Clinical trial NCT03635957
Conditions: Gout
Keywords: gout uncontrolled gout
Sponsor: Amgen
Start date: 2018-09-26; Completion date: 2020-10-26
Enrollment: 14 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The overall objective of the study is to assess the efficacy, safety, tolerability, and pharmacokinetics (PK) of the concomitant use of pegloticase with methotrexate (MTX) to enhance the response rate seen with pegloticase alone in adults with uncontrolled gout.

Detailed description:
The study design will include: 1) up to a 2-week Screening Period (screening should be complete within 2 weeks prior to Week -4), 2) a 4-week MTX Run in Period (Week - 4 through Day 1); 3) a 52-week Pegloticase + IMM (immunomodulator), (Pegloticase + MTX) Period 4) a Safety Follow-up (Phone/Email/Site Visit) and 5) a 3 and 6 month Post Treatment Follow-up.

Study acquired from Horizon in 2024.

Arms: arm 1: Run-In Period: oral MTX at a dose of 15 mg weekly for 4 weeks prior to the first dose of pegloticase.

Pegloticase + Immunomodulator (IMM) Period: pegloticase 8 mg administered intravenously (IV) every 2 weeks from Day 1 through the Week 50 Visit for a total of 26 infusions. MTX 15 mg weekly on the same day each week, within 1 to 3 days prior to each pegloticase infusion and one additional weekly dose after the last infusion.
Interventions: intervention 1: Pegloticase intervention 2: Methotrexate (MTX) intervention 3: Standard Gout Flare Prophylaxis intervention 4: Infusion Reaction (IR) Prophylaxis intervention 5: Folic Acid
Intervention descriptions: intervention 1: pegloticase administered intravenously (IV) intervention 2: oral MTX intervention 3: It is required that before a subject begins the Pegloticase + IMM Period, he or she has been taking at least one protocol standard gout flare prophylaxis regimen (i.e. colchicine and/or nonsteroidal anti-inflammatory drugs and/or low-dose prednisone ≤10 mg/day) for ≥1 week before the first dose of pegloticase and continues flare prophylaxis per American College of Rheumatology guidelines \[Khanna D et al.2012\] for the greater of 1) 6 months, 2) 3 months after achieving target serum urate (sUA \< 6 mg/dL) for patients with no tophi detected on physical exam, or 3) 6 months after achieving target serum urate (sUA \< 5 mg/dL) for patients with one or more tophi detected on initial physical exam that have since resolved. intervention 4: For IR prophylaxis, fexofenadine (60 mg or 180 mg orally based on the Principal Investigator's discretion) will be taken the day before each infusion; fexofenadine (60 mg or 180 mg orally based on the Principal Investigator's discretion) and acetaminophen (1000 mg orally) will be taken the morning of each infusion; and methylprednisolone (125 mg IV) given over the infusion duration 10-30 minutes (recommended) or hydrocortisone (200 mg IV) will be administered immediately prior to each infusion. intervention 5: Subjects will also take folic acid 1 mg orally every day beginning at Week -4 (the start of MTX) and continuing until prior to the Week 52 Visit.

Protocol documents:
Prot_000.pdf: 
 
 
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 


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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 
 






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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 
 
 
 
 


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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 
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                                  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 
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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. 


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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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3  
T A B L E O F C O N T E N T S 
1  
TI T L E P A G E .................................................................................................................... ...... 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 4  Wee k 4 2 .................................................................................................. 1 0 4  
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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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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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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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 
t he a p pr o priat e e C R F. 
 
 
 
 
 


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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 ). 


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 0
 
of
 
1 2 9
 
 
 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
 
of
 
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
 8 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 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
 
of
 
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
 
of
 
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
 
 
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 7
 
of
 
1 2 9
 
 
 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
 
 
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 8
 
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 
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 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
 
 
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 1
 
of
 
1 2 9
 
 
 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
 
 
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 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. 
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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. 
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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. 
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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. 
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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 
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2 0 1 1; 6 3( 1 0): 3 1 3 6 -4 1. 
 




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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 
 
 
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 2 5
 
of
 
1 2 9
 
 
 


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 2 6
 
of
 
1 2 9
 
 
1 7. 3  P ati e nt Gl o b al Assess me nt 
 


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 2 7
 
of
 
1 2 9
 
 
1 7. 4   P h ysici a n Gl o b al Assess me nt 
 


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 2 8
 
of
 
1 2 9
 
 
1 7. 5   J oi nt P ai n Assess me nt 
 


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 2 9
 
of
 
1 2 9
 
 
1 7. 6   S u bject- F aci n g  Di a gr a m 
 
 

SAP_001.pdf: 
 
 
Study: HZNP-KRY-201 
NCT#: 03635957 
TITLE: 
SAP 
Protocol Title: 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: 
 
SAP: 10 July 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
150 S. Saunders Road, Lake Forest, IL 60045 


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  V er si o n  2. 0  1 0- J ul- 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  1   of 8 4  
St a ti sti c al  A n al y si s  Pl a n  
 
S p o n s or  N a m e:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C  
 
Pr ot o c ol  N u m b er:  H Z N P -K R Y -2 0 1  
Pr ot o c ol  Titl e:  A  M ulti c e nt er,  Effi c a c y  a n d  S af et y  St u d y  of  M et h otr e x at e t o  I n cr e a s e 
R e s p o n s e  R at e s i n  P ati e nt s  wit h  U n c o ntr oll e d  G o ut  R e c ei vi n g  K R Y S T E X X A ® 
( p e gl oti c a s e) ( MI R R O R O p e n -L a b el  [ O L]) 
 
Pr ot o c ol  V er si o n  a n d  D at e:   V er si o n  3 . 0  A m e n d m e nt 2  (1 7 A pr 2 0 1 9)  
 
 
 
A ut h or s: 
 
 
S A P  V er si o n:  2. 0  
 
S A P  V er si o n  D at e:  1 0- J u l-2 0 2 0  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N oti c e  of  C o nfi d e nti al  a n d  Pr o pri et ar y I nf or m ati o n:  
T h e i nf or m ati o n  c o nt ai n e d i n t hi s  d o c u m e nt i s  c o nfi d e nti al  b el o n gi n g t o  H ori z o n  T h er a p e uti c s 
Ir el a n d  D A C. A c c e pt a n c e  of t hi s  d o c u m e nt  c o n stit ut e s  a gr e e m e nt  b y t h e r e ci pi e nt t h at  n o 
i nf or m ati o n  c o nt ai n e d  h er ei n  will  b e  p u bli s h e d  or  di s cl o s e d  wit h o ut  pri or  writt e n  a ut h ori z ati o n 
fr o m  a n  offi ci al  of H ori z o n  T h er a p e uti c s Ir el a n d  D A C . H o w e v er, t hi s  d o c u m e nt  m a y  b e  d i s cl o s e d 
t o  a p pr o pri at e I n stit uti o n al  R e vi e w  B o ar d  a n d  Et hi c s  C o m mitt e e s  or  d ul y  a ut h ori z e d 
r e pr e s e nt ati v e s  of  a  n ati o n al r e g ul at or y  a ut h orit y  u n d er t h e  c o n diti o n t h at t h e y  ar e r e q u e st e d t o 
k e e p it  c o nfi d e nti al. I n t h e  e v e nt  of  a n  a ct u al  or  s u s p e ct e d  br e a c h  of t hi s  o bli g ati o n,   
 
s h o ul d  b e  n otifi e d  pr o m ptl y.  






St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  4   of 8 4  
I  c o nfir m t h at I  h a v e r e vi e w e d t hi s  d o c u m e nt  a n d  a gr e e  wit h t h e  c o nt e nt. 
A p pr o v al s  
 
  
M a n a g er  of  Bi o st ati sti c s  
  
 
 
 
N a m e,  Titl e  
L e a d  Bi o st ati sti ci a n  
  
Si g n at ur e  
  
D at e ( D D -M m m -
Y Y Y Y) 
 
A s s o ci at e  Dir e ct or , Bi o st ati sti c s 
  
 
 
 
N a m e,  Titl e  
 
  
Si g n at ur e  
  
D at e ( D D -M m m -
Y Y Y Y) 
 
 
 
Vi c e  Pr e si d e nt,  Bi o m etri c s  
  
 
 
 
N a m e,  Titl e  
S p o n s or  C o nt a ct  
  
Si g n at ur e  
  
D at e ( D D -M m m -
Y Y Y Y) 
 
 
A s s o ci at e  Dir e ct or,  Bi o st ati sti c s 
 
 
 
 
N a m e,  Titl e  
S p o n s or  C o nt a ct  
  
Si g n at ur e  
  
D at e ( D D -M m m -
Y Y Y Y) 
 
 
Vi c e  Pr e si d e nt  a n d  T h er a p e uti c  Ar e a  H e a d,  
R h e u m at ol o g y  
 
 
 
 
N a m e,  Titl e  
S p o n s or  C o nt a ct  
  
Si g n at ur e  
  
D at e ( D D -M m m -
Y Y Y Y) 
 


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  5   of 8 4  
T a bl e  of  C o nt e nt s  
R e vi si o n  Hi st or y  ............................................................................................................................ 2 
A p pr o v al s  .................................................................................................................................... 4 
  
Gl o s s ar y  of  A b br e vi ati o n s  .................................................................................................... 9 
  
P ur p o s e  .............................................................................................................................. 1 2  
  
St u d y  O bj e cti v e s  ................................................................................................................ 1 3  
  
E n d p oi nt s  ........................................................................................................................... 2 9  
  
A n al y si s  P o p ul ati o n s  .......................................................................................................... 3 1  
  
G e n er al  A s p e ct s f or  St ati sti c al  A n al y si s  ............................................................................. 3 2  


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  6   of 8 4  
  
S u bj e ct  Di s p o siti o n  ............................................................................................................. 4 0  
  
D e m o gr a p hi c s,  Ot h er  C h ar a ct eri sti c s,  a n d  M e di c ati o n  ...................................................... 4 1  
  
Effi c a c y  ............................................................................................................................... 4 5  


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  7   of 8 4  
  A n al y si s  of  P h ar m a c o ki n eti c s  a n d  A nti -Dr u g  A nti b o di e s  .................................................... 5 7  
  S af et y  ................................................................................................................................. 5 9  
  C h a n g e s fr o m  A n al y si s  Pl a n n e d i n  Pr ot o c ol  ...................................................................... 6 9  
  Pr o gr a m mi n g  C o n si d er ati o n s  ............................................................................................. 7 0  
  Q u alit y  C o ntr ol  ................................................................................................................... 7 5  
  I n d e x  of  T a bl e s ................................................................................................................... 7 6  
  I n d e x  of  Fi g ur e s ................................................................................................................. 8 1  


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  8   of 8 4  
  I n d e x  of  Li sti n g s ................................................................................................................. 8 2  
  R ef er e n c e s  ......................................................................................................................... 8 4  
 








St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  1 2   of 8 4  
  
P ur p o s e  
T h e  p ur p o s e  of t hi s  st ati sti c al  a n al y si s  pl a n ( S A P) i s t o  e n s ur e t h at t h e  d at a li sti n g s,  s u m m ar y 
t a bl e s   a n d  fi g ur e s  f or  t h e  H Z N P -K R Y -2 0 1  st u d y  t h at   will   b e   pr o d u c e d,   a n d  t h e   st ati sti c al  
m et h o d ol o gi e s  t h at   will   b e   u s e d,   ar e   c o m pl et e   a n d   a p pr o pri at e  t o   all o w   v ali d   c o n cl u si o n s  
r e g ar di n g t h e  st u d y  o bj e cti v e s.  
  
R e s p o n si biliti e s  
 wi ll  p erf or m t h e  st ati sti c al  a n al y s e s  a n d  ar e r e s p o n si bl e f or t h e  pr o d u cti o n  a n d 
q u alit y  c o ntr ol  of  all t a bl e s, fi g ur e s  a n d li sti n g s  f or t h e H Z N P -K R Y -2 0 1  st u d y , i n cl u di n g  s u m m ari e s 
of  st u d y   c o n c e ntr ati o n s  f or   m et h otr e x at e   (M T X )  p ol y gl ut a m at e  a n d   P e gl oti c a s e   a n d   a nti -dr u g 
a nti b o di e s .  T h e  d et ail s  of  s u m m ari e s f or p h ar m a c o ki n eti c ( P K)  p ar a m et er s i s  n ot  c o v er e d i n t h e 
s c o p e  of t hi s  S A P  a n d  will  b e  pr o vi d e d i n  a  s e p ar at e  P K  a n al y si s  pl a n.  
  will  pr o vi d e  s u m m ari z ati o n s  a n d li sti n g s f or s af et y r e vi e w s.  
  
Ti mi n g s  of  A n al y s e s  
T h e   pri m ar y   a n al y si s   of   s af et y ,  effi c a c y   a n d   p h ar m a c o ki n eti c s  i s   pl a n n e d   aft er   all   s u bj e ct s  
c o m pl et e  t h e  fi n al   st u d y   vi sit   or  t er mi n at e   e arl y  fr o m  t h e   st u d y.   A d diti o n all y,   d at a   m a y   b e  
s u m m ari z e d   aft er   all   s u bj e ct s   h a v e   c o m pl et e d   1 4   w e e k s   of  tr e at m e nt  i n  t h e   P e gl oti c a s e  + 
I m m u n o m o d ul at or (I M M) P eri o d  or  di s c o nti n u e d  t h er a p y ( or  st u d y)  pri or t o t h at ti m e,  a n d aft er  all 
s u bj e ct s  h a v e  c o m pl et e d  2 4  w e e k s  of tr e at m e nt i n t h e  P e gl oti c a s e  +  I M M  P eri o d or  di s c o nti n u e d  
t h er a p y ( or  st u d y)  pri or t o t h at ti m e. 
A d diti o n al  s u m m ar y  of t h e  d at a  m a y  b e  p erf or m e d  p eri o di c all y t hr o u g h o ut t h e  st u d y,  a n d  s af et y 
d at a  will  b e  s u m m ari z e d r e g ul arl y f or  s af et y  m o nit ori n g  b y t h e  S p o n s or.   


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  1 3   of 8 4  
  
St u d y  O bj e cti v e s  
T h e  o v er all  o bj e cti v e  of t h e  st u d y i s t o  a s s e s s t h e  effi c a c y,  s af et y, t ol er a bilit y,  a n d  P K  of t h e 
c o n c o mit a nt  u s e  of  p e gl oti c a s e  wit h  M T X  t o  e n h a n c e t h e r e s p o n s e r at e  s e e n  wit h  p e gl oti c a s e 
al o n e i n  a d ult s  wit h  u n c o ntr oll e d  g o ut.  
  
Pri m ar y  O bj e cti v e  
T h e  pri m ar y  o bj e cti v e i s t o  e sti m at e t h e r e s p o n s e r at e  d uri n g  M o nt h  6 ( W e e k s  2 0,  2 2,  a n d  2 4), 
a s  m e a s ur e d  b y t h e  s u st ai n e d  n or m ali z ati o n  of  s er u m  uri c  a ci d ( s U A) t o  < 6  m g/ d L f or  at l e a st 
8 0 %  of t h e ti m e  d uri n g  M o nt h  6 i n  s u bj e ct s r e c ei vi n g  p e gl oti c a s e  wit h  M T X.  
    
S e co n d ar y  O bj e cti v e s 
•   E sti m at e t h e r e s p o n s e r at e  d uri n g  M o nt h  3 ( W e e k s  1 0,  1 2  a n d  1 4),  a s  m e a s ur e d  b y t h e 
s u st ai n e d  n or m ali z ati o n  of  s U A t o  < 6  m g/ d L f or  at l e a st  8 0 %  of t h e ti m e  d uri n g  M o nt h  3 
i n  s u bj e ct s r e c ei vi n g  p e gl oti c a s e  wit h  M T X. 
•   E sti m at e t h e  o v er all r e s p o n s e r at e,  a s  m e a s ur e d  b y t h e  s u st ai n e d  n or m ali z ati o n  of  s U A 
t o  < 6  m g/ d L f or  at l e a st  8 0 %  of t h e ti m e  d uri n g  M o nt h  3 ( W e e k s  1 0,  1 2  a n d  1 4)  a n d 
M o nt h  6 ( W e e k s  2 0,  2 2  a n d  2 4)  c o m bi n e d i n  s u bj e ct s r e c ei vi n g  p e gl oti c a s e  wit h  M T X.  
•   E sti m at e t h e  5  m g/ d L r e s p o n s e r at e  d uri n g  M o nt h  3,  d uri n g  M o nt h  6,  a n d  O v er all 
( M o nt h s  3  a n d  6  c o m bi n e d),  a s  m e a s ur e d  b y t h e  s u st ai n e d  n or m ali z ati o n  of  s U A t o  < 5 
m g/ d L f or  at l e a st  8 0 %  of t h e ti m e i n  s u bj e ct s r e c ei vi n g  p e gl oti c a s e  wit h  M T X.  
•   E sti m at e t h e  m e a n  c h a n g e fr o m  b a s eli n e t o  W e e k s  1 4,  2 4,  3 6,  a n d  5 2 i n  s U A i n  s u bj e ct s 
r e c ei vi n g  p e gl oti c a s e  wit h  M T X. 
  
E x pl or at or y  O bj e cti v e s  
•   E sti m at e t h e r e s p o n s e r at e  d uri n g  M o nt h  9 ( W e e k s  3 2,  3 4  a n d  3 6),  a s  m e a s ur e d  b y t h e 
s u st ai n e d  n or m ali z ati o n  of  s U A t o  < 6  m g/ d L f or  at l e a st  8 0 %  of t h e ti m e  d uri n g  M o nt h  9 
i n  s u bj e ct s r e c ei vi n g  p e gl oti c a s e  wit h  M T X. 
•   E sti m at e t h e r e s p o n s e r at e  d uri n g  M o nt h  1 2 ( W e e k s  4 8,  5 0  a n d  5 2),  a s  m e a s ur e d  b y t h e 
s u st ai n e d  n or m ali z ati o n  of  s U A t o  < 6  m g/ d L f or  at l e a st  8 0 %  of t h e ti m e  d uri n g  M o nt h  1 2 
i n  s u bj e ct s r e c ei vi n g  p e gl oti c a s e  wit h  M T X. 
•   E sti m at e t h e  5  m g/ d L r e s p o n s e r at e  d uri n g  M o nt h  9 ( W e e k s  3 2,  3 4  a n d  3 6),  a s 
m e a s ur e d  b y t h e  s u st ai n e d  n or m ali z ati o n  of  s U A t o  < 5  m g/ d L f or  at l e a st  8 0 %  of t h e ti m e 
d uri n g  M o nt h  9 i n  s u bj e ct s r e c ei vi n g  p e gl oti c a s e  wit h  M T X.  
•   E sti m at e t h e  5  m g/ d L r e s p o n s e r at e  d uri n g  M o nt h  1 2 ( W e e k s  4 8,  5 0  a n d  5 2),  a s 
m e a s ur e d  b y t h e  s u st ai n e d  n or m ali z ati o n  of  s U A t o  < 5  m g/ d L f or  at l e a st  8 0 %  of t h e ti m e 
d uri n g  M o nt h  1 2 i n  s u bj e ct s r e c ei vi n g  p e gl oti c a s e  wit h  M T X.  
•   E sti m at e t h e ti m e t o fir st  s U A  > 6  m g/ d L i n  s u bj e ct s r e c ei vi n g  p e gl oti c a s e  wit h  M T X.  
•   E sti m at e t h e ti m e t o t w o  c o n s e c uti v e  s U A s  > 6  m g/ d L ( st o p pi n g r ul e) i n  s u bj e ct s 
r e c ei vi n g  p e gl oti c a s e  wit h  M T X. 


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  1 4   of 8 4  
•   E sti m at e t h e  m e a n  c h a n g e fr o m  b a s eli n e t o  W e e k  2 4,  3 6  a n d  5 2 i n  ur at e  v ol u m e  a n d 
g o ut  er o si o n s  u si n g  d u al -e n er g y  c o m p ut e d t o m o gr a p h y ( D E C T ) s c a n  of t h e  h a n d s  a n d 
f e et i n  s u bj e ct s r e c ei vi n g  p e gl oti c a s e  wit h  M T X. 
•   E sti m at e t h e  m e a n  c h a n g e fr o m  b a s eli n e i n  n u m b er  of j oi nt s  aff e ct e d  b y t o p hi i n  s u bj e ct s 
r e c ei vi n g  p e gl oti c a s e  wit h  M T X. 
•   E sti m at e t h e  m e a n  c h a n g e fr o m  b a s eli n e t o  W e e k s  1 4,  2 4,  3 6,  a n d  5 2 i n t e n d er j oi nt 
c o u nt ( 6 8  p oi nt  s c al e) i n  s u bj e ct s r e c ei vi n g  p e gl oti c a s e  wit h  M T X.  
•   E sti m at e t h e  m e a n  c h a n g e fr o m  b a s eli n e t o  W e e k s  1 4,  2 4,  3 6,  a n d  5 2 i n  s w oll e n j oi nt 
c o u nt ( 6 6  p oi nt  s c al e) i n  s u bj e ct s r e c ei vi n g  p e gl oti c a s e  wit h  M T X.  
•   E sti m at e t h e  m e a n  c h a n g e fr o m  b a s eli n e t o  W e e k s  1 4,  2 4,  3 6,  a n d  5 2 i n t h e  H e alt h 
A s s e s s m e nt  Q u e sti o n n air e  –  Di s a bilit y I n d e x ( H A Q -DI) i n  s u bj e ct s r e c ei vi n g  p e gl oti c a s e 
wit h  M T X.  
•   E sti m at e t h e  m e a n  c h a n g e fr o m  b a s eli n e t o  W e e k s  1 4,  2 4,  3 6,  a n d  5 2 i n t h e  H A Q  p ai n 
s c or e i n  s u bj e ct s r e c ei vi n g  p e gl oti c a s e  wit h  M T X.  
•   E sti m at e t h e  m e a n  c h a n g e fr o m  b a s eli n e t o  W e e k s  1 4,  2 4,  3 6,  a n d  5 2 i n t h e  H A Q  h e alt h 
s c or e i n  s u bj e ct s r e c ei vi n g  p e gl oti c a s e  wit h  M T X.  
•   E sti m at e t h e  m e a n  c h a n g e fr o m  b a s eli n e t o  W e e k s  1 4,  2 4,  3 6,  a n d  5 2 i n  p ati e nt  gl o b al 
a s s e s s m e nt  of  g o ut i n  s u bj e ct s r e c ei vi n g  p e gl oti c a s e  wit h  M T X.  
•   E sti m at e t h e  m e a n  c h a n g e fr o m  b a s eli n e t o  W e e k s  1 4,  2 4,  3 6,  a n d  5 2 i n  p h y si ci a n 
gl o b al  a s s e s s m e nt  of  g o ut i n  s u bj e ct s r e c ei vi n g  p e gl oti c a s e  wit h  M T X.  
•   E sti m a t e t h e  m e a n  c h a n g e fr o m  b a s eli n e t o  W e e k s  1 4,  2 4,  3 6,  a n d  5 2 i n  s u bj e ct 
a s s e s s m e nt  of  a v er a g e, l e a st,  a n d  w or st j oi nt  p ai n i n  s u bj e ct s r e c ei vi n g  p e gl oti c a s e  wit h 
M T X.  
•   E sti m at e t h e  pr o p orti o n  of  s u bj e ct s  a c hi e vi n g  2 0 %,  5 0 %,  or  7 0 % i m pr o v e m e nt  b a s e d  o n 
g o ut  c hr o ni c r e s p o n s e  crit eri a  at  W e e k s  1 4,  2 4,  3 6,  a n d  5 2 i n  s u bj e ct s r e c ei vi n g 
p e gl oti c a s e  wit h  M T X.  
•   A s s e s s t h e  P K  of  p e gl oti c a s e i n  s u bj e ct s r e c ei vi n g  c o n c o mit a nt  M T X.  
•   A s s e s s t h e i n ci d e n c e  of  a nti -P E G  a n d  a nti -Uri c a s e I g G  a nti b o di e s.  
  
S af et y  a n d  T ol er a bilit y  O bj e cti v e s  
•   A s s e s s t h e i n ci d e n c e  of i nf u si o n r e a cti o n s (I R s),  a n a p h yl a xi s,  g o ut fl ar e s,  c ar di o v a s c ul ar 
e v e nt s,  a n d t h e  a d v er s e  e v e nt ( A E/ S A E)  pr ofil e  o v er all  a n d  p ot e nti all y  attri b ut e d t o t h e 
c o m bi n ati o n  of  p e gl oti c a s e  a n d  M T X.  
  
Bri ef  D e s cri pti o n  
T hi s  st u d y i s  a  m ulti c e nt er,  o p e n -l a b el,  effi c a c y  a n d  s af et y  st u d y  of  p e gl oti c a s e i n  c o m bi n ati o n 


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  1 5   of 8 4  
wit h  M T X i n  a d ult  s u bj e ct s  wit h  u n c o ntr oll e d  g o ut.   
Pri or t o  A m e n d m e nt  2,  t h e  st u d y  d e si g n i n cl u d e d: 1)  a  S cr e e ni n g  P eri o d, l a sti n g  u p t o  6  w e e k s, 
w hi c h i n cl u d e s  a  4 -w e e k  M T X  R u n -i n  P eri o d;  2)  a  2 4-w e e k  D u al  T h er a p y  P eri o d ( K R Y S T E X X A 
+  M T X);  3)  a n   E n d-of -st u d y ( W e e k  2 4)/ E arl y  T er mi n ati o n  Vi sit.  T h e  ori gi n al  pr ot o c ol i n cl u d e d  a 
t el e p h o n e  or  e m ail  c o nt a ct  3 0  d a y s  aft er t h e l a st i nf u si o n.  A m e n d m e nt  1 i n cl u d e d  a  s afet y 
F oll o w -u p  P h o n e/ E m ail  Vi sit  3 0  d a y s  aft er t h e l a st  K R Y S T E X X A i nf u si o n (if f e m al e s  of 
c hil d b e ari n g  p ot e nti al  h a v e  n ot  o v ul at e d  si n c e t a ki n g t h e l a st  d o s e  of  M T X,  a  uri n e  pr e g n a n c y 
t e st  will  b e r e q uir e d)  a n d  5)  a  P h o n e/ E-m ail  Vi sit  will  b e  c o n d u ct e d  3  m o nt h s  aft er  M T X 
di s c o nti n u ati o n t o  n o n -v a s e ct o mi z e d  m al e s  r e g ar di n g  p art n er  pr e g n a n c y. 
 
T h e  st u d y  d e si g n  f or  A m e n d m e nt 2 . 0 i n cl u d es :  1)  u p t o  a  2-w e e k  S cr e e ni n g  P eri o d ( s cr e e ni n g 
s h o ul d  b e  c o m pl et e  wit hi n  2  w e e k s  pri or t o  W e e k  -4),  2)  a  4 -w e e k  M T X  R u n -i n  P eri o d ( W e e k – 
4 t hr o u g h  D a y  1);  3)  a  5 2 -w e e k  P e gl oti c a s e  + I M M ( P e gl oti c a s e  +  M T X )  P eri o d  4) a  S af et y 
F oll o w -u p ( P h o n e/ E m ail/ Sit e  Vi sit)  a n d  5)  a  3  a n d  6  m o nt h  P o st  Tr e at m e nt  F oll o w -u p.  
All  s u bj e ct s  w h o  m e et  eli gi bilit y  crit eri a  at  S cr e e ni n g  will  b e gi n  or al  M T X  at  a  d o s e  of  1 5  m g 
w e e kl y f or  4  w e e k s  pri or t o t h e fir st  d o s e  of  p e gl oti c a s e.   
S u bj e ct s  will  al s o t a k e f oli c  a ci d  1  m g  or all y  e v er y  d a y  b e gi n ni n g  at  W e e k  -4 (t h e  st art  of  M T X) 
a n d  c o nti n ui n g  u ntil  pri or t o t h e  W e e k  5 2  Vi sit.  S u bj e ct s  m u st  b e  a bl e t o t ol er at e  M T X  at  a  d o s e 
of  1 5  m g  d uri n g t h e  M T X  R u n -i n ( W e e k -4 t hr o u g h  D a y  1) t o  b e  eli gi bl e t o  p arti ci p at e i n t h e 
P e gl oti c a s e  + I M M  P eri o d.  S u bj e ct s  w h o  ar e  u n a bl e t o t ol er at e  M T X  at  a  d o s e  of  1 5  m g  d uri n g 
t h e  M T X  R u n-i n  P eri o d  will  b e  c o n si d er e d  s cr e e n f ail ur e s. 
S u bj e ct s  w h o t a k e  at l e a st  o n e  d o s e  of  M T X  a n d  w h o  ar e f e m al e s  of  c hil d b e ari n g  p ot e nti al  will 
r e c ei v e  a  s af et y f oll o w-u p  P h o n e  C all/ E -m ail/ Sit e  Vi sit  a p pr o xi m at el y  3 0  d a y s  aft er t h e l a st  d o s e 
of  M T X t o  v erif y  at l e a st  o n e  o v ul at or y  c y cl e  h a s  o c c urr e d  aft er t h e l a st  d o s e  of  M T X. If t h e 
s u bj e ct  h a s  n ot  o v ul at e d,  a  uri n e  pr e g n a n c y t e st  will  b e  p erf or m e d.  S u bj e ct s , w h o r e c ei v e  at  
l e a st  o n e  d o s e  of  M T X  a n d  w h o  ar e  n o n-v a s e ct o mi z e d  m al e s,  will  b e  a s k e d,  3  m o nt h s  aft er 
M T X  di s c o nti n u ati o n, r e g ar di n g  p art n er  pr e g n a n c y.  
All  s u bj e ct s  w h o  c o m pl et e t h e  R u n -I n  P eri o d  will r e c ei v e t h e fir st  p e gl oti c a s e i nf u si o n  o n  D a y  1. 
All  s u b s e q u e nt  d o s e s  a n d  st u d y  vi sit s  will  b e  s c h e d ul e d  b a s e d  o n t h e  D a y  1  vi sit  d at e.   
D uri n g t h e  P e gl oti c a s e  + I M M  P eri o d,  p e gl oti c a s e  8  m g  will  b e  a d mi ni st er e d i ntr a v e n o u sl y (I V) 
e v er y  2  w e e k s fr o m  D a y  1 t hr o u g h t h e  W e e k  5 0  Vi sit f or  a t ot al  of  2 6 i nf u si o n s;  p e gl oti c a s e  w ill 
b e  a d mi ni st er e d  aft er  all  pr e -d o s e  st u d y  vi sit  a s s e s s m e nt s  h a v e  b e e n  c o m pl et e d  at  e a c h  vi sit. 
T h e  d at e  a n d  st art  a n d  st o p ti m e  of i nf u si o n  will  b e r e c or d e d.  S er u m  uri c  a ci d  st o p pi n g r ul e s  will 
b e  a p pli e d:  s u bj e ct s  wit h  s U A l e v el  >  6  m g/ d L  at  2  c o n s e c uti v e  st u d y  vi sit s  b e gi n ni n g  wit h t h e 
W e e k  2  Vi sit  will  di s c o nti n u e tr e at m e nt,  c o m pl et e t h e  E n d  of  P e gl oti c a s e I nf u si o n  Vi sit 
pr o c e d ur e s  wit hi n  2  w e e k s  a n d  c o nti n u e t h e  s u bj e ct  vi sit s  a c c or di n g t o t h e  pr ot o c ol ( wit h o ut 
tr e at m e nt). 
D uri n g t h e  P e gl oti c a s e  + I M M  P eri o d,  s u bj e ct s  will  b e i n str u ct e d t o t a k e  M T X  w e e kl y  o n t h e 
s a m e  d a y  e a c h  w e e k,  wit hi n  1 t o  3  d a y s  pri or t o  e a c h  P e gl oti c a s e  i nf u si o n  a n d  o n e  a d diti o n al 
w e e kl y  d o s e  aft er t h e l a st i nf u si o n f or  s u bj e ct s  w h o  h a v e  n ot  st o p p e d  P e gl oti c a s e  d u e t o  s U A 
st o p pi n g r ul e s;  h o w e v er, if  a  s u bj e ct  d o e s  n ot  d o  s o,  M T X  m u st  b e t a k e n  ≥  6 0  mi n ut e s  pri or t o 
e a c h  P e gl oti c a s e  i nf u si o n. 


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  1 6   of 8 4  
Aft er  D a y  1, if  a  s u bj e ct  b e c o m e s  u n a bl e t o t ol er at e  1 5  m g  of  M T X, t h e  M T X  d o s e  m a y  b e 
r e d u c e d  a n d/ or  di s c o nti n u e d,  a n d t h e  s u bj e ct  m a y r e m ai n i n t h e  st u d y. 
T h e I n v e sti g at or  will r e vi e w t h e  cli ni c al  st at u s  a n d i n di vi d u al  s u bj e ct tr e at m e nt  g o al s  at  W e e k  2 4, 
a n d t h e  E n d  of  P e gl oti c a s e I nf u si o n s  Vi sit (if  a p pli c a bl e)  a n d t h e  W e e k  5 2/ E n d  of  st u d y/ E arl y 
T er mi n ati o n  Vi sit.  
S er u m  s a m pl e s f or  m e a s ur e m e nt  of  s U A l e v el s  will  b e  c oll e ct e d  at t h e  S cr e e ni n g  Vi sit ( wit hi n  2 
w e e k s  pri or t o t h e fir st  d o s e  of  M T X  at  W e e k  -4), t h e  W e e k  -4  Vi sit ( pri or t o t h e fir st  d o s e  of 
M T X),  a n d t h e  W e e k  -2  Vi sit  d uri n g t h e  M T X  R u n -i n  P eri o d;  wit hi n 4 8  h o ur s  pri or t o  e a c h 
p e gl oti c a s e i nf u si o n ( e x c e pt  o n  D a y  1  w h e n  o nl y  1  pr e -i nf u si o n  s a m pl e i s r e q uir e d)  a n d  aft er t h e 
e n d  of  e a c h  p e gl oti c a s e i nf u si o n  pri or t o  di s c h ar g e, fr o m t h e  P e gl oti c a s e  + I M M  P eri o d t hr o u g h  
W e e k  2 4  a n d  at  W e e k s  3 2,  3 4,  3 6,  4 8  a n d  5 0;  wit hi n  4 8  h o ur s  pri or t o  e a c h  p e gl oti c a s e i nf u si o n 
at  W e e k s  2 6,  2 8,  3 0,  3 8,  4 0,  4 2,  4 4  a n d  4 6  d uri n g t h e  P e gl oti c a s e  + 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 oti c a s e I nf u si o n s  Vi sit (if  a p pli c a bl e);  at t h e  W e e k  5 2/ E n d  of  st u d y/ E arl y 
T er mi n ati o n  Vi sit  a n d  M o nt h  3  a n d  M o nt h  6  Vi sit s.  O pti o n al ( s u bj e ct s  w h o  a gr e e t o  p arti ci p at e) 
vi sit s f or fr e q u e nt  s a m pli n g f or  a d diti o n al  n o n -i nf u si o n  vi sit  s U A  s a m pli n g (r a n d o m,  m or ni n g 
pr ef err e d)  will  o c c ur  at  W e e k  1  a n d  W e e k  7.  A  s u bj e ct  wit h  s U A l e v el  > 6  m g/ d L ( b a s e d  o n t h e 
l o c al  or  c e ntr al l a b or at or y)  at  2  c o n s e c uti v e  st u d y  vi sit s,  b e gi n ni n g  wit h t h e  W e e k  2  Vi sit,  will  b e 
di s c o nti n u e d fr o m  p e gl oti c a s e tr e at m e nt  a n d r e m ai n  o n  st u d y.   
S a m pl e s f or  m e a s ur e m e nt  of  P K  a n al y si s  of  p e gl oti c a s e,  p e gl oti c a s e  i m m u n o g e ni cit y  a n d  M T X 
P ol y gl ut a m at e  a n al y si s  will  b e  c oll e ct e d  at  vi sit s i n di c at e d i n t h e  S c h e d ul e  of  A s s e s s m e nt s 
(Pr ot o c ol  S e cti o n  2. 1).  
S af et y  a s s e s s m e nt s, i n cl u di n g  m o nit ori n g  a n d r e c or di n g  of  all  A E s,  w h et h er  or  n ot  dr u g -r el at e d, 
m e a s ur e m e nt  of  vit al  si g n s,  p h y si c al  e x a mi n ati o n s,  a n d  m o nit ori n g  of  h e m at ol o g y  a n d  bl o o d 
c h e mi str y,  will  b e  p erf or m e d.   
  
