A Multicenter, Randomized, Double-Blind and Placebo-Controlled 16-Week Study Followed by Long Term Evaluation of Efficacy and Safety of Ixekizumab (LY2439821) in Chinese Patients With Radiographic Axial Spondyloarthritis
Phase: PHASE3
Conditions: Spondyloarthritis
Sponsor: Eli Lilly and Company

 Pr o t oc ol I 1 F- M C- R H C H
A M ultice nter, Ra n d o mize d, D o u ble- Bli n d a n d Place b o- C o ntr olle d 1 6- Wee k St u d y 
F oll o we d b y L o n g Ter m E val uati o n of Efficac y a n d Safet y of I xe kiz u ma b ( L Y 2 4 3 9 8 2 1) 
i n C hi nese Patie nts Wit h Ra di o gra p hic A xial S p o n d yl oart hritis
N C T 0 4 2 8 5 2 2 9
A p pr o val Date: 2 0-J u n- 2 0 1 9

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 1
L Y 2 4 3 9 8 2 1
Pr ot o c ol I 1 F-M C -R H C H
A M ulti c e nt er, R a n d o mi z e d, D o u bl e -Bli n d a n d Pl a c e b o -
C o ntr oll e d 1 6 -W e e k St u d y  F oll o w e d b y L o n g T er m E v al u ati o n 
of Effi c a c y  a n d S af et y of I x e ki z u m a b ( L Y 2 4 3 9 8 2 1) i n C hi n e s e
P ati e nt s wit h R a di o gr a p hi c A xi al S p o n d y l o art hriti s
C o nfi d e nti al 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 a n d i s i nt e n d e d f or t h e u s e of 
cli ni c al i n v e sti g at or s.  It i s t h e pr o p ert y of Eli Lill y a n d C o m p a n y or it s s u b si d i ari es a n d 
s h o ul d n ot b e c o pi e d b y or di stri b ut e d t o p er s o n s n ot i n v ol v e d i n t h e cli ni c al i n v e sti g ati o n of 
i x e ki z u m a b ( L Y 2 4 3 9 8 2 1), u nl e s s s u c h p er s o n s ar e b o u n d b y a c o nfi d e nti alit y a gr e e m e nt 
wit h Eli Lill y a n d C o m p a n y or it s s u b si di ari e s.  
N ot e t o R e g ul a t or y A ut h oriti e s:  T hi s d o c u m e nt m a y c o nt ai n pr ot e ct e d p er s o n al d at a 
a n d/ or c o m m er ci all y c o nfi d e nti al i nf or m ati o n e x e m pt fr o m p u bli c di s cl o s ur e.  Eli Lill y a n d 
C o m p a n y r e q u e st s c o n s ult ati o n r e g ar di n g r el e a s e/r e d a cti o n pri or t o a n y p u bli c r el e a s e.  I n 
t h e Unit e d St at e s, t hi s d o c u m e nt i s s u bj e ct t o Fr e e d o m of I nf or m ati o n A ct ( F OI A) 
E x e m pti o n 4 a n d m a y n ot b e r e pr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o ut t h e writt e n 
a p pr o v al of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s.
I x e ki z u m a b ( L Y 2 4 3 9 8 2 1)
St u d y I 1 F -M C -R H C H i s a P h a s e 3, m ulti c e nt er, r a n d o mi z e d, d o u bl e -bli n d, pl a c e b o -
c o ntr oll e d, p ar all el -gr o u p, o ut p ati e nt st u d y t o e v al u at e t h e effi c a c y a n d s af et y of i x e ki z u m a b 
( L Y 2 4 3 9 8 2 1) v er s u s pl a c e b o at 1 6 w e e k s i n C hi n e s e p ati e nt s wit h r a di o gr a p hi c a xi al 
s p o n d yl o art hriti s (r-a x S p A ).  P ati e nt s will b e r a n d o mi z e d t o s u b c ut a n e o u s ( S C) pl a c e b o, or 
i x e ki z u m a b.  T hi s st u d y will al s o e v al u at e l o n g-t er m effi c a c y a n d s af et y of i x e ki z u m a b 
d uri n g a n E xt e n d e d Tr e at m e nt P eri o d ( 3 6 w e e k s).  All p ati e nt s e nt eri n g i nt o t h e E xt e n d e d 
Tr e at m e nt P eri o d fr o m t h e pl a c e b o tr e at m e nt gr o u p will r e c ei v e i x e ki z u m a b 8 0 m g Q 4 W.
Eli Lill y a n d C o m p a n y
I n di a n a p oli s, I n di a n a U S A 4 6 2 8 5
Pr ot o c ol El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n d at e pr o vi d e d b el o w.
A p pr o v al D at e: 2 0 -J u n -2 0 1 9 G M T

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 2
L Y 2 4 3 9 8 2 1
T a bl e of C o nt e nt s
S e cti o n
P a g e
1.
S y n o psis ...........................................................................................................................1 0
2.
Sc he d ule of Act i vities .......................................................................................................1 3
3.
I ntr o d ucti o n ......................................................................................................................2 2
3. 1.
St u d y  Ratio n a le............................................................................................................2 2
3. 2.
Bac k gr o u n d ..................................................................................................................2 2
3. 3.
Be nefit/ Ris k Assess me nt ..............................................................................................2 4
4.  
O bject i ves a n d E n d p oi nts ..................................................................................................2 5
5.
St u d y  Desi g n.....................................................................................................................2 7
5. 1.
O verall Desi g n .............................................................................................................2 7
5. 2.
N u m ber of P arti ci pa nts ................................................................................................. 2 9
5. 3.
E n d of St u d y  Defi niti on ...............................................................................................2 9
5. 4.
S ci e nt ific Rati o nale f or St u d y Desi g n...........................................................................2 9
5. 5.
J ustificati o n f or D ose ...................................................................................................3 0
6.
St u d y  P o p ulat i on ...............................................................................................................3 1
6. 1.
I ncl usi on Cri t eria ..........................................................................................................3 1
6. 2.
E xcl u sio n  Crit eria ........................................................................................................3 3
6. 3.
Lifest yle Restrict i ons ....................................................................................................3 8
6. 4.
Scree n Fail ures .............................................................................................................3 8
7.
Treat me nt s ........................................................................................................................4 0
7. 1.
Treat me nts A d mi nistere d .............................................................................................4 0
7. 1. 1.
A d mi nistrati o n of  I n vestig ati o n al  Pr o d uct ............................................................4 2
7. 1. 2.
Pac ka gi n g a n d La belli n g ......................................................................................4 2
7. 2.
Met h o d of Treat me nt Assi g n me nt
................................................................................4 3
7. 2. 1.
S el ect i on a n d Ti mi n g o f D oses .............................................................................4 3
7. 3.
Bli n di n g .......................................................................................................................4 3
7. 4.
D osa ge M o dificati o n ....................................................................................................4 4
7. 5.
Pre parati o n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y ...............................................................4 4
7. 6.
Treat me nt C o m plia nce ................................................................................................. 4 4
7. 7.
C o nc o mita nt T hera p y ...................................................................................................4 4
7. 7. 1.
C o nti n ue d Access ................................................................................................. 4 8
7. 7. 2.
S peci al Treat me nt C o nsiderat i ons ........................................................................4 8
8.
Di sc o nti n uatio n Cri t eri a....................................................................................................4 9
8. 1.
Di sc o nti n uatio n f r o m St u d y Treat me nt .........................................................................4 9
8. 1. 1.
P er m a ne nt Disc o nt i n uati on fr o m St u d y Treat me nt ...............................................4 9

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 3
L Y 2 4 3 9 8 2 1
8. 1. 2.
Di sc o nti n uatio n of  I na d verte ntl y Enr olle d Patie nts ...............................................5 1
8. 2.
Di sc o nti n uatio n f r o m t he St u d y....................................................................................5 1
8. 3.
L ost t o F oll o w -U p ........................................................................................................5 2
9.
St u d y  Assess me nts a n d Pr oce d ures...................................................................................5 3
9. 1.
Efficac y Assess me nts ...................................................................................................5 3
9. 1. 1.
Pri mar y Efficac y  Assess me nts .............................................................................5 3
9. 1. 1. 1.
A S A S 4 0 (i n b D M A R D -naï ve pat ient s) ...........................................................5 3
9. 1. 2.
Sec o n dar y  Efficac y Assess me nts..........................................................................5 3
9. 1. 2. 1.
A S A S 4 0, A S A S 2 0, A S A S I n di vi d ual C o m p o ne nts, 
A S A S Parti al Re missio n, a n d A S A S 5/ 6 .........................................................5 3
9. 1. 2. 1. 1.
A S A S 4 0 (i n o verall st u d y  p o p ulatio n) .......................................................5 4
9. 1. 2. 1. 2.
A S A S 2 0 ...................................................................................................5 4
9. 1. 2. 1. 3.
A S A S Parti al Re missio n ...........................................................................5 4
9. 1. 2. 1. 4.
A S A S 5/ 6 ................................................................................................. 5 4
9. 1. 2. 2.
P ati e nt Glo b al  ( Assess me nt of Disease Acti vity) ............................................5 4
9. 1. 2. 3.
S pi nal Pai n .....................................................................................................5 4
9. 1. 2. 4.
Bat h A n k yl osi n g S p o n d ylit is Disease Acti vity I nd e x ......................................5 4
9. 1. 2. 5.
Bat h A n k yl osi n g S p o n d ylit is F u nct i onal I n de x ...............................................5 5
9. 1. 2. 6.
Bat h A n k yl osi n g S p o n d ylit is Metr olo g y  I n de x— S pi nal  
M o bilit y .........................................................................................................5 5
9. 1. 2. 7.
C hest E x pa nsi o n .............................................................................................5 5
9. 1. 2. 8.
Occi p ut t o Wall Dista nce ................................................................................5 5
9. 1. 2. 9.
A n k yl osi n g S p o n d ylit is Disease Acti vity Sc ore ..............................................5 5
9. 1. 2. 1 0.
Maastri c ht A n k yl o si n g S p o n d ylitis E nt hesit is Sc ore .......................................5 6
9. 1. 2. 1 1.
N o nster oi dal A nt i-I nflam mat or y  Dr u g I nta ke .................................................5 6
9. 1. 2. 1 2.
La b orat or y  Tests Use d f or Efficac y Meas ures a n d 
Di sease Dia g n osis...........................................................................................5 6
9. 1. 2. 1 2. 1.
Hi g h Se nsi tivit y C -React i ve Pr otei n..........................................................5 6
9. 1. 2. 1 3.
I ma gi n g Use d f or Efficac y Meas ures a n d Disease 
Di a g n osis ........................................................................................................5 7
9. 1. 2. 1 3. 1.
I ma gi n g of Sacr oiliac J o i nts a n d S pi ne ......................................................5 7
9. 1. 2. 1 3. 2.
S p o n d yl oart hrit is Researc h C o ns orti u m of Ca na da –
M RI Sc ore f or S pi ne .................................................................................5 7
9. 1. 2. 1 3. 3.
S p o n d yl oart hrit is Researc h C o ns orti u m of Ca na da –
M RI Sc ore f or Sacr oiliac J o i nts ................................................................5 7
9. 1. 2. 1 3 . 4.
S p o n d yl oart hrit is Researc h C o ns orti u m of Ca na da –
SIJ Str uct ural Sc ore ( S S S) ........................................................................5 8
9. 1. 3.
Heal t h O ut c o me E n d p o i nts...................................................................................5 8
9. 1. 3. 1.
E ur o pea n Q ualit y of  Life– 5 Di me nsi o n s 5– Le vel ...........................................5 8

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 4
L Y 2 4 3 9 8 2 1
9. 1. 3. 2.
Assess me nt of S p o n d yl o art hritis I nter nati onal S ociet y  
Heal t h I n d e x...................................................................................................5 8
9. 1. 3. 3.
Me dical O utc o mes St u d y  3 6-It e m S h ort-F or m  Healt h 
S ur ve y ............................................................................................................5 8
9. 1. 3. 4.
F u nct i onal Assess me nt of C hr o nic Ill ness T hera p y 
Fat i g ue Scale..................................................................................................5 9
9. 1. 3. 5.
W o r k Pr o d ucti vity a n d Act i vity I mp ai r me nt 
Q uest i on naire – S p o n d yl oart hr itis.....................................................................5 9
9. 1. 3. 6.
Q ui c k I n ve nt or y of De pressi ve S y m pt o mat olo g y – Self -
Re p ort ( 1 6 Ite ms) ............................................................................................5 9
9. 1. 4.
A p pr o priate ness of Assess me nts ..........................................................................5 9
9. 2.
A d verse E ve nts ............................................................................................................5 9
9. 2. 1.
S eri o us A d verse E ve nts ........................................................................................6 0
9. 2. 1. 1.
S us pecte d U ne x pecte d Seri o us A d verse React i ons ..........................................6 1
9. 2. 2.
A d verse E ve nts of S pecial I nterest .......................................................................6 1
9. 2. 2. 1.
Aller gic React i on a n d H y perse nsi tivi t y E ve nts ...............................................6 2
9. 2. 3.
C o m plai nt Ha n dli n g .............................................................................................6 3
9. 3.
Treat me nt of O ver d ose ................................................................................................. 6 3
9. 4.
S af et y ...........................................................................................................................6 3
9. 4. 1.
Electr ocar di o gra ms ..............................................................................................6 3
9. 4. 2.
Vi t al Sig ns........................................................................................................... 6 3
9. 4. 3.
La b orat or y  Tests..................................................................................................6 3
9. 4. 4.
I mm u n o ge nicit y Assess me nts ..............................................................................6 4
9. 4. 5.
P h ysical E xa mi nat i on ...........................................................................................6 4
9. 4. 6.
Oc ul ar E xa mi nat i on .............................................................................................6 4
9. 4. 7.
C hest X -Ra y  a n d T u berc ul osis Testi n g................................................................. 6 5
9. 4. 8.
Q ui c k I n ve nt or y of De pressi ve S y m pt o mat olo g y – Self -
Re p ort ( 1 6 Ite ms) ................................................................................................. 6 6
9. 4. 9.
C ol u m bia – S uici de Se veri t y Rati n g Scale ..............................................................6 6
9. 4. 1 0.
S af et y M o ni t ori n g ................................................................................................6 6
9. 4. 1 0. 1.
He pati c Safet y M o ni t ori n g..............................................................................6 7
9. 4. 1 0. 2.
Ne utr o pe nia ....................................................................................................6 7
9. 4. 1 0. 2. 1.
D uri n g Treat m e nt ( Perio ds 2 a n d 3) ..........................................................6 7
9. 4. 1 0. 2. 2.
At  Earl y Ter mi nati on Visit ........................................................................6 8
9. 4. 1 0. 2. 3.
P os t-Treat me nt F oll o w -U p Peri o d .............................................................6 9
9. 4. 1 0. 3.
He pati tis B M o nit ori n g ...................................................................................6 9
9. 4. 1 0. 4.
H y perte nsi o n ..................................................................................................6 9
9. 5.
P har m ac o ki net ics .........................................................................................................7 0
9. 6.
P har mac o d y na mics ......................................................................................................7 0

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 5
L Y 2 4 3 9 8 2 1
9. 7.
Ge net ics .......................................................................................................................7 0
9. 8.
Heal t h Ec o n o mics........................................................................................................7 0
1 0.
Stati stical C o nsi derati o ns ..................................................................................................7 1
1 0. 1.
S a m ple Si ze Deter mi nat i on ..........................................................................................7 1
1 0. 2.
P o p ul at i ons f or A nal yses..............................................................................................7 1
1 0. 3.
Stati stical A nal yses ......................................................................................................7 2
1 0. 3. 1.
Ge neral C o nsi derati o ns f or A nal yses d uri n g t he Bli n de d 
Treat me nt D osi n g Peri o d ( Peri o d 2) .....................................................................7 2
1 0. 3. 2.
Ge neral C o nsi derati o ns f or A nal y ses d uri n g t he E xte n de d 
Treat me nt Peri o d ( Peri o d 3) .................................................................................7 4
1 0. 3. 3.
Ge neral C o nsi derati o ns f or A nal yses d uri n g t he P ost -
Treat me nt F oll o w - Up Peri o d ( Peri o d 4) ...............................................................7 4
1 0. 3. 4.  
Missi n g Data I m p utati o n ......................................................................................7 4
1 0. 3. 4. 1.
N o nres p o n der I m p utati o n ...............................................................................7 4
1 0. 3. 4. 2.
M o difie d Baseli ne O bser vat i on Carrie d F or war d ............................................7 4
1 0. 3. 5.
A d j ustme nt  for M ul tiple C o m paris o ns ..................................................................7 5
1 0. 3. 6.
Treat me nt Gr o u p C o m para bilit y ...........................................................................7 5
1 0. 3. 6. 1.
P ati e nt Dis p ositio n ..........................................................................................7 5
1 0. 3. 6. 2.
P ati e nt C haracteristics ....................................................................................7 5
1 0. 3. 6. 3.
C o nc o mita nt T hera p y .....................................................................................7 6
1 0. 3. 6. 4.
Treat me nt C o m plia nce ....................................................................................7 6
1 0. 3. 7.
Efficac y A nal yses ................................................................................................7 6
1 0. 3. 7. 1 .
Pri mar y A nal yses ...........................................................................................7 6
1 0. 3. 7. 2.
Sec o n dar y  A nal yses........................................................................................7 7
1 0. 3. 7. 3.
Maj or Sec o n dar y  A nal yses .............................................................................7 7
1 0. 3. 7. 4.
Ot her Sec o n dar y  Efficac y A nal yses................................................................7 8
1 0. 3. 7. 4. 1.
P eri o d 3 ( E xte n de d Treat me nt Peri o d) ......................................................7 9
1 0. 3. 7. 5.
Terti ar y/ E x pl orat or y A nal yses........................................................................7 9
1 0. 3. 8.
S af et y A nal yses ....................................................................................................7 9
1 0. 3. 8. 1.
A d verse E ve nts ...............................................................................................7 9
1 0. 3. 8. 2.
Cli nical La b orat or y  Tests................................................................................8 0
1 0. 3. 8. 3.
Vi t al Sig ns, P h ysical Fi n di n gs, a n d Ot her Safet y 
E val uat i ons .....................................................................................................8 0
1 0. 3. 9.
P har mac o ki net ic/ P har mac o d y na mic A nal yses......................................................8 1
1 0. 3. 1 0.
Ot her A nal yses .....................................................................................................8 1
1 0. 3. 1 0. 1.
Heal t h Ec o n o mics...........................................................................................8 1
1 0. 3. 1 0. 2.
S u b gr o u p A nal yses .........................................................................................8 1
1 0. 3. 1 1.
I mm u n o ge nicit y ...................................................................................................8 2
1 0. 3. 1 2.
I nteri m A nal yses ..................................................................................................8 3

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 6
L Y 2 4 3 9 8 2 1
1 1.
Refere nces ........................................................................................................................8 4
1 2.
A p pe n dices .......................................................................................................................9 2

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 7
L Y 2 4 3 9 8 2 1
Li st of T a bl e s
T a bl e
P a g e
Ta ble R H C H. 1.
O bject i ves a n d E n d p oi nts...............................................................................2 5
Ta ble R H C H. 2.
Treat me nt Re gi me ns f or Bli n de d Treat me nt D osi n g Peri o d ( Peri o d 2) 
a n d E xte n de d Treat me nt Peri o d ( Peri o d 3) .....................................................4 1
Ta ble R H C H. 3.
I ma gi n g Re q uire me nts f or Sacr oiliac J o i nts a n d S pi ne ...................................5 7
Ta ble R H C H. 4.
Pri mar y a n d Maj or Sec o n dar y  O ut c o me A nal yses ..........................................7 8

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 8
L Y 2 4 3 9 8 2 1
Li st of Fi g ur e s
Fi g ur e
P a g e
Fi g ure R H C H. 1. Ill ustratio n of  st u d y desi g n f or Cli nical Pr ot oc ol I 1 F-M C -R H C H. ..................2 8

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 9
L Y 2 4 3 9 8 2 1
Li st of A p p e n di c e s
A p p e n di x
P a g e
A p pe n di x 1.
A b bre viat i ons a n d Defi nit i ons ........................................................................9 3
A p pe n di x 2.
Cli nical La b orat or y  Tests...............................................................................9 7
A p pe n di x 3.
St u d y  G o ver na nce C o nsi derati ons ..................................................................9 9
A p pe n di x 4.
He pati c M o nit orin g Tests f or Treat me nt -E m er ge nt A b n or malit y ..................1 0 2
A p pe n di x 5. 
S p o n d yl oart hrit is Feat ures ...........................................................................1 0 3

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 1 0
L Y 2 4 3 9 8 2 1
1.
S y n o p si s
Title of St u d y:
A m ultice nter, ra n d o mize d, d o u ble - bli n d a n d p lace b o-co ntr olle d 1 6 -Wee k st u d y foll o we d b y l o n g ter m eval uati o n of 
efficac y a n d safet y of ixe kiz u ma b ( L Y 2 4 3 9 8 2 1) i n C hi n ese p atie nts wit h ra di o gra p hic a xial sp o n d yl oart hritis
R ati o n ale: 
I xe kiz u ma b ( L Y 2 4 3 9 8 2 1) is a h u ma nize d i m m u n o gl o b uli n G s u bclass 4 (I g G 4) m o nocl o nal a nti b o d y ( M A b) t hat 
ne utralizes t he c yt o ki ne i nterle u ki n -1 7 A (I L -1 7 A, als o k n o w n as I L -1 7).  Str o n g scie ntific e vi de nce e xists i n dicati n g 
a n i m p orta nt r ole of t he I L-2 3/I L -1 7 pat h wa y i n a xial s p o n d yl oart hritis (a x S p A) pat h o ge nesis ( Baete n et al. 2 0 1 0, 
2 0 1 4a; Ma ks y m o w yc h 2 0 1 0; Baralia k os et al. 2 0 1 1; Re veille 2 0 1 1; Yere me n k o et al. 2 0 1 4).   Pi v otal st u dies of 
i xe kiz u ma b ha ve rece ntl y de m o nstrate d t he efficac y of bl oc ki n g I L- 1 7 A i n t he treat me nt of ra di o gra p hic a xial 
s p o n d yl oart hritis (r-a x S p A; a n k yl osi n g s p o n d ylitis [A S]) i n bi ol o gic al disease -m o dif yi n g a ntir he u matic dr u g 
( b D M A R D)-naï ve as well as i n t u m or necr osis fact or ( T N F) i n hi bit or e x perie nce d patie nts (va n der Heij de et al. 
2 0 1 8; De o d har et al. 2 0 1 9 b ).
O bjecti ve(s)/ E n d p oi nts:
O bjecti ves
E n d p oi nts
Pri mar y

T he pri mar y o bjecti ve is t o c o m pare 
i xe kiz u ma b 8 0 m g e very 4 wee ks (Q 4 W) 
vers us place b o i n b D M A R D -naï ve patie nts 
wit h acti ve ra di o gra p hic a xial s p o n d yl oart hritis 
(r-a x S p A) at Wee k 1 6

Pr o p orti o n of patie nts ac hie vi n g a n 
Assess me nt of S p o n d y l oart hritis 
I nter nati o nal S ociet y 4 0 ( A S A S 4 0) 
res p o nse
Maj or Sec o n dar y

T o c o m pare i xe kiz u ma b  8 0 m g Q 4 W t o 
place b o i n o verall st u d y p o p ulati o n at Wee k 1 6

Pr o p orti o n of patie nts ac hie vi n g a n 
A S A S 4 0 res p o nse

Pr o p orti o n of patie n ts ac hie vi n g a n 
A S A S 2 0 res p o nse

C ha n ge f r om baseli ne i n A n k yl osi n g 
S p o n d ylitis Disease Acti vit y Sc ore 
( A S D A S) 

C ha n ge f r om baseli ne i n Bat h A n k yl osi n g 
S p o n d ylitis Disease Acti vit y I n de x  
( B A S D AI) 

C ha n ge f r om baseli ne i n Bat h A n k yl osi n g 
S p o n d ylitis F u ncti o nal I n de x ( B A S FI )

Pr o p orti o n of patie nts ac hie vi n g A S D A S < 
2. 1

C ha n ge f r om baseli ne i n ma g netic 
res o na nce i ma gi n g ( M RI) of t he s pi ne 
( S p o n d yl oart hritis Researc h C o ns orti u m of 
Ca na da [ S P A R C C] sc ore )  

C ha n ge f r om baseli ne i n S h ort F or m 3 6 
( S F-3 6) p h y sical c o m p o ne nt sc ore ( P C S)

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 1 1
L Y 2 4 3 9 8 2 1
S u m m ar y of St u d y Desi g n :  
St u d y I 1 F -M C -R H C H ( R H C H) is a P hase 3, m ultice nter, ra n d o mize d, d o u ble -bli n d , place b o -c o ntr olle d, parallel -
gr o u p, o ut patie nt st u d y t o e val uate t he efficac y a n d safet y of i xe kiz u ma b 8 0 m g Q 4 W s u bc uta ne o us ( S C) vers us 
place b o i n patie nts wit h r -a x S p A, d uri n g a 1 6 -wee k Bli n de d Treat me nt D osi n g Peri o d.
St u d y R H C H will als o e val uate l o n g -ter m efficac y a n d safet y of i xe kiz u ma b d uri n g t he E xte n de d Treat me nt Peri o d 
f or a t otal treat me nt d urati o n of 1 year ( 5 2 wee ks).
Tre at me n t Ar ms a n d D ur ati o n:  
St u d y R H C H h as 2 treat me nt gr o u ps d uri n g t he 1 6-wee k Bli n de d Treat me nt D osi n g Peri o d:  i xe kiz u ma b 8 0 m g 
Q 4 W a n d place b o at 1: 1 rati o.  All patie nts ra n d o mize d t o a n i xe kiz u ma b treat me nt gr o u p will recei ve a starti n g 
d ose of i xe kiz u ma b 1 6 0 m g at Wee k 0 f oll o we d b y i xe kiz u ma b 8 0 m g Q 4 W t hereafter.  All a d mi nistrati o ns are S C.  
Ra n d o mizati o n will be stratifie d b y baseli ne C reacti ve pr otei n ( C R P) stat us a n d pri or T N F i n hi bit or hist or y (if 
a p plica ble) (i.e., naï ve patie nt wit h n or mal C R P, naï ve p at ie nt wit h ele vate d C R P, a n d T N F i n hi bit or e x perie nce d 
patie nt wit h ele vate d C R P, ele vate d defi ne d as > 5. 0 0 m g/ L)
At Wee k 1 6, place b o patie nts will start recei vi n g i xe kiz u ma b 8 0 m g Q 4 W wit h a 1 6 0 m g starti n g d ose .  All patie nts 
will be o n a n i xe kiz u ma b re gi me n f or t he E xte n de d Treat me nt Peri o d ( Wee ks 1 6 t o 5 2).  T he st u d y d urati o n will be 
u p t o 1 year f or i xe kiz u ma b a d mi nistrati o n, a n d u p t o 1 year a n d a p pr o xi matel y 4 m o nt hs f or st u d y partici pati o n 
o ver 4 peri o ds ([ 1] S cr ee ni n g Peri o d:  u p t o 4 2 da ys; [ 2] Bli n de d Treat me nt D osi n g Peri o d:  1 6 wee ks; [ 3] E xte n de d 
Treat me nt Peri o d:  3 6 wee ks; [ 4] P ost -Treat me nt F oll o w -U p Peri o d:  u p t o 1 2 wee ks after t he date of t he patie nt’s 
earl y ter mi nati o n visit [ E T V] or last re g ularl y sc he d ule d visit). 
N u m ber of S u bjects:
T his st u d y will i ncl u de a p pr o xi matel y 1 4 0 ra n d o mize d patie nts.  Patie nts are eli gi ble t o be i ncl u de d i n t he st u d y if 
t he y ha ve a n esta blis he d dia g n osis of r-a x S p A wit h sacr oiliitis defi ne d ra di o gra p hicall y acc or di n g t o t he m o difie d 
Ne w Y or k ( m N Y) criteria, base d o n ce ntral rea di n g, ass ociate d wit h ≥1 s p o n d yl oart hritis ( S p A) feat ure, a n d ha ve 
acti ve disease defi ne d as B A S D AI ≥4 a n d bac k pai n ≥4 o n a n u meric rati n g s cale ( N R S).  Patie nts m ust ha ve ha d a n 
i na de q uate res p o nse or a hist or y of disc o nti n uati o n d ue t o i nt olera nce , as deter mi ne d b y t he i n vesti gat or, t o 2 or 
m ore n o nster oi dal a nti -i nfla m mat or y dr u gs ( N S AI Ds) at t he t hera pe utic d ose ra n ge (f or a t otal d urati o n of at least 4 
wee ks) a n d a hist or y of pri or r-a x S p A t hera p y f or at least1 2 wee ks .  B ot h b D M A R D -naï ve a n d T N F i n hi bit or -
e x perie nce d patie nts ca n be e nr olle d .
St atistic al A n al ysis:
A p pr o xi matel y 1 4 0 patie nts will be ra n d o mize d at a 1: 1 rati o i n t he Bli n de d Treat me nt D osi n g Peri o d t o i xe kiz u ma b 
8 0 m g Q 4 W a n d place b o.  ≥ 6 1 b D M A R D -naï ve patie nts per treat me nt gr o u p will e n s ure ≥ 9 0 % p o wer t o test t he 
s u peri orit y of i xe kiz u ma b Q 4 W t o place b o f or t he A S A S 4 0 at Wee k 1 6 i n b D M A R D-naï ve patie nts .  T he f oll o wi n g 
ass u m pti o ns were use d f or t he p o wer calc ulati o ns f or A S A S 4 0 res p o nse rates i n b D M A R D-naï ve p atie nts at Wee k 
1 6:  4 4 % f or i xe kiz u ma b Q 4 W treat me nt gr o u p a n d 1 6 % f or place b o gr o u p.  A 2 si de d Fis her’ s e xact test at t he 0. 0 5 
le vel is ass u me d.  T he efficac y a nal yses f or t he Bli n de d Treat me nt D osi n g Peri o d will be c o n d ucte d o n t he i nte nt-t o-
treat (I T T) p o p ulati o n, a n d safet y a nal yses will be c o n d ucte d o n t he safet y p o p ulati o n.  
C o m paris o ns bet wee n i xe ki z u ma b treat me nt gr o u p a n d place b o will be perf or me d f or all a nal yses i n t he Bli n de d 
Treat me nt D osi n g Peri o d.  T he pri mar y a nal ysis met h o d f or treat me nt gr o u p c o m paris o ns of cate g orical efficac y a n d 
healt h o utc o mes varia bles will be a l o gistic re gressi o n a n al ysis wit h treat me nt, baseli ne C R P stat us (n o n -ele vate d or  

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 1 2
L Y 2 4 3 9 8 2 1
ele vate d), a n d pri or T N F i n hi bit or e x perie nce d or naï ve as fact ors (if a p plica ble), usi n g t he n o nres p o n der i m p utati o n 
( N RI) met h o d.  U n der N RI, all n o nres p o n ders at Wee k 1 6 ( Visit 8), as well as all patie nts w h o disc o nti n ue st u d y 
treat me nt at a n y ti me pri or t o Wee k 1 6 f or a n y reas o n, will be defi ne d as n o nres p o n ders f or t he N RI a nal ysis at 
Wee k 1 6.  Ra n d o mize d patie nts wit h o ut a n y p ost baseli ne o bser vati o n will als o be
defi ne d as n o nres p o n ders f or t he 
N RI a nal y sis.  A gra p hical m ulti ple testi n g strate g y f or t he pri mar y a n d maj or sec o n dar y o bjecti ves will be 
i m ple me nte d t o c o ntr ol t he fa mil y-wise t y pe I err or rate at a 2 -si de d α le vel of 0. 0 5.  
T he pri mar y a nal yses f or t he c o nti n u o us efficac y a n d healt h o utc o mes varia bles will be ma de usi n g mi xe d-effects 
m o del of re peate d meas ures ( M M R M) a nal ysis wit h treat me nt, baseli ne C R P stat us, pri or T N F i n hi bit or e x perie nce d 
or  naï ve   (if a p plica ble), baseli ne val ue, visit, baseli ne val ue- b y-visit, a n d treat me nt - b y-visit as fi xe d fact ors.
A sec o n dar y a nal ysis f or c o nti n u o us efficac y a n d healt h o utc o mes varia bles ma y be ma de usi n g a nal ysis of 
c o varia nce ( A N C O V A) wit h treat me nt, baseli ne C R P stat us, baseli ne val ue a n d pri or T N F i n hi bi t or e x perie nce d or 
naï ve   (if a p plica ble).
Fis her’s e xact test will be use d f or all a d verse e ve nts ( A Es), baseli ne, disc o nti n uati o n, a n d ot her cate g orical safet y 
data.  C o nti n u o us vital si g n a n d la b orat or y val ues will be a nal yze d b y A N C O V A wit h treat me nt a n d baseli ne val ues 
i n t he m o del.
Efficac y, healt h o utc o mes, a n d safet y varia bles d uri n g t he E xte n de d Treat me nt Peri o d will als o be s u m marize d.

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 1 3
L Y 2 4 3 9 8 2 1
2. S c h e d ul e of A cti viti e s
Scree ni n g
( Peri o d 1)
B aseli ne 
R a n d o miz ati o n
Bli n de d Tre at me nt D osi n g Peri o d ( Peri o d 2) a
C R F Visit ( V) N u m ber
V 1
V 2
V 3
V 4
V 5
V 6
V 7
V 8
Wee ks Si nce Ra n d o mizati o n
W 0
W 1
W 2
W 4
W 8
W 1 2
W 1 6
St u d y Da ys
U p t o -4 2 d
0
7 ± 2 d
1 4 ± 2 d
2 8 ± 2 d
5 6 ± 4 d
8 4 ± 4 d
1 1 2 ± 4 d
I nf or me d c o nse nt
X
De m o gra p hics
b
X
P h y sical e xa mi nati o n
c
X
X
Vital si g ns ( B P a n d p ulse)
d
X
X
d
X  
X  
X  
X  
X  
X
d
Wei g ht
aa
X
X
X  
X  
X  
X
Hei g ht
X
Ha bits
e
X
B o d y te m perat ure
X
A P C h est X- ra y
f
X
I ncl usi o n/ E xcl usi o n criteria
g
X
X
E val uate prese nce of S p A feat ures
X
X
Ra n d o mizati o n
X
C o nc o mita nt me dicati o ns
X
X
X  
X  
X  
X  
X  
X
N S AI D use
X
X
X  
X  
X  
X  
X  
X
Pree xisti n g c o n diti o ns a n d me dical hist or y
h
X
X
X  
X  
X  
X  
X  
X
A d verse e ve nts
X
X
X  
X  
X  
X  
X  
X
E ye s y m pt o m assess me nt
i
X
X
X  
X  
X  
X  
X  
X
Dis pe nse I P
X
X  
X  
X  
X
A d mi nister I P o n site
j
X
X
I P c o m plia nce
k
X  
X  
X  
X
Dis pe nse S D A L
X
X  
X  
X  
X

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 1 4
L Y 2 4 3 9 8 2 1
Scree ni n g
( Peri o d 1)
B aseli ne 
R a n d o miz ati o n
Bli n de d Tre at me nt D osi n g Peri o d ( Peri o d 2) a
C R F Visit ( V) N u m ber
V 1
V 2
V 3
V 4
V 5
V 6
V 7
V 8
Wee ks Si nce Ra n d o mizati o n
W 0
W 1
W 2
W 4
W 8
W 1 2
W 1 6
St u d y Da ys
U p t o -4 2 d
0
7 ± 2 d
1 4 ± 2 d
2 8 ± 2 d
5 6 ± 4 d
8 4 ± 4 d
1 1 2 ± 4 d
C ollect, re vie w, a n d e nter data fr o m S D A L
X
X  
X  
X  
X
Cli nic al Effic ac y/ He alt h O utc o mes
M RI of s pi ne
a n d SIJ
x
X
y
X
z
X- ra y of t he s pi ne
cc
X
X- ra y of t he SIJ
l
X
Li near B A S MI
X
X
X
C hest e x pa nsi o n
X
X
X
Occi p ut t o wall dista nce
X
X
X
E nt hesitis M A S E S
X
X
X
Patie nt Gl o bal Assess me nt of Disease 
Acti vit y  N R S
X
X
X  
X  
X  
X  
X  
X
S pi nal p ai n
X
X
X  
X  
X  
X  
X  
X
B A S FI
X
X
X  
X  
X  
X  
X  
X
B A S D AI
X
X
X  
X  
X  
X  
X  
X
C- S S R S
m
X
X
X  
X  
X  
X  
X  
X
Self -Har m S u p ple me nt F or m
m
X
X
X  
X  
X  
X  
X  
X
F A CI T Fati g ue Scale
X
X
X
X
S F - 3 6
X
X
X  
X
X
A S A S HI
X
X
X  
X
X
QI D S -S R 1 6
X
X
X
E Q - 5 D- 5 L
X
X
W P AI -S p A
X
X
L a b or at or y Tests
H L A -B 2 7
n
X
C R P
X o
X
X  
X  
X  
X  
X  
X
A d mi nister P P D/ C ollect Q ua nti F E R O N ® -
T B G ol d/ T -S P O T ®
p
X

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 1 5
L Y 2 4 3 9 8 2 1
Scree ni n g
( Peri o d 1)
B aseli ne 
R a n d o miz ati o n
Bli n de d Tre at me nt D osi n g Peri o d ( Peri o d 2) a
C R F Visit ( V) N u m ber
V 1
V 2
V 3
V 4
V 5
V 6
V 7
V 8
Wee ks Si nce Ra n d o mizati o n
W 0
W 1
W 2
W 4
W 8
W 1 2
W 1 6
St u d y Da ys
U p t o -4 2 d
0
7 ± 2 d
1 4 ± 2 d
2 8 ± 2 d
5 6 ± 4 d
8 4 ± 4 d
1 1 2 ± 4 d
E C G
X
F S H
q
X
HI V/ H C V
X
H B V r
X
r
X
r
X
r
Ser u m pre g na nc y test
s
X
Ur i ne pre g na nc y test
s
X
X  
X  
X  
X  
X  
X
Ser u m c he mistr y
X
X
X  
X  
X  
X
P T T, P T/I N R
X
X
Li pi d pa nel (fasti n g)
t
X
X
He mat ol o g y
X
X
X  
X  
X  
X
Ur i nal ysis
X
X
T S H a n d free T 4
X
I m m u n o ge nicit y testi n g
u
X
X  
X  
X  
X  
X  
X
P K sa m pli n g
u, v
X
X  
X  
X  
X  
X  
X

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 1 6
L Y 2 4 3 9 8 2 1
E xte n de d Tre at me nt Peri o d
( Peri o d 3)a
E T V
C R F Visit ( V) N u m ber
V 9
V 1 0
V 1 1
V 1 2
V 1 3
V 1 4
V 1 5
V 1 6
V 1 7
E T V
Wee ks Si nce Ra n d o mizati o n
W 2 0
W 2 4
W 2 8
W 3 2
W 3 6
W 4 0
W 4 4
W 4 8
W 5 2
St u d y Da ys
1 4 0 ± 4 d
1 6 8 ± 4 d
1 9 6 ± 4 d
2 2 4 ± 4 d
2 5 2 ± 4 d
2 8 0 ± 4 d
3 0 8 ± 4 d
3 3 6 ± 4 d
3 6 4 ± 4 d
P h y sical e xa mi nati o n
c
X  
X
Vital si g ns ( B P a n d p ulse)
d
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Wei g ht
aa
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
C o nc o mita nt me dicati o ns
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
N S AI D use
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Pree xisti n g c o n diti o ns a n d me dical 
hist or y
h
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
A d verse e ve nts
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
E ye s y m pt o m assess me nt
i
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Dis pe nse I P
X  
X  
X  
X  
X  
X  
X  
X
I P c o m plia ncek
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Dis pe nse S D A L
X  
X  
X  
X  
X  
X  
X  
X
C ollect, re vie w, a n d e nter data fr o m 
S D A L
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Cli nic al Effic ac y/ He alt h O utc o mes
M RI of s pi ne a n d SIJ x
X b b
X
z
Li near B A S MI
X
X
X  
X
C hest e x pa nsi o n
X
X
X  
X
Occi p ut t o wall dista nce
X
X
X  
X
E nt hesitis M A S E S
X
X
X  
X
Patie nt Gl o bal Assess me nt of 
Disease Acti vit y N R S
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
S pi nal Pai n
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
B A S FI
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
B A S D AI
X  
X  
X  
X  
X  
X  
X  
X  
X  
X

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 1 7
L Y 2 4 3 9 8 2 1
E xte n de d Tre at me nt Peri o d
( Peri o d 3)a
E T V
C R F Visit ( V) N u m ber
V 9
V 1 0
V 1 1
V 1 2
V 1 3
V 1 4
V 1 5
V 1 6
V 1 7
E T V
Wee ks Si nce Ra n d o mizati o n
W 2 0
W 2 4
W 2 8
W 3 2
W 3 6
W 4 0
W 4 4
W 4 8
W 5 2
St u d y Da ys
1 4 0 ± 4 d
1 6 8 ± 4 d
1 9 6 ± 4 d
2 2 4 ± 4 d
2 5 2 ± 4 d
2 8 0 ± 4 d
3 0 8 ± 4 d
3 3 6 ± 4 d
3 6 4 ± 4 d
C- S S R S
m
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Self -Har m S u p ple me nt F or m
m
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
F A CI T Fati g ue Scale
X
X  
X
S F - 3 6
X
X  
X
A S A S HI
X
X  
X
QI D S -S R 1 6
X
X  
X
E Q - 5 D- 5 L
X  
X
W P AI -S p A
X  
X
L a b or at or y Tests
C R P
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
H B V r
X
r
X
r
X
r
X
r
X
r
Ur i ne pre g na nc y test
s
X  
X  
X  
X  
X
X
X
X
X  
X
Ser u m c he mistr y
X  
X  
X  
X  
X
X
X  
X
P T T, P T/I N R
X
X
X
Li pi d pa nel (fasti n g)
t
X
X
X
He mat ol o g y
X  
X  
X  
X  
X
X
X  
X
Ur i nal ysis
X
X
X  
X
I m m u n o ge nicit y testi n g
u
X
X
X  
X
P K sa m pli n g
u, v
X
X
X  
X

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 1 8
L Y 2 4 3 9 8 2 1
P ost -Tre at me nt F oll o w -U p f or P atie nts Disc o nti n ui n g Tre at me nt
( Peri o d 4)w
Re q uire d F oll o w -U p Visits
C R F V ( visit) n u m ber
V 8 0 1
V 8 0 2
St u d y Wee ks
L V + 4 W
L V + 1 2 W
St u d y Da ys
± 1 4 d
± 1 4 d
C o nc o mita nt me dicati o ns
X
X
Vital si g ns ( B P a n d p ulse)
d
X
X
Wei g ht
a a
X
X
Pree xisti n g c o n diti o ns a n d me dical hist or y
h
X
X
A d verse e ve nts
X
X
C- S S R S
m
X
X
Self -Har m S u p ple me nt F or m
m
X
X
H B V r
X
r
X
r
Ser u m c he mistr y
X
X
He mat ol o g y
X
X
I m m u n o ge nicit y testi n g
u
X
X
P K sa m pli n g
u ,v
X
X

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 1 9
L Y 2 4 3 9 8 2 1
A b bre viati o ns:   A P = a nteri or p osteri or ; A S A S HI = Assess me nt of S p o n d yl oart hritis I nter nati o nal S ociet y Healt h I n de x; B A S D AI = Bat h A n k yl osi n g 
S p o n d ylitis Disease Acti vit y I n de x; B A S FI = Bat h A n k yl osi n g S p o n d ylitis F u ncti o nal I n de x; B A S MI = Bat h A n k yl osi n g S p o n d ylitis Metr ol o g y I n de x; B P = 
bl o o d press ure; C R F = case re p ort f or m; C R P = hi g h se nsiti vit y C -reacti ve pr otei n; C- S S R S = C ol u m bia – S uici de Se verit y Rati n g Scale; d = da ys; D N A = 
de o x yri b o n ucleic aci d; E C G = electr ocar di o gra m; E Q - 5 D-5 L = E ur o pea n Q ualit y of Life – 5 Di me nsi o ns – 5 Le vel; E T V = earl y ter mi nati o n visit; F A CI T = 
f u ncti o nal assess me nt of c hr o nic ill ness t hera p y; F S H = f ollicle sti m ulati n g h or m o ne; H Bc A b + = p ositi ve f or a nti -he patitis B c ore a nti b o d y; H Bs A b = a nti -
he patitis B s urface a nti b o d y; H B V = he patitis B vir us; H C V = he patitis C vir us; HI V = h u ma n i m m u n o deficie nc y vir us; H L A = h u ma n le u k oc y te a nti ge n; 
I N R = i nter nati o nal n or malize d rati o; I P = i n vesti gati o nal pr o d uct; L V = last visit; M A S E S = Maastric ht A n k yl osi n g S p o n d ylitis E nt hesitis Sc ore ; M RI = 
ma g netic res o na nce i ma gi n g; N R S = n u meric rati n g scale; N S AI D = n o nster oi dal a nti -i nfla m mat ory dr u g; P K = p har mac o ki netic; P P D = p urifie d pr otei n 
deri vati ve; P T = pr ot hr o m bi n ti me; P T T = partial t hr o m b o plasti n ti me; QI D S -S R 1 6 = Q uic k I n ve nt or y of De pressi ve S y m pt o mat ol o g y -self re p ort ( 1 6 ite ms); 
S D A L = St u d y Dr u g A d mi nistra ti o n L o g; S F-3 6 = S h ort F or m 3 6 ; SIJ = sacr oiliac j oi nt; S p A = s p o n d yl oart hritis; T 4 = t h yr o xi ne; T B = t u berc ul osis ; T S H = 
t h yr oi d sti m ulati n g h or m one; V = st u d y  visit; W = st u d y wee k; W P AI-S p A = W or k Pr o d ucti vit y Acti vit y I m pair me nt Q uesti o n naire – S p o n d yl oart hritis.
a
Patie nt w h o h as  recei ve d at least 1 d ose of I P disc o nti n ues fr o m st u d y treat me nt s h o ul d c o m plete earl y ter mi nati o n visit ( E T V) a n d will e nter t he P ost 
Treat me nt F oll o w -U p Peri o d ( Peri o d 4) after E T V.   
b
De m o gra p hics i ncl u des rec or di n g of year of birt h, ge n der a n d et h nicit y .
c
O ne c o m plete p h ysical e xa mi nati o n (e xcl u di n g pel vic, rectal e xa mi nati o n) will be perf or me d at scree ni n g.  All p h ysical e xa mi n ati o ns t hr o u g h o ut t he st u d y 
m ust i ncl u de a s y m pt o m-directe d p h y sical as well as e xa mi nati o n of heart, l u n gs, a b d o me n, e yes, a n d vis ual e xa mi nati o n of t he s ki n.
d
B P a n d p ulse will al wa ys be meas ure d i n sitti n g p ositi o n a n d will be rec or de d bef ore I P d osi n g at all visits; i n a d diti o n, B P a n d p ulse will be rec or de d 
a p pr o xi matel y 1 h o ur p ost -d osi n g at baseli ne ( Wee k 0) a n d Wee k 1 6   Refer t o Secti o n 9. 4. 2 f or m ore details.
e
Ha bits i ncl u de rec or di n g of caffei ne, alc o h ol , a n d t o bacc o c o ns u m pti o n.
f
A p osteri or a nteri or c h est X- ra y will be ta ke n l ocall y at scree ni n g u nless o ne has bee n o btai ne d wit hi n 3 m o nt hs of scree ni n g ( Visit 1) ( pr o vi de d t he X- r a y 
a n d/ or re p ort are a vaila ble f or re vie w). Refer t o Secti o n 9. 4. 7 f or m ore details.
g
Refer t o rescree ni n g g ui da nce as a p pr o priate ( Secti o n 6. 4 ).
h
E val uati o n i ncl u des hist orical e ve nts a n d pree xisti n g c o n diti o ns.
i
Patie nts nee d t o be as ke d a b o ut prese nce of e ye s y m pt o ms; if e ye s y m pt o ms are prese nt, t he n a n e ye e xa mi nati o n is re q ui re d.  Refer t o Secti o n 9. 4. 6 f or 
s pecific i nstr ucti o ns.
j
Refer t o Secti o n 7. 1. 1 f or s pecific I P a d mi nistrati o n i nstr ucti o ns.
k
I P c o m plia nce will be assesse d b y re vie w of t he St u d y Dr u g A d mi nistrati o n L o g, ret ur n of e m pt y or  u n use d i n vesti gati o nal pr o d uct pac ka gi n g, a n d/ or direct 
q uesti o ni n g

