A Randomized, Two-arm, Placebo-controlled, Participant and Investigator-blinded Study Investigating the Efficacy, Safety and Tolerability of DFV890 in Patients With Symptomatic Knee Osteoarthritis
Phase: PHASE2
Conditions: Symptomatic Knee Osteoarthritis
Sponsor: Novartis Pharmaceuticals

N o v arti s R e s e ar c h a n d D e v el o p m e nt  
D F V 8 9 0 
Cli ni c al Tri al Pr ot o c ol C D F V 8 9 0 B 1 2 2 0 1 / N C T 0 4 8 8 6 2 5 8
A r a n d o mi z e d, t w o- ar m, pl a c e b o- c o ntr oll e d, p arti ci p a nt a n d 
i n v e sti g at or- bli n de d st u d y i n v e sti g ati n g t h e effi c a c y, s af et y 
a n d t ol er a bilit y of D F V 8 9 0 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 
D o c u m e nt t y p e:  
A m e n d e d Pr ot o c ol V er si o n  
V er si o n n u m b er:  
v 0 6 ( Cl e a n ) 
Cli ni c al Tri al P h a s e:  
II 
S p o n s or N a m e:  
N o v arti s P h ar m a A G or it s affili at e o ut si d e of t h e E E A 
( w h er e a p pli c a bl e) 
S p o n s or A d dr e s s i n t h e 
E E A:  
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  
R e g ul at or y A g e n c y 
I d e ntifi er N u m b er ( s): 
E u dr a C T: 2 0 2 0 -0 0 6 1 0 4 -1 7, E U C T: 2 0 2 3 -5 0 7 5 5 9 -3 0, 
I N D 1 5 5 7 7 9 
R el e a s e d at e:  
0 6 -D e c -2 0 2 3
Pr o p ert y of N o v arti s  
C o nfi d e nti al  
M a y n ot b e u s e d, di v ul g e d, p u bli s h e d, or ot h er wi s e di s cl o s e d  
wit h o ut t h e c o n s e nt of N o v arti s  
Cli ni c al Tri al Pr ot o c ol T e m pl at e V er si o n 3. 0 d at e d 3 1 -J a n -2 0 2 0  

N o v arti s  
C o nfi d e nti al  
P a g e 2  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
T a bl e of c o nt e nt s  
Ta ble of c o nte nts  ................................................................................................................. 2  
List of ta bles  ........................................................................................................................ 6  
List of fi g ures  ...................................................................................................................... 7  
List of a b bre viati o ns  ............................................................................................................ 8  
Gl ossar y of ter ms  ............................................................................................................... 1 3  
A me n d me nt 6 ( Dece m ber 2 0 2 3)  ....................................................................................... 1 6  
A me n d me nt 5 ( Ma y 2 0 2 2)  ................................................................................................ 2 3  
A me n d me nt 4 ( Marc h 2 0 2 2)  ............................................................................................. 2 6  
A me n d me nt 3 ( Dece m ber 2 0 2 1)  ....................................................................................... 2 7  
A me n d me nt 2 ( A u g ust 2 0 2 1)  ............................................................................................ 3 0  
A me n d me nt 1 ( A pril 2 0 2 1)  ............................................................................................... 3 1  
Pr ot oc ol s u m mar y  .............................................................................................................. 3 4  
1  
I ntr o d ucti o n ....................................................................................................................... 3 8  
1. 1  
Bac k gr o u n d  ............................................................................................................ 3 8  
1. 1. 1  
N o n -cli nical data  ................................................................................... 3 9  
1. 1. 2  
H u ma n safet y a n d t olera bilit y  ............................................................... 4 0  
1. 1. 3  
H u ma n P har mac o ki netics  ...................................................................... 4 1  
1. 2  
P ur p ose  .................................................................................................................. 4 1  
2  
O bjecti ves a n d e n d p oi nts  ................................................................................................... 4 2  
2. 1  
Pri mar y esti ma n ds  ................................................................................................. 4 3  
2. 2  
Sec o n dar y esti ma n ds  ............................................................................................. 4 5  
3  
St u d y desi g n  ...................................................................................................................... 4 5  
3. 1  
Off -site pr oce d ures ................................................................................................ 4 7  
3. 1. 1  
Res p o nsi bilit y of I n vesti gat ors  .............................................................. 4 8  
3. 1. 2  
Res p o nsi bilit y of O H Ps  ......................................................................... 4 8  
3. 1. 3  
Tele me dici ne  ......................................................................................... 4 8  
3. 1. 4  
Data fl o w  ............................................................................................... 4 9  
4  
Rati o nale  ............................................................................................................................ 5 0  
4. 1  
Rati o nale f or st u d y desi g n  ..................................................................................... 5 0  
4. 1. 1  
Rati o nale f or c h oice of bac k gr o u n d t hera p y  ......................................... 5 1  
4. 2  
Rati o nale f or d ose/re gi me n a n d d urati o n of treat me nt  .......................................... 5 1  
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)  ................................. 5 3  
4. 4  
P ur p ose a n d ti mi n g of i nteri m a nal yses  ................................................................. 5 3  
4. 5  
Ris ks a n d be nefits  .................................................................................................. 5 3  
4. 5. 1  
C o m p o u n d ris ks  .................................................................................... 5 3  

N o v arti s  
C o nfi d e nti al  
P a g e 3  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
4. 5. 2  
Pr oce d ural ris ks  ..................................................................................... 5 6  
4. 5. 3  
I ma gi n g ris ks ......................................................................................... 5 6  
4. 5. 4  
Ris ks ass ociate d wit h off -site visits ...................................................... 5 7  
4. 5. 5  
Bl o o d sa m ple v ol u me  ............................................................................ 5 7  
4. 5. 6  
S A R S -C o V -2 ris ks  ................................................................................ 5 8  
4. 5. 7  
O verall ris k be nefit  ................................................................................ 5 8  
4. 6  
Rati o nale f or p u blic healt h e mer ge nc y miti gati o n pr oce d ures  .............................. 5 8  
4. 7  
Rati o nale f or pla n ne d off -site pr oce d ures .............................................................. 5 8  
5  
St u d y P o p ulati o n  ............................................................................................................... 5 9  
5. 1  
I ncl usi o n criteria .................................................................................................... 5 9  
5. 2  
E xcl usi o n criteria  ................................................................................................... 6 0  
6  
St u d y treat me nt(s) a n d c o nc o mita nt t hera p y  ..................................................................... 6 4  
6. 1  
Descri pti o n of St u d y treat me nts a n d treat me nt ar ms  ............................................. 6 4  
6. 1. 1  
I n vesti gati o nal a n d c o ntr ol dr u gs .......................................................... 6 4  
6. 1. 2  
A d diti o nal st u d y treat me nts  .................................................................. 6 5  
6. 1. 3  
Treat me nt ar ms/ gr o u p  ........................................................................... 6 8  
6. 2  
Ot her treat me nt(s)  .................................................................................................. 6 8  
6. 2. 1  
C o nc o mita nt t hera p y  ............................................................................. 6 9  
6. 2. 2  
Pr o hi bite d me dicati o n  ........................................................................... 7 1  
6. 2. 3  
Resc ue me dicati o n  ................................................................................ 7 3  
6. 2. 4  
Restricti o n f or st u d y partici pa nts  .......................................................... 7 3  
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  .............................. 7 4  
6. 3. 1  
Partici pa nt n u m beri n g  ........................................................................... 7 4  
6. 3. 2  
Treat me nt assi g n me nt, ra n d o mizati o n  .................................................. 7 4  
6. 4  
Treat me nt bli n di n g  ................................................................................................ 7 5  
6. 5  
D ose escalati o n a n d d ose m o dificati o n .................................................................. 7 6  
6. 5. 1  
D ose escalati o n g ui deli nes  .................................................................... 7 6  
6. 6  
A d diti o nal treat me nt g ui da nce  ............................................................................... 7 7  
6. 6. 1  
Treat me nt c o m plia nce  ........................................................................... 7 7  
6. 6. 2  
Rec o m me n de d treat me nt of a d verse e ve nts  .......................................... 7 7  
6. 6. 3  
E mer ge nc y brea ki n g of assi g ne d treat me nt c o de  .................................. 7 8  
6. 7  
Pre parati o n a n d dis pe nsati o n  ................................................................................. 7 8  
6. 7. 1  
Ha n dli n g of st u d y treat me nt a n d a d diti o nal treat me nt  .......................... 7 9  
6. 7. 2  
I nstr ucti o n f or prescri bi n g a n d ta ki n g st u d y treat me nt ......................... 8 0  
7  
I nf or me d c o nse nt pr oce d ures ............................................................................................ 8 1  
8  
Visit sc he d ule a n d assess me nts  ......................................................................................... 8 3  

N o v arti s  
C o nfi d e nti al  
P a g e 4  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
8. 1  
Scree ni n g  ............................................................................................................... 8 9  
8. 1. 1  
Eli gi bilit y scree ni n g  .............................................................................. 8 9  
8. 1. 2  
I nf or mati o n t o be c ollecte d o n scree ni n g fail ures ................................. 9 1  
8. 1. 3  
Pre -scree ni n g pr oce d ure ........................................................................ 9 1  
8. 2  
Partici pa nt de m o gra p hics/ ot her baseli ne c haracteristics  ....................................... 9 2  
8. 3  
Efficac y  .................................................................................................................. 9 2  
8. 3. 1  
Patie nt Re p orte d O utc o mes ( P R Os)  ...................................................... 9 3  
8. 3. 2  
K nee M RI  .............................................................................................. 9 4  
8. 3. 3  
A p pr o priate ness of efficac y assess me nts  .............................................. 9 5  
8. 4  
Safet y/ T olera bilit y  ................................................................................................. 9 6  
8. 4. 1  
La b orat or y e val uati o ns  .......................................................................... 9 7  
8. 4. 2  
Electr ocar di o gra m ( E C G)  ..................................................................... 9 8  
8. 4. 3  
Pre g na nc y a n d assess me nts of fertilit y  ................................................. 9 9  
8. 4. 4  
A p pr o priate ness of safet y meas ure me nts  .............................................. 9 9  
8. 5  
A d diti o nal assess me nts  ........................................................................................ 1 0 0  
8. 5. 1  
 1 0 0  
8. 5. 2  
P har mac o ki netics  ................................................................................ 1 0 0  
8. 5. 3  
Bi o mar kers  .......................................................................................... 1 0 1  
8. 5. 4  
S y n o vial fl ui d c ollecti o n  ..................................................................... 1 0 4  
8. 5. 5  
I ma gi n g ............................................................................................... 1 0 4  
8. 5. 6  
Ot her Assess me nts  .............................................................................. 1 0 4  
9  
St u d y disc o nti n uati o n a n d c o m pleti o n  ............................................................................ 1 0 4  
9. 1  
Disc o nti n uati o n a n d c o m pleti o n  .......................................................................... 1 0 4  
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 ................ 1 0 4  
9. 1. 2  
Disc o nti n uati o n fr o m st u d y  ................................................................. 1 0 6  
9. 1. 3  
Wit h dra wal of i nf or me d c o nse nt  ......................................................... 1 0 6  
9. 1. 4  
L ost t o f oll o w -u p  ................................................................................. 1 0 7  
9. 1. 5  
St u d y st o p pi n g r ules  ............................................................................ 1 0 7  
9. 1. 6  
Earl y st u d y ter mi nati o n b y t he s p o ns or  ............................................... 1 0 8  
9. 2  
St u d y c o m pleti o n a n d p ost -st u d y treat me nt ........................................................ 1 0 8  
1 0  Safet y m o nit ori n g a n d re p orti n g  ...................................................................................... 1 0 8  
1 0. 1  
Defi niti o n of a d verse e ve nts a n d re p orti n g re q uire me nts  .................................... 1 0 8  
1 0. 1. 1  
A d verse e ve nts  .................................................................................... 1 0 8  
1 0. 1. 2  
Seri o us a d verse e ve nts  ........................................................................ 1 1 1  
1 0. 1. 3  
S A E re p orti n g ...................................................................................... 1 1 2  
1 0. 1. 4  
Pre g na nc y re p orti n g  ............................................................................ 1 1 3  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 5  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
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  .............. 1 1 4  
1 0. 2  
A d diti o nal Safet y M o nit ori n g  .............................................................................. 1 1 4  
1 0. 2. 1  
Li ver safet y m o nit ori n g  ....................................................................... 1 1 4  
1 0. 2. 2  
Re nal safet y m o nit ori n g  ...................................................................... 1 1 5  
1 1  Data C ollecti o n a n d Data base ma na ge me nt  .................................................................... 1 1 5  
1 1. 1  
Data c ollecti o n  ..................................................................................................... 1 1 5  
1 1. 2  
Data base ma na ge me nt a n d q ualit y c o ntr ol  .......................................................... 1 1 6  
1 1. 3  
Site m o nit ori n g  .................................................................................................... 1 1 7  
1 2  Data a nal ysis a n d statistical met h o ds  .............................................................................. 1 1 7  
1 2. 1  
A nal ysis sets  ........................................................................................................ 1 1 8  
1 2. 2  
Partici pa nt de m o gra p hics a n d ot her baseli ne c haracteristics  ............................... 1 1 8  
1 2. 3  
Treat me nts  ........................................................................................................... 1 1 8  
1 2. 4  
A nal ysis of t he pri mar y e n d p oi nt(s)/esti ma n d(s)  ................................................ 1 1 8  
1 2. 4. 1  
Defi niti o n of pri mar y e n d p oi nt(s)/esti ma n d(s)  ................................... 1 1 8  
1 2. 4. 2  
Statistical m o del, h y p ot hesis, a n d met h o d of a nal ysis  ........................ 1 1 9  
1 2. 4. 3  
Ha n dli n g of i nterc urre nt e ve nts of pri mar y esti ma n d  ......................... 1 1 9  
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 nts  ............ 1 1 9  
1 2. 4. 5  
Se nsiti vit y a nal yses f or pri mar y e n d p oi nt/esti ma n d  ........................... 1 1 9  
1 2. 4. 6  
S u p p orti ve a nal yses  ............................................................................. 1 1 9  
1 2. 4. 7  
S u p ple me ntar y a nal yses  ...................................................................... 1 1 9  
1 2. 5  
A nal ysis of sec o n dar y e n d p oi nts/esti ma n ds  ........................................................ 1 1 9  
1 2. 5. 1  
Efficac y a n d/ or P har mac o d y na mic e n d p oi nt(s)  .................................. 1 2 0  
1 2. 5. 2  
Safet y e n d p oi nts  .................................................................................. 1 2 0  
1 2. 5. 3  
P har mac o ki netics  ................................................................................ 1 2 1  
1 2. 5. 4  
Bi o mar kers  .......................................................................................... 1 2 1  
1 2. 6  
A nal ysis of e x pl orat or y e n d p oi nts  ....................................................................... 1 2 1  
1 2. 6. 1  
 1 2 2  
1 2. 6. 2  
 1 2 2  
1 2. 6. 3  
 1 2 2  
1 2. 6. 4  
 1 2 2  
1 2. 7  
I nteri m a nal yses ................................................................................................... 1 2 2  
1 2. 8  
Sa m ple size calc ulati o n ........................................................................................ 1 2 3  
1 2. 8. 1  
Pri mar y e n d p oi nt(s)  ............................................................................. 1 2 3  
1 2. 8. 2  
Sec o n dar y e n d p oi nt(s)  ......................................................................... 1 2 3  
1 3  Et hical c o nsi derati o ns a n d a d mi nistrati ve pr oce d ures  .................................................... 1 2 3  
1 3. 1  
Re g ulat or y a n d et hical c o m plia nce  ...................................................................... 1 2 3  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 6  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
1 3. 2  
Res p o nsi bilities of t he i n vesti gat or a n d I R B/I E C  ................................................ 1 2 4  
1 3. 3  
P u blicati o n P olic y  ................................................................................................ 1 2 4  
1 3. 4  
Q ualit y C o ntr ol a n d Q ualit y Ass ura nce  ............................................................... 1 2 4  
1 4  Pr ot oc ol a d here nce  .......................................................................................................... 1 2 5  
1 4. 1  
Pr ot oc ol a me n d me nts ........................................................................................... 1 2 5  
1 5  Refere nces  ....................................................................................................................... 1 2 6  
1 6  A p pe n dices  ...................................................................................................................... 1 2 9  
1 6. 1  
A p pe n di x 1: Li ver e ve nt a n d la b orat or y tri g ger defi niti o ns & f oll o w -u p 
re q uire me nts ........................................................................................................ 1 2 9  
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 3 2  
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  .......................................................... 4 2  
Ta ble 2 -2  
O ver vie w of i nterc urre nt e ve nts f or t he pri mar y esti ma n d  ................... 4 4  
Ta ble 4 -1  
Safet y mar gi ns f or D F V 8 9 0 d ose d at 2 5 m g b.i. d. base d o n G L P 
t o xic ol o g y st u dies.................................................................................. 5 2  
Ta ble 6 -1  
I n vesti gati o nal a n d c o ntr ol dr u g ............................................................ 6 5  
Ta ble 6 -2  
Basic pai n me dicati o n  ........................................................................... 6 6  
Ta ble 6 -3  
A d diti o nal st u d y treat me nt  .................................................................... 6 7  
Ta ble 6 -4  
Treat me nt Ar m(s)  .................................................................................. 6 8  
Ta ble 6 -5  
C o nc o mita nt me dicati o ns t o be use d wit h ca uti o n  ................................ 7 0  
Ta ble 6 -6  
Pr o hi bite d me dicati o n  ........................................................................... 7 1  
Ta ble 6 -7  
Pr o hi bite d dr u gs d ue t o D DI ( C Y P 3 A a n d C Y P 2 C 9 m o d ulat ors)  ........ 7 2  
Ta ble 6 -8  
Bli n di n g le vels  ...................................................................................... 7 6  
Ta ble 6 -9  
Pr o visi o nal d ose le vels  .......................................................................... 7 6  
Ta ble 6 -1 0  
D ose a n d treat me nt sc he d ule  ................................................................. 8 0  
Ta ble 8 -1  
Assess me nt Sc he d ule  ............................................................................ 8 4  
Ta ble 8 -2  
Rescree ni n g  ........................................................................................... 8 9  
Ta ble 8 -3  
Safet y Assess me nts a n d S pecificati o ns  ................................................. 9 6  
Ta ble 8 -4  
La b orat or y e val uati o ns  .......................................................................... 9 7  
Ta ble 1 0 -1  
G ui da nce f or ca pt uri n g t he st u d y treat me nt err ors i ncl u di n g 
mis use/a b use  ....................................................................................... 1 1 4  
Ta ble 1 2 -1  
N o n -c o m part me ntal p har mac o ki netic para meters  .............................. 1 2 1  
Ta ble 1 6 -1  
Li ver e ve nt a n d la b orat or y tri g ger defi niti o ns  .................................... 1 2 9  
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 ............................................................................................ 1 3 0  
Ta ble 1 6 -3  
F oll o w u p re q uire me nts f or li ver la b orat or y tri g gers  .......................... 1 3 1  

N o v arti s  
C o nfi d e nti al  
P a g e 7  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
Ta ble 1 6 -4  
S pecific Re nal Alert Criteria a n d Acti o ns  ........................................... 1 3 2  
Ta ble 1 6 -5  
Re nal E ve nt F oll o w U p  ....................................................................... 1 3 3  
Li st of fi g ur e s  
Fi g ure 3 -1  
St u d y desi g n  .......................................................................................... 4 5  

N o v arti s  
C o nfi d e nti al  
P a g e 8  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
Li st of a b br e vi ati o n s  
A C R  
Uri n e Al b u mi n t o Cr e ati ni n e R ati o  
A D L  
A cti viti e s of D ail y Li vi n g  
A D A M T S  
Di si nt e gri n a n d M et all o pr ot ei n a s e wit h T hr o m b o s p o n di n M otif s  
A E  
A d v er s e E v e nt  
A L P  
Al k ali n e P h o s p h at a s e  
A L T  
Al a ni n e A mi n otr a n sf er a s e  
A N C  
A b s ol ut e N e utr o p hil C o u nt  
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 R  
A ut or e gr e s si v e   
A S T  
A s p art at e A mi n otr a n sf er a s e  
A T C  
A n at o mi c al T h er a p e uti c C h e mi c al  
A U C  
Ar e a U n d er t h e C ur v e  
A V  
Atri o V e ntri c ul ar  
A x M P  
A u xili ar y M e di ci n al Pr o d u ct  
B  
Bli n d e d  
B A S -M P s Q  
B A S -–  M ulti di m e n si o n al P s y c h ol o gi c al Q u e sti o n n air e  
b.i. d./ BI D  
bi s i n di e/t wi c e a d a y  
B MI  
B o d y M a s s I n d e x  
B M L  
B o n e M arr o w L e si o n  
B P  
Bl o o d Pr e s s ur e  
B U N  
Bl o o d Ur e a Nitr o g e n  
C D S  
C or e D at a S h e et  
C E -M RI  
C o ntr a st E n h a n c e d M a g n eti c R e s o n a n c e I m a gi n g  
C F R 2 1  
C o d e of f e d er al r e g ul ati o n 2 1  
CI  
C o nfi d e n c e I nt er v al  
C K  
Cr e ati ni n e Ki n a s e  
C K D -E PI  
C hr o ni c Ki d n e y Di s e a s e E pi d e mi ol o g y C oll a b or ati o n  
C m a x  
M a xi m u m Dr u g C o n c e ntr ati o n  
C M O & P S  
C hi ef M e di c al Offi c e a n d P ati e nt S af et y  
C M P -M P s Q  
C M P -–  M ulti di m e n si o n al P s y c h ol o gi c al Q u e sti o n n air e  
C O  
C o u ntr y Or g a ni z ati o n  
 
 
C O VI D -1 9  
C or o n a vir u s Di s e a s e 2 0 1 9  
C O X -2  
C y cl o o x y g e n a s e -2  
C R A  
Cli ni c al R e s e ar c h A s s o ci at e  
C R O  
C o ntr a ct R e s e ar c h Or g a ni z ati o n  
C S R  
Cli ni c al St u d y R e p ort  
C T C  
C o m m o n T er mi n ol o g y Crit eri a  
C T C A E  
C o m m o n T er mi n ol o g y Crit eri a f or A d v er s e E v e nt s  
C TI S  
Cli ni c al Tri al s I nf or m ati o n S y st e m  
Ctr o u g h  
Tr o u g h C o n c e ntr ati o n  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 9  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
C V  
C o effi ci e nt of V ari ati o n  
C X C L 1 0  
C -X -C M otif C h e m o ki n e Li g a n d 1 0  
C Y P 2 C 9  
C yt o c hr o m e P 4 5 0 2 C 9  
C Y P 3 A 4  
C yt o c hr o m e P 4 5 0 3 A 4  
D B P  
Di a st oli c Bl o o d Pr e s s ur e  
D C E -M RI  
D y n a mi c C o ntr a st E n h a n c e d M a g n eti c R e s o n a n c e I m a gi n g  
D D C  
Dir e ct D at a C a pt ur e  
D D E  
Dir e ct D at a E ntr y  
D DI  
Dr u g -Dr u g I nt er a cti o n  
DI N  
Dr u g I n d u ct e d N e p hr ot o xi cit y  
d L  
d e cilit er  
D M C  
D at a M o nit ori n g C o m mitt e e  
D N A  
D e o x yri b o N u cl ei c A ci d  
E C G  
El e ctr o c ar di o gr a m  
 
 
e 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)  
E D C  
El e ctr o ni c D at a C a pt ur e  
e G F R  
E sti m at e d Gl o m er ul ar Filtr ati o n R at e   
E M A  
E ur o p e a n M e di ci n e s A g e n c y   
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  
e S o ur c e  
El e ctr o ni c S o ur c e  
E o S  
E n d of St u d y  
E U C T R  
E ur o p e a n U ni o n Cli ni c al Tri al s R e g ul ati o n  
E X P -M P s Q  
E X P -–  M ulti di m e n si o n al P s y c h ol o gi c al Q u e sti o n n air e  
F A S  
F ull A n al y si s S et  
F D A  
F o o d a n d Dr u g A d mi ni str ati o n  
FI H  
Fir st i n H u m a n  
F M A  
F e m or al M e di al A nt eri or  
F M C  
F e m or al M e di al C e ntr al  
F M P  
F e m or al M e di al P o st eri or   
F S H  
F olli cl e Sti m ul ati n g H or m o n e  
g  
gr a m  
G B C A  
G a d oli ni u m -B a s e d C o ntr a st A g e nt  
G C P  
G o o d Cli ni c al Pr a cti c e  
G C S  
Gl o b al Cli ni c al S u p pl y  
G d -D O T A  
g a d oli ni u m -t etr a a z a c y cl o d o d e c a n et etr a a c eti c a ci d 
gfr  
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  
H o ur  
H A  
H e alt h A ut h orit y  
H B c A g  
H e p atiti s B c or e A nti g e n  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 0  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
H B s A g  
H e p atiti s B s urf a c e A nti g e n  
H B V  
H e p atiti s B Vir u s  
H C V  
H e p atiti s C Vir u s  
( β) h C G 
H u m a n c h ori o ni c g o n a d otr o pi n  b et a  
HI V  
H u m a n I m m u n o d efi ci e n c y Vir u s  
h s C R P  
hi g h s e n siti vit y C -R e a cti v e Pr ot ei n  
i. v. 
I ntr a v e n o u s 
I A C S 
I ntr a-Arti c ul ar C orti c o st er oi d s  
I B 
I n v e sti g at or’ s Br o c h ur e 
I C 5 0 
I n hi bit or y C o n c e ntr ati o n 5 0 %  
I C 9 0 
I n hi bit or y C o n c e ntr ati o n 9 0 % 
I C E 
I nt er-C urr e nt E v e nt  
I C F 
I nf or m e d C o n s e nt F or m 
I C H 
I nt er n ati o n al C o u n cil f or H ar m o ni z ati o n of T e c h ni c al R e q uir e m e nt s f or 
P h ar m a c e uti c al s f or H u m a n U s e  
I E C 
I n d e p e n d e nt Et hi c s C o m mitt e e 
I L 1 R N 
Int erl e u ki n 1 r e c e pt or a nt a g o ni s t 
I L-1 8  
I nt erl e u ki n 1 8 
I L-1 β  
I nt erl e u ki n 1 β 
I L-6  
I nt erl e u ki n 6 
I M P 
I n v e sti g ati o n al M e di ci n al Pr o d u ct 
I N 
I n v e sti g at or N otifi c ati o n 
I N R 
I nt er n ati o n al N or m ali z e d R ati o 
I R B 
I n stit uti o n al R e vi e w B o ar d 
I R T 
I nt er a cti v e R e s p o n s e T e c h n ol o g y 
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 D O QI  
Ki d n e y Di s e a s e O ut c o m e s Q u alit y I niti ati v e 
k g  
Kil o gr a m  
KI M -1  
Ki d n e y I nj ur y M ol e c ul e -1  
K & L  
K ell gr e n -L a wr e n c e  
K O O S  
K n e e i nj ur y a n d O st e o art hriti s O ut c o m e S c or e  
Ktr a n s  
V ol u m e tr a n sf er c o n s t a nt 
L  
Lit er  
L A A M  
L e v o m et h a d yl  
L C -M S  
Li q ui d C hr o m at o gr a p h y -M a s s S p e ctr o m etr y  
L D H  
L a ct at e D e h y dr o g e n a s e  
L F T  
Li v er F u n cti o n T e st  
L L O Q  
L o w er Li mit of Q u a ntifi c ati o n  
L P L V  
L a st P ati e nt L a st Vi sit  
L P S  
Li p o p ol y s a c c h ari d e s  

N o v arti s  
C o nfi d e nti al  
P a g e 1 1  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
m  
M et er  
M A D  
M ulti pl e A s c e n di n g D o s e  
M A R  
Mi s si n g At R a n d o m  
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  
μ g  
mi cr o gr a m ( s)  
µ L  
mi cr olit er  
µ S v  
mi cr o si e v ert  
m S v  
milli si e v ert  
m g  
milli gr a m( s)  
M H R A  
M e di ci n e s a n d H e alt h c ar e pr o d u ct s R e g ul at or y A g e n c y  
m L  
millilit er( s)  
m m ol  
mili m ol e  
M M P s  
M atri x M et all o pr ot ei n a s e s  
M M R M  
Mi x e d eff e ct s M o d el f or R e p e at e d M e a s ur e s  
M P s Q  
M ulti -Di m e n si o n al P s y c h ol o gi c al  Q u e sti o n n air e  
mr e m  
milllir e m  
M RI  
M a g n eti c R e s o n a n c e I m a gi n g  
M S  
M a s s S p e ctr o m etr y  
N CI -
C T C A E/ v 5  
N ati o n al C a n c er I n stit ut e - C o m m o n T er mi n ol o g y Crit eri a f or A d v er s e E v e nt s 
v er si o n 5  
N F S  
N e p hr o g e ni c S y st e mi c Fi br o si s  
n g  
n a n o gr a m  
N G A L  
N e utr o p hil G el ati n a s e -A s s o ci at e d Li p o c ali n  
NI R T  
N o v arti s  I nt er a cti v e R e s p o n s e T e c h n ol o g y 
N L R P 3  
N L R f a mil y p yri n d o m ai n c o nt ai ni n g pr ot ei n 3  
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 b s R O  
O b s er v er R e p ort e d O ut c o m e s  
O H P  
Off -sit e H e alt h c ar e Pr of e s si o n al  
p. o.  
P er Or al  
P A  
P o st er o a nt eri or  
P C  
P er s o n al C o m p ut er  
P C R  
Pr ot ei n -Cr e ati ni n e R ati o  
P. C. R.  
P ol y m er a s e C h ai n R e a cti o n  
P D  
P h ar m a c o d y n a mi c( s)  
P E R -M P s Q  
P E R - M ulti di m e n si o n al P s y c h ol o gi c al Q u e sti o n n air e  
PI  
Pri n ci p al I n v e sti g at or  
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  

N o v arti s  
C o nfi d e nti al  
P a g e 1 2  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
P R O  
P ati e nt R e p ort e d O ut c o m e s  
P S D  
Pr e m at ur e S u bj e ct Di s c o nti n u ati o n  
P T  
Pr ot hr o m bi n Ti m e  
P T T  
P arti al T hr o m b o pl a sti n Ti m e  
Q D  
O n c e a d a y  
Q M S  
Q u alit y M a n a g e m e nt S y st e m  
Q o L  
Q u alit y of Lif e   
Q T c F  
Q T i nt er v al c orr e ct e d b y Fri d eri ci a’ s f or m ul a  
R V al u e  
A L T/ A L P x U L N  
R B C  
R e d Bl o o d C ell( s)  
R N A  
Ri b o n u cl ei c A ci d  
S A D  
Si n gl e A s c e n di n g D o s e  
S A E  
S eri o u s A d v er s e E v e nt  
S A F  
S af et y A n al y si s S et  
S A P  
St ati sti c al A n al y si s Pl a n  
S B P  
S y st oli c Bl o o d Pr e s s ur e  
s C R  
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 D  
S pr a y -dri e d Di s p er si o n  
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 O C  
S u p pr e s s or of C yt o ki n e Si g n ali n g  
S o C  
St a n d ar d of C ar e  
S O P  
St a n d ar d O p er ati v e Pr o c e d ur e  
S T D  
St u d y Tr e at m e nt Di s c o nti n u ati o n  
S U S A R  
S u s p e ct e d U n e x p e ct e d S eri o u s A d v er s e R e a cti o n  
T 1 w  
T 1 -w ei g ht e d  
T B L  
T ot al Bilir u bi n  
T F C  
Ti bi of e m or al C o m p art m e nt  
T m a x  
Ti m e t o r e a c h C m a x  
T N F -α  
T u m or N e cr o si s F a ct or  α  
UI  
U n bli n d e d o n I n di vi d u al p ati e nt l e v el  
U L N  
U p p er Li mit of N or m al  
 
 
U TI  
Uri n ar y Tr a ct I nf e cti o n  
W B C  
W hit e Bl o o d C ell( s)  
W H O  
W orl d H e alt h Or g a ni z ati o n  
W o C  
Wit h dr a w al of C o n s e nt  
W O M A C  
W e st er n O nt ari o a n d M c M a st er U ni v er siti e s Art hriti s I n d e x  
W PI  
Wi d e s pr e a d P ai n I n d e x  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 3  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
Gl o s s ar y of t er m s  
A d diti o n al tr e at m e nt  
M e di ci n al pr o d u ct s t h at m a y b e u s e d d uri n g t h e cli ni c al tri al a s 
d e s cri b e d i n t h e pr ot o c ol, b ut n ot a s a n i n v e sti g ati o n al m e di ci n al 
pr o d u ct ( e. g., a n y b a c k gr o u n d t h er a p y)  
A s s e s s m e nt  
A pr o c e d ur e u s e d t o g e n er at e d at a r e q uir e d b y t h e st u d y  
A u xili ar y M e di ci n al Pr o d u ct  
M e di ci n al pr o d u ct u s e d f or t h e n e e d s of a cli ni c al tri al a s d e s cri b e d 
i n t h e pr ot o c ol, b ut n ot a s a n i n v e sti g ati o n al m e di ci n al pr o d u ct 
( e. g., r e s c u e m e di c ati o n, c h all e n g e a g e nt s, b a c k gr o u n d tr e at m e nt 
or m e di ci n al pr o d u ct s u s e d t o a s s e s s e n d p oi nt s i n t h e cl i ni c al 
tri al). 
C o n c o mit a nt t h er a p y i s n ot c o n si d er e d A x M P.  
B a c k gr o u n d T h er a p y  
G e n er all y c o n si d er e d t o b e t h e c urr e nt st a n d ar d of c ar e f or a 
p arti c ul ar c o n diti o n / di s e a s e, i n a d diti o n t o w hi c h st u d y tr e at m e nt 
i s gi v e n 
Bi ol o gi c S a m pl e s  
A bi ol o gi c al s p e ci m e n i n cl u di n g, f or e x a m pl e, bl o o d ( pl a s m a, 
s er u m), s ali v a, ti s s u e, uri n e, st o ol, et c. t a k e n fr o m a st u d y 
p arti ci p a nt  
C o h ort  
A s p e cifi c gr o u p of p arti ci p a nt s f ulfilli n g c ert ai n crit eri a a n d 
g e n er all y tr e at e d at t h e s a m e ti m e  
C o ntr ol dr u g  
A st u d y dr u g ( a cti v e or pl a c e b o) u s e d a s a c o m p ar at or t o r e d u c e 
a s s e s s m e nt bi a s, pr e s er v e bli n di n g of i n v e sti g ati o n al dr u g, a s s e s s 
i nt er n al st u d y v ali dit y, a n d/ or e v al u at e c o m p ar ati v e eff e ct s of t h e 
i n v e sti g ati o n al dr u g 
C y cl e s  
N u m b er a n d ti mi n g or r e c o m m e n d e d r e p etiti o n s of t h er a p y ar e 
u s u all y e x pr e s s e d a s n u m b er of d a y s ( e. g., q 2 8 d a y s)  
D o s a g e  
D o s e of t h e st u d y tr e at m e nt gi v e n t o t h e p arti ci p a nt i n a ti m e u nit 
( e. g., 1 0 0 m g o n c e a d a y, 7 5 m g t wi c e a d a y) 
El e ctr o ni c D at a C a pt ur e 
( E D C) 
El e ctr o ni c d at a c a pt ur e ( E D C) i s t h e el e ctr o ni c a c q ui siti o n of 
cli ni c al st u d y d at a u si n g d at a c oll e cti o n s y st e m s, s u c h a s W e b -
b a s e d a p pli c ati o n s, i nt er a cti v e v oi c e r e s p o n s e s y st e m s a n d 
cli ni c al l a b or at or y i nt erf a c e s. E D C i n cl u d e s t h e u s e of El e ctr o ni c 
C a s e  R e p ort F or m s ( e C R F s) w hi c h ar e u s e d t o c a pt ur e d at a 
tr a n s cri b e d fr o m p a p er s o ur c e f or m s u s e d at t h e p oi nt of c ar e 
E n d of t h e cli ni c al tri al  
T h e e n d of t h e cli ni c al tri al i s d efi n e d a s t h e l a st vi sit of t h e l a st 
p arti ci p a nt or at a l at er p oi nt i n ti m e a s d efi n e d b y t h e pr ot o c ol  
E nr oll m e nt  
P oi nt/ti m e of p arti ci p a nt e ntr y i nt o t h e st u d y at w hi c h i nf or m e d 
c o n s e nt m u st b e o bt ai n e d  
e S o ur c e ( D D C)  
e S o ur c e Dir e ct D at a C a pt ur e ( D D C) r ef er s t o t h e c a pt ur e of 
cli ni c al st u d y d at a el e ctr o ni c all y, at t h e p oi nt of c ar e. e S o ur c e 
Pl atf or m/ A p pli c ati o n s c o m bi n e s s o ur c e d o c u m e nt s a n d c a s e 
r e p ort f or m s ( e C R F s) i nt o o n e a p pli c ati o n, all o wi n g f or t h e r e al 
ti m e c olle cti o n of cli ni c al tri al i nf or m ati o n t o s p o n s or s a n d ot h er 
o v er si g ht a ut h oriti e s, a s a p pr o pri at e  
E sti m a n d   
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 ati e 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 

N o v arti s  
C o nfi d e nti al  
P a g e 1 4  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
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. 
H e alt h y v ol u nt e er  
A p er s o n wit h n o k n o w n si g nifi c a nt h e alt h pr o bl e m s w h o 
v ol u nt e er s t o b e a st u d y p arti ci p a nt  
I nt er c urr e nt e v e nt s 
E v e nt s o c c urri n g aft er tr e at m e nt i niti ati o n t h at aff e ct eit h er t h e 
i nt er pr et ati o n or t h e e xi st e n c e of t h e m e a s ur e m e nt s a s s o ci at e d 
wit h t h e cli ni c al q u e sti o n of i nt er e st.  
I n v e sti g ati o n al Pr o d u ct/ 
I n v e sti g ati o n al M e di ci n al 
pr o d u ct  
A p h ar m a c e uti c al f or m of a n a cti v e i n gr e di e nt or pl a c e b o b ei n g 
t e st e d or u s e d a s a r ef er e n c e ( s u c h a s a n a cti v e c o m p ar at or) i n a 
cli ni c al tri al, i n cl u di n g a pr o d u ct wit h a m ar k eti n g a ut h ori z ati o n 
w h e n u s e d or a s s e m bl e d (f or m ul at e d or p a c k a g e d) i n a w a y 
dif f er e nt fr o m t h e a p pr o v e d f or m, or w h e n u s e d f or a n u n a p pr o v e d 
i n di c ati o n, or w h e n u s e d t o g ai n f urt h er i nf or m ati o n a b o ut a n 
a p pr o v e d u s e.  
K & L  
T h e  K ell gr e n a n d L a wr e n c e s y st e m  i s a m et h o d of cl a s sif yi n g t h e 
s e v erit y of o st e o art hriti s u si n g fi v e gr a d e s  
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 m e di c ati o n kit s  
Mi s -r a n d o mi z e d p arti ci p a nt s 
Mi s -r a n d o mi z e d p arti ci p a nt s ar e t h o s e w h o w er e n ot q u alifi e d f or 
r a n d o mi z ati o n a n d w h o di d n ot t a k e st u d y tr e at m e nt, b ut h a v e 
b e e n i n a d v ert e ntl y r a n d o mi z e d i nt o t h e st u d y  
Off -sit e  
D e s cri b e s a n y tri al a cti viti e s p erf or m e d wit h t h e p arti ci p a nt at a 
l o c ati o n t h at i s n ot t h e i n v e sti g ati v e sit e w h er e t h e i n v e sti g at or will 
c o n d u ct t h e tri al, b ut i s f or e x a m pl e t h e p arti ci p a nt’ s h o m e or 
a n ot h er a p pr o pri at e l o c ati o n  
Off -sit e H e alt h c ar e 
Pr of e s si o n al ( O H P)  
A q u alifi e d h e alt h c ar e pr of e s si o n al, s u c h a s a n ur s e, w h o p erf or m s 
c ert ai n pr ot o c ol pr o c e d ur e s f or t h e p arti ci p a nt at a n off -sit e 
l o c ati o n s u c h a s a p arti ci p a nt’ s h o m e 
Ot h er tr e at m e nt  
Tr e at m e nt t h at m a y b e n e e d e d/ all o w e d d uri n g t h e c o n d u ct of t h e 
st u d y (i. e., c o n c o mit a nt or r e s c u e t h er a p y)  
P art  
A s u b -di vi si o n of a st u d y u s e d t o e v al u at e s p e cifi c o bj e cti v e s or 
c o nt ai n diff er e nt p o p ul ati o n s. F or e x a m pl e, o n e st u d y c o ul d 
c o nt ai n 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 arti ci p a 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 tri al p arti ci p a nt ( c a n b e a h e alt h y v ol u nt e er or a p ati e nt)  
P arti ci p a nt n u m b er  
A u ni q u e n u m b er a s si g n e d t o e a c h p arti ci p a nt u p o n si g ni n g t h e 
i nf or m e d c o n s e nt. T hi s n u m b er i s t h e d efi niti v e, u ni q u e i d e ntifi er 
f or t h e p arti ci p a nt a n d s h o ul d b e u s e d t o i d e ntif y t h e p arti ci p a nt 
t hr o u g h o ut t h e st u d y f or all d at a c oll e ct e d, s a m pl e l a b el s, et c.  
P eri o d  
T h e s u b di vi si o n s of t h e tri al d e si g n ( e. g., S cr e e ni n g, Tr e at m e nt, 
F oll o w -u p) w hi c h ar e d e s cri b e d i n t h e Pr ot o c ol. P eri o d s d efi n e t h e 
st u d y p h a s e s a n d will b e u s e d i n cli ni c al tri al d at a b a s e s et u p a n d 
e v e nt u all y i n a n al y si s  
P er p etr at or dr u g  
A dr u g w hi c h aff e ct s t h e p h ar m a c o ki n eti c s of t h e ot h er dr u g  
P er s o n al d at a  
P arti ci p a nt i nf or m ati o n c oll e ct e d b y t h e I n v e sti g at or t h at i s c o d e d 
a n d tr a n sf err e d t o N o v arti s f or t h e p ur p o s e of t h e cli ni c al tri al. T hi s 
d at a i n cl u d e s p arti ci p a nt i d e ntifi er i nf or m ati o n, st u d y i nf or m ati o n 
a n d bi ol o gi c al s a m pl e s.  
Pl a c e b ell © ™ 
M et h o d ol o g y  d e v el o p e d a n d  o w n e d b y C o g ni vi a  t o pr o d u c e, 
c o m p ut e a n d d o c u m e nt pr o g n o sti c c o v ari at e.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 5  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
Pr e m at ur e p arti ci p a nt 
wit h dr a w al  
P oi nt/ti m e w h e n t h e p arti ci p a nt 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/ or 
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 p arti ci p a nt  
R u n -i n F ail ur e 
A p arti ci p a nt w h o i s s cr e e n e d b ut n ot r a n d o mi z e d/tr e at e d aft er t h e 
r u n-i n p eri o d ( w h er e r u n-i n p eri o d r e q uir e s a dj u st m e nt t o 
p arti ci p a nt’ s i nt er v e nti o n or ot h er tr e at m e nt)  
S cr e e n F ail ur e  
A p arti ci p a nt w h o di d n ot m e et o n e or m or e crit eri a t h at w er e 
r e q uir e d f or p arti ci p ati o n i n t h e st u d y 
S o ur c e D at a/ D o c u m e nt  
S o ur c e d at a r ef er s t o t h e i niti al r e c or d, d o c u m e nt, or pri m ar y 
l o c ati o n fr o m w h er e d at a c o m e s. T h e d at a s o ur c e c a n b e a 
d at a b a s e, a d at a s et, a s pr e a d s h e et or e v e n h ar d -c o d e d d at a, s u c h 
a s p a p er or e S o ur c e  
St a g e i n c a n c er  
T h e e xt e nt of c a n c er i n t h e b o d y. St a gi n g i s u s u all y b a s e d o n t h e 
si z e of t h e t u m or, w h et h er l y m p h n o d e s c o nt ai n c a n c er, a n d 
w h et h er t h e c a n c er h a s s pr e a d fr o m t h e ori gi n al sit e t o ot h er p art s 
of t h e b o d y  
St art of t h e cli ni c al tri al  
T h e st art of t h e cli ni c al tri al i s d efi n e d a s t h e si g n at ur e of t h e 
i nf or m e d c o n s e nt b y t h e fir st p arti ci p a nt 
St u d y tr e at m e nt  
A n y dr u g or c o m bi n ati o n of dr u g s   or i nt er v e nti o n a d mi ni st er e d t o 
t h e st u d y p arti ci p a nt s a s p art of t h e r e q uir e d st u d y pr o c e d ur e s; 
i n cl u d e s i n v e sti g ati o n al dr u g( s), c o ntr ol( s) or b a c k gr o u n d t h er a p y 
St u d y tr e at m e nt 
di s c o nti n u ati o n  
W h e n t h e p arti ci p a nt p er m a n e ntl y st o p s t a ki n g a n y of t h e st u d y 
dr u g( s) pri or t o t h e d efi n e d st u d y tr e at m e nt c o m pl eti o n d at e (if 
a n y) f or a n y r e a s o n; m a y or m a y n ot al s o b e t h e p oi nt/ti m e of 
st u d y di s c o nti n u ati o n  
T el e vi sit  
Pr o c e d ur e s or c o m m u ni c ati o n s c o n d u ct e d u si n g t e c h n ol o g y s u c h 
a s a t el e p h o n e or vi d e o -c o nf er e n c e, w h er e b y t h e p arti ci p a nt i s n ot 
at t h e i n v e sti g ati v e sit e w h er e t h e i n v e sti g at or will c o n d u ct t h e tri al  
Tr e at m e nt ar m/ gr o u p  
A tr e at m e nt ar m/ gr o u p d efi n e s t h e d o s e a n d r e gi m e n or t h e 
c o m bi n ati o n, a n d m a y c o n si st of 1 or m or e c o h ort s.  
Tr e at m e nt of i nt er e st 
T h e tr e at m e nt of i nt er e st a n d, a s a p pr o pri at e, t h e alt er n ati v e 
tr e at m e nt t o w hi c h c o m p ari s o n will b e m a d e. T h e s e mi g ht b e 
i n di vi d u al i nt er v e nti o n s, c o m bi n ati o n s of i nt er v e nti o n s 
a d mi ni st er e d c o n c urr e ntl y, e. g. a s a d d -o n t o st a n d ar d of c ar e, or 
mi g ht c o n si s t of a n o v er all r e gi m e n i n v ol vi n g a c o m pl e x s e q u e n c e 
of i nt er v e nti o n s. T hi s i s t h e tr e at m e nt of i nt er e st u s e d i n d e s cri bi n g 
t h e r el at e d cli ni c al q u e sti o n of i nt er e st, w hi c h mi g ht or mi g ht n ot b e 
t h e s a m e a s t h e st u d y tr e at m e nt. 
V ari a bl e ( or e n d p oi nt)  
T h e v ari a bl e ( or e n d p oi nt) t o b e o bt ai n e d f or e a c h p arti ci p a nt t h at 
i s r e q uir e d t o a d dr e s s t h e cli ni c al q u e sti o n. T h e s p e cifi c ati o n of t h e 
v ari a bl e mi g ht i n cl u d e w h et h er t h e p arti ci p a nt e x p eri e n c e s a n 
i nt er c urr e nt e v e nt. 
Vi cti m dr u g  
T h e dr u g t h at i s aff e ct e d b y t h e dr u g -dr u g i nt er a cti o n  
Wit h dr a w al of st u d y c o n s e nt 
( W o C) 
Wit h dr a w al of c o n s e nt fr o m t h e st u d y o c c ur s o nl y w h e n a 
p arti ci p a nt d o e s n ot w a nt t o p arti ci p at e i n t h e st u d y a n y l o n g er a n d 
d o e s n ot all o w a n y f urt h er c oll e cti o n of p er s o n al d at a   

N o v arti s  
C o nfi d e nti al  
P a g e 1 6  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
A m e n d m e nt 6 ( D e c e m b er 2 0 2 3)  
T his a me n d me nt is ge nerate d t o i m ple me nt lear ni n gs fr o m o n g oi n g a n d pre vi o us trials i n O A, 
w hic h are e x pecte d t o facilitate t he trial pr ocesses a n d re d uce t he b ur de n t o partici pa nts a n d 
sites, mai nl y b y i ntr o d uci n g a pre-scree ni n g pr oce d ure. F urt her m ore, the s p o ns or is ta ki n g t he 
o p p ort u nit y t o ma ke necessar y c ha n ges t o be pre pare d f or t he u pc o mi n g a n d re q uire d tra nsiti o n 
t o t he E U Cli nical Trial Re g ulati o n - Re g ulati o n ( E U) N o 5 3 6/ 2 0 1 4 ( E U C T R). T he mai n 
m o dificati o ns are detaile d i n t he ne xt para gra p hs.  
T he i ncl usi o n criteri o n f or s y n o vitis was u p date d wit h l o wer t hres h ol ds f or t he o verall s u m 
sc ore. S y n o vitis is bei n g assesse d at scree ni n g usi n g a s u m sc ore base d o n s y n o vial t hic k ness 
i n 1 1 areas of t he j oi nt. T his assess me nt is d o ne usi n g c o ntrast e n ha nce d M RI. D uri n g f oll o w 
u p, s y n o vitis assess me nts rel y o n K -tra ns, w hic h is a m ore se nsiti ve meas ure of c o ntrast 
e n ha nce me nt. K -tra ns d y na micall y meas ures t he per mea bilit y of ne wl y f or me d vessels usi n g a 
2 -c o m part me nt m o del as s urr o gate f or acti ve i nfla m mat or y pr ocesses. Si nce K -tra ns is o nl y 
assesse d at 
 
 ha ve s u g geste d t hat t he sc ores of t he i n di vi d ual re gi o ns 
ma y be m ore rele va nt f or t he o utc o me assess me nt t ha n t he o verall s u m sc ore. T heref ore, t he 
o verall sc ore f or i ncl usi o n was l o were d t o i ncl u de als o partici pa nts wit h mil d s y n o vitis 
(s u m sc ore ≥7), pr o vi de d t hat at least o ne area of t he j oi nt s y n o vi u m prese nts wit h a sc ore of 2 
(i.e., ma xi m u m sc ore). T his mea ns t hat i n t hese s pecific cases a n o verall s y n o vitis sc ore 
i n dicati ve of mil d s y n o vitis (s u m sc ore of ≥7 ), i nstea d of m o derate or se vere as re q uire d i n t he 
pre vi o us pr ot oc ol, is s ufficie nt f or t he i de ntificati o n of t he tar get p o p ulati o n. At t he 3 -m o nt hs 
f oll o w-u p assess me nt, t he s y n o vitis assess me nt is d o ne usi n g K -tra ns, w hic h is a m ore se nsiti ve 
meas ure me n t f or e val uati o n of t he o utc o me. T his assess me nt is perf or me d i n 
 
, f or c ha n ges i n s y n o vitis i n t he k nee j oi nt.  
J S W data c ollecti o n was re m o ve d i n t his a me n d me nt. J S W meas ure me nts f or i ncl usi o n i n t he 
st u d y were re m o ve d wit h A me n d me nt 5.  T heref ore, p urs ui n g t his meas ure f or p ote ntial p ost -
h oc a nal ysis is of li mite d be nefit. Wit h t his c ha n ge, o nl y t he wei g ht beari n g  pr ojecti o ns are 
nee de d, t here b y re d uci n g ra diati o n e x p os ure f or partici pa nts.  
T he ti me i nter val fr o m pre vi o us s ur ger y has bee n s h orte ne d. T his c ha n ge was c o nsi dere d 
acce pta ble as l o n g as partici pa nts are c o ntralaterall y oli g os y m pt o matic, i n w hic h cases t he 
i de ntificati o n of t he tar get k nee is p ossi ble. F urt her m ore, it all o ws f or t he i de ntificati o n of 
oste oart hritis as t he m ost li kel y ca use f or persiste nt pai n.  
T he peri o d assesse d f or t he sta bilit y of t he pai n le vel bef ore scree ni n g has bee n pr ol o n ge d fr o m 
o ne wee k t o t w o wee ks. F urt her m ore, t he re q uire me nt f or c o m plia nce wit h t he pai n diar y has 
bee n a da pte d fr o m 5/ 7 da ys t o 6/ 7 da ys.  T hese c ha n ges were i m ple me n te d t o ali g n  
 
