. 8, a sa m ple size of 
4 5 s u bjects will yiel d 9 0 % p o wer. 
T o acc o u nt f or t he p ossi bilit y of dr o p o uts a n d t o ha ve reas o na ble precisi o n f or esti mati n g c ha n ge i n I Q 
fr o m t he ti me a c hil d reac hes at least a ge 3 0 m o nths u ntil t he e n d of t he st u d y, a mi ni m u m of 
6 0 K u va n-res p o nsi ve s u bjects w ill be e nr olle d i n t he st u d y. 
Pri m ar y Effi c ac y E n d p oi nt a n d A n al ysis  
T he pri mar y efficac y e n d p oi nt is t he I Q sc ore meas ure d b y t he W P P SI-III or WI S C-I V tests. A nal ysis 
of ne ur oc o g niti ve de vel o p me nt usi n g t he I Q sc ores will be perf or m e d usi n g a re peate d meas ures 
m o del. T he o utc o me varia ble will be t he I Q sc ore fr o m W P P SI-III a n d/ or WI S C-I V tests. T he sl o pe of 
t he test sc ores will be calc ulate d. T he treat me nt will be c o nsi dere d s uccessf ul if t he l o wer c o nfi de nce 
li mit of t he mea n c ha n ge i n test sc ore o ver a 2- y ear peri o d e xcl u des a decli ne of greater t ha n 5 p oi nts. 
All data will be i ncl u de d i n a c o m bi ne d a nal ysis, stratifie d b y testi n g se q ue nce use d 
( W P P SI-III/ W P P SI-III, W P P SI-III/ WI S C-I V, or WI S C-I V/ WI S C-I V). 
Sec o n d ar y Effic ac y E n d p oi nt a n d A n al ysis  
T he sec o n dar y efficac y e n d p oi nt is: 
•  
C ha n ge i n de vel o p me ntal gr o wt h fact ors,  meas ure d b y hei g ht, wei g ht, a n d hea d 
circ u mfere nce fr o m baseli ne 
T his sec o n dar y e n d p oi nt will be a nal y ze d usi n g a l o n git u di nal m o del. 


 
P K U- 0 1 5
 Pa ge
 
4 0
 
 
Pr o prietar y a n d C o nfi de ntial 
3 0 N o ve m ber 2 0 1 0 
N A M E O F C O M P A N Y 
Bi o Mari n P har mace utical I nc. 
1 0 5 Di gital Dri ve 
N o vat o, C A 9 4 9 4 9 
 
N A M E O F FI NI S H E D P R O D U C T: 
K u va n ®  
 
N A M E O F A C TI V E I N G R E DI E N T: 
sa pr o pteri n di h y dr oc hl ori de; 6 R- B H 4 
S U M M A R Y T A B L E 
Referri n g t o Part of t he 
D ossier: 
 
V ol u me:  
 
Pa ge:    
 
Refere n ce:  
F O R N A TI O N A L 
A U T H O RI T Y U S E 
O N L Y: 
S afet y A n al ysis 
T he ori gi nal ter ms re p orte d i n case re p ort f or ms ( C R Fs) t o i de ntif y A Es will be c o de d usi n g t he 
Me dical Dicti o nar y f or Re g ulat or y Acti vities ( M e d D R A). T he i nci de nce of treat me nt-e mer ge nt A Es 
will be s u m marize d b y s yste m or ga n class, preferre d ter m, relati o ns hi p t o st u d y dr u g, a n d se verit y. A 
b y-s u bject listi n g will be pr o vi de d f or t h ose s u bjects w h o ha d a n S A E, i ncl u di n g deat h, or ha d a n A E 
res ulti n g i n earl y disc o nti n uati o n of st u d y dr u g. 
La b orat or y data will be s u m marize d b y t he t y pe of  la b orat or y test. T he fre q ue nc y a n d perce nta ge of 
s u bjects w h o e x perie nce a n a b n or malit y (ie, o utsi de of refere nce ra n ges) or cli nicall y si g nifica nt 
a b n or malit y after st u d y dr u g a d mi nistrati o n will be prese nte d f or eac h la b orat or y a nal yte. F or eac h 
la b orat or y a nal yte, descri pti ve statistics will be pr o vide d f or val ues meas ure d at eac h sc he d ule d visit, 
a n d f or c ha n ge i n val ues fr o m baseli n e t o eac h sc he d ule d visit. Si milarl y, descri pti ve statistics of vital 
si g ns will be pr o vi de d. 
I nteri m safet y a nal yses will be c o n d ucte d an n uall y t hr o u g h c o m pleti o n of t he st u d y. 
S u bst u d y 1: S afet y a n d Effic ac y A n al yses  
Efficac y will be assesse d b y t he a bilit y of K u va n, a d mi nistere d o ver a 6- m o nt h peri o d, t o c o ntr ol bl o o d 
P he c o nce ntrati o ns wit hi n acce pta ble ra n ges f or a ge a n d f or t he criteria use d at t he treat me nt ce nters. 
Efficac y e n d p oi nts are: 
•  
Pr o p orti o n of s u bjects w h ose bl o o d P he c o nce n trati o n is wit hi n acce pta ble ra n ges at 
p ost-treat me nt visits 
•  
Mea n c ha n ge i n bl o o d P he c o nce ntrati o n fr o m baseli ne t o p ost-treat me nt m o nt hl y visits 
A n e xact 9 5 % CI f or t he pr o p orti o n of s u bjects w h ose bl o o d P he c o nce ntrati o n wit hi n acce pta ble 
ra n ges at eac h p ost-treat me nt visit a n d a 9 5 % c o nfi de nce i nter val ( CI) f or t he mea n c ha n ge i n bl o o d 
P he c o nce ntrati o n fr o m baseli ne t o p ost-treat me nt m o nt hl y visits will be pr o vi de d f or t he efficac y 
assess me nt. Baseli ne bl o o d P he c o nce ntrati o n will be  calc ulate d usi n g t he mea n of Scree ni n g a n d 
Wee k 0 ( pri or t o d osi n g wit h K u va n) res ults.  
Safet y res ults f or t he first 6 m o nt hs of treat me nt will be a nal y ze d as descri be d a b o ve. 
S u bst u d y 2: P h ar m ac o ki netic A n al yses 
T he ti me c o urse of t he calc ulate d B H 4 c o nce ntrati o n (fr o m plas ma t otal bi o pteri n meas ure me nt) will 
be m o dele d t o esti mate t he f oll o wi n g p o p ulati o n P K pa ra meters f or K u va n: a p pare nt cleara nce ( C L/ F) 
wit h ass ociat e d i nter-i n di vi d ual varia bilit y, a p pare nt v ol u me of distri b uti o n ( Vc/ F) wit h ass ociate d 


 
P K U- 0 1 5
 Pa ge
 
4 1
 
 
Pr o prietar y a n d C o nfi de ntial 
3 0 N o ve m ber 2 0 1 0 
N A M E O F C O M P A N Y 
Bi o Mari n P har mace utical I nc. 
1 0 5 Di gital Dri ve 
N o vat o, C A 9 4 9 4 9 
 
N A M E O F FI NI S H E D P R O D U C T: 
K u va n ®  
 
N A M E O F A C TI V E I N G R E DI E N T: 
sa pr o pteri n di h y dr oc hl ori de; 6 R- B H 4 
S U M M A R Y T A B L E 
Referri n g t o Part of t he 
D ossier: 
 
V ol u me:  
 
Pa ge:    
 
Refere n ce:  
F O R N A TI O N A L 
A U T H O RI T Y U S E 
O N L Y: 
i nter-i n di vi d ual varia bilit y, a n d a bs or pti o n rate c o nsta nt wit h ass ociate d i nter-i n di vi d ual varia bilit y 
( Ka). Data fr o m t he S u bst u d y 2 ma y als o be p o ole d wit h P K data o btai ne d fr o m a d ult s u bjects i n 
pre vi o us cli nical st u dies.  
 
 


 
P K U- 0 1 5
 Pa ge 4 2
 
Pr o prietar y a n d C o nfi de ntial 
3 0 N o ve m ber 2 0 1 0 
2. 1  
Sc he d ule of E ve nts 
T a ble 2. 1:  Sc he d ule of E ve nts, All S u bjects 
P art 1: E v al u ati o n of 
K u v a n Res p o nsi ve ness 
(i ncl u des S u bst u d y 2)a
P art 2: L o n g-ter m Assess me nt of  Ne ur oc o g niti ve A bilit y a n d S afet yb, v  
 
S u bst u d y 1:  6- M o nt h S afet y a n d Effic ac y 
 
F oll o w-
u p/ E T V d 
Assess me nt
 Scree ni n g a W 0
e W 1  W 2  W 3  W 4
f M 2 c M 3
c M 4
c M 5
c M
5M 6
c M 1 2
g
M 1 8
g  M 2 4 g M 3 0
g M 3 6
g M 4 2
g M 4 8
g M 5 4
g
M 6 0/ 
M 8 4
g 
 
I nf or me d
 
c o nse nt
  
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Me dical
 
hist or y
  
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital si g ns  
X  
X h X
 X  
X  
X
 X
 X
 X
 X
 X
 X
  X
  X
 X
 X
 X
 X
 X
  X
  
( X
i) 
Wei g ht
  
X
  X
 X
 X  
X  
X
 X
 X
 X
 X
 X
 X
  X
  X
 X
 X
 X
 X
 X
  X
  
( X i) 
Hei g ht, hea d 
circ u mfere nce v 
X
  X
 
 
 
 X
 
 X
 
 
  X
 X
  X
  X
 X
 X
 X
 X
 X
  X
  
( X i) 
P h ysical
 
e xa mi nati o n
  X
  X
 
 
 
 X
 
 X
 
 
  X
 X
  X
  X
 X
 X
 X
 X
 X
  X
  
( X i) 
La b orat or y tests j 
X
  X
 X
 
 X  
X
 X
 X
 X
 X
 X
 X
  X
  X
 X
 X
 X
 X
 X
  X
  
( X i) 
E C G k 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre g na nc y tests l  
X
  X
 
 
 
 X
 
 
 
  
  X
 X
  X
  X
 X
 X
 X
 X
 X
  X
  
X
 
Bl o o d P he m   
X
  X
 X
 X  
X  
X
 X
 X
 X
 X
 X
 X
  X
  X
 X
 X
 X
 X
 X
  X
 
 
 
Tr y pt o p ha n,
 
t yr osi ne
  X
 
 
 
 
 
 X
 
 X
 
 
 X
 X
 
 
  X
 
 X
 
 X
 
  X
  ( X i) 
C o nc o mita nt
 
me ds
  
X
  X
 X
 X  
X  
X
 X
 X
 X
 X
 X
 X
  X
  X
 X
 X
 X
 X
 X
  X
  
X
 
A d verse e ve nts   
  
Xn X
 X  
X  
X
 X
 X
 X
 X
 X
 X
  X
  X
 X
 X
 X
 X
 X
  X
  
X
 
Treat me nt wit h 
K u va n/ Dis pe nse St u d y 
Dr u g   
 
X 
X
 X  
X  
X
 X
 X
 X
 X
 X
 X
  X
  X
 X
 X
 X
 X
 X
  X
 
 
 
Dietar y P he R x a n d 
dietar y P he i nta ke 
X
  X
 X
 X  
X  
X
 X
 X
 X
 X
 X
 X
  X
  X
 X
 X
 X
 X
 X
  X
  
X
 
Defi niti o ns:  Ba yle y-III, Ba yle y Scales of I nfa nt a n d T o d dler De vel o p me nt, T hir d E diti on; E T V, Earl y Ter mi nati o n Visit; M, M o nt h; P he, p he n ylala ni ne; R x, prescri pti o n; 
W, Wee k; WI S C-I V, Wec hsler I ntelli ge nce Scale f or C hil dre n, F o urt h  E diti o n; W P P SI-III, W ec hsler Presc h o ol a n d Pri mar y Scale of I ntelli ge nce, T hir d E diti o n. 
 


 
P K U- 0 1 5
 Pa ge 4 3
 
Pr o prietar y a n d C o nfi de ntial 
3 0 N o ve m ber 2 0 1 0 
T a ble 2. 1: Sc he d ule of E ve n ts, All S u bjects, c o nt’ d 
 
P art 1: E v al u ati o n of 
K u v a n Res p o nsi ve ness 
(i ncl u des S u bst u d y 2)a 
P art 2: L o n g-ter m Assess me nt of  Ne ur oc o g niti ve A bilit y a n d S afet yb, v  
 
 
S u bst u d y 1: 6- m o nt h S afet y a n d Effic ac y 
F oll o w-
u p/ E T V
d 
Assess me nt  
Scree ni n g  
W 0
e W 1  W 2  W 3  W 4
f M 2
c M 3 c M 4
c M 5
c
M 6
c M 1 2 g M 1 8 g M 2 4
g M 3 0
g M 3 6 g M 4 2 g M 4 8 g M 5 4 g M 6 0/
M 8 4 g  
Dietar y P he 
m o dificati o n o 
  
  X
 X
 X
 X
  X
 X  
X
 X
 X
  X
  X
  X
  X
  X
 X
 X
 X
 X
  
 
Ne ur oc o g niti ve tests p 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
( Xq,r,s,t) 
  Ba yle y-IIIq  
 (a ges 0 t o 
< 3 0 m o nt hs) 
 
 
 
 
 
 X
 
 
 
 X
 X
 X
 X
 
 
 
 
 
 
 
 
 ( X
q) 
  W P P SI-IIIr,s 
  (≥3 0 m o nt hs t o 
   < 7 y ears) 
 
 
 
 
 
 X
 
 
 
 
 X
 
 X
 
 
 X
 
 X
 
 X
u ( X
s,r) 
  WI S C-I Vt 
  (≥ 7 y ears) 
 
 
 
 
 
 X
 
 
 
 
 X
 
 X
 
 
 X
 
 X
 
 X
u ( X
,t) 
S u bst u d y 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  P o p ulati o n P Kw  
  
X
 
X 
X
 X
 X
  
  
    
  
  
  
  
  
  
  
  
  
  
  
 
 
Defi niti o ns:  Ba yle y-III, Ba yle y Scales of I nfa nt a n d T o d dler De vel o p me nt, T hir d E diti on; E T V, Earl y Ter mi nati o n Visit; M, M o nt h; P he, p he n ylala ni ne; R x, prescri pti o n; W, 
Wee k; WI S C-I V, Wec hsler I ntelli ge nce Scale f or C hil dre n, F o urt h E d iti o n; W P P SI-III, Wec hsler Presc h o ol a n d Pri mar y Scale of I ntelli ge nce, T hir d E diti o n.  
a D uri n g Scree ni n g a n d Part 1, wee kl y visits s h o ul d occ ur wit hi n 2 da ys of sc he d ule d ti me p oi nt (ie, ±  2 da ys). All visits will occ ur at t he cli nic. 
b T he Part 2 assess me nt sc he d ule will c o nti n ue u ntil M o nt h 8 4 ( 7 years).  
c M o nt hl y visits s h o ul d occ ur wit hi n 5 da ys of sc he d ule d ti me p oi nt (ie, ±  5 da ys) f or M 2, M 3, M 4, M 5 a n d M 6 . All visits will occ ur at t he cli nic. 
d E ver y s u bject s h o ul d c o m plete a F oll o w- u p or Ter mi n ati o n visit t o  e n d t heir p artici p ati o n i n t he st u d y. F oll o w- u p visit is perf or me d f or s u bjects w h o c o m plete o nl y 
P art 1 of t he st u d y, or w h o are e nr olle d i nt o P art 2 a n d c o m plete  P art 2.  T he Ter mi n ati o n visit is c o m plete d b y s u bjects w h o wit h dr a w or are disc o nti n ue d fr o m t he 


 
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3 0 N o ve m ber 2 0 1 0 
st u d y.  S u bjects will be c o nt acte d b y tele p h o ne 4 wee ks ( 2 8 ±  3 d a ys) after t he l ast d ose of st u d y dr u g, u nless re q uire d t o ret ur n f or a cli nic visit (see f o ot n otes i, q, r, s, 
a n d t). ”   
e All st u d y pr oce d ures f or t he W 0 visit m ust occ ur bef ore t he first d ose of st u d y dr u g is ta ke n d uri n g t hat visit. S u bjects will recei ve t heir first d ose of st u d y dr u g u n der o bser vati o n 
after all ot her pr oce d ures ha ve bee n perf or me d. P h ysical e xa mi na ti o n, cli nical la b orat or y tests, hei g ht a n d hea d circ u mfere nce meas ure me nts will be re peate d o nl y if t he W 0 visit 
is > 7 da ys after t he Scree ni n g visit. 
f S u bjects will be eli gi ble t o partici pate i n Part 2 if t he y ha ve a ≥ 3 0 % a vera ge re d ucti o n i n bl o o d P he c once ntrati o ns calc ulate d as t he mea n of t he wee kl y perce nt c ha n ge fr o m 
baseli ne at Wee ks 1, 2, 3, a n d 4.  
g 6- m o nt h visits s h o ul d occ ur wit hi n 2 wee ks of sc he d ule d ti me p oi nt (ie, ±  2 wee ks). All visits will occ ur at t he cli nic.  
h Vital si g ns will be ta ke n pre- d ose a n d f or 3 h o urs f oll o wi n g t he first d ose i n all s u bjects (at 1 5, 3 0, 4 5, 6 0, 9 0, 1 2 0, a n d 1 8 0 mi n utes p ost- d ose). 
i S u bjects wit h pre vi o us la b orat or y test res ults t hat re veal cli n icall y si g nifica nt a b n or malities will ha ve a cli nic visit at f oll o w- u p rat her t ha n a tele p h o ne visit, wit h re peat vital 
si g ns, p h ysical e xa mi nati o n, a n d cli nical la b orat or y tests. 
j Cli nical la b orat or y tests i ncl u de he mat ol o g y, c he mistr y, a n d uri nal ysis. Uri n al ysis m a y be perf or me d i n t he cli nic al l a b or vi a “ di pstic k ” i n c hil dre n t o o y o u n g t o pr o vi de a 
uri ne s a m ple. 
k A n E C G will be o btai ne d 2- 6 h o urs f oll o wi n g t he first d ose of K u va n o n t he first 8 0 s u bjects e nr olle d u nless data fr o m ot her st u dies are clear t hat K u va n d oes n ot ha ve a n effect 
o n t he Q T i nter val. 
l Pre g na nc y tests will be c o n d ucte d w he n, i n t he esti mati o n of t he i n vesti gat or, t he s u bject reac hes c hil d- beari n g p ote ntial. 
m  Bl o o d sa m ples f or a s u bject s h o ul d be o btai ne d at a p pr o xi matel y t he sa me ti me of da y at eac h visit a n d will be a nal yze d at a l ocal la b orat or y.  
n O nl y seri o us a d verse e ve nts ( S A Es) are c ollecte d at t he W 0 visit (after I nf or me d C o nse nt is si g ne d, b ut pri or t o first d ose of st u d y dr u g). T he re p orti n g peri o d f or n o n-seri o us 
A Es be gi ns after t he first d ose of st u d y dr u g is a d mi nistere d. 
o If a s u bject’s bl o o d P he c o nce ntrati o n dr o ps bel o w 1 2 0 μ m ol/ L , at t he discreti o n of t he i n vesti g at or, t he s u bject’s dietar y P he restricti o n m a y  be m o difie d t o all o w a gr a d u al  
i ncrease d i nta ke of a p pr o xi m atel y  5- 2 0 m g/ k g of P he per da y, a v oi di n g u nst a ble s wi n gs i n t he bl o o d P he v al ues..  
p Ne ur oc o g niti ve testi n g will be perf or me d wit hi n 6 wee ks after a s u bject is deter mi ne d t o be K u va n res p o nsi ve. 
q Ba yle y-III, perf or me d wit hi n 6 wee ks of deter mi nati o n of K u va n res p o nsi ve ness i n K u va n-res p o nsi ve s u bjects a n d at 6 m o nt hs i nter vals t hereafter u ntil t he s u bject is 
≥ 3 0 m o nt hs ol d. At t hat ti me, t he s u bject will be assesse d usi n g t he W P P SI-III test. If a s u bject lea ves t he st u d y bet wee n 4 t o 6 m o nt hs after t he prece di n g Ba yle y-III assess me nt, 
t his test, or t he W P P SI-III test if t he s u bject is ≥3 0 m o nt hs at dr o p o ut, will be d o ne at f oll o w- u p. 
r W P P SI-III, perf or me d wit hi n 6 wee ks of deter mi nati o n of K u va n res p o nsi ve ness i n K u va n-res p o nsi ve s u bjects, t he n  yearl y t hereafter u ntil t he s u bject is ≥7 ye ars ol d . At t hat 
ti me, t he s u bject will be assesse d usi n g t he WI S C-I V test. If a s ubject lea ves t he st u d y bet wee n 9 m o nt hs a n d 1 year after t he prece di n g W P P SI-III assess me nt, t his, or t he 
WI S C-I V test if t he s u bject is ol der t ha n 7 years at dr o p o ut, will be d o ne at f oll o w- u p. 


 
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s T he W P P SI-III h as t w o f or ms. T he y o u n ger c hil dre n will be a d mi nistere d t he first f or m f or a ges 3 0 m o nt hs u p t o 4 ye ars ol d. T h e sec o n d f or m will be use d f or s u bjects 
4 ye ars of a ge u p t o 7 ye ars ol d. 
t WI S C-I V, perf or me d wit hi n 6 wee ks of deter mi nati o n of K u va n res p o nsi ve ness i n K u va n-res p o nsi ve s u bjects a n d e ver y 2 ye ars  t hereafter. If a s u bject lea ves t he st u d y bet wee n 
9 m o nt hs a n d 1 year after t he prece di n g WI S C- VI assess me nt, t his test will be d o ne at f oll o w- u p. 
u T he W P P SI-III or WI S C-I V will c o nti n ue t o be a d mi nistere d o n a n a n n u al or  bi- a n n u al b asis, de pe n de nt o n s u bject’s a g e, at m o nt h s, 6 0, 7 2 a n d 8 4.  
v 3- M o nt h i nteri m p h o ne c o nt act s h o ul d occ ur wi t hi n 1 wee k of sc he d ule d ti me p oi nt (ie, ±  1 wee k). P h o ne c alls will be perf or me d bet wee n cli nic visits t h at occ ur after 
m o nt h 6 a n d t hr o u g h M o nt h 8 4.  S u bjects will be c o nt acte d b y tele p h o ne t o d oc u me nt t he s u bject's wei g ht, st u d y dr u g s u p pl y, A Es , a n d C o n Me ds. 
w T he p o p ulati o n P K st u d y will be perf or me d usi n g 8 0 s u bjects, wit h at least 1 0  s u bjects 0- 1 years ol d, a n d 7 0  s u bjects > 1- 6 years ol d w h o e nr oll i n Part 1 of t he st u d y. 
See Secti o n  1 2. 3 f or details. 
 