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 2 0
L Y 2 4 3 9 8 2 1
l
A n X- r a y of t he SIJ will be perf or me d d uri n g t he Scree ni n g Peri o d ( Peri o d 1) u nless a n X- ra y ta ke n pri or t o scree ni n g is a vaila ble f or ce ntral rea di n g, is of 
g o o d q ualit y , a n d c o nfir ms dia g n osis of r-a x S p A.  All X- r a ys re q uire ce ntral rea di n g O N L Y, re gar dless of date ta ke n.  Ce ntral rea di n g will defi ne eli gi bilit y 
usi n g t he m N Y criteria. If ce ntral rea di n g of a pree xisti n g X- ra y is n ot c o nsiste nt wit h r-a x S p A b y ce ntral rea di n g, a ne w X- ra y of t he SIJ ma y be ta ke n 
d uri n g Peri o d 1 a n d se nt i n f or ce ntral rea di n g. 
m
A Self -Har m F oll o w -U p F or m is t o be c o m plete d f or eac h discrete self-har m e ve nt i de ntifie d o n t he C-S S R S a n d t he Self-Har m S u p ple me nt F or m.
n
H L A -B 2 7 test will be perf or me d ce ntrall y.
o
A p pr o val fr o m t he Lill y cli nical researc h p h ysicia n or cli nical researc h scie ntist m ust be o btai ne d bef ore a C R P retest is per mitte d.   If t he C R P la b is reteste d, 
t he m ost rece nt val ue will be use d f or ra n d o mizati o n.
p
If t h e Q ua nti F E R O N ®-T B G ol d test or T -S P O T ® is a vaila ble, eit her test ma y be use d i nstea d of t he P P D T B test.  T he Q ua nti F E R O N ® -T B G ol d test ma y be 
perf or me d l ocall y or ce ntrall y; t he T -S P O T ® m ust be perf or me d l ocall y.  P P D tests m ust be rea d 2 -3 da ys after Visit 1.  Refer t o Secti o n 9. 4. 7 f or m ore 
details.
q
F or fe male patie nts ≥4 0 a n d < 6 0 years of a ge w h o ha ve ha d a cessati o n of me nses f or at least 1 2 m o nt hs, a n F S H test will be p erf or me d t o c o nfir m n o n -
c hil d beari n g p ote n tial ( F S H ≥4 0 mI U/ m L or  ≥4 0 I U/ L).  F S H test will be perf or me d ce ntrall y.
r
All patie nts will be teste d f or H B V at scree ni n g.  Patie nts t hat are H Bc A b + at scree ni n g, re gar dless of H Bs A b stat us, will ha ve a ser u m H B V D N A o btai ne d 
b y t he ce ntral la b orat or y. Patie nts t hat are f o u n d t o be H B V D N A p ositi ve ( detecta ble) at scree ni n g will be e xcl u de d fr o m t he trial. Patie nts t hat are H B V 
D N A ne gati ve ( u n detecta ble) ma y be e nr olle d i nt o t he st u d y wit h re q uire d H B V D N A m o nit ori n g e ver y 3 m o nt hs d uri n g treat me nt a n d 1 2 wee ks after t he last 
d ose of i xe kiz u ma b.  If t he res ult of t he H B V D N A testi n g is p ositi ve, t he patie nt is t o be disc o nti n ue d fr o m t he st u d y a n d is t o recei ve a p pr o priate f oll o w- u p 
me dical care (refer t o Secti o n 9. 4. 1 0. 3 f or f urt her i nf or mati o n re gar di n g t he ti mi n g of disc o nti n uati o n).
s
O nl y f or fe males of c hil d beari n g p ote ntial.  Ser u m pre g na nc y test will be d o ne at Visit 1 o nl y a n d will be pe rf or me d ce ntrall y.  Patie nts deter mi ne d t o be 
pre g na nt will be disc o nti n ue d fr o m treat me nt a n d will n o l o n ger be a d mi nistere d I P (see Secti o n 8. 1 ).  Patie nts will u n der g o uri ne pre g na nc y testi n g at t he 
cli nic d uri n g sc he d ule d visits t hr o u g h Wee k 5 2 .  A d diti o nal uri ne pre g na nc y testi n g ca n be perf or me d at t he i n vesti gat or’s discreti o n.  If re q uire d per l ocal 
re g ulati o ns, testi n g ca n occ ur at ot her i nter vals d uri n g t he st u d y treat me nt peri o d a n d/ or f oll o w -u p peri o d . 
t
F or t he fasti n g li pi d pr ofile , patie nts are n ot t o eat or dri n k a n yt hi n g e xce pt water f or 1 2 h o urs pri or t o test.
u
I m m u n o ge nicit y sa m ples ma y als o be a nal yze d f or i xe kiz u ma b ser u m c o nce ntrati o n t o facilitate i n t he i nter pretati o n of i m m u n o ge nicit y data.  A n a d diti o nal 
bl o o d sa m ple will be c ollecte d, w he n p ossi ble, f or a n y patie nt w h o e x perie nces a p ote ntial s yste mic aller gic/ h y perse nsiti vit y reacti o n d uri n g t he st u d y as 
j u d ge d b y t he i n vesti gat or.
v
P K s a m ples are t o be c ollecte d bef ore I P i njecti o n.
w
Patie nts recei vi n g I P w h o disc o nti n ue at a n y ti me pri or t o t he e n d of t he st u d y or w h o c o m plete t he st u d y ( Wee k 5 2) will ha ve safet y F oll o w -U p Visits 8 0 1 
a n d 8 0 2 at 4 a n d 1 2 wee ks, respecti vel y , after t he date of t heir last visit.  
x
If M RI is c o n d ucte d o n t he sa me da y as st u d y visit, e ns ure t hat a n y scales/ q uesti o n naires are c o m plete d pri or t o a d mi nisteri ng a n y pre me dicati o n t o facilitate 
patie nt u n der g oi n g a n M RI (f or e xa m ple, m or p hi ne o r e q ui vale nt f or si g nifica nt pai n as j u d ge d b y t he i n vesti gat or or a be nz o diaze pi ne f or cla ustr o p h o bia).  
y
F or all patie nts, scree ni n g M RIs of t he s pi ne m ust be c o m plete d ≤3 0 da y s pri or t o ra n d o mizati o n.  
z
T he Wee k 1 6 M RI ma y be c ollecte d u p t o 1 0 da ys pri or t o Wee k 1 6 ( Visit 8).  T he Wee k 1 6 M RI m ust be c ollecte d pri or t o t he Wee k 1 6 ( Visit 8) d osi n g.  
F or E T V, M RI re q uire me nts are de pe n de nt o n t he ti mi n g of st u d y disc o nti n uati o n.  If disc o nti n uati o n is:

at or  bef ore Visit 5, n o M RI is re q uire d at E T V.  

after Visit 5 u p t o a n d i ncl u di n g Visit 8 ( Wee k 1 6), M RI is re q uire d at E T V. 

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 2 1
L Y 2 4 3 9 8 2 1

after Visit 8, re peat M RI is re q uire d
o n l y if E T V occ urs o n or after Visit 1 2.
a a Wei g ht is o nl y ca pt ure d on e C R F at V 2, V 8, V 1 0 , V 1 7, a n d/ or E T V.  B o d y wei g ht c ollecte d at ot her visits is use d o nl y f or calc ulati o n of creati ni ne cleara nce .  
b b T he Wee k 5 2 M RI ma y be c ollecte d u p t o 1 0 da y s pri or t o Wee k 5 2 ( Visit 1 7).
c c Cer vical a n d l u m bar s pi ne o nl y; ser ves t o e val uate prese nce of t otal a n k yl osis at scree ni n g ( Refer t o Secti o n 6. 2 , e xcl usi o n criteri o n [ 1 0]).  X-r ay of t he s pi ne 
d oes n ot nee d t o be re peate d if o ne is a vaila ble t hat was ta ke n ≤3 m o nt hs pri or t o scree ni n g ( Visit 1; refer t o Secti o ns 6. 2 , a n d 6. 4 ) a n d has passe d q ualit y 
assess me nt b y ce ntral rea di n g ve n d or.

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 2 2
L Y 2 4 3 9 8 2 1
3.
I ntr o d u cti o n
3. 1.
St u d y R ati o n al e
Eli Lill y a n d C o m pa n y ( hereafter Lill y) is i n vesti gati n g i xe kiz u ma b as a treat me nt o pti o n f or 
r a dio gra p hic a xial s p o n d yl oart hrit is (r-a x S p A) base d o n i ts mec ha nis m of actio n ( M o A), 
selecti vel y bl oc ki n g i nterle u ki n-1 7 A ( detaile d i n t he I n ves tigat or’s Br oc h ure [I B]).  T he 
f oll owi n g s u bc uta ne o us (S C ) i xe kiz u ma b treat me nt re gi me n of  8 0 m g e ver y  4 wee ks ( Q 4 W)
wi t h a starti n g d ose of 1 6 0 m g (at Wee k 0) will be st u di e d i n t his trial.  W i de ra n ge of d osi n g 
re gi me ns were e val uate d i n P hase 2 ps oriasis a n d r he u mat oid art hri tis (R A ) st u dies a n d 
d e m o nstrate d efficac y. I xe kiz u ma b 8 0 m g Q 2 W a n d Q 4 W treat m e nt re gi me n s wi t h a 1 6 0 mg 
starti n g d ose were e val uate d i n pi v otal P hase 3 st u dies i n ps oriasis a n d ps oriat ic art hritis ( Ps A) 
a n d de m o nstrate d efficac y, wi t h a fa v ora ble be nefit/ris k pr ofile ( G ottlie b et al. 2 0 1 5; Griffiths et 
al. 2 0 1 5; Mease et al. 2 0 1 5) . Rece nt l y discl ose d data fr o m p hase 3 st u dies of b ot h i xe kiz u ma b 
Q 2 W a n d Q 4 W ha ve rece nt l y de m onstrate d t he efficac y o f bl oc ki n g I L -1 7 A i n t he treat me nt of 
r-a x S p A i n bi ol ogical disease -m o dif yi n g a ntir he u mat ic dr u g ( b D M A R D)-naï ve as well as i n 
t u mor necr osis fact or ( T N F) i n hi bit or e x perie nce d patie nts ( va n der Heij de et al. 2 0 1 8; De o d har 
et al. 2 0 1 9b ). 
3. 2.
B a c k gr o u n d
A xial s p o n d yl oart hrit is (a x S p A) is a c hr o nic i nfla m mat or y disease pre d omi na ntl y affect i n g t he 
a xial s kelet o n (sacr oiliac j o i nts [ SIJ] a n d s pi ne) ( P o d d u b n y y 2 0 1 3).  A xial s p o n d yl oart hritis is 
n o w rec o g nize d as a si n gle disease e nt ity,  wit h a s u bset defi ne d b y t he prese nce of 
r a dio gra p hicall y  defi ne d str uct ural da ma ge of t he SIJ (r-a x S p A) a n d a s u bset wit ho ut cl ear 
str uct ural da ma ge defi ne d ra di o gra p hicall y ( nr-a x S p A).  W he n c o mpari n g a x S p A wit h R A, i t ca n 
be n ote d t hat w hile R A ca n be di vi de d i nt o er osi ve a n d n o ner osi ve or ser o p osit i ve a n d 
ser o ne gati ve s u bsets, it is well acce pte d t hat it is still o ne disease.  A xial s p o n d yl oart hrit is, i n a 
si milar fas hi on, al s o has s u bsets, a n d t h us ca n be c o nsi dere d a si n gle disease ( De o d har et al. 
2 0 1 4).
Ra di o gra p hic a x S p A ( r-a x S p A), for m erl y calle d a n k ylosi n g s p o n d yli tis ( A S), re prese nts a 
di sease i n w hic h t here is e vi de nce of disease feat ures o n ra di o gra p hic i ma gi n g.  It is a c hr o nic 
i nfla m mat or y disease c haracterize d b y c hr o nic i nfla m mati on of t he a xial a n d SIJ a n d varia ble 
i n v ol ve me nt of t he peri p heral j oi nts ( Bra u n a n d Sie per 2 0 0 7).  As t he disease pr o gresses, it ca n 
lea d t o ne w b o ne f or mati on i n t he f or m of s y n des m o p h ytes a n d j o i nt a nk yl osis, pri maril y  in t he 
a xial s kelet o n.  Patie nts wit h r-a x S p A ma y als o ha ve e xtra-artic ular ma nifestati o ns of t he disease 
s uc h as e nt hesitis, a nteri or u veitis, ps oriasis, a n d i nfla m mat or y b o wel disease, as well as 
c o mor bi di ties of a ortitis or car diac c o n d uct i on a b n or m alit ies.  C o m pare d wi t h t he ge neral 
p o p ul at i on, pati e nts wit h r- a x S p A ha ve i ncrease d rates of w or k disa bilit y,  u ne m plo y me nt, a n d 
m o rtality ( B o o ne n a n d va n der Li n de n 2 0 0 6).
A xial s p o n d yl oart hrit is affects u p t o 1. 4 % of t he a d ult p o p ulat i on w orl d wi de ( Bra u n a n d Sie per 
2 0 0 7; Re veille et al. 2 0 1 2; Stra n d et al. 2 0 1 3).  Alt h o u g h t he e xact eti o l og y  is u n k n o w n, it has 
bee n i n dicate d t hat ge netic fact ors a n d se veral l oci are li kel y t o be i n v o l ve d i n s usce pti bility t o 
t he disease ( Re veille 2 0 1 1).  T here is a str o n g ass ociat i on wi t h t he major hist oc o m pat i bility 

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 2 3
L Y 2 4 3 9 8 2 1
c o mple x, h u ma n le u k oc y te a ntige n ( H L A) -B 2 7.  U p t o 9 0 % t o 9 5 % of patie nts wit h r-a x S p A are 
p osi tive f or H L A-B 2 7, a n d t he ris k of t his disease de vel o pi n g is as hi g h as a b o ut 5 % i n H L A -
B 2 7 -p osi tive i n di vi d uals a n d s u bsta nt iall y hi g her i n H L A-B 2 7 -p osi tive relati ves of pat ient s 
( Bra u n a n d Sie per 2 0 0 7).  M ost of t he ot her k n o w n ge netic s usce pti bility c o mes fr om ge nes 
i n v ol ve d i n c yt o ki ne pr o d ucti o n, s pecificall y i ncl u di n g ge nes i n t he T hel per ( T h) 1 7 pat h wa y 
( Ma ks y m o w yc h 2 0 1 0; Re veille 2 0 1 1).
C urre nt sta n dar d of care f or r-a x S p A i ncl u des re g ular e xercise, p h ysical t hera p y, n o nster oi dal 
a nt i-i nfla m mat or y dr u gs ( N S AI Ds), a n d T N F al p ha i n hi bit ors ( Bra u n et al. 2 0 1 1; War d et al. 
2 0 1 5).  C ortic oster oi d i nj e ctio ns ma y  als o be of s o me be nefit.  T h o u g h N S AI Ds are t he first li ne 
of  dr u g treat me nt for a x S p A, t he y  are n ot effecti ve or well t olerate d i n all patie nts ( Bra u n a n d 
Si e per 2 0 0 9).  I n c o ntrast t o patie nts wit h R A, patie nts wit h a x S p A d o n ot res p o n d well t o 
c o n ve nt i onal disease -m o dif yi n g a ntir he u mat ic dr u gs (c D M A R Ds) i ncl u di n g met h otre xate 
( M T X) or s yste mic c ortic oster oi ds ( Bra u n a n d Sie per 2 0 0 9; Hai bel a n d S pec ker 2 0 0 9).
T N F i n hi bit ors are effecti ve a n d fre q ue ntl y prescri be d w he n N S AI D treat me nt has failed or 
ca n n ot be t olerate d ( Z oc hli n g et al. 2 0 0 6).  W hile T N F i n hi bit ors ha ve pr o ve n t o be effect i ve 
treat me nts f or a x S p A, a n u n met nee d re mai ns, as n ot all pat ient s res p o n d well t o or t olerate T N F 
i n hi bit or treat me nts ( va n der Heij de et al. 2 0 0 6; Hei ber g et al. 2 0 0 8; I n ma n et al. 2 0 0 8; Gli nt b or g 
et al. 2 0 1 0).  W hile T N F i n hi bit ors ha ve de m o nstrate d si g nifica nt i m pact o n si g ns a n d 
s y m pt o ms, f u ncti on, a n d q ualit y of  life, t he y ha ve n ot bee n a ble t o de m o nstrate si g nifica nt effect 
o n str uct ural pr o gressi o n i n pr os pecti ve cli nical st u dies.  T he use of t hese bi o l ogic t hera pi es i n 
vari o us diseases als o is ass ociate d wit h safet y c o ncer ns, s uc h as o p p ort u nist ic i nfecti ons, 
de m yeli nat i n g dis or ders, bl o o d d yscrasias, reacti vati o n of t u berc ul osis ( T B), a n d e xacer bati on o f 
c o n gest i ve heart fail ure ( M orela n d 2 0 0 5; S mith et al . 2 0 0 9).  T here re mai ns, t heref ore, a 
sig nifica nt u n met nee d f or safer, m ore effect i ve treat me nts f or patie nts wit h a x S p A ( D o u ga d os 
a n d Baete n 2 0 1 1).  I xe kiz u ma b ma y offer a n alter nati ve treat me nt a p pr oac h t o T N F i n hi bit or 
t hera p y in pat ient s wit h a x S p A.
I xe kiz u ma b ( L Y 2 4 3 9 8 2 1) is a h u ma nize d i m m u n o gl o b uli n G s u bclass 4 (I g G 4) m o n ocl o nal 
a nt i b o d y ( M A b) t hat ne utralizes t he c yt o ki ne i nterle u ki n-1 7 A (I L -1 7 A, al s o k n o w n as I L-1 7).  
I xe kiz u ma b treat me nt is a dmi nistere d b y S C i njecti o ns.  C o m pelli n g scie nt ific i nf or mat i on e xists 
t o date s u g gesti n g a n i m p orta nt r ole of t he I L-2 3/I L -1 7 pat h wa y  in t he pat h o ge nesis o f a x S p A 
( Baete n et al. 2 0 1 0, 2 0 1 4a; Ma ks y m o w yc h 2 0 1 0; Baralia k os et al. 2 0 1 1; Re veille 2 0 1 1; 
Yere m e nk o et al . 2 0 1 4).  T he de mo nstrati o n of  increase d I L- 1 7 pr o d uci n g T h 1 7 l y m p h oc y t e 
n u m bers a n d ser u m I L -1 7 l e vels i n r- a x S p A is c o nsiste nt wit h a direct r ole of T h 1 7 l y m p h oc ytes 
i n t his disease ( We n dli n g et al. 2 0 0 7; Ja n d us et al. 2 0 0 8; Mei et al. 2 0 1 1).  I L-1 7 secreti n g cells 
ha ve als o bee n detecte d i n sit u i n t he b o ne marr o w of facet j o i nts o btai ne d fr om pati e nts wit h r-
a x S p A ( A p pel et al. 2 0 0 8). 
S el ect i vel y tar geti n g I L-1 7 A wi t h ixe kiz u ma b is h y p ot hesize d t o pr o vi de t hera pe ut ic be nefit 
wi t ho ut u n d ul y i m pa ct i n g h ost defe nses.  As s uc h, i xe kiz u ma b ma y offer a t hera pe utic o pti o n f or 
pati e nts w h o are ca n di dates f or i nit ial s yste mic treat me nt as well as t h ose patie nts w h o ha ve l ost 
res p o nse, faile d t o res p o n d, or are i nt olera nt t o c urre ntl y mar kete d dr u gs, a n d ma y als o offer a 
m o r e fa v ora ble safet y pr ofile c o m pare d t o c urre ntl y mar kete d t hera pies.

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3. 3.
B e n efit/ Ri s k A s s e s s m e nt
M ore i nf or mat i on a b o ut t he k n o w n a n d e x pecte d be nefits, ris ks, seri o us a d verse e ve nts ( S A Es) 
a n d reas o na bl y a nt ici pate d a d verse e ve nts ( A Es) of i xe kiz u ma b are t o be f o u n d i n t he I B.  

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4.
O bj e cti v e s a n d E n d p oi nt s
Ta ble R H C H . 1 s h o ws t he o bjecti ves a n d e n d p o i nts of t he st u d y.
T a bl e R H C H . 1.
O bj e cti v e s a n d E n d p oi nt s
O bjecti ves
E n d p oi nts
Pri m ar y

T he pri mar y o bjecti ve is t o 
c o m pare i xe kiz u ma b 8 0 m g Q 4 W 
vers us place b o i n b D M A R D -naï ve 
patie nts wit h acti ve r-a x S p A at 
Wee k 1 6

Pr o p orti o n of patie nts ac hie vi n g a n Assess me nt of 
S p o n d yl oart hritis I nter nati o nal S ociet y 4 0 ( A S A S 4 0) 
res p o nse
Sec o n d ar y
T he m aj or sec o n d ar y o bjecti v es are :

T o c o m pare i xe kiz u ma b 8 0 m g 
Q 4 W t o place b o i n o verall st u d y 
p o p ulati o n at Wee k 1 6

Pr o p orti o n of patie nts ac hie vi n g a n A S A S 4 0 res p o nse

Pr o p orti o n of patie nts ac hie vi n g a n A S A S 2 0 res p o nse

C ha n ge f r om baseli ne i n A n k y l osi n g S p on d y litis Disease 
Acti vit y  Sc ore ( A S D A S)

C ha n ge f r om baseli ne i n Bat h A n k yl osi n g S p o n d ylitis 
Disease Acti vit y I n de x  ( B A S D AI)

C ha n ge f r om baseli ne i n Bat h A n k yl osi n g S p o n d ylitis 
F u ncti o nal I n de x ( B A S FI)

Pr o p orti o n of patie nts ac hie vi n g A S D A S < 2. 1

C ha n ge f r om baseli ne i n ma g netic res o na nce i ma gi n g 
( M RI) of t he s pi ne ( S p o n d yl oart hritis Researc h 
C o ns orti u m of Ca na da [ S P A R C C] sc ore)  

C ha n ge f r om baseli ne i n S h ort F or m 3 6 ( S F -3 6) p h ysical 
c o m p o ne nt sc ore ( P C S)
Ot her sec o n d ar y o bjecti ves are :

T o c o m pare i xe kiz u ma b re gi me n
8 0 m g Q 4 W t o place b o d uri n g t he 
1 6 -wee k place b o -c o ntr olle d peri o d 
( Peri o d 2) i n o verall st u d y  
p o p ulati o n

Pr o p orti o n of patie nts w h o ac hie ve A S A S 2 0, A S A S 4 0, 
A S A S 5/ 6, a n d partial re missi o n b y A S A S criteria

C ha n ge f r om baseli ne i n t he i n di vi d ual c o m p o ne nts of 
t he A S A S criteria

C ha n ge f r om baseli ne i n B A S D AI

Pr o p orti o n of patie nts reac hi n g B A S D AI 5 0

C ha n ge f r om baseli ne i n A S D A S

Pr o p orti o n of patie nts w h o e x perie nce cli nicall y -
i m p orta nt i m pr o ve me nt (c ha n ge of A S D A S fr o m 
baseli ne ≥1. 1) or maj or i m pr o ve me nt (c ha n ge of A S D A S 
fr o m baseli ne ≥2. 0 or  ac hie ve me nt of t he l o west p ossi ble 
sc ore) or i nacti ve disease ( A S D A S sc ore < 1. 3)

C ha n ge f r om baseli ne i n t he meas ure of hi g h se nsiti vit y 
C- reacti ve pr otei n ( C R P)

C ha n ge f r om baseli ne i n B A S FI

C ha n ge f r om baseli ne i n m o bilit y
o
Bat h A n k yl osi n g S p o n d ylitis Metr ol o g y I n de x 
( B A S MI) (li near) a n d i n di vi d ual c o m p o ne nts
o
C hest e x pa nsi o n
o
C ha n ge f r om baseli ne i n occi p ut t o wall 
dista nce

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
C ha n ge f r om baseli ne i n M RI of t he SIJ ( S P A R C C 
sc ore)

C ha n ge f r om baseli ne i n Maastric ht A n k yl osi n g 
S p o n d ylitis E nt hesitis Sc ore ( M A S E S)

I nci de nce rate of a nteri or u veitis or u veitis flares

C ha n ge f r om baseli ne i n t he f oll o wi n g healt h o utc o mes 
meas ures:  F u ncti o nal Assess me nt of C hr o nic Ill ness 
T hera p y  ( F A CI T) Fati g ue Scale, W or k Pr o d ucti vit y 
Acti vit y  I m pair me nt– S p o n d yl oart hritis ( W P AI -S p A) 
sc ores, a n d S F-3 6 ( b ot h P C S a n d me ntal c o m p o ne nt 
sc ores [ M C S]) a n d Q uic k I n ve nt or y of De pressi ve 
S y m pt o mat ol o g y – Self Re p ort 1 6 ite ms ( QI D S -S R 1 6) 
sc ore

T o dete r mi ne if t he effect of 
i xe kiz u ma b is mai ntai ne d t hr o u g h 
Wee k 5 2
All e n d p oi nts assesse d at Wee k 1 6 (a b o ve) a n d d uri n g t he 1 6 -
wee k place b o -c o ntr olle d peri o d (a b o ve) will c o nti n ue t o be 
assesse d t hr o u g h Wee k 5 2.
I n a d diti o n, t he f oll o wi n g e n d p oi nt is a d de d:

N S AI D i nta ke ( A S A S -N S AI D sc ore a n d % of patie nts 
ta ki n g N S AI Ds)

T o meas ure i xe kiz u ma b e x p os ure 
a n d assess t he relati o ns hi p bet wee n 
e x p os ure a n d i m m u n o ge nicit y

Ser u m tr o u g h c o nce ntrati o ns of i xe kiz u ma b

I xe kiz u ma b ser u m tr o u g h c o nce ntrati o ns ass ociate d wit h
A D A titer s u b gr o u ps
E x pl or at or y

T o e val uate ti me t o first res p o nse

O nset of acti o n a n d treat me nt res p o nse ( A S A S,  
A S D A S, C R P, B A S FI) d uri n g t he place b o -c o ntr olle d 
peri o d

T o c o m pare i xe kiz u ma b re gi me n
8 0 m g Q 4 W t o place b o d uri n g t he 
1 6 -wee k place b o -c o ntr olle d peri o d 
( Peri o d 2)

C ha n ge f r om baseli ne i n S P A R C C SIJ Str uct ural Sc ore 
( S S S)

C ha n ge f r om baseli ne i n A S A S HI sc ore

T o e val uate t he i nci de nce of a nti -
i xe kiz u ma b a nti b o dies a n d t heir 
relati ons hi p t o t he efficac y of 
i xe kiz u ma b 

Efficac y res p o nse rates liste d bel o w at Wee ks 1 6 a n d 5 2 
b y treat me nt -e mer ge nt a nti -dr u g a nti b o d y ( T E -A D A) 
stat us a n d b y ne utralizi n g a nti-dr u g a nti b o d y ( N A b) 
stat us:
o
Pr o p orti o n of patie nts ac hie vi n g A S A S 4 0
o
Pr o p orti o n of patie nts ac hie vi n g A S A S 2 0
o
Pr o p orti o n  of patie nts ac hie vi n g A S D A S 
i nacti ve disease
N ote:  Ot her e x pl orat or y o bjecti ves a n d e n d p oi nts will be s pecifie d i n t he statistical a nal ysis pla n ( S A P).

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5.
St u d y  D e si g n
5. 1.
O v er all D e si g n
St u d y  I 1 F-M C -R H C H ( R H C H) i s a P hase 3, m ultice nter, ra n d o mize d, d o u ble-bli n d, place b o -
c o ntr olle d, parallel-gr o u p, o ut pati e nt st u d y t o e val uate t he efficac y a n d safety of  ixe kiz u ma b 8 0 
m g Q 4 W S C wi t h starti n g d ose of 1 6 0 m g at Wee k 0 as c o m pare d t o place b o S C i n patie nts wit h 
r-a x S p A, d uri n g a 1 6-wee k Bli n de d Treat me nt D osi n g Peri o d.
St u d y R H C H will als o e val uate l on g -t er m efficac y a n d safety of  ixe kiz u ma b d uri n g t he E xte n de d 
Treat me nt Peri o d ( Peri o d 3) f or a t otal treat me nt d urati o n of 1 y ear ( 5 2 wee ks) .  
Fi g ure R H C H . 1 ill ustrates t he st u d y desi g n; b ot h treat me nt gr o u ps a n d a d mi nistrati o n of t he 
i n vesti gati onal pr o d uct are descri be d i n Sect i on 7. 1 ; a n d t he St u d y Dr u g A d mi nistratio n L o g is 
descri be d i n Secti o n 7. 2. 1 .
All pr oce d ures t o be c o n d uc te d d uri n g t he st u d y, i ncl u di n g ti mi n g of all pr oce d ures, are i n dicate d 
i n t he Sc he d ule of Act i vities ( Sectio n 2 ).  Selecte d st u d y pr oce d ures are t o be perf or me d pri or t o 
a d mi nistrati o n of t he i n vesti g at i onal pr o d uct, as a p plica ble. A p pe n di x 2 lists t he s pecific 
la b orat or y tests t hat will be perf or me d for t hi s st u d y.  P atie nts disc o nt i n ui n g fr om st u d y 
treat me nt w h o ha ve recei ve d at least 1 d ose of i n vesti gat i onal pr o d uct will c o nt in ue t o t he earl y  
ter mi nati o n visit ( E T V) pri or t o pr ocee di n g t o t he P ost-Treat me nt F oll o w -U p Peri o d.  F or t he 
ma na ge me nt of patie nt safet y,  all patie nts are t o be m o nit ore d t hr o u g h t he P ost -Treat me nt 
F o ll ow- U p Peri o d at l east as fre q ue nt l y as i n dicate d i n t he Sc he d ule of Acti vit ies ( Sectio n 2 ).
E xcl u de d a n d c o nc o mit a nt me dicat i ons are detaile d i n Sect i on 7. 7 .
P har mac o ki netic ( P K) sa m pli n g is detaile d i n Sect i o n 9. 5 .

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Fi g ure R H C H . 1 ill ustrates t he st u d y desi g n.
A b bre viati o ns:  L V = last visit; L Y = i xe kiz u ma b; n = n u m ber of patie nts; Q 4 W = e very 4 wee ks; S C = s u bc uta ne o us; V = st u d y visit; W = st u d y wee k.
a
All patie nts will recei ve 2 i njecti o ns at baseli ne, as detaile d i n Secti o n 7. 1 .  Patie nts ra n d o mize d t o t he i xe kiz u ma b re gi me n will recei ve a 1 6 0 m g starti n g 
d ose.
b
All patie nts will recei ve 2 i njecti o ns at Wee k 1 6, as detaile d i n Secti o n 7. 1 .  Patie nts ra n d o mize d t o place b o at Wee k 0 will be gi n i xe kiz u ma b 8 0 m g Q 4 W at 
Wee k 1 6 wit h a 1 6 0 m g starti n g d ose , a n d patie nts ra n d o mize d t o i xe kiz u ma b at Wee k 0 will recei ve 1 i xe kiz u ma b 8 0 m g i njecti o n a n d 1 place b o i njecti o n at 
Wee k 1 6 t o mai ntai n t he bli n di n g
( Secti o n 7. 1 ).
c
Patie nts w h o disc o nti n ue fr o m st u d y treat me nt f or a n y reas o n a n d w h o ha ve recei ve d at least 1 d ose of i n vesti gati o nal pr o d uct will c o nti n ue t o t he earl y 
ter mi nati o n visit ( E T V) bef ore e nteri n g t he P ost-Treat me nt F oll o w -U p Peri o d.  V 8 0 1 a n d V 8 0 2 are re q uire d f or all patie nts (Secti o n 9. 4. 1 0 ).
Fi g ur e R H C H . 1.
Ill u str ati o n of st u d y d e si g n f or Cli ni c al Pr ot o c ol I 1 F-M C -R H C H .

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5. 2.
N u m b er of P arti ci p a nt s
P arti cipa nts will be scree ne d t o ac hie ve 1 4 0 ra n d o mize d partici pa nts f or a n esti mate d t otal of 7 0
e val ua ble part ici pa nts per treat me nt gr o u p.
5. 3.
E n d of St u d y D efi niti o n
E n d of t he st u d y is t he date of t he last visit or last sc he d ule d proce d ure s h o w n i n t he Sc he d ule o f 
Act i vities ( Sectio n 2 ) f or t he last patie nt i n t he trial .
5. 4.
S ci e ntifi c R ati o n al e f or St u d y D e si g n
Ixe kiz u ma b 8 0 m g Q 4 W wi t h a 1 6 0 mg starti n g d ose will be st u die d as detaile d i n Sect i on 7. 1 .
D ose j ustificat i on is o utli ne d i n Secti on 5. 5 .  T he st u d y bli n d is mai ntai ne d as descri be d i n 
Secti o n 7. 3 .
T he pl ace b o -c o nt r olle d Bli n de d Treat me nt D osi n g Peri o d ( Peri o d 2) i s desi g ne d t o mi ni mize bias 
i n t he e val uati on of i xe kiz u ma b i n pat ient s wit h r-a x S p A f or b ot h efficac y a n d safety.   All 
pati e nts ma y still recei ve treat me nt i n t he f or m of t he all o we d c o nc o mit a nt me dicat i ons as 
descri be d i n t he st u d y  incl usi o n a n d e xcl usi o n cri t eria ( Sectio ns 6. 1 a n d 6. 2 ) a n d c o nc o mita nt 
t hera p y ( Sectio n 7. 7 ).  Patie nts ca n be disc o nt i n ue d fr om st u d y treat me nt at a n y ti me b y 
i n vesti gat or or patie nt decisi on if t he y are c o nsi dere d t o be recei vi n g i ns ufficie nt be nefit fr om 
st u d y tr e at me nt ( Sectio n 8. 1 ).
As of Wee k 1 6 (after c o m pleti o n o f P eri o d 2), i n vesti gat ors are all o we d t o a dj ust s o me 
c o nc o mita nt me dicat i ons, if nee de d, as s pecifie d i n Secti o n 7. 7 , acr oss all treat me nt gr o u ps. 
P ati e nts origi nall y assi g ne d t o pl ace b o d uri n g Peri o d 2 will recei ve i xe kiz u ma b 8 0 m g Q 4 W wit h 
a 1 6 0 mg starti n g d ose at Wee k 1 6.  
I xe kiz u ma b 8 0 m g Q 4 W is c o nt i n ue d be y on d Wee k 1 6 t o f urt her assess safety a n d efficac y 
d uri n g t he E xte n de d Treat me nt Peri o d ( Peri o d 3).   
T he effect i ve ness of i xe kiz u ma b i n treati n g r-a x S p A will be assesse d pri maril y b y  t he A S A S 4 0 
res p o nse rate i n b D M A R D -naï ve pat ient s at Wee k 1 6.  A S A S 4 0 a n d A S A S 2 0 res p o n se will als o 
be assesse d i n o verall  st u d y p o p ulat i on at Wee k 1 6.  T hese meas ures a n d t he Wee k 1 6 e n d p o i nt 
are i n ali g n me nt wit h efficac y e n d p oi nts f or c urre ntl y a p pr o ve d r-a x S p A t hera pies a n d wit h 
re g ulat or y g ui da nce ( E M A 2 0 0 9).  Stea d y state e x p os ure of i xe kiz u ma b is e x pecte d t o be 
reac he d b y Wee k 1 6.  Base d o n pre vio us st u di es wit h ixe kiz u ma b i n patie nts wit h ps ori asis, R A, 
Ps A a n d r - a x S p A, ma xi m u m or near ma xi m u m cli nical effect i n r-a x S p A were ac hie ve d wit hi n 
t his ti me fra me f or i xe kiz u ma b treat me nt (Gr iffiths et al . 2 0 1 5; Ge n o vese et al . 2 0 1 6; Mease el  
al. 2 0 1 7; Nas h et al. 2 0 1 7; va n der Heij de et al. 2 0 1 8; De o d har et al. 2 0 1 9 b) .  
Baseli ne C- reacti ve pr otei n (C R P ) has bee n re p orte d as a pre dict or of res p o nse i n patie nts wit h r-
a x S p A treate d wit h T N F in hi bit ors (I n ma n et al. 2 0 0 8; de Vries et al. 2 0 0 9; Sie per et al. 2 0 1 1; 
Vastesae ger et al. 2 0 1 1); he nce, b y i ncl u di n g it as a stratificati o n fact or, it e ns ures bala nce i n 
baseli ne C R P le vels , res ultin g i n greater c o m para bilit y acr oss treat me nt gr o u ps at baseli ne.  
Si milarl y, t he pri or T N F in hi bit ors use d has bee n re p orte d t o p ote ntiall y i m pact res p o nse rates of 

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s u bse q ue ntl y use d bi ol ogics ( Lie et al. 2 0 1 1; Gli nt b or g et al . 2 0 1 3); t heref ore, patie nts will als o 
be stratifie d base d o n pri or T N F in hi bit or e x per ience d or bi ol o gi cal naï ve . T h us baseli ne stat us 
will pr o d uce t he f o ll owi n g 3 strata:  
1)
A S patie nts w h o are bi o l ogi c naï ve a n d ha ve n or mal baseli ne C R P.
2)
A S patie nts w h o are bi o l ogi c naï ve a n d ha ve ele vate d baseli ne C R P.
3)
A S patie nts w h o ha ve de m o n strate d eit her i nt olera nce or i na de q uate res p o nse t o o ne T N F 
i n hi bit or a n d ha ve ele vate d baseli ne C R P.
T he E xte n de d Treat me nt Peri o d ( Peri o d 3) will per mit c ollecti o n of data f or t he assess me nts of 
mai nte na nce of efficac y a n d l o n g -t er m s afet y wi t h i xe kiz u ma b.
T he P ost -Treat me nt F oll o w -U p Peri o d ( Peri o d 4) is i m p orta nt f or safety a n d efficac y m o nit ori n g 
f oll owi n g a d mi nistrati o n of t he last st u d y  treat me nt.
5. 5.
J u stifi c ati o n f or D o s e
T he treat me nt re gi me n t o be e val uate d i n t his st u d y (i xe kiz u ma b 8 0 m g Q 4 W wit h a starti n g 
d ose of 1 6 0 m g a d mi nistere d s u bc uta ne o usl y ) was selecte d base d o n cli nical a n d 
P K/ p har mac o d y na mic ( P D) data fr o m ps ori asis, R A a n d r-a x S p A st u dies. 
E xt e nsi ve d ose-ra n gi n g st u dies were c o n d ucte d i n ps oriasis a n d R A p o p ul at i ons , e x plori n g 
m ult i ple d oses of i xe kiz u ma b i n b ot h i n dicat i ons.  T he d ose -ra n gi n g st u d y in R A i ncl u de d 2 
differe nt patie nt p o p ulat i ons ( b D M A R D -naï ve a n d T N F-i na de q uate res p o n ders) ( Ge n o vese et al. 
2 0 1 4 .  
Fi nall y , the efficac y of c o m m o n treat me nt re gi me ns of o t her t hera pies ( m ost T N F i n hi bit ors a n d 
sec u ki n u ma b) has bee n d e m o n strate d acr oss vari o us r he u mat ol o gical c o n dit i ons ( R A, Ps A, 
a x S p A) ( Si m p o ni ® pac ka ge i nsert, 2 0 1 5 ; 2 0 1 5 pac ka ge i nserts f or Ci mzia ®, C ose nty x ®, 
E n brel ®, a n d H u mi ra ®; Sa nf or d a n d Mc Kea ge 2 0 1 5). 
C ollect i vel y, t hese c urre nt int er nal (i xe kiz u ma b) a n d e xter nal ( T N F i n hi bit ors a n d sec u ki n u ma b) 
scie ntific data s u p p ort t he rati o nale f or st u d yi n g i xe kiz u ma b i n pat ient s wit h r-a x S p A wi t h t he 
pr o p ose d treat me nt re gi me n of  ixe kiz u ma b 8 0 m g Q 4 W wit h a starti n g d ose of 1 6 0 m g . 

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6.
St u d y  P o p ul ati o n
T he st u d y  p o p ulat i on will i ncl u de patie nts wit h a prior p h y sicia n dia g n osis of a x S p A w h o f ulfill 
pr ot oc ol  criteria for acti ve r- a x S p A ( wit h sacr oiliitis defi ne d ra dio gra p hicall y  acc or di n g t o t he 
m o difie d Ne w Y or k [ m N Y] cri teria, base d o n ce ntral rea di n g, ass ociate d wit h at least 1 S p A 
feat ure a n d [A p pe n di x 5 ]), w h o ha ve gi ve n writte n i nf or me d c o nse nt.  
St u d y  in vesti gat or(s) will re vie w patie nt hist or y  a n d scree ni n g test res ults fr om Visi t 1 (all 
criteria), a n d Visit 2 as per t he Sc he d ule of Activit ies (Secti o n 2 ) t o deter mi ne if t he patient  
meets all i ncl usi o n a n d n o ne of t he e xcl usi o n cri teria t o q ualif y for p arti ci pat i on i n t he st u d y.  All 
scree ni n g acti vities must be c o m plete d a n d re vie we d bef ore t he patie nt is ra n d o mize d.  Patie nts 
ma y be rescree ne d i n t he circ u msta nces descri be d i n Secti o n 6. 4 .
Pr os pecti ve a p pr o val o f pr ot oc ol  de viatio ns t o recr ui t me nt a n d e nr o ll me nt criteria, als o k n o w n as 
pr ot oc ol  wai vers or e xe m pti ons, are n ot per mitte d.
I n t his pr ot oc ol secti on, t he f o ll owi n g defi nit i ons a p pl y:

Scree ni n g is defi ne d as Visit 1, u p t o 4 2 da y s prior t o baseli ne ra n d o mizat i on.  

Baseli ne ra n d o mizati o n visit is defi ne d as Visit 2 ( Wee k 0).
6. 1.
I n cl u si o n Crit eri a
P ati e nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if t he y meet all of t h e foll o wi n g criteria at 
scree ni n g or as s pecifie d:
T y pe of P atie nt a n d Dise ase C h ar acteristics
[ 1] Ha ve a n esta blis he d dia g n osis of r-a x S p A wi t h sacr oiliitis defi ne d ra di o gra p hicall y 
acc or di n g t o t he m N Y criteria ( va n der Li n de n et al. 1 9 8 4) base d o n ce ntral rea di n g:  
sacr oiliitis gra de ≥2 bilaterall y  or gra des 3 t o 4 u nilaterall y.
A N D
At  least 1 S p A feat ure, acc or di n g t o A S A S criteria ( R u dwal eit et al. 2 0 0 9; Sie per et al. 
2 0 0 9 ), liste d i n A p pe n di x 5 .
[ 2] P ati e nts ha ve a hist or y of c hr o nic bac k pai n ≥3 m o n t hs wit h a ge at o nset < 4 5 years.
[ 3] Ha ve act i ve r- a x S p A defi ne d as B A S D AI ≥4 a n d t otal bac k pai n ≥4 ( Sie per et al. 2 0 0 9, 
B o x 2 5 S pi nal Pai n) o n a n N R S at scree ni n g a n d baseli ne.
[ 4] Bi ol o gi c naï ve or ha ve ha d pri or treat me nt wit h 1 T N F i n hi bit or.   T he T N F i n hi bit or 
e x perie nce d pat ient  must ha ve di sc o nti n ue d T N F i n hi bit or d ue t o eit her i nt olera nce or a n 
i na de q uate res p o nse a n d ha ve ele vate d baseli ne C R P ( defi ne d as:  I n t he o pi ni on of t he 
i n vesti gat or, t he patie nt ha d a n i na de q uate res p o nse t o at least 1 2 wee ks of treat me nt wit h 
a T N F i n hi bit or at a n a de q uate d ose a n d baseli ne C R P > 5. 0 0 m g/ L ). Bi ol o gi c naï ve
pati e nt w o uld be e nr olle d re gar dless of t he C R P le vel.