D et er mi n ati o n  of  S a m pl e  Si z e  
A  s a m pl e  si z e  of  a p pr o xi m at el y  1 2 -1 6  s u bj e ct s i s  pl a n n e d f or t hi s  st u d y.  T h e  pri m ar y  effi c a c y 
e n d p oi nt, t h e  pr o p orti o n  of  s u bj e ct s  a c hi e vi n g  a n d  m ai nt ai ni n g  s U A  < 6  m g/ d L f or  at l e a st  8 0 %  of 
t h e ti m e  d uri n g  M o nt h  6 ( W e e k s  2 0,  2 2,  a n d  2 4)  of t h e  P e gl oti c a s e  + I M M  P eri o d,  will  b e 
d e m o n str at e d t o  b e  st ati sti c all y  gr e at er t h a n  4 3. 5 % ( pr o p orti o n  of r e s p o n d er s  d uri n g  M o nt h  6 i n 
p h a s e  3  st u di e s),  a c c or di n g t o  a n  e x a ct t e st f or  pr o p orti o n s  wit h  a  5 % t y p e I  err or, if  at l e a st 
1 0/ 1 3 ( 7 7 %) r e s p o n d er s  ar e  o b s er v e d; i n t h at  c a s e, t h e l o w er  b o u n d  of  a  9 5 %  c o nfi d e n c e 
i nt er v al ( CI) f or t h e  pr o p orti o n  of r e s p o n d er s  will  b e a p pr o xi m at el y  4 6 %.  
  
Tr e at m e nt  A s si g n m e nt  &  Bli n di n g  
T h e  st u d y i s  o p e n -la b el.   
  
A d mi ni str ati o n  of  St u d y  M e di c ati o n  
D uri n g t h e  M T X  R u n -i n  P eri o d,  w hi c h  b e gi n s  4  w e e k s  pri or t o t h e fir st  d o s e  of  p e gl oti c a s e, 
s u bj e ct s  will t a k e  or al  M T X  at  a  d o s e  of  1 5  m g  w e e kl y.  S u bj e ct s  will  b e i n str u ct e d t o t a k e  M T X 
w e e kl y  o n t h e  s a m e  d a y  e a c h  w e e k (if  d o si n g  m or e fr e q u e ntl y t h a n  o n c e i n  a  d a y ( i. e. t wi c e  p er 
d a y ( BI D),  or t hr e e ti m e s  p er  d a y ( TI D )), t h e t ot al  M T X  d o s e  s h o ul d  b e t a k e n  wit hi n  2 4  h o ur s, 
pr ef er a bl y t h e  s a m e  c al e n d ar  d a y)  a n d r e c or d  t h e  d at e  a n d ti m e  of  d o s e/ s i n t h e  d o si n g 


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  1 7   of 8 4  
c al e n d ar.  D uri n g t h e  P e gl oti c a s e  + I M M  P eri o d,  M T X  s h o ul d  b e t a k e n  1 t o  3  d a y s  pri or t o 
p e gl oti c a s e i nf u si o n;  h o w e v er, if  a  s u bj e ct  d o e s  n ot  d o  s o,  M T X  m u st  b e t a k e n  ≥  6 0  mi n ut e s 
pri or t o  p e gl oti c a s e i nf u si o n.  D uri n g t h e  M T X  R u n -i n  P eri o d, if  a  d o s e i s  mi s s e d, it  s h o ul d  b e 
t a k e n  a s  s o o n  a s it i s r e m e m b er e d. If it i s  wit hi n  4 8  h o ur s  of t h e  n e xt  s c h e d ul e d  d o s e, t h e 
s u bj e ct  will  b e i n str u ct e d t o  s ki p t h e  mi s s e d  d o s e  a n d r e s u m e  at t h e  n e xt r e g ul arl y  s c h e d ul e d 
ti m e; t h u s,  s u bj e ct s  will  b e i n str u ct e d  n ot t o  d o u bl e  a  d o s e t o  m a k e  u p f or  a  mi s s e d  d o s e if 
wit hi n  4 8  h o ur s  of t h e  n e xt  d o s e. If  a  s u bj e ct  b e c o m e s  u n a bl e t o t ol er at e t h e  pr e s cri b e d  d o s a g e 
of  M T X  d uri n g t h e  P e gl oti c a s e  + I M M  P eri o d, t h e  d o s a g e  m a y  b e  d e cr e a s e d ( s e e  Pr ot o c ol 
S e cti o n  9. 4. 6. 3. 2. 2).  
S u bj e ct s  w h o  e nr oll e d  u n d er  A m e n d m e nt  1 ( V er si o n  2. 0 ) of t h e  pr ot o c ol , w h o  di d  n ot  c o n s e nt t o 
A m e n d m e nt  2 ( V er si o n  3. 0 ),  will r e c ei v e  1 2 i nf u si o n s  d uri n g t h e  P e gl oti c a s e  + I M M  P eri o d  at t h e 
s a m e  d o s e  of  8  m g  a d mi ni st er e d I V  e v er y  2  w e e k s.  S u bj e ct s  w h o  e nr oll e d t o  V er si o n  3. 0  or 
r e c o n s e nt e d t o  V er si o n  3  will r e c ei v e  p e gl oti c a s e  at t h e  s a m e  d o s e  of  8  m g  a d mi ni st er e d I V 
e v er y  2  w e e k s f or  a t ot al  of  2 6 i nf u si o n s fr o m  D a y  1 t hr o u g h  W e e k  5 0,  i n cl u si v e.  T h e d at e  a n d 
st art  a n d  st o p ti m e  of i nf u si o n i n cl u di n g t h e fl u s h  will  b e r e c or d e d.  S u bj e ct s  will  n ot  b e f a sti n g  o n 
t h e  d a y  of i nf u si o n  a n d  will  b e  e n c o ur a g e d t o  h a v e  a  s n a c k  or  n or m al  m e al  b ef or e  or  aft er t h e 
i nf u si o n.  All  s u bj e ct s  will r e c ei v e  st a n d ar di z e d  pr o p h yl a cti c tr e at m e nt t o r e d u c e t h e ri s k  of  a c ut e 
g o ut fl ar e s,  u nl e s s  m e di c all y  c o ntr ai n di c at e d  or  n ot t ol er at e d,  b e gi n ni n g  ≥ 1  w e e k  b ef or e t h e fir st 
d o s e  of  p e gl oti c a s e.  St a n d ar di z e d I R  pr o p h yl a xi s  c o n si sti n g  of  pr e -tr e at m e nt  wit h 
a nti hi st a mi n e s,  a c et a mi n o p h e n,  a n d  c orti c o st er oi d s  will  a c c o m p a n y  e a c h i nf u si o n.   
S u bj e ct s  will t a k e f oli c  a ci d  1  m g  or all y  e v er y  d a y  b e gi n ni n g  at  W e e k  -4 (t h e  st art  of  M T X)  u ntil 
pri or t o t h e  W e e k  5 2/ E n d  of  St u d y/ E arl y  T er mi n ati o n  Vi sit.   
If t h e  s u bj e ct  di s c o nti n u e s  p e gl oti c a s e  d u e t o t h e  st o p pi n g r ul e s  or  ot h er r e a s o n,  M T X  a n d f oli c 
a ci d  s h o ul d  al s o  b e  di s c o nti n u e d.  
It i s r e q uir e d t h at  b ef or e  a  s u bj e ct  b e gi n s t h e  P e gl oti c a s e  + I M M  P eri o d,  h e  or  s h e  h a s  b e e n 
t a ki n g  at l e a st  o n e  pr ot o c ol  st a n d ar d  g o ut fl ar e  pr o p h yl a xi s r e gi m e n (i. e.  c ol c hi ci n e  a n d/ or  n o n-
s t er oi d al  a nti-i nfl a m m at or y  dr u g s  a n d/ or l o w-d o s e  pr e d ni s o n e  ≤ 1 0  m g/ d a y) f or  ≥ 1  w e e k  b ef or e 
t h e fir st  d o s e  of  p e gl oti c a s e  a n d  c o nti n u e s fl ar e  pr o p h yl a xi s f or t h e  gr e at er  of  1)  6  m o nt h s,  2)  3 
m o nt h s  aft er  a c hi e vi n g t ar g et  s er u m  ur at e ( s U A  <  6  m g/ d L) f or  p ati e nt s  wit h  n o t o p hi  d et e ct e d 
o n  p h y si c al  e x a m,  or  3)  6  m o nt h s  aft er  a c hi e vi n g t ar g et  s er u m  ur at e ( s U A  <  5  m g/ d L) f or 
p ati e nt s  wit h  o n e  or  m or e t o p hi  d et e ct e d  o n i niti al  p h y si c al  e x a m t h at  h a v e  si n c e r e s ol v e d.  
  
St u d y  Pr o c e d ur e s  a n d  Fl o w c h art  
T h e fl o w c h art  c o pi e d fr o m t h e  pr ot o c ol,  A m e n d m e nt  2 , S e cti o n  2. 1 , i s r e pr o d u c e d  h er e. 


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  1 8   of 8 4  
 
 


















St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  2 7   of 8 4  
2 4  a n d  3 6,  W e e k  5 2/ E n d  of  St u d y/ E arl y  T er mi n ati o n  a n d  P ost  Tr e at m e nt  3  a n d  6  m o nt h  F oll o w -u p  Visits,  a n  ass ess m e nt f or  pr es e n c e  of t o p hi  will  b e  c o n d u ct e d  d uri n g t h e 
t ar g et e d  p h ysi c al  e x a mi n ati o n. 
8.  
H e art r at e  a n d  bl o o d  pr ess ur e  m e as ur e m e nts s h o ul d  b e t a k e n  aft er t h e s u bj e ct  h as  b e e n i n  a sitti n g  p ositi o n  a n d i n  a r est e d  a n d  c al m st at e f or  at l e ast  5   mi n ut es a n d, f or st u d y 
visits  d uri n g t h e  P e gl oti c as e  + I M M  P eri o d,  b ef or e t h e  p e gl oti c as e i nf usi o n  a n d  a n y ti m e  aft er t h e  e n d  of t h e i nf usi o n,  b ut  pri or t o s u bj e ct’s  dis c h ar g e/r el e as e fr o m t h e sit e . 
W ei g ht s h o ul d  b e  m e as ur e d i n  kil o gr a ms  or  p o u n ds  wit h o ut s h o es  a n d r e c or d e d  at  S cr e e ni n g  Visit;  pri or t o  p e gl oti c as e  i nf usi o ns o n  D a y  1  a n d  at t h e  W e e k  8 , 1 6 ,  2 4,  3 6, t h e 
E n d  of  P e gl oti c as e  Tr e at m e nt,  at t h e  W e e k  5 2/ E n d - of-st u d y /E arl y  T er mi n ati o n  Visit  a n d t h e  P ost  Tr e at m e nt  3  a n d  6  m o nt h f oll o w -u p  visits.  H ei g ht  will  b e  c oll e ct e d  at  t h e 
S cr e e ni n g  Visit  o nl y.  
9.  
El e ctr o c ar di o gr a m s h o ul d  b e  c o m pl et e d  pri or t o t h e  p e gl oti c as e i nf usi o n  at  D a y  1  Visit.  
1 0.  A Es/ S A Es  will  b e  c oll e ct e d fr o m si g n at ur e  of t h e I C F.  S eri o us  A Es  will  b e  c a pt ur e d/ m o nit or e d  at t h e  S af et y  F oll o w -u p  P h o n e/ E m ail / Sit e  Visit 3 0  d a y s  aft er t h e l ast  d os e  of 
M T X.   At t h e  S af et y  F oll o w -u p  P h o n e/ E m ail/ Sit e  Visit, f e m al es  of  c hil d b e ari n g  p ot e nti al  will  b e  as k e d t o  c o nfir m if  o v ul ati o n  h as  o c c urr e d si n c e t h e l ast  d os e  of  M T X.  If t h e 
s u bj e ct  h a d  n ot  o v ul at e d,  a  uri n e  pr e g n a n c y t est  will  b e r e q uir e d.  A Es/ S A Es  will  c oll e ct e d  u ntil t h e  6  m o nt h  P ost  Tr e at m e nt  F oll o w -u p  Visit.   F or  e a c h  A E, I n v esti g at ors  will 
b e r e c or d if t h e  e v e nt  w as  p ossi bl y  a n i nf usi o n r e a cti o n  or  a n a p h yl a xis  a n d if s o,  will  b e  pr o m pt e d t o  c o m pl et e  a d diti o n al  C R Fs.  
1 1.  F or sit es  wit h  D E C T  c a p a bilit y ,  D E C T  will  b e  o bt ai n e d  at  D a y  1  a n d  W e e ks  1 4,  2 4  a n d t h e E n d  of  P e gl oti c as e I nf usi o ns  Visit (if  a p pli c a bl e)  a n d  W e e k  5 2/ E n d  of  St u d y/ E arl y 
T er mi n ati o n.   T h e  D E C T  m a y  b e  c o m pl et e d  wit hi n  +/ - 5  d a y s  of t h e s c h e d ul e d ti m e p oi nt.  S u bj e cts  w h o  e n d  p e gl oti c as e i nf usi o ns  pri or t o  W e e k  5 2 s h o ul d f oll o w t h e 
s c h e d ul e d ti m e p oi nts  b ut  a v oi d  a r e p e at  D E C T s c a n  wit hi n  6  w e e ks  of  a  pri or s c a n . 
1 2.  M T X  will  b e  dis p e ns e d  a n d  br o u g ht  b a c k  at  e a c h  visit t o  c h e c k  c o m pli a n c e. If s u bj e cts r e q uir e  a  M T X  d os e r e d u cti o n, t h e I n v esti g at or  will  pr es cri b e t h e s u bj e ct t h e  n u m b er  of 
t a bl ets t o t a k e  w e e kl y.   T h e  u p d at e d  n u m b er  of t a bl ets al o n g  wit h t h e  d at e  a n d ti m e  of  e a c h  M T X  d os e s h o ul d  b e r e c or d e d i n t h e  d osi n g  c al e n d ar . 
1 3.  M T X s h o ul d  b e t a k e n  1 t o  3  d a ys  pri or t o  p e gl oti c as e i nf usi o n;  h o w e v er, if  a s u bj e ct  d o es  n ot  d o s o,  M T X  m ust  b e t a k e n  ≥ 6 0  mi n ut es  pri or t o  p e gl oti c as e i nf usi o n.  
1 4.  F or  g o ut  pr o p h yl a xis, s u bj e cts  ar e  r e q uir e d t o t a k e  at l e ast  o n e  pr ot o c ol st a n d ar d  g o ut fl ar e  pr o p h yl a xis r e gi m e n (i. e.  c ol c hi ci n e  a n d/ or  n o n-st er oi dal  a nti -i nfl a m m at or y  dr u gs 
a n d/ or l o w -d os e  pr e d nis o n e  ≤ 1 0  m g/ d a y)  f or  ≥ 1  w e e k  b ef or e t h e first  d os e  of  p e gl oti c as e  a n d  c o nti n u es fl ar e  pr o p h yl a xis  p er  A m eri c a n  C oll e g e  of  R h e u m at ol o g y  g ui d eli n es 
[ K h a n n a  D  et  al. 2 0 1 2] f or t h e  gr e at er  of  1)  6  m o nt hs,  2)  3  m o nt hs  aft er  a c hi e vi n g t ar g et s er u m  ur at e (s U A  <  6  m g/ d L) f or  p ati e nts  wit h  n o t o p hi  d et e ct e d  o n  p h ysi c al  e x a m,  or 
3)  6  m o nt hs  aft er  a c hi e vi n g t ar g et s er u m  ur at e (s U A  <  5  m g/ d L) f or  p ati e nts  wit h  o n e  or  m or e t o p hi  d et e ct e d  o n i niti al  p h ysi c al  e x a m t h at  h a v e  si n c e r es ol v e d.  F or I R 
pr o p h yl a xis, f e x of e n a di n e  (6 0  m g  or  1 8 0  m g  or all y  b as e d  o n t h e  Pri n ci p al I n v esti g at or’s  dis cr eti o n)  will  b e t a k e n t h e  d a y  b ef or e  e a c h i nf usi o n;  f e x of e n a di n e ( 6 0  m g  or  1 8 0 
m g  or all y  b as e d  o n t h e  Pri n ci p al I n v esti g at or’s  dis cr eti o n)  a n d  a c et a mi n o p h e n ( 1 0 0 0  m g  or all y)  will  b e t a k e n t h e  m or ni n g  of  e a c h i nf usi o n;  a n d  m et h yl pr e d nis ol o n e ( 1 2 5  m g 
I V)  gi v e n  o v er t h e i nf usi o n  d ur ati o n  1 0-3 0  mi n ut es (r e c o m m e n d e d)  or  h y dr o c ortis o n e ( 2 0 0  m g I V)  will  b e  a d mi nist er e d i m m e di at el y  pri or t o  e a c h i nf usi o n.  gi v e n  o v er t h e 
i nf usi o n  d ur ati o n  1 0-3 0  mi n ut es  will  b e  a d mi nist er e d i m m e di at el y  pri or t o  e a c h i nf usi o n.   
1 5.  F or I R  pr o p h yl a xis, f e x of e n a di n e ( 6 0  m g  or  1 8 0  m g  or all y  b as e d  o n t h e  Pri n ci p al I n v esti g at or’s  dis cr eti o n)  will  b e t a k e n t h e  d a y  b ef or e  e a c h i n f usi o n. 
1 6.  S u bj e cts  will t a k e f oli c  a ci d  1  m g  or all y  e v er y  d a y  b e gi n ni n g  at  W e e k  -4 (t h e st art  of  M T X)  u ntil  pri or t o t h e  W e e k  5 2/ E n d  of  St u d y/ E arl y  T er mi n ati o n  Visit  d uri n g t h e 
P e gl oti c as e  + I M M  P eri o d.  
1 7.  I nf usi o n r e a cti o n  pr o p h yl a xis i n cl u d es f e x of e n a di n e ( 6 0  m g  or  1 8 0  m g  or all y  b as e d  o n t h e  Pri n ci p al I n v esti g at or’s  dis cr eti o n)  a d mi nist er e d t h e  d a y  b ef or e  e a c h i nf usi o n; 
f e x of e n a di n e ( 6 0  m g  or  1 8 0  m g  or all y  b as e d  o n t h e  Pri n ci p al I n v esti g at or’s  dis cr eti o n)  a n d  a c et a mi n o p h e n ( 1 0 0 0  m g  or all y)  a d m i nist er e d o n t h e  m or ni n g  of  e a c h i nf usi o n; 
a n d  m et h yl pr e d nis ol o n e ( 1 2 5  m g I V)  gi v e n  o v er t h e i nf usi o n  d ur ati o n  1 0 -3 0  mi n ut es (r e c o m m e n d e d)  or  h y dr o c ortis o n e ( 2 0 0  m g I V)  will  b e  a d mi nist er e d i m m e di at el y  pri or 
t o  e a c h i nf usi o n.  a d mi nist er e d i m m e di at el y  pri or t o  e a c h i nf usi o n. 
1 8.  Bl o o d s a m pl es  will  b e  c oll e ct e d  pri or t o  p e gl oti c as e i nf usi o n  o n  D a y  1  a n d  at  W e e ks  4,  8,  2 2,  2 4  a n d  3 6  d uri n g t h e  P e gl oti c as e  + I M M  P eri o d f or  M T X  P ol y gl ut a m at e  l e v els. 
1 9.  F or  all s u bj e cts, s er u m s a m pl es f or  P K  a n al ysis  will  b e  c oll e ct e d  pr i or t o p e gl oti c as e  i nf usi o n  a n d  aft er t h e  e n d  of i nf usi o n ( pri or t o  dis c h ar g e) o n  D a y  1  a n d  at t h e  W e e ks  2,  4, 
6,  8  a n d  3 6  Visits  a n d  pri or t o  p e gl oti c as e  i nf usi o n  o nl y  at t h e W e e ks  1 0,  1 4,  1 8,  2 2,  2 4;  at t h e  E n d  of  P e gl oti c as e I nf usi o ns  Visit (if  a p pli c a bl e);  a n d  W e e k  5 2/ E n d -of -
St u d y/ E arl y  T er mi n ati o n  Visit.  Visits f or fr e q u e nt s a m pli n g  of  a  s u bs et  of s u bj e cts  w h o  c o ns e nt  f or  a d diti o n al  n o n-i nf usi o n  visit  P K s a m pli n g (r a n d o m,  m or ni n g  pr ef err e d) 
will  o c c ur  at  W e e k  1  a n d  W e e k  7 .  
2 0.  S er u m s a m pl es f or  m e as ur e m e nt  of s U A l e v els  will  b e  c oll e ct e d  at t h e  S cr e e ni n g  Visit ( wit hi n  2  w e e ks  pri or t o t h e first  d os e  of  M T X  at  W e e k  -4), t h e  W e e k  -4  Visit ( pri or t o 
t h e first  d os e  of  M T X),  a n d t h e  W e e k -2  Visit;  wit hi n  4 8  h o urs  pri or t o  e a c h  p e gl oti c as e i nf usi o n ( e x c e pt  o n  D a y  1  w h e n  o nl y  1  pr e -i nf usi o n s a m pl e is r e q uir e d  a n d  will  b e 
dr a w n  at t h e sit e j ust  pri or t o t h e i nf usi o n);  a n d  aft er t h e  e n d  of  e a c h  p e gl oti c as e i nf usi o n  pri or t o  dis c h ar g e, fr o m t h e  P e gl oti c as e  + I M M  P eri o d t hr o u g h  w e e k  2 4  a n d  at 
W e e 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  e a c h  p e gl oti c as e i nf usi o n  at  W e e 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 h e  P e gl oti c as e  + 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 oti c as e I nf usi o ns  Visit (if  a p pli c a bl e);   at t h e  W e e k  5 2/ E n d  of st u d y/ E arl y  T er mi n ati o n  Visit  a n d  M o nt h  3  a n d  M o nt h  6  Visits.  Visits f or fr e q u e nt s a m pli n g of  a 


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  2 8   of 8 4  
s u bs et  of s u bj e cts  w h o  c o ns e nt  f or  a d diti o n al  n o n-i nf usi o n  visit  P K s a m pli n g (r a n d o m,  m or ni n g  pr ef err e d) will  o c c ur  at  W e e k  1  a n d  W e e k  7 .  T w o s e p ar at e s a m pl es/t u b es  of 
bl o o d  s h o ul d  b e  c oll e ct e d  wit hi n  4 8  h o urs  pri or t o t h e  p e gl oti c as e  i nf usi o n ( e x c e pt  o n  D a y 1  w h e n  o nl y  1 pr e -i nf usi o n s a m pl e is r e q uir e d f or t h e  c e ntr al l a b or at or y).  O n e 
s a m pl e/t u b e  will  b e  ass ess e d  b y t h e sit e’s l o c al l a b or at or y t o  b e  us e d f or  o n -st u d y s u bj e ct  m a n a g e m e nt;  pr e -i nf usi o n s U A r es ults  m ust  b e r e p ort e d  b y t h e l o c al  or  c e ntr al 
l a b or at or y  pri or t o  e a c h p e gl oti c as e  i nf usi o n. If  a l o c al l a b or at or y s a m pl e is  dr a w n ( wit hi n  4 8  h o urs  pri or t o t h e p e gl oti c as e  i nf usi o n),  a s a m pl e f or t h e  c e ntr al l a b or at or y  will 
b e  dr a w n  pri or t o t h e  p e gl oti c as e  i nf usi o n  o n t h e  d a y  of t h e  visit.  T h e s e c o n d s a m pl e/t u b e  will  b e s e nt t o t h e  c e ntr al l a b or at or y f or  a n al y sis  a n d r e c or di n g i n t h e  d at a b as e.  S e e 
t h e  L a b or at or y  M a n u al f or i nstr u cti o ns f or  alt er n at e s c e n ari os. A s u bj e ct  wit h  s U A l e v el > 6  m g/ d L ( b as e d  o n t h e l o c al  or  c e ntr al l a b or at or y)  at  2  c o ns e c uti v e st u d y  visits, 
b e gi n ni n g  wit h t h e  W e e k  2  Visit,  wi ll  b e  cl assifi e d  as  a  n o n-r es p o n d er  a n d s u bj e cts  will  c o m pl et e t h e  E n d  of  P e gl oti c as e  Tr e at m e nt  Visit.   T h e s u bj e ct  will  c o nti n u e  o n  st u d y 
( wit h o ut tr e at m e nt).  
2 1.  S er u m s a m pl es f or  e v al u ati o n  of  a nti -P E G   a n d a nti -uri c as e I g G  a nti b o di es  will  b e  c oll e ct e d  pri or t o t h e  p e gl oti c as e  i nf usi o n  o n  D a y 1  a n d  at t h e  W e e ks  2,  4,  6,  8 , 1 0,  1 4,  1 8, 
2 2,  2 4,  3 6, if  a p pli c a bl e t h e  E n d  of  P e gl oti c as e I nf usi o ns  Visit  a n d  W e e k  5 2/ E n d  of  St u d y/ E arl y  T er mi n ati o n  Visits  a n d  at t h e  3  M o nt h  P ost  Tr e at m e nt  Visit.  Visits f or 
fr e q u e nt s a m pli n g  of  a s u bs et  of s u bj e cts  w h o  c o ns e nt f or  a d diti o n al  n o n-i nf usi o n  visit  P K s a m pli n g (r a n d o m,  m or ni n g  pr ef err e d) will  o c c ur  at  W e e k  1  a n d  W e e k  7 . I n t h e 
e v e nt  of  a n  A E s us p e ct e d t o  b e  a n i nf usi o n r e a cti o n,  a s er u m s a m pl e  will  b e  c oll e ct e d  at t h at ti m e  or  at t h e s u bs e q u e nt  visit  f or  e v al u ati o n  of p e gl oti c as e   a nti b o di es. 
2 2.  F or  w o m e n  of  c hil d b e ari n g  p ot e nti al,  a s er u m  pr e g n a n c y t est  will  b e  p erf or m e d  at t h e  S cr e e ni n g  Visit.   A  uri n e  pr e g n a n c y t est  will  b e  p erf or m e d  at  e a c h  visit  u ntil  3 0  d a ys 
aft er t h e l ast  M T X  d os e if t h e s u bj e ct  h as  n ot  o v ul at e d;  at t h e  E n d  of  P e gl oti c as e I nf usi o ns  Visit (if  a p pli c a bl e), t h e  W e e k  5 2/ E n d  of st u d y/ E arl y  T er mi n ati o n  Visit  pr o c e d ur es 
a n d  at t h e  3 0  d a y f oll o w  u p  p h o n e/ e -m ail /sit e  visit it is  d et er mi n e d t h at t h e s u bj e ct  h as  n ot  o v ul at e d si n c e t h e l ast  d os e  of  M T X;  a  uri n e  pr e g n a n c y t est  will  b e  p erf or m e d at  all 
ot h er i n di c at e d  visits.  
2 3.  S u bj e cts  w h o  ar e  n o n -v as e ct o mi z e d  m al es  will  b e  as k e d  3  m o nt hs  aft er  M T X  dis c o nti n u ati o n r e g ar di n g  p art n er  pr e g n a n c y.   T his  will  o c c ur  at  a r e g ul at or y s c h e d ul e d  visit  or 
b y  a s e p ar at e  p h o n e/ e m ail /sit e visit . 
2 4.  T h e I n v esti g at or  will r e vi e w t h e  cli ni c al st at us  of t h e s u bj e ct  at t h e  W e e k  2 4  Visit  a n d t h e  E n d  of  P e gl oti c as e I nf usi o ns  Visit (if  a p pli c a bl e)  or t h e  W e e k  5 2/ E n d  of st u d y/ E arl y 
T er mi n ati o n  Visit . 
2 5.    S u bj e cts  w h o  e n d tr e at m e nt  d u e t o t h e st o p pi n g r ul es  or  ot h er r e as o ns s h o ul d  c o m pl et e t h e  E n d  of  P e gl o ti c as e  Tr e at m e nt  Visit  wit hi n  2  w e e ks  of t h e l ast i nf usi o n.   S u bj e cts 
s h o ul d r e m ai n  o n st u d y.   S e e  Pr ot o c ol  S e cti o n  9. 5. 6. 3  f or  d et ails  o n  visits  a n d  pr o c e d ur es. 
2 6.    S u bj e cts  will r et ur n t o t h e sit e  3  m o nt hs  a n d  6  m o nt hs f oll o wi n g t h eir fi n al i nf usi o n f or f oll o w -u p  pr o c e d ur es.   
.


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  V er si o n  2. 0  1 0- J ul- 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  2 9   of 8 4  
  
E n d p oi nt s  
  
Pri m ar y  Effi c a c y  E n d p oi nt  
T h e  pri m ar y  effi c a c y  e n d p oi nt i s t h e  pr o p orti o n  of  M o nt h  6 ( W e e k s  2 0,  2 2,  a n d  2 4) r e s p o n d er s, 
d efi n e d  a s  s u bj e ct s  a c hi e vi n g  a n d  m ai nt ai ni n g  s U A  < 6  m g/ d L f or  at l e a st  8 0 %  of t h e  ti m e  d uri n g 
M o nt h  6.  
  
S e c o n d ar y  Effi c a c y  E n d p oi nt s  
T h e  s e c o n d ar y  effi c a c y  e n d p oi nt s  ar e:   
•  
T h e  pr o p orti o n  of  M o nt h  3 ( W e e k s  1 0,  1 2,  a n d  1 4) r e s p o n d er s,  d efi n e d  a s  s u bj e ct s 
a c hi e vi n g  a n d  m ai nt ai ni n g  s U A  < 6  m g/ d L f or  at l e a st  8 0 %  of t h e ti m e  d uri n g  M o nt h  3.  
•    Th e  pr o p orti o n  of  o v er all r e s p o n d er s,  d efi n e d  a s  s u bj e ct s  a c hi e vi n g  a n d  m ai nt ai ni n g  s U A 
< 6  m g/ d L f or  at l e a st  8 0 %  of t h e ti m e  d uri n g  M o nt h  3 ( W e e k s  1 0,  1 2  a n d  1 4)  a n d  M o nt h 
6 ( W e e k s  2 0,  2 2  a n d  2 4)  c o m bi n e d.  
•  
T h e  pr o p orti o n  of  5  m g/ d L r e s p o n d er s  d uri n g  M o nt h  3,  d uri n g  M o nt h  6,  a n d  o v er all 
( M o nt h s  3  a n d  6  c o m bi n e d),  d efi n e d  a s  s u bj e ct s  a c hi e vi n g  a n d  m ai nt ai ni n g  s U A  <  5 
m g/ d L f or  at l e a st  8 0 %  of t h e ti m e  d uri n g  e a c h ti m e p oi nt.  
•  
T h e  m e a n  c h a n g e fr o m  b a s eli n e t o  W e e k s  1 4,  2 4,  3 6,  a n d  5 2 i n  s U A.  
  
E x pl or at or y  E n d p oi nt s 
T h e  e x pl or at or y  effi c a c y  e n d p oi nt s  ar e:   
•  
T h e  pr o p orti o n  of  M o nt h  9 ( W e e k s  3 2,  3 4  a n d  3 6) r e s p o n d er s,  d efi n e d  a s  s u bj e ct s 
a c hi e vi n g  a n d  m ai nt ai ni n g  s U A  < 6  m g/ d L f or  at l e a st  8 0 %  of t h e ti m e  d uri n g  M o nt h  9.  
•  
T h e  pr o p orti o n  of  M o nt h  1 2 ( W e e k s  4 8,  5 0  a n d  5 2) r e s p o n d er s,  d efi n e d  a s  s u bj e ct s 
a c hi e vi n g  a n d  m ai nt ai ni n g  s U A  < 6  m g/ d L f or  at l e a st  8 0 %  of t h e ti m e  d uri n g  M o nt h  1 2.  
•  
T h e  pr o p orti o n  of  M o nt h  9 ( W e e k s  3 2,  3 4  a n d  3 6)  5  m g/ d L r e s p o n d er s,  d efi n e d  a s 
s u bj e ct s  a c hi e vi n g  a n d  m ai nt ai ni n g  s U A  < 5  m g/ d L f or  at l e a st  8 0 %  of t h e ti m e  d uri n g 
M o nt h  9.  
•  
T h e  pr o p orti o n  of  M o nt h  1 2 ( W e e k s  4 8,  5 0  a n d  5 2)  5  m g/ d L r e s p o n d er s,  d efi n e d  a s 
s u bj e ct s  a c hi e vi n g  a n d  m ai nt ai ni n g  s U A  < 5  m g/ d L f or  at l e a st  8 0 %  of t h e ti m e  d uri n g 
M o nt h  1 2.  
•  
T h e ti m e t o fir st  pr e- i nf u si o n s U A  >  6  m g/ d L  i n  s u bj e ct s r e c ei vi n g  p e gl oti c a s e  wit h  M T X. 
•  
T h e ti m e t o t w o  c o n s e c uti v e  pr e- i nf u si o n s U A s  >  6  m g/ d L ( st o p pi n g r ul e)  i n  s u bj e ct s 
r e c ei vi n g  p e gl oti c a s e  wit h  M T X. 
•  
T h e  m e a n  c h a n g e fr o m  b a s eli n e t o  W e e k s  2 4,  3 6,  a n d  5 2 i n  ur at e  v ol u m e  a n d  b o n e 
er o si o n s  d u e t o  g o ut  u si n g  D E C T.  
•  
T h e  m e a n  c h a n g e fr o m  b a s eli n e i n  n u m b er  of j oi nt s  aff e ct e d  b y t o p hi  
•  
T h e  m e a n  c h a n g e fr o m  b a s eli n e t o  W e e k s  1 4,  2 4,  3 6,  a n d  5 2 i n t e n d er j oi nt  c o u nt ( 6 8 
p oi nt  s c al e).  


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  3 0   of 8 4  
•  
T h e  m e a n  c h a n g e fr o m  b a s eli n e t o  W e e k s  1 4,  2 4,  3 6,  a n d  5 2 i n  s w oll e n j oi nt  c o u nt ( 6 6 
p oi nt  s c al e).  
•  
T h e  m e a n  c h a n g e fr o m  b a s eli n e t o  W e e k s  1 4,  2 4,  3 6,  a n d  5 2 i n  H A Q -DI.  
•  
T h e  m e a n  c h a n g e fr o m  b a s eli n e t o  W e e k s  1 4,  2 4,  3 6,  a n d  5 2 i n  H A Q  p ai n  s c or e.  
•  
T h e  m e a n  c h a n g e fr o m  b a s eli n e t o  W e e k s  1 4,  2 4,  3 6,  a n d  5 2 i n  H A Q  h e alt h  s c or e.  
•  
T h e  m e a n  c h a n g e fr o m  b a s eli n e t o  W e e k s  1 4,  2 4,  3 6,  a n d  5 2 i n  p ati e nt  gl o b al 
a s s e s s m e nt  of  g o ut.  
•  
T h e  m e a n  c h a n g e fr o m  b a s eli n e t o  W e e k s  1 4,  2 4,  3 6,  a n d  5 2 i n  p h y si ci a n  gl o b al 
a s s e s s m e nt  of  g o ut.  
•  
T h e  m e a n  c h a n g e fr o m  b a s eli n e t o  W e e k s  1 4,  2 4,  3 6,  a n d  5 2 i n  s u bj e ct  a s s e s s m e nt  of 
a v er a g e, l e a st,  a n d  w or st j oi nt  p ai n.  
•  
T h e  pr o p orti o n  of  s u bj e ct s  a c hi e vi n g  2 0 %,  5 0 %,  or  7 0 % i m pr o v e m e nt  b a s e d  o n  g o ut 
c hr o ni c r e s p o n s e  crit eri a  at  W e e k s  1 4,  2 4,  3 6,  a n d  5 2.  
  