 
 
 


 
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Pr o prietar y a n d C o nfi de ntial  
3 0 N o ve m ber 2 0 1 0 
3  T A B L E O F C O N T E N T S 
1  TI T L E  P A G E ................................................................................................................... .... 1 
2  S Y N O P SI S......................................................................................................................... 3 2  
2. 1  Sc he d ule of E ve nts.................................................................................................... 4 2  
3  T A B L E O F C O N T E N T S................................................................................................... 4 6  
4  LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S.................................... 5 0  
5  E T HI C S......................................................................................................................... ..... 5 3 
5. 1  I nstit uti o nal Re vie w B oard or Et hics C o m mittee ..................................................... 5 3  
5. 2  Et hical C o n d uct of St u d y .......................................................................................... 5 3  
5. 3  S u bject I nf or mati o n a n d I nf or me d C o nse nt.............................................................. 5 4  
6  I N V E S TI G A T O R S A N D S T U D Y A D MI NI S T R A TI V E S T R U C T U R E ........................ 5 5  
7  I N T R O D U C TI O N ............................................................................................................. 5 6 
7. 1  N o ncli nical St u dies ................................................................................................... 5 6  
7. 2  Pre vi o us Cli nical St u dies .......................................................................................... 5 7  
7. 3  St u d y Rati o nale ......................................................................................................... 5 7  
7. 4  S u m mar y of O verall Ris ks a n d Be nefits................................................................... 5 8  
7. 4. 1  
S u m mar y of Ris ks ....................................................................................... 5 8  
7. 4. 2  
S u m mar y of Be nefits................................................................................... 5 9  
8  S T U D Y O BJ E C TI V E S...................................................................................................... 6 0  
9  I N V E S TI G A TI O N A L P L A N............................................................................................ 6 1 
9. 1  O verall St u d y Desi g n a n d Pla n ................................................................................. 6 1  
9. 2  Disc ussi o n of St u d y Desi g n, I ncl u di n g C h oice of C o ntr ol Gr o u p............................ 6 5  
9. 3  Selecti o n of St u d y P o p ulati o n................................................................................... 6 6  
9. 3. 1  
I ncl usi o n Criteria......................................................................................... 6 6 
9. 3. 2  
E xcl usi o n Criteria........................................................................................ 6 7  
9. 3. 3  
Re m o val of S u bjects fr o m Treat m e nt or Assess me nt ................................. 6 7  
9. 3. 4  
S u bject I de ntificati o n a n d Re place me nt of S u bjects ................................... 6 8  
9. 4  Treat me nts................................................................................................................. 6 9  
9. 4. 1  
Treat me nts A d mi nistere d ............................................................................ 6 9  
9. 4. 2  
I de ntit y of I n vesti gati o nal Pr o d uct (I P)....................................................... 6 9  


 
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Pr o prietar y a n d C o nfi de ntial 
3 0 N o ve m ber 2 0 1 0 
9. 4. 2. 1  
Pr o d uct C haracteristics a n d La beli n g .......................................... 6 9  
9. 4. 3  
St ora ge......................................................................................................... 7 0  
9. 4. 4  
Directi o ns f or A d mi nistrati o n ..................................................................... 7 0  
9. 4. 5  
Met h o d of Assi g ni n g S u bjects t o Treat me nt Gr o u ps .................................. 7 1  
9. 4. 6  
Selecti o n of D oses Use d i n t he St u d y ......................................................... 7 1  
9. 4. 6. 1  
Selecti o n of Ti mi n g of D ose f or Eac h S u bject ............................ 7 2  
9. 4. 7  
Bli n di n g ....................................................................................................... 7 2  
9. 4. 8  
Pri or a n d C o nc o mita nt Me dicati o ns............................................................ 7 2  
9. 4. 9  
Treat me nt C o m plia nce ................................................................................ 7 3  
9. 5  I n vesti gati o nal Pro d uct Acc o u nta bilit y..................................................................... 7 3  
9. 5. 1  
Ret ur n a n d Dis p ositi o n of Cli nical S u p plies ............................................... 7 3  
9. 6  Dietar y or Ot her Pr ot oc ol Restricti o ns...................................................................... 7 3  
9. 7  Efficac y a n d Safet y Varia bles................................................................................... 7 4  
9. 7. 1  
Efficac y a n d Safet y Meas ure me nts Assesse d ............................................. 7 4  
9. 7. 1. 1  
De m o gra p hic Data a n d Me dical Hist or y ..................................... 7 5  
9. 7. 1. 2  
P h ysical E xa mi nati o n Fi n di n gs.................................................... 7 5  
9. 7. 1. 3  
Vital Si g n Meas ure me nts............................................................. 7 5  
9. 7. 1. 4  
Bl o o d P he C o nce ntrati o n ............................................................. 7 5  
9. 7. 1. 5  
Pre g na nc y Testi n g........................................................................ 7 6  
9. 7. 2  
Pri mar y Efficac y Varia ble........................................................................... 7 6  
9. 7. 3  
Sec o n dar y Efficac y Varia bles ..................................................................... 7 6  
9. 7. 4  
Safet y Varia bles .......................................................................................... 7 6  
9. 7. 4. 1  
Cli nical La b orat or y Assess me nts................................................. 7 6  
9. 7. 4. 2  
Electr ocar di o gra ms ...................................................................... 7 8  
9. 7. 5  
S u bst u d y 1: 6- m o nt h Safet y a n d Efficac y St u d y......................................... 7 8  
9. 7. 6  
P o p ulati o n P har mac o ki netic Varia bles ....................................................... 7 8  
1 0  R E P O R TI N G A D V E R S E E V E N T S ................................................................................. 7 9  
1 0. 1  A d verse E ve nts ......................................................................................................... 7 9  
1 0. 2  Seri o us A d verse E ve nts ............................................................................................ 8 1  
1 0. 3  Pre g na nc y.................................................................................................................. 8 2  
1 0. 4  Bi o Mari n P har mac o vi gila n ce C o ntact I nf or mati o n.................................................. 8 2  


 
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Pr o prietar y a n d C o nfi de ntial 
3 0 N o ve m ber 2 0 1 0 
1 1  A P P R O P RI A T E N E S S O F M E A S U R E M E N T S ............................................................... 8 4  
1 1. 1  Ne ur oc o g niti ve Assess me nts .................................................................................... 8 4  
1 2  S T U D Y P R O C E D U R E S ................................................................................................... 8 5  
1 2. 1  Ne ur oc o g niti ve St u d y ............................................................................................... 8 5  
1 2. 1. 1  Prest u d y ....................................................................................................... 8 5  
1 2. 1. 2  Scree ni n g Visit(s) ........................................................................................ 8 5  
1 2. 1. 3  Part 1: E val uati o n of K u va n Res p o nsi ve ness, 4- Wee k Treat me nt 
Visit(s)......................................................................................................... 8 6  
1 2. 1. 3. 1  
Wee k 0 Visit ................................................................................ 8 6  
1 2. 1. 3. 2  
Wee k 1 T hr o u g h Wee k 4 Visits ( ±  2 da ys).................................. 8 6 
1 2. 1. 3. 3  
Wee ks 1, 3, a n d 4 Visits O nl y ( ±  2 da ys) .................................... 8 7 
1 2. 1. 3. 4  
Wee k 4 Visit O nl y ( ±  2 da ys) ...................................................... 8 7 
1 2. 1. 4  Part 2: Ne ur oc o g niti ve St u d y i n  K u va n- Res p o nsi ve S u bjects .................... 8 7 
1 2. 1. 4. 1  
M o nt hs 2- 5 O nl y ( ± 5 da ys)......................................................... 8 7  
1 2. 1. 4. 2  
M o nt h 2 Visit O nl y ( ± 5 da ys)....................................................... 8 7  
1 2. 1. 4. 3  
M o nt h 3 a d diti o nal t o M o nt hs 2- 5 ............................................... 8 7  
1 2. 1. 4. 4  M o nt h 6 Visit O nl y ( ± 5 da ys) ................................................................... 8 8  
1 2. 1. 4. 5  M o nt hs 1 2, 1 8, 2 4, 3 0, etc. ( 6 m o nt h i nter vals ± 2 wee ks)............. 8 8  
1 2. 1. 4. 6  M o nt hs 1 2, 2 4, 3 6, 4 8, 6 0, 7 2 a n d 8 4 (a n n ual i nter vals ±  2 
wee ks) .......................................................................................... 8 8  
1 2. 1. 4. 7   3- M o nt h I nteri m P h o ne C o ntact ( M o nt hs 9, 1 5, 2 1, 2 7, etc, 
±  1 wee k)...................................................................................... 8 8 
1 2. 1. 5  Earl y Ter mi nati o n a n d F oll o w- u p Visit(s) ( wit hi n 2 8 ±  3 da ys of 
last d ose of st u d y dr u g) ............................................................................... 8 9 
1 2. 2  S u bst u d y 1: 6- M o nt h Safe t y a n d Efficac y St u d y...................................................... 9 0 
1 2. 2. 1  Scree ni n g a n d Wee ks 0- 4 ............................................................................ 9 0  
1 2. 2. 2  M o nt hs 2- 6 ( ±  5 Da ys) ................................................................................ 9 0 
1 2. 2. 3  M o nt hs 3 a n d 6 O nl y ( ± 5 da ys) ................................................................... 9 0 
1 2. 2. 4  M o nt h 6 Visit O nl y ( ± 5 da ys) ..................................................................... 9 0  
1 2. 3  S u bst u d y 2: P o p ulati o n P har mac o ki netic  St u d y i n S u bjects 0- 6 Years Ol d............. 9 0 
1 3  D A T A Q U A LI T Y A S S U R A N C E..................................................................................... 9 3  
1 4  S T A TI S TI C A L M E T H O D S A N D D E T E R MI N A TI O N O F S A M P L E SI Z E.................. 9 4  


 
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Pr o prietar y a n d C o nfi de ntial 
3 0 N o ve m ber 2 0 1 0 
1 4. 1  Effect of K u va n o n Ne ur oc o g niti ve F u ncti o n........................................................... 9 4  
1 4. 1. 1  Statistical a n d A nal ytical Pla ns ................................................................... 9 4  
1 4. 1. 2  Pri mar y Efficac y A nal ysis........................................................................... 9 4  
1 4. 1. 3  Sec o n dar y Efficac y A nal ysis....................................................................... 9 5  
1 4. 1. 4  Safet y A nal ysis............................................................................................ 9 5  
1 4. 1. 5  Deter mi nati o n of Sa m ple Size..................................................................... 9 5  
1 4. 2  S u bst u d y 1: Safet y a n d Efficac y A nal yses ............................................................... 9 6  
1 4. 3  S u bst u d y 2: P har mac o ki netic A nal yses .................................................................... 9 6  
1 4. 4  C ha n ges i n t he C o n d uct of t h e St u d y or Pla n ne d A nal yses...................................... 9 7  
1 5  D A T A M O NI T O RI N G C O M MI T T E E ( D M C) ................................................................ 9 8  
1 6  C O M P E N S A TI O N, I N S U R A N C E A N D I N D E M NI T Y .................................................. 9 9  
1 7  C A S E R E P O R T F O R M S A N D S O U R C E D O C U M E N T S ............................................ 1 0 0  
1 8  S T U D Y M O NI T O RI N G A N D A U DI TI N G ................................................................... 1 0 2  
1 9  R E T E N TI O N O F R E C O R D S.......................................................................................... 1 0 3  
2 0  U S E O F I N F O R M A TI O N A N D P U B LI C A TI O N.......................................................... 1 0 4  
2 1  R E F E R E N C E S ................................................................................................................ 1 0 5  
2 2  I N V E S TI G A T O R R E S P O N SI BI LI TI E S ........................................................................ 1 0 8 
2 2. 1  C o n d uct of St u d y a n d Pr otec ti o n of H u ma n S u bjects............................................. 1 0 8 
2 3  SI G N A T U R E P A G E ....................................................................................................... 1 0 9  
List of T a bles 
Ta ble 2. 1:  Sc he d ule of E ve nts, All S u bjects........................................................................... 4 2  
Ta ble 9. 1. 1: Ne ur oc o g niti ve Assess me nts ............................................................................... 6 3  
Ta ble 9. 4. 4. 1:  K u va n D osi n g Ta ble f or Y o u n g C hil dre n ....................................................... 7 1  
Ta ble 9. 7. 1. 1:  S u m mar y of La b orat or y Assess me nts ............................................................. 7 5  
Ta ble 9. 7. 4. 1. 1:  Cli nical La b orat or y Tests ............................................................................. 7 7  
Ta ble 1 2. 3. 1:  Sa m pli n g Wi n d o ws  f or P o p ulati o n P K St u d y .................................................. 9 1 
List of Fi g ures 
Fi g ure 9. 1. 1:  St u d y Sc he matic ................................................................................................ 6 2  
 


 
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Pr o prietar y a n d C o nfi de ntial 
3 0 N o ve m ber 2 0 1 0 
4  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S 
A b bre viati o ns  
A D R  
A d verse Dr u g Reacti o n 
A E
 A d verse
 
E ve nt
 
A L A G
 A bs or pti o n
 
la g-ti me
 
A L T
 Ala ni ne
 
tra nsa mi nase
 
A S T
 As partate
 
tra nsa mi nase
 
Ba yle y-III ®  
Ba yle y Scales of I nfa nt a n d T o d dler De vel o p me nt ®- T hir d E diti o n 
B H 4 
Tetra h y dr o bi o pteri n; K u va n f or m ula ti o n c o ntai ns 6 R- B H 4 (sa pr o pteri n) 
B U N
 Bl o o d
 
urea
 
nitr o ge n
 
C D
 C o m pact
 
dis k
 
C F R 
C o de of Fe deral Re g ulati o ns 
CI
 C o nfi de nce
 
i nter val
 
C L/ F
 A p pare nt
 
cleara nce
 
C R A 
Cli nical Researc h Ass ociate 
C R F 
Case Re p ort F or m 
d/ L 
Deciliter per liter 
D B P 
Diast olic bl o o d press ure 
D M C  
Data M o nit ori n g C o m mittee 
E C
 Et hics
 
C o m mittee
 
E C G
 Electr ocar di o gra m
 
E T V 
Earl y ter mi nati o n visit 
F D A 
F o o d a n d Dr u g A d mi nistrati o n 
F/ U
 F oll o w- u p
 
G C P 
G o o d Cli nical Practice 
G G T 
Ga m ma gl uta m yl tra nsferase 
HI P A A  
Healt h I ns ura nce P orta b ilit y a n d Acc o u nta bilit y Act 
H P A
 H y per p he n ylala ni ne mia
 
I B 
I n vesti gat or’s Br oc h ure  
I C F
 I nf or me d
 
C o nse nt
 
F or m
 
I C H 
I nter nati o nal C o nfere nce o n Har m o nisati o n 
I N D 
I n vesti gati o nal Ne w Dr u g 
I P
 I n vesti gati o nal
 
Pr o d uct ( St u d y Dr u g) 


 
P K U- 0 1 5
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5 1
 
 
Pr o prietar y a n d C o nfi de ntial 
3 0 N o ve m ber 2 0 1 0 
I Q
 I ntelli ge nce
 
q u otie nt
 
I R B
 I nstit uti o nal
 
Re vie w
 
B oar d
 
I V 
Ka 
I ntra ve n o us 
A bs or pti o n rate c o nsta nt 
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities 
M R C 
Britis h Me dical Researc h C o u nsel 
N O A E L  
N o o bser va ble a d verse effect le vel 
P D E 5
 P h os p h o diester ase  t y pe 5 i n hi bit or 
P he
 P he n ylala ni ne
 
PI
 Pri nci pal
 
I n vesti gat or
 
P K
 P har mac o ki netic
 
P K U
 P he n yl ket o n uria
 
Q/ F 
A p pare nt i nter-c o m part me ntal cleara nce 
®
 Re gistere d
 
tra de mar k
 
R E B 
Researc h Et hics B oar d 
S A E 
Seri o us A d verse E ve nt 
S A P 
Statistical A nal ysis Pla n  
S B P 
S yst olic bl o o d press ure 
S D
 Sta n dar d
 
de viati o n
 
S D V  
S o urce data verifie d 
S E
 Sta n dar d
 
err or
 
U S
 U nite d
 
States  
Vc/ F  
A p pare nt v ol u me of distri b uti o n of t he ce ntral c o m part me nt 
W P P SI ™-III   
Wec hsler Presc h o ol a n d Pri mar y Scale of I ntelli ge nce ™- T hir d E diti o n 
WI S C ®-I V   
Wec hsler I ntelli ge nce Scale f or C hil dre n ®- F o urt h E diti o n 
 


 
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Defi niti o n of Ter ms:  
I n vesti gati o nal Pr o d uct (I P): 
“ A p har mace utical f or m of a n ac ti ve i n gre die nt or place b o bei n g teste d or use d as a refere nce 
i n a cli nical trial, i ncl u di n g a pr o d uct wit h a mar keti n g a ut h ori zati o n w he n use d or asse m ble d 
(f or m ulate d or pac ka ge d) i n a wa y differe nt fro m t he a p pr o ve d f or m, or w he n use d f or a n 
u na p pr o ve d i n dicati o n, or w he n use d t o gai n f urt her i nf or mati o n a b o ut a n a p pr o ve d use.” 
(fr o m E 6 I C H)  
T he ter ms “I P” a n d “st u d y dr u g” ma y be use d i nterc ha n gea bl y i n t he pr ot oc ol. 


 
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5  
E T HI C S 
5. 1  
I nstit uti o n al Re vie w B o ar d or Et hics C o m mittee 
Pri or t o i nitiati n g t he st u d y, t he I n vesti gat or will o btai n writte n c o nfir mati o n t hat t he 
I nstit uti o nal Re vie w B oar d (I R B), Et hics C o m mittee ( E C), or Researc h Et hics B oar d ( R E B) 
is pr o perl y c o nstit ute d a n d c o m plia nt wit h I nter nati o nal C o nfere nce o n Har m o nisati o n (I C H) 
a n d G o o d Cli nical Practice ( G C P ) re q uire me nts, a p plica ble laws a n d l ocal re g ulati o ns. A 
c o p y of t he c o nfir mati o n fr o m t he I R B/ E C will be  pr o vi de d t o Bi o Mari n P har mace utical I nc. 
( Bi o Mari n) or its desi g nee. T he Pri nci pal I n vesti gat or ( PI) will pr o vi de t he I R B/ E C wit h all 
a p pr o priate material, i ncl u di n g t h e pr ot oc ol, I n vesti gat or’s Br oc h ure (I B) or Pac ka ge I nsert, 
t he I nf or me d C o nse nt F or m (I C F) i ncl u di n g c om pe nsati o n pr oce d ures, a n d a n y ot her writte n 
i nf or mati o n pr o vi de d t o t he s u bjects, i ncl u din g all c o nse nt f or ms tra nslate d t o a la n g ua ge 
ot her t ha n t he nati ve la n g ua ge of t he cli ni cal site. T he st u d y will n ot be i nitiate d a n d 
I n vesti gati o nal Pr o d uct (I P) s u p plies will n ot be s hi p pe d t o t he site u ntil a p pr o priate 
d oc u me nts fr o m t he I R B/ E C c o nfir mi n g u nc o n diti o na l a p pr o val of t he pr ot oc ol, t he I C F a n d 
all s u bject recr uit me nt materials are o btai ne d i n  writi n g b y t he PI a n d c o pies are recei ve d at 
Bi o Mari n or its desi g nee. T he a p pr o val d oc u me n t s h o ul d refer t o t he st u d y b y pr ot oc ol title 
a n d Bi o Mari n pr ot oc ol n u m ber (if p ossi ble), i de ntif y t he d oc u me nts re vie we d, a n d i ncl u de 
t he date of t he re vie w a n d a p pr o val. Bi o Mari n will e ns ure t hat t he a p pr o priate re p orts o n t he 
pr o gress of t he st u d y were ma de t o t he I R B/ E C or R E B a n d Bi o Mari n b y t he PI i n 
acc or da nce wit h a p plica ble g o ver n me ntal re g ulati o ns. 
5. 2  
Et hic al C o n d uct of St u d y 
T his st u d y will be c o n d ucte d i n acc or da nce wit h t he f oll o wi n g: 
•  U S C o de of Fe deral Re g ulati o ns ( C F R) s ecti o ns t hat a d dress cli nical researc h 
st u dies, a n d/ or ot her nati o nal a n d l ocal re g ulati o ns, as a p plica ble 
•  E 6 I nter nati o nal C o nfere nce o n Har m o nisa ti o n [I C H] G ui deli ne f or G o o d Cli nical 
Practice  
•  T he et hical pri nci ples esta blis he d b y t he Declarati o n of Helsi n ki 
S pecificall y, t his st u d y is base d o n a de q ua tel y perf or me d la b orat or y a n d a ni mal 
e x peri me ntati o n; t he st u d y will be c o n d ucte d u nder a pr ot oc ol re vie we d a n d a p pr o ve d b y a n 
I R B/ E C; t he st u d y will be c o n d ucte d b y scie ntificall y a n d me dicall y q ualifie d pers o ns; t he 
be nefits of t he st u d y are i n pr o p or ti o n t o t he ris ks; t he ri g hts an d welfare of t he s u bjects will 
be res pecte d; t he p h ysicia ns c o n d ucti n g t he st u d y d o n ot fi n d t he hazar ds t o o ut wei g h t he 
p ote ntial be nefits; a n d eac h s u bj ect, or his/ her le gall y a ut h ori ze d re prese ntati ve will pr o vi de 
writte n, i nf or me d c o nse nt bef ore a n y st u d y-re late d tests or e val uati o ns are perf or me d. 


 
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5. 3  
S u bject I nf or m ati o n a n d I nf or me d C o nse nt 
A pr o perl y writte n a n d e xec ute d I C F, i n c o m p lia nce wit h t he Declarati o n of Helsi n ki, 
E 6 I C H ( G C P G ui deli ne, Secti o n 4. 8) a n d 2 1 C F R § 5 0 a n d ot her a p plica ble l ocal re g ulati o ns, 
will be o btai ne d f or eac h s u bject pri or t o e nteri n g t he s u bject i nt o t he st u d y. T he I n vesti gat or 
will pre pare t he I C F a n d pr o vi de t he d oc u me nts t o Bi o Mari n f or a p pr o val pri or t o s u b missi o n 
t o t he I R B/ E C. Bi o Mari n a n d t he I R B/ E C m ust a p pr o ve t he d oc u me nts bef ore t he y are 
i m ple me nte d. A c o p y of t he a p pr o ve d I C F, a n d if a p plica ble, a c o p y of t he a p pr o ve d s u bject 
i nf or mati o n s heet, mi n or asse nt f or m, pare ntal I C F f or st u dies i n v ol vi n g mi n ors, a n d all I C Fs 
tra nslate d t o a la n g ua ge ot her t ha n t he nati ve la n g ua ge of t he cli nical site m ust als o be 
recei ve d b y Bi o Mari n or its desi g nee pri or t o t he deli ver y of st u d y dr u g. 
S u bjects u n der t he a ge of 1 8 years will pr o vi de writte n asse nt (if re q uire d), a n d his/ her 
le gall y a ut h orize d re prese ntati ve ( pare nt or le gal g uar dia n) will pr o vi de writte n i nf or me d 
c o nse nt f or s uc h s u bjects. T he I n vesti gat or wi ll pr o vi de c o pies of t he si g ne d I C F t o eac h 
s u bject ( or t he s u bject’s le gall y a ut h orize d re prese ntati ve) a n d will mai ntai n t he ori gi nal i n 
t he s u bject’s rec or d file. 


 
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I N V E S TI G A T O R S A N D S T U D Y A D MI NI S T R A TI V E S T R U C T U R E 
Pri or t o be gi n ni n g t he st u d y, t he PI at eac h site m ust pr o vi de t o Bi o Mari n or its desi g nee a 
f ull y e xec ute d a n d si g ne d F or m F D A 1 5 7 2 a n d a Fi na ncial Discl os ure F or m. All s u b-
I n vesti gat ors m ust be liste d o n F or m F D A 1 5 7 2. Fi na ncial Discl os ure F or ms m ust als o be 
c o m plete d f or all s u b-I n vesti gat ors liste d  o n t he F or m F D A 1 5 7 2 w h o will be directl y 
i n v ol ve d i n t he treat me nt or e val uati o n of researc h s u bjects i n t his st u d y. 
T he st u d y will be a d mi nistere d b y a n d m o nit o re d b y e m pl o yees or re prese ntati ves of 
Bi o Mari n. Cli nical Researc h Ass ociates ( C R As) or trai ne d desi g nees will m o nit or eac h site 
o n a peri o dic basis a n d perf or m verificati o n of  s o urce d oc u me ntati o n f or eac h s u bject as well 
as ot her re q uire d re vie w pr ocesses. Bi o Mari n ’s Re g ulat or y Affairs Depart me nt ( or desi g nee) 
will be res p o nsi ble f or t he ti mel y re p orti n g of se ri o us a d verse e ve nts ( S A Es) t o a p pr o priate 
re g ulat or y a ut h orities as re q uire d. 
Pri or t o data base l oc k i n m ultice nter st u dies, a c o or di nati n g i n vesti gat or will be i de ntifie d 
w h o will rea d t he cli nical st u d y re p ort a n d c o nf ir m t hat it acc uratel y descri bes t he c o n d uct 
a n d res ults of t he st u d y, t o t he best of his or  her k n o wle d ge. T he c o ordi nati n g i n vesti gat or 
will be c h ose n o n t he basis of acti ve partici pati o n i n t he st u d y, a bilit y t o i nter pret data, a n d 
willi n g ness t o re vie w a n d si g n t he re p ort i n a s pecifie d ti mefra me. 