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N ote:  T he f o ll owi n g was h o ut peri o ds pri or t o baseli ne ra n d o mizat i on m ust be f o ll owe d:  
eta nerce pt ≥2 8 da ys; i nfli xi ma b, a dali m u ma b, or cert oliz u ma b pe g ol ≥6 0 da ys; 
g oli m u ma b ≥9 0 da ys.
[ 5] M ust ha ve ha d a n i na de q uate res p o nse, as deter mi ne d b y t he i n vest i gat or, t o 2 or m ore 
N S AI Ds at t he t hera pe utic d ose ra n ge f or a t otal d urati o n of at least 4 wee ks O R ha ve a 
hist or y  of disc o nt i n uati on d ue t o i ntol era nce t o ≥2 N S AI Ds .  
[ 6] P ati e nts must ha ve a hist or y  of prior t hera p y  for a x S p A of at l east 1 2 wee ks prior t o 
scree ni n g.  E xa m ples of pri or t hera p y ma y incl u de b ut are n ot li mite d t o p h y sical t hera p y,
N S AI D, a n d T N F i n hi bit or treat me nt.
[ 7] If ta ki n g N S AIDs or c y clo o x y ge nase -2 ( C O X - 2) i n hi bit ors, t he d ose m ust be sta ble f or at 
least 2 wee ks pri or t o baseli ne ra n d omizat i on.
P atie nt C h ar acteristics
[ 8] Are a m b ulat or y  male or fe male pat ient s ≥1 8 y ears of a ge at ti me of scree ni n g.
[ 9] M ust a gree t o use a relia ble met h o d of  birt h c o ntr ol:

If a male patie nt, patie nt a grees t o use a relia ble met h o d of birt h c o ntr ol d uri n g 
t he st u d y a n d for at least 1 2 wee ks f o ll owi n g t he l ast d ose of i n vesti gati o nal 
pr o d uct, w hic he ver is l o n ger.  Met h o ds of birt h c o ntr ol i ncl u de, b ut are n ot li mite d 
t o, c o n d o ms with s per mici de a n d male sterilizati o n.
O R

If a fe male patient  is a w o ma n of c hil d beari n g p ote ntial w h o tests ne gati ve f or 
pre g na nc y a n d a grees t o use a relia ble met h o d of birt h c o ntr ol or re mai n a bst i ne nt 
d uri n g t he st u d y  a n d for a t least 1 2 wee ks f oll owi n g t he l ast d ose of i n vest i gati onal 
pr o d uct, w hic he ver is l o n ger.  Met h o ds of c o ntrace pti o n i ncl u de, b ut are n ot 
li mite d t o:  oral c o ntrace pti ves, c o ntrace pti ve patc h, i njecta ble or i m pla nta ble 
c o ntrace pti ves, i ntra uteri ne de vice, va gi nal ri n g, dia p hra g m wit h c o ntrace pti ve gel, 
or c o n d o m wit h c o ntrace pti ve f oa m.
O R

If a fe male patient  is a w o ma n of n o nc hil d beari n g p ote ntial, s he m ust test 
ne gat i ve f or pre g na nc y a n d is n ot re q uire d t o use a n y met h o d of birt h c o ntr ol.  
N o nc hil d beari n g p ote nti al is defi ne d as:  
W o me n w h o ha ve ha d s ur gical sterilizat i on ( h ysterect o m y or bilateral 
o o p h orect o m y  or t u bal li gati on)  
-
or 
W o me n w h o are ≥6 0 y ears of a ge  
-
or 

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W o me n ≥4 0 a n d < 6 0 y ears of a ge w h o ha ve ha d a cessat i on of me nses f or 
≥1 2 m o nt hs a n d a fol licle sti m ulati n g h or m o ne ( F S H) test c o nfir mi n g 
n o nc hil d beari n g p ote ntial ( ≥4 0 m I U/ m L or ≥4 0 I U/ L).
I nf or me d C o nse nt
[ 1 0] Ha ve gi ve n writte n i nf or me d c o nse nt a p pr o ve d b y Lill y, or its desi g nee, a n d 
t he I n vest i gati onal Re vie w B oar d (I R B)/ Et hical Re vie w B oar d ( E R B) 
g o ver ni n g t he site.
6. 2.
E x cl u si o n Crit eri a
P ati e nts will be e xcl u de d fr o m st u d y e nr oll me nt if t he y meet a n y of t he f o ll owi n g cri t eria at
scree ni n g or as s pecifie d:
Me dic al C o n diti o ns
[ 1 1]
Ha ve t otal a n k yl osis of t he s pi ne, as assesse d l ocall y, base d o n l at er al 
r a dio gra p hs of t he cer vical a n d l u m bar s pi ne .
[ 1 2] Ha ve a hist or y  of ot her s yste mic i nfla m mat or y diseases (s uc h as b ut n ot 
li mite d t o:  l u p us, vasc ulitis or R A), or ot her c hr o nic pai n c o n diti ons (s uc h as 
b ut n ot li mite d t o fi br o m yal gia) t hat mi g ht c o nf o u n d t he e val uati o ns of be nefit 
fr om i xe kiz u ma b t hera p y.  
N ote :  Patie nts wit h ps oriasis t hat ha ve ne ver recei ve d a n d d o n ot re q uire
s yste mic treat me nt f or ps oriasis, s uc h as b ut n ot li mite d t o oral a ge nts or 
bi o l ogic t hera pi es, ca n be i ncl u de d pr o vi de d t hese pati e nts fulfill  t he e ntr y 
criteria.
[ 1 3] Ha ve act i ve Cr o h n’s disease ( C D) or acti ve ulcerati ve c olitis ( U C).
N ote :  Patie nts ma y be e nr olle d if t he y ha ve ha d a hist or y of i nfla m mat or y 
b o wel  disease (I B D), i ncl u di n g C D a n d U C, b ut ha ve ha d n o e xacer bati on f or 
≥6 m o nt hs pri or t o baseli ne ra n d o mizat i on a n d, if c urre ntl y o n treat me nt, m ust 
be o n sta ble treat me nt f or ≥6 m o nt hs pri or t o baseli ne ra n d o mizati o n.  
[ 1 4] Ha ve e vi de nce of acti ve a nteri or u veit is (a n ac ute e pis o de) wit hi n t he last 
4 wee ks pri or t o baseli ne ra n d o m izati on.
N ote :  T hese patie nts ma y be rescree ne d o nl y o ne ti me ≥4 wee ks after 
res olut i on of ac ute s y m pt o ms .  
[ 1 5] Ha ve c urre nt or a hist or y  of ly m p h o pr oliferat i ve disease, or si g ns or 
s y m pt o ms of l y m p h o pr oliferat i ve disease wit hi n 5 years pri or t o baseli ne 
ra n d omizat i on; or ha ve acti ve or hist or y  of mali g na nt disease wit hi n 5 years 
pri or t o baseli ne ra n d o mizat i on.
[ 1 6] Ha ve a hist or y  of fl ui d o verl oa d, m y ocar dial i nfarcti o n ( MI), u nc o m pe nsate d 
heart fail ure, or e vi de nce of ne w - o nset isc he mic heart disease or i n the 
o pi ni o n of t he i n vest i gat or ot her seri o us car diac disease, wit hi n 1 2 wee ks pri or 
t o baseli ne ra n d o mizati o n.  

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[ 1 7] Prese nce of si g nifica nt u nc o ntr olle d cere br ocar di o vasc ular e ve nts (f or 
e xa m ple, u nsta ble a n gi na, u nsta ble arterial h y perte nsi o n, m o derate -t o-severe 
heart fail ure [ Ne w Y or k Heart Ass ociat i on class III/I V], or cere br o vasc ular 
accide nt) at scree ni n g t hat, i n t he o pi ni o n of t he i n vesti gat or, p ose a n 
u nacce pta ble ris k t o t he patie nt if partici pat i n g i n t he st u d y or of int erferi n g 
wi t h t he i nter pretatio n of  data. 
[ 1 8] Prese nce of a n y c o m o r bi d res pirat or y, he patic, re nal, gastr oi ntesti nal, 
e n d ocri ne, he mat ol o gic dis or ders, at scree ni n g t hat, i n t he o pi ni o n of t he 
i n vesti gat or, p ose a n u nacce pta ble ris k t o t he patie nt if partici pati n g i n t he 
st u d y or of int er feri n g wit h t he i nter pretati o n of data.
[ 1 9] Prese nce of a n y ne ur o l ogi c or ne ur o ps yc hiatric dis or ders, at scree ni n g t hat, i n 
t he o pini o n of t he i n vest i gat or, p oses a n u nacce pta ble ris k t o t he patie nt if 
parti ci pat i n g i n t he st u d y or of i nterferi n g with t he i nte r pretatio n of  data.
[ 2 0] Prese nce of si g nifica nt u nc o ntr olle d ne ur o ps y c hiatric dis or der; ha ve rece nt 
hist or y  ( wit hi n 3 0 da ys pri or t o scree ni n g visit [ Visit 1] a n d a n y time bet wee n 
scree ni n g visit [ Visit 1] a n d baseli ne ra n d o mizat i on [ Visit 2]) of a s uici de 
att e m pt; or ha ve a sc ore of 3 o n Ite m 1 2 ( T h o u g hts of Deat h or S uici de) of t he 
Q ui c k I n ve nt or y of De pressi ve S y m pt o mat olo g y -self re p ort ( 1 6 ite ms) ( QI D S-
S R 1 6) at scree ni n g or baseli ne ra n d o mizat i on or are cli nicall y  ju d ge d b y  t he 
i n vesti gat or t o be at ris k f or s uici de. 
[ 2 1] Ha ve prese nce or pers o nal hist or y  or fa mil y hist or y ( 1st de gree relati ve) of 
de m yeli nat i n g dis or der.
N ote :  1st de gree mea ns c hil d, pare nt, or si bli n g, pr o vi de d a bl o o d relati o ns hi p 
e xists. 
[ 2 2] P ati e nts w h o ha ve:

i n t he past 1 2 wee ks pri or t o baseli ne ra n d o mizat i on:
o
ha d a seri o us i nfect i on (f or e xa m ple, p ne u m o nia, cell ulit is), 
o
ha ve bee n h os pitalize d f or a n i nfect i on,
o
or ha ve recei ve d i ntra ve n o us (I V) a nti bi ot ics f or a n i nfecti on, 

or i n t he past 2 4 wee ks pri or t o baseli ne ra n d o mizati o n ha d a s erio us 
b o ne or j oi nt  i nfecti on

or ha ve e ver ha d, 
o
a n i nfecti o n of a n artificial j o i nt, 
o
a n i nfecti o n t hat occ urs wit h i ncrease d i nci de nce i n a n 
i m m u n oc o mpr o mise d h ost (i ncl u di n g, b ut n ot li mite d t o, 
P ne u m oc yst is jir o vecii p ne u m onia, s y m pt o m at ic 
hist o pl as mo sis, or c occidi oi d o m yc osis)

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[ 2 3] Ha ve a k n o w n i m m u n o deficie nc y or are i m m u n oc o m pr o mise d t o a n e xte nt 
s uc h t hat partici pati on i n t he st u d y w o uld p ose a n u nacce pta ble ris k t o t he 
patie nt.
[ 2 4] Ha ve or ha d a her pes z oster or a n y ot her cli nicall y a p pare nt varicella -z ost er 
vir us i nfect i on wi t hi n 1 2 wee ks of baseli ne ra n d o mizati on.
[ 2 5] Ha ve a n y ot her acti ve or rece nt i nfect i on wi t hi n 4 wee ks of baseli ne 
ra n d omizat i on t hat i n t he o pi ni o n o f t he i n vest i gat or, w o ul d p ose a n 
u nacce pta ble ris k t o t he patie nt if partici pat i n g i n t he st u d y.
N ote :  T hese patient s ma y be rescree ne d o ne ti me ≥4 wee ks after res ol uti o n o f 
s y m pt o ms.
[ 2 6] Ha ve a k n o w n aller g y or h y perse nsi tivit y t o a n y  bi olo gi c t hera p y t hat w o uld 
p ose a n u nacce pta ble ris k t o t he patie nt if part ici pati n g i n t his st u d y.  
[ 2 7] Ha ve ha d s ur gical treat me nt of a j o i nt t hat is t o be assesse d i n t he st u d y wit hi n 
8 wee ks pri or t o baseli ne ra n d o mizat i on or will re q uire s ur gical treat me nt of a 
j oi nt t h at is t o be assesse d i n t he st u d y d uri n g t he first 1 6 wee ks of t he trial.  
[ 2 8] Ha ve ha d a n y  major s ur ger y wit hi n 8 wee ks pri or t o baseli ne ra n d o mizati on, 
or will re q uire maj or s ur ger y  d uri n g t he st u d y t hat i n t he o pi ni on of t he 
i n vesti gat or a n d i n c o ns ultati on wi t h Lill y or its desi g nee w o uld p ose a n 
u nacce pta ble ris k t o t he patie nt.  
Pri or/ C o nc urre nt T her a p y or Cli nic al Tri al E x perie nce
[ 2 9] Ha ve recei ve d c D M A R Ds a n d/ or ot her t hera pies s uc h as b ut n ot li mite d t o:  
g ol d sal ts, c yclos p ori ne, azat hi o pri ne, da ps o ne, 6 -merca pt o p uri ne, 
m yc o p he n o late mofetil, or a n y  ot her i m m u n os u p pressi ve a ge nts wit hi n 4 
wee ks p rior t o baseli ne ra n d o mizat i on.
E xce pt i on:  M T X ( oral or pare nteral u p t o 2 5 m g/ wee k), s ulfasalazi ne ( u p t o 
3 g/ da y ), or h ydr o x yc hl or o q ui ne ( u p t o 4 0 0 m g/ da y) ma y be all o we d I F at 
sta ble d ose f or at least 4 wee ks pri or t o baseli ne ra n d omizat i on. 
A N D
if us e d, m ust n ot be i n a n y c o m bi nati o n wit h ot her c D M A R Ds.
N ote :  If M T X is use d, l ocal sta n dar d of care is t o be f oll owe d f or 
c o nc o mita nt a d mi nistrati o n o f f olic or f oli nic aci d wit h M T X.
[ 3 0] Use of oral c ortic oster oi ds > 1 0 m g/ da y pre d nis o ne or i ts e q ui vale nt.
N ote :  If patient s are ta ki n g pre d nis one or i ts e q ui vale nt a n d t he d ose is ≤1 0 
m g/ da y , t he d ose must be sta ble f or at least 4 wee ks pri or t o baseli ne 
ra n d omizat i on.

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[ 3 1] Ha ve recei ve d a n y pri or, or are c urre ntl y  recei vi n g, treat me nt wit h biol o gi c or 
ot her i m m u n o m o d ul at or y a ge nts, i ncl u di n g i n vesti gati o nal t hera pies (s uc h as 
b ut n ot li mite d t o Ja n us ki nase (J A K) i n hi bit ors, I L-1, I L -6 , I L -2 3 , I L - 1 7 
(incl u di n g i xe kiz u ma b), I L- 1 7 R, T cell, or B cell tar gete d t hera pies).
N ote :  Pre vi o us T N F i n hi bit or t hera p y is per mitte d.
[ 3 2] Are c urre nt l y e nr olle d i n, ha ve partici pate d, or disc o nti n ue d fr o m a cli nical 
trial in v o l vi n g a n i n vesti gati onal pr o d uct or n o na p pr o ve d use of a dr u g or 
de vice wit hi n t he last 3 0 da ys pri or t o scree ni n g or a peri o d of at least 5 half -
li ves of the last a d mi nistrati o n of t he dr u g, w hic he ver is l o n ger. 
N ote:   I n vesti gati onal pr o d ucts t hat are bi o l ogic or ot her i m m u n o m o d ul at or y 
a ge nts are n ot per mitte d re gar dless of was h o ut peri o d ( descri be d i n criteri o n 
a b o ve).
[ 3 3] Are c urre nt l y e nr olle d i n a n y ot her cli nical st u d y i n v ol vi n g a n i n vesti gati onal 
pr o d uct or a n y  ot her t ype of me dical researc h j u d ge d n ot t o be scie nt ificall y or 
me dicall y c o m pat i ble wit h t his st u d y.
[ 3 4] Are c urre nt l y recei vi n g or ha ve recei ve d treat me nt wit h de n os u ma b wit hi n 
6 m o nt hs pri or t o ba seli ne ra n d omizati o n.
[ 3 5] Ha ve recei ve d a n y pare nteral gl uc oc ortic o i d a d mi nistere d b y i ntra-artic ular, 
i ntr a musc ular, or I V i nject i on wi t hi n 6 wee ks pri or t o baseli ne ra n d omizat i on, 
or f or w h o m a pare nteral i njecti o n of gl uc oc ortic oster oi ds is a ntici pate d 
d uri n g t he Bli n de d Treat me nt D osi n g Peri o d ( Peri o d 2) of t he st u d y.  
[ 3 6] Are c urre nt l y recei vi n g or ha ve recei ve d a n y tr a ditio n al C hi nese m e dici ne 
( T C M) wit hi n 4 wee ks pri or t o baseli ne ra n d o miz atio n.
[ 3 7] Use of a n y  o piate a nal gesic at a vera ge dail y d oses > 3 0 mg/ da y  of  mor p hi ne or 
its e q ui vale nt or use of varia ble d oses of a n y o piate a nal gesic wit hi n 6 wee ks 
pri or t o baseli ne ra n d o mizat i on.  E xce pti o n f or patie nts wit h pai n t hat ma y 
i nterfere wit h u n der g oi n g a n M RI:  patie nt ma y recei ve pre me dicati on of 
≤3 0 m g of m or p hi ne or e q ui vale nt, o n t he da y  of t he M RI, f or sig nifica nt pai n 
as ju d ge d b y  t he i n vesti gat or.  
[ 3 8] Ha d a li ve vacci nat i on wi t hi n 1 2 wee ks pri or t o baseli ne ra n d omizat i on, or 
i nte n d t o ha ve a li ve vacci nat i on d uri n g t he c o urse of t he st u d y , or wit hi n 1 2 
wee ks of  c o mpleti n g treat m e nt i n t his st u d y, or ha ve partici pate d i n a vacci ne 
cli nical st u d y wit hi n 1 2 wee ks prior t o baseli ne ra n d o mizat i on.  I n vesti gat ors 
are t o re vie w t he vacci nati o n stat us of t heir patie nts a n d f o ll ow t he l o c al  
g ui deli nes f or a d ul t vacci nat i on wi t h no nli ve vacci nes i nte n de d t o pre ve nt 
i nfecti ous di sease prior t o t hera p y .  
N ote :  Kille d/i nacti ve or s u b u nit vacci nes are e x pecte d t o be safe; h o we ver, 
t heir efficac y wit h c o nc omit a nt i xe kiz u ma b treat me nt is u n k n o w n.

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 3 7
L Y 2 4 3 9 8 2 1
[ 3 9] Ha d a vacci nat i on wi t h Bacill us Cal mette-G uéri n ( B C G) wit hi n 1 2 m o nt hs 
pri or t o baseli ne ra n d o mizat i on, or i nte n d t o ha ve t his vacci nat i on wi t h B C G 
d uri n g t he c o urse of t he st u d y , or wit hi n 1 2 mo nt hs of c o m plet i n g treat me nt i n 
t his st u d y.
Di a g n ostics Assess me nts
[ 4 0] Ha ve a b o d y  t e mperat ure ≥3 8° C ( 1 0 0. 5° F) at baseli ne ra n d o mizati o n.  
N ote :  T hese patient s ma y be rescree ne d o ne ti me ≥4 wee ks after d oc u me nte d 
res olut i on of ele vate d te m perat ure.
[ 4 1] Ha ve e vi de nce or s us pici o n of act i ve or late nt T B (refer t o Secti o n 6. 4 f or 
rescree ni n g a n d Secti on 9. 4. 7 f or details o n deter mi ni n g f ull T B e xcl usi on 
crit erio n).
[ 4 2] Are p osi tive f or h u ma n i m m u n o deficie nc y vir us ser ol o g y ( HI V); t hat is, 
p osi tive f or h u ma n i m m u n o deficie nc y vir us a nti b o d y ( HI V A b).  
[ 4 3] Ha ve e vi de nce of or test p ositi ve f or he patit is B vir us ( H B V) b y  testi n g 
p osi tive f or:  1) H B V s urface a nti ge n ( H Bs A g +), O R 2) a nti-he pat itis B c ore 
a nt i b o d y p ositive ( H Bc A b +) a n d H B V D N A are p osi tive.
N ote :  Patie nts w h o are H Bc A b + a n d H B V D N A ne gat i ve ma y be e nr o lle d i n 
t he st u d y.  Patie nts w h o meet t hese criteria at scree ni n g will be i de nt ifie d b y 
t he ce ntral la b orat or y a n d mo ni t ore d d uri n g t he st u d y as detaile d i n Secti on
9. 4. 1 0. 2 .
[ 4 4] Ha ve e vi de nce of or test p ositi ve f or he patit is C vir us ( H C V).  A p osit i ve test 
f or H C V is defi ne d as:  1) p ositi ve f or he patitis C a nti b o d y (a nti –H C V A b); 
a n d 2) p osit i ve via a c o nfir mat or y  test f or H C V (f or e xa m ple, 
H C V -p ol y merase c hai n react i on).
[ 4 5] Ha ve electr ocar di o gra m ( E C G) a b n or malit ies t hat are c o nsi dere d cli nicall y 
sig nifica nt a n d w o ul d p ose a n u nacce pta ble ris k t o t he patie nt if part ici pati n g 
i n t he st u d y.  
[ 4 6] P ati e nts ha vi n g c o ntrai n dicat i ons t o M RI (f or e xa m ple, cla ustr o p h o bia, 
pace ma kers, a ne ur ys m cli ps, i ntra oc ular metallic fra g me nts).  
N ote :  F or cla ustr o p h o bia, pre me dicat i on wi t h be nz o diaze pi ne is all o we d 
(in vest i gat or s h o ul d assess f or p otent ial i nteract i ons wi t h ot her c o nc o mita nt 
me dicat i on(s) s uc h as o piates).
L a b or at or y tests m a y n ot be re pe ate d u nless t here is a tec h nic al err or or 
cli nic al re as o n t o belie ve a res ult m a y nee d t o be reteste d wit hi n t he scree ni n g 
peri o d.   La b orat or y tests c a n be re peate d a ma xi m u m of 1 ti me, a n d res ults m ust be 
recei ve d a n d re vie we d pri or t o ra n d o mizati on.  F or eli gi bilit y,  t h e most rece nt l a b 
pa nel m ust n ot meet a n y  of t h e foll o wi n g criteria:   
[ 4 7] At  scree ni n g, ha ve a ne utr o p hil c o u nt < 1 5 0 0 cells/ μ L ( < 1. 5 0 x 1 03 / µ L or 
< 1. 5 0 GI/ L).  

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 3 8
L Y 2 4 3 9 8 2 1
[ 4 8] At  scree ni n g, ha ve a l y m p h oc yte c o u nt < 8 0 0 cells/ μ L ( < 0. 8 0 x 1 03 / µ L or 
< 0. 8 0 GI/ L).  
[ 4 9] At  scree ni n g, ha ve a platelet c o u nt < 1 0 0, 0 0 0 cells/ μ L ( < 1 0 0 x 1 03 / µ L or 
< 1 0 0 GI/ L) .  
[ 5 0] At  scree ni n g, ha ve as partate a mi n otra nsferase ( A S T) or ala ni ne 
a mi n otra nsferase ( A L T) > 2. 5 ti mes t he u p per li mit  of n or mal ( > 2. 5 x U L N).
[ 5 1] At  scree ni n g, ha ve a t otal w hite bl o o d cell ( W B C) c o u nt < 3 0 0 0 cells/ μ L 
( < 3. 0 0 x 1 03 / µ L or < 3. 0 0 GI/ L).  
[ 5 2] At  scree ni n g, ha ve he m o gl obi n < 8. 5 g/ d L ( 8 5. 0 g/ L) f or male patie nts a n d 
< 8. 0 g/ d L ( 8 0 g/ L) f or fe male patie nts.
[ 5 3] Ha ve ot her cli nical la b orat or y  test res ults at scree ni n g t hat are o utsi de t he 
n or m al refere nce ra n ge f or t he p o p ulati on a n d are c o nsi dere d cli nicall y 
sig nifica nt, per i n vest i gat or assess me nt. 
Ot her E xcl usi o ns
[ 5 4] Ha ve d o nate d b l oo d > 4 5 0 m L wi t hi n t he last 4 wee ks pri or t o scree ni n g, or 
i nte n d t o d o nate bl o o d d uri n g t he c o urse of t he st u d y.
N ote :  Patie nts w h o ha ve d o nate d bl o o d ma y be rescree ne d o ne ti me ≥4 wee ks 
ha ve passe d si nce i nit ial scree ni n g.  
[ 5 5] Are w o me n w h o are lactati n g or breastfee di n g.
[ 5 6] Are i n vest i gat or site pers o n nel directl y affiliate d with t his st u d y  a n d/ or t heir 
i m me diate fa milies.  I m me diate fa mil y is defi ne d as a s p o use, pare nt, c hil d, or 
si bli n g, w het her bi ol ogi c al or le gall y a d o pte d.
[ 5 7] Are Lill y  e m plo y e es or its desig nee or are e m pl o yees of t hir d -part y  
or ga ni zat i ons i n v ol ve d i n t he st u d y.
[ 5 8] Are u n willi n g or u na ble t o c o m pl y wit h t he use of a data c ollect i on de vice t o 
di rectl y rec or d data fr o m t he patie nt.
[ 5 9] Ha ve a n y ot her c o n dit i on t hat precl u des t he patie nt fr o m f oll owi n g a n d 
c o mplet i n g t he pr ot oc ol, i n t he o pi ni on of t he i n vesti gat or.  
6. 3.
Lif e st yl e R e stri cti o n s
N ot a p plica ble .
6. 4.
S cr e e n F ail ur e s
I n di vi d uals w h o d o n ot meet t he criteria f or partici pati o n i n t his st u d y (scree n fail ure) ma y b e 
rescree ne d i n t he f oll owi n g circ u msta nces:  patie nts w h o test p ositi ve f or late nt T B at scree ni n g 
ma y be rescree ne d f o ll owi n g a p pr o pri ate treat me nt as descri be d i n Sect i on 9. 4. 7 ; patie nts w h o d o 
n ot q ualif y at scree ni n g u n der E xcl usi o n Cri teria [ 2 5], [ 4 0], or [ 5 4], ma y be rescree ne d o ne ti me, 
≥4 wee ks after d oc u me nte d res ol uti o n of s y m pt o ms or fr o m t i me of bl o o d d o nati o n.  

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 3 9
L Y 2 4 3 9 8 2 1
Scree ni n g M RIs m ust be perf or me d ≤3 0 da ys pri or t o baseli ne ra n d o mizat i on ( Visit 2).  After 
c o ns ultati o n wit h Lill y me dical, pa tie nts ma y be rescree ne d if scree ni n g M RI(s) of t he s pi ne 
a n d/ or SIJ were perf or me d > 3 0 da ys pri or t o baseli ne ra n d o mizati o n.
If a patie nt is u na ble t o c o m plete all scree ni n g pr oce d ures wit hi n t he scree ni n g peri o d, t he patie nt 
ma y be rescree ne d after c o ns u ltatio n wi t h Lill y me dical.
W he n rescree ni n g is perf or me d, t he i n di vi d ual m ust si g n a ne w i nf or me d c o nse nt f or m (I C F) a n d 
will be assi g ne d a ne w i de nt ificati on n u m ber.  T o e ns ure all eli gi bilit y crit eria are met, all 
scree ni n g pr oce d ures m ust be re peate d unless pre vi o usl y c o n d ucte d wit hi n t i mefra mes s pecifie d 
i n t he Sc he d ule of Acti vities (Secti o n 2 ).

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 4 0
L Y 2 4 3 9 8 2 1
7. Tr e at m e nt s
7. 1.
Tr e at m e nt s A d mi ni st er e d
T he Bli n de d Treat me nt D osi n g Peri o d ( Peri o d 2) i n v o l ves a c o m paris o n of i xe kiz u ma b 8 0 m g 
Q 4 W t o place b o.
Ixe kiz u ma b treat me nt re gi me n will i ncl u de pat ient s recei vi n g a 1 6 0 m g 
starti n g d ose. All d oses are a d mi nistere d via S C i nject i on .  Ta ble R H C H . 2 s h o ws t he treat me nt 
re gi me ns.  
At  baseli ne ( Wee k 0), all patient s will be ra n d o mize d t o a treat me nt re gi me n a n d recei ve 2 
i njecti ons.  Pati e nts assi g ne d t o i xe kiz u ma b treat me nt re gi me n wit h 1 6 0 m g i xe kiz u ma b starti n g 
d ose will recei ve 1 6 0 m g of i xe kiz u ma b as 2 S C i nject i ons.  Pati e nts assi g ne d t o t he place b o 
treat me nt gr o u p will recei ve 2 S C i nject i ons of place b o.  D uri n g t he re mai n der of t he Bli n de d 
Treat me nt D osi n g Peri o d ( Peri o d 2; Wee k 0 t o Wee k 1 6), all pat ient s will recei ve 1 i njecti on 
e ver y 4 wee ks.  Details are pr o vi de d i n Ta ble R H C H . 2.
D uri n g t he E xte n de d Treat me nt Peri o d ( Peri o d 3; Wee k 1 6 t o Wee k 5 2), patie nts ori gi nall y 
assi g ne d t o i xe kiz u ma b tr e at me nt will re mai n o n t he sa me tr e at me nt re gi me n t hr o u g h Peri o d 3.  
At  Wee k 1 6, patie nts ori gi nall y assi g ne d t o place b o will recei ve i xe kiz u ma b 8 0 m g Q 4 W with a 
1 6 0 m g starti n g d ose (as t w o 8 0 m g S C i nject i ons).   T o m ai ntai n t he bli n d, all pat ient s, 
re gar dless of treat me nt gr o u p, will recei ve 2 S C i njecti o ns at Wee k 1 6 .  All patient s will recei ve 
o pe n -label i n vesti gati onal pr o d uct starti n g fr o m Wee k 2 0 .
T he i n vest i gat or or his/ her desi g nee is res p o nsi ble f or t he f oll owi n g:

e x plai ni n g t he c orrect use of t he i n vesti gati o nal pr o d uct t o t he patie nt/ patie nt care gi ver

verif yi n g t hat i nstr ucti o ns are f o ll owe d pr o pe rl y

mai ntai ni n g acc urate rec or ds of i n vesti gati o nal pr o d uct dis pe nsi n g, c ollect i on, a n d 
a d mi nistrati o n

ret ur ni n g all u n use d me dicati o n t o Lill y or its desi g nee at t he e n d of t he st u d y.
P ati e nts will be i nstr ucte d t o c o ntact t he i n vesti gat or as s o o n as p oss i ble if he or s he has a 
c o mplai nt or pr o bl e m wit h t he i n vesti gati onal pr o d uct s o t hat t he sit uati o n ca n be assesse d.
F urt her i nstr ucti o ns a n d s pecial c o nsi derat i ons f or t he a d mi nistrati o n of t he i n vest i gati onal 
pr o d uct are pr o vi de d i n S e cti o ns 7. 1. 1 , 7. 2. 1 , a n d 7. 7. 2 .

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 4 1
L Y 2 4 3 9 8 2 1
T a bl e R H C H . 2.
Tr e at m e nt R e gi m e n s f or Bli n d e d Tr e at m e nt D o si n g P eri o d ( P eri o d 2) a n d E xt e n d e d Tr e at m e nt P eri o d 
(P eri o d 3)
I niti al 
Re gi me n
D ose
Wee k 0 ( D a y 1)
D ose
Wee k 4 t o Wee k 1 2
( Re m ai n der of Peri o d 2)
D ose
Wee k 1 6
D ose
Wee k 2 0 t o Wee k 4 8
( Re m ai n der of Peri o d 3)
T ot al i njecti o ns 
per p atie nt
2 i njecti o ns
1 i njecti o n Q 4 W
2 i njecti o ns
1 i njecti o n Q 4 W
I xe kiz u ma b
8 0 m g Q 4 W 
wit h 1 6 0 m g 
starti n g d ose
Treat me nt d ose
2 i xe kiz u ma b 8 0 m g 
i njecti o ns
1 i xe kiz u ma b 8 0 m g i njecti o n 
Q 4 W
1 i xe kiz u ma b 8 0 m g 
i njecti o n
1 i xe kiz u ma b 8 0 m g i njecti o n 
Q 4 W
I njecti o ns t o 
mai ntai n bli n di n g
N o ne
N o ne
1 place b o f or 
i xe kiz u ma b i njecti o n
N o ne
Place b o
Treat me nt d ose
N o ne
N o ne
2 i xe kiz u ma b 8 0 m g 
i njecti o ns 
(starti n g d ose)
1 i xe kiz u ma b 8 0 m g i njecti o n 
Q 4 W
I njecti o ns t o 
mai ntai n bli n di n g
2 place b o f or 
i xe kiz u ma b 
i njecti o ns
1 place b o f or i xe kiz u ma b 
i njecti o n Q 4 W
N o ne
N o ne
A b bre viati o ns: Q 4 W = e ver y 4 wee ks.

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 4 2
L Y 2 4 3 9 8 2 1
7. 1. 1.
A d mi ni str ati o n of I n v e sti g ati o n al Pr o d u ct
I njecti ons will be a d mi nistere d s u bc uta ne o usl y b y t he patie nt or cli nical site staff or care gi ver 
trai ne d b y t he cli nical sit e staff.
Tr ai ni n g:   At Wee k 0 ( baseli ne, Visit 2) eac h pat ie nt is sc he d ule d t o recei ve 2 i njecti o ns of 
bli n de d i n vest i gati onal pr o d uct.  F or trai ni n g p ur p oses, t he first i njecti on will be perf or me d b y 
cli nical sit e staff, a n d t he sec o n d i njecti on at t hat visit will be a d mi nistere d b y t he patie nt or 
care gi ver u n der t he s u per visi o n of cli nical sit e staff.  If a d diti onal trai ni n g is necessar y , a n 
i njecti on ma y be a d mi nistere d b y  t he patie nt or care gi ver u n der t he s u per visi on of cli ni c al sit e 
staff at Wee k 4 ( Visit5 ).  
A d mi nistr ati o n:   If t he patie nt is u na ble t o perf or m t he i njecti on, cli nical site staff or a care gi ver
trai ne d b y t he cli nical site staff ma y a d mi nister t he i n vesti gati onal pr o d uct.  All s u bse q ue nt 
i njecti ons o f i n vesti gati o nal pr o d uct will be a d mi nistere d eit her at t he cli nical sit e for s af et y 
c o ncer ns of t he patie nt or o utsi de t he cli nical sit e, prefera bl y at patie nt’s h o me, e xce pt f or Wee ks 
0 a n d 1 6 w he n t he i nject i ons ha ve t o be d o ne at t he site f or p ost -d ose m o nit ori n g.  
Refer t o t he a p pr o priate M a n u al Syri n ge Directi o ns f or Use
pr o vi de d b y t he s p o ns or f or eac h 
i n vesti gati onal pr o d uct.  N ote t hat i nject i ons are n ot t o be gi ve n i n t he sa me ar m fr o m w hic h 
pati e nt blo o d sa m ples, i ncl u di n g P K/ P D sa m ples, are bei n g dra w n at rel e va nt visits.
St u d y  Dr u g A d mi nistrati o n L o gs will be dis pe nse d t o eac h patie nt as nee de d f or rec or di n g 
perti ne nt data a b o ut eac h i njecti o n; details o f t he use of t hese l o gs are pr o vi de d i n Secti o n 7. 2. 1 .
P ossi ble i nject i on sites are i de ntifie d i n t he M a n u al Syri n ge Directi o ns f or Use .  T he i njecti o n 
sit e is t o be r otate d t o a n ot her area f or s u bse q ue nt d oses.
O bser v ati o n:  Patie nts are t o re mai n u n der o bser vati o n f or at least 1 h o ur after d osi n g at Wee k
0 
( Visit 2) a n d Wee k 1 6 ( Visit 8)
t o mo ni t or for s af et y si nce s ome pat ient s will be recei vi n g 
i xe kiz u ma b f or t he first ti me at t hese visits.  T heref ore, at Wee k 0 ( Visit 2) an d Wee k 1 6 ( Visit 
8), i njecti ons of  t he i n vesti gati o nal pr o d uct will be a d mi nistere d at t he cli nical site t o all o w f or 
o bser vat i on f or a n y AEs a n d c ollect i on of p ost i njecti o n bl o o d press ure ( B P) a n d p ulse 
meas ure me nts a p pr o xi matel y 1 h o ur after a d mi nist rati on of t he i n vest i gati onal pr o d uct (Secti o n
9. 4. 2 a n d Secti o n 2 ).
7. 1. 2.
P a c k a gi n g a n d L a b elli n g
T he i n vest i gati o nal pr o d ucts will be s u p plie d b y t he s p o ns or or its desi g nee i n acc or da nce with 
c urre nt G o o d Ma n ufact uri n g Practices (c G M P).  
Cli nical trial materials will be la bele d acc or di n g t o t he c o u ntr y ’s re g ulat or y re q uire me nts.  All 
i n vesti gati onal pr o d ucts will be st ore d, i n ve nt orie d, rec o ncile d, a n d destr o y e d acc or di n g t o 
a p plica ble re g ulat i ons. 
I xe kiz u ma b a n d place b o t o matc h will be s u p plie d as i njecta ble s ol uti ons i n 1 -m L, si n gle -d ose, 
prefille d, dis p osa ble ma n ual s yri n ges wit h st u d y -s pecific la bels.  Eac h s yrin ge of i xe kiz u ma b is 
desi g ne d t o deli ver i xe kiz u ma b 8 0 m g.  T he s y rin ges (a n d c o nte nts) c o ntai ni n g eit her 

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 4 3
L Y 2 4 3 9 8 2 1
i xe kiz u ma b or placeb o will be visi bl y  in dist i n g uis ha ble fr om eac h ot her.  S yrin ges will be 
s u p plie d i n cart o ns, wit h t he a p pr o priate q ua ntity of s yrin ges s pecific t o t he pla n ne d dis pe nsi n g 
sc he d ule of t he i n vesti gati o nal pr o d uct.
7. 2.
M et h o d of Tr e at m e nt A s si g n m e nt
P ati e nts w h o meet all crit eria for e nr oll me nt will be ra n d o mize d t o d o u ble -bli n d treat me nt at 
Wee k 0 ( Visit 2).  Assi g n me nt t o treat me nt gr o u ps will be deter mi ne d b y a c o m p uter -ge nerate d 
ra n d om se q ue nce usi n g a n i nteracti ve we b-res p o nse s yste m (I W R S).  T he I W R S will be use d t o 
assi g n d o u ble -bli n d i n vest i gati onal pr o d uct t o eac h patie nt.  Site pers o n nel will c o nfir m t hat t he y  
ha ve l ocate d t he c orrect assi g ne d i n vesti gati o nal pr o d uct pac ka ge b y  e nteri n g a c o nfir mati o n 
n u m ber f o u n d o n t he pac ka ge i nt o t he I W R S.
T o ac hie ve b et wee n-gr o u p c o m para bilit y, t he ra n d o mizat i on will be stratifie d b y  baseli ne C R P 
( n o n-ele vate d or ele vate d) a n d T N F i n hi bit or e x perie nce d or naï ve .  T he st u d y will e nr oll 
a p pr o xi matel y 60 % of  patie nts wit h baseli ne C R P ele vate d ( > 5. 0 0 m g/ L) a n d a p pr o xi matel y 
4 0 % of patie nts wit h n o n- ele vate d baseli ne C R P . At  least 6 1 b D M A R D-naï ve pat ient s will be 
e nr o lle d per ar m.
O nce a s pecific strat u m is f ull y e nr o lle d, t he s p o ns or ma y st o p f urt her e nr oll me nt of patie nts 
fitti n g t he crit eria of t hat strat u m.
7. 2. 1.
S el e cti o n a n d Ti mi n g of D o s e s
I n vesti gati onal pr o d uct is t o be a d mi nistere d at a p pr o xi matel y t he sa me t i me eac h da y, as m u c h
as p ossi ble.  F or i njecti o ns n ot a d mi nistere d o n t he sc he d ule d da y of t he wee k fr o m Wee ks 0 t o 
1 6, t he misse d d ose is t o be a d mi nistere d wit hi n 3 da ys of t he sc he d ule d da y; after Wee k 1 6, t he 
misse d d ose is t o be a d mi nistere d wit hi n 5 da ys o f t he sc he d ule d da y.  Dates of s u bse q ue nt st u d y 
visit s are n ot t o be m o difie d acc or di n g t o t his dela y.
A pa per St u d y  Dr u g A d mi nistrati o n L o g will be c o m plete d b y ra n d o mize d patie nts f or eac h 
i njecti on t hr o u g h o ut st u d y  p artici pat i on.  T he data fr o m t he St u d y Dr u g A d mi nistrati o n L o g m ust 
be tra nscri be d i nt o t he electr o nic case re p ort f or m (e C R F) b y site pers o n nel.  
P ati e nts will be i nstr ucte d t o c o ntact t heir st u d y sit e in t he e ve nt of a n i nject i on pr o bl e m.  I n 
a d ditio n, si te pers o n nel re vie w all St u d y Dr u g A d mi nistratio n L o gs at eac h visit t o i de nt if y a n y 
pr o d uct c o m plai nt s, a n d t he y will c o mplete a Pr o d uct C o m plai nt F or m  for eac h o perati o n f ail ure 
re p orte d o n a St u d y  Dr u g A d mi nistrati o n L o g (see Secti o n 9. 2. 3 f or a d ditio nal  instr ucti o ns 
re gar di n g c o m plai nt ha n dli n g).
7. 3.
Bli n di n g
T his is a d o u ble -bli n d st u d y .  
I nitial ra n d o mizati on (st u d y  treat me nt a d mi nistere d bet wee n Wee ks 0 a n d 1 6) will re mai n 
bli n de d t o st u d y  site pers o n nel a nd pati e nts u nt il t he fi nal cli nical trial data base l oc k has
occ urre d . 

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R a n d o mizati o n will  be bli n de d t o s p o ns or u ntil t he cli nical trial data base t hr o u g h Wee k 1 6 has 
l oc ke d
E mer ge nc y  u n bli n di n g f or A Es ma y be perf or me d t hr o u g h t he I W R S, w hic h ma y s u p ple me nt or 
ta ke t he place of e mer ge nc y c o des ge nerate d b y a c o mp uter dr u g -labeli n g s yste m.  T his o pti o n 
ma y be use d O N L Y if t he pati e nt ’s well- bei n g re q uires k n o wle d ge of t he patie nt’s treat me nt 
assi g n me nt.  All act i ons res ult i n g i n a n u n bli n di n g e ve nt are rec or de d a n d re p orte d b y t he I W R S.
If a n i n vesti gat or, site pers o n nel perf or mi n g assess me nts, or patie nt is u n bli n de d, t he patie nt is t o
be disc o nt i n ue d fr om t he st u d y tr e at me nt .  I n cases w here t here are et hical reas o ns t o ha ve t he 
pati e nt re mai n o n st u d y  treat me nt , t he i n vesti gat or m ust o btai n s pecific a p pr o val fr om a Lill y 
cli nical researc h p h ysicia n or Lill y cli nical researc h scie ntist f or t he patie nt t o c o nti n ue o n st u d y  
treat me nt .
I n case of a n e mer ge nc y, t he i n vesti gat or has t he s ole res p o nsi bility f or deter mi ni n g if u n bli n di n g 
of  a patie nt’s treat me nt assi g n me nt is warra nte d f or me dical ma na ge me nt of t he e ve nt.  T he
safety m ust al wa ys be t he first c o nsi derat i on i n ma ki n g s uc h a deter mi nat i on.  If a patie nt’s 
treat me nt assig n m e nt i s u n bli n de d, Lill y must be n otifie d i m me diatel y .  If t he i n vesti gat or 
deci des t hat u n bli n di n g is warra nte d, it is t he res p o nsi bilit y of  t he i n vestigat or t o pr o m ptl y 
d oc u m e nt t he decisi o n a n d rat i onale a n d n otif y Lill y as s o o n as p ossi ble.
7. 4.
D o s a g e M o difi c ati o n
N o i n vest i gati onal pr o d uct d ose m o dificat i ons are per mitte d (refer t o Secti o n 9. 4. 1 0. 2. 1 f or 
i nsta nces w here dr u g ma y be wit hhel d).
7. 5.
Pr e p ar ati o n/ H a n dli n g/ St or a g e/ A c c o u nt a bilit y
I n vesti gati onal pr o d ucts will be s u p plie d b y Lill y or its re prese ntati ve, i n acc or da nce wit h 
c G M P, a n d w ill be s u p plie d wit h l ot n u m bers, e x pir y  dates, a n d certificates of a nal ysis, as 
a p plica ble.
T he i n vest i gati o nal pr o d uct is t o be st ore d at 2° C t o 8° C ( 3 6° F t o 4 6° F) i n its ori gi nal cart o n t o 
pr otect fr o m li g ht.  I n vest i gati onal pr o d uct m ust n ot be fr oze n or s ha ke n.   Si tes will be re q uire d 
t o mo ni t or t e mperat ure of t he o n -site st ora ge c o n ditio ns of t he i n vest i gati onal pr o d uct.  
7. 6.
Tr e at m e nt C o m pli a n c e
P ati e nt c o mplia nce wi t h st u d y me dicat i on will be assesse d at eac h visit.  C o m plia nce will be 
assesse d b y re vie w of t he St u d y Dr u g A d mi nistrati o n L o g, ret ur n of e m pty or u n use d 
i n vesti gati onal pr o d uct pac ka gi n g, a n d/ or direct q uesti o ni n g.  De viat i on(s) fr o m t he prescri be d 
d osa ge re gi me n are t o be rec or de d i n t he eC R F.
C o m plia nce i s defi ne d i n Secti on 1 0. 3. 6. 4 .
7. 7.
C o n c o mit a nt T h er a p y
All c o nc o mit a nt me dicatio n ta ke n d uri n g t he st u d y m ust be rec or de d i n t he e C R F.  Patie nts will 
mai ntai n t heir us ual me dicat i on re gi me n t hr o u g h o ut t he st u d y  u nless s pecificall y e x clu de d i n t he 

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pr ot oc ol .  Patie nts ta ki n g per mitte d me dicat i ons are t o be o n sta ble d oses at t he base li ne visit 
( Wee k 0; Visit 2) t hr o u g h Wee k 1 6 as s pecifie d i n i ncl usi on/e xcl usi o n  crit eria ( Sectio ns 6. 1 a n d 
6. 2 ).  U p t o Wee k 1 6, patie nts s h o ul d n ot start ne w me dicati ons or m a ke a n y c h an ges t o 
c o nc o mita nt me dicat i ons u nless c ha n ges nee d t o be ma de f or a n A E or f or safet y reas o ns.  
Be y o n d Wee k 1 6, s o m e fle xi bilit y is all o we d i n c o nc omit a nt me dicat i on as o utli ne d bel o w.
A d dit i onal dr u gs are t o be a v oi de d d uri n g t he st u d y  u nless re q uire d t o treat a n A E or f or t he 
treat me nt of a n o n g oi n g me dical pr o ble m.  If t he nee d f or c o nc o mita nt me dicati o n arises, t he 
i n vesti gat or is t o base decisi o ns o n t he patie nt a n d r ele va nt cli nical fact ors.  A n y a d dit i onal 
me dicat i on, w het her prescri pti o n or o ver -t he- c o u nter, use d at baseli ne ( Wee k 0, Visit 2) a n d/ or 
d uri n g t he c o urse of t he st u d y  must be d oc u m e nte d wit h t he start a n d st o p dates i n t he eC R F.   
Ot her me dicati o ns ma y be all o we d, if a p pr o ve d b y t he s p o ns or or its desi g nee.   
O nl y f or patie nts w h o disc o nt i n ue d st u d y treat me nt a n d ha ve e ntere d t he P ost-Treat me nt F oll o w -
U p Peri o d ( Peri o d 4) , A S t hera p y wit h a n ot her a ge nt pre vi o usl y e xcl u de d d uri n g t he treat me nt 
p eri o d of  t he st u d y ma y be allo we d, as deter mi ne d a p pr o priate b y  t he i n vestigat or a n d a p pr o ve d 
b y Lill y  me dical.
P ati e nts re q uirin g s ur ger y  at a n y time d uri n g t he st u d y  are t o i nterr u pt a d mi nistrati o n of t he 
i n vesti gati onal pr o d uct be gi n ni n g 8 wee ks pri or t o t he s ur ger y , or as earl y as p ossi ble wit hi n 8 
wee ks of s ur ger y , a n d res u me a d mi nistrati o n of t he i n vest i gati onal pr o d uct o nl y  aft er c o mplete 
w o u n d heali n g.  
V acci nes:
Li ve vacci nes are n ot all o we d d uri n g a n y  of t he st u d y p erio ds.  Use of n o nli ve seas o nal 
vacci nati o ns a n d/ or e mer ge nc y vacci nat i on (s uc h as ra bies or t eta n us vacci nati o ns) is all o we d.
N S AI Ds a n d A n al gesics: 
Bli n de d Treat me nt D osi n g Peri o d ( Peri o d 2):
N o nster oi dal a nt i-i nfla m mat or y dr u gs, i ncl u di n g C O X -2 i n hi bit ors, will be all o we d u p t o t he 
ma xi m u m rec o m me n de d d oses f or pai n.  Patie nts m ust be o n a sta ble d ose of N S AI Ds/ C o x - 2 
i n hi bit ors f or at least 2 wee ks pri or t o baseli ne ra n d o mizati on. I ntr o d ucti o n of a ne w N S AI D or 
d ose a dj ust me nt t o a n e xist i n g N S AI D is n ot per mitte d, u nless re q uir e d for s af et y reas o ns.  
S h ort -acti n g a nal gesics wit h n o a nti-i nflam mat or y  a ctio n (s uc h as paraceta m ol) are per mitte d 
a n d ma y be a d mi nistere d a d h oc as nee de d a n d are t o be wit h hel d wi t hi n t he 2 4-h o ur peri o d pri or 
t o a n y assess me nt.  As piri n ( d ose n ot e xcee di n g 3 5 0 m g/ da y) ma y  be ta ke n t o ma na ge 
car dio vasc ular ris k.
O pi ate a nal gesic use is all o we d b ut n ot t o e xcee d > 3 0 m g/ da y  of mor p hi ne or i ts e q ui vale nt.  
P ati e nts are t o be o n sta ble d ose d uri n g Peri o d 2.  I ntr o d ucti o n of a ne w o piate a nal gesic or d ose 
a djust m e nt t o a n e xist i n g o piate a nal gesic is n ot per mitte d, u nless re q uire d f or safety reas o ns or 
as pre me dicat i on f or M RIs. 