 
T he p ossi bilit y f or a n 
 was i ntr o d uce d base d o n i n vesti gat ors’ fee d bac k. 
Pre -scree ni n g c o nsists of la b orat or y tests, X-ra ys (sta n dar d l o n g le g or k nee ce ntere d wei g ht 
beari n g, per i ma gi n g pr ot oc ol)  a n d cli nical assess me nts as per st u d y re q uire me nts, t o be 
perf or me d a n d e val uate d l ocall y. Data c ollecte d d uri n g t he pre -scree ni n g will o nl y be ke pt i n 
t he s o urce d oc u me nts a n d n o data will be e ntere d i nt o t he C R F. Tra nsiti o n t o f ull scree ni n g will 
re q uire re peat bl o o d sa m pli n g f or ce ntral la b orat or y assess me nt s. T he X -ra y will re mai n vali d 
f or 6 m o nt hs (if perf or me d per pr ot oc ol re q uire me nts). T he o utc o me of t he cli nical assess me nt 
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 7  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
will be vali d f or 2 wee ks, as l o n g as t he patie nt d oes n ot re p ort rele va nt c ha n ges i n 
s y m pt o mat ol o g y. T his pre -scree ni n g all o ws f or a n earl y detecti o n of t he n o n -visi ble, m ost 
fre q ue nt ca uses of scree ni n g fail ure, a n d t he e xcl usi o n of u ns uita ble p ote ntial partici pa nts. T h us, 
sa vi n g res o urces a n d li miti n g b ur de n o n p ote ntial partici pa nts.  
T his a me n d me nt re m o ves t he e xcl usi o n criteri o n f or C Y P 2 C 9 * 3/ * 3 ge n ot y pe. T heref ore, t he 
ass ociate d C Y P 2 C 9 ge n ot y pi n g test was als o re m o ve d fr o m t he scree ni n g assess me nts. 
T he  re m o val of t his criteri o n is p ossi ble beca use safet y mar gi ns at t he e m pl o ye d d oses are 
s ufficie ntl y lar ge u n der t he st u d y s pecific restricti o ns f or c o nc o mita nt me dicati o n. Base d o n 
mea n P K data i n healt h y partici pa nts ( p o p ulati o n of n or mal a n d i nter me diate C Y P 2 C 9 
meta b olizers), t he safet y mar gi ns f or 2 5 m g b.i. d. are at least  
w he n c o m pare d wit h t he 
N O A E L e x p os ure fr o m t he rece ntl y c o m plete d 2 6 -wee k rat a n d 4 6 -wee k m o n ke y st u dies, 
res pecti vel y. Patie nts wit h decrease d C Y P 2 C 9 acti vit y ma y ha ve u p t o -f ol d hi g her A U C of 
D F V 8 9 0 c o m pare d t o n or mal C Y P 2 C 9 meta b olizers res ulti n g i n res pecti vel y l o wer safet y 
mar gi ns. C o nsi deri n g s ufficie nt safet y mar gi ns deri ve d fr o m l o n g -lasti n g a ni mal G L P st u dies, 
all patie nts irres pecti ve of C Y P 2 C 9 ge n ot y pe ca n be i ncl u de d i n t his st u d y.  T o miti gate f or t he 
wit h str o n g or m o derate C Y P 3 A 4 i n hi bit ors, t he e xcl usi o n criteri o n of patie nts 
w h o are ta ki n g c o nc o mita nt me dicati o ns k n o w n t o be str o n g or m o derate i n hi bit ors of C Y P 3 A 
has bee n a d de d. Partici pa nts, w h o were ge n ot y pe d f or C Y P 2 C 9 at scree ni n g a n d a d mitte d t o 
t he st u d y base d o n t he pr ot oc ol versi o n 0 5, ca n c o nti n ue t o f oll o w t he c o nc o mita nt me dicati o n 
restricti o ns as descri be d i n t he pr ot oc ol versi o n 0 5. 
D ue t o a de q uate safet y mar gi ns t he a me n d me nt l o wers restricti o n f or c o nc o mita nt me dicati o ns, 
w hic h are str o n g C Y P 2 C 9 i n hi bit ors. T he C Y P 2 C 9 i n hi bit ors are n o w all o we d t o be use d wit h 
ca uti o n.  
T he ti me wi n d o w w he n t he st u d y treat me nt s h o ul d be ta ke n i n ass ociati o n wit h f o o d i nta ke has 
bee n m o difie d. Partici pa nts are n o w i nstr ucte d t o ta ke t heir st u d y ta blets wit h t heir meal or 
s h ortl y after eati n g, i nstea d of ha vi n g t o wait t o ta ke t he st u d y ta blets wit hi n 5 mi n utes after t he 
meal as per pre vi o us pr ot oc ol versi o ns.  
F urt her t o t he m o dificati o ns a b o ve, s o me ele me nts w hic h are re q uire d f or c o m plia nce wit h E U 
C T R ha ve bee n a d de d:  
•  S p o ns or i nf or mati o n o n t he c o ver pa ge  
•  Defi niti o n a n d safet y re p orti n g of A u xiliar y Me dici nal Pr o d ucts ( A x M Ps)  
T he safet y re p orti n g re q uire me nts f or A u xiliar y Me dici nal Pr o d ucts ( A x M Ps) will a p pl y o nce 
t he trial has tra nsiti o ne d u n der t he E U C T R.  
Mi n or e dit orial c ha n ges are als o ma de t hr o u g h o ut t he pr ot oc ol f or i ncrease d clarit y a n d 
c o nsiste nc y. 
At t he ti me of a me n d me nt, t he st u d y is acti vel y recr uiti n g. T he first partici pa nt was scree ne d 
o n 2 1 -Se pte m ber -2 0 2 1. As of N o ve m ber 6 , 2 0 2 3, 
 partici pa nts ha ve c o m me nce d or 
c o m plete d st u d y treat me nt.  
Scree ni n g s h o ul d c o nti n ue at a site u n der t he pr ot oc ol versi o n 0 5 u ntil a p plica ble a p pr o vals 
ha ve bee n o btai ne d f or t he a me n d me nt, a n d all re q uire d d oc u me nts a n d material ha ve bee n 
pr o vi de d t o t he site.  
C CI
C CI
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 8  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 9  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 2 0  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 C CI

N o v arti s  
C o nfi d e nti al  
P a g e 2 1  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 2 2  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
r 
t 
l 
. 
r 
e 
I R B s/I E C s 
A c o p y of t his a me n de d pr ot oc ol 
will be se nt t o t he I nstit uti o nal 
Re vie w 
B oar d 
(I R Bs)/I n de pe n de nt Et hics C o m mittee (I E Cs) a n d Healt h A ut h orities. T he c ha n ges herei n affect 
t he I nf or me d C o nse nt. I n vesti gati o nal sites are re q uire d t o u p date a n d s u b mit a re vise d I nf or me d 
C o nse nt t hat ta kes i nt o acc o u nt t he c ha n ges descri be d i n t his pr ot oc ol a me n d me nt.  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 2 3  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
A m e n d m e nt 5 ( M a y 2 0 2 2)  
A m e n d m e nt r ati o n al e  
T he pri mar y p ur p ose of t his pr ot oc ol a me n d me nt is t o re d uce patie nt a n d site b ur de n of t he 
st u d y c o n d uct.  Re visi o ns t o t he i ncl usi o n a n d e xcl usi o n criteria are bei n g ma de t o br oa de n 
patie nt eli gi bilit y wit h o ut c o m pr o misi n g safet y or data i nte grit y.  
Re m o val of j oi nt s pace wi dt h (J S W) as a n i ncl usi o n criteri o n is bei n g d o ne base d o n t he pri mar y 
g oal of t his st u d y, w hic h is t o e val uate t he safet y a n d t olera bilit y of D F V 8 9 0 i n partici pa nts 
wit h s y m pt o matic k nee O A, a n d t o deter mi ne t he efficac y of D F V 8 9 0 i n re d uci n g k nee pai n.  
Str uct ural c ha n ge is n ot a ke y f oc us of t his st u d y gi ve n t he s h ort d urati o n of d osi n g ( d uri n g 
w hic h str uct ural c ha n ge w o ul d n ot be e x pecte d), a n d str uct ural re q uire me nts f or i ncl usi o n ha ve 
le d t o t he e xcl usi o n of a p pr o xi matel y 1/ 3 of patie nts scree ne d.  M ore o ver, J S W is se nsiti ve t o 
meas ure me nt err or, f urt her re d uci n g t he val ue of usi n g t his para meter f or i ncl usi o n.  
T he t hres h ol d f or hs C R P is als o bei n g re d uce d, fr o m 2 m g/ L t o 1. 8 m g/ L.  W hile t his is a 
relati vel y mi n or c ha n ge, t he 1. 8 m g/ L le vel is base d o n t he me dia n val ue o bser ve d i n t he 
 st u d y, s u g gesti n g t hat we will still be tar geti n g a p o p ulati o n wit h i nfla m mat or y 
art hritis, w hile all o wi n g m ore patie nts t o p ote ntiall y be eli gi ble f or i ncl usi o n.  
A d diti o nal c ha n ges are i ncl u de d t o pr o vi de f urt her clarificati o n (i.e., re gar di n g use of 
c o nc o mita nt pai n me dicati o ns), i m pr o ve w or di n g, a n d u p date b ot h precli nical a n d cli nical data, 
w here m ore rece nt res ults are n o w a vaila ble.   
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 2 4  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 2 5  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
I R B s/I E C s 
A c o p y of t his 
a me n de d pr ot oc ol  will be se nt t o t he I nstit uti o nal 
Re vie w 
B oar d 
(I R Bs)/I n de pe n de nt Et hics C o m mittee (I E Cs) a n d Healt h A ut h orities. 
T he c ha n ges descri be d i n t his a me n de d pr ot oc ol re q uire I R B/I E C a n d H A a p pr o val pri or t o 
i m ple me ntati o n. 
T he c ha n ges herei n affect t he I nf or me d C o nse nt. I n vesti gati o nal sites are re q uire d t o u p date a n d 
s u b mit a re vise d I nf or me d C o nse nt t hat ta kes i nt o acc o u nt t he c ha n ges descri be d i n t his pr ot oc ol 
a me n d me nt.  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 2 6  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
A m e n d m e nt 4 ( M ar c h 2 0 2 2)  
A m e n d m e nt r ati o n al e  
T his a me n d me nt ai ms at a d dressi n g a re q uest fr o m a Healt h A ut h orit y ( H A).  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 2 7  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
A m e n d m e nt 3 ( D e c e m b er 2 0 2 1)  
A m e n d m e nt r ati o n al e  
T he mai n p ur p ose of t his gl o bal pr ot oc ol a me n d me nt is  t w o-f ol d: 1) t o refi ne t he esti ma n d 
strate g y; a n d 2) t o i ntr o d uce a dece ntralize d trial m o del. 
A dece ntralize d trial m o del offers partici pa nts t he fle xi bilit y t o ha ve s o me visits safel y 
perf or me d at a n off -site l ocati o n. Cl ose c o nsi derati o n of t he assess me nts a n d e n d p oi nts, 
t o get her wit h data i nte grit y a n d partici pa nt safet y were esse ntial i n i de ntif yi n g visits t hat ma y 
be relia bl y c o n d ucte d off -site. 
T his pr ot oc ol a me n d me nt is als o a n o p p ort u nit y t o i nte grate t he latest a vai lable cli nical , n o n-
cli nical  a n d p har mac o ki netic data i n or der t o pr o vi de i n vesti gat ors wit h t he m ost c urre nt 
i nf or mati o n, a n d t o u p date t he secti o n relate d t o S A E ha n dli n g i n or der t o ali g n wit h l ocal 
re g ulati o ns. 
Fi nall y, t his pr ot oc ol a me n d me nt als o c orrects i nc o nsiste ncies i n t he pre vi o us  versi o n a n d 
clarifies p ote ntial s o urces of c o nf usi o n.  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 2 8  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 2 9  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
I R B s/I E C s 
A c o p y of t his 
a me n de d pr ot oc ol  will be se nt t o t he I nstit uti o nal 
Re vie w 
B oar d 
(I R Bs)/I n de pe n de nt Et hics C o m mittee (I E Cs) a n d Healt h A ut h orities. 
T he c ha n ges descri be d i n t his a me n de d pr ot oc ol re q uire I R B/I E C a n d H A a p pr o val pri or t o 
i m ple me ntati o n. 
T he c ha n ges herei n affect t he I nf or me d C o nse nt. I n vesti gati o nal sites are re q uire d t o u p date a n d 
s u b mit a re vise d I nf or me d C o nse nt t hat ta kes i nt o acc o u nt t he c ha n ges descri be d i n t his pr ot oc ol 
a me n d me nt.  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 3 0  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
A m e n d m e nt 2 ( A u g u st 2 0 2 1)  
A m e n d m e nt r ati o n al e  
T he p ur p ose of t his a me n d me nt is t o a d dress c o m me nts a n d re q uests fr o m Healt h A ut h orities. 
T he a me n d me nt clarifies w or di n g relate d t o dece ntralize d trial acti vities, partic ularl y t h ose 
e n visa ge d d uri n g t he C O VI D -1 9 pa n de mic, a n d i n a ge neral ma n ner, e ns ure s ali g n me nt wit h 
l ocal re g ulati o ns. 
At t he ti me of t his a me n d me nt n o partici pa nt has bee n e nr olle d yet i n t he st u d y.  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 3 1  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
A m e n d m e nt 1 ( A pril 2 0 2 1)  
A m e n d m e nt r ati o n al e  
T he mai n p ur p ose of t his gl o bal pr ot oc ol a me n d me nt is t o ali g n wit h ot her st u dies usi n g t he 
sa me i n vesti gati o nal dr u g, D F V 8 9 0, i n res p o nse t o healt h a ut h orit y c o m me nts, i n or der t o 
e ns ure a c o nsiste nt c o m p o u n d -relate d a p pr oac h  t o s o me eli gi bilit y criteria, st u d y st o p pi n g r ules 
a n d i n di vi d ual treat me nt disc o nti n uati o n.  
T his pr ot oc ol a me n d me nt als o c orrects i nc o nsiste ncies i n t he ori gi nal versi o n a n d clarifies 
p ote ntial s o urces of c o nf usi o n.   
A d diti o nall y, t his st u d y i nc or p orates a pla n ne d dece ntralize d trial strate g y t o m ore effecti vel y 
s u p p ort t he trial d uri n g t he C o vi d-1 9 pa n de mic. F or t hat reas o n, sta n dar d pr ot oc ol la n g ua ge 
relate d t o pa n de mic miti gati o n meas ures was re m o ve d t o eli mi nate a ny d u plicati o n w hic h ma y 
ca use c o nf usi o n.  
T his a me n d me nt is iss ue d bef ore t he st u d y start a n d t he ori gi nal pr ot oc ol v 0 0 has n ot bee n 
s u b mitte d t o a n y Re g ulat or y A ut h orities. 
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 3 2  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
I R B s/I E C s 
A c o p y of t his 
a me n de d pr ot oc ol  will be se nt t o t he I nstit uti o nal 
Re vie w 
B oar d 
(I R Bs)/I n de pe n de nt Et hics C o m mittee (I E Cs) a n d Healt h A ut h orities. 
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 3 3  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
T he c ha n ges descri be d i n t his a me n de d pr ot oc ol re q uire I R B/I E C a n d H A a p pr o val pri or t o 
i m ple me ntati o n. 
T he c ha n ges herei n affect t he I nf or me d C o nse nt. I n vesti gati o nal sites are re q uire d t o u p date a n d 
s u b mit a re vise d I nf or me d C o nse nt t hat ta kes i nt o acc o u nt t he c ha n ges descri be d i n t his pr ot oc ol 
a me n d me nt.  

N o v arti s  
C o nfi d e nti al  
P a g e 3 4  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
Pr ot o c ol s u m m ar y  
Pr ot o c ol n u m b er  
D F V 8 9 0 B 1 2 2 0 1  
F ull Titl e  
A r a n d o mi z e d, t w o -ar m, pl a c e b o -c o ntr oll e d, p arti ci p a nt a n d i n v e sti g at or -
bli n d e d st u d y i n v e sti g ati n g t h e effi c a c y, s af et y a n d t ol er a bilit y of D F V 8 9 0 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  
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 D F V 8 9 0 i n p ati e nt s wit h 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 a s e II  
I n v e sti g ati o n t y p e 
Dr u g  
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 P h a s e 2 a pr o of of c o n c e pt st u d y i s t o e v al u at e t h e s af et y 
a n d t ol er a bilit y of D F V 8 9 0 i n p arti ci p a nt s wit h s y m pt o m ati c k n e e O A, a n d t o 
d et er mi n e t h e effi c a c y of D F V 8 9 0 i n r e d u ci n g k n e e p ai n a s e vi d e n c e d b y 
c h a n g e i n K O O S ( k n e e i nj ur y a n d o st e o art hriti s o ut c o m e s c or e).  
Pri m ar y O bj e cti v e( s)  T h e pri m ar y o bj e cti v e i s t o d et er mi n e t h e effi c a c y of D F V 8 9 0 v er s u s pl a c e b o 
i n p arti ci p a nt s wit h k n e e O st e o art hriti s ( O A) f or r eli e vi n g p ai n, b a s e d o n 
c h a n g e fr o m b a s eli n e t o w e e k 1 2 i n t h e k n e e i nj ur y a n d o st e o art hriti s 
o ut c o m e s c or e ( K O O S) p ai n s u b -s c al e . 
T h e pri m ar y cli ni c al q u e sti o n of i nt er e st i s: W h at i s t h e eff e ct of D F V 8 9 0 
v er s u s pl a c e b o o n t h e r e d u cti o n i n k n e e p ai n a s s e s s e d b y K O O S at w e e k  
1 2 i n p arti ci p a nt s wit h s y m pt o m ati c k n e e O A ?  
S e c o n d ar y 
O bj e cti v e s  
•  
T o a s s e s s t h e effi c a c y of tr e at m e nt wit h D F V 8 9 0 v er s u s pl a c e b o i n 
p arti ci p a nt s wit h k n e e O A o n i nfl a m m at or y j oi nt str u ct ur e f e at ur e s 
b a s e d o n c h a n g e fr o m b a s eli n e i n s y n o viti s a cti vit y l e v el m e a s ur e d b y 
V ol u m e tr a n sf er c o n s t a nt (K -tr a n s) b y M a g n eti c R e s o n a n c e I m a gi n g 
( M RI) at w e e k 1 2.  
•  
T o e v al u at e t h e s af et y a n d t ol er a bilit y of D F V 8 9 0 c o m p ar e d t o pl a c e b o 
o v er t h e c o ur s e of t h e st u d y b a s e d o n s y st e mi c a n d l o c al a d v er s e 
e v e nt s a n d s eri o u s a d v er s e e v e nt s; el e ctr o c ar di o gr a m s; vit al si g n s; 
h e m at ol o g y, bl o o d c h e mi str y a n d uri n al y si s.  
•  
T o e v al u at e t h e c h a n g e i n s y st e mi c i nfl a m m at or y m ar k er s ( s er u m hi g h 
s e n siti vit y C -r e a cti v e pr ot ei n l e v el a n d a b s ol ut e n e utr o p hil c o u nt), w h e n 
tr e at e d wit h D F V 8 9 0 c o m p ar e d t o pl a c e b o aft er 2, 4, 8 a n d 1 2 w e e k s of 
tr e at m e nt.  
•  
T o e v al u at e t h e pl a s m a p h ar m a c o ki n eti c s of D F V 8 9 0 aft er 2 a n d 
1 2  w e e k s of tr e at m e nt.  
•  
T o e v al u at e c h a n g e s i n k n e e s y m pt o m s a n d a s s o ci at e d p ar a m et er s, 
w h e n tr e at e d wit h D F V 8 9 0 c o m p ar e d t o pl a c e b o aft er 2, 4, 8 a n d 
1 2  w e e k s of tr e at m e nt b a s e d o n K O O S s u b -s c al e s i n cl u di n g ot h er 
s y m pt o m s, f u n cti o n i n d ail y li vi n g, f u n cti o n i n s p ort a n d r e cr e ati o n, 
k n e e -r el at e d q u alit y of lif e. 
•  
T o e v al u at e t h e effi c a c y of D F V 8 9 0 c o m p ar e d t o pl a c e b o i n r eli e vi n g 
O A  p ai n o v er ti m e b a s e d o n c h a n g e i n K O O S  p ai n s u b s c al e fr o m 
b a s eli n e t o w e e k s 2, 4, 8 a n d 1 2 w e e k s, a n d o n c h a n g e i n N u m eri c 
R ati n g S c al e  ( N R S) f or p ai n fr o m b a s eli n e t o w e e k s 2, 4, 8 a n d 1 2.  

N o v arti s  
C o nfi d e nti al  
P a g e 3 5  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
St u d y d e si g n  
T hi s st u d y i s a r a n d o mi z e d p arti ci p a nt a n d i n v e sti g at or bli n d e d tri al wit h 2 
p ar all el ar m s c o m p ari n g or al D F V 8 9 0 tr e at m e nt v s pl a c e b o.  
Aft er a n u p t o 4 5 d a y s s cr e e ni n g p eri o d (i n cl u di n g m a g n eti c r e s o n a n c e 
i m a gi n g a n d X-r a y), p arti ci p a nt s will b e r a n d o mi z e d i nt o o n e of t w o gr o u p s: 
o n e tr e at e d wit h or al D F V 8 9 0 t wi c e p er d a y; t h e ot h er tr e at e d wit h pl a c e b o.  
T h e tr e at m e nt p eri o d i s c o m pri s e d of t w o p art s: d uri n g t h e fir st t w o w e e k s, 
p arti ci p a nt s will b e tr e at e d wit h 1 0 m g D F V 8 9 0 or pl a c e b o t wi c e p er d a y, 
f oll o w e d b y 1 0 w e e k s of tr e at m e nt wit h 2 5 m g D F V 8 9 0 or pl a c e b o t wi c e p er 
d a y. T hi s p eri o d will i n cl u d e s af e t y a n d effi c a c y a s s e s s m e nt s.  
Aft er t h e tr e at m e nt p eri o d, t h e p arti ci p a nt s will e nt er a 5 -w e e k f oll o w -u p 
p eri o d i n cl u di n g a n e n d of st u d y vi sit a n d a s af et y c all.  
St u d y p o p ul ati o n  
T h e st u d y p o p ul ati o n will c o n si st of a p pr o xi m at el y 1 0 8 m al e a n d f e m al e 
a d ult s b et w e e n 5 0 a n d 8 0 y e ar s of a g e wit h mil d t o m o d er at e, s y m pt o m ati c 
k n e e O A ( K ell gr e n a n d L a wr e n c e ( K & L) s c or e gr a d e 2 -3), cli ni c al si g n s of 
i nfl a m m ati o n, el e v at e d hi g h s e n siti vit y C -r e a cti v e pr ot ei n l e v el ≥1. 8  m g/ L 
a n d c o nfir m ati o n of a cti v e s y n o viti s b y m a g n eti c r e s o n a n c e i m a gi n g.  
K e y I n cl u si o n 
crit eri a  
•  
M al e a n d f e m al e p arti ci p a nt s  ≥ 5 0 a n d ≤ 8 0 y e ar s ol d o n t h e d a y of 
I nf or m e d C o n s e nt si g n at ur e. 
• 
P arti ci p a nt s  m u st w ei g h at l e a st  5 0 k g t o p arti ci p at e i n t h e st u d y, a n d 
m u st h a v e a b o d y m a s s i n d e x ( B MI) wit hi n t h e r a n g e of 1 8 - 3 5 k g/ m 2  at 
s cr e e ni n g.  B MI = B o d y w ei g ht ( k g) / [ H ei g ht ( m)] 2  
•  
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) ≥1. 8 m g/ L at s cr e e ni n g   
•  
S y m pt o m ati c O A  wit h p ai n ( N u m eri c R ati n g S c al e [ N R S] 5 -9, i n cl u si v e) 
i n t h e t ar g et k n e e f or t h e m aj orit y of d a y s i n t h e l a st 3 m o nt h s pri or t o 
s cr e e ni n g  
•  
K O O S  p ai n s u b -s c al e s c or e  ≤ 6 0 i n i n d e x k n e e at s cr e e ni n g a n d 
b a s eli n e  
•  
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 st e o art hriti s i n t h e 
t ar g et k n e e 
•  
A cti v e s y n o vi al i nfl a m m ati o n  at s cr e e ni n g ( d efi n e d a s a s u m m ar y s c or e 
of ≥7 wit h  at l e a st  o n e r e gi o n s c ori n g 2) o n c o ntr a st e n h a n c e d M RI 
( C E-M RI) of t h e w h ol e k n e e f or s y n o viti s d et e cti o n fr o m 1 1 sit e s  

N o v arti s  
C o nfi d e nti al  
P a g e 3 6  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
K e y E x cl u si o n 
crit eri a  
•  
T ot al W B C c o u nt  <  3, 0 0 0/ µ L, a b s ol ut e p eri p h er al bl o o d n e utr o p hil 
c o u nt ( A N C) <  1, 0 0 0/ µ L, h e m o gl o bi n <  8. 5 g/ d L ( 8 5 g/ L) or pl at el et 
c o u nt <  1 0 0, 0 0 0/ µ L  at S cr e e ni n g  
•  
K n o w n a ut oi m m u n e di s e a s e wit h i nfl a m m at or y art hriti d e s (i n cl u di n g b ut 
n ot li mit e d t o r h e u m at oi d art hriti s, p s ori ati c art hriti s, a n k yl o si n g 
s p o n d yliti s, s y st e mi c l u p u s er yt h e m at o s u s), cr y st al -i n d u c e d art hriti d e s 
( g o ut, p s e u d o g o ut a s s o ci at e d art hriti s), a cti v e a c ut e or c hr o ni c i nf e cti o n 
or p a st i nf e cti o n of t h e k n e e j oi nt, L y m e di s e a s e i n v ol vi n g t h e k n e e, 
r e a cti v e art hriti s, s y st e mi c c artil a g e di s or d er s, m o d er at e t o s e v er e 
fi br o m y al gi a ( wi d e s pr e a d p ai n i n d e x, W PI, > 4 o ut of 1 9), or a k n o w n 
s y st e mi c c o n n e cti v e  ti s s u e di s e a s e 
•  
A n y k n o w n a cti v e i nf e cti o n s, i n cl u di n g s ki n or k n e e i nf e cti o n s or 
i nf e cti o n s t h at m a y c o m pr o mi s e t h e i m m u n e s y st e m, s u c h a s HI V or 
c hr o ni c h e p atiti s B or C i nf e cti o n  
C O VI D -1 9 s p e cifi c: P ol y m er a s e C h ai n R e a cti o n ( P. C. R.)  or a nti g e n 
t e st a g ai n st C O VI D-1 9 i s m a n d at or y w h er e r e q uir e d b y t h e l o c al H e alt h 
A ut h orit y a n d/ or b y l o c al r e g ul ati o n, e. g. i n G er m a n y.  
•  
U s e of pr o hi bit e d m e di c ati o n s: a n y l o c al i. a . tr e at m e nt i nt o t h e k n e e, 
i n cl u di n g b ut n ot r e stri ct e d t o vi s c o s u p pl e m e nt ati o n a n d c orti c o st er oi d s 
wit hi n 1 2  w e e k s pri or t o D a y 1; l o n g -t er m tr e at m e nt ( > 1 4 d a y s) wit h or al 
c orti c o st er oi d s > 5 m g/ d a y wit hi n 4  w e e k s pri or t o D a y 1; or al 
gl u c o s a mi n e, c h o n dr oi ti 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 fr o m s cr e e ni n g 1; s y st e mi c N o n-St er oi d al 
A nti -I nfl a m m at or y Dr u g s ( N S AI D s), s el e cti v e C y cl o o x y g e n a s e -2  (C O X -
2 ) i n hi bit or s or ot h er n o n -o pi oi d a n al g e si c s n ot d efi n e d a s b a si c p ai n 
m e di c ati o n  wit hi n 5 h alf -li v e s fr o m P R O a s s e s s m e nt s; a n y ot h er 
i m m u n o m o d ul at or y dr u g s or tr e at m e nt w hi c h c a n n ot b e di s c o nti n u e d or 
s wit c h e d t o a diff er e nt m e di c ati o n wit hi n 2 8 d a y s or 5 h alf -li v e s of 
s cr e e ni n g ( w hi c h e v er i s l o n g er if r e q uir e d b y l o c al r e g ul ati o n s), o r u ntil 
t h e e x p e ct e d P D eff e ct h a s r et ur n e d t o b a s eli n e.   
•  
M o d er at e t o s e v er e p ai n i n t h e c o ntr al at er al k n e e f or t h e m aj orit y of 
d a y s i n t h e l a st 3  m o nt h s pri or t o S cr e e ni n g, a s p er p ati e nt j u d g m e nt  
•  
S e v er e m al ali g n m e nt  gr e at er t h a n 7. 5 d e gr e e s i n t h e t ar g et k n e e 
( eit h er v ar u s or v al g u s), m e a s ur e d u si n g x-r a y at S cr e e ni n g 
St u d y tr e at m e nt  
D F V 8 9 0 ( 1 0 m g t a bl et t wi c e p er d a y f or 2 w e e k s a n d 2 5 m g t a bl et t wi c e p er 
d a y f or 1 0 w e e k s), or m at c hi n g pl a c e b o.  
I n a d diti o n, it i s i m p er ati v e t o h ar m o ni z e a n d d o c u m e nt p arti ci p a nt s' p ai n 
m e di c ati o n a s it c a n p ot e nti all y c o nf o u n d r e s ult s. T h er ef or e, o nl y t h e u s e of 
p ar a c et a m ol/ a c et a mi n o p h e n, u p t o 3 0 0 0 m g/ d a y, al o n e or i n c o m bi n ati o n 
wit h l o w d o s e c o d ei n e, e. g., c o -c o d a m ol, i s all o w e d a s b a si c ( n o n -r e s c u e) 
m e di c ati o n f or p ai n c o ntr ol r e g ar dl e s s of t h e ori gi n of t h e p ai n, u p u ntil 
D a y  8 4. T hi s m e di c ati o n i s r ef err e d t o a s " b a si c p ai n m e di c ati o n" a n d t h e 
i n v e sti g at or will eit h er b e s u p pli e d wit h t h e b a si c p ai n m e di c ati on or s o ur c e 
it l o c all y a n d b e r ei m b ur s e d b y t h e s p o n s or f or it s c o st, d e p e n di n g o n t h e 
c o u ntr y.  
T h e “ b a si c p ai n m e di c ati o n” a n d t h e G a d oli ni u m c o ntr a st a g e nt u s e d f or 
c o ntr a st -e n h a n c e d M RI ar e d efi n e d a s A x M P s.  
Tr e at m e nt of 
i nt er e st 
T h e r a n d o mi z e d tr e at m e nt (t h e i n v e sti g ati o n al tr e at m e nt D F V 8 9 0 or c o ntr ol 
tr e at m e nt).  

N o v arti s  
C o nfi d e nti al  
P a g e 3 7  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
Effi c a c y 
a s s e s s m e nt s  
•  
K O O S q u e sti o n n air e  
•  
C o ntr a st -e n h a n c e d M a g n eti c  R e s o n a n c e  I m a gi n g 
•  
N u m eri c al R ati n g S c al e  
•  
Hi g h s e n siti vit y C -r e a cti v e pr ot ei n 
•  
A b s ol ut e  N e utr o p hil C o u nt  
P h ar m a c o d y n a mi c 
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 s er u m hi g h s e n siti vit y C -r e a cti v e pr ot ei n l e v el a n d 
a b s ol ut e n e utr o p hil c o u nt s at w e e k 2, 4, 8 a n d 1 2  
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 a n d s eri o u s a d v er s e e v e nt m o nit ori n g  
•  
P h y si c al e x a mi n ati o n s,  
•  
Vit al si g n s  
•  
M o nit ori n g of l a b or at or y m ar k er s i n bl o o d a n d uri n e  
•  
E C G p ar a m et er s   
Ot h er a s s e s s m e nt s  
D at a a n al y si s  
T h e c h a n g e fr o m b a s eli n e i n K n e e i nj ur y a n d K O O S p ai n s u b s c al e will b e 
a n al y z e d u si n g a mi x e d eff e ct s m o d el f or r e p e at e d m e a s ur e s ( M M R M). T h e 
m o d el will i n cl u d e b a s eli n e, tr e at m e nt, ti m e p oi nt, b a s eli n e * ti m e p oi nt s a n d 
tr e at m e nt * ti m e p oi nt s a s fi x e d eff e ct A st ati sti c all y si g nifi c a nt diff er e n c e ( p-
v al u e <  0. 0 5) b et w e e n a cti v e dr u g a n d pl a c e b o at W e e k 1 2 will b e c o n si d er e d 
a s a p o siti v e r e s ult.  
K e y w or d s  
O st e o art hriti s, i nfl a m m ati o n, 
D F V 8 9 0, 
N L R P 3 i n hi bit or, i nfl a m m a s o m e 
i n hi biti o n 
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 3 8  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
1  
I ntr o d u cti o n 
1. 1  
B a c k gr o u n d  
Oste oart hritis ( O A), a sl o wl y pr o gressi ve disease wit h a m ultifact orial pat h o p h ysi ol o g y, is o ne 
of t he m ost c o m m o n c hr o nic healt h c o n diti o ns, a n d a lea di n g ca use of pai n a n d disa bilit y a m o n g 
a d ults ( Safiri  et al 2 0 2 0 ). T he k nee j oi nt is t he m ost c o m m o nl y affecte d wei g ht beari n g j oi nt. 
C urre ntl y, t here are fe w effecti ve a n d/ or t olerate d s y m pt o matic t hera pies ot her t ha n a nal gesics 
a n d j oi nt re place me nt s ur ger y o nl y is a last res ort, w hile n o str uct ure -m o dif yi n g dr u gs ar e 
a vaila ble t o date ( L o h ma n der,  Jär vi ne n 2 0 1 9 ). T heref ore, t here is a hi g h nee d f or b ot h disease 
m o dif yi n g, cartila ge a na b olic a ge nts, as well as a nee d t o a d dress t he i nfla m mat or y as pect of 
t he disease. I nfla m mati o n is prese nt i n 3 0-5 0 % of O A partici pa nts wit h m o derate -se vere disease 
i n ac ute flare p hases of cartila ge de gra dati o n a n d/ or as c hr o nic l o w -gra de i nfla m mati o n. 
Es peciall y i n later sta ges of O A, i ntra -artic ular i nfla m mati o n is c o m m o n, b ut t he c urre nt 
sta n dar d of care (i ntra-artic ular c ortic oster oi ds [I A C S]) f or t his i nfla m mati o n ma y ha ve l o n g -
ter m 
detri me ntal 
effects 
o n 
artic ular 
cartila ge, 
accelerati n g 
disease 
pr o gressi o n 
(Wij n  et al 2 0 2 0 ). 
Pr o -i nfla m mat or y c yt o ki nes s uc h as i nterle u ki n-1 β (I L -1 β) are critical me diat ors of t he 
dist ur be d j oi nt 
meta b olis m a n d e n ha nce d cata b olis m of j oi nt tiss ue i n v ol ve d i n 
O A 
(Frae n kel  et al 1 9 9 8 ), ma ki n g a nti-i nfla m mat or y t hera p y a n attracti ve strate g y t o c o u nteract 
O A. T hese i nfla m mat or y me diat ors i n d uce d o w nre g ulati o n of a na b olic e ve nts, i.e., cartila ge 
matri x pr o d ucti o n b y c h o n dr oc ytes a n d pr o d ucti o n of de gra di n g e nz y mes ( M M Ps, A D A M T S) 
b y c h o n dr oc ytes a n d s y n o vial cells, w hic h ca use t he brea k d o w n a n d l oss of t he cartila ge matri x 
(va n  de n  B osc h  2 0 1 9 ). Cli nical trials tar geti n g i nfla m mati o n i n O A ha ve ha d mi xe d res ults, b ut 
p ost -h oc a nal yses of t w o st u dies wit h t he a nti -I L-1 β a nti b o d y ca na ki n u ma b - t he  
 trial 
a n d t he 
 trial - s h o we d p ositi ve res ults o n re d ucti o n of j oi nt re place ment 
a n d/ or effects o n pai n a n d f u ncti o n f or ca na ki n u ma b vs. place b o ( Sc hie ker  et al 2 0 2 0 ). 
T hr o u g h t he pr o d ucti o n of I L -1 β a n d I L -1 8, t he N L R P 3 i nfla m mas o me has bee n i m plicate d as 
a maj or dri ver of i nfla m mati o n ass ociate d wit h c hr o nic i nfla m mat or y diseases. Mec ha nisticall y, 
N L R P 3 se nses a di verse ra n ge of da n ger si g nals, a n d reacts b y f or mi n g a n  i nfla m mas o me 
pr otei n c o m ple x t hat dri ves a n e ns ui n g i nfla m mat or y res p o nse. D F V 8 9 0 is a p ote nt s mall 
m olec ule i n hi bit or of t he N L R P 3 i nfla m mas o me pat h wa y. D F V 8 9 0 bl oc ks I L -1 β secreti o n, 
I L-1 8 secreti o n a n d p yr o pt otic cell deat h i n res p o nse t o a wi de variet y of N L R P 3 -de pe n de nt 
da n ger si g nals i n vitr o a n d i n mec ha nistic m o use m o dels i n viv o, s u g gesti n g t hat N L R P 3 
i n hi biti o n c o ul d ha ve i m pr o ve d efficac y o ver ca na ki n u ma b i n diseases w here I L-1 β a n d I L -1 8 
b ot h dri ve pat h ol o g y.  
It is n ot k n o w n w het her N L R P 3 i n hi biti o n res ults i n t he sa me cli nical be nefits as I L-1 β 
i n hi biti o n i n partici pa nts wit h s y m pt o matic, i nfla m mat or y k nee O A. T here is clear nee d t o 
de vel o p a best -i n-class oral O A dr u g t o re d uce pai n, sl o w j oi nt da ma ge, a n d i m pr o ve f u ncti o n 
i n a d ults wit h s y m pt o matic O A b y a d dressi n g t he i nfla m mat or y as pect of t he disease a n d 
dela yi n g/ pre ve nti n g pr o gressi o n t o e n d -sta ge O A. 
 
 
 
  
  
  
  
  
  
  
 
  
 
 
 
C CI
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 3 9  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
 
1. 1. 1  
N o n -cli ni c al d at a  
D F V 8 9 0 was e val uate d i n c o m plete d re peat -d ose G o o d La b orat or y Practice ( G L P) t o xicit y 
st u dies u p t o 2 6  wee ks d urati o n i n rats ( St u d y 1 9 7 0 4 5 5 ) a n d u p t o 4 6 wee ks i n m o n ke ys ( St u d y 
1 9 7 0 4 5 6 ). I n a d diti o n, safet y p har mac ol o g y  st u dies a n d f ull i n vitr o a n d i n viv o test batteries t o 
assess ge n ot o xicit y a n d p h ot ot o xicit y p ote ntial were perf or me d.  N o si g nifica nt effects of 
D F V 8 9 0 were a p pare nt d uri n g safet y p har mac ol o g y assess me nts of ce ntral ner v o us s yste m, 
res pirat or y a n d car di o vasc ular f u ncti o n. D F V 8 9 0 di d n ot de m o nstrate a n y ge n ot o xic p ote ntial 
i n vitr o or i n viv o, or p h ot ot o xicit y p ote ntial i n vitr o. 
T here were n o fi n di n gs f oll o wi n g D F V 8 9 0 re peate d oral d osi n g i n s pra y -drie d dis persi o n 
( S D D) i n rats u p t o 4-wee ks a n d i n m o n ke ys u p t o 1 3 -wee ks u p t o ma xi m u m feasi ble d oses of 
2 3 8 m g/ k g/ da y a n d 1 5 0  m g/ k g/ da y , res pecti vel y. T he N O A E L i n t he 1 3-wee k m o n ke y st u d y 
was 1 5 0 m g/ k g/ da y. T he d oses i n t hese st u dies were t he ma xi m u m feasi ble d oses d ue t o 
f or m ulati o n li mitati o n i n b ot h s pecies. 
Fi n di n gs i n t he ki d ne y a n d fe male re pr o d ucti ve or ga ns occ urre d i n 1 3 -wee k a n d 2 6-wee k 
t o xicit y st u dies i n rats. T hese i ncl u de d c ha n ges c o nsiste nt wit h retr o gra de ne p hr o pat h y d ue t o 
i ntra-t u b ular preci pitates i n t he ki d ne y at d oses ≥1 0 0 m g/ k g/ da y t hat c orrelate d wit h cli nical 
pat h ol o g y para meter c ha n ges, i ncl u di n g creati ni ne a n d bl o o d urea nitr o ge n. A d diti o nal data 
s u g gest t his ki d ne y fi n di n g is rat her a rat-s pecific effect a n d ma y n ot tra nslate t o h u ma ns (refer 
t o t he D F V 8 9 0 I n vesti gat or’s Br oc h ure f or f urt her details). C ha n ges at d oses of 3 0 0 m g/ k g/ da y 
f or 1 3 wee ks a n d at 1 0 0 m g/ k g/ da y f or 2 6 -wee ks i n fe male re pr o d ucti ve tiss ues ( o varies, va gi na, 
a n d ma m mar y gla n ds) a n d i ncrease d pit uitar y wei g hts ( wit h o ut hist ol o gic c orrelate), were 
c o nsiste nt wit h persiste nt estr us p hase of re pr o d ucti ve se nesce nce n or mall y o bser ve d i n 
S pra g ue Da wle y rats. T he fi n di n gs i n t he ki d ne y a n d fe male re pr o d ucti ve or ga ns were partiall y 
re versi ble after a 4-wee k rec o ver y peri o d. Base d o n t hese o bser vati o ns, t he n o o bser ve d a d verse 
effect le vel ( N O A E L) i n t he 1 3 -wee k a n d i n t he 2 6 -wee k rat st u dies was 3 0 m g/ k g/ da y . 
I n a 4 6-wee k G L P t o xic ol o g y st u d y i n c y n o m ol g us m o n ke ys, m ori b u n dit y was re p orte d i n f o ur 
of t hirtee n a ni mals recei vi n g t he hi g hest d ose of D F V 8 9 0 ( 1 5 0 f oll o we d b y  1 0 0 m g/ k g/ da y). 
T w o of t he a ni mals were e ut ha nize d d ue t o i nj uries n ot relate d t o D F V 8 9 0. I n t he ot her t w o 
m o n ke ys, a d verse cli nical fi n di n gs a n d e vi de nce of j oi nt i nfla m mati o n (c o nsiste nt wit h a p ost -
i nfecti o us reacti ve art hritis) were o bser ve d . T he ca use of m ori b u n dit y has n ot bee n deter mi ne d, 
a n d a p ossi ble relati o n t o D F V 8 9 0 ca n n ot be e xcl u de d. T hese fi n di n gs were n ot see n i n a 
pre vi o us 1 3 -wee k t o xic ol o g y m o n ke y st u d y, w hic h ha d hi g her s yste mic e x p os ures. T he ris k f or 
patie nts i n c urre ntl y o n g oi n g trials is c o nsi dere d l o w base d o n safet y mar gi ns a n d/ or s h ort 
treat me nt d urati o n. N o ot her fi n di n gs were o bser ve d i n t he s ur vi vi n g a ni mals at a n y d ose d uri n g 
t he rest of t he st u d y. T he d ose of 1 0 0  m g/ k g/ da y i n m o n ke y, w here n o fi n di n gs were o bser ve d, 
re prese nte d t he N O A E L i n t he 4 6-wee k m o n ke y st u d y .  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 4 0  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
1. 1. 2  
H u m a n s af et y a n d t ol er a bilit y  
As of 2 4 -Mar -2 0 2 2, a p pr o xi matel y 2 6 4 healt h y s u bjects a n d patie nts ha ve bee n e nr olle d i n t he 
D F V 8 9 0 cli nical de vel o p me nt pr o gra m, of w hic h 1 6 4 partici pa nts/ patie nts ha ve recei ve d 
D F V 8 9 0 at vari o us d oses a n d 1 0 0 recei ve d place b o or sta n dar d of care ( S o C).  
C D F V 8 9 0 A 0 2 1 0 1 FI H (I F M 2 4 2 7 0 0 1) a n d C D F V 8 9 0 D 1 2 2 0 1 ( C o vi d -1 9) st u dies ha ve bee n 
c o m plete d a n d t he cli nical st u d y re p orts ha ve bee n fi nalize d.  
I n t he FI H st u d y ( C D F V 8 9 0 A 0 2 1 0 1 or I F M 2 4 2 7 0 0 1), D F V 8 9 0 or place b o was a d mi nistere d t o 
1 2 2 healt h y v ol u nteers, of w h o m 9 4 partici pa nts recei ve d D F V 8 9 0.  D F V 8 9 0 was ge nerall y 
well t olerate d at all si n gle a n d m ulti ple d ose le vels.  T he hi g hest dail y D F V 8 9 0 d o se e val uate d 
i n healt h y s u bjects i n t he st u d y was 6 0 0 m g i n t he si n gle asce n di n g d ose ( S A D) p hase, a n d 2 0 0 
m g o nce -dail y ( Q D) f or 1 4 da ys i n t he m ulti ple asce n di n g d ose ( M A D) p hase.  
 
 
 
 
 
 
 
 
 
A P hase 2 st u d y, C D F V 8 9 0 D 1 2 2 0 1, has bee n c o m plete d i n patie nts wit h C O VI D -1 9 
p ne u m o nia a n d i m paire d res pirat or y f u ncti o n.  1 4 3 partici pa nts were e nr olle d t o t he st u d y 
( D F V 8 9 0 + S o C or S o C al o ne gr o u ps), of w h o m 7 0 recei ve d 5 0 m g b.i. d. oral D F V 8 9 0 f or 1 4 
d a ys.  D F V 8 9 0 was ge nerall y well t olerate d wit h dr u g e x p os ures as e x pecte d fr o m t he FI H 
st u d y ( CD F V 8 9 0 A 0 2 1 0 1 or I F M 2 4 2 7 0 0 1 ).  T he o verall i nci de nces of re p orte d A Es a n d S A Es 
were si milar bet wee n t he D F V 8 9 0 a n d S o C gr o u ps, wit h n o u ne x pecte d or ne w safet y fi n di n gs 
i n t he C O VI D-1 9 p o p ulati o n.  T here were n o e ve nts relate d t o t he m usc ul os keletal/c o n necti ve 
tiss ue s yste ms f or D F V 8 9 0 or S o C ar ms, a n d n o u ne x pecte d re nal e ve nts or seri o us i nfecti o ns 
i n t he h os pitalize d C O VI D-1 9 p o p ulati o n.  T here was a hi g her i nci de nce of mil d t o m o derate 
ras h e ve nts o bser ve d i n partici pa nts w h o recei ve d D F V 8 9 0.  Mac ul o pa p ular/ pr uritic s ki n ras hes 
were re p orte d as relate d t o D F V 8 9 0 i n 7 partici pa nts (a p pr o xi matel y 1 0 %) of w h o m 2 
partici pa nts disc o nti n ue d t he st u d y treat me nt.  T hese  e ve nts were of mil d a n d m o derate se verit y, 
starte d 5 t o 1 5 da ys after i nitiati o n of D F V 8 9 0 treat me nt, a n d res ol ve d wit hi n 5 t o 1 6 da ys after 
o nset, re q uiri n g vari o us treat me nts i n t he maj orit y of affecte d partici pa nts.  I n s u m mar y, t here 
were n o u ne x pecte d e ve nts f or t he disease i n dicati o n a n d patie nt p o p ulati o n.  T he safet y 
fi n di n gs are c o nsiste nt wit h t he earl y cli nical safet y pr ofile a n d i n c o m bi nati o n wit h t he 
o bser ve d p har mac o d y na mic effects c o nfir mi n g cli nicall y rele va nt re d ucti o n of N L R P 3 -relate d 
i nfla m mat or y mar kers. 
T he o verall n o n -cli nical p har mac ol o g y, p har mac o ki netics, t o xic o ki netics a n d t o xic ol o gical a n d 
cli nical, safet y a n d la b orat or y assess me nts are c o nsi dere d a de q uate t o j ustif y t he c o nti n ue d 
cli nical de vel o p me nt of D F V 8 9 0.  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 4 1  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
1. 1. 3  
H u m a n P h ar m a c o ki n eti c s  
D F V 8 9 0 is a hi g hl y per mea ble c o m p o u n d wit h s ol u bilit y -li mite d a bs or pti o n of cr ystalli ne 
f or m ulati o ns at hi g h d oses. I n healt h y partici pa nts, D F V 8 9 0 as 1 0 0 m g cr ystalli ne ta blet s h o we d 
a p ositi ve f o o d effect wit h pea k c o nce ntrati o n ( C ma x) a n d area u n der t he  c ur ve ( A U Clast) 
i ncrease d b y 2. 0 5 ( 9 0 % CI 1. 7 8 t o 2. 3 5) a n d 1. 4 9-f ol d ( 9 0 % CI 1. 2 1 t o 1. 8 3) i n t he fe d vs faste d 
state, res pecti vel y. Me dia n T ma x f or 1 0 0 m g ta blet was 5 h, w hile s h orter T ma x val ues ( 0. 7 6 –  
3. 0 h) were re p orte d f or s us pe nsi o ns. I n li ne wi t h a ni mal P K, D F V 8 9 0 has a ver y l o w oral 
cleara nce ( C Lss/ F ~ 1. 0 3 L/ h), w hic h relates t o ≤ 2 % of h u ma n li ver bl o o d fl o w a n d l o w v ol u me 
of distri b uti o n ( Vss/ F) of ~ 1 2. 6 t o 2 3. 3 L. Sli g ht dr u g acc u m ulati o n of a b o ut 1. 2 -f ol d was 
o bser ve d i n reac hi n g stea d y sta te after dail y d osi n g, c o nsiste nt wit h a n effecti ve half-life of 
a p pr o xi matel y 1 0 h o urs (f or m ulati o n a n d d ose de pe n de nt). 
 was t he maj or 
circ ulati n g c o m p o ne nt i n plas ma a n d t he 
, 
were t he m ost a b u n da nt meta b olites base d o n se mi -q ua ntitati ve a nal ysis. B ot h meta b olites were 
detecte d i n e xcess i n plas ma fr o m rat a n d/ or m o n ke y i n 1 3 -wee k t o xic ol o g y st u dies at t he 
res pecti ve N O A E L d oses. Fi ve ot her meta b olites i n h u ma n plas ma were detecte d as traces. 
O n l y ≤ 0. 8 % of d ose as D F V 8 9 0 was eli mi nate d via uri ne, i n dicati n g a mi n or c o ntri b uti o n of 
re nal cleara nce t o t he t otal cleara nce pat h wa y. Meta b olis m b y c yt oc hr o me P 4 5 0 2 C 9 ( C Y P 2 C 9) 
a n d c yt oc hr o me P 4 5 0 3 A 4 ( C Y P 3 A 4) is c o nsi dere d t o be t he maj or cleara nce mec ha nis m f or 
D F V 8 9 0 wit h fracti o nal he patic c o ntri b uti o ns of 
 res pecti vel y.  C Y P 2 C 9 is a 
p ol y m or p hic e nz y me. I n t he FI H st u d y ~ 7 0 % of e val uate d partici pa nts ha d h o m oz y g o us wil d -
t y pe C Y P 2 C 9 * 1 * 1 ge n ot y pe (s o calle d n or mal C Y P 2 C 9 meta b olizers). T he p o p ulati o n P K 
a nal ysis  fr o m t his st u d y i n dicate d t hat i de ntifie d s u bjects wit h  heter oz y g o us 
C Y P 2 C 9 
ge n ot y pes  * 1 * 2  ( n = 1 6), * 1 * 3 ( n = 9), * 1 * 5 ( n = 1), * 1 * 1 1 ( n = 1), * 2 * 3 ( n = 1) ha d i ncrease d 
A U C  b y a fact or  of  
 a n d 
 vers us * 1 * 1  ( n = 6 5), res pecti vel y. Base d o n i n 
vitr o res ults a n d p h ysi ol o g y-base d P K pre dicti o n, t he s yste mic 
D F V 8 9 0 e x p os ure i n 
partici pa nts w h o are p o or C Y P 2 C 9 meta b olizers ( * 3 * 3) is li kel y t o be a p pr o xi matel y 
-f ol d 
hi g her c o m pare d t o n or mal (e xte nsi ve) meta b olizers ( * 1 * 1).  
S pecific st u dies t o i n vesti gate dr u g -dr u g i nteracti o ns ( D DI) ha ve n ot yet bee n c o n d ucte d wit h 
D F V 8 9 0. F or n or mal a n d i nter me diate C Y P 2 C 9 meta b olizers,  
 effects 
are e x pecte d wit h c o nc o mita nt a d mi nistrati o n of str o n g a n d m o derate C Y P 2 C 9 a n d C Y P 3 A 4 
i n hi bit ors. 
 wit h str o n g or m o derate C Y P 3 A 4  i n hi bit ors is e x pecte d f or p o or 
C Y P 2 C 9 meta b olizers . W he n d ose d wit h a str o n g C Y P 3 A 4 i n d ucer or a str o n g or m o derate 
d ual C Y P 3 A 4/ C Y P 2 C 9 i n d ucer, m o derate D F V 8 9 0 e x p os ure re d ucti o n b y 
-f old is pre dicte d 
f or n or mal C Y P 2 C 9 meta b olizers.  
 effect of i n d ucers is e x pecte d i n patie nts wit h 
decrease d acti vit y of C Y P 2 C 9. As a per petrat or, D F V 8 9 0 has  
 p ote ntial t o i n d uce C Y P 3 A 4 
a n d t heref ore ma y re d uce A U C of se nsiti ve C Y P 3 A 4 s u bstrates b y u p t o 
-f ol d (refer t o t he 
I n vesti gat or’s Br oc h ure f or f urt her details).   
1. 2  
P ur p o s e  
T he p ur p ose of t his P hase 2a pr o of of c o nce pt st u d y is t o e val uate t he safet y a n d t olera bilit y of 
D F V 8 9 0 i n partici pa nts wit h s y m pt o matic k nee O A a n d t o deter mi ne t he efficac y of D F V 8 9 0 
i n re d uci n g k nee pai n as e vi de nce d b y K O O S ( k nee i nj ur y a n d oste oart hritis o utc o me sc ore). 
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 4 2  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
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 d et er mi n e t h e effi c a c y of or al D F V 8 9 0 
v s. pl a c e b o i n p arti ci p a nt s wit h k n e e O A 
f or r eli e vi n g O A p ai n   
•  
C h a n g e fr o m b a s eli n e i n K n e e i nj ur y a n d 
O st e o art hriti s O ut c o m e S c or e ( K O O S) p ai n 
s u b -s c al e at W e e k 1 2  
S e c o n d ar y o bj e cti v e( s)  
E n d p oi nt( s) f or s e c o n d ar y o bj e cti v e( s)  
•  
T o a s s e s s t h e effi c a c y of D F V 8 9 0 v s. 
pl a c e b o i n p arti ci p a nt s wit h k n e e O A o n 
i nfl a m m at or y j oi nt str u ct ur e f e at ur e s 
•  
C h a n g e fr o m b a s eli n e i n s y n o viti s a cti vit y l e v el 
m e a s ur e d fr o m K -tr a n s b y D C E-M RI at W e e k 
1 2  
•  
T o a s s e s s t h e s af et y a n d t ol er a bilit y of 
D F V 8 9 0 v s. pl a c e b o   
•  
S y st e mi c a n d l o c al A d v er s e E v e nt s a n d 
S eri o u s A d v er s e E v e nt s  
El e ctr o c ar di o gr a m s ( E C G s) p ar a m et er s  
Vit al si g n s  
H e m at ol o g y, bl o o d c h e mi str y a n d uri n al y si s  
•  
T o a s s e s s t h e eff e ct of D F V 8 9 0 
c o m p ar e d t o pl a c e b o o n s y st e mi c 
i nfl a m m at or y st at u s 
•  
C h a n g e fr o m b a s eli n e i n s er u m hi g h s e n siti vit y 
C -r e a cti v e pr ot ei n l e v el a n d a b s ol ut e n e utr o p hil 
c o u nt s at W e e k 2, 4, 8 a n d 1 2  
•  
T o a s s e s s p h ar m a c o ki n eti c s of 
D F V 8 9 0  i n pl a s m a 
•  
Pl a s m a s a m pl e s t o q u a ntif y c o n c e ntr ati o n s of 
D F V 8 9 0 at v ari o u s ti m e p oi nt s ( W e e k 2 a n d 
W e e k 1 2) a n d t o d eri v e P K p ar a m et er s i n 
pl a s m a (i n cl u di n g b ut n ot li mit e d t o C m a x, 
A U Cl a st, A U C 0 -1 2 h, a n d Ctr o u g h)  
•  
T o a s s e s s t h e effi c a c y of D F V 8 9 0 v s. 
pl a c e b o i n i m pr o vi n g p arti ci p a nt s' r e p ort 
of k n e e s y m pt o m s a n d a s s o ci at e d 
pr o bl e m s o v er ti m e  
•  
C h a n g e fr o m b a s eli n e i n K O O S s u b -s c al e s 
( ot h er s y m pt o m s, f u n cti o n i n d ail y li vi n g, 
f u n cti o n i n s p ort a n d r e cr e ati o n, k n e e-r el at e d 
q u alit y of lif e) at w e e k s 2, 4, 8, a n d 1 2  
•  
T o a s s e s s t h e effi c a c y of D F V 8 9 0 v s 
pl a c e b o i n r eli e vi n g O A  p ai n o v er ti m e  
•  
C h a n g e i n K O O S  p ai n s u b s c al e fr o m b a s eli n e 
t o w e e k s 2, 4, 8 a n d 1 2 
•  
C h a n g e i n n u m eri c r ati n g s c al e ( N R S) f or p ai n 
fr o m b a s eli n e t o w e e k s 2, 4, 8 a n d 1 2 
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)  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 4 3  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
2. 1  
Pri m ar y e sti m a n d s  
T he pri mar y cli nical q uesti o n of i nterest is: W hat is t he effect of  D F V 8 9 0 vers us place b o o n t he 
re d ucti o n i n k nee pai n assesse d b y K O O S at Wee k 1 2 i n partici pa nts wit h s y m pt o matic k nee 
O A?  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 4 4  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
T he j ustificati o n f or t he pri mar y esti ma n d is t hat it will ca pt ure t he effect of t he st u d y dr u g 
u n der researc h c o n diti o ns (ass u mi n g c o m plia nce t o t he prescri be d re gi me n) vers us place b o 
wit hi n t he c o nte xt of t he pr ot oc ol -s pecifie d g ui deli nes f or t he use of a d diti o nal basic pai n 
me dicati o n a n d resc ue me dicati o n.  
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: partici pa nts wit h mil d t o m o derate, s y m pt o matic k nee O A ( K & L gra de 2 -3), 
cli nical si g ns of i nfla m mati o n, ele vate d hs C R P ( ≥1. 8 m g/ L) a n d c o nfir mati o n of acti ve 
s y n o vitis b y M RI. F urt her details a b o ut t he p o p ulati o n are pr o vi de d i n  Secti o n  5 . 
2.  E n d p oi nt: c ha n ge fr o m baseli ne i n K O O S pai n s u b -scale at Wee k 1 2. 
3.  Treat me nt of i nterest: t he ra n d o mize d treat me nt (t he i n vesti gati o nal treat me nt D F V 8 9 0 or 
place b o), pl us, if nee de d, t he all o we d basic pai n me dicati o n a n d t he use of resc ue 
me dicati o n o utsi de of t he 4 8 -h o ur wi n d o w pri or t o a st u d y visit.  
4.  I de ntificati o n a n d ha n dli n g of i nterc urre nt e ve nts (I C Es): 
T a bl e 2 -2  
O v er vi e w of i nt er c urr e nt e v e nt s f or t h e pri m ar y e sti m a n d  
I nt er c urr e nt e v e nt 
H a n dli n g of e v e nt  
Mi s s e d tr e at m e nt 
d o s e s  a  
At l e a st 1 mi s s e d d o s e 
wit hi n 4 8 h o ur s pri or t o 
a n a s s e s s m e nt  
O nl y a s s e s s m e nt i m m e di at el y f oll o wi n g t hi s I C E 
will b e e x cl u d e d f or t h e p ur p o s e s of t hi s 
e sti m a n d  
At l e a st 1 2 mi s s e d d o s e s 
wit hi n 4 w e e k s pri or t o 
a s s e s s m e nt  
D at a c oll e ct e d aft er t hi s I C E will n ot b e 
e v al u at e d f or t h e p ur p o s e s of t hi s e sti m a n d  
At l e a st 3 6 mi s s e d d o s e s  
D at a c oll e ct e d aft er t hi s I C E will n ot b e 
e v al u at e d f or t h e p ur p o s e s of t hi s e sti m a n d  
R e s c u e m e di c ati o n  
U nf or e s e e n u s e of 
r e s c u e m e di c ati o n wit hi n 
4 8 h o ur s pri or t o a n 
a s s e s s m e nt or e x c e e di n g 
t h e g ui d eli n e s s p e cifi e d 
i n t h e pr ot o c ol f or u s e of 
r e s c u e m e di c ati o n 
O nl y a s s e s s m e nt i m m e di at el y f oll o wi n g t hi s I C E 
will b e e x cl u d e d f or t h e p ur p o s e s of t hi s 
e sti m a n d  
Pr o hi bit e d 
m e di c ati o n  
U nf or e s e e n u s e of a n y 
m e di c ati o n e x p e ct e d t o 
h a v e a s u st ai n e d eff e ct 
o n t h e pri m ar y e n d p oi nt 
(i. e., a n y i ntr a-arti c ul ar 
i nj e cti o n; s y st e mi c 
c orti c o st er oi d s)  
D at a c oll e ct e d aft er t hi s I C E, w hi c h w o ul d 
r e q uir e p er m a n e nt di s c o nti n u ati o n, will n ot b e 
e v al u at e d f or t h e p ur p o s e s of t hi s e sti m a n d  
U nf or e s e e n u s e of 
m e di c ati o n e x p e ct e d t o 
h a v e a li mit e d eff e ct o n 
t h e pri m ar y e n d p oi nt (i. e., 
a n y ot h er pr o hi bit e d 
m e di c ati o n s)   
O nl y a s s e s s m e nt i m m e di at el y f oll o wi n g t hi s I C E 
will b e e x cl u d e d f or t h e p ur p o s e s of t hi s 
e sti m a n d  
a  r ef er s t o d o s e s mi s s e d f or a n y r e a s o n, i n cl u di n g, b ut n ot li mit e d t o p er m a n e nt di s c o nti n u ati o n of t h e 
st u d y dr u g  

