Clinical trial NCT02334748
Conditions: Systemic Juvenile Idiopathic Arthritis Hereditary Periodic Fevers
Keywords: Juvenile Rheumatoid arthritis (JRA) chronic systemic inflammatory disorder painful joints inflammation of the synovial membrane auto-immune rheumatoid disease reactive rheumatoid arthritis Systemic Juvenile Rheumatoid arthritis (SJRA) Hereditary Periodic Fevers Hereditary periodic fever syndrome(HPFS) Familial Mediterranean fever syndrome(FMFS) Hyperimmunoglobulinemia D Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) Muckle-Wells syndrome (MWS) Familial cold auto inflammatory syndrome
Sponsor: Novartis Pharmaceuticals
Start date: 2014-11-03; Completion date: 2018-08-31
Enrollment: 31 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The objective of this extension protocol is to collect safety data (serious and non-serious adverse events) and to provide continuous canakinumab to patients in France who completed study CACZ885G2301E1(NCT00891046), CACZ885G2306 (NCT02296424) or CACZ885N2301 (NCT02059291) until a decision regarding reimbursement in France is effective for canakinumab (Ilaris®) in these indications.

Detailed description:

Arms: arm 1: Patients will continue the same dose as their last dose administered in the study CACZ885G2301E1, CACZ885N2301 or CACZ885G2306. For all indications, the maximum canakinumab dose is 4 mg/kg or 300 mg for patients ≥ 40 kg. Ilaris® dosage may be adjusted (or interrupted) according to the clinical response and to investigators judgment.
Interventions: intervention 1: canakinumab
Intervention descriptions: intervention 1: canakinumab

Protocol documents:
Prot_000.pdf: 
C li nic al  D e vel o p m e nt  
[ A C Z 8 8 5/ c a n aki n u m a b]  
Cli ni c al  Tri a l Pr ot o c o l C A C Z 8 8 5 G F R 0 1 / N C T 0 2 3 3 4 7 4 8 
A  Fr e n c h  o p e n-l a b el  e xt e n si o n  st u d y  of  c a n a k in u m a b  i n p at i e nt s 
w h o  p arti ci p at e d  i n i nt er nat io n al p h a s e  III st u di e s C AC Z 8 8 5 G 2 3 0 1 E 1  
or  C A C Z 8 8 5 G 2 3 0 6  i n S y st e mi c  J u v e n ile I di o p at hi c  Art h riti s a n d 
C A C Z 8 8 5 N 2 3 0 1  i n H er e di t ar y P er io d i c F e v er s  ( T RA P S,  HI D S , or 
cr F M F).  
A u th o r: 
 M . D. 
D o c u m e n t ty p e : 
A m e n d e d C li ni ca l T ria l Pro to c o l 
E U D R A C T  n u m b e r: 
2 0 1 4 -0 0 2 8 7 2 -9 5  
V e r sio n  n u m b e r: 
V 0 5  (P ro to c o l a m e n d m e nt 5 ) 
D e v e l op m e n t p h a s e : 
III  
R el e a s e  d a te : 
1 5  d e c e m b er 2 0 1 7  
Pr o p ert y of N o v arti s 
C o nfi d e nti al 
M a y n ot b e u s e d, di v ul g e d, p u bli s h e d, or ot h er wi s e di s cl o s e d 
wit h o ut t h e c o n s e nt of N o v arti s 


N o v artis 
C lin ica l T rial P rot o co l v 0 5  
C o n fid e nt ial  
P ag e 2  
P rot o co l N o . C A C Z 8 8 5 G F R 0 1  
 
T a ble of C o nte nts 
List of a b bre vi ati o ns ................................ ........................................................................................ 4 
Gl ossar y of  t er ms ............................................................................................................................. 5 
Pr ot oc ol s y n o psis ............................................................................................................................. 8  
1          I ntr o d u cti o n ....................................................................................................................... 1 3 
1. 1        Bac k gr o u n d ................................................................ ................................................... 1 3 
1. 2        P ur p ose......................................................................................................................... 1 6  
2          St u d y o b jecti ves  ................................................................................................................ 1 6 
3          I n vesti g atio nal p la n ........................................................................................................... 1 6 
3. 1        St u d y d esi g n ................................................................................................................. 1 6  
3. 2        Rati o nal e of st u d y desi g n ............................................................................................. 1 7  
3. 3  
Rati o nal e of d ose/r e gi me n, r o ute of a d mi nistrati o n a n d  durati o n of tr eat m e nt ............... 1 7  
3. 4        P ur p ose a n d ti mi n g of  i nteri m a nal yses / desi g n a da pt ati o ns ......................................... 1 7 
3. 5        Ris ks a n d be nefits ................................................................................................ ........ 1 7 
4          P o p ul atio n ................................ ......................................................................................... 1 7 
4. 1        I ncl usi o n cri t eri a .......................................................................................................... 1 8 
4. 2        E x cl usi o n crit eria ......................................................................................................... 1 8  
5          Treat me nt .......................................................................................................................... 1 9  
5. 1        Pr ot oc ol re q u este d treat me nt ........................................................................................ 2 0  
5 .1 . 1       I n vesti gati o nal treat me nt......................................................................................... 2 0  
5 .1 . 2       A d diti o nal st ud y tr e at me nt ...................................................................................... 2 1  
5. 2        Treat me nt ar ms  ............................................................................................................ 2 1 
5. 3        Treat me nt assi g n m e nt, ran d o miz ati o n ................................................................ ......... 2 1 
5. 4        Treat me nt bli n di n g .......................................................................................................  2 1 
5. 5        Treati n g t he p atie nt ...................................................................................................... 2 1  
5 .5 . 1       Patie nt n u m beri n g ................................................................................................... 2 1 
5 .5 . 2       Di s p e nsi n g t he i nv esti gati o nal tre at me nt ................................................................ 2 1  
5 .5 . 3       H a n dli n g of st ud y tr eat me nt ................................ ................................................... 2 1 
5 .5 . 4       I nstr ucti o ns f or prescri bi n g a n d ta k i n g st ud y treat me nt ................................ ......... 2 2 
5 .5 . 5       Per mitte d d ose a dj ust me nts a n d i nterr u pti o ns of st ud y tr eat me nt .......................... 2 2  
5 .5 . 6       Re s cu e  me dica tio n  .................................................................................................. 2 2 
5 .5 . 7       C o n c o mita nt tr eat me nt ............................................................................................ 2 2  
5 .5 . 8       Pr o hi bite d Trea t me nt .............................................................................................. 2 2 
5 .5 . 9       Di s co nti n uati o n of st ud y treat me nt a n d pre m at ure p atie nt w ith dra w al .................. 2 2  
5 .5 . 10     E m er ge nc y br ea ki n g of tr eat me nt assi g n me nt ........................................................ 2 3  
5 .5 . 11     E arl y st ud y t er mi nati o n ........................................................................................... 2 3 


N o v artis 
C lin ica l T rial P rot o co l v 0 5  
C o n fid e nt ial  
P ag e 3  
P rot o co l N o . C A C Z 8 8 5 G F R 0 1  
 
6          Visit sch e d ule a n d assess m e nts......................................................................................... 2 3 
6. 1  
Patie nt de m o gra p h i cs/ ot her b aseli ne c h aracteristics ....................................................... 2 4 
6. 2        St u d y tr eat m e nt dis pe nsati o n ....................................................................................... 2 4  
6. 3        Efficac y ........................................................................................................................ 2 4  
6. 4        Safet y ........................................................................................................................... 2 4  
7          Safet y m o nit o rin g  ............................................................................................................. 2 4 
7. 1        A d vers e e ve nts ............................................................................................................. 2 4  
7. 2        Seri o us a d verse e ve nt ( S A E) ........................................................................................ 2 5  
7. 2. 1 De fi niti o n of a S A E ...................................................................................................... 2 5 
7 .2 . 2  S eri o us a dverse e ve nt re p orti n g .................................................................................. 2 6 
7. 3        Pre g na n c y re p orti n g ................................................................................................. 2 7 
8          Data r e vie w a n d data b ase ma n a g e me nt ............................................................................ 2 7 
8. 1        Site m o nit ori n g ............................................................................................................ 2 7  
8. 2        Data c oll ecti o n ............................................................................................................. 2 7 
8. 3        Data bas e ma na g e m e nt a n d q ualit y c o ntr ol ................................................................... 2 7 
8. 4        Data M o nit ori n g C o m mittee ........................................................................................ 2 8  
8. 5        A dj u dic ati o n C o m m ittee .............................................................................................. 2 8  
9          Data a n al ysis ..................................................................................................................... 2 8 
9. 1        A n a l ysis sets ................................................................................................................. 2 8 
9. 2        Patie nt de m o gra p hi cs a nd  ot her b as eli ne c haracteristics ............................................. 2 8 
9. 3        Treat me nts ................................................................................................................... 2 8  
9. 4        A n a l ysis of varia b l es .................................................................................................... 2 8 
9 .4 . 1       V aria bles ................................................................................................................. 2 8 
9 .4 . 2       Statistical m o del, h y p o t hesis, a n d m et ho d of a nal ys is ............................................ 2 9 
9 .4 . 3       H a n dli n g of mi ssi n g val ues/cens ori n g/ disc o n ti n uati o ns......................................... 2 9 
9. 5        I nteri m a n al ys es  ........................................................................................................... 2 9 
9. 6        Sa m ple siz e calc u l ati o n ................................................................................................ 2 9 
1 0        Et h ical c o nsi derati o ns ....................................................................................................... 2 9 
1 0. 1      Re g ulat or y a n d et hi cal c om plia n ce .............................................................................. 2 9 
1 0. 2      I nf or me d c o ns e n t pr oce d ures  ....................................................................................... 2 9 
1 0. 3      Res p o nsi biliti es of t he i n vesti gat or a n d I R B/I E C ........................................................ 3 0 
1 0. 4      P u blicati o n of st u d y pr ot o c ol a n d res u lts ..................................................................... 3 0 
1 1        Pr ot o c ol a d here nce  ............................................................................................................ 3 0 
1 1. 1      Pr ot oc ol A me n d me nts .................................................................................................. 3 0  
1 2        Refere n ces  ......................................................................................................................... 3 0 
1 3  A p p e nd i x 1  : S u m ma r y of p r o d uct c har acteristics  ................................................................. 3 2 
 


N o v artis 
C lin ica l T rial P rot o co l v 0 5  
C o n fid e nt ial  
P ag e 4  
P rot o co l N o . C A C Z 8 8 5 G F R 0 1  
 
 
Li st  of  a b br e vi ati o n s 
 
A E  
A d verse E v e nt 
 
C R F  
Ca se Re p ort/ Recor d F or m ( pa pe r o r electr o nic) 
C P O  
C o u ntr y P h ar ma Or ga niz ati o n  
C R O  
C o ntr act Researc h Or ga niz ati o n 
 
D S & E  
Dr u g Saf et y & E pi de mi o l og y 
 
IC H   
I nt er nati o nal C o nfere n ce o n  Har m o nizati o n of Tech nical Re q uire m e nts f or 
Re g istr ati o n of P h ar mace uti cals f or H u ma n Us e 
 
IE C  
I nd e p e nd e nt Et hics C o m mitte e 
I R B  
I nstit uti o nal Re vie w B o ar d 
S A E   
Seri o us A d v ers e E v e nt 


N o v artis 
C lin ica l T rial P rot o co l v 0 5  
C o n fid e nt ial  
P ag e 5  
P rot o co l N o . C A C Z 8 8 5 G F R 0 1  
 
Gl o s s a r y of  t er m s 
 
A s s e s s m e n t 
A p ro c e d u r e u s e d  to  g e n e ra te  d a t a re q ui re d  b y  t he  s tu d y  
In v e s tig a tio n a l d ru g  
T h e  d ru g  w h o s e  p ro p e rtie s  a re  b ei n g  te s te d  in  th e  s tu d y ; th is  d e fin itio n  is 
c o n si s te n t w it h U S 
C F R  2 1  S e c tio n  3 1 2 . 3 a n d  is  s y n o n y m o u s  w it h 
“i nv e s tig a ti o na l n e w  d ru g ” o r “in v e s tig a tio n a l m e d ici n a l p ro d u c t.” 
In v e s tig a tio n a l tre a tm e n t 
A ll i nv e s tig a tio n a l d ru g (s ) w h o s e  p ro p e rti es  a r e b e in g  te s te d  in  th e  s tu d y a s  
w el l a s  th ei r a s s o c i ate d  tre a tm e n t c o n tro l s. 
T hi s  in cl u d e s a n y  p la c e b o s , a n y  a c tiv e  c o n tro ls , a s  w el l a s  a p p ro v e d  d ru g s 
u s e d  o u tsi d e  o f th e ir in d ic a tio n /a p p ro v e d  d o s a g e  o r te s te d  in  a  fix e d 
c o m bi n a tio n . 
In v e s tig a tio n a l tre a tm e n t g e n e rall y  d o e s  n o t in c l u de  o th e r tre a tm e n t s 
a d m in is te re d  a s  c o n c o m ita n t b a c k g ro u n d  th e ra p y  re q ui re d  o r all o w e d  b y t h e  
p ro to c o l w h e n  u s e d  w ithi n  a p p ro v e d  i nd ic a tio n /d o s a g e  
M e di c a ti on  n u m b e r 
A u ni q u e  id e n tifie r o n  t he  l ab e l o f e a c h  i nv e s ti g ati on al /s tu d y  d ru g  p a c k a g e in  
s tu d ie s  th a t d is p e n s e  m e d ic a ti on  u s i ng  a n  IR T  s y s te m  
S u bj e c t N u m b e r 
A n u m b e r a s s i gn e d  to  e a c h  p a ti e nt w h o  e n ro lls  i nt o th e  s tu d y  
Pr e m a tu r e p a tie n t w ith d ra w a l 
P oi n t/tim e  w h e n  t he  p a ti e nt e x it s fro m  th e  s tu d y  p rio r to  th e  p la n n e d 
c o m pl e ti on  o f a ll i nv e s ti g ati on a l/s tu d y  tre a tm e n t a d mi n i stra tio n  a n d  al l 
a s s e s s m e n t s (in cl u di n g  fo ll ow -u p)  
St u d y  d ru g / tre a tm e n t 
A n y  si n g le  d ru g  o r c o m b i n atio n  o f d ru g s  a d mi n i ste re d  t o th e  p a tie n t a s  p a rt o f 
th e  re q u ire d  s tu d y  p ro c e d u re s ; in c l u de s  in v e s ti g ati on a l d r ug  (s ), a c tiv e d ru g  
ru n -in s  o r b a c k g ro u n d  th e ra p y  
St u d y /i nv e s ti ga ti on a l 
tre a tm e n t di s c o n ti nu a tio n  
P oi n t/tim e  w h e n  p a ti e nt p e rm a n e n tly  s to p s  ta k in g  s tu d y /i nv e s ti g ati o na l 
tre a tm e n t fo r a n y  re a s o n ; m a y  o r m a y  n o t a l so  b e  th e  p oi n t/tim e  o f 
p re m a tu r e p a tie n t w ith d ra w a l 
V a ri ab le  
In fo rm a tio n  u s e d  in  th e  d a t a a n al y s is ; d e riv e d  di re c tly  o r i ndi re c tly  fro m d a t a 
c o ll ec te d  u s i ng  s p e ci fi ed  a s s e s s m e n t s a t s p e ci fi ed  tim e  p oi n ts  
 
A me n d me nt 5 
C ha n ges t o t he pr ot oc ol are relate d t o t he f oll o wi n g secti o ns:  
 
Secti o n 4. 1. i ncl usi o n criteria 
 
T he c urre nt versi o n of i n cl usi o n criteria sti p ulates t hat “ p a ti e nts w h o h ave c o m plete d t he 
i nter nati o n al C A C Z 8 8 5 G 2 3 0 6 st u d y a n d w h o s uccessf ully wit h dre w c a n aki n u m a b tre at me nt 
per pr ot oc ol b ut wit h a dise ase rel a pse wit hi n o ne ye ar fr o m t he E n d of st u dy visit will be 
all o we d t o p artici p ate i n C A C Z 8 8 5 G F R 0 1 st u dy ”.  
T he p ur p ose of t he c ha n ge is t o e na ble t hese patie nts w h o e x perie nce d a rela pse t o be i ncl u de d i n t he 
l ocal e xte nsi o n st u d y C A C Z 8 8 5 G F R 0 1 wit h n o ti me li mitati o n after t he e n d of st u d y visit.  
Ca na ki n u ma b is still n ot c o m merciall y a vaila ble i n Fra nce i n t he SJI A ( S yste mic J u ve nile I di o pat hic 
Art hritis) i n dicati o n at t he date of t he a me n d me nt 5. T he i ncl usi o n i n t he l ocal e xte nsi o n st u d y is t he 
o nl y o pti o n t o treat t hese patie nts a n d t o res u me ca na ki n u ma b, w he n me dicall y j ustifie d.  
 
Secti o n 5. Treat me nt 
F or patie nts pre vi o usl y i ncl u de d i n st u d y C A C Z 8 8 5 G 2 3 0 1 E 1 ( SJI A), t he o pti o n t o i nterr u pt 
ca na ki n u ma b after a pr ol o n ge d re missi o n acc or di n g t o t he i n vesti gat ors j u d g me nt has bee n a d de d. 
E ver y patie nt wit h dra w n fr o m C A C Z 8 8 5 G F R 0 1 st u d y d ue t o a re missi o n will be all o we d t o res u me 
ca na ki n u ma b i n case of rela pse a n d will be f oll o we d u p a gai n i n t he st u d y. 
 
Secti o n 5. 1. 1 . I n vesti gati o nal treat me nt  
N o vartis has bee n s u p pl yi n g t he o pe n-la bel i n vesti gati o nal dr u g (ca na ki n u ma b) u n der t he f or m of a 
l y o p hilisate i n vial. A mar keti n g a ut h orizati o n has bee n gra nte d i n Fe br uar y 2 0 1 7 b y t he E ur o pea n 


N o v artis 
C lin ica l T rial P rot o co l v 0 5  
C o n fid e nt ial  
P ag e 6  
P rot o co l N o . C A C Z 8 8 5 G F R 0 1  
 
C o m missi o n f or ca na ki n u ma b as a s ol uti o n f or i njecti o n. 
If necessar y (f or l o gistic reas o ns), N o vartis ma y s u p pl y o ne or t he ot her p har mace utical f or m f or t he 
trial. T here will n ot be a n y c ha n ge f or t he patie nt i n t he wa y t he me dicati o n is a d mi nistere d 
(s u bc uta ne o usl y).  
 
A me n d me nt 4 
T he p ur p ose of a me n d me nt 4 is t o m o dif y t he para gra p h 4. 1 (I ncl usi o n criteria ), t o ta ke i nt o acc o u nt 
partic ular sit uati o ns of s o me patie nts w h o ha ve bee n i ncl u de d i n i nter nati o nal p hase III st u d y 
C A C 8 8 5 G 2 3 0 6, t o e na ble t he m t o be i ncl u de d i n t he l ocal e xte nsi o n st u d y C A C Z 8 8 5 G F R 0 1. T his 
a me n d me nt is ai mi n g: 
 t o e xte n d t he peri o d t o all o w i ncl usi o n of patie nts f or t he patie nts w h o have  c o m plet e d t he 
i nter nati o nal C A C Z 8 8 5 G 2 3 0 6 st u d y a n d w h o s uccessf ull y wit h dre w ca na ki n u ma b treat me nt 
per pr ot oc ol b ut wit h a disease rela pse i n t he f oll o wi n g m o nt hs. After a me n d me nt 4, patie nts 
w h o will rela pse wit hi n o ne ye ar fr o m t he E n d of st u d y visit  (i nstea d of wit hi n o ne year 
fr o m e n d of treat me nt) will be all o we d t o partici pate i n C A C Z 8 8 5 G F R 0 1 st u d y. 
 
 t o a d d a ne w i ncl usi o n criteria t o ta ke i nt o acc o u nt t he s pecific sit uati o n of t he patie nts of 
C A C Z 8 8 5 G 2 3 0 6 st u d y, n ot ra n d o mize d (after ra n d o mizati o n cl os ure), a n d w h o, acc or di n g t o 
t he i nter nati o nal pr ot oc ol, are s u p p ose d t o re mai n at 4 m g/ k g e ver y 4 wee ks u ntil t he e n d of 
t he st u d y. After a sta ble a n d pr ol o n ge d re missi o n i n part II t he i n vesti gat ors ma y pr o p ose t o 
re d uce t he ca na ki n u ma b d ose i n t he i nterest of t he patie nts as pr o p ose d i n c urre nt practice ( b ut 
n ot all o we d i n t he c urre nt pr ot oc ol). T hese patie nts ( 3 t o 5 patie nts), will be wit h dra w n fr o m 
C A C Z 8 8 5 G 2 3 0 6 st u d y a n d will be all o we d t o partici pate i n C A C Z 8 8 5 G F R 0 1 st u d y t o 
c o nti n ue ca na ki n u ma b treat me nt. 
 
