A Randomized, Four-arm, Canakinumab Placebo-controlled, Participant, Investigator and Sponsor-blinded Study Investigating the Safety, Tolerability and Efficacy of Intra-articular Canakinumab Followed by Intra-articular LNA043 in Patients With Knee Osteoarthritis
Phase: PHASE2
Conditions: Knee Osteoarthritis
Sponsor: Novartis Pharmaceuticals

N o v arti s R e s e ar c h a n d D e v el o p m e nt  
L N A 0 4 3 
Cli ni c al Tri al Pr ot o c ol C L N A 0 4 3 A 1 2 2 0 3 / N C T 0 4 8 1 4 3 6 8
A r a n d o mi z e d, f o ur- ar m, c a n a ki n u m a b pl a c e b o- c o ntr oll e d, 
p arti ci p a nt, i n v e sti g at or a n d s p o n s or- bli n d e d st u d y 
i n v e sti g ati n g t h e s af ety, t ol er a bilit y a n d effi c a c y o f 
i ntr a-arti c ul ar c a n a ki n u m a b f oll o w e d b y i ntr a- arti c ul ar 
L N A 0 4 3 i n p ati e nt s wit h k n e e o st e o art hriti s 
D o c u m e nt t y p e:  
A m e n d e d Pr ot o c ol V er si o n  
E U D R A C T n u m b er:  
2 0 2 0 -0 0 3 6 3 1 -2 1  
V er si o n n u m b er:  
v 0 2  (Cl e a n ) 
Cli ni c al Tri al P h a s e:  
II a 
R el e a s e d at e:  
0 8 -D e c -2 0 2 2
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  
Cli ni c al Tri al Pr ot o c ol T e m pl at e V er si o n 3. 0 d at e d 3 1 -J a n -2 0 2 0  

N o v arti s  
C o nfi d e nti al  
P a g e 2  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
T a bl e of c o nt e nt s  
Ta ble of c o nte nts  ................................................................................................................. 2  
List of ta bles  ........................................................................................................................ 6  
List of fi g ures  ...................................................................................................................... 6  
List of a b bre viati o ns  ............................................................................................................ 7  
Gl ossar y of ter ms  ............................................................................................................... 1 0  
A me n d me nt 0 2 ( 0 8 -Dec -2 0 2 2)  .......................................................................................... 1 2  
A me n d me nt 0 1 ( 1 5 -Dec -2 0 2 1)  .......................................................................................... 1 4  
L ocal A me n d me nt 0 0 -H U. 0 1 ( 2 3 -N o v -2 0 2 1)  ................................................................... 1 8  
Pr ot oc ol s u m mar y  .............................................................................................................. 1 9  
1  
I ntr o d ucti o n ....................................................................................................................... 2 4  
1. 1   
Bac k gr o u n d  ............................................................................................................ 2 4  
1. 2   
P ur p ose  .................................................................................................................. 2 5  
2  
O bjecti ves a n d e n d p oi nts  ................................................................................................... 2 5  
2. 1   
Pri mar y esti ma n ds  ................................................................................................. 2 8  
2. 2   
Sec o n dar y esti ma n ds  ............................................................................................. 2 8  
3  
St u d y desi g n  ...................................................................................................................... 2 8  
4  
Rati o nale  ............................................................................................................................ 3 1  
4. 1   
Rati o nale f or st u d y desi g n  ..................................................................................... 3 1  
4. 2   
Rati o nale f or d ose/re gi me n a n d d urati o n of treat me nt  .......................................... 3 2  
4. 3   
Rati o nale f or c h oice of c o ntr ol dr u gs (c o m parat or/ place b o)  ................................. 3 3  
4. 4   
P ur p ose a n d ti mi n g of i nteri m a nal yses/ desi g n a da ptati o ns  .................................. 3 3  
4. 5   
Ris ks a n d be nefits  .................................................................................................. 3 3  
4. 5. 1   
Be nefits  ................................................................................................. 3 4  
4. 5. 2   
Ris ks ass ociate d wit h L N A 0 4 3  ............................................................. 3 4  
4. 5. 3   
Ris ks ass ociate d wit h ca na ki n u ma b  ...................................................... 3 6  
4. 5. 4   
Ris ks ass ociate d wit h i ma gi n g assess me nts  .......................................... 3 7  
4. 5. 5   
Bl o o d sa m ple v ol u me  ............................................................................ 3 8  
4. 6   
Rati o nale f or P u blic Healt h E mer ge nc y miti gati o n pr oce d ures  ............................ 3 8  
5  
St u d y P o p ulati o n  ............................................................................................................... 3 9  
5. 1   
I ncl usi o n criteria .................................................................................................... 3 9  
5. 2   
E xcl usi o n criteria  ................................................................................................... 4 0  
6  
Treat me nt  ........................................................................................................................... 4 4  
6. 1   
St u d y treat me nt  ...................................................................................................... 4 4  
6. 1. 1   
I n vesti gati o nal a n d c o ntr ol dr u gs .......................................................... 4 4  
6. 1. 2   
A d diti o nal st u d y treat me nts  .................................................................. 4 4  
6. 1. 3   
Treat me nt ar ms/ gr o u p  ........................................................................... 4 6  

N o v arti s  
C o nfi d e nti al  
P a g e 3  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
6. 2   
Ot her treat me nt(s)  .................................................................................................. 4 6  
6. 2. 1   
C o nc o mita nt t hera p y  ............................................................................. 4 6  
6. 2. 2   
Pr o hi bite d me dicati o n  ........................................................................... 4 7  
6. 2. 3   
Resc ue me dicati o n  ................................................................................ 4 8  
6. 2. 4   
Restricti o n f or st u d y partici pa nts  .......................................................... 4 8  
6. 3   
Partici pa nt n u m beri n g, treat me nt assi g n me nt, ra n d o mizati o n  .............................. 4 9  
6. 3. 1   
Partici pa nt n u m beri n g  ........................................................................... 4 9  
6. 3. 2   
Treat me nt assi g n me nt, ra n d o mizati o n  .................................................. 4 9  
6. 4   
Treat me nt bli n di n g  ................................................................................................ 5 0  
6. 4. 1   
Site pers o n nel  ........................................................................................ 5 1  
6. 4. 2   
S p o ns or staff or dele gate  ....................................................................... 5 1  
6. 5   
D ose escalati o n a n d d ose m o dificati o n .................................................................. 5 2  
6. 6   
A d diti o nal treat me nt g ui da nce  ............................................................................... 5 2  
6. 6. 1   
Treat me nt c o m plia nce  ........................................................................... 5 2  
6. 6. 2   
Rec o m me n de d treat me nt of a d verse e ve nts  .......................................... 5 2  
6. 6. 3   
E mer ge nc y brea ki n g of assi g ne d treat me nt c o de  .................................. 5 3  
6. 7   
Pre parati o n a n d dis pe nsati o n  ................................................................................. 5 3  
6. 7. 1   
Ha n dli n g of st u d y treat me nt a n d a d diti o nal treat me nt  .......................... 5 4  
6. 7. 2   
I nstr ucti o n f or prescri bi n g a n d ta ki n g st u d y treat me nt ......................... 5 4  
7  
I nf or me d c o nse nt pr oce d ures ............................................................................................ 5 4  
8  
Visit sc he d ule a n d assess me nts  ......................................................................................... 5 6  
8. 1   
Scree ni n g  ............................................................................................................... 6 5  
8. 1. 1   
Eli gi bilit y scree ni n g  .............................................................................. 6 5  
8. 1. 2   
I nf or mati o n t o be c ollecte d o n scree ni n g fail ures ................................. 6 6  
8. 1. 3   
Re -scree ni n g .......................................................................................... 6 7  
8. 2   
Partici pa nt de m o gra p hics/ ot her baseli ne c haracteristics  ....................................... 6 7  
8. 3   
Efficac y  .................................................................................................................. 6 8  
8. 3. 1   
K nee M RI  .............................................................................................. 6 8  
8. 3. 2   
Patie nt Re p orte d O utc o mes ( P R Os)  ...................................................... 7 1  
8. 3. 3  
 7 3  
8. 3. 4   
A p pr o priate ness of efficac y assess me nts  .............................................. 7 3  
8. 4   
Safet y  ..................................................................................................................... 7 4  
8. 4. 1   
P h ysical e xa mi nati o n, vital si g ns a n d hei g ht/ wei g ht  ............................ 7 4  
8. 4. 2   
La b orat or y e val uati o ns  .......................................................................... 7 5  
8. 4. 3   
Electr ocar di o gra m ( E C G)  ..................................................................... 7 6  
8. 4. 4   
Pre g na nc y a n d assess me nt of fertilit y  ................................................... 7 7  
8. 4. 5   
A p pr o priate ness of safet y meas ure me nts  .............................................. 7 7  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 4  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
8. 5   
A d diti o nal assess me nts  .......................................................................................... 7 7  
8. 5. 1   
P har mac o ki netics  .................................................................................. 7 7  
8. 5. 2  
 7 8  
8. 5. 3   
I m m u n o ge nicit y .................................................................................... 8 1  
8. 5. 4  
 8 2  
9  
St u d y disc o nti n uati o n a n d c o m pleti o n  .............................................................................. 8 2  
9. 1   
Disc o nti n uati o n a n d c o m pleti o n  ............................................................................ 8 2  
9. 1. 1   
St u d y treat me nt disc o nti n uati o n a n d st u d y disc o nti n uati o n .................. 8 2  
9. 1. 2   
Wit h dra wal of i nf or me d c o nse nt  ........................................................... 8 4  
9. 1. 3   
L ost t o f oll o w -u p  ................................................................................... 8 4  
9. 1. 4   
St u d y st o p pi n g r ules  .............................................................................. 8 5  
9. 1. 5   
Earl y st u d y ter mi nati o n b y t he s p o ns or  ................................................. 8 5  
9. 2   
St u d y c o m pleti o n a n d p ost -st u d y treat me nt .......................................................... 8 6  
1 0  Safet y m o nit ori n g a n d re p orti n g  ........................................................................................ 8 6  
1 0. 1  
Defi niti o n of a d verse e ve nts a n d re p orti n g re q uire me nts  ...................................... 8 6  
1 0. 1. 1   
A d verse e ve nts  ...................................................................................... 8 6  
1 0. 1. 2   
Seri o us a d verse e ve nts  .......................................................................... 8 7  
1 0. 1. 3   
S A E re p orti n g ........................................................................................ 8 8  
1 0. 1. 4   
Pre g na nc y re p orti n g  .............................................................................. 8 9  
1 0. 1. 5   
Re p orti n g of st u d y treat me nt err ors i ncl u di n g mis use/a b use  ................ 8 9  
1 0. 2  
A d diti o nal Safet y M o nit ori n g  ................................................................................ 9 0  
1 0. 2. 1   
Li ver safet y m o nit ori n g  ......................................................................... 9 0  
1 0. 2. 2   
Re nal safet y m o nit ori n g  ........................................................................ 9 1  
1 1  Data C ollecti o n a n d Data base ma na ge me nt  ...................................................................... 9 1  
1 1. 1  
Data c ollecti o n  ....................................................................................................... 9 1  
1 1. 2  
Data base ma na ge me nt a n d q ualit y c o ntr ol  ............................................................ 9 2  
1 1. 3  
Site m o nit ori n g  ...................................................................................................... 9 2  
1 2  Data a nal ysis a n d statistical met h o ds  ................................................................................ 9 3  
1 2. 1  
A nal ysis sets  .......................................................................................................... 9 3  
1 2. 2  
Partici pa nt de m o gra p hics a n d ot her baseli ne c haracteristics  ................................. 9 3  
1 2. 3  
Treat me nts  ............................................................................................................. 9 4  
1 2. 4  
A nal ysis of t he pri mar y e n d p oi nt(s)/esti ma n d(s)  .................................................. 9 4  
1 2. 4. 1   
Defi niti o n of pri mar y e n d p oi nt(s)  ......................................................... 9 4  
1 2. 4. 2   
Statistical m o del, h y p ot hesis, a n d met h o d of a nal ysis  .......................... 9 4  
1 2. 4. 3   
Ha n dli n g of missi n g val ues n ot relate d t o i nterc urre nt e ve nt  ............... 9 5  
1 2. 5  
A nal ysis of sec o n dar y e n d p oi nts/esti ma n ds  .......................................................... 9 5  
1 2. 5. 1   
Efficac y a n d/ or P har mac o d y na mic e n d p oi nt(s)  .................................... 9 5  
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 5  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
1 2. 5. 2   
Safet y e n d p oi nts  .................................................................................... 9 7  
1 2. 5. 3   
P har mac o ki netics  .................................................................................. 9 8  
1 2. 5. 4   
I m m u n o ge nicit y .................................................................................... 9 9  
1 2. 6  
A nal ysis of e x pl orat or y e n d p oi nts  ......................................................................... 9 9  
1 2. 6. 1  
 9 9  
1 2. 6. 2  
 9 9  
1 2. 6. 3  
 9 9  
1 2. 7  
I nteri m a nal yses ..................................................................................................... 9 9  
1 2. 8  
Sa m ple size calc ulati o n ........................................................................................ 1 0 0  
1 2. 8. 1   
Pri mar y e n d p oi nt(s)  ............................................................................. 1 0 0  
1 3  Et hical c o nsi derati o ns a n d a d mi nistrati ve pr oce d ures  .................................................... 1 0 0  
1 3. 1  
Re g ulat or y a n d et hical c o m plia nce  ...................................................................... 1 0 0  
1 3. 2  
Res p o nsi bilities of t he i n vesti gat or a n d I R B/I E C  ................................................ 1 0 0  
1 3. 3  
P u blicati o n of st u d y pr ot oc ol a n d res ults ............................................................. 1 0 1  
1 3. 4  
Q ualit y C o ntr ol a n d Q ualit y Ass ura nce  ............................................................... 1 0 1  
1 4  Pr ot oc ol a d here nce  .......................................................................................................... 1 0 1  
1 4. 1  
Pr ot oc ol a me n d me nts ........................................................................................... 1 0 2  
1 5  Refere nces  ....................................................................................................................... 1 0 3  
1 6  A p pe n dices  ...................................................................................................................... 1 0 7  
1 6. 1  
A p pe n di x 1: Li ver e ve nt a n d la b orat or y tri g ger defi niti o ns & f oll o w -u p 
re q uire me nts ........................................................................................................ 1 0 7  
1 6. 2  
A p pe n di x 2: S pecific Re nal Alert Criteria a n d Acti o ns a n d E ve nt F oll o w -u p  .... 1 1 0  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 6  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
Li st of t a bl e s  
Ta ble 2 -1   
O bjecti ves a n d relate d e n d p oi nts  .......................................................... 2 5  
Ta ble 6 -1   
I n vesti gati o nal a n d c o ntr ol dr u g ............................................................ 4 4  
Ta ble 6 -2   
Basic pai n me dicati o n  ........................................................................... 4 5  
Ta ble 6 -3   
Pr o hi bite d me dicati o n  ........................................................................... 4 7  
Ta ble 6 -4   
Bli n di n g le vels  ...................................................................................... 5 0  
Ta ble 8 -1   
Assess me nt Sc he d ule  ............................................................................ 5 7  
Ta ble 8 -2   
Assess me nts a n d S pecificati o ns  ............................................................ 7 4  
Ta ble 8 -3   
La b orat or y e val uati o ns  .......................................................................... 7 6  
Ta ble 1 2 -1   
N o n -c o m part me ntal p har mac o ki netic para meters  ................................ 9 8  
Ta ble 1 6 -1   
Li ver e ve nt a n d la b orat or y tri g ger defi niti o ns  .................................... 1 0 7  
Ta ble 1 6 -2   
F oll o w u p re q uire me nts f or li ver la b orat or y tri g gers - A L T, A S T, 
T B L  ..................................................................................................... 1 0 8  
Ta ble 1 6 -3   
F oll o w u p re q uire me nts f or li ver la b orat or y –  Is olate d 
H y per bilir u bi ne mia  ............................................................................. 1 0 9  
Ta ble 1 6 -4   
S pecific Re nal Alert Criteria a n d Acti o ns  ........................................... 1 1 0  
Ta ble 1 6 -5   
Re nal E ve nt F oll o w U p  ....................................................................... 1 1 1  
Li st of fi g ur e s  
Fi g ure 3 -1   
St u d y desi g n  .......................................................................................... 3 0  
Fi g ure 8 -1   
Q Tc F f or m ula  ........................................................................................ 7 6  
 

N o v arti s  
C o nfi d e nti al  
P a g e 7  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
Li st of a b br e vi ati o n s  
A D A  
A nti -Dr u g A nti b o d y  
A E  
A d v er s e E v e nt  
A L P  
Al k ali n e P h o s p h at a s e  
A L T  
Al a ni n e A mi n otr a n sf er a s e  
A N G P T L 3   
A n gi o p o eiti n -li k e Pr ot ei n 3 
A S T  
A s p art at e A mi n otr a n sf er a s e  
A T C  
A n at o mi c al T h er a p e uti c C h e mi c al  
A U C  
Ar e a U n d er t h e C ur v e  
B MI  
B o d y M a s s I n d e x  
 
 
B U N  
Bl o o d Ur e a Nitr o g e n  
C C  
C h o n dr o c al ci n o si s  
C DI S C   
Cli ni c al D at a I nt er c h a n g e St a n d ar d s C o n s orti u m  
C M O & P S   
C hi ef M e di c al Offi c e a n d P ati e nt S af et y  
C R F  
C a s e R e p ort/ R e c or d F or m ( p a p er or el e ctr o ni c)  
C R O  
C o ntr a ct R e s e ar c h Or g a ni z ati o n  
C R P  
C -R e a cti v e Pr ot ei n  
 
 
C V  
C o effi ci e nt of V ari ati o n  
D B P  
Di a st oli c Bl o o d Pr e s s ur e  
D C E -M RI   
D y n a mi c C o ntr a st E n h a n c e d M RI  
DI N  
Dr u g I n d u ct e d N e p hr ot o xi cit y  
D M O A D   
Di s e a s e M o dif yi n g O st e o art hriti s Dr u g  
E C G  
El e ctr o c ar di o gr a m  
E D C  
El e ctr o ni c D at a C a pt ur e  
F A S  
F ull A n al y si s S et  
F D A  
F o o d a n d Dr u g A d mi ni str ati o n  
FI H  
Fir st i n H u m a n  
f J S W 
Fi x e d J oi nt S p a c e Wi dt h  
F M A  
F e m or al M e di al A nt eri or  
F M C  
F e m or al M e di al C e ntr al  
F M P  
F e m or al M e di al P o st eri or  
F S H  
F olli cl e Sti m ul ati n g H or m o n e  
G A G  
Gl y c o s a mi n o gl y c a n  
G B C A   
G a d oli ni u m -B a s e d C o ntr a st A g e nt  
G C P  
G o o d Cli ni c al Pr a cti c e  
G F R  
Gl o m er ul ar Filtr ati o n R at e  
G G T  
G a m m a -Gl ut a m yl Tr a n sf er a s e  
 
 
G L P  
G o o d L a b or at or y Pr a cti c e  
G L D H   
Gl ut a m at e D e h y dr o g e n a s e  
C CI
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 8  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
h  
H o ur  
H A  
H y al ur o ni c A ci d  
H B s A g   
H e p atiti s B vir u s S urf a c e A nti g e n  
H B V  
H e p atiti s B Vir u s  
H C V  
H e p atiti s C Vir u s  
HI V  
H u m a n I m m u n o d efi ci e n c y Vir u s 
h s C R P   
hi g h s e n siti vit y C -R e a cti v e Pr ot ei n  
i. a. 
i ntr a-arti c ul ar  
i. v. 
I ntr a v e n o u s 
I B 
I n v e sti g at or’ s Br o c h ur e 
I C F 
I nf or m e d C o n s e nt F or m 
I C H 
I nt er n ati o n al C o u n cil f or H ar m o ni z ati o n of T e c h ni c al R e q uir e m e nt s f or 
P h ar m a c e uti c al s f or H u m a n U s e  
I C R S 
I nt er n ati o n al C artil a g e R e g e n er ati o n a n d J oi nt Pr e s er v ati o n S o ci et y 
I E C 
I n d e p e n d e nt Et hi c s C o m mitt e e 
I G 
I m m u n o g e ni cit y 
I L 
I nt erl e u ki n 
I N 
I n v e sti g at or N otifi c ati o n 
I N R 
I nt er n ati o n al N or m ali z e d R ati o 
 
 
I R B 
I n stit uti o n al R e vi e w B o ar d 
I R T 
I nt er a cti v e R e s p o n s e T e c h n ol o g y 
K L  
K ell gr e n -L a wr e n c e  
K O O S   
K n e e i nj ur y a n d O st e o art hriti s O ut c o m e S c or e  
L D H  
L a ct at e D e h y dr o g e n a s e  
L F T  
Li v er F u n cti o n T e st  
L L O Q   
L o w er Li mit of Q u a ntifi c ati o n  
M e d D R A   
M e di c al Di cti o n ar y f or R e g ul at or y A cti viti e s  
m g  
Milli gr a m( s)  
M CI D   
Mi ni m al Cli ni c all y I m p ort a nt Diff er e n c e  
m L  
Millilit er( s)  
M RI  
M a g n eti c R e s o n a n c e I m a gi n g  
N O A C s   
N e w Or al A nti c o a g ul a nt s  
N R S  
N u m eri c al R ati n g S c al e  
N S F  
N e p hr o g e ni c S y st e mi c Fi br o si s  
O A  
O st e o art hriti s  
O T C  
O v er -t h e-C o u nt er  
P C R  
P ol y m er a s e C h ai n R e a cti o n  
P D  
P h ar m a c o d y n a mi c( s)  
P K  
P h ar m a c o ki n eti c( s)  
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 9  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
P o C  
Pr o of of C o n c e pt  
P o M  
Pr o of of M e c h a ni s m  
P R N  
Pr o r e n at a ( L at. a s n e e d e d)  
P R O  
P ati e nt R e p ort e d O ut c o m e s  
P T  
Pr ot hr o m bi n ti m e  
 
 
q 4 w x 3   
D o s e a d mi ni str ati o n e v er y f o ur w e e k s, t hr e e ti m e s  
Q M S   
Q u alit y M a n a g e m e nt S y st e m  
Q o L  
Q u alit y of Lif e  
Q T c F   
Q T I nt er v al c orr e ct e d b y Fri d eri ci a’ s F or m ul a  
s. c.  
S u b c ut a n e o u s  
S A E  
S eri o u s A d v er s e E v e nt  
S A P  
St ati sti c al A n al y si s Pl a n  
S B P  
S y st oli c Bl o o d Pr e s s ur e  
S D  
St a n d ar d D e vi ati o n  
SI  
Si g n al I nt e n sit y  
S N P  
Si n gl e N u cl e oti d e P ol y m or p hi s m  
S U S A R   
S u s p e ct e d U n e x p e ct e d S eri o u s A d v er s e R e a cti o n  
T A  
Tr e at m e nt Ar m  
T B  
T u b er c ul o si s  
T F C  
Ti bi of e m or al C o m p art m e nt  
U L N  
U p p er Li mit of N or m al  
U TI  
Uri n ar y Tr a ct I nf e cti o n  
W B C  
w hit e bl o o d c ell( s)  
W H O  
W orl d H e alt h Or g a ni z ati o n  
W o C  
Wit h dr a w al of C o n s e nt  
W O M A C   
W e st er n O nt ari o a n d M c M a st er U ni v er siti e s Art hriti s I n d e x  
W PI  
Wi d e s pr e a d P ai n I n d e x  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 0  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
Gl o s s ar y of t er m s  
A d diti o n al 
tr e at m e nt 
M e di ci n al pr o d u ct s t h at m a y b e u s e d d uri n g t h e cli ni c al tri al a s d e s cri b e d i n 
t h e pr ot o c ol, b ut n ot a s a n i n v e sti g ati o n al m e di ci n al pr o d u ct ( e. g. a n y 
b a c k gr o u n d t h er a p y)  
A s s e s s m e nt   
A pr o c e d ur e u s e d t o g e n er at e d at a r e q uir e d b y t h e tri al  
Bi ol o gi c S a m pl e s   
A bi ol o gi c al s p e ci m e n i n cl u di n g, f or e x a m pl e, bl o o d ( pl a s m a, s er u m), s ali v a, 
ti s s u e, uri n e, st o ol, et c. t a k e n fr o m a tri al p arti ci p a nt 
C o h ort  
A s p e cifi c gr o u p of p arti ci p a nt s f ulfilli n g c ert ai n crit eri a a n d g e n er all y tr e at e d at 
t h e s a m e ti m e 
C o ntr ol dr u g   
A st u d y dr u g ( a cti v e or pl a c e b o) u s e d a s a c o m p ar at or t o r e d u c e a s s e s s m e nt 
bi a s, pr e s er v e bli n di n g of i n v e sti g ati o n al dr u g, a s s e s s i nt er n al tri al v ali dit y, 
a n d/ or e v al u at e c o m p ar ati v e eff e ct s of t h e i n v e sti g ati o n al dr u g  
Di s c o nti n u ati o n 
fr o m st u d y 
P oi nt/ti m e w h e n t h e p arti ci p a nt p er m a n e ntl y st o p s r e c ei vi n g t h e st u d y 
tr e at m e nt a n d f urt h er pr ot o c ol r e q uir e d a s s e s s m e nt s or f oll o w-u p, f or a n y 
r e a s o n. N o s p e cifi c r e q u e st i s m a d e t o st o p t h e u s e of t h eir s a m pl e s or d at a. 
Di s c o nti n u ati o n 
fr o m st u d y 
tr e at m e nt 
P oi nt/ti m e w h e n t h e p arti ci p a nt p er m a n e ntl y st o p s r e c ei vi n g t h e st u d y 
tr e at m e nt f or a n y r e a s o n ( pri or t o t h e pl a n n e d c o m pl eti o n of st u d y dr u g 
a d mi ni str ati o n, if a n y). P arti ci p a nt a gr e e s t o t h e ot h er pr ot o c ol r e q uir e d 
a s s e s s m e nt s i n cl u di n g f oll o w -u p. N o s p e cifi c r e q u e st i s m a d e t o st o p t h e u s e 
of t h eir s a m pl e s or d at a.  
D o s a g e  
D o s e of t h e st u d y tr e at m e nt gi v e n t o t h e p arti ci p a nt i n a ti m e u nit ( e. g. 1 0 0 m g 
o n c e a d a y, 7 5 m g t wi c e a d a y)  
El e ctr o ni c D at a 
C a pt ur e ( E D C)  
El e ctr o ni c d at a c a pt ur e ( E D C) i s t h e el e ctr o ni c a c q ui siti o n of cli ni c al tri al d at a 
u si n g d at a c oll e cti o n s y st e m s, s u c h a s W e b -b a s e d a p pli c ati o n s, i nt er a cti v e 
v oi c e r e s p o n s e s y st e m s a n d cli ni c al l a b or at or y i nt erf a c e s. E D C i n cl u d e s t h e 
u s e of El e ctr o ni c C a s e R e p ort F or m s ( e C R F s) w hi c h ar e u s e d t o c a pt ur e d at a 
tr a n s cri b e d fr o m s o ur c e d at a/ d o c u m e nt s u s e d at t h e p oi nt of c ar e 
E n d of t h e cli ni c al 
tri al 
T h e e n d of t h e cli ni c al tri al i s d efi n e d a s t h e l a st vi sit of t h e l a st p arti ci p a nt  
E nr oll m e nt   
P oi nt/ti m e of p arti ci p a nt e ntr y i nt o t h e st u d y at w hi c h i nf or m e d c o n s e nt m u st 
b e o bt ai n e d  
H e alt h y v ol u nt e er   
A p er s o n wit h n o k n o w n si g nifi c a nt h e alt h pr o bl e m s w h o v ol u nt e er s t o b e a 
st u d y p arti ci p a nt  
I n v e sti g ati o n al 
dr u g/ tr e at m e nt  
T h e dr u g w h o s e pr o p erti e s ar e b ei n g t e st e d i n t h e st u d y  
Ktr a n s  
A m e a s ur e of c a pill ar y p er m e a bilit y o bt ai n e d u si n g d y n a mi c c o ntr a st -
e n h a n c e d ( D C E) M R p erf u si o n.  It i s c al c ul at e d b y m e a s uri n g t h e 
a c c u m ul ati o n of g a d oli ni u m -b a s e d c o ntr a st a g e nt i n t h e e xtr a v a s c ul ar -
e xtr a c ell ul ar s p a c e.  
Mi s -r a n d o mi z e d 
p arti ci p a nt s  
Mi s -r a n d o mi z e d p arti ci p a nt s ar e t h o s e w h o w er e n ot q u alifi e d f or 
r a n d o mi z ati o n a n d w h o di d n ot t a k e st u d y tr e at m e nt, b ut h a v e b e e n 
i n a d v ert e ntl y r a n d o mi z e d i nt o t h e st u d y  
Ot h er tr e at m e nt   
Tr e at m e nt t h at m a y b e n e e d e d/ all o w e d d uri n g t h e c o n d u ct of t h e st u d y (i. e. 
c o n c o mit a nt or r e s c u e t h er a p y)  
P arti ci p a nt   
A tri al p arti ci p a nt ( c a n b e a h e alt h y v ol u nt e er or a p ati e nt)  
P arti ci p a nt n u m b er  
A u ni q u e n u m b er a s si g n e d t o e a c h p arti ci p a nt u p o n si g ni n g t h e i nf or m e d 
c o n s e nt. T hi s n u m b er i s t h e d efi niti v e, u ni q u e i d e ntifi er f or t h e p arti ci p a nt a n d 
s h o ul d b e u s e d t o i d e ntif y t h e p arti ci p a nt t hr o u g h o ut t h e st u d y f or all d at a 
c oll e ct e d, s a m pl e l a b el s, et c.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 1  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
P ati e nt -R e p ort e d 
O ut c o m e ( P R O)  
A m e a s ur e m e nt b a s e d o n a r e p ort t h at c o m e s dir e ctl y fr o m t h e p ati e nt a b o ut 
t h e st at u s of a p arti ci p a nt' s h e alt h c o n diti o n wit h o ut a m e n d m e nt or 
i nt er pr et ati o n of t h e p ati e nt' s r e p ort b y a cli ni ci a n or a n y o n e el s e 
P eri o d  
T h e s u b di vi si o n s of t h e tri al d e si g n ( e. g. S cr e e ni n g, Tr e at m e nt, F oll o w -u p) 
w hi c h ar e d e s cri b e d i n t h e Pr ot o c ol. P eri o d s d efi n e t h e st u d y p h a s e s a n d will 
b e u s e d i n cli ni c al tri al d at a b a s e s et u p a n d e v e nt u all y i n a n al y si s  
P er s o n al d at a   
P arti ci p a nt i nf or m ati o n c oll e ct e d b y t h e I n v e sti g at or t h at i s c o d e d a n d 
tr a n sf err e d t o N o v arti s f or t h e p ur p o s e of t h e cli ni c al tri al. T hi s d at a i n cl u d e s 
p arti ci p a nt i d e ntifi er i nf or m ati o n, st u d y i nf or m ati o n a n d bi ol o gi c al s a m pl e s.  
R a n d o mi z ati o n   
T h e pr o c e s s of a s si g ni n g tri al p arti ci p a nt s t o i n v e sti g ati o n al dr u g or 
c o ntr ol/ c o m p ar at or dr u g u si n g a n el e m e nt of c h a n c e t o d et er mi n e t h e 
a s si g n m e nt s i n or d er t o r e d u c e bi a s  
R a n d o mi z ati o n 
n u m b er  
A u ni q u e i d e ntifi er a s si g n e d t o e a c h r a n d o mi z e d p arti ci p a nt  
R e -s cr e e ni n g   
If a p arti ci p a nt f ail s t h e i niti al s cr e e ni n g a n d i s c o n si d er e d a s a S cr e e n F ail ur e, 
h e/ s h e c a n b e i n vit e d o n c e f or a n e w S cr e e ni n g vi sit aft er m e di c al j u d g m e nt 
a n d a s s p e cifi e d b y t h e pr ot o c ol  
R e m ot e  
D e s cri b e s a n y tri al a cti viti e s p erf or m e d at a l o c ati o n t h at i s n ot t h e i n v e sti g at or 
sit e w h er e t h e i n v e sti g at or will c o n d u ct t h e tri al, b ut i s f or e x a m pl e a h o m e or 
a n ot h er a p pr o pri at e l o c ati o n  
S cr e e n F ail ur e   
A p arti ci p a nt w h o di d n ot m e et o n e or m or e crit eri a t h at w er e r e q uir e d f or 
p arti ci p ati o n i n t h e st u d y  
S o ur c e 
D at a/ D o c u m e nt  
S o ur c e d at a r ef er s t o t h e i niti al r e c or d, d o c u m e nt, or pri m ar y l o c ati o n fr o m 
w h er e d at a c o m e s. T h e d at a s o ur c e c a n b e a d at a b a s e, a d at a s et, a 
s pr e a d s h e et or e v e n h ar d -c o d e d d at a, s u c h a s p a p er or e S o ur c e  
St art of t h e cli ni c al 
tri al 
T h e st art of t h e cli ni c al tri al i s d efi n e d a s t h e si g n at ur e of t h e i nf or m e d c o n s e nt 
b y t h e fir st p arti ci p a nt  
St u d y tr e at m e nt   
A n y dr u g or c o m bi n ati o n of dr u g s or i nt er v e nti o n a d mi ni st er e d t o t h e st u d y 
p arti ci p a nt s a s p art of t h e r e q uir e d st u d y pr o c e d ur e s; i n cl u d e s i n v e sti g ati o n al 
dr u g( s), c o ntr ol( s) or b a c k gr o u n d t h er a p y  
St u d y tr e at m e nt 
di s c o nti n u ati o n  
W h e n t h e p arti ci p a nt p er m a n e ntl y st o p s t a ki n g a n y of t h e st u d y dr u g( s) pri or 
t o t h e d efi n e d st u d y tr e at m e nt c o m pl eti o n d at e (if a n y) f or a n y r e a s o n; m a y or 
m a y n ot al s o b e t h e p oi nt/ti m e of st u d y di s c o nti n u ati o n  
Tr e at m e nt 
ar m/ gr o u p  
A tr e at m e nt ar m/ gr o u p d efi n e s t h e d o s e a n d r e gi m e n or t h e c o m bi n ati o n, a n d 
m a y c o n si st of 1 or m or e c o h ort s.  
Tr e at m e nt of 
i nt er e st 
T h e tr e at m e nt of i nt er e st a n d, a s a p pr o pri at e, t h e alt er n ati v e tr e at m e nt t o 
w hi c h c o m p ari s o n will b e m a d e. T h e s e mi g ht b e i n di vi d u al i nt er v e nti o n s, 
c o m bi n ati o n s of i nt er v e nti o n s a d mi ni st er e d c o n c urr e ntl y, e. g. a s a d d -o n t o 
st a n d ar d of c ar e, or mi g ht c o n si s t of a n o v er all r e gi m e n i n v ol vi n g a c o m pl e x 
s e q u e n c e of i nt er v e nti o n s. T hi s i s t h e tr e at m e nt of i nt er e st u s e d i n d e s cri bi n g 
t h e r el at e d cli ni c al q u e sti o n of i nt er e st, w hi c h mi g ht or mi g ht n ot b e t h e s a m e 
a s t h e st u d y tr e at m e nt.  
V ari a bl e ( or 
e n d p oi nt)  
T h e v ari a bl e ( or e n d p oi nt) t o b e o bt ai n e d f or e a c h p arti ci p a nt t h at i s r e q uir e d 
t o a d dr e s s t h e cli ni c al q u e sti o n. T h e s p e cifi c ati o n of t h e v ari a bl e mi g ht i n cl u d e 
w h et h er t h e p arti ci p a nt e x p eri e n c e s a n i nt er c urr e nt e v e nt.  
Wit h dr a w al of 
st u d y c o n s e nt 
( W o C) /  
Wit h dr a w al of c o n s e nt fr o m t h e st u d y o c c ur s o nl y w h e n a p arti ci p a nt d o e s n ot 
w a nt t o p arti ci p at e i n t h e st u d y a n y l o n g er a n d d o e s n ot all o w a n y f urt h er 
c oll e cti o n of p er s o n al d at a   

N o v arti s  
C o nfi d e nti al  
P a g e 1 2  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
A m e n d m e nt 0 2  (0 8 -D e c -2 0 2 2)   
A m e n d m e nt r ati o n al e  
T his a me n d me nt is ge nerate d t o clarif y per missi ble re-scree ni n g sce nari os a n d t o s pecif y t he 
re q uire d peri o d of c o ntrace pti o n use f or w o me n of c hil d-beari n g p ote ntial after t he last 
i n vesti gati o nal dr u g a d mi nistrati o n . T he a me n d me nt als o descri bes a n Inf or me d C o nse nt F or m 
use d f or healt h y v ol u nteers d uri n g t he 
M RI q ualificati o n pr ocess, if re q uire d b y l ocal 
re g ulati o ns. 
T he pre vi o us pr ot oc ol versi o n all o we d re -scree ni n g of patie nts base d o n case-b y -case 
a gree me nt bet wee n t he i n vesti gat or a n d s p o ns or. T o a v oi d s u bjecti ve or i nc o nsiste nt 
i nter pretati o ns, t he pr ot oc ol n o w descri bes m ore s pecific sce nari os w he n re-scree ni n g is 
per missi ble . 
T he pr ot oc ol has bee n u p date d t o ali g n wit h t he S u m mar y of Pr o d uct C haracteristics  ( S m P C) 
of Ilaris®  (ca na ki n u ma b) w hic h  states t hat w o me n  of c hil d -beari n g p ote ntial s h o ul d use a n 
effecti ve c o ntrace pti ve  met h o d  f or u p t o 3 m o nt hs after t he last d ose.  
 
 
 T he hs C R P i ncl usi o n criteri o n has bee n u p date d acc or di n gl y 
(criteri o n 1 1), 
. T he pre vi o us 
t hres h ol d of ≥2 .0 m g / L has bee n esta blis he d  f or e val uati o n of car di o vasc ular ris ks a n d t heref ore 
less a p plica ble t o t his st u d y.  
C h o n dr ocalci n osis has bee n re m o ve d fr o m t he e xa m ples of e xcl usi o nar y c o n diti o ns (e xcl usi o n 
criteri o n 8)  beca use it was c o ntra dict or y t o  Secti o n 8. 2 , w hic h c orrectl y descri bes t hat 
i nf or mati o n a b o ut c h o n dr ocalci n osis will be c ollecte d as part of t he participa nt’s baseli ne 
c haracteristics.  
A n i nc o nsiste nc y i n t he pre vi o us pr ot oc ol versi o n bet wee n Secti o n 5. 1  (i ncl usi o n criteri o n 1 0), 
Secti o n 5. 2  (e xcl usi o n criteri o n 1 8) a n d  Ta ble 6 -3 , wit h re gar ds t o t he pr o hi biti o n peri o d f or 
gl uc osa mi ne, c h o n dr oiti n a n d ot her n utrace uticals wit h cartila ge -relate d effect, has bee n 
c orrecte d b y c o nsiste ntl y refer t o 4 wee ks fr o m Da y 1.  
If all o we d b y l ocal re g ulati o ns, a healt h y v ol u nteer M RI sca n ma y be  c ollecte d d uri n g set -u p 
f or t he i ma gi n g q ualificati o n of a n i n vesti gat or site. F or t his p ur p ose, a se parate I nf or me d 
C o nse nt F or m has bee n create d a n d ma de a vaila ble t o t he i ma gi n g ce nters as c o urtes y  i n case 
t he y d o n ot ha ve t heir o w n preferre d te m plate .  
Mi n or e dit orial c ha n ges are 
als o ma de t hr o u g h o ut t he pr ot oc ol f or i ncrease d clarit y a n d 
c o nsiste nc y. 
At t he ti me of a me n d me nt, t he st u d y is acti vel y recr uiti n g. T he first partici pa nt was scree ne d 
o n 2 7 A u g 2 0 2 1. Se ve n partici pa nt s ha ve  c o m me nce d st u d y treat me nt.  
Scree ni n g s h o ul d c o nti n ue at a site u n der t he pr ot oc ol versi o n 0 1 u ntil a p plica ble a p pr o vals 
ha ve bee n o btai ne d f or t he a me n d me nt, a n d all re q uire d d oc u me nts a n d material ha ve bee n 
pr o vi de d t o t he site.   
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 3  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
C h a n g e s t o t h e pr ot o c ol  
C ha n ges t o s pecific secti o ns of t he pr ot oc ol are s h o w n i n t he trac k c ha n ges versi o n of t he 
pr ot oc ol usi n g stri ke t hr o u g h re d f o nt f or deleti o ns a n d re d u n derli ne f or i nserti o ns.  
 
I R B s/I E C s 
A c o p y of t his a me n de d pr ot oc ol 
will be se nt t o t he I nstit uti o nal 
Re vie w 
B oar d 
(I R Bs)/I n de pe n de nt Et hics C o m mittee (I E Cs) a n d Healt h A ut h orities. 
T he c ha n ges descri be d i n t his a me n de d pr ot oc ol re q uire I R B/I E C a p pr o val pri or t o 
i m ple me ntati o n.  
T he c ha n ges herei n d o N O T affect t he gl o bal m o del Inf or me d C o nse nt  F or m . H o we ver, if t he 
mi ni m u m re q uire d peri o d of c o ntrace pti o n use after t he last i n vesti gati o nal treat me nt d ose has 
bee n s pecifie d i n a l ocall y a da pte d I nf or me d C o nse nt  F or m , t he site m ust c o nfir m t he c orrect 
peri o d is state d  t herei n, a n d if n ot, e ns ure a re vise d versi o n is a p pr o ve d .  
 
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 4  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
A m e n d m e nt 0 1 ( 1 5 -D e c -2 0 2 1)  
A m e n d m e nt r ati o n al e  
T his a me n d me nt is ge nerate d 
 
 
 
 
 
 
A n a d diti o nal sec o n dar y o bjecti ve is i ntr o d uce d i n or der t o i n vesti gate differe nces i n pai n 
e n d p oi nts bet wee n all t he f o ur treat me nt ar ms (als o c o m pari n g T A 3 vs T A 1 a n d T A 3 vs T A 4).  
 
