A 5-year, Randomized, Double-blind, Placebo-controlled, Multi-center Study Assessing the Efficacy, Safety, and Tolerability of Intra-articular Regimens of LNA043 Versus Placebo in Patients With Symptomatic Knee Osteoarthritis
Phase: PHASE2
Conditions: 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 
A 5- y e ar, r a n d o mi z e d, d o u bl e- bli n d, pl a c e b o -c o ntr oll e d,  
m ulti - c e nt er s t u d y a s s e s si n g th e effi c a c y, s af et y, a n d 
t ol er a bilit y of i ntr a - arti c ul ar re gi m e n s of L N A 0 4 3 v er s u s 
pl a c e b o i n p ati e nt s wit h s y m pt o m ati c k n e e o st e o art hriti s 
( O N W A R D S) 
Cli ni c al Tri al Pr ot o c ol C L N A 0 4 3 A 1 2 2 0 2  / N C T 0 4 8 6 4 3 9 2
V er si o n n u m b er:  
0 2 A m e n d e d Pr ot o c ol (Cl e a n ) 
Cli ni c al Tri al P h a s e:  
II b 
R el e a s e d at e:  
S p o n s or N a m e:  
S p o n s or A d dr e s s:  
R e g ul at or y A g e n c y I d e ntifi er 
N u m b er( s):  
0 3 -J U N -2 0 2 4
N o v arti s  P h ar m a A G  
N o v arti s P h ar m a A G, Li c ht str a s s e 3 5, 4 0 5 6 
B a s el, S wit z erl a n d  
2 0 2 3 -5 0 9 9 3 7 -3 7  
Pr o p ert y of N o v arti s P h ar m a A G  
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 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
T a bl e of c o nt e nt s 
Ta ble of c o nt e nts ................................................................................................................. 2  
List of ta bles  ........................................................................................................................ 5  
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 3- J U N- 2 0 2 4) ......................................................................................... 1 2  
A me n d me nt 0 1 ( 2 9- N O V - 2 0 2 1) ....................................................................................... 1 5  
Pr ot oc ol s u m mar y .............................................................................................................. 1 7  
1  I ntr o d u cti o n ....................................................................................................................... 1 9  
1. 1  
Bac k gr o u n d ............................................................................................................ 1 9  
1. 2  
P ur p ose .................................................................................................................. 2 1  
2  
O bjecti ves a n d e n d p oi nts ................................................................................................... 2 1  
2. 1 
Pri mar y esti ma n ds  ................................................................................................. 2 4  
2. 2  
Sec o n dar y esti ma n ds ............................................................................................. 2 5  
3  
St u d y desi g n ...................................................................................................................... 2 7  
4 
Rati o nale  ............................................................................................................................ 2 9  
4. 1  
Rati o nale f or st u d y desi g n ..................................................................................... 2 9  
4. 2  
Rati o nale f or d ose/r e gi me n a n d d urati o n of treat m e nt .......................................... 3 0  
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) or c o m bi nati o n 
dr u gs ...................................................................................................................... 3 1  
4. 4  
P ur p ose a n d ti mi n g of i nteri m a nal yses/ desi g n a d a ptati o ns .................................. 3 1  
4. 5  
Ris ks a n d be nefits .................................................................................................. 3 1  
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 3  
5  
St u d y P o p ulati o n ............................................................................................................... 3 4  
5. 1 
I n cl usi o n criteria .................................................................................................... 3 4  
5. 2 
E xcl usi o n criteria  ................................................................................................... 3 5  
6 
T reat me nt ........................................................................................................................... 3 8  
6. 1  
St u d y treat me nt ...................................................................................................... 3 8  
6. 1. 1  
I n v esti gati o nal a n d c o ntr ol dr u gs .......................................................... 3 8  
6. 1. 2 
A d diti o nal st u d y treat me nts  .................................................................. 3 9  
6. 1. 3 
Treat me nt ar ms/ gr o u p  ........................................................................... 3 9  
6. 1. 4 
Treat me nt d urati o n  ................................................................................ 3 9  
6. 2 
Ot her treat me nt(s)  .................................................................................................. 4 0  
6. 2. 1  
C o nc o mita nt t hera p y ............................................................................. 4 0  
6. 2. 2 
Pr o hi bite d me dicati o n  ........................................................................... 4 1  
6. 2. 3 
Resc ue me dicati o n  ................................................................................ 4 3  

N o v arti s  
C o nfi d e nti al  
P a g e 3 of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
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 3  
6. 3. 1  
Partici pa nt n u m beri n g ........................................................................... 4 3  
6. 3. 2 
Treat me nt assi g n me nt, ra n d o mizati o n  .................................................. 4 4  
6. 4 
Treat me nt bli n di n g  ................................................................................................. 4 4  
6. 5  
D ose escalati o n a n d d ose m o dificati o n .................................................................. 4 5  
6. 5. 1 
Defi niti o ns of d ose li miti n g t o xicities ( D L Ts)  ...................................... 4 5  
6. 5. 2  
D ose m o dificati o ns ................................................................................ 4 5  
6. 5. 3  
F oll o w- u p f or t o xicities ......................................................................... 4 5  
6. 6  
A d diti o nal treat me nt g ui da nce ............................................................................... 4 6  
6. 6. 1 
Treat me nt c o m plia nce  ........................................................................... 4 6  
6. 6. 2 
Rec o m me n de d treat me nt of a d vers e e ve nts  .......................................... 4 6  
6. 6. 3  
E mer ge nc y brea ki n g of assi g ne d treat me nt c o de .................................. 4 6  
6. 7  
Pre parati o n a n d dis pe ns ati o n ................................................................................. 4 7  
6. 7. 1  
Ha n dli n g of st u d y treat m e nt a n d a d diti o nal treat m e nt .......................... 4 7  
7  I nf or me d c o ns e nt pr oce d ures ............................................................................................ 4 8  
8 
Visit sc he d ule a n d assess me nts  ......................................................................................... 4 9  
8. 1 
Scree ni n g  ............................................................................................................... 6 0  
8. 1. 1 
Pre -scr ee ni n g ......................................................................................... 6 0  
8. 1. 2 
Scree ni n g  ............................................................................................... 6 0  
8. 1. 3  
I nf or mati o n t o be c ollecte d o n scree ni n g fail ures ................................. 6 0  
8. 2 
Partici pa nt de m o gra p hics/ ot her baseli ne c h aracteristics  ....................................... 6 1  
8. 3 
Efficac y  .................................................................................................................. 6 2  
8. 3. 1 
K nee M RI  .............................................................................................. 6 3  
8. 3. 2 
A p pr o priate n ess of efficac y assess me nts  .............................................. 6 3  
8. 4 
Safet y  ..................................................................................................................... 6 4  
8. 4. 1 
La b orat or y e val uati o ns  .......................................................................... 6 4  
8. 4. 2 
E lectr ocar di o gra m ( E C G) ..................................................................... 6 5  
8. 4. 3 
Pre g na nc y a n d assess me nts of fertilit y  ................................................. 6 5  
8. 4. 4 
A p pr o priate n ess of safet y meas ure me nts  .............................................. 6 6  
8. 4. 5  
I m m u n o ge nicit y .................................................................................... 6 6  
8. 5 
A d diti o nal assess me nts  .......................................................................................... 6 7  
8. 5. 1 
Cli nical O utc o me Assess me nts ( C O As)  ............................................... 6 7  
8. 5. 2 
P har mac o ki netics  .................................................................................. 6 9  
8. 5. 3 
Bi o mar kers  ............................................................................................ 7 0  
8. 5. 4  
I ma gi n g ................................................................................................. 7 1  
8. 5. 5 
Ot her Assess me nts  ................................................................................ 7 2  

N o v arti s  
C o nfi d e nti al  
P a g e 4 of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
9  
St u d y disc o nti n uati o n a n d c o m pleti o n .............................................................................. 7 3  
9. 1  
Disc o nti n uati o n a n d c o m pleti o n ............................................................................ 7 3  
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.................. 7 3  
9. 1. 2  
Wit h dra wal of i nf or me d c o nse nt ........................................................... 7 5  
9. 1. 3  
L ost t o f oll o w- u p ................................................................................... 7 5  
9. 1. 4  
Earl y st u d y ter mi nati o n b y t he s p o ns or ................................................. 7 6  
9. 2  
St u d y c o m pleti o n a n d p ost-st u d y treat me nt .......................................................... 7 6  
1 0  Safet y m o nit ori n g a n d re p orti n g ........................................................................................ 7 6  
1 0. 1  
Defi niti o n of a d vers e e v e nts a n d re p orti n g re q uire me nts ...................................... 7 6  
1 0. 1. 1 
A d verse e ve nts  ...................................................................................... 7 6  
1 0. 1. 2 
Seri o us a d verse e ve nts  .......................................................................... 7 8  
1 0. 1. 3  
S A E re p orti n g........................................................................................ 7 9  
1 0. 1. 4  
Pre g na nc y r e p orti n g .............................................................................. 8 0  
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 0  
1 0. 2  
A d diti o nal Safet y M o nit ori n g ................................................................................ 8 1  
1 0. 2. 1  
Li ver saf et y m o nit ori n g ......................................................................... 8 1  
1 0. 2. 2  
Re nal safet y m o nit ori n g ........................................................................ 8 2  
1 0. 2. 3 
Data M o nit ori n g C o m mittee  ................................................................. 8 2  
1 1 Data C ollecti o n a n d Dat a base ma na g e me nt  ...................................................................... 8 3  
1 1. 1 
Data c ollecti o n  ....................................................................................................... 8 3  
1 1. 2 
Data base m a na ge m e nt a n d q ualit y c o ntr ol  ............................................................ 8 3  
1 1. 3 
Site m o nit ori n g  ...................................................................................................... 8 4  
1 2 Data a n al ysis a n d statistical met h o ds  ................................................................................ 8 4  
1 2. 1 
A nal ysis sets  .......................................................................................................... 8 5  
1 2. 2 
Partici pa nt de m o gra p hics a n d ot her bas eli ne c haracteristics  ................................. 8 5  
1 2. 3 
Treat me nts  ............................................................................................................. 8 6  
1 2. 4 
A nal ysis of t he pri mar y e n d p oi nt(s)/esti ma n d(s) .................................................. 8 6  
1 2. 4. 1  
Defi niti o n of pri mar y e n d p oi nt(s)/esti ma n d(s) ..................................... 8 6  
1 2. 4. 2  
Statistical m o del, h y p ot hesis, a n d met h o d of a nal ysis .......................... 8 6  
1 2. 4. 3  
Ha n dli n g of re mai ni n g i nterc urre nt e ve nts of pri mar y esti ma n d .......... 8 7  
1 2. 4. 4  
Ha n dli n g of missi n g val ues n ot relate d t o i nterc urre nt e ve nt ............... 8 7  
1 2. 4. 5  
S u p ple me ntar y a nal ysis ......................................................................... 8 7  
1 2. 4. 6  
Se nsiti vit y a nal yses f or pri mar y e n d p oi nt/esti ma n d ............................. 8 7  
1 2. 5  
A nal ysis of sec o n dar y a n d safet y e n d p oi nts/esti ma n ds ......................................... 8 8  
1 2. 5. 1  
Efficac y E n d p oi nts ................................................................................ 8 8  
1 2. 5. 2  
Safet y e n d p oi nts .................................................................................... 8 8  

N o v arti s  
C o nfi d e nti al  
P a g e 5 of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
1 2. 5. 3 
D N A  ...................................................................................................... 8 9  
1 2. 6  
A nal ysis of t he e x pl orat or y e n d p oi nts/esti ma n ds .................................................. 8 9  
1 2. 6. 1 
P har mac o ki netics  .................................................................................. 9 1  
1 2. 7 
I nteri m a nal yses ..................................................................................................... 9 1  
1 2. 8 
Sa m ple size calc ul ati o n  .......................................................................................... 9 2  
1 2. 8. 1  
Pri mar y e n d p oi nt(s) ............................................................................... 9 2  
1 2. 8. 2  
Sec o n dar y e n d p oi nt(s) ........................................................................... 9 2  
1 3  Et hical c o nsi derati o ns a n d a d mi nistrati ve pr oce d ures ...................................................... 9 2  
1 3. 1  
Re g ulat or y a n d et hical c o m plia nce ........................................................................ 9 2  
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 ................................................. 9 2  
1 3. 3  
P u blicati o n of st u d y pr ot oc ol a n d res ults............................................................... 9 3  
1 3. 4  
Q ualit y C o ntr ol a n d Q ualit y Ass ura nce ................................................................. 9 3  
1 4 Pr ot oc ol a d here n ce  ............................................................................................................ 9 3  
1 4. 1  
Pr ot oc ol a me n d me nts ............................................................................................. 9 4  
1 5 Refere n ces  ......................................................................................................................... 9 5  
1 6  A p pe n dices ........................................................................................................................ 9 8  
1 6. 1  
A p pe n di x 1: Li ver e v e nt a n d la b orat or y tri g g er defi niti o ns & f oll o w- u p 
re q uire me nts .......................................................................................................... 9 8  
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 0 0  
1 6. 3  
A p pe n di x 3: A merica n C olle ge of R he u mat ol o g y Criteria f or t he 
Classificati o n a n d Re p orti n g of Oste oart hritis of t h e K nee ................................. 1 0 2  
1 6. 4  
A p pe n di x 4: G ui deli nes f or a d mi nisteri n g t he q uesti o n naires f or patie nt 
re p orte d o utc o m es ................................................................................................ 1 0 3  
1 6. 5  
A p pe n di x 5: Patie nt Gl o bal I m pressi o n of Se verit y a n d Patie nt Gl o bal 
I m pr essi o n of C ha n ge .......................................................................................... 1 0 6  
1 6. 6  
Bl o o d c ollecti o n l o g ............................................................................................. 1 0 7  
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 1  
Ta ble 3 - 1  
S u m mar y of st u d y peri o d a n d treat me nt ............................................... 2 8  
Ta ble 6 - 1  
I n v esti gati o nal a n d c o ntr ol dr u g ............................................................ 3 9  
Ta b le 6- 2  
Pr o hi bite d me dicati o ns d uri n g C ore Peri o d .......................................... 4 1  
Ta ble 6 - 3  
Pr o hi bite d me dicati o ns d uri n g E xte nsi o n Peri o d .................................. 4 2  
Ta ble 8 - 1 
Assess me nt Sc he d ule  ............................................................................ 5 0  
Ta ble 8 - 2 
Assess me nts &  S pecificati o ns  ............................................................... 6 4  
Ta ble 1 0 - 1  
G ui da nce o n gra di n g of k nee-relate d A Es ............................................ 7 7  
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 ...................................... 9 8  

N o v arti s  
C o nfi d e nti al  
P a g e 6 of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
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 wit h li ver 
s y m pt o ms .............................................................................................. 9 8  
Ta ble 1 6 - 3 
S pecific Re nal Alert Criteria a n d A cti o ns  ........................................... 1 0 0  
Ta ble 1 6 - 4  
Re nal E ve nt F oll o w u p ........................................................................ 1 0 1  
Ta ble 1 6 - 5 
S u m mar y of Criteria f or Classificati o n of I di o pat hic Oste oart hritis 
of t he K nee *  ........................................................................................ 1 0 2  
Ta ble 1 6 - 6  
Sa m ple l o g: Ti me sc he d ule f or sa m pli n g of L N A 0 4 3 P K, 
A N G P T L 3 a n d a nti- dr u g a nti b o d y ...................................................... 1 0 7  
Li st of fi g ur e s 
Fi g ure 3- 1  
St u d y Desi g n ......................................................................................... 2 8  
 

N o v arti s  
C o nfi d e nti al  
P a g e 7 of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
Li st of a b br e vi ati o n s 
A CI  
a ut ol o g o u s c h o n dr o c yt e i m pl a nt ati o n  
A C R  
A m eri c a n C oll e g e of R h e u m at ol o g y  
A D A  
a nti -dr u g a nti b o di e s  
A E  
a d v er s e e v e nt  
AI R  
A c ut e I nfl a m m at or y R e a cti o n  
A KI  
A c ut e ki d n e y i nj ur y  
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 C O V A  
a n al y si s of c o v ari a n c e  
A N G P T L 3  
a n gi o p oi eti n -li k e 3 pr ot ei n 
A P T T  
a cti v at e d p arti al t hr o m b o pl a sti n ti m e  
A S T  
a s p art at e a mi n otr a n sf er a s e  
B MI  
B o d y M a s s I n d e x  
B S P  
Bi o m e c h a ni c al S e n s or Pl atf or m  
B U N  
bl o o d ur e a nitr o g e n  
C F R  
C o d e of F e d er al R e g ul ati o n  
C K  
cr e ati ni n e ki n a s e  
c M T F C  
c e ntr al m e di al ti bi of e m or al c o m p art m e nt  
C O X -2  
C y cl o o x y g e n a s e 2  
C R -M S C s  
c artil a g e r e si d e nt -m e s e n c h y m al str o m al c ell s  
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 TI S  
Cli ni c al Tri al s I nf or m ati o n S y st e m  
C S R  
Cli ni c al St u d y R e p ort  
C V  
c o effi ci e nt of v ari ati o n  
D L T s  
d o s e li miti n g t o xi citi e s  
D M C  
D at a M o nit ori n g C o m mitt e e  
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  
E O S  
E n d of St u d y  
E O T  
E n d of Tr e at m e nt  
e S A E  
El e ctr o ni c S eri o u s A d v er s e E v e nt  
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  
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  
H D L  
hi g h -d e n sit y li p o pr ot ei n 
HI V  
h u m a n i m m u n o d efi ci e n c y vir u s  
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 

N o v arti s  
C o nfi d e nti al  
P a g e 8 of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
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 R e gi str ati o n of 
P h ar m a c e uti c al s f or H u m a n U s e  
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 M U 
i n erti al m e a s ur e m e nt u nit s 
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 
 
 
I U D 
i ntr a ut eri n e d e vi c e 
I U S 
i ntr a ut eri n e s y st e m 
J S W  
j oi nt s p a c e wi dt h 
K -L  
K ell gr e n/ L a wr e n c e  
K A M  
k n e e a d d u cti o n m o m e nt  
K F M  
k n e e fl e xi o n m o m e nt  
k g  
Kil o gr a m  
l at J S N 
l at er al J oi nt S p a c e N arr o wi n g 
L D H  
l a ct at e d e h y dr o g e n a s e 
L D L  
l o w-d e n sit y li p o pr ot ei n  
L L Q  
l o w er li mit of q u a ntifi c ati o n  
M A R  
mi s si n g at r a n d o m  
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 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 e d J S N  
m e di al J oi nt S p a c e N arr o wi n g  
m g  
milli gr a m( s)  
m L  
millilit er( s)  
M M R M  
mi x e d -eff e ct m o d el r e p e at e d m e a s ur e s  
 
  
M R  
M a g n eti c R e s o n a n c e  
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 E L  
N o O b s er v e d A d v er s e Eff e ct L e v el  
N R S  
N u m eri c al r ati n g s c al e  
N S AI D s  
N o n st er oi d al a nti -i nfl a m m at or y dr u g s 
O A  
O st e o art hriti s  
O A R SI  
O st e o art hriti s R e s e ar c h S o ci et y I nt er n ati o n al  
O M E R A C T  
O ut c o m e M e a s ur e s i n R h e u m at ol o g y  
P C R  
Pr ot ei n -cr e ati ni n e r ati o  
P D  
p h ar m a c o d y n a mi c( s)  
P G A  
P ati e nt Gl o b al A s s e s s m e nt  
P GI C  
P ati e nt Gl o b al I m pr e s si o n of C h a n g e  
P GI S  
P ati e nt Gl o b al I m pr e s si o n of S e v erit y  
P K  
p h ar m a c o ki n eti c( s)  
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 O  
P ati e nt R e p ort e d O ut c o m e s  
P R P  
pl at el et -ri c h pl a s m a 
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 9 of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
P T  
pr ot hr o m bi n ti m e  
 
 
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  
S A E  
s eri o u s a d v er s e e v e nt  
s Cr  
s er u m cr e ati ni n e  
S D  
st a n d ar d d e vi ati o n  
S D C  
s m all e st d et e ct a bl e c h a n g e  
S F -1 2  
S h ort F or m 1 2 H e alt h S ur v e y  
S G O T  
s er u m gl ut a mi c o x al o a c eti c tr a n s a mi n a s e  
S G P T  
s er u m gl ut a mi c p yr u vi c tr a n s a mi n a s e  
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 s  
T B L  
t ot al bilir u bi n 
T F C s  
ti bi of e m or al c o m p art m e nt s 
T K R  
t ot al k n e e r e pl a c e m e nt 
U L N  
u p p er li mit of n or m al  
V K R  
Virt u al K n e e R e pl a c e m e nt  
 
 
W H O  
W orl d H e alt h Or g a ni z ati o n  
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   
μ g  
Mi cr o gr a m  
C CI
C CI
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 0  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
Gl o s s ar y of t er m s 
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 st u d y.  
Cli ni c al Tri al T e a m  
A gr o u p of p e o pl e r e s p o n si bl e f or t h e pl a n ni n g, e x e c uti o n a n d r e p orti n g of all 
cli ni c al tri al a cti viti e s. E x a m pl e s of t e a m m e m b er s i n cl u d e t h e St u d y L e a d, M e di c al 
M o nit or, Tri al St ati sti ci a n et c.  
C o ntr ol dr u g  
A n y dr u g ( a n a cti v e dr u g or a n i n a cti v e dr u g, s u c h a s a pl a c e b o) w hi c h i s u s e d a s 
a c o m p ar at or t o t h e i n v e sti g ati o n al dr u g b ei n g t e st e d i n t h e tri al.  
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 s u bj e ct 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).  
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 s u bj e ct 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 (i. e. pri or t o st arti n g a n y of t h e pr o c e d ur e s d e s cri b e d i n t h e pr ot o c ol).  
E p o c h  
I nt er v al of ti m e i n t h e pl a n n e d c o n d u ct of a st u d y. A n e p o c h i s a s s o ci at e d wit h a 
p ur p o s e ( e. g. s cr e e ni n g, r a n d o mi z ati o n, tr e at m e nt, f oll o w -u p), w hi c h a p pli e s 
a cr o s s all ar m s of a st u d y.  
E sti m a n d  
A s d efi n e d i n t h e I C H E 9( R 1) a d d e n d u m, e sti m a n d i s a pr e ci s e d e s cri pti o n of t h e 
tr e at m e nt eff e ct r efl e cti n g t h e cli ni c al q u e sti o n p o s e d b y t h e tri al o bj e cti v e. It 
s u m m ari z e s at a p o p ul ati o n -l e v el w h at t h e o ut c o m e s w o ul d b e i n t h e s a m e 
p arti ci p a nt s u n d er diff er e nt tr e at m e nt c o n diti o n s b ei n g c o m p ar e d. Attri b ut e s of a n 
e sti m a n d i n cl u d e t h e p o p ul ati o n, v ari a bl e ( or e n d p oi nt) a n d tr e at m e nt of i nt er e st, 
a s w ell a s t h e s p e cifi c ati o n of h o w t h e r e m ai ni n g i nt er c urr e nt e v e nt s ar e 
a d dr e s s e d a n d a p o p ul ati o n -l e v el s u m m ar y f or t h e v ari a bl e. 
I n v e sti g ati o n al dr u g 
T h e st u d y 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; t hi s d efi niti o n i s 
c o n si st e nt wit h U S C F R 2 1 S e cti o n 3 1 2. 3 a n d Dir e cti v e 2 0 0 1/ 2 0/ E C a n d i s 
s y n o n y m o u s wit h “i n v e sti g ati o n al n e w dr u g” or “t e st s u b st a n c e”.  
I n v e sti g ati o n al tr e at m e nt 
All i n v e sti g ati o n al dr u g( s) 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 a s w ell 
a s t h eir a s s o ci at e d tr e at m e nt c o ntr ol s. T hi s i n cl u d e s a n y pl a c e b o s, a n y a cti v e 
c o ntr ol s, a s w ell a s a p pr o v e d dr u g s u s e d o ut si d e of t h eir i n di c ati o n/ a p pr o v e d 
d o s a g e or t e st e d  i n a fi x e d c o m bi n ati o n. I n v e sti g ati o n al tr e at m e nt g e n er all y d o e s 
n ot i n cl u d e ot h er tr e at m e nt s a d mi ni st er e d a s c o n c o mit a nt b a c k gr o u n d t h er a p y 
r e q uir e d or all o w e d b y t h e pr ot o c ol w h e n u s e d wit hi n a p pr o v e d i n di c ati o n/ d o s a g e. 
M e di c ati o n n u m b er  
A u ni q u e i d e ntifi er o n t h e l a b el of e a c h st u d y dr u g p a c k a g e i n st u di e s t h at 
di s p e n s e st u d y dr u g u si n g a n I R T s y st e m.  
M e di c ati o n p a c k n u m b er  
A u ni q u e i d e ntifi er o n t h e l a b el of e a c h dr u g p a c k a g e i n st u di e s t h at di s p e n s e 
st u d y tr e at m e nt u si n g a n I R T s y st e m.  
Mi s -r a n d o mi z e d s u bj e ct s 
Mi s -r a n d o mi z e d s u bj e ct 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.  
N o n -i n v e sti g ati o n al 
m e di ci n al Pr o d u ct ( NI M P)  
Pr o d u ct s w hi c h ar e n ot t h e o bj e ct of i n v e sti g ati o n ( e. g. a n y b a c k gr o u n d t h er a p y 
a d mi ni st er e d t o e a c h of t h e cli ni c al tri al s u bj e ct s, r e g ar dl e s s of r a n d o mi z ati o n 
gr o u p, r e s c u e m e di c ati o n, a cti v e dr u g r u n -i n s et c.). 
P art 
A si n gl e c o m p o n e nt of a st u d y w hi c h c o nt ai n s diff er e nt o bj e cti v e s or p o p ul ati o n s 
wit hi n t h at si n gl e st u d y. C o m m o n p art s wit hi n a st u d y ar e: a si n gl e d o s e p art a n d a 
m ulti pl e d o s e p art, or a p art i n p ati e nt s wit h e st a bli s h e d di s e a s e a n d i n t h o s e wit h 
n e wl y -di a g n o s e d di s e a s e.  
P arti ci p a nt  
A n i n di vi d u al p arti ci p ati n g i nt o t h e tri al.  
P ati e nt  
A n i n di vi d u al wit h t h e c o n diti o n of i nt er e st.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 1  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
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 
A mi n or s u b di vi si o n of t h e st u d y ti m eli n e; di vi d e s p h a s e s i nt o s m all er f u n cti o n al 
s e g m e nt s s u c h a s s cr e e ni n g, b a s eli n e, titr ati o n, w a s h o ut, et c.  
Pr e m at ur e s u bj e ct 
wit h dr a w al  
P oi nt/ti m e w h e n t h e s u bj e ct e xit s fr o m t h e st u d y pri or t o t h e pl a n n e d c o m pl eti o n of 
all st u d y dr u g a d mi ni str ati o n a n d a s s e s s m e nt s; at t hi s ti m e all st u d y dr u g 
a d mi ni str ati o n i s di s c o nti n u e d a n d n o f urt h er a s s e s s m e nt s ar e pl a n n e d.  
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 s u bj e ct, c orr e s p o n di n g t o a 
s p e cifi c tr e at m e nt ar m a s si g n m e 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.  
S cr e e n F ail ur e  
A s u bj e ct w h o i s s cr e e n e d b ut i s n ot tr e at e d or r a n d o mi z e d.  
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 a g e  
A m aj or s u b di vi si o n of t h e st u d y ti m eli n e; b e gi n s a n d e n d s wit h m aj or st u d y 
mil e st o n e s s u c h a s e nr oll m e nt, r a n d o mi z ati o n, c o m pl eti o n of tr e at m e nt, et c.  
St u d y c o m pl eti o n  
P oi nt/ti m e at w hi c h t h e s u bj e ct c a m e i n f or a fi n al e v al u ati o n vi sit or w h e n st u d y 
dr u g w a s di s c o nti n u e d w hi c h e v er i s l at er.  
St u d y dr u g 
di s c o nti n u ati o n  
P oi nt/ti m e w h e n s u bj e ct p er m a n e ntl y st o p s t a ki n g st u d y dr u g 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 pr e m at ur e s u bj e ct wit h dr a w al.  
St u d y tr e at m e nt  
A n y dr u g 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 n o n -i n v e sti g ati o n al 
m e di ci n al pr o d u ct( s).  
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 s u bj e ct p er m a n e ntl y st o p s t a ki n g st u d y tr e at m e nt 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.  
S u bj e ct  
A n i n di vi d u al w h o h a s c o n s e nt e d t o p arti ci p at e i n t hi s st u d y. T h e t er m S u bj e ct m a y 
b e u s e d t o d e s cri b e eit h er a h e alt h y v ol u nt e er or a p ati e nt.  
S u bj e ct 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 s u bj e ct 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 s u bj e ct a n d s h o ul d b e u s e d 
t o i d e ntif y t h e s u bj e ct 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.  
Tr e at m e nt n u m b er  
A u ni q u e i d e ntifi er a s si g n e d i n n o n -r a n d o mi z e d st u di e s t o e a c h d o s e d s u bj e ct, 
c orr e s p o n di n g t o a s p e cifi c tr e at m e nt ar m.  
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 st 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 c o n s e nt 
( W o C) / O p p o siti o n t o 
u s e of d at a / bi ol o gi c al 
s a m pl e s  
Wit h dr a w al of c o n s e nt fr o m t h e st u d y i s d efi n e d a s w h e n t h e p arti ci p a nt e x pli citl y 
r e q u e st s t o st o p u s e of t h eir bi ol o gi c al s a m pl e s a n d/ or d at a ( o p p o siti o n t o u s e d at a 
a n d bi ol o gi c al s a m pl e s) A N D n o l o n g er wi s h e s t o r e c ei v e st u d y tr e at m e nt, A N D 
d o e s n ot w a nt a n y f urt h er vi sit s or a s s e s s m e nt s (i n cl u di n g f urt h er st u d y -r el at e d 
c o nt a ct s). T hi s r e q u e st s h o ul d b e i n writi n g ( d e p e n di n g o n l o c al r e g ul ati o n s) a n d 
r e c or d e d i n t h e s o ur c e d o c u m e nt ati o n. 

N o v arti s  
C o nfi d e nti al  
P a g e 1 2  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
A m e n d m e nt 0 2 ( 0 3 - J U N-2 0 2 4)  
E nr oll me nt is c o m plete d;
 patie nts ha ve bee n scree n e d a n d 5 7 6 patie nts ha ve bee n e nr olle d 
i n t he st u d y. 
A me n d me nt rati o nale:  
T he p ur p ose of t his pr ot o c ol a me n d me nt is t o i m ple me nt t he f oll o wi n g c ha n ges: 
•  A d diti o n of 
 
. T he rati o nale f or a d di n g
 
 T his 
i nf or mati o n is n ot c urre ntl y bei n g c ollecte d i n t he trial.  
•  A d diti o n of H y’s La w r e p orti n g la n g ua ge t o f oll o w safet y la n g u a ge u p dat es o n H y’s La w 
re p orti n g g ui da nce of N o vartis.  
•  A d diti o n of rele va nt c o nt e nt fr o m latest N o vartis pr ot oc ol te m plate ( O n e C T P te m plate 
V 8. 0). 
Li st of 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 s ecti 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 d eleti o ns a n d re d u n derli ne f or i ns erti o ns. 
C CI
C CI
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 3  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 4  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
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 d e pe n d e nt Et hics C o m mittee (I E Cs) a n d Healt h A ut h orities. 
T he c ha n g es descri be d i n t his a me n de d pr ot oc ol are s u bsta ntial a n d re q uire I R B/I E C a p pr o v al 
pri or t o i m ple me ntati o n.  
T he c ha n ges her ei 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 n e w a n d re vise d I nf or m e d C o nse nts D o c u me nts t hat ta k e i nt o acc o u nt t he c ha n g es 
descri be d i n t his pr ot oc ol a me n d me nt. 
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 5  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
A m e n d m e nt 0 1 ( 2 9- N O V- 2 0 2 1)  
A m e n d m e nt r ati o n al e  
A me n d me nt 1 is t o c orr ect a n i n c o nsiste nc y i n t he descri pti o n of i n cl usi o n criteri o n # 6 b et wee n 
t he pr ot oc ol s u m mar y a n d b o d y; t o i ntr o d uce fle xi bilit y i n t he assess me nt sc he d ule i ncl u di n g 
pre -scree ni n g; t o defi ne o pti o nal pre-scree ni n g assess me nts; t o clarif y pr o hi bite d me dicati o ns; 
t o a d d P R Os i n t he E xte nsi o n Peri o d; t o better e x plai n h o w t o h a n dle disr u pti o ns of t he d osi n g 
sc he me; t o i ntr o d uce fle xi bilit y i n t he e x pl orat or y Gait assess me nt; a n d t o i ntr o d uce a d diti o nal 
mi n or clarificati o ns a n d a d mi nistra ti ve c ha n ges.  
A re visi o n of i ncl usi o n  criteri o n # 6 w as nee d e d t o c orrect  t he i nc o nsiste nc y bet wee n t he 
pr ot oc ol b o d y a n d t he pr ot oc ol s u m mar y t o clarif y t hat eli gi ble patie nts s h o ul d ha ve sta ble 
W O M A C Pai n, bet w ee n 2 0 a n d 4 5 ( o ut of 5 0) i n t he tar get k n ee, at b ot h assess me nts ( d o u ble 
baseli ne) d uri n g scree ni n g.  
Fle xi bilit y o n t he ti mi n g of assess me nts at Scree ni n g Visit 1 a n d 2 was i ntr o d uce d i n t he 
scree ni n g peri o d i n res p o nse t o t he C O VI D- 1 9 pa n de mic, i n or der t o facilitate e xec uti o n of t he 
pr ot oc ol- ma n date d pr oce d ures re q uire d t o deter mi ne st u d y eli gi bilit y. 
P ossi bilit y f or c o n d ucti n g o pti o nal pre -scree ni n g assess me nts after si g nat ure o n a pre-s cree ni n g 
I C F w as i ntr o d uce d t o f acilitate selecti o n of eli gi ble partici pa nts at a n earlier sta ge w hile 
re d uci n g u n necessar y b ur de n f or i neli gi ble patie nts. 
Pr o hi bite d i.a. i njecti o ns wit h c ortic oster oi ds ha v e bee n cl arifie d, b y all o wi n g treat me nt i n n o n -
k nee j oi nts bef ore d o u ble baseli ne W O M A C pai n assess me nt, beca use of t he li mite d i m pact o n 
pai n assess me nt i n t he k nees, a n d t o ali g n wit h t he 1 i njecti o n/ year all o wa nce d uri n g t he C ore 
a n d E xte nsi o n Peri o ds. 
W O M A C, S F -1 2 a n d P G A assess me nts were c ha n ge d fr o m e ver y 
 
i n t he E xte nsi o n Peri o d, i n or der t o e ns ure pr o per assess me nt of pai n, f u ncti o n a n d q ualit y of 
life. 
T he la n g ua g e d escri bi n g t he gait assess m e nt has b ee n e dite d, i n or d er t o all o w m ore fle xi bilit y 
i n t he de vi ces s et u p a n d par a meters t o be c oll ecte d a n d assesse d i n c o nsi derati o n of t he 
tec h nical c o m ple xit y of t his platf or m. 
Se veral a d mi nistrati ve c ha n ges ha ve bee n i ntr o d uce d t o e ns ure data q ualit y a n d mi ni mize ris k 
of i nc o nsiste nt i nter pretati o n. 
T he a me n d me nt is e x p ecte d t o ha ve a n e gli gi ble i m pact o n t he st u d y p o p ulati o n.  
At t he ti me of a me n d m e nt, t he st u d y is acti vel y recr uiti n g patie nts wit h a p pr o xi matel y 2 0 
patie nts ra n d o mize d. First patie nt scree ne d was 3 1 -Ma y -2 0 2 1 a n d first patie nt ra n d o mize d was 
0 8- Se p -2 0 2 1. Partici pa nts alrea d y ra n d o mize d i n t he st u d y will nee d t o be  re-c o nse nte d as a 
c o nse q ue nce of t his a me n d me nt, mai nl y t o reflect st u d y assess me nts u p dates.  
Scree ni n g ca n be c o nti n u e d u n der ori gi nal pr ot o c ol u ntil a me n d me nt is a p pr o ve d. 
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N o v arti s  
C o nfi d e nti al  
P a g e 1 6  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
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 s ecti 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 d eleti o ns a n d re d u n derli ne f or i ns erti o ns. 
T he f oll o wi n g secti o ns h a ve bee n c ha n g e d i n t he a me n de d pr ot oc 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 d e pe n d e nt Et hics C o m mittee (I E Cs) a n d Healt h A ut h orities. 
T he c h a n ges d escri be d i n t his a me n de d pr ot oc ol are n o n -s u bsta ntial a n d d o n ot re q uire I R B/I E C 
a p pr o val pri or t o i m ple m e ntati o n u nless re q uire d b y l ocal re g ulati o ns. 
T he c ha n ges her ei 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 n e w a n d r e vise d I nf or me d C o nse nts t hat ta ke i nt o acc o u nt t h e c ha n ges des cri be d i n 
t his pr ot oc ol a me n d me nt. 
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N o v arti s  
C o nfi d e nti al  
P a g e 1 7  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
Pr ot o c ol s u m m ar y  
Pr ot o c ol 
n u m b er  
C L N A 0 4 3 A 1 2 2 0 2  
F ull Titl e  
A 5 -y e ar, r a n d o mi z e d, d o u bl e -bli n d, pl a c e b o -c o ntr oll e d, m ulti -c e nt er st u d y a s s e s si n g t h e 
effi c a c y, s af et y, a n d t ol er a bilit y of i ntr a -arti c ul ar r e gi m e n s of L N A 0 4 3 v er s u s pl a c e b o i n 
p ati e nt s wit h s y m pt o m ati c k n e e o st e o art hriti s ( O N W A R D S)  
Bri ef titl e  
St u d y of effi c a c y, s af et y, a n d t ol er a bilit y 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 st e o art hriti s  
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 ar m a A G  
P h a s e II b  
I n v e sti g ati o n 
t y p e 
Bi ol o gi c al  
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 h e p ur p o s e of t hi s st u d y i s t o a s s e s s t h e effi c a c y, s af et y a n d t ol er a bilit y of diff er e nt d o s e s 
( 
 m g a n d  
 m g), n u m b er of i nj e cti o n s i n a d o si n g c y cl e ( 
) a n d d o si n g c y cl e 
fr e q u e n c y (
) of i ntr a-arti c ul ar L N A 0 4 3. T hi s  st u d y will 
d et er mi n e t h e o pti m al d o si n g r e gi m e n of L N A 0 4 3 l e a di n g t o  str u ct ur al c h a n g e s, s y m pt o m ati c 
r eli ef a n d i m pr o v e m e nt i n f u n cti o n/ q u alit y of lif e of p arti ci p a nt s wit h k n e e o st e o art hriti s ( O A). 
R e s ult s of t hi s st u d y will i nf or m l at er p h a s e s of t h e L N A 0 4 3 cli ni c al d e v el o p m e nt pr o gr a m.  
Pri m ar y 
O bj e cti v e( s)  
T o e v al u at e str u ct ur al c h a n g e s fr o m b a s eli n e i n t h e c e ntr al m e di al ti bi of e m or al c o m p art m e nt 
( c M T F C) of L N A 0 4 3 c o m p ar e d wit h pl a c e b o i n t h e t ar g et k n e e at W e e k 1 0 4. 
S e c o n d ar y 
O bj e cti v e s  
•  
T o e v al u at e c h a n g e s fr o m b a s eli n e i n O A p ai n i n t h e t ar g et k n e e of L N A 0 4 3 c o m p ar e d 
wit h pl a c e b o at W e e k 1 0 4  
•  
T o e v al u at e c h a n g e s fr o m b a s eli n e i n p h y si c al f u n cti o n of L N A 0 4 3 c o m p ar e d wit h 
pl a c e b o at W e e k 1 0 4  
•  
T o e v al u at e str u ct ur al c h a n g e s fr o m b a s eli n e i n t h e t ot al, m e di al a n d l at er al ti bi of e m or al 
c o m p art m e nt s ( T F C s) i n t h e t ar g et k n e e  of L N A 0 4 3 c o m p ar e d wit h pl a c e b o at W e e k 
1 0 4  
•  
T o e v al u at e c h a n g e s fr o m b a s eli n e i n p erf or m a n c e -b a s e d p h y si c al f u n cti o n 
a s s e s s m e nt  of L N A 0 4 3 c o m p ar e d wit h pl a c e b o at W e e k 1 0 4  
•  
T o e v al u at e str u ct ur al pr o gr e s si o n i n t h e t ar g et k n e e of L N A 0 4 3 c o m p ar e d wit h pl a c e b o 
u si n g i m a gi n g t e c h ni q u e s   
•  
T o e v al u at e s af et y a n d t ol er a bilit y of t h e v ari o u s L N A 0 4 3 r e gi m e n s   
St u d y d e si g n  
T hi s i s a m ulti c e nt er, r a n d o mi z e d, p ar all el -gr o u p, d o u bl e -bli n d, pl a c e b o -c o ntr oll e d P h a s e II b 
st u d y c o n si sti n g of a 2 -y e ar C or e P eri o d, f oll o w e d b y a 3 -y e ar E xt e n si o n P eri o d ( of 2 -y e ar 
tr e at m e nt a n d 1-y e ar f oll o w -u p).  
St u d y 
p o p ul ati o n  
M al e a n d f e m al e p arti ci p a nt s 4 0 t o 7 5 y e ar s ol d, wit h pr e d o mi n a ntl y u nil at er al m e di al 
r a di o gr a p hi c K ell gr e n/ L a wr e n c e ( K-L) gr a d e 2 -3 k n e e o st e o art hriti s, a n d m o d er at e t o s e v er e 
p ai n i n t h e t ar g et k n e e ( W O M A C P ai n of 2 0 -4 5 o ut of 5 0).  
K e y I n cl u si o n 
crit eri a  
•  
M al e s a n d f e m al e s b et w e e n 4 0 a n d 7 5 y e ar s of a g e  
•  
B o d y m a s s i n d e x ( B MI) < 4 0 k g/ m 2  
•  
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 cli ni c al a n d r a di o gr a p hi c crit eri a  
•  
R a di o gr a p hi c di s e a s e K -L gr a d e 2 or 3 k n e e O A wit h a pr e d o mi n a ntl y m e di al T F C 
i n v ol v e m e nt d efi n e d a s m e di al J oi nt S p a c e N arr o wi n g ( m e d J S N) 1-2 a n d m e d J S N > 
l at er al J oi nt S p a c e N arr o wi n g (l at J S N) i n t h e t ar g et k n e e 
•  
P arti ci p a nt s wit h W O M A C P ai n of 2 0 -4 5 ( o ut of 5 0) f or t h e t ar g et k n e e at b ot h ( d o u bl e 
b a s eli n e) a s s e s s m e nt s d uri n g s cr e e ni n g p eri o d aft er di s c o nti n u ati o n of a n al g e si c s, a nti -
i nfl a m m at ori e s a n d l o w p ot e n c y o pi oi d s wit hi n 4 8 h o ur s or a n e q ui v al e nt of 5 × T1/ 2  w a s h 
o ut p eri o d ( w hi c h e v er i s l o n g er)  
•  
S y m pt o m ati c O A wit h p ai n i n t h e t ar g et k n e e f or at l e a st 6 m o nt h s  
•  
Pri m ar y s o ur c e of p ai n t hr o u g h o ut b o d y i s d u e t o O A i n t h e t ar g et k n e e: Wi d e s pr e a d 
P ai n I n d e x s c or e of ≤6 a n d a S y m pt o m S e v erit y s c or e of < 7  
K e y E x cl u si o n 
crit eri a  
•  
P arti ci p a nt s wit h r a di o gr a p hi c k n e e O A K -L gr a d e = 4 o n t h e n o n -t ar g et k n e e  
•  
P arti ci p a nt s wit h W O M A C P ai n > 1 5 ( o ut of 5 0) i n t h e n o n -t ar g et k n e e 
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N o v arti s  
C o nfi d e nti al  
P a g e 1 8  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
•  
S e v er e m al ali g n m e nt ( > 7. 5° v ar u s or  v al g u s)  i n t h e a n at o mi c al a xi s of t h e t ar g et k n e e 
•  
Cli ni c al si g n s of m o d er at e -s e v er e i nfl a m m ati o n (i. e., r e d n e s s, w ar mt h, eff u si o n) of t h e 
t ar g et k n e e or r e q uiri n g a s pir ati o n i n t h e t ar g et k n e e wit hi n 1 2 w e e k s pri or t o S cr e e ni n g 
•  
Art hr o s c o p y of t h e t ar g et k n e e wit hi n t h e 6 m o nt h s pri or t o S cr e e ni n g  
•  
Pr e vi o u s s ur gi c al tr e at m e nt of t h e t ar g et k n e e u si 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, p arti al or c o m pl et e j oi nt r e pl a c e m e nt or pl a n n e d 
k n e e s ur g er y f or eit h er k n e e d uri n g t h e st u d y  
•  
U n st a bl e t ar g et k n e e j oi nt (i n cl u di n g, b ut n ot li mit e d t o, p o sttr a u m ati c or c o n g e nit al 
l a xit y) or i n s uffi ci e ntl y r e c o n str u ct e d li g a m e nt s b a s e d o n m e di c al hi st or y a n d/ or p h y si c al 
e x a mi n ati o n b y t h e I n v e sti g at or  
•  
Ot h er p at h ol o gi e s aff e cti n g t h e k n e e, i n cl u di n g s u b c h o n dr al i n s uffi ci e n c y fr a ct ur e s, b o n e 
fr a ct ur e ( a c ut e or s u b a c ut e i n l e s s t h a n 6 m o nt h s pri or t o s cr e e ni n g) or b o n e br ui s e, 
o st e o n e cr o si s, m ali g n a nt b o n e m arr o w i nfiltr ati o n, s oli d t u m or s, a n d/ or p at ell of e m or al 
d y s pl a si a b a s e d o n cli ni c al a s s e s s m e nt, X -r a y or M RI 
•  
S y m pt o m ati c hi p O A o n eit h er hi p or hi p pr o st h e si s r e c e ntl y i m pl a nt e d ( wit hi n 1 y e ar) or 
f or e s e e n wit hi n t h e st u d y p eri o d ( eit h er hi p) 
•  
Ot h er p ai n c o n diti o n s t h at c o ul d c o nf o u n d a s s e s s m e nt s of t h e p ai n a s s o ci at e d wit h 
k n e e O A, a s j u d g e d b y t h e I n v e sti g at or  
St u d y 
tr e at m e nt 
I n v e sti g ati o n al dr u g: L N A 0 4 3  
 m g,  
 m g 
C o ntr ol: Pl a c e b o ( s ali n e s ol uti o n)  
Tr e at m e nt of 
i nt er e st 
T hi s st u d y will a s s e s s t h e effi c a c y, s af et y a n d t ol er a bilit y of L N A 0 4 3 i n diff er e nt d o s e s ( 
 
m g a n d  
 m g), n u m b er of i nj e cti o n s i n a c y cl e ( 
) a n d d o si n g c y cl e fr e q u e n c y ( 
 