A me n d me nt 3 
T he p ur p ose of a me n d me nt 3 is t o o pe n t he recr uit me nt of st u d y C A C Z 8 8 5 G F R 0 1 t o patie nts w h o will 
c o m plete: 
 t h e p hase III i nter nati o nal st u d y C A C Z 8 8 5 N 2 3 0 1 desi g ne d t o assess efficac y a n d t olera bilit y 
of c a n a ki n u m a b i n patie nts s ufferi n g fr o m 3  r ar e He re dit ar y Perio d ic F e v ers [ T R AP S  ( T N F 
rece pt or ass ociate d peri o dic s y n dr o me), HI D S ( h y peri m m u n o gl o b uli ne mia D s y n dr o me) or 
crF M F ( c olc hi ci ne resista nt Fa mili al M e dit err a ne a n Fe ver)], 
 or t h e p h as e III i nt er n ati o n al st u d y C A C Z 8 8 5 G 2 3 0 6 d esi g n e d t o assess 2 differe nt 
ca na ki n u ma b ta per re gi me ns i n patie nts s ufferi n g fr o m SJI A ( S yste mic J u ve nile I di o pat hic 
Art hritis) wit h cli nical re missi o n (i nacti ve disease f or at least 2 4 c o nti n u o us wee ks) o n 
ca na ki n u ma b treat me nt. 
T h e o bj e cti v e is t o pr o vi de c o nti n u o us treat me nt t o t hese patie nts o nce C A C Z 8 8 5 N 2 3 0 1 a n d 
C A C Z 8 8 5 G 2 3 0 6 are c o m plete d a n d u ntil t his me dicati o n is c o m merciall y a vaila ble i n Fra nce f or 
t hese ne w i n dicati o ns. 
T a ki n g i nt o acc o u nt t he stat us of t hese o n g oi n g st u dies at t he date of Ma y 2 0 1 6, we ma y a ntici pate t hat 
a ma xi m u m of 8 patie nts i ncl u de d i n C A C Z 8 8 5 N 2 3 0 1 ( wit hi n 4 Fre nc h c e nters) ma y be i ncl u de d i n 
C A C Z 8 8 5 G F R 0 1 fr o m 
N o ve m ber 2 0 1 6 a n d t hat a 
ma xi m u m of 2 1 patie nts i ncl u de d i n 
C A C Z 8 8 5 G 2 3 0 6 ( wit hi n 3 Fre nc h ce nters) fr o m Oct o ber 2 0 1 6. 
T he last visit of st u d y C A C Z 8 8 5 N 2 3 0 1 wi ll be  t he first visit of st u d y C A C Z 8 8 5 G F R 0 1. P atie nts wi ll 
c o nti n ue o n t heir last d osi n g r e g i me n of t he o pe n-l a be l lo n g t er m treat me nt e p ochs  ( Ep o c hs 4) 
c o nsi dere d t o c o nstit ut e t he l o west c linica lly e ffic aci o us d oses t o 
mai nt ai n clini c a l effic ac y i n 
i n di vi d ual patie nts. Patie nts m a y r ecei ve a n u p-titratio n if t he y re-flar e ( ma xi m u m d ose of 3 0 0 m g/ 4 
mg/ k g f or patie nts wei g h in g  ≤4 0 k g) q 4 w. 


N o v artis 
C lin ica l T rial P rot o co l v 0 5  
C o n fid e nt ial  
P ag e 7  
P rot o co l N o . C A C Z 8 8 5 G F R 0 1  
 
T he f oll o w- u p of patie nts wit h Here ditar y Peri o dic Fe ver will be t he sa me as t he o ne f or patie nts wit h 
SJI A.  
T he last visit of st u d y C A C Z 8 8 5 G 2 3 0 6 will als o be t he first visit of st u d y C A C Z 8 8 5 G F R 0 1. P atie nts 
wi ll c o nti nue  o n t heir d osin g  r e gi me n c o nsi dere d  t o c o nstit ut e t he lo west clinica lly e ffic aci o us d ose t o 
ma i nt ai n clini c a l effic ac y i n i n di vi d ual pa tie nts.  
T he st u d y d urati o n of C A C Z 8 8 5 G F R 0 1 st u d y will be e xte n de d u ntil ca na ki n u ma b (Ilaris ® ) is 
c o m merciall y a vaila ble f or all i n dicati o ns.  
C ha n ges t o t he pr ot oc ol are relate d t o t he f oll o wi n g secti o ns:  
 
Secti o n 1. 1. Bac k gr o u n d 
 
Secti o n 1. 2. P ur p ose 
 
Secti o n 3. 1. St u d y desi g n 
 
Secti o n 3. 3. Rati o nale of d ose/re gi me n, r o ute of a d mi nistrati o n a n d d urati o n of treat me nt 
 
Secti o n 3. 5. Ris ks a n d be nefits 
 
Secti o n 4. P o p ulati o n 
 
Secti o n 5. Treat me nt 
 
Secti o n 6. Visit sc he d ule a n d assess me nts 
 
Secti o n 9. 4. A nal ysis of varia bles 
 
A me n d me nt 2  
T he p ur p ose of t his st u d y C A C Z 8 8 5 G F R 0 1 is t o pr o vi de c o nti n u o us Ilaris ®  (ca na ki n u ma b) treat me nt 
t o patie nts i n Fra nce w h o c o m plete d St u d y C A C Z 8 8 5 G 2 3 0 1 E 1 (l o n g ter m p hase III st u d y) u ntil t his 
me dicati o n is c o m merciall y a vaila ble a n d rei m b urse d i n Fra nce f or t he s yste mic J u ve nil e I di o pat hic 
Art hritis i n dicati o n. T he c urre nt versi o n of t he pr ot oc ol sti p ulates t hat t he treat me nt peri o d will be a 
ma xi m u m 1 2 m o nt hs or c o ul d e n d s o o ner if Ilaris
®  was c o m merciall y a vaila ble i n Fra nce. 
Beca use it is a ntici pate d t hat t he rei m b urse me nt of Ilaris ®  (ca na ki n u ma b) ma y n ot be ac hie ve d at 
act ual date of st u d y c o m pleti o n, t he st u d y d urati o n will be e xte n de d ( o ne year e xte nsi o n).  
C ha n ges t o t he pr ot oc ol are relate d t o t he f oll o wi n g secti o ns:  
 
Secti o n 1. 1. Bac k gr o u n d 
 
Secti o n 1. 2. P ur p ose 
 
Secti o n 3. 1. St u d y desi g n 
 
Secti o n 6. Visit sc he d ule a n d assess me nts 
 
A me n d me nt 1 
T he p ur p ose of a me n d me nt 1 is t o ma ke clear t hat N o vartis will s u p pl y t he o pe n-la bel i n vesti gati o nal 
dr u g (ca na ki n u ma b) fr o m c o m mercial pac ka ges or cli nical batc hes.  
F urt her m ore, a me n d me nt 1 als o a d dresses t he re q uest fr o m t he i n vesti gat ors t o a d d t he o pti o n t o 
re d uce t he ca na ki n u ma b d ose i n patie nts wit h a de q uate res p o nse b y pr ol o n gi n g t he ca na ki n u ma b d ose 
i nter val (i.e. e ver y 6 or 8 wee ks) acc or di n g t o cli nical res p o nse a n d i n vesti gat ors j u d g me nt. 
C ha n ges t o t he pr ot oc ol are relate d t o t he f oll o wi n g secti o ns:  
 
Secti o n 5. 1. 1 I n vesti gati o nal treat me nt 
 
Secti o n 5 Treat me nt 
 
Secti o n 6. Visit sc he d ule a n d assess me nts 


N o v artis 
C lin ica l T rial P rot o co l v 0 5  
C o n fid e nt ial  
P ag e 8  
P rot o co l N o . C A C Z 8 8 5 G F R 0 1  
 
Pr ot o c ol  s y n op si s  
 
 
Pr o to c ol  n u m b e r 
C A C Z 8 8 5 G F R 0 1  
T itl e 
A  F re n c h  o p e n -la b e l e x t e n si o n st u d y  o f c a n a ki n u m a b  i n p a tie nt s 
w h o 
p a rti ci pa te d  
i n  
i n te r na tio n a l 
p h a s e  
III 
st u d i e s 
C A C Z 8 8 5 G 2 3 0 1 E 1  
or 
C A C Z 8 8 5 G 2 3 0 6 i n S y st e mi c J u v e ni le  I di o pa t hic A rt hritis  a n d  C A C Z 8 8 5 N 2 3 0 1 i n 
H er e di t ar y P eri o di c F e v er ( T R A P S, HI D S or cr F M F). 
Br ief  titl e 
F re n c h 
st u d y  e x t e n si o n t o st u d y 
C A C Z 8 8 5 G 2 3 0 1 E 1 , C A C Z 8 8 5 G 2 3 0 6 
a n d 
C A C Z 8 8 5 N 2 3 0 1 . 
S p o n s or  a n d  Cli ni c al  
P h a s e  
N o v a rti s P h a r m a S A S  
III 
I nv e s ti g ati o n ty p e  
B i olo g ic a l 
S tu d y  ty p e  
In te r ve nt io n a l 
P u rp o s e  a n d  rati o n al e  
T h e  p ur p o s e  of  t his  st u d y i s  t o p ro vi d e  c o nt in u o u s  c a n a ki n u m a b ( Il aris ® ) tre a tm e nt 
t o pa tie nt s i n F ra n c e w h o  c o m p le t e d s t ud y C A C Z 8 8 5 G 2 3 0 1 E 1 , C A C Z 8 8 5 G 2 3 0 6 or  
C A C Z 8 8 5 N 2 3 0 1 .  
T h e l o c al e xt e n si o n st u d y will b e c o m pl et e d a s s o o n a s c a n a ki n u m a b i s 
c o m m e r ci ally a v a ila bl e a n d r e im b ur s e d i n  F ra n c e  for t h e s e i n di ca tio n s , or if 
a p pli c a bl e, w h e n it will b e c o nfir m e d t h at t h e l a st i n di c ati o n c o ul d n ot b e r ei m b ur s e d 
i n Fr a n c e. H o w e v er, a s t h e c o m m er ci ali z ati o n of t h e diff er e nt i n di c ati o n s will b e 
eff e cti v e at diff er e nt d at e s, p ati e nt s 
will di s c o nti n u e t h e st u d y i n di c ati o n b y 
i n di c ati o n. 
T hi s  st u d y 
will  o n ly  b e  p r o p o se d  t o F re n c h  c e nt e rs  i n v olv e d  i nto  st u d y  
C A C Z 8 8 5 G 2 3 0 1 E 1 , C A C Z 8 8 5 G 2 3 0 6 a n d C A C Z 8 8 5 N 2 3 0 1 .  
 
O bj e c tiv e( s)  
T h e  o bj e c tiv e  of  t his  e x t e n si o n p rot o c ol  i s t o c ol le c t s a fe ty d a t a (s e ri o u s a n d n o n -
s e ri o u s a d v e r s e e v e nt s ) a n d  t o p ro vi d e c o nt in u o u s  c a n a ki n u m a b  to  p a tie nt s  i n 
F ra n c e  
w h o  
c o m p le t e d  
st ud y  
C A C Z 8 8 5 G 2 3 0 1 E 1 , 
C A C Z 8 8 5 G 2 3 0 6  
or 
C A C Z 8 8 5 N 2 3 0 1  u nt il a  d e c i sio n r e g a r din g  r eim b ur s e m e n t i n F ra n c e  i s ef f ec tiv e  f or 
c a n a ki n u m a b ( Il ari s® ) i n t h e s e i n di ca tio n s . 


N o v artis 
C lin ica l T rial P rot o co l v 0 5  
C o n fid e nt ial  
P ag e 9  
P rot o co l N o . C A C Z 8 8 5 G F R 0 1  
 
S tu d y  d e si g n  
T hi s  i s a n  o p e n -l ab e l (s in g l e tre a tm e nt  a rm ) e x t e n si o n s a fe ty  st u d y  f or p ati e nt s 
w h o  c o m p le t e d t h e i nte r na tio n a l st u d i e s: 
 
C A C Z 8 8 5 G 2 3 0 1 E 1  
 
or C A C Z 8 8 5 N 2 3 0 1  
 
or C A C Z 8 8 5 G 2 3 0 6  
T h e  l a st vi s it of  st u d y C A C Z 8 8 5 G 2 3 0 1 E 1 , C A C Z 8 8 5 G 2 3 0 6 or C A C Z 8 8 5 N 2 3 0 1  will  
b e  t h e first  vi s it of t hi s  e x t e n si o n s t ud y .  
P ati e nt s f oll o w u p:  
F or p ati e nt s pr e vi o u sl y i n cl u d e d i n st u d y C A C Z 8 8 5 G 2 3 0 1 E 1  ( S JI A i n di c ati o n) 
T h e s e p a tie nt s  will  c o nt in u e t h e  s a m e  d o si n g  r eg im e n  u s e d  a t t h e e n d  o f 
C A C Z 8 8 5 G 2 3 0 1 E 1.  
Vi s it s will t a k e pl a c e  a t c a n a ki n u m a b d o s e  a d m ini s tra tio n s,  a p pr o x im a t ely e v e ry  
4  w e e k s  ( or l e s s fr e q u e ntl y a c c or di n g t o i n v e sti g at or s j u d g m e nt i. e. 6, 8 or 1 2 
w e e k s ). T h e s a fe ty o f c a n a ki n u m a b will  b e  e v a l u ate d  (a d v e rs e e v e nt s a n d 
s e ri o u s a d v e r s e e v e nt s c ol l ec tio n).  P a tie nt s will  b e f oll o w e d u p a c c o rdi n g  t o 
S m P C (s e e  a p p e n di x  1) a n d l o c a l pra c tic e.  
F or 
p ati e nt s 
pr e vi o u sl y i n cl u d e d i n st u d y 
C A C Z 8 8 5 N 2 3 0 1 ( P eri o di c 
F e v er 
s y n dr o m e s ) 
T h e s e p ati e nt s will c o nti n u e th e  m ai nt e n a n c e d o s e a s d et er mi n e d at t h e e n d 
of t h e o p e n -l a b el p eri o d/ e p o c h 4 (i. e t h e lo w e s t c lin ic a lly  e ffic a c io u s  d o s e  to  
m a i nta in  c lin ic a l e ffic a c y  i n in d iv id u a l p a tie n ts  wit h a g o o d t ol er a bilit y).  
Vi sit s  will  t a k e pl a c e  a t s c h e d ul e d  a d m ini s tra tio n  d a t e s, a p pr o x im a t ely  e v e ry  
4 , 8  or 1 2  w e e k s.  T h e s a fe ty  o f c a n a ki n u m a b will  b e  e v a l u ate d  (a d v e r s e 
e v e nt s  a n d  s e ri o u s a d v e r s e e v e nt s).  P a tie nt s  will t h e n b e  fol lo w e d u p 
a c c o rdi n g t o S m P C a p pr o v e d b y E M A (E ur o p e a n M e di ci n e s A g e n c y ). 
F or p ati e nt s pr e vi o u sl y i n cl u d e d i n st u d y C A C Z 8 8 5 G 2 3 0 6  ( S JI A) 
T h e s e p ati e nt s  w ill c o n tin u e  o n  th e ir d o s in g  re g i me n  c o n s id e re d  to  c o n s titu te  
th e  lo w e s t c lin ic a lly  e ffic a c io u s  d o s e  to  m a i nta in  c lin ic a l e ffic a c y  i n in d iv id u a l 
p a tie n ts.   
Vi s it s will t a k e pl a c e  a t c a n a ki n u m a b  d o s e  a d m ini s tra tio n , a p pr o x im a t ely e v e ry  
4 , 8 or 1 2 w e e k s . T h e s a fe ty o f c a n a ki n u m a b will  b e  e v a l u ate d  (a d v e rs e e v e nt s 
a n d s e ri o u s a d v e r s e e v e nt s c ol l ec tio n).  P a tie nt s will  b e f oll o w e d u p a c c o rdi n g  t o 
S m P C (s e e  a p p e n di x  1) a n d i n v e sti g at or s j u d g m e nt.  
 
P o p u l ati o n 
U p t o 4 0 p ati e nt s m a y b e i n cl u d e d i n t h e Fr e n c h e xt e n si o n st u d y C A C Z 8 8 5 G F R 0 1 (i n 
3 c e nt er s).  
 T w el v e p ati e nt s pr e vi o u sl y e nr oll e d i nt o st u d y C A C Z 8 8 5 G 2 3 0 1 E 1  
 U p t o 2 8  p ot e nti al a d diti o n al p ati e nt s  a c c or di n g t o a m e n d m e nt 3:  
o  
U p t o 2 1  p ati e nt s  i n cl u d e d i n C A C Z 8 8 5 G 2 3 0 6 st u d y (i n 3 Fr e n c h c e nt er s) 
o  
U p t o 7  p ati e nt s i n cl u d e d i n C A C Z 8 8 5 N 2 3 0 1 st u d y (i n 3  Fr e n c h c e nt er s).  
 


N o v artis 
C lin ica l T rial P rot o co l v 0 5  
C o n fid e nt ial  
P ag e 1 0  
P rot o co l N o . C A C Z 8 8 5 G F R 0 1  
 
I n cl u si o n c rit eri a 
Crit eri a a p pli c a bl e f or p ati e nt s wit h S y st e mi c J u v e nil I di o p at hi c Art hriti s S JI A)  
 P ati e nt s  
w h o  
h a v e  
c o m pl et e d  
t h e  
i nt er n ati o n al  
st u di e s 
C A C Z 8 8 5 G 2 3 0 1 E 1 or C A C Z 8 8 5 G 2 3 0 6 wit h o ut a n y si g nifi c a nt s af et y 
i s s u e a c c or di n g t o I n v e sti g at or’ s o pi ni o n . 
 P a tie nt s  w h o  h a v e  c o m p l ete d  t h e i nte r na tio n a l C A C Z 8 8 5 G 2 3 0 6  st u d y  
a n d w h o s u c c e s sf ull y wit h dr e w c a n a ki n u m a b tr e at m e nt p er pr ot o c ol b ut 
wit h a di s e a s e r el a p s e aft er t h e e n d of st u d y vi sit will b e all o w e d t o 
p arti ci p at e i n C A C Z 8 8 5 G F R 0 1 st u d y ( w h at e v er t h e ti m e of r el a p s e fr o m 
t h e e n d of st u d y vi sit), if t h e i n v e sti g at or st at e s t h at t h er e i s a n i n di c ati o n 
t o r e s u m e c a n a ki n u m a b. 
 P a tie nt s  w h o  h a v e  p arti ci p at e d i n t h e i nte r na tio n a l C A C Z 8 8 5 G 2 3 0 6  
st u d y 
b ut 
c o ul d 
n ot 
b e r a n d o mi z e d 
a n d t h e n 
h a v e 
c o nti n u e d 
c a n a ki n u m a b i n p art I u ntil t h e e n d of t h e st u d y at a d o s e of 4 m g/ k g 
e v er y 4 
w e e k s 
m a y b e s wit c h e d t o 
C A C Z 8 8 5 G F R 0 1 st u d y if t h e 
i n v e sti g at or t hi n k s t h at, i n t h e i nt er e st of t h e p ati e nt, t h er e i s a n i n di c ati o n 
t o t a p er off c a n a ki n u m a b d o s e aft er a pr ol o n g e d r e mi s si o n. 
 
Crit eri a  a p pli c a bl e f or p ati e nt s wit h P eri o di c F e v er s y n dr o m e s  ( T R A P S, HI D S, 
cr F M F)  
 P ati e nt s w h o h a v e c o m pl et e d t h e i nt er n ati o n al C A C Z 8 8 5 N 2 3 0 1 st u d y 
wit h o ut a n y si g nifi c a nt s af et y i s s u e  a c c or di n g t o I n v e sti g at or’ s o pi ni o n . 
 
Crit eri a a p pli c a bl e f or all p ati e nt s  
 P ar e nt' s or l e g al g u ar di a n' s writt e n i nf or m e d c o n s e nt a n d c hil d' s a s s e nt, 
if a p pr o pri at e, or p ati e nt' s writt e n i nf or m e d c o n s e nt f or p ati e nt s ≥ 1 8 
y e ar s of a g e 
m u st b e o bt ai n e d b ef or e a n y st u d y r el at e d a cti vit y or 
a s s e s s m e nt i s p erf or m e d.  
E x c lu si o n  c rit eria  
1. Hi st o ry of r e c u rrin g i nf e c tio n s, or u n d e rly in g c o n di ti o n s w hi c h  m a y p r edi s p o s e  
th e m  t o i nfe c tio n s.  T r e atm e nt  wit h  c a n a ki n u m a b s h o ul d  n ot  b e  c o nt in u e d i n  p a tie nt s  
wit h  s e v e r e in f e ctio n s  re q uiri n g m e di c a l int e rv e nt io n.  
2. H y p e rs e n si ti vity t o  t h e a c tiv e  s u b s ta n c e  or  t o a n y of  th e e x c i pie nt s ( s e e  S m P C, 
s e c tio n 6. 1 ). 
3.  C o n c o m it a nt u s e  of  s e c o n d  lin e a g e nt s  s u c h  a s  di s e a s e -m o d ify in g a n d/ or  
im m u n o s u p pr e s s iv e d ru g s  will  n ot b e  a llo w e d  wit h  t h e e x c e pt io n o f: 
• M et h otr e x a t e, a n d  f olic /f oli ni c a c i d s u p pl e m e n ta tio n ( a c c o rdi n g  t o st a n da r d 
m e di c a l pra c tic e ) 
• N o n -st e roi d al a nt i-i nfla m m a t ory  dr u g  (N S A ID ) 
• S y st e mi c  c o rtic o s te r oid tr e a tm e nt.  
4.  C o n c o m it a nt u s e  of  a n ot h er  bi o lo g ic  a g e nt  or  a n y i n v e sti g a tio n a l dru g . 
5.  P r eg n a nt  or  n ur si n g  (la c t atin g ) fe m al e  p a tie nt s , w h e re  p r eg n a n c y i s  d e fi ne d  a s  
t h e st at e  of  a  fe m a le a fte r c o n c e pt io n  a n d  u nt il t h e t erm in a tio n  of  g e st ati o n,  
c o nfi rm e d  b y  a  p o sit iv e  h C G  l a b or at ory t e st or a n uri n a ry  p r eg n a n c y  te st.  
6.  F e m al e p a tie nt s  w h o  a r e of c hi ld -b e a rin g p ot e nt ia l d e fi ne d  a s  a ll fe m al e s  
p h y si o lo g i ca lly c a p a bl e  o f b e c o m in g p r eg n a nt,  u nl e s s  t he y a r e u sin g e ffe c tiv e  
m et h o d s  of  c o ntr a c e pt io n  d uri n g d o si n g of  st u d y tr e a tm e nt.  


N o v artis 
C lin ica l T rial P rot o co l v 0 5  
C o n fid e nt ial  
P ag e 1 1  
P rot o co l N o . C A C Z 8 8 5 G F R 0 1  
 
T re a tm e n t 
All p ati e nt s will b e t r e ate d wit h  c a n a ki n u m a b . 
F or p ati e nt s pr e vi o u sl y i n cl u d e d i n st u d y C A C Z 8 8 5 G 2 3 0 1 E 1 ( S JI A)  
T h e s e p a tie nt s  will  c o nt in u e  th e  s a m e  d o s e  a s  t h eir l a st d o s e  a d m ini s te re d i n  
t h e st u d y  C A C Z 8 8 5 G 2 3 0 1 E 1: c a n a ki n u m a b  4 m g /k g  (o r 3 0 0 m g m a x ) or 2 m g / k g 
( 1 5 0m g /m a x ) e v e ry  4 w e e k s  ( or l e s s fr e q u e ntl y a c c or di n g t o i n v e sti g at or s 
j u d g m e nt i. e. 6, 8 or 1 2 w e e k s ). 
F or p ati e nt s pr e vi o u sl y i n cl u d e d i n st u d y C A C Z 8 8 5 G 2 3 0 1 E 1 , th e c a n a ki n u m a b 
d o s e i nt er v al 
m a y b e pr ol o n g e d (i. e. e v er y 8  or 1 2  w e e k s) i n p ati e nt s wit h 
a d e q u at e r e s p o n s e  a c c or di n g t o t h e cli ni c al r e s p o n s e 
a n d i n v e sti g at or s 
j u d g m e nt. 
 