 
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I N T R O D U C TI O N 
A c o m pre he nsi ve re vie w of K u va n ®  is c o ntai ne d i n t he I B or pac ka ge i nsert s u p plie d b y 
Bi o Mari n; t he I n vesti gat or s h o ul d re vie w t hese d oc u me nts pr i or t o i nitiati n g t his st u d y. 
7. 1  
N o ncli nic al St u dies  
N o ncli nical st u dies were c o n d ucte d i n mice, rats, d o gs, a n d mar m osets at d oses ra n gi n g fr o m 
2 0 t o 4 0 0 0 m g/ k g a n d usi n g i ntra ve n o us (I V) a n d or al r o utes of sa pr o pteri n a d mi nistrati o n. I n 
a 5 2- wee k mar m oset t o xic ol o g y st u d y i n w hic h a ni mals recei ve d oral d osa ges of 2 0, 8 0, or 
3 2 0 m g/ k g/ da y sa pr o pteri n, t he n o o bser va ble a d verse effect le vel ( N O A E L) was deter mi ne d 
t o be 3 2 0 m g/ k g/ da y. T he o nl y o bser ve d A Es i n t his st u d y were sali vati o n a n d v o miti n g, b ot h 
p ossi bl y ca use d b y t he d osi n g met h o d a n d l o w p H  of t he d osi n g s ol uti o n; n o la b orat or y or 
hist o pat h ol o gic a b n or malities were f o u n d. I n a si milar 5 2- wee k rat t o xic ol o g y st u d y, a ni mals 
recei ve d oral d osa ges of 4, 4 0, or 4 0 0 m g/k g/ da y sa pr o pteri n. T he N O A E L was deter mi ne d 
t o be 4 0 m g/ k g/ da y, wit h a l o w i nci de nce of mil d i ncreases i n bas o p hilic i nfiltrates i n t he 
re nal c ollecti n g t u b ules of t he a ni mals treate d wit h 4 0 0 m g/ k g/ da y f or 5 2 wee ks. T he re nal 
hist o pat h ol o gic fi n di n gs we re n ot ass ociate d wit h c ha n ges i n cli nical c he mistr y or uri nal ysis 
res ults, a n d t he fi n di n gs were belie ve d t o be of n o cli nical c o nse q ue nce. A d diti o nall y, n o 
re nal t u b ular c ha n ges were f o u n d i n t he s u bseq ue nt rat carci n o ge nicit y  st u d y, after 1 0 4 wee ks 
of dail y sa pr o pteri n a d mi nistra ti o n at d oses u p t o 2 5 0 m g/ k g/ da y. 
Carci n o ge nicit y st u dies usi n g d oses u p t o 2 ti mes t he ma xi m u m rec o m me n de d h u ma n d ose 
of 2 0 m g/ k g/ da y were c o n d ucte d i n F- 3 4 4 rats  ( 2- year st u d y) a n d C D- 1 mice ( 7 8- wee k 
st u d y) ( Pac ka ge I nsert). T here was a n i ncrease i n t he i nci de nce of be ni g n a dre nal 
p he oc hr o m oc yt o ma i n rats treate d at t he hi g hest  d ose; n o carci n o ge nic effect was see n i n t he 
mice. At 3 ti mes t he ma xi m u m h u ma n d ose of  2 0 m g/ k g/ da y, n o effect o n fertilit y or 
re pr o d ucti o n f u ncti o n was o bser ve d i n male a n d fe male rats. 
T hese data, i n a d diti o n t o t he data re p orte d i n t he re mai n der of t he n o ncli nical p har mac ol o g y, 
p har mac o ki netic, a n d t o xic ol o g y st u die s, s u p p ort t he safet y of K u va n. 
F or m ore i nf or mati o n o n n o ncli nical st u dies , see t he I B or t he Pac ka ge I nsert. 


 
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7. 2  
Pre vi o us Cli nic al St u dies  
T he efficac y a n d safet y of K u va n were e val uate d i n 4 m ultice nter cli nical st u dies i n s u bjects 
wit h P K U. St u d y 1 was a n o pe n-la bel st u d y e val uati n g K u va n at 1 0 m g/ k g / da y i n s u bjects 
w h ose bl o o d p he n ylala ni ne ( P he) c o nce ntrati o ns  were n ot i n c o ntr ol a n d w h o were n ot 
f oll o wi n g a P he-restricte d diet. St u d y 2 was a d o u ble- bli n d, place b o-c o ntr olle d st u d y usi n g a 
K u va n d ose of 1 0 m g/ k g/ da y; St u d y 3 was a d os e-titrati o n st u d y e val uati n g K u va n d osa ges 
of 5, 1 0, a n d 2 0 m g/ k g/ da y i n s u bjects w h o c o m plete d St u d y 2; a n d St u d y 4 was a n 
o pe n-la bel st u d y usi n g K u va n at a d ose of 2 0 m g/ k g/ da y i n c h il dre n a ges 4 t o 1 2 years w h o 
were o n P he-restricte d diets a n d w h ose bl o o d P he c o nce ntrati o ns were ≤ 4 8 0 μ m ol/ L at 
scree ni n g.  
All st u dies s h o we d t hat K u va n l o were d bl o o d P h e c o nce ntrati o ns i n a s u bset of s u bjects 
e nr olle d i n eac h st u d y. I n t he 6- wee k d o u ble- bli n d st u d y ( St u d y 2), t he K u va n-treate d gr o u p 
ha d a mea n c ha n ge i n bl o o d P he c o nce ntrati o n fr o m baseli ne t o Wee k 6 of - 2 3 9 μ m ol/ L 
w hile t he place b o-treate d gr o u p mea n c ha n ge was 6 μ m ol/ L; t he mea n perce nt c ha n ges 
( ± sta n dar d de viati o n, S D) were - 2 9 % ( ± 3 2 ) ( K u va n) a n d 3 % ( ± 3 3) ( place b o). 
T he differe nce bet wee n t he gr o u ps was statisticall y si g nifica nt ( p < 0. 0 0 1). 
7. 3  
St u d y R ati o n ale 
N u mer o us i n vesti gati o ns ha ve re veale d t h e de vastati n g ne ur o ps yc h ol o gical i m pact of 
ele vate d bl o o d P he c o nce ntrati o n i n a d ults a n d c hil dre n wit h P K U ( M o yle, 2 0 0 7, 
Ne ur o ps yc h ol. Re v.) . Ri g or o us c o ntr ol of diet is t y picall y a d v ocate d i n c hil dre n 4 years a n d 
u n der wit h P K U beca use brai n se nsiti vit y t o hi g h P he c o nce ntrati o ns is e x pecte d t o be 
greatest d uri n g t hese years of ra pi d ne ur oc o g niti ve de vel o p me nt.  
T he str o n gest deter mi na nt of i ntelli ge nce q u ot ie nt (I Q) a n d c o g niti ve f u ncti o n is c o m plia nce 
wit h bl o o d P he c o ntr ol. Se vera l cli nical st u dies wit h K u va n ha ve alrea d y de m o nstrate d 
efficac y i n re d uci n g bl o o d P he i n s u bjects ol der t ha n 4 years. T his st u d y will e xa mi ne 
w het her a d diti o n of K u va n t o t he sta n dar d of care at a n earl y a ge i n c hil dre n wit h 
well-c o ntr olle d diets ca n l o wer bl o o d P he le vels (ie, reac h a n d mai ntai n a g oal of 
≤ 2 4 0 μ m ol/ L) a n d preser ve ne ur oc o g niti ve f u ncti o ni n g. I n a d diti o n, Part 1 of t his st u d y will 
pr o vi de data o n K u va n e x p os ure, rate of u pta k e, half-life, a n d clea ra nce i n y o u n g c hil dre n. 


 
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7. 4  
S u m m ar y of O ver all Ris ks a n d Be nefits 
7. 4. 1  S u m m ar y of Ris ks 
Res p o nse t o K u va n treat me nt i n P K U s u bjects is varia ble. N ot all s u bjects res p o n de d t o 
treat me nt wit h K u va n i n cli nical trials, an d t he i nitiati o n of K u va n treat me nt d oes n ot 
eli mi nate t he nee d t o m o nit or f or a de q uate bl o o d P he c o ntr ol. Pr ol o n ge d ele vati o ns i n bl o o d 
P he c o nce ntrati o ns ca n res ult i n ne ur ol o gic i m pair me nt. C o n versel y, s o me s u bjects i n cli nical 
trials w h o were f oll o wi n g P he-restricte d diets a n d recei ve d treat me nt wit h K u va n 
e x perie nce d s u bsta ntial re d ucti o ns of bl o o d P he.  C o nce ntrati o ns of bl o o d P he t hat are t o o 
l o w ma y be ass ociate d wit h cata b olis m a n d pr otei n brea k d o w n. T heref ore, w he n K u va n is 
use d i n c o m bi nati o n wit h a P he-restricte d diet, patie nts s h o ul d be m o nit ore d cl osel y t o e ns ure 
t hat bl o o d P he c o nce ntrati o ns are n ot t o o l o w, a n d, if necessar y, t he d ose of K u va n s h o ul d be 
a dj uste d or dietar y P h e s h o ul d be i ncrease d. 
A d verse reacti o ns ha ve us uall y bee n mil d a n d tra nsie nt. T he i nte grate d safet y data base 
c o nsists of 5 7 9 patie nts i n K u va n cli nical trials. T hese patie nts were treate d at dail y d oses of 
5 m g/ k g, 1 0 m g/ k g, or 2 0 m g/ k g, fr o m 8 da ys t o o ver 6 m o nt hs.  N o d ose-relate d or e xte nt of 
e x p os ure-relate d c ha n ge i n fr e q ue nc y of A Es was o bser ve d. Si x seri o us a d verse e ve nts 
occ urre d i n cli nical trials , n o ne were c o nsi dere d t o be st u d y dr u g relate d. O ne s u bject 
wit h dre w fr o m a cli nical trial d ue t o a n A E of pre g na nc y. T he m ost fre q ue nt A Es t h o u g ht t o 
be relate d t o K u va n i n place b o-c o ntr olle d trials were p har y ng olar y n geal pai n, a n d 
r hi n orr h oea. T he m ost fr e q ue ntl y re p orte d a d verse reacti o ns i n all cli nical trials ( > 4 %), 
re gar dless of relati o ns hi p t o st u d y dr u g, were hea dac he, diarr hea, a b d o mi nal pai n, u p per 
res pirat or y tract i nfecti o n, p har y n g olar y n geal pai n, v o miti n g, a n d na usea .  Mil d t o m o derate 
ne utr o pe nia was n ote d d uri n g K u va n a d mi nistrati o n i n 2 4 of 5 7 9 s u bjects ( 4 %) a n d i n 3 of 5 9 
s u bjects recei vi n g place b o ( 5 %). 
P ote ntial ris ks will be assesse d i n P K U- 0 1 5 b y re c or di n g of me dical hist or y, A Es, a n d vital 
si g ns; perf or mi n g p h ysical e xa mi nati o ns a n d E CGs, if re q uire d; a n d c o n d ucti n g cli nical 
la b orat or y tests (c he mistr y, he mat ol o g y, a n d uri nal ysis). 


 
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7. 4. 2  S u m m ar y of Be nefits 
Pr ol o n ge d hi g h bl o o d P he c o nce ntrati o ns are ne ur ot o xic a n d lea d t o i m pair me nt of 
i ntelli ge nce a n d ot her brai n f u ncti o ns (s uc h as atte nti ve ness). Re d ucti o n of bl o o d P he 
c o nce ntrati o ns t hr o u g h dietar y c o ntr ol is a n i m p orta nt deter mi na nt of l o n g-ter m ne ur ol o gic 
o utc o me i n P K U patie nts, a n d re d ucti o n of bl o o d P he c o nce ntrati o ns i n patie nts wit h P K U 
has bee n s h o w n t o decrease t he l o n g-ter m ris k of ne ur ol o gic i nj ur y. It is diffic ult f or ma n y 
patie nts t o mai ntai n re d uce d bl o o d P he, a n d ma n y patie nts wit h P K U e x perie nce s o me de gree 
of ne ur ol o gical i m pair me nt des pite eff o rts t o mai ntai n dietar y P he c o ntr ol. 
I n cli nical trials wit h K u va n i n s u bjects wit h P K U, re d ucti o ns i n bl o o d P he c o nce ntrati o ns 
were o bser ve d i n s o me s u bjects. Alt h o u g h l o n g-ter m assess me nt of ne ur ol o gic f u ncti o n i n 
s u bjects wit h P K U recei vi n g K u va n f or t he treat me nt of ele vate d bl o o d P he has n ot bee n 
assesse d, K u va n ma y hel p mai ntai n re d uce d bl o o d P he c o nce ntrati o ns as a n a dj u nct t o a 
P he-c o ntr olle d diet. 
S o me s u bjects ma y n ot be nefit fr o m partici p ati o n i n P K U- 0 1 5; h o we ver, t heir partici pati o n 
i n t his st u d y mi g ht hel p i n t he f ut ure treat me nt of ot her in di vi d uals wit h P K U. 


 
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8  
S T U D Y O B J E C TI V E S 
T he pri mar y o bjecti ve of t he st u d y is: 
•  T o e val uate t he l o n g-ter m efficac y of K u va n i n preser vi n g ne ur oc o g niti ve 
f u ncti o n i n c hil dre n wit h P K U w he n treat me nt is i nitiate d at 0-6  years 
T he sec o n dar y o bjecti ve(s) of t he st u d y is (are): 
•  T o e val uate t he l o n g-ter m safet y  of K u va n i n t he st u d y p o p ulati o n  
•  T o e val uate t he effect of K u va n o n gr o wt h para meters i n t he st u d y p o p ulati o n 
S u bst u d y 1:  6- M o nt h S afet y a n d E ffic ac y i n C hil dre n 0- 6 Ye ars Ol d 
Pri mar y O bjecti ve  
•  T o e val uate t he safet y of 6 m o nt hs of treat me nt wit h K u va n i n c hil dre n wit h P K U 
w h o are 0- 6  years ol d  
Sec o n dar y O bjecti ve   
•  T o e val uate t he efficac y of 6 m o nt hs of treat me nt wit h K u va n i n c o ntr olli n g bl o o d 
P he c o nce ntrati o n wit hi n acce pta ble ra n ges i n c hil dre n wit h P K U w h o are 
0- 6  years ol d  
•  T o pr o vi de baseli ne ne ur oc o g niti ve data f or all K u va n-res p o nsi ve s u bjects a n d 
6- m o nt h Ba yle y-III data f or s u bjects w h o are 0- 2 years ol d at e nr oll me nt 
 
S u bst u d y 2:  P o p ul ati o n P h ar m ac o ki netics i n C hil dre n  0- 6 Ye ars Ol d 
Pri mar y O bjecti ve  
•  T o e val uate t he p o p ulati o n p har mac o ki netics of K u va n i n y o u n g c hil dre n 


 
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9  
I N V E S TI G A TI O N A L P L A N 
9. 1  
O ver all St u d y Desi g n a n d Pl a n 
T his 2- part m ultice nter, o pe n-la be l st u d y is desi g ne d t o e val uate t he safet y of K u va n a n d its 
effect o n ne ur oc o g niti ve f u ncti o n, bl o o d P he c o nce n trati o n, a n d gr o wt h i n c hil dre n wit h P K U 
w h o are 0- 6 years ol d. T he st u d y will be c o nsi dere d c o m plete w he n a p pr o xi matel y 
4 5 s u bjects ha ve c o m plete d 7 years of treat me nt.  
O ne of t he g oals of t he st u d y will be t o d ecrease bl o o d P he le vels t o reac h a g oal of 
≤ 2 4 0 μ m ol/ L. S u bjects will meet wit h a dieticia n  at eac h st u d y vi sit t o re vie w dietar y P he 
i nta ke. Dietar y P he ma y be a d de d t o t he diet, at t he discreti o n of t he I n vesti gat or, if a bl o o d 
P he le vel falls bel o w 1 2 0 μ m ol/ L. See Secti o n  9. 6 f or details o n dietar y P he a dj ust me nt.  
A safet y e val uati o n will be c o n d ucte d i n t hese s u bjects d uri n g t he first 6 m o nt hs of t he st u d y 
( S u bst u d y 1) a n d ma y i ncl u de E C G testi n g 2- 6 h o urs f oll o wi n g t he first d ose of K u va n. A 
p o p ulati o n p har mac o ki netic st u d y will be c o n d ucte d i n a s u bs et of t hese c hil dre n d uri n g 
Wee ks 0- 4 ( S u bst u d y 2). 
Fi g ure 9. 1. 1  s h o ws a sc he matic f or t he st u d y. 
 


 
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Fi g ure 9. 1. 1:  St u d y Sc he m atic 
 
 


 
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Pr o prietar y a n d C o nfi de ntial  
3 0 N o ve m ber 2 0 1 0 
P art 1:  E v al u ati o n of  K u v a n Res p o nsi ve ness 
Be gi n ni n g at Wee k 0 a n d after all baseli ne asse ss me nts are c o m plete d, s u bjects e nr olle d i nt o 
t he st u d y will recei ve 2 0 m g/ k g K u va n dail y f or 4 wee ks. S u bjects will re t ur n t o t he cli nic 
wee kl y f or safet y assess me nts a n d bl o o d P h e c o nce ntrati o n meas ure me nt ( S u bst u d y 2, 
P o p ulati o n P K). S u bjects s h o ul d c o nti n ue wit h t heir c urre nt le vel of dietar y P he i nta ke. 
H o we ver, if a s u bject’s bl o o d P h e c o nce ntrati o n dr o ps bel o w 1 2 0 μ m ol/ L , at t he discreti o n 
of t he I n vesti g at or,  a gr a d u al i ncre ase of a p pr o xi m atel y 5 t o 2 0 m g/ k g of dail y dietar y 
P he s u p ple me nt ma y be a d de d t o t he diet. It is i m p ort a n t t o a v oi d u nst a ble s wi n gs i n t he 
bl o o d P he v al ues . N o d ose a dj ust me nts ca n be ma de d uri n g Part 1 wit h o ut c o ns ultati o n wit h 
t he Me dical M o nit or. 
P art 2:  Ne ur oc o g niti ve St u d y 
S u bjects w h o are res p o nsi ve t o K u va n (see t he defi niti o n of res p o nsi ve ness i n I ncl usi o n a n d 
E xcl usi o n  Criteri o n) will c o nti n ue t o recei ve dail y si n gle d oses of 2 0 m g/ k g K u va n orall y. 
At t he discreti o n of t he I n vesti g at or, t he s u bject’s dail y P he i n ta ke ma y be m o difie d if bl o o d 
P he le vels fall bel o w 1 2 0 μ m ol/ L d uri n g t he st u d y. K u va n d ose ma y als o be re d uce d after 
Wee k 5 after c o ns ultati o n wit h  t he Me dical M o nit or, i n su bjects w h o d o n ot t olerate t he 
2 0 m g/ k g/ da y d ose. Ne ur oc o g niti ve testi n g will be perf or me d wit hi n 6 wee ks of 
deter mi nati o n of K u va n res p o nsi ve ness i n all K u va n-res p o nsi ve s u bjects. T he t y pes of 
ne ur oc o g niti ve tests use d (ie, Ba yle y S cale of I nfa nt a n d T o d dler De vel o p me nt ® - T hir d 
E diti o n [ Ba yle y-III], Wec hsler Presc h o ol a n d Pri mar y Scale of I nte lli ge nce ™- T hir d E diti o n 
[ W P P SI-III], a n d/ or Wec hsler I ntelli ge nce Scale f or C hil dre n® - F o urt h E diti o n [ WI S C-I V]), 
will be t h ose c o nsi dere d a p pr o priate f or t he s u bject’s a ge.  
T a ble 9. 1. 1: Ne ur oc o g niti ve Assess me nts 
A ge Gr o u p  
I nf a nc y  
Presc h o ol  
Sc h o ol- A ge 
Assess me nt
 Ba yle y-III
 W P P SI-III
 W P P SI-III
  WI S C-I V
 
A ge
 0
 
m o nt hs
 
t hr o u g h 
 <  3 0 m o nt hs 
≥ 3 0 m o nt hs 
t hr o u g h <  4 years
≥ 4 years 
t hr o u g h 
 <  7 years 
≥ 7 years a n d 
ol der 
Fre q ue nc y  
E ver y 6 m o nt hs 
 ±  2 wee ks 
O nce a year 
 ±  2 wee ks 
O nce a year 
 ±  2 wee ks  
E ver y 
2 years  ±  2 wee ks
 
 


 
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T he B a yle y-III will be a d mi nistere d t o s u bject s w h o are fr o m 0 m o nt hs t o less t h a n 3 0 
m o nt hs of a ge a n d will be a d mi nistere d e ver y  6 m o nt hs ± 2 wee ks. At 3 0 m o nt hs ol d 
or ol der, t he s u bjects will be a d mi nistere d t he W P P SI-III. T he W P P SI-III h as t w o 
f or ms. T he y o u n ger c hil dre n will be a d mi nistere d t he first f or m f or a ges 3 0 m o nt hs t o 
less t h a n 4 ye ars ol d. T he sec o n d f or m will be use d f or s u bjects 4 ye ars of a ge t o less 
t h a n 7 ye ars ol d. T he W P P SI-III will be a d mi nistere d ye arl y ± 2 wee ks. Be gi n ni n g at 7 
ye ars ol d st u d y, s u bjects will be a d mi nistere d t he WI S C-I V e ver y 2 ye ars ± 2 wee ks. 
Gr o wt h, bl o o d P he c o nce ntrati o n, a n d safet y will be m o nit ore d. T hese a n d t he 
ne ur oc o g niti ve  assess me nts will be perf or me d e ver y 6 t o 2 4 m o nt hs, de pe n di n g o n t he 
t y pe of assess me nt, u ntil t he e n d of t he st u d y. Refer t o Ta ble 2. 1  f or details. 
T he st u d y will be c o nsi dere d c o m plete w he n a p pr o xi matel y 4 5 s u bjects ha ve bee n f oll o we d 
f or 7 years a n d ha ve at least 2 p ost-treat me nt W P P SI-III a n d/ or WI S C-I V tests 
a d mi nistere d 2 years a part. 
After st u d y c o m pleti o n, s u bjects will be gi ve n t h e o p p ort u nit y t o partici pate i n a re gistr y 
st u d y t hat will f oll o w l o n ger ter m o utc o mes. 
S u bst u d y 1:  S afet y a n d Effi c ac y i n S u bjects 0- 6 Ye ars Ol d 
All K u va n-res p o nsi ve s u bjects will be e nr olle d  i n S u bst u d y 1 a n d will be assesse d m o nt hl y 
f or t he first 6 m o nt hs of t he st u d y. Bl o o d P he co nce ntrati o ns, vari o us meas ures of gr o wt h, 
a n d safet y data will be c ollecte d. T he s u bject’s dail y P he i nta ke will be i ncrease d o nl y if t he 
s u bject’s bl o o d P he le vels fall bel o w 1 2 0 μ m ol/ L. K u va n d ose ma y als o be re d uce d after 
Wee k 5 a n d  after c o ns ultati o n wit h t he Me dical M o nit or if t he s u bject d oes n ot t olerate t he 
a p pr o xi matel y 5- 2 0 m g/ k g/ da y d ose. Refer t o  Ta ble 2. 1, Sc he d ule of E ve nts f or t he ti mi n g of 
assess me nts. 
S u bst u d y 2: P o p ul ati o n P h ar m ac o ki neti cs ( P K) i n S u bjects 0- 6 Ye ars Ol d 
F or t he p o p ulati o n P K e val uati o n, t he first 1 0  s u bjects i n t he 0- 1 year a ge gr o u p a n d t he first 
7 0  s u bjects i n t he > 1- 6 year a ge gr o u p will be e nr olle d. T hree ( 3) plas ma sa m ples fr o m eac h 
s u bject i n t he 0- 1 year a ge gr o u p a n d 4 plas ma sa m ples fr o m eac h s u bject i n t he > 1- 6 year 
a ge gr o u p will be c ollecte d at t he Wee k 0, Wee k  1, Wee k 2, Wee k 3, a n d/ or Wee k 4 visits 
acc or di n g t o a pre deter mi ne d sc he d ule. See Secti o n  1 2. 3 a n d Ta ble 1 2. 3. 1  f or sa m pli n g 
wi n d o ws. 


