A Randomized, Double-Blind, Placebo-Controlled, Dose Assessment Phase 2 Study to Evaluate the Safety and Efficacy of CCX168 in Subjects With Anti-Neutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis
Phase: PHASE2
Conditions: ANCA-associated Vasculitis
Sponsor: Amgen

C he m o Ce ntr y x, I n c.  
C O N FI D E N TI A L  
Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8 
 
A me n d me nt 4. 0  
                                                                   Pa ge 1 of 1 0 1                                     1 9 Fe br uar y 2 0 1 6 
 
P R O T O C O L 
Pr ot oc ol A me n d me nt 4 . 0 
TI T L E P A G E  
St u d y Title:  A Ra n d o mize d, D o u ble- Bli n d, Place b o- C o ntr olle d, D ose 
Assess me nt P hase 2  St u d y t o E val uat e t he Safet y a n d Efficac y of 
C C X 1 6 8 i n S u bjects wit h A nti- Ne utr o p hil C yt o pl as mic A nti b o d y 
( A N C A)-Ass ociate d V as c ulitis  
Pr ot oc ol N u m ber:  C L 0 0 3 _ 1 6 8 
I n vesti g ati o n al Pr o d uct: C o m ple me nt 5a Rece pt or A nta g o nist C C X 1 6 8 
I n dic ati o n: A N C A -Ass ociate d Vasc ulitis  
S p o ns or:  C he m o Ce ntr y x, I n c.  
De vel o p me nt P h ase:  2  
I N D n u m ber  1 2 0 7 8 4 
S p o ns or's Res p o nsi ble 
Me dic al Officer:  
 
C he m o Ce ntr y x, I n c.  
 
S p o ns or Si g n at or y: 
 
A p pr o v al D ate: 
3 1 Ma y 2 0 1 4 — FI N A L  
1 3 A u g ust 2 0 1 4 — Pr ot o c ol A me n d me nt 1. 0  
3 N o ve m ber 2 0 1 4 — Pr ot oc ol A me n d me nt 1. 1  ( C a n a d a) 
1 2 M a y 2 0 1 5 — Pr ot o c ol A me n d me nt 2. 0  
1 9 A u g ust 2 0 1 5 — Pr ot o c ol A me n d me nt 3. 0  
1 9 Fe br u a r y 2 0 1 6 — Pr ot oc ol A me n d me nt 4. 0   
 
C o nfi de nti al  
T he i nf or mati o n c o ntai ne d herei n is t he pr o pert y of t he S p o ns or a n d ma y n ot be re pr o d u ce d, 
p u blis he d, or discl ose d t o ot hers wit h o ut writte n a ut h orizati o n of t he S p o ns or. 
T his st u d y will be c o n d u cte d acc or di n g t o t he pri n ci ples of G o o d Cli nical Practice as descri be d 
i n I nter nati o nal C o nfer e n ce o n Har m o nizati o n g ui deli nes, i ncl u di n g t he arc hi vi n g of ess e ntial 
d oc u me nts. 
P P D
P P D
P P D

C he m o Ce ntr y x, I n c.  
C O N FI D E N TI A L  
Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8 
 
A me n d me nt 4. 0  
                                                                   Pa ge 2 of 1 0 1                                     1 9 Fe br uar y 2 0 1 6 
 
I N V E S TI G A T O R SI G N A T O R Y P A G E 
Pr ot oc ol N u m ber:  C L 0 0 3 _ 1 6 8 
Pr ot oc ol Title:  A R a n d o mize d, D o u ble- Bli n d, Place b o- C o ntr olle d, D ose Assess me nt P hase 2 
St u d y t o E v al uate t he Saf et y a n d Efficac y of C C X 1 6 8 i n S u bjects wit h A nti- Ne utr o p hil 
C yt o plas mic A nti b o d y ( A N C A) -Ass oci ate d Vas c ulitis  
I a gree: 
•  t o ass u me res p o nsi bilit y f or t he pr o per c o n d u ct of t he st u d y at t his site. 
•  t o c o n d uct t he st u d y i n c o m plia nce wit h t his pr ot oc ol, a n y f ut ure a me n d m e nts, a n d wit h 
a n y ot h er st u d y c o n d uct pr oce d ures pr o vi de d b y C he m o Ce ntr y x, I n c. 
•  n ot t o i m ple me nt a n y de viati o ns fr o m or c ha n ges t o t he pr ot oc ol wit h o ut a gree me nt fr o m 
t he s p o ns or a n d pri or r e vie w a n d writte n a p pr o val fr o m t he I nstit uti o nal Re vie w B oar d 
(I R B)/ Et hics C o m mittee ( E C), e x ce pt w here necessar y t o eli mi nate a n i m me diate hazar d 
t o t he s u bjects, or f or a d mi nistrati ve as pects of t h e st u d y ( w here per mitte d b y all 
a p plica ble r e g ulat or y r e q uire me nts).  
•  t hat I a m t h or ou g hl y fa miliar wit h t he a p pr o priate use of t he i n vesti gati o nal dr u g(s), as 
descri be d i n t his pr ot oc ol, a n d a n y ot her i nf or mati o n pr o vi de d b y t he s p o ns or i ncl u di n g, 
b ut n ot li mite d t o t he f oll o wi n g: t he c urre nt v ersi o n of t he Cli nical I n v esti gat or’s 
Br oc h ure pr e par e d b y C h e m o Ce ntr y x, I nc. a n d a p pr o ve d pr o d uct la b el, if a p plica ble. 
•  t hat I a m a ware of a n d will c o m pl y wit h c urre nt I C H/ F D A g o o d cli nical practices 
g ui deli nes ( G C P) a n d all re g ulat or y re q uire me nts. 
•  t o e ns ure t hat all pers o ns assisti n g me wit h t he st u d y are a d e q uatel y i nf or me d a b o ut t he 
i n vesti gati o nal dr u g(s) a n d t heir st u d y-relate d d uti es a n d f u ncti o n as d escri be d i n t he 
pr ot oc ol. 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _         
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Pri nci pal I n v esti gat or     
  
  
  
  
  
  
 
Date  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pri nte d Na me  
A d dress * _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
P h o ne N u m ber * _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
* If t he a d dr ess or p h o ne n u m ber nee ds t o be c ha n ge d d uri n g t he c o urs e of t he st u d y, t his will be 
d o ne b y t h e I n vesti gat or, wit h writte n n otificati o n t o t he S p o ns or, a n d will n ot re q uire (a) 
pr ot oc ol a me n d me nt(s). 

C he m o Ce ntr y x, I n c.  
C O N FI D E N TI A L  
Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8 
 
A me n d me nt 4. 0  
                                                                   Pa ge 3 of 1 0 1                                     1 9 Fe br uar y 2 0 1 6 
 
S P O N S O R C O N T A C T I N F O R M A TI O N  
Pr ot oc ol N u m ber:  C L 0 0 3 _ 1 6 8 
Pr ot oc ol Title:  A R a n d o mize d, D o u ble- Bli n d, Place b o- C o ntr olle d, D ose Assess me nt P hase 2 
St u d y t o E v al uate t he Saf et y a n d Efficac y of C C X 1 6 8 i n S u bjects wit h A nti- Ne utr o p hil 
C yt o plas mic A nti b o d y ( A N C A) -Ass oci ate d Vas c ulitis  
 
Me dical Offi cer    
 
C hief Me dical Officer  
C he m o Ce ntr y x, I n c.  
 
 
 
 
 
Cli nical      
  
 
 
O perati o ns   
  
 
Cli nical C o ns ulta nt   
Ma na ger     
  
 
C he m o Ce ntr y x, I n c.  
 
 
 
E mail:  
 
 
P P D
P P D
P P D
P P D
P P D

C he m o Ce ntr y x, I n c.  
C O N FI D E N TI A L  
Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8 
 
A me n d me nt 4. 0  
                                                                   Pa ge 5 of 1 0 1                                     1 9 Fe br uar y 2 0 1 6 
 
P R O T O C O L A M E N D M E N T 4 . 0: S U M M A R Y O F C H A N G E S 
1.  Bec a use of t he rel ati vel y s m all s a m ple size of t he st u d y, a n al ysis of t he pri m ar y 
effic ac y e n d p oi nt w as m o difie d. Res ults will be s u m m arize d  a n d n o i nfere nti al 
st atistic al a n al ysis will be perf or me d. M o dific ati o ns h a ve bee n m a de t o t he St u d y 
S y n o psis  a n d Secti o n 7. 1 3. 3  t o i n dic ate t his c h a n ge. 
2.  Si nce t he c o nti n u o us v ari a bles are t y pic all y me as ure d at m ulti ple ti me p oi nts o ver 
t he c o urse of t he st u d y, t he m ai n a n al ysis met h o d ol o g y of c o nti n u o us v ari a bles w as 
c h a n ge d f r o m a n al ysis of c o v ari a nce ( A N C O V A) t o mi xe d m o del f or re pe ate d 
me as ures ( M M R M). M o dific ati o ns h a ve bee n m a de t o t he St u d y S y n o psis  a n d 
Secti o n 7. 1 3. 3  t o reflect t his c h a n ge. 
3.  A n effi c ac y e n d p oi nt of e arl y re missi o n, b ase d o n B V A S of 0 at D a y 2 9 A N D D a y 8 5, 
w as a d de d t o e v al u ate t he a bilit y of C C X 1 6 8 t o i n d uce e arl y re missi o n; t he 
defi niti o n of re missi o n w as m o difie d t o B V A S of 0, si nce p atie nts i n t his tri al d o n ot 
necess aril y h a ve re n al dise ase i n v ol ve me nt; t he t hres h ol d e n d p oi nts re g ar di n g 
he m at uri a w ere re m o ve d f or t he s a me re as o n. M o dific ati o ns h a ve bee n m a de t o t he 
St u d y S y n o psis  a n d Secti o n 7. 1 0  t o reflect t hes e c h a n ges. 
4.  Bec a use of t he rel ati vel y s m all s a m ple size of t he st u d y, t he j ustific ati o n f or t he 
s a m ple size w as m o difie d t o i n dic ate t h at it w as b ase d o n pr actic al a n d n ot st atistic al 
c o nsi der ati o ns. M o dific ati o ns w ere m a de t o t he St u d y S y n o psis  a n d Secti o n 7. 1 4  t o 
reflect t his c h a n ge.   
 
 

C he m o Ce ntr y x, I n c.  
C O N FI D E N TI A L  
Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8 
 
A me n d me nt 4. 0  
                                                                   Pa ge 6 of 1 0 1                                     1 9 Fe br uar y 2 0 1 6 
 
T A B L E O F C O N T E N T S  
I N V E S TI G A T O R SI G N A T O R Y P A G E ......................................................................................... 2 
S P O N S O R C O N T A C T I N F O R M A TI O N  ....................................................................................... 3 
S P O N S O R SI G N A T U R E F O R A P P R O V A L  ................................................................................. 4 
P R O T O C O L A M E N D M E N T 4. 0: S U M M A R Y O F C H A N G E S  ................................................... 5 
T A B L E O F C O N T E N T S  ................................................................................................................. 6 
LI S T O F T A B L E S  ......................................................................................................................... 1 0 
S T U D Y S Y N O P SI S  ...................................................................................................................... 1 1 
S T U D Y S C H E M A ......................................................................................................................... 2 4 
TI M E A N D E V E N T S T A B L E ...................................................................................................... 2 5  
LI S T O F A B B R E VI A TI O N S A N D A C R O N Y M S  ...................................................................... 2 8 
1.  
I N T R O D U C TI O N ...................................................................................................... 3 0 
1. 1.  
Bac k gr o u n d ................................................................................................................. 3 0  
1. 1. 1.  
N o n -Cli nical P har mac ol o g y  ....................................................................................... 3 1 
1. 1. 1. 1.  
I n Vitr o Efficac y a n d Sel ecti vit y f or C 5a R  ................................................................. 3 1 
1. 1. 1. 2.  
Efficac y M o dels  .......................................................................................................... 3 1 
1. 1. 2.  
N o n - Cli nical Safet y a n d T o xic ol o g y .......................................................................... 3 3 
1. 1. 3.  
N o n -Cli nical A D M E  ................................................................................................... 3 6 
1. 2.  
Pri or H u ma n E x perie nce ............................................................................................. 3 8  
1. 3.  
Rati o nale f or t he St u d y ............................................................................................... 4 0  
2.  
O BJ E C TI V E S  ............................................................................................................. 4 0 
2. 1.  
Pri mar y O bj ecti ve  ....................................................................................................... 4 0 
2. 2.  
Sec o n dar y O bj ecti ves  ................................................................................................. 4 0 
3.  
S T U D Y D E SI G N  ....................................................................................................... 4 1 
4.  
S T U D Y P O P U L A TI O N  ............................................................................................. 4 3 
4. 1.  
Size of t he P o p ulati o n ................................................................................................. 4 3  
4. 2.  
I n cl usi o n Criteria ........................................................................................................ 4 3 
4. 3.  
E x cl usi o n Criteria  ....................................................................................................... 4 4 
4. 4.  
Re m o val of S u bjects fr o m T hera p y of Assess me nt  .................................................... 4 5 
5.  
S T U D Y M E DI C A TI O N/ T R E A T M E N T  ................................................................... 4 6 

C he m o Ce ntr y x, I n c.  
C O N FI D E N TI A L  
Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8 
 
A me n d me nt 4. 0  
                                                                   Pa ge 7 of 1 0 1                                     1 9 Fe br uar y 2 0 1 6 
 
5. 1.  
Pr o d uct C haracteristics  ............................................................................................... 4 6 
5. 2.  
Ra n d o mizati o n a n d Met h o d of Treat me nt Assi g n me nt .............................................. 4 6  
5. 3.  
D oses a n d Re gi me ns ................................................................................................... 4 6  
5. 4.  
Rati o nale f or D ose Sel ecti o n  ...................................................................................... 4 8 
5. 5.  
Dr u g S u p pl y ................................................................................................................ 4 9  
5. 5. 1.  
Pac ka gi n g a n d La b eli n g  .............................................................................................. 4 9 
5. 5. 2.  
St ora ge  ........................................................................................................................ 5 0 
5. 6.  
Bli n di n g ...................................................................................................................... 5 0  
5. 7.  
Dr u g Acc o u nta bilit y ................................................................................................... 5 0  
5. 8.  
Treat me nt C o m plia nce  ................................................................................................ 5 1 
5. 9.  
C o nc o mita nt Me dicati o ns a n d Restricti o ns ................................................................ 5 1  
5. 1 0.  
Criteria f or Resc u e C ortic oster oi d Use  ....................................................................... 5 1 
6.  
S T U D Y P R O C E D U R E S  ............................................................................................ 5 2 
6. 1.  
Scree ni n g a n d E nr oll me nt  ........................................................................................... 5 2 
6. 2.  
St u d y Da y 1  ................................................................................................................ 5 3 
6. 3.  
St u d y Da y 2  ................................................................................................................ 5 5 
6. 4.  
St u d y Da y 8  ................................................................................................................ 5 6 
6. 5.  
St u d y D a y 1 5  .............................................................................................................. 5 7 
6. 6.  
St u d y Da y 2 2 .............................................................................................................. 5 8  
6. 7.  
St u d y Da y 2 9 .............................................................................................................. 5 9  
6. 8.  
St u d y Da y 4 3  .............................................................................................................. 6 1 
6. 9.  
St u d y Da y 5 7 .............................................................................................................. 6 2  
6. 1 0.  
St u d y Da y 7 1 .............................................................................................................. 6 3  
6. 1 1.  
St u d y Da y 8 5 .............................................................................................................. 6 4  
6. 1 2.  
St u d y Da y 9 9  .............................................................................................................. 6 6 
6. 1 3.  
St u d y Da y 1 1 3 ............................................................................................................ 6 7  
6. 1 4.  
St u d y Da y 1 4 1 ............................................................................................................ 6 8  
6. 1 5.  
St u d y Da y 1 6 9 ............................................................................................................ 6 8  
7.  
S T U D Y A S S E S S M E N T S  .......................................................................................... 6 9 
7. 1.  
Efficac y Assess me nts  ................................................................................................. 6 9 
7. 1. 1.  
C ortic oster oi d Resc ue Us e  .......................................................................................... 6 9 

C he m o Ce ntr y x, I n c.  
C O N FI D E N TI A L  
Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8 
 
A me n d me nt 4. 0  
                                                                   Pa ge 8 of 1 0 1                                     1 9 Fe br uar y 2 0 1 6 
 
7. 1. 2.  
Esti mate d Gl o mer ular Filtrati o n Rate  ......................................................................... 6 9 
7. 1. 3.  
Uri nar y Assess me nts  .................................................................................................. 7 0 
7. 1. 4.  
Bir mi n g h a m Vasc ulitis Acti vit y Sc ore ( B V A S) ......................................................... 7 0 
7. 1. 5.  
Vasc ulitis Da ma ge I n d e x ( V DI)  ................................................................................. 7 0 
7. 1. 6.  
A nti -Ne utr o p hil C yt o plas mic A nti b o d y ( A N C A) Assess me nts ................................. 7 0  
7. 1. 7.  
Ser u m C -Reacti ve Pr otei n ( C R P)  ............................................................................... 7 0 
7. 1. 8.  
Uri nar y M C P -1 Assess m e nts  ...................................................................................... 7 0 
7. 1. 9.  
Healt h -Relate d Q ualit y of Life Assess me nts  .............................................................. 7 1 
7. 1. 1 0.  
Hist ol o g y ..................................................................................................................... 7 1 
7. 2.  
Safet y Assess me nts  ..................................................................................................... 7 1 
7. 2. 1.  
P h ysical E x a mi nati o ns a n d Vital Si g ns  ...................................................................... 7 1 
7. 2. 2.  
Cli nical Safet y La b orat or y Assess me nts  .................................................................... 7 1 
7. 2. 3.  
Re p orti n g of A d vers e E v e nts ...................................................................................... 7 2  
7. 2. 4.  
Re p orti n g of Seri o us A d verse E ve nts ......................................................................... 7 4  
7. 3.  
P har mac o ki netic Assess me nts  .................................................................................... 7 5 
7. 4.  
P har mac o d y na mic Ass ess me nts  ................................................................................. 7 5 
7. 5.  
St u d y C o m pleti o n a n d Wit h dra wal ............................................................................ 7 5  
7. 6.  
Data M o nit ori n g C o m mittee  ....................................................................................... 7 6 
7. 7.  
Statistical Met h o ds  ...................................................................................................... 7 6 
7. 8.  
S u bject P o p ulati o ns .................................................................................................... 7 6  
7. 9.  
Safet y E n d p oi nts  ......................................................................................................... 7 6 
7. 1 0.  
Efficac y E n d p oi nts ...................................................................................................... 7 7  
7. 1 1.  
P har mac o ki netic E n d p oi nts ........................................................................................ 7 8  
7. 1 2.  
P har mac o d y na mic E n d p oi nts ..................................................................................... 7 8  
7. 1 3.  
Statistical A nal ysis Met h o d ol o g y  ............................................................................... 7 8 
7. 1 3. 1.  
Baseli ne C haracteristics  .............................................................................................. 7 9 
7. 1 3. 2.  
Safet y A nal yses  .......................................................................................................... 7 9 
7. 1 3. 3.  
Efficac y A nal yses  ....................................................................................................... 8 0 
7. 1 3. 4.  
C o variates  ................................................................................................................... 8 0 
7. 1 3. 5.  
P har mac o ki netic A n al ysis  .......................................................................................... 8 1 
7. 1 4.  
Sa m ple Size J ustificati o n  ............................................................................................ 8 1 

C he m o Ce ntr y x, I n c.  
C O N FI D E N TI A L  
Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8 
 
A me n d me nt 4. 0  
                                                                   Pa ge 9 of 1 0 1                                     1 9 Fe br uar y 2 0 1 6 
 
7. 1 5.  
I nteri m A nal ysis .......................................................................................................... 8 1 
7. 1 6.  
Pr ot oc ol De viati o ns .................................................................................................... 8 1  
8.  
S T U D Y C O M P L E TI O N A N D  T E R MI N A TI O N  ...................................................... 8 2 
8. 1.  
St u d y C o m pleti o n  ....................................................................................................... 8 2 
8. 2.  
St u d y Ter mi nati o n  ...................................................................................................... 8 2 
9.  
R E G U L A T O R Y A N D A D MI NI S T R A TI V E R E Q UI R E M E N T S  ............................ 8 2 
9. 1.  
I n v esti gat or Res p o nsi bilities ....................................................................................... 8 2 
9. 2.  
I nstit uti o nal Re vie w B oar d or Et hics C o m mittee ....................................................... 8 2 
9. 3.  
I nf or me d C o nse nt ....................................................................................................... 8 3 
9. 4.  
Pr ot oc ol M o dificati o ns ............................................................................................... 8 3  
9. 5.  
Re g ulat or y D oc u me ntati o n  ......................................................................................... 8 3 
9. 6.  
S u bject I d e ntificati o n Re gister  ................................................................................... 8 3 
9. 7.  
Rec or d Rete nti o n  ........................................................................................................ 8 4 
9. 8.  
Case Re p ort F or m C o m pleti o n  ................................................................................... 8 4 
9. 9.  
M o nit ori n g .................................................................................................................. 8 4  
9. 1 0.  
O n -site A u dits ............................................................................................................. 8 4  
9. 1 1.  
Use of I nf or mati o n a n d P u blicati o n ............................................................................ 8 4  
1 0.  
R E F E R E N C E S  ........................................................................................................... 8 6 
1 1.  
A P P E N DI C E S  ............................................................................................................ 8 7 
1 1. 1.  
State me n t of O bli gati o ns of S p o ns or, M o nit or, a n d Cli nical I n vesti gat or ................. 8 7 
1 1. 2.  
I nf or me d C o nse nt F or m .............................................................................................. 9 0 
1 1. 3.  
Bir mi n g h a m Vasc ulitis Acti vit y Sc ore ( B V A S) Versi o n 3  ........................................ 9 1 
1 1. 4.  
Vasc ulitis Da ma ge I n d e x  ............................................................................................ 9 3 
1 1. 5.  
Pre d nis o ne D ose Sc he d ul e .......................................................................................... 9 4  
1 1. 6.  
C ycl o p h os p ha mi de a n d Azat hi o pri ne D osi n g  ............................................................ 9 5 
1 1. 7.  
Rit u xi ma b D osi n g  ....................................................................................................... 9 7 
1 1. 8.  
A d verse E v e nts Re p orte d wit h C ycl o p h os p ha mi de ................................................... 9 8  
1 1. 9.  
A d verse E v e nts Re p orte d wit h C ortic oster oi d Use .................................................... 9 9  
1 1. 1 0.  
A d verse E v e nts Re p orte d wit h Rit u xi ma b Use  ........................................................ 1 0 1 
1 1. 1 1.  
A d verse E v e nts Re p orte d wit h Azat hi o pri ne Use .................................................... 1 0 1  
 

C he m o Ce ntr y x, I n c.  
C O N FI D E N TI A L  
Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8 
 
A me n d me nt 4. 0  
                                                                   Pa ge 1 0 of 1 0 1                                     1 9 Fe br u ar y 2 0 1 6 
 
LI S T O F T A B L E S  
Ta ble  1: 
O ver vie w of T o xic ol o g y St u dies Perf or me d wit h C C X 1 6 8 ....................................... 3 4  
Ta ble  2: 
O ver vie w of Safet y P har mac ol o g y St u dies Perf or me d wit h C C X 1 6 8 ....................... 3 4  
Ta ble  3: 
P har mac o ki netic Par a meters of C C X 1 6 8 i n C D- 1 Mice, S pra g ue- Da wl e y 
Rats, Bea gle D o gs, a n d C y n o m ol g us M o n k e ys after A d mi nistrati o n of a 
Si n gle Or al Ga va ge or a n I ntra ve n o us D os e of C C X 1 6 8 ........................................... 3 7  

C he m o Ce ntr y x, I n c.  
C O N FI D E N TI A L  
Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8 
 
A me n d me nt 4. 0  
                                                                   Pa ge 1 1 of 1 0 1                                     1 9 Fe br u ar y 2 0 1 6 
 
S T U D Y S Y N O P SI S  
N a me of S p o ns or 
C he m o Ce ntr y x, I n c.  
N a me of Acti ve I n gre die nt  
C C X 1 6 8  
St u d y n u m ber:  
C L 0 0 3 _ 1 6 8 
Title  
A Ra n d o mize d, D o u ble- Bli n d, Place b o- C o ntr olle d, D ose Assess me nt P has e 2 St u d y t o E val uate 
t he Safet y a n d Efficac y of C C X 1 6 8 i n S u bjects wit h A nti-Ne utr o p hil C yt o plas mic A nti b o d y 
( A N C A)-Ass ociate d V as c ulitis  
I n vesti g at ors 
Se veral  
St u d y ce nters  
M ulti -ce nter  
St u d y peri o d  
2 4 m o nt hs 
P h ase of de vel o p me nt  
P hase 2  
Ai m  
T he ai m of t his trial is t o test t he safet y a n d efficac y of t w o d os e re gi me ns of t he c o m ple me nt 
C 5a rece pt or C C X 1 6 8 i n patie nts wit h a nti - ne utr op hil c yt o plas mic a nti b o d y ( A N C A)-
ass ociate d  vas c ulitis ( A A V).  
O bjecti ves  
T he pri mar y safet y o bjecti ve of t his st u d y is t o e v al uate t he safet y a n d t olera bilit y of C C X 1 6 8 
i n s u bjects wit h A AV o n bac k gr o u n d sta n d ar d of care ( S O C) c ycl o p h os p ha mi de or rit u xi ma b  
pl us c ortic oster oi d treat m e nt. 
T he pri mar y efficac y o bj ecti ve is t o e val uate t h e efficac y of C C X 1 6 8 base d o n t he Bir mi n g ha m 
Vasc ulitis Acti vit y Sc ore ( B V A S)  i n s u bjects wit h A A V o n S O C  c ycl o p h os p ha mi de or 
rit u xi ma b pl us c ortic oster oi d treat me nt. 
T he sec o n d ar y o bjecti ves of t his st u d y i ncl u de: 
1.  E val uati o n of t he efficac y of C C X 1 6 8 c o m p are d t o S O C  base d o n c ha n ges i n re nal disease 
acti vit y para meters:  
a. e G F R ( M D R D s er u m cr eati ni ne e q uati o n); 
b.  He mat uria ( ce ntr al la b or at or y micr osc o pic c o u nt of uri nar y R B Cs); a n d  
c. A l b u mi n uria (first m or ni n g uri nar y al b u mi n:creati ni ne rati o); 
2.  Assess me nt of c ha n ges i n re nal i nfla m mat or y acti vit y base d o n uri nar y m o n oc yt e 
c he m oattracta nt pr otei n -1 ( M C P -1):creati ni ne rati o a n d ser u m C -reacti ve pr otei n 
c o nce ntr ati o n wit h C C X 1 6 8 c o m pare d t o S O C ; 

C he m o Ce ntr y x, I n c.  
C O N FI D E N TI A L  
Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8 
 
A me n d me nt 4. 0  
                                                                   Pa ge 1 2 of 1 0 1                                     1 9 Fe br u ar y 2 0 1 6 
 
3.  Assess me nt of healt h -rel ate d q ualit y-of -life c ha n ges base d o n S h ort F or m-3 6 versi o n 2 ( S F -
3 6 v 2) a n d E ur o Q O L- 5 D- 5 L ( E Q - 5 D- 5 L) wit h C C X 1 6 8 c o m pare d t o S O C ; 
4.  Assess me nt of c ha n ges i n Vasc ulitis Da ma ge I n d e x ( V DI) wit h C C X 1 6 8 c o m pare d t o S O C ; 
5.  Assess me nt  of c ha n ges i n A N C A (a nti- P R 3 a n d a nti- M P O) wit h C C X 1 6 8 c o m pare d t o 
S O C ; 
6.  Assess me nt of c ha n ges i n p har mac o d y n a mic mar kers i n plas ma a n d uri n e wit h C C X 1 6 8 
c o m pare d t o S O C ; 
7.  E val uati o n of t he p har m ac o ki netic pr ofile of C C X 1 6 8 i n s u bjects wit h A A V. 
Met h o d ol o g y 
A A V sta n dar d t h era p y i n cl u des c ycl o p h os p ha mi d e or rit u xi ma b  a n d oral c ortic oster oi ds, 
ta pere d o v er a p eri o d of ti me. Se vere disease warra nts a d diti o n of I V c ortic oster oi ds a n d/ or 
plas ma e x c ha n ge. Base d o n c o m pelli n g res ults fr o m precli nical st u dies i n a m o use m o del of 
A N C A -i n d uce d gl o mer ul o ne p hritis, as well as earl y res ults fr o m a n ot her cli nical trial i n 
patie nts wit h A A V ( C L 0 0 2 _ 1 6 8), C C X 1 6 8 has p ote ntial i n t he treat me nt of patie nts wit h A A V. 
A C C X 1 6 8 d ose re gi me n of 3 0 m g t wice dail y has bee n teste d i n st u d y C L 0 0 2 _ 1 6 8. N o ot her 
d ose has bee n t este d pre vi o usl y i n A A V. H e nce, t h e cli nical h y p ot hesis of t he trial is t o test 
w het her a l o w er d os e of C C X 1 6 8, i.e., 1 0 m g t wice dail y i n a d diti o n t o t he 3 0 m g t wice d ail y 
re gi me n is safe a n d efficaci o us i n patie nts wit h A A V recei vi n g S O C c ycl o p h os p ha mi de or 
rit u xi ma b pl us c ortic oster oi ds. T his h y p ot hesis will be teste d i n t his ra n d o mize d, d o u ble- bli n d, 
place b o - c o ntr olle d, P has e 2 cli nical trial i n u p t o a p pr o xi matel y 4 5 s u bjects wit h ne w or 
rela pse d A A V. A n e xter n al data m o nit ori n g c o m mittee ( D M C) will re vie w safet y data, 
i ncl u di n g res c ue c ortic oster oi d use o ver t he c o urs e of t he st u d y a n d a d vise t he S p o ns or 
re gar di n g t he st u d y.  
U p t o a p pr o xi matel y 4 5 s u bjects will be stratifie d pri or t o ra n d o mizati o n base d o n t he f oll o wi n g 
stratificati o n fact ors: 
1.  Eit her ne wl y dia g n ose d A A V or rela pse d A A V;  
2.  Eit her M P O or P R 3 A N C A p ositi vit y; 
3.  Will recei ve eit her c ycl o p h os p ha mi de or rit u xi ma b as part of S O C  treat me nt. 
F o ll o wi n g str atificati o n, s u bjects will be ra n d o mize d 1: 1: 1 t o o ne of t hree gr o u ps: 
Gr o u p A: C C X 1 6 8 1 0 m g t wice dail y pl us c ycl o p h os p ha mi de/rit u xi ma b pl us c ortic oster oi ds;  
Gr o u p B: C C X 1 6 8 3 0 m g t wice dail y pl us c ycl o p h os p ha mi de/rit u xi ma b pl us c ortic oster oi ds; 
Gr o u p C : Place b o t wice dail y pl us c ycl o p h os p h a mi de/rit u xi ma b pl us c ortic oster oi ds.  
If necessar y, resc u e c orti c oster oi ds s h o ul d be gi ve n t o s u bjects wit h w orse ni n g diseas e. 
St u d y dr u g a n d ot her me dicati o n f or vasc ulitis will be ta ke n as f oll o ws b y st u d y s u bjects:  
•  Gr o u p A ( 1 0 m g C C X 1 6 8 t wice dail y):  
− O ne 1 0 -m g C C X 1 6 8 ca ps ule  i n t he m or ni n g a n d 1  i n t he e ve ni n g, a p pr o xi matel y 1 2 

C he m o Ce ntr y x, I n c.  
C O N FI D E N TI A L  
Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8 
 
A me n d me nt 4. 0  
                                                                   Pa ge 1 3 of 1 0 1                                     1 9 Fe br u ar y 2 0 1 6 
 
h o urs after t h e m or ni n g d ose, dail y f or 8 4 da ys.  
− T w o matc hi n g pl ace b o ca ps ules i n t he m or ni n g a n d 2 i n t he e ve ni n g, a p pr o xi matel y 
1 2 h o urs after t h e m or ni n g d ose, d ail y f or 8 4 da ys. 
− Pre d nis o ne ta blets e q ui vale nt t o 6 0 m g orall y per d a y, starti n g o n Da y 1 wit h 
ta peri n g acc or di n g t o t he pr ot oc ol-s pecifi e d sc he d ule. 
− If i n t he c ycl o p h os p ha mi de strat u m, c ycl o p h os p ha mi de I V will be gi v e n o n Da y 1 
a n d als o o n Da ys 1 5, 2 9, 5 7, a n d 8 5 ; starti n g o n D a y 9 9 t hr o u g h Da y 1 6 8, all 
s u bjects will recei ve oral azat hi o pri ne at a tar get d ose of 2 m g/ k g/ da y. 
− If i n t he rit u xi ma b strat u m, rit u xi ma b I V will be gi ve n o n Da ys 1, 8, 1 5, a n d 2 2 ( 3 7 5 
m g / m2 at eac h ti me p oi nt) ; n o oral azat hi o pri ne will be gi ve n t o s u bjects recei vi n g 
rit u xi ma b.  
− Resc ue c ortic o st er oi ds s h o ul d be gi ve n t o s u bjects wit h w orse ni n g dis ease. 
•  Gr o u p B ( 3 0 m g C C X 1 6 8 t wice dail y): 
− T hree 1 0- m g C C X 1 6 8 ca ps ules i n t he m or ni n g a n d 3 i n t he e ve ni n g, a p pr o xi matel y 
1 2 h o urs after t h e m or ni n g d ose, d ail y f or 8 4 da ys. 
− Pre d nis o ne ta blets e q ui vale nt t o 6 0 m g orall y per d a y, starti n g o n Da y 1 wit h 
ta peri n g acc or di n g t o t he pr ot oc ol-s pecifi e d sc he d ule. 
− If i n t he c ycl o p h os p ha mi de strat u m, c ycl o p h os p ha mi de I V will be gi v e n o n Da y 1 
a n d als o o n Da ys 1 5, 2 9, 5 7, a n d 8 5 ; starti n g o n D a y 9 9 t hr o u g h Da y 1 6 8, all 
s u bjects will recei ve oral azat hi o pri ne at a tar get d ose of 2 m g/ k g/ da y. 
− If i n t he rit u xi ma b strat u m, rit u xi ma b I V will be gi ve n o n Da ys 1, 8, 1 5, a n d 2 2 ( 3 7 5 
m g / m2 at eac h ti me p oi nt) ; n o oral azat hi o pri ne will be gi ve n t o s u bjects recei vi n g 
rit u xi ma b. 
− Resc ue c ortic o st er oi ds s h o ul d be gi ve n t o s u bjects wit h w orse ni n g dis ease.  
•  Gr o u p C ( Place b o  t wice dail y):  
− T hree mat c hi n g pl a ce b o ca ps ules i n t he m or ni n g a n d 3 ca ps ules i n t he e v e ni n g, 
a p pr o xi matel y 1 2 h o urs after t he m or ni n g d ose, d ail y f or 8 4 d a ys.  
− Pre d nis o ne ta blets e q ui vale nt t o 6 0 m g orall y per d a y, starti n g o n Da y 1 wit h 
ta peri n g acc or di n g t o t he pr ot oc ol-s pecifi e d sc he d ule. 
− If i n t he c ycl o p h os p ha mi de strat u m, c ycl o p h os p ha mi de I V will be gi v e n o n Da y 1, 
a n d als o o n Da ys 1 5, 2 9, 5 7, a n d 8 5 ; starti n g o n D a y 9 9 t hr o u g h Da y 1 6 8, all 
s u bjects will recei ve oral azat hi o pri ne at a tar get d ose of 2 m g/ k g/ da y. 
− If i n t he rit u xima b strat u m, rit u xi ma b I V will be gi ve n o n Da ys 1, 8, 1 5, a n d 2 2 ( 3 7 5 
m g / m2 at eac h ti me p oi nt) ; n o oral azat hi o pri ne will be gi ve n t o s u bjects recei vi n g 
rit u xi ma b.  

C he m o Ce ntr y x, I n c.  
C O N FI D E N TI A L  
Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8 
 
A me n d me nt 4. 0  
                                                                   Pa ge 1 4 of 1 0 1                                     1 9 Fe br u ar y 2 0 1 6 
 
− Resc ue c ortic ost er oi ds s h o ul d be gi ve n t o s u bjects wit h w orse ni n g dis ease.  
F oll o wi n g t he 8 4- da y d osi n g peri o d, t here will be a n 8 4- da y f oll o w- u p peri o d. All s u bjects will 
visit t he st u d y ce nter d uri n g t he scree ni n g p eri o d, a n d o n Da ys 1, 2, 8, 1 5, 2 2, 2 9, 4 3, 5 7, 7 1, 8 5, 
9 9, 1 1 3, 1 4 1, a n d 1 6 9. S u bjects will n ot ta ke st u d y me dicati o n i n t he m or ni n g of t he d a ys of 
visits t o t he st u d y ce nter, a n d will be i nstr ucte d t o ta ke t he me dicati o n w hile at t he st u d y ce nter. 
F or t he ot her st u d y d a ys, st u d y me dicati o n will be ta ke n at h o me i n t he m or ni n g wit hi n 1 h o ur 
after br ea kfast a n d i n t he e ve ni n g wit hi n 1  h our aft er di n ner.  
T he scree ni n g peri o d will be ke pt as s h ort as p ossi ble i n or der n ot t o dela y i nitiati o n of 
treat me nt. T he scree ni n g peri o d m ust n ot e x cee d 1 4 da ys. Scree ni n g pr oce d ures will i ncl u de 
de m o gr a p hics, me dical hist or y, me dicati o n hist or y, p h ysical e x a mi nati o n a n d vital si g ns, ser u m 
pre g na nc y t est f or w o me n of c hil d beari n g p ote nti al, ser u m c he mistr y, he m at ol o g y, uri nal ysis 
(i ncl u di n g he m at uria, pr otei n uria [A C R ]), E C G, c hest X ra ys, viral s cree ni n g, ser ol o g y a n d 
c o m ple me n t meas ur e me nts (if n ot d o ne wit hi n t he pre vi o us 1 2 m o nt hs), esti mate d gl o mer ular 
filtrati o n rate (e G F R) ass ess me nt, A N C A meas ure me nt (i n direct i m m u n ofl u oresce n ce test f or 
P- A N C A a n d C -A N C A, as well as E LI S A tests f or a nti - P R 3 a n d a nti- M P O), re nal bi o ps y (if 
perf or me d ), a n d B V A S assess me nt. T o e x pe dite t he scree ni n g pr ocess, bl o o d a n d uri ne tests 
will be d o ne at t he l ocal l a b orat ories f or t he Scree ni n g visit. La b orat or y res ults fr o m t he l ocal 
la b orat ories o btai ne d wit hi n 7 2 h o urs of scree ni n g are acce pta ble i n or der t o a v oi d u n necess ar y 
bl o o d dra ws.  Eli gi ble s u bjects m ust be A N C A - p ositi ve a n d m ust ha ve at least o ne “ maj or” ite m, 
or at least 3 n o n- maj or it e ms , or at least 2 re nal ite ms o n t he B V A S  versi o n 3.  
Eli gi ble s u bjects will visit t he st u d y ce nt er o n D a y 1, after a n o ver ni g ht fast of at least 8 h o urs, 
f or p h ysical e x a mi nati o n a n d vital si g ns, ser u m c h e mistr y, he m at ol o g y, uri nal ysis (i ncl u di n g 
he mat uria, pr otei n uri a [ A C R ], a n d M C P-1:creati ni ne rati o asse ss me nt), e G F R, A N C A 
meas ure me nt ( a nti - P R 3 a n d a nti-M P O), a B V A S a n d V DI assess me nt , S F- 3 6 v 2 a n d E Q- 5 D-5 L 
assess me nt,  hs C R P, baseli ne p har mac o ki netics a n d p har mac o d y n a mics ( P K/ P D) bl o o d sa m ple 
c ollecti o n, a n d ra n d o mizati o n. Me dicati o n will be a d mi nistere d (I V) a n d dis pe nse d (f or oral 
me dicati o ns). T he s u bjects will ta ke t he first d ose of C C X 1 6 8 or place b o, a n d pre d nis o ne w hile 
at t he st u d y ce nter. T h e s u bjects will sta y at t he cli nic f or at least 6 h o urs aft er t he first d ose o n 
Da y 1 f or s afet y o bser vati o n a n d P K sa m ple c ollecti o n. A s u bject c o ul d be ke pt o ver ni g ht i n t he 
h os pital o n Da y 1, if n ecessar y. T his h os pital sta y w o ul d n ot be c o nsi dere d a seri o us a d v erse 
e ve nt, u nless ot her S A E criteria are met.  
T wice dail y d osi n g of C C X 1 6 8 or place b o will c o nti n ue f or 8 4 da ys. At p ost- Da y 1 st u d y visits, 
st u d y me dicati o n will be a d mi nistere d acc or di n g t o t he pr ot oc ol sc he d ule, bl o o d a n d uri ne 
sa m ples will be c ollecte d f or saf et y a n d efficac y a n d P K/ P D meas ure me nts. Ser u m pre g na n c y 
test f or w o me n of c hil d beari n g p ote ntial will be d o ne o n Da ys 2 9, 5 7, 8 5, 1 1 3, a n d 1 6 9. B V A S 
assess me nts will be ma de o n Da ys 1,  2 9, 8 5, 1 1 3, a n d 1 6 9. V DI assess me n t will be ma de o n 
Da ys 1, 8 5, a n d 1 6 9. S F - 3 6 v 2 a n d E Q- 5 D-5 L i nstr u me nts will be c o m plete d o n D a ys 1, 2 9, 8 5, 
a n d 1 6 9. P h ysical e x a mi nati o ns, b o d y s yste m re vi e ws, a n d vital si g n assess me nts will be 
perf or me d t hr o u g h o ut t he st u d y. C o nc o mita nt me dicati o n a n d a d verse e v e nt assess me nts will be 
ma de at e v er y st u d y visit.  
S u bjects will be disc har ge d fr o m t he st u d y w he n all t he St u d y D a y 1 6 9 visit pr oce d ures ha ve 
bee n c o m plete d. T h e s u bject’s c o n diti o n will be e val uate d b y t he I n v esti gat or at t he e n d of t he 

C he m o Ce ntr y x, I n c.  
C O N FI D E N TI A L  
Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8 
 
A me n d me nt 4. 0  
                                                                   Pa ge 1 5 of 1 0 1                                     1 9 Fe br u ar y 2 0 1 6 
 
cli nical trial ( Da y 1 6 9) a n d a p pr o priate S O C  me dical treat me nt will be p r o vi de d t o all s u bjects 
as nee de d.  
T o t he e xte nt p os si ble, a n y a d v erse e ve nts t hat are dee me d st u d y dr u g-rel ate d a n d are o n g oi n g 
at disc har ge will be f oll o we d -u p t o res ol uti o n or u ntil a deter mi nati o n is ma de t hat t he 
u nres ol ve d e v e nt is sta ble.  
N u m ber of S u bjects  
U p t o a p pr o xi matel y 4 5 male or fe m ale s u bjects wit h A A V will be ra n d o mize d f or t his st u d y. 
S u bjects w h o dr o p o ut of t he st u d y pre mat urel y will n ot be re place d. T hese s u bjects will be part 
of t he i nte nt-t o-treat p o p ulati o n. 
M ai n Criteri a f or I ncl usi o n  
1.  
Cli nical dia g n osis of gra n ul o mat osis wit h p ol ya n giitis  ( We ge ner’s), micr osc o pic 
p ol ya n giitis or re n al li mite d vasc ulitis, c o nsiste nt wit h C ha pel  Hill c o nse ns us defi niti o ns 
(J e n nette et al., 2 0 1 3); 
2.  
Male a n d f e male s u bjects, a ge d at l east 1 8 years, wit h ne w ( t y picall y wit hi n 4 wee ks pri or 
t o scree ni n g) or rela ps e d A A V w here treat me nt wit h c ycl o p h os p h a mi de or rit u xi ma b 
w o ul d be re q uir e d; Fe m ale s u bjects of c hil d beari n g p ote ntial ma y p artici pate if a de q uat e 
c o ntrace pti o n is use d d uri n g t he st u d y, a n d f or at l east 6 m o nt hs after t he l ast 
c ycl o p h os p ha mi de d ose (if recei vi n g c ycl o p h os p h a mi de) a n d at least 1 2 m o nt hs after t he 
last rit u xi ma b d ose (if recei vi n g rit u xi ma b); Male s u bjects wit h part ners of c hil d beari n g 
p ote ntial ma y p artici pate i n t he st u d y if t he y ha d a vasect o m y at least 6 m o nt hs pri or t o 
ra n d o mizati o n or if a de q uate c o ntrace pti o n is use d d uri n g t he st u d y, a n d f or at least 6 
m o nt hs after t he last c ycl o p h os p ha mi de d ose (if recei vi n g c ycl o p h os p ha mi de) a n d at least 
1 2 m o nt hs after t he last rit u xi ma b d ose (if recei vi n g rit u xi ma b) ; A de q uate c o ntrace pti o n is 
defi ne d as o n e hi g hl y eff ecti ve met h o d pl us o ne effecti ve m et h o d; hi g hl y effecti ve 
met h o ds i ncl u de h or m o nal c o ntrace pti ves, e. g., c o m bi ne d oral c o ntrace pti v es, patc h, 
va gi n al ri n g, i njecta bles, a n d i m pla nts; i ntra uteri ne de vice or i ntra uteri n e s yste m; 
vasect o m y a n d t u bal li gati o n; effecti ve met h o ds i ncl u de barrier met h o ds of c o ntrace pti o n, 
e. g., m ale c o n d o m, f e mal e c o n d o m, cer vical ca p, dia p hra g m, c o ntrace pti ve s p o n ge pl us a 
s per mici de; 
3.  
P ositi ve i n direct i m m u n ofl u oresce n ce (II F) test f or P -A N C A or C - A N C A, or p ositi ve 
E LI S A test f or a nti - pr ot ei nase- 3 ( P R 3) or a nti-m yel o per o xi dase ( M P O) at scree ni n g; If 
o nl y t he II F assa y is p ositi ve at scree ni n g, a n d n o ne of t he E LI S A tests, t h ere m ust be 
d oc u me ntati o n i n t he st u d y r ec or ds of a p ositi ve E LI S A assa y i n t he past;  
4.  
Ha ve at least o ne “ maj or ” ite m , or at least 3 n o n- maj or ite ms , or at least 2 re nal ite ms o n 
t he B V A S versi o n 3; 
5.  
Esti mate d gl o mer ular filtrati o n rate ≥ 2 0 m L per mi n ute per 1. 7 3 m 2 ( M D R D); 
6.  
Willi n g a n d a ble t o gi ve writte n I nf or me d C o nse nt a n d t o c o m pl y wit h t he re q uire me nts of 
t he st u d y pr ot oc ol; a n d 
7.  
J u d ge d t o be ot her wise h ealt h y b y t h e I n vesti gat or, base d o n me dical hist or y, p h ysical 

C he m o Ce ntr y x, I n c.  
C O N FI D E N TI A L  
Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8 
 