F or p ati e nt s pr e vi o u sl y i n cl u d e d i n st u d y C A C Z 8 8 5 N 2 3 0 1  (P eri o di c F e v er 
s y n dr o m e s ) 
T h e s e p ati e nt s  w ill c o n tin u e  o n  th e ir la s t d o s in g  re g i me n  of  th e  o p e n -la b e l lo n g 
te rm tre a tm e n t e p o c h s  ( Ep o c h s  4)  c o n s id e re d  to  c o n s titu te  th e  lo w e s t c lin ic a lly  
e ffic a c io u s  d o s e  to  m a i nta in  c lin ic a l e ffic a c y  i n in d iv id u a l p a tie n ts . 
P ati e nt s will t h e n c o nti n u e o n e of t h e f oll o wi n g r e gi m e n:  
- 
C a n a ki n u m a b 1 5 0 m g  ( or 2 m g/ k g fo r p a tie n ts  w e ig h in g  ≤4 0  k g ) q 4 w   
- 
C a n a ki n u m a b 1 5 0 m g ( or 2 m g/ k g fo r p a tie n ts  w e ig h in g  ≤4 0  k g ) q 8 w   
- 
C a n a ki n u m a b 3 0 0 m g ( or 4 m g/ k g fo r p a tie n ts  w e ig h in g  ≤4 0  k g ) q 4 w   
- 
C a n a ki n u m a b 3 0 0 m g ( or 4 m g/ k g fo r p a tie n ts  w e ig h in g  ≤4 0  k g ) q 8 w . 
I n c a s e of re -fla re ( a c c or di n g t o i n v e sti g at or s j u d g m e nt), p ati e nt s will b e all o w e d 
t o i n cr e a s e t h e d o s e a s f oll o ws : 
- 
If p ati e nt s  r e c ei v e c a n a ki n u m a b 1 5 0 m g q 8 w, t h e d o s e of c a n a ki n u m a b 
will b e i n cr e a s e d t o 1 5 0 m g q 4 w  
- 
If p ati e nt s r e c ei v e c a n a ki n u m a b 1 5 0 m g q4 w, t h e d o s e of c a n a ki n u m a b 
will b e i n cr e a s e d t o 3 0 0 m g q 4 w  
- 
If p ati e nt s r e c ei v e c a n a ki n u m a b 3 0 0  m g q 8 w, t h e d o s e of c a n a ki n u m a b 
will b e i n cr e a s e d t o 3 0 0 m g q 4 w . 
F or p ati e nt s pr e vi o u sl y i n cl u d e d i n st u d y C A C Z 8 8 5 N 2 3 0 1, t h e c a n a ki n u m a b 
d o s e i nt er v al 
m a y b e pr ol o n g e d (i. e. e v er y 8 or 1 2 w e e k s) i n p ati e nt s wit h 
a d e q u at e r e s p o n s e  a c c or di n g t o t h e cli ni c al  r e s p o n s e a n d i n v e sti g at or s 
j u d g m e nt. 
 
F or p ati e nt s pr e vi o u sl y i n cl u d e d i n st u d y C A C Z 8 8 5 G 2 3 0 6  ( S JI A): 
T h e s e p ati e nt s will  c o nt in u e  th e  s a m e  d o s e  a s  t h eir l a st d o s e  a d m ini s te re d at 
t h e e n d of t h e t a p eri n g p eri o d st ud y  C A C Z 8 8 5 G 2 3 0 6 . 
T h e n, p ati e nt s will c o nti n u e o n e of t h e f oll o wi n g r e gi m e n s:  
- 
C a n a ki n u m a b 4 m g/ k g  q 4 w k s  
- 
C a n a ki n u m a b 2 m g/ k g q 4 w k s  
- 
C a n a ki n u m a b 1 m g/ k g q 4 w k s  
- 
C a n a ki n u m a b 4 m g/ k g q 8 w k s  
- 
C a n a ki n u m a b 4 m g/ k g q 1 2 w k s . 
P a tie n ts  m a y  re c e iv e  a n  u p -titra tio n  if th e y  re -fla re ( m a xi m u m d o s e of 3 0 0 m g 
(or  4  m g/ k g  s .c  fo r p a tie n ts  ≤4 0  k g)  q 4 w).  
 
P ati e nt s w h o s u c c e s sf ull y wit h dr e w  c a n a ki n u m a b p er pr ot o c ol b ut wit h a di s e a s e 
r el a p s e will b e all o w e d t o p arti ci p at e i n C A C Z 8 8 5 G F R 0 1 st u d y ( w h at e v er t h e 
ti m e of r el a p s e fr o m t h e e n d of st u d y vi sit) a n d will r e c ei v e a st arti n g d o s e of 4 
m g/ k g s .c  ( 3 0 0 m g fo r p a tie n ts  ≥4 0  k g)  e v er y 4 w e e k s.  T hi s d o s e ( or d o s e 
i nt er v al) m a y b e a dj u st e d a c c or di n g t o t h e r e s p o n s e a n d i nv e sti g at or s j u d g m e nt.  
F or p ati e nt s pr e vi o u sl y i n cl u d e d i n st u d y C A C Z 8 8 5 G 2 3 0 6 , th e c a n a ki n u m a b d o s e 
i nt er v al 
m a y al s o b e pr ol o n g e d (i. e. e v er y 8  or 1 2  w e e k s) i n p ati e nt s wit h 
a d e q u at e r e s p o n s e  a c c or di n g t o t h e cli ni c al r e s p o n s e 
a n d i n v e sti g at or s 
j u d g m e nt.  
F or all i n di c ati o n s, t h e m a xi m u m c a n a ki n u m a b d o s e i s 4 m g/ k g or 3 0 0 m g f or 
p ati e nt s ≥ 4 0 k g.  


N o v artis 
C lin ica l T rial P rot o co l v 0 5  
C o n fid e nt ial  
P ag e 1 2  
P rot o co l N o . C A C Z 8 8 5 G F R 0 1  
 
I n v e sti g ati o n al tr e at m e nt 
N o v arti s h a s b e e n s u p pl yi n g t h e o p e n -l a b el i n v e sti g ati o n al dr u g ( c a n a ki n u m a b) u n d er 
t h e f or m of a l y o p hili s at e i n vi al. A m ar k eti n g a ut h ori z ati o n h a s b e e n gr a nt e d i n 
F e br u ar y 2 0 1 7 b y t h e E ur o p e a n C o m mi s si o n f or c a n a ki n u m a b a s a s ol uti o n f or 
i nj e cti o n. If n e c e s s ar y (f or l o gi sti c r e a s o n s), N o v arti s m a y s u p pl y o n e or t h e ot h er 
p h ar m a c e uti c al f or m f or t h e tri al.  T h er e  will n ot b e a n y c h a n g e f or t h e p ati e nt i n t h e w a y 
t h e m e di c ati o n i s a d mi ni st er e d ( s u b c ut a n e o u sl y). 
E ffi ca c y  a s s e s s m e n ts  
T h e r e i s n o e ffic a c y  a s s e s s m e nt in t h is s tu d y  
S af e ty  a s s e s s m e n ts  
A E s a n d S A E s will  b e  c o lle c t e d 
Ot h er  a s s e s s m e nt s  
N o n e  
D at a  a n al y s is  
T h e d at a will b e pr e s e nt e d i n a d e s cri pti v e m a n n er. A d v er s e e v e nt s will b e c o d e d 
u si n g t h e M e d D R A di cti o n ar y t h at pr o vi d e s t h e pri m ar y s y st e m or g a n cl a s s a n d 
pr ef err e d t er m i nf or m ati o n.  
A d v e r s e e v e nt s  will  b e  s u m m a riz e d  f or e a c h i n di c ati o n b y  p re s e nt in g  t h e n u m b er  a n d 
p e r ce nt a g e  of  p a ti ent s  h a vi n g  a n y a d v e rs e  e v e nt,  h a vi n g  a n y a d v e r s e e v e nt  i n e a c h  
p rim ar y  s y st e m  o rg a n  c l a s s a n d  h a v i n g e a c h  i n divi d u al a d v e r s e e v e nt  b a s e d  o n  t h e 
p r ef err ed  t erm.  All  ot h er i nf o r ma tio n c ol l e ct e d ( e. g. s e v e rit y, r el ati o n s hi p t o st u d y  
d ru g , or  m i cr o or g ani s m f or i nf e c tio u s  a d v e r s e e v e nt s)  will  b e t a b ul at e d  a n d  list e d  a s 
a p pr o p riat e.  
D e a t h s, s e ri o u s a d v e r s e e v e nt s,  a n d  a d v e r s e e v e nt s  l ea di n g t o di s c o nti n u a tio n of  
st u d y  d ru g will  b e  s u m m a riz e d  b y  p ri m ary  s y st e m o rg a n c l a s s a n d p re fe rre d  t erm a n d 
li st e d. 
T h e  e x p o s ur e  t o st u d y d r u g (n u m b er  o f i nje c tio n s)  a n d  d ur a tio n  of e x p o s ur e  (d a y s) 
will  b e  s u m m a riz e d a n d l ist e d . 


N o v artis 
C lin ica l T rial P rot o co l v 0 5  
C o n fid e nt ial  
P ag e 1 3  
P rot o co l N o . C A C Z 8 8 5 G F R 0 1  
 
1          I ntro d u ct i o n 
 
1. 1        B a c k gr o u n d 
 
S yste mic J u ve nile I di o pa t hic Art hritis ( SJI A) is a s u bset of J u ve nile I di o pat hic Art hritis (JI A), a 
seri o us a n d p ote ntiall y disa bli n g f or m of art hritis t hat occu rs i n chi l dren  1 6 years of age  a n d 
y o u n ge r, a n d acco u nts f or a p pr o xi ma tel y 4 - 1 7 % of JI A (Q u artier 2 0 0 7, Ra velli a n d 
Marti ni 
2 0 0 7 ). I n c o ntrast t o ot her JI A s u bt y p es SJI A is ass ociate d wit h s yste mic s ym p t o ms s uc h as fe ver, 
ras h, a ne mia, leu k o c yt osis, ele vate d er yt hr oc yte se di me ntati o n rate a n d acut e- p h ase. T he peak  
a ge of disea se o nset lies bet ween  1 8 m o nt hs a n d 2 years, b ut SJI A ma y occ ur i n c hil dren of a n y 
a ge a n d, rarel y, i n y o u n g a d ults t o o ( W o o 2 0 0 6 ). 
Se veral li nes of e vi de nce s h o w t hat i n terle u ki n- 1 (I L- 1) pl a ys a pi v otal r ole i n t he pat h o ge nesis of 
SJI A ( Di narell o 2 0 0 5 , Pasc u al et al 2 0 0 5). 
Il aris®  ( Ca na ki n u ma b) is a h u ma n m o n ocl o nal a nti- h u ma n i nterle u ki n- 1 be ta (I L- 1 beta) a ntib o d y of 
t he I g G 1/ κ is ot y pe. Ca na ki n u ma b bi n ds wit h hi g h aff i nit y s pecificall y t o h u ma n I L- 1 bet a an d  
n eut ralizes t he bi ol o gi cal activi t y of h u ma n I L- 1 bet a b y bl oc ki n g its i nteracti o n wit h I L- 1 rece pt ors, 
t here b y prev e nti n g I L- 1 beta-i n d uce d gene  acti vati o n a n d t he pr o d ucti o n of i nfla m mat or y me diat ors. 
Ca na ki n u ma b has a half-li fe of a p pr o xi ma tel y 2 1- 2 8 da ys. 
T o  
date, f ou r cli nical st u dies ( C A C Z 8 8 5 A 2 2 0 3, C A C Z 8 8 5 G 2 3 0 5, 
C A C Z 8 8 5 G 2 3 0 1, a n d 
C A C Z 8 8 5 G 2 3 0 1 E 1 ) h a ve b een  perf or me d b y N o vartis t o e val uate cana ki n u ma b as a tr eat me nt f or 
p atie nts wit h SJI A.  
Il aris®  recei ve d Ma r keti n g A ut h orizati o n b y t he E M A f or patie nts wit h S yste mic J u ve nil e I di o pat hic 
Art hritis ( SJIA)  o n A u g ust 2 0 1 3 f or t he tre at me nt of  active Syste mic J u veni le I di o p at hic Art hritis 
( SJI A) i n p atie nts a ge d 2 years a n d ol der w h o h ave res p o n de d i n a de q u at e ly t o previ o us t her a py wi t h 
n o n-ster oi d al a nti- i nfl a m m at ory dr u gs (N S AI Ds) a n d syste m ic c ortic oster oi ds. Il aris®  c a n b e giv e n 
as m o n ot her a py or i n c o m bi n ati o n wi t h met h otrexate.  
S t ud y C A C Z 8 8 5 G 2 3 0 1 E 1 is a P h ase III st u d y desi g ne d t o assess l o n g-t er m safet y a n d effic ac y da ta 
f or patie nts wit h SJI A w h o eit her partici pate d i n t he C A C Z 8 8 5 G 2 3 0 5 a n d C A C Z 8 8 5 G 2 3 0 1 
reg istrati o n st u di es or were treat me nt- nai ve t o ca na ki n uma b . I n Fra nce, 4 8 patie nts were e nrol le d i n 
t he C A C Z 8 8 5 G 2 3 0 1 E 1  st u dy at f ou r ce nters ( Nec ker, Kremli n- B icêtr e, L y o n, a n d Stras b o ur g ). 
S t ud y C A C Z 8 8 5 G 2 3 0 1 E 1 is e n di n g o n N o v e m ber 2 0 1 4 a n d 3 sites ( Nec ker, Kre mli n- Bicê tre, 
a n d L y o n) still ha ve patie nts u n der treat me nt. 
N o vartis P har ma Fra nc e wis he d  t o set u p a l ocal prot oc ol t o all o w patie nts w h o be nefite d fr om 
cana ki n u ma b tr eat me nt recei ve d i n t he C A C Z 8 8 5 G 2 3 0 1 E 1 st u d y t o c o nti n ue 
t o recei ve 
cana ki n u ma b tr eat me nt u ntil c a n a ki n u m a b (Il aris ® ) is a vaila ble a n d r ei m b urse d o n t he Fre n ch 
ma r ket f or t h e SJI A i n dicati o n. 
 
 


N o v artis 
C lin ica l T rial P rot o co l v 0 5  
C o n fid e nt ial  
P ag e 1 4  
P rot o co l N o . C A C Z 8 8 5 G F R 0 1  
 
A me n d me nt 3 has bee n pr o p ose d t o o pe n t he recr uit me nt of st u d y C A C Z 8 8 5 G F R 0 1 t o patie nts w h o 
will c o m pl et e: 
 t he p hase III i nter nati o nal st u d y ( C A C Z 8 8 5 N 2 3 0 1) desi g ne d t o assess efficac y a n d 
t olera bilit y of c a n a ki n u m a b i n patie nts s ufferi n g fr o m 3 r are He re ditar y Perio d i c F e v ers 
( T R AP S,  HI D S or crF M F), 
 a n d t h e p h as e III i nt er n ati o n al st u d y C A C Z 8 8 5 G 2 3 0 6 d esi g n e d t o assess 2 differe nt 
ca na ki n u ma b ta per re gi me ns i n patie nts wit h cli nical re missi o n (i nacti ve disease f or at least 
2 4 c o nti n u o us wee ks) o n ca na ki n u ma b treat me nt i n SJI A. 
T h e o bj e cti v e of a me n d m e nt 3 is t o pr o vi de c o nti n u o us treat me nt t o t hese patie nts o nce t he y ha ve 
c o m plete d C A C Z 8 8 5 N 2 3 0 1 or C A C Z 8 8 5 G 2 3 0 6 u ntil t he me dicati o n is c o m merciall y a vaila ble i n 
Fra nce f or t hese ne w i n dicati o ns. 
 
 St u d y C A C Z 8 8 5 N 2 3 0 1 i n He re ditar y Perio d i c F e v ers ( T R AP S,  HI D S or crF M F)  
C A C Z 8 8 5 N 2 3 0 1 is a ra n d o mi z e d, d o u b l e-bl in d , pl ace bo c o n trol l e d stu d y 
wit h s u b se qu e nt 
ra n d o mize d with d ra wal/ d o si n g fre q ue nc y re d ucti o n a n d o pe n-l a bel lo n g t erm treat me nt e p oc hs. I n 
t his st u d y, a n i nitial d ose re gi me n of 1 5 0 m g s. c ( or 2 mg/ k g f or patie nts ≤ 4 0 k g) e ver y 4 we e ks 
( q 4 w) has bee n use d w hile all o wi n g f or u p -titr ati o n t o a ma xi mal d ose of c a na ki n u ma b 3 0 0 mg ( or 
4  m g/ k g f or patie nts wei g hi n g ≤4 0 k g)  q 4 w t o o pti mize t he re gi me n a n d t h us ac hie ve effic ac y i n 
d iffic ult cases.  
I n or der t o e valuat e if cli nical effic acy ca n be  mai nt ai ne d at a l o wer d osi n g freq u e nc y, ca na ki n u ma b 
1 5 0 mg ( or 2 mg/ k g f or patie nts ≤ 4 0 k g)  at a r e d uce d fr e q ue nc y ( q 8 w) h as b e e n e valua t e d d uri n g a 
r a n d omi z e d wit h dr aw a l e po c h ( Ep o c h 3). 
T he d ose re g i me n use d i n t he o pe n-l a bel lo n g t erm treat me nt e p ochs  ( mai nte n a nc e d os e; E p o c hs 4)  
is c o nsi dere d t o c o nstit ut e t he l o west clinica lly e ffic aci o us d ose t o mai nt ai n clini c a l effic ac y i n 
i n di vi d ual patie nts. A t ot al of 1 8 1  patie nts ( 4 6 T R A P S, 6 3 HI D S, 7 2 cr F M F) was ra n d o mize d i n 1 5 
c o u ntries w orl d wi de. T he pr ot o c ol i ncl u de d pa tie nts as yo u n g as 2 years ol d. 
I n or der t o s u p p ort reg ulat or y fili n g, t he a nal yses of t he pri mar y efficac y va ria ble a n d all seco n dar y 
efficac y a n d safet y varia bles u p t o W eek 1 6 we re perf or me d after all patie nts c o m plete d t he fi nal 
visit of t he ra n d o m ize d treat me nt e p oc h ( E p oc h 2)  of t he st u d y. 
E p oc h 2 res ults fr o m st u d y C A C Z 8 8 5 N 2 3 0 1 pr o vi de str o n g e vi d e nce of t he s up eri ority o f 
cana ki n u ma b o ver place b o. Ca na ki n u ma b has s h o w n a fa st o nset of  res p o nse an d  efficaci o us c o ntr ol 
of cli nical si g ns, s y m p t o ms a n d ser ol o gical ma nifestati o ns i n all 3 c o h orts of cr F M F, HID S  a n d 
T R A P S patie nts.  
As s h o w n i n ta ble 1 bel o w, t he pri mar y o bj ecti ve  was achie ve d f or a ll i n dicati o ns ( T R A P S, HI D S 
a n d cr F M F): cana ki n u ma b was s u peri or t o place b o i n t he pr o p orti o n of p atie nts w h o res ol ve d t heir 
i nd e x disea se flare at Da y 1 5 a n d ha d n o ne w flare o ver t he 1 6 w eeks of  treat me nt. 
Ca na ki n u ma b als o de m o nstrate d s u peri or efficac y c o m pare d t o place b o o n t he sec o n dar y e n d p oi nts 
of gl o bal assess me nt disease acti vit y ( P G A) < 2 a n d C R P ≤ 1 0 m g/ L f or all c o h orts. 
 
 


N o v artis 
C lin ica l T rial P rot o co l v 0 5  
C o n fid e nt ial  
P ag e 1 5  
P rot o co l N o . C A C Z 8 8 5 G F R 0 1  
 
T a ble 1. C o m p aris o n bet w ee n tre at me nt gr o u ps  f or p atie nts wh o  resp o n de d at wee k 1 6 b y 
c o h ort (I T T) 
 
A C Z 8 8 5 1 5 0 m g q 4 w 
Pl ace b o  
Tr e atme nt  
c o m p aris o n 
 
 
C o h o rt 
 
n /M  
(% ) 
 
9 5 %  CI  
 
n /M  
(% ) 
 
9 5 %  CI  
Ri sk  
d ifferen ce 
(9 5 %  
CI)  
O d d s 
R a ti o 
(9 5 %  
CI)  
O n e-
side d p -
v a lu e 
cr FM F  
1 9 /3 1  
(4 2 .1 9 , 7 8 .1 5 ) 
2 /3 2  
(0 .7 7 , 
2 0 .8 1 ) 
0 .5 5  
2 3 .7 5  
< 0 .0 0 0 1 *  
 
(6 1 .2 9 )  
(6 .2 5 )  
(0 .3 1 , 0 .7 3 ) 
(4 .3 8 , 2 2 7 .5 3 )  
HI D S  
1 3 /3 7  
(2 0 .2 1 , 5 2 .5 4 ) 
2 /3 5  
(0 .7 0 , 
1 9 .1 6 ) 
0 .2 9  
8 .9 4  
0 .0 0 2 0 *  
 
(3 5 .1 4 )  
(5 .7 1 )  
(0 .0 6 , 0 .5 0 ) 
(1 .7 2 , 8 6 .4 1 )  
T R A P S  
1 0 /2 2  
(2 4 .3 9 , 6 7 .7 9 ) 
2 /2 4  
(1 .0 3 , 
2 7 .0 0 ) 
0 .3 7  
9 .1 7  
0 .0 0 5 0 *  
 
(4 5 .4 5 )  
(8 .3 3 ) 
 
(0 .0 8 , 0 .6 1 ) 
(1 .5 1 , 9 4 .6 1 ) 
 
n = n u m ber of pati e n ts w h o resp o n d e d; M = n u m b er of p a tie n ts e v al u ate d f or res p o n s e; CI =c o n fi de n ce I nter val. 
* i n dic ates statisti cal si gnifi c an ce ( o n e-s i de d ) at t h e 0. 0 2 5 level b a s ed o n Fis h e r e xa ct test. 
T h ere were n o ne w or u ne x pecte d safet y fi n di n gs i n t he can a ki n u ma b-treate d patie nts t hr o u g h e p oc h 
2. Si milar t o w hat was o bs er ve d i n SJI A patie nts treat e d wit h can a ki n u ma b, t he m o st freq ue nt l y 
affecte d S O C i n cr F M F, HID S  a n d T R A P S patie nts was i nfecti o ns a n d i nfestati o ns, wit h t he m ost 
c o m m o n i nf ecti o ns bei n g t h ose of t h e u p per res pirat or y tract. 
As a res ult of t his p ositi ve i nteri m a nal ys is at t he e n d of E p oc h 2, a re gistrati o n d ossier was 
s u b mitte d t o t he E M A o n A pril 2 0 1 6. A mar keti n g a ut h orizati o n has bee n gra nte d i n E U i n Marc h 
2 0 1 7. 
 