 
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9. 2  
Disc ussi o n of St u d y Desi g n, I n cl u di n g C h oice of C o ntr ol Gr o u p 
T he desi g n of t his cli nical st u d y is i nte n de d t o s u p pl y data t o c o m ple me nt t he res ults 
of 2 c o m plete d d o u ble- bli n d place b o-c o ntr olle d st u dies t hat esta blis he d t he safet y a n d 
efficac y of K u va n i n P K U-affecte d i n di vi d uals. P K U- 0 0 3 a n d P K U- 0 0 6 de m o nstrate d 
acce pta ble safet y pr ofiles a n d sta tisticall y a n d cli nicall y mea nin gf ul re d ucti o ns i n bl o o d P he 
c o nce ntrati o n i n s u bjects > 8 years ol d a n d 4- 1 2 years ol d, res pecti vel y. T he latter st u d y als o 
s h o we d statisticall y a n d cli nicall y mea ni n gf ul i ncrease d t olera nce of a d diti o nal P he i n t he 
diet w hile o verall bl o o d P he c o ntr ol was mai nta i ne d. Beca use neit her st u d y i ncl u de d s u bjects 
less t ha n 4 years ol d n or assesse d t he i m pact of t he dr u g o n ne ur oc o g niti ve de vel o p me nt, 
t hese fact ors beca me t he basis f or u n derta ki n g t he prese nt st u d y.  
P K U- 0 1 5 will all o w assess me nt of safet y, efficac y, a n d P K i n a s ufficie nt n u m ber of y o u n g 
s u bjects t o pr o vi de a c o m para ble e x perie nce wit h t he treat me nt of ol der affecte d i n di vi d uals 
i n c o m plete d K u va n cli nical st u dies. P K U- 0 1 5 c om prises 0- 6 year ol d c hil dre n beca use t his 
is t he a ge ra n ge w here brai n tiss ue is partic ularl y se nsiti ve t o t he effects of ele vate d bl o o d 
P he. T he desi g n d oes n ot i ncl u de a c o ntr ol gr o u p f o r 3 reas o ns. First, fr o m t he pers pecti ve of 
P he re d ucti o n a n d o verall safet y, ot her f or m ul ati o ns of B H 4 ha ve bee n use d s uccessf ull y 
acr oss all a ge gr o u ps (s u m marize d i n Secti o n  9. 4. 6), a n d t here is n o e vi de nce t hat s u bjects 
less t ha n 4 years ol d will res p o n d t o t his f or m ulati o n of B H 4 an y differe ntl y t ha n t h ose ol der 
t ha n 4 years. Sec o n d, use of a place b o is n ot practical beca use K u va n is c o m merciall y 
a vaila ble. T hir d, i ncl usi o n of s u bjects 4- 6 ye ars ol d all o ws f or direct c o m paris o ns wit h 
sa me-a ge s u bjects i n t he dr u g-treate d a n d place b o ar ms of P K U- 0 0 6.  
Part 1 will all o w f or selecti o n of a s uita bl e p o p ulati o n t o carr y o ut l o n g-ter m ne ur oc o g niti ve 
assess me nts i n Part 2. F or i ncl usi o n i n Part 2, a mi ni mal le vel of preser ve d ne ur oc o g niti ve 
f u ncti o n d oc u me nte d b y test sc ores a n d r o b ust, c o nsiste nt re d ucti o ns i n bl o o d P he o ver 
4 wee ks of treat me nt i n Part 1 will e ns ure t hat t he l o n g-ter m be nefits of K u va n ca n be 
a de q uatel y e val uate d. T here is n o val ue i n e nr olli n g s u bjects wit h irre versi ble deficits i n I Q 
or t h ose w h o ha ve a hist or y of dietar y n o nc o m plia nce i n t his st u d y. T he 3 ne ur oc o g niti ve 
tests use d t o c o ver t he a ge ra n ge of P K U- 0 1 5 s u bjects re prese nt t he best a vaila ble t o ols 
(re vie we d i n Secti o n 1 1. 1).  
A p o p ulati o n P K st u d y ( S u bst u d y 2) will be c o n d ucte d o n a s u bset of t he s u bjects e nr olle d i n 
Part 1. Bl o o d will be dra w n f or t otal bi o pteri n meas ure me nt at t he Wee k 0, 1, 2, 3, a n d/ or 
4 visit acc or di n g t o t he sc he d ule descri be d i n Secti o n  1 2. 3.  
I n Part 2, ne ur oc o g niti ve testi n g will be perf or me d i n t hese K u va n-res p o nsi ve s u bjects o ver a 
7- year peri o d, usi n g a ge-a p pr o priate test s. D uri n g S u bst u d y 1 safet y a n d efficac y 


 
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assess me nts will be c o n d ucte d wee kl y d uri n g Wee k 0 t o Wee k 4, t he n m o nt hl y f or M o nt hs 2 
t hr o u g h M o nt h 6.  
9. 3  
Selecti o n of St u d y P o p ul ati o n 
9. 3. 1  I ncl usi o n Criteri a 
I n di vi d uals eli gi ble t o partici pate i n t his st u d y m ust meet all of t he f oll o wi n g criteria: 
•  Pare nt(s) or g uar dia n(s) willi n g a n d a ble  t o pr o vi de writte n, si g ne d i nf or me d 
c o nse nt after t he nat ure of t he st u d y has bee n e x plai ne d, a n d pri or t o a n y researc h-
relate d pr oce d ures. 
•  Pare nt(s) or g uar dia n(s) willi n g a n d a ble  t o c o m pl y wit h all st u d y pr oce d ures. 
•  Fe male s u bjects of c hil d beari n g p ote ntial (as deter mi ne d b y t he i n vesti gat or) a n d 
se x uall y mat ure male s u bjects willi n g t o use a me dicall y acce pte d met h o d of 
c o ntrace pti o n t hr o u g h o ut t he st u d y. Fe male  s u bjects of c hil d beari n g p ote ntial 
willi n g t o u n der g o peri o dic pre g na nc y te sts d uri n g t he c o urse of t he st u d y 
•  Esta blis he d dia g n osis of P K U wit h h y pe r p he n ylala ni ne mia ( H P A) d oc u me nte d i n 
t he me dical rec or d b y at least 2 bl o o d P he c o nce ntrati o ns ≥ 3 6 0 μ m ol/ L 
( 6 m g/ d L) ta ke n at least 3 da ys a part  
•  D oc u me nte d bl o o d P he c o ntr ol ( defi ne d b y t he sta n dar d use d at eac h treat me nt 
ce nter) pri or t o st u d y e nr oll me nt, if a p pli ca ble (e g, t he s u bject is ol d e n o u g h f or 
t hese data t o be c ollecte d); bl o o d P he c o nce ntrati o ns f or s u bjects < 6 m o nt hs ol d 
at Scree ni n g m ust be c o nsi dere d c o ntr o lle d a n d sta ble b y t he I n vesti gat or  
•  Willi n g t o a d here t o a prescri be d P he-rest ricte d diet i n or der t o mai ntai n bl o o d 
P he c o nce ntrati o ns wit hi n t he rec o m me n de d ra n ges esta blis he d at t he s u bject’s 
st u d y site 
•  A ge 0 t o 6 years, i ncl usi ve, at Scree ni n g 
I n di vi d uals eli gi ble t o partici pate i n Part 2: Ne ur oc o g niti ve St u d y a n d S u bst u d y 1 m ust meet 
all  of t he f oll o wi n g criteria: 
•  C o m pleti o n of Wee k 4 visit i n Part 1  
•  Res p o nsi ve t o K u va n d uri n g Part 1, defi ne d as a ≥ 3 0 % a vera ge re d ucti o n i n 
bl o o d P he c o nce ntrati o n calc ulate d as t he mea n of t he wee kl y  perce nt c ha n ge 
fr o m baseli ne i n bl o o d P he c o nce ntrati o n at Wee ks 1, 2, 3, a n d 4 
•  Ba yle y-III or I Q test sc ore ≥ 8 0 w he n teste d wit hi n 6 wee ks of deter mi nati o n of 
K u va n res p o nsi ve ness i n K u va n-res p o nsi ve s u bjects  


 
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9. 3. 2  E xcl usi o n Criteri a 
I n di vi d uals w h o meet a n y of t he f oll o wi n g e xcl usio n criteria will n ot be eli gi ble t o partici pate 
i n t he st u d y: 
•  Has k n o w n h y perse nsiti vit y t o K u va n or its e xci pie nts 
•  Use of K u va n or a n y i n vesti gati o nal pr o d uct or i n vesti gati o nal me dical de vice wit hi n 
3 0 da ys pri or t o scree ni n g, or re q uire me nt f or a n y i n ve sti gati o nal a ge nt pri or t o 
c o m pleti o n of all sc he d ule d st u d y assess me nts 
•  C o nc urre nt disease or c o n diti o n t hat w o ul d i n terfere wit h st u d y partici pati o n or safet y 
(e g, seiz ure dis or der, oral ster oi d- de pe n de nt ast h ma or ot her c o n diti o n re q uiri n g oral 
or pare nteral c ortic oster oi d a d mi nist rati o n, or i ns uli n- de pe n de nt dia betes) 
•  Use of p h os p h o diester ase t y pe 5 i n hi bit o r, ofte n s h orte ne d t o P D E 5 i n hi bit or 
(e g.sil de n afil citr ate, v ar de n afil, t a d al afil, a v a n afil, l o de n afil, mir o de n afil, 
u de n afil)  
•  A n y c o n diti o n t hat, i n t he vie w  of t he PI, places t he su bject at hi g h ris k of p o or 
treat me nt c o m plia nce or of n ot c o m pleti n g t he st u d y 
•  Esta blis he d dia g n osis of pri mar y te tra h y dr o bi o pteri n ( B H 4) deficie nc y  
•  Hist or y of or ga n tra ns pla ntati o n 
•  Percei ve d t o be u nrelia ble or u na vaila ble f or st u d y partici pati o n or t o ha ve pare nts or 
le gal g uar dia ns w h o are percei ve d t o be u nrelia ble or u na vaila ble 
•  Use of met h otre xate or ot her me dicat i o ns t hat i n hi bit f olate meta b olis m 
•  Seri o us ne ur o ps yc hiatric ill ness (e g, maj or de pressi o n) n ot c urre ntl y u n der me dical 
c o ntr ol  
9. 3. 3  Re m o v al of S u bjects fr o m T re at me nt or Assess me nt 
S u bjects ( or t heir le gall y a ut h ori ze d re prese ntati ve) ma y wit h dra w t heir c o nse nt t o partici pate 
i n t he st u d y at a n y ti me wit h o ut prej u dice. T he I n vesti gat or m ust w it h dra w fr o m t he st u d y 
a n y s u bject w h o re q uests t o be  wit h dra w n. A s u bject’s partici pati o n i n t he st u d y ma y be 
disc o nti n ue d at a n y ti me at t he discreti o n of t he I n vesti gat or a n d i n acc or da nce wit h his/ her 
cli nical j u d g me nt. W he n p ossi bl e, t he tests a n d e val uati o ns liste d f or t he ter mi nati o n visit 
s h o ul d be carrie d o ut. 
Bi o Mari n m ust be n otifie d of all s u bject wit h dra wals as s o o n as p o ssi ble. Bi o Mari n als o 
reser ves t he ri g ht t o disc o nti n ue t he st u d y at a n y ti me f or eit her cli nical or a d mi nistrati ve 
reas o ns a n d t o disc o nti n ue partici pati o n b y a n i ndi vi d ual I n vesti gat or or site f or p o or 
e nr oll me nt or n o nc o m plia nce. 


 
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Reas o ns f or w hic h t he I n vesti gat or or Bi o M ari n ma y wit h dra w a s u bject fr o m t he st u d y 
i ncl u de, b ut are n ot li mite d t o, t he f oll o wi n g: 
•  S u bject e x perie nces a seri o us or i nt olera ble A E 
•  S u bject de vel o ps a cli nicall y si g nifica nt la b orat or y a b n or malit y 
•  S u bject re q uires me dicati o n pr o hi bite d b y t he pr ot oc ol 
•  S u bject d oes n ot a d here t o st u d y re q uir e me nts s pecifie d i n t he pr ot oc ol 
•  S u bject was err o ne o usl y a d mitte d i nt o t h e st u d y or d oes n ot meet e ntr y criteria 
•  S u bject is l ost t o f oll o w- u p 
•  S u bject bec o mes pre g na nt (refer t o Secti o n  1 0. 3 f or details o n t he re p orti n g 
pr oce d ures t o f oll o w i n t he e ve nt of pre g na nc y)  
If a s u bject fails t o ret ur n f or sc he d ule d visits, a d oc u me nte d eff ort m ust be ma de t o 
deter mi ne t he reas o n. If t he s u bject ca n n ot be reac he d b y tele p h o ne wit hi n 1 m o nt h, a 
certifie d letter s h o ul d be se nt t o  t he s u bject ( or t he su bject’s le gall y a ut h orize d re prese ntati ve, 
if a p pr o priate) re q uesti n g c o ntact wit h t he I n vesti gat or. T his i nf or mati o n s h o ul d be rec or de d 
i n t he st u d y rec or ds.  
T he I n vesti gat or or desi g nee m ust e x plai n t o eac h s u bject, bef ore e nr oll me nt i nt o t he st u d y, 
t hat f or e val uati o n of st u d y res ults, t he s u bject’s pr otecte d healt h i nf or mati o n o btai ne d d uri n g 
t he st u d y ma y be s hare d wit h t he st u d y s p o ns or, re g ulat or y a ge ncies, a nd I R B/ E C. It is t he 
I n vesti gat or’s ( or desi g nee’s) res p o nsi bilit y t o o btai n writte n per missi o n t o use pr otecte d 
healt h i nf or mati o n per c o u ntr y-s pecific re g ulati o ns, s uc h as Healt h I ns ura nce P orta bilit y a n d 
Acc o u nta bilit y Act ( HI P A A) i n t h e U S, fr o m eac h s u bject, or if a p pr o priate, t he s u bject’s 
le gall y a ut h orize d re prese ntati ve. If per missi o n t o use pr otecte d healt h i nf or mati o n is 
wit h dra w n, it is t he I n vesti gat or ’s res p o nsi bilit y t o o btai n a writte n re q uest, t o e ns ure t hat n o 
f urt her data will be c ollecte d fr o m t he s u bject a n d t he s u bject will be re m o ve d fr o m t he 
st u d y. 
9. 3. 4  S u bject I de ntific ati o n a n d Re pl ace me nt of S u bjects 
Eac h s u bject will be assi g ne d a u ni q ue s u bject i de ntifier. T his u ni q ue i de ntifier will be o n all 
C R F pa ges. I n le gal j uris dicti o ns w here use of i nitials is n ot per mitte d, a s u bstit ute i de ntifier 
will be use d. S u bjects w h o wit h dra w earl y  fr o m t he st u d y will n ot be re place d. 


 
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9. 4  
Tre at me nts 
9. 4. 1  Tre at me nts A d mi nistere d 
Bi o Mari n a n d/ or its desi g nee will pr o vi de t he st u d y site wit h a s u p pl y of K u va n s ufficie nt f or 
t he c o m pleti o n of t he st u d y.  
I n Part 1, be gi n ni n g at Wee k 0, s u bjects will recei ve K u va n at a d ose of 2 0 m g/ k g/ da y orall y, 
pr o vi de d i n ta blets t hat eac h  c o ntai n 1 0 0 m g of sa pr o pteri n, f or a t otal of 4 wee ks. F or e ase 
i n a d mi nistr ati o n a n d f or e ase of i nstr ucti on t o f a milies, t he d ose c a n als o be r o u n de d 
u p or d o w n:  
F or c hil dre n w h o are ol der a n d c a n t a ke t heir me dic ati o n fr o m a c u p or gl ass, r o u n di n g 
of t he d ose t o t he ne arest w h ole t a blet is acce pt a ble. F or e x a m ple, a c hil d wei g hi n g 1 1 
k g w o ul d h a ve a d ose of 2 2 0 m g of K u v a n  t h at m a y be r o u n de d d o w n t o 2 0 0 m g ( 2 
t a blets). A c hil d wei g hi n g 1 4 k g w o ul d h a ve a d ose of 2 8 0 m g t h at m a y be r o u n de d u p t o 
3 0 0 m g ( 3 t a blets). 
W het her t he d ose is deter mi ne d usi n g T a ble 9. 4. 4. 1  or b y r o u n di n g t he d os a ge u p or 
d o w n, be c o nsiste nt wit h t he met h o d. T his is  es peci all y i m p ort a nt t hr o u g h Wee k 4 w he n 
res p o nsi ve ness is bei n g deter mi ne d. 
T he first d ose i n Part 1 will be ta ke n at t he Wee k 0 visit u n der o bser vati o n, after t he 
c o m pleti o n of all ot her st u d y pr oce d ures. T he re mai ni n g d oses i n Part 1 will be ta ke n dail y 
wit h f o o d t o i ncrease a bs or pti o n, prefera bl y  at t he sa me ti me eac h da y. T he K u va n d ose 
ca n n ot be a dj uste d d uri n g Part 1 wit h o ut  c o ns ultati o n wit h t he Me dical M o nit or. 
S u bjects w h o are e nr olle d i nt o Part 2 will i nit iall y c o nti n ue t o ta ke 2 0 m g/ k g/ da y K u va n at 
t he sa me ti me eac h da y wit h a meal. After wee k 5, at t he discreti o n of t he I n vesti gat or a n d 
after c o ns ultati o n wit h t he Me dical M o nit or, a s u bject’s K u va n d ose ma y be l o were d if t he 
s u bject d oes n ot t olerate t he 2 0 m g/ k g/ da y d ose. 
9. 4. 2  I de ntit y of I n vesti g ati o n al Pr o d uct (I P) 
9. 4. 2. 1  Pr o d uct C h ar acteristics a n d L a beli n g 
K u va n (sa pr o pteri n di h y dr oc hl ori de) ta blets are u nsc ore d, u nc oate d, i m me diate-release 
ta blets f or oral use. Eac h ta blet c o ntai ns 1 0 0 m g of sa pr o pteri n di h y dr oc hl ori de (e q ui vale nt t o 
7 6. 8 m g of sa pr o pteri n ba se). Ta blets are r o u n d, r a n gi n g fr o m  off- w hite t o li g ht yell o w, 
li g ht or a n ge/ pi n k, bei ge, or m ottle d (s pec kle d) a p pe ar a nce, a n d de b osse d wit h “ 1 7 7”. 


 
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9. 4. 3  St or a ge 
At t he st u d y site, all st u d y dr u g m ust be st ore d u n der t h e c o n diti o ns s pecifie d i n t he 
I n vesti gat or’s Br oc h ure i n a sec ure area accessi ble o nl y t o t he desi g nate d p har macists a n d 
cli nical site pers o n nel. All I P m ust be st ore d  a n d i n ve nt orie d a n d t he i n ve nt ories m ust be 
caref ull y a n d acc uratel y d oc u me nte d acc or di n g t o a p plica ble state, fe deral a n d l ocal 
re g ulati o ns, I C H G C P, a n d st u d y pr oce d ures. 
9. 4. 4  Directi o ns f or A d mi nistr ati o n 
K u va n (sa pr o pteri n di h y dr oc hl or i de) ta blets s h o ul d be a d mi nistere d orall y wit h f o o d t o 
i ncrease a bs or pti o n, prefera bl y at t he sa me ti me eac h da y wit h a meal. K u va n ta blets c a n be 
diss ol ve d i n 4 t o 8 oz. ( 1 2 0 t o 2 4 0 m L) of wate r or a p ple j uice a n d ta ke n wit hi n 1 5 mi n utes 
of diss ol uti o n. It ma y ta ke a fe w mi n utes f or t he ta blets t o diss ol ve. T o ma ke t he ta blets 
diss ol ve faster, t he y ca n be stirre d or cr us he d. T he ta blets ma y n ot  diss ol ve c o m pletel y. 
S mall pieces ma y be see n fl oati n g o n t o p of t he water or a p ple j uice. T his is n or mal a n d safe 
f or s u bjects t o s wall o w. If after dri n ki n g t he me dici ne, pieces of t he ta blet are still see n, m ore 
water or a p ple j uice ca n be a d de d t o ma ke s ure t hat all of t he me dici ne is ta ke n. 
A d mi nistr ati o n of cr us he d K u v a n t a blets m a y al s o be stirre d i n s oft f o o ds s uc h as a p ple 
s a uce or le m o n p u d di n g. A misse d d ose s h o ul d be ta ke n as s o o n as p ossi ble, b ut 2 d oses 
s h o ul d n ot be ta ke n o n t he sa me da y. If a su bject v o mits t he d ose wit hi n 3 0 mi n utes of 
a d mi nistrati o n, t he d ose s h o ul d be re peate d. If t he d ose is v o mite d after 3 0 mi n utes, t he d ose 
s h o ul d n ot be re peate d. 
St u d y dr u g will be dis pe nse d o nl y b y st u d y sta ff q ualifie d t o perf or m t hat f u ncti o n u n der 
a p plica ble l ocal la ws a n d re g ulati o ns f or t h e st u d y site, acc or di n g t o t he pr ot oc ol a n d 
Sc he d ule of E ve nts ( Ta ble 2. 1 ). I nstr ucti o ns m ust be gi ve n o n h o w ma n y ta blets t o ta ke eac h 
da y, h o w t o pre pare t he d osi n g s ol u ti o n, a n d w he n d osi n g s h o ul d occ ur. 
At t he discreti o n of t he I n vesti g at or, ta blets ma y be diss ol ve d i n  as little as 5 m L water or 
a p ple j uice per t a blet , base d o n t he s u bject’s size a n d ca pa bilit y. F or i nfa nts wei g hi n g 
< 5 k g, a si n gle K u va n ta blet ma y be diss ol ve d i n 5  m L water or a p ple j uice a n d a p orti o n of 
t his s ol uti o n c orres p o n di n g t o a 2 0 m g/ k g d ose may be a d mi nistere d orall y via a n oral d osi n g 
s yri n ge; f or e xa m ple, a n i nfa nt wei g hi n g 3. 5 k g w o ul d be a d mi nistere d 3. 5 m L ( or 7 0 m g) of 
t his K u va n s ol uti o n. A d osi n g ta ble f or s u bjects wei g hi n g 1 0  k g a n d less is s h o w n i n 
Ta ble 9. 4. 4. 1 .     


 
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T a ble 9. 4. 4. 1:  K u v a n D osi n g T a ble f or Y o u n g C hil dre n 
C hil d’s 
Wei g ht 
( k g) 
D ose Gi ve n 
( Milli gr a ms) 
m L of 
S ol uti o n 
N o. of 1 0 0 m g 
T a blets 
Diss ol ve d 
m L A d mi nistere d 
t o S u bject 
1
 2 0
  5
  1
  
1
 
2
 4 0
  5
  1
  
2
 
3
 6 0
  5
  1
  
3
 
4
 8 0
  5
  1
  
4
 
5
 1 0 0
  5
  1
  
5
 
6
 1 2 0
 1 0
  2
  
6
 
7
 1 4 0
 1 0
  2
  
7
 
8
 1 6 0
 1 0
  2
  
8
 
9
 1 8 0
 1 0
  2
  
9
 
1 0
 2 0 0
  1 0
  2
  
1 0
 
 
9. 4. 5  Met h o d of Assi g ni n g S u bjects t o Tre at me nt Gr o u ps 
N ot a p plica ble 
9. 4. 6  Selecti o n of D oses Use d i n t he St u d y 
T he 2 0 m g/ k g/ da y d osa ge of K u va n was selecte d f or t his st u d y i n  or der t o ac hie ve e n ha nce d 
bl o o d P he c o ntr ol. I n st u dies usi n g differe nt f or m ulati o ns of B H 4 i ncl u di n g K u va n, a vera ge 
bl o o d P he re d ucti o n i n res p o n ders at t he 1 0 m g / k g d ose has bee n 5 0 %, w hile t he a vera ge 
re d ucti o n i n res p o n ders at t he 2 0 m g/ k g d ose has bee n 6 4 %. Beca use persiste nt i ncreases as 
l o w as 1 0 0 μ m ol/ L bl o o d P he d uri n g t he critical earl y c hil d h o o d peri o d ca n res ult i n a d verse 
ne ur ol o gical o utc o mes, t here is a nee d f or ti g hter bl o o d P he c o ntr ol i n y o u n g P K U patie nts. 