 
 
T he  u p date d visit sc he d ule als o all o ws f or a n eli gi bilit y c o nfir mati o n pri or t o t he da y of 
first d ose, w hic h re d uces t he partici pa nt a n d site b ur de n c o m pare d t o disc o veri n g p ote ntial 
i neli gi bilit y o nl y at Da y 1. I n a d diti o n, t he scree ni n g perio d wi n d o w is pr ol o n ge d t o facilitate 
visit sc he d uli n g.  
T he i ncl usi o n criteri o n base d o n t he pai n diar y is si m plifie d t o e ns ure c orrect a n d c o nsiste nt 
i nter pretati o n. F urt her m ore, t he p o p ulati o n is br oa de ne d t o i ncl u de patie nts wit h K L gra de 2 -4 
( pre vi o usl y 2-3), si nce t he K L classificati o n has d oc u me nte d i nter -o bser ver varia bilit y a n d t he 
defi ne d ra n ges f or fJ S W will a v oi d t he i ncl usi o n of t o o a d va nce d cases.  
T he necessit y of e xcl u di n g a n acti ve or late nt t u berc ul osis ( T B) i nfecti o n, i n acc or da nce wit h 
t he Ilaris®  (ca na ki n u ma b) la bel, has bee n e m p hasize d. 
Vari o us secti o ns t hat descri be d miti gati o n pla ns i n case of a p ote ntial S A R S -C o V -2 o ut brea k 
are u p date d t o a m ore ge neral sce nari o of maj or disr u pti o n, s uc h as ot her pa n de mics or nat ural 
disasters.  
La b orat or y assess me nts a n d   
 are u p date d t o reflect c urre nt practice i n t he tar get 
p o p ulati o n.  
T he ma na ge me nt of assess me nts w he n a partici pa nt has ta ke n a pr o hi bite d pai n me dicati o n 
pri or t o a visit are u p date d t o a v oi d resc he d uli n g of t he e ntire visit.  
T he c o nse q ue nce f or t he i n di vi d ual partici pa nt i n case of u n bli n di n g of t he ca na ki n u ma b 
treat me nt is clarifie d. 
Ter mi n ol o g y is u p date d t hr o u g h o ut t he d oc u me nt t o ali g n wit h t he latest Cli nical Data 
I nterc ha n ge Sta n dar ds C o ns orti u m ( C DI S C) g ui da nce. 
Mi n or e dit orial c ha n ges are ma de t hr o u g h o ut t he pr ot oc ol f or i ncrease d clarit y a n d c o nsiste nc y.  
T he si m plificati o ns i ntr o d uce d b y t his a me n d me nt, i n partic ular t he eli gi bilit y c o nfir mati o n 
pri or t o first d ose a n d t he p ossi bilit y t o c o nti n ue wit h t he maj orit y of assess me nts des pite use 
of a pr o hi bite d pai n me dicati o n, are e x pecte d t o ha ve a p ositi ve i m pact o n visit c o m plia nce, site 
e n ga ge me nt a n d partici pa nt rete nti o n. T he a d de d P R Os are s h ort a n d s h o ul d t heref ore n ot 
C CI
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 5  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
 
At t he ti me of a me n d me nt, t he st u d y is acti vel y recr uiti n g. T he first partici pa nt was scree ne d 
o n 2 7 A u g 2 0 2 1. O ne partici pa nt has c o m me nce d st u d y treat me nt.  
Scree ni n g s h o ul d c o nti n ue at a site u n der t he ori gi nal pr ot oc ol versi o n u ntil a p plica ble a p pr o vals 
ha ve bee n o btai ne d f or t he a me n d me nt, a n d all re q uire d d oc u me nts a n d material ha ve bee n 
pr o vi de d t o t he site.  
C h a n g e s t o t h e pr ot o c ol  
C ha n ges t o s pecific secti o ns of t he pr ot oc ol are s h o w n i n t he trac k c ha n ges versi o n of t he 
pr ot oc ol usi n g stri ke t hr o u g h re d f o nt f or deleti o ns a n d re d u n derli ne f or i nserti o ns. T he  ke y 
c ha n ges are als o liste d bel o w.  
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 6  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 7  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
I R B s/I E C s 
A c o p y of t his 
a me n de d pr ot oc ol 
will be se nt t o t he I nstit uti o nal 
Re vie w 
B oar d 
(I R Bs)/I n de pe n de nt Et hics C o m mittee (I E Cs) a n d Healt h A ut h orities. 
T he c ha n ges descri be d i n t his a me n de d pr ot oc ol re q uire I R B/I E C a p pr o val pri or t o 
i m ple me ntati o n. 
T he c ha n ges herei n affect t he I nf or me d C o nse nt. Sites are re q uire d t o u p date a n d s u b mit f or 
a p pr o val a re vise d I nf or me d C o nse nt t hat ta kes i nt o acc o u nt t he c ha n ges descri be d i n t his 
pr ot oc ol a me n d me nt.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 8  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
L o c al A m e n d m e nt 0 0 -H U. 0 1 ( 2 3 -N o v -2 0 2 1)  
A m e n d m e nt r ati o n al e  
T his l ocal a me n d me nt is create d 
 
 
 
C ha n ges t o s pecific secti o ns are s h o w n i n t he trac k c ha n ges versi o n of t he pr ot oc ol usi n g stri ke 
t hr o u g h re d f o nt f or deleti o ns a n d re d u n derli ne d f or i nserti o ns. 
C h a n g e s t o t h e pr ot o c ol  
I R B s/I E C s 
A c o p y of t his a me n de d pr ot oc ol 
will be se nt t o t he I nstit uti o nal 
Re vie w 
B oar d 
(I R Bs)/I n de pe n de nt Et hics C o m mittee (I E Cs) 
 
T he c ha n ges descri be d i n t his a me n de d pr ot oc ol re q uire I R B/I E C a p pr o val pri or t o 
i m ple me ntati o n. 
C CI
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 9  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
Pr ot o c ol s u m m ar y  
Pr ot o c ol n u m b er   
L N A 0 4 3 A 1 2 2 0 3  
F ull Titl e  
A r a n d o mi z e d, f o ur -ar m, 
c a n a ki n u m a b 
pl a c e b o -c o ntr oll e d, 
p arti ci p a nt, 
i n v e sti g at or a n d s p o n s or-bli n d e d st u d y i n v e sti g ati n g t h e s af et y, t ol er a bilit y a n d 
effi c a c y of i ntr a -arti c ul ar c a n a ki n u m a b f oll o w e d b y i ntr a -arti c ul ar L N A 0 4 3 i n 
p ati e nt s wit h k n e e o st e o art hriti s  
Bri ef titl e  
A s af et y a n d effi c a c y st u d y of a nti -i nfl a m m at or y ( c a n a ki n u m a b) a n d c artil a g e 
sti m ul ati n g dr u g s ( L N A 0 4 3) i nj e ct e d i nt o t h e k n e e j oi nt of p arti ci p a nt s wit h k n e e 
o st e o art hriti s ( O A)  
S p o n s or a n d 
Cli ni c al P h a s e  
N o v arti s  
P h a s e II a  
I n v e sti g ati o n t y p e  
Bi ol o gi c  
St u d y t y p e   
I nt er v e nti o n al 
P ur p o s e a n d 
r ati o n al e 
T hi s i s a p h a s e 2 a pr o of of c o n c e pt st u d y wit h 4 tr e at m e nt ar m s ( T A 1-4) t o 
e st a bli s h t h e eff e ct of L N A 0 4 3 i n p ati e nt s wit h s y m pt o m ati c,  k n e e O A wit h 
i nfl a m m ati o n, d efi n e d b y M RI. T h e c h o n dr o -a n a b oli c eff e ct of L N A 0 4 3 gi v e n 
i. a. h a s b e e n e st a bli s h e d i n s e v er al k n e e O A st u di e s, b ut wit h o ut s p e cifi c all y
a d dr e s si n g k n e e O A wit h i nfl a m m ati o n.
T h e p ur p o s e of t h e c urr e nt st u d y i s  
• 
t o a s s e s s if t h e eff e ct of i. a. L N A 0 4 3 c a n b e e st a bli s h e d i n p ati e nt s wit h
i nfl a m m at or y k n e e O A
• 
t o a s s e s s if a p o s si bl e n e g ati v e eff e ct of i nfl a m m ati o n o n t h e p ot e nti al
p o siti v e eff e ct of L N A 0 4 3 i n c artil a g e r e g e n er ati o n c a n b e o v er c o m e b y
c o m bi n ati o n tr e at m e nt wit h a n a nti -i nfl a m m at or y t h er a p y (i. a.
c a n a ki n u m a b)
• 
t o a s s e s s t h e effi c a c y of i. a. c a n a ki n u m a b i n r eli e vi n g p ai n,
ot h er  cli ni c al  s y m pt o m s  a n d i m pr o vi n g f u n cti o n
C urr e nt m e di c al tr e at m e nt s of O A f o c u s o n a d dr e s si n g p ai n a n d t h er e ar e n o 
c h o n dr o -a n a b oli c tr e at m e nt s a v ail a bl e t o i n d u c e c artil a g e r e g e n er ati o n. 
L N A 0 4 3 h a s s h o w n c artil a g e a n a b oli c eff e ct s i n e arl y st a g e s of k n e e 
d e g e n er ati o n b ut it i s n ot k n o w n w h et h er L N A 0 4 3 will b e s uffi ci e nt t o 
e x p e diti o u sl y r e d u c e s y m pt o m s a n d r e b uil d str u ct ur e i n p ati e nt s 
wit h 
m o d er at e -s e v er e k n e e O A, w h er e c o n c urr e nt i ntr a arti c ul ar  i nfl a m m ati o n i s 
c o m m o n.  I n a n i nfl a m m at or y e n vir o n m e nt, d e gr a di n g e n z y m e s ar e a b u n d a nt 
a n d c h o n dr o c yt e s ar e l e s s r e s p o n si v e t o a n a b oli c sti m uli d u e t o m et a b oli c 
s h ut d o w n. I n hi biti n g t h e i nfl a m m ati o n wit h c a n a ki n u m a b b ef or e tr e ati n g t h e 
p ati e nt wit h L N A 0 4 3 mi g ht t h er ef or e aff e ct t h e c h o n dr o -a n a b oli c eff e ct.  
Pri m ar y 
O bj e cti v e( s) 
T hi s st u d y h a s t w o pri m ar y o bj e cti v e s;  
• 
T o a s s e s s t h e effi c a c y of q 4 w x 3 ( d o s e a d mi ni str ati o n e v er y f o ur w e e k s,
t hr e e ti m e s) i. a. i nj e cti o n s of L N A 0 4 3 v s. n o i nj e cti o n s of L N A 0 4 3, i n
m ai nt ai ni n g or r e g e n er ati n g arti c ul ar c artil a g e ti s s u e, b y m e a s uri n g t h e
c h a n g e fr o m b a s eli n e i n c artil a g e v ol u m e i n t h e i n d e x r e gi o n b y M RI at
D a y 1 9 7
• 
T o a s s e s s t h e effi c a c y of a si n gl e i. a. i nj e cti o n of c a n a ki n u m a b v s.
pl a c e b o i n r eli e vi n g O A p ai n, b y m e a s uri n g t h e c h a n g e fr o m b a s eli n e i n
K n e e i nj ur y a n d O st e o art hriti s O ut c o m e S c or e ( K O O S) P ai n s u b s c al e at
D a y 8 5

N o v arti s  
C o nfi d e nti al  
P a g e 2 0  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
S e c o n d ar y 
O bj e cti v e s  
• 
T o a s s e s s t h e s af et y a n d t ol er a bilit y of q 4 w x 3 i. a. i nj e cti o n s of L N A 0 4 3, a
si n gl e i. a. i nj e cti o n of c a n a ki n u m a b a n d a si n gl e i nj e cti o n of c a n a ki n u m a b
f oll o w e d b y q 4 w x 3 i. a. i nj e cti o n s of L N A 0 4 3 r el ati v e t o pl a c e b o t o
c a n a ki n u m a b/ n o L N A 0 4 3 i nj e cti o n s, b y e v al u ati n g A d v er s e E v e nt s, E C G,
vit al si g n s a n d st a n d ar d s af et y l a b or at or y a n al y s e s
• 
T o a s s e s s t h e p ot e nti al i m m u n o g e ni cit y of q 4 w x 3 i. a. i nj e cti o n s of
L N A 0 4 3, b y m e a s uri n g a nti -L N A 0 4 3 a nti b o di e s i n s er u m at D a y 1 5, 4 3,
8 5, 1 9 7 a n d 3 6 5
• 
T o a s s e s s e n d o g e n o u s A N G P T L 3, a n d P K of L N A 0 4 3, aft er q 4 w x 3 i. a.
i nj e cti o n s of L N A 0 4 3 a n d aft er a si n gl e i. a. i nj e cti o n of c a n a ki n u m a b
f oll o w e d b y q 4 w x 3 i. a. i nj e cti o n s of L N A 0 4 3, b y m e a s uri n g A N G P T L 3
s er u m c o n c e ntr ati o n s, A N G P T L 3 s y n o vi al fl ui d c o n c e ntr at i o n s a n d
L N A 0 4 3 P K pr ofil e i n s er u m ( C m a x, T m a x, A U C)
• 
T o a s s e s s t h e effi c a c y of a si n gl e i. a. i nj e cti o n of c a n a ki n u m a b f oll o w e d
b y q 4 w x 3 i. a. i nj e cti o n s of L N A 0 4 3 v s. a si n gl e i. a. i nj e cti o n of
c a n a ki n u m a b, i n r e g e n er ati n g arti c ul ar c artil a g e; a n d v s. o nl y q 4 w x 3 i a.
i nj e cti o n s of L N A 0 4 3, b y m e a s uri n g t h e c h a ng e i n c artil a g e v ol u m e a n d
t hi c k n e s s of t h e i n d e x r e gi o n b y M RI at D a y 1 9 7 a n d 3 6 5
• 
T o a s s e s s t h e effi c a c y of q 4 w x 3 i. a. i nj e cti o n s of L N A 0 4 3 v s. n o
i nj e cti o n s of L N A 0 4 3, i n m ai nt ai ni n g or r e g e n er ati n g arti c ul ar c artil a g e, b y
m e a s uri n g t h e c h a n g e i n c artil a g e t hi c k n e s s of t h e i n d e x r e gi o n b y M RI
at D a y 1 9 7, a n d t h e c h a n g e i n c artil a g e v ol u m e a n d t hi c k n e s s of t h e
i n d e x r e gi o n b y M RI at D a y 3 6 5
• 
T o a s s e s s t h e effi c a c y of a si n gl e i. a. i nj e cti o n of c a n a ki n u m a b v s.
pl a c e b o t o c a n a ki n u m a b, o n s y n o viti s, b y m e a s uri n g t h e c h a n g e i n
s y n o viti s l e v el m e a s ur e d fr o m Ktr a n s b y D C E -M RI at D a y 8 5
• 
T o a s s e s s t h e effi c a c y of a si n gl e i. a. i nj e cti o n of c a n a ki n u m a b v s.
pl a c e b o t o c a n a ki n u m a b, i n r eli e vi n g O A p ai n a n d i m pr o vi n g f u n cti o n
o v er ti m e, b y m e a s uri n g t h e c h a n g e i n n u m eri c r ati n g s c al e ( N R S) P ai n
at D a y 1 5, 2 9, 4 3, 5 7, 7 1 a n d 8 5, a n d t h e c h a n g e i n K O O S P ai n a n d
F u n cti o n i n d ail y li vi n g ( A D L) s u b s c al e s at D a y 1 5, 2 9, 4 3, 5 7, 7 1 a n d 8 5
• 
T o a s s e s s t h e effi c a c y of a si n gl e i. a. i nj e cti o n of c a n a ki n u m a b f oll o w e d
b y q 4 w x 3 i. a. i nj e cti o n s of L N A 0 4 3 v s. a si n gl e i. a. i nj e cti o n of
c a n a ki n u m a b, i n r eli e vi n g O A p ai n ( T A 3 v s. T A 4), a n d v s. o nl y q 4 w x 3 i. a.
i nj e cti o n s of L N A 0 4 3 ( T A 3 v s. T A 1), b y m e a suri n g t h e c h a n g e i n n u m eri c
r ati n g s c al e ( N R S) P ai n, a n d c h a n g e i n i n K O O S P ai n a n d A D L
s u b s c al e s, at D a y 1 5, 2 9, 4 3, 5 7, 7 1, 8 5, 1 9 7, 3 6 5
St u d y d e si g n   
T hi s i s a n o n -c o nfir m at or y, r a n d o mi z e d, f o ur ar m, pl a c e b o -c o ntr oll e d, 
p arti ci p a nt, i n v e sti g at or a n d s p o n s or bli n d e d ( wit h r e g ar d s t o c a n a ki n u m a b 
w h er e a s L N A 0 4 3 tr e at m e nt i s o p e n l a b el) st u d y i n p ati e nt s wit h k n e e O A.  
T h e st u d y i n cl u d e s a 1 0  w e e k  tr e at m e nt p eri o d d uri n g w hi c h p arti ci p a nt s 
r e c ei v e a m a xi m u m of f o ur i. a. i nj e cti o n s i nt o t h e k n e e. P arti ci p a nt s ar e 
f oll o w e d u p u ntil o n e y e ar aft er fir st d o s e. 
St u d y p o p ul ati o n   
T h e st u d y p o p ul ati o n c o n si st s of m al e a n d f e m al e a d ult p ati e nt s wit h mil d t o 
m o d er at e r a di o gr a p hi c 
k n e e  
O A ( K L 
gr a d e 
2 -4)  
wit h i nfl a m m ati o n. 
T h e  i nfl a m m ati o n 
will 
b e c o nfir m e d 
b y 
el e v at e d 
h s C R P ( ≥1. 8  m g/ L) 
a n d  o b s er v e d s y n o viti s o n M RI, at s cr e e ni n g. A p pr o xi m at el y 1 3 8 p ati e nt s ar e 
f or e s e e n t o b e e nr oll e d a n d r a n d o mi s e d i n t h e tri al, of w hi c h at l e a st 1 2 4 ar e 
e x p e ct e d t o c o m pl et e t h e D a y 1 9 7 e v al u ati o n ( 1 0 % di s c o nti n u ati o n r at e).  

N o v arti s  
C o nfi d e nti al  
P a g e 2 1  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
K e y I n cl u si o n 
crit eri a  
• 
M al e or f e m al e p ati e nt s 4 0 t o 8 0 y e ar s of a g e, i n cl u si v e
• 
Di a g n o si s of pri m ar y ti bi of e m or al k n e e O A b y st a n d ar d A m eri c a n C oll e g e
of R h e u m at ol o g y ( A C R) cli ni c al a n d r a di o gr a p hi c crit eri a
• 
M o d er at e t o s e v er e O A  p ai n ( c orr e s p o n di n g t o N R S P ai n ≥5 t o ≤9) i n t h e
t ar g et k n e e, c o nfir m e d b y;
• 
K O O S p ai n s u b s c al e < 6 0 f or t h e t ar g et  k n e e at S cr e e ni n g 1, S cr e e ni n g  2
a n d S cr e e ni n g 4
• 
R a di o gr a p hi c di s e a s e K L gr a d e 2 t o 4 k n e e O A a n d j oi nt s p a c e wi dt h
( J S W) 2. 0-4. 0 m m ( m e n) or 1. 5 -3. 5 m m ( w o m e n) i n t h e m e di al T F C i n
t h e t ar g et k n e e, c o nfir m e d b y X-r a y at S cr e e ni n g 1
• 
A cti v e s y n o vi al i nfl a m m ati o n, d efi n e d a s m o d er at e ( s c or e 9 -1 2) or s e v er e
( s c or e ≥1 3) a s p er c o ntr a st-e n h a n c e d M RI ( C E -M RI)  of t h e w h ol e k n e e
f or s y n o viti s d et e cti o n fr o m 1 1 sit e s at S cr e e ni n g 3
K e y E x cl u si o n 
crit eri a  
• 
Hi st or y of, or pl a n n e d, f o ll o wi n g s ur gi c al i nt er v e nti o n s;
• 
K n e e r e pl a c e m e nt ( p arti al or t ot al) i n eit h er k n e e
• 
Art hr o s c o p y or l a v a g e i n eit h er k n e e , wit hi n 6 m o nt h s pri or t o
S cr e e ni n g 1 or pl a n n e d d uri n g t h e st u d y
• 
A n y ot h er pr e vi o u s s ur gi c al i nt er v e nti o n i n t h e t ar g et k n e e, or wit hi n
1 2 m o nt h s pri or t o S cr e e ni n g 1 or pl a n n e d d uri n g t h e st u d y f or t h e
c o ntr al at er al k n e e, i n cl u di n g m o s ai c pl a st y, mi cr ofr a ct ur e,
m e ni s c e ct o m y > 5 0 % or o st e ot o m y
• 
O n s et of s y m pt o m s, or di a g n o si s, of pri m ar y o st e o art hriti s i n ot h er t h a n
t h e k n e e j oi nt s l e s s t h a n 3 m o nt h s pri or t o S cr e e ni n g 1
• 
M o d er at e t o s e v er e p ai n i n t h e c o ntr al at er al k n e e f or t h e m aj orit y of d a y s
i n t h e l a st 3 m o nt h s pri or t o S cr e e ni n g 1, a s p er p ati e nt j u d g m e nt
• 
U n a bl e or u n willi n g t o u n d er g o M RI, or h a vi n g c o ntr ai n di c ati o n s t o M RI
( e. g., m et alli c i m pl a nt s, m et alli c f or ei g n b o di e s, p a c e m a k er, d efi brill at or),
or h a vi n g c o ntr ai n di c ati o n s t o t h e u s e of g a d oli ni u m -b a s e d a g e nt s ( e. g.
p ati e nt s wit h pr e vi o u s s e v er e all er gi c/ a n a p h yl a ct oi d r e a cti o n t o a
g a d oli ni u m -b a s e d c o ntr a st a g e nt, m o d er at e t o s e v er e r e n al di s e a s e, or
a c ut el y d et eri or ati n g r e n al f u n cti o n)
• 
M al ali g n m e nt > 7. 5° i n t h e t ar g et k n e e ( eit h er v ar u s or v al g u s)
St u d y tr e at m e nt  
• 
L N A 0 4 3 1 0 m g, 
 i nj e cti o n, o p e n l a b el b ul k s u p pl y
• 
C a n a ki n u m a b 1 5 0 m g/ 1 m L, s ol uti o n f or i nj e cti o n ( 1 m L), o p e n l a b el b ul k
s u p pl y 
• 
C a n a ki n u m a b 0 m g/ 1 m L, pl a c e b o t o c a n a ki n u m a b s ol uti o n f or i nj e cti o n
( 1 m L), o p e n l a b el b ul k s u p pl y 
I n a d diti o n, it i s i m p er ati v e t o h ar m o ni z e a n d d o c u m e nt p arti ci p a nt s' p ai n 
m e di c ati o n a s it c a n p ot e nti all y c o nf o u n d r e s ult s. T h er ef or e, o nl y t h e u s e of 
p ar a c et a m ol/ a c et a mi n o p h e n, u p t o 3 0 0 0 m g/ d a y, al o n e or i n c o m bi n ati o n wit h 
l o w d o s e c o d ei n e, e. g. c o-c o d a m ol, i s all o w e d a s b a si c ( n o n -r e s c u e) 
m e di c ati o n f or p ai n c o ntr ol r e g ar dl e s s of t h e ori gi n of t h e p ai n, u p u ntil 
D a y  1 9 7. T hi s m e di c ati o n i s r ef err e d t o a s " b a si c p ai n m e di c ati o n" a n d t h e 
C CI
C CI
C CI
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 2 2  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
i n v e sti g at or will eit h er b e s u p pli e d wit h t h e b a si c p ai n m e di c ati o n or s o ur c e it 
l o c all y a n d b e r ei m b ur s e d b y t h e s p o n s or f or it s c o st, d e p e n di n g o n t h e 
c o u ntr y.  
Tr e at m e nt of 
i nt er e st 
P arti ci p a nt s will b e a s si g n e d t o o n e of t h e f oll o wi n g 4 tr e at m e nt ar m s ( T A) i n 
a r ati o of 1: 2: 1: 2:  
• 
T A 1: Si n gl e i. a. i nj e cti o n of pl a c e b o t o c a n a ki n u m a b f oll o w e d b y q 4 w x 3
i. a. i nj e cti o n s of 4 0 m g L N A 0 4 3
• 
T A 2: Si n gl e i. a. i nj e cti o n of pl a c e b o t o c a n a ki n u m a b
• 
T A 3: Si n gl e i. a. i nj e cti o n of 6 0 0 m g c a n a ki n u m a b f oll o w e d b y q 4 w x 3 i. a.
i nj e cti o n s of 4 0 m g L N A 0 4 3
• 
T A 4: Si n gl e i. a. i nj e cti o n of 6 0 0 m g c a n a ki n u m a b
Effi c a c y 
a s s e s s m e nt s  
• 
C artil a g e v ol u m e a n d t hi c k n e s s b y c o n v e nti o n al 3 T M RI
• 
S y n o viti s l e v el b y D y n a mi c C o ntr a st -E n h a n c e d M RI ( D C E -M RI)
• 
K n e e i nj ur y a n d O st e o art hriti s O ut c o m e S c or e ( K O O S); P ai n a n d
F u n cti o n i n d ail y li vi n g ( A D L) s u b s c al e s
• 
N u m eri c al R ati n g S c al e ( N R S)  P ai n
P h ar m a c o ki n eti c 
a s s e s s m e nt s  
• 
S y st e mi c ( s er u m) c o n c e ntr ati o n of e n d o g e n o u s A N G T P L 3, a n d L N A 0 4 3
• 
L o c al ( s y n o vi al fl ui d) c o n c e ntr ati o n of e n d o g e n o u s A N G P T L 3
K e y s af et y 
a s s e s s m e nt s  
• 
A d v er s e e v e nt m o nit ori n g
• 
P h y si c al e x a mi n ati o n s
• 
M o nit ori n g of l a b or at or y m ar k er s i n bl o o d a n d uri n e
• 
E C G
• 
Vit al si g n s
Ot h er 
a s s e s s m e nt s  
D at a a n al y si s   
T h e a n al y si s f or pri m ar y e n d p oi nt s will b e c arri e d o ut u si n g a mi x e d eff e ct 
m o d el f or r e p e at e d m e a s ur e s ( M M R M). T h e m o d el will i n cl u d e b a s eli n e a s 
fi x e d c o v ari at e, tr e at m e nt, ti m e p oi nt, tr e at m e nt * ti m e p oi nt s a s fi x e d eff e ct s 
a n d p arti ci p a nt a s r a n d o m eff e ct. A n u n str u ct ur e d c o v ari a n c e will b e a s s u m e d; 
if n ot p o s si bl e, ot h er a p pr o pri at e c o v ari a n c e str u ct ur e s will b e e x pl or e d s u c h 
a s  
A ut or e gr e s si v e ( A R( 1)),  
C o m p o u n d 
s y m m etr y, 
et c.  
A t w o -si d e d 
9 0 %  c o nfi d e n c e i nt er v al f or t h e tr e at m e nt eff e ct will b e f or m e d. A  st ati sti c all y 
si g nifi c a nt diff er e n c e ( o n e -si d e d p -v al u e < 0. 0 5) b et w e e n a cti v e dr u g a n d 
pl a c e b o at D a y 8 5 (f or A C Z) a n d D a y 1 9 7 (f or L N A) will b e c o n si d er e d a s a 
p o siti v e r e s ult.  
Si mil ar M M R M m o d el s a s f or t h e pri m ar y e n d p oi nt s will b e u s e d f or a n al y si s 
of s e c o n d ar y effi c a c y e n d p oi nt s.  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 2 3  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
D e m o gr a p hi c  
a n d  
ot h er  
b a s eli n e  
d at a,  
s af et y  
a s s e s s m e nt s  
a n d 
i m m u n o g e ni cit y will b e li st e d a n d s u m m ari z e d d e s cri pti v el y. 
P h ar m a c o ki n eti c p ar a m et er s f or L N A 0 4 3 will b e c al c ul at e d, a n d li st e d a n d 
s u m m ari z e d d e s cri pti v el y.  
C o n c o mit a nt m e di c ati o n s a n d si g nifi c a nt n o n -dr u g t h er a pi e s pri or t o a n d aft er 
t h e st art of t h e st u d y tr e at m e nt will b e li st e d a n d s u m m ari z e d a c c or di n g t o t h e 
A n at o mi c al T h er a p e uti c C h e mi c al ( A T C) cl a s sifi c ati o n s y st e m, b y tr e at m e nt 
gr o u p.  
K e y w or d s   
O st e o art hriti s;  
K n e e  
o st e o art hriti s; I nfl a m m ati o n;  
S y n o viti s;  
C artil a g e 
r e g e n er ati o n;  
D y n a mi c  
C o ntr a st-E n h a n c e d  
M RI;  
D C E -M RI;  
Di s e a s e -
M o dif yi n g O st e o art hriti s Dr u g s; D M O A D  

N o v arti s  
C o nfi d e nti al  
P a g e 2 4  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
1   
I ntr o d u cti o n 
1. 1   
B a c k gr o u n d  
Oste oart hritis ( O A), a sl o wl y pr o gressi ve disease wit h a m ultifact orial pat h o p h ysi ol o g y, is o ne 
of t he m ost c o m m o n c hr o nic healt h c o n diti o ns i n a d ults, a n d a lea di n g ca use of pai n a n d 
disa bilit y ( O A R SI  2 0 1 6 ). C urre ntl y, t here are o nl y fe w s y m pt o matic t hera pies ot her t ha n j oi nt 
re place me nt 
s ur ger y, 
a n d 
n o 
str uct ure-m o dif yi n g 
dr u gs 
are 
a vaila ble 
t o 
date 
(L o h ma n der  a n d R o os  2 0 1 9 ). D ue t o t he de m o gra p hic c ha n ges i n a n a gei n g s ociet y, t he 
pre vale nce of O A will stea dil y i ncrease, p osi n g a si g nifica nt b ur de n o n gl o bal healt h -care 
s yste ms (O A R SI  2 0 1 6 ). T he k nee j oi nt is t he m ost c o m m o n wei g ht -beari n g j oi nt affecte d b y 
O A. C urre nt 
me dical treat me nts of 
O A f oc us o n a d dressi n g pai n, b ut t here are n o 
c h o n dr o -a na b olic treat me nts 
a vaila ble t o i n d uce 
cartila ge re ge nerati o n, s o 
calle d 
disease -m o dif yi n g O A dr u gs ( D M O A Ds). E ve nt ual j oi nt fail ure re q uiri n g s ur gical j oi nt 
re place me nt is c o m m o n, wit h o ver a milli o n s uc h o perati o ns a n n uall y i n t he U nite d States 
(Willia ms  et al 2 0 1 5 , W olf or d  et al 2 0 1 5 ). 
T he r ole of A n gi o p oieti n -li ke pr otei n 3 ( A N G P T L 3) i n c h o n dr o ge nesis is a n o vel disc o ver y 
ma de at N o vartis. L N A 0 4 3 is a m o difie d h u ma n A N G P T L 3 pr otei n wit h c h o n dr o ge nic a n d 
c h o n dr o pr otecti ve effects. S o far, L N A 0 4 3 has s h o w n cartila ge a na b olic effects i n ea rl y sta ges 
of k nee de ge nerati o n i n a pr o of of mec ha nis m ( P o M) st u d y ( L N A 0 4 3 X 2 2 0 1) i n patie nts wit h 
cartila ge lesi o ns a n d i n a pr o of of c o nce pt ( P o C) st u d y ( L N A 0 4 3 X 2 2 0 2) i n patie nts wit h earl y 
O A. H o we ver, it is n ot k n o w n w het her a c h o n dr o -a na b olic a ge nt li ke L N A 0 4 3 will be s ufficie nt 
t o e x pe diti o usl y re d uce s y m pt o ms a n d re b uil d str uct ure i n s y m pt o matic k nee O A patie nts 
wit h  i ntra-artic ular  i nfla m mati o n. 
S uc h i nfla m mati o n is prese nt i n 3 0 -5 0 % of O A patie nts wit h m o derate -se vere disease i n ac ute 
flare 
p hases 
of 
cartila ge 
de gra dati o n 
a n d/ or 
as 
c hr o nic l o w-gra de i nfla m mati o n. 
M ore o ver,  i nfla m mati o n is acti vel y i n v ol ve d i n t he pat h o p h ysi ol o g y of O A a n d t he pr o gressi o n 
of t he disease e ve n i n t he a bse nce of o vert s y m pt o ms. Es peciall y i n later sta ges of O A, 
i ntra-artic ular i nfla m mati o n is c o m m o n. U nf ort u natel y, i ntra -artic ular c ortic oster oi ds (I A C S), 
t he c urre nt sta n dar d of care f or i nfla me d O A j oi nts, ha ve bee n sh o w n t o ha ve l o n g -ter m 
detri me ntal effects o n artic ular cartila ge, accelerati n g disease pr o gressi o n.  I n a d diti o n, data o n 
t he p ote ntial be nefit a n d its d urati o n after I A C S are of l o w q ualit y a n d i nc o nsiste nt 
(J ü ni et al 2 0 1 5 ). 
T he i nfla m mati o n is dri ve n b y a plet h ora of pr o -i nfla m mat or y c yt o ki nes (e. g., I L-1 β, T N F α ) 
a n d c he m o ki nes (e. g., C C L 5, I L -8) t hat are prese nt i n j oi nt tiss ues, s y n o vi u m, s y n o vial fl ui d 
a n d cartila ge of O A  patie nts. T hese i nfla m mat or y me diat ors d o w nre g ulate cartila ge matri x 
pr o d ucti o n b y c h o n dr oc ytes a n d i ncrease pr o d ucti o n of matri x -de gra di n g e nz y mes ( M M Ps, 
A D A M T S) b y c h o n dr oc ytes a n d s y n o vial cells, lea di n g t o t he brea k d o w n a n d l oss of t he 
cartila ge matri x  (va n  de n  B osc h  2 0 1 9 , Bere n ba u m  2 0 1 3 ). 
I L-1 β i n hi bits c h o n dr oc yte a n d pr o ge nit or cells a na b olic acti vit y a n d u pre g ulates cata b olic 
e nz y mes a n d oste o ge nic mar kers i n vitr o. I n a n i nfla m mat or y e n vir o n me nt, de gra di n g e nz y mes 
are a b u n da nt a n d c h o n dr oc ytes are less res p o nsi ve t o a na b olic sti m uli d ue t o meta b olic 
s h ut d o w n. I n a d diti o n, str o n g e vi de nce e xists t hat I L-1 pla ys a critical r ole i n 
O A 
(Wa n g  et al 2 0 1 5 ). Pre vi o us cli nical trials of I L -1 i n hi biti o n i n O A ha ve bee n disa p p oi nti n g i n 
ter ms of pai n re d ucti o n (C he valier  et al 2 0 0 9 , C o he n  et al 2 0 1 1 , Fleisc h ma n n  et al 2 0 1 9 , 

N o v arti s  
C o nfi d e nti al  
P a g e 2 5  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
C A C Z 8 8 5 C 2 2 0 1 ( u n p u blis he d data)). T hese st u dies i ncl u de d patie nts wit h cli nical a n d 
ra di o gra p hic 
O A, 
w hereas i n t he c urre nt pr ot oc ol, o nl y patie nts 
wit h k nee 
O A 
wit h 
i nfla m mati o n are t o be i ncl u de d. F urt her m ore, i n s u p p ort of the c urre nt trial desi g n, a p ost -h oc 
a nal yses of t he C A N T O S trial ( A C Z 8 8 5 M 2 3 0 1) s h o we d t hat t he a nti -I L-1 β  a nti b o d y 
ca na ki n u ma b gi ve n s.c. q uarterl y re d uce d t he i nci de nce of hi p or k nee j oi nt re place me nt, a n d 
t he i nci de nce of O A relate d a d verse e ve nts i n m y ocar dial i nfarcti o n patie nts selecte d f or hi g h 
se nsiti vit y C-reacti ve pr otei n ( hs C R P) (Sc hie ker  et al 2 0 2 0 ). T hese res ults s u p p ort t he c o nce pt 
of I L -1 β i n hi biti o n f or O A treat me nt i n patie nts wit h i ncrease d hs C R P le vels.  
1. 2   
P ur p o s e  
T his is a p hase 2a pr o of of c o nce pt st u d y wit h 4 treat me nt ar ms ( T A 1 -4) t o esta blis h t he effect 
of L N A 0 4 3 i n patie nts wit h s y m pt o matic,  k nee O A wit h i nfla m mati o n, defi ne d b y 
M RI. 
T he  c h o n dr o-a na b olic effect of L N A 0 4 3 gi ve n i.a. has bee n esta blis he d i n se veral k nee O A 
st u dies, b ut wit h o ut s pecificall y a d dressi n g k nee O A wit h i nfla m mati o n. 
T he p ur p ose of t he st u d y is  
•
t o assess if t he effect of i.a. L N A 0 4 3 ca n be esta blis he d i n patie nts wit h i nfla m mat or y
k nee O A
•
t o assess if a p ossi ble ne gati ve effect of i nfla m mati o n o n t he p ote ntial p ositi ve effect of
L N A 0 4 3 i n cartila ge re ge nerati o n ca n be o verc o me b y c o nc urre nt treat me nt wit h a n
a nti-i nfla m mat or y t hera p y (i.a. ca na ki n u ma b)
•
t o assess t he efficac y of i.a. ca na ki n u ma b i n relie vi n g pai n, ot her  cli nical s y m pt o ms a n d
i m pr o vi n g f u ncti o n
2   
O bj e cti v e s a n d e n d p oi nt s  
St u d y o bjecti ves a n d e n d p oi nts are liste d i n Ta ble  2 -1  bel o w. W here a n o bjecti ve descri bes a 
c ha n ge, it i m plicitl y refers t o c ha n ge c o m pare d t o t he baseli ne defi ne d i n Secti o n  3 . 
T a bl e 2 -1   
O bj e cti v e s a n d r el at e d e n d p oi nt s  
O bj e cti v e( s)  
E n d p oi nt( s)  
Pri m ar y o bj e cti v e( s)  
E n d p oi nt( s) f or pri m ar y o bj e cti v e( s)  
•
T o a s s e s s t h e effi c a c y of q 4 w x 3 i. a. i nj e cti o n s
of L N A 0 4 3 v s. n o i nj e cti o n s of L N A 0 4 3, i n
r e g e n er ati n g arti c ul ar c artil a g e ti s s u e ( T A 1 v s.
T A 2)
•
C h a n g e i n c artil a g e v ol u m e i n t h e i n d e x
r e gi o n m e a s ur e d b y M RI  at D a y 1 9 7
•
T o a s s e s s t h e effi c a c y of a si n gl e i. a. i nj e cti o n
of c a n a ki n u m a b v s. pl a c e b o i n r eli e vi n g O A
p ai n  ( T A 4 v s. T A 2)
•
C h a n g e i n K n e e i nj ur y a n d O st e o art hriti s
O ut c o m e S c or e ( K O O S) P ai n s u b s c al e at
D a y 8 5

N o v arti s  
C o nfi d e nti al  
P a g e 2 6  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
O bj e cti v e( s)  
E n d p oi nt( s)  
S e c o n d ar y o bj e cti v e( s)  
E n d p oi nt( s) f or s e c o n d ar y o bj e cti v e( s)  
•
T o a s s e s s t h e s af et y a n d t ol er a bilit y of q 4 w x 3
i. a. i nj e cti o n s of L N A 0 4 3, a si n gl e i. a. i nj e cti o n
of c a n a ki n u m a b a n d a si n gl e i nj e cti o n of
c a n a ki n u m a b f oll o w e d b y q 4 w x 3 i. a. i nj e cti o n s
of L N A 0 4 3 ( T A 1, T A 3, T A 4) r el ati v e t o
pl a c e b o t o c a n a ki n u m a b/ n o L N A 0 4 3
i nj e cti o n s ( T A 2)
• 
S y st e mi c a n d l o c al A d v er s e E v e nt s ( A E s)
El e ctr o c ar di o gr a m s ( E C G s)
Vit al si g n s
H e m at ol o g y, bl o o d c h e mi str y a n d
uri n al y si s
•
T o a s s e s s t h e p ot e nti al i m m u n o g e ni cit y of q 4 w x 3
i. a. i nj e cti o n s of L N A 0 4 3 ( T A 1 a n d T A 3)
•
A nti -L N A 0 4 3 a nti b o di e s i n s er u m, at
D a y  1 5, 4 3, 8 5, 1 9 7 a n d 3 6 5
•
T o a s s e s s  e n d o g e n o u s A N G P T L 3, a n d P K of
L N A 0 4 3, aft er q 4 w x 3 i. a. i nj e cti o n s of L N A 0 4 3
a n d aft er a si n gl e i. a. i nj e cti o n of
c a n a ki n u m a b f oll o w e d b y q 4 w x 3 i. a. i nj e cti o n s
of L N A 0 4 3 ( T A 1 a n d T A 3)
•
A N G P T L 3 s er u m c o n c e ntr ati o n s
A N G P T L 3 s y n o vi al fl ui d c o n c e ntr ati o n s
L N A 0 4 3 P K pr ofil e i n s er u m ( C m a x, T m a x,
A U C)
•
T o a s s e s s t h e effi c a c y of a si n gl e i. a. i nj e cti o n
of c a n a ki n u m a b f oll o w e d b y q 4 w x 3 i. a.
i nj e cti o n s of L N A 0 4 3 v s. a si n gl e i. a. i nj e cti o n
of c a n a ki n u m a b, i n r e g e n er ati n g arti c ul ar
c artil a g e ( T A 3 v s. T A 4) a n d v s. o nl y q 4 w x 3 i a.
i nj e cti o n s of L N A 0 4 3 ( T A 3 v s. T A 1)
•
C h a n g e i n c artil a g e v ol u m e a n d t hi c k n e s s
of t h e i n d e x r e gi o n m e a s ur e d  b y M RI  at
D a y 1 9 7 a n d D a y 3 6 5
•
T o a s s e s s t h e effi c a c y of q 4 w x 3 i. a. i nj e cti o n s
of L N A 0 4 3 v s. n o i nj e cti o n s of L N A 0 4 3, i n
m ai nt ai ni n g or r e g e n er ati n g arti c ul ar
c artil a g e  ( T A 1 v s. T A 2)
•
C h a n g e i n c artil a g e t hi c k n e s s of t h e i n d e x
r e gi o n m e a s ur e d b y M RI at  D a y 1 9 7
C h a n g e i n c artil a g e v ol u m e  a n d
t hi c k n e s s of t h e i n d e x r e gi o n m e a s ur e d b y
M RI  at D a y 3 6 5
•
T o a s s e s s t h e effi c a c y  of  a si n gl e i. a.  i nj e cti o n
of c a n a ki n u m a b  v s.  pl a c e b o t o c a n a ki n u m a b,
o n s y n o viti s  ( T A 4 v s. T A 2)
•
C h a n g e i n s y n o viti s l e v el m e a s ur e d fr o m
Ktr a n s b y D y n a mi c C o ntr a st E n h a n c e d
M RI ( D C E -M RI) at D a y 8 5
•
T o a s s e s s t h e effi c a c y of a si n gl e i. a. i nj e cti o n
of c a n a ki n u m a b v s. pl a c e b o t o c a n a ki n u m a b,
i n r eli e vi n g O A p ai n a n d i m pr o vi n g f u n cti o n
o v er ti m e  ( T A 4 v s. T A 2)
•
C h a n g e i n n u m eri c r ati n g s c al e ( N R S) P ai n
at D a y 1 5, 2 9, 4 3, 5 7, 7 1, 8 5
C h a n g e i n K O O S P ai n a n d F u n cti o n i n
d ail y li vi n g ( A D L) s u b s c al e s at D a y 1 5, 2 9,
4 3, 5 7, 7 1, 8 5
• 
T o a s s e s s t h e effi c a c y of a si n gl e i. a. i nj e cti o n
of c a n a ki n u m a b f oll o w e d b y q 4 w x 3 i. a.
i nj e cti o n s of L N A 0 4 3 v s. a si n gl e i. a. i nj e cti o n
of c a n a ki n u m a b, i n r eli e vi n g O A p ai n ( T A 3 v s.
T A 4), a n d v s. o nl y q 4 w x 3 i. a. i nj e cti o n s of
L N A 0 4 3 ( T A 3 v s. T A 1)
• 
C h a n g e i n n u m eri c r ati n g s c al e ( N R S) P ai n
at D a y 1 5, 2 9, 4 3, 5 7, 7 1, 8 5, 1 9 7, 3 6 5
C h a n g e i n K O O S P ai n a n d F u n cti o n i n
d ail y li vi n g ( A D L) s u b s c al e s at D a y 1 5, 2 9,
4 3, 5 7, 7 1, 8 5, 1 9 7, 3 6 5
E x pl or at or y o bj e cti v e( s)  
E n d p oi nt( s) f or e x pl or at or y o bj e cti v e( s)  
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N o v arti s  
C o nfi d e nti al  
P a g e 2 7  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
O bj e cti v e( s)  
E n d p oi nt( s)  
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N o v arti s  
C o nfi d e nti al  
P a g e 2 8  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
O bj e cti v e( s)  
E n d p oi nt( s)  
2. 1   
Pri m ar y e sti m a n d s  
N ot a p plica ble.  
2. 2   
S e c o n d ar y e sti m a n d s  
N ot a p plica ble.  
3   
St u d y d e si g n  
T his is a n o n -c o nfir mat or y, ra n d o mize d, f o ur ar m, place b o -c o ntr olle d, partici pa nt, i n vesti gat or 
a n d s p o ns or bli n de d ( wit h re gar ds t o ca na ki n u ma b w hereas L N A 0 4 3 treat me nt is o pe n la bel) 
st u d y i n patie nts wit h k nee O A wit h i nfla m mati o n. 
T he st u d y c o nsists of f o ur scree ni n g visits ( Scree ni n g 1 -4), of w hic h Scree ni n g 2 a n d 4 ca n be 
perf or me d re m otel y, a n d t he n f o ur treat me nt visits, at Da y  1, 1 5, 4 3 a n d 7 1. U p o n c o m pleti o n 
of t he 1 0 -wee k treat me nt peri o d, partici pa nts will e nter a f oll o w -u p peri o d wit h visits at Da y  8 5, 
Da y  1 9 7 a n d Da y 3 6 5, i.e. partici pa nts will be f oll o we d u p u ntil o ne  year after t he first d ose. 
T he  Da y  3 6 5 visit is t he E n d of St u d y ( E o S) visit.  
F oll o wi n g t heir i nf or me d c o nse nt, partici pa nts will be assesse d f or eli gi bilit y at t he first of f o ur 
scree ni n g visits ( Scree ni n g 1). Scree ni n g 1 ca n be arra n ge d u p t o 4 2 da ys pri or t o Da y  1. 
If eli gi ble at Scree ni n g 1, t he partici pa nt s h o ul d s witc h a n y o n g oi n g pai n me dicati o ns t o t he 
pr o vi de d Basic Pai n Me dicati o n, see  Secti o n 6. 1. 2 . 
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N o v arti s  
C o nfi d e nti al  
P a g e 2 9  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
T he p ur p ose of t he sec o n d scree ni n g visit ( Scree ni n g 2) 
 
 
 
 
 Scree ni n g 2 ca n be perf or me d re m otel y, i.e. as a 
tele p h o ne or o nli ne visit. 
T he t hir d scree ni n g visit ( Scree ni n g 3) is de dicate d t o t he M RI assess me nt a n d s h o ul d o nl y be 
perf or me d if t he partici pa nt q ualifies base d o n all assess me n ts at Scree ni n g 1 a n d Scree ni n g 2. 
Scree ni n g 3 s h o ul d be arra n ge d as cl ose t o b ut n o later t ha n 1 4  da ys pri or t o Da y 1, t o esta blis h 
a n i ma gi n g baseli ne b ut still all o w s ufficie nt t ur nar o u n d ti me f or t he ce ntral i ma gi n g e val uati o n.  
T he f o urt h a n d last scree ni n g visit ( Scree ni n g 4) 
 
. Scree ni n g 4 s h o ul d be perf or me d wit hi n ma xi m u m fi ve da ys fr o m first d ose ( Da y  1) 
a n d ma y be perf or me d re m otel y.  
T o miti gate p ote ntial S A R S -C o V -2 i nfecti o ns a m o n g partici pa nts, g ui da nce a n d re q uire me nts 
pr o vi de d b y t he l ocal re g ulat or y a ut h orities will be f oll o we d, w hic h c o ul d i ncl u de scree ni n g f or 
S A R S -C o V -2 b y P ol y merase C hai n Reacti o n ( P C R) or e q ui vale nt a p pr o ve d met h o d ol o g y pri or 
t o a d missi o n at t he i n vesti gat or site f or a n y o ver ni g ht sta ys (if a p plica ble) f ollo wi n g l ocal 
site-s pecific S O Ps. 
O nce eli gi bilit y has bee n c o nfir me d at Scree ni n g 4, partici pa nts will be ra n d o mize d t o o ne of 
t he f o ur treat me nt ar ms s h o w n b y Fi g ure  3 -1  acc or di n g t o a 1: 2: 1: 2 rati o. Partici pa nts  will t he n 
o n Da y 1 recei ve a n i.a. i njecti o n of eit her ca na ki n u ma b 6 0 0 m g, or  matc hi n g place b o. 
F o urtee n  da ys later, partici pa nts ra n d o mize d t o treat me nt ar ms 1 or 3 will recei ve i.a. i njecti o ns 
of L N A 0 4 3 4 0 m g e ver y 4 wee ks, o n Da y  1 5, 4 3 a n d 7 1, wit h t w o  i nter me diate f oll o w u p 
re m ote visits ( o n-site atte n da nce n ot nee de d), o n Da y 2 9 a n d 5 7. T he L N A 0 4 3 treat me nt 
re gi me n is a b bre viate d 'q 4 w x 3'.  
Partici pa nts ra n d o mise d t o T A 2 a n d 4 will atte n d t he sa me visits b ut will n ot recei ve f urt her 
st u d y dr u g be y o n d t he i njecti o n o n Da y 1, e xce pt a nal gesic treat me nt defi ne d i n Secti o n  6. 1. 2 . 
T he  ca na ki n u ma b treat me nt is place b o c o ntr olle d a n d bli n de d t o partici pa nts a n d i n vesti gat ors 
w hereas t he L N A 0 4 3 treat me nt is o pe n la bel.  
C o n ve nti o nal 3 T M RI will be perf or me d at f o ur visits: Scree ni n g 3, Da y 8 5, Da y 1 9 7 a n d 
Da y  3 6 5. D C E -M RI will be c ollecte d at t w o visits: Scree ni n g 3 a n d Da y 8 5.  
Pai n assess me nts are c ollecte d t hr o u g h o ut t he st u d y, a n d via a pai n diar y u p u ntil Da y 8 5. 
I n a d diti o n, t he partici pa nt s h o ul d c o m plete t he pai n diar y f or o ne wee k pri or t o t he Da y 1 9 7 
a n d Da y 3 6 5 visits.  
 
 Bl o o d sa m ples f or L N A 0 4 3 P K a n d I G a nal ysis will be 
c ollecte d fr o m all partici pa nts w h o are ra n d o mize d t o recei ve L N A 0 4 3 i njecti o ns ( T A 1 a n d 
T A 3) at a li mite d n u m ber of ti me p oi nts, a n d at a d diti o nal ti me p oi nts f or partici pa nts w h o als o 
c o nse nt t o t he o pti o nal L N A 0 4 3 P K c ollecti o ns (see Secti o n  8. 5. 1 ). 
Partici pa nts  will  ret ur n t o t he i n vesti gat or site at Da y 8 5, Da y 1 9 7 a n d Da y 3 6 5 f or f oll o w u p 
assess me nts.  
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N o v arti s  
C o nfi d e nti al  
P a g e 3 0  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
Baseli ne is defi ne d as t he assess me nts c ollecte d pre -d ose o n Da y 1, e xce pt f or M RI f or w hic h 
baseli ne data will be c ollecte d at Scree ni n g 3.  
Assess me nts will be perf or me d at visits a n d ti me p oi nts s pecifie d i n t he Assess me nt sc he d ule 
Ta ble  8 -1 . 
Fi g ur e 3 -1   
St u d y d e si g n  
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N o v arti s  
C o nfi d e nti al  
P a g e 3 1  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
4   
R ati o n al e  
4. 1   
R ati o n al e f or st u d y d e si g n  
T he desi g n of t his st u d y a d dresses t he pri mar y o bjecti ve of assessi n g t he a bilit y of L N A 0 4 3 t o 
re ge nerate artic ular cartila ge tiss ue i n patie nts wit h s y m pt o matic k nee O A wit h i nfla m mati o n 
after i njecti o n of place b o or ca na ki n u ma b i.a. F urt her m ore, t his st u d y is desi g ne d t o a d dress t he 
c o-pri mar y o bjecti ve i n t he a bilit y of ca na ki n u ma b t o re d uce pai n a n d/ or i nfla m mati o n i n 
patie nt s wit h s y m pt o matic k nee O A wit h i nfla m mati o n. 
T his st u d y ta kes i nt o acc o u nt (i) t he cli nical nee d; (ii) cli nical a n d pr ecli nical data o n L N A 0 4 3; 
(iii) cli nical a n d precli nical data o n ca na ki n u ma b; (i v) c urre nt practice wit h i.a. i njecta ble dr u gs;
a n d ( v) t he b ur de n o n patie nts wit h s y m pt o matic k nee O A wit h i nfla m mati o n. T he c o m bi nati o n
of 
M RI 
meas uri n g t he cartila ge v ol u me i n t he i n de x re gi o n as well as s y n o vitis a n d
well -esta blis he d P R Os s uc h as K O O S ( Be k kers  et al 2 0 0 9 ) will e ns ure a p pr o priate e val uati o n
of ca na ki n u ma b a n d/ or L N A 0 4 3 effects i n t his i nfla me d j oi nt e n vir o n me nt, fr o m b ot h a
m or p h ol o gical (cartila ge str uct ure a n d s y n o vitis)  a n d a f u ncti o nal sta n d p oi nt. Gi ve n t he
met h o d ol o gical c halle n ge of meas uri n g rele va nt c ha n ges i n pai n, care has bee n ta ke n t o select
p ote ntial partici pa nts a n d assess me nts base d o n c urre nt rec o m me n dati o ns f or pai n assess me nts
i n t he literat ure (D w or ki n et al 2 0 1 2 , Patel et al 2 0 2 1 ).
F or t he i n vesti gati o n of ca na ki n u ma b treat me nt o n O A pai n t he st u d y has bee n desi g ne d as 
partici pa nt, i n vesti gat or a n d s p o ns or bli n de d i n or der t o e ns ure t hat me nti o ne d parties re mai n 
i n a state of e q ui p oise, s o t hat a p utati ve differe nce bet wee n t he treate d a n d c o ntr ol gr o u ps ca n 
be i nter prete d as a n effect of st u d y treat me nt. H o we ver, place b o t o L N A 0 4 3 will n ot be use d 
f or reas o ns descri be d i n Secti o n  4. 3 . 
 