). 
Effi c a c y 
a s s e s s m e nt s  
•  
C h a n g e fr o m b a s eli n e i n c artil a g e t hi c k n e s s i n t h e c M T F C at W e e k 1 0 4 a s s e s s e d b y 
M RI of t h e t ar g et k n e e  
•  
C h a n g e fr o m b a s eli n e at W e e k 1 0 4 i n W O M A C p ai n  
•  
C h a n g e fr o m b a s eli n e at W e e k 1 0 4 i n W O M A C f u n cti o n  
•  
C h a n g e fr o m b a s eli n e i n c artil a g e t hi c k n e s s i n t h e t ot al, m e di al a n d l at er al T F C s at 
W e e k 1 0 4 a s s e s s e d b y M RI of t h e t ar g et k n e e  
•  
C h a n g e fr o m b a s eli n e i n p h y si c al f u n cti o n at W e e k 1 0 4; 4 0 -m et er ( 4 × 1 0 m) f a st -p a c e d 
w al k t e st, 3 0 -s e c o n d c h air st a n d t e st, a n d 6 -mi n ut e w al ki n g t e st  
•  
Pr o p orti o n of p arti ci p a nt s d e m o n str ati n g str u ct ur al pr o gr e s si o n  at W e e k 1 0 4  i n t h e 
t ar g et k n e e d efi n e d a s c h a n g e a b o v e t h e s m all e st d et e ct a bl e c h a n g e of c artil a g e 
t hi c k n e s s b y M RI a n d a l o s s of m e di al mi ni m u m j oi nt s p a c e wi dt h ≥ 0. 7 0 m m fr o m 
b a s eli n e b y X -r a y 
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, vit al si g n s, h ei g ht a n d w ei g ht  
•  
I n ci d e n c e of A c ut e I nfl a m m at or y R e a cti o n s ( AI R s) 
•  
L a b or at or y e v al u ati o n s ( h e m at ol o g y, c h e mi str y, li pi d s p a n el (f a sti n g), uri n al y si s)  
•  
E C G  
•  
A nti -dr u g a nti b o d y t o L N A 0 4 3  
D at a a n al y si s  
T h e pri m ar y effi c a c y v ari a bl e i s c h a n g e fr o m b a s eli n e i n c artil a g e t hi c k n e s s i n t h e c M T F C at 
W e e k 1 0 4 d et er mi n e d b y q M RI of t h e t ar g et k n e e i n p arti ci p a nt s wit h k n e e O A. T h e pri m ar y 
a n al y si s will b e c o n d u ct e d u si n g mi x e d -eff e ct m o d el r e p e at e d m e a s ur e s ( M M R M) w hi c h i s 
v ali d u n d er t h e mi s si n g at r a n d o m ( M A R) a s s u m pti o n, wit h tr e at m e nt a n d a n al y si s vi sit a s 
f a ct or s a n d b a s eli n e s c or e a s a c o v ari at e i n t h e m o d el. Tr e at m e nt b y a n al y si s vi sit a n d 
b a s eli n e s c or e b y a n al y si s vi sit will b e i n cl u d e d a s i nt er a cti o n t er m s i n t h e m o d el. A n 
u n str u ct ur e d c o v ari a n c e str u ct ur e will b e a s s u m e d f or t hi s m o d el. T h e si g nifi c a n c e of t h e 
tr e at m e nt eff e ct s f or L N A 0 4 3 r e gi m e n s at W e e k 1 0 4 will b e d et er mi n e d fr o m t h e p air wi s e 
c o m p ari s o n s u si n g t h e D u n n ett t e st p erf or m e d b et w e e n L N A 0 4 3 r e gi m e n s a n d pl a c e b o at α 
= 0. 0 5.  
K e y w or d s  
k n e e o st e o art hriti s, L N A 0 4 3, D M O A D  
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N o v arti s  
C o nfi d e nti al  
P a g e 1 9  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
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 diseas e 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 t he w orl d, a n d a lea di n g ca use of p ai n a n d 
disa bilit y  a m o n g  a d ults  ( Oste oart hritis  Researc h  S ociet y  I nter nati o nal  ( O A R SI)  2 0 1 6 ). 
A p pr o xi matel y 1 0 -1 2 % of t he a d ult p o p ulati o n has s y m pt o matic k nee O A wit h a w orl d wi d e 
esti mate of ~ 2 6 3 milli o n pe o ple bei n g affecte d b y k nee O A i n 2 0 1 7 ( G B D 2 0 1 7 Diseas e a n d 
I nj ur y I nci d e nce a n d Pr e vale nce C olla b orat ors 2 0 1 8). T he pre val e nce of O A is pr o gressi vel y 
risi n g d ue t o a n i ncr eas e i n life e x p ecta n c y a n d p o p ulati o n a gei n g, al o n g wit h risi n g pre v ale nce 
of pre dis p osi n g ris k fact ors s uc h as o besit y a n d relate d meta b olic c o m or bi dities. Pai n a n d l oss 
of f u ncti o n d ue t o O A are acc o m pa nie d b y a n i ncrease d ris k of a d diti o nal c o m or bi dities s uc h 
as t y pe 2 dia betes a n d car di o vasc ular disease ( Fer na n des a n d Val d es 2 0 1 5 ). T he hall mar k of 
O A is j oi nt pai n a n d pr o gressi ve de gra d ati o n of artic ular cartila ge, s y n o vitis, a n d alterati o ns i n 
s u bc h o n dral b o ne a n d periartic ular tiss ues (G ol dri n g a n d Oter o 2 0 1 1 ). I n t he U nite d States 
al o ne, o ver 1, 0 0 0, 0 0 0 t otal k nee r e place m e nts ( T K R) were pla n n e d i n 2 0 2 0 ( Si n g h et al 2 0 1 9).  
T he  mai nsta y  of  k nee  O A  treat me nt  i ncl u des  n o n -p har mac ol o gical  a n d  p har mac ol o gical  
meas ures t o re d u ce pai n ( a nal gesic me dicati o n) a n d i m pr o ve k n ee a n d l o w er -e xtre mit y f u ncti o n 
( p h ysi ot hera p y). C urre nt p har mac ol o gical treat m e nts are directe d o nl y at s y m pt o ms  wit h o ut 
str uct ural i m pr o ve me nt or m o dificati o n of disease pr o gressi o n, p osi n g a n u n met me dical nee d 
f or patie nts. Des pite maj or eff orts i n t he past deca des, t here are n o a p pr o v e d disease- m o dif yi n g 
O A dr u gs. T h eref ore, t h e q uest f or n o vel c o m p o u n ds t hat ca n p ote ntiall y halt or re verse t he 
str uct ural c ha n g es ass oci ate d wit h O A c o nti n ues. 
L N A 0 4 3  is  a  m o difie d  C -ter mi nal  fra g me nt  of  a  rec o m bi na nt  versi o n  of  t he  h u ma n  
a n gi o p oieti n-li ke  3  pr ot ei n  ( A N G P T L 3).  Si milar  t o  A N G P T L 3,  L N A 0 4 3  acts  directl y  o n  
cartila ge resi d e nt -mese n c h y mal str o mal cells ( C R -M S Cs) a n d artic ular c h o n dr oc ytes t hr o u g h 
bi n di n g t o α 5 β 1 a n d α V β 3 i nte gri ns t o tra ns mit its a na b olic re pair effects o n cartila ge cells, 
pr o m oti n g  t he  f or mati o n  of  artic ular  cartila ge  e xtracell ular  matri x  pr otei ns  i n  mat ure  
c h o n dr oc ytes  a n d  i n  C R -M S Cs  w hile  s u p p orti n g  re -gr o wt h  of  C R -M S Cs.  I n  c o nt rast t o 
A N G P T L 3, L N A 0 4 3 d o es n ot de m o nstrate tri gl yceri de m o d ulati o n n or a n gi o ge nesis, base d 
o n i n vitr o assa ys, b eca use it d oes n ot c o ntai n t he N -t er mi nal p orti o n of t he f ull pr otei n. T o 
e val uate  L N A 0 4 3  i n  viv o,  r at   
 me niscal  i nj ur y  m o dels  were  utilize d  
(Ger wi n  et al 2 0 1 0).  I n  brief,  8-wee k -ol d  male  Le wis  rats  were  s u bjecte d  t o  s ur ger y  t o  
c o m pletel y se ver t he me dial c ollater al li ga me nt a n d t he me dial me nisc us t o desta bilize t he j oi nt 
s o t hat f ut ure wei g ht-beari n g w o ul d lea d t o ra pi d de ge nerati o n of t he cartila ge.
 
, o n e w ee k 
f oll o wi n g t he s ur ger y, a si n gle d ose of L N A 0 4 3 or sali ne was i njecte d i ntra-artic ularl y (i.a.). 
,  it  was  deter mi ne d  t hat  a  si n gle  i.a.  i njecti o n  u p  t o  2 0 0  μ g  of 
L N A 0 4 3  (r ats) 
  si g nifica ntl y  re p aire d  t he  s ur gicall y  da ma g e d 
cartila ge i n a d os e -r elate d ma n ner. 
 
 
 
 
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N o v arti s  
C o nfi d e nti al  
P a g e 2 0  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T h e c o m plete d first -i n-h u ma n ( FI H) st u d y (C L N A 0 4 3 X 2 1 0 1) of L N A 0 4 3 was perf or me d i n 
pri m ar y O A partici pa nts w h o were sc he d ul e d f or t otal k nee re place me nt ( T K R). U p t o   m g 
L N A 0 4 3 was a d mi nistere d i ntra -artic ularl y as a si n gle d ose 3 wee ks, 1 wee k or 2 h o ur s pri or t o 
s ur ger y a n d safet y, t oler a bilit y, p har mac o ki netics ( P K), a n d i m m u n o ge nicit y (I G) data were 
c ollecte d. I n s u m mar y, (i) n o si g nifica nt dr u g -relat e d A d verse E v e nts ( A E) or Seri o us A d v erse 
E ve nts ( S A E) wer e r e p orte d; (ii) L N A 0 4 3 was ra pi dl y eli mi nat e d fr o m t he s y n o vial fl ui d of t h e 
k nee a n d t he plas ma ( L N A 0 4 3 le vels were b el o w li mit of q ua ntificati o n after 7 d a ys i n b ot h 
sa m ples);  a n d  (iii)  n o  a nti-dr u g  a nti b o dies  ( A D A)  were  det ecte d.  A  d ose  of   
 m g  i n  3  
partici pa nts de m o nstrat e d a f a v ora bl e safet y pr ofile, wit h o nl y 1 p artici pa nt (  m g si n gle d ose) 
re p orti n g A Es of dr y m o ut h a n d d ys ge usia, b ot h mil d i n se verit y. N o parti ci pa nt e x perie nce d a 
h y perse nsiti vit y reacti o n. 
T he  c o m plete d  pr o of  of  mec ha nis m  ( P o M)  st u d y  ( C L N A 0 4 3 X 2 2 0 1)  was  perf or me d  i n  
partici pa nts u n der g oi n g a ut ol o g o us c h o n dr oc yte i m pla ntati o n ( A CI) t o treat a cartila ge lesi o n, 
recei vi n g a si n gle i njecti o n of   m g L N A 0 4 3. B ot h t he e xte nt of tiss ue gr o wt h a n d t he q u alit y 
of tiss ue c o m p ositi o n were e val uat e d wit h 7 Tesla M RI. Res ults s h o we d t hat tiss ue c o m pati ble 
wit h earl y h yali ne cartila ge was detecte d at t he d o n or sites at 4 a n d 1 2 w ee ks p ost -L N A 0 4 3 
d ose. N o dr u g -r elate d safet y si g nal i ncl u di n g h y perse nsiti vity reacti o n w as re p orte d. T h ere 
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N o v arti s  
C o nfi d e nti al  
P a g e 2 1  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
were n o deat hs or S A Es d uri n g t he st u d y a n d all of t he A Es re p orte d were mil d t o m o derate i n 
se verit y. T here w ere n o cli nicall y rele va nt la b orat or y or vital si g ns a b n or malities d uri n g t he 
c o n d uct of t he st u d y, a n d si n gle i ntra -artic ular a d mi nistrati o n of L N A 0 4 3 di d n ot lea d t o 
f or mati o n of A D As. 
T he pr o of of c o nce pt ( P o C) st u d y ( C L N A 0 4 3 X 2 2 0 2 - Part A) c o m plete d d osi n g a n d f oll o w u p 
i n partici pa nts wit h k n ee cartila ge i nj ur y, recei vi n g 4 wee kl y i njecti o ns of   m g L N A 0 4 3 a n d 
f oll o we d u p f or 5 2 wee ks ( Part A). Res ults c o nfir m t he cartila ge a na b olic acti vit y of L N A 0 4 3 
i n h u ma ns at 2 8 w ee ks f oll o w u p meas ure d wit h 3 T M RI. O verall, at t he i nteri m a nal ysis, t he 
treat me nt was well-t oler ate d a n d n o rele v a nt s yste mic safet y si g nal was re p orte d. T here w ere 
n o deat hs a n d n o disc o nti n uati o ns d ue t o st u d y treat me nt. O ne ( 1) S A E was re p orte d (l o w bac k 
pai n) b ut was n ot c o nsi dere d t o be relat e d t o st u d y treat me nt. A hi g her i nci de nce of j oi nt 
s welli n g ( 9. 3 % vs 0 %) a n d art hral gia ( 1 1. 6 % vs 6. 7 %) w as re p orte d f or L N A 0 4 3 vs place b o 
res pecti vel y. M ost of t hese occ urr e d aft er t he i. a. i njecti o n, res ol ve d s p o nta ne o usl y or wit h 
paraceta m ol/ N S AI Ds a n d are c o nsiste nt wit h a mil d/ m o derate l ocal reacti o n of t he k n ee t o t h e 
dr u g. N o A Es c o m pati ble wit h h y perse nsiti vit y reacti o ns ha ve bee n re p orte d. N o  a nti‑ L N A 0 4 3 
a nti b o dies were detecte d i n a n y of t he teste d sa m ples. T he P o C st u d y C L N A 0 4 3 X 2 2 0 2 Part B, 
i n partici pa nts wit h mil d-m o derate k n ee O A, recei vi n g  
 i njecti o ns of   m g or   m g 
L N A 0 4 3, is c urre ntl y o n g oi n g. A n et h nic se nsiti vit y st u d y ( C L N A 0 4 3 A 1 1 1 0 1) i n t he Ja pa ne se 
p o p ulati o n, recei vi n g a si n gle i.a. i njecti o n of   m g or   m g L N A 0 4 3, c o m plete d treat me nt 
a n d f oll o w u p wit h n o S A Es re p orte d. 
A m ore det aile d re vie w of t he a v aila ble pre -cli ni cal a n d cli nical i nf or mati o n o n L N A 0 4 3 ca n 
be f o u n d i n t he I n vesti gat or's Br oc h ure (I B). 
1. 2   
P ur p o s e 
T he p ur p ose of t his st u d y is t o assess t he efficac y, safet y a n d t olera bilit y of differe nt d oses (  
m g a n d   m g), n u m ber of i njecti o ns i n a d osi n g c ycle ( 
) a n d d osi n g c ycle fre q ue n c y 
(
) of i.a. L N A 0 4 3 t o deter mi ne a n o pti mal d osi n g re gi me n 
f or t he treat me nt of k nee O A. 
T his st u d y will deter mi ne t he o pti mal d osi n g re gi m e n of L N A 0 4 3 lea di n g t o str uct ural c h a n ges, 
s y m pt o matic relief a n d i m pr o ve me nt i n f u n cti o n/ q ualit y of life ( Q o L) of p artici pa nts wit h k nee 
O A. Res ults of t his st u d y will i nf or m later p has es of t he L N A 0 4 3 cli nical de vel o p me nt pr o gra m.  
2 
O bj e cti v e s a n d e n d p oi nt s  
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 e v al u at e str u ct ur al c h a n g e s fr o m 
b a s eli n e i n t h e c e ntr al m e di al 
ti bi of e m or al c o m p art m e nt ( c M T F C) of 
L N A 0 4 3 c o m p ar e d wit h pl a c e b o i n t h e 
t ar g et k n e e at W e e k 1 0 4 
•  
C h a n g e fr o m b a s eli n e i n c artil a g e t hi c k n e s s i n t h e c M T F C 
at W e e k 1 0 4 a s s e s s e d b y q M RI  
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)  
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N o v arti s  
C o nfi d e nti al  
P a g e 2 2  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
O bj e cti v e( s)  
E n d p oi nt( s)  
•  
T o e v al u at e c h a n g e s fr o m b a s eli n e i n 
O A p ai n i n t h e t ar g et k n e e of L N A 0 4 3 
c o m p ar e d wit h pl a c e b o at W e e k 1 0 4  
•  
C h a n g e fr o m b a s eli n e at W e e k 1 0 4 i n:  
•  W O M A C p ai n  
•  W O M A C p ai n w al ki n g o n fl at s urf a c e it e m   
•  
T o e v al u at e c h a n g e s fr o m b a s eli n e i n 
p h y si c al f u n cti o n of L N A 0 4 3 c o m p ar e d 
wit h pl a c e b o at W e e k 1 0 4  
•  
C h a n g e fr o m b a s eli n e at W e e k 1 0 4 i n:  
•  W O M A C f u n cti o n 
•  
T o e v al u at e str u ct ur al c h a n g e s fr o m 
b a s eli n e i n t h e t ot al, m e di al a n d l at er al 
ti bi of e m or al c o m p art m e nt s ( T F C s) i n t h e 
t ar g et k n e e of L N A 0 4 3 c o m p ar e d wit h 
pl a c e b o at W e e k 1 0 4  
•  
C h a n g e fr o m b a s eli n e i n c artil a g e t hi c k n e s s i n t h e t ot al, 
m e di al a n d l at er al T F C s at W e e k 1 0 4 a s s e s s e d b y q M RI  
•  
T o e v al u at e c h a n g e s fr o m b a s eli n e i n 
p erf or m a n c e -b a s e d p h y si c al f u n cti o n 
a s s e s s m e nt  of L N A 0 4 3 c o m p ar e d wit h 
pl a c e b o at W e e k 1 0 4  
•  
C h a n g e fr o m b a s eli n e i n p h y si c al f u n cti o n at W e e k 1 0 4   
•  4 0 -m et er ( 4 × 1 0 m) f a st -p a c e d w al k t e st  
•  3 0 -s e c o n d c h air st a n d t e st  
•  6 -mi n ut e w al ki n g t e st  
•  
T o e v al u at e pr o p orti o n of p ati e nt s wit h 
str u ct ur al pr o gr e s si o n i n t h e t ar g et k n e e 
of L N A 0 4 3 c o m p ar e d wit h pl a c e b o u si n g 
i m a gi n g t e c h ni q u e s  
•  
Pr o p orti o n of p arti ci p a nt s d e m o n str ati n g str u ct ur al 
pr o gr e s si o n  at W e e k 1 0 4 d efi n e d a s:  
•  c h a n g e a b o v e t h e s m all e st  d et e ct a bl e c h a n g e ( S D C) 
of c artil a g e t hi c k n e s s b y q M RI   
•  a l o s s of m e di al mi ni m u m j oi nt s p a c e wi dt h ( mi n J S W) 
≥ 0. 7 0 m m fr o m b a s eli n e b y X -r a y 
•  
T o e v al u at e s af et y a n d t ol er a bilit y of t h e 
v ari o u s L N A 0 4 3 r e gi m e n s   
•  
S af et y a n d t ol er a bilit y d e m o n str at e d b y a s s e s si n g:  
•  A d v er s e e v e nt s ( A E s) a n d s eri o u s a d v er s e e v e nt s 
( S A E s) 
•  I n ci d e n c e of A c ut e I nfl a m m at or y R e a cti o n s ( AI R s) o n 
t h e t ar g et k n e e 
•  Cli ni c all y si g nifi c a nt c h a n g e s i n l a b or at or y m e a s ur e s 
a n d vit al si g n s, a s a s s e s s e d b y t h e I n v e sti g at or  
•  I n ci d e n c e of bi n di n g a n d n e utr ali zi n g A D A s i n s er u m 
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)  
•  
T o e v al u at e str u ct ur al c h a n g e s i n t h e 
c M T F C of t h e t ar g et k n e e o v er ti m e  
•  
C h a n g e fr o m b a s eli n e i n c artil a g e t hi c k n e s s i n t h e c M T F C 
a s s e s s e d b y q M RI at W e e k s 
 
  
•  
T o e v al u at e c h a n g e s fr o m b a s eli n e i n 
O A p ai n i n t h e t ar g et k n e e o v er ti m e  
•  
C h a n g e fr o m b a s eli n e at W e e k s 
 
 i n: 
•  W O M A C p ai n  
•  W O M A C p ai n w al ki n g o n fl at s urf a c e it e m  
•  
T o e v al u at e c h a n g e s fr o m b a s eli n e i n 
p h y si c al f u n cti o n o v er ti m e  
•  
C h a n g e fr o m b a s eli n e at W e e k s
 
 i n: 
•  W O M A C f u n cti o n  
•  
T o e v al u at e str u ct ur al c h a n g e s i n t h e 
t ot al, m e di al a n d l at er al T F C s i n t h e 
t ar g et k n e e o v er ti m e  
•  
C h a n g e fr o m b a s eli n e i n c artil a g e t hi c k n e s s i n t h e t ot al, 
m e di al a n d l at er al T F C s a s s e s s e d b y q M RI at W e e k s  
 
  
•  
T o e v al u at e t h e pr o p orti o n of p ati e nt s 
wit h str u ct ur al pr o gr e s si o n o v er ti m e i n 
t h e t ar g et k n e e u si n g i m a gi n g 
t e c h ni q u e s  
•  
Pr o p orti o n of p arti ci p a nt s d e m o n str ati n g at W e e k  
 
 str u ct ur al pr o gr e s si o n d efi n e d a s: 
•  c h a n g e a b o v e t h e S D C of c artil a g e t hi c k n e s s b y q M RI  
•  a l o s s of m e di al mi n J S W ≥ 0. 7 0 m m fr o m b a s eli n e b y 
X -r a y 
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N o v arti s  
C o nfi d e nti al  
P a g e 2 3  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
O bj e cti v e( s)  
E n d p oi nt( s)  
•  
T o e v al u at e c h a n g e s i n p erf or m a n c e -
b a s e d p h y si c al f u n cti o n 
a s s e s s m e nt  o v er ti m e  
•  
C h a n g e fr o m b a s eli n e i n p h y si c al f u n cti o n at W e e k s  
 
  
•  4 0 -m et er ( 4 × 1 0 m) f a st -p a c e d w al k t e st  
•  3 0 -s e c o n d c h air st a n d t e st  
•  6 -mi n ut e w al ki n g t e st  
•  
T o e v al u at e c h a n g e s fr o m b a s eli n e i n 
t ot al W O M A C s c or e o v er ti m e 
•  
C h a n g e fr o m b a s eli n e  at  W e e k s
 
 i n: 
•  W O M A C t ot al s c or e  
•  
T o e x pl or e c h a n g e i n di s e a s e 
a cti vit y  o v er ti m e  
•  
C h a n g e fr o m b a s eli n e at  W e e k s
 
 i n O A di s e a s e a cti vit y a s 
a s s e s s e d b y P ati e nt Gl o b al A s s e s s m e nt ( P G A)  
•  
C h a n g e fr o m b a s eli n e at W e e k s 
 
 i n O A di s e a s e a cti vit y a s a s s e s s e d b y P ati e nt 
Gl o b al I m pr e s si o n of S e v erit y ( P GI S)  
•  
O A di s e a s e a cti vit y at W e e k s 
 
 a s a s s e s s e d b y P ati e nt Gl o b al I m pr e s si o n of 
C h a n g e ( P GI C)  
•  
T o a s s e s s c h a n g e i n Q o L u si n g S F -
1 2 v 2  o v er ti m e  
•  
C h a n g e fr o m b a s eli n e at  W e e k s 
 
 i n Q o L u si n g: 
•  
S F- 1 2 v 2 p h y si c al c o m p o n e nt s u m m ar y  
•  
S F- 1 2 v 2 m e nt al c o m p o n e nt s u m m ar y  
•  
T ot al S F -1 2 v 2 s c or e  
•  
T o e x pl or e c h a n g e i n  
 
 a s m e a s ur e d b y  
 
 
•  
 at W e e k s  
 
: 
•  
C h a n g e fr o m b a s eli n e at W e e k s 
 i n t h e 
f oll o wi n g a s s e s s m e nt s: 
•  
 
 
 
 
•  
C h a n g e fr o m b a s eli n e at  W e e k s 
 
 i n t h e f oll o wi n g a s s e s s m e nt s: 
•  
 
 
 
 
 
•  
T o e v al u at e c h a n g e s i n str u ct ur e o v er 
ti m e u si n g X-r a y 
•  
C h a n g e fr o m b a s eli n e t o W e e k s
 
 i n: 
•  
fi x e d-l o c ati o n m e di al J S W m e a s ur e d o n X-r a y 
•  
m e di al mi n J S W m e a s ur e d o n X -r a y 
•  
T o e x pl or e t h e c h a n g e fr o m b a s eli n e  
 
 
 
•  
C h a n g e fr o m b a s eli n e t o 
 
 
•  
T o e x pl or e r e s p o n d er s u si n g t h e 
W O M A C mi ni m al cli ni c all y i m p ort a nt 
diff er e n c e ( M CI D) o v er ti m e  
•  
Pr o p orti o n of p arti ci p a nt s w h o a c hi e v e d W O M A C p ai n 
M CI D 
 
 
•  
Pr o p orti o n of p arti ci p a nt s w h o a c hi e v e d W O M A C f u n cti o n 
M CI D  
 
 
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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 2 4  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
O bj e cti v e( s)  
E n d p oi nt( s)  
•  
T o e x pl or e r e s p o n d er s u si n g t h e 
O M E R A C T -O A R SI r e s p o n d er 
crit eri a  o v er ti m e  
•  
Pr o p orti o n of O M E R A C T -O A R SI r e s p o n d er s at  
 
 
•  
T o e v al u at e 
 
•  
C h a n g e fr o m b a s eli n e 
 
 
•  
T o e x pl or e t h e p h ar m a c o d y n a mi c eff e ct 
o n c artil a g e e xtr a c ell ul ar m atri x 
m et a b oli s m o v er ti m e   
•  
C h a n g e o v er ti m e i n bi o m ar k er l e v el s, i n cl u di n g b ut n ot 
li mit e d t o: 
•  
 
•  
 
•  
 
•  
T o e v al u at e L N A 0 4 3 p h ar m a c o ki n eti c s 
( P K)  
•  
S er u m c o n c e ntr ati o n s of L N A 0 4 3   
•  
T o e v al u at e e n d o g e n o u s 
A N G P T L 3  l e v el s 
•  
S er u m c o n c e ntr ati o n s of A N G P T L 3  
•  
T o e x pl or e  
 p h y si c al a cti vit y a n d 
m o bilit y  b y wri st a cti gr a p h y o v er ti m e  
•  
C h a n g e fr o m b a s eli n e at W e e k s
 
 i n m e a s ur e s of p h y si c al a cti vit y a n d m o bilit y 
p ar a m et er s . 
•  
T o e x pl or e di s e a s e pr o gr e s si o n b y 
m e a n s of T K R  a n d Virt u al K n e e 
R e pl a c e m e nt ( V K R)  
•  
Pr o p orti o n of p arti ci p a nt s wit h t ot al k n e e r e pl a c e m e nt 
( T K R) at W e e k 
 a n d ti m e t o e v e nt  
•  
Pr o p orti o n of p arti ci p a nt s at W e e k s 
 
 f ulfilli n g t h e f oll o wi n g crit eri a f or V K R a s d efi n e d b y: 
W O M A C P ai n ([ 0 -1 0 0] s c al e) + W O M A C F u n cti o n ([ 0 -1 0 0] 
s c al e) ≥ 8 0 p oi nt s f or at l e a st 2 c o n s e c uti v e vi sit s wit h a n d 
wit h o ut r a di o gr a p hi c pr o gr e s si o n, d efi n e d a s l o s s of 
m e di al mi n J S W ≥ 0. 5 0 m m fr o m b a s eli n e 
(M a n n o  et  al  2 0 1 2 ) 
•  
T o p erf or m e x pl or at or y D N A 
a s s e s s m e nt s r el ati n g t o dr u g 
m et a b oli s m, c artil a g e r e p air, dr u g t ar g et 
p at h w a y, or ot h er g e n eti c p at h w a y s o n 
r e s p o n s e ( o pti o n al) 
•  
E x pl or at or y D N A a s s e s s m e nt s  
•  
T o e x pl or e bi o m e c h a ni c al g ait 
p ar a m et er s b y m e a n s of a 
Bi o m e c h a ni c al S e n s or Pl atf or m ( B S P) i n 
a s u b s et of p arti ci p a nt s o v er ti m e 
( o pti o n al, p erf or m e d at s el e ct e d sit e s 
o nl y)  
•  
E x pl or e c h a n g e s o v er ti m e i n g ait p ar a m et er s  
•  
E x pl or e
 
 
 
 
 
•  
 
 
2. 1   
Pri m ar y e sti m a n d s 
T he cli nical q uesti o n of i nterest is: W hat is t he effect of eac h L N A 0 4 3 re gi me n vers us place b o 
o n c ha n ge fr o m baseli ne i n cartila ge t hic k ness i n t he ce ntral me dial ti bi ofe m oral c o m part me nt 
(c M T F C) of t he t ar get k n ee ass esse d b y q M RI at Wee k 1 0 4 i n partici pa nts wit h k nee O A w h o 
are dr u g n ai ve or r ecei vi n g per mitte d c o nc o mita nt t hera p y, ha d partici pa nts ta ke n t he assi g ne d 
treat me nt f or t he e ntir e c ore st u d y d urati o n a n d re gar dless of a d here nce t o t he all o we d peri o d 
of per mitte d c o nc o mita nt t hera p y? 
C CI
C CI
C CI
C CI
C CI
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 2 5  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
T he j ustificati o n f or tar geti n g t his treat me nt effect is t hat we wis h t o esti mate t he effect of t he 
st u d y dr u g f or t he f ull d urati o n w he n a d mi nistere d wit h or wit h o ut t he per mitte d c o nc o mita nt 
t hera p y. 
T he pri mar y esti ma n d is descri be d b y t he f oll o wi n g attri b utes: 
1.  P o p ulati o n: defi ne d t hr o u g h a p pr o priate i n cl usi o n/e xcl usi o n criteria t o reflect t he tar gete d 
O A p o p ulati o n. F urt her d etails a b o ut t he p o p ulati o n are pr o vi d e d i n Secti o n  5. 
2.  Pri mar y varia ble: c h a n ge fr o m baseli ne t o Wee k 1 0 4 i n cartila ge t hic k ness of t he c M T F C 
of t he tar get k n ee.  
3.  Treat me nt of i nter est: t he ra n d o mize d treat me nt ( L N A 0 4 3 re gi me ns or pl ace b o) ta ke n f or 
t he e ntire c ore st u d y d urati o n wit h or wit h o ut t he per mitte d c o nc o mita nt t hera p y. F urt her 
details a b o ut t he i n vesti gati o nal treat me nt a n d c o ntr ol treat me nt are pr o vi de d i n Secti o n  6. 
Ha n dli n g of re mai ni n g i nterc urr e nt e ve nts: 
•  Treat me nt disc o nti n uati o ns/ disr u pti o ns f or a n y reas o n: ha d partici pa nts ta ke n t he assi g ne d 
treat me nt f or t he e ntire c ore st u d y d urati o n ( h y p ot hetical strate g y) 
•  U nf ores ee n n o n- a d her e n ce i n t he all o we d p eri o d of per mitte d c o nc o mita nt t hera pies: 
i g n ore (treat me nt p olic y strate g y) 
T he s u m mar y meas ur e: differe n ce i n varia ble mea ns bet wee n t he treat me nts.  
2. 2   
S e c o n d ar y e sti m a n d s 
P ai n a n d F u n cti o n  
T he cli nical q uesti o ns of i nterest f or sec o n dar y o bj ecti ves pert ai ni n g t o pai n or f u ncti o n are: 
•  W hat is t he eff ect of eac h L N A 0 4 3 re gi me n v ers us place b o o n c h a n ge fr o m baseli ne i n 
O A pai n at Wee k 1 0 4 i n partici pa nts wit h k nee O A w h o are dr u g nai ve or recei vi n g 
per mitte d c o nc o mita nt t hera p y, ha d p artici pa nts ta ke n t he assi g ne d treat me nt f or t he e ntire 
c ore st u d y d ur ati o n a n d a d here d t o t he all o w e d peri o d of per mitte d c o nc o mita nt t hera p y? 
•  W hat is t he eff ect of eac h L N A 0 4 3 re gi me n v ers us place b o o n c h a n ge fr o m baseli ne i n 
f u ncti o n i n t he tar get k nee at Wee k 1 0 4 i n partici p a nts wit h k nee O A w h o are dr u g nai v e 
or recei vi n g per mitte d c o nc o mita nt t hera p y, ha d p artici pa nts ta ke n t he assi g ne d trea t me nt 
f or t he e ntire c or e st u d y d urati o n a n d a d here d t o t he all o we d peri o d of per mitte d 
c o nc o mita nt t hera p y ? 
•  W hat is t he eff ect of eac h L N A 0 4 3 re gi me n v ers us place b o o n c h a n ge fr o m baseli ne i n 
perf or ma n ce - base d p h ysi cal f u ncti o n assess me nt i n t he tar get k nee at Wee k 1 0 4 i n 
partici pa nts wit h k nee O A w h o are dr u g nai ve or recei vi n g per mitte d c o nc o mita nt t hera p y, 
ha d partici pa nts ta k e n t he assi g ne d treat me nt f or t he e ntire c ore st u d y d urati o n a n d 
a d here d t o t he all o we d p eri o d of per mitte d c o n c o mita nt t hera p y? 
T he j ustificati o n f or tar geti n g t his treat me nt effect is t hat we wis h t o esti mate t he effect of t he 
st u d y dr u g f or t he f ull d urati o n w he n a d mi nistere d wit h t he per mitte d c o nc o mita nt t hera p y. 
T he esti ma n d defi niti o n is descri be d b y t he f oll o wi n g attri b utes: 
1.  P o p ulati o n: defi ne d t hr o u g h a p pr o priate i n cl usi o n/e xcl usi o n criteria t o reflect t he tar gete d 
O A p o p ulati o n. F urt her d etails a b o ut t he p o p ulati o n are pr o vi d e d i n Secti o n  5. 