A me n d me nt 4. 0  
                                                                   Pa ge 1 6 of 1 0 1                                     1 9 Fe br u ar y 2 0 1 6 
 
e x a mi nati o n (i ncl u di n g electr ocar di o gra m [ E C G]), a n d cli nical la b ora t or y assess me nts. 
S u bjects wit h cli nical la b orat or y val ues t hat are o utsi de of n or mal li mits ( ot her t ha n t h ose 
s pecifie d i n t he E x cl usi o n Criteria) a n d/ or wit h ot her a b n or m al cli nical fi n di n gs t hat are 
j u d ge d b y t he I n vesti gat or n ot t o be of cli nical si g nifica nce, m a y be e nt ere d i nt o t he st u d y.     
M ai n Criteri a f or E xcl usi o n  
1.  
Se vere disease as d eter mi ne d b y ra pi dl y pr o gressi ve gl o mer ul o ne p hritis s uc h t hat 
c o m me nce me nt of re n al re place me nt t hera p y c o ul d be a ntici pate d wit hi n 7 da ys, or 
al ve olar he m orr ha ge lea di n g t o Gra de 3 or hi g her h y p o xia (i.e., decrease d o x y ge n 
sat urati o n at rest, e. g., p ulse o xi meter < 8 8 % or Pa O 2 ≤5 5 m m H g); 
2.  
W o me n w h o are pr e g na nt ( p ositi ve pre g n a nc y test) or breastfee di n g at st u d y e ntr y; 
w o me n s h o ul d n ot breastfee d d uri n g t he st u d y, a n d if recei vi n g rit u xi ma b, u ntil dr u g 
le vels are n o l o n ger detecta ble after st u d y c o m pleti o n;  
3.  
A n y ot her m ulti -s yste m a ut oi m m u ne disease i ncl u di n g e osi n o p hilic gra n ul o mat osis wit h 
p ol ya n giitis ( C h ur g Stra uss), s yste mic l u p us er yt h e mat os us, I g A vasc ulitis  (He n oc h -
Sc h ö nlei n p ur p ura), r he u mat oi d vasc ulitis, Sj ö gre n’s disease, a nti- gl o mer ular base me nt 
me m bra ne disease, or cr y o gl o b uli ne mia; 
4.  
Me dical hist or y of c o a g ul o pat h y or blee di n g dis or der; 
5.  
Recei ve d c ycl o p h os p ha mi de wit hi n 1 2 wee ks pri or t o scree ni n g; if o n azat hi o pri ne, 
m yc o p h e n olate m ofetil, or met h otre x ate at t he ti me of scree ni n g, t hese dr u gs m ust be 
wit h dra w n pri or t o r ecei vi n g t he c ycl o p h os p ha mi de  or rit u xi ma b  d ose o n Da y 1;  
6.  
Recei ve d i ntra v e n o us c ortic oster oi ds, > 3 0 0 0 m g m et h yl pre d nis ol o ne e q ui vale nt, wit hi n 1 2 
wee ks pri or t o scree ni n g; 
7.  
Ha ve bee n ta ki n g a n or al dail y d ose of a c ortic oster oi d of m ore t ha n 1 0 m g pre d nis o ne-
e q ui vale nt f or m or e t ha n 6 wee ks c o nti n u o usl y pri or t o t he scree ni n g visit. If o n 
c ortic oster oi d s at t he ti me of scree ni n g, t he n o n-st u d y s u p plie d c ortic oster oi ds will be 
st o p pe d w he n t he s u bject starts ta ki n g t he st u d y s u p plie d 6 0 m g pre d nis o n e d ose o n Da y 
1; 
8.  
Recei ve d rit u xi ma b or ot her B-cell a nti b o d y wit hi n 5 2 wee ks of s cree ni n g or 2 6 wee ks 
pr o vi de d B cell rec o nstit uti o n has occ urre d (i.e., C D 1 9 c o u nt > 0. 0 1 x 1 0 9/ L); recei ve d a nti-
T N F treat me nt, a bat ace pt, ale mt uz u ma b, I VI g, beli m u ma b, t ociliz u ma b,  or plas ma 
e x c ha n ge wit hi n 1 2 wee ks pri or t o scree ni n g; 
9.  
S y m pt o matic c o n gesti ve heart fail ure re q uiri n g prescri pti o n me dicati o n, cli nica ll y e vi de nt 
peri p her al e de ma  of car diac ori gi n, p o orl y-c o ntr olle d h y p erte nsi o n (s yst olic bl o o d 
press ure > 1 6 0 or diast olic bl o o d press ure > 1 0 0), hist or y of u nsta ble a n gi na, m y ocar dial 
i nfarcti o n or str o ke wit hi n 6 m o nt hs pri or t o scree ni n g; 
1 0.  Hist or y or prese n ce of a n y f or m of ca n cer wit hi n t he 5 years pri or t o scree ni n g, wit h t he 
e x ce pti o n of e x cise d basal cell or s q ua m o us cell carci n o ma of t h e s ki n, or cer vical 
carci n o ma i n sit u or br east carci n o ma i n sit u t hat has bee n e x cise d or resecte d c o m pletel y 
a n d is wit h o ut e vi de nce of l ocal rec urre nce or met astasis;  

C he m o Ce ntr y x, I n c.  
C O N FI D E N TI A L  
Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8 
 
A me n d me nt 4. 0  
                                                                   Pa ge 1 7 of 1 0 1                                     1 9 Fe br u ar y 2 0 1 6 
 
1 1.  E vi de nce of t u b erc ul osis base d o n c hest X ra ys perf or me d d uri n g s cree ni n g as part of t he 
B V A S assess me nt;  
1 2.  P ositi ve H B V, H C V, or HI V viral scree ni n g test;  
1 3.  A n y i nf ecti o n re q uiri n g a nti bi otic treat me nt wit h i n 4 wee ks pri or t o scree ni n g (e x ce pt f or 
pr o p h ylactic treat me nt f or P ne u m ocystis c ari nii  p ne u m o nia [ P C P] or treat me nt f or 
s us pecte d i nfecti o n t hat i nstea d t ur ns o ut t o be a c o nse q ue nce of A N C A v asc ulitis, e. g., 
p ne u m o nitis); 
1 4.  Recei ve d a li ve v acci ne wit hi n  4 wee ks pri or t o s cree ni n g; 
1 5.  W B C c o u nt less t ha n 4 0 0 0/ µ L , or ne utr o p hil c o u nt less t ha n 2 0 0 0/µ L, or l y m p h oc yte 
c o u nt less t ha n 1 0 0 0/ µ L; 
1 6.  He m o gl o bi n less t ha n 9 g/ d L ( or 5. 5 6 m m ol/ L) at s cree ni n g;  
1 7.  E vi de nce of h e patic disease; A S T, A L T, al kali ne p h os p hatase, or bilir u bi n > 3 x t he u p per 
li mit of n or mal; 
1 8.  Pr ot hr o m bi n ti me ( P T) or partial t hr o m b o plasti n ti me ( P T T) a b o ve t he n or mal refere nce 
li mit; 
1 9.  Cli nicall y si g nifica nt a b n or mal E C G d uri n g s cree ni n g, e. g., Q Tc F greater t ha n 4 5 0 msec; 
2 0.  Partici pate d i n a n y cli nical st u d y of a n i n vesti gati o nal pr o d uct wit hi n 3 0 da ys pri or t o 
scree ni n g or wit hi n 5 half-li ves after ta ki n g t he last d ose;  
2 1.  K n o w n h y p erse nsiti vit y t o C C X 1 6 8 or i nacti ve i n gre die nts of t he C C X 1 6 8 ca ps ules 
(i ncl u di n g gel ati n, p ol yet h yle n e gl yc ol, or Cre m o p h or), c ycl o p h os p h a mi de or its 
meta b olites (f or s u bjects sc he d ule d t o recei ve c ycl o p h os p ha mi de), or k n o w n T y pe I 
h y perse nsiti vit y or a na p h yl actic reacti o ns t o m uri ne pr otei ns, C hi nese Ha mster O var y cell 
pr otei ns, or t o a n y c o m p o ne nt of rit u xi ma b (f or s u bjects sc he d ule d t o recei ve rit u xi ma b);  
2 2.  Uri nar y o utfl o w o bstr u cti o n, acti ve i nfecti o n (es peciall y v aricell a z oster  i nfecti o n), or 
platelet c o u nt < 5 0, 0 0 0/ μ L (f or s u bjects s c he d ule d t o recei ve c ycl o p h os p ha mi de 
treat me nt), a n d  
2 3.  Hist or y or prese n ce of a n y me dical c o n diti o n or disease w hic h, i n t he o pi ni o n of t he 
I n v esti gat or, ma y place t he s u bject at u nacce pt a ble ris k f or st u d y partici p ati o n. 
Test Pr o d uct  a n d Ref ere nce Pr o d uct  
C C X 1 6 8 will be a d mi nistere d via har d gelati n ca ps ules c o ntai ni n g 1 0 m g C C X 1 6 8. T he 
C C X 1 6 8 ca ps ules will be s u p plie d t o t he st u d y ce nters i n plastic b ottles c o ntai ni n g 3 0 ca ps ules.  
S u bjects i n Gr o u p A ( 1 0 m g C C X 1 6 8) will recei v e o ne kit c o ntai ni n g 1 b ottle of C C X 1 6 8 
ca ps ules a n d 2 b ottles of matc hi n g place b o ca ps ul es o n Da ys 1, 1 5, 2 9, 4 3, 5 7, a n d 7 1. S u bjects 
i n Gr o u p B ( 3 0 m g C C X 1 6 8) will recei v e o ne kit c o ntai ni n g 3 b ottles of C C X 1 6 8 ca ps ules o n 
Da ys 1, 1 5, 2 9, 4 3, 5 7, a n d 7 1. S u bjects i n Gr o u p C ( place b o) will recei v e o ne kit c o ntai ni n g 3 
b ottles  of matc hi n g place b o ca ps ules o n Da ys 1, 1 5, 2 9, 4 3, 5 7, a n d 7 1. 
S u bjects will be as ke d t o ta ke 1 ca ps ule fr o m eac h b ottle e ver y m or ni n g a n d 1 ca ps ule fr o m 
eac h b ottle e v er y e v e ni n g, a p pr o xi matel y 1 2 h o urs after t he m or ni n g d ose, as i nstr ucte d. St u d y 

C he m o Ce ntr y x, I n c.  
C O N FI D E N TI A L  
Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8 
 
A me n d me nt 4. 0  
                                                                   Pa ge 1 8 of 1 0 1                                     1 9 Fe br u ar y 2 0 1 6 
 
me dicati o n will be ta ke n wit hi n 1 h o ur after brea kfast i n t he m or ni n g a n d wit hi n 1 h o ur after 
di n ner i n t he e ve ni n g f or 8 4 da ys c o nti n u o usl y. Ca ps ules will be ta ke n wit h water, prefera bl y 
wit h 5 0 m L, b ut n ot t o e xcee d 1 0 0 m L. Place b o a n d C C X 1 6 8 b ottles a n d ca ps ules will be 
i de ntical i n a p peara nce.  
Pre d nis o ne will be gi v e n acc or di n g t o a st a n dar d t a peri n g sc h e d ule. Pre d nis o ne 2 0 m g a n d 5 m g 
ta blets fr o m a c o m mercial s o urce will be use d a n d pr o vi de d t o t he st u d y ce nters wit h d osi n g 
i nstructi o ns.     
D ur ati o n of Tre at me nt a n d O bser v ati o n   
S u bjects will be scree n e d wit hi n a peri o d n ot t o e xcee d 1 4 d a ys pri or t o St u d y D a y 1 (t he first 
da y of d osi n g). T he tr eat me nt peri o d is 8 4 da ys a n d all s u bjects will be f oll o we d f or 8 4 da ys 
after t he d os i n g peri o d.  
T o t he e xte nt p ossi ble, a n y a d v erse e ve nts t hat are dee me d st u d y dr u g -rel ate d a n d are o n g oi n g 
at disc har ge will be f oll o we d - u p t o res ol uti o n or u ntil a deter mi nati o n is ma de t hat t he 
u nres ol ve d e v e nt is sta ble. T he s u bject’s c o n diti o n will be e val uate d b y t h e I n vesti gat or at t he 
e n d of t he cli nical trial a n d a p pr o priate S O C  me dical treat me nt will be pr o vi de d t o all s u bjects 
as nee de d.  
S af et y Assess me nts  
Safet y assess me nts i ncl u de a d vers e e v e nts, p h ysical e x a mi nati o n a b n or malities, vital si g ns,  a n d 
cli nical la b orat or y tests (i ncl u di n g bl o o d c h e mistr y, he mat ol o g y, a n d uri nal ysis), a n d E C Gs.  
Effic ac y Assess me nts  
E fficac y assess me nts i ncl u de: 
1.  B V A S versi o n 3; 
2.  e G F R b y M o dificati o n of Diet i n Re nal Disease ( M D R D) f or m ula;  
3.  He mat uria a n d pr otei n uri a ( A C R); 
4.  C ortic oster oi d resc u e use ( d ose a n d d urati o n of d osi n g); 
5.  V DI;  
6.  A N C A (a nti - P R 3 a n d a nti-M P O b y E LI S A);  
7.  Ser u m C -reacti ve pr otei n c o nce ntrati o n meas ure d b y hi g h se nsiti vit y C R P assa y;  
8.  Uri nar y M C P -1:creati ni ne rati o , a n d 
9.  S F - 3 6 v 2 a n d E Q- 5 D-5 L meas ure me nt s. 
P h ar m a c o ki netic Assess me nts  
C o nce ntrati o ns of C C X 1 6 8 a n d p ossi ble meta b olites will be deter mi ne d i n plas ma fr o m bl o o d 
sa m ples c ollecte d i n E D T A t u bes o n Da ys 1, 8, 1 5, 2 2, 2 9, 4 3, 5 7, 7 1, a n d 8 5. O n Da y 1, 
sa m ples will be ta ke n at pre- d ose, 0. 5, 1, 2, 3, 4, a n d 6 h o urs after d osi n g.  
Uri ne will be c ollect e d o n Da y 1 starti n g after a c o m plete v oi d pri or t o d osi n g, a n d c ollecti o n of 

C he m o Ce ntr y x, I n c.  
C O N FI D E N TI A L  
Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8 
 
A me n d me nt 4. 0  
                                                                   Pa ge 1 9 of 1 0 1                                     1 9 Fe br u ar y 2 0 1 6 
 
all uri ne u p t o t he 6 -h o ur ti me p oi nt f oll o wi n g d osi n g. C o nce ntrati o ns of C C X 1 6 8 a n d p ossi ble 
meta b olites will be meas ure d i n a r e pres e ntati ve s a m ple fr o m t his 6 - h o ur c ollecti o n. 
P h ar m a c o d y n a mi c Ass ess me nts  
A plas ma sa m ple will be c ollecte d o n D a ys 1, 2 9, 8 5, a n d 1 6 9 f or p har mac o d y na mic m ar ker 
meas ure me nts, i ncl u di n g f or e x a m ple c ystati n C, c o m ple me nt fra g m e nts, a n d i nfla m mat or y 
c yt o ki ne a n d c h e m o ki ne le vels. T he P K plas ma sa m ples ma y als o b e use d f or t hese 
p har mac o d y n a mics mar k er meas ur e me nts.  
Uri ne sa m ples will als o b e c ollecte d o n Da ys 1, 8, 1 5, 2 9, 5 7, 8 5, 1 1 3, a n d 1 6 9 f or bi o mar ker 
assess me nts i ncl u di n g f or e x a m ple c o m ple me nt fra g m e nts, i nfla m mat or y c he m o ki ne a n d 
c yt o ki ne l e vels.  
A sali va sa m ple will be c ollecte d o n Da y 1 fr o m s u bjects w h o ha ve pr o vi de d i nf or me d c o ns e nt 
f or assess me nt of ge netic mar kers of A N C A disease as well as t he c o m ple me nt pat h wa y . 
St atistic al Met h o ds    
De m o gr a p hics a n d B aseli ne C h ar acteristics  
All s u bject baseli ne c h ar acteristics a n d d e m o gra p hic data (a ge, se x, race, et h nicit y, wei g ht, 
hei g ht, b o d y mass i n de x, s m o ki n g stat us, E C G, T B scree n res ults, viral test res ults, A N C A, 
ser ol o g y t est res ults, vasc ulitis disease d urati o n (fr o m ti me of first i n d ucti o n treat me nt), B V A S, 
V DI, S F - 3 6 v 2 s c ore, E Q- 5 D-5 L sc ore,  hs C R P, e G F R, he mat uria, pr otei n uria ( A C R), 
gl o mer ular  hist o pat h ol o g y (if bi o ps y w as ta ke n), uri nar y M C P-1:creati ni ne rati o, p h ysical 
e x a mi nati o n a b n or malities, me dical hist or y, pre vi o us ( wit hi n 6 m o nt hs of scree ni n g) a n d 
c o nc o mita nt me dicati o ns (i ncl u di n g vas c ulitis me dicati o n use) at st u d y e ntr y will be lis te d b y 
treat me nt gr o u p, st u d y ce nter, a n d s u bject n u m ber, a n d will als o be s u m marize d b y treat me nt 
gr o u p.  
S afety A n alysis  
T he pri mar y safet y e n d p oi nt is t he s u bject i nci de nce of a d v erse e ve nts.  
Ot her saf et y e n d p oi nts i ncl u de: 
1.  S u bject i nci de nce of e ve nts p ossi bl y ass ociate d wit h gl uc oc ortic oi d us e: seri o us i nfecti o ns, 
ne w -o nset dia b etes mellit us/ h y per gl yce mia, b o ne fract ure, pe ptic ulcer disease, cat aracts, 
ne w o nset/ w orse ni n g h y p erte nsi o n, wei g ht gai n m ore t ha n 1 0 k g, a n d ps yc hiatric dis or ders; 
2.  S u bject i n ci de nce of i nfecti o ns, seri o us i nfecti o ns, se vere i nfecti o ns (i.e., Gra de 3), a n d 
i nfecti o ns lea di n g t o s u bject wit h dra w al fr o m t he st u d y; 
3.  C ha n ge fr o m bas eli ne i n all safet y la b orat or y para meters;  
4.  C ha n ge fr o m bas eli ne i n vital si g ns; 
5.  I n ci de nce of cli nicall y si g nifica nt E C G c ha n ges fr o m baseli ne. 
All s u bjects w h o are ra n d o mize d a n d recei ve d at least o ne d ose of st u d y me dicati o n will be 
i ncl u de d i n t he safet y p o p ulati o n.  

C he m o Ce ntr y x, I n c.  
C O N FI D E N TI A L  
Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8 
 
A me n d me nt 4. 0  
                                                                   Pa ge 2 0 of 1 0 1                                     1 9 Fe br u ar y 2 0 1 6 
 
All cli nical safet y a n d t ol era bilit y d ata will be liste d b y treat me nt gr o u p a n d b y s u bje ct, a n d will 
be s u m marize d b y tr eat m e nt gr o u p. All re p orte d a d verse e v e nts will be c o d e d usi n g Me d D R A 
a n d liste d b y S yste m Or ga n Class, preferre d ter m, a n d ver bati m ter m. Treat me nt -e mer ge nt 
a d verse e ve nts will be liste d a n d s u m marize d b y S yste m Or ga n Class , b y relate d ness a n d b y 
ma xi m u m se verit y a n d c o m pare d acr oss treat me nt gr o u ps. Seri o us a d v erse e ve nts a n d a d v erse 
e ve nts lea di n g t o wit h dra wal will be s u m marize d a n d c o m pare d acr oss treat me nt gr o u ps. 
I n di vi d ual vital si g ns a n d c ha n ge fr o m baseli ne i n vital si g ns will be liste d b y treat me nt gr o u p, 
s u bject, a n d st u d y visit, a n d s u m marize d descri pti vel y. La b orat or y d ata (act ual val ues a n d 
c ha n ge fr o m baseli ne) will be liste d b y treat me nt gr o u p, s u bject, a n d st u d y visit. A b n or mal 
la b orat or y val u es will be fla g ge d. La b orat or y d ata will als o be s u m marize d b y treat me nt gr o u p 
a n d st u d y visit. E C Gs will be ac q uire d at Baseli ne ( Da y 1) a n d Da y 2 9. E C Gs will be e val uate d 
f or a n y a b n or malities, w hic h will be assesse d f or cli nical si g nifica nce. 
T he i nci de nce of a d v erse e ve nts a n d seri o us a d verse e ve nts will be c o m pare d bet wee n eac h 
C C X 1 6 8 a n d t he S O C  c o ntr ol gr o u p. 
Effic acy A n alysis  
T he pri mar y efficac y e n d p oi nt is t he pr o p orti o n of s u bjects ac hie vi n g disease res p o nse at Da y 
8 5 defi ne d as B V A S perce nt re d ucti o n fr o m b aseli ne of at least 5 0 % pl us n o w orse ni n g i n a n y 
b o d y s yste m c o m p o ne nt.  
Ot her efficac y e n d p oi nts i ncl u de: 
1.  I n p atie nts wit h he mat uri a a n d al b u mi n uria at b aseli ne, t he pr o p orti o n of s u bjects ac hie vi n g 
re nal r es p o nse at D a y 8 5; re nal res p o nse is defi ne d as a n i mpr o ve me nt i n para meters of 
re nal vas c ulitis: 
a. a n i ncrease fr o m baseli ne t o Da y 8 5 i n e G F R ( M D R D ser u m creati ni ne e q u ati o n), pl us 
b.  a decr eas e fr o m bas eli ne t o Da y 8 5 i n h e mat uria (ce ntral la b orat or y micr os c o pic c o u nt 
of uri nar y R B Cs), pl us 
c. a decr eas e fr o m bas eli ne t o Da y 8 5 i n al b u mi n uria (first m or ni n g uri nar y 
al b u mi n:creati ni ne rati o).  
2.  Pr o p orti o n of s u bjects ac hie vi n g diseas e re missi o n at Da y 8 5 defi ne d as B V A S of 0;  
3.  Pr o p orti o n of s u bjects ac hie vi n g e arl y dise ase re missi o n ( B V A S of 0) at D a y 2 9 A N D 
D a y 8 5; 
4.  Perce nt c h a n ge fr o m bas eli ne t o Da y 8 5 i n B V A S ; 
5.  C ha n ge a n d perce nt c ha n ge fr o m baseli ne t o D a y 8 5 i n e G F R; 
6.  I n s u bjects wit h he mat uri a at baseli ne, t he p erce nt c ha n ge fr o m baseli ne t o Da y 8 5 i n 
uri nar y R B C c o u nt; 
7.  I n s u bjects wit h al b u mi n uria at baseli ne, t h e perce nt c ha n ge fr o m baseli ne t o Da y 8 5 i n 
uri nar y A C R;  
8.  Perce nt c h a n ge fr o m bas eli ne t o Da y 8 5 i n uri nar y M C P -1:creati ni ne rati o;  

C he m o Ce ntr y x, I n c.  
C O N FI D E N TI A L  
Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8 
 
A me n d me nt 4. 0  
                                                                   Pa ge 2 1 of 1 0 1                                     1 9 Fe br u ar y 2 0 1 6 
 
9.  Pr o p orti o n of s u bjects re q uiri n g resc ue gl uc o c orti c oi d treat me nt;  
1 0.  C ha n ge fr o m bas eli ne t o Da y 8 5  i n t he Vas c ulitis Da ma ge I n d e x ( V DI);  
1 1.  C ha n ge fr o m bas eli ne t o Da y 8 5  i n healt h-relate d q ualit y- of-life as meas ure d b y t h e S h ort 
F or m - 3 6 versi o n 2. 0 ( S F- 3 6 v 2) a n d E ur o Q O L- 5 D-5 L ( E Q - 5 D-5 L);  
Ot her e n d p oi nts i ncl u de:  
1.  T otal c u m ulati ve st u d y -s u p plie d pre d nis o ne d ose a n d d urati o n of d osi n g d uri n g t he 8 4-da y 
treat me nt peri o d; 
2.  T otal c u m ulati ve s yste mi c c ortic oster oi d d os e (a n y use) a n d d urati o n of d osi n g d uri n g t he 
8 4- da y d osi n g p eri o d; 
3.  T otal c u m ulati ve c ycl o p h os p ha mi de or rit u xi ma b d ose a n d d urati o n of d osi n g d uri n g t he 8 4-
da y d osi n g p eri o d;  
4.  Perce nt c h a n ge fr o m bas eli ne i n hs C R P,  
5.  Perce nt c h a n ge fr o m bas eli ne i n A N C A (a nti - P R 3 a n d a nti-M P O) at D a y 8 5 ,  
6.  Pr o p orti o n of patie nts bec o mi n g A N C A n e gati ve at Da y 8 5, a n d  
7.  C ha n ge a n d perce nt c ha n ge fr o m baseli ne i n plas ma a n d uri ne bi o mar k ers. 
All state d safet y a n d effi cac y e n d p oi nts will be assesse d t hr o u g h t he e n d of t he f oll o w- u p 
peri o d, Da y 1 6 9. S u m mar y statistics will be calc ulate d f or eac h of t he efficac y e n d p oi nts. F or 
cate g orical e n d p oi nts, n u m bers a n d perce nta ges will be calc ulate d. F or c o nti n u o us varia bles, 
n u m bers, mea ns, me dia ns, ra n ges, a n d sta n d ar d d e viati o ns will be calc ulat e d. Ge o metric m ea ns 
will be calc ulate d f or uri nar y A C R, uri nar y R B C c o u nt, uri nar y M C P- 1:creati ni ne, a n d hs C R P. 
S hift ta bles will be ge n er ate d f or uri n ar y para meter s s uc h as he mat uria a n d al b u mi n uria. Res ults 
will be prese nte d b y tr eat me nt gr o u p . Res ults will als o be prese nt e d b y strat u m f or eac h of t he 
t hree stratificati o n fact ors, ne wl y di a g n ose d vs. rela pse d patie nts, rit u xi ma b vs. 
c ycl o p h os p ha mi de use, a n d P R 3 vs. M P O p ositi ve A N C A.  
T he pri mar y efficac y e n d p oi nt is t he pr o p orti o n of s u bjects ac hie vi n g disease res p o nse at Da y 
8 5 defi ne d as B V A S perce nt re d ucti o n fr o m b aseli ne of at least 5 0 % pl us n o w orse ni n g i n a n y 
b o d y s yste m c o m p o ne nt. T he pr o p orti o n of s u bject s ac hie vi n g dise ase res p o nse a n d t he 1-
si de d 9 5 % c o nfi de n ce i nt er val f or t he differe nce i n pr o p orti o n ( C C X 1 6 8 mi n us S O C) will be 
esti mate d f or t he c o m p aris o n bet wee n eac h C C X 1 6 8 gr o u p a n d t he S O C gr o u p. Bec a use of t he 
rel ati vel y s m all s a m ple size of t he st u d y, n o i nfere nti al st atistic al a n al ysis will be 
perf or me d o n t he pri m ar y e n d p oi nt.   
C o nti n u o us varia bles will be a nal yz e d usi n g mi x e d effects m o del f or re pe ate d me as ures 
( M M R M) wit h treat me nt gr o u p , visit, tre at me nt-b y - visit i nter acti o n, a n d r a n d o miz ati o n 
strata ( ne wl y dia g n os e d A A V or r ela pse d A A V, rit u xi ma b or c ycl o p h os p h a mi de, P R 3 or M P O 
A N C A)  as f act ors , a n d b aseli ne as c o variate. P oi nt esti mates a n d c orres p o n di n g 9 5 % 
c o nfi de nce i nter vals will be esti mate d f or t he differe nce b et wee n eac h C C X 1 6 8 gr o u p a n d t he 
place b o gr o u p  usi n g si m ple c o ntr act fr o m t he m o del. A d diti o n all y, a n al ysis of c o v ari a nce 
( A N C O V A) wit h t he s a me f act ors a n d c o v ari ates will be a p plie d f or t he bet w ee n gr o u p 

C he m o Ce ntr y x, I n c.  
C O N FI D E N TI A L  
Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8 
 
A me n d me nt 4. 0  
                                                                   Pa ge 2 2 of 1 0 1                                     1 9 Fe br u ar y 2 0 1 6 
 
c o m p aris o n at e ac h visit . C o nti n u o us varia bles i ncl u de c ha n ge a n d/ or p ercent c ha n ge fr o m 
baseli ne i n B V A S, e G F R, hs C R P, uri nar y A C R, uri nar y M C P- 1:creati ni ne rati o, V DI, S F- 3 6 v 2 
a n d E Q- 5 D- 5 L (t otal a n d s u bsc ores), p h ar mac o d y na mics mar kers, a n d A N C A (a nti- P R 3 a n d 
a nti- M P O). Data t hat are n ot n or mall y distri b ute d, e. g., uri nar y A CR will be l o g -tra nsf or me d 
bef ore a nal ysis.  
Cate g orical varia bles will be s u m m a rize d i n a si mil ar m a n ner as descri be d f or t he pri m ar y 
e n d p oi nt. T hese  i ncl u de t he pr o p orti o n of s u bjects ac hie vi n g re missi o n, defi ne d as B V A S of 
0, at D a y 8 5, e arl y re missi o n, defi ne d as B V A S of 0 at D a y 2 9 A N D D a y 8 5,  a n d re nal 
res p o nse at D a y 8 5.    
S u bjects recei vi n g r esc ue ster oi ds after Da y 1 b ut bef ore Da y 8 5 + 7 d a ys (i.e. Da y 9 2) will be 
c o nsi dere d as treat me nt f ail ures.  
All statistical testi n g will be o ne -si de d a n d wit h t he t y p e I err or rate at α = 0. 0 5. I n t he c o nte xt of 
t his bei n g a P hase 2 tri al, n o a dj ust me nt f or m ulti plicit y will be ma de. If t he t w o C C X 1 6 8 
gr o u ps s h o w e d a si milar res p o nse, t he t w o C C X 1 6 8 gr o u ps ma y b e c o m bi ne d f or testi n g a gai nst 
t he c o ntr ol gr o u p. 
T h e mai n effi cac y a nal ysis will be i n t he i nte nt -t o-treat p o p ulati o n. T his i ncl u des all s u bjects 
w h o ha ve si g ne d i nf or me d c o nse nt t o partici pate i n t he st u d y, w h o w ere ra n d o mize d i n t his 
st u d y, ha v e recei ve d at least o ne d ose of st u d y dr u g, a n d h a ve at least o ne p ost baseli ne, o n 
tre at me nt B V A S assess me nt.  
T he safet y a nal ysis will be perf or me d o n t he safet y p o p ulati o n w hic h i ncl u des all s u bjects w h o 
ha ve si g n e d i nf or me d c o nse nt t o partici pate i n t he st u d y, w h o w ere ra n d o mize d i n t his st u d y, 
a n d ha ve r ecei ve d at least o ne d ose of st u d y dr u g. 
T he s a m ple size esti m ati o n w as b ase d o n pr actic al a n d n ot st atistic al c o nsi der ati o ns.  
P h ar m ac o ki netic a n alysis 
Plas ma sa m ples will be c ollecte d at Baseli ne ( Da y 1) a n d Da ys 8, 1 5, 2 2, 2 9, 4 3, 5 7, 7 1, a n d 8 5 
t o deter mi ne t he P K pr ofile of C C X 1 6 8 (a n d meta b olites). I n di vi d ual plas ma c o nce ntrati o ns of 
C C X 1 6 8 (a n d meta b olites) will be liste d, pl otte d, a n d s u m marize d descri pti vel y a n d 
gr a p hicall y. T he f oll o wi n g para meters will be deter mi ne d, w here p ossi ble: 
C m a x 
Ma xi m u m plas ma c o nce ntrati o n  
tma x  
Ti me of ma xi m u m plas ma c o nce ntrati o n  
A U C 0- 6 Area u n d er t he plas ma c o nce ntrati o n -ti me c ur ve fr o m Ti me 0 t o H o ur 6 o n Da y 1 
C mi n   
Tr o u g h l e vel plas ma c o n ce ntrati o ns at p ost-D a y 1 visits       
T he relati o ns hi p bet wee n P K para meters a n d re nal f u ncti o n base d o n e G F R will be 
e val uate d. T h e data ma y als o be use d t o e val u ate t he P K/ P D relati o ns hi p of C C X 1 6 8 
treat me nt. T o t his e n d, t he c ha n ge a n d/ or perce nt c ha n ge fr o m b aseli ne i n B V A S, e G F R, 
uri nar y A C R, uri nar y M C P- 1:creati ni ne  rati o, ser u m hs C R P, he mat uria, a n d ot her 
bi o mar kers ma y be us e d as P D mar kers.  
Uri nar y c o n ce ntr ati o ns of C C X 1 6 8 a n d p ossi ble meta b olites i n a 6- h o ur uri ne sa m ple 
c ollecte d o n D a y 1 will als o be meas ure d. Res ults will be liste d a n d s u m marize d 

C he m o Ce ntr y x, I n c.  
C O N FI D E N TI A L  
Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8 
 
A me n d me nt 4. 0  
                                                                   Pa ge 2 3 of 1 0 1                                     1 9 Fe br u ar y 2 0 1 6 
 
descri pti vel y . 
Plas ma  c o nce ntr ati o ns of pre d nis ol o ne, c ycl o p h os p ha mi de a n d its meta b olites , a n d 
rit u xi ma b ma y als o b e meas ure d i n t he P K plas ma sa m ples t o e val uate p ote ntial dr u g -
dr u g i nteracti o n. 

C he m o Ce ntr y x, I n c.                                                             C O N FI D E N TI A L                                                            Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8 
 
                                                                                  Ame n d me nt 4. 0 
 
                                                                  Pa ge 2 5 of 1 0 1                                                                      1 9 F e br uar y 2 0 1 6 
TI M E A N D E V E N T S T A B L E 
 
Scree ni n g
1 
St u d y D a y
2 
 
-1 4 t o -1  
1
3 
2   8  
1 5  2 2  
2 9  
4 3  5 7   7 1  8 5  
9 9  
1 1 3  1 4 1  
1 6 9  
I nf or me d C o nse nt 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
De m o gra p hics, M e dical  Hist or y, Pri or 
Me dicati o ns  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P h ysical E x a mi nati o n
4  
X  
X 5 
 
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
B o d y S yste m Re vie w  
 
 
X  
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
Vital Si g ns
6  
X  
X 5  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Ser u m pre g na n c y test f or w o me n of 
c hil d beari n g p ote ntial  
X  
 
 
 
 
 
X  
 
X  
 
X  
 
X  
 
X  
1 2 -lea d E C G 
X  
 
 
 
 
 
X  
 
 
 
X  
 
 
 
 
C hest X ra ys
7 
X  
 
 
 
 
 
( X) 
 
 
 
( X) 
 
( X) 
 
( X) 
HI V, H B V, H C V T esti n g  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A N A, a nti -G B M a nti b o dies, C 3, C 4, 
I g G, I g M, a n d I g A
8 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P T a n d a P T T  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ser u m C he mistr y, He m at ol o g y  
X  
X 5 
X  
X  
X  
 
X  
X  
 
X  
X  
X  
 
X  
X  
W B C c o u nt (l ocal la b)
9 
 
X 5 
 
 
X  
 
X  
 
X  
 
X  
 
 
 
 
Ser u m Creati ni ne ( w h e n f ull 
C he mistr y n ot d o ne) 
 
 
 
 
 
 
 
 
X  
 
 
 
X  
 
 
Uri nal ysis
1 0 
X  
X 5 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Uri ne al b u mi n, M C P -1 a n d creati ni ne 
assa ys  
 
X 5 
 
X  
X  
 
X  
 
X  
 
X  
 
X  
 
X  
A N C A meas ur e me nt
1 1 
X  
X 5 
 
 
 
 
X  
 
 
 
X  
 
X  
 
X  
Re nal bi o ps y ( o pti o nal pr oce d ure )  
X  
 
 
 
 
 
 
 
 
 
X
1 2 
 
 
 
 

C he m o Ce ntr y x, I n c.                                                             C O N FI D E N TI A L                                                            Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8 
 
                                                                                  Ame n d me nt 4. 0 
 
                                                                  Pa ge 2 6 of 1 0 1                                                                      1 9 F e br uar y 2 0 1 6 
 
Scree ni n g
1 
St u d y D a y
2 
 
-1 4 t o -1  
1
3 
2   8  
1 5  2 2  
2 9  
4 3  5 7   7 1  8 5  
9 9  
1 1 3  1 4 1  
1 6 9  
Ra n d o mizati o n  
 
X 5 
 
 
 
 
 
 
 
 
 
 
 
 
 
C C X 1 6 8 or Place b o Dis pe nsi n g  
 
X  
 
 
X  
 
X  
X  
X  
X  
 
 
 
 
 
C C X 1 6 8 or Place b o Acc o u nta bilit y  
 
 
 
 
X  
 
X  
X  
X  
X  
X  
 
 
 
( X)1 3 
Pre d nis o ne Dis pe nsi n g  
 
X  
 
X  
X  
X  
 
X  
X  
X  
X  
X  
X  
 
 
Pre d nis o ne Acc o u nt a bilit y  
 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
( X)1 3 
C ycl o p h os p ha mi de I V d ose
1 4 
 
X  
 
 
X  
 
X  
 
X  
 
X  
 
 
 
 
Azat hi o pri ne d osi n g
1 5 
 
 
 
 
 
 
 
 
 
 
 
X → 
→ 
→ 
→ 
Rit u xi ma b I V d ose
1 6 
 
X  
 
X  
X  
X  
 
 
 
 
 
 
 
 
 
B V A S  
X  
X 5 
 
 
 
 
X  
 
 
 
X  
 
X  
 
X  
V DI  
 
X 5 
 
 
 
 
 
 
 
 
X  
 
 
 
X  
S F -3 6 v 2 a n d E Q -5 D -5 L  
 
X 5 
 
 
 
 
X  
 
 
 
X  
 
 
 
X  
hs C R P  
 
X 5 
 
X  
X  
 
X  
 
X  
 
X  
 
X  
 
X  
P K Plas ma Sa m ple C ollecti o n  
 
X 5 ,1 7 
 
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 
 
P D Plas ma Sa m ple C ollecti o n  
 
X 5 
 
 
 
 
X  
 
 
 
X  
 
 
 
X  
Sali va sa m ple c ollecti o n  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Uri ne sa m ple c ollecti o n f or C C X 1 6 8 
a nal ysis  
 
X
1 8 
 
 
 
 
 
 
 
 
 
 
 
 
 
C o nc o mita nt Me dicati o ns  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
I nstr u ct s u bjects w h o are o n 
c ortic oster oi ds at scree ni n g t o st o p 
w he n st u d y pre d nis o ne is starte d  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A d verse E v e nt Assess me nt  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
1 Scree ni n g m ust occ ur e x pe diti o usl y ( n ot t o e xcee d 1 4 da ys) i n or der n ot t o dela y start of tre at me nt; scree ni n g la bs will be d o ne at t he l ocal la b orat or y t o 
e x pe dite eli gi bilit y assess me nt; res u lts fr o m a re nal bi o ps y, if perf or me d wit hi n 4 wee ks of Da y 1 will be c ollecte d o n t he Hist ol o g y F or m pr o vi de d. La b orat or y 
res ults fr o m t he l ocal la b orat ories o btai ne d wit hi n 7 2 h o urs of scree ni n g are acce pta ble i n or der t o a v oi d u n necessar y bl o o d dra ws.  
2 Visit Da ys 1, 2, 8, a n d 1 5 m ust occ ur o n t he sc he d ule d st u d y da ys. Visit Da ys 2 2, 2 9, 4 3, 5 7, 7 1, a n d 8 5 ma y occ ur wit hi n a + /- 2-da y wi n d o w of t he sc he d ule d 
visit. Visit Da ys 9 9, 1 1 3, 1 4 1, a n d  1 6 9 ma y occ ur wit hi n a +/ - 4-da y wi n d o w of t he sc he d ul e d visit.  
3 A s u bj ect c o ul d be ke pt o ver ni g ht i n t he h os pital o n Da y 1, if necessar y. T his h os pital sta y w o ul d n ot be c o nsi dere d a seri o u s ad verse e ve nt, u nless ot her S A E 
criteria are met.  

C he m o Ce ntr y x, I n c.                                                             C O N FI D E N TI A L                                                            Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8 
 
                                                                                  Ame n d me nt 4. 0 
 
                                                                  Pa ge 2 7 of 1 0 1                                                                      1 9 F e br uar y 2 0 1 6 
4 P h ysical e xa mi nati o n will i ncl u de b o d y wei g ht meas ure me nt; Hei g ht will o nl y be meas ure d at Scree ni n g.  P h ysical e xa mi nati o n will i ncl u de a ne ur ol o gical 
e xa mi nati o n i ncl u di n g s peec h, c o nsci o us ness le vel, m o o d , cra nial ner ves, m ot or, c o or di nati o n a n d gait, refle xes, a n d se ns or y s yste ms. 
5 T hese pr oce d ures m ust be d o ne B E F O R E ta ki n g t he firs t d os e of st u d y me dicati o n. 
6 Assess me nt of heart rate, b o d y te m perat ure, a n d bl o o d press ure (s u pi ne, after at least 3 mi n utes of rest)  
7 C hest X ra ys will be ac q uire d a n d e xa mi ne d at Scree ni n g t o e xcl u de t he prese nce of T B a n d f or baseli ne B V A S a n d V DI. C hest X ra ys at s u bse q ue nt st u d y 
visits will O N L Y be ac q uire d if i n t he cli nical o pi ni o n of t he Pri nci pal I n vesti gat or t here is p ul m o na r y disease i n v ol ve me nt t hat nee ds t o be assesse d f or safet y, 
B V A S, or V DI.  
8 T hese tests d o n ot nee d t o be perf or me d if res ults are a vaila ble fr o m tests d o ne wit hi n t he past 1 2 m o nt hs pri or t o t h e Scree ni n g visit.  
9 F or s u bj ects recei vi n g c ycl o p h os p ha mi de, a bl o o d sa m ple m ust be ta ke n earl y d uri n g t he visit f or W B C c o u nt at t he l ocal la b or at or y; t he W B C c o u nt is  
necessar y f or c ycl o p h os p h a mi de d ose decisi o ns o n t hese da ys.  
1 0 S u bj ects will be as ke d t o v oi d t heir bla d ders c o m pletel y, a n d a re prese ntati ve clea n catc h, mi dstrea m uri ne sa m ple will b e c ollecte d. D uri n g scree ni n g, t he l ocal 
la b orat or y will perf or m a uri nal ysis f or he mat uria a n d pr otei n uria f or eli gi bilit y assess me nt. F or t he rest of t he visits, a uri ne sa m ple will be se nt t o t he ce ntral 
la b orat or y f or uri nal ysis i ncl u di n g p H, s pecific gra vit y, gl uc ose, nitrite, ket o nes, bilir u bi n, ur o bili n o ge n, R B Cs, a n d W B Cs. Uri nar y A C R a n d M C P -
1:creati ni ne will be meas ure d b y t he ce ntral la b orat or y at st u d y visits i n dicate d i n t he ta ble.  
1 1 At scree ni n g, a n i n direct i m m u n ofl u oresce nce test f or P -A N C A a n d C -A N C A, as well as E LI S A tests f or a nti -pr otei nas e -3 ( P R 3) a n d a nti -m yel o per o xi dase 
( M P O) will be perf or me d f or st u d y eli gi bilit y; f or t he rest of t he st u d y visits, o nl y E LI S A t ests f or a nti- P R 3 a n d a nti -M P O will be perf or me d.  
1 2 If p ossi ble, re nal bi o ps y s h o ul d be o btai ne d fr o m s u bj ects wit h a pre-st u d y bi o ps y. 
1 3 T his acc o u nta bilit y is o nl y nec essar y f or  s u bj ects w h o disc o nti n ue bet wee n Da y 8 5 a n d 1 6 9, a n d c o me f or a n earl y ter mi nati o n visit.  
1 4 A p plica ble o nl y t o c ycl o p h os p ha mi de strat u m. C ycl o p h os p ha mi de d oses gi ve n fr o m Da y 1 t hr o u g h 5 7 m ust be gi ve n acc or di n g t o directi o ns pr o vi de d i n t he 
pr ot oc ol . T he date a n d start a n d e n d ti me of t he c ycl o p h os p ha mi de d ose will be rec or de d. 
1 5 Azat hi o pri ne m ust be ta ke n fr o m Da y 9 9 t hr o u g h Da y 1 6 8  b y all s u bj ects i n t he c ycl o p h os p ha mi de b ut n ot t he rit u xi ma b strat u m.  
1 6 A p plica ble o nl y t o t he rit u xi ma b strat u m. A rit u xi ma b d osi n g re gi me n of 3 7 5 m g/ m 2 I V o n Da ys 1, 8, 1 5, a n d 2 2  s h o ul d be use d. 
1 7 P K bl o o d sa m ple will be c ollecte d pri or t o t he m or ni n g d ose o n Da y 1 a n d at 0. 5, 1, 2, 3, 4, a n d 6 h o urs f oll o wi n g d osi n g.  
1 8 S u bj ects will v oi d pri or t o t he m or ni n g d ose of C C X 1 6 8/ place b o o n t his da y, a n d t he n A L L uri ne will be c ollecte d o ver t he fir st 6 h o urs f oll o wi n g 
C C X 1 6 8/ place b o d osi n g. T he 6 -h o ur uri ne v ol u me will be meas ure d a n d a re prese ntati ve s a m ple will be se nt t o meas ure C C X 1 6 8 c o nce ntrati o n i n t he uri ne.  