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E xte n de d Treat me nt a n d P ost -Treat me nt F oll o w -U p Peri o ds ( Peri o ds 3 a n d 4): 
After c o m plet i on of t he Wee k 1 6 assess me nts, a lteratio ns of N S AI Ds, i ncl u di n g C O X - 2 
i n hi bit ors ( d ose c ha n ge, i ntr o d ucti o n, or wit h dra wal) are all o we d.  D oses are rec o m me n de d t o be 
sta ble i n t he 2 wee ks pri or t o a n art hrit is assess me nt.
S h ort -acti n g a nal gesics wit h n o a nti-i nflam mat or y  a ctio n (s uc h as paraceta m ol ) are per mitte d 
a n d ma y be a d mi nistere d a d h oc as nee de d b ut are t o be wit h hel d wi t hi n t he 2 4-h o ur peri o d pri or 
t o a n y assess me nt.  As piri n ( d ose n ot e xcee di n g 3 5 0 m g/ da y) ma y be ta ke n t o ma na ge 
car dio vasc ular ris k.
Use of varia ble d oses of o pia te a nal gesics is all o we d, b ut n ot t o e xcee d a n a vera ge dail y d ose of 
3 0 m g m or p hi ne or i ts e q ui vale nt.
C o n ve nti o n al D M A R Ds: 
Bli n de d Treat me nt D osi n g Peri o d ( Peri o d 2):
Di sc o nti n uatio n of  e xcl u de d oral or i njecta ble c D M A R Ds bef ore st u d y e nr oll me nt must occ ur at 
least 4 wee ks pri or t o baseli ne.  Met h otre xate ( oral or pare nteral u p t o 2 5 m g/ wee k), 
s ulfasalazi ne ( u p t o 3 g/ da y), or h ydr o x y c hlor o q ui ne ( u p t o 4 0 0 m g/ da y) ma y be all o we d I F at 
sta ble d ose f or at least 4 wee ks prior t o baseli ne ra n d o mizat i on.
D uri n g Peri o d 2, al t er atio n of  c D M A R D d ose or r o ute, a n d/ or i ntr o d ucti o n of a ne w c D M A R D 
are n ot per mitte d, u nless re q uire d f or safet y reas o ns.  C o n ve nti onal D M A R Ds ca n o nl y  be use d 
as si n gle a ge nts a n d n ot i n c o m bi nat i on wi t h ot her c D M A R Ds.  If, at a n y time, t he i n vest i gat or 
belie ves t hat si de effects or la b orat or y  a b n or maliti es ma y be attri b uta ble t o t he c D M A R D, t he 
c D M A R D d ose is t o be l o were d or t he me dicat i on st o p pe d. 
E xte n de d Treat me nt a n d P ost -Treat me nt F o ll ow- U p Peri o ds ( Peri o ds 3 a n d 4): 
D uri n g Peri o ds 3 a n d 4, a dj ust me nt  of allo we d c D M A R Ds (f or e xa m ple, d ose c ha n ge, 
i ntr o d uctio n, wi t hdra wal of c D M A R Ds, or re place me nt of a c urre nt c D M A R D wit h t he 
i ntr o d uctio n of  a ne w c D M A R D) is all o we d after all assess me nts at Wee k 1 6 are c o m plete d.  
N ot m ore t ha n 1 a dj ust me nt  of c D M A R Ds at 1 ti me wit hi n 1 2 wee ks is rec om me n de d.  
C o n ve nti o nal D M A R Ds ca n o nl y  be use d as si n gle a ge nts a n d n ot i n c o m bi nat i on wi t h ot her 
c D M A R Ds.  A n y c ha n ges m ust be rec or de d i n t he e C R F.
F or all st u d y p erio ds, t he m a xi m u m allo we d d oses are 2 5 m g/ wee k M T X, 4 0 0 m g/ da y 
h y dr o x yc hl or o q ui ne a n d 3 g/ da y  s ulfasalazi ne.  L ocal sta n dar ds of care are t o be f oll o we d f or 
c o nc o mita nt a d mi nistrati o n o f f olic or f oli nic aci d if M T X is ta ke n, a n d f or a d mi nistr atio n of  
ot her c D M A R Ds. 
C ortic oster oi ds:
Bli n de d Treat me nt D osi n g Peri o d ( Peri o d 2):

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Or al c ortic oster oi ds :  If o n oral c ortic oster oids, t he d ose m ust n ot e xcee d 1 0 m g/ da y  of 
pre d nis o ne or its e q ui vale nt a n d m ust be sta ble f or at least 4 wee ks pri or t o baseli ne 
ra n d omizat i on.  D uri n g Peri o d 2, treat me nt alterati o ns i n oral c ortic oster oi d d ose are str o n gl y 
di sc o ura ge d.
P are nter al c ortic oster oi ds (I V, i ntr a m usc ul ar, i ntr a- artic ul ar) :  Treat me nt wit h a n y parent eral 
c ortic oster oids is n ot per mitte d wit hi n 6 wee ks pri or t o baseli ne or d uri n g Peri o d 2. 
I n h ale d a n d t o pic al ster oi ds:  Re g ular use of i n hale d or t o pical ster oi ds will be per mitte d d uri n g 
a n y st u d y p erio d.
E xte n de d Treat me nt a n d P ost -Treat me nt F oll o w -U p Peri o ds ( Peri o ds 3 a n d 4): 
Or al c ortic oster oi ds :  As of Wee k 1 6, a dj ust me nts of oral c ortic oster oi ds are all o we d, h o we ver 
t he ma xi m u m d ose is n ot t o e xcee d 1 0 m g/ da y of pre d nis o ne or its e q ui vale nt at a n y ti me d uri n g 
t hese perio ds. 
P are nter al c ortic os ter oi ds (I V, i ntr a m usc ul ar, i ntr a-artic ul ar ):  As of Wee k 1 6, i ntra-artic ular 
i njecti on of c ortic oster oi d ma y be all o we d, as nee de d.  T he j o i nt i njecte d m ust be desi g nate d 
alo n g wi t h t he me dicati on i n t he e C R F.
I n h ale d a n d t o pic al ster oi ds:  Re g ular use of i n hale d or t o pical ster oi ds will be per mitte d d uri n g 
a n y st u d y p erio d.
Ot her C o nc o mit a nt Me dic ati o ns ( Peri o ds 2, 3, a n d 4): 
P ati e nts re q uirin g s ur ger y  at a n y time d uri n g t he st u d y  are t o i nterr u pt a d mi nistratio n of  t he 
i n vesti gati onal pr o d uct be gi n ni n g 8 wee ks pri or t o t he s ur ger y , or as earl y as p ossi ble wit hi n 8 
wee ks of s ur ger y , a n d res u me a d mi nistrati o n of t he i n vesti gati onal pr o d uct o nl y  aft er c o mplete 
w o u n d heali n g.
A d dit i onal dr u gs are t o be a v o i de d duri n g t he st u d y u nless re q uire d t o treat a n A E or f or t he 
treat me nt of a n o n g oi n g me dical pr o ble m.  If t he nee d f or c o nc o mita nt me dicati o n arises, t he 
i n vesti gat or is t o base decisi ons o n t he patie nt a n d o n cli nical fact ors.  A n y a d dit i onal 
me dicat i on, w he t her prescri ptio n or o ver -t he- c o u nter, use d at baseli ne ( Wee k 0, Visit 2) a n d/ or 
d uri n g t he c o urse of t he st u d y , must be d oc u m e nte d wit h t he start a n d st o p dates i n t he e C R F.
A d dit i onal s yste mic dr u gs are t o be a v o i de d d uri n g t he st u d y, u nless re q uire d t o treat a n A E.  
Ot her me dicati o ns ma y be all o we d, if a p pr o ve d b y t he s p o ns or or its desi g nee.
O nl y f or patie nts w h o disc o nt i n ue d st u d y treat me nt a n d ha ve e ntere d t he P ost -Treat me nt 
F o ll ow- U p Peri o d, a x S p A t hera p y  wit h a n ot her a ge nt pre vi o usl y e xcl u de d d uri n g t he treat me nt 
p eri o d of  t he st u d y ma y be allo we d, as deter mi ne d a p pr o priate b y  t he i n vestigat or a n d a p pr o ve d 
b y Lill y  me dical.  
A n y c ha n ges i n me dicat i ons n ot a d dresse d a b o ve are t o be disc usse d wit h t he i n vest i gat or.  
P ati e nts must be i nstr ucte d t o c o ns ul t t he i n vesti gat or or ot her a p pr o priate st u d y pers o n nel at t he 
site bef ore ta ki n g a n y ne w me dicat i ons or s u p pl e me nts.

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C o nti n u e d A c c e s s
I n vesti gati onal pr o d uct will n ot be ma de a vaila ble t o patie nts after c o ncl usi o n of t his st u d y .
7. 7. 2.
S p e ci al Tr e at m e nt C o n si d er ati o n s 
P ati e nts will be scree ne d f or eli gi bilit y i n t he st u d y as descri be d i n Sect i ons 6. 1 a n d 6. 2 a n d will
be i nf or me d of t he st u d y-s pecific restricti ons a n d re q uire me nts of t he st u d y .  Patie nts w h o are n ot 
willi n g t o c o m pl y wit h t he st u d y  restrictio ns a n d re q ui re me nts of t he st u d y will n ot be eli gi ble 
f or e nr oll me nt.
All bi o l ogical a ge nts carr y  t he ris k of s yste mic aller gic/ h y perse nsiti vity reactio ns ( See Sectio n 
9. 2. 2. 1 ).
S o m et i mes t hese reacti ons ca n be life t hreate ni n g.  Pr otei ns ma y als o c a use re d ness, itc hi n g, 
s welli n g, or pai n l ocall y at t he i nject i on site; t heref ore, all pat ient s s h o uld be cl osel y m o nit ore d 
f or sig ns or s y m pt o ms t hat c o ul d res ult fr o m s uc h reacti o ns, e d ucate d o n t he si g ns or s y m pt o ms 
of  t hese t yp es of  reacti ons, a n d i nstr ucte d t o c o ntact t he st u d y site i m me diatel y if a n y of t hes e
s y m pt o ms are e x perie nce d f oll owi n g a n i nject i on.  If a patie nt e x perie nces a n ac ute 
aller gic/ h y perse nsit i vity react i on after a n i nject i on of i n vesti gati o nal pr o d uct, he or s he is t o be 
ma na ge d a p pr o pri atel y a n d gi ve n i nstr ucti o n t o recei ve rele va nt s u p p orti ve care.  A d dit i onall y, 
f or a n e ve nt ju d ge d b y  t he i n vesti gat or t o be a p ote ntial s yste mic aller gic/ h y perse nsiti vity 
reactio n, a bl o o d s a m ple is t o be dra w n t o test f or a nt i-dr u g a nt i b o d y (A D A ) as s o o n as p ossi ble 
(see Secti o n 9. 4. 4 ).  
F or pati e nts w h o e x perie nce a p ote ntial aller gic/ h y perse nsit i vity react i on, c o nsi derati o n f or a n y  
pr e m e dicat i on f or fut ure i nject i ons will be a gree d u p o n bet wee n t he i n vesti gat or a n d s p o ns or.  
E xa m ples of p ote ntial aller gic/ h y perse nsit i vity reacti o ns t hat mi g ht merit pre me dicati o n i ncl u de 
mil d -t o-m o derate s ki n ras hes, mil d -t o-m o derate ge neralize d pr urit us a n d/ or urticaria, a n d 
mil d -t o-m o derate i nject i on site react io ns (f or e xa m ple, i nject i on site er y t he ma, i njectio n si t e 
pr uri t us, a n d s o o n).  Patie nts w h o de vel o p cli nicall y si g nifica nt s yste mic aller gic/
h y perse nsit i vity react i ons f oll owi n g a d mi nistrati o n of i n vest i gati onal pr o d uct t hat d o n ot res p o n d 
t o s y m pt o matic me dicat i on or res ul t i n cli nical se q uelae (f or e xa m ple, h os pitalizati on) are t o be 
di sc o nti n ue d fr om st u d y treat me nt a n d n ot recei ve f urt her d oses of i n vest i gati onal pr o d uct, wit h 
or wi t ho ut pre m e dicatio n (see Sect i on 8. 1 ).  Me dicati o ns c o nsi dere d a p pr o priate f or 
pr e m e dicat i on i ncl u de, b ut are n ot restricte d t o, aceta mi n o p he n/ paraceta m o l u p t o 1 0 0 0 m g a n d 
a nt i hista mi nes (f or e xa m ple, oral di p he n h y dra mi ne 5 0 mg) gi ve n after all efficac y assess me nts 
ha ve bee n c o m p lete d f or a gi ve n visit, a n d 3 0 t o 6 0 mi n utes pri or t o i n vesti gati onal pr o d uct S C 
i njecti ons f or visits w here i njecti o ns are a d mi nistere d at t he cli nic.  F or all ot her i njecti ons, 
pati e nts ma y self -pre me dicate at h o m e prior t o a d mi nistrati o n of  in vest i gati onal pr o d uct, as 
di recte d b y t he i n vesti gat or.  All s uc h pre me dicati o ns will be rec or de d as c o nc o mita nt 
me dicat i ons .  C ortic oster oids are n ot per mitte d as a ge nts f or pre me dicat i on.

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8.
Di s c o nti n u ati o n Crit eri a
8. 1.
Di s c o nti n u ati o n fr o m St u d y Tr e at m e nt
T he reas o n f or a n d date of disc o nt i n uati on fr o m st u d y treat me nt (i n vesti gati onal pr o d uct) a n d 
reas o n f or a n d date of disc o nti n uati on fr o m st u d y partici pati on will be c ollecte d f or all 
ra n d omize d patie nts. 
8. 1. 1.
P er m a n e nt Di s c o nti n u ati o n fr o m St u d y Tr e at m e nt
F or a n y pat ient  per ma ne nt l y disc o nti n ui n g fr o m st u d y treat me nt , t he i n vesti gati onal pr o d uct will 
be wit h hel d, a n d t he patie nt will c o m p lete t he E T V a n d t he P os t-treat me nt F oll o w -u p Peri o d 
( Perio d 4), as s h o w n i n t he Sc he d ule of Acti vit ies (Secti o n 2 ).
T he f o ll owi n g criteria must be f o ll owe d f or disc o nti n uat i on fr o m st u d y treat me nt.

S u bje ct Decisi o n
o
t he patie nt or t he pati e nt’s desi g nee, f or  e xa m ple, pare nts or le gal g uar dia n  
re q uests t o disc o nti n ue i n vesti gatio n al pr o d uct.

Disc o nti n u ati o n d ue t o a  he p atic e ve nt  o r li ver test a b n or m alit y.   Patie nts  
w h o are disc o nti n u e d fr o m i n vesti gatio nal pr o d uct d ue t o a he patic e ve nt or  
li ver test a b n or malit y s h oul d  h a ve a d ditio nal h e patic safety data c ollecte d v ia 
el e ctr o ni c d ata e n try .
Di sc on ti n uatio n of  t he i n vesti gatio nal pr o d uct f or a b n or mal li ver tests s h oul d  
be  c o nsi dere d b y  t he i n vesti gat or w he n a patie nt meets on e of t he f oll owi n g  
c on di tio n s, after c o ns ultatio n  wit h t he Lill y desi g nate d me dical m onit or:

al a ni ne a mi n otra nsferase ( AL T ) or as partate a mi n otra nsferase (A S T )
> 8 X u p per li mit of n or mal ( U L N )

A L T or A S T > 5 X U L N f or m ore t ha n 2  wee ks

A L T or A S T > 3 X U L N a n d t otal bilir u b i n ( T B L) le vel > 2 x U L N or 
i nter n atio nal n or m alize d ratio (I N R)  > 1. 5

A L T or A S T > 3 X U L N wit h t he a p peara nce of  fati g ue, na usea, 
v o mi ti n g, ri g ht u p per- qu a dra nt pai n or te n der ness, fe ver, ras h, a n d/ or  
e osi n o p hilia ( > 5 %)

al kali ne p h os p hatase ( A L P) > 3 X  U L N

A L P > 2. 5 X U L N a n d T B L > 2 X U L N

A L P  > 2 . 5X U L N wit h t he a p pear a nce o f fati g ue, na usea, v omi ti n g, 
rig ht u p per q ua dr a nt pai n or te n der ness, fe v er, ras h, a n d / or 
e osi n o p hilia ( > 5 %)

Ot her la b orat or y  t ests 

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 5 0
L Y 2 4 3 9 8 2 1

Ne utr o p hil (se g me nte d) c o u nts (see safet y m o nit ori n g f or ne utr o pe ni a
i n Secti o n 9. 4. 1 0. 2 ):
o
< 5 0 0 cells/ L ( < 0. 5 0 x 1 0 3 / µ L or < 0. 5 0 GI/ L)
o
≥5 0 0 a n d < 1 0 0 0 cells/ L ( ≥0. 5 0 x 1 0 3 /µ L a n d < 1. 0 0 x 1 0 3 /µ L or
≥0. 5 0 GI/ L a n d < 1. 0 0 GI/ L) ( base d o n 2 test res ults; t he sec o n d
test perf or me d wit hi n 1 wee k fr om k n o wl e d ge of t he i nitial
res ult)
o
≥1 0 0 0 a n d < 1 5 0 0 cells/ L ( ≥1. 0 0 x 1 0 3 /µ L a n d < 1. 5 0 x 1 0 3 /µ L
or ≥1. 0 0 GI/ L a n d < 1. 5 0 GI/ L) ( base d o n 3 test res ults as
s pecifie d i n Secti o n 9. 4. 1 0. 2. 1 )
- A N D - a c o nc urre nt i nfect i on

T ot al  W B C c o u nt < 2 0 0 0 cells/L ( < 2. 0 0 x 1 0 3 / µ L or < 2. 0 0 GI/ L)

L y m p h oc y te c o u nt < 5 0 0 cells/ μ L ( < 0. 5 0 x 1 03 / µ L or < 0. 5 0 GI/ L)

Pl at elet c o u nt < 5 0, 0 0 0 cells/ μ L ( < 5 0 x 1 03 / µ L or < 5 0 GI/ L)

T he patie nt e x perie nces a se vere A E, a n S A E, or a cli nicall y si g nifica nt
c ha n ge i n a la b orat or y val ue t hat, i n t he o pi ni o n of t he i n vest i gat or, merits t he
di sc o nti n uati on of t he i n vest i gat i onal pr o d uct a n d a p pr o priate meas ures bei n g
ta ke n.  I n t his case, Lill y or its desi g nee is t o be n otifie d i m me diatel y.  Refer
t o Secti o n 9. 1. 4 .

T he i n vest i gat or, after c o ns ultati on wi t h t he s p o ns or-desi g nate d me dical
m o nit or, deter mi nes t hat a cli nical si g nifica nt h y perse nsi tivit y react i on has
occ urre d.  A cli nicall y si g nifica nt s yste mic h y perse nsit i vity react i on is o ne
t hat occ urs after a d mi nistr atio n of  t he i n vesti gati on al  int er ve nt i on (f or
e xa m ple, dr u g- relate d s y m pt o matic br o nc h os pas m, aller g y -relate d
e de ma/ a n gioe de ma, or h y perte nsi o n) a n d re q ui res pare nteral me dicatio n, d oes
n ot res p o n d t o s y m pt o mat ic me dicati o n, res ults i n cli nical se q uelae, or i n a n
a na p h ylactic reacti o n.

T he patie nt bec o me s pre g na nt.

T he patie nt de vel o ps a mali g na nc y.
N ote :  Patie nts ma y be allo we d t o c o nti n ue if t he y de vel o p n o m ore t ha n
2 n o n mela n o ma s ki n ca ncers d uri n g t he st u d y.

E nr oll me nt i n a n y ot her cli nical tria l i n v ol vi n g a n i n vesti gati o nal pr o d uct or
e nr o ll me nt i n a n y ot her t y pe of me d ical researc h j u d ge d n ot t o be
scie ntificall y or me dicall y c om pati ble wit h t his st u d y .

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 5 1
L Y 2 4 3 9 8 2 1

T he patie nt, at a n y  ti me d uri n g t he st u d y, sc ores a 3 f or Ite m 1 2 ( T h o u g hts of 
Deat h or S uic i de) o n t he QI D S-S R 1 6
-O R -
de vel o ps acti ve s uici dal i deat i on wi t h s o me i nte nt t o act wit h or wit h o ut a 
s pecific pla n ( yes t o q uestio n 4 or 5 o n t he “S uici dal  I deatio n” p orti o n of  t he 
C ol u m bia – S uici de Se veri t y Rati n g Scale [ C-S S R S])
-O R -
de vel o ps s uic i de-r elate d be ha vi ors as rec or de d o n t he C -S S R S .  
It is rec o m me n de d t hat t he s u bject be assesse d b y a ps yc hiatrist or 
a p pr o priatel y trai ne d pr ofessi onal t o assist i n deci di n g w het her t he s u bject is 
t o be disc o nti n ue d fr o m t he st u d y .  

T he i n vest i gat or or atte n di n g p h ysicia n deci des t hat t he patie nt is t o be 
wi t hdra w n fr o m  st u d y tr e at me nt.

Lill y or i ts desig nee st o ps t he pati e nt’s partici pat i on i n t he st u d y or Lill y st o ps 
t he st u d y for m e dical, safety,  re g ulat or y, or ot her reas o ns c o nsiste nt wit h 
a p plica ble la ws, re g ulat i ons, a n d g o o d cli nical practice ( G C P). 

T he patie nt bec o me s H B V D N A p ositi ve, at w hic h ti me the patie nt i s t o be 
referre d t o a s pecialist p h ysicia n. Disc ussi o n of t he ti mi n g of disc o nt i n uati on 
fr om t he st u d y a n d fr om st u d y treat me nt is pr o vi de d i n Sect i on 9. 4. 1 0. 2. 2 .
P ati e nts disc o nti n ui n g fr om t he i n vest i gati onal pr o d uct pre mat urel y f or a n y  r ea s o n s h o ul d 
c o mplete a d verse e ve nt a n d ot her f o ll ow- u p pr oce d ures per Secti o n 2 ( Sc he d ule of 
Act i vities), Sectio n 9. 2 ( A d verse E ve nts), a n d Secti on 9. 4 ( Safety)  of t his pr ot oc ol.
8. 1. 2.
Di s c o nti n u ati o n of I n a d v ert e ntl y E nr oll e d P ati e nt s
If t he s p o ns or or i n vesti gat or i de ntif y a patient  w h o di d n ot meet e nr oll me nt criteria a n d was 
i na d verte ntl y e nr olle d, t he n t he patie nt s h o ul d be disc o nti n ue d fr o m st u d y treat me nt u nless t here 
are e xte n uat i n g circ u msta nces t hat ma ke it me dicall y necessar y f or t he patie nt t o c o nti n ue o n 
st u d y tr e at me nt.  If t he i n vest i gat or a n d t he s p o ns or C R P a gree it is me dicall y a p pr o pr iate t o 
c o nti n ue, t he i n vest i gat or m ust o btai n d oc u me nte d a p pr o val fr om t he s p o ns or C R P t o all o w t he 
i na d verte ntl y e nr olle d patient  t o c o ntin ue i n t he st u d y  wit h or wit ho ut treat m e nt wit h 
i n vesti gati onal pr o d uct.   Safet y f oll ow u p i s as o utli ne d i n Secti on 2 ( Sc he d ule of Acti vities), 
Secti o n 9. 2 ( A d verse E ve nts), a n d Secti o n 9. 4 ( Safet y) of t he pr ot oc o l.
8. 2.
D i s c o nti n u ati o n fr o m t h e St u d y
P ati e nts will be disc o nt i n ue d i n t he f oll owi n g ci rc u msta nces: 

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
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L Y 2 4 3 9 8 2 1

enr o ll me nt i n a n y ot her cli nical st u d y i n v ol vi n g a n i n vesti gati onal pr o d uct or e nr oll me nt 
i n a n y ot her t ype of me dical researc h j u d ge d n ot t o be scie nt ificall y or me dicall y 
c o mpat i ble wit h t his st u d y

p artici pat i on i n t he st u d y nee ds t o be st o p pe d f or me dical, safety,  re g ulat or y, or ot her 
reas ons c o nsiste nt wit h a p plica ble la ws, re g ulati o ns, a n d g o o d cli nical pract ice (G C P )

i n vesti gat or decisi o n
o
T he i n vest i gat or deci des t hat t he patie nt s h o ul d be disc o nti n ue d fr om t he st u d y
o
If t he patie nt, f or a n y reas o n, re q uires treat me nt wit h a n ot her t hera pe u tic a ge nt 
t hat has bee n de m o nstrate d t o be effect i ve f or treat me nt of t he st u d y in dicat i on, 
di sc o nti n uati on fr om t he st u d y occ urs prior t o i ntr o d ucti o n of  t he ne w a ge nt

pati e nt d ecisio n
o
the patie nt or t he pati e nt’s desi g nee, f or e xa m ple, pare nts or le gal g uar dia n 
re q uests t o be wit h dra w n fr om t he st u d y
P ati e nts di sc o nti n ui n g fr om t he st u d y pr e m at urel y f or a n y reas o n s h o uld c o m plete a d verse e ve nt 
a n d ot her safet y f oll ow- u p per Secti o n 2 (Sc he d ule of Act i vities), Secti o n 9. 2 ( A d verse E ve nts), 
a n d Sect i on 9. 4 ( Safet y) of t his pr ot oc ol.
8. 3.
L o st t o F oll o w -U p
A pat ient  will be c o nsi dere d l ost t o f o ll ow- u p i f he or s he re peate dl y fails t o ret ur n f or sc he d ule d 
visit s a n d is u na ble t o be c o ntacte d b y t he st u d y sit e.  Site pers o n nel are e x pecte d t o ma ke 
dili ge nt atte m pts t o c o ntact patie nts w h o fail t o ret ur n f or a sc he d ule d visit or were ot her wise 
u na ble t o be f oll owe d u p b y  t he sit e.

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
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L Y 2 4 3 9 8 2 1
9.
St u d y  As s e s s m e nt s a n d Pr o c e d ur e s
Secti o n 2 lists t he Sc he d ule of Acti vities, wit h t he st u d y pr oce d ures a n d t heir ti mi n g (i ncl u di n g 
t olera nce li mit s for ti mi n g).
A p pe n di x 2 lists t he lab orat or y tests t hat will be perf or m e d for t his st u d y .
A p pe n di x 4 lists He patic M o nit ori ng Tests f or Treat me nt -E m er ge nt A b n or malit y d uri n g t he
st u d y.
U nless ot her wise state d i n t he s u bsect i ons bel o w, all sa m ples c ollecte d f or s pecifie d la b orat or y 
tests will be destr o ye d wit hi n 6 0 da ys of recei pt of c o nfir me d test res ults.  Certai n sa m ples ma y 
be retai ne d f or a l o n ger peri o d, if necessar y, t o c o m pl y wit h a p plica ble la ws, re g ulat i ons, or 
la b orat or y certificatio n sta n dar ds.
9. 1.
Effi c a c y A s s e s s m e nt s
Bel o w are bri ef d es cri ptio ns o f k e y  as pects of t he scales use d i n t he st u d y.  C o m plete 
assess me nts are incl u de d i n site trai ni n g materials.
T he f o ll owi n g A S A S d o mai ns are use d t o deter mi ne A S A S 2 0, A S A S 4 0, A S A S partial 
re missi o n, a n d A S A S 5/ 6 ( Sie per et al. 2 0 0 9, A S A S Ha n d b o o k): 
1)
P ati e nt Glo b al  ( S e ctio n 9. 1. 2. 2 )
2)
S pi nal Pai n ( Secti o n 9. 1. 2. 3 )
3)
F u nct i on ( Secti o n 9. 1. 2. 5 ) 
4)
I nfla m mati on ( m e a n of B A S D AI q uesti o ns 5 a n d 6) ( Secti on 9. 1. 2. 4 ) 
5)
C R P ( Secti o n 9. 1. 2. 1 2. 1 ) a n d 
6)
S pi nal m o bilit y (lat er al s pi nal fle xio n ) ( Sectio n 9. 1. 2. 6 ).
9. 1. 1.
Pri m ar y Effi c a c y A s s e s s m e nt s
9. 1. 1. 1.
A S A S 4 0 (i n b D M A R D-n aï v e p ati e nt s )
T he A S A S 4 0 ( A n ders o n et al . 2 0 0 1; Bra n dt et al. 2 0 0 4; Si e per et al. 2 0 0 9) is deri ve d fr om 
pati e nt -re p orte d assess me nts.  A n A S A S 4 0 res p o nse is defi ne d as a ≥4 0 % i m pr o ve me nt a n d a n 
a bs o l ute i m pr o ve me nt fr o m baseli ne o f ≥2 u ni ts (ra n ge 0 t o 1 0) i n ≥3 of  4 d o m ai ns ( Patie nt 
Gl o bal, S pi nal Pai n, F u nct i on, a n d I nfla m mat i on) wi t ho ut a n y  w orse ni n g i n t he re mai ni n g 
d o m ai n.
9. 1. 2.
S e c o n d ar y Effi c a c y A s s e s s m e nt s
9. 1. 2. 1.
A S A S 4 0, A S A S 2 0, A S A S I n di vi d u al C o m p o n e nt s, A S A S P arti al 
R e mi s si o n, a n d A S A S 5/ 6 
T he A S A S 4 0, A S A S 2 0, A S A S i n di vi d ual c o m p o ne nts, A S A S partial re missi o n , a n d A S A S 5/ 6 
res p o nses ( Da vis et al. 2 0 0 3; Sie per et al. 2 0 0 9) are sec o n dar y efficac y assess me nts t hat are 
calc ulate d as i m pr o ve me nts i n res pect i ve res p o nse rates i n m ulti ple disease do m ai ns.
C o m plete defi nit i ons of eac h assess me nt are pr o vi de d bel o w.  

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9. 1. 2. 1. 1.
A S A S 4 0 ( i n o v er all st u d y p o p ul ati o n)
T he A S A S 4 0 ( A n ders o n et al. 2 0 0 1; Bra n dt et al. 2 0 0 4 ; Si e per et al. 2 0 0 9) is deri ve d fr om 
pati e nt -re p orte d assess me nts.  A n A S A S 4 0 res p o nse is defi ned as a ≥4 0 % i m pr o ve me nt a n d a n 
a bs o l ute i m pr o ve me nt fr o m baseli ne o f ≥2 u ni ts (ra n ge 0 t o 1 0) i n ≥3 of  4 d o m ai ns ( Patie nt 
Gl o bal, S pi nal Pai n, F u nct i on, a n d I nfla m mat i on) wi t ho ut a n y  w orse ni n g i n t he re mai ni n g 
d o m ai n.
9. 1. 2. 1. 2.
A S A S 2 0
T he A S A S 2 0 is deri ve d fr om patie nt -re p orte d assess me nts.  A n A S A S 2 0 res p o nse is defi ne d as a 
≥2 0 % i m pr o ve me nt a n d a n a bs o l ute i m pr o ve me nt fr o m baseli ne o f ≥1 u ni ts (ra n ge 0 t o 1 0) i n 
≥3 of  4 d o m ai ns ( Patie nt Gl ob al , S pi nal Pai n, F u nctio n, a n d I nfla m mat i on) , a n d n o w orse ni n g of 
≥2 0 % a n d ≥1 u nit (ra n ge 0 t o 1 0) i n t he re mai ni n g d o mai n .
9. 1. 2. 1. 3.
A S A S P arti al R e mi s si o n
T he A S A S partial re missi o n i s deri ve d fr om pat ient- re p orte d assess me nts.  A n A S A S parti al 
re missi o n res p o nse is defi ne d as a val ue n ot a b o ve 2 u nits (ra n ge 0 t o 1 0, N R S) i n eac h of t he 
f oll owi n g 4 d o m ai ns : P ati e nt Glo bal, S pi nal Pai n, F u nct i on, a n d I nfla m mat i on . 
9. 1. 2. 1. 4.
A S A S 5/ 6
T he A S A S 5/ 6 i ncl u des assess me nt of all 6 i n di vi d ual A S A S d o mai ns liste d i n Sect i on 9. 1 a n d 
re prese nts i m pr o ve me nt of ≥2 0 % i n at l east 5 d o mai ns .
9. 1. 2. 2.
P ati e nt Gl o b al ( A s s e s s m e nt of Di s e a s e A cti vit y)
Fr o m  t he A S A S Ha n d b o o k ( Sie per et al. 2 0 0 9 ), t he patie nt is as ke d t o res p o n d t o t he f o ll owi n g 
q uesti o n:   “ H o w acti ve was yo ur s p o n d ylit is o n a vera ge d uri n g t he last wee k?”  T he a ns wer is 
rec or de d o n a n N R S a n d is rate d bet wee n “ 0” ( n ot acti ve) a n d “ 1 0” ( ver y acti ve).
9. 1. 2. 3.
S pi n al P ai n
Fr o m  t he A S A S Ha n d b o o k ( Sie per et al. 2 0 0 9), t he patie nt is as ke d t o res p o n d t o t he f o ll owi n g 
2 q uesti o ns ( o n a vera ge d uri n g t he last wee k):
1.
“ H o w muc h pai n o f y o ur s pi ne d ue t o a n k yl o si n g s p o n d ylitis d o y o u ha ve?”
2.
“ H o w muc h pai n o f y o ur s pi ne d ue t o a n k yl o si n g s p o n d ylitis d o y o u ha ve at ni g ht?”
T he a ns wers are rec or de d o n a n N R S a n d are eac h rate d bet wee n “ 0” ( n o pai n) a n d “ 1 0” ( m ost 
se vere pain).  T he first q uesti o n is use d t o deri ve res p o nses (t hat is, A S A S 4 0, A S A S 2 0, a n d s o 
o n).
9. 1. 2. 4.
B at h A n k yl o si n g S p o n d yliti s Di s e a s e A cti vit y I n d e x
T he B A S D AI is a patie nt -re p orte d assess me nt c o nsisti n g of 6 q uestio ns t hat rel ate t o 5 major 
s y m pt o ms rele va nt t o r-a x S p A ( Garrett et al. 1 9 9 4; Sie per et al. 2 0 0 9):  1) Fatig ue, 2) S pi nal  p ai n, 
3) Peri p heral  art hritis, 4) E nt hesitis, 5) I nte nsity, a n d 6) D urati o n of m or ni n g st iff ness.  Patie nts 
nee d t o sc ore eac h ite m wit h a sc ore fr o m 0 t o 1 0 ( N R S).
B A S D AI 5 0 re prese nts a n i m pr o ve me nt of ≥5 0 % of t he B A S D AI sc ore fr o m baseli ne 

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 5 5
L Y 2 4 3 9 8 2 1
9. 1. 2. 5.
B at h A n k yl o si n g S p o n d yliti s F u n cti o n al I n d e x
T he B A S FI is a patie nt -re p orte d assess me nt t hat esta blis hes a patie nt’s f u ncti o nal baseli ne a n d 
s u bse q ue nt res p o nse t o treat me nt ( Cali n et al. 1 9 9 5).  T o c o m plete t he B A S FI, a patie nt is as ke d 
t o rate t he diffic ulty ass o ciat e d wit h 1 0 i n di vi d ual basic f u ncti onal act i vities.  Patie nts res p o n d t o 
eac h q uestio n usi n g a n N R S scale (ra n ge 0 t o 1 0) wi t h a hi g her sc ore i n dicati n g w orse f u ncti on.
T he patie nt’s fi nal B A S FI sc ore is t he mea n of t he 1 0 ite m sc ores c o m plete d o n a n N R S. 
9. 1. 2. 6.
B at h A n k yl o si n g S p o n d yliti s M etr ol o g y I n d e x — S pi n al M o bilit y 
T he B A S MI is a c om bi ne d i n de x c o m pr isi n g t he f oll o wi n g 5 cli nical meas ure me nts of s pi nal 
m o bilit y i n patient s wit h r- a x S p A (Je n ki ns o n et al. 1 9 9 4):

Lateral  spi nal  fle xio n

Tra g us -t o-wall dista nce

L u m bar fle xi on ( m o difie d Sc hr o ber)

Ma xi mal i nter malle o lar dista nce

Cer vical r otati o n .
T he B A S MI i ncl u des t hese 5 m eas ure me nts t hat are eac h scale d t o a sc ore of 0 t o 1 0 de pe n di n g 
o n t he res ult of t he assess me nt ( B A S MI li near f u ncti o n) .  T he a vera ge sc ore of t he 5 assess me nts 
gi ves t he B A S MI li near res ult ( va n der Heij de et al. 2 0 0 8; Sie per et al. 2 0 0 9 ). 
T he B A S MI m ust be assesse d b y a r he u mat ol o gist or healt h care pr o vi der w h o meets t he 
q ualificat i ons f or st u d y assess me nt.
9. 1. 2. 7.
C h e st E x p a n si o n 
W hile pat ient s ha ve t heir ha n ds resti n g o n or be hi n d t he hea d, t he assess or will meas ure t he
c hest ’s e ncircle d le n gt h b y ce nti meter at t he f o urt h i nterc ostal le vel a nteri orl y. T he differe nce
bet wee n m a xi mal ins pi r atio n a n d e x pirati on i n ce nti meters will be rec or de d. T w o tri es will be
rec or de d. T he better meas ure me nt (lar ger differe nce) of 2 tries (i n ce nt i meters) will be use d f or
a nal yses.
T he m eas ure me nt of c hest e x pa nsi o n m ust be assesse d b y a r he u mat ol o gist or healt h care
pr o vi der w h o meets t he q ualificat i ons f or st u d y assess me nt.
9. 1. 2. 8.
O c ci p ut t o W all Di st a n c e 
T he patie nt is t o ma ke a ma xi m u m eff ort t o t o uc h t he hea d a gai nst t he wall w he n sta n di n g wit h 
heels a n d bac k a gai nst t he wall.  Ti p o f n ose a n d tra g us m ust be at t he sa me h oriz o ntal li ne t o 
a v o i d nec k e xte nsi o n.  T he n t he dista nce fr o m occi p ut t o t he wall is meas ure d.  T w o tries will be 
rec or de d.  T he better (s maller) meas ure me nt of 2 tries (i n ce nti meters) will be use d f or a nal yses.  
T he m eas ure me nt of occip ut t o wall dista nce m ust be assesse d b y  a r he u mat olo gist or healt h care 
pr o vi der w h o meets t he q ualificat i ons f or st u d y assess me nt.  
9. 1. 2. 9.
A n k yl o si n g S p o n d yliti s Di s e a s e A cti vit y S c or e
T he A S D A S is a c o m p osite i n de x t o assess disease acti vit y i n A S ( Mac ha d o et al . 2 0 1 1a, 2 0 1 1 b; 
Z oc hli n g 2 0 1 1 ; Mac ha d o et al. 2 0 1 8).  T he para meters use d f or t he A S D A S ( wit h C R P as ac ute 
p hase reacta nt) are t he f o ll owi n g :

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1)
T ot al  bac k pai n ( B A S D AI q uesti on 2)
2)
P ati e nt glo bal ( Sectio n 9. 1. 2. 2 )
3)
P eri p heral  pai n/s welli n g ( B A S D AI q uesti o n 3)
4)
D urati o n of  mor ni n g stiff ness ( B A S D AI q uest i on 6)
5)
C R P i n m g/ L
T he A S D A S cr p is calc ulate d wit h t he f oll owi n g e q uati o n:   0. 1 2 1 6 × t otal bac k pai n + 0. 1 1 0 6 × 
pati e nt glo b al  + 0. 0 7 3 6 × perip heral  pai n/s welli n g + 0. 0 5 8 6 × d urati o n of m or ni n g stiff ness + 
0. 5 7 9 6 × L n( C R P + 1) ( Mac ha d o et al. 2 0 1 5).   ( N ote:  C R P is i n m g/liter, t he ra n ge of ot her 
varia bles is fr o m 0 t o 1 0; L n re prese nts t he nat ural l o garit h m. )
F o ur di sease acti vity states ha ve bee n defi ne d b y AS A S c o nse ns us ( Mac ha d o et al. 2 0 1 8 ):

A S D A S < 1. 3 defi nes i nacti ve disease

1. 3 ≤ A S D A S < 2. 1 defi n es l ow di sease act i vity

2. 1 ≤ A S D A S ≤3. 5 defi nes hi g h disease act i vity

A S D A S > 3. 5 defi nes ver y  hi g h disease acti vity.  
Cli nicall y i m p orta nt i m pr o ve me nt is defi ne d as ≥1. 1 u ni ts decrease fr o m baseli ne , a n d maj or 
i m pr o ve me nt is defi ne d as ≥2. 0 u nits decrease fr o m baseli ne or ac hie ve me nt of t he l owest 
p ossi ble sc ore ( Mac ha d o et al. 2 0 1 1 b; De o d har et al. 2 0 1 9a).
9. 1. 2. 1 0. M a a stri c ht A n k yl o si n g S p o n d yliti s E nt h e siti s S c or e
T he M A S E S is a n i n de x use d t o meas ure t he se verit y of  e nt hesitis ( He uft-D ore n b osc h et al. 
2 0 0 3).  T he M A S E S assesses 1 3 sites f or e nt hesit is usi n g a sc ore of “ 0” f or n o acti vity or “ 1” f or 
acti vit y.   Sites assesse d i ncl u de c ost oc h o n dral 1 (ri g ht/left), c ost oc h o n dral 7 (ri g ht/left), s pi nal 
iliaca a nteri or s u peri or (ri g ht/left), crista iliaca (rig ht/l eft), s pi na iliaca p osteri or (ri g ht/left), 
pr ocess us s pi n os us L 5, a n d Ac hilles te n d o n pr o xi mal i nserti o n (ri g ht/left).  T he M A S E S is t he 
s u m of all site sc ores (ra n ge 0 t o 1 3); hi g her sc ores i n dicate m ore se vere e nt hesit is.
T he M A S E S m u st be assesse d b y a r he u mat ol o gist or healt h care pr o vi de r w h o meets t he 
q ualificat i ons f or st u d y assess me nts.
9. 1. 2. 1 1. N o n st er oi d al A nti -I nfl a m m at or y Dr u g I nt a k e 
I nf or mat i on re gar di n g N S AI D i nta ke will be c ollecte d i n t he e C R F; t he A S A S -N S AI D sc ore will 
be calc ulate d at baseli ne a n d t hr o u g h Wee k 5 2 ( D o u ga d os et al. 2 0 1 1).
9. 1. 2. 1 2. L a b or at or y T e st s U s e d f or Effi c a c y M e a s ur e s a n d Di s e a s e D i a g n o si s
9. 1. 2. 1 2. 1. Hi g h S e n siti vit y C -R e a cti v e Pr ot ei n
Hi g h se nsi tivit y C R P will be t he meas ure of ac ute p hase reacta nt .  It will be meas ure d wit h a 
hi g h se nsit i vity assa y at t he ce ntral la b orat or y t o help assess t he effect of i xe kiz u ma b o n disease 
acti vit y .  T he re s ults will n ot be s hare d wit h t he i n vestigati ve si tes after baseli ne ra n d o mizati on 
t o mai ntai n t he st u d y bli n d.  

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9. 1. 2. 1 3. I m a gi n g U s e d f or Effi c a c y M e a s ur e s a n d Di s e a s e Di a g n o si s
9. 1. 2. 1 3. 1. I m a gi n g of S a cr oili a c J oi nt s a n d S pi ne
F or eac h patie nt, X- r a y a n d M RI i ma ges will be c ollecte d acc or di n g t o t he Sc he d ule of Acti vities 
(Secti o n 2 ) a n d Ta ble R H C H . 3, a n d will f oll ow t he st u d y -s pecific rec o m me n dati ons i ncl u de d i n 
sit e trai ni n g materials f or t his st u d y.  T he SIJ X- ra y will be use d t o c o nfir m pat ient s ha ve 
r a dio gra p hic sacr oiliit is as defi ne d b y t he m N Y criteria.  T he s pi nal M RI, c ollecte d at scree ni n g ,
Wee k 1 6 a n d Wee k 5 2 , will ge nerate o bjecti ve data o n t he a nti-i nfla m mat or y effect of t he 
i n vesti gati onal dr u g.  
T he site will se n d t he i ma ges (X- ra y a nt erior p osteri or [ A P] Pel vis SIJ a n d M RI) t o t he ce ntral 
rea der.  Ima ges f o r eli gi bility a n d/ or f or assess me nt of treat me nt effect. 
T a bl e R H C H . 3.
I m a gi n g R e q uir e m e nt s f or S a cr oili a c J oi nt s a n d S pi n e
Ti me P oi nt a
T y pe of Im a ge b
P ur p ose
Re a di n g
Re q uire me nts
Scree ni n g
X- ra y A P Pel vis ( SIJ)
Eli gi bilit y t o 
deter mi ne r-a x S p A
( per m N Y criteria)
Ce ntrall y rea dc
Se n d t o ce ntral 
rea der; res ults m ust 
be recei ve d fr o m 
ce ntral rea der pri or 
t o e nr oll me nt
Scree ni n g
X- ra y of t he s pi ne 
(cer vical a n d l u m bar)
Eli gi bilit y t o 
deter mi ne t otal 
a n k yl oses
L ocall y rea d ( b y 
i n vesti gat or)d
N ot a p plica ble
Scree ni n g ,
Wee k 1 6 , 5 2 
a n d E T V
M RI of t he s pi ne pl us SIJ
Assess efficac y
Ce ntrall y rea d
Se n d t o ce ntral 
rea der
A b bre viati o ns:  A P = a nteri or p osteri or; E T V = earl y ter mi nati o n visit; m N Y = m o difie d Ne w Y or k; M RI = 
ma g netic res o na nce i ma gi n g; r-a x S p A = ra di o gra p hic a xial s p o n d yl oart hritis; SI J = sacr oiliac j oi nts.
a
Scree ni n g pr oce d ures m ust be c o n d ucte d wit hi n ti mefra mes s pecifie d i n t he Sc he d ule of Acti vities
(Secti o n 2 ).
b
I ma gi n g t o be re vie we d a n d a p pr o ve d f or q ualit y; i ma gi n g t hat d oes n ot pass t he q ualit y assess me nt m ust be 
re peate d pri or t o ra n d o mizati o n.
c
Patie nt ca n n ot be e nr olle d u ntil ce ntrall y rea d res ults are recei ve d b y site.
d
Patie nt ca n be e nr olle d b y i n vesti gat or f or t his i ncl usi o n/e xcl usi o n criteri o n of a n k yl osis.
9. 1. 2. 1 3. 2. S p o n d yl o art hriti s R e s e ar c h C o n s orti u m of C a n a d a – M RI S c or e f or S pi n e
All 2 3 disc o -verte bral u nits ( D V Us) of t he s pi ne (fr o m C 2 t o S 1) are sc ore d f or b o ne marr o w 
e de ma.  A si n gle D V U has a sc ori n g ra n ge of 0 t o 1 8, bri n gi n g t he ma xi m u m t otal sc ore t o 4 1 4, 
wi t h hi g her sc ores reflecti n g w orse disease (Ma ks y m o w yc h et al . 2 0 0 5a).  Sc ori n g will be 
perf or m e d b y c e ntr al rea ders.  
9. 1. 2. 1 3. 3. S p o n d yl o art hriti s R e s e ar c h C o n s orti u m of C a n a d a – M RI S c or e f or 
S a cr oili a c J oi nt s
B ot h l eft a n d rig ht SIJ are sc ore d f or b o ne marr o w e de ma.  T otal SIJ S P A R C C sc ores ca n ra n ge 
fr om 0 t o 7 2 wi t h hi g her sc ores reflecti n g w orse disease (Ma ks y m o w yc h et al . 2 0 0 5 b).  Sc ori n g 
will be perf or me d b y  c e ntr al rea ders.  

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9. 1. 2. 1 3. 4. S p o n d yl o art hriti s R e s e ar c h C o n s orti u m of C a n a d a – SI J Str u ct u r al 
S c or e ( S S S)
Str uct ural lesi o ns i n M RIs of t he SIJ are assesse d usi n g t he S P A R C C S S S met h o d i n w hic h t he 
prese nce or a bse nce of lesi o ns is sc ore d i n SIJ q ua dra nts (f or fat meta plasia a n d er osi o n) or SIJ 
hal ves (f or bac kfill a n d a n k yl osis).  Sc ori n g ra n g es are fat meta plasia ( 0 t o 4 0), er osi o ns ( 0 t o 
4 0), bac kfill ( 0 t o 2 0), a n d a n k yl osis ( 0 t o 2 0) ( Ma ks y m o w yc h et al. 2 0 1 5 ).  Sc ori n g will be 
perf or m e d b y c e ntr al rea ders. 
9. 1. 3.
H e alt h O ut c o m e E n d p oi nt s
9. 1. 3. 1.
E ur o p e a n Q u alit y of Lif e – 5 Di m e n si o n s 5 – L e v el
T he E ur o pea n Q ualit y of Life – 5 Di me nsi o n s –5 Le vel ( E Q - 5 D-5 L) is a sta n dar dize d meas ure of 
healt h stat us use d t o pr o vi de a si m ple, ge neric meas ure of healt h f or cli nical a n d ec o n omic 
a p prais al.  T he E Q- 5 D- 5 L c o nsists of 2 c o mp o ne nts:  a descri pt i ve s yste m of t he res p o n de nt’s 
healt h a n d a rati n g of his/ her c urre nt healt h state usi n g a 0- t o 1 0 0-m m vis ual a nal o g scale 
( V A S).  T he descri pti ve s yste m c om pr ises t he f oll o wi n g 5 di me nsi o ns:  m o bili t y, self-care, us ual 
acti vit ies, pai n/ disc o mf o rt, a n d a n xiety/ de pressi o n .  Eac h di me nsi on has 5 le vels:  n o pr o ble ms, 
sli g ht pr o ble ms, m o derate pr o ble ms, se vere pr o ble ms, a n d e xtre me pr o ble ms.  T he res p o n de nt is 
as ke d t o i n dicate his/ her healt h state b y  tic ki n g ( or placi n g a cr oss) i n t he b o x ass ociate d wit h t he 
m o st a p pr o priate state me nt i n eac h of t he 5 di me nsi o ns.  It s h o ul d be n ote d t hat t he n u merals 1 t o 
5 ha ve n o arit h metic pr o perties a n d are n ot t o be use d as or di nal sc ore s.  T he V A S rec or ds t he 
res p o n de nt’s self-rate d healt h o n a vert ical V A S i n w hic h t he e n d p oi nts are la bele d “ best 
i ma gi na ble health state” a n d “ w orst i ma gi na ble healt h state.”  T his i nf or mat i on ca n be use d as a 
q ua nt itati ve meas ure of healt h o utc o mes.  T he E Q - 5 D- 5 L healt h states, defi ne d b y t he E Q - 5 D-
5 L descri pt i ve s yste m, m a y be c o n verte d i nt o a si n gle s u m mar y in de x b y  a p pl yi n g a f or mula t hat 
esse nt iall y attac hes val ues (als o calle d wei g hts) t o eac h of t he le vels i n eac h di me nsi o n ( E ur o Q ol 
Gr o u p 2 0 1 1).   
9. 1. 3. 2.
A s s e s s m e nt of S p o n d yl o art hriti s I nt er n ati o n al S o ci et y H e alt h I n d e x
T he A S A S HI i s a disease-s pecific healt h-i n de x i nstr u me nt desig ne d t o assess t he i m pact of 
i nter ve nt i ons f or S p A, i ncl u di n g a x S p A.  T his br oa der c o nce pt of h ealt h is i ncl u de d i n t he 
I nter nati o nal Classificati on of F u nct i oni n g, Disa bilit y, a n d Healt h, w hic h has bee n p u blis he d b y 
t he W orl d Healt h Or ga nizat i on ( W H O ).  T he A S A S has a p plie d t his classificati on as a basis t o 
defi ne a c ore set of ite ms rele va nt f or patie nts wit h A S .  T he 1 7 -ite m instr u m e nt has sc ores 
ra n gi n g fr o m 0 ( g o o d h ealt h) t o 1 7 ( p o or h ealt h) ( Kiltz et al. 2 0 1 3).  Eac h ite m c o nsists of o ne
q uesti o n t hat t he patie nt nee ds t o res p o n d t o wit h eit her “I a gree” (sc ore of  1) or “I d o n ot a gree ”
(sc ore of 0). A sc ore of “ 1” is gi ve n w here t he it e m is affir me d, i n dicati n g a d verse health.  All 
ite m sc ores are s u m me d t o give a t otal  sc ore or i n de x.
9. 1. 3. 3.
M e di c al O ut c o m e s St u d y 3 6 -It e m S h ort-F or m H e alt h S ur v e y 
T he S F -3 6 i s a 3 6-ite m patie nt-a d mi nistere d meas ure desi g ne d t o be a s h ort, m ult i p ur p ose 
assess me nt of healt h i n t he areas of p h ysical f u ncti o ni n g, r ole – p h ysical, r ole – e moti o nal , 
b o dil y  pai n, vit alit y, s ocial fu nct i oni n g, me ntal healt h, a n d ge neral hea lth.  T he 2 o verarc hi n g 
d o m ai ns o f me nt al well-bei n g a n d p h ysical well -bei n g are ca pt ure d b y  t he m e nt al co m p o ne nt 
su m mar y ( M C S) a n d p h ysical co m p o ne nt su m mar y ( P C S) sc ores.  T he s u m mar y sc ores ra n ge 

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fr om 0 t o 1 0 0; hi g her sc ores i n dicate better le vels of f u nct i on a n d/ or better healt h.  Ite ms are 
a ns were d o n Li kert scales of var yi n g le n gt hs.  T he S F -3 6 versi o n 2 (ac ute versi o n) will be use d, 
w hic h utilizes a 1 -wee k recall peri o d ( Ware 2 0 0 0 ).  
9. 1. 3. 4.
F u n cti o n al A s s e s s m e nt of C hr o ni c Ill n e s s T h er a p y F ati g u e S c al e
T he F A CI T Fat i g ue Scale is a s h ort, 1 3-ite m, eas y t o a d mi nister t o ol t hat meas ures a n 
i n di vi d ual’s le vel of fati g ue d uri n g t heir us ual dail y acti vities o ver t he past 7 da ys.  T he le vel of 
fati g ue is meas ure d o n a 5 -p oi nt Li kert -scale ( 4 = n ot at all fati g ue d t o 0 = ver y m uc h fati g ue d), 
E X C E P T f or ite ms # 7 a n d # 8 w hic h are re versel y sc ore d. ( We bster et al. 2 0 0 3).   
9. 1. 3. 5.
W or k Pr o d u cti vit y a n d A cti vit y I m p air m e nt Q u e sti o n n air e –
S p o n d yl o art hriti s
T he W P AI -S p A c o nsists of 6 q uesti o ns t o deter mi ne e m pl o y me nt stat us, h o urs misse d fr o m 
w or k beca use o f S p A , h o urs misse d fr om w or k f or ot her reas o ns, h o urs act uall y w or ke d, t he 
de gree t o w hic h S p A affecte d w or k pr o d ucti vit y w hile at w or k, a n d t he de gree t o w hic h S p A
affecte d acti vities o utside of w or k.  T he W P AI -S p A has bee n vali date d i n t he r-a x S p A patie nt 
p o p ul at i on ( Reill y et al. 2 0 1 0).  F o ur sc ores are deri ve d:  perce nta ge of a bse nteeis m, perce nta ge 
of  prese nteeis m (re d uce d pr o d ucti vit y w hile at w or k), a n o verall w or k i m pair me nt sc ore t hat 
c o m bi nes a bse nteeis m a n d prese nteeis m, a n d perce nta ge of i m pair me nt i n act i vities perf or me d 
o utsi d e of  w or k.  Greater sc ores i n dicate greater i m pair me nt (Reill y Ass ociates [ W W W ]).  
9. 1. 3. 6.
Q ui c k I n v e nt or y of D e pr e s si v e S y m pt o m at ol o g y – S elf -R e p ort ( 1 6 It e m s)
See Secti o n 9. 4. 8 .  
9. 1. 4.
A p pr o pri at e n e s s of A s s e s s m e nt s
All o f t he cli nical a n d safet y assess me nts/ meas ures i ncl u de d i n t he pri mar y  a n d major sec o n dar y  
o bj ect i ves i n t his st u d y are sta n dar d, wi del y use d, a n d ge nerall y rec o g nize d as relia ble, 
acc urate,a n d rele va nt.
9. 2.
A d v er s e E v e nt s
A n A E i s defi ne d as:  A n y u nt o war d me dical occ urre nce i n a pat ient  or cli nical i n vesti gati o n 
s u bject a d mi nistere d a p har mace ut ical pr o d uct t hat d oes n ot necessaril y ha ve a ca usal 
r elat i ons hi p wit h t his treat me nt.  A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n 
(incl 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 te m p orall y ass ociate d wit h t he 
use of a me dici nal (i n vest i gati o nal) pr o d uct, w het her or n ot relate d t o t he me dici nal 
(in vest i gati onal) pr o d uct.
I n vesti gat ors are res p o nsi ble f or m o nit ori n g t he safet y of patient s w h o ha ve e ntere d t his st u d y 
a n d f or alerti n g Lill y or its desi g nee t o a n y e ve nt t hat see ms u n us ual, e ve n if t his e ve nt ma y be 
c o nsi dere d a n u na nt ici pate d be nefit t o t he patie nt.
T he i n vest i gat or is res p o nsi ble f or t he a p pr o priate me dical care of patient s d uri n g t he st u d y.
I n vesti gat ors m ust d oc u me nt t heir re vie w of eac h la b orat or y safet y re p ort.

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T he i n vest i gat or re mai ns res p o nsi ble f or f oll owi n g, t hr o u g h a n a p pr o priate healt h care o pti o n, 
A Es t hat are seri o us or ot her wise me dicall y i m p orta nt, c o nsi dere d relate d t o t he i n vest i gati onal 
pr o d uct or t he st u d y , or t hat ca use d t he patie nt t o disc o nti n ue t he i n vesti gati onal pr o d uct bef ore 
c o mplet i n g t he st u d y.  T he patie nt s h o uld b e f ol l owe d u nt il t he e ve nt res ol ves, sta bilizes wit h 
a p pr o priate dia g n o stic e val uati o n, or is reas o na bl y e x plai ne d.  T he fre q ue nc y of fol l ow- u p 
e val uat i ons of t he A E is left t o t he discret i on of t he i n vest i gat or.
Lac k of dr u g effect is n ot a n A E i n cli nical st u dies, beca use t he p ur p ose of t he cli nical st u d y is t o 
esta blis h tr eat me nt effect.
T he i n vest i gat or will rec or d all rele va nt A E a n d S A E i nf or mati on i n t he case re p ort f or m ( C R F). 
After t he i nf or me d c o nse nt f or m (I C F) is si g ne d, st u d y site pers o n nel will rec or d via C R F t he 
occ urre nce a n d nat ure of eac h patie nt’s pree xist i ng c o n di tio ns, i ncl u di n g cli nicall y si g nifica nt 
sig ns a n d s y m pt o ms of t he disease u n der treat me nt i n t he st u d y .  I n a d ditio n, si te pers o n nel will 
rec or d a n y c ha n ge i n t he c o n diti on(s) a n d a n y ne w c o n dit i ons as A Es. I n vesti gat ors s h o uld
rec or d t heir assess me nt of t he p ote ntial relate d ness of eac h A E t o pr ot oc ol pr oce d ure, 
i n vesti gati onal pr o d uct, via C R F.
T he i n vest i gat or will i nter pret a n d d oc u me nt w het her or n ot a n A E as a reas o na bl y p ossi b ility of  
bei n g r elate d t o st u d y treat me nt, st u d y de vice, or a st u d y  pr oce d ure, ta ki n g i nt o acc o u nt t he 
di sease, c o nc o mit a nt treat me nt or pat h ol o gies. T o assess t he relat i ons hi p of t he A Es, t he 
f oll owi n g is defi ne d:
A “r eas o na ble possi b ility” mea ns t hat t here is a ca use a n d effect relat i ons hi p bet wee n t he 
i n vesti gatio nal pr o d uct , st u d y de vice a n d/ or st u d y pr oce d ure a n d t he A E.
T he i n vest i gat or a ns wers yes/ n o w he n ma ki n g t his assess me nt.
Pl a n ne d s ur geries a n d n o ns ur gical i nter ve nt i ons s h o ul d n ot be re p orte d as A Es u nless t he 
u n derl yi n g me dical c o n dit i on has w orse ne d d u rin g t he c o urse of t he st u d y .
If a patie nt’s i n vesti gati o nal pr o d uct is disc o nti n ue d as a res ult of a n A E, st u d y site pers o n nel 
m ust re p ort t his t o Lill y or its desi g nee via electr o nic data e ntr y , clarif yi n g if p ossi ble, t he 
circ u msta nces lea di n g t o a n y d osa ge mo dificat i ons, or di sc o nti n uatio ns of  treat me nt. 
Acc urate start a n d st o p dates (a n d ti mes, w here re q uire d) are t o be re p orte d via electr o nic data 
e ntr y for all  AEs.  O nl y A Es t hat are o n g oi n g at t he last st u d y visit a n d/ or c o m m u nicat i on are t o 
be d oc u m e nte d as “ o n g o i n g”.
9. 2. 1.
S eri o u s A d v er s e E v e nt s
A n S A E is a n y  AE f r o m t his st u d y t hat res ults i n o ne of t he f oll owi n g o utc o m es:

deat h

i nitial or pr ol o n ge d i n patie nt h os pitalizati on

a life-t hreate ni n g e x perie nce (t hat is, i m me diate ris k of d yi n g)

persiste nt or sig nifica nt di sa bilit y/i nca pacity

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
c o n ge nital a n o ma l y/ birt h defect

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 pi talizati on b ut ma y je o par dize t he patie nt or ma y re q uire 
i nter ve nt i on t o pre ve nt o ne of t he ot her o utc o m es liste d i n t he defi nit i on a b o ve.  
E xa m ples of s uc h me dical e ve nts i ncl u de aller gic br o nc h os pas m re q uiri n g 
i nte nsi ve treat me nt i n a n e mer ge nc y r o o m or at h o me, bl o o d d yscrasias or 
c o n v ulsi o ns t hat d o n ot res ult i n i n patie nt h os pitalizati o n, o r t he de vel o p me nt of 
dr u g de pe n de nc y  or dr u g a b use.
All A Es occ urri n g after si g ni n g t he I C F are rec or de d i n t he C R F a n d assesse d f or seri o us criteria.  
T he S A E re p ortin g t o s p o ns or be gi ns after t he patie nt has si g ne d t he I C F a n d has recei ve d
i n vesti gati ona l pr o d uct.  H o we ver, if a n S A E occ urs after si g ni n g t he I C F, b ut pri or t o recei vi n g 
i n vesti gati onal pr o d uct, t he S A E s h o ul d be re p orte d t o t he s p o ns or as per S A E re p orti n g 
re q uire me nts a n d ti meli nes (see Secti on 9. 2 ) if it is c o nsi dere d reas o na bl y p ossi bl y relate d t o 
st u d y pr oce d ure.
St u d y  site pers o n nel must al ert Lill y or its desig nee of  a n y S A E wit hi n 2 4 h o urs of i n vesti gat or 
a ware ness o f t he e ve nt via a s p o ns or -a p pr o ve d met h o d.  If alerts are iss ue d via tele p h o ne, t he y 
are t o be i m me diatel y f o ll ow e d wi t h official notificati o n o n st u d y- s pecific S A E f or ms.  T his 2 4-
h o ur n otificat i on re q uire me nt refers t o t he i nit ial S A E i nf or mati on a n d all f o ll ow- u p S A E 
i nf or mat i on. Patie nts wit h a seri o us he pat ic a d verse e ve nt s h o ul d ha ve a d diti onal data c ollecte d 
usi n g t he electr o nic data e ntr y.
Pre g na nc y ( d uri n g mater nal or pater nal e x p os ure t o i n vest i gati onal pr o d uct) d oes n ot meet t he 
defi nit i on o f a n A E.  H o we ver, t o f ulfill re g ulat or y re q uire me nts a n y pre g na nc y s h o uld be 
re p orte d f oll owi n g t he S A E pr ocess a n d t o c ollect data o n t he o utc o me f o r b ot h mot her a n d fet us.
I n vesti gat ors are n ot o bli gate d t o acti vel y see k A Es or S A Es i n s u bjects o nce t he y ha ve 
di sc o nti n ue d a n d/ or c o m plete d t he st u d y (t he patie nt dis p osit i on C R F has bee n c o m plete d).  
H o we ver, if t he i n vest i gat or lear ns of a n y S A E, i nclu di n g a deat h, at a n y  ti me after a s u bject has 
bee n disc har ge d fr o m t he st u d y , a n d he/s he c o nsi ders t he e ve nt reas o na bl y p ossi bl y relate d t o t he 
st u d y tr e at me nt or st u d y p artici pat i on, t he i n vest i gat or must pr o m ptl y n otif y Lill y .
9. 2. 1. 1.
S u s p e ct e d U n e x p e ct e d S eri o u s A d v er s e R e a cti o n s
Lill y has pr oce d ures t hat will be f o ll owe d f or t he i de ntificati on, rec or di n g a n d e x pe dite d 
re p orti n g of s us pecte d u ne x pecte d seri o us a d verse reacti o ns ( S U S A Rs) t hat are c o nsiste nt wit h 
gl o bal  re g ulati ons a n d t he ass ociate d detaile d g ui da nces.
9. 2. 2.
A d v er s e E v e nt s of S p e ci al I nt er e st
T he f o ll owi n g a d verse e ve nts of s pecial i nterest ( A E SIs) will be use d t o deter mi ne t he safet y a n d 
t olera bilit y of i xe kiz u ma b o ver t he ra n ge of d oses selecte d f or t his cli nical st u d y .
T he A E SIs f or i xe kiz u ma b are:

c yt o p e nias (le u k o pe nia, ne utr o pe nia, a n d t hr o m b oc yt o p e nia)

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
cli nicall y si g nifica nt he patic e ve nts a n d/ or si g nifica nt ele vat i ons i n li ver f u ncti on test 
c ha n ges/e nz y me ele vat i ons ( A L T, A S T, bilir u bi n, a n d al kali ne p h os p hatase)

i nfecti ons

i njecti on site reacti o ns

aller gic reacti o ns/ h y perse nsit i vities

cere br ocar di o vasc ular e ve nts 

mali g na ncies

I B D

int erst itial l u n g disease

de pressi o n.
Si tes will pr o vi de details o n s ome of t hese A Es as i nstr ucte d o n t he C R F.  I n vest i gat ors will als o 
e d ucate patie nts a n d/ or care gi vers a b o ut t he s y m pt o ms of aller gic/ h y perse nsit i vity react i ons a n d 
will pr o vi de i nstr ucti o ns o n deali n g wit h t hese reacti o ns (see als o Secti o n 7. 7. 2 ).  A bl o o d 
sa m ple is t o be c ollecte d as s o o n as p ossi ble f or a n y patie nt w h o e x perie nces a n A E of a p ote ntial 
s yste mic aller gic/ h y perse nsiti vity reacti ons d uri n g t he st u d y  as ju d ge d b y t he i n vesti gat or.
Data o n preferre d ter ms ass ociate d wit h cere br ocar di o vasc ular e ve nts ( defi ne d as deat h, car diac 
isc he mic e ve nts i ncl u di n g MI a n d h os pitalizati o n f or u nsta ble a n gi na, h os pitalizati on f or heart 
fail ure, seri o us arr h yt h mia, res uscitate d s u d de n deat h, car dio ge nic s h oc k, c or o nar y  
re vasc ularizati o n pr oce d ure, str o ke/tra nsie nt isc he mic attac k, peri p heral re vasc ularizati o n 
pr oce d ure, peri p heral arterial e ve nt, a n d h os pitalizati o n f or h y perte nsi o n) will be c o llecte d, a n d 
t hese e ve nts a nd a n y deat hs will be a dj u dicate d b y  a n e xter nal cli nical e ve nts c o m mittee ( C E C) 
ma de u p of a c hair ma n, 2 car di o l ogists, a n d a ne ur ol o gist.  
Data o n s us pecte d I B D, as i de ntifie d b y  e ve nts p ossi bl y i n dicati ve of ulcerati ve c olitis a n d 
Cr o h n’s disease, will be c o llecte d a n d t he e ve nts will be a dj u dicate d b y a n e xter nal C E C wit h 
e x pert ise i n I B D.
T he r ol e of e xter nal C E Cs is t o a dju dicate defi ne d cli nical e ve nts i n a bli n de d, c o nsiste nt, a n d 
u n biase d ma n ner t hr o u g h o ut t he c o urse of a st u d y .  T he p ur p ose of t he C E C f or a dj u dicat i on of 
cere br ocar di o vasc ular e ve nts a n d t he C E C f or a dj u dicat i on of s us pecte d I B D e ve nts is t o e ns ure 
t hat all re p orte d e ve nts are e val uate d u nif or ml y b y a si n gle gr o u p.  
9. 2. 2. 1.
All er gi c R e a cti o n a n d H y p er s e n siti vit y E v e nt s
All bi o l ogic a ge nts carr y t he ris k of s yste mic aller gic/ h y perse nsiti vity react i ons. Cli nical 
ma nifestati o ns of t hese reacti o ns ma y i ncl u de b ut are n ot li mite d t o:

S ki n ras h

Pr uri t us (itc hi n g)

D ys p nea

Urti carial ( hi ves)

A n gi oe de ma (f or e xa m ple, s welli n g of t he li ps a n d/ or t o n g ue)

H y p ote nsi o n

A na p h ylactic reacti o n

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P arti cip a nts wi t h cli nical ma nifestati o ns of s yste mic aller gic/ h y perse nsiti vity reactio ns s h o ul d be 
treate d per l ocal sta n dar d of care. A d dit i onal data descri bi n g eac h s y m pt o m s h o ul d be p r o vide d 
t o t he s p o ns or i n t he e C R F.   
I n case of a na p h yla xis or ge neralize d urticaria, a d diti onal bl o o d sa m ples s h o ul d be c ollecte d as 
close as p ossi ble t o t he o nset of t he e ve nt. F oll o w -u p sa m ples s h o ul d be o btai ne d at t he ne xt 
re g ularl y sc he d ule d visit or 4 wee ks after t he e ve nt, w hic he ver is later. T he l a b res ults are 
pr o vi de d t o t he s p o ns or via t he c e ntral la b orat or y or via e C R F.   
9. 2. 3.
C o m pl ai nt H a n dli n g
Lill y c o llects pr o d uct c o m plai nts o n i n vesti gati onal pr o d ucts a n d dr u g deli ver y s yste ms use d i n 
cli nical st u dies i n or der t o e ns ure t he safet y of  st u d y p artici pa nts, mo ni t or q ualit y, a n d t o 
facilitate pr ocess a n d pr o d uct i m pr o ve me nts.
P ati e nts will be i nstr ucte d t o c o ntact t he i n vesti gat or as s o o n as p ossi ble if he or s he has a 
c o mplai nt or pr o bl e m wit h t he i n vest i gati onal pr o d uct s o t hat t he sit uati o n ca n be assesse d.
9. 3.
Tr e at m e nt of O v er d o s e
Refer t o t he I B.
9. 4.
S af et y
9. 4. 1.
El e ctr o c ar di o gr a m s
F or eac h patie nt, 1 2 -lea d electr ocar di o gra ms ( E C Gs) s h o uld be c ollecte d l ocall y acc or di n g t o t he 
Sc he d ule of Act i vities (Secti o n 2 ).  Patie nts are t o be rest i n g f or 5 mi n utes pri or t o t he E C G.  It is 
rec o m me n de d t hat patie nts be i n a s u pi ne p ositi on.  
A n y cli nicall y  sig nifica nt fi n di n gs fr o m E C Gs t hat res ult i n a dia g n osis a n d t hat occ ur after t he 
pati e nt recei ves t he first d ose o f t he i n vest i gati o nal treat me nt are t o be re p orte d t o Lill y or its 
desi g nee as A E s via C R F.  A n y cli nicall y si g nifica nt E C G f i n di n gs pri or t o recei vi n g dr u g are t o 
be re p orte d as a pree xist i n g c o n diti on.
9. 4. 2.
Vit al Si g n s
F or eac h patie nt, vital si g n s meas ure me nts are t o be c o n d ucte d acc or di n g t o t he Sc he d ule o f 
Act i vities (Secti o n 2 ).  Vit al si g ns i ncl u de B P a n d p uls e.  Patie nts are t o be resti n g f or a 
mi ni m u m o f 5 mi n utes pri or t o vital si g n c o llecti on. 
A n y cli nicall y  sig nifica nt fi n di n gs fr o m vital si g n s meas ure me nt s t hat res ult i n a dia g n osis a n d 
t hat occ ur after t he patie nt recei ves t he first d ose of st u d y treat me nt are t o be re p orte d t o Lill y or 
its desi g nee as A Es via C R F.
9. 4. 3.
L a b or at or y T e st s
F or eac h patie nt, la b orat or y  tests (detaile d i n A p pe n di x 2 ) s h o u d be c o n d ucte d acc or di n g t o t he 
Sc he d ule of Act i vities (Secti o n 2 ).  F or t h ose tests t hat are teste d at t he ce ntral la b, p lease 
refere nce t he ce ntral la b orat or y ma n u al for s pecific i nstr ucti o ns.

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Wit h t he e xce pti o n o f lab orat or y  test res ults t hat ma y u n bli n d t he st u d y, Lill y or its desig nee will  
pr o vi de t he i n vest i gat or wit h t he res ults of la b orat or y tests a nal yze d b y a ce ntral ve n d or, if a 
ce ntral ve n d or is use d f or t he cli nical trial.  
A n y cli ni c all y sig nifica nt fi n di n gs fr o m la b orat or y tests t hat res ult i n a dia g n osis a n d t hat occ ur 
after t he patie nt recei ves t he first d ose of i n vest i gati onal pr o d uct are t o be re p orte d t o Lill y or its 
desi g nee as A E s via C R F.
9. 4. 4.
I m m u n o g e ni cit y A s s e s s m e nt s
W here l ocal re g ulati ons a n d E R Bs all o w, b l oo d sa m ples f or i m m u n o ge nicit y testi n g will be 
c ollecte d t o deter mi ne a nt i b o d y pr o d uctio n a gai nst t he i n vesti gati o nal pr o d uct as s pecifie d i n t he 
Sc he d ule of Act i vities (Secti o n 2 ).
I mm u n o ge nicit y will  be assesse d usi n g a vali date d assa y  desi g ne d t o detect A D As i n t he 
prese nce of t he i n vesti gati o nal pr o d uct at  a la b orat or y a p pr o ve d b y t he s p o ns or.  A nti b o dies ma y 
be f urt her c haracterize d a n d/ or e val uate d f or t heir a bility t o ne utralize t he acti vity of  t he 
i n vesti gati onal pr o d uct. A d dit i onall y , a blo o d sa m pl e is t o be c ollecte d, as s o o n as p ossi ble, f or 
a n y pat ient  w h o e x perie nces a p ote ntial s yste mic aller gic/ h y perse nsit i vity reactio n d uri n g t he 
st u d y as j u d ge d b y t he i n vesti gat or.  T hese sa m ples will be teste d f or i m m u n o ge nicit y a n d P K, 
w hile ot her la b orat or y  tests ma y be perf or me d as nee de d t o el uci date t he ca use of t he aller gic/
h y perse nsit i vity react i on.   
S a m ples will  be retai ne d f or a ma xi m u m of 1 5 years after t he last patie nt visit f or t he st u d y, or 
f or a s h orter perio d if re g ulat i ons a n d E R Bs allo w, at a facilit y selecte d b y  t he s p o ns or.  T he 
d urati o n all o ws t he s p o ns or t o res p o n d t o f ut ure re g ulat or y re q uests relate d t o t he i n vesti gati onal 
pr o d uct .  A n y sa m ples re mai ni n g after 1 5 years will be destr o ye d.  
9. 4. 5.
P h y si c al E x a mi n ati o n
F or eac h patie nt, a c o m plete p h ysical e xa mi nat i on m ust be c o n d ucte d acc or di n g t o t he Sc he d ule 
of  Acti vities (Secti o n 2 ).  
A n y cli nicall y  sig nifica nt fi n di n gs fr o m a c o m plete p h ysical e xa mi nat i on t hat res ult i n a 
di a g n osis a n d t hat occ ur after t he patie nt recei v es t he first d ose of st u d y tr e at me nt are t o be 
re p orte d t o Lill y or its desi g nee as A Es via C R F.
9. 4. 6.
O c ul ar E x a mi n ati o n
At  eac h st u d y visit, i n vesti gat or or st u d y health care pr o viders will e val uate t he pati e nt for a n y  
s y m pt o ms of a nterior u veit is as s pecifie d i n t he Sc he d ule of Acti vities (Secti o n 2 ).  If t he patie nt 
de vel o ps e ye pai n or disc o mf o rt, e ye re d ness, bl urri n g of visi o n, or a n y  ot her s y m pt o ms
s u g gesti ve of a nterior u veit is, t he patie nt m ust be e val uate d b y a n o p ht hal m ol ogist . T he 
o p ht hal m o l ogist dia g n osi s is c o mplete d i n t he C R F .  

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9. 4. 7.
C h e st X -R a y a n d T u b er c ul o si s T e sti n g
A p osteri or -a nteri or vie w c hest X- ra y will be o btai ne d, u nless t he X- r a y or res ults fr o m a c hest 
X- r a y o btai ne d withi n 3 m o nt hs pri or t o scree ni n g are a vaila ble.  T he c hest X- ra y or res ults will 
be re vie we d b y t he i n vesti gat or or desi g nee t o e xcl u de patie nts wit h acti ve T B i nfect i on.  
I n a d diti on, pati e nts will be teste d at scree ni n g a n d at visit s as i n dicate d o n t he St u d y Sc he d ule, 
( Sectio n 2 ) for e vi de nce of acti ve or late nt T B i n dicate d b y a p ositive p urifie d pr otei n deri vati ve
(P P D ) s ki n test res p o nse (≥5 m m i n d urat i on, bet wee n a p pr o xi matel y  2 a n d 3 da ys after test 
a p plicat i on, re gar dl ess of B C G vacci nat i on hist or y).  If t he Q ua nt i F E R O N® -T B G ol d test or T -
S P O T ® is a vaila ble a n d i n t he j u d g me nt of t he i n vesti gat or preferre d as a n alter nati ve t o t he P P D 
s ki n test f or t he e val uati o n of T B i nfect i on, eit her test ma y be use d i nstea d of t he P P D test 
( p ositive tests e xcl u de d) a n d ma y be rea d l ocall y. If t he Q ua nti F E R O N® -T B G ol d or T - SP O T ®
test is i n deter mi nate, 1 retest is all o we d.  If t he retest is i n deter mi nate, t he n t he patie nt is 
e xcl u de d fr o m t he st u d y.
P ati e nts wit h d oc u me nt atio n of  a ne gati ve test res ult wit hi n 3 m o nt hs pri or t o baseli ne ( Wee k 0; 
Vi sit 2) d o n ot nee d a T B scree n at Visit 1.  D oc u me ntati o n of t his test res ult m ust i ncl u de a 
rec or d of t he size of t he i n d urati o n res p o nse.  A P P D test rec or de d as ne gati ve wit h o ut 
d oc u m e nti n g t he size of i n d urat i on will res ult i n a retest.
If t he P P D test is perf or me d a n d p ositi ve (≥5 -m m i n d urati on) a n d t he patie nt has n o me dical 
hist or y  or c hest X- ra y fi n di n gs c o nsiste nt wit h acti ve T B, a retest ca n be perf or me d usi n g a 
q ua nt i F E R O N® -T B G ol d ( Q T F) or T -S P O T ® . T B ( T-S P O T) test. 
N ote:
If retest is d o ne with Q T F or T -S P O T, t his res ult will be use d t o deter mi ne eli gi bilit y i n 
pl ace o f t he P P D res ult. I n deter mi nate res ults of eit her test are t o be ha n dle d as directe d a b o ve.
H o we ver, patie nts wit h a P P D s ki n test ≥5 m m i n d uratio n or a p osit i ve Q ua nt i F E R O N® -T B 
G ol d or p osit i ve T-S P O T ® test at scree ni n g b ut n o ot her e vi de nce of acti ve T B ma y be 
rescree ne d 1 ti me a n d ma y be e nr olle d wit ho ut re peati n g a P P D or Q ua nti F E R O N ® -T B G O L D
or T- S P O T ® test if t he f oll owi n g c o n di tio n s are met:

after recei vi n g at least 4 wee ks of a p pr o priate late nt T B i nfecti o n ( L T BI) t hera p y, 

wi t h n o e vi de nce of he pat ot o xicit y ( A L T/ A S T m ust re mai n ≤2 ti mes U L N) u p o n 
retesti n g of ser u m A L T/ A S T pri or t o ra n d o mizati on.  S uc h patie nts m ust c o m plete 
a p pr o priate L T BI t hera p y d uri n g t he c o urse of t he st u d y i n or der t o re mai n eli gi ble, a n d

meet all ot her I ncl usi o n/ E xcl usi o n cri t eria for partici pat i on.  
If rescree ni n g occ urs wit hi n 3 m o nt hs of t he scree ni n g c hest X- ra y, t here is n o necessity f or 
re peat of c hest X- r a y for c o nsi deri n g e nr oll me nt .  P atie nts w h o ha ve a d oc u me nte d hist or y  of 
c o mplet i n g an a p pr o priate T B treat me nt re gi me n wit h n o hist or y of r e-e x p os ure t o T B si nce 
t heir treat me nt was c o mplete d a n d n o e vi de nce of acti ve T B are eli gi ble t o partici pate i n t he 
st u d y.  P ati e nts w h o ha ve ha d h o use h o l d c o ntact with a pers o n wi t h acti ve T B are e xcl u de d, 
u nless a p pr o priate a n d d oc u me nte d pr o p h yla xis f or T B was gi ve n.

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P a g e 6 6
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9. 4. 8.
Q ui c k I n v e nt or y of D e pr e s si v e S y m pt o m at ol o g y – S elf -R e p ort 
( 1 6 It e m s)
F or eac h patie nt, a QI D S -S R 1 6 assess me nt will be c ollecte d acc or di n g t o t he Sc he d ule of 
Act i vities (Secti o n 2 ).
A n y cli nicall y  sig nifica nt fi n di n gs fr o m t he QI D S -S R 1 6 assess me nt t hat res ult i n a di a g n osis a n d 
t hat occ ur after t he patie nt recei ves t he first d ose of st u d y treat me nt are t o be re p orte d t o Lill y or 
its desi g nee as A Es via C R F.
T he QI D S -S R 1 6 is a self-a d mi nistere d, 1 6 -ite m instr u m e nt i nte n de d t o assess t he e xiste nce a n d 
se verity of  s y m pt o ms of de pressi on as liste d i n t he A merica n Ps yc hiatric Ass ociat i on’s 
Di a g n ostic a n d St atistic al M a n u al of Me nt al Dis or ders , 4t h E ditio n ( A P A 1 9 9 4).  A patie nt is 
as ke d t o c o nsi der e ac h state me nt as it r elates t o t he wa y t he y ha ve felt for t he past 7 da ys.  T here 
is a 4-p oi nt scale f or eac h ite m ra n gi n g fr o m 0 t o 3.  T he 1 6 ite ms c orres p o n di n g t o 9 de pressi o n 
d o m ai ns are s u m me d t o gi ve a si n gle sc ore ra n gi n g fr o m 0 t o 2 7, wit h hi g her sc ores de n oti n g 
greater s y m pt o m se verit y.   T he d o mai ns assesse d b y t he i nstr u me nt are ( 1) sa d m o o d, 
( 2) c o nce ntrati o n, ( 3) self -criticis m, ( 4) s uici dal id e ati o n, ( 5) i nterest, ( 6) e ner g y/fati g ue, 
( 7) slee p dist ur ba nce (i nitial, mi d dle, a n d late i ns o m nia or h y pers o m nia), ( 8) decrease/i ncrease i n 
a p petit e/ w eig ht, a n d ( 9) ps y c h o m o t or a git atio n/retar dati o n.  A d di tio nal i nf or mat i on a n d t he 
QI D S -S R 1 6 q uesti o ns ma y be f o u n d at t he U ni versit y of  Pitts b ur g h I D S/ QI D S i nter net pa ge 
(htt p:// w w w.i ds -qi ds. or g/ ).
9. 4. 9.
C ol u m bi a – S ui ci d e S e v erit y R ati n g S c al e
T he C- S S R S (P os ner et al. 2 0 0 7; C o l um bia U ni versit y Me dical  Ce nter [ W W W]) is a scale t hat 
ca pt ures t he occ urre nce, se verit y,  a n d fre q ue nc y of s uici de-relate d id e ati o ns a n d be ha vi ors 
d uri n g t he assess me nt peri o d.  T he C -S S R S m ust be a d mi nistere d b y  a p pr o priatel y trai ne d site 
pers o n nel.  T he t o ol was de vel o pe d b y  t he Nati onal I ns tit ut e of Me ntal Healt h ( NI M H) 
Treat me nt of A d o lesce nt S uici de Atte mpters ( T A S A) tri al gr o u p f or t he p ur p ose of bei n g a 
c o u nter part t o t he C ol u m bia Classificat i on Al g ori t h m of S uici de Assess me nt ( C -C A S A) 
cate g orizat i on of s uici dal e ve nts .  Patie nts will be assesse d acc or di n g t o t he Sc he d ule of 
Act i vities (Secti o n 2 ).
T he Self -H ar m  S u p ple me nt F or m is a o ne-q uest i on f or m t hat is c om p lete d, at a n y visit, i ncl u di n g 
baseli ne visits, t hat as ks f or t he n u m ber of s uici dal or n o ns uici dal self-i nj urio us be ha vi ors t he 
patie nt has e x perie nce d si nce t he last assess me nt. F or eac h u ni q ue e ve nt i de nt ifie d, a 
q uesti o n naire ( Self -H ar m  Fol l ow- u p F or m ) w hic h c ollects s u p ple me ntal i nf or mati on o n t he self -
i nj urio us be ha vi or is t o be c o m plete d . T hi s i nf or matio n is t he n d oc u m e nte d i n t he e C R F. 
9. 4. 1 0. S af et y M o nit ori n g 
Lill y will peri o dicall y  re vie w e v ol vi n g a g gre gate safety data wi t hi n t he st u d y b y a p pr o priate 
met h o ds.

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
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9. 4. 1 0. 1. H e p ati c S af et y M o nit ori n g
If a st u d y patie nt e x perie nces ele vate d A L T ≥3 X U L N, A L P ≥2 X U L N, or el e vate d T B L ≥2 X 
U L N, li ver testi n g (A p pe n di x 4 ) s h o uld be re peate d wi t hi n 3 t o 5 da ys i ncl u di n g A L T, A S T, 
A L P, T B L, direct bilir u bi n, ga m ma -gl uta m yl  tra nsferase, a n d creati ne ki nase t o c o nfir m t he 
a b n or malit y a n d t o deter mi ne if it is i ncreasi n g or decreasi n g.  If t he a b n or mality persists or 
w orse ns, cli nical a n d la b orat or y mo ni t ori n g s h o uld be i nitiate d b y t he i n vesti gat or a n d i n 
c o ns ultati o n wit h t he st u d y  me dical m o nit or .  M o nit ori n g of A L T, A S T, T B L, a n d A L P s h o ul d 
c o nti n ue u ntil le vels n or malize or ret ur n t o a p pr o xi mate baseli ne le vels.  Details f or he pat ic 
m o nit ori n g de pe n d u p o n t he se verit y a n d persiste nce of o bser ve d la b orat or y test a b n or malities.  
A d di tio n al safety data s h o ul d be c o llecte d via t he C R F/electr o nic data e ntr y/ desi g nate d data 
tra ns missi on met h o ds if 1 or m ore of t he f o ll owi n g c o n di tio ns occ ur: 

e levat i on of ser u m  AL T t o ≥5 X U L N o n 2 or m ore c o nsec uti ve bl o o d tests

ele vate d ser u m T B L t o ≥2 X U L N (e xce pt f or cases of k n o w n Gil bert’s 
s y n dr ome)

ele vat i on of ser u m  AL P t o ≥2 X U L N o n 2 or m ore c o nsec uti ve bl o o d tests

pati e nt disc o nt i n ue d fr om treat me nt d ue t o a he patic e ve nt or a b n or malit y of 
li ver tests

he pat ic e ve nt c o nsi dere d t o be a S A E
9. 4. 1 0. 2. N e utr o p e ni a
9. 4. 1 0. 2. 1. D uri n g Tr e at m e nt ( P eri o d s 2 a n d 3)
D uri n g treat me nt wit h i n vest i gati onal p r o d uct, patie nts wit h ne utr o p hil c o u nts < 1 5 0 0 cells/L 
( < 1. 5 0 x1 0 3 /µ L or < 1. 5 0 GI/ L) are t o be ma na ge d f or ne utr o pe nia as f o ll ows:

< 5 0 0 cells/ L ( < 0. 5 0 x 1 0 3 / µ L or < 0. 5 0 GI/ L), see Disc o nti n uati o n Criteria ( Sectio n 8. 1 )

≥5 0 0 cells/ L a n d < 1 0 0 0 cells/ L ( ≥0. 5 0 x 1 0 3 /µ L a n d < 1. 0 0 x 1 0 3 /µ L or ≥0. 5 0 GI/ L a n d 
< 1. 0 0 GI/ L), see Disc o nt i n uati on Cri t eria ( Sectio n 8. 1 )

≥1 0 0 0 cells/ L a n d < 1 5 0 0 cells/ L ( ≥1. 0 0 x 1 0 3 /µ L a n d < 1. 5 0 x 1 0 3 /µ L or ≥1. 0 0 GI/ L a n d 
< 1. 5 0 GI/ L), a n d t he patie nt has a c o nc urre nt i nfecti o n t hat re q uires s yste mic a nti-
i nfecti ve t hera p y (f or e xa m ple, a nti bi otic, a ntif u n gal a ge nt, a nti viral a ge nt):  
o
T he d ose of i n vest i gati onal pr o d uct is t o be wit h hel d, t he patie nt is t o recei ve 
a p pr o priate me dical care, a n d a re peat test f or ne utr o p hil c o u nt is t o be perf or me d 
wi t hi n 4 wee ks fr o m k n o wle d ge of t he i nitial re p ort.  If t he re peat ne utr o p hil 
c o u nt has ret ur ne d t o ≥1 5 0 0 cells/ L ( ≥1. 5 0 x 1 0 3 /µ L or ≥1. 5 0 x 1 0 3 /µ L) a n d t he 
i nfecti on has res ol ve d or is res ol vi n g, t he patie nt ma y res u me d osi n g of 
i n vesti gati onal pr o d uct a n d e val uat i on at sc he d ule d visits.  If t he ne utr o p hil c o u nt 
r e mai ns ≥1 0 0 0 cells/ L a n d < 1 5 0 0 cells/ L ( ≥1. 0 0 x 1 0 3 /µ L a n d < 1. 5 0 x 1 0 3 /µ L or 
≥1. 0 0 GI/ L a n d < 1. 5 0 GI/ L), i n vest i gati onal pr o d uct is t o c o nt i n ue t o be wit h hel d 
a n d a re peat ne utr o p hil c o u nt is t o a gai n be perf or me d wit hi n a n ot her 4 wee ks.  If, 
after 2 re peat tests, t he ne utr o p hil c o u nt still re mai ns ≥1 0 0 0 cells/ L a n d 

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< 1 5 0 0 cells/L ( ≥1. 0 0 x 1 0 3 / µ L a n d < 1. 5 0 x 1 0 3 /µ L or ≥1. 0 0 GI/ L a n d < 1. 5 0 GI/ L), 
a n d:

t he i nfect i on has n ot f ull y  res ol ve d, t he patie nt will be disc o nti n ue d fr o m 
t he st u d y treat me nt .

t he i nfect i on has res o l ve d, t he patie nt ma y res u me d osi n g a n d e val uati on 
at sc he d ule d visit s.  H o we ver, if res u m pti on of d osi n g is n ot dee me d 
a p pr o priate b y t he i n vestigat or, t he pati e nt will be disc o nti n ue d fr o m t he 
st u d y tr e at me nt .

≥1 0 0 0 cells/ L a n d < 1 5 0 0 cells/ L ( ≥1. 0 0 x 1 0 3 /µ L a n d < 1. 5 0 x 1 0 3 /µ L or ≥1. 0 0 GI/ L a n d 
< 1. 5 0 GI/ L), a n d t he patie nt has n o c o nc urr e nt i nfecti o n t hat re q uires s yste mic a nt i-
i nfecti ve t hera p y (f or e xa m ple, a nti bi otic, a ntif u n gal a ge nt, a nti viral a ge nt):  
o
D osi n g ma y c o nti n ue, a n d a re peat ne utr o p hil c o u nt is t o be perf or me d 4 t o 
8 wee ks fr o m k n o wle d ge of t he i nit ial re p ort.  Testi n g may be at a re g ularl y 
sc he d ule d visit or at a n u nsc he d ule d visit, as necessar y.
Re peat testi n g is t o be perf or me d at 4- t o 8-wee k i nter vals u nt il t he ne utr o p hil 
c o u nt has ret ur ne d t o ≥1 5 0 0 cells/L ( ≥1. 5 0 x 1 0 3/ µ L or ≥1. 5 0 GI/ L) .  If t he 
pati e nt has 3 or mor e p ost baseli ne ne utr o p hil c o u nts of ≥1 0 0 0 cells/L 
(≥1. 0 0 x 1 0 3 /µ L or ≥1. 0 0 GI/ L) a n d < 1 5 0 0 cells/L ( < 1. 5 0 x 1 0 3 /µ L or 
< 1. 5 0 GI/ L) , n o val ue of < 1 0 0 0 cells/L ( < 1. 0 0 x 1 0 3 /µ L or < 1. 0 0 GI/ L), a n d n o 
p ost baseli ne i nfecti o n re q uiri n g s yste mic a nt i-i nfecti ve t hera p y, t he patie nt ma y 
c o nti n ue or res u me f urt her e val uati o n at sc he d ule d visits, as dee me d a p pr o priate 
b y t he i n vesti gat or.
If a patie nt wit h o ut i nitial c o nc urre nt i nfecti o n de vel o ps a n i nfecti o n t hat re q uires s yste mic a nt i-
i nfecti ve t hera p y, t he n t he patie nt is t o be ma na ge d as i n dicate d a b o ve f or patie nts wit h 
c o nc urre nt i nfect i on.  
9. 4. 1 0. 2. 2. At E arl y T er mi n ati o n Vi sit
If at t he last sc he d ule d st u d y visit, t he patie nt’s ne utr o p hil c o u nt is < 1 5 0 0 cells/ L 
( < 1. 5 0 x 1 03 / µ L or < 1. 5 0 GI/ L) a n d less t ha n t he patie nt’s baseli ne ne utr o p hil c o u nt, t he 
f oll owi n g meas ures are t o be ta ke n:

P atie nts wit h C o nc urre nt I nfecti o n:   If t here is a c o nc urre nt i nfecti on t hat re q uires 
s yste mic a nti-i nfecti ve t hera p y, t he patie nt is t o recei ve a p pr o priate me dical care a n d a 
re peat test f or ne utr o p hil c o u nt is t o be perf or me d at least Q 4 W ( or s o o ner as 
a p pr o priate) u ntil res o l uti on of i nfect i on.  U p o n res ol ut i on of i nfecti o n, t he ne utr o p hil 
c o u nt is t o be m o nit ore d usi n g t he re q uire d st u d y visit s i n P ost-Treat me nt F oll o w -U p 
P eri o d ( Peri o d 4) :  Visit 8 0 1 ( 4 wee ks p ost -res ol uti o n of i nfecti o n) a n d Visi t 8 0 2 ( 8 
wee ks after Visit 8 0 1 u nless ot her wise s pecifie d) . A d di tio n al m o nit ori n g ma y be 
re q uire d if it is dee me d necessar y  b y t he i n vestig a t or.  

P atie nts wit h o ut C o nc urre nt I nfecti o n:   If t here is n o c o nc urre nt i nfecti o n t hat re q uires 
s yste mic a nti-i nfecti ve t hera p y, t he ne utr o p hil c o u nt is t o be m o nit ore d usi n g t he 
re q uire d st u d y visits i n t he P ost-Treat me nt F oll o w -U p Peri o d ( Peri o d 4) : Vi sit 8 0 1 ( 4 

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wee ks p ost -E T V or last re g ularl y sc he d ule d visit) a n d Visi t 8 0 2 . A d di tio nal  m o nit ori n g 
ma y be re q uire d if it is dee me d necessar y  b y t he i n vesti gat or.
9. 4. 1 0. 2. 3. P o st - Tr e at m e nt F oll o w-U p P eri o d
At Visit 8 0 1 a n d V 8 0 2, t he f o ll owi n g m o nit ori n g a p plies:

As l on g as a patie nt’s ne utr o p hil c o u nt is < 1 0 0 0 cells/ L ( < 1. 0 0 x 1 0 3 /µ L or < 1. 0 0 GI/ L)
at a n y fol l ow- u p visit, t he patie nt is t o ret ur n f or visits at least Q 4 W ( ma y re q uire 
u nsc he d ule d visits).  

As l o n g as a pa tie nt’s ne utr o p hil c o u nt is ≥1 0 0 0 cells/ L a n d < 1 5 0 0 cells/ L 
(≥1. 0 0 x 1 0 3 /µ L a n d < 1. 5 0 x 1 0 3 /µ L or ≥1. 0 0 GI/ L a n d < 1. 5 0 GI/ L) at a n y f o ll ow- u p visit, 
t he patie nt is t o ret ur n f or a d diti onal visi t(s) at least e ver y 4 t o 8 wee ks ( ma y re q uire 
u nsc he d ule d visits) .  
If, at Visit 8 0 2 , t he patie nt’s ne utr o p hil c o u nt re mai ns < 1 5 0 0 cells/ L ( < 1. 5 0 x 1 03 / µ L or 
< 1. 5 0 GI/ L) a n d less t ha n t he patie nt’s baseli ne ne utr o p hil c o u nt, or if t he i n vest i gat or dee ms 
a d ditio nal  f oll o w-u p m a y be necessar y, t he i n vesti gat or will deter mi ne t he a p pr o priate 
ma na ge me nt of t he patie nt a n d t he a p pr o priate ti mi n g of a d dit i on al  c o ntact(s).
9. 4. 1 0. 3. H e p atiti s B M o nit ori n g
P ati e nts t hat are H Bc A b + at scree ni n g, re gar dless of ot her he pat itis B testi n g res ults, will ha ve a 
ser u m H B V D N A s peci me n o btai ne d t o be a nal yze d b y t he ce ntral la b orat or y.  S uc h p atie nts t hat 
are deter mi ne d t o be H B V D N A ne gat i ve ( u n detecta ble) ma y be e nr olle d i nt o t he st u d y wit h 
re q uire d H B V D N A m onit ori n g e ver y  3 t o 4 m o nt hs d ur i n g treat me nt a n d 1 2 wee ks after t he last 
d ose of i xe kiz u ma b .  P ati e nts t hat are f o u n d t o be H B V D N A p osit i ve ( detecta ble) at scree ni n g 
will be e xcl u de d fr o m t he trial.  
If t he res ult of a n y s u bse q ue nt H B V D N A testi n g is p osit i ve, t he patie nt is t o be dis c o nt i n ue d 
fr om t he st u d y treat me nt, is t o c o nti n ue safety f oll o w u p, a n d is t o recei ve a p pr o priate f oll ow- u p 
me dical care, i ncl u di n g c o nsi derat i on f or a nti viral t hera p y. A s pecialist p h ysicia n i n t he care of 
pati e nts wit h he patitis (f or e xa m ple, i nfecti ou s disease or he pat ol o gist s u bs pecialists) is t o be 
c o ns ulte d a n d p ote ntiall y start a nti viral t hera p y pri or t o disc o nti n uati on of a n y  
i m m u n os u p pressa nt or i m m u n o m o d ul at or y t hera p y (i ncl u di n g i n vest i gati onal dr u g). Ti mi n g of 
di sc o nti n uati on fr om t he st u d y an d of a n y  i m m u n os u p pressa nt/i m m u n om o d ul at or y t hera p y 
(incl u di n g i n vesti gat i onal pr o d uct) nee ds t o be base d o n t he rec o m me n dat i ons of t he c o ns ult i n g 
s pecialist p h ysicia n i n c o nj u nct i on wi t h t he i n vesti gat or a n d me dical g ui deli nes/sta n dar d of care.
9. 4. 1 0. 4. H y p ert e n s i o n
P ati e nts w h o e x perie nce c ha n ges i n B P (s yst olic B P at ≥1 6 0 m m H g pl us ≥2 0 m m H g i ncrease 
fr om baseli ne [ Wee k 0, Vi sit 2]; a n d/ or diast olic B P at ≥1 0 0 m m H g pl us ≥1 0 m m H g i ncrease 
fr om baseli ne) o n 2 c o nsec uti ve visit s are t o recei ve i nter ve nti on f or the ma na ge me nt of 
h y perte nsi o n.  I nter ve nt i on c o ul d i ncl u de t he ma xi mal i nter ve nt i on of wit h h ol di n g t he d ose of 
i n vesti gati onal pr o d uct a n d/ or t he i ntr o d ucti o n of a nt i-h y perte nsi ve a ge nt(s) as me dicall y 
a p pr o priate. 

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F or ot her A E SIs or a b n or mal la b res ults, pl ease refer t o t he a p pr o priate pr ot oc ol sect i on t hat 
a d dresses t hese t o pics.  T o e ns ure patie nt safet y a n d c o mpl y wit h re g ulat or y  g uida nce, t he 
i n vesti gat or is t o c o ns ult wit h t he Lill y cli nical researc h p h ysicia n/cli nical researc h scie ntist 
re gar di n g c ollecti on of s pecific rec o m me n de d cli nical i nf or mat i on a n d f o ll ow- u p la b orat or y  
tests.  See A p pe n di x 4 .
9. 5.
P h ar m a c o ki n eti c s
At  t he visits a n d ti mes s pecifie d i n t he Sc he d ule of Act i vities (Secti o n 2 ), ve n o us bl o o d sa m ples 
of  a p pr o xi matel y 4 m L eac h will  be c ollecte d t o deter mi ne t he ser u m c o nce ntrati o ns of 
i xe kiz u ma b.  T hese bl o o d sa m ples f or P K a nal ysis are matc he d t o t he ti mi n g of sa m ples f or t he 
assess me nt of i m m u n o ge nicity.   It is e x pecte d t hat t hese P K sa m ples will all ow s ufficie nt 
descri pt i on of i xe kiz u ma b P K pr ofiles at stea d y  state t hr o u g h o ut t he st u d y.  I nstr uctio ns f or t he 
c ollect i on a n d ha n dli n g of bl o o d sa m ples will be pr o vi de d b y t he s p o ns or .  T he act ual date a n d 
ti me ( 2 4- h o ur cl oc k ti me) of eac h sa m pli n g will be rec or de d.
S a m ples c o llecte d f or P K a nal ysis will be teste d at a la b orat or y a p pr o ve d b y Lill y or its desi g nee.  
C o nce ntrati o ns of i m m u n oreacti ve i xe kiz u ma b i n h u ma n ser u m will be deter mi ne d b y a 
vali date d m et h o d.
Bi oa nal y tic al sa m ples c ollecte d t o meas ure i n vest i gati o nal pr o d uct c o nce ntrati o n will be retai ne d 
f or a ma xi m u m of 1 year f oll o wi n g last patie nt visit f or t he st u d y.
9. 6.
P h ar m a c o d y n a mi c s
N ot a p plica ble
9. 7.
G e n eti c s
N ot a p plica ble.
9. 8.
H e alt h E c o n o mi c s
Refer t o 9. 1. 3.

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 7 1
L Y 2 4 3 9 8 2 1
1 0. St ati sti c al C o n si d er ati o n s
1 0. 1. S a m pl e Si z e D et er mi n ati o n
A p pr o xi matel y  1 4 0 pat ient s will be ra n d omize d at a 1: 1 rati o i n t he Bli n de d Treat me nt D osi n g 
P eri o d ( Peri o d 2) t o i xe kiz u ma b 8 0 m g Q 4 W w ith a starti n g d ose 1 6 0 m g a n d place b o. 
F or 9 0 % p o wer t o test t he s u peri orit y of  ixe kiz u ma b Q 4 W t o place b o f or A S A S 4 0 at Wee k 1 6 i n 
b D M A R D -naï ve patie nts, at least 6 1 b D M A R D -naï ve pat ient s per treat me nt gr o u p w o ul d be 
nee de d .  T he f oll owi n g ass u m pt i ons were use d f or t he p o wer calc ulat i ons f or A S A S 4 0 res p o nse 
rates:  4 4 % f or i xe kiz u ma b 8 0 m g Q 4 W treat me nt gr o u p a n d 1 6 % f or t he pl ace b o gr o u p i n 
b D M A R D naï ve patie nts .  
F or t he ke y  sec o n dar y efficac y e n d p oi nt A S A S 4 0 res p o nse at Wee k 1 6 c o m pare d t o place b o 
gr o u p i n o verall st u d y  p o p ulatio n, t he p o wer w o ul d be > 9 0 %. T he ass u m pt i ons are 4 2 % res p o nse 
rate f or i xe kiz u ma b 8 0 m g Q 4 W treat me nt gr o u p a n d 1 5 % f or t he pl ace b o gr o u p i n o verall st u d y 
p o p ul at i on.
T hese ass u m pt i ons are base d o n t he re vie w o f hist ori cal cli nical st u dies i n r-a x S p A (eta nerce pt, 
a dali m u ma b, i nfli xi ma b, cert oliz u ma b, a n d g o li m u ma b [ Da vis et al. 2 0 0 3; va n der Heij de et al. 
2 0 0 5, 2 0 0 6; I n ma n et al. 2 0 0 8, La n de w é et al . 2 0 1 4]) a n d rece nt sec u ki n u ma b trials i ncl u di n g 
b ot h T N F in hi bit or e x perie nce d pat ient s a n d naï ve patie nts ( Baete n et al. 2 0 1 4b ; Sie per et al.
2 0 1 4).  
A 2 -si de d Fis her’s e xact test at t he 0. 0 5 le vel is ass u me d. S a m ple size a n d p o wer esti mates were 
o btai ne d fr o m n Q uer y ® A d vis or 7. 0.
1 0. 2. P o p ul ati o n s f or A n al y s e s
F or p ur p oses of a nal ysis, t he f oll o wi n g p o p ulat i ons are defi ne d:
P o p ul ati o n
Descri pti o n
I nte nt-t o-Tre at P o p ul ati o n 
(I T T)
U n less ot her wise s pecifie d, efficac y a n d healt h o utc o mes a nal yses f or Peri o d 2 
will be c o n d ucte d o n t he I T T p o p ulati o n, defi ne d as all ra n d o mize d patie nts, 
e ve n if t he patie nt d oes n ot ta ke t he assi g ne d treat me nt, d oes n ot recei ve t he 
c orrect treat me nt, or ot her wise d oes n ot f oll o w t he pr ot oc ol.  Patie nts will be 
a nal yze d acc or di n g t o t he treat me nt t o w hic h t he y were assi g ne d.
Per -Pr ot oc ol Set ( P P S)
I n a d diti o n, t he pri mar y efficac y a nal ysis will be re peate d usi n g t he P P S, 
w h ic h is defi ne d as all ra n d o mized patie nts w h o are c o m plia nt wit h t hera p y, 
w h o d o n ot ha ve a s u bset of i m p orta nt pr ot oc ol de viati o ns t hat i m pact t he 
pri mar y  efficac y e n d p oi nt, a n d w h ose i n vesti gat or site d oes n ot ha ve 
si g nifica nt G C P iss ues t hat re q uire a re p ort t o t he re g ulat or y a ge ncies pri or t o 
Wee k 1 6 ( Visit 8).  C o m plia nce wit h t hera p y is defi ne d t o be missi n g n o m ore 
t ha n 2 0 % of e x pecte d d oses, n ot missi n g 2 c o nsec uti ve d oses (all i njecti o ns at 
a visit are c o u nte d as 1 d ose), a n d n ot ha ve a n y occ urre nce of o ver -d osi n g (t hat 
is, t o o k m ore i njecti o ns at t he sa me ti me p oi nt t ha n s pecifie d i n t he pr ot oc ol) 

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 7 2
L Y 2 4 3 9 8 2 1
d uri n g Peri o d 2.
I m p orta nt pr ot oc ol de viati o ns will be descri be d i n t he S A P.  Patie nts will be 
a nal yze d acc or di n g t o t he treat me nt t o w hic h t he y were assi g ne d.
S afet y P o p ul ati o n
Safet y a nal yses f or Peri o d 2 will be c o n d ucte d o n t he Safet y P o p ulati o n, 
defi ne d as all ra n d o mize d patie nts w h o recei ve d at least 1 d ose of st u d y 
treat me nt.  Patie nts will be a nal yze d acc or di n g t o t he treat me nt t o w hic h t he y 
were assi g ne d i n t hat peri o d.
E xte n de d Tre at me nt Peri o d 
P o p ul ati o n
Efficac y, healt h o utc o mes, a n d safet y a nal yses f or Peri o d 3 will be c o n d ucte d 
o n t he E xte n de d Treat me nt Peri o d P o p ulati o n, defi ne d as all patie nts w h o 
recei ve d at least 1 d ose of i xe kiz u ma b treat me nt d uri n g Peri o d 3.
F oll o w -U p P o p ul ati o n
Safet y a nal yses f or Peri o d 4 will be c o n d ucte d o n t he F oll o w - U p Po p ulati o n, 
defi ne d as all ra n d o mize d patie nts w h o recei ve d at least 1 d ose of st u d y 
treat me nt a n d ha ve e ntere d Peri o d 4.  Patie nts will be a nal yze d acc or di n g t o 
t he treatme nt t he y recei ve d bef ore e nteri n g Peri o d 4 .
A b bre viati o n s: G C P = g o o d cli nical practice; I T T = I nte nt-t o-Treat P o p ulati o n; P P S = Per -Pr ot oc ol Set; S A P = 
statistical a nal ysis pla n.
1 0. 3. St ati sti c al A n al y s e s
Stati stical a nal ysis of t his st u d y will be t he res p o nsi bility of  Lill y.
C o nti n u o us data will be s u m marize d i n ter ms of t he mea n, sta n dar d de viat i on, mi ni m u m, 
ma xi m u m, me dia n, a n d n u m ber of o bser vat i ons.  Cate g orical data will be s u m marize d as 
fre q ue nc y c o u nts a n d perce nta ges.
A n y c ha n ge t o t he data a na l ysis met h o ds descri be d i n t he pr ot oc ol will re q uire a n a me n d me nt 
O N L Y if it c ha n ges a pri nci pal feat ure of t he pr ot oc ol.  A n y ot her c ha n ge t o t he data a nal ysis 
met h o ds descri be d i n t he pr ot oc ol, a n d t he j ust ificati o n f or ma ki n g t he c ha n ge, will be descri be d 
i n t he cli nical st u d y re p ort ( C S R).  A d ditio nal e x pl orat or y  a nal yses of t he data will be c o n d ucte d 
as dee me d a p pr o priate.  
C o m plete details of t he pla n ne d a nal yses will be d oc u me nte d i n t he S A P.
1 0. 3. 1. G e n er al C o n si d er ati o n s f or A n al y s e s d uri n g t h e Bli n d e d 
Tr e at m e nt D o si n g P eri o d ( P eri o d 2)
C o m paris o n bet wee n i xe kiz u ma b 8 0 m g Q 4 W a n d place b o will be perf or me d f or all a nal yses i n 
P eri o d 2 .  
P eri o d 2 starts at t he first i nject i on of st u d y  treat me nt at Wee k 0 ( Visit 2) a n d e n ds pri or t o t he 
first i njecti on of st u d y  treat me nt at Wee k 1 6 ( Visit 8 ) or t he E T V ( bet wee n Wee ks 0 a n d 1 6).
Baseli ne will be defi ne d as t he last a vaila ble val ue bef ore t he first i nject i on f or efficac y, health 
o utc o m es, a n d safet y a nal yses.  I n m ost cases, t his will be t he meas ure rec or de d at Wee k 0 ( Vi sit
2).  F or efficac y meas ures, if t he patie nt d oes n ot ta ke a n y i njecti o n, t he last a vaila ble val ue o n or 
pri or t o ra n d o mizat i on date will be use d.  C ha n ge fr o m baseli ne will be calc ulate d as t he visit 
val ue of i nterest mi n us t he baseli ne val ue .  F or safet y a nal yses usi n g a baseli ne peri o d, t he 
baseli ne peri o d is defi ne d as t he ti me fr o m Visi t 1 t o t he date/ti me of t he first i njecti on.

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 7 3
L Y 2 4 3 9 8 2 1
T he ra n d o mizat i on t o treat m e nt gr o u ps is stratifie d b y baseli ne C R P stat us ( n o n- ele vate d or 
ele vate d) a n d T N F in hi bit or e x perie nce d or naï ve as descri be d i n Secti o n 7. 2 . U nless ot her wise 
s pecifie d, t he statistical a nal ysis m o dels will a dj ust f or baseli ne C R P stat us, a n d pri or T N F
in hi bi t or e x perie nce d or naï ve (if a p plica ble) . 
T he pri mar y  a nal ysis met h o d for treat m e nt c o mparis o ns of cate g ori cal efficac y a n d healt h 
o utc o m es varia bles at s pecific ti me p oi nts will be ma de usi n g a l o gistic re gressi o n a nal ysis wit h 
treat me nt, baseli ne C R P stat us, a n d T N F in hi bit or e x perie nce d or naï ve (if a p plica ble) i n t he 
m o de l.  T he pr o p orti o ns, o d ds rati o a n d 9 5 % c o nfi de nce i nter vals ( CIs) will be re p orte d; 
treat me nt differe nce a n d 9 5 % CIs will als o be re p orte d.  Sec o n dar y  a nal ysis will be c o n d ucte d 
usi n g a Fis her’s e xact test.
T he pri mar y  a nal yses f or c o nti n u o us efficac y a n d healt h o utc o m es varia bles will be ma de usi n g 
M M R M.  A sec o n dar y  a nal ysis f or c o nti n u o us efficac y a n d healt h o utc o mes varia bles ma y als o
be ma de usi n g a nal ysis of c o varia nce ( A N C O V A ).
W he n t he M M R M is use d, t he m o del will i ncl u de treat me nt, baseli ne C R P st at us, T N F in hi bit or 
e x perie nce d or naï ve , baseli ne val ue, baseli ne val ue- b y-visi t, visit, a n d treat me nt - b y-visi t 
i nteract i on as fi xe d fact ors.  T he c o varia nce str uct ure t o m o del t he wit hi n -pat ient  err ors will be 
u nstr uct ure d.  If t he u nstr uct ure d c o varia nce matri x res ults i n a lac k of c o n ver ge nce, t he 
heter o ge ne o us T oe plitz c o varia nce str uct ure, f o ll owe d b y  t he heter o ge ne o us a ut ore gressi ve 
c o varia nce str uct ure, f oll o we d b y t he c o m p o u n d s y m metr y , will be use d.  T hi s or der is s pecifie d 
acc or di n g t o a decreasi n g n u m ber of c o varia nce para meters i n t he str uct ure. T he Ke n war d -
R o ger m et h o d will be use d t o esti mate t he de n o mi nat or de grees of free d o m.   T y pe III tests f or 
t he least -s q uares ( L S) mea ns will be use d f or t he statist ical c o mparis o n; t he 9 5 % CI wi ll als o be 
re p orte d.  Treat me nt gr o u p c o m paris o ns wit h place b o at Wee k 1 6 ( Visit 8) a n d all ot her visits 
will be teste d.
W he n t he A N C O V A is use d, t he m o del will i ncl u de treat me nt, baseli ne C R P stat us, T N F
in hi bi t or e x perie nce d or naï ve , a n d baseli ne val ue.  T y pe III s u ms of s q uares f or t he L S mea ns 
will be use d f or t he statist ical c om par is o n; t he 9 5 % CI will als o be re p orte d.
F or vari a bles t hat are n ot c ollecte d at eac h p ost baseli ne visit, data ma y  e xist at visits w here t he 
varia ble was n ot sc he d ule d t o be c ollecte d, d ue t o earl y disc o nt i n uati on visit s.  I n t hese 
sit u atio ns, data fr o m  t he earl y disc o nti n uatio n visi t t hat d o n ot c orres p o n d t o t he pla n ne d 
c ollect i on sc he d ule will be e xcl u de d fr o m t he M M R M a nal yses.  H o we ver, t he data will st ill be 
use d i n ot he r a nal yses, i ncl u di n g s hift a nal yses, m o difie d baseli ne o bser vati on carri e d for war d 
( mB O C F) e n d p o i nt a nal yses a n d ot her cate g orical a nal yses.
Fis her’s e xact test will be use d f or all A E, baseli ne, disc o nti n uat i on, a n d ot her cate g orical safet y 
data.  C o nt i nu o us vi t al si g n a n d la b orat or y val ues will be a nal yze d b y a n A N C O V A wit h 
treat me nt a n d baseli ne val ue i n t he m o del.

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 7 4
L Y 2 4 3 9 8 2 1
1 0. 3. 2. G e n er al C o n si d er ati o n s f or A n al y s e s d uri n g t h e E xt e n d e d 
Tr e at m e nt P eri o d ( P eri o d 3) 
U nless ot her wise s pecifie d, Peri o d 3 starts at t he first i njecti o n of st u d y tr e at me nt at Wee k 1 6 
( Visit 8) a n d e n ds o n t he date of Wee k 5 2 ( Visit 17 ) or t he E T V ( bet wee n Wee ks 1 6 a n d 5 2).
F or t he efficac y a n d healt h o utc o mes a nal yses, baseli ne is defi ne d as t he last a vaila ble val ue 
bef ore t he first i nject i on in Peri o d 2 a n d, i n m ost cases, t his will be t he val ue rec or de d at Wee k 0 
( Visit 2).
U nless ot her wise s pecifie d, f or t he safet y a nal yses d uri n g Peri o d 3, baseli ne is defi ne d as t he last 
a vaila ble val ue bef ore first i nject i on of i xe kiz u ma b i n Peri o d 3.  I n m ost cases, t his will be t he 
meas ure rec or de d at Wee k 1 6 ( Visit 8 ).
All efficac y a n d safety data c ollecte d will be s u m marize d usi n g descri pti ve statist ics.
1 0. 3. 3. G e n er al C o n si d er ati o n s f or A n al y s e s d uri n g t h e P o st -
Tr e at m e nt F oll o w -U p P eri o d ( P eri o d 4)
F or t he safet y a nal yses d uri n g Peri o d 4, baseli ne is defi ne d as t he last n o n missi n g assess me nt o n 
or pri or t o e nteri n g Peri o d 4, t hat is, o n or pri or t o Wee k 5 2 ( Visit 1 7 ), or E T V.  
S af et y data c ollecte d will be s u m marize d usi n g descri pt i ve statistics.
1 0. 3. 4. Mi s si n g D at a I m p ut ati o n 
I n acc or da nce wit h prece de nt set wit h ot her P hase 3 a x S p A trials ( va n der Heij de et al. 2 0 0 6; 
I n ma n et al. 2 0 0 8), t he f oll owi n g met h o ds f or i m p utati o n of missi n g data will be use d.
1 0. 3. 4. 1. N o nr e s p o n d er I m p ut ati o n 
A nal ysis of cate g orical eff icac y a n d health o utc o mes varia bles will be assesse d usi n g a 
n o nres p o n der i m p utati o n ( N RI) met h o d .  Patie nts will be c o nsi dere d n o nres p o n ders f or t he N RI 
a nal ysis if t he y d o n ot meet t he cli nical res p o nse criteria or ha ve missi n g cli nical res p o nse data at 
t he pri mar y a nal ysis t i me p oi nt.  All n o nres p o n ders at Wee k 1 6 ( Visit 8), as well as all patie nts 
w h o disc o nt i n ue st u d y treat me nt at a n y time pri or t o Wee k 1 6 f or a n y  reas o n, will be defi ne d as 
n o nres p o n ders f or t he N RI a nal ysis at Wee k 1 6.  Ra n d o mize d pat ient s wit ho ut at l east 
1 p ost baseli ne o bser vati o n will als o be defi ne d as n o nres p o n ders f or t he N RI a nal ysis.
T he N RI m a y be a p plie d at a n y time p oi nt s pecifie d f or a nal ysis.
1 0. 3. 4. 2. M o difi e d B a s eli n e O b s er v ati o n C arri e d F or w ar d
A n m B O C F a nal ysis will be perf or me d o n efficac y a n d healt h o utc o mes varia bles i n t he maj or 
a n d ot her sec o n dar y o bject i ves.  F or patie nts disc o nti n ui n g st u d y dr u g d ue t o a n A E, t he baseli ne 
o bser vat i on will  be carrie d for war d t o t he c orres p o n di n g ti me p oi nt f or e val uat i on.  F or pati e nts 
di s co nti n ui n g st u d y  dr u g f or a n y ot her reas o n, t he last n o n missi n g o bser vati o n bef ore 
di sc o nti n uati on will  be carrie d for war d t o t he c orres p o n di n g t i me p oi nt f or e val uati o n.  
Ra n d o mize d patie nts wit h o ut at least 1 p ost baseli ne o bser vat i on will n ot be i ncl u de d f or 
e val uat i on wi t h t he e xce pti on of pat ient s disc o nti n ui n g st u d y treat me nt beca use of a n A E.

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P a g e 7 5
L Y 2 4 3 9 8 2 1
1 0. 3. 5. A dj u st m e nt f or M ulti pl e C o m p ari s o n s 
A m ult i ple testi n g strate g y for t he pri mar y  a nd m aj or sec o n dar y o bjecti ves will be i m ple me nte d 
t o c o ntr ol t he o verall fa mil y-wise t y pe I err or rate at a 2 -si de d α le vel of 0. 0 5.  A gra p hical 
m ult i ple testin g pr oce d ure ( Bretz et al. 2 0 1 1) will be use d .  T he gra p hical a p pr oac h is a cl ose d 
testi n g pr oce d ure; he nce, it str o n gl y c o ntr ols t he fa mil y-wise err or rate ( Al os h et al. 2 0 1 4) .  T he 
f oll owi n g is a list of pri mar y  a n d major sec o n dar y  o ut co m es t o be teste d f or i xe kiz u ma b 8 0 m g 
Q 4 W at Wee k 1 6:

Pri mar y:
pr o p orti o n of  patient s ac hie vi n g a n A S A S 4 0 res p o nse [ A S A S 4 0 naï ve ] i n 
b D M A R D -naï ve patie nts

Sec o n dar y  1: pr o p orti o n of  patient s achie vi n g a n A S A S 4 0 res p o nse [ A S A S4 0 o verall ]
i n o verall st u d y p o p ulatio n

Sec o n dar y  2: pr o p orti o n of  patient s ac hie vi n g a n A S A S 2 0 res p o nse [ A S A S 2 0] i n 
o verall st u d y  p o p ulat i on

Sec o n dar y  3: c ha n ge fr o m baseli ne i n A S D A S sc ore [ A S D A S C F B] i n o verall st u d y 
p o p u lati on

Sec o n dar y  4: c ha n ge fr o m baseli ne i n B A S D AI [ B A S D AI C F B ] i n o verall st u d y 
p o p ul at i on

Sec o n dar y  5: c ha n ge fr o m baseli ne i n B A S FI [ B A S FI C F B] i n o verall st u d y p o p ulati on

Sec o n dar y  6: pr o p orti o n of  patient s ac hie vi n g A S D A S < 2. 1 [ A S D A S < 2. 1 ] i n o verall 
st u d y p o p ulat i on

Sec o n dar y  7: c ha n ge fr o m baseli ne i n M RI of t he s pi ne [ M RI s pi ne S P A R C C sc ore 
C F B] i n o verall st u d y p o p ulat i on

Sec o n dar y  8: c ha n ge fr o m baseli ne i n S F-3 6 P C S sc ore [ S F -3 6 P C S C F B] i n o verall 
st u d y p o p ulat i on
Details o f t he s pec ific gra p hical testi n g sc he me (i ncl u di n g testi n g or der, i nterrelati ons hi ps, t y pe I
err or all ocat i on f or t he maj or sec o n dar y e n d p oi nts, a n d t he ass ociate d pr o pa gati o n of α ) t o be
i m ple me nte d will be pres pecifie d i n t he S A P pri or t o first u n bli n di n g.
T here will be n o a dj ust me nt  for m ul tiple c o m paris o ns f or a n y  ot her a nal yses.  
1 0. 3. 6. Tr e at m e nt Gr o u p C o m p ar a bilit y
1 0. 3. 6. 1. P ati e nt Di s p o siti o n
All patie nts w h o pre mat urel y disc o nti n ue fr o m t he st u d y tr e at me nt a n d/ or fr o m t he st u d y will be 
i de ntifie d, a n d t he e xte nt of their partici pati o n i n t he st u d y  will be re p orte d.
P ati e nt dis p ositio n will be s u m marize d f or eac h treat me nt peri o d wit h reas o ns f or 
di sc o nti n uati on.  T he reas o ns f or disc o nti n uati o n d uri n g Peri o d 2 will be c o m pare d bet wee n 
treat me nt gr o u ps usi n g Fis her’s e xact test.
1 0. 3. 6. 2. P ati e nt C h ar a ct eri sti c s
P ati e nt c haracterist ics a n d baseli ne cli nical meas ures will be s u m marize d f or eac h treat me nt 
p eri o d.  Baseli ne c haracterist ics will i ncl u de se x, a ge, a ge cate g or y, w eig ht, b o d y  mass i n de x 

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 7 6
L Y 2 4 3 9 8 2 1
( B MI), race, baseli ne disease acti vity ( B A S D AI), d urati o n of disease, H L A -B 2 7 p osi tivit y,  
baseli ne C R P ( % of n o n- ele vate d or ele vate d), baseli ne M RI stat us, n u m ber of pri or T N F
in hi bi t or e x perie nce d or naï ve , a n d hist or y of e xtra-a xial disease ma nifestati o ns.  Baseli ne 
cli nical meas ure me nts ma y i ncl u de A S D A S, C R P, B A S FI, B A S MI, c hest e x pa nsi o n, F A CI T , 
P ati e nt Glo b al  N R S, t otal bac k pai n, s pi nal pai n at ni g ht d ue t o A S, s pi nal pai n d ue t o A S, 
i nfla m mati on ( mea n of q uest i ons 5 a n d 6 of B A S D AI), M A S E S .
Treat me nt gr o u p c o m paris o ns i n Peri o d 2 will be c o n d ucte d usi n g Fis her’s e xact test f or 
cate g orical data a n d a n a nal ysis o f varia nce ( A N O V A ) wi t h tr e at me nt as a fact or f or c o nti n u o us 
data.
1 0. 3. 6. 3. C o n c o mit a nt T h er a p y 
Pre v i ous a n d c o nc o mita nt me dicat i ons will be s u m marize d f or patie nts w h o e nter eac h treat me nt 
p eri o d a n d will be prese nte d b y  W H O A nat o mic T hera pe utic Class Le vel 4 a n d W H O preferre d 
t er m.  C o nc omit a nt D M A R Ds, c o nc o mit a nt oral c ortic oster oids, a n d c o nc o mit a nt N S AI Ds will 
als o be s u m marize d.  Treat me nt gr o u p c o m paris o ns i n Peri o d 2 will be c o n d ucte d usi n g Fis her’s 
e xact test.
1 0. 3. 6. 4. Tr e at m e nt C o m pli a n c e
Treat me nt c o m plia nce wit h i n vesti gati o nal pr o d uct will be s u m marize d f or patie nts w h o e nter 
eac h treat me nt peri o d.   A patie nt will be c o nsi dere d o verall c o m p lia nt f or eac h st u d y p erio d if  
he/s he is missi n g n o m ore t ha n 2 0 % of t he e x pecte d d oses, d oes n ot miss 2 c o nsec ut i ve d oses 
a n d d oes n ot o ver - d ose (t hat is, ta ke m ore i njecti ons at t he sa me ti me p o i nt t ha n s pecifie d in t he 
pr ot oc ol ).
Pr o p orti o ns of pat ient s c o mplia nt b y  visit a n d o verall will be c o m pare d bet wee n treat me nt 
gr o u ps d uri n g Peri o d 2 usi n g Fis her’s e xact test.
1 0. 3. 7. Effi c a c y A n al y s e s
1 0. 3. 7. 1. Pri m ar y A n al y s e s
T he pri mar y  a nal ysis, t he pr o p orti o n of  patie nts wit h A S A S 4 0 at Wee k 1 6 c o m pare d wit h 
pl ace b o, will be base d o n t he I T T P o p ulat i on i n b D M A R D -naï ve patie nts .  I n a d ditio n, a n 
a nal ysis of t he P P S P o p ulat i on will be use d t o s u p p ort t he pri mar y efficac y a nal ysis.
Treat me nt c o m paris o ns bet wee n t he i xe kiz u ma b treat me nt gr o u p a n d place b o i n t he pr o p orti o n 
of  p atie nts ac hie vi n g a n A S A S 4 0 res p o nse at Wee k 1 6 ( Visit 8) will be a nal yze d usi n g t he 
l ogist ic re gressi on m o d el  defi ne d i n Sect i on 1 0. 3. 1 .  Missi n g data will be i m p ute d usi n g t he N RI 
met h o d descri be d i n Sect i on 1 0. 3. 4 .
Sec o n dar y  a nal yses f or A S AS 4 0 at Wee k 1 6 will be c o n d ucte d usi n g Fis her’s e xact test as 
descri be d i n Secti o n 1 0. 3. 1 .

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L Y 2 4 3 9 8 2 1
1 0. 3. 7. 2. S e c o n d ar y A n al y s e s
1 0. 3. 7. 3. M aj or S e c o n d ar y A n al y s e s 
T he m ajor sec o n dar y a nal yses at Wee k 1 6 will be base d o n t he I T T p o p ulati o n f or Perio d 2 .  T he 
maj or sec o n dar y  c o mparis o ns will be base d o n t he m ult i ple testin g pr oce d ure detaile d i n 
Secti o n 1 0. 3. 5 .  Treat me nt c o m paris o ns i n t he pr o p orti o n of patie nts ac hie vi n g a cate g orical 
res p o nse at Wee k 1 6 ( Visit 8) will be a nal yze d usi n g t he l ogi stic re gressi on m o d el  defi ne d i n 
Secti o n 1 0. 3. 1 . F or cate g orical res p o nses, missi n g data will be i m p ute d usi n g t he N RI met h o d 
descri be d i n Secti o n 1 0. 3. 4 .  Treat me nt c o m paris o ns i n t he c o nt i n u o us meas ures will be a nal yze d 
usi n g t he M M R M m o del defi ne d i n Sect i on 1 0. 3. 1 .
Ta ble R H C H. 4 s u m marizes t he pri mar y a n d major sec o n dar y  o ut c o mes a n d a nal ysis met h o ds. 
All a nal yses liste d will be perf or me d base d o n t he I T T P o p ulat i on u nless ot her wise s pecifie d.

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 7 8
L Y 2 4 3 9 8 2 1
T a bl e R H C H. 4.
Pri m ar y a n d M aj or S e c o n d ar y O ut c o m e A n al y s e s
O utc o me Me as ure
Pri m ar y A n al ysis Met h o d 
Sec o n d ar y A n al ysis Met h o d 
A S A S 4 0 ( pri mar y efficac y 
o utc o me) i n b D M A R D-naï ve 
patie nts
L o gistic re gressi o n a nal ysis wit h 
N RI 
Fis her’s e xact test wit h N RI
L o gistic re gressi o n a nal ysis wit h 
N RI o n P P S 
A S A S 4 0 ( maj or sec o n dar y 
o utc o me) i n o verall st u d y 
p o p ulati o n
L o gistic re gressi o n a nal ysis wit h 
N RI 
Fis her’s e xact test wit h N RI
L o gistic re gressi o n a nal ysis wit h 
N RI o n P P S 
A S A S 2 0 ( maj or sec o n dar y 
o utc o me)
L o gistic re gressi o n a nal ysis wit h 
N RI
Fis her’s e xact test wit h N RI
C ha n ge f r om baseli ne i n A S D A S 
( maj or sec o n dar y o utc o me)
M M R M
A N C O V A wit h m B O C F
C ha n ge f r om baseli ne i n B A S D AI 
( maj or sec o n dar y o utc o me)
M M R M
A N C O V A wit h m B O C F
C ha n ge f r om baseli ne i n B A S FI 
( maj or sec o n dar y o utc o me)
M M R M
A N C O V A wit h m B O C F
A S D A S < 2. 1 ( maj or sec o n dar y 
o utc o me)
L o gistic re g ressi o n a nal ysis wit h 
N RI
Fis her’s e xact test wit h N RI
C ha n ge f r om baseli ne i n M RI of 
s pi ne [ S P A R C C sc ore] ( maj or 
sec o n dar y o utc o me)
A N C O V A wit h o bser ve d case 
a nal ysisa
Sec o n dar y a nal ysis ma y be 
s pecifie d i n S A P
C ha n ge f r om baseli ne i n S F -3 6 
P C S ( maj or sec o n dar y o utc o me)
M M R M
A N C O V A wit h m B O C F
A b bre viati o ns:  A N C O V A = a nal ysis of c o varia nce; A S A S = Assess me nt of S p o n d yl oart hritis I nter nati o nal S ociet y; 
A S D A S = A n k yl osi n g S p o n d ylitis Disease Acti vit y Sc ore; B A S D AI 5 0 = Bat h A n k yl osi n g S p o n d ylitis Disease 
Acti vit y  I n de x 5 0; B A S FI = Bat h A n k yl osi n g S p o n d ylitis F u ncti o nal I n de x; m B O C F =  m o difie d baseli ne 
o bser vati o n carrie d f or war d; M M R M = mi xe d -effects m o del of re peate d meas ures; M RI = ma g netic res o na nce 
i ma gi n g; N RI = n o nres p o n der i m p utati o n; P P S = per-pr o t oc ol set; S A P = statistical a nal ysis pla n; S F-3 6 P C S = 
S h ort F or m -3 6 p h ysical c o m p o ne nt sc ores; S P A R C C = S p o n d yl oart hritis Researc h C o ns orti u m of Ca na da. 
a
O nl y patie nts wit h b ot h baseli ne a n d Wee k 1 6 M RI sc ores will be i ncl u de d i n t he o bser ve d case a nal ysis.
1 0. 3. 7. 4. Ot h er S e c o n d ar y Effi c a c y A n al y s e s 
T here will be n o a dj ust me nt  for m ul tiple c o m paris o ns.  A nal yses will be c o n d ucte d f or t he ot her 
sec o n dar y efficac y o bjecti ves defi ne d i n Sect i on 4 .  S pecific details o f a nal yses will be s pecifie d 
i n t he S A P.
P eri o d 2 ( Bli n de d Treat me nt D osi n g Peri o d)
U nless ot her wise s pecifie d , t he ot her sec o n dar y a nal yses d uri n g Peri o d 2 will be base d o n t he 
I T T P o p ulat i on.
Treat me nt c o m paris o ns i n t he pr o p orti o n of patient s ac hie vi n g a cate g orical res p o nse at s pecifie d 
ti me p oi nts will be a nal yze d usi n g t he l ogist ic re gressi on m o d el  defi ne d i n Secti on 1 0. 3. 1 . 
Missi n g data will be i m p ute d usi n g t he N RI met h o d descri be d i n Sect i on 1 0. 3. 4 .
F or all c o nti n u o us efficac y varia bles t hat are c ollecte d at re peate d visit s, treat me nt gr o u p 
c o mparis o ns will be a nal yze d usi n g t he M M R M m o del  defi ne d i n Secti o n 1 0. 3. 1 .  N o i m p utati o n 

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
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met h o ds are a p plie d t o M M R M a nal ysis.  A d dit i on al  a nal yses will be c o n d ucte d usi n g t he 
A N C O V A m o del defi ne d i n Sect i on 1 0. 3. 1 ; missi n g data will be i m p ute d b y t he m B O C F met h o d 
as descri be d i n Sect i on 1 0. 3. 4 .  F or c o ntin u o us efficac y  varia bles t hat are c ollecte d o nl y o nce 
wi t hi n Perio d 2, a nal yses will be m a de usi n g t he A N C O V A m o del wit h t he m B O C F met h o d.
1 0. 3. 7. 4. 1. P eri o d 3 ( E xt e n d e d Tr e at m e nt P eri o d) 
Data c ollecte d i n t his st u d y  p erio d will  be s u m marize d f or t he E xte n de d Treat me nt Peri o d 
P o p ul at i on.  
1 0. 3. 7. 5. T erti ar y/ E x pl or at or y A n al y s e s
Details a b o ut e x pl orat or y  a nal yses will be i ncl u de d i n t he S A P.  
1 0. 3. 8. S af et y A n al y s e s
S af et y will be assesse d b y s u m marizi n g a n d a nal yzi n g A Es i ncl u di n g a dj u dicate d 
cere br ocar di o vasc ular e ve nts, la b orat or y a nal ytes i ncl u di n g ne utr o p hil c o u nts, QI D S-S R 1 6, 
C- S S R S, a n d vital si g ns .  T he d urati o n of treat me nt e x p os ure will als o be s u m marize d
F or Peri o d 2 ( Bli n de d Treat me nt D osi n g Peri o d), safet y data will be s u m marize d f or t he Safet y 
P o p ul at i on .  Tre at me nt gr o u p c o m paris o ns will be perf or me d o n cate g orical safet y data usi n g 
Fis her’s e xact test as descri be d i n Sect i on 1 0. 3. 1 ; c o nti n u o us safety da ta will be a nal yze d b y a n 
A N C O V A m o del.
F or Peri o d 3 ( E xte n de d Treat me nt Peri o d), t he safet y  data will be s u m marize d.  
F or Peri o d 4 ( P ost -Treat me nt F oll o w -U p Peri o d), safety data will be s u m marize d acc or di n g t o 
t he treat me nt patie nts were o n pri or t o e nte ri n g Peri o d 4. 
T he cate g orical safet y meas ures will be s u m marize d wit h i nci de nce rates.  T he mea n c ha n ge of 
t he c o nti n u o us safet y me as ures will be s u m marize d b y visits.
F urt her details will be descri be d i n t he S A P.
1 0. 3. 8. 1. A d v er s e E v e nt s
A d verse e ve nts are classifie d base d u p o n t he Me dical Dict i onar y  for Re g ul at or y Act i vities 
( Me d D R A).  A treat me nt-e mer ge nt a d verse e ve nt ( T E A E) is defi ne d as a n e ve nt t hat first 
occ urre d or w orse ne d i n se verit y after baseli ne a n d o n or pri or t o t he date of t he last visit wit hi n 
t he treat me nt peri o d.  B ot h t he date/ti me of t he e ve nt o nset a n d t he date/ti me of t he first st u d y  
dr u g i nject i on are c o nsi dere d w he n deter mi ni n g T E A Es.  Treat me nt -e mer ge nt a d verse e ve nts 
will be assi g ne d t o t he treat me nt peri o d i n w hi c h t he y first occ urre d or w orse ne d.  A f oll ow- u p 
e mer ge nt a d verse e ve nt ( F E A E) is defi ne d as a n e ve nt t hat first occ urre d or w orse ne d i n se verit y 
after t he date of Wee k 5 2 ( Visit 17 ) or t he E T V.  F or e ve nts t hat are ge n der s pecific, t he 
de n o mi nat or a n d c o m p ut ati o n of  t he perce nta ge will i ncl u de o nl y patient s fr o m t he gi ve n ge n der.
A n o verall s u m mar y o f A Es will be pr o vi de d f or eac h o f t he treat me nt peri o ds, i ncl u di n g t he 
n u m ber a n d perce nta ge of patie nts w h o e x perie nce d T E A Es, T E A Es b y  ma xi m u m se verit y, 
dea t hs, S A Es, T E A Es relate d t o st u d y dr u g, disc o nti n uati ons fr om t he treat me nt d ue t o a n A E, 
a n d treat me nt -e mer ge nt A E SIs.  Treat me nt -e mer ge nt a d verse e ve nts (all, b y ma xi m u m se verit y, 

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 8 0
L Y 2 4 3 9 8 2 1
a n d T E A Es p ossi bl y relate d t o st u d y dr u g b y t he i n vestigat or), S A Es i ncl u d i n g deat hs, a n d A Es 
t hat lea d t o treat me nt disc o nt i n uati on will be s u m marize d a n d a nal yze d b y Me d D R A s yste m 
or ga n class ( S O C) a n d preferre d ter m. 
I n a d diti on t o ge neral safet y para m eters, safet y i nf or matio n o n s pecific t o pi cs of AE SIs will als o 
be prese nt e d.  P ote nti al AE SIs will  be i de nt ifie d b y a sta n dar dize d Me d D R A q uer y ( S M Q) or a 
Lill y defi ne d Me d D R A preferre d ter m list i n g.
F o ll ow- u p e m er ge nt a d verse e ve nts, S A Es i ncl u di n g deat hs, a n d A Es t hat lea d t o st u d y  
di sc o nti n uati on will  be s u m marize d f or Perio d 4 .  
1 0. 3. 8. 2. Cli ni c al L a b or at or y T e st s
La b orat or y  assess me nts will be prese nte d as mea n c ha n ges fr o m baseli ne, a n d as i nci de nce of 
treat me nt -e mer ge nt a b n or mal, hi g h, or l o w la b orat or y val ues (see bel o w).  S hift ta bles will be 
prese nte d f or selecte d para meters. 

F or cate g orical la b tests: 
o
Treat me nt -e mer ge nt a b n or m al v al ue = a c ha n ge fr o m  n or mal at all baseli ne visits 
t o a b n or mal at a n y time p ost baseli ne.

F or c o nti n u o us la b tests: 
o
Treat me nt -e mer ge nt hi g h val ue = a c ha n ge fr o m a val ue less t ha n or e q ual t o t he 
h i g h li mit at all baseli ne visits t o a val ue greater t ha n t he hi g h li mit at a n y time 
p ost baseli ne.  
o
Treat me nt -e mer ge nt l o w val ue = a c ha n ge fr o m a val ue greater t ha n or e q ual t o 
t he lo w li mi t at all baseli ne visits t o a val ue less t ha n t he lo w li mi t at a n y time 
p ost baseli ne.
1 0. 3. 8. 3. Vit al Si g n s, P h y si c al Fi n di n g s, a n d Ot h er S af et y E v al u ati o n s
Vi t al si g ns will be prese nte d as mea n c ha n ges fr o m baseli ne a n d as i nci de nce of treat me nt -
e mer ge nt hig h or l o w val ues (see bel o w) a n d will be s u m marize d b ot h pre - a n d p ost d ose at  Wee k 
0 ( Visit 2) a n d Wee k 1 6 ( Visit 8) as a p plica ble.

F or treat m e nt -e mer ge nt hi g h a n d l o w:
o
A treat me nt -e mer ge nt hig h res ul t is defi ne d as a c ha n ge fr o m a val ue less t ha n or 
e q ual t o t he hi g h li mit at baseli ne t o a val ue greater t ha n t he hi g h li mit at an y t i me 
t hat meets t he s pecifie d c ha n ge criteria d uri n g t he treat me nt peri o d.
o
A treat me nt -e mer ge nt lo w res ul t is defi ne d as a c ha n ge fr o m a val ue greater t ha n 
or e q ual t o t he l o w li mit at baseli ne t o a val ue less t ha n t he l o w li mit at a n y t i me 
t hat meets t he s pecifie d c ha n ge criteria d uri n g t he treat me nt peri o d.
T he m a xi m u m p ost baseli ne QI D S-S R 1 6 t otal  sc ore will be s u m marize d b y treat me nt gr o u p, a n d 
a s hift ta ble will be pr o d uce d f or t he c ha n ge fr o m baseli ne i n QI D S -S R 1 6 t otal  sc ore cate g or y.
S ui ci de-relate d t h o u g hts a n d be ha vi ors a n d self-i nj urio us be ha vi or wit h n o s uici dal i nte nt, base d 
o n t he C -S S R S, will be liste d b y  patient .

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1 0. 3. 9. P h ar m a c o ki n eti c/ P h ar m a c o d y n a mi c A n al y s e s
O bser ve d i xe kiz u ma b ser u m c o nce ntrati o ns will be s u m marize d b y  tr e at me nt re gi me n, visits a n d 
c orres p o n di n g ti me w he n sa m pli n g occ urre d.
As a p pr o pri ate, t he P K a n d t he e x p os ure -res p o nse relati ons hi p bet wee n i xe kiz u ma b e x p os ure 
a n d cli nicall y i m p orta nt efficac y meas ures (f or e xa m ple, A S A S 4 0 or A S A S 2 0) ma y be e x pl ore d 
usi n g gra p hi cal met h o ds a n d/ or a mo deli n g a p pr oac h.  P har mac o ki netic a n d/ or e x p os ure-
res p o nse data fr o m t his st u d y ma y be c o m bi ne d wit h e xist i n g P K a n d/ or e x p os ure-res p o nse data 
fr om ot h er st u dies, if c o nsi dere d a p pr o priate.  
I n a d diti on, t he p ote ntial i m pact of i m m un o ge nicit y o n i xe kiz u ma b e x p os ure m a y be e val uate d 
b y gra p hical assess me nts, as a p pr o priate, t o c o m pare dr u g e x p os ure bet wee n A D A ne gati ve a n d 
A D A p osit i ve patient s at c orres p o n di n g visits, or bef ore a n d after A D A de vel o p me nt f or patie nts 
w h o de vel o p A D A. B ot h treat me nt -e mer ge nt o nl y a n d all A D A p osit i ve/ ne gati ve patie nts ma y 
be e x pl ore d.  A si milar a p pr oac h ma y be ta ke n if patie nts bec o me N A b p osit i ve.  
1 0. 3. 1 0.
Ot h er A n al y s e s
1 0. 3. 1 0. 1.
H e alt h E c o n o mi c s
T here will be n o a dj ust me nt  for m ul tiple c o m paris o ns.  A nal yses will b e c o n d ucte d f or t he ot her 
sec o n dar y he alt h o ut c o mes o bject i ves as defi ne d i n Secti o n 4 .
Peri o d 2 ( Bli n de d Tre at me nt D osi n g Peri o d):   
U nless ot her wise s pecifie d , t he ot her sec o n dar y a nal yses d uri n g Peri o d 2 will be base d o n t he 
I T T P o p ul at i on.  
Treat me nt c o m paris o ns i n t he pr op orti o n of pat ient s ac hie vi n g a cate g orical res p o nse at s pecifie d 
ti me p oi nts will be a nal yze d usi n g t he l ogist ic re gressi on m o d el  defi ne d i n Secti on 1 0. 3. 1 . 
Missi n g data will be i m p ute d usi n g t he N RI met h o d descri be d i n Sect i on 1 0. 3. 4 .
F or all c o nti n u o us healt h o utc o mes varia bles t hat are c ollecte d at re peate d visits, treat me nt gr o u p 
c o mparis o ns will be a nal yze d usi n g t he M M R M m o del  defi ne d i n Secti o n 1 0. 3. 1 if a p pr o priat e.  
N o i m p ut ati o n met h o ds are a p plie d t o M M R M a nal ysis.  A d dit i onal a nal ys e s ma y be c o n d ucte d 
usi n g t he A N C O V A m o del defi ne d i n Sect i on 1 0. 3. 1 ; missi n g data will be i m p ute d b y t he 
m B O C F met h o d as descri be d i n Sect i on 1 0. 3. 4 .  F or c o nti n u o us health o utc o m es varia bles t hat 
are c ollecte d o nl y o nce wit hi n t he Peri o d 2, a nal yses will be m a de usi n g t he A N C O V A m o del 
wi t h t h e mB O C F met h o d.
Peri o d 3 ( E xte n de d Tre at me nt Peri o d):   
Data c ollecte d i n Peri o d 3 will be s u m marize d f or t he E xte n de d Treat me nt Peri o d P o p ulat i on.  
A d dit i onal a nal yses of healt h o utc o mes meas ures will be s pecifie d i n t he S A P.
1 0. 3. 1 0. 2.
S u b gr o u p A n al y s e s
S u b gr o u p a nal ys es will be c o n d ucte d f or A S A S 4 0 a n d selecti ve maj or sec o n dar y o utc o mes 
( defi ne d i n t he S A P) at Wee k 1 6 ( Visit 8) usi n g t he I T T Po p ul at i on. 

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S u b gr o u p a nal yses ma y  be c o n d ucte d base d o n ge n der, a ge cate g or y, baseli ne disease se verity,  
baseli ne C R P stat us, baseli ne M RI stat us, pri or T N F in hi bit or e x perie nce, a n d prese nce of H L A-
B 2 7.
F or A S A S 4 0, a l o gistic re gressi o n m o d el  wit h tr e at me nt, s u b gr o u p, a n d t he i nteracti o n of 
s u b gr o u p- b y-tr e at me nt i ncl u de d as fact ors will be use d.  T he s u b gr o u p - b y-tr e at me nt i nteractio n 
will be teste d at t he sig nifica nce l e v el of 0. 1 0.  Treat me nt gr o u p differe nces will be e val uate d 
wi t hi n eac h cate g or y of t he s u b gr o u p usi n g Fis her’s e xact test, re gar dless of w het her t he 
i nteract i on is statisticall y si g nifica nt.  Missi n g data will be i m p ute d usi n g N RI as descri be d i n 
Secti o n   1 0. 3. 4 .  If a n y gr o u p wit hi n t he s u b gr o u p is < 1 0 % of t he t otal p o p ulati on, o nl y 
s u m maries of t he efficac y data will be pr o vide d (t hat is, n o i nfere nt ial testi n g).
F or c o nti n u o us efficac y  o ut c o me (for e xa m ple, m ea n c ha n ge fr o m baseli ne i n A S D A S), a n 
A N C O V A m o del wit h treat me nt, baseli ne val ue, s u b gr o u p, a n d t he i nteracti o n of s u b gr o u p - b y-
treat me nt will be use d.  T he s u b gr o u p - b y-tr e at me nt i nteractio n will be teste d at t he si g nifica nce 
le vel of 0. 1 0.  Treat me nt gr o u p differe nces will be e val uate d wit hi n eac h cate g or y of t he 
s u b gr o u p usi n g a n A N C O V A m o del with treat me nt a n d baseli ne val ue as a c o variate, re gar dless 
of  w het her t he i nteracti on is statisticall y si g nifica nt.  Missi n g data will be i m p ute d usi n g t he 
m B O C F met h o d as descri be d i n Sect i on 1 0. 3. 4 .
Detaile d descri pt i on of t he s u b gr o u p varia bles will be pr o vi de d i n t he S A P.  A d dit i onal s u b gr o u p 
a nal yses o n efficac y or s u b gr o u p a nal yses o n safet y ma y be perf or me d as dee me d a p pr o priate 
a n d necessar y.
1 0. 3. 1 1.
I m m u n o g e ni cit y
T he a nal yses of A D A effects will be c o n d ucte d o n all e val ua ble pat ie nts wit hi n t he defi ne d 
safety p o p ul at i on.  E val ua ble pat ient s will be defi ne d as eit her a) patie nts wit h a n e val ua ble 
baseli ne sa m ple a n d at least 1 e val ua ble p ost baseli ne sa m ple (t hat is, sa m ple after a d mi nistrati o n 
of  st u d y dr u g); or b) patie nts wit h no e val ua ble baseli ne sa m ple w h ose e val ua ble p ost baseli ne 
sa m ples were all A D A ne gat i ve. 
A T E -A D A p osit i ve patient  will be defi ne d as a n y occ urre nce of a ≥4 -f ol d or 2 dil uti on i ncrease 
i n i m m u n o ge nicity ti ter o ver t he baseli ne titer.  T his is e q ui vale nt t o a n i ncrease i n t iter t o ≥1: 1 0, 
i n t he case of a ne gati ve res ult at baseli ne.  T he fre q ue nc y a n d perce nta ge (i nci de nce) of patie nts 
wi t h p ositi ve, ne gati ve, or i nc o ncl usi ve A D A at baseli ne a n d p ost baseli ne (a n d N A b at baseli ne 
a n d p ost baseli ne) will be s u m marize d b y  tr e at me nt gr o u p.  Patie nts w h o are T E-A D A p osit i ve, 
T E -A D A persiste nt p osit i ve, a n d T E-A D A tra nsie nt p ositi ve will als o be s u m marize d.  
T he p ote ntial i m pact of i m m u n o ge nicit y o n i xe kiz u ma b e x p os ure a n d/ or efficac y res p o nses will 
be e val uate d, a s a p pr o priate.  
Assess me nt of i m m u n o ge nicit y wi t h res pect t o safet y will i ncl u de c o mparis o n of patie nts w h o 
e x perie nce T E A Es of s yste mic aller g y/ h y perse nsit i vity a n d of i nject i on- site reactio ns a n d w h o 
als o de vel o p treat me nt -e mer ge nt a nt i-i xe kiz u ma b a nti b o d y p ositivit y wi t h patie nts w h o 
e x perie nce t he sa me t y pes of T E A Es b ut w h o re mai n treat me nt -e mer ge nt a nti-i xe kiz u ma b 

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a nt i b o d y ne gati ve.  A nti-i xe kiz u ma b a nti b o d y titers will als o be e val uate d i n a nti-i xe kiz u ma b 
a nt i b o d y p ositive patie nts w h o e x perie nce t hese e ve nts.
1 0. 3. 1 2.
I nt eri m A n al y s e s
A n i nteri m data base l oc k a n d u n bli n di n g will occ ur, a n d i nteri m a nal yse s will be perf or me d at 
t he ti me (t hat is , a c ut off date) t he last patie nt c o m pletes Visit 8 ( Bli n de d D osi n g Treat me nt 
P eri o d [ Peri o d 2]), Wee k 1 6) or E T V. T his i nteri m data base l oc k will i ncl u de all data c ollecte d 
b y t he c ut off date i ncl u di n g t he data fr o m t he E xte n de d Treat me nt Peri o d ( Peri o d 3) a n d f o ll ow-
u p data fr o m pat ient s t hat ha ve be g u n t he P ost-Treat me nt F oll o w -u p Peri o d ( Peri o d 4). T he 
a nal yses fr o m t he Wee k 16 l oc k will be treate d as a pri mar y  a nal ysis beca use all pri mar y a n d 
maj or sec o n dar y  st u d y o bject i ves will be assesse d at t his ti me.
A d dit i onal a nal yses a n d s na ps h ots of st u d y data ma y be perf or me d d uri n g t he Peri o d 3 or after 
c o mplet i on of Peri o d 4 t o f ul fill t he nee d f or re g ulat or y int eractio ns or p u blicat i on p ur p oses .
U n bli n di n g details are s pecifie d i n t he bli n di n g/ u n bli n di n g pla n.

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1 1.
R ef er e n c e s
Al os h M, Bretz F, H u q ue M. A d va nce d m ult i plicity a dj ust me nt  met h o ds i n cli nical trials. St at 
Me d . 2 0 1 4; 3 3( 4): 6 9 3-7 1 3.
A n ders o n JJ, Bar o n G, va n der Heij de D, Fels o n D T, D o u ga d os M. A n k yl o si n g s p o n d ylitis 
assess me nt gr o u p preli mi nar y defi nit i on of s h ort -t er m im pr o ve me nt i n a n k yl osi n g s p o n d ylit is. 
Art hritis R he u m . 2 0 0 1; 4 4( 8): 1 8 7 6- 1 8 8 6.
[ A P A] A merica n Ps yc hiatric Ass ociati on. Di a g n ostic a n d statistical ma n ual  of me nt al dis or ders. 
4t h e d. Was hi n gt o n, D C: A merica n Ps yc hiatric Ass ociati o n; 1 9 9 4.
A p pel H, He y dric h R, L o d de n ke m per C, He m pfi n g A, Sie per J. I n sit u detecti o n of I L - 1 7 
secreti n g cells i n t he b o ne marr o w of facet j oi nts o btai ne d fr om pati e nts wit h a n k ylosi n g 
s p o n d ylitis. Art hritis R he u m. 2 0 0 8; 5 8(s u p pl): S 3 5 1.
Baete n D, Sie per J, E mer y  P, Bra u n J, Heij de D, McI n nes I, va n Laar J M, La n de we R, 
W o r ds w ort h P, W olle n ha u pt J, Kell ner H, Para marta J, Ber oli n o A P, Wri g ht A M, H ue ber W. 
T he a nt i-I L-1 7 A m o n o cl o nal a nt i b o d y sec u ki n u ma b ( AI N 4 5 7) s h o we d g o o d safety a n d 
efficac y in t he treat m e nt of acti ve a n k yl osi n g s p o n d ylitis [ p oster]. P oster prese nte d at: A n n ual 
Meet i n g of t he A merica n C olle ge of R he u mat ol o g y; 1 0 N o ve m ber 2 0 1 0; At lant a, G A. 
A vaila ble at: 
ht t p:// w w w.a bstracts 2 vie w.c om/acr/ vie w. p h p? n u = 4 3 5 0 &t y pe =a bstract &sesI d = 5 4 1 & n u m = A P
S &tr k =). Accesse d Fe br uar y 2 1, 2 0 1 1. 
Baete n D, Baralia k os X, Bra u n J, Sie per J, E mer y P, va n der Heij de D, McI n nes I, va n Laar J M, 
La n de wé R, W or ds w ort h P, W olle n ha u pt J, Kell ner H, Para marta J, Wei J, Brac hat A, Be k S, 
La ure nt D, Li Y, Wa n g Y A, Bert oli n o A P, Gstei ger S, Wri g ht A M, H ue ber W. A nt i-
i nterle u ki n-1 7 A m o n o cl o nal  a nti b o d y sec u ki n u ma b i n treat me nt of a n k yl o si n g s p o n d ylitis: a 
ra n d omise d, d o u ble -bli n d, pl ace b o -c o ntr olle d trial. L a ncet. 2 0 1 3; 3 8 2( 9 9 0 6): 1 7 0 5 -1 7 1 3. 
Errat u m  in: L a ncet. 2 0 1 4 a; 3 8 3( 9 9 2 8): 1 5 4 8.
Baete n D, Bra u n J, Baralia k os X, Sie per J, D o u ga d os M, E mer y  P, De o d har A, P orter B, Marti n 
R, M p of u S, Ric har ds H. Sec u ki n u ma b, a m o n ocl o nal a nt i b o d y t o i nterle u ki n-1 7 A, 
sig nifica nt l y i m pr o ves si g ns a n d s y m pt o ms of acti ve a n k yl osi n g s p o n d ylit is: res ults of a 5 2-
wee k p hase 3 ra n d o mize d place b o -c o ntr olle d trial wit h int ra ve n o us l oa di n g a n d s u bc uta ne o us 
mai nte na nce d osi n g [a bstract]. I n: A C R/ A R H P A n n ual Meet i n g A bstract S u p ple me nt. 1 4 -1 9 
N o v 2 0 1 4; B ost o n, M A. Art hritis R he u m. 2 0 1 4 b; 6 6( S 1 0): S 3 6 0 . A bstract 8 1 9.
Baralia k os X, Bra u n J, La ure nt D D, Baete n D, va n der Heij de D, Sie per J, E mer y P, McI n nes I, 
va n Laar J, La n de we R, W or ds w ort h P, W o lle n ha u pt J, Kell ner H, Wri g ht A M, Gstei ger S, 
H ue ber W. I nterle u ki n -1 7 A bl oc ka de wit h sec u ki n u ma b re d uces s pi nal i nfla m mat i on i n 
pati e nts wit h a n k yl osi n g s p o n d ylitis as earl y as wee k 6, as detecte d b y ma g netic res o na nce 
i ma gi n g. Art hritis R he u m. 2 0 1 1; 6 3(s u p pl 1 0): 2 4 8 6 D.
B o o ne n A, va n der Li n de n S M. T he b ur de n of a n k yl osi n g s p o n d ylit is. J R he u m. 2 0 0 6; 7 8: 4 -1 1.
Bra n dt J, List i n g J, Sie per J, R u d waleit M, va n der Heij de D, Bra u n J. De vel o p me nt a n d 
preselect i on of criteria f or s h ort ter m i m pr o ve me nt after a nt i-T N F alp ha treat m e nt i n 
a n k yl o si n g s p o n d ylitis. A n n R he u m Dis. 2 0 0 4; 6 3( 1 1): 1 4 3 8 - 1 4 4 4.

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
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Bra u n J, va n de n Ber g R, Baralia k os X, B oe h m H, B ur g os -Var gas R, C olla ntes - Este vez E, 
Da gfi nr u d H, Dij k ma ns B, D o u ga d os M, E mer y  P, Ge her P, Ha m m o u de h M, I n ma n R D, 
J o n g kees M, K ha n M A, Kilt z U, K vie n T, Leirisal o -Re p o M, Ma ks y m o w yc h W P, Oli vieri I, 
Pa vel ka K, Sie per J, Sta nisla ws ka -Bier nat E, We n dli n g D, Oz g oc me n S, va n Dr o ge n C, va n 
R o ye n B, va n der Heij de D.
2 0 1 0 u p date of t he A S A S/ E U L A R rec o m me n dat i ons f or t he 
ma na ge me nt of a n k yl o si n g s p o n d ylitis. A n n R he u m Dis. 2 0 1 1; 7 0( 6): 8 9 6 -9 0 4.
Bra u n J, Sie per J. A n k yl osi n g s p o n d ylit is. L a ncet . 2 0 0 7; 3 6 9( 9 5 7 0): 1 3 7 9- 1 3 9 0.
Bra u n J, Sie per J. Treat me nt of r he u mat oi d art hrit is a n d a n k yl osi n g s p o n d ylitis. Cli n Ex p 
R he u m at ol . 2 0 0 9; 2 7( 4 s u p pl 5 5): S 1 4 6-S 1 4 7.
Bra u n et al. 2 0 1 0 u p date of t he A S A S/ E U L A R rec o m me n dat i ons f or t he ma na ge me nt of 
a n k yl o si n g s p o n d ylitis. A n n R he u m Dis . 2 0 1 1; 7 0: 8 9 6- 9 0 4.
Bretz F, P osc h M, Gli m m E, Kli n gl m ueller F, Ma urer W, R o h me yer K. Gra p hical a p pr oac hes f or 
m ult i ple c o m paris o n pr oce d ures usi n g wei g hte d B o nferr o ni, Si mes, or para metric tests. Bi o m 
J. 2 0 1 1; 5 3( 6): 8 9 4-9 1 3.
Cali n A, J o nes S D, Garrett S L, Ke n ne d y L G. Bat h A n k yl osi n g S p o n d ylit is F u nct i onal I n de x. Br 
J R he u m at ol . 1 9 9 5; 3 4( 8): 7 9 3-7 9 4.
Ci mzia [ pac ka ge i nsert]. S m yr na, Ge or gi a: U C B; 2 0 1 5. A vaila ble at: 
ht t p:// me dli brar y. or g/li b/r x/ me ds/ci mzia/. Accesse d Oct o ber 1 9, 2 0 1 5.
C ol u m bia U ni versit y Me dical Ce nter. C ol u m bia – S ui ci de Se verit y Rati n g Scale ( C-S S R S) we b 
site. A vaila ble at: htt p:// w w w.cssrs.c ol u m bia.e d u. Accesse d A pril 2 1, 2 0 1 1.
C ose nt y x [ pac ka ge i nsert]. East Ha n o ver, Ne w Jerse y: N o vartis; 2 0 1 5. A vaila ble at: 
ht t p:// w w w. p har ma. us. n o vartis.c o m/ pr o d uct/ pi/ p df/c ose nty x. p df. Accesse d Oct o ber 1 9, 2 0 1 5.
Da vis J C Jr, Va n Der Heij de D, Bra u n J, D o u ga d os M, C us h J, Cle g g D O, Ki vitz A, 
Fleisc h ma n n R, I n ma n R, Ts uji W; E n brel A n k yl o si n g S p o n d ylitis St u d y Gr o u p. Rec o m bi na nt 
h u ma n t u m or necr osis fact or rece pt or (eta nerce pt) f or treati n g a n k yl osi n g s p o n d ylit is: a 
ra n d omize d, c o ntr olle d trial. Art hritis R he u m . 2 0 0 3; 4 8( 1 1): 3 2 3 0- 3 2 3 6.
De o d har A, Ge nsler L S, Ka y J, Ma ks y m o w yc h W P,
Har o o n N, La n de wé R, R u d waleit M, Hall 
S, Ba uer L, H o e p ke n B, de Pe y reca ve N, Kil galle n B, va n der Heij de D . A fifty- t w o-wee k, 
ra n d omize d, place b o -c o ntr olle d trial o f cert oliz u ma b pe g o l i n n o nra di o gra p hic a xial 
s p o n d yl oart hritis. Art hritis R he u m at ol. 2 0 1 9a. [ E p u b a hea d of pri nt]
De o d har A, P o d d u b n y y D, Pac hec o -Te na C, Sal vara ni C, Les pessailles E, Ra h ma n P, Jär vi ne n P, 
Sa nc hez - B urs o n J, Gaff ne y K, Lee E B, Kris h na n E, Sa ntiste ba n S, Li X, Z ha o F, Carlier H, 
Re veille J D; C O A S T -W St u d y  Gr o u p. Efficac y a n d Safet y of  I xe kiz u ma b i n t he Treat me nt of 
Ra di o gra p hic A xial S p o n d yl oart hrit is: Si xtee n-Wee k Res ults
Fr o m a P hase III Ra n d o mize d, 
D o u bl e- Bli n d, Pl ace b o -C o ntr olle d Trial i n Pat ient s Wit h Pri or I na de q uate Res p o nse t o or 
I nt olera nce of T u mor Necr osis Fact or I n hi bit ors. Art hritis R he u m at ol. 2 0 1 9 b ; 7 1( 4): 5 9 9- 6 1 1.
De o d har A, Re veille J D, va n de n B osc h F, Bra u n J, B ur g os -Var gas R, Ca pla n L, Cle g g D O, 
C ol bert R A, Ge nsler L S, va n der Heij de D, va n der H orst -Br ui ns ma I E, I n ma n R D, 
Ma ks y m o w yc h W P, Mease PJ, Ra yc ha u d h uri S, Rei m o l d A, R u d waleit M, Sie per J, Weis ma n 
M H, La n de wé R B. T he c o nce pt of a xial s p o n d yl oart hrit is: j oi nt state me nt of t he 
s p o n d yl oart hritis researc h a n d treat me nt net w or k a n d t he Assess me nt of S p o n d yl oArt hr itis 

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
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i nter nat i onal S ociet y i n res p o nse t o t he U S F o o d a n d Dr u g A d mi nistrati o n’s c o m me nts a n d 
c o ncer ns. Art hritis R he u m at ol. 2 0 1 4; 6 6( 1 0): 2 6 4 9 - 2 6 5 6.
de Vries M K, va n Eij k I C, va n der H orst -Br ui ns ma I E, Peters MJ, N ur m o ha me d M T, Dij k ma ns 
B A, Haze n ber g B P, W o lbi n k GJ. Er y t hr o c yte se di me ntatio n rate, C -reacti ve pr otei n le vel, a n d 
ser u m a m yloi d A pr otei n f or patie nt select i on a n d m o nit ori n g of a nt i-t u mor necr osi s fa ct or 
treat me nt i n a n k yl osi n g s p o n d ylit is. Art hritis R he u m . 2 0 0 9; 6 1( 1 1): 1 4 8 4-1 4 9 0.
D o u ga d os M, Si m o n P, Bra u n J, B ur g os -Var gas R, Ma ks y m o w yc h W P, Si e per J, va n der Heij de 
D. A S A S rec o m me n dati o ns f or c ollect i n g, a nal ysi n g a n d re p orti n g N S AI D i nta ke i n cli nical 
trials/e pi de mi o l ogical  st u dies i n a xial s p o n d yl oart hritis. A n n R he u m Dis . 2 0 1 1; 7 0( 2): 2 4 9- 2 5 1.
D o u ga d os M, Baete n D. S p o n d yl oart hrit is. L a ncet . 2 0 1 1; 3 7 7( 9 7 8 3): 2 1 2 7- 2 1 3 7.
[ E M A] E ur o pea n Me dici nes A ge nc y, C o m mittee f or Me dici nal Pr o d ucts f or H u ma n Use 
( C H M P). G ui deli ne o n cli nical i n vesti gati on of me di ci nal pr o d ucts f or t he treat me nt of 
a n k yl o si n g s p o n dylit is. 2 0 0 9. A vaila ble at: 
ht t p:// w w w.e ma.e ur o pa.e u/ d ocs/e n _ G B/ d oc u me nt _li brar y/ Scie ntific _ g ui deli ne/ 2 0 0 9/ 0 9/ W C 5 0
0 0 0 3 4 2 4. p df. Accesse d Oct o ber 2 6, 2 0 1 5 . 
E n brel  [ pac ka ge i nsert]. T h o usa n d Oa ks, Calif or nia: A m ge n I nc; 2 0 1 5. A vaila ble at: 
ht t p:// pi.a m ge n.c om/ u nite d _states/e n brel/ der m/e n brel _ pi. p df. Accesse d Oct o ber 1 9, 2 0 1 5.
E ur o Q ol  Gr o u p. E Q- 5 D-5 L user g ui de. Versi o n 1. 0. A pril 2 0 1 1. A vaila ble at: 
ht t p:// w w w.e ur o q ol. or g/filea d mi n/ user _ u pl oa d/ D oc u me nte n/ P D F/ F ol ders _ Fl yers/ User G ui de _
E Q - 5 D-5 L. Accesse d Se pte m b er 1 4, 2 0 1 2. 
Garrett S, Je n ki ns o n T, Ke n ne d y L G, W hitel oc k H, Gaisf or d P, Cali n A. A ne w a p pr oac h t o 
defi ni n g disease stat us i n a n k yl osi n g s p o n d ylit is: t he Bat h A n k yl osi n g S p o n d ylitis Disease 
Act i vity I nde x. J R he u m at ol . 1 9 9 4; 2 1( 1 2): 2 2 8 6-2 2 9 1.
Ge n o vese M C , Bra u n D K, Eric ks o n J S, Bercl az P Y, Ba nerjee S, Heffer na n M P, Carlier H. 
S af et y a n d Efficac y of O pe n-la bel S u bc uta ne o us I xe kiz u ma b Treat m e nt for 4 8 Wee ks i n a 
P hase II St u d y  in Bi o l ogic -nai ve a n d T N F -I R Patie nts wit h R he u mat oi d Art hri tis. J 
R he u m at ol. 2 0 1 6 ;4 3( 2): 2 8 9 - 9 7.
Ge n o vese M C, Gree n wal d M, C h o C S, Ber ma n A, Ji n L, Ca mer o n G S, Be nic h o u O, Xie L, 
Bra u n D, Berclaz P Y, Ba nerjee S. A p hase II ra n d o mize d st u d y  of s u bc uta ne o us i xe kiz u ma b, 
a n a nt i-i nterle u ki n-1 7 m o n o cl o nal a nti b o d y , i n r he u mat oid art hri tis patie nts w h o were naï ve t o 
bi o l ogic a ge nts or ha d a n i na de q uate res p o nse t o t u m or necr osis fact or i n hi bit ors. Art hritis 
R he u m at ol. 2 0 1 4; 6 6( 7): 1 6 9 3 - 1 7 0 4.
Gli nt b or g B, Oster gaar d M, Kr o g h N S, Dre y er L, Kriste nse n H L, Hetla n d M L. Pre dict ors of 
treat me nt resp o nse a n d dr u g c o nti n uati o n i n 8 4 2 patie nts wit h a n k yl o si n g s p o n d ylitis treate d 
wi t h a nti-t u mo ur necr osis fact or: res ults fr o m 8 years’ s ur veilla nce i n t he Da nis h nati o n wi de 
D A N BI O re gi str y. A n n R he u m Dis . 2 0 1 0; 6 9( 1 1): 2 0 0 2- 2 0 0 8.
Gli nt b or g B, Øster gaar d M, Kr o g h N S, Tar p U, Ma nil o N, L oft A G, Ha nse n A, Sc hle m mer A, 
Fa na V, Li n de gaar d H M, N or di n H, Ras m usse n C, Ejstr u p L, Je nse n D V, Peterse n 
P M, Hetl a n d M L. Cli nical res p o nse, dr u g s ur vi val a n d pre dict ors t here of i n 4 3 2 a n k yl o si n g 
s p o n d ylitis patient s after s witc hi n g t u mo ur necr osis fact or α i n hi bit or t hera p y : res ults fr o m t he 
Da nis h nat i on wi de D A N BI O re gistr y . A n n R he u m Dis . 2 0 1 3; 7 2( 7): 1 1 4 9- 1 1 5 5.

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 8 7
L Y 2 4 3 9 8 2 1
G ottlie b A B, Mease PJ, C uc hac o vic h R S, S h uler C L, Li n C Y, B ur ge R T, Sa ma nta S, Lee C H, 
Gl a d ma n D D. I xe kiz u ma b i m pr o ves p h ysical f u ncti o n, q ualit y of  life, a n d w or k pr o d ucti vity i n 
bi o l ogic disease -m o dif yi n g a nt irhe u mat ic dr u g-naï ve pat ient s wit h acti ve ps oriat ic art hritis 
[a bstract]. Art hritis R he u m at ol . 2 0 1 5; 6 7(s u p pl 1 0).
Griffit hs C E, Reic h K, Le b w o hl M, va n de Ker k h o f P, Pa ul  C, Me nter A, Ca mer o n G S, Eric ks o n 
J, Z ha n g L, Secrest RJ, Ball S, Bra u n D K, Os u nt o k u n O O, Heffer na n M P, Nic k o l off BJ, Pa p p 
K, U N C O V E R -2 a n d U N C O V E R -3 i n vest i gat ors. C o m paris o n of i xe kiz u ma b wi t h eta nerce pt 
or pl ace b o i n mo d er at e -t o-se vere ps oriasis ( U N C O V E R-2 a n d U N C O V E R -3): res ults fr o m 
t wo p hase 3 ra n d o mise d trials. L a ncet. 2 0 1 5; 6 7 3 6( 1 5): 6 0 1 2 5 - 8.
Hai bel H, S pec ker C. Disease -m o dif yi n g a nt i-r he u matic dr u gs i n r he u mat oi d art hritis a n d 
a n k yl o si n g s p o n d ylitis. Cli n Ex p R he u m at ol . 2 0 0 9: 2 7( 4 s u p pl 5 5): S 1 5 9 -S 1 6 3.
Hei ber g M S, K o l di n gs nes W, Mi k kelse n K, R ø de va n d E, Ka uf ma n n C, M o wi nc kel P, K vie n T K. 
T he c o m parat i ve o ne-year perf or ma nce of a nti -t u mor necr osis fact or al p ha dr u gs i n patie nts 
wi t h r he u mat oid art hri tis, ps oriat ic art hritis, a n d a n k yl osi n g s p o n d ylitis: res ults fr om a 
l on git u di nal, o bser vat i onal, m ult ice nter st u d y. Art hritis R he u m. 2 0 0 8; 5 9( 2): 2 3 4 -2 4 0.
He uft -D ore n b osc h L, S p o ore n ber g A, va n T u ber ge n A, La n de wé R, va n ver Te m pel H, Miela nts 
H, D o u ga d os M, va n der Heij de D. Assess me nt of e nt hesi tis i n a n k yl osi n g s p o n d ylitis. A n n 
R he u m Dis. 2 0 0 3; 6 2( 2): 1 2 7 - 1 3 2.
H u mira [ pac ka ge i nsert]. N ort h C hica g o, I L: A b b Vie I nc; 2 0 1 5. A vaila ble at: 
ht t p:// w w w.r xa b b vie.c om/ p df/ h u mira. p df. Accesse d Oct o ber 1 9, 2 0 1 5.
I n ma n R D, Da vis J C Jr, va n der Heij de D, Die k man L, Si e per J, Ki m SI, Mac k M, Ha n J, 
Vi s va nat ha n S, X u Z, Hs u B, Be utler A, Bra u n J. Efficac y a n d safet y of  g oli m u ma b i n patient s 
wi t h a n k yl osi n g s p o n d ylitis: res ults of a ra n d omize d, d o u ble -bli n d, place b o -c o ntr olle d, p hase 
III trial. Art hritis R he u m. 2 0 0 8; 5 8( 1 1): 3 4 0 2 - 3 4 1 2.
Ja n d us C, Bi oley G, Ri vals J P, D u dler J, S peiser D, R o mer o P. I ncrease d n u m bers of circ ulat i n g 
p ol yf u ncti o nal T h 1 7 me m or y  cells i n patient s wit h ser o ne gati ve s p o n d ylart hriti des. Art hritis 
R he u m . 2 0 0 8; 5 8( 8): 2 3 0 7- 2 3 1 7.
Je n ki ns o n T R, Mall orie P A, W hit eloc k H C, Ke n ne d y  L G, Garrett S L, Cali n A. Defi ni n g s pi nal 
m o bilit y i n a n k yl o si n g s p o n d ylitis ( A S). T he Bat h A S Metr ol o g y I n de x. J R he u m at ol.
1 9 9 4; 2 1( 9): 1 6 9 4 - 1 6 9 8.
Kiltz U, va n der Heij de D, B o o ne n A, Cieza A, St uc ki G, K ha n M A, Ma ks y m o w yc h W P,
Marz o -Orte ga H, Re veille J, Ste b bi n gs S, B osta n C, Bra u n J. De vel o p me nt of a healt h i n de x i n 
pati e nts wit h a n k yl osi n g s p o n d ylitis ( A S A S HI): fi nal res ult of a gl o bal i nitiati ve base d o n t he 
I C F g uide d b y  AS A S. A n n R he u m Dis. 2 0 1 3; 7 4( 5): 8 3 0 - 8 3 5.
La n de wé R, Bra u n J, De o d har A, D o u ga d os M, Ma ks y m o w yc h W P, Mease PJ, Re veille J D, 
R u d waleit M, va n der Heij de D, Stac h C, H oe p ke n B, Fic ht ner A, C ote ur G, de L o n g ue ville 
M, Si e per J. Efficac y of cert oliz u ma b pe g ol o n si g ns a n d s y m pt o ms of a xial s p o n d yl oart hrit is 
i ncl u di n g a n k yl osi n g s p o n d ylitis: 2 4-wee k res ults of a d o u ble -bli n d ra n d o mise d place b o -
c o ntr olle d P hase 3 st u d y. A n n R he u m Dis. 2 0 1 4; 7 3( 1): 3 9 -4 7.

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 8 8
L Y 2 4 3 9 8 2 1
Lie E, va n der Heij de D, U hli g T, Mi k kelse n K, R ø de va n d E, K ol di n gs nes W, Ka uf ma n n C, 
K vie n T K. Effecti ve ness of s witc hi n g bet wee n T N F i n hi bit ors i n a n k yl osi n g s p o n d ylitis: data 
fr om t he N O R-D M A R D re gi ster. A n n R he u m Dis. 2 0 1 1; 7 0( 1): 1 5 7- 1 6 3.
Mac ha d o P, Castrej o n I, Katc ha mart W, K oe v oets R, K uri ya B, Sc h oels M, Sil va -Fer ná n dez L, 
T he visse n K, Verc o utere W, Ville ne u ve E, Aleta ha D, Car m o na L, La n de wé R, va n der Heij de 
D, Bijls ma J W, B y ker k V, Ca n hã o H, Catri na AI, D urez P, E d war ds CJ, Mjaa vatte n M D, Lee b 
B F, L osa da B, Martí n -M ola E M, Marti nez -Os u na P, M o ntec ucc o C, M üller -La d ner U, 
Øster gaar d M, S hea ne B, Xa vier R M, Z o c hli n g J, B o m bar dier C. M ult i nati onal e vi de nce -
base d rec o m me n dat i ons o n h o w t o i n vest i gate a n d f oll ow- u p u n differe nt iate d peri p heral 
i nfla m mat or y art hritis: i nte grati n g s yste matic literat ure researc h a n d e x pert o pi ni on of a br oa d 
i nter nat i onal pa nel o f r heu m at ol o gi sts i n t he 3 E I nitiati ve. A n n R he u m Dis . 2 0 1 1a; 7 0( 1): 1 5-2 4.
Mac ha d o P M, La n de wé R, Heij de D V, Assess me nt of S p o n d yl o Art hri tis i nter nati onal S ociet y 
( A S A S). A n k yl o si n g S p o n d ylitis Disease Acti vity Sc ore ( A S D A S): 2 0 1 8 u p date of t he 
n o me nclat ure f or disease acti vit y states . A n n R he u m Dis. 2 0 1 8; 7 7 (1 0): 1 5 3 9 - 1 54 0.
Mac ha d o P M, La n de wé R B, va n der Heij de D M. E n d orse m e nt of defi nit i ons of disease act i vity 
states a n d i m pr o ve me nt sc ores f or t he A n k yl o si n g S p o n d ylitis Disease Acti vity Sc ore: res ults 
fr om O M E R A C T 1 0. J R he u m at ol. 2 0 1 1 b; 3 8( 7): 1 5 0 2 - 1 5 0 6.
Mac ha d o P, La n de wé R, Lie E, K vie n T K, Bra u n J, Ba ker D, va n de r Heij de D, Assess me nt of 
S p o n d yl o Art hri tis I nter nati onal S ociet y . A n k ylosi n g S p o n d yli tis Disease Acti vity Sc ore 
( A S D A S): defi ni n g c ut-off val ues f or disease acti vit y states a n d i m pr o ve me nt sc ores. A n n 
R he u m Dis . 2 0 1 1c; 7 0( 1): 4 7-5 3.
Mac ha d o P,
Na varr o -C o m pá n V, La n de wé R, va n Gaale n F A, R o u x C, va n der Heij de D. 
Calc ulati n g t he a n k yl osi n g s p o n d ylit is disease acti vity sc ore if t he c o n ve nti onal c -reacti ve 
pr otei n le vel is bel o w t he li mit of detecti o n or if hi g h- se nsitivit y c -reacti ve pr otei n is use d: a n 
a nal ysis i n t he D E SI R c o h ort. Art hritis R he u m at ol. 2 0 1 5; 6 7( 2): 4 0 8 - 4 1 3.
Ma ks y m o w yc h W P, I n ma n R D, Sal o ne n D, D hill o n S S, Kri s h na na nt ha n R, St o ne M, C o n ner-
S pa d y  B, P alsat J, La m bert R G W. S p o n d yl oart hritis Researc h C o ns orti u m of Ca na da ma g net ic 
res o na nce i ma gi n g i nde x f or assess me nt of s pi nal i nfla m mat i on i n a n k yl o si n g s p o n d ylitis. 
Art hritis R he u m . 2 0 0 5a; 5 3( 4): 5 0 2-5 0 9.
Ma ks y m o w yc h W P, I n ma n R D, Sal o ne n D, D hill o n S D, Willia ms M, St o ne M, C o n ner -S pa d y  
B, Palsat J, La m bert R G W. S p o n d yl oart hrit is Researc h C o ns orti u m of Ca na da ma g net ic 
res o na nce i ma gi n g i n de x f or assess me nt of sacr oiliac j oi nt i nflam mat i on i n a n k yl osi n g 
s p o n d ylitis. Art hritis R he u m . 2 0 0 5 b; 5 3( 5): 7 0 3- 7 0 9.
Ma ks y m o w yc h W P, Mall o n C, M orr o w S, S h oja nia K, Olsz y ns ki W P, W o n g R L, Sa m palis J, 
C o n ner -S pa d y  B. De velo p me nt a n d vali dat i on of t he S p o n d yl o art hritis Researc h C o ns orti u m 
of  Ca na da ( S P A R C C) E nt hesitis I n de x. A n n R he u m Dis. 2 0 0 9; 6 8( 6): 9 4 8 -9 5 3.
Ma ks y m o w yc h W P. Disease m o dificat i on i n a n k yl osi n g s p o n d ylitis. N at Rev R he u m at ol . 
2 0 1 0: 6( 2): 7 5 -8 1.
Ma ks y m o w yc h W P , Wic h u k S , C hi o wc ha n wisa wa kit P, La m bert R G , Pe derse n SJ . 
De vel o p me nt a n d preli mi nar y  vali dat i on of t he s p o n d yl oart hrit is researc h c o ns orti u m of 
Ca na da ma g netic res o na nce i ma gi n g sacr oiliac j o i nt str uct ural sc ore. 
J R he u m at ol . 2 0 1 5; 4 2( 1): 7 9 -8 6.