N o v arti s  
C o nfi d e nti al  
P a g e 2 6  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
2.  Varia ble: c h a n ge fr o m baseli ne t o Wee k 1 0 4 i n t he varia ble of i nterest. 
3.  Treat me nt of i nter est: t he ra n d o mize d treat me nt ( L N A 0 4 3 re gi me ns or pl ace b o) ta ke n f or 
t he e ntire c ore st u d y d urati o n wit h t he per mitte d c o nc o mita nt t hera p y. F urt her details 
a b o ut t he i n vesti gati o nal treat me nt a n d c o ntr ol treat me nt are pr o vi de d i n Secti o n  6. 
Ha n dli n g of re mai ni n g i nterc urr e nt e ve nts: 
•  Treat me nt disc o nti n uati o ns/ disr u pti o ns f or a n y reas o n: ha d partici pa nts ta ke n t he assi g ne d 
treat me nt f or t he e ntire c ore st u d y d urati o n ( h y p ot hetical strate g y) 
•  U nf ores ee n n o n- a d her e n ce i n t he all o we d p eri o d of per mitte d c o nc o mita nt t hera pies: ha d 
partici pa nts a d here d t o t h e all o we d peri o d of per mitte d c o nc o mita nt t hera pi es 
( h y p ot hetical strate g y) 
T he s u m mar y meas ur e: differe n ce i n varia ble mea ns bet wee n t he treat me nts.  
Str u ct ur e  
T he cli nical q uesti o ns of i nterest f or sec o n dar y o bj ecti ves pert ai ni n g t o str uct ure are: 
•  W hat is t he eff ect of eac h L N A 0 4 3 re gi me n v ers us place b o o n c h a n ge fr o m baseli ne i n  t he 
t otal, me dial a n d lateral ti bi ofe m oral c o m part me nts ( T F Cs) i n t he tar g et k nee at Wee k 
1 0 4 i n partici pa nts wit h k nee O A w h o are dr u g nai ve or recei vi n g per mitte d c o nc o mi ta nt 
t hera p y, ha d p artici pa nts ta ke n t he assi g ne d treat m e nt f or t he e ntire c ore st u d y d urati o n 
a n d re gar dless of a d her e nce t o t he all o we d p eri o d of per mitte d c o nc o mita nt t hera p y? 
•  W hat is t he eff ect of eac h L N A 0 4 3 re gi me n v ers us place b o o n t he pr o p orti o n of 
partici pa nts de m o nstrati n g str uct ural pr o gressi o n i n t he tar get k nee at Wee k 1 0 4 i n 
partici pa nts wit h k nee O A w h o are dr u g nai ve or recei vi n g per mitte d c o nc o mita nt t hera p y, 
ha d partici pa nts ta k e n t he assi g ne d treat me nt f or t he e ntire c ore st u d y d urati o n a n d 
re gar dl ess of a d here n ce t o t he all o we d peri o d of p er mitte d c o nc o mita nt t hera p y? 
T he j ustificati o n f or tar geti n g t his treat me nt effect is t hat we wis h t o esti mate t he effect of t he 
st u d y dr u g f or t he f ull d urati o n w he n a d mi nistere d wit h or wit h o ut a d here nce t o t he all o w e d 
peri o d of per mitte d c o n c o mita nt t hera p y.  
T he esti ma n d d efi niti o n f or  t he sec o n dar y o bjecti v e relate d t o c h a n ge fr o m baseli ne is d escri be d 
b y t he f oll o wi n g attri b utes: 
1.  P o p ulati o n: defi ne d t hr o u g h a p pr o priate i n cl usi o n/e xcl usi o n criteria t o reflect t he tar gete d 
O A p o p ulati o n. F urt her d etails a b o ut t he p o p ulati o n are pr o vi d e d i n Secti o n  5. 
2.  Varia ble: c h a n ge fr o m baseli ne t o Wee k 1 0 4 i n t he varia ble of i nterest.  
3.  Treat me nt of i nter est: t he ra n d o mize d treat me nt ( L N A 0 4 3 re gi me ns or pl ace b o) ta ke n f or 
t he e ntire c ore st u d y d urati o n wit h or wit h o ut a d here nce t o t he all o we d peri o d of per mitte d  
c o nc o mita nt t hera p y. F urt her details a b o ut t he i n v esti gati o nal treat me nt a n d c o ntr ol 
treat me nt ar e pr o vi de d i n Secti o n  6. 
Ha n dli n g of re mai ni n g i nterc urr e nt e ve nts: 
•  Treat me nt disc o nti n uati o ns/ disr u pti o ns f or a n y reas o n: ha d partici pa nts ta ke n t he assi g ne d 
treat me nt f or t he e ntire c ore st u d y d urati o n ( h y p ot hetical strate g y) 
•  U nf ores ee n n o n- a d her e n ce i n t he all o we d p eri o d of per mitte d c o nc o mita nt t hera pies: 
i g n ore (treat me nt p olic y strate g y) 

N o v arti s  
C o nfi d e nti al  
P a g e 2 7  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
T he s u m mar y meas ur e: differe n ce i n varia ble mea ns bet wee n t he treat me nts.  
T he esti ma n d defi niti o n f or t he sec o n dar y o bjecti ve relate d t o pr o p orti o n is descri be d b y t he 
f oll o wi n g attri b utes: 
1.  P o p ulati o n: defi ne d t hr o u g h a p pr o priate i n cl usi o n/e xcl usi o n criteria t o reflect t he tar gete d 
O A p o p ulati o n. F urt her d etails a b o ut t he p o p ulati o n are pr o vi d e d i n Secti o n  5. 
2.  Varia ble: pr o p orti o n of p artici pa nts de m o nstrati n g str uct ural pr o gressi o n at Wee k 1 0 4 i n 
t he varia ble of i nterest. 
3.  Treat me nt of i nter est: t he ra n d o mize d treat me nt ( L N A 0 4 3 re gi me ns or pl ace b o) ta ke n f or 
t he e ntire c ore st u d y d urati o n wit h or wit h o ut a d here nce t o t he all o we d peri o d of per mitte d 
c o nc o mita nt t hera p y. F urt her details a b o ut t he i n v esti gati o nal treat me nt a n d c o ntr ol 
treat me nt ar e pr o vi de d i n Secti o n  6. 
Ha n dli n g of re mai ni n g i nterc urr e nt e ve nts: 
•  Treat me nt disc o nti n uati o ns/ disr u pti o ns f or a n y reas o n: ha d partici pa nts ta ke n t he assi g ne d 
treat me nt f or t he e ntire c ore st u d y d urati o n ( h y p ot hetical strate g y) 
•  U nf ores ee n n o n- a d her e n ce i n t he all o we d p eri o d of per mitte d c o nc o mita nt t hera pies: 
i g n ore (treat me nt p olic y strate g y) 
T he  s u m mar y  meas ure:  differ e nce  i n  pr o p orti o ns  of  partici p a nts  de m o nstrati n g  str uct ural  
pr o gressi o n bet wee n t he treat me nts. 
3 
St u d y d e si g n  
C L N A 0 4 3 A 1 2 2 0 2  is  a  2 -peri o d,  m ultice nter,  ra n d o mize d,  parallel -gr o u p,  d o u ble - bli n d, 
place b o -c o ntr olle d P hase II b st u d y c o nsisti n g of a 2 -year C ore Peri o d, f oll o we d b y a 3 -y ear 
E xte nsi o n Peri o d ( wit h 2 -year tr eat me nt a n d 1 -year f oll o w -u p) ai mi n g t o assess t he s h ort a n d 
l o n g ter m efficac y, safet y a n d t olera bilit y of m ulti ple i ntra-artic ular re gi me ns of L N A 0 4 3 vers us 
place b o.  O pti o nal  pre -s cree ni n g  ca n  be  c o nsi dere d  (s ee  Secti o n  8. 1. 1 ).  Partici pa nts  wit h  
ra di o gra p hicall y deter mi ne d K-L gra d es 2 or 3 a n d m o deratel y t o se verel y s y m pt o matic k nee 
O A i n t he tar g et k nee as i n dicate d b y  a W O M A C pai n sc ore of 2 0 -4 5 o n a 0 -5 0 scale pri or t o 
i nitiati n g st u d y dr u g will be e nr olle d.  
F oll o wi n g t he si g ni n g of i nf or me d c o nse nt, partici pa nts will be assesse d f or eli gi bilit y d uri n g a 
scree ni n g p eri o d. T he scr ee ni n g peri o d s h o ul d last u p t o 8 wee ks.  
O n Wee k 0 ( Ra n d o mizati o n Visits) of t he C ore Peri o d, eli gi ble partici pa nts will be ra n d o mize d 
t o o ne of t he fi ve treat me nt gr o u ps at a 1: 1: 1: 1: 1 all ocati o n. D uri n g t he e ntire st u d y, partici pa nts 
will recei ve   m L i.a. i njecti o ns of eit her L N A 0 4 3   m g or   m g or place b o ( Fi g ure 3- 1 ). 
A p pr o xi matel y 5 5 0 parti ci pa nts will be ra n d o mize d. 
D uri n g t he C ore Peri o d, all partici pa nts will recei v e i.a. i njecti o ns of L N A 0 4 3 or place b o ( 
 
)  e v er y   
 f or  2  years  (Ta ble  3- 1).  L N A 0 4 3  treat me nt  ar ms  will  recei ve  acti v e  
L N A 0 4 3   m g  
 e ver y  
,   m g  
 e ver y  
,   m g  
 e v er y   
, or   m g  
 e ver y  
 a d mi nistere d i.a. t o t he tar get k nee. Partici pa nts 
ra n d o mize d t o pl ace b o will recei ve i.a. i njecti o ns of sali ne s ol uti o n f or i njecti o n  
 e v er y 
 i n t he C ore Peri o d. At t he e n d of t he C ore Peri o d, partici pa nts will e nter t he E xte nsi o n 
Peri o d. D uri n g t he E xt e nsi o n Peri o d, all partici pa nts will recei ve o ne i.a. i njecti o n of L N A 0 4 3 
C CI
C CI
C CI
C CI
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C CI
C CI
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C CI
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C CI

N o v arti s  
C o nfi d e nti al  
P a g e 2 8  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
or place b o e ver y  
 f or 2 years ( T a ble  3- 1). Partici pa nts w h o recei ve d acti ve L N A 0 4 3 
e ver y 
 i n t he C ore Peri o d will recei ve o ne i njecti o n of t h e s a me d ose of acti ve 
L N A 0 4 3 c orres p o n di n gl y i n t he E xte nsi o n Peri o d (e ver y 6
, res pecti vel y). Place b o 
i njecti o ns will be us e d t hr ou g h o ut t he st u d y i n or d er t o k ee p t he s a me n u m ber of i njecti o ns f or 
all ar ms a n d e ns ur e bli n di n g, base d o n t h e assi g ne d fre q ue n c y of treat me nt. Partici pa nts i n at 
least o ne of t hese f o ur L N A 0 4 3 ar ms ma y be disc o nti n ue d fr o m t he E xte nsi o n Peri o d base d o n 
efficac y a n d s afet y res ults fr o m t he Wee k 1 0 4 pri mar y e n d p oi nt d ata bas e l oc k. Partici pa nts w h o 
recei v e d place b o d uri n g t he C ore Peri o d will c o nti n ue t o recei v e place b o e ver y  
 f or 
t he E xte nsi o n Peri o d. T h e last 1 year of t he E xt e nsi o n Peri o d will be a n o-treat me nt f oll o w- u p 
f or all ar ms.  
Fi g ur e 3- 1 
St u d y D e si g n  
 
T a bl e 3- 1 
S u m m ar y of st u d y p eri o d a n d tr e at m e nt  
S cr e e ni n g  
C or e P eri o d  
E xt e n si o n P eri o d  
8 w e e k s  
1 0 4 w e e k s  
1 0 4 w e e k s  
  
L N A 0 4 3  
 m g i. a.  
 e v er y   
 
L N A 0 4 3  
 m g i. a.  
 e v er y   
 
  
L N A 0 4 3  
 m g i. a.  
 a n d  
 
i. a.  
 e v er y 
 
L N A 0 4 3  
 m g i. a.  
 e v er y   
 
  
L N A 0 4 3  
 m g i. a.  
 
f oll o w e d 
 ( aft er fir st 
i nj e cti o n) b y  
 i. a.  
  
C y cl e e v er y 
 
L N A 0 4 3  
 m g i. a.  
 f oll o w e d  
 
 b y 
 i. a. 
 
C y cl e e v er y  
  
  
L N A 0 4 3  
 m g i. a. 
 
e v er y 
 
L N A 0 4 3  
 m g i. a. 
 
e v er y 
 
  
Pl a c e b o i. a. 
 
e v er y 
 
Pl a c e b o i. a. 
 
e v er y 
 
C CI
C CI
C CI
C CI
C CI
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C CI
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C CI
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N o v arti s  
C o nfi d e nti al  
P a g e 2 9  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
T he pri mar y o bjecti ve will be t o assess t he efficac y of eac h re gi me n of L N A 0 4 3 c o m pare d t o 
place b o at Wee k 1 0 4 as meas ure d b y t he mea n c ha n ge fr o m baseli ne i n cartila ge t hic k ness of 
t he c M T F C  usi n g  q M RI  of  t he  tar get  k nee.  A n  i nteri m  a nal ysis  will  be  c o n d ucte d  w he n  
 
A d diti o nal i nteri m a nal yses ma y be c o n d u cte d. 
I n t he e ve nt a P u blic H ealt h e mer ge nc y as decl are 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 t he c o n d uct of o n -site st u d y visits, 
st u d y treat me nt at h o me ma y be c o nsi dere d. S pecial eff ort s h o ul d be ma d e f or t he E O T/ E O S 
visit. If it is n ot feasi ble t o c o n d uct t he E O T/ E O S visit o n -site, virt ual visits or visits t o t he 
partici pa nt´s h o me mi g ht be c o nsi dere d. 
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 dress es  t he  pri mar y  o bjecti ve  of  cartila g e  re g e nerati o n  a n d  
s u bse q ue nt cli nical be n efit i n partici pa nts wit h m o deratel y t o se v erel y s y m pt o matic ( W O M A C 
Pai n 2 0- 4 5) k nee O A ( K- L 2 - 3) a n d ta k es i nt o acc o u nt (i) t he cli nical nee d f or dr u gs i n halti n g 
O A  disease  pr o gressi o n  a n d  c o ntr olli n g  s y m pt o ms;  (ii)  cli nical  a n d  precli nical  data  o n  
L N A 0 4 3; (iii)  c urre nt pr actice wit h i ntra -artic ular i njecta ble dr u gs;  a n d (i v)  t he b ur de n o n  
partici pa nts wit h k nee O A. 
Acc or di n g  t o  t he  latest  F D A  draft  g ui da n ce  “ Oste oart hritis:  Str uct ural  E n d p oi nts  f or  t he  
De vel o p me nt of Dr u gs, De vices, a n d Bi ol o gical pr o d ucts f or treat me nt” ( C D E R  2 0 1 8), t he 
a bilit y of str uct ural c ha n ges t o pre di ct cli nical b e nefit i n ter ms of i m pr o v e me nt i n pai n a n d 
f u ncti o n has n ot bee n esta blis he d. F or t his reas o n, b ot h str uct ural pr o gressi o n a n d cli nical 
be nefit m ust be assess e d w he n de v el o pi n g a dr u g f or t he treat me nt of O A. T he c urre nt st u d y 
desi g n, w hic h 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(H oc h ber g et al 2 0 1 9, 
), well‑esta blis he d P R Os i n k nee O A 
(C olli ns  et al 2 0 1 1), a n d perf or ma n ce-base d f u n cti o nal assess me nts ( D o bs o n et al 2 0 1 3) will 
e ns ure  a p pr o priate  e val uati o n  of  L N A 0 4 3  effect,  fr o m  b ot h  a  str uct ural  a n d  a  cli nical  
sta n d p oi nt. K nee j oi nt s ur vi val will als o b e ass esse d b y mea ns of virt ual k nee re place me nt 
e n d p oi nt, a s urr o gate o ut c o me f or O A pr o gressi o n ( Ma n n o et al 2 0 1 2), as well as T K R. 
T he parallel desi g n f or t he e ntire st u d y d urati o n e ns ures (i) c o m p aris o n of p ote ntial a d vers e 
e ve nts b y d ose/fr e q ue nc y of a d mi nistrati o n, as well as t he a bilit y t o disti n g uis h A Es fr o m 
pr oce d ur e- r elate d A Es (i ntra-artic ul ar i njecti o ns); a n d (ii) differe nti ati o n fr o m a c o nf o u n di n g 
place b o effect of i.a i njecti o ns o n pai n. T he trial will c o nsist of a scree ni n g peri o d of u p t o 8 
wee ks, a c ore treat me nt  peri o d of 1 0 4 w ee ks, a n e xte nsi o n peri o d c o m p ose d of a 2 -y ear 
mai nte na nce treat me nt a n d a 1 y ear treat me nt -free peri o d t o all o w f or: (i) e val uati o n of b ot h 
artic ular cartila ge h eali n g a n d c o nse q ue ntial cli nical i m pr o ve me nt; (ii) better u n dersta n di n g of 
t he ki netics  of L N A 0 4 3 i n d uce d cartila ge gr o wt h a n d d ura bilit y of t he re ge nerate d tiss ue  
f oll o wi n g re d ucti o n a n d disc o nti n uati o n of treat me nt; a n d (iii) assess me nt of t he safet y a n d 
t olera bilit y of i.a. L N A 0 4 3 (  m g a n d   m g) o v er a p eri o d of 4 years wit h a n a d diti o nal year 
of treat me nt -free f oll o w- u p. 
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N o v arti s  
C o nfi d e nti al  
P a g e 3 0  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
T he st u d y has bee n desi g ne d as partici pa nt - a n d I n v esti gat or - bli n de d i n or der t o re d uce bias 
fr o m b ot h I n vesti gat ors a n d partici pa nts, s o t hat a differe nce bet w ee 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. I n a d diti o n, i n or der t o mai ntai n t h e 
bli n d i.a. L N A 0 4 3 or place b o i njecti o ns will be a d mi nistere d t o kee p t he s a me n u m ber of t otal 
i njecti o ns ( 
 e v er y  
 i n t he C ore Peri o d a n d  
 e ver y  
 f or 2 years i n 
t he E xte nsi o n Peri o d) i n all treat me nt gr o u ps (Fi g ure  3- 1). 
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 his st u d y is ai me d at defi ni n g t he o pti mal d ose re gi me n of i.a. L N A 0 4 3 i n m o deratel y t o 
se verel y s y m pt o matic ( W O M A C Pai n 2 0-4 5) k nee O A ( K -L 2 -3) partici pa nts. T o t his p ur p ose, 
we will test
 
. T he rati o nale f or t hes e o pti o ns is e x plai ne d bel o w. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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N o v arti s  
C o nfi d e nti al  
P a g e 3 1  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
T his 4 -year tr eat me nt  d urati o n ( C ore + E xte nsi o n Peri o d)  is c o nsi dere d necessar y, bas e d o n 
pre vi o us st u dies ( H oc h ber g et al 2 0 1 9), t o pr o vi de e n o u g h ti me t o de m o nstrate b ot h persiste nt 
str uct ure m o dificati o n a n d cli nical be nefit as j ustifie d b y t he sl o w pr o gressi o n of k nee O A. 
I n s u m mar y, 
 
 
 
 
 
Base d o n t hese eff orts, t he o pti mal re gi me n(s) f or t he L N A 0 4 3 P hase III cli nical pr o gra m will 
be esta blis he d.  
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) or 
c o m bi n ati o n dr u g s 
Si nce t here ar e n o a p pr o ve d disease -m o dif yi n g dr u gs f or k n ee O A, place b o (sali ne s ol uti o n) 
i ntra-artic ular i njecti o ns will be use d as a c o ntr ol. Sta n dar d of care treat me nts a n d me dicati o ns 
f or k nee O A pai n are all o we d t hr o u g h o ut t he st u d y, as descri be d i n Secti o n  6. 2. T o mai ntai n 
t he bli n di n g, b ot h t he i ntra-artic ul ar i njecti o ns of acti ve L N A 0 4 3 a n d place b o will be pr o vi de d 
s o t hat eac h ar m of t he st u d y will i ncl u de i njecti o ns o nce  
 f or  
 e ver y   
 f or 2 years d uri n g t he C ore Peri o d (Fi g ure 3- 1 ), t he n o nce e ver y  
 f or 2 years 
d uri n g t he E xte nsi o n Peri o d. T he place b o s ol uti o n will be c o m p ose d of sali ne f or i njecti o n 
pre par e d b y a n u n bli n de d p har macist ( w h o will n ot be i n v ol ve d i n partici pa nt e val uati o n). A 
v ol u me of   m L of L N A 0 4 3 or place b o will be use d  f or eac h i ntra-arti c ular i njecti o n. T he 
place b o will n ot c o ntai n a preser v ati ve as it is t o be use d f or si n gle -d ose a d mi nistrati o n o nl y 
a n d it is i n disti n g uis ha ble fr o m L N A 0 4 3, e ns uri n g bli n di n g of t he I n v esti gat or perf or mi n g t h e 
i.a. i njecti o n. 
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 
T he pri mar y efficac y a n al ysis will be perf or m e d at Wee k 1 0 4 t o assess efficac y a n d safet y 
varia bles. T he fi nal a nal ysis at Wee k 2 6 0 will be p erf or me d as a safet y a n d efficac y f oll o w - u p 
assess me nt.
 
 
 
 
4. 5   
Ri s k s a n d b e n efit s 
Base d o n precli nical data a n d a vaila ble cli nical dat a fr o m t he c o m plete d a n d o n g oi n g st u dies, a 
cartila ge a n a b olic effect res ulti n g i n re ge nerati o n of t he artic ular cartila ge is e x pecte d i n k nee 
O A partici pa nts. Bas e d o n t he p ositi ve res ults fr o m earl y p has e st u dies, a disease m o dif yi n g 
effect is a ntici pate d, alt h o u g h t o be c o nfir me d i n t he k nee O A K- L 2 - 3 p o p ulati o n. T he o verall 
ris k t o k nee O A partici p a nts i n t his st u d y is e x pecte d t o be l o w d u e t o t he s afet y pr ofile o bser ve d 
i n c o m plete d cli nical trials. T his ris k will be mi ni mize d b y a d here nce t o t he i ncl usi o n/e xcl usi o n 
criteria, cl ose cli nical m o nit ori n g, selecti o n of I n vesti gat ors wit h e x perie n ce i n i.a. i njecti o ns, 
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N o v arti s  
C o nfi d e nti al  
P a g e 3 2  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
a n d safet y r e vie ws p erf or me d at least o nce e ver y 6 m o nt hs b y a n i n de pe n de nt Data M o nit ori n g 
C o m mittee ( D M C).  
T he o ver all ris k/ be nefit assess me nt of L N A 0 4 3 is s u p p orti ve of t h e c o n d uct of t his P hase II b 
st u d y i n k nee O A partici pa nts. 
A m ore detaile d descri pti o n of p ote ntial ris ks relate d t o t he i.a. a d mi nistrati o n of L N A 0 4 3, a n d 
relate d miti gati o n strate gies are r e p orte d b el o w. 
I n v asi ve, st u d y-s pecific pr oce d ur es 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. 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 o cc ur b ot h at t h e i njecti o n site a n d 
wit hi n t he j oi nt s pace.  Rece nt  r e p orts f o u n d i nfecti o n rates f oll o wi n g i.a. i njecti o n of ster oi ds 
bet wee n  1  i n 3, 0 0 0  a n d  1  i n 5 0, 0 0 0  ( La v elle  et  al 2 0 0 7).  H o w e ver,  fe w  ort h o pe dists  a n d  
r he u mat ol o gists ha ve see n a cas e of p ost-ster oi d s e ptic art hritis (C harala m b o us et al 2 0 0 3). I n 
a d diti o n, w he n pr o per tec h ni q ue is a p plie d i n a h ealt h y p o p ulati o n, a n d w he n a n o n -ster oi d al 
dr u g is use d, t his rate is c o nsi dera bl y l o wer. Ase pti c  tec h ni q ue will be use d i n all p hases of  
 
 a d mi nistrati o n t o f urt her pre ve nt t he a b o v e-me nti o ne d ris ks. L ocal reacti o ns 
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, o nl y if e n o u g h s y n o vial fl ui d is prese nt i n t he j oi nt as j u d ge d b y t he 
I n v esti gat or, wit h n o a d diti o nal har m or disc o mf ort f or t he partici pa nt. 
 
 
 
Base d o n a c o m pre he nsi ve a n al 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 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 ncr eases t he ris k of h y pers e nsiti vit y i n h u ma ns. N o dr u g -relate d seri o us a d vers e 
e ve nts ( S A E) ha v e bee n r e p orte d t o date. 
T o miti gate t he p ossi ble ris k of 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 will be e xcl u de d fr o m 
partici pati o n i n t his st u d y ( Secti o n  5. 2), partici pa nts w h o e x perie nce a n y gra de h y pers e nsiti vit y 
reacti o n t o st u d y tr eat me nt 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 saf et y re vie w if t w o ( 2) or m ore p artici pa nts de vel o p a n ac ut e 
aller gic reacti o n of Gr a de 3 se verit y or greater, or o ne or m ore partici p a nts wit h life-t hreate ni n g 
( Gra d e 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 5. 0 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). E ve nts of h y pers e nsiti vit y reacti o ns will als o be 
re vie we d b y a n i n de pe n d e nt D M C. 
N o partici pa nt de vel o pe d A D A after a si n gle i.a. i njecti o n of u p t o   m g L N A 0 4 3 n or u p o n 
f o ur wee kl y i.a. i njecti o ns of   m g 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 ser i o us effects. 
De vel o p me nt of a nti -L N A 0 4 3 a nti b o dies as w ell as a n y p ote ntial reacti o ns relate d t o s uc h 
a nti b o dies 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. 
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N o v arti s  
C o nfi d e nti al  
P a g e 3 3  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
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 h e f et us if pr e g na nc y w ere t o occ ur d uri n g t he st u d y, a n d a gree t h at i n or d er 
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  a n d  pre g na nc y  testi n g  
re q uire me nt f or t he d urati o n of t he st u d y. If t h ere is a n y q uesti o n t hat t he p artici 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 i n t he st u d y 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 ncreas e  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 p er mea bilit y b y i n d uci n g F -acti n rearra n g e me nt w hi c 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 m a n a n gi o p oieti n -li ke 
pr otei n 3 ( A N G P T L 3), c o m prisi n g t he maj or p art 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, partici pa 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.  
W hile t here is n o i n dicati o n of he pat ot o xicit y or re nal t o xicit y fr o m pre -cli nical or cli nical 
st u dies c o n d ucte d t o d ate, partici pa nts wit h cli nicall y si g nifica nt li ver disease or li ver i nj ur y, or 
partici pa nts wit h m o der ate t o se vere re n al i m pair me nt (esti mate d gl o mer ular filtrati o n rat e 
( G F R) < 5 0 m L/ mi n/ 1. 7 3 m2 b y t he C K D -E PI f or m ula) are e x cl u de d fr o m t his 5 -year st u d y d u e 
t o t he p o or pr o g n osis a n d life e x pect a nc y ass o ciate d wit h t hese c o n diti o ns. 
M ore detaile d i nf or mati o n is a vaila ble i n t he c urre nt I B.  
T here ma y b e u n k n o w n ris ks of L N A 0 4 3 w hic h m a y be seri o us. 
Ri s k s of i m a gi n g pr o c e d ur e s  
A p oster oa nt eri or vi e w X -ra y of t h e tar g et 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 p er partici pa nt fr o m t hese X -ra ys will be a b o ut 1 5 0 µ S v i n 5 years. 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 " mi ni mal". Yearl y bac k gr o u n d ra di ati o n is 
ar o u n d 3 m S v ( 2. 7 m S v base d o n U K g ui da nce) w hic h is  m ore t ha n 6 5 ti mes hi g her t ha n t he 1st 
st u d y year e x p os ure ( 4 5 µ S v) or 2 0 ti mes hi g her t ha n t otal st u d y e x p os ure ( 1 5 0 µ S v i n 5 years). 
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 partici p a nts a n d t o m o nit or disease pr o gressi o n. 
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. N o M RI 
c o ntrast a ge nt will be a d mi nistere d i n t his st u d y. T h us, i n pri nci ple, M RI s ca ns ca n be re peat e d 
i n t he sa me partici pa nt as ofte n as necess ar 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 us ce pti ble pers o ns. T he pres e nce of metal i n t he b o d y ma y als o be a safet y 
hazar d or affect M RI i ma ge q ualit y.   
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 
D uri n g a P u blic Healt h e mer ge nc y as decl are 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 ur al disaster, miti gati o n pr oce d ures t o e ns ure partici p a nt safet y a n d trial i nte grit y 
are liste d i n rele va nt secti o ns. N otificati o n of t he p u blic healt h e mer ge n c y as declare d b y l ocal 
or re gi o nal a ut h orities s h o ul d be disc usse d a m o n g i n vesti gat ors a n d N o v artis. All pr oce d ures 

N o v arti s  
C o nfi d e nti al  
P a g e 3 4  of 1 0 8  
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Pr ot o c ol  N o. C L N A 0 4 3 A 1 2 2 0 2  
 
a da pte d t o t he sit uati o n m ust be s u b mitte d, if re q uire d as per l ocal re g ulati o ns, t hr o u g h a 
pr ot oc ol  a me n d me nt  f or  a p pr o val  b y  l ocal  or  re gi o nal  Healt h  A ut h orities  a n d  Et hics  
C o m mittees pri or t o i m ple me ntati o n of miti gati o n pr oce d ures .  
5 
St u d y P o p ul ati o n  
T he st u d y p o p ulati o n will be c o m prise d of male a n d fe male partici pa nts 4 0 t o 7 5 years ol d wit h 
pre d o mi na ntl y u nilateral me dial ra di o gra p hic K -L gra de 2 -3 k nee oste o art hritis a n d m o derate 
t o se vere p ai n i n t he tar g et k nee ( W O M A C Pai n of 2 0-4 5 o ut of 5 0  o n n o me dicati o n or aft er 
pai n  me dicati o n  was h o ut)  i n  t he  tar get  k nee  d uri n g  t he  scree ni n g  peri o d.  A  t otal  of  
a p pr o xi matel y 5 5 0 partici pa nts will be ra n d o mize d. Partici pa nt selecti o n is t o be esta blis he d b y 
a p pl yi n g all eli gi bilit y criteria at Scree ni n g Visits  1 a n d 2. A  rele va nt rec or d (e. g., c h ec klist) of 
t he eli gi bilit y criteria m ust be st ore d wit h t he s o urce d oc u me nt ati o n at t he st u d y site. 
De viati o n fr o m a n y e ntr y criteri o n e x cl u des a partici pa nt fr o m ra n d o mizati o n i nt o t he st u d y. 
Partici pa nts  faili n g  d uri n g  t he  scree ni n g  peri o d  ma y  be  eli gi ble  f or  rescree ni n g  as  per  
i nstr ucti o ns i n Secti o n  8. 1 . 
Partici pa nts w h o are r a n d o mize d a n d fail t o start treat me nt, e. g., partici p a nts ra n d o mize d i n 
err or, will be c o nsi dere d as mis-ra n d o mize d. 
Partici pa nts w h o ha ve b ee n ra n d o mize d o n ce ca n n ot be scree ne d or ra n d o mize d a gai n. 
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  t he f oll o wi n g criteria: 
1.  Partici pa nt m ust be a bl e t o u n dersta n d a n d c o m m u nicate wit h t he I n vesti gat or, c o m pl y wit h 
t he re q uire me nts of t he st u d y, a n d m ust gi ve a writte n, si g ne d a n d date d i nf or me d c o nse nt 
bef ore a n y st u d y assess m e nt is perf or me d. 
2.  Males a n d fe m ales bet w ee n 4 0 a n d 7 5 years of a ge. 
3.  B o d y mass i n de x ( B MI) < 4 0 k g/ m 2 at Scree ni n g Visit 1.  
4.  Dia g n osis of pri mar y ti bi ofe m oral k nee O A i n t h e tar get k nee 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  criteri a  ( Secti o n  1 6. 3)  at  Scree ni n g  
Visits.  
5.  Ra di o gra p hic  disease  K -L  gra de  2  or  3  k nee  O A  wit h  a  pre d o mi na ntl y  me dial  T F C  
i n v ol ve me nt defi ne d as me dial J oi nt S pace Narr o wi n g ( me dJ S N) 1-2 a n d me dJ S N >  lateral 
J oi nt S pace Narr o wi n g (l atJ S N) i n t he tar get k nee at Scree ni n g Visit 1. 
6.  Partici pa nts wit h W O M A C Pai n of 2 0 -4 5 ( o ut of 5 0) f or t he tar get k nee at b ot h ( d o u ble 
baseli ne) assess me nts d uri n g scree ni n g peri o d after dis c o nti n uati o n of a nal gesics, a nti -
i nfla m mat ories a n d l o w p ote nc y o pi oi ds wit hi n 4 8 h o urs or a n e q ui vale nt of 5 × T1/ 2 was h 
o ut peri o d ( w hic he v er is l o n ger).  
7.  S y m pt o matic O A wit h pai n i n t he tar get k nee f or at least 6 m o nt hs pri or t o Scree ni n g Visit 
1. 
8.  Pri mar y s o urce of pai n t hr o u g h o ut b o d y is d ue t o O A i n t h e tar g et k nee: Wi des prea d Pai n 
I n d e x ( W PI) sc or e of ≤6 a n d a S y m pt o m Se verit y sc ore ( S S sc ore) of < 7 at Scree ni n g Visit 
2. 

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9.  Partici pa nts wit h de pressi o n or a n xiet y m ust be cli nicall y sta ble f or 1 2 wee ks pri or t o 
scree ni n g, a n d, if o n treat me nt f or de pressi o n or a n xiet y, be o n 1 2 wee ks of sta ble t hera p y. 
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 criteri a are n ot eli gi ble f or i ncl usi o n i n t his st u d y: 
1.  Ra di o gra p hic k nee O A K- L = 4 o n t he n o n- tar get k nee at Scree ni n g Visit 1.  
2.  W O M A C Pai n > 1 5 ( o ut of 5 0) i n t he n o n- tar g et k nee at Scree ni n g Visit 2. 
3.  Se vere malali g n me nt ( > 7. 5° var us or  val g us) i n t he a nat o mical a xis of t he tar get k nee, 
meas ure d usi n g X- ra y at Scree ni n g Visit 1. 
4.  Cli nical si g ns of m o derate -se v ere i nfla m mati o n (i.e., re d ness, w ar mt h, eff usi o n) of t he 
tar get k nee or cli nicall y re q uiri n g as pirati o n i n t he tar g et k nee wit hi n 1 2 wee ks pri or t o 
Scree ni n g Visit 1 or d uri n g t he scree ni n g peri o d. 
5.  Art hr osc o p y of t he tar get k nee wit hi n t he 6 m o nt hs pri or t o Scree ni n g Visit 1 or pla n ne d 
d uri n g t he st u d y. 
6.  Pre vi o us  s ur gical  treat me nt  of  t he  tar get  k nee  usi n g  m osaic plast y,  micr ofract ure,  
me niscect o m y > 5 0 % or oste ot o m y; partial or c o m plete j oi nt re place me nt f or eit her k nee; 
pla n ne d k nee s ur ger y f or eit her k nee d uri n g t he st u d y. 
7.  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. 
8.  Ot her pat h ol o gies affecti n g t he k nee, i n cl u di n g s u bc h o n dral i ns uffi cie nc y fract ures, b o n e 
fract ur e  (ac ute  or  s u bac ute  i n  less  t ha n  6  m o nt hs  pri or  t o  scree ni n g)  or  b o ne  br uise,  
oste o necr osis,  mali g na nt  b o ne  marr o w  i nfiltrati o n,  s oli d  t u m ors,  a n d/ or  patell of e m oral 
d ys plasia base d o n cli nical assess me nt, or i ma gi n g. 
9.  S y m pt o matic ( m o derate -se vere pai n o n m ost da ys) hi p O A o n eit her hi p at Scree ni n g Visit 
1 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 Visit 1) or f oresee n 
wit hi n t he st u d y peri o d (eit her hi p). 
1 0.  Ot her pai n c o n diti o ns t hat c o ul d c o nf o u n d ass ess me nts of t he pai n ass ociate d wit h k nee O A, 
as j u d ge d b y t he I n vesti g at or: 
•  Dia g n osis of a s yste mic disease t hat ma y affect j oi nts  
•  Ne ur o pat hic dis or d ers 
•  Pa get’s disease aff ecti n g t he k nees  
•  Re gi o nal pai n ca use d b y l u m bar c o m pressi o n wit h ra dic ul o pat h y 
•  A n y ot her pai n c o n diti o n t hat c o ul d c o nf o u n d t he efficac y ass ess me nts 
1 1.  I n a bilit y t o u n der g o M RI (e. g., cla ustr o p h o bi a, b o d y size, le g n ot fitti n g i n t he c oil) or 
c o ntrai n dicati o ns t o M RI ( e. g., n o n M RI -c o m pati ble metallic i m pla nts, metallic f orei g n 
b o dies, pace ma k er, d efi brillat or).  
1 2.  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 d eficie nc y, etc.) or 
me dical c o n diti o n re q uiri n g a ntic oa g ulati o n w hic h w o ul d precl u d e k nee i njecti o n. N ote: 
A ntic oa g ula nt  ma na ge m e nt  is  all o we d  as  per  l ocal  practice,  h o we v er,  patie nts  t a ki n g 
c o u mari ns (e. g., w arf ari n) m ust ha ve I N R < 3 bef ore t he st u d y dr u g i njecti o n. L o w - d ose 
as piri n  is  all o we d.  S us pe nsi o n  of  n o vel  oral  a ntic oa g ula nts  ( N O A Cs;  e. g.,  a pi xa ba n,  

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da bi gatra n, ri var o x a ba n, a n d e d o x a 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 ysicia n, base d o n l ocal prescri bi n g i nf or mati o n. 
1 3.  K n o w n a ut oi m m u ne disease wit h i nfla m mat or y art hriti des (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,  s yste mic  l u p us  
er yt he mat os us), cr ystal -i n d uce d art hriti des ( g o ut, pse u d o g o ut ass o ciate d art hritis), active 
ac ute or c hr o nic i nf ecti o n or past i nfecti o n of t h e k nee j oi nt, reacti ve art hritis, s yste mic 
cartila ge dis or d ers, or a k n o w n s yste mic c o n necti v e tiss ue disease.  
1 4.  Meta b olic or ge n etic a b n or malities ass ociate d wit h art hr o pat h y.  
1 5.  Hist or y of l y m p h o pr oliferati ve diseas e 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 x ce pt f or bas al 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 n ce i n t he past 3 m o nt hs, 
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), r e gar dless of w het her t here is e vi de n ce of l ocal rec urre nce or m etastases. 
1 6.  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 e x ci pie nts or t o dr u gs of si milar 
classes.  
1 7.  Dr u g or alc o h ol a b us e us e wit hi n t he 1 2 m o nt hs pri or t o t he st u d y dr u g a d mi nistrati o n, or 
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 ni a, or sc hiz o affecti ve dis or der.  
1 8.  A n y k n o w n acti ve i nfecti o ns, i ncl u di n g i nfecti o n of s ki n at t he i njecti o n site, or k nee 
i nfecti o ns or i nf ecti o ns t hat ma y c o m pr o mise t he i m m u ne s yste m s uc h as HI V or c hr o ni c 
he patitis B or C i nfecti o n.  
1 9.  Partici pa nts wit h w o u n ds at t he i n vesti gati o nal pr o d uct a d mi nistrati o n site. 
2 0.  Hist or y  or  c urr e nt  dia g n osis  of  electr ocar di o gra m  ( E C G)  a b n or malities:  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 di a,  a n d  
cli nicall y si g nifica nt sec o n d or t hir d de gree atri o ve ntric ular bl oc k wit h o ut a pace ma k er, 
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 de d e P oi ntes. 
2 1.  Hist or y or c urre nt cli nicall y si g nifica nt li ver disease or li ver i nj ur y as i n dicate d b y a b n or mal 
li ver f u ncti o n tests s uc h as S G O T ( A S T), S G P T ( A L T), al kali ne p h os p h atase, or s er u m 
bilir u bi n. T he I n v esti gat or s h o ul d be g ui de d b y t he f oll o wi n g criteria: 
•  A n y si n gle para met er m a y n ot e xcee d 2 × u p p er li mit of n or mal ( U L N). A si n gle 
para meter ele vate d u p t o a n d i ncl u di n g 2 × U L N s h o ul d be re -c hec ke d o n ce m ore as 
s o o n as p ossi ble, a n d i n all cases, at least pri or t o e nr oll me nt/ra n d o mizati o n, t o r ule o ut 
la b error 
2 2.  Ne p hr otic  s y n dr o me  a n d/ or  si g nifica nt  pr otei n uria  ( ≥ 3 +  at  uri nal ysis  test  or  pr otei n -
creati ni ne rati o ≥ 1 g/ g Cr). 
2 3.  M o derate t o se vere re nal i m pair me nt (esti mate d G F R < 5 0 m L/ mi n/ 1. 7 3  m2 b y t he C K D -
E PI f or m ula).  
2 4.  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. 
2 5.  Use  of  electr ot h era p y,  tra diti o nal  C hi nese  m e dici ne  (i n cl u di n g  b ut  n ot  li mite d  t o  
ac u p u nct ur e, massa g e, h er bs) a n d/ or c hir o practic treat me nts f or k nee O A pai n wit hi n 4 
wee ks pri or t o Scr ee ni n g Visit 1 a n d d uri n g Scree ni n g peri o d. 
2 6.  Use of t he f oll o wi n g me dicati o ns is pr o hi bite d: 

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•  Wit hi n 2 6 wee ks pri or t o d o u ble baseli ne assess me nt of W O M A C Pai n, l ocal i.a. 
treat me nt i nt o t he t ar get k nee, i ncl u di n g b ut n ot restricte d t o l o n g-acti n g c ortic oster oi ds 
(e. g., Zilrett a ® ), platelet-ric h plas ma ( P R P) a n d ste m cell t hera pies  
•  Wit hi n 1 2 wee ks pri or t o d o u ble bas eli ne assess m e nt of W O M A C Pai n, hi g h p ote nc y 
o pi oi ds (e. g., met ha d o ne, h y dr o m or p h o ne, m or p hi ne, o x yc o d o ne), c ortic oster oi d use 
b y a n y r o ute (e xce pt t o pical, i n hale d a n d i. a. i nj ecti o n i n ot her n o n -k n ee j oi nts), i.a 
visc os u p ple me ntati o n (e. g., h yal ur o na ns) i n t he tar get k nee, ce ntrall y acti n g a nal gesics 
(e. g., d ul o xeti ne) u nless o n a sta ble d ose f or at least 1 2 wee ks, a ntic o n v ulsa nts u nless 
use d f or seiz ure a n d o n a sta ble d ose f or at least 1 2 wee ks  
•  Wit hi n 4 8 h o urs or 5 × T
1/ 2 ( w hic he ver is l o n g er) pri or t o eac h of t he W O M A C Pai n 
assess me nts d uri n g scree ni n g peri o d, N S AI Ds b y a n y r o ute, as piri n ( great er t ha n 1 0 0 
m g/ da y), par acet a m ol/aceta mi n o p he n, l o w p ote n c y o pi oi ds (e. g., tra ma d ol), C O X -2 
i n hi bit ors 
•  Wit hi n 4 wee ks pri or t o eac h of t he W O M A C Pai n assess me nts d uri n g scree ni n g 
peri o d,  oral  gl uc osa mi n e,  c h o n dr oiti n  s ulfate,  or  a n y  n utrace utical  wit h  p ote ntial  
acti vit y o n t he artic ular cartila ge, u nless sta ble f or at least 4 wee ks   
2 7.  W o me n w h o ha ve a p ositi ve pre g na nc y res ult pri or t o i nitiati o n of st u d y dr u g, or are 
pre g na nt or lactati n g. 
2 8.  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 d uri n g 
d osi n g of i n vesti gati o nal dr u g a n d f or 1 5 da ys aft er st o p pi n g me dicati o n. 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 ( 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 
•  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 b al 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 cas e 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 v e 
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 ass ess me nt 
•  Male sterilizati o n (at least 6 m o nt hs pri or t o scree ni n g). F or fe mal e 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 p artici pa nt 
•  Use of oral, ( estr o ge n a n d pr o gester o n e), 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 ot h er f or ms of h or m o nal c o ntrace pti o n t hat ha v e c o m para ble efficac y 
(fail ure  rate  < 1 %),  f or  e xa m ple  h or m o ne  v a gi nal  ri n g  or  tra ns der m al  h or m o ne  
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)  
I n case of use of oral c o ntrace pti o n w o me n s h o ul d ha ve bee n 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. 
W o me n  are  c o nsi der e 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 cas e of 
o o p h orect o m y al o ne, o nl y w he n t he re pr o d u cti ve stat us of t he w o ma n has bee n c o nfir m e d 

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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. If 
l ocal re g ul ati o ns de viate fr o m t he c o ntrace pti o n m et h o ds liste d a b o ve t o pre ve nt pre g n a nc y, 
l ocal re g ulati o ns a p pl y a n d will be descri be d i n t h e I C F.  
2 9.  A n y s ur gical, me dical, ps yc hiatric or a d diti o nal p h ysical c o n diti o n t hat t he I n vesti gat or feels 
ma y p ote ntiall y je o par dize t he partici pa nt d uri n g t he st u d y or c o ul d i nterfere wit h t he st u d y 
o bjecti ves, c o n d uct or e v al uati o n. 
3 0.  A n y si g nifica nt c hr o ni c c o n diti o n t hat has n ot bee n w ell -c o ntr olle d f or a mi ni m u m of 3 
m o nt hs e. g. - U nc o ntr oll e d h y perte nsi o n, dia bet es or c hr o nic h eart fail ure ( p atie nts wit h 
Ne w Y or k Heart Ass ociati o n stat us of class III or I V), or p o or f u ncti o nal stat us u na ble t o 
perf or m self -care.  
3 1.  V ul nera ble partici pa nts, e. g., partici pa nts ke pt i n dete nti o n, s ol diers, a n d e m pl o yees of t he 
s p o ns or or a cli nical r esearc h or g a nizati o n i n v ol ve d i n t his st u d y. 
3 2.  Use of ot her i n vesti gati o nal dr u gs wit hi n 5 half -li ves of e nr oll me nt, or u ntil t he e x pecte d 
p har mac o d y n a mic effect has ret ur ne d t o b aseli ne, w hic he ver is l o n ger. 
3 3.  Pre vi o us partici pati o n i n t he treat me nt ar m of a n ot her L N A 0 4 3 tri al. 
6 
Tr e at m e nt  
6. 1   
St u d y tr e at m e nt 
6. 1. 1  
I n v e sti g ati o n al a n d c o ntr ol dr u g s 
N o vartis will s u p pl y o pe n -la bel L N A 0 4 3   m g 
, w hic h will be use d as t h e 
i n vesti gati o nal  dr u g.
 