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 2 8 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
LI S T O F A B B R E VI A TI O N S A N D A C R O N Y M S  
A A V  
a nti-ne utr o p hil c yt o plas mic a nti b o d y ass o ciate d vasc ulitis    
A C R  
al b u mi n:creati ni ne rati o  
A E  
a d verse e ve nt  
A L T  
ala ni ne a mi n otra nsf eras e (als o calle d S G P T)  
A N A  
a nti- n uclear a nti b o dies 
A N C A  
a nti- ne utr o p hil c yt o plas mic a nti b o dies 
A PI  
acti ve p har m ace utical i n gre die nt  
a P T T 
acti vate d partial t hr o m b o plasti n ti me  
A S T  
as partate a mi n otra nsferas e (als o calle d S G O T)  
A U C 0- 6  
area u n d er t he c ur ve fr o m h o ur 0 t o 6 
B L Q  
bel o w li mit of q ua ntificati o n  
B U N   
bl o o d urea nitr o ge n 
B V A S  
Bir mi n g h a m Vasc ulitis Acti vit y Sc ore v ersi o n 3  
C 3  
c o m ple me nt 3  
C 4  
c o m ple me nt 4  
C 3a 
c o m ple me nt 3a 
C 4a 
c o m ple me nt 4a 
C 5a 
c o m ple me nt 5a 
C 5a R  
c o m ple me nt 5a rece pt or  
C 5 b 9  
c o m ple me nt 5 b 9 
C A  
c o m pete nt a ut h orit y 
C- A N C A  
c yt o plas mic -a nti- ne utr o p hil c yt o plas mic a nti b o d y 
c G M P  
c urre nt g o o d cli nical practice  
C ma x  
ma xi m u m ( plas ma) c o nce ntrati o n  
C P K   
creati ni ne p h os p h o ki nas e 
C R A  
Cli nical Researc h Ass o ciate (als o k n o w n as t he St u d y M o nit or)  
C R F  
case r e p ort f or m  
C R O  
c o ntract  r esearc h or ga nizati o n 
D M C  
data m o nit ori n g c o m mittee  
E C  
et hics c o m mittee 
E C 5 0  
5 0 % eff ecti ve c o n ce ntrati o n  
E C G  
electr ocar di o gr a m  
e G F R  
esti mate d gl o mer ular filtrati o n rate  
E Q - 5 D-5 L   
E ur o Q ol- 5 D-5 L  
F A C S  
fl u oresce n ce acti vate d cell s orti n g 
F D A   
F o o d a n d Dr u g A d ministrati o n  
g 
gr a m  
G B M   
gl o mer ular base m e nt me m bra ne 
G C P  
g o o d cli nical practice  
G G T   
ga m ma -gl uta m yl tr a ns pe pti dase  
G P A  
gr a n ul o mat osis wit h p ol ya n giitis ( We ge ner’s)  
G P C R   
G pr otei n-c o u ple d rece pt or  
H E E N T   
hea d, e yes, ears, n ose, t hr oat 
HI V  
h u ma n i m m u n o deficie nc y vir us 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 2 9 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
h pf 
hi g h p o wer fiel d 
I C5 0 
c o nce ntr ati o n t o i n hi bit 5 0 % 
I C H 
I nter nati o nal C o nfere nce o n Har m o nisati o n 
II F 
I n dir ect i m m u n ofl u oresce nce 
I R B 
I nstit uti o nal Re vie w B oar d 
I VI g  
i ntra ve n o us i m m u n o gl o b uli n 
K 3E D T A  
tri-p otassi u m et h yle n e dia mi ne tetra -acetic aci d 
k g 
kil o gra m 
KI M - 1  
ki d ne y i nj ur y m olec ul e- 1 
L D H  
lactate de h y dr o ge nas e 
M A C  
me m bra ne attac k c o m ple x  
M C H  
mea n cell he m o gl o bi n  
M C H C  
mea n cell he m o gl o bi n c o nce ntrati o n  
M D R D  
M o dificati o n of Diet i n Re nal Diseas e  
Me d D R A   
Me dical Dicti o nar y f or Dr u g Re g ul at or y Affairs 
m g  
milli gra m  
m L  
milliliter  
M P A  
micr osc o pic p ol ya n giitis  
M P O   
m yel o per o xi dase 
N 
n u m ber 
N G A L   
ne utr o p hil gel ati nase-ass ociate d li p ocali n  
N O A E L  
N o o bser ve d a d vers e effect le vel  
P- A N C A  
peri n uclear -a nti-n e utr o p hil c yt o plas mic a nti b o d y  
P C P  
P ne u m ocystis c ari nii p ne u m o nia 
P D  
p har mac o d y n a mic(s)  
P K  
p har mac o ki netic(s) 
P R 3  
pr otei nase 3  
P T  
pr ot hr o m bi n ti me 
R B C   
re d bl o o d cell 
S A E  
seri o us a d vers e e v e nt 
S F - 3 6 v 2  
S h ort F or m- 3 6 versi o n 2 
S G P T  
ser u m gl uta mic p yr u vic tra nsa mi nase (als o calle d A L T) 
S G O T  
ser u m gl uta mic o x al oacetic tra nsa mi nase (als o calle d as A S T)  
S L E  
s yste mic l u p us er yt h e mat os us 
S O P  
sta n dar d o per ati n g pr oce d ure 
S U S A R  
s us pecte d u ne x pecte d seri o us a d verse reacti o n 
T ma x  
ti me of ma xi m u m ( plas ma) c o nce ntrati o n 
T P M T   
t hi o p uri ne S-met h yltra nsferas e  
V DI  
vasc ulitis da ma ge i n de x  
W B C   
w hite bl o o d cell 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 3 0 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
1.  
I N T R O D U C TI O N 
1. 1.  
B ac k gr o u n d  
T he acti vati o n of t he c o m ple me nt pat h wa y ge n erates bi ol o gicall y acti ve fra g m e nts of  
c o m ple me nt pr otei ns, e. g. C 3a, C 4a a n d C 5a a na p h ylat o xi ns a n d C 5 b- 9 me m bra ne attac k 
c o m ple x es ( M A C), all of w h ic h me diate i nfla m mat or y res p o nses b y i n d uci ng le u k o c yt e 
c he m ota xis, acti vati n g m acr o p ha ges, ne utr o p hils, platelets, mast cells a n d e n d ot helial cells a n d 
b y i ncr easi n g vas c ular p er mea bilit y, c yt ol ysis a n d tiss ue i nj ur y.  
C 5a is o ne of t he m ost p ote nt pr o- i nfla m mat or y m e diat ors of t he c o m ple m e nt s yste m, bei n g at 
least 10 0 ti mes m ore p ote nt t ha n C 3a. T his 1 9 0 k D p ol y pe pti de, al o n g wit h a C 5 b fra g me nt, is 
pr o d uce d b y e nz y matic clea va ge of a C 5 prec urs or d uri n g acti vati o n of a n y of t he 3 c o m ple me nt 
pat h wa ys. C 5a i n d uces e x pressi o n of a d hesi o n m olec ules a n d c h e m otactic mi grati o n of 
ne utr o p hils, e osi n o p hils, bas o p hils a n d m o n oc yt es. It als o me di ates i nfla m mat or y reacti o ns b y 
ca usi n g s m o ot h m uscle c o ntracti o n, i ncreasi n g v asc ular per m ea bilit y, i n d u ci n g b as o p hil a n d 
mast cell de gra n ul ati o n a n d i n d uci n g r eleas e of l ys os o mal pr oteases a n d o xi dati ve free ra dicals. 
T he a na p h ylactic a n d c he m otactic eff ects of C 5a are me diate d t hr o u g h its i nteracti o n wit h t he 
C 5a rece pt or ( C 5a R), a G pr otei n-c o u ple d rece pt or ( G P C R) e x presse d o n h u ma n ne utr o p hils, 
m o n oc ytes, b as o p hils, e osi n o p hils, re nal gl o mer ul ar tiss ues, a n d l u n g s m o ot h m uscle a n d 
e n d ot helial cells.  
Rece ntl y, s e ver al re p orts ha ve s h o w n t hat a nti -n e utr o p hil c yt o plas mic a nti b o d y ( A N C A) -i n d uce d 
gl o mer ul o ne p hritis i n mice (a m o d el t hat cl osel y reca pit ulates t he hist ol o gi cal feat ures of h u m a n 
pa uci -i m m u ne necr otizi n g cresce ntic gl o mer ul o ne p hritis i n gra n ul o mat osis wit h p ol ya n giitis 
[ G P A; We ge ner’s] a n d micr osc o pic p ol ya n giitis [ M P A]) is dra maticall y a meli orate d b y ge netic 
deleti o n of eit her C 5 or C 5a R ( Sc hrei ber et al., 2 0 0 9 ). T he de v el o p me nt of s yste mic l u p us 
er yt h e mat os us ( S L E) is ass ociate d wit h t he de p ositi o n of I g G-c o ntai ni n g i m m u ne c o m ple x es i n 
vari o us tiss ues/ or ga ns, wit h t he e ns ui n g acti vati o n of t he c o m ple me nt casca de a n d pr o d ucti o n of 
i nfla m mat or y sti m uli s uc h as C 5a. Gl o mer ular e x pressi o n of C 5a R m R N A a n d pr otei n was 
s h o w n t o c orrel ate p ositi vel y wit h t he d e gree of mesa n gi al h y p ercell ularit y a n d l e vel of ser u m 
creati ni ne i n mesa n gial gl o mer ul o ne p hritis, i ncl u di n g l u p us ne p hritis ( A be et al., 2 0 0 1 ). Rece nt 
st u dies s h o we d t hat C 5a R-deficie nt mice a n d mice treate d wit h a s mall pe pti dic a nti -C 5a R 
a nta g o nist are pr ot ecte d fr o m tiss ue i nj ur y i n d uce d b y i m m u ne c o m ple x f or mati o n. I n a d diti o n, 
use of a C 5 m A b i n a s p o nta ne o us m o use m o del of l u p us- li ke a ut oi m m u ne disease res ulte d i n 
si g nifica nt a meli orati o n of t he c o urse of gl o mer ul o ne p hritis a n d i n mar ke dl y i ncrease d s ur vi val. 
A ge netic versi o n of t he disease ( M R Ll pr mice) is als o atte n uate d si g nifica ntl y w he n t he C 5a R 
rece pt or is delete d fr o m t hat ge netic bac k gr o u n d. 
T he t hera p e utic i n dicati o n  bei n g p urs ue d i nitiall y f or C C X 1 6 8, a p ote nt a n d selecti ve C 5a R 
a nta g o nist, is i n t he treat me nt of A N C A -ass o ciate d vasc ulitis  ( A A V).  
A A V  c urre ntl y is treate d wit h gl uc oc ortic oster oi ds a n d c ycl o p h os p ha mi de, azat hi o pri ne, 
m yc o p h e n olate m ofetil, rit u xi ma b, a n d plas ma e x c ha n ge i n se vere cases. St u d y Dr u g 
De vel o p me nt 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 3 1 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
1. 1. 1.  
N o n - Cli nic al P h ar m ac ol o g y 
1. 1. 1. 1.  
I n Vitr o  Effic ac y a n d Selecti vit y f or C 5 a R  
C C X 1 6 8 is a p ote nt a nta g o nist of t he h u ma n C 5a rece pt or ( h C 5a R). As meas ure d i n vitr o wit h a 
m yel oi d h u ma n cell li ne, C C X 1 6 8 f u ncti o nal l y i n hi bits C 5a-me diate d c he m ota xis wit h a p ote nc y 
(I C5 0) of 0. 9 2 n M. A d diti o nall y, C C X 1 6 8 dis places 1 2 5I- C 5a fr o m h C 5a R wit h a p ote nc y (I C5 0) 
of 0. 6 5 n M. W he n teste d o n fres hl y is olate d h u ma n ne utr o p hils, C C X 1 6 8 i n hi bits t he C 5a-
me diate d i ncrease i n c yt o plas mic calci u m le vels wit h a p ote nc y (I C 5 0) of 0. 2 n M.  
C C X 1 6 8 has bee n e v al uate d f or its a bilit y t o i n hi bit t he C 5a- me diate d c h e m ota xis of ne utr o p hils 
i n fres hl y is olat e d h u ma n w h ole bl o o d. C C X 1 6 8 pr o d uce d 5 0 % i n hi biti o n (I C5 0) of C 5a-
me diati o n ne utr o p hil mi grati o n i n t his assa y at a c o nce ntrati o n of 1. 7 n M; 9 0 % i n hi biti o n ( A 1 0 
val ue) was d eter mi ne d i n h u ma n w h ole bl o o d at a C C X 1 6 8 c o nce ntrati o n of 1 5. 4 n M. C C X 1 6 8 
als o i n hi bits C 5a R i n c y n o m ol g us m o n ke ys a n d ha msters wit h p ote nc ies si milar t o t hat o bser ve d 
wit h h u ma n w h ole bl o o d. H o we ver, C C X 1 6 8 p ossesses m o derat e p ote nc y f or ra b bit C 5a R (I C 5 0 
~ 1. 4 µ M) a n d lac ks affi nit y f or m o use, rat or d o g C 5a R (I C 5 0 > 1 0 µ M). 
O ne maj or meta b olite ( C C X 1 6 8 - M 1) has bee n i de ntifie d i n h u ma n plas ma i n P hase 1 st u d y 
C L 0 0 1 _ 1 6 8. T his c o m p o u n d, als o referre d t o a C 0 3 3 5 2 7 3, has bee n s h o w n t o be e q ui vale nt t o 
C C X 1 6 8 i n its p ote nc y t o war ds h C 5a R, ha vi n g a p ote nc y (I C 5 0) of 3 n M f or i n hi biti o n of C 5a-
me diate d w h ole bl o o d ne utr o p hil c he m ota xis a n d a p ote nc y of 7 n M f or i n hi biti o n of C 5a-
me diate d ne utr o p hil C D 1 1 b u pre g ulati o n assa y i n w h ole bl o o d. Li ke C C X 1 6 8, t he meta b olite 
C C X 1 6 8- M 1 has a c o m p ara ble hi g h p ote n c y f or c y n o m ol g us m o n ke y, ha mster, a n d h u ma n 
C 5a R, m o derate p ote nc y a gai nst ra b bit C 5a R (I C 5 0 ~ 1. 4 µ M), b ut lac ks affi nit y f or m o use, rat or 
d o g C 5a R (I C 5 0 > 1 0 µ M). 
C C X 1 6 8 dis pla ys greater t ha n 1 0, 0 0 0-f ol d selecti vit y f or h C 5a R relati ve t o ot her c he m ot actic 
rece pt ors, i ncl u di n g C C R 1, C C R 2, C C R 4, C C R 5, C C R 6, C C R 7, C C R 8, C C R 9, C C R 1 0, C C R 1 2, 
C X C R 1, C X C R 2, C X C R 3, C X C R 4, C X C R 6, C X C R 7, C 5 L 2, C 3a R, C he m R 2 3, G P R 1 a n d 
F P R L 1. C C X 1 6 8 has bee n f urt her e v al uate d a gai nst a pa nel of 5 5 u nrelate d rece pt ors a n d 
me m bra ne - ass ociate d pr otei ns. Wea k le vels of acti vit y ( > 1, 0 0 0-f ol d s electi vit y relati ve t o 
h C 5a R) were n ot e d a gai nst t he site 2 s o di u m c ha n nel ( 5 9 % i n hi biti o n wit h 1 0 µ M C C X 1 6 8). 
C C X 1 6 8- M 1 was teste d a gai nst a pa nel of 1 7 relate d c he m otactic rece pt ors a n d a pa n el of 5 5 
u nrelate d r ece pt ors a n d me m bra ne- ass ociate pr otei ns. T he o nl y acti vit y d etecte d was w ea k 
( > 1, 0 0 0-f ol d sel ecti vit y r elati ve t o h C 5a R) a gai nst C B 1 ( 5 3 % i n hi biti o n wit h 1 0 µ M C C X 1 6 8-
M 1), t he site 2 s o di u m c ha n nel ( 6 4 % i n hi biti o n wit h 1 0 µ M C C X 1 6 8- M 1) a n d t he G A B A- gate d 
c hl ori ne c ha n n el ( 5 1 % i n hi biti o n wit h 1 0 µ M C C X 1 6 8- M 1).  
1. 1. 1. 2.  
Effic ac y M o dels  
C C X 1 6 8 has bee n e v al uate d i n viv o utilizi n g m o dels t hat are rel e va nt t o t he i nte n de d t hera p e utic 
use i n h u ma ns. W he n C 5a is ge n er ate d l ocall y i n t he bl o o dstrea m, C 5a R- beari n g l e u k oc ytes i n 
t he vici nit y i m me diatel y u pre g ulate a d h esi o n m olec ules a n d a d here t o t he i n ner face of t h e bl o o d 
vessel. If C 5a is i ntr o d uce d s yste micall y b y i ntra v e n o us i njecti o n, le u k oc yt e a d here nce occ urs 
i m me diatel y t hr o u g h o ut t he vasc ulat ure a n d, as a res ult, t he n u m ber of le u k oc yt es still fl o wi n g i n 
t he bl o o dstrea m dr o ps tra nsie ntl y b y a s u bsta ntial a m o u nt. I n ge neral, e val u ati o n of C 5a R 
a nta g o nists i n a ni mal m o dels p oses a c h alle n ge beca use C 5a R a nta g o nists t hat are p ote nt f or 
h u ma n C 5a R, i ncl u di n g C C X 1 6 8, are less p ote nt f or C 5a R ort h ol o gs i n m ost ot her m o del s pecies 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 3 2 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
(s uc h as mice, rats a n d r a b bits). F or t his reas o n, C C X 1 6 8 has bee n e v al uate d i n C 5a-i n d uce d 
le u k o pe nia m o dels usi n g tra ns ge nic mice i n w hi c h t he m o use C 5a R ge n e has bee n re pl ace d wit h 
t he h u ma n C 5a R ge ne a n d n o n- h u ma n pri mates. 
C he m o Ce ntr y x ge n er ate d a h u ma n C 5a R k n oc k-i n ( h C 5a R KI) m o use strai n i n w hic h t he m o use 
C 5a R ge n e has bee n re pl ace d wit h t he h u ma n C 5a R ge ne. T he i n nate i m m u ne cells of t hese mice 
res p o n d n or mall y t o C 5a, i n a ma n ner hi g hl y se nsiti ve t o C C X 1 6 8. I n vitr o, C C X 1 6 8 bl oc ks 
h C 5a- me diate d c h e m ota xis of le u k oc yt es fres hl y is olate d fr o m t hese h C 5a R KI mice wit h hi g h 
p ote nc y (I C 5 0 = 0. 5 n M i n 1 0 0 % m o use plas ma). T his val ue is nearl y i de ntical t o t he p ote nc y 
( 1. 7 n M) e x hi bite d b y C C X 1 6 8 i n its i n hi biti o n of ne utr o p hil mi grati o n t o h C 5a i n w h ole h u ma n 
bl o o d, i n dicati n g t hat t he h C 5a R KI mice are s uita ble f or p har m ac o d y na mi c e val uati o n of 
C C X 1 6 8. I n t he h u ma n C 5a R k n oc k-i n mice, a n i ntra ve n o us d ose of 2 0 µ g/ k g h C 5a r o b us tl y 
i n d uces t his le u k o pe nia wit hi n o ne mi n ute after i njecti o n. Pretreat me nt of t he mice wit h a n oral 
d ose of 0. 3 m g/ k g C C X 1 6 8, w hic h res ulte d i n a pl as ma c o nce ntrati o n of a p pr o xi matel y 7 5 n M at 
6 0 mi n. p ost- d ose, al m ost c o m pletel y bl oc k e d t he C 5a-i n d uce d le u k o p e nia. A d ose of 0. 0 3 
m g/ k g C C X 1 6 8, pr o d uci n g a pl as ma c o nce ntrati o n of 1 5 n M, res ulte d i n a 5 0 % re d ucti o n i n t he 
C 5a-i n d uce d le u k o p e nic res p o nse. 
I n c y n o m ol g us m o n ke ys, it was deter mi ne d t hat a n i ntra ve n o us h C 5a d ose of 1 0 µ g/ k g r o b ustl y 
i n d uces a dr o p i n ne utr o p hils ( ne utr o pe nia) wit hi n o ne mi n ute. Pre-treat me nt of t he c y n o m ol g us 
m o n ke ys wit h a 3 0 m g/ k g or al d ose of C C X 1 6 8 c o m pletel y bl oc k e d t he C 5a-i n d uce d 
ne utr o pe nia. T his d ose of C C X 1 6 8 res ulte d i n a plas ma c o nce ntrati o n of a p pr o xi matel y 2 3 0 n M 
at t he ti me of h C 5a a d mi nistrati o n. A d ose of 3 m g/ k g res ulte d i n greater t ha n 5 0 % re d u cti o n of 
t he h C 5a res p o nse, a n eff ect t hat was ass o ciate d wit h a C C X 1 6 8 plas ma c o nce ntrati o n of 
a p pr o xi matel y 3 8 n M. 
T he effi cac y of C C X 1 6 8 i n a m o use m o del of A N C A- ass ociate d gl o mer ul o ne p hritis was 
e val uate d i n or d er t o assess t he cli nical p ote ntial of C C X 1 6 8 i n t he treat me nt of A N C A-
ass ociate d vas c ulitis. I n t hese st u dies, i ntra ve n o us i njecti o n of m o use a nti- m yel o per o xi dase (a nti-
M P O) I g G i nt o t he h u ma n C 5a R k n oc k- i n mice ca use d gl o mer ul o ne p hritis i n a ma n ner 
mi mic ki n g A N C A diseas e i n h u ma ns. At dail y oral d oses of 3 0 m g/ k g C C X 1 6 8, a mar ke d 
i n hi biti o n of a nti- M P O i n d uce d gl o mer ul o ne p hritis was d oc u me nte d hist ol o gicall y, as assesse d 
b y t he n u m ber of necr oti c ( 8. 2 % wit h ve hicl e, 1. 1 % wit h C C X 1 6 8; p < 0. 0 0 0 1) a n d cresce nt-
c o ntai ni n g gl o mer uli ( 2 9. 3 % wit h ve hicle, 3. 3 % wit h C C X 1 6 8; p < 0. 0 0 0 1). T hese res ults w ere 
c o nsiste nt wit h re d uce d pr otei n, le u k oc ytes a n d R B C le vels i n t he uri ne a n d re d uce d s er u m B U N 
a n d creati ni ne i n mice rece i vi n g C C X 1 6 8. S o me t hera pe utic b e nefit ( 3 0 % re d ucti o n i n t he 
n u m ber of gl o mer uli wit h cresce nts) was n ot e d at C C X 1 6 8 d oses as l o w as 0. 1 m g/ k g/ da y. 
A d mi nistrati o n of 4 m g/ k g C C X 1 6 8 t wice d ail y w as i de ntifie d as t he l o west d osi n g re gi me n t hat 
pr o d uce d a n ear- ma xi mal t hera pe utic b e nefit. At t his d ose, plas ma le vels ra n ge d fr o m 3 5 n g/ m L 
( Cmi n ) t o 2 0 0 n g/ m L ( Cma x ) t hr o u g h o ut t he da y. T h e sa me bl o o d bi o mar ker of C 5a R bl oc ka de 
use d i n t he P hase 1 cli nical trial was als o use d wit h t he h C 5a R KI mice; C C X 1 6 8 ha d si m ilar 
C 5a R a nta g o nist p ote nc y o n h u ma n a n d h C 5a R KI m o use n e utr o p hils (i n hi biti o n of C 5a-i n d uce d 
C D 1 1 b u pre g ulati o n i n bl o o d, I C 5 0 4 n M). T he e xte nt of f u ncti o nal C 5a R bl oc ka de o n bl o o d 
ne utr o p hils ass ociate d wit h t he plas ma le vels of 4 m g/ k g C C X 1 6 8 t wice d ail y was d eter mi ne d t o 
ra n ge fr o m 9 9 % ( at Cma x ) t o 9 5 % (at Cmi n ), wit h a ti me-a vera ge d le v el of rece pt or bl oc ka de of 
9 7 %. 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 3 3 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
T hese mec h a nis m - base d p har mac ol o g y st u dies, ta ke n t o get her, s u p p ort o ur esti mate t hat 
mai ntai ni n g h u ma n plas ma C C X 1 6 8 c o nce ntrati o ns s ufficie ntl y hi g h t o pr o vi de ≥ 9 5 % rece pt or 
c o vera ge will pr o vi de si g nifica nt cli nical be n efit i n i nfla m mat or y c o n diti o ns ass ociate d wit h 
C 5a R acti vati o n.  
1. 1. 2.  
N o n - Cli nic al S af et y a n d T o xic ol o g y 
T he t o xic ol o g y pr o gra m was desi g ne d t o s u p p ort t his P hase 2 st u d y t o assess t he safet y, 
t olera bilit y, p har mac o ki n etics, a n d efficac y of C C X 1 6 8 i n s u bjects wit h A AV. I n t his re gar d, a 
c o m pre he nsi ve s afet y p h ar mac ol o g y a n d t o xic ol o g y pr o gra m has b ee n c o n d ucte d i n acc or da n ce 
wit h c urre nt I C H n o n cli nical t o xic ol o g y g ui da n ce (i ncl u di n g M 3( R 2) N o ncli nical Safet y St u dies 
f or t he C o n d uct of H u ma n Cli nical trials f or P har mace uticals; S 2( R 1) Ge n ot o xicit y Testi n g a n d 
Data I nter pretati o n f or P har mace uticals I nte n d e d f or H u ma n Us e, S 7 A Safet y P har m ac ol o g y 
St u dies f or H u ma n P har mace uticals, S 7 B N o n- Cli nical E val uati o n of t he P ote ntial f or Dela ye d 
Ve ntric ular Re p ol arizati o n ( Q T I nter v al Pr ol o n gati o n) b y H u ma n P har mace uticals, a n d S 8 
I m m u n ot o xicit y St u dies f or H u ma n P har mace uticals. T he s pecies selecte d f or t hese st u dies (rats 
a n d m o n ke ys) are w ell esta blis he d m o dels acce pte d b y re g ulat or y a ut h orities f or t o xic ol o g y 
st u dies a n d wer e select e d base d u p o n meta b olic, p har mac o ki netic, a n d p har mac ol o gi cal 
pr o perties of C C X 1 6 8 i n t hese s pecies; i nf or m ati o n gai n e d wit h t hese s pecies was e x pecte d t o be 
of pre dicti ve cli nical utilit y. C C X 1 6 8 - M 1, pres u m e d t o be t he o nl y maj or h u ma n meta b olite, was 
a p pr o priatel y q u alifie d i n b ot h t he rat a n d t he c y n o m ol g us m o n ke y; n o a d diti o nal maj or h u ma n 
meta b olites are a ntici p ate d base d o n e xisti n g e xte nsi ve i n vitr o a n d i n viv o d ata. A d diti o nall y, 
C C X 1 6 8 a n d C C X 1 6 8- M 1 are hi g hl y acti ve i n t he c y n o m ol g us m o n ke y w hic h i n dicate d t he 
latter s pecies s h o ul d be pre dicti ve of a n y t o xicit y relate d t o C 5a R i n hi biti o n. 
T he t o xic ol o g y st u dies ( oral a d mi nistrati o n) c o n d u cte d t o d ate i ncl u de a si n gle - d os e ac ute st u d y 
i n rats, d ose-r a n ge fi n di n g st u dies i n rats a n d c y n o m ol g us m o n ke ys, a n d G L P 2 8- da y a n d 1 3/ 2 0-
wee k st u dies i n rats a n d c y n o m ol g us m o n ke ys, res pecti vel y. T he defi niti ve 2 8- da y a n d 1 3/ 2 0-
wee k st u dies i n v ol ve d t h e a d mi nistrati o n of C C X 1 6 8 at dail y d oses u p t o 1 0 0 m g/ k g/ da y i n rats 
a n d u p t o 5 0 m g/ k g/ da y i n c y n o m ol g us m o n ke ys a n d i ncl u de d c o m pre h e nsi ve cli nical a n d  
o p ht hal m ol o gical e v al uati o ns, cli nical pat h ol o g y a n d t he micr osc o pic ass ess me nt of a f ull list of 
tiss ues. T he defi niti ve c y n o m ol g us st u dies i ncl u de d electr ocar di o gra p hic m eas ure m e nts. 
T o xic o ki netic data were als o c ollecte d i n t he m ulti ple - d ose rat a n d c y n o m ol g us st u dies. T he 
hi g hest d oses use d i n t he defi niti ve 1 3/ 2 0- wee k st u dies ( u p t o 1 0 0 a n d 3 0 m g/ k g/ da y, i n r ats a n d 
c y n o m ol g us m o n ke ys, r es pecti vel y) re prese nt e d H u ma n E q ui vale nt D oses ( H E D’s) of 1 5. 6 a n d 
1 1. 1 m g/ k g/ da y, res p ecti vel y.  
T he eff ects of C C X 1 6 8 u p o n t he ce ntral n er v o us, res pirat or y, re nal, a n d car di o vasc ular s yste ms 
were als o assesse d i n si n gle - d os e sta n d-al o ne safet y p har m ac ol o g y e x peri me nts i n rats a n d 
c y n o m ol g us m o n ke ys. I n vitr o st u dies t o assess t he p ote ntial effects of C C X 1 6 8 a n d C C X 1 6 8-
M 1 u p o n h E R G c ha n nel i o nic c o n d ucta nce was als o c o n d ucte d. A n assess me nt of C C X 1 6 8 
p ote ntial effects u p o n T- cell de pe n d e nt h u m oral res p o nses was perf or m e d i n t he rat. Wit h re gar d 
t o ge n ot o xicit y, i n vitr o bacterial (re v erse m utati o n i n histi di ne -re q uiri n g strai ns of S. 
ty p hi m uri u m a n d tr y pt o p ha n-re q uiri n g strai ns of E. c oli ) a n d ma m malia n ( m utati o n at t he 
t h y mi dine ki nase l oc us of m o use l y m p h o ma L 5 1 7 8 Y cells) m uta ge nicit y tests were perf or me d. 
A d diti o nall y, a n i n viv o r at b o ne marr o w micr o n u cle us test was als o perf or me d. 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 3 4 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
All t o xic ol o g y st u dies a n d safet y p har m ac ol o g y st u dies wit h t he e x ce pti o n of d ose a nal ys es 
per f or me d i n s u p p ort of t he ac ute rat t o xic ol o g y a n d C C X 1 6 8- M 1 h E R G st u dies were c o n d ucte d 
i n acc or d a nce wit h G L P re g ulati o ns. A s u m mar y of t he n o ncli nical t o xic ol o g y, ge n ot o xic ol o g y, 
a n d safet y p h ar mac ol o g y st u dies perf or me d i n s u p p ort of C C X 1 6 8 are d escri be d i n Ta ble 1 a n d 
Ta ble 2.  
T a ble 1: 
O ver vie w of T o xic ol o g y St u dies Perf or me d wit h C C X 1 6 8  
St u d y T y pe  
Met h o d of 
A d mi nistr ati o n/ D osi n g 
Sc he d ule  
S pecies  
D oses  
Ac ute  
Oral / Si n gle -D ose  
Rat  
0, 5, 2 5, 1 0 0 m g/ k g  
Re peat D ose  
Oral / 7 -Da y  
Rat  
0, 3 0, 1 0 0 m g/ k g  
 
Oral / 4 / ( 2) -d a y  
C y n o m ol g us m o n ke y  
3, 5 0, 6 5, ( 8 0), ( 1 2 0) 
m g/ k g  
 
Oral/ 2 8 -Da y   
Rat  
0, 5, 2 5, 1 0 0 m g/ k g  
 
Oral/ 2 8 -Da y  
C y n o m ol g us m o n ke y  
0, 5, 1 5,  5 0 m g/ k g  
 
Oral/ 1 3 -Wee k  
Rat  
0, 3, 1 5, 1 0 0 m g/ k g  
 
Oral/ 2 0 -Wee k  
C y n o m ol g us m o n ke y  
0, 5, 1 5, 3 0 m g/ k g  
Ge n ot o xicit y  
 
 
 
A mes  
N A  
S. ty p hi m uri u m  a n d 
tr y pt o p ha n-re q uiri n g 
strai ns of E. c oli  
U p t o 5 0 0 0 µ g/ plate  
M o use 
L y m p h o ma  
N A  
M o use l y m p h o ma 
cells 
U p t o 5 0 0 µ g/ m L  
Rat B o ne 
Marr o w 
Micr o n ucle us  
N A  
Rat  
0, 5 0 0, 1 0 0 0 a n d 2 0 0 0  
m g/ k g  
I m m u n ot o xicit y 
Oral/ 2 8 -Da y  
Rat  
0, 3, 1 5, 1 0 0 m g/ k g  
 
T a ble 2:  
O ver vie w of S af et y P h a r m ac ol o g y St u dies Perf or me d wit h C C X 1 6 8 
St u d y T y pe  
Met h o d of 
A d mi nistr ati o n/ D osi n g 
Sc he d ule  
S pecies  
D oses  
Ce ntral Ner v o us 
S yste m  
Oral/ Si n gle -D ose  
Rat  
0, 5, 2 5, 1 0 0 m g/ k g  
Res pirat or y  
Oral/ Si n gle -D ose  
Rat  
0, 5, 2 5, 1 0 0 m g/ k g  
Re nal  
Oral/ Si n gle -D ose  
Rat  
0, 5, 2 5, 1 0 0 m g/ k g  
Car di o vasc ular –  
I n viv o 
Oral/ Si n gle -D ose  
C y n o m ol g us m o n ke y  
0, 5, 1 5, 5 0 m g/ k g  
 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 3 5 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
T a ble 2:  
O ver vie w of S af et y P h a r m ac ol o g y St u dies Perf or me d wit h C C X 1 6 8 
( C o nti n ue d) 
Car di o vasc ular –  
I n vitr o ( hE R G  
wit h C C X 1 6 8) 
I n vitr o 
H u ma n cells 
tra nsfect e d wit h 
h u ma n K-c ha n nel 
ge n e  
0. 6, 1. 2, 2. 3 a n d 6. 9  µ M  
Car di o vasc ular –  
I n vitr o ( hE R G  
wit h C C X 1 6 8-
M 1 ) 
I n vitr o 
H u ma n cells 
tra nsfect e d wit h 
h u ma n K-c ha n nel 
ge n e  
1 , 3 , 1 0, a n d 1 5. 8  µ M  
T here w ere n o re mar ka bl e ce ntr al ner v o us or res pirat or y s yste m effects i n rats f oll o wi n g n o mi nal 
si n gle or al d oses u p t o 1 0 0 m g/ k g (act ual d ose of 7 3 m g/ k g c o nfir m e d b y d ose s ol uti o n a nal ysis), 
or re nal eff ects i n rats f oll o wi n g si n gle oral d oses u p t o 1 0 0 m g/ k g, or effects o n car di o vasc ular 
para meters i n c y n o m ol g us m o n ke ys f oll o wi n g si n gle oral d oses of u p t o 5 0 m g/ k g. A d diti o nall y, 
n o e vi de nce of electr ocar di o gra p hi c a b n or m alities was see n i n vi v o i n t he 2 8- da y a n d 2 0-wee k 
m ulti ple d ose st u dies i n c y n o m ol g us m o n ke ys. I n t he i n vitr o car di o vas c ular safet y st u dies, t he 
I C5 0 val ues f or h E R G i n hi biti o n f or C C X 1 6 8 a n d C C X 1 6 8-M 1 were d eter mi ne d t o be > 2. 3 µ M  
a n d 3 µ M (t he res pecti ve li mits of s ol u bilit y), f urt her i n dicati n g C C X 1 6 8 is u nli kel y t o ca us e 
arr h yt h m ias i n viv o. Pr ot ei n bi n di n g, re d bl o o d cell partiti o ni n g, he pat oc yt e meta b olis m, 
c yt o c hr o me P 4 5 0 i n hi biti o n a n d i n d ucti o n, effects of C C X 1 6 8 o n c ycl o p h os p ha mi de meta b olic 
acti vati o n a n d pre d nis o n e meta b olis m , Cac o- 2 per mea bilit y a n d ge n ot o xicit y st u dies, i ncl u di n g 
i n vitr o bacterial m uta ge nicit y ( A mes t est), i n vitr o ma m malia n cell m uta ge nicit y ( m o us e 
l y m p h o ma) st u dies, a n d i n viv o rat b o ne m arr o w micr o n ucle us test were als o c o n d ucte d a n d di d 
n ot i de ntif y a n y s afet y c o ncer ns or i n dicate a si g nifica nt ris k f or dr u g- dr u g i nteracti o ns wit h 
ot her c o nc urre nt me dicati o ns i n t he i nte n de d patie nt p o p ulati o n. I n a n ac ute t o xic ol o g y st u d y, 
si n gle d oses of C C X 1 6 8 u p t o 1 0 0 m g/ k g i n rats pr o d uce d n o re mar k a ble effects. I n a 2 8-da y 
i m m u n ot o xicit y st u d y i n rats, C C X 1 6 8 a d mi nistere d orall y at d oses u p t o 1 0 0 m g/ k g/ da y, di d n ot 
affect T-cell de pe n de nt a nti b o d y res p o ns es i n d uce d b y K L H. 
C C X 1 6 8 was well t olerat e d i n 2 8- da y st u dies u p t o d oses of 1 0 0 m g/ k g i n rats a n d 5 0 m g/ k g i n 
c y n o m ol g us m o n ke ys. T here w ere n o si g nifica nt t o xic ol o gical fi n di n gs of c o ncer n i n t hes e 
st u dies. At selecte d ti me p oi nts, mi n or b ut statisticall y si g nifica nt differe nces e xiste d i n selecte d 
cli nical pat h ol o g y p ara m eters bet w ee n c o ntr ol a n d C C X 1 6 8 treate d rats. T hese i ncl u de d a n 
i ncreas e i n retic ul oc ytes i n 1 0 0 m g/ k g/ da y rec o ver y- p h ase fe males, a n i n crease i n pr ot hr o m bi n 
ti me i n males gi ve n d oses > 2 5 m g/ k g/ da y a n d a mi ni mal i ncrease i n A L T le vels o n Da y 3 0 i n 
fe males a d mi nister e d 1 0 0 m g/ k g/ da y. T hes e differe nces were n ot clearl y test article-relate d a nd 
n ot c o nsi dere d t o be of t o xic ol o gical i m p orta nce b eca use of t heir s mall ma g nit u de, mea n a n d/ or 
i n di vi d ual val ues falli n g wit hi n t he ra n ge of n or m al varia bilit y a n d/ or re v ersi bilit y of t he fi n di n g 
f oll o wi n g a 2-wee k treat me nt -free peri o d. 
C C X 1 6 8 was als o well t olerate d i n a 1 3 - wee k st u d y i n rats u p t o d oses of 1 0 0 m g/ k g/ da y a n d i n 
a 2 0- wee k st u d y i n c y n o m ol g us m o n ke ys u p t o 3 0 m g/ k g/ da y. T here w ere n o si g nifica nt 
t o xic ol o gical fi n di n gs of c o ncer n i n t hes e st u dies. T he o nl y C C X 1 6 8-relate d cli nical o bser vatio n 
i n t he rat st u d y w as i nfre q ue nt sali vati o n, w hic h was n ote d i n t he mi d a n d hi g h d ose gr o u ps. 
T here w ere n o C C X 1 6 8 r elate d c h a n ges i n b o d y w ei g hts, f o o d c o ns u m pti o n, o p ht hal mic 
e x a mi nati o ns, he mat ol o g y, c o a g ulati o n, gr oss o bs er vati o ns, or ga n wei g hts, a n d micr osc o pic 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 3 6 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
e val uati o n. T her e were n o C C X 1 6 8- relate d effects o n cli nical c he mistr y at ter mi nati o n or 
rec o ver y. Ser u m A S T, A L T, a n d s or bit ol de h y dr o ge n ase w ere mil dl y i ncrease d i n t w o fe mal es at 
1 0 0 m g/ k g/ da y at ter mi n ati o n. Gi ve n t he ma g nit u de a n d l o w i nci de n ce of t hese fi n di n gs, t he y 
were c o nsi dere d i n ci de nt al. I n t h e m o n ke y st u d y, C C X 1 6 8 was well t olerat e d at d oses u p t o 3 0 
m g/ k g/ da y. T here w ere n o C C X 1 6 8-relate d c h a n ges i n cli nical o bser vati o ns, b o d y w ei g hts, 
o p ht hal mic e x a mi nati o ns, electr ocar di o gra p hic e x a mi nati o ns, bl o o d press ure, a n d res pirat or y 
e x a mi nati o ns, cli nical pat h ol o g y, gr oss o bser v ati o ns, or ga n wei g hts, a n d micr osc o pic e v al uati o n. 
Gi ve n t he lac k of si g nifica nt safet y c o n cer ns i n t he t o xic ol o g y st u dies a n d t he P hase 1 st u d y i n 
healt h y v ol u nt eers, a n d t he safet y r es ults fr o m cli nical trial C L 0 0 2 _ 1 6 8 s o far, t he ris k f or 
seri o us or u na ntici pate d u nt o war d e ve nts t o occ ur i n t his cli nical trial is c o nsi dere d l o w. 
1. 1. 3.  
N o n -Cli nic al A D M E  
T he p har mac o ki netic be h a vi or of C C X 1 6 8 has bee n assesse d i n fe m ale C D -1 mice, male 
S pra g u e -D a wle y r ats, male bea gle d o gs,  a n d m ale c y n o m ol g us m o n ke ys t hr o u g h i ntra v e n o us 
(i. v.) a n d/ or or al ( p. o.) d osi n g a n d t he d ata are s u m marize d i n Ta ble  3. F oll o wi n g i ntra v e n o us 
d osi n g, t he c o m p o u n d has a m o derate t o me di u m t otal b o d y cl eara nce i n mi ce, rats, a n d d o gs 
( 3 0 - 5 0 % of li ver bl o o d fl o w). T he ter mi nal eli mi nati o n half-life is m o derate t o l o n g, at ca. 2 h 
i n mice a n d rats, a n d 1 4. 2 h i n d o gs, w hile t he v ol u me of distri b uti o n is m o derate ( 1. 5, 2. 5, a n d 
4. 7 L/ k g f or mice, r ats a n d d o gs, r es pecti vel y). F oll o wi n g oral d osi n g i n mice a n d rats, C C X 1 6 8 
is rea dil y a bs or be d, s h o wi n g m o der ate bi oa vaila bilit y f or t he a q ue o us h y dr o x y pr o p yl 
met h ylcell ul ose ( H P M C) s us pe nsi o n a n d hi g h bi o a vaila bilit y f or t he P E G- 4 0 0/ S ol ut ol H S- 1 5 
s ol uti o n.   

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 3 7 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
T a ble 3:  
P h ar m a c o ki netic P ar a meters of C C X 1 6 8 i n C D- 1 Mice, S pr a g ue -D a wle y 
R ats, Be a gle D o gs, a n d C y n o m ol g us M o n ke ys after A d mi nistr ati o n of a 
Si n gle Or al G a v a ge or a n I ntr a ve n o us D ose of C C X 1 6 8 
a. I ntr a ve n o us d osi n g 
P ar a me t er 
M o use  
R at  
D o g  
d ose ( m g/ k g)  
0. 5  
0. 5  
0. 5  
F or m ul ati o n 
Et ha n ol / N, N -
di met h ylaceta mi de / 
pr o p yle n e gl yc ol / 
0. 9 % sali ne 
( 1 0: 1 0: 3 0: 7 5)  
N, N-
di met h ylaceta mi de / 
et ha n ol / pr o p yl e ne 
gl yc ol ( 3 1. 6: 3 6. 8: 3 1. 6) 
pr o p yle n e gl yc ol / 
N, N -
di met h ylaceta mi de / 
water ( 3 1. 6/ 3 1. 6/ 3 6. 8) 
N =  
9  a 
2  
3  
C L [ m L/ mi n/ k g]  
2 6. 6  
2 1. 2  
1 1. 9  
t1/ 2 [ h] 
1. 8  
1. 9  
1 4. 2  
V d ss [ L/ k g] 
1. 5  
1. 8  
4. 7  
a N o n -serial bl o o d sa m pli n g was use d a n d a c o m p osite P K pr ofile was o btai ne d usi n g t he mea n c o nce ntrati o n at 
eac h ti me p oi nt  
b. Or al d osi n g 
P ar a met er  
M o use  
R at  
M o n ke y  
p. o. d ose ( m g/ k g)  
2  
3 0  
2  
3 0  
1 0 0  
F or m ul ati o n 
1 % H P M C 
(s us pe nsi o n) 
P E G -
4 0 0/s ol ut ol 
H S - 1 5 
( 7 0: 3 0) 
(s ol uti o n) 
1 % H P M C 
(s us pe nsi o n) 
P E G -
4 0 0/ S ol ut ol 
H S - 1 5 
( 7 0: 3 0) 
(s ol uti o n) 
P E G - 4 0 0 / 
s ol ut ol H S-
1 5 ( 7 0: 3 0) 
(s ol uti o n) 
N =  
9  a 
9  a 
2  
3  
3  
C m a x  [ n g/ m L] 
7 5  
4 6 3 0  
1 5 2  
2 5 3 0  
3 5 0 0  
A U C [ n g• h/ m L]  
2 4 0  
1 8 6 0 0  
4 6 4  
2 4 6 0 0  
3 3 3 0 0  
t1/ 2 [ h] 
  