P h ar m a c o ki n eti c  a n d  A nti -dr u g  A nti b o d y  E n d p oi nt s  
T h e  P K  a n d  a nti -dr u g  a nti b o d y  e n d p oi nt s  ar e:   
•   P K  of  p e gl oti c a s e i n  s u bj e ct s r e c ei vi n g  c o n c o mit a nt  M T X.  
•   I n ci d e n c e  of  a nti-P E G  a n d  a nti -Uri c a s e I g G  a nti b o di e s.  
    
S af et y a n d  T ol er a bilit y  E n d p oi nt s  
S af et y  a n d t ol er a bilit y  e n d p oi nt s  ar e:  
•   I n ci d e n c e  of I R s,  a n a p h yl a xi s,  g o ut fl ar e s,  c ar di o v a s c ul ar  e v e nt s,  a n d t h e  A E/ S A E  pr ofil e 
o v er all,  a n d  p ot e nti all y  attri b ut e d t o t h e  c o m bi n ati o n  of  p e gl oti c a s e  a n d  M T X.  


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  3 1   of 8 4  
  
A n al y si s  P o p ul ati o n s  
T h e f oll o wi n g  a n al y si s  p o p ul ati o n s  will  b e  d efi n e d f or t hi s  st u d y:   
  
I nt e nt-t o-Tr e at  P o p ul ati o n  
T h e I nt e nt -t o-Tr e at  (I T T)  p o p ul ati o n will i n cl u d e  all  e nr oll e d  s u bj e ct s  w h o t a k e  at l e a st  o n e  d o s e 
of  M T X.  
T h e I T T  will  b e  u s e d f or  effi c a c y  a n al y s e s  a n d  s af et y  a n al y s e s .  
  
M o difi e d I nt e nti o n -t o-Tr e at  P o p ul ati o n  
T h e  M o difi e d I nt e nti o n -t o-Tr e at ( mI T T)  p o p ul ati o n  will i n cl u d e  all  e nr oll e d  s u bj e ct s  w h o r e c ei v e 
at l e a st  1  d o s e  of  p e gl oti c a s e .  
T h e  mI T T  p o p ul ati o n  will  b e  u s e d f or  effi c a c y  a n al y s e s  a n d  s af et y  a n al y s e s.  
If t h e  mI T T  p o p ul ati o n  a n d I T T  p o p ul ati o n  ar e i d e nti c al, t h e  s u m m ari e s  will  b e  p erf or m e d  o nl y 
f or t h e  mI T T  p o p ul ati o n. 
  
P h ar m a c o ki n eti c  P o p ul ati o n  
T h e  P h ar m a c o ki n eti c ( P K)  P o p ul ati o n  will i n cl u d e  all  e nr oll e d  s u bj e ct s  w h o r e c ei v e  at l e a st  1 
d o s e  of  p e gl oti c a s e  a n d  h a v e  a  p o st -p e gl oti c a s e  s a m pl e  e v al u a bl e f or  P K  a n al y si s.  
T h e  P K  p o p ul ati o n  will  b e  u s e d f or  all  p h ar m a c o ki n eti c  a n al y s e s.  
  
Pr ot o c ol  D e vi ati o n s  
Pr ot o c ol  d e vi ati o n s  ar e  e nt er e d i nt o t h e  e C R F  s y st e m.  D e vi ati o n s  will  b e  c at e g ori z e d  a s  m aj or  or  
mi n or.  D e vi ati o n s  will  b e  cl a s sifi e d  a s  o c c urri n g i n t h e  S cr e e ni n g,  M T X  R u n -i n  P eri o d, P e gl oti c a s e 
+ I M M   P eri o d,  or  F oll o w-u p  P eri o d . U si n g t h e I T T,  mI T T,  a n d  P K  p o p ul ati o n,  m aj or  d e vi ati o n s  will 
b e  s u m m ari z e d  b y t y p e  a n d  p eri o d  of  o c c urr e n c e .  


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  3 2   of 8 4  
  
G e n er al  A s p e ct s f or  St ati sti c al  A n al y si s  
  
G e n er al  M et h o d s  
T h e f oll o wi n g  c o n v e nti o n s  will  b e  utili z e d i n t h e  a n al y s e s:   
•   I n  g e n er al,  d e s cri pti v e  s u m m ari e s  will  b e  pr o vi d e d.  Effi c a c y  s u m m ari e s will  b e  pr o vi d e d 
s h o wi n g  c ol u m n s  f or  b ot h t h e I T T  a n d  mI T T  p o p ul ati o n.  S af et y  s u m m ari e s  will b e 
pr o vi d e d f or t h e I T T  a n d  mI T T  p o p ul ati o n.  If t h e I T T  p o p ul ati o n  a n d  mI T T  p o p ul ati o n  ar e 
i d e nti c al, t h e n  o nl y t h e  mI T T  p o p ul ati o n  s u m m ari e s  will  b e  pr o d u c e d. 
•   T h e f oll o wi n g  c ol u m n l a b el s  will  b e  u s e d: “I T T  P o p ul ati o n”, “ mI T T  P o p ul ati o n”,  or “ P K 
P o p ul ati o n” . If  a  s u m m ar y t a bl e i s  a p pli c a bl e t o  a  si n gl e  p o p ul ati o n, t h e  p o p ul ati o n  will  b e 
st at e d i n t h e  s u m m ari z ati o n  c ol u m n.  
•   U nl e s s  ot h er wi s e i n di c at e d,  c o nti n u o u s  v ari a bl e s  will  b e  s u m m ari z e d  u si n g t h e  n u m b er 
of  o b s er v ati o n s ( n),  m e a n,  st a n d ar d  d e vi ati o n ( S D),  m e di a n,  mi ni m u m ( mi n),  a n d 
m a xi m u m ( m a x).  C at e g ori c al  v ari a bl e s  will  b e  s u m m ari z e d  u si n g  n u m b er  of  o b s er v ati o n s 
( n), fr e q u e n c y  a n d  p er c e nt a g e s  of  s u bj e ct s. 
•   T h e  s a m e  n u m b er  of  d e ci m al  pl a c e s  a s t h e r a w  d at a  will  b e  pr e s e nt e d  w h e n r e p orti n g 
mi n  a n d  m a x,  1  m or e  d e ci m al  pl a c e t h a n i n t h e r a w  d at a  will  b e  pr e s e nt e d  w h e n 
r e p orti n g  m e a n  a n d  m e di a n,  a n d  2  m or e  d e ci m al  pl a c e s t h a n i n t h e r a w  d at a  will  b e 
pr e s e nt e d  w h e n r e p orti n g  S D.  
•   U nl e s s  s p e cifi e d,  c o nfi d e n c e i nt er v al s ( CI)  will  b e  b a s e d  o n  9 5 %  c o nfi d e n c e  a n d t w o -
si d e d.  
•   If  m ulti pl e  a s s e s s m e nt s  o c c ur  at  a  gi v e n ti m e  p oi nt, t h e l at e st  v al u e  will  b e  u s e d.  
•   All r el e v a nt  s u bj e ct  d at a  will  b e i n cl u d e d i n li sti n g s.  All  s u bj e ct s  e nt er e d i nt o t h e 
d at a b a s e  will  b e i n cl u d e d i n  s u bj e ct  d at a li sti n g s.  
•   A d diti o n al  pr o gr a m mi n g  c o n si d er ati o n s  ar e  pr o vi d e d i n  S e cti o n  1 2 . 
  
K e y  D efi niti o n s  
  
B a s eli n e  
T w o  diff er e nt  b a s eli n e  v al u e s  will  b e  d efi n e d.   
T h e fir st  b a s eli n e  v al u e  will  b e  d efi n e d  a s t h e l a st  m e a s ur e m e nt t a k e n  pri or t o fir st  d o si n g  of 
M T X i n t h e  M T X  R u n -i n P eri o d  ( c o n si d eri n g  u n s c h e d ul e d  vi sit s  w h e n  a v ail a bl e). T hi s  b a s eli n e  
will  b e r ef err e d t o  a s t h e  M T X  b a s eli n e.  C h a n g e fr o m  M T X  B a s eli n e  will  b e  d efi n e d  a s t h e 
m e a s ur e m e nt  at  e a c h ti m e  p oi nt  mi n u s t h e  B a s eli n e  v al u e.  T h e  M T X  b a s eli n e  will  b e  d efi n e d f or 
all  a s s e s s m e nt s , i n cl u di n g  s U A,  D E C T  a s s e s s m e nt s, j oi nt s  aff e ct e d  b y t o p hi, t e n d er j oi nt 
c o u nt s,  s w oll e n j oi nt  c o u nt s,  p ati e nt  gl o b al  a s s e s s m e nt,  p h y si ci a n  gl o b al  a s s e s s m e nt,  s u bj e ct 
a s s e s s m e nt  of  p ai n  a s s o ci at e d  wit h  g o ut,  G C R, l a b or at or y r e s ult s,  vit al  si g n s,  a n d  
el e ctr o c ar di o gr a m s.  
T h e  s e c o n d  b a s eli n e  v al u e, t o  b e  u s e d i n t h e  a s s e s s m e nt s  of  c h a n g e fr o m  b a s eli n e i n  s U A, 
H A Q -DI,  H A Q -H e alt h  s c or e,  H A Q -p ai n  s c or e,  p ati e nt  gl o b al  a s s e s s m e nt,  p h y si ci a n  gl o b al 
a s s e s s m e nt,  t e n d er j oi nt  c o u nt,  a n d  s w oll e n j oi nt  c o u nt,  will  b e  d efi n e d  a s t h e l a st  m e a s ur e m e nt 
t a k e n  pri or t o t h e fir st i nf u si o n  of t h e  p e gl oti c a s e i n t h e  P e gl oti c a s e  + I M M  p eri o d. T hi s  b a s eli n e 


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  3 3   of 8 4  
will  b e r ef err e d t o  a s t h e  p e gl oti c a s e  b a s eli n e.  C h a n g e fr o m  p e gl oti c a s e  b a s eli n e  will  b e  d efi n e d 
a s t h e  m e a s ur e m e nt  at  e a c h ti m e  p oi nt  mi n u s t h e  b a s eli n e  v al u e.  
  
St u d y  D a y  
T w o  diff er e nt  st u d y  d a y s  will  b e  c al c ul at e d.  T h e  fir st  st u d y  d a y  will  b e  d et er mi n e d r el ati v e t o t h e 
fir st  d o s e  of  M T X i n t h e  M T X  R u n-i n P eri o d.  T h e  s e c o n d  st u d y  d a y  will  b e  d et er mi n e d r el ati v e t o 
t h e fir st i nf u si o n of  p e gl oti c a s e . 
F or  b ot h  st u d y  d a y  c al c ul ati o n s,  f or st u d y  d a y s  o n  or  aft er t h e  fir st  d o s e  d at e t h e  st u d y d a y  will 
b e  c al c ul at e d  a s  a s s e s s m e nt  d at e  –  fir st  d o s e  d at e  +  1.  F or  st u d y  d a y s  pri or t o t h e fir st  d o s e 
d at e,  s t u d y d a y  will  b e  c al c ul at e d  a s  a s s e s s m e nt  d at e  –  fir st  d o s e  d at e. T h er e  will  b e  n o  s t u d y 
d a y  0.   
  
A g e   
A g e  will  b e  c al c ul at e d  a s  (i nf or m e d  c o n s e nt  d at e - d at e  of  birt h  +  1) /  3 6 5. 2 5  a n d tr u n c at e d t o 
c o m pl et e  y e ar s . If t h e  d at e  of  birt h i s  o nl y  p arti all y  a v ail a bl e, t h e fir st  of t h e  m o nt h  will  b e 
i m p ut e d f or  a n y  mi s si n g  d a y s  a n d  J a n u ar y  will  b e i m p ut e d f or  a n y  mi s si n g  m o nt h s. 
  
Mi s si n g  D at a  
  
M e di c ati o n  D at e s  
F or  pri or  a n d  c o n c o mit a nt  m e di c ati o n s  wit h i n c o m pl et e  d at e s, t h e f oll o wi n g r ul e s  will  b e  u s e d t o 
i m p ut e  st art  a n d/ or  st o p  d at e s f or t h e  p ur p o s e s  of  d et er mi ni n g if  a  m e di c ati o n i s  pri or,  c o n c o mit a nt 
i n t h e  M T X  R u n-i n P eri o d,  or  c o n c o mit a nt  i n t h e P e gl oti c a s e  +  I M M  Peri o d . I m p ut e d  d at e s  will  n ot 
b e  pr e s e nt e d i n t h e  d at a li sti n g s.  
F or  p arti al  st art  d at e s:  
•   If t h e  m o nt h  a n d  y e ar  ar e  pr o vi d e d  a n d  d a y i s  mi s si n g,  a n d t h e  m o nt h  a n d  y e ar  m at c h t h e 
m o nt h  a n d t h e  y e ar  of t h e fir st   pe gl oti c a s e  d o s e  d at e  A N D  m at c h t h e  m o nt h  a n d t h e  y e ar 
of t h e fir st  M T X  d o s e (i. e. t h e  M T X  a n d  p e gl oti c a s e  st art e d i n t h e  s a m e  m o nt h), t h e  d a y  of 
t h e fir st  d o s e  d at e of  M T X  will  b e i m p ut e d.  Ot h er wi s e, if t h e  m o nt h  a n d  y e ar  m at c h t h e 
m o nt h  a n d  y e ar  of t h e fir st  p e gl oti c a s e  d o s e  d at e, t h e n t h e fir st  d o s e  d at e  of  p e gl oti c a s e 
will  b e i m p ut e d.  Ot h er wi s e, if t h e  m o nt h  a n d  y e ar  m at c h t h e  m o nt h  a n d  y e ar  of t h e fir st 
M T X  d o s e  d at e, t h e n t h e fir st  d o s e  d at e  of  M T X  will  b e i m p ut e d.  Ot h er wi s e, t h e fir st  of t h e 
m o nt h  will  b e  u s e d.   
•   If t h e  y e ar i s pr o vi d e d  a n d t h e  m o nt h  a n d  d a y   ar e mi s si n g  a n d t h e  y e ar  m at c h e s t h e  y e ar 
of t h e fir st   pe gl oti c a s e  d o s e  d at e  a n d t h e  y e ar  m at c h e s t h e  y e ar  of t h e fir st  M T X  d o s e 
d at e,  t h e   m o nt h   a n d   d a y   of   t h e  fir st   M T X   d at e   will   b e  i m p ut e d.  Ot h er wi s e,  if  t h e   y e ar  
m at c h e s t h e  y e ar  of t h e fir st  d o s e  of  p e gl oti c a s e , t h e fir st  d o s e  d at e  of p e gl oti c a s e  will  b e 
i m p ut e d.  Ot h er wi s e, if t h e  y e ar  m at c h e s t h e  y e ar  of t h e fir st  M T X  d at e, t h e n t h e fir st  d o s e 
d at e  of  M T X  will  b e i m p ut e d.  Ot h er wi s e,  J a n u ar y  will  b e  u s e d.   
•   If t h e  st art  d at e i s  c o m pl et el y  mi s si n g, t h e  st art  d at e  will  n ot  b e i m p ut e d. If t h e  st o p  d at e i s 
aft er fir st  d o s e  d at e  of  p e gl oti c a s e , t h e  m e di c ati o n  will  b e  c o n si d er e d t o  b e  b ot h  pri or, 
c o n c o mit a nt i n t h e  M T X  R u n -i n  Peri o d,  a n d  c o n c o mit a nt i n t h e  P e gl oti c a s e  + I M M   Peri o d. 


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  3 4   of 8 4  
If  t h e   st o p   d at e  i s   aft er  t h e  fir st   d o s e   d at e   of   M T X,   b ut   pri or  t o  t h e  fir st  d o s e   d at e   of  
p e gl oti c a s e , t h e  m e di c ati o n  will b e  c o n si d er e d t o  b e  pri or  a n d  c o n c o mit a nt i n t h e  M T X 
R u n -i n P eri o d.  If t h e  st o p  d at e i s  pri or t o t h e fir st  d o s e  d at e of  M T X , t h e  m e di c ati o n  will  b e 
c o n si d er e d t o  b e  pri or  o nl y.   
•   If t h e  st o p  d at e i s  c o m pl et e  a n d t h e i m p ut e d  st art  d at e i s  aft er t h e  a ct u al  st o p  d at e, t h e n 
t h e  st art  d at e  will  b e i m p ut e d  a s t h e  st o p  d at e. 
F or  p arti al  st o p  d at e s:  
•   If t h e  m o nt h  a n d  y e ar  of  st o p  ar e  pr o vi d e d,  b ut t h e  d a y i s  mi s si n g, t h e n t h e l a st  d a y  of t h e 
m o nt h  will  b e  u s e d.  
•   If t h e  y e ar  of  st o p i s  pr o vi d e d,  b ut t h e  m o nt h  a n d  d a y  ar e  mi s si n g, t h e n  D e c e m b er 3 1 st of 
t h at  y e ar  will  b e  u s e d.  
•   If t h e  st o p  d at e i s  c o m pl et el y  mi s si n g, t h e n t h e  d at e  of l a st  st u d y  vi sit  will  b e  u s e d.  
  
A d v er s e  E v e nt s  
F or  a d v er s e  e v e nt s  wit h i n c o m pl et e  d at e s, t h e f oll o wi n g r ul e s  will  b e  u s e d t o i m p ut e  st art  a n d/ or 
st o p  d at e s f or t h e  s ol e  p ur p o s e  of  d et er mi ni n g if  a n  A E i s tr e at m e nt -e m er g e nt  i n t h e  M T X R u n -i n 
P eri o d  or  P e gl oti c a s e  + I M M  P eri o d.  I m p ut e d  d at e s  will  n ot  a p p e ar i n t h e  d at a li sti n g s. 
F or  p arti al  st art  d at e s:  
•   If t h e  m o nt h  a n d  y e ar  of  a d v er s e  e v e nt  o n s et  ar e  pr o vi d e d  b ut  d a y i s  mi s si n g 
o   If t h e  m o nt h  a n d  y e ar  m at c h t h e  m o nt h  a n d  y e ar  of t h e fir st  d o s e  of  M T X i n t h e 
M T X   R u n -i n   P eri o d  A N D  m at c h  t h e   m o nt h   a n d   y e ar   of  t h e  fir st  i nf u si o n   of  
p e gl oti c a s e i n t h e  P e gl oti c a s e  + I M M  P eri o d, t h e fir st  d o s e  d at e  of  M T X i n t h e  R u n -
i n  P eri o d  will  b e i m p ut e d  a n d t h e  e v e nt  will  b e  c o n si d er e d tr e at m e nt  e m er g e nt i n 
t h e  M T X  R u n-i n  P eri o d a n d  P e gl oti c a s e  + I M M  P e ri o d.  
o   Ot h er wi s e, i f t h e  m o nt h  a n d  y e ar  m at c h t h e  m o nt h  a n d t h e  y e ar  of t h e fir st  d o s e 
d at e  of  p e gl oti c a s e , t h e  d a y  of t h e fir st i nf u si o n d at e  of  p e gl oti c a s e  will  b e i m p ut e d 
a n d  t h e   A E   will   b e   c o n si d er e d  tr e at m e nt -e m er g e nt   i n  t h e  P e gl oti c a s e  +  I M M  
P eri o d.   
o   Ot h er wi s e, if t h e  m o nt h  a n d  y e ar  m at c h t h e  m o nt h  a n d t h e  y e ar  of t h e fir st  d o s e 
d at e  of  M T X, t h e  d a y  of t h e fir st  d o s e  d at e  of  M T X  will  b e i m p ut e d  a n d t h e  A E  will 
b e  c o n si d er e d tr e at m e nt -e m er g e nt i n t h e  M T X  R u n -i n P eri o d.   
o   Ot h er wi s e,  t h e fir st  of t h e  m o nt h  will  b e  u s e d  a n d t h e tr e at m e nt-e m er g e nt  st at u s 
will  b e  a s s e s s e d r el ati v e t o t h e  fir st i nf u si o n d at e  of  p e gl oti c a s e  a n d t h e fir st  d o s e 
d at e  of  M T X .  
•   If t h e  y e ar  of  a d v er s e  e v e nt  o n s et i s  pr o vi d e d,  b ut t h e  m o nt h  a n d  d a y  ar e  mi s si n g 
o   If t h e  y e ar  m at c h e s t h e  y e ar  of t h e fir st  d o s e  of  M T X i n t h e  M T X  R u n-i n  P eri o d 
A N D  m at c h e s  t h e y e ar  of t h e fir st i nf u si o n  of  p e gl oti c a s e i n t h e  P e gl oti c a s e  + 
I M M  P eri o d, t h e fir st  d o s e  d at e  of  M T X i n t h e  R u n-i n  P eri o d  will  b e i m p ut e d  a n d 


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  3 5   of 8 4  
t h e  e v e nt  will  b e  c o n si d er e d tr e at m e nt  e m er g e nt i n t h e  M T X  R u n-i n  P eri o d a n d 
P e gl oti c a s e  + I M M  P eri o d . 
o   Ot h er wi s e, If  t h e  y e ar  m at c h e s t h e  y e ar  of t h e fir st i nf u si o n d at e  of  p e gl oti c a s e , t h e 
m o nt h  a n d t h e  d a y  of t h e fir st  i nf u si o n d at e  of  p e gl oti c a s e  will  b e i m p ut e d,  a n d t h e  
A E  will  b e  c o n si d er e d tr e at m e nt -e m er g e nt  i n t h e P e gl oti c a s e  + I M M  P eri o d.   
o   Ot h er wi s e, if t h e  y e ar  m at c h e s t h e  y e ar  of t h e fir st  d o s e  d at e  of  M T X, t h e  m o nt h 
a n d  d a y  of t h e fir st  d o s e  of  M T X  will  b e i m p ut e d  a n d t h e  A E  will  b e  c o n si d er e d 
tr e at m e nt-e m er g e nt i n t h e  M T X  R u n -i n  P eri o d.  
o   Ot h er wi s e,   J a n u ar y   1 st   will   b e   u s e d   a n d  t h e  tr e at m e nt -e m er g e nt   st at u s   will   b e  
a s s e s s e d r el ati v e t o t h e  d o si n g  st art  d at e  of  p e gl oti c a s e  a n d t h e fir st  d o s e  d at e  of 
M T X.  
•    If t h e  st art  d at e i s  c o m pl et el y  mi s si n g, t h e  A E  will  b e  c o n si d er e d tr e at m e nt-e m er g e nt  i n 
t h e    P e gl oti c a s e  +  I M M     Peri o d   a n d   t h e   M T X   R u n-i n   P eri o d,  u nl e s s  t h e   st o p   d at e  i s  
c o m pl et e  or  pr o vi d e s  e n o u g h  p arti al i nf or m ati o n t o r ul e  o ut  a tr e at m e nt -e m er g e nt  st at u s  
i n t h e  Tr e at m e nt P eri o d.  T hi s  s h o ul d  b e  a r ar e  o c c urr e n c e . 
If t h e  st o p  d at e i s  c o m pl et e  a n d t h e i m p ut e d  st art  d at e i s  aft er t h e  a ct u al  st o p  d at e, t h e n t h e  st art 
d at e  will  b e i m p ut e d  a s t h e  st o p  d at e.  
E v e nt s   wit h   mi s si n g  r el ati o n s hi p  t o   st u d y   dr u g  i n  t h e   M T X   R u n -i n   p eri o d   will   b e   c o n si d er e d  
“r el at e d” t o  M et h otr e x at e f or st ati sti c al  s u m m ari e s . E v e nt s  wit h  mi s si n g r el ati o n s hi p t o  st u d y  dr u g 
i n t h e  M T X  + I M M  p eri o d  will  b e  c o n si d er e d “r el at e d” t o  M et h otr e x at e a n d “r el at e d” t o  p e gl oti c a s e 
f or  st ati sti c al  s u m m ari e s. 
Mi s si n g  s e v eriti e s  will  b e  c o n si d er e d “ s e v er e” f or  st ati sti c al  s u m m ari e s.  
  
Vi sit  Wi n d o w s  
F or  all  a n al y s e s,  d at a  will  b e  s u m m ari z e d  a c c or di n g t o t h e  s c h e d ul e d  vi sit  a n d ti m e  p oi nt s  a s 
o utli n e d i n t h e  pr ot o c ol  a n d  b y t h e  vi sit  d e n ot e d  o n t h e  el e ctr o ni c  c a s e r e p ort f or m ( e C R F).  T h e 
r ef er e n c e  d at e  a s s o ci at e d  wit h  e a c h  vi sit i s  c oll e ct e d  o n t h e  Vi sit  D at e  e C R F  p a g e. F urt h er , t h e 
E n d   of   St u d y/ E arl y   T er mi n ati o n  ( E T)   vi sit  a n d  t h e  E n d   of   P e gl oti c a s e  I nf u si o n   Vi sit   will   b e  
wi n d o w e d  t o   a  vi sit   b a s e d   o n  t h e   st u d y   d a y   of   o c c urr e n c e  r el ati v e  t o  t h e  t ar g et   d a y   of   e a c h  
s c h e d ul e d  vi sit  a c c or di n g t o  T a bl e  1 ,  T a bl e  2, T a bl e  3 ,  T a bl e  4,  T a bl e  5,  a n d  T a bl e  6 b el o w . T a bl e 
1  s h o w s  wi n d o w s f or t h e  vit al  si g n  a s s e s s m e nt s,  g o ut  a s s e s s m e nt s,  a n d  s U A  c oll e cti o n s.  T a bl e 
2   s h o w s   wi n d o w s  f or  t h e   cli ni c al  l a b or at or y   a s s e s s m e nt s.   T a bl e   3   s h o w s  t h e   wi n d o w s  f or  
s w oll e n/t e n d er  j oi nt s,   H A Q,   p ati e nt   a n d   cli ni c i a n  gl o b al   a s s e s s m e nt   p ar a m et er s,  j oi nt   p ai n  
a s s e s s m e nt s . T a bl e  4  s h o w s t h e  wi n d o w s f or t h e  a s s e s s m e nt  of  D E C T  a n d t h e  n u m b er  of j oi nt s 
aff e ct e d  b y t o p hi.  T a bl e  5  s h o w  wi n d o w s f or  pr e -i nf u si o n  M T X  p oly gl ut a m at e  P K  a s s e s s m e nt s. 
T a bl e  6  s h o w s  wi n d o w s f or  p e gl oti c a s e  P K  a s s e s s m e nt s.  U n s c h e d ul e d  s U A  vi sit s,  a s s e s s e d  b y 
t h e  c e ntr al l a b or at or y  or l o c al l a b or at or y ( s e e  S e cti o n  9. 1),   will  b e  a s si g n e d  a n  a n al y si s  wi n d o w 
a c c or di n g t o t h e  wi n d o w  b el o w.  T h e s e  u n s c h e d ul e d  will  b e  u s e d f or t h e  d et er mi n ati o n  o f  s U A 
r e s p o n d er. 
T a bl e  1:  Vi sit  Wi n d o w s f or  A s si g ni n g  E n d  of  St u d y/ E T  a n d  E n d  of  P e gl oti c a s e  Vi sit s t o  a 
S c h e d ul e d  Vi sit  ( Vit al  Si g n s,  G o ut  A s s e s s m e nt s,  s U A  c oll e cti o n s) 


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  3 6   of 8 4  
St u d y  P eri o d  
 
Vi sit  
 
T ar g et  D a y a   
Wi n d o w f or 
R e a s si g n m e nt t o 
S c h e d ul e d  Vi sit  ( d a y s) 
P e gl oti c a s e  + I M M   
D a y  1  
1  
1  
 
W e e k  2  
1 5  
2  –  2 2  
 
W e e k  4  
2 9  
2 3  –  3 6  
 
W e e k  6  
4 3  
3 7  –  5 0  
 
W e e k  8  
5 7  
5 1  –  6 4  
 
W e e k  1 0  
7 1  
6 5  –  7 8  
 
W e e k  1 2  
8 5  
7 9  - 9 2  
 
W e e k  1 4  
9 9  
9 3  –  1 0 6  
 
W e e k  1 6  
1 1 3  
1 0 7  –  1 2 0  
 
W e e k  1 8  
1 2 7  
1 2 1  –  1 3 4  
 
W e e k  2 0  
1 4 1  
1 3 5  –  1 4 8  
 
W e e k  2 2  
1 5 5  
1 4 9  –  1 6 2  
 
W e e k  2 4  
1 6 9  
1 6 3  –  1 7 6  
 
W e e k  2 6  
1 8 3  
1 7 7  –  1 9 0  
 
W e e k  2 8  
1 9 7  
1 9 1  –  2 0 4  
 
W e e k  3 0  
2 1 1  
2 0 5  –  2 1 8  
 
W e e k  3 2  
2 2 5  
2 1 9  –  2 3 2  
 
W e e k  3 4  
2 3 9  
2 3 3  –  2 4 6  
 
W e e k  3 6  
2 5 3  
2 4 7  –  2 6 0  
 
W e e k  3 8  
2 6 7  
2 6 1  –  2 7 4  
 
W e e k  4 0  
2 8 1  
2 7 5  –  2 8 8  
 
W e e k  4 2  
2 9 5  
2 8 9  –  3 0 2  
 
W e e k  4 4  
3 0 9  
3 0 3  –  3 1 6  
 
W e e k  4 6  
3 2 3  
3 1 7  –  3 3 0  
 
W e e k  4 8  
3 3 7  
3 3 1  –  3 4 4  
 
W e e k  5 0  
3 5 1  
3 4 5  –  3 5 8  
 
W e e k  5 2  
3 6 5  
≥  3 5 9   
a St u d y   d a y s  i n  t h e   P e gl oti c a s e  +  I M M  P eri o d   will   b e   c al c ul at e d  r el ati v e  t o  t h e  fir st   d o s e   of  
P e gl oti c a s e . 
T a bl e  2 :  Vi sit  Wi n d o w s f or  A s si g ni n g E n d  of  St u d y/ E T  a n d  E n d  of  P e g l oti c a s e  Vi sits t o  a 
S c h e d ul e d  Vi sit  ( L a b or at or y  A s s e s s m e nt s) 
St u d y  P eri o d  
 
Vi sit  
 
T ar g et  D a y a   
Wi n d o w f or 
R e a s si g n m e nt t o 
S c h e d ul e d  Vi sit  ( d a y s) 
P e gl oti c a s e  +  I M M  
D a y  1  
1  
1  
 
W e e k  2  
1 5  
2  –  2 9  
 
W e e k  6  
4 3  
3 0  –  7 1  
 
W e e k  1 4  
9 9  
7 2  –  1 2 7  
 
W e e k  2 2  
1 5 5  
1 2 8  -1 6 2  


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  3 7   of 8 4  
St u d y  P eri o d  
 
Vi sit  
 
T ar g et  D a y a   
Wi n d o w f or 
R e a s si g n m e nt t o 
S c h e d ul e d  Vi sit  ( d a y s) 
 
W e e k  2 4  
1 6 9  
1 6 3  - 2 1 1  
 
W e e k  3 6  
2 5 3  
2 1 2  - 3 0 9  
 
W e e k  5 2  
3 6 5  
≥  3 1 0   
a St u d y   d a y s  i n  t h e   P e gl oti c a s e   +  I M M   P eri o d   will   b e   c al c ul at e d  r el ati v e  t o  t h e  fir st   d o s e   of  
P e gl oti c a s e.  
T a bl e  3 :  Vi sit  Wi n d o w s f or  A s si g ni n g  E T  a n d  E n d  of  P eg l oti c a s e  Vi sit s t o  a  S c h e d ul e d  Vi sit 
(S w oll e n/ T e n d er  J oi nt  C o u nt s,  H A Q,  P ati e nt  a n d  Cli ni ci a n  Gl o b al  A s s e s s m e nt s,  J oi nt  P ai n ) 
St u d y  P eri o d  
 
Vi sit  
 
T ar g et  D a y a   
Wi n d o w f or 
R e a s si g n m e nt t o 
S c h e d ul e d  Vi sit  ( d a y s) 
P e gl oti c a s e  + I M M   
D a y  1  
1  
1  
 
W e e k  1 4  
9 9  
2  –  1 3 4  
 
W e e k  2 4  
1 6 9  
1 3 5  –  2 1 1  
 
W e e k  3 6  
2 5 3  
2 1 2  –  3 0 9  
 
W e e k  5 2  
3 6 5  
≥  3 1 0   
a St u d y   d a y s  i n  t h e   P e gl oti c a s e   +  I M M   P eri o d   will   b e   c al c ul at e d  r el ati v e  t o  t h e  fir st   d o s e   of  
P e gl oti c a s e.  
 
T a bl e  4 :  Vi sit  Wi n d o w s f or  A s si g ni n g  E T  a n d  E n d  of  P eg l oti c a s e  Vi sit s t o  a  S c h e d ul e d  Vi sit 
( D E C T  a n d  J oi nt s  Aff e ct e d  b y  T o p hi) 
St u d y  P eri o d  
 
Vi sit  
 
T ar g et  D a y a   
Wi n d o w f or 
R e a s si g n m e nt t o 
S c h e d ul e d  Vi sit  ( d a y s) 
P e gl oti c a s e  + I M M   
D a y  1  
1  
1  
 
W e e k  2 4  
1 6 9  
2  –  2 1 1  
 
W e e k  3 6  
2 5 3  
2 1 2  –  3 0 9  
 
W e e k  5 2  
3 6 5  
≥  3 1 0   
a St u d y   d a y s  i n  t h e   P e gl oti c a s e   +  I M M   P eri o d   will   b e   c al c ul at e d  r el ati v e  t o  t h e  fir st   d o s e   of  
P e gl oti c a s e.  
T a bl e  5 :  Vi sit  Wi n d o w s f or  A s si g ni n g  E T  a n d  E n d  of  P e gl oti c a s e  Vi sit s t o  a  S c h e d ul e d  Vi sit  
( Pr e-i nf u si o n  M T X  P ol y gl ut a m at e  P K) 
St u d y  P eri o d  
 
Vi sit  
 
T ar g et  D a y a   
Wi n d o w f or 
R e a s si g n m e nt t o 
S c h e d ul e d  Vi sit  ( d a y s) 
P e gl oti c a s e  + I M M   
D a y  1  
1  
1  
 
W e e k  4  
2 9  
2  –  4 3  
 
W e e k  8  
5 7  
4 4  –  1 0 6  


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  3 8   of 8 4  
St u d y  P eri o d  
 
Vi sit  
 
T ar g et  D a y a   
Wi n d o w f or 
R e a s si g n m e nt t o 
S c h e d ul e d  Vi sit  ( d a y s) 
 
W e e k  2 2  
1 5 5  
1 0 7  –  1 6 2  
 
W e e k  2 4  
1 6 9  
1 6 3  –  2 1 1  
 
W e e k  3 6  
2 5 3  
≥  2 1 2   
a St u d y   d a y s  i n  t h e   P e gl oti c a s e   +  I M M   P eri o d   will   b e   c al c ul at e d  r el ati v e  t o  t h e  fir st   d o s e   of  
P e gl oti c a s e.  
T a bl e  6 :  Vi sit  Wi n d o w s f or  A s si g ni n g  E T  a n d  E n d  of  P e gl oti c a s e  Vi sit s t o  a  S c h e d ul e d  Vi sit  
( P e gl oti c a s e  P K) 
St u d y  P eri o d  
 
Vi sit  
 
T ar g et  D a y a   
Wi n d o w f or 
R e a s si g n m e nt t o 
S c h e d ul e d  Vi sit  ( d a y s) 
P e gl oti c a s e  + I M M   
D a y  1  
1  
1  
 
W e e k  1  
8  
2  –  1 1  
 
W e e k  2  
1 5  
1 2  –  2 2  
 
W e e k  4  
2 9  
2 3  –  3 6  
 
W e e k  6  
4 3  
3 7  –  4 6  
 
W e e k  7  
5 0  
4 7  –  5 3  
 
W e e k  8  
5 7  
5 4  –  6 4  
 
W e e k  1 0  
7 1  
6 5  –  8 5  
 
W e e k  1 4  
9 9  
8 6  –  1 1 3  
 
W e e k  1 8  
1 2 7  
1 1 4  –  1 4 1  
 
W e e k  2 2  
1 5 5  
1 4 2  –  1 6 2  
 
W e e k  2 4  
1 6 9  
1 6 3  –  2 1 1  
 
W e e k  3 6  
2 5 3  
2 1 2  –  3 0 9  
 
W e e k  5 2  
3 6 5  
≥  3 1 0   
a St u d y   d a y s  i n  t h e   P e gl oti c a s e   +  I M M   P eri o d   will   b e   c al c ul at e d  r el ati v e  t o  t h e  fir st   d o s e   of  
P e gl oti c a s e.  
 