. Sali ne s ol uti o n, pr o vi de d l ocall y b y t he site, will be use d as 
place b o a n d f or dil uti o n of L N A 0 4 3 s ol uti o n. 
 sali ne use d f or st u d y 
treat me nt pr e par ati o n s h o ul d be f or t he st u d y us e o nl y a n d dis pe ns ati o n of  
 sali ne 
s h o ul d be rec or de d i n P har mac y Dr u g Acc o u nta bilit y L o g. 
T he v ol u me of t he i.a. i njecti o n will be fi xe d at   m L f or b ot h L N A 0 4 3 a n d place b o (sali ne) 
a n d pre pare d b y t he u n bli n de d p har macist ( or d el e gate d u n bli n de d a n d q u alifie d site staff) t o 
reac h t h e fi nal d ose of L N A 0 4 3 or place b o t o be deli vere d. 
Pre pare d s yri n ges wit h t he I R T assi g ne d st u d y treat me nt ( L N A 0 4 3   m g,   m g or place b o) 
will be pr o vi de d t o bli n de d staff b y t he u n bli n de d p har macist/ dele gat e f or i.a. i njecti o n at eac h 
visit. A d oc u me nt wit h t he partici pa nt n u m ber a n d details o n t he pre parati o n ( wit h o ut discl osi n g 
a n y u n bli n di n g i nf or mati o n) e. g., dat e/ti me/c o n diti o n of t he me dicati o n will d oc u me nt t he 
tra nsfer. 
Details o n t he r e q uire me nts f or st or a ge a n d m a 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 prescri bi n g/ dis pe nsi n g b y u n bli n de d p har macists are o utli ne d i n t he P har mac y 
Ma n ual. Details o n t he re q uire me nts f or i.a. i njecti o n of st u d y treat me nt b y bli n de d I n vesti gat or 
are o utli ne d i n t he Dir ecti o ns f or Use of St u d y Treat me nt. 
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N o v arti s  
C o nfi d e nti al  
P a g e 3 9  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
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  
S u p pl y T y p e  
S p o n s or ( gl o b al 
or l o c al)  
L N A 0 4 3  
 m g  
 
I ntr a-arti c ul ar u s e  
O p e n l a b el s u p pl y; 
 
N o v arti s P h ar m a 
A G  
Pl a c e b o  
S ali n e s ol uti o n  
I ntr a-arti c ul ar u s e  
N ot s u p pli e d b y 
S p o n s or  
  
6. 1. 2  
A d diti o n al st u d y tr e at m e nt s  
N o ot her treat me nt be y o n d i n vesti gati o nal dr u g is i ncl u de d i n t his trial. 
6. 1. 3  
Tr e at m e nt ar m s/ gr o u p  
I n t he C or e Peri o d, partici pa nts will be assi g ne d t o o ne of t he f oll o wi n g 5 treat me nt ar ms/ gr o u ps 
i n a rati o of 1: 1: 1: 1: 1: 
•  L N A 0 4 3   m g  
 , C ycle e ver y  
 
•  L N A 0 4 3   m g   a n d 
, C ycle e v er y  
 
•  L N A 0 4 3   m g  
 f oll o we d  
 later (after first i njecti o n) b y 
 
, C ycle e ver y  
  
•  L N A 0 4 3   m g  
 , C ycle e ver y  
 
•  Place b o  
 , C y cle e ver y 6 
 
D uri n g t he first t w o years of t he E xt e nsi o n Peri o d, partici pa nts assi g ne d t o eit her of L N A 0 4 3 
 m g or   m g e ver y  
 c ycle ar ms i n C ore Peri o d will tra nsiti o n t o a si n gle i njecti o n 
e ver y  
 of t he s a me d ose of L N A 0 4 3 as i n C ore Peri o d). Parti ci pa nts assi g ne d t o 
L N A 0 4 3   m g  
 e v er y  
 c y cle ar m i n C ore Peri o d will recei ve L N A 0 4 3   m g 
e ver y  
 a n d  
 e ver y ot her  
. Partici pa nts w h o recei ve d place b o d uri n g 
t he C ore Peri o d will c o nti n ue t o recei ve place b o e ver y  
 f or t he E xte nsi o n Peri o d. O ne 
or m ore L N A 0 4 3 ar ms ma y be disc o nti n ue d fr o m t he E xte nsi o n Peri o d base d o n effi cac y a n d 
safet y res ults fr o m t he Wee k 1 0 4 pri mar y e n d p oi nt data base l oc k, a n d partici pa nts i n t he 
disc o nti n ue d ar m(s) will be f oll o we d -u p f or at least 6 m o nt hs. T he last 1 year of t he E xte nsi o n 
Peri o d will be a treat me nt -free f oll o w- u p. 
I n eac h c ycle i n t he C or e Peri o d, i nter vals of c o ns ec uti ve st u d y treat me nt i njecti o ns s h o ul d be 
. After c o m pleti o n of t he first c ycle ( Wee k   t o Wee k  ), t he date of first st u d y 
treat me nt i n eac h c ycle s h o ul d be calc ulate d base d o n t he Wee k 0 (ra n d o mizati o n visit) date, 
a n d it ca n b e   w ee ks fr o m t he calc ulate d date; e. g. Wee k 2 6 date s h o ul d b e deter mi ne d as 2 6 
wee ks after t he Wee k 0 visit date, a n d st u d y treat me nt at Wee k 2 6 s h o ul d be bet w ee n 2 6 a n d 
3 0 wee ks aft er t he Wee k 0 date. I n t he E xte nsi o n Peri o d (
 c y cles) t he date of t he 
st u d y treat me nt s h o ul d als o be calc ulat e d base d o n t he Wee k 0 (ra n d o mizati o n visit) date, a n d 
it ca n be   w ee ks fr o m t he calc ul ate d date. 
6. 1. 4  
Tr e at m e nt d ur ati o n  
T he pla n ne d d ur ati o n of t he C ore Peri o d is 2 years f oll o we d b y t he E xte nsi o n Peri o d of 3 years 
( 2-year treat me nt a n d 1 -y ear f oll o w -u p), f or a t otal of 5 years. Partici pa nts ma y be disc o nti n ue d 
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N o v arti s  
C o nfi d e nti al  
P a g e 4 0  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
fr o m treat me nt earlier d ue t o u nacce pta ble t o xicit y, disease pr o gressi o n a n d/ or at t he discreti o n 
of t he I n vesti gat or or t h e partici pa nt.  
6. 2   
Ot h er tr e at m e nt( s) 
N o a d diti o nal treat me nt be y o n d i n vesti gati o nal dr u g is pr o vi de d i n t his trial. 
6. 2. 1  
C o n c o mit a nt t h er a p y  
All me dicati o ns, pr oce d ures, a n d si g nifica nt n o n -dr u g t hera pies (i ncl u di n g b ut n ot li mite d t o 
p h ysical t hera p y, diet f or wei g ht l oss, i ns ole we d g es a n d bl o o d tra nsf usi o ns) a d mi nistere d after 
t he partici pa nt was e nr olle d i nt o t he st u d y m ust be rec or de d o n the a p pr o priate Case Re p ort 
F or ms.  
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  
partici pa nt or all o wi n g a ne w me dicati o n t o be starte d. If t he partici pa nt is alrea d y e nr olle d 
w he n a pr o hi bite d me dicati o n is use d, t he I n vesti gat or s h o ul d c o ntact N o v artis 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. 
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  
Partici pa nts u n der g oi n g p h ysical or occ u pati o nal t hera p y (e. g., diet f or wei g ht l oss, i ns ole 
we d ges)
 a n d/ or
 t a ki n g
 N S AI Ds,
 C O X -2
 i n hi bit ors,
 l o w
 p ote nc y
 o pi oi ds
 or
 
paraceta m ol/aceta mi n o p he n ca n c o nti n ue t o d o s o i n t he st u d y as l o n g as t he y are o n a sta bl e  
re gi me n i n t he o pi ni o n of t he I n vesti gat or f or at least 4 wee ks pri or t o scree ni n g. Partici pa nts 
ca n c o nti n ue ta ki n g t hese me dicati o ns d uri n g t he trial b ut will nee d t o te m p oraril y wit h dra w 
pri or t o W O M A C assess me nts, as des cri be d i n S ecti o n  6. 2. 2. I n vesti gat ors are e nc o ura g e d t o 
mi ni mize  c ha n ges  t o  c o nc o mita nt  t hera pies  i ncl u di n g  p h ysical  a n d  occ u pati o nal  t hera pies  
d uri n g t he C ore Peri o d. 
 
(see  
Secti o n  6. 2. 2 f or Pr o hi bite d me dicati o n). 
•  Ca uti o n s h o ul d be e xercise d w he n usi n g oral N S AI Ds i ncl u di n g C O X- 2 i n hi bit ors wit h 
re gar ds t o t heir p ot e ntial gastr oi ntesti nal, li ver a n d car di o-re nal t o xicit y; t heref ore, w he n 
c h o osi n g a n a ge nt a n d d ose, i n di vi d ual partici pa nt ris k fact ors ( di a betes, h y perte nsi o n, 
car di o vas c ular disease, g astr oi ntesti nal blee di n g, re nal i m pair me nt, etc.) i n cl u di n g a ge 
s h o ul d be c o nsi dere d. It is rec o m me n de d t o prescri be oral N S AI Ds/ C O X- 2 i n hi bit ors at 
t he l o west eff ecti ve d ose f or t he s h ortest p ossi ble peri o d wit h a d diti o nal pr otecti ve 
me dicati o n, s uc h as pr ot o n p u m p i n hi bit ors as per p h ysicia n’s j u d ge me nt 
•  Re g ular m o nit ori n g f or h e pat ot o xicit y is re q uire d f or partici pa nts w h o recei ve 
aceta mi n o p he n o n a re g ular basis, partic ularl y at t he rec o m me n d e d ma xi m u m d osa ge of 
4 g dail y i n di vi de d d oses 
•  Pai n at ot her j oi nts s h o ul d be treate d caref ull y, wit h re gar d t o t he p ote ntial i m pact of t he 
assess me nt of pai n i n t he tar get k nee. If nee de d, 1 i njecti o n per year of c ortic oster oi d is 
all o we d i n ot her k nee a n d a n o n- k nee j oi nt at least 1 2 wee ks pri or t o t he 5 2- wee k a n d 1 0 4-
wee k ass ess me nts  
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N o v arti s  
C o nfi d e nti al  
P a g e 4 1  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
It is a d vise d t h at I n v esti gat ors c o nsi der ot her a n al gesics/a nal gesic f or m ul ati o ns (e. g., t o pical 
N S AI Ds) t ha n or al N S AI Ds i n a pers o n wit h oste o art hritis o n l o w -d ose as piri n or a ntic oa g ula nts 
li ke c o u mari ns or he p ari n. Blee di n g diat hesis m o nit ori n g s h o ul d be c o n d ucte d bef ore eac h 
L N A 0 4 3 or place b o i njecti o n, wit h I N R < 3 q ualif yi n g f or t he st u d y dr u g a d mi nistrati o n t o 
partici pa nts o n c o u mari ns (e. g., warfari n). S us pe nsi o n of N O A Cs 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 ysicia n, base d o n l ocal prescri bi n g i nf or m ati o n. 
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 are n ot all o we d after scree ni n g, as i n dicate d.  
T a bl e 6- 2 
Pr o hi bit e d m e di c ati o n s d uri n g C or e P eri o d  
M e di c ati o n  
Pr o hi bit e d p eri o d  
A cti o n t o b e 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 l o n g-a cti n g c orti c o st er oi d s 
( e. g., Zilr ett a ® ), P R P a n d st e m 
c ell t h er a pi e s  
2 6 w e e k s pri or t o t h e fir st 
W O M A C P ai n a s s e s s m e nt d uri n g 
s cr e e ni n g p eri o d u ntil W e e k 1 0 4  
Di s c o nti n u e st u d y tr e at m e nt  
R e c or d i n C R F  
A n y t h er a p y t h at m a y b e 
a ut h ori z e d d uri n g t h e c o n d u ct of 
t hi s st u d y a s a di s e a s e m o dif yi n g 
tr e at m e nt i n O A 
2 6 w e e k s pri or t o t h e fir st 
W O M A C P ai n a s s e s s m e nt d uri n g 
s cr e e ni n g p eri o d u ntil W e e k 1 0 4  
Di s c o nti n u e st u d y tr e at m e nt  
R e c or d i n C R F  
L o c al i. a. tr e at m e nt wit h 
h y al ur o n a n s i n t h e t ar g et k n e e  
1 2 w e e k s pri or t o t h e fir st 
W O M A C P ai n a s s e s s m e nt d uri n g 
s cr e e ni n g p eri o d u ntil W e e k 1 0 4  
R e c or d i n C R F  
U s e of hi g h p ot e n c y o pi oi d s ( e. g., 
m et h a d o n e, h y dr o m or p h o n e, 
m or p hi n e, o x y c o d o n e)  
1 2 w e e k s pri or t o t h e fir st 
W O M A C P ai n a s s e s s m e nt d uri n g 
s cr e e ni n g p eri o d u ntil W e e k 1 0 4  
R e c or d i n C R F  
C orti c o st er oi d u s e b y a n y r o ut e 
( e x c e pt t o pi c al, i n h al e d a n d i. a. 
i nj e cti o n i n ot h er n o n-k n e e j oi nt s) 1  
1 2 w e e k s pri or t o t h e fir st 
W O M A C P ai n a s s e s s m e nt d uri n g 
s cr e e ni n g p eri o d u ntil W e e k 1 0 4  
R e c or d i n C R F  
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), i n cl u di n g a s piri n 
( gr e at er t h a n 1 0 0 m g/ d a y); l o w 
p ot e n c y o pi oi d s ( e. g., tr a m a d ol); 
a n d C O X -2 i n hi bit or s b y a n y r o ut e  
4 8 h o ur s or 5 × T 1/ 2  ( w hi c h e v er i s 
l o n g er) pri or t o e a c h W O M A C 
P ai n a s s e s s m e nt  
R e c or d i n C R F  
P ar a c et a m ol / A c et a mi n o p h e n  
4 8 h o ur s pri or t o e a c h W O M A C 
P ai n a s s e s s m e nt  
R e c or d i n C R F  
Or al gl u c o s a mi n e, c h o n dr oiti n 
s ulf at e, or a n y 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 u nl e s s st a bl e f or at l e a st 4 
w e e k s b ef or e S cr e e ni n g Vi sit 1  
4 w e e k s pri or t o t h e fir st W O M A C 
P ai n a s s e s s m e nt d uri n g 
s cr e e ni n g p eri o d u ntil W e e k 1 0 4   
R e c or d i n C R F  
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) u nl e s s o n a st a bl e 
d o s e f or at l e a st 1 2 w e e k s b ef or e 
S cr e e ni n g Vi sit 1  
1 2 w e e k s pri or t o t h e fir st 
W O M A C P ai n a s s e s s m e nt d uri n g 
s cr e e ni n g p eri o d u ntil W e e k 1 0 4  
R e c or d i n C R F  
A nti c o n v ul s a nt s ( e. g., g a b a p e nti n, 
pr e g a b ali n) u nl e s s u s e d f or 
s ei z ur e a n d o n a st a bl e d o s e f or 
at l e a st 1 2 w e e k s  b ef or e 
S cr e e ni n g Vi sit 1  
1 2 w e e k s pri or t o t h e fir st 
W O M A C P ai n a s s e s s m e nt d uri n g 
s cr e e ni n g p eri o d u ntil W e e k 1 0 4  
R e c or d i n C R F  
El e ctr ot h er a p y, Tr a diti o n al 
C hi n e s e M e di ci n e (i n cl u di n g b ut 
4 w e e k s pri or t o e a c h of t h e t w o 
W O M A C P ai n a s s e s s m e nt s 
R e c or d i n C R F  

N o v arti s  
C o nfi d e nti al  
P a g e 4 2  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
n ot li mit e d t o a c u p u n ct ur e, 
m a s s a g e, h er b s) a n d/ or 
c hir o pr a cti c tr e at m e nt s f or k n e e 
O A p ai n  
d uri n g s cr e e ni n g p eri o d, W e e k s 
 
A n y ot h er t h er a p y/i nt er v e nti o n 
t h at c o ul d h a v e a n i m p a ct o n 
k n e e O A   
2 6 w e e k s pri or t o t h e fir st 
W O M A C P ai n a s s e s s m e nt d uri n g 
s cr e e ni n g p eri o d u ntil W e e k 1 0 4  
R e c or d i n C R F  
1 O n e i nj e cti o n p er y e ar i n a n o n -k n e e j oi nt i s all o w e d f or t h e tr e at m e nt of n o n -k n e e j oi nt p ai n; a n d o n e 
i nj e cti o n p er y e ar i n t h e ot h er k n e e i s all o w e d f or t h e tr e at m e nt of j oi nt p ai n u ntil 1 2 w e e k s b ef or e W e e k s  
 
  
 
T a bl e 6- 3 
Pr o hi bit e d m e di c ati o n s d uri n g E xt e n si o n P eri o d  
M e di c ati o n  
Pr o hi bit e d p eri o d  
A cti o n t o b e 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 l o n g a cti n g st er oi d s 
( e. g., Zilr ett a ® ), P R P a n d st e m 
c ell t h er a pi e s  
U ntil W e e k 2 6 0 vi sit  
Di s c o nti n u e st u d y tr e at m e nt  
R e c or d i n C R F  
A n y t h er a p y t h at m a y b e 
a ut h ori z e d d uri n g t h e c o n d u ct of 
t hi s st u d y a s a di s e a s e m o dif yi n g 
tr e at m e nt i n O A 
U ntil W e e k 2 6 0 vi sit  
Di s c o nti n u e st u d y tr e at m e nt   
R e c or d i n C R F  
L o c al i. a. tr e at m e nt wit h 
h y al ur o n a n s i n t h e t ar g et k n e e  
1 2 w e e k s pri or t o e a c h W O M A C 
P ai n a s s e s s m e nt  
R e c or d i n C R F  
U s e of hi g h p ot e n c y o pi oi d s ( e. g., 
m et h a d o n e, h y dr o m or p h o n e, 
m or p hi n e, o x y c o d o n e)  
U ntil W e e k 2 6 0 vi sit  
R e c or d i n C R F  
C orti c o st er oi d u s e b y a n y r o ut e 
( e x c e pt t o pi c al, i n h al e d a n d i. a. 
i nj e cti o n i n ot h er n o n-k n e e j oi nt s) 1  
U ntil W e e k 2 6 0 vi sit  
R e c or d i n C R F  
L o c al i. a. tr e at m e nt wit h 
c orti c o st er oi d s i n eit h er k n e e 2  
1 2 w e e k s pri or t o e a c h W O M A C 
P ai n a s s e s s m e nt  
R e c or d i n C R F  
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), i n cl u di n g a s piri n 
( gr e at er t h a n 1 0 0 m g/ d a y); l o w 
p ot e n c y o pi oi d s ( e. g., tr a m a d ol); 
a n d C O X -2 i n hi bit or s b y a n y r o ut e  
4 8 h o ur s or 5 × T 1/ 2  ( w hi c h e v er i s 
l o n g er) pri or t o e a c h W O M A C 
P ai n a s s e s s m e nt  
R e c or d i n C R F  
P ar a c et a m ol / A c et a mi n o p h e n  
4 8 h o ur s pri or t o e a c h W O M A C 
P ai n a s s e s s m e nt  
R e c or d i n C R F  
Or al gl u c o s a mi n e, c h o n dr oiti n 
s ulf at e, or a n y 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 u nl e s s o n a st a bl e d o s e 
d uri n g C or e P eri o d  
U ntil W e e k 2 6 0 vi sit   
R e c or d i n C R F  
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) u nl e s s o n a st a bl e 
d o s e d uri n g  C or e P eri o d  
U ntil W e e k 2 6 0 vi sit  
R e c or d i n C R F  
A nti c o n v ul s a nt s ( e. g., g a b a p e nti n, 
pr e g a b ali n) u nl e s s u s e d f or 
s ei z ur e a n d o n a st a bl e d o s e 
d uri n g C or e P eri o d  
U ntil W e e k 2 6 0 vi sit  
R e c or d i n C R F  
El e ctr ot h er a p y, Tr a diti o n al 
C hi n e s e M e di ci n e (i n cl u di n g b ut 
n ot li mit e d t o a c u p u n ct ur e, 
m a s s a g e, h er b s) a n d/ or 
4 w e e k s pri or t o e a c h W O M A C 
P ai n a s s e s s m e nt  
R e c or d i n C R F  
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N o v arti s  
C o nfi d e nti al  
P a g e 4 3  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
c hir o pr a cti c tr e at m e nt s f or k n e e 
O A p ai n  
A n y ot h er t h er a p y/i nt er v e nti o n 
t h at c o ul d h a v e a n i m p a ct o n 
k n e e O A   
U ntil W e e k 2 6 0 vi sit  
R e c or d i n C R F  
1 O n e i nj e cti o n p er y e ar i n a n o n -k n e e j oi nt i s all o w e d f or t h e tr e at m e nt of n o n -k n e e j oi nt p ai n.  
2 O n e i nj e cti o n p er y e ar i n eit h er k n e e i s all o w e d a s r e s c u e m e di c ati o n f or ot h er wi s e i ntr a ct a bl e p ai n u ntil 1 2 
w e e k s b ef or e W e e k s 
 
 
6. 2. 3  
R e s c u e m e di c ati o n  
F or all partici pa nts e x peri e nci n g pai n or eff usi o n t o t he tar get k nee d uri n g t he trial a n d re q uiri n g 
a nal gesic a n d/ or a nti -i nfla m mat or y me dicati o n, t he use of t o pical N S AI Ds (e. g. dicl ofe nac 
t o pical)/ca psaici n a n d/ or paraceta m ol/aceta mi n o p he n is t he rec o m me n de d/ preferre d treat me nt 
of c h oice. I n case t hese are n ot eff ecti ve or offer i ns ufficie nt pai n relief, t he n s u bstit uti o n or 
a d diti o n res pecti vel y of N S AI Ds/ C O X -2 i n hi bit ors is all o we d, as per t he rec o m me n de d d os e 
a n d  treat me nt  d ur ati o n  defi ne d  b y  l ocal  g ui deli nes.  It  is  rec o m me n de d  t o  pres cri be  oral  
N S AI Ds/ C O X -2 i n hi bit ors at t he l o west effecti ve d ose f or t he s h ortest p ossi ble peri o d ( Refer 
t o Secti o n  6. 2. 1. 1).  
D uri n g  t he  C ore  Peri o d,  use  of  i.a.  c ortic oster oi ds  i njecti o ns  is  n ot  per mitte d  as  resc ue  
me dicati o n f or t he treat me nt of tar g et k nee eff usi o n a n d/ or pai n, w hile o ne i.a. i njecti o n of 
c ortic oster oi ds per year is all o we d i n t he n o n -tar get k nee, u p u ntil 1 2 wee ks pri or t o t he 
c ollecti o n of W O M A C Pai n at Wee ks 
. D uri n g t he E xte nsi o n Peri o d, o ne i.a. 
i njecti o n per y ear is all o we d as a resc u e me dicati o n w he n eit her k nee eff usi o n a n d/ or pai n 
ca n n ot  be  treate d  a p pr o priatel y  wit h  paraceta m ol/aceta mi n o p he n  a n d  N S AI Ds/ C O X -2 
i n hi bit ors u p u ntil 1 2 wee ks pri or t o t he c ollecti o n of W O M A C Pai n at Wee ks 
 
 
D uri n g t he w h ole st u d y, o ne i.a. i njecti o n of c ortic oster oi ds per year is all o we d i n n o n -k nee 
j oi nts f or ot her wise i ntracta ble pai n. 
I n t he e v e nt of a h y p ers e nsiti vit y reacti o n, t he treat me nt will be d eter 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 t he se verit y, 
usi n g  s y m pt o matic  treat me nt,  a nti hista mi nes,  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 n ali ne. 
If t he p artici pa nt re q uir es re g ular narc otic a nal gesia t o c o ntr ol his/ her art hritis pai n, he/s he 
s h o ul d n ot be c o nsi dere d f or t he trial. 
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 nifica nt n o n -
dr u g t hera pies C R F after start of st u d y dr u g. 
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 p artici 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 first e nr olle d f or scree ni n g a n d is retai ne d as t he pri mar y 
i de ntifier f or t he partici p a nt t hr o u g h o ut his/ her e ntire partici pati o n i n t he trial. T he Partici pa nt 
N o. c o nsists of t he Ce nt er N u m ber ( Ce nt er N o.) (as assi g ne d b y N o v artis t o t he i n vesti gati ve 
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N o v arti s  
C o nfi d e nti al  
P a g e 4 4  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
site) wit h a se q ue ntial p artici pa nt n u m ber s uffi x e d t o it, s o t hat eac h p artici pa nt 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 s e q u e ntial Partici pa nt N o. a vaila ble. A ne w  Partici pa nt N o. will be assi g ne d 
at t he s u bse q ue nt e nr ol m e nt if t he Partici pa nt is re- scree ne d. 
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  
At Wee k 0,  all eli gi ble partici pa nts will be ra n d o mize d via I nteracti ve Res p o nse Tec h n ol o g y 
(I R T) t o o n e of t h e treat me nt ar ms. At Wee k 0, t he site pers o n nel ( bli n de d or u n bli n de d) will 
c o ntact  t he  I R T  f or  ra n d o mizati o n  after  c o nfir mi n g  t hat  t he  partici pa n t  f ulfills  all  t he  
i ncl usi o n/e xcl usi o n criteria. T he I R T will assi g n a ra n d o mizati o n n u m ber t o t he partici pa nt, 
w hic h will be use d t o li n k t he partici pa nt t o a treat me nt ar m a n d will s pecif y (a) u ni q ue 
me dicati o n kit n u m ber(s) of st u d y treat me nt t o be dis pe nse d t o t he partici pa nt f or L N A 0 4 3 
treat me nt ar ms. F or t he p artici pa nt ra n d o mize d t o place b o ar m, a me dicati o n n u m ber w o ul d n ot 
be s pecifie d a n d n o st u d y me dicati o n will be dis pe nse d i n I R T. 
O nl y t he u n bli n de d p har macist will recei v e t he treat me nt ar m of ra n d o mize d partici pa nt a n d t h e 
assi g ne d kit n u m ber(s) b y I R T. T h e u n bli n de d p har macist will pre pare a s yri n ge wit h st u d y 
treat me nt ( L N A 0 4 3  
m g,  
m g, or place b o) a n d deli ver it t o t he bli n de d i n vesti gati o nal site 
staff f or a d mi nistrati o n t o t he partici pa nt. T he u n bli n de d p har m acist m ust n ot discl ose treat me nt 
ar m or assi g ne d kit n u m b er(s) t o a n y bli n de d staff. 
T he ra n d o mizati o n n u m bers will be ge nerate d usi n g t he f oll o wi n g pr oce d ure 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 p a nts a n d I n vesti gat or staff. A 
partici pa nt r a n d o mizati o n list will be pr o d uce d b y t he I R T pr o vi der usi n g a v ali date d s yste m 
t hat a ut o mates t he r a n d o m assi g n me nt of partici p a nt n u m bers t o ra n d o mizati o n n u m bers. T hes e 
ra n d o mizati o n n u m bers are li n ke d t o t he differe nt treat me nt ar ms, w hic h i n t ur n are li n ke d t o 
me dicati o n n u m bers. A s e parat e me dicati o n list will b e pr o d uce d b y or u n d er t he res p o nsi bilit y 
of N o vartis usi n g a vali d ate d s yste m t hat a ut o mates t he ra n d o m assi g n me nt of kit n u m ber(s) of 
t he st u d y treat me nt. 
T here will be n o str atificati o n at ra n d o mizati o n.  
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 
Partici pa nts, bli n de d i n vesti gati o nal site staff, pers o ns perf or mi n g t he assess me nts, a n d select 
bli n de d s p o ns or tea m will re mai n bli n de d t o t he i de ntit y of t he treat me nt fr o m t he ti me of 
ra n d o mizati o n u ntil fi nal data bas e l oc k, usi n g t he f oll o wi n g met h o ds: ( 1) ra n d o mizati o n dat a 
are ke pt strictl y c o nfi de ntial u ntil t he ti me of u n bli n di n g a n d will n ot be accessi ble b y a n y o ne 
else  i n v ol ve d  i n  t he  st u d y  wit h  t he  f oll o wi n g  e xce pti o ns:  ra n d o mizati o n  office  ( 2)  o nl y  
u n bli n de d site p har macists a n d u n bli n de d C R As ca n access t o t h e st u d y m e dicati o ns, a n d t h e 
mas ki n g of t he treat me nts pre par e d b y u n bli n de d site p har macists will be e ns ure d. 
U n bli n di n g of desi g nate d s p o ns or staff will als o occ ur at t he ti me of t he i nteri m a nal yses 
(see Secti o n  1 2. 7). Bli n de d c ore s p o ns or st u d y tea m will re mai n bli n de d u ntil at least pri mar y 
efficac y ( Wee k 1 0 4) data base l oc k. Bli n de d i n vesti gati o nal site staff, partici pa nts a n d bli n de d 
C R As will re mai n bli n de d e ve n aft er t he i nteri m a nal ysis , u ntil fi nal data base l oc k. 
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N o v arti s  
C o nfi d e nti al  
P a g e 4 5  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
O nce p har macists a n d C R As are assi g n e d as u n bli n de d site p har macist a n d u n bli n de d C R As i n 
t his st u d y, t he y s h o ul d n ot be assi g ne d as bli n de d site staff or bli n de d C R A. 
O pe n la bel s u p pl y ( L N A 0 4 3   m g 
) will be pr o vi de d t o sites. 
T he ra n d o mizati o n c o des ass ociate d wit h partici p a nts fr o m w h o m P K sa m ples are t a ke n will be 
discl ose d t o P K a nal ysts w h o will kee p P K res ults c o nfi de ntial u ntil data base l oc k. 
U n bli n di n g ma y occ ur i n t he case of p artici pa nt e m er ge nci es a n d at t he c o ncl usi o n of t he st u d y.  
U n bli n di n g of a partici pa nt f or saf et y reas o n will res ult i n t he partici pa nt disc o nti n uati o n fr o m 
t he st u d y. See Secti o n  6. 6. 3 f or details. 
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 v esti gati o nal st u d y treat me nt d ose a dj ust me nts (i ncl u di n g partial d osi n g) are n ot per mitte d. 
6. 5. 1  
D efi niti o n s of d o s e li miti n g t o xi citi e s ( D L T s)  
N ot a p plica ble.  
6. 5. 2  
D o s e m o difi c ati o n s  
N o m o dificati o ns t o t he d ose are p er mitte d d uri n g t his st u d y. 
I njecti o ns t o t he tar get k nee s h o ul d n ot b e c o nsi d ere d w he n o v erl yi n g s ki n i nfecti o ns, w o u n ds 
or i nfla m mat or y diseases s uc h as ps oriasis are prese nt, if t he k nee is ac ut el y i nfla me d (flare), 
t he partici pa nt has a n I N R > 3 or si g nifica nt t hr o m b oc yt o pe nia ( platelet c o u nt < 7 5, 0 0 0/ m m3), 
or i n a n y ot her me dical -r elate d iss ue w he n t he safet y of t he partici pa nts ca n be je o par dize d b y 
t he i njecti o n, acc or di n g t o t he I n v esti gat or's j u d ge me nt. 
I n s u c h cases, a n d i n a n y ot her case w h e n t he partici pa nt ca n n ot recei ve t h e first i.a. i njecti o n 
of eac h c y cle as pla n ne d, t he start of t h e c y cle ca n be dela y e d b y a m a xi m u m of 4 wee ks. 
I nter vals bet w ee n i njecti o ns of t he sa me c y cle s h o ul d be mai ntai ne d at 
 wee k. 
E ve n if a n y of t he i.a. i nj ecti o ns ar e resc h e d ule d i n t he pre vi o us c y cle, t h e date of first visit i n 
eac h c ycle s h o ul d be cal c ulate d bas e d o n Wee k 0 (f or e xa m ple, i.a. i njecti o n at Wee k   w as 
dela ye d b y 1 wee k, t he sc he d ule d date of Wee k   s h o ul d be u naffecte d a n d   wee ks after 
Wee k 0.  
I n a n y case, f or i nterr u pti o ns of t he d osi n g sc h e me d ue t o A Es or f or a n y ot her reas o ns, 
c o ns ultati o n a n d a gree m e nt wit h N o vartis will be necess ar y t o d eci de w het her t he p artici pa nt 
ca n c o nti n ue or n ee ds t o disc o nti n ue t he st u d y treat me nt. 
See Secti o n  9. 1. 1 f or criteria f or dis c o nti n uati o n of st u d y me dicati o n. 
6. 5. 3  
F oll o w -u p f or t o xi citi e s  
Partici pa nts w h ose treat me nt is i nterr u pte d or p er m a ne ntl y disc o nti n ue d d ue t o a n a d vers e e v e nt 
or cli nicall y si g nifica nt la b orat or y val ue, m ust be f oll o we d u p at least o nce a wee k ( or m ore 
fre q ue ntl y if r e q uire d b y i nstit uti o nal practices, or if cli nically i n dicate d) f or 4 wee ks, a n d 
s u bse q ue ntl y at a p pr o xi matel y 4-wee k i nter vals, u ntil res ol uti o n or sta bilizati o n of t he e ve nt, 
w hic he ver  c o m es  first.  A p pr o priate  cli nical  e x perts  s uc h  as  a n  o p ht hal m ol o gist,  
e n d ocri n ol o gist, der mat ol o gist, ne p hr ol o gist, etc., s h o ul d be c o ns ulte d as dee me d n ecessar y. 
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N o v arti s  
C o nfi d e nti al  
P a g e 4 6  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
All partici pa nts m ust be f oll o we d u p f or a d verse e ve nts a n d seri o us a d verse e ve nts u ntil E O S 
( Wee k 2 6 0), or u ntil t he partici pa nt disc o nti n ues st u d y partici pati o n. 
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  
L N A 0 4 3 ser u m c o nce ntrati o ns ( meas ures of treat me nt e x p os ure) will be deter mi ne d i n all 
partici pa nts treat e d wit h L N A 0 4 3. 
C o m plia nce t o t he tr eat m e 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 i.a. i njecti o ns b y 
t he I n v esti 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 r ec or de d i n t he Case Re p ort F or m ( C R F). 
T he u n bli n de d p har macist will pre pare t he s yri n ge f or i.a. i njecti o n of L N A 0 4 3 (at t he assi g ne d 
d ose)  or  place b o  (s ali ne  s ol uti o n),  dis pe nse  a n  u n disti n g uis ha ble  st u d y  me dicati o n  t o  t he  
bli n de d i n vesti gati o nal site staff a n d rec or d all det ails (i ncl u di n g t he kit n u m ber/s if a p plica ble) 
i n P har mac y Dr u g A cc o u nta bilit y L o g. T he bli n de d i n vesti gati o nal site staff will d oc u me nt t he 
dis pe nsati o n (i.a. i njecti o n) t o t he partici pa nts i n t he partici pa nt Dr u g Acc o u nta bilit y L o g. 
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 gati o nal site pr oce d ures. T o pre ve nt p ost -
i njecti o n flares, w h ere p ossi ble, partici pa nts s h o ul d refrai n fr o m p h ysical acti vit y f or 4 8 h o urs 
p ost- d ose, ele vate t h e le g, a n d  a p pl y ice o n t he k n ee aft er t he i njecti o n. 
N o case of  s yste mic h y perse nsiti vit y reacti o ns ha ve bee n o bser v e d wit h L N A 0 4 3 t o date fr o m 
past cli nical st u dies, 
 
I n case of a n y si g n of ac ute reacti o n i n t his st u d y, t he partici pa nt will be ma na ge d wit h 
treat me nt as det er mi ne d b y t he treati n g p h ysicia n o n a cas e- b y-case b asis, acc or di n g t o l ocal 
pr ot oc ols,  a n d  de p e n di n g  o n  t he  se v erit y,  usi n g  s y m pt o matic  treat m e nt,  a nti hista mi nes,  
N S AI Ds, acet a mi n o p he n, i ntra ve n o us fl ui ds,  c ortic oster oi ds, or a dre n ali ne.  Partici pa nts w h o 
e x perie n ce h y p erse nsiti vit y reacti o n of a n y gra de c o nsi dere d t o be ca us e d b y st u d y dr u g m ust 
n ot be re- d ose d. 
Me dicati o n 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 her a pies C R F. 
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 t o treat t he partici pa nt 
safel y. 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 uffi cie nt  t o  treat  a  st u d y  partici pa nt  w h o  prese nts  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  p erf or me d  usi n g  t h e  I R T.  W he n  t he  
I n v esti gat or c o nt acts t he s yste m t o brea k a treat me nt c o de f or a p artici pa nt, he/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  
treat me nt  c o de  f or  t he  partici pa nt.  T he  I n v esti 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 k e n. 
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N o v arti s  
C o nfi d e nti al  
P a g e 4 7  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
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 d a 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. T h e I n vesti gat or will pr o vi de: 
•  Pr ot oc ol n u m ber 
•  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 n c y, or w he n he/s he is u na vaila ble, t o e ns ure t hat u n bli n di n g 
ca n be p erf or m e d at a n y ti me.  
A n y partici pa nt w h ose e mer ge nc y c o de was br o k e n d ue t o safet y reas o ns m ust disc o nti n ue t he 
st u d y treat me nt; h o we ver, w her e p ossi ble, t he p artici pa nt s h o ul d ret ur n f or t he ass ess me nts 
i n dicate d i n t he Assess m e nt Sc he d ule.  
6. 7   
Pr e p ar ati o n a n d di s p e n s ati o n 
Eac h st u d y 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 des cri be d u n der i n vesti gati o nal 
a n d c o ntr ol dr u gs secti o n. 
Please  ref er  t o  t he  P har mac y  Ma n u al  f or  i nf or mati o n  o n  dr u g  pre parati o n  pri or  t o  
a d mi nistrati o n.  
L N A 0 4 3   m g 
 will be s u p plie d i n a kit la bele d wit h a u ni q ue kit n u m ber. 
Eac h kit will c o ntai n  
 la bele d wit h t he sa me kit n u m ber. T he place b o will be sali ne, 
pr o vi de d b y t he site. 
O nl y partici pa nts o n a n y of t he L N A 0 4 3 treat me nt ar ms will o btai n st u d y me dicati o ns kit a n d 
n o kits will be assi g ne d f or partici pa nts o n place b o ar m. T he u n bli n de d p har macist will o btai n 
t he kit  
 fr o m t he I R T f or eac h partici p a nt at eac h visit f or st u d y treat me nt:  
 
f or L N A 0 4 3  
m g,
 f or L N A 0 4 3  
m g, or
 f or place b o. 
T he kit b o x c o ntai ni n g t he st u d y me dicati o n  
 has a 2 -part l a bel ( b ase pl us tear -off la b el). 
I m me diat el y bef or e starti n g t o pre pare t he s yri n ge wit h t he L N A 0 4 3, t he u n bli n de d p har macist 
will detac h t he o uter p art of t he la bel fr o m t he p ac ka gi n g a n d affi x it t o t he s o urce d oc u m e nt. 
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 v e d b y a desi g nate d pers o n at t he st u d y site, ha n dle d a n d st ore d 
safel y a n d pr o p erl y a n d k e pt i n a sec ure d l ocati o n t o w hic h o nl y desi g nate d site pers o n nel ha v e 
access. U p o n recei pt, all st u d y treat me nt m ust be st ore d acc or di n g t o t he i nstr ucti o ns s pecifie d 
o n t he la bels a n d i n t he I n vesti gat or’s Br oc h ure. Cli nical s u p plies are t o be dis pe nse d o nl y i n 
acc or d a nce wit h t he pr ot oc ol. Te c 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 Q ualit y Ass ura nce.  
Me dicati o n la bels will be i n t he l ocal la n g u a 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 y will i ncl u d e st ora ge c o n diti o ns f or t he st u d y treat me nt b ut n o i nf or mati o n a b o ut 
t he partici pa nt e x ce pt f or t he me dicati o n n u m ber. 
C CI
C CI
C CI
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 4 8  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
T he I n vesti gat or  m ust  e ns ure t he mai nte na n ce of 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 tr eat 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 nt a bilit y 
will be perf or me d b y u n bli n de d m o nit ors. 
As  per  Secti o n  4. 6,  d uri n g  a  P u blic  Healt h  e mer ge nc y  as  d eclare 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 disast er, t hat li mits or pre ve nts o n -site st u d y visits, 
st u d y treat me nt at h o me ma y be c o nsi dere d. 
I n t he e v e nt t he I n vesti gat or has deci de d t hat a n o n-site visit b y t he partici pa nt is n ot a p pr o priate 
or p ossi ble, t he st u d y treat me nt ma y be st o p pe d. I n t his case, re g ular p h o ne calls or virt ual 
c o ntacts  ( p ossi bl y  e ver y  4  wee ks)  will  occ ur  bet wee n  t he  site  a n d  t he  partici pa nt  f or  
i nstr ucti o nal  p ur p oses,  safet y  m o nit ori n g,  i n vesti gati o n  of  a n y  a d vers e  e ve nts,  e ns uri n g  
partici pa nts c o nti n ue st u d y self -assess me nts as a p pr o priate, a n d disc ussi n g of t he partici pa nt's 
healt h stat us u ntil t he partici pa nts ca n res u me visits at t he st u d y site.  
At t he c o n cl usi o n of t he st u d y, a n d as a p pr o pri ate d uri n g t he st u d y, t he I n v esti gat or will ret ur n 
all u n use d st u d y treat me nt, pac ka gi n g, 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 v esti gat or f ol der at eac h site. 
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 r e g ulati o n), I R B/I E C-a p pr o v e d i nf or me d c o nse nt. 
If  a p plica ble,  i n  cases  w here  t he  p artici pa nt's  re pres e ntati ve(s)  gi ves  c o nse nt  (if  all o we d  
acc or di n g t o l ocal re q uir e me nts), t he p artici pa nt m ust be i nf or me d a b o ut t h e st u d y t o t he e xte nt 
p ossi ble gi ve n his/ her u n dersta n di n g. If t he partici pa nt is ca pa ble  of d oi n g s o, he/s he m ust 
i n dicate a gr ee me nt b y pers o nall y si g ni n g a n d dati n g t he writte n i nf or me d c o nse nt d oc u me nt. 
I nf or me d c o nse nt m ust b e 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 ur es 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 o c u me nts. 
N o vartis will pr o vi de t o I n vesti gat ors i n a se parat e 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 v esti gat or m ust be a gr ee d b y N o vartis bef ore s u b missi o n t o t he I R B/I E C. 
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 n vesti gat or's Br oc h ure (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 g ar 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 d ates will be c o m m u nicate d as a p pr o priate, f or e x a m ple, via a n I n vesti gat or 
n otificati o n or a n a g gre g ate 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 h e n m ust be disc usse d wit h t he partici pa nt. 
W o me n of c hil d beari n g p ote ntial m ust be i nf or m e 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 h at 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 m e nts. 