 
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T he data descri be d bel o w s u p p ort t he safet y of  t he 2 0 m g/ k g/ da y d osa ge of K u va n ( 6 R B H 4): 
•  Si n gle oral 6 R- B H 4 d oses of 7. 5- 2 0 m g/ k g/ da y ha ve bee n a d mi nistere d as l oa di n g 
d oses t o e xcl u de B H 4 deficie nc y i n m ore t ha n 1 9 0 0 P K U patie nts  ( Ber ne g ger, 
2 0 0 2, M ol. Ge net. Meta b) ( S hi nta k u H, 2 0 0 3, J I n herit Meta b Dis) . 
•  I n p u blis he d st u dies of l o n g-ter m B H 4 t hera p y i n patie nts wit h P K U, patie nts 
recei ve d treat me nt f or peri o ds of 5 da ys t o 5 6 m o nt hs. I n t hese st u dies t he B H 4 
d oses ra n ge d fr o m 1. 7 t o 2 0 m g/ k g/ da y. N o  A Es ass ociate d wit h B H 4 t hera p y 
were re p orte d i n t hese st u dies. ( D u dese k, 2 0 0 1, E ur.J Pe diatr.) ( S hi nta k u H, 2 0 0 3, 
J I n herit Meta b Dis) ( M u nta u, 2 0 0 2, N. E n gl.J. Me d.) ( He n ner ma n n, 2 0 0 5, 
M ol. Ge net. Meta b) ( La m br us c hi ni, 2 0 0 5, M ol. Ge net. Meta b) . 
•  T he c u m ulati ve data fr o m t he treat me nt e x perie nce i n m ulti ple re p orts offers 
s u p ple me ntar y e vi de nce of a n a deq uate l o n g-ter m safet y pr ofile. ( Trefz, 2 0 0 1, 
E ur.J. Pe diatr.) ( Bla u, 2 0 0 3, E ur.J. Pe di atr.) ( Stei nfel d, 2 0 0 2, E ur.J. Pe diatr.) 
( Cer o ne, 2 0 0 4, M ol. Ge net. Meta b) ( S paa pe n, 2 0 0 3, M ol. Ge net. Meta b) ( Li n d ner, 
2 0 0 3, H u m. M utat.) ( Lass ker, 2 0 0 2, J.I n herit. Meta b Dis.) ( K oc h, 2 0 0 2, 
M ol. Ge net. Meta b) ( We gla ge, 2 0 0 2, J.I n herit. Meta b Dis.) . 
I n s u m mar y, t he a vaila ble data i n dicate t hat K u va n ma y ser ve as a safe a n d well t olerate d 
t hera p y w he n gi ve n at d oses of 2 0 m g/ k g/ da y t o s u bjects wit h P K U. 
9. 4. 6. 1  Selecti o n of Ti mi n g of D ose f or E ac h S u bject 
Res ults fr o m a p o p ulati o n P K st u d y s h o we d t h at t he mea n half-life i n t he ter mi nal 
eli mi nati o n p hase is a p pr o xi matel y 6. 6 9 h o urs (ra n ge: 3. 9 1 t o 1 6. 6 h o urs). Gi ve n t hat it ta kes 
a p pr o xi matel y 4 half-li ves t o ac hie ve cleara nce, c o vera ge w o ul d be esti mate d t o last 
2 6. 8 h o urs, o n a vera ge, f oll o wi n g d osi n g, w hic h s u p p orts t he use of o nce- dail y d osi n g. 
Res ults fr o m st oc hastic si m ulati o ns base d o n t his m o del s h o w t hat  t here is little acc u m ulati o n 
wit h dail y d oses.  
Ta ki n g t he dail y d ose at t he s a me ti me of d a y wit h a me al  ma y hel p t o facilitate treat me nt 
c o m plia nce. 
9. 4. 7  Bli n di n g 
N ot a p plica ble i n t his o pe n-la bel o ne-ar m st u d y. 
9. 4. 8  Pri or a n d C o nc o mit a nt Me dic ati o ns 
All prescri pti o n a n d o ver-t he-c o u nter me dicati o ns ta ke n b y a s u bject f or 3 0 da ys bef ore 
scree ni n g will be rec or de d o n t he desi g nate d C R F. T he I n vesti gat or ma y prescri be a d diti o nal 
me dicati o ns d uri n g t he st u d y, as l o n g as t he pr escri be d me dicati o n is n ot pr o hi bite d b y t he 
pr ot oc ol. I n t he e ve nt of a n e mer ge nc y, a n y n ee de d me dicati o ns ma y be prescri be d wit h o ut 
pri or a p pr o val, b ut t he me dical m o nit or m ust be  n otifie d of t he use of a n y c o ntrai n dicate d 


 
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me dicati o ns i m me diatel y t herea fter. A n y c o nc o mita nt me dicati o ns a d de d or disc o nti n ue d 
d uri n g t he st u d y s h o ul d be  rec or de d o n t he C R F. 
9. 4. 9  Tre at me nt C o m pli a nce 
S u bjects will be i nstr ucte d t o ret ur n all use d  a n d u n use d st u d y dr u g co ntai ners at eac h st u d y 
visit. S u bject c o m plia nce wit h t he d osi n g re gi me n will be assesse d b y rec o nciliati o n of t he 
use d a n d u n use d st u d y dr u g. T he q ua ntit y dis pe nse d, ret ur ne d, use d, l ost, etc. m ust be 
rec or de d o n t he dis pe nsi n g l o g pr o vi de d f or t he st u d y. 
9. 5  
I n vesti g ati o n al Pr o d uct Acc o u nt a bilit y 
T he PI or desi g nee is res p o nsi ble f or mai n tai ni n g acc urate rec or ds (i ncl u di n g dates a n d 
q ua ntities) of I P(s) recei ve d, s u bjects t o w h o m I P is dis pe nse d (s u bject- b y-s u bject d ose 
s pecific acc o u nti n g), a n d I P l ost or acci de ntall y or deli beratel y  destr o ye d. T he PI or desi g nee 
m ust retai n all u n use d or e x pire d st u d y s u p p lies u ntil t he st u d y m o nit or ( o n-site C R A) has 
c o nfir me d t he acc o u nta bilit y data. 
9. 5. 1  Ret ur n a n d Dis p ositi o n of Cli nic al S u p plies 
U n use d st u d y dr u g m ust be ke pt i n a sec ure  l ocati o n f or acc o u nta bilit y a n d rec o nciliati o n b y 
t he st u d y m o nit or. T he I n vesti gat or or desig nee m ust pr o vi de a n e x pla nati o n f or a n y 
destr o ye d or missi n g st u d y dr u g or st u d y materials. 
U n use d st u d y dr u g ma y be destr o ye d o n site, per t he site’s sta n dar d o perati n g pr oce d ures, b ut 
o nl y after Bi o Mari n has gra nte d a p pr o val f or dr u g destr ucti o n. T he m o nit or m ust acc o u nt f or 
all st u d y dr u g i n a f or mal rec o nciliati o n pr o cess pri or t o st u d y dr u g destr ucti o n. All st u d y 
dr u g destr o ye d o n site m ust be d oc u me nte d. D oc u me ntati o n m ust be pr o vi de d t o Bi o Mari n 
a n d retai ne d i n t he PI’s st u d y files. If a site is u na ble t o destr o y st u d y dr u g a p pr o priatel y, t he 
site ca n ret ur n u n use d st u d y dru g t o Bi o Mari n u p o n re q uest. T he ret ur n of st u d y dr u g or 
st u d y dr u g materials m ust be acc o u nte d f or o n a St u d y Dr u g Ret ur n F or m pr o vi de d b y 
Bi o Mari n. 
All st u d y dr u g a n d relate d materials s h o ul d be st ore d, i n ve nt orie d, rec o ncile d, a n d destr o ye d 
or ret ur ne d acc or di n g t o a p p lica ble state a n d fe deral re g ulati o ns a n d st u d y pr oce d ures. 
9. 6  
Diet ar y or Ot her Pr ot oc ol Restricti o ns 
S u bjects m ust be willi n g t o a d here t o a prescri b e d P he-restricte d diet i n or der t o mai ntai n 
bl o o d P he c o nce ntrati o ns wit hi n t he rec o m me n de d ra n ges esta blis he d at t he s u bject’s st u d y 
site. T he g oal f or bl o o d P he co nce ntrati o n d uri n g t he st u d y is ≤ 2 4 0 μ m ol/ L. F oll o wi n g 
sta n dar d of care, all s u bjects a n d t heir parent(s) or g uar dia n(s) will meet wit h a st u d y 
dietici a n  at eac h visit t o re vie w dietar y P he i nta ke. A 3- da y dietar y rec or d will be ke pt pri or 


 
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t o cli nic visits a n d re vie we d at t he cli nic. T he dietar y rec or d will be mai ntai ne d wit h t he 
st u d y s o urce d oc u me nts. Dietar y P he i nta ke will be assesse d al o n g wit h t otal cal oric i nta ke 
( kcals) a n d pr otei n i nta ke b y t he dietitia n t o e ns ure t hat t he s u bject is meeti n g dail y 
prescri be d a m o u nts. A dj ust me nts t o diet a n d/ or me dical f o o d will be ma de per cli nic 
g ui deli nes t o mai ntai n s ufficie nt i nta ke  t o pr o m ote gr o wt h a n d de vel o p me nt. 
If bl o o d P he le vels fall bel o w 1 2 0 μ m ol/ L, dietar y P he ma y be a d de d t o t he diet. I n or der t o 
deter mi ne t he a p pr o priate a m o u nt of dail y P he t o be gi ve n, pre defi ne d i ncreases i n P he 
s u p ple me nt (i nfa nt f or m ula, n o n-fat dr y mil k, li q ui d mil k, drie d e g g w hite p o w der) will be 
prescri be d a n d bl o o d P he le vels will be m o n it ore d cl osel y. I ncreases i n P he s u p ple me nt will 
be base d o n bl o o d P he le vel, a ge, a n d  i deal b o d y wei g ht f or a su bject’s ge n der, wei g ht, a n d 
hei g ht. 
If a s u bject’s bl o o d P he f alls bel o w 1 2 0 μ m ol/ L, at t he discreti o n of t he i n vesti g at or, 
a gr a d u al i ncre ase of a p pr o xi m atel y 5- 2 0 m g/ k g of P he s u p ple me nt m a y be 
a d de d t o t he diet. It is i m p ort a nt t o a v oi d u nst a ble s wi n gs i n t he bl o o d P he v al ues 
If a s u bject’s bl o o d P he le vel g oes a b o ve 2 4 0 μ m ol/ L, diet ar y P he m a y be decre ase d 
b y a p pr o xi m atel y 5 t o 2 0 m g/ k g or defi ne d b y t he st a n d ar d use d at e ac h 
tre at me nt ce nter, at t he discreti o n of t he i n vesti g at or. 
O nce a s u bject reac hes a de q uate P he s u p ple me n tati o n, defi ne d as 4 sta ble bl o o d P he val ues 
(st u d y visits or n o n-st u d y visits) wit h o ut a n y diet m o dificati o ns, t he n nat ural pr otei n f o o ds 
rat her t ha n P he-c o ntai ni n g s u p ple me nts ma y be prescri be d. T he a m o u nt of milli gra ms of P he 
i n nat ural f o o ds per da y t o be gi ve n t o t he su bject will be e q ui vale nt t o t he i ncrease i n 
milli gra ms of P he s u p ple me nt t olerate d b y t he s u bject.  
C o n versi o n of P he fr o m t he s u p pl e me nt t o nat ural f o o ds s h o ul d n ot be d o ne d uri n g t he first 
6 m o nt hs of t he st u d y. 
9. 7  
Effic ac y a n d S afet y V ari a bles 
9. 7. 1  Effic ac y a n d S afet y Me as ure me nts Assesse d 
T he Sc he d ule of E ve nts i n t he S y n o psis (Ta ble 2. 1 ) descri bes t he ti mi n g of re q uire d 
e val uati o ns. 
F or t he la b orat or y assess me nts, t he part y res p o nsi ble f or perf or mi n g t he assess me nt a n d t he 
perti ne nt pr ot oc ol secti o n descri bi n g t he details of t he test are liste d i n  Ta ble 9. 7. 1. 1. 


 
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T a ble 9. 7. 1. 1:  S u m m ar y of L a b or at or y Assess me nts  
L a b or at or y Assess me nt 
P art y Res p o nsi ble f or 
Perf or mi n g Test 
Secti o n i n Pr ot oc ol f or 
Det ails 
Cli nical la b orat or y tests 
Ce ntral la b orat or y 
9. 7. 4. 1 
P har mac o ki netic varia bles 
Ce ntral la b orat or y 
9. 7. 6, 1 2. 3 
Bl o o d P he c o nce ntrati o ns 
L ocal la b orat or y 
9. 7. 1. 4 
 
9. 7. 1. 1  De m o gr a p hic D at a a n d Me dic al Hist or y 
De m o gra p hic data a n d a detaile d me dical hist or y will be o btai ne d at Scree ni n g. T he me dical 
hist or y will i ncl u de s pecific i nf or mati o n c o n cer ni n g a n y pri or or e xisti n g me dical c o n diti o ns 
t hat mi g ht i nterfere wit h st u d y partici pati o n or safet y. T his medical hist or y s h o ul d elicit all 
maj or ill nesses, dia g n oses, a n d s ur geries t hat t he s u bject has ha d. 
9. 7. 1. 2  P h ysic al E x a mi n ati o n Fi n di n gs 
C o m plete p h ysical e xa mi nati o ns will i ncl u d e t he e val uati o n of all maj or b o d y s yste ms, 
hei g ht, wei g ht, a n d hea d circ u mfere nce.  Ot her b o d y s yste ms ma y be e xa mi ne d. Wee k 1  of 
Part 1 res ults will be t he baseli ne val ues, a n d cl i nicall y si g nifica nt c ha n ges fr o m baseli ne will 
be rec or de d as a n A E. 
9. 7. 1. 3  Vit al Si g n Me as ure me nts 
Vital si g ns will be meas ure d af ter resti n g f or 5 mi n utes, a n d i ncl u de seate d s yst olic bl o o d 
press ure ( S B P) a n d diast olic bl o o d press ure ( D B P) meas ure d i n m m H g, heart rate i n beats 
per mi n ute, res pirati o n rate i n breat hs per mi n ute, a n d te m perat ure. All s u bjects will be 
m o nit ore d at t he cli nic f or 3 h o urs after t he first d ose of K u va n, wit h vital si g ns ta ke n 
pre- d ose, a n d 1 5, 3 0, 4 5, 6 0, 9 0, 1 2 0, a n d 1 8 0 mi n utes p ost- d ose.  
9. 7. 1. 4  Bl o o d P he C o nce ntr ati o n 
Sa m ples f or bl o o d P he c o nce ntrati o n s h o ul d be dra w n si m ulta ne o usl y wit h sa m ples dra w n 
f or P K o n da ys w he n b ot h t y pes of bl o o d dra w are re q uire d. Wit h t he e xce pti o n of t he P K 
s a m ples ( Part 1), bl o o d f or P he c o nce ntrati o n meas ure me nts will be dra w n at ti me p oi nts 
i n dicate d i n t he Sc he d ule of E ve nts (Ta ble 2. 1 ). L ocal la b orat ories s h o ul d use t he sa me 
met h o d ol o g y t hr o u g h o ut t he st u d y, if p ossi ble, f or perf or mi n g bl o o d P he testi n g.  


 
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9. 7. 1. 5  Pre g n a nc y Testi n g 
Fe male s u bjects w h o are, i n t he esti mati o n of t he I n vesti gat or, of c hil d beari n g p ote ntial will 
ha ve a uri ne pre g na nc y test at t he ti me p oi nts s pecifie d i n t he Sc he d ule of E ve nts ( Ta ble 2. 1 ).  
A d diti o nal uri ne pre g na nc y tests wi ll be perf or me d at a n y visit i n w hic h pre g na nc y stat us is 
i n q uesti o n. Ser u m pre g na nc y tests will be perf or me d i n t he e ve nt of a p ositi ve or e q ui v ocal 
uri ne pre g na nc y test res ult. 
Refer t o Secti o n 1 0. 3  f or details o n t he re p orti n g pr oce d ures t o f oll o w i n t he e ve nt of 
pre g na nc y. 
9. 7. 2  Pri m ar y Effic ac y V ari a ble 
Ne ur oc o g niti ve testi n g will be perf or me d w it hi n 6 wee ks of deter mi nati o n of K u va n 
res p o nsi ve ness i n all K u va n-res p o nsi ve s u bjects. S u bse q ue nt ne ur oc o g niti ve meas ure me nts 
will be o btai ne d e ver y 6 m o nt hs u ntil t he s u bject is ≥ 3 0 m o nt hs ol d, e ver y 1 2 m o nt hs u ntil 
t he s u bject reac hes a ge 7, t he n e ver y 2 years t hr o u g h t he e n d of t he st u d y. T he t y pes of 
ne ur oc o g niti ve tests use d f or t he pri mar y effi cac y varia ble (ie, WP P SI-III a n d/ or WI S C-I V), 
will be t h ose c o nsi dere d a p pr o priate f or t he s u bject’s a ge.  
9. 7. 3  Sec o n d ar y Effic ac y V ari a bles 
T he first  sec o n dar y efficac y e n d p oi nt is c ha n ge i n de vel o p me ntal gr o wt h fact ors, as 
meas ure d b y hei g ht, a n d hea d circ u mfere nce fr o m baseli ne. T hese meas ure me nts will be 
ma de at Scree ni n g, Wee k 0, Wee k 4, M o nt h 3, M o nt h 6, a n d e ver y 6 m o nt hs t hereafter, 
w hile t he wei g ht will be me as ure d at e ver y visit.  T he sec o n d sec o n dar y efficac y varia ble is 
t he baseli ne a n d 6- m o nt h f oll o w u p ne ur oc o g niti ve testi n g res ults usi n g Ba yle y-III i n 
c hil dre n a ge 0 t o less t h a n 3 0 m o nt hs ol d.  
9. 7. 4  S afet y V ari a bles 
9. 7. 4. 1  Cli nic al L a b or at or y Assess me nts 
A n y a b n or mal test res ults deter mi ne d t o be cl i nicall y si g nifica nt b y t he I n vesti gat or s h o ul d 
be re peate d (at t he I n vesti gat or ’s discreti o n) u ntil t he ca use of t he a b n or malit y is deter mi ne d, 
t he val ue ret ur ns t o baseli ne or t o wit hi n n or mal li mits, or t he I n vesti gat or deter mi nes t hat t he 
a b n or mal val ue is n o l o n ger cli nicall y si g nifica nt. 
All cli nical la b orat or y res ult pa ges s h o ul d be i nitiale d a n d date d b y a n I n vesti gat or, al o n g 
wit h a c o m me nt re gar di n g w het her or n ot  a n y res ult is cli nicall y si g nifica nt. 
T he dia g n osis, if k n o w n, ass ociate d wit h a b n or ma lities i n cli nical la b orat or y tests t hat are 
c o nsi dere d cli nicall y si g nif ica nt b y t he I n vesti gat or will be rec or de d o n t he A E C R F. 


 
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S pecific da ys f or o btai ni n g sa m ples are pr o vi de d i n Ta ble 2. 1 , Sc he d ule of E ve nts. 
T he cli nical la b orat or y tests t h at will be perf or me d i n t his  st u d y are s h o w n i n Ta ble 9. 7. 4. 1. 1. 
T a ble 9. 7. 4. 1. 1:  Cli nic al L a b or at or y Tests 
Bl o o d C he mistr y  
He m at ol o g y  
Uri ne Tests  
Ot her  
Al b u mi n   
He m o gl o bi n  
Uri nal ysis 
He mat ocrit  
A p peara nce 
Bl o o d p he n ylala ni ne 
Al kali ne 
P h os p hatase  
W B C c o u nt 
C ol or 
Bl o o d t yr osi ne 
A L T ( S G P T)   
R B C c o u nt 
p H 
Bl o o d tr y pt o p ha n 
A S T ( S G O T)  
Platelet c o u nt 
S pecific gra vit y  
 
T otal bilir u bi n  
Differe ntial cell c o u nt  
Ket o nes  
P har mac o ki netics 
(t otal bi o pteri n, 
a nal yze d b y ce ntral 
la b orat or y 
Direct bilir u bi n  
Se di me ntati o n rate  
Pr otei n  
 
B U N
 
  
Gl uc ose
 
 
Creati ni ne
 
 
Bilir u bi n
 
 
G G T
 
  
Nitrite
 
 
T otal pr otei n  
 
Ur o bili n o ge n  
 
Calci u m
 
 
He m o gl o bi n
 
 
S o di u m
 
 
 
 
 
P otassi u m
 
 
 
 
Gl uc ose
 
 
 
 
 
Uric aci d  
 
 
 
C hl ori de 
 
 
 
C O 2 
 
 
 
 
 
 
A L T, ala ni ne a mi n otra nsferase; A S T, as partate a mi n otra nsferase; B U N, bl o o d urea nitr o ge n; G G T, 
ga m ma- gl uta m yltra nsferase;  R B C, re d bl o o d cell; S G O T, ser u m gluta mic- o xal oacetic tra nsa mi nase; 
S G P T, ser u m gl uta mic- p yr u vic tra nsa mi nase; W B C, w hite bl o o d cell. Uri n al ysis m a y be perf or me d i n t he 
cli nic al l a b or vi a “ di pstic k ” i n c hil d re n t o o y o u n g t o pr o vi de a uri ne s a m ple. 
 


 
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9. 7. 4. 2  Electr oc ar di o gr a ms 
Electr ocar di o gra ms will be perf or me d 2- 6 h o urs af ter t he first d ose of K u va n i n t he first 
8 0 s u bjects e nr olle d u nless data fr o m ot her st u d ies s h o w clearl y t hat K u va n d oes n ot ha ve a n 
effect o n t he Q T i nter val. 
9. 7. 5  S u bst u d y 1: 6- m o nt h S afet y a n d Effic ac y St u d y 
Pri m ar y Effic ac y V ari a bles 
T he pri mar y efficac y varia ble is bl o o d P he le ve l. T he g oal is t o l o wer bl o o d P he le vels a n d 
mai ntai n t he m at ≤ 2 4 0 μ m ol/ L. I n a d diti o n, baseli ne ne ur oc o g niti ve testi n g res ults will be 
re p orte d f or all s u bjects, a n d 6- m o nt h f oll o w- u p testi n g will be d o ne usi n g t he Ba yle y-III test 
f or s u bjects a ge 0- 2 4 m o nt hs at e nr oll me nt. 
S afet y V ari a bles 
T he safet y varia bles are t he sa me as t h os e descri be d f or t he e ntire st u d y i n Secti o n  9. 7. 4. 
9. 7. 6  P o p ul ati o n P h ar m ac o ki netic V ari a bles 
T he f oll o wi n g P K para meters will be assesse d: a p pare nt cleara nce ( C L/ F), a p pare nt v ol u me 
of distri b uti o n of t he peri p hera l c o m part me nt ( V p/ F), a p pare nt v ol u me of distri b uti o n of t he 
ce ntral c o m part me nt ( Vc/ F), a n d a p pare nt i nte r-c o m part me ntal cleara nce ( Q/ F), a bs or pti o n 
rate c o nsta nt ( Ka), a bs or pti o n la g-ti me ( A LA G), a n d dr u g half-life. Refer t o Secti o n 1 2. 3  f or 
a d diti o nal details. 


 
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1 0  
R E P O R TI N G A D V E R S E E V E N T S 
1 0. 1  
A d verse E ve nts 
Acc or di n g t o t he I C H defi niti o n, a n a d verse e v e nt ( or a d verse e x perie nce) is “a n y u nt o war d 
me dical occ urre nce i n a patie nt or cli ni cal i n vesti gati o n s u bject a d mi nistere d a 
p har mace utical pr o d uct, a n d t hat d oes n ot necessa ril y ha ve a ca usal relati o ns hi p wit h t his 
treat me nt. A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n ded si g n (i ncl u di n g a n 
a b n or mal la b orat or y fi n di n g), s y m pt o m, or diseas e te m p orall y ass ociate d wit h t he use of a 
me dici nal (i n vesti gati o nal) pr o d uct, w het her or n ot c o nsi dere d relate d t o t he I P.” 
A n a d verse dr u g reacti o n ( A D R) is descri be d b y t he I C H as “all n o x i o us a n d u ni nte n de d 
res p o nses t o a me dici nal pr o d uct relate d t o a n y d ose.” T his mea ns t hat a ca usal relati o ns hi p 
bet wee n a me dici nal pr o d uct a n d a n A E is at least a reas o na ble p ossi bilit y, ie, t he 
relati o ns hi p ca n n ot be r ule d o ut. 
A n A E ma y i ncl u de i nterc urre nt ill nesses or i n j uries t hat re prese nt a n e xacer bati o n (i ncrease 
i n fre q ue nc y, se verit y, or s pecificit y) of pre-e xisti n g c o n diti o ns (e g, w orse ni n g of ast h ma). 
W he ne ver p ossi ble, it is prefera ble  t o rec or d a dia g n osis as t he A E ter m rat her t ha n a series 
of ter ms relati n g t o a dia g n osis.  
T he re p orti n g peri o d f or n o n-seri o us A Es is t he peri o d fr o m t he first a d mi nistrati o n of st u d y 
dr u g t hr o u g h 4 wee ks after t he fi nal d ose (ie, F/ U or E T V). If a n o n-seri o us A E re mai ns 
u nres ol ve d at t he c o ncl usi o n of t he st u d y, t he PI a n d me dical m o nit o r will ma ke a j oi nt 
cli nical assess me nt as t o w het her c o nti n ue d f oll o w- u p of t he A E is warra nte d, a n d t he res ults 
of t his assess me nt m ust be d oc u me nte d. Res ol uti o n is defi ne d as t he ret ur n t o baseli ne stat us 
or sta bilizati o n of t he c o n d iti o n wit h t he e x pectati o n t hat it will re mai n c hr o nic. 
T he I n vesti gat or will assess A Es f or se verit y, f o r relati o ns hi p t o I P, an d as t o w het her t he 
e ve nt meets o ne or m ore of t he defi niti o ns of a n S A E (see Secti o n  1 0. 2). 
T he I n vesti gat or will deter mi ne t he se verit y of eac h A E a n d will rec or d it o n t he s o urce 
d oc u me nts a n d A E C R F, usi n g t h e cate g ories defi ne d bel o w.  
 