T he first Fre nc h patie nts i ncl u de d C A C Z 8 8 5 N 2 3 0 1 will c o m plete t he st u d y fr o m N o ve m ber 2 0 1 6 . 
Acc or di n g t o a me n d me nt 3, patie nts w h o ha ve be neficiate d fr o m ca na ki n u ma b treat me nt will t he n 
bee n e nr olle d i n t he Fre nc h C A C Z 8 8 5 G F R 0 1 st u d y. 
 
 St u d y C A C Z 8 8 5 G 2 3 0 6 i n SJI A  
St u d y C A C Z 8 8 5 G 2 3 0 6 has bee n re q ueste d b y E M A a n d desi g ne d t o assess 2 differe nt ca na ki n u ma b 
ta per re gi me ns i n patie nts wit h SJI A wit h cli nical re missi o n o n ca na ki n u ma b treat me nt (i nacti ve disease 
f or at least 2 4 c o nti n u o us wee ks) wit h o ut c o nc o mita nt C S or M T X. Data fr o m t his st u d y will be use d t o 
hel p g ui de p h ysicia ns re gar di n g ca na ki n u ma b d ose re d ucti o n i n a p pr o priate SJI A patie nts. 
Eli gi ble patie nts were e ntere d St u d y Part I d uri n g w hic h all patie nts were treate d wit h ca na ki n u ma b 4 
m g/ k g e ver y 4 wee ks u ntil t he y q ualif y a n d e nter Part II of t he st u d y.  
Patie nts w h o bec o me eli gi ble f or ra n d o mizati o n e nter t he St u d y Part II a n d u n der g o ca na ki n u ma b 
ta peri n g (t o recei ve ca na ki n u ma b at eit her a re d uce d d ose or a pr ol o n ge d d ose i nter val). Part II is a 7 2-
wee k ra n d o mize d treat me nt / f oll o w- u p peri o d ( 4 8 wee ks of ca na ki n u ma b ta peri n g f oll o we d b y 2 4 
wee ks of f oll o w- u p w hile c o m pletel y off-treat me nt). 
Patie nts w h o d o n ot bec o me eli gi ble f or ra n d o mizati o n ma y re mai n i n St u d y Part I f or t he d urati o n of 
t he st u d y, a n d si nce patie nts w h o fail a n y of t he 3 ca na ki n u ma b ta peri n g ste ps d uri n g Part II ma y 
re mai n i n St u d y Part II f or t he d urati o n of t he st u d y, b ot h st u d y parts ha ve bee n assi g ne d a n esti mate d 
ma xi m u m d urati o n (f or a gi ve n patie nt) of 2 1 6 wee ks ).   
 
T he st u d y p o p ulati o n c o nsists of male a n d fe male patie nts a ge d ≥ 2 t o < 2 0 years i n t w o c o h orts: 
C o h ort 1 : Patie nts pre vi o usl y partici pati n g i n St u d y C A C Z 8 8 5 G 2 3 0 1 E 1 w h o at t he ti me of 
e val uati o n f or partici pati o n i n C A C Z 8 8 5 G 2 3 0 6 were treate d wit h ca na ki n u ma b 4 m g/ k g 
a n d ha d i nacti ve disease  
C o h ort 2: Patie nts, w h o at scree ni n g ha d acti ve SJI A a n d were ca na ki n u ma b treat me nt- naï ve.  
 


N o v artis 
C lin ica l T rial P rot o co l v 0 5  
C o n fid e nt ial  
P ag e 1 6  
P rot o co l N o . C A C Z 8 8 5 G F R 0 1  
 
A t ot al of 1 7 2 patie nts ha ve bee n e nr olle d ( 2 5 patie nts were e nr olle d i n 3 Fre nc h ce nters).  
 
T he o bjecti ve of C A C Z 8 8 5 G F R 0 1 st u d y is t o c ollect a d diti o nal safet y data (seri o us a n d n o n- seri o us 
a d verse e ve nts) a n d pr o vi de c o nti n u o us ca na ki n u ma b treat me nt f or patie nts c o m pleti n g st u dies 
C A C Z 8 8 5 G 2 3 0 1 E 1, C A C Z 8 8 5 N 2 3 0 1 or C A C Z 8 8 5 G 2 3 0 6 i n Fra nce pe n di n g rei m b urse me nt of 
ca na ki n u ma b (Ilaris ® ) i n t hese i n dicati o ns.  
 
1. 2        P ur p o s e 
 
T he p ur p ose of t his st u d y is t o pr o vi d e c o nti n u o us ca na ki n u ma b treat me nt t o patie nts i n Fra nce w h o 
c o m plete d t he f oll o wi n g st u dies: C A C Z 8 8 5 G 2 3 0 1 E 1, C A C Z 8 8 5 N 2 3 0 1 or C A C Z 8 8 5 G 2 3 0 6 u ntil 
ca na ki n u ma b (Il aris ® ) is c o m mer ciall y a vaila ble a n d r ei m b urse d i n Fra nce f or t h ese i n dicati o ns.  
 
T his l ocal e xte nsi o n st u d y 
will o nl y be pr o p os e d t o t he 4 Fre nc h ce nters i n v ol ve d i nt o 
C A C Z 8 8 5 G 2 3 0 1 E 1, C A C Z 8 8 5 N 2 3 0 1 or C A C Z 8 8 5 G 2 3 0 6 st u d y. 
 
2          St u d y o b j e cti ve s  
 
T he o bjecti ve  of t his pr ot oc ol is t o col lect a d diti o nal safety d ata (serio us  a n d n o n-seri o us a d verse 
e ve nts) a n d t o pr o vi de c o nti n u o us Il aris®  (ca n a ki n u ma b) treat me nt t o patie nts i n Fra n ce w h o 
c o m plete d C A C Z 8 8 5 G 2 3 0 1 E 1, C A C Z 8 8 5 N 2 3 0 1 or C A C Z 8 8 5 G 2 3 0 6 st u d y. 
 
3          I n ve st i gat io n al pl a n  
3. 1        St u d y d e si g n 
 
T his is a n o pe n-lab el (si n g le treat me nt ar m) e xte nsi o n peri o d f or patie nts i n Fra nce w h o h a ve 
c o m plete d t he i nter nati o nal st u dies: 
 
C A C Z 8 8 5 G 2 3 0 1 E 1  
 
or C A C Z 8 8 5 N 2 3 0 1  
 
or C A C Z 8 8 5 G 2 3 0 6. 
T he last visit of C A C Z 8 8 5 G 2 3 0 1 E 1, C A C Z 8 8 5 N 2 3 0 1 or C A C Z 8 8 5 G 2 3 0 6 st u dies wi ll be  t he first 
visit of t h is e xte nsi o n st u d y.  
Patie nts f oll o w u p: 
Patie nts pre vi o usl y i ncl u de d i n st u d y C A C Z 8 8 5 G 2 3 0 1 E 1 ( SJI A): 
T hese patie nts will c o nti n ue t he sa me  d osi n g regi me n use d at t he e n d of C A C Z 8 8 5 G 2 3 0 1 E 1 .  
Visits will ta ke place at ca na ki n u ma b d ose a d mi nistrati o n  dates, a p pr o xi matel y e ver y 4 weeks  
( or less fre q ue ntl y acc or di n g t o i n vesti gat ors j u d g me nt i.e. 6, 8 or 1 2 wee ks). T h e safet y of 
cana ki n u ma b will be e val uate d (a d verse e ve nts a n d seri o us a d verse e ve nts). Pa tie nts will be 
f oll o we d u p accor di n g t o S m P C (see a p p e n di x 1) wit h p ossi ble a da ptati o n base d o n i n vesti gat ors 
j u d g me nt relate d t o s pecific patie nt me dical c o nsi derati o n.  
Patie nts pre vi o usl y i ncl u d e d i n st u d y C A C Z 8 8 5 N 2 3 0 1 ( Peri o dic Fe ver s y n dr o mes i n dicati o ns: 
T R A P S, HI D S or cr F M F): 
T hese patie nts will c o nti n ue t he m ai nt e n a n c e d os e as deter mi ne d at t he e n d of t he o pe n-la bel 
peri o d/ e p oc h 4 (i. e t h e l o west c linica lly e ffic acio us d ose t o mai nt ai n clini c a l effic ac y i n 
i n di vi d ual pa tie nts wit h a g o o d t olera bilit y). Visits will ta ke place at sc he d ule d a d mi nistrati o n 


N o v artis 
C lin ica l T rial P rot o co l v 0 5  
C o n fid e nt ial  
P ag e 1 7  
P rot o co l N o . C A C Z 8 8 5 G F R 0 1  
 
d ates, a p pr o xi ma tel y e ver y 4, 8 or 1 2 weeks . T h e safet y of ca na ki n u ma b will be e val uate d 
(a d verse e ve nts a n d seri o us a d verse e ve nts c ollecti o n). Patie nts will t he n be f oll o we d u p 
acco r di n g t o S m PC wit h p ossi ble a da ptati o n base d o n i n vesti gat ors j u d g me nt relate d t o s pecific 
patie nt me dical c o nsi derati o n.  
Patie nts pre vi o usl y i ncl u de d i n st u d y C A C Z 8 8 5 G 2 3 0 6 ( SJI A i n dicati o n): 
T hese p atie nts wi ll c o nti nue  o n t heir d osi n g re gi me n c o nsi der e d  t o c o nstit ut e t he lo west clinica lly 
e ffic aci o us d ose t o mai nt ai n clini c a l effic ac y i n i n di vi d ual patie nts.  
Visi ts will ta ke place at ca na ki n u ma b d ose a d mi nistrati o ns, a p pr o xi mately e ver y 4, 8 or 1 2 wee ks 
acc or di n g t o t he i n di vi d ual dr u g re gi me n of t he e n d C A C Z 8 8 5 G 2 3 0 6 a n d i n vesti gat ors j u d g me nt . 
T he safet y of ca na ki n u ma b will be e val uate d (a d v ers e e ve nts a n d seri o us a d verse e ve nts 
c ollecti o n). Patie nts will be f oll o we d u p acc or di n g t o S m PC (see a p pe n di x 1) wit h p ossi ble 
a da ptati o n base d o n i n vesti gat ors j u d g me nt relate d t o s pecific patie nt me dical c o nsi derati o n.  
 
T he st u d y d urati o n will de pe n d o n t he da te of rei m b urse me nt of ca na ki n u ma b (Ilaris® ) i n Fra n ce f or 
t he ne w i n dicati o ns a n d will be e xte n de d u ntil t he me dicati o n is c o m merciall y a vaila ble f or eac h 
i n dicati o n. H o we ver, as t he c o m mercializati o n of  t he differe nt i n dicati o ns ma y be effecti ve at 
differe nt dates, t he patie nts will disc o nti n ue i n dicati o n b y i n dicati o n (see secti o n 5 ; e n d of treat me nt). 
 
3. 2        R ati o n al e of  st u d y d e si g n 
 
Gi ve n t he p ur p ose of t his e xte nsi o n st u d y, a n o pe n-la bel desi g n is a p pr o p riate. 
 
3 . 3 
R ati o n al e of  d o s e/r e gi m e n, r o ut e of  a d mi ni str ati o n an d  d ur ati o n of 
tr e at m e nt 
 
Patie nts wit h SJI A will be treate d wit h ca na ki n u ma b i n a n o pe n-la bel ma n ner a n d f oll o we d u p 
accor di n g t o t he a p pr o ve d E ur o pea n S m Pc (a p p e n di x 1). 
F or patie nts wit h Peri o dic Fe ver s y n dr o mes ( T R A P S, HI D S or cr F M F), t he d ose of use d i n t he 
e xte nsi o n st u d y will n ot e xcee d t he ma xi m u m d ose use d i n C A C Z 8 8 5 N 2 3 0 1 ( 3 0 0 m g/ 4 mg/ k g f or 
patie nts wei g h i n g ≤4 0 k g). T he patie nts will t he n be f oll o we d u p acc or di n g t he E ur o pea n S m Pc o nce 
a vaila ble after E M A a ut h orizati o n.  
 
3. 4        P ur p o s e a n d ti mi n g of  i nt eri m a n al y s e s / d e si g n a d a pt ati o n s 
 
N ot a p pli cable. 
 
3. 5        Ri s k s a n d  b e n efit s 
Ca na ki n u ma b offers a ne w t hera pe utic o pti o n f or patie nts wit h SJI A or Peri o dic Fe ver s y n dr o mes 
w h o d o n ot res p o n d t o sta n dar d t hera p y. Ca na ki n u ma b e na bles patie nts t o c o ntr ol t heir disease a n d 
re d uce t heir use of ster oi ds, a mai n ca use of i m paire d gr o wt h a n d si de effects i n SJI A or Peri o di c 
Fe ver s y n dr o mes c hil dre n. All t he patie nts i ncl u de d i n t his e xte nsi o n st u d y ha ve d e m o nstrate d 
cli nical res p o nse t o c a na ki n u ma b treat me nt f or at least 2 years i n st u d y C A C Z 8 8 5 G 2 3 0 1 E 1, 
C A C Z 8 8 5 G 2 3 0 6 or C A C 8 8 5 N 2 3 0 1. T he ris k t o patie nts i n t his trial will be 
mi ni mi ze d b y 
c o m plia n ce wit h t he eli gi bilit y criteria, cl ose cli nic al m o nit ori n g a n d a d here nce t o t he pr ot oc ol 
g ui deli nes f or d os e a d mi nistrati o n / re d ucti o n / i nter val pr ol o n gati o n / disc o nti n uati o n. 
4          P o p u lat i o n 
 
U p t o 4 1 patie nts ma y be i ncl u de d i n t he Fre nc h e xte nsi o n st u d y C A C Z 8 8 5 G F R 0 1 (i n 3 centers). 


N o v artis 
C lin ica l T rial P rot o co l v 0 5  
C o n fid e nt ial  
P ag e 1 8  
P rot o co l N o . C A C Z 8 8 5 G F R 0 1  
 
 T wel ve patie nts pre vi o usl y e nr olle d i nt o st u d y C A C Z 8 8 5 G 2 3 0 1 E 1  
 
 T we nt y ni ne p ote ntial a d diti o nal patie nts acc or di n g t o a me n d me nt 3: 
- 
u p t o 2 1  p atie nts pre vi o usl y e nr olle d i nt o C A C Z 8 8 5 G 2 3 0 6 st u d y (i n 3 ce nters) 
- 
u p t o 8 patie nts pre vi o usl y e nr olle d i nt o C A C Z 8 8 5 N 2 3 0 1 st u d y (i n 4 Fre nc h ce nters). 
4. 1        I n cl u si o n crit eri a 
 
Patie nts eli g i ble f or i ncl usi o n i n t his pr ot oc ol ha ve t o f ulfill all of t he fol l o wi n g criteria: 
Cr iteria ap p licable f or p atie nts wit h S yste mic J u ve nil I di o pat hic Art hritis ( SJI A) 
1.  Pa tients w h o ha ve  c o m plete d t he i nter nati o nal CA C Z 8 8 5 G 2 3 0 1 E 1 or C A C Z 8 8 5 G 2 3 0 6 st u dies 
wit h o ut a ny si g nifi cant  safety iss ue acc or di n g t o I n vesti gat or’s o pi ni o n.  
2.  Patie nts w h o ha ve c o m plete d t he i nter nati o nal C A C Z 8 8 5 G 2 3 0 6 st u d y a n d w h o s uccessf ull y 
wit h dre w ca na ki n u ma b treat me nt per pr ot oc ol b ut wit h a disease rela pse after t he e n d of st u d y 
visit will be all o we d t o partici pate i n C A C Z 8 8 5 G F R 0 1 st u d y ( w hate ver t he ti me of rela pse 
fr o m t he e n d of st u d y visit), if t he i n vesti gat or states t hat t here is a n i n dicati o n t o res u me 
ca na ki n u ma b. 
3.  Patie nts w h o ha ve partici pate d i n t he i nter nati o nal C A C Z 8 8 5 G 2 3 0 6 st u d y b ut c o ul d n ot be 
ra n d o mize d a n d t he n ha ve c o nti n ue d ca na ki n u ma b i n part I u ntil t he e n d of t he st u d y at a d ose 
of 4 m g/ k g e ver y 4 wee ks ma y be s witc he d t o C A C Z 8 8 5 G F R 0 1 st u d y if t he i n vesti gat or 
t hi n ks t hat, i n t he i nterest of t he patie nt, t here is a n i n dicati o n t o ta per off ca na ki n u ma b d ose 
after a pr ol o n ge d re missi o n 
Cr iteria ap p licable f or p atie nts wit h P eri o di c F e v er s y n dr o m es ( T R A P S, HI D S, cr F M F) 
1.  Patie nts w h o ha ve c o m plete d t he i nter nati o nal C A C Z 8 8 5 N 2 3 0 1 st u d y wit h o ut a n y si g nifica nt 
safet y iss ue acc or di n g t o I n vesti gat or’s o pi ni o n. 
Cr iteria a p plicable f or all patie nts 
1.  Pare nt's or le gal g uar dia n's writte n i nf or me d c o nse nt a n d c hil d's asse nt, if a p pr o priate, or 
patie nt's writte n i nf or me d c o nse nt f or patie nts ≥ 1 8 years of a ge m ust be o btai ne d bef ore a n y 
st u d y relate d acti vit y or assess me nt is perf or me d. 
 
4. 2        E x cl u si o n  crit eri a  
 
1.  Hist or y of r ecu rri n g i nf ecti o ns, or  u n derl yi n g c o n diti o ns w hic h ma y pre dis p ose t he m t o 
i nfecti o ns. Treat me nt wit h c a n a ki n u ma b s h o ul d n ot be c o nti n ue d i n patie nts wit h se vere 
i nfecti o ns re q uiri n g me dical i nter ve nti o n. 
2.  H y perse nsiti vit y t o t he acti ve s u bsta nce or t o a n y of t he e xci pie nts (see S m P C, secti o n 6. 1). 
3.  C o nc o mita nt use of sec o n d li ne a ge nts s uc h as disease- m o dif yi n g a n d/ or i m m u n os u p pressi ve 
dr u gs will n ot be all o we d wit h t he e xce pti o n of: 
 
Met h otr e x ate, a n d f olic/f oli nic 
aci d s u p pl e me ntati o n (acc or di ng t o sta n dar d 
me dical 
p ractice) 
 
N o n -ster oi dal ant i-i nfl a m mat or y dr u g (N S AI D)  
 
S yste mic c ortic oste r oi d treat me nt. 
4.  C o nc o mita nt use of a n ot her bi ol o gic a ge nt or a n y i n vesti gati o nal dr u g. 
5.  Pre g na nt or n ursi n g (lactati n g) fe male patie nts, w here pre g na nc y is defi ne d as t he state of a 
fe male after c o nce pti o n a n d u ntil t he ter mi nati o n of gestati o n, c o nfir me d b y a p ositi ve h C G 
la b orat or y test or a n uri nar y pre g na nc y test. 
6.  Fe male patie nts w h o are of c hil d- beari n g p ote ntial, defi ne d as all fe males p h ysi ol o gicall y 
ca pa ble of bec o mi n g pre g n a nt, u nless t he y are usi n g effecti ve met h o ds of c o ntrace pti o n d uri n g 
d osi n g of st u d y treat me nt. Effecti ve c o ntrace pti o n met h o ds i ncl u de: 
 
T otal a bsti ne nce ( w he n t his is i n li ne wit h t he preferred  a n d us ual lifest yle of t he 
s u bject). Peri o dic a bsti ne nce (e. g., cale n dar, o v ulati o n, s ym p t ot her mal, p ost- o v ulati o n 
met h o ds) a n d wit h dra wa l are n ot acce pta ble met h o ds of c o ntracept i o n 


N o v artis 
C lin ica l T rial P rot o co l v 0 5  
C o n fid e nt ial  
P ag e 1 9  
P rot o co l N o . C A C Z 8 8 5 G F R 0 1  
 
 
Fe male sterilizati o n ( ha ve  ha d s ur gic al bilateral o o p h orec t om y 
wit h or 
wit h o ut 
h yster ect om y) or t ub al li gati o n at least si x weeks be f ore t a ki n g st u d y treat me nt. I n case 
of o o p h orec t om y al o ne, o nl y w h e n t he re pr o d ucti ve  stat us of t he w o ma n has bee n 
c o nfir me d b y f oll o w u p h or m o ne le vel asse ssme nt 
 
Male sterilizati o n (a t least 6 m o nt hs pri or t o i ncl usi o n). F or fe male s u bj ects o n t he st u d y, 
t he vasect omize d male part ner s h o ul d be t he s ole pa rtn er f or t hat s u bject 
 
Bar rier met h o ds 
of c o ntrace pti o n: 
C o n d o m 
or 
Occl usi ve  cap ( di a p hra g m 
o r 
cer vical/ va ult caps) wit h s per mici dal f oa m/ gel/ fil m/crea m/ va gi nal s u p p osit or y 
 
Use of oral, i nj ecte d or i m p la nte d h or m o nal met h o ds of c o ntracept i o n or ot her f or ms of 
h or m o nal c o ntr acepti o n t hat ha ve c o m para ble efficac y (fail ure rate 
 
< 1 % ), f or e x a m ple h or m o ne va gi nal ri n g or tra ns d er mal h or m o ne c o ntrace pti o n 
 
P laceme nt of a n i n tra uteri ne de vice (I U D) or i ntra uteri ne s yste m (I U S) 
I n case of use of  oral c o ntracept i o n w o me n s h o ul d have  bee n sta ble o n t he same  pill f or a mi ni m u m 
of 3 m o nt hs be f ore t aki n g st u d y tr eat me nt. 
Relia ble c o ntra cepti o n s h o ul d be 
mai ntai ne d t hr o u g h o ut t he st u d y a n d u ntil 3 
m o nt hs after 
ca na ki n u ma b disc o nti n uati o n. 
5          Tr e at m e nt 
 
I nitial ca na ki n u ma b d ose: 
F or patie nts pre vi o usl y i ncl u de d i n st u d y C A C Z 8 8 5 G 2 3 0 1 E 1 ( SJI A) 
Patie nts 
will c o nti n ue t he sa me d ose as t heir last d ose a d mi nistere d i n t he st u d y 
C A C Z 8 8 5 G 2 3 0 1 E 1: ca na ki n u ma b 4 m g/ k g ( or 3 0 0 m g ma x) or 2 m g/ k g ( 1 5 0 m g ma x) e ver y 4 
wee ks. 
Ca na ki n u ma b d ose re d ucti o n fr o m 4 m g/ k g t o 2 m g/ k g e ver y 4 wee ks i n ster oi d-free patie nts wit h 
pr ol o n ge d str o n g res p o nse was per mitte d i n t he o n g oi n g e xte nsi o n st u d y C A C Z 8 8 5 G 2 3 0 1 E 1 at 
t he re q uest of t he treati n g p h ysicia n a n d wit h t he a gree me nt of N o vartis. 
Si milarl y, i n t his st u d y, t he ca na ki n u ma b d ose ma y be re d uce d fr o m 4 m g/ k g ( 3 0 0 m g ma x) t o 
2 m g/ k g ( 1 5 0 m g ma x) e ver y 4 wee ks a n d t he n i nterr u pte d after a pr ol o n ge d re missi o n acc or di n g 
t o t he i n vesti gat ors j u d g me nt.  
 