I n t h e  e v e nt t h at a n  E n d  of  St u d y/ E T  or  E n d  of  P e gl oti c a s e  vi sit i s  r e a s si g n e d t o  a  vi sit f or  w hi c h 
t h e  s u bj e ct  h a s  s c h e d ul e d  d at a  c oll e ct e d, t h e  d at a fr o m t h e  n o mi n al  s c h e d ul e d  vi sit  will t a k e 
pr e c e d e n c e  a n d t h e  d at a fr o m t h e  E n d  of  St u d y/ E T  or  E n d  of  P e gl oti c a s e  vi sit  will  n ot  b e 
s u m m ari z e d.  If t h e  E n d  of  St u d y/E T  or  E n d  of  P e gl oti c a s e  vi sit  m a p s t o  a  vi sit  w h er e t h e 
a s s e s s m e nt  w a s  s c h e d ul e d t o  b e  c oll e ct e d,  a n d  a  s c h e d ul e d  c oll e cti o n i s  n ot  a v ail a bl e  at t h at 
ti m e  p oi nt, t h e  E n d  of  St u d y/E T  or  E n d  of  P e gl oti c a s e  vi sit  d at a  will  b e  s u m m ari z e d  i n t h e 
s c h e d ul e d  vi sit  a s s e s s m e nt.  
F or  vi sit  s u m m ari e s  a n d  c h a n g e s fr o m  b a s eli n e  s u m m ari e s,  E T  a n d  E n d  of  P e gl oti c a s e  vi sit s 
will  al s o  b e  s u m m ari z e d  s e p ar at el y, i n  a d diti o n t o  t h e  vi sit t o  w hi c h it  w a s  wi n d o w e d, f or 
s u m m ari e s  b y  vi sit . 


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  3 9   of 8 4  
  
P o oli n g  of  C e nt er s 
D at a fr o m  all  sit e s  will  b e  s u m m ari z e d t o g et h er f or  a n al y s e s . 
  
S u b gr o u p s  
N o  s u b gr o u p  a n al y s e s  ar e  pl a n n e d f or t h e  st u d y.  


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  4 0   of 8 4  
  
S u bj e ct  Di s p o siti o n   
A  s u m m ar y  of  s u bj e ct  di s p o siti o n  will  b e  pr o vi d e d i n cl u di n g t h e  n u m b er  of  s u bj e ct s  s cr e e n e d  a n d 
n u m b er   of   s cr e e n  f ai l ur e s  (r e c ei v e d   M T X   or   di d   n ot  r e c ei v e   M T X),   a s   w ell   a s  t h e   n u m b er   of  
s u bj e ct s i n  e a c h  a n al y si s  p o p ul ati o n (I T T,  mI T T,  a n d  P K  P o p ul ati o n s). I n  a d diti o n, t h e  n u m b er 
a n d  p er c e nt  of  s u bj e ct s i n  e a c h  of t h e f oll o wi n g  c at e g ori e s  will  b e  pr o vi d e d:  
•   E nt er e d t h e  M T X  R u n -i n  P eri o d 
•   C o m pl et e d t h e  M T X  R u n -i n P eri o d   
•   Di s c o nti n u e d  e arl y fr o m t h e  M T X  R u n -i n  P eri o d ( n oti n g  all  s u bj e ct s i n t h e  mI T T  will  h a v e 
c o m pl et e d  t h e   M T X   R u n -i n  P eri o d   b y   d efi niti o n)   al o n g   wit h   Pri m ar y  R e a s o n  f or  
Di s c o nti n u ati o n fr o m  R u n -I n  P eri o d. 
•     E nter e d t h e  P e gl oti c a s e  + I M M  P eri o d   
o   C o m pl et e d  Tr e at m e nt   
o   C o m pl et e d tr e at m e nt  at  W e e k  2 4 ( A m e n d m e nt  1 ) 
o   C o m pl et e d  tr e at m e nt  at t h e  5 2  W e e k ( A m e n d m e nt 2)  
o   Di s c o nti n u e d  Pr e m at ur el y fr o m t h e  P e gl oti c a s e  + I M M  P eri o d  al o n g  wit h  R e a s o n 
f or tr e at m e nt  di s c o nti n u ati o n  
o   C o m pl et e d  St u d y  
o   C o m pl et e d t h e  st u d y  at  W e e k  2 4   (A m e n d m e nt  1)  
o   C o m pl et e d t h e  st u d y  at  W e e k  5 2 ( A m e n d m e nt  2 ) 
o   Di s c o nti n u e d  Pr e m at ur el y fr o m t h e  st u d y i n  P e gl oti c a s e  + I M M  P eri o d  al o n g  wit h 
re a s o n f or  st u d y  di s c o nti n u ati o n i n t h e  P e gl oti c a s e  + I M M  P eri o d  
•   H a v e  3  m o nt h f oll o w -u p  
•   H a v e  6  m o nt h f oll o w -u p  
P er c e nt a g e s  will  b e  b a s e d  o n t h e  n u m b er  of  s u bj e ct s i n  e a c h  p o p ul ati o n.   
A  s e p ar at e  s u m m ar y  will  b e  pr o vi d e d  of t h e  n u m b er  a n d  p er c e nt a g e  of  s u bj e ct s  att e n di n g  e a c h 
vi sit   u si n g  t h e  I T T,   mI T T,   a n d   P K   P o p ul ati o n s.   P er c e nt a g e s   will   b e   b a s e d   o n  t h e   n u m b er   of  
s u bj e ct s i n t h e  p o p ul ati o n  s u m m ari z e d.  C o u nt s  a n d  p er c e nt a g e s  will  n ot  b e  pr e s e nt e d f or t h e 
di s c o nti n u ati o n s i n t h e  P e gl oti c a s e  + I M M  p eri o d f or t h e I T T  p o p ul ati o n. I T T  p o p ul ati o n  s u bj e ct s 
w h o r e c ei v e d  a n i nf u si o n  of  P e gl oti c a s e  ar e  al s o i n cl u d e d i n t h e  mI T T  p o p ul ati o n.   
A  s u m m ar y  of  s u bj e ct s,  wit h  s c h e d ul e d  vi sit s  c o m pl et e d,  will  b e  pr e s e nt e d f or t h e I T T,  mI T T,  a n d 
P K   p o p u l ati o n.  P er c e nt a g e s   will   b e   b a s e d   o n  t h e   n u m b er   of   s u bj e ct s  i n  t h e   p o p ul ati o n  
s u m m ari z e d.  
 


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  4 1   of 8 4  
  
D e m o gr a p hi c s,  Ot h er  C h ar a ct eri sti c s,  a n d  M e di c ati o n   
  
D e m o gr a p hi c  a n d  Ot h er  B a s eli n e  C h ar a ct eri sti c s  
D e s cri pti v e  s u m m ari e s  of  d e m o gr a p hi c  a n d  b a s eli n e  c h ar a ct eri sti c s  will  b e  pr e s e nt e d  o v er all f or 
t h e I T T  P o p ul ati o n,  mI T T  P o p ul ati o n,  a n d  P K  P o p ul ati o n.  T h e  c h ar a ct eri sti c s b ei n g  s u m m ari z e d  
i n cl u d e:  a g e,   a g e   c at e g or y  ( 1 8 -4 0   y e ar s ,  >4 0 -6 5   y e ar s),   s e x,  r a c e,   et h ni cit y,  ti m e   si n c e  fir st  
s y m pt o m s  of  g o ut  (i n  y e ar s), ti m e  si n c e fir st  di a g n o si s  of  g o ut (i n  y e ar s),  n u m b er  of g o ut  fl ar e s i n 
j oi nt s  o v er t h e  p a st  1 2  m o nt h s,  o c c urr e n c e s  of  o v er ni g ht  st a y s i n t h e  h o s pit al  d u e t o  g o ut pri or t o 
s cr e e ni n g ,  pri or  o c c urr e n c e  of t o p hi,  pri or  o c c urr e n c e  of  ki d n e y  st o n e s,  ki d n e y f u n cti o n  aff e ct e d 
b y  g o ut  hi st ori c all y, t o b a c c o  u s e  hi st or y ,  c urr e nt t o b a c c o  u s e  st at u s,  al c o h ol  u s e,  ot h er  s u b st a n c e 
u s e,  b a s eli n e  w ei g ht,  b a s eli n e  h ei g ht,  b a s eli n e  b o d y  m a s s i n d e x  ( B MI),  b a s eli n e  b o d y  s urf a c e 
ar e a ( B S A) . A g e, ti m e  si n c e fir st  s y m pt o m s  of  g o ut, ti m e  si n c e fir st  di a g n o si s  of  g o ut,  n u m b er  of 
g o ut fl ar e s  o v er t h e  p a st  1 2  m o nt h s,  b a s eli n e  w ei g ht,  b a s eli n e  h ei g ht,  b a s eli n e  B M A,  a n d  b a s eli n e 
B S A  will  b e  s u m m ari z e d  a s  c o nti n u o u s  v ari a bl e s  s h o wi n g  n u m b er  of  n o n -mi s si n g  v al u e s,  m e a n,  
st a n d ar d  d e vi ati o n,  m e di a n,  mi ni m u m  a n d  m a xi m u m.  A g e  c at e g or y,  s e x, r a c e,  o c c urr e n c e s  of 
o v er ni g ht  st a y s i n t h e  h o s pit al  d u e t o  g o ut,  pri or  o c c urr e n c e  of t o p hi,  pri or  o c c urr e n c e  of  ki d n e y 
st o n e s,  ki d n e y f u n cti o n  aff e ct e d  b y  g o ut,  t h e  ur at e l o w eri n g t h er a p y  hi st or y  ( all o p uri n ol  hi st or y, 
f e b o x u st at   hi st or y,   a n d   ot h er   ur at e-l o w eri n g  t h er a pi e s,   w hi c h   ar e  fr o m  t h e  i n v e sti g at or  
a s s e s s m e nt  of  cli ni c al  st at u s f or m), t o b a c c o  u s e  hi st or y,  c urr e nt t o b a c c o  u s e  st at u s,  al c o h ol  u s e, 
a n d  ot h er  s u b st a n c e  u s e  will  b e  s u m m ari z e d  u si n g  c at e g ori c al  v al u e s.  
 
W ei g ht  will  b e  c o n v ert e d t o  kil o gr a m s ( k g)  w h e n r e p ort e d i n  p o u n d s (l b s)  a s f oll o w s:  W ei g ht (i n 
k g)  =  w ei g ht (i n l b s) *  0. 4 5 3 6  
B MI  will  b e  c al c ul at e d  a s  W ei g ht ( k g) /  H ei g ht ( m) 2 . 
Ti m e   si n c e  fir st   g o ut   s y m pt o m s   will   b e  c al c ul at e d   a s:  (i nf or m e d   c o n s e nt   d at e  -  d at e   of   fir st 
s y m pt o m s  +  1) /  3 6 5. 2 5, r o u n d e d t o t w o  d e ci m al  pl a c e s. I n t h e  e v e nt  of  a  p arti al fir st  s y m pt o m 
d at e, t h e  e arli e st  p o s si bl e  d at e i m pli e d  b y t h e  d at a  pr o vi d e d  will  b e i m p ut e d.  
Ti m e   si n c e  fir st   g o ut   di a g n o si s   will   b e   c al c ul at e d   a s:  (i nf or m e d   c o n s e nt   d at e  -  d at e   of  fir st  
di a g n o si s  +  1) /  3 6 5. 2 5, r o u n d e d t o t w o  d e ci m al  pl a c e s. I n t h e  e v e nt  of  a  p arti al  di a g n o si s  d at e, 
t h e  e arli e st  p o s si bl e  d at e i m pli e d  b y t h e  d at a  pr o vi d e d  will  b e i m p ut e d. 
D e m o gr a p hi c  d at a  a n d  b a s eli n e  c h ar a ct eri sti c s  will  b e  pr o vi d e d i n  s u bj e ct li sti n g s.  
  
M e di c al  Hi st or y  a n d  C o n c o mit a nt  Di s e a s e s  
M e di c al   hi st or y  i nf or m ati o n   will   b e   c o d e d   u si n g   M e di c al   Di cti o n ar y  f or   R e g ul at or y   A cti viti e s  
( M e d D R A)  v er si o n 2 0. 1,  s u m m ari z e d  a n d  pr e s e nt e d  o v er all f or t h e I T T,  a n d  MI T T  P o p ul ati o n s. 
S u m m ari e s  will  b e  or d er e d  al p h a b eti c all y  b y  s y st e m  or g a n  cl a s s ( S O C)  a n d t h e n,  wit hi n  a  S O C, 
al p h a b eti c all y  b y  pr ef err e d t er m ( P T).  
M e di c al  hi st or y  d at a  will  b e li st e d.  
  
M e di c ati o n  
M e di c ati o n s   will   b e   c o d e d   u si n g   W H O Dr u g   Gl o b al   B 3   S e pt e m b er   2 0 1 8   di cti o n ar y .   Pri or  
m e di c ati o n s,   c o n c o mit a nt   m e di c ati o n s   u s e d   d uri n g  t h e   M T X   R u n -i n   P eri o d,   a n d   c o n c o mit a nt  
m e di c ati o n  u s e d i n t h e  P e gl oti c a s e  + I M M  P eri o d  will  b e  s u m m ari z e d  b y  pr e s e nti n g  t h e  c o u nt s 
a n d   p er c e nt a g e   of   s u bj e ct s   u si n g   m e di c ati o n s   o v er all  f or  t h e  I T T   a n d  mI T T   P o p ul ati o n s . 


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  4 2   of 8 4  
S u m m ari e s   will   b e   pr e s e nt e d   b y   A n at o mi c al   T h er a p e uti c   C h e mi c al  ( A T C)   L e v el   4  t er m   a n d  
pr ef err e d  dr u g  n a m e.  M e di c ati o n  s u m m ari e s  will  b e  s ort e d  al p h a b eti c all y  b y  A T C  L e v el  4  a n d  b y 
pr ef err e d   dr u g   n a m e   wit hi n   A T C   L e v el   4   f or  t h e  I T T  a n d  mI T T   P o p ul ati o n s.   S u bj e ct s   will   b e  
c o u nt e d  o nl y  o n c e f or  e a c h  m e di c ati o n  cl a s s  a n d  e a c h  pr ef err e d  dr u g  n a m e.   
Pri or  m e di c ati o n s,  c o n c o mit a nt  m e di c ati o n s ,  a n d  m e di c ati o n s  d uri n g f oll o w-u p  p eri o d  will  b e li st e d 
t o g et h er   wit h   a   d e si g n ati o n  t o  i d e ntif y  t h e   p eri o d( s)   of   u s a g e   a n d   s ort e d   b y   st art   d at e.  F or 
d et er mi n ati o n  of  p eri o d( s)  of  u s e,  mi s si n g  d at e i m p ut ati o n r ul e s  ar e  pr o vi d e d i n  S e cti o n  6. 3. 1 . 
F or  m e di c ati o n s  wit h  c o m pl et el y  mi s si n g  d at e s, t h e f oll o wi n g r ul e s  will  b e  u s e d t o  a s si g n  pri or, 
c o n c o mit a nt,  a n d f oll o w -u p ( c o n c o mit a nt  m e di c ati o n s  u s e d  >  3 0  d a y s  aft er t h e l a st  d o s e  of 
p e gl oti c a s e  or  M T X) : 
M e di c ati o n  St art 
D at e  
M e di c ati o n  E n d 
D at e  
Pri o r 
C o n c o mit a nt i n 
M T X  R u n -i n 
P eri o d  
C o n c o mit a nt i n 
P e gl oti c a s e 
Tr e at m e nt  P eri o d  
F oll o w -u p  ( >  3 0 
d a y s  of  eit h er 
E n d  of 
P e gl oti c a s e  or 
W e e k  5 2  Vi sit s)  
U n k n o w n  
U n k n o w n   
Y e s  
Y e s  
Y e s  
Y e s  
U n k n o w n   
< fir st  d o s e  of  M T X   
Y e s  
N o  
N o  
N o  
U n k n o w n  
≥ fir st  d o s e  of  M T X 
a n d  < fir st  d o s e  of 
p e gl oti c a s e   
Y e s  
Y e s  
N o  
N o  
U n k n o w n  
≥ fir st  d o s e  of 
p e gl oti c a s e  a n d  ≤  3 0 
d a y s  aft er  l a st 
p e gl oti c a s e/ M T X 
d o s e  
Y e s  
Y e s  
Y e s  
N o  
U n k n o w n   
>  3 0  d a y s  aft er  l a st 
p e gl oti c a s e/ M T X 
d o s e  t 
Y e s  
Y e s  
Y e s  
Y e s  
< fir st  d o s e  of  M T X   
U n k n o w n   
Y e s  
Y e s  
Y e s  
Y e s  
≥ fir st  d o s e  of  M T X 
a n d  < fir st  d o s e  of 
p e gl oti c a s e  
U n k n o w n  
N o  
Y e s  
Y e s  
Y e s  
≥ fir st  d o s e  of 
p e gl oti c a s e  a n d  ≤ 
3 0  d a y s  aft er  l a st 
p e gl oti c a s e/ M T X 
d o s e  
U n k n o w n  
N o  
N o  
Y e s  
Y e s  
>  3 0  d a y s  aft er  l a st 
p e gl oti c a s e/ M T X 
d o s e  
U n k n o w n  
N o  
N o  
N o  
Y e s  
 
A n y  m e di c ati o n  wit h  a  st art  d at e  pri or t o t h e  d at e  of fir st  d o s e  of tr e at m e nt i n t h e  M T X  R u n -i n 
P eri o d  will  b e  c o n si d er e d  a  pri or  m e di c ati o n.   
T h e f oll o wi n g  m e di c ati o n s  will  b e  c o n si d er e d  c o n c o mit a nt i n t h e  M T X  R u n -i n  P eri o d  
•  
A  m e di c ati o n  wit h  a  st art  d at e  o n  or  aft er t h e fir st  d o s e  d at e  of  M T X i n t h e  M T X  R u n -i n 
P eri o d  b ut  e x cl u di n g  m e di c ati o n s  wit h:  
o  
St art  d at e  o n  or  aft er t h e fir st i nf u si o n  d at e  of  p e gl oti c a s e  a n d   


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  4 3   of 8 4  
o  
T h o s e  st art e d  m or e t h a n  3 0  d a y s  aft er t h e l a st  M T X  d o s e, f or  s u bj e ct s  w h o  di d  n ot 
r e c ei v e  a n i nf u si o n  of  p e gl oti c a s e.  
•   M e di c ati o n s  wit h  a  p arti al  st art  d at e  wit h  m o nt h  a n d  y e ar  of  st art  pr o vi d e d  a n d t h e  y e ar  of 
st art  a n d  m o nt h  of  st art  m at c h t h e  m o nt h  a n d  y e ar  of fir st  M T X  d at e  a n d  m at c h t h e  m o nt h 
a n d  y e ar  of fir st  P e gl oti c a s e i nf u si o n  will  b e  cl a s sifi e d  a s  b ei n g  u s e d i n t h e  M T X  R u n -i n 
P eri o d  a n d i n t h e  P e gl oti c a s e  + I M M  P eri o d.  
•  
A  m e di c ati o n  wit h  a  st art  d at e  pri or t o t h e fir st  d o s e  d at e  of  M T X i n t h e  M T X  R u n -i n  P eri o d 
wit h  a  st o p  d at e  stri ctl y  aft er t h e fir st  d o s e  d at e  of  M T X i n t h e  M T X  R u n -i n  P eri o d 
•  
A  m e di c ati o n  wit h  a  st art  d at e  pri or t o t h e fir st  d o s e  d at e  of  M T X i n t h e  M T X  R u n -i n  P eri o d 
t h at  w a s  o n g oi n g. 
T h e f oll o wi n g  m e di c ati o n s  will  b e  c o n si d er e d  c o n c o mit a nt i n t h e  P e gl oti c a s e  + I M M  P eri o d   
•  
A  m e di c ati o n  wit h  a  st art  d at e  o n  or  aft er t h e fir st i nf u si o n  d at e  of  p e gl oti c a s e  b ut  e x cl u di n g 
m e di c ati o n s   wit h   st art   d at e   m or e  t h a n   3 0   d a y s   aft er  t h e   d at e   of  t h e   e n d   of  t h e  l a st  
p e gl oti c a s e i nf u si o n.   
•  
A   m e di c ati o n   wit h   a   st art   d at e   pri or  t o  t h e  fir st  i nf u si o n   d at e   of   p e gl oti c a s e  i n  t h e  
P e gl oti c a s e  + I M M  P eri o d  wit h  a  st o p  d at e  stri ctl y  aft er t h e fir st i nf u si o n  d at e  of  p e gl oti c a s e 
i n t h e  P e gl oti c a s e  + I M M  P eri o d. 
•  
A   m e di c ati o n   wit h   a   st art   d at e   pri or  t o  t h e  fir st  i nf u si o n   d at e   of   p e gl oti c a s e  i n  t h e  
P e gl oti c a s e  + I M M  P eri o d t h at  w a s  o n g oi n g.  
•  
M e di c ati o n s  wit h  a  p arti al  st art  d at e  wit h  m o nt h  a n d  y e ar  of  st art  pr o vi d e d  a n d t h e  y e ar  of 
st art  a n d  m o nt h  of  st art  m at c h t h e  m o nt h  a n d  y e ar  of fir st  M T X  d at e  a n d  m at c h t h e  m o nt h 
a n d  y e ar  of fir st  P e gl oti c a s e i nf u si o n  will  b e  cl a s sifi e d  a s  b ei n g  u s e d i n t h e  M T X  R u n -i n 
P eri o d  a n d i n t h e  P e gl oti c a s e  + I M M  P eri o d.  
T h e f oll o wi n g  m e di c ati o n s  will  b e  c o n si d er e d i n t h e  F oll o w -u p  P eri o d:  
•   A n y  m e di c ati o n s  wit h  1)  a  st art  d at e  pri or t o  3 0  d a y s  aft er l a st  d o s e  of  st u d y  m e di c ati o n 
t h at  c o nti n u e d  u s e  or  h a d  a  st o p  d at e  o n  or  aft er  3 0  d a y s  aft er t h e l a st  d o s e  of  st u d y 
m e di c ati o n,  or  2)  a  m e di c ati o n  wit h  a  st art  d at e  m or e t h a n  3 0  d a y s  aft er t h e l a st  d o s e  of 
st u d y  m e di c ati o n  
A s  s u c h, t h e  s a m e  m e di c ati o n  m a y  b e  s u m m ari z e d i n  o n e  or  m or e  of  pri or,  c o n c o mit a nt i n t h e 
M T X  R u n -i n  P eri o d,  or  c o n c o mit a nt i n t h e  P e gl oti c a s e  + I M M  P eri o d,  or i n t h e  F oll o w-u p  P eri o d . 
T h e  s u m m ar y t a bl e s  will  n ot  b e  m ut u all y  e x cl u si v e.  Mi s si n g  d at e i m p ut ati o n r ul e s  ar e  pr o vi d e d  i n 
S e cti o n  6. 3. 1.  
F or t h e I T T  p o p ul ati o n,  pri or  m e di c ati o n s  a n d  c o n c o mit a nt  m e di c ati o n s i n t h e  M T X  R u n -i n P eri o d 
will  b e  s u m m ari z e d.  F or t h e  mI T T  p o p ul ati o n,  pri or  m e di c ati o n s,  c o n c o mit a nt  m e di c ati o n s i n t h e 
M T X  R u n -i n  P eri o d,  c o n c o mit a nt  m e di c ati o n s i n t h e  P e gl oti c a s e  + I M M  P eri o d,  a n d  m e di c ati o n s 
i n t h e  F oll o w-u p  P eri o d  will  b e  s u m m ari z e d . I n  a d diti o n, f or t h e  mI T T   p o p ul ati o n, m e di c ati o n s 
u s e d f or  g o ut tr e at m e nt  aft er t h e l a st  p e gl oti c a s e i nf u si o n  will  b e  s u m m ari z e d.   
 


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  4 4   of 8 4  
  
C o n c o mit a nt  Pr o c e d ur e s  
A li sti n g  will  b e  pr o vi d e d f or  c o n c o mit a nt  pr o c e d ur e s t h e  s u bj e ct  u n d er w e nt  d uri n g t h e  st u d y.  N o 
ot h er  a n al y si s i s  pl a n n e d f or  c o n c o mit a nt  pr o c e d ur e s.  


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  4 5   of 8 4  
    
Effi c a c y 
  
H a n dli n g  R ul e s f or  s U A  V al u e s   
S er u m  s a m pl e s f or  m e a s ur e m e nt  of  s U A l e v el s  ar e  s c h e d ul e d f or  c oll e cti o n  at t h e  S cr e e ni n g  Vi sit 
( wit hi n  2  w e e k s  pri or t o t h e fir st  d o s e  of  M T X  at  W e e k -4), t h e  W e e k  -4  Vi sit ( pri or t o t h e fir st  d o s e 
of  M T X),  a n d t h e  W e e k  -2  Vi sit;  wit hi n  4 8  h o ur s  pri or t o  e a c h  p e gl oti c a s e i nf u si o n ( e x c e pt  o n  D a y 
1   w h e n   o nl y   1   pr e -i nfu si o n   s a m pl e  i s  r e q uir e d   a n d   will   b e   dr a w n   at  t h e   sit e  j u st   pri or  t o  t h e  
i nf u si o n);  a n d  aft er t h e  e n d  of  e a c h  p e gl oti c a s e i nf u si o n  pri or t o  di s c h ar g e, fr o m t h e  P e gl oti c a s e 
+ I M M  P eri o d t hr o u g h  w e e k  2 4  a n d  at  W e e k s  3 2,  3 4,  3 6,  4 8  a n d  5 0;  wit hi n  4 8  h o ur s  pri or t o  e a c h 
p e gl oti c a s e i nf u si o n  at  W e e k s  2 6,  2 8,  3 0,  3 8,  4 0,  4 2,  4 4  a n d  4 6  d uri n g t h e  P e gl oti c a s e  + 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 oti c a s e I nf u si o n s  Vi sit (if  a p pli c a bl e);  at t h e  W e e k  5 2/ E n d  of 
st u d y/ E arl y  T er mi n ati o n  Vi sit  a n d  M o nt h  3  a n d  M o nt h  6  Vi sit s.  Vi sit s f or fr e q u e nt  s a m pli n g  of  a 
s u b s et  of  s u bj e ct s  w h o  c o n s e nt f or  a d diti o n al  n o n -i nf u si o n vi sit  P K  s a m pli n g (r a n d o m,  m or ni n g 
pr ef err e d)  will  o c c ur  at  W e e k  1  a n d  W e e k  7,  w hi c h  will  b e  c o n si d er e d  a s  pr e -i nf u si o n. 
 
•   F or  t h e   d et er mi n ati o n   of   s U A  r e s p o n d er   e n d p oi nt s ,   s c h e d ul e d   a s s e s s m e nt s   of   s U A   a n d  
u n s c h e d ul e d   a s s e s s m e nt s   of   s U A ,  r e p ort e d   b y  t h e   c e ntr al  l a b or at or y,  will   b e   u s e d.   L o c al  
l a b or at or y-pr o c e s s e d  pr e -i nf u si o n  s U A r e s ult s  will  b e  u s e d  o nl y  w h e n t h e  c e ntr al l a b or at or y-
pr o c e s s e d  v al u e  at  a ti m e  p oi nt i s  n ot  a v ail a bl e,  b ut t h e l o c al l a b -pr o c e s s e d  pr e -i nf u si o n  v al u e, 
c oll e ct e d  v al u e  at t h e  s a m e ti m e  p oi nt , i s  a v ail a bl e.  
 
•   W h e n t h e  c e ntr al l a b or at or y  or l o c al l a b or at or y r e p ort s  a  v al u e f or  s U A  a s  b ei n g l o w er t h a n 
t h e l a b  a s s a y’ s li mit  of  q u a ntifi c ati o n ( e. g. “ < 0. 0 2”),  z er o  will  b e  u s e d  a s t h e  n u m eri c  v al u e f or 
t h e  p ur p o s e  of  d et er mi ni n g r e s p o n s e  a n d f or  s u m m ari e s  of  o b s er v e d  v al u e s  a n d t h e  c h a n g e 
fr o m  b a s eli n e. W h e n t h e  c e ntr al l a b or at or y  or l o c al l a b or at or y r e p ort s  a  v al u e f or  s U A  a s  b ei n g 
hi g h er t h a n  a  c ert ai n  v al u e  of  q u a ntifi c ati o n ( e. g. “ > 8. 7 ”), t h e  n u m eri c  v al u e ( e. g.  8. 7)  aft er ‘ >’ 
i s  u s e d f or t h e  p ur p o s e  of  d et er mi ni n g r e s p o n s e  a n d f or  s u m m ari e s  of  o b s er v e d  v al u e s  a n d 
t h e  c h a n g e fr o m  b a s eli n e. 
 
  
Pri m ar y  Effi c a c y  E n d p oi nt  a n d  A n al y si s  
T h e  pri m ar y  effi c a c y  e n d p oi nt i s t h e  pr o p orti o n  of  M o nt h  6  ( W e e k s  2 0, 2 2 , a n d  2 4) r e s p o n d er s, 
d efi n e d  a s  s u bj e ct s  a c hi e vi n g  a n d  m ai nt ai ni n g  s U A  <  6  m g/ d L f or  at l e a st  8 0 %  of t h e ti m e  d uri n g 
M o nt h  6. 
T h e  s U A ti m e  c ur v e  will  b e  u s e d t o  e sti m at e t h e  pr o p orti o n  of ti m e t h at t h e  s U A i s  <  6  m g/ dl   usi n g 
t h e a v ail a bl e  pr e- i nf u si o n  a n d  p o st-i nf u si o n  s a m pl e s wit h  n o n -mi s si n g  s U A  v al u e s .  
 
T h e  M o nt h  6  p eri o d  will i n cl u d e  pr e -i nf u si o n  a n d  p o st-i nf u si o n r e s ult s  at W e e k  2 0,  pr e -i nf u si o n 
a n d   p o st -i nf u si o n  r e s ult s   at   W e e k  2 2 ,   pr e-i nf u si o n  r e s ult s   at   W e e k  2 4,   a n d   u n s c h e d ul e d   pr e -
i nf u sio n  a s s e s s m e nt s  of  s U A  c oll e ct e d  b et w e e n  W e e k  2 0  a n d  W e e k  2 4  pr o c e s s e d  b y t h e  c e ntr al 
l a b or at or y. S e c ti o n  9. 1 s h o w s t h e r ul e s f or i n cl u si o n  of  s U A  v al u e s r e p ort e d  b y l o c al l a b or at ori e s.  
 
A  r o b u st  e sti m at e  of  pr o p orti o n  of ti m e t h e  s U A <  6  m g/ d L  c a n  b e  d et er mi n e d  b y  c o n n e cti n g  a 
s u bj e ct’ s  n ei g h b ori n g  d at a  p oi nt s  wit h  a  str ai g ht  li n e. If t h e  s U A  c ur v e  g o e s fr o m  b el o w  6  m g/ d L 
t o  a b o v e  6  m g/ d L, li n e ar i nt er p ol ati o n  will  b e  u s e d t o  e sti m at e t h e ti m e  at  w hi c h t h e  s U A  c ur v e 


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  4 6   of 8 4  
i nt er s e ct s 6  m g/ d L,  u si n g t h e l a st  s a m pl e  c oll e ct e d t h at  w a s  <  6  m g/ d L  a n d t h e fir st  s a m pl e t h at 
w a s  >  6  m g/ d L.   A n al g o u sl y, if t h e  s U A  c ur v e  g o e s fr o m  a b o v e  6  m g/ d L t o  b el o w  6  m g/ d L, li n e ar 
i nt er p ol ati o n  will  b e  u s e d t o  e sti m at e t h e ti m e  at  w hi c h t h e  s U A  c ur v e i nt er s e ct s  6  m g/ d L,  u si n g 
t h e l a st  s a m pl e t h at  w a s  a b o v e  6  m g/ d L  a n d t h e fir st  v al u e  <  6  m g/ d L  aft er t h e  S U A  h a d  b e e n 
a b o v e  6  m g/ d L  
 
T h er e   will   b e   n o  i m p ut ati o n   of   s U A   v al u e s   d u e  t o   mi s s e d   c oll e cti o n s   a m o n g  t h o s e   c oll e ct e d  
b et w e e n  W e e k  2 0  a n d  W e e k  2 4 .  O nl y  o b s er v e d  v al u e s  will  b e i n cl u d e d i n t h e  c al c ul ati o n. If  a 
s u bj e ct  d o e s  n ot r e c ei v e  a  p e gl oti c a s e i nf u si o n  at  vi sit s  d uri n g  M o nt h  6  b ut  h a s  s U A r e s ult s  at 
t h o s e  vi sit s, t h o s e  s U A r e s ult s  will  b e  u s e d i n t h e  c al c ul ati o n  of r e s p o n s e. 
 
L et  T 1  = t h e  n u m b er  of  el a p s e d  h o ur s  b et w e e n t h e fir st  a n d l a st  n o n -mi s si n g  s U A  c o n c e ntr ati o n 
a m o n g t h o s e  c oll e ct e d  b et w e e n  W e e k  2 0  a n d  W e e k  2 4  c oll e cti o n s.   
L et  W 1  = t h e  n u m b er  of  h o ur s  a m o n g t h e  T 1  h o ur s  w h er e t h e  s U A  c o n c e ntr ati o n  w a s  b el o w  6 
m g/ d L.   
 
T h e  pr o p orti o n  of  h o ur s  𝑃𝑃 = 1 0 0 ∗
𝑊𝑊 1
𝑇𝑇 1  
 
If t h e  s u bj e ct’ s  pr o p orti o n  of  h o ur s,  P, i s  gr e at er t h a n  or  e q u al t o  8 0 % t h e  s u bj e ct  will  b e  c all e d  a 
r e sp o n d er f or t h e  pri m ar y  effi c a c y  e n d p oi nt .  S u bj e ct s m e eti n g t h e  st o p pi n g r ul e, i. e. t h e  s u bj e ct 
h a s  pr e- i nf u si o n s U A  v al u e s  gr e at er t h a n  6  m g/ d L  at  2  c o n s e c uti v e  s c h e d ul e d  vi sit s  (st arti n g  at 
W e e k  2 ) t hr o u g h  W e e k  2 4, will  b e  c o u nt e d  a s  n o n -r e s p o n d er s. If  o nl y  o n e  s U A r e s ult i s  c oll e ct e d 
d uri n g  M o nt h  6  p eri o d, r e s p o n s e  will  b e  b a s e d  o n t h e  si n gl e  v al u e  b ei n g  stri ctl y  <  6  m g/ d L . A 
s u bj e ct  wit h t h e  pr o p orti o n  of  h o ur s,  P, l e s s t h a n  8 0 %  will  b e  c o u nt e d  a s  n o n -r e s p o n d er s.  A n y 
ot h er  s u bj e ct  will  b e  c o u nt e d  a s  a  n o n -r e s p o n d er if  s U A  v al u e s  ar e  n ot  c oll e ct e d  d uri n g t h e  M o nt h 
6  p eri o d.  
 
T hi s  e n d p oi nt  will  b e  a n al y z e d  f or t h e I T T  a n d  mI T T  p o p ul ati o ns .  B y  d efi niti o n,  a  s u bj e ct  w h o i s i n 
t h e I T T  b ut  n ot t h e mI T T  p o p ul ati o n  will  b e  c o u nt e d  a s  a  n o n -r e s p o n d er f or t h e  pri m ar y  effi c a c y 
e n d p oi nt   f or  t h e  I T T   p o p ul ati o n,   a s  t h e y   will   n ot   h a v e   s U A   v al u e s   b e y o n d   D a y   1.    T h e   mI T T  
a n al y si s  will  b e  c o n si d er e d t h e  pri m ar y  a n al y si s f or t hi s  e n d p oi nt.  
 
