A Multicenter, Efficacy and Safety Study of Methotrexate to Increase Response Rates in Patients With Uncontrolled Gout Receiving KRYSTEXXA® (Pegloticase) (MIRROR Open-Label [OL])
Phase: PHASE4
Conditions: Gout
Sponsor: Amgen

 
 
Study: HZNP-KRY-201 
NCT#: 03635957 
TITLE: 
Protocol 
A Multicenter, Efficacy and Safety Study of Methotrexate to Increase Response Rates in Patients 
with Uncontrolled GOut Receiving 
KRYSTEXXA® (pegloticase) (MIRROR Open-Label [OL]) 
 
 
Date of Document: 
 
Protocol: 01 April 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
150 S. Saunders Road, Lake Forest, IL 60045 

H oriz o n T hera pe utics  Irela n d D A C  
  
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C LI NI C A L S T U D Y P R O T O C O L  
F O R K R Y S T E X X A  
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Versi o n 3. 0, A me n d me nt 2, A d mi nistr ati ve C h a n ge 1 
 
A M ultice nter, Effic ac y a n d S afet y St u d y of Met h otre x ate t o I ncre ase 
Res p o nse R ates i n P atie nts wit h  U nc o ntr olle d G O ut Recei vi n g 
K R Y S T E X X A ®  ( pe gl otic ase) ( MI R R O R O pe n- L a bel [ O L]) 
S h ort Title: MI R R O R O L 
 
Effecti ve D ate: 0 1 A pril 2 0 2 0 
 
S p o ns or: 
H oriz o n T her a pe utics Irel a n d D A C 
1 B urli n gt o n R o a d 
C o n n a u g ht H o use, 1 st Fl o or  
D u bli n Irel a n d  
D 0 4 C 5 Y 6 
 
 
 
T his pr ot oc ol is t he c o nfi de ntial i nf or mati o n of H oriz o n T hera pe utics Irela n d D A C a n d is i nte n de d s olel y f or t he g ui da nce of t he cli nical 
i n vesti gati o n. T his pr ot oc ol ma y n ot be discl ose d t o parties n ot ass ociate d wit h t he cli nical i n vesti gati o n or use d f or a n y p ur p ose wit h o ut t he 
pri or writte n c o nse nt of H oriz o n T hera pe utics Irela n d D A C. 
C O N FI D E N TI A L 
 

H oriz o n T hera pe utics  Irela n d D A C  
  
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P RI N CI P A L I N V E S TI G A T O R SI G N A T U R E P A G E  
 
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H Z N P- K R Y- 2 0 1    
Versi o n: 
3. 0, A me n d me nt 2, A d mi nistrati ve C ha n ge 1 
Pr ot oc ol Title:   
A M ultice nter, Effi cac y a n d Safet y St u d y of M et h otre x ate t o Increas e 
R es p o nse R at es i n Patie nts wit h U nc o ntr olle d G O ut R ecei vi n g 
K R Y S T E X X A ®  ( pe gl oticase) ( MI R R O R O pe n- La bel [ O L]) 
Versi o n Date:  
0 1 A pril 2 0 2 0 
I a gree t o c o n d uct t he st u d y acc or di n g t o t he pr ot oc ol na me d a b o v e. I f ull y u n dersta n d t hat a n y 
c ha n ges i nstit ute d b y t h e Pri nci pal I n v esti gat or wit h o ut pre vi o us disc ussi o n wit h t he S p o ns or 
c o nstit ute a vi olati o n of t he pr ot oc ol, u nless ne cessar y t o eli mi nate a n i m me diate hazar d t o t he 
safet y or well- bei n g of a s u bject. 
I ac k n o wle d ge t hat I h a v e rea d a n d u n dersta n d t he pr ot oc ol na me d a b o v e a n d a gree t o carr y o ut 
all of its ter ms i n acc or da nce wit h a p plica bl e re g ul ati o ns a n d la ws. 
I ass ure t hat t he st u d y dr u g s u p plie d b y t he S p o ns or will be use d o nl y as descri be d i n t he 
pr ot oc ol na me d a b o v e. 
Si g nat ure: 
 
 
 
 
 
 
 Na me  
St u d y C e nter  
A d dress  
Cit y State  C o u ntr y 
 
Date 
 
 
 
 

H oriz o n T hera pe utics  Irela n d D A C  
  
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Versi o n 3. 0, A d mi nistrati ve C ha n ge 1 
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Pa ge 5 of 1 2 9 
 
 
S U M M A R Y T A B L E O F C H A N G E S 
 
S U M M A R Y T A B L E O F C H A N G E S 
Pr ot oc ol V ersi o n 1. 0, Ori gi n al ( 2 7 J ul y 2 0 1 8) t o 
Pr ot oc ol V ersi o n 2. 0, A me n d me nt 1 ( 1 6 A u g ust 2 0 1 8) 
                                  Pr ot oc ol Versi o n 3. 0, A me n d me nt 2 ( 1 7 A pril 2 0 1 9) 
Pr ot oc ol V ersi o n 3. 0, A me n d me nt 2, A d mi nistr ati ve C h a n ge 1 ( 0 1 A pril 2 0 2 0) 
 
T he A d mi nistr ative C h a n ge  i n cl u des  t he re m ov al of t he Scie n tific A dvis ory C o m mittee a n d 
a n u p d ate t o t he Me dic al M o nit or i nf or m ati o n , S p o ns or e ntity a n d c o m p a ny n a m e c h a n ge, 
cl arific ati o n of A dverse Eve nt f oll o w- u p l a n g u a ge a n d s afety re p orti n g e- m ail, c orrecti o n of 
ty p o gr a p hic al err ors a n d c orrecti o ns a n d u p d ates t o refere nces s ecti o n . Tr ac k c h a n ges 
versi o n of t he Pr ot oc ol Versi o n 3. 0, A m e n d m e nt 2,  A d mi nistr ative C h a n ge 1 c a n be pr ovi de d 
o n re q uest.  
 

H oriz o n T hera pe utics Ir ela n d D A C
 
  
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2  
S Y N O P SI S 
Pr ot oc ol Title : A M ultice nter, Efficac y a n d Safet y St u d y of M et h otre xate t o Increase R es p o nse R ates i n 
P atie nts wit h U nc o ntr olle d G O ut R ecei vi n g K R Y S T E X X A ®  ( pe gl oticase) ( MI R R O R O pe n- La bel) 
Pr ot oc ol N u m ber: H Z N P- K R Y- 2 0 1  
P h ase : 4 
Pr ot oc ol Versi o n:  3. 0, A me n d me nt 2, A d mi nistrati ve 
C ha n ge 1  
 
Test Dr u gs: K R Y S T E X X A; met h otre xate ( M T X)  
I n dic ati o n: C hr o nic g o ut i n a d ult patie nts 
refract or y t o c o n ve nti o nal t her a p y 
N u m ber a n d C o u ntr y of St u d y Sites: A p pr o xi matel y 8 st u d y ce nters i n t he U nite d States  
O bjecti ves:   
T he o verall o bj ecti ve of t he st u d y is t o assess t he eff icac y, s afet y, t olera bilit y, a n d p har ma c o ki netics ( P K) of t he 
c o nc o mita nt use of pe gl oticas e wit h M T X t o e n ha nce t he res p o nse rate see n wit h pe gl otic ase al o ne i n a d ults 
wit h u nc o ntr olle d g o ut.   
Pri mar y O b j ecti ve 
T he pri mar y o bj ecti ve is t o esti mate t he res p o nse rate d u ri n g M o nt h 6 ( Wee ks 2 0, 2 2, a n d 2 4), as meas ure d b y 
t he s ustai ne d n or malizati o n of ser u m uric aci d (s U A) t o < 6 m g/ d L f or at least 8 0 % of t he ti me d uri n g M o nt h 6 
i n s u bj ects recei vi n g pe gl oticase wit h M T X. 
Sec o n dar y O bj ecti ves  
 
Esti mate t he res p o nse rate d uri n g M o nt h 3 ( Wee ks 1 0, 1 2 a n d 1 4), as meas ure d b y t he s ust ai ne d 
n or malizati o n of s U A t o < 6 m g/ d L f or at least 8 0 % of t he ti me d uri n g M o nt h 3 i n s u bj ects recei vi n g 
pe gl oticase wit h M T X. 
 
Esti mate t he o verall res p o nse rate, as meas ure d b y t he s ustai ne d n or malizati o n of s U A t o < 6 m g/ d L f or 
at least 8 0 % of t he ti me d uri n g M o nt h 3 ( Wee ks 1 0, 1 2 a n d 1 4) a n d M o nt h 6 ( Wee ks 2 0, 2 2 a n d 2 4) 
c o m bi ne d i n s u bj ects recei vi n g pe gl oticase wit h M T X. 
 
Esti mate t he 5 m g/ d L res p o ns e rate d uri n g M o nt h 3,  d uri n g M o nt h 6, a n d O verall ( M o nt hs 3 a n d 6 
c o m bi ne d), as meas ure d b y t he s ustai ne d n or malizati o n of s U A t o < 5 m g/ d L f or at least 8 0 % of t he 
ti me i n s u bj ects recei vi n g pe gl oticase wit h M T X. 
 
Esti mate t he mea n c ha n ge fr o m baseli ne t o Wee ks 1 4, 2 4, 3 6, a n d 5 2 i n s U A i n s u bj ects recei vi n g 
pe gl oticase wit h M T X. 
E x pl orat or y O bj ecti ves  
 
Esti mate t he res p o nse rate d uri n g M o nt h 9 ( Wee ks 3 2, 3 4 a n d 3 6), as meas ure d b y t he s ust ai ne d 
n or malizati o n of s U A t o < 6 m g/ d L f or at least 8 0 % of t he ti me d uri n g M o nt h 9 i n s u bj ects recei vi n g 
pe gl oticase wit h M T X. 
 
Esti mate t he res p o nse rate d uri n g M o nt h 1 2 ( Wee ks 4 8, 5 0 a n d 5 2), as meas ure d b y t he s ustai ne d 
n or malizati o n of s U A t o < 6 m g/ d L f or at least 8 0 % of t he ti me d uri n g M o nt h 1 2 i n s u bj ects recei vi n g 
pe gl oticase wit h M T X. 
 
Esti mate t he 5 m g/ d L res p o ns e rate d uri n g M o nt h 9 ( Wee ks 3 2, 3 4 a n d 3 6), as meas ure d b y t he 
s ustai ne d n or malizati o n of s U A t o < 5 m g/ d L f or at least 8 0 % of t he ti me d uri n g M o nt h 9 i n s u bj ects 
recei vi n g pe gl oticase wit h M T X. 
 
Esti mate t he 5 m g/ d L res p o ns e rate d uri n g M o nt h 1 2 ( Wee ks 4 8, 5 0 a n d 5 2), as meas ure d b y t he 
s ustai ne d n or malizati o n of s U A t o < 5 m g/ d L f or at least 8 0 % of t he ti me d uri n g M o nt h 1 2 i n s u bj ects 
recei vi n g pe gl oticase wit h M T X. 
 
Esti mate t he ti me t o first s U A > 6 m g/ d L i n  s u bj ects recei vi n g pe gl oticase wit h M T X. 
 
Esti mate t he ti me t o t w o c o ns ec uti ve s U As > 6 m g/ d L (st o p pi n g r ule) i n s u bj ects recei vi n g pe gl oticase 
wit h M T X. 

H oriz o n T hera pe utics Ir ela n d D A C
 
  
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Date: 0 1 A pril 2 0 2 0  
  
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Esti mate t he mea n c ha n ge fr o m baseli ne t o Wee k 2 4, 3 6 a n d 5 2 i n urate v ol u me a n d g o ut er osi o ns 
usi n g d ual-e ner g y c o m p ute d t o m o gra p h y ( D E C T) sca n of t he ha n ds a n d feet i n s u bj ects recei vi n g 
pe gl oticase wit h M T X. 
 
Esti mate t he mea n c ha n ge fr o m baseli ne i n n u m ber of  j oi nts affecte d b y t o p hi i n s u bj ects recei vi n g 
pe gl oticase wit h M T X. 
 
Esti mate t he mea n c ha n ge fr o m baseli ne t o We e ks 1 4, 2 4, 3 6, a n d 5 2 i n te n der j oi nt c o u nt ( 6 8- p oi nt 
scale) i n s u bj ects recei vi n g pe gl oticase wit h M T X. 
 
Esti mate t he mea n c ha n ge fr o m baseli ne t o Wee k s 1 4, 2 4, 3 6, a n d 5 2 i n s w olle n j oi nt c o u nt ( 6 6-p oi nt 
scale) i n s u bj ects recei vi n g pe gl oticase wit h M T X. 
 
Esti mate t he mea n c ha n ge fr o m baseli ne t o Wee k s 1 4, 2 4, 3 6, a n d 5 2 i n t he Healt h Assess me nt 
Q uesti o n naire –  Disa bilit y I n de x ( H A Q- DI) i n s u bj ects recei vi n g pe gl oticase wit h M T X 
 
Esti mate t he mea n c ha n ge fr o m baseli ne t o Wee ks 1 4, 2 4, 3 6, a n d 5 2 i n t he H A Q P ai n sc ore i n s u bj ects 
recei vi n g pe gl oticase wit h M T X. 
 
Esti mate t he mea n c ha n ge fr o m baseli ne t o Wee k s 1 4, 2 4, 3 6, a n d 5 2 i n t he H A Q Healt h s c ore i n 
s u bj ects recei vi n g pe gl oticase wit h M T X. 
 
Esti mate t he mea n c ha n ge fr o m baseli ne  t o Wee ks 1 4, 2 4, 3 6, a n d 5 2 i n patie nt gl o bal assess me nt of 
g o ut i n s u bj ects recei vi n g pe gl oticase wit h M T X. 
 
Esti mate t he mea n c ha n ge fr o m baseli ne t o Wee ks 1 4, 2 4, 3 6, a n d 5 2 i n p h ysicia n gl o bal assess me nt of 
g o ut i n s u bj ects recei vi n g pe gl oticase wit h M T X. 
 
Esti mate t he mea n c ha n ge fr o m baseli ne t o Wee ks 1 4, 2 4, 3 6, a n d 5 2 i n s u bj ect assess me nt of a vera ge, 
least, a n d w orst j oi nt p ai n i n s u bj ects recei vi n g pe gl oticase wit h M T X. 
 
Esti mate t he pr o p orti o n of s u bj ects ac hie vi n g 2 0 %, 5 0 %, or 7 0 % i m pr o ve me nt base d o n g o ut c hr o nic 
res p o nse criteria at W ee ks 1 4, 2 4, 3 6, a n d 5 2 i n s u bj ects recei vi n g pe gl oticase wit h M T X. 
 
Assess t he P K of pe gl oticase i n s u bj ects recei vi n g c o nc o mit a nt M T X 
 
Assess t he i nci de nce of a nti- P E G  a n d a nti- Uricase I g G a nti b o dies 
Safet y a n d T olera bilit y O bj ecti ves 
 
Assess t he i nci de nce of i nf usi o n reacti o ns (I Rs), a n a p h yla xis, g o ut flares, car di o vasc ular e ve nts, a n d 
t he a d verse e ve nt ( A E)/seri o us A E pr ofile o verall a n d p ote ntiall y attri b ute d t o t he c o m bi nati o n of 
pe gl oticase a n d M T X.  
St u d y Desi g n  
T his is a m ultice nter, o pe n-la b el, efficac y a n d safet y st u d y of pe gl oticase wit h M T X i n a d ult s u bj ects wit h 
u nc o ntr olle d  g o ut.  
T he st u d y desi g n will i ncl u de: 1) u p t o a 2- wee k Scre e ni n g P eri o d (scree ni n g s h o ul d be c o m plete wit hi n 2 
wee ks pri or t o W ee k - 4), 2) a 4- wee k M T X R u n-i n P eri o d; 3) a 5 2- wee k P e gl oticase + I M M ( P e gl oticase + 
M T X) P eri o d  4) a Safet y F oll o w- u p ( P h o ne/ E mail/ Site Visit) a n d 5) a 3 a n d 6 m o nt h P ost Treat me nt F oll o w -
u p.   
All s u bj ects w h o meet eli gi bilit y criteria at Scree ni n g will be gi n oral M T X at a d ose of 1 5 m g wee kl y f or 
4  wee ks pri or t o t he first d ose of pe gl oticase.  
S u bj ects will als o ta ke f olic aci d 1 m g orall y e ver y da y be gi n ni n g at Wee k - 4 (t he start of M T X) c o nti n ui n g u ntil 
pri or t o t he W ee k 5 2 Visit. S u bj ects m ust b e a ble t o t olerate M T X at a d ose of 1 5 m g d uri n g t he 4 wee k M T X 
R u n -i n P eri o d ( pri or t o Da y 1) t o be eli gi ble t o partici pate i n t he P e gl oticase + I M M P eri o d. S u bj ects w h o are 
u na ble t o t olerate M T X at a d ose of 1 5  m g d uri n g t he M T X R u n-i n P eri o d will be c o nsi dere d scree n fail ures. 
S u bj ects w h o ta ke at least o ne d ose of M T X a n d w h o are fe males of c hil d beari n g p ote ntial, will recei ve a safet y 
f oll o w- u p p h o ne call/e- mail a p pr o xi matel y 3 0 da ys after t he last d ose of M T X t o verif y at least o ne o v ulat or y 
c ycle has occ urre d after t he last  d ose of M T X.  If t he s u bj ect has n ot o v ulate d, a uri ne pre g na nc y test will be 
perf or me d. F or t h ose s u bj ects w h o ta ke at least o ne d ose of M T X a n d w h o are n o n- vasect o mize d males a n 
i n q uir y will be c o n d ucte d at t he P ost- Treat me nt 3 m o nt h f oll o w- u p visit ( or 3 m o nt hs after t he s u bj ect’s last 

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d ose of M T X) after M T X disc o nti n uati o n re gar di n g part ner pre g na nc y. 
All s u bj ects w h o c o m plete t he R u n -I n P eri o d will recei ve t he first pe gl oticase i nf usi o n o n Da y 1. All s u bse q ue nt 
d oses a n d st u d y visits will be sc he d ule d  base d o n t he Da y 1 visit date.  
It is req uire d t hat bef ore a s u bj ect b e gi ns t he P e gl otica se + I M M P eri o d, he or s he has bee n ta ki n g at least o ne 
pr ot oc ol sta n dar d g o ut flare pr o p h yla xis re gi me n ( i.e. c olc hi ci ne a n d/ or n o n-ster oi dal a nti-i nfla m mat or y dr u gs 
a n d/ or l o w- d ose pre d nis o ne ≤1 0 m g/ da y ) f or ≥1 wee k bef or e t he first d ose of pe gl oticase a n d c o nti n ues flare 
pr o p h yla xis per A merica n C olle ge of R he u mat ol o g y g ui deli nes [ K ha n na D et al. 2 0 1 2] f or t he greater of 1) 6 
m o nt hs, 2) 3 m o nt hs after ac hi e vi n g tar get ser u m urate (s U A < 6 m g/ d L) f or patie nts wit h n o t o p hi detecte d o n 
p h ysical e xa m, or 3) 6 m o nt hs after ac hie vi n g tar get ser u m urate (s U A < 5 m g/ d L) f or patie nts wit h o ne or m ore 
t o p hi d etecte d o n i nitial p h ysi cal e xa m t hat ha ve si nce res ol ve d. F or I R pr o p h yla xis, fe x ofe na di ne (6 0 m g or 1 8 0 
m g orall y base d o n t he Pri nci p al I n vesti gat or’s discreti o n ) will be ta ke n t he da y bef ore eac h i nf usi o n; 
fe x ofe na di ne (6 0 m g or 1 8 0 m g orall y base d o n t he Pri nci pal I n vesti gat or’s discreti o n ) a n d aceta mi n o p he n 
( 1 0 0 0 m g orall y) will be ta ke n t he m or ni n g of eac h i nf usi o n; a n d met h yl pre d nis ol o ne ( 1 2 5 m g I V) gi ve n o ver 
t he i nf usi o n d urati o n 1 0- 3 0 mi n utes (rec o m me n de d) or h y dr oc ortis o ne ( 2 0 0 m g I V) will b e a d mi nistere d 
i m me diatel y pri or t o eac h i nf usi o n.  
D uri n g t he P e gl oticase + I M M P eri o d, pe gl oticase 8 m g will be a d mi nistere d i ntra ve n o usl y (I V) e ver y 2 wee ks 
fr o m Da y 1 t hr o u g h t he W ee k 5 0 Visit f or a t otal of 2 6 i nf usi o ns; pe gl oticase will be a d mi nistere d after all pre-
d ose st u d y visit assess me nts ha ve bee n c o m plete d at eac h visit. T he date a n d start a n d st o p ti me of i nf usi o n will 
be rec or de d.  
D uri n g t he P e gl oticase + I M M P eri o d, s u bj ects will be i nstr ucte d t o ta ke M T X wee kl y o n t he sa me da y eac h 
wee k , wit hi n 1 t o 3 da ys pri or t o eac h pe gl oticase i nf usi o n a n d o ne a d diti o nal wee kl y d ose after t he last i nf usi o n 
f or s u bj ects w h o ha ve n ot st o p pe d pe gl oticase d ue t o s U A st o p pi n g r ules; h o we ver, if a s u bj ect d oes n ot d o s o, 
M T X  m ust b e ta ke n ≥6 0  mi n utes pri or t o eac h pe gl oticase i nf usi o n 
After Da y 1, i f a s u bj ect b ec o mes u na ble t o t olerate 1 5 m g of M T X, t he M T X d ose ma y be re d uce d a n d/ or 
disc o nti n ue d, a n d t he s u bj ect ma y re mai n i n t he st u d y . 
T he  I n vesti gat or will re vie w t he cli nical stat us a n d i n di vi d ual s u bj ect treat me nt g oals at Wee k 2 4, a n d t he E n d 
of  P e gl oticase I nf usi o ns Visit (if a pplica ble) a n d t he Wee k 5 2/ E n d of st u d y/ Earl y T er mi nati o n Visit.   
Sa m ples f or meas ure me nt of s U A le vels, P K a nal ysis of pe gl oticase, pe gl oticase i m m u n o ge nicit y a n d M T X 
P ol y gl uta mate  a nal ysis will be c ollecte d at visits i n dicate d i n t he Sc he d ule of Assess me nts (Secti o n 2. 1 ) 
Safet y assess me nts, i ncl u di n g m o nit ori n g a n d rec or di n g of all A Es, w het her or n ot dr u g -relate d, meas ure me nt of 
vital si g ns, p h ysical e xa mi nati o ns, a n d m o nit ori n g of he mat ol o g y a n d bl o o d c he mistr y, will be perf or me d.  
A n o ver vie w of t he st u d y desi g n is pres e nte d i n t he sc he matic bel o w, a n d details of st u d y acti vities are pr o vi de d 
i n Secti o n 2. 1 . 
St u d y Desi g n (c o nti n ue d): 

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S u bject P o p ul ati o n: 
S u bj ects eli gi ble f or t his  st u d y will ha ve s U A ≥6 m g/ d L  a n d a n i na bilit y t o mai ntai n s U A < 6 m g/ d L o n ot her 
urate -l o weri n g t hera p y, i nt oler a ble si de effects ass ociated wit h c urre nt urate-l o weri n g t hera p y, a n d/ or 
f u ncti o nall y li miti n g t o p hace o us de p osits (i ncl u di n g t h ose d etecte d clinicall y or b y D E C T i ma gi n g). 
I ncl usi o n Criteri a: 
Eli gi ble s u bj ects m ust meet/ pr o vi de all  of t he f oll o wi n g criteria: 
1.  Willi n g a n d a ble t o gi ve i nf or me d c o nse nt. 
2.  Willi n g a n d a ble t o c o m pl y wit h t he pres cri be d treat me nt pr ot oc ol a n d e val uati o ns, f or t he d urati o n of 
t he st u d y. 
3.  A d ult me n or w o me n ≥1 8 t o ≤6 5 years of a ge . 
4.  W o me n of c hil d beari n g p ote ntial (i ncl u di n g t h ose wit h a n o nset of me n o pa use < 2 years pri or t o 
scree ni n g, n o n-t hera p y-i n d uce d a me n orr hea f or < 1 2 m o nt hs pri or t o scree ni n g, or n ot s u r gi call y sterile 
[a bse nce of o varies a n d/ or uter us]) m ust ha ve ne gati ve ser u m/ uri ne pre g na nc y tests d uri n g t he 
Scree ni n g a n d M T X R u n- i n P eri o d; s u bj ects m ust a gree t o use 2 relia ble f or ms of c o ntrace pti o n d uri n g 
t he st u d y, o ne of w hic h is rec o m me n de d t o be h or m o nal, s uc h as a n oral c o ntrace pti ve. H or m o nal 
c o ntrace pti o n m ust b e starte d ≥1 f ull c ycle pri or t o Wee k -4 (start of M T X d osi n g) a n d c o nti n ue f or 
3 0 da ys after t he last d ose of pe gl oticase, or at leas t o ne o v ul at or y c ycle after t he last d ose of M T X 
( w hic he ver is t he l o n gest d urati o n after t he last d ose of pe gl oticase or M T X). Hi g hl y effecti ve 
c o ntrace pti ve met h o ds ( wit h a fail ure rate < 1 % per yea r), w he n use d c o nsiste ntl y a n d c orrectl y, i ncl u de 
i m pla nts, i nj ecta bles, c o m bi ne d oral c o ntrace pti ves, s o me i ntra uteri ne de vices, se x ual a bsti ne nce, or 
vasect o mize d part ner.  
5.  Me n w h o are n ot vasect o mize d m ust a gree t o n ot i m pre g nat e t heir fe male part ner d uri n g t he st u d y a n d 
f or at least 3 m o nt hs after t he l ast d ose of M T X. 
6.  H y per urice mia at t he Scree ni n g, W ee k - 4, or Wee k - 2 Visit of t he Scree ni n g or R u n-i n P eri o d, as 
d oc u me nte d b y s U A ≥6  m g/ d L. 
7.  U nc o ntr olle d g o ut, defi ne d as meeti n g t he f oll o wi n g criteria: 
 
s U A ≥6 m g/ d L  pri or t o e ntr y i nt o t he pe gl oticase +IM M P eri o d ( a n y la b orat or y tests d uri n g 
scree ni n g u p t o a n d i ncl u di n g d uri n g t he M T X R u n-i n P eri o d) a n d at least 1 of t he f oll o wi n g: 
o  
i na bilit y t o mai ntai n s U A < 6 m g/ d L o n ot her urate-l o weri n g t hera p y 
o  
i nt olera ble si de effects ass ociate d wit h c urre nt urate-l o weri n g t hera p y 
o  
f u ncti o nall y li miti n g t o p hace o us de p osits (i ncl u di n g t h ose d etecte d cli nicall y or b y D E C T 
i ma gi n g) 
8.  A ble t o t olerate M T X 1 5 m g f or 4 wee ks d uri n g t he M T X R u n-i n P eri o d pri or t o t he first d ose of 
pe gl oticase. 

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E xcl usi o n Criteri a: 
S u bj ects will be i neli gi ble f or st u d y partici pati o n if t he y meet a n y  of t he f oll o wi n g criteria: 
1.  Wei g ht > 1 6 0 k g ( 3 5 2 p o u n ds). 
2.  A n y seri o us ac ute bacterial i nfecti o n, u nless treate d a n d c o m pletel y res ol ve d wit h a nti bi oti cs at least 
2 wee ks pri or t o t he W ee k - 4 Vi sit of t he M T X R u n-i n P eri o d.  
3.  Se vere c hr o nic or rec urre nt b a cterial i nfecti o ns, s uc h as rec urre nt  p ne u m o nia or c hr o nic br o nc hiectasis. 
4.  C urre nt i m m u n oc o m pr o mise d c o n diti o n, i ncl u di n g c urre nt or c hr o nic treat me nt wit h s yste mic 
i m m u n os u p pressi ve a ge nts, i ncl u di n g pre d nis o ne > 1 0 m g/ da y or e q ui vale nt d ose of ot her 
c ortic oster oi d. 
5.  Hist or y of a n y tra ns pla nt s ur ger y re q uiri n g mai nte na nce i m m u n os u p pressi ve t hera p y. 
6.  K n o w n hist or y of he p atitis B vir us s urface a nti ge n p ositi vit y or he patitis B D N A p ositi vit y. 
7.  K n o w n hist or y of he p atitis C vir us R N A p ositi vit y. 
8.  H u ma n I m m u n o deficie nc y Vir us ( HI V) p ositi vit y (teste d at Scree ni n g Visit). 
9.  Gl uc ose- 6- p h os p hate de h y dr o ge nase deficie nc y (teste d at t he Scree ni n g Visit). 
1 0.  Se vere c hr o nic re nal i m pair me nt ( gl o me r ular filtrati o n rate < 2 5 m L/ mi n/ 1. 7 3 m2) or c urre ntl y o n 
dial ysis. 
1 1.  N o n-c o m pe nsate d c o n gesti ve heart fail ure or h os pitalizati o n f or c o n gesti ve heart fail ure wit hi n 
3 m o nt hs of t he Scree ni n g Visit, u nc o ntr olle d ar r h yt h mia, treat me nt f or ac ute c or o nar y s y n dr o me 
( m y ocar dial i nfarcti o n or u nst a ble a n gi na), or u nc o ntr olle d bl o o d press ure ( > 1 6 0/ 1 0 0 m m H g) at t he e n d 
of t he Scr ee ni n g a n d M T X R u n-i n P eri o d. 
1 2.  Pre g na nt, pla n ni n g t o bec o me pre g na nt, breastfe e di n g, pla n ni n g t o i m pre g nate fe male part ner, or n ot o n 
a n effecti ve f or m of birt h c o ntr ol,  as deter mi ne d b y t he I n vesti gat or. 
1 3.  Pri or treat me nt wit h pe gl oticase ( K R Y S T E X X A ®), a n ot her rec o m bi na nt uricase (ras b uric ase), or 
c o nc o mita nt t hera p y wit h a p ol yet h yle ne gl yc ol-c o nj u gate d dr u g. 
1 4.  K n o w n aller g y t o pe g ylate d pr o d ucts or hist or y of a na p h ylactic reacti o n t o a rec o m bi na nt pr otei n or 
p orci ne pr o d uct. 
1 5.  C o ntrai n dicati o n t o M T X treat me nt or M T X treat me nt c o nsi dere d i na p pr o priate. 
1 6.  K n o w n i nt olera nce t o M T X. 
1 7.  Recei pt of a n i n vesti gati o nal dr u g wit hi n 4 wee ks or 5 half- li ves, w hic he ver is l o n ger, pri or t o M T X 
a d mi nistrati o n at W ee k - 4 or pla ns t o ta ke  a n i n vesti gati o nal dr u g d uri n g t he st u d y. 
1 8.  C urre nt li ver disease, as deter mi ne d b y ala ni ne tra nsa mi nas e or as partate tra nsa mi nase le vels > 3 ti mes 
u p per li mit of n or mal at t he Scree ni n g Visit. 
1 9.  C urre ntl y recei vi n g s yste mic or ra di ol o gic treat me nt f or o n g oi n g ca ncer, e xcl u di n g n o n- mela n o ma s ki n 
ca ncer. 
2 0.  Hist or y of mali g na nc y wit hi n 5 years ot her t ha n n o n- mela n o ma s ki n ca ncer or i n sit u carci n o ma of 
cer vi x. 
2 1.  U nc o ntr olle d h y per gl yce mia wit h a plas ma gl uc ose val ue > 2 4 0 m g/ d L at scree ni n g t hat is n ot 
s u bse q ue ntl y c o ntr olle d b y t he e n d of t he Scree ni n g/ M T X R u n-i n P eri o d. 
2 2.  Dia g n osis of oste o m yelitis. 
2 3.  K n o w n hist or y of h y p o xa nt hi ne- g ua ni ne p h os p h ori b os yl-tra nsferase deficie nc y, s uc h as Lesc h- N y ha n 
a n d Kelle y- See g miller s y n dr o me. 
2 4.  U ns uita ble ca n di date f or t he st u d y, base d o n t he o pi ni o n of t he I n vesti gat or (e. g., c o g niti ve 
i m pair me nt), s uc h t hat partici pati o n mi g ht create u n d ue ris k t o t h e s u bj ect or i nterfere wit h t he 
s u bj ect’s a bilit y t o c o m pl y wit h t he pr ot oc ol re q uire me nts or c o m plete t he st u d y . 
2 5.  Alc o h ol use i n e xcess of 3 alc o h olic be vera ges per wee k. 
2 6.  C urre ntl y recei vi n g all o p uri n ol a n d u na ble t o disc o nti n ue me dicati o n 7 da ys pri or t o M T X d osi n g at 
W ee k - 4 a n d u na ble t o disc o nti n ue treat me nt d uri n g t he d urati o n of t he st u d y.  

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D ose Re gi me n/ R o ute of A d mi nistr ati o n: 
M T X:  
D uri n g t he M T X R u n -i n P eri o d, w hic h be gi ns 4 wee ks pri or t o t he first d ose of pe gl oticase, s u bj ects will ta ke 
oral  M T X at a d ose of 1 5 m g wee kl y.  
S u bj ects will be i nstr ucte d t o t a ke M T X wee kl y o n t he sa me da y eac h wee k (if d osi n g m or e fre q ue ntl y t ha n 
o nce i n a da y (ie. BI D, TI D), t he t otal M T X d ose s h o ul d be ta ke n wit hi n 2 4 h o urs, prefera bl y t he sa me cale n dar 
da y) a n d rec or d t he date a n d ti me of eac h  d ose i n t he d osi n g cale n dar.  
D uri n g t he M T X R u n -i n P eri o d, if a d ose is misse d, it s h o ul d be ta ke n as s o o n as it is re me m bere d. If it is wit hi n 
4 8  h o urs of t he ne xt sc he d ule d d ose, t he s u bj ect will be i nstr ucte d t o s ki p t he misse d d ose a n d res u me at t he ne xt 
re g ularl y sc he d ule d ti me; t h us, s u bj ects will be i nstr ucte d n ot t o d o u ble a d ose t o ma ke u p f or a misse d d ose if 
wit hi n 4 8 h o urs of t he ne xt d ose.  I n vesti gat ors ma y c h o ose t o ha ve s ubj ects ta ke t he wee kl y d ose di vi de d o ver 
t he da y (ie. BI D, TI D). T he t otal M T X d ose s h o ul d be ta ke n wit hi n 2 4 h o urs, prefera bl y t he sa me cale n dar da y 
eac h wee k, wit h t he date a n d ti me of eac h M T X d ose rec or de d i n t he d osi n g cale n dar. 
D uri n g t he P e gl oticase + I M M P eri o d, M T X s h o ul d be ta ke n 1 t o 3 da ys pri or t o t he pe gl oticase i nf usi o n a n d 
o ne a d diti o nal wee kl y d ose  after t he last i nf usi o n (at We e k 5 1) f or s u bj ects w h o ha ve n ot st o p pe d pe gl oticase 
d ue t o s U A st o p pi n g r ules.  If a s u bj ect is n ot a ble t o ta ke t he M T X 1 t o 3 da ys pri or t o t he p e gl oticase i nf usi o n, 
M T X m ust b e ta ke n ≥6 0  mi n utes pri or t o t he pe gl oticase i nf usi o n. 
D uri n g t he P e gl oticase + I M M P eri o d, if  a s u bj ect bec o mes u na ble t o t olerate t he M T X t he d osa ge ma y be 
decrease d . 
S u bj ects will als o ta ke f olic aci d 1 m g orall y e ver y da y be gi n ni n g at Wee k - 4 (t he start of M T X) u ntil pri or t o 
t he W ee k 5 2 Visit. 
Pe gl otic ase : 
All s u bj ects w h o meet t he i ncl usi o n/e xcl usi o n criteria a n d t olerate oral M T X 1 5 m g wee kl y d uri n g t he M T X 
R u n -i n P eri o d will recei ve pe gl oticase at a d ose of 8 m g a d mi nistere d I V e ver y 2 wee ks f or a t otal of 2 6 
i nf usi o ns fr o m Da y 1 t hr o u g h Wee k 5 0 Visit, i ncl usi ve ( P e gl oticase + I M M P eri o d). T he date a n d start a n d st o p 
ti me of i nf usi o n will be rec or de d. S u bj ects will n ot be fasti n g o n t he da y of i nf usi o n a n d will be e nc o ura ge d t o 
ha ve a s nac k or n or mal meal b ef ore or after t he i nf u si o n. All s u bj ects will recei ve sta n dar di ze d pr o p h ylactic 
treat me nt t o re d uce t he ris k of ac ute g o ut flares, be gi n ni n g ≥1  wee k bef ore t he first d ose of pe gl oticase a n d 
c o nti n ues flare pr o p h yla xis  per A merica n C olle ge of R he u mat ol o g y g u i deli nes [ K ha n na D et al. 2 0 1 2] f or t he 
greater of 1) 6 m o nt hs, 2) 3 m o nt hs after ac hie vi n g tar get ser u m urate (s U A < 6 m g/ d L) f or patie nts wit h n o 
t o p hi d etecte d o n p h ysical e xa m, or 3) 6 m o nt hs after ac hie vi n g tar g et ser u m urate (s U A < 5 m g/ d L) f or patie nts 
wit h o ne or m ore t o p hi d etecte d o n i nitial p h ysical e xa m t h at ha ve si nce res ol ve d.  Sta n dar dize d I R pr o p h yla xis 
c o nsisti n g of pre -treat me nt wit h a nti hista mi nes, aceta mi n o p he n a n d c ortic oster oi ds will ac c o m pa n y ea c h 
i nf usi o n. 
D os a ge F or m a n d Stre n gt h F or m ul ati o n ( Pe gl otic ase a n d M T X): 
P e gl oticase ( K R Y S T E X X A) is c o m merciall y a vaila ble i n t he U nite d  States a n d will be pac ka ge d i n sterile, 
si n gle- use 2- m L glass vials wit h a T efl o n® -c oate d (late x-free) r u b ber i nj ecti o n st o p per t o deli ver pe gl oticase as 8 
m g of uricase pr otei n i n 1 m L v ol u me . P e gl oticase will be a d mi nistere d as a n a d mi xt ure of 8 m g i n 2 5 0 m L of 
0. 4 5 % or 0. 9 %  S o di u m C hl ori de I nj ecti o n, U nite d States P har mac o peia ( U S P) for I V i nf usi o n b y gra vit y fee d or 
i nf usi o n p u m p. P e gl oticase will n ot b e a d mi nistere d as a n I V p us h or b ol us. 
M T X  2. 5 m g ta blets f or oral a d mi nistrati o n will be pr o vi de d t o s u bj ects as a c o m merciall y a vaila ble ge neric. 
D ur ati o n of Tre at me nt a n d F oll o w- u p: 
Scree ni n g: C o m plete d wit hi n 2 wee ks pri or t o t he Wee k - 4 visit   
M T X R u n-i n Peri o d ( Wee k - 4 t hr o u g h D a y 1):  I ncl u des 4 wee ks of M T X wee kl y d osi n g 
Pe gl otic ase + I M M Peri o d ( D a y 1 t hr o u g h Wee k 5 2) : M T X d ose d wee kl y a n d 5 0 wee ks of pe gl oticase 
i nf usi o ns visits e ver y 2 wee ks); N o n-i nf usi o n visits at Wee ks 1, 7 a n d 5 2. 

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E n d of Pe gl otic ase I nf usi o ns Visit (if a p plic a ble) : If t he s u bj ect disc o nti n ues pe gl oticase treat me nt pri or t o 
i nf usi o n W ee k 5 0, s uc h as d ue t o t he s U A st o p pi n g r ules, t he s u bj ect will c o m plete t his visit wit hi n 
a p pr o xi matel y 2 wee ks of t he last i nf usi o n.  S u bj ects will c o nti n ue st u d y. 
Wee k 5 2/ E n d- of-st u d y/ E arl y Ter mi n ati o n Visit:  Wee k 5 2 or earlier if t he s u bj ect wit h dr a ws c o nse nt t o 
partici pate i n t he st u d y. 
S afet y F oll o w- u p Visits:  All s u bj ects will recei ve a safet y f oll o w- u p p h o ne call/e- mail/ visit ap pr o xi matel y 3 0 
da ys after t he last d ose of pe gl oticase/ M T X t o assess if a n y S A E’s ha ve occ urred .  S u bj ects w h o recei ve at 
least o ne d ose of M T X a n d are fe males of c hil d beari n g p ote ntial, will recei ve a safet y f oll o w- u p p h o ne call/e-
mail/ Site Visit a p pr o xi matel y 3 0 da ys after t he last d ose of M T X t o verif y at least o ne o v ulat or y c ycle has 
occ urre d after t he last d ose of M T X.  If t he s u bj ect has n ot o v ulate d, a uri ne pre g na nc y test will be perf or me d. 
S u bj ects w h o recei ve at least o ne d os e of M T X a n d are n o n- vasect o mize d males, a p h o ne/ e- mail/ Site Visit  
i n q uir y will be c o n d ucte d 3 m o nt hs after M T X disc o nti n uati o n  re gar di n g part ner pre g nanc y (i n q uir y ca n occ ur 
d uri n g t he 3 m o nt h P ost Treat me nt F oll o w- u p). 
3 a n d 6 M o nt h P ost Tre at me nt F oll o w- u p Visits:  All s u bj ects will be f oll o we d f or a mi ni m u m of 6 m o nt hs 
f oll o wi n g t he last i nf usi o n, wit h f oll o w- u p after Wee k 5 2 as warra nte d.  
Criteri a f or E v al u ati o n: 
Efficac y will be assesse d b y s U A le vels, te n der a n d s w olle n j oi nt c o u nts, patie nt a n d p h ysi cia n gl o bal 
assess me nts of g o ut, j oi nt p ai n, a n d D E C T.  
Q ualit y of life will b e assesse d usi n g t he H A Q. 
T he P K  of pe gl oticase a n d pe gl oticase i m m u n o ge nicit y as assesse d b y t he i nci de nce of a nti- P E G a n d 
a nti - uricase I g G a nti b o dies will be assesse d at s pecifie d ti me p oi nts.  
Safet y assess me nts will i ncl u d e m o nit ori n g a n d re c or di n g of all A Es, w het her or n ot dr u g-relate d , meas ure me nt 
of vital si g ns, p h ysical e xa mi nati o ns, a n d m o n it ori n g of he mat ol o g y a n d bl o o d c he mistr y.  
St o p pi n g R ules: 
I n di vi d u al S u bject St o p pi n g R ule: 
S u bj ects wit h  a n s U A le vel > 6 m g/ d L at 2 c o nsec uti ve st u d y visits be gi n ni n g wit h t he Wee k 2 Visit ( n ot 
i ncl u di n g p ost-i nf usi o n sa m pl es) will disc o nti n ue treat me nt a n d re mai n i n t he st u d y. 

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St atistic al A n al yses:   
Pri mar y Efficac y E n d p oi nt  
T he pri mar y efficac y e n d p oi nt is t he pr o p orti o n of M o nt h 6 ( Wee ks 2 0, 2 2, a n d 2 4) res p o n ders, defi ne d as 
s u bj ects ac hie vi n g a n d mai ntai ni n g s U A < 6 m g/ d L f or at least 8 0 % of t he ti me d uri n g M o nt h 6. 
Sec o n dar y Efficac y E n d p oi nts  
 
T he pr o p orti o n of M o nt h 3 ( W ee ks 1 0, 1 2, a n d 1 4) res p o n ders, defi ne d as s u bj ects ac hie vi n g a n d 
mai ntai ni n g s U A < 6 m g/ d L f or at least 8 0 % of t he ti me d uri n g M o nt h 3. 
 
T he pr o p orti o n of o verall res p o n ders, defi ne d as s u bj ects ac hie vi n g a n d mai ntai ni n g s U A < 6 m g/ d L f or 
at least 8 0 % of t he ti me d uri n g M o nt h 3 ( Wee ks  1 0, 1 2 a n d 1 4) a n d M o nt h 6 ( Wee ks 2 0, 2 2 an d 2 4) 
c o m bi ne d 
 
T he pr o p orti o n of 5 m g/ d L res p o n ders d uri n g M o nt h 3, M o nt h 6, a n d o verall ( M o nt hs 3 a n d 6 
c o m bi ne d), defi ne d as s u bj ects ac hie vi n g a n d mai ntai ni n g s U A < 5 m g/ d L f or at least 8 0 % of t he ti me 
d uri n g eac h ti me p oi nt. 
 
T he mea n c ha n ge fr o m baseli ne t o Wee ks 1 4, 2 4, 3 6, a n d 5 2 i n s U A. 
E x pl orat or y Efficac y E n d p oi nts  
 
T he pr o p orti o n of M o nt h 9 ( Wee ks 3 2, 3 4 a n d 3 6) res p o n ders, defi ne d as s u bj ects ac hie vi n g a n d 
mai ntai ni n g s U A < 6 m g/ d L f or at least 8 0 % of t he ti me d uri n g M o nt h 9. 
 
T he pr o p orti o n of M o nt h 1 2 ( W ee ks 4 8, 5 0 a n d 5 2) res p o n ders, defi ne d as s u bj ects ac hie vi n g a n d 
mai ntai ni n g s U A < 6 m g/ d L f or at least 8 0 % of t he ti me d uri n g M o nt h 1 2. 
 
T he pr o p orti o n of M o nt h 9 ( Wee ks 3 2, 3 4 a n d 3 6) 5 m g/ d L res p o n ders, defi ne d as s u bj ects ac hie vi n g 
a n d mai ntai ni n g s U A < 5 m g/ d L f or at least 8 0 % of t he ti me d uri n g M o nt h 9. 
 
T he pr o p orti o n of M o nt h 1 2 ( W ee ks 4 8, 5 0 a n d 5 2) 5 m g/ d L res p o n ders, defi ne d as s u bj ects ac hie vi n g 
a n d mai ntai ni n g s U A < 5 m g/ d L f or at least 8 0 % of t he ti me d uri n g M o nt h 1 2. 
 
T he ti me t o first s U A > 6 m g/ d L. 
 
T he ti me t o t w o c o nsec uti ve s U As > 6 m g/ d L (st o p pi n g  r ule) i n s u bj ects recei vi n g pe gl otic ase wit h 
M T X. 
 
T he mea n c ha n ge fr o m baseli ne t o Wee ks 2 4, 3 6, a n d 5 2 i n urate v ol u me a n d b o ne er osi o ns d ue t o g o ut 
usi n g D E C T. 
 
T he mea n c ha n ge fr o m baseli ne i n n u m ber of j oi nts affecte d b y t o p hi. 
 
T he mea n c ha n ge fr o m baseli ne t o Wee ks 1 4, 2 4, 3 6,  a n d 5 2 i n te n der j oi nt c o u nt ( 6 8- p oi nt scale). 
 
T he mea n c ha n ge fr o m baseli ne t o Wee ks 1 4, 2 4, 3 6, a n d 5 2 i n s w olle n j oi nt c o u nt ( 6 6- p oi nt scale). 
 
T he mea n c ha n ge fr o m baseli ne t o Wee ks 1 4, 2 4, 3 6, a n d 5 2 i n H A Q- DI. 
 
T he mea n c ha n ge fr o m baseli ne t o Wee ks 1 4, 2 4, 3 6, a n d 5 2 i n H A Q P ai n sc ore. 
 
T he mea n c ha n ge fr o m baseli ne t o Wee ks 1 4, 2 4, 3 6, a n d 5 2 i n H A Q Healt h sc ore. 
 
T he mea n c ha n ge fr o m baseli ne t o Wee ks 1 4, 2 4, 3 6, a n d 5 2 i n patie nt gl o bal assess me nt of g o ut. 
 
T he mea n c ha n ge fr o m baseli ne t o Wee ks 1 4, 2 4, 3 6, a n d 5 2 i n p h ysicia n gl o bal assess me nt of g o ut. 
 
T he mea n c ha n ge fr o m baseli ne t o Wee ks 1 4, 2 4, 3 6, a n d 5 2 i n s u bj ect as sess me nt of a vera ge, least, 
a n d w orst j oi nt p ai n. 
 
T he pr o p orti o n of s u bj ects ac hie vi n g 2 0 %, 5 0 %, or 7 0 % i m pr o ve me nt base d o n g o ut c hr o nic res p o nse 
criteria at Wee ks 1 4, 2 4, 3 6, a n d 5 2. 
  
P har mac o ki netic a n d A nti - dr u g A nti b o d y E n d p oi nts 
 
P K of pe gl oticase. 
 
I nci de nce of a nti- P E G a n d a nti- Uricase I g G a nti b o dies. 

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Safet y a n d T olera bilit y E n d p oi nts 
 
I nci de nce of I Rs, a na p h yla xis, g out flares, car di o vasc ular e ve nts, a n d t he A E/seri o us A E pr ofile 
Statistical A nal ysis o n Efficac y P ara meters 
T he efficac y a nal ysis will b e perf or me d usi n g t he m o difie d i nte nti o n-t o-treat ( mI T T) p o p ulati o n, defi ne d as all 
e nr olle d s u bj ects w h o recei ve d ≥1 d ose of pe gl oticase. T he pr o p orti o n of M o nt h 6 res p o n ders will be 
s u m marize d, al o n g wit h a 9 5 % c o nfi de nce i nter val f or t he pr o p orti o n. T he pr o p orti o n of M o nt h 3 a n d o verall 
( M o nt hs 3 a n d 6 c o m bi ne d) res p o n ders will be a nal yze d si milarl y. 
A s u bj ect will b e declare d a n o n -res p o n der if t he s u bj ect ha d s U A le vel > 6 m g/ d L at 2 c o nsec uti ve st u d y visits 
be gi n ni n g wit h t he W ee k 2 Visit. I n a d diti o n, a s u bj ect w h o wit h dra ws fr o m st u d y treat me nt f or a n y reas o n after 
t he first d ose of pe gl oticase i n t he P e gl oticase + I M M P eri o d a n d pri or t o M o nt h 6 (f or t he pri mar y e n d p oi nt) or 
M o nt h 3 (f or t he sec o n dar y e n d p oi nt) will be c o nsi dere d a n o n-res p o n der if s U A val ues are n ot c ollecte d at t he 
pla n ne d ti me p oi nts . 
S w olle n/te n der j oi nt c o u nts, H A Q sc ores, patie nt a n d p h ysici a n gl o bal assess me nt sc ores, s u bj ect assess me nt of 
j oi nt p ai n sc ores, a n d mea n s U A c ha n ges fr o m baseli ne a n d val ues at baseli ne a n d eac h visit will be s u m marize d 
wit h descri pti ve statistics. T he pr o p orti o n of s u bj ects  ac hie vi n g 2 0 %, 5 0 %, or 7 0 % i m pr o ve me nt base d o n g o ut 
c hr o nic res p o nse criteria will b e s u m marize d. F or s u bj ects wit h D E C T sca ns, c ha n ges fr o m baseli ne a n d val ues 
at W ee ks 2 4, 3 6 a n d 5 2 f or urate v ol u me will be  s u m marize d wit h descri pti ve statistics. 
S a m ple Size Esti m ate : 
A sa m ple size of a p pr o xi matel y 1 2- 1 6 s u bj ects is pla n ne d f or t his st u d y. T he pri mar y effic ac y e n d p oi nt, t he 
pr o p orti o n of s u bj ects ac hie vi n g a n d mai ntai ni n g s U A < 6 m g/ d L f or at least 8 0 % of t he ti me d uri n g M o nt h 6 
( Wee ks 2 0, 2 2, a n d 2 4) of t he P e gl oticase + I M M P eri o d, will be de m o nstrate d t o  be statisticall y greater t ha n 
4 3. 5 % ( pr o p orti o n of res p o n ders d uri n g M o nt h 6 i n p hase 3 st u di es) , acc or di n g t o a e xact t est f or pr o p orti o ns 
wit h a 5 %  t y pe I err or, if at least 1 0/ 1 3 ( 7 7 %) res p o n ders are o bser ve d; i n t hat case, t he l o wer b o u n d of a 
9 5 %  c o nfi de nce i nter val f or t he pr o p orti o n of res p o n ders will be a b o ut 4 6 %.  