N o v arti s  
C o nfi d e nti al  
P a g e 4 9  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
T he st u d y i ncl u des a n o pti o nal D N A c o m p o ne nt w hic h re q uires a se p arate si g nat ure if t he 
partici pa nt a grees t o p artici pate. It is re q uire d as part of t his pr ot o c 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 p er mitte d b y l ocal g o ver ni n g re g ul ati 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 h e sa m e as descri be d a b o ve f or t he mai n i nf or me d 
c o nse nt. 
T he  st u d y  i ncl u des  a n  o pti o nal  st u d y  s pecific  pre -s cree ni n g  c o nse nt  f or  pre-s cree ni n g 
assess me nts.  
Eli gi ble trial partici pa nts a p pr oac hi n g t heir Wee k  
 visit,
 
 Wee k  
 visit, will be eli gi ble t o partici pate i n t he 
 
 Partici pa nts m ust i n dicate t heir c o nse nt t o partici pate b y si g nat ure i n t he mai n I C F.  
Decli ni n g t o partici pate i n t hese o pti o nal assess me nts ( Pre -scree ni n g, D N A, 
) 
will i n n o wa y affect t he partici pa nt’s a bilit y t o partici pate or re mai n i n t he mai n researc h st u d y.  
A c o p y of t he a p pr o v e d v ersi o n of all c o nse nt f or ms m ust be pr o vi de d t o N o vartis/s p o ns or after 
I R B/I E C a p pr o v al. 
Partici pa nts mi g ht be as ke d t o c o m plete a n o pti o n al q uesti o n naire t o pr o vi de fee d b ac k o n t heir 
cli nical trial e x peri e nce.  
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 h e d ule ( Ta ble  8- 1) lists all of t he assess me nts w h e n t he y are p erf or me d. All 
data  o btai ne d  fr o m  t h ese  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 os e t o t he desi g nate d da y/ti me as p ossi ble. X-ra ys of b ot h k nees, M RIs of 
tar get k nee a n d/ or a n y ot her ass ess me nts at t h e sit e visit ma y be c o n d u cte d o n a differe nt d a y. 
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. Partici pa nts w h o 
pre mat urel y disc o nti n ue t he st u d y f or a n y reas o n d uri n g C ore Treat me nt p eri o d or E xte nsi o n 
Treat me nt p eri o d s h o ul d be sc h e d ule d f or a 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  E n d  of  Treat me nt  visit  ( E O T 1  or  E O T 2)  will  be  perf or me d.  
Partici pa nts  w h o  pre mat urel y  disc o nti n ue  st u d y  treat me nt  f or  a n y  reas o n  d uri n g  t he  C ore  
Treat me nt peri o d or t he E xte nsi o n Treat me nt peri o d, a n d wis h t o c o nti n ue i n t he st u d y, are n ot 
re q uire d t o b e sc h e d ule d f or a visit as s o o n as p ossi ble a n d ca n c o nti n ue per assess me nt  
sc he d ule. T he E n d of St u d y ( E O S) visit will be perf or me d at least 6 m o nt hs after t he last st u d y 
treat me nt  a d mi nistrati o n  u nless  t he  partici pa nt  wis hes  t o  c o nti n ue  i n  t he  st u d y  after  
disc o nti n uati o n of st u d y treat me nt. If t he p artici pa nt deci des t o disc o nti n ue  t he st u d y at a later 
sta ge, t he saf et y f oll o w-u p ( E O S) visit s h o ul d be c o n d ucte d at least 6 m o nt hs after t he last 
i njecti o n of st u d y treat me nt, u nless assess me nts at t he disc o nti n uati o n visit were perf or me d at 
least 6 m o nt hs after t he l ast i njecti o n of st u d y treat me nt. At t his fi nal visit, all dis pe nse d a n d 
a d mi nistere d st u d y me dicati o ns s h o ul d be rec o ncile d a n d t he a d verse e ve nt a n d c o nc o mita nt 
me dicati o ns s h o ul d be rec or de d o n t he C R F. 
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 0  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
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  
C or e P eri o d  
Vi sit N a m e  
S cr e e n
i n g 
Vi sit 1 
( S V 1) 
S cr e e n
i n g 
Vi sit 2 
( S V 2) 
0 
1 0 4/ E O T 1  
W e e k s  
-8 t o -1*  
0  
1 0 4  
I n-offi c e vi sit  
X  
X  
X  
X  
T el e p h o n e 
vi sit 1  
  
  
  
  
I nf or m e d 
c o n s e nt 2  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
P h ar m a c o g e n
eti c I nf or m e d 
C o n s e nt 
( O pti o n al) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
G ait a n al y si s 
i nf or m e d 
c o n s e nt 
( o pti o n al, at 
s el e ct e d sit e s 
o nl y)  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
D e m o gr a p h y / 
M e di c al 
hi st or y  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
I n cl u si o n / 
E x cl u si o n 
crit eri a  
X 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Vit al Si g n s 3  
X  
X  
X  
X  
B o d y H ei g ht  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
B o d y W ei g ht  
X  
  
X  
X  
P h y si c al 
E x a mi n ati o n  
S 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
S 
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 1  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
P eri o d  
S cr e e ni n g  
C or e P eri o d  
Vi sit N a m e  
S cr e e n
i n g 
Vi sit 1 
( S V 1) 
S cr e e n
i n g 
Vi sit 2 
( S V 2) 
0 
1 0 4/ E O T 1  
W e e k s  
-8 t o -1*  
0  
1 0 4  
P h y si c al 
e x a mi n ati o n 
( s y m pt o m 
ori e nt e d)  
  
S 
S 
  
P h y si c al 
e x a mi n ati o n 
(t ar g et k n e e) 
X 
 
X 
X 
T e m p or ar y 
di s c o nti n u ati o
n of p ai n 
m e di c ati o n s
4  
B ef or e 
W O M A
C P ai n 
a s s e s s
m e nt 
p erf or m
e d at 
h o m e  
X 
  
X 
W O M A C
5  
P erf or
m e d at 
h o m e 
aft er 
t e m p or
ar y 
di s c o nti
n u ati o n 
of p ai n 
m e di c a
ti o n 
X 
  
X 
Wi d e s pr e a d 
P ai n I n d e x 
( W PI) s c or e 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
C CI
C CI

N o v arti s  
 
C o nfi d e nti al  
 
P a g e 5 2  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
P eri o d  
S cr e e ni n g  
C or e P eri o d  
Vi sit N a m e  
S cr e e n
i n g 
Vi sit 1 
( S V 1) 
S cr e e n
i n g 
Vi sit 2 
( S V 2) 
0 
1 0 4/ E O T 1  
W e e k s  
-8 t o -1*  
0  
1 0 4  
S y m pt o m 
S e v erit y ( S S) 
s c or e  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
S F- 1 2 
St a n d ar d v 2  
  
X 
  
Tri al 
F e e d b a c k 
Q u e sti o n n air e  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
P ati e nt Gl o b al 
A s s e s s m e nt 
( P G A) 
  
X 
  
P ati e nt Gl o b al 
I m pr e s si o n of 
S e v erit y 
( P GI S)6  
  
  
X 
P ati e nt Gl o b al 
I m pr e s si o n of 
C h a n g e 
( P GI C)6  
  
  
  
P erf or m a n c e 
b a s e d t e st s  
( 3 0 s e c o n d 
c h air st a n d 
t e st, 4 × 1 0 m 
f a st-p a c e d 
w al k t e st, 6 
mi n ut e s 
w al ki n g 
di st a n c e t e st)  
  
  
X 
C CI
C CI
C CI

N o v arti s  
 
C o nfi d e nti al  
 
P a g e 5 3  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
P eri o d  
S cr e e ni n g  
C or e P eri o d  
Vi sit N a m e  
S cr e e n
i n g 
Vi sit 1 
( S V 1) 
S cr e e n
i n g 
Vi sit 2 
( S V 2) 
0 
1 0 4/ E O T 1  
W e e k s  
-8 t o -1*  
0  
1 0 4  
El e ctr o c ar di o g
r a m ( E C G)7  
X 
  
  
X 
H e m at ol o g y  
X  
  
X  
X  
Cli ni c al 
C h e mi str y  
X 
  
X 
X 
h s C R P  
X  
  
X  
X  
Uri n al y si s 
( M a cr o s c o pi c 
p a n el. 
Mi cr o s c o pi c 
p a n el o nl y if 
m a cr o s c o pi c 
i s a b n or m al) 
X 
  
X 
X 
C o a g ul ati o n 
t e st8  
X 
  
H e p atiti s a n d 
HI V S cr e e n 9  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
F a sti n g li pi d 
p a n el  
X 
  
X 
X 
Pr e g n a n c y 
T e st ( s er u m) 1 0  
S 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
S 
Pr e g n a n c y 
t e st ( uri n e)1 1  
  
  
K n e e X -r a y1 2  
X  
  
  
X  
M RI of t ar g et 
k n e e 1 3  
  
X 
  
X 
P K bl o o d 
c oll e cti o n 1 4  
  
  
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 4  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
P eri o d  
S cr e e ni n g  
C or e P eri o d  
Vi sit N a m e  
S cr e e n
i n g 
Vi sit 1 
( S V 1) 
S cr e e n
i n g 
Vi sit 2 
( S V 2) 
0 
1 0 4/ E O T 1  
W e e k s  
-8 t o -1*  
0  
1 0 4  
A N G P T L 3 
bl o o d 
c oll e cti o n 1 5  
  
  
S er u m, uri n e 
a n d s y n o vi al 
fl ui d 
bi o m ar k er s 1 6  
  
  
A nti- dr u g 
a nti b o d y t o 
L N A 0 4 3 1 7  
  
  
X 
E x pl or at or y 
D N A S a m pli n g 
( o pti o n al) 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
A cti gr a p h y 1 8  
G ait 
a s s e s s m e nt 
( o pti o n al, at 
s el e ct e d sit e s 
o nl y) 1 9  
  
  
X 
R a n d o mi z ati o
n  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
St u d y dr u g 
a d mi ni str ati o n
2 0  
  
  
A d v er s e 
E v e nt s  
 X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C CI
C CI
C CI
C CI
C CIC CI

N o v arti s  
 
C o nfi d e nti al  
 
P a g e 5 5  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
P eri o d  
S cr e e ni n g  
C or e P eri o d  
Vi sit N a m e  
S cr e e n
i n g 
Vi sit 1 
( S V 1) 
S cr e e n
i n g 
Vi sit 2 
( S V 2) 
0 
1 0 4/ E O T 1  
W e e k s  
-8 t o -1*  
0  
1 0 4  
Pri or/ c o n c o mit
a nt 
m e di c ati o n s  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
N o n -dr u g 
t h er a pi e s 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
e Di ar y f or 
a s s e s s m e nt of 
AI R ( s elf 
r e p ort e d l o c al 
s w elli n g a n d 
N R S p ai n) 2 3  
 
4  
 
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 6  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
P eri o d  
E xt e n si o n P eri o d  
E xt e n si o n P eri o d - F oll o w -u p  
Vi sit N a m e  
2 6 0/ E O S  
W e e k s  
2 6 0  
I n-offi c e vi sit  
X  
T el e p h o n e vi sit 1  
Vit al Si g n s 3  
X  
B o d y W ei g ht  
X  
P h y si c al E x a mi n ati o n  
S  
P h y si c al e x a mi n ati o n 
( s y m pt o m ori e nt e d) 
P h y si c al e x a mi n ati o n (t ar g et 
k n e e)  
X 
T e m p or ar y di s c o nti n u ati o n 
of p ai n m e di c ati o n s 4  
W O M A C
5  
S F -1 2 St a n d ar d v 2  
Tri al F e e d b a c k 
Q u e sti o n n air e  
X 
P ati e nt Gl o b al A s s e s s m e nt 
( P G A) 
P ati e nt Gl o b al I m pr e s si o n of 
S e v erit y ( P GI S) 6  
P ati e nt Gl o b al I m pr e s si o n of 
C h a n g e ( P GI C) 6  
P erf or m a n c e b a s e d t e st s  
( 3 0 s e c o n d c h air st a n d t e st, 
4 × 1 0 m f a st -p a c e d w al k t e st, 
6 mi n ut e s w al ki n g di st a n c e 
t e st) 
El e ctr o c ar di o gr a m ( E C G) 7  
X  
H e m at ol o g y  
X  
Cli ni c al C h e mi str y  
X  
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 7  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
P eri o d  
E xt e n si o n P eri o d  
E xt e n si o n P eri o d - F oll o w -u p  
Vi sit N a m e  
2 6 0/ E O S  
W e e k s  
2 6 0  
h s C R P  
X  
Uri n al y si s ( M a cr o s c o pi c 
p a n el. Mi cr o s c o pi c p a n el 
o nl y if m a cr o s c o pi c i s 
a b n or m al)  
X 
C o a g ul ati o n t e st 8  
F a sti n g li pi d p a n el  
X  
Pr e g n a n c y T e st ( s er u m) 1 0  
  
  
  
  
  
  
  
  
  
S  
  
  
  
  
S  
Pr e g n a n c y t e st ( uri n e) 1 1  
K n e e X -r a y1 2  
M RI of t ar g et k n e e
1 3  
S er u m a n d uri n e bi o m ar k er s  
S y n o vi al fl ui d bi o m ar k er s 1 6  
A nti- dr u g a nti b o d y t o 
L N A 0 4 3 1 7  
A cti gr a p h y 1 8  
G ait a s s e s s m e nt ( o pti o n al, 
at s el e ct e d sit e s o nl y) 1 9  
St u d y dr u g a d mi ni str ati o n 2 0  
A d v er s e E v e nt s  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Pri or/ c o n c o mit a nt 
m e di c ati o n s  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
N o n -dr u g t h er a pi e s  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 C CI
C CI
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 8  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
P eri o d  
E xt e n si o n P eri o d  
E xt e n si o n P eri o d - F oll o w -u p  
Vi sit N a m e  
2 6 0/ E O S  
W e e k s  
2 6 0  
e Di ar y f or a s s e s s m e nt of 
AI R ( s elf r e p ort e d l o c al 
s w elli n g a n d N R S p ai n) 2 3  
X  A s s e s s m e nt t o b e r e c or d e d i n t h e cli ni c al d at a b a s e or r e c ei v e d el e ctr o ni c all y fr o m a v e n d or.  
S  A s s e s s m e nt t o b e r e c or d e d i n t h e s o ur c e d o c u m e nt ati o n o nl y.  
* T h e s cr e e ni n g p eri o d s h o ul d l a st u p t o 8 w e e k s a n d i n cl u d e c o m pl eti o n of t w o S cr e e ni n g Vi sit s. S V 1 c a n b e -8 t o -4 w e e k s b ef or e W e e k 0 a n d S V 2 c a n b e s c h e d ul e d 
a n y ti m e aft er S V 1 u p t o -1 w e e k b ef or e W e e k 0 pr o vi d e d X -r a y eli gi bilit y r e p ort i s a v ail a bl e a n d fir st W O M A C p ai n a s s e s s m e nt h a s b e e n c o m pl et e d.  
1  T el e p h o n e vi sit s s h o ul d b e c o n d u ct e d t o a s s e s s A E s a n d c o n c o mit a nt m e di c ati o n u s e.  
2  I nf or m e d c o n s e nt m u st b e si g n e d pri or t o a n y st u d y-r el at e d pr o c e d ur e s. S cr e e ni n g pr o c e d ur e s m a y b e c o n d u ct e d t hr o u g h o ut t h e S cr e e ni n g p eri o d i n cl u di n g t h e 
S cr e e ni n g 1 a n d S cr e e ni n g 2 vi sit s.  
3  Vit al si g n s i n cl u d e h e art r at e, bl o o d pr e s s ur e a n d b o d y t e m p er at ur e.  
4  F or s u bj e ct s o n p ai n m e di c ati o n, i n cl u di n g N S AI D s/ C O X -2 i n hi bit or s, o pi oi d s, p ar a c et a m ol a n d a n y o v er -t h e-c o u nt er ( O T C) a n d t o pi c al a n al g e si c s, it i s r e q uir e d t o 
di s c o nti n u e t h e s e a n al g e si c s f or at l e a st 4 8 h o ur s or 5 h alf -li v e s ( w hi c h e v er i s l o n g er) pri or t o a n y W O M A C p ai n a n d f u n cti o n a s s e s s m e nt vi sit s, i n cl u di n g S cr e e ni n g, 
W e e k s  
 1 0 4, 
. 
5  T h e fir st W O M A C p ai n a s s e s s m e nt o n t h e t ar g et k n e e will b e p erf or m e d at h o m e o n t h e h a n d h el d d e vi c e aft er S V 1 a n d t e m p or ar y p ai n  m e di c ati o n s w a s h -o ut (if 
n e e d e d) a n d at l e a st 4 d a y s b ef or e S V 2. D uri n g S V 2, t h e s e c o n d W O M A C p ai n f or t h e t ar g et k n e e will b e r e c or d e d o n t h e t a bl et ( c o m pl et e W O M A C a s s e s s m e nt), w hil e 
t h e W O M A C p ai n f or t h e n o n-t ar g et k n e e will b e c oll e ct e d o n t h e h a n d h eld d e vi c e.”  
6  P ati e nt Gl o b al I m pr e s si o n of S e v erit y a n d P ati e nt Gl o b al I m pr e s si o n of C h a n g e will b e a s s e s s e d o nl y w h e n a l o c al l a n g u a g e v er si o n f or t h e sit e/ c o u ntr y i s a v ail a bl e. 
T h e y s h o ul d b e c o m pl et e d aft er p erf or m a n c e b a s e d t e st s.  
7  E C G c a n b e p erf or m e d l o c all y at ot h er ti m e p oi nt s if cli ni c all y i n di c at e d.  
8  P T T at c e ntr al l a b will b e c o n d u ct e d f or all t h e p ati e nt s at S V 1. P arti ci p a nt s u n d er k n o w n a nti c o a g ul ati o n tr e at m e nt wit h c o u m ari n s ( e. g., w arf ari n) will p erf or m P T -I N R 
at l o c al l a b b ef or e t h e st u d y dr u g i nj e cti o n.  
9  H e p atiti s s cr e e n d o n e wit h H B s A g a n d H C V -R N A.  
1 0  Pr e g n a n c y t e st: o nl y f or w o m e n of c hil d b e ari n g p ot e nti al, s er u m pr e g n a n c y t e st will b e p erf or m e d l o c all y at S V 1, W e e k 1 0 4, W e e k 2 0 8 a n d W e e k 2 6 0/ E O S. F or all 
ot h er vi sit s, a uri n e pr e g n a n c y t e st ( u si n g l o c all y s o ur c e d kit s or pr o vi d e d b y t h e c e ntr al l a b  if a v ail a bl e a n d c o m pli a nt wit h l o c al r e q uir e m e nt s) will b e p erf or m e d b ef or e 
st u d y dr u g i nj e cti o n.   
1 1  Uri n e pr e g n a n c y t e st will b e p erf or m e d o n a 
 b a si s o n sit e or at h o m e fr o m W e e k 0 u ntil W e e k  
.  
1 2  All k n e e X -r a y s will b e c e ntr all y r e a d. P o st er o a nt eri or X-r a y s of b ot h k n e e s will b e t a k e n at S V 1, W e e k 
. A n a d diti o n al p o st er o a nt eri or 
vi e w of t h e t ar g et k n e e will b e p erf or m e d at W e e k  
 a n d W e e k  
. Pr e -s cr e e n e d or r e -s cr e e n e d p arti ci p a nt s m a y utili z e pr e vi o u s k n e e X -r a y s if t a k e n wit hi n t h e p a st 3 
m o nt h s a c c or di n g t o t h e pr ot o c ol i m a gi n g crit eri a a n d u si n g a S y n afl e x er ™ l e g h ol d er. 
1 3  All M RI s will b e c e ntr all y r e a d. M RI at S V 2 s h o ul d b e p erf or m e d aft er c o nfir m ati o n of cli ni c al, l a b or at or y a n d X -r a y eli gi bilit y crit eri a. M RI s aft er W e e k 0 m a y b e 
p erf or m e d u p t o 2 w e e k s b ef or e st u d y dr u g i nj e cti o n.  
1 4  Bl o o d s a m pl e s f or P K t o b e dr a w n pri or t o t h e st u d y dr u g i nj e cti o n at W e e k s  
. Bl o o d s a m pl e s f or P K 2 h o ur s ( ± 1 5 mi n ut e s) aft er t h e st u d y dr u g i nj e cti o n will b e 
c oll e ct e d at W e e k s 
. Bl o o d s a m pl e s f or P K 1 5 mi n ut e s ( ± 5 mi n ut e s) aft er t h e st u d y dr u g i nj e cti o n will b e c oll e ct e d at W e e k s 
 at 
C CI
C CI
C CI
C CI
C CI
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 9  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
P eri o d  
E xt e n si o n P eri o d  
E xt e n si o n P eri o d - F oll o w -u p  
Vi sit N a m e  
2 6 0/ E O S  
W e e k s  
2 6 0  
s el e ct e d sit e s.  
1 5  Bl o o d s a m pl e s f or A N G P T L 3 t o b e dr a w n pri or t o t h e st u d y dr u g i nj e cti o n at W e e k s  
. Bl o o d s a m pl e s f or 2 h o ur s ( ± 1 5 mi n ut e s) aft er t h e st u d y dr u g i nj e cti o n 
will b e c oll e ct e d at W e e k s 
 
1 6  S y n o vi al fl ui d t o b e a s pir at e d j u st b ef or e t h e st u d y dr u g i nj e cti o n at e a c h d o si n g vi sit. If s y n o vi al fl ui d i s u n a bl e t o b e a s pir at e d o n W e e k  , t h e n f urt h er c oll e cti o n of 
s y n o vi al fl ui d d uri n g t h e st u d y i s n ot r e q uir e d.  
1 7  W h e n c oll e ct e d o n t h e st u d y dr u g a d mi ni str ati o n d a y s, i m m u n o g e ni cit y s a m pl e s s h o ul d b e c oll e ct e d b ef or e t h e i nj e cti o n. 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 a n d a s a m pl e t o a s s e s s i m m u n o g e ni cit y c oll e ct e d a s n e ar a s p o s si bl e t o t h e e v e nt. 
1 8  A cti gr a p h y will n ot b e p erf or m e d at sit e s w h er e H e alt h A ut h orit y a n d/ or I R B/I E C di d n ot a p pr o v e A cti gr a p h y a s s e s s m e nt s, if t h e d e vi c e i s n ot a v ail a bl e o n sit e or i n 
c a s e t h e i n v e sti g at or c o nfir m s t h at t h e p ati e nt s s h o ul d b e e x e m pt e d. A cti gr a p h y d uri n g 
 
1 9  O nl y f or p ati e nt s u n d er g oi n g g ait a s s e s s m e nt. M or e d et ail s c a n b e f o u n d i n t h e s e p ar at e G ait A s s e s s m e nt M a n u al.  
2 0  W o m e n of c hil d -b e ari n g p ot e nti al will r e c ei v e st u d y dr u g o nl y aft er a n e g ati v e pr e g n a n c y t e st at e a c h vi sit.  
2 1
  
 
2 3  S elf r e p ort e d l o c al s w elli n g a n d N R S p ai n will b e c oll e ct e d vi a e Di ar y b ef or e e v er y i. a. i nj e cti o n a n d d ail y f or 3 d a y s t h er e aft er.  
2 4 
t o b e c o n d u ct e d 
 
C CI
C CI
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 6 0  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
8. 1   
S cr e e ni n g 
8. 1. 1  
Pr e -s cr e e ni n g  
Pri or t o Scree ni n g Visit 1, o pti o nal st u d y s pecifi c pre -scree ni n g ass ess me nts ma y be carrie d 
o ut, i ncl u di n g b ut n ot li mite d t o X -ra y usi n g a S y nafle xer™ 
le g h ol der a n d k nee p h ysical 
e xa mi nati o n  (e. g.  ass ess me nt  of  k nee  O A  l ateralit y),  t o  assess  partici p a nt  eli gi bilit y  f or  
i ncl usi o n. Pri or t o a n y st u d y s pecific assess me nts b ei n g carri e d o ut, t he pre-s cree ni n g i nf or me d 
c o nse nt f or m m ust be si g ne d b y t he par tici pa nt. 
O nl y data relate d t o S A E ca usall y relate d t o pre -scree ni n g st u d y pr oce d ures ( X-ra y, k nee 
e xa mi nati o n) will be c ollecte d (s ee Secti o n 1 0. 1. 3 ). All ot her d ata relate d t o pre-s cree ni n g will 
o nl y be rec or de d i n s o urce d oc u me ntati o n.  
If a n X-ra y is ta k e n d uri n g pre-s cree ni n g acc or di n g t o t he pr ot oc ol i ma gi n g criteria it will n ot 
nee d t o b e re peate d d uri n g scree ni n g. If t he s u bject is t he n scree n e d wit hi n 3 m o nt hs, t he X -ra y 
ta ke n d uri n g t he pre-scr ee ni n g acc or di n g t o t he pr ot oc ol i ma gi n g criteria ca n be s u b mitte d f or 
ce ntral r ea di n g r e vie w.  
8. 1. 2  
S cr e e ni n g  
T he scree ni n g peri o d s h o ul d last u p t o 8 wee ks.  
It is per missi ble t o re-scree n a partici pa nt o nce, i ncl u di n g, b ut n ot li mite d f or t he reas o ns b el o w. 
Ot her reas o ns s h o ul d be disc usse d a n d a gree d wit h t he S p o ns or o n a cas e- b y-case b asis.  
1) Partici pa nts wit h s y n o vitis -relate d eff usi o n wit hi n 1 2 wee ks fr o m Scree ni n g Visit 1. It is 
a d visa ble t o rescr ee n t h os e partici pa nts o nce t he y h a ve a 1 2 -w ee k peri o d free of k nee eff usi o ns.  
2) I n t he case w her e a saf et y la b orat or y assess me nt at scree ni n g is o utsi de of t he ra n g e s pecifie d 
i n t he e xcl usi o n criteria, t his assess me nt ma y b e re peate d o nce pri or t o ra n d o mizati o n per t h e 
I n v esti gat or’s  discr eti o n.  If  t he  re peat  val ue  re mai ns  o utsi de of  t he  s pecifie d  ra n ges,  t h e  
partici pa nt m ust be e xcl u de d fr o m t he st u d y. 
T he scree ni n g wi n d o w s h o ul d be utilize d t o acc o m m o date t he re peate d tests. 
8. 1. 3  
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 
S u bjects w h o si g n 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 t o b e 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, e xce pt f or t h ose cases w he n rescree ni n g is 
all o we d  o nce  (s ee  Secti o n  8. 1).  T he  reas o n  f or  scree n  fail ure  s h o ul d  be  rec or de d  o n  t h e  
a p pr o priate  Cas e  Re p ort  F or m.  T he  d e m o gra p hic  i nf or mati o n,  i nf or me d  c o nse nt  a n d  
I n cl 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 
will be e nter e d i nt o t he cli nical data b ase f or p artici pa nts w h o are s cree n fail ures, u nless t he 
partici pa nt e x perie n ce d a seri o us a d verse e v e nt d uri n g t he scree ni n g p hase (see S A E secti o n f or 
re p orti n g details). T hir d-part y data s uc h as ce ntral la b orat or y res ults f or p artici pa nts w h o are 
scree n fail ur es ma y b e tra nsferr e d t o N o vartis data base.  If t he partici pa nt fails t o be ra n d o mize d, 
t he  I R T  m ust  be  n otifie d  i m me diatel y  after  t h e  scree n  fail  t hat  t he  partici pa nt  was  n ot  
ra n d o mize d. 

N o v arti s  
C o nfi d e nti al  
P a g e 6 1  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
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 ali g n me nt wit h C R F.  
Partici pa nt de m o gra p hics (a ge, s e x, hei g ht a n d wei g ht) a n d baseli ne c haracteristic data will b e 
c ollecte d u p o n si g n off of t he i nf or me d c o nse nt. 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 v ariati o ns i n safet y or efficac y d ue t o t hese fact ors as w ell 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.  Rele va nt  me dical 
hist or y/c urre nt me dical c o n diti o ns data will be c ollecte d at Scree ni n g Visit 1 wit h partic ular 
atte nti o n t o c o n diti o ns li ke ot her i n fla m mat or y art hr o pat hies or ge n eralise d p ai n s y n dr o mes a n d 
c o nc o mita nt treat me nts li ke i.a t hera pi es affecti n g partici pa nt's eli gi bilit y.  
Pai n assess me nt (i n cl u di n g pai n f or t he last 6 m o nt hs), d o u ble b aseli ne  pai n (t w o i n de p e n de nt 
pai n meas ure me nts at least 4 da ys a part o n a 0 -5 0 W O M A C pai n scale) o n t he tar get k nee, W PI, 
P G A ( N R S) a n d S F -1 2 v 2 q uesti o n naires m ust be c o m plete d f or eli gi bilit y at or b y Scree ni n g 
Visit 2 as baseli ne. Eac h W O M A C Pai n assess me nt will be c ollecte d after at least 4 8 h o urs or 
5 half -li ves of a nal gesics (e. g., N S AI Ds/ C O X 2 i n hi bit ors, l o w p ote nc y o pi oi ds, paraceta m ol / 
aceta mi n o p he n a n d a n y ot her O T C/t o pical a n al gesic me dicati o n) w as h -o ut. Partici pa nts will be 
i nf or me d  of  t he  a nal gesics  was h-o ut  re q uire me nts.
 
 
 
W O M A C pai n o n t he tar get k nee will be c ollecte d t wice d uri n g scree ni n g p eri o d: at least 4 da ys 
pri or t o Scree ni n g Visit 2 at h o me, a n d at Scree ni n g Visit 2. D o u ble bas eli ne pai n ass ess me nt 
o n t he tar get k nee has bee n selecte d t o e ns ure t he m ost acc urate e v al uati o n a gai nst t he pai n 
eli gi bilit y criteri o n.  W O M A C Pai n o n n o n-tar get k nee will be assess e d at Scree ni n g Visit 2.  
Bilateral  p oster oa nteri or k nee X -r a y will be perf or me d t o c o nfir m K-L gra de o n b ot h k nees, 
J S W a n d J S N gra de o n t h e tar get k nee at Scree ni n g Visit 1. Alter nati vel y, K-L gra d e, J S W a n d 
J S N gra de c o ul d be assesse d b y a pre-scree ni n g X-ra y, if it was ta ke n acc or di n g t o t he pr ot oc ol 
i ma gi n g criteria a n d wit hi n 3 m o nt hs bef ore Scree ni n g Visit 1. 
La b orat or y assess me nts will be perf or me d at Scree ni n g Visit 1 a n d as cl ose t o visit Wee k 0 f or 
eli gi bilit y a n d baseli ne. C oa g ulati o n tests will be carri e d o ut at t h e ce ntral l a b f or all patie nts at 
Scree ni n g  Visit  1  f or  eli gi bilit y.  A ntic oa g ula nt  ma na ge me n t  is  all o we d  per  l ocal  practice  
h o we ver p artici pa nts u n der k n o w n c o u mari ns (e. g., warfari n) are still eli gi ble f or e nr oll me nt 
a n d ca n recei ve st u d y dr u g as l o n g as I N R < 3 is certifie d at l ocal la b orat or y bef ore st u d y dr u g 
a d mi nistrati o n  at  a n y  d osi n g  visit.  S us pe nsi o n  of  N O A Cs  bef ore  i. a.  i njecti o n  s h o ul d  be  
assesse d b y t he tr eati n g p h ysicia n, base d o n l ocal prescri bi n g i nf or mati o n. 
Partici pa nts will als o be pr o vi de d a wrist acti gra p h y se ns or, trai ne d a n d i nstr ucte d t o wear t h e 
se ns or 
 t o c ollect b aseli ne data. 
Baseli ne data f or t he g ait assess me nt will be c ollecte d d uri n g t he visit at Wee k 0 pri or t o i.a. 
i njecti o n. 
I n v esti gat ors ha ve t he dis creti o n t o rec or d a b n or m al test fi n di n gs o n t he me dical hist or y e C R F, 
if i n t heir j u d g me nt, t he test a b n or malit y occ urre d pri or t o t he i nf or me d c o nse nt si g nat ure. 
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N o v arti s  
C o nfi d e nti al  
P a g e 6 2  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
8. 3   
Effi c a c y 
T he pri mar y assess me nt of efficac y i n t his trial will f oc us o n q ua ntitati ve M RI e val u ati o n of t he 
treat me nt eff ect o n k nee cartila ge t hic k ness i n t he c M T F C. Sec o n dar y assess me nts of efficac y 
i ncl u de q ua ntitati ve M RI e val uati o n of k nee s u b c o m part me nts ( me d ial a n d lateral) a n d of k nee 
f u ncti o n a n d pai n. 
T he effect o n cartila ge will be e v al uate d b y m ea ns of a q ua ntitati ve M RI as des cri be d i n 
Secti o n  8. 3. 1 a n d b y mea ns of X -ra y (J S W meas ure me nt), w hile a n y treat me nt effect o n t he 
oste oart hritic 
 
of t he tar get  k nee. 
C ha n ges i
 
 T he S D C t hres h ol d f or cartila ge t hic k ness o n q M RI will 
be  c o m p ute d  fr o m  st u d y -s pecific  test-retest  dat a  (Ec kstei n  et al 2 0 1 2).  T he  S D C  will  be  
calc ulate d as 1. 9 6 × t he S D of t he differe nces bet w ee n c h a n ges o bs er ve d at t est -retest. Str uct ural 
pr o gressi o n will als o be assesse d o n X -ra y, acc or di n g t o t he defi niti o n of t he F o u n dati o n f or t h e 
Nati o nal I nstit utes of H ealt h ( F NI H)  O A bi o m ar kers c o ns orti u m:  a decreas e i n mi ni m u m  
me dJ S W of ≥ 0. 7 m m, w hic h has a less t ha n 1 0 % c ha nce of bei n g d ue t o meas ure me nt err or 
(H u nter et al 2 0 1 4). 
T he sec o n dar y treat me nt effect d ue t o re g e nerati n g cartila ge o n cli nical o utc o mes  will be 
assesse d b y a set of perf or ma nce -base d f u n cti o nal tests a n d  Patie nt Re p orte d O utc o me ( P R O) 
q uesti o n naires o n f u ncti o n, pai n, s y m pt o ms, a n d q ualit y of life s uc h as W O M A C, P G A, P GI S, 
P GI C,   
 a n d  S F -1 2  v 2.  T he  W O M A C  is  a  wi del y  use d,  pr o prietar y  o utc o m e  
meas ure me nt t o ol use d t o e val uate t he c o n diti o n of partici pa nts wit h O A of t he k nee, i ncl u di n g 
pai n ( 5 q u esti o ns) a n d p h ysical f u ncti o ni n g ( 1 7 q uesti o ns) of t he j oi nts. Eac h q uesti o n is 
meas ure d o n a n 1 1 -p oi nt N R S scale (ra n ge 0 -1 0). 
 
 
P GI S a n d P GI C will be use d t o 
ca pt ure  t h e  partici pa nt's  gl o bal  i m pressi o n  of  t heir  tar get  k n ee  p ai n  d uri n g   f u ncti o nal 
assess me nts a n d meas ur e gl o bal i m pr o ve me nt wit h treat me nt. P R Os a n d perf or m a nce -base d 
f u ncti o nal tests are f urt her descri be d i n Secti o n  8. 5. 1. 
T he  O utc o me  Meas ures  i n  R he u mat ol o g y  – Oste oart hritis  Researc h  S ociet y  I nter n ati o nal  
( O M E R A C T-O A R SI) res p o n der r ate ( P ha m  et al 2 0 0 4) will be d eter mi ne d as a n e x pl orat or y 
a nal ysis. T he O M E R A C T -O A R SI res p o n der crit eria i n v ol ve c ha n g es t hat are dee me d t o be 
cli nicall y rele va nt i n t hree d o mai ns: pai n, f u ncti o n, a n d Patie nt’s Gl o bal Assess me nt.  
C o nti n u o us p h ysical acti vit y o ver  
 will be e x pl ore d b y mea ns of a wrist acti gra p h y 
se ns or. T he acti gra p h y s e ns or will be w or n 
 
 
 At selecte d sites, gait te m p or os patial 
para meters will be e x pl ore d b y mea ns of t he Bi o mec ha nical Se ns or Platf or m ( B S P). F urt her 
details o n t he use of t hes e di gital de vices are pr o vi de d i n Secti o n  8. 5. 5. 1 a n d Secti o n  8. 5. 5. 2. 
All efficac y assess me nts s h o ul d be perf or me d pri or t o a d mi nistrati o n of st u d y treat me nt. Details 
relate d t o t he a d mi nistrati o n of all P R Os are pr o vi de d i n Secti o n  1 6. 4. 
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N o v arti s  
C o nfi d e nti al  
P a g e 6 3  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
8. 3. 1  
K n e e M RI  
M RI will be o btai ne d fr o m t he tar get k nee t o vis ualize t he cartila g e tiss ue i n t he me dial a n d 
lateral f e m oral a n d ti bial re gi o ns, as w ell as i n t he t otal T F c o m part me nt. I n a d diti o n, 
 
 
Details of t he M RI ac q uisiti o n pr ot oc ol a n d c orres p o n di n g i ma ge a n al ysis will be pr o vi de d i n 
t he i ma ge ac q uisiti o n ma n ual a n d i ma gi n g c hart er. 
I m a g e c oll e cti o n 
Ma g netic Res o na nce ( M R) i ma ges ac q uisiti o n will be perf or m e d b y a trai ne d M RI pr ofessi o nal 
at t he i ma gi n g facilit y. I ma gi n g facilit y f or t he st u d y s h o ul d be trai ne d a n d q ualifie d b y ce ntral 
i ma gi n g la b pri or t o t he first i ma ge is ta ke n f or t he st u d y assessme nt. T he M RI ra di ol o gist will 
be bli n de d t o t he treat me nt recei ve d b y t he partici pa nt. All partici pa nts will be i ma ge d usi n g a 
cli nical hi g h-fiel d M RI sca n ner. F or eac h M RI sessi o n, i ma ges will be ac q uire d as descri be d i n 
t he I ma gi n g Ac q uisiti o n G ui deli ne t o assess o ver t he c o urse of t he st u d y t he e xte nt of cartila ge 
l oss or re ge nerati o n i n t he i n de x re gi o n as w ell as p ote ntiall y rele va nt k nee O A str uct ures s u c h 
as b o ne marr o w lesi o ns. 
M R i ma ges will be ac q uire d at t he i ma gi n g site(s) a n d se nt f or i n de pe n de nt ce ntral re vie w b y 
t he i ma gi n g c ore l a bs. T h e r e vie wers will be bli n de d t o t he treat me nt recei ve d b y t he partici pa nt. 
M RI a nal ysis res ults will n ot be s hare d wit h t he I n vesti gat ors t o mai ntai n t he bli n d. H o we ver, 
j oi nt-relate d fi n di n gs i de ntifie d i n M R sca ns will be re p orte d i n cases of safet y c o ncer ns or a n y 
i nci de ntal fi n di n g of rele va nce f or partici p a nt's healt h.  
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 c harter, i n or der t o 
assess c ha n g es i n cartila ge str uct ure (i. e., t hic k ness a n d v ol u me) i n pre -defi ne d areas of t h e 
k nee, i ncl u di n g i n t he t ar get re gi o n. Ot h er e n d p oi nts will i ncl u de sc ori n g of feat ures ass u me d 
t o be m ost r ele va nt t o t h e nat ur al hist or y of t he disease i ncl u di n g ( b ut n ot restricte d t o) b o n e 
s ha pe of t he fe m ur a n d t he ti bia, b o ne marr o w lesi o ns, c ysts, cartila ge, oste o p h ytes, s y n o vitis, 
eff usi o n, me nisc us, li ga me nts a n d te n d o n. 
T he c o de d me dical i ma g es will be use d pri maril y f or a nal ysis as descri b e d i n t his pr ot oc ol, 
h o we ver, t he i ma g es ma y als o be use d f or t he d e vel o p me nt a n d e v al uati o n of n e 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. 
P ost- baseli ne a nal y ze d d ata of M R a n d X -ra y i ma ges will n ot be pr o vi de d t o t he bli n de d st u d y 
pers o n nel bef ore D ata bas e L oc k.  
8. 3. 2  
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  
L N A 0 4 3, a m o difie d pr otei n fr o m t he h u ma n A N G P L T fa mil y is c haracterize d b y its ca pacit y 
t o re ge ner ate cartila ge as e vi de nce d b y mea ns of c o m p ositi o nal a n d q ua ntitati ve M RI met h o ds 
use d  i n  t he  FI H,  P o M  a n d  P o C  st u dies,  i n  partici pa nts  wit h  cartila ge  defects.  I n  ter ms  
of se nsiti vit y a n d res p o nsi ve ness, q ua ntitati ve M RI (C o na g ha n et al 2 0 1 1, Pelletier  et al 2 0 1 3) 
has  bee n  s h o w n  b etter  s uite d  f or  t he  detecti o n  of  c h a n ges  i n  cartila ge  m or p h ol o g y  t ha n  
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N o v arti s  
C o nfi d e nti al  
P a g e 6 4  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
se mi q ua ntitati ve M RI s c ori n g s yste ms a n d tra diti o nal X-ra ys. T heref ore, it is c o nsi dere d as t he 
tec h n ol o g y of c h oice t o de m o nstrate t he treat me nt effect of L N A 0 4 3 o n cartila ge.  
8. 4   
S af et y 
Safet y assess me nts are s p ecifie d bel o w wit h t he Ta ble  8- 1 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, refer t o A E secti o n ( Secti o n  1 0. 1. 1). 
As  per  Secti o n 4. 6 ,  d uri n g  a P u blic H ealt h  e m er ge nc y  as  decl are 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 disast er, t hat li mits or pre ve nts o n -site st u d y visit, 
re g ular p h o ne calls or virt ual c o ntacts ca n occ ur ( p ossi bl y e ver y 4 wee ks) 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.  
T a bl e 8- 2 
A s s e s s m e nt s &  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  hi 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.  C ar ef ul 
e x a mi n ati o n of t h e t ar g et k n e e will b e p erf or m e d at all vi sit s b y a s s e s si n g r e d n e s s, w ar mt h, 
s w elli n g,  p ai n,  r a n g e  of  m oti o n,  st a bilit y,  a n d  b ul g e  si g n,  cr e pit u s,  fl e xi o n  c o ntr a ct ur e, 
v ar u s/ v al g u s l a xit y, a nt er o -p o st l a xit y,  m a x e xt e n si o n a n d m a x fl e xi o n s h o ul d b e r e c or d e d. 
F ull  p h y si c al  e x a mi n ati o n  i s  n ot  r e q uir e d  at  all  vi sit s,  b ut  t ar g et  k n e e  e x a mi n ati o n  a n d 
s y m pt o m ori e nt e d e x a mi n ati o n s will b e p erf or m e d at all sit e vi sit s.  
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 st u d y sit e. P h y si c al e x a mi n ati o n s o n t h e t ar g et k n e e s h o ul d b e r e c or d e d o 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 n t  m u st  b e 
r e c or d e d o n t h e a p pr o pri at 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 i n cl u d e B P a n d p ul s e m e a s ur e m e nt s. 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, 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  t hr e e  ti m e 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 uff. T h e r e p e at sitti n g m e a s ur e m e nt s will b e m a d e at 
1 - 2 mi n ut e i nt er v al s a n d 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. 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.  
H ei g ht a n d 
w ei g ht  
H ei g ht a n d b o d y w ei g ht (t o t h e n e ar e st 0. 1 u nit 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.  
8. 4. 1  
L a b or at or y e v al u ati o n s  
U nless ot her wise s pecifie d, la b assess me nts will be se nt t o a ce ntral la b f or a nal ysis.  
Cli nicall y n ota ble la b orat or y fi n di n gs are d efi ne d i n Secti o n  1 6. 1 a n d Secti o n  1 6. 2. 
Cli nicall y si g nifica nt a b n or malities m ust be rec or d e d as eit her me dical hist or y/c urre nt me dical 
c o n diti o ns or a d verse e ve nts as a p pr o priate. 