F or patie nts pre vi o usl y i ncl u de d i n st u d y C A C Z 8 8 5 N 2 3 0 1 ( Peri o dic Fe ver s y n dr o mes i n dicati o ns: 
T R A P S, HI D S or cr F M F)  
Patie nts will c o nti n ue o ne of t he f oll o wi n g re gi me ns as recei ve d at t he e n d of t he st u d y: 
- 
ca na ki n u ma b 1 5 0 m g ( or 2 m g/ k g  f or patie nts wei g h i n g ≤ 4 0 k g) q 4 w  
- 
ca na ki n u ma b 1 5 0 m g ( or 2 m g/ k g  f or patie nts wei g h i n g ≤ 4 0 k g) q 8 w  
- 
ca na ki n u ma b 3 0 0  m g ( or 4 m g/ k g  f or patie nts wei g h i n g ≤ 4 0 k g) q 4 w  
- 
ca na ki n u ma b 3 0 0  m g ( or 4 m g/ k g  f or patie nts wei g h i n g ≤ 4 0 k g) q 8 w  
I n c ase of r e-flar e (acc or di n g t o i n vesti gat ors j u d g me nt), patie nts will be all o we d t o i ncrease t he 
d ose as f oll o w: 
- 
If patie nts recei ve ca na ki n u ma b 1 5 0 m g q 8 w, t he d ose of ca na ki n u ma b will be i ncrease d t o 
1 5 0 m g q 4 w 
- 
If patie nts recei ve ca na ki n u ma b 1 5 0 m g q 4 w, t he d ose of ca na ki n u ma b will be i ncrease d t o 
3 0 0 m g q 4 w 
- 
If patie nts recei ve ca na ki n u ma b 3 0 0  m g q 8 w, t he d ose of ca na ki n u ma b will be i ncrease d t o 
3 0 0 m g q 4 w 
 
F or patie nts pre vi o usl y i ncl u de d i n st u d y C A C Z 8 8 5 G 2 3 0 6 ( SJI A): 


N o v artis 
C lin ica l T rial P rot o co l v 0 5  
C o n fid e nt ial  
P ag e 2 0  
P rot o co l N o . C A C Z 8 8 5 G F R 0 1  
 
T he patie nts will c o nti n ue t he sa me  d ose as t heir last d ose a d mi nistere d at t he e n d of t he ta peri n g 
peri o d st u d y C A C Z 8 8 5 G 2 3 0 6.  
T he n, patie nts will c o nti n ue o ne of t he f oll o wi n g re gi me ns: 
- 
Ca na ki n u ma b 4 m g/ k g q 4 w ks 
- 
Ca na ki n u ma b 2 m g/ k g q 4 w ks 
- 
Ca na ki n u ma b 1 m g/ k g q 4 w ks 
- 
Ca na ki n u ma b 4 m g/ k g q 8 w ks 
- 
Ca na ki n u ma b 4 m g/ k g q 1 2 w ks 
T he patie nts w h o ha ve wit h dra w n ca na ki n u ma b per pr ot oc ol ma y res u me ca na ki n u ma b after a rela pse 
at a starti n g d ose of 4 m g/ k g ( ma xi m u m 3 0 0 m g) e ver y 4 wee ks. 
 
D ose a dj ust me nts (f or all patie nts): 
Patie nts ma y r ecei ve a n u p-titr ati o n o r m a y r e s u m e c a n a ki n u m a b if t he y r e-flar e 
( ma xi m u m d ose of 3 0 0 m g ( or 4 mg/ k g s. c f or patie nts ≤4 0 k g  q 4 w). 
T he ca na ki n u ma b d ose i nter val (i.e. e ver y 6, 8 or 1 2 wee ks) ma y als o be pr ol o n ge d i n patie nts 
wit h a de q uate res p o nse acc or di n g t o i n vesti gat ors j u d g me nt.  
E ver y patie nt wit h dra w n fr o m C A C Z 8 8 5 G F R 0 1 st u d y d ue t o a re missi o n will be all o we d t o res u me 
ca na ki n u ma b i n case of rela pse a n d will be f oll o we d u p a gai n i n t he st u d y. 
 
Ca na ki n u ma b will be a d mi nistere d at t he st u d y ce nter.  
 
E n d of treat me nt 
F or patie nts treate d f or SJI A:  
I n vesti gat ors will be i nf or me d as s o o n as t his i n dicati o n is c o m merciall y a vaila ble i n or der t o 
or ga nize at t he ne xt pla n ne d visit t he dr o p o ut of t he patie nts. If n o visit is pla n ne d wit hi n 2 m o nt hs of 
n otificati o n rece pti o n, t he i n vesti gat ors will ha ve t o c o ntact t he patie nt i n or der t o or ga nize patie nt's 
st u d y ter mi nati o n. I n vesti gat ors 
will ha ve t he p ossi bilit y t o perf or m a last can a ki n u ma b 
a d mi nistrati o n d uri n g t he last visit of t he pr ot oc ol .  
 
F or patie nts treate d f or T R A P S, HI D S a n d cr F M F:  
I n vesti gat ors will be i nf or me d as s o o n as t his i n dicati o n is c o m merciall y a vaila ble i n or der t o 
or ga nize at t he ne xt pla n ne d visit t he dr o p o ut of t he patie nts. If n o visit is pla n ne d wit hi n 2 m o nt hs of 
n otificati o n rece pti o n, t he i n vesti gat ors will ha ve t o c o ntact t he patie nt i n or der t o or ga nize patie nt's 
st u d y ter mi nati o n. I n vesti gat ors 
will ha ve t he p ossi bilit y t o perf or m a last can a ki n u ma b 
a d mi nistrati o n d uri n g t he last visit of t he pr ot oc ol. 
 
5. 1        Pr ot o c ol r e q u e st e d tr e at m e nt  
 
5. 1. 1       I n v e sti g ati o n al tr e at m e nt 
 
N o vartis will s u p pl y o n e of t he f oll o wi n g o pe n-la bel i n ve sti gati o nal dr u gs as c o m mercial pack a ges 
or cli nical bat c hes w hic h are la belle d acc or di n g t o legislati o n i n Fra n ce relate d t o cli nical trial pr o d uct: 
 A C Z 8 8 5 1 5 0 m g: Acti ve  cana ki n u ma b i n i n di vi d ual 6 m L glass vials, eac h c o ntai ni n g 1 5 0 m g 
ca na ki n u ma b l y o p hilisate i n via l. 
Or  


N o v artis 
C lin ica l T rial P rot o co l v 0 5  
C o n fid e nt ial  
P ag e 2 1  
P rot o co l N o . C A C Z 8 8 5 G F R 0 1  
 
 A C Z 8 8 5 1 5 0 m g/ 1 m L : 1 m L of s ol uti o n f or i njecti o n i n a 2 m L vial (t y pe I glass) wit h a st o p per 
(la mi nate d c hl or o b ut yl r u b ber) a n d fli p- off ca p (al u mi ni u m). 
T he ma xi mal t otal si n gle d ose of  can a ki n u ma b all o we d is 3 0 0 m g, w hic h is a d mi nistere d as t w o 
s u bc uta ne o us 1 5 0 m g i njecti o ns o nce e ver y 4 weeks. 
5. 1. 2       A d diti o n al st u d y tr e at m e nt 
 
N o a d diti o nal tr eat me nt be y o n d i n vestigati o na l treat me nt is req u este d f or t his t rial. 
 
5. 2        Tr e at m e nt  arm s  
 
All patie nts will recei ve can a ki n u ma b as i n vesti gati o nal dr u g me di cati o n. 
 
5. 3        Tr e at m e nt  a s si g n m e nt, r an d o mi z ati o n 
 
All patie nts will be treate d wit h acti ve o pe n-l a bel cana ki n u ma b. 
 
5. 4        Tr e at m e nt  bli n di n g 
 
N ot a p plica bl e. 
 
5. 5        Tr e ati n g t h e p ati e nt  
 
5. 5. 1       P ati e nt n u m b eri n g 
 
E ach  patie nt is u ni q uel y i de ntifie d b y a S u bject N u m ber, assi g ne d at i ncl usi o n c o m p ose d b y t he site 
n u m ber a ssi g ne d b y N o vartis a n d a se q u ent ial n u m ber. I n t his st u d y, t h e patient  will keep t he sa me 
i de ntifier as i n st u d y C A C Z 8 8 5 G 2 3 0 1 E 1/ C A C Z 8 8 5 N 2 3 0 1/ C A C Z 8 8 5 G 2 3 0 6. 
5 . 5. 2       Di s p e n si n g t h e i nv e sti g ati o n al tr e at m e nt 
 
Eac h st u d y site will be s u p plie d b y N o vartis wit h i n vesti gati o nal treat me nt la belle d acc or di n g t o 
le gislati o n i n Fra nce relate d t o cli nical trial pr o d uct. 
5. 5. 3       H a n dli n g of st u d y tr e at m e nt 
5. 5. 3. 1    H a n dli n g of i n v e s ti g ati o n al tr e at m e nt 
 
I n vesti gati o nal treatme nt m u st be recei ve d b y a desig n ate d pers o n at t he st u d y site, ha n dle d a n d 
st ore d safel y a n d pr o perl y, a n d kept  i n a secu red l ocati o n t o w hic h o nl y t h e i n vesti gat or a n d 
d esig n ees have  access. U p o n recei pt, all i n vesti gati o nal treat me nt s h o ul d be st ore d acco r di n g t o t he 
i nstr ucti o ns s pecifie d o n t he la bels. Cl i nical s u p plies are t o be  dis pe nse d o nl y i n accor da nce wit h t he 
p r ot oc ol. 
Me di cati o n la bels will be i n t he l ocal la n g uage  a n d c o m pl y wit h t he le gal re q uire me nts. T he y will 
i ncl u de st ora ge c o ndi ti o ns f or t he i n vesti gati o nal treat me nt b ut n o i nf or mati o n a b o ut t he patie nt. 
T he i n vesti gat or m ust mai ntai n a n acc u rate recor d of t h e s hi p me nt a n d dis pe nsi n g of i n vesti gati o nal 
treat me nt i n a dr u g acc o u nta bilit y l og. M o nit ori n g of dr u g acc o u nta bilit y will be p erf or me d b y t he 
fiel d m o nit or d uri n g site visits a n d at the  c o m pleti o n of t he trial. 
At  t he c o ncl usio n  of t he st u d y, a n d as a p pr o priate d uri n g t he c o urs e of t he st u d y, t he i n vesti gat or 
will ret ur n a ll u n use d i n vesti gati o n al treat me nt, pack a gi n g, dr u g lab els, a n d a c o p y of t he 
c o m plete d dr u g acc o u nta bilit y l o g t o t he N o vartis m o nit or or  t o t he N o vartis ad dr ess pr o vi de d i n t he 
i n vesti gat or f ol der at eac h site. 


N o v artis 
C lin ica l T rial P rot o co l v 0 5  
C o n fid e nt ial  
P ag e 2 2  
P rot o co l N o . C A C Z 8 8 5 G F R 0 1  
 
5. 5. 3. 2          H a n dli n g of ot h er st u d y tr e at m e nt 
 
N ot a p pli cable. 
 
5. 5. 4       I n str u cti o n s f or pr e s cri bi n g a n d t a ki n g st u d y tr e at m e nt 
 
All d osa ge s prescri be d an d  dis pe nse d t o t he patie nt a n d all d ose c ha n ges d uri n g t h e st u d y m ust 
be rec or d e d o n t he D osa ge A d mi nistrati o n Rec or d C R F . 
 
5. 5. 5       P er mitt e d d o s e a dj u st m e nt s a n d i nt err u pti o n s of st u d y tr e at m e nt 
 
S t ud y dr u g d ose a dj ust me nts a n d/ or i nterr u pti o ns are per mitte d, accor di n g t o t he i n vesti gat or 
j u d g me nt. T hes e c ha n ges m ust be rec or de d o n t he D osa ge A d mi nistrati o n Rec ord C R F. 
 
5. 5. 6       R e s c u e m e di c ati o n 
 
N ot a p pli cable 
5. 5. 7       C o n c o mit a nt tr e at m e nt  
 
T he i n vesti gat or s h o ul d i nstr uct t he p atie nt  t o n otif y t he st u d y site a b o ut a ny n e w me di cati o ns he/s he 
ta kes after t he start of t he st u d y dr u g.  
5 . 5. 8       Pr o hi bit e d Tr e at me nt  
 
T he e x p ressi o n of he patic C Y P 4 5 0 e nz y mes may b e s u p presse d b y t he c yt o ki nes t hat sti m u late 
c hr o nic i nfla m mati o n, s uc h as I L- 1 b eta. T h us, C Y P 4 5 0 e x pressio n  ma y be re verse d w he n p ote nt 
c yt o ki ne i n hi bi t or y t hera p y, s uc h as cana ki n u ma b, is i ntr o d u ced.  T his is cli nicall y relev ant  f or 
C Y P 4 5 0 s u bstrates wit h a narr o w t hera pe ut ic i n de x w h ere t he d ose is i n di vi d ually a dj uste d. I n 
p atie nts bei n g tr eate d wit h t his t y pe of  me dici nal pr o d uct w hile o n cana ki n u ma b, t hera pe uti c 
m o nit ori n g of t h e effect or of t he active  s u bsta nce c o nce ntrati o n s h o ul d be perf or me d an d  t he 
i n di vi d ual d ose of t he me dici nal pr o d uct a dj uste d as necessar y. 
Use of ca na ki n u ma b wit h T N F i n hi bi t ors is n ot reco m me n de d be cause t his may i ncrease t he ris k of 
seri o us i nfecti o ns (a n i ncrease d i nci de nce of seri o us i nfecti o ns has bee n ass ociate d 
wit h 
a d mi nistrati o n of a n ot her I L- 1 bl oc ker i n c o m bi nati o n wit h T N F i n hi bi t ors) 
N o  data are a vaila ble o n eit her t he effects of  live  vacci nati o n or  t he sec o n dar y tra ns missi o n of 
i nfectio n  b y live  vacci nes i n patie nts recei vi n g ca na ki n u ma b. T h eref ore, live  vacci nes s h o ul d n ot be 
gi ve n c o nc urre nt l y wit h ca na ki n u ma b, b ut pri or t o i nitiati n g Ilaris®  t herap y. 
5. 5. 9       Di s c o nti n u ati o n of st u d y tr e at m e nt a n d pr e m at ur e p ati e nt  with dr a w al  
 
Patie nts ma y v ol u nta ril y wit h draw fr o m t he st u d y f or a n y reas o n at a n y ti me. St ud y treat me nt m ust 
be disc o nti n ue d u n der t he f oll o wi n g cir c u msta n ces: 
 T he a vaila bi lit y of re pai d pr o d uct i n Fra nce f or t he patie nt’s disease, 
 If, o n b ala nce t he i n vesti gat or belie ves t hat c o ntin u ati o n w o ul d be detri me nt al t o t he 
p atie nt’s well- b e i ng, 
 U nsati sfact or y t hera pe utic effect base d o n i n vesti gat or j u d g me nt, 
 Use of pr o hi bite d treat me nt / Pr ot oc ol vi olati o n, 
 O nset of mali g n a nc y, 
 O ccurre nce of  a n u nc o ntr olle d li fe-t hreate ni n g i nfectio n , 
 Pr e gn a nc y, 
 Ot he r A d verse E v e nt nee di n g st u d y disc o nti n uati o n, 
 L ost t o f oll o w- u p, 
 A d mi nistrati ve reas o ns, 


N o v artis 
C lin ica l T rial P rot o co l v 0 5  
C o n fid e nt ial  
P ag e 2 3  
P rot o co l N o . C A C Z 8 8 5 G F R 0 1  
 
 D eat h. 
If pre mat ure wit h dra wal occurs f or a n y reas o n, t he i n vesti gat or m ust ma ke  e very eff ort t o c o m ple te 
E n d of st u d y visi t i n t he C R F  a n d t o deter mi ne t he prima r y reas o n f or a patie nt’s premat ure 
wit h dra wal fr o m t he st u d y a n d recor d t his i nf or mati o n. 
5. 5. 1 0     E m er g e n c y br e a ki n g of tr e at m e nt  a s si g n m e nt 
 
N ot a p pli cable 
5. 5. 1 1     E arl y st u d y t er mi n ati o n 
T he st u d y ca n be  ter mi nate d at a n y time  f or a ny reas o n b y N o vartis. S h o ul d t his be necessar y, t he 
p atient  s h o ul d be see n as s o o n as p ossi ble a n d treate d f or a premat urel y wit h dr a w n  patie nt. T he 
i n vesti gat or may be i nf or me d of a d diti o nal p r oced u res t o be f oll o we d i n or der t o e ns ure t hat 
a de q ua te c o nsi derati o n is gi ve n t o t he pr otecti o n of t he patie nt’s i nterests. 
 
6          Vi sit s c h e d u l e a n d a s s e s s me n t s 
 
Visits will ta ke place at t he patie nt’s sc he d ule d dr u g  a d mi nistrati o n date (a p pr o xi matel y e ver y 4 
w eeks  or less fre q ue ntl y acc or di n g t o i n vesti gat ors j u d g me nt i.e. 6, 8 or 1 2 wee ks ). 
If n o a d mi nistrati o n is perf or me d wit hi n t he 1 2 wee ks of pre vi o us i njecti o n, a c o ntr ol visit will be 
perf or me d at Wee k 1 3 +/- 7 da y s after t he last a d mi nistrati o n i n or der t o e val uate safet y a n d nee d f or 
t he patie nt t o c o nti n ue t he treat me nt a n d t he st u d y. 
T a ble : sc he d ule d visits a n d e val u ati o ns  
 
 
Visits  
I ncl usi o n(1 ) Visits f or c a n a ki n u m a b 
a d mi nistr ati o n (4 )  
E n d  o f t he 
st ud y vis it (2 ) 
 
 
 
 
Visit w in d o w  ( d a ys) 
+/ - 7  
+/ - 7  
+/ - 7  
In cl usio n/ e x cl usio n criteria 
X  
 
 
W ritte n i nf orme d co nse n t 
X  
 
 
D em o gr ap hic d ata 
X  
 
 
T reatm ent a d mi n istratio n  
X  
X  
X  
C o n co m ita nt treatm ent  
X (3 ) 
X  
X  
A d v erse ev ents  
 
X  
X  
E n d of  t he st ud y  
 
 
X  
 
 
1)   T he date of last visit of C A C Z 8 8 5 G 2 3 0 1 E 1/ C A C Z 8 8 5 N 2 3 0 1/ C A C Z 8 8 5 G 2 3 0 6 st u d y will be t he f irst visit 
of t h is e xtensi o n st u d y. 
2)   T he e n d of st u d y is defi ne d  as pr e mat ure ter mi nati o n or e n d of t he st u d y acc or di n g t o pr ot oc ol: i n t he 
m o nt h f o llo wi n g t he a vaila bilit y of re pai d pr o d u ct i n Fr anc e. 
3)   C or ticos ter oi ds a n d met h otre xate o nl y. 
4)    Visits will ta ke place at sc he d ule d a d mi nistrati o n date e ver y 4, 6, 8 or 1 2 wee ks (secti o n 5). D ose i nter val 
ma y be pr ol o n ge d d uri n g t he st u d y (i.e. visits e ver y 6 , 8 or 1 2 wee ks or l o n ger i n case of a de q uate res p o nse at 
t he discreti o n of t he i n vesti gat or (secti o n 5). If n o a d mi nistrati o n is perf or me d wit hi n t he 1 2 wee ks of 
pre vi o us i nj ecti o n, a c o ntr ol visit will be perf or me d at W ee k 1 3 +/- 7 da ys after t he l ast a d mi nistrati o n i n 
or der t o e val uate safet y a n d ne e d f or t he patie nt t o c o nti n ue t he treat me nt a n d t he st u d y. 
 


N o v artis 
C lin ica l T rial P rot o co l v 0 5  
C o n fid e nt ial  
P ag e 2 4  
P rot o co l N o . C A C Z 8 8 5 G F R 0 1  
 
6. 1 
P ati e nt d e m o gr a p hi c s/ ot h er b a s eli n e c h ar a ct eri sti c s 
 
De m o gra p h y 
i nf or mati o n 
a n d 
ot her 
baseli ne 
c har acteristics 
are 
t h ose 
col lecte d 
i n 
C A C Z 8 8 5 G 2 3 0 1 E 1 / C A C Z 8 8 5 N 2 3 0 1 / C A C Z 8 8 5 G 2 3 0 6 st u d y. 
6. 2        St u d y tr e at m e nt  di s p e n s ati o n 
 
Basic st u d y treat me nt dis pe nsati o n  data will be col lecte d ( date of i nj ecti o n a n d t otal v ol u me 
i njecte d). 
6. 3        Effi c a c y 
 
N o efficac y d ata a re col lecte d i n t his st u d y. 
6. 4        S af et y 
 
Safet y assess me nts 
will c o nsist of  rec or di n g a n d 
m o nit ori n g of 
A d vers e E v e nts ( AE)  a n d 
Seri o us A d verse E ve nts ( SA E). 
 
7          S af et y mo n it orin g 
 
7. 1        A d v er s e e v e nt s 
 
A n  a d vers e e ve nt ( A E) is a n y u nt o war d me dic al occ urre nce (i.e., a n y u nfa v o ra ble a n d u ni nte n de d 
sig n [i ncl u di n g a b n or mal la b o rat ory fi n di n gs], s ym p to m  or disease) i n a s u bject or cli nical 
i n vesti gati o n s u bject af ter pr ovi di n g writte n i nf or me d c o nse nt f or partici pati o n i n t he st u d y. 
T heref o re, a n A E ma y or ma y n ot be t e m p orall y or causall y ass oci ate d wit h t he use of  a me dici nal 
(i n vesti gati o nal) pr o d uct. 
T he occ urre nce of  a d vers e e ve nts s h o ul d b e s ou g ht b y n o n- dir ective  q uesti o ni n g of t he patie nt at 
eac h visit d uri n g t he st u d y. A d verse e ve nts als o ma y b e detecte d w h e n t he y are v ol u nteere d b y t he 
p atient  d uri n g or bet ween visi ts or t hr o u g h p h y sical e xa mi nati o n, la b orat or y t est, or ot her 
assess me nts. 
A b n or mal la b o rat or y val ues or test res ults c o nstitute a d verse e ve nts o nl y if t he y f ulfill at least o ne 
of t he f ol l o wi n g criteria: 
 t he y i n d uce cli nical si g ns or s y m pt o ms, 
 t he y are c o nsi dere d cli nicall y si g nifica nt, 
 t he y re q uire t hera p y. 
 
A d verse e ve nts s h o ul d be rec o r de d i n t he A d vers e E v e nts C R F  u n der t he sig ns, s y m p t o ms or 
dia g n osis ass ociate d wit h t he m, a cco m pa nie d b y t he f oll o wi n g i nf o r mati o n: 
 t he se verit y gra de 
- mil d: us uall y tra nsie nt i n nat ure a n d ge nerall y n ot i nterferi n g wit h n or mal acti vities 
- m o derate: s ufficie ntl y disc o mf orti n g t o i nterfere wit h n or mal acti vities 
- se vere: pre ve nts n or mal acti vities 
 its relati o ns hi p t o t he st u d y me dicati o n 
 st u d y treat me nt ( n o/ yes), or 
 i n vesti gati o nal treat me nt ( n o/ yes), or 
 t he ot her st u d y treat me nt ( n o n-i n vesti gati o nal) ( n o/ yes), or 
 b ot h or i n disti n g uis ha ble, 
 its d urati o n (start a n d e n d dates) or if t he e ve nt is o n g oi n g a n o utc o me of n ot rec o ver e d/ n ot 
res ol ve d s h o ul d be re p orte d 


N o v artis 
C lin ica l T rial P rot o co l v 0 5  
C o n fid e nt ial  
P ag e 2 5  
P rot o co l N o . C A C Z 8 8 5 G F R 0 1  
 
 w het her it c o nstit utes a seri o us a d verse e ve nt ( S A E - See secti o n 7. 2 f or defi niti o n) acti o n 
ta ke n re gar di n g ca na ki n u ma b treat me nt. 
All a d verse e v e nts s h o ul d be treate d a p pr o priatel y. Treat me nt ma y i n cl u de o ne or m ore of t he 
f oll o wi n g: 
 n o acti o n ta ke n (i.e. f urt her o bser vati o n o nl y) 
 st u d y treat me nt d osa ge a dj uste d/te m p oraril y i nterr u pte d 
 st u d y treat me nt per ma ne ntl y disc o nti n ue d d ue t o t his a d verse e ve nt 
 c o nc o mita nt me dicati o n gi ve n 
 n o n- dr u g t hera p y gi ve n 
 patie nt h os pitalize d/ patie nt’s h os pitalizati o n pr ol o n ge d 
 its 
o utc o me ( n ot reco v ere d/ n ot 
res ol ve d; reco v ere d /res ol ve d; r ec o ve rin g/res ol vi n g, 
rec o vered/ r es ol ve d wit h se q uelae; fatal; or u n k n o w n) 
O n ce a n a d verse e ve nt  is detecte d, it s h o ul d be f oll o we d u ntil its res ol uti o n or  u ntil it is 
j u d ge d t o be per ma n e nt, a n d assess me nt s h o ul d b e ma de at eac h visit ( or m ore fre q u e ntl y, if 
n ecessar y) of  a ny c ha n ges i n se verit y, t he s us pecte d relati o ns hi p t o t he st u d y treat me nt, t he 
i nter ve nti o ns re q uire d t o treat it, a n d t he o utc o me. 
I nf or mati o n a b o ut c o m mo n  si de effects alrea d y k n o w n a b o ut t he i n vesti gati o nal dr u g can  be f o u n d 
i n t he S m P C or will be c o m m u nicate d bet ween S m P C u p dates i n t he f or m of I n ve sti gat or 
N otifi cati o ns. T his i nf or mati o n will be i ncl u de d i n t he patient  i nf or me d c o nse nt a n d s h o ul d be 
disc usse d wit h t he patie nt d uri n g t h e st u d y as nee de d. 
T he i n vesti gat or s h o ul d als o i nst r uct each  patie nt t o re p ort a n y n e w a d verse e ve nt ( be y o n d t he 
p r ot oc ol o bser vati o n peri o d) t hat t he patie nt, or t he patie nt’s pers o nal p h ysicia n, belie ves mi ght  
reas on a bl y be relate d t o st u d y treat me nt. 
T his i nf or mati o n s ho ul d be rec o r de d i n t he 
i n vesti gat or’s s o urce d oc u me nts. H o we ver, if t he A E meets t he criteria of a n S A E, it m u st be 
re p orte d t o N o vartis. 
 
7. 2        S eri o u s a d v er s e e v e nt ( S A E) 
7. 2. 1 D efi niti o n of a S A E 
 
A S A E  is defi ne d as an y  a d verse e vent  (ap p eara nce of  ( or w orse ni n g of a n y p re-e xisti ng ) 
u n desira ble si g n (s), s ym p t o m(s) or me dical c o n diti o ns(s) w hic h mee ts a n y o ne of t he f oll o wi n g 
criteria: 
 is fatal or life-t hreate ni n g 
 res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y 
 c o nstit utes a c o n ge nital a n o mal y/ birt h defect 
 re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n, u nless 
h os pitalizati o n is f or: 
 r o uti ne treat me nt or 
m o nit ori n g of t he st u die d i n dicati o n, n ot ass ociate d 
wit h a n y 
deteri orati o n i n c o n diti o n (s pecif y w hat t his i ncl u des) 
 electi ve or pre- pla n ne d treat me nt f or a pre-e xisti n g c o n diti o n t hat is u nrelate d t o t he 
i n dicati o n u n der st u d y a n d has n ot w orse ne d si nce si g ni n g t he i nf or me d c o nse nt 
 treat me nt o n a n e mer ge nc y o ut patie nt basis f or a n e ve nt n ot f ulfilli n g a n y of t he defi niti o ns 
of a S A E gi ve n a b o ve a n d n ot res ulti n g i n h os pital a d missi o n 
 s ocial reas o ns a n d res pite care i n t he a bse nce of a n y deteri orati o n i n t he patie nt’s 
 ge neral c o n diti o n 
 is me dicall y si g nifica nt, i.e. defi ne d as a n e ve nt t hat je o par dizes t he patie nt or ma y re q uire 
me dical or s ur gical i nter ve nti o n. 
 


N o v artis 
C lin ica l T rial P rot o co l v 0 5  
C o n fid e nt ial  
P ag e 2 6  
P rot o co l N o . C A C Z 8 8 5 G F R 0 1  
 
Life-t hreate ni n g i n t he c o nte xt of a S A E refers t o a reacti o n i n w hic h t he patie nt was at ris k of d eat h 
at t he ti me of t he reacti o n; it d oes n ot refer t o a reacti o n t hat h y p ot heticall y mi g ht ha ve cause d d eat h 
if m ore se vere (s ee I C H- E 2 D G ui deli ne a vaila ble at: 
htt p:// w w w.ic h. or g/file a d mi n/ P u blic _ We b _ Site/I C H _ Pr o d uc ts/ G ui deli nes/ Efficac y/ E 2 D/ St e p4/ E 2 D _
G ui deli ne. p df ). 
All 
mali g na nt ne o plas ms 
will 
be  assesse d as seri o us u n der “ me di call y sig nifi cant ” if ot her 
seri o us ness criteria are n ot met. 
A n y s us pect e d tra ns mi ssio n  via a me dici nal pr o d uct of a n i nfecti o us a gent  is als o c o nsi dere d a 
seri o us a d vers e reacti o n. 
Me di cal a n d scie ntific j u d g me nt s h o ul d be e xercise d i n deci di n g w h et her ot her sit uati o ns s h o ul d be 
c o nsi dere d seri o us re acti o ns, s uc h as i m p ort ant  me dical e ve nts t hat mi g ht n ot be i m me diatel y life 
t hreat e ni n g or res ult i n deat h or h os pitalizati o n b ut mi g ht j e o par dize t he patie nt or  mi g ht re q uire 
i nter ve nti o n t o preve nt o ne of t he ot her o utc o mes liste d a b o ve. E xa m p les of s uc h e ve nts are i nte nsi ve 
treat me nt i n a n eme r ge nc y r o o m or at h o me f or aller gic br o nc h os pas m, bl o o d d ys crasias or 
c o n v ulsi o ns t hat d o n ot res ult i n h os pitalizati o n or de vel o p me nt of de pe n de nc y or a b use (see I C H-
E 2 D G ui deli ne  a vaila bl e at: 
htt p:// w w w.ic h. or g/file a d mi n/ P u blic _ We b _ Site/I C H _ Pr o d uc ts/ G ui deli nes/ Efficac y/ E 2 D/ Ste p 4/ E 2 D _
G ui deli ne. p df ). 
 
7. 2. 2 S eri o u s a d v er s e e v e nt  r e p orti n g 
 
T o  e ns ure patient  safet y, e ver y S A E, regar dle ss of causalit y, o ccu rri n g after t he patie nt  has 
p r o vi de d i nf or me d c o nse nt a n d u ntil 3 0 da ys [ after t he last st u d y visit/ f oll o wi n g t he last 
a d mi nistrati o n of  st u dy treat me nt if t here are p ost-treat me nt f oll o w- u p visits wit h n o  re q uired 
p r oced ure s] m ust be re p orte d t o N o vartis wit hi n 2 4 h o urs of lear ni n g of its occurre nce. A n y S A Es 
e x perie nce d a fter t he 3 0 da ys peri o d s h o ul d o nl y b e re p orte d t o N o vartis if t he i nv esti gat or s us pects 
a cau sal relati o ns hi p t o st u d y treat me nt. 
R ecurre nt  e pis o des, c om p licati o ns, or pr o gressi o n of t he i nitial S A E m ust be re p orte d as f oll o w- u p 
t o t he ori gi nal e pis o de, regar dle ss of w h e n t he e ve nt occur s. T his re p ort m ust be s u b mitte d 
wit hi n 2 4 h o u rs of t he i n vesti gat or recei vi n g t h e f oll o w- u p i nf or mati o n. A n  S A E t hat is c o nsi dere d 
c o m pletel y u nrelate d t o a previ o usl y re p orte d o n e s h o ul d be re p orte d se parat el y as a ne w e ve nt. 
I nf or mati o n a b o ut all S A Es (eit her i niti al or f oll o w u p i nf or m ati o n) is c ollecte d a n d rec or de d o n t he 
p a per Seri o us A d verse E ve nt Re p ort F or m.  T h e i n vesti gat or m ust assess t h e relati o ns hi p t o t he 
st u dy tre at me nt c o m plete t he S A E Re p ort F or m i n E n glis h, a n d se n d t he c o m plete d, sig ne d f o r m 
b y fa x wit hi n 2 4 h o urs a fter a ware ness of  t he SA E  t o t he l ocal N o vartis Dr u g Safet y a n d 
E pi de mi ol o g y De p art me nt. T he tele p h o ne a n d fa x n u m ber of t he c o ntact pers o ns i n t he l ocal 
d e part me nt of Dr u g Safet y a n d E pi de mi ol o g y, s pecific t o t he site, are liste d i n t he i n vesti gat or f ol der 
p r o vi de d t o eac h site. T he ori gi nal c o p y of t he SA E  Re p ort F or m a n d t he fa x c o nfir mati o n s heet 
m ust be ke pt wit h t he case re p ort f or m d oc u me ntati o n at t he st u d y site. Fol l o w- u p i nf or mati o n 
s h o uld be pr o vi de d usi n g a ne w pa per S A E  Re p ort F or m stati n g t h a t t his is a f oll o w- u p t o a 
p revi o usl y re p orte d S A E  
F oll o w- u p i nf o r matio n  pr o vi de d s h o ul d descri be w h et her t h e e ve nt has res ol ve d or c o nti n ues, if a n d 
h o w  it was treate d w h et her t he patie nt c o nti n ue d or  wit h dre w fr o m st u d y partici pati o n. Each re-
o ccur ren ce, c o m plicati o n, or pr o gressio n  of t he ori gi nal e vent  s h o ul d be re p orte d as a f oll o w- u p t o 
t hat e ve nt r e gar dless of w he n it occur s. 
If t he SA E  is n ot previ o usl y d oc u me nte d i n t he S m P C (see a p pe n di x 1) ( ne w occur ren ce) a n d is 
t h o u g ht t o be relate d t o t he st u d y treat me nt a Dr u g S afet y a n d E pi de mi ol o gy D e part me nt ass ocia te 
ma y ur ge ntl y re q uire f urt her i nf or mati o n fr o m t he i n vesti gat or f or  Healt h A ut h orit y re p orti n g. 
N o va rtis ma y nee d t o issue  a n I n vesti gat or N otificatio n  (IN)  t o i nf or m all i n vesti gat ors i n v ol ve d i n 


N o v artis 
C lin ica l T rial P rot o co l v 0 5  
C o n fid e nt ial  
P ag e 2 7  
P rot o co l N o . C A C Z 8 8 5 G F R 0 1  
 
a n y st u d y wit h t he sa me  i n vesti gati o nal treat me nt t hat t his SA E  has been re p o rte d. S us pecte d 
U n e x pecte d Seri o us A d verse Reacti o ns ( S U S A Rs) will be col lecte d a n d re p orte d t o t he c o m pet ent  
a ut h orities a n d  rele va nt et hics c o m mittees i n acc or da nce wit h Dir ective  2 0 0 1/ 2 0/ E C or as per 
n ati o nal reg ulat or y req uire me nts. 
 
7. 3        Pr e g n a n c y r e p orti n g 
 
T o  e ns ure patient  safet y, eac h pre g n a nc y occ urri n g w hile t he patient  is o n st u d y treat me nt m ust 
be re p orte d t o N o vartis wit hi n 2 4  h o urs of lear ni n g of its occurre n ce. T he p reg na n c y s h o ul d be  
f oll o we d u p t o deter mi ne o utc o me, i ncl u di n g s p o nta ne o us or v o lu ntar y ter mi nati o n, details of t he 
birt h, a n d t he p rese n ce or  a bse nce of a n y birt h defects, c o n ge nital a b n or malities, or mater nal a n d/ or 
ne w b or n c o m pl icati o ns. 
Pr e gn a nc y s h o ul d be rec or de d o n a Cl i nical Trial Pre gn a nc y F o r m a n d re p orte d b y t he i n vesti gat or 
t o t he l ocal N o vartis Dr u g Safet y a n d E pi de mi ol o g y De p art me n t. Preg na nc y f oll o w- u p s h o ul d be 
rec or de d o n t he sa me f o r m a n d s h o ul d i n cl u de a n assess me nt of t he p ossi ble relati o ns hi p t o t he st u d y 
treat me nt. 
A n y S A E  e x perie nced d uri n g p reg na n c y m ust be re p orte d o n t he S A E Re p ort F or m.  
 
8          D at a r e vi e w a nd d at a b a s e m a n a g e m e nt 
 
8. 1        Sit e m o nit ori n g 
 
Bef o re st u d y i niti ati o n, at a site i nitiati o n visit or  at a n i nv esti gat or’s me eti n g, a N o vartis 
re prese ntati ve will revi e w t he pr ot oc ol a n d C R Fs wit h t he i n vesti gat ors a n d t heir staf f. 
T he i n vesti gat or m ust gi ve  t he m o nit or access t o all rele va nt s o urce d o c u me nts t o c o nfir m t heir 
c o nsiste nc y wit h t he C R F  e ntries. N o vartis m o nit ori n g sta n dar ds re q uire f ull verificati o n f or t he 
p rese nce of  i nf or me d c o nse nt, ad h ere nce t o t he i ncl usi o n/ex cl usi o n criteria, d oc u me ntati o n of 
S A Es, a n d of  data t hat 
will be use d f or all pri mar y varia bles. 
A d diti o n al c hecks  of t h e 
c o nsiste n c y of t he s o urce d a ta wit h t he C R Fs are perf or me d a ccor di n g t o t he st u d y-s pecific 
m o nit ori n g pla n. N o  i nf or mati o n i n s o urce d oc u me nts a b out  t he i de ntit y of t he patie nts will be  
discl ose d. 
8. 2        D at a c o ll e cti o n 
 
De sig n ate d i n vesti gat or staff m ust e nter t he i nf or mati o n re q uire d b y t h e pr ot oc ol o nt o t h e N o va rtis 
C R Fs t hat a re pri nte d o n 3  - p art, n o n-car b o n-re q uire d p a per. Fiel d m o nit ors will re vie w t he C R Fs f or 
c o m p lete ness an d  acc urac y a n d i nstr uct site pers o n nel t o 
ma ke a n y re q uire d c orrecti o ns or  
a d diti o ns. T he C R Fs pa ges will be c ol lecte d b y fiel d m o nit ors after m o nit ori n g vali dati o n, wit h 
o ne c o p y b ei n g retai ne d at t he i n vesti gati o nal site. O n ce t h e C R Fs pa ges c oll ecte d, t he ori gi nal c o p y 
w ill be  placed i n t he st u d y Trial Mast er file, a n d t he n o n- car b o n-re q uire d c o py will be  f or war de d t o 
t h e C R O  i n c h ar ge of  Dat a Ma na ge me nt f or pr o cessi n g. 
8. 3        D at a b a s e m a n a g e m e nt a n d q u alit y c o ntr ol 
 
Da ta fr o m t he C R Fs will be  e ntered i nt o t he st u d y datab ase b y C R O staff, usi n g d o u ble data e ntr y 
a n d f oll o wi n g t he ir o w n i nter nal sta n d ar d o perati n g pr o ced ures (t hat ha ve  bee n re vie we d an d 
a p pr o ve d b y N o va rtis). 
S u bse q ue nt l y, t he e ntered da ta will be s yste maticall y c hec ke d b y Data Ma na ge me nt staff, usi n g 
err or messa ges pri nte d fr o m  vali datio n  pr o grams  an d  data bas e listi n gs. Ot her err ors or o missi o ns 
will be e nte red  o n Data Q u er y F or ms, w hi c h will be ret ur ne d  t o t he i n vesti gati o nal site f or 
res ol uti o n. T he sig ne d ori gi nal a n d res ol ve d Da ta Q u er y F or ms  will be kept  wit h t he C R Fs at t he 
i n vesti gat or site, a n d a c o p y will be  sent  t o t he CR O  s o t he res ol uti o ns can  be e ntered  i nt o t he 


N o v artis 
C lin ica l T rial P rot o co l v 0 5  
C o n fid e nt ial  
P ag e 2 8  
P rot o co l N o . C A C Z 8 8 5 G F R 0 1  
 
d atab ase. Q u alit y c o ntr ol a u dits of  all key d a ta i n t he data base will be ma d e pri or t o l oc ki n g t he 
d a tab ase. 
A d verse e ve nts will be c o d e d usi n g t he 
Me di cal dicti o nar y f or re g ul at ory activi ties ( Me d D R A) 
ter mi n ol o g y. 
After t he se acti o ns ha ve been  c o m plete d a n d t he data bas e has been d ecl are d t o b e c o m plete a n d 
acc urate, it will be  l oc ked.  A n y c ha n ges t o t he data base after t hat ti me  can o n ly b e ma d e after 
writte n a gr eeme nt b y N o v artis. 
8. 4        D at a M o nit ori n g C o m mitt e e 
 
N ot req uire d. 
8. 5        A dj u di c ati o n C o m mitt e e 
 
N ot req uire d. 
 
9          D at a a n al y si s 
 
9. 1        A n a l y si s s et s 
 
Safet y Set: C o nsists of  all patie nts w h o recei ve d at least o n e d ose of st u d y dr u g a n d ha d at least 
o ne p ost- treat me nt safet y assess me nt i n t he st u d y. T he state me nt t hat a patient  ha d n o a d verse e ve nt 
( A E) als o c o nstit utes a safet y assess me nt. 
9. 2        P ati e nt d e m o gr a p hi c s  a n d ot h er ba s el in e  c h ar a ct eri sti c s 
 
De m o gra p hic s, back gr o u n d  data an d  ke y bas eli ne c h aracteristics are t h ose col lect e d i n t h e 
C A C Z 8 8 5 G 2 3 0 1 E 1 st u d y. Se x a n d date of birt h will be  re-c ollecte d i n t he C R F. 
9. 3        Tr e at m e nt s 
 
T he e x p os ure t o st u d y dr u g ( n u m ber of i njecti o ns) a n d d urati o n of e x p os ure ( da ys) will be 
s u m marize d a n d liste d b y d ose. 
9. 4        A n a l y si s of v ari a bl es 
9. 4. 1       V ari a bl e s 
 
a.   Effic ac y v ar i ables  
 
T h ere is n o efficac y ass essme nt i n t his st u d y 
 
b.   S af et y v ari ables  
 
A d verse e ve nts will be c o de d usi n g t he Me d D R A  dicti o nar y t h at pr o vi d es t he pri mar y s yste m or gan 
class a n d preferre d term i nf or mati o n. A d verse e ve nts will be  p resent e d i n t w o parts: 
o  A d verse e ve nts (i ncl u di n g i nfecti o ns) 
o  I nf ecti o us a d verse e ve nts 
A d verse e ve nts will be s u m ma rize d f or e a c h dis e as e b y prese nti n g t he n u m b er a n d  percent a ge of  
p atie nts ha vi n g a n y a d verse e ve n t, ha vi n g a n y a d verse e ve nt i n eac h prima ry s yst e m or ga n class a n d 
h a vi n g each i n di vi d ual a d v erse e ve nt  base d o n t he preferre d term.  All ot her i nf or mati o n c ollecte d 
(e. g. se verit y, relati o ns hi p t o st u d y dr u g, or micr o or ga nis m f or i nfecti o us a d verse e ve nts) will be 
ta b ulate d a n d liste d as a p pr o priate. 
D eat hs, seri o us a d verse e ve nts, an d  a d verse e ve nts lea di n g t o disc o nti n uati o n of st u d y dr u g will 
be s u m marize d b y pri mar y s yste m or ga n class a n d p referre d ter m a n d liste d. 


N o v artis 
C lin ica l T rial P rot o co l v 0 5  
C o n fid e nt ial  
P ag e 2 9  
P rot o co l N o . C A C Z 8 8 5 G F R 0 1  
 
9. 4. 2       St ati sti c al m o d el, h y p o t h e si s, a n d m et h o d of a n al y si s 
 
T his is a n o pe n-l a bel sin gle-a r m s afet y trial f or patie nts a n d t he d ata will be prese nte d i n a 
d escri pti ve ma n ne r. 
9. 4. 3       H a n dli n g of mi s si n g v al u e s/ c e n s ori n g/ di s c o n ti n u ati o n s 
 
Missi n g val ues will n ot be ha n dle d b ut pre mat ure disc o nti n uati o n will be f ull y desc ri be d. 
 
9. 5        I nt eri m a n al y s e s  
 
N ot req uire d 
 
9. 6        S a m pl e si z e c al c u l ati o n 
 
N o  sam p le size calc ulati o n was perf or me d f or t his e xte nsi o n st ud y w hic h will i ncl u de all eli g i ble 
s u bj ects w h o c om p lete C A C Z 8 8 5 G 2 3 0 1E 1  or C A C Z 8 8 5 N 2 3 0 1 st u d y a n d me et t he eli gi bilit y 
criteria. 
1 0        Et hi c al c o n si d er ati o n s 
 
1 0. 1      R e g ul at or y a n d et hi c al c o m pli a n c e  
 
T his cli nical st u d y was de sig n e d a n d s hall be i m ple me nte d a n d re p ort e d i n accor da nce wit h t he 
IC H  
Har m o nize d 
Tri partite 
G ui deli nes f or 
G o o d Cl i nical Practice, 
wit h a p plicable l o cal 
reg ulati o ns (i ncl u di n g E ur o pea n Directi ve  2 0 0 1/ 2 0/ E C, U S  C o de of Fe deral Re g ulati o ns Title 2 1, 
a n d J a pa nese Mi nistr y of Healt h, La b or, a n d Welfare), a n d wit h t he et hical pri nci ples lai d d o w n i n 
t he Declarati o n of Helsi n ki. 
1 0. 2      I nf or m e d c o n s e nt pr o c e d u re s  
 
Eli g i ble patie nts ma y o nl y be i ncl u de d i n t he st u d y after pr o vi di n g writte n ( wit nesse d, w h ere 
re q uire d by l a w or reg ul ati o n), I R B/I E C-a p pr o ve d  i nf or me d c o nse nt, or, if i nca pa ble of  d oi n g s o, 
after s uc h c o nse nt has been  pr o vi de d b y a le gally ac ce pta ble re prese ntati ve of t he patie nt. I n cases 
w h ere t he p atie nt’s re prese nt ati ve gi ves c o nse nt, t he patient  s h o ul d be i nf or me d a b o ut t he st u d y t o 
t he e xte nt p ossi ble gi ve n his/ her u n dersta n di n g. If t he patient  is capa ble of  d oi n g s o,  he/s he  s h o ul d  
i n dicate  asse nt  b y pers o nall y  si g ni n g  a n d  dati n g  t h e  writte n  i nf or me d c o nse nt d o c u me nt or  a 
se parate asse nt f orm.  I nf or me d c o nse nt m ust be o btai ne d bef ore c o n d ucti n g a n y st u d y-s pecific 
p r oced ures (i.e. all of  t he pr oced ures descri be d i n t he pr ot oc ol). T he pr ocess of o btai ni n g i nf or me d 
c o ns ent  s h o ul d be d oc u me nte d i n t he patient  s o urce d oc u me nts. 
N o vartis will pr o vi de t o i n vesti gat ors i n a se parate d oc u me nt a pr o p ose d i nf or me d c o nse nt f or m t hat 
c o m plies wit h t he IC H  G C P g ui deli ne a n d re gu l at or y re q uire me nts a n d is c o nsi dere d a p pr o priate 
f or t his st u d y. A n y c ha n ges t o t he pr o p ose d c o ns ent  f or m s u g geste d b y t he i n vesti gat or m ust be  
a gree d t o b y N o v artis bef ore s u b missi o n t o t he I R B/I E C, a n d a c o p y of t he a p pr o ve d versi o n m ust 
be pr o vi de d t o t he N o vartis m o nit or after I R B/I E C a p pr o va l. 
W o me n of c hil d b eari n g p ote ntial s h o ul d be  i nf or me d t hat ta ki n g t he st u d y treat me nt ma y i n v ol ve 
u n k n o w n ris ks t o t he fet us if pre g na ncy we re t o occ ur d uri n g t he st u dy a n d a gree t hat i n or der t o 
p artici p ate i n t he st u d y t he y m ust a d h ere t o t he c o ntrace ptio n  re q uir e me nt f or t h e d uratio n  of t he 
st u d y. If t here is a n y q uesti o n t hat t he patient  will n ot reliab ly c o m pl y, t he y s h o ul d n ot be e ntered i n 
t he st u d y. 
 


N o v artis 
C lin ica l T rial P rot o co l v 0 5  
C o n fid e nt ial  
P ag e 3 0  
P rot o co l N o . C A C Z 8 8 5 G F R 0 1  
 
1 0. 3      R e s p o n si biliti e s  of t h e i n v e sti g ator  a n d I R B/I E C 
 
T he pr ot oc ol a n d t he p r o p ose d i nf or me d c o nse nt f or m m ust be re vie we d a n d a p pr o ve d b y a pr o perly 
c o nstit ute d I nstit uti o nal 
Re vie w 
B o ar d/In d e pen d ent  Et hics 
C o m mittee/ Researc h Et hics 
B oar d 
(I R B/I E C) bef ore st u d y start. A sig ne d a n d  date d state me nt t hat t he pr ot oc ol a n d i nf or me d c o nse nt 
h a ve  been  a p pr o ve d b y t h e IR B /IE C  m ust be gi ve n t o N o vartis bef ore st u d y i nitiati o n. Pri or t o 
st u d y start, t he i n vesti gat or is re q uire d t o sig n a pr ot oc ol  sig n at ure p a ge c o nfir mi n g his/ her 
a gree me nt t o c o n d uct t he st u d y i n acc or da n ce wit h t hese d oc u me nts a n d all of t he i nstr ucti o ns a n d 
p r oced ures f o u n d i n t his pr ot oc ol a n d t o gi ve access t o all rele vant  data a n d rec or ds t o N o vartis 
m o nit ors, a u dit or s, 
N o vartis Cl i nical Q u alit y Ass ura nce re pres e ntati ves, desi g nat e d a ge nts of  
N o vartis, I R Bs/I E Cs, a n d reg ula t ory a ut h orities as re q uire d. If a n  i ns pectio n  of t he cli nical site is 
re q ueste d b y a reg ula t ory a ut h orit y, t he i n vesti gat or m ust i nf or m N o vartis i m me diat el y t h a t t his 
req u est has been ma de. 
 
1 0. 4      P u bli c ati o n  of st u d y pr ot o col  a n d r e s ult s 
 
N o vartis ass ures t hat t he ke y d e sig n ele me nts of t his pr ot oc ol will be  p oste d i n a p u blicly accessi ble 
d ata base s uc h as cli nicalt rials. g o v. I n a d diti o n, u p o n st u d y c o m pleti o n a n d fi nal izati o n of t he st u d y 
re p ort t he res ults of t his trial will be eit her s u b mitte d f or p u blicati o n a n d/ or p oste d i n a p u blicl y 
accessi ble data base of  cli nical trial res ults. 
1 1        Pr ot o c ol ad h er e n c e  
 
I n vesti gat ors ascertai n t h e y will a p pl y d u e di li ge nce t o a v oi d pr ot oc ol d e viati o ns. U n der n o 
circ u msta nces s h o ul d t he i n vesti gat or c o nta ct N o vartis or  its a ge nts, if a n y, m o nit ori n g t he trial 
t o re q uest a p pr o val of a pr ot oc ol d e viati o n, as re q uests t o a p pr o ve d e viati o ns will n ot be gra nte d. 
T his pr ot oc ol defi nes t he st u d y o bjecti ve s, t he st u d y pr oced u res a n d t he data t o be c ollecte d o n 
st u d y partici pa nts. U n der n o circ u msta nces s h o ul d a n i n vesti gat or c ollect a d diti o nal data or 
c o n d uct a n y a d diti o nal pr o ced ures f or a n y researc h relate d p ur p ose i n v ol vi n g a n y i n vesti gati o na l 
dr u g s. 
If t h e i n vesti gat or feels a pr ot oc ol de viati o n w o ul d i m pr o ve t he c o n d uct of  t he st u d y t his m ust be 
c o nsi dere d a pr ot o c ol a me n d me nt, a n d u nless s uc h a n a me n d me nt is a g ree d u p o n b y N o va rtis a n d 
a p pr ove d  b y t he I R B/IE C  it can n ot  be i m ple me nte d. All sig nifi cant  pr ot oc ol de viati o ns will be  
rec or de d a n d re p orte d i n the  C S R.  
 
1 1. 1      Pr ot o c ol A m e n d m e nt s 
 
A n y c ha n ge or a d diti o n t o t he pr ot oc ol ca n o nl y b e ma de i n a writte n prot o c ol a me n d me nt t hat m ust 
be a p pr o ve d  by N o vartis, H ealt h A ut h orities w h ere re q uire d, a n d t he I R B/I E C. O n ly ame n d me nts 
t hat are req uire d f or patie nt safet y ma y b e i m ple me nte d pri or t o I R B/I E C a p pr ova l. N ot wit hsta n di n g 
t he need  f or a p pr o val of  f or mal prot o c ol a me n d me nts, t he i n vesti gat or is e x pecte d t o ta ke a n y 
i m me diate acti o n r e q uire d f or t he safet y of a n y patie nt i ncl u de d i n t his st u d y, e ve n if t his acti o n 
re prese nts a de vi ati o n fr o m t h e prot o c ol. I n s uc h cases, N o v artis s h o ul d be n otifie d of t his acti o n a n d 
t he I R B/IE C  at t he st ud y site s h o ul d be i nf or me d wit hi n 1 0 w or ki n g da ys or less, i f req uire d b y l o cal 
r e g ulati o ns. 
 
1 2        R ef er e n c e s 
 
Di narell o C A ( 1 9 9 6) Bi ol o gic basis f or i nterle u ki n- 1 i n disease. Bl o o d; 8 7( 6): 2 0 9 5- 1 4 7. Re vie w. 
Di narell o C A ( 2 0 0 5) Bl oc ki n g I L- 1 i n s yste mic i nfla m mati o n. J E x p Me d; 2 0 1( 9): 1 3 5 5- 9. 


N o v artis 
C lin ica l T rial P rot o co l v 0 5  
C o n fid e nt ial  
P ag e 3 1  
P rot o co l N o . C A C Z 8 8 5 G F R 0 1  
 
Pasc ual V, Alla ntaz F, Arce E, et al ( 2 0 0 5) R ole of i nterle u ki n- 1 (I L- 1) i n t he pat h o ge nesis of 
s yste mic o nset j u ve nile i di o pat hic art hritis a n d cli nical res p o nse t o I L- 1 bl oc ka de. J E x p 
Me d; 
2 0 1( 9): 1 4 7 9 -8 6.  
Q uartier P, Prie ur A M. Art hrite j u ve nile i di o pat hi q ues. Les différe ntes f or mes cli ni q ues. 
Re v  
Praticie n 2 0 0 7 ; 5 7( 1 1).  
Ra velli A, Marti ni A ( 2 0 0 7) J u ve nile i di o pat hic art hritis. La ncet; 3 6 9: 7 6 7 – 7 8. 
R u pert o N, Q uartier P, W ulffraat N, et al ( 2 0 0 8 b) A p hase II trial wit h ca na ki n u ma b, a ne w I L- 1 ß 
bl oc ki n g m o n ocl o nal a nti b o d y ( A C Z 8 8 5), t o e val uate preli mi nar y d osi n g, safet y a n d effic ac y pr ofile 
i n c hil dre n wit h s yste mic J u ve nile I di o pat hic art hritis (sJI A) [ oral prese ntati o n]. 1 5t h Pae diatric 
R he u mat ol o g y E ur o pea n S ociet y ( Pre S) C o n gress, 1 4- 1 7 Se pte m ber 2 0 0 8, L o n d o n ( U K). 
W o o P ( 2 0 0 6) S yste mic j u ve nile i di o pat hic art hritis: dia g n osis, ma na ge me nt, a n d o utc o me. Nat Cli n 
Pract R he u mat ol; 2( 1): 2 8- 3 4. 
Di narell o C A, Si m o n A, va n der Meer J W. Treati n g i nfla m mati o n b y bl oc ki n g i nterle u ki n- 1 i n a 
br oa d s pectr u m of diseases. Nat Re v Dr u g Disc o v. 2 0 1 2 ( 8): 6 3 3- 5 2. 
Dre nt h J P, va n der Meer J W. Here ditar y peri o dic f e ver. N E n gl J Me d. 2 0 0 1; 3 4 5: 1 7 4 8- 5 7. 
G ul A, Oz d o ga n H, Erer B, et al. Efficac y a n d Safet y of Ca na ki n u ma b i n A d olesce nt a n d a d ults wit h 
C olc hici ne Resista nt Fa milial Me diterra nea n Fe ver. Art hritis Res T her. 2 0 1 5; 1 7 ( 1): 2 4 3 . 
T er Haar N, Lac h ma n n H, Oze n S, et al ( 2 0 1 2). Treat me nt of a ut oi nfla m mat or y diseases:  res ultsfr o m 
t he E ur ofe ver Re gistr y a n d a literat ure re vie w. A n n R he u m Dis. 2 0 1 3; 7 2: 6 7 8-8 5. . 
 
 
 


N o v artis 
C lin ica l T rial P rot o co l v 0 5  
C o n fid e nt ial  
P ag e 3 2  
P rot o co l N o . C A C Z 8 8 5 G F R 0 1  
 
1 3  
A p p en d i x 1:  S u mm a r y of pro d u ct  c h ara ct e risti c s  

SAP_001.pdf: 
Clinical Development 
ACZ885/ canakinumab /Illaris® 
ACZ885GFR01 / NCT02334748
A French open-label extension study of canakinumab in 
patients who participated in international phase III studies 
CACZ885G2301E1 or CACZ885G2306 in Systemic Juvenile 
Idiopathic Arthritis and CACZ885N2301 in Hereditary 
Periodic Fevers (TRAPS, HIDS, or crFMF) 
Statistical Analysis Plan (SAP) 
Author: 
Trial Statistician, 
 
Document type: 
SAP Documentation 
Document status: 
Final 1.0 
Release date: 
31-08 -2018
Number of pages: 
18 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted 
(Current) 
None 
…. 
 
 
 
 


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Table of contents 
Table of contents ................................................................................................................. 3 
List of abbreviations ............................................................................................................ 5 
Introduction ................................................................................................................................ 6 
1.1 
Study design ............................................................................................................ 6 
1.2 
Study objectives and endpoints ............................................................................... 7 
2 
Statistical methods ............................................................................................................... 7 
2.1 
Data analysis general information ........................................................................... 7 
2.1.1 
General definitions .................................................................................. 7 
2.2 
Analysis sets ............................................................................................................ 8 
2.2.1 
Subgroup of interest ................................................................................ 8 
2.3 
Patient disposition, demographics and other baseline characteristics ..................... 8 
2.3.1 
Patient disposition ................................................................................... 8 
2.3.2 
Protocol deviations .................................................................................. 9 
2.3.3 
Background and demographic characteristics ......................................... 9 
2.3.4 
Medical history and current medical condition ....................................... 9 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................ 10 
2.4.1 
Study treatment / compliance ................................................................ 10 
2.4.2 
Prior, concomitant and post therapies ................................................... 11 
2.5 
Analysis of the primary objective .......................................................................... 11 
2.5.1 
Primary endpoint ................................................................................... 11 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 11 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 11 
2.5.4 
Supportive analyses ............................................................................... 11 
2.6 
Analysis of the key secondary objective ............................................................... 11 
2.6.1 
Key secondary endpoint ........................................................................ 11 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................... 11 
2.6.3 
Handling of missing values/censoring/discontinuations ....................... 11 
2.7 
Analysis of secondary efficacy objective(s) .......................................................... 11 
2.7.1 
Secondary endpoints ............................................................................. 12 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 12 
2.7.3 
Handling of missing values/censoring/discontinuations ....................... 12 
2.8 
Safety analyses....................................................................................................... 12 
2.8.1 
Adverse events (AEs) ............................................................................ 12 
2.8.2 
Deaths .................................................................................................... 13 


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2.8.3 
Laboratory data ..................................................................................... 13 
2.8.4 
Other safety data ................................................................................... 13 
2.9 
Pharmacokinetic endpoints .................................................................................... 14 
2.10 
PD and PK/PD analyses ........................................................................................ 14 
2.11 
Patient-reported outcomes ..................................................................................... 14 
2.12 
Biomarkers ............................................................................................................. 14 
2.13 
Other Exploratory analyses.................................................................................... 14 
2.14 
Interim analysis ...................................................................................................... 14 
3 
Sample size calculation ..................................................................................................... 14 
4 
Change to protocol specified analyses .............................................................................. 14 
5 
Appendix ........................................................................................................................... 14 
5.1 
Imputation rules ..................................................................................................... 14 
5.1.1 
Study drug ............................................................................................. 14 
5.1.2 
AE date imputation ............................................................................... 14 
5.1.3 
Concomitant medication date imputation ............................................. 16 
5.2 
AEs coding/grading ............................................................................................... 17 
5.3 
Laboratory parameters derivations ........................................................................ 18 
5.4 
Statistical models ................................................................................................... 18 
5.5 
Rule of exclusion criteria of analysis sets.............................................................. 18 
6 
Reference ........................................................................................................................... 18 


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List of abbreviations 
 
AE 
Adverse event  
TEAE 
Treatment emergent adverse event 
CRF  
Case Report/Record Form  
CPO 
Country Pharma Organization  
CRO  
Contract Research Organization  
CSR 
Clinical Study Report  
DS&E 
Drug Safety and Epidemiology  
ICH 
International Conference on Harmonization  
IEC 
Independent Ethics Committee  
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
MTX 
Methotrexate 
NSAID 
Non-steroidal anti-inflammatory drug 
RAP 
Report and Analysis Process 
SAE 
Serious adverse event  
SAP 
Statistical Analysis Plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Introduction 
This document contains details of the statistical methods which will be used in the phase IV 
clinical trial CACZ885GFR01. This is an extension study to collect additional safety data 
(serious and non-serious adverse events) and to provide continuous Ilaris® (canakinumab) to 
patients in France who completed study CACZ885G2301E1, CACZ885N2301 or 
CACZ885G2306 until canakinumab (Ilaris®) is commercially available and reimbursed in 
France for these indications. 
Data will be analyzed by Novartis and/or by the designated CRO and statistical software SAS 
version 9.4 according to the data analysis section 9 of the study protocol version 04 which is 
available in Appendix 16.1.1 of the CSR.  Important information is given in the following 
sections and details are provided, as applicable, in Appendix 16.1.9 of the CSR. 
Unless otherwise  specified, the statistical methodologies including the analysis sets, analysis 
models, algorithms and conventions are following then interventional study protocol 
ACZ885GFR01. 
The planned analysis is described in Section 9 of the protocol (Appendix 16.1.1 of CSR). 
1.1 
Study design 
This is an open-label (single treatment arm) extension period for patients in France who have 
completed the international studies CACZ885G2301E1, CACZ885N2301 or CACZ885G2306. 
The last visit of CACZ885G2301E1, CACZ885N2301 or CACZ885G2306 studies will be the 
first visit of this extension study. 
Patients follow up previously included in studies: 
1. CACZ885G2301E1 (SJIA): These patients will continue the same dosing regimen as 
at the end of CACZ885G2301E1. 
2. CACZ885N2301 (HPF indications: TRAPS, HIDS or crFMF): These patients will 
continue the maintenance dose as determined at the open-label period/ epoch 4(i.e the 
lowest clinically efficacious does to maintain clinical efficacy in individual patients 
with a good tolerability). 
3. CACZ885G2306 (SJIA indication): These patients will continue on their dosing 
regimen considered to constitute the lowest clinically efficacious does to maintain 
clinical efficacy in individual patients. 
Visits will take place at scheduled administration dates, approximately every 4, 8 or 12 
weeks. The safety of canakinumab (Ilaris®) will be evaluated (adverse events and serious 
adverse events collection). Patients will followed up according to SmPC with possible 


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adaptation based on investigators judgment related to specific patient medical 
consideration. 
The study duration will depend on the date of reimbursement of canakinumab (Ilaris®) in 
France for the new indications and will be extended until the medication is commercially 
available for each indication. However, as the commercialization of the different 
indications may be effective at different dates, the patients will discontinue indication by 
indication (see section 5; end of treatment). 
 
1.2 
Study objectives and endpoints 
The objective of this protocol is to collect additional safety data (serious and non-serious 
adverse events) and to provide continuous Ilaris® (canakinumab) treatment to patients in 
France who completed CACZ885G2301E1, CACZ885N2301 or CACZ885G2306 study. 
The end of study is defined as premature termination or end of the study according to protocol: 
in the month following the availability of repaid product in France. 
Visits will take place at scheduled administration date every 4, 6, 8 or 12 weeks (section 5). If 
no visit is performed within 12 weeks of previous injection, a control visit will be performed 
at week 13 +/- 7 days after the last administration in order to evaluate safety and need for the 
patient to continue the treatment and study.  
Patients may voluatarily withdraw from study for any reason at any time. If premature 
withdrawal occurs, the investigator must make every effort to complete End of study visit in 
the CRF and to determine the primary reason for patient’s premature withdrawal from the 
study and record this information. 
 
2 
Statistical methods 
2.1 
Data analysis general information 
All categorical data will be presented in terms of frequencies and percentages. Summaries of 
continuous data will be presented in terms of mean, median, lower and upper quartile (for 
most variables), minimum and maximum, and the number of missing data points (for most 
variables) and the number of non- missing data points. 
For descriptive statistics, the following number of decimal places will used: arithmetic mean, 
and median to 1 more decimal places than the raw data; minimum and maximum to the same 
number of decimal places as the raw data and SD to 2 more decimal places than the raw data. 
Percentages will be presented to 1 decimal place. Patient disposition, background and 
demographic characteristics. 
 
2.1.1 
General definitions  
Study treatment: refers to: Illaris = ACZ885  


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Study treatment start and end date: Study treatment start date is defined as the first date of 
study drug is administered and recorded on the Study Medication Dosing Record in CRF page. 
Similarly, study drug end date is defined as the last date of study drug is administered. 
Study day: Study day will be calculated as (event date – study drug start date + 1 day) for 
events that occurred on or after study drug start date (e.g. visit, adverse events). For events 
prior to study drug start date (e.g., time of diagnosis), study day will be negative and 
calculated as (event date – study drug start date).  
Baseline and post baseline: In general, a baseline value refers to the last measurement made 
prior to administration of the first dose of study treatment or the average values taken prior to 
administration of the first dose of study treatment. A post-baseline value refers to a 
measurement taken after the first dose of study treatment. 
2.2 
Analysis sets 
Safety Set: Consists of all patients who received at least one dose of study drug and had at 
least one post-treatment safety assessment in the study. The statement that a patient had no 
adverse event (AE) also constitutes a safety assessment. 
 
Analysis set  
 
Population codes that cause 
subjects to be excluded 
Non-PD criteria that cause 
subjects to be excluded 
Safety 
1 
Did not provide informed 
consent, No treatment taken 
Population code: 0=Include in everything, 1=Exclude from safety set  
2.2.1 
Subgroup of interest 
All planned table will be repeated on following subgroup. 
 Pathology: SJIA, HIDS/ MKD and FMF 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
2.3.1 
Patient disposition 
The eligible subjects in study protocol ACZ885GFR01 have to fulfill inclusion and exclusion 
criteria. Inclusion and exclusion information will collected in CRF ACZ885GFR01.  
Frequency and percentage of patients passing and failing Screening will be presented for all 
screened patients. Percentage will be computed using the total number of screened patients as 
denominator.  
The total number of patients who were completed the study and discontinued the study 
(and/or treatment) will be presented by number and percentage along with reason of 
discontinuation for safety set. Patient identification number and whether they completed the 
study or discontinued from the study will be listed, along with date of last dose and primary 
reason for premature discontinuation for safety set. Separate listing of all screened failure 
patients will also be provided for safety set.  


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2.3.2 
Protocol deviations 
The number and percentage of patients with protocol deviations will be tabulated by category 
and deviation for the safety set. Protocol deviations will be listed with date and study day of 
occurrence, deviation code and severity code for the safety set. 
The number of patients included in safety set will be tabulated for all screened patients by 
number and percentage. Subject exclusion from analysis sets will be listed for all patients with 
reasons of exclusion (i.e., both protocol and non-protocol deviation). 
2.3.3 
Background and demographic characteristics 
Demographics data (except sex and age) and baseline characteristics are collected from the 
CACZ885G2301E1, CACZ885N2301 or CACZ885G2306 study. Sex and date of birth will 
be re-collected in the CRF. The following demographic characteristics collected in the CRF at 
screening will be summarized using the Safety set. 
Continuous variables: 
 Age (years) 
Categorical variables: 
 Age group (years)  (  ≥2 - <4, ≥4 - <6,  ≥6 - <12,  ≥12 - <20) 
 Sex (Male, Female) 
 Race (Caucasian, Black, Asian, Native  American, Pacific Islander, Other) 
The following baseline disease characteristics will be summarized using the Safety set. 
 Steroid (oral) free at baseline( Yes, No) 
 Median dose of steroid 
 MTX free at baseline(Yes, No) 
 
C-reactive protein (mg/L) 
 
The below information will be included for (SJIA ) 
 Number of active joints 
 Number active joints(≤ 26, >26) 
 Number of joints with limitation of motion  
2.3.4 
Medical history and current medical condition 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
terminology (MedDRA version 18.1 and above). History/conditions will be summarized for 
the safety set by primary system organ class and preferred term. Verbatim recorded 
history/conditions will be listed together with the coded terms, date of diagnosis/surgery and 
whether the problem was ongoing at start of the study ACZ885FR01.  
All medical history data will be taken from the the CACZ885G2301E1, CACZ885N2301 or 
CACZ885G2306 study.  
 


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2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
The maximal total single dose of canakinumab (ACZ885) allowed is 300 mg, which is 
administered as two subcutaneous 150 mg injections once every 4 weeks. 
The canakinumab dose interval (i.e. every 6, 8 or 12 weeks) may also be prolonged in patients 
with adequate response according to the clinical response and investigators judgment. 
 
The extent of exposure will be examined to determine the degree to which safety can be 
assessed for canakinumab (ACZ885). The extent of exposure to study drug will be 
characterized according to the duration of exposure and the number of patients exposed. 
Duration of exposure to the treatment will be calculated as the number of days between the 
first dose date and the last dose date exposed to that treatment over the specified period in 
Ilaris (ACZ885GRR01) study, expressed as: Duration of exposure = ((Date of last known 
dose of study drug – Date of first dose of study drug) – Number of days interrupted) + 1.  
The duration of exposure (in days) and the cumulative volume administered (in mL) will be 
summarized with descriptive statistics (n, mean, median, standard deviation, minimum, 
maximum, Q1, Q3) for the safety set. 
The total number of doses (injections) administered, number of 2 mg/kg doses administered, 
number of 4 mg/kg doses administered will be summarized with number and percentage for 
overall, 2mg/kg and 4 mg/kg dose group for safety set. By subject listing along with dose date 
will be provided for safety set. 
The duration of exposure (in days) and number of injection will be summarized for the safety 
set as  
 a continuous variable with the standard descriptive statistics 
 a categorical variable for number of does (injections) administered classified into 
1-4, 5-8, 9-12, 13-16, 17-20, 21-24 with number and percentage for below group. 
o Number of doses (injections) administered 
o Number of 1 mg/kg q4w doses administered 
o Number of 2 mg/kg q4w doses administered 
o Number of 4 mg/kg q4w doses administered 
o Number of 2 mg/kg q8w doses administered 
o Number of 4 mg/kg q12w doses administered 
o Other dose administered 
o No dose administered 
 Number of subject and percentage at baseline, reduction in dose at end of study, 
increase in dose at end of study and stable dose with all dose amount. 


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 a continuous variable total cumulative volume injected with the standard descriptive 
statistics. 
2.4.2 
Prior, concomitant and post therapies 
 
Prior medications are those medications which were taken and stopped prior to the first dose 
of study drug in this study. 
Concomitant medications are those medications which were taken prior to and continued 
after the first dose of the study drug or those medication which were given at least once 
between the day of first dose of study treatment and the date of the last study visit.  
All prior and concomitant medications will be summarized for steroid, MTX and NSAIDS 
table seperataly. Medications started and stopped prior to study drug, and then taken again 
concomitantly will be included in both prior and concomitant summaries separately. 
All prior and concomitant medication will be coded using WHO drug dictionary with most 
updated version. The number and percentage of patients taking concomitant medications prior 
to start and after start of study drug will presented by ATC class and preferred term. Separate 
tables showed the frequencies and percentages of patients who took Methotrexate and Oral 
corticosteroids medications, also by ATC class and preferred term.  
All information collected will be listed by patient and visit using safety set. 
 
2.5 
Analysis of the primary objective 
Not applicable  
2.5.1 
Primary endpoint 
2.5.2 
Statistical hypothesis, model, and method of analysis 
2.5.3 
Handling of missing values/censoring/discontinuations 
2.5.4 
Supportive analyses 
2.6 
Analysis of the key secondary objective 
Not applicable 
2.6.1 
Key secondary endpoint 
2.6.2 
Statistical hypothesis, model, and method of analysis 
2.6.3 
Handling of missing values/censoring/discontinuations 
2.7 
Analysis of secondary efficacy objective(s) 
Not applicable 


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2.7.1 
Secondary endpoints 
2.7.2 
Statistical hypothesis, model, and method of analysis 
2.7.3 
Handling of missing values/censoring/discontinuations 
 
2.8 
Safety analyses 
Safety measurements include, Extent of exposure and adverse events. All safety endpoints 
will be summarized for the safety set. All data will be used in safety analyses; however, no 
imputation will be carried out for missing data.   
2.8.1 
Adverse events (AEs) 
Adverse events starting on or after the time of the first dose of study drug but not later than 7 
days (30 days in the case of a SAE) after the date of last dose of study drug taken or those AE 
present at baseline with increased severity will be classified as a TEAE and will be included 
in all summaries. AEs which started and ended prior to baseline and AEs which started prior 
to baseline but whose severity does not change post baseline will not be included in treatment 
emergent adverse event. In addition, all the treatment emergent AEs will also be listed. 
The by-patient listing includes, SOC/PT/Verbatim term, start date, end date, the severity of an 
AE, Seriousness ,whether or not an AE is related to study drug, and whether or not it is a 
serious AE, action taken with study drug, outcome, duration, discontinue from study. 
Duration will be calculated as end date – start date +1 and for ongoing last visit date – start 
date +1. 
 
2.8.1.1 
Adverse events of special interest / grouping of AEs 
AEs by primary system organ class and preferred term 
The number and percentage of patients who reported treatment emergent adverse events will 
be summarized for each primary system organ class and preferred term. Primary system organ 
classes will be sorted alphabetically and, within each primary system organ class, the 
preferred terms will be sorted in descending order of frequency.  
If a patient reported more than one adverse event with the same preferred term, the adverse 
event will be counted only once at the preferred term level. If a patient reported more than one 
adverse event within the same primary system organ class, the patient will be counted only 
once at the system organ class level.  
Treatment emergent adverse events will be presented in two parts:  
 Adverse events (including infections) 
 Infectious adverse events  


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AEs by severity 
All treatment emergent adverse events will be summarized by maximum severity for each 
primary system organ class and preferred term. If a patient reports more than one adverse 
event within the same primary system organ class, only one adverse event will be counted for 
that patient at the highest severity level in the total row for each primary system organ class. If 
a patient reported more than one adverse event with the same preferred term, the highest 
(maximum) severity will be presented.  
AEs suspected to be related to study drug 
The treatment emergent adverse events suspected to be related to the study drug (according to 
the investigators) will be summarized by primary system organ class and preferred term. 
Relationship to study drug is considered as suspected for those events where "Relationship to 
study drug" is answered by the investigator as "Suspected". 
AEs leading to permanent study drug discontinuation 
Treatment emergent adverse events leading to permanent study drug discontinuation will be 
summarized by primary system organ class and preferred term. 
Serious Adverse Event (SAE) 
Number and percentage of patients with serious adverse events, regardless of study drug 
relationship, will be presented by primary system organ class and preferred term. 
2.8.2 
Deaths 
All the deaths in the clinical database will be listed with the last dose date/visit, date of death 
and investigator-reported principal cause. Deaths occurring after the first dose of study 
treatment until 30 days after the date of last treatment will be summarized with numbers and 
percentages for safety set. 
2.8.3 
Laboratory data 
Baseline measurements for laboratory evaluations will be taken from the last visit of the 
CACZ885G2301E1, CACZ885N2301 or CACZ885G2306 study. 
All laboratory parameter  will be listed and summarized with standard descriptive statistics.   
 All lab value by laboratory  test category and parameter  name 
o BIOCHEM (BUN, GLUC etc) 
o HEMA (BAS,EOS etc) 
o URINE (UGLUCST, USPGR etc) 
2.8.4 
Other safety data 
Not applicable 
2.8.4.1 
ECG and cardiac imaging data 
Not applicable 


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2.8.4.2 
Vital signs 
Not applicable 
2.9 
Pharmacokinetic endpoints   
Not applicable 
2.10 
PD and PK/PD analyses 
Not applicable 
2.11 
Patient-reported outcomes 
Not applicable 
2.12 
Biomarkers 
Not applicable 
2.13 
Other Exploratory analyses 
Not applicable 
2.14 
Interim analysis 
Not applicable 
3 
Sample size calculation 
No sample size calculation was performed for this extension study which will include all eligible 
subjects who complete CACZ885G2301E1 or CACZ885N2301 study and meet the eligibility criteria. 
4 
Change to protocol specified analyses 
Not applicable 
5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study drug 
No imputation for study drug. 
5.1.2 
AE date imputation 
AE date imputation is based only on a comparison of the partial AE start date to the treatment 
start date.   


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1. If the AE start date year value is missing, the date uncertainty is too high to impute a 
rational date. Therefore, if the AE year value is missing, the imputed AE start date is set to 
NULL. 
2. If the AE start date year value is less than the treatment start date year value, the AE 
started before treatment. Therefore: 
a. If the AE year is less than the treatment year and the AE month is missing, the 
imputed AE start date is set to the mid-year point (01JulYYYY). 
b. Else if the AE year is less than the treatment year and the AE month is not missing, 
the imputed AE start date is set to the mid-month point (15MONYYYY). 
3. If the AE start date year value is greater than the treatment start date year value, the AE 
started after treatment.  Therefore: 
a. If the AE year is greater than the treatment year and the AE month is missing, the 
imputed AE start date is set to the year start point (01JanYYYY). 
b. Else if the AE year is greater than the treatment year and the AE month is not 
missing, the imputed AE start date is set to the month start point (01MONYYYY). 
4. If the AE start date year value is equal to the treatment start date year value: 
a. And the AE month is missing or the AE month is equal to the treatment start 
month, the imputed AE start date is set to one day after treatment start. 
b. Else if the AE month is less than the treatment start month, the imputed AE start 
date is set to the mid-month point (15MONYYYY). 
c. Else if the AE month is greater than the treatment start month, the imputed AE 
start date is set to the start month point (01MONYYYY). 
Table 1-2: AE date imputation 
 
MON 
MON < CFM 
MON = CFM 
MON > CFM 
 
MISSING 
YYYY 
MISSING NULL 
NULL 
NULL 
NULL 
 
Uncertain 
Uncertain 
Uncertain 
Uncertain 
YYYY < 
CFY 
( D ) = 01JULYYYY 
( C )= 15MONYYYY ( C )= 15MONYYYY ( C )= 15MONYYYY 
 
Before Treatment Start Before Treatment Start Before Treatment Start Before Treatment Start 
YYYY = 
CFY 
(B)= TRTSTD+1 
( C )= 15MONYYYY (A)= TRTSTD+1 
(A)= 01MONYYYY 
 
Uncertain 
Before Treatment Start Uncertain 
After Treatment Start 
YYYY > 
CFY 
(E)= 01JANYYYY 
(A)= 01MONYYYY 
(A)= 01MONYYYY 
(A)= 01MONYYYY 
 
After Treatment Start  After Treatment Start  After Treatment Start  After Treatment Start  
 
 
 
 
 
Before Treatment Start  
Partial indicates date prior to Treatment Start Date 
After Treatment Start  
Partial indicates date after Treatment Start Date 


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Uncertain 
Partial insufficient to determine relationship to Treatment Start Date 
LEGEND: 
(A) 
MAX(01MONYYYY,TRTSTD+1) 
 
(B) 
TRTSTD+1 
 
 
(C) 
15MONYYYY 
 
 
(D) 
01JULYYYY 
 
 
(E) 
01JANYYYY 
 
 
 
5.1.3 
Concomitant medication date imputation 
Concomitant medication (CMD) date imputation uses both a comparison of the partial CMD 
start date to the treatment start date, and the value of the CMDTYP1C flag (1, 2, or 3).  Event 
date comparisons to treatment start date are made based on the year and month values only 
(any day values are ignored) in Table 1-3 below. 
1. If the CMD start date year value is missing, the date will be imputed based on the 
CMDTYP1C flag value.  If the flag value is 1 or 3, the imputed CMD start date is set to 
one day before the treatment start date.  Else, if the flag value is missing or 2, the imputed 
CMD start date is set to one day after the treatment start date.  (Note that for some legacy 
data, the CMDTYP1C variable may not exist in the data.  When this happens and the 
CMD start date year value is missing, the imputed date value will be NULL.) 
2. If the CMD start date year value is less than the treatment start date year value, the CMD 
started before treatment.  Therefore: 
a. if the CMD year is less than the treatment year and the CMD month is missing, the 
imputed CMD start date is set to the mid-year point (01JulYYYY). 
b. Else if the CMD year is less than the treatment year and the CMD month is not 
missing, the imputed CMD start date is set to the mid-month point 
(15MONYYYY). 
If the CMD start date year value is greater than the treatment start date year value, the CMD 
started after treatment. Therefore: 
a. If the CMD year is greater than the treatment year and the CMD month is missing, 
the imputed CMD start date is set to the year start point (01JanYYYY). 
b. Else if the CMD year is greater than the treatment year and the CMD month is not 
missing, the imputed CMD start date is set to the month start point 
(01MONYYYY). 
3. If the CMD start date year value is equal to the treatment start date year value: 
a. and the CMD month is missing or the CMD month is equal to the treatment start 
month, 
i. 
If the flag value is 1 or 3, the imputed CMD start date is set to one day 
before the treatment start date. 


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ii. 
Else, if the flag value is missing or 2, the imputed CMD start date is set to 
one day after the treatment start date. 
a. Else if the CMD month is less than the treatment start month, the imputed CMD 
start date is set to the mid-month point (15MONYYYY). 
b. Else if the CMD month is greater than the treatment start month, the imputed 
CMD start date is set to the start month point (01MONYYYY). 
 
Table 1-3:  CMD date imputation 
 
 
MON MISSING 
MON < CFM 
MON = CFM 
MON > CFM 
YYYY 
MISSING (F) 
(F) 
(F) 
(F) 
 
Uncertain 
Uncertain 
Uncertain 
Uncertain 
YYYY < 
CFY 
(D)=01JULYYYY 
(C)=15MONYY 
(C)=15MONYY 
(C)=15MONYY 
 
Before Treatment Start 
Before Treatment Start Before Treatment Start 
Before Treatment Start 
YYYY = 
CFY 
(B) 
(C)=15MONYY 
(B) 
(A)=01MONYYYY 
 
Uncertain 
Before Treatment Start Uncertain 
After Treatment Start 
YYYY > 
CFY 
(E)= 01JANYYYY 
(A)=01MONYYYY 
(A)=01MONYYYY 
(A)=01MONYYYY 
 
After Treatment Start 
After Treatment Start After Treatment Start 
After Treatment Start 
 
Before Treatment Start  
Partial indicates date prior to Treatment Start Date 
After Treatment Start  
Partial indicates date after Treatment Start Date 
Uncertain 
Partial insufficient to determine relationship to Treatment Start Date 
         LEGEND: 
(A) 
MAX(01MONYYYY,TRTSTD+1) 
(B) 
 
IF CMDTYP1C IN (1,3) THEN TRTSTD-1 
     ELSE IF CMDTYP1C in(. , 2) THEN TRTSTD+1 
(C) 
15MONYYYY 
(D) 
01JULYYYY 
(E) 
01JANYYYY 
(F) 
IF CMDTYP1C IN (1,3) THEN TRTSTD-1 
    ELSE IF CMDTYP1C in  (. , 2) THEN TRTSTD+1 
 
5.2 
AEs coding/grading 
The verbatim term recorded on CRF will be identified as adverse event and will be coded by 
primary system organ class and preferred term using Medical Dictionary for Regulatory 
Activities (MedDRA) version 20.1 and above.   


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5.3 
Laboratory parameters derivations 
Not applicable  
 
5.4 
Statistical models 
This is an open-label single arm safety trial for patients and the data will be presented in 
descriptive manner. 
5.5 
Rule of exclusion criteria of analysis sets  
 
All protocol deviations defined at the start of the study are listed with associated population 
codes in below table. The list will be updated before CDBL. 
 
Protocol 
Deviation ID 
Protocol Deviation Description 
Population 
code 
I01 
Written informed consent was not obtained before performing any 
assessment.  
1 
M01 
Patient took prohibited concomitant medication 
0 
E01 
Pregnant or nursing female patients,where pregnancy is defined as 
state of a female after conception and until termination of 
gestation,confirmed by +ve hCG laboratory test or urinary 
pregnancy test 
0 
S01 
Canakinumab not administered as per protocol dosage different 
than 2mg/kg or 4 mg/kg 
0 
S02 
Canakinumab not aministered per protocol schedule. Difference 
between the dose on consecutive visits (dd-mmm-yyyy) and (dd-
mmm-yyyy) is not between 6 weeks to 8 weeks. 
0 
 
No treatment is taken. 
1 
 
6 
Reference 
Clinical Study Protocol CACZ885G2301E1: An open-label extension study of canakinumab 
(ACZ885) in patients with Systemic Juvenile Idiopathic Arthritis (SJIA) and active systemic 
manifestations who participated in studies ACZ885G2301 and ACZ885G2305; and response 
characterization study in canakinumab treatment-naïve patients with active SJIA with and 
without fever