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
Phase: PHASE3
Conditions: Phenylketonuria
Sponsor: BioMarin Pharmaceutical

 
 
 
 
    
 
 
 
 
 
 
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 

 
P K U- 0 1 5
 Pa ge 4 4
 
Pr o prietar y a n d C o nfi de ntial 
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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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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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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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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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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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) 

 
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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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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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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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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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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 
of a n y p ositi ve or e q ui v ocal uri ne pre g na nc y test res ult.) 

 
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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 
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•  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
 Pa ge
 
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. 

 
P K U- 0 1 5
 Pa ge
 
9 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 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
 Pa ge
 
9 4
 
 
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 

 
P K U- 0 1 5
 Pa ge
 
9 5
 
 
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
 Pa ge
 
9 6
 
 
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
 Pa ge
 
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
 Pa ge
 
9 8
 
 
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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9 9
 
 
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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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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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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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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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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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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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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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.