T h e   pr o p orti o n   of   h o ur s   d uri n g  t h e   p eri o d   w h er e  t h e   s U A   w a s  l e s s  t h a n   6   m g/ d L   will   b e  
s u m m ari z e d  u si n g  d e s cri pti v e  st ati sti c s (i. e.  n,  m e a n,  st a n d ar d  d e vi ati o n,  m e di a n,  mi ni m u m,  a n d 
m a xi m u m).   T h e   n u m b er   a n d   pr o p orti o n   of   s u bj e ct s  t h at   di s c o nti n u e d  tr e at m e nt   d u e  t o  t h e  
st o p pi n g r ul e  will  b e  s u m m ari z e d.  T h e  n u m b er  a n d  pr o p orti o n  of r e s p o n d er s  will  b e  s u m m ari z e d 
al o n g  wit h  a  9 5 %  e x a ct ( Cl o p p er -P e ar s o n)  CI  f or t h e  pr o p orti o n. 
 
  
S e c o n d ar y  Effi c a c y  E n d p oi nt s  a n d  A n al y s e s  
  
Pr o p orti o n  of  M o nt h  3  R e s p o n d er s  
T h e  pr o p orti o n  of  M o nt h  3  ( W e e k s  1 0, 1 2,  1 4 ) r e s p o n d er s, will  b e  d efi n e d  a s  s u bj e ct s  a c hi e vi n g 
a n d  m ai nt ai ni n g  s U A  <  6  m g/ d L f or  at l e a st  8 0 %  of t h e ti m e  d uri n g  M o nt h  3. 
 
T hi s   e n d p oi nt   will   b e   a n al y z e d  f or  t h e  I T T   a n d   mI T T   p o p ul ati o n s.   T h e   mI T T   a n al y si s   will   b e  
c o n si d er e d t h e  pri m ar y  a n al y si s f or t hi s  e n d p oi nt.  
 
T hi s  d et er mi n ati o n  will  b e  c o m pl et e d  u si n g t h e  s a m e li n e ar i nt er p ol ati o n  m et h o d  d e s cri b e d f or t h e 
pri m ar y  effi c a c y  e n d p oi nt i n  S e cti o n  9. 2 . T h e  M o nt h  3  p eri o d  will i n cl u d e  pr e- i nf u si o n  a n d  p o st-


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  4 7   of 8 4  
i nf u si o n r e s ult s  at  W e e k  1 0,  pr e-i nf u si o n  a n d  p o st-i nf u si o n r e s ult s  at  W e e k  1 2,  pr e-i nf u si o n r e s ult s 
at  W e e k  1 4,  a n d  u n s c h e d ul e d  pr e -i nf u si o n  a s s e s s m e nt s  of  s U A  c oll e ct e d  b et w e e n  W e e k 1 0  a n d 
W e e k  1 4  pr o c e s s e d  b y t h e  c e ntr al l a b or at or y . S e cti o n  9. 1  s h o w s t h e r ul e s f or i n cl u si o n  of  s U A 
v al u e s r e p ort e d  b y l o c al l a b or at ori e s.   
 
If t h e  s u bj e ct’ s  pr o p orti o n  of  h o ur s i s  gr e at er t h a n  or  e q u al t o  8 0 % t h e  s u bj e ct  will  b e  c all e d  a 
r e s p o n d er f or t h e  M o nt h  3 r e s p o n d er  e n d p oi nt.  S u bj e ct s  m e eti n g t h e  st o p pi n g r ul e, i. e.  h a s  pr e -
i nf u si o n  s U A  v al u e s  gr e at er t h a n  6  m g/ d L  at  2  c o n s e c uti v e  s c h e d ul e d  vi sit s ( st arti n g  at  W e e k  2) 
t hr o u g h  W e e k  1 4  will  b e  c o u nt e d  a s  n o n-r e s p o n d er s. If  o nl y  o n e  s U A r e s ult i s  c oll e ct e d  d uri n g 
M o nt h  3  p eri o d, r e s p o n s e  will  b e  b a s e d  o n t h e  si n gl e  v al u e  b ei n g l e s s t h a n  6  m g/ d L.  A  s u bj e ct 
wit h  t h e   pr o p orti o n   of   h o ur s,   P,  l e s s  t h a n   8 0 %   will   b e   c o u nt e d   a s   n o n -r e s p o n d er s.   A n y   ot h er  
s u bj e ct  will  b e  c o u nt e d  a s  a  n o n -r e s p o n d er if  s U A  v al u e s  ar e  n ot  c oll e ct e d  d uri n g t h e  M o nt h  3 
p eri o d.  
 
T h e   pr o p orti o n   of   h o ur s   d uri n g  t h e   p eri o d   w h er e  t h e   s U A   w a s  l e s s  t h a n   6   m g/ d L   will   b e  
s u m m ari z e d  u si n g  d e s cri pti v e  st ati sti c s (i. e.  n,  m e a n,  st a n d ar d  d e vi ati o n,  m e di a n,  mi ni m u m,  a n d 
m a xi m u m).   T h e   n u m b er   a n d   pr o p orti o n   of   s u bj e ct s  t h at   di s c o nti n u e d  tr e at m e nt   d u e  t o  t h e  
st o p pi n g r ul e  will  b e  s u m m ari z e d.  T h e  n u m b er  a n d  pr o p orti o n  of r e s p o n d er s  will  b e  s u m m ari z e d 
al o n g  wit h  a  9 5 %  e x a ct ( Cl o p p er -P e ar s o n)  CI f or t h e  pr o p orti o n . 
 
  
Pr o p orti o n  of  O v er all  R e s p o n d er s  T hr o u g h  M o nt h  6  
T h e   pr o p orti o n   of   o v er all  r e s p o n d er s   t hr o u g h   M o nt h   6  i s  d efi n e d   a s   s u bj e ct s   a c hi e vi n g   a n d  
m ai nt ai ni n g  s U A  <   6 m g/ d L f or  at l e a st  8 0 %  of t h e ti m e  d uri n g  M o nt h s  3  a n d  6  c o m bi n e d . S e e 
S e cti o n  9. 2  f or t h e  s U A r e s ult s i n cl u d e d i n  M o nt h  6.  S e e S e cti o n  9. 3. 1  f or t h e  s U A r e s ult s i n cl u d e d 
i n  M o nt h  3. S e cti o n  9. 1  s h o w s t h e r ul e s f or i n cl u si o n  of  s U A  v al u e s r e p ort e d  b y l o c al  l a b or at ori e s. 
 
T h e  d efi niti o n  of  o v er all r e s p o n d er s t hr o u g h  M o nt h  6 i s  d e p e n d e nt  o n  t h e n u m b er  of  a v ail a bl e 
s U A r e s ult s  a v ail a bl e  d uri n g  M o nt h  3  a n d  d uri n g  M o nt h  6.  
 
C a s e    
N u m b er  of  s U A 
V al u e s  at  M o nt h  3  
N u m b er  of  s U A  V al u e s 
at  M o nt h  6  
O v er all  R e s p o n s e 
D et er mi n ati o n  
1   
A n y  N u m b er  
0  
D e cl ar e d  O v er all  N o n -r e s p o n d er  
2   
0  
A n y  N u m b er  
D e cl ar e d  O v er all  N o n -r e s p o n d er  
3   
1  
≥  1  R e c or d  
If r e s p o n d er f or  b ot h  M o nt h  3  a n d 
M o nt h  6, t h e n  D e cl ar e d  O v er all 
R e s p o n d er  
 
If  N o n-r e s p o n d er f or  M o nt h  3 
a n d/ or  M o nt h  6 t h e n  d e cl ar e d 
O v er all  N o n -R e s p o n d er   
4   
≥  1  R e c or d  
1  
If r e s p o n d er f or  b ot h  M o nt h  3  a n d 
M o nt h  6, t h e n  D e cl ar e d  O v er all 
R e s p o n d er  
 
If  N o n-r e s p o n d er f or  M o nt h  3 
a n d/ or  M o nt h  6 t h e n  d e cl ar e d 
O v er all  N o n -R e s p o n d er   


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  4 8   of 8 4  
C a s e    
N u m b er  of  s U A 
V al u e s  at  M o nt h  3  
N u m b er  of  s U A  V al u e s 
at  M o nt h  6  
O v er all  R e s p o n s e 
D et er mi n ati o n  
5   
>  1  R e c or d  
>  1  R e c or d  
O v er all  R e s p o n s e i s  d efi n e d 
b a s e d  o n t h e  w ei g ht e d  pr o p orti o n 
of  h o ur s  b el o w t h e  s U A  <  6 
m g/ d L  c ut off.   S e e t h e r e m ai n d er 
of t hi s  s e cti o n.  
  
 
L et  T 1  = t h e  n u m b er  of  el a p s e d  h o ur s  b et w e e n t h e fir st  a n d l a st  n o n -mi s si n g  s U A  c o n c e ntr ati o n 
a m o n g t h o s e  c oll e ct e d  b et w e e n   pr e-i nf u si o n W e e k  1 0  a n d  pr e -i nf u si o n W e e k  1 4  c oll e cti o n s.   
 
L et  T 2  = t h e  n u m b er  of  el a p s e d  h o ur s  b et w e e n t h e fir st  a n d l a st  n o n -mi s si n g  s U A  c o n c e ntr ati o n 
a m o n g t h o s e  c oll e ct e d  b et w e e n  pr e- i nf u si o n W e e k  2 0  a n d  pr e -i nf u si o n W e e k  2 4  c oll e cti o n s.   
 
L et  W 1  = t h e  n u m b er  of  h o ur s  a m o n g t h e  T 1  h o ur s  w h er e t h e  s U A  c o n c e ntr ati o n  w a s  b el o w  6 
m g/ d L.   
 
L et  W 2  = t h e  n u m b er  of  h o ur s  a m o n g t h e  T 2  h o ur s  w h er e t h e  s U A  c o n c e ntr ati o n  w a s  b el o w  6 
m g/ d L.   
 
T h e  pr o p orti o n  of  h o ur s  P   = 1 0 0 ∗
W 1 + W 2
T 1 + T 2  
T hi s i s t h e  w ei g ht e d  pr o p orti o n  of  h o ur s  b el o w  6  m g/ d L .  
 
If t h e  s u bj e ct’ s  pr o p orti o n  of  h o ur s,  P, i s  gr e at er t h a n  or  e q u al t o  8 0 % t h e  s u bj e ct  will  b e  c all e d  a 
r e s p o n d er f or t h e  o v er all r e s p o n d er  e n d p oi nt.  A  s u bj e ct  wit h t h e  pr o p orti o n  of  h o ur s,  P, l e s s  t h a n 
8 0 %  will  b e  c o u nt e d  a s  n o n -r e s p o n d er s. 
 
S u bj e ct s  m e eti n g t h e  st o p pi n g r ul e, i. e.  h a s  pr e -i nf u si o n  s U A  v al u e s  gr e at er t h a n  6  m g/ d L  at  2 
c o n s e c uti v e  s c h e d ul e d  vi sit s ( st arti n g  at  W e e k  2) t hr o u g h  W e e k  2 4  will  b e  c o u nt e d  a s  o v er all  n o n -
r e s p o n d er s.  
 
T hi s   e n d p oi nt   will   b e   a n al y z e d   f or  t h e  I T T   a n d   mI T T   p o p ul ati o n.  T h e   mI T T   a n al y si s   will   b e  
c o n si d er e d t h e  pri m ar y  a n al y si s f or t hi s  e n d p oi nt.  
 
T h e   pr o p orti o n   of   h o ur s   d uri n g  t h e   p eri o d   w h er e  t h e   s U A   w a s  l e s s  t h a n   6   m g/ d L   will   b e  
s u m m ari z e d  u si n g  d e s cri pti v e  st ati sti c s (i. e.  n,  m e a n,  st a n d ar d  d e vi ati o n,  m e di a n,  mi ni m u m,  a n d 
m a xi m u m).   T h e   n u m b er   a n d   pr o p orti o n   of   s u bj e ct s  t h at   di s c o nti n u e d  tr e at m e nt   d u e  t o  t h e  
st o p pi n g r ul e  will  b e  s u m m ari z e d.  T h e  n u m b er  a n d  pr o p orti o n  of r e s p o n d er s  will  b e  s u m m ari z e d 
al o n g  wit h  a  9 5 %  e x a ct ( Cl o p p er -P e ar s o n)  CI  f or t h e  pr o p orti o n.  
  
Pr o p orti o n  of  R e s p o n d er s  A c hi e vi n g  a n d  M ai nt ai ni n g  a  s U A  B el o w  5  m g/ d L  
T h e  pr o p orti o n  of r e s p o n d er s  i s d efi n e d  a s  s u bj e ct s  a c hi e vi n g  a n d  m ai nt ai ni n g  s U A  <  5  m g/ d L f or 
at l e a st  8 0 %  of t h e ti m e  d uri n g  M o nt h  3,  M o nt h  6,  a n d  O v er all ( M o nt h s  3  a n d  6  c o m bi n e d).  T h e s e 
will  b e  c al c ul at e d  u si n g t h e  s a m e  m et h o d  d e s cri b e d f or t h e  pri m ar y  effi c a c y  e n d p oi nt  ( S e cti o n 
9. 2) ,  a n d s e c o n d ar y  e n d p oi nt s  r e p ort e d i n S e cti o n s  9. 3 . 1 a n d  S e cti o n  9. 3 . 2. T h e  e n d p oi nt s  will 
b e  a n al y z e d  u si n g t h e  s a m e  m et h o d ol o g y  d e s cri b e d i n  S e cti o n  9. 2 , S e cti o n  9. 3. 1 ,  a n d S e cti o n 
9. 3. 2 . T hi s  e n d p oi nt  will  b e  a n al y z e d f or t h e I T T  a n d  mI T T  p o p ul ati o n.  T h e  mI T T  a n al y si s  will  b e 
c o n si d er e d t h e  pri m ar y  a n al y si s f or t hi s  e n d p oi nt.  


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  4 9   of 8 4  
  
C h a n g e fr o m  B a s eli n e i n  s U A   
O b s er v e d  v al u e s  a n d  c h a n g e fr o m  M T X  b a s eli n e  at  e a c h  s c h e d ul e d ti m e  p oi nt, i n cl u di n g  pr e -
i nf u si o n   a n d   p o st-i nf u si o n  r e s ult s  f or   s U A   will  b e   s u m m ari z e d  f or  t h e   mI T T   p o p ul ati o n   u si n g  
d e s cri pti v e  st ati sti c s  (i n cl u di n g  n,  m e a n,  st a n d ar d  d e vi ati o n,  m e di a n,  mi ni m u m,  a n d  m a xi m u m) 
b a s e d  o n  o b s er v e d  v al u e s  b y  p e gl oti c a s e  tr e at m e nt  st at u s  of t h e  s u bj e ct ( O n  Tr e at m e nt,  P o st-
Tr e at m e nt,  a n d  O v er all) . S u bj e ct s  will  o nl y  b e  s u m m ari z e d i n t h e  O n  Tr e at m e nt  vi sit s f or  vi sit s 
t h at  o c c ur ( a n d r e s ult s  a v ail a bl e)  w hil e  still r e c ei vi n g  p e gl oti c a s e i nf u si o n s.  E n d  of  p e gl oti c a s e 
i nf u si o n  vi sit ( wi n d o w e d) if  o c c ur s,  will  al s o  b e  c o n si d er e d  O n  Tr e at m e nt,  a s  w ell  a s t h e  W e e k  5 2 
vi sit f or  s u bj e ct s  w h o  c o m pl et e tr e at m e nt  a n d  st u d y  at  W e e k  5 2.  P o st -Tr e at m e nt  vi sit s  ar e  a n y 
p o st -b a s eli n e  vi sit s  aft er t h e  e n d  of  p e gl oti c a s e i nf u si o n s ( or  W e e k  5 2/ E O S if  s u bj e ct s  c o m pl et e 
tr e at m e nt).  O v er all  st at u s  will i n cl u d e  all  vi sit s f or  all  s u bj e ct s r e g ar dl e s s  of  p e gl oti c a s e tr e at m e nt 
st at u s.  F or t h e  O v er all  st at u s,  s U A r e s ult s  at  vi sit s  wit h o ut  a n i nf u si o n  will  b e  s u m m ari z e d f or t h e 
pr e- i nf u si o n ti m e  p oi nt. S e e  S e cti o n  9. 1  f or t h e  d e s cri pti o n  of i n cl u si o n  of l o c al l a b or at or y r e s ult s. 
T h e  n u m b er  a n d  p er c e nt a g e  of  s u bj e ct s  at  e a c h  vi sit  wit h  a  s U A  <  6  m g/ d L  will  al s o  b e  pr o vi d e d. 
T h e  d e n o mi n at or  will  b e t h e  n u m b er  of  s u bj e ct s i n t h e  p o p ul ati o n .  A t w o-si d e d  9 5 %  n or m al -t h e or y 
b a s e d  CI  will  b e  pr e s e nt e d f or t h e  m e a n  o b s er v e d  v al u e,  m e a n  c h a n g e fr o m  M T X  b a s eli n e , a n d 
m e a n  c h a n g e fr o m  M T X  b a s eli n e  f or  e a c h  vi sit.  A  si mil ar  a n al y si s  of  c h a n g e fr o m  p e gl oti c a s e 
b a s eli n e  b a s e d  o n  o b s er v e d  v al u e s  - will  b e  pr e s e nt e d f or t h e  mI T T  p o p ul ati o n.  
 
A n  a n al y si s  of t h e  o b s er v e d  v al u e s  a n d  c h a n g e fr o m  M T X  b a s eli n e  at  e a c h  s c h e d ul e d ti m e  p oi nt 
will  b e  c o m pl et e d f or   s u bj e ct s  w h o  a c hi e v e d t h e  pri m ar y  s U A r e s p o n d er  e n d p oi nt  v s.  s u bj e ct s 
w h o  di d  n ot  a c hi e v e t h e  s U A r e s p o n s e  at  M o nt h  6  ( s e e S e cti o n  9. 2 ) will  b e  pr o d u c e d  u si n g t h e 
mI T T  p o p ul ati o n.  
 
Li n e  pl ot s  of t h e  o b s er v e d  m e a n   pr e-i nf u si o n s U A  v al u e s  at  e a c h  s c h e d ul e d  vi sit  will  b e  pr e s e nt e d 
u si n g  t h e   mI T T   p o p ul ati o n.   A   gr a p hi c al   pr e s e nt ati o n   of  t h e   m e a n   pr e- i nf u si o n   s U A   v al u e s  b y 
M o nt h  6  s U A r e s p o n d er s  v s.  n o n -r e s p o n d er s, b a s e d  o n t h e  pri m ar y  e n d p oi nt  d efi niti o n  of  M o nt h 
6 r e s p o n s e , will  b e  pr o d u c e d f or t h e  mI T T  p o p ul ati o n.  
 
B y- s u bj e ct  pl ot s  of  s U A  v al u e s  b y ti m e  will   b e  pr o d u c e d f or t h e  mI T T  p o p ul ati o n.  R e s ult s fr o m 
t h e   c e ntr al  l a b or at or y   will   b e   u s e d.  S e cti o n   9. 1   s h o w s  t h e  r ul e s  f or  i n cl u si o n   of   s U A   v al u e s  
r e p ort e d  b y l o c al l a b or at ori e s.  R ef er e n c e li n e s  at  5  m g/ d L  a n d  6  m g/ d L  will   b e i n cl u d e d.  
 
  
E x pl or at or y  Effi c a c y  E n d p oi nt s  a n d  A n al y s e s  
  
Pr o p orti o n  of  M o nt h  9  R e s p o n d er s  
T h e  pr o p orti o n  of  M o nt h  9 ( W e e k s  3 2,  3 4,  3 6) r e s p o n d er s,  will  b e  d efi n e d  a s  s u bj e ct s  a c hi e vi n g 
a n d  m ai nt ai ni n g  s U A  <  6  m g/ d L f or  at l e a st  8 0 %  of t h e ti m e  d uri n g  M o nt h  9.  
 
T hi s  d et er mi n ati o n  will  b e  c o m pl et e d  u si n g t h e  s a m e li n e ar i nt er p ol ati o n  m et h o d  d e s cri b e d f or t h e 
pri m ar y  effi c a c y  e n d p oi nt i n  S e cti o n  9. 2 . T h e  M o nt h  9  p eri o d  will i n cl u d e  pr e -i nf u si o n  a n d  p o st-
i nf u si o n r e s ult s  at  W e e k  3 2,  pr e-i nf u si o n  a n d  p o st-i nf u si o n r e s ult s  at  W e e k  3 4,  pr e-i nf u si o n r e s ult s 
at  W e e k  3 6,  a n d  u n s c h e d ul e d  pr e -i nf u si o n  a s s e s s m e nt s  of  s U A  c oll e ct e d  b et w e e n  W e e k  3 2  a n d 
W e e k  3 6  pr o c e s s e d  b y t h e  c e ntr al l a b or at or y.  S e cti o n  9. 1  s h o w s t h e r ul e s f or i n cl u si o n  of  s U A 
v al u e s r e p ort e d  b y l o c al l a b or at ori e s.   
 
S u bj e ct s  w h o  c o m pl et e d t h e  st u d y  at  W e e k  2 4 ( p er  A m e n d m e nt  1  of t h e  pr ot o c ol)  will  b e  e x cl u d e d 
fr o m t hi s  a n al y si s.  F or  e a c h  s u bj e ct  o n-st u d y  wit h  p arti ci p ati o n  p er  A m e n d m e nt  2, i f t h e  s u bj e ct’ s 


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  5 0   of 8 4  
pr o p orti o n  of  h o ur s i s  gr e at er t h a n  or  e q u al t o  8 0 %  d uri n g  M o nt h  9,  t h e  s u bj e ct  will  b e  c all e d  a 
r e s p o n der f or t h e  M o nt h  9 r e s p o n d er  e n d p oi nt.  S u bj e ct s  m e eti n g t h e  st o p pi n g r ul e, i. e.  h a s  pr e -
i nf u si o n  s U A  v al u e s  gr e at er t h a n  6  m g/ d L  at  2  c o n s e c uti v e  s c h e d ul e d  vi sit s ( st arti n g  at  W e e k  2) 
t hr o u g h  W e e k  3 6  will  b e  c o u nt e d  a s  n o n-r e s p o n d er s. If  o nl y  o n e  s U A r e s ult i s  c oll e ct e d  d uri n g 
M o nt h  9  p eri o d, r e s p o n s e  will  b e  b a s e d  o n t h e  si n gl e  v al u e  b ei n g l e s s  t h a n 6  m g/ d L.  A  s u bj e ct 
wit h t h e  pr o p orti o n  of  h o ur s,  P, l e s s t h a n  8 0 %  will  b e  c o u nt e d  a s  n o n -r e s p o n d er s.  S u bj e ct s  w h o 
di s c o nti n u e d t h e  st u d y  pri or t o  W e e k  2 4  u n d er  A m e n d m e nt  1  of t h e  pr ot o c ol  will  b e  c o n si d er e d 
n o n -r e s p o n d er s.   A n y   ot h er   s u bj e ct   will   b e   c o u nt e d   a s   a   n o n-r e s p o n d er  if   s U A   v al u e s   ar e   n ot  
c oll e ct e d  d uri n g t h e  M o nt h  9  p eri o d.  
 
T h e   pr o p orti o n   of   h o ur s   d uri n g  t h e   p eri o d   w h er e  t h e   s U A   w a s  l e s s  t h a n   6   m g/ d L   w ill   b e  
s u m m ari z e d  u si n g  d e s cri pti v e  st ati sti c s (i. e.  n,  m e a n,  st a n d ar d  d e vi ati o n,  m e di a n,  mi ni m u m,  a n d 
m a xi m u m).   T h e   n u m b er   a n d   pr o p orti o n   of   s u bj e ct s  t h at   di s c o nti n u e d  tr e at m e nt   d u e  t o  t h e  
st o p pi n g r ul e  will  b e  s u m m ari z e d.  T h e  n u m b er  a n d  pr o p orti o n  of r e s p o n d er s  will  b e  s u m m ari z e d 
al o n g  wit h  a  9 5 %  e x a ct ( Cl o p p er -P e ar s o n)  CI f or t h e  pr o p orti o n.  
 
  
Pr o p orti o n  of  M o nt h  1 2  R e s p o n d er s  
T h e  pr o p orti o n  of  M o nt h  1 2 ( W e e k s  4 8,  5 0,  5 2) r e s p o n d er s,  will  b e  d efi n e d  a s  s u bj e ct s  a c hi e vi n g 
a n d  m ai nt ai ni n g  s U A  <  6  m g/ d L f or  at l e a st  8 0 %  of t h e ti m e  d uri n g  M o nt h  9.  
 
T hi s  d et er mi n ati o n  will  b e  c o m pl et e d  u si n g t h e  s a m e li n e ar i nt er p ol ati o n  m et h o d  d e s cri b e d f or t h e 
pri m ar y  effi c a c y  e n d p oi nt i n  S e cti o n  9. 2 . T h e  M o nt h  1 2  p eri o d  will i n cl u d e  pr e- i nf u si o n  a n d  p o st-
i nf u si o n r e s ult s  at  W e e k  4 8,  pr e-i nf u si o n  a n d  p o st-i nf u si o n r e s ult s  at  W e e k  5 0,  pr e-i nf u si o n r e s ult s 
at  W e e k  5 2,  a n d  u n s c h e d ul e d  pr e -i nf u si o n  a s s e s s m e nt s  of  s U A  c oll e ct e d  b et w e e n  W e e k  4 8  a n d 
W e e k  5 2  pr o c e s s e d  b y t h e  c e ntr al l a b or at or y . S e cti o n  9. 1  s h o w s t h e r ul e s f or i n cl u si o n  of  s U A 
v al u e s r e p ort e d  b y l o c al l a b or at ori e s.   
 
S u bj e ct s  w h o  c o m pl et e d t h e  st u d y  at  W e e k  2 4 ( p er  A m e n d m e nt  1  of t h e  pr ot o c ol)  will  b e  e x cl u d e d 
fr o m t hi s  a n al y si s. If t h e  s u bj e ct’ s  pr o p orti o n  of  h o ur s i s  gr e at er t h a n  or  e q u al t o  8 0 % t h e  s u bj e ct 
will  b e  c all e d  a r e s p o n d er f or t h e  M o nt h  1 2 r e s p o n d er  e n d p oi nt.  S u bj e ct s  m e eti n g t h e  st o p pi n g 
r ul e,  i. e.   h a s   pr e-i nf u si o n   s U A   v al u e s   gr e at er  t h a n   6   m g/ d L   at   2   c o n s e c uti v e   s c h e d ul e d   vi sit s  
( st arti n g  at  W e e k  2) t hr o u g h  W e e k  5 2  will  b e  c o u nt e d  a s  n o n-r e s p o n d er s. If  o nl y  o n e  s U A r e s ult 
i s  c oll e ct e d  d uri n g  M o nt h  1 2  p eri o d, r e s p o n s e  will  b e  b a s e d  o n t h e  si n gl e  v al u e b ei n g  <  6  m g/ d L . 
A   s u bj e ct   wit h  t h e   pr o p orti o n   of   h o ur s,   P,  l e s s  t h a n   8 0 %   will   b e   c o u nt e d   a s   n o n -r e s p o n d er s. 
S u bj e ct s  w h o  di s c o nti n u e d t h e  st u d y  pri or t o  W e e k  2 4  u n d er  A m e n d m e nt  1  of t h e  pr ot o c ol  will  b e 
c o n si d er e d  n o n -r e s p o n d er s.  A n y  ot h er  s u bj e ct  will  b e  c o u nt e d  a s  a  n o n-r e s p o n d er if  s U A  v al u e s 
ar e  n ot  c oll e ct e d  d uri n g t h e  M o nt h  1 2  p eri o d.  
 
T h e   pr o p orti o n   of   h o ur s   d uri n g  t h e   p eri o d   w h er e  t h e   s U A   w a s  l e s s  t h a n   6   m g/ d L   will   b e  
s u m m ari z e d  u si n g  d e s cri pti v e  st ati sti c s (i. e.  n,  m e a n,  st a n d ar d  d e vi ati o n,  m e di a n,  mi ni m u m,  a n d 
m a xi m u m).   T h e   n u m b er   a n d   pr o p orti o n   of   s u bj e ct s  t h at   di s c o nti n u e d  tr e at m e nt   d u e  t o  t h e  
st o p pi n g r ul e  will  b e  s u m m ari z e d.  T h e  n u m b er  a n d  pr o p orti o n  of r e s p o n d er s  will  b e  s u m m ari z e d 
al o n g  wit h  a  9 5 %  e x a ct ( Cl o p p er -P e ar s o n)  CI f or t h e  pr o p orti o n.  
T h e  pr o p orti o n  of  M o nt h  1 2 ( W e e k s  4 8,  5 0,  5 2) r e s p o n d er s,  d efi n e d  a s  s u bj e ct s  a c hi e vi n g  a n d 
m ai nt ai ni n g  s U A  <  6  m g/ d L f or  at l e a st  8 0 %  of t h e ti m e  d uri n g  M o nt h  1 2.  
 


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  5 1   of 8 4  
  
Pr o p orti o n  of  M o nt h  9  5  m g/ d L  R e s p o n d er s  
T h e  pr o p orti o n  of r e s p o n d er s,  d efi n e d  a s  s u bj e ct s  a c hi e vi n g  a n d  m ai nt ai ni n g  s U A  <  5  m g/ d L f or 
at l e a st  8 0 %  of t h e ti m e  d uri n g  M o nt h  9  will  b e  c al c ul at e d  u si n g t h e  s a m e  m et h o d  u s e d f or  M o nt h 
9  R e s p o n d er s ( 6  m g/ d L) ( S e cti o n  9. 4. 1 )  will  b e  u s e d.  T h e  a n al y si s  will  b e  c o m pl et e d f or t h e I T T 
a n d  mI T T  p o p ul ati o n.  
 
  
Pr o p orti o n  of  M o nt h  1 2  5  m g/ d L  R e s p o n d er s  
T h e  pr o p orti o n  of r e s p o n d er s,  d efi n e d  a s  s u bj e ct s  a c hi e vi n g  a n d  m ai nt ai ni n g  s U A  <  5  m g/ d L f or 
at l e a st  8 0 %  of t h e ti m e  d uri n g  M o nt h  1 2  will  b e  c al c ul at e d  u si n g t h e  s a m e  m et h o d  u s e d f or  M o nt h 
1 2  R e s p o n d er s ( 6  m g/ d L) ( S e cti o n  9. 4. 2 )  will  b e  u s e d.  T h e  a n al y si s  will  b e  c o m pl et e d f or t h e I T T 
a n d  mI T T  p o p ul ati o n.  
  
  
Ti m e t o  s U A  >  6  m g/ d L  
T h e ti m e t o  s U A  >  6  m g/ d L  will  b e  a n al y z e d f or t h e  mI T T  p o p ul ati o n.  T h e fir st  p e gl oti c a s e i nf u si o n 
d at e  will  b e t h e r ef er e n c e  d at e.  O nl y  t h e  s c h e d ul e d pr e- i nf u si o n  s U A  v al u e s st arti n g  wit h  W e e k  2  
will   b e   c o n si d er e d  f or   d et er mi n ati o n   of  t h e   e n d p oi nt.   A s   w a s   n ot e d  i n   S e cti o n   9. 1 ,  t h e  l o c al  
l a b or at or y’ s  v al u e,  m a y  b e  u s e d if t h e  c e ntr al l a b or at or y’ s  v al u e at t h e  s c h e d ul e d ti m e  p oi nt  i s 
u n a v ail a bl e.  T h e  d a y s  u ntil t h e  s U A  >  6  m g/ d L  will  b e  c al c ul at e d  a s:  
E V T D A Y S  =  E V N T D A T E  –  R E F D A T E  +  1,  w h er e  E V N T D A T E i s t h e  d at e  of t h e  e arli e st  p o st -
r ef er e n c e  d at e  w h er e t h e pr e- i nf u si o n s U A  v al u e (fr o m  eit h er t h e l o c al l a b  or  c e ntr al l a b)  i s >  6 
m g/ d L.   F or   s u bj e ct s   w h o   d o   n ot   h a v e   a n y   s U A   v al u e s   >   6   m g/ d L,  t h eir   E V N T D A T E   will   b e  
c e n s or e d  at  t h e l at e st  c oll e ct e d s a m pl e  wit h  n o n -mi s si n g  s U A r e s ult  t hr o u g h  W e e k  5 2.  K a pl a n-
M ei er ( K M)  e sti m at e s  of t h e ti m e t o  e v e nt  will  b e r e p ort e d  al o n g  wit h  a  9 5 %  CI  f or t h e  m e di a n 
ti m e. T h e ti m e t o  e v e nt  will  al s o  b e  pr e s e nt e d  gr a p hi c all y  u si n g  a  K M  c ur v e.  
  
Ti m e t o t w o  c o n s e c uti v e  s U A s  >  6  m g/ d L   
T h e ti m e t o t w o  c o n s e c uti v e  s U A  >  6  m g/ d L  ( st arti n g  at  w e e k  2)  will  b e  a n al y z e d for t h e  mI T T 
p o p ul ati o n.  T h e fir st  p e gl oti c a s e i nf u si o n  d at e  will  b e t h e r ef er e n c e  d at e.  O nl y t h e  s c h e d ul e d  pr e-
i nf u si o n   s U A   v al u e s  fr o m  t h e   c e ntr al  l a b or at or y   st arti n g   wit h   W e e k   2   will   b e   c o n si d er e d  f or  
d et er mi n ati o n  of t h e  e n d p oi nt.  A s  w a s  n ot e d i n  S e cti o n  9. 1 , t h e l o c al l a b or at or y’ s  v al u e,  m a y  b e 
u s e d if t h e  c e ntr al l a b or at or y’ s  v al u e i s  u n a v ail a bl e.  T h e  d a y s  u ntil t h e  s U A  >  6  m g/ d L  will  b e 
c al c ul at e d  a s:  
E V T D A Y S  =  E V N T D A T E  –  R E F D A T E  +  1,  w h er e  E V N T D A T E i s t h e  d at e  of t h e fir st  of t h e  t w o 
c o n s e c uti v e  p o st -r ef er e n c e  d at e s  w h er e t h e pr e- i nf u si o n s U A  v al u e  (fr o m  eit h er t h e l o c al l a b  or 
c e ntr al  l a b)   w a s   >   6   m g/ d L.   S u bj e ct s   wit h   o nl y   a   si n gl e   el e v at e d   pr e- i nf u si o n  s U A  a n d   n o  
s u b s e q u e nt  s U A  r e s ult s  a v ail a bl e  will  b e  c o n si d er e d t o  h a v e t h e  e v e nt.  Ot h erwi s e, f or  s u bj e ct s 
w h o  di d  n ot  h a v e t w o  c o n s e c uti v e  s U A  v al u e s  >  6  m g/ d L, t h eir  E V N T D A T E  will  b e  c e n s or e d  at  
t h e l at e st  c oll e ct e d  s a m pl e  wit h  n o n-mi s si n g  s U A  r e s ult t hr o u g h  W e e k  5 2. K M  e sti m at e s  of t h e 
ti m e t o  e v e nt  will  b e r e p ort e d  al o n g  wit h  a  9 5 % CI  f or t h e  m e di a n ti m e.  T h e ti m e t o  e v e nt  will  al s o 
b e  pr e s e nt e d  gr a p hi c all y  u si n g  a  K M  c ur v e.  