5. 6  
2. 3  
4. 6  
6. 0  
tm a x  [ h] 
1. 0  
1. 0  
1. 0  
1. 5  
4. 0  
F [ %]  
1 7  
8 7  
2 7  
1 0 4  
- 
C C X 1 6 8 dis pla ys m o d er ate i n vitr o meta b olic t ur n o ver i n cr y o- pres er ve d m o use, rat, a n d d o g 
he pat oc ytes a n d l o w t o m o derate t ur n o v er i n h u ma n he pat oc ytes. T his res ult ge n erall y c orrel ates 
well wit h t he o bser ve d i n viv o cleara n ce i n mice, rats , a n d d o gs a n d pre dicts a l o w t o m o derate 
clear a nce i n h u ma ns. I n vitr o meta b olis m of C C X 1 6 8 is pri maril y t hr o u g h m o n o h y dr o x ylati o n i n 
m o n ke y a n d h u ma n he p at oc ytes a n d t hr o u g h m o n o h y dr o x yl ati o n, deal k yl ati o n, a n d 
gl uc ur o ni d ati o n i n rat a n d d o g he p at oc ytes. A P hase I m o n o h y dr o x ylati o n meta b olite, C C X 1 6 8-
M 1, was f o u n d t o be a si g nifica nt circ ulati n g met a b olite i n h u ma n v ol u nteers i n t he P hase 1 
a N o n -serial bl o o d sa m pli n g was use d a n d a c o m p osite P K 
pr ofile was o btai ne d usi n g t he mea n c o nce ntrati o n at eac h 
ti me p oi nt. 
C L = t otal b o d y cleara nce  
t½  = ter mi nal half -life 
V d ss = v ol u me of distri b uti o n at stea d y state  
i. v. = i ntra ve n o us 
T ma x  = ti me of pea k c o nce ntrati o n  
p. o. = oral  
F = bi oa vaila bilit y  
C ma x  = ma xi m u m c o nce ntrati o n  
A U C = area u n der t he c o nce ntrati o n -vs. -ti me c ur ve 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 3 8 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
st u d y. Its e x p os ure was a de q uatel y c o v ere d i n rats a n d c y n o m ol g us m o n ke ys i n t he t o xic ol o g y 
st u dies t hat s u p p ort t he c urre nt P hase 2 cli nical trial.    
T he e x creti o n  pat h wa ys of C C X 1 6 8 i n a ni mals were i n vesti gate d i n bile-d uct ca n n ulate d 
S pra g u e - D a wle y r ats a n d i ntact c y n o m ol g us m o n k e ys. Neit her C C X 1 6 8 n or t he meta b olite 
C C X 1 6 8- M 1 is si g nifica ntl y e x crete d i nt o uri ne or bile i n rats or uri ne i n c y n o m ol g us m o n ke ys.  
T h e c o m p o u n d is ver y hi g hl y pr otei n b o u n d i n m o use, rat, d o g, a n d h u ma n plas ma, at 
a p pr o xi matel y 9 9 % or hi g her, wit h c orres p o n di n g u n b o u n d fracti o ns at a p pr o xi matel y 1 % or 
l o wer. C C X 1 6 8 has a l o w meta b olis m-me diate d dr u g - dr u g i nteracti o n p ote ntial as a per petrat or, 
as its i n hi biti o n a gai nst maj or h u ma n c yt oc hr o m e P 4 5 0 is of or ms is mi ni mal ( ne gli gi ble f or 
C Y P 1 A 2, 2 C 9, 2 C 1 9, a n d 2 D 6, a n d C Y P 3 A 4) a n d it s h o ws n o C Y P 3 A 4 a n d C Y P 2 B 6 i n d ucti o n 
p ote ntial at 1 0 μ M i n a h u ma n he pat oc yte c yt oc hr o me P 4 5 0 assa y. 
T he a bilit y of C C X 1 6 8 or C C X 1 6 8- M 1 t o i n hi bit t he ster oi d - meta b olizi n g e nz y mes 1 1 β-H S D 1 
a n d 1 1 β- H S D 2 was e val uate d usi n g s uita ble i n vitr o s yste ms a n d b ot h c o m p o u n ds were f o u n d t o 
be i nacti ve a gai nst t hese e nz y mes. C C X 1 6 8 was als o f o u n d t o ha ve n o i m pact o n t he u n b o u n d 
c o nce ntr ati o n of pre d nis o ne a n d pre d nis ol o ne i n h u ma n plas ma.  
F urt her m ore, neit her C C X 1 6 8 n or C C X 1 6 8- M 1 i nterfere s wit h t he a nti pr oliferati ve effects of 
c ycl op h os p ha mi de, w hic h is k n o w n t o re q uire C Y P- me diate d c o n versi o n t o a n acti ve meta b olite. 
T heref ore, C C X 1 6 8 has l o w p ote ntial f or i nterferi n g wit h t he bi ol o gical effects of eit her 
c ycl o p h os p ha mi de or c ortic oster oi ds. 
1. 2.  
Pri or H u m a n E x perie nce  
A P hase 1 st u d y i n 4 8 healt h y v ol u nteers has bee n c o m plete d. T his is a ra n d o mize d, d o u ble-
bli n d, place b o-c o ntr olle d, t w o- peri o d st u d y i n w hic h s u bjects recei ve d eit her C C X 1 6 8 or place b o 
( 3: 1 rati o) as a si n gle d os e i n Peri o d 1 a n d as m ulti ple o nce dail y or t wice d ail y d oses i n Peri o d 
2. Si n gle d oses of 1, 3, 1 0, 3 0, a n d 1 0 0 m g C C X 1 6 8 were st u die d, 6 s u bjects i n eac h d ose c o h ort 
recei v e d CC X 1 6 8 a n d 2 r ecei ve d pl ace b o, e x ce pt i n c o h ort 1 i n w hic h 5 s u bjects recei ve d 
C C X 1 6 8 a n d 3 recei ve d place b o. I n Peri o d 2, C C X 1 6 8 d oses of 1, 3, a n d 1 0 m g o nce dail y f or 7 
da ys, a n d 3 0 a n d 5 0 m g t wice dail y f or 7 d a ys, were st u die d.  
C C X 1 6 8 a p pear e d t o be well t olerate d b y st u d y s u bjects i n t his st u d y. N o seri o us a d vers e e v e nts 
or wit h dra wals d u e t o a d verse e v e nts ha ve b ee n o bser ve d. A s u m mar y  of all t he treat me nt -
e mer ge nt a d v erse e ve nts o bser ve d i n t he si n gle - d ose peri o d a n d t he m ulti- d ose peri o d of t he 
st u d y is pr o vi de d i n t he I n vesti gat or’s Br oc h ure. 
All a d verse e ve nts i n t he si n gle- d os e peri o d w ere mil d e x ce pt f or o ne A E of i njecti o n site 
p hle bitis i n t he 3 m g C C X 1 6 8 gr o u p a n d o ne of W B C c o u nt decrease i n t he 1 m g gr o u p t hat 
were c o nsi dere d m o d erat e i n i nte nsit y.  
T he m ost c o m m o n A E re p orte d i n s u bjects recei vi n g C C X 1 6 8 i n t he m ulti- d ose peri o d was 
hea dac he, r e p orte d i n 2 1 % of s u bjects recei vi n g C C X 1 6 8 c o m pare d t o 1 8 % i n t he place b o gr o u p. 
Diarr h oea ( 7 % vs. 9 % i n place b o), dizzi ness ( 7 % vs. 0 % i n place b o), l o w er a b d o mi nal pai n ( 7 % 
vs. 0 % i n place b o), n a usea ( 7 % vs. 0 % i n place b o), a n d or o p har y n geal pai n ( 7 % vs. 9 % i n 
place b o) w er e t he ot her m o re c o m m o nl y o bs er ve d A Es. T he o ne case of A S T a n d C P K ele vati o n 
was c o nsi der e d li kel y rel ate d t o stre n u o us e x ercis e a n d n ot c o nsi dere d rel ate d t o C C X 1 6 8. T he 
o ne s u bject wit h l o w W B C c o u nt i n t he 1 m g C C X 1 6 8 gr o u p was t he sa m e s u bject w h o ha d l o w 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 3 9 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
W B C d uri n g t he si n gle - d ose peri o d of t he st u d y. T he W B C c o u nt na dir was 2. 2 2 x 1 0 9/ L o n D a y 
4. N o cli nicall y si g nifica nt c ha n ges i n la b orat or y para meters, vital si g ns, or E C G para m eters 
were o bs er ve d. I n t he m ulti- d ose peri o d of t he st u d y, a sli g ht decrease i n mea n W B C a n d 
ne utr o p hil c o u nt was o bs er ve d i n s u bjects recei vi n g C C X 1 6 8 c o m pare d t o place b o. T hes e W B C 
a n d ne utr o p hil c o u nts m ost ofte n re mai ne d wit hi n t he refere n ce ra n ge, d ecreases w ere o bs er ve d 
wit hi n 1 t o 2 da ys aft er st art of d osi n g, a p peare d t o be m ost pr o n o u nce d i n s u bjects wit h baseli ne 
W B C a n d ne utr o p hil c o u nts at t he hi g her e n d of t h e n or mal ra n ge, a n d di d n ot a p pear t o 
pr o gressi vel y w ors e n o ver t he 7- da y d osi n g peri o d. O nl y a fe w s u bjects ha d W B C or ne utr o p hil 
c o u nts bel o w t he l o wer li mit of n or mal o ve r t he c o urse of t he st u d y, a n d t hese cases were 
o bser ve d i n b ot h C C X 1 6 8 a n d place b o gr o u ps. T h ese sli g ht c h a n ges i n W B C a n d ne utr o p hil 
c o u nts ma y b e rel ate d t o t he p har mac ol o g y of C C X 1 6 8 as a C 5a R bl oc ker.  
N o cli nicall y si g nifica nt c ha n ges i n la b orat or y para meters, vital si g ns, or E C G para meters were 
o bser ve d. K e y p har m ac o ki netic res ults ( mea n, S D) fr o m t he si n gle- d ose p eri o d a n d t he m ulti ple 
d ose peri o d of cli nical trial C L 0 0 1 _ 1 6 8 are pr o vi d e d i n t he I n vest i gat or’s Br oc h ure.  
F oll o wi n g a si n gle d ose of 1- 1 0 0 m g, m ea n e x p os ures as meas ure d b y A U C 0- i nf ra n ge d fr o m 6. 1 4 
t o 2 0 3 0 n g• hr/ m L w hile Cma x  ra n ge d fr o m 1. 8 4 t o 1 9 7 n g/ m L. T he a p pare nt mea n ter mi nal half-
life ra n ge d fr o m 1. 9 2 t o 7 1. 8 hr, w hile cleara n ce ra n ge d fr o m 5 1. 7 t o 1 9 5 L/ hr. 
F oll o wi n g a d mi nistrati o n at 1 t o 1 0 m g C C X 1 6 8 Q D f or 7 da ys, m ea n e x p os ures as meas ure d b y 
A U C 0- ta u ra n ge d fr o m 8. 7 2 t o 1 0 4 n g• hr/ m L o n Da y 1 a n d fr o m 1 1. 2 t o 1 7 8 n g• hr/ m L o n D a y 7, 
w hile C ma x  ra n ge d fr o m 2. 5 9 t o 1 9. 2 n g/ m L o n Da y 1 a n d 2. 8 6 t o 3 1. 4 n g/ m L o n D a y 7.    
F oll o wi n g BI D a d mi nistrati o n at 3 0 t o 5 0 m g, mea n e x p os ures as meas ure d b y A U C 0- ta u ra n ge d 
fr o m 3 8 0 t o 1 4 0 0 n g• hr/ m L o n D a y 1 a n d fr o m 8 8 0 t o 2 3 4 0 n g• hr/ m L o n Da y 7, w hile Cma x 
ra n ge d fr o m 9 7. 2 t o 4 2 3 n g/ m L o n Da y 1 a n d 1 6 1 t o 4 2 5 n g/ m L o n Da y 7.  
C C X 1 6 8 le vels decli ne d i n a bi p hasic e x p o ne ntial ma n ner, wit h a ra pi d distri b uti o n p hase a n d a n 
a p pare nt mea n plas ma ter mi nal t 1/ 2 ra n gi n g fr o m 1 2. 2 t o 1 6 2 hr f oll o wi n g o nce dail y 
a d mi nistrati o n.  
Re peat a d mi nistrati o n f or se ve n da ys of C C X 1 6 8 res ulte d i n m o derate acc u m ulati o n (at 1 a n d 3 
m g Q D) or hi g h acc u m ulati o n ( 1 0 m g Q D or 3 0 – 5 0 m g BI D) of C C X 1 6 8, c o nsiste nt wit h t he 
o bser ve d ter mi nal h alf -lif e i n t hese d osi n g gr o u ps. After Q D d osi n g, t he e x p os ure of C C X 1 6 8 as 
meas ur e d b y C ma x  a n d A U C is a p pr o xi matel y d os e pr o p orti o nal i n t he 1 – 1 0 m g d ose ra n ge. 
After BI D d osi n g, t he e x p os ure i ncrease of C C X 1 6 8 statisticall y a p pears t o be li nearl y 
pr o p orti o nal f or 3 0 m g a n d 5 0 m g d oses. Base d o n t he meas ure d tr o u g h c o nce ntrati o ns, i n 
ge n eral, C C X 1 6 8 a p p ear e d t o reac h stea d y state after 3 - 4 da ys of d osi n g. 
F o o d effect w as als o i n vesti gate d b y c o m p ari n g t h e Da y 7 0 - 1 2 h (faste d) a n d 1 2-2 4 h (fe d) 
para meters. N o si g nifica nt effects wer e see n i n eit her d ose gr o u p.  
C C X 1 6 8- M 1, a m o n o h y dr o x ylati o n meta b olite of C C X 1 6 8, was f o u n d t o be a maj or circ ulati n g 
meta b olite i n h u ma ns. F oll o wi n g 7 da ys of oral a d mi nistrati o n of C C X 1 6 8 at 3 0 m g a n d 5 0 m g 
BI D, t he A U C 0- 2 4 f or C C X 1 6 8- M 1 was 1 6 0 0 a n d 2 3 4 0 n g• hr/ m L, res pecti v el y. T h ese val u es 
re pres e nt 8 5 % a n d 5 2 %, res pecti vel y, of t h e le vels of C C X 1 6 8 meas ure d at t h ose d oses. Its 
e x p os ure was a de q u atel y c o vere d i n rats a n d c y n o m ol g us m o n ke ys i n t he t o xic ol o g y st u dies t hat 
s u p p ort t his P hase 2 cli nical trial. 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 4 0 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
Cli nical trial C L 0 0 2 _ 1 6 8 i n patie nts wit h A A V is o n g oi n g. T his is a ra n d o mize d, d o u ble- bli n d, 
place b o - c o ntr olle d cli nical trial bei n g c o n d ucte d i n t hree se q u e ntial ste ps. A t otal of 2 6 s u bjects 
ha ve bee n e nr olle d i n t he first t w o ste ps of t his cli nical trial. A s u m mar y of t he safet y a n d 
efficac y r es ults , as well as t he P K res ults  fr o m t he first t w o ste ps are pr o vi de d i n t he 
I n v esti gat or’s Br oc h ure.  
1. 3.  
R ati o n ale f or t he St u d y  
A A V sta n dar d t h era p y i n cl u des c ycl o p h os p ha mi d e (I V or oral, alt h o u g h I V is preferre d b eca us e 
of a l o wer c u m ulati ve d ose  a n d l o wer t o xicit y) or I V rit u xi ma b, pl us oral c ortic oster oi ds, ta pere d 
o ver a peri o d of ti me. Se vere disease warra nts a d diti o n of I V c ortic oster oi ds a n d/ or plas ma 
e x c ha n ge. T her e ar e u n m et nee ds t o s h orte n t he ti me t o re missi o n, i m pr o ve c o m plete re missi o n 
rates a nd r e d uce c ortic ost er oi d e x p os ure. 
Base d o n e nc o ura gi n g res ults fr o m precli nical st u dies i n a h u ma n C 5a R k n oc k-i n m o use m o del 
of A N C A -i n d uce d gl o mer ul o ne p hritis ( descri b e d i n S ecti o n 1. 1. 1. 2 , as well as t he I n vesti gat or’s 
Br oc h ure ), as well as res ults fr o m t he first t w o ste ps of st u d y C L 0 0 2 _ 1 6 8 (see I n vesti gat or’s 
Br oc h ure) , C C X 1 6 8 c o ul d offer b e nefit i n t he treat me nt of patie nts wit h A A V.  
A si n gle d ose re gi me n of 3 0 m g C C X 1 6 8 gi v e n t wice dail y is bei n g teste d i n st u d y C L 0 0 2 _ 1 6 8. 
N o assess me nt of ot her C C X 1 6 8 d ose re gi me ns has bee n ma de t o dat e. He n ce, t he rati o nale f or 
t his cli nical trial is t o e val uate safet y a n d efficac y of a n ot her d os e re gi me n, 1 0 mg C C X 1 6 8 
t wice dail y, i n patie nts wit h A A V. Bas e d o n P K-P D m o deli n g, t his l o wer d ose re gi me n ma y als o 
pr o vi de effi cac y.  
C C X 1 6 8 will be gi ve n o n t o p of sta n dar d of care ( S O C), i.e., eit her c ycl o p h os p ha mi de or 
rit u xi ma b pl us gl uc oc orti c oi ds. 
2.  
O B J E C TI V E S 
2. 1.  
Pri m ar y O bjecti ve  
T he pri mar y safet y o bjecti ve of t his st u d y is t o e v al uate t he safet y a n d t olera bilit y of C C X 1 6 8 i n 
s u bjects wit h A A V o n S O C c ycl o p h os p ha mi de or rit u xi ma b pl us c ortic oster oi d treat me nt.  
T he pri mar y efficac y o bj ecti ve is t o e val uate t h e ef ficac y of C C X 1 6 8 base d o n t he Bir mi n g ha m 
Vasc ulitis Acti vit y Sc ore ( B V A S)  i n s u bjects wit h A A V o n S O C  c ycl o p h os p ha mi de or rit u xi ma b 
pl us c ortic oster oi d treat m e nt. 
2. 2.  
Sec o n d ar y O bjecti ves  
T he sec o n d ar y o bjecti ves of t he st u d y i ncl u d e t he f oll o wi n g: 
1.  E val uati o n of t he efficac y of C C X 1 6 8 c o m p are d t o S O C  base d o n c ha n ges i n re nal disease 
acti vit y para meters:  
a. e G F R ( M D R D s er u m cr eati ni ne e q uati o n);  
b.  He mat uria ( ce ntr al la b or at or y micr osc o pic c o u nt of uri nar y R B Cs); a n d 
c. Al b u mi n uria (first m or ni n g uri nar y al b u mi n:creati ni ne rati o);  

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 4 1 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
2.  Assess me nt of c ha n ges i n re nal i nfla m mat or y acti vit y base d o n uri nar y m o n oc yt e 
c he m oattracta nt pr otei n - 1 ( M C P 1):creati ni ne rati o a n d ser u m C-reacti ve pr otei n 
c o nce ntr ati o n wit h C C X 1 6 8 c o m pare d t o S O C ; 
3.  Assess me nt of healt h -rel ate d q ualit y- of-life c ha n ges base d o n S h ort F or m- 3 6 versi o n 2 ( S F-
3 6 v 2) a n d E ur o Q O L- 5 D- 5 L ( E Q - 5 D- 5 L) wit h C C X 1 6 8 c o m pare d t o S O C ; 
4.  Assess me nt of c ha n ges i n Vasc ulitis Da ma ge I n d e x ( V DI) wit h C C X 1 6 8 c o m pare d t o S O C ; 
5.  Assess me nt of c ha n ges i n A N C A (a nti - P R 3 a n d a nti- M P O) wit h C C X 1 6 8 c o m pare d t o S O C ; 
6.  Assess me nt of c ha n ges i n p har mac o d y n a mic mar kers i n plas ma a n d uri n e wit h C C X 1 6 8 
c o m pare d t o S O C ; 
7.  E val uati o n of t he p har m ac o ki netic pr ofile of C C X 1 6 8 i n s u bjects wit h A A V. 
3.  
S T U D Y D E SI G N  
A A V st a n dar d t h era p y i n cl u des c ycl o p h os p ha mi d e or rit u xi ma b  a n d oral c ortic oster oi ds, ta pere d 
o ver a peri o d of ti me. Se vere disease warra nts a d diti o n of I V c ortic oster oi ds a n d/ or plas ma 
e x c ha n ge. Base d o n c o m pelli n g res ults fr o m precli nical st u dies i n a m o use m o del of A N C A -
i n d uce d gl o mer ul o ne p hritis, as well as earl y res ults fr o m a n ot her cli nical trial i n patie nts wit h 
A A V ( C L 0 0 2 _ 1 6 8 ), C C X 1 6 8 has p ote ntial i n t he treat me nt of patie nts wit h A A V. A C C X 1 6 8 
d ose re gi me n of 3 0 m g t wice dail y has bee n teste d i n st u d y C L 0 0 2 _ 1 6 8. N o ot her d ose has b ee n 
teste d pre vi o usl y i n A A V. He nce, t he cli nical h y p ot hesis of t he trial is t o test w het her a l o wer 
d ose of C C X 1 6 8, i.e., 1 0 m g t wice d ail y as a n alter nati ve t o  3 0 m g t wice dail y re gi me n is safe 
a n d effi caci o us i n patie nts wit h A A V recei vi n g S O C c ycl o p h os p ha mi de or rit u xi ma b pl us 
c ortic oster oi ds. T his h y p ot hesis will be teste d i n t his ra n d o mize d, d o u ble- bli n d, place b o-
c o ntr olle d, P hase 2 cli nical trial i n u p t o a p pr o xi matel y 4 5 s u bjects wit h ne w or rela ps e d A A V. 
A n e xter nal data m o nit ori n g c o m mittee ( D M C) will re vie w safet y d ata, i ncl u di n g res c ue 
c ortic oster oi d use o v er t h e c o urse of t he st u d y a n d a d vise t he S p o ns or re gar di n g t he st u d y. 
U p t o a p pr o xi matel y 4 5 s u bjects will be stratifie d pri or t o ra n d o mizati o n base d o n t he f oll o wi n g 
stratificati o n fact ors: 
1.  Eit her ne wl y dia g n ose d A A V or r ela pse d A A V; 
2.  Eit her M P O or P R 3 A N C A p ositi vit y; 
3.  Will recei ve eit her c ycl o p h os p ha mi de or rit u xi ma b as part of S O C treat me nt.  
F oll o wi n g str atificati o n, s u bjects will be ra n d o mize d 1: 1: 1 t o o ne of t hree gr o u ps: 
Gr o u p A: C C X 1 6 8 1 0 m g t wice dail y pl us c ycl o p h os p ha mi de/rit u xi ma b pl us c ortic oster oi ds; 
Gr o u p B: C C X 1 6 8 3 0 m g t wice dail y pl us c ycl o p h os p ha mi de/rit u xi ma b pl us c ortic oster oi ds; 
Gr o u p C: Place b o t wice dail y pl us c ycl o p h os p h a mi de/rit u xi ma b pl us c ortic oster oi ds.  
If necessar y, resc u e c orti c oster oi ds s h o ul d be gi ve n t o s u bjects wit h w orse ni n g diseas e. 
F oll o wi n g t he 8 4- da y d osi n g peri o d, t here will be a n 8 4- da y f oll o w- u p peri o d. A ll s u bjects will 
visit t he st u d y ce nter d uri n g t he scree ni n g p eri o d, a n d o n Da ys 1, 2, 8, 1 5, 2 2, 2 9, 4 3, 5 7, 7 1, 8 5, 
9 9, 1 1 3, 1 4 1, a n d 1 6 9. S u bjects will n ot ta ke st u d y me dicati o n i n t he m or ni n g of t he d a ys of 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 4 2 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
visits t o t he st u d y ce nter, a n d will be i nstr ucte d t o ta ke t he me dicati o n w hile at t he st u d y ce nter. 
F or t he ot her st u d y d a ys, st u d y me dicati o n will be ta ke n at h o me i n t he m or ni n g wit hi n 1 h o ur 
after br ea kfast a n d i n t he e ve ni n g wit hi n 1 h o ur aft er di n ner. 
T he scree ni n g peri o d will be ke pt as s h ort as p ossi ble i n or der n ot t o dela y i nitiati o n of treat me nt. 
T he scree ni n g peri o d m ust n ot e x cee d 1 4 da ys. Scree ni n g pr o ce d ures will i ncl u de de m o gra p hi cs, 
me dical hist or y, m e dicati o n hist or y, p h ysical e x a mi nati o n a n d vital si g ns, ser u m c he mistr y, 
he mat ol o g y, uri n al ysis (i ncl u di n g he m at uria, pr ot ei n uria), E C G, c h est X ra ys, viral s cree ni n g, 
ser ol o g y a n d c o m ple me nt meas ure me nts (if n ot d o ne wit hi n t he pre vi o us 1 2 m o nt hs), esti mate d 
gl o mer ular filtrati o n rat e (e G F R) assess me nt  ( M D R D), A N C A meas ure me nt (i n direct 
i m m u n ofl u oresce nce test f or P-A N C A a n d C -A N C A, as well as E LI S A tests f or a nti - P R 3 a n d 
a nti- M P O), re nal bi o ps y (if perf or me d), a n d B V A S assess me nt. T o e x pe dite t he scree ni n g 
pr ocess, bl o o d a n d uri n e tests will be d o ne at t he l ocal la b orat ories f or t he Scre e ni n g visit. 
La b orat or y res ults fr o m t he l ocal la b or at ories o btai ne d wit hi n 7 2 h o urs of scree ni n g are 
acce pta ble i n or der t o a v oi d u n necessar y bl o o d dra ws. Eli gi ble s u bjects m ust be A N C A- p ositi ve 
a n d m ust ha ve at least o n e “ maj or” ite m, or at least 3 n o n- m aj or ite ms, or at least 2 re nal ite ms 
o n t he B V A S versi o n 3 (see S ecti o n 1 1. 3 ).  
Eli gi ble s u bjects will visit t he st u d y ce nt er o n D a y 1, after a n o ve r ni g ht fast of at least 8 h o urs, 
f or p h ysical e x a mi nati o n a n d vital si g ns, ser u m c h e mistr y, he m at ol o g y, uri nal ysis (i ncl u di n g 
he mat uria, pr otei n uri a [ A C R], a n d M C P- 1:creati ni ne rati o assess me nt), e G F R, A N C A 
meas ure me nt ( a nti - P R 3 a n d a nti-M P O), a B V A S a n d V DI assess me nt, S F - 3 6 v 2 a n d E Q- 5 D-5 L 
assess me nt, hs C R P, baseli ne p har mac o ki netics a n d p har mac o d y n a mics ( P K/ P D) bl o o d sa m ple 
c ollecti o n, a n d ra n d o mizati o n. Me dicati o n will be a d mi nistere d (I V) a n d dis pe nse d (f or oral 
me dicati o ns). T he s u bjects will ta ke t he first d ose of C C X 1 6 8 or place b o, a n d pre d nis o ne w hile 
at t he st u d y ce nter. T h e s u bjects will sta y at t he cli nic f or at least 6 h o urs aft er t he first d ose o n 
Da y 1 f or s afet y o bser vati o n a n d P K sa m ple c ollecti o n. A s u bject c o ul d be ke pt o ver ni g ht i n t he 
h os pital o n Da y 1, if n ecessar y. T his h os pital sta y w o ul d n ot be c o nsi dere d a seri o us a d v erse 
e ve nt, u nless ot her S A E criteria are met.  
T wice dail y d osi n g of C C X 1 6 8 or place b o will c o nti n ue f or 8 4 da ys. At p ost- Da y 1 st u d y visits, 
st u d y me dicati o n will be a d mi nistere d acc or di n g t o t he pr ot oc ol sc he d ule, bl o o d a n d uri ne 
sa m ples will be c ollecte d f or saf et y a n d efficac y a n d P K/ P D meas ure me nts. B V A S assess me nts 
will be ma de o n Da ys 1, 2 9, 8 5, 1 1 3, a n d 1 6 9. V DI assess me nt will be ma d e o n Da ys 1, 8 5, a n d 
1 6 9. S F- 3 6 v 2 a n d E Q- 5 D - 5 L i nstr u me nts will be c o m plete d o n Da ys 1, 2 9, 8 5, a n d 1 6 9. P h ysical 
e x a mi nati o ns, b o d y s yste m re vie ws, a n d vital si g n assess me nts will be perf or me d t hr o u g h o ut t he 
st u d y. C o nc o mita nt me dicati o n a n d a d v erse e ve nt assess me nts will be ma de at e ver y st u d y visit.  
S u bjects will be disc har ge d fr o m t he st u d y w he n all t he St u d y D a y 1 6 9 visit pr oce d ures ha ve 
bee n c o m plete d. T h e s u bject’s c o n diti o n will be e val uate d b y t he I n v esti gat or at t he e n d of t he 
cli nical trial ( Da y 1 6 9) a n d a p pr o priate S O C me dical treat me nt will be pr o vi de d t o all s u bjects as 
nee de d.  
T o t he e xte nt p ossi ble, a n y a d v erse e ve nts t hat are dee me d st u d y dr u g -rel ate d a n d are o n g oi n g at 
disc har ge will be f oll o w e d - u p t o res ol uti o n or u ntil a deter mi nati o n is ma de t hat t he u nres ol ve d 
e ve nt is sta ble. 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 4 3 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
4.  
S T U D Y P O P U L A TI O N  
4. 1.  
Size of t he P o p ul ati o n  
T he  ai m is t o e nr oll u p t o a p pr oxi matel y f ort y fi v e ( 4 5) s u bjects f or t h e st u d y. S u bjects w h o dr o p 
o ut of t he st u d y pr e mat ur el y will n ot be re place d.  
4. 2.  
I ncl usi o n Criteri a 
S u bjects m ust meet all of t he f oll o wi n g i ncl usi o n criteria i n or der t o e nter t h e st u d y:  
1.  Cli nical dia g n osis of gra n ul o mat osis wit h p ol ya n giitis ( We ge ner's), micr osc o pic p ol ya n giitis 
or re nal li mite d vasc ulitis, c o nsiste nt wit h C ha pel  Hill c o nse ns us defi niti o ns (Je n nette et al., 
2 0 1 3);  
2.  Male a n d f e male s u bjects, a ge d at least 1 8 years, wit h ne w ( t y picall y wit hi n 4 wee ks pri or t o 
scree ni n g) or rel a pse d A A V w her e treat me nt wit h c ycl o p h os p ha mi de or rit u xi ma b w o ul d be 
re q uire d; Fe male s u bjects of c hil d beari n g p ote ntial ma y partici pate if a d e q u ate c o ntrace pti o n 
is use d d uri n g t he st u d y, a n d f or at least 6 m o nt hs after t he l ast c ycl o p h os p ha mi de d ose (if 
recei vi n g c ycl o p h os p ha mi de) a n d at least 1 2 m o nt hs after t he last rit u xi ma b d ose (if 
recei vi n g rit u xi ma b); Male s u bjects wit h part ners of c hil d beari n g p ote ntial ma y p artici pate i n 
t he st u d y if t he y h a d a vasect o m y at least 6 m o nt hs pri or t o ra n d o mizati o n or if a de q u ate 
c o ntrace pti o n is use d d uri n g t he st u d y, a n d f or at l east 6 m o nt hs after t he l ast 
c ycl o p h os p ha mi de d ose (if recei vi n g c ycl o p h os p h a mi de) a n d at least 1 2 m o nt hs after t he last 
rit u xi ma b d ose (if recei vi n g rit u xi ma b); A de q uate c o ntrace pti o n is defi ne d as o ne hi g hl y 
effecti ve met h o d pl us o ne eff ecti ve met h o d; hi g hl y effecti ve met h o ds i ncl u de h or m o nal 
c o ntrace pti ves,  e. g., c o m bi ne d oral c o ntrace pti ves, patc h, va gi nal ri n g, i njecta bles, a n d 
i m pla nts; i ntra uteri ne de vice or i ntra uteri ne s yste m; vasect o m y a n d t u bal li gati o n; effecti ve 
met h o ds i ncl u de barrier met h o ds of c o ntrace pti o n, e. g., m ale c o n d o m, fe male c o n d o m, 
cervical ca p, dia p hra g m, c o ntrace pti ve s p o n ge pl us a s per mici de; 
3.  P ositi ve i n direct i m m u n ofl u oresce n ce (II F) test f or P -A N C A or C - A N C A, or p ositi ve E LI S A 
test f or a nti- pr otei nas e- 3 ( P R 3) or a nti-m yel o p er o xi dase ( M P O) at scree ni n g; If o nl y t he II F 
assa y is p osi ti ve at scree ni n g, a n d n o n e of t he E LI S A tests, t here m ust be d oc u me ntati o n i n 
t he st u d y r ec or ds of a p ositi ve E LI S A ass a y i n t he past;  
4.  Ha ve at least o ne " maj or" ite m, or at least 3 n o n- maj or ite ms, or at least 2 re nal ite ms o n t he 
B V A S versi o n 3 (s ee Sec ti o n 1 1. 3 ); 
5.  Esti mate d gl o mer ular filtrati o n rate ≥ 2 0 m L per mi n ute per 1. 7 3 m 2 ( M D R D); 
6.  Willi n g a n d a ble t o gi ve writte n I nf or me d C o nse nt a n d t o c o m pl y wit h t he re q uire me nts of 
t he st u d y pr ot oc ol; a n d 
7.  J u d ge d t o be ot her wise h ealt h y b y t h e I n vesti gat or, base d o n me dical hist or y, p h ysical 
e x a mi nati o n (i ncl u di n g electr ocar di o gra m [ E C G]), a n d cli nical la b orat or y assess me nts. 
S u bjects wit h cli nical la b o rat or y val ues t hat are o utsi de of n or mal li mits ( ot her t ha n t h ose 
s pecifie d i n t he E x cl usi o n Criteria) a n d/ or wit h ot her a b n or m al cli nical fi n di n gs t hat are 
j u d ge d b y t he I n vesti gat or n ot t o be of cli nical si g nifica nce, m a y be e nt ere d i nt o t he st u d y. 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 4 4 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
4. 3.  
E xcl u si o n Criteri a 
1.  Se vere disease as d eter mi ne d b y r a pi dl y pr o gressi ve gl o mer ul o ne p hritis s uc h t hat 
c o m me nce me nt of re n al re place me nt t hera p y c o ul d be a ntici pate d wit hi n 7 da ys, or al ve olar 
he m orr ha ge lea di n g t o Gra de 3 or hi g h er h y p o xia (i.e., decreas e d o x y ge n s at urati o n at rest, 
e. g., p uls e o xi meter < 8 8 % or P aO 2 ≤5 5 m m H g); 
2.  W o me n w h o are pr e g na nt ( p ositi ve pre g n a nc y test) or breastfee di n g at st u d y e ntr y; w o me n 
s h o ul d n ot breastfee d d uri n g t he st u d y, a n d if recei vi n g rit u xi ma b, u ntil dr u g le v els are n o 
l o n ger detect a ble aft er st u d y c o m pleti o n;  
3.  A n y ot her m ulti -s yste m a ut oi m m u ne disease i ncl u di n g e osi n o p hilic gra n ul o mat osis wit h 
p ol ya n giitis ( C h ur g Stra uss), s yste mic l u p us er yt h e mat os us, I g A vasc ulitis ( He n oc h-
Sc h ö nlei n p ur p ura), r he u mat oi d vasc ulitis, Sj ö gre n's d iseas e, a nti-gl o mer ul ar base m e nt 
me m bra ne disease, or cr y o gl o b uli ne mia; 
4.  Me dical hist or y of c o a g ul o pat h y or blee di n g dis or der; 
5.  Recei ve d c ycl o p h os p ha mi de wit hi n 1 2 wee ks pri or t o scree ni n g; if o n azat hi o pri ne, 
m yc o p h e n olate m ofetil, or met h otre x ate at t he ti me of scree ni n g, t hese dr u gs m ust be 
wit h dra w n pri or t o r ecei vi n g t he c ycl o p h os p ha mi de or rit u xi ma b d ose o n Da y 1;  
6.  Recei ve d i ntra v e n o us c ortic oster oi ds, > 3 0 0 0 m g m et h yl pre d nis ol o ne e q ui vale nt, wit hi n 1 2 
wee ks pri or t o scree ni n g; 
7.  Ha ve bee n ta ki n g a n or al d ail y d ose of a c ortic oster oi d of m ore t ha n 1 0 m g pre d nis o ne-
e q ui vale nt f or m or e t ha n 6 wee ks c o nti n u o usl y pri or t o t he scree ni n g visit. If o n 
c ortic oster oi d s at t he ti me of scr ee ni n g, t he n o n-st u d y s u p plie d c ortic oster oi ds will be 
st o p pe d w he n t he s u bject starts ta ki n g t he st u d y s u p plie d 6 0 m g pre d nis o n e d ose o n Da y 1; 
8.  Recei ve d rit u xi ma b or ot her B-cell a nti b o d y wit hi n 5 2 wee ks of s cree ni n g or 2 6 wee ks 
pr o vi de d B cell rec o nstit uti o n has occ urre d (i.e., C D 1 9 c o u nt > 0. 0 1 x 1 0 9/ L); recei ve d a nti-
T N F treat me nt, a bat ace pt, ale mt uz u ma b, I VI g, beli m u ma b, t ociliz u ma b, or plas ma e x c ha n ge 
wit hi n 1 2 wee ks pri or t o scree ni n g; 
9.  S y m pt o matic c o n gesti ve heart f ail ure re q uiri n g prescri pti o n me dicati o n, cli nicall y e vi de nt 
peri p her al e de ma of car diac ori gi n, p o orl y-c o ntr olle d h y p erte nsi o n (s yst olic bl o o d press ure 
> 1 6 0 or diast olic bl o o d press ure > 1 0 0), hist or y of u nsta ble a n gi na, m y ocar dial i nfarcti o n or 
str o ke wit hi n 6 m o nt hs pri or t o scree ni n g; 
1 0.  Hist or y or prese n ce of a n y f or m of ca n cer wit hi n t he 5 years pri or t o scree ni n g, wit h t he 
e x ce pti o n of e x cise d basal cell or s q ua m o us cell carci n o ma of t h e s ki n, or cer vical carci n o ma 
i n sit u or breast car ci n o ma i n sit u t hat has bee n e x cise d or res ecte d c o m plet el y a n d is wit h o ut 
e vi de nce of l ocal r ec urre nce or metast asis;  
1 1.  E vi de nce of t u b erc ul osis base d o n c hest X ra ys perf or me d d uri n g s cree ni n g as part of t he 
B V A S assess me nt;  
1 2.  P ositi ve H B V, H C V, or HI V viral scree ni n g test;  
1 3.  A n y i nf ecti o n re q uiri n g a nti bi otic treat me nt wit hi n 4 wee ks pri or t o scree ni n g (e x ce pt f or 
pr o p h ylactic treat me nt f or  P ne u m ocystis c ari nii  p ne u m o nia [ P C P] or treat me nt f or s us pecte d 
i nfecti o n t hat i nstea d t ur ns o ut t o be a c o nse q ue n ce of A N C A vasc ulitis, e. g., p ne u m o nitis); 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 4 5 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
1 4.  Recei ve d a li ve v acci ne wit hi n 4 wee ks pri or t o s cree ni n g;  
1 5.  W B C c o u nt less t ha n 4 0 0 0/ μ L, or ne utr o p hil c o u nt less t ha n 2 0 0 0/ μ L, or l y m p h oc yte c o u nt 
less t ha n 1 0 0 0/ μ L; 
1 6.  He m o gl o bi n less t ha n 9 g/ d L ( or 5. 5 6 m m ol/ L) at s cree ni n g; 
1 7.  E vi de nce of h e patic disease; A S T, A L T, al kali ne p h os p hatase, or bilir u bi n > 3 x t he u p per 
li mit of n or mal; 
1 8.  Pr ot hr o m bi n ti me ( P T) or partial t hr o m b o plasti n ti me ( P T T) a b o ve t he n or mal refere nce 
li mit; 
1 9.  Cli nicall y si g nifica nt a b n or mal E C G d uri n g s cree ni n g, e. g., Q Tc F greater t ha n 4 5 0 msec; 
2 0.  Partici pate d i n a n y cli nical st u d y of a n i n vesti gati o nal pr o d uct wit hi n 3 0 da ys pri or t o 
scree ni ng or wit hi n 5 half- li ves after ta ki n g t he last d ose;  
2 1.  K n o w n h y p erse nsiti vit y t o C C X 1 6 8 or i nacti ve i n gre die nts of t he C C X 1 6 8 ca ps ules 
(i ncl u di n g gel ati n, p ol yet h yle n e gl yc ol, or Cre m o p h or), c ycl o p h os p h a mi de or its meta b olites 
(f or s u bjects sc h e d ule d t o recei v e c ycl o p h os p h a mi de), or k n o w n T y p e I h y perse nsiti vit y or 
a na p h ylactic reacti o ns t o m uri ne pr otei ns, C hi nese Ha mster O var y cell pr otei ns, or t o a n y 
c o m p o ne nt of rit u xi ma b (f or s u bjects sc h e d ule d t o recei v e rit u xi ma b),  
2 2.  Uri nar y o utfl o w o bstr u cti o n, acti ve i nfecti o n ( es peciall y v aricell a z oster  i nfecti o n), or 
platelet c o u nt < 5 0, 0 0 0/ μ L (f or s u bjects s c he d ule d t o recei ve c ycl o p h os p ha mi de treat me nt), 
a n d 
2 3.  Hist or y or prese n ce of a n y me dical c o n diti o n or disease w hic h, i n t he o pi ni o n of t he 
I n v esti gat or, ma y place t he s u bject at u nacce pt a ble ris k f or st u d y partici p ati o n . 
4. 4.  
Re m o v al of S u bjects fr o m T her a p y of Assess me nt  
S u bjects ma y be t er mi nat e d earl y fr o m t he st u d y f or a n y of t he f oll o wi n g reas o ns: 
1.  S u bject re q uest:  S u bjects ma y wit h dra w t heir c o nse nt t o partic i pate i n t he st u d y at a n y ti me 
wit h o ut prej u dice.   
2.  I n v esti gat or re q u est:  T he I n vesti gat or ma y wit h dra w a s u bject if, i n his/ her cli nical 
j u d g me nt, it is i n t he best i nterest of t he s u bject or if t he s u bject ca n n ot c o m pl y wit h t he 
pr ot oc ol.   
3.  S p o ns or re q u est.  
If a s u bject d e vel o ps gra de t w o or w ors e le u k o pe nia ( W B C < 3 x 1 09/ L) O R a n a bs ol ute 
ne utr o p hil c o u nt < 1 x 1 0 9/ L, d osi n g wit h C C X 1 6 8 or place b o m ust be ceas e d i n t his s u bject. 
St u d y dr u g ma y be res u me d o nl y if W B C a n d a bs ol ute ne utr o p hil c o u nt b ot h e x cee d t he l o wer 
li mit of t he res pecti ve n or mal ra n ge, t h e I n vesti gat or dee ms res u m pti o n t o b e a p pr o pri ate, a n d 
t he W B C a n d A N C ar e m o nit ore d cl osel y t h ereafter. 
I n t he e ve nt of wit h dra w al fr o m t he st u d y pri or t o t he Da y 8 5 visit, t he tests a n d e val uati o ns 
liste d f or St u d y Da y 8 5 s h o ul d be carrie d o ut as p art of t he Earl y Ter mi nati o n visit, w he ne ver 
p ossi ble. F or s u bjects w h o wit h dra w aft er D a y 8 5, t he Da y 1 6 9 st u d y pr oce d ures s h o ul d be 
perf or me d. T he S p o ns or s h o ul d be n otifie d of all st u d y wit h dra wals i n a ti mel y ma n n er. 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 4 6 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
I n t he e ve nt of tr eat me nt fail ure w h ere resc u e c orti c oster oi d t hera p y is n ee d e d, t he st u d y dr u g 
( C C X 1 6 8 or place b o) a n d st u d y-s u p plie d pre d nis o ne/ place b o will be disc o nti n ue d, a n d 
a p pr o priate o p e n- la b el S O C  meas ures will be ta k e n. H o we v er, t he s u bject will be as ke d t o 
re mai n i n t he st u d y a n d c o m plete all re mai ni n g st u d y visits. If t his is n ot p ossi ble, a n atte m pt will 
be ma de t o c o m plete all pr oce d ur es sc he d ul e d f or t he Da y 8 5 visit (if t he resc ue e v e nt occ urre d 
pri or t o t he Da y 8 5 visit) a n d Da y 1 6 9 (if t h e res c u e e ve nt occ urre d aft er t he Da y 8 5 visit). 
5.  
S T U D Y M E DI C A TI O N/ T R E A T M E N T  
5. 1.  
Pr o d uct C h ar acteristics  
C C X 1 6 8 will be a d mi nistere d as h ar d gelati n ca ps ules c o ntai ni n g 1 0 m g C C X 1 6 8. T he ca ps ules 
are ma n ufact ur e d u n der c G M P. All d oses of st u d y me dicati o n will be a d mi nistere d orall y. T he 
C C X 1 6 8 ca ps ules will be s u p plie d t o t he st u d y ce nters i n plastic b ottles c o ntai ni n g 3 0 ca ps ules.  
5. 2.  
R a n d o miz ati o n a n d Met h o d of Tre at me nt Assi g n me nt  
Eli gi ble s u bjects will be e nr olle d, stratifie d i n t hree  strata: ( 1) n e wl y dia g n ose d or rela psi n g 
disease, ( 2) P R 3 or M P O A N C A, a n d ( 3) c ycl o p h os p ha mi de or rit u xi ma b use, a n d t he n 
ra n d o mize d t o o ne of t he t hree treat me nt gr o u ps i n a rati o of 1: 1: 1, 1 0 m g C C X 1 6 8 t wice 
dail y : 3 0 m g C C X 1 6 8 t wice dail y:Place b o . Ra n d o mizati o n  will be perf or me d ce ntrall y via a n 
i nteracti ve v oice res p o ns e s yste m (I V R S). I n or d er t o pr otect t he bli n di n g, t he ra n d o mizati o n 
sc he d ule will n ot be accessi ble t o st u d y p ers o n nel directl y i n v ol ve d i n t he st u d y.   
5. 3.  
D oses a n d Re gi me ns  
T here will be t hr ee gr o u ps i n t he st u d y: 
•  Gr o u p A: C C X 1 6 8 1 0 m g t wice dail y pl us c ycl o p h os p ha mi de/rit u xi ma b pl us 
c ortic oster oi ds; 
•  Gr o u p B: C C X 1 6 8 3 0 m g t wice dail y pl us c ycl o p h os p ha mi de/rit u xi ma b pl us 
c ortic oster oi ds; 
•  Gr o u p C: Place b o t wice dail y pl us c ycl o p h os p h a mi de/rit u xi ma b pl us c ortic oster oi ds. 
St u d y dr u g a n d ot her me dicati o n f or vasc ulitis will be ta ke n as f oll o ws b y st u d y s u bjects:  
•  Gr o u p A ( 1 0 m g C C X 1 6 8 t wice dail y):  
− O ne 1 0- m g C C X 1 6 8 ca ps ule i n t he m or ni n g a n d 1 i n t he e ve ni n g, a p pr o xi matel y 1 2 
h o urs after t h e m or ni n g d ose, dail y f or 8 4 da ys.  
− T w o matc hi n g pl ace b o ca ps ules i n t he m or ni n g a n d 2 i n t he e ve ni n g, a p pr o xi matel y 
1 2 h o urs after t h e m or ni n g d ose, d ail y f or 8 4 da ys. 
− Pre d nis o ne ta blets e q ui vale nt t o 6 0 m g orall y per d a y, starti n g o n Da y 1 wit h ta peri n g 
acc or di n g t o  t he pr ot oc ol-s pecifie d s c he d ule. 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 4 7 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
− If i n t he c ycl o p h os p ha mi de strat u m, c ycl o p h os p ha mi de I V will be gi v e n o n Da y 1 
a n d als o o n Da ys 1 5, 2 9, 5 7, a n d 8 5; starti n g o n D a y 9 9 t hr o u g h Da y 1 6 8, all s u bjects 
will recei ve oral azat hi o pri ne at a tar get d ose of 2 m g/ k g/ da y.  
− If i n t he rit u xi ma b strat u m, rit u xi ma b I V will be gi ve n o n Da ys 1, 8, 1 5, a n d 2 2 ( 3 7 5 
m g/ m 2 at eac h ti me p oi nt ); n o oral azat hi o pri ne will be gi ve n t o s u bjects recei vi n g 
rit u xi ma b.  
− Resc ue c ortic ost er oi ds s h o ul d be gi ve n t o s u bjects wit h w orse ni n g dis ease  (see 
S ecti o n 5. 1 0 ). 
•  Gr o u p B ( 3 0 m g C C X 1 6 8 t wice dail y): 
− T hree 1 0 - m g C C X 1 6 8 ca ps ules i n t he m or ni n g a n d 3 i n t he e ve ni n g, a p pr o xi matel y 
1 2 h o urs after t h e m or ni n g d ose, d ail y f or 8 4 da ys. 
− Pre d nis o ne ta blets e q ui vale nt t o 6 0 m g orall y per d a y, starti n g o n Da y 1 wit h ta peri n g 
acc or di n g t o t he pr ot oc ol- s pecifie d s c he d ule. 
− If i n t he c ycl o p h os p ha mi de strat u m, c ycl o p h os p ha mi de I V will be gi v e n o n Day 1 
a n d als o o n Da ys 1 5, 2 9, 5 7, a n d 8 5; starti n g o n D a y 9 9 t hr o u g h Da y 1 6 8, all s u bjects 
will recei ve oral azat hi o pri ne at a tar get d ose of 2 m g/ k g/ da y. 
− If i n t he rit u xi ma b strat u m, rit u xi ma b I V will be gi ve n o n Da ys 1, 8, 1 5, a n d 2 2 ( 3 7 5 
m g/ m 2 at eac h ti me p oi nt); n o oral azat hi o pri ne will be gi ve n t o s u bjects recei vi n g 
rit u xi ma b. 
− Resc ue c ortic ost er oi ds s h o ul d be gi ve n t o s u bjects wit h w orse ni n g dis ease (see 
S ecti o n 5. 1 0 ).  
•  Gr o u p C ( Place b o t wice dail y):  
− T hree mat c hi n g pl ace b o ca ps ules i n t he m or ni n g a n d 3 ca ps ules i n t he e v e ni n g, 
a p pr o xi matel y 1 2 h o urs after t he m or ni n g d ose, d ail y f or 8 4 d a ys.  
− Pre d nis o ne ta blets e q ui vale nt t o 6 0 m g orall y per d a y, starti n g o n Da y 1 wit h ta peri n g 
acc or di n g t o t he pr ot oc ol- s pecifie d s c he d ule. 
− If i n t he c ycl o p h os p ha mi de strat u m, c ycl o p h os p ha mi de I V will be gi v e n o n Da y 1, 
a n d als o o n Da ys 1 5, 2 9, 5 7, a n d 8 5; starti n g o n D a y 9 9 t hr o u g h Da y 1 6 8, all s u bjects 
will recei ve  oral azat hi o pri ne at a tar get d ose of 2 m g/ k g/ da y. 
− If i n t he rit u xi ma b strat u m, rit u xi ma b I V will be gi ve n o n Da ys 1, 8, 1 5, a n d 2 2 ( 3 7 5 
m g/ m 2 at eac h ti me p oi nt) ; n o oral azat hi o pri ne will be gi ve n t o s u bjects recei vi n g 
rit u xi ma b.  
− Resc ue c ortic ost er oi ds s h o ul d be gi ve n t o s u bjects wit h w orse ni n g dis ease (see 
S ecti o n 5. 1 0 ). 
All s u bjects will ta ke st u d y me dicati o n as i nstr uct e d o n t he da ys of visits t o t he st u d y ce nter. F or 
t he ot her st u d y d a ys, st u d y me dicati o n will be ta ke n at h o me as i nstr ucte d. F oll o wi n g t he 8 4-da y 
d osi n g peri o d, t here will be a n 8 4- da y f oll o w - u p p eri o d.   