N o v arti s  
C o nfi d e nti al  
P a g e 4 5  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
A ll I C Es will be ha n dle d b y a h y p ot hetical strate g y t o i m p ute w hat t he treat me nt effect w o ul d 
ha ve bee n  at Wee k 1 2 if partici pa nts ha d a d here d t o t he i nitiall y ra n d o mize d treat me nt u p u ntil 
t hat ti me p oi nt, i.e. a n y affecte d data will be e xcl u de d fr o m t he pri mar y a nal ysis a n d (i m plicitl y) 
i m p ute d u n der t he ass u m pti o n t hat t he o utc o me i n t he affecte d partici pa nts w o ul d be n o 
differe nt t ha n i n t he re mai ni n g p o p ulati o n (see Secti o n 1 2. 4. 3  f or i m ple me ntati o n details). 
Alt h o u g h data p ost -I C Es are n ot re q uire d f or t he pri mar y esti ma n d, t hese assess me nts will be 
c ollecte d f or e val uati o n of s u p p orti ve esti ma n ds.  
5.  S u m mar y meas ure:  differe nce bet wee n treat me nt gr o u ps i n mea n c ha n ge i n K O O S pai n 
s u bscale sc ore fr o m baseli ne t o Wee k 1 2. 
2. 2  
S e c o n d ar y e sti m a n d s  
T he ke y sec o n dar y cli nical q uesti o n of i nterest is: W hat is t he effect of  D F V 8 9 0 vers us place b o 
o n t he s y n o vitis acti vit y le vel, assesse d b y K -tra ns b y D C E-M RI at Wee k 1 2 i n partici pa nts 
wit h s y m pt o matic k nee O A.  
T he j ustificati o n f or t he ke y sec o n dar y esti ma n d, as well as t he p o p ulati o n, treat me nt of i nterest 
a n d ha n dli n g of I C Es a p pl y i n t he sa me wa y as f or t he pri mar y esti ma n d. I n a d diti o n, t he 
attri b utes of t he ke y sec o n dar y esti ma n d are:  
E n d p oi nt: C ha n ge fr o m baseli ne i n K -tra ns at Wee k 1 2 
S u m mar y meas ure: differe nce bet wee n treat me nt gr o u ps i n mea n c ha n ge i n  K -tra ns fr o m 
baseli ne t o Wee k  1 2 . 
3  
St u d y d e si g n  
Fi g ur e 3 -1  
St u d y d e si g n  
 

N o v arti s  
C o nfi d e nti al  
P a g e 4 6  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
T his st u d y uses a ra n d o mize d, 2 treat me nt ar m, parallel -gr o u p, partici pa nt a n d i n vesti gat or -
bli n de d, place b o -c o ntr olle d desi g n wit h t he p ur p ose of e val uati n g t he safet y a n d t olera bilit y of 
oral D F V 8 9 0 i n a p pr o xi matel y 1 0 8 partici pa nts wit h s y m pt o matic, i nf la m mat or y k nee O A, a n d 
deter mi ni n g efficac y of D F V 8 9 0 as e vi de nce d b y re d ucti o n i n k nee pai n b y K O O S ( k nee i nj ur y 
a n d oste oart hritis o utc o me sc ore) after 1 2 wee ks of treat me nt.  
T he st u d y c o nsists of a scree ni n g peri o d of u p t o 4 5 da ys, use d t o assess eli gi bilit y a n d t o ta per 
partici pa nts off disall o we d me dicati o ns. At Da y 1 visit, eli gi ble partici pa nts will be ra n d o mize d 
t o o ne of t he treat me nt ar ms. Eli gi ble partici pa nts will e nter t he treat me nt peri o d, w hic h will 
be gi n wit h a 2 -wee k titrati o n peri o d w here t he y will recei ve D F V 8 9 0 1 0 m g b.i. d. or place b o 
orall y f or 1 4  da ys. T he last 1 0 m g d ose will be ta ke n i n t he m or ni n g of Visit Da y 1 4 at t he site 
after t he pre -d ose P K sa m ples are c ollecte d. T he first 2 5 m g d ose will be ta ke n o n Da y 1 4 i n 
t he e ve ni n g. Treat me nt wit h t he 2 5 m g d ose will c o nti n ue f or a 1 0 wee k treat me nt peri o d ( u ntil 
Da y  8 4 i n t he m or ni n g o nl y). D uri n g t his peri o d partici pa nts will recei ve D F V 8 9 0 2 5  m g b.i. d. 
or place b o orall y. A n e n d of st u d y visit will occ ur 1 5  da ys after t he last d ose a n d a p ost st u d y 
safet y c o ntact will occ ur 3 0 da ys after last d ose. T he t otal st u d y d urati o n fr o m scree ni n g u ntil 
e n d of st u d y is e x pecte d t o be a ma xi m u m of 2 1  wee ks.  
T he assess me nt t o a d dress t he pri mar y o bjecti ve will be perf or me d at t he e n d of t he treat me nt 
peri o d ( Wee k 1 2).  
S cr e e ni n g p eri o d  
T he scree ni n g peri o d c o nsists of 2 visits, a scree ni n g visit a n d a baseli ne visit.  
Scree ni n g visit: F oll o wi n g t heir i nf or me d c o nse nt, partici pa nts will u n der g o assess me nts t o 
c o nfir m st u d y eli gi bilit y. T he re q uire d assess me nts ma y be c o n d ucte d o ver se veral da ys if it is 
i n t he best i nterest of t he partici pa nt, or f or l o gistical reas o ns. M RI s h o ul d o nl y be arr a n ge d 
if t he p artici p a nt q u alifies b ase d o n all ot her assess me nts. T he or der of assess me nts t hat 
s h o ul d be f oll o we d t o mi ni mize partici pa nt b ur de n is descri be d i n Secti o n  8. 1 . Partici pa nts 
treate d wit h pr o hi bite d me dicati o ns (see Ta ble 6 -6 ) at scree ni n g will i nitiate was h o ut at t he 
scree ni n g visit.  
A n 
 (acc or di n g t o pr ot oc ol i ma gi n g criteria, i.e., sta n dar d 
wei g ht beari n g l o n g le g or k nee f oc use d pr ojecti o n), l ocal la b orat or y a nal ysis (e. g., hs C R P), as 
well as a k nee p h ysical e xa mi nati o n is p ossi ble, after t he trial a n d t he pr oce d ures of pre -
scree ni n g ha ve bee n e x plai ne d t o partici pa nts a n d t he y ha ve si g ne d t he pre-scree ni n g i nf or me d 
c o nse nt. I n case of act ual scree ni n g, la b orat or y a nal yses will ha ve t o be re peate d ce ntrall y, t he 
X -ra y will re mai n vali d f or 6 m o nt hs a n d t he o utc o me of t he cli nical assess me nt will be vali d 
f or 2 wee ks, as l o n g as t he patie nt d oes n ot re p ort rele va nt c ha n ges i n s y m pt o mat ol o g y. Baseli ne 
visit: T he baseli ne visit will i ncl u de assess me nts liste d i n t he Assess me nt Sc he d ule ( Ta ble  8 -1 ). 
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 4 7  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
Tr e at m e nt p eri o d  
T he treat me nt peri o d will c o nsist of 5 visits:  
•  Treat me nt i nitiati o n visit ( Da y 1): Partici pa nts w h o meet all i ncl usi o n a n d n o e xcl usi o n 
criteria, will be e nr olle d a n d will be gi n ta ki n g a t otal dail y d ose of 2 0 m g ( 1 0 m g b.i. d.) of 
D F V 8 9 0 or matc hi n g place b o ta blets b.i. d. f or 1 4 da ys (last d ose o n Da y 1 4, m or ni n g d ose). 
T he first d ose, eit her D F V 8 9 0 1 0 m g or place b o, will be a d mi nistere d a n d st u d y treat me nt 
will be dis pe nse d t o t he partici pa nt f or c o nti n ue d treat me nt at h o me. Partici pa nts  ma y be 
d o micile d t he e ve ni n g pri or t o a sc he d ule d visit f or t heir  c o n ve nie nce a n d l o gistical as pects, 
at t he discreti o n of t he partici pa nt a n d i n vesti gat or.  
•  Partici pa nts will be e val uate d o n Da y 1 4 as o utli ne d i n t he assess me nt sc he d ule. 
Pr o vi de d  t he treat me nt was well t olerate d base d o n t he I n vesti gat or’s j u d ge me nt a n d 
g ui da nce pr o vi de d i n Secti o n  6. 5. 1 , t he y will start ta ki n g a t otal dail y d ose of 5 0 m g ( 2 5 m g 
b.i. d.) of D F V 8 9 0 or matc hi n g place b o ta blets b.i. d. starti n g o n Da y 1 4 (e ve ni n g d ose o nl y) 
f or 1 0 wee ks. T he last d ose will be a d mi nistere d o n Da y 8 4 ( m or ni n g d ose o nl y).  
•  Partici pa nts will ha ve assess me nts o n Da y 2 8, Da y 5 6, a n d Da y 8 4. T he site staff will 
perf or m p h o ne calls at least o nce bet wee n t w o m o nt hl y visits t o re mi n d partici pa nts t o ta ke 
t heir st u d y treat me nt. 
D uri n g  t he treat me nt peri o d, partici pa nts will u n der g o t he efficac y, P K a n d P D assess me nts as 
o utli ne d i n t he Assess me nt Sc he d ule ( Ta ble  8 -1 ) 
F oll o w -u p p eri o d  
Partici pa nts will be f oll o we d -u p f or a n e n d of st u d y e val uati o n at t he E n d of st u d y visit, 
a p pr o xi matel y 1 5 da ys after last d ose ( Da y 9 9). A safet y f oll o w -u p call will be perf or me d 
a p pr o xi matel y 3 0 da ys after t he last d osi n g ( Da y 1 1 4) t o rec or d a n y p ote nti al safet y e ve nt. 
F or  assess me nts, see Assess me nt Sc he d ule ( Ta ble  8 -1 ). 
U n s c h e d ul e d  vi sit  
Partici pa nts will be i nstr ucte d t o c o ntact t he i n vesti gat or if t he y de vel o p ras h or pr urit us bet wee n 
visits fr o m Da y 1 t o t he E n d of St u d y visit, a n d a n u nsc he d ule d visit s h o ul d be arra n ge d a n d 
relate d assess me nts perf or me d (Ta ble  8 -1 ). 
3. 1  
Off -sit e pr o c e d ur e s  
At t he i n vesti gat or’s discreti o n a n d base d o n be nefit -ris k c o nsi derati o ns of t he partici pa nt’s 
cli nical c o n diti o n, q ualif yi n g partici pa nts ma y be offere d t he o pti o n t o ha ve certai n cli nical trial 
pr oce d ures perf or me d at a n off -site l ocati o n, as defi ne d i n Secti o n 8 . A h y bri d m o del is pla n ne d 
f or t his st u d y i nc or p orati n g b ot h o nsite a n d off-site visits. T he off -site pr oce d ures will be 
utilize d i n certai n c o u ntries a n d sites as deter mi ne d b y pr ot oc ol nee ds a n d base d o n nati o nal 
a n d l ocal/site re g ulati o ns .  Patie nts  ha ve t he o pti o n of partici pati n g i n o ne or m ore off -site visits, 
base d o n t heir prefere nce a n d t he i n vesti gat or’s discreti o n.  
O ne or m ore of t he f oll o wi n g ele me nts ma y be i m ple me nte d t o s u p p ort off -site visits w here 
all o we d b y nati o nal a n d l ocal re g ulati o ns:  
•  Tele me dici ne  

N o v arti s  
C o nfi d e nti al  
P a g e 4 8  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
•  Off -site healt hcare pr ofessi o nals ( O H P) 
•  Direct -t o-patie nt s hi p me nt of st u d y s u p plies  
•  Direct -t o-patie nt s hi p me nt of st u d y treat me nt (refer t o Secti o n 6 ) 
•  Electr o nic S o urce (e S o urce) Direct Data Ca pt ure ( D D C)  
3. 1. 1  
R e s p o n si bilit y of I n v e sti g at or s  
Pr oce d ures t hat are perf or me d off -site re mai n u n der t he o versi g ht of t he i n vesti gat or, w h o 
retai ns acc o u nta bilit y f or t he c o n d uct of  all safet y a n d efficac y assess me nts dele gate d  t o a n 
O H P , a n d will e ns ure t he ri g hts, safet y a n d well bei n g of partici pa nts. T his i ncl u des t he 
f oll o wi n g (i ncl u di n g, b ut n ot li mite d t o): 
•  t he i de ntificati o n, ma na ge me nt a n d re p orti n g of A Es a n d S A Es are perf or me d  i n 
acc or da nce wit h t he pr ot oc ol a n d a p plica ble re g ulati o ns  
•  O H Ps ha ve a p pr o priate q ualificati o ns, trai ni n g, a n d e x perie nce t o s uccessf ull y c o n d uct 
off -site pr oce d ures 
•  s o urce data c ollecte d off-site are re vie we d a n d e val uate d i n a ti mel y ma n ner 
•  t he i n vesti gat or or dele gate is a vaila ble t o be c o ntacte d b y t he O H P if a n y iss ues or 
c o ncer ns are n ote d d uri n g a n off -site visit  
•  w here rele va nt, t he i n vesti gat or or dele gate will be prese nt via tele me dici ne f or a p orti o n 
of t he off -site visit t o s u p p ort t he p h ysical e xa mi nati o n  
3. 1. 2  
R e s p o n si bilit y of O H P s  
O H Ps m ust ha ve t he re q uire d q ualificati o ns, trai ni n g, a n d e x perie nce t o c o n d uct off -site 
assess me nts. O H Ps are res p o nsi ble t o c o n d uct dele gate d assess me nts a n d c ollect rele va nt data 
at off -site visits i n acc or da nce wit h t he cli nical trial pr ot oc ol, I nter nati o nal C o nfere nce f or 
Har m o nizati o n (I C H) G o o d Cli nical Practice ( G C P) g ui deli nes, a n d nati o nal a n d l ocal 
re g ulati o ns a n d g ui deli nes.   
T he O H Ps  will be pr o vi de d b y a t hir d -part y ve n d or s o urce d b y N o vartis. W here a site wis hes 
t o use O H Ps t hat are n ot pr o vi de d b y N o vartis t his m ust be a gree d wit h N o vartis bef ore use. 
A n y iss ues or safet y c o ncer ns i de ntifie d b y t he O H P will be pr o m ptl y c o m m u nicate d t o t he 
i n vesti gat or or dele gate acc or di n g t o a pre-defi ne d c o m m u nicati o n pla n.  
3. 1. 3  
T el e m e di ci n e  
T he s p o ns or has q ualifie d a n d c o ntracte d a t hir d -part y ve n d or t o pr o vi de tele me dici ne platf or m 
tec h n ol o g y f or t his st u d y. T he selecte d platf or m is a vali date d s yste m c o m pl yi n g wit h rele va nt 
I C H E 6 G C P g ui deli nes. Trial partici pa nts ca n i nteract wit h site pers o n nel usi n g o nli ne 
c o m m u nicati o n t o ols b uilt i nt o t he platf or m, e na bli n g t he f oll o wi n g ca pa bilities:  
•  Sec ure vi de oc o nfere nci n g w hic h all o ws t he patie nt, O H P a n d site pers o n nel t o be 
c o n necte d 
•  Re mi n ders t o be a ut o maticall y se nt t o partici pa nts (e. g. visit or d osi n g re mi n ders)  
•  e S o urce D D C (see Secti o n 3. 1. 4 ) 

N o v arti s  
C o nfi d e nti al  
P a g e 4 9  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
3. 1. 4  
D at a fl o w  
T he O H Ps will e nter data at off -site visits i nt o electr o nic s o urce d oc u me ntati o n f or ms c o ntai ne d 
i n a n e S o urce D D C platf or m, w hic h has bee n vali date d f or use i n cli nical researc h. W here pa per 
s o urce d oc u me ntati o n e xists, i ma ges of d oc u me ntati o n will be u ploa de d electr o nicall y i nt o t he 
sa me platf or m as certifie d c o pies, a n d t he ori gi nal d oc u me ntati o n will t he n be se nt t o t he trial 
site.  
Data c o ntai ne d i n t he platf or m are a vaila ble t o site a n d s p o ns or staff base d o n r ole -base d access 
a n d per missi o ns a n d will be st ore d i n a r o b ust a n d sec ure cl o u d -base d bac k -e n d e n vir o n me nt. 
O nl y s p o ns or staff w h o are res p o nsi ble f or fiel d m o nit ori n g acti vi ties will ha ve access t o t he 
s o urce data, w hic h ma y i ncl u de s o me pers o nall y i de ntifia ble i nf or mati o n, c o nsiste nt wit h t he 
access t hat is pr o vi de d t o a fiel d m o nit or i n a tra diti o nal o nsite cli nical trial m o del.  
Rele va nt data i n t he e S o urce D D C platf or m ma y be ma n uall y tra nscri be d b y site staff i nt o t he 
st u d y E D C s yste m. Alter nati vel y, t he platf or m all o ws f or c o nfi g urati o n t hat e na bles data t o be 
a ut o maticall y e x p orte d i nt o t he st u d y E D C s yste m.  
Certifie d c o pies of data i n t he e S o urce D D C platf or m will be pr o vi de d t o i n vesti gat or a n d/ or 
site pers o n nel, a n d pr o m ptl y a n d re g ularl y u pl oa de d i nt o t he partici pa nt’s me dical rec or ds, 
acc or di n g t o l ocal g ui deli nes.  
I n vesti gat ors will ha ve c o nti n u o us , near real ti me access t o t his st u dy  a n d all partici pa nt rec or ds 
wit hi n t h is st u dy i n t he e S o urce D D C platf or m , wit h t he a bilit y t o a d d, e dit, re vie w a n d si g n 
f or ms wit hi n partici pa nt rec or ds.  
T he platf or m mai ntai ns a sec ure, G C P -c o m plia nt a u dit trail a n d uses meas ures s uc h as 
e ncr y pti o n a n d access c o ntr ols t o e ns ure t hat data pri vac y a n d sec urit y is mai ntai ne d. A d diti o nal 
details will be c o ntai ne d i n a se parate ma n ual.  
S A R S -C o V -2  
If a n e pi de mic or pa n de mic (e. g., C O VI D-1 9 pa n de mic) li mits or pre ve nts o n -site st u d y visits, 
a d diti o nal off -site assess me nts (as defi ne d i n Ta ble 8 -1  ) ma y be i m ple me nte d w here all o we d 
b y nati o nal a n d l ocal re g ulati o ns, a n d as a gree d b y t he i n vesti gat or a n d partici pa nt. T o miti gate 
p ote ntial S A R S -C o V -2 a n d ot her i nfecti o ns a m o n g partici pa nts, a n d beca use a n N L R P 3 
i n hi bit or has t he p ote ntial t o be i m m u n os u p pressi ve, g ui da nce a n d re q uire me nts pr o vi de d b y 
t he l ocal re g ulat or y a ut h orities or l ocal site-s pecific S O Ps will be f oll o we d (e. g., partici pa nts 
ma y be scree ne d f or S A R S -C o V -2 b y P. C. R. or c o m para ble a p pr o ve d met h o d ol o g y pri or t o 
a d missi o n at t he st u d y/ h os pital site f or a n y o ver ni g ht sta ys  f oll o wi n g l ocal site-s pecific S O Ps). 

N o v arti s  
C o nfi d e nti al  
P a g e 5 0  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
4  
R ati o n al e  
4. 1  
R ati o n al e f or st u d y d e si g n  
T he desi g n of t his st u d y a d dresses t he pri mar y o bjecti ve of deter mi ni n g t he efficac y of dail y 
oral D F V 8 9 0 vs. place b o i n partici pa nts wit h s y m pt o matic, i nfla me d k nee O A  f or relie vi n g 
O A  pai n. T his st u d y ta kes i nt o acc o u nt: 1) t he u n met cli nical nee d, 2) cl i nical a n d pre-cli nical 
data o n D F V 8 9 0, a n d 3) t he b ur de n o n partici pa nts wit h s y m pt o matic, i nfla me d k nee O A. 
T he  c o m bi nati o n of M RI  meas ure me nt of s y n o vitis, as well as p ote ntiall y cartila ge v ol u me i n 
t he i n de x re gi o n a n d t he w h ole fe m ur, b o ne marr o w lesio n a n d eff usi o n v ol u me, a n d well -
esta blis he d Patie nt Re p orte d O utc o mes ( P R Os) s uc h as K O O S ( Be k kers  et al 2 0 0 9 ), will e ns ure 
a p pr o priate e val uati o n of t he effects of D F V 8 9 0 i n a n i nfla me d j oi nt.  
Partici pa nts will be ra n d o mize d i n a 1: 1 rati o t o eit her D F V 8 9 0 or matc hi n g place b o t o decrease 
t he c ha nce of a n i m bala nce i n partici pa nt c haracteristics bet wee n gr o u ps, t here b y facilitati n g 
u n biase d assess me nts of t he st u d y e n d p oi nts.  
T his st u d y has bee n desi g ne d as partici pa nt a n d i n vesti gat or bli n de d i n or der t o e ns ure t hat b ot h 
i n vesti gat ors a n d partici pa nts re mai n a g n ostic, a n d a p utati ve differe nce bet wee n treat me nt a n d 
c o ntr ol gr o u ps ca n be a p pr o priatel y i nter prete d as a n effect o f st u d y treat me nt. Gi ve n t hat t he 
pri mar y e n d p oi nt ( K O O S  pai n) is a s u bjecti ve assess me nt a n d t heref ore p ote ntiall y i nfl ue nce d 
b y t he place b o effect ( m ore s o t ha n ot her o bjecti ve e n d p oi nts s uc h as cartila ge v ol u me, f or 
e xa m ple), s pecific assess me nts a n d a n al ytic meas ures are i nc or p orate d t o all o w f or a dj ust me nt 
base d o n v ul nera bilit y t o place b o effects.  
Base d o n fi n di n gs fr o m pri or p har mac ot hera p y st u dies ( Da ki n  et al 2 0 1 9 ), 1 2 wee ks of d osi n g 
is c o nsi dere d t o be a de q uate f or detecti n g a c ha n ge i n t he pri mar y e n d p oi nt, K O O S pai n; 
partici pa nts will t heref ore be d ose d f or 1 2 wee ks. A n i nitial d ose of 1 0 m g b.i. d. is pla n ne d t o 
miti gate t he ris k of ras h pri or t o a d va nci n g t o 2 5 m g b.i. d.  
T he Scree ni n g visit will be use d t o c o nfir m t hat t he st u d y i ncl usi o n a n d e xcl usi o n criteria are 
met, a n d f or o btai ni n g cli nical assess me nts a n d bi ol o gical sa m pli n g. Partici pa nts w h o ha ve bee n 
treate d wit h pr o hi bite d me dicati o ns ma y be scree ne d if t he y are willi n g t o disc o nti n ue t he 
pr o hi bite d me dicati o n as descri be d i n  Ta ble 6 -6 . 
I ncl usi o n criteria (e. g., ele vate d hs C R P ≥1. 8 m g/ L, K & L Gra de as meas ure d b y X-ra y, a ge 5 0 -
8 0, i ncrease d baseli ne pai n, si g ns of s y n o vitis base d o n M RI) ha ve bee n selecte d t o e nric h f or 
partici pa nts wit h i nfla me d k nee O A a n d e ns ure h o m o ge neit y i n a relati vel y s mall n u m ber of 
partici pa nts. M ore o ver, t his p o p ulati o n is bei n g selecte d i n or der t o mi ni mize bias ca use d b y 
pai n fr o m t he c o ntralateral k nee affecti n g t he re p orti n g of pai n fr o m t he i n de x k nee as well as 
k nee f u ncti o n. T he e xcl usi o n of partici pa nts w it h 
Wi des prea d Pai n I n de x ( W PI) > 4 is t o 
mi ni mize bias p ote ntiall y affecti n g t he re p orti n g of pai n a n d f u ncti o n b y t he prese nce of 
ge neralize d pai n ( Yazici  et al 2 0 2 0 ). 

N o v arti s  
C o nfi d e nti al  
P a g e 5 1  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
4. 1. 1  
R ati o n al e f or c h oi c e of b a c k gr o u n d t h er a p y  
It is necessar y t o har m o nize a n d d oc u me nt partici pa nts' pai n me dicati o n as it ca n p ote ntiall y 
c o nf o u n d st u d y res ults; t his is partic ularl y i m p orta nt si nce t he pri mar y e n d p oi nt i n t he st u d y is 
base d o n a pai n assess me nt. T heref ore, o nl y t he use of paraceta m ol/aceta mi n o p he n, u p t o 
3 0 0 0  m g/ da y, al o ne or i n c o m bi nati o n wit h l o w -d ose c o dei ne (e. g., c o -c o da m ol) is all o we d as 
basic ( n o n -resc ue) me dicati o n f or pai n c o ntr ol u ntil t he E o S visit. 
4. 2  
R ati o n al e f or d o s e/r e gi m e n a n d d ur ati o n of tr e at m e nt  
T he starti n g d ose f or D F V 8 9 0 f or partici pa nts e nr olle d i n t his trial is set at 1 0 m g p. o. t wice 
dail y ( b.i. d.) f or t w o wee ks t o assess t olera bilit y, f oll o we d b y a si n gle -ste p d ose escalati o n t o 
2 5 m g p. o. b.i. d. f or 1 0 wee ks, f or a t otal treat me nt peri o d o f 1 2 wee ks. T he i nitial d ose le vel 
was selecte d base d pri maril y o n data fr o m t he FI H st u d y C D F V 8 9 0 A 0 2 1 0 1 (I F M -2 4 2 7 -0 0 1), 
i n w hic h s ki n ras hes ha ve bee n o bser ve d i n s o me partici pa nts d ose d o nce dail y wit h 3 0, 1 0 0, 
a n d 2 0 0 m g or t wice dail y wit h 5 0 m g D F V 8 9 0 .  N o ras hes were o bser ve d i n partici pa nts i n t he 
2 5 m g b.i. d. d ose c o h ort. T he mec ha nis m of t he s ki n ras h is li kel y 
 
 
. I n a d diti o n t o assessi n g t he t olera bilit y 
of D F V 8 9 0, t he t w o -wee k r u n -i n peri o d at a l o wer d ose of 1 0 m g b.i. d. will als o i nf or m a b o ut 
t he e xte nt of peri p heral P D mar ker i n hi biti o n.  
T here is n o esta blis he d occ u pa nc y mar ker f or N L R P 3. A n ex viv o w h ole bl o o d assa y of 
li p o p ol ysacc hari des ( L P S)-sti m ulate d I L-1 β secreti o n i n healt h y partici pa nts has bee n use d as 
a p har mac o d y na mic rea d o ut t o esti mate efficaci o us d ose. Base d o n t he res ults of t his assa y, t he 
mea n t otal D F V 8 9 0 plas ma tr o u g h c o nce ntrati o n re q uire d t o i n hi bit 9 0 % of sti m ulate d I L -1 β 
release (I C9 0) i n healt h y partici pa nts is o n a vera ge
 
F or  partici pa nts wit h O A, t he bi n di n g m o de of D F V 8 9 0 t o  N L R P 3 is e x pecte d t o be si milar t o 
healt h y partici pa nts. Ass u mi n g plas ma le vels a b o ve I C 9 0 f or a 2 4-h o ur peri o d are nee de d t o 
mai ntai n c o m plete tar get occ u pa nc y, a D F V 8 9 0 d ose of 2 5 m g b.i. d. w he n gi ve n as a cr ystalli ne 
ta blet has bee n pre dicte d t o meet t his criteri o n. T he i nitial d ose of 1 0 m g b.i. d. will pr o vi de 
plas ma tr o u g h c o nce ntrati o ns w hic h are a b o ve I C 5 0 of I L -1 β release. Si milar u n b o u n d D F V 8 9 0 
c o nce ntrati o ns are e x pecte d i n plas ma a n d s y n o vial fl ui d alrea d y after t he first d ose base d o n 
t he prelimi nar y res ults fr o m t he rat P K st u d y.  
Pat h wa y P D mar kers f or I L -1 β i n hi biti o n ha ve bee n esta blis he d i n ca na ki n u ma b trials, a n d 
i ncl u de hi g h se nsiti vit y C-reacti ve pr otei n ( hs C R P) a n d a bs ol ute ne utr o p hil c o u nt ( A N C). I n t he 
 trial, re d ucti o n i n t hese 
mar kers platea ue d at hi g her ca na ki n u mab d oses 
(Ri d ker  et al 2 0 1 7 ), s u g gesti n g sat urati o n of P D effects. 
A N C a n d hs C R P ha ve bee n m o nit ore d i n t he FI H st u d y C D F V 8 9 0 A 0 2 1 0 1 (I F M -2 4 2 7 -0 0 1). 
Si milar t o t he re d ucti o n see n u p o n ca na ki n u ma b d osi n g i n a wi de ra n ge of trials, a ra pi d dr o p 
of ~ 1 2 -2 2 % i n A N C was o bser ve d i n all M A D c o h orts. T here  was n o o bser ve d d ose res p o nse 
i n A N C decrease, t h o u g h t he data was li mite d t o 8 partici pa nts per c o h ort ( 6 o n D F V 8 9 0 a n d 2 
o n place b o). A nal ysis of hs C R P data i n healt h y partici p a nts i n dicates re d ucti o n i n t he 3 0  m g 
M A D c o h ort, b ut wit h hi g her varia bilit y a n d less c o nsiste nc y t ha n see n wit h ne utr o p hil data. 
N o effect o n hs C R P was see n i n ot her M A D c o h orts, b ut healt h y v ol u nteers e nr olle d i n t hese 
c o h orts di d n ot ha ve ele vate d hs C R P at baseli ne. T he A N C a n d hs C R P c ha n ges s u g gest t hat 
C CI
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 5 2  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
D F V 8 9 0 c o ul d i n hi bit P D res p o nse at d oses l o wer t ha n t h ose pre dicte d b y t he ex viv o L P S 
c halle n ge assa y, b ut m ore data will be nee de d t o b uil d t hese relati o ns hi ps.  
I n t his st u d y, D F V 8 9 0 will be a d mi nistere d wit h a meal or s h ortl y after c o m pleti o n of a meal 
a n d all d oses s h o ul d be ta ke n a p pr o xi matel y 1 2 h a part ( +/ - 2 h).  A p ositi ve f o o d effect o n P K 
( 2. 0 5-f ol d i ncrease i n C ma x a n d 1. 4 9-f ol d i ncrease i n A U Clast) was dem o nstrate d wit h 1 0 0  m g 
cr ystalli ne ta blet i n FI H st u d y C D F V 8 9 0 A 0 2 1 0 1 (I F M -2 4 2 7 -0 0 1), b ut a l o wer effect, es peciall y 
o n C ma x, is e x pecte d f or t he 2 5 m g d ose d ue t o a better s ol u bilit y at l o wer d ose.  T he a p pare nt 
ter mi nal eli mi nati o n half-life of D F V 8 9 0 ta blet u n der fe d c o n diti o ns is a p pr o xi matel y 1 0 h o urs, 
t h us after m ulti ple d oses, t he stea d y state is a ntici pate d b y Da y 4. 
Base d o n FI H st u d y C D F V 8 9 0 A 0 2 1 0 1 (I F M -2 4 2 7 -0 0 1), t he mea n ( % C V) stea d y -state plas ma 
e x p os ure t o D F V 8 9 0 f or 2 5 m g b.i. d. was 2 7. 5 µ g * h/ m L ( 1 7. 2 %) f or A U Cta u, 3. 5 0  µ g/ m L 
( 1 3. 1 %) f or C ma x a n d 1. 4 0 µ g/ m L ( 3 1. 0 %) f or Ctr o u g h. T hese para meters were deri ve d fr o m 
healt h y partici pa nts, w h o were n or mal ( n = 3) or i nter me diate C Y P 2 C 9 meta b olizers ( n = 2 wit h 
* 1 * 2 a n d n = 1 wit h * 1 * 3 di pl ot y pes).  
T he safet y of t he treat me nt peri o d is s u p p orte d b y c o m plete d 1 3 -wee k G L P t o xic ol o g y st u dies 
i n rats a n d c y n o m ol g us m o n ke ys a n d b y t he 2 6-wee k st u d y i n rats a n d t he 4 6 -wee k G L P st u d y 
i n m o n ke ys. Base d o n t he o bser ve d mea n A U C 0-2 4 h at stea d y -state i n healt h y partici pa nts, t he 
safet y mar gi ns f or 2 5 m g b.i. d. are at least 
 w he n c o m pare d wit h t he 
N O A E L e x p os ure fr o m t he c hr o nic t o xic ol o g y st u dies. F or  u n b o u n d e x p os ure (c orrecte d f or 
plas ma pr otei n bi n di n g) safet y mar gi ns t o be m ulti plie d b y 
 
(Ta ble  4 -1 ). Patie nts wit h decrease d C Y P 2 C 9 acti vit y ma y ha ve u p t o -f ol d hi g her e x p os ure  
of D F V 8 9 0 c o m pare d t o n or mal C Y P 2 C 9 meta b olizers res ulti n g i n res pecti vel y l o wer safet y 
mar gi ns . C o nsi deri n g s ufficie nt safet y mar gi ns all patie nts irres pecti ve of C Y P 2 C 9 di pl ot y pe 
are all o we d i n t his st u d y.   
T a bl e 4 -1  
S af et y m ar gi n s f or D F V 8 9 0 d o s e d at 2 5 m g b.i. d. b a s e d o n G L P 
t o xi c ol o g y st u di e s 
H u m a n 
D o s e  
M e a n h u m a n P K b  
E x p o s ur e m ulti pl e s b a s e d o n t ot al N O A E L e x p o s ur e  
R at 1 3 -w e e k  
M o n k e y 1 3 -
w e e k  
R at 2 6 -w e e k  
M o n k e y 4 6 -
w e e k  
 
C m a x 
( µ g/ m L) 
A U C 0 -
2 4 h  
( µ g* h/ m L) 
C m a x  A U C  
C m a x  
A U C  
C m a x  A U C  
C m a x  A U C  
2 5 m g 
b.i. d./ 
cr y st alli n e 
t a bl et 
wit h f o o d  
a: N O A E L C m a x a n d A U C 0 -2 4 h o n d a y l a st fr o m t o x st u di e s a v er a g e d f or f e m al e s a n d m al e s i n r at 
( 1 3-w e e k a n d 2 6 -w e e k st u d y, 3 0 m g/ k g) a n d m o n k e y ( 1 3 -w e e k st u d y, 1 5 0 m g/ k g; 4 6 -w e e k st u d y, 
1 0 0  m g/ k g). F or u n b o u n d e x p o s ur e ( c orr e ct e d f or pl a s m a pr ot ei n bi n di n g ) s af et y m ar gi n s t o b e 
m ulti pli e d b y 
; b: m e a s ur e d  m e a n h u m a n pl a s m a e x p o s ur e at st e a d y 
st at e f or 2 5 m g b.i. d,  A U C 0 -2 4 h c orr e s p o n d s t o 2 x A U Ct a u ( C D F V 8 9 0 A 0 2 1 0 1 (I F M -2 4 2 7 -0 0 1) ). 
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 3  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
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)  
Place b o treat me nt will be use d as c o m parat or t o pr o vi de o bjecti ve c o ntr ol f or t he e val uati o n of 
safet y, cli nical efficac y a n d P D d uri n g t he 1 2-wee k treat me nt wit h D F V 8 9 0. T he oral cr ystalli ne 
ta blet f or m ulati o n will c o ntai n eit her acti ve dr u g or place b o a n d will be i n disti n g uis ha ble i n 
a p peara nce a n d taste.  
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  
N o f or mal i nteri m a nal ysis is pla n ne d. I nteri m a nal yses ma y be c o n d ucte d t o s u p p ort decisi o n 
ma ki n g c o ncer ni n g t he c urre nt cli nical st u d y, t he s p o ns or's cli nical de vel o p me nt pr ojects i n 
ge neral, or i n case of a n y safet y c o ncer ns. A d diti o nal i nf or mati o n is prese nte d i n t he i nteri m 
a nal ysis secti o n.  
4. 5  
Ri s k s a n d b e n efit s  
4. 5. 1  
C o m p o u n d ri s k s  
It is n ot k n o w n w het her t here will be a be nefit f or partici pa nts wit h s y m pt o matic, i nfla me d k nee 
O A  partici pati n g i n t his st u d y.  N o disease m o dif yi n g t hera p y e xists as sta n dar d of care f or 
partici pa nts wit h k nee O A. T heref ore, n o s uc h t hera pies are p ote nti all y wit h hel d f or st u d y 
partici pa nts.  
A p pr o priate eli gi bilit y criteria a n d s pecific d ose -li miti n g t o xicit y defi niti o ns, as well as s pecific 
d ose m o dificati o n a n d st o p pi n g r ules, are i ncl u de d i n t his pr ot oc ol. Rec o m me n de d g ui deli nes 
f or pr o p h ylactic or s u p p orti ve ma na ge me nt of st u d y-dr u g i n d uce d a d verse e ve nts are pr o vi de d.  
T he ris k t o partici pa nts i n t his trial ma y be mi ni mize d b y c o m plia nce wit h t he eli gi bilit y criteria 
a n d st u d y pr oce d ures, as well as cl ose cli nical m o nit ori n g, a n d st u d y st o p pi n g r ules. Please refer 
t o t he I n vesti gat or’s Br oc h ure. 
4. 5. 1. 1  
P ot e nti al ri s k a n d r e c o m m e n d e d m a n a g e m e nt of s ki n r a s h  
I n t he FI H ( C D F V 8 9 0 A 0 2 1 0 1 or I F M-2 4 2 7 -0 0 1) a n d P hase 2 C O VI D -1 9 ( C D F V 8 9 0 D 1 2 2 0 1) 
st u dies, D F V 8 9 0 was ge nerall y well-t olerate d at si n gle a n d m ulti ple d ose le vels. I n t he 
C D F V 8 9 0 A 0 2 1 0 1 (I F M -2 4 2 7 -0 0 1) FI H st u d y, 
 
 
 
 
 
 
 
 
 
 
  
 
  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 5 4  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
I n t he c o m plete d C D F V 8 9 0 D 1 2 2 0 1 P hase 2 st u d y i n C O VI D-1 9, partici pa nts i n t he acti ve ar m 
were a d mi nistere d D F V 8 9 0 5 0 m g t wice dail y + S o C f or 1 4 da ys. Mac ul o pa p ular/ pr uritic s ki n 
ras hes c o nsi dere d relate d t o D F V 8 9 0 were re p orte d i n 7 partici pa nts, of w h o m 2 partici pa nts 
disc o nti n ue d t he st u d y treat me nt. T hese e ve nts were of mil d a n d m o derate se verit y, starte d 5 t o 
1 4 da ys after i nitiati o n of D F V 8 9 0 treat me nt a n d res ol ve d wit hi n 5 t o 1 6 da ys after o nset, wit h 
treat me nt a d mi nistere d t o 6 o ut of t he 7 partici pa nts. 
Decisi o n -ma ki n g criteria f or ma na gi n g a ras h, as well as m o nit ori n g pr oce d ures, are i ncl u de d 
i n t his pr ot oc ol (Secti o n  6. 6. 2 ). 
T o re d uce t he p ote ntial ris ks of t he de vel o p me nt of mac ul o pa p ular a n d/ or pr uritic ras hes, f or 
earl y partici pa nt st u dies b.i. d. d osi n g will be e m pl o ye d t o ac hie ve ma xi mal, s ustai ne d i n hi biti o n 
of t he N L R P 3 tar get w hile mi ni mizi n g D F V 8 9 0 C ma x a n d t he p ote nti al f or tri g geri n g s ki n ras h 
if dri ve n b y C ma x. I n a d diti o n, t he d ose a n d d urati o n of D F V 8 9 0 a d mi nistere d i n t his st u d y will 
be li mite d t o a ma xi m u m of 2 5 m g b.i. d. f or 1 2 wee ks.  
I n vesti gat ors s h o ul d be vi gila nt f or s y m pt o ms of pr urit us a n d si g ns of ras h (e. g., mac ul o pa p ular 
o n u p per tr u n k, s prea di n g ce ntri petall y a n d us uall y ass ociate d wit h pr urit us) a n d s h o ul d i nstr uct 
partici pa nts t o c o ntact t he i n vesti gat or if t he y de vel o p ras h  or pr urit us t o e ns ure a ra pi d cli nical 
assess me nt. See  Secti o n  6. 6. 2  f or rec o m me n de d ma na ge me nt of mac ul o pa p ular/ pr uritic ras hes. 
4. 5. 1. 2  
P ot e nti al ri s k of r e n al a b n or m aliti e s a n d r e c o m m e n d e d m o nit ori n g  
I n n o n-cli nical st u dies, a nal ysis of t he data fr o m t he ≥ 1 3 -wee k G L P re peat -d ose st u d y i n rats 
s h o we d u ne x pecte d a d verse effects i n ki d ne ys c o nsiste nt wit h o bstr ucti ve ne p hr o pat h y at 
d oses  ≥ 1 0 0 
m g/ k g/ da y acc o m pa nie d b y c ha n ges i n ki d ne y -s pecific uri nar y a n d bl o o d 
para meters. I n t he n o n -cli nical m o n ke y st u dies, u p t o 4 6 wee ks ( 4 -, 1 3- a n d 4 6-wee k G L P 
st u dies at d oses u p t o 1 5 0, 1 5 0 a n d 1 5 0/ 1 0 0 m g/ k g/ da y) n o a d verse effects o n ki d ne ys or re nal 
f u ncti o n were o bser ve d.  T he a bse nce of t he re nal fi n di n g i n m o n ke ys wit h ki d ne y p h ysi ol o g y 
a n d uri ne c o nce ntrati o n m ore si milar t o h u ma ns, a n d t he hi g her c o nce ntrati o ns of D F V 8 9 0 
meta b olite i n rat uri ne t ha n i n h u ma ns, are s u g gesti ve of a rat -s pecific s pecies effect a n d t hat 
t here is a l o w p ote ntial ris k t o h u ma ns. 
Cli nicall y, i n t he C D F V 8 9 0 A 0 2 1 0 1 (I F M -2 4 2 7 -0 0 1) FI H a n d C D F V 8 9 0 D 1 2 2 0 1 C O VI D -1 9 
st u dies, base d o n a vaila ble cli nical safet y data fr o m b ot h st u dies, t here has bee n n o e vi de nce of 
a d verse effects o n ki d ne ys or re nal f u ncti o n relate d t o D F V 8 9 0 a d mi nistrati o n i n C O VI D -1 9 
partici pa nts a n d healt h y partici pa nts.  
Alt h o u g h it is n ot clear w het her t here are p ote ntial effects of D F V 8 9 0 o n ki d ne y i n h u ma ns, 
mar kers of re nal f u ncti o n i ncl u di n g electr ol ytes, creati ni ne a n d bl o o d urea nitr o ge n 
( B U N)/ Urea, uri ne -creati ne rati o a n d uri nal ysis 
will be 
m o nit ore d i n t his st u d y 
(see Secti o n  1 0. 2. 2  f or f urt her details a n d g ui da nce).  
4. 5. 1. 3  
P ot e nti al ri s k a n d r e c o m m e n d e d m o nit ori n g of h e m at ol o gi c al 
p ar a m et er s  
Tra nsie nt as y m pt o matic decreases i n A N C a n d W B C were o bser ve d i n t he C D F V 8 9 0 A 0 2 1 0 1 
(I F M-2 4 2 7 -0 0 1) FI H a n d C D F V 8 9 0 D 1 2 2 0 1 C O VI D -1 9 st u dies. T hese tra nsie nt self -li miti n g 
decreases i n A N C a n d W B C were n ot ass ociate d wit h a n i ncrease d ris k of i nfecti o n w hic h c o ul d 
be c o nsiste nt wit h a P D effect of D F V 8 9 0 res ulti n g fr o m i n hi biti o n of I L -1  si g nali n g 

N o v arti s  
C o nfi d e nti al  
P a g e 5 5  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
d o w nstrea m of N L R P 3 ( N L R P 3 bl oc ka de, si milar t o k n o w n effects of ca na ki n u ma b). T o  re d uce 
t he ris k of de vel o pi n g cli nicall y rele va nt ne utr o pe nia i n partici pa nts treate d wit h D F V 8 9 0, all 
partici pa nts wit h e vi de nce of a n A N C c o u nt < 1 0 0 0/ m m 3 s h o ul d be e xcl u de d fr o m e ntr y i nt o 
t his st u d y (see Secti o n  5. 2 ). 
4. 5. 1. 4  
P ot e nti al ri s k a n d r e c o m m e n d e d tr e at m e nt of i nf e cti o n  
As wit h a n y i m m u ne -m o d ulati n g c o m p o u n d, t here is a t he oretical ris k of i m m u ne s yste m 
i m pair me nt, w hic h mi g ht i ncrease ris k of i nfecti o n i n treate d partici pa nts. H o we ver, D F V 8 9 0 
is n ot e x pecte d t o elicit br oa d i m m u ne s u p pressi o n. M ore o ver, t he tar get N L R P 3 is n ot esse ntial 
f or healt h ( N L R P 3 deficie nt mice are ge nerall y healt h y). I n a 4 6-wee k G L P t o xic ol o g y st u d y 
i n c y n o m ol g us m o n ke ys, m ori b u n dit y was re p orte d i n f o ur of t hirtee n a ni mals recei vi n g t he 
hi g hest d ose of D F V 8 9 0 ( 1 5 0 f oll o we d b y 1 0 0 m g/ k g/ da y). T w o of t he a ni mals were e ut ha nize d 
d ue t o i nj uries ( n ot relate d t o D F V 8 9 0). I n t he ot her t w o m o n ke ys, a d verse cli nical fi n di n gs 
were see n wit h e vi de nce of j oi nt i nfla m mati o n (c o nsiste nt wit h a p ost -i nfecti o us reacti ve 
art hritis). T he ca use has n ot bee n deter mi ne d, a n d a p ossi ble relati o n t o D F V 8 9 0 ca n n ot be 
e xcl u de d. T hese fi n di n gs were n ot see n i n a pre vi o us 1 3 -wee k t o xic ol o g y m o n ke y st u d y, w hic h 
ha d hi g her s yste mic e x p os ures. T he ris k f or patie nts i n c urre ntl y o n g oi n g  trials is c o nsi dere d 
l o w base d o n safety mar gi ns a n d/ or s h ort treat me nt d urati o n.  T o miti gate p ote ntial ris ks of 
i m m u ne s u p pressi o n a n d i nfecti o n i n t his st u d y, e xcl usi o n criteria i ncl u de ot her i m m u ne 
s u p pressi ve treat me nts a d mi nistere d 2 8 da ys or 5 half-li ves, w hic he ver is l o n ger, pri or t o 
scree ni n g. Partici pa nts will als o be e xcl u de d wit h k n o w n or s us pecte d i m m u n o deficie nc y state 
or e vi de nce of acti ve or late nt, seri o us bacterial, f u n gal or viral i nfecti o ns. See  Secti o n  5. 2 . 
I n res p o nse t o t he C O VI D-1 9 pa n de mic site -s pecific pr oce d ures s h o ul d be i m ple me nte d t o 
mi ni mize C O VI D -1 9 i nfecti o n ris ks f or partici pa nts a n d site staff as per l ocal g ui da nce. 
T hese  d oc u me nts ma y c o ver, b ut are n ot li mite d t o, l ocal C O VI D -1 9 testi n g, i nfecti o n 
pre ve nti o n/c o ntr ol, h y gie ne a n d s ocial dista nci n g 
meas ure s. I n vesti gat or 
m ust i nstr uct 
partici pa nts t o c o ntact t he i n vesti gat or i m me diatel y if t he partici pa nts de vel o p a n y s y m pt o ms 
a n d/ or si g ns of i nfecti o n (e. g., fe ver, l oss of s mell, l oss of taste, m uscle ac hes, persiste nt or 
pr o d ucti ve c o u g h, a b d o mi nal pai n, v o miti n g, na usea, s h ort ness of breat h, d ys uria a n d/ or 
diarr hea).  
I n t he e ve nt of a n i nfecti o n, i n vesti gat ors s h o ul d c o nsi der earl y treat me nt wit h s pecific 
a nti micr o bial t hera p y base d o n cli nical dia g n osis or s us pici o n t here of (e. g., a nti -viral treat me nt 
f or her pes si m ple x or z oster or S A R S-C o V -2) i n c o ns ultati o n wit h i nfecti o us disease e x perts, 
as a p pr o priate.  
4. 5. 1. 5  
P ot e nti al ri s k a n d g ui d a n c e o n v a c ci n ati o n s  
T o miti gate t he ris k fr o m li ve vacci nati o ns, partici pa nts w h o ha ve recei ve d li ve vacci nati o ns 
wit hi n o ne m o nt h pri or t o t he first d ose of t he st u d y will be e xcl u de d fr o m e ntr y i n t his st u d y.  
A d diti o nall y, it is rec o m me n de d t hat all partici pa nts s h o ul d c o m plete all i m m u nizati o ns i n 
acc or da nce wit h c urre nt i m m u nizati o n g ui deli nes at least o ne m o nt h pri or t o a d mi nistrati o n of 
t he first d ose of D F V 8 9 0.   