Gr a de 
Descri pti o n 
Mil d 
N o li mitati o n of us ual acti vities 
M o derate  
S o me li mitati o n of us ual acti vities 
Se vere  
I na bilit y t o carr y o ut us ual acti vities 
 


 
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T he ter m “se vere” is ofte n use d t o descri be t he i nte nsit y (se verit y) of a s pecific e ve nt (as i n 
mil d, m o derate or se vere m y ocar dial i nfarc ti o n); t he e ve nt itself, h o we ver, ma y be of 
relati vel y mi n or me dical si g nifica nce (s uc h as severe hea dac he). T his is n ot t he sa me as 
“seri o us”, w hic h is base d o n s u bject/e ve nt o utc o me  or acti o n criteria us uall y ass ociate d wit h 
e ve nts t hat p ose a t hreat t o a s u bject’s life or  f u ncti o ni n g. Seri o us ness ( n ot se verit y) ser ves as 
a g ui de f or defi ni n g re g ulat o r y re p orti n g o bli gati o ns.  
T he I n vesti gat or will deter mi ne t he relati o ns hi p of a n A E t o t he I P a n d will rec or d it o n t he 
s o urce d oc u me nts a n d A E C R F, usi n g t he cate g ories defi ne d bel o w. 
 
Rel ati o ns hi p 
Descri pti o n 
N ot Relate d  
E x p os ure t o t he I P has n ot occ urre d 
O R 
T he a d mi nistrati o n of t he I P a n d t he occ urre nce of t he A E are n ot 
reas o na bl y relate d i n ti me  
O R 
T he A E is c o nsi dere d li kel y t o be  relate d t o a n eti ol o g y ot her t ha n 
t he use of t he I P; t hat is, t here are n o facts [e vi de nce] or ar g u me nts 
t o s u g gest a ca usal relati o ns hi p t o t he I P. 
P ossi bl y Relate d  
T he a d mi nistrati o n of t h e I P a n d t he occ urre nce of t he A E are 
reas o na bl y relate d i n ti me 
A N D 
T he A E c o ul d be e x plai ne d e q uall y well b y fact ors or ca uses ot her 
t ha n e x p os ure t o t he I P. 
Pr o ba bl y Relate d  
T he a d mi nistrati o n of I P a n d t he occ urre nce of t he A E are 
reas o na bl y relate d i n ti me  
A N D 
T he A E is m ore li kel y e x plai ne d b y e x p os ure t o t he I P t ha n b y ot her 
fact ors or ca uses. 
 
I n or der t o classif y A Es a n d diseases, preferred ter ms will be assi g ne d b y t he s p o ns or t o t he 
ori gi nal ter ms e ntere d o n t he C R F, usi n g Me d D R A ( Me dical Dicti o nar y f or Re g ulat or y 
Acti vities ter mi n ol o g y). 


 
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1 0. 2  
Seri o us A d verse E ve nts 
A seri o us a d verse e ve nt ( S A E) is defi ne d as a n y A E t hat: 
•  Res ults i n deat h 
•  Is life t hreate ni n g, t hat is, places t he s u bject at i m me diate ris k of deat h fr o m t he 
e ve nt as it occ urre d. T his defi niti o n d oe s n ot i ncl u de a reacti o n t hat, ha d it 
occ urre d i n a m ore se vere f or m, mi g ht ha ve ca use d deat h 
•  Re q uires i n- patie nt h os pitalizati o n or pr ol o n gati o n of a n e xisti n g i n- patie nt 
h os pitalizati o n. A d missi o n of a s u bject t o t he h os pital as a n  i n- patie nt as a res ult 
of a n A E, e ve n if t he s u bject is release d o n t he sa me da y, q ualifies as 
h os pitalizati o n 
•  Res ults i n persiste nt or si g nifica nt disa bilit y or i nca pacit y. A n e ve nt q ualifies as 
res ulti n g i n a persiste nt or si g nifica nt disa bilit y or i nca pacit y if it i n v ol ves a 
s u bsta ntial disr u pti o n of t he s u bject’s a bilit y t o carr y  o ut us ual life f u ncti o ns. 
T his defi niti o n is n ot i nte n de d t o i ncl u de  e x perie nces of relati vel y mi n or or 
te m p orar y me dical si g nifica nce. 
•  Is a c o n ge nital a n o mal y or birt h defect, t hat is, a n A E t hat occ urs i n t he c hil d or 
fet us of a s u bject e x p ose d t o I P pri or t o c o nce pti o n or d uri n g pre g na nc y 
•  Is a n i m p orta nt me dical e ve nt t hat d oes n ot meet a n y of t he a b o ve criteria, b ut 
ma y je o par dize t he s u bject or re q uire me di cal 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 are i nte nsi ve treat me nt 
i n t he e mer ge nc y r o o m, aller gic br o nch os pas m, bl o o d d yscrasias or c o n v ulsi o ns 
t hat d o n ot res ult i n h os pitalizati o n; or de vel o p me nt of dr u g de pe n de nc y or dr u g 
a b use. 
M ore t ha n o ne of t he a b o ve criteria ma y a p pl y t o a n y s pecific e ve nt. 
T he re p orti n g peri o d f or S A Es be gi ns earlier t h a n n o n-seri o us A Es a n d is t he peri o d fr o m t he 
ti me of si g ni n g of t he I C F t hr o u g h t he 4 wee ks after t he fi nal d ose (ie, F/ U or E T V). S A Es 
re p orte d t o t he I n vesti gat or o utside of t his re p orti n g peri o d will be  re p orte d t o Bi o Mari n if, i n 
g o o d me dical j u d g me nt, t he e ve nt has a n y beari n g o n t he st u d y data. S A Es m ust be f oll o we d 
b y t he I n vesti gat or u ntil res ol u ti o n, e ve n if t his e xte n ds be y o n d t he st u d y-re p orti n g peri o d. 
Res ol uti o n of a n S A E is defi ne d as t he ret ur n t o baseli ne st at us or sta bilizati o n of t he 
c o n diti o n wit h t he e x pectati o n t hat it will re mai n c hr o nic. 
A n y S A E, w het her or n ot c o ns i dere d relate d t o st u d y dr u g, will be re p orte d i m me diatel y 
( wit hi n 2 4 h o urs) t o Bi o Mari n P har mac o vigila nce b y fa x usi n g t he st u d y-s pecific S A E 
Re p ort F or m. I n a d diti o n t o t he o utc o me of t h e S A E, a n y me dicati o n or ot her t hera pe utic 
meas ures use d t o treat t he e ve nt will be rec or de d o n t he a p pr o priate C R F pa ge(s). 
I n vesti gat ors s h o ul d n ot wait t o c ollect a d diti o nal i nf or mati o n t hat f ull y d oc u me nts t he e ve nt 


 
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bef ore n otif yi n g Bi o Mari n P har mac o vi gila nce of a n S A E. Bi o Mari n ma y be re q uire d t o 
re p ort certai n S A Es t o re g ulat or y a ut h orities wit hi n 7 cale n dar da ys of bei n g n otifie d a b o ut  
t he e ve nt; t heref ore, it is i m p orta nt t hat I n vesti gat ors s u b mit a d diti o nal i nf or mati o n re q ueste d 
b y Bi o Mari n as s o o n as it bec o mes a vaila ble. 
Re p orti n g of S A Es t o t he I R B/ E C will be d o ne  i n c o m plia nce wit h t he sta n dar d o perati n g 
pr oce d ures a n d p olicies of t he I R B/ E C a n d wit h a p plica ble re g ulat or y re q uire me nts. 
A de q uate d oc u me ntati o n m ust be o btai ne d b y Bi o Mari n s h o wi n g t hat t he I R B/ E C was 
pr o perl y a n d pr o m ptl y n otifie d as re q uire d. 
1 0. 3  
Pre g n a nc y  
Pre g na nc y i n a s u bject or part ner s h o ul d be  re p orte d i m me diatel y ( wit hi n 2 4 h o urs) t o 
Bi o Mari n P har mac o vi gila nce b y fa x usi n g t h e Pre g na nc y F or m i n t he st u d y refere nce 
materials. I n a d diti o n, pre g na nc y i n a s u bj ect is als o re p orte d o n t he E n d of St u d y C R F. 
T he I n vesti gat or m ust ma ke e ver y eff ort t o  f oll o w t he s u bject t hr o u g h res ol uti o n of t he 
pre g na nc y ( deli ver y or ter mi na ti o n) a n d t o re p ort t he res ol uti o n o n t he Pre g na nc y F oll o w- u p 
F or m i n t he st u d y refere nce materials. I n t he e ve nt of pre g na nc y i n t he part ner of a st u d y 
s u bject, t he I n vesti gat or s h o ul d ma ke e very reas o na ble atte m pt t o o btai n t he w o ma n’s 
c o nse nt f or release of pr ot ecte d healt h i nf or mati o n.  
1 0. 4  
Bi o M ari n P h ar m ac o vi gil a nce C o nt act I nf or m ati o n 
C o ntact i nf or mati o n f or Bi o Mari n P har mac o vi gila nce is as f oll o ws: 
Bi o Mari n P har mace utical I nc. 
1 0 5 Di gital Dri ve 
N o vat o, C A  9 4 9 4 9 
P h o ne: ( 4 1 5) 5 0 6- 6 1 7 9 
Fa x:
 ( 4 1 5)
 5 3 2- 3 1 4 4  
E mail: dr u gsafet y @ b mr n.c o m 


 
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T he I n vesti gat or is e nc o ura ge d t o disc uss w it h t he me dical m o nit or a n y A Es f or w hic h t he 
iss ue of seri o us ness is u nclear or q uesti o ne d. Co ntact i nf or mati o n f or t he me dical m o nit or is 
as f oll o ws: 
Na me:  
, M D  
C o m pa n y:  
Bi o Mari n P har mace utical I nc. 
A d dress:  
1 0 5 Di gital Dri ve, N o vat o, C A 9 4 9 4 9, U S A 
P h o ne:  
 
Fa x:
 
 
 
E mail:  
 


 
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1 1  
A P P R O P RI A T E N E S S O F M E A S U R E M E N T S 
T he efficac y, safet y, a n d P K assess me nts i n t h is st u d y are use d wi del y a n d are ge nerall y 
rec o g nize d as relia ble, acc urate, a n d rele va nt. 
1 1. 1  
Ne ur oc o g niti ve Assess me nts 
T hree a ge-a p pr o priate scales wi ll be use d t o assess t he ne uroc o g niti ve f u ncti o n of s u bjects 
e nr olle d i n Part 2 of t his st u d y. 
T he Ba yle y-III is a t o ol f or assessi n g all facets of de vel o p me nt i n i nfa nts wit hi n a n a ge ra n ge 
of 1 2 m o nt hs u p t o 3 0 m o nt hs, wit h n or mati ve da ta a vaila ble f or i nfa nts as y o u n g as 1 6 da ys 
( Ba yle y, 2 0 0 6, Ps yc h ol o gical C or p.). ( Ba yle y N, 2 0 0 6, J of Ps yc h oe d ucati o nal Assess me nt). 
T he test i ncl u des t he f oll o wi n g de vel o p me n t scales: A da pti ve Be ha vi or, C o g niti ve, 
La n g ua ge, M ot or, a n d S ocial- E m oti o nal. T hree of t he scales, C o g niti ve, M ot or, La n g ua ge, 
are a d mi nistere d wit h c hil d i nteracti o n. T he 2 re mai ni n g scales, A da pti ve Be ha vi or a n d 
S ocial-e m oti o n, are c o n d ucte d wit h pare nt q uesti o n naires . 
T he W P P SI-III is a t o ol f or assessi n g t he i ntelli ge nce of c hil dre n ≥ 3 0 m o nt hs t hr o u g h 
< 7 years 3 m o nt hs ol d. T he W P P SI-III is a d mi ni stere d o n t w o f or ms as a ge a p pr o priate. It 
pr o vi des c o m p osite sc ores t hat re prese nt i nte llect ual f u ncti o ni n g i n s pecifie d c o g niti ve 
d o mai ns ( Ver bal I Q a n d Perf or ma nce I Q) as well  as t he c hil d’s ge neral i ntellect ual a bilit y 
( F ull-scale I Q) ( Wec hsler D, 2 0 0 2, Ps yc h ol o gical C or p). ( Sattler, 2 0 0 4, Jer o me S. Sattler, 
I nc.). 
T he WI S C-I V assesses t he i nte lli ge nce of c hil dre n 7 years 0 m o nt hs t hr o u g h 1 6 years 
1 1 m o nt hs ol d. T his test als o pr o vi des c o m p osite sc ores t hat re prese nt i ntellect ual 
f u ncti o ni n g i n s pecifie d c o g nitive areas ( Ver bal C o m pre he nsi o n I n de x, Perce pt ual Reas o ni n g 
I n de x, W or ki n g Me m or y I n de x, a n d Pr ocessi n g S pee d I n de x) i n a d diti o n t o a c o m p osite 
sc ore reflecti n g t he c hil d’s ge neral i ntellect ual a bilit y ( F ull Scale I Q) ( Wec hsler D, 2 0 0 4, 
Ps yc h ol o gical C or p)  


 
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1 2  
S T U D Y P R O C E D U R E S 
1 2. 1  
Ne ur oc o g niti ve St u d y 
1 2. 1. 1  Prest u d y 
A n I C F m ust be si g ne d a n d date d b y t he s u bject ( or t he s u bject’s le gall y a ut h orize d 
re prese ntati ve if t he s u bject is less t ha n 1 8 years of a ge), t he PI or desi g nee a n d wit ness 
(if re q uire d) bef ore a n y st u d y-relate d pr oce d ures are perf or me d. 
1 2. 1. 2  Scree ni n g Visit(s) 
After pare nt(s) or g uar dia n(s) ha ve si g ne d a n I C F, t he y will be scree ne d f or e nr oll me nt 
i nt o t he st u d y. T he f oll o wi n g st u d y acti vities will be perf or me d at Scree ni n g (refer t o  
Ta ble 2. 1 , Sc he d ule of E ve nts): 
•  Me dical hist or y, i ncl u di n g de m o gra p hics 
•  P h ysical e xa mi nati o n 
•  Wei g ht  
•  Hei g ht a n d hea d circ u mfere nce 
•  Vital si g ns 
•  Cli nical la b orat or y tests 
•  Bl o o d P he c o nce ntrati o n 
•  Bl o o d tr y pt o p ha n a n d t yr osi ne 
•  C o nc o mita nt me dicati o ns 
•  Dietar y re vie w wit h dieticia n  
•  Pre g na nc y test if, i n t he esti mati o n of t he i n vesti gat or, t he s u bject has reac he d 
c hil d- beari n g p ote ntial.   ( A ser u m pre g na nc y test will be perf or me d i n t he e ve nt 
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1 2. 1. 3  P art 1: E v al u ati o n of K u v a n Res p o n si ve ness, 4- Wee k Tre at me nt Visit(s) 
1 2. 1. 3. 1  Wee k 0 Visit 
Wit hi n 2 8 da ys of c o m pleti n g scree ni n g assess me nts, t he f oll o wi n g st u d y acti vities will be 
perf or me d o n Wee k 0 of Part 1. Assess me n ts will be d o ne pre d ose u nless ot her wise 
s pecifie d: 
•  Wei g ht 
•  Vital si g ns ( m o nit ore d at pre- d ose a n d f or 3 h o urs after t he first d ose of K u va n i n 
all s u bjects) 
•  A d mi nister st u d y dr u g 
•  C o nc o mita nt me dicati o ns 
•  Dietar y re vie w wit h dieticia n  
•  Assess me nt of S A Es ( pre d ose a n d p ost d ose) a n d all A Es ( p ost d ose) 
•  P K sa m ple (refer t o Secti o n  1 2. 3) 
•  E C G 2- 6 h o urs after t he firs t d ose of K u va n i n t he first 8 0 s u bjects e nr olle d, if 
re q uire d 
•  Bl o o d P he c o nce ntrati o n 
•  Pre g na nc y test if, i n t he esti mati o n of t he i n vesti gat or, t he s u bject has reac he d 
c hil d- beari n g p ote ntial. ( A ser u m pre g na nc y test will be perf or me d i n t he e ve nt of 
a n y p ositi ve or e q ui v ocal ur i ne pre g na nc y test res ult.) 
•  P h ysical e xa mi nati o n, cli ni cal la b orat or y tests, hei g ht  a n d hea d circ u mfere nce 
meas ure me nts will be re peate d o nl y if t he W 0 visit is > 7 da ys after t he Scree ni n g 
visit 
•  Dis pe nse St u d y Dr u g 
1 2. 1. 3. 2  Wee k 1 T hr o u g h W ee k 4 Visits (±  2 d a ys) 
•  Vital si g ns 
•  Wei g ht 
•  Bl o o d P he c o nce ntrati o n 
•  P K sa m ples ( Wee ks 1, 2, 3, a n d/ or 4, refer t o Secti o n  1 2. 3) 
•  C o nc o mita nt me dicati o ns 
•  Dietar y re vie w wit h P he m o dificati o n (if necessar y) wit h a dieticia n  
•  Assess me nt of A Es 


 
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•  Dis pe nse St u d y Dr u g 
1 2. 1. 3. 3  Wee ks 1, 3, a n d 4 Visits O nl y ( ±  2 d a ys) 
•  Cli nical la b orat or y tests  
1 2. 1. 3. 4  Wee k 4 Visit O nl y ( ±  2 d a ys) 
•  P h ysical e xa mi nati o n 
•  Hei g ht a n d hea d circ u mfere nce 
•  Pre g na nc y test if, i n t he esti mati o n of t he i n vesti gat or, t he s u bject has reac he d 
c hil d- beari n g p ote ntial. ( A ser u m pre g na nc y te st will be perf or me d i n t he e ve nt of a n y 
p ositi ve or e q ui v ocal uri ne pre g na nc y test res ult.)  
•  Bl o o d t yr osi ne a n d tr y pt o p ha n 
1 2. 1. 4  P art 2: Ne ur oc o g niti ve St u d y i n K u v a n- Res p o nsi ve S u bjects  
1 2. 1. 4. 1  M o nt hs 2- 5 O nl y ( ± 5 d a ys) 
•  Vital si g ns 
•  Wei g ht 
•  Cli nical la b orat or y tests 
•  Bl o o d P he c o nce ntrati o n 
•  C o nc o mita nt me dicati o ns 
•  Assess me nt of A Es 
•  Dietar y re vie w wit h P he m o dificati o n (if necessar y) wit h a dieticia n  
•  Dis pe nse St u d y Dr u g 
1 2. 1. 4. 2  M o nt h 2 Visit O nl y ( ±  5  d a ys)  
•  A d mi nistrati o n of a ge-a p pr o pr iate I Q test; t his test m ust be c o m plete d wit hi n 
6 wee ks of deter mi nati o n of K u va n res p o nsi ve ness i n K u va n-res p o nsi ve s u bjects 
w h o c o nti n ue i nt o t he Ne ur oc o g niti ve St u d y 
1 2. 1. 4. 3  M o nt h 3 a d diti o n al  t o M o nt hs 2- 5 
•  Hei g ht a n d hea d circ u mfere nce 
•  P h ysical e xa mi nati o n 
•  Bl o o d tr y pt o p ha n a n d t yr osi ne 


 
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1 2. 1. 4. 4  M o nt h 6 Visit O nl y ( ±  5 d a ys) 
•  Pre g na nc y test, if i n t he esti mati o n of t he i n vesti gat or, t he s u bject has reac he d 
c hil d- beari n g p ote ntial ( A ser u m pre g na nc y test will be perf or me d i n t he e ve nt of 
a n y p ositi ve or e q ui v ocal uri n e pre g na nc y test res ult.)  
•  6- m o nt h re peat testi n g wit h Ba yle y-III i n c hil dre n 0- 2 years ol d at e nr oll me nt 
 
1 2. 1. 4. 5  M o nt hs 1 2, 1 8, 2 4,  3 0, etc. ( 6 m o nt h i nter v als ± 2 wee ks) 
•  Vital si g ns 
•  Bl o o d P he c o nce ntrati o n 
•  Wei g ht 
•  Hei g ht a n d hea d circ u mfere nce 
•  P h ysical e xa mi nati o n 
•  Cli nical la b orat or y tests 
•  Pre g na nc y test, if i n t he esti mati o n of t he i n vesti gat or, t he s u bject has reac he d 
c hil d- beari n g p ote ntial.  ( A ser u m pre g na nc y test will be perf or me d i n t he e ve nt 
of a n y p ositi ve or e q ui v ocal uri ne pre g na nc y test res ult.) 
•  C o nc o mita nt me dicati o ns 
•  Dietar y re vie w wit h P he m o dificati o n (if necessar y) wit h a dieticia n  
•  Assess me nt of A Es 
•  Dis pe nse St u d y Dr u g 
•  Ne ur oc o g niti ve testi n g (see Secti o n 2 . 1, S u m mar y of E ve nts a n d Secti o n 9, 
I n vesti gati o nal Pla n) 
1 2. 1. 4. 6  M o nt hs 1 2, 2 4, 3 6, 4 8, 6 0, 7 2 a n d 8 4 ( a n n u al i nter v als ±  2 wee ks)    
•  Bl o o d tr y pt o p ha n, t yr osi ne 
1 2. 1. 4. 7   3- M o nt h I nteri m P h o ne C o nt act ( M o nt hs 9, 1 5, 2 1, 2 7, etc, ±  1 wee k)  
•  Wei g ht 
•  Assess me nt of A Es 
•  C o nc o mit a nt Me dic ati o ns 
•  Dis pe nse St u d y Dr u g 


 
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1 2. 1. 5  E arl y Ter mi n ati o n a n d F oll o w- u p Visit(s) ( wit hi n 2 8 ±  3 d a ys of l ast d ose of 
st u d y dr u g) 
E ver y s u bject s h o ul d c o m plete eit her a F oll o w- u p or Ter mi n ati o n Visit, t o e n d t heir 
p artici p ati o n i n t he st u d y.  T he F oll o w- u p Visit is c o m plete d b y a s u bject w h o c o m pletes 
o nl y P art 1 of t he st u d y, or w h o is e nr o lle d i nt o P art 2 a n d c o m pletes P art 2.  
T he Ter mi n ati o n Visit is c o m plete d b y a s u bj ect w h o wit h dr a ws or is disc o nti n ue d fr o m 
t he st u d y.  T he F oll o w- u p or Ter mi n ati o n Visit s h o ul d occ ur 2 8 d a ys after t he s u bject’s 
fi n al d ose of dr u g. E ver y re as o n a ble eff ort will be m a de t o h a ve t he s u bject c o m plete a 
F oll o w- u p or Ter mi n ati o n Visit.  If t he s u bject d oes n ot c o m plete a F oll o w- u p or 
Ter mi n ati o n Visit i n t he cli nic, mi ni m a ll y a f oll o w- u p p h o ne c all will be m a de. 
A n y A E t hat ca uses a s u bject t o wit h dra w fr o m t he st u d y or a n y cli nicall y si g nifica nt 
a b n or mal la b orat or y val ue or vital si g n meas ure m e nt i de ntifie d at t he Ter mi nati o n Visit will 
be f oll o we d b y t he I n vesti gat or, a n d ma y re q uire a cli nic visit.  
T we nt y-ei g ht da ys after t he fi nal d ose, t he f oll o wi n g st u d y acti vities will  be perf or me d at t he 
F oll o w- u p or Earl y Ter mi nati o n Visit: 
•  C o nc o mita nt me dicati o ns 
•  Assess me nt of A Es 
•  Dietar y re vie w wit h dietici a n  
•  P h ysical e xa mi nati o n (if at a cli nic visit ) 
•  Vital si g ns (if at a cli nic visit ) 
•  Wei g ht 
•  Hei g ht a n d hea d circ u mfere nce (if at a cli nic visit)  
•  Cli nical la b orat or y tests (if at a cli nic visit)  
•  Bl o o d tr y pt o p ha n a n d t yr osi ne (if at a cli nic visit) 
•  Pre g na nc y test if, i n t he esti mati o n of t he i n vesti gat or, t he s u bject has reac he d 
c hil d- beari n g p ote ntial ( A ser u m pre g na nc y test will be perf or me d i n t he e ve nt of 
a n y p ositi ve or e q ui v ocal ur i ne pre g na nc y test res ult.) (if at a cli nic visit) 
•  Ne ur oc o g niti ve test usi n g B a yle y-III if  t he f oll o w u p or e arl y ter mi n ati o n 
visit is 4- 6 m o nt hs after t he l ast assess me nt. 
•  Ne ur oc o g niti ve tests usi n g W P P SI III or WI S C I V if t he f oll o w- u p or earl y 
ter mi nati o n visit is 9 m o nt hs or m ore after t he last assess me nt (if at a cli nic visit) 
E ver y reas o na ble eff ort s h o ul d be ma de t o c o ntact a n y s u bject w h o is l ost t o f oll o w- u p. 