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 4 8 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
S u bjects i n Gr o u p A ( 1 0 m g C C X 1 6 8) will recei v e o ne kit c o ntai ni n g 1 b ottle of C C X 1 6 8 
ca ps ules a n d 2 b ottles of matc hi n g place b o ca ps ul es o n Da ys 1, 1 5, 2 9, 4 3, 5 7, a n d 7 1. S u bjects 
i n Gr o u p B ( 3 0 m g C C X 1 6 8) will recei v e o ne kit c o ntai ni n g 3 b ottles of C C X 1 6 8 ca ps ules o n 
Da ys 1, 1 5, 2 9, 4 3, 5 7, a n d 7 1. S u bjects i n Gr o u p C ( place b o ) will recei v e o ne kit c o ntai ni n g 3 
b ottles of matc hi n g place b o ca ps ules o n Da ys 1, 1 5, 2 9, 4 3, 5 7, a n d 7 1. 
S u bjects will be as ke d t o ta ke 1 ca ps ule fr o m eac h b ottle e ver y m or ni n g a n d 1 ca ps ule fr o m eac h 
b ottle e ver y e v e ni n g, a p pr o xi matel y 1 2 h o urs after t he m or ni n g d ose, as i nstr ucte d. St u d y 
me dicati o n will be ta ke n wit hi n 1 h o ur after brea kfast i n t he m or ni n g a n d wit hi n 1 h o ur after 
di n ner i n t he e ve ni n g f or 8 4 da ys c o nti n u o usl y. Ca ps ules will be ta ke n wit h water, prefera bl y 
wit h 5 0 m L, b ut n ot t o e xcee d 1 0 0 m L. Place b o a n d C C X 1 6 8 b ottles a n d ca ps ules will be 
i de ntical i n a p peara nce.  
Pre d nis o ne will be gi v e n acc or di n g t o a st a n dar d t a peri n g sc h e d ule (see Secti o n 1 1. 5 ). 
Pre d nis o ne 2 0 m g a n d 5 m g ta blets fr o m a c o m mercial s o urce will be use d a n d pr o vi de d t o t he 
st u d y ce nt ers wit h d osi n g i nstr ucti o ns. 
If a s u bject is o n c ortic oster oi ds at t he ti me of scree ni n g, t he n o n-st u d y s u p plie d c ortic oster oi ds 
wil l be st o p pe d o n Da y 1 w he n t he st u d y s u p plie d d ose of 6 0 m g pre d nis o n e is starte d. 
F or s u bjects i n t he c ycl o p h os p ha mi de strat u m, c ycl o p h os p ha mi de I V will be gi v e n o n Da y 1 a n d 
als o o n Da ys 1 5, 2 9, 5 7, a n d 8 5 ; starti n g o n D a y 9 9  t hr o u g h D a y 1 6 8, all s u bjects will recei ve 
oral azat hi o pri ne at a tar get d ose of 2 m g/ k g/ d a y (s ee Secti o n 1 1. 6  f or i nstr u cti o ns). 
F or s u bjects i n t he rit u xi ma b strat u m, rit u xi ma b I V will be gi ve n o n Da ys 1, 8, 1 5, a n d 2 2 ( 3 7 5 
m g / m2 at eac h ti me p oi nt; see Secti o n 1 1. 7 ).   
T he pr ot oc ol all o ws c ortic oster oi d use, u p t o 3 0 0 0 m g met h yl pre d nis ol o ne e q ui vale nt, wit hi n t he 
1 2 wee ks pri or t o Scr ee ni n g. T his c ortic oster oi d us e m ust be d oc u me nte d i n t he electr o nic d ata 
ca pt ure ( E D C)  s yste m. 
R esc ue gl uc oc ortic oi d t hera p y will be gi ve n acc or di n g t o S ecti o n 5. 1 0 . 
5. 4.  
R ati o n ale f or D ose Selecti o n  
Si n gle d oses of 1 m g u p t o 1 0 0 m g C C X 1 6 8 were st u die d i n a P hase 1 st u d y ( C L 0 0 1 _ 1 6 8) i n 4 8 
healt h y v ol u nteers, a n d m ulti ple o nce dail y d oses of 1, 3, a n d 1 0 m g C C X 1 6 8 a n d m ulti ple t wice 
dail y d oses of 3 0 m g a n d 5 0 m g f or u p t o 7 d a ys were st u die d i n t he m ulti ple d ose peri o d of t he 
st u d y. All d oses u p t o 1 0 0 m g (si n gle d ose) a n d 5 0 m g t wice d ail y f or 7 da ys w ere w ell t olerate d 
wit h n o si g nifica nt safet y c o ncer ns. A d ose of 3 0 m g C C X 1 6 8 t wice dail y has bee n teste d i n 
st u d y C L 0 0 2 _ 1 6 8 i n patie nts wit h A A V. N o d ose-ra n gi n g P h ase 2 st u d y has bee n perf or me d 
pre vi o usl y. A d os e of 1 0 m g C C X 1 6 8 t wice dail y, i n a d diti o n t o t he 3 0 m g t wice dail y d ose 
re gi me n, has bee n selecte d f or t his P hase 2 st u d y i n s u bjects wit h A A V. It is a ntici pate d t hat b ot h 
C C X 1 6 8 d ose re gi me ns w o ul d be well t olerate d i n patie nts wit h A A V. At stea d y st ate, b ot h d ose 
re gi me ns are a ntici pate d t o pr o vi de at least 9 0 % C 5a R c o vera ge o n bl o o d n e utr o p hils 
c o nti n u o usl y t hr o u g h o ut t he da y.   
Base d o n t h e g o o d saf et y pr ofile o bser v e d i n t he t o xic ol o g y st u dies, a n d t h e safet y a n d 
t olera bilit y res ults fr o m t he P hase 1 cli nical trial C L 0 0 1 _ 1 6 8 a n d P has e 2 cli nical trial 
C L 0 0 2 _ 1 6 8, t he ris k f or seri o us or u na ntici pate d u nt o war d e ve nts ass ociat e d wit h C C X 1 6 8 
occ urri n g i n t his cli nical trial is c o nsi dere d l o w.  

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 4 9 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
5. 5.  
Dr u g S u p pl y  
5. 5. 1.  
P ac k a gi n g a n d L a beli n g 
C C X 1 6 8 ca ps ules c o ntai ni n g 1 0 m g C C X 1 6 8 a n d i de ntical a p peari n g place b o ca ps ules will be 
pac ka ge d i n hi g h d e nsit y p o l yet h yle n e ( H D P E) b ottles wit h c hil d-resista nt scre w ca ps a n d 
pr o vi de d t o t he st u d y sites i n kits ( b o x es) c o ntai ni n g t hree  b ottles of C C X 1 6 8 or place b o 
ca ps ules. Eac h b ottle will c o ntai n 3 0 ca ps ules. All b ottles will be la bele d a p pr o priatel y t o 
i n dicate, at a mi ni m u m, pr ot oc ol n u m ber, t he b ottle n u m ber, t he st u d y dr u g, t he c o nte nts, st ora ge 
c o n diti o ns, ca uti o nar y state me nt t o kee p o ut of reac h of c hil dre n, a n d t he e x pir y dat e. O ne kit 
will be dis pe nse d t o a s u bject o n St u d y Da ys 1, 1 5, 2 9, 4 3, 5 7, a n d 7 1 . All kits will be la bele d 
a p pr o priatel y t o i n dicate, at a mi ni m u m, pr ot oc ol n u m ber, t he st u d y dr u g, t he c o nte nts, st ora ge 
c o n diti o ns, ca uti o nar y state me nt t o kee p o ut of reac h of c hil dre n, a n d t he e x pir y dat e. 
T here will be t hr ee C C X 1 6 8/ place b o kit c o nfi g urati o ns: 
1.  F or Gr o u p A, t he 1 0 m g C C X 1 6 8 t wice dail y gr o u p: 
•  B ottle 1: T hirt y 1 0 - m g C C X 1 6 8 ca ps ules 
•  B ottle 2: T hirt y place b o ca ps ules 
•  B ottle 3: T hirt y place b o ca ps ules 
2.  F or Gr o u p B, t he 3 0 m g C C X 1 6 8 t wice dail y gr o u p: 
•  B ottle 1: T hirt y 1 0 - m g C C X 1 6 8 ca ps ules 
•  B ottle 2: T hirt y 1 0 - m g C C X 1 6 8 ca ps ules 
•  B ottle 3: T hirt y 1 0 - m g C C X 1 6 8 ca ps ules 
3.  F or Gr o u p C, t he pl ace b o t wice dail y gr o u p: 
•  B ottle 1: T hirt y place b o ca ps ules 
•  B ottle 2: T hirt y place b o ca ps ules 
•  B ottle 3: T hirt y place b o ca ps ules 
Pre d nis o ne ta blets, c o ntai ni n g eit her 2 0 m g or 5 m g pre d nis o ne, will be pac ka ge d i n hi g h d e nsit y 
p ol yet h yle n e ( H D P E) b ottles wit h c hil d -resista nt scre w ca ps a n d pr o vi de d t o t he st u d y sites. 
Eac h b ottle will c o ntai n 3 0 ta blets of eit her 2 0 m g or 5 m g pre d nis o ne . All b ottles will be la bele d 
a p pr o priatel y t o i n dicate, at a mi ni m u m, pr ot oc ol n u m ber, t he pre d nis o ne d ose stre n gt h, t he 
c o nte nts, st ora ge c o n diti o ns, ca uti o nar y state me nt t o kee p o ut of reac h of c hil dre n, a n d t he e x pir y 
date. T he pre d nis o ne b ottles will be pr o vi de d t o eac h s u bject acc or di n g t o d etails pr o vi de d i n 
S ecti o n 1 1. 5  wit h d etaile d d osi n g i nstr ucti o ns. 
C ycl o p h os p ha mi de, rit u xi ma b, a n d azat hi o pri ne will be prescri be d b y t he i n vesti gat ors acc or di n g 
t o i nstr ucti o ns i n Secti o ns 1 1. 6  a n d 1 1. 7 . T he d ose gi ve n a n d d osi n g d ates a n d ti mes (f or I V 
i nf usi o ns) m ust be rec or d e d i n t he E D C.  

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 5 0 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
5. 5. 2.  
St or a ge 
C C X 1 6 8 a n d C C X 1 6 8 place b o ca ps ules, as well as pre d nis o ne ta blets will be st ore d acc or di n g t o 
la bel i nstr ucti o ns. Access s h o ul d be restricte d t o p har mac y staff or t o t he d esi g nat e d res p o nsi ble 
me m ber of t he I n v esti gat or’s staff, a n d t o t he st u d y m o nit or. T he I n v esti gat or a grees t hat neit her 
s/ he n or a n y of t he st u d y staff will s u p pl y st u d y m e dicati o n t o a n y pers o ns ot her t ha n t h ose 
e nr olle d i n t he st u d y.   
5. 6.  
Bli n di n g  
T his is a d o u ble- bli n d st u d y. Bli n di n g of t h e st u d y will be ac hie ve d b y t h e f oll o wi n g meas ures: 
1.  T he st u d y dr u g b ottles a n d ca ps ule a p p eara nce f or C C X 1 6 8 a n d its matc hi n g place b o wi ll be 
i de ntical; 
2.  Li mite d access t o t he r a n d o mizati o n c o de; st u d y  site pers o n nel, st u d y s u bj ects, pers o n nel 
res p o nsi ble f or st u d y m o nit ori n g, a n d bi ostatisticia ns a n d data ma n a gers i n v ol ve d i n data 
a nal ysis of t he st u d y will re mai n bli n de d t o treat m e nt assi g n me nt f or t he d urati o n of t he 
st u d y; 
3.  W hile la b orat or y p ers o n n el c o n d ucti n g t he P K ass a ys will n ot be bli n de d t o treat me nt 
assi g n me nt, u n bli n de d C C X 1 6 8 plas ma c o nce ntrati o n res ults will n ot be s hare d wit h t he 
st u d y site pers o n n el or t he st u d y staff wit h direct c o ntact wit h st u d y sites d uri n g t he st u d y;  
4.  Efficac y data t h at w o ul d p ote ntiall y be u n bli n di n g, i.e, a nti- P R 3 a n d a nti- M P O a nti b o dies, 
uri nar y M C P- 1:creati ni ne rati o, uri nar y A C R, W B C a n d ne utr o p hil c o u nt data wit hi n t he 
n or mal ra n ge,  a n d hs C R P data, will n ot be ma de a vaila ble t o st u d y site p ers o n nel, st u d y 
s u bjects, pers o n nel r es p o nsi ble f or st u d y m o nit ori n g, a n d bi ostatisticia ns a n d data ma na gers 
d uri n g t he st u d y u nless f or safet y m o nit ori n g. 
Treat me nt assi g n me nts f or i n di vi d ual s u bjects will re mai n bli n de d t o t he st u d y tea m, 
i n vesti gat ors, a n d s u bj ects u ntil after t he st u d y d at a base has b ee n clea n e d a n d l oc ke d. Desi g nate d 
st u d y staff will be pr o vi de d wit h i nstr ucti o ns re gar di n g h o w t o u n bli n d i n di vi d ual s u bject 
treat me nt assi g n me nt; i n di vi d ual s u bject treat me nt assi g n me nt ma y be u n bli n de d o nl y i n t he case 
of a n a d verse e v e nt t hat r e q uires k n o wle d ge of t he st u d y me dicati o n recei ve d b y t h e s u bject i n 
or der t o pr o vi de a p pr o pri ate treat me nt or m a na ge me nt of t he a d verse e v e nt. T he st u d y m o nit or 
s h o ul d be n otifie d as s o o n as p ossi ble i n t he e ve nt t hat u n bli n di n g of a n i n di vi d ual s u bject’s 
treat me nt assi g n me nt occ urs pri or t o st u d y c o m pleti o n. 
A n e xter nal data m o nit ori n g c o m mittee ( D M C) will be c o nstit ute d pri or t o start of t he st u d y (see 
S ecti o n 7. 6 ). T he D M C me m bers will re vie w d ata peri o dicall y o ver t he c o urse of t he st u d y i n a n 
u n bli n de d ma n ner. T he D M C will pr o vi de rec o m me n dati o ns t o t he S p o ns or re gar di n g f urt her 
c o n d uct of t he st u d y. T he D M C will o perate acc or di n g t o a c h arter de vel o p e d pri or t o st u d y 
i nitiati o n.   
5. 7.  
Dr u g Acc o u nt a bilit y  
T he st u d y p h ar macist a n d i n vesti gat or m ust mai ntai n acc urate rec or ds of d ates a n d q ua ntities of 
pr o d uct(s) r ecei v e d, t o w h o m dis pe nse d (s u bject- b y -s u bject acc o u nti n g), a n d acc o u nts of a n y 
pr o d uct acci de ntall y or d eli beratel y destr o ye d. T h e I n vesti gat or m ust retai n all u n use d a n d/ or 
e x pire d st u d y s u p plies u ntil t he st u d y m o nit or has c o nfir me d t he acc o u nt a bilit y d ata.  

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 5 1 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
5. 8.  
Tre at me nt C o m pli a nce  
T he C C X 1 6 8 a n d C C X 1 6 8 place b o ca ps ules, a n d pre d nis o ne a n d azat hi o pri ne ( w here 
a p plica ble) ta bl ets , will be self-a d mi nistere d b y partici pati n g st u d y s u bjects. T h e m or ni n g d os es 
of st u d y dr u g o n Da y 1 will be ta ke n i n t he prese n ce of st u d y site pers o n n el. S u bjects will be 
pr o vi de d wit h d osi n g i nstr ucti o ns at t he start of t he st u d y, a n d will be e n c o u ra ge d b y st u d y site 
pers o n nel t o ta ke t he st u d y me dicati o n acc or di n g t o t he i nstr ucti o ns f or t he d urati o n of t he st u d y. 
S u bjects will be i nstr ucte d t o bri n g t he assi g ne d b ottles of st u d y me dicati o n t o t he site staff at 
eac h st u d y visit, w het her e m pt y or n ot. T h e st u d y dr u g dis pe ns e d will be c h ec ke d f or a n y u n us e d 
st u d y dr u g, a n d a d ose u nit c o u nt will be d o ne of a n y re mai ni n g C C X 1 6 8 a n d pre d nis o ne st u d y 
me dicati o n.  T his i nf or mati o n will be rec or de d i n t he C R F.  
C C X 1 6 8 plas ma c o nce ntrati o n meas ure m e nts o ver t he c o urse of t he st u d y ma y als o be use d t o 
assess s u bject c o m plia nce. A n y e ve nts of n o n-c o m plia nce t o t he pr ot oc ol will be d oc u me nte d i n 
t he st u d y r ec or ds. 
5. 9.  
C o nc o mit a nt Me dic ati o ns a n d Restricti o ns  
Use of a n y dr u g ot her t ha n pr ot oc ol-s pecifi e d C C X 1 6 8 or C C X 1 6 8 place b o, oral pre d nis o ne, I V 
c ycl o p h os p ha mi de  or rit u xi ma b , or resc ue c ortic oster oi ds t o treat AA V is pr o hi bite d o ver t he 
c o urse of t he 8 4- da y tr eat me nt peri o d. T his i ncl u des use of oral c ycl o p h os p ha mi de, azat hi o pri ne, 
m yc o p h e n olate m ofetil, met h otre x ate, a nti -T N F  treat me nt, a b atace pt, ale mt uz u ma b, I VI g, 
beli m u ma b, t ociliz u ma b,  or ot her i m m u n os u p pressi ve a ge nts. H o w e ver, s u bjects i n t he 
c ycl o p h os p ha mi de strat u m will ta ke oral azat hi o pri ne at a tar get d ose of 2 m g/ k g/ da y fr o m D a y 
9 9 t hr o u g h D a y 1 6 8. 
Si nce st u d y s u bjects will recei v e a n u m ber of i m m u n os u p pressi ve dr u gs, all st u d y s u bjects m ust 
recei v e P ne u m o cystis c ari nii  p ne u m o nia ( P C P) pr o p h ylactic treat me nt. Pr o p h ylactic treat me nt 
f or oste o p or osis, gastr o pr otecti o n, a n d a nti- na us ea me dicati o n (e. g., o n da ns etr o n), acc or di n g t o 
l ocal practice, is rec o m me n de d. 
I n case of ne utr o p e nic fe ver i n a s u bject recei vi n g c ycl o p h os p ha mi de, a nti bi otics a n d/ or 
a nti m yc otics m u st be gi v e n, acc or di n g t o t he pres cri bi n g i nf or mati o n. 
S u bjects will als o be e nc o ura ge d t o r e mai n o n sta ble d oses of all ot her c o n c o mita nt me dicati o n 
o ver t he c o urse of t he st u d y. If a s u bject is o n n o n-st u d y s u p plie d c ortic oster oi d s at t he ti me of 
scree nin g, t he n o n-st u d y s u p plie d c ortic oster oi ds will be st o p pe d o n Da y 1 w he n t he st u d y 
s u p plie d pre d nis o ne d ose of 6 0 m g is starte d. 
All c o nc o mita nt me dicati o ns ta ke n d uri n g t he c o urse of t he st u d y m ust be rec or de d o n t he 
c o nc o mita nt me dicati o n pa ges of t he C R F.  
5. 1 0.  
Criteri a f or Resc ue C ortic oster oi d Use  
Use of r esc ue c ortic oster oi ds is dee me d a treat me nt fail ure a n d s h o u l d o nl y be us e d u n der t h e 
f oll o wi n g cir c u msta nces: 
•  S uccessi ve deteri orati o n of e G F R o ver 3 da ys s u g gesti n g t hat, i n t he vie w of t he pri nci pal 
i n vesti gat or, if n o e xtra i nter ve nti o n is ta ke n, t he re nal f u ncti o n w o ul d c o nti n ue t o 
deteri orat e;  

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 5 2 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
•  W orse ni n g of r e nal f u n cti o n as j u d ge d b y e G F R decrease of > 1 0 m L/ mi n fr o m baseli ne 
d uri n g t he 8 4- da y treat me nt peri o d or d uri n g t he 8 4- da y f oll o w- u p p eri o d; 
•  Persiste nce or n e w occ urre nce of a maj or n o n -re n al ite m as per B V A S, s uc h as ga n gre n e, 
s u d de n visi o n l oss, reti nal c ha n ges, se ns ori n e ural heari n g l oss, massi ve 
he m o pt ysis/al ve olar h e m orr ha ge, res pirat or y fail ure, car di o m y o p at h y, isc h e mic 
a b d o mi nal pai n i n dica ti ve of mese nteric isc he mia, or ner v o us s yste m diseas e; or 
•  If, base d o n t h e st u d y site p h ysicia n’s assess me nt, it w o ul d be i n t he best i nterest of t he 
s u bject.  
T he reas o n f or r esc ue c ortic oster oi d use will be ca pt ure d o n t he C R F. 
T he sta n dar d I V r esc ue tr eat me nt will c o nsist of 5 0 0 m g met h yl pre d nis ol o ne gi v e n o nce d ail y f or 
3 da ys. T his will be f oll o we d b y oral c ortic oster oi ds acc or di n g t o t he l ocal S O C .  
If res c ue c ortic oster oi d tr eat me nt is necess ar y, it w o ul d be c o nsi dere d a treat me nt fail ure a n d 
st u d y dr u g ( C C X 1 6 8 or place b o) a n d st u d y-s u p plie d pre d nis o ne will be dis c o nti n ue d. T he 
s u bject will recei v e a p pr o priate o pe n-l a bel S O C . Ne vert hel ess, t he s u bject will c o nti n ue t o be 
f oll o we d i n t he st u d y (s ee Secti o n 4. 4 ).   
6.  
S T U D Y P R O C E D U R E S  
6. 1.  
Scree ni n g a n d E nr oll me nt  
I nf or me d C o nse nt m ust be o btai ne d pri or t o perf or ma nce of a n y st u d y-s pecific tests or 
e val uati o ns. It is i m p orta nt t o c o m plete t he scree ni n g pr oce d ures i n t he s h ortest ti me p ossi ble t o 
all o w s u bjects t o start treat me nt. Wit hi n a peri o d n ot t o e x cee d 1 4 da ys pri or t o ra n d o mizati o n, 
s u bjects will u n der g o t h e f oll o wi n g e v al uati o ns t o deter mi ne t heir eli gi bilit y f or st u d y 
partici pati o n:  
•  De m o gra p hics, me di cal hist or y, a n d pri or a n d c o nc o mita nt me dicati o n usa ge; 
•  I n or der t o e x pe dite t he s cree ni n g pr ocess, bl o o d will be c ollecte d f or testi n g at t he l o cal 
la b orat or y f or t he f oll o wi n g:  
− Fasti n g bl o o d c he mistr y, he mat ol o g y, P T T a n d a P T T;  
− A n esti mate d gl o mer ular filtrati o n rate will be calc ulate d base d o n t he f oll o wi n g 
M o dificati o n of Diet i n Re nal Diseas e ( M D R D) st u d y e q u ati o n: 
e G F R ( m L/ mi n/ 1. 7 3 m 2) = 1 7 5 x (ser u m creati ni ne i n m g/ d L)-1. 1 5 4 x ( A ge) -0. 2 0 3 x 
( 0. 7 4 2 if fe male) x ( 1. 2 1 2 if Africa n-A meri ca n/ Blac k)  
− A N C A meas ur e me nt (i n direct i m m u n ofl uresce nce test f or P -A N C A a n d C -A N C A, as 
well as E LI S A test f or P R 3 a n d M P O);  
− Vir ol o g y assess me nts as detaile d i n S ecti o n 7. 2. 2 ; 
− Ser ol o g y a n d c o m ple me nt assess me nts as detaile d i n  S ecti o n 7. 2. 2 . T hese tests d o n ot 
nee d t o be perf or me d if r es ults are a v aila ble fr o m tests d o ne wit hi n t he past 1 2 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 5 3 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
m o nt hs pri or t o t he Scree ni n g visit. Res ults fr o m t he pri or tests m ust be rec or de d i n 
t he e C R Fs.  
•  B V A S assess me nt (s ee S ecti o n 1 1. 3 ); t o be eli gi ble f or e nr oll me nt, a s u bject m ust ha ve: 
− At least o ne “ maj or ” ite m (see ite ms mar ke d wit h “ #” i n S ecti o n 1 1. 3 ), or 
− At least t hree n o n- m aj or ite ms  o n t he B V A S, or 
− A t least t w o re nal ite ms d ue t o vasc ulitis, i.e.: 
o  H y p erte nsi o n ( diast olic B P > 9 5 m m H g),  
o  Pr otei n uria > 1 + o n uri n al ysis or > 0. 2 g/ g creati ni ne,  
o  He mat uria  (‘ m o der ate” o n uri nal ysis or ≥1 0 R B C per hi g h p o wer fiel d, us u all y 
acc o m pa ni e d b y R B C casts ),  
o  Ser u m creati ni ne ≥1 2 5 μ m ol/ L, or  
o  > 3 0 % rise i n creati ni ne or > 2 5 % fall i n creati ni ne cleara nce;  
•  S u bjects will be as ke d t o v oi d t heir bla d ders c o m p letel y, a n d a re pres e ntati ve clea n catc h, 
mi dstrea m uri ne sa m ple will be c ollecte d:  
− T he l ocal la b or at or y will perf or m a uri nal ysis f or h e mat uria  a n d pr otei n uria; 
•  A p h ysical e x a mi nati o n (e x cl u di n g ge nit o uri nar y, o p ht hal mic, a n d fe male breast 
assess me nts) wi ll be perf or me d; b o d y wei g ht, hei g ht, a n d b o d y mass i n de x will be 
deter mi ne d;  
•  Vital si g ns (te m perat ure, bl o o d press ure, heart rate) will be meas ure d s u pi n e after at least 
3 mi n utes of rest; 
•  Ser u m pre g na n c y test f or w o me n of c hil d beari n g p ote ntial; 
•  A 1 2- lea d E C G will be r ec or de d a n d assess e d f or a n y cli nicall y si g nifica nt a b n or malit y; 
•  C hest X ra ys will be ac q uire d f or B V A S assess m e nt a n d e x cl usi o n of T B;  
•  If a re nal bi o ps y has bee n perf or me d wit hi n 4 wee ks pri or t o scree ni n g, t he sta n dar d 
Hist ol o g y F or m will be c o m plete d;  a c o p y of t he bi o ps y res ults will be ke pt i n t he st u d y 
rec or ds; 
•  After all scree ni n g pr o ce d ures ha ve b ee n c o m plete d, a n d t he s u bject s atisfies all 
eli gi bilit y criteria, t he st u d y sc h e d ule will be disc usse d wit h t he s u bject a n d t he sc he d ule 
will be pr o vi de d t o t he s u bject t o e ns ure c o m plia nce wit h t he st u d y visits; 
•  If t he s u bject has b ee n o n c ortic oster oi ds at t he ti me of scree ni n g, i.e., c ortic oster oi ds t hat  
are n ot c o nsi dere d part of t he st u d y me dicati o n, t he s u bject will as ke d t o st o p t he n o n-
st u d y s u p plie d c ortic oster oi ds a n d start wit h t he st u d y s u p plie d pre d nis o ne d ose of 6 0 m g 
o n Da y 1.  
6. 2.  
St u d y D a y 1  
If eli gi ble f or t he st u d y, t he s u bject will visit t he st u d y ce nter o n Da y 1, after a n o ver ni g ht fast of 
at least 8 h o urs, f or t he f oll o wi n g pr oce d ures: 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 5 4 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
•  A p h ysical e x a mi nati o n (e x cl u di n g ge nit o uri nar y, o p ht hal mic, a n d fe male breast 
assess me nts); b o d y wei g ht assess me nt will be perf or me d;  
•  Vital si g ns (te m perat ur e, bl o o d press ure, heart rate); 
•  Bl o o d will be c ollecte d f or s hi p me nt t o t he ce ntral la b orat or y f or ser u m c h e mistr y, 
he mat ol o g y, hs C R P, A N C A (a nti- P R 3 a n d a nti- M P O E LI S A) m eas ure me nt, a n d P K 
baseli ne meas ur e me nts; t he s u bjects ma y eat after t he ser u m c he mistr y sa m ple has bee n 
c ollecte d;  
•  A bl o o d sa m ple will als o be ta ke n f or a n e x pe dite d W B C c o u nt at t he l ocal la b orat or y i n 
or der t o deter mi ne t he a p pr o priate c ycl o p h os p ha mi de d ose  f or s u bjects w h o are i n t he 
c ycl o p h os p ha mi de strat u m (see S ecti o n 1 1. 6 ); 
•  B V A S assess me nt (s ee  S ecti o n 1 1. 3 ); 
•  V DI assess me nt (s ee Secti o n 1 1. 4 ); 
•  S u bjects will be as ke d t o c o m plete t he S F 3 6 v 2 a n d E Q - 5 D- 5 L q u esti o n naires; 
•  A n y pre -tr eat me nt a d v ers e e ve nts (fr o m ti me of t he scree ni n g visit) will be rec or d e d; 
•  T he s u bject will be ra n d o mize d; 
•  St u d y m e dicati o n ( 1 kit of C C X 1 6 8 or C C X 1 6 8 place b o, a n d 1 b ottle of 2 0 m g 
pre d nis o ne ta blets will be pr o vi de d t o t he s u bject wit h d osi n g i nstr ucti o ns; 
•  S u bjects will be as ke d t o v oi d t heir bla d ders c o m pletel y, a n d a re pres e ntati ve clea n catc h, 
mi dstrea m uri ne sa m ple will be c ollecte d:  
− A uri ne sa m ple will be se nt t o t he ce ntral la b orat or y f or uri nal ysis i ncl u di n g p H, 
s pecific gr a vit y, gl uc os e, nitrite, ket o nes, bilir u bi n, ur o bili n o ge n, R B Cs, a n d W B Cs, 
as well as q ua ntitati ve m eas ure m e nt of al b u mi n a n d creati ni ne t o calc ulate t he A C R;  
− T w o a d diti o nal uri ne sa m ples will be fr oze n a n d se nt t o t he ce ntral la b orat or y f or 
q ua ntitati ve M C P -1 a n d creati ni ne meas ure m e nts t o calc ulate t he M C P -1:creati ni ne 
rati o, a n d f or e x pl orat or y uri nar y mar k ers; 
•  T he s u bject will be as ke d t o ta ke t he first d ose of st u d y me dicati o n w hile at t he st u d y 
ce nter; t he C C X 1 6 8 or C C X 1 6 8 place b o ca ps ul es will be ta ke n at least 3 0 mi n utes bef ore 
t he pre d nis o ne ta blets are ta ke n;  
•  T he ti me of t he d osi n g of C C X 1 6 8 or C C X 1 6 8 place b o , as w ell as pre d nis o ne, will be 
rec or d e d; 
•  Bl o o d sa m ples will be c ollecte d at 0. 5, 1, 2, 3, 4, a n d 6 h o urs f oll o wi n g C C X 1 6 8 or 
C C X 1 6 8 place b o d osi n g f or plas ma C C X 1 6 8 c o nce ntrati o n meas ure me nts; t he act ual 
ti me of eac h bl o o d sa m pl e c ollecti o n will be rec or de d; 
•  All uri ne will be c ollecte d f or a peri o d of 6 h o urs f oll o wi n g C C X 1 6 8 or C C X 1 6 8 place b o 
d osi n g; t he t otal uri ne v ol u me will be meas ure d a n d rec or d e d, a n d a re pres e ntati ve uri ne 
sa m ple will be o btai ne d f or C C X 1 6 8 meas ure me nt; 
•  A bl o o d sa m ple will b e c ollecte d f or p h ar mac o d y na mic  mar ker meas ure m e nts;  

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 5 5 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
•  A sali va sa m ple will be c ollecte d f or ge netic mar k er assess me nts;  
•  C ycl o p h os p ha mi de I V d ose will be gi ve n after recei pt of t he l ocal W B C c o u nt ( see 
S ecti o n 1 1. 6 ) t o s u bjects i n t he c ycl o p h os p ha mi de strat u m; T he start  a n d e n d ti mes of t he 
i nf usi o n will be rec or d e d; 
•  Rit u xi ma b will be gi ve n t o s u bjects i n t he rit u xi ma b strat u m  (see Secti o n 1 1. 7 ); A d ose of 
3 7 5 m g / m2 will be gi ve n;  T he start a n d e n d ti mes of t he i nf usi o n will be rec or de d; 
•  If a s u bject h as bee n o n n o n- st u d y s u p plie d c ortic oster oi ds, t he n o n-st u d y s u p plie d 
c ortic oster o i ds nee d t o be st o p pe d a n d t he 6 0 m g st u d y s u p plie d pre d nis o n e starte d; 
•  A n y c ha n ges i n c o nc o mita nt me dicati o n use will be rec or de d;  
•  A n y p ost- d osi n g a d v erse e ve nts will be rec or de d;  
•  A s u bject c o ul d be ke pt o ver ni g ht i n t he h os pital o n Da y 1, if necessar y. T his h os pital 
sta y w o ul d n ot be c o nsi dere d a s eri o us a d v erse e v e nt, u nless ot her S A E criteria are met; 
•  After all st u d y pr oce d ures ha ve bee n c o m plete d, t he s u bject will be re mi n d e d t o: 
− C o me t o t he st u d y ce nt er f or t he Da y 2 st u d y visit t he ne xt da y, if n ot ke pt o ver ni g ht;  
− St ore t he st u d y me dicati o ns i n a c o ol a n d dr y place acc or di n g t o la b el i nstr ucti o ns f or 
t he d urati o n of t he st u d y;  
− Ta ke t he C C X 1 6 8 or C C X 1 6 8 place b o me di cati o n i n t he e ve ni n g a p pr o xi matel y 1 2 
h o urs after t h e m or ni n g d ose;  
− N ot t o ta ke C C X 1 6 8 a n d pre d nis o ne me dicati o n o n t he m or ni n g of Da y 2, u nless t he 
visit is sc he d ule d i n t he after n o o n, i n w hic h case C C X 1 6 8 a n d pre d nis o ne me dicati o n 
s h o ul d be ta ke n t he m or ni n g of D a y 2; a n d 
− C o nti n ue ta ki n g all t heir ot her c o nc o mita nt me dicati o ns as us ual.  
6. 3.  
St u d y D a y 2  
T he St u d y D a y 2 visit m ust occ ur o n t he sc h e d ule d date. T he s u bjects m ust fast o ver ni g ht f or at 
least 8 h o urs bef ore t he st u d y visit. D uri n g t his visit, t he f oll o wi n g st u d y pr oce d ures will be 
perf or me d:  
•  B o d y s yste m re vie w t o deter mi ne if t here were a n y c h a n ges fr o m Da y 1;  
•  All treat me nt -e mer ge nt a d verse e v e nts will be rec or de d;  
•  Vital si g ns (te m perat ure, bl o o d press ure, heart rate); 
•  Bl o o d will be c ollecte d f or s hi p me nt t o t he ce ntral la b orat or y f or ser u m c h e mistr y a n d 
he mat ol o g y; t he s u bject s ma y eat aft er t he ser u m c he mistr y sa m ple c ollecti o n; 
•  S u bjects will be as ke d t o v oi d t heir bla d ders c o m pletel y, a n d a re pres e ntati ve clea n catc h, 
mi dstrea m uri ne sa m ple will be c ollecte d:  
− A uri ne sa m ple will be se nt t o t he ce ntral la b orat or y f or uri nal ysi s i ncl u di n g p H, 
s pecific gr a vit y, gl uc os e, nitrite, ket o nes, bilir u bi n, ur o bili n o ge n, R B Cs, a n d W B Cs; 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 5 6 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
•  T he s u bject will be as ke d t o ta ke t he m or ni n g d os es of st u d y me dicati o n w hile at t he 
st u d y ce nt er, u nless alr ea d y ta k e n; t he C C X 1 6 8 or C C X 1 6 8 place b o ca psul es will be 
ta ke n at least 3 0 mi n utes bef ore t h e pre d nis o ne t a blets are ta k e n;  
•  A n y c ha n ges i n c o nc o mita nt me dicati o n use will be rec or de d; a n d  
•  After all st u d y pr oce d ures ha ve bee n c o m plete d, t he s u bject will be re mi n d e d t o: 
− C o me t o t he st u d y ce nt er f or t h e Da y 8 st u d y visit;  
− St ore t he st u d y me dicati o ns i n a c o ol a n d dr y place acc or di n g t o la b el i nstr ucti o ns f or 
t he d urati o n of t he st u d y;  
− Ta ke t he C C X 1 6 8 or C C X 1 6 8 place b o me di cati o n as i nstr ucte d;  
− Ta ke t he pr e d nis o ne d ose as i nstr ucte d;  
− N ot t o ta ke C C X 1 6 8 a n d pre d nis o ne me dicati o n o n t he m or ni n g of Da y 8, u nless t he 
visit is sc he d ule d i n t he after n o o n, i n w hic h case C C X 1 6 8 a n d pre d nis o ne me dicati o n 
s h o ul d be ta ke n t he m or ni n g of D a y 8; a n d 
− C o nti n ue ta ki n g all t heir ot her c o nc o mita nt me dicati o ns as us ual.  
6. 4.  
St u d y D a y 8  
T he St u d y D a y 8 visit m ust occ ur o n t he sc h e d ule d date. T he s u bjects m ust fast o ver ni g ht f or 
at least 8 h o urs bef ore t h e st u d y visit. D uri n g t his visit, t he f oll o wi n g st u d y pr oce d ures will 
be perf or me d:  
•  B o d y s yste m re vie w t o deter mi ne if t here were a n y c h a n ges fr o m Da y 2;  
•  All treat me nt -e mer ge nt a d verse e v e nts will be rec or de d;  
•  Vital si g ns (te m perat ure, bl o o d press ure, heart rate); 
•  Bl o o d will be c ollecte d f or s hi p me nt t o t he ce ntral la b orat or y f or ser u m c h e mistr y, 
he mat ol o g y, a n d hs C R P meas ure me nts; t he s u bjects ma y eat after t he ser u m c he mistr y 
sa m ple c ollecti o n; 
•  T he date a n d ti me of t he last d ose of C C X 1 6 8 or C C X 1 6 8 place b o will be rec or d e d;  
•  A bl o o d sa m ple will be c ollecte d f or C C X 1 6 8 plas ma c o nce ntrati o n meas ure me nt, a n d 
t he date a n d ti me of t he s a m ple c ollecti o n will be rec or de d; 
•  S u bjects will be as ke d t o v oi d t heir bla d ders c o m pletel y, a n d a re pres e ntati ve clea n catc h, 
mi dstrea m uri ne sa m ple will be c ollecte d:  
− A uri ne sa m ple will be se nt t o t he ce ntral la b orat or y f or uri nal ysis i ncl u di n g p H, 
s pecific gr a vit y, gl uc os e, nitrite, ket o nes, bilir u bi n, ur o bili n o ge n, R B Cs, a n d W B Cs, 
as well as q ua ntitati ve m eas ure m e nt of al b u mi n a n d creati ni ne t o calc ulate t he A C R;  
− T w o a d diti o nal uri ne sa m ples will be fr oze n a n d se nt t o t he ce ntral la b orat or y f or 
q ua ntitati ve M C P -1 a n d creati ni ne meas ure m e nts t o calc ulate t he M C P -1:creati ni ne 
rati o, a n d f or e x pl orat or y uri nar y mar k ers; 
•  Dr u g acc o u nta bilit y of pr e d nis o ne b ottles; 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 5 7 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
•  C ortic oster oi d me dicati o n ( 1 b ottle of 2 0 m g pre d nis o ne a n d 1 b ottle of 5 m g pre d nis o n e ) 
will be pr o vi de d t o t he s u bject wit h d osi n g i nstr ucti o ns; t he s u bject will ta ke t he m or ni n g 
d oses fr o m t he pr e vi o usl y-s u p plie d C C X 1 6 8 or pl ace b o kits a n d t he n e w s u p pl y of 
pre d nis o ne w hile at t he st u d y site, u nless t he m or ni n g d oses ha v e alrea d y b ee n ta ke n b y 
t he s u bject; 
•  Rit u xi ma b will be gi ve n t o s u bjects  i n t he rit u xi ma b strat u m (see Secti o n 1 1. 7 ); A d ose of 
3 7 5 m g/ m 2 will be gi ve n ; T he start a n d e n d ti mes of t he i nf usi o n will be rec or de d; 
•  A n y c ha n ges i n c o nc o mita nt me dicati o n use will be rec or de d; a n d  
•  After all st u d y pr oce d ures ha ve bee n c o m plete d, t he s u bject will be re mi n d e d t o: 
− C o me t o t he st u d y ce nt er f or t he Da y 1 5 st u d y visit; 
− St ore t he st u d y me dicati o ns i n a c o ol a n d dr y place acc or di n g t o la b el i nstr ucti o ns f or 
t he d urati o n of t he st u d y;  
− Ta ke t he C C X 1 6 8 or C C X 1 6 8 place b o me di cati o n as i nstr ucte d;  
− Ta ke t he pr e d nis o ne d ose as i nstr ucte d; 
− N ot t o ta ke C C X 1 6 8 a n d pre d nis o ne me dicati o n o n t he m or ni n g of Da y 1 5, u nless t he 
visit is sc he d ule d i n t he after n o o n, i n w hic h case C C X 1 6 8 a n d pre d nis o ne me dicati o n 
s h o ul d be ta ke n t he m or ni n g of D a y 1 5;  
− Bri n g all st u d y m e dicati o n c o ntai ners t o t he ne xt st u d y visit, w het her e m pt y or n ot, 
a n d 
− C o nt i n ue ta ki n g all t heir ot her c o nc o mita nt me dicati o ns as us ual. 
6. 5.  
St u d y D a y 1 5  
T he St u d y D a y 1 5 visit m ust occ ur o n t he sc he d ule d date. T he s u bjects m ust fast o ver ni g ht f or at 
least 8 h o urs bef ore t he st u d y visit. D uri n g t his visit, t he f oll o wi n g st u d y pr oce d ures will be 
perf or me d:  
•  A p h ysical e x a mi nati o n (e x cl u di n g ge nit o uri nar y, o p ht hal mic, a n d fe male breast 
assess me nts) will be perf or me d; b o d y wei g ht will als o be meas ure d;  
•  All treat me nt -e mer ge nt a d verse e v e nts w ill be rec or de d; 
•  Vital si g ns (te m perat ure, bl o o d press ure, heart rate); 
•  Bl o o d will be c ollecte d f or s hi p me nt t o t he ce ntral la b orat or y f or ser u m c h e mistr y, 
he mat ol o g y, a n d hs C R P meas ure me nts; t he s u bjects ma y eat after t he ser u m c he mistr y 
sa m ple c ollecti o n; 
•  A bl o o d sa m ple will als o be ta ke n f or a n e x pe dite d W B C c o u nt at t he l ocal la b orat or y i n 
or der t o deter mi ne t he a p pr o priate c ycl o p h os p ha mi de d ose (see S ecti o n 1 1. 6 ) f or s u bjects 
w h o are i n t he c ycl o p h os p ha mi de strat u m; 
•  S u bjects will be as ke d t o v oi d t heir bla d ders c o m pletel y, a n d a re pres e ntati ve clea n catc h, 
mi dstrea m uri ne sa m ple will be c ollecte d:  

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 5 8 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
− A uri ne sa m ple will be se nt t o t he ce ntral la b orat or y f or uri nal ysis i ncl u di n g p H, 
s pecific gr a vit y, gl uc os e, nitrite, ket o nes, bilir u bi n, ur o bili n o ge n, R B Cs, a n d W B Cs, 
as well as q ua ntitati ve m eas ure m e nt of al b u mi n a n d creati ni ne t o calc ulate t he A C R;  
− T w o a d diti o nal uri ne sa m ples will be fr oze n a n d se nt t o t he ce ntral la b orat or y f or 
q ua ntitati ve M C P -1 a n d creati ni ne meas ure m e nts t o calc ulate t he M C P -1:creati ni ne 
rati o, a n d f or e x pl orat or y uri nar y mar k ers; 
•  Dr u g acc o u nta bilit y of C C X 1 6 8 or C C X 1 6 8 place b o b ottles; 
•  Dr u g acc o u nta bilit y of pr e d nis o ne b ottles;  
•  St u d y m e dicati o n a n d c ortic oster oi ds ( 1 kit of C C X 1 6 8 or C C X 1 6 8 place b o, 1 b ottle of 
2 0 m g pr e d nis o ne a n d 1 b ottle of 5 m g pre d nis o ne) will be pr o vi de d t o t he s u bject wit h 
d osi n g i nstr ucti o ns; t he s u bject will ta ke t he m or ni n g d oses fr o m t hese kits w hile at  t he 
st u d y site, u nless t he m or ni n g d oses ha v e alrea d y bee n ta ke n b y t h e s u bject; 
•  C ycl o p h os p ha mi de I V d ose will be gi ve n after recei pt of t he l ocal W B C c o u nt (see 
S ecti o n 1 1. 6 ) t o s u bjects i n t he c ycl o p h os p ha mi de strat u m; T he start a n d e n d ti mes of t he 
i nf usi o n will be rec or d e d; 
•  Rit u xi ma b will be gi ve n t o s u bjects i n t he rit u xi ma b strat u m (see S ecti o n 1 1. 7 ); A d ose of 
3 7 5 m g/ m 2 will be gi ve n ; T he start a n d e n d ti mes of t he i nf usi o n will be rec or de d; 
•  A bl o o d sa m ple will be c ollecte d f or C C X 1 6 8 plas ma c o nce ntrati o n meas ure me nt; t he 
date a n d ti me of t he last d ose pri or t o sa m ple c oll ecti o n will be rec or de d; 
•  A n y c ha n ges i n c o nc o mita nt me dicati o n use will be rec or de d; a n d  
•  After all st u d y pr oce d ures ha ve bee n c o m plete d, t he s u bject will be re mi n d e d t o: 
− C o me t o t he st u d y ce nt er f or t he Da y 2 2 st u d y visit; 
− St ore t he st u d y me dicati o ns i n a c o ol a n d dr y place acc or di n g t o la b el i nstr ucti o ns f or 
t he d urati o n of t he st u d y;  
− Ta ke t he C C X 1 6 8 or C C X 1 6 8 place b o me di cati o n as i nstr ucte d;  
− Ta ke t he pr e d nis o ne d ose as i nstr ucte d ;  
− N ot t o ta ke C C X 1 6 8 a n d pre d nis o ne me dicati o n o n t he m or ni n g of Da y 2 2, u nless t he 
visit is sc he d ule d i n t he after n o o n, i n w hic h case C C X 1 6 8 a n d pre d nis o ne me dicati o n 
s h o ul d be ta ke n t he m or ni n g of D a y 2 2; 
− Bri n g all st u d y m e dicati o n c o ntai ners t o t he ne x t st u d y visit, w het her e m pt y or n ot, 
a n d 
− C o nti n ue ta ki n g all t heir ot her c o nc o mita nt me dicati o ns as us ual. 
6. 6.  
St u d y D a y 2 2  
T he St u d y D a y 2 2 visit m ust occ ur wit hi n a +/- 2- da y wi n d o w of t he s c he d ule d date. D uri n g t his 
visit, t he f oll o wi n g st u d y pr oce d ur es will be perf or me d:  
•  B o d y s yste m re vie w t o deter mi ne if t here were a n y c h a n ges fr o m Da y 1 5;  