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8.  
Heart rate a n d bl o o d press ure meas ure me nts s h o ul d be ta ke n after t he s u bject has bee n i n a sitti n g p ositi o n a n d i n a reste d a n d cal m state f or at least 5 mi n utes a n d, f or st u d y 
visits d uri n g t h e P e gl oticase + I M M P eri o d, bef ore t h e pe gl oti case i nf usi o n a n d a n y ti me after t he e n d of t h e i nf usi o n, b ut p ri or t o s u bject’s disc har ge/releas e fr o m t h e site. 
Wei g ht s h o ul d be meas ure d i n kil o gra ms or p o u n ds wit h o ut s h oes a n d rec or de d at Scree ni n g Visit; pri or t o pe gl oticase i nf usi o ns o n Da y 1 a n d at t h e Wee k 8, 1 6, 2 4, 3 6, t he 
E n d of P e gl oticase Tre at me nt, at t h e Wee k 5 2/ E n d- of-st u d y/ Earl y  Ter mi nati o n Visit a n d t h e P ost Treat me nt 3 a n d 6 m o nt h f oll o w- up visits. Hei g ht will be c ollecte d at t h e 
Scree ni n g Visit o nl y. 
9.  
Electr o car di o gra m s h o ul d be c o m plete d pri or t o t he pe gl oticase i nf usi o n at Da y 1 Visit. 
1 0.  A Es/ S A Es will be c ollecte d fr o m si g nat ure of t h e I C F. Seri o us A Es will be ca pt ure d/ m o nit ore d at t he Safet y F oll o w- u p P h o ne/ E mail/ Site Visit 3 0 da ys after t he last d ose of 
M T X.  At t he Safet y F oll o w- u p P h o ne/ E mail/ Site Visit, fe males of  c hil d beari n g p ote ntial will be as ke d t o c o nfir m if o v ulati o n h as occ urre d si nce t he last d ose of M T X.  If t he 
s u bject ha d n ot o v ulate d, a uri ne pre g na nc y test will be re q uire d. A Es/ S A Es will c ollecte d u ntil t h e 6 m o nt h P ost Treat me nt F oll o w- u p Visit.  F or eac h A E, I n vesti gat ors will 
be rec or d if t h e e ve nt was p ossi bl y a n i nf usi o n reacti o n or a na p h yla xis a n d if s o, will be pr o m pte d t o c o m plete a d diti o nal C R Fs .    
1 1.  F or sites wit h D E C T ca pa bilit y, D E C T will be o btai ne d at Da y 1 a n d Wee ks 1 4, 2 4 a n d t he E n d of Pe gl oticase I nf usi o ns Visit (if a p plica ble) a n d Wee k 5 2/ E n d of St u d y/ Earl y 
Ter mi n ati o n.  T he D E C T ma y be c o m plete d wit hi n +/- 5 da ys of t h e sc he d ule d ti me p oi nt. S u bjects w h o e n d pe gl oticase i nf usi o ns pr i or t o Wee k 5 2 s h o ul d f oll o w t h e 
sc he d ule d ti me p oi nts b ut a v oi d a re peat D E C T sca n wit hi n 6 wee ks of a pri or sca n. 
1 2.  M T X will be dis pe nse d a n d br o u g ht bac k at eac h visit t o c hec k  c o m plia nce. If s u bjects re q uire a M T X d ose re d ucti o n, t he I n vesti gat or will prescri b e t h e s u bject t he n u m ber of 
ta blets t o ta ke wee kl y.  T he u p date d n u m ber of ta blets al o n g wit h t h e date a n d ti me of eac h M T X d ose s h o ul d be rec or de d i n t he d osi n g cale n dar. 
1 3.  M T X s h o ul d be ta ke n 1 t o 3 da ys pri or t o pe gl oticase i nf usi o n; h o we ver, if a s u bject d oes n ot d o s o, M T X m ust b e ta ke n ≥6 0 mi n utes pri or t o pe gl oticase i nf usi o n. 
1 4.  F or g o ut pr o p h yla xis, s u bjects are re q uire d t o ta ke at least o ne pr ot oc ol sta n dar d g o ut flare pr o p h yla xis re gi me n (i.e. c ol c hici ne a n d/ or n o n-ster oi dal a nti-i nfla m mat or y dr u gs 
a n d/ or l o w- d ose pre d nis o ne ≤1 0 m g/ d a y) f or ≥1 wee k bef ore t h e first d ose of pe gl oticase a n d c o nti n ues flare  pr o p h yla xis per A merica n C olle ge of R he u mat ol o g y g ui d eli nes 
[ K ha n na D et al. 2 0 1 2] f or t h e greater of 1) 6 m o nt hs, 2) 3 m o nt hs after ac hie vi n g tar get ser u m urate (s U A < 6 m g/ d L) f or pati e nts wit h n o t o p hi detecte d o n p h ysical e xa m, or 
3) 6 m o nt hs after ac hie vi n g tar get ser u m urate (s U A < 5 m g/ d L) f or patie nts wit h o ne or m ore t o p hi detecte d o n i nitial p h ysical  e xa m t hat ha ve si n ce res ol ve d. F or I R 
pr o p h yla xis, fe x ofe na di ne ( 6 0 m g or 1 8 0 m g orall y base d o n t he Pri nci pal I n vesti gat or’s discreti o n ) will be ta ke n t h e da y bef ore ea c h i nf usi o n; fe x ofe na di ne ( 6 0 m g or 1 8 0 
m g orall y base d o n t h e Pri nci pal I n vesti gat or’s discreti o n ) a n d aceta mi n o p he n ( 1 0 0 0 m g orall y) will be ta ke n t h e m or ni n g of eac h i nf usi o n; a n d met h yl pre d nis ol o ne ( 1 2 5 m g 
I V) gi ve n o ver t h e i nf usi o n d urati o n 1 0- 3 0 mi n utes (rec o m me n de d) or h y dr oc ortis o ne ( 2 0 0 m g I V) will be a d mi nistere d i m me diatel y pri or t o eac h i nf usi o n. gi ve n o ver t he 
i nf usi o n d urati o n 1 0- 3 0 mi n utes will be a d mi nistere d i m me diatel y pri or t o eac h i nf usi o n.  
1 5.  F or  I R  pr o p h yla xis,  fe x ofe na di n e  ( 6 0 m g or 1 8 0 m g orall y base d o n t h e Pri nci pal I n vesti gat or’s discreti o n ) will be ta ke n t he da y bef or e eac h i nf usi o n. 
1 6.  S u bjects will ta ke f olic aci d 1 m g orall y e ver y da y be gi n ni n g at We e k - 4 (t h e start of M T X) u ntil pri or t o t he Wee k 5 2/ E n d of St u d y/ Earl y Ter mi n ati o n Visit d uri n g t he 
P e gl oticase + I M M P eri o d. 
1 7.  I nf usi o n reacti o n pr o p h yla xis i ncl u des fe x ofe na di n e ( 6 0 m g or 1 8 0 m g orall y base d o n t h e Pri nci pal I n vesti gat or’s discreti o n ) a d mi nistere d t h e da y bef ore eac h i nf usi o n; 
fe x ofe na di ne (6 0 m g or 1 8 0 m g orall y base d o n t h e Pri n ci pal I n vesti gat or’s discreti o n ) a n d aceta mi n o p he n ( 1 0 0 0 m g orall y) a d mi nistere d o n t h e m or ni n g of eac h i nf usi o n; 
a n d met h yl pre d nis ol o ne ( 1 2 5 m g I V) gi ve n o ver t h e i nf usi o n d urati o n 1 0- 3 0 mi n utes (rec o m me n de d) or h y dr oc ortis o ne ( 2 0 0 m g I V) w ill be a d mi nistere d i m me diatel y pri or 
t o eac h i nf usi o n. a d mi nistere d i m me diatel y pri or t o eac h i nf usi o n. 
1 8.  Bl o o d sa m ples will be c ollecte d pri or t o pe gl oticase i nf usi o n o n Da y 1 a n d at Wee ks 4, 8, 2 2, 2 4 a n d 3 6 d uri n g t h e P e gl otic ase + I M M P eri o d f or M T X P ol y gl uta mat e le vels. 
1 9.  F or all s u bjects, ser u m sa m ples f or P K a nal ysis will be c oll ecte d pri or t o pe gl oticase i nf usi o n a n d after t h e e n d of i nf usi o n ( pri or t o disc har ge) o n Da y 1 a n d at t he Wee ks 2, 4, 
6, 8 a n d 3 6 Visits a n d pri or t o pe gl oticase i nf usi o n o nl y at t h e Wee ks 1 0, 1 4, 1 8, 2 2, 2 4; at t h e E n d of P e gl oticase I nf usi o ns Visit (if a p plica ble);  a n d Wee k 5 2/ E n d- of-
St u d y/ Earl y Ter mi n ati o n Visit. Visits f or fre q ue nt sa m pli n g of a s u bset of s u bjects w h o c o nse nt f or a d diti o nal n o n-i nf usi o n vis it P K sa m pli n g (ra n d o m, m or ni n g preferr e d) 
will occ ur at Wee k 1 a n d Wee k 7.  
2 0.  Ser u m sa m ples f or meas ure me nt of s U A le vels will be c ollecte d  at t h e Scree ni n g Visit ( wit hi n 2 wee ks pri or t o t he first d ose of M T X at Wee k - 4), t h e Wee k - 4 Visit ( pri or t o 
t h e first d ose of M T X), a n d t h e Wee k - 2 Visit; wit hi n 4 8 h o urs pri or t o eac h pe gl oticase i nf usi o n (e xce pt o n Da y 1 w he n o nl y 1 pre-i nf usi o n sa m ple is re q uire d a n d will be 
dra w n at t h e site j ust pri or t o t he i nf usi o n); a n d after t h e e n d of eac h pe gl oticase i nf usi o n pri or t o disc har ge, fr o m t h e P e gl oticase + I M M P eri o d t hr o u g h wee k 2 4 a n d at 
Wee ks 3 2, 3 4, 3 6, 4 8 a n d 5 0;  wit hi n 4 8 h o urs pri or t o eac h pe gl oticase i nf usi o n at Wee ks 2 6, 2 8, 3 0, 3 8, 4 0, 4 2, 4 4 a n d 4 6 d ur i n g t h e P e gl oticase + I M M P eri o d; a n d at t h e at 
t h e E n d of P e gl oticase I nf usi o ns Visit (if a p plica ble);  at t h e Wee k 5 2/ E n d of st u d y/ Earl y Ter mi n ati o n Visit a n d M o nt h 3 a n d M ont h 6 Visits. Visits f or fre q ue nt sa m pli n g of a 
s u bset of s u bjects w h o c o nse nt f or a d diti o nal n o n-i nf usi o n visit P K sa m pli n g (ra n d o m, m or ni n g preferre d) will occ ur at Wee k 1 a n d Wee k 7.  T w o se parate sa m ples/t u bes of 

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bl o o d s h o ul d be c ollecte d wit hi n 4 8 h o urs pri or t o t he pe gl oticase i nf usi o n (e xce pt o n Da y 1 w he n o nl y 1 pre-i nf usi o n sa m ple is re q uire d f or t h e ce ntral la b orat or y). O ne 
sa m ple/t u be will be assesse d b y t he site’s l o cal la b orat or y t o be use d f or o n-st u d y s u bject ma na ge me nt; pre-i nf usi o n s U A res ults m ust b e re p orte d b y t h e l o cal or ce ntral 
la b orat or y pri or t o eac h pe gl oticase i nf usi o n. If a l o cal la b orator y sa m ple is dra w n ( wit hi n 4 8 h o urs pri or t o t h e pe gl oticase i nf usi o n), a sa m ple f or t h e ce ntral la b orat or y will 
be dra w n pri or t o t he pe gl oticase i nf usi o n o n t he da y of t he visit. T he sec o n d sa m ple/t u be will be se nt t o t he ce ntral la b orat o r y f or a nal ysis a n d rec or di n g i n t he data base. See 
t h e La b orat or y Ma n ual f or i nstr ucti o ns f or alter nate sce nari os. A s u bject wit h s U A le vel > 6 m g/ d L ( base d o n t he l o cal or ce ntral la b orat or y) at 2 c o nsec uti ve st u d y visits, 
be gi n ni n g wit h t h e Wee k 2 Visit, will be classifie d as a n o n-r es p o n der a n d s u bjects will c o m plete t h e E n d of P e gl oticase Treat m e nt Visit.  T he s u bject will c o nti n ue o n st u d y 
( wit h o ut treat me nt).  
2 1.  Ser u m sa m ples f or e val u ati o n of a nti- P E G a n d a nti- uricase I g G a nti b o dies will be c ollecte d pri or t o t he pe gl oticase i nf usi o n o n Da y 1 a n d at t he Wee ks 2, 4, 6, 8, 1 0, 1 4, 1 8, 
2 2, 2 4, 3 6, if a p plica ble t he E n d of P e gl oticase I nf usi o ns Visit a n d Wee k 5 2/ E n d of St u d y/ Earl y Ter mi n ati o n Visits a n d at t he 3  M o nt h P ost Treat me nt Visit. Visits f or 
fre q ue nt sa m pli n g of a s u bset of s u bjects w h o c o nse nt f or a d diti o nal n o n-i nf usi o n visit P K sa m pli n g (ra n d o m, m or ni n g preferre d) will occ ur at Wee k 1 a n d Wee k 7. I n t he 
e ve nt of a n A E s us pecte d t o be a n i nf usi o n reacti o n, a ser u m sa m p l e will be c ollecte d at t h at ti me or at t h e s u bse q ue nt visit for e val uati o n of pe gl oticase a nti b o dies. 
2 2.  F or w o me n of 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 at t h e Scree ni n g Visit.  A uri n e pre g na nc y test w ill be perf or me d at eac h visit u ntil 3 0 da ys 
after t he last M T X d ose if t h e s u bject has n ot o v ulate d; at t he E n d of P e gl oticase I nf usi o ns Visit (if a p plica ble), t h e Wee k 5 2 / E n d of st u d y/ Earl y Ter mi nati o n Visit pr oce d ures 
a n d at t he 3 0 da y f oll o w u p p h o ne/e- mail/site visit it is d eter mi n e d t hat t h e s u bject has n ot o v ulate d si nce t h e last d ose of M T X; a uri n e pre g na nc y test will be perf or me d at all 
ot h er i n dicate d visits. 
2 3.  S u bjects w h o are n o n- vasect o miz e d males will be as ke d 3 m o nt hs after M T X disc o nti n uati o n re gar di n g part ner pre g na nc y.  T his wil l occ ur at a re g ulat or y sc he d ule d visit or 
b y a se parate p h o ne/e mail/site visit. 
2 4.  T he I n vesti gat or will re vie w t h e cli nical stat us of t h e s u bject at t h e Wee k 2 4 Visit a n d t he E n d of P e gl oticase I nf usi o ns V isit (if a p plica ble) or t h e Wee k 5 2/ E n d of st u d y/ Earl y 
Ter mi n ati o n Visit. 
2 5.   S u bjects w h o e n d treat me nt d ue t o t he st o p pi n g r ules or ot her reas o ns s h o ul d c o m plete t he E n d of P e gl oticase Treat me nt Vi sit wit hi n 2 wee ks of t h e last i nf usi o n.  S u bjects 
s h o ul d re mai n o n st u d y.  S ee Secti o n 9. 5. 6. 3  f or details o n visits a n d pr oce d ures. 
2 6.   S u bjects will ret ur n t o t h e site 3 m o nt hs a n d 6 m o nt hs f oll o wi n g t h eir fi nal i nf usi o n f or f oll o w- u p pr oce d ures.  

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T A B L E O F C O N T E N T S 
1  
TI T L E P A G E .................................................................................................................... ...... 2 
2  
S Y N O P SI S ...................................................................................................................... ........ 6 
2. 1  
Sc he d ule of Assess me nts ............................................................................................... 1 6  
3  
T A B L E O F C O N T E N T S ...................................................................................................... 2 6  
4  
LI S T O F A B B R E VI A TI O N S ............................................................................................... 3 2  
5  
E T HI C S ........................................................................................................................ ......... 3 3 
5. 1  
I nstit uti o nal Re vie w B oar d/I n d e pe n d e nt Et hics C o m mittee .......................................... 3 3 
5. 2  
Et hical C o n d uct of t he St u d y ......................................................................................... 3 3  
5. 3  
S u bject I nf or mati o n a n d C o nse nt ................................................................................... 3 3  
5. 4  
C o m pe nsati o n f or Healt h Da ma ge of S u bjects/I ns ura nce .............................................. 3 4  
5. 5  
C o nfi de ntialit y ............................................................................................................... . 3 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............................ 3 4 
7  
I N T R O D U C TI O N ................................................................................................................ 36  
7. 1  
Bac k gr o u n d ....................................................................................................................  3 6 
7. 1. 1  
G o ut......................................................................................................................... 3 6  
7. 1. 2  
Pe gl oticase .............................................................................................................. 3 6  
7. 1. 2. 1  P h ysi oc he mical Pr o perties .................................................................................. 3 8  
7. 1. 2. 2  Safet y P h ar mac ol o g y........................................................................................... 3 8  
7. 1. 2. 3  N o n-cli nical P har mac o ki netics ........................................................................... 3 9  
7. 1. 2. 4  Cli nical E x perie nce ............................................................................................. 4 0  
7. 1. 2. 4. 1  I ntr o d u cti o n ................................................................................................... 4 0 
7. 1. 2. 4. 2  Efficac y ..........................................................................................................  4 0  
7. 1. 2. 4. 3  P har mac o ki netics ...........................................................................................  4 0  
7. 1. 2. 4. 4  Safet y ............................................................................................................. 4 0  
7. 1. 3  
Met h otre x ate ........................................................................................................... 4 1  
7. 2  
Rati o nale f or t his St u d y .................................................................................................. 4 1  
7. 3  
Rati o nale f or D ose Sel ecti o n .......................................................................................... 4 2  
8  
S T U D Y O BJ E C TI V E S ......................................................................................................... 4 2  
9  
I N V E S TI G A TI O N A L P L A N ............................................................................................... 4 4 
9. 1  
O verall St u d y Desi g n a n d Pla n ...................................................................................... 4 4  

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9. 2  
Disc ussi o n of St u d y Desi g n ........................................................................................... 4 7  
9. 3  
Selecti o n of St u d y P o p ulati o n ........................................................................................ 4 7  
9. 3. 1  
I n cl usi o n Criteria .................................................................................................... 4 7 
9. 3. 2  
E x cl usi o n Criteria ................................................................................................... 4 8  
9. 3. 3  
Re m o val of S u bjects fr o m T hera p y or St u d y ......................................................... 5 0  
9. 3. 3. 1  Re m o val of S u bjects fr o m Pe gl oticase T h era p y ................................................. 5 0  
9. 3. 3. 1. 1  St u d y c o nsi derati o ns f or s u bjects e n di n g p e gl oticase i nf usi o ns pri or t o 5 2 
wee ks
 5 0  
9. 3. 3. 2  Re m o val of S u bjects Fr o m St u d y........................................................................ 5 1  
9. 3. 4  
Re place me nt P olic y ................................................................................................ 5 2  
9. 3. 4. 1  S u bjects ............................................................................................................... 5 2  
9. 3. 4. 2  Ce nters .................................................................................................................  5 2  
9. 3. 4. 3  Scree n Fail ures .................................................................................................... 5 2  
9. 4  
Treat me nts .................................................................................................................... .. 5 2 
9. 4. 1  
Treat me nts A d mi nistere d ........................................................................................ 5 2  
9. 4. 1. 1  F olic Aci d ............................................................................................................ 5 3  
9. 4. 1. 2  G o ut Flare Pr o p h yl a xis........................................................................................ 5 3  
9. 4. 1. 3  I nf usi o n Reacti o n Pr o p h yl a xis ............................................................................ 5 3 
9. 4. 2  
I d e ntit y of I n vesti gati o nal Pr o d ucts ........................................................................ 5 4 
9. 4. 2. 1  Pe gl oticase ...........................................................................................................  5 4  
9. 4. 2. 2  Met h otre x ate........................................................................................................ 5 4  
9. 4. 3  
La b eli n g .................................................................................................................. 5 4  
9. 4. 4  
St ora ge .................................................................................................................... 5 5  
9. 4. 5  
Dr u g Acc o u nta bilit y................................................................................................ 5 5  
9. 4. 6  
St u d y Dr u g A d mi nistrati o n a n d Ti mi n g of D os e f or eac h S u bject ......................... 5 5  
9. 4. 6. 1  Descri pti o n of Cli nical S u p plies ......................................................................... 5 5  
9. 4. 6. 2  Deter mi nati o n of D ose V ol u me .......................................................................... 5 5  
9. 4. 6. 3  Details C o ncer ni n g Ti mi n g a n d D ose A d mi nistrati o n ........................................ 5 6  
9. 4. 6. 3. 1  Pre parati o n a n d A d mi nistrati o n ..................................................................... 5 6  
9. 4. 6. 3. 2  D ose M o dificati o ns, I nterr u pti o ns, a n d Dela ys ............................................. 5 7  
9. 4. 7  
Met h o d of Assi g ni n g S u bjects t o Treat me nt Gr o u ps .............................................. 6 1  
9. 4. 8  
Pri or a n d C o nc o mita nt T hera p y .............................................................................. 6 1  

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Restricte d Me dicati o ns............................................................................................ 6 1  
9. 4. 1 0  Treat me nt C o m plia nce ............................................................................................ 6 1  
9. 4. 1 1  C o ntrace pti o n Re q uire m e nts ................................................................................... 6 2  
9. 5  
Efficac y, Q ualit y- of- Life, P har mac o ki netic, a n d S afet y Varia bles ............................... 6 2  
9. 5. 1  
Efficac y Varia bles ................................................................................................... 6 2  
9. 5. 1. 1  Ser u m Uric Aci d.................................................................................................. 6 2  
9. 5. 1. 2  Te n der a n d S w olle n J oi nt C o u nts........................................................................ 6 3  
9. 5. 1. 3  Patie nt Gl o bal Assess me nt .................................................................................. 6 5  
9. 5. 1. 4  P h ysicia n Gl o bal Ass ess me nt.............................................................................. 6 5  
9. 5. 1. 5  J oi nt Pai n Assess me nt ......................................................................................... 6 6 
9. 5. 1. 6  D ual-e ner g y C o m p ute d T o m o gra p h y ( D E C T) ................................................... 6 6  
9. 5. 2  
Q ualit y- of- Life Assess m e nt .................................................................................... 6 6  
9. 5. 3  
P har mac o ki netic a n d A nti- dr u g A nti b o d y M eas ure me nts ...................................... 6 7  
9. 5. 4  
Safet y Vari a bles ...................................................................................................... 6 7  
9. 5. 4. 1  A d verse E v e nts .................................................................................................... 6 8  
9. 5. 4. 1. 1  Defi niti o ns ..................................................................................................... 6 8  
9. 5. 4. 1. 2  D oc u me ntati o n of A d verse E ve nts ................................................................ 7 2  
9. 5. 4. 1. 3  I nte nsit y of A d verse E ve nts ........................................................................... 7 2 
9. 5. 4. 1. 4  Relati o ns hi p t o St u d y Dr u g ........................................................................... 7 2  
9. 5. 4. 1. 5  Re p orti n g a n d D oc u me nti n g S A Es a n d Pr o d uct C o m plai nts ........................ 7 3  
9. 5. 4. 1. 6  F oll o w- u p of A d v erse E v e nts ........................................................................ 7 4  
9. 5. 4. 1. 7  Me dicati o n Err or a n d O ver d ose .................................................................... 7 4  
9. 5. 4. 1. 8  Re vie w of A d verse E v e nts a n d E mer gi n g Ne w Safet y I nf or m ati o n ............. 7 5  
9. 5. 4. 1. 9  Re p orti n g of I N D Safet y Re p orts .................................................................. 7 5  
9. 5. 4. 1. 1 0  De vel o p me nt Safet y U p date Re p orts ........................................................ 7 5  
9. 5. 4. 2  Pre g n a nc y Re p orti n g ........................................................................................... 7 5  
9. 5. 4. 3  Me dical Hist or y ................................................................................................... 7 6  
9. 5. 4. 4  Vital Si g ns, Hei g ht, a n d Wei g ht.......................................................................... 7 6  
9. 5. 4. 5  P h ysical E x a mi nati o ns ........................................................................................ 7 6  
9. 5. 4. 6  Electr ocar di o gra m ............................................................................................... 7 7  
9. 5. 4. 7  Cli nical La b orat or y Safet y Tests ......................................................................... 7 7  

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9. 5. 4. 8  Assess me nt of G o ut Flare ................................................................................... 7 7  
9. 5. 5  
A p pr o priate n ess of Meas ure me nts .......................................................................... 7 8  
9. 5. 6  
St u d y Pr oce d ures .................................................................................................... 7 8  
9. 5. 6. 1  Scree ni n g/ M T X R u n-i n Peri o d ........................................................................... 7 8  
9. 5. 6. 1. 1  Scree ni n g Visit ( Wit hi n 2 Wee ks Pri or t o t he First D ose of M T X at Wee k - 4)
 7 8
 
9. 5. 6. 1. 2  Wee k - 4 .......................................................................................................... 7 9  
9. 5. 6. 1. 3  Wee k - 2 .......................................................................................................... 8 0  
9. 5. 6. 2  Pe gl oticase + I M M Peri o d .................................................................................. 8 1  
9. 5. 6. 2. 1  Da y 1.............................................................................................................. 8 1  
9. 5. 6. 2. 2  Wee k 1 ( N o n-i nf usi o n visit f or t h ose w h o c o nse nt o nl y) .............................. 8 2  
9. 5. 6. 2. 3  Wee k 2 ........................................................................................................... 8 3  
9. 5. 6. 2. 4  Wee k 4 ........................................................................................................... 8 4  
9. 5. 6. 2. 5  Wee k 6 ........................................................................................................... 8 5  
9. 5. 6. 2. 6  Wee k 7 ( N o n-i nf usi o n visit f or t h ose w h o c o nse nt o nl y) .............................. 8 6  
9. 5. 6. 2. 7  Wee k 8 ........................................................................................................... 8 6  
9. 5. 6. 2. 8  Wee k 1 0 ......................................................................................................... 8 8  
9. 5. 6. 2. 9  Wee k 1 2 ......................................................................................................... 8 9  
9. 5. 6. 2. 1 0  Wee k 1 4 .................................................................................................... 9 0  
9. 5. 6. 2. 1 1  Wee k 1 6 .................................................................................................... 9 1  
9. 5. 6. 2. 1 2  Wee k 1 8 .................................................................................................... 9 2  
9. 5. 6. 2. 1 3  Wee k 2 0 .................................................................................................... 9 3  
9. 5. 6. 2. 1 4  Wee k 2 2 .................................................................................................... 9 4  
9. 5. 6. 2. 1 5  Wee k 2 4 .................................................................................................... 9 5  
9. 5. 6. 2. 1 6  Wee k 2 6 .................................................................................................... 9 7  
9. 5. 6. 2. 1 7  Wee k 2 8 .................................................................................................... 9 7  
9. 5. 6. 2. 1 8  Wee k 3 0 .................................................................................................... 9 8  
9. 5. 6. 2. 1 9  Wee k 3 2 .................................................................................................... 9 9  
9. 5. 6. 2. 2 0  Wee k 3 4 .................................................................................................. 1 0 0  
9. 5. 6. 2. 2 1  Wee k 3 6 .................................................................................................. 1 0 1  
9. 5. 6. 2. 2 2  Wee k 3 8 .................................................................................................. 1 0 3  
9. 5. 6. 2. 2 3  Wee k 4 0 .................................................................................................. 1 0 3  

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9. 5. 6. 2. 2 5  Wee k 4 4 .................................................................................................. 1 0 5  
9. 5. 6. 2. 2 6  Wee k 4 6 .................................................................................................. 1 0 6  
9. 5. 6. 2. 2 7  Wee k 4 8 .................................................................................................. 1 0 7  
9. 5. 6. 2. 2 8  Wee k 5 0 .................................................................................................. 1 0 8  
9. 5. 6. 3  E n d of Pe gl otic ase I nf usi o ns Visit .................................................................... 1 0 9  
9. 5. 6. 4  Wee k 5 2/ E n d of St u d y/ E arl y Ter mi nati o n Visit ............................................... 1 1 0  
9. 5. 6. 5  Safet y F oll o w- u p P h o ne/ E mail/ Site Visits ........................................................ 1 1 1  
9. 5. 6. 6  M T X Part ner Pre g n a nc y F oll o w- u p .................................................................. 1 1 1  
9. 5. 6. 7  P ost Treat me nt F oll o w- u p ................................................................................. 1 1 1  
9. 6  
Statistical Met h o ds a n d Deter mi na ti o n of Sa m ple Size ............................................... 1 1 2 
9. 6. 1  
E n d p oi nts .............................................................................................................. 1 1 2  
9. 6. 1. 1  Pri mar y E n d p oi nt .............................................................................................. 1 1 2  
9. 6. 1. 2  Sec o n dar y E n d p oi nts ......................................................................................... 1 1 2  
9. 6. 1. 3  E x pl orat or y E n d p oi nts....................................................................................... 1 1 2  
9. 6. 1. 4  P har mac o ki netic a n d A nti- dr u g A nti b o d y E n d p oi nts ....................................... 1 1 3  
9. 6. 1. 5  Safet y a n d T olera bilit y E n d p oi nts ..................................................................... 1 1 3  
9. 6. 2  
P o p ulati o ns f or A nal ysis ....................................................................................... 1 1 4  
9. 6. 3  
De m o gra p hic Varia bl es ........................................................................................ 1 1 4  
9. 6. 4  
S u bject Dis p ositi o n ............................................................................................... 1 1 4  
9. 6. 5  
Efficac y E n d p oi nt A nal ysis .................................................................................. 1 1 4  
9. 6. 5. 1  Pri mar y a n d Sec o n dar y E n d p oi nt A nal ysis ....................................................... 1 1 4  
9. 6. 5. 2  E x pl orat or y E n d p oi nt A nal ysis ......................................................................... 1 1 5  
9. 6. 6  
P har mac o ki netic a n d A nti- dr u g A nti b o d y A nal ysis ............................................. 1 1 5  
9. 6. 7  
Safet y A nal ysis ..................................................................................................... 1 1 5  
9. 6. 8  
I nteri m A nal yses ................................................................................................... 1 1 6 
9. 6. 9  
Sa m ple Siz e a n d P o wer C o nsi derati o ns ................................................................ 1 1 6  
9. 7  
C ha n ges i n t he C o n d uct of t he St u d y ........................................................................... 1 1 6  
1 0  S O U R C E D O C U M E N T A TI O N A N D I N V E S TI G A T O R FI L E S ..................................... 1 1 7  
1 1  C A S E R E P O R T F O R M S ................................................................................................... 1 1 7  
1 2  S T U D Y M O NI T O RI N G .................................................................................................... 1 1 8  

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1 3  D A T A M A N A G E M E N T .................................................................................................... 1 1 9  
1 4  R E T E N TI O N O F R E C O R D S ............................................................................................. 1 1 9  
1 5  P U B LI C A TI O N .................................................................................................................. 1 1 9  
1 6  R E F E R E N C E S ................................................................................................................... 1 2 0  
1 7  A P P E N DI C E S ....................................................................................................................  1 2 2 
1 7. 1  A d mi nistrati ve A p pe n di x ............................................................................................. 1 2 2  
1 7. 2  Healt h Assess me nt Q uesti o n naire ( Disa bilit y I n de x, Pai n a n d Healt h Scales) ............ 1 2 3  
1 7. 3  Patie nt Gl o bal Assess me nt ........................................................................................... 1 2 6  
1 7. 4  P h ysicia n Gl o bal Ass ess me nt....................................................................................... 1 2 7  
1 7. 5  J oi nt Pai n Assess me nt .................................................................................................. 1 2 8 
1 7. 6  S u bject- Faci n g Dia gra m ............................................................................................... 1 2 9  
LI S T O F T A B L E S 
Ta ble 6. 1  Ta ble of N o n- S p o ns or St u d y Res p o nsi bilities ........................................................... 3 5  
 
LI S T O F FI G U R E S 
Fi g ure 9. 1  Sc he matic of St u d y D esi g n ........................................................................................ 4 7  
Fi g ure 9. 2  R he u mat oi d Art hritis 6 6- 6 8 Te n der a n d S w olle n J oi nt C o u nts ................................. 6 5  
 

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4  
LI S T O F A B B R E VI A TI O N S 
A b bre vi ati o n 
Defi niti o n 
A E 
a d verse e ve nt 
C F R 
C o de of Fe deral Re g ulati o ns 
D E C T 
D ual e ner g y c o m p ute d t o m o gr a p h y 
E C G 
electr ocar di o gra m 
e C R F 
electr o nic case re p ort f or m  
F D A 
F o o d a n d Dr u g A d mi nistrati o n  
G 6 P D 
gl uc ose- 6- p h os p hate de h y dr o ge nase 
G C P 
G o o d Cli nical Practice  
H A Q 
Healt h Assess me nt Q uesti o n naire 
H A Q- DI 
Healt h Assess me nt Q uesti o n naire –  Disa bilit y I n de x 
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 u ncil f or Har m o nisati o n 
I M M 
I m m u n o m o d ulat or 
I N D 
I n vesti gati o nal Ne w Dr u g 
I R 
i nf usi o n reacti o n 
I R B 
I nstit uti o nal Re vie w B oar d 
I V 
i ntra ve n o us(l y) 
mI T T 
m o difie d i nte nti o n-t o-treat 
M T X 
met h otre xate  
N S AI D 
n o nster oi dal a nti-i nfla m mat or y dr u g 
P K 
p har mac o ki netic(s) 
S A E 
seri o us a d verse e ve nt 
S A P 
statistical a nal ysis pla n 
s U A 
ser u m uric aci d 
U S P 
U nite d States P har mac o peia  
N ote: A b bre viati o ns use d o nl y o nce i n a para gra p h or i n ta bles or fi g ures are defi ne d wit hi n t he rele va nt para gra p h, 
ta ble, or fi g ure.

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5  
E T HI C S 
5. 1  
I nstit uti o n al Re vie w B o ar d/I nde pe n de nt Et hics C o m mittee 
T he Pri nci pal I n vesti gat or (I n vesti gat or), t he S p o ns or a n d/ or desi g nee a ut h orize d b y t he S p o ns or 
will s u b mit t his pr ot oc ol, a n y pr ot oc ol m o dificati o ns, t he i nf or me d c o nse nt f or m (I C F), a n d all 
a p plica ble st u d y d oc u me ntati o n t o be use d i n t his st u d y t o t he a p pr o priate I nstit uti o nal Re vie w 
B oar d (I R B) f or re vie w a n d a p pr o val/fa v ora ble o pi ni o n. A letter c o nfir mi n g t he I R B 
a p pr o val/fa v ora ble o pi ni o n of t he pr ot oc ol, t he s u bject I C F, a n d a p plica ble st u d y d oc u me ntati o n, 
a list of t he I R B me m bers i n v ol ve d i n t he v ote, as well as a state me nt t hat t he I R B is or ga nize d 
a n d o perat es acc or di n g t o G o o d Cli nical Practice ( G C P) a n d t he a p plica bl e la ws a n d re g ul ati o ns, 
m ust be f or war de d t o t he S p o ns or or its desi g nee pri or t o t he e nr oll me nt of s u bjects i nt o t he 
st u d y. A c o p y of t he a p pr o ve d I C F will als o be f or war de d t o t he S p o ns or or its desi g nee. 
A p pr o priate re p orts o n t h e pr o gress of t he st u d y will be ma de t o t he I R B a n d t he S p o ns or or its 
desi g nee b y t he I n v esti gat or i n acc or da nce wit h a p plica ble g o ver n me nt al re g ulati o ns a n d i n 
a gree m e nt wit h t he p olic y esta blis he d b y t h e S p o ns or. 
5. 2  
Et hic al C o n d uct of t he St u d y 
T he I n vesti gat ors will e ns ure t hat t his st u d y is c o n d ucte d i n a ma n ner t hat f ull y c o nf or ms wit h 
t he pri nci ples of t he Decl arati o n of H elsi n ki or wit h t he la ws a n d re g ulati o ns of t he c o u ntr y i n 
w hic h t he res earc h is c o n d ucte d, w hic he v er aff or ds t he greater pr otecti o n t o t he i n di vi d ual. T he 
st u d y m ust f ull y a d h ere t o t he pri nci ples o utli ne d b y I nter nati o nal C o u ncil f or Har m o nisati o n 
(I C H) Tri partite G ui deli ne f or G C P or wit h l ocal l a w if it aff or ds greater pr otecti o n t o t he 
s u bject. T he I n vesti gat or will a d diti o nall y e ns ure a d here n ce t o t he basic pri nci ples of G C P, as 
o utli ne d i n t he c urre nt versi o n of 2 1 C o de of Fe deral Re g ulati o ns ( C F R), s u bc ha pter D, part 3 1 2, 
“ Res p o nsi bilities of S p o ns ors a n d I n vesti gat ors ,” p art 5 0, “ Pr otecti o n of H u ma n S u bjects ,” a n d 
part 5 6, “I nstit uti o nal Re vie w B oar ds .” 
5. 3  
S u bject I nf or m ati o n a n d C o nse nt 
It is t he res p o nsi bilit y of t he I n v esti gat or or a pers o n desi g n ate d b y t he I n v esti gat or (if acce pta bl e 
b y l oc al re g ulati o ns) t o o btai n a si g ne d I C F fr o m eac h s u bject pri or t o parti ci pati n g i n t his st u d y 
after a de q uat e e x pla nati o n of t he ai ms, met h o ds, a ntici pate d be nefits, a n d p ote ntial hazar ds of t he 
st u d y. 
T he I n vesti gat or or d esi g nee m ust als o e x plai n t hat t he s u bjects are c o m pletel y free t o ref use t o 
e nter t he st u d y or t o wit h dra w fr o m it at a n y ti me, f or a n y reas o n.  
T he I C F a n d a n y ot her writte n i nf or mati o n pr o vi de d t o s u bjects will be re vise d w he ne ver 
i m p orta nt ne w i nf or mati o n bec o mes a v aila ble t hat ma y be rele va nt t o t he s u bject’s c o nse nt, or 
t here is a n a m e n d me nt t o t he pr ot oc ol t hat necessitates a c h a n ge t o t he c o nt e nt of t he s u bject 
i nf or mati o n a n d/ or t he writte n I C F. T he I n v esti gat or will i nf or m t he s u bject of c ha n ges i n a 
ti mel y ma n ner a n d will as k t he s u bject t o c o nfir m his/ her partici pati o n i n t he st u d y b y si g ni n g t he 
re vise d I C F. A n y re vise d writte n I C F a n d writte n i nf or mati o n m ust recei v e t he I R B`s 
a p pr o val/fa v ora ble o pi ni o n i n a d va nce of use. 

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All si g ne d I C Fs are t o re mai n i n t he I n v esti gat or’s site file or, if l ocall y re q uire d, i n t he s u bjects’ 
n otes/files of t he me dical i nstit uti o n. 
T he electr o nic cas e re p ort f or ms (e C R Fs) f or t his st u d y c o ntai n a s ecti o n f or d oc u me nti n g all 
s u bject I C Fs, a n d t his m ust be c o m plete d a p pr o priatel y. If ne w safet y i nf or mati o n res ults i n 
si g nifica nt c ha n ges i n t he ris k/ be nefit assess me nt, t he I C F s h o ul d be re vie we d a n d u p date d, if 
necessar y. All s u bjects (i ncl u di n g t h ose alrea d y b ei n g tr eate d) s h o ul d be i nf or me d of t he ne w 
i nf or mati o n, gi ve n a c o p y of t he re vise d I C F, a n d gi ve t heir c o nse nt t o c o nti n ue i n t he st u d y. 
5. 4  
C o m pe ns ati o n f or He alt h D a m a g e of S u bjects/I ns ur a nce 
T he S p o ns or mai ntai ns cli nical trial i ns ura nce c o v era ge f or t his st u d y i n acc or da nce wit h t he 
la ws a n d re g ul ati o ns of t he c o u ntr y i n w hic h t he st u d y is perf or me d. 
5. 5  
C o nfi de nti alit y 
All rec or ds i de ntif yi n g t h e s u bject will be ke pt c o nfi de ntial a n d, t o t he e xte nt per mitte d b y t he 
a p plica ble la ws a n d/ or re g ulati o ns, will n ot be ma de p u blicl y a vaila ble. 
S u bject na mes will n ot be s u p plie d t o t he S p o ns or. O nl y t he s u bject n u m ber will be rec or de d i n 
t he e C R F, a n d if t he s u bj ect na me a p pears o n a n y ot her d oc u me nt, it m ust be o bliterate d bef ore a 
c o p y of t he d oc u me nt is s u p plie d t o t he S p o ns or. St u d y fi n di n gs st ore d o n a c o m p uter will be 
st ore d i n acc or da nce wit h l ocal data pr otecti o n la ws. As part of t he i nf or me d c o nse nt pr o cess, t he 
s u bjects will be i nf or me d i n writi n g t hat re prese nt ati ves of t he S p o ns or, I R B, or re g ulat or y 
a ut h orities ma y i ns pe ct t heir me dical r ec or ds t o v erif y t he i nf or m ati o n c ollecte d, a n d t h at all 
pers o nal i nf or mati o n ma de a vaila ble f or i ns pecti o n will be ha n dle d i n stri ctest c o nfi de nce a n d i n 
acc or da nce wit h l ocal dat a pr otecti o n la ws. 
If t he res ults of t he st u d y are p u blis he d, t he s u bject’s i de ntit y will re mai n c o nfi de ntial. 
T he I n vesti gat or will mai ntai n a list t o e na ble s u bjects t o be i de ntifie d. 
T he S p o ns or will e ns ure t hat t he use a n d discl os ur e of pr otecte d healt h i nf or mati o n o btai ne d 
d uri n g a researc h st u d y c o m plies wit h t he fe deral a n d/ or re gi o nal le gislati o n relate d t o t he 
pri vac y a n d pr otecti o n of pers o nal i nf or mati o n ( HI P A A). 
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 
T he S p o ns or of t his st u d y is H oriz o n T hera pe utics Irela n d D A C ( H oriz o n). H oriz o n pers o n nel 
will ser ve as t he Me di cal M o nit or a n d t he S p o ns or’s re g ulat or y re prese ntati ve (see  Secti o n 1 7. 1 
f or details). T he S p o ns or’s re g ulat or y re prese ntati ve, or desi g nee will be res p o nsi ble f or ti mel y 
re p orti n g of seri o us a d verse e ve nts ( S A Es) t o re g ulat or y a ut h orities, as re q uire d. T he S p o ns or 
will be res p o nsi ble f or ti mel y re p orti n g of S A Es a n d a n y ot h er ne w perti ne nt safet y i nf or mati o n 
t o all I n vesti gat ors, as re q uire d. 

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7  
I N T R O D U C TI O N 
7. 1  
B ac k gr o u n d 
7. 1. 1  G o ut 
G o ut affects a p pr o xi matel y 4 % of t h e U nite d St ates p o p ulati o n, is t he m ost c o m m o n f or m of 
i nfla m mat or y art hritis i n me n, a n d is ass ociate d wit h decrease d q ualit y of life [ Saa g a n d C h oi, 
2 0 0 6; Si n g h a n d Stra n d, 2 0 0 8; Z h u et al, 2 0 1 1; Satt ui et al, 2 0 1 4]. T h e fre q ue nc y of g o ut is 
i ncreasi n g w orl d wi de, wit h pre vale nce rates esti mate d t o be as hi g h as 7 % i n ol der me n [ Mi k uls 
et al, 2 0 0 5; Saa g a n d C h oi, 2 0 0 6; R o d d y a n d D o hert y, 2 0 1 0]. U p t o 4 0 0, 0 0 0 pers o ns ( u p t o 5 % 
of t he esti mate d 8 milli o n pers o ns wit h g o ut) i n  t he U nite d States e x perie nce c hr o ni c s y m pt o ms 
of g o ut, d es pite trials of urate-l o w eri n g t hera p y.  G o ut, w hic h is s o meti mes referre d t o as c hr o nic 
refract or y g o ut, is c haracteriz e d b y o n g oi n g s y m pt o ms of acti ve diseas e a n d a fail ure t o 
c o ntr ol/ mai ntai n ser u m uric aci d (s U A) < 6 m g/ d L wit h c o n ve nti o nal x a nt hi ne o xi dase i n hi bit ors 
(i.e., all o p uri n ol a n d fe b u x ostat) a n d uric os uric a ge nts (i.e., pr o be n eci d) [ A A C Briefi n g 
D oc u me nt 2 0 0 9; Br o o k et al, 2 0 1 0; W ert hei mer et al, 2 0 1 3; K ha n na et al, 2 0 1 6]. T hese patie nts 
ofte n ha ve si g nifica nt, disa bli n g urate de p osit s i n s oft tiss ues a n d b o ne k n o w n as t o p hi. 
K R Y S T E X X A ( pe gl otic ase, a rec o m bi na nt m o difie d ma m malia n urate o xi dase [ uricase]), is 
a p pr o ve d b y t he U nite d States F D A a n d t he E ur o pea n C o m missi o n f or use i n patie nts wit h g o ut, 
at a d ose of 8 m g I V e ver y t w o w ee ks. Pe gl oticase is efficaci o us i n re d uci n g s U A l e vels a n d 
i m pr o vi n g cli nical si g ns a n d s y m pt o ms of g o ut. Pe gl oticase pr o vi des me di cal be nefits b y 
l o weri n g s U A a n d eli mi nati n g t o p hi i n patie nts w h o c urre ntl y ha v e n o t hera pe utic o pti o ns. T he 
p o ole d res p o nse rate f or pe gl otic ase 8 m g at 6 m o nt hs is 4 2 %, base d o n at least 8 0 % of t he s U A 
val ues bei n g less t ha n 6 at b ot h t he 3 m o nt h a n d 6 m o nt h ti me p oi nts, wit h place b o res p o nse 
rates of 0 %, a differe n ce t hat was cli nicall y i mp orta nt a n d staticall y si g nifi ca nt.     
H o we ver, pe gl oticase h as bee n ass ociat e d wit h i nf usi o n reacti o ns (I Rs), i ncl u di n g a n a p h yla xis. 
I n P has e 3 st u dies, I Rs o cc urre d i n 2 6 % of s u bjects recei vi n g pe gl oticas e c o m pare d t o 5 % of 
s u bjects recei vi n g pla ce b o, a n d a na p h yla xis was re p orte d i n 5 % of s u bjects recei vi n g pe gl oticase 
a n d 0 % of s u bjects recei vi n g place b o ( Pe gl oticas e ( K R Y S T E X X A) I n vesti gat or’s Br oc h ure). 
T hese a d v erse e ve nts are t h o u g ht t o be rel ate d  t o t he de vel o p me nt of a nti- dr u g a nti b o di es a n d 
ca n be re d uce d b y a v oi di n g i nf usi o ns i n patie nts w h o i nitiall y res p o n d a n d t he n ha ve a re b o u n d 
of t heir ser u m uric aci d a b o ve 6 m g/ m L. T hes e a nti- dr u g a nti b o dies are als o ass ociate d wit h l oss 
of effic ac y as reflecte d i n t his i ncrease i n s U A le v els [ Sc helle ke ns 2 0 0 5; S u n d y et al, 2 0 1 1]. 
Re d uci n g a nti- pe gl oticas e a nti b o dies via pre-treat me nt wit h, a n d c o nc o mita nt a d mi nistrati o n of 
a n i m m u ne- m o dif yi n g dr u g, met h otre x ate ( M T X), has bee n s h o w n t o be us ef ul i n ot her i nf use d 
pr o d ucts, s uc h as a d ali m u ma b, i n t he setti n g of r h e u mat oi d art hritis treat m e nt [ B ur mester G R, 
Ki vitz AJ, K u p per H, 2 0 1 5]. T his st u d y will test w het her t he l oss of res p o nse t o pe gl oticase ca n 
be pre ve nt e d or del a ye d b y t he pre-tr eat me nt a n d c o nc o mita nt use of M T X wit h pe gl oticas e. 
7. 1. 2  Pe gl otic ase 
Pe gl oticase is effic aci o us i n re d uci n g s U A le vels a n d i m pr o vi n g cli nical si g ns a n d s y m pt o ms of 
g o ut. T he ris ks of pe gl oticase use are d etaile d i n t he f ull prescri bi n g i nf or mati o n a n d i ncl u de: 

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 I Rs, i ncl u di n g a na p h yl a xis 
 He m ol ysis a n d met h e m o gl o bi ne mia i n patie nts wit h gl uc ose- 6- p h os p hate de h y dr o ge nas e 
( G 6 P D) defi cie nc y 
 G o ut flares 
 C o n gesti ve heart fail ure e x acer bati o n 
S u bjects wit h diseases or c o n diti o ns (e. g., n o n-c o m pe nsate d c o n gesti ve h eart fail ure) t hat c o ul d 
p ote ntiall y place t he m at i ncreas e d ris k f or t hes e e ve nts will be e x cl u de d fr o m t he st u d y. 
It is re q uire d t hat all s u bj ects recei ve pr o p h yl actic treat me nt t o re d uce t he ris k of ac ute g o ut 
flares, u nless me dic all y c o ntrai n dicate d or n ot t olerate d, as n ote d i n t he p e gl oticase prescri bi n g 
i nf or mati o n. S u bjects s h o ul d be gi n a re gi me n of c olc hici ne ( 0. 6 m g/ da y) a n d/ or n o nster oi dal 
a nti-i nfla m mat or y dr u g ( N S AI D) a n d/ or l o w- d ose pre d nis o ne ( ≤1 0 m g/ da y) pr o p h yl a xis 
≥1  wee k bef ore t he first d ose of pe gl oticase a n d co nti n ue flare pr o p h yl a xis per A meri ca n C olle ge 
of R he u mat ol o g y g ui deli nes [ K ha n na D et al. 2 0 1 2] f or t he greater of 1) 6 m o nt hs, 2) 3 m o nt hs 
after ac hie vi n g tar get ser u m urate (s U A < 6 m g/ d L) f or patie nts wit h n o t o p hi detecte d o n 
p h ysical e x a m, or 3) 6 m o nt hs after ac hie vi n g tar get ser u m urate (s U A < 5 m g/ d L) f or patie nts 
wit h o ne or m ore t o p hi d etecte d o n i nitial p h ysi cal e xa m t hat ha ve si nce res ol ve d.  All s u bjects 
w h o e x perie nce a g o ut fl are d uri n g t he st u d y will be prescri be d a nti-i nfla m mat or y tr eat me nt 
(e. g., N S AI Ds, c olc hici n e), as dee me d cli nicall y i n dicate d b y t he st u d y p h ysicia n. 
Si nce I Rs ca n occ ur, all s u bjects will recei v e pre-treat me nt pr o p h yla xis c o nsisti n g of a n 
a nti hista mi ne, aceta mi n o p he n, a n d a c ortic oster oi d pri or t o eac h i nf usi o n of pe gl oticase. T o 
sta n dar dize t his re gi me n, s u bjects will recei ve fe x ofe na di ne ( 6 0 m g or 1 8 0 m g orall y bas e d o n 
t he Pri nci pal I n vesti gat or’s discreti o n) t he da y b ef ore eac h i nf usi o n; fe x ofe na di ne ( 6 0 m g or 1 8 0 
m g orall y bas e d o n t he Pri nci pal I n vesti gat or’s dis creti o n ) a n d aceta mi n o p he n ( 1 0 0 0 m g orall y) 
t he m or ni n g of eac h i nf usi o n; a n d met h yl pre d nis ol o ne ( 1 2 5 m g I V) gi ve n o ver t he i nf usi o n 
d urati o n 1 0- 3 0 mi n utes (rec o m me n de d) or h y dr oc ortis o ne ( 2 0 0 m g I V) will be a d mi nistere d 
i m me diatel y pri or t o e ac h i nf usi o n.  
T he ris k of a n a p h yl a xis a n d I Rs is hi g h er i n patie nts w h ose s U A le vel i ncreases t o > 6 m g/ d L. 
T heref ore, b e gi n ni n g wit h Wee k 2, 2 pre- d os e bl o o d sa m ples ( wit hi n 4 8 h o urs pri or t o d osi n g 
pe gl otic ase) will be o btai ne d t o verif y t he s U A le v el is ≤6 m g/ d L pri or t o i nf usi o n of pe gl oticase 
(see Secti o n 9. 5. 1. 1 ). A s u bject wit h s U A le vel > 6 m g/ d L at 2 c o ns ec uti ve st u d y visits, 
be gi n ni n g wit h t he Wee k 2 Visit, will be cla ssifie d as a n o n-res p o n der a n d c o m plete t he E n d of 
Pe gl oticase Treat me nt Visit wit hi n 2 wee ks of t he s u bjects last i nf usi o n.  T he s u bject will ret ur n 
f or st u d y visits ( wit h o ut treat me nt).  See Secti o n 9. 3. 3. 1. 1  f or details.  
Bef ore starti n g pe gl oticase, s u bjects s h o ul d disc o nti n ue oral urate-l o weri n g t hera p y a n d n ot 
i nstit ute t hera p y wit h t hese a ge nts w hile ta ki n g pe gl oticase. 
Refer t o t he c urre nt v ersi o n of t he F D A-a p pr o ve d K R Y S T E X X A F ull Pres cri bi n g I nf or mati o n  
a n d pe gl oticase ( K R Y S T E X X A) I n v esti gat or’s Br oc h ure f or detaile d i nf or mati o n c o ncer ni n g t he 
safet y pr ofile of pe gl otic ase. 

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7. 1. 2. 1  P h ysi oc he mic al Pr o perties 
Pe gl oticase is a uric aci d-s pecific e nz y me t hat is a m o n o met h o x y- p ol y(et h yl e ne gl yc ol) 
( P E G) yl ate d pr o d u ct c o nsisti n g of rec o m bi na nt m o difie d ma m malia n urate o xi dase ( uricase) 
pr o d uce d b y a ge neticall y m o difie d strai n of Esc h eric hi a c oli . Uricas e is c o vale ntl y c o nj u gate d 
t o met h o x y P E G ( m P E G) ( 1 0 k Da m olec ular wei g ht). T he c D N A c o di n g f or uricase is b ase d o n 
ma m malia n se q ue nces. E ac h uricase s u b u nit has a m olec ular wei g ht of a p pr o xi matel y 3 4 k D a. 
T he a vera ge m olec ular w ei g ht of p e gl oticase (t etra meric e nz y m e c o nj u gate d t o m P E G) is 
a p pr o xi matel y 5 4 5 k Da. 
I N N: 
Pe gl oticase 
C he mic al n a me (I N N): 
O xi dase, urate (s y nt hetic S us scr of a  varia nt pi g K S-Δ N s u b u nit), 
h o m otetra mer, a mi de wit h α -car b o x y-ω - met h o x y p ol y( o x y-1, 2-
et ha ne di yl) 
N ati o n al dr u g c o de 
( N D C): 
7 5 9 8 7- 0 8 0- 1 0 
C A S n u m ber 
8 8 5 0 5 1- 9 0- 1 
M olec ul ar f or m ul a: 
C xH yN 1 6 3 2O zS 3 2 
W herei n, x = ~ 2 2, 9 2 0, y = ~ 4 3, 0 9 5, z = ~ 1 0, 1 9 1 
M olec ul ar wei g ht: 
M o n o mer pe gl oticase a p pr o xi matel y 5 4 5 k Da  
( b as e d o n t he esti m ati o n of a mi n o aci d se q ue nce of uric ase a n d 
a n aver a ge of 1 0. 2 str a n ds of a p pr oxi m ately 1 0 k D a 
m o n o met h oxy p ol y ( et hyl e ne glyc ol) ( m P E G) per uric ase 
m o n o meric s u b u nit. T he m o n o met h oxy p ol y (et hyl e ne glyc ol) 
str a n ds att ac he d t o t he uric ase pr otei n c o m prise a p pr oxi m ately 
t hree- q u arters of t he m ol ec ul ar wei g ht of pe gl otic ase.) 
C he mic al Str uct ur al 
F or m ul a:  
{ [ H 3 C - O - ( C H 2 C H 2 - O ) m - C O - ] n - N H -   
[ T Y K K N D E V E F  V R T G Y G K D M I  K V L H I Q R D G K   Y H S I K E V A T T   V Q L T L S S K K D  
Y L H G D N S D V I  P T D T I K N T V N  V L A K F K G I K S  I E T F A V T I C E  H F L S S F K H V I  
R A Q V Y V E E V P  W K R F E K N G V K  H V H A F I Y T P T  G T H F C E V E Q I  R N G P P V I H S G  
I K D L K V L K T T  Q S G F E G F I K D  Q F T T L P E V K D  R C F A T Q V Y C K  W R Y H Q G R D V D  
F E A T W D T V R S  I V L Q K F A G P Y  D K G E Y S P S V Q  K T L Y D I Q V L T  L G Q V P E I E D M  
E I S L P N I H Y L   N I D M S K M G L I   N K E E V L L P L D  N P Y G K I T G T V  K R K L S S R L ] } 4  
W herei n, m = ~ 2 2 5, n = ~ 1 0. 2 a n d eac h uricas e m o n o meric s u b u nit 
ha vi n g t he a mi n o aci d se q ue nce liste d a b o v e.  
A p pr o xi matel y 1 0. 2 u nits of met h o x y p ol y(et h yl e ne gl yc ol) are 
attac he d t o L ysi ne( K) resi d ues per uricase m o n o m eric s u b u nit. 
A p pe ar a nce: 
Clear c ol orless s ol uti o n, free of visi ble particles. 
 
7. 1. 2. 2  S afet y P h ar m ac ol o g y 
U nli ke m ost ma m malia n s pecies, h u ma ns lac k t h e urate o xi dase e nz y matic pat h wa y f or t h e 
o xi dati o n a n d dis p ositi o n of uric aci d a n d are s usce pti ble t o t he de vel o p me nt of g o ut. T o de v el o p 
a n a ni mal m o del of h y per urice mia a n d g o ut f or a t hera pe utic uricas e pr o of- of-c o nce pt st u d y, a 
m o use was ge neticall y m o difie d b y k n o c ki n g o ut its e n d o ge n o us uricas e ge ne ( U ox ). T his 
ge n etic lesi o n res ults i n a mar ke d ele v ati o n of plas ma uric aci d le v els, lea di n g t o de p ositi o n of 
urate i n ki d ne y tiss ue a n d ca usi n g a pr of o u n d defect i n re nal c o nce ntrati n g a bilit y a n d 

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ne p hr o ge nic dia b etes i nsi pi d us. T he st u dies i n t he m o use U ox-/- s yste m de m o nstrate t he 
t hera pe utic p ote ntial of p e gl otic ase a d mi nistrati o n f or t he treat me nt of h y per urice mia a n d 
pr o vi de d a “ pr o of of pri nci ple” f or t h e cli nical use of pe gl oticase.  
I n a d diti o n, i n n o ncli nical t o xicit y st u dies i n w hic h uric aci d le v els were meas ure d, a decli ne i n 
uric aci d le v els f oll o wi n g a d mi nistrati o n of pe gl ot i case (all pe gl oticase d os es ass ociate d wit h 
t hese st u dies) was o bser ve d. 
T he res ults fr o m t he ac ut e a n d c hr o ni c t o xicit y st u dies di d n ot i n dicate a n y t o xic or a d verse 
effect of pe gl oticas e a d mi nistere d wit h a h u ma n e x p os ure 6 4 5 ti mes hi g her t ha n t hat i n t he 
P hase 3 cli nical st u dies ( 8 m g e v er y 2 wee ks) base d o n t he area u n der t he c ur ve val u es fr o m t he 
3 9- wee k, re peat- d ose, d o g st u d y ( hi g h- d ose). 
A n o bser vati o n i n t he c hr o nic t o xic ol o g y st u dies is t he fi n di n g of a d ose- d e pe n de nt i ncrease i n 
vac u olate d cells. T here w ere n o ass o ciate d cli n ical ma nifestati o ns i n a n y a ni mals i n w hic h 
vac u olate d cells were prese nt. E vi de nce of vac u ol a te d cells, es p eciall y i n t he s plee n, has b ee n 
o bser ve d wit h pe gl oticas e a d mi nistrati o n i n all t he c hr o nic t o xicit y st u dies as well as t he 
e m br y o/fetal de v el o p me nt a n d a bs or pti o n, distri b uti o n, meta b olis m, a n d e x creti o n st u dies i n t he 
rat. It is t h o u g ht t hat va c u olati o n of s plee n macr o p ha ges is a res ult of l ys os o mal o verl oa di n g 
f oll o wi n g p ha g o c yt osis of persiste nt circ ul ati n g m acr o m olec ul es of hi g h m olec ular wei g ht. I n t he 
3 9- wee k, l o n g-t er m t o xicit y st u dies i n d o gs, v ac u o late d cells were als o pr es e nt i n t he basal area 
of t he la mi na pr o pria wit hi n t he d u o de n u m a n d jej u n u m, a dre nal c ortical cells, he patic K u pffer 
cells, a n d t he i nti mal cells wit hi n t he a ortic o utfl o w area of t he h eart. T he vac u olate d cells i n t he 
heart a n d a dre n al gla n d di d n ot stai n as macr o p ha ge s. I n t he a ortic o utfl o w tract of t he h eart, 
vac u oles were see n i n t he c yt o plas m of e n d ot helial cells i n t he i nti mal li ni n g of t he a orta. I n t he 
a dre nal gla n d, v ac u oles were l oc ate d wit hi n c ort i cal cells i n t he z o na retic ularis a n d z o na 
fascic ulat a. T he cli nic al si g nifica n ce of t hese fi n di n gs a n d f u ncti o nal c o nse q ue nces are u n k n o w n. 
Refer t o t he c urre nt v ersi o n of t he pe gl oticase ( K R Y S T E X X A) I n vesti gat o r’s Br oc h ure f or 
detaile d i nf or mati o n. 
7. 1. 2. 3  N o n-cli nic al P h ar m ac o ki netics 
A series of p h ar mac o ki netic ( P K) st u dies was c o n d ucte d i n rats, ra b bits, d o gs, a n d pi gs t o 
deter mi ne t he cir c ulati o n half-life a n d bi o a vaila b ilit y as a f u ncti o n of t he r o ute of pe gl oticas e 
a d mi nistrati o n. Plas ma pe gl otic ase le vels w ere d eter mi ne d b y assa yi n g uri case bi oacti vit y i n 
plas ma. As part of t he P K st u dies, a nti b o d y le vel s i n plas ma were d eter mi ne d 2 wee ks after t h e 
last i njecti o n i n t he ra b bit, d o g, a n d rat. C ollecti vel y, t he res ults of t he P K st u dies i n t hese 
a ni mals le n d s u p p ort t o t he e x pectati o n of hi g h  bi oa vaila bilit y a n d pr ol o n ge d rete nti o n of 
pe gl otic ase after a d mi nistrati o n i n h u ma ns. 
A bs or pti o n, distri b uti o n, meta b olis m, a n d e x creti o n of  pe gl oticase were e x a mi ne d i n rat st u dies. 
A p pr o xi matel y 7 0 % of t he d ose was e x crete d i n  t he uri ne d uri n g t he c o urse of 7 da ys after 
i njecti o n.  

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Refer t o t he c urre nt v ersi o n of t he pe gl oticase ( K R Y S T E X X A) I n vesti gat or’s Br oc h ure f or 
detaile d i nf or mati o n. 
7. 1. 2. 4  Cli nic al E x perie nce 
7. 1. 2. 4. 1  I ntr o d ucti o n 
Pe gl oticase was gra nte d or p ha n desi g nati o n b y t h e F D A o n 2 1 Fe br uar y 2 0 0 1 
 
a n d pe gl oticase 8 m g e v er y 2 wee ks w as a p pr o ve d b y t he F D A o n 1 4 Se pte m ber 2 0 1 0 f or t he 
treat me nt of a d ult patie nts wit h c hr o nic g o ut refract or y t o c o n ve nti o nal t hera p y. 
7. 1. 2. 4. 2  Effic ac y 
Res ults of t he 2 pi v otal P hase 3 st u dies de m o ns trate d t hat pe gl oticase 8 m g i nf use d e ver y 
2 wee ks r es ults i n cli nical i m pr o ve me nts a n d dis ease m o dificati o n a n d pr o vi des a n effecti ve 
t hera p y f or t h e c o ntr ol of t he cli nical c o nse q u e nces of h y p er urice mia i n patie nts wit h 
s y m pt o matic g o ut i n w h o m c o n ve nti o nal t hera p y is co ntrai n dicate d or has b ee n i neffecti ve, wit h 
a fa v ora ble ris k/ be n efit pr ofile. T he pri n ci pal safet y ris ks ass o ciate d wit h pe gl oticase i n cl u de 
a na p h yla xis, I Rs, a n d g o ut flares. T he l o n ger-ter m e x p os ure e vi de nce d b y t he o pe n-la bel 
e xte nsi o n st u d y s u p p orts t he be nefit-t o-ris k assess me nt of 8 m g of pe gl oticase I V e ver y 2 wee ks 
as a n effecti ve t h era p y i n c hr o nic g o ut patie nts, partic ularl y t h ose wit h t o p hi w h o are 
u nres p o nsi ve t o ot her t hera pies. 
7. 1. 2. 4. 3  P h ar m a c o ki netics 
Pe gl oticase l e vels were d eter mi ne d i n ser u m bas e d o n meas ure me nts of uricase e nz y me acti vit y.  
F oll o wi n g si n gle I V i nf usi o ns of 0. 5 m g t o 1 2 m g pe gl oticase i n 2 3 patie nts wit h s y m pt o matic 
g o ut, ma xi m u m ser u m c o nce ntrati o ns of pe gl oti case i ncrease d i n pr o p orti o n t o t he d ose 
a d mi nistere d.  
T he P K of pe gl oticase h as n ot bee n st u die d i n c hil dre n a n d a d ol esce nts.  
I n p atie nts u n der g oi n g he m o dial ysis 
 pe gl oticase ser u m c o n ce ntrati o ns were n ot 
cli nicall y me a ni n gf ull y affect e d b y 2 he m o dial ysis sessi o ns. Pre- a n d p ost- dial yz er sa m ples, as 
well as sa m ples ta ke n d uri n g dial ysis, de m o nstrat e d t hat st u d y dr u g was n ot re m o ve d b y t he 
dial ysis pr ocess. 
N o f or mal st u dies ha ve b ee n c o n d u cte d t o e x a mi ne t he effects of h e patic i m pair me nt o n 
pe gl otic ase P K. 
7. 1. 2. 4. 4  S afet y 
T he pri nci pal safet y ris ks ass ociate d wit h pe gl oticase i ncl u de a n a p h yla xis, I Rs, a n d g o ut fl ares. 
Pe gl oticase h as n ot bee n f or mall y st u die d i n p atie nts wit h c o n gesti ve h eart fail ure, b ut s o me 
s u bjects i n t he cli nical trials e x perie n ce d e x acer bati o n. E x ercise ca uti o n w he n usi n g p e gl oticase 
i n patie nts w h o ha ve c o n gesti ve h eart fail ure a n d m o nit or patie nts cl osel y f oll o wi n g i nf usi o n. 

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T he data s u p p ort t hat m o nit ori n g of s U A a n d disc o nti n uati o n of pe gl oticas e t hera p y i n patie nts 
w h o l ose t he a bilit y t o m ai ntai n uric aci d < 6 m g/ d L ca n lea d t o t he a v oi da nce of t he maj orit y of 
I Rs a n d u n n ecessar y e x p os ure t o dr u g. T he l o n ger-ter m e x p os ure e vi de nce d b y t he o pe n-la bel 
e xte nsi o n st u d y s u p p orts t he be nefit-t o-ris k assess me nt of 8 m g of pe gl oticase I V e ver y 2 wee ks 
as a n effecti ve t h era p y i n c hr o nic g o ut patie nts, partic ularl y t h ose wit h t o p hi w h o are 
u nres p o nsi ve t o ot her t hera pies. 
Base d o n t h e res ults o bser ve d i n t he P hase 4 o bser vati o nal st u d y of pe gl oticase 8 m g I V e v er y 
2 wee ks f or u p t o 5 2 wee ks, pe gl oticas e re m ai ns a be neficial tr eat me nt f or  a d ult patie nts wit h 
c hr o nic g o ut refract or y t o c o n ve nti o nal t hera p y. T he safet y pr ofile re mai ns u nc ha n ge d f or 
pe gl otic ase i n ter ms of I Rs, a na p h yl a xis, a n d ot her S A Es. Li miti n g f ut ure i nf usi o ns o nce s U A 
has bee n de m o nstr ate d t o be ele v at e d o n 2 c o nsec uti ve occasi o ns a p p eare d t o decrease t he ris k of 
a na p h yla xis, w hic h i m pr o ves t he be nefit-t o-ris k e q uati o n fa v ori n g t he use of pe gl oticase. N o ne w 
safet y i nf or mati o n w as i de ntifie d. 
7. 1. 3  Met h otre x ate 
M T X is a f olic aci d r e d u ctase i n hi bit or use d as a disease- m o dif yi n g, a nti-r he u matic dr u g f or t h e 
treat me nt of a ut oi m m u ne diseases.  
A d verse e ve nts ( A Es) t hat ma y b e e x perie nce d b y s u bjects treate d wit h M T X i ncl u de: 
 Gastr oi ntesti nal: na usea, v o mit i n g, diarr hea, st o matitis 
 He mat ol o gi c a n d o nc ol o gic: le u k o pe nia, t hr o m b o c yt o p e nia 
 He patic: he p at ot o xicit y, i ncreas e d ser u m al kali ne p h os p hatase, i ncrease d s er u m bilir u bi n, 
i ncreas e d ser u m tra ns a mi nases 
 I nfecti o n: i ncrease d s us ce pti bilit y t o i nfecti o n 
 Ge neral: malaise, fati g ue, diz zi ness, al o pecia, p h ot ose nsiti vit y 
A d diti o nall y, M T X ca n ca use fet al deat h or terat o ge ni c effects.  Pre g n a nc y s h o ul d be a v oi de d if 
eit her part n er is recei vi n g M T X, d uri n g, a n d f or a mi ni m u m of t hree m o nt hs after M T X t h era p y 
f or t he n o n- vas ect o miz e d male.  F or fe males of c hil d beari n g p ot e ntial, pre g na n c y s h o ul d be 
a v oi de d f or at least o ne o v ulat or y c ycle after M T X t hera p y.  Refer t o t he c urre nt versi o n of t he 
F D A- a p pr o ve d M T X F ull Prescri bi n g I nf or mati o n  f or detaile d i nf or mati o n c o ncer ni n g t he s afet y 
pr ofile of M T X. 
7. 2  
R ati o n ale f or t his St u d y 
I m m u n o ge nicit y (a nti- pe gl oticase a nti b o dies) i n r es p o nse t o pe gl oticase t h era p y ma y lea d t o l oss 
of t hera p e utic res p o nse a n d/ or A Es, i ncl u di n g I Rs. I Rs occ urre d m ore c o m m o nl y i n s u bjects 
w h ose s U A val ues i n crease d a b o ve 6 m g/ d L aft er i nitiall y s h o wi n g res p o ns e f oll o wi n g t he first 
1 or 2 i nf usi o ns. I n t h e P hase 3 pr o gra m, t he titer  of t he a nti- dr u g a nti b o d y was als o ass ociat e d 
wit h l oss of res p o nse, wit h s u bjects ha vi n g t h e hi g hest le vels of a nti- dr u g a nti b o dies s h o wi n g t he 
l o west res p o nse rates. 

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T he de vel o p me nt of a nti- dr u g a nti b o dies ca n b e i nfl ue nce d b y dr u g a n d treat me nt-relate d fact ors, 
as well as patie nt c h aract eristics. A p ote ntial pr o p h ylactic strate g y t o ma na ge a nti- dr u g a nti b o d y 
res p o nse wit h pe gl oticas e is t he c o-a d mi nistrati o n of i m m u n o m o d ulati n g t hera p y. Vari o us 
met h o ds are use d t o r e d u ce a nti b o d y pr o d ucti o n, t he m ost c o m m o n of w hic h is t he use of 
tra diti o nal r he u mat oi d art hritis disease- m o dif yi n g dr u gs, s u c h as M T X, azat hi o pri ne, 
m yc o p h e n olate m ofetil, l efl u n o mi d e, a n d ot hers, as is c o m m o nl y i m ple me nte d wit h r he u mat oi d 
art hritis bi ol o gical t hera p y (e. g., i nfli xi ma b a n d ot her i nf usi ble a n d s u bc ut a ne o us a nti b o d y 
pr o d ucts) [ Stra n d et al, 2 0 1 7 ].  
M T X is t he m ost c o m m o nl y use d n o n- bi ol o gical disease m o dif yi n g a ge nt w orl d wi de a n d is 
fre q ue ntl y use d i n c o m bi nati o n wit h ot her bi ol o gi cal t hera pi es [Stra n d et al, 2 0 1 7 ].  
I n t he c urre nt st u d y, M T X will be e val uate d f or its a bilit y t o re d uce a nti dr u g a nti b o dies a gai nst 
pe gl otic ase t hat lea d t o l oss of res p o nse a n d t h at are ass ociate d wit h I Rs, t here b y all o wi n g 
patie nts t o recei ve a l o n ger c o urs e of t hera p y or re peate d c o urses of t hera p y, as nee de d. 
7. 3  
R ati o n ale f or D ose Sele cti o n 
T he d ose a n d d os e re gi m e ns use d i n t his st u d y are t h ose s pecifie d b y t he prescri bi n g i nf or mati o n 
f or pe gl oticase a n d M T X, res pecti vel y. 
8  
S T U D Y O B J E C TI V E S 
T he o verall o bjecti ve of t he st u d y is t o a ssess t he efficac y, safet y, t ol era bilit y, a n d 
p har mac o ki netics ( P K) of t he c o nc o mita nt use of M T X wit h pe gl oticase t o e n ha nce t he res p o ns e 
rate see n wit h pe gl oticas e al o ne i n a d ults wit h u nc o ntr olle d g o ut.   
Pri mar y O bj ecti ve 
T he pri mar y o bje cti ve is t o esti mate t he res p o ns e rate d uri n g M o nt h 6 ( Wee ks 2 0, 2 2, a n d 2 4), as 
meas ure d b y t he s ustai n e d n or maliz ati o n of ser u m uric aci d (s U A) t o < 6 m g/ d L f or at least 8 0 % 
of t he ti me d uri n g M o nt h 6 i n s u bjects recei vi n g p e gl oticase wit h M T X. 
Sec o n dar y O bj ecti ves 
 Esti mate t he res p o nse rat e d uri n g M o nt h 3 ( Wee ks 1 0, 1 2 a n d 1 4), as me as ure d b y t he 
s ustai ne d n or maliz ati o n of s U A t o < 6 m g/ d L f or at least 8 0 % of t he ti me d uri n g M o nt h 3 
i n s u bjects recei vi n g pe gl oticase wit h M T X. 
 Esti mate t he o verall res p o nse rate, as meas ure d b y t he s ustai ne d n or malizati o n of s U A t o 
< 6 m g/ d L f or at least 8 0 % of t he ti me d uri n g M o nt h 3 ( Wee ks 1 0, 1 2 a n d 1 4) a n d M o nt h 
6 ( Wee ks 2 0, 2 2 a n d 2 4) c o m bi ne d i n s u bjects recei vi n g pe gl oticase wit h M T X. 
 Esti mate t he 5 m g/ d L res p o nse rate d uri n g M o nt h 3, d uri n g M o nt h 6, a n d O v erall 
( M o nt hs 3 a n d 6 c o m bi ne d), as me as ure d b y t he s ustai ne d n or malizati o n of s U A t o < 5 
m g/ d L f or at least 8 0 % of t he ti me i n s u bjects recei vi n g pe gl oticase wit h M T X. 

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 Esti mate t he mea n c ha n ge fr o m baseli ne t o  Wee ks 1 4, 2 4, 3 6, a n d 5 2 i n s U A i n s u bjects 
recei vi n g pe gl otic ase wit h M T X. 
E x pl orat or y O bjecti ves 
 Esti mate t he res p o nse rat e d uri n g M o nt h 9 ( Wee ks 3 2, 3 4 a n d 3 6), as me as ure d b y t he 
s ustai ne d n or maliz ati o n of s U A t o < 6 m g/ d L f or at least 8 0 % of t he ti me d uri n g M o nt h 9 
i n s u bjects recei vi n g pe gl oticase wit h M T X. 
 Esti mate t he res p o nse rat e d uri n g M o nt h 1 2 ( Wee ks 4 8, 5 0 a n d 5 2), as me as ure d b y t he 
s ustai ne d n or maliz ati o n of s U A t o < 6 m g/ d L f or at least 8 0 % of t he ti me d uri n g M o nt h 
1 2 i n s u bjects recei vi n g p e gl oticase wit h M T X. 
 Esti mate t he 5 m g/ d L res p o nse rate d uri n g M o nt h 9 ( Wee ks 3 2, 3 4 a n d 3 6), as meas ure d 
b y t he s ustai ne d n or malizati o n of s U A t o < 5 m g/ d L f or at least 8 0 % of t he ti me d uri n g 
M o nt h 9 i n s u bjects recei vi n g pe gl oticas e wit h M T X. 
 Esti mate t he 5 m g/ d L res p o nse rate d uri n g M o nt h 1 2 ( Wee ks 4 8, 5 0 a n d 5 2), as meas ure d 
b y t he s ustai ne d n or malizati o n of s U A t o < 5 m g/ d L f or at least 8 0 % of t he ti me d uri n g 
M o nt h 1 2 i n s u bjects recei vi n g pe gl oticase wit h M T X. 
 Esti mate t he ti me t o first s U A > 6 m g/ d L i n s u bjects recei vi n g pe gl oticase wit h M T X. 
 Esti mate t he ti me t o t w o c o nsec uti ve s U As > 6 m g/ d L (st o p pi n g r ule) i n s u bjects 
recei vi n g pe gl otic ase wit h M T X. 
 Esti mate t he mea n c ha n ge fr o m baseli ne t o Wee k 2 4, 3 6 a n d 5 2 i n urate v ol u me a n d g o ut 
er osi o ns usi n g D E C T sca n of t he ha n ds a n d feet i n s u bjects recei vi n g p e gl oticase wit h 
M T X. 
 Esti mate t he mea n c ha n ge fr o m baseli ne i n n u m be r of j oi nts affecte d b y t o p hi i n s u bjects 
recei vi n g pe gl otic ase wit h M T X. 
 Esti mate t he mea n c ha n ge fr o m baseli ne t o  Wee ks 1 4, 2 4, 3 6, a n d 5 2 i n te n der j oi nt c o u nt 
( 6 8 p oi nt scale) i n s u bjects recei vi n g pe gl oticas e wit h M T X. 
 Esti mate t he mea n c ha n ge fr o m baseli ne t o Wee ks 1 4, 2 4, 3 6, a n d 5 2 i n s w olle n j oi nt 
c o u nt ( 6 6 p oi nt scale) i n s u bjects recei vi n g p e gl oticase wit h M T X. 
 Esti mate t he mea n c ha n ge fr o m baseli ne t o Wee ks 1 4, 2 4, 3 6, a n d 5 2 i n t he Healt h 
Assess me nt Q uesti o n nair e –  Disa bilit y I n d e x ( H A Q- DI) i n s u bjects recei vi n g pe gl oticase 
wit h M T X. 
 Esti mate t he mea n c ha n ge fr o m baseli ne t o Wee ks 1 4, 2 4, 3 6, a n d 5 2 i n t he H A Q pai n 
sc ore i n s u bjects r ecei vi n g pe gl oticase wit h M T X. 
 Esti mate t he mea n c ha n ge fr o m baseli ne t o Wee ks 1 4, 2 4, 3 6, a n d 5 2 i n t he H A Q healt h 
sc ore i n s u bjects r ecei vi n g pe gl oticase wit h M T X. 
 Esti mate t he mea n c ha n ge fr o m baseli ne t o Wee ks 1 4, 2 4, 3 6, a n d 5 2 i n patie nt gl o bal 
assess me nt of g o ut i n s u bjects recei vi n g p e gl oticas e wit h M T X. 
 Esti mate t he mea n c ha n ge fr o m baseli ne t o Wee ks 1 4, 2 4, 3 6, a n d 5 2 i n p h ysicia n gl o bal 
assess me nt of g o ut i n s u bjects recei vi n g p e gl oticas e wit h M T X. 

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 Esti mate t he mea n c ha n ge fr o m baseli ne t o Wee ks 1 4, 2 4, 3 6, a n d 5 2 i n s u bject 
assess me nt of a v era ge, le ast, a n d w orst j oi nt pai n i n s u bjects recei vi n g p e gl oticase wit h 
M T X. 
 Esti mate t he pr o p orti o n of s u bjects ac hie vi n g 2 0 %, 5 0 %, or 7 0 % i m pr o ve m e nt base d o n 
g o ut c hr o nic res p o ns e criteria at Wee ks 1 4, 2 4, 3 6, a n d 5 2 i n s u bjects r ecei vi n g 
pe gl otic ase wit h M T X. 
 Assess t he P K of pe gl oticase i n s u bjects r ecei vi n g c o nc o mita nt M T X. 
  Assess t he i nci de nce of a nti- P E G a n d a nti- Uricase I g G a nti b o dies. 
 
Safet y a n d T olera bilit y O bjecti ves 
 Assess t he i nci de nce of i nf usi o n reacti o ns (I Rs), a na p h yl a xis, g o ut flares, car di o vasc ular 
e ve nts, a n d t he a d v erse e ve nt ( A E/ S A E) pr ofile o verall a n d p ote ntiall y attri b ute d t o t he 
c o m bi nati o n of pe gl oticase a n d M T X. 
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 st u d y is a m ultice nter, o pe n-l a bel, efficac y a n d safet y st u d y of pe gl oti case i n c o m bi nati o n 
wit h M T X i n a d ult s u bjects wit h u nc o ntr olle d g o ut.  
T he st u d y d esi g n will i ncl u de: 1) u p t o a 2- wee k Scree ni n g Peri o d (scree ni n g s h o ul d be c o m plete 
wit hi n 2 wee ks pri or t o Wee k - 4), 2) a 4- wee k M T X R u n-i n Peri o d ( Wee k –  4 t hr o u g h Da y 1); 3) 
a 5 2- wee k Pe gl oticase + I M M ( Pe gl oticase  + M T X) Peri o d 4) a Safet y F oll o w- u p 
( P h o ne/ E mail/ Site Visit) a n d 5) a 3 a n d 6 m o nt h P ost Treat me nt F oll o w- u p.   
All s u bjects w h o meet eli gi bilit y criteria at Scree ni n g will b e gi n oral M T X at a d ose of 1 5 m g 
wee kl y f or 4 wee ks pri or t o t he first d ose of pe gl oticase.  
S u bjects will als o ta ke f olic aci d 1 m g orall y e v er y da y b e gi n ni n g at Wee k - 4 (t he start of M T X) 
a n d c o nti n ui n g u ntil pri or t o t he Wee k 5 2 Visit. S u bjects m ust be a ble t o t olerate M T X at a d ose 
of 1 5 m g d uri n g t he M T X R u n-i n ( Wee k - 4 t hr o u g h Da y 1) t o be eli gi ble t o partici pate i n t he 
Pe gl oticase + I M M Peri o d. S u bjects w h o are u n a ble t o t olerate M T X at a d ose of 1 5 m g d uri n g 
t he M T X R u n-i n Peri o d will be c o nsi dere d scree n fail ures. 
S u bjects w h o ta ke at least o ne d ose of M T X a n d w h o are fe males of c hil d beari n g p ote ntial, will 
recei v e a safet y f oll o w- u p P h o ne Call/ E- mail/ Site Visit a p pr o xi matel y 3 0 d a ys after t h e last d ose 
of M T X t o verif y at least o ne o v ulat or y c ycl e has occ urre d aft er t he last d ose of M T X.  If t h e 
s u bject has n ot o v ulate d, a uri ne pre g na nc y t est will be perf or me d. S u bjects w h o recei ve at least 
o ne d ose of M T X a n d w h o are n o n- v asect o mize d males, will be as ke d, 3 m o nt hs after M T X 
disc o nti n uati o n, re gar di n g part ner pre g na n c y. 

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All s u bjects w h o c o m plete t he R u n-I n Peri o d will recei v e t he first pe gl oticase i nf usi o n o n Da y 1. 
All s u bse q ue nt d oses a n d st u d y visits will be sc he d ule d base d o n t he Da y 1 visit date.  
It is re q uire d t hat bef ore a s u bject be gi ns t he Pe gl oticase + I M M Peri o d, he or s he has b ee n 
ta ki n g at least o ne pr ot oc ol sta n dar d g o ut flare pr o p h yla xis re gi me n (i.e.  c olc hici ne a n d/ or n o n-
ster oi dal a nti-i nfla m mat or y dr u gs a n d/ or l o w- d os e pre d nis o ne ≤1 0 m g/ d a y) f or ≥1 wee k bef ore 
t he first d ose of pe gl oticase a n d c o nti n ues flare pr o p h yla xis per A merica n C olle ge of 
R he u mat ol o g y g ui deli nes [ K ha n na D et al. 2 0 1 2] f or t he greater of 1) 6 m o nt hs, 2) 3 m o nt hs after 
ac hie vi n g tar get ser u m ur ate (s U A < 6 m g/ d L) f or  patie nts wit h n o t o p hi detecte d o n p h ysical 
e x a m, or 3) 6 m o nt hs after ac hi e vi n g t ar get ser u m urate (s U A < 5 m g/ d L) f or patie nts wit h o ne 
or m ore t o p hi detect e d o n i nitial p h ysic al e xa m t hat ha ve si nce res ol ve d. F or I R pr o p h yl a xis, 
fe x ofe na di ne ( 6 0 m g or 1 8 0 m g orall y bas e d o n t h e Pri nci pal I n vesti gat or’s discreti o n) will be 
ta ke n t he da y b ef ore eac h i nf usi o n; fe x ofe na di ne ( 6 0 m g or 1 8 0 m g orall y b ase d o n t he Pri nci pal 
I n v esti gat or’s discreti o n) a n d aceta mi n o p he n ( 1 0 0 0 m g orall y) will be ta ke n t he m or ni n g of eac h 
i nf usi o n; a n d met h yl pre d nis ol o ne ( 1 2 5 m g I V) gi v e n o ver t he i nf usi o n d ur ati o n 1 0- 3 0 mi n utes 
(rec o m me n d e d) or h y dr oc ortis o ne ( 2 0 0 m g I V) will be a d mi nistere d i m me diatel y pri or t o eac h 
i nf usi o n.  
D uri n g t h e Pe gl oticase + I M M Peri o d, p e gl oticase 8 m g will be a d mi nistere d i ntra ve n o usl y (I V) 
e ver y 2 w ee ks fr o m Da y 1 t hr o u g h t he Wee k 5 0 Visit f or a t otal of 2 6 i nf usi o ns; pe gl oticas e will 
be a d mi nistere d after all pre- d ose st u d y visit asse ss me nts ha ve bee n c o m plete d at eac h visit. T he 
date a n d start a n d st o p ti m e of i nf usi o n will be rec or de d.  Ser u m uric aci d st o p pi n g r ules will be 
a p plie d: s u bjects wit h s U A le vel > 6 m g/ d L at 2 c o nsec uti ve st u d y visits be gi n ni n g wit h t he 
Wee k 2 Visit will disc o nti n ue treat me nt, c o m plete t he E n d of Pe gl oticase I nf usi o n Visit 
pr oce d ures wit hi n 2 wee ks a n d c o nti n ue t he s u bj ect visits acc or di n g t o t he pr ot oc ol ( wit h o ut 
treat me nt). 
D uri n g t h e Pe gl oticase + I M M Peri o d, s u bjects will be i nstr ucte d t o ta ke M T X wee kl y o n t he 
sa me da y eac h w ee k, wit hi n 1 t o 3 da ys pri or t o eac h pe gl oticas e i nf usi o n a n d o ne a d diti o nal 
wee kl y d ose after t he l ast i nf usi o n f or s u bjects  w h o ha ve n ot st o p pe d pe gl oticase d ue t o s U A 
st o p pi n g r ules; h o we v er, if a s u bject d oes n ot d o s o, M T X m ust be ta ke n ≥6 0  mi n utes pri or t o 
eac h p e gl oticase i nf usi o n. 
After D a y 1, if a s u bject bec o mes u na ble t o t olerate 1 5 m g of M T X, t he M T X d ose ma y be 
re d uce d a n d/ or disc o nti n ue d, a n d t he s u bject ma y re mai n i n t he st u d y (see Secti o n 9. 4. 6. 3. 2. 2 ). 
T he I n vesti gat or will re vi e w t he cli nical stat us a n d i n di vi d ual s u bject treat me nt g o als at Wee k 
2 4, a n d t he E n d of Pe gl oticase I nf usi o ns Vi sit (if a p plica ble) a n d t he Wee k 5 2/ E n d of 
st u d y/ Earl y T er mi nati o n Visit.   
Ser u m sa m ples f or meas ure me nt of s U A  l e vels will be c ollecte d at t he Scree ni n g Visit, t he Wee k 
- 4 Visit ( pri or t o t he first d ose of M T X), a n d t he Wee k - 2 Visit d uri n g t he M T X R u n-i n Peri o d; 
wit hi n 4 8 h o urs pri or t o eac h pe gl oticas e i nf usi o n a n d after t he e n d of eac h pe gl oticase i nf usi o n 
pri or t o disc har ge fr o m t he site d uri n g t h e Pe gl oticase + I M M Peri o d; at t he n o n-i nf usi o n 
Wee k 5 2/ E n d of St u d y/ E arl y Ter mi nati o n Visits  a n d at t he P ost Treat me nt 3 a n d 6 M o nt h 
F oll o w- u p Visits. A d diti o nal ser u m sa m ples f or s U A le vels will be c ollect e d at o pti o nal n o n-

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i nf usi o n ( Fre q u e nt Sa m pli n g) Visits at Wee ks 1 a n d 7.  If a p plica bl e a n s U A sa m ple will nee d t o 
be c ollecte d at t he E n d of Pe gl oticase Visit if a s u bject d oes n ot c o nti n ue treat me nt.  S u bjects 
wit h s U A le vel > 6 m g/ d L at 2 c o nsec uti ve visits  be gi n ni n g at Wee k 2 visit will disc o nti n ue 
treat me nt, c o m plete t he E n d of Pe gl oticase I nf usi o n Visit pr oce d ures wit hi n 2 wee ks a n d 
c o nti n ue t he s u bject visits acc or di n g t o t he pr ot o c ol ( wit h o ut treat me nt).  
Sa m ples f or meas ur e me nt of s U A le vels, P K a nal ysis of pe gl oticas e, pe gl oti case 
i m m u n o ge nicit y a n d M T X P ol y gl ut a mate a n al ysis will be c ollecte d at visits i n dicate d i n t he 
Sc he d ule of Assess me nts ( Secti o n 2. 1 ). 
Safet y assess me nts, i ncl u di n g m o nit ori n g a n d rec or di n g of all A Es, w het her or n ot dr u g-rel ate d, 
meas ure me nt of vital si g ns, p h ysical e x a mi nati o ns, a n d m o nit ori n g of he m at ol o g y a n d bl o o d 
c he mistr y, will be perf or me d.  
T he t otal bl o o d v ol u me t o be c ollecte d fr o m eac h  s u bject d uri n g t his st u d y is a p pr o xi matel y 7 0 0 
m L, i ncrease d t o 7 5 0 m L f or t he s u bjects partici pat i n g i n t he o pti o nal visits at Wee k 1 a n d W ee k 
7. 
A n o ver vie w of t he st u d y desi g n is prese nte d i n t h e sc he matic bel o w, a n d d etails of st u d y 
acti vities are pr o vi d e d i n Secti o n 9. 1 . 

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Fi g ure 9. 1  
Sc he m atic of St u d y Desi g n 
 
 
9. 2  
Disc ussi o n of St u d y Desi g n 
T his st u d y is a m ultice nter, o pe n-l a bel, efficac y  a n d safet y st u d y of pe gl oti case i n c o m bi nati o n 
wit h M T X i n a d ult s u bjects wit h u nc o ntr olle d g o ut.  
I m m u n o ge nicit y (a nti- pe gl oticase a nti b o dies) i n r es p o nse t o pe gl oticase t h era p y ma y lea d t o l oss 
of t hera p e utic res p o nse a n d/ or A Es, i ncl u di n g I Rs. A p ote ntial pr o p h yl actic strate g y t o ma na ge 
a nti- dr u g a nti b o d y res p o nse wit h pe gl oticase is t he c o-a d mi nistrati o n of i m m u n o m o d ulati n g 
t hera p y. M T X is t he m ost c o m m o nl y use d n o n- bi ol o gical disease m o dif yi n g a ge nt w orl d wi de 
a n d is fre q ue ntl y use d i n c o m bi nati o n wit h ot her bi ol o gical t hera pies [ Stra n d et al, 2 0 1 7 ]. 
T he st u d y d esi g n will i ncl u de: 1) u p t o a 2- wee k Scree ni n g Peri o d (scree ni n g s h o ul d be c o m plete 
wit hi n 2 wee ks pri or t o Wee k - 4), 2) a 4- wee k M T X R u n-i n Peri o d; 3) a n E n d of Pe gl oticase 
Treat me nt Visit if a p plica ble 4) a 5 2- wee k Pe gl oticase + I M M ( Pe gl oticase + M T X) Peri o d 5) a 
Safet y F oll o w- u p ( P h o ne/ E mail/ Site Visit) a n d 6) a 3 a n d 6 m o nt h P ost Treat me nt F oll o w- u p.   
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 
Eli gi ble s u bjects m ust meet all of t he f oll o wi n g criteria: 
1.   Willi n g a n d a ble t o gi ve i nf or me d c o nse nt. 

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2.  Willi n g a n d a ble t o c o m pl y wit h t he pres cri be d tr eat me nt pr ot oc ol a n d e v al uati o ns f or t he 
d urati o n of t he st u d y. 
3.  A d ult me n or w o me n ≥1 8 t o ≤6 5 years of a ge.  
4.  W o me n of c hil d beari n g p ote ntial (i ncl u di n g t h ose wit h a n o nset of me n o pa use < 2 years 
pri or t o scree ni n g, n o n-t hera p y-i n d u ce d a m e n orr h ea f or < 1 2 m o nt hs pri or t o scree ni n g, or 
n ot s ur gic all y sterile [a bse nce of o varies a n d/ or ut er us]) m ust ha ve ne gati v e ser u m/ uri ne 
pre g na nc y t ests d uri n g t h e Scree ni n g/ M T X R u n-i n Peri o d; s u bjects m ust a gree t o use 
2 relia ble f or ms of c o ntrace pti o n d uri n g t h e st u d y, o ne of w hic h is rec o m me n de d t o be 
h or m o nal, s uc h as a n oral c o ntrace pti ve. H or m o nal c o ntrace pti o n m ust be starte d ≥1 f ull 
c ycle pri or t o Wee k - 4 (start of M T X d osi n g) a n d c o nti n ue f or 3 0 da ys after t he last d ose 
of pe gl oticase or at least o ne o v ulat or y c ycl e af t er t he last d ose of M T X ( w hic he ver is t he 
l o n gest d ur ati o n after t h e last d ose of pe gl oticase or M T X). Hi g hl y effecti v e 
c o ntrace pti ve met h o ds ( wit h a fail ure rate < 1 % p er year), w he n use d c o nsiste ntl y a n d 
c orrectl y, i n cl u de i m pla nts, i njecta bles, c o m bi ne d oral c o ntrace pti ves, s o me i ntra uteri ne 
de vices, se x ual a bsti ne nce, or vasect o mize d part ner.  
5.  Me n w h o are n ot vasect o miz e d m ust n ot i m pre g nate t heir fe male p art ner d uri n g t he st u d y 
a n d f or at least 3 m o nt hs after t he l ast d ose of M T X.   
6.  H y per urice mia at t he Scree ni n g, Wee k - 4, or Wee k - 2 Visit of t he Scree ni n g/ M T X 
R u n- i n Peri o d, as d oc u me nte d b y s U A ≥6  m g/ d L.  
7.  U nc o ntr olle d g o ut, defi n e d as meeti n g t he f oll o wi n g criteria:  
 s U A ≥6 m g/ d L pri or t o e ntr y i nt o t he Pe gl oticase + I M M Peri o d (a n y l a b orat or y 
tests d uri n g scree ni n g u p t o a n d i ncl u di n g d uri n g t he M T X R u n-i n Peri o d) a n d at 
least 1 of t he f oll o wi n g: 
 
i na bilit y t o mai ntai n s U A < 6 m g/ d L o n ot her urate-l o weri n g t hera p y 
 
i nt olera ble si de effects ass ociate d wit h c urre nt urat e-l o weri n g t hera p y 
 
f u ncti o nall y li miti n g t o p hace o us dep osits (i ncl u di n g t h ose d etecte d 
cli nicall y or b y D E C T i ma gi n g) 
8.  A ble t o t olerate M T X 1 5 m g f or 4 wee ks d uri n g t h e Scree ni n g/ M T X R u n-i n Peri o d pri or 
t o t he first d ose of pe gl oticase.  
9. 3. 2  E xcl usi o n Criteri a 
S u bjects will be i neli gi ble f or st u d y partici p ati o n if t he y m eet a n y  of t he f oll o wi n g criteria: 
1.  Wei g ht > 1 6 0 k g ( 3 5 2 p o u n ds). 
2.  A n y s eri o us ac ut e bacteri al i nfecti o n, u nless treate d a n d c o m pletel y res ol v e d wit h 
a nti bi otics at least 2 wee ks pri or t o t he Wee k - 4 Visit of t he Scree ni n g/ M T X R u n-i n 
Peri o d. 
3.  Se vere c hr o nic or rec urre nt bacterial i nfecti o ns, s uc h as rec urre nt p ne u m o ni a or c hr o ni c 
br o nc hiectasis. 

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4.  C urre nt i m m u n oc o m pr o mise d c o n diti o n, i ncl u di n g c urre nt or c hr o nic tr eat me nt wit h 
s yste mic i m m u n os u p pressi ve a ge nts, i ncl u di n g pre d nis o ne > 1 0 m g/ da y or e q ui vale nt 
d ose of ot her c ortic oster oi d. 
5.  Hist or y of a n y tra ns pla nt s ur ger y re q uiri n g mai nte na nce i m m u n os u p pressi v e t hera p y. 
6.  K n o w n hist or y of he patitis B vir us s urface a nti ge n p ositi vit y or he patitis B D N A 
p ositi vit y.  
7.  K n o w n hist or y of he patitis C vir us R N A p ositi vit y. 
8.  K n o w n hist or y of H u ma n I m m u n o deficie nc y Vir us ( HI V) p ositi vit y (t este d at Scree ni n g 
Visit). 
9.  Gl uc ose - 6- p h os p h a ge de h y dr o ge nase ( G 6 P D) deficie nc y (teste d at t he Scree ni n g Visit). 
1 0.  Se vere c hr o nic re nal i m pair me nt ( gl o mer ular filtrati o n rate < 2 5 m L/ mi n/ 1. 7 3 m 2) or 
c urre ntl y o n dial ysis. 
1 1.  N o n-c o m pe nsat e d c o n gesti ve heart fail ure or h o s pitalizati o n f or c o n gesti ve heart fail ure 
wit hi n 3 m o nt hs of t he Scree ni n g Visit, u nc o ntr olle d arr h yt h mia, treat me nt f or ac ut e 
c or o nar y s y n dr o me ( m y o car dial i nfarcti o n or u nst a ble a n gi na), or u nc o ntr olle d bl o o d 
press ure ( > 1 6 0/ 1 0 0 m m H g) at t he e n d of t he Scree ni n g/ M T X R u n-i n Peri o d. 
1 2.  Pre g n a nt, pla n ni n g t o b ec o me pre g na nt, br eastf ee di n g, pla n ni n g t o i m pre g n ate fe mal e 
part ner, or n ot o n a n effecti ve f or m of birt h c o ntr ol, as deter mi ne d b y t he I n vesti gat or. 
1 3.  Pri or treat me nt wit h pe gl oticase ( K R Y S T E X X A), a n ot her rec o m bi na nt uri case 
(ras b uricase), or c o nc o mita nt t hera p y wit h a p ol yet h yle ne gl yc ol-c o nj u gat e d dr u g. 
1 4.  K n o w n aller g y t o pe g ylat e d pr o d ucts or hist or y of a na p h ylactic reacti o n t o a rec o m bi na nt 
pr otei n or p orci ne pr o d uct. 
1 5.  C o ntrai n dicati o n t o M T X treat me nt or M T X tr eat me nt c o nsi dere d i na p pr o priate. 
1 6.  K n o w n i nt olera nce t o M T X. 
1 7.  Recei pt of a n i n vesti gati o nal dr u g wit hi n 4 wee ks or 5 half-li ves, w hic h e ver is l o n ger, 
pri or t o M T X a d mi nistrati o n at Wee k - 4 or p la ns t o ta ke a n i n vesti gati o nal dr u g d uri n g 
t he st u d y. 
1 8.  C urre nt li ver diseas e, as deter mi ne d b y ala n i n e tra nsa mi nase or as p artate tra nsa mi nase 
le vels > 3 ti mes u p per li mit of n or mal at t he Scree ni n g Visit. 
1 9.  C urre ntl y recei vi n g s yste mic or ra di ol o gic treat me nt f or o n g oi n g ca ncer, e x cl u di n g 
n o n- mela n o ma s ki n ca n cer. 
2 0.  Hist or y of m ali g na n c y wit hi n 5 years ot h er t ha n n o n- mela n o ma s ki n ca n cer or i n sit u 
carci n o ma of cer vi x. 
2 1.  U nc o ntr olle d h y per gl yce mia wit h a plas ma gl u c os e val ue > 2 4 0 m g/ d L at s cree ni n g t hat is 
n ot s u bse q ue ntl y c o ntr oll e d b y t h e e n d of t he Scree ni n g/ M T X R u n-i n Peri o d. 
2 2.  Dia g n osis of oste o m yelitis. 

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2 3.  K n o w n hist or y of h y p o x a nt hi ne- g ua ni ne p h os p h ori b os yl-tr a nsferase d efici e nc y, s uc h as 
Les c h- N y h a n a n d K elle y- See g miller s y n dr o me. 
2 4.  U ns uita ble ca n di date f or t he st u d y, bas e d o n t he o pi ni o n of t he I n v esti gat or 
(e. g., c o g niti ve i m pair me nt), s uc h t hat partici pati o n mi g ht create u n d ue ris k t o t he s u bject 
or i nterfere wit h t he s u bj ect’s a bilit y t o c o m pl y wit h t h e pr ot oc ol re q uire m e nts or 
c o m plete t he st u d y. 
2 5.  Alc o h ol use i n e x cess of 3 alc o h olic be vera ges p er wee k. 
2 6.  C urre ntl y recei vi n g all o p uri n ol a n d u na ble t o disc o nti n ue me dicati o n 7 da ys pri or t o 
M T X d osi n g at W ee k - 4 a n d u na ble t o disc o nti n ue treat me nt d uri n g t he d urati o n of t he 
st u d y. 
9. 3. 3  Re m o v al of S u bjects fr o m T her a p y or St u d y 
All s u bjects are free t o wit h dra w fr o m st u d y partici pati o n at a n y ti me, f or a n y reas o n, a n d 
wit h o ut prej u dice t o t heir f urt her me dical care. I n a d diti o n, t he I n v esti gat or ma y ter mi nate a 
s u bject fr o m t he st u d y at a n y ti me. H o we ver, su bjects w h o are re m o v e d fr o m pe gl oticas e t hera p y 
s h o ul d re mai n o n st u d y b arri n g wit h dra wal of c o nse nt f or st u d y p artici pati o n. 
9. 3. 3. 1  Re m o v al of S u bjects fr o m Pe gl otic ase T her a p y 
I n a d diti o n t o c o m pleti o n of t hera p y t hr o u g h Wee k 5 2, t he reas o n f or disc o nti n uati o n fr o m t he 
t hera p y s h o ul d be rec or de d o n t he e C R F usi n g 1 of t he f oll o wi n g cate g ories: 
 Lac k of Efficac y. (i.e., s U A le vel > 6 m g/ d L at 2 c o nsec uti ve st u d y visits be gi n ni n g wit h 
t he Wee k 2 Visit). 
 A d verse E v e nt. T he s u bj ect e x perie nces a n A E t h at i m p oses a n u nacce pta ble ris k t o t he 
s u bject’s healt h (e. g., a na p h ylactic reacti o n), or t h e s u bject is u n willi n g t o c o nti n ue 
t hera p y beca use of a n A E. S u bjects w h o disc o nti n ue d ue t o a n A E s h o ul d be f oll o we d 
u ntil res ol uti o n or sta bilizati o n of t he A E, or  a n a de q uate e x pla nati o n f or t he e ve nt is 
o btai ne d. 
 T he I n vesti gat or h as deter mi ne d t hat pe gl ot icase a d mi nistrati o n p oses a n u nacce pta ble 
ris k t o t he s u bject (s pecif y reas o n).  
 S u bject ref usal of a d diti o nal t hera p y (s pecif y reas o n). 
 St u d y Ter mi nate d b y S p o ns or. T he S p o ns or, I R B, or re g ulat or y a ge nc y t er mi nates t he 
st u d y  
 Pre g n a nc y 
 Deat h 
9. 3. 3. 1. 1  St u d y c o nsi der ati o ns f or s u bjects e n di n g pe gl otic ase i nf usi o ns pri or t o 5 2 wee ks 
 Met h otre x ate, al o n g wit h f olic aci d, will be disc o nti n ue d at t he ti me of cess ati o n of 
pe gl otic ase i nf usi o ns pri or t o Wee k 5 2.  

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 All s u bjects will c o m plete t he E n d of Pe gl oticase I nf usi o ns Visit a n d will re mai n o n 
st u d y t hr o u g h wee k 5 2 re gar dless of w h et her t he y st o p i nf usi o ns d ue t o s U A st o p pi n g 
r ules or ot her reas o n (e. g. wit h dra wal of c o nse nt f or pe gl oticase i nf usi o ns). 
 S u bjects are e n c o ura ge d t o c o nti n ue t o part ici pate i n all visits t hr o u g h t he e n d of t he 
st u d y. S u bjects are es peciall y e n c o ura ge d t o c o m plete st u d y visits at t he st u d y site d uri n g 
ke y effi cac y a n d safet y c ollecti o ns at Wee ks 1 0, 1 2, 1 4, 2 0, 2 2, 2 4, 3 2, 3 4, 3 6, 4 8, 5 0 a n d 
5 2, s o t hat s U A la bs a n d ot her ke y assess m e nts ca n be c o m plete d. S u bjects w h o ha ve 
st o p pe d i nf usi o ns, ma y c o m plete t he ot her stu d y visits i n pers o n or vi a tele p h o ne t o 
c ollect A Es, c o n me ds a n d g o ut flare i nf or m ati o n.   
 Acti vities relate d t o pre/ p ost i nf usi o n m o nit ori n g or me dicati o n dis pe nsati o n will n ot be 
c o m plete d o nce a s u bject has st o p pe d pe gl otica se i nf usi o ns. T hese acti vities i ncl u de:  
o  M T X c o m plia nce/r ec o nciliati o n 
o  I nf usi o n reacti o n pr o p h yl a xis 
o  I R pr o p h yl a xis c o m plia nce 
o  F olic aci d c o m plia nce 
o  Pe gl oticase i nf usi o n 
o  Pe gl oticase P K s a m pli n g 
o  Pre-i nf usi o n M T X P ol y gl uta mate sa m pli n g  
o  M T X dr u g/ dis pe nsati o n relate d ite ms   
P ost Treat me nt F oll o w- u p: 
Eac h s u bject will be f oll o we d u p f or at least 6 m o nt hs after cessati o n of pe gl oticase i nf usi o ns. If 
t hese 6 m o nt hs occ ur pri or t o e n d of st u d y at Wee k 5 2, s uc h as i n t he cas e of a s u bject w h o e n ds 
pe gl otic ase i nf usi o ns o n or bef ore Wee k 2 4, t here will be n o f oll o w- u p visits after t he Wee k 
5 2/ E n d of St u d y Visit. F or s u bjects w h o e n d p e gl oticase i nf usi o ns bet wee n Wee ks 2 6 a n d 3 6, 
t here will be at least 3 m o nt hs of f oll o w- u p w hile t he s u bject re mai ns o n-st u d y pri or t o Wee k 5 2, 
a n d t he n o ne f oll o w- u p visit after t he Wee k 5 2/ E n d of St u d y Visit. F or s u bj ects w h o e n d 
pe gl otic ase i nf usi o ns bet wee n Wee ks 3 8 a n d 5 2, t her e will be t w o f oll o w- u p visits at i nter vals of 
3 m o nt hs after t he Wee k 5 2/ E n d of St u d y Visit. 
9. 3. 3. 2  Re m o v al of S u bjects Fr o m St u d y 
I n a d diti o n t o c o m pleti o n of t hera p y a n d desi g nate d st u d y visits t hr o u g h Wee k 5 2, t he reas o n f or 
disc o nti n uati o n fr o m t he st u d y s h o ul d be rec or de d o n t he e C R F usi n g 1 of t he f oll o wi n g 
cate g ories: 
 L ost t o F oll o w- u p. T h e s u bject d oes n ot ret ur n t o t he cli nic f or sc h e d ule d assess me nts, 
a n d d oes n ot res p o n d t o t he site’s atte m pts t o c o ntact t he s u bject.  
 Wit h dra wal of C o nse nt. T he s u bject wit h dra ws fr o m t he st u d y. T he cli nical site s h o ul d 
atte m pt t o deter mi ne t he u n derl yi n g reas o n f or t he wit h dra wal a n d d oc u me nt it o n t he 
e C R F; (i.e. A E, v ol u ntar y wit h dra w), S pecif y. 
 St u d y Ter mi nate d b y S p o ns or. T he S p o ns or, I R B, or re g ulat or y a ge nc y t er mi nates t he 
st u d y.  

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9. 3. 4  Re pl ace me nt P olic y 
9. 3. 4. 1  S u bjects 
N o s u bject pre mat urel y disc o nti n ue d fr o m t he st u d y f or a n y reas o n will be re place d. 
9. 3. 4. 2  Ce nters 
A ce nter m a y be cl os e d a n d/ or re place d f or t h e f oll o wi n g a d mi nistrati ve reas o ns:  
 E x cessi vel y sl o w recr uit me nt. 
 P o or pr ot oc ol a d here nce. 
9. 3. 4. 3  Scree n F ail ures 
S u bjects w h o d o n ot meet all of t he i ncl usi o n criteria or meet a n y of t he e x cl usi o n criteria will be 
c o nsi dere d scree n fail ures. I n a d diti o n, s u bjects  w h o are u na bl e t o t olerate M T X at a n oral d ose 
of 1 5 m g w ee kl y d uri n g t he M T X R u n-i n Peri o d will be c o nsi dere d scree n fail ures. Scree n 
fail ure s u bjects w h o are fe males of c hil d beari n g p ote ntial w h o t o o k at least o ne d ose of M T X, 
will recei ve a Safet y F oll o w- u p P h o ne call/ E- mail/ Site Visit a p pr o xi matel y 3 0 da ys after t h e last 
d ose of M T X t o verif y at least o ne o v ulat or y c ycle after t he l ast d ose of M T X.  If t he s u bject has 
n ot o v ulate d, a uri ne pre g na n c y test will be perf or me d at t he st u d y site. Scree n fail ure s u bjects 
w h o recei ve at least 1 d ose of M T X a n d are n o n- v asect o mize d males will recei ve a P h o ne/ E-
mail/ Site Visit 3 m o nt hs af ter M T X dis c o nti n uati o n re gar di n g p art ner pre g n a nc y. 
Scree n fail ure s u bjects ma y b e all o we d t o r escree n f or t he st u d y if b ot h t he I n v esti gat or a n d 
S p o ns or are i n a gree me nt re gar di n g rescree ni n g a n d if t he I n vesti gat or det er mi nes t hat t he 
s u bject ca n satisf y all of t he eli gi bilit y criteria. 
9. 4  
Tre at me nts 
9. 4. 1  Tre at me nts A d mi nistere d 
D uri n g t h e M T X R u n-i n Peri o d, w hic h be gi ns 4 wee ks pri or t o t he first d os e of pe gl oticas e, 
s u bjects will ta ke oral M T X at a d ose of 1 5 m g wee kl y. S u bjects will be i nstr ucte d t o ta ke M T X 
wee kl y o n t he sa me d a y eac h w ee k (if d osi n g m or e fre q u e ntl y t h a n o nce i n a da y (i.e. BI D, TI D), 
t he t otal M T X d ose s h o ul d be ta ke n wit hi n 2 4 h o urs, prefera bl y t he s a me cale n dar da y) a n d 
rec or d t h e date a n d ti me of d ose/s i n t he d osi n g cale n dar. D uri n g t he Pe gl oticase + I M M Peri o d, 
M T X s h o ul d be ta ke n 1 t o 3 da ys pri or t o pe gl oticase i nf usi o n; h o we ver, if a s u bject d oes n ot d o 
s o, M T X m ust be ta ke n ≥6 0  mi n utes pri or t o pe gl oticase i nf usi o n. D uri n g t h e M T X R u n-i n 
Peri o d, if a d ose is misse d, it s h o ul d be ta ke n as s o o n as it is re me m bere d. If it is wit hi n 4 8 h o urs 
of t he ne xt sc he d ule d d ose, t he s u bject will be i nstr ucte d t o s ki p t he misse d d ose a n d res u m e at 
t he ne xt re g ularl y s c he d ule d ti me; t h us, s u bjects will be i nstr ucte d n ot t o d o u ble a d ose t o ma ke 
u p f or a misse d d ose if wit hi n 4 8 h o urs of t he ne xt d ose. D uri n g t he Pe gl oticase + I M M Peri o d, 
M T X s h o ul d be ta ke n 1 t o 3 da ys pri or t o pe gl oticase i nf usi o n; h o we ver, if a s u bject d oes n ot d o 
s o, M T X m ust be ta ke n ≥6 0  mi n utes pri or t o pe gl oticase i nf usi o n. If a s u bj ect bec o mes u na bl e t o 

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t olerate t he prescri be d d osa ge of M T X d uri n g t he Pe gl oticase + I M M Peri o d, t he d osa ge ma y be 
decrease d (s ee Secti o n 9. 4. 6. 3. 2. 2 ). 
D uri n g t h e pe gl oticase +I M M Peri o d all s u bject s will recei ve p e gl oticase at t he sa me d ose of 
8 m g a d mi nistere d I V e v er y 2 wee ks f or a t otal of 2 6 i nf usi o ns fr o m Da y 1 t hr o u g h Wee k 5 0, 
i ncl usi ve ( Pe gl otic ase + I M M Peri o d). T he date a nd start a n d st o p ti me of i nf usi o n i ncl u di n g t he 
fl us h will be rec or de d. S u bjects will n ot be fasti n g o n t he d a y of i nf usi o n a n d will be e nc o ura ge d 
t o ha ve a s nac k or n or mal meal bef ore or after t he i nf usi o n. All s u bjects will recei ve st a n dar dize d 
pr o p h yla ctic treat me nt t o re d uce t h e ris k of ac ute g o ut flares, u nless me dicall y c o ntr ai n dicate d or 
n ot t olerate d, be gi n ni n g ≥1  wee k bef ore t he first d ose of pe gl oticase. Sta n dar dize d I R 
pr o p h yla xis c o nsisti n g of pre-treat me nt wit h a n ti hista mi nes, aceta mi n o p he n, a n d c ortic oster oi ds 
will acc o m pa n y eac h i nf usi o n.  
9. 4. 1. 1  F olic A ci d 
S u bjects will ta ke f olic aci d 1 m g orall y e ver y d a y be gi n ni n g at Wee k - 4 (t he start of M T X) u ntil 
pri or t o t he Wee k 5 2/ E n d of St u d y/ Earl y T er mi nati o n Visit.  
If t he s u bject disc o nti n ues pe gl oticas e d ue t o t he st o p pi n g r ules or ot her reas o n, M T X a n d f olic 
aci d s h o ul d als o be disc o nti n ue d.   
Prescri pti o ns are t o be fille d at a l ocal p har mac y, as nee de d. At st u d y visits, t he s u bject will be 
as ke d a Y es/ N o q uesti o n w het her f olic aci d w as ta ke n per pr ot o c ol. 
9. 4. 1. 2  G o ut Fl are Pr o p h yl a xis  
It is re q uire d t hat bef ore a s u bject be gi ns t he Pe gl oticase + I M M Peri o d, he or s he has b ee n 
ta ki n g at least o ne pr ot oc ol sta n dar d g o ut flare pr o p h yla xis re gi me n (i.e. c ol c hici ne a n d/ or n o n-
ster oi dal a nti-i nfla m mat or y dr u gs a n d/ or l o w- d os e pre d nis o ne ≤1 0 m g/ d a y) f or ≥1 wee k bef ore 
t he first d ose of pe gl oticase a n d c o nti n ues flare pr o p h yla xis per A merica n C olle ge of 
R he u mat ol o g y g ui deli nes [ K ha n na D et al. 2 0 1 2] f or t he greater of 1) 6 m o nt hs, 2) 3 m o nt hs 
after ac hie vi n g tar get ser u m urate (s U A < 6 m g/ d L) f or patie nts wit h n o t o p hi detecte d o n 
p h ysical e x a m, or 3) 6 m o nt hs after ac hie vi n g tar get ser u m urate (s U A < 5 m g/ d L) f or patie nts 
wit h o ne or m ore t o p hi d etecte d o n i nitial p h ysi cal e xa m t hat ha ve si nce res ol ve d.   
Prescri pti o ns are t o be fille d at a l ocal p har mac y, as nee de d. At st u d y visits, t he s u bject will be 
as ke d a Y es/ N o q uesti o n w het her g o ut flare pr o p h yl a xis was ta ke n per pr ot oc ol. 
9. 4. 1. 3  I nf usi o n Re acti o n Pr o p h yl a xis 
Si nce I Rs ca n occ ur wit h pe gl otic ase, all s u bjects will recei ve I R pr o p h yl a xis pri or t o eac h 
i nf usi o n, c o nsisti n g of a n a nti hista mi ne, aceta mi no p he n, a n d a c ortic oster oi d.  T o sta n dar dize 
t his re gi me n, s u bjects will recei ve fe x ofe na di ne ( 6 0 m g or 1 8 0 m g orall y b ase d o n t he Pri nci pal 
I n v esti gat or’s discreti o n) t he da y bef ore eac h i nf usi o n; fe x ofe na di ne ( 6 0 m g or 1 8 0 m g orall y 
base d o n t he Pri nci pal I n vesti gat o r’s discreti o n) a n d aceta mi n o p he n ( 1 0 0 0 m g orall y) t h e 
m or ni n g of eac h i nf usi o n; a n d met h yl pr e d nis ol o ne ( 1 2 5 m g I V) gi ve n o ver t he i nf usi o n d urati o n 
1 0- 3 0 mi n utes (rec o m me n de d) or h y dr oc ortis o ne ( 2 0 0 m g I V) will be a d mi nistere d i m me diatel y 
pri or t o eac h i nf usi o n. S u bstit uti o n of t he c ortic oster oi d is n ot all o we d. T he na me, d ose, r o ute, 

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be pr o vi de d t o st u d y s u bj ects after t he Wee k - 4 Visit f or wee kl y d osi n g after visit pr oce d ures a n d 
i ncl usi o n/e x cl usi o n criteria are c o nfir me d. 
9. 4. 4  St or a ge 
Bef ore pre parati o n f or us e, pe gl oticase will be st or e d i n t he cart o n, mai ntai n e d u n der 
refri gerati o n bet w ee n 2º C a n d 8º C ( 3 6º F a n d 4 6º F), pr otecte d fr o m li g ht, a n d will n ot be s ha ke n 
or fr oze n. Pe gl oticase dil ute d i n i nf usi o n ba gs is st a ble f or 4 h o urs at 2° C t o 8° C ( 3 6° F t o 4 6° F) 
a n d f or 4 h o urs at r o o m te m perat ur e ( 2 0° C t o 2 5° C, 6 8° F t o 7 7° F). 
M T X will be st ore d bet w ee n 2 0° C t o 2 5° C ( 6 8° F t o 7 7° F) a n d pr otecte d fr o m li g ht. 
9. 4. 5  Dr u g Acc o u nt a bilit y 
Cli nical s u p plies will be dis pe nse d o nl y i n acc or da nce wit h t he pr ot o c ol. A cc urat e rec or ds of t he 
cli nical s u p plies recei ve d, t he a m o u nt dis pe nse d f or eac h s u bj ect, a n d t he a m o u nt re mai ni n g at 
t he c o ncl usi o n of t he st u d y will be mai ntai ne d. E ac h st u d y site will als o mai ntai n s u bject dr u g 
l o gs/electr o nic l o gs t o acc o u nt f or M T X dis pe nse d, a n d s u bject c o m plia nce will be m o nit ore d b y 
t he site at eac h visit (see Secti o n 9. 4. 9 ). 
S u bjects will bri n g t he M T X d osi n g cale n dar t o eac h st u d y visit f or ass ess me nt of c o m plia nce. 
S u bjects will bri n g t he M T X b ottle t o eac h visit f or a c o m plia nce c hec k b y t he site. T he site will 
ma n uall y c o u nt t he pills a n d re- dis pe ns e t he b ottle t o  t he s u bject. At t he e n d of t he st u d y or if t he 
s u bject pre mat urel y dis c o nti n ues t he st u d y, t he s ubjects will ret ur n a n y u n use d or partiall y use d 
st u d y dr u gs t o t he site. 
I n v esti gati o nal cli nical s u p plies will be recei v e d b y a d esi g nate d pers o n at t he st u d y site, ha n dle d 
a n d st ore d safel y a n d pr o perl y, a n d ke pt i n a s e c ure d l ocati o n t o w hic h o nl y t he I n v esti gat or a n d 
desi g nat e d assista nts ha v e access.  
Please refere nce t h e St u d y P har mac y Ma n u al f or m ore detaile d i nf or m ati o n o n M T X a n d 
pe gl otic ase pac ka gi n g, la beli n g, st ora ge, a n d d estr ucti o n. 
9. 4. 6  St u d y Dr u g A d mi nistr ati o n a n d Ti mi n g of D ose f or e ac h S u bject 
9. 4. 6. 1  Descri pti o n of Cli nic al S u p plies 
 will s u p pl y st u d y dr u gs ( pe gl oticase a n d M T X) t o cli nical sites. A ncillar y 
s u p plies f or d osi n g will b e pr o vi de d b y t he st u d y site (i.e., i nf usi o n ba gs c o ntai ni n g n or mal 
sali ne, s yri n ges, nee dl es, alc o h ol s wa bs, ga uze pads, ba n da ges, a n d bi o h azar d c o ntai ners f or safe 
st ora ge of use d n ee dles a n d s yri n ges). 
9. 4. 6. 2  Deter mi n ati o n of D ose V ol u me  
Pe gl oticase will be a d mi nistere d as a n a d mi xt ure of 8 m g i n 2 5 0 m L of 0. 4 5 % or 0. 9 % S o di u m 
C hl ori de I nje cti o n, U nite d States P har mac o peia ( U S P) f or I V i nf usi o n.  
I n t he e ve nt of a n I R, t he i nf usi o n s h o ul d be sl o we d, or st o p pe d, a n d restart e d at a sl o wer rate at 
t he discreti o n of t he I n v esti gat or. I nf usi o ns s u bse q ue nt t o a n I R i n a n i n di vi d ual s u bject ma y be 

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gi ve n i n a l ar ger v ol u me of dil ue nt, n ot t o e x cee d 5 0 0 m L. I n t his cas e, t he i nf usi o n d urati o n will 
als o be e xte n de d t o a mi ni m u m of 3 h o urs. 
9. 4. 6. 3  Det ails C o ncer ni n g Ti mi n g a n d D ose A d mi nistr ati o n 
9. 4. 6. 3. 1  Pre p ar ati o n a n d A d mi nistr ati o n 
9. 4. 6. 3. 1. 1  Pre p ar ati o n 
Vials of pe gl oticase will be vis uall y i ns pe cte d  f or partic ulate matter a n d dis c ol orati o n bef ore 
a d mi nistrati o n, w he ne ver s ol uti o n a n d c o ntai ner pe r mit. Vials will n ot be use d if eit her is 
prese nt. Usi n g a p pr o priat e ase ptic te c h ni q ue, 1 m L  of p e gl oticase will be wit h dra w n fr o m t he 
vial i nt o a sterile s yri n ge. A n y u n us e d p orti o n of  pr o d uct re mai ni n g i n t he vial will be discar de d. 
S yri n ge c o nte nts will be i njecte d i nt o a si n gl e 2 5 0 m L ba g of 0. 4 5 % or 0. 9 % S o di u m C hl ori de 
I nje cti o n, U S P f or I V i nf usi o n a n d will n ot be mi xe d or dil ute d wit h ot her dr u gs. T h e i nf usi o n 
ba g c o ntai ni n g t he dil ute pe gl otic ase s ol uti o n wi ll be i n verte d a n u m b er of ti mes t o e ns ure 
t h or o u g h mi xi n g b ut will n ot be s ha ke n. I n acc orda nce wit h g o o d p har mac y practice, gl o v es will 
be w or n d uri n g pre parati o n of t he d ose. 
Pe gl oticase m ust be start e d wit hi n 4 h o urs of  dil uti o n.  Bef ore a d mi nistrati o n, t he dil ute d 
s ol uti o n of pe gl oticase will be all o we d t o reach r o o m te m perat ure. Pe gl oticase m ust ne ver be 
s u bjecte d t o artificial h eati n g. 
9. 4. 6. 3. 1. 2  D ose a n d A d mi nistr ati o n 
Met h otre x ate 
D uri n g t h e M T X R u n-i n Peri o d, w hic h be gi ns 4 wee ks pri or t o t he first d os e of pe gl oticas e, 
s u bjects will ta ke oral M T X at a d ose of 1 5 m g wee kl y. S u bjects will be i nstr uct e d t o ta ke M T X 
o nce wee kl y o n t he sa me da y eac h wee k (if d osi n g m ore fre q u e ntl y t h a n o nce i n t he da y (i. e. 
BI D, TI D), t he t otal M T X d ose s h o ul d be ta ke n wit hi n t he sa me cale n dar da y) a n d rec or d t h e 
date a n d ti me of eac h d os e o n eac h cal e n dar da y of M T X a d mi nistrati o n.  
D uri n g t h e M T X R u n-i n Peri o d, if a d ose is misse d, it s h o ul d be ta ke n as s o o n as it is 
re me m bere d. If it is wit hi n 4 8 h o urs of t he ne xt sc he d ule d d ose, t he s u bject will be i nstr ucte d t o 
s ki p t he misse d d ose a n d res u me at t he n e xt re g ularl y sc h e d ule d ti me; t h us, s u bjects will be 
i nstr ucte d n ot t o d o u ble a d ose t o ma ke u p f or a misse d d ose if wit hi n 4 8 h o urs of t he ne xt d ose.  
If a d ose is misse d, or if i nf usi o n sc he d ules are a dj uste d a n d M T X d ose m ust be m o ve d fr o m t he 
re g ular d a y, it is rec o m m e n de d t hat t he d oses are at least 5 da ys a p art if p ossi ble, h o we ver it is 
safe f or M T X d oses t o be a d mi nistere d wit h a mi ni m u m of 3 da ys a part. 
D uri n g t h e Pe gl oticase + I M M Peri o d, s u bjects will be i nstr ucte d t o ta ke M T X 1 t o 3 da ys pri or 
t o t he d ose of pegl oticase; h o we ver, if a s u bject d o es n ot d o s o, M T X m ust be ta ke n ≥6 0  mi n utes 
pri or t o pe gl oticase i nf usi o n. S u bjects will d os e Met h otre x ate wee kl y u ntil o ne wee k after t he 
last i nf usi o n.  
If a s u bject b ec o mes u n a ble t o t olerate t he prescri be d d osa ge of M T X aft er Da y 1 d uri n g t he 
Pe gl oticase + I M M Peri o d, t he d osa ge ma y be d ecrease d (see Secti o n 9. 4. 6. 3. 2. 2 ). 

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Refer t o Secti o n 9. 4. 1 1  f or c o ntrace pti o n re q uir e me nts.  
S u bjects will ta ke f olic aci d 1 m g orall y e ver y d a y be gi n ni n g at Wee k - 4 (t he start of M T X) u ntil 
pri or t o t he Wee k 5 2 Visit or t he last i nf usi o n vi sit.  F olic aci d will be s u p pli e d b y a l ocal 
p har mac y. 
Pe gl otic ase 
All s u bjects will recei ve pe gl otic ase at t he s a me d ose of 8 m g a d mi nistere d I V e ver y 2 wee ks f or 
a t otal of 2 6 i nf usi o ns fr o m Da y 1 t hr o u g h Wee k 5 0, i ncl usi ve ( Pe gl oticase + I M M Peri o d). 
S u bjects will n ot be fasti n g o n t he d a y of i nf usi o n  a n d will be e nc o ura ge d t o ha ve a s nac k or 
n or mal meal bef ore or aft er t he i nf usi o n. Pre-i nf usi o n s U A res ults m ust be re p orte d b y t he l ocal 
or ce ntr al la b orat or y pri or t o pe gl otic ase i nf usi o n (see Secti o n 9. 5. 1. 1 ). 
Sta n dar dize d I R pr o p h yl a xis c o nsisti n g of pre- treat me nt wit h a nti hista mi nes, acet a mi n o p he n, 
a n d c ortic oster oi ds will acc o m pa n y eac h i nf usi o n (see Secti o n 9. 4. 1. 3 ). T h e dr u g na me, d os e, 
a n d ti mi n g of t hese pr o p h yla ctic me dicati o ns will be rec or de d. 
Pe gl oticase will be a d mi nistere d as a n a d mi xt ure of 8 m g i n 2 5 0 m L of 0. 4 5 % or 0. 9 % S o di u m 
C hl ori de I nje cti o n, U S P f or I V i nf usi o n b y gra vit y fee d or i nf usi o n p u m p. P e gl oticase will n ot be 
a d mi nistere d as a n I V p us h or b ol us. 
I n a pate nt I V site, usi n g t u bi n g wit h n o i n-li ne filter, t he pe gl oticas e pre p arati o n will be i nf use d 
o ver a p pr o xi matel y 1 2 0 ± 1 5 mi n utes w hile t he s u bject is u n der cl ose o bs er vati o n f or a n y si g ns of 
distress. If a n i n-li ne filter is use d, it s h o ul d be 0. 2 μ m or lar ger. At t he e n d of t he i nf usi o n, t he 
I V li ne will be fl us he d wit h 1 0 m L of n or mal saline t o e ns ure t he f ull d ose is a d mi nistere d. T he 
date a n d ti me of i nf usi o n start a n d st o p (i ncl u si ve of t he I V fl us h) will be rec or de d.   
9. 4. 6. 3. 2  D ose M o dific ati o ns, I nterr u pti o ns, a n d Del a ys 
9. 4. 6. 3. 2. 1  Pe gl otic ase M o dific ati o ns 
A d mi nistrati o n of pe gl oti case will be i m me diatel y hel d if t he s u bject e x peri e nces a n y si g nifica nt 
I R s uc h as res pir at or y distress, a gitati o n, c hest or b ac k pai n, urticaria, or a n ot her cli nicall y 
si g nifica nt e ve nt occ urri n g d uri n g i nf usi o n. If t he A E meets t he defi niti o n of a n S A E f or I R, t he 
i nf usi o n s h o ul d n ot be restarte d u nless t he site I nv esti gat or d eter mi nes it is safe t o res u m e t he 
i nf usi o n. If t h e A E d oes n ot meet t he defi niti o n of a n S A E f or I R, t he site I n vesti gat or m a y ma ke 
t he decisi o n t o re-start t he i nf usi o n de pe n di n g u p o n t he nat ure a n d s e verit y of t he A E.  
I nf usi o ns s u bse q ue nt t o a n I R i n a n i n di vi d ual s u bject ma y be gi ve n i n a lar ger v ol u me of 
dil ue nt, n ot t o e x cee d 5 0 0 m L. I n t his cas e, t he i nf usi o n d urati o n will als o be e xte n de d t o a 
mi ni m u m of 3 h o urs. T he t otal v ol u me a n d d urati o n of i nf usi o n will be ca pt ure d i n t he me dical 
rec or d a n d e C R F. 
9. 4. 6. 3. 2. 2  M T X D ose Titr ati o n Al g orit h m  a n d I nt oler a nce Criteri a 
D uri n g t h e M T X R u n-i n a s u bject will be c o nsi der e d a scree n fail ure if a n y of t he f oll o wi n g n e w 
la b orat or y fi n di n gs or s y m pt o ms reflecti n g M T X i nt olera nce o cc ur: 

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1.  A b n or mal He mat ol o g y fi n di n gs: 
a. W B C < 3. 5 x 1 0
9/ L 
b.  Platelets < 7 5 x 1 0 9/ L 
c. He mat ocrit < 3 2 % 
2.  A b n or mal he patic f u ncti o n fi n di n gs: 
a. A S T/ A L T > 1. 5 x u p per li mit of refere nce ra n ge a n d  
b.  Al b u mi n < l o wer li mit of refere nce ra n ge 
3.  A b n or mal re n al f u ncti o n: e G F R < 4 0 ml/ mi n/ 1. 7 3 m 2 (as esti mate d wit h t he M D R D 
e q uati o n). 
4.  Ne w cli nicall y i m p orta nt si g ns a n d s y m pt o ms, s uc h as t he f oll o wi n g: 
a. Ras h or oral ulcerati o n 
b.  Persiste nt na usea, v o miti n g a n d di arr h ea  
c. Ne w or i ncreasi n g d ys p n ea or dr y c o u g h, or u n e x plai ne d c o u g h wit h fe v er  
d.  Se vere s or e t hr oat, a b n or mal br uisi n g  
e. Se vere hea dac hes, f ati g u e, a n d pr o ble ms c o n ce ntr ati n g  
N ote t hat if mi n or cli nical s y m pt o ms e mer ge, s u c h  as mil d st o matitis, mil d GI disc o mf ort, etc., 
t he i n vesti gat or m a y i ncrease f olic aci d d ose (e. g. 2 m g dail y) or rec o m me n d a di vi de d d ose of 
M T X (e. g. 3 ta bs of 2. 5 m g i n t he m or ni n g a n d e ve ni n g o n t he da y of d osi n g); if s y m pt o ms 
i m pr o ve, s u bject will n ot be c o nsi dere d a scree n fail ure o n t he basis of t hat s y m pt o m. 
D uri n g t h e R u n-I n a n d P e gl otic ase +I M M Peri o d, M T X d ose g ui da nce base d o n ne w la b orat or y 
fi n di n gs or n e w s y m pt o ms is as f oll o ws: 
La b Para met ers 
Val ue 
M T X D ose C ha n ge 
W B C 
3. 0 x 1 0 9/ L ~  3. 5 x 1 09/ L 
Decrease t o 1 0 m g 
< 3. 0 x 1 0 9/ L 
Te m p orar y st o p 
Platelets 
< 5 0 x 1 0 9/ L 
Te m p orar y st o p 
He mat ocrit 
< 2 7 % 
Te m p orar y st o p 
A S T/ A L T 
Bet wee n 1. 5 ~ 2 x U L N 
Decrease t o 1 0 m g 
                    > 2 x U L N  
Te m p orar y st o p 
                         e G F R 
< 3 0  ml/ mi n/ 1. 7 3 m 2 
Te m p orar y st o p 
Ne w cli nicall y i m p orta nt 
s y m pt o ms/si g ns * 
Yes 
Te m p orar y st o p 
* Ne w cli nicall y i m p orta nt s y m pt o ms or i m p orta nt me dical e ve nts: 

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a. Ras h or oral ulcerati o n  
b.  Persiste nt na usea, v o miti n g a n d di arr h ea  
c. Ne w or i ncreasi n g d ys p n ea or dr y c o u g h, or u n e x plai ne d c o u g h wit h fe v er  
d.  Se vere s or e t hr oat, a b n or mal br uisi n g  
e. Se vere hea dac hes, f ati g u e, a n d pr o ble ms c o n ce ntr ati n g 
f. A n y ot her i m p orta nt me dical e ve nts t hat mi g ht i ncrease m et h otre x ate t o xicit y or 
pre- dis p ose t o ne w or w orse ni n g i nfecti o n ( e. g. u n der g oi n g s ur ger y, 
h os pitaliz ati o n, bei n g treate d wit h a nti bi otics, ha vi n g a cli nical i nfecti o n, 
de vel o pi n g n e w cli nic all y si g nifica nt p ericar dial / ple ural eff usi o n or ascites) 
N ote t hat if mi n or cli nical s y m pt o ms e mer ge, s u c h  as mil d st o matitis, mil d GI disc o mf ort, etc., 
t he i n vesti gat or m a y i ncrease f olic aci d d ose t o 2 m g dail y or rec o m me n d a di vi de d d ose of M T X 
(e. g. 3 ta bs of 2. 5 m g i n t he m or ni n g a n d e ve ni n g o n t he da y of d osi n g) a n d m o nit or f or s y m pt o m 
res ol uti o n. 
I n v esti gat ors s h o ul d disc uss t he e mer ge n ce of a n y o ne of t he f oll o wi n g crit eria wit h t he me dical 
m o nit or t o re vie w t he case: 
1.  A L T/ A S T > 1. 5 x U L N o n 3 of a n y 5 c o nsec uti ve meas ures  
2.  Al b u mi n < 0. 8 x L L N o n 2 c o nsec uti ve meas ures 
3.  A n y la b orat or y or cli nical s y m pt o ms lea di n g t o te m p orar y st o p o n 3 c o nsec uti ve 
meas ures, i n w hic h case t he me dical m o nit or will re vie w t o c o nsi der re-i niti ati o n, a 
c o nti n ue d te m p orar y st o p, or a per m a ne n t st o p i n disc ussi o n wit h t he PI. 
G ui da nce f or i ncreasi n g M T X bac k t o war ds 1 5 m g after d ose re d u cti o n, base d o n i m pr o ve me nt 
or res ol uti o n of a b n or mal li ver e nz y mes ( > 2 × u p p er li mit of n or mal): 
1.  W he n li ver e nz y mes ret ur n t o val ues ≤1. 5 × u p p er li mit of n or mal, i ncrease M T X or d ose 
b y 2. 5 m g a n d reass ess i n 2 wee ks. 
2.  If li ver e nz y m es re m ai n ≤1. 5 × u p per li mit o f n or mal, i ncreas e M T X or d ose b y 2. 5 m g 
a n d reass ess i n 2 wee ks. 
I m pr o v e me nt of ot her la b orat or y a b n or malities p ote ntiall y attri b ute d t o M T X or ma y als o 
warra nt titrati o n bac k u p t o 1 5 m g wee kl y, b ase d o n PI j u d ge me nt a n d i n disc ussi o n wit h t he 
S p o ns or me dical m o nit or. 
9. 4. 6. 3. 2. 3  G o ut Fl are Tre at me nt 
A n i ncreas e i n g o ut flares is fre q ue ntl y o bser ve d u p o n i nitiati o n of a nti- h y per urice mic t hera p y, 
i ncl u di n g pe gl oticas e. S u bjects will be i nstr ucte d t o c o ntact t he site wit hi n 1 2 h o urs of t he o nset 
of s y m pt o ms. G o ut flares will be c o nfir me d t hr o u g h q uesti o ni n g or direct o bser vati o n, as 
detaile d i n Secti o n 9. 5. 4. 8 . All s u bjects w h o e x perie nce a g o ut fl are d uri n g t he st u d y will be 
prescri be d a nti-i nfla m mat or y tr eat me nt (e. g., N S AI D, c olc hici ne, c ortic oster oi ds a n d i ntra-
artic ular ster oi d i njecti o ns), as is cli nicall y i n di cate d or dee m e d necessar y o n a n i n di vi d ual basis 
at t he discreti o n of t he i n vesti gat or. Pai n me di cati o ns f or g o ut flare s h o ul d be a d mi nistere d 
acc or di n g t o sta n d ar d of care as is cli nicall y i n dicate d or dee me d necessar y o n a n i n di vi d ual 

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basis at t he discreti o n of t he i n vesti gat or.  All me dicati o ns s h o ul d be d oc u me nte d o n t he 
c o nc o mita nt me dicati o n e C R F. 
C olc hici ne will be prescri be d i n a me dicall y a p pr o priate d ose ra n ge of 0. 6 t o 1. 8 m g/ da y, us uall y 
d ose d as 0. 6 m g orall y t wice per da y u nless re d u ce d d osi n g is necessitate d b y re nal i ns uffici e nc y 
or gastr oi ntesti nal i nt olera nce. T h e precise d os e a n d re gi me n of c ol c hici ne will be i n di vi d ualize d 
f or eac h s u bject b y t he I n vesti gat ors a n d d oc u me nt e d o n t he c o nc o mita nt m e dicati o n e C R F. 
9. 4. 6. 3. 2. 4  I nf usi o n Re acti o n Tre at me nt 
S u bjects m ust be m o nit ore d cl osel y f or si g ns a n d s y m pt o ms of I Rs. I n t he e ve nt of a n I R, t he 
i nf usi o n s h o ul d be sl o we d, or st o p pe d, a n d restart ed at a sl o wer rate at t he discreti o n of t he 
I n v esti gat or. If a seri o us I R occ urs, t he i nf usi o n s h o ul d be disc o nti n ue d a n d treat me nt s h o ul d be 
pr o vi de d, as nee de d.  
If a s u bject e x perie nces a n A E s us pecte d t o be a n I R:  
 A p h ysic al e x a mi nati o n will be perf or me d t o ca pt ure me dicall y rele va nt details, 
i ncl u di n g, b ut n ot li mite d t o, a t h or o u g h d er mat ol o gic e x a mi nati o n f or detecti o n of 
er yt h e ma, urticaria ( hi v es), or peri- oral or li n g ual e de ma; a c hest e x a mi nati o n f or breat h 
s o u n ds, stri d or or w heezi n g; a n d a car diac e x a mi nati o n wit h atte nti o n t o irre g ul ar 
heart beat. 
 Vital si g ns (sitti n g or s u pi ne bl o o d press ure, h eart rate, res pirat or y rate, a n d b o d y 
te m perat ur e) will be ca pt ure d at least e ver y 3 0 mi n utes u ntil t he res ol uti o n or 
sta bilizati o n of t he A E. 
 A ser u m sa m ple will be c ollecte d i n a ser u m -s e parati n g t u be at t hat ti me or at t he 
s u bse q ue nt visit. T he sa m ple will be ce ntrif u ge d, fr oze n at - 2 0° C or c ol der, a n d st ore d f or 
t he batc h s hi p me nt t o a H oriz o n desi g nate d l a b orat or y f or e v al uati o n of pe gl oticase 
a nti b o dies at a f ut ure d at e. 
If, i n t he I n vesti gat or’s o pi ni o n, t he s u bject is e x perie nci n g a n a na p h ylactic reacti o n (see 
Secti o n  9. 5. 4. 1. 1. 5 ), pe gl oticase s h o ul d be i m me diatel y disc o nti n ue d. A n y i nci de nce of 
a na p h yla xis s h o ul d be re p orte d as a n S A E. 
T he I n vesti gat or ma y a d mi nister a n y me di call y i n dicate d p har m ac ol o gic a ge nt or pr oce d ure 
i nte n de d t o relie ve s y m pt o ms ( C A U TI O N: n o ot h er dr u gs ca n be mi x e d i n t he pe gl oticase 
i nf usi o n ba g). Si g ns a n d s y m pt o ms of t he A E a n d dr u gs gi ve n f or tr eat me nt are t o be rec or de d i n 
t he me dical rec or d a n d i n t he e C R F. 
After t he first i nci de nce of a n I R t hat d oes n ot meet t he criteria of a n a p h yl a xis (see 
Secti o n 9. 5. 4. 1. 1. 5 ) or d o es n ot meet seri o us criteria, t he I n vesti gat or ma y elect t o i nitiate t he 
ne xt i nf usi o n at a sl o wer rate. A d diti o nall y, t h e I n vesti gat or m a y c h o ose t o prescri be pre d nis o ne 
(e. g. 2 0 m g) t o be ta k e n i n t he m or ni n g of t h e ne xt i nf usi o n. All c ha n ges t o i nf usi o n rate or 
dil uti o n, a n d dr u gs gi ve n f or pr o p h yla xis or treat me nt, are t o be rec or de d i n t he me dical rec or d 
a n d i n t he e C R F. 

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9. 4. 7  Met h o d of Assi g ni n g S u bjects t o Tre at me nt Gr o u ps 
T his st u d y is a n o pe n-la b el, si n gle- ar m desi g n i n  w hic h all s u bjects will recei ve t he sa m e st u d y 
dr u gs (i.e., M T X a n d p e gl oticase).  
9. 4. 8  Pri o r a n d C o nc o mit a nt T her a p y  
Me dicati o n hist or y (i.e., pri or me dicati o ns) will i n cl u de all pri or g o ut me di cati o ns, starti n g at t he 
ti me of dia g n osis a n d u p t o t he Scree ni n g Visit, a n d all ot her me dicati o ns ta ke n fr o m 1 year pri or 
a n d u p t o t he Scree ni n g Visit.  
C o nc o mita nt me dicati o ns are defi ne d as dr u g or bi ol o gical pr o d u cts ot her t ha n t he st u d y dr u gs 
( or pri or g o ut me dic ati o ns) ta ke n b y a s u bject fr o m Scree ni n g t hr o u g h t he P ost Treat me nt 
F oll o w- u p Visits.  T his i ncl u des ot her prescri p ti o n me dicati o ns (i ncl u di n g pre ve nti ve vacci nes), 
o ver t he c o u nter me dic ati o ns, her bal me di cati o ns, vita mi ns, a n d f o o d s u p ple me nts. 
I nf or mati o n a b o ut pri or a n d c o nc o mita nt me dicati o ns, i ncl u di n g t h ose use d f or a n y d urati o n t o 
treat a n A E, will be c ollecte d o n s o urce d oc u me nts a n d t he a p pr o priate e C R Fs at eac h visit. T he 
ge n eric n a me of t he m e dicati o n, i n dicati o n, d ose,  u nit, fre q ue nc y, r o ute of a d mi nistrati o n, a n d 
start a n d st o p dates will be rec or de d. 
S u bjects will be directe d t o disc o nti n ue c urre nt ur ate-l o weri n g t h era p y pri or t o i nitiati o n of 
pe gl otic ase t hera p y as per t he c urre nt pac k a ge i ns e rt. Ot her me di cati o ns use d at t he ti me of st u d y 
i nitiati o n ma y b e c o nti n u e d at t he discreti o n of t he I n v esti gat or.  
9. 4. 9  Restricte d Me dic ati o ns 
S u bjects s h o ul d n ot recei ve t he f oll o wi n g m e dicati o ns fr o m t he ti me of Scree ni n g t hr o u g h t he 
e n d of pe gl oticas e a n d M T X treat me nt:  
 Oral urat e-l o weri n g t h era pies i ncl u di n g all o p uri n ol, fe b u x ostat, pr o be neci d, lesi n ura d, or 
ot her U L T f or g o ut. 
 A n y P E G- c o nj u gate d dr u g 
 A n y ot her i n vesti gati o nal a ge nt 
 Met h otre x ate ( ot her t ha n st u d y i n vesti g ati o nal pr o d uct), azat hi o pri ne, m yc o p he n olate 
m ofetil, or ot her s yst e mic i m m u n os u p pressa nts asi de fr o m gl uc oc ortic oi ds f or g o ut flare 
pr o p h yla xis ( < 1 0 m g pre d nis o ne or e q ui vale nt per da y) or i nter mitte nt g o ut flare 
treat me nt 
 If a s u bject is treate d wit h a nti bi otics, refer t o Secti o n 9. 4. 6. 3. 2. 2 . 
  S yste mic i m m u n os u p pressi ve a ge nts 
9. 4. 1 0  Tre at me nt C o m pli a nce 
A d osi n g cale n dar will be pr o vi de d t o s u bjects at t he Wee k - 4 Visit f or rec or di n g eac h d os e of 
M T X o n eac h cale n d ar da y of M T X a d mi nistrati o n ( A d diti o nal cale n dar pa ges ma y be pr o vi de d 

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at f ut ure visits as re q uir e d). T he d osi n g cale n dar a n d b ottle of M T X s h o ul d be br o u g ht t o eac h 
st u d y visit f or assess me nt of c o m plia nce wit h M T X. A d here nce t o t he M T X re gi me n will als o be 
rec or de d b y t he st u d y c o or di nat or at st u d y visits i n t he e C R F b y rec or di n g t he date of eac h M T X 
d ose ( m g), fre q ue n c y a n d ti me of eac h d os e per cal e n dar da y. S u bjects w h o ha ve ta ke n at least 
8 0 % of t he pr ot oc ol s pecifie d a m o u nt of M T X will  be c o nsi dere d c o m plia nt. N o nc o m plia nt 
s u bjects will be re- e d ucat e d o n c o m plia nce.  
At st u d y visits, t he s u bject will be as ke d a Yes/ N o q uesti o n w het her f olic aci d, g o ut flare, a n d I R 
pr o p h yla xis were a d mi nistere d. 
Pe gl oticase will be a d mi nistere d at t he st u d y site b y trai n e d pers o n nel. T he date a n d ti me of 
i nf usi o n start a n d st o p (i ncl usi ve of t he 1 0- m L fl us h) will be rec or de d. 
9. 4. 1 1  C o ntr ace pti o n Re q uire me nts 
W o me n of c hil d beari n g p ote ntial (i ncl u di n g t h ose wit h a n o nset of me n o pa use < 2 years pri or t o 
scree ni n g, n o n-t hera p y-i n d uce d a me n orr hea f or < 1 2 m o nt hs pri or t o scree ni n g, or n ot s ur gicall y 
sterile [a bse nce of o varies a n d/ or uter us]) m ust a gree t o use 2 relia ble f or ms of c o ntrace pti o n 
d uri n g t he st u d y, o ne of w hic h is rec o m me n d e d t o be h or m o nal, s uc h as a n oral c o ntrace pti ve. 
H or m o nal c o ntrace pti o n m ust be starte d ≥1 f ull c ycle pri or t o Wee k - 4 (start of M T X d osi n g) 
a n d c o nti n ue f or 3 0 da ys after t he l ast d ose of pe gl oticase or at least o ne o v ulat or y c ycle after t h e 
last d ose of M T X ( w hic h e ver is t he l o n gest d ur ati o n after t he l ast d ose of pe gl oticase or M T X).  
Hi g hl y effecti ve c o ntrace pti ve met h o ds ( wit h a fail ure rate < 1 % per year), w he n use d 
c o nsiste ntl y a n d c orrectl y, i ncl u de i m pla nts, i n jecta bles, c o m bi ne d oral c o ntrace pti ves, s o me 
i ntra uteri ne de vic es, se x ual a bsti ne nce, or vasect o mize d part ner. 
Me n w h o are n ot vasect o miz e d m ust a gree t o use a p pr o priate c o ntrace pti o n s o as t o n ot 
i m pre g n ate a fe male p art ner of re pr o d ucti ve p ot e ntial d uri n g t he st u d y a n d f or at least 3 m o nt hs 
after t he l ast d ose of M T X.  C o ntrace pti o n met h o ds i ncl u de c o n d o m use a n d a bsti ne nce. 
9. 5  
Effic ac y, Q u alit y- of- Life, P h ar m ac o ki netic, a n d S afet y V ari a bles 
T he Sc he d ule of Assess me nts is pr o vi de d i n Secti o n 2. 1 . 
9. 5. 1  Effic ac y V ari a bles 
Efficac y will be assesse d base d o n meas ure me nt of s U A fr o m bl o o d sa m ples, te n der a n d s w olle n 
j oi nt c o u nts, patie nt a n d p h ysicia n gl o bal assess me nt of g o ut, j oi nt pai n, urate v ol u me a n d g o ut 
er osi o n d ue t o g o ut b y D E C T.  
9. 5. 1. 1  Ser u m Uric Aci d 
Ser u m sa m ples f or meas ure me nt of s U A l e vels will be c ollecte d at t he Scree ni n g Visit ( wit hi n 2 
wee ks pri or t o t he first d ose of M T X at Wee k - 4),  t he Wee k - 4 Visit ( pri or t o t he first d ose of 
M T X), a n d t he Wee k - 2 Visit d uri n g t he M T X R u n-i n Peri o d; wit hi n 4 8 h o urs pri or t o eac h 
pe gl otic ase i nf usi o n (e x ce pt o n Da y 1 w he n o nl y 1 pre-i nf usi o n sa m ple is r e q uire d) a n d after t he 
e n d of eac h pe gl oticas e i nf usi o n pri or t o disc ha r ge, fr o m t he Pe gl oticase + I M M Peri o d t hr o u g h 

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wee k 2 4 a n d at W ee ks 3 2, 3 4, 3 6, 4 8 a n d 5 0;  wit hi n 4 8 h o urs pri or t o eac h pe gl oticase i nf usi o n 
at W ee ks 2 6, 2 8, 3 0, 3 8, 4 0, 4 2, 4 4 a n d 4 6 d uri n g t he Pe gl oticas e + I M M P eri o d; a n d at t he at t he 
E n d of Pe gl otic ase I nf usi o ns Visit (if a p plica ble);  at t he Wee k 5 2/ E n d of st u d y/ Earl y 
Ter mi nati o n Visit a n d M o nt h 3 a n d M o nt h 6 Visits. ( Secti o n 2. 1 )  O pti o nal (s u bjects w h o a gree 
t o partici pate) visits f or fre q ue nt sa m pli n g f or a d diti o nal n o n-i nf usi o n visit s U A sa m pli n g 
(ra n d o m, m or ni n g preferre d) will occ ur at Wee k 1 a n d Wee k 7. 
T w o se parate sa m ples/t u be s of bl o o d will be c ollecte d wit hi n 4 8 h o urs pri or t o t he pe gl oticase 
i nf usi o n f or assess me nt of s U A (e x ce pt o n D a y 1 w he n o nl y 1 pre-i nf usi o n sa m ple is re q uire d f or 
t he ce ntral la b orat or y). O ne sa m ple/t u be will be assesse d b y t he site’s l ocal la b orat or y t o be use d 
f or o n-st u d y s u bject ma n a ge me nt; pre-i nf usi o n s U A res ults m ust be re p orte d b y t he l ocal or 
ce ntral la b orat or y pri or t o eac h p e gl oticase i nf usi o n. If a l ocal la b orat or y s a m ple is dra w n ( wit hi n 
4 8 h o urs pri or t o t he pe gl oticase i nf usi o n), a sa m pl e f or t he ce ntral la b orat or y will be dra w n pri or 
t o t he pe gl otic ase i nf usi o n o n t he da y of t he visit. T he sec o n d sa m ple/t u be will be se nt t o t he 
ce ntral la b orat or y f or a nal ysis a n d rec or di n g i n t he data base. E ac h sa m ple/t u be will be l a belle d 
wit h t he date a n d ti me of t he sa m ple c ollecti o n. T h e date a n d ti me of bl o o d sa m ple c ollecti o n 
will be rec or de d. See t he La b orat or y M a n ua l f or i nstr ucti o ns f or alter nate sce nari os. 
A s u bject wit h s U A le vel > 6 m g/ d L ( base d o n t he l ocal or ce ntral la b orat or y) at 2 c o nsec uti ve 
st u d y visits, be gi n ni n g wit h t he Wee k 2 Visit, will be disc o nti n ue d fr o m pe gl oticase treat me nt 
a n d re mai n o n st u d y. 
Sa m ples t hat res ult i n disc or da nt r es ults bet wee n l ocal a n d ce ntral la b orat ories will be e val uate d 
a n d disc usse d wit h t he I n vesti gat or a n d t he S p o ns or’s Me dical M o nit or o n a case - b y-case b asis 
t o deter mi ne w het her t he s u bject s h o ul d c o nti n ue o n st u d y or disc o nti n ue.   
9. 5. 1. 2  Te n der a n d S w olle n J oi nt C o u nts 
Te n der a n d s w olle n (e x cl u des hi p) j oi nt c o u nts will be rec or de d at t he Wee k - 4 ( pri or t o t he first 
d ose of M T X) Visit d uri n g t he M T X R u n-i n Peri o d; pri or t o pe gl oticase i nf usi o n at t he Da y 1 
a n d Wee ks 1 4, 2 4 a n d 3 6 Visits d uri n g t he Pe gl oticase + I M M Peri o d; a n d at t he E n d of 
Pe gl oticase I nf usi o ns Visit (if a p plica ble) a n d t he Wee k 5 2/ E n d of St u d y/ E arl y Ter mi nati o n Visit 
a n d t he P ost Treat me nt 3 a n d 6 m o nt h F oll o w- u p visits ( Secti o n 2. 1 ). 
Te n der a n d s w olle n j oi nt c o u nts will be assesse d b y p h ysical e x a mi nati o n a n d d oc u me nte d usi n g 
t he r he u mat oi d art hritis 6 6- 6 8 met h o d s h o w n i n Fi g ure 9. 2 R he u mat oi d Art hritis 6 6- 6 8 Te n der 
a n d S w olle n J oi nt C o u nts or via ot her site s o urce d oc u me nt.  All i nf or mati o n will be e ntere d i nt o 
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Fi g ure 9. 2  
R he u m at oi d Art hritis 6 6- 6 8 Te n der a n d S w olle n J oi nt C o u nts 
 
9. 5. 1. 3  P ati e nt Gl o b al Assess me nt 
T he patie nt gl o bal assess me nt will be c ollecte d at  t he Scree ni n g a n d Wee k - 4 ( pri or t o t he first 
d ose of M T X) Visits d uri n g t he M T X R u n-i n Peri o d; pri or t o pe gl oticase i nf usi o n at t he Da y 1 
a n d Wee ks 1 4, 2 4 a n d 3 6 Visits d uri n g t he Pe gl otic ase + I M M Peri o d; at t he E n d of Pe gl oticase 
I nf usi o ns Visit (if a p plica ble); t he Wee k 5 2/ E n d of St u d y/ Earl y T er mi nati o n Visit a n d t he P ost 
Treat me nt Peri o ds 3 a n d 6 M o nt h F oll o w- u p Visits ( Secti o n 2. 1 ). S u bjects will res p o n d t o t he 
state me nt, “ C o nsi deri n g all t he wa ys t hat g o ut affects y o u, circl e t he n u m b er bel o w t hat best 
re pres e nts h o w y o ur g o ut has affecte d y o u o v er t h e last wee k” usi n g a n u m eric rati n g scale 
ra n gi n g fr o m 0 (e x celle nt) t o 1 0 ( ver y p o or) (see A p pe n di x 1 7. 3 ). 
9. 5. 1. 4  P h ysici a n Gl o b al Assess me nt 
T he p h ysi cia n gl o bal ass ess me nt will be c ollecte d at t he Scree ni n g a n d Wee k - 4 ( pri or t o t he first 
d ose of M T X) Visits d uri n g t he M T X R u n-i n Peri o d; pri or t o pe gl oticase i nf usi o n at t he Da y 1 
a n d Wee ks 1 4, 2 4 a n d 3 6 Visits d uri n g t he Pe gl oti case + I M M Peri o d; at t he E n d of Pe gl oticase 
I nf usi o ns Visit (if a p plica ble), t he Wee k 5 2/ E n d of St u d y/ Earl y T er mi nati o n Visit a n d t he P ost 
Treat me nt Peri o ds 3 a n d 6 M o nt h F oll o w- u p Visits ( Secti o n 2. 1 ). T he p h ysicia n will res p o n d t o 
t he state me nt, “ C o nsi deri n g t he s u bject’s o verall healt h relate d t o g o ut, r ate t heir g o ut o verall” 
usi n g a n u meric rati n g scale ra n gi n g fr o m 0 (e x celle nt) t o 1 0 ( ver y p o or) (s ee A p pe n di x 1 7. 4 ).  
F or a gi v e n s u bject, if p ossi ble, t he sa me q ualifie d I n v esti gat or s h o ul d perf or m t he assess me nt at 
eac h ti me p oi nt. 

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9. 5. 1. 5  J oi nt P ai n Assess me nt 
J oi nt pai n will be assesse d at t he Scree ni n g a n d Wee k - 4 ( pri or t o t he first d ose of M T X) Visits 
d uri n g t he M T X R u n-i n Peri o d; pri or t o pe gl oticase i nf usi o n at t he Da y 1 a n d Wee ks 1 4, 2 4 a n d 
3 6 Visits d uri n g t he Pe gl oticase + I M M Peri o d; at t he E n d of Pe gl oticase I nf usi o ns Visit (if 
a p plica ble); t he Wee k 5 2/ E n d of St u d y/ E arl y Ter m i nati o n Visit a n d t he P ost Treat me nt Peri o ds 3 
a n d 6 M o nt h F oll o w- u p Visits ( Secti o n 2. 1 ). S u bjects will res p o n d t o t he f oll o wi n g state me nts 
usi n g a n u meric rati n g scale ra n gi n g fr o m 0 ( n o j o i nt pai n) t o 1 0 ( w orst p ossi ble j oi nt pai n) (see 
A p pe n di x 1 7. 5 ).  
  Rate t he a vera ge p ai n y o u ha ve ha d i n y o ur j oi nts d uri n g t he last w ee k. 
 Rate t he least pai n y o u h a ve ha d i n y o ur j oi nts d uri n g t he last w ee k. 
 Rate t he w orst pai n y o u ha ve ha d i n y o ur j oi nts d uri n g t he last w ee k. 
9. 5. 1. 6  D u al-e ner g y C o m p ute d T o m o gr a p h y ( D E C T) 
F or sites wit h D E C T ca p a bilit y, D E C T will be o btai ne d at Da y 1 a n d Wee ks 2 4, 3 6 Visits d uri n g 
t he Pe gl oticas e + I M M P eri o d; at t he E n d of Pe gl oticase I nf usi o ns Visit (if a p plica ble), t he Wee k 
5 2/ E n d of St u d y/ E arl y T er mi nati o n Visit d uri n g t he a n d 5 2/ E n d of St u d y/ Earl y Ter mi nati o n.  
T he D E C T ma y be c o m plete d wit hi n +/- 5 da ys of t he sc he d ule d ti me p oi nt.  
S u bjects w h o e n d pe gl oticase i nf usi o ns pri or t o Wee k 5 2 s h o ul d f oll o w t he sc he d ule d ti me p oi nts 
b ut a v oi d a re peat D E C T sca n wit hi n 6 wee ks of a pri or sca n.  
I ma ges will be o btai ne d f or t he ha n ds/ wrists, k nees, a n kles/feet, a n d t h e I n v esti gat or will i de ntif y 
t he pri mar y area of maj or urate de p ositi o n. T he i m a gi n g will be p erf or m e d b y a st u d y-s p ecific, 
q ualifie d ra di ol o gist. 
9. 5. 2  Q u alit y- of- Life Assess me nt 
T he H A Q will be a d mi nistere d at t he Scree ni n g a n d Wee k - 4 ( pri or t o t he first d ose of M T X) 
Visits d uri n g t he M T X R u n-i n Peri o d; pri or t o pe gl oticase i nf usi o n at t he Da y 1 a n d Wee ks 1 4, 
2 4 a n d 3 6 Visits d uri n g t he Pe gl otic ase + I M M Peri o d; at t he E n d of Pe gl oticase I nf usi o ns Visit 
(if a p plica ble), t he Wee k 5 2/ E n d of St u d y/ E arly T er mi nati o n Visit a n d t he P ost Treat me nt 
Peri o ds 3 a n d 6 M o nt h F oll o w- u p Visits ( Secti o n 2. 1 ). 
T he H A Q- DI is a self-re p ort f u ncti o nal stat us i n str u me nt t hat ca n be fille d o ut b y a s u bject i n 
less t ha n 5 mi n utes a n d re q uires 1 mi n ute t o sc ore (A p pe n di x 1 7. 2 ). T he i n de x meas ures 
disa bilit y o v er t he p ast wee k b y as ki n g a t ota l of 2 0 q uesti o ns c o veri n g 8 d o mai ns of f u ncti o n: 
dressi n g a n d gr o o mi n g, arisi n g, eati n g, wal ki n g, h y gie ne, reac h, gri p, a n d us ual acti vities. T here 
are at least 2 q uesti o ns i n eac h d o mai n a n d t he 8 d o mai ns re pres e nt a c o m pre he nsi ve set of 
f u ncti o nal acti vities. T he H A Q- DI is calc ulat e d b y sc ori n g t h e a ns w er t o eac h q uesti o n i n t he 
H A Q fr o m 0 t o 3, wit h 0 re pres e nti n g t he a bilit y t o d o wit h o ut a n y diffi c ult y, a n d 3 re prese nti n g 
i na bilit y t o d o. A n y acti vit y t hat re q uir es assista nce fr o m a n ot her i n di vi d ual or re q uires t h e use of 
a n assisti ve de vice raises a 0 or 1 sc ore t o a 2. T he hi g hest sc ore f or eac h of t he 8 d o mai ns is 

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s u m me d (ra n ge fr o m 0 t o 2 4) a n d di vi de d b y 8 t o yi el d, o n a s cale wit h 2 5 p ossi ble val ues, a 
F u ncti o nal Disa bilit y I n d e x wit h a ra n ge fr o m 0 t o 3. T he disa bilit y i n de x is base d o n t he n u m ber 
of d o mai ns a ns were d a n d is c o m p ute d o nl y if t he s u bject c o m pletes a ns w ers t o at least 6 d o mai ns 
[Br uce a n d Fri es, 2 0 0 3 ]. 
T he H A Q p ai n scale as ks s u bjects t o rec or d h o w m u c h pai n t he y ha ve h a d i n t he past wee k o n a 
scale of 0 t o 1 0 0, w h ere zer o re pres e nts “ n o pai n” a n d 1 0 0 re prese nts “s e vere pai n”.   
T he H A Q h ealt h scale is a m eas ur e of o verall heal t h.  S u bjects are as ke d t o rate h o w well t he y 
are d oi n g o n a s c ore of 0 t o 1 0 0, w here zer o re pres e nts “ ver y well” a n d 1 0 0 re pres e nts “ ver y 
p o or” healt h.     
9. 5. 3  P h ar m a c o ki netic a n d A nti- dr u g A nti b o d y Me as ure me nts 
Ser u m sa m ples f or P K a n al ysis of p e gl oticase will  be c ollecte d pri or t o t he pe gl oticase i nf usi o n 
a n d after t he e n d of i nf usi o n ( pri or t o disc har ge) o n Da y 1 a n d at t he Wee ks 2, 4, 6, 8 a n d 3 6 
Visits a n d pri or t o t he pe gl oticase i nf usi o n o nl y at t he Wee ks 1 0, 1 4, 1 8, 2 2, 2 4; at t he E n d of 
Pe gl oticase I nf usi o ns Visit (if a p plica ble); a n d t h e Wee k 5 2/ E n d of St u d y/ E arl y Ter mi nati o n 
Visits. Visits f or fre q ue nt sa m pli n g of a s u bs et of s u bjects w h o c o nse nt f or a d diti o nal n o n-
i nf usi o n visit P K sa m pli n g will occ ur at Wee ks 1 a n d 7. 
I m m u n o ge nicit y of pe gl oticase will be assesse d vi a s er u m sa m ples f or e val uati o n of a nti- P E G 
a n d a nti- uricase I g G a nti b o dies. Sa m ples will be c ollecte d pri or  t o t he pe gl oticase i nf usi o n o n 
Da y 1 a n d at t he Wee ks 2, 4, 6, 8, 1 0, 1 4, 1 8, 2 2, 2 4, 3 6, at t he E n d of Pe gl oticase I nf usi o ns Visit 
(if a p plica ble);  a n d 5 2/ E n d of St u d y/ Earl y T er mi nati o n Visits a n d P ost Treat me nt 3 m o nt h 
F oll o w- u p Visit. Visits f or fre q u e nt sa m pli n g of a s u bset of s u bjects w h o c o nse nt f or a d diti o nal 
n o n-i nf usi o n visit P K sa m pli n g will occ ur at Wee ks 1 a n d 7.  I n t he e v e nt of a n A E s us pecte d t o 
be a n i nf usi o n reacti o n, a ser u m sa m ple will be c o llecte d at t hat ti me or at t he s u bse q ue nt visit 
f or e val u ati o n of pe gl otic ase a nti b o dies.  
Bl o o d sa m ples will be c ollecte d pri or t o pe gl oticas e i nf usi o n o n Da y 1 a n d at t he Wee ks 4, 8, 2 2 
a n d 3 6 Visits d uri n g t he Pe gl oticase + I M M f or M T X P ol y gl ut a mate a n al ysis. 
Eac h sa m ple c ollecti o n date a n d ti me will be rec or de d i n s o urce d o c u me nts a n d t he e C R F. 
Detaile d i nstr ucti o ns re gar di n g bl o o d s a m ple ti mi n g a n d h a n dli n g are pr o vi de d i n t he La b orat or y 
Ma n ual.  
9. 5. 4  S afet y V ari a bles 
Safet y will be assesse d vi a A E a n d c o n c o mita nt me dicati o n use m o nit ori n g, p h ysical 
e x a mi nati o ns, vital si g ns, cli nical safet y la b orat or y e val uati o ns ( he mat ol o g y, c he mistr y, uri ne 
uric aci d:creati ni ne rati o), pre g na nc y t esti n g (if a p plica ble), electr ocar di o gra ms ( E C Gs), a n d A Es 
of s pecial i nterest (i.e., I Rs, a na p h yl a xis, g o ut flares, a n d car di o vas c ular e ve nts).  

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9. 5. 4. 1  A d verse E ve nts 
9. 5. 4. 1. 1  Defi niti o ns 
9. 5. 4. 1. 1. 1  A d verse E ve nt Defi niti o n 
As defi ne d b y t he I C H, a n A E is a n y u nt o w ar d me dical occ urre n ce i n a cli nical st u d y s u bject 
a d mi nistere d a me dici nal (i n vesti gati o nal or n o n -i n vesti gati o nal) pr o d uct, w het her or n ot t he 
e ve nt is c o nsi dere d relat e d t o t he st u d y dr u g. A n A E is t heref ore a n y u nfa v ora ble a n d u ni nte n d e d 
si g n (i ncl u di n g a n a b n or mal la b orat or y fi n di n g), s y m pt o m, or disease ( ne w or e x acer bate d) 
te m p orall y ass ociate d wit h t he use of t he st u d y dr u g. T his i ncl u des a n y o cc urre nce t hat is ne w i n 
o nset or a g gra vate d i n se verit y or fre q ue nc y fr o m t he baseli ne c o n diti o n, or a b n or mal res ults of 
dia g n ostic pr o ce d ures, i n cl u di n g la b orat or y test a b n or malities.  
E x a m ples of a n A E i ncl u de:  
 C o n diti o ns ne wl y d etect e d or dia g n ose d after t he si g ni n g of t he I C F, i ncl u di n g c o n diti o ns 
t hat ma y h a ve bee n pres e nt b ut u n detecte d pri or t o t he start of t he st u d y 
 C o n diti o ns k n o w n t o ha ve bee n prese nt pri or t o t h e start of t he st u d y t hat w orse n after t he 
si g ni n g of t he I C F 
 Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d dr u g i nteracti o n 
 Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d o ver d ose of eit her 
i n vesti gati o nal pr o d u ct or a c o nc o mita nt me dicati o n ( o ver d ose p er se s h o ul d n ot be 
re p orte d as a n A E) 
Iss u es t hat will n ot be c o nsi dere d a n A E i ncl u de:  
 C o n diti o ns prese nt at t he start of t he st u d y s h o ul d be rec or de d as me dical hist or y 
  Me dical or s ur gic al pr oce d ures (e. g., e n d osc o p y, a p pe n dect o m y; h o w e ver, a c o n diti o n 
t hat lea ds t o a pr oce d ure is a n A E if it q ualifies acc or di n g t o t he d efi niti o ns a b o ve) 
 Sit uati o ns w here a n u nt o war d me dical occ urre n ce di d n ot occ ur (e. g., s o cial, dia g n ostic, 
electi ve, or c o n ve nie n ce a d missi o n t o a h os pital) 
 Fl uct uati o ns of pre-e xisti n g diseas e(s) or c o n diti o n(s) pres e nt or detecte d at t he start of 
t he st u d y t hat d o n ot re prese nt a cli nicall y si g nifica nt c ha n ge fr o m baseli ne 
 A b n or mal la b orat or y or t est fi n di n gs t hat are n ot assesse d b y t h e I n vesti gat or as a 
cli nicall y si g nifica nt c ha n ge fr o m baseli ne 
A Es are di vi de d i nt o t he cate g ories “seri o us” a n d “ n o n -seri o us.” T his deter mi nes t he pr oce d ures 
t hat m ust be use d t o re p ort/ d oc u me nt t he A E. 
9. 5. 4. 1. 1. 2  Seri o us A d verse E ve nt Defi niti o n 
Base d o n I C H g ui deli nes, a n S A E is a n y u nt o w ar d me dical occ urre n ce t hat at a n y d ose: 
a. Res ults i n deat h 

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b.  Is life t hreat e ni n g 
N O T E: T he ter m ‘lif e t hr eate ni n g’ i n t he defi niti o n of ‘seri o us’ refers t o a n  e ve nt i n 
w hic h t he s u bject was at ris k of deat h at t he ti me of t he e ve nt. It d o es n ot refer t o a n e ve nt 
t hat h y p ot hetic all y mi g ht ha ve ca use d deat h if it were m or e se vere, pr ol o n ge d, or 
u ntreate d. 
c. Re q uires h os pitaliz ati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n  
N O T E: H os pitalizati o n si g nifies t hat t he s u bject has bee n a d mitte d t o t he h os pital as a n 
i n patie nt f or a n y le n gt h of ti me. Treat me nt o n a n e mer ge nc y, o ut patie nt b asis f or a n e ve nt 
n ot f ulfilli n g a n y of t he d efi niti o ns of S A Es a n d n ot res ulti n g i n h os pital a d missi o n d oes 
n ot q ualif y f or t his cate g or y, b ut ma y b e a p pr o priatel y i n cl u de d i n cate g or y g (see bel o w). 
C o m plicati o ns t hat occ ur d uri n g h os pitalizat i o n are us uall y A Es. If a c o m plicati o n 
pr ol o n gs h os pitaliz ati o n or f ulfills a n y ot h er seri o us criteri o n, t he e v e nt will be 
c o nsi dere d as seri o us. W he n i n d o u bt as t o w het her ‘ h os pitalizati o n’ occ urre d, c o ns ult t he 
S p o ns or’s Me dical M o nit or.  
H os pitalizati o n will n ot be c o nsi dere d a n A E i n a n d of itself. It will be c o nsi dere d a n 
o utc o me of a n A E. T h eref ore, if t here is n o ass oci ate d A E, t here is n o S A E. F or e x a m ple, 
h os pitaliz ati o n f or electi ve or pre- pla n ne d tr eat me nt of a pre-e xisti n g c o n diti o n t hat di d 
n ot w orse n fr o m bas eli ne will n ot be c o nsi dere d a n A E. 
d.  Res ults i n persiste nt or si g nifica nt disa bilit y/i n ca p acit y 
N O T E: T he ter m disa bilit y mea ns a s u bsta ntia l disr u pti o n of a pers o n’s a bilit y t o c o n d uct 
n or mal 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 me dical si g nifica n ce, s uc h as u n c o m pl icate d hea dac he, na us ea, v o miti n g, diarr hea, 
i nfl ue nza, a n d acci de ntal tra u ma (e. g., s prai ne d a n kle) t hat ma y te m p oraril y i nterfere wit h 
or pre ve nt e ver y d a y life f u ncti o ns b ut d o n ot c o nstit ute a s u bsta ntial disr u pti o n. 
e. Is a c o n ge nital a n o mal y/ birt h defect 
f. Is a s us pecte d tra ns missi o n of a n y infecti o us a ge nt via a me dici nal pr o d uct 
g.  Is a n i m p orta nt me dical e ve nt 
N O T E: Me dical a n d s cie ntific j u d g me nt s h o ul d b e e x ercise d i n deci di n g w het her 
e x pe dite d re p orti n g as seri o us is a p pr o priate i n ot her sit uati o ns; s pecificall y, i m p orta nt 
me dical e ve nts t hat ma y n ot be i m me diatel y life t hreate ni n g or res ult i n deat h or 
h os pitaliz ati o n b ut ma y j e o par dize t he s u bject or ma y re q uire m e dical or s ur gical 
i nter ve nti o n t o pre ve nt 1 of t he ot her o utc o mes list e d i n t he a b o ve d efi niti o n. T hese 
s h o ul d us uall y be c o nsi d ere d seri o us. E x a m ples of s uc h e ve nts are i n vasi v e ca n cers, 
i nte nsi ve treat me nt i n a n e mer ge n c y r o o m or at h o me f or aller gi c br o nc h 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 n c y or dr u g a b us e. If i n d o u bt as t o w het h er or n ot a n e ve nt q ualifi es as a n 
‘i m p orta nt me dical e ve nt,’ c o ns ult t he S p o ns or’s Me dical M o nit or. 

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9. 5. 4. 1. 1. 3  N o n- Seri o us A d verse E ve nt Defi niti o n 
A Es t hat d o n ot res ult i n a n y of t he o utc o mes liste d i n Secti o n 9. 5. 4. 1. 1. 2  are c o nsi dere d 
n o n-seri o us. 
9. 5. 4. 1. 1. 4  U ne x pecte d A d ve rse E v e nt Defi niti o n 
A n A E or s us pect e d a d verse reacti o n is c o nsi dere d u ne x pecte d if it is n ot liste d i n t he Refere nce 
Safet y I nf or m ati o n secti o n of t he I n vesti gat or’s Br oc h ure or is n ot liste d wit h t he s pecificit y or 
se verit y t hat has bee n o bser ve d. U n e x pecte d, as use d i n t his defi niti o n, als o refers t o A Es or 
s us pecte d a d v erse reacti o ns t hat are me nti o ne d i n t he Refere nce Safet y I nf or mati o n as occ urri n g 
wit h a class of dr u gs or as a ntici pate d fr o m t he p h ar mac ol o gical pr o perties of t he dr u g, b ut are 
n ot s pecificall y me nti o ne d as occ urri n g wit h t he partic ular dr u g u n d er i n vesti gati o n. 
9. 5. 4. 1. 1. 5  A d verse E ve nts of S peci al I nterest 
A Es of s pecial i nterest i ncl u de I Rs, a na p h yla xis, g o ut flares, a n d car di o v asc ular e ve nts. A Es of 
s pecial i nterest will be c ollecte d o n a se p arate e C R F t hat ca pt ur es data relat e d t o eac h A E of 
s pecial i nterest. 
I nf usi o n Re acti o n 
A n I R will be d efi ne d as a n y i nf usi o n-relat e d A E or cl uster of te m p orall y-relate d A Es, n ot 
attri b uta ble t o a n ot her ca use, w hic h occ ur d uri n g t he pe gl oticase i nf usi o n a n d f or 1 h o ur p ost 
i nf usi o n.  Ot her A Es t hat occ ur o utsi de of t he 1- h o ur wi n d o w f oll o wi n g t h e i nf usi o n ma y als o be 
cate g orize d as a n I R at t h e Pri nci pal I n vesti gat or’s discreti o n. Si g ns a n d s y m pt o ms of t he I R a n d 
treat me nts a d mi nistere d will be d oc u me nted i n t he me dical r ec or d a n d i n t he e C R F.  
E x a m ples of A Es n ot c o nsi dere d p ossi ble I Rs i ncl u de, b ut are n ot li mite d t o: la b orat or y 
a b n or malities t hat are u nli kel y t o ha v e occ urre d d uri n g or wit hi n 1 h o ur f oll o wi n g t he i nf usi o n 
(e. g., a ne mia), g o ut flares, m ost i nfecti o us diseases, or t he rec urre n ce or w orse ni n g of a k n o w n 
c hr o nic me dical pr o ble m i de ntifie d i n t he s u bject’s me dical hist or y. 
A n a p h yl a xis 
A n y i nci d e nce of a na p h yla xis s h o ul d be re p orte d as a n S A E. A na p h yla xis will be defi ne d usi n g 
t he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases/ F o o d Aller g y a n d A na p h yl a xis Net w or k 
criteria [ Sa m ps o n et al, 2 0 0 6 ]:  
1.  Ac ute o nset of a n ill ness ( mi n utes t o se veral h o urs) wit h i n v ol ve me nt of t he s ki n, 
m uc osal tiss ue, or b ot h (e. g., ge neralize d hi ves; pr urit us or fl us hi n g; urtic aria, a n d 
a n gi o e de ma ( of li ps, t o n g ue, or u v ula) a n d ≥1 of t h e f oll o wi n g:  
a. 
 Res pirat or y c o m pr o mise (e. g., d ys p nea, w heeze- br o nc h os pas m, stri d or, re d uce d 
pea k e x pirat or y fl o w, h y p o x e mia)  
b.  
Re d uce d bl o o d press ure or ass ociate d s y m pt o ms of e n d- or ga n d ysf u ncti o n 
(e. g., h y p ot o nia [c olla pse], s y n c o pe, i nc o nti ne nce) 

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2.  T w o or m ore of t h e f oll o wi n g t hat occ ur ra pi dl y after e x p os ure t o a li kel y aller ge n f or 
t hat s u bject ( mi n utes t o se veral h o urs): 
a. 
I n v ol ve m e nt of t he s ki n- m uc osal tiss ue (e. g., ge n eralize d hi ves, itc h-fl us h, 
s w olle n li ps-t o n g ue, u v ul a) 
b.  
Res pirat or y c o m pr o mise (e. g., d ys p nea, w heeze- br o nc h os pas m, stri d or, re d uce d 
pea k e x pirat or y fl o w, h y p o x e mia) 
c. 
Re d uce d bl o o d press ure or ass ociate d s y m pt o ms ( e. g., h y p ot o nia [c olla pse], 
s y nc o p e, i nc o nti ne nce) 
d.  
Persiste nt gastr oi ntesti nal s y m pt o ms (e. g., cra m p y, a b d o mi nal pai n, v o miti n g) 
3.  Re d uce d bl o o d press ure after e x p os ure t o k n o w n aller ge n f or t hat s u bject ( mi n utes t o 
se veral h o urs): s yst olic bl o o d press ure < 9 0 m m H g or > 3 0 % decrease fr o m t hat s u bject’s 
baseli ne 
G o ut Fl ares 
It is c o m m o n f or p ot e nt urate-l o w eri n g t hera pies t o lea d t o ac ute attac ks of g o ut. G o ut flares will 
be c o nfir me d t hr o u g h q u esti o ni n g or direct o bser v ati o n, detaile d i n Secti o n 9. 5. 4. 8 . 
C ar di o v asc ul ar E ve nts 
 T he f oll o wi n g car di o v asc ular e ve nts will be c ollecte d. Maj or A d verse Car di o vasc ular 
E ve nts ( M A C E) defi ne d as: 
o     N o n- Fatal M y ocar dial I nfarcti o n: T he prese nce of at least 2 of t he 3 f oll o wi n g 
criteria: 1) c hest pai n c o nsiste nt wit h a n gi na, 2) a b n or mal val ues of car diac 
e nz y mes ( > u p per li mit of  n or mal of t he M B fracti o n of creati ni ne 
p h os p h o ki nase  a n d/ or tr o p o ni n t hat f oll o ws a patter n of m y ocar dial i nj ur y), 3) 
m y ocar dial i nj ur y  c urre nt ( S T se g me nt ele vati o n) or t he de vel o p me nt of ne w Q 
wa ves i n 2 c o nti g u o us  lea ds of t he electr ocar di o gra m. 
o     N o n- Fatal Str o ke: isc he mic or he m orr ha gic str o ke defi ne d as a n ac ute, f ocal 
ne ur ol o gic e ve nt t hat persiste d f or > 2 4 h o urs. If n e ur ol o gic s y m pt o ms last f or 
< 2 4 h o urs b ut ma g netic  res o na nce i ma gi n g ( M RI) c o nfir ms a n i nfarct, it will 
be c o nsi dere d as a str o ke. C o nfir mati o n b y i ma gi n g st u dies ( ma g netic 
res o na nce i ma gi n g or c o m p uterize d t o m o gra p h y of t he brai n) will be s o u g ht 
i n all cases, b ut will n ot be a n a bs ol ute re q uire me nt f or c o nsi d erati o n of t he 
e ve nt. 
o    Car di o vasc ular deat hs: i ncl u di n g a n y deat h fr o m a car di o vasc ular ca use 
i ncl u di n g:  m y ocar dial i nfarcti o n, str o ke, heart fail ure, arr h yt h mic deat h, a ortic 
dissecti o n or  r u pt ure, a n y fatal t hr o m b oe m b olic e ve nt, s u d de n car diac deat h, 
a n y deat h of u n k n o w n ca use a n d u n wit nesse d deat h. 
• 
C o n gesti ve heart fail ure defi ne d as: h os pitalizati o n or pr ol o n ge d ( > 1 2 h o urs) 

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e mer ge nc y de part me nt visit d ue t o d ys p nea, s h ort ness of breat h, wit h pr o gressi ve 
e de ma acc o m pa nie d b y cli nical fi n di n gs of p ul m o nar y vasc ular c o n gesti o n. 
Ra di o gra p hic a n d/ or ec h ocar di o gra p hic d oc u me ntati o n is desira ble b ut n ot re q uire d. 
Treat me nt b y i ntra ve n o us ( Pare nteral) di uretics or i n otr o pes is re q uire d t o c o nfir m 
t his dia g n osis vers us ultrafiltrati o n, he m o dial ysis or left ve ntric ular assist de vices. 
9. 5. 4. 1. 2  D oc u me nt ati o n of A d verse E ve nts 
A E m o nit ori n g will be gi n fr o m t he si g n at ure of t h e I C F u ntil t he 6 m o nt h P ost Treat me nt 
F oll o w- u p Visit. 
S A E m o nit ori n g will be gi n fr o m t he si g nat ure of t he I C F u ntil t he 6 m o nt h P ost Treat me nt 
F oll o w- u p Visit. 
S u bjects will be q uesti o ne d a b o ut A Es at eac h st u d y visit, usi n g n o ns pecifi c q uesti o ns, s uc h as 
“ H o w ha v e y o u bee n feeli n g si nce t he l ast st u d y visit? ” A Es m ust be rec or de d o n t he A E e C R F 
a n d d oc u me nte d i n t he s o urce rec or d after t he si g ni n g of t he I C F. 
A Es rec or de d bef ore t h e first d ose of M T X i n t he R u n-I n Peri o d will be rec or de d as me dical 
hist or y. 
9. 5. 4. 1. 3  I nte nsit y of A d verse E ve nts 
All A Es, b ot h seri o us a n d n o n-seri o us, will be ass esse d f or se verit y usi n g t he R he u mat ol o g y 
C o m m o n T o xicit y Criteri a v 2. 0 [ W o o d w ort h et al, 2 0 0 7 ]. T he scale dis pla ys Gra des 1 t hr o u g h 4 
wit h u ni q ue cli nical descri pti o ns of se verit y f or  eac h A E (i ncl u di n g a b n or m al la b orat or y v al ues) 
base d o n t his ge neral g ui deli ne.  
 Gra de 1 ( mil d) –  as y m pt o matic or tra nsie nt, s h ort d urati o n ( < 1 wee k), n o c ha n ge i n 
lifest yle, n o me di cati o n or o ver-t he-c o u nter 
 Gra de 2 ( m o derat e) –  s y m pt o matic, d urati o n 1 t o 2 wee ks, alter lifest yl e occasi o nall y, 
me dicati o ns gi ve relief ( ma y b e pres cri pti o n) 
 Gra de 3 (se vere) –  pr ol o n ge d s y m pt o ms, re v ersi ble, maj or f u ncti o nal i m pair me nt, 
prescri pti o n me dicati o ns/ partial relief, h os pitalize d < 2 4 h o urs, te m p orar y or per ma n e nt 
st u d y dr u g disc o nti n uati o n 
 Gra de 4 (i ncl u des life-t hreate ni n g) –  at ris k of deat h, s u bsta ntial disa bilit y, es peciall y if 
per ma ne nt, h os pitalize d > 2 4 h o urs, per m a ne nt st u d y dr u g disc o nti n uati o n 
9. 5. 4. 1. 4  Rel ati o ns hi p t o St u d y Dr u g 
T he relati o ns hi p of eac h A E t o M T X a n d/ or pe gl oti case will be deter mi ne d b y t he I n vesti gat or 
a n d t he S p o ns or base d o n t he f oll o wi n g defi niti o ns: 

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 N ot relate d: T here is n o pla usi ble te m p oral relati o ns hi p or t here is a n ot her e x pla nati o n 
t hat u ne q ui v ocall y pr o vi des a m ore pla usi ble e x pla nati o n f or t he e ve nt. 
 Relate d: T here is e vi de nce i n fa v or of a ca usal  rel ati o ns hi p (i.e., t here is a pl a usi ble ti me 
c o urse) a n d ≥1 of t he f oll o wi n g criteria a p pl y:  
o  T here is a reas o n a ble p har mac ol o gical r elati o ns hi p ( or k n o w n class effect). 
o  T here is n o ot her m or e pl a usi ble e x pla nati o n. 
o  T here is a p ositi ve de-c h alle n ge ( wit h o ut acti ve tr eat me nt of t he e v e nt). 
o  T here is a p ositi ve re-c h alle n ge. 
o  T here is a disti n g uis ha ble d ose effect. 
T he assess me nt of ca usalit y will be base d o n t he i nf or mati o n a vaila ble a n d ma y c ha n ge b ase d 
u p o n recei pt of a d diti o nal i nf or mati o n. 
9. 5. 4. 1. 5  Re p orti n g a n d D oc u me nti n g S A Es a n d Pr o d uct C o m pl ai nts 
9. 5. 4. 1. 5. 1  Seri o us A d verse E ve nts 
A n y d eat h, life-t hr eate ni n g e v e nt, or ot her S A E e x perie nce d b y a s u bject d uri n g t he c o urse of t he 
st u d y, w het h er or n ot j u d ge d dr u g-relate d, m ust be re p orte d wit hi n 2 4 h o urs of k n o wle d ge of t h e 
e ve nt b y e nteri n g t he i nf or mati o n i nt o t he e C R F. If u na ble t o access t he e C R F, t he e ve nt m ust be 
re p orte d b y s u b mitti n g t h e c o m plete d S A E f or m vi a e mail or fa x t o t he c o ntact n u m bers 
pr o vi de d bel o w.   
Fa x 
 
E- mail 
l
 
T he e ve nt m ust be d oc u me nte d i n s o urce d o c u me ntati o n a n d t he e C R F. T he f oll o wi n g ste ps will 
be ta ke n t o re p ort pr o m ptl y a n d d o c u me nt acc urat el y a n y S A E, w het her or n ot it a p pears t o be 
relate d t o M T X a n d/ or pe gl oticase: 
1.  Re p ort t he S A E t o t he S p o ns or b y e nt eri n g t he i nf or mati o n i nt o t he e C R F wit hi n 2 4 h o urs 
after bec o mi n g a w are t hat a s u bject has e x perie nce d a n S A E. If u na bl e t o access t he 
e C R F, t he e ve nt m ust be re p orte d b y s u b mitti n g t h e c o m plete d S A E f or m b y e m ail t o 
or fa x wit hi n 2 4 h o urs after bec o mi n g a ware t h at 
a s u bject has e x perie n ce d a n S A E. 
2.  Perf or m a p pr o priate dia g n ostic tests a n d t her a pe utic meas ures, a n d s u b mit all f oll o w- u p 
s u bsta ntiati n g data, s uc h as dia g n ostic t est re p orts, h os pital disc har ge s u m maries, a n d 
a ut o ps y re p ort t o t he S p o ns or’s re prese ntati ve.  
3.  Res p o n d i n a ti mel y ma n ner t o a n y q ueries fr o m S p o ns or re gar di n g t h e S A E. 
4.  C o n d uct a p pr o priate c o ns ultati o n a n d f oll o w- u p e val uati o n u ntil t he S A E is res ol ve d, 
sta bilize d, or ot her wise e x plai ne d b y t h e I n v esti gat or. 

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5.  Re vie w eac h S A E re p ort a n d e val uat e t he rel ati o ns hi p of t he S A E t o M T X a n d/ or 
pe gl otic ase. 
6.  T he I n vesti gat or m ust re p ort all A Es or S A Es t hat meet t he criteri a f or U na ntici pate d 
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 t o t he I R B. 
After recei pt of t h e i nitial re p ort, t he i nf or m ati o n will be re vie we d a n d t he I n v esti gat or ma y be 
c o ntacte d wit h re q uests f or a d diti o nal i nf or mati o n or f or data clarifi cati o n. 
F oll o w- u p will be o btai n e d via t he e C R F, fa x, or e- mail, as necessar y, u ntil t he e v e nt res ol ves or 
attai ns a sta ble o utc o me.  
or desi g n ee is res p o nsi ble f or t he pre p arati o n of 
Me d Watc h 3 5 0 0 A/ C o u ncil f or I nter n ati o nal Or ga nizati o ns of Me dical Scie nces I f or ms a n d 
a nal ysis of si milar e ve nts f or i n di vi d ual occ urr e nces (t o be s u b mitt e d as I n vesti gati o nal N e w 
Dr u g [I N D] safet y letters t o t he F D A a n d I n vesti gat ors acc or di n g t o 2 1 C F R 3 1 2. 3 2 b y  
. 
9. 5. 4. 1. 5. 2  Pr o d uct C o m pl ai nts 
A pr o d uct c o m plai nt pr o cess will be descri be d i n t he St u d y Refere nce Ma n ual. A n y pr o d uct 
c o m plai nt m ust be re p ort e d t o t he S p o ns or usi n g t his pr ocess. 
9. 5. 4. 1. 6  F oll o w- u p of A d verse E ve nts 
After t he i nitial rec or di n g of a n A E, t he I n vesti gat or s h o ul d pr oacti vel y f oll o w t he s u bject. A n y 
n o n seri o us A Es t hat are still o n g oi n g at t he e n d of  partici pati o n i n t he st u d y a n d/ or t he f oll o w-
u p peri o d s h o ul d be re vie we d t o deter mi ne if f urt h er f oll o w u p is re q uir e d. T he I n vesti gat or will 
d oc u me nt o n t he A E e C R F all o n g oi n g n o n seri o us A Es t hat will n ot be f oll o we d f urt her at t he 
e n d of partici p ati o n i n t he st u d y a n d/ or t he f oll o w u p peri o d. If i n d o u bt, t he I n vesti gat or s h o ul d 
c o ns ult t he S p o ns or’s Me dical M o nit or.  
All S A Es s h o ul d be f oll o we d u ntil res ol uti o n, u ntil t he c o n diti o n sta bilizes, or u ntil t he s u bject is 
l ost t o f oll o w- u p. O nce t he S A E is res ol ved, t he c orres p o n di n g A E e C R F p a ge s h o ul d be 
u p date d. 
9. 5. 4. 1. 7  Me dic ati o n Err or a n d O ver d ose 
A n o ver d ose is defi ne d as a k n o w n deli berate or acci de ntal a d mi nistrati o n of i n vesti gati o nal 
dr u g, t o, or b y a st u d y s u bject, at a d ose a b o ve t hat w hic h is assi g ne d t o t hat i n di vi d ual s u bject 
acc or di n g t o t he st u d y pr ot oc ol. 
All cases of me dic ati o n err ors a n d o v er d ose ( wit h or wit h o ut ass ociate d A Es) will be 
d oc u me nte d o n t he e C R F i n or der t o ca pt ur e t his i m p orta nt safet y i nf or mati o n c o nsiste ntl y i n t he 
data base. A Es ass ociate d wit h a n o ver d ose a n d S A Es  of o ver d ose are t o be re p ort e d acc or di n g t o 
t he pr oce d ures o utli ne d i n Secti o n 9. 5. 4. 1. 2  a n d Secti o n 9. 5. 4. 1. 5 , res pecti vel y. 
I n t he e ve nt of dr u g o ver d ose, t he s u bject is t o be treate d as a p pr o pri ate. 

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9. 5. 4. 1. 8  Re vie w of A d verse E ve nts a n d E mer gi n g Ne w S afet y I nf or m ati o n 
T he S p o ns or will n otif y all I n vesti gat ors i n v ol ve d i n t he cli nical i n vesti gati o n of i m p orta nt safet y 
i nf or mati o n re gar di n g t h e st u d y tr eat me nt, as re q uire d b y t h e a p plica bl e re g ulati o ns. 
I n v esti gat ors will n otif y t heir I R B of all s uc h n otificati o ns, as re q uir e d. 
9. 5. 4. 1. 9  Re p orti n g of I N D S afet y Re p orts 
T he S p o ns or will n otif y t he U nite d States F D A a n d all I n v esti gat ors o n a n y ne w seri o us ris ks 
ass ociate d wit h t he dr u g. 
9. 5. 4. 1. 1 0  De vel o p me nt S af et y U p d ate Re p orts 
T he S p o ns or will pre pare a n d s u b mit a n n ual safet y re p orts t o c o m pete nt a ut h orities. 
9. 5. 4. 2  Pre g n a nc y Re p orti n g 
W o me n of c hil d beari n g p ote ntial (i ncl u di n g t h os e wit h a n o nset of me n o pa use < 2 years pri or t o 
t he scree ni n g, n o n-t hera p y-i n d uc e d a me n orr hea f or < 1 2 m o nt hs pri or t o t he scree ni n g, or n ot 
s ur gic all y sterile [a bse nce of o vari es a n d/ or uter us]) will ha ve a ser u m pre g na nc y test at t he 
Scree ni n g Visit.  Uri ne pre g na nc y t ests will als o be perf or me d at all ot her ti me p oi nts, as 
i n dicate d i n Secti o n 2. 1 . Pre g n a nc y will n ot be c o nsi dere d a n A E i n t his st u d y, h o we ver, a n y 
pre g na nc y c o m plicati o ns, i ncl u di n g a n electi ve  ter mi nati o n f or me dical reas o ns, s h o ul d be 
re p orte d as a n A E.  
Male s u bjects w h o are n ot vasect o miz e d m ust n ot i m pre g n ate t heir fe male p art ner d uri n g t he 
st u d y u ntil at least 3 m o nt hs after t he last d ose of M T X. 
I nf or mati o n m ust be o btai ne d a n d re p orte d if a fe male s u bject s us pects t hat s he has bec o me 
pre g na nt d uri n g t he st u d y (i ncl u di n g t he M T X R u n-i n Peri o d) u p t o 3 0 da ys after t he last d ose of 
st u d y treat me nt (eit her p e gl otic ase or M T X), or if a fe male p art ner of male s u bject s us pects t hat 
s he has bec o m e pre g n a nt d uri n g t he st u d y (i ncl u di n g t he M T X R u n-i n Peri o d) u p t o 3 m o nt hs 
(a p pr o xi matel y 9 0 da ys) after t heir m ale s u bject p art ner disc o nti n ues M T X. T he I n vesti gat or will 
i nstr uct t he fe male s u bje ct t o st o p ta ki n g all st u d y dr u gs. A s er u m pre g na n c y t est s h o ul d be 
perf or me d if a n y fe male s u bject or fe mal e part n e r of a male s u bject s us pects t hat s he has bec o me 
pre g na nt d uri n g t he ti me fra me as defi ne d a b o ve. If  pre g na n c y is c o nfir me d, fe male s u bj ect will 
be wit h dra w n fr o m t he st u d y. Pre g n a nc y will be f oll o we d u p u ntil t he o utc o me of pre g n a nc y.  
C o m plete pre g na nc y i nf or mati o n, i ncl u di n g t he o utc o me of t he pre g na nc y, s h o ul d be c ollecte d i n 
t he s o urce d o c u me nts o n t he fe male s u bject or part ner of a m ale s u bject. I n t he a bse nce of 
c o m plicati o ns, f oll o w- u p after deli ver y will be n o l o n ger t h a n 8 wee ks. A n y still birt hs or 
pre mat ure t er mi nati o ns of pre g na n cies, w h et her el ecti ve, t hera pe utic, or s p o nta ne o us, s h o ul d be 
re p orte d o n t he pre g na n c y o utc o me f or m. A n y pre g na n c y c o m plicati o ns, i n cl u di n g a n electi ve 
ter mi nati o n f or me dical r eas o ns, sh o ul d be re p orte d as a n A E. 
A s p o nta ne o us a b orti o n s h o ul d al wa ys be c o nsi der e d a n S A E, as s h o ul d a n y c o n ge nital defects 
i n t he ne w b or n. A n y S A E occ urri n g as a res ult of a p ost-st u d y pre g na n c y a n d c o nsi dere d 

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reas o na bl y relate d t o t he i n vesti gati o nal pr o d u ct b y t he I n v esti gat or s h o ul d be re p ort e d t o t he 
S p o ns or. 
W o me n w h o are breastfee di n g are n ot eli gi ble t o partici pate i n t he st u d y. 
9. 5. 4. 3  Me dic al Hist or y 
Me dical hist or y, i n cl u di n g g o ut hist or y (e. g., ti me of first dia g n osis a n d hist or y of t o p hi, 
c ollecte d o n a g o ut-s p ecific e C R F) a n d s y m pt o m se verit y, will be c o n d uct e d at t he Scree ni n g 
a n d Wee k - 4 Visits.  
9. 5. 4. 4  Vit al Si g ns, Hei g ht, a n d Wei g ht 
R o uti ne vital si g ns, i ncl u di n g bl o o d press ur e, res pirat or y rate, t e m perat ure, a n d heart rate will be 
meas ure d at Scree ni n g, Wee k - 4 a n d at all i nf usi o n visits d uri n g t he Pe gl oticase + I M M Peri o d 
a n d t he E n d of Pe gl oticas e I nf usi o ns Visit (if a p plica ble), Wee k 5 2/ E n d of St u d y/ E arl y 
Ter mi nati o n a n d 3 a n d 6 m o nt h P ost Treat me nt F oll o w- u p Visits. ( Secti o n 2. 1 ). Heart rate a n d 
bl o o d press ure me as ure m e nts s h o ul d be ta ke n aft er t h e s u bject has bee n i n a sitti n g p ositi o n a n d 
i n a reste d a n d cal m state wit h pr o per p ositi o ni n g i ncl u di n g bac k s u p p ort, feet flat o n t he fl o or, 
f or at least 5 mi n utes.  S u bject’s ar m s h o ul d be s u p p orte d at heart le vel; a n d c uff place d o n t he 
bare ar m.  A lar ge c uff s h o ul d be use d as nee de d t o fit t he u p per ar m a n d a c o nsiste nt ar m is t o 
be use d at e ac h st u d y visit.  T he K or ot k off p h ase V will be use d t o deter mi ne diast olic bl o o d 
press ure.  D uri n g t he Pe gl oticase + I M M Peri o d st u d y visits, vitals s h o ul d be ta ke n bef ore t h e 
pe gl otic ase i nf usi o n a n d a n y ti me after t he e n d of t he i nf usi o n, b ut pri or t o s u bject’s 
disc har ge/r eleas e fr o m t h e site.   
W he n p ossi ble, t he sa me staff me m ber s h o ul d ta ke all B P meas ure m e nts f or a gi v e n s u bject. 
Wei g ht s h o ul d be meas ur e d i n kil o gra ms or p o u n ds wit h o ut s h oes a n d rec or de d at t he Scree ni n g 
Visit; pri or t o pe gl oticase i nf usi o n o n Da y 1 a n d at t he Wee ks 8, 1 6, 2 4, 3 6 a n d at t he n o n-
i nf usi o n E n d of Pe gl oticase I nf usi o ns Visit (if a p plica ble), Wee k 5 2/ E n d of St u d y/ E arl y 
Ter mi nati o n a n d M o nt hs 3 a n d 6 P ost Treat me nt F oll o w- u p Visits. 
Hei g ht will be c ollecte d at t he Scree ni n g Visit o nl y. 
Vital si g n m o nit ori n g d uri n g I R is descri be d i n Secti o n 9. 4. 6. 3. 2. 4 . 
9. 5. 4. 5  P h ysic al E x a mi n ati o ns 
A c o m plete p h ysical e x a mi nati o n will be perf or m e d at t he Scree ni n g Visit, i ncl u di n g assess me nt 
of H E E N T, heart, l u n gs, a b d o me n, s ki n, e xtre mities, a n d ne ur ol o gical stat us. T he e x a m will 
i ncl u de assess me nt f or prese nce of t o p hi, as well as g o ut hist or y a n d s y m pt o m se verit y (Secti o n 
2. 1 ).  
A tar gete d p h ysic al e x a mi nati o n per t he i n vesti gat or j u d ge m e nt b ut at a mi ni m u m s h o ul d i ncl u de 
heart, l u n gs a n d a b d o mi n al e x a m a n d i ncl u de a j oi nt a n d s ki n e val uati o n a n d assess me nt of A Es 
at W ee k - 4, Da y 1, a n d pri or t o a d mi nistrati o n of pe gl oticase at Wee ks 4, 8, 1 2, 1 6, 2 0, 2 4, 3 6, 

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t he E n d of Pe gl oticase I nf usi o ns Visit (if a p plica ble), Wee k 5 2/ E n d of St u d y/ Earl y T er mi nati o n 
a n d 3 a n d 6 m o nt h P ost Treat me nt F oll o w- u p Visits. 
P h ysical e x a mi nati o n fi n di n gs at scree ni n g s h o ul d be rec or de d o n t he m e dical a n d s ur gical 
hist or y e C R F.  
Cli nicall y si g nifica nt fi n di n gs fr o m t he tar gete d p h ysical e x a mi nati o ns will be rec or de d as A Es.  
9. 5. 4. 6  Electr oc a r di o gr a m 
A 1 2-lea d E C G will be p erf or me d o n Da y 1 b ef ore t he pe gl oticase i nf usi o n f or all s u bjects a n d at 
t he discreti o n of t he I n v esti gat or t hereafter (Secti o n 2. 1 ). 
9. 5. 4. 7  Cli nic al L a b or at or y S afet y Tests 
Bl o o d (f or he mat ol o g y a n d cli nical c he mistr y) a n d uri ne (f or uric aci d:creati ni ne rati o) sa m ples 
will be c ollecte d at t he S cree ni n g, Wee k - 4 ( pr i or t o t he first d ose of M T X), a n d Wee k - 2 Visits 
d uri n g t he Scree ni n g/ M T X R u n-i n Peri o d; pri or t o pe gl oticase i nf usi o n o n Da y 1 a n d at t he 
Wee ks 2, 6, 1 4, 2 2, 2 4 a n d 3 6, Visits d uri n g t he Pe gl oticase + I M M Peri o d; a n d t he n o n-i nf usi o n 
E n d of Pe gl otic ase I nf usi o ns Visit (if a p plica ble), Wee k 5 2/ E n d of St u d y/ E arl y Ter mi nati o n a n d 
3 a n d 6 m o nt h P ost Treat m e nt F oll o w- u p Visits.  
Safet y l a b orat or y assess me nts will i ncl u de:  
 He mat ol o g y: c o m plete bl o o d c o u nt wit h differe nti al ( he m o gl o bi n c o nce ntrati o n, 
he mat ocrit, er yt hr o c yte c o u nt, platelet c o u nt, le u k oc yt e c o u nt, a n d differe ntial le u k oc yte 
c o u nt) 
 C he mistr y: al b u mi n, tra nsa mi nases (as p artate a mi n otra nsferase, al a ni ne 
a mi n otra nsferase), al kali ne p h os p hatase, t otal bilir u bi n, creati ni ne (i ncl u di n g calc ulati o n 
f or e G F R calc ulat e d b y t he a b bre vi ate d M D R D e q uati o n : creati ni ne (i ncl u di n g 
calc ulati o n f or e G F R cal c ulate d b y t he M D R D st u d y  e q u ati o n : 1 7 5 x ( S cr[ m g/ d L])- 1. 1 5 4 x 
(a ge)- 0. 2 0 3x ( 0. 7 4 2 if fe male) x ( 1. 2 1 2 if Africa n A merica n) or 1 7 5 x ( S cr[μ m ol/ L]/ 8 8. 4) - 1. 1 5 4 x 
(a ge)- 0. 2 0 3x ( 0. 7 4 2 if fe male) x ( 1. 2 1 2 if Africa n A merica n), gl u c ose, s o di u m, p otassi u m, 
calci u m, c hl ori de, t otal pr otei n, bl o o d urea nitr o ge n, a n d h u ma n c h ori o nic g o na d otr o pi n 
(at t he Scree ni n g Visit f or all fe male s u bjects of c hil d beari n g p ot e ntial) 
 Uri ne: uric aci d:creati ni ne rati o a n d h u ma n c h ori o nic g o n a d otr o pi n (at all visits e x ce pt 
t he Scree ni n g Visit f or all fe male s u bjects of c hil d beari n g p ote ntial) 
Safet y l a b orat or y s a m ples will be a nal yze d b y t h e ce ntral la b orat or y. Sa m pl es will be c ollecte d 
f or a nal ysis at t he l oc al la b orat or y, if n ee de d. 
9. 5. 4. 8  Assess me nt of G o ut Fl a re 
T here is n o vali date d i nstr u me nt t o assess g o ut f lares. G o ut flares will be assesse d b y as ki n g 
s u bjects t he f oll o wi n g q u esti o ns at t he ti me p oi nts s pecifie d i n Secti o n 2. 1 . T o be c o nsi dere d a 
g o ut flare, s u bjects m ust a ns wer p ositi vel y t o 3 of t he f oll o wi n g 4 q uesti o ns [ Gaff o et al, 2 0 1 2 ].  

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1.  Ha ve y o u ha d a g o ut flare i n y o ur j oi nts i n t he last 2 wee ks ( Scree ni n g Visit o nl y) or 
si nce last visit (all ot her visits)? ( Yes/ N o) 
2.  If yes t o flare, was t h ere pai n i n t he j oi nt(s) t hat was differe nt t ha n n or mal? ( Yes/ N o) 
3.  If yes t o flare, was t h ere pai n i n t he j oi nt(s) at rest t hat was greater t ha n a 3 o ut of 1 0 
( w here 0 = n o pai n a n d 1 0 = t he w orst pai n i ma gi na ble)? ( Yes/ N o) 
4.  If yes, w as t here s w elli n g i n t he j oi nt(s)? ( Yes/ N o) 
A d diti o nall y, t he s u bject s h o ul d re p ort: 
 t he j oi nts affecte d usi n g a s u bject-faci n g dia gra m (see A p pe n di x 1 7. 6 ); 
 t he t hera p y ta k e n t o treat t he g o ut flare ( p art of sta n dar d A E ass ess me nt); 
 h o w l o n g t he g o ut flare l aste d a n d w he n it res ol ve d ( part of sta n d ar d A E assess me nt). 
Eac h c o nfir me d flare will be ca pt ure d i n t he e C R F t o all o w s u m mar y of t h e n u m ber of fl ares. 
I nte nsit y of g o ut fl ares will be d oc u me nte d.  G o ut Flares s h o ul d b e ca pt ur e d as a n A d verse 
E ve nts/ Seri o us A d verse E ve nt (see 9. 5. 4. 1 ) 
9. 5. 5  A p pr o pri ate ness of Me as ure me nts 
T he st u d y p o p ulati o n is well- defi ne d a n d is c o nsiste nt wit h t he e x pecte d tar get p o p ulati o n f or 
w h o m pe gl otic ase is i n dicate d (a d ult s u bjects wi t h u nc o ntr olle d g o ut a n d wit h t he a bilit y t o 
t olerate M T X). 
9. 5. 6  St u d y Pr oce d ures 
S u bjects w h o pr o vi de i nf or me d c o nse nt a n d w h o meet all t he e ntr y criteria f or partici pati o n i n 
t his st u d y will be e nr olle d. 
9. 5. 6. 1  Scree ni n g/ M T X R u n-i n Peri o d 
D uri n g t h e Scree ni n g / M T X R u n-i n Peri o d, st u d y ca n di dates will be e v al uate d f or st u d y e ntr y 
acc or di n g t o t he stat e d i ncl usi o n a n d e x cl usi o n criteria ( Secti o n 2. 1 ).  T h e f oll o wi n g pr oce d ures 
will be perf or me d d uri n g scree ni n g t o esta blis h eac h ca n di dat e’s eli gi bilit y f or e nr oll me nt i nt o 
t he st u d y. 
9. 5. 6. 1. 1  Scree ni n g Visit ( Wit hi n 2 Wee ks Pri or t o t he First D ose of M T X at Wee k - 4) 
 O btai n si g ne d, writte n i nf or me d c o nse nt. Re f usal t o pr o vi de t his per missi o n e xcl u des a n 
i n di vi d ual fr o m eli gi bilit y f or st u d y p artici pati o n. Rec or d date i nf or me d c o nse nt was 
gi ve n a n d w h o c o n d u cte d t he pr ocess o n t he a p pr o priate s o urce d oc u me nt ati o n. 
 Deter mi ne st u d y eli gi bilit y t hr o u g h re vie w of t he i ncl usi o n/e xcl usi o n criteria (see 
(Secti o n 9. 3 ). 
 C ollect c o m plete g o ut hist or y ( o n g o ut-s p ecific C R F), ot her rele va nt me di cal/s ur gical 
hist or y, a n d me di cati o n hist or y, i ncl u di n g g o ut me dicati o ns starti n g at t he ti me of 

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dia g n osis a n d u p t o scree ni n g ( o n g o ut me dicati o ns-s pecific C R F), s u bsta nce use hist or y. 
Hist or y of n o n- g o ut me dicati o n use i n t he year pri or will be c ollecte d (see  Secti o n 9. 4. 9 
f or restricti o ns re gar di n g me dicati o ns).  
 Assess f or t he prese nce of t o p hi. 
 O btai n de m o gra p hic i nf or mati o n. 
 Perf or m a c o m plet e p h ysical e xa mi nati o n. 
 D oc u me nt g o ut flares a n d i nte nsit y. 
 Rec or d vital si g ns ( bl o o d press ure, res pirat or y rate, te m perat ur e, a n d heart rat e), 
i ncl u di n g meas ure me nts of hei g ht a n d wei g ht (see Secti o n 9. 5. 4. 4 ).  
 O btai n bl o o d sa m ples f or he mat ol o g y a n d cli nical c he mistr y a nal ysis.  
 O btai n a uri ne sa m ple f or uric aci d:creati ni ne rati o. 
 O btai n a ser u m sa m ple fr o m  all fe males of c hil d beari n g p ot e ntial f or perf or ma nce of a 
pre g na nc y t est. 
 O btai n bl o o d sa m ples t o e val uate s U A ( o nl y 1 sa m ple f or ce ntr al la b orat or y), G 6 P D, a n d 
HI V a nti b o d y. 
 A d mi nister H A Q a n d rec or d patie nt a n d p h ys icia n gl o bal ass ess me nts a n d j oi nt pai n 
assess me nt res p o nses. 
 I n q uir e a b o ut A Es. 
9. 5. 6. 1. 2  Wee k - 4 
 C o nfir m st u d y eli gi bilit y t hr o u g h re vie w of t he i ncl usi o n/e xcl usi o n criteria (see 
Secti o n 9. 3 ).  
 C ollect me dical/s ur gi cal hist or y, s u bsta nce use hist or y, a n d m e dicati o n hist or y (see 
Secti o n 9. 4. 9  f or restricti o ns re gar di n g me dicati o ns).  
 Perf or m a tar gete d p h ysi cal e x a mi nati o n s h o ul d i ncl u de heart, l u n gs a n d a b d o mi nal e xa m 
a n d j oi nt a n d s ki n e val uati o n a n d assess me nt of  A Es. A n y fi n di n g will be rec or de d as a n 
A E. 
 D oc u me nt g o ut flares a n d i nte nsit y. 
 Rec or d vital si g ns ( bl o o d press ure, res pirat or y rate, te m perat ur e, a n d heart rate) (see 
Secti o n 9. 5. 4. 4 ). 

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 O btai n bl o o d sa m ples f or he mat ol o g y a n d cli nical c he mistr y a nal ysis.  
 O btai n a uri ne sa m ple f or uric aci d:creati ni ne rati o. 
 O btai n a uri ne sa m ple fr o m all fe males of c hil d beari n g p ote ntial f or perf or ma nce of a 
pre g na nc y t est. 
 O btai n a bl o o d sa m ple f or meas ure m e nt of s U A  ( o nl y 1 sa m ple f or ce ntral l a b orat or y). 
 C ollect s w olle n/te n der j oi nt c o u nts; a d mi nister  H A Q; a n d rec or d patie nt a n d p h ysicia n 
gl o bal ass ess me nts a n d j oi nt pai n assess me nt res p o nses. 
 
Pr o vi de d osi n g cale n dar f or s u bjects t o rec or d t he date a n d ti me t he y ta ke M T X  
( A d diti o nal cale n dar pa ges ma y b e pr o vi de d at f ut ure visits as nee de d). 
 Dis pe nse M T X. 
 Fill g o ut pr o p h yla xis, fe x ofe na di ne, acet a mi n o p he n, a n d f olic aci d prescri pti o ns, as 
nee de d.  
 I n q uir e a b o ut A Es. 
 Scree n fail ure s u bjects t hat ta ke M T X d uri n g Wee k - 4 or Wee k - 3, a n d w h o are fe males 
of c hil d beari n g p ote ntial, will recei ve a sa fet y f oll o w- u p p h o ne call/e- mail/site visit 
a p pr o xi matel y 3 0 da ys after t he last d ose of M T X t o verif y at least o ne o v ul at or y c ycle 
has occ urre d si nce t he last d ose of M T X. If t he s u bject has n ot o v ulate d, a uri ne 
pre g na nc y t est will be perf or me d. Scree n fail ure s u bjects w h o are n o n- vas ect o mize d 
males, a p h o ne/e- mail/site visit i n q uir y w ill be c o n d ucte d 3 m o nt hs after M T X 
disc o nti n uati o n re gar di n g part ner pre g na n c y. 
9. 5. 6. 1. 3  Wee k - 2 
 C o nfir m st u d y eli gi bilit y t hr o u g h re vie w of t he i ncl usi o n/e xcl usi o n criteria (see 
Secti o n 9. 3 ). 
 O btai n bl o o d sa m ples f or he mat ol o g y a n d cli nical c he mistr y a nal ysis.  
 O btai n a uri ne sa m ple f or uric aci d:creati ni ne rati o. 
 O btai n a uri ne sa m ple fr o m all fe males of c hil d beari n g p ote ntial f or perf or ma nce of a 
pre g na nc y t est. 
 O btai n a bl o o d sa m ple f or meas ure m e nt of s U A ( o nl y 1 sa m ple f or ce ntral l a b orat or y). 
 Assess M T X c o m plia nce a n d re- dis pe ns e M T X. 

H oriz o n T hera pe utics Irela n d D A C
 
 
K R Y S T E X X A I N D: 0 1 0 1 2 2 
Date: 0 1 A pril 2 0 2 0 
 
Pr ot oc ol: H Z N P- K R Y- 2 0 1 
 
 
Versi o n 3. 0, A d mi nistrati ve C ha n ge 1 
P RI V A T E A N D C O N FI D E N TI A L I N F O R M A TI O N O F H O RI Z O N T H E R A P E U TI C S I R E L A N D D A C  Pa ge
 8 1
 
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1 2 9
 
 
 D oc u me nt g o ut flares a n d i nte nsit y. 
 As k Yes/ N o q uesti o n re gar di n g f olic aci d a n d g o ut flare pr o p h yla xis c o m plia nce. 
 Fill g o ut pr o p h yla xis, fe x ofe na di ne, acet a mi n o p he n, a n d f olic aci d prescri pti o ns, as 
nee de d.  
 C ollect s u bsta nce use hist or y, a n d m e dicati o n hist or y (see Secti o n 9. 4. 9  f or restricti o ns 
re gar di n g me di cati o ns). 
 I n q uir e a b o ut A Es. 
 Scree n fail ure s u bjects t hat ta ke n M T X d uri n g Wee k - 4 or Wee k - 3, Wee k - 2 or Wee k - 1, 
a n d w h o are fe m ales of c hil d beari n g p ot e ntial, will recei ve a safet y f oll o w- u p p h o ne 
call/e- mail/site visit a p pr o xi matel y 3 0 da ys afte r t he last d ose of M T X t o v erif y at least 
o ne o v ulat or y c ycl e has o cc urre d si nce t he l ast d ose of M T X. If t he s u bject has n ot 
o v ulate d, a uri ne pre g na n c y t est will be perf or me d. Scree n fail ure s u bjects w h o are n o n-
vasect o miz e d males, a p h o ne/e- mail/site visit i n q uir y will be c o n d ucte d 3 m o nt hs after 
M T X disc o nti n uati o n re gar di n g p art ner pre g n a nc y. 
9. 5. 6. 2  Pe gl otic ase + I M M Peri o d 
9. 5. 6. 2. 1  D a y 1 
O n Da y 1, s u bjects will r et ur n t o t he cli nic f or t he f oll o wi n g ass ess me nts a n d t he first d ose of 
pe gl otic ase.  
 O btai n 1 bl o o d sa m ple f or meas ure m e nt of s U A pri or t o t he pe gl oticase i nf usi o n.  
 C o nfir m st u d y eli gi bilit y t hr o u g h re vie w of t he i ncl usi o n/e xcl usi o n criteria (see  
Secti o n 9. 3 ). 
 A d mi nister M T X ≥6 0  mi n utes pri or t o pe gl oticase i nf usi o n if s u bject has n ot ta ke n M T X 
wit hi n t he pre vi o us 1 t o 3 da ys. 
 Perf or m a tar gete d p h ysi cal e x a mi nati o n s h o ul d i ncl u de heart, l u n gs a n d a b d o mi nal e xa m 
a n d j oi nt a n d s ki n e val uati o n a n d assess me nt of  A Es. A n y fi n di n g will be rec or de d as a n 
A E. 
 D oc u me nt g o ut flares a n d i nte nsit y. 
 Rec or d vital si g ns ( bl o o d press ure [ pri or a n d p ost i nf usi o n], res pirat or y rate, te m perat ur e, 
a n d heart rate [ pri or a n d p ost i nf usi o n]), i n cl u di n g meas ure me nt of wei g ht pri or t o 
i nf usi o n (see Secti o n 9. 5. 4. 4 ).  
 Perf or m 1 2-le a d E C G pri or t o t he pe gl oticase i nf usi o n. 

H oriz o n T hera pe utics Irela n d D A C
 
 
K R Y S T E X X A I N D: 0 1 0 1 2 2 
Date: 0 1 A pril 2 0 2 0 
 
Pr ot oc ol: H Z N P- K R Y- 2 0 1 
 
 
Versi o n 3. 0, A d mi nistrati ve C ha n ge 1 
P RI V A T E A N D C O N FI D E N TI A L I N F O R M A TI O N O F H O RI Z O N T H E R A P E U TI C S I R E L A N D D A C  Pa ge
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1 2 9
 
 
 C ollect s w olle n/te n der j oi nt c o u nts; a d mi nister  H A Q; a n d rec or d patie nt a n d p h ysicia n 
gl o bal ass ess me nts a n d j oi nt pai n assess me nt res p o nses. 
 Assess M T X c o m plia nce a n d re- dis pe ns e M T X. 
 As k Yes/ N o q uesti o n re gar di n g f olic aci d, g o ut fl are pr o p h yla xis, a n d I R pr o p h yla xis 
c o m plia nce. 
 Fill g o ut pr o p h yla xis, fe x ofe na di ne, acet a mi n o p he n, a n d f olic aci d prescri pti o ns, as 
nee de d.  
 O btai n bl o o d sa m ples f or he mat ol o g y a n d cli nical c he mistr y a nal ysis.  
 O btai n a uri ne sa m ple f or uric aci d:creati ni ne rati o. 
 O btai n a uri ne sa m ple fr o m all fe males of c hil d beari n g p ote ntial f or perf or ma nce of a 
pre g na nc y t est. 
 O btai n bl o o d sa m ples f or M T X P ol y gl ut a mate a n al ysis pri or t o t he i nf usi o n. 
 O btai n bl o o d sa m ples f or a nti- P E G a n d a nti- uri cas e I g G a nti b o dies pri or t o t he i nf usi o n. 
 O btai n bl o o d sa m ples f or pe gl oticase P K a nal ysis pri or t o t he i nf usi o n.  
 A d mi nister I R pr o p h yla xis (i.e., fe x ofe na di ne, aceta mi n o p he n, a n d met h yl pre d nis ol o ne 
or h y dr oc ortis o ne) (see Secti o n 9. 4. 1. 3 ). 
 A d mi nister t he first d ose of pe gl oticase a n d rec or d date, v ol u me, a n d d urati o n of 
i nf usi o n, a n d start/st o p (i ncl usi ve of 1 0- m L fl us h) ti mes of d osi n g. 
 O btai n a bl o o d sa m ple ( 1 sa m ple) f or me as ure m e nt of s U A after t he e n d of t he 
pe gl otic ase i nf usi o n pri or t o disc har ge. 
 O btai n bl o o d sa m ples f or pe gl oticase P K a nal ys is after t he e n d of t he i nf usi o n pri or t o 
disc har ge.  
 I n q uir e a b o ut A Es a n d c o nc o mita nt me dicati o n use. 
 Perf or m D E C T (if a p plica bl e).  
9. 5. 6. 2. 2  Wee k 1 ( N o n-i nf usi o n visit f or t h ose w h o c o nse nt o nl y) 
 I n q uir e a b o ut A Es a n d c o nc o mita nt me dicati o n use. 
 O btai n bl o o d sa m ples f or pe gl oticase P K a nal ysis.  

H oriz o n T hera pe utics Irela n d D A C
 
 
K R Y S T E X X A I N D: 0 1 0 1 2 2 
Date: 0 1 A pril 2 0 2 0 
 
Pr ot oc ol: H Z N P- K R Y- 2 0 1 
 
 
Versi o n 3. 0, A d mi nistrati ve C ha n ge 1 
P RI V A T E A N D C O N FI D E N TI A L I N F O R M A TI O N O F H O RI Z O N T H E R A P E U TI C S I R E L A N D D A C  Pa ge
 8 3
 
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1 2 9
 
 
 O btai n bl o o d sa m ples f or a nti- P E G a n d a nti- uricas e I g G a nti b o dies. 
 O btai n a bl o o d sa m ple ( 1 sa m ple) f or meas ure m e nt of s U A.  
9. 5. 6. 2. 3  Wee k 2 
 O btai n 2 bl o o d sa m ples f or meas ure m e nt of s U A  wit hi n 4 8 h o urs pri or t o t his visit’s 
pe gl otic ase i nf usi o n. Pre-i nf usi o n s U A res ults m ust be re p orte d b y t h e l ocal or ce ntr al 
la b orat or y pri or t o p e gl oticase i nf usi o n. If a l ocal l a b orat or y sa m ple is dr a w n at a ce nt er 
ot her t ha n t he researc h site ( wit hi n 4 8 h o urs pri or t o t he pe gl oticase i nf usi o n), a sa m ple 
f or t he ce ntral la b orat or y will be dra w n pri or t o t he pe gl oticase i nf usi o n o n t he da y of t he 
visit (see Secti o n 9. 5. 1. 1 ). 
 A d mi nister M T X ≥6 0  mi n utes pri or t o pe gl oticase i nf usi o n if s u bject has n ot ta ke n M T X 
wit hi n t he pre vi o us 1 t o 3 da ys. 
 D oc u me nt g o ut flares a n d i nte nsit y. 
 Rec or d vital si g ns ( bl o o d press ure [ pri or a n d p ost i nf usi o n], res pirat or y rate, te m perat ur e, 
a n d heart rate [ pri or a n d p ost i nf usi o n]) (see Secti o n 9. 5. 4. 4 ). 
 Assess M T X c o m plia nce a n d re- dis pe ns e M T X. 
 As k Yes/ N o q uesti o n re gar di n g f olic aci d, g o ut fl are pr o p h yla xis, a n d I R pr o p h yla xis 
c o m plia nce. 
 Fill g o ut pr o p h yla xis, fe x ofe na di ne, acet a mi n o p he n, a n d f olic aci d prescri pti o ns, as 
nee de d.  
 O btai n bl o o d sa m ples f or he mat ol o g y a n d cli nical c he mistr y a nal ysis.  
 O btai n a uri ne sa m ple f or uric aci d:creati ni ne rati o. 
 O btai n a uri ne sa m ple fr o m all fe males of c hil d beari n g p ote ntial f or perf or ma nce of a 
pre g na nc y t est. 
 O btai n bl o o d sa m ples f or pe gl oticase P K  a nal ysis pri or t o t he i nf usi o n.  
 O btai n bl o o d sa m ples f or a nti- P E G a n d a nti- uri cas e I g G a nti b o dies pri or t o t he i nf usi o n. 
 A d mi nister I R pr o p h yla xis (i.e., fe x ofe na di ne, aceta mi n o p he n, a n d met h yl pre d nis ol o ne 
or h y dr oc ortis o ne) (see Secti o n 9. 4. 1. 3 ). 
 A d mi nister pe gl otic ase a n d rec or d date, v ol u me, a n d d urati o n of i nf usi o n, a n d start/st o p 
(i ncl usi ve of 1 0- m L fl us h) ti mes of d osi n g. 

H oriz o n T hera pe utics Irela n d D A C
 
 
K R Y S T E X X A I N D: 0 1 0 1 2 2 
Date: 0 1 A pril 2 0 2 0 
 
Pr ot oc ol: H Z N P- K R Y- 2 0 1 
 
 
Versi o n 3. 0, A d mi nistrati ve C ha n ge 1 
P RI V A T E A N D C O N FI D E N TI A L I N F O R M A TI O N O F H O RI Z O N T H E R A P E U TI C S I R E L A N D D A C  Pa ge
 8 4
 
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1 2 9
 
 
 O btai n a bl o o d sa m ple ( 1 sa m ple) f or meas ure m e nt of s U A after t he e n d of pe gl oticase 
i nf usi o n pri or t o disc har ge. 
 O btai n bl o o d sa m ples f or pe gl oticase P K a nal ys is after t he e n d of t he i nf usi o n pri or t o 
disc har ge  
 I n q uir e a b o ut A Es a n d c o nc o mita nt me dicati o n use. 
9. 5. 6. 2. 4  Wee k 4 
 O btai n 2 bl o o d sa m ples f or meas ure m e nt of s U A wit hi n 4 8 h o urs pri or t o t his visit’s 
pe gl otic ase i nf usi o n. Pre-i nf usi o n s U A res ults m ust be re p orte d b y t h e l ocal or ce ntr al 
la b orat or y pri or t o p e gl oticase i nf usi o n. If a l ocal l a b orat or y sa m ple is dr a w n at a ce nt er 
ot her t ha n t he researc h site ( wit hi n 4 8 h o urs pri or t o t he pe gl oticase i nf usi o n), a sa m ple 
f or t he ce ntral la b orat or y will be dra w n pri or t o t he pe gl oticase i nf usi o n o n t he da y of t he 
visit (see Secti o n 9. 5. 1. 1 ). 
• 
St o p pi n g R ule:  S u bjects wit h a n s U A le vel > 6 m g/ d L at 2 c o ns ec uti ve st u d y 
visits be gi n ni n g wit h t he Wee k 2 Visit ( n ot i ncl u di n g p ost-i nf usi o n sa m ples) 
will disc o nti n ue treat me nt a n d re mai n i n t he st u d y.  
 A d mi nister M T X ≥6 0  mi n utes pri or t o pe gl oticase i nf usi o n if s u bject has n ot ta ke n M T X 
wit hi n t he pre vi o us 1 t o 3 da ys. 
 Perf or m a tar gete d p h ysi cal e x a mi nati o n s h o ul d i ncl u de heart, l u n gs a n d a b d o mi nal e xa m 
a n d j oi nt a n d s ki n e val uati o n a n d assess me nt of  A Es. A n y fi n di n g will be rec or de d as a n 
A E. 
 D oc u me nt g o ut flares a n d i nte nsit y. 
 Rec or d vital si g ns ( bl o o d press ure [ pri or a n d p ost i nf usi o n], res pirat or y rate, te m perat ur e, 
a n d heart rate [ pri or a n d p ost i nf usi o n]) (see Secti o n 9. 5. 4. 4 ). 
 Assess M T X c o m plia nce a n d re- dis pe ns e M T X. 
 O btai n bl o o d sa m ples f or M T X P ol y gl ut a mate a n al ysis pri or t o t he i nf usi o n. 
 O btai n bl o o d sa m ples f or pe gl oticase P K a nal ysis pri or t o t he i nf usi o n. 
 O btai n bl o o d sa m ples f or a nti- P E G a n d a nti- uri cas e I g G a nti b o dies pri or t o t he i nf usi o n 
 As k Yes/ N o q uesti o n re gar di n g f olic aci d, g o ut fl are pr o p h yla xis, a n d I R pr o p h yla xis 
c o m plia nce. 
 Fill g o ut pr o p h yla xis, fe x ofe na di ne, acet a mi n o p he n, a n d f olic aci d prescri pti o ns, as 
nee de d.  

H oriz o n T hera pe utics Irela n d D A C
 
 
K R Y S T E X X A I N D: 0 1 0 1 2 2 
Date: 0 1 A pril 2 0 2 0 
 
Pr ot oc ol: H Z N P- K R Y- 2 0 1 
 
 
Versi o n 3. 0, A d mi nistrati ve C ha n ge 1 
P RI V A T E A N D C O N FI D E N TI A L I N F O R M A TI O N O F H O RI Z O N T H E R A P E U TI C S I R E L A N D D A C  Pa ge
 8 5
 
of
 
1 2 9
 
 
 O btai n a uri ne sa m ple fr o m all fe males of c hil d beari n g p ote ntial f or perf or ma nce of a 
pre g na nc y t est. 
 A d mi nister I R pr o p h yla xis (i.e., fe x ofe na di ne, aceta mi n o p he n, a n d met h yl pre d nis ol o ne 
or h y dr oc ortis o ne) (see Secti o n 9. 4. 1. 3 ). 
 A d mi nister pe gl otic ase a n d rec or d date, v ol u me, a n d d urati o n of i nf usi o n, a n d start/st o p 
(i ncl usi ve of 1 0- m L fl us h) ti mes of d osi n g. 
 O btai n bl o o d sa m ples f or pe gl oticase P K a nal ys is after t he e n d of t he i nf usi o n pri or t o 
disc har ge.  
 O btai n a bl o o d sa m ple ( 1 sa m ple) f or meas ure m e nt of s U A after t he e n d of pe gl oticase 
i nf usi o n pri or t o disc har ge. 
 I n q uir e a b o ut A Es a n d c o nc o mita nt me dicati o n use. 
9. 5. 6. 2. 5  Wee k 6 
 O btai n 2 bl o o d sa m ples f or meas ure m e nt of s U A wit hi n 4 8 h o urs pri or t o t his visit’s 
pe gl otic ase i nf usi o n. Pre-i nf usi o n s U A res ults m ust be re p orte d b y t h e l ocal or ce ntr al 
la b orat or y pri or t o p e gl oticase i nf usi o n. If a l ocal l a b orat or y sa m ple is dr a w n at a ce nt er 
ot her t ha n t he researc h site ( wit hi n 4 8 h o urs pri or t o t he pe gl oticase i nf usi o n), a sa m ple 
f or t he ce ntral la b orat or y will be dra w n pri or t o t he pe gl oticase i nf usi o n o n t he da y of t he 
visit (see Secti o n 9. 5. 1. 1 ). 
• 
St o p pi n g R ule:  S u bjects wit h a n s U A le vel > 6 m g/ d L at 2 c o ns ec uti ve st u d y 
visits be gi n ni n g wit h t he Wee k 2 Visit ( n ot i ncl u di n g p ost-i nf usi o n sa m ples) 
will disc o nti n ue treat me nt a n d re mai n i n t he st u d y.  
 A d mi nister M T X ≥6 0  mi n utes pri or t o pe gl oticase i nf usi o n if s u bject has n ot ta ke n M T X 
wit hi n t he pre vi o us 1 t o 3 da ys. 
 D oc u me nt g o ut flares a n d i nte nsit y. 
 Rec or d vital si g ns ( bl o o d press ure [ pri or a n d p ost i nf usi o n], res pirat or y rate, te m perat ur e, 
a n d heart rate [ pri or a n d p ost i nf usi o n]) (see Secti o n 9. 5. 4. 4 ). 
 Assess M T X c o m plia nce a n d re- dis pe ns e M T X. 
 As k Yes/ N o q uesti o n re gar di n g f olic aci d, g o ut fl are pr o p h yla xis, a n d I R pr o p h yla xis 
c o m plia nce. 
 Fill g o ut pr o p h yla xis, fe x ofe na di ne, acet a mi n o p he n, a n d f olic aci d prescri pti o ns, as 
nee de d.  

H oriz o n T hera pe utics Irela n d D A C
 
 
K R Y S T E X X A I N D: 0 1 0 1 2 2 
Date: 0 1 A pril 2 0 2 0 
 
Pr ot oc ol: H Z N P- K R Y- 2 0 1 
 
 
Versi o n 3. 0, A d mi nistrati ve C ha n ge 1 
P RI V A T E A N D C O N FI D E N TI A L I N F O R M A TI O N O F H O RI Z O N T H E R A P E U TI C S I R E L A N D D A C  Pa ge
 8 6
 
of
 
1 2 9
 
 
 O btai n a uri ne sa m ple fr o m all fe males of c hil d beari n g p ote ntial f or perf or ma nce of a 
pre g na nc y t est. 
 O btai n bl o o d sa m ples f or he mat ol o g y a n d cli nical c he mistr y a nal ysis.  
 O btai n a uri ne sa m ple f or uric aci d:creati ni ne rati o. 
 O btai n bl o o d sa m ples f or pe gl oticase P K a nal ysis pri or t o t he i nf usi o n. 
 O btai n bl o o d sa m ples f or a nti- P E G a n d a nti- uri cas e I g G a nti b o dies pri or t o t he i nf usi o n. 
 A d mi nister I R pr o p h yla xis (i.e., fe x ofe na di ne, aceta mi n o p he n, a n d met h yl pre d nis ol o ne 
or h y dr oc ortis o ne) (see Secti o n 9. 4. 1. 3 ). 
 A d mi nister pe gl otic ase a n d rec or d date, v ol u me, a n d d urati o n of i nf usi o n, a n d start/st o p 
(i ncl usi ve of 1 0- m L fl us h) ti mes of d osi n g. 
 O btai n a bl o o d sa m ple ( 1 sa m ple) f or meas ure m e nt of s U A after t he e n d of pe gl oticase 
i nf usi o n pri or t o disc har ge. 
 O btai n bl o o d sa m ples f or pe gl oticase P K a nal ys is after t he e n d of t he i nf usi o n pri or t o 
disc har ge.  
 I n q uir e a b o ut A Es a n d c o nc o mita nt me dicati o n use. 
9. 5. 6. 2. 6  Wee k 7 ( N o n-i nf usi o n visit f or t h ose w h o c o nse nt o nl y) 
 I n q uir e a b o ut A Es a n d c o nc o mita nt me dicati o n use. 
 O btai n bl o o d sa m ples f or pe gl oticase P K a nal ysis  
 O btai n bl o o d sa m ples f or a nti- P E G a n d a nti- uri cas e I g G a nti b o dies pri or t o t he i nf usi o n. 
 O btai n a bl o o d sa m ple ( 1 sa m ple) f or meas ure m e nt of s U A  
9. 5. 6. 2. 7  Wee k 8 
 O btai n 2 bl o o d sa m ples f or meas ure m e nt of s U A  wit hi n 4 8 h o urs pri or t o t his visit’s 
pe gl otic ase i nf usi o n. Pre-i nf usi o n s U A res ults m ust be re p orte d b y t h e l ocal or ce ntr al 
la b orat or y pri or t o p e gl oticase i nf usi o n. If a l ocal l a b orat or y sa m ple is dr a w n at a ce nt er 
ot her t ha n t he researc h site ( wit hi n 4 8 h o urs pri or t o t he pe gl oticase i nf usi o n), a sa m ple 
f or t he ce ntral la b orat or y will be dra w n pri or t o t he pe gl oticase i nf usi o n o n t he da y of t he 
visit (see Secti o n 9. 5. 1. 1 ). 
• 
St o p pi n g R ule:  S u bjects wit h a n s U A le vel > 6 m g/ d L at 2 c o ns ec uti ve st u d y 
visits be gi n ni n g wit h t he Wee k 2 Visit ( n ot i ncl u di n g p ost-i nf usi o n sa m ples) 
will disc o nti n ue treat me nt a n d re mai n i n t he st u d y.  

H oriz o n T hera pe utics Irela n d D A C
 
 
K R Y S T E X X A I N D: 0 1 0 1 2 2 
Date: 0 1 A pril 2 0 2 0 
 
Pr ot oc ol: H Z N P- K R Y- 2 0 1 
 
 
Versi o n 3. 0, A d mi nistrati ve C ha n ge 1 
P RI V A T E A N D C O N FI D E N TI A L I N F O R M A TI O N O F H O RI Z O N T H E R A P E U TI C S I R E L A N D D A C  Pa ge
 8 7
 
of
 
1 2 9
 
 
 A d mi nister M T X ≥6 0  mi n utes pri or t o pe gl oticase i nf usi o n if s u bject has n ot ta ke n M T X 
wit hi n t he pre vi o us 1 t o 3 da ys. 
 Perf or m a tar gete d p h ysi cal e x a mi nati o n s h o ul d i ncl u de heart, l u n gs a n d a b d o mi nal e xa m 
a n d j oi nt a n d s ki n e val uati o n a n d assess me nt of A Es. A n y fi n di n g will be rec or de d as a n 
A E. 
 D oc u me nt g o ut flares a n d i nte nsit y. 
 Rec or d vital si g ns ( bl o o d press ure [ pri or a n d p ost i nf usi o n], res pirat or y rate, te m perat ur e, 
a n d heart rate [ pri or a n d p ost i nf usi o n]), i ncl u di n g meas ure me nt of wei g ht pri or t o 
i nf usi o n (see Secti o n 9. 5. 4. 4 ). 
 Assess M T X c o m plia nce a n d re- dis pe ns e M T X. 
 As k Yes/ N o q uesti o n re gar di n g f olic aci d, g o ut fl are pr o p h yla xis, a n d I R pr o p h yla xis 
c o m plia nce. 
 Fill g o ut pr o p h yla xis, fe x ofe na di ne, acet a mi n o p he n, a n d f olic aci d prescri pti o ns, as 
nee de d.  
 O btai n bl o o d sa m ples f or M T X P ol y gl ut a mate a n al ysis pri or t o t he i nf usi o n. 
 O btai n bl o o d sa m ples f or pe gl oticase P K a nal ysis pri or t o t he i nf usi o n. 
 O btai n bl o o d sa m ples f or a nti- P E G a n d a nti- uri cas e I g G a nti b o dies pri or t o t he i nf usi o n. 
 O btai n a uri ne sa m ple fr o m all fe males of c hil d beari n g p ote ntial f or perf or ma nce of a 
pre g na nc y t est. 
 A d mi nister I R pr o p h yla xis (i.e., fe x ofe na di ne, aceta mi n o p he n, a n d met h yl pre d nis ol o ne 
or h y dr oc ortis o ne) (see Secti o n 9. 4. 1. 3 ). 
 A d mi nister pe gl otic ase a n d rec or d date, v ol u me, a n d d urati o n of i nf usi o n, a n d start/st o p 
(i ncl usi ve of 1 0- m L fl us h) ti mes of d osi n g. 
 O btai n a bl o o d sa m ple ( 1 sa m ple) f or meas ure m e nt of s U A after t he e n d of pe gl oticase 
i nf usi o n pri or t o disc har ge. 
  O btai n bl o o d sa m ples f or pe gl oticase P K a n al ysis after t he e n d of t he i nf usi o n pri or t o 
disc har ge.  
 I n q uir e a b o ut A Es a n d c o nc o mita nt me dicati o n use. 

H oriz o n T hera pe utics Irela n d D A C
 
 
K R Y S T E X X A I N D: 0 1 0 1 2 2 
Date: 0 1 A pril 2 0 2 0 
 
Pr ot oc ol: H Z N P- K R Y- 2 0 1 
 
 
Versi o n 3. 0, A d mi nistrati ve C ha n ge 1 
P RI V A T E A N D C O N FI D E N TI A L I N F O R M A TI O N O F H O RI Z O N T H E R A P E U TI C S I R E L A N D D A C  Pa ge
 8 8
 
of
 
1 2 9
 
 
9. 5. 6. 2. 8  Wee k 1 0 
 O btai n 2 bl o o d sa m ples f or meas ure m e nt of s U A  wit hi n 4 8 h o urs pri or t o t his visit’s 
pe gl otic ase i nf usi o n. Pre-i nf usi o n s U A res ults m ust be re p orte d b y t h e l ocal or ce ntr al 
la b orat or y pri or t o p e gl oticase i nf usi o n. If a l ocal l a b orat or y sa m ple is dr a w n at a ce nt er 
ot her t ha n t he researc h site ( wit hi n 4 8 h o urs pri or t o t he pe gl oticase i nf usi o n), a sa m ple 
f or t he ce ntral la b orat or y will be dra w n prior t o t he pe gl oticase i nf usi o n o n t he da y of t he 
visit (see Secti o n 9. 5. 1. 1 ). 
• 
St o p pi n g R ule:  S u bjects wit h a n s U A le vel > 6 m g/ d L at 2 c o ns ec uti ve st u d y 
visits be gi n ni n g wit h t he Wee k 2 Visit ( n ot i ncl u di n g p ost-i nf usi o n sa m ples) 
will disc o nti n ue treat me nt a n d re mai n i n t he st u d y.  
 A d mi nister M T X ≥6 0  mi n utes pri or t o pe gl oticase i nf usi o n if s u bject has n ot ta ke n M T X 
wit hi n t he pre vi o us 1 t o 3 da ys. 
 D oc u me nt g o ut flares a n d i nte nsit y. 
 Rec or d vital si g ns ( bl o o d press ure [ pri or a n d p ost i nf usi o n], res pirat or y rate, te m perat ur e, 
a n d heart rate [ pri or a n d p ost i nf usi o n]) (see Secti o n 9. 5. 4. 4 ). 
 Assess M T X c o m plia nce a n d re- dis pe ns e M T X. 
 As k Yes/ N o q uesti o n re gar di n g f olic aci d, g o ut fl are pr o p h yla xis, a n d I R pr o p h yla xis 
c o m plia nce. 
 Fill g o ut pr o p h yla xis, fe x ofe na di ne, acet a mi n o p he n, a n d f olic aci d prescri pti o ns, as 
nee de d.  
 O btai n bl o o d sa m ples f or pe gl oticase P K a nal ysis pri or t o t he i nf usi o n. 
 O btai n bl o o d sa m ples f or a nti- P E G a n d a nti- uri cas e I g G a nti b o dies pri or t o t he i nf usi o n. 
 O btai n a uri ne sa m ple fr o m all fe males of c hil d beari n g p ote ntial f or perf or ma nce of a 
pre g na nc y t est. 
 A d mi nister I R pr o p h yla xis (i.e., fe x ofe na di ne, aceta mi n o p he n, a n d met h yl pre d nis ol o ne 
or h y dr oc ortis o ne) (see Secti o n 9. 4. 1. 3 ). 
 A d mi nister pe gl otic ase a n d rec or d date, v ol u me, a n d d urati o n of i nf usi o n, a n d start/st o p 
(i ncl usi ve of 1 0- m L fl us h) ti mes of d osi n g. 
 O btai n a bl o o d sa m ple ( 1 sa m ple) f or meas ure m e nt of s U A after t he e n d of pe gl oticase 
i nf usi o n pri or t o disc har ge. 
 I n q uir e a b o ut A Es a n d c o nc o mita nt me dicati o n use. 

H oriz o n T hera pe utics Irela n d D A C
 
 
K R Y S T E X X A I N D: 0 1 0 1 2 2 
Date: 0 1 A pril 2 0 2 0 
 
Pr ot oc ol: H Z N P- K R Y- 2 0 1 
 
 
Versi o n 3. 0, A d mi nistrati ve C ha n ge 1 
P RI V A T E A N D C O N FI D E N TI A L I N F O R M A TI O N O F H O RI Z O N T H E R A P E U TI C S I R E L A N D D A C  Pa ge
 8 9
 
of
 
1 2 9
 
 
9. 5. 6. 2. 9  Wee k 1 2 
 O btai n 2 bl o o d sa m ples f or meas ure m e nt of s U A  wit hi n 4 8 h o urs pri or t o t his visit’s 
pe gl otic ase i nf usi o n. Pre-i nf usi o n s U A res ults m ust be re p orte d b y t h e l ocal or ce ntr al 
la b orat or y pri or t o p e gl oticase i nf usi o n. If a l ocal l a b orat or y sa m ple is dr a w n at a ce nt er 
ot her t ha n t he researc h site ( wit hi n 4 8 h o urs pri or t o t he pe gl oticase i nf usi o n), a sa m ple 
f or t he ce ntral la b orat or y will be dra w n pri or t o t he pe gl oticase i nf usi o n o n t he da y of t he 
visit (see Secti o n 9. 5. 1. 1 ). 
• 
St o p pi n g R ule:  S u bjects wit h a n s U A le vel > 6 m g/ d L at 2 c o ns ec uti ve st u d y 
visits be gi n ni n g wit h t he Wee k 2 Visit ( n ot i ncl u di n g p ost-i nf usi o n sa m ples) 
will disc o nti n ue treat me nt a n d re mai n i n t he st u d y.  
 A d mi nister M T X ≥6 0  mi n utes pri or t o pe gl oticase i nf usi o n if s u bject has n ot ta ke n M T X 
wit hi n t he pre vi o us 1 t o 3 da ys. 
 Perf or m a tar gete d p h ysi cal e x a mi nati o n s h o ul d i ncl u de heart, l u n gs a n d a b d o mi nal e xa m 
a n d j oi nt a n d s ki n e val uati o n a n d assess me nt of  A Es. A n y fi n di n g will be rec or de d as a n 
A E. 
 D oc u me nt g o ut flares a n d i nte nsit y. 
 Rec or d vital si g ns ( bl o o d press ure [ pri or a n d p ost i nf usi o n], res pirat or y rate, te m perat ur e, 
a n d heart rate [ pri or a n d p ost i nf usi o n]) (see Secti o n 9. 5. 4. 4 ).  
 Assess M T X c o m plia nce a n d re- dis pe ns e M T X. 
 As k Yes/ N o q uesti o n re gar di n g f olic aci d, g o ut fl are pr o p h yla xis, a n d I R pr o p h yla xis 
c o m plia nce. 
 Fill g o ut pr o p h yla xis, fe x ofe na di ne, acet a mi n o p he n, a n d f olic aci d prescri pti o ns, as 
nee de d.  
 O btai n a uri ne sa m ple fr o m all fe males of c hil d beari n g p ote ntial f or perf or ma nce of a 
pre g na nc y t est. 
 A d mi nister I R pr o p h yla xis (i.e., fe x ofe na di ne, aceta mi n o p he n, a n d met h yl pre d nis ol o ne 
or h y dr oc ortis o ne) (see Secti o n 9. 4. 1. 3 ). 
 A d mi nister pe gl otic ase a n d rec or d date, v ol u me, a n d d urati o n of i nf usi o n, a n d start/st o p 
(i ncl usi ve of 1 0- m L fl us h) ti mes of d osi n g. 
 O btai n a bl o o d sa m ple ( 1 sa m ple) f or meas ure m e nt of s U A after t he e n d of pe gl oticase 
i nf usi o n pri or t o disc har ge. 
 I n q uir e a b o ut A Es a n d c o nc o mita nt me dicati o n use. 

H oriz o n T hera pe utics Irela n d D A C
 
 
K R Y S T E X X A I N D: 0 1 0 1 2 2 
Date: 0 1 A pril 2 0 2 0 
 
Pr ot oc ol: H Z N P- K R Y- 2 0 1 
 
 
Versi o n 3. 0, A d mi nistrati ve C ha n ge 1 
P RI V A T E A N D C O N FI D E N TI A L I N F O R M A TI O N O F H O RI Z O N T H E R A P E U TI C S I R E L A N D D A C  Pa ge
 9 0
 
of
 
1 2 9
 
 
9. 5. 6. 2. 1 0    Wee k 1 4 
 O btai n 2 bl o o d sa m ples f or meas ure m e nt of s U A  wit hi n 4 8 h o urs pri or t o t his visit’s 
pe gl otic ase i nf usi o n. Pre-i nf usi o n s U A res ults m ust be re p orte d b y t h e l ocal or ce ntr al 
la b orat or y pri or t o p e gl oticase i nf usi o n. If a l ocal l a b orat or y sa m ple is dra w n at a ce nt er 
ot her t ha n t he researc h site ( wit hi n 4 8 h o urs pri or t o t he pe gl oticase i nf usi o n), a sa m ple 
f or t he ce ntral la b orat or y will be dra w n pri or t o t he pe gl oticase i nf usi o n o n t he da y of t he 
visit (see Secti o n 9. 5. 1. 1 ). 
• 
St o p pi n g R ule:  S u bjects wit h a n s U A le vel > 6 m g/ d L at 2 c o ns ec uti ve st u d y 
visits be gi n ni n g wit h t he Wee k 2 Visit ( n ot i ncl u di n g p ost-i nf usi o n sa m ples) 
will disc o nti n ue treat me nt a n d re mai n i n t he st u d y.  
 A d mi nister M T X ≥6 0  mi n utes pri or t o pe gl oticase i nf usi o n if s u bject has n ot ta ke n M T X 
wit hi n t he pre vi o us 1 t o 3 da ys. 
 D oc u me nt g o ut flares a n d i nte nsit y. 
 Rec or d vital si g ns ( bl o o d press ure [ pri or a n d p ost i nf usi o n], res pirat or y rate, te m perat ur e, 
a n d heart rate [ pri or a n d p ost i nf usi o n]) (see Secti o n 9. 5. 4. 4 ). 
 C ollect s w olle n/te n der j oi nt c o u nts; a d mi nister  H A Q; a n d rec or d patie nt a n d p h ysicia n 
gl o bal ass ess me nts a n d j oi nt pai n assess me nt res p o nses. 
 Assess M T X c o m plia nce a n d re- dis pe ns e M T X. 
 As k Yes/ N o q uesti o n re gar di n g f olic aci d, g o ut fl are pr o p h yla xis, a n d I R pr o p h yla xis 
c o m plia nce. 
 Fill g o ut pr o p h yla xis, fe x ofe na di ne, acet a mi n o p he n, a n d f olic a ci d prescri pti o ns, as 
nee de d.  
 O btai n a uri ne sa m ple fr o m all fe males of c hil d beari n g p ote ntial f or perf or ma nce of a 
pre g na nc y t est. 
 O btai n bl o o d sa m ples f or he mat ol o g y a n d cli nical c he mistr y a nal ysis.  
 O btai n a uri ne sa m ple f or uric aci d:creati ni ne rati o. 
 O btai n a bl o o d sa m ple f or pe gl oticase P K a n al ysis pri or t o t he i nf usi o n. 
 O btai n a bl o o d sa m ple f or M T X P ol y gl uta mate a n al ysis pri or t o t he i nf usi o n.  
 O btai n bl o o d sa m ples f or a nti- P E G a n d a nti- uri cas e I g G a nti b o dies pri or t o t he i nf usi o n. 

H oriz o n T hera pe utics Irela n d D A C
 
 
K R Y S T E X X A I N D: 0 1 0 1 2 2 
Date: 0 1 A pril 2 0 2 0 
 
Pr ot oc ol: H Z N P- K R Y- 2 0 1 
 
 
Versi o n 3. 0, A d mi nistrati ve C ha n ge 1 
P RI V A T E A N D C O N FI D E N TI A L I N F O R M A TI O N O F H O RI Z O N T H E R A P E U TI C S I R E L A N D D A C  Pa ge
 9 1
 
of
 
1 2 9
 
 
 A d mi nister I R pr o p h yla xis (i.e., fe x ofe na di ne, aceta mi n o p he n, a n d met h yl pre d nis ol o ne 
or h y dr oc ortis o ne) (see Secti o n 9. 4. 1. 3 ). 
 A d mi nister pe gl otic ase a n d rec or d date, v ol u m e, a n d d urati o n of i nf usi o n, a n d start/st o p 
(i ncl usi ve of 1 0- m L fl us h) ti mes of d osi n g. 
 O btai n a bl o o d sa m ple ( 1 sa m ple) f or meas ure m e nt of s U A after t he e n d of pe gl oticase 
i nf usi o n pri or t o disc har ge. 
 I n q uir e a b o ut A Es a n d c o nc o mita nt me dicati o n use. 
9. 5. 6. 2. 1 1  Wee k 1 6 
 O btai n 2 bl o o d sa m ples f or meas ure m e nt of s U A  wit hi n 4 8 h o urs pri or t o t his visit’s 
pe gl otic ase i nf usi o n. Pre-i nf usi o n s U A res ults m ust be re p orte d b y t h e l ocal or ce ntr al 
la b orat or y pri or t o p e gl oticase i nf usi o n. If a l ocal l a b orat or y sa m ple is dra w n at a ce nt er 
ot her t ha n t he researc h site ( wit hi n 4 8 h o urs pri or t o t he pe gl oticase i nf usi o n), a sa m ple 
f or t he ce ntral la b orat or y will be dra w n pri or t o t he pe gl oticase i nf usi o n o n t he da y of t he 
visit (see Secti o n 9. 5. 1. 1 ). 
• 
St o p pi n g R ule:  S u bjects wit h a n s U A le vel > 6 m g/ d L at 2 c o ns ec uti ve st u d y 
visits be gi n ni n g wit h t he Wee k 2 Visit ( n ot i ncl u di n g p ost-i nf usi o n sa m ples) 
will disc o nti n ue treat me nt a n d re mai n i n t he st u d y.  
 A d mi nister M T X ≥6 0  mi n utes pri or t o pe gl oticase i nf usi o n if s u bject has n ot ta ke n M T X 
wit hi n t he pre vi o us 1 t o 3 da ys. 
 Perf or m a tar gete d p h ysi cal e x a mi nati o n s h o ul d i ncl u de heart, l u n gs a n d a b d o mi nal e xa m 
a n d j oi nt a n d s ki n e val uati o n a n d assess me nt of A Es. A n y fi n di n g will be rec or de d as a n 
A E. 
 D oc u me nt g o ut flares a n d i nte nsit y. 
 Rec or d vital si g ns ( bl o o d press ure [ pri or a n d p ost i nf usi o n], res pirat or y rate, te m perat ur e, 
a n d heart rate [ pri or a n d p ost i nf usi o n]) i ncl u di n g meas ure me nt of wei g ht pri or t o 
i nf usi o n (see Secti o n 9. 5. 4. 4 ).  
 Assess M T X c o m plia nce a n d re- dis pe ns e M T X. 
 As k Yes/ N o q uesti o n re gar di n g f olic aci d, g o ut fl are pr o p h yla xis, a n d I R pr o p h yla xis 
c o m plia nce. 
 Fill g o ut pr o p h yla xis, fe x ofe na di ne, acet a mi n o p he n, a n d f olic aci d prescri pti o ns, as 
nee de d.  

H oriz o n T hera pe utics Irela n d D A C
 
 
K R Y S T E X X A I N D: 0 1 0 1 2 2 
Date: 0 1 A pril 2 0 2 0 
 
Pr ot oc ol: H Z N P- K R Y- 2 0 1 
 
 
Versi o n 3. 0, A d mi nistrati ve C ha n ge 1 
P RI V A T E A N D C O N FI D E N TI A L I N F O R M A TI O N O F H O RI Z O N T H E R A P E U TI C S I R E L A N D D A C  Pa ge
 9 2
 
of
 
1 2 9
 
 
 O btai n a uri ne sa m ple fr o m all fe males of c hil d beari n g p ote ntial f or perf or ma nce of a 
pre g na nc y t est. 
 A d mi nister I R pr o p h yla xis (i.e., fe x ofe na di ne, aceta mi n o p he n, a n d met h yl pre d nis ol o ne 
or h y dr oc ortis o ne) (see Secti o n 9. 4. 1. 3 ). 
 A d mi nister pe gl otic ase a n d rec or d date, v ol u me, a n d d urati o n of i nf usi o n, a n d start/st o p 
(i ncl usi ve of 1 0- m L fl us h) ti mes of d osi n g. 
 O btai n a bl o o d sa m ple ( 1 sa m ple) f or meas ure m e nt of s U A after t he e n d of pe gl oticase 
i nf usi o n pri or t o disc har ge. 
 I n q uir e a b o ut A Es a n d c o nc o mita nt me dicati o n use. 
9. 5. 6. 2. 1 2    Wee k 1 8 
 O btai n 2 bl o o d sa m ples f or meas ure m e nt of s U A  wit hi n 4 8 h o urs pri or t o t his visit’s 
pe gl otic ase i nf usi o n. Pre-i nf usi o n s U A res ults m ust be re p orte d b y t h e l ocal or ce ntr al 
la b orat or y pri or t o p e gl oticase i nf usi o n. If a l ocal l a b orat or y sa m ple is dr a w n at a ce nt er 
ot her t ha n t he researc h site ( wit hi n 4 8 h o urs pri or t o t he pe gl oticase i nf usi o n), a sa m ple 
f or t he ce ntral la b orat or y will be dra w n pri or t o t he pe gl oticase i nf usi o n o n t he da y of t he 
visit (see Secti o n 9. 5. 1. 1 ). 
• 
St o p pi n g R ule:  S u bjects wit h a n s U A le vel > 6 m g/ d L at 2 c o ns ec uti ve st u d y 
visits be gi n ni n g wit h t he Wee k 2 Visit ( n ot i ncl u di n g p ost-i nf usi o n sa m ples) 
will disc o nti n ue treat me nt a n d re mai n i n t he st u d y.  
 A d mi nister M T X ≥6 0  mi n utes pri or t o pe gl oticase i nf usi o n if s u bject has n ot ta ke n M T X 
wit hi n t he pre vi o us 1 t o 3 da ys. 
 D oc u me nt g o ut flares a n d i nte nsit y. 
 Rec or d vital si g ns ( bl o o d press ure [ pri or a n d p ost i nf usi o n], res pirat or y rate, te m perat ur e, 
a n d heart rate [ pri or a n d p ost i nf usi o n]) (see Secti o n 9. 5. 4. 4 ). 
 Assess M T X c o m plia nce a n d re- dis pe ns e M T X. 
 As k Yes/ N o q uesti o n re gar di n g f olic aci d, g o ut fl are pr o p h yla xis, a n d I R pr o p h yla xis 
c o m plia nce. 
 Fill g o ut pr o p h yla xis, fe x ofe na di ne, acet a mi n o p he n, a n d f olic aci d prescri pti o ns, as 
nee de d.  
 O btai n a uri ne sa m ple fr o m all fe males of c hil d beari n g p ote ntial f or perf or ma nce of a 
pre g na nc y t est. 

H oriz o n T hera pe utics Irela n d D A C
 
 
K R Y S T E X X A I N D: 0 1 0 1 2 2 
Date: 0 1 A pril 2 0 2 0 
 
Pr ot oc ol: H Z N P- K R Y- 2 0 1 
 
 
Versi o n 3. 0, A d mi nistrati ve C ha n ge 1 
P RI V A T E A N D C O N FI D E N TI A L I N F O R M A TI O N O F H O RI Z O N T H E R A P E U TI C S I R E L A N D D A C  Pa ge
 9 3
 
of
 
1 2 9
 
 
 O btai n bl o o d sa m ples f or pe gl oticase P K a nal ysis pri or t o t he i nf usi o n. 
 O btai n bl o o d sa m ples f or a nti- P E G a n d a nti- uri cas e I g G a nti b o dies pri or t o t he i nf usi o n. 
 A d mi nister I R pr o p h yla xis (i.e., fe x ofe na di ne, aceta mi n o p he n, a n d met h yl pre d nis ol o ne 
or h y dr oc ortis o ne) (see Secti o n 9. 4. 1. 3 ). 
 A d mi nister pe gl otic ase a n d rec or d date, v ol u me, a n d d urati o n of i nf usi o n, a n d start/st o p 
(i ncl usi ve of 1 0- m L fl us h) ti mes of d osi n g. 
 O btai n a bl o o d sa m ple ( 1 sa m ple) f or meas ure m e nt of s U A after t he e n d of pe gl oticase 
i nf usi o n pri or t o disc har ge. 
 I n q uir e a b o ut A Es a n d c o nc o mita nt me dicati o n use. 
9. 5. 6. 2. 1 3    Wee k 2 0 
 O btai n 2 bl o o d sa m ples f or meas ure m e nt of s U A wi t hi n 4 8 h o urs pri or t o t his visit’s 
pe gl otic ase i nf usi o n. Pre-i nf usi o n s U A res ults m ust be re p orte d b y t h e l ocal or ce ntr al 
la b orat or y pri or t o p e gl oticase i nf usi o n. If a l ocal l a b orat or y sa m ple is dr a w n at a ce nt er 
ot her t ha n t he researc h site ( wit hi n 4 8 h o urs pri or t o t he pe gl oticase i nf usi o n), a sa m ple 
f or t he ce ntral la b orat or y will be dra w n pri or t o t he pe gl oticase i nf usi o n o n t he da y of t he 
visit (see Secti o n 9. 5. 1. 1 ). 
• 
St o p pi n g R ule:  S u bjects wit h a n s U A le vel > 6 m g/ d L at 2 c o ns ec uti ve st u d y 
visits be gi n ni n g wit h t he Wee k 2 Visit ( n ot i ncl u di n g p ost-i nf usi o n sa m ples) 
will disc o nti n ue treat me nt a n d re mai n i n t he st u d y.  
 A d mi nister M T X ≥6 0  mi n utes pri or t o pe gl oticase i nf usi o n if s u bject has n ot ta ke n M T X 
wit hi n t he pre vi o us 1 t o 3 da ys. 
 Perf or m a tar gete d p h ysi cal e x a mi nati o n s h o ul d i ncl u de heart, l u n gs a n d a b d o mi nal e xa m 
a n d j oi nt a n d s ki n e val uati o n a n d assess me nt of  A Es. A n y fi n di n g will be rec or de d as a n 
A E. 
 D oc u me nt g o ut flares a n d i nte nsit y. 
 Rec or d vital si g ns ( bl o o d press ure [ pri or a n d p ost i nf usi o n], res pirat or y rate, te m perat ur e, 
a n d heart rate [ pri or a n d p ost i nf usi o n]) (see Secti o n 9. 5. 4. 4 ).  
 Assess M T X c o m plia nce a n d re- dis pe ns e M T X. 
 As k Yes/ N o q uesti o n re gar di n g f olic aci d, g o ut fl are pr o p h yla xis, a n d I R pr o p h yla xis 
c o m plia nce. 

H oriz o n T hera pe utics Irela n d D A C
 
 
K R Y S T E X X A I N D: 0 1 0 1 2 2 
Date: 0 1 A pril 2 0 2 0 
 
Pr ot oc ol: H Z N P- K R Y- 2 0 1 
 
 
Versi o n 3. 0, A d mi nistrati ve C ha n ge 1 
P RI V A T E A N D C O N FI D E N TI A L I N F O R M A TI O N O F H O RI Z O N T H E R A P E U TI C S I R E L A N D D A C  Pa ge
 9 4
 
of
 
1 2 9
 
 
 Fill g o ut pr o p h yla xis, fe x ofe na di ne, acet a mi n o p h e n, a n d f olic aci d prescri pti o ns, as 
nee de d.  
 O btai n a uri ne sa m ple fr o m all fe males of c hil d beari n g p ote ntial f or perf or ma nce of a 
pre g na nc y t est. 
 A d mi nister I R pr o p h yla xis (i.e., fe x ofe na di ne, aceta mi n o p he n, a n d met h yl pre d nis ol o ne 
or h y dr oc ortis o ne) (see Secti o n 9. 4. 1. 3 ). 
 A d mi nister pe gl otic ase a n d rec or d date, v ol u me, a n d d urati o n of i nf usi o n, a n d start/st o p 
(i ncl usi ve of 1 0- m L fl us h) ti mes of d osi n g. 
 O btai n a bl o o d sa m ple ( 1 sa m ple) f or meas ure m e nt of s U A after t he e n d of pe gl oticase 
i nf usi o n pri or t o disc har ge. 
 I n q uir e a b o ut A Es a n d c o nc o mita nt me dicati o n use. 
9. 5. 6. 2. 1 4    Wee k 2 2 
 O btai n 2 bl o o d sa m ples f or meas ure m e nt of s U A wit hi n 4 8 h o urs pri or t o t his visit’s 
pe gl otic ase i nf usi o n. Pre-i nf usi o n s U A res ults m ust be re p orte d b y t h e l ocal or ce ntr al 
la b orat or y pri or t o p e gl oticase i nf usi o n. If a l ocal l a b orat or y sa m ple is dr a w n at a ce nt er 
ot her t ha n t he researc h site ( wit hi n 4 8 h o urs pri or t o t he pe gl oticase i nf usi o n), a sa m ple 
f or t he ce ntral la b orat or y will be dra w n pri or t o t he pe gl oticase i nf usi o n o n t he da y of t he 
visit (see Secti o n 9. 5. 1. 1 ). 
• 
St o p pi n g R ule:  S u bjects wit h a n s U A le vel > 6 m g/ d L at 2 c o ns ec uti ve st u d y 
visits be gi n ni n g wit h t he Wee k 2 Visit ( n ot i ncl u di n g p ost-i nf usi o n sa m ples) 
will disc o nti n ue treat me nt a n d re mai n i n t he st u d y.  
 A d mi nister M T X ≥6 0  mi n utes pri or t o pe gl oticase i nf usi o n if s u bject has n ot ta ke n M T X 
wit hi n t he pre vi o us 1 t o 3 da ys. 
 D oc u me nt g o ut flares a n d i nte nsit y. 
 Rec or d vital si g ns ( bl o o d press ure [ pri or a n d p ost i nf usi o n], res pirat or y rate, te m perat ur e, 
a n d heart rate [ pri or a n d p ost i nf usi o n]) (see Secti o n 9. 5. 4. 4 ). 
 Assess M T X c o m plia nce a n d re- dis pe ns e M T X. 
 As k Yes/ N o q uesti o n re gar di n g f olic aci d, g o ut fl are pr o p h yla xis, a n d I R pr o p h yla xis 
c o m plia nce. 
 Fill g o ut pr o p h yla xis, fe x ofe na di ne, acet a mi n o p he n, a n d f olic aci d prescri pti o ns, as 
nee de d.  

H oriz o n T hera pe utics Irela n d D A C
 
 
K R Y S T E X X A I N D: 0 1 0 1 2 2 
Date: 0 1 A pril 2 0 2 0 
 
Pr ot oc ol: H Z N P- K R Y- 2 0 1 
 
 
Versi o n 3. 0, A d mi nistrati ve C ha n ge 1 
P RI V A T E A N D C O N FI D E N TI A L I N F O R M A TI O N O F H O RI Z O N T H E R A P E U TI C S I R E L A N D D A C  Pa ge
 9 5
 
of
 
1 2 9
 
 
 O btai n a uri ne sa m ple fr o m all fe males of c hil d beari n g p ote ntial f or perf or ma nce of a 
pre g na nc y t est. 
 O btai n bl o o d sa m ples f or he mat ol o g y a n d cli nical c he mistr y a nal ysis.  
 O btai n a uri ne sa m ple f or uric aci d:creati ni ne rati o. 
 O btai n bl o o d sa m ples f or M T X P ol y gl ut a mate a n al ysis pri or t o t he i nf usi o n. 
 O btai n a bl o o d sa m ple f or pe gl oticase P K a n al ysis pri or t o t he i nf usi o n. 
 O btai n a bl o o d sa m ple f or a nti- P E G a n d a nti- uri case I g G a nti b o dies pri or t o t he i nf usi o n. 
 A d mi nister I R pr o p h yla xis (i.e., fe x ofe na di ne, aceta mi n o p he n, a n d met h yl pre d nis ol o ne 
or h y dr oc ortis o ne) (see Secti o n 9. 4. 1. 3 ). 
 A d mi nister pe gl otic ase a n d rec or d date, v ol u me, a n d d urati o n of i nf usi o n, a n d start/st o p 
(i ncl usi ve of 1 0- m L fl us h) ti mes of d osi n g. 
 O btai n a bl o o d sa m ple ( 1 sa m ple) f or meas ure m e nt of s U A after t he e n d of pe gl oticase 
i nf usi o n pri or t o disc har ge. 
 I n q uir e a b o ut A Es a n d c o nc o mita nt me dicati o n use. 
9. 5. 6. 2. 1 5      Wee k 2 4 
 O btai n 2 bl o o d sa m ples f or meas ure m e nt of s U A  wit hi n 4 8 h o urs pri or t o t his visit’s 
pe gl otic ase i nf usi o n. Pre-i nf usi o n s U A res ults m ust be re p orte d b y t h e l ocal or ce ntr al 
la b orat or y pri or t o p e gl oticase i nf usi o n. If a l ocal l a b orat or y sa m ple is dr a w n at a ce nt er 
ot her t ha n t he researc h site ( wit hi n 4 8 h o urs pri or t o t he pe gl oticase i nf usi o n), a sa m ple 
f or t he ce ntral la b orat or y will be dra w n pri or t o t he pe gl oticase i nf usi o n o n t he da y of t he 
visit (see Secti o n 9. 5. 1. 1 ). 
• 
St o p pi n g R ule:  S u bjects wit h a n s U A le vel > 6 m g/ d L at 2 c o ns ec uti ve st u d y 
visits be gi n ni n g wit h t he Wee k 2 Visit ( n ot i ncl u di n g p ost-i nf usi o n sa m ples) 
will disc o nti n ue treat me nt a n d re mai n i n t he st u d y.  
 A d mi nister M T X ≥6 0  mi n utes pri or t o pe gl oticase i nf usi o n if s u bject has n ot ta ke n M T X 
wit hi n t he pre vi o us 1 t o 3 da ys. 
 Perf or m a tar gete d p h ysi cal e x a mi nati o n s h o ul d i ncl u de heart, l u n gs a n d a b d o mi nal e xa m 
a n d j oi nt a n d s ki n e val uati o n a n d assess me nt of  A Es. A n y fi n di n g will be rec or de d as a n 
A E. 
 D oc u me nt g o ut flares a n d i nte nsit y. 

H oriz o n T hera pe utics Irela n d D A C
 
 
K R Y S T E X X A I N D: 0 1 0 1 2 2 
Date: 0 1 A pril 2 0 2 0 
 
Pr ot oc ol: H Z N P- K R Y- 2 0 1 
 
 
Versi o n 3. 0, A d mi nistrati ve C ha n ge 1 
P RI V A T E A N D C O N FI D E N TI A L I N F O R M A TI O N O F H O RI Z O N T H E R A P E U TI C S I R E L A N D D A C  Pa ge
 9 6
 
of
 
1 2 9
 
 
 Rec or d vital si g ns ( bl o o d press ure [ pri or a n d p ost i nf usi o n], res pirat or y rate, te m perat ur e, 
a n d heart rate [ pri or a n d p ost i nf usi o n]), i ncl u di n g meas ure me nt of wei g ht pri or t o 
i nf usi o n (see Secti o n 9. 5. 4. 4 ).  
 C ollect s w olle n/te n der j oi nt c o u nts; a d mi nister  H A Q; a n d rec or d patie nt a n d p h ysicia n 
gl o bal ass ess me nts a n d j oi nt pai n assess me nt res p o nses. 
 Assess f or t he prese nce of t o p hi. 
 Assess M T X c o m plia nce a n d re- dis pe ns e M T X. 
 As k Yes/ N o q uesti o n re gar di n g f olic aci d, g o ut fl are pr o p h yla xis, a n d I R pr o p h yla xis 
c o m plia nce. 
 Fill g o ut pr o p h yla xis, fe x ofe na di ne, acet a mi n o p he n, a n d f olic aci d prescri pti o ns, as 
nee de d.  
 O btai n bl o o d sa m ples f or he mat ol o g y a n d cli nical c he mistr y a nal ysis.  
 O btai n a uri ne sa m ple f or uric aci d:creati ni ne rati o. 
 O btai n a uri ne sa m ple fr o m all fe males of c hil d beari n g p ote ntial f or perf or ma nce of a 
pre g na nc y t est. 
 O btai n bl o o d sa m ples f or M T X P ol y gl ut a mate a n al ysis pri or t o t he i nf usi o n. 
 O btai n bl o o d sa m ples f or pe gl oticase P K a nal ysis pri or t o t he i nf usi o n. 
 O btai n bl o o d sa m ples f or a nti- P E G a n d a nti- uri cas e I g G a nti b o dies pri or t o t he i nf usi o n.  
 A d mi nister I R pr o p h yla xis (i.e., fe x ofe na di ne, aceta mi n o p he n, a n d met h yl pre d nis ol o ne 
or h y dr oc ortis o ne) (see Secti o n 9. 4. 1. 3 ). 
 A d mi nister t he first d ose of pe gl oticase a n d rec or d date, v ol u me, a n d d urati o n of 
i nf usi o n, a n d start/st o p (i ncl usi ve of 1 0- m L fl us h) ti mes of d osi n g. 
 O btai n a bl o o d sa m ple ( 1 sa m ple) f or meas ure m e nt of s U A after t he e n d of pe gl oticase 
i nf usi o n pri or t o disc har ge. 
 I n q uir e a b o ut A Es a n d c o nc o mita nt me dicati o n use. 
 Perf or m D E C T (if a p plica ble). 
 Perf or m I n vesti gat or assess me nt of Cli nical Stat us. 

H oriz o n T hera pe utics Irela n d D A C
 
 
K R Y S T E X X A I N D: 0 1 0 1 2 2 
Date: 0 1 A pril 2 0 2 0 
 
Pr ot oc ol: H Z N P- K R Y- 2 0 1 
 
 
Versi o n 3. 0, A d mi nistrati ve C ha n ge 1 
P RI V A T E A N D C O N FI D E N TI A L I N F O R M A TI O N O F H O RI Z O N T H E R A P E U TI C S I R E L A N D D A C  Pa ge
 9 7
 
of
 
1 2 9
 
 
9. 5. 6. 2. 1 6    Wee k 2 6 
 O btai n 2 bl o o d sa m ples f or meas ure m e nt of s U A  wit hi n 4 8 h o urs pri or t o t his visit’s 
pe gl otic ase i nf usi o n. Pre-i nf usi o n s U A res ults m ust be re p orte d b y t h e l ocal or ce ntr al 
la b orat or y pri or t o p e gl oticase i nf usi o n. If a l ocal l a b orat or y sa m ple is dr a w n at a ce nt er 
ot her t ha n t he researc h site ( wit hi n 4 8 h o urs pri or t o t he pe gl oticase i nf usi o n), a sa m ple 
f or t he ce ntral la b orat or y will be dra w n pri or t o t he pe gl oticase i nf usi o n o n t he da y of t he 
visit (see Secti o n 9. 5. 1. 1 ). 
• 
St o p pi n g R ule:  S u bjects wit h a n s U A le vel > 6 m g/ d L at 2 c o ns ec uti ve st u d y 
visits be gi n ni n g wit h t he Wee k 2 Visit ( n ot i ncl u di n g p ost-i nf usi o n sa m ples) 
will disc o nti n ue treat me nt a n d re mai n i n t he st u d y.  
 A d mi nister M T X ≥6 0  mi n utes pri or t o pe gl oticase i nf usi o n if s u bject has n ot ta ke n M T X 
wit hi n t he pre vi o us 1 t o 3 da ys. 
 D oc u me nt g o ut flares a n d i nte nsit y. 
 Rec or d vital si g ns ( bl o o d press ure [ pri or a n d p ost i nf usi o n], res pirat or y rate, te m perat ur e, 
a n d heart rate [ pri or a n d p ost i nf usi o n]) (see Secti o n 9. 5. 4. 4 ).  
 Assess M T X c o m plia nce a n d re- dis pe ns e M T X. 
 As k Yes/ N o q uesti o n re gar di n g f olic aci d, g o ut fl are pr o p h yla xis, a n d I R pr o p h yla xis 
c o m plia nce. 
 Fill g o ut pr o p h yla xis, fe x ofe na di ne, acet a mi n o p he n, a n d f olic aci d prescri pti o ns, as 
nee de d.  
 O btai n a uri ne sa m ple fr o m all fe males of c hil d beari n g p ote ntial f or perf or ma nce of a 
pre g na nc y t est. 
 A d mi nister I R pr o p h yla xis (i.e., fe x ofe na di ne, aceta mi n o p he n, a n d met h yl pre d nis ol o ne 
or h y dr oc ortis o ne) (see Secti o n 9. 4. 1. 3 ). 
 A d mi nister pe gl otic ase a n d rec or d date, v ol u me, a n d d urati o n of i nf usi o n, a n d start/st o p 
(i ncl usi ve of 1 0- m L fl us h) ti mes of d osi n g. 
 I n q uir e a b o ut A Es a n d c o nc o mita nt me dicati o n use. 
9. 5. 6. 2. 1 7    Wee k 2 8 
 O btai n 2 bl o o d sa m ples f or meas ure m e nt of s U A  wit hi n 4 8 h o urs pri or t o t his visit’s 
pe gl otic ase i nf usi o n. Pre-i nf usi o n s U A res ults m ust be re p orte d b y t h e l ocal or ce ntr al 
la b orat or y pri or t o p e gl oticase i nf usi o n. If a l ocal l a b orat or y sa m ple is dr a w n at a ce nt er 
ot her t ha n t he researc h site ( wit hi n 4 8 h o urs pri or t o t he pe gl oticase i nf usi o n), a sa m ple 

H oriz o n T hera pe utics Irela n d D A C
 
 
K R Y S T E X X A I N D: 0 1 0 1 2 2 
Date: 0 1 A pril 2 0 2 0 
 
Pr ot oc ol: H Z N P- K R Y- 2 0 1 
 
 
Versi o n 3. 0, A d mi nistrati ve C ha n ge 1 
P RI V A T E A N D C O N FI D E N TI A L I N F O R M A TI O N O F H O RI Z O N T H E R A P E U TI C S I R E L A N D D A C  Pa ge
 9 8
 
of
 
1 2 9
 
 
f or t he ce ntral la b orat or y will be dra w n pri or t o t he pe gl oticase i nf usi o n o n t he da y of t he 
visit (see Secti o n 9. 5. 1. 1 ). 
• 
St o p pi n g R ule:  S u bjects wit h a n s U A le vel > 6 m g/ d L at 2 c o ns ec uti ve st u d y 
visits be gi n ni n g wit h t he Wee k 2 Visit ( n ot i ncl u di n g p ost-i nf usi o n sa m ples) 
will disc o nti n ue treat me nt a n d re mai n i n t h e st u d y.  
 A d mi nister M T X ≥6 0  mi n utes pri or t o pe gl oticase i nf usi o n if s u bject has n ot ta ke n M T X 
wit hi n t he pre vi o us 1 t o 3 da ys. 
 D oc u me nt g o ut flares a n d i nte nsit y. 
 Rec or d vital si g ns ( bl o o d press ure [ pri or a n d p ost i nf usi o n], res pirat or y rate, te m perat ur e, 
a n d heart rate [ pri or a n d p ost i nf usi o n]) (see Secti o n 9. 5. 4. 4 ).  
 Assess M T X c o m plia nce a n d re- dis pe ns e M T X. 
 As k Yes/ N o q uesti o n re gar di n g f olic aci d, g o ut fl are pr o p h yla xis, a n d I R pr o p h yla xis 
c o m plia nce. 
 Fill g o ut pr o p h yla xis, fe x ofe na di ne, acet a mi n o p he n, a n d f olic aci d prescri pti o ns, as 
nee de d.  
 O btai n a uri ne sa m ple fr o m all fe males of c hil d beari n g p ote ntial f or perf or ma nce of a 
pre g na nc y t est. 
 A d mi nister I R pr o p h yla xis (i.e., fe x ofe na di ne, aceta mi n o p he n, a n d met h yl pre d nis ol o ne 
or h y dr oc ortis o ne) (see Secti o n 9. 4. 1. 3 ). 
 A d mi nister pe gl otic ase a n d rec or d date, v ol u me, a n d d urati o n of i nf usi o n, a n d start/st o p 
(i ncl usi ve of 1 0- m L fl us h) ti mes of d osi n g. 
 I n q uir e a b o ut A Es a n d c o nc o mita nt me dicati o n use. 
9. 5. 6. 2. 1 8    Wee k 3 0 
 O btai n 2 bl o o d sa m pl es f or meas ure m e nt of s U A wit hi n 4 8 h o urs pri or t o t his visit’s 
pe gl otic ase i nf usi o n. Pre-i nf usi o n s U A res ults m ust be re p orte d b y t h e l ocal or ce ntr al 
la b orat or y pri or t o p e gl oticase i nf usi o n. If a l ocal l a b orat or y sa m ple is dr a w n at a ce nt er 
ot her t ha n t he researc h site ( wit hi n 4 8 h o urs pri or t o t he pe gl oticase i nf usi o n), a sa m ple 
f or t he ce ntral la b orat or y will be dra w n pri or t o t he pe gl oticase i nf usi o n o n t he da y of t he 
visit (see Secti o n 9. 5. 1. 1 ). 
• 
St o p pi n g R ule:  S u bjects wit h a n s U A le vel > 6 m g/ d L at 2 c o ns ec uti ve st u d y 
visits be gi n ni n g wit h t he Wee k 2 Visit ( n ot i ncl u di n g p ost-i nf usi o n sa m ples) 
will disc o nti n ue treat me nt a n d re mai n i n t he st u d y.  

H oriz o n T hera pe utics Irela n d D A C
 
 
K R Y S T E X X A I N D: 0 1 0 1 2 2 
Date: 0 1 A pril 2 0 2 0 
 
Pr ot oc ol: H Z N P- K R Y- 2 0 1 
 
 
Versi o n 3. 0, A d mi nistrati ve C ha n ge 1 
P RI V A T E A N D C O N FI D E N TI A L I N F O R M A TI O N O F H O RI Z O N T H E R A P E U TI C S I R E L A N D D A C  Pa ge
 9 9
 
of
 
1 2 9
 
 
 A d mi nister M T X ≥6 0  mi n utes pri or t o pe gl oticase i nf usi o n if s u bject has n ot ta ke n M T X 
wit hi n t he pre vi o us 1 t o 3 da ys. 
 D oc u me nt g o ut flares a n d i nte nsit y. 
 Rec or d vital si g ns ( bl o o d press ure [ pri or a n d p ost i nf usi o n], res pirat or y rate, te m perat ur e, 
a n d heart rate [ pri or a n d p ost i nf usi o n]) (see Secti o n 9. 5. 4. 4 ).  
 Assess M T X c o m plia nce a n d re- dis pe ns e M T X. 
 As k Yes/ N o q uesti o n re gar di n g f olic aci d, g o ut fl are pr o p h yla xis, a n d I R pr o p h yla xis 
c o m plia nce. 
 Fill g o ut pr o p h yla xis, fe x ofe na di ne, acet a mi n o p he n, a n d f olic aci d prescri pti o ns, as 
nee de d.  
 O btai n a uri ne sa m ple fr o m all fe males of c hil d beari n g p ote ntial f or perf or ma nce of a 
pre g na nc y t est. 
 A d mi nister I R pr o p h yla xis (i.e., fe x ofe na di ne, aceta mi n o p he n, a n d met h yl pre d nis ol o ne 
or h y dr oc ortis o ne) (see Secti o n 9. 4. 1. 3 ). 
 A d mi nister pe gl otic ase a n d rec or d date, v ol u me, a n d d urati o n of i nf usi o n, a n d start/st o p 
(i ncl usi ve of 1 0- m L fl us h) ti mes of d osi n g. 
 I n q uir e a b o ut A Es a n d c o nc o mita nt me dicati o n use. 
9. 5. 6. 2. 1 9    Wee k 3 2  
 O btai n 2 bl o o d sa m ples f or meas ure m e nt of s U A wit hi n 4 8 h o urs pri or t o t his visit’s 
pe gl otic ase i nf usi o n. Pre-i nf usi o n s U A res ults m ust be re p orte d b y t h e l ocal or ce ntr al 
la b orat or y pri or t o p e gl oticase i nf usi o n. If a l ocal l a b orat or y sa m ple is dr a w n at a ce nt er 
ot her t ha n t he researc h site ( wit hi n 4 8 h o urs pri or t o t he pe gl oticase i nf usi o n), a sa m ple 
f or t he ce ntral la b orat or y will be dra w n pri or t o t he pe gl oticase i nf usi o n o n t he da y of t he 
visit (see Secti o n 9. 5. 1. 1 ). 
• 
St o p pi n g R ule:  S u bjects wit h a n s U A le vel > 6 m g/ d L at 2 c o ns ec uti ve st u d y 
visits be gi n ni n g wit h t he Wee k 2 Visit ( n ot i ncl u di n g p ost-i nf usi o n sa m ples) 
will disc o nti n ue treat me nt a n d re mai n i n t he st u d y.  
 A d mi nister M T X ≥6 0  mi n utes pri or t o pe gl oticase i nf usi o n if s u bject has n ot ta ke n M T X 
wit hi n t he pre vi o us 1 t o 3 da ys. 
 D oc u me nt g o ut flares a n d i nte nsit y. 

H oriz o n T hera pe utics Irela n d D A C
 
 
K R Y S T E X X A I N D: 0 1 0 1 2 2 
Date: 0 1 A pril 2 0 2 0 
 
Pr ot oc ol: H Z N P- K R Y- 2 0 1 
 
 
Versi o n 3. 0, A d mi nistrati ve C ha n ge 1 
P RI V A T E A N D C O N FI D E N TI A L I N F O R M A TI O N O F H O RI Z O N T H E R A P E U TI C S I R E L A N D D A C  Pa ge
 1 0 0
 
of
 
1 2 9
 
 
 Rec or d vital si g ns ( bl o o d press ure [ pri or a n d p ost i nf usi o n], res pirat or y rate, te m perat ur e, 
a n d heart rate [ pri or a n d p ost i nf usi o n]) (see Secti o n 9. 5. 4. 4 ).  
 Assess M T X c o m plia nce a n d re- dis pe ns e M T X. 
 As k Yes/ N o q uesti o n re gar di n g f olic aci d, g o ut fl are pr o p h yla xis, a n d I R pr o p h yla xis 
c o m plia nce. 
 Fill g o ut pr o p h yla xis, fe x ofe na di ne, acet a mi n o p he n, a n d f olic aci d prescri pti o ns, as 
nee de d.  
 O btai n a uri ne sa m ple fr o m all fe males of c hil d beari n g p ote ntial f or perf or ma nce of a 
pre g na nc y t est. 
 A d mi nister I R pr o p h yla xis (i.e., fe x ofe na di ne, aceta mi n o p he n, a n d met h yl pre d nis ol o ne 
or h y dr oc ortis o ne) (see Secti o n 9. 4. 1. 3 ). 
 A d mi nister pe gl otic ase a n d rec or d date, v ol u me, a n d d urati o n of i nf usi o n, a n d start/st o p 
(i ncl usi ve of 1 0- m L fl us h) ti mes of d osi n g. 
 O btai n a bl o o d sa m ple ( 1 sa m ple) f or meas ure m e nt of s U A after t he e n d of pe gl oticase 
i nf usi o n pri or t o disc har ge. 
 I n q uir e a b o ut A Es a n d c o nc o mita nt me dicati o n use. 
9. 5. 6. 2. 2 0    Wee k 3 4 
 O btai n 2 bl o o d sa m ples f or meas ure m e nt of s U A wit h i n 4 8 h o urs pri or t o t his visit’s 
pe gl otic ase i nf usi o n. Pre-i nf usi o n s U A res ults m ust be re p orte d b y t h e l ocal or ce ntr al 
la b orat or y pri or t o p e gl oticase i nf usi o n. If a l ocal l a b orat or y sa m ple is dr a w n at a ce nt er 
ot her t ha n t he researc h site ( wit hi n 4 8 h o urs pri or t o t he pe gl oticase i nf usi o n), a sa m ple 
f or t he ce ntral la b orat or y will be dra w n pri or t o t he pe gl oticase i nf usi o n o n t he da y of t he 
visit (see Secti o n 9. 5. 1. 1 ). 
• 
St o p pi n g R ule:  S u bjects wit h a n s U A le vel > 6 m g/ d L at 2 c o ns ec uti ve st u d y 
visits be gi n ni n g wit h t he Wee k 2 Visit ( n ot i ncl u di n g p ost-i nf usi o n sa m ples) 
will disc o nti n ue treat me nt a n d re mai n i n t he st u d y.  
 A d mi nister M T X ≥6 0  mi n utes pri or t o pe gl oticase i nf usi o n if s u bject has n ot ta ke n M T X 
wit hi n t he pre vi o us 1 t o 3 da ys. 
 D oc u me nt g o ut flares a n d i nte nsit y. 
 Rec or d vital si g ns ( bl o o d press ure [ pri or a n d p ost i nf usi o n], res pirat or y rate, te m perat ur e, 
a n d heart rate [ pri or a n d p ost i nf usi o n]) (see Secti o n 9. 5. 4. 4 ).  

H oriz o n T hera pe utics Irela n d D A C
 
 
K R Y S T E X X A I N D: 0 1 0 1 2 2 
Date: 0 1 A pril 2 0 2 0 
 
Pr ot oc ol: H Z N P- K R Y- 2 0 1 
 
 
Versi o n 3. 0, A d mi nistrati ve C ha n ge 1 
P RI V A T E A N D C O N FI D E N TI A L I N F O R M A TI O N O F H O RI Z O N T H E R A P E U TI C S I R E L A N D D A C  Pa ge
 1 0 1
 
of
 
1 2 9
 
 
 Assess M T X c o m plia nce a n d re- dis pe ns e M T X. 
 As k Yes/ N o q uesti o n re gar di n g f olic aci d, g o ut fl are pr o p h yla xis, a n d I R pr o p h yla xis 
c o m plia nce. 
 Fill g o ut pr o p h yla xis, fe x ofe na di ne, acet a mi n o p he n, a n d f olic aci d prescri pti o ns, as 
nee de d.  
 O btai n a uri ne sa m ple fr o m all fe males of c hil d beari n g p ote ntial f or perf or ma nce of a 
pre g na nc y t est. 
 A d mi nister I R pr o p h yla xis (i.e., fe x ofe na di ne, aceta mi n o p he n, a n d met h yl pre d nis ol o ne 
or h y dr oc ortis o ne) (see Secti o n 9. 4. 1. 3 ). 
 A d mi nister pe gl otic ase a n d rec or d date, v ol u me, a n d d urati o n of i nf usi o n, a n d start/st o p 
(i ncl usi ve of 1 0- m L fl us h) ti mes of d osi n g. 
 O btai n a bl o o d sa m ple ( 1 sa m ple) f or meas ure m e nt of s U A after t he e n d of pe gl oticase 
i nf usi o n pri or t o disc har ge. 
 I n q uir e a b o ut A Es a n d c o nc o mita nt me dicati o n use. 
9. 5. 6. 2. 2 1    Wee k 3 6 
 O btai n 2 bl o o d sa m ples f or meas ure m e nt of s U A  wit hi n 4 8 h o urs pri or t o t his visit’s 
pe gl otic ase i nf usi o n. Pre-i nf usi o n s U A res ults m ust be re p orte d b y t h e l ocal or ce ntr al 
la b orat or y pri or t o p e gl oticase i nf usi o n. If a l ocal l a b orat or y sa m ple is dr a w n at a ce nt er 
ot her t ha n t he researc h site ( wit hi n 4 8 h o urs pri or t o t he pe gl oticase i nf usi o n), a sa m ple 
f or t he ce ntral la b orat or y will be dra w n pri or t o t he pe gl oticase i nf usi o n o n t he da y of t he 
visit (see Secti o n 9. 5. 1. 1 ). 
• 
St o p pi n g R ule:  S u bjects wit h a n s U A le vel > 6 m g/ d L at 2 c o ns ec uti ve st u d y 
visits be gi n ni n g wit h t he Wee k 2 Visit ( n ot i ncl u di n g p ost-i nf usi o n sa m ples) 
will disc o nti n ue treat me nt a n d re mai n i n t h e st u d y.  
 A d mi nister M T X ≥6 0  mi n utes pri or t o pe gl oticase i nf usi o n if s u bject has n ot ta ke n M T X 
wit hi n t he pre vi o us 1 t o 3 da ys. 
 D oc u me nt g o ut flares a n d i nte nsit y. 
 Perf or m a tar gete d p h ysi cal e x a mi nati o n s h o ul d i ncl u de heart, l u n gs a n d a b d o mi nal e xa m 
a n d j oi nt a n d s ki n e val uati o n a n d assess me nt of  A Es. A n y fi n di n g will be rec or de d as a n 
A E. 

H oriz o n T hera pe utics Irela n d D A C
 
 
K R Y S T E X X A I N D: 0 1 0 1 2 2 
Date: 0 1 A pril 2 0 2 0 
 
Pr ot oc ol: H Z N P- K R Y- 2 0 1 
 
 
Versi o n 3. 0, A d mi nistrati ve C ha n ge 1 
P RI V A T E A N D C O N FI D E N TI A L I N F O R M A TI O N O F H O RI Z O N T H E R A P E U TI C S I R E L A N D D A C  Pa ge
 1 0 2
 
of
 
1 2 9
 
 
 Rec or d vital si g ns ( bl o o d press ure [ pri or a n d p ost i nf usi o n], res pirat or y rate, te m perat ur e, 
a n d heart rate [ pri or a n d p ost i nf usi o n]) i ncl u di n g meas ure me nt of wei g ht (see Secti o n 
9. 5. 4. 4 ).  
 C ollect s w olle n/te n der j oi nt c o u nts; a d mi nister  H A Q; a n d rec or d patie nt a n d p h ysicia n 
gl o bal ass ess me nts a n d j oi nt pai n assess me nt res p o nses. 
 Assess f or t he prese nce of t o p hi. 
 Assess M T X c o m plia nce a n d re- dis pe ns e M T X. 
 As k Yes/ N o q uesti o n re gar di n g f olic aci d, g o ut fl are pr o p h yla xis, a n d I R pr o p h yla xis 
c o m plia nce. 
 Fill g o ut pr o p h yla xis, fe x ofe na di ne, acet a mi n o p he n, a n d f olic aci d pres cri pti o ns, as 
nee de d.  
 O btai n a uri ne sa m ple fr o m all fe males of c hil d beari n g p ote ntial f or perf or ma nce of a 
pre g na nc y t est. 
 O btai n bl o o d sa m ples f or he mat ol o g y a n d cli nical c he mistr y a nal ysis.  
 O btai n a uri ne sa m ple f or uric aci d:creati ni ne rati o. 
 O btai n bl o o d sa m ples f or pe gl oticase P K a nal ysis pri or t o t he i nf usi o n  
 O btai n bl o o d sa m ples f or a nti- P E G a n d a nti- uricas e I g G a nti b o dies pri or t o t he i nf usi o n. 
 O btai n bl o o d sa m ples f or M T X P ol y gl ut a mate a n al ysis pri or t o t he i nf usi o n. 
 A d mi nister I R pr o p h yla xis (i.e., fe x ofe na di ne, aceta mi n o p he n, a n d met h yl pre d nis ol o ne 
or h y dr oc ortis o ne) (see Secti o n 9. 4. 1. 3 ). 
 A d mi nister pe gl otic ase a n d rec or d date, v ol u me, a n d d urati o n of i nf usi o n, a n d start/st o p 
(i ncl usi ve of 1 0- m L fl us h) ti mes of d osi n g. 
 O btai n a bl o o d sa m ple ( 1 sa m ple) f or meas ure m e nt of s U A after t he e n d of pe gl oticase 
i nf usi o n pri or t o disc har ge. 
  O btai n bl o o d sa m ples f or pe gl oticase P K a n alysis after t he e n d of t he i nf usi o n pri or t o 
disc har ge.  
 Perf or m D E C T (if a p plica ble). 
 I n q uir e a b o ut A Es a n d c o nc o mita nt me dicati o n use. 

H oriz o n T hera pe utics Irela n d D A C
 
 
K R Y S T E X X A I N D: 0 1 0 1 2 2 
Date: 0 1 A pril 2 0 2 0 
 
Pr ot oc ol: H Z N P- K R Y- 2 0 1 
 
 
Versi o n 3. 0, A d mi nistrati ve C ha n ge 1 
P RI V A T E A N D C O N FI D E N TI A L I N F O R M A TI O N O F H O RI Z O N T H E R A P E U TI C S I R E L A N D D A C  Pa ge
 1 0 3
 
of
 
1 2 9
 
 
9. 5. 6. 2. 2 2    Wee k 3 8 
 O btai n 2 bl o o d sa m ples f or meas ure m e nt of s U A wit hi n 4 8 h o urs pri or t o t his visit’s 
pe gl otic ase i nf usi o n. Pre-i nf usi o n s U A res ults m ust be re p orte d b y t h e l ocal or ce ntr al 
la b orat or y pri or t o p e gl oticase i nf usi o n. If a l ocal l a b orat or y sa m ple is dr a w n at a ce nt er 
ot her t ha n t he researc h site ( wit hi n 4 8 h o urs pri or t o t h e pe gl oticase i nf usi o n), a sa m ple 
f or t he ce ntral la b orat or y will be dra w n pri or t o t he pe gl oticase i nf usi o n o n t he da y of t he 
visit (see Secti o n 9. 5. 1. 1 ). 
• 
St o p pi n g R ule:  S u bjects wit h a n s U A le vel > 6 m g/ d L at 2 c o ns ec uti ve st u d y 
visits be gi n ni n g wit h t he Wee k 2 Visit ( n ot i ncl u di n g p ost-i nf usi o n sa m ples) 
will disc o nti n ue treat me nt a n d re mai n i n t he st u d y.  
 A d mi nister M T X ≥6 0  mi n utes pri or t o pe gl oticase i nf usi o n if s u bject has n ot ta ke n M T X 
wit hi n t he pre vi o us 1 t o 3 da ys. 
 D oc u me nt g o ut flares a n d i nte nsit y. 
 Rec or d vital si g ns ( bl o o d press ure [ pri or a n d p ost i nf usi o n], res pirat or y rate, te m perat ur e, 
a n d heart rate [ pri or a n d p ost i nf usi o n]) (see Secti o n 9. 5. 4. 4 ).  
 Assess M T X c o m plia nce a n d re- dis pe ns e M T X. 
 As k Yes/ N o q uesti o n re gar di n g f olic aci d, g o ut fl are pr o p h yla xis, a n d I R pr o p h yla xis 
c o m plia nce. 
 Fill g o ut pr o p h yla xis, fe x ofe na di ne, acet a mi n o p he n, a n d f olic aci d prescri pti o ns, as 
nee de d.  
 O btai n a uri ne sa m ple fr o m all fe males of c hil d beari n g p ote ntial f or perf or ma nce of a 
pre g na nc y t est. 
 A d mi nister I R pr o p h yla xis (i.e., fe x ofe na di ne, aceta mi n o p he n, a n d met h yl pre d nis ol o ne 
or h y dr oc ortis o ne) (see Secti o n 9. 4. 1. 3 ). 
 A d mi nister pe gl otic ase a n d rec or d date, v ol u me, a n d d urati o n of i nf usi o n, a n d start/st o p 
(i ncl usi ve of 1 0- m L fl us h) ti mes of d osi n g. 
 I n q uir e a b o ut A Es a n d c o nc o mita nt me dicati o n use. 
9. 5. 6. 2. 2 3    Wee k 4 0 
 O btai n 2 bl o o d sa m ples f or meas ure m e nt of s U A  wit hi n 4 8 h o urs pri or t o t his visit’s 
pe gl otic ase i nf usi o n. Pre-i nf usi o n s U A res ults m ust be re p orte d b y t h e l ocal or ce ntr al 
la b orat or y pri or t o p e gl oticase i nf usi o n. If a l ocal l a b orat or y sa m ple is dr a w n at a ce nt er 
ot her t ha n t he researc h site ( wit hi n 4 8 h o urs pri or t o t he pe gl oticase i nf usi o n), a sa m ple 

H oriz o n T hera pe utics Irela n d D A C
 
 
K R Y S T E X X A I N D: 0 1 0 1 2 2 
Date: 0 1 A pril 2 0 2 0 
 
Pr ot oc ol: H Z N P- K R Y- 2 0 1 
 
 
Versi o n 3. 0, A d mi nistrati ve C ha n ge 1 
P RI V A T E A N D C O N FI D E N TI A L I N F O R M A TI O N O F H O RI Z O N T H E R A P E U TI C S I R E L A N D D A C  Pa ge
 1 0 4
 
of
 
1 2 9
 
 
f or t he ce ntral la b orat or y will be dra w n pri or t o t he pe gl oticase i nf usi o n o n t he da y of t he 
visit (see Secti o n 9. 5. 1. 1 ). 
• 
St o p pi n g R ule:  S u bjects wit h a n s U A le vel > 6 m g/ d L at 2 c o ns ec uti ve st u d y 
visits be gi n ni n g wit h t he Wee k 2 Visit ( n ot i ncl u di n g p ost-i nf usi o n sa m ples) 
will disc o nti n ue treat me nt a n d re mai n i n t he st u d y.  
 A d mi nister M T X ≥6 0  mi n utes pri or t o pe gl oticase i nf usi o n if s u bject has n ot ta ke n M T X 
wit hi n t he pre vi o us 1 t o 3 da ys. 
 D oc u me nt g o ut flares a n d i nte nsit y. 
 Rec or d vital si g ns ( bl o o d press ure [ pri or a n d p ost i nf usi o n], res pirat or y rate, te m perat ur e, 
a n d heart rate [ pri or a n d p ost i nf usi o n]) (see Secti o n 9. 5. 4. 4 ).  
 Assess M T X c o m plia nce a n d re- dis pe ns e M T X. 
 As k Yes/ N o q uesti o n re gar di n g f olic aci d, g o ut fl are pr o p h yla xis, a n d I R pr o p h yla xis 
c o m plia nce. 
 Fill g o ut pr o p h yla xis, fe x ofe na di ne, acet a mi n o p h e n, a n d f olic aci d prescri pti o ns, as 
nee de d.  
 O btai n a uri ne sa m ple fr o m all fe males of c hil d beari n g p ote ntial f or perf or ma nce of a 
pre g na nc y t est. 
 A d mi nister I R pr o p h yla xis (i.e., fe x ofe na di ne, aceta mi n o p he n, a n d met h yl pre d nis ol o ne 
or h y dr oc ortis o ne) (see Secti o n 9. 4. 1. 3 ). 
 A d mi nister pe gl otic ase a n d rec or d date, v ol u me, a n d d urati o n of i nf usi o n, a n d start/st o p 
(i ncl usi ve of 1 0- m L fl us h) ti mes of d osi n g. 
 I n q uir e a b o ut A Es a n d c o nc o mita nt me dicati o n use. 
9. 5. 6. 2. 2 4    Wee k 4 2 
 O btai n 2 bl o o d sa m ples f or meas ure m e nt of s U A  wit hi n 4 8 h o urs pri or t o t his visit’s 
pe gl otic ase i nf usi o n. Pre-i nf usi o n s U A res ults m ust be re p orte d b y t h e l ocal or ce ntr al 
la b orat or y pri or t o p e gl oticase i nf usi o n. If a l ocal l a b orat or y sa m ple is dr a w n at a ce nt er 
ot her t ha n t he researc h site ( wit hi n 4 8 h o urs pri or t o t he pe gl oticase i nf usi o n), a sa m ple 
f or t he ce ntral la b orat or y will be dra w n pri or t o t he pe gl oticase i nf usi o n o n t he da y of t he 
visit (see Secti o n 9. 5. 1. 1 ). 
• 
St o p pi n g R ule:  S u bjects wit h a n s U A le vel > 6 m g/ d L at 2 c o ns ec uti ve st u d y 
visits be gi n ni n g wit h t he Wee k 2 Visit ( n ot i ncl u di n g p ost-i nf usi o n sa m ples) 
will disc o nti n ue treat me nt a n d re mai n i n t he st u d y.  

H oriz o n T hera pe utics Irela n d D A C
 
 
K R Y S T E X X A I N D: 0 1 0 1 2 2 
Date: 0 1 A pril 2 0 2 0 
 
Pr ot oc ol: H Z N P- K R Y- 2 0 1 
 
 
Versi o n 3. 0, A d mi nistrati ve C ha n ge 1 
P RI V A T E A N D C O N FI D E N TI A L I N F O R M A TI O N O F H O RI Z O N T H E R A P E U TI C S I R E L A N D D A C  Pa ge
 1 0 5
 
of
 
1 2 9
 
 
 A d mi nister M T X ≥6 0  mi n utes pri or t o pe gl oticase i nf usi o n if s u bject has n ot ta ke n M T X 
wit hi n t he pre vi o us 1 t o 3 da ys. 
 D oc u me nt g o ut flares a n d i nte nsit y. 
 Rec or d vital si g ns ( bl o o d press ure [ pri or a n d p ost i nf usi o n], res pirat or y rate, te m perat ur e, 
a n d heart rate [ pri or a n d p ost i nf usi o n]) (see Secti o n 9. 5. 4. 4 ).  
 Assess M T X c o m plia nce a n d re- dis pe ns e M T X. 
 As k Yes/ N o q uesti o n re gar di n g f olic aci d, g o ut fl are pr o p h yla xis, a n d I R pr o p h yla xis 
c o m plia nce. 
 Fill g o ut pr o p h yla xis, fe x ofe na di ne, acet a mi n o p he n, a n d f olic aci d prescri pti o ns, as 
nee de d.  
 O btai n a uri ne sa m ple fr o m all fe males of c hil d beari n g p ote ntial f or perf or ma nce of a 
pre g na nc y t est. 
 A d mi nister I R pr o p h yla xis (i.e., fe x ofe na di ne, aceta mi n o p he n, a n d met h yl pre d nis ol o ne 
or h y dr oc ortis o ne) (see Secti o n 9. 4. 1. 3 ). 
 A d mi nister pe gl otic ase a n d rec or d date, v ol u me, a n d d urati o n of i nf usi o n, a n d start/st o p 
(i ncl usi ve of 1 0- m L fl us h) ti mes of d osi n g. 
 I n q uir e a b o ut A Es a n d c o nc o mita nt me dicati o n use. 
9. 5. 6. 2. 2 5    Wee k 4 4 
 O btai n 2 bl o o d sa m ples f or meas ure m e nt of s U A wit hi n 4 8 h o urs pri or t o t his visit’s 
pe gl otic ase i nf usi o n. Pre-i nf usi o n s U A res ults m ust be re p orte d b y t h e l ocal or ce ntr al 
la b orat or y pri or t o p e gl oticase i nf usi o n. If a l ocal l a b orat or y sa m ple is dr a w n at a ce nt er 
ot her t ha n t he researc h site ( wit hi n 4 8 h o urs pri or t o t he pe gl oticase i nf usi o n), a sa m ple 
f or t he ce ntral la b orat or y will be dra w n pri or t o t he pe gl oticase i nf usi o n o n t he da y of t he 
visit (see Secti o n 9. 5. 1. 1 ). 
• 
St o p pi n g R ule:  S u bjects wit h a n s U A le vel > 6 m g/ d L at 2 c o ns ec uti ve st u d y 
visits be gi n ni n g wit h t he Wee k 2 Visit ( n ot i ncl u di n g p ost-i nf usi o n sa m ples) 
will disc o nti n ue treat me nt a n d re mai n i n t he st u d y.  
 A d mi nister M T X ≥6 0  mi n utes pri or t o pe gl oticase i nf usi o n if s u bject has n ot ta ke n M T X 
wit hi n t he pre vi o us 1 t o 3 da ys. 
 D oc u me nt g o ut flares a n d i nte nsit y. 

H oriz o n T hera pe utics Irela n d D A C
 
 
K R Y S T E X X A I N D: 0 1 0 1 2 2 
Date: 0 1 A pril 2 0 2 0 
 
Pr ot oc ol: H Z N P- K R Y- 2 0 1 
 
 
Versi o n 3. 0, A d mi nistrati ve C ha n ge 1 
P RI V A T E A N D C O N FI D E N TI A L I N F O R M A TI O N O F H O RI Z O N T H E R A P E U TI C S I R E L A N D D A C  Pa ge
 1 0 6
 
of
 
1 2 9
 
 
 Rec or d vital si g ns ( bl o o d press ure [ pri or a n d p ost i nf usi o n], res pirat or y rate, te m perat ur e, 
a n d heart rate [ pri or a n d p ost i nf usi o n]) (see Secti o n 9. 5. 4. 4 ).  
 Assess M T X c o m plia nce a n d re- dis pe ns e M T X. 
 As k Yes/ N o q uesti o n re gar di n g f olic aci d, g o ut fl are pr o p h yla xis, a n d I R pr o p h yla xis 
c o m plia nce. 
 Fill g o ut pr o p h yla xis, fe x ofe na di ne, acet a mi n o p he n, a n d f olic aci d prescri pti o ns, as 
nee de d.  
 O btai n a uri ne sa m ple fr o m all fe males of c hil d beari n g p ote ntial f or perf or ma nce of a 
pre g na nc y t est. 
 A d mi nister I R pr o p h yla xis (i.e., fe x ofe na di ne, aceta mi n o p he n, a n d met h yl pre d nis ol o ne 
or h y dr oc ortis o ne) (see Secti o n 9. 4. 1. 3 ). 
 A d mi nister pe gl otic ase a n d rec or d date, v ol u me, a n d d urati o n of i nf usi o n, a n d start/st o p 
(i ncl usi ve of 1 0- m L fl us h) ti mes of d osi n g. 
 I n q uir e a b o ut A Es a n d c o nc o mita nt me dicati o n use. 
9. 5. 6. 2. 2 6    Wee k 4 6  
 O btai n 2 bl o o d sa m ples f or meas ure m e nt of s U A  wit hi n 4 8 h o urs pri or t o t his visit’s 
pe gl otic ase i nf usi o n. Pre-i nf usi o n s U A res ults m ust be re p orte d b y t h e l ocal or ce ntr al 
la b orat or y pri or t o p e gl oticase i nf usi o n. If a l ocal l a b orat or y sa m ple is dr a w n at a ce nt er 
ot her t ha n t he researc h site ( wit hi n 4 8 h o urs pri or t o t he pe gl oticase i nf usi o n), a sa m ple 
f or t he ce ntral la b orat or y will be dra w n pri or t o t he pe gl oticase i nf usi o n o n t he da y of t he 
visit (see Secti o n 9. 5. 1. 1 ). 
• 
St o p pi n g R ule:  S u bjects wit h a n s U A le vel > 6 m g/ d L at 2 c o ns ec uti ve st u d y 
visits be gi n ni n g wit h t he Wee k 2 Visit ( n ot i ncl u di n g p ost-i nf usi o n sa m ples) 
will disc o nti n ue treat me nt a n d re mai n i n t he st u d y.  
 A d mi nister M T X ≥6 0  mi n utes pri or t o pe gl oticase i nf usi o n if s u bject has n ot ta ke n M T X 
wit hi n t he pre vi o us 1 t o 3 da ys. 
 D oc u me nt g o ut flares a n d i nte nsit y. 
 Rec or d vital si g ns ( bl o o d press ure  [ pri or a n d p ost i nf usi o n], res pirat or y rate, te m perat ur e, 
a n d heart rate [ pri or a n d p ost i nf usi o n]) (see Secti o n 9. 5. 4. 4 ).  
 Assess M T X c o m plia nce a n d re- dis pe ns e M T X. 

H oriz o n T hera pe utics Irela n d D A C
 
 
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Date: 0 1 A pril 2 0 2 0 
 
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 As k Yes/ N o q uesti o n re gar di n g f olic aci d, g o ut fl are pr o p h yla xis, a n d I R pr o p h yla xis 
c o m plia nce. 
 Fill g o ut pr o p h yla xis, fe x ofe na di ne, acet a mi n o p he n, a n d f olic aci d prescri pti o ns, as 
nee de d.  
 O btai n a uri ne sa m ple fr o m all fe males of c hil d beari n g p ote ntial f or perf or ma nce of a 
pre g na nc y t est. 
 A d mi nister I R pr o p h yla xis (i.e., fe x ofe na di ne, aceta mi n o p he n, a n d met h yl pre d nis ol o ne 
or h y dr oc ortis o ne) (see Secti o n 9. 4. 1. 3 ). 
 A d mi nister pe gl otic ase a n d rec or d date, v ol u me, a n d d urati o n of i nf usi o n, a n d start/st o p 
(i ncl usi ve of 1 0- m L fl us h) ti mes of d osi n g. 
  I n q uir e a b o ut A Es a n d c o nc o mita nt me dicati o n use. 
9. 5. 6. 2. 2 7    Wee k 4 8 
 O btai n 2 bl o o d sa m ples f or meas ure m e nt of s U A wit hi n 4 8 h o urs pri or t o t his visit’s 
pe gl otic ase i nf usi o n. Pre-i nf usi o n s U A res ults m ust be re p orte d b y t h e l ocal or ce ntr al 
la b orat or y pri or t o p e gl oticase i nf usi o n. If a l ocal l a b orat or y sa m ple is dr a w n at a ce nt er 
ot her t ha n t he researc h site ( wit hi n 4 8 h o urs pri or t o t he pe gl oticase i nf usi o n), a sa m ple 
f or t he ce ntral la b orat or y will be dra w n pri or t o t he pe gl oticase i nf usi o n o n t he da y of t he 
visit (see Secti o n 9. 5. 1. 1 ). 
• 
St o p pi n g R ule:  S u bjects wit h a n s U A le vel > 6 m g/ d L at 2 c o ns ec uti ve st u d y 
visits be gi n ni n g wit h t he Wee k 2 Visit ( n ot i ncl u di n g p ost-i nf usi o n sa m ples) 
will disc o nti n ue treat me nt a n d re mai n i n t he st u d y.  
 A d mi nister M T X ≥6 0  mi n utes pri or t o pe gl oticase i nf usi o n if s u bject has n ot ta ke n M T X 
wit hi n t he pre vi o us 1 t o 3 da ys. 
 D oc u me nt g o ut flares a n d i nte nsit y. 
 Rec or d vital si g ns ( bl o o d press ure [ pri or a n d p ost i nf usi o n], res pirat or y rate, te m perat ur e, 
a n d heart rate [ pri or a n d p ost i nf usi o n]) (see Secti o n 9. 5. 4. 4 ).  
 Assess M T X c o m plia nce a n d re- dis pe ns e M T X. 
 As k Yes/ N o q uesti o n re gar di n g f olic aci d, g o ut fl are pr o p h yla xis, a n d I R pr o p h yla xis 
c o m plia nce. 
 Fill g o ut pr o p h yla xis, fe x ofe na di ne, acet a mi n o p he n, a n d f olic aci d prescri pti o ns, as 
nee de d.  

H oriz o n T hera pe utics Irela n d D A C
 
 
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Date: 0 1 A pril 2 0 2 0 
 
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of
 
1 2 9
 
 
 O btai n a uri ne sa m ple fr o m all fe males of c hil d beari n g p ote ntial f or perf or ma nce of a 
pre g na nc y t est. 
 A d mi nister I R pr o p h yla xis (i.e., fe x ofe na di ne, aceta mi n o p he n, a n d met h yl pre d nis ol o ne 
or h y dr oc ortis o ne) (see Secti o n 9. 4. 1. 3 ). 
 A d mi nister pe gl otic ase a n d rec or d date, v ol u me, a n d d urati o n of i nf usi o n, a n d start/st o p 
(i ncl usi ve of 1 0- m L fl us h) ti mes of d osi n g. 
 O btai n a bl o o d sa m ple ( 1 sa m ple) f or meas ure m e nt of s U A after t he e n d of pe gl oticase 
i nf usi o n pri or t o disc har ge. 
  I n q uir e a b o ut A Es a n d c o nc o mita nt me dicati o n use. 
9. 5. 6. 2. 2 8    Wee k 5 0 
 O btai n 2 bl o o d sa m ples f or meas ure m e nt of s U A  wit hi n 4 8 h o urs pri or t o t his visit’s 
pe gl otic ase i nf usi o n. Pre-i nf usi o n s U A res ults m ust be re p orte d b y t h e l ocal or ce ntr al 
la b orat or y pri or t o p e gl oticase i nf usi o n. If a l ocal l a b orat or y sa m ple is dr a w n at a ce nt er 
ot her t ha n t he researc h site ( wit hi n 4 8 h o urs pri or t o t he pe gl oticase i nf usi o n), a sa m ple 
f or t he ce ntral la b orat or y will be dra w n pri or t o t he pe gl oticase i nf usi o n o n t he da y of t he 
visit (see Secti o n 9. 5. 1. 1 ). 
• 
St o p pi n g R ule:  S u bjects wit h a n s U A le vel > 6 m g/ d L at 2 c o ns ec uti ve st u d y 
visits be gi n ni n g wit h t he Wee k 2 Visit ( n ot i ncl u di n g p ost-i nf usi o n sa m ples) 
will disc o nti n ue treat me nt a n d re mai n i n t he st u d y.  
 A d mi nister M T X ≥6 0  mi n utes pri or t o pe gl oticase i nf usi o n if s u bject has n ot ta ke n M T X 
wit hi n t he pre vi o us 1 t o 3 da ys. 
 D oc u me nt g o ut flares a n d i nte nsit y. 
 Rec or d vital si g ns ( bl o o d press ure, o n e mea s ure m e nt [ pri or a n d p ost i nf usi o n], 
res pirat or y rate, te m perat ure, a n d heart rate [ pri or a n d p ost i nf usi o n]) (see Secti o n 
9. 5. 4. 4 ). 
 Assess M T X c o m plia nce a n d dis pe nse. 
 As k Yes/ N o q uesti o n re gar di n g f olic aci d, g o ut fl are pr o p h yla xis, a n d I R pr o p h yla xis 
c o m plia nce. 
 O btai n a uri ne sa m ple fr o m all fe males of c hil d beari n g p ote ntial f or perf or ma nce of a 
pre g na nc y t est. 
 A d mi nister I R pr o p h yla xis (i.e., fe x ofe na di ne, aceta mi n o p he n, a n d met h yl pre d nis ol o ne 
or h y dr oc ortis o ne) (see Secti o n 9. 4. 1. 3 Err or! Refere nce s o urce n ot f o u n d. ). 

H oriz o n T hera pe utics Irela n d D A C
 
 
K R Y S T E X X A I N D: 0 1 0 1 2 2 
Date: 0 1 A pril 2 0 2 0 
 
Pr ot oc ol: H Z N P- K R Y- 2 0 1 
 
 
Versi o n 3. 0, A d mi nistrati ve C ha n ge 1 
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 1 0 9
 
of
 
1 2 9
 
 
 A d mi nister pe gl otic ase a n d rec or d date, v ol u me, a n d d urati o n of i nf usi o n, a n d start/st o p 
(i ncl usi ve of 1 0- m L fl us h) ti mes of d osi n g. 
 O btai n a bl o o d sa m ple ( 1 sa m ple) f or meas ure m e nt of s U A after t he e n d of pe gl oticase 
i nf usi o n pri or t o disc har ge. 
 I n q uir e a b o ut A Es a n d c o nc o mita nt me dicati o n use. 
N ote:  M T X will be ta ke n o ne wee k f oll o wi n g t he Wee k 5 0 Visit a n d F olic Aci d will be ta ke n 
u ntil j ust pri or t o t he Wee k 5 2 Visit.  
9. 5. 6. 3  E n d of Pe gl otic ase I nf usi o ns Visit 
S u bjects w h o e n d pe gl oticase i nf usi o ns pri or t o  Wee k 5 2 will c o m plete t he E n d of Pe gl oticase 
I nf usi o ns Visit pr oce d ures f oll o wi n g t heir fi n al inf usi o n. S u bjects s h o ul d c o nti n ue t o partici pate 
i n all visits t hr o u g h t he e n d of t he st u d y. S u bjects m ust c o m plete selecte d st u d y visits at t he st u d y 
site d uri n g ke y effi cac y a n d safet y c ollecti o ns Wee ks 1 0, 1 2, 1 4, 2 0, 2 2, 2 4, 3 2, 3 4, 3 6, 4 8, 5 0 
a n d 5 2, s o t hat s U A la bs a n d ot her ke y assess me nts ca n be c o m plet e d. Visits bet wee n t hes e ke y 
effic ac y a n d s afet y c ollecti o n visits, f or s u bjects w h o ha ve st o p pe d i nf usi o ns, ma y be c o m plete d 
i n pers o n or via a tel e p h o ne visit o pti o n t o c ollect A Es, c o n c o mita nt me dicati o n a n d g o ut fl are 
i nf or mati o n ( See 9. 3. 3. 1. 1 ).  
T he f oll o wi n g pr oce d ures will be c o m plete d at t he E n d of Pe gl oticase Visit:  
 I n v esti gat or Assess me nt of Cli nical Stat us.  
 D oc u me nt g o ut flares a n d i nte nsit y. 
 Perf or m a tar gete d p h ysi cal e x a mi nati o n s h o ul d i ncl u de heart, l u n gs a n d a b d o mi nal e xa m 
a n d j oi nt a n d s ki n e val uati o n a n d assess me nt of  A Es. A n y fi n di n g will be rec or de d as a n 
A E. 
 Rec or d vital si g ns ( bl o o d press ure, res pirat or y rate, te m perat ur e, a n d heart rate i ncl u di n g 
t he meas ure m e nt of wei g ht. (see Secti o n 9. 5. 4. 4 ). 
 C ollect s w olle n/te n der j oi nt c o u nts; a d mi nister  H A Q; a n d rec or d patie nt a n d p h ysicia n 
gl o bal ass ess me nts a n d j oi nt pai n assess me nt res p o nses. 
 Assess me nt of T o p hi. 
 Assess M T X c o m plia nce.  
 As k Yes/ N o q uesti o n re gar di n g f olic aci d, g o ut fl are pr o p h yla xis, a n d I R pr o p h yla xis 
c o m plia nce. 

H oriz o n T hera pe utics Irela n d D A C
 
 
K R Y S T E X X A I N D: 0 1 0 1 2 2 
Date: 0 1 A pril 2 0 2 0 
 
Pr ot oc ol: H Z N P- K R Y- 2 0 1 
 
 
Versi o n 3. 0, A d mi nistrati ve C ha n ge 1 
P RI V A T E A N D C O N FI D E N TI A L I N F O R M A TI O N O F H O RI Z O N T H E R A P E U TI C S I R E L A N D D A C  Pa ge
 1 1 0
 
of
 
1 2 9
 
 
 O btai n a uri ne sa m ple fr o m all fe males of c hil d beari n g p ote ntial f or perf or ma nce of a 
pre g na nc y t est. 
 O btai n bl o o d sa m ples f or he mat ol o g y a n d cli nical c he mistr y a nal ysis.  
 O btai n a uri ne sa m ple f or uric aci d:creati ni ne rati o. 
 O btai n bl o o d sa m ples f or pe gl oticase P K a nal ysis.  
 O btai n bl o o d sa m ples f or a nti- P E G a n d a nti- uricas e I g G a nti b o dies. 
 O btai n a bl o o d sa m ple ( 1 sa m ple) f or meas ure m e nt of s U A. 
 I n q uir e a b o ut A Es a n d c o nc o mita nt me dicati o n use. 
 Perf or m D E C T (if a p plica ble). D E C T ma y b e c o m plete d wit hi n +/- 5 da ys of t he 
sc he d ule d visit. S u bjects w h o e n d pe gl oticase i nf usi o ns pri or t o Wee k 5 2 s h o ul d f oll o w 
t he sc he d ule d ti me p oi nts b ut a v oi d a re peat D E C T sca n wit hi n 6 wee ks of a pri or sca n. 
9. 5. 6. 4    Wee k 5 2/ E n d of St u d y/E arl y Ter mi n ati o n Visit  
 I n v esti gat or Assess me nt of Cli nical Stat us. 
 Perf or m a tar gete d p h ysi cal e x a mi nati o n s h o ul d i ncl u de heart, l u n gs a n d a b d o mi nal e xa m 
a n d j oi nt a n d s ki n e val uati o n a n d assess me nt of  A Es. A n y fi n di n g will be rec or de d as a n 
A E. 
 Assess me nt of T o p hi. 
 D oc u me nt g o ut flares a n d i nte nsit y. 
 Rec or d vital si g ns ( bl o o d press ure, res pirat or y rate, te m perat ur e, heart rate i ncl u de 
meas ure me nt of wei g ht. (see Secti o n 9. 5. 4. 4 ).  
 C ollect s w olle n/te n der j oi nt c o u nts; a d mi nister  H A Q; a n d rec or d patie nt a n d p h ysicia n 
gl o bal ass ess me nts a n d j oi nt pai n assess me nt res p o nses. 
 Assess M T X c o m plia nce. 
 As k Yes/ N o q uesti o n re gar di n g f olic aci d, g o ut fl are pr o p h yla xis, a n d I R pr o p h yla xis 
c o m plia nce. 
 O btai n a sa m ple fr o m all fe males of c h il d beari n g p ote ntial f or perf or ma nce of a 
pre g na nc y t est. 
 O btai n bl o o d sa m ples f or he mat ol o g y a n d cli nical c he mistr y a nal ysis.  

H oriz o n T hera pe utics Irela n d D A C
 
 
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Date: 0 1 A pril 2 0 2 0 
 
Pr ot oc ol: H Z N P- K R Y- 2 0 1 
 
 
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 1 1 1
 
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 O btai n a uri ne sa m ple f or uric aci d:creati ni ne rati o. 
 O btai n a bl o o d sa m ple ( 1 sa m ple) f or meas ure m e nt of s U A. 
 O btai n bl o o d sa m ples f or pe gl oticase P K a nal ysis. 
 O btai n bl o o d sa m ples f or a nti- P E G a n d a nti- uricas e I g G a nti b o dies. 
 I n q uir e a b o ut A Es a n d c o nc o mita nt me dicati o n use. 
 Perf or m D E C T (if a p plica ble). D E C T ma y b e c o m plete d wit hi n +/- 5 da ys of t he 
sc he d ule d visit. 
9. 5. 6. 5    S afet y F oll o w- u p P h o ne/ E m ail/ Site Visits 
T hirt y ( 3 0) da ys after t he last M T X d ose, s u bjects will be c o ntacte d b y tele p h o ne or e mail or 
ma y visit t he site t o re vie w S A Es. S u bjects w h o are fe males of c hil d beari n g p ote ntial will be 
as ke d t o c o nfir m t hat o v ulati o n has occ urre d.   If t he s u bject has n ot o v ulat e d, t he s u bject will be 
re q ueste d t o r et ur n t o t he site f or a uri ne pre g na n c y test. 
9. 5. 6. 6  M T X P a rt ner Pre g n a nc y F oll o w- u p 
S u bjects w h o are n o n- vasect o miz e d males, a p h o ne/e - mail/site visit i n q uir y will be c o n d u cte d 3 
m o nt hs after M T X disc o nti n uati o n re gar di n g part ner pre g n a nc y (t his ca n b e c o n d ucte d at t he 3 
m o nt h P ost Treat me nt F oll o w- u p Visit). 
9. 5. 6. 7  P ost Tre at me nt F oll o w- u p  
T he i nte nt is f or at least 6 m o nt hs of f oll o w- u p o n eac h s u bject after cess ati o n of pe gl oticase 
i nf usi o ns. If t h ese 6 m o nt hs occ ur pri or t o e n d of st u d y at Wee k 5 2, s uc h as i n t he case of a 
s u bject w h o e n ds pe gl oti case i nf usi o ns o n or b ef ore Wee k 2 4, t here will be n o f oll o w- u p visits 
after t he Wee k 5 2/ E n d of St u d y Visit. F or s u bjects w h o e n d pe gl oticase i nf usi o ns bet wee n 
Wee ks 2 6 a n d 3 6, t here will be at least 3 m o nt hs  of f oll o w- u p w hile t he s u bject re mai ns o n-st u d y 
pri or t o W ee k 5 2, a n d t he n o ne f oll o w- u p visit after t he Wee k 5 2/ E n d of St u d y Visit. F or 
s u bjects w h o e n d pe gl oti case i nf usi o ns bet w ee n Wee ks 3 8 a n d 5 2, t here will be t w o f oll o w- u p 
visits at i nter vals of 3 m o nt hs a part after t h e Wee k 5 2/ E n d of St u d y Visit. T he f oll o wi n g 
pr oce d ures will be c o m pl ete d at t he 3 a n d 6 m o nt h P ost Treat me nt F oll o w- u p Visits: 
 D oc u me nt g o ut flares a n d i nte nsit y. 
 Rec or d vital si g ns ( bl o o d press ure, res pirat or y rate, te m perat ur e, heart rate a n d wei g ht). 
(see Secti o n 9. 5. 4. 4 ). 
 Perf or m a tar gete d p h ysi cal e x a mi nati o n s h o ul d i ncl u de heart, l u n gs a n d a b d o mi nal e xa m 
a n d j oi nt a n d s ki n e val uati o n a n d assess me nt of  A Es. A n y fi n di n g will be rec or de d as a n 
A E. 

H oriz o n T hera pe utics Irela n d D A C
 
 
K R Y S T E X X A I N D: 0 1 0 1 2 2 
Date: 0 1 A pril 2 0 2 0 
 
Pr ot oc ol: H Z N P- K R Y- 2 0 1 
 
 
Versi o n 3. 0, A d mi nistrati ve C ha n ge 1 
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 1 1 2
 
of
 
1 2 9
 
 
 C ollect s w olle n/te n der j oi nt c o u nts; a d mi nister  H A Q; a n d rec or d patie nt a n d p h ysicia n 
gl o bal ass ess me nts a n d j oi nt pai n assess me nt res p o nses. 
 Assess me nt of T o p hi. 
 O btai n bl o o d sa m ples f or he mat ol o g y a n d cli nical c he mistr y a nal ysis.  
 O btai n a bl o o d sa m ple ( 1 sa m ple) f or meas ure m e nt of s U A. 
 O btai n bl o o d sa m ples f or a nti- P E G a n d a nti- uri cas e I g G a nti b o dies pri or t o t he i nf usi o n 
( 3 M o nt h P ost Treat me nt F oll o w- u p Visit o nl y).  
 I n q uir e a b o ut A Es a n d c o nc o mita nt me dicati o n use. 
9. 6  
St atistic al Met h o ds a n d Deter mi n ati o n of S a m ple Size  
Detaile d statistical a nal ys es will be prese nte d i n a se parat e statistical a nal ysis pla n ( S A P). S o me 
ke y p oi nts i de ntifie d f or statistical  a nal ys es are o utli ne d bel o w. 
9. 6. 1  E n d p oi nts 
9. 6. 1. 1  Pri m ar y E n d p oi nt 
T he pri mar y effic ac y e n d p oi nt is t he pr o p orti o n of M o nt h 6 ( Wee ks 2 0, 2 2, a n d 2 4) res p o n d ers, 
defi ne d as s u bjects ac hie vi n g a n d mai ntai ni n g s U A < 6 m g/ d L f or at least 8 0 % of t he ti me d uri n g 
M o nt h 6.  
9. 6. 1. 2  Sec o n d ar y E n d p oi nts 
T he sec o n d ar y efficac y e n d p oi nts are:  
 T he pr o p orti o n of M o nt h 3 ( Wee ks 1 0, 1 2, a n d 1 4) res p o n ders, defi ne d as s u bjects 
ac hie vi n g a n d mai ntai ni n g s U A < 6 m g/ d L f or at least 8 0 % of t he ti me d uri n g M o nt h 3. 
 T he pr o p orti o n of o verall res p o n ders, defi ne d as  s u bjects ac hie vi n g a n d m ai ntai ni n g s U A 
< 6 m g/ d L f or at least 8 0 % of t he ti me d uri n g M o nt h 3 ( We e ks 1 0, 1 2 a n d 1 4) a n d M o nt h 
6 ( Wee ks 2 0, 2 2 a n d 2 4) c o m bi ne d. 
 T he pr o p orti o n of 5 m g/ d L res p o n ders d uri n g M o nt h 3, d uri n g M o nt h 6, a n d o verall 
( M o nt hs 3 a n d 6 c o m bi ne d), defi n e d as s u bjects a c hie vi n g a n d mai ntai ni n g s U A < 5 
m g/ d L f or at least 8 0 % of t he ti me d uri n g eac h ti me p oi nt. 
  T he mea n c h a n ge fr o m baseli ne t o Wee ks 1 4, 2 4, 3 6, a n d 5 2 i n s U A. 
9. 6. 1. 3  E x pl or at or y E n d p oi nts 
T he e x pl orat or y effi cac y e n d p oi nts are:  
 T he pr o p orti o n of M o nt h 9 ( Wee ks 3 2, 3 4 a n d 3 6) res p o n ders, defi ne d as s u bjects 
ac hie vi n g a n d mai ntai ni n g s U A < 6 m g/ d L f or at least 8 0 % of t he ti me d uri n g M o nt h 9. 

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 T he pr o p orti o n of M o nt h 1 2 ( Wee ks 4 8, 5 0 a n d 5 2) res p o n ders, defi ne d as s u bjects 
ac hie vi n g a n d mai ntai ni n g s U A < 6 m g/ d L f or at least 8 0 % of t he ti me d uri n g M o nt h 1 2. 
 T he pr o p orti o n of M o nt h 9 ( Wee ks 3 2, 3 4 a n d 3 6) 5 m g/ d L res p o n d ers, defi ne d as 
s u bjects ac hie vi n g a n d m ai ntai ni n g s U A < 5 m g/ d L f or at least 8 0 % of t he ti me d uri n g 
M o nt h 9. 
 T he pr o p orti o n of M o nt h 1 2 ( Wee ks 4 8, 5 0 a n d 5 2) 5 m g/ d L res p o n ders, defi ne d as 
s u bjects ac hie vi n g a n d m ai ntai ni n g s U A < 5 m g/ d L f or at least 8 0 % of t he ti me d uri n g 
M o nt h 1 2. 
 T he ti me t o first s U A > 6 m g/ d L. 
 T he ti me t o t w o c o nsec uti ve s U As > 6 m g/ d L (st o p pi n g r ule). 
 T he mea n c h a n ge fr o m b aseli ne t o Wee ks 2 4, 3 6, a n d 5 2 i n urate v ol u me a n d b o ne 
er osi o ns d ue t o g o ut usi n g D E C T. 
 T he mea n c h a n ge fr o m b aseli ne i n n u m ber of j oi nts affect e d b y t o p hi 
 T he mea n c h a n ge fr o m b aseli ne t o Wee ks 1 4, 2 4, 3 6, a n d 5 2 i n te n der j oi nt c o u nt ( 6 8 
p oi nt scale). 
 T he mea n c h a n ge fr o m b aseli ne t o Wee ks 1 4, 2 4, 3 6, a n d 5 2 i n s w olle n j oi nt c o u nt ( 6 6 
p oi nt scale). 
 T he mea n c h a n ge fr o m b aseli ne t o Wee ks 1 4, 2 4, 3 6, a n d 5 2 i n H A Q- DI. 
 T he mea n c h a n ge fr o m b aseli ne t o Wee ks 1 4, 2 4, 3 6, a n d 5 2 i n H A Q p ai n sc ore. 
 T he mea n c h a n ge fr o m b aseli ne t o Wee ks 1 4, 2 4, 3 6, a n d 5 2 i n H A Q healt h sc ore. 
 T he mea n c h a n ge fr o m b aseli ne t o Wee ks 1 4, 2 4, 3 6, a n d 5 2 i n patie nt gl o b al assess me nt 
of g o ut. 
 T he mea n c h a n ge fr o m b aseli ne t o Wee ks 1 4, 2 4, 3 6, a n d 5 2 i n p h ysicia n gl o bal 
assess me nt of g o ut. 
 T he mea n c h a n ge fr o m b aseli ne t o Wee ks 1 4, 2 4, 3 6, a n d 5 2 i n s u bject assess me nt of 
a vera ge, least, a n d w orst j oi nt pai n. 
 T he pr o p orti o n of s u bjects ac hie vi n g 2 0 %, 5 0 %, or 7 0 % i m pr o ve me nt bas e d o n g o ut 
c hr o nic res p o nse criteria at Wee ks 1 4, 2 4, 3 6, a n d 5 2. 
9. 6. 1. 4  P h ar m a c o ki netic a n d A nti- dr u g A nti b o d y E n d p oi nts 
T he P K a n d a nti- dr u g a nti b o d y e n d p oi nts are:  
 P K of pe gl oticase i n s u bjects recei vi n g c o nc o mita nt M T X. 
 I n ci de nce of a nti- P E G a n d a nti- Uricas e I g G a nti b o dies. 
 
9. 6. 1. 5  S afet y a n d T oler a bilit y E n d p oi nts 
Safet y a n d t olera bilit y e n d p oi nts are: 

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 I n ci de nce of I Rs, a n a p h yla xis, g o ut flares, car di o v asc ular e ve nts, a n d t he A E/ S A E pr ofile 
o verall, a n d p ote ntiall y attri b ute d t o t he c o m bi nati o n of pe gl oticase a n d M T X. 
9. 6. 2  P o p ul ati o ns f or A n al ysis 
T he f oll o wi n g a nal ysis p o p ulati o ns will be defi ne d f or t his st u d y:  
 I nte nt-t o-treat (I T T) p o p ulati o n: all s u bjects w h o ta ke at least o ne d os e of M T X 
 M o difie d i nte nti o n-t o-treat ( mI T T) p o p ulati o n:  all s u bjects w h o recei ve at l east 1 d ose of 
pe gl otic ase 
 P har mac o ki netic ( P K) p o p ulati o n: all s u bjects w h o recei v e at least 1 d ose of pe gl oticase 
a n d ha ve a p ost- pe gl oticase sa m p le e val u a ble f or P K a nal ysis 
9. 6. 3  De m o gr a p hic V ari a bles 
De m o gra p hic d ata, i ncl u di n g a ge, race, a n d ge n der, me dical hist or y, a n d ot her diseas e 
c haracteristics, will be s u m marize d usi n g descri pti ve statistics. S u m maries of de m o gra p hic 
varia bles will be pr o vi de d f or t he I T T a n d mI T T p o p ulati o ns. Listi n gs will i ncl u de all scree ne d 
s u bjects. 
9. 6. 4  S u bject Dis p ositi o n 
T he n u m ber a n d p erce nta ge of s u bjects w h o c o m plete d t he st u d y a n d w h o disc o nti n ue d t he st u d y 
pre mat urel y al o n g wit h t he reas o ns f or disc o nti n u ati o n will be s u m marize d f or eac h a n al ysis 
p o p ulati o n. 
9. 6. 5  Effic ac y E n d p oi nt A n al ysis 
Efficac y a nal ys es will be perf or me d usi n g t he mI T T a n d I T T p o p ulati o ns. T here will be n o 
statistical testi n g. C o nti n u o us varia bles will be s u m marize d usi n g descri pti ve statistics ( n u m ber 
of s u bjects, mea n, me dia n, sta n dar d de viati o n, mi ni m u m, a n d ma xi m u m). Cate g orical varia bles 
will be s u m mariz e d usi n g fre q ue n cies a n d p erc e nta ges. U nless ot her wis e s pecifie d, bas eli ne is 
defi ne d as t he l ast n o n- missi n g o bser vati o n pri or t o t he first d ose of M T X. A d diti o nal details will 
be pr o vi de d i n t he S A P. 
9. 6. 5. 1  Pri m ar y a n d Sec o n d ar y E n d p oi nt A n al ysis 
T he pri mar y effic ac y e n d p oi nt is t he pr o p orti o n of res p o n ders d uri n g M o nt h 6. A res p o n der is 
defi ne d as a s u bject f or w h o m t he pr o p orti o n of ti me t hat t he s U A-ti me c ur ve is < 6 m g/ d L d uri n g 
M o nt h 6 ( Wee ks 2 0, 2 2, a n d 2 4) is at least 8 0 %. T he pr o p orti o n of ti me t hat t he s U A le vel is 
bel o w 6 m g/ d L is defi n e d as t he rati o of t he ti me d uri n g w hi c h t he s U A le vel re mai ns bel o w 
6 m g/ d L ( usi n g li near i nt er p olati o n, if necessar y) t o t he e ntire ti me i nter val d uri n g M o nt h 6. T he 
pr o p orti o n of res p o n d ers will be s u m marize d, al o n g wit h a 9 5 % e x act ( Cl o p per- Pears o n) 
c o nfi de nce i nter val f or t h e pr o p orti o n. T he pr o p or ti o n of M o nt h 3, o verall ( M o nt hs 3 a n d M o nt h 
6 c o m bi ne d), a n d 5 m g/ d L res p o n ders ( d uri n g M o nt h 3, M o nt h 6, a n d o verall) will be 
s u m marize d si milarl y. 

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A s u bject will be declare d a n o n-res p o n d er if t he s u bject ha d s U A le vel > 6 m g/ d L at 
2 c o nsec uti ve st u d y visits be gi n ni n g wit h t he Wee k 2 Visit. I n a d diti o n, a s u bject w h o wit h dra ws 
fr o m t he st u d y f or a n y reas o n ( ot her t ha n st o p pi n g r ule) aft er t he first d ose of pe gl oticase i n t he 
pe gl otic ase + I M M Peri o d a n d pri or t o or d uri n g M o nt h 6 (f or t he pri mar y e n d p oi nt) or M o nt hs 3 
or 6 (f or t he s ec o n d ar y e n d p oi nts) will be c o nsi dere d a n o n-res p o n der if s U A val ues are n ot 
c ollecte d at pla n n e d ti me p oi nts. 
s U A will be s u m marize d at eac h visit a n d c h a n ge fr o m baseli ne t o eac h visit wit h descri pti ve 
statistics. 
9. 6. 5. 2  E x pl or at or y E n d p oi nt A n al ysis 
S w olle n/te n der j oi nt c o u nts, H A Q sc ores, p atie nt a n d p h ysi cia n gl o bal assess me nt sc ores, a n d 
s u bject assess me nt of j oi nt pai n sc ores will be s u m marize d at eac h visit al o n g wit h c h a n ges fr o m 
baseli ne usi n g d escri pti v e statistics.   
T he pr o p orti o n of s u bjects ac hie vi n g 2 0 %, 5 0 %, or 7 0 % i m pr o ve me nt bas e d o n g o ut c hr o nic 
res p o nse criteria will be calc ulate d b ase d o n i m pr o ve me nt i n eac h of t he c o m p o ne nts a n d 
s u m marize d at W ee ks 1 4, 2 4, 3 6 a n d 5 2. T he pr o p orti o n of res p o n ders at M o nt h 9 a n d M o nt h 1 2 
will be s u m mariz e d i n a si milar ma n ner as t he pri mar y a n d sec o n dar y res p o n der e n d p oi nts. 
F or s u bjects wit h D E C T sca ns, t he urat e v ol u me a n d b o ne er osi o n d ue t o g o ut at eac h visit a n d 
c ha n ges fr o m baseli ne will be s u m marize d usi n g descri pti ve statistics. 
9. 6. 6  P h ar m a c o ki netic a n d A nti- dr u g A nti b o d y A n al ysis 
C o nce ntrati o ns of pe gl oti case a n d M T X p ol y g l uta mate (as a p pr o priate) will be s u m marize d 
usi n g descri pti ve statistics f or t he P K p o p ulati o n. Details will be pr o vi de d i n a se parate P K 
a nal ysis pla n. 
I n ci de nce of a nti- dr u g a nti b o dies a n d titer le vels will be s u m marize d. 
9. 6. 7  S afet y A n al ysis 
Treat me nt- e mer ge nt A Es ( T E A Es) d uri n g t he R u n-I n peri o d are d efi ne d as e ve nts wit h a n o nset 
date o n or after t he first d ose of M T X t hr o u g h t he first pe gl oticase i nf usi o n, or 3 0 da ys aft er t he 
last d ose of M T X f or s u bjects w h o d o n ot recei ve pe gl oticase. T E A Es d uri n g t he Pe gl oticas e + 
I M M Peri o d are d efi ne d as e ve nts t hat occ ur after t he start of t he first pe gl oticase i nf usi o n 
t hr o u g h 3 0 d a ys after t he last d ose of pe gl oticase a n d/ or M T X ( w hic he ver is later). T E A Es 
d uri n g t he M T X R u n-i n Peri o d will be s u m mar ize d wit h t he I T T p o p ulati o n, a n d T E A Es d uri n g 
t he Pe gl oticas e + I M M P eri o d will be s u m marize d wit h b ot h t he I T T a n d mI T T p o p ul ati o ns. 
T E A Es d uri n g a n y peri o d ( M T X R u n-i n Peri o d or Pe gl oticas e + I M M Peri o d) will be 
s u m marize d f or t he mI T T p o p ulati o n. A Es t hat occ ur m ore t ha n 3 0 da ys after t he last d ose of 
pe gl otic ase a n d/ or M T X t hr o u g h t he 6 m o nt h f oll o w- u p visit will als o be s u m marize d. T he 
n u m ber a n d perce nt a ge of s u bjects e x perie nci n g A Es will be s u m marize d b y s yste m or ga n class 
a n d preferre d ter m. S u m maries b y ma xi m u m se ve rit y a n d rel ati o ns hi p t o M T X a n d pe gl oticase 

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will als o be pr o vi de d. S A Es a n d A Es lea di n g t o disc o nti n uati o n of M T X a n d pe gl oticase will be 
prese nte d b y s yste m or ga n class a n d preferre d ter m. 
I n ci de nce of I Rs, g o ut flares, a n d ot her A Es of s pecial i nterest will be s u m marize d.  
La b orat or y test r es ults, i ncl u di n g uri ne uric aci d :creati ni ne rati o, will be s u m marize d b y st u d y 
visit a n d c ha n ge fr o m b aseli ne. S hift ta bles f or la b orat or y para meters b y C o m m o n Ter mi n ol o g y 
Criteria f or A d v erse E v e nts gra d e will be pres e nte d. La b orat or y test res ults will als o be classifie d 
relati ve t o t he n or mal refere nce ra n ge ( n or mal, l o w, or hi g h). 
Vital si g ns, i ncl u di n g bl o o d press ure, res pirat or y rate, te m perat ure, a n d h eart rate, will be 
s u m marize d b y st u d y visit a n d c ha n ge fr o m baseli ne.  
Pri or a n d c o nc o mita nt m e dicati o ns will be s u m marize d a n d/ or i ncl u de d i n t he data listi n gs. 
Data f or t h e M T X R u n-i n Peri o d a n d Pe gl oticase + I M M Peri o d will be s u m marize d se paratel y, 
w here a p plica ble. 
9. 6. 8  I nteri m A n al yses 
N o f or mal i nteri m a nal ysis is pla n ne d f or t h is st u d y. Efficac y a n d safet y dat a ma y be 
s u m marize d after all s u bj ects e nr olle d i n t he st u d y ha ve c o m plete d t h e Wee k 1 4 visit or 
disc o nti n ue d, a n d after all s u bjects ha ve c o m plete d Wee k 2 4 or disc o nti n ue d. A d diti o nal 
s u m mar y of t he data ma y be perf or me d peri o dicall y t hr o u g h o ut t he st u d y, a n d safet y data will be 
s u m marize d re g ul arl y f or safet y m o nit ori n g. Fi nal a nal ysis will occ ur w he n all s u bjects ha ve 
c o m plete d t he st u d y.   
9. 6. 9  S a m ple Size a n d P o w er C o nsi der ati o ns 
A sa m ple siz e of a p pr o xi matel y 1 2- 1 6 s u bj ects is pla n ne d f or t his st u d y. T he pri mar y efficac y 
e n d p oi nt, t he pr o p orti o n of s u bjects ac hie vi n g a n d mai ntai ni n g s U A < 6 m g/ d L f or at least 
8 0 % of t he ti me d uri n g M o nt h 6 ( Wee ks 2 0, 2 2, a n d 2 4) of t he Pe gl oticas e + I M M Peri o d, will 
be de m o nstrate d t o be statisticall y great er t ha n 4 3. 5 % ( pr o p orti o n of res p o n ders d uri n g M o nt h 6 
i n p hase 3 st u dies), acc or di n g t o a n e x act test f or pr o p orti o ns wit h a 5 % t y p e I err or, if at least 
1 0/ 1 3 ( 7 7 %) res p o n d ers are o bser ve d; i n t hat cas e, t he l o wer b o u n d of a 9 5 % c o nfi de n ce i nter val 
f or t he pr o p orti o n of res p o n ders will be a b o ut 4 6 %.  
9. 7  
C h a n ges i n t he C o n d uct of t he St u d y 
If a n y m o dificati o ns i n t h e e x peri me ntal desi gn, d osa ges, para meters, s u bject selecti o n, or a n y 
ot her secti o ns of t he pr ot oc ol are i n dicate d or re q uire d, t he I n vesti gat or will c o ns ult wit h t he 
S p o ns or bef ore a n y s uc h c ha n ges are i nstit ute d. M o dificati o ns will be acc o m plis he d t hr o u g h 
f or mal a me n d me nts t o t his pr ot oc ol b y t he S p o ns or a n d a p pr o ve d fr o m t he a p pr o priate I R B. 
T he S p o ns or’s Me dical M o nit or will c o nsi der a n y re q uests f or e x ce pti o ns t o pr ot oc ol e ntr y 
criteria o n a cas e- b y- case basis. T he I n vesti gat or or ot her healt h pr ofessi o nal i n atte n da nce m ust 
c o ntact t he S p o ns or as s o o n as p ossi ble. All pr ot oc ol de viati o ns a n d t he reas o ns f or s uc h 

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de viati o ns m ust  b e d oc u me nte d i n t he e C R F. I n t he e ve nt of a maj or pr ot o c ol de viati o n, t he 
I n v esti gat or a n d S p o ns or’s Me dical M o nit or will deter mi ne w het h er t he s u bject s h o ul d c o nti n ue 
t o partici pate i n t he st u d y. 
T he S p o ns or has a le gal r es p o nsi bilit y t o r e p ort f ull y t o re g ulat or y a ut h orities all res ults of 
a d mi nistrati o n of i n vesti gati o nal dr u gs t o h u ma ns.  N o i n vesti gati o nal pr o ce d ures ot her t h a n t h ose 
descri be d i n t his pr ot oc ol will be u n derta ke n o n t h e e nr olle d s u bjects wit h o ut t he a gree m e nt of 
t he I R B a n d S p o ns or. 
1 0  S O U R C E D O C U M E N T A TI O N A N D I N V E S TI G A T O R FI L E S 
T he I n vesti gat or m ust mai ntai n a de q uate a n d acc urate rec or ds t o d oc u m e nt f ull y t he c o n d u ct of 
t he st u d y a n d t o e ns ure t hat st u d y data ca n b e s u bse q ue ntl y v erifie d. T h ese d oc u me nts s h o ul d be 
classifie d i n 2 se parate cate g ori es: ( 1) I n v esti gat or st u d y file a n d ( 2) s u bject cli nical s o urce 
d oc u me nts t hat c orr o b orate data c ollect e d i n t h e e C R Fs. S u bject cli nical s o urce d oc u m e nts 
w o ul d i ncl u de, as a p plica ble, ori gi nal h os pital/cli n ic s u bject rec or ds; p h ysi cia ns’ a n d n urses’ 
n otes; a p p oi nt me nt b o o k; ori gi nal la b orat or y, E C G, electr oe n ce p h al o gra m, r a di ol o g y, pat h ol o g y, 
a n d s pecial ass ess me nt re p orts; dis pe nsi n g rec or ds; si g ne d I C Fs; c o ns ulta nt letters; a n d s u bject 
scree ni n g a n d e nr oll me nt l o gs. 
I n or der t o c o m pl y wit h r e g ul at or y re q uir e me nts, it is t he p olic y of t he S p o ns or t hat, at a 
mi ni m u m, t he f oll o wi n g be d oc u me nte d i n s o urce d oc u me nts at t he st u d y ce nter: 
 Me dical hist or y/ p h ysic al c o n diti o n a n d dia g n osis of t he s u bject bef ore i n v ol ve me nt i n t he 
st u d y s uffici e nt t o verif y t hat t he s u bject meets pr ot oc ol e ntr y criteri a.  
 St u d y n u m b er, assi g ne d s u bject n u m ber, a n d v erifi cati o n t hat writte n i nf or me d c o nse nt 
was o btai ne d (eac h rec or de d i n d ate d a n d si g ne d pr o gress n otes). 
 Pr o gress n otes f or eac h s u bject visit (eac h d ate d a n d si g ne d). 
 Rec or ds of eac h st u d y visit i ncl u di n g eac h st u d y assess me nt a n d t he i de ntit y of t he st aff 
me m ber perf or mi n g t he assess me nt. 
 St u d y dr u g dis pe nsi n g a n d ret ur n. 
 Re vie w b y t he I n vesti gat or or q ualifie d pe rs o n nel o n t he 1 5 7 2 of la b orat or y test res ults. 
 A Es (start a n d st o p date, descri p ti o n, acti o n ta ke n, a n d res ol uti o n). 
 I n v esti gat or or s u b-i n vesti gat or’s si g n e d assess me nt of A Es. 
 C o nc o mita nt me dicati o ns (start a n d st o p dates, reas o n f or use). 
 C o n diti o n of s u bject u p o n c o m pleti o n of, or pre m at ure wit h dra wal fr o m, t h e st u d y. 
1 1  C A S E R E P O R T F O R M S 
A n e C R F is re q uir e d f or e ver y s u bject w h o si g ns t he I C F. Re q uir e d data m ust be e ntere d o n t h e 
e C R F wit hi n t he re q uire d ti me peri o d, w hic h will be o utli ne d wit hi n eac h site a gree m e nt, after 
data c ollecti o n or t he a vaila bilit y of t est res ult s. Se parate s o urce rec or ds are re q uire d t o s u p p ort 
all e C R F e ntries. D ata ca pt ure d o n t he e C R F, a n d re q ueste d a n o n y mize d c o pies of s u p p orti n g 
d oc u me nts, will be tra nsf erre d t o t he S p o ns or at st u d y c o m pleti o n. 

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T he I n vesti gat or will e ns ure t hat t he e C R Fs are ac c urate, c o m plete, le gi ble, a n d ti mel y, a n d will 
re vie w a n d pr o vi de a n el ectr o nic si g nat ur e f or t he e C R F acc or di n g t o t he sta n dar d o perati n g 
pr oce d ure of t he Data M a na ge me nt S yste m. Fi nal e C R Fs will be pr o vi de d t o t he I n v esti gat or a n d 
S p o ns or b y Dat a Ma na ge me nt. 
1 2  S T U D Y M O NI T O RI N G 
T he I n vesti gat or will e ns ure t hat t he st u d y is c o n d ucte d i n acc or da n ce wit h all re g ulati o ns 
g o ver ni n g t he pr ote cti o n of h u ma n s u bjects. T he I n vesti gat or will a d here t o t he basic pri nci ples 
of G C P as o utli ne d i n Title 2 1 of t he C F R, Part 3 1 2, S u b part D, “ Res p o nsi bilities of S p o ns ors 
a n d I n vesti gat ors,” 2 1 C F R, Part 5 0, “ Pr ot ecti o n of H u ma n S u bjects”; 2 1 C F R, Part 5 6, 
“I nstit uti o nal Re vie w B o ar ds”; 2 1 C F R, Part 5 4 “ Fi na ncial Discl os ur e b y Cli nical I n vesti gat ors ”; 
a n d t he I C H g ui deli ne e ntitle d “ G o o d Cli nical Practice: C o ns oli date d G ui da nce. ” A d diti o nall y, 
t his st u d y will be c o n d ucte d i n c o m plia nce wit h t he Decl arati o n of Helsi n ki a n d wit h all l ocal 
la ws a n d re g ul ati o ns. 
T he I n vesti gat or will e ns ure t hat all w or k a n d ser vices descri b e d i n, or ass o ciate d wit h, t his 
pr ot oc ol are c o n d ucte d i n acc or da nce wit h t he i n vesti gati o nal pla n, a p plica ble re g ulati o ns, a n d 
t he hi g hest sta n d ar ds of me dical a n d cli nical researc h practice. T he I n v esti gat or will pr o vi de 
c o pies of t he st u d y pr ot o c ol a n d I n v esti gat or’s Br oc h ure t o all S u b -I n vesti gat ors, p h ar macists, 
a n d ot her staff res p o nsi bl e f or st u d y c o n d u ct. 
All as pects of t he st u d y will be m o nit ore d b y q ualifie d i n di vi d uals desi g nate d b y t he S p o ns or. 
T he S p o ns or will e ns ure t hat t he st u d y is m o nit ore d a d e q uatel y i n acc or da n ce wit h G C P 
g ui deli nes. 
Pri or t o i nitiati o n of t he st u d y, t he S p o ns or’s re prese ntati ves will re vie w wit h st u d y ce nter 
pers o n nel i nf or mati o n r e gar di n g t h e i n vesti gati o nal dr u g, pr ot oc ol re q uire me nts, m o nit ori n g 
re q uire me nts, a n d re p orti n g of S A Es. 
At i nter vals d uri n g t h e st u d y, as well as after t he c o m pleti o n of s u bject e nr oll me nt, t he st u d y 
ce nter will be m o nit ore d b y t he S p o ns or or d esi g n ee f or c o m plia nce. D uri n g t hese visits, t he 
m o nit or will disc uss st u d y pr o gress, verif y a d he re nce t o t he pr ot oc ol a n d t h e c o m plete ness, 
c o nsiste nc y, a n d acc urac y of t he d ata bei n g e ntere d o n t he e C R F (s o urce data verificati o n); 
o versee t h e res ol uti o n of o utsta n di n g data discre pa ncies, a n d c h ec k o n vari o us as pects of st u d y 
c o n d uct (e. g., dr u g acc o u nta bilit y, s a m ple st ora ge). T he I n vesti gat or a grees t o all o w m o nit ors 
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 cli nical r ec or ds of t he st u d y 
s u bjects, a n d, if re q u este d, a grees t o assist t he m o nit ors. T he I n vesti gat or m ust c o o perate wit h 
t he m o nit ors t o e ns ure t hat a n y pr o ble ms detecte d i n t he c o urse of t hes e m o nit ori n g visits are 
res ol ve d. 
A sec o n dar y a u dit ma y b e c o n d ucte d b y Q ual it y Ass ura nce desi g nate d b y t he S p o ns or. T he 
I n v esti gat or will be i nf or me d if t his is t o ta ke place a n d a d vise d as t o t he nat ure of t he a u dit. 
Re prese ntati ves of t h e U nite d States F D A a n d/ or re pres e ntati ves of ot her re g ul at or y a ut h orities 
ma y als o c o n d uct a n i ns p ecti o n of t he st u d y at t he i n vesti gati ve site. If i nf or me d of s uc h a n 
i ns pecti o n, t he I n vesti gat or s h o ul d n otif y t he S p o ns or i m me diatel y. 

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E ver y eff ort will be ma d e t o mai ntai n t he a n o n y mit y a n d c o nfi de ntialit y of s u bjects partici pati n g 
i n t his cli nical st u d y. H o we ver, beca us e of t he i n v esti gati o nal nat ure of t his treat me nt, t he 
I n v esti gat or a grees t o all o w re prese ntati ves of t he S p o ns or, its desi g nate d a ge nts, a n d a ut h orize d 
e m pl o yees of t he a p pr o priate re g ulat or y a ge nci es t o i ns pect t he facilities use d i n t his st u d y a n d t o 
ha ve direct access t o i ns pect, f or p ur p os es of veri fi cati o n, t he h os pital or cli nic al rec or ds of all 
s u bjects e nr olle d i n t his st u d y. A state me nt t o t his effect s h o ul d be i ncl u de d i n t he I C F. 
1 3  D A T A M A N A G E M E N T 
Data will be e ntere d i nt o a cli nical data b ase, as s p ecifie d i n t he Data Ma n a ge m e nt Pla n. Q ualit y 
c o ntr ol a n d data v ali dati o n pr oce d ures will be a p pl ie d t o e ns ure t he vali dit y a n d acc urac y of t he 
cli nical data bas e. Data will be re vie we d a n d c hec k e d f or o missi o ns, a p pare nt err ors, a n d v al ues 
re q uiri n g f urt her clarificati o n usi n g c o m p uterize d a n d ma n ual pr oce d ures. Data q ueri es re q uiri n g 
clarificati o n will be c o m m u nicate d t o t he i n vest i gati o nal site f or res ol uti o n. O nl y a ut h orize d 
pers o n nel will ma ke c orrecti o ns t o t he cli nical da t a base, a n d all c orrectio ns will be d oc u me nte d 
i n a n a u dit trail. 
T he c o di n g of a n A E, me dical hist or y a n d c o nc o m ita nt me dicati o n ter ms will be perf or me d b y 
t he S p o ns or or desi g n ate d ve n d or a n d re vie we d a n d a p pr o ve d b y t he S p o ns or. C o nc o mita nt 
me dicati o ns will be c o de d usi n g t he W orl d He alt h Or ga nizati o n Dr u g Dicti o nar y ( W H O Dr u g) 
a n d A E/ me dical hist or y/s ur ger y/ n o n dr u g t hera p y ter ms will be c o de d usi n g t he Me dical 
Dicti o nar y f or Re g ul at or y A cti vities ( Me d D R A). 
1 4  R E T E N TI O N O F R E C O R D S 
N o st u d y d oc u m e nts at t he st u d y site s h o ul d be  destr o ye d wit h o ut pri or writte n a gree me nt 
bet wee n t he S p o ns or a n d t he I n v esti gat or. Al l s u bjects’ me dical rec or ds, t he I n v esti gat or’s c o p y 
of t he e C R F, ot her s u p p orti n g data, rec or ds of dr u g dis pe nsi n g a n d acc o u nt a bilit y, si g n e d I C Fs, 
I R B c orres p o n de n ce, a n d c orres p o n d e nce wit h t he S p o ns or m ust be ke pt b y t he I n v esti gat or f or 
at least 2 years a n d/ or as re q uire d b y t he l o cal la w f oll o wi n g t he dat e of t he last a p pr o val of a 
mar keti n g a p plicati o n i n a n I C H re gi o n (i n cl u di n g t he U nite d States) a n d u ntil 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 a n y ot h er I C H re gi o n. If a n a p plicati o n is n ot 
file d or n ot a p pr o ve d f or t he i n dicati o n u n der st u d y, all st u d y-relate d files m ust be retai ne d f or at 
least 2 years a n d f or a peri o d i n c o m plia nce wit h all fe deral, state, a n d l ocal re g ulati o ns. T he 
S p o ns or m ust be n otifie d pri or t o t he dis p osal of a n y st u d y-relate d files. If t he I n vesti gat or lea ves 
t he practice or i nstit uti o n d uri n g t he re q uire d rete nti o n peri o d, it is i m p orta nt t hat arra n ge me nts 
be ma de f or c o nti n ue d rec or d ret e nti o n. I n t h at e ve nt, t he rec or ds ge nerall y will be retai ne d at t he 
i nstit uti o n at w hic h t he st u d y w as c o n d uct e d. 
1 5  P U B LI C A TI O N 
T o a v oi d discl os ures t hat c o ul d je o par dize pr o prietar y ri g hts, t he i nstit uti o n a n d/ or t he 
I n v esti gat or a gree t o c ert ai n restricti o ns o n p u blicati o ns (e. g., a bstracts, s peec h es, p osters, 
ma n uscri pts, a n d ele ctr o nic c o m m u nicati o ns), as detaile d i n t he Cli nical Trial A gree me nt. 

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1 6  R E F E R E N C E S 
B ur mester G R, Ki vitz AJ, K u p per H, et al.  Ef ficac y a n d safet y of as ce n di n g met h otre x ate d ose 
i n c o m bi nati o n wit h a dali m u ma b: t he ra n d o mise d C O N C E R T O trial. A n n R he u m Dis. 2 0 1 5 
J u n; 7 4( 6): 1 0 3 7- 4 4 
Br o o k R A, F ors yt he A, S mee di n g J E, La wre nce E d war ds N. C hr o nic g o ut: e pi de mi ol o g y, 
disease pr o gressi o n, treat me nt a n d disease b ur de n. C urr Me d Res O pi n. 2 0 1 0; 2 6( 1 2): 2 8 1 3 -2 1. 
Br uce B, Fri es J F. T he Sta nf or d Healt h Assess m e nt Q uesti o n naire: di me nsi o ns a n d practical 
a p plicati o ns. Healt h Q ual Lif e O utc o mes. 2 0 0 3; 1: 2 0. 
F o o d a n d Dr u g A d mi nistrati o n. Ce nter f or Dr u g E val uati o n a n d Researc h, Di visi o n of 
A nest hesia, A nal gesia, a n d R he u mat ol o g y Pr o d ucts. A A C Briefi n g D oc u m e nt K R Y S T E X X A 
( Pe gl oticas e). 2 0 0 9. 
htt p:// w w w.f da. g o v/ d o w nl oa ds/ A d vis or y C o m mittees/ C o m mittees Meeti n g Materials/ Dr u gs/ Art hri
tis Dr u gs A d vis or y C o m mittee/ U C M 1 6 5 7 1 4. p df. [ Accesse d 2 0 1 8 M a y 3 1]. 
Gaff o A L, Sc h u mac h er R H, Saa g K G, et al. De v el o pi n g a pr o visi o nal defi niti o n of flare i n 
patie nts wit h esta blis he d g o ut. Art hritis R he u m. 2 0 1 2; 6 5( 5): 1 5 0 8- 1 7. 
K ha n na D et al. 2 0 1 2 A C R g ui deli nes f or m a na ge me nt of g o ut; part 2. A C R V ol 6 4, N o 1 0, Oct 
2 0 1 2, p 1 4 4 7- 1 4 6 1. 
K ha n na P, K ha n n a D, St or gar d C, Ba u m gart ner S, M orl oc k R. A w orl d of h urt: fail ure t o ac hi e ve 
treat me nt g oals i n patie nts wit h g o ut re q uir es a para di g m s hift. P ost gra d Me d. 
2 0 1 6; 1 2 8( 1): 3 4 -4 0. 
Mi k uls T R, Farrar J T, Bil ker W B, Fer na n d es S, Sc h u mac her H R, Saa g K G. G o ut e pi de mi ol o g y: 
res ults fr o m t he U K G e n eral Practice Researc h Data base, 1 9 9 0 1 9 9 9. A n n R he u m Dis. 
2 0 0 5; 6 4( 2): 2 6 7 -7 2. 
R o d d y E, D o hert y M. E pi de mi ol o g y of g o ut. Art hritis Res T her. 2 0 1 0; 1 2( 6): 2 2 3. 
Saa g K G, C h oi H. E pi de mi ol o g y, ris k fact ors, a n d lifest yle m o dificati o ns f or g o ut. Art hritis Res 
T her. 2 0 0 6; 8 S u p pl 1: S 2. 
Sa m ps o n H A, M u ñ oz- F url o n g A, Ca m p b ell R L, et al. Sec o n d s y m p osi u m o n t he defi niti o n a n d 
ma na ge me nt of a na p h yla xis: s u m mar y re p ort – sec o n d Nati o nal I nstit ute of Aller g y a n d I nfecti o us 
Disease/ F o o d Aller g y a n d A na p h yl a xis Net w or k s y m p osi u m. J Aller g y Cli n I m m u n ol. 
2 0 0 6; 1 1 7( 2): 3 9 1- 7. 
Satt ui S E, Si n g h J A, Gaff o A L. C o m or bi dities i n patie nts wit h cr yst al diseases a n d 
h y per uric e mia. R he u m Dis Cli n N ort h A m. 2 0 1 4; 4 0( 2): 2 5 1 -7 8. 

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Sc helle ke ns H. Fact ors i nfl ue nci n g t he i m m u n o ge nicit y of t hera pe utic pr otei ns. Ne p hr ol Dial 
Tra ns pla nt. 2 0 0 5; 2 0 S u p pl 6: vi 3 -9. 
Si n g h J A, Stra n d V. G o ut is ass ociate d wit h m ore c o m or bi dities, p o orer healt h relate d q ualit y of 
life a n d hi g h er healt hcare utilisati o n i n U S vetera ns. A n n R he u m Dis. 2 0 0 8; 6 7( 9): 1 3 1 0-6. 
Stra n d V, Bals a A, Al- Sale h J, et al. I m m u n o ge nicit y of bi ol o gi cs i n c hr o ni c i nfla m mat or y 
diseases: a s yste matic re vie w. Bi o Dr u gs. 2 0 1 7: 3 1( 4): 2 9 9- 3 1 6. 
S u n d y J S, Baraf H S, Y o o d R A, et al. Efficac y a n d t olera bilit y of pe gl oticase f or t he treat me nt of 
c hr o nic g o ut i n patie nts r efract or y t o c o n ve nti o nal treat me nt: t w o ra n d o mize d c o ntr olle d trials. 
J A M A. 2 0 1 1; 3 0 6( 7): 7 1 1-2 0. 
Wert hei mer A, M orl oc k R, Bec k er A. A re vise d esti mate of t he b ur de n of ill ness of g o ut. C urr 
T her Res Cli n E x p. 2 0 1 3; 7 5: 1 -4. 
W o o d w ort h T, F urst D E, Alte n R, et al. Sta n dar di zi n g assess me nt a n d re p orti n g of a d verse 
effects i n r he u mat ol o g y cli nical trials II: t he R h e u mat ol o g y C o m m o n T o xicit y Criteria v 2. 0. 
J R he u mat ol. 2 0 0 7; 3 4( 6): 1 4 0 1- 1 4. 
Z h u Y, Pa n d ya BJ, C h oi H K. Pre vale n ce of g o ut a n d h y per urice mia i n t he U S ge n eral 
p o p ulati o n: t he Nati o nal Healt h a n d N utriti o n E x a mi nati o n S ur ve y 2 0 0 7 -2 0 0 8. Art hritis R he u m. 
2 0 1 1; 6 3( 1 0): 3 1 3 6 -4 1. 
 

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1 7. 6   S u bject- F aci n g  Di a gr a m