N o v arti s  
C o nfi d e nti al  
P a g e 6 5  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
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, Pl at el et s, R e d bl o o d c ell s, W hit e bl o o d c ell s, 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 utr o p hil s)  ( a b s ol ut e v al u e 
pr ef err e d, % s ar e a c c e pt a bl e)  
C h e mi str y  
Al b u mi n, Al k ali n e p h o s p h at a s e, A L T, A S T, G a m m a -gl ut a m yl -tr a n sf er a s e ( G G T), L a ct at e 
d e h y dr o g e n a s e ( L D H), C al ci u m, M a g n e si u m, P h o s p h or u s, S o di u m, P ot a s si u m, Cr e ati ni n e, 
Cr e ati n e ki n a s e  ( C K), Dir e ct Bilir u bi n, I n dir e ct Bilir u bi n, T ot al Bilir u bi n, Bl o o d Ur e a Nitr o g e n 
( B U N) or Ur e a, Uri c A ci d, A m yl a s e, Li p a s e, Gl u c o s e, H b A 1 c 
Li pi d s p a n el 
(f a sti n g) 
T ot al C h ol e st er ol, L D L, H D L,  T ot al Pr ot ei n, Tri gl y c eri d e s  
Uri n al y si s  
M a cr o s c o pi c P a n el ( Di p sti c k i n all c o u ntri e s e x c e pt C hi n a, l a b t e st s i n C hi n a) ( C ol or, 
Bilir u bi n, Bl o o d ( H e m ol y z e d a n d n o n -h e m ol y z e d), Gl u c o s e, K et o n e s, L e u k o c yt e s e st er a s e, 
Nitrit e, p H, Pr ot ei n, S p e cifi c Gr a vit y, Ur o bili n o g e n)  
Mi cr o s c o pi c P a n el ( R e d Bl o o d C ell s, W hit e Bl o o d C ell s, C a st s, Cr y st al s, B a ct eri a, 
E pit h eli al c ell s) N ot e: O nl y i n c a s e of a b n or m al m a cr o s c o pi c p a n el.  
C o a g ul ati o n  
P T T at c e ntr al l a b will b e c o n d u ct e d at s cr e e ni n g f or all p ati e nt s. P T -I N R t o b e c o m pl et e d 
l o c all y pri or t o st u d y dr u g i nj e cti o n f or p ati e nt s t a ki n g c o u m ari n s ( e. g., w arf ari n). 
H e p atiti s m ar k er s  
H b s A g, H C V R N A -P C R  
A d diti o n al t e st s  
Hi g h -s e n siti vit y C -R e a cti v e pr ot ei n ( h s C R P), HI V -1 a n d HI V -2 a nti b o di e 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 (l o c al, w h er e p o s si bl e), F S H (l o c al) 
8. 4. 2  
El e ctr o c ar di o gr a m ( E C G)  
Si n gle 1 2 -lea d E C Gs are c ollecte d a n d rea d l ocall y. T he ori gi nal E C Gs, a p pr o priatel y si g ne d, 
m ust be c ollecte d a n d arc hi ve d at t he st u d y site. 
F or a n y E C Gs wit h partici pa 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 saf et y fi n di n g. A m o nit ori n g or re vie w pr ocess s h o ul d b e i n place f or cli nicall y 
si g nifica nt E C G fi n di n gs t hr o u g h o ut t he st u d y a n d es peciall y at b aseli ne b ef ore a d mi nistrati o n 
of st u d y treat me nt. 
I n t he e v e nt t hat a cli nicall y si g nifica nt E C G a b n or malit y is i de ntifie d at t he site (e. g. se vere 
arr h yt h mia, c o n d u cti o n a b n or malit y of Q Tc F > 5 0 0 ms), t he E C G is re peate d t o c o nfir m t he 
dia g n osis. If t h e partici pa nt is he m o d y na micall y c o m pr o mise d, t he I n v esti gat or or a me dicall y 
q ualifie d  pers o n  m ust  i nitiate  a p pr o priate  safet y  pr oce d ures  wit h o ut  dela y  (f or  e x a m pl e  
car di o versi o n). 
Cli nicall y  si g nifica nt  a b n or malities  m ust  be  rec or d e d  o n  t he  C R F  as  eit her  me dical  
hist or y/c urre nt me dical c o n diti o ns or a d verse e v e nts as a p pr o priate. 
8. 4. 3  
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  
C o ntrace pti o n f or mal e st u d y partici pa nts is n ot re q uire d.  
 All w o me n of c hil d beari n g p ote ntial will ha ve pre g na nc y testi n g as o utli ne d i n  Ta ble 8 - 1. A 
w o ma n is c o nsi dere d of c hil d beari n g p ote ntial fr o m me narc he u ntil bec o mi n g p ost - me n o pa usal 
u nless per ma n e ntl y sterile. A p ost me n o pa us al state is defi n e d as n o me nses f or 1 2 m o nt hs 
wit h o ut a n alter nati ve me dical ca use a n d a n a p pr o priate cli nical pr ofile . 
Per ma ne nt  sterilizati o n  met h o ds  i ncl u de  h ysterect o m y,  bilateral  t u bal  li gati o n,  bilateral  
sal pi n gect o m y a n d bilateral o o p h orect o m y. 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 

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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 t o be n ot of c hil d- beari n g p ote ntial. 
Me dical d oc u m e ntati o n of t he p er ma n e nt met h o d of sterilizati o n m ust be ret ai ne d as s o urce 
d oc u me nts. 
I n t he a bse n ce of me dical d oc u me ntati o n c o nfir mi n g per ma ne nt sterilizati o n, or if t he p ost-
me n o pa usal  stat us  is  n ot  clear,  t he  i n vesti gat or  s h o ul d  use  his/ her  me dical  j u d g me nt  t o  
a p pr o priatel y e val uate t he fertilit y state of t he w o ma n a n d d oc u m e nt it i n t h e s o urce d oc u me nt.  
8. 4. 4  
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 s electe d are sta n d ar d f or t his i n dicati o n/ partici pa nt p o p ulati o n.  
8. 4. 5  
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 bl e  8- 1) a n d e val uate d i n all partici pa nts. 
I n case of s us pect e d aller gic h y perse nsiti vit y, a n u nsc he d ule d sa m ple t o assess i m m u n o ge nicit y 
will be c ollecte d. U nsc he d ule d 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 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 nsi ti vit y after 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 P K sa m ples c o ul d be use d t o better 
c haracteri ze t he o nset of i m m u n o ge nicit y res p o nse. 
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. 
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 -r eacti vit y t o A N G P T L 3. I n cas e of t he det ecti 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- r eacti 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 n al yze d  f or  pres e 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.  
I G sa m ples re m ai ni n g after i m m u n o ge nicit y a nal ysis ma y be use d f or e x pl orat or y assess me nt 
or ot her bi oa n al ytical p ur p oses (e. g. cr oss c h ec k b et wee n differe nt sites). Gi ve n t he e x pl or at 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.  

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8. 5   
A d diti o n al a s s e s s m e nt s 
8. 5. 1  
Cli ni c al O ut c o m e A s s e s s m e nt s ( C O A s)  
P ati e nt r e p ort e d o ut c o m e s ( P R O)  
P R Os c o m plete d at st u d y visits s h o ul d be  c o m plete d bef ore a n y assess me nts (e. g., p h ysical 
e xa mi nati o n) are c o n d ucte d, e xce pt Patie nt Gl o bal I m pressi o n of Se v erit y ( P GI S) a n d Patie nt 
Gl o bal I m pressi o n of C h a n ge ( P GI C) t o be perf or me d aft er p erf or ma nce base d  tests. T h e PI 
s h o ul d  f oll o w  t he  i nstr ucti o ns  f or  P R O  q uesti o n naires  a n d  s h o ul d  i nstr uct  t he  partici pa nt  
a p pr o priatel y. T he 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 st u d y data ca pt ure s yste m a n d s h o ul d n ot be c o nsi dere d as a pr ot oc ol  
de viati o n. Ha n dli n g of pr ot oc ol de viati o ns ca n be m o difie d if nee de d p er st u d y pr ot oc ol. 
Partici pa nt 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). 
T he site pers o n nel  s h o ul d c hec k P R O meas ure(s) 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. C o m plete d meas ure(s) m ust be re vi e we d a n d assesse d b y t h e 
I n v esti gat or f or res p o nses w hic h ma y i n dicate p ot e ntial A Es or S A Es bef ore a n y cli nical st u d y 
e xa mi nati o ns. T his assess me nt s h o ul d be d oc u me nte d i n st u d y s o urce rec or ds. If A es or S A Es 
are c o nfir me d, st u d y I n v esti gat ors s h o ul d n ot e n c o ura ge t h e 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. T he res p o ns es st ore d electr o nicall y i n t he d ata bas e will be c o nsi dere d 
t he s o urce file. 
Wester n O nt ari o a n d Mc M ast er U ni versities Oste o art hritis I n de x ( W O M A C)   
T he W O M A C has bee n de vel o pe d t o assess t he c o urse of disease or res p o nse t o treat me nt i n 
patie nts wit h k nee or hi p oste oart hritis ( C olli ns  et al 2 0 1 1). It i ncl u d es 2 4 ite ms a n d t hree 
s u bscales:  1)  pai n  se v erit y  d uri n g  vari o us  p ositi o ns  or  m o ve me nts  (“W O M A C  Pai n ”),  2)  
se verit y of j oi nt stiff ness (“W O M A C Stiff n ess ”), a n d 3) diffic ult y perf or mi n g dail y f u ncti o nal 
acti vities (“W O M A C F u ncti o n ”). T he 2 4 ite ms will be sc ore d wit h a n u meric rati n g scale 
usi n g 1 1- b o x h oriz o ntal scale, wit h t he left e n d mar ke d as “ n o ne” a n d t he ri g ht e n d mar ke d as 
“e xtre me”.  T he
 recall
 peri o d
 is
 4 8
 h o urs.
 A p pr o pri ate
 tra nslati o ns
 of
 t he
 
e ntire W O M A C
®  versi o n 3. 1 q uesti o n naire ( 1 1 -b o x n u merical  scal e versi o n) will be use d. F or 
a d mi nistrati o n of t he q u esti o n naire, i nstr ucti o ns i n t he W O M A C 3. 1 Us er ’s G ui de s h o ul d be 
f oll o we d. T his v ersi o n of W O M A C q uesti o n naire has bee n vali date d als o f or re m ote ca pt ure 
usi n g m o bile tec h n ol o g y ( Bella m y  et al 2 0 1 0). T h e W O M A C will be c ollecte d usi n g a ha n d hel d 
de vice a n d t a blet.  
 
Partici pa nts will
 
 
will be 
c ollecte d
 
 
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S h ort F or m 1 2 He alt h S ur ve y ( S F- 1 2)  
T he S F -1 2 is o ne of t he m ost c o m m o nl y use d ge neric healt h -relat e d q ualit y of life ( H R Q L) 
meas ures i n p atie nts wit h hi p or k nee dis or ders. T he S F -1 2 has a l o wer res p o n der b ur de n 
c o m pare d t o S F-3 6 a n d has bee n vali date d f or use i n k nee O A trials ( Ga n d hi et al 2 0 0 1). T he 
S F -1 2 c o ntai ns a s u bs et of 1 2 ite ms fr o m t he S F -3 6, i ncl u di n g o ne or t w o ite ms fr o m eac h of 
t he  ei g ht  S F-3 6  scales  ( Ga n de k  et al 1 9 9 8).  T w o  ite ms  are  i ncl u de d  fr o m  t he  P h ysical  
F u ncti o ni n g a n d Me ntal Healt h scales beca use  t h ese scales ha v e bee n s h o w n t o best pre dict 
p h ysical a n d me ntal healt h; t w o ite ms eac h are als o i ncl u de d fr o m b ot h R ole F u ncti o ni n g scales, 
beca use t hes e ar e relati v el y c oarse scales. O ne it e m eac h is i ncl u de d fr o m t he re mai ni n g f o ur 
scales. I nf or mati o n fr o m all 1 2 ite ms is use d t o c o nstr uct p h ysical a n d me ntal c o m p o ne nt 
s u m mar y meas ures. T he S F -1 2 will be c ollecte d usi n g a ta blet de vice. I n t his st u d y, S F -1 2 v 2 
Sta n dar d will be use d. 
P atie nt ’s Gl o b al Assess m e nt of P ai n ( P G A) 
T he P G A is c o m m o nl y use d i n O A trials ( Mc Ali n d o n et al 2 0 1 5). Partici pa nts will a ns wer t he 
q uesti o n: “ C o nsi deri n g all t he wa ys y o ur oste oart hritis of t he k n ee h as affecte d y o u d uri n g t he 
last 4 8 h o urs, select t he n u m ber t hat best descri bes t he i m pact of y o ur k nee oste oart hritis o n 
y o ur dail y life? ” b y usi n g a n 1 1 -b o x h oriz o nt al s cale, wit h t he left e n d m ar ke d as “ n o ne” a n d 
t he ri g ht e n d mar ke d as “e xtre me”. T he P G A will be c ollecte d usi n g a t a blet de vice. 
P atie nt Gl o b al I m pressi o n of Se verit y ( P GI S) a n d P atie nt Gl o b al I m pressi o n of C h a n ge 
( P GI C) 
T he P GI S a n d P GI G pr o vi de a res p o nsi ve a n d rea dil y i nter pret a ble meas ure of partici pa nt ’s 
assess me nts of t he cli nical i m p orta nce of t heir i m pr o ve me nt or w orse ni n g of t heir k nee pai n 
d uri n g  f u ncti o nal  perf or ma nce  o utc o m e  assess me nts  o ver  t he  c o urse  of  t he  cli nical  trial  
(D w or ki n  et al 2 0 0 5).  Partici pa nts  will  a ns wer  q uesti o ns  a b o ut  t heir  perce pti o n  of  diseas e  
acti vit y b y usi n g a 4 -p oi nt a n d a 5 -p oi nt s cale, f or P GI S a n d P GI C, res p ecti vel y. P GI S a n d 
P GI C will be c ollecte d  usi n g a ta blet de vice aft er perf or ma nce base d tests d uri n g visits  at 
W ee ks   ( o nl y P GI S), 
. P GI S a n d P GI C q uesti o ns are re p orte d 
i n Secti o n  1 6. 5. P GI S a n d P GI C will be assess e d o nl y w he n a l ocal la n g u a ge versi o n f or t he 
site/c o u ntr y is a vaila ble. 
Wi des pre a d P ai n I n de x ( W PI) a n d S y m pt o m Se verit y Sc ale ( S S sc ale)  
W PI  a n d S S scale will be c ollecte d o nl y at Scree ni n g Visit 2 wit h a ta blet t o e xcl u de partici pa nts 
wit h fi br o m yal gia, acc or di n g t o rece nt criteria b y t he A merica n C olle ge of R he u mat ol o g y 
(W olfe  et al 2 0 1 0).  T he  use  of  b ot h  scales  all o ws f or  hi g hl y  acc urat e  i de ntificati o n  a n d  
differe ntiati o n of fi br o m yal gia patie nts. 
P erf or m a n c e O ut c o m e s ( P erf O)  
A  series  of  perf or ma n ce -base d  tests,  acc or di n g  t o  t he  O A R SI  g ui deli ne  “Rec o m me n d e d 
perf or ma n ce -base d tests  t o assess p h ysical f u ncti o n i n pe o ple dia g n ose d wit h hi p or k nee 
oste oart hritis ” (D o bs o n et al 2 0 1 3), will be perf or me d at baseli ne a n d at Wee ks 
 
. T hes e  tests  are  i nte n d e d  f or  use  b y  b ot h  cli nicia ns  a n d  researc h ers  as  
perf or ma n ce o utc o me m eas ures a n d are vie w e d as c o m ple me ntar y t o esta blis he d self -re p ort 
meas ures s u c h as  q uesti o n naires. T h e g ui deli ne d escri bes a C ore set a n d a Rec o m me n de d s et 
C CI
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of tests. T he C ore set i ncl u des:  3 0 sec o n d c hair sta n d test, 4 × 1 0 m fast -pace d wal k test, a n d stair 
cli m b test. T he Rec o m m e n de d set i ncl u d es t he C ore set pl us ti me d u p & g o test a n d  6 mi n utes 
wal ki n g dista nce test.   
Wit h t he ai m of mi ni mizi n g partici pa nts ’ b ur de n a n d i n c o nsi derati o n of p ote ntial o perati o nal 
c halle n ges i n i m ple me nti n g all tests i n a lar ge m ulti -ce nter st u d y, o nl y 3 0 sec o n d c hair st a n d 
test, 4 × 1 0 m fast-pace d w al k test, a n d 6 mi n utes wal ki n g dista nce test will be perf or me d. F urt her 
details o n  t he e xec uti o n of t he tests are descri b e d i n t he O A R SI g ui deli ne, pr o vi de d as a se parate 
ma n ual.  
8. 5. 1. 1  
 
 
 
T he o bjecti ves of t he 
 
 
. T his i nf or mati o n is n ot ot her wise 
c ollecte d i n t he trial wit h ot her assess me nts.   
A t otal sa m ple size of 
 st u d y partici pa nts is pla n ne d f or 
 
. D etails re g ar di n g t he 
 
  
 
 
 
Patie nts w h o ha v e c o nse nte d t o t he 
 
 
8. 5. 2  
P h ar m a c o ki n eti c s  
P har mac o ki netic ( P K) s a m ples will be c ollecte d at t he  ti me p oi nts defi ne d i n t he Assess me nt 
Sc he d ule ( T a ble  8- 1), f o ot n otes 1 4 a n d 1 5) i n all partici pa nts. F oll o w i nstr ucti o ns o utli ne d i n 
t he la b orat or y ma n u al 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. 
L N A 0 4 3  P K  will  be  meas ure d  o nl y  i n  partici pa nts  a d mi nistere d  L N A 0 4 3  a n d  will  be  
deter mi ne d b y a vali dat e 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 o w er 
Li mit of Q ua ntificati o n ( L L O Q) is 1 0 n g/ m L i n ser u m.  
T he e n d o ge n o us A N G P T L 3 will be meas ure d i n all partici pa nts a n d will be deter mi ne d b y a 
vali date d li ga n d bi n di n g assa y; t he a ntici pate d L L O Q is 3 9. 7 p m ol/ L i n ser u m. 
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 ort. 
P K  sa m ples  re mai ni n g  after  c o m pleti o n  of  t he  deter mi nati o n  of  pare nt  ma y  be  use d  f or  
e x pl orat or y  assess me nt  of  meta b olites  or  ot her  bi oa nal ytical  p ur p os es  (e. g.,  cr oss  c hec k  
C CI
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bet wee n differ e nt sites, sta bilit y assess me nt). 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. 
D ue t o a li mite d P K sa m pli n g, o nl y s u m mar y statistics of meas ure d P K c o nce ntrati o ns will be 
re p orte d, a n d n o f urt her P K para meters will be deter mi ne d i n t his st u d y. 
8. 5. 3  
Bi o m ar k er s  
T he list ma y be c ha n g e d or e x p a n de d f urt her, as it is rec o g nize d t hat m ore rel e va nt or n o vel 
bi o mar kers ma y be dis c o vere d d uri n g t he c o n d uct of t he st u d y. 
Sa m ple(s) will be c ollecte d at t he ti me p oi nt(s) defi ne d i n t he Assess me nt Sc he d ule ( Ta bl e  8- 1), 
at st u d y sites i n all partici pati n g c o u ntries e xce pt C hi na.  
Ser u m, uri ne a n d s y n o vial fl ui d bi o mar kers st u die d ma y i ncl u de, b ut are n ot li mite d t o s urr o gate 
bi o mar kers of cartila ge tiss ue t ur n o ver: 
 
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•  
  
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Pr o vi de d  t hat  L N A 0 4 3  has  de m o nstrate d  re pair  acti vit y  b y  h yali ne  cartila ge  f or mati o n  i n 
da ma ge d artic ul ar cartila ge i n precli nical a n d earl y h u ma n st u dies, ser u m, uri ne a n d s y n o vial 
fl ui d bi o mar kers of e xtr acell ular m atri x re m o deli n g ma y be st u die d. T h e g oal is t o f urt her 
c haracteri ze t he mec ha nis m of acti o n of t he dr u g i n partici pa nts wit h m o derate t o se v ere k n ee 
O A, a n d t o i de ntif y p ote ntial ass ociati o ns wit h res p o nse t o treat me nt wit h L N A 0 4 3 a n d diseas e 
pr o gressi o n.  
 
 
 
 
 
 I n partic ular, 
 
 
 
Ser u m sa m ples ma y als o be use d t o l o o k f or pr otei n mar kers t hat ma y be ass ociate d wit h 
treat me nt res p o ns e or pr e dict res p o nse t o treat me nt. 
F oll o w i nstr ucti o ns f or 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 pr o vi de d i n t he 
la b orat or y ma n u al. 
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N o v arti s  
C o nfi d e nti al  
P a g e 7 1  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
D N A s a m pli n g / P h ar m a c o g e n eti c s  
T he st u d y i ncl u des a n o pti o nal ge netic researc h c o m p o ne nt w hic h re q uires a se parate i nf or me d 
c o nse nt si g nat ure if t he partici pa nt a grees t o p artici pate. As per mitte d b y l ocal g o ver ni n g 
re g ulati o ns a n d b y I R B/I E C, 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 hese o pti o ns t o t he partici pa nt. 
T he  p ur p ose  of  g e netic  researc h  ma y  b e  t o  better  u n dersta n d  t he  s afet y  a n d  efficac y  of  
L N A 0 4 3, or t o lear n m ore a b o ut h u m a n diseas es, or t o hel p d e vel o p wa ys t o detect, m o nit or 
a n d treat diseases.  
As tec h n ol o g y c ha n ges o ver ti me, t he m ost a p pr o priate tec h n ol o g y will be use d at t he ti me t he 
e x pl orat or y ge n etic res earc h is perf or me d. T his ma y i ncl u de t he st u d y of t h e e ntire ge n o m e. 
La b orat or y ma n uals will be pr o vi de d wit h det aile d i nf or mati o n o n s a m ple c ollecti o n, ha n dli n g, 
a n d s hi p me nt.  
T o ma xi mize c o nfi de ntialit y, all sa m ples a n d t he i nf or mati o n ass ociate d wit h t he sa m ples will 
be d o u ble -c o d e d t o pre v e nt t he e x p os ure of t h e partici pa nt’s i nf or mati o n a n d i de ntit y. T his 
d o u ble- c o di n g pr ocess all o ws N o vartis  t o g o bac k a n d destr o y t he sa m ple at t he partici pa nt’s 
re q uest. I n a d diti o n, sa m ple i nf or mati o n is st ore d i n o ne sec ure d dat a base w hile ge netic d ata is 
st ore d i n a n i n de pe n d e nt sec ure d d ata bas e. 
8. 5. 3. 1  
A d diti o n al bi o m ar k er a s s e s s m e nt s  
T his  cli nical  st u d y  ma y  i ncl u de  a d diti o nal,  o pti o nal  bi o mar ker  c o m p o ne nts  o n  a vaila bl e  
sa m ples  or  i ma gi n g  data,  a n d  c o ul d  be  use d  f or  e x pl orat or y  h y p ot hesis  ge nerati o n  (e. g.,  
disc o ver y- bas e d r esear c h).  
8. 5. 4  
I m a gi n g 
Sta n dar d, s h ort -fil m X-ra y of t he k nees at 1 0° of fle xi o n will be perf or me d d uri n g scree ni n g 
a n d d uri n g t he st u d y at Wee ks  , 1 0 4, 
. Sta n dar dizati o n will be e ns ure d b y 
mea ns of a S y nafl e x le g h ol der a n d ce ntral rea di n g. T hese X -ra ys will be use d t o meas ure J S W 
wi t h b ot h fi xe d l ocati o n a n d mi ni mal J S W met h o ds.  
I n  or der  t o  c o m ple me nt  t he  pri mar y  a n d  sec o n dar y  q M RI  e n d p oi nts  assessi n g  cartila ge  
t hic k ness i n t he tar get k nee, a series of e x pl orat or y a nal yses will be perf or me d. T he a nal yses 
bel o w will pr o vi de a n alter nati ve meas ure me nt of t he artic ul ar cartila ge a n d assess t he ot her 
tiss ues of t he k nee j oi nt. 
•  
 
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•  
 
•  
 
 
T he met h o ds f or ass ess me nt a n d rec or di n g f or b ot h X -ra y a n d M RI are s pecifie d  i n t he i ma gi n g 
c harter.  
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N o v arti s  
C o nfi d e nti al  
P a g e 7 2  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
T he c o d e d me di cal i ma g es will be use d pri maril y f or a nal ysis as des cri b e d i n t his pr ot o c ol; 
h o we ver, t he i ma g es ma y als o be use d f or t he d e vel o p me nt a n d e v al uati o n of n e 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. 
8. 5. 5  
Ot h er A s s e s s m e nt s  
8. 5. 5. 1  
A cti gr a p h y  
Acti gra p h y is a well -esta blis he d, wi del y -acce pte d a n d vali date d tec h n ol o g y, c o m m o nl y use d 
f or p h ysical acti vit y assess me nt (Farr  et al 2 0 0 8). 
Partici pa nts will be pr o vi de d wit h a me dical -gra de wrist -w or n acti gra p h y se ns or a n d will be 
i nstr ucte d t o wear t he se ns or 
 
 as i n dicate d i n Ta ble  8- 1. T h e wrist acti gra p h y se ns or s h o ul d b e w or n o n t he n o n-
d o mi na nt ha n d. Bef ore weari n g t he wrist -base d acti gra p h y se ns or, partici pa nts will be trai ne d 
i n place me nt a n d use of t he se ns or b y site staff pri or t o first use a n d after war d as nee de d. 
Partici pa nts will bri n g bac k t he acti gra p h y s e ns or t o eac h visit f or data tra nsfer as i n dicate d i n 
Ta ble  8- 1.  
T his wrist acti gra p h y s e ns or will assess p h ysical acti vit y a n d m o bilit y para meters .  D ata will be 
pr ocesse d b y t he ve n d or ce ntrall y, a n d t he dail y s u m mar y data will be se nt electr o nicall y t o 
N o vartis. 
Detaile d i nstr ucti o ns c o n cer ni n g t he acti gra p h y s e ns ors will be pr o vi de d t o t he I n v esti gat ors 
a n d partici pa nts i n t he A cti gra p h y Ma n ual pri or t o usi n g t he acti gra p h y se ns or. 
Acti gra p h y will n ot b e perf or me d at sites w here Healt h A ut h orit y a n d/ or I R B/I E C di d n ot 
a p pr o ve Acti gr a p h y assess me nts, if t he de vice is n ot a vaila ble o n site f or l o gistics or ot her 
reas o ns, or i n case t he I n vesti gat or c o nfir ms t hat t he patie nts s h o ul d be e xe m pte d. 
8. 5. 5. 2  
G ait a s s e s s m e nt  
T he o pti o nal gait ass ess me nt (at sel ecte d sites o nl y) will be perf or me d usi n g t he B S P, w hic h 
c o nsists i n a series of weara ble di gital de vices. St u d y partici pa nts at selecte d sites will be i n vite d 
t o partici pate i n t he gait assess me nt, e xce pt t h ose w h o meet a n y of t he f oll o wi n g e xcl usi o n 
criteria:  
•  B o d y wei g ht > 1 2 0 k g at Scree ni n g Visit 1 
•  S h oe size: < 3 4 or > 4 7 ( E U), < 4. 5 or > 1 1. 0 ( U S) at Scree ni n g Visit 1 
Partici pa nts will be as ke d t o perf or m a batter y of i nstr u me nte d p h ysical perf or ma nce tests w hile 
weari n g t h e B S P t o meas ure a seri es of g ait para meters, w hic h c o ul d i ncl u de: gait s pee d, 
ca de n ce, stri de le n gt h a n d k nee d y n a mic l oa di n g para m eters. T h ese g ait  para m eters will b e 
e xtracte d fr o m t he r a w d ata c ollecte d at site i n t he bac ke n d p ost - d ata c ollecti o n b y N o vartis.  
All t he I n vesti gat ors i n gait assess me nt s h o ul d f oll o w f urt her i nstr ucti o ns as descri be d i n t he 
Gait Assess me nt Ma n ual. Partici pa nts will be i nstr ucte d h o w t o c o m plet e t he gait assess me nt 
b y t he I n vesti gat ors. 
O n N o ve m ber 1 8t h, 2 0 2 2, it was c o m m u nicate d t o st u d y i n vesti gat ors partici pati n g i n t he 
o pti o nal gait assess me nt t hat t he e x pl orat or y g ait assess me nt was ter mi nat e d wit h i m me diate 
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N o v arti s  
C o nfi d e nti al  
P a g e 7 3  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
effect d ue t o l o w e nr ol me nt, a n d, t heref ore, t he y w o ul d n o l o n ger ha v e t h e gait assess me nts 
c o m plete d at t he f oll o w - u p visits. 
8. 5. 5. 3  
T ot al K n e e R e pl a c e m e nt ( T K R) a n d Virt u al K n e e R e pl a c e m e nt ( V K R)  
T K R is a rele va nt o utc o me i n oste oart hritis trials ( Maillefert  et al 2 0 0 5). Assessi n g disease 
pr o gressi o n b y T K R is dic h ot o m o us a n d will be a nal yze d b ot h as i nci de n ce a n d ti me t o e ve nt 
i n t his trial. H o w e ver, o v erall t he n u m ber of O A p artici pa nts w h o reac h t his e n d p oi nt wit hi n a n 
O A trial is us uall y s mall, a n d i m p orta nt dis pari ti es i n T K R b y race, ge n der, s oci oec o n o mic 
stat us, access t o care, s ur ge o n pr efere nce, a n d healt h care s yste ms li mit its use i n O A  tri als 
(Ma n n o et al 2 0 1 2). 
I n or der t o o ver c o me t he li mitati o n a n d biases of T K R, t he c o nce pt of V K R has bee n p urs ue d. 
V K R is a c o m p osite sc ore, i ncl u di n g b ot h cli nical ( W O M A C) a n d str u ct ural criteri a (J S W). 
Partici pa nts meeti n g criteria f or t his c o m p osite sc ore c o ul d be c o nsi dere d as reac hi n g a sta ge 
wit h s ustai ne d pai n, r e d u ce d f u n cti o n, a n d e vi de n ce  of X -ra y pr o gressi o n, w here a T K R w o ul d 
be warra nte d, alt h o u g h n ot necessaril y occ urri n g.  
8. 5. 5. 4  
 
 will be c ollecte d 
 as 
i n dicate d  i n  Ta ble  8- 1.   
 t o  b e  rec or de d  i ncl u de
 
 
 
 
 
8. 5. 5. 5  
Tri al F e e d b a c k Q u e sti o n n air e ( T F Q)  
T his st u d y is i ncl u di n g a n o pti o nal q uesti o n naire, t he " Trial Fee d bac k Q uesti o n naire" f or trial 
partici pa nts t o pr o vi d e f ee d bac k o n t heir cli nical trial e x p erie nce. I n di vi d ual trial partici pa nt 
res p o nses  will  n ot  be  re vie we d  b y  I n vesti gat ors.  Res p o nses  ma y be  use d  b y  t he  s p o ns or  
( N o vartis) t o u n d ersta n d w her e i m pr o ve me nts ca n be ma de i n f ut ure cli nical trial pr o cesses. 
T his  q uesti o n naire  d oes  n ot  as k  q uesti o ns  a b o ut  t he  trial  partici pa nt's  disease,  s y m pt o ms,  
treat me nt effect, or A Es, a n d, t heref ore is n ot co nsi dere d as trial d ata.  
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 h e 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 v esti gat or. 
Partici pa nts ma y v ol u ntaril y disc o nti n ue st u d y treat me nt (ref use st u d y treat me nt b ut c o nti n ue 
wit h  st u d y  partici pati o n)  or  c o m pletel y  disc o nti n ue  fr o m  t he  st u d y  ( n o  f urt her  st u d y  
partici pati o n) f or a n y reas o n, at a n y ti me. 
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N o v arti s  
C o nfi d e nti al  
P a g e 7 4  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
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 p a nt if he/s he belie ves t hat 
c o nti n uati o n w o ul d ne gati vel y i m pact 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 u n der t he f oll o wi n g circ u msta nces: 
•  Partici pa nt/ g uar dia n decisi o n 
•  Pre g na nc y  
•  Use of certai n pr o hi bite d treat me nt as per t he pr o hi bite d treat me nt secti o n ( Secti o n  6. 2. 2) 
•  A n y sit uati o n i n w hic h 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 
•  F oll o wi n g e mer ge n c y u n bli n di n g f or safet y reas o n (s) 
•  T K R i n eit her k nee 
•  A n y s ur ger y t o t he tar get k nee 
•  A n y tra u ma t o t he tar g et k nee t hat ca n ha ve a n i m pact o n cartila ge gr o wt h, acc or di n g t o 
I n v esti gat or's j u d ge me nt 
•  E mer ge nce of t he f oll o wi n g a d verse e ve nts:  
•  H y perse nsiti vit y reacti o n / a na p h yla xis 
•  He mart hr osis  
•  Se ptic art hritis  
•  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 ui n g 
partici pati o n i n t he st u d y 
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  f or  t h e  partici pa nt’s  pre mat ure  disc o nti n uati o n  of  st u d y  
treat me nt a n d r ec or d t his i nf or mati o n. 
Disc o nti n uati o n of st u d y treat me nt d oes n ot re q uire t he s u bject t o be dis c o nti n ue d fr o m t he 
st u d y a n d all o n g oi n g visit assess me nts. 
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 ' Wit h dra wal of I nf or me d C o nse nt' secti o n). 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 t he Assess me nt Sc he d ule. 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/ pre-desi g nate d c o nta ct as s pecifie d i n t he l ost t o f oll o w -u p secti o n. 
T his c o ntact s h o ul d pref era bl y be d o ne acc or di n g t o t he st u d y visit sc he d ule. 
If t he p artici pa nt ca n n ot or is u n willi n g t o atte n d a n y visit(s), t he site staff s h o ul d mai ntai n 
re g ular  tele p h o ne  c o ntact  wit h  t he  p artici pa nt,  or  wit h  a  pers o n  pre-desi g nate d  b y  t h e  
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. 
After st u d y treat me nt disc o nti n uati o n, at a mi ni m u m, i n a b bre viate d visits, 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 v e nts / Seri o us A d verse E v e nts 

N o v arti s  
C o nfi d e nti al  
P a g e 7 5  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
T he I n v esti gat or m ust als o c o ntact t he I R T t o re gister t he p artici pa nt’s disc o nti n uati o n fr o m 
st u d y treat me nt. 
If disc o nti n uati o n occ urs beca us e treat me nt c o de has bee n br o ke n, please refer t o E mer g e nc y 
brea ki n g of tr eat me nt c o de secti o n.  
9. 1. 2  
Wit h dr a w al of i nf or m e d c o n s e nt  
Patie nts ma y v ol u ntaril y wit h dra w c o nse nt t o p artici 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/ o p p ositi o n t o use data/ bi ol o gical sa m ples occ urs w he n a partici p a nt: 
E x plicitl y re q uests t o st o p use of t heir bi ol o gical s a m ples a n d/ or data ( o p p ositi o n t o use 
partici pa nt’s data a n d bi ol o gical sa m ples)  
a n d 
N o l o n ger wis hes t o recei ve st u d y treat me nt 
a n d 
D oes n ot wa nt a n y f urt her visits or assess me nts (i ncl u di n g f urt her st u d y- relate d c o ntacts) 
T his re q uest s h o ul d be i n writi n g ( de pe n di n g o n l ocal re g ulati o ns) a n d rec or de d i n t he s o urce 
d oc u me ntati o n. 
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/ o p p ositi o n t o use data/ bi ol o gical sa m ple a n d rec or d t his i nf or m ati o n. 
W here c o nse nt t o t he use of Pers o nal a n d C o de d D ata is n ot re q uire d i n a certai n c o u ntr y's le g al 
fra me w or k, t he partici pa nt t heref ore ca n n ot wit h dra w c o nse nt. H o we ver, t he y still retai n t he 
ri g ht t o o bject t o t he f urt her use of t heir Pers o nal Data. 
St u d y treat me nt m ust be disc o nti n ue d a n d n o f urt her ass ess me nts c o n d uct e d, a n d t h e data t hat 
w o ul d ha ve bee n c ollect e 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  p artici 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. 
If t he p artici pa nt a grees, a fi nal e val uati o n at t he ti me of t he  partici pa nt’s wit h dra wal of  
c o nse nt/ o p p ositi o n t o use data/ bi ol o gical sa m ples s h o ul d be ma de as d etaile d i n t he ass ess me nt 
ta ble (refer t o Secti o n  8). 
N o vartis/ S p o ns or will c o nti n ue t o retai n a n d use all researc h res ults ( data) t hat ha ve alr ea d y 
bee n c ollecte d f or t he st u d y e val uati o n, i ncl u di n g pr ocessi n g of bi ol o gical sa m ples t hat has 
alrea d y start e d at ti me of c o nse nt wit h dra w al/ o p p ositi o n. N o ne w Pers o nal Data (i ncl u di n g 
bi ol o gical sa m ples) will be c ollecte d f oll o wi n g wit h dra wal of c o nse nt/ o p p ositi 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 wit h dra w c o nse nt/ o p p ose t o t he use of t heir data/ bi ol o gical sa m ples, t he 
I n v esti gat or m ust s h o w " d ue dili ge nce" b y d oc u m e 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 partici 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 o v arti s  
C o nfi d e nti al  
P a g e 7 6  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
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 plet e d or u ntil t he e n d 
of t he st u d y. 
9. 1. 4  
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 b e ter mi nate d b y N o v artis  at a n y ti me f or a n y reas o n. T his ma y i ncl u de reas o ns 
relate d t o t he be nefit/ ris k assess me nt of p artici pati n g i n t he st u d y, practical reas o ns (i n cl u di n g 
sl o w e nr oll me nt), or f or re g ulat or y or me dical reas o ns. 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 t he partici pa nt welfare a n d safet y. S h o ul d earl y ter mi nati o n be 
necessar y, p artici 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. T he I n vesti g at 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 v esti gat or or s p o ns or de pe n di n g o n t he 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. 
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 h e n t he last p artici pa nt fi nis hes t heir Wee k 2 6 0 visit a n d a n y 
re peat  assess me nts  ass ociate d  wit h  t his  visit  ha ve  b ee n  d o c 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. I n case of a n earl y st u d y ter mi nati o n, eac h p artici 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.  
All partici pa nts w h o r ecei ve d at least o ne st u d y treat me nt s h o ul d ha ve a safet y f oll o w -u p visit 
( E O S) c o n d ucte d at least 6 m o nt hs after t he last i njecti o n of st u d y treat me nt, u nless assess me nts 
at disc o nti n uati o n visit were perf or me d at least  6 m o nt hs after t h e last  i njecti o n of st u d y 
treat me nt. T he i nf or mati o n c ollecte d is ke pt as s o urce d o c u me ntati o n. All A Es, S A Es a n d 
c o nc o mita nt me dicati o ns re p orte d d uri n g t his ti me peri o d m ust be re p orte d as des cri be d i n 
Secti o n  1 0. 1. D oc u me ntati o n of atte m pts t o c o ntact t he partici pa nt s h o ul d be rec or d e d i n t he 
s o urce d oc u m e ntati o n. 
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 di cal  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 n cl 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 me dical c o n diti o n or 
w orse ni n g  of  a n y  pr e -e xisti n g  si g n  or  s y m pt o m)  i n  a  partici pa nt  or  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. 
A b n or mal la b orat or y val ues or test res ults c o nstit ute A Es 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 