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 5 9 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
•  All treat me nt -e mer ge nt a d verse e v e nts will be rec or de d;  
•  Vital si g ns (te m perat ure, bl o o d press ure, heart rate); 
•  S u bjects will be as ke d t o v oi d t heir bla d ders c o m plete l y, a n d a re pres e ntati ve clea n catc h, 
mi dstrea m uri ne sa m ple will be c ollecte d:  
− A uri ne sa m ple will be se nt t o t he ce ntral la b orat or y f or uri nal ysis i ncl u di n g p H, 
s pecific gr a vit y, gl uc os e, nitrite, ket o nes, bilir u bi n, ur o bili n o ge n, R B Cs, a n d W B Cs; 
•  Dr u g ac c o u nta bilit y of pr e d nis o ne b ottles; 
•  C ortic oster oi d  me dicati o n ( 1 b ottle of 2 0 m g pre d nis o ne a n d 1 b ottle of 5 m g pre d nis o n e ) 
will be pr o vi de d t o t he s u bject wit h d osi n g i nstr ucti o ns; t he s u bject will ta ke t he m or ni n g 
d ose fr o m t he pr e vi o usl y-s u p plie d C C X 1 6 8 or place b o kits a n d t he ne w s u p pl y of 
pre d nis o ne w hile at t he st u d y site, u nless t he m or ni n g d ose h as alrea d y bee n ta ke n b y t he 
s u bject; 
•  A bl o o d sa m ple will be c ollecte d f or C C X 1 6 8 plas ma c o nce ntrati o n meas ure me nt; t he 
date a n d ti me of t he last d ose pri o r t o sa m ple c oll ecti o n will be rec or de d; 
•  Rit u xi ma b will be gi ve n t o s u bjects  i n t he rit u xi ma b strat u m (see Secti o n 1 1. 7 ); A d ose of 
3 7 5 m g/ m 2 will be gi ve n; T he start a n d e n d ti mes of t he i nf usi o n will be rec or de d; 
•  A n y c ha n ges i n c o nc o mita nt me dicati o n use will be rec or de d; a n d  
•  After all st u d y pr oce d ures ha ve bee n c o m plete d, t he s u bject will be re mi n d e d t o: 
− C o me t o t he st u d y ce nt er f or t he Da y 2 9 st u d y visit; 
− St ore t he st u d y me dicati o ns i n a c o ol a n d dr y place acc or di n g t o la b el i nstr ucti o ns f or 
t he d urati o n of t he st u d y;  
− Ta ke t he C C X 1 6 8 or C C X 1 6 8 place b o me di cati o n as i nstr ucte d;  
− Ta ke t he p r e d nis o ne d ose as i nstr ucte d; 
− N ot t o ta ke C C X 1 6 8 a n d pre d nis o ne me dicati o n o n t he m or ni n g of Da y 2 9, u nless t he 
visit is sc he d ule d i n t he after n o o n, i n w hic h case C C X 1 6 8 a n d pre d nis o ne me dicati o n 
s h o ul d be ta ke n t he m or ni n g of D a y 2 9;  
− Bri n g all st u d y m e dicati o n c o ntai ners t o t he ne xt st u d y visit, w het her e m pt y or n ot, 
a n d 
− C o nti n ue ta ki n g all t heir ot her c o nc o mita nt me dicati o ns as us ual. 
6. 7.  
St u d y D a y 2 9  
T he St u d y D a y 2 9 visit m ust occ ur wit hi n a +/- 2- da y wi n d o w of t he s c he d ule d date. T he 
s u bjects m ust fast o ver ni g ht f or at least 8 h o urs bef ore t he st u d y visit. D uri n g t his visit, t he 
f oll o wi n g st u d y pr oce d ur es will be perf or me d: 
•  A p h ysical e x a mi nati o n (e x cl u di n g ge nit o uri nar y, o p ht hal mic, a n d fe male breast 
assess me nts) will be perf or me d; b o d y wei g ht will als o be meas ure d;  
•  All treat me nt -e mer ge nt a d verse e v e nts wi ll be rec or de d; 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 6 0 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
•  Vital si g ns (te m perat ure, bl o o d press ure, heart rate); 
•  Ser u m pre g na n c y test f or w o me n of c hil d beari n g p ote ntial; 
•  A 1 2 -lea d E C G will be r ec or de d a n d assess e d f or a n y cli nicall y si g nifica nt a b n or malit y; 
•  Bl o o d will be c ollecte d f or s hi p me nt t o  t he ce ntral la b orat or y f or ser u m c h e mistr y, 
he mat ol o g y, a n d hs C R P meas ure me nts; t he s u bjects ma y eat after t he ser u m c he mistr y 
sa m ple c ollecti o n; 
•  A bl o o d sa m ple will als o be ta ke n f or a n e x pe dite d W B C c o u nt at t he l ocal la b orat or y i n 
or der t o deter mi ne t he a p pr o priate c ycl o p h os p ha mi de d ose (see S ecti o n 1 1. 6 ) f or s u bjects 
w h o are i n t he c ycl o p h os p ha mi de strat u m; 
•  A bl o o d sa m ple will be c ollecte d f or p h ar mac o d y na mics mar ker m eas ure me nts;  
•  S u bjects will be as ke d t o v oi d t heir bla d ders c o m pletel y, a n d a re pres e ntati ve clea n catc h, 
mi dstrea m uri ne sa m ple will be c ollecte d:  
− A uri ne sa m ple will be se nt t o t he ce ntral la b orat or y f or uri nal ysis i ncl u di n g p H, 
s pecific gr a vit y, gl uc os e, nitrite, ket o nes, bilir u bi n, ur o bili n o ge n, R B Cs, a n d W B Cs, 
as well as q uantitati ve m eas ure m e nt of al b u mi n a n d creati ni ne t o calc ulate t he A C R;  
− T w o a d diti o nal uri ne sa m ples will be fr oze n a n d se nt t o t he ce ntral la b orat or y f or 
q ua ntitati ve M C P -1 a n d creati ni ne meas ure m e nts t o calc ulate t he M C P -1:creati ni ne 
rati o, a n d f or e x pl orat or y uri nar y mar k ers; 
•  A N C A (a nti - P R 3 a n d a nti-M P O E LI S A) m eas ure me nt;  
•  B V A S assess me nt; c h est X ra ys will o nl y b e ac q uire d if dee me d cli nicall y n ecessar y b y 
t he Pri nci pal I n vesti gat or (see S ecti o n 1 1. 3 ); 
•  S u bjects will be as ke d t o c o m plete t he S F 3 6 v 2 a n d E Q- 5 D- 5 L q u esti o n naires; 
•  Dr u g acc o u nta bilit y of C C X 1 6 8 or C C X 1 6 8 place b o b ottles; 
•  St u d y m e dicati o n ( 1 kit of C C X 1 6 8 or C C X 1 6 8 place b o) will be pr o vi de d t o t he s u bject 
wit h d osi n g i nstr ucti o ns; t he s u b ject will ta ke t he m or ni n g d ose fr o m t his kit a n d fr o m t he 
pre vi o usl y-s u p plie d pre d nis o ne w hile at t he st u d y site, u nless t he m or ni n g d oses ha ve 
alrea d y b ee n ta k e n b y t he s u bject;  
•  Dr u g acc o u nta bilit y of pr e d nis o ne b ottles; 
•  C ycl o p h os p ha mi de I V d ose will be gi ve n after recei pt of t he l ocal W B C c o u nt (see 
S ecti o n 1 1. 6 ) t o s u bjects i n t he c ycl o p h os p ha mi de strat u m; T he start a n d e n d ti mes of t he 
i nf usi o n will be rec or d e d; 
•  A bl o o d sa m ple will be c ollecte d f or C C X 1 6 8 plas ma c o nce ntrati o n meas ure me nt; t he 
date a n d ti me of t he last d ose pri or t o sa m ple c oll ecti o n will be rec or de d; 
•  A n y c ha n ges i n c o nc o mita nt me dicati o n use will be rec or de d; a n d  
•  After all st u d y pr oce d ures ha ve bee n c o m plete d, t he s u bject will be re mi n d e d t o: 
− C o me t o t he st u d y ce nt er f or t he Da y 4 3 st u d y visit; 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 6 1 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
− St ore t he st u d y me dicati o ns i n a c o ol a n d dr y place acc or di n g t o la b el i nstr ucti o ns f or 
t he d urati o n of t he st u d y; 
− Ta ke t he C C X 1 6 8 or C C X 1 6 8 place b o me di cati o n as i nstr ucte d;  
− Ta ke t he p r e d nis o ne d ose as i nstr ucte d; 
− N ot t o ta ke C C X 1 6 8 a n d pre d nis o ne me dicati o n o n t he m or ni n g of Da y 4 3, u nless t he 
visit is sc he d ule d i n t he after n o o n, i n w hic h case C C X 1 6 8 a n d pre d nis o ne me dicati o n 
s h o ul d be ta ke n t he m or ni n g of D a y 4 3;  
− Bri n g all st u d y m e dicati o n c o ntai ners t o t he ne xt st u d y visit, w het her e m pt y or n ot, 
a n d 
− C o nti n ue ta ki n g all t heir ot her c o nc o mita nt me dicati o ns as us ual. 
6. 8.  
St u d y D a y 4 3  
T he St u d y D a y 4 3 visit m ust occ ur wit hi n +/- 2 d a ys of t he sc h e d ule d date. T he s u bjects m ust 
fast o ver ni g ht f or at least 8 h o urs bef ore t he st u d y visit. D uri n g t his visit, t he f oll o wi n g st u d y 
pr oce d ur es will be perf or me d: 
•  B o d y s yste m re vie w t o deter mi ne if t here were a n y c h a n ges fr o m Da y 2 9;  
•  All treat me nt -e mer ge nt a d verse e v e nts will be rec or de d;  
•  Vital si g ns (te m perat ure, bl o o d press ure, heart rate); 
•  Bl o o d will be c o llecte d f or s hi p me nt t o t he ce ntral la b orat or y f or ser u m c h e mistr y a n d 
he mat ol o g y meas ure m e nts; t he s u bjects ma y eat after t he ser u m c he mistr y sa m ple 
c ollecti o n;  
•  S u bjects will be as ke d t o v oi d t heir bla d ders c o m pletel y, a n d a re pres e ntati ve clea n catc h, 
mi dstrea m uri ne sa m ple will be c ollecte d:  
− A uri ne sa m ple will be se nt t o t he ce ntral la b orat or y f or uri nal ysis i ncl u di n g p H, 
s pecific gr a vit y, gl uc os e, nitrite, ket o nes, bilir u bi n, ur o bili n o ge n, R B Cs, a n d W B Cs; 
•  Dr u g acc o u nta bilit y of C C X 1 6 8 or C C X 1 6 8 place b o b ottles;  
•  St u d y m e dicati o n a n d c ortic oster oi ds ( 1 kit of C C X 1 6 8 or C C X 1 6 8 place b o, a n d 1 b ottle 
of 2 0 m g pr e d nis o ne) will be pr o vi de d t o t he s u bject wit h d osi n g i nstr ucti o ns; t he s u bject 
will ta ke t he m or ni n g d os es fr o m t he ne w s u p pl y w hile at t he st u d y si te, u nless t he 
m or ni n g d oses h a ve alr ea d y bee n ta ke n b y t h e s u bject; 
•  Dr u g acc o u nta bilit y of pr e d nis o ne b ottles; 
•  A bl o o d sa m ple will be c ollecte d f or C C X 1 6 8 plas ma c o nce ntrati o n meas ure me nt; t he 
date a n d ti me of t he last d ose pri or t o sa m ple c oll ecti o n will  be rec or de d;  
•  A n y c ha n ges i n c o nc o mita nt me dicati o n use will be rec or de d; a n d  
•  After all st u d y pr oce d ures ha ve bee n c o m plete d, t he s u bject will be re mi n d e d t o: 
− C o me t o t he st u d y ce nt er f or t he Da y 5 7 st u d y visit; 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 6 2 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
− St ore t he st u d y me dicati o ns i n a c o ol a n d dr y place acc or di n g t o la b el i nstr ucti o ns f or 
t he d urati o n of t he st u d y; 
− Ta ke t he C C X 1 6 8 or C C X 1 6 8 place b o me di cati o n as i nstr ucte d;  
− Ta ke t he pr e d nis o ne d ose as i nstr ucte d;  
− N ot t o ta ke C C X 1 6 8 a n d pre d nis o ne me dicati o n o n t he m or ni n g of Da y 5 7, u nless t he 
visit is sc he d ule d i n t he after n o o n, i n w hic h case C C X 1 6 8 a n d pre d nis o ne me dicati o n 
s h o ul d be ta ke n t he m or ni n g of D a y 5 7;  
− Bri n g all st u d y m e dicati o n c o ntai ners t o t he ne xt st u d y visit, w het her e m pt y or n ot, 
a n d 
− C o nti n ue ta ki n g all t heir ot her c o nc o mita nt me dicati o ns as us ual. 
6. 9.  
St u d y D a y 5 7  
T he St u d y D a y 5 7 visit m ust occ ur wit hi n +/- 2 d a ys of t he sc h e d ule d date. D uri n g t his visit, t he 
f oll o wi n g st u d y pr oce d ur es will be perf or me d: 
•  A p h ysic al e x a mi nati o n (e x cl u di n g ge nit o uri nar y, o p ht hal mic, a n d fe male breas t 
assess me nts) will be perf or me d; b o d y wei g ht will als o be meas ure d;  
•  All treat me nt -e mer ge nt a d verse e v e nts will be rec or de d;  
•  Vital si g ns (te m perat ure, bl o o d press ure, heart rate); 
•  Ser u m pre g na n c y test f or w o me n of c hil d beari n g p ote ntial; 
•  Bl o o d will be c ollecte d f or s hi p me nt t o t he ce ntral la b orat or y f or ser u m creati ni ne a n d 
hs C R P meas ure me nt;  
•  A bl o o d sa m ple will als o be ta ke n f or a n e x pe dite d W B C c o u nt at t he l ocal la b orat or y i n 
or der t o deter mi ne t he a p pr o priate c ycl o p h os p ha mi de d ose (see s ecti o n 1 1. 6 ) f or s u bjects 
w h o are i n t he c ycl o p h os p ha mi de strat u m; 
•  S u bjects will be as ke d t o v oi d t heir bla d ders c o m pletel y, a n d a re pres e ntati ve clea n cat c h, 
mi dstrea m uri ne sa m ple will be c ollecte d:  
− A uri ne sa m ple will be se nt t o t he ce ntral la b orat or y f or uri nal ysis i ncl u di n g p H, 
s pecific gr a vit y, gl uc os e, nitrite, ket o nes, bilir u bi n, ur o bili n o ge n, R B Cs, a n d W B Cs, 
as well as q ua ntitati ve m eas ure m e nt of al b u mi n a n d creati ni ne t o calc ulate t he A C R; 
− T w o a d diti o nal uri ne sa m ples will be fr oze n a n d se nt t o t he ce ntral la b orat or y f or 
q ua ntitati ve M C P -1 a n d creati ni ne meas ure m e nts t o calc ulate t he M C P -1:creati ni ne 
rati o, a n d f or e x pl orat or y uri nar y mar k ers; 
•  Dr u g acc o u nta bilit y of C C X 1 6 8 or C C X 1 6 8 place b o b ottles; 
•  St u d y m e dicati o n a n d c ortic oster oi ds ( 1 kit of C C X 1 6 8 or C C X 1 6 8 place b o, a n d 2 b ottle s 
of 5 m g pr e d nis o ne) will be pr o vi de d t o t he s u bject wit h d osi n g i nstr ucti o ns; t he s u bject 
will ta ke t he m or ni n g d os es fr o m t he ne w s u p pl y w hile at t he st u d y site, u nless t he 
m or ni n g d oses h a ve alr ea d y bee n ta ke n b y t h e s u bject; 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 6 3 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
•  Dr u g acc o u nta bilit y of pr e d nis o ne b ottles; 
•  C ycl o p h os p ha mi de I V d ose will be gi ve n after recei pt of t he l ocal W B C c o u nt (see 
S ecti o n 1 1. 6 ) t o s u bjects i n t he c ycl o p h os p ha mi de strat u m; T he start a n d e n d ti mes of t he 
i nf usi o n will be rec or d e d; 
•  A bl o o d sa m ple will be c ollecte d f or C C X 1 6 8 plas ma c o nce ntrati o n meas ure me nt; t he 
date a n d ti me of t he last d ose pri or t o sa m ple c oll ecti o n will be rec or de d; 
•  A n y c ha n ges i n c o nc o mita nt me dicati o n use will be rec or de d; a n d  
•  After all st u d y pr oce d ures ha ve bee n c o m plete d, t he s u bject will be re mi n d e d t o: 
− C o me t o t he st u d y ce nt er f or t he Da y 7 1 st u d y visit; 
− St ore t he st u d y me dicati o ns i n a c o ol a n d dr y place acc or di n g t o la b el i nstr ucti o ns f or 
t he d urati o n of t he st u d y;  
− Ta ke t he C C X 1 6 8 or C C X 1 6 8 place b o me di cati o n as i nstr ucte d; 
− Ta ke t he p r e d nis o ne d ose as i nstr ucte d; 
− N ot t o ta ke C C X 1 6 8 a n d pre d nis o ne me dicati o n o n t he m or ni n g of Da y 7 1, u nless t he 
visit is sc he d ule d i n t he after n o o n, i n w hic h case C C X 1 6 8 a n d pre d nis o ne me dicati o n 
s h o ul d be ta ke n t he m or ni n g of D a y 7 1;  
− Bri n g all st u d y m e dicati o n c o ntai ners t o t he ne xt st u d y visit, w het her e m pt y or n ot, 
a n d 
− C o nti n ue ta ki n g all t heir ot her c o nc o mita nt me dicati o ns as us ual. 
6. 1 0.  
St u d y D a y 7 1  
T he St u d y D a y 7 1 visit m ust occ ur wit hi n +/- 2 d a ys of t he sc h e d ule d date. T he s u bjects m ust 
fast o ver ni g ht f or at least 8 h o urs bef ore t he st u d y visit. D uri n g t his visit, t he f oll o wi n g st u d y 
pr oce d ur es will be perf or me d: 
•  B o d y s yste m re vie w t o deter mi ne if t here were a n y c h a n ges fr o m Da y 5 7;  
•  All treat me nt -e mer ge nt a d verse e v e nts will be rec or de d;  
•  Vital si g ns (te m perat ure, bl o o d pre ss ure, heart rate); 
•  Bl o o d will be c ollecte d f or s hi p me nt t o t he ce ntral la b orat or y f or ser u m c h e mistr y a n d 
he mat ol o g y meas ure m e nts; t he s u bjects ma y eat after t he ser u m c he mistr y sa m ple 
c ollecti o n;  
•  S u bjects will be as ke d t o v oi d t heir bla d ders c o m pletel y, a n d a re pres e ntati ve clea n catc h, 
mi dstrea m uri ne sa m ple will be c ollecte d:  
− A uri ne sa m ple will be se nt t o t he ce ntral la b orat or y f or uri nal ysis i ncl u di n g p H, 
s pecific gr a vit y, gl uc os e, nitrite, ket o nes, bilir u bi n, ur o bili n o ge n, R B Cs, a n d W B Cs; 
•  Dr u g acc o u n ta bilit y of C C X 1 6 8 or C C X 1 6 8 place b o b ottles; 
•  Dr u g acc o u nta bilit y f or pre d nis o ne b ottles; 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 6 4 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
•  St u d y m e dicati o n a n d c ortic oster oi ds ( 1 kit of C C X 1 6 8 or C C X 1 6 8 place b o, a n d 1 b ottle 
of 5 m g pr e d nis o ne) will be pr o vi de d t o t he s u bject wit h d osi n g i nstr ucti o ns; t he s u bject 
will ta ke t he m or ni n g d os e fr o m t his ne w s u p pl y w hile at t he st u d y site, u nless t he 
m or ni n g d ose h as alrea d y bee n ta ke n b y t h e s u bject; 
•  A bl o o d sa m ple will be c ollecte d f or C C X 1 6 8 plas ma c o nce ntrati o n meas ure me nt; t he 
date a n d ti me of t he last d ose pri or t o sa m ple c oll ecti o n will be rec or de d; 
•  A n y c ha n ges i n c o nc o mita nt me dicati o n use will be rec or de d; a n d  
•  After all st u d y pr oce d ures ha ve bee n c o m plete d, t he s u bject will be re mi n d e d t o: 
− C o me t o t he st u d y ce nt er f or t he Da y 8 5 st u d y visit; 
− St ore t he st u d y me dicati o ns i n a c o ol a n d dr y place acc or di n g t o la b el i nstr ucti o ns f or 
t he d urati o n of t he st u d y; 
− Ta ke t he C C X 1 6 8 or C C X 1 6 8 place b o me di cati o n as i nstr ucte d;  
− Ta ke t he p r e d nis o ne d ose as i nstr ucte d; 
− N ot t o ta ke C C X 1 6 8 a n d pre d nis o ne me dicati o n o n t he m or ni n g of Da y 8 5, b ut t o 
ta ke t he pre d nis o n e me di cati o n at t he st u d y ce nter o n t he da y of t he visit;  
− Bri n g all st u d y m e dicati o n c o ntai ners t o t he ne xt st u d y visit, w het her e m pt y or n ot, 
a n d 
− C o nti n ue ta ki n g all t heir ot her c o nc o mita nt me dicati o ns as us ual. 
6. 1 1.  
St u d y D a y 8 5  
T he St u d y D a y 8 5 visit m ust occ ur wit hi n +/- 2 d a ys of t he sc h e d ule d date. T he s u bjects m ust 
fast o ver ni g ht f or at least 8 h o urs bef ore t he st u d y visit. D uri n g t his visit, t he foll o wi n g st u d y 
pr oce d ur es will be perf or me d: 
•  A p h ysical e x a mi nati o n (e x cl u di n g ge nit o uri nar y, o p ht hal mic, a n d fe male breast 
assess me nts) will be perf or me d; b o d y wei g ht will als o be meas ure d;  
•  All treat me nt -e mer ge nt a d verse e v e nts will be rec or de d;  
•  Vital si g ns (te m perat ure, bl o o d press ure, heart rate); 
•  Ser u m pre g na n c y test f or w o me n of c hil d beari n g p ote ntial; 
•  A 1 2 -lea d E C G will be r ec or de d a n d assess e d f or a n y cli nicall y si g nifica nt a b n or malit y; 
•  Bl o o d will be c ollecte d f or s hi p me nt t o t he ce ntral la b orat or y f or ser u m c h e mistr y, 
he mat ol o g y a n d hs C R P meas ure me nts; t he s u bjects ma y eat after t he ser u m c he mistr y 
sa m ple c ollecti o n; 
•  A bl o o d sa m ple will als o be ta ke n f or a n e x pe dite d W B C c o u nt at t he l ocal la b orat or y i n 
or der t o deter mi ne t he a p pr o priate c ycl o p h os p ha mi de d ose (see S ecti o n 1 1. 6 ) f or s u bjects 
w h o are i n t he c ycl o p h os p ha mi de strat u m; 
•  A bl o o d sa m ple will be c ollecte d f or p h ar mac o d y na mics mar ker m eas ure me nts;  

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 6 5 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
•  C ycl o p h os p ha mi de I V d ose will be gi ve n after recei pt of t he l ocal W B C c o u nt (see 
S ecti o n 1 1. 6 ) t o s u bjects i n t he c ycl o p h os p ha mi de strat u m; T he start a n d e n d ti mes of t he 
i nf usi o n will be rec or d e d; 
•  S u bjects will be as ke d t o v oi d t heir bla d ders c o m pletel y, a n d a re pres e ntati ve clea n catc h, 
mi dstrea m uri ne sa m ple will be c ollecte d:  
− A uri ne sa m ple will be se nt t o t he ce ntral la b orat or y f or uri nal ysis i ncl u di n g p H, 
s pecific gr a vit y, gl uc os e, nitrite, ket o nes, bilir u bi n, ur o bili n o ge n, R B Cs, a n d W B Cs, 
as well as q ua ntitati ve m eas ure m e nt of al b u mi n a n d creati ni ne t o calc ulate t he A C R;  
− T w o a d diti o nal uri ne sa m ples will be fr oze n a n d se nt t o t he ce ntral la b orat or y f or 
q ua ntitati ve M C P -1 a n d creati ni ne meas ure m e nts t o calc ulate t he M C P -1:creati ni ne 
rati o, a n d f or e x pl orat or y uri nar y mar k ers; 
•  A N C A (a nti - P R 3 a n d a nti-M P O E LI S A) m eas ure me nt;  
•  B V A S assess me nt; c h est X ra ys will o nl y b e ac q uire d if dee me d cli nicall y n ecessar y b y 
the Pri nci pal I n vesti gat or (see Secti o n 1 1. 3 ); 
•  V DI assess me nt (s ee Secti o n 1 1. 4 ); 
•  S u bjects will be as ke d t o c o m plete t he S F 3 6 v 2 a n d E Q- 5 D- 5 L q u esti o n naires; 
•  Dr u g acc o u nta bilit y of C C X 1 6 8 or C C X 1 6 8 place b o b ottles; 
•  Dr u g acc o u nta bilit y of pr e d nis o ne b ottles; 
•  C ortic oster oi d  me dicati o n ( 1 b ottle of 5 m g pre d nis o ne) will be pr o vi de d t o t he s u bject 
wit h d osi n g i nstr ucti o ns; t he s u bject will ta ke t he m or ni n g d ose fr o m t his b ottle  w hile at 
t he st u d y site, u nless t he m or ni n g d ose h as alrea d y bee n ta ke n b y t h e s u bject; 
•  A bl o o d sa m p le will be c ollecte d f or C C X 1 6 8 plas ma c o nce ntrati o n meas ure me nt; t he 
date a n d ti me of t he last d ose pri or t o sa m ple c oll ecti o n will be rec or de d; 
•  If a r e nal bi o ps y has bee n perf or me d pri or t o Da y 1 f or re n al disease assess me nt, if 
p ossi ble, a re nal bi o ps y will be ta ke n at/ wit hi n  1 wee k after t he Da y 8 5 visit a n d t he 
Hist ol o g y F or m c o m plete d ; 
•  A n y c ha n ges i n c o nc o mita nt me dicati o n use will be rec or de d; a n d  
•  After all st u d y pr oce d ures ha ve bee n c o m plete d, t he s u bject will be re mi n d e d t o: 
− C o me t o t he st u d y ce nt er f or t he Da y 9 9 st u d y visit; 
− St ore t he st u d y me dicati o ns i n a c o ol a n d dr y place acc or di n g t o la b el i nstr ucti o ns f or 
t he d urati o n of t he st u d y; 
− Ta ke t he pr e d nis o ne d ose as i nstr ucte d;  
− N ot t o ta ke t he pre d nis o n e me dicati o n o n t he m or ni n g of D a y 9 9, u nless t he visit is 
sc he d ule d i n t he after n o o n, i n w hic h case pre d nis o ne me dicati o n s h o ul d be ta ke n t he 
m or ni n g of D a y 9 9;   
− Bri n g all st u d y m e dicati o n c o ntai ners t o t he ne xt st u d y visit, w het her e m pt y or n ot, 
a n d 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 6 6 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
− C o nti n ue ta ki n g all t heir ot her c o nc o mita nt me dicati o ns as us ual. 
6. 1 2.  
St u d y D a y 9 9  
T he St u d y D a y 9 9 visit m ust occ ur wit hi n +/- 4 d a ys of t he sc h e d ule d date. T he s u bjects m ust 
fast o ver ni g ht f or at least 8 h o urs bef ore t he st u d y visit. D uri n g t his visit, t he f oll o wi n g stu d y 
pr oce d ur es will be perf or me d: 
•  B o d y s yste m re vie w t o deter mi ne if t here were a n y c h a n ges fr o m Da y 8 5;  
•  All treat me nt -e mer ge nt a d verse e v e nts will be rec or de d;  
•  Vital si g ns (te m perat ure, bl o o d press ure, heart rate); 
•  Bl o o d will be c ollecte d f or s hi p me nt t o t he ce ntral la b orat or y f or ser u m c h e mistr y a n d 
he mat ol o g y meas ure m e nts; t he s u bjects ma y eat after t he ser u m c he mistr y sa m ple 
c ollecti o n;  
•  S u bjects will be as ke d t o v oi d t heir bla d ders c o m pletel y, a n d a re pres e ntati ve clea n  catc h, 
mi dstrea m uri ne sa m ple will be c ollecte d:  
− A uri ne sa m ple will be se nt t o t he ce ntral la b orat or y f or uri nal ysis i ncl u di n g p H, 
s pecific gr a vit y, gl uc os e, nitrite, ket o nes, bilir u bi n, ur o bili n o ge n, R B Cs, a n d W B Cs; 
•  Dr u g acc o u nta bilit y of pr e d nis o ne b ot tles; 
•  C ortic oster oi d  me dicati o n ( 1 b ottle of 5 m g pre d nis o ne) will be pr o vi de d t o t he s u bject 
wit h d osi n g i nstr ucti o ns; t he s u bject will ta ke t he m or ni n g d ose fr o m t his b ottle  w hile at 
t he st u d y site, u nless t he m or ni n g d ose h as alrea d y bee n ta ke n b y t h e s u bject; 
•  S u bjects i n t he c ycl o p h os p ha mi de strat u m will start oral azat hi o pri ne after t he W B C 
c o u nt fr o m t he l ocal la b orat or y has bee n recei v e d, a n d will c o nti n ue ta ki n g it t hr o u g h 
Da y 1 6 8 (see S ecti o n 1 1. 6  f or d osi n g rec o m me n d ati o ns); S u bjects i n t he rit u xi ma b 
strat u m will n ot start azat hi o pri ne d osi n g; 
•  A n y c ha n ges i n c o nc o mita nt me dicati o n use will be rec or de d; a n d  
•  After all st u d y pr oce d ures ha ve bee n c o m plete d, t he s u bject will be re mi n d e d t o: 
− C o me t o t he st u d y ce nt er f or t he Da y 1 1 3 st u d y visit; 
− St ore t he st u d y me dicati o n i n a c o ol a n d dr y place acc or di n g t o la b el i nstr ucti o ns f or 
t he d urati o n of t he st u d y; 
− Ta ke t he p r e d nis o ne d ose as i nstr ucte d; 
− N ot  t o ta ke t he pre d nis o n e me dicati o n o n t he m or ni n g of D a y 1 1 3, u nless t h e visit is 
sc he d ule d i n t he after n o o n, i n w hic h case pre d nis o ne me dicati o n s h o ul d be ta ke n t he 
m or ni n g of D a y 1 1 3; 
− F or t he c ycl o p h os p ha mi d e strat u m, ta ke t he azat hi o pri ne d ose as i nstr u cte d;   
− Bri n g all st u d y m e dicati o n c o ntai ners t o t he ne xt st u d y visit, w het her e m pt y or n ot, 
a n d 
− C o nti n ue ta ki n g all t heir ot her c o nc o mita nt me dicati o ns as us ual. 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 6 7 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
6. 1 3.  
St u d y D a y 1 1 3  
T he St u d y D a y 1 1 3 visit m ust occ ur wit hi n +/- 4 d a ys of t he sc h e d ule d date. D uri n g t his visit, t he 
f oll o wi n g st u d y pr oce d ur es will be perf or me d: 
•  A p h ysical e x a mi nati o n (e x cl u di n g ge nit o uri nar y, o p ht hal mic, a n d fe male breast 
assess me nts) will be perf or me d; b o d y wei g ht will als o be meas ure d;  
•  All treat me nt -e mer ge nt a d verse e v e nts will b e rec or de d; 
•  Vital si g ns (te m perat ure, bl o o d press ure, heart rate); 
•  Ser u m pre g na n c y test f or w o me n of c hil d beari n g p ote ntial; 
•  Bl o o d will be c ollecte d f or s hi p me nt t o t he ce ntral la b orat or y f or ser u m creati ni ne a n d 
hs C R P meas ure me nt;  
•  B V A S assess me nt; c h est X  ra ys will o nl y b e ac q uire d if dee me d cli nicall y n ecessar y b y 
t he Pri nci pal I n vesti gat or (see S ecti o n 1 1. 3 ); 
•  S u bjects will be as ke d t o v oi d t heir bla d ders c o m pletel y, a n d a re pres e ntati ve clea n catc h, 
mi dstrea m uri ne sa m ple will be c ollecte d:  
− A uri ne sa m ple will be se nt t o t he ce ntral la b orat or y f or uri nal ysis i ncl u di n g p H, 
s pecific gr a vit y, gl uc os e, nitrite, ket o nes, bilir u bi n, ur o bili n o ge n, R B Cs, a n d W B Cs, 
as well as q ua ntitati ve m eas ure m e nt of al b u mi n a n d creati ni ne t o calc ulate t he A C R;  
− T w o a d diti o nal uri ne sa m ples will be fr oze n a n d se nt t o t he ce ntral la b orat or y f or 
q ua ntitati ve M C P -1 a n d creati ni ne meas ure m e nts t o calc ulate t he M C P -1:creati ni n e 
rati o, a n d f or e x pl orat or y uri nar y mar k ers; 
•  Dr u g acc o u nta bilit y of pr e d nis o ne b ottles; 
•  C ortic oster oi d  me dicati o n ( 1 b ottle of 5 m g pre d nis o ne) will be pr o vi de d t o t he s u bject 
wit h d osi n g i nstr ucti o ns; t he s u bject will ta ke t he m or ni n g d ose fr o m t his b ott le w hile at 
t he st u d y site, u nless t he m or ni n g d ose h as alrea d y bee n ta ke n b y t h e s u bject; 
•  Azat hi o pri ne will be pr o vi de d t o s u bjects i n t he c ycl o p h os p h a mi de strat u m;   
•  A N C A (a nti - P R 3 a n d a nti-M P O E LI S A) m eas ure me nt;  
•  A n y c ha n ges i n c o nc o mita nt me dicati o n us e will be rec or de d; a n d  
•  After all st u d y pr oce d ures ha ve bee n c o m plete d, t he s u bject will be re mi n d e d t o: 
− C o me t o t he st u d y ce nt er f or t he Da y 1 4 1 st u d y visit;  
− St ore t he st u d y me dicati o n i n a c o ol a n d dr y place acc or di n g t o la b el i nstr ucti o ns f or 
t he d urati o n of t he st u d y; 
− Ta ke t he pr e d nis o ne d ose as i nstr ucte d; 
− F or t he c ycl o p h os p ha mi d e strat u m, ta ke t he azat hi o pri ne d ose as i nstr ucte d; 
− N ot t o ta ke t he pre d nis o n e me dicati o n o n t he m or ni n g of D a y 1 4 1; a n d 
− C o nti n ue ta ki n g all t heir ot her c o nc o mita nt me dicati o ns as us ual. 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 6 8 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
6. 1 4.  
St u d y D a y 1 4 1  
T he St u d y D a y 1 4 1 visit m ust occ ur wit hi n +/- 4 d a ys of t he sc h e d ule d date. T he s u bjects m ust 
fast o ver ni g ht f or at least 8 h o urs bef ore t he st u d y visit. D uri n g t his visit, t he f oll o wi n g st u d y 
pr oce d ur es will be perf or me d: 
•  B o d y s yste m re vie w t o deter mi ne if t here were a n y c h a n ges fr o m Da y 1 1 3;  
•  All treat me nt -e mer ge nt a d verse e v e nts will be rec or de d;  
•  Vital si g ns (te m perat ure, bl o o d press ure, heart rate); 
•  Bl o o d will be c ollecte d f or s hi p me nt t o t he ce ntral la b orat or y f or ser u m c h e mistr y a n d 
he mat ol o g y meas ure m e nts; t he s u bjects ma y eat after t he ser u m c he mistr y sa m ple 
c ollecti o n;  
•  S u bjects will be as ke d t o v oi d t heir bla d ders c o m pletel y, a n d a re pres e ntati ve clea n catc h, 
mi dstrea m uri ne sa m ple will be c ollecte d:  
− A uri ne sa m ple will be  se nt t o t he ce ntral la b orat or y f or uri nal ysis i ncl u di n g p H, 
s pecific gr a vit y, gl uc os e, nitrite, ket o nes, bilir u bi n, ur o bili n o ge n, R B Cs, a n d W B Cs; 
•  Dr u g acc o u nta bilit y of pr e d nis o ne b ottles; 
•  Azat hi o pri ne will be pr o vi de d t o s u bjects i n t he c ycl o p h os p h a mi de strat u m; 
•  A n y c ha n ges i n c o nc o mita nt me dicati o n use will be rec or de d; a n d  
•  After all st u d y pr oce d ures ha ve bee n c o m plete d, t he s u bject will be re mi n d e d t o: 
− Ta ke t he azat hi o pri ne d ose as i nstr ucte d t hr o u g h Da y 1 6 8, if i n t he c ycl o p h os p ha mi de 
strat u m; 
− C o me t o t he st u d y ce nt er f or t he Da y 1 6 9 st u d y visit; a n d 
− C o nti n ue ta ki n g all t heir ot her c o nc o mita nt me dicati o ns as us ual. 
6. 1 5.  
St u d y D a y 1 6 9  
T he St u d y D a y 1 6 9 visit m ust occ ur wit hi n +/- 4 d a ys of t he sc h e d ule d date. T he s u bjects m ust 
fast o ver ni g ht f or at least 8 h o urs bef ore t he st u d y visit. D uri n g t his visit, t he f oll o wi n g st u d y 
pr oce d ur es will be perf or me d: 
•  A p h ysical e x a mi nati o n (e x cl u di n g ge nit o uri nar y, o p ht hal mic, a n d fe male breast 
assess me nts) will be perf or me d; b o d y wei g ht will als o be meas ure d;  
•  All treat me nt -e mer ge nt a d verse e v e nts will be rec or de d;  
•  Vital si g ns (te m perat ure, bl o o d press ure, heart rate); 
•  Ser u m pre g na n c y test f or w o me n of c hil d beari n g p ote ntial; 
•  Bl o o d will be c ollecte d f or s hi p me nt t o t he ce ntral la b orat or y f or ser u m c h e mistr y, 
he mat ol o g y, a n d hs C R P meas ure me nts; t he s u bjects ma y eat after t he ser u m c he mistr y 
sa m ple c ollecti o n; 
•  A bl o o d sa m ple will be c ollecte d f or p h ar mac o d y na mics mar k er m eas ure me nts;  

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 6 9 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
•  S u bjects will be as ke d t o v oi d t heir bla d ders c o m pletel y, a n d a re pres e ntati ve clea n catc h, 
mi dstrea m uri ne sa m ple will be c ollecte d:  
− A uri ne sa m ple will be se nt t o t he ce ntral la b orat or y f or uri nal ysis i ncl u di n g p H, 
s pecific gr a vit y, gl ucos e, nitrite, ket o nes, bilir u bi n, ur o bili n o ge n, R B Cs, a n d W B Cs, 
as well as q ua ntitati ve m eas ure m e nt of al b u mi n a n d creati ni ne t o calc ulate t he A C R;  
− T w o a d diti o nal uri ne sa m ples will be fr oze n a n d se nt t o t he ce ntral la b orat or y f or 
q ua ntitati ve M C P - 1 a n d creati ni ne meas ure m e nts t o calc ulate t he M C P -1:creati ni ne 
rati o, a n d f or e x pl orat or y uri nar y mar k ers; 
•  A N C A (a nti - P R 3 a n d a nti-M P O E LI S A) m eas ure me nt;  
•  B V A S assess me nt; c h est X ra ys will o nl y b e ac q uire d if dee me d cli nicall y n ecessar y b y 
t he Pri nci pal I n vesti gat or (see S ecti o n 1 1. 3 ); 
•  V DI assess me nt (s ee  Secti o n 1 1. 4 ); 
•  S u bjects will be as ke d t o c o m plete t he S F 3 6 v 2 a n d E Q- 5 D- 5 L q u esti o n naires; 
•  Dr u g acc o u nta bilit y of C C X 1 6 8 or place b o, a n d pre d nis o ne b ottles, o nl y if t his is a n earl y 
ter mi nati o n visit; 
•  A n y c ha n ges i n c o nc o mita nt me dicati o n use will be rec or de d; a n d 
•  After all st u d y pr oce d ures ha ve bee n c o m plete d, t he s u bject will be disc har ge d fr o m t he 
st u d y. T he s u bject’s c o n diti o n will be e val uate d b y t he I n v esti gat or at t he e n d of t he 
cli nical trial ( Da y 1 6 9) a n d a p pr o priate S O C  me dical treat me nt will  be pr o vi de d t o all 
s u bjects as nee d e d. 
7.  
S T U D Y A S S E S S M E N T S  
7. 1.  
Effic ac y Assess me nts  
7. 1. 1.  
C ortic ost er oi d Resc ue Use  
If res c ue c ortic oster oi ds are nee de d, it is dee me d a treat me nt fail ure f or p ur p oses of data a nal ysis 
(see S ecti o n 5. 1 0 ). R es c u e c ortic oster oi d us e m ust be rec or de d i n t he E D C f or all s u bjects a n d 
will be c o m pare d a m o n g treat me nt gr o u ps. 
7. 1. 2.  
Esti m at e d Gl o mer ul ar Filtr ati o n R ate  
Esti mate d gl o mer ular filtrati o n rate ( e G F R) will be calc ul ate d at all a p plica ble st u d y visits usi n g 
t he f oll o wi n g M D R D e q uati o n: 
e G F R ( m L/ mi n/ 1. 7 3 m 2) = 1 7 5 x (ser u m creati ni ne i n m g/ d L)-1. 1 5 4 x ( A ge) -0. 2 0 3 x ( 0. 7 4 2 if 
fe male) x ( 1. 2 1 2 if Africa n-A meri ca n/ Bl ac k)  
C ystati n C meas ure me nts ma y b e use d t o cal c ulate e G F R usi n g t he f oll o wi n g e q u ati o n:  
e G F R c ys ( m L/ mi n/ 1. 7 3 m2) = 1 2 7. 7 x ( c ystati n C  i n m g/ L)−1. 1 7 x ( A ge) −0. 1 3 x ( 0. 9 1 if fe male) 
x ( 1. 0 6 if Africa n -A m eri ca n/ Blac k)  

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 7 0 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
7. 1. 3.  
Uri n ar y Assess me nts  
U ri ne sa m ples c ollecte d at all st u d y visits will be a nal yze d f or he m at uria, R B C casts, a n d 
pr otei n uria ( A C R). A clea n catc h mi dstrea m uri ne sa m ple nee ds t o be c ollecte d acc or di n g t o 
i nstr ucti o ns pr o vi de d se paratel y. T h e uri ne sa m ples will be se nt t o t he ce ntral la b orat or y f or 
a nal ysis. Micr osc o pic r e vie w is tri g gere d if a uri n ar y di pstic k test is p ositi ve f or W B C, R B C, 
nitrite or pr otei n. W he n micr osc o p y is perf or me d, he mat uria will be cate g orize d as f oll o ws:  
N o ne, Occasi o nal ( O cc), 1 - 2, 3 - 5, 6 - 9, 1 0 - 1 5, 1 6 - 2 9, 3 0 - 4 9, 5 0 - 7 5, a n d > 7 5 R B Cs per 
hi g h p o wer fiel d. F or t he p ur p ose of a n al yzi n g t he c ha n ge fr o m baseli ne i n uri nar y R B Cs, t he 
f oll o wi n g val ues will be assi g ne d f or eac h cate g or y: 
N o ne = 0. 1, O cc = 0. 5, 1 - 2 = 1, 3 - 5 = 3, 6 - 9 = 6, 1 0 - 1 5 = 1 0, 1 6 - 2 9 = 1 6, 3 0 - 4 9 = 3 0; 
5 0 - 7 5 = 5 0, > 7 5 = 7 5.  
Pr otei n uria will be assess e d b y m eas uri n g t he al b u mi n a n d creati ni ne c o nce ntrati o ns a n d 
calc ulati n g t he uri nar y A C R. Res ults will be e x presse d as m g al b u mi n/ g creati ni ne. T his will be 
d o ne b y t h e ce ntr al la b or at or y.  
7. 1. 4.  
Bir mi n g h a m V asc ulitis Acti vit y Sc ore ( B V A S)  
T he B V A S ( versi o n 3) will be calc ulate d bas e d o n res p o nses i n 1 0 d o mai ns: ge n eral, c ut a ne o us, 
m uc o us me m bra nes a n d e yes, ear/ n ose/t hr oat ( E N T), c hest, car di o vasc ul ar, a b d o mi nal, re nal, 
ner v o us s yst e m, a n d ot her. Secti o n 1 1. 3  pr o vi des a list of ite ms t hat nee d t o be assesse d. B V A S 
data will be a dj u dicate d  bef ore fi nalizati o n.  
7. 1. 5.  
V asc uliti s D a m a g e I n de x ( V DI) 
T he V DI (acc or di n g t o L u q ma ni a n d Hall, 2 0 0 4) will be calc ulate d b ase d o n res p o nses i n 1 1 
or ga n s yste ms as pr o vi de d i n S ecti o n 1 1. 4 . V DI d ata will be a dj u dicate d  b ef ore fi nalizati o n.  
7. 1. 6.  
A nti -Ne utr o p hil C yt o pl as mic A nti b o d y ( A N C A) Assess me nts  
A N C A assess me nts will i ncl u de i n direct i m m u n ofl u oresce n ce test f or P -A N C A a n d C -A N C A as 
well as E LI S A tests f or a nti - P R 3 a n d a nti-M P O at Scree ni n g a n d o nl y E LI S A tests f or a nti - P R 3 
a n d a nti- M P O o n Da ys 1 ( pri or t o d osi n g), 2 9, 8 5, 1 1 3, a n d 1 6 9. E LI S A assa ys will be 
perf or me d b y a ce ntral la b orat or y.  
7. 1. 7.  
Ser u m C -Re a cti ve Pr ot ei n ( C R P)  
Ser u m C R P will be meas ure d b y t he ce ntral la b orat or y o n D a ys 1 ( pri or t o d osi n g), 8, 1 5, 2 9, 5 7, 
8 5, 1 1 3, a n d 1 6 9 b y hi g h se nsiti vit y C R P assa y.  
7. 1. 8.  
Uri n ar y M C P -1 Assess me nts  
Uri ne M C P -1 will be meas ure d b y t he ce ntral la b orat or y i n uri ne sa m ples c ollecte d o n St u d y 
Da ys 1 ( pri or t o d osi n g), 8, 1 5, 2 9, 5 7, 8 5, 1 1 3, a n d 1 6 9 b y s pecific E LI S A. Uri ne creati ni ne will 
be meas ur e d i n t he sa me uri ne sa m ples a n d M C P - 1 le vels will be sta n dar di ze d t o uri ne creati ni ne 
a n d e x presse d as p g M C P -1/ m g cr eati ni ne. A d diti o nal uri ne sa m ples will be st ore d at - 7 0° C a n d 
ma y als o be use d t o meas ure ot her c yt o ki n e, i nfla m mat or y, a n d c o m ple me nt mar kers. 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 7 1 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
7. 1. 9.  
He alt h -Rel ate d Q u alit y of Life Assess me nts  
T he S F - 3 6 v 2 a n d E Q- 5 D-5 L h ealt h -r elate d q ualit y of life q uesti o n naires will be c o m plete d b y 
st u d y s u bjects at t he D a y 1 ( pre- d os e), 2 9, 8 5, a n d 1 6 9 st u d y visits t o meas ure c ha n ges fr o m 
baseli ne i n healt h -r elate d q ualit y of life. Pr o v e n tra nslati o ns will be used f or n o n- E n glis h 
s pea ki n g s u bj ects. A n a d mi nistrat or will facilitate c o m pleti o n of t he q uesti o n naires b y t he 
s u bjects. T he a d mi nistrat or will esta blis h a ra p p ort wit h t he s u bject, e m p hasize t he i m p orta nce of 
c o m pleti n g t he f or m, a n d ser ve t o a ns w er q uesti o ns a n d a d dress c o ncer ns. T he q uesti o n naires 
s h o ul d be c o m plete d b y s u bjects bef or e seei n g t he I n v esti gat or.  
7. 1. 1 0.  
Hist ol o g y 
A sta n dar d H ist ol o g y F or m will be pr o vi de d t o i n vesti gat ors t o d oc u m e nt hist ol o gic fi n di n gs i n a 
sta n dar d ma n ner f or all s u bjects fr o m w h o m re n al bi o psies are ta ke n. T his will be c o m plete d f or 
a vaila ble bas eli ne a n d D a y 8 5 re nal bi o psies. T o t he e xte nt p ossi ble, c ha n ges fr o m baseli ne i n 
t y pical hist ol o gi c fi n di n gs, e. g., p erce nta ge of gl o mer uli wit h cresce nts or scler osis will be 
a nal yze d.  
7. 2.  
S afet y Assess me nts  
7. 2. 1.  
P h ysic al E x a mi n ati o ns a n d Vit al Si g ns 
A c o m plete p h ysical e x a mi nati o n (i ncl u di n g e val uati o n of ge neral a p peara nce/ me ntal stat us, 
H E E N T [ hea d, e yes, ears, n ose, t hr oat], a n d t he f oll o wi n g b o d y s yst e ms: der mat ol o gic, 
car di o vas c ular , r es pirat or y, gastr oi ntesti nal, m usc ul os keletal a n d ne ur ol o gic) f or safet y 
assess me nt will be perf or me d at Scree ni n g a n d St u d y D a ys 1, 1 5, 2 9, 5 7, 8 5, 1 1 3, a n d 1 6 9. 
P h ysical e x a mi nati o n s will i ncl u de a ne ur ol o gical e x a mi nati o n i ncl u di n g s peec h, c o nsci o us ness 
le vel, m o o d, cra nial n er v es, m ot or, c o or di nati o n a n d gait, refle x es, a n d se ns or y s yste ms. P h ysical 
e x a mi nati o ns d uri n g scree ni n g a n d o n St u d y D a ys 1, 2 9, 8 5, 1 1 3, a n d 1 6 9 m ust be s ufficie ntl y 
c o m pre he nsi ve t o i ncl u d e A L L c o m p o ne nts of t h e B V A S (see S ecti o n 1 1. 3 ) a n d V DI (see 
S ecti o n 1 1. 4 ). Fi n di n gs m ust be rec or d e d i n t he s o urce d oc u m e nts. S yste matic b o d y s yste m 
re vie ws will be d o ne at St u d y Da ys 2, 8, 2 2, 4 3, 7 1, 9 9, a n d 1 4 1. 
A n y n e w or w orse ni n g fi n di n gs u p o n p h ysical e x a mi nati o n or b o d y s yste m re vie w nee d t o be 
rec or d e d as a d v erse e ve nts. 
B o d y wei g ht will be meas ure d at Scree ni n g a n d D a ys 1, 1 5, 2 9, 5 7, 8 5, 1 1 3, a n d 1 6 9.  
Vital si g ns will be meas ure d d uri n g Scree ni n g a n d o n eac h sc h e d ule d st u d y da y as i n dicate d i n 
t he Ti me a n d E ve nts T a ble. Bl o o d press ure, p ulse rate, a n d b o d y te m p erat ure will be meas ure d.  
All assess me n ts will be perf or me d w hile t he s u bject is i n t he s u pi ne p ositi o n a n d after t he s u bject 
has reste d f or at least t hr ee mi n utes.  
T wel ve -lea d E C Gs will be ac q uir e d d uri n g Scree ni n g a n d o n D a ys 2 9 a n d 8 5, a n d will be 
assesse d f or a n y cli nicall y si g nifica nt a b n or malities.  
7. 2. 2.  
Cli nic al S af et y L a b or at or y Assess me nts 
T he f oll o wi n g t es ts will be perf or me d at t he visits i de ntifie d i n t he Ti me a n d E ve nts Ta ble . 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 7 2 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
•  He mat ol o g y:  h e m o gl o bi n, he mat ocrit, re d bl o o d cell ( R B C) c o u nt, w hite bl o o d cell 
( W B C) c o u nt wit h differ e ntial, platelet c o u nt, mea n cell he m o gl o bi n ( M C H), mea n cell 
he m o gl o bi n c o n ce ntrati o n ( M C H C), mea n c or p us c ular v ol u me. 
•  Ser u m C he mistr y:  li ver pa nel ( bilir u bi n, lactate d e h y dr o ge nas e [ L D H], S G O T/ A S T, 
S G P T/ A L T), r e nal pa n el ( B U N, creati n i ne), pa n creatic e nz y m es (a m ylas e a n d li pase),  
creati ne p h os p h o ki n ase ( C P K), al b u mi n, s o di u m, p otassi u m, ma g nesi u m, bicar b o nate, 
c hl ori de, cal ci u m, i n or ga nic p h os p h or us, gl u c ose, t otal pr otei ns, al kali ne p h os p hatase, 
c h olester ol, uric aci d.  
•  C oa g ulati o n ( meas ure d o nl y at Scree ni n g at t he l o cal la b orat or y): pr ot hr o m bi n ti me ( P T), 
a n d acti vate d p artial t hr o m b o plasti n ti me (a P T T)  
•  Uri nal ysis:  At t he ce ntral la b orat or y, p H, s pecific gra vit y, gl uc os e, nitrite, ket o nes, 
bilir u bi n, ur o bili n o ge n, R B C, a n d W B C tests, as w ell as q ua ntificati o n of al b u mi n a n d 
creati ni ne f or A C R calc ulati o n will be perf or me d. A sec o n d sa m ple will be a nal yze d 
q ua ntitati vel y f or M C P -1 a n d creati ni ne at visits s pecifie d i n t he Ti me a n d E ve nts T a ble. 
A nal ysis at t he l o cal la b orat or y will i ncl u de he mat uria a n d al b u mi n uria assess me nts at 
scree ni n g. 
•  Vir ol o g y ( m eas ur e d o nl y at Scree ni n g at t he l o cal la b orat or y): he p atitis B s urface 
a nti ge n, h e patitis C a nti b o dies, HI V 1 a n d 2 a nti b o dies. 
•  Ser ol o g y a n d C o m ple me nt ( meas ure d o nl y at Scree ni n g at t he l ocal la b orat or y): a nti -
n uclear a n d a nti - G B M a nti b o d y le vels, C 3, C 4, I g G, I g M, a n d I g A. T h ese t ests d o n ot 
nee d t o be perf or me d if r es ults are a v aila ble fr o m tests d o ne wit hi n t he past 1 2 m o nt hs 
pri or t o t he Scree ni n g visit. Res ult s fr o m t hese pri or tests m ust be rec or d e d i n t he e C R Fs. 
•  T B scr ee n: C hest X r a ys, d o ne as part of B V A S, will be perf or me d at scree ni n g t o r ule 
o ut T B. C hest X ra ys at s u bse q ue nt visits will o nl y be p erf or me d if dee me d cli nicall y 
necessar y b y t he Pri nci pal I n vesti gat or. 
7. 2. 3.  
Re p orti n g of A d verse E ve nts  
A n a d vers e e ve nt ( A E) is defi ne d as a n y u nt o war d me dical occ urre n ce i n a s u bject partici pati n g 
i n a cli nical trial w h o is a d mi nistere d a n i n vesti gati o nal pr o d uct, at a n y d os e; t he a d vers e e v e nt 
d oes n ot necess aril y h a ve t o ha ve a ca usal relati o ns hi p wit h t his pr o d uct. A n a d verse e ve nt c o ul d 
t heref or e be a n y u nfa v or a ble a n d/ or u ni nte n de d si g n (i ncl u di n g a b n or mal l a b orat or y fi n di n gs), 
s y m pt o m, or disease t e m p orall y ass ociate d wit h t he use of a n i n v esti gati o n al pr o d uct, w het her or 
n ot c o nsi dere d r elate d t o t he i n vesti gati o nal pr o d u ct. T his defi niti o n i ncl u des i nterc urre nt 
ill nesses or i nj uries, a n d e x acer bati o n of pre-e xisti n g c o n diti o ns. 
A n u ne x pecte d a d verse e ve nt is a n a d vers e e ve nt t hat is n ot i de ntifie d i n nat ure, se verit y, or 
fre q ue n c y i n t he c urre nt Cli nical I n vesti gat or’s Br oc h ure, or t h at is of great er se verit y t ha n 
e x pecte d base d o n t he i nf or mati o n i n t he Cli nical I n vesti gat or’s Br oc h ure. 
All a d verse e ve nts occ urri n g i n s u bjects w h o ha v e bee n ra n d o mize d t o treat me nt will be rec or d e d 
o n t he C R F a n d will be r e p orte d i n acc or d a nce wit h re g ul at or y re q uire me nts. A d verse e ve nts 
re p orte d pri or t o c o m me nce me nt of a d mi nistrati o n of st u d y me dicati o n will be c o nsi dere d pre-
treat me nt e ve nts. 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 7 3 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
All a d verse e ve nts will be m o nit ore d u ntil res ol uti o n or, if t he A E is deter mi ne d t o be c hr o nic, 
u ntil a ca use is i de ntifie d. If a n a d v erse e ve nt re mai ns u nres ol ve d at t he c o ncl usi o n of t he st u d y, 
a cli nical assess me nt will be ma de b y t he I n v esti gat or a n d t he S p o ns or’s M e dical M o nit or 
w het her c o nti n ue d f oll o w- u p of t he a d v erse e ve nt is warra nte d.  
T he se verit y of eac h a d v erse e v e nt will be deter mi ne d b y t he i n v esti gat or usi n g t he f oll o wi n g 
scale: 
•  Mil d ( Gra de 1):  n o li mitati o n of us ual acti vities.  
•  M o derate ( Gra d e 2):  s o me li mitati o n of us ual acti vities.  
•  Se vere ( Gra d e 3):  i na bilit y t o carr y o ut us ual acti vities.  
•  Lif e -t hreate ni n g ( Gra de 4):  a n i m me diate ris k of deat h. 
•  Deat h ( Gra de 5)  
T he relati o ns hi p of C C X 1 6 8/ place b o t o a n a d v ers e e ve nt will be det er mi ne d b y t he I n vesti gat or 
a n d S p o ns or base d o n t he f oll o wi n g defi niti o ns: 
•  Pr o ba bl y N ot Relat e d:  t he a d vers e e v e nt was m ore li kel y e x plai ne d b y ca uses ot her t ha n 
C C X 1 6 8/ place b o.  
•  P ossi bl y Relate d:  C C X 1 6 8/ place b o a d mi nistrati o n a n d t he a d verse e v e nt o cc urre nce 
were reas o n a bl y relat e d i n ti me, a n d t he A E was e x plai ne d e q uall y well b y ca uses ot her 
t ha n C C X 1 6 8/ place b o or was m ore li kel y e x plai ne d b y e x p os ure t o C C X 1 6 8/ place b o 
t ha n b y ot her ca us es. 
T he rel ati o ns hi p of c ortic oster oi d use, c ycl o p h os p ha mi de, azat hi o pri ne, or rit u xi ma b use  t o a n 
a d verse e ve nt will als o b e deter mi ne d b y t he I n vesti gat or a n d S p o ns or b as e d o n t he f oll o wi n g 
defi niti o ns: 
•  Pr o ba bl y N ot Relat e d:  t he a d vers e e v e nt was m ore li kel y e x plai ne d b y ca uses ot her t ha n 
c ortic oster oi d , c ycl o p h os p ha mi de, azat hi o pri ne, or rit u xi ma b  use.  
•  P ossi bl y Relate d:  t he c ortic oster oi d , c ycl o p h os p ha mi de, azat hi o pri ne, or rit u xi ma b  
a d mi nistrati o n a n d t he a d verse e v e nt occ urre n ce w ere reas o na bl y relate d i n ti me, a n d t he 
A E was e x plai ne d e q uall y w ell b y ca uses ot her t ha n c ortic oster oi d , c ycl o p h osp ha mi de, 
azat hi o pri ne, or rit u xi ma b  use or was m ore li kel y e x plai ne d b y e x p os ure t o c ortic oster oi d, 
c ycl o p h os p ha mi de, azat hi o pri ne, or rit u xi ma b  use t ha n b y ot her ca us es. 
A seri o us a d verse e v e nt ( S A E) is defi ne d as a n y u nt o war d me dical o cc urre nce t hat at a n y d os e: 
•  Res ults i n deat h. 
•  Is life-t hreate ni n g (i.e., t h e patie nt was, i n t he o pi ni o n of t he I n vesti gat or, at i m me diate 
ris k of deat h fr o m t he e v e nt as it occ urre d). 
•  Re q uires or pr ol o n gs h os pitalizati o n. 
•  Res ults i n persiste nt or si g nifica nt disa bilit y or i nca pacit y.  
•  Is a c o n ge nital a n o mal y or birt h defect. 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 7 4 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
•  Is a n i m p orta nt a n d si g nifica nt me dical e ve nt t hat, base d o n a p pr o priate me dical 
j u d g me nt, ma y je o p ar dize t he patie nt a n d/ or ma y re q uire me di cal or s ur gical i nter ve nti o n 
t o pre ve nt o ne of t h e ot her o utc o mes defi ni n g s eri o us. Mali g na n cies a n d se vere i nfecti o ns 
re q uiri n g a nti bi otics, lea di n g t o h os pitalizati o n, or meeti n g ot h er seri o us ness criteria are 
c o nsi dere d seri o us. 
Electi ve s ur ger y, alrea d y k n o w n d uri n g s cree ni n g t o occ ur i n c o urse of t he st u d y a n d electi ve 
h os pitalizati o ns f or c o n ve nie nce of t he s u bject w hic h are clearl y u nrelate d t o a n y m e dical 
c o n diti o n, a n d a gree d bet wee n t he i n vesti gat or a n d t he s u bject pri or t o ra n d o mizati o n, will n ot 
ha ve t o be r e p orte d as S A Es. O ver ni g ht h os pitalizati o n o n Da y 1 will n ot be c o nsi dere d a n S A E. 
A s us pecte d u ne x pecte d seri o us a d vers e reacti o n ( S U S A R) is defi ne d as a n S A E t hat is 
c o nsi dere d at least p ossi bl y rel ate d t o st u d y dr u g ( C C X 1 6 8/ place b o) a n d t h at is u ne x pecte d, i.e., 
n ot descri be d i n ter ms of nat ure, se v erit y, or fre q u e nc y i n t he c urre nt I n v esti gat or’s Br oc h ur e. 
A n y pre g na n cies t hat occ ur i n fe male s u bjects or p art ners of m ale st u d y s u bjects m ust be 
re p orte d wit hi n 2 4 h o urs of a ware ness as i n dicate d i n Secti o n 7. 2. 4 . All pre g na n cies m ust be 
f oll o we d u p u ntil c o ncl usi o n a n d t he o utc o me of t he pre g na n c y re p orte d wit hi n 2 4 h o urs of 
a war e ness as i n dicate d i n S ecti o n 7. 2. 4 .   
T he t hera pi es use d t o treat patie nts wit h A A V, i.e., c ycl o p h os p ha mi de , rit u xi ma b, azat hi o pri ne, 
a n d c ortic oster oi ds, are ofte n ass ociate d wit h a d verse e ve nts. A list of re p orte d a d vers e e ve nts 
o bser ve d wit h c ycl o p h os p ha mi de use is pr o vi de d i n S ecti o n 1 1. 8 , wit h c ortic oster oi d use i n 
S ecti o n 1 1. 9 , wit h rit u xi ma b use i n Secti o n 1 1. 1 0 , a n d wit h azat hi o pri ne use i n Secti o n 1 1. 1 1 . I n 
assessi n g p ote ntial ca usalit y of a d v erse e ve nts t o C C X 1 6 8/ place b o, t he k n o w n ass ociati o n 
bet wee n c y cl o p h os p ha mi de, c ortic oster oi ds, azat hi o pri ne,  a n d rit u xi ma b  t o t hese a d verse e v e nts 
will be ta ke n i nt o acc o u nt. 
7. 2. 4.  
Re p orti n g of Seri o us A d verse E ve nts  
A n y s eri o us a d verse e v e nt, w het her or n ot c o nsi d ere d st u d y rel ate d, will be re p ort e d i m me diatel y 
( wit hi n 2 4 h o urs) t o t he Safet y t ea m. Re p orti n g is d o ne b y c o m pleti n g t h e S A E f or m 
electr o nicall y i n t he Electr o nic Data Ca pt ure ( E D C) s yste m . If it is n ot p ossi ble t o access t he 
E D C s yste m, t he I n v esti gat or will se n d a n e mail t o t he a p pr o priat e re gi o nal Cli nical sa fet y 
mail b o x or call t heir re gi o nal S A E h otli ne a n d fa x t he c o m plete d S A E re p ort f or m wit hi n 2 4 
h o urs of a w are n ess. C o ntact details ar e as f oll o ws:  
S A E h otli ne – U S A:  
 
 
  
A n y me di cati o n or ot her t hera pe utic meas ures us e d t o treat t he e ve nt will b e rec or de d o n t he 
a p pr o priate C R F p a ge(s) i n a d diti o n t o t he o utc o me of t he a d v erse e ve nt. T he s p o ns or will re p ort 
all S U S A Rs t o F D A a n d ot her rele v a nt nati o nal healt h a ut h orities , I R Bs, a n d et hics c o m mittees 
i n a n e x pe dite d ma n ner. E ve nts relate d t o t he u n d erl yi n g disease w h ere c ortic oster oi d resc u e 
me dicati o n is  gi ve n, will n ot be c o nsi dere d as S U S A Rs, u nless t here is a reas o na ble p ossi bilit y 
t hat C C X 1 6 8 use was ass ociate d wit h t he e v e nt. T hese e ve nts will be i ncl u de d i n t he a n n ual 
safet y re p orts. 
P P D
P P D

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 7 5 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
7. 3.  
P h ar m ac o ki netic Assess me nts  
C o nce ntrati o ns of C C X 1 6 8 (a n d p ote ntial meta b olites) will be deter mi ne d i n plas ma fr o m 6- m L  
bl o o d sa m ples c ollecte d i n K 3E D T A t u bes o n Da ys 1, 8, 1 5, 2 2, 2 9, 4 3, 5 7, 7 1,  a n d 8 5. T he 
sa m ples o n Da y 1 will be c ollecte d j ust pri or t o t he m or ni n g d os e o n t hat d a y, a n d at 0. 5, 1, 2, 3, 
4, a n d 6 h o urs f oll o wi n g t he m or ni n g d ose. T h e date a n d ti me of t he last d ose pri or t o t he sa m ple 
c ollecti o ns o n Da ys 8, 1 5, 2 2, 2 9, 4 3, 5 7, 7 1,  a n d 8 5 will be rec or d e d i n t he E D C . T he bl o o d 
sa m ples will be mi x e d ge ntl y a n d ke pt o n w et ice u ntil ce ntrif u ge d ( wit hi n 3 0 mi n utes after 
c ollecti o n) at a p pr o xi matel y 2 0 0 0 x g, f or a p pr o xi matel y 1 0 mi n utes. Res ulta nt plas ma nee ds t o 
be s plit i n t o t hree ~ 1- m L ali q u ots a n d tra nsferre d t o t hree a p pr o priatel y la b ele d p ol y pr o p yl e ne 
t u bes a n d st ore d at a p pr o xi matel y - 7 0° C or b el o w u ntil a nal ysis. If t he site d oes n ot ha ve access 
t o a - 7 0° C freezer, t he sa m ples m ust be p ut o n dr y ice a n d s hi p pe d t o t he ce ntral la b orat or y as 
e x pe diti o usl y as p ossi ble, or st ore d at - 2 0° C a n d s hi p pe d t o t he ce ntral la b orat or y acc or di n g t o 
i nstr ucti o ns pr o vi de d.  
T otal plas ma c o nce ntrati o ns of C C X 1 6 8 (a n d p ote ntial meta b olites) will be deter mi ne d usi n g 
vali date d a nal ytical met h o ds. I n a d diti o n, plas ma c o nce ntrati o ns of c ycl o p h os p ha mi de, 4-
h y dr o x yc ycl o p h os p ha mi de or ot her met a b olites, rit u xi ma b, pre d nis o ne, a n d pre d nis ol o ne ma y be 
meas ure d i n t hese s a m ples. T hese plas ma s a m ples ma y als o b e use d t o meas ure c yt o ki nes, 
c o m ple me n t fra g m e nts, or ot her mar k ers ass o ciate d wit h A N C A vasc ulitis.  
A re pr ese ntati ve uri n e sa m ple fr o m a 6 - h o ur uri nar y c ollecti o n f oll o wi n g t he m or ni n g d os e o n 
Da y 1 will be use d t o det er mi ne t he C C X 1 6 8 uri n e c o nce ntrati o n. After t he 6- h o ur c ollecti o n, t he 
uri ne v ol u me will be meas ure d a n d r ec or d e d, a n d a re prese ntati ve uri ne sa m ple ( 2 0 m L) will als o 
be st ore d at - 7 0° C or b el o w u ntil a nal ysis. If t h e site d oes n ot ha ve access t o a - 7 0° C freezer, t he 
sa m ples m ust be p ut o n dr y ice a n d s hi p pe d t o t he ce ntral la b orat or y as e x pe diti o usl y as p ossi ble, 
or st ore d at - 2 0° C a n d s hi p pe d t o t he ce ntral la b orat or y acc or di n g t o i nstr ucti o ns pr o vi de d.  
7. 4.  
P h ar m ac o d y n a mic Assess me nts  
A plas ma sa m ple will be c ollecte d o n D a ys 1, 2 9, 8 5, a n d 1 6 9 f or p har mac o d y na mic m ar ker 
meas ure me nts, i ncl u di n g, f or e x a m ple, c ystati n C, c o m ple me nt fra g m e nts, a n d i nfla m mat or y 
c yt o ki ne a n d c h e m o ki ne le vels. T he P K plas ma sa m ples ma y als o b e use d f or t hese 
p har mac o d y n a mic  mar k er meas ure m e nts.  
Uri ne sa m ples will als o b e c ollecte d o n Da ys 1, 8, 1 5, 2 9, 5 7, 8 5, 1 1 3, a n d 1 6 9 f or bi o mar ker 
assess me nts i ncl u di n g, f or e x a m ple, re nal i nj ur y a n d i nfla m mati o n mar kers (e. g., ki d ne y i nj ur y 
m olec ule - 1 [KI M - 1] a n d ne utr o p hil gel ati nase-ass ociate d li p ocali n [ N G A L] ), c o m ple me nt 
fra g me nts, i nfla m mat or y c he m o ki ne a n d cyt o ki n e le vels.  
A sali va sa m ple will be c ollecte d o n Da y 1 fr o m s u bjects w h o ha ve pr o vi de d i nf or me d c o ns e nt 
f or assess me nt of ge netic mar kers of A N C A disease as well as t he c o m ple me nt pat h wa y. 
P ote ntial mar kers i ncl u de H L A D P B 1 * 0 4 0 1 , S E R PI N A 1 , P R T N 3 , a n d H L A -D Q . C 5a R 
p ol y m or p his m ma y als o be i n vesti gat e d. 
7. 5.  
St u d y C o m pleti o n a n d Wit h dr a w al  
Da y 1 6 9 will be t he last St u d y Da y f or all s u bjects. Pr oce d ures f or t his da y will be c o m plete d per 
t he Ti me a n d E ve nts Ta ble. T he  s u bject’s c o n diti o n will b e e val uate d b y t h e I n vesti gat or at t he 
e n d of t he cli nical trial a n d a p pr o priate S O C  me dical treat me nt will be pr o vi de d t o all s u bjects as 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 7 6 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
nee de d. F or earl y wit h dr a wals ( pri or t o D a y 8 5), t he pr oce d ures sc h e d ule d f or St u d y D a y 8 5 will 
be p erf or me d a n d rec or d e d as a n E arl y Ter mi nati o n visit. F or wit h dra wals after D a y 8 5, 
pr oce d ur es f or Da y 1 6 9 will be perf or me d. 
7. 6.  
D at a M o nit ori n g C o m mittee  
I n a d diti o n t o o n g oi n g safet y m o nit ori n g b y t he M e dical M o nit or a n d Cli nical staff, a n e xter nal 
Data M o ni t ori n g C o m mittee ( D M C) will m o nit or t he safet y of s u bj ects, i ncl u di n g res c ue 
c ortic oster oi d use, o v er t he c o urse of t he st u d y. T he D M C will c o nsist of t w o i n de pe n de nt 
p h ysicia ns a n d o ne bi ostatisticia n. A D M C c harter will be de vel o pe d b ef ore start of t he st u d y a n d 
t he D M C will f u ncti o n acc or di n g t o t he c h arter. T he D M C will re vie w data o nce e v er y 3 t o 6 
m o nt hs, de pe n di n g o n t h e e nr oll me nt rate, or i f a n y u na ntici p ate d safet y iss ues occ ur. 
It is a ntici pate d t hat t here will be a p pr o xi matel y 4  D M C meeti n gs: a kic k -off meeti n g a n d 3 
meeti n gs o ver t he c o urse of t he st u d y. A d h o c meeti n gs ma y be sc h e d ule d if u na ntici pate d safet y 
e ve nts occ ur. After re vie w of data at eac h m eeti n g, t he D M C will ma ke rec o m me n dati o ns a b o ut 
f urt her c o n d u ct of t he st u d y. 
If t here ar e u na ntici pate d safet y or t olera bilit y iss u es i n patie nts recei vi n g C C X 1 6 8 pl us 
c ycl o p h os p ha mi de or rit u xi ma b pl us c ortic oster oi ds, c o nsi derati o n will be gi ve n t o a n alter nati ve 
d osi n g strate g y, f or e x a m ple l o weri n g t he C C X 1 6 8 or c ortic oster oi d d ose. 
7. 7.  
St a tistical Met h o ds  
Statistical a nal ysis of effi cac y d ata will be perf or m e d usi n g S A S ® ( S A S I nstit ute, C ar y, N C) 
s oft ware, b ase d o n a pre d efi ne d Statistical A nal ysis Pla n. Data a nal ysis a n d writi n g of a n 
I nte grate d Cli nical a n d Statistical Re p ort (I C S R) f or all st u d y dat a will be p erf or me d b y t h e 
desi g nat e d C R O i n acc or da nce wit h its S O Ps. Data a nal ysis of p har mac o ki netic data, usi n g 
Wi n N o nli n s oft ware, a n d writi n g of a p har mac o ki netic a p pe n di x t o t he I C S R will be perf or me d 
b y a d esi g nate d p har mac o ki netic tea m i n acc or da nce wit h its S O Ps.  
7. 8.  
S u bject P o p ul ati o n s 
F or t he p ur p os es of dat a a nal ysis, t he I T T P o p ulati o n will i ncl u de all s u bjects w h o are 
ra n d o mize d, ha ve r ecei v ed at least o ne d os e of st u d y dr u g, a n d ha v e at least o ne p ost baseli ne 
B V A S assess me nt. T h e s afet y p o p ulati o n will i ncl u de all s u bjects w h o are ra n d o mize d a n d ha ve 
recei v e d at least o ne d ose of st u d y dr u g. A per pr ot oc ol ( P P) p o p ulati o n ma y als o be defi ne d if 
t here are maj or pr ot oc ol de viati o ns t hat c o ul d affect st u d y o utc o me. 
7. 9.  
S afet y E n d p oi nts  
T he pri mar y safet y e n d p oi nt is t he s u bject i nci de nce of a d v erse e ve nts.  
Ot her saf et y e n d p oi nts i ncl u de: 
1.  S u bject i nci de nce of e ve nts p ossi bl y ass ociate d wit h gl uc oc ortic oi d us e: seri o us i nfecti o ns, 
ne w -o nset dia b etes mellit us/ h y per gl yce mia,  b o ne fract ure, pe ptic ulcer disease, cat aracts, 
ne w o nset/ w orse ni n g h y p erte nsi o n, wei g ht gai n m ore t ha n 1 0 k g, a n d ps yc hiatric dis or ders; 
2.  S u bject i nci de nce of i nfecti o ns, seri o us i nfecti o ns, se vere i nfecti o ns (i.e., Gra de 3), a n d 
i nfecti o ns lea di n g t o s u bject wit h dra w al fr o m t he st u d y; 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 7 7 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
3.  C ha n ge fr o m bas eli ne i n all safet y la b orat or y para meters;  
4.  C ha n ge fr o m bas eli ne i n vital si g ns; 
5.  I n ci de nce of cli nicall y si g nifica nt E C G c ha n ges fr o m baseli ne. 
7. 1 0.  
Eff ic ac y E n d p oi nts 
T he pri mar y efficac y e n d p oi nt is t he pr o p orti o n of s u bjects ac hie vi n g disease res p o nse at Da y 8 5 
defi ne d as B V A S perce nt re d ucti o n fr o m bas eli ne of at least 5 0 % pl us n o w orse ni n g i n a n y b o d y 
s yste m c o m p o ne nt.  
Ot her efficac y e n d p oi nts i ncl u de: 
1.  I n p atie nts wit h he mat uri a a n d al b u mi n uria at b aseli ne, t he pr o p orti o n of s u bjects ac hie vi n g 
re nal r es p o nse at D a y 8 5; re nal r es p o nse is defi ne d as a n i m pr o ve me nt i n para meters of re n al 
vasc ulitis:  
a. a n i ncrease fr o m baseli ne t o Da y 8 5 i n e G F R ( M D R D ser u m creati ni ne e q u ati o n), pl us 
b.  a decr eas e fr o m bas eli ne t o Da y 8 5  i n h e mat uria (ce ntral la b orat or y micr os c o pic c o u nt of 
uri nar y R B Cs), pl us 
c. a decr eas e fr o m bas eli ne t o Da y 8 5 i n al b u mi n uria (first m or ni n g uri nar y 
al b u mi n:creati ni ne rati o).  
2.  Pr o p orti o n of s u bjects ac hie vi n g diseas e re missi o n at Da y 8 5 defi ne d as B V A S of 0; 
3.  Pr o p orti o n of s u bjects ac hie vi n g e arl y dise ase re missi o n ( B V A S of 0) at D a y 2 9 A N D 
D a y 8 5; 
4.  Perce nt c h a n ge fr o m bas eli ne t o Da y 8 5 i n B V A S ; 
5.  C ha n ge a n d perce nt c ha n ge fr o m baseli ne t o D a y 8 5 i n e G F R; 
6.  I n s u bjects wit h he mat uri a at baseli ne, t he p erce nt c ha nge fr o m baseli ne t o Da y 8 5 i n uri nar y 
R B C c o u nt; 
7.  I n s u bjects wit h al b u mi n uria at baseli ne, t h e perce nt c ha n ge fr o m baseli ne t o Da y 8 5 i n 
uri nar y A C R;  
8.  Perce nt c h a n ge fr o m bas eli ne t o Da y 8 5 i n uri nar y M C P -1:creati ni ne rati o;  
9.  Pr o p orti o n of s u bjects re q uiri n g r esc ue gl uc o c orti c oi d treat me nt;  
1 0.  C ha n ge fr o m bas eli ne t o Da y 8 5 i n t he Vas c ulitis Da ma ge I n d e x ( V DI); 
1 1.  C ha n ge fr o m bas eli ne t o Da y 8 5 i n healt h- relate d q ualit y- of-life as meas ure d b y t h e S h ort 
F or m - 3 6 versi o n 2. 0 ( S F- 3 6 v 2) a n d E ur o Q O L- 5 D-5 L ( E Q - 5 D-5 L);  
Ot her e n d p oi nts i ncl u de: 
1.  T otal c u m ulati ve st u d y -s u p plie d pre d nis o ne d ose a n d d urati o n of d osi n g d uri n g t he 8 4-da y 
treat me nt peri o d; 
2.  T otal c u m ulati ve s yste mi c c ortic oster oi d d os e (a n y use) a n d d urati o n of d osi n g d uri n g t he 
8 4- da y d osi n g p eri o d; 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 7 8 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
3.  T otal c u m ulati ve c ycl o p h os p ha mi de or rit u xi ma b d ose a n d d urati o n of d osi n g d uri n g t he 8 4-
da y d osi n g p eri o d;  
4.  Perce nt c h a n ge fr o m bas eli ne i n hs C R P ;  
5.  Perce nt c h a n ge fr o m bas eli ne i n A N C A (a nti - P R 3 a n d a nti- M P O) at D a y 8 5,  
6.  Pr o p orti o n of patie nts bec o mi n g A N C A n e gati ve at Da y 8 5 , a n d  
7.  C ha n ge a n d perce nt c ha n ge fr o m baseli ne i n plas ma a n d uri ne bi o mar k ers. 
All state d safet y a n d effi cac y e n d p oi nts  will be assesse d t hr o u g h t he e n d of t he f oll o w- u p peri o d, 
Da y 1 6 9. 
7. 1 1.  
P h ar m ac o ki netic E n d p oi nts  
Plas ma sa m ples will be c ollecte d o n Da ys 1, 8, 1 5, 2 2, 2 9, 4 3, 5 7, 7 1, a n d 8 5 t o deter mi ne t he P K 
pr ofile of C C X 1 6 8 a n d p ote ntial meta b olites . T he f oll o wi n g para meters will be deter mi ne d o n 
Da y 1, w here p ossi ble: 
C ma x    
Ma xi m u m plas ma c o nce ntrati o n  
tma x   
 
Ti me of ma xi m u m plas ma c o nce ntrati o n  
A U C 0- 6 
Area u n d er t he plas ma c o nce ntrati o n -ti me c ur ve fr o m Ti me 0 t o H o ur 6 o n Da y 1 
C mi n     
Tr o u g h l e vel plas ma c o n ce ntrati o ns at p ost-D a y 1 visits  
7. 1 2.  
P h ar m ac o d y n a mic E n d p oi nts  
Plas ma sa m ples will be c ollecte d o n Da ys 1, 2 9, 8 5, a n d 1 6 9 t o meas ure p ote ntial c h a n ge a n d 
perce nt c ha n ge  fr o m bas eli ne i n bi o mar kers s uc h as c ystati n C, c o m ple me nt fra g me nts, 
i nfla m mat or y c he m o ki ne a n d c yt o ki ne le vels. T h e c ystati n C le vels ma y b e use d i n calc ulati n g 
e G F R c h a n ges fr o m baseli ne usi n g t he f oll o wi n g e q uati o n: 
e G F R c ys ( m L/mi n/ 1. 7 3 m 2) = 1 2 7. 7 x (c ystati n C i n m g/ L)−1. 1 7  x ( A ge) −0. 1 3  x ( 0. 9 1 if fe male) 
x ( 1. 0 6 if Africa n -A m eri ca n/ Blac k)  
Uri ne sa m ples will be c ollecte d o n Da ys 1, 8, 1 5, 2 9, 5 7, 8 5, 1 1 3, a n d 1 6 9 t o meas ure p ote ntial 
c ha n ge a n d per ce nt c h a n ge  fr o m baseli ne i n bi o m ar kers s u c h as re nal i nj ur y a n d i nfl a m mati o n 
mar kers ( e. g., KI M - 1 a n d N G A L ), c o m ple m e nt fra g me nts, i nfla m mat or y c h e m o ki ne a n d 
c yt o ki ne l e vels. 
A sali va sa m ple will be c ollecte d o n Da y 1 t o e v al uate t he effect of ge netic mar kers o n treat me nt 
res p o nse t o C C X 1 6 8 treat me nt. P ote ntial mar kers i ncl u de H L A D P B 1 * 0 4 0 1 , S E R PI N A 1 , 
P R T N 3 , a n d H L A -D Q . C 5a R p ol y m or p his m ma y als o be i n vesti gate d. 
7. 1 3.  
St atistic al A n al ysis Met h o d ol o g y  
A statistical a nal ysis pla n wit h s pecific details of all t he pla n ne d a nal yses will be ge n erate d a n d 
a p pr o ve d bef ore u n bli n di n g t he d ata f or a nal ysis. 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 7 9 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
7. 1 3. 1.  
B aseli ne C h ar acteristics  
All s u bject baseli ne c h ar acteristics a n d d e m o gra p hic data (a ge , se x, race, et h nicit y, wei g ht, 
hei g ht, b o d y mass i n de x, s m o ki n g stat us, E C G, T B scree n res u lts, viral test res ults, A N C A, 
vasc ulitis disease d urati o n  (fr o m ti me of first i n d u cti o n treat me nt), B V A S, V DI, S F - 3 6 v 2, E Q-
5 D- 5 L, hs C R P, e G F R, h e mat uria, uri ne R B C casts, pr otei n uria ( A C R), gl o mer ular 
hist o pat h ol o g y (if bi o ps y was ta ke n), uri nar y M C P- 1:creati ni ne rati o, p h ysical e x a mi nati o n 
a b n or malities, me dical hist or y, pr e vi o us ( wit hi n 6 m o nt hs of scree ni n g) a n d c o nc o mita nt 
me dicati o ns (i ncl u di n g v asc ulitis me dicati o n use) at st u d y e ntr y will be liste d b y treat me nt 
gr o u p, st u d y ce nter, a n d s u bject n u m ber, a n d will als o be s u m marize d b y treat me nt gr o u p. 
Baseli ne is defi ne d as t he last val ue pri or t o start of d osi n g wit h st u d y me di cati o n (t y pi call y t he 
Da y 1 pre- d os e val u e). D ata will als o be pres e nte d se parat el y f or t he c ycl o p h os p ha mi de a n d 
rit u xi ma b strata. 
T he n u m ber of p atie nts r a n d o mize d, c o m plete d, or disc o nti n ue d fr o m t he st u d y, al o n g wit h t he 
reas o n f or disc o nti n uati o n, will be prese nte d o v erall a n d b y treat me nt gr o u p. Patie nt c o u nt b y 
a nal ysis p o p ulati o n will als o be ta b ulate d. 
7. 1 3. 2.  
S af et y A n al yses 
Safet y a nal yses wi ll be perf or me d o n t h e Safet y P o p ulati o n. T he t w o C C X 1 6 8 treat me nt gr o u ps 
will be s u m marize d descri pti vel y i n ter ms of t he s u bject i nci de nce of a d v erse e ve nts . 
All safet y data will be s u m marize d descri pti vel y b y treat me nt gr o u p.  
A d verse e ve nts will be c o de d usi n g Me d D R A a n d liste d, i ncl u di n g all a vaila ble i nf or mati o n of 
i nterest s uc h as o nset a n d res ol uti o n dates, st u d y d a y of o nset rel ati ve t o first d osi n g da y, 
se verit y, seri o us ness, ca usal relati o ns hi p t o st u d y me dicati o n, c ortic oster oi d , c ycl o p h os p ha mi de, 
or rit u xi ma b  use, acti o n ta ke n, a n d o utc o m e. A d verse e ve nts will be c o nsi d ere d as “ pre-
treat me nt” if t hes e occ ur pri or t o t he ti me of a d mi nistrati o n of t he first d ose of st u d y m e dicati o n. 
All ot her a d vers e e ve nts will be c o nsi dere d “treat me nt -e mer ge nt”. Pre-treat me nt a d verse e ve nts 
will be liste d se paratel y fr o m treat me nt -e m er ge nt a d verse e ve nts. S y m pt o ms or si g ns of 
vasc ulitis will be c o nsi de re d a d verse e v e nts if t hes e i ncrease i n se verit y or fre q ue nc y w hile a 
s u bject is o n-st u d y. A d v erse e ve nts will be liste d b y s u bject, a n d treat me nt gr o u p. A Es will be 
s u m marize d b y treat me nt gr o u p a n d ta b ulate d s e paratel y f or ma xi m u m se verit y, relati o ns hi p t o 
st u d y dr u g, a n d relati o ns hi p t o s yst e mic c ortic oster oi d, c ycl o p h os p ha mi de, or rit u xi ma b use. A Es 
lea di n g t o wit h dr a wal a n d S A Es will be ta b ulate d se parat el y. 
Safet y l a b orat or y d ata will be liste d b y treat me nt gr o u p a n d s u bject n u m ber, a n d will be 
s u m marize d b y treat me nt gr o u p. Act ual la b orat or y val ues a n d c h a n ge fr o m baseli ne i n la b orat or y 
val ues will be liste d a n d s u m marize d. La b orat or y val ues o utsi de t he refere nce ra n ges will be 
fla g ge d i n t he listi n gs. La b orat or y s hift ta bles fr o m baseli ne t o s u bse q uent st u d y visits will als o 
be ge ner ate d f or all saf et y la b or at or y para meters.  Vital si g ns data will be liste d a n d s u m marize d 
si milarl y. I nci de n ce of cli nicall y si g nifica nt E C G c ha n ges fr o m baseli ne will be liste d a n d 
s u m marize d b y treat me nt gr o u p. 
N o i nfere ntial statistical a nal ysis will be p erf or m e d o n a d verse e ve nt or ot h er safet y  d ata.   

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 8 0 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
7. 1 3. 3.  
Effic ac y A n al yses 
T he pri mar y efficac y e n d p oi nt is t he pr o p orti o n of s u bjects ac hie vi n g disease res p o nse at Da y 8 5 
defi ne d as B V A S r e d ucti o n fr o m baseli ne of at least 5 0 % pl us n o w orse ni n g i n a n y b o d y s yste m 
c o m p o ne nt.  
T he pr o p orti o n of s u bjects ac hie vi n g dise ase res p o nse a n d t he 1 -si de d 9 5 % c o nfi de nce 
i nter v al f or t he diff ere nce i n pr o p orti o n ( C C X 1 6 8 mi n us S O C) will be calc ulate d f or t he 
c o m paris o n bet wee n eac h C C X 1 6 8 gr o u p a gai nst t he S O C gr o u p. Bec a use of t he rel ati vel y 
s m all s a m ple size of t he st u d y, n o i nfere nti al st atistic al a n al ysis will be perf or me d o n t he 
pri m ar y e n d p oi nt.   
C o nti n u o us varia bles will be a nal yz e d usi n g mi x e d effects m o del f or re pe ate d me as ures 
( M M R M) wit h treat me nt gr o u p , visit, tre at me nt-b y - visit i nter acti o n, a n d ra n d o mizati o n strata 
( ne wl y dia g n ose d A A V or rela pse d A A V, rit u xi ma b or c ycl o p h os p ha mi d e, P R 3 or M P O A N C A) 
as f act ors, a n d b aseli ne as c o variate. P oi nt esti mates a n d c orres p o n di n g 9 5 % c o nfi de n ce 
i nter vals will be c o m p ute d f or t he differe n ce bet w ee n eac h C C X 1 6 8 gr o u p a n d t he place b o gr o u p 
usi n g si m ple c o ntr ast f r o m t he m o del. A d diti o n all y, a n al ysis of c o v ari a nce ( A N C O V A) wit h 
t he s a me f act ors a n d c o v ari ates will be a p plie d f or t he bet w een gr o u p c o m p aris o n at e a c h 
visit . Data t hat ar e n ot n or mall y distri b ute d, e. g., uri nar y A C R will  be l o g-tra nsf or me d bef ore 
a nal ysis.  
Cate g orical varia bles will be  s u m m a rize d i n a si mil ar m a n ner as descri be d f or t he pri m ar y 
e n d p oi nt. T hese i ncl u de t he pr o p orti o n of s u bjects ac hie vi n g re missi o n, defi ne d as B V A S of 
0, at D a y 8 5, e arl y re missi o n, defi ne d as B V A S of 0 at D a y 2 9 A N D D a y 8 5, a n d re n al 
res p o nse at D a y 8 5 . S u bjects recei vi n g resc u e ster oi ds after D a y 1 b ut bef ore Da y 8 5 + 7 da ys 
(i.e. Da y 9 2) will be c o nsi dere d as tr eat me nt fail ures.  
S u m mar y statistics will be pr o vi de d f or eac h of t h e effi cac y e n d p oi nts. F or cate g orical e n d p oi nts, 
n u m bers a n d perce nta ges will be calc ulate d. F or c o nti n u o us varia bles, n u m bers, mea ns, me dia ns, 
ra n ges, sta n dar d de viati o ns, a n d st a n d ar d err ors of me a n will be cal c ulat e d. Ge o metric m ea ns 
will be calc ulate d f or uri nar y A C R, uri nar y R B C c o u nt, uri nar y M C P- 1:creati ni ne, a n d hs C R P. 
S hift ta bles will be ge n er ate d f or uri n ar y para meters s uc h as he mat uria a n d al b u mi n uria. Res ults 
will be prese nte d se p ar atel y b y tr eat me nt gr o u p. If t he t w o C C X 1 6 8 gr o u ps s h o we d a si milar 
res p o nse, t he t w o C C X 1 6 8 gr o u ps ma y b e c o m bi ne d f or testi n g a gai nst t h e c o ntr ol gr o u p. 
T he mai n effi cac y a nal ysis will be i n t he I T T p o p ulati o n. Se nsiti vit y a nal ys es ma y  als o be d o ne 
i n t he P P p o p ulati o n.  
7. 1 3. 4.  
C o v ari ates 
T he eff ect of t h e f oll o wi n g bas eli ne para meters (i n a d diti o n t o t he defi ne d strata, i.e., ne wl y 
dia g n ose d A A V or rela ps e d A A V, rit u xi ma b or c ycl o p h os p ha mi de bac k gr o u n d treat me nt, a n d 
P R 3 vs. M P O A N C A ) o n st u d y o utc o me ma y b e assesse d: 
•  Ge n der  
•  B MI  
•  A ge at dia g n osis of A A V 
•  S m o ki n g 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 8 1 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
•  S u bject’s a ge a n d et h nicit y (if pla usi ble) 
•  Baseli ne e G F R  
•  Baseli ne h e mat uria  
•  Baseli ne uri nar y A C R  
•  Baseli ne B V A S  
•  Baseli ne V DI  
•  Baseli ne hs C R P  
•  Baseli ne uri nar y M C P -1:creati ni ne rati o  
7. 1 3. 5.  
P h a r m a c o ki netic A n al ysis  
I n di vi d ual plas ma c o nce ntrati o ns of C C X 1 6 8 a n d rele va nt meta b olites, as well as 
c ycl o p h os p ha mi de, 4- h y dr o x yc ycl o p h os p ha mi de (a n d p ossi ble ot her meta b olites), pre d nis o ne, 
a n d pre d nis ol o ne, a n d rit u xi ma b (if meas ure d) will be liste d, plotte d, a n d s u m marize d 
descri pti vel y a n d gr a p hicall y. P har mac o ki netic para meters will be calc ulat e d base d o n plas ma 
C C X 1 6 8 c o nce ntrati o ns at t he ti me of sa m ple c oll ecti o n i n relati o n t o ti me of a d mi nistrati o n of 
t he m ost rece nt d ose of st u d y me dicati o n. Plas ma le vels of si g nifica nt meta b olites ma y als o be 
deter mi ne d a n d P K para meters cal c ulate d.  
It is of i nterest t o e val uat e w het her t h e P K pr ofile of s u bjects wit h A N C A-ass ociate d vasc ulitis is 
si milar t o t he pr ofile i n healt h y v ol u nteers. T he rel ati o ns hi p bet wee n P K para meters a n d re n al 
f u ncti o n base d o n e G F R will als o be e val uate d. T he data ma y als o be use d t o e val uate t he P K/ P D 
relati o ns hi p of C C X 1 6 8 treat me nt. T o t his e n d, t he c ha n ge a n d/ or perce nt c ha n ge fr o m b aseli ne 
i n e G F R, B V A S, V DI, s er u m hs C R P, A NC A (a nti - P R 3 a n d a nti- M P O), A C R, he mat uria, or 
uri nar y M C P- 1:creati ni ne rati o ma y be us e d as P D mar kers.  
7. 1 4.  
S a m ple Size J ustific ati o n  
T he s a m ple size esti m ati o n f or t his st u d y w as b ase d o n pr actic al a n d n ot st atistic al 
c o nsi der ati o ns . 
7. 1 5.  
I nteri m A n al ysis 
Efficac y a n d safet y data fr o m t he st u d y will be s u m marize d f or re vie w b y t he D M C at vari o us 
p oi nts o ve r t he c o urse of t he st u d y (s ee Secti o n 7. 6 ). T he D M C c harter will i ncl u de details of t he 
a nal ys es.  
W he n all s u bjects ha ve c o m plete d t he 8 4- da y treat me nt peri o d, data ma y b e a nal yz e d t o ma ke 
decisi o ns re gar di n g f ut ur e cli nical de vel o p me nt pl a ns. Beca use t his is a P hase 2  st u d y, 
m ulti plicit y a dj ust me nt will n ot be a p plie d t o t he al p ha le vel f or t he fi nal a nal ysis.      
7. 1 6.  
Pr ot oc ol De vi ati o ns  
Si g nifica nt pr ot oc ol d e viati o ns will be liste d a n d s u m m arize d b y cate g or y. T he effect of 
si g nifica nt pr ot o c ol de viati o ns o n t he safet y a n d efficac y o utc o m es will be assesse d b y 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 8 2 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
c o n d ucti n g s e nsiti vit y a n al yses e x cl u di n g s u bjects a n d/ or st u d y visits wit h si g nifica nt pr ot o c ol 
de viati o ns. 
8.  
S T U D Y C O M P L E TI O N A N D  T E R MI N A TI O N  
8. 1.  
St u d y C o m pleti o n  
A s u bject has c o m plete d t he st u d y w h e n s/ he has c o m plete d t he st u d y pr o ce d ures per pr ot oc ol. 
8. 2.  
St u d y Ter mi n ati o n  
T he e n d of st u d y is defi n e d as t he last st u d y visit of t he last cli nical trial s u bject.  
9.  
R E G U L A T O R Y A N D A D MI N I S T R A TI V E R E Q UI R E M E NT S 
9. 1.  
I n vesti g at or Res p o nsi bilities 
Pri o r t o trial i nitiati o n, t he I n vesti gat or will pr o vi d e t he S p o ns or wit h a f ull y e x ec ute d a n d si g n e d 
F D A F or m 1 5 7 2 a n d a Fi na ncial Discl os ure F or m. Fi na ncial Discl os ure F or ms als o will be 
c o m plete d f or all S u b- I n vesti gat ors liste d o n t he F or m 1 5 7 2 w h o will be i n v ol ve d directl y i n t he 
treat me nt or e v al uati o n of researc h s u bjects i n t his trial.  
T he st u d y will be c o n d ucte d i n acc or d a nce wit h t he Decl arati o n of H elsi n ki (a me n de d b y t he 
5 9t h W orl d Me dical Ass ociati o n Ge neral Asse m bl y, Oct o b er 2 0 0 8) a n d G o o d Cli nic al Practice 
( G C P) acc or di n g t o I nter nati o nal C o nfere n ce o n Har m o nisati o n (I C H) g ui deli nes.  S pecificall y, 
t he st u d y is base d o n a de q uatel y p erf or me d la b orat or y a n d a ni mal e x peri me ntati o n; t he st u d y 
will be c o n d ucte d u n der a pr ot oc ol re vi e we d b y a pr o perl y c o nstit ute d I R B/ E C; t he st u d y will be 
c o n d ucte d b y scie ntifi call y a n d me di call y q ualifie d pers o ns; t he be nefits of t he st u d y are i n 
pr o p orti o n t o t he ris ks; t he ri g hts a n d welfare of t he s u bjects will be res p ect e d; a n d eac h s u bject 
will gi ve his/ her i nf or m e d c o nse nt bef ore a n y pr ot oc ol- s pecific t ests or e val uati o ns are 
perf or me d.  
9. 2.  
I nstit uti o n al Re vie w B o ar d or Et hics C o m mittee 
Pri or t o i nitiati n g t he st u d y, t he I n vesti gat or will o btai n writte n c o nfir mati o n fr o m t he I R B/ E C 
t hat t he I R B/ E C was pr o perl y c o nstit ute d a n d met t he defi niti o n of all U nite d States C o de of 
Fe deral Re g ulati o ns Title 2 1, Secti o n 3 1 2. 3( b) a n d Part 5 6, a n d/ or t he a p pli ca ble l ocal, re gi o nal 
or nati o nal Re g ulat or y r e q u ire me nts. A c o p y of t h e c o n fir mati o n will be pr o vi de d t o t he S p o ns or.  
T he  Pri nci pal I n vesti gat or will pr o vi de t he I R B/ E C wit h all a p pr o priate materials, i ncl u di n g t he 
pr ot oc ol a n d I nf or me d C o nse nt d oc u me nts. T he trial will n ot be i nitiate d u ntil I R B/ E C a p pr o v al 
of t he pr ot oc ol, t he I nf or me d C o nse nt d oc u me nt, a n d all recr uiti n g materials are o btai ne d i n 
writi n g b y t he I n v esti gat or a n d c o pies are recei ve d b y t he S p o ns or. A p pr o priate re p orts o n t he 
pr o gress of t he st u d y will be ma de t o t he I R B/ E C a n d t he S p o ns or b y t h e Pri nci pal I n vesti gat or 
i n acc or d a nce wit h a p plica ble g o ver n me ntal re g ulati o ns a n d i n a gree me nt wit h t he p olic y 
esta blis he d b y t h e S p o ns or. 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 8 3 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
9. 3.  
I nf or me d C o nse nt 
A pr o perl y e x ec ute d, writte n, a n d a p pr o pri atel y e x plai ne d I nf or me d C o nse nt F or m, i n 
c o m plia nce wit h t he D eclarati o n of Helsi n ki, I C H G C P, a n d U S C o de of Fe deral Re g ul ati o ns f or 
Pr otecti o n of H u ma n S u bjects ( 2 1 C F R 5 0. 2 5[a, b], C F R 5 0. 2 7, a n d C F R Part 4 6, S u b part A), 
a n d Ca na dia n G ui da n ce D oc u me nt: “ C o nsi derati o ns f or I ncl usi o n of W o me n i n Cli nical Trials 
a n d A nal ysis of Se x Differe nces ”, Ma y 2 9, 2 0 1 3, will be si g ne d b y eac h s u bject pri or t o e nteri n g 
t he trial. Eit her t he i n vesti gat or or t he i n vesti gat or’s desi g nee will o btai n t he c o nse nt of t he st u d y 
s u bject. T he s u bject will be pr o vi de d as m uc h ti m e as necessar y t o re vie w t he d oc u me nt, t o 
i n q uire a b o ut details of t he trial, a n d t o deci d e w h et her or n ot t o partici p ate i n t he st u d y. T he 
i nf or me d c o nse nt will be si g ne d a n d date d b y t he st u d y s u bject a n d b y t h e p ers o n w h o c o n d u cte d 
t he i nf or me d c o nse nt dis c ussi o n. T he I n vesti gat or will pr o vi de a c o p y of t h e si g ne d I nf or m e d 
C o nse nt F or m t o eac h s u bject a n d will mai ntai n a c o p y i n t he s u bject’s rec or d file.  
9. 4.  
Pr ot oc ol M o dific ati o ns  
O nl y t he S p o ns or ma y m o dif y t he pr ot oc ol. A me n d me nts t o t he pr ot oc ol will be ma de o nl y after 
c o ns ultati o n a n d a gree me nt bet wee n t he S p o ns or a n d t he Pri nci pal I n vesti gat or. T he o nl y 
e x ce pti o n is w he n t he I n vesti gat or c o nsi ders t hat a s u bject’s safet y w o ul d be c o m pr o m ise d 
wit h o ut i m me diate acti o n. I n t his cir c u msta nce, i m me diate a p pr o v al of t he c hair pers o n of t h e 
I R B/ E C m ust be s o u g ht, a n d t he I n vesti gat or s h o ul d i nf or m t he S p o ns or’s Me dical M o nit or a n d 
t he f ull I R B/ E C wit hi n fi ve w or kin g da ys  after t he e mer ge n c y occ urre d. All ot her a me n d me nts 
t hat ha ve a n i m pact o n s u bject ris k or t he st u d y o bjecti ves, a n d/ or t hat re q uire re visi o n of t he 
I nf or me d C o nse nt F or m, m ust recei ve a p pr o val fr o m t he I R B/ E C pri or t o t heir i m ple me ntati o n, 
e x ce pt w he n t he c h a n ges i n v ol ve o nl y l o gistical or a d mi ni strati ve as pects of t he trial. T he 
I R B/ E C m ust be n otifie d of c ha n ges t h at are m a de t o st u d y c o ntact p ers o n nel, b ut I R B/ EC 
re vie w or a p pr o val of t hese c ha n ges is n ot re q uire d. If pr ot oc ol a me n d m e nts are s u bsta ntial a n d 
are li kel y t o ha ve a n i m pact o n t he saf et y of t he tri al s u bjects or t o c ha n ge t he i nter pret ati o n of 
t he scie ntific d oc u me nts i n s u p p ort of t he c o n d uct of t he trial, or if t he y are ot her wise si g nifica nt, 
t he s p o ns or s hall n otif y t he F D A a n d ot her a p plica ble c o m pete nt a ut h orities of t he reas o ns f or, 
a n d c o nte nt of, t hes e a me n d me nts.  
9. 5.  
Re g ul at or y D oc u me nt ati o n  
All re g ul at or y d oc u me nt ati o n i ncl u di n g re g ul at or y s u b missi o ns, 1 5 7 2 f or ms, a n d c orres p o n d e nce 
re gar di n g t his st u d y will be ke pt b y t he S p o ns or. T he C R O t hat will c o n d uct t he st u d y o n be h alf 
of t he S p o ns or will mai ntai n all st u d y d oc u me nt ati o n acc or di n g t o t heir S O Ps.  
9. 6.  
S u bject I de ntific ati o n Re gister  
T he I n vest i gat or a grees t o c o m plete a s u bject i de ntificati o n re gister, w hic h will be use d f or t he 
p ur p ose of l o n g- ter m f oll o w- u p, if nee d e d. T his f or m will be treate d as c o nfi de ntial, a n d will be 
file d b y t he I n vesti gat or i n a sec ur e l oc ke d pl ace. Ot her wise, all re ports a n d c o m m u nicati o ns 
relati n g t o t he st u d y will i de ntif y partici pa nts b y i nitials a n d assi g ne d n u m ber o nl y. 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 8 4 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
9. 7.  
Rec or d Rete nti o n  
T he I n vesti gat or m ust ret ai n all  st u d y rec or ds re q uire d b y t h e S p o ns or a n d b y t he a p plica ble 
re g ulati o ns i n a sec ure a n d safe f acilit y. T h e I n vesti gat or m ust c o ns ult a S p o ns or C R A bef ore 
dis p osal of a n y st u d y rec or ds, a n d m ust n otif y t he S p o ns or of a n y c ha n ge i n t he l ocati o n, 
dis p ositi o n, or c ust o d y of t he st u d y files. T h e F D A re q uires rete nti o n of rec or ds f or t w o years 
f oll o wi n g t he dat e a mar keti n g a p plicati o n is a p pr o ve d, or f or t w o years aft er t he F D A is n otifie d 
t hat t he I N D is disc o nti n ue d if t here is no mar keti n g a p plicati o n. Rec or ds m ust be retai ne d f or a 
peri o d at least as l o n g as t hat s pecifie d b y F D A re g ulati o ns .  
9. 8.  
C ase Re p ort F or m C o m pleti o n  
Electr o nic C ase Re p ort F or ms ( C R Fs) will be ge n erate d f or eac h s u bject. T he electr o ni c s yst e m 
m ust c o m pl y wit h C F R 2 1 Part 1 1. 
It is t he p olic y of t he S p o ns or t hat st u d y data m ust be verifia bl e t o t he s o urce data, w hic h 
necessitates access t o all ori gi nal r ec or di n gs, la b orat or y re p orts, a n d s u bjects’ rec or ds. T he 
I n v esti gat or m ust t heref ore a gr ee t o all o w access t o s u bjects’ rec or ds, a n d s o urce dat a m ust be 
ma de  a vaila ble f or all st u d y dat a. T he s u bjects ( or t heir le gal r e prese ntati ves) m ust als o all o w 
access t o t he s u bjects’ m e dical rec or ds, a n d t h e y will be i nf or me d of t his re q uire me nt a n d will 
i n dicate t heir a gr ee me nt w he n gi vi n g I nf or me d C o nse nt. U p o n c o m pleti o n of t he st u d y, 
electr o nic c o pies of t he C R Fs will be pr o vi de d t o t he i n vesti gat ors a n d s h o ul d be i ncl u de d as part 
of his/ her st u d y files a n d retai ne d as p er F D A or l o cal re g ulati o ns. 
9. 9.  
M o nit ori n g  
At i nter vals d uri n g t h e st u d y, as well as after t he c o m pleti o n of s u bject e nr oll me nt, t he st u d y 
ce nter will be m o nit ore d  b y a C R A f or c o m plia nce, w hic h will i ncl u de e ns uri n g t hat acc urate a n d 
c o m plete data are r ec or d e d o n C R Fs, a n d r e vi e wi n g s o urce d oc u m e ntati o n a n d dr u g 
acc o u nta bilit y rec or ds. T he st u d y will be c o n d u cte d acc or di n g t o t he pri nci ples of G C P as 
acce pte d i n t h e U nite d States a n d acc or di n g t o C P M P/I C H/ 1 3 5/ 9 5. 
9. 1 0.  
O n- site A u dits 
T he S p o ns or’s re prese ntati ves will visit t he st u d y ce nter pri or t o i nitiati o n of t he st u d y t o re vie w 
wit h t he ce nter p ers o n nel i nf or mati o n re gar di n g t h e i n vesti gati o nal a ge nt, pr ot oc ol re q uire m e nts, 
m o nit ori n g re q uir e me nts, a n d re p orti n g of s eri o us a d verse e ve nts. 
I n cert ai n circ u msta nces, a sec o n dar y a u dit ma y be c o n d ucte d b y me m bers of a Q ualit y 
Ass ura nce gr o u p desi g nate d b y t he S p o ns or. T h e I n vesti gat or will be i nf or me d if t his is t o ta ke 
p lace a n d a d vise d as t o t he nat ure of t he a u dit. Re prese ntati ves of t h e F D A a n d/ or re prese ntati ves 
of ot her re g ul at or y a ut h orities ma y als o c o n d uct a n a u dit of t he st u d y. If i nf or me d of s uc h a n 
a u dit, t he I n v esti gat or s h o ul d n otif y t he S p o ns or i m me diatel y. 
9. 1 1.  
Use of I nf or m ati o n a n d P u blic ati o n  
It is u n derst o o d b y t he I n vesti gat or t h at t he i nf or m ati o n ge n erat e d i n t his st u d y will be use d b y 
t he S p o ns or i n c o n necti o n wit h t he de vel o p me nt of t he pr o d uct a n d t h eref ore ma y be discl ose d t o 
g o ver n me nt a ge n cies i n vari o us c o u ntries. T o all o w f or t he use of i nf or mati o n deri ve d fr o m t he 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 8 5 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
st u d y, it is u n derst o o d t hat t he I n vesti gat or is o bli ge d t o pr o vi de t he S p o ns or wit h c o m plete test 
res ults, all st u d y data, a n d access t o all st u d y rec or ds. 
T he S p o ns or rec o g nizes t he i m p orta nce of c o m m u nicati n g st u d y data a n d will discl ose or p u blis h 
t he res ults i n a s uita ble f or m re gar dl ess of o utc o me. T he S p o ns or ma y elect t o p u blis h s o me or 
all of t he res ults of t his st u d y i n scie ntific j o ur n als, at se mi nars or c o nfere nces, a n d/ or i n ot her 
ma n ner(s) it s o c h o os es. Res ults fr o m t his st u d y s hall n ot be ma de a v aila ble t o a n y t hir d part y b y 
t he i n vesti gati n g tea m wit h o ut t he e x press per missi o n of t he S p o ns or. 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 8 6 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
1 0.  
R E F E R E N C E S  
A be K, Mi yaza ki M, K oji T, et al. 2 0 0 1 E n ha nce d es pressi o n of c o m ple me n t C 5a rece pt or 
m R N A i n h u ma n disease d ki d ne y assesse d b y i n sit u h y bri dizati o n. Ki d ne y I nt 6 0: 1 3 7- 1 4 6. 
J e n nette J C, Fal k RJ, Bac o n P A, et al. 2 0 1 3 2 0 1 2 Re vise d I nter nati o nal C h a pel Hill C o nse ns us 
C o nfere nce N o me n clat ur e of V as c uliti des. Art hritis R he u m 6 5: 1 – 1 1. 
J o nes J H, Ter vaert J W C, Ha user T, et al. 2 0 1 0 Rit u xi ma b vers us c ycl o p h os p ha mi de i n A N C A-
ass ociate d r e nal vas c ulitis. N E n gl J Me d 3 6 3: 2 1 1- 2 2 0. 
Sc hrei ber A, Xia o H, J e n nette J C, et al.  2 0 0 9. C 5a Rece pt or m e diates ne utr o p hil acti vati o n a n d 
A N C A -i n d uce d gl o mer ul o ne p hritis. J A m S oc Ne p hr ol 2 0: 2 8 9- 2 9 8. 
St o ne J H, Mer kel P A, S piera R, et al. 2 0 1 0 Rit u xi ma b vers us c ycl o p h os p h a mi de f or A N C A-
ass ociate d vas c ulitis. N E n gl J Me d 3 6 3: 2 2 1- 2 3 2. 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 8 7 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
1 1.  
A P P E N DI C E S  
1 1. 1.  
St ate me nt of O bli g ati o ns of S p o ns or, M o nit or, a n d Cli nic a l 
I n vesti g at or 
S p o ns or a n d M o nit or 
If t he S p o ns or is n ot fa miliar wit h t he St u d y Site, t he S p o ns or or its desi g n ate d re prese ntati ve, 
will:  
A.   C o n d uct a prest u d y visit t o: 
1.  Esta blis h t he acce pt a bilit y of t he facilit y, t he recr uit me nt p ote ntial a n d t he sta n da r d of p atie nt 
care at t his site, a n d rec or d t his i n a writte n re p ort.  
2.  Disc uss t he pr o p ose d cli nical trial wit h t he I n vesti gat or, re vie w t h e C R F re q uire me nts, a n d 
s u p pl y t he I n v esti gat or Br oc h ure a n d t he draft pr ot oc ol f or re vi e w a n d a p pr o val. 
3.  Disc uss wit h t he I n v esti gat or F D A a n d ot her re g ul at or y re q uire me nts wit h res pect t o 
I nf or me d C o nse nt, c o m p ete nt a ut h orit y ( C A) a n d i nstit uti o nal re vie w b oar d (I R B)/et hics 
c o m mittee ( E C) a p pr o v al of t he trial, t he pr ot oc ol, pr ot oc ol a me n d me nts, a n d I nf or me d 
C o nse nt c ha n ges.  
B.   C o n d uct peri o dic site visits t o: 
1.  Ass ure a d h ere n ce t o t he pr ot oc ol.  
2.  Re vie w C R Fs a n d me dical rec or ds f or acc urac y a n d c o m plete ness of i nf or mati o n. 
3.  E x a mi ne p har mac y rec or ds f or d oc u me ntati o n of q ua ntit y a n d d ate of recei pt of 
i n vesti gati onal s u p plies, dis pe nsati o n a n d acc o u nta bilit y data f or a d mi nistrati o n t o eac h 
s u bject, l oss of materials, c o nta mi nati o n, a n d u n use d s u p plies. 
4.  Rec or d a n d r e p ort o bser v ati o ns o n t he pr o gress of t he trial a n d c o nti n ue d acce pta bilit y of t h e 
facilities i n a Site Visit Re p ort.   
5.  Re vie w I n vesti gat or files f or re q uire d d oc u me nts, e. g., pr ot oc ols, pr ot oc ol a me n d me nts, C A 
a n d I R B/E C a p pr o v als ( pr ot oc ols, a me n d me nts, I nf or me d C o nse nt, etc.), I R B/E C c hart er a n d 
me m bers hi p, a n d c o m m u nicati o ns bet wee n t he I R B/E C a n d t he I n v esti gat or.  
Cli nical I n vesti gat or  
A.  I R B/E C  
T he I n vesti gat or m ust ass ure t he m o nit or t hat t he I R B/E C:  
1.  Meets F D A re g ulati o ns as defi ne d i n 2 1 C F R Part 5 6 a n d ot her a p plica ble I C H a n d G C P 
re q uire me nts. 
2.  Has a ut h orit y dele gate d b y t he p are nt i nstit uti o n a n d f o u n d i n I R B/E C b y -l a ws, o perati o n 
g ui deli nes, or c hart er t o a p pr o ve or disa p pr o v e cli nical trials a n d pr ot oc ols, i ncl u di n g 
I nf or me d C o nse nt F or ms a n d ot her d oc u me nts ( pr ot oc ol a me n d me nts, i nf or mati o n t o be 
s u p plie d t o s u bjects c o ncer ni n g I nf or m e d C o nse nt, etc.). 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 8 8 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
3.  C o m plies wit h pr o per pers o n nel ma ke u p of a n I R B/E C a n d mai ntai ns a n acti ve u p- t o-date 
r oster of all I R B/E C me m bers partici pati n g i n t he meeti n gs.  
4.  C o n ve nes meeti n gs usi n g acce pta ble r ules of or der f or ma ki n g decisi o ns, rec or di n g s u c h 
decisi o ns, a n d i m ple me nti n g t he m. 
5.  Files c o ntai n ( a) d oc u me ntati o n of its decisi o ns s uc h as are f o u n d i n I R B/E C mi n utes a n d 
c orres p o n d e nce, ( b) writte n g ui d eli nes or b y- la ws g o ver ni n g I R B/E C f u ncti o ns, (c) pr ot oc ols, 
( d) pr ot oc ol i nf or mati o n t o be s u p plie d t o t he s u bject, (e) c orres p o n de n ce b et wee n t he 
I R B/E C a n d t he I n v esti gat or (I nf or me d C o nse nt F or m c ha n ges, pr ot oc ol a me n d me nts, etc.). 
B.   I nf or me d C o nse nt of H u ma n S u bjects. 
T he Pri nci pal I n vesti gat or m ust ass ure t he m o nit or t hat t he I nf or me d C o nse nt F or m: 
1.  Meets F D A re g ulati o ns as defi ne d i n 2 1 C F R Part 5 0 I nf or me d C o nse nt, a n d ot her a p plica ble 
I C H a n d G C P re q uire m e nts. 
2.  Has bee n a p pr o ve d b y t h e I R B/E C, i ncl u di n g, w h e n re q uire d, i nf or mati o n t o be gi ve n t o t he 
s u bject regar di n g t h e trial i n w hic h s/ he is e nr olle d.  
a. T he I nf or m e d C o nse nt F or m i ncl u des t he Basic Ele me nts a n d a n y A d diti o nal Ele me nts 
necessar y.  
b.  T he s u bject a n d a st u d y ce nter re pres e ntati ve si g n t he I nf or me d C o nse nt F or m a n d t he 
s u bject is gi ve n a c o p y. 
C.  St ora ge a n d Dis pe nsi n g of St u d y S u p plies. 
T he I n vesti gat or ( or p har macist or p har mac y tec h nicia n) m ust de m o nstrate t o t he m o nit or t hat: 
1.  A de q uate a n d acc urat e writte n rec or ds s h o w recei pt a n d dis p ositi o n of all st u d y s u p plies, 
i ncl u di n g dates, s erial or l ot n u m bers, q ua ntities recei ve d, a n d eac h q ua ntit y dis pe nse d, 
a d mi nistere d, or use d, wit h i de ntificati o n of eac h s u bject. 
2.  P ur p ose a n d reas o ns ar e gi ve n i n writte n rec or ds f or st u d y material dis p osal, e. g., t he a m o u nt 
c o nta mi nate d, br o ke n, or l ost, a n d t he q ua ntit y ret ur ne d t o t he S p o ns or. 
D.  Case Re p ort F or ms.  
T he I n vesti gat or m ust ass ure t he m o nit or t hat: 
1.  Case re p ort f or ms, w he n c o m plete d, acc urat el y reflect t he me dical rec or ds o n eac h s u bject.  
2.  Case re p ort f or ms a n d m e dical rec or ds will be accessi ble t o t h e m o nit or or F D A a n d ot h er 
Re g ulat or y i ns pect ors d uri n g site visits.  
E.  Files a n d Rec or ds.  
T he I n vesti gat or m ust ass ure t he q ualit y, i nte grit y, a n d c o nte nt of his or her files t hat will be 
i ns pecte d b y t he m o nit or a n d re g ulat or y i ns pect ors.  T he files m ust c o ntai n, at a mi ni m u m: 
1.  C orres p o n de nce bet w ee n t he I R B/E C a n d t he I n v esti gat or. 
2.  T he f oll o wi n g d o c u me nts: 
a. I R B/E C -a p pr o v e d pr ot oc ols. 
b.  I R B/E C -a p pr o v e d pr ot oc ol a me n d me nts. 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 8 9 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
c. I R B/E C -a p pr o v e d I nf or me d C o nse nt F or m a n d i nf or mati o n s u p plie d t o t he s u bject. 
d.  I R B/E C c hart er, me m bers hi p, a n d q ualificati o ns. 
3. Cli nical s u p plies:  
a. Rec or d of r ecei pt, date a n d q ua ntit y, a n d b atc h or l ot n u m ber. 
b.  Dis p ositi o n dates a n d q ua ntit y a d mi nistere d t o eac h s u bject. 
c. I n v e nt or y rec or ds. 
T he F D A re q uir es ret e nti o n of rec or ds f or t w o year s f oll o wi n g t he d ate a m ar keti n g a p plicati o n 
is a p pr o ve d, or f or t w o years after t he F D A is n otifie d t hat t he I N D is disc o nti n ue d if t here is n o 
mar keti n g a p plicati o n. Rec or ds m ust be retai ne d f or a peri o d at least as l o n g as t hat s p ecifie d b y 
F D A r e g ulati o ns.  

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 9 0 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
1 1. 2.  
I nf or me d C o nse nt F or m  
I n s ee ki n g I nf or me d C o nse nt, t he f oll o wi n g i nf or mati o n s hall be pr o vi de d t o eac h s u bject: 
1.  A state me nt t hat t he st u d y i n v ol ves researc h, a n e x pla nati o n of t he p ur p oses of t he researc h 
a n d t he e x pecte d d ur ati o n of t he s u bject's partici p ati o n, a descri pti o n of t he pr oce d ures t o be 
f oll o we d, a n d i de ntificati o n of a n y pr oce d ures w hic h are e x peri me ntal. 
2.  A descri pti o n of a n y reas o na bl y f oreseea ble ris ks or disc o mf orts t o t he s u bject. 
3.  A descri pti o n of a n y b e n efits t o t he s u bject or t o ot hers t hat ma y reas o na bl y be e x pecte d fr o m 
t he researc h. 
4.  A discl os ure of a p pr o priate alter nati ve pr o ce d ures or c o urses of treat me nt, if a n y, t hat mi g ht 
be a d va nta ge o us t o t he s u bject. 
5.  A state me nt descri bi n g t he e xte nt, if a n y, t o w hic h c o nfi de ntialit y of rec or ds i de ntif yi n g t he 
s u bject will be mai ntai ne d a n d t hat n otes t he p ossi bilit y t hat t he F o o d a n d Dr u g 
A d mi nistrati o n or ot her Re g ulat or y a ge n c y ma y i ns pect t he rec or ds. 
6.  F or r esearc h i n v ol vi n g m ore t ha n mi ni mal ris k, a n e x pla nati o n as t o w het her a n y 
c o m pe nsati o n a n d as t o w het her a n y m e dical treat me nts are a v aila ble if i nj ur y o cc urs a n d, if 
s o, w hat t he y c o nsist of, or w her e f urt her i nf or mati o n ma y be o bt ai ne d. 
7.  A n e x pla nati o n of w h o m t o c o ntact f or a ns wers t o perti ne nt q uesti o ns a b o ut t he researc h a n d 
researc h s u bjects' ri g hts, a n d w h o m t o c o ntact i n t he e ve nt of a res earc h rel ate d i nj ur y t o t he 
s u bject. 
8.  A state me nt t hat partici p ati o n is v ol u ntar y, t hat ref usal t o partici pate will i n v ol ve n o pe nalt y 
or l oss of be nefits t o w hi c h t he s u bject is ot her wis e e nt itle d, a n d t hat t he s u bject ma y 
disc o nti n ue partici pati o n at a n y ti me wit h o ut pe nalt y or l oss of be n efits t o w hic h t he s u bject 
is ot her wise e ntitle d. 
A D DI TI O N A L E L E M E N T S O F I N F O R M E D C O N S E N T  
1.  A state me nt t hat t he parti c ular treat me nt or pr oce d ure ma y i n v ol ve  ris ks t o t he s u bject ( or t o 
t he e m br y o or f et us if t he s u bject is or ma y b ec o m e pre g na nt) w hic h are c urre ntl y 
u nf oreseea ble.  
2.  A ntici pate d circ u msta n ces u n der w hic h t he s u bject’s partici pati o n ma y be ter mi nate d b y t h e 
I n v esti gat or wit h o ut re gar d t o t he s u bject’s c o nse nt.  
3.  A n y a d diti o nal c osts t o t he s u bject t hat ma y res ult fr o m partici pati o n i n t he researc h.  
4.  T he c o nse q u e nces of a s u bject’s decisi o n t o wit h dra w fr o m t he researc h a n d pr oce d ures f or 
or derl y ter mi nati o n of p artici pati o n b y t he s u bject.  
5.  A state me n t t hat si g nifica nt ne w fi n di n gs de vel o p e d d uri n g t he c o urs e of t he researc h w hic h 
ma y r elate t o t he s u bject’s willi n g ness t o c o nti n ue partici pati o n will be pr o vi de d t o t he 
s u bject. 
6.  T he a p pr o xi mate n u m ber of s u bjects i n v ol ve d i n t he st u d y. 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 9 3 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
1 1. 4.  
V asc ulitis D a m a ge I n de x  
T he Vasc ulitis Da ma ge I n de x ( V DI) is use d t o rec or d c u m ulati ve or ga n d a ma ge si nce t he o ns et 
of vasc ulitis, re gar dl ess of w het her it is attri b ute d t o vasc ulitis. It d oes n ot gi ve a n i n dicati o n of 
c urre nt disease acti vit y; t he B V A S is use d t o rec or d t he latter. T he V DI sc ore ca n o nl y re mai n 
t he sa me or get w orse o v er ti me. Ne wl y dia g n os e d patie nts (i.e., wit hi n t he pre vi o us 3 m o nt hs) 
t y picall y will ha ve a V DI of zer o. I n patie nts wit h vasc ulitis dia g n ose d m ore t ha n 3 m o nt hs a g o, 
t he sc ore c o ul d be n o n-zer o. 
T he V DI will be s c ore d acc or di n g t o t he g ui da nce pr o vi de d b y R. A. L u q ma ni a n d C. Hall f or 
T he L ot hia n U ni versit y H os pitals N H S Tr ust ( 2 0 0 4). T he V DI ca pt ures da ma ge i n t he f oll o wi n g 
or ga n s yste ms: M usc ul os keletal, S ki n/ M uc o us me m bra nes, Oc ul ar, E N T, P ul m o nar y, 
Car di o vasc ular, Peri p her al vasc ular disease, G astr oi ntesti nal, Re nal, Ne ur o ps yc hiatric, a n d 
Ot her. O ne p oi nt will be sc ore d f or eac h p ositi ve ite m a n d t he V DI is t he s u m of all sc ores. Ite ms 
sc ore d at a partic ular visit will be carrie d f or w ar d t o s u bse q ue nt visits. 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 9 4 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
1 1. 5.  
Pre d nis o ne D ose Sc he d ule  
S u bjects will be all o we d t o recei ve u p t o 3 0 0 0 m g of I V met h yl pre d nis ol o n e e q ui vale nt wit hi n 
1 2 wee ks pri or t o t he Scr ee ni n g peri o d. 
S u bject s will start at a n oral pre d nis o ne d os e of 6 0 m g per d a y o n D a y 1 a n d will ta per t he d ose 
d o w n t o zer o b y t he e n d of t he 1 6 8- da y st u d y peri o d.  
T he ta peri n g sc h e d ule f or all  s u bjects is pr o vi de d i n t he ta ble bel o w: 
St u d y D a ys  
Pre d nis o ne D ose  
1 t o 7  
6 0 m g  
8  t o 1 4 
4 5 m g  
1 5 t o 2 1  
3 0 m g  
2 2 t o 2 8  
2 5 m g  
2 9 t o 3 5  
2 5 m g  
3 6 t o 4 2  
2 5 m g  
4 3 t o 4 9  
2 0 m g  
5 0 t o 5 6  
2 0 m g  
5 7 t o 6 3  
1 5 m g  
6 4 t o 7 0  
1 5 m g  
7 1 t o 7 7  
1 0 m g  
7 8 t o 8 4  
1 0 m g  
8 5 t o 9 8  
1 0 m g  
9 9 t o 1 4 0  
5 m g  
1 4 1 t o 1 6 8  
0  
S u bjects will recei ve pr e d nis o ne b ottles c o ntai ni n g eit her 2 0 m g pre d nis o n e ta blets or 5 m g 
pre d nis o ne ta blets or b ot h, de pe n di n g o n t he st u d y visit (see ta bl e bel o w): 
St u d y 
Visit  
Pre d nis o ne 
d ose  
N u m ber of 2 0 m g 
pre d nis o ne b ottles 
dis pe nse d  
D osi n g i nstr ucti o ns 
f or 2 0 m g b ottle 
N u m ber of 5  
m g pre d nis o ne 
b ottles 
dis pe nse d  
D osi n g i nstr ucti o ns 
f or 5 m g b ottle 
Da y 1  
6 0 m g  
1  
T a ke 3 ta blets per da y  
0  
N A  
Da y 8  
4 5 m g  
1  
T a ke 2 ta blets per da y  
1  
T a ke 1 ta blet per da y  
Da y 1 5  
3 0 m g  
1  
T a ke 1 ta blet per da y  
1  
T a ke 2 ta blets per da y  
Da y 2 2  
2 5 m g  
1  
T a ke 1 ta blet per da y  
1  
T a ke 1 ta blet per da y  
Da y 4 3  
2 0 m g  
1  
T a ke 1 ta blet per da y  
0  
N A  
Da y 5 7  
1 5 m g  
0  
N A  
2  
T a ke 3 ta blets per da y  
Da y 7 1  
1 0 m g  
0  
N A  
1  
T a ke 2 ta blets per da y  
Da y 8 5  
1 0 m g  
0  
N A  
1  
T a ke 2 ta blets per da y  
Da y 9 9  
5 m g  
0  
N A  
1  
T a ke 1 ta blet per da y  
Da y 1 1 3  
5 m g  
0  
N A  
1  
T a ke 1 ta blet per da y  
Da y 1 4 1  
0  
0  
N A  
0  
N A  
N A = n ot a p plica ble  

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 9 5 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
1 1. 6.  
C ycl o p h os p h a mi de a n d Az at hi o pri ne D osi n g  
•  F or s u bjects i n t he c ycl o p h os p ha mi de strat u m, c ycl o p h os p ha mi de d oses gi ve n fr o m Da y 
1 t hr o u g h 8 5 m ust be gi v e n acc or di n g t o directi o ns pr o vi de d bel o w. 
•  A d ose of 1 5 m g/ k g c ycl o p h os p ha mi de will be gi ve n I V t o all s u bjects, u nless a l o wer 
d ose is re q uire d p er i nstr ucti o ns bel o w. T he ma xi m u m per mitte d d ose is 1. 2 g.  
•  Mes na a n d a ntie m etic treat me nt nee d t o be gi ve n acc or di n g t o l ocal practice. 
O n da nsetr o n 8 m g is rec o m me n de d. 
•  C ycl o p h os p ha mi de n ee ds t o be a d mi nistere d o ver a 1- h o ur peri o d.  
•  C ycl o p h os p ha mi de d ose will be deter mi ne d b y f o ur fact ors: s u bject a ge, e G F R, W B C at 
t he st u d y visit, a n d W B C na dir i n bet wee n d os e p ulses ( w here a p plica bl e).  
•  A ge:  
− If < 6 0 years, a f ull d ose will be gi ve n ( u nl ess i nfl ue nce d b y t he ot h er t hree fact ors); 
− If 6 0 t o 7 0 years, t he d os e will be re d uce d b y 2. 5 m g/ k g; 
− If > 7 0 years, t he d os e will be re d uce d b y 5 m g/ k g. 
•  e G F R:  
− If ≥3 0 m L/ mi n, a f ull d os e will be gi v e n ( u nless i nfl ue nce d b y t he ot h er t hree fact ors); 
− If < 3 0 m L/ mi n, t he d ose will be re d uce d b y 2. 5 m g/ k g. 
•  W B C c o u nt at t he ti me of c ycl o p h os p ha mi de d ose (l ocal la b W B C c o u nts):  
− If ≥4 x 1 09/ L, a f ull d ose will be gi ve n ( u nl ess i nfl ue nce d b y t he ot h er t hree fact ors); 
− If 2 t o 3. 9 x 1 09/ L, t he d ose will be re d uce d b y 2 5 %; 
− If < 2 x 1 09/ L, t he d os e will be wit h hel d u ntil t he W B C c o u nt i ncreas es t o a b o ve 3 x 
1 0 9/ L. 
•  W B C c o u nt na dir i n bet wee n c ycl o p h os p ha mi de d oses:  
− If > 3 x 1 09/ L, a f ull d ose will be gi ve n ( u nl ess i nfl ue nce d b y t he ot h er t hree fact ors); 
− If 2 t o 3 x 1 09/ L, t he d ose will be re d uce d b y 2 0 %; 
− If 1 t o 1. 9 x 1 09/ L, t he d ose will be re d uce d b y 4 0 %;  
− If < 1 x 1 09/ L, t he n e xt d ose will be wit h hel d a n d f urt her d osi n g w o ul d o nl y be gi v e n 
if t he W B C is > 3 x 1 09/ L. 
•  N ote t hat t he c ycl o p h os p ha mi de d ose a dj ust me nt is c u m ulati ve, e. g., a s u bj ect > 7 0 years, 
wit h a n e G F R < 3 0 m L/ mi n, a n d a W B C at ti me of d osi n g of 3 x 1 0 9/ L, will recei v e a 
d ose of 5. 6 m g/ k g ( 1 5 m g/ k g mi n us 5 m g/ k g f or a ge, mi n us 2. 5 m g/ k g f or e G F R, a n d 
re d uce d 2 5 % f or W B C). 
•  Oral azat hi o pri ne will be starte d o n Da y 9 9 a n d c o nti n ue t hr o u g h D a y 1 6 8. T y picall y t he 
d ose will be i ncrease d gr a d uall y u ntil t he tar get d ose of 2 m g/ k g/ da y is reac he d aft er 2 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 9 6 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
wee ks. D oses will be r o u n de d d o w n t o t he nearest 2 5 m g i ncre me nt, e. g., a s u bject 
wei g hi n g 6 0 k g will ha v e  a tar get d ose of 1 0 0 m g azat hi o pri ne per da y. T esti n g f or 
t hi o p uri ne S- met h yltra nsferas e ( T P M T) p ol y m or p his m a n d d ose a dj ust me nt s h o ul d be 
i m ple me nte d acc or di n g t o t he l ocal i nstit uti o n p olic y. Azat hi o pri ne will n ot be i nitiate d if 
t he W B C c o u nt is < 2 x 1 09/ L. I n t his case treat me nt i nitiati o n will be dela ye d u ntil t he 
W B C has i ncreas e d t o a b o ve 2 x 1 0
9/ L. I n case az at hi o pri ne is n ot t olerate d, met h otre x ate 
or m yc o p he n olate m of etil c o ul d be use d i nstea d. 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 9 7 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
1 1. 7.  
Rit u xi m a b D osi n g  
•  T he f oll o wi n g d osi n g r e gi me n of rit u xi ma b will be gi ve n : 
− 3 7 5 m g / m2 gi ve n as a n I V i nf usi o n o n St u d y Da ys 1, 8, 1 5, a n d 2 2. 
•  It is rec o m me nde d t o pr e- me dicate b ef ore eac h i nf usi o n wit h aceta mi n o p he n a n d a n a nti-
hista mi ne. F or t he first rit u xi ma b i nf usi o n, 1 0 0 m g met h yl pre d nis ol o ne, or e q ui vale nt is 
rec o m me n de d. 
•  F or t he first I V i nf usi o n, i nitiate t he i nf usi o n at a rate of 5 0 m g/ hr. I n t he a bs e nce of 
i nf usi o n t o xicit y, i n creas e i nf usi o n rate b y 5 0 m g/ hr i ncre me nts e v er y 3 0 mi n utes, t o a 
ma xi m u m of 4 0 0 m g/ hr. 
•  F or s u bse q u e nt i nf usi o ns, i nitiate t he i nf usi o n at a rate of 1 0 0 m g/ hr. I n t h e a bse nce of 
i nf usi o n t o xicit y, i n creas e rate b y 1 0 0 m g/ hr i ncre me nts at 3 0 -mi n ute i nter vals, t o a 
ma xi m u m of 4 0 0 m g/ hr. 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 9 8 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
1 1. 8.  
A d verse E ve nts Re p orte d wit h C ycl o p h os p h a mi de  
Carci n o ge nesis  
I n crease d ris k of ca n cer; m ost fre q ue ntl y, t h ese ha ve bee n uri n ar y bla d d er, m yel o pr oliferati ve, or 
l y m p h o pr olifer ati ve mali g na n cies. 
C ar diac S yste m  
C o n gesti ve heart f ail ure, he m orr ha gic m y o car ditis, he m o pericar di u m, m y o car dial necr osis, 
pericar ditis  
Di gesti ve S yste m  
Na usea, v o miti n g, a n or e xia, a b d o mi nal disc o mf ort, a b d o mi nal pai n, diarr h ea, he m orr ha gic 
c olitis, oral m uc osal ulcerati o n, ja u n dice 
He mat o p oietic S yste m  
Le u k o p e nia, ne utr o pe nia, fe ver i n n e utr o pe nic p atie nts, t hr o m b oc yt o p e nia, a ne mia  
I nfecti o ns 
Viral, bacterial, f u n gal, pr ot oz oa n, or hel mi nt hic i nfecti o ns 
Re pr o d ucti ve S yste m 
C ycl o p h os p ha mi de i nterf eres wit h o o ge n esis a n d s per mat o ge nesis. It ma y ca use sterilit y i n b ot h 
se x es. Me n treate d wit h c ycl o p h os p h a mi de ma y de vel o p oli g os per mia, az o os per mia, i m paire d 
se x ual p ote nc y or li bi d o, testic ular atr o p h y  
Res pirat or y S yste m  
I nterstitial p ne u m o nitis, i nterstitial p ul m o nar y fi br osis 
S ki n a n d Its Str uct ures 
Al o pecia, s ki n ras h, s ki n pi g me ntati o n, nail dis or d ers, Ste ve ns-J o h ns o n s y n dr o me, t o xic 
e pi der mal necr ol ysis  
Uri nar y S yste m  
C ystitis, uri nar y bl a d der fi br osis, he m orr ha gic ureteritis, re nal t u b ular necr osis 
Ot her  
A na p h yl actic r eacti o ns; deat h ass ociat e d wit h a na p h ylactic reacti o ns, SI A D H (s y n dr o me of 
i na p pr o priate A D H secreti o n), malaise, ast he nia 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 9 9 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
1 1. 9.  
A d verse E ve nts Re p orte d wit h C ortic oster oi d Use  
Aller gi c Reacti o ns  
A na p h yl act oi d or h y pers e nsiti vit y reacti o ns, a na p h yla xis, a n gi oe d e ma 
C ar di o vasc ular S yste m  
Bra d ycar di a, car diac arr est, car diac arr h yt h mias, car diac e nlar ge me nt, circ ulat or y c olla pse, 
c o n gesti ve heart fail ur e, E C G c ha n ges ca use d b y p otassi u m deficie nc y, e d e ma, fat e m b olis m, 
h y perte nsi o n or a g gra vati o n of h y p erte nsi o n, m y ocar dial r u pt ure f oll o wi n g rece nt m y ocar dial 
i nfarcti o n, necr otizi n g a n giitis, p ul m o nar y e de ma, s y nc o p e, tac h ycar di a, t hr o m b oe m b olis m, 
t hr o m b o p hle bitis, vasc ulitis 
Der mat ol o gic  
Ac ne, ac neif or m er u pti o ns, aller gic der m atitis, al o pecia, a n gi o e de ma, a n gi o ne ur otic e de m a, 
atr o p h y a n d t hi n ni n g of s ki n, dr y scal y s ki n, ecc h y m oses a n d petec hi ae ( br uisi n g), er yt h e ma, 
facial e d e ma, hirs utis m, i m paire d w o u n d heali n g, i ncreas e d s weati n g, Kar p osi’s sarc o ma, l u p us 
er yt h e mat os us -li ke lesi o ns, peri neal irritati o n, p ur p ura, ras h, stri ae, s u bc uta ne o us fat atr o p h y, 
s u p pressi o n of reacti o ns t o s ki n tests, striae, tela n giectasis, t hi n fra gile s ki n, t hi n ni n g scal p hair, 
urticaria  
E n d ocri ne  
A dre nal i ns uffi cie nc y- gr eatest p ote ntial ca us e d b y hi g h p ote nc y gl u c oc ortic oi ds wit h l o n g 
d urati o n of acti o n ( ass oci ate d s y m pt o ms i ncl u de; art hral gias, b uffal o h u m p, dizzi ness, life-
t hreate ni n g h y p ote nsi o n, na usea, se v ere tire d ness or wea k n ess), a me n orr hea, p ost me n o pa usal 
blee di n g or ot her me nstr ual irre g ularities, d ecreas e d car b o h y drate a n d gl uc ose t olera nce, 
de vel o p me nt of c us hi n g oi d state, dia betes mellit us ( ne w o nset or m a nifestati o ns of late nt), 
gl yc os uri a, h y per gl yce mia, h y p ertric h osis, h y pert h yr oi dis m, h y p ot h yr oi dis m, i ncrease d 
re q uire me nts f or i ns uli n or oral h y p o gl yce mic a ge nts i n dia betics, li pi ds a b n or mal, m o o n face, 
ne gati ve nitr o ge n bal a nce ca use d b y pr otei n cata b olis m, sec o n dar y a dre n oc ortical a n d pit uitar y 
u nres p o nsi ve ness ( p artic ularl y i n ti mes of stress, as i n tra u ma, s ur ger y or ill ness) 
Fl ui d a n d Electr ol yte Dist ur ba nces  
C o n gesti ve heart f ail ure i n s usce pti ble patie nts, fl ui d rete nti o n, h y p o k ale mia, h y p o k ale mic 
al kal osis, meta b olic al kal osis, h y p ote nsi o n or s h oc k-li ke reacti o n, p otassi u m l oss, s o di u m 
rete nti o n wit h res ulti n g e de ma 
Gastr oi ntesti nal  
A b d o mi nal diste nti o n, a b d o mi nal pai n, a n ore xia w hic h ma y res ult i n wei g ht l oss, c o nsti pati o n, 
diarr hea, ele v ati o n i n ser u m li ver e nz y me le v els ( us uall y re versi ble u p o n disc o nti n uati o n), 
gastri c irritati o n, he pat o me gal y, i n crease d a p p etite a n d wei g ht gai n, n a usea, or o p har y n geal 
ca n di diasi s, pa ncr eatitis, pe ptic ulcer wit h p ossi ble perf orati o n a n d he m orr ha ge, perf orati o n of 
t he s mall a n d lar ge i ntesti ne ( partic ularl y i n p atie nts wit h i nfla m mat or y b o wel disease), 
ulcerati ve es o p ha gitis, v o miti n g  
He mat ol o gi c  
A ne mia, ne utr o pe ni a (i ncl u di n g fe brile ne utr o pe ni a) 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 1 0 0 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
Meta b olic  
Ne gati ve nitr o ge n b ala nce d ue t o pr otei n cata b olis m 
M usc ul os keletal  
Art hral gias, as e ptic necr osis of fe m oral a n d h u meral hea ds, i ncreas e ris k of fract ure, l oss of 
m uscle mass, m uscle wea k ness, m yal gias, oste o p e nia, oste o p or osis, pat h ol o gic fract ure of l o n g 
b o nes, ster oi d m y o p at h y, te n d o n r u pt ure ( p artic ularl y of t h e Ac hilles te n d o n), verte bral 
c o m pressi o n fr act ures  
Ne ur ol o gical/ Ps yc hiatric  
A m nesia, a n xiet y, be ni g n i ntracra ni al h y p erte nsi o n, c o n v ulsi o ns, deliri u m, de me ntia 
(c har acterize d b y d eficits i n me m or y r ete nti o n, atte nti o n, c o nce ntrati o n, me ntal s pee d a n d 
efficie n c y, a n d o cc u pati o nal perf or m a nce), de pressi o n, dizzi ness, E E G a b n or malities, e m oti o nal 
i nsta bilit y a n d irrita bilit y, e u p h oria, hall uci nati o ns, hea dac he, i m paire d c o g niti o n, i nci de nce of 
se vere ps yc hiatric s y m pt o ms, i ncrease d i ntracra nial press ure wit h pa pille de ma ( pse u d ot u m or 
cere bri) us uall y f oll o wi n g disc o nti n uati o n of treat me nt, i ncreas e d m ot or acti vit y, i ns o m nia, 
isc he mic ne ur o p at h y, l o n g-ter m me m or y l oss, mania, m o o d s wi n gs, ne uritis, ne ur o pat h y, 
parest hesia, p ers o nalit y c ha n ges, ps yc hiatric dis or ders i ncl u di n g ster oi d ps yc h os es or 
a g gra vati o n of pre- e xisti n g ps yc hi atric c o n diti o ns, restless ness, sc hiz o p hre nia, ver bal me m or y 
l oss, verti g o, wit h dra w n be ha vi or 
O p ht hal mic  
Bl urre d visi o n, catar acts (i ncl u di n g p osteri or s u bca ps ular cataracts), ce ntral ser o us 
c h ori oreti n o pat h y, esta blis h me nt of sec o n dar y bact erial, f u n gal a n d viral i nfecti o ns, 
e x o p ht hal m os, gla uc o ma, i ncreas e d i ntra oc ular press ure, o ptic ner ve da m a ge, p a pille de ma  
Ot her  
A b n or mal fat de p osits, a g gr a vati o n/ mas ki n g of i nfecti o ns, decreas e d resist a nce t o i nfecti o n, 
hicc u ps, i m m u n os u p presi o n, i ncreas e d or decrease d m otilit y a n d n u m ber of s per mat oz oa, 
malaise, i ns o m nia, m o o n face, p yr e xia 

C he m o Ce ntr y x, I n c.                            C O N FI D E N TI A L                                 Pr ot oc ol C L 0 0 3 _ 1 6 8 
C C X 1 6 8                                                                                                                    A me n d me nt 4. 0 
                                                                   Pa ge 1 0 1 of 1 0 1                                 1 9 Fe br uar y 2 0 1 6 
1 1. 1 0.  
A d verse E ve nts Re p orte d wit h Rit u xi m a b Use  
T he f oll o wi n g a d vers e e v e nts were re p ort e d at a n i nci de nce of ≥ 1 0 % i n s u bjects recei vi n g 
rit u xi ma b i n patie nts wit h G P A or M P A: na usea, diarr hea, hea d ac h e, m uscle s pas ms, a ne mia, 
peri p her al e de ma, i ns o m nia, art hral gia, c o u g h, fati g ue, i ncreas e d A L T, h y p erte nsi o n, e pista xis, 
d ys p nea, le u k o pe nia, a n d ras h. I nf usi o n reacti o ns i ncl u de d c yt o ki ne releas e s y n dr o me, fl us hi n g, 
t hr oat irritati o n, a n d tre m or. I nfecti o ns i ncl u di n g u p per res pirat or y tract i nfecti o ns, uri nar y tract 
i nfecti o ns, a n d her p es z oster ha ve b ee n re p orte d. H y p o ga m ma gl o b uli ne mia was als o re p orte d. 
1 1. 1 1.  
A d verse E ve nts Re p orte d wit h Az at hi o pri ne Use  
Azat hi o pri ne use has bee n ass ociate d wit h a n i ncrease d ris k of cert ai n t y p es of ca ncers i ncl u di n g 
s ki n ca ncer a n d l y m p h o ma. Azat hi o pri ne ma y als o ca use seri o us (rarel y fatal) bl o o d dis or ders 
( decr ease d b o n e marr o w f u ncti o n lea di n g t o a ne mia, l o w W B C a n d platelet c o u nt). Its use is als o 
ass ociate d wit h i ncr ease d ris k of i nfecti o n.