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  5 2   of 8 4  
    
Peri p h er al  J oi nt  U r at e D e p o siti o n  V ol u m e  a n d  B o n e  Er o si o n  S c or e  u si n g  D E C T   
F or  s u bj e ct s fr o m  sit e s  wit h t h e  c a p a biliti e s t o  d et er mi n e j oi nt  ur at e  d e p o siti o n  v ol u m e  a n d  b o n e 
er o si o n  u si n g  D E C T, t h e t ot al  ur at e  v ol u m e i s  s c h e d ul e d f or  c oll e cti o n  at  D a y  1  of t h e  P e gl oti c a s e  
+ I M M  P eri o d,  W e e k  2 4,  W e e k  3 6,  at t h e  E n d  of  P e gl oti c a s e I nf u si o n  Vi sit s (if  a p pli c a bl e),  a n d  
W e e k  5 2/ E n d  of  St u d y/ E arl y  T er mi n ati o n  Vi sit.  S u bj e ct s  w h o  e n d  p e gl oti c a s e i nf u si o n s  pri or t o 
W e e k  5 2  s h o ul d f oll o w t h e  s c h e d ul e d ti m e p oi nt s  b ut  a v oi d  a r e p e at  D E C T  s c a n  wit hi n  6  w e e k s  of 
a  pri or  s c a n.  T h e  a n al y si s  of  D E C T  e n d p oi nt s  will  b e  c o m pl et e d  u si n g t h e  mI T T  p o p ul ati o n.  
If t h er e  ar e  3  or  m or e  s u bj e ct s  w h o  h a v e  an  a s s e s s m e nt  of j oi nt  ur at e  d e p o siti o n  v ol u m e, t h e  
o b s er v e d  v al u e s  a n d t h e  c h a n g e fr o m  D a y  1  i n t h e t ot al  ur at e  v ol u m e  at  e a c h  s c h e d ul e d  vi sit  will 
b e  s u m m ari z e d  u si n g  d e s cri pti v e  st ati sti c s  (i. e.  n,  m e a n,  st a n d ar d  d e vi ati o n,  m e di a n,  mi ni m u m, 
a n d  m a xi m u m).  Si mil arl y, if  3  or  m or e  s u bj e ct s  h a v e  a n  a s s e s s m e nt  of  b o n e  er o si o n, t h e  o b s er v e d 
v al u e s   a n d  t h e   c h a n g e  fr o m   D a y   1  i n  t h e  t ot al   b o n e   er o si o n   at   e a c h   s c h e d u l e d   vi sit   will   b e  
s u m m ari z e d  u si n g  d e s cri pti v e  st ati sti c s  (i. e.  n,  m e a n,  st a n d ar d  d e vi ati o n,  m e di a n,  mi ni m u m,  a n d 
m a xi m u m).  
  
J oi nt s  Aff e ct e d  b y  T o p hi  
T h e  n u m b er  of j oi nt s  aff e ct e d  b y t o p hi  ( vi a t o p hi  a s s e s s m e nt  e C R F) ar e  s c h e d ul e d t o  b e  a s s e s s e d 
at  S cr e e ni n g,  W e e k  2 4,  W e e k  3 6,  E n d  of  P e gl oti c a s e I nf u si o n s  vi sit (if  a p pli c a bl e),  W e e k  5 2/ E n d 
of  St u d y/ E arl y  T er mi n ati o n  Vi sit,  P o st -tr e at m e nt  F oll o w-u p  M o nt h  3,  a n d  P o st -tr e at m e nt  F oll o w-
u p   M o nt h   6 .  U si n g  t h e   mI T T   p o p ul ati o n,   o b s er v e d   v al u e s   a n d   c h a n g e  fr o m  s cr e e ni n g  i n  t h e  
n u m b er  of j oi nt s  aff e ct e d  b y t o p hi  at  e a c h  s c h e d ul e d  vi sit  will  b e  s u m m ari z e d  u si n g  d e s cri pti v e 
st ati sti c s  (i. e.  n,  m e a n,  st a n d ar d  d e vi ati o n,  m e di a n,  mi ni m u m,  a n d  m a xi m u m). If  a s u bj e ct  h a s  n o 
j oi nt s  aff e ct e d  b y t o p hi,  0  will  b e  u s e d f or n u m b er  of j oi nt s  aff e ct e d.   
  
C h a n g e fr o m  B a s eli n e i n  T e n d er/ S w oll e n  J oi nt s   
T e n d er  a n d  s w oll e n ( e x cl u d e s  hi p) j oi nt  c o u nt s  will  b e r e c or d e d  at t h e  W e e k  -4 ( pri or t o t h e fir st 
d o s e  of  M T X)  Vi sit  d uri n g t h e  M T X  R u n -i n  P eri o d;  pri or t o  p e gl oti c a s e i nf u si o n  at t h e  D a y  1  a n d 
W e e k s 1 4,  2 4  a n d  3 6  Vi sit s  d uri n g t h e  P e gl oti c a s e  + I M M  P eri o d;  a n d  at t h e  E n d  of  P e gl oti c a s e 
I nf u si o n s   Vi sit  (if   a p pli c a bl e)   a n d  t h e   W e e k   5 2/ E n d   of   St u d y/ E arl y   T er mi n ati o n   Vi sit,    P o st 
Tr e at m e nt  F oll o w -u p  M o nt h  3,  a n d  P o st- tr e at m e nt  F oll o w-u p  M o nt h  6 . 
T e n d er  a n d  s w oll e n j oi nt  c o u nt s  will  b e  a s s e s s e d  u si n g t h e r h e u m at oi d  art hriti s  6 6 -6 8  j oi nt s. 
O b s er v e d  v al u e s,  c h a n g e fr o m  M T X  b a s eli n e,  a n d  c h a n g e fr o m  p e gl oti c a s e  b a s eli n e  i n t h e t e n d er 
a n d   s w oll e n  j oi nt   c o u nt s   at   e a c h   s c h e d ul e d  ti m e   p oi nt   will   b e   s u m m ari z e d   u si n g   d e s cri pti v e  
st ati sti c s  (i. e.  n,  m e a n,  st a n d ar d  d e vi ati o n,  m e di a n,  mi ni m u m,  a n d  m a xi m u m). A  9 5 %  n or m al -
t h e or y  b a s e d CI  f or t h e  c h a n g e s fr o m  b a s eli n e will  b e  pr e s e nt e d . T h e s e  a n al y s e s  will  b e  pr o vi d e d 
f or t h e  mI T T  p o p ul ati o ns .  
  
C h a n g e fr o m  B a s eli n e i n  H A Q -DI ,  H A Q  P ai n,  a n d  H A Q  H e alt h  
T h e  H A Q  will  b e  a d mi ni st er e d  at t h e  S cr e e ni n g  a n d  W e e k  -4 ( pri or t o t h e fir st  d o s e  of  M T X)  Vi sit s 
d uri n g t h e  M T X  R u n -i n  P eri o d;  pri or t o  p e gl oti c a s e i nf u si o n  at t h e  D a y  1  a n d  W e e k s  1 4,  2 4  a n d 
3 6   Vi sit s   d uri n g  t h e   P e gl oti c a s e   +  I M M   P eri o d;   at  t h e   E n d   of   P e gl oti c a s e  I nf u si o n s   Vi sit  (if  


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  5 3   of 8 4  
a p pli c a bl e), t h e  W e e k  5 2/ E n d  of  St u d y/ E arl y  T er mi n ati o n  Vi sit,  P o st  Tr e at m e nt  F oll o w -u p  M o nt h 
3,  a n d  P o st -tr e at m e nt  F oll o w-u p  M o nt h  6.  
T h e   H A Q -DI  i n d e x   m e a s ur e s   di s a bilit y   o v er  t h e   p a st   w e e k   b y   a s ki n g   a  t ot al   of   2 0   q u e sti o n s  
c o v eri n g  8  d o m ai n s  of f u n cti o n:  dr e s si n g  a n d  gr o o mi n g,  ari si n g,  e ati n g,  w al ki n g,  h y gi e n e, r e a c h, 
gri p,   a n d   u s u al   a cti viti e s.   T h er e   ar e   at  l e a st   2   q u e sti o n s  i n   e a c h   d o m ai n   a n d  t h e   8   d o m ai n s  
r e pr e s e nt  a  c o m pr e h en si v e  s et  of f u n cti o n al  a cti viti e s.  T h e  H A Q -DI i s  c al c ul at e d  b y  s c ori n g t h e 
a n s w er t o  e a c h  q u e sti o n i n t h e  H A Q fr o m  0 t o  3,  wit h  0 r e pr e s e nti n g t h e  a bilit y t o  d o  wit h o ut  a n y 
diffi c ult y,   a n d   3  r e pr e s e nti n g   u n a bl e   t o   d o.   A n y   a cti vit y  t h at  r e q uir e s   a s si st a n c e  fr o m   a n ot h er  
i n di vi d u al  or r e q uir e s t h e  u s e  of  a n  a s si sti v e  d e vi c e r ai s e s  a  0  or  1  s c or e t o  a  2.  T h e  hi g h e st  s c or e 
f or  e a c h  of t h e  8  d o m ai n s i s  s u m m e d (r a n g e fr o m  0 t o  2 4)  a n d  di vi d e d  b y  8 t o  yi el d,  o n  a  s c al e 
wit h  2 5  p o s si bl e  v al u e s,  a  F u n cti o n al  Di s a bilit y I n d e x  wit h  a r a n g e fr o m  0 t o  3.  T h e  di s a bilit y i n d e x 
i s   b a s e d   o n t h e   n u m b er   of   d o m ai n s   a n s w er e d  a n d  i s   c o m p ut e d   o nl y if  t h e   s u bj e ct   c o m pl et e s  
a n s w er s t o  at l e a st  6  d o m ai n s [ Br u c e  a n d  Fri e s,  2 0 0 3]. If  at l e a st  6  d o m ai n s,  b ut l e s s t h a n  8 
d o m ai n s  h a v e  a r e s p o n s e, t h e  H A Q -DI  will  b e  c al c ul at e d  a s t h e  s u m  of t h e  d o m ai n s  a n s w er e d 
a n d  di vi di n g  b y t h e  n u m b er  of  d o m ai n s  a n s w er e d . If  a  s c or e i s  a v ail a bl e  o n l e s s t h a n  6  d o m ai n s, 
t h e  di s a bilit y i n d e x i s  mi s si n g. 
T h e  H A Q  P ai n  q u e sti o n  a s k s, “ H o w  m u c h  p ai n  h a v e  y o u  h a d i n t h e  p a st  w e e k ?”  o n  a  s c al e  of  0 -
1 0 0  w h er e  0 r e pr e s e nt s  n o  p ai n  a n d  1 0 0 r e pr e s e nt s  s e v er e  p ai n.  
T h e  H A Q  H e alt h  q u e sti o n  a s k s “ Pl e a s e r at e  h o w  w ell  y o u  ar e  d oi n g  o n  a  s c al e  of  0 t o  1 0 0 ( 0 
r e pr e s e nt s ‘ v er y  w ell’  a n d  1 0 0 r e pr e s e nt s ‘ v er y  p o or’  h e alt h)”. 
O b s er v e d  v al u e s  a n d  c h a n g e fr o m  M T X  b a s eli n e ,  a n d  c h a n g e fr o m  p e gl oti c a s e  b a s eli n e i n t h e 
H A Q -DI ,   H A Q-P ai n,   a n d   H A Q -H e alt h   s c or e   at   e a c h   s c h e d ul e d  ti m e   p oi nt   will   b e   s u m m ari z e d  
u si n g  d e s cri pti v e  st ati sti c s  (i.e.  n,  m e a n,  st a n d ar d  d e vi ati o n,  m e di a n,  mi ni m u m,  a n d  m a xi m u m) . 
A  t w o-si d e d  9 5 %  n or m al -t h e or y  b a s e d CI  f or t h e  c h a n g e s fr o m  b a s eli n e  will  b e  pr e s e nt e d.  T h e s e 
a n al y s e s  will  b e  c o m pl et e d f or t h e  mI T T  p o p ul ati o n . 
  
C h a n g e fr o m  B a s eli n e i n  P ati e nt  Gl o b al  A s s e s s m e nt  of  G o ut  
T h e  p ati e nt  gl o b al  a s s e s s m e nt  will  b e  c oll e ct e d  at t h e  S cr e e ni n g  a n d  W e e k  -4 ( pri or t o t h e fir st 
d o s e  of  M T X)  Vi sit s  d uri n g t h e  M T X  R u n -i n  P eri o d;  pri or t o  p e gl oti c a s e i nf u si o n  at t h e  D a y  1  a n d 
W e e k s   1 4,   2 4   a n d   3 6   Vi sit s   d uri n g  t h e   P e gl oti c a s e   +  I M M   P eri o d;   at  t h e   E n d   of   P e gl oti c a s e  
I nf u si o n s  Vi sit (if  a p pli c a bl e); t h e  W e e k  5 2/ E n d  of  St u d y/ E arl y  T er mi n ati o n  Vi sit, P o st  Tr e at m e nt 
F oll o w -u p   M o nt h   3,   a n d   P o st -tr e at m e nt   F oll o w-u p   M o nt h   6.   S u bj e ct s   will  r e s p o n d  t o  t h e  
st at e m e nt,  “ C o n si d eri n g   all  t h e   w a y s  t h at   g o ut   aff e ct s   y o u,   cir cl e  t h e   n u m b er   b el o w  t h at   b e st  
r e pr e s e nt s   h o w   y o ur   g o ut   h a s   aff e ct e d   y o u   o v er  t h e  l a st   w e e k”   u si n g   a   n u m eri c  r ati n g   s c al e  
r a n gi n g fr o m  0 ( e x c ell e nt) t o  1 0 ( v er y  p o or)  
O b s er v e d  v al u e s , c h a n g e fr o m  M T X  b a s eli n e ,  a n d  c h an g e fr o m  p e gl oti c a s e  b a s eli n e  i n t h e  p ati e nt 
gl o b al  a s s e s s m e nt  at  e a c h  s c h e d ul e d ti m e  p oi nt  will  b e  s u m m ari z e d  u si n g  d e s cri pti v e  st ati sti c s  
(i. e.  n,  m e a n,  st a n d ar d  d e vi ati o n,  m e di a n,  mi ni m u m,  a n d  m a xi m u m). A  9 5 %  n or m al -t h e or y  b a s e d 
CI   f or  t h e   c h a n g e s  fr o m   b a s eli n e   will   b e   pr e s e nt e d.  T h e   a n al y s is   will   b e   c o m pl et e d  f or   mI T T  
p o p ul ati o n.   


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  5 4   of 8 4  
  
C h a n g e fr o m  B a s eli n e i n  P h y si ci a n  Gl o b al  A s s e s s m e nt  of  G o ut  
T h e  p h y si ci a n  gl o b al  a s s e s s m e nt  will  b e  c oll e ct e d  at t h e  S cr e e ni n g  a n d  W e e k  -4 ( pri or t o t h e fir st 
d o s e  of  M T X)  Vi sit s  d uri n g t h e  M T X  R u n -i n  P eri o d;  pri or t o  p e gl oti c a s e i nf u si o n  at t h e  D a y  1  a n d 
W e e k s   1 4,   2 4   a n d   3 6   Vi sit s   d uri n g  t h e   P e gl oti c a s e   +  I M M   P eri o d;   at  t h e   E n d   of   P e gl oti c a s e  
I nf u si o n s  Vi sit (if  a p pli c a bl e), t h e  W e e k  5 2/ E n d  of  St u d y/ E arl y  T er mi n ati o n  Vi sit, P o st  Tr e at m e nt 
F oll o w -u p  M o nt h  3,  a n d  P o st -tr e at m e nt  F oll o w-u p  M o nt h  6 . T h e  s a m e  a n al y s e s  d e s cri b e d f or t h e 
p ati e nt  gl o b al  a s s e s s m e nt  of  g o ut  (S e cti o n  9. 4. 1 1 ) will  b e  u s e d f or t h e  a n al y si s  of t hi s  v ari a bl e.  
T h e  a n a l y si s will  b e  c o m pl et e d f or t h e  mI T T  p o p ul ati o n .  
  
C h a n g e fr o m  B a s eli n e i n  S u bj e ct  A s s e s s m e nt  of  A v er a g e  P ai n,  L e a st  P ai n,  a n d  W or st 
P ai n   
J oi nt  p ai n  will  b e  a s s e s s e d  at t h e  S cr e e ni n g  a n d  W e e k  -4 ( pri or t o t h e fir st  d o s e  of  M T X)  Vi sit s 
d uri n g t h e  M T X  R u n -i n P eri o d;  pri or t o  p e gl oti c a s e i nf u si o n  at t h e  D a y  1  a n d  W e e k s  1 4,  2 4  a n d 
3 6   Vi sit s   d uri n g  t h e   P e gl oti c a s e   +  I M M   P eri o d;   at  t h e   E n d   of   P e gl oti c a s e  I nf u si o n s   Vi sit  (if  
a p pli c a bl e); t h e  W e e k  5 2/ E n d  of  St u d y/ E arl y  T er mi n ati o n  Vi sit , P o st  Tr e at m e nt  F oll o w -u p  M o nt h 
3,  a n d  P o st -tr e at m e nt  F oll o w-u p  M o nt h  6.  
S u bj e ct s r at e t h eir  a v er a g e  p ai n, l e a st  p ai n  a n d  w or st  p ai n  o v er t h e  p a st  w e e k  o n  a  s c al e fr o m  0 
t o  1 0  wit h  0  =  N o j oi nt  p ai n  a n d  1 0  =  W or st  P o s si bl e  J oi nt  P ai n.  T h e  s a m e  a n al y s e s  d e s cri b e d f or 
t h e   p ati e nt   gl o b al   a s s e s s m e nt   of   g o ut   will   b e   u s e d  f or  t h e   a n al y si s   of  t he s e  v ari a bl e s.  T h e s e 
a n al y s e s  will  b e  c o m pl et e d f or t h e  mI T T  p o p ul ati o n .  
  
G o ut  C hr o ni c  R e s p o n s e  
G o ut  c hr o ni c r e s p o n s e ( G C R)  crit eri a  will  b e  u s e d t o  d efi n e  s u bj e ct s  w h o  a c hi e v e  2 0 %,  5 0 %,  or 
7 0 %  i m pr o v e m e nt i n  3  of t h e  4 f oll o wi n g  m e a s ur e s at  a  s c h e d ul e d ti m e  p oi nt :  
•   s w oll e n j oi nt  c o u nt  
•   t e n d er j oi nt  c o u nt 
•   H A Q  h e alt h  s c or e  
•   H A Q  p ai n  s c or e   
T e n d er  a n d  s w oll e n ( e x cl u d e s  hi p) j oi nt  c o u nt s  will  b e r e c or d e d  at t h e  W e e k  -4 ( pri or t o t h e fir st 
d o s e  of  M T X)  Vi sit  d uri n g t h e  M T X  R u n -i n  P eri o d;  pri or t o  p e gl oti c a s e i nf u si o n  at t h e  D a y  1  a n d 
W e e k s 1 4,  2 4  a n d  3 6  Vi sit s  d uri n g t h e  P e gl oti c a s e  + I M M  P eri o d;  a n d  at t h e  E n d  of  P e gl oti c a s e 
I nf u si o n s   Vi sit  (if   a p pli c a bl e),  W e e k   5 2/ E n d   of   St u d y/ E arl y   T er mi n ati o n   Vi sit ,  P o st   Tr e at m e nt  
F oll o w -u p  M o nt h  3,  a n d  P o st -tr e at m e nt  F oll o w-u p  M o nt h  6.  T h e  H A Q  will  b e  a d mi ni st er e d  at t h e 
S cr e e ni n g  a n d  W e e k  -4 ( pri or t o t h e fir st  d o s e  of  M T X)  Vi sit s  d uri n g t h e  M T X  R u n -i n  P eri o d;  pri or 
t o  p e gl oti c a s e i nf u si o n  at t h e  D a y  1  a n d  W e e k s  1 4, 2 4  a n d  3 6  Vi sit s  d uri n g t h e  P e gl oti c a s e  + I M M 
P eri o d;  at t h e  E n d  of  P e gl oti c a s e I nf u si o n s  Vi sit (if  a p pli c a bl e), t h e  W e e k  5 2/ E n d  of  St u d y/ E arl y 
T er mi n ati o n  Vi sit,  P o st  Tr e at m e nt  F oll o w -u p  M o nt h  3,  a n d  P o st -tr e at m e nt  F oll o w-u p  M o nt h  6.  
T h e  G C R r e s p o n s e  will  b e  d et er mi n e d  at  D a y  1,  W e e k  1 4,  W e e k  2 4,  W e e k  3 6,  E n d  of  P e gl oti c a s e 
I nf u si o n  Vi sit s,  W e e k  5 2/ E n d  of  St u d y/ E arl y  T er mi n ati o n  Vi sit, P o st  Tr e at m e nt  F oll o w -u p  M o nt h 
3,  a n d  P o st -tr e at m e nt  F oll o w-u p  M o nt h  6.  


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  5 5   of 8 4  
A  s u bj e ct  will  b e  d efi n e d  a s  a  G C R 2 0  ( G C R 5 0,  G C R 7 0) r e s p o n d er  at  a  p o st-b a s eli n e  a s s e s s m e nt 
if t h e y  h a v e  at l e a st  a  2 0 % ( 5 0 %,  7 0 %) r e d u cti o n fr o m t h e  M T X  b a s eli n e i n  3  or  m or e  of t h e 
m e a s ur e s  n ot e d  a b o v e.  If  a  s u bj e ct  h a s  3  of t h e  4  m e a s ur e s  a n d  all  3  m e et t h e r e d u cti o n  g o al, 
t h e  s u bj e ct  will  b e  a r e s p o n d er.  
I n t h e ot h er  c a s e s, i n cl u di n g  s u bj e ct s  wit h f e w er t h a n  4  of t h e  crit eri o n  c o m pl et e d  at t h e  s c h e d ul e d 
a s s e s s m e nt , a n d  s u bj e ct s  wit h  all  4  crit eri a  c o m pl et e d  at t h e  s c h e d ul e d  a s s e s s m e nt  w h o  d o  n ot 
m e et  t h e   2 0 %   ( 5 0 %,   7 0 %)  r e d u cti o n   crit eri a,  s u bj e ct s  will  b e  d e cl ar e d   n o n -r e s p o n d er s   at  t h e  
s c h e d ul e d  a s s e s s m e nt.   
S u bj e ct s  w h o  c o m pl et e d t h e  st u d y  at  W e e k  2 4 ( p er  A m e n d m e nt  1  of t h e  pr ot o c ol)  will  b e  e x cl u d e d 
fr o m  W e e k  3 6,  W e e k  5 2,  a n d  3  a n d  6  m o nt h f oll o w-u p  a n al y s e s.  
T hi s   a n al y si s   will   b e   p erf or m e d  f or   b ot h  t h e   M T X   a n d   p e gl oti c a s e   b a s eli n e s  f or  t h e   mI T T  
p o p ul ati o n.   
G C R 2 0,  G C R 5 0,  a n d  G C R 7 0 r e s p o n s e s,  a n d t h e  n u m b er/ p er c e nt a g e  of  s u bj e ct s  w h o  a c hi e v e d 
a   2 0 %,   5 0 %,   a n d   7 0 %  r e d u cti o n  i n   e a c h   c o m p o n e nt   e n d p oi nt   i n  t h e   G C R  r e s p o n s e,  will   b e 
s u m m ari z e d . T h e  p er c e nt a g e  of  G C R 2 0,  G C R 5 0,  a n d  G C R 7 0 r e s p o n d er s  will  b e  c al c ul at e d  u si n g 
t h e  n u m b er  of  s u bj e ct s i n t h e  p o p ul ati o n  b ut  e x cl u di n g  s u bj e ct s  w h o  c o m pl et e d t h e  st u d y  at  W e e k 
2 4 ( p er  A m e n d m e nt  1  of t h e  pr ot o c ol).  A  9 5 %  Cl o p p er -P e ar s o n  c o nfi d e n c e i nt er v al  will  b e f or t h e 
p er c e nt a g e  of  G C R 2 0,  G C R 5 0,  a n d  G C R 7 0 r e s p o n s e s.  T h e  mI T T  p o p ul ati o n  will  b e  u s e d f or 
t h e s e a n al y s e s .  
  
Ot h er  Effi c a c y  E n d p oi nt s  a n d  A n al y s e s  
  
I n v e sti g at or  A s s e s s m e nt  of  Cli ni c al  St at u s 
At  t h e  W e e k 2 4,  E n d  of  P e gl oti c a s e I nf u si o n  Vi sit (if l a st i nf u si o n  o c c urr e d  e arli er t h a n  W e e k  5 0), 
a n d  W e e k  5 2 /  E arl y  T er mi n ati o n  vi sit, t h e i n v e sti g at or  will  a s s e s s t h e f oll o wi n g it e m s r el at e d t o 
g o ut:  
•   C urr e nt  cli ni c al  st at u s  
o   Pr e s e n c e  of t o p hi   
o   N ot a bl e t o p hi  c h ar a ct eri sti c s   
•   G o ut fl ar e s  o c c urri n g  at  a fr e q u e n c y  of  2  or  m or e  p er  y e ar ( y e s/ n o)  
o   N u m b er  of fl ar e s  o c c urri n g i n t h e  p a st  6  m o nt h s  
•   Pr e s e n c e  of  c hr o ni c all y  s w oll e n j oi nt s  d u e t o  g o ut ( y e s/ n o)  
•   Pr e s e n c e  of  c hr o ni c j oi nt  p ai n  attri b ut e d t o  g o ut ( y e s/ n o)  
•   S y m pt o m s t h e  p ati e nt i s  s p e cifi c a ll y  s e e ki n g t o i m pr o v e ( y e s/ n o) 
o   T o p hi  pr e s e n c e/  si z e   
o   P h y si c al f u n cti o n  d u e t o t o p hi  
o   Fr e q u e n c y  of fl ar e s   
o   C hr o ni c j oi nt  s w elli n g  attri b ut e d t o  g o ut   
o   C hr o ni c j oi nt  p ai n  attri b ut e d t o  g o ut   
o   Ot h er  s y m pt o m s  


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  5 6   of 8 4  
T hi s  a s s e s s m e nt  w a s  a d d e d  a s  p art  of  P r ot o c ol  A m e n d m e nt  2  a n d  m a y  n ot  h a v e  d at a  a v ail a bl e 
f or  all  s u bj e ct s. T h e  q u e sti o n s  will  b e  s u m m ari z e d  d e s cri pti v el y  b y  vi sit.  T h e  s u m m ari z ati o n  of 
cli ni c al  st at u s  will  b e  s u m m ari z e d  u si n g t h e  mI T T  p o p ul ati o n.  


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  5 7   of 8 4  
  
A n al y si s  o f  P h ar m a c o ki n eti c s a n d  A nti - Dr u g  A nti b o di e s 
F or  all  s u bj e ct s,  s er u m  s a m pl e s f or  P K  a n al y si s  will  b e  c oll e ct e d  pri or t o  p e gl oti c a s e i nf u si o n  a n d 
aft er t h e  e n d  of i nf u si o n ( pri or t o  di s c h ar g e)  o n  D a y  1  a n d  at t h e  W e e k s  2,  4,  6,  8  a n d  3 6  Vi sit s 
a n d  pri or t o  p e gl oti c a s e i nf u si o n  o nl y  at t h e  W e e k s  1 0,  1 4,  1 8,  2 2,  2 4;  at t h e  E n d  of  P e gl oti c a s e 
I nf u si o n s   Vi sit  (if   a p pli c a bl e);   a n d   W e e k   5 2/ E n d-of -St u d y/ E arl y   T er mi n ati o n   Vi sit.   Vi sit s  f or  
fr e q u e nt   s a m pli n g   of   a   s u b s et   of   s u bj e ct s   w h o   c o n s e nt  f or   a d diti o n al   n o n-i nf u si o n   vi sit   P K  
s a m pli n g (r a n d o m,  m or ni n g  pr ef err e d)  will  o c c ur  at  W e e k  1  a n d  W e e k  7.  
T h e f oll o wi n g  pr e s e nt ati o n s  of  s u bj e ct  s er u m  p e gl oti c a s e  c o n c e ntr ati o n  d at a  c o v er e d i n t hi s  S A P 
will  b e  pr o vi d e d f or  p e gl oti c a s e .: 
•   A  li sti n g  i n cl u di n g   s u bj e ct,   w e e k/ti m e   p oi nt  ( a ct u al,   pl a n n e d),  tr e at m e nt   a n d   s er u m 
c o n c e ntr ati o n s.  E n d  of i nf u si o n  s a m pli n g ti m e s  ar e  e x pr e s s e d r el ati v e t o t h e  st art ti m e  of 
i nf u si o n. 
•   A t a bl e  s u m m ar y  of  s er u m  p e gl oti c a s e  c o n c e ntr ati o n s  at  e a c h ti m e  p oi nt ( n;  m e a n,  S D, 
c o effi ci e nt  of  v ari ati o n ( C V) %  c al c ul at e d  a s  1 0 0 %   × S D/ m e a n,  mi ni m u m,  2 5
t h p er c e ntil e, 
m e di a n,  7 5
t h p er c e ntil e  a n d  m a xi m u m) f or t h e  P K  P o p ul ati o n  
C o n c e ntr ati o n s   b el o w  t h e  li mit   of   q u a ntifi c ati o n  ( B L Q)   c oll e ct e d   o n   D a y   1   pr e -d o s e   will   b e  
s u m m ari z e d  a s  z er o.  All  ot h er  c o n c e ntr ati o n s  B L Q  will  b e  e x cl u d e d fr o m t h e  a n al y si s  s u m m ari e s.  
T h e  s u m m ar y  of i n di vi d u al  5  M T X  p ol y gl ut a m at e  v al u e s,  P G 1 -2 (i. e.,  P G 1  +  P G 2),  P G 3 -5 (i. e., 
P G 3  +  P G 4  +  P G 5),  P G 4 -5 (i. e.,  P G 4  +  P G 5),  a n d t ot al  P G 1 -5 (i. e.,  P G 1  +  P G 2  +  P G 3  +  P G 4 
+ P G 5)  o v er ti m e f or  all  mI T T  s u bj e ct s,  a s  w ell  a s  b y  M o nt h  6  s U A  R e s p o n d er s  a n d  M o nt h  6  s U A 
N o n -r e s p o n d er s   will   b e   pr o vi d e d.  A   b y   s u bj e ct   pl ot   of  t ot al   P G 1 -5,   a n d  i n di vi d u al   5   M T X  
p ol y gl ut a m at e  v al u e s  o v er ti m e  will  b e  pr o vi d e d  wit h  M o nt h  6  s U A  R e s p o n d er s  a n d  M o nt h  6  s U A 
N o n -r e s p o n d er s i d e ntifi e d i n t h e mI T T  p o p ul at i o n.  A  sp a g h etti  pl ot  of i n di vi d u al  s u bj e ct s  f or t ot al 
P G 1 -5,  P G 1 -2,  P G 3,  P G 3 -5  will  b e  pr o vi d e d  wit h  M o nt h  6  s U A  R e s p o n d er s  a n d  M o nt h  6  s U A 
N o n -r e s p o n d er s i d e ntifi e d i n t h e  mI T T  p o p ul ati o n.  T h e  p er c e nt a g e  of t ot al  P G 1-5 f or  P G 1,  P G 2, 
P G 3,  a n d  P G 4 -5  o v er ti m e f or  all  s u bj e ct s i n  mI T T  p o p ul ati o n  a s  w ell  a s  M o nt h  6  s U A  R e s p o n d er s 
a n d  M o nt h  6  s U A  N o n -r e s p o n d er s  will  b e  pl ott e d i n a  b ar  gr a p h.  A li sti n g  of  M T X  p ol y gl ut a m at e 
c o n c e ntr ati o n s  will  b e  pr o vi d e d,  s h o wi n g t h e  s u bj e ct,  w e e k/ti m e  p oi nt,  c oll e cti o n  d at e  a n d ti m e 
al o n g  wit h  st u d y  d a y r el ati v e t o fir st  M T X tr e at m e nt  d at e,  a n d t h e  5  M T X  p ol y gl ut a m at e  v al u e s 
a n d t ot al  M T X  p ol y gl ut a m at e  v al u e s.   
I m m u n o g e ni cit y  of  p e gl oti c a s e  will  b e  a s s e s s e d  vi a  s er u m  s a m pl e s f or  e v al u ati o n  of  a nti- P E G 
a n d  a nti -uri c a s e I g G  a nti b o di e s.  S a m pl e s  will  b e  c oll e ct e d  pri or t o t h e  p e gl oti c a s e i nf u si o n  o n  D a y 
1  a n d  at t h e  W e e k s  2,  4,  6,  8,  1 0,  1 4,  1 8,  2 2,  2 4,  3 6,  at t h e  E n d  of  P e gl oti c a s e I nf u si o n s  Vi sit (if 
a p pli c a bl e);  a n d  5 2/ E n d  of  St u d y/ E arl y  T er mi n ati o n  Vi sit s  a n d  P o st  Tr e at m e nt  3  m o nt h  F oll o w -u p 
Vi sit.  Vi sit s f or fr e q u e nt  s a m pli n g  of  a  s u b s et  of  s u bj e ct s  w h o  c o n s e nt f or  a d diti o n al  n o n -i nf u si o n 
vi sit  P K  s a m pli n g  will  o c c ur  at  W e e k s  1  a n d  7. I n t h e  e v e nt  of  a n  A E  s u s p e ct e d t o  b e  a n i nf u si o n 
r e a cti o n,  a  s er u m  s a m pl e f or i m m u n o g e ni cit y will  b e  c oll e ct e d  at t h at ti m e  or  at t h e  s u b s e q u e nt 
vi sit . 


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  5 8   of 8 4  
U si n g t h e  mI T T  P o p ul ati o n  f or  a nti-P E G I g G  a nti b o di e s, t h e  n u m b er  a n d  p er c e nt a g e  of  s u bj e ct s 
wit h   A D A   p o siti v e   at   b a s eli n e,   A D A   p o siti v e   at   p o st -b a s eli n e   b ut   n e g ati v e   at   b a s eli n e   or   wit h  
i n cr e a s e i n tit er fr o m  b a s eli n e,  A D A  p o siti v e  at  p o st-b a s eli n e  b ut  n e g ati v e  at  b a s eli n e,  a n d  A D A 
wit h i n cr e a s e i n tit er fr o m  b a s eli n e,  will  b e  s u m m ari z e d  b y  s c h e d ul e d ti m e p oi nt.  Si mil arl y f or  a nti -
uri c a s e I g G  a nti b o di e s, t h e  n u m b er  a n d  p er c e nt a g e  of  s u bj e ct s  wit h  A D A  p o siti v e  at  b a s eli n e  a n d 
p o st -b a s eli n e  will  b e  s u m m ari z e d  b y  s c h e d ul e d ti m e p oi nt.  
K a pl a n -M ei er  e sti m at e s  of t h e ti m e t o  p o siti v e  a nti -P E G r e s p o n s e,  a n d t h e ti m e t o  a nti -uri c a s e 
r e s p o n s e  wit h  2 5t h p er c e ntil e,  m e di a n,  7 5 t h p er c e ntil e,  a n d  9 5 %  CI,  al o n g  wit h  a  K a pl a n -M ei er 
c ur v e  will  b e  pr o d u c e d.  
F urt h er, t h e  m e a n  a n d  C V %  of  p e gl oti c a s e  c o n c e ntr ati o n s  will  b e  pr o vi d e d  b y  vi sit i n t h e  s u b s et 
of  s u bj e ct s  w h o  ar e  A D A  p o siti v e ( d efi n e d  a s  p o siti v e f or  a nti -P E G  or  a nti -uri c a s e  a nti b o di e s)  a n d 
A D A  n e g ati v e ( d efi n e d  a s  n e g ati v e f or  b ot h  a nti -P E G  a n d  a nti -uri c a s e  a nti b o di e s) f or  e a c h  vi sit. 
T hi s  a n al y si s  will  b e  pr o vi d e d f or t h e  mI T T  P o p ul ati o n.  
 