 
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1 2. 2  
S u bst u d y 1: 6- M o nt h S afet y a n d Effic ac y St u d y 
1 2. 2. 1  Scree ni n g a n d Wee ks 0- 4 
See Secti o ns 1 2. 1. 1 , 1 2. 1. 2 , a n d 1 2. 1. 3  f or assess me nts t hat will be d o ne at t he scree ni n g visit 
a n d Wee k 0 t hr o u g h Wee k 4 ( M o nt h 1); t hese are i de ntical t o t he mai n st u d y. 
1 2. 2. 2  M o nt hs 2- 6 ( ±  5 D a ys) 
•  Bl o o d P he c o nce ntrati o n 
•  Cli nical la b orat or y tests  
•  Vital si g ns 
•  Wei g ht 
•  C o nc o mita nt me dicati o ns 
•  Dietar y re vie w wit h P he m o dificati o n (if necessar y) wit h a dieticia n  
•  Assess me nt of A Es 
•  Dis pe nse St u d y Dr u g 
1 2. 2. 3  M o nt hs 3 a n d 6 O nl y ( ±  5 d a ys) 
•  Hei g ht a n d hea d circ u mfere nce  
•  P h ysical e xa mi nati o n  
•  Bl o o d t yr osi ne a n d tr y pt o p ha n 
1 2. 2. 4  M o nt h 6 Visit O nl y ( ±  5 d a ys) 
•  Pre g na nc y test, if i n t he esti mati o n of t he i n vesti gat or, t he s u bject has reac he d 
c hil d- beari n g p ote ntial ( A ser u m pre g na nc y test will be perf or me d i n t he e ve nt of 
a n y p ositi ve or e q ui v ocal uri n e pre g na nc y test res ult.)  
•  6- m o nt h re peat testi n g wit h Ba yle y-III i n c hil dre n 0- 2 years ol d at e nr oll me nt 
1 2. 3  
S u bst u d y 2: P o p ul ati o n P h ar m ac o ki netic St u d y i n S u bjects 0- 6 Ye ars Ol d 
A p o p ulati o n P K st u d y will be c o m plete d i n a t o tal of 8 0 s u bjects. Of t hese 8 0 s u bjects, 
1 0  will be a ges 0 t o ≤ 1 years a n d 7 0  will be > 1 t o 6 years ol d.  
Fr o m Wee ks 0 t o 4, a t otal of 3 plas ma sa m ple s will be c ollecte d fr o m s u bjects a ges 0 t o 
≤ 1 year a n d 4 plas ma sa m ples fr o m s u bjects > 1 t o 6 years ol d. 
Eac h of t he sa m ples will be c ollecte d at diffe re nt ti mes i n relati o n t o t he s u bjects’ m or ni n g 
K u va n d ose.  


 
P K U- 0 1 5
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Pr o prietar y a n d C o nfi de ntial 
3 0 N o ve m ber 2 0 1 0 
•  S u bjects a ge d 0 t o ≤ 1 year will ha ve a pre- d ose sa m ple ta ke n at Wee ks 1 a n d 2 
a n d a p ost- d ose sa m ple ta ke n at Wee ks 1, 2, 3, or 4.  
S u bjects > 1 t o 6 years ol d will ha ve a pre- d ose sa m ple o n Wee k 0 a n d 3 p ost- d ose 
sa m ples. T he 3 p ost- d ose sa m ples: 
o  ha ve 3 differe nt sa m pli n g ti mes 
o  ma y be o btai ne d d uri n g a n y of t h e Wee k 2, 3, or 4 st u d y visits 
o  ma y be o btai ne d i n a n y or der 
T he st u d y staff will c o or di nate t he m ost c o n ve nie nt c ollecti o n sc he d ule f or eac h i n di vi d ual 
s u bject a n d t heir pare nts or g uar dia ns. 
T he c ollecti o n sc he d ule is descri be d i n Ta ble 1 2. 3. 1.  
T a ble 1 2. 3. 1:  S a m pli n g Wi n d o ws f or P o p ul ati o n P K St u d y 
 
 
 
 
P ost- d ose S a m pli n g Wi n d o w 
A ge 
Gr o u p 
( Ye ars) 
Visit 
O pti m al S a m pli n g 
Ti me 
( H o urs, Mi n utes) 
L o wer B o u n d 
( H o urs, Mi n utes) 
U p per B o u n d 
( H o urs, 
Mi n utes) 
0 t o ≤ 1  
Wee k 1  
Pre- d ose  
--  
-- 
0 t o ≤ 1  
Wee k 2  
Pre- d ose  
--  
-- 
0 t o ≤ 1 
Wee k 1, 2, 
3, or 4 
4. 9 hrs ( 2 9 4 mi n) 
p ost- d ose 
4. 5 hrs ( 2 7 0 mi n)  
5. 5 hrs ( 3 3 0 mi n) 
> 1 t o 6  
Wee k 0  
Pre- d ose 
-- 
-- 
> 1 t o 6 
Wee k 2, 3, 
a n d/ or 4 a 
0. 2 2 hrs ( 1 3 mi n) 
p ost- d ose 
0. 1 2 hrs ( 7 mi n)  
1. 2 hrs ( 7 2 mi n) 
> 1 t o 6 
Wee k 2, 3, 
a n d/ or 4 a 
3. 2 hrs ( 1 9 2 mi n) 
p ost- d ose 
2. 6 hrs ( 1 5 6 mi n)  
5. 2 hrs ( 3 1 2 mi n) 
> 1 t o 6 
Wee k 2, 3, 
a n d/ or 4 a 
7 hrs ( 4 2 0 mi n) 
p ost- d ose 
6 hrs ( 3 6 0 mi n)  
8 hrs ( 4 8 0 mi n) 
--N ot a p plica ble  
a S u bjects ma y ha ve all 3 sa m ples dra w n at o ne visit, at 2 of t he 3 visits, or ha ve 1 sa m ple dra w n at eac h of t he 
3 visits 
 
S u bjects will ta ke t heir d ose at  t he sa me ti me of da y wit h a meal, per site i nstr ucti o ns, t o 
o btai n sa m ples f or t he p o p ulati o n P K a nal ysis wit hi n t he s pecifie d ti me wi n d o ws (e g, bef ore 
d osi n g a n d 0. 2 2 t o 8 h o urs or 7 t o 4 8 0 mi n utes, after d osi n g). T he e xact  ti mes of d osi n g will 
be rec or de d. Bl o o d sa m ples will be c ollecte d a p pr o xi m atel y  2. 5 t o 5 h o urs after t he meal t o 


 
P K U- 0 1 5
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9 2
 
 
Pr o prietar y a n d C o nfi de ntial 
3 0 N o ve m ber 2 0 1 0 
o btai n bl o o d P he c o nce ntrati o ns w hile i n P h ase I of t his st u d y ( Wee k 0- Wee k 6). 
P o p ul ati o n P K bl o o d dr a ws m a y alter t h e 2. 5- 5 h o ur bl o o d P he s a m pli n g ti me.  
I n a d diti o n, i n vesti gat ors will be as ke d t o c ollect a bl o o d sa m ple f or t otal bi o pteri n testi n g at 
t he ti me of a n S A E, w he n p ossi ble, if t he S AE is c o nsi dere d b y t he i n vesti gat or t o be 
pr o ba bl y or p ossi bl y relate d t o K u va n. 


 
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Pr o prietar y a n d C o nfi de ntial 
3 0 N o ve m ber 2 0 1 0 
1 3  
D A T A Q U A LI T Y A S S U R A N C E 
Bi o Mari n pers o n nel or desi g nees will visit t he st u d y site pri or t o i nitia ti o n of t he st u d y t o 
re vie w wit h t he site pers o n nel i nf or mati o n a b o ut t he I P, prot oc ol a n d ot her re g ulat or y 
d oc u me nt re q uire me nts, a n y a p plica ble ra n d o mizati o n pr oce d ures, s o urce d oc u me nt 
re q uire me nts, C R Fs, m o nit ori n g re q uire me nts, a n d pr oce d ures f or re p orti n g A Es, i ncl u di n g 
S A Es.  
At visits d uri n g a n d after t he st u d y, a C R A will m o nit or t he site f or c o m plia nce wit h 
re g ulat or y d oc u me ntati o n, wit h a f oc us o n acc urate a n d c o m plete rec or di n g of data o n C R Fs 
fr o m s o urce d oc u me nts, a d here nce t o pr ot oc ol, ra n d o mizati o n (if a p plica ble), S A E re p orti n g 
a n d dr u g acc o u nta bilit y rec or ds.  
T he desi g nate d cli nical data ma na ge me nt gr o u p will e nter or tra nsfer C R F data i nt o a st u d y 
data base. 
Data q ualit y c o ntr ol a n d a nal ys is will be perf or me d b y Bi o Mari n or a desi g nee, base d o n a 
pre defi ne d a nal ysis pla n. 


 
P K U- 0 1 5
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Pr o prietar y a n d C o nfi de ntial 
3 0 N o ve m ber 2 0 1 0 
1 4  
S T A TI S TI C A L M E T H O D S A N D D E T E R MI N A TI O N O F S A M P L E SI Z E 
1 4. 1  
Effect of K u v a n o n Ne ur oc o g niti ve F u ncti o n 
1 4. 1. 1  St atistic al a n d A n al ytic al Pl a ns 
T he statistical a nal ysis pla n ( S A P) will pr o vi de  a d diti o nal details o n t he pla n ne d statistical 
a nal ysis. 
1 4. 1. 2  Pri m ar y Effic ac y A n al ysis 
T he pri mar y efficac y e n d p oi nt is t he I Q sc or e meas ure d b y t he W P P SI-III or WI S C-I V tests. 
A nal ysis of ne ur oc o g niti ve de vel o p me nt usi n g t he I Q sc ores will be perf or me d usi n g a 
re peate d meas ures m o del. T he o utc o me varia ble will be t he I Q sc ore fr o m W P P SI-III a n d/ or 
WI S C-I V tests. T he sl o pe of t he test sc ores  will be calc ulate d. T he treat me nt will be 
c o nsi dere d s uccessf ul if t he l o wer c o nfi de nce li m it of t he mea n c ha n ge i n test sc ore o ver a 
2- year peri o d e xcl u des a decli ne of greater t h a n 5 p oi nts. All data will be i ncl u de d i n a 
c o m bi ne d a nal ysis, stratifie d b y test i n g se q ue nce use d ( W P P SI-III/ W P P SI-III, 
W P P SI-III/ WI S C-I V, or WI S C-I V/ WI S C-I V). 
A n o mi nal decli ne i n I Q will be c o nsi dere d acce pta ble beca use researc h has s h o w n t hat 
des pite earl y a n d c o nti n u o us dietar y ma na ge me nt of P K U, t hese patie nts ha ve l o wer 
I Q sc ores t ha n si bli n gs or n o n- P K U c o ntr ols matc he d f or a ge,  se x, a n d pare nt’s e d ucati o n. 
Res ults fr o m a pr os pecti ve st u d y s p o ns ore d b y t he Britis h Me dical Researc h C o u ncil ( M R C) 
of I Q i n 5 4 5 c hil dre n wit h P K U s h o we d t hat P K U patie nts attai n mea n I Q le vels 8 p oi nts 
bel o w t he n or ms ( S mit h, 1 9 8 9, E ur.J. Cli n. N utr.) A re p ort fr o m t he P K U C olla b orati ve St u d y 
s h o we d t hat at 4 years of a ge, 3 6 P K U c hil dre n w h o ha d recei ve d earl y a n d c o nti n u o us 
dietar y ma na ge me nt of P K U ha d si g nifica ntl y l o wer ( P = . 0 2) mea n [sta n dar d err or, S E] I Q 
sc ores of 9 4. 0 [ 1 7. 6] t ha n t heir matc he d n o n- P K U si bli n g c o ntr ols, 9 9. 0 [ 1 5. 0] ( D o bs o n, 
1 9 7 6, Pe diatrics) . F oll o w u p of t hese sa me c hil dre n at 8 years ol d c o nfir me d t he earlier 
fi n di n gs; mea n WI S C F ull Scale I Q sc ore i n t he P K U c hil dre n was 1 0 0 c o m pare d wit h 
1 0 7 f or t heir matc he d si bli n g c o ntr ols ( P = . 0 0 1; ( K oc h, 1 9 8 4, J.I n herit. Meta b Dis.). I n a 
st u d y of 3 7 P K U patie nts bet wee n 3 a n d 1 9 years ol d w h o ha d recei ve d earl y a n d c o nti n u o us 
dietar y ma na ge me nt of P K U, c o g niti ve f u ncti o n wa s c o m pare d wit h t hat of c o ntr ols matc he d 
f or a ge, se x, a n d ge o gra p hic l ocati o n ( Gassi o, 2 0 0 5, De v. Me d. C hil d Ne ur ol.). T he mea n 
I Q ( ± sta n dar d de viati o n, S D) was si g nifica ntl y l o wer i n t he P K U gr o u p ( 1 0 0 ± 1 1) c o m pare d 
wit h t hat of t he c o ntr ol gr o u p ( 1 1 1 ± 8. 8) ( P = . 0 0 1). Si milarl y, ( Ris, 1 9 9 4, J. Pe diatr.) 
c o m pare d 1 0 a d ults wit h P K U w h ose disease wa s dietar y ma na ge d earl y i n life wit h t heir 
u naffecte d c o ntr ol si bli n gs. A gai n, P K U patie nt s ha d si g nifica ntl y l o wer mea n I Q res ults 
( 9 1 ± 1 2) t ha n di d t heir n o n- P K U si bli n gs (1 0 0 ± 1 1, P = . 0 4). T heref ore, beca use patie nts 


 
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Pr o prietar y a n d C o nfi de ntial 
3 0 N o ve m ber 2 0 1 0 
wit h P K U w h ose bl o o d P he c o nce ntrati o ns ha ve bee n ma na ge d earl y a n d c o nti n u o usl y wit h a 
P he-restricte d diet are n ot e x pecte d t o ha ve n or mal I Q, a n o mi nal decli ne of u p t o 5 I Q p oi nts 
o ver a 2- year peri o d will be c o nsi dere d t he e x pecte d baseli ne meas ure me nt f or t he st u d y. 
1 4. 1. 3  Sec o n d ar y Effic ac y A n al ysis 
T he sec o n dar y efficac y e n d p oi nt is: 
C ha n ge i n de vel o p me ntal gr o wt h fact ors,  meas ure d b y hei g ht, wei g ht, a n d hea d 
circ u mfere nce fr o m baseli ne 
T his sec o n dar y e n d p oi nt will be a nal yze d usi n g a l o n git u di nal m o del. 
1 4. 1. 4  S afet y A n al ysis 
T he ori gi nal ter ms re p orte d i n C R Fs t o i de ntif y A Es will be c o de d usi n g t he Me dical 
Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A) . T he i nci de nce of treat me nt-e mer ge nt A Es 
will be s u m marize d b y s yste m or ga n class, pr eferre d ter m, relati o ns hi p t o st u d y dr u g, a n d 
se verit y. A b y-s u bject listi n g will be pr o vi de d f or t h ose s u bjects w h o ha d a S A E, i ncl u di n g 
deat h, or ha d a n A E res ulti n g i n earl y disc o nti n uati o n of st u d y dr u g. 
La b orat or y data will be s u m marize d b y t he t y pe of la b or at or y test. T he fre q ue nc y a n d 
perce nta ge of s u bjects w h o e x perie nce a n a b n or malit y (ie, o utsi de of refere nce ra n ges) or 
cli nicall y si g nifica nt a b n or malit y after st u d y dr u g  a d mi nistrati o n will be prese nte d f or eac h 
la b orat or y a nal yte. F or eac h la b orat or y a nal yte, descri pti ve statistics will be pr o vi de d f or 
val ues meas ure d at eac h sc he d ule d visit, a n d f or c ha n ge i n val ues fr o m baseli ne t o eac h 
sc he d ule d visit. Si milarl y, descri pti ve statistics of vital si g ns will be pr o vi de d. 
I nteri m safet y a nal yses will be c o n d ucte d a n n uall y t hr o u g h c o m pleti o n of t he st u d y. 
1 4. 1. 5  Deter mi n ati o n of S a m ple Size 
T he calc ulati o n of sa m pl e size ass u mes t hat eac h c hil d will ha ve 2 p ost-treat me nt test res ults 
fr o m t he W P P SI-III a n d/ or WI S C-I V tests at least 2 years a part. T he g oal is t o e xcl u de a 
mea n 2. 5- p oi nt l oss per year i n sc ore. Gi ve n a 2-si de d T y pe I err or ra te of 0. 0 5, if t he mea n 
I Q sc ore at baseli ne is 1 0 0, t he sta n dar d deviati o n is 1 5, a n d t he c o rrelati o n bet wee n t he 
2 test res ults is 0. 8, a sa m ple size of 4 5 s u bjects will yiel d 9 0 % p o wer. 
T o acc o u nt f or t he p ossi bilit y of dr o p o uts a n d t o ha ve reas o na ble precisi o n f or esti mati n g 
c ha n ge i n I Q fr o m t he ti me a c hil d reac hes at  least a ge 3 0 m o nt hs u ntil t he e n d of t he st u d y, 
a p pr o xi matel y 6 0- 8 0 K u va n-res p o nsi ve s u bjects will be e nr olle d i n t he st u d y. 


 
P K U- 0 1 5
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Pr o prietar y a n d C o nfi de ntial 
3 0 N o ve m ber 2 0 1 0 
1 4. 2  
S u bst u d y 1: S afet y a n d Effic ac y A n al yses  
Efficac y will be assesse d b y t he a bilit y of K u va n, a d mi nistere d o ver a 6- m o nt h peri o d, t o 
c o ntr ol bl o o d P he c o nce ntrati o ns wit hi n acce pta bl e ra n ges f or a ge a n d f or t he criteria use d at 
t he treat me nt ce nters. Efficac y e n d p oi nts are: 
•  Pr o p orti o n of s u bjects w h ose bl o o d P he c o n ce ntrati o n is wit hi n acce pta ble ra n ges 
at p ost-treat me nt visits 
•  Mea n c ha n ge i n bl o o d P he c o nce ntrati o n fr o m baseli ne t o p ost-treat me nt m o nt hl y 
visits 
A n e xact 9 5 % c o nfi de nce i nter val ( CI) f o r t he pr o p orti o n of s u bjects w h ose bl o o d P he 
c o nce ntrati o n wit hi n acce pta ble ra n ges at eac h  p ost-treat me nt visit a n d a 9 5 %  CI f or t he 
mea n c ha n ge i n bl o o d P he c o nce ntrati o n fr o m baseli ne t o p ost-treat me nt m o nt hl y visits will 
be pr o vi de d f or t he efficac y assess me nt. Baseli ne bl o o d P he c o nce ntrati o n will be calc ulate d 
usi n g t he mea n of Scree ni n g a n d Wee k 0 ( pri or t o d osi n g wit h K u va n) res ults.  
Safet y res ults f or t he first 6 m o nt hs of treat me nt will be a nal yze d as descri be d a b o ve. 
1 4. 3  
S u bst u d y 2: P h ar m ac o ki netic A n al yses 
T he ti me c o urse of t he calc ulate d B H 4 c o nce ntrati o n (fr o m plas ma t otal bi o pteri n 
meas ure me nt) will be m o dele d t o esti mate  t he f oll o wi n g p o p ulati o n P K para meters f or 
K u va n: a p pare nt cleara nce ( C L/ F) wit h ass ociate d i nter-i n di vi d ual varia bi lit y, a p pare nt 
v ol u me of distri b uti o n ( Vc/ F) wit h ass ociate d i nter-i n di vi d ual varia bilit y, a n d a bs or pti o n rate 
c o nsta nt wit h ass ociate d i nter-i n di vi d ual varia bilit y ( Ka). Data  fr o m t he S u bst u d y 2 ma y als o 
be p o ole d wit h P K data o btai ne d fr o m a d u lt s u bjects i n pre vi o us cli nical st u dies. 


 
P K U- 0 1 5
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9 7
 
 
Pr o prietar y a n d C o nfi de ntial 
3 0 N o ve m ber 2 0 1 0 
1 4. 4  
C h a n ges i n t he C o n d uct of t he St u d y or Pl a n ne d A n al yses 
O nl y Bi o Mari n ma y m o dif y t he pr ot oc ol. A n y c ha n ge i n st u d y c o n d uct c o nsi dere d necessar y 
b y t he PI will be ma de o nl y after c o ns ultati o n wit h Bi o Mari n, w h o will t he n iss ue a f or mal 
pr ot oc ol a me n d me nt t o i m ple me nt t he c ha n ge. T he o nl y e xce pti o n is w he n a n I n vesti gat or 
c o nsi ders t hat a s u bject’s safet y is c o m p r o mise d wit h o ut i m me diate acti o n. I n t hese 
circ u msta nces, i m me diate a p pr o val of t he c hai r ma n of t he I R B/ E C m ust be s o u g ht, a n d t he 
I n vesti gat or s h o ul d i nf or m Bi o Mari n a n d t he f ull I R B/ E C wit hi n 2 w or ki n g da ys after t he 
e mer ge nc y occ urs.  
Wit h t he e xce pti o n of mi n or a d mi nistrati ve or  t y p o gra p hical c ha n ges, t he I R B/ E C m ust 
re vie w a n d a p pr o ve all pr ot oc ol a me n d me nts. Pr ot oc ol a me n d me nts t hat ha ve a n i m pact o n 
s u bject ris k or t he st u d y o bjecti ves, or re q uire re visi o n of t he I C F, m ust recei ve a p pr o val 
fr o m t he I R B/ E C pri or t o t heir i m ple me ntati o n. 
W he n a pr ot oc ol a me n d me nt s u bsta ntiall y alte rs t he st u d y desi g n or t he p ote ntial ris ks or 
b ur de n t o s u bjects, t he I C F will be a me n de d a n d a p pr o ve d b y Bi o Mari n a n d t he I R B/ E C, a n d 
all acti ve s u bjects m ust a gai n pr o vi de i nf or me d c o nse nt. 
N ote: If discre pa ncies e xist bet wee n t he te xt of t he statistical a nal ysis as pla n ne d i n t he 
pr ot oc ol, a n d t he fi nal S A P, a pr ot oc ol a me n d me nt will n ot be iss ue d a n d t he S A P will 
pre vail. 


 
P K U- 0 1 5
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Pr o prietar y a n d C o nfi de ntial 
3 0 N o ve m ber 2 0 1 0 
1 5  
D A T A M O NI T O RI N G C O M MI T T E E ( D M C) 
T his o pe n-la bel o ne-ar m st u d y will n ot ha ve a D M C.  
 


 
P K U- 0 1 5
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Pr o prietar y a n d C o nfi de ntial 
3 0 N o ve m ber 2 0 1 0 
1 6  
C O M P E N S A TI O N, I N S U R A N C E A N D I N D E M NI T Y 
T here will be n o c har ge t o st u d y s u bjects t o be i n t his st u d y. Bi o Mari n will pa y all c osts of 
tests, pr oce d ures, a n d treat me nts t hat are part of t his st u d y. I n a d diti o n, after I R B/ E C 
a p pr o val, Bi o Mari n ma y rei m b urse t he c ost of tra vel f or st u d y-relate d visits. Bi o Mari n will 
n ot pa y f or a n y h os pitalizati o ns, tests, or tr eat me nts f or me dical pr o ble ms of a n y s ort, 
w het her or n ot relate d t o t he st u d y s u bject’s disease, t hat are n ot part of t his st u d y. C osts 
ass ociate d wit h h os pitalizati o ns, tests, a n d trea t me nts s h o ul d be bille d a n d c ollecte d i n t he 
wa y t hat s uc h c osts are us uall y bille d a n d c ollecte d. 
T he I n vesti gat or s h o ul d c o ntac t Bi o Mari n i m me diatel y u p o n n otificati o n t hat a st u d y s u bject 
has bee n i nj ure d b y t he I P or b y pr oce d ures pe rf or me d as part of t he st u d y. A n y s u bject w h o 
e x perie nces a st u d y-relate d i nj ur y s h o ul d be i nst r ucte d b y t he I n vesti gat or t o see k me dical 
treat me nt at a pre-s pecifie d me dical i nstit uti o n if p ossi ble, or at t he cl osest me dical treat me nt 
facilit y if necessar y. T he s u bject s h o ul d be gi ve n t he na me of a pers o n t o c o ntact t o see k 
f urt her i nf or mati o n a b o ut, a n d assista nce wit h, treat me nt f or st u d y-relate d i nj uries. 
T he treati n g p h ysicia n s h o ul d bill t he s u bject’s healt h i ns ura nce c o m pa n y or ot her t hir d part y 
pa yer f or t he c ost of t his me dical treat me nt. If t he s u bject has f oll o we d t he I n vesti gat or’s 
i nstr ucti o ns, Bi o Mari n will pa y f or reas o na ble a n d necessar y me dical ser vices t o treat t he 
i nj uries ca use d b y t he I P or st u d y pr oce d ures, if t hese c osts are n ot c o vere d b y healt h 
i ns ura nce or a n ot her t hir d part y t hat us uall y pa ys t hese c osts. I n s o me j uris dicti o ns, Bi o Mari n 
is o bli gate d b y la w t o pa y f or st u d y-relate d i nj uries wit h o ut pri or rec o urse t o t hir d part y 
pa yer billi n g. If t his is t he case, Bi o Mari n will c o m pl y wit h t he la w. 