N o v arti s  
C o nfi d e nti al  
P a g e 5 6  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
A p pr o ve d (i ncl u di n g 
Healt h 
A ut h orities’ c o n diti o nal 
mar keti n g a ut h orizati o n) kille d, 
i nacti vate d, pe pti de, D N A a n d R N A vacci nes are per mitte d acc or di n g t o t he i n vesti gat or’s 
discreti o n a n d per l ocal g ui da nce.  D ue t o t he mec ha nis m of acti o n of D F V 8 9 0, s pec ificall y 
tar geti n g t he N L R P 3 i nfla m mas o me, it is u nli kel y t hat treat me nt wit h t his c o m p o u n d w o ul d 
i nterfere 
wit h vacci nati o n res p o nses. 
H o we ver, n o s pecific precli nical n or cli nical 
i n vesti gati o ns of vacci ne efficac y ha ve bee n c o n d ucte d t o date wit h D F V 8 9 0. 
4. 5. 1. 6  
Ot h er p ot e nti al c o m p o u n d ri s k s  
At t his sta ge of de vel o p me nt, D F V 8 9 0 has n ot yet bee n st u die d  i n re pr o d ucti ve t o xic ol o g y 
st u dies, a n d w o me n of c hil d-beari n g p ote ntial a n d se x uall y acti ve males m ust be i nf or me d t hat 
ta ki n g t he st u d y treat me nt ma y i n v ol ve u n k n o w n ris ks t o t he fet us if pre gna nc y were t o occ ur 
d uri n g t he st u d y, a n d a gree t hat i n or der t o partici pate i n t he st u d y t he y m ust a d here t o t he 
c o ntrace pti o n re q uire me nts o utli ne d i n t he e xcl usi o n criteria.  Oral  h or m o nal c o ntrace pti o n is 
n ot all o we d u ntil a dr u g -dr u g i nteracti o n st u d y is perf or me d, as D F V 8 9 0, base d o n t he i n vitr o 
data, ma y i n d uce C Y P 3 A 4 e nz y me i n t he i ntesti ne, w here it is i n v ol ve d i n t he meta b olis m of 
s o me h or m o nal c o ntrace pti ves. If t here is a n y q uesti o n t hat t he partici pa nt will n ot relia bl y 
c o m pl y, t he y s h o ul d n ot be e ntere d or c o nti n ue i n t he st u d y.  
A D DI ris k e xists f or D F V 8 9 0 as a victi m w he n d ose d wit h C Y P 2 C 9 a n d/ or C Y P 3 A i n hi bit ors 
a n d i n d ucers. M ore t ha n -f ol d hi g her D F V 8 9 0 plas ma e x p os ure is e x pecte d i n partici pa nts 
w h o are p o or C Y P 2 C 9 meta b olizers (a p pr o xi matel y 2 -4 % of t he p o p ulati o n) u p o n c o -
a d mi nistrati o n of str o n g or m o derate i n hi bit ors of C Y P 3 A. U p t o -f ol d l o wer plas ma e x p os ure 
is e x pecte d wit h i n d ucers of C Y P 2 C 9 a n d/ or C Y P 3 A p osi n g a n i ncrease d D DI ris k. T o miti gate 
t hese ris ks, str o n g or m o derate i n hi bit ors of C Y P 3 A, str o n g/ m o derate i nd ucers of C Y P 2 C 9 a n d 
str o n g i n d ucers of C Y P 3 A will be e xcl u de d u ntil a D DI st u d y is perf or me d.  
4. 5. 2  
Pr o c e d ur al ri s k s  
I n vasi ve, st u d y-s pecific, pr oce d ures i ncl u de s y n o vial fl ui d as pirati o n. Sterile tec h ni q ue will be 
use d. P ote ntial a d verse effects ma y i ncl u de l ocal reacti o ns at t he site of as pirati o n, s uc h as l ocal 
pai n, s welli n g or i nfla m mati o n, or j oi nt i nfecti o n (ris k 1/ 3 0, 0 0 0 p r oce d ures, Fi n k  et al 2 0 0 8 ). 
P ote ntial a d verse e ve nts will be m o nit ore d cli nicall y.  
4. 5. 3  
I m a gi n g ri s k s 
T his cli nical st u d y i n v ol ves e x p os ure t o ra diati o n fr o m t he X -ra y assess me nt. F or scree ni n g 
p ur p oses, a sta n di n g l o n g le g vie w of t he l o wer li m b (tar get k nee) is re q uire d. T hese are ofte n 
perf or me d d uri n g t he r o uti ne e val uati o n of partici pa nts wit h k nee pa i n, b ut n ot al wa ys. 
C o nse q ue ntl y, i n s o me partici pa nts t his assess me nt will be o btai ne d o nl y f or researc h p ur p oses. 
T he t otal a m o u nt of ra diati o n e x p os ure per partici pa nt fr o m t his X -ra y will be a b o ut 6 0 µ S v 
( 6 mre m), w hic h is e q ui vale nt t o a p pr o xi matel y 7  da ys of e x p os ure t o nat ural bac k gr o u n d 
ra diati o n ( n or mal e x p os ure is a p pr o x. 0. 3 µ S v per h o ur at sea le vel f or t he a vera ge pers o n i n 
t he U nite d States). F or effecti ve ra diati o n d oses u n der 3 m S v ( 3 0 0  mre m), t he ris k is c o nsi dere d 
t o be " mi ni mal". T heref ore, t he ra diati o n e x p os ure i n t his st u d y i n v ol ves mi ni mal ris k a n d is 
necessar y t o e ns ure eli gi bilit y of partici pa nts.  
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 5 7  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
Ma g netic res o na nce i ma gi n g ( M RI) will be use d i n t his st u d y b ot h f or partici pa nt selecti o n a n d 
f oll o w-u p p ur p oses. M RI is a n o n‑i n vasi ve ra di ol o g y tec h ni q ue t hat  d oes n ot i n v ol ve  X -ra y 
ra diati o n e x p os ure. T h us, i n pri nci ple, M RI sca ns ca n be re peate d i n t he sa me partici pa nt as 
ofte n as necessar y. T he M RI sca n ni n g e q ui p me nt ma y ca use a feeli n g of cla ustr o p h o bia i n 
s usce pti ble pers o ns. T he prese nce of metal i n t he b o d y ma y als o be a safet y hazar d or affect t he 
M R i ma ge q ualit y. F or m ore i nf or mati o n, see e xcl u si o n criteri o n 1 6.  
I n a d diti o n, f or s y n o vitis assess me nts, a ga d oli ni u m-base d c o ntrast a ge nt ( G B C A, A T C C o de: 
V 0 8 C A) will be a d mi nistere d as a n i. v. b ol us d uri n g eac h D C E -M RI sessi o n. Ris ks of i. v. 
i nf usi o n i ncl u de i nfecti o n, pai n or t hr o m b osis. T here is rece nt e vi de nce of ga d oli ni u m 
de p ositi o n i n brai n tiss ues f oll o wi n g use of G B C As. Alt h o u g h n o s y m pt o ms or diseases li n ke d 
t o ga d oli ni u m acc u m ulati o n i n t he brai n ha ve bee n i de ntifie d, healt h a ut h orities t o o k 
a preca uti o nar y a p pr oac h (e. g.,  E M A rec o m me n dati o ns o n G B C As , E M A 2 0 1 7 ), n oti n g t hat 
data o n t he l o n g -ter m effects i n t he brai n are li mite d. T his le d t o t he s us pe nsi o n of se veral li near 
G B C As a n d t he rec o m me n dati o n t hat a n ot her class of G B C As k n o w n as macr oc yclic a ge nts 
be  use d as a n alter nati ve s ol uti o n, as t he y are dee me d m ore sta ble a n d ha ve a l o wer pr o pe nsit y 
t o release ga d oli ni u m t ha n li near a ge nts. Alt h o u g h t his is hi g hl y de bate d, t he c urre nt belief is 
t hat s uc h a ge nts, es peciall y t he li near ga d oli ni u m a ge nts, ma y als o i ncrease t he ris k of a rare 
b ut seri o us  disease  calle d ne p hr o ge nic s yste mic fi br osis ( N F S). T o pre ve nt t his ris k a n d i n 
acc or da nce wit h healt h a ut h orit y g ui da nce (e. g.,  Me dici nes a n d Healt hcare pr o d ucts Re g ulat or y 
A ge nc y Dr u g Safet y U p date o n G B C As  (M H R A 2 0 1 7 ), F o o d a n d Dr u g A d mi nistrati o n Dr u g 
Safet y C o m m u nicati o ns o n G B C As  (F D A 2 0 1 7a , F D A 2 0 1 7 b )), partici pa nts wit h pre vi o us 
se vere aller gic/a na p h ylact oi d reacti o n t o a ga d oli ni u m-base d c o ntrast a ge nt; partici pa nts wit h 
se vere re nal disease (e G F R < 6 0 m L/ mi n/ 1. 7 3 m2), or ac utel y deteri orati n g re nal f u ncti o n, w h o 
w o ul d be at ris k of ne p hr o ge nic s yste mic fi br osis m ust be e xcl u de d fr o m partici pati n g i n t his 
st u d y. 
4. 5. 4  
Ri s k s a s s o ci at e d wit h off -sit e vi sit s  
Partici pa nts are n ot a ntici pate d  t o be e x p ose d t o greater ris ks w he n partici pati n g i n off -site 
assess me nts. O H Ps will perf or m assess me nts acc or di n g t o t he sa me pr ocesses a n d i nstr ucti o ns 
defi ne d i n t he pr ot oc ol a n d st u d y ma n uals f or o nsite visits, t h us data i nte grit y is als o e x pecte d 
t o be c o m para ble t o o nsite assess me nts. Safet y ma na ge me nt i n an  off -site setti n g will a d here t o 
t he sa me q ualit y sta n dar ds as f or t he tra diti o nal o nsite 
m o del a n d re mai ns u n der t he 
res p o nsi bilit y of t he i n vesti gat or (refer t o Secti o n 3. 1 ). 
4. 5. 5  
Bl o o d s a m pl e v ol u m e  
A v ol u me s maller t ha n a t y pical bl o o d d o nati o n is pla n ne d t o be c ollecte d o ver a peri o d 
of  1 9  wee ks, fr o m eac h partici pa nt as part of t he st u d y. T he a p pr o xi mate v ol u mes are me nti o ne d 
i n t he I nf or me d C o nse nt F or m (I C F). A d diti o nal sa m ples ma y be re q uire d f or safet y m o nit ori n g.  
Ris ks of c ollecti n g bl o o d ma y i ncl u de fai nti n g, pai n a n d/ or blee di n g a n d/ or br uisi n g at t he site 
of nee dle p u nct ure.  
Ti mi n gs of bl o o d sa m ple c ollecti o n are o utli ne d i n t he assess me nt sc he d ule ( Ta ble  8 -1 ). 
A s u m mar y bl o o d l o g is pr o vi de d i n t he la b orat or y ma n ual. I nstr ucti o ns f or sa m ple c ollecti o n, 
pr ocessi n g, st ora ge a n d s hi p me nt i nf or mati o n are als o a vaila ble i n t he la b orat or y ma n ual.  

N o v arti s  
C o nfi d e nti al  
P a g e 5 8  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
See Secti o n  8. 5. 3. 7  o n t he p ote ntial use of resi d ual sa m ples.  
4. 5. 6  
S A R S -C o V -2 ri s k s  
T he c urre nt S A R S -C o V -2 pa n de mic ma y p ose a c halle n ge t o i nte grit y of t he trials, pr otecti o n 
of partici pa nts’ ri g hts, safet y a n d well bei n g, as well as t he safet y of st u d y staff. T heref ore, ris k 
miti gati o n strate gies ha ve bee n esta blis he d a n d will be e val uat e d o n a n o n g oi n g basis f or t he 
d urati o n of t he st u d y, i n li ne wit h healt h a n d g o ver n me ntal a ut h orit y g ui da nce.  
4. 5. 7  
O v er all ri s k b e n efit  
Base d o n t he cli nical e x perie nce wit h D F V 8 9 0 i n t he C D F V 8 9 0 A 0 2 1 0 1 (I F M -2 4 2 7 -0 0 1) FI H 
st u d y, t he C D F V 8 9 0 D 1 2 2 0 1 p hase II st u d y i n C O VI D-1 9, rele va nt n o ncli nical fi n di n gs, t he 
bi ol o gical u n dersta n di n g of t he pat h wa ys a n d t heir rele va nce t o O A, t he o verall ris k -be nefit of 
D F V 8 9 0 is, t o date, c o nsi dere d fa v ora ble. T he a vaila ble cli nical, safet y a n d la b orat or y 
assess me nts fr o m t he FI H st u d y a n d t he C O VI D -1 9 st u d y s h o w t hat D F V 8 9 0 is ge nerall y well 
t olerate d a n d has a ma na gea ble safet y pr ofile. Base d o n t he a vailable n o n -cli nical a n d cli nical 
data t he p ote ntial ris ks t o be c o nsi dere d f or D F V 8 9 0 i ncl u de re nal a b n or malities a n d c ha n ges 
i n fe male re pr o d ucti ve tiss ues, w hic h were o bser ve d i n t he rat, a n d self-li miti n g s ki n ras hes 
o bser ve d i n t he cli nical st u dies. I n a d diti o n t o t he ris ks n ote d a b o ve, t here ma y be ris ks t o 
D F V 8 9 0 t hat are seri o us a n d u nf oresee n. T heref ore, t he ris ks t o O A partici pa nts i n t his trial will 
be mi ni mize d b y a d here nce t o t he eli gi bilit y criteria, cl ose cli nical m o nit ori n g, fre q ue nt f oll o w 
u p, mi ni mal d urati o n of t he st u d y a n d st o p pi n g r ules.  
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 declare d b y l ocal or re gi o nal a ut h orities e. g., pa n de mic, 
e pi de mic, or nat ural disaster, miti gati o n pr oce d ures t o e ns ure partici pa nt safet y a n d trial 
i nte grit y ma y be i m ple me nte d. N otificati o n of t he p u blic healt h e mer ge nc y as declare d b y l ocal 
or re gi o nal a ut h orities s h o ul d be disc usse d a m o n g i n vesti gat ors a n d N o vartis. All pr oce d ures 
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.  
4. 7  
R ati o n al e f or pl a n n e d off -sit e pr o c e d ur e s  
Off -site pr oce d ures are pla n ne d i n t his st u d y t o mi ni mize b ur de n o n partici pa nts, a n d offer t he m 
i ncrease d fle xi bilit y t o partici pate i n t he st u d y fr o m a n off-site l ocati o n (as descri be d i n 
Secti o n  3  a n d defi ne d i n  Secti o n 8 ). T his has t he p ote ntial t o br oa de n access t o cli nical trials f or 
b ot h partici pa nts a n d i n vesti gat ors. T he h y bri d a p pr oac h will all o w partici pa nts t o mai ntai n 
c o ntact wit h i n vesti gat or, b ot h i n pers o n d uri n g cli nic visits at site a n d t hr o u g h t he tele me dic i ne 
platf or m d uri n g off -site partici pati o n. 
T he sc o pe of off -site pr oce d ures was deter mi ne d base d o n t h or o u g h o perati o nal feasi bilit y 
assess me nts t o ass ure c o m para bilit y wit h o nsite assess me nts, t o get her wit h c o nsi derati o n of 
patie nt safet y, i n vesti gat or, a n d patie nt fee d bac k.  

N o v arti s  
C o nfi d e nti al  
P a g e 5 9  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
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 c o nsist of a p pr o xi matel y 1 0 8 male a n d fe male a d ult partici pa nts wit h 
mil d t o m o derate, s y m pt o matic k nee O A ( K & L gra de 2 -3), cli nical si g ns of i nfla m mati o n a n d 
c o nfir mati o n of acti ve s y n o vitis b y M RI. T o matc h t he p o p ulati o n t o t he o ne e val uate d a n d 
ha vi n g be nefite d acc or di n g t o t he p ost -h oc a nal ysis of t he  
 st u d y (Sc hie ker  et al 2 0 2 0 ) 
partici pa nts will als o be selecte d base d o n ele vate d hs C R P ( ≥1. 8 m g/ L).  
T he i n vesti gat or m ust e ns ure t hat a partici pa nt meets all of t he i ncl usi o n a n d n o ne of t he 
e xcl usi o n criteria bef ore e nr olli n g hi m/ her i nt o t he trial. N o a d diti o nal criteria s h o ul d be a p plie d 
b y t he i n vesti gat or w he n c o nsi deri n g a partici pa nt's eli gi bilit y . I n t he case w here a safet y 
la b orat or y assess me nt at scree ni n g meets a n y of t he e xcl usi o n criteria b ut t he c o n diti o n is 
e x pecte d t o be tra nsie nt a n d res ol ve d pri or t o first d ose, t he assess me nt ma y be re peate d o nce 
pri or t o ra n d o mizati o n. If t he re peat va l ue re mai ns a b n or mal a n d cli nicall y si g nifica nt, t he n t he 
partici pa nt will be e xcl u de d fr o m t he st u d y.  
5. 1  
I n cl u si o n crit eri a 
Ple ase n ote t h at t he ter m “ Scree ni n g ” t hr o u g h o ut t his secti o n refers t o t he first scree ni n g visit. 
Partici pa nts eli gi ble f or i ncl usi o n i n t his st u d y m ust meet all  of t he f oll o wi n g criteria:  
1.  Writte n i nf or me d c o nse nt m ust be o btai ne d bef ore a n y assess me nt is perf or me d.  
2.  A ble t o c o m m u nicate well wit h t he i n vesti gat or, t o u n dersta n d a n d c o m pl y wit h t he 
re q uire me nts of t he st u d y. 
3.  Male a n d fe male partici pa nts ≥5 0 a n d ≤ 8 0 years ol d o n t he da y of I nf or me d C o nse nt 
si g nat ure. 
4.  Partici pa nts m ust wei g h at least 5 0 k g t o partici pate i n t he st u d y, a n d m ust ha ve a b o d y mass 
i n de x ( B MI) wit hi n t he ra n ge of 1 8 - 3 5 k g/ m 2 at scree ni n g. B MI = B o d y wei g ht ( k g) / 
[ Hei g ht ( m)]2  
5a. Hi g h se nsiti vit y C -reacti ve pr otei n ( hs C R P) ≥1. 8 m g/ L at scree ni n g  
6 b . S y m pt o matic O A wit h pai n (c orres p o n di n g t o N u meric Rati n g Scale [ N R S] 5 -9, i ncl usi ve) 
i n t he tar get k nee f or t he maj orit y of da ys i n t he last 3 m o nt hs pri or t o scree ni n g, as per 
partici pa nt’s j u d ge me nt.  At Scree ni n g, t he patie nt will be gi ve n a diar y t o rec or d pai n a n d 
use of a nal gesic me dicati o ns. T he  partici pa nt m ust be c o m plia nt wit h filli n g i n t he diar y at 
least 6 o ut of 7 da ys pri or t o Baseli ne, a n d ha ve diar y N R S Pai n ≥5 t o  ≤9 f or eac h of t he 
t w o wee ks pri or t o baseli ne at least 6 da ys o ut of 7 da ys A N D ha ve P R O re p orte d N R S pai n 
≥5 t o  ≤9 at Scree ni n g  a n d Baseli ne 
7.  Pri mar y s o urce of pai n is d ue t o O A  i n tar get k nee base d o n wi des prea d pai n i n de x ( W PI) 
sc ore ≤4 at scree ni n g 
8.  K O O S  pai n s u b -scale sc ore ≤6 0 i n i n de x k nee at scree ni n g a n d baseli ne  
9a.  Ra di o gra p hic disease: K & L gra de 2 or 3 k nee oste oart hritis i n t he tar get k nee, c o nfir me d 
b y X -ra y at scree ni n g. 
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 6 0  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
1 0 a. Acti ve s y n o vial i nfla m mati o n at scree ni n g ( defi ne d as at least mil d s y n o vitis (s u m sc ore 
≥7) a n d at least o ne i n di vi d ual area wit h a sc ore of 2/ 2; a p peara nce of s y n o vitis at y pical f or 
O A will be e xcl usi o nar y base d o n t he ce ntral rea ders j u d g me nt) base d o n c o ntrast e n ha nce d 
M RI ( C E -M RI) 
of t he 
w h ole 
k nee f or 
s y n o vitis 
detecti o n fr o m 
1 1 
sites 
(G uer mazi  et al 2 0 1 1 ). 
1 1.  Dia g n osis of pri mar y ti bi ofe m oral k nee O A b y sta n dar d A meric a n C olle ge of  R he u m at ol o gy  
cli nical a n d ra di o gra p hic criteria at Scree ni n g  
1 2 a. C urre nt use of a nal gesic t hera p y f or c o ntr ol of l ocal pai n i n t he tar get k nee: 
•  Patie nts ta ki n g paraceta m ol/aceta mi n o p he n, i ncl u di n g c o m bi nati o n dr u gs c o ntai ni n g 
l o w d ose o pi oi ds, ca n c o nti n ue usi n g t his as per t he pac ka ge i nsert/ d oct or's i nstr ucti o n.  
•  Patie nts ta ki n g a n y ot her a nal gesic me dicati o n, i ncl u di n g N S AI Ds a n d selecti ve C O X -
2 i n hi bit ors or ce ntral a nal gesic or pai n -m o d ulat or y me dicati o n b ut e xcl u di n g t o pical 
N S AI Ds or t o pical ster oi ds, f or a n y pai n i n dicati o n i ncl u di n g k nee pai n, m ust be willi n g 
t o s witc h at Scree ni n g t o paraceta m ol/aceta mi n o p he n, i ncl u di n g c o m bi nati o n dr u gs 
c o ntai ni n g l o w d ose o pi oi ds, as per t he pac ka ge i nsert/ d oct or's i nstr ucti o n. N S AI Ds or 
ot her n o n -o pi oi d a nal gesics (e xcl u di n g ce ntrall y acti n g s u bsta nces) are all o we d o nl y a s 
resc ue me dicati o n as i n dicate d base d o n t he patie nt pr ofile ( bac k gr o u n d me dicati o n), 
b ut m ust n ot be use d wit hi n 4 8 h o urs or fi ve half -li ves, w hic he ver is l o n ger, pri or t o 
a n y P R O assess me nt.  
•  Patie nts ta ki n g gl uc osa mi ne or c h o n dr oiti n m ust be willi n g t o disc o nti n ue t hese fr o m 
Scree ni n g.  
5. 2  
E x cl u si o n crit eri a  
Partici pa nts meeti n g a n y of t he f oll o wi n g criteria are n ot eli gi ble f or i ncl usi o n i n t his st u d y.  
1.  T otal W B C c o u nt <  3, 0 0 0/ µ L, a bs ol ute peri p heral bl o o d ne utr o p hil c o u nt ( A N C) 
<  1, 0 0 0/ µ L, he m o gl o bi n <  8. 5 g/ d L ( 8 5 g/ L) or platelet c o u nt <  1 0 0, 0 0 0/ µ L  at scree ni n g 
2.  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 ociate d art hritis), active 
ac ute or c hr o nic i nfecti o n or past i nfecti o n of t he k nee j oi nt, L y me disease i n v ol vi n g t he 
k nee, reacti ve art hritis, s yste mic cartila ge dis or ders, m o derate t o se vere fi br o m yal gia 
( wi des prea d pai n i n de x, W PI, > 4 o ut of 1 9), or a k n o w n s yste mic c o n necti ve tiss ue 
disease  
4.  Meta b olic or ge neticall y -base d a b n or malities ass ociate d wit h art hr o pat h y  
5a.  Partici pa nt has a n u nsta ble tar get k nee j oi nt 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 p h ysical e xa mi nati o n b y t he I n vesti gat or at scree ni n g  
6.  Partici pa nt has s y m pt o matic, is olate d patell ofe m oral pai n i n t he i n de x k nee as per t he 
I n vesti gat or's e xa mi nati o n at scree ni n g 
7.  Use of electr ot hera p y, ac u p u nct ure, a n d/ or c hir o practic treat me nts f or k nee O A wit hi n 
4  wee ks pri or t o scree ni n g  

N o v arti s  
C o nfi d e nti al  
P a g e 6 1  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
8.  A n y k n o w n acti ve i nfecti o ns, i ncl u di n g s ki n or k nee i nfecti o ns or i nfecti 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 nic he patitis B or C i nfecti o n.  
C O VI D -1 9 s pecific: P. C. R. or a nti ge n test a gai nst C O VI D -1 9 is ma n dat or y w here 
re q uire d b y t he l ocal Healt h A ut h orit y a n d/ or b y l ocal re g ulati o n, e. g. i n Ger ma n y. N ote 
t hat s o me c o u ntries ma y re q uire P. C. R. testi n g o nl y, e. g. Czec h Re p u blic. It is hi g hl y 
rec o m me n de d t hat P. C. R. or a ntige n testi n g f or C O VI D -1 9 be c o m plete d wit hi n 1 wee k 
pri or t o first d osi n g. If testi n g is perf or me d, ne gati ve test res ults are re q uire d pri or t o 
e nr ol me nt i nt o t he st u d y. A d diti o nal testi n g ma y occ ur at t he discreti o n of t he 
i n vesti gati n g p h ysicia n. C O VI D-1 9 testi n g s h o ul d be c o m plete d via nasal or t hr oat 
s wa bs. If testi n g is n ot perf or me d, t he i n vesti gat or m ust d oc u me nt t heir disc ussi o n wit h 
t he partici pa nt re gar di n g testi n g, a n d t he rati o nale f or n ot testi n g, i n t he s o urce 
d oc u me ntati o n. T his re q uire me nt m a y be i g n ore d if t he pa n de mic is declare d e n de d b y t he 
c o u ntr y w here t he site is l ocate d, a n d res u me d if t he pa n de mic rec urs.  
9a.  A n y dia g n ose d ps yc hiatric c o n diti o n t hat i ncl u des, b ut is n ot li mite d t o, a hist or y of ma nia, 
bi p olar dis or der, ps yc h otic dis or der, sc hiz o p hre nia, or sc hiz oaffecti ve dis or der, de pressi o n 
or a n xiet y dis or der.  
1 0.  Hist or y of l y m p h o pr oliferati ve disease or a n y k n o w n mali g na nc y or hist or y of mali g na nc y 
of a n y or ga n s yste m wit hi n 5 years of scree ni n g (e xce pt f or basal cell carci n o ma or acti nic 
kerat oses t hat ha ve bee n treate d wit h n o e vi de nce of rec urre nce i n t he 3 m o n t hs pri or t o 
scree ni n g, or carci n o ma i n sit u of t he cer vi x or n o n-i n vasi ve mali g na nt c ol o n p ol y ps t hat 
ha ve bee n re m o ve d)  
1 1a.  
S y m pt o matic hi p O A or hi p pr ost hesis rece ntl y i m pla nte d ( ≥6 m o nt hs pri or t o 
scree ni n g, if f ull y rec o vere d after ≥ 6 m o nt hs i ncl usi o n is acce pta ble) or f oresee n wit hi n 
t he st u d y peri o d (eit her si de) 
1 2.  Ot her pat h ol o gies affecti n g t he k nee, i ncl u di n g s u bc h o n dral i ns ufficie nc y fract ures, b o ne 
fract ure (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, oste oc h o n dral lesi o n, mali g na nt b o ne marr o w i nfiltrati o n, s oli d t u m ors, 
me nisc us e xtr usi o n greater t ha n 5 0 % a n d/ or macerate d me nisc us  a n d/ or patell ofe m oral 
d ys plasia base d o n cli nical or i ma gi n g assess me nts  
1 4a.  
Use of pr o hi bite d me dicati o ns  i ncl u di n g b ut n ot li mite d t o: 
a. a n y l ocal i.a. treat me nt i nt o t he k nee, i ncl u di n g b ut n ot li mite d t o 
visc os u p ple me ntati o n a n d c ortic oster oi ds wit hi n 1 2  wee ks pri or t o Da y 1  (ster oi d 
i njecti o ns i nt o ot her j oi nts are pr o hi bite d fr o m Scree ni n g); 
b.  l o n g-ter m treat me nt ( > 1 4 da ys) wit h oral c ortic oster oi ds > 5 m g/ da y wit hi n 4 wee ks 
pri or t o Da y 1;  
c. oral gl uc osa mi ne, 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 
cartila ge re pair wit hi n 2  wee ks pri or t o scree ni n g;  
d.  s yste mic N o n-Ster oi dal A nti -I nfla m mat or y Dr u gs ( N S AI Ds) or selecti ve C O X-2 
i n hi bit ors or ot her n o n -o pi oi d a nal gesics  wit hi n 4 8 h o urs or fi ve half -li ves, w hic he ver 
is l o n ger, fr o m P R O assess me nts;  

N o v arti s  
C o nfi d e nti al  
P a g e 6 2  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
e. a n y ot her i m m u n o m o d ulat or y dr u gs or treat me nt w hic h ca n n ot be disc o nti n ue d or 
s witc he d t o a differe nt me dicati o n wit hi n 2 8 da ys or 5 half-li ves of 
scree ni n g( w hic he ver is l o n ger if re q uire d b y l ocal re g ulati o ns), or u ntil t he e x pecte d 
P D  effect has ret ur ne d  t o baseli ne. 
f. See als o Ta ble 6 -6  
1 5.  Se vere malali g n me nt greater t ha n 7. 5 de grees i n t he tar get k nee  (eit her var us or val g us), 
meas ure d usi n g X -ra y at Scree ni n g 
1 6a.  
Partici pa nt u na ble or u n willi n g t o u n der g o M RI or ha vi n g c o ntrai n dicati o ns t o M RI 
(e. g., M RI -i nc o m pati ble metallic i m pla nts, metallic f orei g n b o dies, pace ma ker, 
defi brillat or) or t o t he use of ga d oli ni u m -base d a ge nts, e. g., patie nts wit h pre vi o us se vere 
aller gic/a na p h ylact oi d reacti o n t o a ga d oli ni u m -base d c o ntrast a ge nt; patie nts wit h 
se vere re nal disease (e GF R <  6 0 m L/ mi n calc ulate d usi n g t he C K D -E PI f or m ula 
[ htt ps:// w w w. ki d ne y. or g/ pr ofessi o nals/ K D O QI/ gfr _calc ulat or] or > = 2 + pr otei n o n uri ne 
di pstic k testi n g at scree ni n g), or ac utel y deteri orati n g  re nal f u nctio n.  
1 7a.  
M o derate t o se vere pai n i n t he c o ntralateral k nee f or t he maj orit y of da ys i n t he last 3 
m o nt hs pri or t o Scree ni n g, as per patie nt j u d g me nt  
1 8a.  
Hist or y of, or pla ns f or t he f oll o wi n g s ur gical i nter ve nti o ns;  
a. K nee re place me nt ( partial or t otal) i n t he tar get k nee;  
b.  K nee re place me nt partial or t otal i n t he c o ntralateral k nee wit h resi d ual pai n or 
wit hi n 6 m o nt hs pri or t o scree ni n g  
c. Art hr osc o p y  or la va ge  i n eit her k nee, wit hi n 3 m o nt hs pri or t o Scree ni n g or 
pla n ne d d uri n g t he st u d y   
d.  M osaic plast y, micr ofract ure or ot her cartila ge re pair s ur ger y, me niscect o m y 
> 5 0 % i n t he tar get k nee.  
e. A n y ot her pre vi o us s ur gical i nter ve nti o n i n t he eit her k nee, or wit hi n 6 m o nt hs 
pri or t o Scree ni n g 1 ( 1 2 m o nt hs f or oste ot o mies) or pla n ne d d uri n g t he st u d y. 
If i n d o u bt, please c o ntact t he S p o ns or. 
1 9 a. 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 a n d f or 1 5 da ys  after st o p pi n g of i n vesti gati o nal dr u g.   
Hi g hl y effecti ve c o ntrace pti o n met h o ds i ncl u de:  
•  T otal a bsti ne nce fr o m heter ose x ual i nterc o urse ( w he n t his is i n li ne wit h t he preferre d 
a n d us ual lifest yle of t he partici pa nt). Peri o dic a bsti ne nce (e. g., cale n dar, o v ulati o n, 
s y m pt ot her mal, p ost-o v ulati o n met h o ds) a n d wit h dra wal are n ot acce pta ble met h o d s 
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 bal li gati o n at least si x wee ks bef ore 
ta ki n g i n vesti gati o nal dr u g. I n case of o o p h orect o m y al o ne, o nl y w he n t he 
re pr o d ucti ve stat us of t he w o ma n has bee n c o nfir me d b y f oll o w u p h or m o ne le vel 
assess me nt. 
•  Male sterilizati o n (at least 6 m o nt hs pri or t o scree ni n g). F or fe male partici pa nts o n t he 
st u d y t he vasect o mize d male part ner s h o ul d be t he s ole part ner f or t hat partici pa nt . 

N o v arti s  
C o nfi d e nti al  
P a g e 6 3  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
•  Use of i njecte d or i m pla nte d h or m o nal met h o ds of c o ntrace pti o n or place me nt of a n 
i ntra uteri ne de vice (I U D) or i ntra uteri ne s yste m (I U S) or ot her f or ms of h or m o nal 
c o ntrace pti o n t hat ha ve c o m para ble efficac y (fail ure rate < 1 %), f or e xa m ple h or m o ne 
va gi nal ri n g or tra ns der mal h or m o ne c o ntrace pti o n.  
•  D ue t o its i n vitr o 
 C Y P 3 A 4 i n d ucti o n p ote ntial, D F V 8 9 0 ca n 
p ote ntiall y decrease s yste mic e x p os ure of se nsiti ve C Y P 3 A 4 s u bstrates b y 
a p pr o xi matel y -f ol d or s o me oral h or m o nal c o ntrace pti ves w hic h are C Y P 3 A 4 
s u bstrates (e. g., et hi n ylestra di ol), b y 
. T heref ore, oral h or m o ne-base d 
c o ntrace pti ves ma y n ot be c o nsi dere d as a hi g hl y effecti ve c o ntrace pti o n met h o d.  
If l ocal re g ulati o ns de viate fr o m t he c o ntrace pti o n met h o ds liste d a b o ve a n d re q uire m ore 
e xte nsi ve meas ures t o pre ve nt pre g na nc y, l ocal re g ulati o ns a p pl y a n d will be descri be d i n 
t he I C F. 
W o me n are c o nsi dere d p ost -me n o pa usal if t he y ha ve ha d 1 2 m o nt hs of nat ural 
(s p o nta ne o us) a me n orr hea wit h a n a p pr o priate cli nical pr ofile (e. g., a ge a p pr o priate, 
hist or y of vas o m ot or s y m pt o ms). W o me n are c o nsi dere d n ot of c hil d -beari n g p ote ntial if 
t he y are p ost -me n o pa usal or ha ve ha d s ur gical bilateral o o p h orect o m y ( wit h or wit h o ut 
h ysterect o m y), t otal h ysterect o m y or t u bal li gati o n at least si x wee ks a g o. I n t he case of 
o o p h orect o m y al o ne, o nl y w he n t he re pr o d ucti ve stat us of t he w o ma n has bee n c o nfir me d 
b y f oll o w u p h or m o ne le vel assess me nt is s he c o nsi dere d n ot of c hil d -beari n g 
p ote ntial.  Refer t o  Secti o n  8. 4. 3  ( Pre g na nc y a n d Assess me nts of Fertilit y).  
2 0.  Pre g na nt or n ursi n g (lactati n g) w o me n.  
2 1.  Hist or y or c urre nt dia g n osis of E C G a b n or malities i n dicati n g si g nifica nt safet y ris k f or 
partici pa nts partici pati n g i n t he st u d y s uc h as:  
•  C o nc o mita nt cli nicall y si g nifica nt car diac arr h yt h mias, e. g., s ustai ne d ve ntric ular 
tac h ycar dia, a n d cli nicall y si g nifica nt sec o n d or t hir d de gree A V bl oc k wit h o ut a 
pace ma ker  
•  Hist or y of fa milial l o n g Q T s y n dr o me or k n o w n fa mil y hist or y of T orsa des de P oi ntes  
2 2.  Hist or y of dr u g a b use or u n healt h y alc o h ol use wit hi n t he 1 2 m o nt hs pri or t o e x pecte d first 
d ose, or e vi de nce of s uc h a b use as i n dicate d b y t he la b orat or y assa ys c o n d ucte d at 
scree ni n g visit. 
U n healt h y alc o h ol use is defi ne d as a hist or y of, or c urre nt, alc o h ol mis use/a b use or “ Fi ve 
or m ore dri n ks o n t he sa me occasi o n o n eac h of 5 or m ore da ys i n t he past 3 0 da ys."  
2 3.  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 xci pie nts or t o dr u gs of 
si milar c he mical classes. 
2 4.  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 na mic effect has ret ur ne d t o baseli ne, w hic he ver is l o n ger.  
2 5.  If, i n a d diti o n t o pri mar y k nee oste oart hritis, s pi ne/ ha n d/s h o ul der/ hi p/f o ot/ ot her pri mar y 
oste oart hritis is prese nt, it s h o ul d ha ve bee n prese nt f or at least 3 m o nt hs pri or t o 
scree ni n g a n d s h o ul d be d oc u me nte d wit h a dia g n osis a n d s y m pt o ms as b y i n vesti g at or's 
j u d ge me nts. 
C CI
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 6 4  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
2 6.  Sec o n dar y oste oart hritis wit h hist or y or a n y e vi de nce i n t he p ote ntial tar get j oi nt of t he 
f oll o wi n g diseases: se ptic art hritis, i nfla m mat or y j oi nt disease, g o ut, rec urre nt e pis o des of 
pse u d o g o ut, Pa get's disease of b o ne, artic ular fract ure, oc hr o n osis, ac r o me gal y, 
he m oc hr o mat osis, Wils o n's disease, pri mar y oste oc h o n dr o mat osis, herita ble dis or ders, 
c olla ge n ge ne m utati o ns.  
2 7a.  
Partici pa nts recei vi n g c o nc o mita nt me dicati o ns t hat are k n o w n t o be str o n g or 
m o derate i n d ucers of c yt oc hr o me C Y P 2 C 9 e nz y me a n d/ or str o n g/ m o derate d ual i n hi bit ors 
of C Y P 2 C 9/ C Y P 3 A , str o n g or m o derate i n hi bit ors of C Y P 3 A a n d/ or str o n g i n d ucers of 
C Y P 3 A (see list of pr o hi bite d dr u gs: Secti o n  6. 2. 2 ) a n d t he treat me nt ca n n ot be 
disc o nti n ue d or s witc he d t o a differe nt me dicati o n wit hi n 5 half -li ves or 1 wee k 
( w hic he ver is l o n ger) pri or t o Da y 1 a n d f or d urati o n of t he st u d y.  
2 8.  Hist or y of 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 (as defi ne d bel o w) i ncl u di n g b ut n ot li mite d t o S G O T ( A S T), S G P T ( A L T), 
al kali ne p h os p hatase, ser u m bilir u bi n, al b u mi n a n d pr ot hr o m bi n ti me. T he I n vesti 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 meter ma y n ot e xcee d 2 x u p per li mit of n or mal ( U L N).  
3 1.  Li ve vacci nes wit hi n 4 wee ks of Da y 1 (i.e. first d ose of D F V 8 9 0).  
3 2.  K n o w n hist or y of re nal disease i ncl u di n g ne p hr olit hiasis.  
3 3.  A n y s ur gical or me dical c o n diti o n w hic h mi g ht si g nifica ntl y alter t he a bs or pti o n, 
distri b uti o n, meta b olis m, or e xcreti o n of dr u gs, or w hic h ma y je o par dize t he patie nt i n 
case of partici pati o n i n t he st u d y.  T he i n vesti gat or s h o ul d ma ke t his deter mi nati o n i n 
c o nsi derati o n of t he patie nt’s me dical hist or y a n d/ or cli nical or la b orat or y ass ess me nts, i n 
c o ns ultati o n wit h t he S p o ns or w he n necessar y.  
6  
St u d y tr e at m e nt( s) a n d c o n c o mit a nt t h er a p y  
6. 1  
D e s cri pti o n of St u d y tr e at m e nt s a n d tr e at m e nt ar m s  
6. 1. 1  
I n v e sti g ati o n al a n d c o ntr ol dr u g s 
T he i n vesti gati o nal dr u g D F V 8 9 0 will  be pre pare d b y t he s p o ns or as 1 0 a n d 2 5 m g ta blets. 
I n vesti gati o nal dr u g will be s u p plie d t o t he i n vesti gat or as d o u ble-bli n d  partici pa nt -s pecific 
kits. D F V 8 9 0 will be a d mi nistere d orall y wit h f o o d or s h ortl y after meal  t wice per da y 
a p pr o xi matel y 1 2 h o urs a part ( m or ni n g a n d e ve ni n g).  

N o v arti s  
C o nfi d e nti al  
P a g e 6 5  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
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 
Tr e at m e nt Titl e  
D F V 8 9 0  
D F V 8 9 0  
D F V 8 9 0 m at c hi n g 
pl a c e b o  
D F V 8 9 0 m at c hi n g 
pl a c e b o  
Tr e at m e nt 
D e s cri pti o n  
T a bl et, 1 0 m g, BI D  
T a bl et, 2 5 m g, BI D  
T a bl et, 1 0 m g, 
D F V 8 9 0 m at c hi n g 
pl a c e b o, BI D  
T a bl et, 2 5 m g, 
D F V 8 9 0 m at c hi n g 
pl a c e b o, BI D  
T y p e  
Dr u g  
Dr u g  
Dr u g  
Dr u g  
D o s e 
F or m ul ati o n  
T a bl et  
T a bl et  
T a bl et  
T a bl et  
U nit D o s e 
Str e n gt h( s)  
1 0 m g  
2 5 m g  
1 0 m g m at c hi n g 
pl a c e b o  
2 5 m g m at c hi n g 
pl a c e b o  
D o s a g e 
L e v el( s)  
1 0 m g BI D  
2 5 m g BI D  
1 0 m g m at c hi n g 
pl a c e b o BI D  
2 5 m g m at c hi n g 
pl a c e b o BI D  
R o ut e of 
A d mi ni str ati o n  
Or al  
Or al  
Or al  
Or al  
U s e  
e x p eri m e nt al  
e x p eri m e nt al  
pl a c e b o  
pl a c e b o  
I M P 
Y e s  
Y e s  
Y e s  
Y e s  
S o ur ci n g  
Pr o vi d e d c e ntr all y 
b y t h e s p o n s or  
Pr o vi d e d c e ntr all y b y 
t h e s p o n s or  
Pr o vi d e d c e ntr all y b y 
t h e s p o n s or  
Pr o vi d e d c e ntr all y b y 
t h e s p o n s or  
P a c k a gi n g a n d 
L a b eli n g  
St u d y tr e at m e nt 
will b e pr o vi d e d i n 
c o nt ai n er. S u p pl y 
t y p e i s d o u bl e 
bli n d e d p ati e nt 
s p e cifi c kit s. E a c h 
c o nt ai n er will b e 
l a b el e d a s 
r e q uir e d p er 
c o u ntr y 
r e q uir e m e nt. 
St u d y tr e at m e nt will 
b e pr o vi d e d i n 
c o nt ai n er. S u p pl y 
t y p e i s d o u bl e 
bli n d e d p ati e nt 
s p e cifi c kit s. E a c h 
c o nt ai n er will b e 
l a b el e d a s r e q uir e d 
p er c o u ntr y 
r e q uir e m e nt. 
St u d y tr e at m e nt will 
b e pr o vi d e d i n 
c o nt ai n er. S u p pl y 
t y p e i s d o u bl e 
bli n d e d p ati e nt 
s p e cifi c kit s. E a c h 
c o nt ai n er will b e 
l a b el e d a s r e q uir e d 
p er c o u ntr y 
r e q uir e m e nt. 
St u d y tr e at m e nt will 
b e pr o vi d e d i n 
c o nt ai n er. S u p pl y 
t y p e i s d o u bl e 
bli n d e d p ati e nt 
s p e cifi c kit s. E a c h 
c o nt ai n er will b e 
l a b el e d a s r e q uir e d 
p er c o u ntr y 
r e q uir e m e nt. 
6. 1. 2  
A d diti o n al st u d y tr e at m e nt s  
It is i m perati ve t o har m o nize a n d d oc u me nt partici pa nts’ pai n me dicati o n as it ca n p ote ntiall y 
c o nf o u n d res ults. T heref ore, o nl y t he use of paraceta m ol/aceta mi n o p he n, u p t o 3 0 0 0 m g/ da y, 
al o ne or i n c o m bi nati o n wit h l o w d ose c o dei ne, e. g., c o -c o da m ol, is al l o we d as basic 
( n o nresc ue) me dicati o n f or pai n c o ntr ol, re gar dless of t he ori gi n of t he pai n, u p u ntil Wee k 1 2. 
T his me dicati o n is herei n referre d t o as " basic pai n me dicati o n". T he basic pai n me dicati o n is 
c o nsi dere d t o be A x M P as per E U C T R Re g ulati o n ( E U) N o 5 3 6/ 2 0 1 4.  

N o v arti s  
C o nfi d e nti al  
P a g e 6 6  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
T he i n vesti gat or will eit her be s u p plie d wit h t he basic pai n me dicati o n or s o urce it l ocall y a n d 
be rei m b urse d b y t he s p o ns or f or its c ost, de pe n di n g o n t he c o u ntr y.  
At eac h st u d y visit ( Visit 1 - Wee k 1 2), partici pa nts will be pr o vi de d wit h a q ua ntit y of t he basic 
pai n me dicati o n, eit her t he paraceta m ol/aceta mi n o p he n or t he paraceta m ol/aceta mi n o p he n pl us 
c o dei ne c o m bi nati o n pr o d uct, t hat is esti mate d t o be s ufficie nt u ntil t he ne xt pla n ne d st u d y visit. 
T he i n vesti gat or will dis pe nse a k n o w n q ua ntit y of basic pai n me dicati o n at eac h visit a n d will 
f oll o w u p wit h a c o u nt of t he ret ur ne d pills at eac h s u bse q ue nt visit (starti n g at Visit 2), 
rec or di n g t he n u m ber of pills take n o n t he a p pr o priate case rec or d f or m. T he i n vesti gat or a n d 
partici pa nt ca n a gree t o s witc h fr o m o ne t o t he ot her t y pe of basic pai n me dicati o n, f or e xa m ple 
fr o m si n gle c o m p o u n d paraceta m ol/aceta mi n o p he n t o t he c o dei ne c o m bi nati o n pr o d uct or vice 
versa, if dee me d necessar y a n d pr o vi de d b ot h t y pes are a vaila ble t o t he i n vesti gat or. 
Partici pa nts w h o use ot her pai n me dicati o ns m ust be willi n g t o s witc h t o t he basic pai n 
me dicati o n at Scree ni n g (i ncl usi o n criteri o n).  
T he partici pa nt s h o ul d o nl y use t he basic pai n me dicati o n pr o vi de d b y t he i n vesti gat or, e ve n if 
he/s he t y picall y uses or p urc hases t he sa me ge neric c o m p o u n d pri vatel y.  
T he basic pai n me dicati o n ca n be ta ke n at a n y p oi nt i n t he st u d y, als o wit hi n 4 8 h o urs of a st u d y 
visit. T o t he e xte nt p ossi ble, n o ot her pai n me dicati o n s h o ul d be use d u p u ntil 
Wee k  1 2, 
see Secti o n  6. 2. 3  (resc ue me dicati o n i.e. c o nc o mita nt dr u gs t hat are all o we d b y pr ot oc ol, e. g., 
N S AI Ds or ot her n o n -o pi oi d a nal gesics, is n ot t o be ta ke n wit hi n 4 8 h or 5 half -li ves, w hic he ver 
is l o n ger, of P R O assess me nts). See Secti o n  6. 2. 3  f or i nf or mati o n o n h o w t o pr ocee d i n case 
me nti o ne d me dicati o ns were ta ke n wit hi n 4 8 h o urs fr o m t he visit.  
Partici pa nts will be pr o vi de d wit h a diar y i n w hic h t he y will d oc u me nt t heir dail y pai n 
( via N u meric Rati n g Scale) a n d t he use of (a n y) pai n me dicati o n fr o m scree ni n g u p t o Wee k  1 2, 
see Secti o n  8. 3. 1 . T he i n vesti gat or or dele gate s h o ul d re vie w t he pai n diar y at eac h visit t o 
e ns ure t he n u m ber of ret ur ne d basic pai n me dicati o n ta blets is reas o na ble c o m pare d t o t he 
d oc u me nte d use i n t he pai n diar y.  
T he use of basic pai n me dicati o n s h o ul d be d oc u me nte d i n t he c o nc o mita nt me dicati o n pa ge 
(i ncl u di n g A x M Ps) of t he C R F, i ncl u di n g f or w hic h i n dicati o n t he me dicati o n is ta ke n 
(e. g., tar get k nee pai n, hea dac he, bac k pai n). 
6. 1. 2. 1  
S u p pl y of a d diti o n al st u d y tr e at m e nt s  
T a bl e 6 -2  
B a si c p ai n m e di c ati o n  
M e di c ati o n ( N a m e 
a n d Str e n gt h)  
P h ar m a c e uti c al 
D o s a g e F or m  
R o ut e of 
A d mi ni str ati o n  
S u p pl y T y p e  
S u p pli er  S p o n s or 
( gl o b al or l o c al) 
P ar a c et a m ol/ a c et a
mi n o p h e n 5 0 0 m g  
T a bl et  
Or al u s e  
O p e n l a b el b ul k 
s u p pl y  
S p o n s or (l o c al)  or 
sit e  
P ar a c et a m ol/ a c et a
mi n o p h e n i n 
c o m bi n ati o n wit h 
l o w d o s e c o d ei n e 
5 0 0/ 3 0 m g  
T a bl et  
Or al u s e  
O p e n l a b el b ul k 
s u p pl y  
S p o n s or (l o c al)  or 
sit e  
T a bl et str e n gt h s c a n b e diff er e nt, d e p e n di n g o n t h e c o u ntr y. O nl y o n e or b ot h of t h e alt er n ati v e s m a y 
b e s u p pli e d t o t h e i n v e sti g at or sit e, d e p e n di n g o n t h e c o u ntr y.  

N o v arti s  
C o nfi d e nti al  
P a g e 6 7  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
T a bl e 6 -3  
A d diti o n al st u d y tr e at m e nt  
Tr e at m e nt Titl e  
P ar a c et a m ol/ a c et a mi n o p h
e n 5 0 0 m g  
P ar a c et a m ol/ a c et a mi n o p h
e n i n c o m bi n ati o n wit h 
l o w d o s e c o d ei n e 5 0 0/ 3 0 
m g  
V 0 8 C A 
P ar a m a g n eti c 
c o ntr a st m e di a 
( G a d oli ni u m b a s e d 
c o ntr a st a g e nt)  
Tr e at m e nt 
D e s cri pti o n  
5 0 0 m g T a bl et, u p t o 
3 0 0 0 m g p er d a y, a s n e e d e d  
5 0 0/ 3 0 m g 
p ar a c et a m ol/ c o d ei n e t a bl et, 
u p t o 3 0 0 0 m g/ 1 8 0 m g 
p ar a c et a m ol/ c o d ei n e a s 
n e e d e d  
IV  c o ntr a st a g e nt f or 
si n gl e i nj e cti o n at 
3 ml/ s e c  
T y p e  
dr u g  
dr u g  
dr u g  
D o s e F or m ul ati o n  
T a bl et  
T a bl et  
S ol uti o n f or i nj e cti o n  
U nit D o s e Str e n gt h( s)  
5 0 0 m g  
5 0 0 m g ( p ar a c et a m ol/ 3 0 m g 
c o d ei n e  
M ulti pl e, i n li n e wit h 
l o c al m ar k eti n g 
a ut h ori z ati o n.  
D o s a g e L e v el( s)  
u p t o 3 0 0 0 m g/ d a y  
u p t o 3 0 0 0 m g/ d a y al o n e or 
i n c o m bi n ati o n wit h l o w d o s e 
c o d ei n e  
m ulti pl e, a s p er l o c al 
g ui d eli n e s a n d 
cli ni c al pr a cti c e, i n 
li n e wit h t h e 
m ar k eti n g 
a ut h ori z ati o n of t h e 
di a g n o sti c dr u g  
R o ut e of 
A d mi ni str ati o n  
or al  
or al  
I V I nj e cti o n 
U s e  
B a c k gr o u n d i nt er v e nti o n  
b a c k gr o u n d i nt er v e nti o n  
di a g n o sti c  
A ut h ori z ati o n st at u s 
of t h e A x M P i n E E A  
Y e s  
Y e s  
Y e s  
S o ur ci n g  
l o c all y b y t h e st u d y sit e  
l o c all y b y t h e st u d y sit e  
L o c all y b y t h e st u d y 
sit e /i m a gi n g f a cilit y 
P a c k a gi n g a n d 
L a b eli n g  
Ori gi n al p a c k a gi n g.  
S u p pli e d l o c all y  a n d will b e 
l a b el e d a s p er c o u ntr y 
r e q uir e m e nt. 
Ori gi n al p a c k a gi n g.  
S u p pli e d l o c all y  a n d will b e 
l a b el e d a s p er c o u ntr y 
r e q uir e m e nt. 
Ori gi n al p a c k a gi n g, 
c o m p o u n d s s o ur c e d 
b y st u d y sit e/ i m a gi n g 
f a cilit y p er l o c al 
pr a cti c e  
N o ot her treat me nt be y o n d i n vesti gati o nal dr u gs, c o ntr ol dr u g a n d a d diti o nal st u d y treat me nt 
(as a u xiliar y me dici nal pr o d ucts) are pr o vi de d i n t his trial. T he c h oice of t he ga d oli ni u m-base d 
c o ntrast a ge nt is left t o t he st u d y site/i ma gi n g facilit y base d o n  l ocal practice, i n li ne wit h l ocal 
mar keti n g a ut h orizati o n a n d i ncl u de d as part of t he i ma gi n g pr oce d ure . 