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 8 9
L Y 2 4 3 9 8 2 1
Mease PJ, v a n der Heij de D, Ritc hli n C T, C uc hac o vic h R, S h uler C L, Lee C H, Sa ma nta S, Li n 
C- Y, Gl a d ma n D D, Va n ger o w H. A ra n d o mize d, d o u ble -bli n d, act i ve- a n d place b o -c o ntr olle d 
p hase 3 st u d y  of efficac y a n d safety of  ixe kiz u ma b, a dali m u ma b, a n d place b o t hera p y  in 
pa tie nts naï ve t o biol o gi c disease mo dif yi n g a nt i-r he u matic dr u gs wit h acti ve ps oriatic art hritis 
[a bstract]. Art hritis R he u m at ol . 2 0 1 5; 6 7(s u p pl 1 0). 
Mease PJ, va n der Heij de D, Ritc hli n C T, O ka da M, C uc hac o vic h R S, S h uler C L, Li n C Y, Bra u n 
D K, Lee C H, Gla d ma n D D; S PI RI T -P 1 St u d y Gr o u p. I xe kiz u ma b, a n i nterle u ki n-1 7 A s pecific 
m o n ocl o nal a nti b o d y , for t he treat m e nt of bi o l ogic -nai ve patie nts wit h act i ve ps ori at ic 
art hritis: res ults fr o m t he 2 4-wee k ra n d o mise d, d o u ble -bli n d, place b o -c o ntr olle d a n d act i ve 
(a dali m u ma b)-c o ntr olle d peri o d of t he p hase III trial S PI RI T -P 1. 2 0 1 7; 7 6( 1): 7 9 -8 7. 
Mei  Y, Pa n F, Ga o J, Ge R, D ua n Z, Ze n g Z, Lia o F, Xia G, Wa n g S, X u S, X u J, Z ha n g L, Ye 
D. I ncrease d ser u m I L -1 7 a n d I L -2 3 i n t he patie nt wit h a n k yl o si n g s p o n d ylitis. Cli n 
R he u m at ol. 2 0 1 1; 3 0( 2): 2 6 9 -2 7 3. 
M orel a n d L. U n met nee ds i n r he u mat oi d art hrit is. Art hritis Res T her . 2 0 0 5: 7(s u p pl 3): S 2-S 8.
Nas h P, Kir k ha m B, O ka da M, Ra h ma n P, C o m be B, B ur mester G R, A da ms D H, Kerr L, Lee C, 
S h uler C L, Ge n o vese M; S PI RI T -P 2 St u d y Gr o u p. I xe kiz u ma b f or t he treat me nt of patie nts 
wi t h acti ve ps ori at ic art hritis a n d a n i na de q uate res p o nse t o t u m o ur necr osis fact or i n hi bit ors: 
res ults fr o m t he 2 4-wee k ra n d o mise d, d o u ble -bli n d, pl ace b o -c o ntr olle d peri o d of t he S PI RI T -
P 2 p hase 3 trial. 2 0 1 7; 3 8 9 ( 1 0 0 8 6): 2 3 1 7-2 3 2 7. 
P o d d u b n y y  D. A xial s p o n d yl oart hritis: is t here a treat me nt of c h oice? T her A dv M usc ul oskelet 
Dis . 2 0 1 3; 5( 1): 4 5- 5 4.
P os ner K, O q ue n d o M A, G o ul d M, Sta nle y B, Da vies M. C ol u m bia Classificat i on Al g orit h m o f 
S ui ci de Assess me nt ( C -C A S A): cla ssificati on of s ui ci dal e ve nts i n t he F D A’s pe diatric 
s uicid al  ris k a nal ysis of a nti de pressa nts. A m J Pysc hi atry. 2 0 0 7; 1 6 4( 7): 1 0 3 5 - 1 0 4 3.
Reill y Ass ociates. Healt h O utc o mes Researc h we b site. 2 0 0 2. A vaila ble at: 
ht t p:// w w w.reill yass ociates. net/. Accesse d Se pte m ber 1 4, 2 0 1 2 .
Reill y M C, G o oc h K L, W o n g R L, K u p per H, va n der Heij de D. Vali dit y, relia bilit y a n d 
res p o nsi ve ness of t he W or k Pr o d ucti vity a n d Act i vity I mpair me nt Q uesti o n nai re i n a n k yl osi n g 
s p o n d ylitis. R he u m at ol o gy ( Oxf or d). 2 0 1 0; 4 9( 4): 8 1 2 - 8 1 9.
Re veil le J D. T he ge netic basis o f s p o n d yl oart hritis. A n n R he u m Dis . 2 0 1 1; 7 0(s u p pl 1):i 4 4-i 5 0.
Re veille J D, Wittier J P, Weis ma n M H. Pre vale nce of a xial s p o n d ylart hrit is i n t he U nite d States: 
esti mates fr o m a cr oss-secti o nal s ur ve y. Art hritis C are Res ( H o b oke n) . 20 1 2; 6 4( 6): 9 0 5 - 9 1 0.
R u d waleit M, va n der Heij de D, La n de wé R, List i n g J, A k k oc N, Bra n dt J, Bra u n J, C h o u C T, 
C olla ntes - Este vez E, D o u ga d os M, H ua n g F, G u J, K ha n M A, Kirazli Y, Ma ks y m o w yc h W P, 
Miela nts H, S øre nse n IJ, Oz g oc me n S, R o uss o u E, Valle -O ñate R, We ber U, Wei J, Sie per J. 
T he de vel o p me nt of Assess me nt of S p o n d yl o Art hrit is I nter nati onal S ociet y classificat i on 
criteria f or a xial s p o n d ylo art hri tis ( part II): vali dati o n a n d fi nal selecti on. A n n R he u m Dis .  
2 0 0 9; 6 8( 6): 7 7 7 - 7 8 3.
Si e per J, P o d d u b n y y D. A xial s p o n d yl oart hrit is. L a ncet. 2 0 1 7; 3 9 0( 1 0 0 8 9): 7 3 -8 4.
Si e per J, R u d waleit M, Baralia k os X, Bra n dt J, Bra u n J, B ur g os- Var gas R, D o u ga d os M, 
H er m a n n K G, La n de wé R, Ma ks y m o w yc h W, va n der Heij de D. T he Assess me nt of 

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 9 0
L Y 2 4 3 9 8 2 1
S p o n d yl o Art hri tis I nter nati onal S ociet y  ( AS A S) ha n d b o o k: a g ui de t o assess s p o n d yl oart hrit is. 
A n n R he u m Di s. 2 0 0 9; 6 8(s u p pl 2):ii 1-ii 4 4.
Si e per J, va n der Heij de D, D o u ga d os M, Mease PJ, Ma ks y m o w yc h W P, Br o w n M A, Ar ora V, 
Pa n ga n A L. Efficac y  a n d safety of  a dali m u ma b i n patie nts wit h n o n-r a dio gra p hic a xial 
s p o n d yl oart hritis: res ults fr o m a p hase 3 st u d y. Prese nte d at: A n n ual Meet i n g of t he A merica n 
C olle ge o f R he u mat ol o g y; 4 -9 N o ve m ber 2 0 1 1; C hica g o, I L. Prese ntati o n n u m ber 2 4 8 6 A.
Si e per J, Bra u n J, Baralia k os X, Baete n D, D o u ga d os M, E mer y  P, De o d har A, P orter B, 
A n derss o n M, M p of u S, Ric har ds H . Sec u ki n u ma b, a m o n ocl o nal  a nti b o d y t o i nterle u ki n-1 7 A, 
sig nifica nt l y i m pr o ves si g ns a n d s y m pt o ms of acti ve a n k yl osi n g s p o n d ylit is: res ults of a p hase 
3, ra n d o mize d, place b o -c o ntr olle d trial wit h s u bc uta ne o us l oa di n g a n d mai nte na nce d osi n g 
[ p oster]. P oster prese nte d at: A merica n C olle ge of R he u mat ol o g y 2 0 1 4 A n n ual Scie nt ific 
Meet i n g; 1 4-1 9 N o ve m ber 2 0 1 4; B ost o n, M A. P oster 5 3 6.
Si m p o ni [ pac ka ge i nsert]. H ors ha m, P A: Ja nsse n Bi otec h I nc; 2 0 1 5. A vaila ble at: 
ht t p:// me dli brar y. or g/li b/r x/ me ds/si m p o ni/. Accesse d Oct o ber 1 9, 2 0 1 5.
S m ith C H, A nste y  AV, Bar ker J N, B ur de n A D, C hal mers RJ, C ha n dler D A, Fi nla y A Y, Griffit hs 
C E, Jac ks o n K, Mc H u g h NJ, Mc Ke n na K E, Re y n ol ds NJ, Or mer o d A D. Brit is h Ass ociati on of 
D er m at olo gi sts’ g uideli nes f or bi ol o gi c i nter ve ntio ns f or ps ori asis 2 0 0 9. Br J Der m at ol . 
2 0 0 9; 1 6 1( 5): 9 8 7 - 1 0 1 9.
Stra n d V, Ra o S A, S hilli n gt o n A C, Cifal di M A, Mc G uire M, R u der ma n E M. Pre vale nce of a xial 
s p o n d yl oart hritis i n U nite d States r he u mat ol o g y practices: Assess me nt of S p o n d yl o Art hri tis 
I nter nati o nal S ociety crit eria vers us r he u mat olo g y  e x pert cli nical dia g n osis. Art hritis C are Res 
( H o b oke n). 2 0 1 3; 6 5( 8): 1 2 9 9- 1 3 0 6.
va n der Heij de D, C he n g -C h u n g Wei J, D o u ga d os M, Mease P, De o d har A, Ma ks y m o w yc h W P, 
Va n de n B osc h F, Sie per J, T o mita T, La n de wé R, Z ha o F, Kris h na n E, A da ms D H, Pa n gall o 
B, Carlier H; C O A S T -V st u d y  gr o u p; I xe kiz u ma b, a n i nterle u ki n-1 7 A a nta g o nist i n t he 
treat me nt of a n k yl o si n g s p o n d ylitis or ra di o gra p hic a xial s p o n d yl oart hritis i n patient s 
pre vi o usl y u ntreate d wit h bi o l ogical disease -m o dif yi n g a nti -r he u mat ic dr u gs ( CO A S T -V): 1 6 
wee k res ults of a p hase 3 ra n d o mise d, d o u ble -bli n d, acti ve -c o ntr olle d a n d place b o -c o ntr olle d 
trial. L a ncet. 2 0 1 8; 3 9 2( 1 0 1 6 3): 2 4 4 1 - 2 4 5 1.
va n der Heij de D, Dij k ma ns B, Ge use ns P, Sie per J, De W o o d y  K, Willia ms on P, Bra u n J; 
A n k yl osi n g S p o n d ylit is St u d y for t he E val uat i on of Rec o m bi na nt I nfli xi ma b T hera p y St u d y 
Gr o u p. Efficac y a n d safet y of  infli xi ma b i n patie nts wit h a n k yl o si n g s p o n d ylitis: res ults of a 
ra n d omize d, place b o -c o ntr olle d trial ( A S S E R T). Art hritis R he u m . 2 0 0 5; 5 2( 2): 5 8 2-5 9 1.
va n der Heij de D, Ki vitz A, Sc hiff M H, Sie per J, Dij k ma ns B A, Bra u n J, D o u ga d os M, Re veille 
J D, W o n g R L, K u p per H, Da vis J C Jr; A T L A S St u d y Gr o u p. Efficac y a n d safety of  
a dali m u ma b i n pat ient s wit h a n k yl osi n g s p o n d ylitis: res ults of a mul tice nter, ra n d o miz e d, 
d o u bl e- bli n d, place b o -c o ntr olle d trial. Art hritis R he u m . 2 0 0 6; 5 4( 7): 2 1 3 6-2 1 4 6.
va n der Heij de D, La n de wé R, Fel dt keller E. Pr o p osal of a li near defi nit i on of t he Bat h 
A n k yl osi n g S p o n d ylit is Metr ol o g y  I n de x ( B A S MI) a n d c o m paris o n wit h t he 2-ste p a n d 
1 0 -ste p defi niti ons. A n n R he u m Dis. 2 0 0 8; 6 7( 4): 4 8 9 - 4 9 3.

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 9 1
L Y 2 4 3 9 8 2 1
va n der Li n de n S, Val ke n b ur g H A, Cats A. E val uati o n of dia g n ost ic criteria f or a n k yl osi n g 
s p o n d ylitis. a pr o p osal f or m o dificati on of t he Ne w Y or k criteria. Art hritis R he u m.
1 9 8 4; 2 7( 4): 3 6 1 - 3 6 8.
Vastesae g er N, va n der Heij de D, I n ma n R D, Wa n g Y, De o d har A, Hs u B, Ra h ma n M U, 
Dij k ma ns B, Ge use ns P, Va n der Cr u y sse n B, C olla ntes E, Sie per J, Bra u n J. Pre dicti n g t he 
o utc o m e of a n k ylosi n g s p o n d yli tis t hera p y. A n n R he u m Dis. 2 0 1 1; 7 0( 6): 9 7 3 -9 8 1.
War d M M, De o d har A , A kl E A, L ui A, Er ma n n J, Ge nsler L S, S mith J A, B ore nstei n D, Hiratz ka 
J, Weiss P F, I n ma n R D, Majithia V, Har o o n N, Ma ks y m o w yc h W P, J o yce J, Clar k B M, 
C ol bert R A, Fi g gie M P, Halle g ua D S, Prete P E, R ose n ba u m J T, Ste b ulis J A, va n de n B osc h F, 
Y u D T, Miller A S, Re veille J D, Ca pla n L. A merica n C o lle ge of R he u mat ol o g y/ S p o n d ylitis 
Ass oci at i on of A merica/ S p o n d yl o art hritis Researc h a n d Treat me nt Net w or k 2 0 1 5 
Rec o m me n dat i ons f or t he Treat me nt of A n k yl osi n g S p o n d ylitis a n d N o nra di o gra p hic A xial 
S p o n d yl oart hrit is. Ar t hritis R he u m at ol. 2 0 1 5. d oi: 1 0. 1 0 0 2/art. 3 9 2 9 8 [ E p u b a hea d of pri nt].
Ware J E Jr. S F -3 6 healt h s ur ve y u p date. S pi ne. 2 0 0 0; 2 5( 2 4): 3 1 3 0 - 3 1 3 9..
We bster, K. , & Cella, D., & Y ost, K. T he f u ncti o nal assess me nt of c hr o nic ill ness t hera p y 
( F A CI T) meas ure me nt s yste m: Pr o perties, a p plicati o ns, a n d i nter pretati o n. He alt h a n d Q u ality 
of Life O utc o mes. 2 0 0 3; 1( 7 9), 1 - 7.
We n dli n g D, Ce d oz J P, Raca d ot E, D u m o uli n G. Ser u m I L -1 7, B M P -7, a n d b o ne t ur n o ver 
mar kers i n pat ient s wit h a n k yl osi n g s p o n d ylitis. J oi nt B o ne S pi ne. 2 0 0 7; 7 4( 3): 3 0 4 - 3 0 5.
Yere m e n k o N, Para marta J E, Baete n D. T he i nterle u ki n -2 3/i nterl e u ki n-1 7 i m m u ne a xis as a 
pr o misi n g ne w tar get i n t he treat me nt of s p o n d yl oart hrit is. C urr O pi n R he u m at ol.
2 0 1 4; 2 6( 4): 3 6 1 - 3 7 0.
Z oc hli n g J, va n der Heij de D, B ur g os -Var gas R, C o lla ntes E, Da vis J C Jr, Dij k ma ns B, 
D o u ga d os M, Gé her P, I n ma n R D, K ha n M A, K vie n T K, Leirisal o -Re p o M, Oli vieri I, 
Pa vel ka K, Sie per J, St uc ki G, St urr oc k R D, va n der Li n de n S, We n dli n g D, B ö h m H, va n 
R o ye n BJ, Bra u n J, A Ssess me nt i n A S i nter nat i onal w or k i n g gr o u p, E ur o pea n Lea g ue A gai nst 
R he u matis m. A S A S/ E U L A R rec o m me n dati o ns f or t he ma na ge me nt of a n k yl osi n g s p o n d ylit is. 
A n n R he u m Dis. 2 0 0 6; 6 5( 4): 4 4 2 - 4 5 2.
Z oc hli n g J. Meas ures of s y m pt o ms a n d disease stat us i n a n k yl o si n g s p o n d ylitis: A n k yl osi n g 
S p o n d ylit is Disease Acti vit y Sc ore ( A S D A S), A n k yl osi n g S p o n d ylit is Q uality of  Life Scale 
( A S Q o L), Bat h A n k yl osi n g S p o n d ylitis Disease Acti vity I nde x ( B A S D AI), Bat h A n k yl osi n g 
S p o n d ylit is F u ncti onal I n de x ( B A S FI), Bat h A n k yl osi n g S p o n d ylit is Gl obal Sc ore ( B A S- G), 
Bat h A n k yl osi n g S p o n d ylit is Metr olo g y  I n de x ( B A S MI), D o u ga d os F u ncti onal I n de x ( D FI), 
a n d Healt h Assess me nt Q uesti o n naire f or t he S p o n d ylart hr o pat hies ( H A Q -S). Art hritis C are 
Res ( H o b oke n) . 2 0 1 1; 6 3(s u p pl 1 1): S 4 7-S 5 8.

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 9 2
L Y 2 4 3 9 8 2 1
1 2.
A p p e n di c e s

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 9 3
L Y 2 4 3 9 8 2 1
A p p e n di x 1.
A b br e vi ati o n s a n d D efi niti o n s
T er m
D efi niti o n
A E
a d verse e ve nt:  A n y u nt o war d me dical occ urre nce i n a patie nt or cli nical i n vesti gati o n 
s u bject a d mi nistere d a p har mace utical pr o d uct t hat d oes n ot necessaril y ha ve a ca usal 
relati ons hi p wit h t his treat me nt.  A n a d verse e ve nt ca n t heref ore be a n y u nfa v ora ble a n d 
u ni nte n de d si g n (i ncl u di n g a n a b n or mal la b orat or y fi n di n g), s y m pt o m, or disease 
te m p orall y ass ociate d wit h t he use of a me dici nal (i n vesti gati o nal) pr o d uct, w het her or 
n ot relate d t o t he me dici nal (i n vesti gati o nal) pr o d uct.
A E SI
a d verse e ve nt of s pecial i nterest
A L T
ala ni ne a mi n otra nsferase
A N C O V A
a nal ysis of c o varia nce
A S
a n k yl osi n g s p o n d ylitis:  c urre ntl y referre d t o as ra di o gra p hic a xial s p o n d yl oart hritis (r-
a x S p A)
A S A S
Assess me nt of S p o n d yl oart hritis I nter nati o nal S ociet y
A S A S HI
Assess me nt of S p o n d yl oart hritis I nter nati o nal S ociet y Healt h I n de x
A S D A S
A n k y l osi n g S p o n d ylitis Disease Acti vit y Sc ore.  I n t his st u d y, it refers t o t he A S D A Scr p
sc ore w hic h i ncl u des hi g h se nsiti vit y C-reacti ve pr otei n ( C R P).
A S T
as partate a mi n otra nsferase
a x S p A
a xial s p o n d yl oart hritis:  a si n gle disease e ntit y wit h a s u bset defi ne d b y t he prese nce of 
clear str uct ural da ma ge (r-a x S p A) a n d a s u bset wit h n o clear str uct ural da ma ge as 
defi ne d b y c o n ve nti o nal X- ra ys ( nr-a x S p A)
B A S D AI 5 0
Bat h A n k yl osi n g S p o n d ylitis Disease Acti vit y I n de x 5 0
B A S FI
Bat h A n k yl osi n g S p o n d ylitis F u ncti o nal I n de x
B A S M I
Bat h A n k yl osi n g S p o n d ylitis Metr ol o g y I n de x
B C G
Bacill us Cal mette -G uéri n
b D M A R D
bi ol o gic al disease -m o dif yi n g a ntir he u matic dr u g
Bli n di n g
A s i n gle-bli n d st u d y is o ne i n w hic h t he i n vesti gat or a n d/ or his staff are a ware of t he 
treat me nt b ut t he patie nt is n ot, or vice versa, or w he n t he s p o ns or is a ware of t he 
treat me nt b ut t he i n vesti gat or a n d/ his staff a n d t he patie nt are n ot.
A d o u ble -bli n d s t u d y is o ne i n w hic h neit her t he patie nt n or a n y of t he i n vesti gat or or 
s p o ns or staff w h o are i n v ol ve d i n t he treat me nt or cli nical e val uati o n of t he s u bjects are 
a ware of t he treat me nt recei ve d.

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 9 4
L Y 2 4 3 9 8 2 1
T er m
D efi niti o n
B P
bl o o d press ure
c G M P
c urre nt G o o d Ma n ufact uri n g Pr actices
C E C
Cli nical E ve nts C o m mittee
CI
c o nfi de nce i nter val
C L R M
Cli nical La b orat or y Res ults M o der nizati o n
c D M A R D
c o n ve nti o nal disease-m o dif yi n g a ntir he u matic dr u g
C o m pl ai nt
A c o m plai nt is a n y writte n, electr o nic, or oral c o m m u nicati o n t hat alle ges deficie ncies 
relate d t o t he i de ntit y, q ualit y, p urit y, d ura bilit y, relia bilit y, safet y or effecti ve ness, or 
perf or ma nce of a dr u g or dr u g deli ver y s yste m.
C R P
C- reacti ve pr otei n
C- S S R S
C ol u m bia – S uici de Se verit y Rati n g Scale
C S R
cli nical st u d y re p ort
D V U
disc o -verte bral u nit
E C G
electr ocar di o gra m
e C R F
electr o nic case re p ort f or m
E nr oll
T he act of assi g ni n g a patie nt t o a treat me nt.  Patie nts w h o are e nr olle d i n t he trial are 
t h ose w h o ha ve bee n assi g ne d t o a treat me nt.
E nt er
Patie nts e ntere d i nt o a trial are t h ose w h o si g n t he i nf or me d c o nse nt f or m directl y or 
t hr o u g h t heir le gall y acce pta ble re prese ntati ves.
E Q -5 D -5 L
E ur o pea n Q ualit y of Life – 5 Di me nsi o ns – 5 Le vel
E R B
Et hical Re vie w B oar d
E T V
earl y ter mi nati o n visit
F S H
f ollicle sti m ulati n g h or m o ne
G C P
g o o d cli nical practice
H B V
he patitis B vir us
H L A
h u ma n le u k oc yte a nti ge n
I B
I n vesti gat or’s Br oc h ure
I B D
i nfla m mat or y b o wel disease

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 9 5
L Y 2 4 3 9 8 2 1
T er m
D efi niti o n
I C F
i nf or me d c o nse nt f or m
i n v e sti g ati o n al 
pr o d u ct
A p har mace utical f or m of a n acti ve i n gre die nt or place b o bei n g teste d o r use d as a 
refere nce i n a cli nical trial, i ncl u di n g pr o d ucts alrea d y o n t he mar ket w he n use d or 
asse m ble d (f or m ulate d or pac ka ge d) i n a wa y differe nt fr o m t he a ut h orize d f or m, or 
mar kete d pr o d ucts use d f or a n u na ut h orize d i n dicati o n, or mar kete d pr o d ucts use d t o 
gai n f urt her i nf or mati o n a b o ut t he a ut h orize d f or m.
I T T
i nte nt-t o-treat:  T he pri nci ple t hat asserts t hat t he effect of a treat me nt p olic y ca n be best 
assesse d b y e val uati n g o n t he basis of t he i nte nti o n t o treat a patie nt (t hat is, t he pla n ne d 
treat me nt re gi me n) rat her t ha n t he act ual treat me nt gi ve n.  It has t he c o nse q ue nce t hat 
patie nts all ocate d t o a treat me nt gr o u p s h o ul d be f oll o we d u p, assesse d, a n d a nal yze d as 
me m bers of t hat gr o u p irres pecti ve of t heir c o m plia nce t o t he pla n ne d c o urse of 
treat me nt.
I W R S
i nteracti ve we b-res p o nse s yste m
L T BI
late nt T B i nfecti o n
m B O C F
m o difie d baseli ne o bser vati o n carrie d f or war d
M M R M
mi xe d -effects m o del of re peate d meas ures
m N Y
m o difie d Ne w Y or k
M RI
ma g netic res o na nce i ma gi n g
M T X
met h otre xate
nr- a x S p A
n o nra di o gra p hic a xial s p o n d yl oart hritis:  a s u bset of a x S p A i n w hic h t here is n o clear 
str uct ural da ma ge as defi ne d b y c o n ve nti o nal i ma gi n g
N RI
n o nres p o n der i m p utati o n
N R S
n u meric rati n g scale
N S AI D
n o nster oi dal a nti -i nfla m mat or y dr u g
P C S
p h y sical c o m p o ne nt sc ore
P K/ P D
p har mac o ki netics/ p har mac o d y na mics
P P D
p urifie d pr otei n deri vati ve
P P S
per -pr ot oc ol set:  T he set of data ge nerate d b y t he s u bset of patie nts w h o s ufficie ntl y 
c o m plie d wit h t he pr ot oc ol t o e ns ure t hat t hese data w o ul d be li kel y t o e x hi bit t he 
effects of treat me nt, acc or di n g t o t he u n derl yi n g scie ntific m o del.
P s A
ps oriatic art hritis

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 9 6
L Y 2 4 3 9 8 2 1
T er m
D efi niti o n
Q 2 W
e ver y 2 wee ks
Q 4 W
e ver y 4 wee ks
QI D S -S R 1 6
Q uic k I n ve nt or y of De pressi ve S y m pt o mat ol o g y -self re p ort ( 1 6 ite ms)
r-a x S p A
ra di o gra p hic a xial s p o n d yl oart hritis:  a s u bset of a x S p A i n w hic h t here is e vi de nce of 
disease feat ures o n ra di o gra p hic i ma gi n g
S A E
seri o us a d verse e ve nt
S A P
statistical a nal ysis pla n
S C
s u bc uta ne o us
s cr e e n
T he act of deter mi ni n g if a n i n di vi d ual meets mi ni m u m re q uire me nts t o bec o me part of 
a p o ol of p ote ntial ca n di dates f or partici pati o n i n a cli nical st u d y. 
S F -3 6 M C S
S h ort F or m 3 6 me ntal c o m p o ne nt sc ore
S F -3 6 P C S
S h ort F or m 3 6 p h ysical c o m p o ne nt sc ore
S I J
sacr oiliac j oi nt(s)
S p A
s p o n d yl oart hritis
S P A R C C
S p o n d yl oart hritis Researc h C o ns orti u m of Ca na da
T E A E
treat me nt-e mer ge nt a d verse e ve nt:  A n y u nt o war d me dical occ urre nce t hat eit her occ urs 
or  w orse ns at a n y ti me after treat me nt baseli ne a n d t hat d oes n ot necessaril y ha ve t o 
ha ve a ca usal relati o ns hi p wit h t his treat me nt.
T B
t u berc ul osis
T N Fi
t u m or necr osis fact or i n hi bit or
U L N
u p per li mit of n or mal
V A S
vis ual a nal o g scale
w B C
w h ite bl o o d cell
W P AI -S p A
W or k Pr o d ucti vit y Acti vit y I m pair me nt– S p o n d yl oart hritis

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 9 7
L Y 2 4 3 9 8 2 1
A p p e n di x 2.
Cli ni c al L a b or at or y  T e st s
Cli nic al S afet y L a b or at or y Tests t o be Perf or me d b y S p o ns or -Desi g n ate d L a b or at or y
He m at ol o g y a:
Ser u m C he mistr y a:
He m o gl o bi n
   S o di u m
He mat ocrit
   P otassi u m
Er y t hr oc yte c o u nt ( R B C)
   Bicar b o nate
Mea n cell v ol u me ( M C V)
   C hl ori de
Mea n cell he m o gl o bi n c o nce ntrati o n ( M C H C)
   P h os p h or us
Le u k oc ytes ( W B C)
   T otal bilir u bi n
Platelets
   Direct bilir u bi n
A bs ol ute c o u nts of: 
   Al kali ne p h os p hatase
Ne utr o p hils, se g me nte d
   Ala ni ne a mi n otra nsferase ( A L T/ S G P T)
Ne utr o p hils, j u ve nile ( ba n ds)
   As partate a mi n otra nsferase ( A S T/ S G O T)
L y m p h oc y t es
   Bl o o d urea nitr o ge n ( B U N)
M o n oc ytes
   Ur ic aci d
E osi n o p hils
   Cr eati ni ne
Bas o p hils
   Calci u m
Uri n al ysis ( di pstic k) a:
   Gl uc ose
C ol or
   Al b u mi n
S pecific gra vit y
   C h olester ol (t otal)
p H
   T otal pr otei n
Pr otei n
   Calc ulate d creati ni ne cleara nce b
Gl uc ose
   Cr eati ne p h os p h o ki nase ( C P K)
Ket o nes
   Tri gl yceri des
Bilir u bi n
   Ga m ma -gl uta m yl tra nsferase ( G G T)
Ur o bili n o ge n
L i pi d P a nel c:
Bl o o d
   L o w de nsit y li p o pr otei n ( L D L)
Nitrite
   Hi g h de nsit y li p o pr otei n ( H D L)
Ur i ne creati ni ne
   Ver y  l o w de nsit y li p o pr otei n ( V L D L)
Le u k oc yte esterase
Ot her Tests :
H u ma n i m m u n o deficie nc y vir us a nti b o d y ( HI V) f
Pre g na nc y test (ser u m) d
He patitis B s urface a nti ge n ( H Bs A g) f
F ollicle -sti m ulati n g h or m o ne ( F S H) e
A nti – he patitis B s urface a nti b o d y ( H Bs A b) f
T h y r oi d-sti m ulati n g h or m o ne ( T S H) a n d free T 4
A nti – he patitis B c ore a nti b o d y ( H Bc A b) f
I xe kiz u ma b ser u m c o nce ntrati o n ( p har mac o ki netic [ P K])
A nti – he patitis C a nti b o d y f, h
Partial t hr o m b o plasti n ti me ( P T T)
H B V D N A g
Pr ot hr o m bi n ti me/i nter nati o nal n or malize d rati o ( P T/I N R)
Hi g h se nsiti vit y C -reacti ve pr otei n ( C R P)
I m m u n o ge nicit y testi n g (a nti-i xe kiz u ma b A b)
P urifie d pr otei n deri vati ve ( P P D) i
Ur i ne pre g na nc y testd (assa ye d b y cli nical st u d y site)
Q ua nti F E R O N ® -T B G ol d test i
T- S P O T ® i
H L A -B 2 7
A b bre viati o ns:  A b = a nti b o d y; D N A = de o x yri b o n ucleic aci d; H B V = he patitis B vir us; m R N A = messe n ger 
ri b o n ucleic aci d; R B C = re d bl o o d cells; S G O T = ser u m gl uta mic o xal oacetic tra nsa mi nase; S G P T = ser u m 
gl uta mic p yr u vic tra nsa mi nase; T 4 = t h yr o xi ne; W B C = w hite bl o o d cells.

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 9 8
L Y 2 4 3 9 8 2 1
a
U n sc he d ule d bl o o d c he mistr y, he mat ol o g y, a n d uri nal ysis pa nels ma y be perf or me d at t he discreti o n of t he 
i n vesti gat or.  
b
C oc kcr oft -Ga ult calc ulati o n is use d f or t he calc ulate d creati ni ne cleara nce.
c
F or t he fasti n g li pi d pr ofile, p atie nts are n ot t o eat or dri n k a n yt hi n g e xce pt water f or 1 2 h o urs pri or t o test.  
Fasti n g is n ot re q uire d f or t he scree ni n g v isit ( Visit 1).
d
Ser u m pre g na nc y test f or all w o me n < 6 0 years of a ge w h o are still of c hil d beari n g p ote ntial at Visit 1 o nl y a n d 
will be perf or me d ce ntrall y ; after Visit 1, uri ne pre g na nc y test perf or me d l ocall y f or w o me n of c hil d beari n g 
p ote ntial.
e
W o me n ≥4 0 a n d < 6 0 years of a ge w h o ha ve ha d a cessati o n of me nses f or ≥1 2 m o nt hs will ha ve a n F S H test 
c o nfir mi n g n o nc hil d beari n g p otential ( ≥4 0 mI U/ m L).
f
Test re q uire d at Visit 1 t o deter mi ne eli gi bilit y of patie nt f or t he st u d y.  H B V D N A testi n g will be d o ne i n t h ose 
patie nts w h o are H Bc A b + at scree ni n g.
g
H B V D N A testi n g will be d o ne i n t h ose patie nts w h o are H Bc A b + at scree ni n g.
h
See e xcl usi o n criteria ( Secti o n 6. 2 ) s pecific t o He patitis C a nti b o d y.  A c o nfir mat or y test f or H C V will be 
perf or me d if t he patie nt is p ositi ve f or H C V a nti b o d y.
i
If t h e Q ua nti F E R O N ®-T B G ol d test, or T -S P O T ® is a va ila ble, it ma y be use d i nstea d of t he P P D T B test, a n d 
m a y  be perf or me d l ocall y or ce ntrall y.
Selecte d tests m a y be o bt ai ne d i n t he e ve nt of a n a p h yl a xis or ge ner alize d urtic ari a.
H y perse nsiti vit y Tests a
A nti- L Y a nti b o dies (i m m u n o ge nicit y)
Tr y ptase
L Y c o nce ntrati o n ( P K)
N- Met h y l hista mi ne
Dr u g S pecific I g E b
Bas o p hil Acti vati o n Test b
C o m ple me nts
C y t o ki ne Pa nel
A b bre viati o ns:  P K = p har mac o ki netic
a
Assa y e d b y Lill y-desi g nate d la b orat or y   
b
Bas o p hil Acti vati o n test will be perf or me d if a dr u g s pecific I g E assa y is u na vaila ble.

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 9 9
L Y 2 4 3 9 8 2 1
A p p e n di x 3.
St u d y  G o v er n a n c e C o n si d er ati o n s
A p p e n di x 3. 1 . R e g ul at or y a n d Et hi c al C o n si d er ati o n s, I n cl u di n g t h e 
I nf or m e d C o n s e nt Pr o c e s s
A p p e n di x 3. 1. 1 .
I nf or m e d C o n s e nt
T he i n vest i gat or is res p o nsi ble f or:

e ns uri n g t hat t he patie nt u n dersta n ds t he nat ure of t he st u d y , t he p ote ntial ris ks 
a n d be nefits of partici pat i n g i n t he st u d y, a n d t hat t heir partici pati on is 
v o l unt ar y.

e ns uri n g t hat i nf or me d c o nse nt is gi ve n b y eac h patie nt or le gal re prese ntati ve.  
T his i ncl u des o btai ni n g t he a p pr o priate si g nat ures a n d dates o n t he I C F pri or 
t o t he perf or ma nce of a n y pr ot oc ol pr oce d ures a n d pri or t o t he a d mi nistrati o n 
of  in vesti gati o nal pr o d uct.

a ns weri n g a n y q uest i ons t he pati e nt ma y ha ve t hr o u g h o ut t he st u d y a n d 
s hari n g i n a timel y ma n ner a n y ne w i nf or mat i on t hat m a y be rele va nt t o t he 
pati e nt’s willi n g ness t o c o nti n ue his or her partici pati o n i n t he st u d y.

e ns uri n g t hat a c o p y of t he I C F is pr o vide d t o t he partici pa nt or t he 
parti ci pa nt’s le g al re prese ntati ve a n d is ke pt o n file.

e ns uri n g t hat t he me dical rec or d i ncl u des a state me nt t hat writte n i nf or me d 
c o nse nt was o btai ne d bef ore t he partici pa nt was e nr ol le d i n t he st u d y a n d t he 
date t he writte n c o nse nt was o btai ne d.  T he a ut h orize d pers o n o btai ni n g t he 
i nf or me d c o nse nt must a ls o sig n t h I C F. 
A p p e n di x 3. 1. 2.
Et hi c al R e vi e w
T he i n vest i gat or m ust gi ve ass ura nce t hat t he E R B was pr o perl y c o nstitute d a n d c o n ve ne d as 
re q uire d b y I nter nati onal C o nfere nce o n Har m o nisati o n (I C H) g ui deli nes a n d ot her a p plica ble 
la ws a n d re g ulati o ns.
D o c u me ntati o n of E R B a p pr o val o f t he pr ot oc ol a n d t he I C F m ust be pr o vi de d t o Lill y before t he 
st u d y ma y be gi n at t he i n vestigati ve si te(s).  Lill y or its re prese ntati ves m ust a p pr o ve t he I C F, 
i ncl u di n g a n y c ha n ges ma de b y t he E R Bs, bef ore it is use d at t he i n vesti gati ve site(s).  All I C Fs 
m ust be c o m plia nt wit h t he I C H g ui deli ne o n G C P.
T he st u d y  site’s E R B(s) s h o uld be pr o vi de d wi t h t h e fol l owi n g :

t he pr ot oc ol a n d relate d a me n d me nts a n d a d de n da, c urre nt I B a n d u p dates 
d uri n g t he c o urse of t he st u d y

I C F

ot he r rele va nt d oc u m e nts (f or e xa m ple, c urric ula vit a e, a d vertise me nts)

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 1 0 0
L Y 2 4 3 9 8 2 1
A p p e n di x 3. 1. 3.
R e g ul at or y C o n si d er ati o n s
T his st u d y  will be c o n d ucte d i n acc or da nce with t he pr ot oc ol a n d wit h t he :

c o nse ns us et hics pri nci ples deri ve d fr o m i nter nat i onal et hics g ui deli nes, i ncl u di n g 
t he Declarat i on of Helsi n ki a n d C o u ncil f or I nter nati o nal Or ga nizati o ns of 
Me dical Scie nces ( CI O M S) I nter nati o nal Et hical G ui deli nes

a p plica ble I C H G C P G ui deli nes

a p plica ble la ws a n d re g ulati o ns
S o m e of t he o bli gati ons of t he s p o ns or will be assi g ne d t o a t hir d -part y .
A p p e n di x 3. 1. 4.
I n v e sti g at or I nf or m ati o n
P h ysicia ns wit h a s pecialt y i n r he u mat ol o g y will p artici pate as i n vest i gat ors i n t his cli nical trial.
A p p e n di x 3. 1. 5.
Pr ot o c ol Si g n at ur e s
T he s p o ns or’s res p o nsi ble me dical o fficer will a p pr o ve t he pr ot oc ol, c o nfir mi n g t hat, t o t he best 
of  his or her k n o wle d ge, t he pr ot oc ol acc uratel y descri bes t he pla n ne d desi g n a n d c o n d uct of t he 
st u d y.
After rea di n g t he pr ot oc ol, eac h pri nci pal i n vest i gat or will si g n t he pr ot oc ol si g nat ure pa ge a nd 
se n d a c o p y of t he si g ne d pa ge t o a Lill y re prese ntati ve.
A p p e n di x 3. 1. 6.
Fi n al R e p ort Si g n at ur e
T he C S R c o or di nat i n g i n vesti gat or will si g n t he fi nal C S R f or t his st u d y, i n dicati n g a gree me nt 
t hat, t o t he best of his or her k n o wle d ge, t he re p ort acc urate l y descri bes t he c o n d uct a n d res ults 
of  t he st u d y.
T he C S R c o or di nat i n g i n vesti gat or will be selecte d b y t he s p o ns or.  If t his i n vesti gat or is u na ble 
t o f ulfill t his f u ncti on, a n ot her i n vest i gat or will be c h ose n b y Lill y t o ser ve as t he C S R 
c o or di nat i n g i nvesti g at or.
T he s p o ns or’s res p o nsi ble me dical o fficer a n d statisticia n will  a p pr o ve t he fi nal C S R f or t his 
st u d y, c o nfir mi n g t hat, t o t he best of his or her k n o wle d ge, t he re p ort acc uratel y descri bes t he 
c o n d uct a n d res ults of t he st u d y.
A p p e n di x 3. 2.
D at a Q u alit y A s s ur a n c e
T o e ns ure acc urate, c o m plete, a n d relia ble data, Lill y or its re prese ntati ves will d o t he f o ll owi n g:

pr o vi de i nstr ucti o nal materi al t o t he st u d y sites, as a p pr o priate.

s p o ns or start-u p trai ni n g t o i nstr uct t he i n vest i gat ors a n d st u d y c o or di nat ors.  T his 
trai ni n g will gi ve i nstr ucti o n o n t he pr ot oc ol, t he c o m pleti on of t he C R Fs, a n d 
st u d y pr oce d ures.

ma ke peri o dic visit s t o t he st u d y sit e.

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 1 0 1
L Y 2 4 3 9 8 2 1

be a vaila ble f or c o ns ultati o n a n d sta y  in c o ntact wit h t he st u d y site pers o n nel b y 
mail, tel e p h o ne, an d/ or fa x.  

re vie w a n d e val uate C R F data a n d use sta n dar d c o m p uter e dits t o detect err ors i n 
data c ollect i on.

c o n d uct a q ualit y re vie w of t he data base.
I n a d diti on, Lill y or its re prese ntati ves will peri o dicall y c hec k a sa m ple of t he patie nt data 
rec or de d a gai nst s o urce d oc u me nts at t he st u d y sit e.  T he st u d y ma y be a u dit e d b y Lill y or its 
re prese ntati ves, a n d/ or re g ulat or y a ge ncies at a n y ti me.  I n vesti gat ors will be gi ve n n otice bef ore 
a n a u dit occ urs.
T he i n vest i gat or will kee p rec or ds of all ori gi nal so urce data.  T his mi g ht i ncl u de la b orat or y  
tests, me dical rec or ds, a n d cli nical n otes.  If re q ueste d, t he i n vest i gat or will pr o vi de t he s p o ns or, 
a p plica ble re g ulat or y a ge ncies, a n d a p plica ble E R Bs wit h direct access t o ori gi nal s o urce 
d oc u m e nts.
A p p e n di x 3 . 2. 1.
D at a C a pt ur e S y st e m
A n electr o nic data ca pt ure s y st e m will be use d i n t his st u d y. T he site mai ntai ns a se parate s o urce 
f or t he data e ntere d b y t he site i nt o t he s p o ns or-pr o vi de d electr o nic data ca pt ure s yste m. S o m e 
or all of a patie nt’s data will b e directl y e ntere d i nt o t he e C R F at t he ti me t hat t he i nf or mati on is 
o btai ne d. I n i nsta nces w here direct data e ntr y is n ot use d, t he site will mai ntai n s o urce 
d oc u m e nt atio n i n t he tri al files, a n d t he patie nt’s data will be tra nscri be d i nt o t he e C R F. Pa p er 
d oc u m e nt atio n pr o vi de d b y  t he pat ient  will ser ve as t he s o urce d oc u me nt, i ncl u di n g a st u d y  dr u g 
a d mi nistrati o n l o g a n d a n e ve nt -me d icati on diar y , t hat will be i de ntifie d a n d d oc u me nte d b y eac h 
site i n t hat site’s st u d y file.
Data m a na ge d b y a ce ntral ve n d or, s uc h as la b orat or y test data or E C G data, will be st ore d 
ele ctr o nicall y i n t he ce ntral ve n d or’s data base s yst e m. Data will s u bse q ue nt l y be tra nsferre d 
fr om t he ce ntral ve n d or t o t he Cli nical La b orat or y  Res ults M o der nizatio n ( C L R M).
Data fr o m c o m p lai nt f or ms s u b mitte d t o Lill y will be e nc o de d a n d st ore d i n t he gl o bal pr o d uct 
c o mplai nt m a na ge me nt s yst e m.
A p p e n di x 3. 3.
St u d y a n d Sit e Cl o s ur e
A p p e n di x 3. 3. 1.
Di s c o nti n u ati o n of St u d y Sit e s
St u d y  sit e p artici pat i on ma y be disc o nt i n ue d if Lill y  or its desig nee , the i n vesti gat or, or t he E R B 
of  t he st u d y sit e j u d ges it necessar y f or me dical, safety,  re g ulat or y, or ot her reas o ns c o nsiste nt 
wi t h a p plica ble la ws, re g ulat i ons, a n d G C P.
A p p e n di x 3. 3. 2.
Di s c o nti n u ati o n of t h e St u d y
T he st u d y  will b e disc o nti n ue d if Lill y or its desi g nee j u d ges it necessar y for m e dical, safet y,  
re g ulat or y, or ot her reas o ns c o nsiste nt wit h a p plica ble la ws, re g ulati ons, a n d G C P.

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 1 0 2
L Y 2 4 3 9 8 2 1
A p p e n di x 4.
H e p ati c M o nit ori n g T e st s f or Tr e at m e nt -
E m er g e nt A b n or m alit y
He p atic M o nit ori n g
Tests
He p atic He m at ol o g y a
H a pt o gl o bi n a
He m o gl o bi n
He mat ocrit
He p atic C o a g ul ati o n a
R B C
Pr ot hr o m b i n Ti me
W B C
Pr ot hr o m bi n Ti me, I N R
Ne utr o p hils, se g me nte d
L y m p h oc y t es
He p atic Ser ol o gies a , b
M o n oc ytes
He patitis A a nti b o d y, t otal
E osi n o p hils
He patitis A a nti b o d y, I g M
Bas o p hils
He patitis B s urface a nti ge n
Platelets
He patitis B s urface a nti b o d y
He patitis B C ore a nti b o d y
He p atic C he mistr y a
He patitis C a nti b o d y
T otal bilir u bi n
He patitis E a nti b o d y, I g G
Direct bilir u bi n
He patitis E a nti b o d y, I g M
Al kali ne p h os p hatase
A L T
A nti -n ucle ar a nti b o d y a
A S T
G G T
Al k ali ne P h os p h at ase Is oe nz y mes a
C P K
A nti -s m o ot h m uscle a nti b o d y ( or a nti -acti n 
a nti b o d y) a
A b bre viati o ns:  A L T = ala ni ne a mi n otra nsferase; A S T = as pirate a mi n otra nsferase; C P K = creati ni ne 
p h os p h o ki nase; G G T = ga m ma -gl uta m yl tra nsferase; I g = i m m u n o gl o b uli n; I N R = i nter nati o nal n or malise d 
rati o; R B C = re d bl o o d cells; W B C = w hite bl o o d cells.
a
Assa y e d b y Lill y-desi g nate d or l ocal la b orat or y.
b
Refle x/c o nfir mati o n de pe n de nt o n  re g ulat or y re q uire me nts a n d/ or testi n g a vaila bilit y..

I 1 F-M C -R H C H Cli ni c al Pr ot o c ol
P a g e 1 0 3
L Y 2 4 3 9 8 2 1
A p p e n di x 5.
S p o n d y l o art hriti s F e at ur e s
T o be i ncl u de d i n St u d y  R H C H, p atie nts must ha ve sacr oiliit is defi ne d ra di o gra p hicall y 
acc or di n g t o t he m N Y criteria base d o n ce ntral rea di n g
A N D
at least o ne of t he s p o n d yl oart hritis feat ures (fr om B o x 4, A S A S criteria f or classificat i on of 
a x S p A [t o be a p plie d i n patie nts wit h c hr o nic bac k pai n ≥3 m o nt hs a n d a ge at o nset of bac k pai n 
< 4 5 y ears]) b ullete d bel o w:

I nfl a m m at or y b ac k p ai n (I B P):  A cc or di n g t o e x perts, 4 o ut of 5 of t he f o ll owi n g 
para m eters prese nt:  ( 1) a ge at o nset < 4 0 years, ( 2) i nsi di o us o nset, ( 3) i m pr o ve me nt wit h 
e xercise, ( 4) n o i m pr o ve me nt wit h rest, ( 5) pai n at ni g ht ( wit h i m pr o ve me nt u p o n getti n g 
u p).

Art hritis:   Past or prese nt acti ve s y n o vit is dia gn ose d b y  a d oct or.

E nt hesitis ( heel):  P ast or prese nt s p o nta ne o us pai n or te n der ness at e xa mi nat i on at t he 
sit e of t he i nserti on of t he Ac hilles te n d o n or pla ntar fascia at t he calca ne us.

U veitis:   Past or prese nt u veit is a nteri or, c o nfir me d b y a n o p ht hal m ol ogist.

D act ylitis:   Past or prese nt dact ylit is dia g n ose d b y a d oct or.

Ps ori asis:   Past or prese nt ps oriasis dia g n ose d b y a d oct or.

Cr o h n’s/ C olitis:   Past or prese nt Cr o h n’s disease or ulcerat i ve c o litis dia g n ose d b y a 
d oct or.

G o o d res p o nse t o N S AI Ds:   At  2 4 t o 4 8 h o urs after a f ull d ose of N S AI D, t he bac k pai n 
was n ot prese nt a n y m ore or m uc h better.
N ote:  As patie nts e nr o lli n g i nt o t he st u d y s h o ul d ha ve faile d 2 N S AI Ds or be i nt olera nt 
t o N S AI Ds, a d oct or s h o ul d assess w het her patie nts ha d “ g o o d” pri or res p o nse t o 
N S AI Ds.

F a mil y hist or y f or S p A:   Prese nce i n first -de gree or sec o n d -de gree relat i ves of a n y of 
t he f o ll owi n g:  (a) A S, ( b) ps oriasis, (c) u veit is, ( d) reacti ve art hritis, (e) I B D.
N ote:   A d oct or s h o ul d c o nfir m wit h his/ her patie nt t here was a clear dia g n osis ( n ot self -
di a g n osis) f or a n y of t hese i n first- or sec o n d-de gree relat i ves.

H L A -B 2 7:   P osit i ve testi n g acc or di n g t o sta n dar d la b orat or y tec h ni q ues.

Ele v ate d C R P:   C R P > 5. 0 0 m g/ L i n t he prese nce of bac k pai n, after e xcl usi o n of ot her 
ca uses f or ele vate d C R P c o nce ntrati o n.
Refere nces:  R u d waleit et al. 2 0 0 9; Si e per et al. 2 0 0 9; Sie per et al. 2 0 1 7.

L e o  D o c u m e n t  I D  =  9 2 c 3 1 e c a - 7 2 5 e - 4 7 3 b - b 8 e 2 - 4 2 6 b f 5 e f 2 e 6 9
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  1 9 - J u n - 2 0 1 9  0 2 : 5 3 : 4 3  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  2 0 - J u n - 2 0 1 9  2 0 : 4 7 : 5 1  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
I 1 F- M C- R H C H Cli ni c al Pr ot o c ol
P a g e 1 0 4
L Y 2 4 3 9 8 2 1
P P D
P P D