 
 Patie nts will ne vert heless be f oll o we d u p f or 
1 2  m o nt hs t o p urs ue t he preser vati o n of t he cartila ge. T he pai n effe ct will be i n vesti gate d after 
3  m o nt hs 
. 
I ncl usi o n criteria (e. g., ele vate d hs C R P ≥1. 8  m g/ L, fJ S W 2. 0 -4. 0 m m ( me n) or 1. 5 -3. 5 m m 
( w o me n), a ge 4 0-8 0 years, N R S Pai n le vel at 
of ≥5 t o ≤9, K O O S le vel of < 6 0, a n d 
si g ns of s y n o vitis i n M RI) ha ve bee n selecte d t o e nric h f or patie nts wit h k nee O A wit h 
i nfla m mati o n. 
T he partici pa nt p o p ulati o n wit h s y m pt o matic, k nee O A of t he me dial c o m part me nt, wit h 
i nfla m mati o n f ulfilli n g t he i ncl usi o n criteria has bee n selecte d i n or der t o i) f oc us o n cartila ge 
re ge nerati o n i n a hi g h-ris k p o p ulati o n; ii) ma xi mize t he rele va nce of t he fi n di n gs as t he me dial 
c o m part me nt is t he 
m ost fre q ue ntl y affecte d re gi o n of t he k nee i n patie nts wit h O A 
(Wise  et al 2 0 1 2 ); T he  e xcl usi o n criteria of m o derate t o se vere pai n i n t he c o ntralateral k nee f or 
t he maj orit y of da ys i n t he last 3 m o nt hs pri or t o Scree ni n g 1 has bee n c h ose n t o mi ni mize bias 
ca use d b y se vere pai n fr o m t he c o ntralateral k nee affecti n g t he re p orti n g of pai n fr o m t he tar get 
k nee as well as k nee f u ncti o n. Patie nts a ge d < 4 0 years are e xcl u de d beca use t heir k nee 
i nfla m mati o n is ofte n ac ute or s u bac ute ca use d b y tra u ma.  
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N o v arti s  
C o nfi d e nti al  
P a g e 3 2  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
T he i ncl usi o n of patie nts wit h Wi des prea d Pai n I n de x ( W PI) ≤4 is t o mi ni mize bias p ote ntiall y 
affecti n g t he re p orti n g of pai n a n d f u ncti o n b y t he prese nce of ge neralize d pai n 
(Yazici  et al 2 0 1 7 ). Si milarl y, patie nts wit h ne wl y dia g n ose d O A i n ot her j oi nts, or i psilateral 
hi p O A/j oi nt re place me nt s ur ger y, are e xcl u de d t o mi ni mize bias.  
4. 2   
R ati o n al e f or d o s e/r e gi m e n a n d d ur ati o n of tr e at m e nt  
T he d ose of L N A 0 4 3 i n t his st u d y will be 4 0 m g, gi ve n b y i.a. i njecti o n t hree ti mes at 
f o ur-wee kl y i nter vals. 
I n t he first-i n-h u ma n st u d y L N A 0 4 3 X 2 1 0 1, f oll o wi n g a si n gle i.a. i nj ecti o n of 0. 2, 2, 1 0, 2 0, or 
4 0  m g, L N A 0 4 3 de m o nstrate d a n acce pta ble safet y pr ofile a n d was well t olerate d, a n d c o ul d 
n ot be meas ure d i n s y n o vial fl ui d 7 da ys p ost -d ose. At t he 4 0 m g d ose le vel, L N A 0 4 3 was 
q ua ntifia ble i n ser u m u p t o 8 h o urs p ost -d ose, b ut bel o w q ua ntificati o n li mit at 2 -4  da ys 
p ost -d ose.  
Wee kl y i.a. d osi n g i n t he d o g di d n ot res ult i n acc u m ulati o n of L N A 0 4 3 i n ser u m ( u n detecta ble 
or cl ose t o t he 2 5 n g/ m L l o wer li mit of q ua ntificati o n ( L L O Q) at 2 4 h p ost -d ose), a n d base d o n 
t he ra pi d cleara nce o bser ve d s o far i n h u ma n, acc u m ulati o n i n ser u m is n ot e x pecte d f oll o wi n g 
m o nt hl y d osi n g i n h u ma ns. T he s yste mic e x p os ure data fr o m t he L N A 0 4 3 X 2 1 0 1 st u d y at 4 0  m g 
are base d o n a li mite d set of ti me -p oi nts (f o ur c o nce ntrati o ns per s u bject a b o ve t he L L O Q), a n d 
acc or di n gl y t he A U C 0 -8 h of 1 4 6 0 n g. h/ m L s h o ul d be treate d wit h ca uti o n si nce t he y are li kel y 
t o be s o me w hat u n der-esti mate d. 
 
 W he n c o m pari n g t he cli nical e x p os ure 
data wit h t h ose fr o m t he rat a n d d o g i. v. d osi n g st u dies, t here is a s u bsta ntial s yste mic safet y 
mar gi n. T h us, t he cli nical C ma x of 2 5 9 n g/ m L f oll o wi n g a 4 0 m g d ose i n h u ma ns is 8 9 9 1 -f ol d 
l o wer t ha n t he C ma x o bser ve d at t he 2 0 m g/ k g d ose i n t he 4 -wee k i. v. d o g st u d y, a n d 1 6 8 -f ol d 
l o wer t ha n t he C ma x o bser ve d at 5 m g/ k g i n t he 2 6-wee k i. v. rat st u d y. T he cli nical A U C 0 -8 h 
4 0  m g d ose of 1 4 6 0 n g. h/ m L f oll o wi n g a 4 0 m g d ose is 9 1 -f ol d l o wer t ha n t he A U C i n t he d o g 
f oll o wi n g a 2 0 m g/ k g d ose a n d 2 6 6-f ol d l o wer t ha n t he A U C i n t he rat at 5 m g/ k g d ose le vel. 
As  state d earlier, h o we ver, t hese m ulti ples s h o ul d be i nter prete d wit h ca uti o n. 
A d ose of 4 0 m g is e x pecte d t o deli ver a p har mac ol o gical effect si nce i n n o n -cli nical efficac y 
m o dels, effects start t o bec o me o bser va ble at 2 μ g L N A 0 4 3 i n t he rat k nee ( w hic h scales t o 
5 6 0  μ g i n h u ma n, base d o n b o d y wei g ht) a n d 1 0 0 μ g i n t he d o g (e q ui vale nt t o 7 0 0 μ g i n h u ma n). 
I n b ot h disease m o dels, i ncreasi n g t he d ose i ncrease d t he efficac y a n d a si n gle d ose was e n o u g h 
t o elicit a si g nifica nt effect. H u ma n cartila ge is k n o w n t o be t hic ker a n d less easil y re paire d t ha n 
i n a ni mal m o dels, t heref ore t he 4 0 m g d ose le vel has bee n selecte d base d o n feasi bilit y, safet y 
a n d t olera bilit y i n pre vi o us cli nical e x perie nce, safet y mar gi ns wit h res pect t o a ni mals, a n d le vel 
of desire d p har mac ol o g y. Rece nt data i n rats i n dicate t hat efficac y f oll o wi n g a si n gle d ose te n ds 
t o be tra nsie nt, a n d t hat re peat d osi n g res ults i n m ore lasti n g effects. T heref ore, t he c urre nt st u d y 
is desi g ne d t o e val uate t he effecti ve ness of t hree d oses, a d mi niste re d e ver y f o ur wee ks, at t he 
4 0  m g le vel t o a si n gle k nee j oi nt per patie nt.  
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N o v arti s  
C o nfi d e nti al  
P a g e 3 3  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
I n c o ncl usi o n, cli nical e x perie nce t o date wit h L N A 0 4 3 i n dicates t hat t his c o m p o u n d 
de m o nstrates a n acce pta ble safet y pr ofile a n d is well -t olerate d, see als o Secti o n  4. 5. 2  or t he 
I n vesti gat or's Br oc h ure (I B). A d ose of 4 0 m g has bee n selecte d f or re peat d osi n g, f or 
t hree d oses, e ver y f o ur wee ks, base d o n safet y a n d feasi bilit y, a n d i n or der t o ma xi mize t he 
li keli h o o d of deli veri n g a s ustai ne d, p har mac o d y na mic effect lea di n g t o cartila ge re pair i n t he 
k nee.  
T he d ose of ca na ki n u ma b gi ve n i n t his st u d y will be  6 0 0 m g, as a si n gle i.a. i njecti o n.  
 
 
 
 T he m ost fre q ue nt class of A Es was 
I nfecti o ns a n d i nfestati o ns, w hic h is c o nsiste nt wit h t he k n o w n safet y pr ofile of ca na ki n u ma b. 
4. 3   
R ati o n al e f or c h oi c e of c o ntr ol dr u g s ( c o m p ar at or/ pl a c e b o)  
N o cartila ge -a na b olic c o m p o u n d a ble t o pr o m ote cartila ge re ge nerati o n has bee n a p pr o ve d t o 
date. T he a na b olic effect of L N A 0 4 3 c o m pare d t o place b o, i n a n o n -i nfla me d k nee O A 
p o p ulati o n, is bei n g i n vesti gate d i n ot her trials ( L N A 0 4 3 X 2 2 0 2, 
L N A 0 4 3 A 1 2 2 0 2). 
T o  i n vesti gate t he cartila ge re ge nerati ve effect of L N A 0 4 3 i n i nfla me d j oi nts t he effect will be 
meas ure d wit h M RI i n t his st u d y. Place b o t o L N A 0 4 3 is o mitte d t o a v oi d a d diti o nal i.a. place b o 
i njecti o ns a n d t o all o w f or t he i n vesti gati o n of t he effect of ca naki n u ma b treat me nt o n pai n 
wit h o ut t he c o nf o u n di n g effect of a d diti o nal i.a. i njecti o ns. T he lac k of place b o is n ot e x pecte d 
t o i m pact t he M RI a nal ysis (str uct ural e n d p oi nts a n d ce nt ral rea der bli n de d assess me nt). 
Place b o t o ca na ki n u ma b ( T A 1 a n d T A 2) c o ntai ns t he sa me f or m ulati o n a n d e xci pie nts as t he 
i n vesti gati o nal dr u g, wit h o ut t he acti ve a ge nt. 
4. 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  
A n i nteri m a nal ysis is pla n ne d after all t he partici pa nts ha ve c o m plete d Da y 8 5 i n t he st u d y. 
T he p ur p ose is t o e val uate t he pri mar y o bjecti ve relate d t o t he ca na ki n u ma b treat me nt, al o n g 
wit h a n e xa mi nati o n of rele va nt safet y data.  
A sec o n d i nteri m a nal ysis is pla n ne d after all t he partici pa nts ha ve c o m plete d Da y 1 9 7 i n t he 
st u d y. T he p ur p ose is t o e val uate t he pri mar y o bjecti ve relate d t o t he L N A 0 4 3 treat me nt, al o n g 
wit h a n e xa mi nati o n of rele va nt safet y data.  
A d diti o nal i nteri m a nal yses ma y be c o n d ucte d t o s u p p ort decisi o n ma ki n g c o ncer ni n g t he 
c urre nt cli nical st u d y, t he s p o ns or’s cli nical de vel o p me nt pr ojects i n ge neral, or i n case of a n y 
safet y c o ncer ns. 
A d diti o nal i nf or mati o n is prese nte d i n Secti o n  1 2. 7 . 
4. 5   
Ri s k s a n d b e n efit s  
T he ris k t o patie nts i n t his trial will be mi ni mize d b y a d here nce t o t he eli gi bilit y criteria, cl ose 
cli nical m o nit ori n g, a n d st o p pi n g r ules.  
Ris ks ass ociate d wit h L N A 0 4 3, ca na ki n u ma b a n d i ma gi n g are descri be d i n se parate secti o ns 
bel o w. F or ris ks ass ociate d wit h t he o ver -t he-c o u nter ( O T C) me dicati o ns paraceta m ol, wit h or 
wit h o ut l o w -d ose c o dei ne, refere nce is ma de t o t he prescri bi n g i nf or mati o n . 
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 3 4  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
4. 5. 1   
B e n efit s  
It is n ot k n o w n w het her t here will be a be nefit f or t he patie nts wit h s y m pt o matic k nee O A wit h 
i nfla m mati o n partici pati n g i n t his st u d y.  Precli nical data a n d data fr o m cli nical st u dies of 
L N A 0 4 3 i n patie nts wit h cartila ge da ma ge eit her i n t he c o nte xt of O A or of cartila ge i nj ur y; 
C L N A 0 4 3 X 2 1 0 1 ( First i n H u ma n), C L N A 0 4 3 X 2 2 0 1 ( Pr o of of 
Mec ha nis m) a n d o n g oi n g 
C L N A 0 4 3 X 2 2 0 2 ( Pr o of of C o nce pt) i n dicate t he c h o n dr o-a na b olic a n d c h o n dr o -pr otecti ve 
effects of L N A 0 4 3 o n da ma ge d artic ular cartila ge at b ot h m olec ular a n d tiss ue le vel. S o far, n o 
a p pr o ve d t hera p y e xists as sta n dar d of care a d dressi n g t he u n met me dical nee d of cartila ge 
re pair i n patie nts wit h de ge nerati ve cartila ge dis or ders. T heref ore, n o s uc h t hera pies will be 
wit h hel d b y j oi ni n g t his st u d y.  
Partici pa nts will als o recei ve ca na ki n u ma b a n d  base d o n pre vi o us ( p ost -h oc) a nal ysis, t here is 
a n h y p ot hesis t hat ca na ki n u ma b ca n re d uce pai n i n patie nts wit h  k nee O A wit h i nfla m mati o n.  
4. 5. 2   
Ri s k s a s s o ci at e d wit h L N A 0 4 3  
I n vasi ve, st u d y-s pecific pr oce d ures i ncl u de s y n o vial fl ui d as pirati o n a n d i.a. i njecti o n of 
L N A 0 4 3. As wit h a n y i n vasi ve pr oce d ure (i.a. i njecti o n), a ris k of i nfla m mati o n/s welli n g, pai n, 
i nfecti o n, a n d/ or blee di n g e xists; f or i.a. i njecti o ns t hese c o m plicati o ns ca n occ ur b ot h at t he 
i njecti o n site a n d wit hi n t he j oi nt s pace.  Rece nt  re p orts i n dicate a n i nci de nce of 0. 0 4-0. 1 % of 
se ptic art hritis after i ntra-artic ular i nfiltrati o ns ( Kjaer Peterse n  et al 2 0 1 9 , Ke m merer  et al 2 0 1 7 , 
Geirss o n  et al 2 0 0 8 ).  
I n  
a d diti o n,  
w he n  
pr o per 
tec h ni q ue  
(O' R o ur ke  
2 0 2 0 , 
A W M F  S 1  Leitli nie  2 0 1 5 ) is a p plie d i n a healt h y p o p ulati o n, a n d w he n a n o n-ster oi dal dr u g is 
use d, t his rate is c o nsi dera bl y l o wer. Pr o per ase ptic   tec h ni q ue will be use d i n all p hases of  
 
 a n d 
a d mi nistrati o n t o f urt her 
pre ve nt t he 
a b o ve 
me nti o ne d ris ks. 
P ote ntial  a d verse effects ma y i ncl u de l ocal reacti o ns at t he site of i njecti o n, s uc h as l ocal pai n, 
s welli n g or i nfla m mati o n, a n d will be m o nit ore d cli nicall y. S y n o vial fl ui d as pirati o n will be 
perf or me d at t he sa me ti me as t he i.a. i njecti o n of L N A 0 4 3, wit h n o a d di ti o nal har m or 
disc o mf ort f or t he partici pa nt.  
S yste mic c o nce ntrati o ns of L N A 0 4 3 f oll o wi n g i.a. a d mi nistrati o n t o t he partici pa nts st u die d i n 
t he FI H st u d y ( L N A 0 4 3 X 2 1 0 1) re mai ne d < 3 0 0 n g/ m L a n d wit hi n t he p h ysi ol o gic ra n ge f or 
circ ulati n g c o nce ntrati o ns of A N G P T L 3, t he e n d o ge n o us pr otei n fr o m w hic h L N A 0 4 3 is 
deri ve d. I n a d diti o n, base d o n t he c urre nt data a vaila ble, L N A 0 4 3 is n ot e x pecte d t o persiste ntl y 
bi n d t o or bl oc k i ts rece pt ors. 
Bei n g a m o difie d pr otei n, h y perse nsiti vit y a n d or i m m u n o ge nicit y t o L N A 0 4 3 ma y occ ur. 
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 3 5  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
I n t he c o m plete d a n d o n g oi n g cli nical st u dies, n o case of l ocal or s yste mic h y perse nsiti vit y 
reacti o ns ha ve bee n o bser ve d, a n d n o patie nt de vel o pe d A D A after a si n gle or m ulti ple 
i ntraartic ular i njecti o n of L N A 0 4 3. T he i m pact of ne utralizi n g a nti b o dies t hat ma y cr oss-react 
wit h e n d o ge n o us A N G P T L 3 is n ot k n o w n, b ut t he li kel y i m pact is c o nsi dere d relati vel y l o w.  
H u ma ns wit h l oss -of -f u ncti o n varia nts i n b ot h c o pies of t he A N G P T L 3 ge ne ha ve l o w plas ma 
L D L -C, l o w H D L -C, a n d l o w tri gl yceri des, b ut n o o b vi o us a d verse c o nse q ue nces, s u g gesti n g 
t hat a bse nce of A N G P T L 3 d oes n ot res ult i n a n y seri ous effects. De vel o p me nt of a nti -L N A 0 4 3 
a nti b o dies will be m o nit ore d, as well as a n y p ote ntial reacti o ns relate d t o s uc h a nti b o dies, s uc h 
as a nti b o d y-me diate d art hr o pat h y or i m pact o n li pi d meta b olis m or re nal f u ncti o n, will be 
m o nit ore d cl osel y wit h t he c orres p o n di n g safet y pla n i n  place.  
Base d o n a c o m pre he nsi ve a nal ysis of all safet y data fr o m b ot h c o m plete d a n d o n g oi n g 
precli nical a n d cli nical st u dies, t here is n o e vi de nce t o s u g gest t hat treat me nt wit h L N A 0 4 3 
i ncreases t he ris k of h y perse nsiti vit y i n h u ma ns. 
 
 
 
 
 
 
T o miti gate t he p ossi ble ris k of se vere h y perse nsiti vit y reacti o ns i n h u ma ns,  partici pa nts wit h a 
hist or y of h y perse nsiti vit y reacti o ns t o a n y of t he st u d y treat me nts or e xci pie nts, or t o dr u gs of 
si milar classes, will be e xcl u de d fr o m partici pati o n i n t his st u d y. Partici pa nts w h o e x perie nce 
a n y gra de h y perse nsiti vit y reacti o n will n ot be re -d ose d, a n d t he st u d y will be pa use d a n d n o 
f urt her d osi n g will occ ur pe n di n g a f ull safet y re vie w if t w o or m ore partici pa nts de vel o p a n 
ac ute aller gic reacti o n of Gra d e 3 se verit y or greater, or o ne or m ore partici pa nts wit h 
life-t hreate ni n g ( Gra de 4) or fatal ac ute aller gic reacti o n acc or di n g t o t he N CI-C T C A E/ v 4. 0 3 
Criteria wit hi n 2 4 h o urs f oll o wi n g L N A 0 4 3 a d mi nistrati o n (i.e., acti ve dr u g), u nless clearl y 
ca use d b y e x p os ure t o a k n o w n aller ge n (i.e. pea n ut aller g y).  
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 3 6  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
W o me n of c hil d -beari n g p ote ntial m ust 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 nc y were t o occ ur d uri n g t he st u d y, a n d a gree t hat i n or der 
t o partici pate i n t he st u d y t he y m ust a d here t o t he c o ntrace pti o n re q uire me nts o utli ne d i n t he 
e xcl usi o n criteria. If t here is a n y q uesti o n t hat t he partici pa nt will n ot relia bl y c o m pl y, t he y 
s h o ul d n ot be e ntere d or c o nti n ue i n t he st u d y. 
A N G P T L 3 is e x presse d i n h u ma n gl o mer ular e n d ot helial cells a n d c o ul d i ncrease t he 
per mea bilit y, res ulti n g i n pr otei n uria. T he C -ter mi nal of e n d o ge n o us A N G P T L 3 affects 
gl o mer ular per mea bilit y b y i n d uci n g F -acti n rearra n ge me nt w hic h is i n v ol ve d i n p o d oc yte 
d etac h me nt a n d a p o pt osis. P o d oc ytes are a n i nte gral me m ber of t he filtrati o n barrier i n re nal 
gl o mer uli. As L N A 0 4 3 is a 
m o difie d, rec o m bi na nt versi o n of t he h u ma n A N G P T L 3, 
c o m prisi n g t he maj or part of its C -ter mi nal d o mai n, t here is a t he oretical ris k of pr otei n uria. 
F or  t his reas o n, patie nts wit h ne p hr otic s y n dr o me a n d or  si g nifica nt pr otei n uria ( ≥ 3 + o n 
di pstic k or pr otei n:creati ni ne rati o ≥ 1 g/ g Cr) are e xcl u de d fr o m t his st u d y.  
T here ma y be u n k n o w n ris ks of L N A 0 4 3 w hic h ma y be seri o us.  
4. 5. 3   
Ri s k s a s s o ci at e d wit h c a n a ki n u m a b  
S yste mic c o nce ntrati o ns of ca na ki n u ma b f oll o wi n g i.a. a d mi nistrati o n t o t he oste oart hritis 
partici pa nts st u die d i n t he c o m plete d trial A C Z 8 8 5 C 2 2 0 1 were c o m para ble wit h s.c. i njecti o n 
a n d are c o nsi dere d n ot t o c o nfer a d diti o nal safet y ris ks. N o a d diti o nal s afet y ris k is e x pecte d 
fr o m a si n gle l ocal a d mi nistrati o n. 
Ca na ki n u ma b is ass ociate d wit h a n i ncrease d i nci de nce of seri o us i nfecti o ns (see t he Refere nce 
Safet y I nf or mati o n  i n t he ca na ki n u ma b  I n vesti gat or's Br oc h ure). T heref ore, partici pa nts s h o ul d 
be m o nit ore d caref ull y f or si g ns a n d s y m pt o ms of i nfecti o ns bef ore, d uri n g a n d after treat me nt 
wit h ca na ki n u ma b. P h ysicia ns s h o ul d e xercise ca uti o n w he n a d mi nisteri n g ca na ki n u ma b t o 
partici pa nts wit h  i nfecti o ns, a hist or y of rec urri n g i nfecti 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. T he prese nce of late nt or acti ve t u berc ul osis m ust be 
e xcl u de d bef ore a d mi nistrati o n.  
O ver 2, 6 0 0 patie nts i ncl u di n g a p pr o xi matel y 4 8 0 c hil dre n (a ge d 2 t o 1 7 years) ha ve bee n treate d 
wit h ca na ki n u ma b i n i nter ve nti o nal st u dies i n Peri o dic fe ver s y n dr o mes, Still’s disease, g o ut y 
art hritis, or ot her I L -1 beta me diate d diseases, a n d healt h y v ol u nteers. T he m ost fre q ue ntl y 
re p orte d a d verse dr u g reacti o ns were i nfecti o ns, pre d o mi na ntl y of the u p per res pirat or y tract. 
T he  maj orit y of t he e ve nts were mil d t o m o derate alt h o u g h seri o u s i nfecti o ns were o bser ve d. 
N o  im pact o n t he t y pe reacti o ns a n d o p p or t u nistic i nfecti o ns ha ve bee n re p orte d i n patie nts 
treate d wit h ca na ki n u ma b. Ne utr o pe nia a n d le u k o pe nia has als o bee n o bser ve d wit h I L-1 
i n hi bit ors i ncl u di n g ca na ki n u ma b, wit h tra nsie nt decreases t o < 1 x 1 09/ L o bser ve d d uri n g 
cli nical trials wit h ca na ki n u ma b. I n a d diti o n t o e x perie nce i n a p pr o ve d i n dicati o ns, o ver 
1 0, 0 0 0  patie nts were e nr olle d i n C A N T O S st u d y e val uati n g ca na ki n u ma b f or t he pre ve nti o n of 
rec urre nt car di o vasc ular e ve nts a m o n g sta ble p ost-m y ocar dial i nfa rcti o n patie nts wit h ele vate d 
C -reacti ve 
pr otei n ( C R P), 
wit h 
a 
c u m ulati ve 
e x p os ure 
of 
3 2 6 6 2. 6 
patie nt-years 
( 2 1 7 4 5. 1 patie nt -years f or t otal ca na ki n u ma b a n d 1 0 9 1 7. 5 patie nt -years t otal f or place b o). 
N o  cli nicall y mea ni n gf ul differe nces bet wee n ca na ki n u ma b a n d place b o were o bser ve d f or 
m ost safet y t o pics of i nterest, a part fr o m a n i ncrease i n seri o us i nfecti o ns a n d of fatal 
i nfecti o ns/se psis; h o we ver, t he o verall i nci de nce was l o w. T he patter n of i nfecti ons was sta ble 
o ver ti me, wit h ver y fe w c o nfir me d o p p ort u nistic i nfecti o ns distri b ute d e ve nl y acr oss t he 

N o v arti s  
C o nfi d e nti al  
P a g e 3 7  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
treat me nt gr o u ps. T here was n o e vi de nce of t u berc ul osis reacti vati o n i n ca na ki n u ma b-treate d 
patie nts.  
N o vartis is c o m mitte d t o s u p p orti n g t he safet y a n d well -bei n g of o ur st u d y partici pa nts, 
i n vesti gat ors, a n d site staff. All l ocal re g ulati o ns a n d site re q uire me nts s h o ul d be a p plie d i n t he 
c o u ntries t hat are affecte d b y t he C O VI D -1 9 pa n de mic. T he N o vartis cli nical trial tea m will 
re vie w t he sit uati o n i n eac h partici pati n g c o u ntr y a n d w or k wit h I n vesti gat ors t o c o nti n ue t o 
e ns ure t he safet y of partici pa nts d uri n g t he c o n d uct of t he trial. A be nefit/ris k assess me nt has 
bee n ma de a n d has bee n deter mi ne d t o n ot  si g nifica ntl y c ha n ge f or t he partici pa nts t hat are 
pla n ne d t o be e nr olle d i n t he pr o p ose d cli nical trial. As t he C O VI D -1 9 sit uati o n e v ol ves, 
I n vesti gat ors m ust use t heir best j u d ge me nt t o mi ni mize ris k t o partici pa nts d uri n g t he c o n d uct 
of t he st u d y.  
Li ve vacci nes s h o ul d n ot be gi ve n c o nc urre ntl y wit h ca na ki n u ma b. N o data are a vaila ble o n 
eit her t he effects of li ve vacci nati o n or t he sec o n dar y tra ns missi o n of i nfecti o n b y li ve vacci nes 
i n patie nts recei vi n g ca na ki n u ma b. It is rec o m me n de d t hat, if p ossible, pe diatric a n d a d ult 
patie nts s h o ul d c o m plete all i m m u nizati o ns i n acc or da nce wit h c urre nt i m m u nizati o n g ui deli nes 
3  m o nt hs pri or t o or after i nitiati n g ca na ki n u ma b t hera p y. O n t he ot her ha n d, t he res ults of a 
st u d y i n healt h y a d ult partici pa nts de m o nstrate d t hat a si n gle d ose of ca na ki n u ma b 3 0 0  m g 
a d mi nistere d s u bc uta ne o usl y di d n ot affect t he i n d ucti o n a n d persiste nce of a nti b o d y res p o nses 
after vacci nati o n wit h i nfl ue nza a n d gl yc os ylate d pr otei n -base d me ni n g oc occ us vacci nes. 
A d diti o nall y, t here was n o e vi de nce of her pes z oster i nfecti o n relate d  t o recei pt of her pes z oster 
li ve (atte n uate d) vacci ne i n 6 0 patie nts w h o recei ve d t he vacci ne after starti n g treat me nt wit h 
ca na ki n u ma b i n t he C A N T O S st u d y ( 2 0, 1 6 a n d 1 8 patie nts o n 3 0 0 m g, 1 5 0 m g, a n d 5 0  m g, 
res pecti vel y). 
T he res ults of a 5 6 -wee k, o pe n -la bel st u d y i n C A P S patie nts a ge d 4 years a n d y o u n ger 
de m o nstrate d t hat all patie nts w h o recei ve d n o n -li ve, sta n dar d of care c hil d h o o d vacci nati o ns 
de vel o pe d pr otecti ve le vels of a nti b o d y. I n a d diti o n, ti me t o t he first i nfec ti o n i n patie nts w h o 
were vacci nate d wit hi n t he 3 m o nt hs pri or t o baseli ne, f or i n vesti gat or -re p orte d i nfecti o ns, 
i n vesti gat or-re p orte d seri o us i nfecti o ns a n d I A C-c o nfir me d i nfecti o ns i n t he C A N T O S st u d y 
di d n ot s h o w a n y cli nicall y 
mea ni n gf ul differe nces b et wee n t he treat me nt gr o u ps. 
Si milar  o bser vati o ns were re p orte d f or ti me t o t he first i nfecti o n b y vacci nati o n wit hi n 6 m o nt hs 
fr o m baseli ne. 
4. 5. 4   
Ri s k s a s s o ci at e d wit h i m a gi n g a s s e s s m e nt s  
A n a nter o p osteri or vie w x -ra y of t he tar get a n d c o ntralateral k nees are ofte n perf or me d d uri n g 
t he r o uti ne e val uati o n of patie nts wit h k nee pai n, b ut n ot al wa ys. C o nse q ue ntl y, i n s o me 
partici pa nts t he y will be o btai ne d o nl y f or researc h p ur p oses. T he t otal  a m o u nt of ra diati o n 
e x p os ure per partici pa nt fr o m t hese X -ra ys will be a b o ut 1 0 0 µ S v. T his a m o u nt of ra diati o n is 
e q ui vale nt t o a p pr o xi matel y 1 3. 8  da ys of bac k gr o u n d e x p os ure ( 0. 3  µ S v per h o ur at sea le vel). 
F or  effecti ve ra diati o n d oses u n der 3  m S v ( 3 0 0  mre m), t he ris k is c o nsi dere d t o be " mi ni mal". 
T heref ore,  t he ra diati o n e x p os ure i n t his st u d y i n v ol ves mi ni mal ris k a n d is necessar y t o e ns ure 
eli gi bilit y of patie nts.  

N o v arti s  
C o nfi d e nti al  
P a g e 3 8  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
Ma g netic res o na nce i ma gi n g ( M RI) will be use d i n t his st u d y b ot h f or patie nt selecti o n a n d 
f oll o w-u p p ur p oses. M RI is a n o n -i n vasi ve ra di ol o g y tec h ni q ue t hat has n o x-ra y ra diati o n 
e x p os ure. T h us i n pri nci ple, M RI sca ns ca n be re peate d i n t he sa me patie nt as ofte n as necessar y. 
T he M RI sca n ni n g e q ui p me nt ma y ca use a feeli n g of cla ustr o p h o bia i n s usce pti ble pers o ns. 
T he  prese nce of metal i n t he b o d y ma y als o be a safet y hazar d or a ffect t he M R i ma ge q ualit y. 
F or  m ore i nf or mati o n, see e xcl usi o n criteri o n i n Secti o n  5. 2 . 
I n a d diti o n, f or t he sa ke of s y n o vitis assess me nts, a ga d oli ni u m-base d c o ntrast a ge nt ( G B C A) 
will be a d mi nistere d as a n i. v. b ol us d uri n g eac h D C E -M RI sessi o n. T here is rece nt e vi de nce 
of ga d oli ni u m de p ositi o n i n brai n tiss ues f oll o wi n g use of G B C As. Alt h o u g h n o s y m pt o ms or 
diseases li n ke d t o ga d oli ni u m acc u m ulati o n i n t he brai n ha ve bee n i de nti fie d, healt h a ut h orities 
t o o k a preca uti o nar y a p pr oac h (e. g., E M A/ 6 2 5 3 1 7/ 2 0 1 7 ), n oti n g t hat data o n t he l o n g-ter m 
effects i n t he brai n are li mite d. T his le d t o t he s us pe nsi o n of se veral li near G B C As a n d t he 
rec o m me n dati o n t hat a n ot her class of G B C As k n o w n as macr oc yclic a ge nts be use d as a n 
alter nati ve s ol uti o n, as t he y are dee me d m ore sta ble a n d ha ve a l o wer pr o pe nsit y t o release 
ga d oli ni u m t ha n li near a ge nts. Alt h o u g h t his is hi g hl y de bate d, t he c urre nt belief is t hat s uc h 
a ge nts, es peciall y t he li near ga d oli ni u m a ge nts, ma y als o i ncrease t he ris k of a rare b ut 
seri o us disease  calle d ne p hr o ge nic s yste mic fi br osis ( N F S). T o pre ve nt t his ris k a n d i n 
acc or da nce 
wit h rec o m me n de d g ui da nce (e. g., T he  R o yal  C olle ge  of  Ra di ol o gists  2 0 1 9 , 
Ma g ne vist
®  Prescri bi n g  i nf or mati o n 2 0 1 8 ), pe o ple wit h se vere ki d ne y fail ure, patie nts wit h 
pre vi o us se vere aller gic/a na p h ylact oi d reacti o n t o a G B C A; patie nts wit h m o derate t o se vere  
re nal disease or ac utel y deteri orati n g  re nal f u ncti o n, w h o w o ul d be at ris k of ne p hr o ge nic 
s yste mic fi br osis, m ust be e xcl u de d fr o m partici pati n g i n t his st u d y. 
4. 5. 5   
Bl o o d s a m pl e v ol u m e  
A v ol u me s maller t ha n a t y pical bl o o d d o nati o n is pla n ne d t o be c ollecte d fr o m eac h partici pa nt 
o ver a peri o d of  a p pr o xi matel y 1 3 m o nt hs. T he a p pr o xi mate v ol u mes are me nti o ne d i n t he I C F. 
A d diti o nal sa m ples ma y be re q uire d f or safet y m o nit ori n g.  
Ti mi n gs of bl o o d sa m ple c ollecti o n are o utli ne d i n t he assess me nt sc he d ule ( Ta ble  8 -1 ). 
A s u m mar y bl o o d l o g is pr o vi de d i n t he la b orat or y ma n ual. I nstr ucti o ns f or sa m ple c ollecti o n, 
pr ocessi n g, st ora ge a n d s hi p me nt i nf or mati o n are als o a vaila ble i n t he la b orat or y ma n ual.  
See  Secti o n  8. 5. 2. 9  o n t he p ote ntial use of resi d ual sa m ples.  
4. 6   
R ati o n al e f or P u bli c H e alt h E m er g e n c y miti g ati o n pr o c e d ur e s  
I n t he e ve nt of a P u blic Healt h e mer ge nc y as declare d b y L ocal or Re gi o nal a ut h orities i.e. 
pa n de mic, e pi de mic or nat ural disaster, miti gati o n pr oce d ures ma y be re q uire d t o e ns ure 
partici pa nt safet y a n d trial i nte grit y are liste d i n rele va nt secti o ns of t h e st u d y pr ot oc ol. 
N otificati o n of t he P u blic healt h e mer ge nc y s h o ul d be disc usse d wit h N o vartis pri or t o 
i m ple me ntati o n of miti gati o n pr oce d ures, a n d per mitte d/a p pr o ve d b y L ocal or Re gi o nal Healt h 
A ut h orities a n d Et hics C o m mittees as a p pr o priate.  

N o v arti s  
C o nfi d e nti al  
P a g e 3 9  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
5   
St u d y P o p ul ati o n  
T he st u d y p o p ulati o n c o nsists of male a n d fe male a d ult patie nts wit h s y m pt o matic mil d t o 
m o derate ra di o gra p hic k nee O A ( Kell gre n -La wre nce ( K L) gra de 2 -4) wit h i nfla m mati o n. 
T he  i nfla m mati o n will be c o nfir me d b y ele vate d hs C R P ( ≥1. 8  m g/ L) a n d  o bser ve d s y n o vitis o n 
M RI, at Scree ni n g 2.  
A p pr o xi matel y 1 3 8 patie nts are f oresee n t o be e nr olle d a n d ra n d o mise d i n t he trial, of w hic h at 
least 1 2 4 are e x pecte d t o c o m plete t he Da y 1 9 7 e val uati o n per pr ot oc ol ( 1 0 % disc o nti n uati o n 
rate). A d diti o nal patie nts ma y be e nr olle d if t he disc o nti n uati o n rate e xcee ds 1 0 %. 
T he i n vesti gat or m ust e ns ure t hat a patie nt meets all of t he i ncl usi o n a n d n o ne of t he e xcl usi o n 
criteria bef ore e nr olli n g hi m/ her i nt o t he trial. N o a d diti o nal criteria s h o ul d be a p plie d b y t he 
i n vesti gat or w he n c o nsi deri n g a patie nt's eli gi bilit y. 
T he s uffi x a , b, c, etc., i n t he n u m beri n g of criteria i n Secti o n 5. 1  a n d Secti o n 5. 2  de n otes t he  
n u m ber of ti mes t he criteri o n te xt has bee n u p date d c o m pare d t o t he i nitial pr ot oc ol versi o n  
(i nsi g nifica nt c ha n ges t hat d o n ot alter t he act ual re q uire me nts are n ot c o u nte d). 
5. 1   
I n cl u si o n crit eri a 
Partici pa nts eli gi ble f or i ncl usi o n i n t his st u d y m ust meet all  of t he f oll o wi n g criteria:  
1.   
Writte n i nf or me d c o nse nt m ust be o btai ne d bef ore a n y assess me nt is perf or me d  
2.   
A ble t o c o m m u nicate well wit h t he i n vesti gat or at Scree ni n g 1, t o u n dersta n d a n d 
c o m pl y wit h t he re q uire me nts of t he trial  
3.   
Male or fe male patie nts 4 0 t o 8 0 years of a ge, i ncl usi ve  
4.   
B o d y wei g ht of at least  5 0 k g a n d b o d y mass i n de x ( B MI)  wit hi n t he ra n ge of  
1 8. 0 - 3 5. 0 k g/ m 2 
5.   
Dia g n osis of pri mar y ti bi ofe m oral k nee O A b y sta n dar d A merica n C olle ge of 
R he u mat ol o g y ( A C R) cli nical a n d ra di o gra p hic criteria ( Alt ma n  et al 1 9 8 6 ) 
6.   
M o derate t o se vere O A  pai n (c orres p o n di n g t o N R S Pai n ≥5 t o ≤9) i n t he tar get k nee f or 
t he maj orit y of da ys i n t he last 3 m o nt hs pri or t o Scree ni n g 1, as per patie nt j u d g me nt 
7a.  Pri mar y s o urce of pai n t hr o u g h o ut t he b o d y is d ue t o O A i n t he tar get k nee, a n d 
Wi des prea d Pai n I n de x ( W PI) sc ore of ≤4, at Scree ni n g 1  
8a.  M o derate t o se vere O A  pai n (c orres p o n di n g t o N R S Pai n ≥5 t o ≤9) i n t he tar get k nee, 
c o nfir me d b y  
9a.  K O O S pai n s u bscale < 6 0 f or t he tar get k nee at Scree ni n g 1, Scree ni n g 2 a n d 
Scree ni n g  4  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 4 0  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
1 0 a. C urre nt use of a nal gesic t hera p y, i ncl u di n g P R N (as nee de d) use, f or c o ntr ol of l ocal pai n i n 
t he tar get k nee 
•  Patie nts ta ki n g gl uc osa mi ne , c h o n dr oiti n, or a n y ot her n utrace utical wit h p ote ntial 
acti vit y o n cartila ge re pair m ust be willi n g t o disc o nti n ue use fr o m Scree ni n g 1 . 
1 1 a. Hi g h se nsiti vit y C -reacti ve Pr otei n ( hs C R P) ≥1. 8  m g/ L  
1 2a.  Ra di o gra p hic K L gra de 2 t o 4 k nee O A a n d j oi nt s pace wi dt h (J S W) 2. 0 -4. 0  m m ( me n) 
or 1. 5 -3. 5 m m ( w o me n) i n t he me dial ti bi ofe m oral c o m part me nt ( T F C) i n t he tar get 
k nee, c o nfir me d b y X -ra y at Scree ni n g 1 
1 3a.  C o ntrast -e n ha nce d M RI ( C E -M RI) dia g n ose d m o derate or se vere k nee s y n o vitis base d 
o n a n esta blis he d s y n o vitis sc ori n g s yste m ( m o derate sc ore 9 -1 2 or se vere sc ore ≥1 3) 
(G uer mazi  et al 2 0 1 1 ), at Scree ni n g 3. O nl y patie nts wit h cli nical s us pici o n of s y n o vitis 
(e. g. war mt h, s welli n g/ b ul ge si g n or patellar ta p si g n, as per i n vesti gat or j u d g me nt) 
s h o ul d u n der g o C E-M RI.  
5. 2   
E x cl u si o n crit eri a  
Partici pa nts meeti n g a n y of t he f oll o wi n g criteria are n ot eli gi ble f or i ncl usi o n i n t his st u d y.  
1a.  Hist or y of, or pla n ne d, f oll o wi n g s ur gical i nter ve nti o ns;  
•  K nee re place me nt ( partial or t otal) i n eit her k nee  
•  Art hr osc o p y  or la va ge  i n eit her k nee, wit hi n 6 m o nt hs pri or t o Scree ni n g 1 or pla n ne d 
d uri n g t he st u d y  
•  A n y ot her pre vi o us s ur gical i nter ve nti o n i n t he tar get k nee, or wit hi n 1 2 m o nt hs pri or 
t o Scree ni n g 1 or pla n ne d d uri n g t he st u d y f or t he c o ntralateral k nee, i ncl u di n g 
m osaic plast y, micr ofract ure, me niscect o m y > 5 0 % or oste ot o m y  
2.   
O nset of s y m pt o ms, or dia g n osis, of pri mar y O A i n ot her t ha n t he k nee j oi nts less t ha n 
3  m o nt hs pri or t o Scree ni n g 1  
3.   
M o derate t o se vere pai n i n t he c o ntralateral k nee f or t he maj orit y of da ys i n t he last 
3  m o nt hs pri or t o Scree ni n g 1, as per patie nt j u d g me nt  
4a.  U na ble or u n willi n g t o u n der g o M RI, or ha vi n g c o ntrai n dicati o ns t o M RI (e. g.,  metallic 
i m pla nts, metallic f orei g n b o dies, pace ma ker, defi brillat or), or ha vi n g c o ntrai n dicati o ns 
t o t he use of ga d oli ni u m-base d a ge nts (e. g. patie nts wit h pre vi o us se vere 
aller gic/a na p h ylact oi d reacti o n t o a ga d oli ni u m -base d c o ntrast a ge nt, m o derate t o 
se vere re nal disease, or ac utel y deteri orati n g re nal f u ncti o n) 
5.   
Malali g n me nt > 7. 5° i n t he tar get k nee (eit her var us or val g us)  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 4 1  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
6.   
U nsta ble tar get k nee j oi nt (i ncl u di n g, b ut n ot li mite d t o, p osttra u matic or c o n ge nital 
la xit y) or i ns ufficie ntl y rec o nstr ucte d li ga me nts base d o n me dical hist or y a n d/ or 
p h ysical e xa mi nati o n b y t he I n vesti gat or  
7a.  A n y dia g n osis of s yste mic i nfla m mat or y art hritis or c o n necti ve tiss ue disease, 
esta blis he d b y a na m nestic i nf or mati o n, cli nical si g ns a n d s y m pt o ms wit h la b orat or y or 
i ma gi n g mar kers, i ncl u di n g b ut n ot li mite d t o r he u mat oi d art hritis, ps oriatic art hritis, 
a n k yl osi n g s p o n d ylitis, g o u t, Pa get's disease, s yste mic l u p us er yt he mat os us or ot her 
s yste mic c o n diti o n t hat mi g ht c o nf o u n d assess me nt of O A (e. g. fi br o m yal gia) 
8 b . A n y dia g n osis of l ocal c o n diti o ns affecti n g t he tar get j oi nt, esta blis he d b y a na m nestic 
i nf or mati o n, or cli nical si g ns a n d s y m pt o ms wit h la b orat or y or i ma gi n g mar kers, 
i ncl u di n g b ut n ot li mite d t o se ptic art hritis, reacti ve art hritis, rec urre nt cli nical e pis o des 
of pse u d o g o ut, artic ular fract ure, or ot her l ocal c o n diti o ns t hat mi g ht c o nf o u n d 
assess me nt of O A  
9a.  S y m pt o matic patell o -fe m oral pai n i n t he tar get k nee as per t he I n vesti gat or's 
e xa mi nati o n 
1 0.  I psilateral hi p O A or hi p pr ost hesis rece ntl y i m pla nte d ( wit hi n 1 year pri or t o 
Scree ni n g  1) or hi p re place me nt o n eit her si de pla n ne d wit hi n t he st u d y peri o d  
1 1.  Hist or y of c oa g ul o pat h y ( he m o p hilia, v o n Wille bra n d disease, Fact or X deficie nc y, etc) 
or me dical c o n diti o n re q uiri n g a ntic oa g ulati o n treat me nt t hat w o ul d precl u de k nee 
i njecti o n 
•  N ote: L o w -d ose as piri n ( < 3 2 5 m g) or a ntic oa g ula nt ma na ge me nt (c u mari nics, 
he pari n,  direct oral a ntic oa g ula nts)  is all o we d as per l ocal practice a n d as l o n g as I N R 
< 3 bef ore t he pla n ne d first i njecti o n. S us pe nsi o n of ne w oral a ntic oa g ula nts ( N O A Cs; 
e. g., a pi xa ba n, da bi gatra n, ri var o xa ba n, a n d e d o xa ba n) bef ore i.a. i njecti o n s h o ul d be 
assesse d b y t he treati n g p h ysici a n, base d o n l ocal prescri bi n g i nf or mati o n.  
1 2a.  Meta b olic or ge netic a b n or malities ass ociate d wit h art hr o pat h y, e. g., art hr o gr y p osis 
m ulti ple x c o n ge nita, he m o p hilia, ne ur o ge nic art hr o pat h y, h y per m o bilit y or 
h y perelasticit y s y n dr o mes  
1 3a.  U nc o ntr olle d h y perte nsi o n, defi ne d as s yst olic bl o o d press ure ( S B P) > 1 6 0  m m H g a n d/ or 
diast olic bl o o d press ure ( D B P) > 1 0 0 m m H g at Scree ni n g 1  
1 4.  Hist or y or c urre nt dia g n osis of E C G a b n or malities i n dicati n g si g nifica nt safet y ris k f or 
patie nts partici pati n g i n t he st u d y s uc h as c o nc o mita nt cli nicall y si g nifica nt car diac 
arr h yt h mias (e. g. s ustai ne d ve ntric ular tac h ycar dia a n d cli nicall y si g nifica nt sec o n d or 
t hir d de gree A V bl oc k wit h o ut a pace ma ker), hist or y of fa milial l o n g Q T s y n dr o me or 
k n o w n fa mil y hist or y of T orsa des de P oi ntes  
1 5a.  A n y k n o w n acti ve i nfecti o ns, i ncl u di n g s ki n or k nee i nfecti o ns, or s us pecte d or 
c o nfir me d i m m u n oc o m pr o mise d state, i ncl u di n g b ut n ot li mite d t o e vi de nce of acti ve or 
late nt t u berc ul osis ( T B), c hr o nic or acti ve he patitis B or C, k n o w n hist or y of, or testi n g 
p ositi ve f or, HI V i nfecti o n  
1 6.  S ki n i nfecti o n, or w o u n d, at t he i n vesti gati o nal pr o d uct a d mi nistrati o n site  
1 7.  T otal W B C c o u nt < 3, 0 0 0/ µ L, ne utr o p hils < 1, 5 0 0/ µ L, he m o gl o bi n < 8. 5 g/ d L ( 8 5 g/ L) or 
platelet c o u nt < 1 0 0, 0 0 0/ µ L  

N o v arti s  
C o nfi d e nti al  
P a g e 4 2  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
1 8 b . Use of t he f oll o wi n g pr o hi bite d me dicati o ns ( wit hi n t he peri o d defi ne d bel o w pri or t o 
pla n ne d Da y 1):  
•  A n y l ocal i.a. treat me nt i nt o t he k nee, i ncl u di n g b ut n ot li mite d t o h yal ur o nic aci d, 
visc os u p ple me ntati o n a n d c ortic oster oi ds ( 1 2  wee ks)  
•  Diacet ylr hei n or ce ntrall y acti n g a nal gesics ( 1 2  wee ks)  
•  A n y bi ol o gical dr u g ( 2 6 wee ks)  
•  A n y pre vi o us e x p os ure t o L N A 0 4 3  
•  L o n g -ter m treat me nt ( > 1 4 da ys) wit h oral c ortic oster oi ds > 5 m g/ da y ( 8 wee ks)  
•  Oral gl uc osa mi ne, c h o n dr oiti n s ulfate, or a n y ot her n utrace utical wit h p ote ntial 
acti vit y o n cartila ge re pair ( 4  wee ks)  
•  A n y li ve vacci ne ( 1 2 wee ks)  
1 9.  Use of ot her i n vesti gati o nal dr u gs wit hi n 5 half -li ves fr o m Scree ni n g 1, or u ntil t he 
e x pecte d p har mac o d y na mic ( P D) effect has ret ur ne d t o baseli ne, w hic he ver is l o n ger; or 
l o n ger if re q uire d b y l ocal re g ulati o ns 
2 0.  Hist or y of h y perse nsiti vit y t o a n y of t he st u d y treat me nts or its e xci pie nts or t o dr u gs of 
si milar c he mical classes 
2 1.  Hist or y of l y m p h o pr oliferati ve disease or a n y k n o w n mali g na nc y or hist or y of 
mali g na nc y of a n y or ga n s yste m wit hi n t he past 5 years (e xce pt f or basal cell carci n o ma 
or acti nic kerat oses t hat ha ve bee n treate d wit h n o e vi de nce of rec urre nce i n t he past 
3  m o nt hs, or carci n o ma i n sit u of t he cer vi x or n o n -i n vasi ve mali g na nt c ol o n p ol y ps t hat 
ha ve bee n re m o ve d)  
2 2a.  A n y dia g n ose d ps yc hiatric c o n diti o n t hat i ncl u des, b ut is n ot li mite d t o, a hist or y of 
ma nia, bi p olar dis or der, ps yc h otic dis or der, sc hiz o p hre nia, or sc hiz oaffecti ve dis or der, 
de pressi o n or a n xiet y w hic h ma y je o par dize patie nt safet y, pai n perce pti o n or 
c o m plia nce wit h st u d y pr oce d ures, as j u d ge d b y t he i n vesti gat or  
2 3.  Hist or y of dr u g a b use or u n healt h y alc o h ol use wit hi n t he 1 2 m o nt hs pri or t o e x pecte d 
first d ose, or e vi de nce of s uc h a b use as i n dicate d b y t he la b orat or y assa ys c o n d ucte d 
d uri n g scree ni n g  
•  U n healt h y alc o h ol use is defi ne d as a hist or y of, or c urre nt, alc o h ol mis use/a b use or 
“ Fi ve or m ore dri n ks o n t he sa me occasi o n o n eac h of 5 or m ore da ys i n t he past 
3 0  da ys."  
2 4.  Pre g na nt or n ursi n g (lactati n g) w o me n  
2 5 b . W o me n of c hil d -beari n g p ote ntial, defi ne d as all w o me n p h ysi ol o gicall y ca pa ble of 
bec o mi n g pre g na nt, u nless  t he y are usi n g hi g hl y effecti ve met h o ds of c o ntrace pti o n 
w hile ta ki n g st u d y treat me nt a n d f or 3 m o nt hs after t he ca na ki n u ma b/ place b o i njecti o n, 
or 1 5 da ys  after t he last L N A 0 4 3 i njecti o n, w hic he ver is later 
  
Hi g hl y effecti ve c o ntrace pti o n met h o ds i ncl u de:  
•  T otal a bsti ne nce fr o m heter ose x ual i nterc o urse ( w he n t his is i n li ne wit h t he preferre d 
a n d us ual lifest yle of t he partici pa nt). Peri o dic a bsti ne nce (e. g. cale n dar, o v ulati o n, 
s y m pt ot her mal, p ost-o v ulati o n met h o ds) a n d wit h dra wal are n ot acce pta ble met h o ds  
of c o ntrace pti o n.  