N o v arti s  
C o nfi d e nti al  
P a g e 6 8  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
6. 1. 3  
Tr e at m e nt ar m s/ gr o u p  
Partici pa nts will be assi g ne d at t he Da y 1 visit t o o ne of t he f oll o wi n g 2 treat me nt gr o u ps i n a 
rati o of 1: 1. 
T a bl e 6 -4  
Tr e at m e nt Ar m( s)  
Ar m Titl e  
D F V 8 9 0 1 0 m g  
D F V 8 9 0 2 5 m g  
Pl a c e b o  
Ar m T y p e  
I n v e sti g ati o n al dr u g 
I n v e sti g ati o n al dr u g 
pl a c e b o  
Ar m D e s cri pti o n  
D F V 8 9 0 1 0 m g BI D 
fr o m D a y 1 u ntil D a y 
1 4 ( m or ni n g d o s e o nl y)  
D F V 8 9 0 2 5 m g BI D 
fr o m D a y 1 4 ( e v e ni n g 
d o s e) u ntil D a y 8 5 
( m or ni n g d o s e o nl y) 
M at c hi n g pl a c e b o BI D 
fr o m D a y 1 u ntil D a y 
8 5 ( m or ni n g d o s e o nl y)  
6. 2  
Ot h er tr e at m e nt( s)  
D DI wit h D F V 8 9 0 a s a vi cti m  
D F V 8 9 0 is e x pecte d t o be eli mi nate d mai nl y via he patic C Y P -me diate d meta b olis m wit h 
C Y P 2 C 9 ( 
) a n d C Y P 3 A 4  
) as t he mai n c o ntri b uti n g e nz y mes. D F V 8 9 0 ma y t heref ore 
be affecte d b y C Y P 2 C 9 a n d/ or C Y P 3 A 4 i nteracti o ns a n d t he effect de pe n ds o n C Y P 2 C 9 
ge n ot y pe. I n partic ular,  
•  f or patie nts w h o are C Y P 2 C 9 n or mal meta b olizers ( ge n ot y pes * 1 * 1, maj orit y of 
p o p ulati o n), c hr o nic d osi n g wit h d ual C Y P 2 C 9/ C Y P 3 A 4 i n d ucers is e x pecte d t o i n d uce 
b ot h e nz y mes, t here b y ma y re d uce D F V 8 9 0 dr u g e x p os ure b y a p pr o xi matel y -f ol d t o 
s u b-t hera pe utic le vels.  
 effects are f oresee n f or patie nts, w h o are p o or or 
i nter me diate meta b olizers of C Y P 2 C 9. 
•  c o-a d mi nistrati o n of D F V 8 9 0 wit h str o n g i n hi bit ors of C Y P 2 C 9 is e x pecte d t o re d uce 
e nz y matic meta b olic ca pacit y, t here b y ma y i ncrease D F V 8 9 0 dr u g e x p os ure b y 
a p pr o xi matel y -f ol d.  
•  w he n C Y P 2 C 9 n or mal meta b olizers are d ose d wit h str o n g/ m o derate C Y P 3 A i n hi bit ors or 
d ual m o derate i n hi bit ors of C Y P 2 C 9/ C Y P 3 A (e. g fl uc o naz ole), t he D F V 8 9 0 A U C is 
e x pecte d t o i ncrease o n a vera ge b y a p pr o xi matel y 
-f ol d, res pecti vel y. Hi g her 
D DI ri s k wit h C Y P i n hi bit ors is li kel y f or patie nts, w h o are p o or (
-f ol d) or 
i nter me diate (
-f ol d) C Y P 2 C 9 meta b olizers.  
D DI wit h D F V 8 9 0 a s p er p etr at or  
D ue t o its i n vitr o 
 C Y P 3 A 4 i n d ucti o n p ote ntial, D F V 8 9 0 ca n p ote ntiall y 
decrease s yste mic e x p os ure of se nsiti ve C Y P 3 A 4 s u bstrates b y a p pr o xi matel y 
-f ol d or s o me 
oral h or m o nal c o ntrace pti ves (e. g., et hi n ylestra di ol) b y 
. 
C o nsi deri n g D DI ris k, certai n c o nc o mita nt me dicati o ns w he n d ose d wit h D F V 8 9 0 are re q uire d 
t o be use d wit h ca uti o n or t he y are pr o hi bite d.  List of c o nc o mita nt me dicati o ns t o be use d wit h 
ca uti o n is prese nte d i n  Ta ble 6 -5  a n d pr o hi bite d dr u gs are liste d i n  Ta ble 6 -7  (please n ote t hat 
t he lists ma y n ot be c o m pre he nsi ve ). I n case of d o u bt, please c o ntact t he s p o ns or.  
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 6 9  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
6. 2. 1  
C o n c o mit a nt t h er a p y  
N S AI Ds 
or 
ot her 
n o n -o pi oi d 
a nal gesics 
are rec o m me n de d 
as resc ue 
me dicati o n 
(see Secti o n  6. 2. 3 ) b ut are n ot per mitte d f or basic pai n me dicati o n. Partici pa nts will be as ke d 
t o rec or d pai n a n d a nal gesic use i n a diar y fr o m scree ni n g a n d t hr o u g h o ut t he 1 2 wee ks 
treat me nt peri o d. 
T he i n vesti gat or m ust i nstr uct t he partici pa nt t o n otif y t he st u d y site a b o ut a n y ne w me dicati o ns 
he/s he ta kes after t he partici pa nt was e nr olle d i nt o t he st u d y.  
All prescri pti o n 
me dicati o ns, o ver -t he-c o u nter dr u gs a n d si g nifica nt n o n -dr u g t hera pies 
(i ncl u di n g p h ysical t hera p ya n d bl o o d tra nsf usi o ns) a d mi nistere d or ta ke n wit hi n t he ti mefra me 
defi ne d i n t he e ntr y criteria pri or t o t he start of t he st u d y a n d d uri n g t he st u d y, m ust be rec or de d 
o n t he C o nc o mita nt me dicati o ns/ Si g nifica nt n o n -dr u g t hera pies C R F.  
Me dicati o n e ntries s h o ul d be s pecific t o tra de na me, t he si n gle d ose a n d u nit, t he fre q ue nc y a n d 
r o ute of a d mi nistrati o n, t he start a n d disc o nti n uati o n date a n d t he reas o n f or t hera p y. 
Eac h c o nc o mita nt dr u g m ust be i n di vi d uall y assesse d a gai nst all e xcl usi o n criteria/ pr o hi bite d 
me dicati o n. If i n d o u bt, t he i n vesti gat or s h o ul d c o ntact t he N o vartis  me dical m o nit or 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, c o ntact N o vartis  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  
T o pical N S AI Ds a n d t o pical ster oi ds are all o we d d uri n g t he st u d y.  
Cli nical st u dies  t o i n vesti gate D DIs wit h C yt oc hr o me P 4 5 0 ( C Y P) s u bstrates/ m o d ulat ors a n d 
D F V 8 9 0 ha ve n ot bee n perf or me d yet. E val uati o n a n d rec o m me n dati o ns are base d o n i n vitr o / 
precli nical data a n d p h ysi ol o g y -base d P K si m ulati o ns, a n d t here are n o cli n ical data c o nfir mi n g 
w het her s uc h i nteracti o ns will occ ur i n partici pa nts, alt h o u g h ver y li kel y.  
I n vesti gat ors at t heir discreti o n 
ma y a d mi nister c o nc o mita nt 
me dicati o ns k n o w n t o be 
meta b olize d b y C Y P 3 A. Partici pa nts recei vi n g s uc h me dicati o ns ma y re q uire d ose titrati o n or 
i ncrease of t he c o nc o mita nt dr u g. Partic ularl y, ca uti o n is a d vise d 
w he n 
D F V 8 9 0 is 
c o-a d mi nistere d wit h dr u gs t hat are se nsiti ve s u bstrates of C Y P 3 A a n d/ or ha ve a narr o w 
t hera pe utic i n de x (Ta ble 6 -5 ).  
If it ca n n ot be re place d b y ot her me dicati o ns, i n vesti gat ors ma y, at t heir discreti o n, c o-
a d mi nister k n o w n str o n g or m o derate i n hi bit ors of C Y P 2 C 9, b ut t heir d urati o n s h o ul d be ke pt 
as s h ort as p ossi ble, a n d partici pa nts m ust be cl osel y m o nit ore d.  

N o v arti s  
C o nfi d e nti al  
P a g e 7 0  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
T a bl e 6 -5  
C o n c o mit a nt m e di c ati o n s t o b e u s e d wit h c a uti o n  
S e n siti v e s u b str at e s of C Y P 3 A  
a b e m a ci cli b,  
a c al a br uti ni b,  
ali s p ori vir,  
al m or e x a nt, 
alf e nt a nil, al p h a -di h y dr o er g o cr y pti n e, a pl a vir o c, a pr e pit a nt, 
a s u n a pr e vir, at a z a n a vir, at or v a st ati n, a v a n afil, a v a priti ni b, 
bl o n a n s eri n, b o s uti ni b, br e c a n a vir, bri g ati ni b, br oti z ol a m, 
b u d e s o ni d e,  
b u s pir o n e,  
c a b a zit a x el,  
c a pr a viri n e, 
c a s o pit a nt,  
c o bi ci st at,  
c o bi m eti ni b,  
c o ni v a pt a n, 
c y cl o s p ori n e, d a n o pr e vir, d arif e n a ci n, d ar u n a vir, d a s ati ni b, 
dr o n e d ar o n e, e b a sti n e, el etri pt a n, eli gl u st at, el vit e gr a vir, 
e ntr e cti ni b, e pl er e n o n e, e v er oli m u s, f el o di pi n e, fl uti c a s o n e, 
gr a z o pr e vir, i br uti ni b, , i s a v u c o n a z ol e, it a citi ni b, i v a br a di n e, 
i v a c aft or, l e v o m et h a d yl ( L A A M), l o mit a pi d e, l o pi n a vir, 
l o v a st ati n, l u m ef a ntri n e, l ur a si d o n e, m ar a vir o c, mi d a z ol a m, 
mi d o st a uri n,  
m or p h ot hi a di n,  
n al o x e g ol,  
n er ati ni b, 
ni s ol di pi n e,  
p arit a pr e vir,  
p er o s pir o n e,  
q u eti a pi n e, 
ri d af or oli m u s,  
s a q ui n a vir,  
sil d e n afil,  
si m e pr e vir, 
si m v a st ati n, 
sir oli m u s, t a cr oli m u s, ti c a gr el or, tili di n e, 
ti pr a n a vir, t ol v a pt a n, tri a z ol a m, 
u br o g e p a nt, 
uli pri st al, 
v ar d e n afil, v e n et o cl a x, vi cri vir o c, vil a pri s a n, v o cl o s p o ri n, 
v ori c o n a z ol e, z a n u br uti ni b  
N arr o w th er a p e uti c i n d e x s u b str at e s of 
C Y P 3 A  
a b e m a ci cli b,  
a c al a br uti ni b ,  
al e cti ni b  
a mi o d ar o n e, 
a mitri pt yli n e, a st e mi z ol e, a xiti ni b, b ari citi ni b, b o s uti ni b, 
bri g ati ni b,  
c a b a zit a x el,  
c a b o z a nti ni b,  
c eriti ni b, 
cl o mi pr a mi n e ,  
c o bi m eti ni b, 
c o ni v a pt a n ,  
c o p a nli si b, 
cri z oti ni b,  
c y cl o s p ori n e,  
d a br af e ni b, 
d a s ati ni b , 
di h y dr o er g ot a mi n e, d o c et a x el,  dr o n e d ar o n e , e ntr e cti ni b , 
er d afiti ni b,  er g ot a m i n e, e v er oli m u s , i mi pr a mi n e, i x a z o mi b, 
l o mit a pi d e, mi d o st a uri n, n er ati ni b , nil oti ni b , p a n o bi n o st at, 
p e xi d arti ni b, pi m o zi d e, p o n ati ni b , q ui ni di n e, r e g or af e ni b, 
r o mi d e p si n, 
sir oli m u s, 
s o ni d e gi b, 
sor af e ni b , 
s u niti ni b, 
t a cr oli m u s, t a m o xif e n, te m sir oli m u s , t ol v a pt a n, tr a b e ct e di n, 
v e n et o cl a x, vi n bl a sti n e , z a n u br uti ni b 
Str o n g i n hi bit or s of C Y P 2 C 9  
mi c o n a z ol e, s ulf a p h e n a z ol e, t a si s ul a m  
M o d er at e i n hi bit or s of C Y P 2 C 9  
a mi o d ar o n e,  
at a ci g u at,  
a z a pr o p a z o n e,  
b u c ol o m e, 
b e n z br o m ar o n e,  
mil k  
t hi stl e  
( sil y m ari n,  
sili bi ni n) 1 , 
niti si n o n e , o x a n dr ol o n e, p h e n yl b ut a z o n e, pi p eri n e 2 , ti e nili c 
a ci d  
1  H er b al pr o d u ct  
2  F o o d pr o d u c t 

N o v arti s  
C o nfi d e nti al  
P a g e 7 1  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
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 bel o w ta ble are n ot all o we d f or t he d urati o n i n dicate d. 
T a bl e 6 -6  
Pr o hi bit e d m e di c ati o n  
M e di c ati o n  
Pr o hi biti o n p eri o d  
A cti o n t a k e n  
L o c al i. a. tr e at m e nt i nt o t h e k n e e, 
i n cl u di n g b ut n ot li mit e d t o 
h y al or o ni c a ci d, 
vi s c o s u p pl e m e nt ati o n a n d 
c orti c o st er oi d s ( st er oi d i nj e cti o n s 
i nt o ot h er j oi nt s ar e pr o hi bit e d fr o m 
S cr e e ni n g)  
1 2 w e e k s pri or t o D a y 1 t o w e e k 1 2 
vi sit (i n cl u si v e)  
Di s c o nti n u e st u d y tr e at m e nt a n d 
r e p ort pr ot o c ol d e vi ati o n 
Or al c orti c o st er oi d s > 5 m g/ d a y f or 
m or e t h a n 1 4 c o n s e c uti v e d a y s  
4 w e e k s pri or t o D a y 1 t o W e e k 1 2 
vi sit (i n cl u si v e)  
Di s c o nti n u e st u d y tr e at m e nt a n d 
r e p ort pr ot o c ol d e vi ati o n 
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  
Fr o m s cr e e ni n g t o  W e e k 1 2 vi sit 
(i n cl u si v e) 
M u st b e r e c or d e d o n C o n c o mit a nt 
m e di c ati o n s/ Si g nifi c a nt n o n -dr u g 
t h er a pi e s s e cti o n of e C R F  
R e p ort pr ot o c ol d e vi ati o n  
Di a c er ei n/ di a c et ylr h ei n of t h e cl a s s 
a nt hr a q ui n o n e  
1 2 w e e k s pri or t o S cr e e ni n g vi sit t o  
W e e k 1 2 vi sit (i n cl u si v e)  
Di s c o nti n u e st u d y tr e at m e nt a n d 
r e p ort pr ot o c ol d e vi ati o n 
I n d o m et h a ci n 
2 w e e k s pri or t o S cr e e ni n g vi sit t o  
W e e k 1 2 vi sit (i n cl u si v e)  
Di s c o nti n u e st u d y tr e at m e nt a n d 
r e p ort pr ot o c ol d e vi ati o n 
A c et yl s ali c yli c a ci d > 3 2 5 m g/ d a y or 
a n y s y st e mi c N S AI D , s el e cti v e 
C O X -2 i n hi bit or or ot h er n o n -o pi oi d 
a n a g e si c  i n cl u di n g c o m bi n ati o n 
dr u g s wit h c o d ei n e or c aff ei n e 
ot h er t h a n t h e tri al r e s c u e 
m e di c ati o n ( S e e S e cti o n  6. 2. 3 ). 
T o pi c al N S AI D s i s p er mitt e d  
Fr o m S cr e e ni n g t o  W e e k 1 2 vi sit 
(i n cl u si v e) 
M u st b e r e c or d e d o n t h e 
C o n c o mit a nt 
m e di c ati o n s/ Si g nifi c a nt n o n -dr u g 
t h er a pi e s s e cti o n of e C R F 
R e p ort pr ot o c ol d e vi ati o n a n d 
r e s c h e d ul e p ai n-r el at e d 
a s s e s s m e nt s if t a k e n wit hi n t h e 
l a st 4 8 h o ur s or fi v e h alf -lif e 
( w hi c h e v er i s l o n g er * 
P ar a c et a m ol/ a c et a mi n o p h e n > 3 0 0
0 m g p er d a y ( S e e  S e cti o n  6. 2. 3 ) 
Fr o m S cr e e ni n g vi sit t o E o S  
M u st b e r e c or d e d o n t h e 
C o n c o mit a nt 
m e di c ati o n s/ Si g nifi c a nt n o n -dr u g 
t h er a pi e s s e cti o n of e C R F 
R e p ort pr ot o c ol d e vi ati o n a n d 
r e s c h e d ul e p ai n-r el at e d 
a s s e s s m e nt s if t a k e n wit hi n t h e 
l a st 4 8 h o ur s* 
O pi oi d s, eit h er or al (i. e., tr a m a d ol) 
or tr a n s d er m al (i. e., f e nt a n yl 
p at c h e s) f or m ul ati o n s e x c e pt or al 
l o w d o s e c o d ei n e c o m bi n ati o n 
dr u g s  
Fr o m S cr e e ni n g vi sit t o  W e e k 1 2 
vi sit (i n cl u si v e)  
M u st b e r e c or d e d o n t h e 
C o n c o mit a nt 
m e di c ati o n s/ Si g nifi c a nt n o n -dr u g 
t h er a pi e s s e cti o n of e C R F 
R e p ort pr ot o c ol d e vi ati o n a n d 
r e s c h e d ul e p ai n-r el at e d 
a s s e s s m e nt s if t a k e n wit hi n t h e 
l a st 4 8 h o ur s or fi v e h alf -lif e 
( w hi c h e v er i s l o n g er * 
A n y bi ol o gi c dr u g  i nt erf eri n g wit h 
i m m u n e p at h w a y s, o st e o art hriti s 
pr o c e s s e s/ c artil a g e  or p ai n  
2 6 w e e k s pri or t o D a y 1 u ntil  
W e e k 1 2 vi sit (i n cl u si v e)  
Di s c o nti n u e st u d y tr e at m e nt a n d 
r e p ort pr ot o c ol d e vi ati o n 

N o v arti s  
C o nfi d e nti al  
P a g e 7 2  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
M e di c ati o n  
Pr o hi biti o n p eri o d  
A cti o n t a k e n  
C e ntr all y a cti n g a n al g e si c s ( e. g., 
d ul o x eti n e, m e di c al m arij u a n a a n d 
C B D oil, n e ur ol e pti c s or ot h er 
p s y c h o a cti v e m e di c ati o n ( u nl e s s 
pr e s cri b e d f or i n s o m ni a a n d d o s e d 
a c c or di n gl y)  
T ol p eri s o n a s c e ntr all y a cti n g 
m u s cl e r el a x a nt i s all o w e d, f or 
ot h er s u b st a n c e s pl e a s e di s c u s s 
wit h t h e s p o n s or t o e n s ur e n o 
di sti n ct i m p a ct o n p ai n pr o c e s si n g.  
1 2 w e e k s pri or t o D a y 1 u ntil  
W e e k 1 2 vi sit (i n cl u si v e)  
M u st b e r e c or d e d o n t h e 
C o n c o mit a nt 
m e di c ati o n s/ Si g nifi c a nt n o n -dr u g 
t h er a pi e s s e cti o n of e C R F 
R e p ort pr ot o c ol d e vi ati o n a n d 
r e s c h e d ul e p ai n-r el at e d 
a s s e s s m e nt s if t a k e n wit hi n t h e 
l a st 4 8 h o ur s* 
I n hi bit or s a n d i n d u c er s of C Y P 3 A 
or i n d u c er s of C Y P 2 C 9 a c c or di n g 
t o T a bl e 6 -7  
1 w e e k or at l e a st 5 ti m e s t h e h alf -
lif e of t h e m e di c ati o n ( w hi c h e v er i s 
l o n g er) pri or t o D a y 1 u ntil  W e e k 
1 2 vi sit (i n cl u si v e)  
Di s c o nti n u e st u d y tr e at m e nt a n d 
r e p ort pr ot o c ol d e vi ati o n 
 
* Pai n -relate d assess me nts t hat s h o ul d be resc he d ule d if pr o hi bite d me dicati o ns were ta ke n 
wit hi n 4 8 h o urs  of t he visit refer t o N R S Pai n a n d  K O O S. T he assess me nts s h o ul d be 
resc he d ule d t o t he first p ossi ble ti me p oi nt o utsi de t he 4 8-h o ur li mit (after last i nta ke), e ve n if 
t his p us hes t he c o m pleti o n t o o utsi de t he visit wi n d o w s pecifie d i n Ta ble 8 -1 . T he resc he d ule d 
assess me nts ma y be d o ne as a re m ote c o ntact, i n w hic h case t he site pers o n nel m ust re me m ber 
t o pr o vi de t he relate d P R Os t o t he partici pa nt at t he c urre nt visit. Bef ore t he pai n assess me nts 
are c o m plete d at t he resc he d ule d ti me p oi nt, t he res p o nsi ble site staff me m ber s h o ul d e ns ure 
a n y of t he rele va nt pr o hi bite d me dicati o ns were n ot a gai n ta ke n wit hi n 4 8 h o urs of t he c o ntact.  
T a bl e 6 -7  
Pr o hi bit e d dr u g s d u e t o D DI ( C Y P 3 A a n d C Y P 2 C 9 m o d ul at or s)  
C at e g or y of 
i nt er a cti o n 
Dr u g N a m e s  
Str o n g i n hi bit or s of 
C Y P 3 A  
b o c e pr e vir, c eriti ni b, cl arit hr o m y ci n, c o bi ci st at, c o ni v a pt a n, d a n o pr e vir/rit o n a vir 3 , 
el vit e gr a vir/rit o n a vir 3 , gr a p efr uit j ui c e2 , i d el ali si b, i n di n a vir, i n di n a vir/rit o n a vir3 , 
itr a c o n a z ol e, j o s a m y ci n, k et o c o n a z ol e, kr a z ati, l o pi n a vir/rit o n a vir3 , mi b efr a dil, 
mif e pri st o n e, n ef a z o d o n e, n elfi n a vir,  o m bit a s vir/ p arit a pr e vir/ d a s a b u vir/rit o n a vir ( Vi e kir a 
P a k) 3 , p o s a c o n a z ol e, ri b o ci cli b, rit o n a vir, s a q ui n a vir, s a q ui n a vir/rit o n a vir3 , t el a pr e vir, 
t elit hr o m y ci n, ti pr a n a vir/rit o n a vir3 , tr ol e a n d o m y ci n, t u c ati ni b, v ori c o n a z ol e 
M o d er at e i n hi bit or s 
of C Y P 3 A  
a pr e pit a nt, a m pr e n a vir, at a z a n a vir,  at a z a n a vir/rit o n a vir 3 , c a s o pit a nt, ci m eti di n e, 
ci pr ofl o x a ci n, cri z oti ni b, d ar u n a vir, d ar u n a vir/rit o n a vir 3 , dilti a z e m, dr o n e d ar o n e, 
d u v eli si b, er yt hr o m y ci n, f al d a pr e vir, f e dr ati ni b, fl u c o n a z ol e, gr a p efr uit j ui c e, i m ati ni b, 
i s a v u c o n a z ol e, i str a d ef ylli n e, l ef a m uli n, l et er m o vir, M a g n oli a vi n e (S c hi s a n dr a 
s p h e n a nt h er a )1 , n et u pit a nt, nil oti ni b, r a v u c o n a z ol e, s u nl e n c a, t ofi s o p a m, v er a p a mil, 
v o x el ot or  
Str o n g i n d u c er s of 
C Y P 2 C 9  
N o n e r e p ort e d t o d at e  
M o d er at e i n d u c er s 
of C Y P 2 C 9  
e n z al ut a mi d e, rif a m pi ci n  
Str o n g i n d u c er s of 
C Y P 3 A  
a p al ut a mi d e, a v a si mi b e, c ar b a m a z e pi n e, e n z al ut a mi d e, i v o si d e ni b, 
l u m a c aft or, mit ot a n e, p h e n yt oi n, rif a m pi ci n, rif a p e nti n e, St.  J o h n’ s w ort ( H y p eri c u m 
p erf or at u m )1  
1  H er b al pr o d u ct  
2  T h e eff e ct of gr a p efr uit j ui c e v ari e s wi d el y a m o n g br a n d s a n d i s c o n c e ntr ati o n -, d o s e-, a n d pr e p ar ati o n-d e p e n d e nt. 
St u di e s h a v e s h o w n t h at it c a n b e cl a s sifi e d a s a “ str o n g C Y P 3 A i n hi bit or” w h e n a c ert ai n pr e p ar ati o n w a s u s e d 
( e. g., hi g h d o s e, d o u bl e str en gt h) or a s a “ m o d er at e C Y P 3 A i n hi bit or” w h e n a n ot h er pr e p ar ati o n w a s u s e d ( e. g., l o w 
d o s e, si n gl e str e n gt h).  
3  c o m bi n ati o n t h er a p y  

N o v arti s  
C o nfi d e nti al  
P a g e 7 3  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
D ue t o 
D DI ris k, 
m o d ulat ors (str o n g or 
m o derate i n d ucers) of C Y P 2 C 9 a n d/ or d ual 
str o n g/ m o derate i n hi bit ors of C Y P 2 C 9/ C Y P 3 A, str o n g or m o derate i n hi bit ors of C Y P 3 A a n d/ or 
str o n g i n d ucers of C Y P 3 A a n d oral h or m o ne-base d c o ntrace pti ves are pr o hi bite d (f or detaile d 
list see Ta ble 6 -7 ).  
N ote t hat if pr o hi bite d me dicati o ns were ta ke n wit hi n 4 8 h o urs or fi ve half -li ves ( w hic he ver is 
l o n ger) of Scree ni n g or Baseli ne visit t he n t he e ntire visit will ha ve t o be resc he d ule d wit h a 
was h o ut peri o d of a mi ni m u m of 4 8 h or fi ve half -li ves ( w hic he ver is l o n ger) f or t he a b o ve-
me nti o ne d pr o hi bite d me dicati o ns.  
E xce pt f or me dicati o n t hat ma y be re q uire d t o treat a d verse e ve nts a n d sta n dar d of care 
me dicati o n i n li ne wit h i ncl usi o n a n d e xcl usi o n criteria, n o me dicati o n ot her t ha n st u d y dr u g 
will be all o we d fr o m Scree ni n g visit or d osi n g o n Da y 1 u ntil E o S.  
C o nsi deri n g D DI ris k, s h o ul d a partici pa nt ha ve a n i nci de ntal a n d li mite d nee d f or a pr o hi bite d 
me dicati o n ( Ta ble 6 -6 , Ta ble 6 -7 ) t o be ta ke n wit hi n t he restricte d ti mefra me, i n vesti gat ors 
s h o ul d disc uss t he case wit h t he s p o ns or. T he a d mi nistrati o n of a n y pr o hi bite d c o nc o mita nt 
me dicati o n ma y re q uire t he partici pa nt t o be wit h dra w n or D F V 8 9 0 treat me nt t o be p ut o n h ol d.  
N o li ve vacci nati o ns are per mitte d wit hi n 4 wee ks pri or t o Da y 1 (first d ose of D F V 8 9 0), u ntil 
st u d y c o m pleti o n. A p pr o ve d kille d, i nacti vate d, pe pti de, de o x yri b o n ucleic aci d ( D N A) a n d 
ri b o n ucleic aci d ( R N A) vacci nes ma y be per mitte d acc or di n g t o t he i n vesti gat or’s discreti o n 
a n d per l ocal g ui da nce.  
6. 2. 3  
R e s c u e m e di c ati o n  
If 
a de q uate 
pai n 
c o ntr ol 
is 
n ot 
ac hie ve d 
wit h 
basic 
pai n 
me dicati o n 
( paraceta m ol/aceta mi n o p he n al o ne or i n c o m bi nati o n wit h l o w-d ose c o dei ne as descri be d a b o ve 
i n Secti o n  6. 1. 2 ), t he n N S AI Ds or ot her n o n -o pi oi d a nal gesics will be per mitte d as resc ue 
me dicati o n  f or u p t o t hree o ut of se ve n c o nsec uti ve da ys, b ut m ust n ot be ta ke n wit hi n 4 8 h o urs 
or fi ve half -li ves, w hic he ver is l o n ger, pri or t o a n y pai n relate d assess me nts ( N R S Pai n or 
K O O S). I n t he e ve nt t hat N S AI Ds are ta ke n wit hi n 4 8 h o urs of a st u d y visit, please refer t o 
S ecti o n  6. 2. 2 . 
Resc ue me dicati o n will n ot be pr o vi de d b y t he S p o ns or.  
Decisi o ns re gar di n g s pecific N S AI Ds or ot her n o n -o pi oi d me dicati o n t o be use d as resc ue 
me dicati o n s h o ul d be ma de b y t he site Pri nci pal I n vesti gat or ( PI) , base d o n l ocal practice a n d 
i n di vi d ual partici pa nt nee ds. The ma xi m u m d ose s h o ul d n ot e xcee d t he a p pr o ve d d ose i n eac h 
c o u ntr y.  
All o wa ble treat me nt f or s ki n ras h is descri be d i n  Secti o n  6. 6. 2 . 
A n y use of resc ue me dicati o n m ust be rec or de d o n t he  a p pr o priate C R F.  
6. 2. 4  
R e stri cti o n f or st u d y p arti ci p a nt s  
F or t he d urati o n of t he st u d y, partici pa nts s h o ul d be i nf or me d a n d re mi n de d of t he restricti o ns 
o utli ne d i n t his secti o n.  
A n y n o n -dr u g treat me nts (i.e., p h ysi ot hera p y) 
m ust be re p orte d i n t he 
C o nc o mita nt 
me dicati o ns/ Si g nifica nt n o n -dr u g t hera pies e C R F.  

N o v arti s  
C o nfi d e nti al  
P a g e 7 4  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
6. 2. 4. 1  
Di et ar y r e stri cti o n s a n d s m o ki n g  
1.  N o ci garettes/ use of nic oti ne pr o d ucts are all o we d d uri n g t he sta y at t he i n vesti gati o nal 
site.  
2.  A ma xi m u m of 2 u nits ( 2 0 m L) p ure alc o h ol per da y is all o we d i n t he last 4 8 h o urs pri or 
t o eac h st u d y visit (e. g. 3 3 0 m L of beer ( 5 % alc o h ol c o nte nt) is e q ui vale nt t o a p pr o x. 
1. 7  u nits)  
3.  Gra pefr uit or gra pefr uit j uice s h o ul d be a v oi de d bet wee n Baseli ne a n d E o S.  
4.  St u d y treat me nt will be ta ke n t wice dail y 1 2 h a part wit h t he meal or  s h ortl y after 
c o m pleti o n of t he meal i n t he m or ni n g e. g., at 7 a. m. a n d i n t he e ve ni n g e. g., at 7 p. m. 
( wit h/after brea kfast a n d di n ner) 
6. 2. 4. 2  
Ot h er r e stri cti o n s  
•  N o u n us ual stre n u o us acti vities ca usi n g hea v y l oa di n g or ra pi d m o ve me nts/r otati o ns of t he 
k nee are all o we d fr o m 4 8 h o urs pri or t o first d osi n g u ntil after E o S.  
•  Partici pa nts will be re q uire d t o a d here t o t he meas ures a n d pr oce d ures o utli ne d b y t he 
st u d y site, t o pre ve nt S A R S-C o V -2 i nfecti o ns a m o n g trial partici pa nts a n d cli nical site 
staff. 
6. 3  
P arti ci p a nt n u m b eri n g, tr e at m e nt a s si g n m e nt, r a n d o mi z ati o n  
6. 3. 1  
P arti ci p a nt n u m b eri n g  
Eac h partici pa nt is i de ntifie d i n t he st u d y b y a Partici pa nt N u m ber ( Partici pa nt N o.), t hat is 
assi g ne d w he n t he partici pa nt is e nr olle d f or scree ni n g a n d is retai ne d f or t he partici pa nt 
t hr o u g h o ut his/ her partici pati o n i n t he trial. A ne w Partici pa nt N o. will be assi g ne d at e ver y 
s u bse q ue nt e nr oll me nt if t he partici pa nt is re-scree ne d. T he Partici pa nt N o. c o nsists of t he 
Ce nter N u m ber ( Ce nter N o.) (as assi g ne d b y N o vartis t o t he i n vesti gati ve site) wit h a se q ue ntial 
partici pa nt n u m ber s uffi xe d t o it, s o t hat eac h partici pa nt’s partici pati o n is n u m bere d u ni q uel y 
acr oss t he e ntire data base. U p o n si g ni n g t he i nf or me d c o nse nt f or m, t he partici pa nt is assi g ne d 
t o t he ne xt se q ue ntial Partici pa nt N o. a vaila ble. 
A ne w I C F will nee d t o be si g ne d if t he i n vesti gat or c h o oses t o re -scree n t he partici pa nt after a 
partici pa nt has scree n faile d, a n d t he partici pa nt will be assi g ne d a ne w Partici pa nt N o.  
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 Da y 1, all eli gi ble partici pa nts will be ra n d o mize d via N o vartis I nteracti ve Res p o nse 
Tec h n ol o g y ( NI R T) t o o ne of t he treat me nt ar ms. T he i n vesti gat or or his/ her dele gate will 
c o ntact t he NI R T after c o nfir mi n g t hat t he partici pa nt f ulfills all t he i ncl u si o n/e xcl usi o n criteria. 
T he NI 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 n u m ber f or t he first pac ka ge 
of st u d y treat me nt t o be dis pe nse d t o t he partici pa nt.  
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 pa nts a n d i n vesti gat or staff. 
A  partici pa nt ra n d o mizati o n list will be pr o d uce d b y t he NI R T pr o vi der usi n g a  vali date d 
s yste m t hat a ut o mates t he ra n d o m assi g n me nt of partici pa nt n u m bers t o ra n d o mizati o n 

N o v arti s  
C o nfi d e nti al  
P a g e 7 5  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
n u m bers. T hese 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 se parate me dicati o n list will be pr o d uce d u n der t he 
res p o nsi bilit y of N o vartis Gl o bal Cli nical S u p pl y ( G C S) usi n g a vali date d s yste m t hat 
a ut o mates t he ra n d o m assi g n me nt of me dicati o n n u m bers t o pac ks c o ntai ni n g t he st u d y 
treat me nt. 
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  
T his is a partici pa nt a n d i n vesti gat or -bli n de d st u d y. Partici pa nts a n d i n vesti gat ors will re mai n 
bli n de d t o st u d y treat me nt t hr o u g h o ut t he st u d y, e xce pt w here i n dicate d bel o w.  
T he i de ntit y of t he treat me nts will be c o nceale d b y t he use of st u d y dr u gs t hat are all i de ntical 
i n pac ka gi n g, la beli n g, sc he d ule of a d mi nistrati o n, a p peara nce, a n d o d or. 
Sit e st aff  
Wit h t he e xce pti o n of a n y u n bli n de d site staff i de ntifie d bel o w, all site staff (i ncl u di n g st u d y 
i n vesti gat or, st u d y n urse a n d O H Ps) will be bli n de d t o st u d y treat me nt t hr o u g h o ut t he st u d y. 
U n bli n di n g a si n gle partici pa nt at site f or safet y reas o ns ( necessar y f or partici pa nt ma na ge me nt) 
will occ ur via a n e mer ge nc y s yste m i n place at t he site.  
S p o n s or st aff or d el e g at e  
T he f oll o wi n g u n bli n de d s p o ns or r oles are re q uire d f or t his st u d y  
•  U n bli n de d sa m ple a nal yst(s) ( P K, P D)  
T he sa m ple a nal ysts will recei ve a c o p y of t he ra n d o mizati o n sc he d ule ( via re q uest t o t he 
Ra n d o mizati o n Office), t o facilitate a nal ysis of t he sa m ples. T he sa m ple a nal ysts will pr o vi de 
t he sa m ple data t o t he st u d y tea m u n der bli n de d c o n diti o ns u nless ot herwise all o we d.  
T he st u d y statisticia n will be a ble t o access t he ra n d o mizati o n list f or i nteri m a nal yses a n d is 
all o we d t o s hare u n bli n de d i nf or mati o n wit h t he rest of t he cli nical tea m as a p pr o priate f or 
i nter nal decisi o n p ur p oses, as o utli ne d i n Ta ble 6 -8 . F or e xa m ple, u n bli n de d s u m maries a n d 
u n bli n de d i n di vi d ual data ca n be s hare d wit h t he tea m f or i nteri m a nal yses.  
St u d y pr o gra m mers a n d ot her pers o n nel i n v ol ve d i n st u d y data a nal ysis (e. g., bi o mar ker e x pert) 
are all o we d t o access treat me nt assi g n me nt i nf or mati o n f or t he p ur p ose of c o n d ucti n g i nteri m 
a nal yses. 
T he cli nical trial tea m is all o we d t o s hare u n bli n de d res ults wit h ot her s p o ns or staff (e. g., 
decisi o n b oar ds) as re q uire d f or i nter nal decisi o n ma ki n g o n t he st u d y or t he pr oject at t he ti me 
of i nteri m a nal yses w hile t he st u d y is o n g oi n g.  
All u n bli n de d pers o n nel will ot her wise kee p ra n d o mizati o n lists a n d data or i nf or mati o n t hat 
c o ul d u n bli n d ot her st u d y tea m me m bers c o nfi de ntial a n d sec ure e xce pt as descri be d a b o ve.  
F oll o wi n g fi nal data base l oc k all r oles ma y be c o nsi dere d u n bli n de d.  

N o v arti s  
C o nfi d e nti al  
P a g e 7 6  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
T a bl e 6 -8  
Bli n di n g l e v el s  
R ol e  
Ti m e or E v e nt  
R a n d o mi z ati o n 
li st g e n er at e d 
Tr e at m e nt 
all o c ati o n & 
d o si n g  
S af et y e v e nt 
( si n gl e s u bj e ct 
u n bli n d e d)  
I nt eri m 
A n al y si s & 
d o s e e s c al ati o n  
P arti ci p a nt s  
B  
B  
UI  
B  
Sit e st aff (i n cl u di n g O H P)  
B  
B  
UI  
B  
Dr u g S u p pl y a n d 
R a n d o mi z ati o n Offi c e  
UI  
UI  
UI  
UI  
St ati sti ci a n/ st ati sti c al 
pr o gr a m m er/ d at a a n al y st s  
B  
B  
UI  
UI  
U n bli n d e d s p o n s or st aff 
( s e e t e xt f or d et ail s) 
B  
UI  
UI  
UI  
All ot h er s p o n s or st aff n ot 
i d e ntifi e d a b o v e 
B  
B  
UI  
UI  
B R e m ai n s bli n d e d  
UI All o w e d t o b e u n bli n d e d o n i n di vi d u al p ati e nt l e v el  
6. 5  
D o s e e s c al ati o n a n d d o s e m o difi c ati o n  
I n vesti gati o nal or ot her st u d y treat me nt d ose a dj ust me nts a n d/ or i nterr u pti o ns are n ot per mitte d. 
6. 5. 1  
D o s e e s c al ati o n g ui d eli n e s  
Partici pa nts ra n d o mize d t o t he D F V 8 9 0 treat me nt ar m will recei ve 1 0 m g oral D F V 8 9 0 t wice 
dail y fr o m Da y 1 t o Da y 1 4 ( m or ni n g d ose o nl y). Pr o vi de d t he treat me nt was well t olerate d a n d 
base d o n t he I n vesti gat or's j u d ge me nt, t he y will start ta ki n g a t otal dail y d ose of 5 0 m g ( 2 5  m g 
b.i. d.) of D F V 8 9 0 o n Da y 1 4 (e ve ni n g d ose) f or 1 0 wee ks ( o n Da y 8 4 o nl y t he m or ni n g d ose 
will be ta ke n).  
6. 5. 1. 1  
St arti n g d o s e  
T he starti n g d ose f or D F V 8 9 0 will be 1 0 m g b.i. d. f or 2 wee ks ( 1 4 da ys). N ote t hat o n Da y  1 4 
t he 1 0 m g d ose will o nl y be ta ke n i n t he m or ni n g. 
6. 5. 1. 2  
Pr o vi si o n al d o s e l e v el s  
Ta ble 6 -9  descri bes t he starti n g d ose a n d t he d ose le vels t hat ma y be e val uate d d uri n g t his trial.  
T a bl e 6 -9  
Pr o vi si o n al d o s e l e v el s  
D o s e l e v el  
Pr o p o s e d d ail y d o s e  
I n cr e m e nt fr o m pr e vi o u s 
d o s e  
1.  
2 0 m g ( a s 1 0 m g b.i. d.)  
St arti n g d o s e  
2.  
5 0 m g ( a s 2 5 m g b.i. d.)  
2 5 0 %  

N o v arti s  
C o nfi d e nti al  
P a g e 7 7  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
Partici pa nts will be ra n d o mize d i n a 1: 1 rati o t o recei ve D F V 8 9 0 or place b o f or 1 2 wee ks.  
Partici pa nts ra n d o mize d t o t he D F V 8 9 0 ar m will recei ve:  
1 0 m g oral D F V 8 9 0 t wice dail y f or 2 wee ks ( fr o m Da y 1 t o Da y 1 4 m or ni n g d ose), f oll o we d 
b y 2 5 m g oral D F V 8 9 0 t wice dail y f or 1 0 wee ks (fr o m Da y 1 4 e ve ni n g d ose t o Da y 8 4). N ote 
t hat o n Da y 8 4 o nl y t he m or ni n g d ose will be ta ke n.  
O n Da y 1, after t he first d ose i nta ke, t he partici pa nt m ust sta y o nsite f or o bser vati o n as per l ocal 
practice a n d i n vesti gat or decisi o n b ut f or a mi ni mal d urati o n of 1 h o ur.  
6. 6  
A d diti o n al tr e at m e nt g ui d a n c e  
6. 6. 1  
Tr e at m e nt c o m pli a n c e  
P har mac o ki netic para meters ( meas ures of treat me nt e x p os ure) will be deter mi ne d i n all 
partici pa nts treate d 
wit h 
D F V 8 9 0, as detaile d i n t he p har mac o ki netics Secti o n  8. 5. 2 . 
T he  i n vesti gat or m ust pr o m ote c o m plia nce b y i nstr ucti n g t he partici pa nt t o ta ke t he st u d y 
treat me nt e xactl y as prescri be d a n d b y stati n g t hat c o m plia nce is necessar y f or t he partici pa nt’s 
safet y a n d t he vali dit y of t he st u d y. T he partici pa nt m ust als o be i nstr ucte d t o c o ntact t he 
i n vesti gat or if he/s he is u na ble f or a n y reas o n t o ta ke t he st u d y treat me nt as prescri be d. 
C o m plia nce will be assesse d b y t he i n vesti gat or a n d/ or st u d y pers o n nel at eac h visit usi n g pill 
c o u nts a n d i nf or mati o n pr o vi de d b y t he partici p a nt. T his i nf or mati o n s h o ul d be ca pt ure d i n t he 
s o urce d oc u me nt at eac h visit. All st u d y treat me nt dis pe nse d a n d ret ur ne d m ust be rec or de d i n 
t he Dr u g Acc o u nta bilit y L o g. 
Off -site treat me nt a d mi nistrati o n c o m plia nce will be assesse d b y t he O H P a n d i nf or mati o n 
pr o vi de d t o t he I n vesti gat or a n d/ or st u d y pers o n nel.  
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  
Tr e at m e nt  a n d m a n a g e m e nt of s ki n r a s h:  
T he  f oll o wi n g rec o m me n dati o n f or ma na gi n g p ote ntial s us pecte d D F V 8 9 0-relate d s ki n ras hes 
are pr o vi de d.  
De pe n di n g o n se verit y, i n vesti gat ors ca n c o nsi der as per me dical j u d g me nt earl y treat me nt of 
mil d ras hes ( mac ul o pa p ular ras h c o veri n g < 1 0 % b o d y s urface area wit h or wit h o ut s y m pt o ms, 
e. g., pr urit us, b ur ni n g) wit h s y m pt o matic treat me nt (e. g., t o pical ster oi ds) a n d cl ose m o nit ori n g 
of t he partici pa nt's res p o nse.  
F or s ki n ras hes c o veri n g > 1 0 % b o d y s urface area, i n vesti gat ors s h o ul d disc o nti n ue D F V 8 9 0 
a n d cl osel y m o nit or partici pa nts t o e ns ure res ol uti o n of t he ras h. I n t he case of partici pa nts wit h 
s yste mic or c uta ne o us si g ns or s y m pt o ms s u g gesti n g a se vere c uta neo us reacti o n, a s h ort c o urse 
of s yste mic c ortic oi ds ster oi d (e. g., pre d nis o ne 1 t o 2 m g/ k g per da y f or fi ve t o se ve n da ys) ma y 
be c o nsi dere d.  

N o v arti s  
C o nfi d e nti al  
P a g e 7 8  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
Tr e at m e nt of o v er d o s e:  
T here is n o cli nical e x perie nce wit h D F V 8 9 0 o ver d ose. S h o ul d a n o ver d ose occ ur, t he 
partici pa nt s h o ul d be caref ull y m o nit ore d f or a n y p ote ntial s y m pt o ms, a n d if necessar y, 
a p pr o priate s u p p orti ve care s h o ul d be pr o vi de d u ntil t he partici pa nt has rec o vere d. At prese nt, 
t here is i ns ufficie nt i nf or mati o n t o pr o vi de s pecific rec o m me n dati o ns re gar di n g treat me nt of 
ot her p ote ntial A Es i n t his partici pa nt p o p ulati o n. 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 hera pies  e 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 i n or der t o treat t he 
partici pa nt safel y. Bli n di n g c o des ma y als o be br o ke n after a partici pa nt disc o nti n ues treat me nt 
d ue t o disease pr o gressi o n if dee me d esse ntial t o all o w t he i n vesti gat or t o select t he partici pa nt’s  
ne xt treat me nt re gi me n, a n d after disc ussi o n a n d a gree me nt wit h t he s p o ns or. M ost ofte n, st u d y 
treat me nt disc o nti n uati o n ( S T D) a n d k n o wle d ge of t he p ossi ble treat me nt assi g n me nts are 
s ufficie nt t o treat a st u d y partici pa nt 
w h o 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 perf or me d usi n g t he I R T/ NI R T. W he n t he i n vesti gat or 
c o ntacts t he s yste m t o brea k a treat me nt c o de f or a partici pa nt, 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 vesti gat or will t he n recei ve details of t he i n vesti gati o nal dr u g 
treat me nt f or t he s pecifie d partici pa nt a n d a fa x or e mail c o nfir mi n g t his i nf or mati o n. 
T he  s yste m will a ut o maticall y i nf or m t he N o vartis m o nit or f or t he site a n d t he st u d y tea m t hat 
t he c o de has bee n br o ke n. 
It is t he i n vesti gat or’s res p o nsi bilit y t o e ns ure t hat t here is a de pe n da ble pr oce d ure i n place t o 
all o w access t o t he I R T/ NI R T at a n y ti me i n case of e mer ge nc y. T he i n vesti gat or will pr o vi de:  
•  pr ot oc ol n u m ber  
•  na me  
•  partici pa nt n u m ber  
I n a d diti o n, oral a n d writte n i nf or mati o n t o t he partici pa nt m ust be pr o vi de d o n h o w t o c o ntact 
his/ her bac k u p i n cases of e mer ge nc y, or w he n 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 perf or me d at a n y ti me.  
I n t he e ve nt of a n e mer ge nc y brea ki n g of assi g ne d treat me nt c o de, partici pa nt s h o ul d be 
per ma ne ntl y disc o nti n ue d of st u d y treat me nt.  
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 descri be d u n der i n vesti gati o nal 
a n d c o ntr ol dr u gs secti o n.  
A u ni q ue me dicati o n n u m ber is pri nte d o n t he st u d y me dicati o n la bel.  

N o v arti s  
C o nfi d e nti al  
P a g e 7 9  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
I n vesti gat or staff will i de ntif y t he st u d y me dicati o n kits t o dis pe nse t o t he partici pa nt b y 
c o ntacti n g t he I R T/ NI R T a n d o btai ni n g t he me dicati o n n u m ber(s). T he st u d y me dicati o n has a 
2 -part la bel ( base pl us tear -off la bel), i m me diatel y bef ore dis pe nsi n g t he me dicati o n kit t o t he 
partici pa nt, site pers o n nel will detac h t he o uter part of t he la bel fr o m t he pac ka gi n g a n d affi x it 
t o t he s o urce d oc u me nt. 
F or off -site visits b y O H Ps, w here deli ver y of st u d y me dicati o n directl y t o a partici pa nt’s sec ure 
off -site l ocati o n (e. g., h o me) is per mitte d b y nati o nal a n d l ocal g o ver ni n g re g ulati o ns, t he n 
dis patc h of st u d y 
me dicati o n directl y t o t he partici pa nt 
ma y be  perf or me d u n der t he 
acc o u nta bilit y of t he I n vesti gat or. T he dis patc h of I n vesti gati o nal Me dici nal Pr o d uct  (I M P) 
fr o m t he site t o t he partici pa nt’s h o me re mai ns u n der t he acc o u nta bilit y of t he I n vesti gat or. 
Eac h s hi p me nt/ pr o visi o ni n g will be f or a ma xi m u m of 1 -m o nt h s u p pl y. I n t his case, re g ular 
p h o ne calls or virt ual c o ntacts 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 verse e ve nts, a n d disc ussi o n of t he 
partici pa nt's healt h stat us.  
I n a d diti o n t o I M P, a s ufficie nt q ua ntit y of Basic Pai n Me dicati o n will be s u p plie d t o last u ntil 
t he ne xt visit, as descri be d i n Secti o n 6. 1. 2 . 
T he treat me nt f or off -site a d mi nistrati o n will be ha n dle d a n d s hi p pe d i n li ne wit h t he p har mac y 
ma n ual a n d re q uire d pr oce d ures  a n d c o n diti o ns  f or s hi p pi n g. 
6. 7. 1  
H a n dli n g of st u d y tr e at m e nt a n d a d diti o n al tr e at m e nt  
6. 7. 1. 1  
H a n dli n g of st u d y tr e at m e nt  
St u d y treat me nt m ust be recei ve d b y a desi g nate d pers o n at t he st u d y site, ha n dle d a n d st ore d 
safel y a n d pr o perl y a n d ke pt i n a sec ure d l ocati o n t o w hic h o nl y t he i n vesti gat or a n d desi g nate d 
site pers o n nel ha ve access. U p o n recei pt, all st u d y treat me nt m us t 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 or 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 da nce wit h t he pr ot oc ol. Tec h nical c o m plai nts 
are t o be re p orte d t o t he res pecti ve N o vartis  C O Q ualit y Ass ura nce.  
Me dicati o n la bels will be i n t he l ocal la n g ua ge a n d c o m pl y wit h t he le gal re q uire me nts of eac h 
c o u ntr y. T he y will i ncl u de 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 xce pt f or t he me dicati o n n u m ber. 
T he i n vesti gat or or desi g nate d site staff m ust mai ntai n a n acc urate rec or d of t he s hi p me nt a n d 
dis pe nsi n g of st u d y treat me nt i n a dr u g acc o u nta bilit y l o g. M o nit ori n g of dr u g acc o u nta bilit y 
will be perf or me d b y m o nit ors d uri n g site visits or re m otel y a n d at  t he c o m pleti o n of t he trial. 
Partici pa nts will be as ke d t o ret ur n all u n use d st u d y treat me nt a n d pac ka gi n g at t he e n d of t he 
st u d y or at t he ti me of disc o nti n uati o n of st u d y treat me nt. 
T he site ma y destr o y a n d d oc u me nt destr ucti o n of u n use d st u d y treat me nt, dr u g la bels a n d 
pac ka gi n g as a p pr o priate i n c o m plia nce wit h site pr ocesses, m o nit ori n g pr ocesses, a n d per l ocal 
re g ulati o n/ g ui deli nes. Ot her wise, t he i n vesti gat or will ret ur n all u n use d st u d y treat me nt, 
pac ka gi n g, dr u g la bels, a n d a c o p y of t he c o m plete d dr u g acc o u nta bilit y l o g t o t he 
N o vartis/ S p o ns or m o nit or or t o t he N o vartis/ S p o ns or a d dress pr o vi de d i n t he i n vesti gat or f ol der 
at eac h site. 

N o v arti s  
C o nfi d e nti al  
P a g e 8 0  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
6. 7. 1. 2  
H a n dli n g of a d diti o n al tr e at m e nt  
T he f oll o wi n g a d diti o nal treat me nt has t o be m o nit ore d s pecificall y:  
•  Paraceta m ol/aceta mi n o p he n - all o we d per i nstr ucti o ns i n Ta ble  6 -2  
•  C o dei ne - all o we d per i nstr ucti o ns i n Ta ble  6 -2  
•  Para ma g netic c o ntrast me dia ( Ga d oli ni u m base d c o ntrast a ge n t, A T C c o de V 0 8 C A) 
Detaile d g ui da nce is pr o vi de d i n Secti o n  6. 1. 2 . 
6. 7. 2  
I n str u cti o n f or pr e s cri bi n g a n d t a ki n g st u d y tr e at m e nt 
T a bl e 6 -1 0  
D o s e a n d tr e at m e nt s c h e d ul e  
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) 
D ail y D o s e  
Fr e q u e n c y a n d/ or R e gi m e n  
D F V 8 9 0 1 0 m g or m at c hi n g 
pl a c e b o  
2 0 m g ( 1 0 m g i n t h e m or ni n g 
a n d 1 0 m g i n t h e e v e ni n g)  
T wi c e d ail y wit h f o o d or s h ortl y 
aft er m e al (fr o m D a y 1 t o D a y 
1 4 i n cl u d e d)  
N. B. l a st d o s e t o b e t a k e n o n 
D a y 1 4 i n t h e m or ni n g o nl y.  
D F V 8 9 0 2 5 m g or m at c hi n g 
pl a c e b o  
5 0 m g ( 2 5 m g i n t h e m or ni n g 
a n d 2 5 m g i n t h e e v e ni n g)  
T wi c e d ail y wit h f o o d  or s h ortl y 
aft er m e al  (fr o m D a y 1 4 i n t h e 
e v e ni n g t o D a y  8 4 i n cl u d e d)  
N. B. l a st d o s e t o b e t a k e n o n 
D a y 8 4 i n t h e m or ni n g o nl y.  
All kits of st u d y treat me nt assi g ne d b y t he I R T/ NI R T will be rec or de d i n t he I R T/ NI R T s yste m.  
•  Partici pa nts s h o ul d ta ke D F V 8 9 0 or place b o  t wice dail y at a p pr o xi matel y t he sa me ti me 
eac h da y i n t he m or ni n g a n d e ve ni n g a p pr o xi matel y 1 2 h ( +/ -2 h) a part. O n da ys t hat P K 
sa m ples are o btai ne d, t he partici pa nt s h o ul d ta ke D F V 8 9 0 or place b o visit after t he  pre -
d ose P K sa m ples a n d pri or t o p ost -d ose P K sa m ples, w he n i nstr ucte d b y t he st u d y staff.  
•  Fr o m Da y 1 t o Da y 1 4 ( m or ni n g d ose o nl y), partici pa nts will ta ke 1 ta blet of 1 0  m g 
stre n gt h D F V 8 9 0 or matc hi n g place b o i n t he m or ni n g a n d 1 ta blet of 1 0 m g stre n gt h 
D F V 8 9 0 or matc hi n g place b o i n t he e ve ni n g. T he last d ose will be ta ke n o n Da ys  1 4 i n t he 
m o r ni n g o nl y. 
•  Fr o m Da y 1 4 (e ve ni n g d ose o nl y) t o Da y 8 4 partici pa nts will ta ke 1 ta blet of 2 5 m g 
stre n gt h D F V 8 9 0 or matc hi n g place b o i n t he m or ni n g a n d 1 ta blet of 2 5 m g 
stre n gt h D F V 8 9 0 or matc hi n g place b o  i n t he e ve ni n g. T he last d ose will be ta ke n o n 
Da y  8 4 i n t he m or ni n g o nl y.  
•  O n Da y 8 4 partici pa nts will ta ke t heir last st u d y dr u g a d mi nistrati o n i n t he m or ni n g i.e., 
1  ta blet of 2 5 m g stre n gt h D F V 8 9 0 or matc hi n g place b o. 
•  Partici pa nts s h o ul d ta ke D F V 8 9 0 or place b o  wit h f o o d. Eac h d ose s h o ul d be ta ke n wit h a 
glass of water wit h t he meal or s h ortl y after c o m pleti o n of t heir meal.  O n  Da y 1 4 a n d Da y 
8 4 w he n serial P K sa m ples are c ollecte d, t he m or ni n g d ose s h o ul d be ta ke n wit hi n 5 mi n 
after c o m pleti o n of a brea kfast, w hic h s h o ul d n ot ta ke l o n ger t ha n 3 0  mi n.  
•  Partici pa nts s h o ul d be i nstr ucte d t o s wall o w w h ole ta blets a n d n ot t o c he w or brea k t he m.  

N o v arti s  
C o nfi d e nti al  
P a g e 8 1  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
•  If v o miti n g occ urs d uri n g t he c o urse of treat me nt, partici pa nts s h o ul d n ot ta ke t he st u d y 
treat me nt D F V 8 9 0 or place b o a gai n bef ore t he ne xt sc he d ule d d ose.  
•  Partici pa nts s h o ul d be i nstr ucte d n ot t o ma ke u p misse d d oses. A misse d d ose is defi ne d as 
a case w he n t he f ull d ose is n ot ta ke n wit hi n 8 h o urs after t he a p pr o xi mate ti me of t he 
us uall y dail y d osi n g. T hat da y's d ose s h o ul d be o mitte d, a n d t he partici pa nt s h o ul d 
c o nti n ue treat me nt wit h t he ne xt sc he d ule d d ose.  
•  Partici pa nts will be pr o vi de d wit h i n di vi d ual diar y t o rec or d eac h a d mi nistrati o n of st u d y 
treat me nt as well as use of basic pai n a n d resc ue me dicati o n, a n d N R S pai n, as descri be d 
i n Secti o n  8. 3. 1 . T hese will be c hec ke d re g ularl y b y site staff. 
F or p har mac o ki netic assess me nt da ys, bl o o d c ollecti o n will be d o ne i n relati o n t o t he m or ni n g 
d ose.  
T he basic pai n me dicati o n s h o ul d be ta ke n acc or di n g t o t he pac ka ge i nsert a n d i n vesti gat or 
i nstr ucti o ns. 
7  
I nf or m e d c o n s e nt pr o c e d ur e s 
Eli gi ble partici pa nts ma y o nl y be i ncl u de d i n t he st u d y after pr o vi di n g ( wit nesse d, w here 
re q uire d b y la w or re g ulati o n) I R B/I E C-a p pr o ve d i nf or me d c o nse nt.  
If a p plica ble, i n cases w here t he partici pa nt's re prese 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 uire me nts), t he partici pa nt  m ust be i nf or me d a b o ut t he st u d y t o t he e xte nt 
p ossi ble gi ve n his/ her le vel of 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 gree 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.  
Pri or t o scree ni n g, 
 ma y be carrie d o ut, 
i ncl u di n g X-ra y (rea d l ocall y), s pecific l ocal la b orat or y a nal yses (e. g., hs C R P) as well as a k nee 
p h ysical e xa mi nati o n, t o assess partici pa nts p ote ntial eli gi bilit y base d o n t hese criteria. Pri or t o 
t he c o n d uct of a n y st u d y s pecific assess me nts, a pre-scree 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 partici pa nt. If a n X-ra y is ta ke n d uri n g pre-scree ni n g acc or di n g t o t he pr ot oc ol 
i ma gi n g criteria (re q uiri n g sta n dar d wei g ht beari n g l o n g le g or k nee f oc use d pr ojecti o n), it will 
n ot nee d t o be re peate d d uri n g t he act ual scree ni n g if s u b mitte d wit hi n 6 m o nt hs of t he X -ra y 
ac q uisiti o n if t here is n o c ha n ge i n s y m pt o ms. It  will t he n ha ve t o u n der g o a ce ntral rea d. T he 
o utc o me of t he cli nical assess me nt will re mai n vali d f or 2 wee ks as l o n g as t he patie nt d oes n ot 
re p ort a c ha n ge i n s y m pt o mat ol o g y. A n e val uati o n of la b orat or y mar kers at t he ce ntral 
la b orat or y will be necessary bef ore i ncl usi o n i n t he st u d y re q uiri n g re peat  sa m pli n g. 
A f ull i nf or me d c o nse nt m ust be o btai ne d bef ore c o n d ucti n g a n y a d diti o nal st u d y -s pecific 
pr oce d ures (e. g., scree ni n g tests or a n y ot her pr oce d ures descri be d i n t he pr ot oc ol). T he pr ocess 
of o btai ni n g i nf or me d c o nse nt m ust be d oc u me nte d i n t he partici pa nt  so urce d oc u me nts.  
N o vartis  will pr o vi de t o i n vesti gat ors i n a se parate d oc u me nt a pr o p ose d i nf or me d c o nse nt f or m 
t hat c o m plies wit h t he I C H E 6 G C P g ui deli nes a n d re g ulat or y re q uire me nts a n d is c o nsi dere d 
a p pr o priate f or t his st u d y. A n y c ha n ges t o t he pr o p ose d c o nse nt f or m s u g geste d b y t he 
i n vesti gat or m ust be a gree d b y N o vartis bef ore s u b missi o n t o t he I R B/I E C.  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 8 2  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
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 treat me nt ca n 
be f o u n d i n t he I n vesti gat or's Br oc h ure (I B) a n d C D S f or mar kete d dr u gs . T his i nf or mati o n will 
be i ncl u de d i n t he partici pa nt  i nf or me d c o nse nt a n d s h o ul d be disc usse d 
wit h t he 
partici pa nt  d uri n g t he st u d y as nee de d. A n y ne w i nf or mati o n re gar di n g t he safet y pr ofile of t he 
i n vesti gati o nal dr u g t hat is i de ntifie d bet wee n I B u p dates will be c o m m u nicate d as a p pr o priate, 
f or e xa m ple, via a n i n vesti gat or n otificati o n or a n a g gre gate safet y fi n di n g. Ne w i nf or mati o n 
mi g ht re q uire a n u p date t o t he i nf or me d c o nse nt a n d t he n m ust be disc usse d wit h t he partici pa nt.  
T he st u d y ma y i ncl u de t he o pti o n f or t he partici pa nt t o ha ve certai n st u d y pr oce d ures perf or me d 
off -site b y a n O H P i nstea d of at t he st u d y site, as per mitte d b y nati o nal a n d l ocal g o ver ni n g 
re g ulati o ns. A se parate si g nat ure is re q uire d if t he partici pa nt agrees t o partici pate. T he pr ocess 
f or o btai ni n g c o nse nt s h o ul d be e xactl y t he sa me as descri be d a b o ve f or t he mai n i nf or me d 
c o nse nt. 
T he f oll o wi n g i nf or me d c o nse nts are i ncl u de d i n t his st u d y:  
•  Mai n st u d y c o nse nt, w hic h als o i ncl u de d:  
•  
 
 
 
•  
 
 
•  As a p plica ble, Pre g na nc y O utc o mes Re p orti n g C o nse nt f or fe male partici pa nts  or t he 
fe male part ners of a n y male partici pa nts w h o t o o k st u d y treat me nt 
•  
•  
•  
W o me n of c hil d -beari n g p ote ntial m ust be i nf or me d t hat ta ki n g t he st u d y treat me nt ma y i n v ol ve 
u n k n o w n ris ks t o t he fet us if pre g na nc y were t o occ ur d uri n g t he st u d y a n d a gree t hat i n or der 
t o partici pate i n t he st u d y t he y m ust a d here t o t he c o ntrace pti o n re q uire me nts. 
Male partici pa nts m ust be i nf or me d t hat if a fe male part ner bec o mes pre g na nt w hile he is 
e nr olle d i n t he st u d y, c o ntact wit h t he fe male part ner will be atte m pte d t o re q uest her c o nse nt 
t o c ollect pre g na nc y o utc o me i nf or mati o n. 
 
 
 
 
 
 
 
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 3  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
T his st u d y i ncl u des t he o pti o n f or t he partici pa nt t o ha ve certai n st u d y pr oce d ures perf or me d 
off -site b y a n O H P i nstea d of at t he st u d y site, f or w hic h a se parate si g nat ure is re q uire d if t he 
partici pa nt a grees. It is re q uire d as part of t his pr ot oc ol t ha t t he I n vesti gat or prese nts t his o pti o n 
t o t he partici pa nt i n c o u ntries w here t his ser vice is bei n g offere d, as per mitte d b y nati o nal a n d 
l ocal g o ver ni n g re g ulati o ns. T he pr ocess f or o btai ni n g c o nse nt s h o ul d be e xactl y t he sa me as 
descri be d a b o ve f or t he m ai n i nf or me d c o nse nt.  
A c o p y of t he a p pr o ve d versi o n of all c o nse nt f or ms m ust be pr o vi de d t o N o vartis  after I R B/I E C 
a p pr o val.  
As per Secti o n  4. 6 , d uri n g a P u blic Healt h e mer ge nc y as declare d b y L ocal or Re gi o nal 
a ut h orities i.e., pa n de mic, e pi de mic or nat ural disaster, t hat ma y c halle n ge t he a bilit y t o o btai n 
a sta n dar d writte n i nf or me d c o nse nt d ue t o li mits t hat pre ve nt a n o n -site visit, I n vesti gat or ma y 
c o n d uct t he i nf or me d c o nse nt disc ussi o n re m otel y (e. g., tele p h o ne, vi de oc o nfere nce) if 
all o wa ble b y a l ocal Healt h A ut h orit y. G ui da nce iss ue d b y l ocal re g ulat or y b o dies o n t his as pect 
pre vail a n d m ust be i m ple me nte d a n d a p pr o priatel y d oc u me nte d (e . g., t he prese nce of a n 
i m partial wit ness, si g n/ dati n g se parate I C Fs b y trial partici pa nt a n d pers o n o btai ni n g i nf or me d 
c o nse nt, etc.).  
8  
Vi sit s c h e d ul e a n d a s s e s s m e nt s  
T he Assess me nt Sc he d ule ( Ta ble  8 -1 ) lists all of t he assess me nts a n d w he n t he y are 
perf or me d.  All data o btai ne d fr o m t hese assess me nts m ust be s u p p orte d i n t he partici pa nt's 
s o urce d oc u me ntati o n. 
Partici pa nts s h o ul d be see n f or all visits/assess me nts as o utli ne d i n t he assess me nt sc he d ule 
(Ta ble  8 -1 ) or as cl ose t o t he desi g nate d da y/ti me as p ossi ble. Misse d or resc he d ule d visits 
s h o ul d n ot lea d t o a ut o matic disc o nti n uati o n.  
Partici pa nts w h o disc o nti n ue fr o m st u d y treat me nt are t o ret ur n f or t he e n d of treat me nt visit as 
s o o n as p ossi ble, a n d atte n d t he f oll o w-u p visits as i n dicate d i n t he Assess me nt Sc he d ule.  
Partici pa nts w h o disc o nti n ue fr o m st u d y or wit h dra w t heir c o nse nt/ o p p ose t he use of t heir 
data/ bi ol o gical sa m ples s h o ul d be sc he d ule d f or a fi nal e val uati o n visit if t he y a gree, as s o o n as 
p ossi ble, at w hic h ti me all of t he assess me nts liste d f or t he fi nal  visit will be perf or me d. At t his 
fi nal visit, all dis pe nse d i n vesti gati o nal pr o d uct 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 n ot pre vi o usl y re p orte d m ust be rec or de d o n t he e C R F.  

N o v arti s  
C o nfi d e nti al  
P a g e 8 4  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
T a bl e 8 -1  
A s s e s s m e nt S c h e d ul e  
E p o c h  
S cr e e ni n g  
Tr e at m e nt  
F oll o w -U p  
Vi sit N a m e  
S cr e e ni n g  
B a s eli n e  
W e e k 1  
W e e k 2 
3  
W e e k 4 
3  
W e e k 8 
3  
W e e k 1 2  
E o S 3  
P o st -
St u d y 
S af et y 
C o nt a ct  
Vi sit N u m b er s 1  
1  
2  
1 0 1  
1 0 2  
1 0 3  
1 0 4  
1 0 5  
2 0 1  
 
D a y s  
-4 5 t o -2  
-1  
1  
1 4  
2 8  
± 3  
5 6  
± 3  
8 4  
± 3  
9 9  
± 3  
1 1 4  
± 5  
Ti m e ( p o st -d o s e)  
- 
- 
- 
pr e -d o s e 2  1 h  3 h  5 h  8 h  pr e -d o s e 2  pr e -d o s e 2  pr e -d o s e 2  1 h  3 h  5 h  8 h  
- 
- 
I nf or m e d 
c o n s e nt s  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
I n cl u si o n / 
E x cl u si o n crit eri a  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
M e di c al 
hi st or y/ c urr e nt 
m e di c al 
c o n diti o n s  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
H e p atiti s s cr e e n  
S  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
HI V s cr e e n  
S  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Al c o h ol T e st a n d 
Dr u g S cr e e n  
S  
S  
  
  
  
  
  
  
S  
S  
  
  
  
  
  
  
  
S m o ki n g hi st or y  
X  
  
  
X  
  
  
  
  
X  
X  
X  
  
  
  
  
  
  
B o d y H ei g ht  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
B o d y W ei g ht  
X  
X  
  
  
  
  
  
  
X  
  
  
  
  
  
  
X  
  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 8 5  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
E p o c h  
S cr e e ni n g  
Tr e at m e nt  
F oll o w -U p  
Vi sit N a m e  
S cr e e ni n g  
B a s eli n e  
W e e k 1  
W e e k 2 
3  
W e e k 4 
3  
W e e k 8 
3  
W e e k 1 2  
E o S 3  
P o st -
St u d y 
S af et y 
C o nt a ct  
Vi sit N u m b er s 1  
1  
2  
1 0 1  
1 0 2  
1 0 3  
1 0 4  
1 0 5  
2 0 1  
 
D a y s  
-4 5 t o -2  
-1  
1  
1 4  
2 8  
± 3  
5 6  
± 3  
8 4  
± 3  
9 9  
± 3  
1 1 4  
± 5  
Ti m e ( p o st -d o s e)  
- 
- 
- 
pr e -d o s e 2  1 h  3 h  5 h  8 h  pr e -d o s e 2  pr e -d o s e 2  pr e -d o s e 2  1 h  3 h  5 h  8 h  
- 
- 
Vit al Si g n s  1 3  
X  
X  
X  
X  
  
  
  
  
X  
X  
X  
  
  
  
  
X  
  
B o d y 
T e m p er at ur e  
X  
X  
X  
X  
  
  
  
  
X  
X  
X  
  
  
  
  
X  
  
P h y si c al 
E x a mi n ati o n  
S  
S  
  
 S  
  
  
  
  
S  
S  
S  
  
  
  
  
S  
  
El e ctr o c ar di o gr a
m ( E C G)  
X  
X  
X  
 
  
  X 4  
  
X  
X  
 
  
  
X 4   
  
X  
  
H e m at ol o g y  
X  
X  
  
X  
  
  
  
  
X  
X  
X  
  
  
  
  
X  
  
C o a g ul ati o n 
P a n el  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Cli ni c al C h e mi str y  
X  
X  
  
X  
  
  
  
  
X  
X  
X  
  
  
  
  
X  
  
h s C R P 3  
X  
X  
  
X  
  
  
  
  
X  
X  
X  
  
  
  
  
X  
  
Uri n al y si s  
X  
X  
  
X  
  
  
  
  
X  
X  
X  
  
  
  
  
X  
  
Pr e g n a n c y a n d 
a s s e s s m e nt s of 
f ertilit y5  
X  
X  
  
X  
  
  
  
  
X  
X  
X  
  
  
  
  
X  
  
W PI  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
N R S P ai n  
X  
X  
  
X  
  
  
  
  
X  
X  
X  
  
  
  
  
  
  
K O O S  
X  
X  
  
X  
  
  
  
  
X  
X  
X  
  
  
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 8 6  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
E p o c h  
S cr e e ni n g  
Tr e at m e nt  
F oll o w -U p  
Vi sit N a m e  
S cr e e ni n g  
B a s eli n e  
W e e k 1  
W e e k 2 
3  
W e e k 4 
3  
W e e k 8 
3  
W e e k 1 2  
E o S 3  
P o st -
St u d y 
S af et y 
C o nt a ct  
Vi sit N u m b er s 1  
1  
2  
1 0 1  
1 0 2  
1 0 3  
1 0 4  
1 0 5  
2 0 1  
 
D a y s  
-4 5 t o -2  
-1  
1  
1 4  
2 8  
± 3  
5 6  
± 3  
8 4  
± 3  
9 9  
± 3  
1 1 4  
± 5  
2
2
2
2
X -r a y (t ar g et 
k n e e)  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
M RI (t ar g et k n e e)  
X 6  
  
  
  
  
  
  
  
  
  
X  
  
  
D C E -M RI (t ar g et 
k n e e)  
X 6  
  
  
  
  
  
  
  
  
  
X  
  
  
P ati e nt di ar y 
( p ai n) 
X  
  
  
P ati e nt di ar y 
( st u d y tr e at m e nt) 
  
  
X  
  
  
R a n d o mi z ati o n  
  
 
 X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Dr u g di s p e n s ati o n  
  
  
S  
S  
  
  
  
  
S  
S  
  
  
  
  
  
  
  
St u d y dr u g 
a d mi ni str ati o n  
  
  
X  
  
  
  
  
  
  
P K bl o o d 
c oll e cti o n 7  
  
  
  
X 8  
X  
X  
X  
X  
X 8  
X 8  
X 8  
X  
X  
X  
X  
X  
  
M e al r e c or d  
 
 
 
X  
 
 
 
 
X  
X  
X  
 
 
 
 
 
 
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 8 7  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
E p o c h  
S cr e e ni n g  
Tr e at m e nt  
F oll o w -U p  
Vi sit N a m e  
S cr e e ni n g  
B a s eli n e  
W e e k 1  
W e e k 2 
3  
W e e k 4 
3  
W e e k 8 
3  
W e e k 1 2  
E o S 3  
P o st -
St u d y 
S af et y 
C o nt a ct  
Vi sit N u m b er s 1  
1  
2  
1 0 1  
1 0 2  
1 0 3  
1 0 4  
1 0 5  
2 0 1  
 
D a y s  
-4 5 t o -2  
-1  
1  
1 4  
2 8  
± 3  
5 6  
± 3  
8 4  
± 3  
9 9  
± 3  
1 1 4  
± 5  
Ti m e ( p o st -d o s e)  
- 
- 
- 
pr e -d o s e 2  1 h  3 h  5 h  8 h  pr e -d o s e 2  pr e -d o s e 2  pr e -d o s e 2  1 h  3 h  5 h  8 h  
- 
- 
Bl o o d c oll e cti o n 
f or pr ot ei n 
pr ofili n g ( pl a s m a)  
  
X  
  
X  
  
  
  
  
  
  
X  
  
  
  
  
  
  
C o n c o mit a nt 
m e di c ati o n s / 
n o n -dr u g 
t h er a pi e s 
X  
  
A d v er s e E v e nt s  
X  
  
St u d y c o m pl eti o n 
i nf or m ati o n 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X  
  
S af et y F oll o w u p 
C all  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
S  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 8 8  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
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  
1  Vi sit str u ct ur e gi v e n f or i nt er n al pr o gr a m mi n g p ur p o s e o nl y  
2  R ef er s t o m or ni n g d o s e  
3  B a s e d o n n ati o n al a n d l o c al r e g ul ati o n s a n d c a p a biliti e s, t h e s e vi sit s m a y b e p erf or m e d at a n off -sit e l o c ati o n. S cr e e ni n g, B a s eli n e a n d w e e k 1 2 a s s e s s m e nt s will b e 
p erf or m e d o n sit e. If a n y s ki n r a s h i s r e p ort e d pri or t o t h e D a y 1 4 vi sit, t h e n t hi s vi sit h a v e t o b e c o m pl et e d at t h e sit e. If t h e p a n d e mi c ( e. g. C O VI D -1 9) li mit s or pr e v e nt s 
o n sit e st u d y vi sit s, t h e m a n d at or y o n sit e vi sit s ( S cr e e ni n g, B a s eli n e, w e e k 1 2 a n d p ot e nti all y D a y 1 4 i n t h e e v e nt of a r a s h)  m a y b e p erf or m e d off -sit e  d e p e n di n g o n 
n ati o n al a n d l o c al  r e g ul ati o n s a n d c a p a biliti e s, a n d a s a gr e e d b y t h e i n v e sti g at or a n d p ati e nt. 
4  T o b e p erf or m e d ar o u n d T m a x, i. e. 5 h aft er t h e fir st a d mi ni str ati o n  
5  S er u m pr e g n a n c y t e st at S cr e e ni n g a n d E o S vi sit, uri n e pr e g n a n c y t e st at all ot h er vi sit s.  
6  M RI/ D C E -M RI a t S cr e e ni n g vi sit s h o ul d o nl y b e c o m pl et e d aft er all ot h er eli gi bilit y crit eri a h a v e b e e n c o nfir m e d. 
7  I n c a s e n e e d e d ( e. g. s ki n r a s h), a n u n s c h e d ul e d s a m pl e s h o ul d b e c oll e ct e d t o a s s e s s P K r el ati o n s hi p a s n e ar a s p o s si bl e t o t h e e v e nt.  
8  T a k e n at 0 h pri or t o m or ni n g d o s e a n d 1 2 h aft er t h e e v e ni n g d o s e t h e d a y b ef or e.  
 
 
 
 
 
 
 
  
 
 
 
 
1 3 I n cl u di n g bl o o d pr e s s ur e a n d p ul s e r at e 
 
 
 
 
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 8 9  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
8. 1  
S cr e e ni n g  
It is per missi ble t o re-scree n a partici pa nt if s/ he fails t he i nitial scree ni n g; h o we ver, eac h case 
m ust be disc usse d a n d a gree d wit h t he S p o ns or o n a case -b y -case basis,  a ne w Scree ni n g 
n u m ber assi g ne d, a n d a ne w writte n i nf or me d c o nse nt si g ne d b y t he partici pa nt a n d i n vesti gat or.  
I n t he case w here a safet y la b orat or y (i ncl u di n g hs C R P if ≥1. 5 m g/ L) assess me nt at scree ni n g 
a n d/ or i nitial baseli ne is o utsi de of t he ra n ge s pecifie d i n t he eli gi bilit y criteria, t he assess me nt 
ma y be re peate d o nce pri or t o ra n d o mizati o n. If t he re peat val ue re mai ns o utsi de of t he s pecifie d 
ra n ges, t he partici pa nt m ust be e xcl u de d fr o m t he st u d y.   
T a bl e 8 -2  
R e s cr e e ni n g  
If r e a s o n f or s cr e e n 
f ail ur e i s: 
T h e n  
A cti o n s  
R ati o n al e  
U nr el at e d t o k n e e X -r a y  R e -s cr e e ni n g i s 
p er mitt e d.  
P arti ci p a nt will n ot 
r e q uir e a r e p e at k n e e 
X -r a y I F r e-s cr e e ni n g 
o c c ur s wit hi n 6 
m o nt h s of ori gi n al X -
r a y d at e. Pl e a s e r ef er 
t o S e cti o n 8. 1. 1. 3  f or 
d et ail s  
A v oi d s a d diti o n al 
r a di ati o n e x p o s ur e, gi v e n 
t h at m e a ni n gf ul 
r a di ol o gi c c h a n g e s ar e 
u nli k el y t o o c c ur d uri n g 
r e-s cr e e ni n g p eri o d  
R el at e d t o k n e e X -r a y;  
R e -s cr e e ni n g i s 
p er mitt e d.  
P arti ci p a nt will n ot 
r e q uir e a r e p e at k n e e 
X -r a y I F r e-s cr e e ni n g 
o c c ur s wit hi n 6 
m o nt h s of ori gi n al X -
r a y d at e. Pl e a s e r ef er 
t o S e cti o n 8. 1. 1. 3  f or 
d et ail s  
P arti ci p a nt will r e q uir e 
all ot h er a s s e s s m e nt s 
t o b e r e p e at e d u nl e s s 
r e-s cr e e ni n g i s d o n e 
wit hi n 7  d a y s of 
ori gi n al a s s e s s m e nt.  
A v oi d s a d diti o n al 
r a di ati o n e x p o s ur e, gi v e n 
t h at m e a ni n gf ul 
r a di ol o gi c c h a n g e s ar e 
u nli k el y t o o c c ur d uri n g 
r e-s cr e e ni n g p eri o d  
R e p e at of l a b or at or y 
a s s e s s m e nt s a n d P R O s 
n e e d e d d u e t o v ari a bl e 
n at ur e of t h e s e 
a s s e s s m e nt s  
8. 1. 1  
Eli gi bilit y s cr e e ni n g  
T his secti o n descri bes assess me nts w hic h are perf or me d at scree ni n g i n or der t o e val uate a 
partici pa nt's eli gi bilit y. Eli gi bilit y assess me nts w hic h are perf or me d at scree ni n g t o descri be t he 
p o p ulati o n or als o later d uri n g t he st u d y t o e val uate efficac y, s afet y or ot her o utc o mes, are 
descri be d i n se parate secti o ns.  
T he scree ni n g assess me nts s h o ul d be c o m plete d as per assess me nt sc he d ule ( Ta ble  8 -1 ), 
starti n g wit h i nf or me d c o nse nts. T he assess me nts s h o ul d be perf or me d fr o m t he less 
i n vasi ve/ b ur de ns o me t o t he m ore i n vasi ve/ b ur de ns o me assess me nts f or t he partici pa nt. 
T he scree ni n g 
M RI 
will o nl y be c o m plete d u p o n c o nfir m ati o n t h at all ot her 
i ncl usi o n/e xcl usi o n criteri a are f ulfille d. 

N o v arti s  
C o nfi d e nti al  
P a g e 9 0  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
D uri n g scree ni n g, t he i n vesti gat or s h o ul d detect a n y acti ve i nfecti o ns t hat w o ul d dis q ualif y t he 
partici pa nt f or t his st u d y (e xcl usi o n criteri o n). T he decisi o n t o l ocall y test t he partici pa nt f or 
acti ve S A R S -C o v -2 i nfecti o n i n or der t o e val uate t he e xcl usi o n criteri o n is at t he i n vesti gat or's 
discreti o n a n d s h o ul d be i n a d here nce t o l ocal p olicies or re g ulati o ns. H o we ver, it is hi g hl y 
rec o m me n de d t hat P. C. R. or a nti ge n testi n g f or C O VI D-1 9 be c o m plete d wit hi n 1 wee k pri or 
t o first d osi n g. If testi n g is perfor me d, ne gati ve test res ults are re q uire d pri or t o e nr ol me nt i nt o 
t he st u d y. P. C. R. or a nti ge n test a gai nst C O VI D -1 9 is ma n dat or y w here re q uire d b y t he l ocal 
Healt h A ut h orit y a n d/ or b y l ocal re g ulati o n, e. g. i n Ger ma n y.  A d diti o nal testi n g t hr o u g h o ut t he 
st u d y ma y occ ur at t he discreti o n of t he i n vesti gati n g p h ysicia n. C O VI D -1 9 testi n g s h o ul d be 
c o m plete d via nasal or t hr oat s wa bs.  If testi n g is n ot perf or me d, t he i n vesti gat or m ust d oc u me nt 
t heir disc ussi o n wit h t he partici pa nt re gar di n g testi n g, a n d t he rat i o nale f or n ot testi n g, i n t he 
s o urce d oc u me ntati o n. T his re q uire me nt ma y be i g n ore d if t he pa n de mic is declare d e n de d b y 
t he c o u ntr y w here t he site is l ocate d, a n d res u me d if t he pa n de mic rec urs. 
8. 1. 1. 1  
H e p atiti s s cr e e n, HI V s cr e e n  
All partici pa nts will be scree ne d f or He patitis B s urface a nti ge n ( H Bs A g). A d diti o nal sta n dar d 
l ocal practices c o ul d a p pl y. Scree ni n g f or He patitis C will be base d o n H C V a nti b o dies a n d if 
p ositi ve, H C V R N A le vels s h o ul d be deter mi ne d.  
E val uati o n f or HI V ser o p ositi vit y will be perf or me d, a n d, if p ositi ve, c o nfir mati o n b y a sec o n d 
tec h ni q ue a vaila ble at t he la b orat or y site e. g., Wester n bl ot. A p pr o priate c o u nseli n g will be 
ma de a vaila ble b y t he I n vesti gat or i n t he e ve nt of a p ositi ve c o nf ir mat or y test. N otificati o n of 
state a n d fe deral a ut h orities, as re q uire d b y la w, will be t he res p o nsi bilit y of t he I n vesti gat or.  
8. 1. 1. 2  
Al c o h ol t e st, Dr u g s cr e e n, Uri n e c oti ni n e  
Partici pa nts will be teste d f or s u bsta nces of a b use (e. g., alc o h ol, a m p heta mi nes, bar bit urates, 
be nz o diaze pi nes, ca n na bi n oi ds, c ocai ne a n d o piates).  
C oti ni ne i n uri ne will n ot be a nal yze d at scree ni n g b ut t he i n vesti gat or s h o ul d clarif y t o bacc o 
use ha bits f or partici pa nts w h o use t o bacc o pr o d ucts t o e ns ure it is realistic t hat t he partici pa nt 
ca n c o m pl y wit h t he restricti o n descri be d i n Secti o n  6. 2. 4. 1 . Nic oti ne re place me nt t hera pies are 
all o we d. 
8. 1. 1. 3  
K n e e X -r a y 
A l o n g le g or k nee ce ntere d wei g ht beari n g X -ra y will be perf or me d o nl y at Scree ni n g t o 
e val uate t he K & L gra de eli gi bilit y criteria, usi n g a n o n -fl u or o, sta n dar dize d a n d q ualit y-
c o ntr olle d met h o d, as descri be d i n t he I ma gi n g c harter.  A ce ntral rea der will a nal yze t he i ma ges 
as descri be d i n t he I ma gi n g c harter.  
If a patie nt has bee n scree ne d f or a si milar trial wit h t he sa me c o n ve nti o nal X-ra y pr ojecti o n, 
t he i ma ge ac q uire d d uri n g scree ni n g ca n be use d wit hi n 6 m o nt hs of t he X-ra y date. 
8. 1. 1. 4  
P ai n  
Wi des prea d Pai n I n de x  ( W PI) (W olfe  et al 2 0 1 6 ) is assesse d at scree ni n g o nl y, t o e xcl u de 
partici pa nts wit h s u bsta ntial pai n ori gi nati n g fr o m  ot her re gi o ns t ha n t he tar get k nee, s uc h as 
fi br o m yal gia or ot her u n dia g n ose d diseases. 

N o v arti s  
C o nfi d e nti al  
P a g e 9 1  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
Ot her pai n P R Os are c ollecte d f or scree ni n g p ur p oses as well as f or efficac y e val uati o n, see 
Secti o n  8. 3. 1 . 
T he sa me met h o d of c ollecti o n as f or t he P R Os descri be d i n Secti o n  8. 3. 1  will be use d.  
8. 1. 1. 5  
C o ntr a st -e n h a n c e d M RI  
C o ntrast -e n ha nce d M RI will be ac q uire d f or scree ni n g p ur p oses as well as f or efficac y, base d 
o n s y n o vitis e val uati o n. F or a d diti o nal details o n t he assess me nt, see Secti o n  8. 3. 2   
8. 1. 2  
I nf or m ati o n t o b e c oll e ct e d o n s cr e e ni n g f ail ur e s 
Partici pa nts w h o si g n a n i nf or me d c o nse nt f or m a n d are s u bse q ue ntl y f o u n d t o be 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. All reas o ns f or scree n fail ure s h o ul d 
be rec or de d o n t he a p pr o priate Case Re p ort F or m. T he visit date, de m o gra p hic i nf or mati o n, 
i nf or me d c o nse nt, a n d I ncl usi o n/ E xcl usi o n pa ges m ust als o be c o m plete d f or scree n fail ure 
partici pa nts. N o ot her data nee d t o be e ntere d i nt o t he cli nical data base f or partici pa nts w h o are 
scree n fail ures, u nless t he partici pa nt e x perie nce d a seri o us a d verse e ve nt or a n a d verse e ve nt 
relate d t o A x M Ps d uri n g t he scree ni n g peri o d (see S A E secti o n f or re p orti n g details). Data a n d 
sa m ples c ollecte d fr o m partici pa nts pri or t o scree n fail ure ma y still be a nal yze d. 
Partici pa nts w h o are ra n d o mize d a n d fail t o start treat me nt, e. g., partici pa nts ra n d o mize d i n 
err or, will be c o nsi dere d a n earl y ter mi nat or. T he reas o n f or earl y ter mi nati o n s h o ul d be 
rec or de d o n t he a p pr o priate Case Re p ort F or m. T he I R T/ NI R T m ust be n otifie d wit hi n 2 da ys 
of t he scree n fail ure/earl y ter mi nati o n.  
8. 1. 3  
Pr e -s cr e e ni n g pr o c e d ur e  
Pri or t o t he Scree ni n g 1 visit, 
 ma y be carrie d 
o ut, i ncl u di n g X -ra y as per st u d y g ui da nce b ut rea d l ocall y (Secti o n 8. 1. 1. 3 ), i n di vi d ual l ocal 
la b orat or y a nal yses s uc h as hs C R P a n d k nee p h ysical e xa mi nati o n (e. g., assess me nt of k nee O A 
lateralit y or eff usi o n) t o assess partici pa nts p ote ntial eli gi bilit y base d o n t hese har d t o pre dict 
feat ures. Pre-scree ni n g tests ca n o nl y be re peate d i n case of tec h nical iss ues.  Pri or t o a n y st u d y 
s pecific assess me nts bei n g carrie d o ut, t he pre-scree 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 partici pa nt.  
Data fr o m t he pre -scree ni n g will n ot be e ntere d i nt o t he st u d y cli nical data base, u nless eit her 1) 
t he partici pa nt e x perie nces a n S A E ca usall y relate d t o pre-scree ni n g st u d y pr oce d ures or 
A x M Ps, i n 
w hic h case t he 
S A E 
will be c ollecte d usi n g pa per 
S A E fr o m 
o nl y 
(see Secti o n  1 0. 1. 3 ), or 2) t he partici pa nt si g ns t he mai n c o nse nt a n d is scree ne d wit hi n 
6  m o nt hs of t he X -ra y ac q uisiti o n, i n w hic h case t he pre-scree ni n g X-ra y ca n re place t he 
scree ni n g X-ra y, if perf or me d as per st u d y re q uire me nts. T he partici pa nt will be e ntere d i n 
I R T/ NI R T o nl y after si g ni n g t he mai n c o nse nt. All ot her data relate 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 me nts.  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 9 2  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
I n case of act ual scree ni n g, all la b orat or y tests use d f or scree ni n g (Ta ble 8 -1 ) will nee d t o be 
perf or me d b y t he ce ntral la b orat or y. L ocal a nal yses perf or me d at pre -scree ni n g are s olel y 
i nf or mati ve f or i n vesti gat ors’ decisi o n f or patie nts t o c o nti n ue t o f ull scree ni n g. I n t he case 
w here a safet y la b orat or y (i ncl u di n g hs C R P if ≥1. 5 m g/ L) assess me nt at scree ni n g is o utsi de of 
t he ra n ge s pecifie d i n t he eli gi bilit y criteria, t he assess me nt ma y be re peate d o nce pri or t o 
ra n d o mizati o n. If t he re peat val ue re mai ns o utsi de of t he s pecifie d ra n ges, t he partici pa nt m ust 
be e xcl u de d fr o m t he s t u d y. 
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 e C R F.  
Partici pa nt race a n d et h nicit y are c ollecte d a n d a nal yze d t o i de ntif y variati o ns i n safet y or 
efficac y d ue t o t hese fact ors as well as t o assess t he di versit y of t he st u d y p o p ulati o n as re q uire d 
b y Healt h A ut h orities.  
Partici pa nt de m o gra p hics: a ge, se x, race, pre d o mi na nt et h nicit y (if per mitte d) a n d rele va nt 
me dical hist or y/c urre nt me dical c o n diti o ns ( u ntil date of si g nat ure of i nf or me d c o nse nt) will be 
rec or de d i n t he e C R F. W here p ossi ble, t he dia g n osis a n d n ot s y m pt o ms s h o ul d be rec or de d. 
All prescri pti o n me dicati o ns, o ver -t he-c o u nter dr u gs a n d si g nifica nt n o n -dr u g t hera pies pri or t o 
t he start of t he st u d y m ust be d oc u me nte d. See t he pr ot oc ol Secti o n  6. 2. 1  f or f urt her details o n 
w hat i nf or mati o n m ust be rec or de d o n t he a p pr o priate pa ge of t he e C R F.  
8. 3  
Effi c a c y  
T he efficac y assess me nts descri be d i n t his secti o n will be e val uate d i n all partici pa nts i n b ot h 
treat me nt ar ms. 
Pai n ( pri mar y e n d p oi nt) will be assesse d b y Patie nt Re p orte d O utc o mes ( P R Os) as descri be d i n 
Secti o n  8. 3. 1 . 
P har mac o d y na mic sa 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 ( Ta ble  8 -1 ). 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.  
S y n o vitis (sec o n dar y e n d p oi nt), p ote ntiall y artic ular cartila ge v ol u me/t hic k ness, b o ne marr o w 
lesi o ns, a n d 
 ca n be e val uate d fr o m M RI as descri be d 
i n Secti o n  8. 3. 2 . 
P har mac o d y na mic ( P D) sa m ples will be o btai ne d a n d e val uate d i n all partici pa nts at all d ose 
le vels, i ncl u di n g t he place b o gr o u p. 
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 9 3  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
8. 3. 1  
P ati e nt R e p ort e d O ut c o m e s ( P R O s)  
T he partici pa nt m ust be gi ve n t he P R O  meas ure(s) t o be c o m plete d at t he sc he d ule d visit bef ore 
ot her cli nical assess me nts are c o n d ucte d. T he q uesti o n naires s h o ul d be c o m plete d i n t he 
la n g ua ge m ost fa miliar t o t he partici pa nt. T he partici pa nt s h o ul d be gi ven s ufficie nt s pace a n d 
ti me t o c o m plete t he P R O meas ure(s). A partici pa nt's ref usal t o c o m plete all or a n y part of a 
P R O  meas ure s h o ul d be d oc u me nte d i n t he e C R F. St u d y staff s h o ul d c hec k t he P R O meas ure(s) 
c ollecte d f or c o m plete ness a n d as k t he partici pa n t t o c o m plete a n y missi n g res p o nses. 
C o m plete d P R Os, i ncl u di n g a n y u ns olicite d c o m me nts writte n b y t he partici pa nt, m ust be 
re vie we d a n d assesse d b y t he i n vesti gat or f or res p o nses w hic h ma y i ncl u de p ote ntial A Es or 
S A Es bef ore a n y cli nical st u d y e xa mi nati o ns are c o n d ucte d. If A Es or S A Es are c o nfir me d, 
t he n st u d y i n vesti gat ors s h o ul d n ot e nc o ura ge t he partici pa nt t o c ha n ge res p o nses re p orte d i n 
t he c o m plete d q uesti o n naires. St u d y i n vesti gat ors m ust f oll o w re p orti n g i nstr ucti o ns descri be d 
i n Secti o n  1 0 . 
K n e e I nj ur y a n d O st e o art hriti s O ut c o m e s  S c or e ( K O O S)  
K nee -relate d pai n will be assesse d as t he pri mar y e n d p oi nt b y mea ns of t he K nee I nj ur y a n d 
Oste oart hritis 
O utc o mes 
Sc ore 
( K O O S) 
meas ure 
c ollecte d 
at 
re g ular 
i nter vals 
(R o os , Da vis  2 0 1 2 ). T he K O O S i ncl u des 4 2 ite ms gr o u pe d i nt o fi ve s u b-scales: Pai n, Ot her 
S y m pt o ms, Acti vities of Dail y Li vi n g ( A D L), F u ncti o n i n S p ort a n d Recreati o n ( S p ort/ Rec), 
a n d K nee -relate d Q ualit y of Life ( Q o L). Eac h s u b-scale is sc ore d se paratel y o n a scale fr o m 0 
t o 1 0 0, wit h a hi g her n u m ber i n dicati n g better c o n diti o n (C olli ns  et al 2 0 1 1 ). T he P R O 
K O O S  sc ore is a n e x pa n de d versi o n of t he W O M A C sc ore, w hic h tra diti o nall y has bee n use d 
i n O A cli nical trials ( K O O S  User  G ui de  2 0 0 3 ). K O O S i ncl u des W O M A C O A I n de x L K 3. 0 i n 
its c o m plete a n d ori gi nal f or mat a n d W O M A C sc ores are a ble t o be calc ulate d. T heref ore, t he 
K O O S  sc ore pr o vi des a m ore c o m pre he nsi ve assess me nt as it als o i ncl u des f u ncti o ni n g i n s p ort 
a n d recreati o n, as well as k ne e-relate d q ualit y of life. K O O S re q uires a p pr o xi matel y 1 0 mi n utes 
f or partici pa nts t o c o m plete. 
N u m eri c al R ati n g S c al e ( N R S)  
T he N u merical Rati n g Scale ( N R S) f or Pai n ( Ha w ker  et al 2 0 1 1 ) wit h a recall peri o d of 
2 4  h o urs a n d tra diti o nall y use d t o assess pai n i n cli nical trials, is assesse d at re g ular i nter vals t o 
c o nfir m eli gi bilit y a n d t o e val uate pai n stat us t hr o u g h o ut t he st u d y.  
Wi d e s pr e a d P ai n I n d e x ( W PI)  
Wi des prea d Pai n I n de x ( W PI) is assesse d at scree ni n g o nl y t o e xcl u de partici pa nts wit h 
s u bsta ntial pai n ori gi nati n g fr o m ot her re gi o ns t ha n t he tar get k nee, fi br o m yal gia, or ot her 
u n dia g n ose d diseases w hic h ma y i nterfere wit h pai n assess me nt.  
P ai n di ar y  
A pai n diar y will als o be c o m plete d b y t he partici pa nt dail y d uri n g t he 1 2 -wee ks st u d y a n d 
tra nsferre d t o t he e C R F at eac h visit, be gi n ni n g wit h Scree ni n g. T his diar y will be use d t o rec or d 
basic pai n me dicati o n, resc ue me dicati o n a n d pai n le vels, dail y. T he partici pa nt ma y c h o ose 
w he n, b ut s h o ul d assess t heir pai n i nte nsit y at a p pr o xi matel y t he sa me ti me e ver y da y. 

N o v arti s  
C o nfi d e nti al  
P a g e 9 4  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
T he  N R S  pai n assess me nt i n t he diar y a n d t he N R S pai n assess me nt perf or me d d uri n g st u d y 
visits s h o ul d be d oc u me nte d se paratel y i n t he e C R F. At eac h st u d y visit fr o m Scree ni n g t o 
Da y  8 4, partici pa nts m ust be pr o vi de d wit h a ne w pai n diar y t hat c o vers at lea st t he peri o d u ntil 
t he ne xt pla n ne d visit. Prescri pti o n or use of pai n me dicati o ns will still nee d t o be d oc u me nte d 
as C o nc o mita nt Me dicati o ns acc or di n g t o Secti o n  6. 2. 1 . 
St u d y tr e at m e nt di ar y  
A  st u d y treat me nt diar y  will als o be c o m plete d b y t he partici pa nt dail y d uri n g t he 1 2 -wee ks 
st u d y a n d tra nsferre d t o t he e C R F at eac h visit, be gi n ni n g wit h Da y 1.  T his diar y will be use d 
t o rec or d st u d y treat me nt o n a dail y basis. At eac h st u d y visit fr o m Da y 1 t o Da y 8 4, partici pa nts 
m ust be pr o vi de d wit h a ne w diar y t hat c o vers at least t he peri o d u ntil t he ne xt pla n ne d visit.  
P R Os will be c o m plete d b y t he partici pa nts w he n atte n di n g sc he d ule d visits ( Ta ble  8 -1 ). If a n 
electr o nic versi o n of t he q uesti o n naires is use d, data will be tra nsferre d a n d sa ve d i n t he ve n d or's 
st u d y data base o n a re g ular basis. Ot her wise, a pa per versi o n will be pr o vi de d.  
8. 3. 2  
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 i de ntif y p ote ntial partici pa nts wit h acti ve s y n o vitis 
a n d t o vis ualize t he cartila ge a n d ot her str uct ures of t he k nee. T he i ma gi n g pr ot oc ol will all o w 
a q ua ntificati o n of c ha n ges i n s y n o vitis, eff usi o n v ol u me, a n d b o ne marr o w lesi o ns a n d v ol u me 
a n d t hic k ness of cartila ge i n t he i n de x re gi o n as well as t he w h ole fe m oral j oi nt c o m part me nt 
(i.e., t he re gi o n w here m ost cartila ge da ma ge occ urs i n O A partici pa nts wit h K & L 2-3) d uri n g 
treat me nt. T he i n de x re gi o n is define d as t he u ni o n of t he fe m oral me dial a nteri or ( F M A), 
ce ntral ( F M C) a n d p osteri or ( F M P) cartila ge s u b -re gi o ns i n t he k nee. T his a p pr oac h will 
de m o nstrate t he effecti ve ness of D F V 8 9 0 i n re d uci n g k nee i nfla m mati o n a n d w het her t his 
res p o nse is c orrelate d with a decrease i n pai n.  It will als o be use d t o p ote ntiall y q ua ntif y c ha n ges 
i n v ol u me a n d t hic k ness of cartila ge i n t he i n de x re gi o n a n d t he w h ole fe m ur. 
I n a d diti o n, t he assess me nt of t he s y n o vitis acti vit y le vel usi n g a d y na mic-c o ntrast -e n ha nce d 
( D C E)-M RI a p pr oac h will de m o nstrate t he effecti ve ness of D F V 8 9 0 i n re d uci n g k nee 
i nfla m mati o n a n d w het her t his res p o nse is c orrelate d wit h a decrease i n pai n. 
8. 3. 2. 1  
I m a g e c oll e cti o n 
T he  ac q uisiti o n of ma g netic res o na nce i ma ges will be perf or me d b y a trai ne d M RI pr ofessi o nal 
at eac h site. T he M RI  tec h n ol o gist will be bli n de d t o t he treat me nt recei ve d b y t he partici pa nt. 
All partici pa nts will be i ma ge d usi n g a cli nical M RI 3 T sca n ner  after e ns uri n g t here are n o 
c o ntrai n dicati o ns f or M RI (s uc h as metallic i m pla nts, cla ustr o p h o bia etc.). F or eac h M RI 
sessi o n, i ma ges fr o m t he i n de x k nee will be ac q uire d  as descri be d i n t he i ma gi n g pr ot oc ol t o 
assess s y n o vitis, cartila ge q ua ntit y as well as ot her k nee feat ures s uc h as eff usi o n a n d B o ne 
Marr o w Lesi o n ( B M L).  Partici pa nt set u p will e ns ure c orrect re pr o d uci ble p ositi o ni n g of t he 
k nee as well as s ufficie nt c o mf ort t o li mit m oti o n artifacts.  T he d urati o n of t he sca n ni n g sessi o ns 
w o ul d be 3 0 -4 0 
mi n u tes. 3 D n o n-c o ntrast 
M RI p ulse se q ue nces 
will be  ac q uire d  f or 
q ua ntitati ve  assess me nts. As t he last ac q uisiti o n i n t he pr ot oc ol,  f or s y n o vitis assess me nt 
T 1 wei g hte d ( T 1 w) D C E -M R i ma ges will be o btai ne d bef ore a n d after t he i njecti o n of t he 
ga d oli ni u m c o ntr ast a ge nt.  Macr oc yclic G B C As, w hic h ha ve hi g her sta bilit y t ha n li near a ge nts, 
s h o ul d be use d t o miti gate t he ris k of ga d oli ni u m de p ositi o n. M R i ma ges will be ac q uire d at 

N o v arti s  
C o nfi d e nti al  
P a g e 9 5  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
selecte d a n d q ualifie d 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 i ma gi n g 
s pecialists. T he re vie wers will be bli n de d t o t he treat me nt recei ve d b y t he partici pa nt. 
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:  
1.  Scree n f or partici pa nts wit h acti ve s y n o vitis  pri or t o t he D F V 8 9 0 a d mi nistrati o n. 
At  scree ni n g, a c o m pre he nsi ve se mi-q ua ntitati ve sc ori n g s yste m  will be perf or me d o n 
o ne of t he sca ns o btai ne d fr o m t he D C E -M RI series  t o assess w h ole-k nee s y n o vitis as 
pr e vi o usl y descri be d ( G uer mazi  et al 2 0 1 1 ). S y n o vitis will be assesse d at 1 1 sites of t he 
j oi nt a n d w h ole-k nee s y n o vitis will be cate g orize d as f oll o ws: 0 – 4 n or mal or e q ui v ocal 
s y n o vitis; 5– 8 mil d s y n o vitis; 9 – 1 2 m o derate s y n o vitis a n d ≥1 3 se vere s y n o vitis.  
2.  Assess c ha n ges i n t he acti vit y le vel of s y n o vitis, e val uate d usi n g pri maril y t he v ol u me 
tra nsfer rate of t he G B C A fr o m t he bl o o d plas ma i n s y n o vi u m, or K-
tra ns (Riis  et al 2 0 1 7 ) fr o m t he D C E-M RI sca ns. C ha n ges i n t he  t hic k ness of t he s y n o vial 
me m bra ne,  v ol u me of b o ne marr o w  lesi o n a n d k nee eff usi o n will als o be assesse d. Ot her 
q ua ntifia ble meas ures ma y als o be i n vesti gate d.  
3.  P ote ntiall y assess c ha n ges i n b o ne marr o w lesi o ns a n d eff usi o n v ol u me, as well as 
cartila ge v ol u me,  a n d t hic k ness b ot h i n t he i n de x re gi o n a n d t he rest of t he j oi nt, i n 2 1 
se parate k nee re gi o ns usi n g 
 f or 
t he v ol u metric c ha n ges. 
T he c o de d me dical i ma ges will be use d pri maril y f or a nal ysis as descri be d i n t his pr ot oc ol; 
h o we ver, t he i ma ges ma y als o be use d f or t he de vel o p me nt a n d e val uati o n of ne w a nal ysis 
met h o ds directl y relate d t o t he area of researc h t hat t his st u d y c o vers.  
I nci de ntal 
fi n di n gs 
are 
be y o n d 
t he 
sc o pe 
of 
ce ntral 
i ma gi n g 
ve n d or. 
If 
a n i n vesti gat or/ra di ol o gist rec o g nizes a n y i nci de ntal fi n di n g i n t he i ma ges d uri n g t he c o urse of 
c o n d ucti n g t he cli nical trial, t he i n vesti gat or s h o ul d f oll o w u p as part of his/ her d ut y  of care t o 
e ns ure t he safet y a n d well bei n g of t he partici pa nt.  
8. 3. 3  
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  
Efficac y assess me nts were selecte d o n t he f oll o wi n g basis:  
•  Patie nt Re p orte d O utc o me meas ures use d (e. g., K O O S, N R S) are sta n dar d meas ure me nts 
f or assessi n g pai n i n partici pa nts wit h O A (G uer mazi  et al 2 0 1 1 ). T he K O O S P R O is a n 
e x pa n de d versi o n of t he 
Wester n O ntari o a n d 
Mc Master U ni versities Art hritis I n de x 
( W O M A C) sc ore, w hic h tra diti o nall y has bee n use d i n O A trials ( K O O S User G ui de, 
2 0 0 3). K O O S  i ncl u des W O M A C O A i n de x L K 3. 0 i n its c o m plete a n d ori gi nal f or mat a n d 
W O M A C sc ores ca n be deri ve d fr o m t he K O O S  i nstr u me nt. C o m pare d t o W O M A C, t he 
K O O S  sc ore pr o vi des a 
m ore c o m pre he nsi ve pict ure beca use it i ncl u des a d diti o nal 
d o mai ns, " F u ncti o n i n s p ort a n d recreati o n" a n d " K nee relate d Q o L". T he N R S  pai n sc ore 
is tra diti o nall y use d t o assess pai n. 
•  I ma gi n g tec h ni q ues i ncl u di n g M RI are sta n dar d meas ures use d f or assessi n g j oi nt str uct ure 
i n partici pa nts wit h O A (Ha yas hi  et al 2 0 1 9). F or a d diti o nal details o n a p pr o priate ness of 
k nee M RI para meters, see Secti o n  8. 3. 2 . 
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 9 6  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
8. 4  
S af et y/ T ol er a bilit y  
Safet y assess me nts are s pecifie d bel o w wit h t he assess me nt sc he d ule detaili n g w he n eac h 
assess me nt is t o be perf or me d.  
F or details o n A E c ollecti o n a n d re p orti n g, refer t o A E secti o n.  
T a bl e 8 -3  
S af et y A s s e s s m e nt s a n d S p e cifi c ati o n s  
A s s e s s m e nt  
S p e cifi c ati o n  
P h y si c al e x a mi n ati o n  
A c o m pl et e p h y si c al e x a mi n ati o n will i n cl u d e t h e e x a mi n ati o n of g e n er al 
a p p e ar a n c e, s ki n, n e c k (i n cl u di n g t h yr oi d), e y e s, e ar s, n o s e, t hr o at, l u n g s, 
h e art, 
a b d o m e n, 
b a c k, l y m p h 
n o d e s, 
e xtr e miti e s, 
v a s c ul ar, 
a n d 
n e ur ol o gi c al. If i n di c at e d b a s e d o n m e di c al 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 alia, br e a st, a n d p el vi c e x a m s will b e p erf or m e d.  
A k n e e j oi nt e x a mi n ati o n will al s o b e p erf or m e d, i n cl u di n g e x a mi n ati o n f or 
b ul g e si g n a n d p at ell ar t a p si g n a s w ell a s f or p at ell of e m or al p ai n. 
T ar g et e d p h y si c al e x a mi n ati o n s t o el a b or at e s elf - r e p ort e d s y m pt o m s, 
c o m pl ai nt s, i nj e cti o n sit e r e a cti o n s or p o s t-i nj e cti o n fl ar e s a s a p pli c a bl e, 
c a n b e d o n e at a n y vi sit.  
 
I nf or m ati o n f or all p h y si c al e x a mi n ati o n s m u st b e i n cl u d e d i n t h e s o ur c e 
d o c u m e nt ati o n at t h e st u d y sit e. Cli ni c all y r el e v a nt fi n di n g s t h at ar e 
pr e s e nt pri or t o si g ni n g i nf or m e d c o n s e nt 
m u st b e r e c or d e d o n t h e 
a p pr o pri at e e C R F t h at c a pt ur e s m e di c al hi st or y . Si g nifi c a nt fi n di n g s m a d e 
aft er si g ni n g i nf or m e d c o n s e nt w hi c h m e et t h e d efi niti o n of a n A d v er s e 
E v e nt m u st b e r e c or d e d a s a n a d v er s e e v e nt.  
Vit al si g n s  
Vit al si g n s will i n cl u d e t h e c oll e cti o n of b o d y t e m p er at ur e (r e c or d e d i n ° C), 
bl o o d pr e s s ur e ( B P) a n d p ul s e m e a s ur e m e nt s.  
T h e s a m e 
m et h o d f or 
m e a s uri n g b o d y t e m p er at ur e s h o ul d b e u s e d 
t hr o u g h o ut t h e st u d y. 
Aft er t h e p arti ci p a nt h a s b e e n sitti n g f or 3 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 B P a n d D B P will b e m e a s ur e d 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. 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.  
I n c a s e of r e p e at e d vit al a s s e s s m e nt s, t h e e C R F s h o ul d c o nt ai n all r e p e at 
m e a s ur e m e nt s.  
H ei g ht a n d w ei g ht  
H ei g ht i s o bt ai n e d i n c e nti m et er s ( c m) a n d b o d y w ei g ht i s o bt ai n e d i n 
kil o gr a m s ( k g) a n d r o u n d e d t o t h e n e ar e st 0. 1 k g. W ei g ht i s o bt ai n e d i n 
i n d o or cl ot hi n g, b ut wit h o ut s h o e s). H ei g ht a n d w ei g ht will b e m e a s ur e d 
a s s p e cifi e d i n T a bl e  8 -1 . 
B o d y m a s s i n d e x ( B MI) will b e c al c ul at e d u si n g t h e f oll o wi n g f or m ul a:  
• 
B MI = B o d y w ei g ht ( k g) / [ H ei g ht ( m)] 2  
R o u n di n g s h o ul d b e d o n e t o n e ar e st w h ol e n u m b er ( e. g., c al c ul at e d B MI 
i s 3 0. 4 4, t h e B MI v al u e c a n b e r o u n d e d t o 3 0 k g/ m 2 ). 
T h e S cr e e ni n g Vi sit h ei g ht m e a s ur e m e nt will b e u s e d f or B MI c al c ul ati o n s 
t hr o u g h o ut t h e st u d y. 

N o v arti s  
C o nfi d e nti al  
P a g e 9 7  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
8. 4. 1  
L a b or at or y e v al u ati o n s  
Cli nicall y si g nifica nt a b n or malities m ust be rec or de 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.  
I n t he case w here a la b orat or y ra n ge is n ot s pecifie d b y t he pr ot oc ol, b ut a val ue is o utsi de t he 
refere nce ra n ge f or t he la b orat or y at scree ni n g a n d/ or i nitial baseli ne, a decisi o n re gar di n g 
w het her t he res ult is of cli nical si g nifica nce or n ot s hall be m a de b y t he I n vesti gat or 
(i n c o ns ultati o n wit h t he s p o ns or) a n d s hall be base d, i n part, u p o n t he nat ure a n d de gree of t he 
o bser ve d a b n or malit y. T he assess me nt ma y be re peate d o nce pri or t o ra n d o mizati o n.  
I n all cases, t he I n vesti gat or m ust d oc u me nt i n t he s o urce d oc u me nts, t he cli nical c o nsi derati o ns 
(i.e., res ult was/ was n ot cli nicall y si g nifica nt a n d/ or me dicall y rele va nt) i n all o wi n g or 
disall o wi n g t he partici pa nt t o c o nti n ue i n t he st u d y.  
A ce ntral la b orat or y will be use d f or a nal ysis of all safet y s peci me ns c ollecte d. Details o n t he 
c ollecti o n, s hi p me nt of sa m ples a n d re p orti n g of res ults b y t he ce ntral la b orat or y are pr o vi de d 
t o i n vesti gat ors i n t he Ce ntral La b orat or y Ma n ual. 
If t he C O VI D-1 9 pa n de mic li mits or pre ve nts t he use of ce ntral la b orat or y ser vices, e. g., d ue t o 
tra ns p ort restricti o ns of tiss ue sa m ples, t he s p o ns or ma y re q uest esse ntial la b orat or y scree ni n g 
a n d/ or safet y assess me nts t o be a nal yze d b y a l ocal la b orat or y , if a vaila ble. If use d, rele va nt 
d oc u me ntati o n s h o ul d be o btai ne d fr o m t he l ocal la b orat or y t o e val uate t he vali dit y of t he data, 
c o nsi deri n g p ote ntial differe nces i n a nal ysis assa ys, refere nce ra n ges, etc. bet wee n t he l ocal a n d 
ce ntral la b orat ories. It m ust be clear fr o m t he fi nal data set w hic h data ori gi nate fr o m l ocal 
la b orat or y a nal yses. 
Uri n al y si s  
A mi dstrea m uri ne sa m ple (a p pr o x. 3 0 m L) will be o btai ne d, i n or der t o a v oi d c o nta mi nati o n 
wit h e pit helial cells a n d se di me nts t o all o w pr o per assess me nts.  
S p e ci al cli ni c al l a b or at or y e v al u ati o n s  
All a b n or mal la b res ults m ust be e val uate d f or criteria defi ni n g a n a d verse e ve nt a n d re p orte d 
as s uc h if t he criteria are met. F or t h ose la b a d verse e ve nts, re peate d e val uati o ns are ma n dat or y 
u ntil n or malizati o n of t he res ult(s) or u ntil t he res ult is n o l o n g er c o nsi dere d t o be cli nicall y 
si g nifica nt. 
T a bl e 8 -4  
L a b or at or y e v al u ati o n s  
T e st C at e g or y  
T e st N a m e  
H e m at ol o g y  
H e m at o crit, 
H e m o gl o bi n, 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, 
B a n d s).  
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), Bi c ar b o n at e, C al ci u m, M a g n e si u m, 
P h o s p h or u s, C hl ori d e, 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, Dir e ct 
Bilir u bi n, I n dir e ct Bilir u bi n, T ot al Bilir u bi n, 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, 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 ( n o n -f a sti n g) 

N o v arti s  
C o nfi d e nti al  
P a g e 9 8  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
T e st C at e g or y  
T e st N a m e  
If t h e t ot al bilir u bi n c o n c e ntr ati o n i s i n cr e a s e d a b o v e 1. 5 ti m e s t h e u p p er li mit 
of n or m al, dir e ct a n d i n dir e ct r e a cti n g bilir u bi n s h o ul d b e diff er e nti at e d. I n 
a d diti o n, 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) will b e m e a s ur e d f or 
i n cl u si o n a n d f or a ss e s si n g s y st e mi c i nfl a m m ati o n. Cli ni c al c h e mi str y s a m pl e s 
will b e u s e d a s p er a s s e s s m e nt s c h e d ul e if still f e a si bl e. I n c a s e r e s p e cti v e 
cli ni c al c h e mi str y s a m pl e s h a v e b e e n alr e a d y d e str o y e d, 
 
 
 
Uri n al y si s  
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)  
M a cr o s c o pi c P a n el ( Di p sti c k) ( C ol or, Bilir u bi n, Bl o o 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)  
C o a g ul ati o n  
Pr ot hr o m bi n ti m e ( P T), I nt er n ati o n al n or m ali z e d r ati o [I N R]),   A cti v at e d p arti al 
t hr o m b o pl a sti n ti m e ( A P T T) 
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,  s e e S e cti o n  8. 4. 3  
8. 4. 2  
El e ctr o c ar di o gr a m ( E C G)  
E C Gs m ust be rec or de d after 1 0 mi n utes rest i n t he s u pi ne p ositi o n t o e ns ure a sta ble baseli ne . 
I n t he case of a series of assess me nts, E C G s h o ul d be first assess me nt o btai ne d w hile partici pa nt 
is at rest. 
T he Fri dericia Q T c orrecti o n f or m ula ( Q Tc F) m ust be use d f or cli nical decisi o ns.  
U nless a ut o -calc ulate d b y t he E C G mac hi ne, t he i n vesti gat or m ust calc ulate Q Tc F at t he 
Scree ni n g a n d Baseli ne visit(s) t o assess eli gi bilit y acc or di n g t o t he f oll o wi n g f or m ula:  
 
Si n gle 1 2 -lea d E C Gs are c ollecte d a n d res ults are e ntere d i nt o t he a p pr o priate e C R F pa ge. 
T he  ori gi nal E C Gs o n n o n -heat -se nsiti ve pa per, a p pr o priatel y si g ne d, m ust be c ollecte d a n d 
arc hi ve d. 
Eac h E C G traci n g m ust be la bele d wit h st u d y n u m ber, partici pa nt i nitials, partici pa nt n u m ber, 
date a n d ti me, a n d file d i n t he st u d y site s o urce d oc u me nts. I n vesti gat or s h o ul d d oc u me nt 
cli nical e val uati o n i n s o urce. F or a n y E C Gs wit h partici pa nt safet y c o nc er ns, t w o a d diti o nal 
E C Gs m ust be perf or me d t o c o nfir m t he safet y fi n di n g. Cli nicall y si g nifica nt E C G fi n di n gs at 
baseli ne m ust be disc usse d wit h t he s p o ns or bef ore a d mi nistrati o n of st u d y treat me nt.  
Cli nicall y si g nifica nt a b n or malities m ust be rec or de d o n t he rele va nt secti o n of t he me dical 
hist or y/ C urre nt me dical c o n diti o ns/ A E e C R F as a p pr o priate.  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 9 9  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
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  
A c o n d o m is re q uire d f or all se x uall y acti ve male partici pa nts t o pre ve nt t he m fr o m fat heri n g a 
c hil d A N D t o pre ve nt deli ver y of st u d y treat me nt via se mi nal fl ui d t o t heir part ner.  I n a d diti o n, 
male partici pa nts s h o ul d n ot d o nate s per m w hile ta ki n g st u d y t reat me nt a n d f or 9 0 da ys after 
st o p pi n g st u d y treat me nt. 
All pre -me n o pa usal w o me n w h o are n ot s ur gicall y sterile will ha ve pre g na nc y testi n g. 
A d diti o nal pre g na nc y testi n g mi g ht be perf or me d if re q ueste d b y l ocal re q uire me nts.  
Ser u m pre g na nc y testi n g is re q uire d at Scree ni n g a n d E o S. Uri ne pre g na nc y testi n g is re q uire d 
at all ot her visits as s pecifie d i n t he Assess me nt Sc he d ule ( Ta ble  8 -1 ). A d diti o nal pre g na nc y 
testi n g mi g ht be perf or me d if re q ueste d b y l ocal re q uire me nts. L ocal pre g na nc y test a n d 
ass ociate d res ults will n ot be c ollecte d o n e C R F a n d res ults will be rec or de d i n s o urce 
d oc u me ntati o n.  
A p ositi ve uri ne pre g na nc y test re q uires i m me diate i nterr u pti o n of st u d y treat me nt u ntil ser u m 
β -h C G is perf or me d a n d f o u n d t o be ne gati ve.  
If partici pa nts ca n n ot visit t he site t o ha ve ser u m pre g na nc y tests d uri n g a P u blic Healt h 
e mer ge nc y as declare d b y L ocal or Re gi o nal a ut h orities i.e. pa n de mic, e pi de mic or nat ural 
disaster, t hat li mits or pre ve nts o n -site st u d y visits, uri ne pre g na nc y test kits ma y be use d, if a n d 
w here per mitte d b y t he l ocal re g ulati o ns a n d a gree d wit h t he l ocal Healt h A ut h orities (i n 
Ger ma n y o nl y ser u m pre g na nc y tests are per mitte d at scree ni n g a n d E o S visits) . Rele va nt 
partici pa nts ca n perf or m t he uri ne pre g na nc y test a t h o me a n d re p ort t he res ult t o t he site. It is 
i m p orta nt t hat partici pa nts are i nstr ucte d t o perf or m t he uri ne pre g na nc y test first a n d o nl y if 
t he test res ult is ne gati ve pr ocee d 
wit h t he a d mi nistrati o n of t he st u d y treat me nt. 
A  c o m m u nicati o n pr ocess s h o ul d be esta blis he d wit h t he partici pa nt s o t hat t he Site is i nf or me d 
a n d ca n verif y t he pre g na nc y test res ults (e. g., f oll o wi n g c o u ntr y s pecific meas ures).  
A s s e s s m e nt s of f ertilit y  
Me dical d oc u me ntati o n of o o p h orect o m y, h ysterect o m y, or t u bal li gati o n m ust be retai ne d as 
s o urce d oc u me nts. S u bse q ue nt h or m o ne le vel assess me nt t o c o nfir m t he w o ma n is n ot of c hil d -
beari n g p ote ntial m ust als o be a vaila ble as s o urce d oc u me ntati o n i n t he f o ll o wi n g cases: 
1.  S ur gical bilateral o o p h orect o m y wit h o ut a h ysterect o m y  
2.  Re p orte d 1 2 m o nt hs of nat ural (s p o nta ne o us) a me n orr hea wit h a n a p pr o priate cli nical 
pr ofile.  
I n t he a bse nce of t he a b o ve me dical d oc u me ntati o n, F S H testi n g is re q uire d of a n y fe male 
partici pa nt re gar dless of re p orte d re pr o d ucti ve/ me n o pa usal stat us at scree ni n g/ baseli ne.  
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 selecte d are sta n dar d f or t his i n dicati o n/ partici pa nt p o p ulati o n.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 0  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
8. 5  
A d diti o n al a s s e s s m e nt s  
8. 5. 1  
 
 
 
 
 
 
 
  
8. 5. 2  
P h ar m a c o ki n eti c s  
P K sa m ples will be c ollecte d at t he visits defi ne d i n t he assess me nt sc he d ule. F oll o w 
i nstr ucti o ns o utli ne d i n t he Ce ntral 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. See t he p ote ntial use of resi d ual sa m ples f or m ore  i nf or mati o n. I n 
case nee de d (e. g., s ki n ras h), a n u nsc he d ule d sa m ple s h o ul d be c ollecte d as near as p ossi ble t o 
t he e ve nt i n or der t o assess a p ote ntial P K relati o ns hi p. 
P har mac o ki netic ( P K) plas ma sa m ples will be o btai ne d fr o m all partici pa nts a n d e val uate d o nl y 
i n partici pa nts e x p ose d t o D F V 8 9 0 ( place b o gr o u p e xcl u de d fr o m a nal ysis). 
 
 
 
D F V 8 9 0 a n d  
, a meta b olite of D F V 8 9 0, i n plas ma will be deter mi ne d b y a vali date d 
L C -M S/ M S  met h o d; t he a ntici pate d l o wer li mit of q ua ntificati o n ( L L O Q) is 1 n g/ m L. D F V 8 9 0 
i n s y n o vial fl ui d will be deter mi ne d b y a q ualifie d L C-M S/ M S  met h o d; t he a ntici p ate d l o wer 
li mit of q ua ntificati o n ( L L O Q) is 1 n g/ m L. 
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. I n or der t o better defi ne t he P K pr ofile, t he ti mi n g of t he P K sa m ple c ollecti o n ma y be 
altere d base d o n e mer ge nt data wit h alterati o n ± 5 mi n f or ti me p oi nts ≤ 2 h p ost -d ose; ± 3 0 mi n 
f or ti me p oi nts 2 h < 1 2 h p ost-d ose; ± 1 h f or Ctr o u g h ( bef ore d ose a d mi nistrati o n).  
F or sta n dar d p har mac o ki netic a b bre viati o ns a n d defi niti o ns see t he list pr o vi de d at t he 
be gi n ni n g of t his pr ot oc ol.  T he f oll o wi n g plas ma p har mac o ki netic para meters 
will be 
deter mi ne d usi n g t he act ual rec or de d sa m pli n g ti mes a n d n o n -c o m part me ntal met h o d(s) wit h 
P h oe ni x Wi n N o nli n ( Versi o n 8): C ma x, T ma x, A U Cta u ( A U C 0 -1 2 h), A U Clast. T o calc ulate 
A U Cta u, t he c o nce ntrati o n at 0 h will be use d als o as a 1 2 h ti me p oi nt or it will be e xtra p olate d. 
Calc ulati o n met h o d will be s pecifie d i n t he re p ort. Meta b olite t o p are nt rati o f or A U C a n d C ma x 
will be deri ve d. Als o tr o u g h c o nce ntrati o ns ( Ctr o u g h) i n plas ma a n d s y n o vial fl ui d will be 
meas ure d  at t he visits defi ne d i n t he assess me nt sc he d ule.  
T he li near tra pez oi dal r ule will be use d f or A U C calc ulati o n.  
C CI
C CI
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 1  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
8. 5. 3  
Bi o m ar k er s  
8. 5. 3. 1  
S ol u bl e bi o m ar k er s  
 
 
 
 
A d diti o nal bi o mar ker assess me nts i n ser u m/s y n o vial fl ui d ma y i ncl u de bi o mar kers reflecti ve 
 or ot hers, w hic h are gate d a n d ma y 
be tri g gere d u p o n t he o verall o utc o me of t his or ot her st u dies.  
T he list of bi o mar kers ma y be c ha n ge d or e x pa n de d, if it is rec o g nize d t hat m ore rele va nt or 
a d diti o nal bi o mar kers s h o ul d be assesse d d uri n g t he c o n d uct of t he st u d y.  
I n a d diti o n, h y p ot hesis-free platf or ms s uc h as S o ma Sca n, 
 arra ys or ot hers ma y be use d 
t o i de ntif y m olec ular partici pa nt pr ofiles a n d ne w p har mac o d y na mic mar kers i n ser u m a n d 
s y n o vial fl ui d. Res ults o btai ne d ma y be a ble t o s u p p ort t he i de ntificati o n of pat h wa ys/ mar kers 
t hat c haracterize t he disease i n a d diti o n t o res p o nse t o treat me nt wit h D F V 8 9 0, t o i nf or m j oi nt 
tra ns missi o n i nt o circ ulati o n, a n d t o c orrelate mar kers wit h ot her cli nical rea d o uts. 
N L R P 3 -pat h wa y bi o mar kers or res ults ge nerate d b y pr ofili n g assess me nts will be c orrelate d 
wit h ot her rea d o uts, s uc h as i ma gi n g -base d rea d o uts or pai n, t o u n dersta n d t he tra nslati o n of 
p ote ntial m olec ular c ha n ges i nt o a re d ucti o n of s y n o vitis, a n d s u bse q ue n tl y, partici pa nt be nefit. 
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 2  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
8. 5. 3. 4  
R e n al i m p air m e nt bi o m ar k er s  
 
 
 
 
 
 
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 ble  8 -1 ). 
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 ual. 
8. 5. 3. 5  
D N A s a m pli n g / P h ar m a c o g e n eti c s  
T his st u d y i n v ol ves b ot h a ma n dat or y a n d a n 
. 
P h ar m a c o g e n eti c s a m pl e f or C Y P 2 C 9 g e n ot y pi n g  
 
  
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 3  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 4  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
8. 5. 4  
S y n o vi al fl ui d c oll e cti o n  
 
 C ollecti o n will de pe n d 
o n w het her or n ot s y n o vial fl ui d is prese nt i n t he k nee,  a n d o n partici pa nt willi n g ness t o u n der g o 
t his pr oce d ure a n d base d o n t he i n vesti gat or j u d ge me nt. S y n o vial fl ui d sa m ples will be 
c ollecte d b y a p pr o priatel y e q ui p pe d a n d trai ne d staff. F or m ore details o n t he pr oce d ure, please 
refer t o t he Ce ntral La b orat or y Ma n ual.  
8. 5. 5  
I m a gi n g 
T he met h o ds f or assess me nt a n d rec or di n g are s pecifie d i n t he I ma gi n g c harter.  
T he c o de d me dical i ma ges will be use d pri maril y f or a nal ysis as descri be d i n t his pr ot oc ol; 
h o we ver, t he i ma ges ma y als o be use d f or t he de vel o p me nt a n d e val uati o n of ne w a nal ysis 
met h o ds directl y relate d t o t he area of researc h t hat t his st u d y c o vers.  
8. 5. 6  
Ot h er A s s e s s m e nt s  
 
 
 
 
 
 
  
  
 
  
  
  
  
  
  
  
 
 
8. 5. 6. 2  
M e al R e c or d  
Meal rec or ds are re q uire d f or o nsite meals i n c o nj u ncti o n wit h st u d y treat me nt i nta ke i n or der 
t o assess f o o d i nta ke i m pact o n P K data. F or t hese meals t he date, start a n d e n d ti me of meal 
c o ns u m pti o n will be ca pt ure d i n t he e C R Fs. Data will n ot be c ollect e d o utsi de of st u d y visits.  
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 per ma ne ntl y 
st o p pe d f or a n y reas o n pri or t o t he pr ot oc ol pla n ne d c o m pleti o n of st u d y dr u g a d mi nistrati o n. 
Disc o nti n uati o n of st u d y treat me nt ca n be i nitiate d b y eit her t he partici pa nt or t he i n vesti gat or.  
T he i n vesti gat or m ust disc o nti n ue st u d y treat me nt f or a gi ve n partici pa nt if 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.  
Disc o nti n uati o n fr o m st u d y treat me nt is re q uire 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  
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 5  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
•  Use of pr o hi bite d treat me nt as per rec o m me n dati o ns i n t he pr o hi bite d treat me nt secti o n 
(see Secti o n 6. 2. 2 )  
•  A n y sit uati o n i n w hic h c o nti n ue d st u d y partici pati o n mi g ht res ult i n a safet y ris k t o t he 
partici pa nt  
•  F oll o wi n g e mer ge nc y u n bli n di n g  
•  E mer ge nce of at least o ne of t he f oll o wi n g a d verse e ve nts:  
•  A life -t hreate ni n g a d verse e ve nt (c orres p o n di n g t o C T C A E Gra de 4 or hi g her) 
c o nsi dere d relate d t o D F V 8 9 0 treat me nt  
•  A n A E of se vere i nte nsit y (c orres p o n di n g t o C T C A E Gra de 3 or hi g her) c o nsi dere d 
relate d t o D F V 8 9 0 treat me nt 
•  S ki n ras hes greater t ha n mil d (c o veri n g > 1 0 % of t he b o d y s urface area, 
c orres p o n di n g t o C T C A E Gra de 2 or hi g her), c o nsi dere d as relate d t o D F V 8 9 0  
•  If a n a b n or mal re nal e ve nt is c o nfir me d, a n d ot her ca uses are e xcl u de d, t he st u d y dr u g 
will be i nterr u pte d i n t he case of:  
•  Ser u m creati ni ne i ncrease of 5 0 % (i.e., ac ute ki d ne y i nj ur y)  
•  Ne w o nset di pstic k pr otei n uria ≥ 3 +  
•  Uri ne Pr otei n -creati ni ne rati o ( P C R, g Cr) ≥ 1 g/ g  
•  Ne w e vi de nce of cli nicall y si g nifica nt cr ystals o n micr osc o p y  
Please refer t o Secti o n 1 0. 2. 2  a n d A p pe n di x 2  f or f urt her i nstr ucti o ns a n d m o nit ori n g. 
•  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 a li ver e ve nt occ urs, f oll o w g ui deli nes o utli ne d i n A p pe n di x  1  re gar di n g disc o nti n uati o n 
of st u d y treat me nt.  
If disc o nti n uati o n fr o m 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 he partici pa nt’s disc o nti n uati o n fr o m st u d y treat me nt a n d 
rec or d t his i nf or mati o n. 
Partici pa nts w h o disc o nti n ue fr o m st u d y treat me nt a gree t o ret ur n f or t he e n d of treat me nt a n d 
f oll o w-u p visits i n dicate d i n t he Assess me nt Sc he d ule (refer t o Secti o n  8 ) 
If t he partici pa nt ca n n ot or is u n willi n g t o atte n d a n y 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 partici pa nt, or wit h a pers o n pre-desi g nate d b y t he 
partici pa nt. T his tele p h o ne c o ntact s h o ul d prefera bl y be d o ne acc or di n g t o t he st u d y visit 
sc he d ule. 
After disc o nti n uati o n fr o m st u d y treat me nt, 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 visits or via tele p h o ne/e mail c o ntact:  
•  Ne w / c o nc o mita nt treat me nts  
•  A d verse E ve nts / Seri o us A d verse E ve nts  
T he i n vesti gat or m ust als o c o ntact t he I R T/ NI R T t o re gister t he partici pa nt’s disc o nti n uati o n 
fr o m st u d y treat me nt. 

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 6  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
If disc o nti n uati o n occ urs beca use treat me nt c o de has bee n br o ke n, please refer t o E mer ge nc y 
brea ki n g of treat me nt c o de secti o n.  
9. 1. 1. 1  
R e pl a c e m e nt p oli c y  
A d diti o nal partici pa nts ma y be e nr olle d t o re place disc o nti n ue d partici pa nts if t he dr o p -o ut rate 
( base d o n disc o nti n uati o ns pri or t o Wee k 1 2) e xcee ds 1 0 %. 
9. 1. 2  
Di s c o nti n u ati o n fr o m st u d y  
Disc o nti n uati o n fr o m st u d y is w he n t he partici pa nt per ma ne ntl y st o ps recei vi n g t he st u d y 
treat me nt, a n d f urt her pr ot oc ol-re q uire d assess me nts or f oll o w-u p, f or a n y reas o n.  
If t he partici pa nt a grees, a fi nal e val uati o n at t he ti me of t he partici pa nt’s st u d y disc o nti n uati o n 
s h o ul d be ma de as detaile d i n t he assess me nt ta ble (refer t o Secti o n  8 ). 
9. 1. 3  
Wit h dr a w al of i nf or m e d c o n s e nt  
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 pa nt:  
•  E x plicitl y re q uests t o st o p use of t heir bi ol o gical sa 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 t heir 
c o nse nt/ o p p ositi o n t o use data/ bi ol o gical sa m ples 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 Data is n ot re q uire d i n a certai n c o u ntr y's le gal 
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 c ollecti o n or 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 assess me nts c o n d ucte d, a n d t he data t hat 
w o ul d ha ve bee n c ollecte d at s u bse q ue nt visits will be c o nsi dere d missi n g.  
F urt her atte m pts t o c o ntact t he partici pa nt are n ot all o we d u nless safet y fi n di n gs re q uire 
c o m m u nicati n g or f oll o w -u p.  
If t he partici 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 detaile d i n t he assess me nt 
ta ble (refers t o Secti o n  8 ). 

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 7  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
N o vartis  will c o nti n ue t o retai n a n d use all researc h res ults ( data) t hat ha ve alrea d y bee n 
c ollecte d f or t he st u d y e val uati o n, i ncl u di n g pr ocessi n g of bi ol o gical sa m ples t hat has alrea d y 
starte d at ti me of c o nse nt wit h dra wal/ o p p ositi o n. N o ne w Pers o nal Da ta (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. 4  
L o st t o f oll o w -u p  
F or partici pa nts w h ose stat us is u nclear beca use t he y fail t o a p pear f or st u d y visits wit h o ut 
stati n g a n i nte nti o n t o disc o nti n ue fr o m st u d y treat me nt or disc o nti n ue fr o m st u d y or 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 me nti n g i n t he s o urce d oc u me nts ste ps ta ke n t o c o ntact t he 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 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 b ee n c o m plete d or u ntil t he e n d of t he st u d y.  
9. 1. 5  
St u d y st o p pi n g r ul e s  
O v er all st u d y st o p pi n g r ul e s  
T he st u d y will be st o p pe d a n d n o f urt her d osi n g a n d/ or ne w recr uit me nt will occ ur pe n di n g f ull 
safet y re vie w, if a n y of t he f oll o wi n g criteria are met: 
•  A n y deat h or life -t hreate ni n g e ve nt (c orres p o n di n g t o C T C A E Gra de 4 or hi g her) 
c o nsi dere d t o be relate d t o D F V 8 9 0 treat me nt  
•  T w o ( 2) or m ore S A Es of a si milar t y pe ( ot her t ha n deat h or life -t hreate ni n g e ve nt, 
c orres p o n di n g t o C T C A E Gra de 3 or hi g her) c o nsi dere d t o be relate d t o D F V 8 9 0 treat me nt  
•  T w o ( 2) or m ore partici pa nts are disc o nti n ue d d ue t o a re nal e ve nt as defi ne d i n Secti o n  1 6. 2  
•  T w o ( 2) or m ore partici pa nts e x perie nce t hree or m ore A Es of si milar t y pe w hic h are 
assesse d as se vere i n i nte nsit y (c orres p o n di n g t o C T C A E Gra de 3 or hi g her) a n d c o nsi dere d 
t o be relate d t o D F V 8 9 0 treat me nt 
•  N u m ber a n d/ or se verit y of A Es, a b n or mal safet y m o nit ori n g tests, or a b n or mal la b orat or y 
fi n di n gs j ustif y p utti n g t he st u d y o n h ol d 
•  T w o ( 2) or m ore partici pa nts prese nti n g D F V 8 9 0 treat me nt relate d ac ute e xacer bati o ns of 
k nee s y m pt o ms, as j u d ge d b y t he I n vesti gat or a n d/ or t he S p o ns or  
T he safet y re vie w will be c o n d ucte d j oi ntl y bet wee n me dicall y q ualifie d re prese ntati ves of t he 
S p o ns or a n d t he I n vesti gat ors.  T he st u d y ma y res u me f oll o wi n g t he safet y re vie w, if t he 
I n vesti gat or a n d S p o ns or a gree it is safe t o pr ocee d a n d necessar y a p pr ovals ha ve bee n o btai ne d 
fr o m a ut h orities. 

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 8  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
9. 1. 6  
E arl y st u d y t er mi n ati o n b y t h e s p o n s or  
T he st u d y ca n be ter mi nate d b y N o vartis  at a n y ti me. 
Reas o ns f or earl y ter mi nati o n:  
•  U ne x pecte d, si g nifica nt, or u nacce pta ble safet y ris k t o partici pa nts e nr olle d i n t he st u d y  
•  Decisi o n base d o n rec o m me n dati o ns fr o m a p plica ble b oar d(s) after re vie w of safet y a n d 
efficac y data  
•  Disc o nti n uati o n of st u d y dr u g de vel o p me nt  
I n ta ki n g t he decisi o n t o ter mi nate, N o vartis will al wa ys c o nsi der partici pa nt welfare a n d safet y. 
S h o ul d earl y ter mi nati o n be necessar y, partici pa nts m ust be see n as s o o n as p ossi ble  a n d treate d 
as a partici pa nt w h o disc o nti n ue d fr o m st u d y treat me nt: i nst r ucti o ns f or c o ntacti n g t he 
partici pa nt, w he n t he partici pa nt s h o ul d st o p ta ki n g dr u g, a n d w he n t he partici pa nt s h o ul d c o me 
i n f or a fi nal visit, will be pr o vi de d at t hat ti me. T he i n vesti gat or ma y be i nf or me d of a d diti o nal 
pr oce d ures t o be f oll o we d i n or d er t o e ns ure t hat a de q uate c o nsi derati o n is gi ve n t o t he 
pr otecti o n of t he partici pa nt’s i nterests. T he i n vesti gat or or s p o ns or, de pe n di n g o n l ocal 
re g ulati o n, will be res p o nsi ble f or i nf or mi n g I R Bs/I E Cs of t he earl y ter mi nati o n of t he trial. 
9. 2  
St u d y c o m pl eti o n a n d p o st -st u d y tr e at m e nt  
St u d y c o m pleti o n is defi ne d as w he n t he last partici pa nt fi nis hes t heir E o S visit a n d a n y re peat 
assess me nts ass ociate d wit h t his visit ha ve bee n d oc u me nte d a n d f oll o we d -u p a p pr o priatel y b y 
t he I n vesti gat or or, i n t he e ve nt of a n earl y st u d y ter mi nati o n decisi o n, t he date of t hat decisi o n. 
Eac h partici pa nt will be re q uire d t o c o m plete t he st u d y i n its e ntiret y a n d t hereafter n o f urt her 
st u d y treat me nt will be ma de a vaila ble t o t he m. 
All treate d partici pa nts s h o ul d ha ve a safet y f oll o w -u p call c o n d ucte d 3 0 da ys after last 
a d mi nistrati 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 oc u me ntati o n. 
All S A Es re p orte d d uri n g t his ti me peri o d m ust be re p orte d as descri be d i n Secti o n 1 0. 1. 3 . 
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 de d i n t he s o urce 
d oc u me ntati o n.  
C o nti n ui n g care s h o ul d be pr o vi de d b y t he i n vesti gat or a n d/ or referri n g p h ysicia n. N o f urt her 
st u d y treat me nt will be pr o vi de d. 
1 0  
S af et y m o nit ori n g a n d r e p orti n g  
1 0. 1  
D efi niti o n of a d v er s e e v e nt s a n d r e p orti n g r e q uir e m e nt s  
1 0. 1. 1  
A d v er s e e v e nt s  
A n a d verse e ve nt ( A E) is a n y u nt o war d me dical occ urre nce (e. g. a n y u nfa v ora ble a n d 
u ni nte n de d si g n [i ncl u di n g a b n or mal la b orat or y fi n di n gs], s y m pt o m or disease) i n a cli nical 
i n vesti gati o n partici pa nt after pr o vi di n g writte n i nf or me d c o nse nt f or partici pati o n i n t he st u d y. 
T heref ore, a n A E ma y or ma y n ot be te m p orall y or ca usall y ass ociate d wit h t he use of a 
me dici nal (i n vesti gati o nal) pr o d uct.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 9  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
F or me dical de vices (i n vesti gati o nal or mar kete d), a n a d verse e ve nt ( A E) is a n y u nt o war d 
me dical, u ni nte n de d disease or i nj ur y or u nt o war d cli nical si g ns, i ncl u di n g a n a b n or mal 
la b orat or y fi n di n g, i n partici pa nts, users or ot her pers o ns, i n t he c o nte xt of a cli nical 
i n vesti gati o n, w het her or n ot relate d t o t he de vice. F or i n vesti gati o nal de vices, t his i ncl u des 
e ve nts relate d t o t he i n vesti gati o nal de vice or t he c o m parat or a n d e ve nts relate d t o t he 
pr oce d ures i n v ol ve d i n t he cli nical i n vesti gati o n pla n.  
T he I n vesti gat or a n d a n y q ualifie d desi g nees are res p o nsi ble f or ma na gi n g t he safet y of 
i n di vi d ual partici pa nts. T he y are als o res p o nsi ble f or detecti n g, d oc u me nti n g, a n d rec or di n g 
e ve nts t hat meet t he defi niti o n of a n A E or S A E a n d f or f oll o wi n g u p all A E s a n d S A Es. 
N o vartis  q ualifie d me dical pers o n nel will be rea dil y a vaila ble t o a d vise o n trial relate d me dical 
q uesti o ns or pr o ble ms.  
T he occ urre nce of a d verse e ve nts m ust be s o u g ht b y n o n -directi ve q uesti o ni n g of t he partici pa nt 
at eac h visit d uri n g t he st u d y. A d verse e ve nts als o ma y be detecte d w he n t he y are v ol u nteere d 
b y t he partici pa nt d uri n g or bet wee n visits or t hr o u g h p h ysical e x a mi nati o n fi n di n gs, la b orat or y 
test fi n di n gs, or ot her assess me nts (e. g. i n dicate d b y c o m me nts i n t he pai n diar y). 
A d verse e ve nts m ust be rec or de d u n der t he si g ns, s y m pt o ms, or dia g n osis ass ociate d wit h t he m, 
acc o m pa nie d b y t he f oll o wi n g i nf or mati o n (as far as p ossi ble); if t he e ve nt is seri o us, refer t o 
Secti o n  1 0. 1. 2 : 
1.  T he se verit y gra de  
•  mil d:  A t y pe of A E t hat is us uall y tra nsie nt a n d ma y re q uire o nl y mi ni mal treat me nt 
or t hera pe utic i nter ve nti o n. T he e ve nt d oes n ot ge nerall y i nterfere wit h us ual acti vities 
of dail y li vi n g.  
•  m o derate:  A t y pe of A E t hat is us uall y alle viate d wit h a d diti o nal s pecific t hera pe utic 
i nter ve nti o n. T he e ve nt i nterferes wit h us ual acti vities of dail y li vi n g, ca usi n g 
disc o mf ort b ut p oses n o si g nifica nt or per ma ne nt ris k of har m t o t he researc h 
partici pa nt.  
•  se vere: A t y pe of a d verse e ve nt t hat i nterr u pts us ual acti vities of dail y li vi n g, 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.  
2.  T he ca usalit y  
T he i n vesti gat or is o bli gate d t o assess t he relati o ns hi p bet wee n a n y treat me nt use d i n t he 
st u d y (st u d y treat me nt, A x M P(s)) a n d eac h occ urre nce of eac h A E. T he i n vesti gat or will 
use cli nical j u d g me nt t o deter mi ne t he relati o ns hi p. A reas o na ble p ossi bilit y of a 
relati o ns hi p c o n ve ys t hat t here are facts, e vi de nce, a n d/ or ar g u me nts t o s u g gest a ca usal 
relati o ns hi p, rat her t ha n a relati o ns hi p ca n n ot be r ule d o ut. Alter nati ve ca uses, s uc h as 
u n derl yi n g disease(s), c o nc o mita nt t hera p y, a n d ot her ris k fact ors, as well as t he te m p oral 
relati o ns hi p of t he e ve nt t o st u d y i nter ve nti o n a d mi nistrati o n, will be c o nsi dere d a n d 
i n vesti gate d. F or ca usalit y assess me nt, t he i n vesti gat or will als o c o ns ult t he I B a n d/ or 
pr o d uct i nf or mati o n, f or mar kete d pr o d ucts.  
T he ca usalit y assess me nt is o ne of t he criteria use d w he n deter mi ni n g re g ulat or y re p orti n g 
re q uire me nts. 
3.  Its d urati o n (start a n d e n d dates or o n g oi n g) a n d t he o utc o me m ust be re p orte d 

N o v arti s  
C o nfi d e nti al  
P a g e 1 1 0  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
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 gar di n g st u d y treat me nt.  
All a d verse e ve nts m ust be treate d a p pr o priatel y. Treat me nt ma y i ncl u de o ne or m ore of t he 
f oll o wi n g: 
•  D ose n ot c ha n ge d  
•  D ose Re d uce d/i ncrease d  
•  Dr u g i nterr u pte d/ per ma ne ntl y disc o nti n ue d  
6.  Its o utc o me 
•  n ot rec o vere d/ n ot res ol ve d;  
•  rec o vere d/res ol ve d; 
•  rec o vere d/res ol ve d wit h se q uelae; 
•  fatal; or u n k n o w n. 
C o n diti o ns t hat were alrea d y prese nt at t he ti me of i nf or me d c o nse nt s h o ul d be rec or de d i n 
me dical hist or y of t he partici pa nt.  
A d verse e ve nts (i ncl u di n g la b a b n or malities t hat c o nstit ute A Es) s h o ul d be descri be d usi n g a 
dia g n osis w he ne ver p ossi ble, rat her t ha n i n di vi d ual u n derl yi n g si g ns a n d s y m pt o ms.  
A d verse e ve nt m o nit ori n g s h o ul d be c o nti n ue d f or at least 3 0 da ys f oll o wi n g t he last d ose of 
st u d y treat me nt. 
O nce a n a d verse e ve nt is detecte d, it m ust be f oll o we d u ntil its res ol uti o n or u ntil it is j u d ge d t o 
be per ma ne nt (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 be ma de at eac h 
visit ( or m ore fre q ue ntl y, if necessar y) of a n y c ha n ges i n se ve rit y, t he s us pecte d relati o ns hi p t o 
t he i nter ve nti o ns re q uire d t o treat it, a n d t he o utc o me. 
I nf or mati o n a b o ut a d verse dr u g reacti o ns ca n be f o u n d i n t he I n vesti gat or's Br oc h ure (I B) f or 
t he i n vesti gati o nal dr u g or i n t he pr o d uct i nf or mati o n f or mar kete d pr o d ucts. 
A b n or mal la b orat or y val ues or test res ults c o nstit ute a d verse e ve nts o nl y if t he y f ulfill at least 
o ne of t he f oll o wi n g criteria:  
•  t he y i n d uce cli nical si g ns or s y m pt o ms 
•  t he y are c o nsi dere d cli nicall y si g nifica nt 
•  t he y re q uire t hera p y 
Cli nicall y si g nifica nt a b n or mal la b orat or y val ues or test res ults m ust be i de ntifie d t hr o u g h a 
re vie w of val ues o utsi de of n or mal ra n ges/cli nicall y n ota ble ra n ges, si g nifica nt c ha n ges fr o m 
baseli ne or t he pre vi o us visit, or val ues w hic h are c o nsi dere d t o b e n o n-t y pical i n a partici pa nt 
wit h t he u n derl yi n g disease.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 1 1  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
R e p orti n g of A E s r el at e d t o A x M P( s)  
All A Es relate d t o a n y a ut h orize d a u xiliar y me dici nal pr o d uct use d i n t his st u d y m ust be 
re p orte d t o N o vartis.  
I n assessi n g ca usalit y, t he i n vesti gat ors will use t he p oi nts a b o ve.  
If a s us pici o n t hat me dical occ urre nce c o ul d be relate d t o st u d y treat me nt (a n d/ or i nteracti o n 
wit h st u d y treat me nt) ca n n ot be r ule d o ut, t he re p orti n g r ules f or st u d y treat me nt a p pl y.  
T he A E re p orti n g re q uire me nts f or A x M Ps will a p pl y o nce t his trial has bee n tra nsiti o ne d u n der 
E U Cli nical Trial Re g ulati o n 5 3 6/ 2 0 1 4.  
1 0. 1. 2  
S eri o u s a d v er s e e v e nt s  
A n S A E is defi ne d as a n y a d verse e ve nt [a p peara nce of ( or w orse ni n g of a n y pre -e xisti n g)] 
u n desira ble si g n(s), s y m pt o m(s), or me dical c o n diti o ns(s) w hic h meets a n y o ne of t he f oll o wi n g 
criteria: 
•  fatal 
•  life-t hreate ni n g 
Life -t hreate ni n g i n t he c o nte xt of a S A E refers t o a reacti o n i n w hic h t he partici pa nt was at ris k 
of deat h at t he ti me of t he reacti o n; it d oes n ot refer t o a reacti o n t hat h y p ot heticall y mi g ht ha ve 
ca use d deat h if it were m ore se vere ( please refer t o t he  I C H-E 2 D G ui deli nes).  
•  res ults i n 
persiste nt 
or si g nifica nt 
disa bilit y/i nca pacit y. c o nstit utes a c o n ge nital 
a n o mal y/ birt h defect. re q uires i n -patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g 
h os pitalizati o n, u nless h os pitalizati o n is f or:  
•  r o uti ne treat me nt or m o nit ori n g of t he st u die d i n dicati o n, n ot ass ociate d wit h a n y 
deteri orati o n i n t he partici pa nt's O A c o n diti o n  
•  electi ve or pre -pla n ne d treat me nt f or a pre -e xisti n g c o n diti o n t hat is u nrelate d t o t he 
i n dicati o n u n der st u d y a n d has n ot w orse ne d si nce si g ni n g t he i nf or me d c o nse nt 
•  s ocial reas o ns a n d res pite care i n t he a bse nce of a n y deteri orati o n i n t he partici pa nt’s 
ge neral c o n diti o n  
•  treat me nt o n a n e mer ge nc y o ut-patie nt basis f or a n e ve nt n ot f ulfilli n g a n y of t he 
defi niti o ns of a S A E gi ve n a b o ve a n d n ot res ulti n g i n h os pital a d missi o n  
•  is me dicall y si g nifica nt, e. g., defi ne d as a n e ve nt t hat je o par dizes t he partici pa nt or ma y 
re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d a b o ve 
Treat me nt -e mer ge nt ele 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 per 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 ntial 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 pecte d a d verse e ve 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 ness 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 ve 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 nee de d f or e val 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 u d 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 

N o v arti s  
C o nfi d e nti al  
P a g e 1 1 2  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
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 atte m pts t o o btai n s u p ple me ntar y data. 
Me dical a n d scie ntific j u d g me nt s h o ul d be e xercise d i n deci di n g w het her ot her sit uati o ns s h o ul d 
be c o nsi dere d seri o us reacti o ns, s uc h as i m p orta nt me dical e ve nts t hat mi g ht n ot be i m me diatel y 
life t hreate ni n g or res ult i n deat h or h os pitalizati o n b ut mi g ht je o par dize t he partici pa nt or mi g ht 
re q uire i nter ve nti o n t o pre ve nt o ne of t he ot her o utc o mes liste d a b o ve. S uc h e ve nts s h o ul d be 
c o nsi dere d as “ me dicall y si g nifica nt.” E xa m ples of s uc h e ve nts are i nte nsi ve treat me nt i n a n 
e mer ge nc y r o o m or at h o me f or al ler gic br o nc h os pas m, bl o o d d yscrasias, or c o n v ulsi o ns t hat 
d o n ot res ult i n h os pitalizati o n or de vel o p me nt of de pe n de nc y or a b use  ( please refer t o t he 
I C H-E 2 D G ui deli nes ). 
All ne w mali g na nt ne o plas ms will be assesse d as seri o us u n der “ me dicall y si g nifica nt” if ot her 
seri o us ness criteria are n ot met a n d t he mali g na nt ne o plas m is n ot a disease pr o gressi o n of t he 
st u d y i n dicati o n 
A n y s us pecte d tra ns missi o n via a me dici nal pr o d uct of a n i nfecti o us a ge nt is als o c o nsi dere d a 
seri o us a d verse reacti o n. 
All re p orts of i nte nti o nal mis use a n d a b use of t he pr o d uct are als o c o nsi dere d a S A E irres pecti ve 
of w het her or n ot a cli nical e ve nt has occ urre d.  
1 0. 1. 3  
S A E r e p orti n g  
T o e ns ure partici pa nt safet y, e ver y S A E, re gar dless of ca usalit y, occ urri n g after t he partici pa nt 
has pr o vi de d i nf or me d c o nse nt a n d u ntil 3 0 da ys f oll o wi n g t he last a d mi nistrati o n of st u d y 
treat me nt m ust be re 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 nces later t ha n wit hi n 2 4 h o urs of o btai ni n g k n o wle d ge of t he e ve nts ( N ote: If m ore 
stri n ge nt, l ocal re g ulati o ns re gar di n g re p orti n g ti meli nes pre vail). 
Detaile d i n str ucti o ns 
re gar di n g t he s u b missi o n pr ocess a n d re q uire ments are t o be f o u n d i n t he I n vesti gat or f ol der 
pr o vi de d t o eac h site. I nf or mati o n a b o ut all S A Es is c ollecte d a n d rec or de d o n Seri o us A d verse 
E ve nt Re p ort F or m ) e S A E wit h pa per bac k u p ). All a p plica ble secti o ns of t he f or m m ust be 
c o m plete d i n or der t o pr o vi de a cli nicall y t h or o u g h re p ort.  
T he i n vesti gat or m ust re vie w a n d pr o vi de a n assess me nt of ca usalit y f or eac h S A E. T here ma y 
be sit uati o ns i n w hic h a n S A E has occ urre d, a n d t he i n vesti gat or has mi ni mal i nf or mati o n t o 
i ncl u de i n t he i nitial re p ort t o N o vartis. H o we ver, it is ver y i m p orta nt t hat t he i n vesti gat or 
al wa ys ma kes a n assess me nt of ca usalit y f or e ver y e ve nt bef ore t he i nitial tra ns missi o n of t he 
S A E data t o N o vartis. T he i n vesti gat or ma y c ha n ge t heir o pi ni o n of ca usalit y i n li g ht of f oll o w -
u p i nf or mati o n a n d se n d a n S A E f oll o w -u p r e p ort wit h t he u p date d ca usalit y assess me nt.  
All f oll o w -u p i nf or mati o n f or t he S A E i ncl u di n g i nf or mati o n o n c o m plicati o ns, pr o gressi o n of 
t he i nitial S A E a n d rec urre nt e pis o des m ust be re p orte d as f oll o w-u p t o t he ori gi nal e pis o de 
i m me diatel y, wit h o ut u n d ue dela y, b ut u n der n o circ u msta nces later t ha n wit hi n 2 4 h o urs of t he 
I n vesti gat or recei vi n g t he f oll o w-u p i nf or mati o n ( N ot e: If m ore stri n ge nt, l ocal re g ulati o ns 
re gar di n g re p orti n g ti meli nes pre vail). 
A n y S A Es e x perie nce d after t he 3 0 -da y peri o d f oll o wi n g t he last a d mi nistrati o n of st u d y 
treat me nt s h o ul d o nl y be re p orte d t o N o vartis Safet y if t he I n vesti gat or s us pects a ca usal 
relati o ns hi p t o st u d y treat me nt, u nless ot her wise s pecifie d b y l ocal la w/re g ulati o ns. 

N o v arti s  
C o nfi d e nti al  
P a g e 1 1 3  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
R e p orti n g of S A E s r el at e d t o A x M P( s)  
T he S A E re p orti n g re q uire me nts f or A x M Ps will a p pl y o nce t his trial has bee n tra nsiti o ne d 
u n der E U Cli nical Trial Re g ulati o n 5 3 6/ 2 0 1 4.  
All S A Es relate d t o a n y a u xiliar y me dici nal pr o d uct ( w het her a ut h orize d or n ot) use d i n t his 
st u d y m ust be re p orte d t o N o vartis wit hi n 2 4 h o urs of t he site bec o mi n g a ware of it. I n assessi n g 
ca usalit y, t he i n vesti gat ors will use t he p oi nts a b o ve. If a s us p ici o n t hat t he me dical occ urre nce 
c o ul d be relate d t o st u d y treat me nt ( or a n d i nteracti o n wit h st u d y treat me nt) ca n n ot be r ule d 
o ut, t he re p orti n g r ules f or st u d y treat me nt a p pl y.  
R e p orti n g of 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 ( S U S A R s)  
If a n S A E is n ot pre vi o usl y d oc u me nte d i n t he I B or pr o d uct i nf or mati o n f or mar kete d pr o d ucts 
a n d is t h o u g ht t o be relate d t o a n y 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 t he i n vesti gat or f or H A re p orti n g. N o vartis ma y nee d to 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. S U S A Rs will be re p orte d t o t he c o m pete nt a ut h orities a n d rele va nt et hics c o m mittees 
i n acc or da nce wit h nati o nal re g ulat or y re q uire me nts i n partici pati n g c o u ntries, i ncl u di n g E U 
Cli nical Trial Re g ulati o n 5 3 6/ 2 0 1 4.  
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  
If a fe male trial partici pa nt bec o mes pre g na nt, t he st u d y treat me nt s h o ul d be st o p pe d, a n d t he 
pre g na nc y c o nse nt f or m s h o ul d be prese nte d t o t he trial partici pa nt. T he partici pa nt m ust be 
gi ve n a de q uate ti me t o rea d, re vie w a n d si g n t he pre g na nc y c o nse nt f or m. T his c o nse nt f or m is 
necessar y  t o all o w t he i n vesti gat or t o c ollect a n d re p ort i nf or mati o n re gar di n g t he pre g na nc y. 
T o e ns ure partici pa nt safet y, eac h pre g na nc y occ urri n g after si g ni n g t he i nf or me d c o nse nt m ust 
be re p orte d t o N o vartis  wit hi n 2 4 h o urs of lear ni n g of its occ urre nce. T he pre g na nc y s h o ul d be 
f oll o we d 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 ge nital a b n or malities, or mater nal 
a n d/ or ne w b or n c o m plicati o ns.  
Pre g na nc y s h o ul d be rec or de d a n d re p orte d b y t he i n vesti gat or t o t he N o vartis  C hief Me dical 
Office a n d Patie nt Safet y ( C M O & P S). Pre g na nc y f oll o w -u p s h o ul d be rec or de d o n t he sa me 
f or m a n d s h o ul d i ncl u de a n assess me nt of t he p ossi ble relati o ns hi p t o t he st ud y treat me nt 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 nc y m ust be re p orte d.  
If a fe male part ner of a male trial partici pa nt w h o t o o k st u d y treat me nt i n t his st u d y bec o mes 
pre g na nt, pre g na nc y o utc o mes s h o ul d be c ollecte d. C o nse nt t o re p ort i nf or mati o n re gar di n g 
t hese pre g na nc y o utc o mes s h o ul d be o btai ne d fr o m t he m ot her. 
After c o nse nt is pr o vi de d, t he pre g na nc y re p orti n g will occ ur u p t o o ne year after t he esti mate d 
date of deli ver y.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 1 4  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
1 0. 1. 5  
R e p orti n g of st u d y tr e at m e nt err or s i n cl u di n g mi s u s e/ a b u s e  
Me dicati o n err ors are u ni nte nti o nal err ors i n t he prescri bi n g, dis pe nsi n g, a d mi nistrati o n or 
m o nit ori n g of a me dici ne w hile u n der t he c o ntr ol of a healt hcare pr ofessi o nal, partici pa nt or 
c o ns u mer ( E M A defi niti o n).  
Mis use refers t o sit uati o ns w here t he me dici nal pr o d uct is i nte nti o nall y a n d i na p pr o priatel y use d 
n ot i n acc or da nce wit h t he pr ot oc ol.  
A b use c orres p o n ds t o t he persiste nt or s p ora dic, 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 will be rec or de d o n 
t he a p pr o priate e C R F irres pecti ve of w het her or n ot ass ociate d wit h a n A E/ S A E a n d re p orte d 
t o Safet y o nl y if ass ociate d wit h a n S A E. Mis use or a b use will be c ollecte d a n d re p orte d i n t he 
safet y data base irres pecti ve of it bei n g ass ociate d wit h a n A E/ S A E wit hi n 2 4 h o urs of 
I n vesti gat or’s a ware ness. 
T a bl e 1 0 -1  
G ui d a n c e f or c a pt uri n g t h e 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  
Tr e at m e nt err or t y p e  
D o c u m e nt i n D o si n g 
e C R F ( Y e s/ N o)  
D o c u m e nt i n A E 
e C R F  
C o m pl et e S A E f or m  
U ni nt e nti o n al st u d y 
tr e at m e nt err or 
Y e s  
O nl y if a s s o ci at e d wit h 
a n A E  
O nl y if a s s o ci at e d wit h 
a n S A E  
Mi s u s e/ A b u s e  
Y e s  
Y e s  
Y e s, e v e n if n ot 
a s s o ci at e d wit h a S A E  
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 he 
res pecti ve Secti o n 1 0. 1 . 
1 0. 2  
A d diti o n al S af et y M o nit ori n g  
1 0. 2. 1  
Li v er s af et y m o nit ori n g  
T o e ns ure partici pa nt safet y a n d e n ha nce relia bilit y i n deter mi ni n g t he he pat ot o xic p ote ntial of 
a n i n vesti gati o nal dr u g, a sta n dar dize d pr ocess f or i de ntificati o n, m o nit ori n g a n d e val uati o n of 
li ver e ve nts has t o be f oll o we d. 
Please refer t o Ta ble  1 6 -1  i n A p pe n di x 1  f or c o m plete defi niti o ns of li ver la b orat or y tri g gers. 
O nce a partici pa nt is e x p ose d t o st u d y treat me nt, e ver y li ver e ve nt defi ne d i n Secti o n  1 6. 1  
s h o ul d be f oll o we d u p b y t he i n vesti gat or or desi g nate d pers o n nel at t he trial site, as s u m marize d 
bel o w. A d diti o nal details o n acti o ns re q uire d i n case of li ver e ve nts are o utli ne d i n Ta ble  1 6 -2  
a n d Ta ble  1 6 -3 . Re peat li ver c he mistr y tests (i.e., A L T, A S T, T B L, P T/I N R, A L P a n d G G T) t o 
c o nfir m ele vati o n.  
•  Perf or m li ver c he mistr y re peats 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 n tl y re p orte d, a n y l ocal li ver 
c he mistr y tests pre vi o usl y c o n d ucte d t hat are ass ociate d wit h t his e ve nt s h o ul d ha ve res ults 
rec or de d o n t he a p pr o priate e C R F. 

N o v arti s  
C o nfi d e nti al  
P a g e 1 1 5  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
•  I nitiate cl ose o bser vati o n of t he partici pa nt if t he i nitial ele vati o n is c o nfir me 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 ue 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  9. 1. 1 ), if a p pr o priate 
•  H os pitalize t he partici pa nt, if a p pr o priate  
•  Assess ca usalit y of t he li ver e ve nt  
•  I ncl u de t h or o u g h f oll o w-u p of t he li ver e ve nt:  
•  T hese i n vesti gati o ns ma y i ncl u de, base d o n i n vesti gat or’s discreti o n: ser ol o g y tests, 
i ma gi n g a n d pat h ol o g y assess me nts, he pat ol o gist’s c o ns ulta nc y; o btai ni n g 
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 u se, e xcl 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 perf or me d m ust be rec or de d as a p pr o priate i n t he 
e 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 ories of a b n or mal re nal 
la b orat or y alert val ues s h o ul d be assesse d d uri n g t he st u d y peri o d: 
•  Ser u m creati ni ne i ncrease ≥ 2 5 % c o m pare d t o baseli ne d uri n g n or mal h y drati o n stat us  
•  A n y o ne of t he f oll o wi n g:  
•  Uri ne pr otei n -creati ni ne rati o ( P C R) ≥1 g/ g or ≥1 0 0 m g/ m m ol, O R  
•  Ne w o nset di pstic k pr otei n uria ≥ 3 +, O R  
•  Ne w o nset di pstic k he mat uria ≥ 3 + (after e xcl u di n g me nstr uati o n, U TI, e xtre me 
e xercise, or tra u ma) O R  
•  Ne w e vi de nce of cli nicall y si g nifica nt cr ystals o n micr osc o p y  
A b n or mal re nal e ve nt fi n di n gs m ust be c o nfir me d wit hi n 2 4 -4 8 h o urs after t he first assess me nt.  
O nce a partici 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, 
as defi ne d i n Ta ble  1 6 -4 , 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 vesti gat or or desi g nate d 
trial staff as s u m marize d i n Ta ble  1 6 -5  
1 1  
D at a C oll e cti o n a n d D at a b a s e m a n a g e m e nt  
1 1. 1  
D at a c oll e cti o n  
Desi g nate d i n vesti gat or staff will e nter t he data re q uire d b y t he pr ot oc ol i nt o t he Electr o nic 
Case Re p ort F or ms (e C R F). T he e C R Fs ha ve bee n b uilt usi n g f ull y vali date d sec ure we b -
e na ble d s oft ware t hat c o nf or ms t o 2 1 C F R Part 1 1 re q uire me nts. I n vesti gat or site staff will n ot 
be gi ve n access t o t he E D C s yste m u ntil t he y ha ve bee n trai ne d. A ut o matic vali dati o n pr o gra ms 
c hec k f or data discre pa ncies i n t he e C R Fs, a n d 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.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 1 6  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
Partici pa nts will be as ke d t o c o m plete P R Os o n a pa per c o p y. T he partici pa nt's res p o nses will 
be tra nscri be d i nt o t he e C R F b y t he st u d y staff.  W he n a pa per c o p y is use d off -site, t he 
partici pa nt s h o ul d bri n g t he c o m plete d q uesti o n naire(s) t o t he ne xt st u d y  visit at earliest 
c o n ve nie nce.  
T he pai n / me dicati o n diaries will be pa per -base d a n d s h o ul d be c o m plete d a n d ret ur ne d b y t he 
partici pa nts at eac h visit u p t o Da y 8 4. T he diar y data will be tra nscri be d i nt o t he e C R F b y t he 
site pers o n nel. 
C o m plete d pa per q uesti o n naires (if a n y) a n d diaries  will be ke pt as s o urce d oc u me ntati o n at t he 
i n vesti gat or site a n d are n ot t o be c ollecte d b y t he s p o ns or. 
T he i n vesti gat or/ desi g nee 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 urate, a n d t hat e ntr y a n d u p dates are perf or me d i n a ti mel y ma n ner. T he 
I n vesti gat or m ust certif y t hat t he data e ntere d are c o m plete a n d acc urate. 
After fi nal data base l oc k, t he i n vesti gat or will recei ve c o pies of t he partici pa nt data f or 
arc hi vi n g at t he i n vesti gati o nal site.  
All data s h o ul d be rec or de d, ha n dle d, a n d st ore d i n a wa y t hat all o ws its acc urate re p orti n g, 
i nter pretati o n, a n d verificati o n. 
1 1. 2  
D at a b a s e m a n a g e m e nt a n d q u alit y c o ntr ol  
N o vartis  pers o n nel ( or desi g nate d C R O) will re vie w t he data e ntere d b y i n vesti gati o nal staff 
f or c o m plete ness a n d acc urac y. Electr o nic data q ueries stati n g t he nat ure of t he pr o ble m a n d 
re q uesti n g clarificati o n will be create d f or discre pa ncies a n d missi n g val ues 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 nate d i n vesti gat or site staff are re q uire d t o 
res p o n d pr o m ptl y t o q ueries a n d t o ma ke a n y necessar y c ha n ges t o t he data. 
C o nc o mita nt treat me nts a n d pri or me dicati o ns e ntere d i nt o t he data base will be c o de d usi n g t he 
W orl d Healt h Or ga nizati o n ( W H O) Dr u g Refere nce List, w hic h e m pl o ys t he A nat o mical 
T hera pe utic C he mical classificati o n s yste m. Me dical hist or y/c urre nt me dical c o n diti o ns a n d 
a d verse e ve nts will be c o de d usi n g t he Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A) 
ter mi n ol o g y. 
Dates of scree ni n gs, ra n d o mizati o ns, scree n fail ures a n d st u d y c o m pleti o n, as well as 
ra n d o mizati o n c o des 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) or N o vartis 
I nteracti ve Res p o nse Tec h n ol o g y ( NI R T). T he s yste m will be s u p plie d b y a ve n d or, w h o will 
als o ma na ge t he data base. T he data will be se nt electr o nicall y t o N o vartis  ( or a desi g nate d C R O) 
at s pecific ti meli nes.  
Eac h occ urre nce of a c o de brea k via I R T/ NI R T will be re p orte d t o t he cli nical tea m a n d m o nit or. 
T he c o de brea k f u ncti o nalit y will re mai n a vaila ble u ntil st u d y s h ut d o w n or u p o n re q uest of 
N o vartis.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 1 7  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
O nce all necessar y acti o ns ha ve bee n c o m plete d a n d t he data base has bee n declare d c o m plete 
a n d acc urate, it will be l oc ke d a n d t he tre at me nt c o des will be u n bli n de d  a n d ma de a vaila ble 
f or data a nal ysis/ m o ve d t o restricte d area t o be accesse d b y t he i n de pe n de nt pr o gra m mer a n d 
statisticia n. A n y c ha n ges t o t he data base after t hat ti me ca n o nl y be ma de after writte n 
a gree me nt b y N o vartis  de vel o p me nt ma na ge me nt.  
1 1. 3  
Sit e m o nit ori n g  
Bef ore st u d y i nitiati o n, at a site i nitiati o n visit or at a n i n vesti gat or’s 
meeti n g, a 
N o vartis/ dele gate d C R O re prese ntati ve will re vie w t he pr ot oc ol a n d data ca pt ure re q uire me nts 
(i.e., e S o urce D D E or e C R Fs) wit h t he i n vesti gat ors a n d t heir staff. D uri n g t he st u d y, 
N o vartis  e m pl o ys se veral 
met h o ds of e ns uri n g pr ot oc ol a n d G C P c o m plia nce a n d t he 
q ualit y/i nte grit y of t he sites’ data. T he fiel d m o nit or will visit t he site t o c hec k t he c o m plete ness 
of partici pa nt rec or ds, t he acc urac y of data ca pt ure / data e n tr 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 nte d f or acc or di n g t o s pecificati o ns. Ke y st u d y pers o n nel 
m ust be a vaila ble t o assist t he fiel d m o nit or d uri n g t hese visits. C o nti n u o us re m ote m o nit ori n g 
of eac h site’s data 
ma y be perf or me d b y a ce ntralize d N o vartis/ dele gate d C R O/ C R A 
or ga nizati o n. A d diti o nall y, a ce ntral a nal ytics or ga nizati o n ma y a nal yze data & i de ntif y ris ks 
a n d tre n ds f or s ite o perati o nal para meters, a n d pr o vi de re p orts t o N o vartis cli nical tea ms t o 
assist wit h trial o versi g ht.  
T he i n vesti gat or m ust mai ntai n s o urce d oc u me nts f or eac h partici pa nt i n t he st u d y, c o nsisti n g 
of case a n d visit n otes ( h os pital or cli nic me dical rec or ds) c o ntai ni n g de m o gra p hic a n d me dical 
i nf or mati o n, la b orat or y data, electr ocar di o gra ms, a n d t he res ults of a n y ot her tests or 
assess me nts. All i nf or mati o n o n e C R Fs m ust be tracea ble t o t hese s o urce d oc u me nts i n t he 
partici pa nt's file. T he i n vesti gat or m ust als o kee p t he ori gi nal i nf or me d c o nse nt f or m si g ne d b y 
t he partici pa nt (a si g ne d c o p y is gi ve n t o t he partici pa nt). 
T he i n vesti gat or m ust gi ve t he m o nit or access t o all rele va nt s o urce d oc u me nts t o c o nfir m t heir 
c o nsiste nc y wit h t he data ca pt ure a n d/ or data e ntr y. N o vartis  m o nit ori n g sta n dar ds re q uire f ull 
verificati o n f or t he prese nce of i nf or me d c o nse nt, a d here nce t o t he i ncl usi o n/e xcl usi o n criteria, 
d oc u me ntati o n of S A Es, a n d of data t hat 
will be use d f or all pri mar y varia bles. 
A d diti o nal  c hec ks of t he c o nsiste nc y of t he s o urce data wit h t he e C R Fs are perf or me d acc or di n g 
t o t he st u d y-s pecific m o nit ori n g pla n. N o i nf ormati o n i n s o urce d oc u me nts a b o ut t he i de ntit y 
of t he partici pa nts will be discl ose d.  
Rec or ds a n d d oc u me nts, i ncl u di n g si g ne d I C Fs, pertai ni n g t o t he c o n d uct of t his st u d y m ust be 
retai ne d b y t he I n vesti gat or f or 1 5 years after st u d y c o m pleti o n u nless l ocal re g ulati o ns or 
i nstit uti o nal p olicies re q uire a l o n ger rete nti o n peri o d. N o rec or ds ma y be destr o ye d d uri n g t he 
rete nti o n peri o d wit h o ut t he writte n a p pr o val of N o vartis. N o rec or ds ma y be tra nsferre d t o 
a n ot her l ocati o n or part y wit h o ut writte n n otificati o n t o N o vartis.  
1 2  
D at a a n al y si s a n d st ati sti c al m et h o d s  
T he a nal ysis will be c o n d ucte d o n all partici pa nt data at t he ti me t he trial e n ds. A n y data a nal ysis 
carrie d o ut i n de pe n de ntl y b y t he i n vesti gat or s h o ul d be s u b mitte d t o N o vartis bef ore p u blicati o n 
or prese ntati o n.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 1 8  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
1 2. 1  
A n al y si s s et s  
F or all a nal ysis sets, partici pa nts will be a nal yze d acc or di n g t o t he st u d y treat me nts recei ve d.   
T he f ull a nal ysis set ( F A S) will i ncl u de all partici pa nts w h o recei ve d a n y st u d y dr u g.  
T he safet y a nal ysis set ( S A F) will i ncl u de all partici pa nts w h o recei ve d a n y st u d y dr u g.  
T he P K a nal ysis set will i ncl u de all partici pa nts wit h at least o ne a vaila ble vali d (i.e., n ot fla g ge d 
f or e xcl usi o n) P K c o nce ntrati o n meas ure me nt, w h o recei ve d a n y st u d y dr u g a n d wit h n o 
pr ot oc ol de viati o ns t hat i m pact o n P K data.  
T he P D a nal ysis set will i ncl u de all partici pa nts wit h a vaila ble P D data a n d  n o pr ot oc ol 
de viati o ns wit h rele va nt i m pact o n P D data.  
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 s u m marize d 
descri pti vel y b y treat me nt gr o u p f or t he F A S.  
Cate g orical data will be prese nte d as fre q ue ncies a n d perce nta ges. F or c o nti n u o us data, mea n, 
sta n dar d de viati o n, me dia n, mi ni m u m, a n d ma xi m u m will be prese nte d. 
Rele va nt me dical hist ories a n d c urre nt me dical c o n diti o ns at baseli ne will be s u m marize d 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. 
1 2. 3  
Tr e at m e nt s  
T he Safet y set will be use d f or t he a nal yses bel o w. Cate g orical data will be s u m marize d as 
fre q ue ncies a n d perce nta ges. F or c o nti n u o us data, mea n, sta n dar d de viati o n, me dia n, 2 5t h a n d 
7 5t h perce ntiles, mi ni m u m, a n d ma xi m u m will be prese nte d.  
T he d urati o n of e x p os ure i n da ys t o D F V 8 9 0 will be s u m marize d b y mea ns of descri pti ve 
statistics usi n g t he safet y set. 
C o nc o mita nt me dicati o ns a n d si g nifica nt n o n -dr u g t hera pies pri or t o a n d after t he start of t he 
st u d y treat me nt will be liste d a n d s u m marize d acc or di n g t o t he A nat o mical T hera pe utic 
C he mical ( A T C) classificati o n s yste m, b y treat me nt gr o u p.  
1 2. 4  
A n al y si s of t h e pri m ar y e n d p oi nt( s)/ e sti m a n d( s)  
T he pri mar y ai m of t he st u d y is t o e val uate t he efficac y of D F V 8 9 0 vs. place b o i n partici pa nts 
wit h s y m pt o matic, i nfla me d k nee O A as e vi de nce d b y re d ucti o n i n t he i n de x k nee pai n b y 
K O O S ( k nee i nj ur y a n d oste oart hritis o utc o me sc ore) at 1 2 wee ks.  
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 defi niti o n of t he pri mar y esti ma n d is pr o vi de d i n Secti o n 2. 1 . 
T he pri mar y efficac y e n d p oi nt of t he st u d y is t he c ha n ge fr o m baseli ne i n K nee i nj ur y a n d 
Oste oart hritis O utc o me Sc ore ( K O O S), pai n s u bscale at W ee k 1 2. 

N o v arti s  
C o nfi d e nti al  
P a g e 1 1 9  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
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 c ha n ge fr o m baseli ne i n K nee i nj ur y a n d Oste oart hritis O utc o me Sc ore ( K O O S) pai n 
s u bscale will be a nal yze d usi n g a mi xe d effects m o del f or re peate d meas ures ( M M R M). 
T he  m o del will i ncl u de baseli ne, treat me nt, ti me p oi nt, baseli ne * ti me p oi nts a n d trea t me nt * 
ti me p oi nts as fi xe d effects. A n u nstr uct ure d c o varia nce or ot her c o varia nce str uct ures will be 
ass u me d t o acc o u nt f or wit hi n -partici pa nt varia bilit y. A t w o -si de d 9 5 % c o nfi de nce i nter val f or 
t he treat me nt effect (i.e., D F V 8 9 0 mi n us Place b o) at Wee k 1 2 will be re p orte d.  
1 2. 4. 3  
H a n dli n g of i nt er c urr e nt e v e nt s of pri m ar y e sti m a n d  
As descri be d i n Secti o n 2. 1 , I C Es relate d t o misse d d oses a n d u nf oresee n use of resc ue 
me dicati o ns or pr o hi bite d me dicati o ns will be ha n dle d acc or di n g t o a h y p ot hetical strate g y, i.e., 
eit her t he K O O S assess me nt at t he ne xt visit or all s u bse q ue nt K O O S assess me nts will be 
e xcl u de d f r o m t he pri mar y a nal ysis, as detaile d i n Ta ble 2 -2 . Data affecte d b y t he I C E will 
i nstea d be c o nsi dere d missi n g a n d i m plicitl y i m p ute d b y t he M M R M u n der t he missi n g at 
ra n d o m ( M A R) ass u m pti o n (i.e. ass u mi n g t hat partici pa nts wit h missi n g data w o ul d ha ve 
efficac y o utc o mes li ke t h ose of si milar partici pa nts  i n t heir treat me nt gr o u p w h o c o nti n ue t heir 
ra n d o mize d treat me nt).  
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 s  
T he M M R M m o del use d f or t he a nal ysis of t he pri mar y e n d p oi nt 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 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  
A n y de viati o n fr o m t he i m p utati o n tec h ni q ues ass u mi n g M A R a n d its i m pact o n t he pri mar y 
esti ma n d will be assesse d via j u m p t o refere nce i m p utati o n as a c o nser vati ve o pti o n.  
1 2. 4. 6  
S u p p orti v e a n al y s e s  
T he c ha n ge fr o m baseli ne i n K nee i nj ur y a n d Oste oart hritis O utc o me Sc ore ( K O O S) pai n 
s u bscale will be a nal yze d se paratel y f or partici pa nts wit h a n d wit h o ut prese nce of c o ntralateral 
k nee O A.  
Als o, t he a vera ge a m o u nt of c o nc o mita nt  ( basic pai n me dicati o n) a n d resc ue me dicati o ns will 
be prese nte d b y treat me nt gr o u p.  
1 2. 4. 7  
S u p pl e m e nt ar y a n al y s e s  
A d diti o nal a nal yses ma y be carrie d o ut, e. g., i n w hic h t he assess me nts f or partici pa nts w h o use 
resc ue me dicati o n wit hi n 4 8 h o urs pri or t o t he visit a n d/ or f or at least t hree c o nsec uti ve da ys 
w o ul d n ot be c o nsi dere d a n I C E, a n d/ or i n w hic h treat me nt p olic y strate g y w o ul d be a p plie d t o 
all I C E (i.e., use all data as c ollecte d). T hese s u p ple me ntar y esti ma n ds will be s pecifie d i n t he 
S A P.  
1 2. 5  
A n al y si s of s e c o n d ar y e n d p oi nt s/ e sti m a n d s  
T he statistical a nal ysis f or sec o n dar y e n d p oi nts will be descri be d i n detail i n t he S A P.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 2 0  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
1 2. 5. 1  
Effi c a c y a n d/ or P h ar m a c o d y n a mi c e n d p oi nt( s)  
T he sec o n dar y efficac y o bjecti ves are as f oll o ws:  
•  T o assess t he efficac y of D F V 8 9 0 vs. place b o i n partici pa nts wit h s y m pt o matic, i nfla me d 
k nee O A o n i nfla m mat or y j oi nt str uct ure feat ures. T he varia ble ass ociate d wit h t his 
o bjecti ve is c ha n ge fr o m baseli ne i n s y n o vitis acti vit y le vel meas ure d fr o m K -tra ns b y D C E -
M RI at Wee k 1 2, a n d  will be a nal yze d usi n g A N C O V A a dj usti n g f or baseli ne . 
•  T o assess t he efficac y of D F V 8 9 0 vs. place b o i n i m pr o vi n g partici pa nts' re p ort a b o ut t heir 
k nee s y m pt o ms a n d ass ociate d pr o ble ms o ver ti me. T he varia ble ass ociate d wit h t his 
o bjecti ve is c ha n ge i n K O O S s u b -scales ( ot her s y m pt o ms, f u ncti o n i n dail y li vi n g, f u ncti o n 
i n s p ort a n d recreati o n, k nee-relate d q ualit y of life) fr o m baseli ne t o wee ks 2, 4, 8, a n d 1 2, 
a n d will be a nal yze d usi n g a n M M R M m o del.  
•  T o assess t he efficac y of D F V 8 9 0 vs. place b o i n relie vi n g O A  pai n o ver ti me. T he t w o 
varia bles ass ociate d wit h t his o bjecti ve are: 1.) c ha n ge i n K O O S  pai n s u bscale fr o m baseli ne 
t o wee ks 2, 4 a n d 8, a n d 1 2. 2.) c ha n ge i n n u meric rati n g scale ( N R S) f or pai n fr o m baseli ne 
t o wee ks 2, 4, 8 a n d 1 2. T hese t w o e n d p oi nts will be a nal yze d se paratel y usi n g a n M M R M 
m o del.  
T he str uct ure of t he a b o ve M M R M m o dels will be t he sa me as t he o ne me nti o ne d i n t he a nal ysis 
of t he pri mar y e n d p oi nt.  
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 a nal ysis set will be use d. All listi n gs a n d ta bles will be 
prese nte d b y treat me nt gr o u p . 
A d v er s e e v e nt s  
All i nf or mati o n o btai ne d o n a d verse e ve nts will be dis pla ye d b y treat me nt gr o u p  a n d 
partici pa nt.  
T he n u m ber (a n d perce nta ge) of partici pa nts wit h treat me nt e mer ge nt a d verse e ve nts will be 
s u m marize d b y treat me nt, pri mar y s yste m or ga n class a n d preferre d ter m, wit h a brea k d o w n b y 
treat me nt. 
A partici pa nt wit h m ulti ple a d verse e ve nts wit hi n a pri mar y s yste m or ga n class is o nl y c o u nte d 
o nce t o war ds t he t otal of t he pri mar y s yste m or ga n class.  
Vit al si g n s  
All vital si g ns data will be s u m marize d b y treat me nt a n d visit/ti me.  
1 2 -l e a d E C G 
All E C G data will be s u m marize d b y treat me nt a n d visit/ti me.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 2 1  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
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 s u m marize d b y treat me nt gr o u p a n d visit/ti me. S hift ta bles usi n g t he 
l o w/ n or mal/ hi g h/ (l o w a n d hi g h) classificati o n will be use d t o c o m pare baseli ne t o t he w orst 
o n -treat me nt val ue. 
1 2. 5. 3  
P h ar m a c o ki n eti c s  
Descri pti ve s u m mar y statistics of D F V 8 9 0 (sec o n dar y e n d p oi nt) a n d 
 
 plas ma c o nce ntrati o n data will be pr o vi de d b y visit/sa m pli n g ti me p oi nt, i ncl u di n g 
t he fre q ue nc y ( n, %) of c o nce ntrati o ns bel o w t he L L O Q a n d re p orte d as zer o. 
D F V 8 9 0 c o nce ntrati o ns bel o w t he L L O Q will als o be treate d as zer o f or t he calc ulati o n of P K 
para meters.  
Descri pti ve s u m mar y statistics will i ncl u de mea n (arit h metic a n d ge o metric), S D, a n d C V 
(arit h metic a n d ge o metric), me dia n, mi ni m u m, a n d ma xi m u m. A n e xce pti o n t o t his is T m ax  
w here me dia n, mi ni m u m, a n d ma xi m u m will be prese nte d.  
T a bl e 1 2 -1  
N o n -c o m p art m e nt al p h ar m a c o ki n eti c p ar a m et er s  
A U Cl a st  
T h e A U C fr o m ti m e z er o t o t h e l a st m e a s ur a bl e c o n c e ntr ati o n s a m pli n g ti m e 
(tl a st) ( m a s s x ti m e x v ol u m e-1)  
A U Ct a u  
T h e A U C c al c ul at e d t o t h e e n d of a d o si n g i nt er v al (t a u) at st e a d y -st at e ( a m o u nt 
x ti m e x v ol u m e -1)  
C m a x  
T h e m a xi m u m ( p e a k) o b s er v e d pl a s m a, bl o o d, s er u m, or ot h er b o d y fl ui d dr u g 
c o n c e ntr ati o n aft er si n gl e d o s e a d mi ni str ati o n ( m a s s x v ol u m e -1)  
Ctr o u g h  
T h e c o n c e ntr ati o n t h at i s j u st pri or t o t h e b e gi n ni n g of, or at t h e e n d, of a d o si n g 
i nt er v al ( m a s s x v ol u m e-1)  
T m a x  
T h e ti m e t o r e a c h m a xi m u m ( p e a k) pl a s m a, bl o o d, s er u m, or ot h er b o d y fl ui d 
dr u g c o n c e ntr ati o n aft er si n gl e d o s e a d mi ni str ati o n (ti m e)  
1 2. 5. 4  
Bi o m ar k er s  
 
 
 
 
 
1 2. 6  
A n al y si s of e x pl or at or y e n d p oi nt s  
 
 
 
 
 
 
 
C CI
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 2 2  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
1 2. 7  
I nt eri m a n al y s e s 
I nteri m a nal yses ma y be c o n d ucte d t o s u p p ort decisi o n ma ki n g c o ncer ni n g t he c urre nt cli nical 
st u d y, t he s p o ns or’s cli nical de vel o p me nt pr ojects i n ge neral or i n case of a n y safet y c o ncer ns.  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 2 3  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
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 p ositi ve treat me nt effect is i n dicate d b y a n i ncrease i n K O O S pai n sc ore. Ass u mi n g a tr ue 
treat me nt differe nce i n K O O S pai n sc ore of 1 2 p oi nts a n d a sta n dar d de viati o n of 1 9, a sa m ple 
size of 1 0 8 partici pa nts pr o vi des a p pr o xi matel y 8 0 % p o wer t hat t he pri mar y a nal ysis will be 
statisticall y si g nifica nt at t he t w o-si de d 5 % si g nifica nce le vel ass u mi n g 2 5 % of l osses t o f oll o w-
u p i ncl u di n g earl y disc o nti n uati o ns beca use of  
 or ot her reas o ns.   
1 2. 8. 2  
S e c o n d ar y e n d p oi nt( s)  
Ass u mi n g 1: 1 ra n d o mizati o n rati o a n d a tr ue treat me nt effect of 0. 0 7 mi n -1 a n d varia bilit y of 
0. 1 mi n -1 ( H o d gs o n et al 2 0 0 8 ) i n K-tra ns, a sa m ple size of ar o u n d 7 0 partici pa nts (i ncl u di n g 
dr o p o ut rate 2 5 %) pr o vi des 8 0 % p o wer t o s h o w statistical si g nifica nce at o ne -si de d 5 % 
si g nifica nce le vel.    
1 3  
Et hi c al c o n si d er ati o n s a n d a d mi ni str ati v e pr o c e d ur e s  
1 3. 1  
R e g ul at or y a n d et hi c al c o m pli a n c e  
T his cli nical st u d y was desi g ne d a n d will be i m ple me nte d, e xec ute d a n d re p orte d i n acc or da nce 
wit h t he pr ot oc ol a n d t he f oll o wi n g:  
•  C o nse ns us et hical pri nci ples deri ve d fr o m i nter nati o nal g ui deli nes i ncl u di n g t he  
Declarati o n of Helsi n ki a n d C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical Scie nces  
( CI O M S) i nter nati o nal et hical g ui deli nes 
•  A p plica ble I C H Tri partite G ui deli nes f or G o o d Cli nical Practice ( G C P)  
•  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 or E ur o pea n  
Cli nical Trial Re g ulati o n 5 3 6/ 2 0 1 4, U S C F R 2 1)  
T he pr ot oc ol, pr ot oc ol a me n d me nts, I C F, I n vesti gat or’s Br oc h ure, a n d ot her rele va nt 
d oc u me nts (e. g., a d vertise me nts) m ust be s u b mitte d t o a n I R B/I E C b y t he I n vesti gat or a n d 
re vie we d a n d a p pr o ve d b y t he I R B/I E C bef ore t he st u d y is i nitiate d at t hat s pecific site. A n y 
a me n d me nts t o t he pr ot oc ol will re q uire I R B/I E C a n d Healt h A ut h orit y a p pr o val bef ore 
i m ple me ntati o n of c ha n ges ma de t o t he st u d y desi g n, e xce pt f or c ha n ges necessar y t o eli mi nate 
a n i m me diate hazar d t o st u d y partici pa nts.  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 2 4  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
1 3. 2  
R e s p o n si biliti e s of t h e i n v e sti g at or a n d I R B/I E C  
Bef ore i nitiati n g a trial, t he i n vesti gat or/i nstit uti o n m ust o btai n a p pr o val/fa v ora ble o pi ni o n fr o m 
t he I nstit uti o nal Re vie w B oar d/I n de pe n de nt Et hics C o m mittee (I R B/I E C) f or t he trial pr ot oc ol, 
writte n i nf or me d c o nse nt f or m, c o nse nt f or m u p dates, partici pa nt recr uit me nt pr oce d ures 
(e. g., a d vertise me nts) a n d a n y ot her writte n i nf or mati o n t o be pr o vi de d t o partici pa nts. Pri or t o 
st u d y start, t he i n vesti gat or is re q uire d t o si g n a pr ot oc ol si g nat ure pa ge c o nfir mi n g his/ her 
a gree me nt t o c o n d uct t he st u d y i n acc or da nce wit h t hese d oc u me nts a n d all of t he i nstr ucti o ns 
a n d pr oce d ures f o u n d i n t his pr ot oc ol a n d t o gi ve access t o all rele va nt data a n d rec or ds 
t o N o vartis m o nit ors, a u dit ors, N o vartis  Q ualit y Ass ura nce re prese ntati ves, desi g nate d a ge nts 
of N o vartis, I R Bs/I E Cs, a n d re g ulat or y a ut h orities as re q uire d. If a n i ns pecti o n of t he cli nical 
site is re q ueste d b y a re g ulat or y a ut h orit y, t he i n vesti gat or m ust i nf or m N o vartis  i m me diatel y 
t hat t his re q uest has bee n ma de. 
1 3. 3  
P u bli c ati o n P oli c y  
T he pr ot oc ol will be re gistere d i n a p u blicl y accessi ble data base s uc h as cli nicaltrials. g o v a n d 
as re q uire d i n E u dra C T or 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 ( defi ne d as 
last partici pa nt last visit) a n d fi nalizati o n of t he st u d y re p ort t he res ults of t his trial will be 
s u b mitte d f or p u blicati o n a 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 trial res ults we bsite a n d all re q uire d Healt h A ut h orit y we bsites 
(e. g. Cli nicaltrials. g o v, Eu dra C T or C TI S p u blic we bsite etc.).  
S u m mar y res ults of pri mar y a n d sec o n dar y e n d p oi nts will be discl ose d base d u p o n t he gl o bal 
Last Partici pa nt Last Visit ( L P L V) date, si nce m ulti nati o nal st u dies are l oc ke d a n d re p orte d 
base d u p o n t he gl o bal L P L V.  
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 he 
N o vartis  p u blicati o n p olic y trai ni n g materials t hat were pr o vi de d.  
1 3. 4  
Q u alit y C o ntr ol a n d Q u alit y A s s ur a n c e  
N o vartis  mai ntai ns a r o b ust Q ualit y Ma na ge me nt S yste m ( Q M S) t hat i ncl u des all acti vities 
i n v ol ve d i n q ualit y ass ura nce a n d q ualit y c o ntr ol, t o e ns ure c o m plia nce wit h writte n Sta n dar d 
O perati n g Pr oce d ures as well as a p plica ble gl o bal/l ocal G C P re g ulati o ns a n d I C H G ui deli nes.  
A u dits of i n vesti gat or sites, ve n d ors, a n d N o vartis  s yste ms are perf or me d b y a u dit ors, 
i n de pe n de nt fr o m t h ose i n v ol ve d i n c o n d ucti n g, m o nit ori n g or perf or mi n g q ualit y c o ntr ol of t he 
cli nical trial. T he cli nical a u dit pr ocess uses a k n o wle d ge/ris k -base d a p 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 perf or me d acc or di n g t o writte n N o vartis pr ocesses.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 2 5  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
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 he p ur p ose of t he st u d y. If des 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 vesti gat or s hall i m me diatel y discl ose it t o 
N o vartis a n d n ot use it f or a n y p ur p ose ot her t ha n t he st u d y, e xce pt f or t he a p pr o priate 
m o nit ori n g o n st u d y partici pa nts.  
I n vesti 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 vesti gat or feels a pr ot oc ol de viati o n w o ul d i m pr o ve t he c o n d uct of t he st u d y t his m ust be 
c o nsi dere d a pr ot oc ol a me n d me nt, a n d u nless s uc h a n a me n d me nt is a gree d u p o n b y 
N o vartis  a n d a p pr o ve d b y t he I R B/I E C a n d Healt h A ut h orities, w here re q uire d, it ca n n ot be 
i m ple me nte d. 
1 4. 1  
Pr ot o c ol a m e n d m e nt s  
A n y c ha n ge or a d diti o n t o t he pr ot oc ol ca n o nl y be ma de i n a writte n pr ot oc ol a me n d me nt t hat 
m ust be a p pr o ve d b y N o vartis, healt h a ut h orities 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 bse q ue ntl y n otifie d b y pr ot oc ol a me n d me nt a n d t he 
re vie wi n g I R B/I E C is n otifie d. 
N ot wit hsta n di n g t he nee d f or a p pr o val of f or mal pr ot oc ol a me n d me nts, t he i n vesti gat or is 
e x pecte d t o ta ke a n y i m me diate acti o n re q uire d f or t he safet y of a n y partici pa nt  i ncl u de d i n t his 
st u d y, e ve n if t his acti o n re prese nts a de viati o n fr o m t he pr ot oc ol. I n s uc h cases, N o vartis s h o ul d 
be n otifie d of t his acti o n a n d t he I R B/I E C at t he 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 1 2 6  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
1 5  
R ef er e n c e s  
Refere nces are a vaila ble u p o n re q uest  
Be k kers J E, I n klaar M, Saris D B ( 2 0 0 9) Treat me nt selecti o n i n artic ular cartila ge lesi o ns of 
t he k nee: a s yste matic re vie w. A m J S p orts Me d. p. 1 4 8 S-5 5 S.  
C olli ns NJ, Misra D, Fels o n D T, et al ( 2 0 1 1) Meas ures of k nee f u ncti o n: I nter 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 nee E val uati o n F or m, K nee I nj ur y a n d 
Oste oart hritis O utc o me Sc ore ( K O O S), K nee I nj ur y a n d Oste oart hritis O utc o me Sc ore 
P h y sical 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 Acti 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 Master U ni versities Oste oart hritis I n de x ( W O M A C), Acti vit y Rati n g Scale 
( A R S), an d Te g ner Acti vit y Sc ore ( T A S). Art hritis Care Res ( H o b o ke n). p. S 2 0 8 -2 8.  
Da ki n P, Di Marti n o SJ, Ga o H, et al ( 2 0 1 9) T he Efficac y, T olera bilit y, a n d J oi nt Safet y of 
Fasi n u ma b i n Oste oart hritis Pai n: A P hase II b/III D o u ble -Bli n d, Place b o -C o ntr olle d, 
Ra n d o mize d Cli nical Trial. p. 1 8 2 4 -1 8 3 4.  
E ur o pea n Me dici nes A ge nc y  ( 2 0 1 7) Rec o m me n dati o ns o n G B C As. E M A’s fi nal o pi ni o n 
c o nfir ms restricti o ns o n use of li near ga d oli ni u m a ge nts i n b o d y sca ns E M A/ 4 5 7 6 1 6/ 2 0 1 7, 
2 0 1 7. htt ps:// w w w.e ma.e ur o pa.e u/e n/ me dici nes/ h u ma n/referrals/ ga d oli ni u m -c o ntai ni n g -
c o ntrast -a ge nts . Accesse d 2 3 -J u n-2 0 2 3 . 
F o o d a n d Dr u g A d mi nistrati o n  ( 2 0 1 7a) Dr u g Safet y C o m m u nicati o n. F D A i de ntifies n o 
har mf ul effects t o date wit h brai n rete nti o n of ga d oli ni u m -base d c o ntrast a ge nts f or M RIs. 
htt ps:// w w w.f da. g o v/ dr u gs/f da -dr u g -safet y-p o dcasts/f da -dr u g -safet y-p o dcast -f da-i de ntifies-
n o -har mf ul -effects-date -brai n -rete nti o n-ga d oli ni u m -base d . Accesse d 2 3 -J u n-2 0 2 3 . 
F o o d a n d Dr u g A d mi nistrati o n  ( 2 0 1 7b ) Dr u g Safet y P o dcast. F D A war ns t hat ga d oli ni u m -
base d c o ntrast a ge nts ( G B C As) are retai ne d i n t he b o d y; re q uires ne w class war ni n gs. 
htt ps:// w w w.f da. g o v/ dr u gs/f da -dr u g -safet y-p o dcasts/f da -dr u g -safet y-p o dcast -f da-war ns -
ga d oli ni u m -base d -c o ntrast -a ge nts -g bcas -are-retai ne d-b o d y -re q uires. Accesse d 2 3 -J u n-2 0 2 3 . 
Fi n k B, Ma k o wia k C, F uerst M, et al ( 2 0 0 8) T he val ue of s y n o vial bi o ps y, j oi nt as pirati o n a n d 
C -reacti ve pr otei n i n t he dia g n osis of late peri-pr ost hetic i nfecti o n of t otal k nee re place me nts. 
J B o ne J oi nt S ur g Br. p. 8 7 4-8.  
Frae n kel L, R o u be n off R, La Valle y M, et al ( 1 9 9 8) T he ass ociati o n of peri p heral m o n oc yte 
deri ve d i nterle u ki n 1 beta (I L -1 beta), I L -1 rece pt or a nta g o nist, a n d t u m or necr osis fact or -al p ha 
wit h oste oart hritis i n t he el derl y. J R he u mat ol. p. 1 8 2 0 -6.  
G uer mazi A, R oe mer F W, Ha yas hi D, et al ( 2 0 1 1) Assess me nt of s y n o vitis wit h c o ntrast -
e n ha nce d M RI usi n g a w h ole -j oi nt se mi q ua ntitati ve sc ori n g s yste m i n pe o ple wit h, or at hi g h 
ris k of, k nee oste oart hritis: t he M O S T st u d y. A n n. R he u m. Dis. p. 8 0 5-1 1.  
Ha w ker G A, Mia n S, Ke n dzers ka T, et al ( 2 0 1 1) Meas ures of a d ult pai n: Vis ual A nal o g Scale 
f or Pai n ( V A S Pai n), N u meric Rati n g Scale f or Pai n ( N R S Pai n), Mc Gill Pai n Q uesti o n naire 
( M P Q), S h ort-F or m Mc Gill Pai n Q uesti o n naire ( S F -M P Q), C hr o nic Pai n Gra de Scal e 
( C P G S), S h ort F or m-3 6 B o dil y Pai n Scale ( S F -3 6 B P S), a n d Meas ure of I nter mitte nt a n d 
C o nsta nt Oste oart hritis Pai n (I C O A P). Art hritis Care Res ( H o b o ke n). p. S 2 4 0 -5 2.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 2 7  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
Ha yas hi D, R oe mer F W, G uer mazi A ( 2 0 1 9) Ma g netic res o na nce i ma gi n g assess me nt of k nee 
oste oart hritis: c urre nt a n d de vel o pi n g ne w c o nce pts a n d tec h ni q ues. Cli n E x p R he u mat ol. 
p.  8 8 -9 5.  
K O O S User G ui de ( 2 0 0 3) (I nter net) A vaila ble fr o m 
< htt p:// w w w. k o os. n u/ K O O S G ui de 2 0 0 3. p df > ( Accesse d 2 6 Fe br uar y 2 0 2 1).  
L o h ma n der L S, Jär vi ne n T L N ( 2 0 1 9) T he i m p orta nce of getti n g it ri g ht t he first ti me. 
Oste oart hritis Cartila ge. p. 1 4 0 5 -1 4 0 7.  
Me dici nes a n d Healt hcare pr o d ucts Re g ulat or y A ge nc y  ( 2 0 1 7) Dr u g Safet y U p date. 
Ga d oli ni u m -c o ntai ni n g c o ntrast a ge nts: re m o val of O m nisca n a n d i v Ma g ne vist, restricti o ns 
t o t he use of ot her li near a ge nts - G O V. U K ( w w w. g o v. u k), M H R A 2 0 1 7 
htt ps:// w w w. g o v. u k/ dr u g -safet y-u p date/ ga d oli ni u m -c o ntai ni n g -c o ntrast-a ge nts -re m o val-of -
o m nisca n -a n d-i v-ma g ne vist -restricti o ns-t o-t he-use -of -ot her -li near-a ge nts. 
Accesse d  2 3 -J u n-2 0 2 3 . 
H o d gs o n  RJ , Bar nes  T , C o n n oll y  S , et al ( 2 0 0 8) C ha n ges u n derl yi n g t he d y na mic c o ntrast -
e n ha nce d M RI res p o nse t o treat me nt i n r he u mat oi d art hritis. S keletal Ra di ol o g y ; 3 7: 2 0 1 -7 . 
Ri d ker P M, E verett B M, T h ure n T, et al ( 2 0 1 7) A ntii nfla m mat or y T hera p y wit h 
Ca na ki n u ma b f or At her oscler otic Disease. N E n gl J Me d. p. 1 1 1 9 -1 1 3 1.  
Riis R G C, He nri kse n M, Kl o k ker L, et al ( 2 0 1 7) T he effects of i ntra -artic ular gl uc oc ortic oi ds 
a n d e xercise o n pai n a n d s y n o vitis assesse d o n static a n d d y na mic ma g netic res o na nce 
i ma gi n g i n k nee oste oart hritis: e x pl orat or y o utc o mes fr o m a ra n d o mize d c o ntr olle d trial. 
Oste oart hritis Cartila ge. p. 4 8 1 -4 9 1.  
R o os E M, Da vis A M ( 2 0 1 2) Rec o m me n dati o ns f or p u blicati o n of cr oss -c ult ural vali dati o n 
st u dies of patie nt-re p orte d o utc o mes ( P R Os) i n Oste oart hritis a n d Cartila ge. Oste oart hritis 
Cartila ge. p. 4 -5.  
Safiri S, K ola hi A A, S mit h E, et al ( 2 0 2 0) Gl o bal, re gi o nal a n d nati o nal b ur de n of 
oste oart hritis 1 9 9 0 -2 0 1 7: a s yste matic a nal ysis of t he Gl o bal B ur de n of Disease St u d y 2 0 1 7. 
A n n R he u m Dis. p. 8 1 9 -8 2 8.  
Sc hie ker M, C o na g ha n P G, Mi n de h ol m L, et al ( 2 0 2 0) Effects of I nterle u ki n -1 β I n hi biti o n o n 
I nci de nt Hi p a n d K nee Re place me nt : E x pl orat or y A nal yses Fr o m a Ra n d o mize d, D o u ble-
Bli n d, Place b o -C o ntr olle d Trial. A n n I nter n Me d. p. 5 0 9 -5 1 5.  
Wij n S R W, R o vers M M, va n Tie ne n T G, et al ( 2 0 2 0) I ntra -artic ular c ortic oster oi d i njecti o ns 
i ncrease t he ris k of re q uiri n g k nee art hr o plast y. B o ne J oi nt J. p. 5 8 6-5 9 2.  
W olfe F, E gl off N, Hä user W ( 2 0 1 6) Wi des prea d Pai n a n d L o w Wi des prea d Pai n I n de x 
Sc ores a m o n g Fi br o m yal gia -p ositi ve Cases Assesse d wit h t he 2 0 1 0/ 2 0 1 1 Fi br o m yal gia 
Criteria. J R he u mat ol. p. 1 7 4 3 -8.  
Yazici Y, Mc Ali n d o n T E, Gi b ofs k y A, et al ( 2 0 2 0) L oreci vi vi nt, a N o vel I ntraartic ular C D C -
li ke Ki nase 2 a n d D ual-S pecificit y T yr osi ne P h os p h or ylati o n -Re g ulate d Ki nase 1 A I n hi bit or 
a n d W nt Pat h wa y M o d ulat or f or t he Treat me nt of K nee Oste oart hritis: A P hase II 
Ra n d o mize d Trial. Art hritis R he u mat ol. p. 1 6 9 4 -1 7 0 6.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 2 8  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
va n de n B osc h M HJ ( 2 0 1 9) I nfla m mati o n i n oste oart hritis: is it ti me t o da m pe n t he alar m(i n) 
i n t his de bilitati n g disease? Cli n E x p I m m u n ol. p. 1 5 3-1 6 6.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 2 9  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
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  

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

N o v arti s  
C o nfi d e nti al  
P a g e 1 3 2  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
1 6. 2  
A p p e n di x 2: S p e cifi c R e n al Al ert Crit eri a a n d A cti o n s a n d E v e nt 
F oll o w -u p  
T a bl e 1 6 -4  
S p e cifi c R e n al Al ert Crit eri a a n d A cti o n s  
R e n al E v e nt  
 A cti o n s  
C o nfir m e d s er u m cr e ati ni n e i n cr e a s e 2 5 –  4 9 %  
•  
C o n si d er c a u s e s a n d p o s si bl e i nt er v e nti o n s 
•  
F oll o w u p wit hi n 2 -5 d a y s  
S er u m cr e ati ni n e i n cr e a s e  5 0 % +  
 
•  
C o n si d er c a u s e s a n d p o s si bl e i nt er v e nti o n s  
•  
R e p e at a s s e s s m e nt wit hi n 2 4 -4 8 h if 
p o s si bl e  
•  
C o n si d er dr u g i nt err u pti o n or di s c o nti n u ati o n 
u nl e s s ot h er c a u s e s ar e di a g n o s e d a n d 
c orr e ct e d  
•  
C o n si d er p arti ci p a nt h o s pit ali z ati o n a n d 
s p e ci ali z e d tr e at m e nt  
N e w o n s et di p sti c k pr ot ei n uri a ≥ 3 +  
O R  
Pr ot ei n -cr e ati ni n e  r ati o ( P C R) ≥ 1 g/ g Cr ( or 
m g/ m m ol e q ui v al e nt a s c o n v ert e d b y t h e 
m e a s uri n g l a b or at or y)  
•  
C o n si d er c a u s e s a n d p o s si bl e i nt er v e nti o n s  
•  
A s s e s s s er u m al b u mi n & s er u m t ot al pr ot ei n  
•  
R e p e at a s s e s s m e nt t o c o nfir m  
•  
C o n si d er dr u g i nt err u pti o n or di s c o nti n u ati o n 
u nl e s s ot h er c a u s e s ar e di a g n o s e d a n d 
c orr e ct e d  
N e w o n s et h e m at uri a ≥ 3 + o n uri n e di p sti c k   
 
•  
R e p e at a s s e s s m e nt t o c o nfir m  
•  
Di sti n g ui s h h e m o gl o bi n uri a fr o m h e m at uri a  
•  
Uri n e s e di m e nt mi cr o s c o p y  
•  
A s s e s s s Cr  
•  
E x cl u d e i nf e cti o n, tr a u m a, bl e e di n g fr o m t h e 
di st al uri n ar y tr a ct/ bl a d d er, m e n str u ati o n  
•  
C o n si d er bl e e di n g di s or d er  
•  
 
N e w e vi d e n c e of cli ni c all y si g nifi c a nt cr y st al s o n 
mi cr o s c o p y  
•  
R e p e at a s s e s s m e nt t o c o nfir m  
•  
A s s e s s s er u m cr e ati ni n e, ur e a a n d 
el e ctr ol yt e s  
•  
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  
•  
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 orres p o n ds t o K DI G O criteria f or Ac ute Ki d ne y I nj ur y  
A d diti o nal s pecialize d assess me nts are a vaila ble 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 ases, 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 sli de s peci me n 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.)  

N o v arti s  
C o nfi d e nti al  
P a g e 1 3 3  of 1 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 6  (Cl e a n ) 
 
Pr ot o c ol N o. C D F V 8 9 0 B 1 2 2 0 1  
 
 
W he ne ver a re nal e ve nt is i de ntifie d, a detaile d partici pa 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 me nt (after 5 -mi n ute rest, wit h a n a p pr o priate c uff size)  
•  Si g ns a n d s y m pt o ms li ke fe ver, hea dac he, s h ort ness of breat h, bac k or a b d o mi nal pai n, 
d ys uria or he mat uria, de pe n de nt or peri or bital e de ma  
•  C ha n ges i n bl o o d press ure, 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., de h y drati o n d ue t o deliri u m, t u m or l ysis  
T a bl e 1 6 -5  
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  
•  
Uri n e di p sti c k a n d s e di m e nt mi cr o s c o p y e vi d e n c e of DI N:  cr y st al s, r e d bl o o d c ell s 
( d y s m or p hi c/ gl o m er ul ar v s. n o n-d y s m or p hi c/ n o n -gl o m er ul ar), w hit e bl o o d c ell s, t u b ul ar 
e pit h eli al c ell s  
•  
Bl o o d pr e s s ur e a n d b o d y w ei g ht  
•  
S er u m cr e ati ni n e, B U N, el e ctr ol yt e s ( s o di u m, p ot a s si u m, p h o s p h at e, c al ci u m), bi c ar b o n at e a n d 
uri c a ci d  
•  
Uri n e o ut p ut  
R e vi e w a n d r e c or d p o s si bl e c o ntri b uti n g f a ct or s t o t h e r e n al e v e nt ( c o -m e di c ati o n s, ot h er c o -m or bi d 
c o n diti o n s) a n d a d diti o n al di a g n o sti c pr o c e d ur e s ( M RI et c.) i n t h e e C R F  
•  
E v e nt r e s ol uti o n: ( s Cr wit hi n 1 0 % of b a s eli n e or P C R < 1 g/ g Cr, or A C R < 3 0 0 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 pr ot ei n -cr e ati ni n e r ati o 
st a bili z ati o n at a n e w l e v el wit h ± 5 0 % v ari a bilit y o v er l a st 6 m o nt h s.  
•  
A n al y si s of uri n e m ar k er s i n s a m pl e s c oll e ct e d o v er t h e c o ur s e of t h e DI N e v e nt