 
P K U- 0 1 5
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1 0 0
 
 
Pr o prietar y a n d C o nfi de ntial 
3 0 N o ve m ber 2 0 1 0 
1 7  
C A S E R E P O R T F O R M S A N D S O U R C E D O C U M E N T S 
Electr o nic case re p ort f or ms will be pr o vi de d f or eac h s u bject. T he I n vesti gat or m ust re vie w 
a n d electr o nicall y si g n t he c o m plete d C R F case b o o k t o verif y its acc urac y. 
C R Fs m ust be c o m plete d usi n g a we b – base d a p p licati o n de vel o pe d a n d vali date d. St u d y site 
pers o n nel will be trai ne d o n t he a p plicati o n a n d will e nter t he cli nical data fr o m s o urce 
d oc u me ntati o n. U nless e x plicitl y all o we d i n t he C R F i nstr ucti o ns, bla n k data fiel ds are n ot 
acce pta ble.  
I n t he e ve nt of a n e ntr y err or, or if ne w i nf or mati o n bec o mes a vai la ble, t he site pers o n nel will 
c orrect t he val ue b y deselecti n g t he err o ne o us res p o nse a n d t h e n selecti n g or e nteri n g t he 
fact ual res p o nse. I n c o m plia nce wit h 2 1 C F R Part 1 1, t he s yste m will re q uire t he site 
pers o n nel t o e nter a reas o n f or c ha n gi n g t he va l ue. T he d oc u me nte d au dit trail will i ncl u de 
t he reas o n f or t he c ha n ge, t he ori gi nal val ue, t he ne w val ue, t he ti me of t he c orrecti o n a n d t he 
i de ntit y of t he o perat or. 
Bi o Mari n’s p olic y is t hat st u d y data o n t he C R Fs m ust be verifi a ble t o t he s o urce data, w hic h 
necessitates access t o all ori gi n al rec or di n gs, la b orat or y re p orts, a n d s u bject rec or ds. 
I n a d diti o n, all s o urce data s h o uld be attri b uta ble (si g ne d a n d date d). T he I n vesti gat or m ust 
t heref ore a gree t o all o w direct access t o all s o urce data. S u bject s ( or t heir le gall y a ut h orize d 
re prese ntati ve) m ust als o all o w access t o t heir me dical rec or ds, a n d s u bjects will be i nf or me d 
of t his a n d will c o nfir m t heir a gree me nt w he n gi vi n g i nf or me d c o nse nt. If a n I n vesti gat or or 
i nstit uti o n ref uses t o all o w access t o s u bject rec or ds beca use of c o nfi de ntialit y, arra n ge me nts 
m ust be ma de t o all o w a n “i nter vie w” st yle of data verificati o n. 
A C R A desi g nate d b y Bi o Mari n will c o m pare t h e C R Fs wit h t he ori gi nal s o urce d oc u me nts 
at t he st u d y site a n d e val uate t he m f or c o m plete ness a n d acc urac y bef ore desi g nati n g t he m as 
“ S o urce Data Verifie d” ( S D V). If a n err or is disc o vere d at a n y ti me or  a clarificati o n is 
nee de d, t he C R A, or desi g nee, will create a n electr o nic q uer y o n t he ass ociate d fiel d. Site 
pers o n nel will t he n a ns wer t he q uer y b y eit her c o rrecti n g t he data or res p o n di n g t o t he q uer y. 
T he C R A will t he n re vie w t he res p o nse a n d deter mi ne eit her t o cl ose t he q uer y or re – q uer y 
t he site if t he res p o nse d oes n ot f ull y a d dress t he q uesti o n. T his pr ocess is re peate d u ntil all 
o pe n q ueries ha ve bee n a ns were d a n d cl ose d.  
Bef ore a s u bject’s C R F case b o o k ca n be l oc ke d, all data fiel ds m ust be s o urce data verifie d 
a n d all q ueries cl ose d. T he I n vesti gat or will  t he n electr o nicall y sig n t he case b o o k, s pecif yi n g 
t hat t he i nf or mati o n o n t he C R Fs is acc urate an d c o m plete. T he Data Ma na ger, or desi g nee, 
will t he n set t he stat us of t he f or ms, visits, a n d t he e ntire case b o o k t o L oc ke d. U p o n 


 
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c o m pleti o n of t he Cli nical St u d y Re p ort, a n el ectr o nic c o p y of eac h s ite’s case b o o ks will be 
c o pie d t o a c o m pact dis k ( C D) a n d se nt t o eac h site f or rete nti o n wit h ot her st u d y d oc u me nts. 


 
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S T U D Y M O NI T O RI N G  A N D A U DI TI N G 
Q ualifie d i n di vi d uals desi g nate d b y Bi o Mari n w ill m o nit or all as pects of t he st u d y acc or di n g 
t o G C P a n d sta n dar d o perati n g pr oce d ures f or c o m plia nce wit h a p plica ble g o ver n me nt 
re g ulati o ns. T he PI a grees t o all o w t hese m o nit ors direct access t o t he cli nical s u p plies, 
dis pe nsi n g, a n d st ora ge areas a n d t o  t he cli nical files, i ncl u di n g ori gi nal me dical rec or ds, of 
t he st u d y s u bjects, a n d, if re q ueste d, a grees t o assist t he m o nit ors. T he PI a n d staff are 
res p o nsi ble f or bei n g prese nt or a vaila ble f or c o ns ultati o n d uri n g r o uti nel y sc he d ule d site 
visits c o n d ucte d b y Bi o M ari n or its desi g nees. 
Me m bers of Bi o Mari n’s G C P C o m plia nce De part me nt or desi g nees ma y c o n d uct a n a u dit of 
a cli nical site at a n y ti me d uri n g or after c o m pleti o n of t he st u d y. T he PI will be i nf or me d if 
a n a u dit is t o ta ke place a n d a d vise d as t o t he sc o pe of t he a u dit. Re prese ntati ves of t he F D A 
or ot her Re g ulat or y A ge ncies ma y als o c o n d uct a n a u dit of t he st u d y. If i nf or me d of s uc h a n 
i ns pecti o n, t he PI s h o ul d n otif y Bi o Mari n i m me diatel y. T he PI will e ns ure t hat t he a u dit ors 
ha ve access t o t he cli nical s u p pl ies, st u d y site facilities, ori gi nal s o urce d oc u me ntati o n, a n d 
all st u d y files. 


 
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R E T E N TI O N O F R E C O R D S 
T he PI m ust retai n all st u d y rec or ds re q uire d b y Bi o Mari n a n d b y t he a p plica ble re g ulati o ns 
i n a sec ure a n d safe facilit y. T he PI m ust c o nsult a Bi o Mari n re prese nta ti ve bef ore dis p osal 
of a n y st u d y rec or ds, a n d m ust n otif y Bi o Mari n of a n y c ha n ge i n t he l ocati o n, dis p ositi o n or 
c ust o d y of t he st u d y files. T he PI/i nstit uti o n m ust ta ke meas ures t o pre ve nt acci de ntal or 
pre mat ure destr ucti o n of esse ntial d oc u me nts,  t hat is, d oc u me nts t hat i n di vi d uall y a n d 
c ollecti vel y per mit e val uati o n of t he c o n d uct of a st u d y a n d t he q ualit y of t he data pr o d uce d, 
i ncl u di n g pa per c o pies of st u d y rec or ds (e g, s u bject c harts) as well as a n y ori gi nal s o urce 
d oc u me nts t hat are electr o nic as re q uire d  b y a p plica ble re g ulat or y re q uire me nts.  
All st u d y rec or ds m ust be retai ne d  f or at least 2 years after t he last a p pro val of a mar keti n g 
a p plicati o n i n t he U. S. or a n I C H re gi o n a n d u ntil ( 1) t here are n o pe n di n g or c o nte m plate d 
mar keti n g a p plicati o ns i n t he U. S. or a n I C H re gi o n or ( 2) at least 2 ye ars ha ve ela pse d si nce 
t he f or mal disc o nti n uati o n of cli nical de vel o p me nt of t he I P. T he PI/i nstit uti o n s h o ul d retai n 
s u bject i de ntifiers f or at least 1 5 years after t he c o m pleti o n or disc o nti n uati o n of t he st u d y. 
S u bject files a n d ot her s o urce data m ust be ke pt f or t he ma xi m u m peri o d of ti me per mitte d 
b y t he h os pital, i nstit uti o n or pri vate practice,  b ut n ot less t ha n 1 5 years. T hese d oc u me nts 
s h o ul d be retai ne d f or a l o n ger peri o d, h o we ver, if re q uire d b y t he a p plica ble  re g ulat or y 
re q uire me nts or b y a Bi o Mari n a gree me nt. Bi o Mari n m ust be n otifie d a n d will assist wit h 
rete nti o n s h o ul d PI/i nstit uti o n be u na ble t o c o nti n ue mai nte na n ce of s u bject files f or t he f ull 
1 5 years. It is t he res p o nsi bilit y of Bi o Mari n  t o i nf or m t he PI/i nstit uti o n as t o w he n t hese 
d oc u me nts n o l o n ger nee d t o be retai ne d. 


 
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2 0  
U S E O F I N F O R M A TI O N A N D P U B LI C A TI O N 
Bi o Mari n rec o g nizes t he i m p or ta nce of c o m m u nicati n g me dical st u d y data a n d t heref ore 
e nc o ura ges t heir p u blicati o n i n re p uta ble scie ntific j o ur nals a n d at se mi nars or c o nfere nces. 
T he details of t he pr ocesse s of pr o d uci n g a n d re vie win g re p orts, ma n uscri pts, a n d 
prese ntati o ns base d o n t he data fr o m t his st u d y will be descri be d i n t he Cli nical St u d y 
A gree me nt bet wee n Bi o Mari n a n d t he PI. 


 
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Pr o prietar y a n d C o nfi de ntial 
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2 1  
R E F E R E N C E S 
Ba yle y N. Test Re vie w: Ba yle y Scales of I nfa nt a n d T o d dler De vel o p me nt ( Ba yle y-III). 
Tec h nical Ma n ual. J of Ps yc h oe d uc ati o nal Assess me nt 2 5[ 2], 1 8 0- 1 9 0. 2 0 0 6.  
Ba yle y N. Ba yle y Scales of I nfa nt a n d T o d dl er De vel o p me nt ( Ba yle y- III). Tec h nical Ma n ual. 
T hir d e d. Sa n A nt o ni o: Ps yc h ol o gical C or p., 2 0 0 6. [ T his p u blic ati o n is a b o ok a n d t heref ore 
is n ot i ncl u de d i n t he s u b missi o n.] 
Ber ne g ger, C, Bla u, N. Hi g h fre q ue nc y of tetra h y dr o bi o pteri n-res p o nsi ve ness a m o n g 
h y per p he n ylala ni ne mias: a st u d y of 1, 9 1 9 pa tie nts o bser ve d fr o m 1 9 8 8 t o 2 0 0 2. M ol Ge net 
Meta b 7 7[ 4], 3 0 4- 3 1 3. 2 0 0 2.  
Bla u, N, Ber ne g ger, C, Trefz, F K. Tetra h y dr o bi o pteri n-res p o nsi ve h y per p he n ylala ni nae mia 
d ue t o h o m oz y g o us m utati o ns i n t he p he n ylala n i ne h y dr o x ylase ge ne. E ur J Pe diatr 1 6 2[ 3], 
1 9 6. 2 0 0 3.  
Cer o ne, R, Sc hiaffi n o, M C, Fa ntasia, A R, Perf u m o, M et. al. L o n g-ter m f oll o w- u p of a 
patie nt wit h mil d tetra h y dr o bi o pteri n-res p o ns i ve p he n yl ket o n uria. M ol Ge net Meta b 8 1[ 2], 
1 3 7- 1 3 9. 2 0 0 4.  
D o bs o n, J C, K us hi da, E, Willia ms o n, M, Frie d m a n, E G. I ntellect ual perf or ma nce of 3 6 
p he n yl ket o n uria patie nts a n d t heir n o naffect e d si bli n gs. Pe diatrics 5 8[ 1], 5 3- 5 8. 1 9 7 6.  
D u dese k, A, R osc hi n ger, W, M u nta u, A C, Sei del , J et. al. M olec ular a nal ysis a n d l o n g-ter m 
f oll o w- u p of patie nts wit h differe nt f or ms of 6- p yr u v o yl-tetra h y dr o pteri n s y nt hase 
deficie nc y. E ur J Pe diatr 1 6 0[ 5], 2 6 7- 2 7 6. 2 0 0 1.  
Gassi o, R, Art uc h, R, Vilaseca, M A, F uste, E et. al. C o g niti ve f u ncti o ns i n classic 
p he n yl ket o n uria a n d mil d h y per p he n ylala ni nae m ia: e x perie nce i n a pae diatric p o p ulati o n. 
De v Me d C hil d Ne ur ol 4 7[ 7], 4 4 3- 4 4 8. 2 0 0 5.  
He n ner ma n n, J B, B u hrer, C, Bla u, N, Vette r, B et. al. L o n g-ter m treat me nt wit h 
tetra h y dr o bi o pteri n i ncreases p he n ylala ni ne t olera nce i n c hil dre n wit h se vere p he n ot y pe of 
p he n yl ket o n uria. M ol Ge net Meta b 8 6 S u p pl 1, S 8 6- S 9 0. 2 0 0 5.  
K oc h, R, Aze n, C, Frie d ma n, E G, Willia ms o n, M L. Paire d c o m paris o ns bet wee n earl y 
treate d P K U c hil dre n a n d t heir matc he d si bli n g c o ntr ols o n i ntelli ge nce a n d sc h o ol 
ac hie ve me nt test res ults at ei g ht years of a ge. J I n heri t Meta b Dis 7[ 2], 8 6- 9 0. 1 9 8 4.  
K oc h, R, G uttler, F, Bla u, N. Me ntal ill ness i n mil d P K U res p o n ds t o bi o pteri n. M ol Ge net 
Meta b 7 5[ 3], 2 8 4- 2 8 6. 2 0 0 2.  


 
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1 0 6
 
 
Pr o prietar y a n d C o nfi de ntial 
3 0 N o ve m ber 2 0 1 0 
La m br usc hi ni, N, Perez- D ue nas, B, Vilaseca, M A, Mas, A et. al. Cli nical a n d n utriti o nal 
e val uati o n of p he n yl ket o n uric patie nts o n te tra h y dr o bi o pteri n mo n ot hera p y. M ol Ge net 
Meta b 8 6 S u p pl 1, S 5 4- S 6 0. 2 0 0 5.  
Lass ker, U, Zsc h oc ke, J, Bla u, N, Sa nter , R. Tetra h y dr o bi o pteri n res p o nsi ve ness i n 
p he n yl ket o n uria. T w o ne w cases a n d a re vie w of  m olec ular ge netic fi n di n gs. J I n herit Meta b 
Dis 2 5[ 1], 6 5- 7 0. 2 0 0 2.  
Li n d ner, M, Stei nfel d, R, B ur gar d, P, Sc h ulze, A et. al. Tetra h y dr o bi o pteri n se nsiti vit y i n 
Ger ma n patie nts wit h mil d p he n ylala ni ne h y dr o x ylase deficie nc y. H u m M utat 2 1[ 4], 4 0 0. 
2 0 0 3.  
M o yle, JJ, F o x, A M, Art h ur, M, B y ne velt, M et. al. Meta- A nal ysis of Ne ur o ps yc h ol o gical 
S y m pt o ms of A d olesce nts a n d A d ults w it h P K U. Ne ur o ps yc h ol Re v 1 7[ 2], 9 1- 1 0 1. 2 0 0 7.  
M u nta u, A C, R osc hi n ger, W, Ha bic h, M, De m m el mair, H et. al. Tetra h y dr o bi o pteri n as a n 
alter nati ve treat me nt f or mil d p he n yl ket o n uria. N E n gl J Me d 3 4 7[ 2 6], 2 1 2 2- 2 1 3 2. 2 0 0 2.  
Ris, M D, Willia ms, S E, H u nt, M M, Berr y, H K et. al. Earl y-treate d p he n yl ket o n uria: a d ult 
ne ur o ps yc h ol o gic o utc o me. J Pe diatr 1 2 4[ 3], 3 8 8- 3 9 2. 1 9 9 4.  
Sattler J. Assess me nt of C hil dre n, WI S C-I V a n d W P P SI-III S u p ple me nt, Sa n Die g o. Jer o me 
S. Sattler, I nc., 2 0 0 4. [ T his p u blic ati o n is a b o ok a n d t heref ore is n ot i ncl u de d i n t he 
s u b missi o n.] 
S hi nta k u H, K ure S, O h ura T, ka n o Y et. al. Di a g n osis a n d l o n g-ter m treat me nt of tetra h y dr o-
bi o pteri n-res p o nsi ve h y per p he n ylala ni ne nia wit h  a m uta nt p he n ylala ni ne h y dr o x ylase ge ne. J 
I n herit Meta b Dis 2 6[ S u p pl 2]. 2 0 0 3.  
S mit h, I, Beasle y, M. I ntelli ge nce a n d be ha vi o ur i n c hil dre n wit h earl y treate d 
p he n yl ket o n uria. A re p ort fr o m t he M R C/ D H S S p he n yl ket o n uria re gister. E ur J Cli n N utr 4 3 
S u p pl 1, 1- 5. 1 9 8 9.  
S paa pe n, LJ, R u bi o- G ozal b o, M E. Tetra h y dr o bi o pteri n-res p o nsi ve p he n ylala ni ne 
h y dr o x ylase deficie nc y, state of t he ar t. M ol Ge net Meta b 7 8[ 2], 9 3- 9 9. 2 0 0 3.  
Stei nfel d, R, K o hlsc h utter, A, Zsc h oc ke, J, Li n d ner, M et. al. Tetra h y dr o bi o pteri n 
m o n ot hera p y f or p he n yl ket o n uria patie nts w it h c o m m o n mil d m utati o ns. E ur J Pe diatr 
1 6 1[ 7], 4 0 3- 4 0 5. 2 0 0 2.  
Trefz, F K, A ulela- Sc h olz, C, Bla u, N. S u ccessf ul treat me nt of p he n yl ket o n uria wit h 
tetra h y dr o bi o pteri n. E ur J Pe diatr 1 6 0[ 5], 3 1 5. 2 0 0 1.  


 
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Pr o prietar y a n d C o nfi de ntial 
3 0 N o ve m ber 2 0 1 0 
Wec hsler D. Presc h o ol a n d Pri mar y Scale of I ntelli g nece ( W P P SI-III). T hir d e d. Sa n 
A nt o ni o: Ps yc h ol o gical C or p, 2 0 0 2. [ T his p u blic ati o n is a b o ok a n d t heref ore is n ot i ncl u de d 
i n t he s u b missi o n.] 
Wec hsler D. I ntelli ge nce Scale f or C hil dre n ( WI S C-I V). F o urt h e d. Sa n A nt o ni o: 
Ps yc h ol o gical C or p, 2 0 0 4. [ T his p u blic ati o n is a b o ok a n d t heref ore is n ot i ncl u de d i n t he 
s u b missi o n.] 
We gla ge, J, Gre nze bac h, M, Teeffele n- Heit h off, A, Mar q uar dt, T et. al . Tetra h y dr o bi o pteri n 
res p o nsi ve ness i n a lar ge series of p he n yl ket o n uria patie nt s. J I n herit Meta b Dis 2 5[ 4], 3 2 1-
3 2 2. 2 0 0 2.  
 
 


 
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Pr o prietar y a n d C o nfi de ntial 
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2 2  
I N V E S TI G A T O R R E S P O N SI BI LI TI E S 
2 2. 1  
C o n d uct of St u d y a n d Pr otecti o n of H u m a n S u bjects  
I n acc or da nce wit h F D A F or m 1 5 7 2, t he I n vesti gat or will e ns ure t hat: 
He or s he will c o n d uct t he st u d y i n acc or da nce wit h t he releva nt, c urre nt pr ot oc ol a n d 
will o nl y ma ke c ha n ges i n a pr ot oc ol after n otif yi n g t he s p o ns or, e xce pt w he n 
necessar y t o pr otect t he safet y, ri g hts, or welfare of s u bjects. 
He or s he will pers o nall y c o n d uct or s u per vise t he st u d y. 
He or s he will i nf or m a n y p ote ntial s u bjects, or a n y pers o ns use d as c o ntr ols, t hat t he 
dr u gs are bei n g use d f or i n vesti gati o nal p ur p oses a n d he or s he will e ns ure t hat t he 
re q uire me nts relati n g t o o btai ni n g i nf or me d c o nse nt i n 2 1 Part 5 0 a n d i nstit uti o nal 
re vie w b oar d (I R B) re vie w a n d a p pr o val i n 2 1 C F R Part 5 6 are met.  
He or s he will re p ort t o t he s p o ns or a d verse e x perie nces t hat occ ur i n t he c o urse of t he 
i n vesti gati o n i n acc or da nce wit h 2 1 C F R 3 1 2. 6 4. 
He or s he has rea d a n d u n dersta n ds t he i n f or mati o n i n t he I n vesti gat or’s Br oc h ure, 
i ncl u di n g p ote ntial ris ks an d si de effects of t he dr u g. 
His or her staff a n d all pers o ns w h o assist i n t he c o n d uct of t he st u d y are i nf or me d a b o ut 
t heir o bli gati o ns i n meeti n g t he a b o ve c o m mit me nts 
He or s he will e ns ure t hat a de q uate a n d acc urate rec or ds i n acc or da nce wit h 
2 1 C F R 3 1 2. 6 2 a n d t o ma ke t h ose rec or ds a v aila ble f or i ns pecti o n i n acc or da nce wit h 
2 1 C F R 3 1 2. 6 8. 
He or s he will e ns ure t hat t h e I R B/ E C c o m plies wit h t he re q uire me nts of 2 1 C F R Part 5 6, 
a n d ot her a p plica ble re g ulati o ns, a n d c o n d ucts i nitial a n d o n g oi n g re vie ws a n d 
a p pr o vals of t he st u d y. He or s he will als o e n s ure t hat a n y c ha n ge i n researc h acti vit y 
a n d all pr o ble ms i n v ol vi n g ris ks t o h u ma n s u bjects or ot hers are re p orte d t o t he 
I R B/ E C. A d diti o nall y, he or s he will n ot ma ke a n y c ha n ges i n t he researc h wit h o ut 
I R B/ E C a p pr o val, e xce pt w here necessar y t o eli mi nate a p pare nt i mme diate hazar ds t o 
h u ma n s u bjects. 
He or s he a grees t o c o m pl y wit h all ot he r re q uire me nts re gar di n g t he o bli gati o ns of 
cli nical I n vesti gat ors a n d all ot her perti ne nt re q uir e me nts i n 2 1 C F R Part 3 1 2. 



SAP_001.pdf: 
 
 
 
 
    
 
 
 
 
 
 
Official Title: A Phase 3b Open-Label Study to Evaluate the Effect of Kuvan® on Neurocognitive 
Function, Maintenance of Blood Phenylalanine Concentrations, Safety, and 
Population Pharmacokinetics in Young Children with Phenylketonuria 
 
NCT Number: NCT00838435 
 
Applicant/MAH: BioMarin Pharmaceutical Inc. 
 
Version Date: 26 April 2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PKU-015 7-year Neurocognitive 
Function
Page 1
Proprietary and Confidential
16.1.9 Documentation of Statistical Methods
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statistical-methods.pdf Page 1
































































Proprietary and Confidential
16.1.9.2 Errata Table
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statistical-methods.pdf Page 33
PKU-015 Final CSR
Page 33