N o v arti s  
C o nfi d e nti al  
P a g e 7 7  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
•  t he y are c o nsi dere d cli nicall y si g nifica nt 
•  t he y re q uire t h era p y 
Cli nicall y si g nifica nt a b n or mal la b orat or y v al ues or test res ults m ust be i de ntifie d t hr o u g h a 
re vie w of val u es 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 g es 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 be n o n -t y pical i n partici pa nts 
wit h t he u n derl yi n g disease. Alert ra n ges f or la b orat or y a n d ot her test a b n or malities are i ncl u de d 
i n Secti o n  1 6. 1 a n d Secti o n  1 6. 2. 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 vers e 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. 
F or p artici pa nts w h o si g n t he pr e -scree ni n g I C F, A Es occ urri n g aft er t h e si g nat ure of t his 
c o nse nt will be ca pt ure d o nl y if t he y m eet t he defi niti o n of seri o us a d vers e e ve nt as o utli ne d i n 
Secti o n 1 0. 1. 2  a n d are re p orte d t o b e ca usall y relate d t o pre -scree ni n g st u d y pr oce d ures (e. g., 
bl o o d sa m pli n g). T he occ urre nce of a d v erse e v e 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 als o ma y be de tecte d w he n t he y 
are v ol u nteere d b y t he p artici pa nt d uri n g or bet wee n visits or t hr o u g h p h ysical e xa mi nati o n 
fi n di n gs, la b orat or y test fi n di n gs, or ot her assess m e nts. 
A d verse e ve nts m ust be r ec or de d 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 h e m, 
acc o m pa ni e d b y t he f oll o wi n g i nf or mati o n (as far as p ossi ble) (if t he e v e nt is seri o us refer t o 
Secti o n  1 0. 1. 2): 
1.  T he classificati o n of A Es is se verit y gra di n g of Mil d, M o derate, or Se v ere. 
Mil d: us uall y tra nsie nt i n nat ure  a n d ma y re q uire o nl y mi ni mal treat me nt or t hera p e utic 
i nter ve nti o n 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 b ut p oses n o 
si g nifica nt or per ma n e nt ris k of har m t o t he partici pa nt. 
•  Se vere: i nterr u pts d ail y  acti vities or si g nifica ntl y affects cli nical stat us or ma y re q uire 
i nte nsi ve t hera pe utic i nter ve nti o n. 
Wit h res pect t o t he p ossi ble k nee-relate d A Es, t he f oll o wi n g g ui da nce o n gra di n g is pr o vi de d: 
T a bl e 1 0 - 1 
G ui d a n c e o n gr a di n g of k n e e -r el at e d A E s 
A E t er m  
Mil d  
M o d er at e  
S e v er e  
Art hr al gi a 
Mil d p ai n  
M o d er at e p ai n; li miti n g 
i n str u m e nt al A D L 
S e v er e p ai n; li miti n g s elf 
c ar e A D L  
Art hriti s 
Mil d p ai n wit h 
i nfl a m m ati o n, er yt h e m a, 
or j oi nt s w elli n g  
M o d er at e p ai n 
a s s o ci at e d wit h si g n s of 
i nfl a m m ati o n, er yt h e m a, 
or j oi nt s w elli n g; li miti n g 
i n str u m e nt al A D L 
S e v er e p ai n a s s o ci at e d 
wit h si g n s of 
i nfl a m m ati o n, er yt h e m a, 
or j oi nt s w elli n g; 
irr e v er si bl e j oi nt 
d a m a g e; li miti n g s elf 
c ar e A D L  
J oi nt eff u si o n  
A s y m pt o m ati c; cli ni c al or 
di a g n o sti c o b s er v ati o n s 
o nl y; i nt er v e nti o n n ot 
i n di c at e d 
S y m pt o m ati c; li miti n g 
i n str u m e nt al A D L 
S e v er e s y m pt o m s; 
li miti n g s elf c ar e A D L; 
i n v a si v e i nt er v e nti o n 
i n di c at e d 

N o v arti s  
C o nfi d e nti al  
P a g e 7 8  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
J oi nt r a n g e of m oti o n 
d e cr e a s e d  
< = 2 5 % l o s s of R O M 
(r a n g e of m oti o n); 
d e cr e a s e d R O M li miti n g 
at hl eti c a cti vit y  
> 2 5 - 5 0 % d e cr e a s e i n 
R O M; li miti n g 
i n str u m e nt al A D L 
> 5 0 % d e cr e a s e i n R O M; 
li miti n g s elf-c ar e A D L  
 
2.  Its r elati o ns hi p t o t he st u d y 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’, u nless t here is reas o na ble pr o ba bilit y t hat t he st u d y 
dr u g/ pr oce d ur e le d t o a w orse pr o gressi o n of t he k nee O A (i n i nte nsit y or ti me c o urse). 
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 tri al 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 disease ca n o nl y 
be e val uat e d mea ni n gf ull y b y a n a nal ysis of treat me nt gr o u ps, n ot o n a si n gle partici pa nt. 
3.  Its d ur ati 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 v e 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 f or defi niti o n of S A E) a n d w hic h 
seri o us ness criteria ha ve bee n met. 
5.  Acti o n ta ke n re g ar di n g wit h st u d y treat me nt. 
6.  Treat me nt of t he A E, if a n y. 
7.  Its o utc o me. 
C o n diti o ns t hat were alrea d y pres e nt at t he ti me of i nf or me d c o nse nt s h o ul d be rec or d e d i n 
me dical hist or y of t he partici pa nt.  
A d verse e v e nts (i ncl u di n g la b 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 h a 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 v e nt rec or di n g f or eac h partici pa nt s h o ul d be c o nti n ue d f or at least 1 8 0 da ys f oll o wi n g 
t he last d ose of st u d y tr eat me nt, or e n d of st u d y visit ( E O S), w hic he v er is l o n ger.O n ce 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 (e. g., 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 b e ma de at eac h visit 
( or m ore fre q ue ntl y, if n ecessar y) of a n y c ha n g es 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. 
A d verse e ve nt trai ni n g f or
 
I nf or mati o n a b o ut a d verse dr u g reacti o ns f or t h e i n vesti gati o nal dr u g ca n be f o u n d i n t he 
I n v esti gat or's Br oc h ur e (I B). 
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 v e 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 
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 7 9  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
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 wer e m ore se vere ( pl ease refer t o t he  I C H- E 2 D G ui deli n es). 
•  Res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y  
•  C o nstit utes a c o n ge nital a n o mal y/ birt h defect 
•  Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n, u nless 
h os pitalizati o n is f or:  
•  R o uti ne treat me nt or m o nit ori n g of t he st u die d i n dicati o n, n ot ass ociate d wit h a n y 
deteri orati o n i n c o n diti o n  
•  Electi ve or pr e - 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 bs e 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 g e 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 di call y si g nifica nt, e. g. defi ne d as a n e v e nt t hat je o par dizes t he partici pa nt or ma y 
re q uire me di cal or s ur gical i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d a b o ve 
Me dical a n d s cie ntific j u d g me nt s h o ul d be e xercis e d i n deci di n g w h et her ot her sit uati o ns s h o ul d 
be c o nsi dere d seri o us 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 v e 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 x a m ples of s uc h e ve nts are i nte nsi ve treat me nt i n a n 
e mer ge n c y r o o m or at h o me f or 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 d e pe n de n c y or a b us e  ( please refer t o t he I C H-
E 2 D G ui deli nes). 
All 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 ar e 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 vers e reacti o n. 
1 0. 1. 3  
S A E r e p orti n g  
T o e ns ure partici pa nt saf et y, e ver y S A E, re gar dless of ca usalit y, occ urri n g after t he p artici pa nt 
has pr o vi de d i nf or m e d c o nse nt a n d u ntil 1 8 0 da ys f oll o wi n g t he last d ose of treat me nt, or E O S, 
w hic he ver is l o n ger, m ust be r e p orte d t o N o vartis  Safet y 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 n ces l ater 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. A n y 
S A Es e x perie nce d after t he 1 8 0 -da y peri o d after E O S 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 v esti gat or  s us p ects  a  ca us al  relati o ns hi p  t o  st u d y  treat me nt.  D etaile d  i nstr ucti o ns  
re gar di n g t h e s u b missi o n pr ocess a n d re q uire me nts are t o b e f o u n d i n t h e I n v esti 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 n cl 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 
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. A n S A E occ urri n g at a 

N o v arti s  
C o nfi d e nti al  
P a g e 8 0  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
differe nt ti me i nter val or 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 s e p aratel 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 ns ert ( n e w 
occ urr e 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, N o vartis ma y ur ge ntl y re q uire 
f urt her i nf or mati o n fr o m the 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 n e x pect e d S eri o us A d verse Reacti o ns ( S U S A Rs) will be c ollecte d a n d re p ort e d t o 
t he c o m pete nt a ut h orities a n d rel e va nt et hics c o m mittees i n acc or d a nce wit h E U Cli nical Trial 
Re g ulati o n 5 3 6/ 2 0 1 4 or as per nati o nal re g ul at or y re q uire me nts i n partici pati n g c o u ntries. 
O nl y data r elate d t o S A Es ca usall y relate d t o pre -scree ni n g st u d y pr o ce d ures ( X-ra y, k nee 
e xa mi nati o n) will be c ollecte d. All ot her data relat e d t o pre -scree ni n g will o nl y be rec or de d i n 
s o urce d oc u m e ntati o n.  
Treat me nt -e mer ge nt  el e vati o ns  i n  A S T  or  A L T  ( > 3 x  U L N)  i n  c o m bi nati o n  wit h  t otal  
bilir u bi n > 2 x U L N or ja u n dice i n t he a bse nce of c h olestasis ( defi ne d as A L P < 2 U L N) or ot her 
ca uses of h y p er bilir u bi ne mia ca n be a n i n dicat or of se vere dr u g i n d uce d li ver i nj u r y ( H y’s La w). 
F or t his reas o n, a p ote nti al H y’s La w case re q uires e x pe dite d re p orti n g a n d will be ha n dle d as 
a seri o us u ne x pect e d a d v erse e v e nt (assessi n g it as me dicall y si g nifica nt i n t he a bse nce of a n y 
ot her seri o us n ess criteria). It m ust be re p orte d as a n S A E t o t he s p o ns or pr o m ptl y (i.e., e v e n 
bef ore all ot her p ossi ble ca uses of li ver i nj ur y ha ve bee n e xcl u de d). Re p orti n g s h o ul d i ncl u de 
all a vaila ble i nf or mati o n, es peciall y t hat n ee de d f or e v al uati n g t he dia g n osis, se verit y a n d 
li keli h o o d t hat t he st ud y treat me nt ca use d t he reacti o n. F or patie nt m o nit ori n g a n d t o better 
u n dersta n d p ote ntial eti ol o gies, t he i n vesti gat or m ust i nitiate a cl ose f oll o w -u p u ntil c o m plete 
res ol uti o n of t he pr o ble m a n d c o m pleti o n of all att e m pts t o o btai n s u p ple me ntar y data.  
1 0. 1. 4  
Pr e g n a n c y r e p orti n g  
Pr e g n a n ci e s  
T o e ns ure partici pa nt saf et y, eac h pre g n a 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 u p t o deter mi ne o utc o me, i ncl u di n g s p o nta ne o us or v 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 g e nital a b n or malities, or mater nal 
a n d/ or ne w b or n c o m plicati o ns. Li ve birt hs will be f oll o we d -u p t o 1 2 m o nt hs of a ge t o c ollect 
i nf or mati o n o n a n y a b n or malities w hic h were n ot a p pare nt at t he ti me of birt h. 
Pre g na nc y s h o ul d be r ec or de d a n d r e p orte d b y t he I n v esti gat or t o  N o vartis. Pre g na nc y f oll o w -
u p s h o ul d be r ec or d e 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 m e nt of t he p ossi ble 
relati o ns hi p bet wee n t he st u d y treat me nt a n d a n y pre g na nc y o utc o me. A n y S A E e x perie nce d 
d uri n g pre g na n c y m ust be re p ort e 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  
St u d y treat me nt err ors ar e u ni nte nti o nal err ors i n t he prescri bi n g, dis pe nsi n g, or a d mi nistrati o n  
of st u d y treat me nt. 

N o v arti s  
C o nfi d e nti al  
P a g e 8 1  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
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 us e d 
n ot i n acc or da n ce wit h t h e pr ot oc ol. 
A b use  c orr es p o n ds  t o  t he  persiste nt  or  s p ora di c,  i nte nti o nal  e xcessi ve  use  of  a  me dici nal  
pr o d uct, w hic h is acc o m pa nie d b y har mf ul p h ysical or ps yc h ol o gical effects. 
St u d y 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, i ncl u di n g mis use or 
a b use, m ust be re p orte d o n t he A E ( or S A E, if t he e ve nt meets t he defi niti o n of a n S A E) C R F  
wit hi n 2 4 h o urs of I n v esti gat or’s a ware n ess. 
F or m ore i nf or mati o n o n A E a n d S A E defi niti o n a n d re p orti n g re q uire me nts, please see t h e 
res pecti ve s ecti o ns. 
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 s af et y a n d e n h a nce relia bilit y i n deter mi ni n g t he he p at 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. 
T he f oll o wi n g t w o cate g ories of a b n or malities / a d verse e v e nts ha ve t o be c o nsi dere d d uri n g 
t he c o urse of t h e st u d y (irres pecti ve of w h et her cl assifie d/re p orte d as A E/ S A E): 
•  Li ver la b orat or y tri g gers, w hic h will re q uire re peate d assess me nts of t he a b n or mal 
la b orat or y para meter 
•  Li ver e ve nts, w hic h will re q uire cl ose o bser v ati o n, f oll o w- u p m o nit ori n g a n d c o ntri b uti n g 
fact ors are r ec or de d o n t h e a p pr o pri ate C R Fs 
Please refer t o 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 g ers 
a n d li ver e ve nts. 
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 cas e 
of li ver e ve nts are o utli n e d i n Ta ble  1 6- 2. Re p eat li ver c h e 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) t o c o nfir m ele vati o n. 
•  T hese li ver c h e mistr y re p eats will be perf or me d usi n g t he ce ntral la b orat or y. If res ults will 
n ot be a vaila ble fr o m t he ce ntral la b orat or y, t he n 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 u bse 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 o ciate d wit h t his 
e ve nt s h o ul d ha ve r es ults rec or d e d o n t he a p pr o pri ate C R F 
•  If t he i nitial ele vati o n is c o nfir me d, cl ose o bs er 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 
•  Disc o nti n uati o n of t he i n vesti gati o nal dr u g (refer t o t he Disc o nti n uati o n of st u d y treat me nt 
secti o n), if a p pr o priate 
•  H os pitalizati o n of t he partici pa nt if a p pr o priate  
•  Ca usalit y assess me nt of t he li ver e ve nt  
•  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 v esti 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 

N o v arti s  
C o nfi d e nti al  
P a g e 8 2  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
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 x cl usi o n of u n derl yi n g li ver disease 
•  All f oll o w - u p i nf or mati o n a n d pr oce d ures p erf or me d m ust be rec or d e d as a p pr o priate i n 
t he C R F 
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 ori es of a b n or mal re nal 
la b orat or y al ert 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 ncreas e ≥ 2 5 % c o m pare d t o bas eli 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 r ati 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 x cl u di n g me nstr uati o n, U TI, e xtre me 
e xercis e, or tra u m a)  
A b n or mal re n al 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.  
O nce a p artici pa nt is e x p ose d t o st u d y treat me nt, re nal la b orat or y alerts or re nal safet y e ve nts 
s h o ul d be m o nit ore d a n d f oll o we d u p b y t he I n v esti gat or or desi g nate d trial staff as s u m marize d 
i n Secti o n  1 6. 2.  
E ver y re nal la b or at or y tri g ger or re nal e ve nt as defi ne d i n Ta ble  1 6- 3 s h o ul d be f oll o we d u p b y 
t he I n v esti gat or or d esi g nate d pers o n n el at t he trial site as s u m marize d i n Ta ble  1 6- 4. 
1 0. 2. 3  
D at a M o nit ori n g C o m mitt e e  
A n  i n de pe n de nt  ( of  t h e  st u d y  a n d  L N A 0 4 3  de vel o p me nt  pr o gra m)  D M C  will  re vie w  
c u m ulati ve, se mi -bli n de d safet y d ata c o nti n u o usl y a n d at sc h e d ule d at l east se mi -a n n ual ( e ver y 
6 m o nt hs) meeti n gs. T he D M C will re vie w S A Es as i n di vi d ual cases a n d will als o be a b le t o 
re vie w s u m maries of n o n-seri o us a d verse e v e nts a n d la b orat or y data f or patter ns a n d tre n ds. All 
S A Es occ urri n g i n t his st u d y will be re p orte d t o t he D M C i n a ti mel y ma n ner. T h e D M C will 
re vie w dat a relati n g t o t h ose e ve nts a n d treat me nt i nf or mati o n in a se mi -bli n de d ma n ner at t he 
le vel of treat me nt ar m. T he I n d e pe n d e nt Statisticia n a n d I n de pe n d e nt Pr o gra m mer will recei v e 
se mi-bli n de d treat me nt c o des per treat me nt ar m (e. g., A, B, C a n d D) acc or di n g t o t he a p plica ble 
a n d d oc u me nte d N o vartis pr oce d ures.  T h us, all a n al ysis o ut p uts se nt t o t he D M C will be se mi -
bli n de d, a n d t he I n de p e n de nt Statisticia n a n d I n d e pe n de nt Pr o gra m mer will re mai n partiall y 
bli n de d  t o  t he  act ual  treat me nt  assi g n me nts.  T he  I n de p e n de nt  Statisticia n  will  pr o vi de  
electr o nic re p orts t o  t he D M C a n d t he n c o m m u nicate wit h t h e D M C as nee de d. T o e n ha n ce t h e 
i nte grit y a n d cr e di bilit y of t he trial, pr o ce d ures will be i m ple me nte d t o e ns ure t hat t he D M C 
has s ole access t o i nf or mati o n fr o m t he cli nical trial re gar di n g u n bli n de d or se mi - bli n de d 
res ults. 
Base d o n t h eir r e vie w a n d cli nical j u d ge m e nt, t he D M C will rec o m me n d a p pr o priate acti o n t o 
t he st u d y tea m w hic h ma y i ncl u de st o p pi n g t he trial c o m pletel y, m o dif yi n g t he trial, st o p pi n g a 
d ose ar m, m o dif yi n g a d ose ar m or pr o cee di n g as per pr ot oc ol. 

N o v arti s  
C o nfi d e nti al  
P a g e 8 3  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
Details o n t he or ga nizati o n a n d f u ncti o n of t he D M C will be descri be d i n t he D M C c hart er. 
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 
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 v erificati o n. 
Desi g nate d I n v esti gat or staff will e nter t he d ata re q uire d b y t he pr ot o c ol i nt o t he Electr o ni c 
Case Re p ort F or ms (e C R F). T he e C R Fs ha v e b ee n b uilt usi n g f ull y vali date d sec ure w e b -
e na ble d s oft w are t hat c o nf or ms t o 2 1 C F R Part 1 1 re q uire me nts, I n v esti gat or site staff will n ot 
be gi ve n access t o t h e 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 p a 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. 
T he  I n vesti gat or/ desi g n ee  is  res p o nsi ble  f or  ass uri n g  t hat  t he  data  e ntere d  i nt o  e C R F  is  
c o m plete,  acc urat e,  a n d  t hat  e ntr y  a n d  u p dates  are  perf or m e d  i n  a  ti mel y  ma n ner.  T h e  
I n v esti 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 b ase  l oc k,  t he  I n vesti gat or  will  recei ve  c o pi es  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 v erificati o n. 
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 d esi 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 n ess 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 a n d se nt t o t he 
i n vesti gati o nal site via t he E D C s yste m. Desi g n ate d I n v esti gat or site st aff 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 n ecessar y c ha n g es 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 bas e will be c o de d usi n g t he 
W orl d  Healt h  Or ga ni zati o n  ( W H O)  Dr u g  Refere nce  List,  w hi c h  e m pl o ys  t he  A nat o mical  
T hera p e utic C he mical cl assificati o n s yste m. Me dical hist or y/c urre nt me di cal 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 Di cti o nar y f or Re g ulat or y A cti vities ( Me d D R A) 
ter mi n ol o g y. 
Ra n d o mizati o n c o des a n d data a b o ut all st u d y treat me nt (s) dis pe nse d t o t he partici pa nt a n d all 
d osa ge c ha n ges will be trac ke d usi n g a n I nteracti ve Res p o nse Tec h n ol o g y (I R T). T he s yste m 
will  be s u p plie d b y a  v e n d or, w h o will  als o m a na ge t h e data b ase. T he  d ata will be  se nt 
electr o nicall y t o N o vartis ( or a desi g nat e d C R O) at s pecific ti meli nes.  
Eac h occ urr e nce of a c o d e 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  br ea k  f u n cti 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 h e d ata base has bee n d eclare 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 

N o v arti s  
C o nfi d e nti al  
P a g e 8 4  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
a vaila ble f or dat a a nal ysis/ m o ve d t o restricte d area t o be access e 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 d ata base aft er t hat ti me ca n o nl y be ma de after writte n 
a gree m e nt b y N o vartis d e vel o p me nt ma na g e 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/ dele gate d C R O re pres e ntati ve will re vie w t he pr ot oc ol a n d d ata ca pt ure re q uire me nts 
(i.e. e C R Fs) wit h t he I n v esti gat ors a n d t heir staff. D uri n g t he st u d y, N o vartis/ dele gate d C R O 
e m pl o ys se ver al 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’  dat a.  T he  fiel d  m o nit or  will  c hec k  t h e  c o m plete n ess  of  parti ci pa nt  rec or ds,  t h e  
acc ur ac y of data ca pt ur e / 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 o d 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 nt e d f or acc or di n g t o s p ecificati 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 d ata 
ma y be perf or me d b y a ce ntralize d N o v artis/ dele g ate d C R O/ C R A or ga nizati o n. A d diti o nall y, 
a ce ntr al a nal ytics or g a nizati o n ma y a nal yze data & i de ntif y ris ks & tre n ds f or site o perati o nal 
para me ters a n d pr o vi d e r e 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 p artici 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 m ati 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 v e sti gat or m ust als o kee p t he ori gi nal i nf or me d c o ns e nt f or m si g ne d b y 
t he partici pa nt (a si g n e d c o p y is gi ve n t o t he parti ci pa nt). 
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 ur e a n d/ or data e ntr y. N o vartis m o nit ori n g st a n dar ds re q uire f ull 
verificati o n f or t he pres e nce of i nf or m e d c o nse nt, a d here n ce 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 n c y of t he s o urce d ata wit h t he C R Fs are perf or m e 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 m e 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 yses 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 d at t he ti me 
w he n a n y i nteri m a n al yses are p erf or me d. A n y d ata a nal ysis carrie d o ut i n de pe n de ntl y b y t h e 
I n v esti 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 pres e ntati o n. 
S u m mar y  statistics  f or  c o nti n u o us  varia bles  will  i ncl u de  N,  mea n,  sta n dar d  de viati o n,  
mi ni m u m, l o wer q uartile, me dia n, u p p er q u artile, ma xi m u m. S u m mar y statistics f or discrete 
varia bles will be pr ese nte d i n t he n u m ber a n d perce nt of partici pa nts i n eac h cate g or y. 
U nless ot her wise s pecifi e d, p -val u es will be prese nte d as t w o -si de d p-val ues a n d t w o -si d e d 
c o nfi de nce i nter vals will be dis pla ye d. T he d efa ult le vel of si g nifica nce will be set t o 5 %. 
Efficac y a n d safet y data will be prese nte d b y t he f oll o wi n g treat me nt gr o u ps: 
•  L N A 0 4 3   m g  
, C ycle e ver y  
 
C CI
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 8 5  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
•  L N A 0 4 3   m g   a n d 
, C ycle e v er y  
 
•  L N A 0 4 3   m g  
, C ycle e ver y  
 
•  L N A 0 4 3   m g  
 f oll o we d  
 later (after first i njecti o n) b y 
 
, C ycle e ver y   
 
•  Place b o  
, C y cle e ver y  
 
T he baseli ne val ue is defi ne d as t he last assess me nt pri or t o first d ose a d mi nistrati o n. If t he 
sc he d ule d bas eli ne assess me nt val ue is missi n g, t he scree ni n g val ue will be use d i nstea d.  
1 2. 1  
A n al y si s s et s  
T he f oll o wi n g a nal ysis sets will be use d i n t his st u d y: 
T he Ra n d o mize d A nal ysis Set ( R A S) c o nsists of all ra n d o mize d partici pa nts. U nless ot her wise 
s pecifie d, mis-ra n d o mize d partici pa nts ( mis-ra n d o mize d i n I R T) will be e xcl u de d fr o m t he 
R A S.  
Mis -ra n d o mize d partici p a nts are defi ne d as t h ose partici pa nts w h o were mista ke nl y ra n d o mize d 
i nt o t he I R T pri or t o t he site c o nfir mi n g all eli gi bilit y criteria ha d bee n met a n d t o w h o m n o 
st u d y me dicati o n was gi ve n. Mis-ra n d o mize d p arti ci pa nts are treate d as scree n fail ures. 
T he F ull A n al ysis Set ( F A S) c o m prises all partici pa nts i n t he R A S t o w h o m st u d y treat me nt 
has bee n assi g ne d b y ra n d o mizati o n. Acc or di n g t o t he i nte nt t o treat pri nci ple, partici pa nts will 
be a nal yze d acc or di n g t o t he treat me nt t he y h a ve bee n assi g ne d t o d uri n g t he ra n d o mizati o n 
pr oce d ur e. 
T he Safet y Set i ncl u des all partici pa nts w h o recei ve d at least o ne d os e of st u d y treat me nt. 
partici pa nts will be a nal y ze d acc or di n g t o t he st u d y treat me nt recei ve d.  
T he P K a nal ysis set will i ncl u de all partici p a nts w h o recei ve d st u d y dr u g, ha ve at l east o n e 
a vaila ble vali d (i.e., n ot fla g ge d f or e xcl usi o n) P K ( L N A 0 4 3) c o nce ntrati o n meas ure me nt, a n d 
f or w h o m t her e ar e n o pr ot oc ol de viati o ns wit h i m pact o n P K data. 
T he A N G P T L 3 a nal ysis set will i ncl u de all partici pa nts w h o ha ve at least o ne a vaila ble vali d 
(i.e., n ot fla g ge d f or e x cl usi o n) A N G P T L 3 c o nce ntrati o n meas ure me nt. 
T he I G a nal ysis set will i ncl u de all partici pa nts w h o recei v e d st u d y dr u g, ha ve at least o ne 
a vaila ble vali d (i.e., n ot fla g ge d f or e x cl usi o n) I G meas ure me nt, a n d f or w h o m t here are n o 
pr ot oc ol de viati o ns wit h 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  i ncl u di n g  disease  c haracteristics  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 a n d Safet y set. 
Cate g orical d ata will be prese nte d as fre q u e ncies a n d perce nta g es. 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 ori es a n d c urre nt m e dical c o n diti o ns at baseli ne will be s u m marize d 
se parat el y b y s yste m or ga n class a n d preferre d ter m, b y treat me nt gr o u p. 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
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 8 6  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
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 n cies a n d per ce 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.  
T he n u m ber of visits wit h acti ve a n d place b o i njecti o ns recei ve d will be prese nte d b y treat me nt 
gr o u p. T he d urati o n of e x p os ure t o st u d y treat me nt will als o be s u m mari ze d b y treat me nt gr o u p.  
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 h e 
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 n at o mical  T hera pe utic  
C he mical ( A T C) classifi cati 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) 
1 2. 4. 1  
D efi niti o n of pri m ar y e n d p oi nt( s)/ e sti m a n d( s)  
T he pri mar y efficac y varia ble is c ha n ge fr o m baseli ne i n cartila ge t hic k ness i n t he c M T F C at 
Wee k 1 0 4 deter mi ne d b y q M RI of t he tar g et k nee i n partici pa nts wit h k nee O A. T he a n al ysis 
of t he pri mar y varia ble will be base d o n t he F A S p o p ulati o n. 
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 n ull statistical h y p ot hesis bei n g teste d is t hat t here is n o differe nce b et wee n eac h of t h e 
L N A 0 4 3 re gi me ns v ers us Place b o i n t he mea n c h a n ge fr o m b aseli ne i n cartila ge t hic k ness of 
t he c M T F C at Wee k 1 0 4. 
Let µ j de n ote t he mea n c ha n ge fr o m baseli ne i n cartila ge t hic k ness of t he c M T F C at Wee k 1 0 4 
f or treat me nt re gi me ns j, j = 0, 1, 2, 3 or 4 w here 
•  0 c orres p o n ds t o Place b o 
•  1 c orres p o n ds t o L N A 0 4 3   m g  
, C ycle e ver y  
 
•  2 c orres p o n ds t o L N A 0 4 3   m g  
 a n d 
, C ycle e ver y  
 
•  3 c orres p o n ds t o L N A 0 4 3   m g  
 f oll o w e d  
 later (after first i njecti o n) 
b y 
, C y cle e ver y  
 
•  4 c orres p o n ds t o L N A 0 4 3   m g  
, C ycle e ver y  
 
I n statistical ter ms, Hj: µj ≤ µ 0, HAj : µj > µ0, 
H 1: L N A 0 4 3   m g  
, C ycle e ver y  
 is n ot differe nt t o Place b o wit h res pect t o 
mea n c ha n g e fr o m b aseli ne i n cartila ge t hic k n ess of t he c M T F C at Wee k 1 0 4  
H 2: L N A 0 4 3   m g  
 a n d 
, C ycle e ver y  
 is n ot differe nt t o Place b o 
wit h res pect t o mea n c ha n ge fr o m baseli ne i n cartila ge t hic k ness of t he c M T F C at Wee k 1 0 4 
H 3: L N A 0 4 3   m g  
 f oll o we d  
 later (after first i njecti o n) b y 
 
, C ycle e ver y  
 is n ot differe nt t o Place b o wit h res pect t o mea n c ha n ge fr o m 
baseli ne  i n cartila ge t hic k ness of t he c M T F C at Wee k 1 0 4 
H 4: L N A 0 4 3   m g  
, C ycle e ver y  
 is n ot differe nt t o Place b o wit h res pect t o 
mea n c ha n g e fr o m b aseli ne  i n cartila ge t hic k n ess of t he c M T F C at Wee k 1 0 4 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
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 8 7  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
T he pri mar y a n al ysis will be c o n d ucte d usi n g mi xe d -effect m o del re p eate d meas ures ( M M R M) 
w hic h is vali d u n der t he missi n g at ra n d o m ( M A R) ass u m pti o n, wit h treat me nt a n d a nal ysis 
visit as fact ors a n d bas eli ne sc or e as a c o v ariate i n t he m o del. Treat me nt b y a nal ysis visit a n d 
baseli ne  sc or e  b y  a nal ysis  visit  will  be  i ncl u de d  as  i nteracti o n  ter ms  i n  t he  m o del.  A n  
u nstr uct ure d c o v aria n ce str uct ure will be ass u m e d f or t his m o del. T he si g nifica nce of t h e 
treat me nt eff ects f or L N A 0 4 3 re gi me ns at Wee k 1 0 4 will be deter mi ne d fr o m t he pair wise 
c o m paris o ns  usi n g  t he D u n nett  test  perf or me d  bet wee n  L N A 0 4 3  re gi me ns  a n d  place b o  at  α 
= 0. 0 5. 
1 2. 4. 3  
H a n dli n g of r e m ai ni n g i nt er c urr e nt e v e nt s of pri m ar y e sti m a n d  
T he pri mar y a nal ysis will acc o u nt f or t h e differe nt i nterc urre nt e v e nts as e x plai ne d i n t he 
f oll o wi n g: 
•  Treat me nt disc o nti n uati o ns/ disr u pti o ns f or a n y reas o n: data will be ce ns ore d after 
treat me nt disc o nti n uati o n or first disr u pti o n f or t he pri mar y a nal ysis 
•  U nf ores ee n n o n- a d her e n ce i n t he all o we d p eri o d of per mitte d c o nc o mita nt t hera pies: data 
c ollecte d after n o n - a d her e nce i n t he all o we d peri o d of per mitte d c o nc o mita nt t hera pies 
will be use d f or t he pri m ar y a nal ysis 
T he  pri mar y  M M R M  m o del  i m plicitl y  i m p utes  missi n g  data  u n der  a  missi n g  at  ra n d o m  
ass u m pti o n. F or a nal yses, if all p ost- baseli ne val u es are missi n g t he n t hese missi n g val ues will 
n ot be i m p ute d a n d t his partici pa nt will be re m o ve d fr o m t he a nal ysis, i.e., i t mi g ht be t hat t he 
n u m ber of partici pa nts pr o vi di n g data t o t he a nal ysis is s maller t ha n t h e n u m ber of partici pa nts 
i n t he F A S. 
1 2. 4. 4  
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  
T he  pri mar y  M M R M  m o del  i m plicitl y  i m p utes  missi n g  data  u n der  a  missi n g  at  ra n d o m  
ass u m pti o n. 
1 2. 4. 5  
S u p pl e m e nt ar y a n al y si s  
T he tar g et p o p ulati o n, t he pri mar y v aria ble a n d t he s u m mar y meas ure of t he s u p ple me ntar y 
esti ma n d f or t h e s u p ple m e ntar y esti ma n d are t he sa me as f or t he pri mar y esti ma n d. Differe ntl y 
fr o m t he pri mar y esti ma n d, t he i nter v e nti o n effect f or t his s u p ple me nt ar y esti ma n d is t he effect 
i n a treat me nt p olic y sce nari o w here partici pa nts w o ul d n ot be a ble t o al w a ys a d here t o st u d y 
treat me nt re gi me n. 
T he esti mati o n met h o d is t he sa me as f or t he pri mar y esti ma n d e x ce pt t h at data after st u d y 
treat me nt disc o nti n uati o n/ disr u pti o n f or a n y reas o n i n all treat me nt ar ms will be i ncl u de d a n d 
missi n g data will be i m p ute d.  
1 2. 4. 6  
S e n siti vit y a n al y s e s f or pri m ar y e n d p oi nt/ e sti m a n d  
T he f oll o wi n g se nsiti vit y a nal ysis will be perf or me d f or t he pri mar y esti ma n d, t o assess t he 
r o b ust ness of t he esti mati o n i n t he prese n ce of de vi ati o ns fr o m t he ass u m pti o ns s pecifie d i n t he 
pri mar y a nal ysis. 
T he sa me a nal ysis of c o varia nce ( A N C O V A) m o del as f or t he pri mar y esti mati o n will be 
a d o pte d. I nt erc urre nt e ve nts will be ha n dle d i n t he sa me wa y as i n t he pri mar y a nal ysis. I n t he 

N o v arti s  
C o nfi d e nti al  
P a g e 8 8  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
first ste p, missi n g data after st u d y treat me nt disc o nti n uati o n/ disr u pti o n will be i m p ute d i n t he 
sa me wa y as f or t he pri mar y a nal ysis. S u bse q ue ntl y, f or t he acti ve treat me nt ar ms t hese i m p ute d 
val ues will be f urt her w orse ne d via t he a p plicati o n of i ncreasi n gl y lar ge pe nalties s pecifie d via 
a se nsiti vit y para meter acc or di n g t o t he ti p pi n g p oi nt met h o d ( Per m utt  2 0 1 6). 
1 2. 5   
A n al y si s of s e c o n d ar y a n d s af et y e n d p oi nt s/ e sti m a n d s 
1 2. 5. 1  
Effi c a c y E n d p oi nt s  
T he a nal ysis f or all sec o n dar y efficac y e n d p oi nts will be base d o n t he F A S p o p ulati o n. 
T he c h a n ge fr o m bas eli ne at Wee k 1 0 4 f or t he f oll o wi n g varia bles will be a nal y ze d usi n g a 
si milar M M R M m o del as i n t he pri mar y a nal ysis: 
•  W O M A C pai n  
•  W O M A C pai n wal ki n g o n flat s urface 
•  W O M A C f u ncti o n 
•  Cartila ge t hic k ness i n t he t otal, me dial a n d lateral T F Cs  
•  P h ysical f u ncti o n ( 4 0- meter fast -p ace d wal k test, 3 0 -sec o n d c h air sta n d test, 6-mi n ute 
wal ki n g test)  
Res p o nse at Wee k 1 0 4 f or str uct ural pr o gressi o n i n t he tar get k nee will be e val uate d usi n g a 
l o gistic re gressi o n m o del wit h treat me nt re gi me n as a fact or. 
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, C ust o mize d Me d D R A Q u er y ( C M Q) a n d preferre d ter m. 
Safet y s u m maries (ta bles, fi g ures) i ncl u de o nl y data fr o m t he o n -treat m e nt peri o d wit h t he 
e xce pti o n of baseli ne dat a w hic h will als o be s u m marize d w here a p pr o priat e (e. g., c ha n g e fr o m 
baseli ne s u m maries). I n a d diti o n, a se parate s u m m ar y f or d eat h i ncl u di n g o n treat me nt a n d p ost 
treat me nt deat hs will be pr o vi de d. I n partic ular, s u m mar y ta bles f or a d verse e ve nts ( A Es) will 
s u m marize  o nl y  o n-treat me nt  e ve nts,  wit h  a  start  date  d uri n g  t he  o n-treat me nt  peri o d  
(treat me nt-e mer ge nt A Es).  
T he o n -treat me nt peri o d lasts fr o m t he date of first a d mi nistrati o n of st u d y treat me nt u p t o last 
a d mi nistrati o n + 6 m o nt hs. 
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 p artici pa nts wit h treat me nt e mer ge nt a d verse e v e nts (e v e 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 ncr ease d i n se verit y bas e d o n preferre d ter m) will be s u m mari ze 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 t er 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 s e verit y 

N o v arti s  
C o nfi d e nti al  
P a g e 8 9  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
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 v e nts lea di n g t o disc o nti n uati o n. 
T he n u m ber (a n d pr o p orti o n) of partici pa nts wit h a d vers e e v e nts of s p ecial i nterest  will b e 
s u m marize d b y treat me nt. 
A partici pa nt wit h m ulti ple a d vers e 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 h e 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)  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/ (lo 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. 
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  per ce 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. 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. 
A c ut e I nfl a m m at or y R e a cti o n s ( AI R)  
I n ci de nce of ac ute i nfla m mat or y reacti o ns ( AI Rs), defi ne d as i ncrease of pai n b y 3 p oi nts o n a n 
1 1- p oi nts N R S  (ra n ge 0- 1 0) a n d a self -re p orte d s y n o vial fl ui d eff usi o n (i.e., j oi nt s welli n g) 
wit hi n 3 da ys f oll o wi n g i.a. i njecti o n d oc u me nte d i n t he partici pant e Diar y. 
1 2. 5. 3  
D N A  
E x pl orat or y D N A st u dies are desi g n e d t o i n vesti gate t he ass oci ati o n bet wee n ge n etic fact ors 
( ge n ot y pes) a n d cli nical assess me nts ( p he n ot y pes) w hic h are c ollecte d d uri n g t he cli nical trial. 
Wit h o ut pri or e vi de nce of a str o n g ass ociati o n, a n u m ber of p ossi bl e ass oci ati o ns are e v al uate d 
wit h e x pl orat or y a n al yses. A ra n ge of statistical tests are use d f or t he a n al yses. A d diti o nal data, 
fr o m ot her cli nical trials, are ofte n n ee d e d t o c o nfir m ass ociati o ns. Alter nati vel y, if t he n u m ber 
of partici pa nts e nr olle d i n t he st u d y is t o o s mall t o c o m plete pr o per statistical a nal yses, t he dat a 
ma y be c o m bi ne d, as a p pr o priate, wit h t h ose fr o m ot her st u dies t o e nlar ge t he datas et f or 
a nal ysis. 
Data ge n erate d o n h y p ot hesis -free platf or ms will be re p ort e d se paratel y (e. g., C S R a d de n d u m). 
1 2. 6   
A n al y si s of t h e e x pl or at or y e n d p oi nt s/ e sti m a n d s 
T he f oll o wi n g e x pl orat or y efficac y varia bles are pla n ne d t o be a n al yze d usi n g t he F A S. 

N o v arti s  
C o nfi d e nti al  
P a g e 9 0  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
1.  C ha n ge fr o m bas eli ne i n cartila ge t hic k n ess i n t he c M T F C assess e d b y q M RI of t he t ar get 
k nee at Wee ks 
. 
2.  C ha n ge fr o m bas eli ne at Wee ks 
 i n:  
•  W O M A C pai n  
•  W O M A C pai n wal ki n g o n flat s urface res p o nse 
•  W O M A C f u ncti o n 
3.  C ha n ge fr o m bas eli ne i n cartila ge t hic k n ess i n t he t otal, me dial a n d lateral T F Cs assesse d 
b y q M RI at Wee ks 
. 
4.  Pr o p orti o n of partici pa nts de m o nstrati n g at Wee k 
 str uct ural 
pr o gressi o n i n t he tar get k nee defi n e d as: 
•  C ha n ge a b o ve t he S D C of cartila g e t hic k ness b y q M RI 
•  L oss of me dial mi nJ S W ≥ 0. 7 0 m m fr o m baseli ne b y X -ra y 
5.  C ha n ge fr o m bas eli ne i n p h ysical f u ncti o n at Wee ks 
:  
•  4 0- meter ( 4 × 1 0 m) fast -p ace d w al k test  
•  3 0- sec o n d c h air sta n d test 
•  6- mi n ute wal ki n g test  
6.  C ha n ge fr o m bas eli ne i n W O M A C t otal sc ore at Wee ks 
 
 
7.  C ha n ge fr o m bas eli ne at Wee ks 
 i n O A disease acti vit y 
as assesse d b y t he P GI S.  
8.  O A disease acti vit y at Wee ks 
 as assess e d b y t he P GI C. 
9.  C ha n ge fr o m bas eli ne at Wee ks 
 i n O A 
disease acti vit y as assesse d b y t he P G A.  
1 0.  C ha n ge fr o m bas eli ne at Wee ks 
 i n Q o L 
usi n g:  
•  S F - 1 2 v 2 p h ysical c o m p o ne nt s u m mar y 
•  S F - 1 2 v 2 me ntal c o m p o n e nt s u m mar y 
•  T otal S F - 1 2 v 2 sc or e 
1 1.  
 at Wee ks 
. 
1 2.  C ha n ge fr o m bas eli ne at Wee ks 
 i n t he f oll o wi n g 
assess me nts:  
•  
 
 
 
 
 
 
 
 
 
1 3.  C ha n ge fr o m bas eli ne t o Wee ks 
: 
•  Fi xe d -l ocati o n me dial J S W meas ure d o n X-ra y 
•  Me dial mi nJ S W meas ure d o n X- ra y 
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N o v arti s  
C o nfi d e nti al  
P a g e 9 1  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
1 4.  C ha n ge fr o m bas eli ne t o Wee ks
 
1 5.  Pr o p orti o n of partici pa nts w h o ac hie ve d W O M A C pai n M CI
 
1 6.  Pr o p orti o n of partici pa nts w h o ac hie ve d W O M A C f u ncti o n M CI D
 
1 7.  Pr o p orti o n of O M E R A C T- O A R SI res p o n ders at Wee ks 
 
 
1 8.  C ha n ge fr o m bas eli ne t o Wee ks
 i n acti gra p h y-deri v e d 
metrics s uc h as  meas ures of p h ysical acti vit y a n d m o bilit y para meters . 
1 9.  C ha n ge fr o m bas eli ne t o Wee k  
 i n B S P deri ve d metrics. 
2 0.  C ha n ge fr o m bas eli ne i n 
 
2 1.  Pr o p orti o n of partici pa nts wit h T K R at 
. 
2 2.  Pr o p orti o n of partici pa nts f ulfilli n g t he criteria f or V K R at 
 
  
2 3.  C ha n ge o ver ti me i n bi o mar ker le v els.  
A nal yses ma y i ncl u de s u m mar y statistics a n d listi n gs a n d as a p pr o pri ate gra p hical pres e ntati o ns 
of t he ori gi nal val ues a n d t he c ha n ges fr o m baseli n e. 
 