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  5 9   of 8 4  
    
S af et y 
S af et y  a n al y s e s  will  b e  b a s e d  o n t h e I T T  p o p ul ati o n  a n d t h e  MI T T  p o p ul ati o n,  a s  a p pr o pri at e .  
S af et y  will  b e  a s s e s s e d  vi a  A E s ,  c o n c o mit a nt  m e di c ati o n  u s e  m o nit ori n g (r ef er t o S e cti o n  8. 3 ), 
p h y si c al  e x a mi n ati o n s,  vit al  si g n s,  cli ni c al  s af et y l a b or at or y  e v al u ati o n s ( c o m pl et e  bl o o d  c o u nt, 
c h e mi str y,  uri n e  uri c  a ci d:  cr e ati ni n e  r ati o), pr e g n a n c y t e sti n g (if  a p pli c a bl e),  el e ctr o c ar di o gr a m s 
( E C G s),  a n d  A E s  of  s p e ci al i nt er e st (i. e., i nf u si o n r e a cti o n s (I R s),  a n a p h yl a xi s,  g o ut fl ar e s,  a n d 
c ar di o v a s c ul ar  e v e nt s).  
All  s af et y i nf or m ati o n  will  b e  pr o vi d e d i n  s u bj e ct li sti n g s.  
  E xt e nt  of  E x p o s ur e  
St u d y  dr u g  e x p o s ur e  will  b e  s u m m ari z e d  u si n g  t h e  d ur ati o n  of tr e at m e nt (i n  d a y s),  n u m b er  of 
d o s e s ,  a n d t ot al  d o s a g e r e c ei v e d f or M T X  a n d  p e gl oti c a s e .  T h e  u s a g e  of pr o p h yl a xi s  tr e at m e nt s 
(f oli c  a ci d, I R u s a g e  of f e x of e n a di n e i n t h e  e v e ni n g  pri or t o  p e gl oti c a s e  i nf u si o n, I R  pr o p h yl a xi s  of 
f e x of e n a di n e,   a c et a mi n o p h e n,  m et h yl pr e di s o n e,  a n d   h y dr o c orti s o n e   o n  t h e   m or ni n g   pri or  t o  
p e gl oti c a s e  i nf u si o n)  will  b e  pr o vi d e d i n li sti n g s  o nl y. I nt err u pti o n s i n p e gl oti c a s e  i nf u si o n s will  b e 
s u m m ari z e d.  R e a s o n s f or  i nf u si o n i nt err u pti o n s  will  b e  pr o vi d e d i n t h e li sti n g s.  
F or t h e  M T X  R u n -i n  P eri o d, t h e f oll o wi n g will  b e  s u m m ari z e d:   
•   D ur ati o n  of tr e at m e nt  d efi n e d  a s t h e l a st  d o s e  of  M T X  pri or t o t h e  D a y  1  vi sit  d at e  –  fir st 
d o s e   d at e   of   M T X   +   1   ( s u m m ari z e d   wit h   d e s cri pti v e   st ati sti c s   of   m e a n,   S D,   m e di a n,  
mi ni m u m,  a n d  m a xi m u m)  
•   T ot al  M T X  d o s a g e t a k e n  b et w e e n t h e fir st  a n d l a st  d o s e  d at e s i n t h e  M T X  R u n -i n  P eri o d, 
i n cl u si v e (i n  m g) ( s u m m ari z e d  wit h  d e s cri pti v e  st ati sti c s  of  m e a n,  S D,  m e di a n, mi ni m u m,  
a n d  m a xi m u m)  
•   A v er a g e  M T X  d o s e ( i n m g) (t ot al  d o s a g e f or  t h e  M T X R u n -i n  P eri o d  di vi d e d  b y  n u m b er  of 
d o s e s  t a k e n   d uri n g   t h e   M T X  R u n -i n   P eri o d)  ( s u m m ari z e d   wit h   d e s cri pti v e   st ati sti c s   of  
m e a n,  S D,  m e di a n,  mi ni m u m,  a n d  m a xi m u m)  
•   N u m b er  of  s u bj e ct s  wit h  M T X  d o s a g e r e d u cti o n s fr o m  pl a n n e d  1 5  m g/ w e e k . 
F or t h e  P e gl oti c a s e  + I M M  P eri o d,  t h e f oll o wi n g  will  b e  s u m m ari z e d: 
•   P e gl oti c a s e  
o   N u m b er   of   p e gl oti c a s e   i nf u si o n s  r e c ei v e d  o v er all   ( s u m m ari z e d   wit h  fr e q u e n c y  
s u m m ar y   al o n g   wit h   d e s cri pti v e   st ati sti c s   of   m e a n,   S D,   m e di a n,   mi ni m u m,   a n d 
m a xi m u m)  
o   D ur ati o n i n  d a y s  b et w e e n fir st  a n d l a st  p e gl oti c a s e  i nf u si o n,  d efi n e d  a s l a st i nf u si o n 
d at e  –  fir st i nf u si o n  d at e  +  1 ( s u m m ari z e d  wit h  d e s cri pti v e  st ati sti c s  of  m e a n,  S D, 
m e di a n,  mi ni m u m  a n d  m a xi m u m)  
o   N u m b er  of  i nc o m pl et e i nf u si o n s  r e c ei v e d ( s u m m ari z e d  wit h fr e q u e n c y  s u m m ar y 
al o n g  wit h  d e s cri pti v e  st ati sti c s  of  m e a n,  S D,  m e di a n,  mi ni m u m  a n d  m a xi m u m)  
o   N u m b er  of i nt err u pt e d i nf u si o n s   


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  6 0   of 8 4  
o   s u m m ari z e d  wit h fr e q u e n c y  s u m m ar y  al o n g  wit h  d e s cri pti v e  st ati sti c s  of  m e a n,  S D, 
m e di a n,  mi ni m u m  a n d  m a xi m u m)  
•   At  e a c h  s c h e d ul e d  P e gl oti c a s e  i nf u si o n  vi sit 
o   N u m b er  of  s u bj e ct s r e c ei vi n g  a  c o m pl et e i nf u si o n (i. e. f ull  d o s e  a d mi ni st er e d)  
o   N u m b er  of i nf u si o n s  a d mi ni st er e d  wit h o ut i nt err u pti o n  
o   N u m b er  of  s u bj e ct s  wit h  a n i nt err u pt e d i nf u si o n  
•   M T X  
o   D ur ati o n  of  M T X  d o si n g  d uri n g t h e  P e gl oti c a s e  + I M M  P eri o d,  d efi n e d  a s t h e l a st 
M T X  d at e  –  fir st  M T X  d o si n g  d at e ( o n  or  aft er t h e  d at e  of t h e  D a y  1  vi sit)  +  1 
o   C u m ul ati v e  M T X  d o s a g e (i n  m g) r e c ei v e d  d uri n g t h e  P e gl oti c a s e  + I M M  p eri o d   
o   A v er a g e  M T X  d o s e ( i n m g) (t ot al  d o s a g e f or  t h e P e gl oti c a s e  + I M M  P eri o d  di vi d e d 
b y  n u m b er  of  d o s e s t a k e n  d uri n g  t h e P e gl oti c a s e  + I M M  P eri o d) ( s u m m ari z e d  wit h 
d e s cri pti v e  st ati sti c s  of  m e a n,  S D,  m e di a n,  mi ni m u m,  a n d  m a xi m u m)  
o   N u m b er  of  s u bj e ct s  wit h  M T X  d o s a g e r e d u cti o n s  fr o m  pl a n n e d  1 5  m g/w e e k . 
F or t h e  o v er all  st u d y, t h e f oll o wi n g  will  b e  s u m m ari z e d:  
•   M T X  
o   D ur ati o n  of  M T X  d o si n g,  d efi n e d  a s t h e l a st  M T X  d at e  –  fir st  M T X  d o si n g  d at e ( o n 
or  aft er t h e  d at e  of t h e  D a y  1  vi sit)  +  1  
o   C u m ul ati v e  M T X  d o s a g e (i n  m g) r e c ei v e d  
o   N u m b er  of  s u bj e ct s  wit h  M T X  d o s a g e r e d u cti o n s fr o m  pl a n n e d  1 5  m g/ w e e k . 
o   T ot al  M T X  d o s a g e ( i n m g)  p er  d o s e  o v er all  
  Tr e at m e nt  C o m pli a n c e   
Ot h er t h a n t h e  s u m m ari z ati o n s  of  P e gl oti c a s e  i nf u si o n s  d e s cri b e d i n S e cti o n  1 1. 1 , t h e  c o m pli a n c e 
wit h  P e gl oti c a s e  will  n ot  b e  s u m m ari z e d.   
Ot h er  t h a n  t h e   s u m m ari z ati o n s   of   M T X   e x p o s ur e,  t h e   c o m pli a n c e   wit h   M T X   will   n ot   b e  
s u m m ari z e d.  
  A d v er s e  E v e nt s   
All  a d v er s e  e v e nt s  will  b e  c o d e d  u si n g  M e d D R A  v er si o n  2 0. 1.  A E  m o nit ori n g  will  b e gi n fr o m t h e 
si g n at ur e  of t h e I C F  u ntil t h e  6  m o nt h  P o st  Tr e at m e nt  F oll o w -u p  Vi sit.  S A E  m o nit ori n g  will  b e gi n 
fr o m t h e  si g n at ur e  of t h e I C F  u ntil t h e  6  m o nt h  P o st  Tr e at m e nt  F oll o w-u p  Vi si t. 
A d v er s e   e v e nt s   wit h   a n   o n s et   d at e   stri ctl y  pri or  t o  t h e fir st   M T X tr e at m e nt  i n  t h e  M T X  R u n -i n 
P eri o d  will  b e  c all e d  n o n -tr e at m e nt-e m er g e nt  e v e nt s.  
Tr e at m e nt -e m er g e nt  A E s ( T E A E s)  f or t h e M T X  R u n -I n  p eri o d  ar e  d efi n e d  a s  e v e nt s  wit h  a n  o n s et 
d at e  o n  or  aft er t h e fir st  d o s e  of  M T X  ( b ut  n ot  o n  or  aft er t h e fir st i nf u si o n  d at e  of  p e gl oti c a s e i n 
s u bj e ct s  w h o  e nt er e d t h e  P e gl oti c a s e  + I M M  P eri o d)  t hr o u g h  3 0  d a y s  aft er t h e l a st  d o s e  of  M T X 
f or  s u bj ect s  w h o  d i d n ot r e c ei v e  p e gl oti c a s e.   


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  6 1   of 8 4  
T E A E s  f or t h e  P e gl oti c a s e  + I M M  P eri o d  ar e  d efi n e d  a s  e v e nt s t h at  o c c ur  o n  or  aft er t h e  st art 
d at e  of t h e fir st  p e gl oti c a s e i nf u si o n t hr o u g h  3 0  d a y s  aft er t h e l a st  d o s e  of  p e gl oti c a s e  a n d/ or  M T X 
( w hi c h e v er i s l at er).  
A d v er s e  e v e nt s  wit h  a n  o n s et  d at e  m or e t h a n  3 0  d a y s  aft er t h e l a st  d o s e  of  p e gl oti c a s e  a n d/ or 
M T X ( w hi c h e v er i s l at er),  will  b e  a d v er s e  e v e nt s i n t h e f oll o w -u p  p eri o d.  
All  A E s,  b ot h  s eri o u s  a n d  n o n -s eri o u s,  will  b e  a s s e s s e d f or  s e v erit y  u si n g t h e  R h e u m at ol o g y  
C o m m o n  T o xi cit y  Crit eri a ( C T C)  v 2. 0.  Mi s si n g  d at a  c o n v e nti o n s f or  A E s  ar e  d e s cri b e d i n S e cti o n 
6 . 3. 2.  T h e  i m p ut e d   o n s et   d at e s   will   b e   u s e d  t o   d et er mi n e  t h e   p eri o d   of   o n s et.   S u m m ari e s   of  
T E A E s i n t h e  M T X  R u n -i n  P eri o d  will  b e pr o vi d e d  u si n g t h e I T T  a n d  mI T T  p o p ul ati o n s . S u m m ari e s 
of  T E A E s  i n t h e  P e gl oti c a s e  + I M M  P eri o d  will  b e  s u m m ari e s for  t h e  mI T T  p o p ul ati o n.  
 
A n  o v er all  s u m m ar y  of  T E A E s  will  b e  pr o vi d e d  b y f or t h e  M T X  R u n -i n  P eri o d  a n d  P e gl oti c a s e  + 
I M M  P eri o d, i n cl u di n g t h e  n u m b er  a n d  p er c e nt a g e  of  s u bj e ct s  wit h  e a c h  A E t y p e  a s  w ell  a s t h e 
n u m b er  of  e v e nt s f or  e a c h  of t h e f oll o wi n g:  
•     T E A E s 
•   S eri o u s  T E A E s  
•     T E A E s R el at e d t o  M T X  
•   T E A E s  R el at e d t o  p e gl oti c a s e  ( a p pli c a bl e t o P e gl oti c a s e  + I M M  P eri o d  o nl y)  
•     Seri o u s  T E A E s  R el at e d t o  M T X  
•   S eri o u s  T E A E s  R el at e d t o  p e gl oti c a s e ( a p pli c a bl e  t o  P e gl oti c a s e  + I M M P eri o d  o nl y)  
•   T E A E s  wit h  a n  R h e u m at ol o g y  C T C  Crit eri a  of  3  or  hi g h er   
•   T E A E s l e a di n g t o  p er m a n e nt  wit h dr a w al  of  M T X  
•   T E A E s l e a di n g t o  p er m a n e nt  wit h dr a w al  of  p e gl oti c a s e  ( a p pli c a bl e t o  P e gl oti c a s e  + I M M 
P eri o d  o nl y)  
•     T E A E s R el at e d t o  M T X l e a di n g t o  p er m a n e nt  wit h dr a w al  of  M T X   
•   T E A E s  R el at e d t o  p e gl oti c a s e  l e a di n g t o  p er m a n e nt  wit h dr a w al  of p e gl oti c a s e  ( a p pli c a bl e 
t o  P e gl oti c a s e  + I M M  P eri o d  o nl y) 
•   T E A E s l e a di n g t o  st u d y  di s c o nti n u ati o n  
•     T E A E s R el at e d t o  M T X l e a di n g t o  st u d y  di s c o nti n u ati o n  
•     T E A E s R el at e d t o  p e gl oti c a s e  l e a di n g t o  st u d y  di s c o nti n u ati o n ( a p pli c a bl e t o  P e gl oti c a s e 
+ I M M  P eri o d  o nl y)  


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  6 2   of 8 4  
•   T E A E s l e a di n g t o  d e at h  
U si n g t h e  mI T T  p o p ul ati o n,  a n  o v er all  s u m m ar y  of  A E s  o c c urri n g  d uri n g t h e f oll o w -u p  p eri o d ( wit h 
o n s et   m or e  t h a n   3 0   d a y s   aft er  t h e  l a st   d o s e   of   st u d y   m e di c ati o n),  i n cl u di n g  t h e   n u m b er   a n d  
p er c e nt a g e   of   s u bj e ct s   wit h   e a c h   A E  t y p e   a s   w ell   a s  t h e   n u m b er   of   e v e nt s  f or   e a c h   of  t h e  
f oll o wi n g: 
•     A E s 
•   S eri o u s  A E s  
•   A E s  wit h  a n  R h e u m at ol o g y  C T C  Crit eri a  of  3  or  hi g h er   
•   A E s l e a di n g t o  st u d y  di s c o nti n u ati o n  
•   A E s l e a di n g t o  d e at h  
P er c e nt a g e s  f or t h e  o v er all  s u m m ar y  of   A E s  d uri n g f oll o w-u p  will  b e  b a s e d  o n t h e  n u m b er  of 
s u bj e ct s  w h o  h a d f oll o w -u p  m or e t h a n  3 0  d a y s  aft er l a st  d o s e  of  m e di c ati o n.  
 
A d diti o n al  A E  s u m m ari e s  will  b e  pr o vi d e d  b y  o n s et  p eri o d, i n cl u di n g t h e  n u m b er , p er c e nt a g e  of 
s u bj e ct s,  e x p eri e n ci n g  T E A E s f or t h e f oll o wi n g:  
•   T E A E s  o v er all  a n d  b y  S O C  a n d  P T  f or t h e:  M T X  R u n-i n  P eri o d,  P e gl oti c a s e  + I M M  P eri o d, 
a n d  F oll o w -u p  P eri o d   
•   T E A E s  b y  m a xi m u m  s e v erit y,  o v er all  a n d  b y  S O C  a n d  P T f or t h e:  M T X  R u n -i n  P eri o d a n d  
P e gl oti c a s e  + I M M  P eri o d   
•     T E A E s  r el at e d  t o   M T X   o v er all   a n d   b y   S O C   a n d   P T  f or  t h e:   M T X   R u n-i n   P eri o d   a n d  
P e gl oti c a s e  + I M M  P eri o d  
•   T E A E s  r el at e d  t o   p e gl oti c a s e  o v er all   a n d   b y   S O C   a n d   P T   f or  t h e  P e gl oti c a s e   +  I M M  
P eri o d  o nl y  
•   T E A E s  R el at e d t o  M T X  b y  m a xi m u m  s e v erit y,  o v er all  a n d  b y  S O C  a n d  P T f or t h e:  M T X 
R u n -i n  P eri o d  a n d  P e gl oti c a s e  + I M M  P eri o d. 
•   T E A E s  R el at e d t o  P e gl oti c a s e  b y  m a xi m u m  s e v erit y,  o v er all  a n d  b y  S O C  a n d  P T f or t h e 
P e gl oti c a s e  + I M M  P eri o d  o nl y  
•   S eri o u s  T E A E s,  o v er all  a n d  b y  S O C  a n d  P T  f or t h e:  M T X  R u n-i n  P eri o d,  P e gl oti c a s e  + 
I M M  P eri o d,  a n d  F oll o w-u p  P eri o d  
•   T E A E s l e a di n g t o  p er m a n e nt  wit h dr a w al  of  M T X ,  o v er all  a n d  b y  S O C  a n d  P T f or t h e:  M T X 
R u n -i n  P eri o d,  a n d  P e gl oti c a s e  + I M M  P eri o d) 
•   T E A E s l e a di n g t o  p er m a n e nt  wit h dr a w al  of  p e gl oti c a s e ,  o v er all  a n d  b y  S O C  a n d  P T f or 
t h e P e gl oti c a s e  + I M M  P eri o d  o nl y  


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  6 3   of 8 4  
 
T h e i n ci d e n c e  p er  p er s o n  y e ar s  of  e x p o s ur e t o  M T X,  a n d i n ci d e n c e  p er  p er s o n  y e ar s  of  e x p o s ur e 
t o  p e gl oti c a s e   will   b e   pr o vi d e d   o n   all  t a bl e s   e x c e pt  t h o s e   s u m m ari zi n g   e v e nt s   b y   m a xi m u m  
i nt e n sit y,   a n d  t h o s e  f or  t h e   p o st-tr e at m e nt  f oll o w-u p   p eri o d.   F or   s u m m ari e s   b y   S O C,   P T,   a n d  
m a xi m u m  s e v erit y ,  a  s u bj e ct  will  o nl y  b e  c o u nt e d  o n c e f or  e a c h  S O C  b a s e d  o n t h e  m a xi m u m 
i nt e n sit y l e v el r e p ort e d f or t h at  S O C  a n d  o n c e f or  e a c h  u ni q u e  P T  wit hi n t h at  S O C l e v el  at t h e 
m a xi m u m i nt e n sit y l e v el r e p ort e d f or t h at  P T.  F or  s u m m ari e s  b y  S O C  a n d  P T  o nl y,  a  s u bj e ct  will 
b e  c o u nt e d  at  m o st  o n c e  at t h e  S O C l e v el  a n d  at  m o st  o n c e  at  e a c h  u ni q u e  P T  wit hi n t h e  S O C 
l e v el.   S u m m ari e s   pr e s e nti n g  t h e  fr e q u e n c y   of   T E A E s   b y   S O C   a n d   P T   will   b e   or d er e d  
al p h a b eti c all y  b y  S O C  a n d t h e n,  wit hi n  a  S O C,  al p h a b eti c all y  b y  P T.   
 
I n  a d diti o n t o t h e li sti n g  of  all  A E s,  s e p ar at e li sti n g s  will  b e  pr o vi d e d f or s eri o u s  A E s,  A E s l e a di n g 
t o   wit h dr a w al   of   M T X,   A E s  l e a di n g  t o   wit h dr a w al   of  p e gl oti c a s e ,   A E s  l e a di n g  t o   st u d y  
di s c o nti n u ati o n,  A E s  of  s p e ci al i nt er e st,  a n d  A E s l e a di n g t o  d e at h.  T E A E s  a n d t h e  p eri o d  of  o n s et 
will  b e i d e ntifi e d  o n  e a c h li sti n g.   
 
  
A d v er s e  E v e nt s  of  S p e ci al I nt er e st  
A d v er s e  e v e nt s  of  s p e ci al i nt er e st  will i n cl u d e: i nf u si o n r e a cti o n s (I R s),  a n a p h yl a xi s , g o ut fl ar e s, 
a n d  c ar di o v a s c ul ar  e v e nt s : 
I R s a n d  A n a p h yl a xi s  
I R s  a n d   a n a p h yl a xi s  r e a cti o n s   ar e   d efi n e d  i n  t h e   pr ot o c ol  ( s e e   Pr ot o c ol  s e cti o n   9. 5. 4. 1. 1. 5).  
T h e s e  e v e nt s  ar e i d e ntifi e d  b y t h e i n v e sti g at or  o n t h e  e C R F.  T h e  si g n s  a n d  s y m pt o m s  a s s o ci at e d 
wit h  e a c h  e v e nt  ar e  e nt er e d  o n  t h e e C R F  a n d  will  b e  c o d e d t o t h e  M e d D R A  di cti o n ar y. I R s  a n d 
a n a p h yl a xi s  e v e nt s,  a n d t h e  a s s o ci at e d  si g n s  a n d  s y m pt o m s,  will  b e  s u m m ari z e d  b y  S O C,  P T, 
s e v erit y,  a n d t h e ti m e r el ati v e t o t h e  m o st r e c e nt  p e gl oti c a s e i nf u si o n.  Ti m e r el ati v e t o t h e  m o st 
r e c e nt  p e gl oti c a s e i nf u si o n  will  b e  c at e g ori z e d  a s:  d a y  of i nf u si o n,  1-2  d a y s  aft er i nf u si o n,  a n d  > 
2   d a y s   aft er  i nf u si o n.   S u m m ari e s   of  I R s   a n d   a n a p h yl a xi s   will   b e  t a b ul at e d   o nl y  if   5   or   m or e  
s u bj e ct s  wit h  eit h er I R  or  a n a p h yl a xi s  o c c ur.  
C ar di o v a s c ul ar  E v e nt s  
C ar d i ov a s c ul ar   ev e nt s  will i n cl u d e  M aj or  A d v er s e  C ar di o v a s c ul ar  E v e nt s ( M A C E) .  
A n y  M A C E  i n cl u di n g  N o n-f at al  m y o c ar di al i nf ar cti o n,  n o n-f at al  str o k e, c ar di o v a s c ul ar  d e at h , a n d 
c o n g e sti v e  h e art f ail ur e . T h e  foll o wi n g  s e ar c h  al g orit h m  will  b e  u s e d t o i d e ntif y  p o s si bl e  M A C E:  
•   F or  c ar di o v a s c ul ar  d e at h:  St a n d ar di z e d  M e d D R A  Q u eri e s ( S M Q) :  M y o c ar di al i nf ar cti o n 
( br o a d), H a e m orr h a gi c  c e ntr al  n er v o u s  s y st e m  v a s c ul ar  c o n diti o n s ( n arr o w),  I s c h a e mi c 
C e ntr al  N er v o u s  S y st e m ( C N S)  V a s c ul ar  c o n diti o n s ( n arr o w),   C e ntr al  n er v o u s  s y st e m 
v a s c ul ar  di s or d er s,  n ot  s p e cifi e d  a s  h a e m orr h a gi c  or i s c h a e mi c  ( n arr o w), E m b oli c  a n d 
t hr o m b oti c   e v e nt s  ( art eri al,   v e n o u s,   v e s s el  t y p e   u n s p e cifi e d   a n d   mi x e d   art eri al   a n d  
v e n o u s)  ( n arr o w),   C ar di a c  f ail ur e  ( br o a d),     S h o c k -a s s o ci at e d   cir c ul at or y   or   c ar di a c  
c o n diti o n s  ( e x cl  t or s a d e s   d e   p oi nt e s)   ( br o a d),  T or s a d e   d e   p oi nt e s/ Q T   pr ol o n g ati o n  
( br o a d),  Arr h yt h mi a  r el at e d  i n v e sti g ati o n s,   si g n s   a n d   s y m pt o m s   ( br o a d), 


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  6 4   of 8 4  
C ar di o m y o p at h y   ( br o a d),  S u pr a v e ntri c ul ar  t a c h y arr h yt h mi a s  ( n arr o w),   V e ntri c ul ar  
t a c h y arr h yt h mi a s ( n arr o w),  C o n d u cti o n  d ef e ct s ( n arr o w),  All  P T s  u n d er  S O C  of  C ar di a c 
di s or d er s,  H L G T  A n e ur y s m  
•   F or  n o n -f at al  m y o c ar di al i nf ar cti o n:  S M Q M y o c ar di al  i nf ar cti o n ( br o a d)  
•   F or   n o n -f at al   str o k e:   S M Q:  I s c h ae mi c  C e ntr al   N er v o u s   S y st e m  ( C N S )  V a s c ul ar 
c o n diti o n s  ( n arr o w),  H a e m orr h a gi c   c e ntr al   n er v o u s   s y st e m   v a s c ul ar   c o n diti o n s  
( n arr o w),  C e ntr al  n er v o u s  s y st e m  v a s c ul ar  di s or d er s,  n ot  s p e cifi e d  a s  h a e m orr h a gi c  or 
i s c h a e mi c ( n arr o w) 
•   C o n g e sti v e  h e art f ail ur e:  S M Q  C ar di a c f ail ur e  ( br o a d) 
C ar di o v a s c ul ar   e v e nt s   will   b e  t a b ul at e d   o nl y  if   5   or   m or e   s u bj e ct s   h a v e   e x p eri e n c e d   a  
c ar di o v a s c ul ar   e v e nt.   U si n g  t h e  I T T   a n d   mI T T   p o p ul ati o n,   c ar di o v a s c ul ar   e v e nt s   will   b e  
s u m m ari z e d  b y  M e d D R A  S O C  a n d  P T  f or t h e  M T X  R u n-i n  P eri o d.  U si n g t h e  mI T T  p o p ul ati o n, 
c ar di o v a s c ul ar  e v e nt s  will  b e  P e gl oti c a s e  + I M M  P eri o d.   
 
G o ut  Fl ar e s  
T h e  n u m b er  a n d  p er c e nt a g e  of  s u bj e ct s  w h o  e x p eri e n c e d  a  g o ut fl ar e (r e c or d e d i n t h e  A E  e C R F) , 
a n d  n u m b er  of  g o ut fl ar e  p er  s u bj e ct  will  b e  s u m m ari z e d f or t h e  M T X  R u n -i n  P eri o d  u si n g t h e I T T 
p o p ul ati o n.  P er c e nt a g e s  will  b e  c al c ul at e d  u si n g t h e  n u m b er  of  s u bj e ct s i n t h e I T T  p o p ul ati o n.  
T h e  n u m b er  a n d  p er c e nt a g e  of  s u bj e ct s  w h o  e x p eri e n c e d  a  g o ut fl ar e  a n d  n u m b er  of  g o ut fl ar e s 
p er  s u bj e ct  d uri n g t h e  p e gl oti c a s e  + I M M  P eri o d (r e c or d e d i n t h e  A E  e C R F)  will  b e  pr o vi d e d f or 
t h e  mI T T  p o p ul ati o n.  T h e s e  e v e nt s  will  b e f urt h er  s u m m ari z e d  a s  o c c urri n g fr o m t h e  p eri o d fr o m 
D a y   1 t o  W e e k  1 2,  aft er  W e e k  1 2 –  W e e k  2 4,  aft er  W e e k  2 4  –  W e e k  3 6,  a n d  aft er  W e e k  3 6  – 
W e e k  5 2,  a n d  aft er  W e e k  5 2.  F or t h e f ull  p e gl oti c a s e  + I M M  p eri o d,  p er c e nt a g e s  will  b e  c al c ul at e d 
u si n g t h e  n u m b er  of  s u bj e ct s i n t h e  mI T T  p o p ul ati o n.  E v e nt s  ar e  s u m m ari z e d  f or e a c h  p eri o d 
a c c or di n g t o t h e  o n s et  d at e  of t h e fl ar e,  a n d  o nl y  s u m m ari z e d i n t h e  p eri o d  of  o n s et . F or t h e  D a y 
1 t o  W e e k  1 2,  p er c e nt a g e s  will  b e  b a s e d  o n t h e  n u m b er  of  s u bj e ct s i n t h e  mI T T  p o p ul ati o n.  I n 
a d diti o n, t h e s e  e v e nt s  d uri n g t h e  p e gl oti c a s e  + I M M  p eri o d  will  b e f urt h er  s u m m ari z e d  b y  m o nt h 
of  o c c ur r e n c e,  e. g.,  M o nt h  1,  M o nt h  2,  u p t o  M o nt h  1 2. O n e  m o nt h i s  d efi n e d  a s  3 0  d a y s.  F or t h e 
ot h er ti m e  p eri o d s  of t h e  p e gl oti c a s e  + I M M  p eri o d,  p er c e nt a g e s  will  b e  b a s e d  o n t h e  n u m b er  of 
s u bj e ct s  w h o  h a d f oll o w -u p  at l e a st  a s f ar  a s t h e  st art  of t h e  p eri o d -s p e cifi c ti m e  p eri o d . T h e  3 0 
d a y s f oll o wi n g t h e  e n d  of tr e at m e nt  ar e i n cl u d e d i n t h e f oll o w -u p ti m e  p eri o d . 
At t h e  a s s e s s m e nt s  W e e k  -4,  W e e k  -2,  D a y  1,  W e e k  2,  W e e k  4,  W e e k  6,  W e e k  8,  W e e k  1 0, 
W e e k  1 2,  W e e k 1 4,  W e e k  1 6,  W e e k  1 8,  W e e k  2 0,  W e e k  2 2,  W e e k  2 4,  W e e k  2 6,  W e e k  2 8,  W e e k 
3 0,  W e e k  3 2,  W e e k  3 4,  W e e k  3 6,  W e e k  3 8,  W e e k  4 0,  W e e k  4 2,  W e e k  4 4,  W e e k  4 6,  W e e k  4 8, 
W e e k   5 0,   W e e k   5 2/ E n d   of   St u d y/ E arl y   T er mi n ati o n,   M o nt h   3   a n d   M o nt h   6   F oll o w -u p, 
a s s e s s m e nt s  of  g o ut fl ar e s  ar e  c oll e ct e d  o n  a  g o ut fl ar e  a s s e s s m e nt  e C R F . U si n g t h e I T T  a n d 
mI T T  p o p ul ati o n, t h e i n ci d e n c e  of  g o ut fl ar e s  i s  a s s e s s e d. If t h e  s u bj e ct  h a s  e x p eri e n c e d  a  g o ut 
fl ar e, t h e i n ci d e n c e  of  p ai n  diff er e nt t h a n  n or m al, i n ci d e n c e  of p ai n  at r e st  gr e at er t h a n  3  o n  a 
s c al e fr o m  0 -1 0,  i n ci d e n c e  of s w elli n g i n j oi nt s ,  a n d i nt e n sity  of t h e fl ar e s ( o n  a  s c al e  of  0 -1 0)  ar e 
a s s e s s e d.   All   q u e sti o n s   e x c e pt  t h e  i nt e n sit y   of  fl ar e s   will   b e   s u m m ari z e d   u si n g   n u m b er   a n d  


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  6 5   of 8 4  
p er c e nt a g e  of r e s p o n s e s.  P er c e nt a g e s  will  b e  b a s e d  o n t h e  n u m b er  of  s u bj e ct s  a s s e s s e d  at t h e 
vi sit.  T h e i nt e n sit y  of fl ar e s  will  b e  s u m m ari z e d  u si n g  d e s cri pti v e  st ati sti c s ( n,  m e a n,  st a n d ar d 
d e vi ati o n,  m e di a n,  mi ni m u m,  a n d  m a xi m u m)  will  b e  s u m m ari z e d . 
  L a b or at or y  E v al u ati o n s  
 
Bl o o d (f or  h e m at ol o g y  a n d  cli ni c al  c h e mi str y)  a n d  uri n e (f or  uri c  a ci d:  cr e ati ni n e  r ati o)  s a m pl e s 
will  b e  c oll e ct e d  at t h e  S cr e e ni n g,  W e e k  -4 ( pri or t o t h e fir st  d o s e  of  M T X),  a n d  W e e k  -2  Vi sit s 
d uri n g t h e  S cr e e ni n g/ M T X  R u n -i n  P eri o d;  pri or t o  p e gl oti c a s e i nf u si o n  o n  D a y  1  a n d  at t h e  W e e k s 
2,  6,  1 4,  2 2,  2 4  a n d  3 6  Vi sit s  d uri n g t h e  P e gl oti c a s e  + I M M  P eri o d;  a n d t h e  E n d  of  P e gl oti c a s e 
I nf u si o n s  Vi sit (if  a p pli c a bl e),  W e e k  5 2/ E n d  of  St u d y/ E arl y  T er mi n ati o n, a n d  3  a n d  6  m o nt h  P o st 
Tr e at m e nt  F oll o w -u p  Vi sit s.  
 
S af et y l a b or at or y  a s s e s s m e nt s  will i n cl u d e:  
•   H e m at ol o g y:   c o m pl et e   bl o o d   c o u nt   wit h   diff er e nti al  ( h e m o gl o bi n   c o n c e ntr ati o n,  
h e m at o crit,  er yt hr o c yt e  c o u nt,  pl at el et  c o u nt, l e u k o c yt e  c o u nt,  a n d  diff er e nti al l e u k o c yt e 
c o u nt)  
•   C h e mi str y:  tr a n s a mi n a s e s  ( a s p art at e   a mi n otr a n sf er a s e,   al a ni n e   a mi n otr a n sf er a s e),  
al k ali n e   p h o s p h at a s e,  t ot al   bilir u bi n,   cr e ati ni n e,   gl u c o s e,   s o di u m,   p ot a s si u m,   c al ci u m,  
c hl ori d e,  t ot al   pr ot ei n,   bl o o d   ur e a   nitr o g e n,   a n d   h u m a n   c h ori o ni c   g o n a d otr o pi n  ( at  t h e  
S cr e e ni n g  Vi sit f or  all f e m al e  s u bj e ct s  of  c hil d b e ari n g  p ot e nti al)   
•   Uri n e:  uri c  a ci d:  cr e ati ni n e  r ati o  a n d  h u m a n  c h ori o ni c  g o n a d otr o pi n ( at  all  vi sit s  e x c e pt t h e 
S cr e e ni n g  Vi sit f or  all f e m al e  s u bj e ct s  of  c hil d b e ari n g  p ot e nti al)  
 
A  c e ntr al  st u d y l a b or at or y  will  b e  u s e d f or  all  pr ot o c ol -s p e cifi e d  cli ni c al l a b or at or y  p ar a m et er s.  
 
L a b or at or y r e s ult s  will  b e  di s pl a y e d  u si n g t h e  c o n v e nti o n al  u nit s. f or  all  s u m m ari e s  a n d li sti n g s. 
Cli ni c al  l a b or at or y t e st  r e s ult s  ( h e m at ol o g y,   c h e mi str y,   a n d   uri n al y si s)   a n d  t h eir   c h a n g e s  fr o m  
M T X  b a s eli n e   will   b e   s u m m ari z e d   b y   vi sit  f or  t h e  I T T   a n d   mI T T   p o p ul ati o n   u si n g   d e s cri pti v e  
st ati sti c s.   
If  a  c o nti n u o u s l a b or at or y  v al u e i s r e p ort e d  a s  eit h er  b el o w  or  a b o v e t h e li mit s  of  q u a ntifi c ati o n, 
t h e   q u alifi er s   will   b e   dr o p p e d   a n d  t h e   n u m eri c   v al u e   u s e d  i n  t h e   a n al y si s  ( e. g.,  “ <   3”   will   b e  
s u m m ari z e d  a s “ 3”  a n d “ >  2 0 0”  will  b e  s u m m ari z e d  a s “ 2 0 0”).   
F or  all l a b or at or y t e st s, r e s ult s  will  b e  c at e g ori z e d  a s l o w,  n or m al,  or  hi g h  b a s e d  o n t h eir  n or m al 
r a n g e s.  R e s ult s  o ut  of r a n g e  will  b e i d e ntifi e d  a s  s u c h  o n  s u bj e ct li sti n g s.  
U si n g  t h e  I T T   a n d   mI T T   p o p ul ati o n s,   s hift  t a bl e s   u si n g   c at e g ori e s   of  l o w,   n or m al,   a n d   hi g h,  
c o m p ari n g  l a b or at or y  t e st  r e s ult s  fr o m   M T X   b a s eli n e  t o   e a c h   vi sit   will   b e   pr e s e nt e d   wit h  
p er c e nt a g e s  b a s e d  o n  s u bj e ct s  wit h  a  n o n -mi s si n g  v al u e  at  b a s eli n e  a n d  p o st -b a s eli n e  vi sit.  A 
s u m m ar y  of  el e v at e d li v er f u n cti o n t e st  v al u e s  a s  w ell  a s  H y’ s l a w  will  b e  pr o vi d e d  b y  vi sit  a n d f or 
a n y  p o st -b a s eli n e  vi sit  f or t h e I T T  a n d  mI T T  p o p ul ati o n s: 
•   al a ni n e  a mi n otr a n sf er a s e  >  U L N,  2 x U L N,  3 x U L N,  5 x U L N,  1 0 x U L N,  a n d  2 0 x U L N   


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  6 6   of 8 4  
•   a s p art at e  a mi n otr a n sf er a s e  >  U L N,  2 x U L N,  3 x U L N,  5 x U L N,  1 0 x U L N,  a n d  2 0 x U L N   
•   al k ali n e  p h o s p h at a s e  ≥  1. 5 x U L N,  2. 5 x U L N,  a n d  3 x U L N   
•   t ot al  bilir u bi n  ≥  1. 5 x U L N,  2 x U L N,  a n d  3 x U L N  
H y’ s l a w:  
•   ( al a ni n e  a mi n otr a n sf er a s e or  a s p art at e  a mi n otr a n sf er a s e  >  3 x U L N)  a n d t ot al  bilir u bi n  ≥ 
2 x U L N   
•   ( al a ni n e  a mi n otr a n sf er a s e or  a s p art at e  a mi n otr a n sf er a s e  >  3 x U L N)  a n d t ot al  bilir u bi n  ≥ 
2 x U L N  a n d  al k ali n e  p h o s p h at a s e  <  2 x U L N  
F or  t e st s   w h er e  t h e   C o m m o n   T er mi n ol o g y   Crit eri a  f or   A d v er s e   E v e nt s  ( C T C A E)   crit eri a  i s  
a v ail a bl e,  s hift t a bl e s  will  b e  b a s e d  o n t h e  C T C A E  gr a d e.  T h e  C T C A E  v er si o n  4. 0 3  will  b e  u s e d 
f or t h e s e  s u m m ari e s.  
  Pr e g n a n c y  T e st s  
Pr e g n a n c y t e st r e s ult s  will  b e  pr o vi d e d i n  a li sti n g.  
  Vit al  Si g n s   
R o uti n e  vit al  si g n s, i n cl u di n g  bl o o d  pr e s s ur e, r e s pir at or y r at e, t e m p er at ur e,  a n d  h e art r at e  will  b e 
m e a s ur e d  at  S cr e e ni n g,  W e e k  -4  a n d  at  all i nf u si o n  vi sit s  d uri n g t h e  P e gl oti c a s e  + I M M  P eri o d 
a n d t h e  E n d  of  P e gl oti c a s e I nf u si o n s  Vi sit (if  a p pli c a bl e),  W e e k  5 2/ E n d  of  St u d y/ E arl y  T er mi n ati o n 
a n d  3  a n d  6  m o nt h  P o st  Tr e at m e nt  F oll o w -u p  Vi sit s.  D uri n g t h e  P e gl oti c a s e  + I M M  P eri o d  st u d y 
vi sit s,  vit al s  s h o ul d  b e t a k e n  b ef or e t h e  p e gl oti c a s e i nf u si o n  a n d  a n y ti m e  aft er t h e  e n d  of t h e 
i nf u si o n,  b ut  pri or t o  s u bj e ct’ s  di s c h ar g e/r el e a s e fr o m t h e  sit e. I n  a d diti o n, if i m m e di at e i nf u si o n-
a s s o ci at e d  e v e nt s  ar e  n ot e d  d uri n g t h e i nf u si o n,  vit al  si g n s  will  b e  m o nit or e d  at l e a st  e v er y  3 0 
mi n ut e s  u ntil r e s ol uti o n  or  st a bili z ati o n  of t h e  A E.  
W ei g ht  will  b e  s u m m ari z e d i n  kil o gr a m s.  W ei g ht  a n d  B S A  i s r e c or d e d  at t h e  S cr e e ni n g  Vi sit;  pri or 
t o  p e gl oti c a s e i nf u si o n  o n  D a y  1  a n d  at t h e  W e e k s  8,  1 6,  2 4,  3 6, a n d  at t h e  n o n -i nf u si o n  E n d  of 
P e gl oti c a s e I nf u si o n s  Vi sit (if  a p pli c a bl e),  W e e k  5 2/ E n d  of  St u d y/ E arl y  T er mi n ati o n  a n d  M o nt h s  3  
a n d  6  P o st  Tr e at m e nt  F oll o w -u p  Vi sit s.  
H ei g ht  will  b e  c oll e ct e d  at t h e  S cr e e ni n g  Vi sit  o nl y.  H ei g ht i s r e c or d e d i n  u nit s  of  c e nti m et er s ( c m). 
B o d y   M a s s  I n d e x  ( B MI)   will   b e   d et er mi n e d   u si n g  t h e   w ei g ht  r e c or d e d  i n   k g  a n d  t h e   h ei g ht  
m e a s ur e d  at  s cr e e ni n g.  
D e s cri pti v e  s u m m ari e s  of  o b s er v e d  a n d  c h a n g e fr o m  M T X  b a s eli n e  v al u e s  will  b e  pr e s e nt e d f or 
e a c h  vit al  si g n  p ar a m et er  b y  vi sit,  u si n g t h e I T T  a n d  m I T T  p o p ul ati o ns .  Vit al  si g n  m e a s ur e m e nt s 
t h at   ar e   m o nit or e d   a s   a  r e s ult   of   a n  i nf u si o n-a s s o ci at e d   e v e nt,   will   n ot   b e  i n cl u d e d  i n  t h e  
d e s cri pti v e  s u m m ari e s  b ut  will  b e  pr e s e nt e d i n  s u bj e ct li sti n g s.  
 
T h e f oll o wi n g  c o n v er si o n f a ct or  will  b e  u s e d t o  c o n v ert  a n y t e m p er at ur e s r e p ort e d i n  d e gr e e s 
F a hr e n h eit t o  C el si u s:  


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  6 7   of 8 4  
 
T e m p er at ur e (i n ° C)  =  5/ 9 ( T e m p er at ur e [i n ° F] -3 2) . 
 
T h e  f oll o wi n g   c o n v er si o n  f a ct or   will   b e   u s e d  t o   c o n v ert   a n y   w ei g ht s  r e p ort e d  i n   p o u n d s  t o  
kil o gr a m s:  
 
W ei g ht [ k g]  =  W ei g ht [i n l b s ] *  0. 4 53 6 . 
 
T h e f oll o wi n g f or m ul a  will  b e  u s e d t o  d et er mi n e t h e  B MI (i n  k g/ m 2 ) u si n g  w ei g ht [i n  k g]  a n d  h ei g ht 
[i n  c m]:  
 
B MI  =  W ei g ht / ((  H ei g ht/ 1 0 0) * ( H ei g ht/ 1 0 0));  
 
    El e ctr o c ar di o gr a m s 
A n  el e ctr o c ar di o gr a m ( E C G)  will  b e  p erf or m e d  o n  D a y  1  b ef or e t h e  fir st P e gl oti c a s e  i nf u si o n f or 
all  s u bj e ct s  a n d  at t h e  di s cr eti o n  of t h e I n v e sti g at or t h er e aft er.  T h e r e s ult s  will  b e r e c or d e d  a s 
n or m al  or  a b n or m al  o n t h e  e C R F  a n d  all  a b n or m al r e s ult s  will  b e  e v al u at e d  a s  cli ni c all y  si g nifi c a nt 
( C S)  or  n ot  cli ni c all y  si g nifi c a nt ( N C S)  b y t h e i n v e sti g at or. 
 
U si n g t h e  mI T T  p o p ul ati o n,  a  s u m m ar y  will  b e  pr o vi d e d  of  s u bj e ct s  at  D a y  1 ( u si n g t h e  c o u nt  a n d 
p er c e nt a g e  of  s u bj e ct s)  wit h:   
•   N or m al  
•   A b n or m al  N C S  
•   A b n or m al  C S   
P er c e nt a g e s  will  b e  b a s e d  o n t h e  n u m b er  of  s u bj e ct s  wit h  a n  a s s e s s m e nt  c o m pl et e d . 
B e c a u s e t h e  p o st -D a y  1  E C G s  ar e  d o n e  at t h e  di s cr eti o n  of t h e i n v e sti g at or s,  o nl y t h e f oll o wi n g 
s u m m ari e s  will  b e  pr o vi d e d  u si n g t h e  mI T T  p o p ul ati o n :  
•   I n ci d e n c e  of  p o st-D a y  1  A b n or m al  E C G s (i n cl u d e s  N C S  a n d  C S) fi n di n g s  
•   I n ci d e n c e  of  p o st-D a y  1  A b n or m al,  Cli ni c all y  Si g nifi c a nt  E C G s  
F or t h e  p o st -D a y  1  E C G  s u m m ar y,  p er c e nt a g e s  will  b e  c al c ul at e d  u si n g t h e  n u m b er  of  s u bj e ct s  
i n t h e  MI T T  p o p ul ati o n. 
  P h y si c al  E x a mi n ati o n  
A   c o m pl et e   p h y si c al   e x a mi n ati o n   will   b e   p erf or m e d   at  t h e   S cr e e ni n g   Vi sit   a n d   will   i n cl u d e 
a s s e s s m e nt s  f or   pr e s e n c e   of  t o p hi,  a s   w ell   a s   g o ut   hi st or y  a n d   s y m pt o m  s e v erit y.   A  t ar g et e d  
p h y si c al  e x a mi n ati o n  p er t h e i n v e sti g at or j u d g e m e nt  b ut  at  a  mi ni m u m  s h o ul d i n cl u d e  h e art, l u n g s 
a n d  a b d o mi n al  e x a m  a n d i n cl u d e  a j oi nt  a n d  s ki n  e v al u ati o n  a n d  a s s e s s m e nt  of  A E s  at  W e e k  4, 
D a y  1,  a n d  pri or t o  a d mi ni str ati o n  of  p e gl oti c a s e  at  W e e k s  4,  8,  1 2,  1 6,  2 0,  2 4,  3 6, t h e  E n d  of 
P e gl oti c a s e I nf u si o n s  Vi sit (if  a p pli c a bl e),  W e e k  5 2/ E n d  of  St u d y/ E arl y  T er mi n ati o n , a n d  3  a n d  6 


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  6 8   of 8 4  
m o nt h  P o st  Tr e at m e nt  F oll o w -u p  Vi sit s.  
P h y si c al  e x a mi n ati o n  d at a  will  b e li st e d.  N o  s u m m ari z ati o n s  of t h e  p h y si c al  e x a mi n ati o n  d at a  will 
b e  pr e s e nt e d.  


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  6 9   of 8 4  
    
Ch a n g e s  fr o m  A n al y si s  Pl a n n e d i n  Pr ot o c ol 
F or t h e  s u m m ar y  of  s U A, t h e  n u m b er  a n d  p er c e nt a g e  of  s u bj e ct s  wit h  a  v al u e  <  6  m g/ d L  at  e a c h 
vi sit  w a s  a d d e d.  
T h e  e x pl or at or y  e n d p oi nt  of ti m e t o fir st  s U A  >  6  m g/ d L i n  s u bj e ct s r e c ei vi n g  p e gl oti c a s e  wit h  M T X 
w a s  a dj u st e d t o ti m e t o t h e fir st  pr e -i nf u si o n  s U A  >  6  m g/ d L i n  s u bj e ct s r e c ei vi n g  p e gl oti c a s e  wit h 
M T X.  
T h e  e x pl or at or y  e n d p oi nt  of ti m e t o  t w o  c o n s e c uti v e  s U A  >  6  m g/ d L ( st o p pi n g r ul e) i n  s u bj e ct s 
r e c ei vi n g  p e gl oti c a s e  wit h  M T X  w a s  a dj u st e d t o ti m e t o t w o  c o n s e c uti v e  pr e-i nf u si o n s U A  >  6 
m g/ dl ( st o p pi n g r ul e) i n  s u bj e ct s r e c ei vi n g  p e gl oti c a s e  wit h  M T X.  
T h e  s u m m ar y  of i n v e sti g at or  a s s e s s m e nt  of  cli ni c al  st at u s  w a s  a d d e d,  b a s e d  o n t h e  a d diti o n  of  a 
n e w  e C R F  c oll e cti n g t hi s i nf or m ati o n.  
 


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  7 0   of 8 4  
  
Pr o gr a m mi n g  C o n si d er ati o n s  
  G e n er al  C o n si d er ati o n s  
•   All  T L F s  will  b e  pr o d u c e d i n l a n d s c a p e f or m at.  
•   All  T L F s  will  b e  pr o d u c e d  u si n g t h e  C o uri er  N e w f o nt,  si z e  8   
•   T h e  d at a  di s pl a y s f or  all  T L F s  will  h a v e  a  mi ni m u m  1 -i n c h  m ar gi n  o n  all  4  si d e s. 
•   H e a d er s  a n d f o ot er s f or fi g ur e s  will  b e i n  C o uri er  N e w f o nt,  si z e  8.  
•   L e g e n d s  will  b e  u s e d f or  all fi g ur e s  wit h  m or e t h a n  1  v ari a bl e,  gr o u p,  or it e m  di s pl a y e d.  
•   T L F s  will  b e i n  bl a c k  a n d  w hit e ( n o  c ol or)  
•   S p e ci ali z e d t e xt  st yl e s,  s u c h  a s  b ol di n g, it ali c s,  b or d er s,  a n d  s h a di n g  will  n ot  b e  u s e d i n t h e 
T L F s,  u nl e s s  ot h er wi s e  s p e cifi e d.  O n  s o m e  o c c a si o n s,  s u p er s cri pt s  1,  2,  or  3  m a y  b e  u s e d.  
•   O nl y  st a n d ar d  k e y b o ar d  c h ar a ct er s  will  b e  u s e d i n t h e  T L F s.  S p e ci al  c h ar a ct er s,  s u c h  a s  n o n -
pri nt a bl e   c o ntr ol   c h ar a ct er s,   pri nt er -s p e cifi c,   or  f o nt -s p e cifi c   c h ar a ct er s,   will   n ot   b e   u s e d.  
H e x a d e ci m al -d eri v e d  c h ar a ct er s  will  b e  u s e d,  w h er e  p o s si bl e, if t h e y  ar e  a p pr o pri at e t o  h el p 
di s pl a y  m at h  s y m b ol s  ( e. g.,  μ).  C ert ai n  s u b s cri pt s  a n d  s u p er s cri pt s  ( e. g.,  m 2 ,  Ctr o u g h)  will  b e 
e m pl o y e d  o n  a  c a s e -b y -c a s e  b a si s.  
•   Mi x e d  c a s e  will  b e  u s e d f or  all titl e s, f o ot n ot e s,  c ol u m n  h e a d er s,  a n d  pr o gr a m m er -s u p pli e d 
f or m at s,  a s  a p pr o pri at e. 
•    
  T a bl e,  Li sti n g,  a n d  Fi g ur e  F or m at  
  
G e n er al  
•   H e a d er s  a n d f o ot er s f or fi g ur e s  will  b e i n  C o uri er  N e w f o nt,  si z e  8  w hi c h i s  t h e  s m all e st 
a c c e pt a bl e  p oi nt  si z e f or t h e  R e g ul at or y  A ut h oriti e s . 
•   L e g e n d s  will  b e  u s e d f or  all fi g ur e s  wit h  m or e t h a n  1  v ari a bl e,  gr o u p,  or it e m  di s pl a y e d.  
•   T F L s  will  b e i n  bl a c k  a n d  w hit e ( n o  c ol or),  u nl e s s  ot h er wi s e  s p e cifi e d  
•   S p e ci ali z e d t e xt  st yl e s,  s u c h  a s  b ol di n g, it ali c s,  b or d er s,  s h a di n g,  a n d  s u p er s cri pt e d  a n d 
s u b s cri pt e d t e xt,  will  n ot  b e  u s e d i n t h e  T F L s,  u nl e s s  ot h er wi s e  s p e cifi e d.  O n  s o m e 
o c c a si o n s,  s u p er s cri pt s  1,  2,  or  3  m a y  b e  u s e d ( s e e  b el o w).  
•   O nl y  st a n d ar d  k e y b o ar d  c h ar a ct er s  will  b e  u s e d i n t h e  T F L s.  S p e ci al  c h ar a ct er s,  s u c h  a s 
n o n -pri nt a bl e  c o ntr ol  c h ar a ct er s,  pri nt er -s p e cifi c,  or f o nt -s p e cifi c  c h ar a ct er s,  will  n ot  b e 
u s e d.  H e x a d e ci m al -d eri v e d  c h ar a ct er s  will  b e  u s e d,  w h er e  p o s si bl e, if t h e y  ar e 
a p pr o pri at e t o  h el p  di s pl a y  m at h  s y m b ol s ( e. g.,  μ).  C ert ai n  s u b s cri pt s  a n d  s u p er s cri pt s 
( e. g.,  c m 2,  C m a x)  will  b e  e m pl o y e d  o n  a  c a s e-b y -c a s e  b a si s.  
•   Mi x e d  c a s e  will  b e  u s e d f or  all titl e s, f o ot n ot e s,  c ol u m n  h e a d er s,  a n d  pr o gr a m m er -
s u p pli e d f or m at s,  a s  a p pr o pri at e.  
  
H e a d er s  
•   All  o ut p ut  s h o ul d  h a v e t h e f oll o wi n g  h e a d er  at t h e t o p l eft  of  e a c h  p a g e:  


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  7 1   of 8 4  
H ori z o n  T h er a p e uti c s Ir el a n d  D A C   
Pr ot o c ol  H Z N P - K R Y-2 0 1  
•   All  o ut p ut  s h o ul d  h a v e  P a g e  n  of  N  at t h e t o p  or  b ott o m ri g ht  c or n er  of  e a c h  p a g e.  T F L s 
ar e  i nt er n all y  p a gi n at e d i n r el ati o n t o t h e t ot al l e n gt h (i. e., t h e  p a g e  n u m b er  s h o ul d  a p p e ar 
s e q u e nti all y  a s  p a g e  n  of  N,  w h er e  N i s t h e t ot al  n u m b er  of  p a g e s i n t h e t a bl e).  
•   T h e  d at e  o ut p ut  w a s  g e n er at e d  s h o ul d  a p p e ar  al o n g  wit h t h e  pr o gr a m  n a m e  a s  a f o ot er 
o n  e a c h  p a g e.  
  
Di s pl a y  Titl e s  
•     E a c h T a bl e,  Fi g ur e,  a n d  Li sti n g  i s i d e ntifi e d  b y t h e  d e si g n ati o n  a n d  a  n u m er al. (i. e.,  T a bl e 
1 4. 1. 1). I C H  E 3  n u m b eri n g i s  str o n gl y r e c o m m e n d e d , b ut  s p o n s or  pr ef er e n c e s  ar e 
o bt ai n e d  b ef or e  fi n al  d et er mi n ati o n  A  d e ci m al  s y st e m ( x. y  a n d  x. y. z) ar e  u s e d t o i d e ntif y 
T F L s  wit h r el at e d  c o nt e nt s.  T h e titl e i s  c e nt er e d.  T h e  a n al y si s  s et  ar e  i d e ntifi e d  o n t h e li n e 
i m m e di at el y f oll o wi n g t h e titl e.  T h e titl e  a n d t a bl e  d e si g n ati o n  ar e  si n gl e  s p a c e d.  A  s oli d 
li n e  s p a n ni n g t h e  m ar gi n s  will  s e p ar at e t h e  di s pl a y titl e s fr o m t h e  col u m n  h e a d er s.  T h er e 
will  b e  1  bl a n k li n e  b et w e e n t h e l a st titl e  a n d t h e  s oli d li n e.  
T a bl e  x. y. z  
Fir st  Li n e  of  Titl e  
S e c o n d  Li n e  of  Titl e if  N e e d e d  
(I T T  P o p ul ati o n) 
 
  
C ol u m n  H e a d er s  
•   C ol u m n  h e a di n g s  ar e  di s pl a y e d i m m e di at el y  b el o w t h e  s oli d li n e  d e s cri b e d  a b o v e i n i niti al 
u p p er -c a s e  c h ar a ct er s .  
•   I n t h e  c a s e  of  effi c a c y t a bl e s, t h e  v ari a bl e ( or  c h ar a ct eri sti c)  c ol u m n  will  b e  o n t h e f ar l eft 
f oll o w e d  b y t h e  p o p ul ati o n  c ol u m n s. Wit hi n -tr e at m e nt  c o m p ari s o n s  m a y  h a v e  p-v al u e s 
pr e s e nt e d i n  a r o w  b e n e at h t h e  s u m m ar y  st ati sti c s f or t h at tr e at m e nt.  
•   F or  n u m eri c  v ari a bl e s, i n cl u d e “ u nit” i n  c ol u m n  or r o w  h e a di n g  w h e n  a p pr o pri at e.  
•   A n al y si s  s et  si z e s  will  b e  pr e s e nt e d f or  e a c h tr e at m e nt  gr o u p i n t h e  c ol u m n  h e a di n g  a s 
( N = x x) ( or i n t h e r o w  h e a di n g s, if  a p pli c a bl e).  T hi s i s  di sti n ct fr o m t h e ‘ n’  u s e d f or t h e 
d e s c ri pti v e  st ati sti c s r e pr e s e nti n g t h e  n u m b er  of  s u bj e ct s i n t h e  a n al y si s  s et. 
  
B o d y  of t h e  D at a  Di s pl a y  
1 3. 2. 5. 1.  
G e n er al  C o n v e nti o n s  
D at a i n  c ol u m n s  of  a t a bl e  or li sti n g  ar e  f or m att e d  a s f oll o w s: 
•     Al p h a n u m eri c  v al u e s  ar e l eft-j u stifi e d; 


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  7 2   of 8 4  
•     Wh ol e  n u m b er s ( e. g.,  c o u nt s)  ar e ri g ht -j u stifi e d;  a n d 
•     Nu m b er s  c o nt ai ni n g fr a cti o n al  p orti o n s  ar e  d e ci m al  ali g n e d.  
1 3. 2. 5. 2.  
T a bl e  C o n v e nti o n s  
•   U nit s  will  b e i n cl u d e d  w h er e  a v ail a bl e  
•   If t h e  c at e g ori e s  of  a  p ar a m et er  ar e  or d er e d, t h e n  all  c at e g ori e s  b et w e e n t h e  m a xi m u m 
a n d  mi ni m u m  c at e g or y  ar e  pr e s e nt e d i n t h e t a bl e,  e v e n if  n = 0 f or  all tr e at m e nt  gr o u p s i n  a 
gi v e n  c at e g or y t h at i s  b et w e e n t h e  mi ni m u m  a n d  m a xi m u m l e v el f or t h at  p ar a m et er.  F or 
e x a m pl e, t h e fr e q u e n c y  di stri b uti o n f or  s y m pt o m  s e v erit y  w o ul d  a p p e ar  a s:  
S e v erit y 
R ati n g  
N  
s e v er e   
0  
m o d er at e   
8  
mil d   
3  
 
W h er e  p er c e nt a g e s  ar e  pr e s e nt e d i n t h e s e t a bl e s,  z er o  p er c e nt a g e s  will  n ot  b e  pr e s e nt e d  a n d 
s o  c o u nt s  of  0  will  b e  pr e s e nt e d  a s  0  a n d  n ot  a s  0 ( 0 %).  
•   If t h e  c at e g ori e s  ar e  n ot  or d er e d ( e. g.,  M e di c al  Hi st or y,  R e a s o n s f or  Di s c o nti n u ati o n fr o m 
t h e  St u d y,  et c.), t h e n  o nl y t h o s e  c at e g ori e s f or  w hi c h t h er e i s  at l e a st  1  s u bj e ct 
r e pr e s e nt e d i n  1  or  m or e  gr o u p s ar e  i n cl u d e d. 
•   A n  U n k n o w n  or  Mi s si n g  c at e g or y  ar e  a d d e d t o  e a c h  p ar a m et er f or  w hi c h i nf or m ati o n i s 
n ot  a v ail a bl e f or  1  or  m or e  s u bj e ct s.   
•   U nl e s s  ot h er wi s e  s p e cifi e d, t h e  e sti m at e d  m e a n  a n d  m e di a n f or  a  s et  of  v al u e s  ar e  pri nt e d 
o ut t o  1  m or e  si g nifi c a nt  di git t h a n t h e  ori gi n al  v al u e s,  a n d  st a n d ar d  d e vi ati o n s  ar e  pri nt e d 
o ut t o  2  m or e  si g nifi c a nt  di git s t h a n t h e  ori gi n al  v al u e s.  T h e  mi ni m u m  a n d  m a xi m u m 
s h o ul d r e p ort t h e  s a m e  si g nifi c a nt  di git s  a s t h e  ori gi n al  v al u e s.  F or  e x a m pl e, f or  s y st oli c 
bl o o d  pr e s s ur e:  
n  
  X X  
M e a n  
X X X. X  
S D  
     X. X X  
M e di a n  
X X X. X  
Mi ni m u m  
X X X  
M a xi m u m  
X X X  
 
•   P er c e nt a g e  v al u e s  ar e  pri nt e d t o  o n e  d e ci m al  pl a c e, i n  p ar e nt h e s e s  wit h  n o  s p a c e s,  o n e 
s p a c e  aft er t h e  c o u nt ( e. g.,  7 ( 1 2. 8 %),  1 3 ( 5. 4 %)).  U nl e s s  ot h er wi s e  n ot e d, f or  all 
p er c e nt a g e s, t h e  n u m b er  of  s u bj e ct s i n t h e  a n al y si s  s et f or t h e tr e at m e nt  gr o u p  w h o  h a v e 


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  7 3   of 8 4  
a n  o b s er v ati o n  will  b e t h e  d e n o mi n at or.  P er c e nt a g e s  aft er  z er o  c o u nt s  s h o ul d  n ot  b e 
di s pl a y e d  a n d  p er c e nt a g e s  e q u ati n g t o  1 0 0 %  ar e  pr e s e nt e d  a s  1 0 0 %,  wit h o ut  d e ci m al 
pl a c e s.   
•   T a b ul ar  di s pl a y  of  d at a f or  m e di c al  hi st or y,  pri or/ c o n c o mit a nt  m e di c ati o n s,  a n d  all t a b ul ar 
di s pl a y s  of  a d v er s e  e v e nt  d at a  ar e  pr e s e nt e d  b y t h e  b o d y  s y st e m, tr e at m e nt  cl a s s,  or 
S O C  wit h t h e  S O C ( or tr e at m e nt  cl a s s)  s ort e d  al p h a b eti c all y . Wit hi n t h e  b o d y  s y st e m, 
dr u g  cl a s s  a n d  S O C,  m e di c al  hi st or y ( b y  pr ef err e d t er m),  dr u g  t er m ( b y  pr ef err e d  n a m e, 
a n d  a d v er s e  e v e nt s ( b y  pr ef err e d t er m)  ar e  di s pl a y e d  al p h a b eti c all y . 
•   T h e  p er c e nt a g e  of  s u bj e ct s i s  n or m all y  c al c ul at e d  a s  a  pr o p orti o n  of t h e  n u m b er  of 
s u bj e ct s  a s s e s s e d i n t h e r el e v a nt tr e at m e nt  gr o u p ( or  o v er all) f or t h e  a n al y si s  s et 
pr e s e nt e d.  H o w e v er,  c ar ef ul  c o n si d er ati o n i s r e q uir e d i n  m a n y i n st a n c e s  d u e t o t h e 
c o m pli c at e d  n at ur e  of  s el e cti n g t h e  d e n o mi n at or,  u s u all y t h e  a p pr o pri at e  n u m b er  of 
s u bj e ct s  e x p o s e d.  D e s cri b e  d et ail s  of t hi s i n f o ot n ot e s  or  pr o gr a m mi n g  n ot e s.  
•   F or  c at e g ori c al  s u m m ari e s ( n u m b er  a n d  p er c e nt a g e  of  s u bj e ct s)  w h er e  a  s u bj e ct  c a n  b e 
i n cl u d e d i n  m or e t h a n  o n e  c at e g or y,  d e s cri b e i n  a f o ot n ot e  or  pr o gr a m mi n g  n ot e if t h e 
s u bj e ct  ar e  i n cl u d e d i n t h e  s u m m ar y  st ati sti c s f or  all r el e v a nt  c at e g ori e s  or j u st  1  c at e g or y 
a n d t h e  crit eri a f or  s el e cti n g t h e  crit eri a.  
•   W h er e  a  c at e g or y  wit h  a  s u b h e a di n g ( s u c h  a s  s y st e m  or g a n  cl a s s)  h a s t o  b e  s plit  o v er 
m or e t h a n  o n e  p a g e,  o ut p ut t h e  s u b h e a di n g f oll o w e d  b y “( c o nt)”  at t h e t o p  of  e a c h 
s u b s e q u e nt  p a g e . T h e  o v er all  s u m m ar y  st ati sti c s f or t h e  s u b h e a di n g  s h o ul d  o nl y  b e 
o ut p ut  o n t h e fir st r el e v a nt  p a g e.  
1 3. 2. 5. 3.  
Li sti n g  C o n v e nti o n s  
•   Li sti n g s  will  b e  s ort e d f or  pr e s e nt ati o n i n  or d er  of  t h e  p o p ul ati o n s t h e  s u bj e ct  w a s tr e at e d 
i n (I T T  o nl y, I T T  a n d  mI T T  p o p ul ati o n,  N ot  Tr e at e d,  S cr e e n  F ail ur e) s u bj e ct  n u m b er, 
vi sit/ c oll e cti o n  d a y,  a n d  vi sit/ c oll e cti o n ti m e.  
•   Mi s si n g  d at a  ar e  r e pr e s e nt e d  o n  s u bj e ct li sti n g s  a s  eit h er  a  h y p h e n (“-”)  wit h  a 
c orr e s p o n di n g f o ot n ot e (“ - =  u n k n o w n  or  n ot  e v al u at e d”),  or  a s “ N/ A”,  wit h t h e f o ot n ot e 
“ N/ A  =  n ot  a p pli c a bl e”,  w hi c h e v er i s  a p pr o pri at e. 
•   D at e s  ar e  pri nt e d i n  S A S  D A T E 9.f or m at (“ d d M M M y y y y”:  0 1 J U L 2 0 0 0).  Mi s si n g  p orti o n s  of 
d at e s  s h o ul d  b e r e pr e s e nt e d  o n  s u bj e ct li sti n g s  a s “ U N” f or  mi s si n g  d a y s  a n d “ U N K” f or 
mi s si n g  m o nt h s ( e. g.  U N J U L 2 0 0 0,  U N U N K 2 0 0 0).  D at e s t h at  ar e  mi s si n g  b e c a u s e t h e y  ar e 
n ot  a p pli c a bl e f or t h e  s u bj e ct  ar e  o ut p ut  a s “ N A”,  u nl e s s  ot h er wi s e  s p e cifi e d.  
•   All  o b s er v e d ti m e  v al u e s  ar e t o  b e  pr e s e nt e d  u si n g  a  2 4 -h o ur  cl o c k  H H: M M  or  H H: M M: S S 
f or m at ( e. g.,  1 1: 2 6: 4 5,  or  1 1: 2 6).  Ti m e  will  o nl y  b e r e p ort e d if it  w a s  m e a s ur e d  a s  p art  of 
th e  st u d y.  
•   U nit s  will  b e i n cl u d e d  w h er e  a v ail a bl e  


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  7 4   of 8 4  
1 3. 2. 5. 4.  
Fi g ur e  C o n v e nti o n s  
•   U nl e s s  ot h er wi s e  s p e cifi e d, f or  all fi g ur e s,  st u d y  vi sit s  will  b e  di s pl a y e d  o n t h e  X -a xi s  a n d 
e n d p oi nt ( e. g., tr e at m e nt  m e a n  c h a n g e fr o m  B a s eli n e)  v al u e s  will  b e  di s pl a y e d  o n t h e  Y -
a xi s.  
    
Fo ot n ot e s  
•   A  s oli d li n e  s p a n ni n g t h e  m ar gi n s  will  s e p ar at e t h e  b o d y  of t h e  d at a  di s pl a y fr o m t h e 
f o ot n ot e s.  
•   All f o ot n ot e s  will  b e l eft j u stifi e d  wit h  si n gl e -li n e  s p a ci n g i m m e di at el y  b el o w t h e  s oli d li n e 
u n d er n e at h t h e  d at a  di s pl a y.  
•   F o ot n ot e s  s h o ul d  al w a y s  b e gi n  wit h “ N ot e:” if  a n i nf or m ati o n al f o ot n ot e,  or  1,  2,  3,  et c. if  a 
r ef er e n c e f o ot n ot e.  E a c h  n e w f o ot n ot e  s h o ul d  st art  o n  a  n e w li n e, w h er e  p o s si bl e.  
•   S u bj e ct  s p e cifi c f o ot n ot e s  ar e  a v oi d e d,  w h er e  p o s si bl e.  
•   F o ot n ot e s  will  b e  u s e d  s p ari n gl y  a n d  a d d  v al u e t o t h e t a bl e, fi g ur e,  or li sti n g. If  m or e t h a n 
si x li n e s  of f o ot n ot e s  ar e  pl a n n e d, t h e n  a  c o v er  p a g e i s  str o n gl y r e c o m m e n d e d t o  b e  u s e d 
t o  di s pl a y f o ot n ot e s,  a n d  o nl y t h o s e  e s s e nti al t o  c o m pr e h e n si o n  of t h e  d at a  will  b e 
r e p e at e d  o n  e a c h  p a g e.  
•   T h e l a st li n e  of t h e f o ot n ot e  s e cti o n  will  b e  a  st a n d ar d  s o ur c e li n e t h at i n di c at e s t h e  n a m e 
of t h e  pr o gr a m  u s e d t o  pr o d u c e t h e  d at a  di s pl a y,  d at e t h e  pr o gr a m  w a s r u n,  a n d t h e li sti n g 
s o ur c e (i. e., ‘ Pr o gr a m :  m y pr o gr a m. s a s     Li sti n g  s o ur c e:  1 6. x. y. z’).  


St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  7 5   of 8 4  
  
Q u alit y  C o ntr ol  
S A S  pr o gr a m s  ar e  d e v el o p e d t o  pr o d u c e  o ut p ut  s u c h  a s  a n al y si s  d at a  s et s,  s u m m ar y t a bl e s,  d at a 
li sti n g s, fi g ur e s  or  st ati sti c al  a n al y s e s.  A n  o v er vi e w  of t h e  d e v el o p m e nt  of  pr o gr a m s i s  d et ail e d i n 
 
 
  a n d  
 
d e s cri b e s t h e  q u alit y  c o ntr ol  pr o c e d ur e s t h at  ar e  p erf or m e d f or 
all  S A S  pr o gr a m s  a n d  o ut p ut.  Q u alit y  c o ntr ol i s  d efi n e d  h er e  a s t h e  o p er ati o n al t e c h ni q u e s  a n d 
a cti viti e s  u n d ert a k e n t o  v erif y t h at t h e  S A S  pr o gr a m s  pr o d u c e t h e  o ut p ut  b y  c h e c ki n g f or t h eir 
l o gi c,  effi ci e n c y  a n d  c o m m e nti n g  a n d  b y r e vi e w  of t h e  pr o d u c e d  o ut p ut. 


















St ati sti c al  A n al y si s  Pl a n   
S p o n s or:  H ori z o n  T h er a p e uti c s Ir el a n d  D A C;  Pr ot o c ol  N o.:  H Z N P- K R Y - 2 0 1 
 
T hi s  d o c u m e nt i s  c o nfi d e nti al. 
S A P  V er si o n:  2. 0 /  1 0 J U L 2 0 2 0 
C o ntr oll e d  D o c u m e nt I D:  3 9 0 3 A. 0 1 ,  Eff e cti v e  D at e  2 9-O ct - 2 0 1 8 
Fili n g r e q uir e m e nt s:  T M F 
P a g e  8 4   of 8 4  
  
R ef er e n c e s  
K ar v a n e n  J.  T h e  st ati sti c al  b a si s  of l a b or at or y  d at a  n or m ali z ati o n.  Dr u g I nf or m ati o n  J o ur n al. 
2 0 0 3;  3 7: 1 0 1 -1 0 7