N o v arti s  
C o nfi d e nti al  
P a g e 4 3  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
•
Fe male sterilizati o n ( ha ve ha d s ur gical bilateral o o p h orect o m y wit h or wit h o ut
h ysterect o m y), t otal h ysterect o m y or bilateral t u bal li gati o n at least si x wee ks bef ore
ta ki n g i n vesti gati o nal dr u g. I n case of o o p h orect o m y al o ne, o nl y w he 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
assess me nt.
•
Male sterilizati o n (at least 6 m o nt hs pri or t o Scree ni n g 1). F or fe male partici pa nts o n
t he st u d y t he vasect o mize d male part ner s h o ul d be t he s ole part ner f or t hat
partici pa nt .
•
Use of oral (estr o ge n a n d pr o gester o ne), i njecte d or i m pla nte d h or m o nal met h o ds of
c o ntrace pti o n or place me nt of a n i ntra uteri ne de vice (I U D) or i ntra uteri ne s yste m
(I U S) or ot her f or ms of h or m o nal c o ntrace pti o n t hat ha ve c o m para ble efficac y
(fail ure rate < 1 %), f or e xa m ple h or m o ne va gi nal ri n g or tra ns der mal h or m o ne
c o ntrace pti o n
I n case of use of oral c o ntrace pti o n, w o me n s h o ul d be sta ble o n t he sa me pill f or a 
mi ni m u m of 3 m o nt hs bef ore ta ki n g i n vesti gati o nal dr u g.  
If l ocal re g ulati o ns de viate fr o m t he c o ntrace pti o n met h o ds liste d a b o ve a n d re q uire 
m ore e xte nsi ve meas ures t o pre ve nt pre g na nc y, l ocal re g ulati o ns a p pl y a n d will be 
descri be d i n t he i nf or me d c o nse nt f or m (I C F).  
W o me n are c o nsi dere d p ost -me n o pa usal if t he y ha ve ha d 1 2 m o nt hs of nat ural 
(s p o nta ne o us) a me n orr hea wit h a n a p pr o priate cli nical pr ofile (e. g., a ge a p pr o priate, 
hist or y of vas o m ot or s y m pt o ms). W o me n are c o nsi dere d n ot of c hil d beari n g p ote ntial if 
t he y are p ost-me n o pa usal or ha ve ha d s ur gical bilateral o o p h orect o m y ( wit h or wit h o ut 
h ysterect o m y), t otal h ysterect o m y or t u bal li gati o n at least si x wee ks a g o. I n t he case of 
o o p h orect o m y al o ne, o nl y w he 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 assess me nt is s he c o nsi dere d n ot of c hil d beari n g 
p ote ntial.  See als o  Secti o n  8. 4. 4  ( Pre g na nc y a n d Assess me nts of Fertilit y).  
2 6a.  A n y s ur gical or me dical c o n diti o n w hic h mi g ht si g nifica ntl y alter t he a bs or pti o n, 
distri b uti o n, meta b olis m, or e xcreti o n of dr u gs, or w hic h ma y je o par dize t he patie nt i n 
case of partici pati o n i n t he st u d y, ta ki n g i nt o c o nsi derati o n t he patie nt’s me dic al hist or y, 
p h ysical e xa mi nati o n a n d/ or cli nical or la b orat or y e vi de nce, i ncl u de d b ut n ot li mite d t o : 
•
A ut oi m m u ne disease a me na ble t o, or u n der o n g oi n g, i m m u n o m o d ulat or y treat me nt
•
I nfla m mat or y b o wel disease, pe ptic ulcers, gastr oi ntesti nal i ncl u di n g rectal blee di n g
•
Maj or gastr oi ntesti nal tract s ur ger y s uc h as gastrect o m y, gastr o e nter ost o m y, or b o wel
resecti o n
•
Pa ncreatic i nj ur y or pa ncreatitis
•
K n o w n acti ve or rec urre nt he patic dis or der, i ncl u di n g b ut n ot li mite d t o cirr h osis,
he patitis B a n d he patitis C, or a b n or mal li ver f u ncti o n tests (e. g., a b n or mal ala ni ne
a mi n otra nsferase/ as partate a mi n otra nsferase ( A L T/ A S T), al kali ne p h os p hatase
le vels, ser u m bilir u bi n, al b u mi n a n d pr ot hr o m bi ne ti me, w here a n y si n gle para meter
> 2 ti mes U L N s h o ul d be c o nsi dere d e xcl usi o nar y
•
M o derate t o se vere re nal i m pair me nt, defi ne d as esti mate d G F R
<  5 0  m L/ mi n/ 1. 7 3  m 2 b y t he C K D -E PI f or m ula

N o v arti s  
C o nfi d e nti al  
P a g e 4 4  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
•  Ne p hr otic s y n dr o me a n d/ or si g nifica nt pr otei n uria, defi ne d as ≥ 3 + at uri nal ysis 
di pstic k test or pr otei n:  creati ni ne rati o ≥ 1 g/ g Cr  
•  E vi de nce of uri nar y o bstr ucti o n or diffic ult y i n v oi di n g at Scree ni n g 1  
6   
Tr e at m e nt  
6. 1   
St u d y tr e at m e nt  
Details o n t he re q uire me nts f or st ora ge a n d ma na ge me nt of st u d y treat me nt, a n d i nstr ucti o ns t o 
be f oll o we d f or partici pa nt n u m beri n g, prescri bi n g/ dis pe nsi n g, a n d a d mi nisteri n g st u d y 
treat me nt are o utli ne d i n t he P har mac y Ma n ual. 
See Secti o n  6. 2. 4. 1  f or rele va nt dietar y a n d s m o ki n g restricti o ns li n ke d t o d ose a d mi nistrati o n 
visits.  
6. 1. 1   
I n v e sti g ati o n al a n d c o ntr ol dr u g s 
T a bl e 6 -1   
I n v e sti g ati o n al a n d c o ntr ol dr u g 
I n v e sti g ati o n al/ 
C o ntr ol Dr u g  
( N a m e a n d 
Str e n gt h)  
P h ar m a c e uti c al 
D o s a g e F or m  
R o ut e of 
A d mi ni str ati o n  
Pr e s e nt ati o n   
S p o n s or ( gl o b al 
or l o c al)  
L N A 0 4 3 1 0 m g  
 
 
i nj e cti o n 
I ntr a-arti c ul ar 
i nj e cti o n 
O p e n l a b el b ul k 
s u p pl y  
 
S p o n s or ( gl o b al)  
A C Z 8 8 5 
1 5 0  m g/ 1 m L  
S ol uti o n f or 
i nj e cti o n ( 1 m L) 
I ntr a-arti c ul ar 
i nj e cti o n 
O p e n l a b el b ul k 
s u p pl y  
 
S p o n s or ( gl o b al)  
A C Z 8 8 5 0 
m g/ 1  m L  
Pl a c e b o t o 
A C Z 8 8 5 s ol uti o n 
f or i nj e cti o n 
( 1 m L)  
I ntr a-arti c ul ar 
i nj e cti o n 
O p e n l a b el b ul k 
s u p pl y  
 
S p o n s or ( gl o b al)  
All d ose pre parati o ns, re gar dless of t he treat me nt re gi me n, re q uire  
 of t he i nte n de d 
i n vesti gati o nal/c o ntr ol dr u g a n d are pre pare d i n a s yri n ge wit h a  m L i njecti o n v ol u me. 
See  Secti o n  6. 1. 3  f or a s pecificati o n of t he treat me nt ar ms. 
Ca na ki n u ma b is t he ge neric na me of A C Z 8 8 5. T he ge neric na me is ge nerall y use d t hr o u g h o ut 
t he pr ot oc ol a n d i n st u d y d oc u me ntati o n b ut refere nce t o ' A C Z 8 8 5' ma y als o e xist. L N A 0 4 3 has 
n ot bee n assi g ne d a ge neric na me.  
6. 1. 2   
A d diti o n al st u d y tr e at m e nt s  
It is i m perati ve t o har m o nize a n d d oc u me nt partici pa nts pai n me dicati o n as it ca n p ote ntiall y 
c o nf o u n d res ults. T heref ore, o nl y t he use of paraceta m ol/aceta mi n o p he n, u p t o 3 0 0 0 
m g/ da y,al o ne or i n c o m bi nati o n wit h l o w d ose c o dei ne, e. g. c o -c o da m ol, is all o we d as basic 
( n o n-resc ue) me dicati o n f or pai n c o ntr ol, re gar dless of t he ori gi n of t he pai n, u p u ntil Da y  1 9 7. 
T his  me dicati o n is herei n referre d  t o as " basic pai n me dicati o n". 
T he i n vesti gat or will eit her be s u p plie d wit h t he basic pai n me dicati o n or s o urce it l ocall y a n d 
be rei m b urse d b y t he s p o ns or f or its c ost, de pe n di n g o n t he c o u ntr y.  
C CI
C CI
C CI
C CI
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 4 5  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
At eac h st u d y visit, partici pa nts will be pr o vi de d wit h a q ua ntit y of t he basic pai n me dicati o n, 
eit her t he paraceta m ol/aceta mi n o p he n or t he paraceta m ol/aceta mi n o p he n pl us c o dei ne 
c o m bi nati o n pr o d uct, t hat is esti mate d t o be s ufficie nt u ntil t he ne xt pla n ne d st u d y visit, starti n g 
at Scree ni n g 1 a n d u ntil Da y 1 9 7. As t here are 1 6 wee ks bet wee n Da y 8 5 a n d Da y 1 9 7, a s maller 
a m o u nt of me dicati o n will be pr o vi de d at Da y 8 5 a n d t he partici pa nt will be res u p plie d b y t he 
site w he n nee de d a n d as per l ocal arra n ge ment. T he i n vesti gat or a n d partici pa nt ca n a gree t o 
s witc h fr o m o ne t o t he ot her t y pe of basic pai n me dicati o n, f or e xa m ple fr o m si n gle c o m p o u n d 
paraceta m ol/aceta mi n o p he n t o t he c o dei ne c o m bi nati o n pr o d uct or vice versa, if dee me d 
necessar y a n d pr o vi de d b ot h  t y pes are a vaila ble t o t he i n vesti gat or. 
Patie nts w h o use ot her pai n me dicati o ns m ust be willi n g t o s witc h t o t he basic pai n me dicati o n 
at Scr ee ni n g 1 (i ncl usi o n criteri o n).  
T he partici pa nt s h o ul d o nl y use t he basic pai n me dicati o n pr o vi de d b y t he i n vesti gat or, e ve n if 
s/ he uses or p urc hases t he sa me ge neric c o m p o u n d pri vatel y. 
T he basic pai n me dicati o n ca n be ta ke n at a n y p oi nt i n t he st u d y, als o wit hi n 4 8 h o urs of a st u d y 
visit. T o t he e xte nt p ossi ble, n o ot her pai n me dicati o n s h o ul d be use d u p u ntil Da y 1 9 7 (see 
Secti o n  6. 2. 3  Resc ue me dicati o n).  
Partici pa nts will be pr o vi de d wit h a diar y i n w hic h t he y will d oc u me nt t heir dail y pai n a n d t he 
use of (a n y) pai n me dicati o n fr o m Scree ni n g 1 u p t o Da y 8 5, pl us o ne wee k pri or t o eac h of t he 
Da y  1 9 7 a n d Da y 3 6 5 visits (see  Secti o n  8. 3. 2 ). T he i n vesti gat or or dele gate s h o ul d re vie w t he 
pai n diar y at eac h visit t o e ns ure t he n u m ber of ret ur ne d basic pai n me dicati o n ta blets are 
reas o na ble c o m pare d t o t he d oc u me nte d use i n t he pai n diar y b ut f ull dr u g acc o u nta bilit y will 
n ot be m o nit ore d.  
T he use of basic pai n me dicati o n s h o ul d be d oc u me nte d i n t he c o nc o mita nt me dicati o n pa ge of 
t he C R F, i ncl u di n g f or w hic h i n dicati o n t he me dicati o n is ta ke n (e. g., tar get k nee pai n, hea dac he, 
bac k pai n).  
T a bl e 6 -2   
B a si c p ai n m e di c ati o n  
M e di c ati o n  
( N a m e a n d 
Str e n gt h)  
P h ar m a c e uti c al 
D o s a g e F or m  
R o ut e of 
A d mi ni str ati o n  
S u p pl y T y p e   
S p o n s or ( gl o b al 
or l o c al)  
P ar a c et a m ol/ a c et a
mi n o p h e n 5 0 0 m g  
T a bl et  
Or al u s e   
O p e n l a b el b ul k 
s u p pl y  
S p o n s or (l o c al)  
P ar a c et a m ol/ a c et a
mi n o p h e n i n 
c o m bi n ati o n wit h 
l o w d o s e c o d ei n e; 
5 0 0/ 3 0 m g  
T a bl et  
Or al u s e   
O p e n l a b el b ul k 
s u p pl y  
S p o n s or (l o c al)  
T a bl et str e n gt h s c a n b e diff er e nt, d e p e n di n g o n t h e c o u ntr y.  
O nl y o n e or b ot h of t h e alt er n ati v e s m a y b e s u p pli e d t o t h e i n v e sti g at or sit e, d e p e n di n g o n t h e c o u ntr y.  
N o ot her treat me nt be y o n d i n vesti gati o nal dr u g, c o ntr ol dr u g a n d basic pai n me dicati o n are 
pr o vi de d i n t his trial.  
T he basic pai n me dicati o n m ust be rec or de d o n t he c o nc o mita nt me dicati o ns Case Re p ort F or m 
( C R F). 

N o v arti s  
C o nfi d e nti al  
P a g e 4 6  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
6. 1. 3   
Tr e at m e nt ar m s/ gr o u p  
Partici pa nts will be assi g ne d at Da y 1  t o o ne of t he f oll o wi n g 4 treat me nt ar ms i n a rati o of 
1: 2: 1: 2:  
•
T A 1: Si n gle i.a. i njecti o n of place b o t o ca na ki n u ma b f oll o we d b y q 4 w x 3 i.a. i njecti o ns of
4 0 m g L N A 0 4 3
•
T A 2: Si n gle i.a. i njecti o n of place b o t o ca na ki n u ma b
•
T A 3: Si n gle i.a. i njecti o n of 6 0 0 m g ca na ki n u ma b f oll o we d b y q 4 w x 3 i.a. i njecti o ns of
4 0  m g L N A 0 4 3
•
T A 4: Si n gle i.a. i njecti o n of 6 0 0 m g ca na ki n u ma b
6. 2   
Ot h er tr e at m e nt( s)  
6. 2. 1   
C o n c o mit a nt t h er a p y  
T he i n vesti gat or m ust i nstr uct t he partici pa nt t o n otif y t he i n vesti gat or site a b o ut a n y ne w 
me dicati o ns s/ he ta kes after t he partici pa nt was e nr olle d i nt o t he st u d y.  
All prescri pti o n 
me dicati o ns, o ver -t he-c o u nter dr u gs, i ncl u di n g t he pr o vi de d basic pai n 
me dicati o n, a n d si g nifica nt n o n -dr u g t hera pies (i ncl u di n g p h ysical t hera p y, ac u p u nct ure a n d 
bl o o d tra nsf usi o ns) a d mi nistere d or ta ke n wit hi n t he ti mefra me defi ne d i n t h e e ntr y criteria pri or 
t o t he start of t he st u d y a n d d uri n g t he st u d y, m ust be rec or de d o n t he C o nc o mita nt 
me dicati o ns/ Si g nifica nt n o n -dr u g t hera pies C R F.  
Me dicati o n e ntries s h o ul d be s pecific t o tra de na me, t he si n gle d ose a n d u nit, t he fre q ue nc y a n d 
r o ute of a d mi nistrati o n, t he start a n d disc o nti n uati o n date a n d t he reas o n f or t hera p y. 
Eac h c o nc o mita nt dr u g m ust be i n di vi d uall y assesse d a gai nst all e xcl usi o n criteria/ pr o hi bite d 
me dicati o n. If i n d o u bt, t he i n vesti gat or s h o ul d c o ntact N o vartis bef ore ra n d o mizi n g a patie nt 
or, if t he patie nt is alrea d y e nr olle d, t o deter mi ne if t he partici pa nt s h o ul d c o nti n ue partici pati o n 
i n t he st u d y. 
If a C O VI D-1 9 vacci ne is a vaila ble, vacci nati o n of trial partici pa nts wit h n o n -li ve vacci nes will 
be per mitte d d uri n g t he st u d y d urati o n. T he i n vesti gat or m ust d oc u me nt t heir disc ussi o n wit h 
t he partici pa nt re gar di n g C O VI D-1 9 vacci nati o n i n t he s o urce d oc u me ntati o n, a n d f oll o w t he 
i nstr ucti o ns descri be d a b o ve relate d t o t he C R F. 
6. 2. 1. 1  
P er mitt e d c o n c o mit a nt t h er a p y r e q uiri n g c a uti o n a n d/ or a cti o n  
T o pical N S AI Ds a n d t o pical ster oi ds are all o we d d uri n g t he st u d y.  
L o w -d ose as piri n ( < 3 2 5 m g)  are all o we d d uri n g t he st u d y.  
N o n -p har mace utical t hera pies, s uc h as electr ot hera p y,  ac u p u nct ure, p h ysi ot hera p y a n d 
c hir o practic treat me nt are all o we d d uri n g t he st u d y b ut m ust be re p orte d i n t he C o nc o mita nt 
me dicati o ns/ Si g nifica nt n o n -dr u g t hera pies e C R F.  
N S AI Ds are all o we d after Da y 1 9 7 b ut s h o ul d still n ot be ta ke n wit hi n 4 8  h o urs fr o m a n y  visit 
w here N R S Pai n or K O O S assess me nts are c o n d ucte d.  See  Secti o n 6. 2. 3  f or i nf or mati o n o n 
h o w t o pr ocee d i n case me nti o ne d me dicati o ns were ta ke n wit hi n 4 8 h o urs fr o m t he E o S visit.  

N o v arti s  
C o nfi d e nti al  
P a g e 4 7  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
T he i n vesti gat or m ust i nstr uct t he partici pa nt t o n otif y t he st u d y site a b o ut a n y ne w me dicati o ns 
a n d t hera pies s/ he ta kes or i nitiates after t he partici pa nt was e nr olle d i nt o t he st u d y.  
6. 2. 2   
Pr o hi bit e d m e di c ati o n  
Use of t he treat me nts dis pla ye d i n t he ta ble bel o w is N O T all o we d i n t he re p orte d ti mefra me. 
If re q uire d o utsi de of t he defi niti o ns of Resc ue me dicati o n (Secti o n  6. 2. 3 ), acti o ns ha ve t o be 
ta ke n as descri be d b y Ta ble  6 -3  bel o w.  
T a bl e 6 -3   
Pr o hi bit e d m e di c ati o n  
M e di c ati o n  
Pr o hi biti o n p eri o d  
A cti o n t a k e n  
L o c al i. a. tr e at m e nt i nt o t h e 
t ar g et k n e e, i n cl u di n g b ut n ot 
r e stri ct e d t o h y al ur o ni c a ci d, 
vi s c o s u p pl e m e nt ati o n a n d 
c orti c o st er oi d s  
1 2 w e e k s pri or t o D a y 1 t o E o S   
R e p ort pr ot o c ol d e vi ati o n a n d 
di s c o nti n u e st u d y tr e at m e nt  
L o n g t er m tr e at m e nt ( > 1 4 d a y s) 
wit h or al c orti c o st er oi d > 5 m g 
(t o pi c al, i ntr a n a s al a n d 
o p ht h al mi c ar e p er mitt e d)  
8 w e e k s pri or t o D a y 1 t o E o S   
R e p ort pr ot o c ol d e vi ati o n a n d 
di s c o nti n u e st u d y tr e at m e nt  
A n y bi ol o gi c dr u g  
2 6 w e e k s pri or t o D a y 1 u ntil 
E o S  
R e p ort pr ot o c ol d e vi ati o n a n d 
di s c o nti n u e st u d y tr e at m e nt  
Gl u c o s a mi n e, c h o n dr oiti n 
s ulf at e ( or al), or a n y ot h er 
n utr a c e uti c al wit h p ot e nti al 
a cti vit y o n c artil a g e r e p air  
4  w e e k s pri or t o D a y 1 t o E o S   
R e p ort pr ot o c ol d e vi ati o n  
Di a c et ylr h ei n  
1 2 w e e k s pri or t o D a y 1 t o E o S   
R e p ort pr ot o c ol d e vi ati o n a n d 
r e s c h e d ul e p ai n-r el at e d 
a s s e s s m e nt s* if t a k e n wit hi n 
t h e l a st 4 8 h o ur s fr o m a n y vi sit 
A c et yl s ali c yli c a ci d 
> 3 2 5  m g/ d a y  
S cr e e ni n g 1 t o E o S  
R e p ort pr ot o c ol d e vi ati o n a n d 
r e s c h e d ul e p ai n-r el at e d 
a s s e s s m e nt s* if  t a k e n wit hi n 
t h e l a st 4 8 h o ur s fr o m a n y vi sit 
P ar a c et a m ol/ a c et a mi n o p h e n 
> 3 0 0 0 m g/ d a y  
S cr e e ni n g 1 t o E o S  
R e p ort pr ot o c ol d e vi ati o n a n d 
r e s c h e d ul e p ai n-r el at e d 
a s s e s s m e nt s* if  t a k e n wit hi n 
t h e l a st 4 8 h o ur s  fr o m a n y vi sit 
O pi oi d s, i n cl u di n g tr a m a d ol a n d 
tr a n s d er m al f e nt a n yl p at c h e s, 
e x c e pt or al l o w d o s e c o d ei n e 
c o m bi n ati o n dr u g s  
S cr e e ni n g 1 t o E o S  
R e p ort pr ot o c ol d e vi ati o n a n d 
r e s c h e d ul e p ai n-r el at e d 
a s s e s s m e nt s* if  t a k e n wit hi n 
t h e l a st 4 8 h o ur s  fr o m a n y vi sit 

N o v arti s  
C o nfi d e nti al  
P a g e 4 8  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
M e di c ati o n  
Pr o hi biti o n p eri o d  
A cti o n t a k e n  
S y st e mi c N o n -St er oi d al A nti -
I nfl a m m at or y Dr u g s ( N S AI D s) 
ot h er t h a n t h o s e li st e d a b o v e, 
i n cl u di n g c o m bi n ati o n dr u g s 
wit h c o d ei n e or c aff ei n e  
N ot e N S AI D s u s e d a s r e s c u e 
m e di c ati o n ( s e e S e cti o n  6. 2. 3 ) 
a n d t o pi c al N S AI D s ar e 
p er mitt e d  
S cr e e ni n g 1 t o D a y 1 9 7 ,  
4 8 h o ur s pri or t o E o S  
R e p ort pr ot o c ol d e vi ati o n a n d 
r e s c h e d ul e p ai n-r el at e d 
a s s e s s m e nt s* if  t a k e n wit hi n 
t h e l a st 4 8 h o ur s  fr o m a n y vi sit 
C e ntr all y a cti n g a n al g e si c s, 
e. g. d ul o x eti n e, m e di c al 
m arij u a n a a n d C B D oil  
1 2 w e e k s pri or t o D a y 1 u ntil 
E o S  
R e p ort pr ot o c ol d e vi ati o n a n d 
r e s c h e d ul e p ai n-r el at e d 
a s s e s s m e nt s* if  t a k e n wit hi n 
t h e l a st 4 8 h o ur s  fr o m a n y vi sit 
A n y li v e v a c ci n e  
1 2 w e e k s pri or t o D a y 1 u ntil 1 2 
w e e k s p o st D a y 1  
R e p ort pr ot o c ol d e vi ati o n. 
If pri or t o D a y 1 a n d still 
c o m pli a nt wit h vi sit wi n d o w s, 
r e s c h e d ul e D a y 1 t o aft er t h e 
1 2 w e e k p eri o d, el s e s cr e e n f ail 
t h e p arti ci p a nt a n d p ot e nti all y 
r e-s cr e e n l at er.  
* N R S Pai n, K O O S, 
 
If nee de d, t he pai n-relate d assess me nts s h o ul d be resc he d ule d t o t he first p ossi ble ti me p oi nt 
o utsi de t he 4 8 -h o ur li mit (after last i nta ke), als o if t his p us hes t he c o m pleti o n t o o utsi de t he visit 
wi n d o w s pecifie d i n  Ta ble 8 -1 . T he resc he d ule d assess me nts ma y be d o ne as a re m ote c o ntact, 
i n w hic h case t he site pers o n nel m ust re me m ber t o pr o vi de t he P R Os t o t he partici pa nt at t he 
c urre nt visit. Bef ore t he pai n assess me nts are c o m plete d at t he resc he d ule d ti me p oi nt, t he 
res p o nsible site staff me m ber s h o ul d e ns ure a n y of t he rele va nt pr o hi bite d me dicati o ns were 
n ot ta ke n a gai n wit hi n 4 8 h o urs of t he c o ntact.  
6. 2. 3   
R e s c u e m e di c ati o n  
I n case t he basic pai n me dicati o n descri be d i n Secti o n  6. 1. 2  is i ns ufficie nt f or pai n c o ntr ol, 
N S AI Ds will be all o we d f or u p t o 3 da ys per cale n dar -wee k as resc ue me dicati o n, b ut m ust n ot 
be ta ke n wit hi n 4 8 h o urs of a n y visit w here pai n relate d assess me nts ( N R S  Pai n, K O O S,   
 
 are c o n d ucte d u p u ntil Da y 1 9 7, i ncl u de d. 
Resc ue me dicati o n will n ot be pr o vi de d b y t he s p o ns or.  
Use of resc ue me dicati o n m ust be d oc u me nte d b y t he partici pa nt i n t he pai n diar y, see 
Secti o n  8. 3. 2 . 
Use of resc ue me dicati o n m ust be rec or de d o n t he C o nc o mita nt me dicati o ns/ Si g n ifica nt n o n-
dr u g t hera pies C R F.  
6. 2. 4   
R e stri cti o n f or st u d y p arti ci p a nt s  
F or t he d urati o n of t he st u d y, partici pa nts s h o ul d be i nf or me d a n d re mi n de d of t he restricti o ns 
o utli ne d i n Secti o n  6. 2. 4. 1 . 
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 4 9  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
6. 2. 4. 1  
Di et ar y r e stri cti o n s a n d s m o ki n g  
N o ci garettes/ use of nic oti ne pr o d ucts are all o we d d uri n g t he sta y at t he i n vesti gati o nal site.  
Fr o m Scree ni n g 1 t o E o S, t he partici pa nt s h o ul d n ot s m o ke > 1 0 ci garettes per da y or use ot her 
t o bacc o pr o d ucts i n a m o u nts c orres p o n di n g t o > 1 0 ci garettes per da y. 
T he partici pa nt s h o ul d n ot c o ns u me > 2 u nits alc o h ol per da y i n t he last 4 8 h o urs pri or t o eac h 
st u d y visit. 
I n or der t o a v oi d wi de variati o ns i n uri ne v ol u mes o n P K c ollecti o n da ys, partici pa nts s h o ul d 
be e nc o ura ge d t o ha ve a fl ui d i nta ke of a p pr o xi matel y 2 4 0 m L e ver y 4 h o urs d uri n g t heir wa ki n g 
h o urs, i n a d diti o n t o t he fl ui d ta ke n wit h meals ( o nl y o n P K c ollec ti o n da ys). 
6. 2. 4. 2  
Ot h er r e stri cti o n s  
After d osi n g, p h ysical acti vit y (e. g., cli m bi n g stairs, r u n ni n g, bic ycli n g) s h o ul d be mi ni mize d 
f or 7 2 h o urs. N or mal pace wal ki n g is all o we d. 
N o stre n u o us p h ysical e xercise is all o we d fr o m 4 8 h o urs pri or t o first d osi n g u ntil Da y 1 9 7 (e. g., 
wei g ht lifti n g, l o n g -dista nce r u n ni n g ( > 3 0 0 0 m), i nte nsi ve ball ga mes (f o ot ball, ha n d ball, 
v olle y ball a n d bas ket ball), or te n nis o n a re g ular basis > 1 ti me w ee kl y). I n ge neral, acti vities 
ca usi n g hea v y l oa di n g or ra pi d m o ve me nts/r otati o ns of t he k nee s h o ul d be a v oi de d.  
Partici pa nts will be re q uire d t o a d here t o t he meas ures a n d pr oce d ures o utli ne d b y t he 
i n vesti gat or site t o pre ve nt S A R S-C o V -2 i nfecti o ns a m o n g trial partici pa nts a n d cli nical site 
pers o n nel.  
6. 3   
P arti ci p a nt n u m b eri n g, tr e at m e nt a s si g n m e nt, r a n d o mi z ati o n  
6. 3. 1   
P arti ci p a nt n u m b eri n g  
Eac h partici pa nt is i de ntifie d i n t he st u d y b y a Partici pa nt N u m ber ( Partici pa nt N o.), t hat is 
assi g ne d w he n t he partici pa nt is e nr olle d f or scree ni n g a n d retai ne d f or t he partici pa nt 
t hr o u g h o ut his/ her partici pati o n i n t he trial. A ne w Partici pa nt N o. will be assi g ne d at e ver y 
s u bse q ue nt e nr oll me nt if t he partici pa nt is re-scree ne d. T he Partici pa nt N o. c o nsists of t he 
Ce nter N u m ber ( Ce nter N o.), as assi g ne d b y N o vartis t o t he i n vesti gati ve site, wit h a se q ue ntial 
partici pa nt n u m ber s uffi xe d t o it s o t hat e ac h partici pa nt’s partici pati o n is n u m bere d u ni q uel y 
acr oss t he e ntire data base. U p o n si g ni n g t he i nf or me d c o nse nt f or m, t he partici pa nt is assi g ne d 
t o t he ne xt se q ue ntial Partici pa nt N o. a vaila ble. 
6. 3. 2   
Tr e at m e nt a s si g n m e nt, r a n d o mi z ati o n  
T he f oll o wi n g ra n d o mizati o n pr oce d ure will be use d t o e ns ure t hat treat me nt assi g n me nt is 
u n biase d a n d c o nceale d fr o m partici pa nts a n d i n vesti gat or staff.  
T he st u d y will use a vali date d  I nteracti ve Res p o nse Tec h n ol o g y (I R T) s yste m f or ra n d o mizi n g 
partici pa nts t o t he treat me nt ar ms. After eli gi bilit y is c o nfir me d at Scree ni n g 4, t he i n vesti gat or 
or dele gate will l o g i n t o t he I R T s yste m a n d re q uest t he ra n d o mizati o n. T he  partici pa nt will be 
assi g ne d a ra n d o mizati o n n u m ber w hic h is l i n ke d t o t he treat me nt ar m. T he ra n d o mizati o n 
n u m ber is differe nt fr o m t he partici pa nt n u m ber descri be d i n Secti o n  6. 3. 1  a n d is o nl y use d f or 
treat me nt all ocati o n. 

N o v arti s  
C o nfi d e nti al  
P a g e 5 0  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
T he treat me nt ar m i nf or mati o n will n ot be c o m m u nicated t o t he bli n de d re q uester. T he  assi g ne d 
treat me nt ar m will o nl y be c o m m u nicate d t o t he u n bli n de d p har macist/ n urse. 
T he ra n d o mizati o n sc he me f or partici pa nts will be re vie we d a n d a p pr o ve d b y a me m ber of t he 
Ra n d o mizati o n Office.  
6. 4   
Tr e at m e nt bli n di n g  
F or reas o ns descri be d i n Secti o n  4. 3 , t he L N A 0 4 3 treat me nt i n t his st u d y is o pe n la bel. As t here 
is n o L N A 0 4 3 place b o treat me nt ar m, partici pa nts, i n vesti gat ors, a n d t he s p o ns or will k n o w 
fr o m t he p oi nt of ra n d o misati o n if a partici pa nt is t o recei ve t he L N A 0 4 3 treat me nt, alt h o u g h it 
is n ot discl ose d w het her t he partic pa nt was ra n d o mise d t o T A 1 or T A 3. T he i nf or mati o n 
pr o vi de d i n t his secti o n t heref ore refers t o bli n di n g/ u n bli n di n g wit h re gar ds t o t he ca na ki n u ma b 
treat me nt. 
T his is a partici pa nt, i n vesti gat or, a n d s p o ns or -bli n de d st u d y. Partici pa nts, i n vesti gat ors, a n d 
t he s p o ns or will re mai n bli n de d t o st u d y treat me nt t hr o u g h o ut t he st u d y, e xce pt w here i n dicate d 
bel o w.  
T he i de ntit y of t he treat me nts will be c o nceale d b y t he use of st u d y dr u gs t hat are all i de ntical 
i n pac ka gi n g, la beli n g, sc he d ule of a d mi nistrati o n, a p peara nce, a n d o d or. 
T a bl e 6 -4   
Bli n di n g l e v el s  
R ol e  
Ti m e or E v e nt  
R a n d o mi z ati o n 
li st g e n er at e d 
Tr e at m e nt 
all o c ati o n & 
d o si n g  
S af et y e v e nt 
( si n gl e s u bj e ct 
u n bli n d e d)  
I nt eri m 
A n al y si s & 
d o s e e s c al ati o n  
P arti ci p a nt s  
B  
B  
UI  
B  
Sit e st aff  
B  
B  
UI  
B  
U n bli n d e d sit e st aff ( s e e 
t e xt f or d et ail s)  
B  
UI  
UI  
UI  
Dr u g S u p pl y a n d 
R a n d o mi z ati o n Offi c e  
UI  
UI  
UI  
UI  
U n bli n d e d s p o n s or st aff 
( s e e t e xt f or d et ail s) 
B  
UI  
UI  
UI  
St ati sti ci a n/ st ati sti c al 
pr o gr a m m er/ d at a a n al y st s  
B  
B  
UI  
UI  
All ot h er s p o n s or st aff n ot 
i d e ntifi e d a b o v e 
B  
B  
UI  
UI  
B R e m ai n s bli n d e d  
UI All o w e d t o b e u n bli n d e d o n i n di vi d u al p ati e nt l e v el  

N o v arti s  
C o nfi d e nti al  
P a g e 5 1  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
6. 4. 1   
Sit e p er s o n n el  
Wit h t he e xce pti o n of a n y u n bli n de d site pers o n nel i de ntifie d bel o w, all site pers o n nel 
(i ncl u di n g st u d y i n vesti gat or a n d st u d y n urse) will be bli n de d t o st u d y treat me nt t hr o u g h o ut t he 
st u d y. 
U n bli n di n g a si n gle partici pa nt at site f or safet y reas o ns (if necessar y f or partici pa nt 
ma na ge me nt) will occ ur via a n e mer ge nc y f u ncti o nalit y i n t he I R T s yste m. If t he u n bli n di n g 
occ urs after t he i njecti o n at Da y 1 a n d t he me dical stat us all o ws, t he parti ci pa nt ma y c o nti n ue 
t he st u d y, i ncl u di n g t he o pe n la bel treat me nt L N A 0 4 3 (if ra n d o mize d t o T A 1 or T A 3). 
Dr u g pr o d uct 
will be s u p plie d i n b ul k a n d nee ds 
 b y a n u n bli n de d 
p har macist/st u d y n urse w h o is i n de pe n de nt of t he st u d y tea m. T his u n bli n de d p har macist/ n urse 
will recei ve a n e mail fr o m t he I R T  s yste m wit h t he assi g ne d treat me nt ar m f or a ra n d o mize d 
partici pa nt. A p pr o priate meas ures m ust be ta ke n b y t he u n bli n de d p har macist/ n urse t o e ns ure 
t hat t he treat me nt assi g n me nts are c o nceale d fr o m t he rest of t he site pers o n nel. 
If 
 of L N A 0 4 3 d oses is ma de b y a bli n de d site staff me m ber, t he st ora ge a n d dr u g 
acc o u nta bilit y d oc u me ntati o n of t he L N A 0 4 3  
 m ust be ke pt se parate fr o m t he ca na ki n u ma b 
 a n d d oc u me nts t o a v oi d acci de ntal u n bli n di n gs.  
6. 4. 2   
S p o n s or st aff or d el e g at e  
T he f oll o wi n g u n bli n de d s p o ns or r oles are re q uire d f or t his st u d y:  
•  U n bli n de d fiel d m o nit or(s)  
•  U n bli n de d cli nical staff ma na gi n g dr u g re -s u p pl y t o site 
•  
 
•  U n bli n de d sa m ple a nal yst(s) ( hs C R P a n d  
 
T he u n bli n de d fiel d m o nit ors are re q uire d t o re vie w dr u g acc o u nta bilit y a n d all ocati o n at site. 
T he u n bli n de d m o nit ors are n ot pr o vi de d wit h a ra n d o mizati o n list directl y b ut will be u n bli n de d 
t hr o u g h re vie w of s o urce d oc u me ntati o n c o m pile d b y t he u n bli n ded p har macist/ n urse, w hic h 
details treat me nt all ocati o n t o i n di vi d ual partici pa nts.  
S p o ns or cli nical staff are re q uire d t o assist i n t he ma na ge me nt a n d re -s u p pl y of i n vesti gati o nal 
dr u g pr o d uct. T hese i n di vi d uals are n ot pr o vi de d wit h ra n d o mizati o n lists directl y, b ut ma y be 
u n bli n de d t hr o u g h c o m m u nicati o n of dr u g re -s u p pl y nee ds via t he u n bli n de d site p har macists.  
T he sa m ple a nal ysts will recei ve a c o p y of t he ra n d o mizati o n sc he d ule ( via re q uest t o t he 
Ra n d o mizati o n Office), t o facilitate a nal ysis of t he sa m ples. T he sa m ple a nal ysts will pr o vi de 
t he sa m ple data t o t he st u d y tea m u n der bli n de d c o n diti o ns. Sa m ple data ma y be pr o vi de d t o 
t he i n de pe n de nt c o m mittee/a nal ysis tea m, if use d, u n der u n bli n de d c o n diti o ns. 
F or i nteri m a nal ysis p ur p oses, t he i n de pe n de nt statisticia n / pr o gra m mer / m o deler will recei ve 
u n bli n de d sa m ple data fr o m t he sa m ple a nal ysts t o re p ort res ults f or re vie w.  
All ot her s p o ns or staff (st u d y statisticia n, st u d y pr o gra m mer, 
, cli nical trial 
tea m, decisi o n b oar ds etc.) will sta y bli n de d t o treat me nt assi g n me nts (e xce pt i n t he case of a 
safet y e ve nt necessitati n g u n bli n di n g) u ntil after t he Da y 8 5 i nteri m a nal ysis. 
C CI
C CI
C CI
C CI
C CI
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 5 2  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
All u n bli n de d s p o ns or pers o n nel will ot her wise kee p ra n d o mizati o n lists a n d data or 
i nf or mati o n t hat c o ul d u n bli n d ot her st u d y tea m me m bers c o nfi de ntial a nd sec ure u ntil after t he 
Da y  8 5 i nteri m  a nal ysis. 
Ra n d o mizati o n data a n d treat me nt gr o u p i nf or mati o n m ust n ot be discl ose d t o t he ce ntral 
i ma gi n g e x perts c o n d ucti n g t he X-ra y a n d M RI rea d assess me nts. 
F oll o wi n g fi nal 
data base l oc k all r oles 
ma y 
be c o nsi dere d 
u n bli n de d. 
See t he 
bli n di n g/ u n bli n di n g ta ble f or a n o ver vie w of t he bli n di n g/ u n bli n di n g pla n.  
6. 5   
D o s e e s c al ati o n a n d d o s e m o difi c ati o n  
I n vesti gati o nal or ot her st u d y treat me nt d ose a dj ust me nts a n d/ or i nterr u pti o ns are n ot per mitte d. 
6. 6   
A d diti o n al tr e at m e nt g ui d a n c e  
6. 6. 1   
Tr e at m e nt c o m pli a n c e  
P har mac o ki netic para meters ( meas ures of treat me nt e x p os ure) will be deter mi ne d i n all 
partici pa nts treate d wit h L N A 0 4 3 a n d ca na ki n u ma b, as detaile d i n Secti o n  8. 5. 2 . 
C o m plia nce t o t he treat me nt re gi me n is e ns ure d b y a d mi nistrati o n of L N A 0 4 3 a n d 
ca na ki n u ma b i.a. i njecti o ns b y t he i n vesti gat or. I nf or mati o n o n t he st u d y treat me nt 
a d mi nistrati o n or a n y de viati o n fr o m t he d ose re gi me n m ust be rec or de d i n t he Case Re p ort 
F or m ( C R F). All 
, dis pe nse d s yri n ges f or st u d y treat me nt a n d p ote ntiall y 
ret ur ne d  
 or s yri n ges m ust be rec or de d i n t he Dr u g Acc o u nta bilit y L o g.  
Dis pe nse d a n d ret ur ne d basic pai n me dicati o n m ust be rec or de d i n t he s o urce rec or ds b ut it is 
n ot a p plica ble t o assess c o m plia nce beca use t he c o ns u m pti o n de pe n ds o n t he partici pa nts nee d 
f or pai n relief. 
6. 6. 2   
R e c o m m e n d e d tr e at m e nt of a d v er s e e v e nt s  
Treat me nt of A Es s h o ul d be i n li ne wit h t he i n vesti gat or site pr oce d ures.  
F or t he ma na ge me nt of aller gic reacti o n a n d a na p h yla xis, it is rec o m me n de d t o f oll o w t he 
g ui deli nes b y t he Nati o nal Ca ncer I nstit ute C o m m o n T o xicit y Criteria ( C T C -A E).  
I n case of a n y si g n of ac ute reacti o n, t he partici pa nt will be ma na ge d wit h treat me nt as 
deter mi ne d b y t he treati n g p h ysicia n o n a case -b y -case basis, acc or di n g t o l ocal pr ot oc ols, a n d 
de pe n di n g o n se verit y, usi n g s y m pt o matic treat me nt s uc h as a nti hista mi n es, 
N S AI Ds, 
aceta mi n o p he n, i ntra ve n o us fl ui ds, c ortic oster oi ds, or a dre nali ne.  
Me dicati o n or ot her t hera pies use d t o treat A Es m ust be rec or de d o n t he C o nc o mita nt 
me dicati o ns/ Si g nifica nt n o n -dr u g t hera pies C R F.  
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 5 3  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
6. 6. 3   
E m er g e n c y br e a ki n g of a s si g n e d tr e at m e nt c o d e  
E mer ge nc y c o de brea ks m ust o nl y be u n derta ke n w he n it is re q uire d i n or der t o treat t he 
partici pa nt safel y. Bli n di n g c o des ma y als o be br o ke n after a partici pa nt disc o nti n ues treat me nt 
d ue t o disease pr o gressi o n if dee me d esse ntial t o all o w t he i n vesti gat o r t o select t he partici pa nt’s 
ne xt treat me nt re gi me n, a n d after disc ussi o n a n d a gree me nt wit h t he s p o ns or. M ost ofte n, st u d y 
treat me nt disc o nti n uati o n a n d k n o wle d ge of t he p ossi ble treat me nt assi g n me nts are s ufficie nt 
t o treat a st u d y partici pa nt w h o presents wit h a n e mer ge nc y c o n diti o n.  
E mer ge nc y treat me nt c o de brea ks are perf or me d usi n g t he I R T. W he n t he i n vesti gat or c o ntacts 
t he s yste m t o brea k a treat me nt c o de f or a partici pa nt, s/ he m ust pr o vi de t he re q ueste d 
partici pa nt i de ntif yi n g i nf or mati o n a n d c o nfir m t he necessit y t o brea k t he t reat me nt c o de f or 
t he partici pa nt. T he i n vesti gat or will t he n recei ve details of t he i n vesti gati o nal dr u g treat me nt 
f or t he s pecifie d partici pa nt a n d a fa x or e mail c o nfir mi n g t his i nf or mati o n. T he s yste m will 
a ut o maticall y i nf or m t he N o vartis m o nit or f or t he site a n d t he st u d y tea m t hat t he c o de has bee n 
br o ke n.  
It is t he i n vesti gat or’s res p o nsi bilit y t o e ns ure t hat t here is a de pe n da ble pr oce d ure i n place t o 
all o w access t o t he I R T at a n y ti me i n case of e mer ge nc y. If re q ueste d i n a n e mer ge nc y sit uati o n, 
t he i n vesti gat or will nee d t o pr o vi de: 
•  pr ot oc ol n u m ber  
•  st u d y dr u g na me 
•  partici pa nt n u m ber  
I n a d diti o n, oral a n d writte n i nf or mati o n t o t he partici pa nt m ust be pr o vi de d o n h o w t o c o ntact 
his/ her bac k u p i n cases of e mer ge nc y, or w he n s/ he is u na vaila ble, t o e ns ure t hat u n -bli n di n g 
ca n be perf or me d at a n y ti me.  
See als o Secti o n  9. 1  f or a d diti o nal i nf or mati o n o n st u d y or treat me nt disc o nti n uati o n. 
6. 7   
Pr e p ar ati o n a n d di s p e n s ati o n  
Eac h i n vesti gat or site will be s u p plie d wit h st u d y dr u g i n pac ka gi n g as descri be d i n 
Secti o n  6. 1. 1 . 
T he ca na ki n u ma b treat me nt is bli n de d a n d t he s ol uti o n f or i.a. i njecti o n m ust be pre pare d b y a n 
a de q uatel y trai ne d u n bli n de d p har macist/site pers o n nel after t he i n vesti gat or or dele gate has 
ra n d o mize d a patie nt a n d i nf or mati o n a b o ut t he assi g ne d treat me nt ar m has bee n recei ve d fr o m t he 
I R T s yste m. T he st u d y me dicati o n will be a d mi nistere d b y t he i n vesti gat or i nt o t he k nee j oi nt. 
T he L N A 0 4 3 treat me nt is o pe n la bel a n d t he s ol uti o n f or i.a. i njecti o n ca n be pre pare d b y a n y 
a de q uatel y trai ne d p har macist/site pers o n nel. T he st u d y me dicati o n will be a d mi nistere d b y t he 
i n vesti gat or i nt o t he k nee j oi nt. 
T he i n vesti gat or site will be pr o vi de d wit h a P har mac y Ma n ual, i n w hic h details o n all dr u g 
ha n dli n g is descri be d.  

N o v arti s  
C o nfi d e nti al  
P a g e 5 4  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
6. 7. 1   
H a n dli n g of st u d y tr e at m e nt a n d a d diti o n al tr e at m e nt  
6. 7. 1. 1  
H a n dli n g of st u d y tr e at m e nt  
St u d y treat me nt m ust be recei ve d b y a desi g nate d pers o n at t he i n vesti gat or st u d y, ha n dle d a n d 
st ore d safel y a n d pr o perl y a n d ke pt i n a sec ure d l ocati o n t o w hic h o nl y t he desi g nate d pers o n nel 
ha ve access. U p o n recei pt, all st u d y treat me nt m ust be st ore d ac c or di n g t o t he i nstr ucti o ns 
s pecifie d i n t he P har mac y Ma n ual. 
Cli nical s u p plies are t o be dis pe nse d o nl y i n acc or da nce wit h t he pr ot oc ol. Tec h nical c o m plai nts 
are t o be re p orte d t o t he res pecti ve N o vartis  C o u ntr y Or ga nizati o n Q ualit y Ass ura nce.  
Me dicati o n la bels will be i n t he l ocal la n g ua ge a n d c o m pl y wit h t he le gal re q uire me nts of eac h 
c o u ntr y. 
T he res p o nsi ble site pers o n nel m ust mai ntai n a n acc urate rec or d of t he s hi p me nt a n d dis pe nsi n g 
of st u d y treat me nt i n a dr u g acc o u nta bilit y l o g. M o nit ori n g of dr u g acc o u nta bilit y will be 
perf or me d b y m o nit ors d uri n g site visits or re m otel y a n d at t he c o m ple ti o n of t he trial. 
At t he c o ncl usi o 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 urse of t he st u d y, t he res p o nsi ble 
site pers o n nel will ret ur n all u n use d st u d y treat me nt, pac ka gi n g, dr u g la bels, 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  a d dress pr o vi de d 
i n t he i n vesti gat or f ol der at eac h site. 
6. 7. 1. 2  
H a n dli n g of a d diti o n al tr e at m e nt  
Basic pai n me dicati o n will be s u p plie d a n d ha n dle d as descri be d i n Secti o n  6. 1. 2 . 
6. 7. 2   
I n str u cti o n 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 
B ot h L N A 0 4 3 a n d ca na ki n u ma b treat me nts will be a d mi nistere d i nt o t he k nee b y t he 
I n vesti gat or or a p pr o priatel y trai ne d dele gate wit h a n i.a. i njecti o n prefera bl y usi n g t he 
s u per olateral a p pr oac h b ut alter nati ve a p pr oac hes ma y be use d de pe n di n g o n t he i n vesti gat or 
site r o uti ne. A detaile d i nstr ucti o n f or dr u g a d mi nistrati o n is descri be d i n t he P har mac y Ma n ual. 
T he basic pai n me dicati o n s h o ul d be ta ke n acc or di n g t o t he pac ka ge i nsert a n d i n vesti gat or 
i nstr ucti o ns. 
7   
I nf or m e d c o n s e nt pr o c e d ur e s 
Eli gi ble partici pa 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 ( wit nesse d, w here 
re q uire d b y la w or re g ulati o n) I R B/I E C-a p pr o ve d i nf or me d c o nse nt.  
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 pr oce d ures (e. g. all of 
t he pr oce d 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 nse nt m ust be 
d oc u me nte d i n t he partici pa nt  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 I C H G C P g ui deli nes a n d re g ulat 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 nse nt f or m s u g geste d b y t he 
i n vesti gat or m ust be a gree d b y N o vartis bef ore s u b missi o n t o t he I R B/I E C.  

N o v arti s  
C o nfi d e nti al  
P a g e 5 5  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
I nf or mati o n a b o ut c o m m o 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 ca n be 
f o u n d i n t he I B. T his i nf or mati o n will be i ncl u de d i n t he partici pa nt 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 partici pa nt d uri n g t he st u d y as nee de d. A n y ne w i nf or mati o n 
re gar di n g t he safet y pr ofile of t he i n vesti gati o nal dr u g t hat is i de ntifie d bet wee n I B u p dates will 
be c o m m u nicate d as a p pr o priate, f or e xa m ple, via a n i n vesti gat or n otificati o n or a n a g gre gate 
safet y fi n di n g. Ne w i nf or mati o n mi g ht re q uire a n u p date t o t he i nf or me d c o nse nt a n d t he n m ust 
be disc usse d wit h t he partici pa nt.  
T he f oll o wi n g i nf or me d c o nse nts are i ncl u de d i n t his st u d y:  
•  Mai n st u d y c o nse nt, w hic h als o i ncl u des;  
•  a s u bsecti o n t hat re q uires a se parate si g nat ure f or t he ‘ O pti o nal C o nse nt f or 
A d diti o nal Researc h’ t o all o w f ut ure researc h o n data/sa m ples c ollecte d d uri n g t his 
st u d y 
•  a s u bsecti o n t hat re q uires a se parate si g nat ure f or t he ' O pti o nal C o nse nt f or a d diti o nal 
bl o o d c ollecti o n' t o a nal yse L N A 0 4 3 P K  at a d diti o nal ti me p oi nts ( pr o vi de d t he 
patie nt is ra n d o mize d t o T A 1 or T A 3)  
•  As a p plica ble, Pre g na nc y O utc o mes Re p orti n g C o nse nt f or fe male partici pa nts  
•  As a p plica ble per l ocal re g ulati o ns a n d if n o ot her l ocal versi o n is a vaila ble, c o nse nt f or 
healt h y v ol u nteer M RI sca n, t o be use d f or t he i ma gi n g q ualificati o n of t he site  
W o me n of c hil d -beari n g p ote ntial m ust 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 nc y were t o occ ur d uri n g t he st u d y a n d a gree t hat i n or der 
t o partici pate i n t he st u d y t he y m ust a d here t o t he c o ntrace pti o n re q uire me nts. 
T he st u d y i ncl u des 
 w hic h re q uires a se parate si g nat ure if t he 
partici pa nt  a grees t o partici pate. It is re q uire d as part of t his pr ot oc ol t hat t he I n vesti gat or 
prese nts t his o pti o n t o t he partici pa nts, as per mitte d b y l ocal g o ver ni n g re g ulati o ns. T he  pr ocess 
f or o btai ni n g c o nse nt s h o ul d be e xactl y t he sa me as descri be d a b o ve f or t he mai n i nf or me d 
c o nse nt. 
Decli ni n g t o partici pate i n t he o pti o nal assess me nts 
 
 will i n n o wa y 
affect t he partici pa nt’s a bilit y t o j oi n t he mai n researc h st u d y.  
As per  Secti o n 4. 6 , d uri n g a P u blic Healt h e mer ge nc y as declare d b y L ocal or Re gi o nal 
a ut h orities, i.e. pa n de mic, e pi de mic or nat ural disaster, t hat ma y  pre ve nt o n -site visits a n d 
t here b y c halle n ge t he a bilit y t o o btai n a sta n dar d writte n i nf or me d c o nse nt, t he I n vesti gat or ma y 
c o n d uct t he i nf or me d c o nse nt disc ussi o n re m otel y (e. g. tele p h o ne, vi de oc o nfere nce). 
G ui da nce  iss ue d b y l ocal re g ulat or y b o dies o n t his as pect pre vail a n d m ust be i m ple me nte d a n d 
a p pr o priatel y d oc u me nte d (e. g. t he prese nce of a n i m partial wit ness, si g n/ dati n g se parate I C Fs 
b y trial partici pa nt a n d pers o n o btai ni n g i nf or me d c o nse nt, etc.).  
A c o p y of t he a p pr o ve d versi o n of all c o nse nt f or ms m ust be pr o vi de d t o N o vartis  after I R B/I E C 
a p pr o val.  
C CI
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 5 6  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
Partici pa nts mi g ht be as ke d t o c o m plete a n o pti o nal q uesti o n naire t o pr o vi de fee d bac k o n t heir 
cli nical trial e x perie nce. T he q uesti o n naire data will be ke pt a n o n y mize d, a n d will be use d t o 
u n dersta n d w here i m pr o ve me nt ca n be ma de i n t he cli nical trial pr o cess. T his q uesti o n naire 
w o ul d n ot as k a b o ut t he partici pa nt's disease or s y m pt o ms a n d t heref ore will n ot be c o nsi dere d 
t o be trial data. 
8   
Vi sit s c h e d ul e a n d a s s e s s m e nt s  
T he Assess me nt Sc he d ule ( Ta ble  8 -1 ) lists all of t he pla n ne d assess me nts a n d w he n t he y are 
perf or me d. All data o btai ne d fr o m t hese assess me nts m ust be s u p p orte d i n t he partici pa nt’s 
s o urce d oc u me ntati o n. 
Partici pa nts s h o ul d be see n f or all visits/assess me nts as o utli ne d i n t he assess me nt sc he d ule 
(Ta ble  8 -1 ) or as cl ose t o t he desi g nate d da y/ti me as p ossi ble. Misse d or resc he d ule d visits 
s h o ul d n ot lea d t o a ut o matic disc o nti n uati o n. 
W he n t he f oll o wi n g assess me nts are sc he d ule d t o be perf or me d at t he sa me ti me p oi nt, t he or der 
of pri orit y s h o ul d be as f oll o ws:  
1.  P R Os, i n t he or der W PI, N R S  Pai n,  
 K O O S,
 
2.  Pai n diar y re vie w a n d basic pai n me dicati o n re vie w/ dis pe nsati o n  
3.  E C G  
4.  Vital si g ns  
5.  Bl o o d sa m pli n g  
6.  All ot her cli nical assess me nts  
Ot her or ders of pri orit y t o c o nsi der are:  
•  Ra n d o mizati o n m ust occ ur after eli gi bilit y has bee n re -c o nfir me d at Scree ni n g 4.  
•  Bl o o d a n d uri ne c ollecti o n m ust be c ollecte d pre -d ose  
•  S y n o vial fl ui d m ust be c ollecte d pri or t o t he st u d y dr u g i njecti o n.  
•  E ver y eff ort s h o ul d be ma de t o ta ke t he P K sa m ples at t he s pecifie d ti me p oi nts.  
•  X -ra y, M RI  a n d D C E-M RI  ca n be perf or me d bef ore or after ot her cli nical assess me nts at a 
visit, als o o n a differe nt da y if nee de d f or l o gistical reas o ns, b ut s h o ul d al wa ys be d o ne 
wit hi n t he visit wi n d o w.  
As per  Secti o n 4. 6 , d uri n g a P u blic Healt h e mer ge nc y as declare d b y L ocal or Re gi o nal 
a ut h orities i.e. pa n de mic, e pi de mic or nat ural disaster t hat li mits or pre ve nts o n -site st u d y visits, 
alter nati ve met h o ds of pr o vi di n g c o nti n ui n g care ma y be i m ple me nte d b y t he i n vesti gat o r as 
t he sit uati o n dictates. P h o ne calls, virt ual c o ntacts (e. g. telec o ns ult) or visits b y site 
pers o n nel/ h o me n ursi n g ser vice t o t he partici pa nt´s h o me de pe n di n g o n l ocal re g ulati o ns a n d 
ca pa bilities, ca n re place o n -site st u d y visits w here p ossi ble, f or the d urati o n of t he disr u pti o n 
u ntil it is safe f or t he partici pa nt t o visit t he site a gai n.  
T he “ X” i n t he ta ble de n otes assess me nts t hat are t o be rec or de d i n t he C R F or recei ve d 
electr o nicall y fr o m a ve n d or. T he “ S” i n t he ta ble de n otes assess me nts t hat are o nl y re q uire d i n 
t he partici pa nt’s s o urce d oc u me ntati o n a n d d o n ot nee d t o be rec or de d i n t he C R F/cli nical 
da ta base.
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 5 7  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
T a bl e 8 -1   
A s s e s s m e nt S c h e d ul e  
P eri o d  
S cr e e ni n g  
Vi sit N a m e   
S cr e e ni n g 1  
S cr e e ni n g 2 1  
S cr e e ni n g 3  
S cr e e ni n g 4 1  
D a y s   
-4 2 t o -2 8  
-3 5 t o -1 4  
-2 8 t o -1 4  
-5 t o -1  
W e e k s   
-6 t o -4  
-5 t o -2  
-4 t o -2  
-1  
Ti m e ( p o st -d o s e)  
- 
- 
- 
- 
I nf or m e d c o n s e nt 
X  
 
 
 
D e m o gr a p h y  
X  
 
 
 
M e di c al hi st or y/ c urr e nt m e di c al c o n diti o n s  
X  
 
 
 
B o d y H ei g ht  
X  
 
 
 
B o d y W ei g ht  
X  
 
 
 
Bl o o d Pr e s s ur e  
X  
 
 
 
P ul s e r at e  
X  
 
 
 
B o d y T e m p er at ur e  
X  
 
 
 
P h y si c al E x a mi n ati o n  
S  
 
 
 
W PI  
X  
 
 
 
N R S P ai n  
X  
X  
 
X  
K O O S  
X  
X  
 
X  
El e ctr o c ar di o gr a m ( E C G)  
X  
 
 
 
Cli ni c al C h e mi str y  
X  
 
 
 
H e m at ol o g y  
X  
 
 
 
Uri n al y si s  
X  
 
 
 
C o a g ul ati o n P a n el  
X  
 
 
 
h s C R P  
X  
 
 
 
H e p atiti s s cr e e n  
S  
 
 
 
C CI
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 5 8  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
P eri o d  
S cr e e ni n g  
Vi sit N a m e   
S cr e e ni n g 1  
S cr e e ni n g 2 1  
S cr e e ni n g 3  
S cr e e ni n g 4 1  
D a y s   
-4 2 t o -2 8  
-3 5 t o -1 4  
-2 8 t o -1 4  
-5 t o -1  
W e e k s   
-6 t o -4  
-5 t o -2  
-4 t o -2  
-1  
Ti m e ( p o st -d o s e)  
- 
- 
- 
- 
HI V s cr e e n  
S  
 
 
 
T B s cr e e n  
S  
 
 
 
Al c o h ol T e st a n d Dr u g S cr e e n  
S  
 
 
 
Pr e g n a n c y a n d a s s e s s m e nt s of f ertilit y  
S 3, 4  
 
 
 
X -r a y (t ar g et k n e e) 
X  
 
 
 
M RI (t ar g et k n e e)  
 
 
X  
 
D C E M RI (t ar g et k n e e)  
 
 
X  
 
I n cl u si o n / E x cl u si o n crit eri a 
X  
X  
X 6  
X  
P ai n di ar y  
X 8  
X  
 
X  
B a si c p ai n m e di c ati o n di s p e n s ati o n/r et ur n  
S  
S  
 
S  
R a n d o mi z ati o n  
 
 
 
X  
A C Z 8 8 5 i nj e cti o n  
 
 
 
 
L N A 0 4 3 i nj e cti o n 9  
 
 
 
 
L N A 0 4 3 P K 1 2  
 
 
 
 
A N G P T L 3 P K  
 
 
 
 
L N A 0 4 3 I m m u n o g e ni cit y1 0  
 
 
 
 
C CI
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 5 9  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
P eri o d  
S cr e e ni n g  
Vi sit N a m e   
S cr e e ni n g 1  
S cr e e ni n g 2 1  
S cr e e ni n g 3  
S cr e e ni n g 4 1  
D a y s   
-4 2 t o -2 8  
-3 5 t o -1 4  
-2 8 t o -1 4  
-5 t o -1  
W e e k s   
-6 t o -4  
-5 t o -2  
-4 t o -2  
-1  
Ti m e ( p o st -d o s e)  
- 
- 
- 
- 
C o n c o mit a nt m e di c ati o n s 1 7  
X  
C o n c o mit a nt n o n -dr u g t h er a pi e s 1 7  
X  
A d v er s e E v e nt s 1 7  
X  
St u d y c o m pl eti o n i nf or m ati o n  
  
  
 
 
 
P eri o d  
Tr e at m e nt  
Vi sit N a m e  A C Z 8 8 5 I nj.  
L N A 0 4 3 I nj. 1  
R e m ot e 1 1  L N A 0 4 3 I nj. 2  R e m ot e 2 1  L N A 0 4 3 I nj. 3  
D a y s   
1  
1 5 ± 3  
2 9 ± 3   
4 3 ± 3   
5 7 ± 3   
7 1 ± 3  
W e e k s   
0  
2  
4  
6  
8  
1 0  
Ti m e ( p o st -d o s e)   
0 mi n 2   
0 mi n 2  2 0 mi n  
± 1 0  
6 0 mi n  
± 1 0  
1 2 0 mi n  
± 1 5  
2 4 0 mi n  
± 3 0  
8 h  
-2 + 4  
2 4 h  
-2 + 4  
-  
0 mi n 2  6 0 mi n  
± 1 0  
-  
0 mi n 2  
I nf or m e d c o n s e nt 
  
  
  
  
  
  
  
  
  
  
  
 
 
D e m o gr a p h y  
  
  
  
  
  
  
  
  
  
  
  
 
 
M e di c al hi st or y/ c urr e nt m e di c al c o n diti o n s   
  
  
  
  
  
  
  
  
  
  
  
 
 
B o d y H ei g ht  
  
  
  
  
  
  
  
  
  
  
  
 
 
B o d y W ei g ht  
  
  
  
  
  
  
  
  
  
  
  
 
 
Bl o o d Pr e s s ur e  
X   
X   
  
  
X 9   
  
  
  
  
X   
  
 
X  
P ul s e r at e  
X   
X   
  
  
X 9   
  
  
  
  
X   
  
 
X  
B o d y T e m p er at ur e  
X   
X   
  
  
  
  
  
  
  
X   
  
 
X  
P h y si c al E x a mi n ati o n  
S   
S   
  
  
  
  
  
  
  
  
  
 
 
W PI  
  
  
  
  
  
  
  
  
  
  
  
 
 
N R S P ai n  
X   
X   
  
  
  
  
  
  
X   
X   
  
X  
X  
K O O S  
X   
X   
  
  
  
  
  
  
X   
X   
  
X  
X  
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 6 0  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
P eri o d  
Tr e at m e nt  
Vi sit N a m e  A C Z 8 8 5 I nj.  
L N A 0 4 3 I nj. 1  
R e m ot e 1 1  L N A 0 4 3 I nj. 2  R e m ot e 2 1  L N A 0 4 3 I nj. 3  
D a y s   
1  
1 5 ± 3  
2 9 ± 3   
4 3 ± 3   
5 7 ± 3   
7 1 ± 3  
W e e k s   
0  
2  
4  
6  
8  
1 0  
Ti m e ( p o st -d o s e)   
0 mi n 2   
0 mi n 2  2 0 mi n  
± 1 0  
6 0 mi n  
± 1 0  
1 2 0 mi n  
± 1 5  
2 4 0 mi n  
± 3 0  
8 h  
-2 + 4  
2 4 h  
-2 + 4  
-  
0 mi n 2  6 0 mi n  
± 1 0  
-  
0 mi n 2  
El e ctr o c ar di o gr a m ( E C G)  
X   
X   
  
  
  
  
  
  
  
  
  
 
 
Cli ni c al C h e mi str y  
X   
X   
  
  
  
  
  
  
  
X   
  
 
 
H e m at ol o g y  
X   
X   
  
  
  
  
  
  
  
X   
  
 
 
Uri n al y si s  
X   
X   
  
  
  
  
  
  
  
X   
  
 
 
C o a g ul ati o n P a n el  
  
  
  
  
  
  
  
  
  
  
  
 
 
h s C R P  
X   
X   
  
  
  
  
  
  
  
X   
  
 
 
H e p atiti s s cr e e n  
  
  
  
  
  
  
  
  
  
  
  
 
 
HI V s cr e e n  
  
  
  
  
  
  
  
  
  
  
  
 
 
T B s cr e e n  
  
  
  
  
  
  
  
  
  
  
  
 
 
Al c o h ol T e st a n d Dr u g S cr e e n  
  
  
  
  
  
  
  
  
  
  
  
 
 
Pr e g n a n c y a n d a s s e s s m e nt s of f ertilit y   
S 5   
S 5   
  
  
  
  
  
  
  
S 5   
  
 
S 5  
X -r a y (t ar g et k n e e) 
  
  
  
  
  
  
  
  
  
  
  
 
 
M RI (t ar g et k n e e)  
  
  
  
  
  
  
  
  
  
  
  
 
 
D C E M RI (t ar g et k n e e)  
  
  
  
  
  
  
  
  
  
  
  
 
 
I n cl u si o n / E x cl u si o n crit eri a 
  
  
  
  
  
  
  
  
  
  
  
 
 
P ai n di ar y  
X   
X   
  
  
  
  
  
  
  
X   
  
 
X  
B a si c p ai n m e di c ati o n di s p e n s ati o n/r et ur n   
S   
S   
  
  
  
  
  
  
  
S   
  
 
S  
R a n d o mi z ati o n  
  
  
  
  
  
  
  
  
  
  
  
 
 
A C Z 8 8 5 i nj e cti o n 
X   
  
  
  
  
  
  
  
  
  
  
 
 
L N A 0 4 3 i nj e cti o n 9  
  
X   
  
  
  
  
  
  
  
X   
  
 
X  
C CI
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 6 1  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
P eri o d  
Tr e at m e nt  
Vi sit N a m e  A C Z 8 8 5 I nj.  
L N A 0 4 3 I nj. 1  
R e m ot e 1 1  L N A 0 4 3 I nj. 2  R e m ot e 2 1  L N A 0 4 3 I nj. 3  
D a y s   
1  
1 5 ± 3  
2 9 ± 3   
4 3 ± 3   
5 7 ± 3   
7 1 ± 3  
W e e k s   
0  
2  
4  
6  
8  
1 0  
Ti m e ( p o st -d o s e)   
0 mi n 2   
0 mi n 2  2 0 mi n  
± 1 0  
6 0 mi n  
± 1 0  
1 2 0 mi n  
± 1 5  
2 4 0 mi n  
± 3 0  
8 h  
-2 + 4  
2 4 h  
-2 + 4  
-  
0 mi n 2  6 0 mi n  
± 1 0  
-  
0 mi n 2  
L N A 0 4 3 P K 1 2  
  
X 1 1   
X   
X   
X   
X 1 3   
X 1 3   
X 1 3   
  
X 1 1   
X   
 
 
A N G P T L 3 P K  
X 1 1   
X 1 1   
  
X 7   
  
  
  
  
  
X 1 1   
  
 
 
L N A 0 4 3 I m m u n o g e ni cit y 1 0  
  
X 1 1   
  
  
  
  
  
  
  
X 1 1   
  
 
 
C o n c o mit a nt m e di c ati o n s
1 7  
X  
C o n c o mit a nt n o n -dr u g t h er a pi e s 1 7  
X  
A d v er s e E v e nt s 1 7  
X  
St u d y c o m pl eti o n i nf or m ati o n  
   
   
   
   
   
   
   
   
   
   
   
  
  
 
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 6 2  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
P eri o d  
F oll o w -u p  
Vi sit N a m e  
F oll o w -u p 1  
F oll o w -u p 2  
E o S  
D a y s  
8 5 ± 3  
1 9 7 ± 7  
3 6 5 ± 1 4  
W e e k s  
1 2  
2 8  
5 2  
Ti m e ( p o st-d o s e)  
- 
- 
- 
I nf or m e d c o n s e nt 
 
 
 
D e m o gr a p h y  
 
 
 
M e di c al hi st or y/ c urr e nt m e di c al c o n diti o n s  
 
 
 
B o d y H ei g ht  
 
 
 
B o d y W ei g ht  
X  
 
X  
Bl o o d Pr e s s ur e  
X  
X  
X  
P ul s e r at e  
X  
X  
X  
B o d y T e m p er at ur e  
X  
X  
X  
P h y si c al E x a mi n ati o n  
S  
S  
S  
W PI  
 
 
 
N R S P ai n  
X  
X  
X  
K O O S  
X  
X  
X  
El e ctr o c ar di o gr a m ( E C G)  
 
 
X  
Cli ni c al C h e mi str y  
X  
X  
X  
H e m at ol o g y  
X  
X  
X  
Uri n al y si s  
X  
X  
X  
C o a g ul ati o n P a n el  
 
 
 
h s C R P  
X  
X  
X  
H e p atiti s s cr e e n  
 
 
 
HI V s cr e e n  
 
 
 
T B s cr e e n  
 
 
 
C CI
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 6 3  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
P eri o d  
F oll o w -u p  
Vi sit N a m e  
F oll o w -u p 1  
F oll o w -u p 2  
E o S  
D a y s  
8 5 ± 3  
1 9 7 ± 7  
3 6 5 ± 1 4  
W e e k s  
1 2  
2 8  
5 2  
Ti m e ( p o st-d o s e)  
- 
- 
- 
Al c o h ol T e st a n d Dr u g S cr e e n  
 
 
 
Pr e g n a n c y a n d a s s e s s m e nt s of f ertilit y  
S 3  
S 3  
S 3  
X -r a y (t ar g et k n e e) 
 
 
 
M RI (t ar g et k n e e)  
X  
X  
X  
D C E M RI (t ar g et k n e e)  
X  
 
 
I n cl u si o n / E x cl u si o n crit eri a 
 
 
 
P ai n di ar y  
X  
X  
X  
B a si c p ai n m e di c ati o n di s p e n s ati o n/r et ur n  
S  
S  
 
R a n d o mi z ati o n  
 
 
 
A C Z 8 8 5 i nj e cti o n  
 
 
 
L N A 0 4 3 i nj e cti o n 9  
 
 
 
L N A 0 4 3 P K 1 2  
 
 
 
A N G P T L 3 P K  
X  
X  
X  
L N A 0 4 3 I m m u n o g e ni cit y 1 0  
X  
X  
X  
C o n c o mit a nt m e di c ati o n s 1 7  
X  
C o n c o mit a nt n o n -dr u g t h er a pi e s 1 7  
X  
C CI
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 6 4  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
P eri o d  
F oll o w -u p  
Vi sit N a m e  
F oll o w -u p 1  
F oll o w -u p 2  
E o S  
D a y s  
8 5 ± 3  
1 9 7 ± 7  
3 6 5 ± 1 4  
W e e k s  
1 2  
2 8  
5 2  
Ti m e ( p o st-d o s e)  
- 
- 
- 
A d v er s e E v e nt s 1 7  
X  
St u d y c o m pl eti o n i nf or m ati o n  
 
 
X  
1  C a n b e p erf or m e d a s r e m ot e vi sit  
2  Pr e -d o s e (f or p arti ci p a nt s r a n d o mi z e d t o T A 2 or T A 4, f or w h o m t h er e i s n o i nj e cti o n ti m e p oi nt  o n D a y 1 5 , a s s e s s m e nt s s h o ul d b e p erf or m e d/ c oll e ct e d at t h e s a m e ti m e 
a n d or d er a s if a n i nj e cti o n w o ul d t a k e pl a c e)  
3  S er u m pr e g n a n c y t e st (if a p pli c a bl e)  
4  F S H a n al y si s (if a p pli c a bl e)  
5  Uri n e pr e g n a n c y t e st (if a p pli c a bl e)  
6  O nl y crit eri a b a s e d o n M RI  
7  F or p arti ci p a nt s r a n d o mi z e d t o T A 2 or T A 4, f or w h o m t h er e i s n o i nj e cti o n ti m e p oi nt, s a m pl e s h o ul d b e c oll e ct e d 6 0 t o 1 8 0 m i n ut e s aft er c oll e cti o n of t h e 0 mi n-s a m pl e  
8  O nl y i n str u cti o n s a n d di s p e n s ati o n of t h e di ar y  
9  O nl y f or p arti ci p a nt s w h o w er e r a n d o mi z e d t o r e c ei v e L N A 0 4 3 ( T A 1 a n d T A 3)  
1 0  I n c a s e of s u s p e ct e d all er gi c h y p er s e n siti vit y, t h e p arti ci p a nt s h o ul d r et ur n t o t h e sit e f or a n u n s c h e d ul e d s a m pl e c oll e cti on t o a s s e s s i m m u n o g e ni cit y a s n e ar a s 
p o s si bl e t o t h e e v e nt.  
1 1  Wit hi n 2 h o ur s b ef or e i nj e cti o n  
1 2  O nl y t o b e c oll e ct e d f or p arti ci p a nt s w h o r e c ei v e L N A 0 4 3 ( T A 1 a n d T A 3)  
1 3
1 7  S oli cit e d q u e sti o n m u st b e a s k e d b y sit e p er s o n n el at all sit e -a n d r e m ot e vi sit s a n d u n s oli cit e d r e p ort s of e v e nt s or c h a n g e s m u st b e d o c u m e nt e d t hr o u g h o ut t h e st u d y 
wit h o ut d el a y  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 6 5  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
8. 1   
S cr e e ni n g  
8. 1. 1   
Eli gi bilit y s cr e e ni n g  
T his secti o n descri bes assess me nts w hic h are o nl y perf or me d at scree ni n g i n or der t o e val uate 
a patie nt's eli gi bilit y. Eli gi bilit y assess me nts w hic h are perf or me d at scree ni n g t o descri be t he 
p o p ulati o n b ut als o later d uri n g t he st u d y t o e val uate efficac y, safet y or ot her o utc o mes, are 
descri be d i n se parate secti o ns.  
I n t he case w here a safet y la b orat or y assess me nt at scree ni n g meets a n y of t he e xcl usi o n criteria 
b ut w here t he c o n diti o n is e x pecte d t o be tra nsie nt a n d res ol ve d pri or t o first d ose, or if a 
la b orat or y err or is s us pecte d, t he assess me nt ma y be re peate d o nce pri or t o ra n d o mizati o n. If  t he 
re peat val ue still meets t he e xcl usi o n criteri o n, t he patie nt d oes n ot q ualif y f or t he st u d y. 
8. 1. 1. 1  
P ai n  
Wi des prea d Pai n I n de x  ( W PI) (W olfe  et al 2 0 1 0 ) is assesse d at Scree ni n g 1 t o e xcl u de patie nts 
wit h s u bsta ntial pai n ori gi nati n g fr o m  ot her re gi o ns t ha n t he tar get k nee, s uc h as fi br o m yal gia 
or ot her u n dia g n ose d diseases.  
Ot her patie nt re p orte d o utc o mes ( P R Os) f or assessi n g pai n are c ollecte d f or scree ni n g p ur p oses 
as well as f or efficac y e val uati o n, see Secti o n  8. 3. 2 . 
T he sa me met h o d of c ollecti o n as f or t he P R Os descri be d i n Secti o n  8. 3. 2  will be use d.  
8. 1. 1. 2  
C o a g ul ati o n  
Pr ot hr o m bi ne Ti me ( P T) a n d I nter nati o nal N or malize d Rati o (I N R) will be a nal yse d at 
Scree ni n g 1 t o e val uate c o n diti o ns relate d t o i m paire d c oa g ulati o n.  
8. 1. 1. 3  
S cr e e ni n g f or I nf e cti o n s  
D uri n g scree ni n g, t he i n vesti gat or s h o ul d detect a n y acti ve i nfecti o ns t hat w o ul d dis q ualif y t he 
patie nt f or t his st u d y (e xcl usi o n criteri o n). T he decisi o n t o l ocall y test t he patie nt f or acti ve 
S A R S -C o v -2 i nfecti o n i n or der t o e val uate t he e xcl usi o n crite ri o n is at t he i n vesti gat or's 
discreti o n a n d s h o ul d be i n a d here nce t o l ocal p olicies or re g ulati o ns. H o we ver, it is hi g hl y 
rec o m me n de d t hat P C R or a nti ge n testi n g f or C O VI D-1 9 be c o m plete d wit hi n 1 wee k pri or t o 
first d osi n g. If testi n g is perf or me d, ne gati ve test res ults are re q uire d pri or t o e nr ol me nt i nt o t he 
st u d y. A d diti o nal testi n g t hr o u g h o ut t he st u d y ma y occ ur at t he discreti o n of t he i n vesti gati n g 
p h ysicia n. C O VI D -1 9 testi n g s h o ul d be c o m plete d via nasal or t hr oat s wa bs. If testi n g is n ot 
perf or me d, t he i n vesti gat or m ust d oc u me nt t heir disc ussi o n wit h t he patie nt re gar di n g testi n g, 
a n d t he rati o nale f or n ot testi n g, i n t he s o urce d oc u me ntati o n. T his re q uire me nt ma y be i g n ore d 
if t he pa n de mic is declare d e n de d b y t he c o u ntry w here t he site is l ocate d, a n d res u me d if t he 
pa n de mic rec urs.  
All partici pa nts will be scree ne d f or He patitis B Vir us S urface A nti ge n a n d He patitis B Vir us 
C ore A nti b o dies . If p ositi ve, He patitis B Vir us S urface A nti b o dies a n d He patitis B Vir us D N A 
s h o ul d be deter mi ne d. 
Scree ni n g f or He patitis C will be base d o n He patitis C Vir us A nti b o dies a n d if p ositi ve, 
He patitis C Vir us R N A le vels s h o ul d be deter mi ne d.  

N o v arti s  
C o nfi d e nti al  
P a g e 6 6  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
E val uati o n f or HI V ser o p ositi vit y will be perf or me d a n d if p ositi ve, c o nfir mati o n b y a sec o n d 
tec h ni q ue a vaila ble at t he la b orat or y site, e. g. Wester n bl ot. A p pr o priate c o u nseli n g will be 
ma de a vaila ble b y t he I n vesti gat or i n t he e ve nt of a p ositi ve c o nfir mat or y test. N otificati o n  of 
state a n d fe deral a ut h orities, as re q uire d b y la w, will be t he res p o nsi bilit y of t he I n vesti gat or.  
Deter mi nati o n of T B stat us is re q uire d bef ore st u d y partici pati o n per eli gi bilit y criteria a n d m ust 
i ncl u de a Q ua nti F E R O N test perf or me d b y t he ce ntral la b orat or y. If prese nce of acti ve or late nt 
T B is esta blis he d, treat me nt f or T B m ust ha ve bee n c o m plete d  pri or t o p ote ntial re -scree ni n g 
f or t he st u d y. I n case a partici pa nt de vel o ps T B d uri n g t he st u d y, t he e ve nt m ust be f oll o we d u p 
a n d rec or de d as a n A E i n t he C R F.  
8. 1. 1. 4  
Al c o h ol t e st, Dr u g s cr e e n, Uri n e c oti ni n e  
Partici pa nts will be teste d f or s u bsta nces of a b use (e. g. alc o h ol, a m p heta mi nes, bar bit uates, 
be nz o diaze pi nes, ca n na bi n oi ds, c ocai ne a n d o piates).  
C oti ni ne i n uri ne will n ot be a nal yse d at scree ni n g b ut t he i n vesti gat or s h o ul d clarif y t o bacc o 
use ha bits f or partici pa nts w h o use t o bacc o pr o d ucts t o e ns ure it is realistic t hat t he patie nt ca n 
c o m pl y wit h t he restricti o n descri be d i n Secti o n  6. 2. 4. 1  ( nic oti ne re place me nt t hera pies are 
all o we d). 
8. 1. 1. 5  
K n e e X -r a y 
A tar get k nee X -ra y will be perf or me d at Scree ni n g 1 t o e val uate t he K L a n d me dial fJ S W 
eli gi bilit y criteri o n, usi n g a n o n -fl u or o, sta n dar dize d a n d q ualit y c o ntr olle d 
met h o d, as 
descri be d i n t he I ma gi n g Ma n ual. A ce ntral rea der will a nal yze t he i ma ges as descri be d i n t he 
I ma gi n g Ma n ual. 
I nci de ntal fi n di n gs are be y o n d t he sc o pe of t he ce ntral i ma gi n g ve n d or. If a n 
i n vesti gat or/ra di ol o gist rec o g nizes a n y i nci de ntal fi n di n g i n t he i ma ges, t he i n vesti gat or s h o ul d 
f oll o w u p as part of his/ her d ut y of care t o e ns ure t he safet y a n d well bei n g of t he partici pa nt. 
If a patie nt has bee n scree ne d f or a si milar trial wit h t he sa me c o n ve nti o nal X-ra y pr ojecti o ns, 
t he i ma ges ac q uire d d uri n g scree ni n g ca n be use d wit hi n 6 m o nt hs of t he X-ra y date, pr o vi de d 
t he patie nt c o nfir ms t here are n o si g nifica nt c ha n ges i n l ocal s y mpt o ms si nce t he i nitial i ma ge 
was ta ke n.  
8. 1. 2   
I nf or m ati o n t o b e c oll e ct e d o n s cr e e ni n g f ail ur e s 
A partici pa nt w h o si g ns a n i nf or me d c o nse nt f or m a n d s u bse q ue ntl y f o u n d i neli gi ble pri or t o 
ra n d o mizati o n will be c o nsi dere d a scree n fail ure. 
T he reas o n(s) f or t he scree n fail ure s h o ul d be rec or de d o n t he a p pr o priate Case Re p ort F or m. 
T he  visit date, de m o gra p hic i nf or mati o n, i nf or me d c o nse nt, a n d I ncl usi o n/ E xcl usi o n pa ges 
m ust als o be c o m plete d f or scree n fail ure partici pa nts. N o ot her data nee d t o be e ntere d i nt o t he 
cli nical data base f or partici pa nts w h o are scree n fail ures, u nless t he pa rtici pa nt e x perie nce d a 
seri o us a d verse e ve nt d uri n g t he scree ni n g p hase (see Secti o n  1 0. 1. 3  f or S A E re p orti n g details). 
A partici pa nt w h o is ra n d o mize d a n d fail t o start treat me nt, e. g. w he n ra n d o mize d i n err or, will 
be c o nsi dere d a n earl y ter mi nat or. T he reas o n f or earl y ter mi nati o n s h o ul d be rec or de d o n t he 
a p pr o priate Case Re p ort F or m.  

N o v arti s  
C o nfi d e nti al  
P a g e 6 7  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
T he I R T m ust be n otifie d wit hi n 2 da ys of t he scree n fail ure/earl y ter mi nati o n.  
8. 1. 3   
R e -s cr e e ni n g  
It is per missi ble t o re-scree n a partici pa nt if t he i nitial scree n failure  reas o n is l o gistical b y 
nat ure, e. g., a patie nt  w h o bec o me s u na vaila b le d u e t o fa mil y e mer ge ncies, or if t he scree n 
fail ure reas o n is c o nsi dere d  tra nsie nt, e. g. o n g oi n g mi n or i nfecti o n or  i ns ufficie nt was h o ut of 
pr o hi bite d me dicati o n.  S uc h re -scree ni n g ma y occ ur o nce t he scree n fail ure reas o n is c o nsi dere d 
res ol ve d. 
Re -scree ni n g is als o per missi ble, o ne ti me o nl y, if t he scree n fail ure reas o n is i ns ufficie nt le vel 
of O A, pr o vi de d t he a na m nesis a n d p h ysical e xa mi nati o n i n dicate a tr ue a n d s ustai ne d 
deteri orati o n of t he partici pa nt’s O A  c o m pare d t o t he stat us at t he i nitial scree ni n g. S uc h re-
scree ni n g m ust n ot be perf or me d s o o ner t ha n 6 m o nt hs fr o m t he i nitial scree ni n g. I ns ufficie nt 
le vel of O A pr o gressi o n refers t o t he i ncl usi o n criteria f or tar get k nee pai n, hs C R P , J S W a n d 
s y n o vitis b y M RI . 
Eli gi bilit y criteria assesse d b y X -ra y ca n be base d o n t he i nitial scree ni n g X-ra y res ults if t he 
re-scree ni n g occ urs wit hi n  6 m o nt hs  of t he X -ra y date a n d t he patie nt re p orts t here are n o 
si g nifica nt c ha n ges i n l ocal s y m pt o ms si nce t he i nitial i ma ge was ta ke n. 
E ac h case of re -scree ni n g s h o ul d be disc usse d a n d a gree d wit h S p o ns or o n a case-b y -case basis.  
8. 2   
P arti ci p a 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  
C o u ntr y -s pecific re g ulati o ns s h o ul d be c o nsi dere d f or t he c ollecti o n of de m o gra p hic a n d 
baseli ne c haracteristics i n t he C R F.  
Partici pa nt de m o gra p hics i ncl u de a ge at scree ni n g, se x, race, pre d o mi na nt et h nicit y (if 
per mitte d).  
Partici pa nt race a n d et h nicit y are c ollecte d a n d a nal yze d t o i de ntif y variati o ns i n safet y or 
efficac y d ue t o t hese fact ors as well as t o assess t he di versit y of t he st u d y p o p ulati o n as re q uire d 
b y Healt h A ut h orities.  
Hei g ht will be meas ure d o nl y at Scree ni n g 1 t o e val uate t he B MI  eli gi bilit y criteri o n. 
Rele va nt  me dical hist or y/c urre nt me dical c o n diti o ns ( u ntil i nf or me d c o nse nt si g nat ure date) 
will be rec or de d i n t he e C R F. W here p ossi ble, t he dia g n osis a n d n ot s y m pt o ms s h o ul d be 
rec or de d. 
All prescri pti o n me dicati o ns, o ver -t he-c o u nter dr u gs a n d si g nifica nt n o n -dr u g t hera pies pri or t o 
t he start of t he st u d y m ust be d oc u me nte d. See Secti o n  6. 2. 1  f or f urt her details o n w hat 
i nf or mati o n m ust be rec or de d o n t he a p pr o priate pa ge of t he e C R F. 
A n ass ociati o n bet wee n  O A a n d ra di o gra p hic e vi de nce of  c h o n dr ocalci n osis  ( C C) has bee n 
rec o g nise d f or years, a n d C C ma y be prese nt i n u p t o 1 5 % of t he patie nts wit h O A 
(R y u  et al 2 0 1 4 ). H o we ver, it is n ot yet clear t o w hat e xte nt C C is t he ca use of O A i n patie nts 
e x perie nci n g ac ute flares of j oi nt pai n li n ke d t o pse u d o g o ut, or if it de vel o ps as a res ult of 
c ha n ges i n c h o n dr oc yte meta b olis m or i n t he e xtracell ular matri x. Beca use gr oss calci u m 
de p ositi o ns i n artic ular cartila ge c o ul d i nterfere wit h t he e x pecte d treat me nt effect, C C will be 
i de ntifie d as part of t he baseli ne c haracteristics b y M RI at Scree ni n g 3 , usi n g h y p oi nte nse f oci 
of a de dicate d M RI p ulse se q ue nce, e. g., fat sat urati o n gra die nt recalle d ec h o –  Fat Sat G R E –  

N o v arti s  
C o nfi d e nti al  
P a g e 6 8  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
se q ue nce. A si n gle d ose of ca na ki n u ma b is u nli kel y t o re d uce C C a n d C C is t heref ore n ot use d 
as a st u d y e n d p oi nt.  
8. 3   
Effi c a c y  
T he efficac y assess me nts descri be d i n t his secti o n will be e val uate d i n all partici pa nts i n all 
treat me nt ar ms. 
Artic ular cartila ge str uct ure ( pri mar y e n d p oi nt) 
 as well as 
s y n o vitis (sec o n dar y e n d p oi nt) 
 
 will be e val uate d b y M RI as descri be d 
i n Secti o n  8. 3. 1 . 
Pai n ( pri mar y e n d p oi nt) will be assesse d b y P R Os as descri be d i n Secti o n  8. 3. 2 . 
8. 3. 1   
K n e e M RI  
Alterati o ns i n n or mal k nee ki ne matics s hift l oa di n g fr o m cartila ge re gi o ns a da pte d f or l oa di n g 
t o re gi o ns less well s uite d. T his lea ds t o t he i nitiati o n a n d pr o gressi o n of de ge nerati ve pr ocesses 
c o nsiste nt wit h O A i n m ulti ple k nee areas, p ote ntiall y e ve n m ore s o i n prese nce of a n 
i nfla m mat or y flare. H yali ne cartila ge is c haracterize d b y t w o mai n disti nct la yers bet wee n t he 
artic ular s urface a n d b o ne i nterface, mar ke d b y orie ntati o n of c olla ge n fi brils. Besi des t he 
c olla ge n matri x bei n g hi g hl y str uct ure d, gl yc osa mi n o gl yca ns ( G A G) are als o a b u n da nt i n 
h yali ne cartila ge. I n  earl y sta ges of cartila ge de ge nerati o n a n d fi br ocartila ge, s u btle c ha n ges 
t y picall y i n v ol ve t hese maj or c o nstit ue nts of t he cartila ge s oli d matri x w hic h i n t ur n c o ntri b ute 
t o a c ha n ge i n its  
 
M RI will be o btai ne d fr o m t he tar get k nee t o i) select patie nts wit h s y n o vitis a n d ii) vis ualize 
t he cartila ge tiss ue a n d ot her str uct ures t hr o u g h t he k nee. T h us, t he i ma gi n g pr ot oc ol will be 
de vel o pe d t o mai nl y q ua ntif y c ha n ges i n v ol u me a n d t hic k ness of cartila ge i n t he i n de x re gi o n 
(i.e. t he re gi o n w here m ost cartila ge da ma ge occ urs i n O A patie nts wit h K L 2-4), b ut als o t o 
detect s y n o vitis a n d q ua ntif y a n y c ha n ges d uri n g treat me nt. T he i n de x re gi o n is defi ne d as t he 
u ni o n of t he fe m oral me dial a nteri or ( F M A), ce ntral ( F M C) a n d p osteri or ( F M P) cartila ge 
s u bre gi o ns i n t he k nee. 
 
 
O verall, t hese meas ures will de m o nstrate t he effecti ve ness of L N A 0 4 3 
i n re ge nerati n g cartila ge i n t he a bse nce a n d prese nce of ca na ki n u ma b, b ut als o all o w 
ve rificati o n of t he q ualit y of t he cartila ge ne wl y f or me d u p o n treat me nt. T his i nf or mati o n 
s h o ul d ma ke it p ossi ble t o pre dict t o w hat e xte nt t he re pair is d ura ble o ver ti me. 
I n a d diti o n, t he assess me nt of t he s y n o vitis le vel usi n g a d y na mic -c o ntrast-e n ha nce d ( D C E) 
M RI a p pr oac h 
will de m o nstrate t he effecti ve ness of ca na ki n u ma b i n re d uci n g k nee 
i nfla m mati o n a n d w het her t his res p o nse is c orrelate d wit h a decrease i n pai n. 
8. 3. 1. 1  
I m a g e c oll e cti o n 
T he ac q uisiti o n of ma g netic res o na nce i ma ges will be perf or me d b y a trai ne d M RI pr ofessi o nal 
at eac h site. T he M RI tec h n ol o gist will be bli n de d t o t he treat me nt recei ve d b y t he patie nt. 
All  partici pa nts will be i ma ge d usi n g a cli nical M RI 3 T sca n ner, after e ns uri n g t here is n o 
c o ntrai n dicati o ns f or M RI (s uc h as metallic i m pla nts, cla ustr o p h o bia etc). F or eac h M RI sessi o n, 
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C o nfi d e nti al  
P a g e 6 9  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
i ma ges will be ac q uire d fr o m t he tar get k nee as descri be d i n t he i ma gi n g pr ot oc ol t o assess 
s y n o vitis, cartila ge str uct ure
 
. Patie nt set u p will e ns ure c orrect re pr o d uci ble p ositi o ni n g of t he k nee via t he 
use of a f o ot b oar d de vice a n d a c us hi o n i n t he k nee c oil as well as s ufficie nt c o mf ort t o li mit 
m oti o n artefacts. Sca n ni n g sessi o ns, i ncl u di n g t h ose usi n g t he a d diti o nal se q ue nces f or t he 
a d diti o nal D C E -M RI  meas ure me nt ( baseli n e a n d Da y 8 5), s h o ul d n ot e xcee d o ne h o ur t o 
mi ni mize patie nt b ur de n. 
 
 As t he last ac q uisiti o n i n t he pr ot oc ol f or s y n o vitis 
assess me nt at baseli ne a n d Da y 8 5, T 1 -wei g hte d ( T 1 w) D C E -M R i ma ges will be o btai ne d 
bef ore a n d after t he i njecti o n of t he G B C A b y ac q uiri n g a ti me series of T 1 w i ma ges of t he 
k nee wit h i nter vals of a fe w sec o n ds. If necessar y, partici pa nts ma y be all o we d t o ta ke a brea k 
bet wee n t he str uct ural M RI  a n d t he D C E -M RI part s o t hat t he y are n ot re q uire d t o lie still i n 
t he M RI sca n ner f or t he e ntire ti me. 
M R i ma ges will be ac q uire d at selecte d a n d q ualifie d i ma gi n g site(s). T he  M R i ma ges will be 
se nt f or i n de pe n de nt ce ntral re vie w b y i ma gi n g s pecialists. T he re vie wers will be bli n de d t o t he 
treat me nt recei ve d b y t he patie nt. 
I nci de ntal fi n di n gs are be y o n d t he sc o pe of t he ce ntral i ma gi n g ve n d or. If a n 
i n vesti gat or/ra di ol o gist rec o g nizes a n y i nci de ntal fi n di n g i n t he i ma ges d uri n g t he c o urse of t he 
trial, t he i n vesti gat or s h o ul d f oll o w u p as part of his/ her d ut y of care t o e ns ure t he safet y a n d 
well bei n g of t he partici pa nt.  
8. 3. 1. 2  
I m a g e pr o c e s si n g 
T he i ma ge a nal ysis will be perf or me d ce ntrall y, as defi ne d i n t he i ma gi n g ma n ual, i n or der t o 
pri maril y:  
1.  Scree n f or patie nts wit h s y n o vitis pri or t o t he L N A 0 4 3 i njecti o n  
2.  Assess c ha n ges i n cartila ge v ol u me, t hic k ness a n d  
 b ot h i n t he i n de x re gi o n a n d t he 
rest of t he j oi nt 
3.  Assess c ha n ges i n t he le vel of s y n o vitis as well as c ha n ges i n t he t hic k ness of t he s y n o vial 
me m bra ne, 
 
T he c o de d me dical i ma ges will be use d pri maril y f or a nal ysis as descri be d i n t his pr ot oc ol; 
h o we ver, t he i ma ges ma y als o be use d f or t he de vel o p me nt a n d e val uati o n of ne w a nal ysis 
met h o ds directl y relate d t o t he area of researc h t hat t his st u d y c o vers.  
At scree ni n g, a c o m pre he nsi ve se mi -q ua ntitati ve sc ori n g s yste m will be use d f or t he assess me nt 
of w h ole -k nee s y n o vitis ( G uer mazi  et al 2 0 1 1 ). T his a nal ysis will be perf or me d o n o ne of t he 
sca ns o btai ne d fr o m t he D C E-M RI series, i deall y t he o ne rec or de d ~ 2 mi n utes after t he i njecti o n 
of G B C A, fr o m w hic h t he ma xi mal s y n o vial e n ha nce me n t s h o ul d be o bser ve d. S y n o vitis will 
be assesse d at 1 1 sites of t he j oi nt a n d s y n o vial t hic k ness at eac h of t hese sites will be sc ore d 
se mi-q ua ntitati vel y: gra de 0 ( < 2 m m), gra de 1 ( 2 – 4 m m) a n d gra de 2 ( > 4 m m) at eac h site. 
W h ole -k nee s y n o vitis will t he n be assesse d b y s u m mi n g t he sc ores  fr o m all sites a n d 
cate g orise d as f oll o ws: 0 – 4 n or mal or e q ui v ocal s y n o vitis; 5 – 8 mil d s y n o vitis; 9 – 1 2 m o derate 
s y n o vitis a n d ≥1 3 se vere s y n o vitis. 
D C E -M RI sca ns will be use d f or t he l o n git u di nal assess me nt of s y n o vitis b ot h at baseli ne a n d 
Da y  8 5. D uri n g t he D C E -M RI ac q uisiti o n, w hile t he c o ntrast a ge nt is prefere ntiall y ta ke n u p at 
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C o nfi d e nti al  
P a g e 7 0  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
sites wit h hi g h perf usi o n (s uc h as t he i nfla me d s y n o vial me m bra ne), a te m p oral variati o n of t he 
M RI si g nal i nte nsit y occ urs. 
W he n 
t he c o ntrast distri b utes t hr o u g h t he i ntra vasc ular a n d 
e xtra vasc ular s paces, t he M R si g nal i nte nsit y i n t he i ma ge v ol u me ele me nts ( v o xels) of t he 
tar get tiss ue c ha n ges o ver ti me, ge nerati n g s o-calle d si g nal i nte nsit y ( SI) c ur ves. T hese  c ur ves 
ca n t he n be a nal yze d t o deri ve para meters relate d t o tiss ue perf usi o n. T he para meter of pri mar y 
i nterest will be t he v ol u me tra nsfer rate of t he G B C A fr o m t he bl o o d plas ma i n s y n o vi u m, 
c o m m o nl y referre d t o as Ktra ns ( Riis  et al 2 0 1 7 ), 
 
 
 
Ktra ns res ults are p ote ntiall y u n bli n di n g wit h re gar ds t o t he ca na ki n u ma b treat me nt a n d will 
t heref ore n ot be discl ose d t o bli n de d s p o ns or staff u ntil after t he data base has bee n fr oze n f or 
t he first i nteri ma nal ysis at Da y 8 5.  
Se g me ntati o n of k nee artic ular cartila ge will be perf or me d f or t he meas ure me nt of cartila ge 
v ol u me a n d t hic k ness b y usi n g a n a ut o mate d se g me ntati o n s oft ware ( C h o n dral Healt h, Sie me ns, 
Erla n ge n, Ger ma n y). T he s oft ware all o ws a r o b ust a ut o mate d se g me ntati o n o f t he fe m oral, 
ti bial a n d patellar cartila ge as well as t he Re gi o n-of -I nterest a nal ysis. 
 
 
 As a res ult, t he c o m ple te set of para meters is pr o vi de d ( v ol u metr y 
a n d descri pti ve statistics of q ua ntitati ve M R para meters). Meas ure d varia bles will i ncl u de 
v ol u mes (i n m m 3) a n d cartila ge t hic k ness (i n milli meters) se paratel y f or 2 1 k nee re gi o ns 
( Fe m ur: 
me dial p osteri or-F M P, 
me dial ce ntral -F M C, 
me dial a nteri or -F M A, tr oc hlea 
me dial -F T M, tr oc hlea ce ntral -F T C, tr oc hlea lateral -F T C, lateral p osteri or -F L P, lateral 
ce ntral -F L C a n d lateral a nteri or -F L A; Ti bia: lateral p osteri or -T L P, lateral ce ntral -T L C, lateral 
a nteri or-T L A, me dial p os teri or-T M P, me dial a nteri or -T M A a n d me dial ce ntral -T M C; Patella: 
lateral i nferi or-P LI, lateral ce ntral -P L C, lateral s u peri or -P L S, me dial i nferi or -P MI, me dial 
ce ntral -P M C, me dial s u peri or -P M S). T his defi niti o n of t he s u bfiel ds is base d o n a m o difie d 
I C R S score ( S ur o wiec  et al 2 0 1 4 ). T he a ut o mate d s oft ware will calc ulate cartila ge v ol u me a n d 
cartila ge t hic k ness wit hi n eac h of t hese s u bfiel ds.  
Str uct ural a n d c o ntrast -e n ha nce d M R i ma ges will als o be a nal yse d f or t he deter mi nati o n of 
 as descri be d i n t he 
literat ure, e. g.
 
. 
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N o v arti s  
C o nfi d e nti al  
P a g e 7 1  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
8. 3. 2   
P ati e nt R e p ort e d O ut c o m e s ( P R O s)  
T he P R Os use d i n t his st u d y are W PI ( descri be d i n Secti o n  8. 1. 1. 1 ), N R S Pai n, K O O S,  
 
 a n d a Pai n I nte nsit y a n d Pai n 
Me dicati o ns Diar y. T he P R Os are 
c o m plete d o n pa per a n d tra nscri be d i nt o t he C R F b y t he site staff.  
T he c o m pleti o n of t he f ull set of P R Os is e x pecte d t o ta ke a p pr o xi matel y 3 5 mi n utes, wit h t he 
K O O S bei n g t he m ost ti me c o ns u mi n g (ar o u n d 2 0 mi n utes),
 
a n d last t he re mai ni n g P R Os (ar o u n d 5 mi n utes c o m bi ne d). T he d iar y is e x pecte d t o re q uire 
1 -5  mi n of t he partici pa nt’s ti me per da y de pe n di n g o n h o w m uc h pai n me dicati o n t he 
partici pa nt nee ds t o re p ort.  
T he partici pa nt m ust be gi ve n t he P R O meas ure(s) t o be c o m plete d at t he sc he d ule d visit bef ore 
a n y ot her cli nical assess me nts are c o n d ucte d.  
T he partici pa nt will p ote ntiall y als o c o m plete  N R S  Pai n, K O O S, 
 at h o me 
d uri n g t he re m ote visits ( Scree ni n g 2, Scree ni n g 4, Da y  2 9 a n d Da y 5 7). T he i n vesti gat or or 
dele gate s h o ul d, if a p plica ble, pr o vi de t he  
 P R Os t o t he partici pa nt latest at t he prece di n g 
visit a n d re mi n d t he partici pa nt t o c o m plete t he q uesti o n naires d uri n g t he re m ote visit c o ntact. 
If c o m plete d off -site, t he partici pa nt s h o ul d ret ur n t he c o m plete d ori gi nal q uesti o n naires at t he 
f oll o wi n g visit t o t he i n vesti gat or site. 
T he q uesti o n naires s h o ul d be c o m plete d i n t he la n g ua ge m ost fa miliar t o t he partici pa nt. 
T he  partici pa nt s h o ul d be gi ve n s ufficie nt s pace a n d ti me t o c o m plete t he P R O meas ure(s). 
A  partici pa nt’s ref usal t o c o m plete all or a n y part of a P R O meas ure s h o ul d be d oc u me nte d i n 
t he C R F b ut s h o ul d n ot be ca pt ure d as a pr ot oc ol de viati o n. 
T he site pers o n nel s h o ul d c hec k t he P R O meas ure(s) c ollecte d o n -site f or c o m plete ness a n d as k 
t he partici pa nt t o c o m plete a n y missi n g res p o nses. 
F or P R Os c o m plete d off -site, a pr o visi o nal s u b missi o n of t he P R Os via ver bal c o m m u nicati o n, 
fa x, e mail, te xt-messa ge or ot her preferre d di gital met h o d is all o we d. If t he P R Os are c o m plete d 
at h o me b ut t he a ns wers are nee de d t o e val uate t he partici pa nt’s eli gi bilit y, i.e. if N R S Pai n a n d  
K O O S are c o m plete d re m otel y at Scree ni n g 2 a n d/ or Scree ni n g 4, t he eli gi bilit y c hec k ca n be 
base d o n t he pr o visi o nal data as l o n g as t he y are verifie d a gai nst t he c o m plete d ori gi nal at Da y  1.  
C o m plete d P R Os, i ncl u di n g a n y u ns olicite d c o m me nts writte n b y t he partici pa nt, m ust be 
re vie we d a n d assesse d b y t he i n vesti gat or f or res p o nses w hic h ma y i n dicate p ote ntial A Es or 
S A Es bef ore a n y cli nical st u d y e xa mi nati o ns. If A Es or S A Es are c o nfir me d, st u d y i n vesti gat ors 
s h o ul d n ot e nc o ura ge t he partici pa nt t o c ha n ge res p o nses re p orte d i n t he c o m plete d 
q uesti o n naires. St u d y i n vesti gat ors m ust f oll o w re p orti n g i nstr ucti o ns o utli ne d i n Secti o n  1 0 . 
8. 3. 2. 1  
N R S P ai n  
N u merical Rati n g Scale ( N R S) f or Pai n ( Ha w ker  et al 2 0 1 1 ) is assesse d at re g ular i nter vals t o 
c o nfir m eli gi bilit y a n d t o e val uate pai n stat us t hr o u g h o ut t he st u d y.  
T he N R S  Pai n i nstr u me nt has 
 a n d t he partici pa nts will be as ke d t o 
rate 
 
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N o v arti s  
C o nfi d e nti al  
P a g e 7 2  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
8. 3. 2. 2  
K O O S  
K nee -relate d s y m pt o ms a n d f u ncti o n 
will 
be assesse d 
b y 
mea ns 
of t he 
K O O S 
meas ure  (R o os  et al 2 0 1 1 ) c ollecte d at re g ular i nter vals. T he K O O S has a recall peri o d of se ve n 
da ys a n d i ncl u des 4 2 ite ms gr o u pe d i nt o 5 s u bscales: Pai n, ot her S y m pt o ms, Acti vities of Dail y 
Li vi n g ( A D L), F u ncti o n i n S p ort a n d Recreati o n ( S p ort/ Rec), a n d K nee relate d Q ualit y of Lif e 
( Q o L). Sta n dar dize d a ns wer o pti o ns are gi ve n ( 5 Li kert b o xes) a n d eac h q uesti o n gets a sc ore 
fr o m 0-4. A n or malize d sc ore ( 1 0 0 i n dicati n g n o s y m pt o ms a n d 0 i n dicati n g e xtre me 
s y m pt o ms) is calc ulate d f or eac h s u bscale ( K O O S User G ui de).  
8. 3. 2. 3   
 
8. 3. 2. 4   
 
8. 3. 2. 5   
 
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N o v arti s  
C o nfi d e nti al  
P a g e 7 3  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
8. 3. 2. 6   
 
8. 3. 2. 7  
P ai n I nt e n sit y a n d P ai n M e di c ati o n s Di ar y  
Dail y assess me nts of pai n i nte nsit y ( N R S  Pai n), as well as a n y pai n me dicati o n i nta ke  will be 
rec or de d b y t he partici pa nt i n t he st u d y s pecific pai n diar y, fr o m Scree ni n g 1 u ntil Da y 8 5, a n d 
a gai n d uri n g o ne wee k (se ve n c o nsec uti ve da ys) pri or t o t he Da y 1 9 7 a n d Da y 3 6 5 w here t he 
se ve n da ys s h o ul d fall wit hi n 3 wee ks fr o m t he visit. Use of prescri be d or O T C pai n me dicati o ns 
will still nee d t o be d oc u me nte d as C o nc o mita nt Me dicati o ns acc or di n g t o  Secti o n  6. 2. 1 . 
T he partici pa nt ma y c h o ose w he n b ut s h o ul d assess t he pai n i nte nsit y at a p pr o xi matel y t he sa me 
ti me o n e ver y da y, als o o n st u d y visit da ys. T he N R S Pai n assess me nt i n t he diar y a n d t he 
N R S  Pai n assess me nt perf or me d at site d uri n g st u d y visits are d o ne at differe nt ti me p oi nts a n d 
t heref ore d oc u me nte d se paratel y i n t he C R F. 
At eac h visit, partici pa nts m ust be pr o vi de d wit h a ne w pai n diar y t hat c o vers at least t he peri o d 
t he y s h o ul d c o m plete u ntil t he ne xt pla n ne d visit. T he site pers o n nel s h o ul d re mi n d t he 
partici pa nt a b o ut t he diar y c o m pleti o n ar o u n d t hree wee ks pri or  t o t he pla n ne d Da y 1 9 7 a n d 
Da y  3 6 5.  
8. 3. 3  
 
8. 3. 4   
A p pr o pri at e n e s s of effi c a c y a s s e s s m e nt s  
F or a p pr o priate ness of k nee M RI para meters, see Secti o n  8. 3. 1 . 
T he P R O K O O S sc ore is a n e x pa n de d versi o n of t he 
Wester n O ntari o a n d 
Mc Master 
U ni versities Art hritis I n de x ( W O M A C) sc ore, w hic h tra diti o nall y has bee n use d i n O A trials 
(K O O S user g ui de 2 0 0 3 ). K O O S i ncl u des W O M A C O A i n de x L K 3. 0 i n its c o m plete a n d 
ori gi nal f or mat, all o wi n g 
W O M A C sc ores t o be deri ve d fr o m t he K O O S i nstr u me nt. 
C o m pare d  t o W O M A C, t he K O O S sc ore gi ves a m ore c o m pre he nsi ve pict ure beca use it als o 
i ncl u des " F u ncti o n i n s p ort a n d recreati o n" a n d " K nee relate d Q o L". 
T he N R S pai n sc ore is tra diti o nall y use d t o assess pai n.  
C CI
C CI
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 7 4  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
. 
8. 4   
S af et y  
As per  Secti o n 4. 6 , d uri n g a P u blic Healt h e mer ge nc y as declare d b y L ocal or Re gi o nal 
a ut h orities i.e. pa n de mic, e pi de mic or nat ural disaster, t hat li mits or pre ve nts o n -site st u d y visits, 
re g ular p h o ne or virt ual calls ca n occ ur (e ver y f o ur wee ks or m ore fre q ue ntl y if nee de d) f or 
safet y m o nit ori n g a n d disc ussi o n of t he partici pa nt´s healt h stat us u ntil it is safe f or t he 
partici pa nt t o visit t he site a gai n.  
8. 4. 1   
P h y si c al e x a mi n ati o n, vit al si g n s a n d h ei g ht/ w ei g ht  
Safet y assess me nts are s pecifie d bel o w, wit h t he assess me nt sc he d ule detaili n g w he n eac h 
assess me nt is t o be perf or me d.  
F or details o n A E c ollecti o n a n d re p orti n g, see  Secti o n  1 0. 1. 1 . 
T a bl e 8 -2   
A s s e s s m e nt s a n d S p e cifi c ati o n s  
A s s e s s m e nt  
S p e cifi c ati o n  
P h y si c al E x a mi n ati o n   
A c o m pl et e p h y si c al e x a mi n ati o n will i n cl u d e t h e e x a mi n ati o n of g e n er al 
a p p e ar a n c e, s ki n, n e c k (i n cl u di n g t h yr oi d), e y e s, e ar s, n o s e, t hr o at, 
l u n g s, h e art, a b d o m e n, b a c k, l y m p h n o d e s, e xtr e miti e s, v a s c ul ar, a n d 
n e ur ol o gi c al. If i n di c at e d b a s e d o n m e di c al h i st or y a n d/ or s y m pt o m s, 
r e ct al, e xt er n al g e nit ali a, br e a st, a n d p el vi c e x a m s will b e p erf or m e d. 
A  c o m pl et e p h y si c al e x a mi n ati o n m u st b e p erf or m e d at S cr e e ni n g 1 a n d 
D a y 1 9 7. A s h ort p h y si c al e x a mi n ati o n, i. e. wit h f o c u s e d e x a mi n ati o n s 
a s j u d g e d b y t h e i n v e sti g at or, c a n b e p erf or m e d at D a y 1, D a y 1 5, 
D a y  8 5 a n d D a y 3 6 5.  
A k n e e j oi nt e x a mi n ati o n will al s o b e p erf or m e d a s p art of t h e p h y si c al 
e x a mi n ati o n at all ti m e p oi nt s s p e cifi e d i n T a bl e  8 -1 , a n d i n cl u d e s 
e x a mi n ati o n f or r a n g e of m oti o n, st a bilit y, w ar mt h, s w elli n g/ b ul g e si g n 
a n d p at ell ar t a p si g n a s w ell a s f or p at ell of e m or al p ai n.  
T ar g et e d p h y si c al e x a mi n ati o n s t o el a b or at e s elf - r e p ort e d s y m pt o m s, 
c o m pl ai nt s, i nj e cti o n sit e r e a cti o n s or p o st -i nj e cti o n fl ar e s a s a p pli c a bl e, 
c a n b e d o n e at a n y vi sit.  
I nf or m ati o n f or all p h y si c al e x a mi n ati o n s m u st b e i n cl u d e d i n t h e s o ur c e 
d o c u m e nt ati o n at t h e i n v e sti g at or sit e b ut will n ot b e r e c or d e d i n t h e 
C R F. Cli ni c all y r el e v a nt fi n di n g s t h at ar e pr e s e nt pri or t o si g ni n g 
i nf or m e d c o n s e nt 
m u st b e r e c or d e d o n t h e a p pr o pri at e e C R F t h at 
c a pt ur e s  m e di c al hi st or y. 
Si g nifi c a nt fi n di n g s  m a d e aft er si g ni n g 
i nf or m e d c o n s e nt, w hi c h m e et t h e d efi niti o n of a n A d v er s e E v e nt, m u st 
b e r e c or d e d a s a n a d v er s e e v e nt.  
Vit al si g n s  
Vit al si g n s will i n cl u d e t h e c oll e cti o n of b o d y t e m p er at ur e b y l o c all y 
a c c e pt e d st a n d ar d m et h o d, e. g. di git al or i nfr ar e d s e n s or a n d or al, oti c, 
a xill ar y, 
et c (r e c or d e d i n ° C), 
bl o o d 
pr e s s ur e ( B P) 
a n d 
p ul s e 
m e a s ur e m e nt s.  
T h e s a m e m et h o d f or m e a s uri n g t h e b o d y t e m p er at ur e s h o ul d b e u s e d 
t hr o u g h o ut t h e st u d y. 
S y st oli c a n d di a st oli c bl o o d pr e s s ur e 
will b e 
m e a s ur e d aft er t h e 
p arti ci p a nt h a s b e e n sitti n g f or fi v e mi n ut e s, wit h b a c k s u p p ort e d a n d 
b ot h f e et pl a c e d o n t h e fl o or, t hr e e ti m e s at 3 -mi n ut e i nt er v al s u si n g a n 
a ut o m at e d v ali d at e d d e vi c e, e. g. O M R O N, wit h a n a p pr o pri at el y si z e d 
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 7 5  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
A s s e s s m e nt  
S p e cifi c ati o n  
c uff. T h e m e a n of t h e t hr e e m e a s ur e m e nt s will b e u s e d f or e v al u ati o n s 
a n d e nt er e d i n t h e e C R F. I n c a s e t h e c uff si z e s a v ail a bl e ar e n ot l ar g e 
e n o u g h f or t h e p arti ci p a nt' s ar m cir c u mf er e n c e, a s p h y g m o m a n o m et er 
wit h a n a p pr o pri at el y si z e d c uff m a y b e u s e d.  
If t h e bl o o d pr e s s ur e i s o ut-of -r a n g e at s cr e e ni n g a n d/ or b a s eli n e t hr e e 
a d diti o n al r e a di n g s c a n b e o bt ai n e d aft er a p pr o xi m at el y 3 0 mi n ut e s, i n 
t h e m a n n er d e s cri b e d a b o v e. T h e m e a n of t h e l a st t hr e e r e a di n g s m u st 
b e wit hi n t h e r a n g e s pr o vi d e d i n t h e eli gi b ilit y crit eri a i n or d er f or t h e 
p ati e nt t o q u alif y.  
I n c a s e of r e p e at e d bl o o d pr e s s ur e a s s e s s m e nt s, t h e m e a n v al u e fr o m 
b ot h s et of m e a s ur e m e nt s (i niti al a n d r e p e at) s h o ul d b e e nt er e d i n t h e 
e C R F.  
H ei g ht a n d w ei g ht   
H ei g ht i n c e nti m et er s ( c m) a n d b o d y w ei g ht (t o t h e n e ar e st 0. 1 kil o gr a m 
( k g) i n i n d o or cl ot hi n g, b ut wit h o ut s h o e s) will b e m e a s ur e d. 
B o d y m a s s i n d e x ( B MI) will b e c al c ul at e d  t o o n e d e ci m al u si n g t h e 
f oll o wi n g f or m ul a: 
B MI = B o d y w ei g ht ( k g) /[ H ei g ht ( m)] 2  
T h e 
S cr e e ni n g vi sit h ei g ht  m e a s ur e m e nt 
will b e u s e d f or 
B MI 
c al c ul ati o n s t hr o u g h o ut t h e st u d y.  
8. 4. 2   
L a b or at or y e v al u ati o n s  
I n t he case w here a la b orat or y ra n ge is n ot s pecifie d b y t he pr ot oc ol, b ut a val ue is o utsi de t he 
refere nce ra n ge, a decisi o n re gar di n g w het her t he res ult is of cli nical si g nifica nce or n ot s hall 
be ma de b y t he I n vesti gat or (i n c o ns ultati o n wit h t he s p o ns o r if nee de d) a n d s hall be base d, i n 
part, u p o n t he nat ure a n d de gree of t he o bser ve d a b n or malit y.  
I n all cases, t he I n vesti gat or m ust d oc u me nt i n t he s o urce d oc u me nts, t he cli nical c o nsi derati o ns 
(i.e., res ult was/ was n ot cli nicall y si g nifica nt a n d/ or me dicall y rele va nt) i n all o wi n g or 
disall o wi n g t he partici pa nt t o c o nti n ue i n t he st u d y.  
A ce ntral la b orat or y will be use d f or a nal ysis of all safet y s peci me ns c ollecte d  e xce pt f or t he 
p ote ntial S A R S -C o v -2 tests a n d uri ne pre g na nc y test, w hic h will be perf or me d a n d rea d -o ut 
l ocall y. Details o n t he c ollecti o n, s hi p me nt of sa m ples a n d re p orti n g of res ults b y t he ce ntral 
la b orat or y are pr o vi de d t o i n vesti gat ors i n t he ce ntral la b orat or y ma n ual. 
If partici pa nts ca n n ot visit t he site f or safet y assess me nts c o n d ucte d t hr o u g h t he ce ntral 
la b orat or y, l ocal la b orat or y c ollecti o n ma y be use d d uri n g a P u blic Healt h e mer ge nc y as 
declare d b y L ocal or Re gi o nal a ut h orities i.e. pa n de mic, e pi de mic or nat ural disaster, t hat li mits 
or pre ve nts o n -site st u d y visits.  If use d, rele va nt d oc u me ntati o n s h o ul d be o btai ne d fr o m t he 
l ocal la b orat or y t o e val uate t he vali dit y of t he data, c o nsi deri n g p ote ntial differe nces i n a nal ysis 
assa ys, refere nce ra n ges, etc. bet wee n  t he l ocal a n d ce ntral la b orat ories. It m ust be clear fr o m 
t he fi nal data set w hic h data ori gi nate fr o m l ocal la b orat or y a nal yses. 
F or uri nal ysis, a mi dstrea m uri ne sa m ple (a p pr o x. 3 0 m L) will be o btai ne d, i n or der t o a v oi d 
c o nta mi nati o n wit h e pit helial cells a n d se di me nts, a n d all o w pr o per assess me nts.  

N o v arti s  
C o nfi d e nti al  
P a g e 7 6  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
All a b n or mal la b orat or y res ults m ust be e val uate d f or criteria defi ni n g a n a d verse e ve nt a n d 
re p orte d as s uc h if t he criteria are met, see Secti o n  1 0. 1. 1 . F or la b orat or y relate d a d verse e ve nts, 
f oll o w-u p e val uati o ns are ma n dat or y u ntil n or malizati o n of t he res ult(s) or u ntil t he res ult is n o 
l o n ger c o nsi dere d t o be cli nicall y si g nifica nt. 
T a bl e 8 -3   
L a b or at or y e v al u ati o n s  
T e st C at e g or y  
T e st N a m e  
H e m at ol o g y  
H e m at o crit, H e m o gl o bi n, Er y. M e a n C or p u s c ul ar H e m o gl o bi n, Er y. 
C or p u s c ul ar H G B C o n c e ntr ati o n, Er y. 
M e a n C or p u s c ul ar V ol u m e, 
Pl at el et s, Er yt hr o c yt e s, L e u k o c yt e s, Er yt hr o c yt e s C ell 
M or p h ol o g y, 
Diff er e nti al 
( B a s o p hil s,  
E o si n o p hil s,  
L y m p h o c yt e s,  
M o n o c yt e s, 
N e u tr o p hil s) 
If a b n or m al r e s ult s ar e o bt ai n e d fr o m Diff er e nti al, a m a n u al ( s m e ar) 
diff er e nti al a n al y si s will b e p erf or m e d.  
Cli ni c al c h e mi str y  
S o di u m, 
P ot a s si u m,  M a g n e si u m, 
P h o s p h at e, 
Bi c ar b o n at e, 
Ur e a 
Nitr o g e n, Cr e ati ni n e ( a n d G F R), Uri c A ci d, C hl ori d e, Al b u mi n, C al ci u m, 
Al k ali n e p h o s p h at a s e, T ot al Bilir u bi n, Dir e ct a n d I n dir e ct Bilir u bi n, 
L a ct at e d e h y dr o g e n a s e ( L D H), G a m m a -gl ut a m yl -tr a n sf er a s e ( G G T), 
A S T, A L T, Cr e ati n e ki n a s e, H b A 1 c, T ot al Pr ot ei n, T ot al C h ol e st er ol, 
L D L C h ol e st er ol, H D L C h ol e st er ol, Tri gl y c eri d e s  
Uri n al y si s  
Pr ot ei n, cr e ati ni n e, pr ot ei n: cr e ati ni n e r ati o  
M a cr o s c o pi c p a n el ( di p sti c k): L e u k o c yt e s e st er a s e, Nitrit e, p H, Pr ot ei n, 
Gl u c o s e, K et o n e s, Bl o o d/ H e m o gl o bi n.  
If t h e di p sti c k r e s ult i s p o siti v e f or Pr ot ei n, Nitrit e, L e u k o c yt e s e st er a s e 
a n d/ or Bl o o d, t h e s a m pl e will b e s e nt f or mi cr o s c o pi c a n al y si s.  
Pr e g n a n c y T e st  
S er u m / Uri n e pr e g n a n c y t e st, F S H (if a p pli c a bl e) s e e S e cti o n  8. 4. 4  
8. 4. 3   
El e ctr o c ar di o gr a m ( E C G)  
E C Gs m ust be rec or de d after 1 0 mi n utes rest i n t he s u pi ne p ositi o n t o e ns ure a sta ble baseli ne. 
I n t he case of a series of assess me nts, E C G s h o ul d be first assess me nt o btai ne d w hile t he 
partici pa nt is at rest.  
T he Fri dericia Q T c orrecti o n f or m ula ( Q Tc F) m ust be use d f or cli nical decisi o ns.  
U nless a ut o -calc ulate d b y t he E C G mac hi ne, t he i n vesti gat or m ust calc ulate Q Tc F at t he Scree ni n g 
a n d/ or Baseli ne visit(s) (as a p plica ble) t o assess eli gi bilit y acc or di n g t o t he f oll o wi n g f or m ula : 
Fi g ur e 8 -1   
Q T c F f or m ul a  
 
Si n gle 1 2 -lea d E C Gs are c ollecte d a n d res ults are e ntere d i nt o t he a p pr o priate e C R F pa ge. 

N o v arti s  
C o nfi d e nti al  
P a g e 7 7  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
A d diti o nal, u nsc he d ule d safet y E C Gs ma y be perf or me d at t he discreti o n of t he i n vesti gat or at 
a n y ti me d uri n g t he st u d y. F or a n y E C Gs wit h patie nt safet y c o ncer ns, t w o a d diti o nal E C Gs 
m ust be perf or me d t o c o nfir m t he safet y fi n di n g. E C G safet y m o nit ori n g, or a re vie w pr ocess, 
s h o ul d be i n place f or cli nicall y si g nifica nt E C G fi n di n gs at baseli ne, a n d d uri n g t he st u d y, 
bef ore a d mi nistrati o n of st u d y treat me nt.  
Cli nicall y si g nifica nt a b n or malities m ust be rec or de d o n t he rele va nt secti o n of t he me dical 
hist or y/ C urre nt me dical c o n diti o ns/ A E e C R F as a p pr o priate.  
8. 4. 4   
Pr e g n a n c y a n d a s s e s s m e nt of f ertilit y 
All pre -me n o pa usal w o me n w h o are n ot s ur gicall y sterile will ha ve pre g na nc y testi n g. 
A d diti o nal pre g na nc y testi n g mi g ht be perf or me d if re q ueste d b y l ocal re q uire me nts.  
If partici pa nts ca n n ot visit t he site t o ha ve ser u m pre g na nc y tests d uri n g a P u blic Healt h 
e mer ge nc y as declare d b y L ocal or Re gi o nal a ut h orities i.e. pa n de mic, e pi de mic or nat ural 
disaster, t hat li mits or pre ve nts o n -site st u d y visits, uri ne pre g na nc y test kits ma y be use d 
(s u bject t o pri or a p pr o val fr o m l ocal a ut h orities, as a p pr o priate). Rele va nt partici pa nts ca n 
perf or m t he uri ne pre g na nc y test at h o me a n d re p ort t he res ult t o t he site. T he  I n vesti gat or 
s h o ul d esta blis h a c o m m u nicati o n pr ocess wit h t he partici pa nt s o t hat t he Site is i nf or me d a n d 
ca n verif y t he pre g na nc y test res ults (e. g. f oll o wi n g c o u ntr y s pecific meas ures).  
Me dical d oc u me ntati o n of o o p h orect o m y, h ysterect o m y or t u bal li gati o n m ust be retai ne d as 
s o urce d oc u me nts. S u bse q ue nt h or m o ne le vel assess me nt t o c o nfir m t he w o ma n is n ot of 
c hil d-beari n g p ote ntial m ust als o be a vaila ble as s o urce d oc u me ntati o n i n t he f ol l o wi n g cases: 
1.  S ur gical bilateral o o p h orect o m y wit h o ut a h ysterect o m y  
2.  Re p orte d 1 2 m o nt hs of nat ural (s p o nta ne o us) a me n orr hea wit h a n a p pr o priate cli nical 
pr ofile.  
I n t he a bse nce of t he a b o ve me dical d oc u me ntati o n, F S H testi n g is re q uire d of a n y fe male 
partici pa nt re gar dless of re p orte d re pr o d ucti ve/ me n o pa usal stat us at scree ni n g.  
8. 4. 5   
A p pr o pri at e n e s s of s af et y m e a s ur e m e nt s  
T he safet y assess me nts selecte d are sta n dar d f or t his i n dicati o n/ partici pa nt p o p ulati o n.  
8. 5   
A d diti o n al a s s e s s m e nt s  
8. 5. 1   
P h ar m a c o ki n eti c s  
P K sa m ples will be c ollecte d at t he ti me p oi nts defi ne d i n Ta ble  8 -1 . Detaile d i nstr ucti o ns 
re gar di n g sa m ple c ollecti o n, n u m beri n g, pr ocessi n g a n d s hi p me nt are descri be d i n t he 
la b orat or y ma n ual. 
Arra n ge me nts s h o ul d be ma de t o facilitate t he l o gistics f or partici pa nts w h o c o nse nt t o t he 
o pti o nal L N A 0 4 3 P K  c ollecti o ns at Da y 1 5, w here i n partic ular t he 8 a n d 2 4 h o urs p ost d ose 
c ollecti o n ti me p oi nts ca n be c halle n gi n g f or b ot h t he i n vesti gat or site a n d partici pa nts. 
De pe n di n g o n l ocal re q uire me nts/a p pr o vals, partici pa nt prefere nce, t he i n vesti gat or site 
res ources or facilities, a n d s u bc o ntracte d ve n d or re prese ntati o n i n t he re gi o n, t hese 
arra n ge me nts c o ul d i ncl u de o ne or a c o m bi nati o n of t he f oll o wi n g:  

N o v arti s  
C o nfi d e nti al  
P a g e 7 8  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
•  A m b ula nt p hle b ot o mist w h o visits t he partici pa nt at his/ her h o me f or t he bl o o d dra ws  
•  Partici pa nt bei n g d o micile d at t he i n vesti gat or site o ver ni g ht  
•  Tra ns p ort arra n ge me nts w hic h facilitates t he partici pa nt's ret ur n t o t he i n vesti gat or site  
I n or der t o better defi ne t he P K pr ofile, t he ti mi n g of t he P K sa m ple c ollecti o n ma y be altere d 
base d o n e mer ge nt data.  
 
 L N A 0 4 3 P K sa m ples will 
o nl y be o btai ne d fr o m t h ose w h o recei ve d L N A 0 4 3 treat me nt. A N G P T L 3 sa m ples will be 
c ollecte d a n d a nal yze d fr o m all partici pa nts i n all treat me nt ar ms.  
U nsc he d ule d P K sa m ple ma y be c ollecte d o n re q uest fr o m t he s p o ns or or i n vesti gat or, if 
c o nsi dere d usef ul t o i n vesti gate a n A E.  
8. 5. 1. 1  
P K a n al yti c al m et h o d( s)  
[ L N A 0 4 3] will be deter mi ne d b y a vali date d i m m u n o -ca pt ure a n d L C -M S/ M S  met h o d; t he 
a ntici pate d L L O Q is 1 0 n g/ m L i n ser u m.  
[ A N G P T L 3] will be deter mi ne d b y a vali date d  li ga n d bi n di n g assay; t he a ntici pate d L L O Q is 
3 9. 7  p m ol/ L i n ser u m a n d 5 1. 1 p m ol/ L i n s y n o vial fl ui d.  
 
 
C o nce ntrati o ns will be e x presse d i n mass per v ol u me u nits.  
C o nce ntrati o ns bel o w t he L L O Q will be re p orte d as “zer o” a n d missi n g data will be la bele d as 
s uc h i n t he Bi oa nal ytical Data Re p orts. 
P K sa m ples re mai ni n g after c o nce ntrati o n a nal ysis ma y be use d f or e x pl orat or y assess me nt or 
ot her bi oa nal ytical p ur p oses (e. g. cr oss c hec k bet wee n differe nt sites). Gi ve n t he e x pl orat or y 
nat ure of t he w or k, t he a nal ytical met h o d use d f or t h ose assess me nts will n ot be vali date d.  
F or sta n dar d p har mac o ki netic a b bre viati o ns a n d defi niti o ns, see  Ta ble  1 2 -1 . 
T he f oll o wi n g p har mac o ki netic para meters will be deter mi ne d, i n partici pa nts wit h s ufficie nt 
data, fr o m t he ser u m c o nce ntrati o n -ti me data usi n g t he act ual rec or de d sa m pli n g ti mes a n d 
n o n -c o m part me ntal met h o d(s) wit h P h oe ni x Wi n N o nli n ( Versi o n 8  or hi g her):  
•  C ma x, T ma x, a n d A U Clast will be deter mi ne d f or L N A 0 4 3  
•  C ma x, Ca v, a n d C mi n will be deter mi ne d f or A N G P T L 3  
T he  li near tra pez oi dal r ule will be use d f or A U C calc ulati o n. 
8. 5. 2  
 
C CI
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N o v arti s  
C o nfi d e nti al  
P a g e 7 9  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
8. 5. 2. 1  
 
8. 5. 2. 2  
 
C CI
C CI
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N o v arti s  
C o nfi d e nti al  
P a g e 8 0  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
8. 5. 2. 3  
 
8. 5. 2. 4  
 
8. 5. 2. 5  
 
8. 5. 2. 6  
 
8. 5. 2. 7  
 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
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N o v arti s  
C o nfi d e nti al  
P a g e 8 1  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
8. 5. 2. 8  
 
8. 5. 2. 9  
 
8. 5. 3   
I m m u n o g e ni cit y 
I m m u n o ge nicit y (I G) sa m ples will be o btai ne d at t he ti me p oi nts defi ne d i n t he Assess me nt 
sc he d ule (Ta ble  8 -1 ) a n d e val uate d i n all partici pa nts i n all treat me nt ar ms, i ncl u di n g t he 
place b o/ u ntreate d treat me nt ar ms.  
I n case of s us pecte d aller gic h y perse nsiti vit y, t he partici pa nt s h o ul d ret ur n t o t he site as s o o n as 
p ossi ble t o ha ve sa m ples c ollecte d f or i m m u n o ge nicit y assess me nt. U nsc he d ule d p ost -d ose 
sa m ples s h o ul d als o be c ollecte d, i n a d diti o n t o pla n ne d pre-d ose sa m ples, d uri n g sc he d ule d 
visits i n case of s us pecte d aller gic h y perse nsiti vit y is n otice d after t he i njecti o n of st u d y 
treat me nt. 
I n case of p ositi ve i m m u n o ge nicit y, bac k u p of pre vi o us pre-d ose P K sa m ples c o ul d be use d t o 
better c haracterize t he o nset of i m m u n o ge nicit y res p o nse.  
T he i n vesti gat or s h o ul d f oll o w i nstr ucti o ns o utli ne d i n t he la b orat or y ma n ual re gar di n g sa m ple 
c ollecti o n, n u m beri n g, pr ocessi n g, a n d s hi p me nt.  
C CI
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N o v arti s  
C o nfi d e nti al  
P a g e 8 2  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
8. 5. 3. 1  
I m m u n o g e ni cit y a n al yti c al m et h o d( s) 
A 
vali date d 
li ga n d-bi n di n g 
assa y 
will 
be 
use d f or t he 
detecti o n 
of 
p ote ntial 
a nti-L N A 0 4 3  a nti b o dies, a n d cr oss -reacti vit y t o A N G P T L 3. I n case of t he detecti o n of 
a nti b o dies cr oss reacti n g wit h A N G P T L 3, a vali date d li ga n d bi n di n g assa y will be use d f or t he 
detecti o n of p ote ntial cr oss -reacti ve a nti-A N G P T L 4 a nti b o dies.  
 
 
C o nfir me d i m m u n o ge nicit y p ositi ve sa m ples will be f urt her a nal yze d f or prese nce of 
ne utralizi n g a nti b o dies usi n g a vali date d met h o d perf or me d usi n g li ga n d bi n di n g assa y . 
T he detaile d met h o ds f or i m m u n o ge nicit y assess me nt will be descri be d i n t he Bi oa nal ytical 
Data Re p orts.  
 
 
 
8. 5. 4  
 
9   
St u d y di s c o nti n u ati o n a n d c o m pl eti o n  
9. 1   
Di s c o nti n u ati o n a n d c o m pl eti o n  
9. 1. 1   
St u d y tr e at m e nt di s c o nti n u ati o n a n d st u d y di s c o nti n u ati o n  
Disc o nti n uati o n of st u d y treat me nt f or a partici pa nt occ urs w he n st u d y treat me nt is st o p pe d 
earlier t ha n t he pr ot oc ol pla n ne d d urati o n a n d ca n be i nitiate d b y eit her t he partici pa nt or t he 
i n vesti gat or. 
T he i n vesti gat or m ust disc o nti n ue st u d y treat me nt f or a gi ve n partici pa nt if s/ he belie ves t hat 
c o nti n uati o n w o ul d ne gati vel y i nfl ue nce t he partici pa nt's well -bei n g.  
St u d y treat me nt m ust be disc o nti n ue d if a n y of t he f oll o wi n g circ u msta nces occ ur f or t he 
i n di vi d ual partici pa nt: 
•  Partici pa nt/ g uar dia n decisi o n  
•  Pre g na nc y  
•  Use of pr o hi bite d treat me nt f or w hic h disc o nti n ue d st u d y treat me nt is ma n dat or y 
acc or di n g t o Ta ble  6 -3  
•  A n y sit uati o n i n w hic h c o nti n ue d st u d y partici pati o n mi g ht res ult i n a safet y ris k t o t he 
partici pa nt  
C CI
C CI
C CI
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N o v arti s  
C o nfi d e nti al  
P a g e 8 3  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
•  E mer ge nce of t he f oll o wi n g a d verse e ve nts:  
•  S A E s us pecte d t o be relate d t o t he L N A 0 4 3 treat me nt  
•  Se vere l ocal t olera bilit y reacti o n  
•  Aller gic reacti o n of a n y se verit y gra de, u nless clearl y ca use d b y e x p os ure t o a k n o w n 
aller ge n (i.e. pea n ut aller g y).  
•  Se ptic art hritis or hae mart hr osis i n t he tar get j oi nt  
•  A n y la b orat or y a b n or malities t hat i n t he j u d g me nt of t he i n vesti gat or, ta ki n g i nt o 
c o nsi derati o n t he partici pa nt’s o verall stat us, pre ve nts t he partici pa nt fr o m c o nti n ue d st u d y 
treat me nt 
•  If a li ver or re nal e ve nt occ urs, f oll o w g ui deli nes o utli ne d i n Secti o n  1 6. 1  a n d Secti o n  1 6. 2  
re gar di n g disc o nti n uati o n of st u d y treat me nt.  
If disc o nti n uati o n of st u d y treat me nt occ urs, t he i n vesti gat or s h o ul d ma ke a reas o na ble eff ort 
t o u n dersta n d t he pri mar y reas o n a n d d oc u me nt t his i nf or mati o n i n t he C R F a n d s o urce rec or ds.  
Partici pa nts w h o disc o nti n ue st u d y treat me nt or w h o deci de t he y d o n ot wis h t o partici pate i n 
t he st u d y f urt her s h o ul d N O T be c o nsi dere d wit h dra w n fr o m t he st u d y U N L E S S t he y wit h dra w 
t heir c o nse nt, see Secti o n 9. 1. 2 . 
W here p ossi ble, t he y s h o ul d ret ur n f or t he assess me nts 
i n dicate d i n Ta ble  8 -1  ( Assess me nt sc he d ule), wit h t he e xce pti o ns descri be d bel o w. If t he y fail 
t o ret ur n f or t hese assess me nts f or u n k n o w n reas o ns, e ver y eff ort (e. g. tele p h o ne, e-mail, letter) 
s h o ul d be ma de t o c o ntact t he partici pa nt as s pecifie d i n Secti o n  9. 1. 3 . T his c o ntact s h o ul d 
prefera bl y be d o ne acc or di n g t o t he st u d y visit sc he d ule.  
T he f oll o wi n g assess me nts are n ot e x pecte d t o be perf or me d f or partici pa nts w h o ha ve 
disc o nti n ue d st u d y treat me nt b ut c o nti n ue t o be f oll o we d u p as part of t he st u d y:  
•  Partici pa nts w h o disc o nti n ue st u d y treat me nt d ue t o a re nal e ve nt pri or t o first L N A 0 4 3 
i njecti o n s h o ul d n ot perf or m t he D C E-M RI assess me nt at Da y 8 5  
•  Partici pa nts w h o disc o nti n ue st u d y treat me nt s h o ul d n ot ha ve s y n o vial fl ui d sa m ples 
c ollecte d f or a n y s u bse q ue nt visit  
•  Partici pa nts w h o are ra n d o mize d t o T A 1 or T A 3 b ut disc o nti n ue st u d y treat me nt pri or t o 
first L N A 0 4 3 i njecti o n s h o ul d n ot ha ve bl o o d sa m ples f or L N A 0 4 3 P K a nal ysis c ollecte d 
•  Fe male partici pa nts w h o bec o me pre g na nt s h o ul d n ot perf or m a n y assess me nt t hat is 
c o nsi dere d a ris k d uri n g pre g na nc y, i ncl u di n g b ut n ot li mite d t o M RI sca n ni n g  
If t he partici pa nt ca n n ot or is u n willi n g t o atte n d a n y f urt her visit(s) as per t he assess me nt 
sc he d ule, t he site pers o n nel s h o ul d e x pl ore t he p ossi bilit y t o arra n ge a n u nsc he d ule d visit as 
s o o n as p ossi ble, at w hic h ti me all of t he assess me nts liste d f or t he fi nal visit ( E o S) s h o ul d be 
perf or me d. At t his fi nal visit, all dis pe nse d pai n me dicati o n s h o ul d be ret ur ne d. If p ossi ble, t he 
site pers o n nel s h o ul d mai ntai n re g ular tele p h o ne c o ntact wit h t he partici pa nt, or wit h a pers o n 
pre -desi g nate d b y t he partici pa nt. T his tele p h o ne c o ntact s h o ul d prefera bl y be d o ne acc or di n g 
t o t he st u d y visit sc he d ule. 

N o v arti s  
C o nfi d e nti al  
P a g e 8 4  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
After st u d y treat me nt disc o nti n uati o n, at a mi ni m u m a n d ass u mi n g partici pa nt c o nse nt, t he 
f oll o wi n g data s h o ul d be c ollecte d at cli nic visits or via tele p h o ne/e mail c o ntact: 
•  Ne w / c o nc o mita nt treat me nts  
•  A d verse E ve nts / Seri o us A d verse E ve nts  
9. 1. 1. 1  
R e pl a c e m e nt p oli c y  
A d diti o nal patie nts ma y be e nr olle d if t he disc o nti n uati o n rate e xcee ds 1 0 % a n d if feasi ble f or 
t he st u d y ti meli nes, see Secti o n  5 . 
9. 1. 2   
Wit h dr a w al of i nf or m e d c o n s e nt  
Partici pa nts ma y v ol u ntaril y wit h dra w c o nse nt t o partici pate i n t he st u d y f or a n y reas o n at a n y 
ti me. Wit h dra wal of c o nse nt occ urs o nl y w he n a partici pa nt: 
•  D oes n ot wa nt t o partici pate i n t he st u d y a n y m ore, a n d  
•  D oes n ot wa nt a n y f urt her visits or assess me nts, a n d  
•  D oes n ot wa nt a n y f urt her st u d y relate d c o ntacts  
I n t his sit uati o n, t he i n vesti gat or s h o ul d ma ke a reas o na ble eff ort (e. g. tele p h o ne, e-mail, letter) 
t o u n dersta n d t he pri mar y reas o n f or t he partici pa nt’s decisi o n t o wit h dra w his/ her c o nse nt a n d 
rec or d t his i nf or mati o n. 
St u d y treat me nt m ust be disc o nti n ue d a n d n o f urt her assess me nts c o n d ucte d, a n d t he data t hat 
w o ul d ha ve bee n c ollecte d at s u bse q ue nt visits will be c o nsi dere d missi n g.  
F urt her atte m pts t o c o ntact t he partici pa nt are n ot all o we d u nless safet y fi n di n gs re q uire 
c o m m u nicati n g or f oll o w -u p.  
All eff orts s h o ul d be ma de t o c o m plete t he assess me nts pr i or t o st u d y disc o nti n uati o n. A fi nal 
e val uati o n at t he ti me of t he partici pa nt’s st u d y disc o nti n uati o n s h o ul d be ma de as detaile d i n 
t he assess me nt ta ble (Ta ble 8 -1 ). 
N o vartis  will c o nti n ue t o retai n a n d use all researc h res ults ( data) t hat ha ve alrea d y bee n 
c ollecte d f or t he st u d y e val uati o n.  
9. 1. 3   
L o st t o f oll o w -u p  
F or partici pa nts w h ose stat us is u nclear beca use t he y fail t o a p pear f or st u d y visits wit h o ut 
stati n g a n i nte nti o n t o disc o nti n ue or wit h dra w, t he i n vesti gat or m ust s h o w " d ue dili ge nce" b y 
d oc u me nti n g i n t he s o urce d oc u me nts ste ps ta ke n t o c o ntact t he part ici pa nt, e. g. dates of 
tele p h o ne calls, re gistere d letters, etc. A partici pa nt s h o ul d n ot be c o nsi dere d as l ost t o 
f oll o w-u p u ntil d ue dili ge nce has bee n c o m plete d or u ntil t he e n d of t he st u d y.  

N o v arti s  
C o nfi d e nti al  
P a g e 8 5  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
9. 1. 4   
St u d y st o p pi n g r ul e s  
T he st u d y will be pa use d a n d n o f urt her d osi n g pe n di n g f ull safet y re vie w, if a n y of t he 
f oll o wi n g criteria are met: 
•  T hree ( 3) or m ore partici pa nts o n acti ve t hera p y prese nti n g ne w u ne x pecte d S A Es 
c o nsi dere d relate d t o L N A 0 4 3 or ca na ki n u ma b  
•  T w o ( 2) or m ore partici pa nts prese nti n g ac ute aller gic reacti o ns of se verit y gra de 3, 
acc or di n g t o t he N CI -C T C A E ( versi o n 4. 0 3 or hi g her), wit hi n 2 4 h o urs f oll o wi n g 
L N A 0 4 3 a d mi nistrati o n, u nless clearl y ca use d b y e x p os ure t o a k n o w n aller ge n (e. g., 
pea n ut aller g y) 
•  O ne ( 1) or m ore partici pa nt prese nti n g life -t hreate ni n g or fatal ac ute aller gic reacti o n 
(se verit y gra de 4 or greater), acc or di n g t o t he N CI-C T C A E ( versi o n 4. 0 3 or hi g her), 
wit hi n 2 4 h o urs f oll o wi n g L N A 0 4 3 a d mi nistrati o n, u nless clearl y ca use d b y e x p os ure t o a 
k n o w n aller ge n (e. g. pea n ut aller g y)  
•  T w o ( 2) or m ore partici pa nts o n acti ve t hera p y prese nti n g s us pecte d a n d se vere 
L N A 0 4 3  treat me nt relate d A Es of l ocal ori gi n, as j u d ge d b y t he I n vesti gat or a n d/ or t he 
S p o ns or  
•  T w o ( 2) or m ore partici pa nts o n acti ve t hera p y prese nti n g s us pecte d a n d se vere 
ca na ki n u ma b  treat me nt relate d A Es of l ocal ori gi n, as j u d ge d b y t he I n vesti gat or a n d/ or 
t he S p o ns or 
T he c urre nt S A R S -C o V -2 pa n de mic ma y p ose a c halle n ge t o t he i nte grit y of trial, pr otecti o n of 
partici pa nts’ ri g hts, safet y a n d 
well bei n g, as 
well as t he safet y  of st u d y pers o n nel. 
T heref ore,  ris k miti gati o n strate gies ha ve bee n esta blis he d a n d will be e val uate d o n a n o n g oi n g 
basis f or t he d urati o n of t he st u d y, i n li ne wit h healt h a n d g o ve r n me ntal a ut h orit y g ui da nce. 
If t he safet y of t he partici pa nts a n d st u d y pers o n nel, or i nte grit y of t he data c ollecte d ca n n ot be 
g uara ntee d at a n y p oi nt, t he st u d y will be  halte d.  
9. 1. 5   
E arl y st u d y t er mi n ati o n b y t h e s p o n s or  
T he st u d y ca n be ter mi nate d b y N o vartis  at a n y ti me. 
Reas o ns f or earl y ter mi nati o n ca n be:  
•  U ne x pecte d, si g nifica nt, or u nacce pta ble safet y ris k t o partici pa nts e nr olle d i n t he st u d y  
•  Decisi o n base d o n rec o m me n dati o ns fr o m a p plica ble b oar d(s) after re vie w of safet y a n d 
efficac y data  
•  Disc o nti n uati o n of st u d y dr u g de vel o p me nt  
I n ta ki n g t he decisi o n t o ter mi nate, N o vartis will al wa ys c o nsi der partici pa nt welfare a n d safet y. 
S h o ul d earl y ter mi nati o n be necessar y, partici pa nts m ust be see n as s o o n as p ossi ble  a n d treate d 
as a pre mat urel y wit h dra w n partici pa nt. N o m ore treat me nt wit h ca na ki n u ma b or L N A 0 4 3 
s h o ul d ta ke place after t he i n vesti gat or has bee n i nf or me d of t he earl y st u d y ter mi nati o n. 
T he  i n vesti gat or ma y be i nf or me d of a d diti o nal pr oce d ures t o be f oll o we d i n or der t o e ns ure 
t hat a de q uate c o nsi derati o n is gi ve n t o t he pr otecti o n of t he partici pa nt’s i nterests. 
T he  i n vesti gat or or s p o ns or de pe n di n g o n l ocal re g ulati o n will be res p o nsi ble f or i nf or mi n g 
I R Bs/I E Cs of t he earl y ter mi nati o n of t he trial.  

N o v arti s  
C o nfi d e nti al  
P a g e 8 6  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
9. 2   
St u d y c o m pl eti o n a n d p o st -st u d y tr e at m e nt  
St u d y c o m pleti o n is defi ne d as w he n t he last partici pa nt fi nis hes t heir E o S visit a n d a n y re peat 
assess me nts ass ociate d wit h t his visit ha ve bee n d oc u me nte d a n d f oll o we d -u p a p pr o priatel y b y 
t he I n vesti gat or or, i n t he e ve nt of a n earl y st u d y ter mi nati o n decisi o n, t he date of t hat decisi o n. 
Eac h partici pa nt will be re q uire d t o c o m plete t he st u d y i n its e ntiret y a n d t hereafter n o f urt her 
st u d y treat me nt will be ma de a vaila ble t o t he m. 
After st u d y partici pati o n, t he patie nts will c o nti n ue t o be treate d acc or di n g t o t he l ocal sta n dar d 
cli nical practice. T he i n vesti gat or m ust pr o vi de f oll o w -u p me dical care f or all partici pa nts w h o 
pre mat urel y wit h dra w fr o m t he st u d y, or m ust refer t he m f or  a p pr o priate o n g oi n g care.  
1 0   
S af et y m o nit ori n g a n d r e p orti n g  
1 0. 1   
D efi niti o n of a d v er s e e v e nt s a n d r e p orti n g r e q uir e m e nt s  
1 0. 1. 1  
A d v er s e e v e nt s  
A n a d verse e ve nt ( A E) is a n y u nt o war d me dical occ urre nce (e. g. a n y u nfa v ora ble a n d 
u ni nte n de d si g n [i ncl u di n g a b n or mal la b orat or y fi n di n gs], s y m pt o m or disease) i n a cli nical 
i n vesti gati o n partici pa nt after pr o vi 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 ore, a n A E ma y or ma y n ot be te m p orall y or ca usall y ass ociate d wit h t he use of a 
me dici nal (i n vesti gati o nal) pr o d uct.  
T he i n vesti gat or has t he res p o nsi bilit y f or ma na gi n g t he safet y of i n di vi d ual partici pa nt a n d 
i de ntif yi n g a d verse e ve nts. 
N o vartis  q ualifie d me dical pers o n nel will be rea dil y a vaila ble t o a d vise o n trial relate d me dical 
q uesti o ns or pr o ble ms.  
T he occ urre nce of a d verse e ve nts m ust be s o u g ht b y n o n -directi ve q uesti o ni n g of t he partici pa nt 
at eac h visit d uri n g t he st u d y. A d verse e ve nts ma y als o be detecte d w he n t he y are v ol u nteere d 
b y t he partici pa nt d uri n g or bet wee n visits or t hr o u g h p h ysical e x a mi nati o n fi n di n gs, la b orat or y 
test fi n di n gs, or ot her assess me nts (e. g. i n dicate d b y c o m me nts i n t he pai n diar y). 
A d verse e ve nts m ust be rec or de d o n t he A E C R F u n der t he si g ns, s y m pt o ms, or dia g n osis 
ass ociate d wit h t he m, acc o m pa nie d b y t he f oll o wi n g i nf or mati o n (as far as p ossi ble):  
1.  T he se verit y gra de, cate g orize d as;  
•  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 
2.  Its relati o ns hi p t o t he st u d y treat me nt a n d ot her i n vesti gati o nal treat me nt. If t he e ve nt is 
d ue t o lac k of efficac y or pr o gressi o n of u n derl yi n g ill ness (i.e. pr o gressi o n of t he st u d y 
i n dicati o n) t he assess me nt of ca usalit y will us uall y be ‘ N ot s us pecte d.’ T he rati o nale f or 
t his g ui da nce is t hat t he s y m pt o ms of a lac k of efficac y or pr o gressi o n of u n derl yi n g 
ill ness are n ot ca use d b y t he trial dr u g, t he y ha p pe n i n s pite of its a d mi nistrati o n a n d/ or 
b ot h lac k of efficac y a n d pr o gressi o n of u n derl yi n g diseas e ca n o nl y be e val uate d 
mea ni n gf ull y b y a n a nal ysis of c o h orts, n ot o n a si n gle partici pa nt  

N o v arti s  
C o nfi d e nti al  
P a g e 8 7  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
3.  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 vere d/ n ot res ol ve d m ust be re p orte d 
4.  W het her it c o nstit utes a S A E, see Secti o n  1 0. 1. 2 , a n d w hic h seri o us ness criteria ha ve bee n 
met  
5.  Acti o n ta ke n re gar di n g st u d y treat me nt. All a d verse e ve nts m ust be treate d a p pr o priatel y. 
Treat me nt ma y i ncl u de o ne or m ore of t he f oll o wi n g:  
•  D ose n ot c ha n ge d  
•  Dr u g i nterr u pte d/ per ma ne ntl y disc o nti n ue d  
6.  Its o utc o me  
C o n diti o ns t hat were alrea d y prese nt at t he ti me of i nf or me d c o nse nt s h o ul d be rec or de d i n 
me dical hist or y of t he partici pa nt.  
A d verse e ve nts (i ncl u di n g la b orat or y a b n or malities t hat c o nstit ute A Es) s h o ul d be descri be d 
usi n g a dia g n osis w he ne ver p ossi ble, rat her t ha n i n di vi d ual u n derl yi n g si g ns a n d s y m pt o ms.  
A d verse e ve nt m o nit ori n g s h o ul d be c o nti n ue d f or at least 6 0 da ys f oll o wi n g t he last d ose of 
st u d y treat me nt. 
O nce a n a d verse e ve nt is detecte d, it m ust 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 ne nt (c o nti n ui n g at t he e n d of t he st u d y), a n d assess me nt m ust be ma de at eac h visit 
( or m ore fre q ue ntl y, if necessar y) of a n y c ha n ges i n se verit y, t he s us pecte d relati o ns hi p t o 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 a d verse dr u g reacti o ns f or t he i n vesti gati o nal dr u g ca n be f o u n d i n t he I B. 
A b n or mal la b orat or y val ues or test res ults c o nstit ute a d verse e ve nts o nl y if t he y f ulfill at least 
o ne of t he f oll 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 
Cli nicall y si g nifica nt a b n or mal la b orat or y val ues or test res ults m ust be i de ntifie d t hr o u g h a 
re vie w of val ues o utsi de of n or mal ra n ges/cli nicall y n ota ble ra n ges, si g nifica nt c ha n ges fr o m 
baseli ne or t he pre vi o us visit, or val ues w hic h are c o nsi dere d t o b e n o n-t y pical i n partici pa nt 
wit h t he u n derl yi n g disease.  
1 0. 1. 2  
S eri o u s a d v er s e e v e nt s  
A n S A E is defi ne d as a n y a d verse e ve nt [a p peara nce of ( or w orse ni n g of a n y pre -e xisti n g)] 
u n desira ble si g n(s), s y m pt o m(s), or me dical c o n diti o ns(s) w hic h meets a n y o ne of t he f oll o wi n g 
criteria: 
•  fatal 
•  life-t hreate ni n g  
•  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 partici pa nt 
was at ris k of deat 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 ca use d deat h if it were m ore se vere ( please refer t o t he  
I C H-E 2 D G ui deli nes).  

N o v arti s  
C o nfi d e nti al  
P a g e 8 8  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
•  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 t he partici pa nt's O A c o n diti o n  
•  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 
•  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 partici pa nt’s 
ge neral c o n diti o n  
•  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  
•  is me dicall y si g nifica nt, e. g. defi ne d as a n e ve nt t hat je o par dizes t he partici pa nt or ma y 
re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d a b o ve 
Me dical 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 het her ot her sit uati o ns s h o ul d 
be c o nsi dere d seri o us reacti o ns, s uc h as i m p orta nt me dical e ve nts t hat mi g ht n ot be i m me diatel y 
life t hreate ni n g or res ult i n deat h or h os pitalizati o n b ut mi g ht je o par dize t he partici pa nt or mi g ht 
re q uire i nter ve nti o n t o pre ve nt o ne of t he ot her o utc o mes liste d a b o ve. S uc h e ve nts s h o ul d be 
c o nsi dere d as “ me dicall y si g nifica nt.” E xa m ples of s uc h e ve nts are i nte nsi ve treat me nt i n a n 
e mer ge nc y r o o m or at h o me f or al ler gic br o nc h os pas m, bl o o d d yscrasias, or c o n v ulsi o ns t hat 
d o n ot res ult i n h os pitalizati o n or de vel o p me nt of de pe n de nc y or a b use  (see I C H-E 2 D 
G ui deli nes).  
All ne w mali g na nt ne o plas ms will be assesse d as seri o us u n der “ me dicall y si g nifica nt” if ot her 
seri o us ness criteria are n ot met. 
A n y s us pecte d tra ns missi o n via a me dici nal pr o d uct of a n i nfecti o us a ge nt is als o c o nsi dere d a 
seri o us a d verse reacti o n. 
All re p orts of i nte nti o nal mis use a n d a b use of t he pr o d uct are als o c o nsi dere d seri o us a d verse 
e ve nt irres pecti ve if a cli nical e ve nt has occ urre d.  
1 0. 1. 3  
S A E r e p orti n g  
T o e ns ure partici pa nt safet y, e ver y S A E, re gar dless of ca usalit y, occ urri n g after t he partici pa nt 
has pr 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  m ust be re p orte d t o 
N o vartis  i m me diatel y, wit h o ut u n d ue dela y, b ut u n der n o circ u msta nces later t ha n wit hi n 
2 4  h o urs of o btai ni n g k n o wle d ge of t he e ve nts ( N ote: If m ore stri n ge nt, l ocal re g ulati o ns 
re gar di n g re p orti n g ti meli nes pre vail). Detaile d i nstr ucti o ns re gar di n g t he s u b missi o n pr ocess 
a n d re q uire me nts are t o be f o u n d i n t he i n vest i gat or f ol der pr o vi de d t o eac h site. 
All f oll o w -u p i nf or mati o n f or t he S A E i ncl u di n g i nf or mati o n o n c o m plicati o ns, pr o gressi o n of 
t he i nitial S A E a n d rec urre nt e pis o des 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 
i m me diatel y, wit h o ut u n d ue dela y, b ut u n der n o circ u msta nces later t han wit hi n 2 4 h o urs of t he 
i n vesti gat or recei vi n g t he f oll o w-u p i nf or mati o n ( N ote: If m ore stri n ge nt, l ocal re g ulati o ns 
re gar di n g re p orti n g ti meli nes pre vail). A n S A E occ urri n g at a differe nt ti me i nter val or 

N o v arti s  
C o nfi d e nti al  
P a g e 8 9  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
ot her wise c o nsi dere d c o m pletel y u nrelate d t o a pre vi o usl y re p orte d o ne m ust be re p orte d 
se paratel y as a ne w e ve nt. 
If t he S A E is n ot pre vi o usl y d oc u me nte d i n t he I n vesti gat or’s Br oc h ure or Pac ka ge I nsert 
( ne w occ urre nce) 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 C hief Me dical Office 
a n d Patie nt Safet y ( C M O & P S) de part me nt ass ociate 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 vartis ma y nee d t o iss ue a n I n vesti gat or 
N otificati o n (I N) t o i nf or m all i n vesti gat ors i n v ol ve d i n a n y st u d y wit h t he sa me st u d y treat me nt 
t hat t his S A E has bee n re p orte d. 
S us pecte d U ne x pecte d Seri o us A d verse Reacti o ns ( S U S A Rs) will be c ollecte d a n d re p orte d t o 
t he c o m pete nt a ut h orities a n d rele va nt et hics c o m mittees i n acc or da nce 
wit h 
E U 
G ui da nce  2 0 1 1/ C 1 7 2/ 0 1 or as per nati o nal re g ulat or y re q uire me nts i n partici pati n g c o u ntries.  
A n y S A Es e x perie nce d after t he 3 0 -da y peri o d after t he last st u d y visit s h o ul d o nl y be re p orte d 
t o N o vartis Safet y if t he i n vesti gat or s us pects a ca usal relati o ns hi p t o st u d y treat me nt, u nless 
ot her wise s pecifie d b y l ocal la w/re g ulati o ns.  
1 0. 1. 4  
Pr e g n a n c y r e p orti n g  
If a fe male trial partici pa nt bec o mes pre g na nt, t he st u d y treat me nt s h o ul d be st o p pe d, a n d t he 
trial partici pa nt m ust be as ke d t o rea d a n d si g n t he pre g na nc y c o nse nt f or m t o all o w t he 
i n vesti gat or t o as k a b o ut her pre g na nc y. T o e ns ure partici pa nt safet y, eac h pre g na nc y occ urri n g 
after si g ni n g t he i nf or me d c o nse 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 occ urre nce. T he pre g na nc y s h o ul d be f oll o we d f or u p t o 1 2 m o nt hs f oll o wi n g t he birt h t o 
deter mi ne o utc o me, i ncl u di n g s p o nta ne o us or v ol u ntar y ter mi nati o n, details of t he birt h, a n d 
t he prese nce 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 plicati o ns.  
Pre g na nc y s h o ul d be rec or de d a n d re p orte d b y t he i n vesti gat or t o t he N o vartis  C M O & P S. 
Pre g 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 or m a n d s h o ul d i ncl 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 nce d d uri n g pre g na nc y 
m ust be re p orte d.  
1 0. 1. 5  
R e p orti n g of st u d y tr e at m e nt err or s i n cl u di n g mi s u s e/ a b u s e  
Me dicati o n err ors are u ni nte nti o nal err ors i n t he prescri bi n g, dis pe nsi n g, a d mi nistrati o n or 
m o nit ori n g of a me dici ne w hile u n der t he c o ntr ol of a healt hcare pr ofessi o nal, partici pa nt or 
c o ns u mer ( E M A defi niti o n).  
Mis use refers t o sit uati o ns w here t he me dici nal pr o d uct is i nte nti o nall y a n d i na p pr o priatel y use d 
n ot i n acc or da nce wit h t he pr ot oc ol.  
I n vesti gati o nal treat me nt err ors a n d uses o utsi de of w hat is f oresee n i n t he pr ot oc ol will be 
rec or de d as pr ot oc ol de viati o ns irres pecti ve of w het her or n ot ass ociate d wit h a n A E/ S A E a n d 
re p orte d t o C M O & P S o nl y if ass ociate d wit h a n S A E. 

N o v arti s  
C o nfi d e nti al  
P a g e 9 0  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
1 0. 2   
A d diti o n al S af et y M o nit ori n g  
1 0. 2. 1  
Li v er s af et y m o nit ori n g  
T o e ns ure partici pa nt safet y a n d e n ha nce relia bilit y i n deter mi ni n g t he he pat ot o xic p ote ntial of 
a n i n vesti gati o nal dr u g, a sta n dar dize d pr ocess f or i de ntificati o n, m o nit ori n g a n d e val uati o n of 
li ver e ve nts has t o be f oll o we d. 
See Ta ble  1 6 -1  i n Secti o n 1 6. 1 f or c o m plete defi niti o ns of li ver la b orat or y tri g gers.  
O nce a partici pa nt is e x p ose d t o st u d y treat me nt, e ver y li ver e ve nt defi ne d i n Ta ble  1 6 -1  s h o ul d 
be f oll o we d u p b y t he i n vesti gat or or desi g nate d pers o n nel at t he trial site, as s u m marize d bel o w. 
A d diti o nal details o n acti o ns re q uire d i n case of li ver e ve nts are o utli ne d i n Ta ble  1 6 -2 . 
Li ver  c he mistr y tests (i.e. A L T, A S T, T B L, P T/I N R, A L P a n d G -G T) s h o ul d be re peate d t o 
c o nfir m ele vati o n.  
•  T hese li ver c he mistr y re peats will be perf or me d usi n g t he ce ntral la b orat or y. If res ults are 
n ot a vaila ble fr o m t he ce ntral la b orat or y, t he re peats ca n als o be perf or me d at a l ocal 
la b orat or y t o m o nit or t he safet y of t he partici pa nt. If a li ver e ve nt is s ubse q ue ntl y re p orte d, 
a n y l ocal li ver c he mistr y tests pre vi o usl y c o n d ucte d t hat are ass ociate d wit h t his e ve nt 
s h o ul d ha ve res ults rec or de d o n t he a p pr o priate C R F. 
•  If t he i nitial ele vati o n is c o nfir me d, cl ose o bser vati o n of t he partici pa nt will be i nitiate d, 
i ncl u di n g c o nsi derati o n of treat me nt i nterr u pti o n if dee me d a p pr o priate. 
•  T he i n vesti gati o nal dr u g s h o ul d be disc o nti n ue d, if a p pr o priate, as per Secti o n  9. 1. 1  
•  T he partici pa nt s h o ul d be h os pitalize d, if a p pr o priate  
•  Ca usalit y assess me nt of t he li ver e ve nt s h o ul d be perf or me d  
•  T h or o u g h f oll o w -u p of t he li ver e ve nt s h o ul d i ncl u de, base d o n i n vesti gat or's discreti o n:  
•  Ser ol o g y tests, i ma gi n g a n d pat h ol o g y assess me nts, he pat ol o gist’s c o ns ulta nc y  
•  O btai ni n g a m ore detaile d hist or y of s y m pt o ms a n d pri or or c o nc urre nt diseases.  
•  O btai ni n g a hist or y of c o nc o mita nt dr u g use (i ncl u di n g n o n prescri pti o n me dicati o ns 
a n d her bal a n d dietar y s u p ple me nt pre parati o ns), alc o h ol use, recreati o nal dr u g use, 
a n d s pecial diets.  
•  E xcl usi o n of u n derl yi n g li ver disease, as s pecifie d i n Ta ble  1 6 -2  
•  I ma gi n g s uc h as a b d o mi nal U S, C T or M RI, as a p pr o priate 
•  O btai ni n g a hist or y of e x p os ure t o e n vir o n me ntal c he mical a ge nts.  
•  C o nsi deri n g gastr oe nter ol o g y or he pat ol o g y c o ns ultati o ns.  
All f oll o w -u p i nf or mati o n a n d pr oce d ures perf or me d m ust be rec or de d as a p pr o priate i n t he 
C R F.  

N o v arti s  
C o nfi d e nti al  
P a g e 9 1  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
1 0. 2. 2  
R e n al s af et y m o nit ori n g  
O nce a partici pa nt is e x p ose d t o st u d y treat me nt, t he f oll o wi n g t w o cate g ories of a b n or mal re nal 
la b orat or y alert val ues s h o ul d be assesse d d uri n g t he st u d y peri o d: 
•  Ser u m creati ni ne i ncrease ≥2 5 % c o m pare d t o baseli ne d uri n g n or mal h y drati o n stat us  
•  A n y o ne of t he f oll o wi n g:  
•  Uri ne pr otei n -creati ni ne rati o ( P C R) ≥1 g/ g or ≥1 0 0 m g/ m m ol, O R  
•  Ne w o nset di pstic k pr otei n uria ≥3 +, O R  
•  Ne w o nset di pstic k he mat uria ≥3 + (after e xcl u di n g me nstr uati o n, U TI, e xtre me 
e xercise, or tra u ma)  
A b n or mal re nal e ve nt fi n di n gs m ust be c o nfir me d after ≥2 4 h o urs b ut ≤5 da ys after first 
assess me nt.  
E ver y re nal la b orat or y tri g ger or re nal e ve nt as defi ne d i n Ta ble  1 6 -4  s h o ul d be f oll o we d u p b y 
t he i n vesti gat or or desi g nate d pers o n nel at t he trial site as s u m marize d i n Ta ble  1 6 -5 . 
1 1   
D at a C oll e cti o n a n d D at a b a s e m a n a g e m e nt  
1 1. 1   
D at a c oll e cti o n  
Desi g nate d i n vesti gat or staff will e nter t he data re q uire d b y t he pr ot oc ol i nt o t he Electr o nic 
Case Re p ort F or ms (e C R F). T he e C R Fs ha ve bee n b uilt usi n g f ull y vali date d sec ure 
we b -e na ble d s oft ware t hat c o nf or ms t o 2 1 C F R Part 1 1 re q uire me nts. I n vesti gat or site 
pers o n nel will n ot be gi ve n access t o t he E D C s yste m u ntil t he y ha ve bee n trai ne d. A ut o matic 
vali dati o n pr o gra ms c hec k f or data discre pa ncies i n t he e C R Fs, all o w m o dificati o n a n d/ or 
verificati o n of t he e ntere d data b y t he i n vesti gat or staff.  
Partici pa nts will be as ke d t o c o m plete P R Os o n a pa per c o p y. T he partici pa nt's res p o nses will 
be tra nscri be d i nt o t he e C R F b y t he site pers o n nel.  W he n a pa per c o p y is use d off -site, e. g. at 
t he re m ote Da y 2 9 a n d Da y 5 7 visits, t he partici pa nt s h o ul d bri n g or se n d t he c o m plete d 
q uesti o n naire(s) t o t he site at earliest c o n ve nie nce.  
T he pai n diar y will be pa per base d a n d s h o ul d be c o m plete d a n d ret ur ne d b y t he partici pa nts at 
eac h visit u p t o Da y 8 5, a n d a gai n o ne wee k pri or t o Da y 1 9 7 a n d Da y 3 6 5. T he diar y data will 
be tra nscri be d i nt o t he C R F b y t he site pers o n nel.  
C o m plete d pa per q uesti o n naires (if a n y) a n d diaries  will be ke pt as s o urce d oc u me ntati o n at t he 
i n vesti gat or site a n d are n ot t o be c ollecte d b y t he s p o ns or. 
T he i n vesti gat or or dele gate is res p o nsi ble f or ass uri n g t hat t he data (e ntere d i nt o t he e C R F) is 
c o m plete, acc urate, a n d t hat e ntr y a n d u p dates are perf or me d i n a ti mel y 
ma n ner. 
T he  I n vesti gat or m ust certif y t hat t he data e ntere d are c o m plete a n d acc urate. 
After fi nal data base l oc k, t he i n vesti gat or will recei ve c o pies of t he partici pa nt data f or 
arc hi vi n g at t he i n vesti gati o nal site.  
All data s h o ul d be rec or de d, ha n dle d, a n d st ore d i n a wa y t hat all o ws its acc urate re p orti n g, 
i nter pretati o n, a n d verificati o n. 

N o v arti s  
C o nfi d e nti al  
P a g e 9 2  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
1 1. 2   
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  
N o vartis  pers o n nel ( or desi g nate d C R O) will re vie w t he data e ntere d b y i n vesti gati o nal staff 
f or c o m plete ness a n d acc urac y. Electr o nic data q ueries stati n g t he nat ure of t he pr o ble m a n d 
re q uesti n g clarificati o n will be create d f or discre pa ncies a n d missi n g val ues an d se nt t o t he 
i n vesti gat or site via t he E D C s yste m. Desi g nate d i n vesti gat or site pers o n nel are re q uire d t o 
res p o n d pr o m ptl y t o q ueries a n d t o ma ke a n y necessar y c ha n ges t o t he data. 
C o nc o mita nt treat me nts a n d pri or me dicati o ns e ntere d i nt o t he data base will be c o de d usi n g t he 
W orl d Healt h Or ga nizati o n ( W H O) Dr u g Refere nce List, w hic h e m pl o ys t he A nat o mical 
T hera pe utic C he mical classificati o n s yste m. Me dical hist or y/c urre nt me dical c o n diti o ns a n d 
a d verse e ve nts will be c o de d usi n g t he Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A) 
ter mi n ol o g y. 
Dates of scree ni n gs, ra n d o mizati o ns, scree n fail ures, disc o nti n uati o ns a n d st u d y c o m pleti o n, as 
well as ra n d o mizati o n c o des will be trac ke d usi n g a n I R T s yste m.  
Eac h occ urre nce of a c o de brea k via I R T will be re p orte d t o t he  cli nical tea m a n d m o nit or. 
T he  c o de brea k f u ncti o nalit y will re mai n a vaila ble u ntil st u d y s h ut d o w n or u p o n re q uest of 
N o vartis.  
O nce all t he necessar y acti o ns ha ve bee n c o m plete d a n d t he data base has bee n declare d t o be 
c o m plete a n d acc urate, it will be l oc ke d a n d t he treat me nt c o des will be u n bli n de d a n d ma de 
a vaila ble f or data a nal ysis/ m o ve d t o restricte d area t o be accesse d b y i n de pe n de nt pr o gra m mer 
a n d statisticia n . A n y c ha n ges t o t he data base after t hat ti me ca n o nl y be ma de after writte n 
a gree me nt b y N o vartis  de vel o p me nt ma na ge me nt.  
1 1. 3   
Sit e m o nit ori n g  
Bef ore st u d y i nitiati o n, at a site i nitiati o n visit or at a n i n vesti gat or’s meeti n g, a N o vartis 
re prese ntati ve will re vie w t he pr ot oc ol a n d data ca pt ure re q uire me nts wit h t he i n vesti gat ors a n d 
t heir staff. D uri n g t he st u d y, N o vartis e m pl o ys se veral met h o ds of e ns uri n g pr ot oc ol a n d G C P 
c o m plia nce a n d t he q ualit y/i nte grit y of t he sites’ data. T he fiel d m o nit or will visit t he site t o 
c hec k t he c o m plete ness of partici pa nt rec or ds, t he acc urac y of data ca pt ure/ data e ntr y, t he 
a d here nce t o t he pr ot oc ol a n d t o G o od Cli nical Practice, t he pr o gress of e nr oll me nt, a n d t o 
e ns ure t hat st u d y treat me nt is bei n g st ore d, dis pe nse d, a n d acc o u nte d f or acc or di n g t o 
s pecificati o ns. Ke y st u d y pers o n nel m ust be a vaila ble t o assist t he fiel d m o nit or d uri n g t hese 
visits. C o nti n u o us  re m ote m o nit ori n g of eac h site’s data ma y be perf or me d b y a ce ntralize d 
N o vartis C R A or ga nizati o n. A d diti o nall y, a ce ntral a nal ytics or ga nizati o n ma y a nal yze data a n d 
i de ntif y ris ks & tre n ds f or site o perati o nal para meters, a n d pr o vi de re p orts t o N o vartis cli nical 
tea ms t o assist wit h trial o versi g ht. 
T he i n vesti gat or m ust mai ntai n s o urce d oc u me nts f or eac h partici pa nt i n t he st u d y, c o nsisti n g 
of case a n d visit n otes ( h os pital or cli nic me dical rec or ds) c o ntai ni n g de m o gra p hic a n d me dical 
i nf or mati o n, la b orat or y data, electr ocar di o gra ms, a n d t he res ults of a n y ot her tests or 
assess me nts. All i nf or mati o n o n C R Fs m ust be tracea ble t o t hese s o urce d oc u me nts i n t he 
partici pa nt's file. T he i n vesti gat or m ust als o kee p t he ori gi nal i nf or me d c o nse nt f or m si g ne d b y 
t he partici pa nt (a si g ne d c o p y is gi ve n t o t he partici pa nt). 

N o v arti s  
C o nfi d e nti al  
P a g e 9 3  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
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 oc u me nts t o c o nfir m t heir 
c o nsiste nc y wit h t he data ca pt ure a n d/ or data e ntr y. 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 prese nce of i nf or me d c o nse nt, a d here nce t o t he i ncl usi o n/e xcl 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 nal  c hec ks of t he c o nsiste nc y of t he s o urce data wit h t he C R Fs are perf or me d acc or 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 o ut t he i de ntit y 
of t he partici pa nts will be discl ose d.  
1 2   
D at a a n al y si s a n d st ati sti c al m et h o d s  
T he a nal ysis will be c o n d ucte d o n all partici pa nt data at t he ti me t he trial e n ds. A n y data a nal ysis 
carrie d o ut i n de pe n de ntl y b y t he i n vesti gat or s h o ul d be s u b mitte d t o N o vartis bef ore p u blicati o n 
or prese ntati o n.  
1 2. 1   
A n al y si s s et s  
F or all a nal ysis sets, partici pa nts will be a nal yze d acc or di n g t o t he st u d y treat me nt(s) recei ve d.  
T he F ull A nal ysis Set ( F A S) will i ncl u de all partici pa nts t o w h o m st u d y treat me nt has bee n 
assi g ne d. 
T he Safet y Set will i ncl u de all partici pa nts w h o recei ve d at least  o ne d ose of st u d y me dicati o n.  
T he P K a nal ysis set will i ncl u de all partici pa nts w h o recei ve d a n y st u d y dr u g, a n d has at least 
o ne a vaila ble vali d (i.e. n ot fla g ge d f or e xcl usi o n) P K c o nce ntrati o n meas ure me nt, a n d f or 
w h o m t here is n o pr ot oc ol de viati o ns wit h i m pact o n P K data.  
T he P D a nal ysis set will i ncl u de all partici pa nts wit h a vaila ble P D data a n d n o pr ot oc ol 
de viati o ns wit h rele va nt i m pact o n P D data.  
T he I G a nal ysis set will i ncl u de all partici pa nts wit h at least o ne a vaila ble vali d (i.e. n ot fla g ge d 
f or e xcl usi o n) I G c o nce ntrati o n meas ure me nt, w h o recei ve d a n y st u d y dr u g a n d n o pr ot oc ol 
de viati o ns t hat i m pact o n I G data. 
1 2. 2   
P arti ci p a nt d e m o gr a p hi c s a n d ot h er b a s eli n e c h ar a ct eri sti c s  
De m o gra p hic a n d ot her baseli ne data will be liste d a n d s u m marize d descri pti vel y b y treat me nt 
gr o u p f or t he F A S.  
Cate g orical data will be prese nte d as fre q ue ncies a n d perce nta ges. F or c o nti n u o us data, mea n, 
sta n dar d de viati o n, me dia n, mi ni m u m, a n d ma xi m u m will be prese nte d. F or selecte d para meters, 
2 5t h a n d 7 5t h perce ntiles will als o be prese nte d . 
Rele va nt me dical hist ories a n d c urre nt me dical c o n diti o ns at baseli ne will be s u m marize d f or 
all partici pa nts b y treat me n t gr o u p. 

N o v arti s  
C o nfi d e nti al  
P a g e 9 4  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
1 2. 3   
Tr e at m e nt s  
T he Safet y set will be use d f or t he a nal yses bel o w. Cate g orical data will be s u m marize d as 
fre q ue ncies a n d perce nta ges. F or c o nti n u o us data, mea n, sta n dar d de viati o n, me dia n, 2 5t h a n d 
7 5t h perce ntiles, mi ni m u m, a n d ma xi m u m will be prese nte d.  
C o nc o mita nt me dicati o ns a n d si g nifica nt n o n -dr u g t hera pies pri or t o a n d after t he start of t he 
st u d y treat me nt will be liste d a n d s u m marize d acc or di n g t o t he A nat o mical T hera pe utic 
C he mical ( A T C) classificat i o n s yste m, b y treat me nt gr o u p. 
1 2. 4   
A n al y si s of t h e pri m ar y e n d p oi nt( s)/ e sti m a n d( s)  
T his st u d y has t w o c o -pri mar y ai ms.  
T he pri mar y ai m f or ca na ki n u ma b ( T A 4) is t o assess its efficac y vs. place b o ( T A 2) i n relie vi n g 
O A pai n i n partici pa nts wit h s y m pt o matic k nee O A wit h i nfla m mati o n.  
T he pri mar y ai m f or L N A 0 4 3 ( T A 1)  is t o assess its efficac y vs n o i njecti o n ( T A 2) i n 
re ge nerati n g t he artic ular cartila ge i n patie nts wit h s y m pt o matic k nee O A wit h i nfla m mati o n 
after b ot h ( T A 1 a n d T A 2) ha ve bee n a d mi nistere d place b o f or relie vi n g O A pai n.  
1 2. 4. 1  
D efi niti o n of pri m ar y e n d p oi nt( s)  
T he pri mar y efficac y varia ble f or ca na ki n u ma b is t he c ha n ge fr o m baseli ne i n K O O S, pai n 
s u bscale at Da y 8 5. 
T he pri mar y efficac y varia ble f or L N A 0 4 3 is t he c ha n ge fr o m baseli ne i n cartila ge v ol u me i n 
t he i n de x re gi o n at Da y 1 9 7. 
1 2. 4. 2  
St ati sti c al m o d el, h y p ot h e si s, a n d m et h o d of a n al y si s  
T he a nal ysis f or pri mar y e n d p oi nts will be carrie d o ut usi n g a mi xe d effect m o del f or re peate d 
meas ures ( M M R M).  
•  T he pri mar y efficac y varia ble f or ca na ki n u ma b, c ha n ge fr o m baseli ne i n K O O S pai n 
s u bscale will be a nal yze d usi n g a mi xe d effect m o del f or re peate d meas ures ( M M R M). 
T he  m o del will i ncl u de baseli ne as fi xe d c o variate, treat me nt, ti me p oi nt, treat me nt * 
ti me p oi nts as fi xe d effects a n d partici pa nt as ra n d o m effect. A n u nstr uct ure d c o varia nce 
will be ass u me d; if n ot p ossi ble, ot her a p pr o priate c o varia nce str uct ures will be e x p l ore d 
s uc h as A ut ore gressi ve ( A R( 1)), C o m p o u n d s y m metr y etc. A t w o-si de d 9 0 % c o nfi de nce 
i nter val f or t he treat me nt effect (i.e., ca na ki n u ma b mi n us Placeb o) at Da y 8 5 will be 
f or me d. A statisticall y si g nifica nt differe nce ( o ne-si de d p-val ue < 0. 0 5) bet wee n acti ve 
dr u g a n d place b o at Da y 8 5 will be c o nsi dere d as a p ositi ve res ult.  
•  T he pri mar y efficac y varia ble f or L N A 0 4 3, c ha n ge fr o m baseli ne i n cartila ge v ol u me i n 
t he i n de x re gi o n, will be a nal yze d usi n g a mi xe d effect m o del f or re peate d meas ures 
( M M R M). T he m o del will i ncl u de baseli ne as fi xe d c o variate, treat me nt, ti me p oi nt, a n d 
treat me nt * ti me p oi nts as fi xe d effects a n d partici pa nt as ra n d o m effect. A n u nstr uct ure d 
c o varia nce will be ass u me d; if n ot p ossi ble, ot her a p pr o priate c o varia nce str uct ure will be 
e x pl ore d s uc h as A ut ore gressi ve ( A R( 1)), C o m p o u n d s y m metr y etc. A t w o -si ded 9 0 % 
c o nfi de nce i nter val f or t he treat me nt effect (i.e., L N A 0 4 3 mi n us N o i njecti o n) at Da y  1 9 7 

N o v arti s  
C o nfi d e nti al  
P a g e 9 5  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
will be f or me d. A statisticall y si g nifica nt differe nce ( o ne -si de d p-val ue < 0. 0 5) bet wee n 
acti ve dr u g a n d n o i njecti o n at Da y 1 9 7 will be c o nsi dere d as a p ositi ve res ult.  
1 2. 4. 3  
H a n dli n g of mi s si n g v al u e s n ot r el at e d t o i nt er c urr e nt e v e nt  
All dr u g c o nce ntrati o ns bel o w t he l o wer li mit of q ua ntificati o n ( L L O Q) will be re p orte d as 
“zer o” a n d will be treate d as zer o f or t he calc ulati o n of P K para meters.  
Missi n g data f or M RI o utc o mes will n ot be i m p ute d.   
Missi n g data f or K O O S will n ot be i m p ute d.  
1 2. 5   
A n al y si s of s e c o n d ar y e n d p oi nt s/ e sti m a n d s  
See Secti o n  2  f or sec o n dar y o bjecti ves of t his st u d y. 
1 2. 5. 1  
Effi c a c y a n d/ or P h ar m a c o d y n a mi c e n d p oi nt( s)  
T he sec o n dar y efficac y o bjecti ves f or L N A 0 4 3 are as f oll o ws:  
•  T o assess t he efficac y of q 4 w x 3 i.a. i njecti o ns of L N A 0 4 3 after i.a. i njecti o n of place b o 
( T A 1) vs q 4 w x 3 i.a. i njecti o ns of L N A 0 4 3 after i.a. i njecti o n of ca na ki n u ma b ( T A 3) i n 
re ge nerati n g t he artic ular cartila ge i n partici pa nts wit h s y m pt o matic k nee O A wit h 
i nfla m mati o n. T he varia bles ass ociate d wit h t his o bjecti ve are c ha n ge fr o m baseli ne i n 
cartila ge v ol u m e a n d c ha n ge fr o m baseli ne i n cartila ge t hic k n ess i n t he i n de x re gi o n at 
Da ys  1 9 7 a n d 3 6 5. B ot h varia bles will be a nal yze d se paratel y usi n g t w o se parat e M M R M 
m o dels. T he str uct ure of b ot h M M R M m o dels will be sa me as t he o ne me nti o ne d i n 
pri mar y a nal ysis of L N A 0 4 3.  
•  T o assess t he efficac y of q 4 w x 3  i.a. i njecti o ns of L N A 0 4 3 ( T A 3) vs n o L N A 0 4 3 
i njecti o ns ( T A 4) i n re ge nerati n g t he artic ular cartila ge i n partici pa nts wit h s y m pt o matic 
k nee O A wit h i nfla m mati o n after b ot h trial ar ms (i.e. T A 3 a n d T A 4) ha ve bee n 
a d mi nistere d wit h a n i.a. i njecti o n of ca na ki n u ma b t o relie ve O A pai n.  T he  varia bles 
ass ociate d wit h t his o bjecti ve are  c ha n ge fr o m baseli ne i n cartila ge v ol u me a n d c ha n ge 
fr o m baseli ne i n cartila ge t hic k ness i n t he i n de x re gi o n at Da ys 1 9 7 a n d 3 6 5. 
B ot h  varia bles wil l be a nal yze d se paratel y usi n g t w o se parate M M R M m o dels. 
T he  str uct ure of b ot h M M R M m o dels will be sa me as t he o ne me nti o ne d i n pri mar y 
a nal ysis of L N A 0 4 3.  
•  T o assess t he efficac y of  q 4 w x 3  i.a. i njecti o ns of L N A 0 4 3 ( T A 1) vs n o L N A 0 4 3 
i njecti o ns ( T A 2) i n re ge nerati n g t he artic ular cartila ge i n partici pa nts wit h s y m pt o matic 
k nee O A wit h i nfla m mati o n after b ot h trial ar ms (i.e. T A 1 a n d T A 2) ha ve bee n 
a d mi nistere d wit h a n i.a. i njecti o n of place b o t o relie ve O A pai n.  T he varia bles ass ociate d 
wit h t his o bjecti ve are  c ha n ge fr o m baseli ne i n cartila ge v ol u me at Da y 3 6 5  a n d c ha n ge 
fr o m baseli ne i n cartila ge t hic k ness at Da ys 1 9 7 a n d 3 6 5 i n t he i n de x re gi o n. 
B ot h  varia b les will be a nal yze d se paratel y usi n g t w o se parate M M R M m o dels. 
T he  str uct ure of b ot h M M R M m o dels will be sa me as t he o ne me nti o ne d i n pri mar y 
a nal ysis of L N A 0 4 3.  

N o v arti s  
C o nfi d e nti al  
P a g e 9 6  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
•  T o assess t he efficac y of a si n gle i.a. i njecti o n of ca na ki n u ma b f oll o we d b y q 4 w x 3 i.a. 
i njecti o ns of L N A 0 4 3 ( T A 3) vs a si n gle i.a. i njecti o n of ca na ki n u ma b ( T A 4) i n 
partici pa nts wit h s y m pt o matic k nee O A wit h i nfla m mati o n i n i m pr o vi n g f u ncti o ns of dail y 
li vi n g o ver ti me. T he varia bles ass ociate d wit h t his o bjecti ve are c ha n ge fr o m baseli ne i n 
K O O S pai n s u bscale a n d F u ncti o n i n dail y li vi n g ( A D L) s u bscales at Da y 1 5, 2 9, 4 3, 5 7, 
7 1, 8 5, 1 9 7, 3 6 5 a n d it will be a nal yze d usi n g a M M R M m o del. T he str uct ure of t he 
M M R M m o del will be sa me as t he o ne me nti o ne d i n pri mar y a nal ysis of L N A 0 4 3.  
•  T o assess t he efficac y of a si n gle i.a. i njecti o n of ca na ki n u ma b f oll o we d b y q 4 w x 3 i.a. 
i njecti o ns of L N A 0 4 3 ( T A 3) vs a si n gle i.a. i njecti o n of ca na ki n u ma b ( T A 4) i n 
partici pa nts wit h s y m pt o matic k nee O A wit h i nfla m mati o n t o relie ve O A pai n. 
T he  varia ble ass ociate d wit h it is c ha n ge fr o m baseli ne i n t he n u meric rati n g scale ( N R S) 
pai n at Da y 1 5, 2 9, 4 3, 5 7, 7 1, 8 5, 1 9 7, 3 6 5 a n d it will be a nal yze d usi n g a M M R M m o del. 
T he  str uct ure of t he M M R M m o del will be sa me as t he o ne me nti o ne d i n pri mar y a nal ysis 
of L N A 0 4 3.  
T he sec o n dar y efficac y o bjecti ves f or ca na ki n u ma b are as f oll o ws:  
•  T o assess t he efficac y of ca na ki n u ma b ( T A 4) vs place b o ( T A 2) i n partici pa nts wit h 
s y m pt o matic k nee O A wit h i nfla m mati o n i n relie vi n g pai n. T he varia ble ass ociate d wit h 
t his o bjecti ve is c ha n ge fr o m baseli ne i n K O O S pai n s u bscale at Da y 1 5, 2 9, 4 3, 5 7, 7 1, 8 5 
a n d it will be a nal yze d usi n g a M M R M m o del. T he str uct ure of t he M M R M will be sa me 
as t he o ne me nti o ne d i n pri mar y a nal ysis of ca na ki n u ma b.  
•  T o assess t he efficac y of ca na ki n u ma b ( T A 4) vs place b o ( T A 2) i n partici pa nts wit h 
s y m pt o matic k nee O A wit h i nfla m mati o n i n i m pr o vi n g f u ncti o ns of dail y li vi n g o ver ti me. 
T he varia ble ass ociate d wit h t his o bjecti ve is c ha n ge fr o m baseli ne i n K O O S f u ncti o n 
d ail y li vi n g s u bscale at Da y 1 5, 2 9, 4 3, 5 7, 7 1, 8 5 a n d it will be a nal yze d usi n g a M M R M 
m o del. T he str uct ure of t he M M R M will be sa me as t he o ne me nti o ne d i n pri mar y 
a nal ysis of ca na ki n u ma b.  
•  T o assess t he efficac y of ca na ki n u ma b ( T A 4) vs place b o ( T A 2) o n s y n o vitis i n 
partici pa nts wit h s y m pt o matic k nee O A wit h i nfla m mati o n at Da y 8 5. T he varia ble 
ass ociate d wit h t his o bjecti ve is c ha n ge fr o m baseli ne i n s y n o vitis le vel meas ure d fr o m 
Ktra ns b y D C E -M RI at Da y 8 5 a n d it will be a nal yze d usi n g a M M R M m o del. 
T he  str uct ure of t he M M R M will be sa me as t he o ne me nti o ne d i n pri mar y a nal ysis of 
ca na ki n u ma b.  
•  T o assess t he efficac y of ca na ki n u ma b ( T A 4) vs place b o ( T A 2) i n relie vi n g O A pai n i n 
partici pa nts wit h s y m pt o matic k nee O A wit h i nfla m mati o n. T he varia ble ass ociate d wit h it 
is c ha n ge fr o m baseli ne i n t he n u meric rati n g scale ( N R S) pai n at Da y 1 5, 2 9, 4 3, 5 7, 7 1, 
8 5 a n d it will be a nal yze d usi n g a M M R M m o del. T he str uct ure of t he M M R M will be 
sa me as t he o ne me nti o ne d i n pri mar y a nal ysis of ca na ki n u ma b. 
•  T o assess t he efficac y of a si n gle i.a. i njecti o n of ca na ki n u ma b f oll o we d b y q 4 w x 3 i.a. 
i njecti o ns of L N A 0 4 3 ( T A 3) vs o nl y q 4 w x 3 i.a. i njecti o ns of L N A 0 4 3 i njecti o ns ( T A 1) i n 
partici pa nts wit h s y m pt o matic k nee O A wit h i nfla m mati o n i n i m pr o vi n g f u ncti o ns of  dail y 
li vi n g o ver ti me. T he varia bles ass ociate d wit h t his o bjecti ve are c ha n ge fr o m baseli ne i n 
K O O S pai n s u bscale a n d F u ncti o n i n dail y li vi n g ( A D L) s u bscales at Da y 1 5, 2 9, 4 3, 5 7, 
7 1, 8 5, 1 9 7, 3 6 5 a n d it will be a nal yze d usi n g a M M R M m o del. T he str uct ure of t he 
M M R M m o del will be sa me as t he o ne me nti o ne d i n pri mar y a nal ysis of ca na ki n u ma b.  

N o v arti s  
C o nfi d e nti al  
P a g e 9 7  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
•  T o assess t he efficac y of a si n gle i.a. i njecti o n of ca na ki n u ma b f oll o we d b y q 4 w x 3 i.a. 
i njecti o ns of L N A 0 4 3 ( T A 3) vs o nl y q 4 w x 3 i.a. i njecti o ns of L N A 0 4 3 i njecti o ns ( T A 1) i n 
partici pa nts wit h s y m pt o matic k nee O A wit h i nfla m mati o n t o relie ve O A pai n. 
T he  varia ble ass ociate d wit h it is c ha n ge fr o m baseli ne i n t he n u meric rati n g scale ( N R S) 
pai n at Da y 1 5, 2 9, 4 3, 5 7, 7 1, 8 5, 1 9 7, 3 6 5 a n d it will be a nal yze d usi n g a M M R M m o del. 
T he  str uct ure of t he M M R M m o del will be sa me as t he o ne me nti o ne d i n pri mar y a nal y sis 
of ca na ki n u ma b.  
1 2. 5. 2  
S af et y e n d p oi nt s  
F or all safet y a nal yses, t he safet y set will be use d. All listi n gs a n d ta bles will be prese nte d b y 
treat me nt gr o u p. 
A d v er s e e v e nt s  
All i nf or mati o n o btai ne d o n a d verse e ve nts will be dis pla ye d b y treat me nt gr o u p  a n d partici pa nt. 
T he n u m ber (a n d perce nta ge) of partici pa nts 
wit h treat me nt e mer ge nt a d verse e ve nts 
(e ve nts starte d after t he first d ose of st u d y me dicati o n or e ve nts prese nt pri or t o start of 
d o u ble -bli n d treat me nt b ut i ncrease d i n se verit y base d o n preferre d ter m) will be s u m marize d 
i n t he f oll o wi n g wa ys: 
•  b y treat me nt, pri mar y s yste m or ga n class a n d preferre d ter m.  
•  b y treat me nt, pri mar y s yste m or ga n class, preferre d ter m a n d ma xi m u m se verit y.  
Se parate s u m maries will be pr o vi de d f or st u d y me dicati o n relate d a d verse e ve nts, deat h, seri o us 
a d verse e ve nts, ot her si g nifica nt a d verse e ve nts lea di n g t o disc o nti n uati o n.  
A partici pa nt wit h m ulti ple a d verse e ve nts wit hi n a pri mar y s yste m or ga n class is o nl y c o u nte d 
o nce t o war ds t he t otal of  t he pri mar y s yste m or ga n class. 
Vit al si g n s  
All vital si g ns data will be liste d b y treat me nt gr o u p, partici pa nt, a n d visit/ti me a n d if ra n ges 
are 
a vaila ble, 
a b n or malities (a n d rele va nt 
ort h ostatic 
c ha n ges) 
wi ll 
be fla g ge d. 
S u m mar y  statistics will be pr o vi de d b y treat me nt a n d visit/ti me. 
1 2 -l e a d E C G 
All E C G data will be liste d b y treat me nt gr o u p, partici pa nt a n d visit/ti me, a b n or malities will be 
fla g ge d. S u m mar y statistics will be pr o vi de d b y treat me nt a n d visit/ti me. 
Cli ni c al l a b or at or y e v al u ati o n s  
All la b orat or y data will be liste d b y treat me nt gr o u p, partici pa nt, a n d visit/ti me a n d if n or mal 
ra n ges are a vaila ble a b n or malities will be fla g ge d. S u m mar y statistics will be pr o vi de d b y 
treat me nt a n d visit/ti me. S hift ta bles usi n g t he l o w/ n or mal/ hi g h (l o w a n d hi g h) classificati o n 
will be use d t o c o m pare baseli ne t o t he w orst o n -treat me nt val ue. 

N o v arti s  
C o nfi d e nti al  
P a g e 9 8  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
1 2. 5. 3  
P h ar m a c o ki n eti c s  
L N A 0 4 3, 
A N G P T L 3, a n d 
 ser u m a n d s y n o vial fl ui d ( o nl y 
A N G P T L 3) 
c o nce ntrati o n data will be liste d b y treat me nt, partici pa nt, a n d visit/sa m pli n g ti me p oi nt. 
Descri pti ve s u m mar y statistics will be pr o vi de d b y treat me nt a n d visit/sa m pli n g ti me p oi nt,  
i ncl u di n g t he fre q ue nc y ( n, %) of c o nce ntrati o ns bel o w t he L L O Q a n d re p orte d as zer o. 
S u m mar y statistics will i ncl u de mea n (arit h metic a n d ge o metric), S D, C V (arit h metic a n d 
ge o metric), me dia n, mi ni m u m, a n d ma xi m u m.  
P har mac o ki netic para meters will be calc ulate d f or L N A 0 4 3 at Da y 1 5 as descri be d i n 
Secti o n  8. 5. 1. 1  a n d will be liste d b y treat me nt a n d partici pa nt. Descri pti ve s u m mar y statistics 
will i ncl u de mea n (arit h metic a n d ge o metric), S D, a n d C V (arit h metic a n d ge o metric), me dia n, 
mi ni m u m, a n d ma xi m u m. A n e xce pti o n t o t his is T ma x w here me dia n, mi ni m u m,  a n d 
ma xi m u m will be prese nte d.  
P har mac o ki netic para meters  will be calc ula te d f or A N G P T L 3 as descri be d i n Secti o n  8. 5. 1. 1  
a n d will be liste d b y treat me nt a n d partici pa nt. Descri pti ve s u m mar y statistics will i ncl u de mea n 
(arit h metic a n d ge o metric), S D, a n d C V (arit h metic a n d ge o metric), me dia n, mi ni m u m, a n d 
ma xi m u m.  
 
 
C o nce ntrati o ns bel o w L L O Q will be treate d as zer o i n s u m mar y statistics a n d f or P K para meter 
calc ulati o ns. A ge o metric mea n will n ot be re p orte d if t he dataset i ncl u des zer o val ues.  
T a bl e 1 2 -1   
N o n -c o m p art m e nt al p h ar m a c o ki n eti c p ar a m et er s  
A U Cl a st   
T h e ar e a u n d er t h e pl a s m a ( or s er u m or bl o o d) c o n c e ntr ati o n -ti m e c ur v e fr o m ti m e 
z er o t o t h e ti m e of t h e l a st q u a ntifi a bl e c o n c e ntr ati o n [ m a s s x ti m e / v ol u m e]  
C a v  
T h e a v er a g e c o n c e ntr ati o n  o b s er v e d i n pl a s m a, bl o o d, s er u m, or ot h er b o d y fl ui d, 
d efi n e d a s A U C o v er a d efi n e d p eri o d of ti m e di vi d e d b y t h at l e n gt h of ti m e( m a s s x 
v ol u m e -1)  
C m a x   
T h e m a xi m u m ( p e a k) o b s er v e d pl a s m a, bl o o d, s er u m, or ot h er b o d y fl ui d dr u g 
c o n c e ntr ati o n aft er si n gl e d o s e a d mi ni str ati o n ( m a s s x v ol u m e -1)  
C mi n  
T h e mi ni m u m (l o w e st) o b s er v e d pl a s m a, bl o o d, s er u m, or ot h er b o d y fl ui d a n al yt e 
c o n c e ntr ati o n o v er a d efi n e d p eri o d ( m a s s x v ol u m e -1)  
T m a x   
T h e ti m e t o r e a c h m a xi m u m ( p e a k) pl a s m a, bl o o d, s er u m, or ot h er b o d y fl ui d dr u g 
c o n c e ntr ati o n aft er si n gl e d o s e a d mi ni str ati o n (ti m e)  
M o deli n g of t he data 
ma y be perf or me d as a p pr o priate. 
D uri n g 
m o deli n g of t he 
p har mac o ki netics of t he st u d y dr u gs, t he br oa d pri nci ples o utli ne d i n t he ‘ F D A G ui da nce f or 
I n d ustr y: P o p ulati o n P har mac o ki netics’ will be f oll o we d. As t he P K data fr o m t he c urre nt st u d y 
ma y be p o ole d wit h data fr o m pre vi o us st u dies, t he P K m o deli n g will be descri be d a n d re p orte d 
se paratel y. 
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N o v arti s  
C o nfi d e nti al  
P a g e 9 9  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
1 2. 5. 4  
I m m u n o g e ni cit y 
All i m m u n o ge nicit y res ults will be liste d b y treat me nt gr o u p, partici pa nt a n d visit/ti me.  
T he n u m ber a n d perce nta ge of partici pa nts wit h p ositi ve i m m u n o ge nicit y res ults will be 
ta b ulate d b y treat me nt gr o u p f or b ot h L N A 0 4 3
 A partici pa nt wit h m ulti ple 
p ositi ve sa m ples is o nl y c o u nte d o nce.  
1 2. 6   
A n al y si s of e x pl or at or y e n d p oi nt s  
1 2. 6. 1  
 
1 2. 6. 2   
 
1 2. 6. 3  
 
1 2. 7   
I nt eri m a n al y s e s 
First i nteri m a nal ysis i n t he st u d y will be c o n d ucte d after all t he partici pa nts ha ve c o m plete d 
Da y  8 5 a n d t he sec o n d i nteri m a nal ysis i n t he st u d y will be c o n d ucte d after all t he partici pa nts 
ha ve c o m plete d Da y 1 9 7.  
T he p ur p ose of t he first i nteri m a nal ysis is t o e val uate t he pri mar y o bjecti ve relate d t o 
ca na ki n u ma b a n d t he p ur p ose of t he sec o n d i nteri m a nal ysis is t o e val uate t he pri mar y o bjecti ve 
relate d t o L N A 0 4 3. I n b ot h i nteri m a nal yses, rele va nt safet y data will be a nal yze d.  
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N o v arti s  
C o nfi d e nti al  
P a g e 1 0 0  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
A d diti o nal i nteri m a nal yses ma y be c o n d ucte d t o s u p p ort decisi o n ma ki n g c o ncer ni n g t he 
c urre nt cli nical st u d y, t he s p o ns or’s cli nical de vel o p me nt pr ojects i n ge neral or i n case of a n y 
safet y c o ncer ns. 
U n bli n de d i nteri m a nal ysis res ults will be re vie we d b y t he cli nical tea m.  
T he cli nical tea m ma y c o m m u nicate i nteri m res ults (e. g. e val uati o n of P o C criteria or 
i nf or mati o n nee de d f or pla n ni n g/ m o dif yi n g a n ot her st u d y) t o rele va nt N o vartis tea ms f or 
i nf or mati o n, c o ns ulti n g a n d/ or decisi o n p ur p oses. 
I nteri m res ults ma y be use d t o pre pare a bstracts t o scie ntific meeti n gs. T his w o ul d t y picall y 
re q uire i n vesti gat or i n p ut t o a bstract pre parati o n. E ver y atte m pt will be ma de t o ass ure t hat t he 
i n vesti gat or will n ot ha ve access t o i n di vi d ual partici pa nt data, b ut rat her will re vie w a g gre gate, 
s u m mar y data. 
1 2. 8   
S a m pl e si z e c al c ul ati o n  
1 2. 8. 1  
Pri m ar y e n d p oi nt( s)  
F or L N A 0 4 3, a p ositi ve treat me nt effect is i n dicate d b y a n i ncrease i n v ol u me i n t he i n de x 
re gi o n a n d i n t his st u d y we h o pe t o detect a differe nce of 1 0 0 m m 3. 
 
 
  
 
 
  
 a t otal of 2 3 e val ua ble partici pa nts per ar m will pr o vi de m ore t ha n 
8 0 %  p o wer, wit h a 1 -si de d al p ha of 0. 0 5, t o detect 1 0 0 m m 3 diff ere nce bet wee n L N A 0 4 3 a n d 
n o i njecti o n at Da y 1 9 7.  
F or ca na ki n u ma b, a p ositi ve treat me nt effect is i n dicate d b y a n i ncrease i n K O O S pai n sc ore 
a n d i n t his st u d y we h o pe t o detect a differe nce of 1 2 p oi nts. 
 
. 
T h us,  ass u mi n g a sta n dar d de viati o n of 2 0 p oi nts, a t otal of 4 6 e val ua ble partici pa nts per ar m 
will pr o vi de m ore t ha n 8 0 % p o wer, wit h a 1 -si de d al p ha of 0. 0 5, t o detect 1 2-p oi nt differe nce 
bet wee n ca n a ki n u ma b a n d place b o at Da y 8 5.  
1 3   
Et hi c al c o n si d er ati o n s a n d a d mi ni str ati v e pr o c e d ur e s  
1 3. 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 desi g ne d a n d s hall be i m ple me nte d, e xec ute d a n d re p orte d i n acc or da nce 
wit h t he I C H Har m o nize d Tri partite G ui deli nes f or G o o d Cli nical Practice, wit h a p plica ble 
l ocal re g 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 F R 2 1), 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 3. 2   
R e s p o n si biliti e s of t h e i n v e sti g at or a n d I R B/I E C  
Bef ore i nitiati n g a trial, t he i n vesti gat or/i nstit uti o n m ust o btai n a p pr o val/fa v ora ble o pi ni o n fr o m 
t he I nstit uti o nal Re vie w B oar d/I n de pe n de nt Et hics C o m mittee (I R B/I E C) f or t he trial pr ot oc ol, 
writte n i nf or me d c o nse nt f or m, c o nse nt f or m u p dates, partici pa nt recr uit me nt pr oce d ures (e. g., 
a d vertise me nts) a n d a n y ot her writte n i nf or mati o n t o be pr o vi de d t o partici pa nts. Pri or t o st u d y 
start, t he i n vesti gat or is re q uire d t o si g n a pr ot oc ol si g nat ure pa ge c o nfir mi n g his/ her a gree me nt 
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N o v arti s  
C o nfi d e nti al  
P a g e 1 0 1  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
t o c o n d uct t he st u d y i n acc or da nce wit h t hese d oc u me nts a n d all of t he i nstr ucti o ns a n d 
pr oce d ures f o u n d i n t his pr ot oc ol a n d t o gi ve access t o a ll rele va nt data a n d rec or ds t o N o vartis 
m o nit ors, a u dit ors, N o vartis  Q ualit y Ass ura nce re prese ntati ves, desi g nate d a ge nts of N o vartis, 
I R Bs/I E Cs, a n d re g ulat or y a ut h orities as re q uire d. If a n i ns pecti o n of t he cli nical site is 
re q ueste d b y a re g ulat or y a ut h orit y, t he i n vesti gat or m ust i nf or m N o vartis i m me diatel y t hat t his 
re q uest has bee n ma de. 
1 3. 3   
P u bli c ati o n of st u d y pr ot o c ol a n d r e s ult s  
T he pr ot oc ol will be re gistere d i n a p u blicl y accessi ble data base s uc h as cli nicaltrials. g o v a n d 
as re q uire d i n E u dra C T. I n a d diti o n, after st u d y c o m pleti o n a n d fi nalizati o n of t he st u d y re p ort 
t he res ults of t his trial will be s u b mitte d f or p u blicati o n a nd p oste d i n a p u blicl y accessi ble 
data base of cli nical trial res ults, s uc h as t he N o vartis cli nical trial res ults we bsite a n d all re q uire d 
Healt h A ut h orit y we bsites (e. g. Cli nicaltrials. g o v, E u dra C T etc.).  
F or details o n t he N o vartis  p u blicati o n p olic y i ncl u di n g a ut h ors hi p criteria, t he i n vesti gat or 
s h o ul d c o ns ult t he N o vartis p u blicati o n p olic y trai ni n g materials t hat will be pr o vi de d at t he 
trial i n vesti gat or meeti n gs. 
1 3. 4   
Q u alit y C o ntr ol a n d Q u alit y A s s ur a n c e  
N o vartis  mai ntai ns a r o b ust Q ualit y Ma na ge me nt S yste m ( Q M S) t hat i ncl u des all acti vities 
i n v ol ve d i n q ualit y ass ura nce a n d q ualit y c o ntr ol, t o e ns ure c o m plia nce wit h writte n Sta n dar d 
O perati n g Pr oce d ures as well as a p plica ble gl o bal/l ocal G C P re g ulati o ns a n d I C H G u i deli nes. 
A u dits of i n vesti gat or sites, ve n d ors, a n d N o vartis  s yste ms are perf or me d b y a u dit ors, 
i n de pe n de nt fr o m t h ose i n v ol ve d i n c o n d ucti n g, m o nit ori n g or perf or mi n g q ualit y c o ntr ol of t he 
cli nical trial. T he cli nical a u dit pr ocess uses a k n o wle d ge/ris k -base d a p pr oac h.  
A u dits are c o n d ucte d t o assess G C P c o m plia nce wit h gl o bal a n d l ocal re g ulat or y re q uire me nts, 
pr ot oc ols a n d i nter nal S O Ps, a n d are perf or me d acc or di n g t o writte n N o vartis  pr ocesses.  
1 4   
Pr ot o c ol a d h er e n c e  
T his pr ot oc ol defi nes t he st u d y o bjecti ves, t he st u d y pr oce d ures a n d t he data t o be c ollecte d o n 
st u d y partici pa nts. A d diti o nal assess me nts re q uire d t o e ns ure safet y of partici pa nts s h o ul d be 
a d mi nistere d as dee me d necessar y o n a case b y case basis. U n der n o circ u msta nc es, i ncl u di n g 
i nci de ntal c ollecti o n, is a n i n vesti gat or all o we d t o c ollect a d diti o nal data or c o n d uct a n y 
a d diti o nal pr oce d ures f or a n y p ur p ose i n v ol vi n g a n y i n vesti gati o nal dr u gs u n der t he pr ot oc ol, 
ot her t ha n t he p ur p ose of t he st u d y. If des pite t his i nt er dicti o n pr o hi biti o n, data, i nf or mati o n, 
o bser vati o n w o ul d be i nci de ntall y c ollecte d, t he i n vesti gat or s hall i m me diatel y discl ose it t o 
N o vartis a n d n ot use it f or a n y p ur p ose ot her t ha n t he st u d y, e xce pt f or t he a p pr o priate 
m o nit ori n g o n st u d y partici pa n ts. 
I n vesti gat ors ascertai n t he y will a p pl y d ue dili ge nce to a v oi d pr ot oc ol de viati o ns. If  a n 
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 oc 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 gree d u p o n b y N o vartis 
a n d a p pr o ve d b y t he I R B/I E C a n d Healt h A ut h orities, w here re q uire d, it ca n n ot be i m ple me nte d.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 2  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
1 4. 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 be ma de i n a writte n pr ot oc ol a me n d me nt t hat 
m ust be a p pr o ve d b y N o vartis, healt h a ut h orities a n d t he I R B/I E C, w here re q uire d, pri or t o 
i m ple me ntati o n. 
O nl y a me n d me nts t hat are re q uire d f or partici pa nt safet y ma y be i m ple me nte d i m me diatel y 
pr o vi de d t he healt h a ut h orities are s u bse q ue ntl y n otifie d b y pr ot oc ol a me n d me nt a n d t he 
re vie wi n g I R B/I E C is n otifie d. 
N ot wit hsta n di n g t he nee d f or a p pr o val of f or mal pr ot oc 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 re q uire d f or t he safet y of a n y partici pa 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 viati o n fr o m t he pr ot oc ol. I n s uc h cases, N o vartis s h o ul d 
be n otifie d of t his acti o n a n d t he I R B/I E C at t he i n vesti gat or site s h o ul d be i nf or me d acc or di n g 
t o l ocal re g ulati o ns. 

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 3  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
1 5   
R ef er e n c e s  
Refere nces are a vaila ble u p o n re q uest  
Alt ma n R, Asc h E, Bl oc h D, et al ( 1 9 8 6) De vel o p me nt of criteria f or t he classificati o n a n d re p orti n g 
of oste oart hritis. Classificati o n of oste oart hritis of t he k nee. Dia g n ostic a n d T hera pe utic Criteria 
C o m mittee of t he A merica n R he u matis m Ass ociati o n. Art hritis R he u m. p. 1 0 3 9 -4 9.  
A W M F S 1 Leitli nie ( 2 0 1 5) «I ntraarti k uläre P u n kti o ne n u n d I nje kti o ne n: 
H y gie ne ma ß na h me n », Re gister n u m mer 0 2 9 –  0 0 6 . A vaila ble fr o m: 
< htt ps:// w w w.a w mf. or g/ u pl oa ds/t x _szleitli nie n/ 0 2 9 -0 0 6l _ S 1 _ H y gie ne _i ntraarti k ulaere _  
P u n kti o ne n _ u n d _I nje kti o ne n _ 2 0 1 5 -0 8 _ 0 1 -a b gela ufe n. p df > . Accesse d o n ( 2 7 J ul y 2 0 2 1).  
 
 
 
Ba yer Healt hcare P har mace uticals ( 2 0 1 8) Ma g ne vist i njecti o n; Prescri bi n g i nf or mati o n 
p.  1 -1 4. Vie we d o n 2 5 N o ve m ber 2 0 2 0.  
Be k kers J E, de Wi n dt T S, Raij ma kers NJ, et al ( 2 0 0 9) Vali dati o n of t he K nee I nj ur y a n d 
Oste oart hritis O utc o me Sc ore ( K O O S) f or t he treat me nt of f ocal cartila ge lesi o ns. Oste oart hr. 
Cartil. p. 1 4 3 4 -9.  
Bere n ba u m F ( 2 0 1 3) Oste oart hritis as a n i nfla m mat or y disease ( oste oart hritis is n ot 
oste oart hr osis!). Oste oart hr. Cartil. p. 1 6 -2 1.  
 
 
C he valier X, G o u pille P, Bea ulie u A D, et al ( 2 0 0 9) I ntraartic ular i njecti o n of a na ki nra i n 
oste oart hritis of t he k nee: a m ultice nter, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d st u d y. 
Art hritis R he u m. p. 3 4 4 -5 2.  
C o he n S B, Pr o u d ma n S, Ki vitz AJ, et al ( 2 0 1 1) A ra n d o mize d, d o u ble -bli n d st u d y of A M G 
1 0 8 (a f ull y h u ma n m o n ocl o nal a nti b o d y t o I L -1 R 1) i n patie nts wit h oste oart hritis of t he k nee. 
Art hritis Res. T her. p. R 1 2 5.  
 
  
D w or ki n R H, T ur k D C, Peirce -Sa n d ner S, et al ( 2 0 1 2) C o nsi derati o ns f or i m pr o vi n g assa y 
se nsiti vit y i n c hr o nic pai n cli nical trials: I M M P A C T rec o m me n dati o ns. Pai n; 1 5 3( 6): 1 1 4 8 -5 8.  
E M A/ 6 2 5 3 1 7/ 2 0 1 7; E ur o pea n Me dici nes A ge nc y ( 2 0 1 7) E M A’s fi nal o pi ni o n c o nfir ms restricti o ns 
o n use of li near ga d oli ni u m a ge nts i n b o d y sca ns p. 1 -4. Vie we d o n 2 5 N o ve m ber 2 0 2 0.  
 
 
Fleisc h ma n n R M, Bli d dal H, Bla nc o FJ, et al ( 2 0 1 9) A P hase II Trial of L uti kiz u ma b, a n 
A nti -I nterle u ki n-1 α/ β D ual Varia ble D o mai n I m m u n o gl o b uli n, i n K nee Oste oart hritis Patie nts 
Wit h S y n o vitis. p. 1 0 5 6 -1 0 6 9.  
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N o v arti s  
C o nfi d e nti al  
P a g e 1 0 4  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
 
 
 
Geirss o n ÁJ, Stat ke vici us S, Ví ki n gss o n A ( 2 0 0 8) Se ptic art hritis i n Icela n d 1 9 9 0 – 2 0 0 2: 
i ncreasi n g i nci de nce d ue t o iatr o ge nic i nfecti o ns. A n n R he u m Dis; 6 7: 6 3 8 -4 3.  
G uer mazi A, R oe mer F W, Ha yas hi D, et al ( 2 0 1 1) Assess me nt of s y n o vitis wit h c o ntrast -
e n ha nce d M RI usi n g a w h ole -j oi nt se mi q ua ntitati ve sc ori n g s yste m i n pe o ple wit h, or at hi g h 
ris k of, k nee oste oart hritis: t he M O S T st u d y. A n n. R he u m. Dis. p. 8 0 5-1 1.  
 
 
 
 
Ha w ker G A, Mia n S, Ke n dzers ka T, et al ( 2 0 1 1) Meas ures of a d ult pai n: Vis ual A nal o g Scale 
f or Pai n ( V A S Pai n), N u meric Rati n g Scale f or Pai n ( N R S Pai n), Mc Gill Pai n Q uesti o n naire 
( M P Q), S h ort-F or m Mc Gill Pai n Q uesti o n naire ( S F -M P Q), C hr o nic Pai n Gra de Scal e 
( C P G S), S h ort F or m-3 6 B o dil y Pai n Scale ( S F -3 6 B P S), a n d Meas ure of I nter mitte nt a n d 
C o nsta nt Oste oart hritis Pai n (I C O A P). Art hritis Care Res ( H o b o ke n) p. S 2 4 0 -5 2.  
 
 
 
J ü ni P, Hari R, R utjes A W S, et al ( 2 0 1 5) I ntra  - artic ular c ortic oster oi d f or k nee oste oart hritis. 
C oc hra ne Data base of S yste matic Re vie ws, Iss ue 1 0. Art. N o.: C D 0 0 5 3 2 8. D OI: 
1 0. 1 0 0 2/ 1 4 6 5 1 8 5 8. C D 0 0 5 3 2 8. p u b 3. Accesse d 3 0 A u g ust 2 0 2 1.  
Ke m merer M, Gra mlic h Y, Walter G, et al  ( 2 0 1 7) I nfecti o ns of lar ge j oi nts –  dia g n ostics a n d 
t hera pe utic strate g y. O U P; 1: 0 3 1 -6.  
Kj ær Peterse n S, Je nse n Ha nse n I M, As m usse n A n drease n  ( 2 0 1 9) L o w fre q ue nc y of se ptic art hritis 
after art hr oce ntesis a n d i ntra-artic ular gl uc oc ortic oi d i njecti o n. Sca n di na via n J o ur nal of 
R he u mat ol o g y ; 4 8( 5) :3 9 3 -7.  
 
 
. 
L o h ma n der L S, R o os E M ( 2 0 1 9) Disease m o dificati o n i n O A - will we e ver get t here? Nat 
Re v R he u mat ol p. 1 3 3 -1 3 5.  
 
 
 
 
 
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N o v arti s  
C o nfi d e nti al  
P a g e 1 0 5  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
O' R o ur ke K ( 2 0 2 0) A p pr oac h t o As pirati o n a n d I njecti o ns. A C R Virt ual R he u mat ol o g y Practic u m. 
d oi: 1 0. 1 1 3 6/ar d. 2 0 0 7. 0 7 7 1 3 1 Via A C R  
Oste oart hritis Researc h S ociet y I nter nati o nal ( 2 0 1 6) Oste oart hritis: a seri o us disease. W hite pa per 
s u b mitte d t o t he U. S. F o o d a n d Dr u g A d mi nistrati o n, vie we d 1 6 Dece m ber 2 0 1 9  p. 1 -1 0 3.  
Patel K V, A mt ma n n D, Je nse n M P, et al ( 2 0 2 1) Cli nical o utc o me assess me nt i n cli nical trials 
of c hr o nic pai n treat me nts. Pai n Re p ; 6( 1):e 7 8 4.  
Riis R G C, He nri kse n M, Kl o k ker L, et al ( 2 0 1 7) T he effects of i ntra -artic ular gl uc oc ortic oi ds 
a n d e xercise o n pai n a n d s y n o vitis assesse d o n static a n d d y na mic ma g netic res o na nce 
i ma gi n g i n k nee oste oart hritis: e x pl orat or y o utc o mes fr o m a ra n d o mize d c o ntr olle d trial. 
Oste oart hr. Cartil. p. 4 8 1 -4 9 1.  
R o os E M, E n gel hart L, Ra nsta m J, et al ( 2 0 1 1) I C R S Rec o m me n dati o n D oc u me nt: Patie nt -
Re p orte d O utc o me I nstr u me nts f or Use i n Patie nts wit h Artic ular Cartila ge Defects. Cartila ge 
p. 1 2 2 -3 6.
R y u K, Iri uc his hi ma T, Os hi da M, et al ( 2 0 1 4) T he pre vale nce of a n d fact ors relate d t o calci u m 
p yr o p h os p hate di h y drate cr ystal de p ositi o n i n t he k nee j oi nt. Oste oart hritis Cartila ge p. 9 7 5 -9.  
Sc hie ker M, C o na g ha n P G, Mi n de h ol m L, et al ( 2 0 2 0) Effects of I nterle u ki n -1 β I n hi biti o n o n 
I nci de nt Hi p a n d K nee Re place me nt : E x pl orat or y A nal yses Fr o m a Ra n d o mize d, 
D o u ble -Bli n d, Place b o -C o ntr olle d Trial. A n n I nter n Me d p. 5 0 9 -5 1 5.  
 
 
S ur o wiec R K, L ucas E P, Fitzc harles E K, et al ( 2 0 1 4) T 2 val ues of artic ular cartila ge i n 
cli nicall y rele va nt s u bre gi o ns of t he as y m pt o matic k nee. K nee S ur g S p orts Tra u mat ol 
Art hr osc p. 1 4 0 4 -1 4.  
Ter pstra S E S, va n der Vel de J H P M, de M utsert R, et al ( 2 0 2 1) T he ass ociati o n of cli nical a n d 
str uct ural k nee oste oart hritis wit h p h ysical acti vit y i n t he mi d dle-a ge d p o p ulati o n: t he N E O 
st u d y. Oste oart hritis Cartila ge; 2 4: S 1 0 6 3 -4 5 8 4( 2 1) 0 0 8 4 5 -1.  
T he R o yal C olle ge of Ra di ol o gists ( 2 0 1 9) G ui da nce o n ga d oli ni u m -base d c o ntrast a ge nt 
a d mi nistrati o n t o a d ult patie nts p. 1 -2 3. Vie we d o n 2 5 N o ve m ber 2 0 2 0.  
 
 
.
Wa n g X, H u nter D, X u J, et al ( 2 0 1 5) Meta b olic tri g gere d i nfla m mati o n i n oste oart hritis. 
Oste oart hr. Cartil. p. 2 2 -3 0.  
Willia ms S N, W olf or d M L, Berc o vitz A ( 2 0 1 5) H os pitalizati o n f or T otal K nee Re place me nt 
A m o n g I n patie nts A ge d 4 5 a n d O ver: U nite d States, 2 0 0 0 -2 0 1 0. N C H S Data Brief p. 1 -8.  
Wise B L, Ni u J, Ya n g M, et al ( 2 0 1 2) Patter ns of c o m part me nt i n v ol ve me nt i n ti bi ofe m oral 
oste oart hritis i n me n a n d w o me n a n d i n w hites a n d Africa n A merica ns. Art hritis Care Res 
( H o b o ke n) p. 8 4 7-5 2.  
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N o v arti s  
C o nfi d e nti al  
P a g e 1 0 6  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
W olfe F, Cla u w DJ, Fitzc harles M A, et al ( 2 0 1 0) T he A merica n C olle ge of R he u mat ol o g y 
preli mi nar y dia g n ostic criteria f or fi br o m yal gia a n d meas ure me nt of s y m pt o m se verit y. 
Art hritis Care Res ( H o b o ke n) p. 6 0 0 -1 0.  
W olf or d M L, Pals o K, Berc o vitz A ( 2 0 1 5) H os pitalizati o n f or t otal hi p re place me nt a m o n g 
i n patie nts a ge d 4 5 a n d o ver: U nite d States, 2 0 0 0-2 0 1 0. N C H S Data Brief p. 1 -8.  
Yazici Y, Mc Ali n d o n T E, Fleisc h ma n n R, et al ( 2 0 1 7) A n o vel W nt pat h wa y i n hi bit or, 
S M 0 4 6 9 0, f or t he treat me nt of m o derate t o se vere oste oart hritis of t he k nee: res ults of a 
2 4 -wee k, ra n d o mize d, c o ntr olle d, p hase 1 st u d y. Oste oart hr. Cartil. p. 1 5 9 8 -1 6 0 6.  
va n de n B osc h M HJ ( 2 0 1 9) I nfla m mati o n i n oste oart hritis: is it ti me t o da m pe n t he alar m(i n) 
i n t his de bilitati n g disease? Cli n. E x p. I m m u n ol. p. 1 5 3 -1 6 6.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 7  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
1 6   
A p p e n di c e s  
1 6. 1   
A p p e n di x 1: Li v er e v e nt a n d l a b or at or y tri g g er d efi niti o n s & 
f oll o w-u p r e q uir e m e nt s  
T a bl e 1 6 -1   
Li v er e v e nt a n d l a b or at or y tri g g er d efi niti o n s  
  
D efi niti o n/ t hr e s h ol d  
Li v er l a b or at or y tri g g er s  
If A L T, A S T a n d t ot al bilir u bi n n or m al at 
b a s eli n e:  
•   A L T or A S T > 5 × U L N  
•   A L P > 2 × U L N (i n t h e a b s e n c e of k n o w n b o n e 
p at h ol o g y)  
•   T ot al bilir u bi n > 3 × U L N (i n t h e a b s e n c e of k n o w n 
Gil b ert s y n dr o m e)  
•   A L T or A S T > 3 × U L N a n d I N R > 1. 5  
•   P ot e nti al H y’ s L a w c a s e s ( d efi n e d a s A L T or A S T 
> 3 × U L N a n d T ot al bilir u bi n > 2 × U L N [ m ai nl y 
c o nj u g at e d fr a cti o n] wit h o ut n ot a bl e i n cr e a s e i n A L P 
t o > 2 × U L N) 
•   A n y cli ni c al e v e nt of j a u n di c e ( or e q ui v al e nt t er m)  
•   A L T or A S T > 3 × U L N a c c o m p a ni e d b y ( g e n er al) 
m al ai s e, f ati g u e, a b d o mi n al p ai n, n a u s e a, or 
v o miti n g, or r a s h wit h e o si n o p hili a  
•   A n y a d v er s e e v e nt p ot e nti all y i n di c ati v e of a li v er 
t o xi cit y 
If A L T or A S T a b n or m al at b a s eli n e: 
•   A L T or A S T > 3 x b a s eli n e or > 3 0 0 U/ L ( w hi c h e v er 
o c c ur s fir st)  

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 8  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
T a bl e 1 6 -2   
F oll o w u p r e q uir e m e nt s f or li v er l a b or at or y tri g g er s - A L T, A S T, T B L  
   
A L T  
T B L  
Li v er S y m pt o m s   
A cti o n  
A L T i n cr e a s e wit h o ut bilir u bi n i n cr e a s e:  
  
   
If n or m al at b a s eli n e:  
A L T > 3 x U L N  
N or m al  
F or p arti ci p a nt s wit h 
Gil b ert’ s s y n dr o m e: 
N o c h a n g e i n 
b a s eli n e T B L  
N o n e  
•  
N o c h a n g e 
t o st u d y 
tr e at m e nt 
•  
M e a s ur e 
A L T, A S T, 
A L P, G G T, 
T BI L, I N R, 
al b u mi n, C K, 
a n d G L D H (if 
a v ail a bl e) i n 
4 8 -7 2 h o ur s.  
•  
F oll o w -u p f or 
s y m pt o m s.  
If el e v at e d at b a s eli n e:  
A L T > 2 x b a s eli n e  
or > 3 0 0 U/ L ( w hi c h e v er 
o c c ur s ﬁr st)  
   
If n or m al at b a s eli n e: 
A L T > 5 x U L N f or m or e 
t h a n t w o w e e k s 
N or m al  
F or p arti ci p a nt s wit h 
Gil b ert’ s s y n dr o m e: 
N o c h a n g e i n 
b a s eli n e T B L  
N o n e  
•  
I nt err u pt 
st u d y dr u g  
•   M e a s ur e 
A L T, A S T, 
A L P, G G T, 
T BI L, I N R, 
al b u mi n, C K, 
a n d G L D H (if 
a v ail a bl e) i n 
4 8 -7 2 h o ur s.  
•  
F oll o w -u p f or 
s y m pt o m s.  
•  
I niti at e cl o s e 
m o nit ori n g 
a n d w or k u p 
f or c o m p eti n g 
eti ol o gi e s.  
•  
St u d y dr u g 
c a n b e 
r e st art e d o nl y 
if a n ot h er 
eti ol o g y i s 
i d e nti ﬁe d a n d 
li v er e n z y m e s 
r et ur n t o 
b a s eli n e.  
If el e v at e d at b a s eli n e: 
A L T > 3 x b a s eli n e  
or > 3 0 0 U/ L ( w hi c h e v er 
o c c ur s ﬁr st) f or m or e 
t h a n t w o w e e k s 
   
If n or m al at b a s eli n e: 
A L T > 8 x U L N  
N or m al  
N o n e  
A L T i n cr e a s e wit h bilir u bi n i n cr e a s e:  
   
If n or m al at b a s eli n e: 
A L T > 3 x U L N  
T B L > 2 x U L N ( or I N R 
> 1. 5)  
F or p arti ci p a nt s wit h 
Gil b ert’ s s y n dr o m e: 
D o u bli n g of dir e ct 
bilir u bi n  
N o n e  
If el e v at e d at b a s eli n e: 
A L T > 2 x b a s eli n e  
or > 3 0 0 U/ L ( w hi c h e v er 
o c c ur s ﬁr st)  
   
If n or m al at b a s eli n e: 
A L T > 3 x U L N  
N or m al or el e v at e d  
S e v er e f ati g u e, 
n a u s e a, v o miti n g, 
ri g ht u p p er 
q u a dr a nt p ai n  
If el e v at e d at b a s eli n e: 
A L T > 2 x b a s eli n e  
or > 3 0 0 U/ L ( w hi c h e v er 
o c c ur s ﬁr st)  

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 9  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
T a bl e 1 6 -3   
F oll o w u p r e q uir e m e nt s f or li v er l a b or at or y –  I s ol at e d 
H y p er bilir u bi n e mi a  
Crit eri a  
A cti o n s r e q uir e d  
F oll o w -u p m o nit ori n g  
T ot al Bilir ui n (i s ol at e d)   
  
  
> 1. 5 –  3. 0 U L N  
•   M ai nt ai n tr e at m e nt  
•   R e p e at L F T s wit hi n 4 8 -7 2 
h o ur s  
M o nit or L F T s w e e kl y u ntil 
r e s ol uti o n t o ≤ Gr a d e 1 or t o 
b a s eli n e  
> 3 - 1 0 × U L N (i n t h e a b s e n c e of 
k n o w n Gil b ert s y n dr o m e)  
•   I nt err u pt tr e at m e nt 
•   R e p e at L F T wit hi n 4 8 -7 2 
h o ur s  
•   H o s pit ali z e if cli ni c all y 
a p pr o pri at e  
•   E st a bli s h c a u s alit y  
•   R e c or d t h e A E a n d 
c o ntri b uti n g f a ct or s ( e. g. 
c o n m e d s, m e d h x, l a b) i n 
t h e a p pr o pri at e C R F 
M o nit or L F T s w e e kl y u ntil 
r e s ol uti o n t o ≤ Gr a d e 1 or t o 
b a s eli n e ( A L T, A S T, t ot al 
bilir u bi n, Al b, P T/I N R, A L P a n d 
G G T)  
T e st f or h e m ol y si s ( e. g. 
r eti c ul o c yt e s, h a pt o gl o bi n, 
u n c o nj u g at e d [i n dir e ct] 
bilir u bi n)  
> 1 0 x U L N  
•   Di s c o nti n u e t h e st u d y 
tr e at m e nt i m m e di at el y 
•   H o s pit ali z e t h e p arti ci p a nt  
•   E st a bli s h c a u s alit y  
•   R e c or d t h e A E a n d 
c o ntri b uti n g f a ct or s( e. g. 
c o n m e d s, m e d h x, l a b) i n 
t h e a p pr o pri at e C R F 
A L T, A S T, t ot al bilir u bi n, Al b, 
P T/I N R, A L P a n d G G T u ntil 
r e s ol uti o n (fr e q u e n c y at 
i n v e sti g at or di s cr eti o n) 
A n y A E p ot e nti all y i n di c ati v e of 
a li v er t o xi cit y  
•   C o n si d er st u d y tr e at m e nt 
i nt err u pti o n or 
di s c o nti n u ati o n  
•   H o s pit ali z ati o n if cli ni c all y 
a p pr o pri at e  
•   E st a bli s h c a u s alit y  
•   R e c or d t h e A E a n d 
c o ntri b uti n g f a ct or s ( e. g., 
c o n m e d s, m e d h x, l a b) i n 
t h e a p pr o pri at e C R F 
I n v e sti g at or di s cr eti o n 
Base d o n i n vesti gat or’s discreti o n i n vesti gati o n(s) f or c o ntri b uti n g fact ors f or t he li ver e ve nt 
ca n i ncl u de: Ser ol o g y tests, i ma gi n g a n d pat h ol o g y assess me nts, he pat ol o gist’s c o ns ulta nc y; 
o btai ni n g m ore detaile d hist or y of s y m pt o ms a n d pri or or c o nc urre nt  diseases, hist or y of 
c o nc o mita nt dr u g use, e xcl usi o n of u n derl yi n g li ver disease.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 1 0  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
1 6. 2   
A p p e n di x 2: S p e cifi c R e n al Al ert Crit eri a a n d A cti o n s a n d E v e nt 
F oll o w -u p  
T a bl e 1 6 -4   
S p e cifi c R e n al Al ert Crit eri a a n d A cti o n s  
R e n al E v e nt  
A cti o n s  
C o nfir m e d s er u m cr e ati ni n e i n cr e a s e 2 5 –  4 9 %  
•   C o n si d er c a u s e s a n d p o s si bl e i nt er v e nti o n s  
•   F oll o w u p wit hi n 2 -5 d a y s  
S er u m cr e ati ni n e i n cr e a s e  ≥5 0 % * O R if < 1 8 
y e ar s ol d, e G F R 3 5 m L/ mi n/ 1. 7 3 m 2  
•   C o n si d er c a u s e s a n d p o s si bl e i nt er v e nti o n s  
•   R e p e at a s s e s s m e nt wit hi n 2 4 -4 8 h if 
p o s si bl e  
•   C o n si d er dr u g i nt err u pti o n or di s c o nti n u ati o n 
u nl e s s ot h er c a u s e s ar e di a g n o s e d a n d 
c orr e ct e d  
•   C o n si d er p ati e nt h o s pit ali z ati o n a n d 
s p e ci ali z e d tr e at m e nt  
N e w o n s et di p sti c k pr ot ei n uri a ≥3 +  
O R  
Pr ot ei n -cr e ati ni n e r ati o ( P C R) ≥1 g/ g Cr ( or 
m g/ m m ol e q ui v al e nt a s c o n v ert e d b y t h e 
m e a s uri n g l a b or at or y)  
•   C o n si d er c a u s e s a n d p o s si bl e i nt er v e nti o n s  
•   A s s e s s s er u m al b u mi n & s er u m t ot al pr ot ei n  
•   R e p e at a s s e s s m e nt t o c o nfir m  
•   C o n si d er dr u g i nt err u pti o n or di s c o nti n u ati o n 
u nl e s s ot h er c a u s e s ar e di a g n o s e d a n d 
c orr e ct e d  
N e w o n s et h e m at uri a ≥3 + o n uri n e di p sti c k   
A s s e s s & d o c u m e nt  
•   R e p e at a s s e s s m e nt t o c o nfir m  
•   Di sti n g ui s h h e m o gl o bi n uri a fr o m h e m at uri a  
•   Uri n e s e di m e nt mi cr o s c o p y  
•   A s s e s s s Cr  
•   E x cl u d e i nf e cti o n, tr a u m a, bl e e di n g fr o m t h e 
di st al uri n ar y tr a ct/ bl a d d er, m e n str u ati o n  
•   C o n si d er bl e e di n g di s or d er  
* C orr e s p o n d s t o  K DI G O  crit eri a  f or A c ut e Ki d n e y I nj ur y  

N o v arti s  
C o nfi d e nti al  
P a g e 1 1 1  of 1 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C L N A 0 4 3 A 1 2 2 0 3  
 
T a bl e 1 6 -5   
R e n al E v e nt F oll o w U p  
A s s e s s, d o c u m e nt a n d r e c or d i n C R F:  
•   Uri n e di p sti c k a n d s e di m e nt mi cr o s c o p y e vi d e n c e of DI N:  cr y st al s, r e d bl o o d c ell s 
( d y s m or p hi c/ gl o m er ul ar v s. n o n-d y s m or p hi c/ n o n -gl o m er ul ar), w hit e bl o o d c ell s, t u b ul ar 
e pit h eli al c ell s  
•   Bl o o d pr e s s ur e a n d b o d y w ei g ht  
•   S er u m cr e ati ni n e, B U N, el e ctr ol yt e s ( s o di u m, p ot a s si u m, p h o s p h at e, c al ci u m), bi c ar b o n at e a n d 
uri c a ci d  
•   Uri n e o ut p ut  
R e vi e w a n d r e c or d p o s si bl e c o ntri b uti n g f a ct or s t o t h e r e n al e v e nt ( c o -m e di c ati o n s, ot h er c o -m or bi d 
c o n diti o n s) a n d a d diti o n al di a g n o sti c pr o c e d ur e s ( M RI et c.) i n t h e C R F.  
M o nit or p ati e nt r e g ul arl y (fr e q u e n c y at i n v e sti g at or’ s di s cr eti o n) u ntil;  
•   E v e nt r e s ol uti o n: ( s Cr wit hi n 1 0 % of b a s eli n e or P C R < 1 g/ g Cr, or A C R < 3 0 0 g ="" li ="" >  
•   E v e nt st a bili z ati o n: s Cr l e v el wit h ± 1 0 % v ari a bilit y o v er l a st 6 m o nt h s or pr ot ei n - cr e ati ni n e r ati o 
st a bili z ati o n at a n e w l e v el wit h ± 5 0 % v ari a bilit y o v er l a st 6 m o nt h s.  
•   A n al y si s of uri n e m ar k er s i n s a m pl e s c oll e ct e d o v er t h e c o ur s e of t h e DI N e v e nt