 
  
1 2. 6. 1  
P h ar m a c o ki n eti c s  
L N A 0 4 3 a n d A N G P T L 3 ser u m  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 u e nc y ( n, %) of c o n ce ntrati o ns bel o w t he L L O Q 
a n d re p ort e 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. 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. N o p har mac o ki netic p ara meters will be calc ulate d i n t his st u d y as 
s parse sa m pli n g d oes n ot all o w vali d esti mati o n b y n o n-c o m part me ntal a nal ysis. 
M o deli n g  of  t he  data  ma y  be  perf or me d  as  a p pr o priat e.  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 d a 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 ol e d wit h d ata fr o m pr e vi o us st u dies, t h e P K m o deli n g will be d escri be d a n d re p orte d 
se parat el y. 
1 2. 7  
I nt eri m a n al y s e s 
W he n a n i nteri m a n al ysis is perf or me d, desi g n ate d N o vartis staff will be u n bli n de d; h o we ver, 
t he bli n de d c ore N o v artis st u d y tea m will re mai n bli n de d u ntil at least t he pri mar y efficac y 
( Wee k 1 0 4) data b ase l oc k. 
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N o v arti s  
C o nfi d e nti al  
P a g e 9 2  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
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)  
A t otal of  
 partici pa nts per eac h gr o u p is dee me d a p pr o priate t o ac hie ve a de q uate p o wer f or 
t he pri mar y a n d k e y sec o n dar y e n d p oi nts f or t his st u d y. 
T he mea n c h a n ge fr o m b aseli n  
e i n cartila ge t hic k ness of t he c M T F C f or place b o at Wee k 5 2 is -0. 1 1 6 m m wit h t he sta n dar d 
de viati o n of 0. 2 7 f or place b o base d o n t he res ults of t he Gala pa g os a n d Ser vier R O C C E L L A 
P hase 2 st u d y, w hic h e nr olle d a c o m para ble k nee O A p o p ulati o n ( Ber nar d  et al 2 0 2 0). Cartila ge 
l oss  is  ass u me d  t o  be  c o nsta nt  o ver  a  2-y ear  peri o d  as  s h o w n  i n  t he  s prifer mi n  trial  
(H oc h ber g et al 2 0 1 9), t h eref ore a -0. 2 3 m m mea n c ha n ge fr o m bas eli ne i n cartila ge t hic k ness 
of t he c M T F C f or place b o at Wee k 1 0 4 is use d f or t his st u d y. Ass u mi n g t hat at t he ver y least 
L N A 0 4 3 st o ps f urt her cartila ge de gra d ati o n c o m pare d t o place b o, a treat me nt differe n ce of 0. 2 3 
m m i n fa v or of L N A 0 4 3 wit h a c o m m o n sta n dar d de viati o n of  
 will be o bser ve d at Wee k 
1 0 4, a sa m ple size of   partici pa nts i n eac h treat me nt gr o u p yiel ds a p pr o xi matel y  
 p o w er 
at α = 0. 0 5 ( o n e-si de d) usi n g D u n nett c o ntrasts ( A d d pla n D F 4. 0. 9). 
1 2. 8. 2  
S e c o n d ar y e n d p oi nt( s)  
As it is als o i m p orta nt t o s h o w a n effect o n a cli nical e n d p oi nt, a sa m ple size calc ulati o n w as 
d o ne  usi n g  t he  W O M A C  pai n  s u bscale.  It  was  s h o w n  i n  t he  E U F L E X X A  trial  
(Alt ma n  et al 2 0 0 9)  t hat  a  c ha n g e fr o m  bas eli ne  at  Wee k  2 6  usi n g  i ntra-artic ul ar  sali n e  
de m o nstrate d a mea n  of  1 6. 3 m m  wit h sta n dar d de viati o n of  2 6. 8 o n t he W O M A C  p ai n  
s u bscale. A treat me nt differe n ce of  
 i n fa v or of L N A 0 4 3 at Wee k 1 0 4 will nee d a sa m ple 
of 
 p o wer at α = 0. 0 5 ( o ne-si de d) usi n g D u n nett 
c o ntrasts ( A d d pla n D F 4. 0. 9). C o nsi deri n g a 
 dr o p o ut rate, a s a m ple size of  
 partici p a nts 
i n eac h treat me nt gr o u p will be nee de d. 
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 d esi 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 d a 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 Decl arati o n of H elsi 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 d e 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 ns e nt f or m, c o nse nt f or m u p d ates, partici pa nt recr uit m e 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 v esti gat or is r e q uire d t o si g n a pr ot o c ol si g nat ure p a ge c o nfir mi n g his/ her a gree m e nt 
t o  c o n d uct  t he  st u d y  i n  acc or da nce  wit h  t hes e  d oc u me nts  a n d  all  of  t he  i nstr ucti o ns  a n d  
pr oce d ur es f o u n d i n t his pr ot oc ol a n d t o gi ve access t o all rele va nt data a n d rec or ds t o N o vartis 
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N o v arti s  
C o nfi d e nti al  
P a g e 9 3  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
m o nit ors, a u dit ors, N o vartis  Q ualit y Ass ura nce re prese ntati ves, d esi g nate d a ge nts of N o vartis, 
I R Bs/I E Cs,  a n d  re g ul at 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 v esti 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 uir e d i n C TI S p u blic we bsite. I n a d diti o n, after st u d y c o m pleti o n ( d efi ne d as last patie nt 
last visit) a n d fi n alizati o n of t he st u d y re p ort t h e res ults of t his trial will be s u b mitte d f or 
p u blicati o n a n d 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  tri al  r es 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, C TI S p u blic we bs ite 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, please refer t o t h e 
N o vartis p u blicati o n  p olic y  trai ni n g  materials  t hat  were  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 b al/l ocal G C P re g ulati o ns a n d I C H G ui d eli nes. 
A u dits  of  I n v esti gat or  sites,  ve n d ors,  a n d  N o vartis  s yste ms  are  p erf 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 p r 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 p erf or me d acc or di n g t o writte n N o v artis 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 nces 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 h e p ur p os e of t he st u d y. If d es p ite t his i nter 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 v esti 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 os e  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 nts. 
I n v esti gat ors  ascertai n  t he y  will  a p pl y  d ue  dili ge nce  t o  a v oi d  pr ot oc ol  de viati o ns.  If  a n  
I n v esti 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 u ct of t he st u d y t his m ust be 
c o nsi dere d a pr ot oc ol a m e n d me nt, a n d u nless s u c 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  H ealt 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 9 4  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
1 4. 1  
Pr ot o c ol a m e n d m e nt s  
A n y c ha n g e or a d diti o n t o t he pr ot oc ol ca n o nl y b e ma de i n a writte n pr ot o c 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 w here re q uire d, a n d t he I R B/I E C 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 bs e 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 v esti gat or is 
e x pecte d t o ta ke a n y i m m e diate acti o n re q uire d f or t he safet y of a n y partici p a 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 st u d y 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 9 5  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
1 5  
R ef er e n c e s  
Refere n ces are a vaila ble u p o n re q uest.  
G B D 2 0 1 7 Disease a n d I nj ur y I n ci de nce a n d Pre v ale nce C olla b orat ors ( 2 0 1 8) Gl o bal, 
re gi o nal, a n d nati o nal i nci de nce, pr e vale n ce, a n d y ears li ve d wit h disa bilit y f or 3 5 4 diseases 
a n d i nj uries f or 1 9 5 c o u ntries a n d territ ories, 1 9 9 0- 2 0 1 7: a s yste matic a nal ysis f or t he Gl o bal 
B ur de n of Diseas e St u d y 2 0 1 7. La ncet; 3 9 2( 1 0 1 5 9): 1 7 8 9- 1 8 5 8 
Alt ma n R, Asc h E, Bl oc h D, et al ( 1 9 8 6) D e 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 p e 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; 
2 9( 8): 1 0 3 9- 4 9 
Alt ma n R D, R ose n J E, Bl oc h D A, et al ( 2 0 0 9) A d o u ble- bli n d, ra n d o mize d, sali ne-c o ntr olle d 
st u d y of t he efficac y a n d safet y of E U F L E X X A f or treat me nt of p ai nf ul oste oart hritis of t he 
k nee, wit h a n o pe n- la bel safet y e xte nsi o n (t h e F L E X X trial). Se mi n Art hritis R he u m; 3 9( 1): 1-
9 
 
 
 
Bella m y N, Patel B, Da vis T, et al ( 2 0 1 0) Electr o nic data ca pt ure usi n g t he W o mac N R S 3. 1 
I n d e x ( m- W o m ac): a pil ot st u d y of re peate d i n d e p e n de nt re m ote d ata ca pt ure i n O A. 
I nfla m m o p har mac ol o g y; 1 8( 3): 1 0 7- 1 1 
Ber nar d K, Gra n k o v S, V a n der St oe p M, et al ( 2 0 2 0) F RI 0 3 9 3 B A S E LI N E 
C H A R A C T E RI S TI C S O F T H E S T U D Y P O P U L A TI O N I N R O C C E L L A, A P H A S E 2 
C LI NI C A L T RI A L E V A L U A TI N G T H E E F FI C A C Y A N D T H E S A F E T Y O F 
S 2 0 1 0 8 6/ G L P G 1 9 7 2 I N P A TI E N T S WI T H K N E E O S T E O A R T H RI TI S. A n nals of t h e 
R he u matic Diseases; 7 9: 7 9 4 - 7 9 5 
 
 
C D E R  ( 2 0 1 8) Oste oart hritis: Str uct ural E n d p oi nts f or t he De v el o p me nt of Dr u gs, De vices, 
a n d Bi ol o gical pr o d ucts f or treat me nt. G ui da n ce f or I n d ustr y; 1- 3 
C harala m b o us C P, Tr yf o ni dis M, Sa di q S, et al ( 2 0 0 3) Se ptic art hritis f oll o wi n g i ntra- artic ular 
ster oi d i njecti o n of t he k nee--a s ur ve y of c urre nt practice re g ar di n g a ntise ptic tec h ni q ue use d 
d uri n g i ntra-artic ul ar ster oi d i njecti o n of t he k nee. Cli n R he u mat ol; 2 2( 6): 3 8 6- 9 0 
C olli ns NJ, Misra D, Fels o n D T, et al ( 2 0 1 1) M eas ures of k nee f u ncti o n: I nt er nati o nal K nee 
D oc u me ntati o n C o m mittee (I K D C) S u bjecti ve K n ee E val uati o n F or m, K nee I nj ur y a n d 
Oste oart hritis O utc o me S c ore ( K O O S), K n ee I nj ur y a n d Oste oart hritis O utc o me Sc ore 
P h ysical F u ncti o n S h ort F or m ( K O O S- P S), K nee O utc o me S ur ve y A cti vities of Dail y Li vi n g 
Scale ( K O S - A D L), L ys h ol m K nee Sc ori n g Scale, O xf or d K nee Sc ore ( O K S), Wester n 
O ntari o a n d Mc M aster U ni versities Oste oart hritis I n d e x ( W O M A C), Acti vit y Rati n g Scale 
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 9 6  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
( A R S), a n d Te g ner Acti vit y Sc ore ( T A S). Art hritis Care Res ( H o b o k e n); 6 3 S u p pl 1 1( 0 
1 1): S 2 0 8- 2 8 
C o na g ha n P G, H u nter DJ, Maillefert J F, et al ( 2 0 1 1) S u m mar y a n d rec o m me n dati o ns of t he 
O A R SI F D A oste o art hritis Assess me nt of Str uct ural C ha n ge W or ki n g Gr o u p. Oste oart hritis 
Cartila ge; 1 9( 5): 6 0 6- 1 0 
D o bs o n F, Hi n ma n R S, R o os E M, et al ( 2 0 1 3) O A R SI rec o m me n de d p erf or ma nce- base d tests 
t o assess p h ysical f u ncti o n i n pe o ple dia g n ose d wit h hi p or k nee oste oart hritis. Oste oart hritis 
Cartila ge; 2 1( 8): 1 0 4 2- 5 2 
D w or ki n R H, T ur k D C, Farrar J T, et al ( 2 0 0 5) C ore o utc o me meas ures f or c hr o nic pai n 
cli nical trials: I M M P A C T rec o m me n d ati o ns. Pai n; 1 1 3( 1 -2): 9 - 1 9 
 
 
Ec kstei n F, Mc C ull oc h C E, L y nc h J A, et al ( 2 0 1 2) H o w d o s h ort- ter m rat es of fe m or oti bial 
cartila ge c ha n ge c o m par e t o l o n g -ter m c ha n ges ? F o ur year f oll o w- u p data fr o m t he 
oste oart hritis i nitiati ve. Oste oart hritis Cartila ge p. 1 2 5 0 - 7. 
Farr J N, G oi n g S B, L o h ma n T G, et al ( 2 0 0 8) P h ysical acti vit y le vels i n patie nts wit h earl y 
k nee oste oart hritis meas ure d b y acceler o metr y. Art hritis R he u m; 5 9( 9): 1 2 2 9- 3 6 
Fer n a n des G S, Val d es A M ( 2 0 1 5) Car di o vasc ul ar disease a n d oste o art hritis: c o m m o n 
pat h wa ys a n d p atie nt o utc o mes. E ur J Cli n I n v est; 4 5( 4): 4 0 5- 1 4 
Ga n de k B, Ware J E, A ar o ns o n N K, et al ( 1 9 9 8) Cr oss- vali dati o n of ite m selecti o n a n d sc ori n g 
f or t he S F- 1 2 Healt h S ur ve y i n ni ne c o u ntries: res ults fr o m t he I Q O L A Pr oject. I nter n ati o nal 
Q ualit y of Life Assess me nt. J Cli n E pi de mi ol; 5 1( 1 1): 1 1 7 1- 8 
Ga n d hi S K, Sal m o n J W, Z ha o S Z, et al ( 2 0 0 1) Ps yc h o metric e v al uati o n of t he 1 2- ite m s h ort-
f or m healt h s ur ve y ( S F-1 2) i n oste oart hritis a n d r h e u mat oi d art hritis cli nical trials. Cli n T her; 
2 3( 7): 1 0 8 0- 9 8 
Ger wi n N, Be n d ele A M, Glass o n S, et al ( 2 0 1 0) T he O A R SI hist o pat h ol o g y i nitiati ve - 
rec o m me n dati o ns f or hist ol o gical assess me nts of oste oart hritis i n t he rat. Oste oart hris a n d 
Cartila ge; 1 8 S u p pl 3: S 2 4- 3 4. 
G ol dri n g M B, Oter o M ( 2 0 1 1) I nfla m mati o n i n oste oart hritis. C urr O pi n R he u mat ol; 
2 3( 5): 4 7 1- 8 
H oc h ber g M C, G u er mazi A, G ue hri n g H, et al ( 2 0 1 9) Effect of I ntra- Artic ular S prifer mi n vs 
Place b o o n Fe m or oti bial J oi nt Cartila ge T hic k ness i n Patie nts Wit h Oste oart hritis: T he 
F O R W A R D Ra n d o mize d Cli nical Trial. J A M A; 3 2 2( 1 4): 1 3 6 0- 1 3 7 0 
 
 
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 9 7  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
H u nter DJ, Ne vitt M, L osi na E, et al ( 2 0 1 4) Bi o mar kers f or oste oart hritis: c urre nt p ositi o n a n d 
ste ps t o war ds f urt her vali dati o n. Best Pract Res Cli n R he u mat ol p. 6 1- 7 1. 
Kra us V B, C olli ns J E, Har gr o ve D, et al ( 2 0 1 7) Pre dicti ve vali dit y of bi oc he mical bi o mar kers 
i n k nee oste oart hritis: dat a fr o m t he F NI H O A Bi o mar kers C o ns orti u m. A n n R he u m Dis; 
7 6( 1): 1 8 6- 1 9 5 
La velle W, L a velle E D, La velle L ( 2 0 0 7) I ntra -artic ular i njecti o ns. Me d Cli n N ort h A m; 
9 1( 2): 2 4 1- 5 0. 
Maillefert J F, Ha w k er G A, G ossec L, et al ( 2 0 0 5) C o nc o mita nt t hera p y: a n o utc o me varia ble 
f or m usc ul os keletal dis or ders? Part 2: t otal j oi nt re place me nt i n oste oart hritis trials. J 
R he u mat ol; 3 2( 1 2): 2 4 4 9- 5 1 
Ma n n o R L, Bi n g ha m C O, Pater n otte S, et al ( 2 0 1 2) O A R SI- O M E R A C T i nitiati ve: defi ni n g 
t hres h ol ds f or s y m pt o matic se verit y a n d str u ct ural c ha n ges i n diseas e m o dif yi n g oste oart hritis 
dr u g ( D M O A D) cli nical trials. Oste oart hritis a n d Cartila ge; 2 0( 2): 9 3 - 1 0 1 
Mc Ali n d o n T E, Dri ba n J B, He nr oti n Y, et al ( 2 0 1 5) O A R SI Cli nical Tri als 
Rec o m me n dati o ns: Desi g n, c o n d uct, a n d re p orti n g of cli nical trials f or k n ee oste oart hritis. 
Oste oart hritis a n d Cartila ge; 2 3( 5): 7 4 7- 6 0 
Oste oart hritis Resear c h S ociet y I nter n ati o nal ( O A R SI) ( 2 0 1 6) Oste oart hritis: A Seri o us 
Disease. 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. 
Pelletier J P, C o o per C, Peterf y C, et al ( 2 0 1 3) W h at is t he pre dicti ve val ue of M RI f or t he 
occ urr e nce of k nee re pl ace me nt s ur ger y i n k nee oste oart hritis? A n n R he u m Dis; 7 2( 1 0): 1 5 9 4-
6 0 4 
Per m utt T ( 2 0 1 6) Se nsiti vit y a nal ysis f or missi n g data i n re g ulat or y s u b missi o ns. Stat Me d; 
3 5( 1 7): 2 8 7 6- 9 
P ha m T, va n der H eij de D, Alt ma n R D, et al ( 2 0 0 4) O M E R A C T- O A R SI i nitiati ve: 
Oste oart hritis Resear c h S ociet y I nter n ati o nal set of res p o n der criteria f or oste oart hritis cli nical 
trials re visite d. Oste oart hritis a n d Cartila ge; 1 2( 5): 3 8 9- 9 9 
 
 
 
Si n g h J A, Y u S, C he n L, et al ( 2 0 1 9) Rates of T otal J oi nt Re place me nt i n t he U nite d States: 
F ut ure Pr ojecti o ns t o 2 0 2 0- 2 0 4 0 Usi n g t he Nati o n al I n p atie nt Sa m ple. J R he u mat ol; 
4 6( 9): 1 1 3 4- 1 1 4 0 
 
 
 
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 y al 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); 6 2( 5): 6 0 0- 1 0 
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 9 8  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
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 A N D > 5 x U L N  
* T h e s e e v e nt s c o v er t h e f oll o wi n g: h e p ati c f ail ur e, fi br o si s a n d cirr h o si s, a n d ot h er li v er d a m a g e-r el at e d 
c o n diti o n s; n o n -i nf e cti o u s h e p atiti s; b e ni g n, m ali g n a nt a n d u n s p e cifi e d li v er n e o pl a s m s U L N: u p p er li mit of 
n or m al  
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 wit h li v er 
s y m pt o m s   
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 > 5 x U L N f or m or e 
t h a n t w o w e e k s 
O R  
A L T > 8 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  
•  
I nt err u pt 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 a n d C K 
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 tr e at m e nt c a n 
b e r e st art e d if 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  
A N D > 5 x U L N f or m or e 
t h a n t w o w e e k s 
O R  
A L T ≥ 5 x b a s eli n e  
A N D ≥ 8 x U L N  
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: 
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  

N o v arti s  
C o nfi d e nti al  
P a g e 9 9  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
A L T  
T B L  
Li v er S y m pt o m s  
A cti o n  
A N D > 3 x U L N  
D o u bli n g of dir e ct 
bilir u bi n  
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  
A N D > 3 x U L N  
* T hi s sit u ati o n s u g g e st s li v er i nj ur y b a s e d o n (i) el e v ati o n of A L T, a n d (ii) t h e pr e s e n c e of s y m pt o m s of li v er 
i nj ur y. E v e n if bilir u bi n i s n or m al, t h e pr e s e n c e of li v er s y m pt o m s i n di c at e s p ot e nti all y s e v er e li v er i nj ur y. 

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 0  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
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 - 3 
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  
• R e p e at l a b or at or y v al u e s wit hi n 4 8 hr s of r e c ei pt of 
a b n or m al t e st r e s ult s. A s s e s s p ati e nt f or si g n s a n d 
s y m pt o m s of ill n e s s, A KI, et c.  
·  
S er u m cr e ati ni n e i n cr e a s e  ≥ 5 0 % * 
• 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  
• R e p e at l a b or at or y v al u e s wit hi n 4 8 hr s of r e c ei pt of 
a b n or m al t e st r e s ult s. A s s e s s p ati e nt f or si g n s a n d 
s y m pt o m s of ill n e s s, A KI, et c.  
• 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 r ef err al t o n e p hr ol o gi st f or di a g n o si s a n d 
m a n a g e m e nt  
 • 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 C  
 
• C o nfir m pr e s e n c e of tr u e pr ot ei n uri a b y 
q u a ntifi c ati o n: pr ot ei n: cr e ati ni n e o n fir st m or ni n g v oi d  
• 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  
• C o n si d er r ef err al t o a n e p hr ol o gi st 
 
N e w o n s et h e m at uri a ≥ 3 + o n uri n e di p sti c k  
• O bt ai n uri n e mi cr o s c o p y t o di sti n g ui s h 
h e m o gl o bi n uri a or m y o gl o bi n uri a fr o m h e m at uri a • 
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, c al c uli, 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  
A d diti o nal s pecialize d assess me nts are a vaila bl e t o assess re nal f u ncti o n or re nal pat h ol o g y. 
( N ote: I n exce pti o n al c as es, w he n a ne p hr ol o gist c o nsi ders a re n al bi o psy, it is rec o m me n de d 
t o m ake hist ol o gy i m a ges  av ail a ble f or ev al u ati o n by t he R S G t o p ote nti ally i de ntify pr oject -
wi de p atter ns of ne p hr ot oxicity.)  
W he ne v er a re nal e ve nt is i de ntifie d, a detaile d p atie nt hist or y a n d e xa mi nati o n are i n dicate d t o 
i de ntif y a n d p ote ntiall y eli mi nate ris k fact ors t hat ma y ha ve i nitiate d or c o ntri b ute d t o t he e ve nt: 
•  
Bl o o d  press ure  assess m e nt  (sitti n g  after  5 -mi n ute  rest,  wit h  a n  a p pr o priate  c uff  size;  
c o nsi der ort h ostatic e v al uati o n) 

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 1  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
•  
Si g ns a n d s y m pt o ms li ke f e ver, hea dac h e, s h ort ness of breat h, car diac m ur m ur, bac k or 
a b d o mi nal pai n, he pat o m e gal y, d ys uria or h e mat uria, de pe n de nt or p eri or bit al e de ma 
•  
C ha n ges i n b o d y wei g ht, fl ui d i nta ke, v oi di n g patter n, or uri ne o ut p ut 
•  
C o nc o mita nt e ve nts or pr oce d ures s uc h as tra u ma, s ur gical pr oce d ures, car diac or he patic 
fail ure, c o ntrast me dia or ot her k n o w n ne p hr ot o xi n a d mi nistrati o n, or ot her diseases or 
ca uses, e. g., d e h y dr ati o n d ue t o deliri u m, t u m or l ysis 
T a bl e 1 6 - 4 
R e n al E v e nt F oll o w u p  
F O L L O W -U P O F R E N A L E V E N T S  
· 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 pr ot ei n -cr e ati ni n e r ati o ( P C R ) < 1 g/ g Cr, or A C R < 3 0 0 m g/ g 
Cr), or  
· 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 P C R 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 

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 2  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
1 6. 3   
A p p e n di x 3: A m eri c a n C oll e g e of R h e u m at ol o g y Crit eri a f or t h e 
Cl a s sifi c ati o n a n d R e p orti n g of O st e o art hriti s of t h e K n e e 
T a bl e 1 6 - 5 
S u m m ar y of Crit eri a f or Cl a s sifi c ati o n of I di o p at hi c O st e o art hriti s of 
t h e K n e e* 
Cli ni c al a n d L a b or at or y  
Cli ni c al a n d R a di o gr a p hi c  
Cli ni c al †  
K n e e p ai n  
+ at l e a st 5 of 9:  
•  
A g e > 5 0 y e ar s  
•  
Stiff n e s s < 3 0 mi n ut e s  
•  
Cr e pit u s  
•  
B o n y t e n d er n e s s  
•  
B o n y e nl ar g e m e nt  
•  
N o p al p a bl e w ar mt h  
•  
E S R < 4 0 m m/ h o ur  
•  
R F < 1: 4 0  
•  S F O A  
K n e e p ai n  
+ at l e a st 1 of 3:  
•  
A g e > 5 0 y e ar s  
•  
Stiff n e s s < 3 0 mi n ut e s  
•  
Cr e pit u s  
•  
O st e o p h yt e s  
K n e e p ai n  
+ at l e a st 3 of 6:  
•  
A g e > 5 0 y e ar s  
•  
Stiff n e s s < 3 0 mi n ut e s  
•  
Cr e pit u s  
•  
B o n y T e n d er n e s s  
•  
B o n y e nl ar g e m e nt  
•  
N o p al p a bl e w ar mt h  
9 2 % s e n siti v e  
9 1 % s e n siti v e  
9 5 % s e n siti v e  
7 5 % s p e cifi c  
8 6 % s p e cifi c  
6 9 % s p e cifi c  
* Alt m a n  et  al  1 9 8 6  
E S R = er yt hr o c yt e s e di m e nt ati o n r at e ( W e st er gr e n); R F = r h e u m at oi d f a ct or; S F O A = s y n o vi al fl ui d si g n s of 
O A ( cl e ar, vi s c o u s, or w hit e bl o o d c ell c o u nt < 2, 0 0 0/ m m 3).  
†  Alt er n ati v e f or t h e cli ni c al c at e g or y w o ul d b e 4 of 6, w hi c h i s 8 4 % s e n siti v e a n d 8 9 % s p e cifi c.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 3  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
1 6. 4   
A p p e n di x 4: G ui d eli n e s f or a d mi ni st eri n g t h e q u e sti o n n air e s f or 
p ati e nt r e p ort e d o ut c o m e s 
B ef or e st u d y st art  
St u d y c o or di nat ors s h o ul d fa miliarize t he msel v es wit h t he P R O q uesti o n naire(s) i n t he st u d y 
a n d i de ntif y  a n y  ite ms  w here  a  partici pa nt’s  res p o nse  mi g ht  hi g hli g ht  iss ues  of  p ote ntial  
c o ncer n.  
B ef or e c o m pl eti o n  
1.  S u bjects s h o ul d be pr o vi de d wit h t he c orrect q uesti o n naire at t he a p pr o priate visits a n d i n 
t he a p pr o priat e la n g ua g e. 
2.  S u bjects s h o ul d ha ve a de q uate s pace a n d ti me t o c o m plete t he f or ms. 
3.  Q uesti o n naire a d mi nister e d at site s h o ul d be a d mi nistere d bef ore t he cli nical e xa mi nati o n.  
D uri n g c o m pl eti o n  
1.  A d mi nistrat or ma y clarif y t he q uesti o ns b ut s h o ul d n ot i nfl ue nce t he res p o nse. 
2.  O nl y o ne res p o nse f or eac h q uesti o n. 
3.  Als o see “ A d dressi n g Pr o ble ms a n d C o ncer ns”. 
Aft er c o m pl eti o n  
1.  C hec k f or c o m plet e ness a n d n ot f or c o nte nt *. 
2.  C hec k f or m ulti ple res p o nses t hat were ma de i n err or. 
* H o we ver,  a n y  res p o ns e  w hic h  ma y  directl y  i m pact  or  reflect  t he  partici pa nt’s  me dical  
c o n diti o n (e. g., n oti n g of de pressi o n) s h o ul d be c o m m u nicate d b y t he st u d y c o or di nat or t o t he 
I n v esti gat or). 
A d dr e s si n g pr o bl e m s a n d c o n c er n s  
Occasi o nall y  a  partici p a nt  ma y  ha ve  c o ncer ns  or  q uesti o ns  a b o ut  t he  q uesti o n naires  
a d mi nistere d. G ui da n ce r elate d t o s o me of t he m ost c o m m o n c o ncer ns a n d q uesti o ns are gi ve n 
bel o w. 
T h e p arti ci p a nt d o e s n ot w a nt t o c o m pl et e t h e q u e sti o n n air e( s)  
Tell t he partici pa nt t hat c o m pleti o n of t he q uesti o n naire(s) is v ol u ntar y. T he g oal is t o better 
u n dersta n d t he p h ysical, me ntal a n d s ocial healt h pr o ble ms of partici pa nts. E m p hasize t hat s uc h 
i nf or mati o n is as i m p orta nt as a n y ot her me dical i nf or mati o n a n d t hat t he q uesti o n naire(s) is 
si m ple t o c o m plete. S u g gest  t hat  t he q uesti o n naire(s) ma y b e differe nt  fr o m  a n yt hi n g t he 
res p o n de nt has fille d i n t he past. If t he partici pa nt still decli nes, retrie ve t he q uesti o n naires. 
Rec or d t he r eas o n f or t he decli ne a n d t ha n k t h e partici pa nt. 

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 4  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
T h e p arti ci p a nt i s t o o ill or w e a k t o c o m pl et e t h e q u e sti o n n air e( s)  
I n t hese i nsta n ces, t he c o or di nat or ma y o bt ai n partici pa nt res p o nses b y rea di n g o ut l o u d eac h 
q uesti o n, f oll o we d b y t he c orres p o n di n g res p o nse cate g ori es, a n d e nteri n g t he partici pa nt’s 
res p o nse. N o hel p s h o ul d be pr o vi de d t o t h e partici pa nt b y a n y p ers o n ot her t ha n t he desi g nate d 
st u d y  c o or di nat or.  T he  c o or di nat or  s h o ul d  n ot  i nfl ue nce  partici pa nt  res p o nses.  T he  st u d y  
c o or di nat or ca n n ot tra nsl ate t he q uesti o n i nt o si m pler la n g ua ge a n d has t o be rea d v er b ati m. 
T h e p arti ci p a nt w a nt s s o m e o n e el s e t o c o m pl et e t h e q u e sti o n n air e( s)  
I n n o case s h o ul d t he c o or di nat or or a n y o ne ot her t ha n t he partici pa nt pr o vi de res p o nses t o t he 
q uesti o ns. U nless s pecifi e d i n t he st u d y pr ot oc ol, pr o x y data are n ot a n acce pta ble s u bstit ute f or 
partici pa nt self -r e p ort. Partici pa nts s h o ul d be disc o ura ge d fr o m as ki n g a fa mil y me m ber or 
frie n d f or h el p i n c o m pleti n g a q uesti o n naire. 
T h e p arti ci p a nt d o e s n ot w a nt t o fi ni s h c o m pl eti n g t h e q u e sti o n n air e( s)  
If n o n-c o m pleti o n is a r es ult of t he partici pa nt ha vi n g tr o u ble u n dersta n di n g partic ular ite ms, 
as k t he partici pa nt t o e x plai n t he diffic ult y. Re -rea d t he q uesti o n f or t he m ver b ati m b ut d o n ot 
re p hras e t he q u esti o n. If t he res p o n de nt is still u na ble t o c o m plete t he q uesti o n naire, acce pt it 
as i nc o m plete. T ha n k t he partici pa nt. 
T h e p arti ci p a nt i s c o n c er n e d t h at s o m e o n e will l o o k at hi s/ h er r e s p o n s e s  
E m p hasize t hat all res p o nses are t o be ke pt c o nfi de ntial. P oi nt o ut t hat t heir na mes d o n ot a p pear 
a n y w her e o n t he q u esti o n naire, s o t hat t heir res ults will be li n ke d wit h a n I D n u m ber a n d n ot 
t heir na me. Tell t he partici pa nt t hat his/ her a ns w ers will be po ole d wit h ot her partici pa nts’ 
a ns wers a n d t hat t he y will be a nal yze d as a gr o u p rat her t ha n as i n di vi d uals. Tell t he partici pa nt 
t hat c o m plete d f or ms are n ot r o uti nel y s hare d wit h treati n g staff a n d t hat t heir res p o nses will 
o nl y be see n b y y o u (t o c hec k f or c o m plete n ess) a n d b y t he I n vesti gat or. A n y res p o nse w hic h 
ma y directl y i m pact o n or reflect t heir me dical c o n diti o n (e. g., n oti n g of se vere de pressi o n) will 
be c o m m u nicate d b y t he c o or di nat or t o t he p h ysicia n. 
T h e p arti ci p a nt a s k s t h e m e a ni n g of a q u e sti o n/it e m  
W hile c o m pleti n g t he q uesti o n naire, s o me partici pa nts mi g ht as k t he mea ni n g of s pecific ite ms 
s o  t hat  t he y  ca n  better  u n dersta n d  a n d  res p o n d.  If  t his  ha p pe ns,  assist  t he  partici pa nt  b y  
rerea di n g t he q uesti o n f or t he m ver b ati m. If t he p artici pa nt as ks t o i nter pret t he mea ni n g of a n 
ite m, d o n ot tr y t o e x plai n it, b ut s u g gest t hat he/s he use his/ her o w n i nter pretati o n of t he 
q uesti o n. Partici pa nts s h o ul d a ns wer t h e q uesti o ns base d o n w h at t hey t hi n k t he q uesti o ns mea n. 
G e n er al i nf or m ati o n a b o ut all q u e sti o n n air e( s):  
All q uesti o n naires ha ve t o be c o m plete d b y t he p artici pa nts i n t heir l ocal la n g ua ges usi n g a n 
electr o nic d e vice. T h e q uesti o n naires s h o ul d be c o m plete d b y t he partici pa nts i n a q uiet area 
free fr o m dist ur ba nce, a n d bef or e a n y visit assess me nts. Partici pa nts s h o ul d recei ve n o hel p 
fr o m fa mil y me m bers; if q uesti o ns ca n n ot be a ns w ere d al o ne ( d u e t o pr o ble ms wit h rea di n g or 
u n dersta n di n g), t he n t he d oct or or n urse s h o ul d rea d t he q uesti o ns a n d rec or d t he partici pa nt’s 

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 5  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
res p o nses wit h o ut i nfl ue nci n g t heir a ns wers. T he i nf or mati o n pr o vi de d is strictl y c o nfi de ntial 
a n d will be treate d as s uc h. If a partici pa nt has misse d a q uesti o n or gi ve n m ore t ha n o ne 
res p o nse p er q uesti o n, t h e n t his s h o ul d be br o u g ht t o partici p a nt. I n c o m plete q uesti o ns s h o ul d 
n ot be acce pte d wit h o ut first e nc o ura gi n g t he p arti ci pa nt t o c o m plete u na ns were d q u esti o ns. 
T he I n v esti gat or m ust c o m plete t he partici pa nt/ visit i nf or mati o n o n t he electr o nic de vice a n d 
e ns ure t hat t he ce nt er n u m ber, partici pa nt’s n u m b er a n d i nitials are i de ntical t o t he Case Rec or d 
F or m. As t her e ar e n o s o urce dat a f or t his q uesti o n naire, t he da t a q ueri es will be restricte d t o 
partici pa nt/ visit i nf or mati o n.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 6  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
1 6. 5   
A p p e n di x 5: P ati e nt Gl o b al I m pr e s si o n of S e v erit y a n d P ati e nt 
Gl o b al I m pr e s si o n of C h a n g e 
P atie nt Gl o b al I m pressi o n of Se verit y of K nee P ai n d uri n g 6 Mi n ute W al ki n g Test  
Please c h o ose t he r es p o nse bel o w t hat b est descri bes t he se v erit y of y o ur  k nee p ai n w hile 
perf or mi n g t he 6 mi n utes wal ki n g test t o da y. 
□ N o ne  
□ Mil d  
□ M o derat e  
□ Se vere  
P atie nt Gl o b al I m pressi o n of Se verit y of K nee P ai n d uri n g 4 0 meters F ast -P ace d W al k 
Test  
Please c h o ose t he r es p o nse bel o w t hat b est descri bes t he se v erit y of y o ur  k nee p ai n  w hile 
perf or mi n g t he 4 0 meters fast- pace d wal k test t o da y. 
□ N o ne  
□ Mil d  
□ M o derat e  
□ Se vere  
P atie nt Gl o b al I m pressi o n of Se verit y of K nee P ai n d uri n g 3 0- sec o n d C h air St a n d Test 
Please c h o ose t he r es p o nse bel o w t hat b est descri bes t he se v erit y of y o ur k nee p ai n w hile 
perf or mi n g t he 3 0-s ec o n d c hair sta n d test t o da y. 
□ N o ne  
□ Mil d  
□ M o derat e  
□ Se vere  
P atie nt Gl o b al I m pressi o n of C h a n ge i n K nee P ai n d uri n g 6 Mi n ute W al ki n g Test  
Please c h o ose t he res p o ns e bel o w t hat best descri bes t he o verall c ha n ge i n y o ur k nee p ai n w hile 
perf or mi n g t he 6 mi n utes wal ki n g test c o m pare d t o w he n y o u starte d ta ki n g t he st u d y treat me nt 
(select o ne res p o nse). 
□ M uc h better  
□ A little better  
□ N o c ha n g e  
□ A little w orse  
□ M uc h w ors e  

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 7  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
P atie nt Gl o b al I m pressi o n of C h a n ge d uri n g 4 0 meters F ast- P a ce d W al k Test  
Please c h o ose t he res p o ns e bel o w t hat best descri bes t he o verall c ha n ge i n y o ur k nee p ai n w hile 
perf or mi n g t he 4 0 m eters fast -pace d w al k test c o m pare d t o w h e n y o u starte d ta ki n g t he st u d y 
treat me nt (select o ne r es p o nse). 
□ M uc h better  
□ A little better  
□ N o c ha n g e  
□ A little w orse  
□ M uc h w ors e  
P atie nt Gl o b al I m pressi o n of C h a n ge of K nee P ai n d uri n g 3 0- sec o n d C h air St a n d Test 
Please c h o ose t he res p o ns e bel o w t hat best descri bes t he o verall c ha n ge i n y o ur k nee p ai n  w hile 
perf or mi n g t he 3 0 -s ec o n d c hair sta n d test c o m p are d t o w he n y o u starte d ta ki n g t he st u d y 
treat me nt (select o ne r es p o nse). 
□ M uc h better  
□ A little better  
□ N o c ha n g e  
□ A little w orse  
□ M uc h w ors e  
1 6. 6   
Bl o o d c oll e cti o n l o g 
Refer  t o  t he  ce ntral  la b orat or y  ma n ual  f or  sa m ple  c ollecti o n,  pre parati o n  a n d  s hi p pi n g  
i nf or mati o n. 
T a bl e 1 6 - 6 
S a m pl e l o g: Ti m e s c h e d ul e f or s a m pli n g of L N A 0 4 3 P K, A N G P T L 3 a n d 
a nti -dr u g a nti b o d y  
P eri o d  
Vi sit 
N a m e  
Ti m e 
( p o st-
d o s e)  
L N A 0 4 3 P K bl o o d c oll e cti o n  
A N G P T L 3 bl o o d 
c oll e cti o n  
A nti -dr u g 
a nti b o d y t o 
L N A 0 4 3  
Si z e 
( m L) 
D o s e 
R ef I D.  
S a m pl e 
N o.  
Si z e 
( m L) 
S a m pl e 
N o.  
Si z e 
( m L) 
S a m pl e 
N o.  
C or e 
P eri o d  
 
pr e -d o s e  
2  
1  
1 0 1  
2  
2 0 1  
3. 5  
3 0 1  
1 5 ± 5 
mi n*  
2 
1 
1 0 2  
 
 
 
 
1 2 0 ± 1 5 
mi n  
2 
1 
1 0 3  
2 
2 0 2  
 
 
 
pr e -d o s e  
2  
3  
1 0 4  
2  
2 0 3  
3. 5  
3 0 2  
1 5 ± 5 
mi n*  
2 
3 
1 0 5  
 
 
 
 
1 2 0 ± 1 5 
mi n  
2 
3 
1 0 6  
2 
2 0 4  
 
 
 
pr e -d o s e  
 
 
 
 
 
3. 5  
3 0 3  
C CI
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 8  of 1 0 8  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 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 2  
 
 
P eri o d  
Vi sit 
N a m e  
Ti m e 
( p o st-
d o s e)  
L N A 0 4 3 P K bl o o d c oll e cti o n  
A N G P T L 3 bl o o d 
c oll e cti o n  
A nti -dr u g 
a nti b o d y t o 
L N A 0 4 3  
Si z e 
( m L) 
D o s e 
R ef I D.  
S a m pl e 
N o.  
Si z e 
( m L) 
S a m pl e 
N o.  
Si z e 
( m L) 
S a m pl e 
N o.  
 
pr e -d o s e  
 
 
 
 
 
3. 5  
3 0 4  
 
pr e -d o s e  
 
 
 
 
 
 
 
1 5 ± 5 
mi n*  
2 
7 
1 0 7  
 
 
 
 
1 2 0 ± 1 5 
mi n  
2 
7 
1 0 8  
2 
2 0 5  
 
 
 
pr e -d o s e  
 
 
 
 
 
3. 5  
3 0 5  
1 5 ± 5 
mi n*  
2 
9 
1 0 9  
 
 
 
 
1 2 0 ± 1 5 
mi n  
2 
9 
1 1 0  
2 
2 0 6  
 
 
 
pr e -d o s e  
 
 
 
 
 
3. 5  
3 0 6  
 
pr e -d o s e  
 
 
 
 
 
3. 5  
3 0 7  
1 5 ± 5 
mi n*  
2 
1 3  
1 1 1  
 
 
 
 
1 2 0 ± 1 5 
mi n  
2 
1 3  
1 1 2  
2 
2 0 7  
 
 
E xt e n si o n 
P eri o d  
 
pr e -d o s e  
 
 
 
 
 
3. 5  
3 0 8  
 
 
 
 
 
 
 
3. 5  
3 0 9  
E xt e n si o n 
P eri o d – 
F oll o w -u p  
 
 
 
 
 
 
 
3. 5  
3 1 0  
U n s c h e d ul e d  
 
2 
 
1 1 0 1  
1 1 0 2  
1 1 0 3  
1 1 0 4  
 
 
3. 5  
1 3 0 1  
1 3 0 2  
1 3 0 3  
1 3 0 4  
* P o st-d o s e at 1 5 ± 5 mi n i s at t h e s el e ct e d sit e s o nl y.  
 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI