Efficacy, Safety, Tolerability and Quality of Life of Ongoing Individually Optimized Lipid-lowering Therapy With or Without Inclisiran (KJX839) - a Randomized, Placebo-controlled, Double-blind Multicenter Phase IV Study in Participants With Hypercholesterolemia
Phase: PHASE4
Conditions: Hypercholesterolemia
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  
K J X 8 3 9 
Cli ni c al Tri al Pr ot o c ol C K J X 8 3 9 A 1 2 4 0 2  / N C T 0 5 1 9 2 9 4 1 
Effi c a c y, s af e t y, t ol er a bility a n d q u alit y of lif e of o n g oi n g 
i n di vi d u all y o ptimi z e d  li pi d-l o w eri n g t h er a p y wit h or 
wit h o ut i ncli sir a n ( K J X 8 3 9) –  a r a n d o mi z e d, pl a c e b o-
c o ntr oll e d, d o u bl e- bli n d m ulti c e nt er p h a s e I V st u d y i n 
p arti ci p a n t s wit h h y p er c h ol e st er ol e mi a 
D o c u m e nt t y p e:   
A m e n d e d Pr ot o c ol  
R e g ul at or y A g e n c y I d e ntifi er N u m b er:  
2 0 2 4 -5 1 1 2 6 3 -2 8  
V er si o n n u m b er:   
0 3 ( Cl e a n ) 
Cli ni c al Tri al P h a s e:   
I V 
St u d y A cr o n y m :  
VI C T O RI O N DI F F E R E N C E  
S p o n s or :  
N o v arti s P h ar m a A G  
S p o n s or a d dr e s s i n t h e E E A : 
N o v arti s P h ar m a A G, Li c ht str a s s e 3 5, 4 0 4 6 
B a s el, S wit z erl a n d  
R el e a s e d at e:  
0 2 -S e p -2 0 2 4 ( c o nt e nt fi n al)
Pr o p ert y o f 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 4. 0 d at e d 1 5 -F e b -2 0 2 1  

N o v arti s  
C o nfi d e nti al  
P a g e  2  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
T a bl e of c o nt e nt s  
Ta ble of c o nt e nts  ................................................................................................................. 2  
List of ta bles  ........................................................................................................................ 6  
List of fi g ures  ...................................................................................................................... 6  
List of a b bre viati o ns  ............................................................................................................ 7  
Gl ossar y of ter ms  ............................................................................................................... 1 0  
A me n d me nt 3 ( 0 2 -Se p -2 0 2 4)  ............................................................................................ 1 3  
A me n d me nt 2 ( 0 1 -N o v -2 0 2 2)  ........................................................................................... 1 6  
A me n d me nt 1 ( 1 1 -N o v -2 0 2 1)  ........................................................................................... 1 8  
Pr ot oc ol s u m mar y  .............................................................................................................. 2 0  
1  
I ntr o d u cti o n ....................................................................................................................... 2 4  
1. 1  
Bac k gr o u n d  ............................................................................................................ 2 4  
1. 2  
P ur p ose  .................................................................................................................. 2 6  
2  
O bjecti ves, e n d p oi nts a n d esti ma n ds  ................................................................................. 2 6  
2. 1  
Pri mar y esti ma n ds  ................................................................................................. 2 8  
2. 2  
Sec o n dar y esti ma n ds  ............................................................................................. 2 9  
3  
St u d y desi g n  ...................................................................................................................... 3 0  
3. 1  
Scree ni n g peri o d  .................................................................................................... 3 0  
3. 2  
O pti o nal R u n -i n peri od  .......................................................................................... 3 2  
3. 3  
O pti o nal Baseli ne peri o d ( Da y -1 0)  ....................................................................... 3 3  
3. 4  
D o u ble -bli n d trea t me nt p eri o d ............................................................................... 3 3  
4  
Rati o nale  ............................................................................................................................ 3 8  
4. 1  
Rati o nale f or st u d y desi g n  ..................................................................................... 3 8  
4. 1. 1  
Rati o nale f or c h oice of bac k gr o u n d t hera p y  ......................................... 4 0  
4. 2  
Rati o nale f or d ose/r e gi me n a n d d urati o n of tr eat m e nt  .......................................... 4 1  
4. 3  
Rati o nale f or c h oic e of c o ntr ol dr u gs (c o m parat or/ place b o) or c o m bi nati o n 
dr u gs  ...................................................................................................................... 4 2  
4. 4  
P ur p ose  a n d ti mi n g of i nteri m a nal yses/ desi g n a da ptati o ns  .................................. 4 2  
4. 5  
Ris ks a n d be nefits  .................................................................................................. 4 2  
4. 5. 1  
C o vi d -1 9 i m pact o n ris k -be nefit  ........................................................... 4 4  
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  ............................ 4 4  
5  
St u d y P o p ulati o n  ............................................................................................................... 4 4  
5. 1  
I n cl usi o n criteria .................................................................................................... 4 5  
5. 2  
E xcl usi o n criteria  ................................................................................................... 4 7  
6  
Treat me nt  ........................................................................................................................... 4 9  

N o v arti s  
C o nfi d e nti al  
P a g e  3  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
6. 1  
St u d y treat me nt  ...................................................................................................... 4 9  
6. 1. 1  
I n v esti gati o nal a n d c o ntr ol dr u gs .......................................................... 4 9  
6. 1. 2  
A d diti o nal st u d y treat me nts  .................................................................. 5 0  
6. 1. 3  
Treat me nt ar ms/ gr o u p  ........................................................................... 5 1  
6. 1. 4  
Treat me nt d ur ati o n  ................................................................................ 5 1  
6. 2  
Ot her treat me nt(s)  .................................................................................................. 5 1  
6. 2. 1  
C o nc o mita nt t hera p y  ............................................................................. 5 1  
6. 2. 2  
Pr o hi bite d me dicati o n  ........................................................................... 5 3  
6. 2. 3  
Resc ue me dicati o n  ................................................................................ 5 4  
6. 3  
Pre parati o n a n d dis pe ns ati o n  ................................................................................. 5 4  
6. 3. 1  
Ha n dli n g of st u d y treat m e nt a n d ot her treat me nt  .................................. 5 5  
6. 3. 2  
I nstr u cti o ns f or prescri bi n g a n d ta ki n g st u d y treat me nt ........................ 5 5  
6. 4  
Partici pa nt n u m beri n g, treat m e nt assi g n me nt, ra n d o mizati o n  .............................. 5 6  
6. 4. 1  
Partici pa nt n u m beri n g  ........................................................................... 5 6  
6. 4. 2  
Treat me nt assi g n me nt, r a n d o mizati o n  .................................................. 5 6  
6. 5  
Treat me nt bli n di n g  ................................................................................................. 5 7  
6. 6  
D ose escalati o n a n d d ose m o dificati o n  .................................................................. 5 7  
6. 6. 1  
D ose escalati o n g ui deli nes  .................................................................... 5 7  
6. 6. 2  
Defi niti o ns of d ose li miti n g t o xicities ( D L Ts)  ...................................... 5 8  
6. 6. 3  
D ose m o dificati o ns  ................................................................................ 5 9  
6. 6. 4  
F oll o w -u p f or t o xicities  ......................................................................... 5 9  
6. 7  
A d diti o nal treat me nt g ui da n ce  ............................................................................... 6 0  
6. 7. 1  
Treat me nt c o m plia nce  ........................................................................... 6 0  
6. 7. 2  
Rec o m me n de d treat me nt of a d verse e ve nts  .......................................... 6 0  
6. 7. 3  
E mer ge nc y brea ki n g of assi g ne d treat me nt c o de  .................................. 6 0  
7  
I nf or me d c o ns e nt pr oce d ures ............................................................................................ 6 1  
8  
Visit sc he d ule a n d assess me nts  ......................................................................................... 6 3  
8. 1  
Scree ni n g  ............................................................................................................... 6 8  
8. 1. 1  
I nf or mati o n t o be c ollecte d o n scree ni n g fail ures ................................. 6 8  
8. 2  
Partici pa nt de m o gra p hics/ ot her baseli ne c h aracteristics  ....................................... 6 8  
8. 3  
Efficac y  .................................................................................................................. 6 9  
8. 3. 1  
L D L C h olester ol  .................................................................................... 6 9  
8. 3. 2  
A p pr o priate n ess of efficac y assess me nts  .............................................. 6 9  
8. 4  
Safet y  ..................................................................................................................... 7 0  
8. 4. 1  
La b orat or y e val uati o ns  .......................................................................... 7 0  

N o v arti s  
C o nfi d e nti al  
P a g e  4  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
8. 4. 2  
Electr ocar di o gra m ( E C G)  ..................................................................... 7 1  
8. 4. 3  
Pre g na nc y  .............................................................................................. 7 2  
8. 4. 4  
Ot her safet y e val uati o ns  ........................................................................ 7 3  
8. 4. 5  
A p pr o priate n ess of safet y meas ure me nts  .............................................. 7 4  
8. 5  
A d diti o nal assess me nts  .......................................................................................... 7 4  
8. 5. 1  
Cli nical O utc o me Assess me nts ( C O As)  ............................................... 7 4  
8. 5. 2  
Ot her e x pl or at or y bi o mar kers  ............................................................... 7 8  
9  
Disc o nti n uati o n a n d c o m pleti o n  ........................................................................................ 7 8  
9. 1  
Disc o nti n uati o n fr o m st u d y treat me nt a n d fr o m st u d y  .......................................... 7 8  
9. 1. 1  
Disc o nti n uati o n fr o m st u d y treat me nt ................................................... 7 8  
9. 1. 2  
Disc o nti n uati o n fr o m st u d y  ................................................................... 7 9  
9. 1. 3  
L ost t o f oll o w -u p  ................................................................................... 8 0  
9. 2  
Wit h dra wal of i nf or me d c o nse nt/ O p p ositi o n t o use data/ bi ol o gical sa m ples  ....... 8 0  
9. 3  
St u d y c o m pleti o n a n d p ost -st u d y treat me nt .......................................................... 8 0  
9. 4  
Earl y st u d y ter mi nati o n b y t he s p o ns or  ................................................................. 8 1  
1 0  Safet y m o nit ori n g, re p orti n g a n d c o m mittees  ................................................................... 8 1  
1 0. 1  
Defi niti o n of a d vers e e v e nts a n d re p orti n g re q uir e me nts  ...................................... 8 1  
1 0. 1. 1  
A d verse e ve nts  ...................................................................................... 8 1  
1 0. 1. 2  
Seri o us a d verse e ve nts  .......................................................................... 8 3  
1 0. 1. 3  
S A E re p orti n g........................................................................................ 8 4  
1 0. 1. 4  
Pre g na nc y re p orti n g  .............................................................................. 8 5  
1 0. 1. 5  
Re p orti n g of st u d y  treat me nt err ors i ncl u di n g mis use/a b use ................ 8 6  
1 0. 2  
A d diti o nal Safet y M o nit ori n g  ................................................................................ 8 6  
1 0. 2. 1  
Li ver safet y m o nit ori n g  ......................................................................... 8 6  
1 0. 2. 2  
Re nal safet y m o nit ori n g  ........................................................................ 8 8  
1 0. 2. 3  
S keletal m uscle safet y m o nit ori n g  ........................................................ 8 8  
1 0. 2. 4  
Se vere c ut a ne o us reacti o n m o nit ori n g  .................................................. 8 8  
1 0. 2. 5  
I nterstitial l u n g disease .......................................................................... 8 8  
1 0. 2. 6  
I m m u ne-me diate d necr otizi n g m y o p at h y (I M N M)  .............................. 8 9  
1 0. 2. 7  
Pr ot hr o m bi n ti me a n d I nt er nati o nal N or m alize d R ati o  ......................... 8 9  
1 0. 3  
C o m mittees  ............................................................................................................ 8 9  
1 0. 3. 1  
Steeri n g C o m mittee  ............................................................................... 8 9  
1 1  Data C ollecti o n a n d Dat a base ma na g e me nt  ...................................................................... 8 9  
1 1. 1  
Data c ollecti o n  ....................................................................................................... 8 9  
1 1. 2  
Data base m a na ge m e nt a n d q ualit y c o ntr ol  ............................................................ 9 0  

N o v arti s  
C o nfi d e nti al  
P a g e  5  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
1 1. 3  
Site m o nit ori n g  ...................................................................................................... 9 1  
1 2  Data a n al ysis a n d statistical met h o ds  ................................................................................ 9 1  
1 2. 1  
A nal ysis sets  .......................................................................................................... 9 1  
1 2. 2  
Partici pa nt de m o gra p hics a n d ot her bas eli ne c haracteristics  ................................. 9 2  
1 2. 3  
Treat me nts  ............................................................................................................. 9 2  
1 2. 3. 1  
St u d y dr u g  ............................................................................................. 9 3  
1 2. 3. 2  
Pri or a n d c o nc o mita nt t h era pies  ............................................................ 9 3  
1 2. 4  
A nal ysis s u p p orti n g pri mar y o bjecti ves  ................................................................ 9 4  
1 2. 4. 1  
Defi niti o n of pri mar y e n d p oi nt(s)  ......................................................... 9 4  
1 2. 4. 2  
Statistical m o del, h y p ot hesis, a n d met h o d of a nal ysis  .......................... 9 4  
1 2. 4. 3  
Ha n dli n g of i nterc urre nt e ve nts of pri mar y esti ma n d  ........................... 9 4  
1 2. 4. 4  
Ha n dli n g of missi n g val ues n ot relate d t o i nterc urre nt e ve nt  ............... 9 5  
1 2. 4. 5  
Se nsiti vit y a nal yses  ............................................................................... 9 5  
1 2. 4. 6  
S u p ple me ntar y a nal ysis  ......................................................................... 9 5  
1 2. 4. 7  
S u p p orti ve a nal yses  ............................................................................... 9 5  
1 2. 5  
A nal ysis s u p p orti n g sec o n dar y o bjecti ves  ............................................................. 9 6  
1 2. 5. 1  
C o ntr ol of Fa mil y wise t y pe I err or rate  ................................................. 9 7  
1 2. 5. 2  
Efficac y e n d p oi nts  ................................................................................. 9 8  
1 2. 5. 3  
Safet y e n d p oi nts  .................................................................................. 1 0 0  
1 2. 5. 4  
Patie nt re p orte d o utc o mes  ................................................................... 1 0 1  
1 2. 6  
A nal ysis of e x pl orat or y e n d p oi nts  ....................................................................... 1 0 1  
1 2. 7  
I nteri m a nal yses ................................................................................................... 1 0 1  
1 2. 8  
Sa m ple size calc ul ati o n  ........................................................................................ 1 0 1  
1 2. 8. 1  
Pri mar y e n d p oi nt(s)  ............................................................................. 1 0 1  
1 2. 8. 2  
Sec o n dar y e n d p oi nt(s)  ......................................................................... 1 0 2  
1 3  Et hical c o nsi derati o ns a n d a d mi nistrati ve pr oce d ures  .................................................... 1 0 2  
1 3. 1  
Re g ulat or y a n d et hical c o m plia nc e ...................................................................... 1 0 2  
1 3. 2  
Res p o nsi bilities of t he i n vesti gat or a n d I R B/I E C  ................................................ 1 0 2  
1 3. 3  
P u blicati o n of st u d y pr ot oc ol a n d res ults ............................................................. 1 0 3  
1 3. 4  
Q ualit y C o ntr ol a n d Q ualit y Ass ura nce  ............................................................... 1 0 3  
1 3. 5  
Partici pa nt E n ga ge me nt  ....................................................................................... 1 0 3  
1 4  Pr ot oc ol a d here n ce  .......................................................................................................... 1 0 4  
1 4. 1  
Pr ot oc ol a me n d me nts  ........................................................................................... 1 0 4  
1 5  Refere n ces  ....................................................................................................................... 1 0 5  
1 6  A p pe n dices  ...................................................................................................................... 1 1 1  

N o v arti s  
C o nfi d e nti al  
P a g e  6  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
1 6. 1  
A p pe n di x 1: Cli nicall y n ota ble la b orat or y v al ues a n d vital si g ns  ....................... 1 1 1  
1 6. 2  
A p pe n di x 2: Li ver e v e nt a n d la b orat or y tri g g er defi niti o ns & f oll o w -u p 
re q uire me nts ........................................................................................................ 1 1 1  
1 6. 3  
A p pe n di x 3: S pecific Re nal Alert Criteria a n d Acti o ns a n d E ve nt F oll o w -u p  .... 1 1 1  
1 6. 4  
D oc u me nte d A S C V D  .......................................................................................... 1 1 1  
1 6. 5  
E C G fi n di n gs s u p p orti n g dia g n osis of m y ocar dial i nfarcti o n  ............................. 1 1 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  .......................................................... 2 6  
Ta ble 3 -1  
Perce nta g es of stati n use at scre e ni n g i n refere n ce t o t he e ntire 
st u d y p o p ulati o n. * ................................................................................. 3 1  
Ta ble 3 -2  
A p pr o ve d stati n d ose ra n ges a n d rec o m me n de d st ati n titrati o n ste ps ... 3 3  
Ta ble 6 -1  
I n v esti gati o nal a n d c o ntr ol dr u g ............................................................ 4 9  
Ta ble 6 -2  
A u xilliar y Me dici nal Pr o d ucts  .............................................................. 5 0  
Ta ble 6 -3  
Pr o hi bite d me dicati o n  ........................................................................... 5 3  
Ta ble 8 -1  
A ssess me nt Sc he d ule ............................................................................ 6 4  
Ta ble 8 -2  
Assess me nts & S pecificati o ns  ............................................................... 7 0  
Ta ble  8 -3  
La b orat or y Ass ess me nts  ........................................................................ 7 1  
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  ......................................................................................... 8 6  
Ta ble 1 2 -1  
Acc o u nt f or differe nt p ost ra n d o mizati o n e ve nts f or t he pri mar y 
e n d p oi nt reac hi n g L D L -C tar get at da y 9 0  ........................................... 9 5  
Li st of fi g ur e s  
Fi g ure 3 -1  
St u d y Desi g n  ......................................................................................... 3 7  
Fi g ure 3 -2  
Rec o m me n de d treat me nt sc he me bas e d o n E S C/ E A S g ui d eli nes i n 
c o m bi nati o n wit h rele va nt H T A re q uire m e nts  ...................................... 3 8  
Fi g ure 1 2 -1  
A p plie d testi n g pr oce d ure  ..................................................................... 9 8  
 

N o v arti s  
C o nfi d e nti al  
P a g e  7  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
Li st of a b br e vi ati o n s  
A BI  
A n kl e -br a c hi al i n d e x  
A C L  
a d e n o si n e tri p h o s p h at e citr at e l y a s e   
A C S  
A c ut e c or o n ar y s y n dr o m e 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 P  
A n gi n a P e ct ori s   
A S C V D  
At h er o s cl er oti c c ar di o v a s c ul ar di s e a s e  
A S T  
A s p art at e A mi n otr a n sf er a s e  
A x M P  
A u xili ar y M e di ci n al Pr o d u ct  
C C S  
c hr o ni c c or o n ar y s y n dr o m e s  
C H D  
C or o n ar y H e art Di s e a s e  
C K  
Cr e ati n e Ki n a s e  
c m  
C e nti m et er  
C M H  
C o c hr a n e -M a nt el -H a e n s z el t e st   
C O A  
Cli ni c al O ut c o m e A s s e s s m e nt  
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 R A  
Cli ni c al R e s e ar c h A s s o ci at 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)  
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 T  
Cli ni c al Tri al T e a m  
C V  
C ar di o v a s c ul ar  
C V D  
C ar di o v a s c ul ar Di s e a s e  
D B P  
Di a st oli c Bl o o d Pr e s s ur e  
D D E  
Dir e ct d at a e ntr y  
DI LI  
Dr u g -I n d u c e d Li v er I nj ur y 
d L  
D e cilit er  
D L T  
D o s e Li miti n g T o xi cit y  
D M  
Di a b et e s M ellit u s  
E A S  
E ur o p e a n  At h er o s cl er o si s S o ci et y  
E A S D  
E ur o p e a n A s s o ci ati o n f or t h e St u d y of Di a b et e s  
E C G  
El e ctr o c ar di o gr a m  
e C O A  
El e ctr o ni c Cli ni c al O ut c o m e A s s e s s m e nt  
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 O S  
E n d of St u d y  
E O T  
E n d of Tr e at m e nt  
e S A E  
El e ctr o ni c S eri o u s A d v er s e E v e nt  
E S C  
E ur o p e a n S o ci et y of C ar di ol o g y  
e S o ur c e  
El e ctr o ni c S o ur c e  
E S S  
Eli gi bl e s cr e e n e d s et  
E U  
E ur o p e a n U ni o n  
F A S  
F ull a n al y si s s et  
F P G  
F a sti n g pl a s m a gl u c o s e  
G C P  
G o o d Cli ni c al Pr a cti c e  

N o v arti s  
C o nfi d e nti al  
P a g e  8  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
G G T  
G a m m a -gl ut a m yl tr a n sf er a s e  
G S R S  
G a str oi nt e sti n al S y m pt o m R ati n g S c al e   
h  
H o ur  
H D L -C  
Hi g h -d e n sit y li p o pr ot ei n c h ol e st er ol  
H e F H  
H et er o z y g o u s f a mili al h y p er c h ol e st er ol e mi a  
H M G -C o A  
β -H y dr o x y β -m et h yl gl ut ar yl -C o A  
H R Q o L  
H e alt h -R el at e d Q u alit y of Lif e  
H T A  
H e at h t e c h n ol o g y a s s e s s m e nt  
I B 
I n v e sti g at or' s Br o c h ur e 
I C F 
I nf or m e d C o n s e nt F or m 
I C H 
I nt er n ati o n al C o u n cil f or H ar m o ni z ati o n of T e c h ni c al R e q uir e m e nt s f or P h ar m a c e uti c al s f or 
H u m a n U s e  
I E C 
I n d e p e n d e nt Et hi c s C o m mitt e e 
I M N M 
I m m u n e-m e di at e d n e cr oti zi n g m y o p at h y  
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 
k g  
Kil o gr a m  
L D L -C  
l o w-d e n sit y li p o pr ot ei n c h ol e st er ol  
L D L R  
l o w-d e n sit y li p o pr ot ei n r e c e pt or  
L F T  
Li v er f u n cti o n t e st  
L L T  
Li pi d -L o w eri n g T h er a p y  
m A b  
m o n o cl o n al A nti b o d y  
M A C E  
M aj or a d v er s e  c ar di o v a s c ul ar  e v e nt  
M A L E  
M aj or a d v er s e li m b e v e nt  
M C H  
M e a n C or p u s c ul ar H e m o gl o bi n   
M C H C  
M e a n C or p u s c ul ar H e m o gl o bi n C o n c e ntr ati o n  
M C S  
M e nt al C o m p o n e nt S c or e  
M C V  
M e a n C or p u s c ul ar V ol u m e   
M D R D  
M o difi c ati o n of Di et i n R e n al Di s e a s e  
M e d D R A  
M e di c al di cti o n ar y f or r e g ul at or y a cti viti e s  
m g  
milli gr a m( s)  
MI  
M y o c ar di al i nf ar cti o n  
Mi n  
Mi ni m u m  
m L  
millilit er( s)  
m m ol  
Milli m ol e s  
M M R M  
mi x e d m o d el f or r e p e at e d m e a s ur e s   
m R N A  
m e s s e n g er R N A  
M T D  
M a xi m u m T ol er at e d D o s e  
N Y H A  
N e w Y or k H e art A s s o ci ati o n  
O H P  
Off -sit e h e alt h c ar e pr of e s si o n al  
P A D  
P eri p h er al Art eri al Di s e a s e  
P C S  
P h y si c al C o m p o n e nt S c or e  
P C S K 9  
Pr o pr ot ei n C o n v ert a s e S u btili si n/ K e xi n T y p e 9  
P R O  
P ati e nt R e p ort e d O ut c o m e s  

N o v arti s  
C o nfi d e nti al  
P a g e  9  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
P T A  
P o st -tri al a c c e s s 
P V & P S  
P h ar m a c o vi gil a n c e a n d P h ar m a S af et y  
Q L MI  
Q u alit y of Lif e aft er M y o c ar di al I nf ar cti o n   
Q M S  
Q u alit y M a n a g e m e nt S y st e m  
R A N  
R a n d o mi z e d s et  
R B C  
R e d bl o o d c ell s  
R D  
R e c o m m e n d e d D o s e  
R D O  
R etri e v e d Dr o p O ut D at a   
RI S  
R u n -i n s et 
RI S C s  
R N A -i n d u c e d sil e n ci n g c o m pl e x e s   
s. c.  
s u b c ut a n e o u s  
S A E  
S eri o u s A d v er s e E v e nt  
S A F  
S af et y s et  
S A P  
St ati sti c al A n al y si s Pl a n  
S A R S -C o V -2  
S e v er e A c ut e R e s pir at or y S y n dr o m e C or o n a vir u s 2  
S B P  
S y st oli c Bl o o d Pr e s s ur e  
s Cr  
s er u m Cr e ati ni n e  
S C O R E 2  
S y st e mi c C or o n ar y Ri s k E sti m ati o n 2  
S C O R E 2 -O P  
S y st e mi c C or o n ar y Ri s k E sti m ati o n 2 -Ol d er P er s o n s  
S F -3 6  
S h ort f or m h e alt h s ur v e y  
S F -B PI  
S h ort -f or m Bri ef P ai n I n v e nt or y 
si R N A  
S m all i nt erf eri n g R N A  
S m P C  
S u m m ar y of Pr o d u ct C h ar a ct eri sti c s  
S M Q  
St a n d ar di z e d M e d D R A Q u eri e s  
S O P  
St a n d ar d o p er ati n g pr o c e d ur e  
S U S A R  
S u s p e ct e d U n e x p e ct e d S eri o u s A d v er s e R e a cti o n  
T E A E  
Tr e at m e nt -E m er g e nt A d v er s e E v e nt  
T F Q  
Tri al f e e d b a c k q u e sti o n n air e  
TI A  
Tr a n si e nt I s c h a e mi c Att a c k  
T S Q M  
Tr e at m e nt S ati sf a cti o n Q u e sti o n n air e f or M e di c ati o n   
U L N  
u p p er li mit of n or m al  
U N S  
U n s c h e d ul e d  
U S  
U nit e d St at e  
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  
WI Q  
W al ki n g i m p air m e nt q u e sti o n n air e   
W o C  
Wit h dr a w al of C o n s e nt  

N o v arti s  
C o nfi d e nti al  
P a g e  1 0  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
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 (I M P) ( 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 ( A x M P)  
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 n t 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 
cli 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 s A x M P.  
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 s t u d y p arti ci p a nt  
Cli ni c al O ut c o m e 
A s s e s s m e nt ( C O A)  
A m e a s ur e t h at d e s cri b e s or r efl e ct s h o w a p arti ci p a nt f e el s, f u n cti o n s, or s ur vi v e s  
Cli ni c al Tri al T e a m  
A gr o u p of p e o pl e r e s p o n si bl e f or t h e pl a n ni n g, e x e c uti o n a n d r e p orti n g of all cli ni c al 
tri al a cti viti e s. E x a m pl e s of t e a m m e m b er s i n cl u d e t h e St u d y L e a d, M e di c al M o nit or, 
Tri al St ati sti ci a n et c.  
C o d e d D at a  
P er s o n al D at a w hi c h h a s b e e n d e -i d e ntifi e d b y t h e i n v e sti g ati v e c e nt er t e a m b y 
r e pl a ci n g p er s o n al i d e ntifi er s wit h a c o d 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.  
Di s c o nti n u ati o n fr o m 
st u d y  
P oi nt/ti m e w h e n t h e p arti ci p a nt p er m a n e ntl y st o p s r e c ei vi n g t h e st u d y tr e at m e nt a n d 
f urt h er pr ot o c ol r e q uir e d a s s e s s m e nt s or f oll o w-u p, f or a n y r e a s o n. N o s p e cifi c 
r e q u e st i s m a d e t o st o p t h e u s e of t h eir s a m pl e s or d at a. 
Di s c o nti n u ati o n fr o m 
st u d y tr e at m e nt  
P oi nt /ti m e w h e n t h e p arti ci p a nt p er m a n e ntl y st o p s r e c ei vi n g t h e st u d y tr e at m e nt f or 
a n y r e a s o n ( pri or t o t h e pl a n n e d c o m pl eti o n of st u d y dr u g a d mi ni str ati o n, if a n y). 
P arti ci p a nt a gr e e s t o t h e ot h er pr ot o c ol r e q uir e d a s s e s s m e nt s i n cl u di n g f oll o w -u p. 
N o s p e cifi c  r e q u e st i s m a d e t o st o p t h e u s e of t h eir s a m pl e s or d at a. 
D o s a g e  
D o s e of t h e st u d y tr e at m e nt gi v e n t o t h e p arti ci p a nt i n a ti m e u nit ( e. g. 1 0 0 m g o n c e 
a d a y, 7 5 m g t wi c e a d a y).  
El e ctr o ni c D at a 
C a pt ur e ( E D C)  
El e ctr o ni c d at a c a pt ur e ( E D C) i s t h e el e ctr o n i 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 u r e d at a tr a n s cri b e d 
fr o m s o ur c e d at a/ d o c u m e nt s u s e d at t h e p oi nt of c ar e. 
E n d of t h e cli ni c al tri al  
T h e e n d of t h e cli ni c al tri al i s d efi n e d a s t h e l a st vi sit of t h e l a st p arti ci p a nt.  
E nr oll m e nt  
P oi nt/ti m e of p arti ci p a nt e ntr y i nt o t h e st u d y at w hi c h i nf or m e d c o n s e nt m u st b e 
o bt ai n e d. T h e a cti o n of e nr olli n g o n e or m or e p arti ci p a nt s.  
e S o ur c e ( D D E)  
e S o ur c e Dir e ct D at a E ntr y ( D D E) 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 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 oll e 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 s d efi n e d i n t h e I C H E 9( R 1) a d d e n d u m, e sti m a n d i s a pr e ci s e d e s cri pti o n of t h e 
tr e at m e nt eff e ct r efl e cti n g t h e cli ni c al q u e sti o n p o s e d b y t h e tri al o bj e cti v e. It 
s u m m ari z e s at a p o p ul ati o n -l e v el w h at t h e o ut c o m e s w o ul d b e i n t h e s a m e 
p arti ci p a nt s u n d er diff er e nt tr e at m e nt c o n diti o n s b ei n g c o m p ar e d. Attri b ut e s of a n 
e sti m a n d i n cl u d e t h e p o p ul ati o n, v ari a bl e ( or e n d p oi nt) a n d tr e at m e nt of i nt er e st, a s 
w ell a s t h e s p e cifi c ati o n of h o w t h e r e m ai ni n g i nt er c urr e nt e v e nt s ar e a d dr e s s e d a n d 
a p o p ul ati o n -l e v el s u m m ar y f or t h e v ari a bl e. 
I 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.  

N o v arti s  
C o nfi d e nti al  
P a g e  1 1  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
I n v e sti g ati o n al dr u g/ 
tr e at m e nt 
T h e dr u g w h o s e pr o p erti e s ar e b ei n g t e st e d i n t h e st u d y. 
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 or t h e p arti ci p a nt all o c at e d t o a n i n v ali d str atifi c ati o n f a ct or.  
Off -sit e  
D e s cri b e s tri al a cti viti e s t h at ar e p erf or m e d at r e m ot e l o c ati o n b y a n off -sit e 
h e alt h c ar e pr of e s si o n al, s u c h a s pr o c e d ur e s p erf or m e d at t h e  p arti ci p a nt' s h o m e.  
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 i n cl u d e t h o s e u s e d i n t h e st u d y e. g. 
N ur s e, P hl e b ot o mi st, P h y si ci a n, 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 i n 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 dif f 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" t er mi n ol o g y 
i s u s e d i n t h e pr ot o c ol w h er e a s t er m " S u bj e ct" i s u s e d i n d at a c oll e cti o n. 
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 ati e nt -R e p ort e d 
O ut c o m e ( P R O)  
A m e a s ur e m e nt b a s e d o n a r e p ort t h at c o m e s dir e ctl y fr o m t h e p ati e nt a b o ut t h e 
st a t u s of a p arti ci p a nt' s h e alt h c o n diti o n wit h o ut a m e n d m e nt or i nt er pr et ati o n of t h e 
p ati e nt' s r e p ort b y a cli ni ci a n or a n y o n e el s e.  
P eri o d  
T h e s u b di vi si o n s of t h e tri al d e si g n ( e. g. S cr e e ni n g, Tr e at m e nt, F oll o w -u p) w hi c h ar e 
d e s cri b e d i n t h e Pr ot o c ol. P eri o d s d efi n e t h e st u d y p h a s e s a n d will b e u s e d i n 
cli ni c al tri al d at a b a s e s et u p a n d e v e nt u all y i n a n al y si s.  
P er s o n al d at a  
P arti ci p a nt i nf or m ati o n c oll e ct e d b y t h e I n v e sti g at or t h at i s c o d e d a n d tr a n sf err e d t o 
N o v arti s f or t h e p ur p o s e of t h e cl i ni c al tri al. T hi s d at a i n cl u d e s p arti ci p a nt i d e ntifi er 
i nf or m ati o n, st u d y i nf or m ati o n a n d bi ol o gi c al s a m pl e s. 
R a n d o mi z ati o n  
T h e pr o c e s s of a s si g ni n g tri al p arti ci p a nt s t o i n v e sti g ati o n al dr u g or 
c o ntr ol/ c o m p ar at or dr u g u si n g a n el e m e nt of c h a n c e t o d et er mi n e t h e a s si g n m e nt s 
i n or d er t o r e d u c e bi a s. 
R a n d o mi z ati o n n u m b er  
A u ni q u e i d e ntifi er a s si g n e d t o e a c h r a n d o mi z e d p arti ci p a nt.  
R e -s cr e e ni n g  
If a p arti ci p a nt f ail s t h e i niti al s cr e e ni n g a n d i s c o n si d er e d a s a S cr e e n F ail ur e, 
h e/ s h e c a n b e i n vit e d o n c e f o r a n e w S cr e e ni n g vi sit aft er m e di c al j u d g m e nt a n d a s 
s p e cifi e d b y t h e pr ot o c ol.  
R e m ot e  
D e s cri b e s a n y tri al a cti viti e s p erf or m e d at a l o c ati o n t h at i s n ot t h e i n v e sti g 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 a h o m e or a n ot h er 
a p pr o pri at e l o c ati o n.  
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.  

N o v arti s  
C o nfi d e nti al  
P a g e  1 2  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
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.  
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 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 o r 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 st of a n o v er all r e gi m e n i n v ol vi n g a c o m pl e x s e q u e n c e of i nt er v e nti o n s. T hi s i s 
t h e tr e at m e nt of i nt er e st u s e d i n d e s cri bi n g t h e r el at e d cli ni c al q u e sti o n of i nt er e st, 
w hi c h mi g ht or mi g ht n ot b e t h e s a m e a s t h e st u d y tr e at m e nt. 
V ari a bl e ( or e n d p oi nt)  
T h e v ari a bl e ( or e n d p oi nt) t o b e o bt ai n e d f or e a c h p arti ci p a nt t h at i s r e q uir e d t o 
a d dr e s s t h e cli ni c al q u e sti o n. T h e s p e cifi c ati o n of t h e v ari a bl e mi g ht i n cl u d e w h et h er 
t h e p arti ci p a nt e x p eri e n c e s a n i nt er c urr e nt e v e nt. 
Wit h dr a w al of st u d y 
c o n s e nt ( W o C) / 
O p p o siti o n t o u s e of 
d at a / bi ol o gi c al 
s a m pl e s  
Wit h dr a w al of c o n s e nt fr o m t h e st u d y o c c ur s w h e n t h e p arti ci p a nt e x pli citl y r e q u e st s 
t o st o p u s e of t h eir d at a a n d bi ol o gi c al s a m pl e s ( o p p o siti o n t o u s e d at a a n d 
bi ol o gi c al s a m pl e s) A N D n o l o n g er wi s h e s t o r e c ei v e st u d y tr e at m e nt, A N D d o e s n ot 
a gr e e t o f urt h er pr ot o c ol r e q uir e d a s s e s s m e nt s. T hi s r e q u e st s h o ul d b e i n writi n g 
( d e p e n di n g o n l o c al r e g ul ati o n s) a n d r e c or d e d i n t h e s o ur c e d o c u m e nt ati o n. 
O p p o siti o n t o u s e d at a/ bi ol o gi c al s a m pl e s o c c ur s i n t h e c o u ntri e s w h er e c oll e cti o n 
a n d pr o c e s si n g of p er s o n al d at a i s j u stifi e d b y a diff er e nt l e g al r e a s o n t h a n c o n s e nt.  

N o v arti s  
C o nfi d e nti al  
P a g e  1 3  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
A m e n d m e nt 3 ( 0 2 -S e p -2 0 2 4 ) 
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 pri maril y t o ali g n t he pr ot oc ol wit h t he c urre nt practice of 
iss ui n g pr ot oc ol de viati o ns ( P Ds) f or n o n-c o m plia nce wit h q uesti o n naires t hat c o ntri b ute t o t he 
sec o n dar y e n d p oi nts. I n a d diti o n, as t his st u d y will ha ve t o a d here t o E U -C T R sta n dar ds, 
c ha n ges ha v e bee n ma de acr oss t he pr ot o c ol t o f ulfil ke y E U -C T R re q uir e me nts.  
Ot her mi n or p oi nt s of clarificati o n a n d ali g n me nt, e dit orial c ha n ges were ma de.  
T he a me n d me nt is bei n g de vel o pe d after t he release of t he pr ot o c ol a me n d me nt versi o n 0 2 
w hic h is alrea d y a p pr o ve d b y t he Healt h A ut h orities ( H A) a n d I n d e pe n d e nt Et hics C o m mittees 
(I E C) i n all t he 8 all ocate d st u d y c o u ntries a n d h as tra nsiti o ne d t o E U-C T R. T he st u d y ac hie ve d 
Last Partici pa nt First treat me nt o n 2 6 -Fe b -2 0 2 4 wit h 1 7 7 6 ra n d o mize d partici pa nts. O n 2 -Se p -
2 0 2 4, 1 3 9 1  partici pa nts h a d  c o m plete d treat me nt.  
C h a n g e s t o t h e pr ot o c ol  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e  1 4  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e  1 5  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
I R B s/I E C s 
T he c ha n g es descri be d i n t his a me n de d pr ot oc ol  are n o n -s u bsta ntial. 
T he c ha n g es herei n are ali g ne d t o t he trial s pecific m o del I C F. 

N o v arti s  
C o nfi d e nti al  
P a g e  1 6  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
A m e n d m e nt 2 ( 0 1 -N o v -2 0 2 2)  
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  re m o ve of m m ol/ L u nit fr o m i ncl usi o n criteria t o be 
c o nsiste nt wit h relate d e n d p oi nt, u p date  t he st u d y disc o nti n uati o n la n g ua ge, clarif y starti n g 
d ose f or R os u vastati n at Da y 1, ali g n wit h c urre nt a p pr o val stat us of i nclisira n o ver t he w orl d,  
c orrect s o me  ti me p oi nt i n t he sc he d ule of assess me nt. 
Ot her mi n or p oi nt of clarificati o n a n d ali g n me nt, e dit orial c ha n ges w ere ma de.  
T he a me n d me nt is bei n g de vel o pe d after t he release of t he pr ot o c ol a me n d me nt versi o n 0 1 
w hic h is alrea d y a p pr o ve d b y t he Healt h A ut h orities ( H A) a n d I n d e pe n d e nt Et hics C o m mittees 
(I E C) i n all t he 8 all ocat e d st u d y c o u ntries. 
C h a n g e s t o t h e pr ot o c ol  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e  1 7  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
I RB s/I E C s  
A c o p y of t his a me n de d pr ot oc ol 
will be se nt t o t he I nstit uti o nal 
Re vie w 
B oar d 
(I R Bs)/I n d e pe n d e nt Et hics C o m mittee (I E Cs) a n d Healt h A ut h orities. 
T he c ha n ges des cri 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 Healt h A ut h orit y 
a p pr o val a cc or di n g  t o l ocal re g ulati o ns pri or t o i m ple me ntati o n.  
T he c ha n g es herei n are ali g ne d i n t he trial s pecific m o del I C F.  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e  1 8  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
A m e n d m e nt 1 ( 1 1 -N o v -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 u p date seri o us a d verse e v e nt ( S A E) re p orti n g la n g ua ge t o 
i ncl u de stricter re q uir e me nts f or t he re p orti n g of S A Es, if re q uir e d b y l ocal re g ulati o ns. 
A d diti o nall y, war ni n gs, preca uti o ns, f oll o w -u p f or t o xicities a n d pr o hi bite d me dicati o ns were 
a d de d f or t h e st u d y treat me nt, r os u vastati n. Ot her mi n or, e dit orial c ha n ges were ma de.  
T he a me n d me nt is bei n g de vel o pe d after t he releas e of t he ori gi nal pr ot oc ol versi o n 0 0 b ut pri or 
t o t he s u b missi o n t o Healt h A ut h orities ( H A) a n d I n de pe n d e nt Et hics C o m mittees (I E C). 
He nce, Pr ot oc ol A me n d me nt Versi o n 0 1 will be t he first pr ot oc ol s u b mitte d a n d i m ple me nte d 
at all trial sites.   
C h a n g e s t o t h e pr ot o c ol  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e  1 9  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
I RB s/I E C s  
A c o p y of t his a me n de d pr ot oc ol 
will be se nt t o t he I nstit uti o nal 
Re vie w 
B oar d 
(I R Bs)/I n d e pe n d e nt Et hics C o m mittee (I E Cs) a n d Healt h A ut h orities. 
T he c ha n ges des cri 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 Healt h A ut h orit y 
a p pr o val a cc or di n g  t o l ocal re g ulati o ns pri or t o i m ple me ntati o n.  
T he c ha n g es herei n are ali g ne d i n t he trial s pecific m o del I C F.  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e  2 0  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
Pr ot o c ol s u m m ar y  
Pr ot o c ol 
n u m b er  
C K J X 8 3 9 A 1 2 4 0 2  
F ull Titl e  
Effi c a c y, s af et y, t ol er a bilit y a n d q u alit y of lif e of o n g oi n g i n di vi d u all y o pti mi z e d li pi d-l o w eri n g 
t h er a p y wit h or wit h o ut i n cli sir a n ( K J X 8 3 9) –  a r a n d o mi z e d, pl a c e b o -c o ntr oll e d, d o u bl e -bli n d 
m ulti c e nt er p h a s e I V st u d y i n p arti ci p a nt s wit h h y p er c h ol e st er ol e mi a.  
Bri ef titl e  
St u d y of effi c a c y, s af et y, t ol er a bilit y a n d q u alit y of lif e of i n cli sir a n ( K J X 8 3 9) v s pl a c e b o, o n 
t o p of o n g oi n g i n di vi d u all y o pti mi z e d li pi d-l o w eri n g t h er a p y, i n p arti ci p a nt s wit h 
h y p er c h ol e st er ol e mi a.  
S p o n s or a n d 
Cli ni c al P h a s e  
N o v arti s  
P h a s e I V  
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  
T h e p ur p o s e of t hi s st u d y i s  t o d e m o n str at e t h e s u p eri orit y of i n cli sir a n c o m p ar e d t o 
pl a c e b o, b ot h o n t o p of o n g oi n g i n di vi d u all y o pti mi z e d li pi d -l o w eri n g t h er a p y ( L L T), o n 
r e a c hi n g a p arti ci p a nt' s L D L-C t ar g et ( <  5 5  m g/ d L or <  7 0  m g/ d L, d e p e n di n g o n t h e 
c ar d i o v a s c ul ar ri s k c at e g or y, a c c or di n g t o t h e 2 0 1 9 E S C/ E A S g ui d eli n e s f or t h e 
m a n a g e m e nt of d y sli pi d e mi a s ( M a c h  et  al  2 0 2 0 ) a s w ell a s o n p ati e nt-
r el e v a nt s af et y,  t ol er a bilit y o ut c o m e s a n d q u alit y of lif 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 of t hi s st u d y i s t o d e m o n str at e t h e s u p eri orit y of i n cli sir a n o n t o p of 
o n g oi n g i n di vi d u all y o pti mi z e d L L T c o m p ar e d t o pl a c e b o o n t o p of o n g oi n g i n di vi d u all y 
o pti mi z e d L L T o n r e a c hi n g a p arti ci p a nt' s i n di vi d u al L D L -C t ar g et a s m e a s ur e d b y t h e 
pr o p orti o n of p arti ci p a nt s a c hi e vi n g i n di vi d u al L D L -C t ar g et ( < 5 5 m g/ d L or < 7 0 m g/ d L) at 
d a y 9 0.  
S e c o n d ar y 
O bj e cti v e s  
T h e s e c o n d ar y o bj e cti v e s of t hi s st u d y ar e t o d e m o n str at e t h e s u p eri orit y of i n cli sir a n o n t o p 
of o n g oi n g i n di vi d u all y o p ti mi z e d L L T c o m p ar e d t o pl a c e b o o n t o p of o n g oi n g i n di vi d u all y 
o pti mi z e d L L T o n:  
•  
R e d u ci n g m e a n L D L -C l e v el s o v er t h e d o u bl e -bli n d st u d y p eri o d, a s m e a s ur e d b y t h e 
r el ati v e c h a n g e ( p er c e nt a g e fr o m b a s eli n e t o m e a n L D L -C l e v el).  
•  
M u s cl e -r el at e d a d v er s e e v e nt s, a s 
m e a s ur e d b y t h e pr o p orti o n of p arti ci p a nt s 
e x p eri e n ci n g at l e a st  o n e m u s cl e -r el at e d A E a s d efi n e d i n t h e S M Q r h a b d o m y ol y si s / 
m y o p at h y  fr o m d a y 1 t o d a y 3 6 0. 
•  
A n n u ali z e d n u m b er of d a y s p ai n i s e x p eri e n c e d, a s m e a s ur e d b y t h e pr o p orti o n of 
p arti ci p a nt s e x p eri e n ci n g s elf -r e p ort e d p ai n fr o m b a s eli n e t o d a y 3 6 0, u si n g a p ai n di ar y. 
•  
P ai n -r el at e d q u alit y of lif e at d a y 3 6 0 u si n g t h e S h ort-F or m Bri ef P ai n I n v e nt or y  
( S F-B PI)  a s m e a s ur e d b y t h e c h a n g e i n t h e S F -B PI p ai n s e v erit y  a n d i nt erf er e n c e s c or e s 
fr o m b a s eli n e t o d a y 3 6 0 a n d t h e pr o p orti o n of p arti ci p a nt s wit h cli ni c all y r el e v a nt c h a n g e 
i n S F-B PI p ai n s e v erit y a n d i nt erf er e n c e s c or e s fr o m b a s eli n e t o d a y 3 6 0.  
St u d y d e si g n  
T hi s st u d y i s a d o u bl e -bli n d, pl a c e b o -c o ntr oll e d m ulti c e nt er st u d y i n a d ult p arti ci p a nt s wit h 
v er y hi g h or hi g h c ar di o v a s c ul ar ri s k ( a s d efi n e d b y t h e c ar di o v a s c ul ar ri s k c at e g ori e s i n t h e 
2 0 1 9 E S C/ E A S g ui d eli n e s f or t h e m a n a g e m e nt of d y sli pi d e mi a s ( M a c h  et  al  2 0 2 0 ) w ho d o 
n ot m e et t h eir i n di vi d u al L D L -C t ar g et d e s pit e b ei n g tr e at e d wit h t h eir i n di vi d u al m a xi m u m 
t ol er at e d d o s e ( M T D) of a st ati n, a n d if a p pli c a bl e, f urt h er L L T. 
L D L -C t ar g et will b e e v al u at e d a c c or di n g t o m o st r e c e nt a s s e s s m e nt of c ar di o v a s c ul ar ri s k 
c at e g or y a s d et er mi n e d b y t h e i n v e sti g at or. T hi s i n cl u d e s a s s e s s m e nt of c ar di o v a s c ul ar 
e v e nt s a n d n e w -o n s et or w or s e ni n g of c ar di o v a s c ul ar ri s k f a ct or s a s d efi n e d i n t h e c urr e nt 
g ui d eli n e s t hr o u g h o ut t h e tri al.  
T hi s i s a tr e at m e nt str at e g y st u d y w h er e t h e p art i ci p a nt s ar e b ot h r a n d o mi z e d t o i n cli sir a n 
v er s u s pl a c e b o a n d al s o si m ult a n e o u sl y s wit c h e d t o r o s u v a st ati n, a n d t h e n h a v e t h eir L L T 
i n di vi d u all y o pti mi z e d b y i n v e sti g at or s r e s ulti n g i n li k el y l e s s i nt e n s e L L T i n t h e i n cli sir a n ar m 
a n d 
 i n t h e pl a c e b o ar m. 
T h e st u d y c o n si st s of:  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e  2 1  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
•  
A S cr e e ni n g p eri o d of a p pr o xi m at el y 1 4  d a y s f or all p arti ci p a nt s.  
•  
A n o pti o n al R u n -i n p eri o d of u p t o 1 2 0 d a y s a s i n di vi d u all y a p pli c a bl e f or st ati n or ot h er 
L L T u p titr ati o n.  
•  
A n o pti o n al a d diti o n al b a s eli n e p eri o d of a p pr o xi m at el y 1 0 d a y s a s i n di vi d u all y a p pli c a bl e 
f or r e q uir e d l a b s  
•  
A Tr e at m e nt p eri o d of 3 6 0  d a y s ( e x cl u di n g a s af et y f oll o w -u p c all 3 0  d a y s aft er t h e e n d 
of st u d y (E O S ) vi sit). 
All p arti ci p a nt s, w h o f ulfill t h e  i n cl u si o n/ e x cl u si o n crit eri a, will b e r a n d o mi z e d at D a y 1 
(tr e at m e nt p eri o d) i n a 1: 1 d o u bl e -bli n d  f a s hi o n t o eit h er i n cli sir a n or pl a c e b o.  I n a d diti o n, at 
D a y 1 all p arti ci p a nt s will b e s wit c h e d  fr o m t h eir i n di vi d u al st ati n t o r o s u v a st ati n, w hi c h i s 
c o n s i d er e d o p e n l a b el st u d y tr e at m e nt i n t hi s tri al. 
A s p er l o c al S m P C,  t h e r e c o m m e n d e d st art d o s e f or r o s u v a st ati n at b a s eli n e i s  5  m g/ d a y or 
1 0  m g/ d a y.  If a p arti ci p a nt' s L D L-C i s n ot at t ar g et at d a y 3 0 a n d at t h e f oll o wi n g vi sit s, 
b a s e d o n m o st r e c e nt  L D L -C m e a s ur e m e nt,  r o s u v a st ati n s h o ul d b e i n di vi d u all y titr at e d. 
If aft er t h e r o s u v a st ati n titr ati o n t o a n i n di vi d u al M T D, a p arti ci p a nt’ s i n di vi d u al L D L-C i s n ot 
at t ar g et i n  eit h er tr e at m e nt ar m, t h e L L T m u st b e f urt h er e s c al at e d a s p er r e c o m m e n d e d 
pr o c e s s.  
T h e o v er all st u d y d ur ati o n i s at l e a st 3 6 0 d a y s b ut c a n b e l o n g er d e p e n di n g o n i n di vi d u al 
s cr e e ni n g a n d r u n -i n p eri o d ti m e. 
R ati o n al e  
I n cli sir a n i s i n di c at e d, i n t h e E U, i n a d ult s wit h pri m ar y h y p er c h ol e st er ol e mi a ( h et er o z y g o u s 
a n d n o n -f a mili al) or mi x e d d y sli pi d e mi a, a s a n a dj u n ct t o di et i n c o m bi n ati o n wit h a st ati n or 
st ati n wit h ot h er L L T s i n p ati e nt s u n a bl e t o r e a c h L D L ‑C t ar g et s wit h t h e M T D  of a st ati n, or 
al o n e or i n c o m bi n ati o n wit h ot h er L L T s i n p ati e nt s w h o ar e st ati n -i nt ol er a nt, or f or w h o m a 
s t ati n i s c o ntr ai n di c at e d. T h e ai m of t hi s st u d y i s t o c o m p ar e t h e effi c a c y, s af et y, t ol er a bilit y 
a n d q u alit y of lif e  of a tr e at m e nt str at e g y i n cl u di n g i n cli sir a n ( o n t o p of o n g oi n g i n di vi d u all y 
o pti mi z e d L L T f oll o wi n g a s wit c h t o R o s u v a st ati n at b a s eli n e) wit h a tr e at m e nt str at e g y 
b a s e d o n t h e c urr e nt E S C/ E A S g ui d eli n e s,  i n p arti ci p a nt s w h o s e L D L-C i s n ot a d e q u at el y 
c o ntr oll e d u si n g t h e M T D of a st ati n f or H e alt h T e c h n ol o g y A s s e s s m e nt.  
St u d y 
p o p ul ati o n  
T hi s i s a m ulti -c e nt er, m ulti -c o u ntr y st u d y, e x p e ct e d t o e nr oll 1 7 6 0 p arti ci p a nt s, r a n d o mi z e d 
1: 1 a cr o s s t w o ar m s. Si n c e 3 5 % of p arti ci p a nt s ar e e x p e ct e d t o b e s cr e e ni n g or r u n -i n 
f ail ur e s, a p pr o xi m at el y 2 7 0 0 p arti ci p a nt s ar e a nti ci p at e d t o b e s cr e e n e d. P arti ci p a nt s 
eli gi bl e f or t hi s tri al will i n cl u d e m al e a n d f e m al e p arti ci p a nt s a g e 1 8 y e ar s a n d ol d er at v er y 
hi g h a n d hi g h ri s k f or c ar di o v a s c ul ar e v e nt s a s d efi n e d b y t h e c ar di o v a s c ul ar ri s k c at e g ori e s 
i n t h e 2 0 1 9 E S C/ E A S g ui d eli n e s f or t h e m a n a g e m e nt of d y sli pi d e mi a s (M a c h  et  al  2 0 2 0 ) 
w h o d o n ot m e et t h eir i n di vi d u al L D L -C t ar g et d e s pit e b ei n g tr e at e d wit h t h eir i n di vi d u al 
M T D  of a st ati n f or at l e a st 3 0 d a y s, a n d if a p pli c a bl e, a n ot h er L L T o n t o p of st ati n st a bl e f or 
at l e a st 3 0 d a y s pri or t o s cr e e ni n g ( u p t o a p pr o xi m at el y 2 0 % of r a n d o mi z e d p arti ci p a nt s).  
K e y I n cl u si o n 
crit eri a  
•  
M al e or f e m al e p arti ci p a nt s ≥1 8 y e ar s of a g e.  
•  
P arti ci p a nt s m e eti n g o n e of t h e f oll o wi n g C V c at e g ori e s:  
•  
V er y hi g h ri s k p arti ci p a nt s wit h at l e a st o n e of t h e f oll o wi n g:  
•  
D o c u m e nt e d At h er o s cl er oti c c ar di o v a s c ul ar di s e a s e ( A S C V D)  
i 
A c ut e c or o n ar y s y n dr o m e: U n st a bl e a n gi n a or m y o c ar di al i nf ar cti o n.  
ii 
St a bl e a n gi n a.  
iii C or o n ar y r e v a s c ul ari z ati o n.  
i v U n e q ui v o c all y d o c u m e nt e d A S C V D u p o n pri or i m a gi n g.  
v  
Str o k e a n d TI A.  
vi  P eri p h er al art er y di s e a s e ( P A D).  
•  
Di a b et e s m ellit u s  ( D M) wit h t ar g et or g a n d a m a g e ( d efi n e d a s mi cr o al b u mi n uri a, 
r eti n o p at h y, or n e ur o p at h y), or at l e a st ≥ 3 m aj or ri s k f a ct or s, or e arl y o n s et of  
T y p e 1 D M of l o n g d ur ati o n ( > 2 0 y e ar s).  
•  
A c al c ul at e d S C O R E 2 ≥ 7. 5 % f or a g e < 5 0 y e ar s; S C O R E 2 ≥1 0 % f or a g e 5 0 -6 9 
y e ar s; S C O R E 2 -O P ≥1 5 % f or a g e ≥7 0 y e ar s t o e sti m at e 1 0 -y e ar ri s k of f at al a n d 
n o n -f at al c ar di o v a s c ul ar di s e a s e ( C V D). 

N o v arti s  
C o nfi d e nti al  
P a g e  2 2  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
•  
Pr e -e xi sti n g di a g n o si s of  h et er o z y g o u s f a mili al h y p er c h ol e st er ol e mi a  ( H e F H) wit h 
A S C V D or wit h a n ot h er m aj or ri s k f a ct or.  
O R  
•  
Hi g h ri s k p arti ci p a nt s wit h at l e a st o n e of t h e f oll o wi n g:  
•  
M ar k e dl y el e v at e d si n gl e ri s k f a ct or s, i n p arti c ul ar t ot al c h ol e st er ol > 3 1 0 m g/ d L, 
L D L -C > 1 9 0 m g/ d L, or bl o o d pr e s s ur e ≥ 1 8 0/ 1 1 0 m m H g  
•  
Pr e -e xi sti n g di a g n o si s of  H e F H wit h o ut ot h er m aj or ri s k f a ct or s.  
•  
Di a b et e s M ellit u s ( D M) wit h o ut t ar g et or g a n d a m a g e ( d efi n e d a s mi cr o al b u mi n uri a, 
r eti n o p at h y, or n e ur o p at h y), wit h D M d ur ati o n ≥ 1 0 y e ar s or ot h er a d diti o n al ri s k 
f a ct or. 
•  
M o d er at e c hr o ni c ki d n e y di s e a s e ( e G F R 3 0 -5 9 m L/ mi n/ 1. 7 3 m 2 ). 
•  
A c al c ul at e d S C O R E 2 2. 5 t o < 7. 5 % f or a g e < 5 0 y e ar s, S C O R E 2 5 t o < 1 0 % f or 
a g e 5 0 -6 9 y e ar s; S C O R E 2 -O P 7. 5 t o < 1 5 % f or a g e ≥7 0 y e ar s t o e sti m at e 1 0 -y e ar 
ri s k of f at al a n d n o n-f at al C V D. 
 
•  L D L -C l e v el s at s cr e e ni n g a n d b a s eli n e:  
•  
i n p arti ci p a nt s wit h v er y hi g h c ar di o v a s c ul ar ri s k: s er u m L D L-C ≥5 5 m g/ d L.  
•  
i n p arti ci p a nt s wit h hi g h  c ar di o v a s c ul ar  ri s k: s er u m L D L-C ≥7 0 m g/ d L.  
•  
P arti ci p a nt o n a st a bl e d o s e of a st ati n f or ≥ 3 0 d a y s at s cr e e ni n g.  
•  
P arti ci p a nt s o n t h e i n di vi d u al M T D  of st ati n f or ≥ 3 0 d a y s at b a s eli n e.  
•  
F a sti n g tri gl y c eri d e < 4 0 0 m g/ d L at s cr e e ni n g a n d b a s eli n e.  
K e y E x cl u si o n 
crit eri a  
•  
P arti ci p a nt s o n m or e t h a n  o n e ot h er li pi d -l o w eri n g dr u g o n t o p of st ati n at s cr e e ni n g 
vi sit.  
•  
P arti ci p a nt s wit h a k n o w n i nt ol er a n c e t o r o s u v a st ati n at s cr e e ni n g or b a s eli n e vi sit.  
•  Pr e vi o u s ( wit hi n 9 0 d a y s of s cr e e ni n g), c urr e nt or pl a n n e d tr e at m e nt wit h a m o n o cl o n al 
a nti b o d y ( m A b) dir e ct e d t o w ar d s P C S K 9 ( e. g. e v ol o c u m a b, alir o c u m a b) at s cr e e ni n g or 
b a s eli n e vi sit.  
•  Pr e vi o u s e x p o s ur e t o i n cli sir a n or a n y ot h er n o n -m A b P C S K 9 t ar g et e d t h er a p y, eit h er a s 
a n i n v e sti g ati o n al or m ar k et e d dr u g wit hi n 2 y e ar s pri or t o s cr e e ni n g or b a s eli n e vi sit.  
•  Pr e vi o u s, c urr e nt or pl a n n e d tr e at m e nt wit h L D L -a p h er e si s at s cr e e ni n g or b a s eli n e vi sit.  
•  Li v er a n d C K: ( a) A cti v e li v er di s e a s e d efi n e d a s a n y c urr e nt i nf e cti o u s, n e o pl a sti c, or 
m et a b oli c p at h ol o g y of t h e li v er or ( b) u n e x pl ai n e d  al a ni n e a mi n otr a n sf er a s e ( A L T), 
a s p art at e a mi n otr a n sf er a s e ( A S T) el e v ati o n > 3 x U L N, or t ot al bilir u bi n el e v ati o n > 2 x 
U L N ( e x c e pt f or p arti ci p a nt s wit h Gil b ert' s s y n dr o m e), or ( c) cr e ati n e ki n a s e ( C K) > 5 x 
U L N at s cr e e ni n g or b a s eli n e vi sit.  
•  P arti ci p a nt  wit h s e v er e r e n al i m p air m e nt d efi n e d b y e G F R < 3 0 m L/ mi n/ 1. 7 3 m 2  a s 
c al c ul at e d b y t h e M o difi c ati o n i n Di et i n R e n al Di s e a s e ( M D R D) f or m ul a at s cr e e ni n g or 
b a s eli n e vi sit.  
•  A c ut e c or o n ar y s y n dr o m e, i s c h e mi c str o k e or TI A,  c or o n ar y r e v a s c ul ari z ati o n 
or  p eri p h er al art eri al r e v a s c ul ari z ati o n pr o c e d ur e or a m p ut ati o n d u e t o at h er o s cl er oti c 
di s e a s e < 3 m o nt h s pri or t o t h e s cr e e ni n g or b a s eli n e vi sit.  
•  H e art f ail ur e N e w Y or k H e art A s s o ci ati o n ( N Y H A) cl a s s I V at s cr e e ni n g or b a s eli n e vi sit.  
•  Pr e g n a nt or n ur si n g ( l a ct ati n g) w o m e n at s cr e e ni n g or b a s eli n e vi sit. 
•  W o m e n of c hil d -b e ari n g p ot e nti al, u nl e s s t h e y ar e u si n g hi g hl y eff e cti v e m et h o d s of 
c o ntr a c e pti o n d uri n g d o si n g of st u d y tr e at m e nt.  
St u d y 
tr e at m e nt 
•  D o u bl e -bli n d i n v e sti g ati o n al tr e at m e nt i n cli sir a n/ pl a c e b o: s u b c ut a n e o u s i nj e cti o n s of 
i n cli sir a n s o di u m 3 0 0 m g ( e q ui v al e nt t o 2 8 4 m g i n cli sir a n) or pl a c e b o, i n 1. 5 m L s ol uti o n. 
•  O p e n l a b el st u d y tr e at m e nt r o s u v a st ati n: all p arti ci p a nt s will r e c ei v e r o s u v a st ati n, st arti n g 
at t h e l o w e st i n di c at e d d o s e a n d titr ati n g u p u ntil t h e y r e a c h t h eir i n di vi d u al L D L-C t ar g et 
or M T D, w hi c h e v er o c c ur s fir st.  
•  O n g oi n g i n di vi d u al o pti mi z ati o n of li pi d -l o w eri n g b a c k gr o u n d t h er a p y if L D L-C i s n ot y et 
at t ar g et.  

N o v arti s  
C o nfi d e nti al  
P a g e  2 3  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
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: bli n d e d i n v e s ti g ati o n al tr e at m e nt i n cli sir a n ( o n t o p of 
pr e s u m a bl y a l e s s i nt e n s e b a c k gr o u n d L L T) or pl a c e b o ( o n t o p of a 
 
 b a c k gr o u n d L L T), 
A n d a s b a c k gr o u n d L L T: u n bli n d e d r o s u v a st ati n 5 or 1 0 m g at b a s eli n e w hi c h i s i n di vi d u all y 
o pti mi z e d o n a n o n g oi n g b a si s.  
Effi c a c y 
a s s e s s m e nt s  
•  
L D L -C a n al y si s, a s p erf or m e d b y t h e C e ntr al L a b.  
K e y s af et y 
a s s e s s m e nt s  
•  
A d v er s e e v e nt m o nit ori n g  
•  
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  
Ot h er 
a s s e s s m e nt s  
•  
P arti ci p a nt R e p ort e d O ut c o m e ( P R O) q u e sti o n n air e s t o i n cl u d e:  
•  D ail y P ai n Di ar y  
•  S h ort F or m Bri ef P ai n I n v e nt or y  
•  G a str oi nt e sti n al S y m pt o m R ati n g S c al e  
•  S F -3 6  
•  W al ki n g I m p air m e nt Q u e sti o n n air e (i n P A D s u b p o p ul ati o n)  
•  M a c N e w H e art Di s e a s e H e alt h R el at e d Q u alit y of Lif e (i n A n gi n a p e ct ori s 
s u b p o p ul ati o n)  
•  Tr e at m e nt S ati sf a cti o n Q u e sti o n n air e f or M e di c ati o n  
D at a a n al y si s  
T h e pri m ar y e sti m a n d i s d e s cri b e d b y t h e f oll o wi n g attri b ut e s:  
1  P o p ul ati o n: A d ult p arti ci p a nt s c at e g ori z e d a s v er y hi g h ri s k or hi g h ri s k a s d efi n e d b y t h e 
c ar di o v a s c ul ar ri s k c at e g ori e s i n t h e 2 0 1 9 E S C/ E A S g ui d eli n e s  f or t h e m a n a g e m e nt of 
d y sli pi d e mi a s  (M a c h  et  al  2 0 2 0 ) wit h el e v at e d L D L-C d e s pit e b ei n g tr e at e d wit h t h e 
i n di vi d u al M T D of st ati n a n d, if a p pli c a bl e, al s o ot h er L L T.  
2  E n d p oi nt: Pr o p orti o n of p arti ci p a nt s a c hi e vi n g i n di vi d u al L D L -C t ar g et  ( < 5 5  m g/ d L  or 
<  7 0  m g/ d L)  at d a y 9 0. T h e i n di vi d u al L D L -C t ar g et  of t h e p arti ci p a nt s  i s d et er mi n e d 
a c c or di n g t o t h eir  i n di vi d u al c ar di o v a s c ul ar ri s k  c at e g or y.  
3  Tr e at m e nt of i nt er e st:  I n cli sir a n, c o m p ar e d t o pl a c e b o, b ot h o n t o p of a n 
o n g oi n g  p arti ci p a nt -i n di vi d u all y o pti mi z e d L L T. R a n d o mi z e d tr e at m e nt s ar e t h e 
i n v e sti g ati o n al tr e at m e nt i n cli sir a n or t h e pl a c e b o c o ntr ol tr e at m e nt. I n b ot h tr eat m e nt 
ar m s, p arti ci p a nt s r e c ei v e a n i n di vi d u all y o pti mi z e d r o s u v a st ati n t h er a p y f or r e a c hi n g t h e 
i n di vi d u al L D L-C t ar g et a n d t ol er a bilit y. If r e q uir e d t o a c hi e v e t h eir L D L -C t ar g et, 
f urt h er p arti ci p a nt -i n di vi d u all y o pti mi z e d L L T c a n b e a d mi ni st er e d.  
4  S u m m ar y m e a s ur e: T h e  o d d s r ati o  of a c hi e vi n g i n di vi d u al L D L -C t ar g et at d a y 9 0 
c o m p ar e d b et w e e n tr e at m e nt ar m s. A l ar g er pr o p orti o n of p arti ci p a nt s i n di c at e s a 
s u p eri or o ut c o m e.  
T h e s e c o n d ar y e sti m a n d s ar e d efi n e d b y t h e e v al u ati o n of tr e at m e nt eff e ct o n t h e  f oll o wi n g 
e n d p oi nt s a n d s u m m ar y m e a s ur e s:  
1  R el ati v e  c h a n g e  ( p er c e nt a g e c h a n g e) fr o m b a s eli n e t o m e a n  L D L -C  l e v el o v er t h e 
d o u bl e -bli n d st u d y p eri o d ( a v er a g e d o v er all p o st b a s eli n e vi sit s).  
2  Pr o p orti o n of p arti ci p a nt s e x p eri e n ci n g at l e a st o n e m u s cl e -r el at e d A E a s d efi n e d i n t h e 
S M Q r h a b d o m y ol y si s / m y o p at h y fr o m d a y 1 t o d a y 3 6 0.  
3  A n n u ali z e d n u m b er of d a y s p arti ci p a nt s e x p eri e n ci n g s elf -r e p ort e d p ai n fr o m d a y 1 t o 
d a y 3 6 0.  
4  C h a n g e fr o m b a s eli n e i n S F -B PI  p ai n s e v erit y s c or e fr o m  at d a y 3 6 0.  
5  C h a n g e f r o m b a s eli n e i n S F-B PI  p ai n i nt erf er e n c e s c or e  at d a y 3 6 0.  
K e y w or d s  
I n cli sir a n, r o s u v a st ati n, P C S K 9, d y sli pi d e mi a, a n gi n a p e ct ori s, p eri p h er al art er y di s e a s e, 
c ar di o v a s c ul ar di s e a s e, L D L -C   
C CI

N o v arti s  
C o nfi d e nti al  
P a g e  2 4  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
1  
I ntr o d u cti o n 
1. 1  
B a c k gr o u n d  
Car di o vasc ular diseas e ( C V D) is t he lea di n g ca use of deat h w orl d wi de, res ulti n g i n o ver 1 7 
milli o n deat hs a n n uall y ( W H O  2 0 1 7 ). Ele v ate d l o w-de nsit y li p o pr otei n c h olester ol ( L D L -C) is 
a 
well -rec o g nize d 
maj or ris k fact or f or t he de vel o p me nt of C V D (Gr u n d y  et al 2 0 0 4 , 
Bai ge nt  et al 2 0 0 5 , M ozaffaria n  et al 2 0 1 5 ). L o weri n g L D L-C has bee n s h o w n t o re d uce t he 
ris k of deat h or m y ocar dial i nfarcti o n ( MI) or str o ke a n d wit hi n t he ra n ge of effects ac hie ve d 
s o far, t he cli nical ris k re d ucti o n is li nearl y pr o p orti o nal t o t he a bs ol ute L D L -C re d ucti o n 
(Bai ge nt  et al 2 0 0 5 , Castilla -G uerra  et al 2 0 1 6 ). 
Des pite t he a vaila bilit y of m ulti ple t hera pe utic o pti o ns f or li pi d l o weri n g, i ncl u di n g H M G -C o A 
re d uctas e i n hi bit ors (stati ns) a n d c h olester ol a bs or pti o n i n hi bit ors (ezeti mi be), o ver 5 0 % of 
pa tie nts 
d o 
n ot reac h t heir 
L D L-C tar gets ( J o nes et al 2 0 1 2 , Ja mes o n et al 2 0 1 4 , 
Bar kas  et al 2 0 1 5 , Fitz geral d  et al 2 0 1 7 ). T his is partic ularl y tr u e i n p arti ci pa nts wit h pre-
e xisti n g c or o nar y heart disease ( C H D) w h o are at t he hi g h est ris k of 
maj or a d verse 
car di o vas c ular 
e v e nts 
( M A C E) 
a n d 
re q uire 
t he 
m ost 
i nte nsi ve 
ma na ge me nt 
(Da vi ds o n  et al 2 0 0 5 ). F urt her m ore, s o me o bs er vati o nal st u dies de m o nstrate d t hat m ore t ha n 
5 0 % of partici pa nts di d n ot a d here t o stati n t hera p y f or m ore t ha n si x m o nt hs, ma ki n g p o or 
c o m plia nce 
wit h stati ns o ne of t he reas o ns f or l o w treat me nt g oal ac hie ve m e nt 
(P ol uzzi  et al 2 0 0 8 , Ma n n  et al 2 0 1 0 , Hirs h  et al 2 0 1 5 ). 
T he 2 0 1 9 E S C/ E A S G ui deli nes f or t he ma na ge me nt of d ysli pi de mias defi nes car di o vasc ul ar 
ris k cate g ories a n d t heir c orres p o n di n g L D L -C tar gets acc or di n g t o ris k wit h a L D L -C tar get of 
< 5 5 m g/ d L f or patie nts at ver y hi g h ris k a n d < 7 0 m g/ d L f or patie nts at hi g h ris k f or a 
car di o vas c ular e v e nt ( M ac h  et al 2 0 2 0 ). Stati ns are t he first-c h oice p har m ac ol o gical treat me nt 
f or patie nts wit h h y perc h olester ole mia a n d at ris k f or C V D. H o we ver, a pr o p orti o n of patie nts 
e x perie n ce stati n -ass ociate d m uscle s y m pt o ms, i ncl u di n g m y o pat h y, m yal gia a n d i n ver y rare 
cases r ha b d o m y ol ysis. Stati n -ass ociate d m uscl e s y m pt o ms wit h or wit h o ut a n ele vati o n i n 
creati ne ki n ase are mar k e dl y m ore fre q ue nt at hi g her stati n d oses a n d are t he m ost c o m m o n 
ca use of treat me nt disc o nti n uati o n ( Str oes  et al 2 0 1 5 , Ne w ma n  et al 2 0 1 9 , War d  et al 2 0 1 9 ). 
Ot her li pi d -l o weri n g me dicati o ns, s uc h as ezeti mi be, bile aci d se q uestr a nts, or be m pe d oic aci d 
are ass ociate d wit h m uscle -relat e d s y m pt o ms or w orse ni n g of m uscle -relate d s y m pt o ms w he n 
a d mi nistere d t o get her wit h a stati n or are ass ociate d wit h gastr oi ntesti nal si de effects 
(Gr u n d y  et al 2 0 1 9 , M ac h  et al 2 0 2 0 , S m P Cs). C o nseq ue ntl y, i n a d diti o n t o efficie ntl y l o weri n g 
L D L -C, i n di vi d ual patie nt -rele va nt t olera bilit y of li pi d-l o weri n g m o n o- or c o m bi nati o n t hera p y 
o pti o ns a n d q ualit y of life nee ds t o be c o nsi dere d.  
Pr o pr otei n c o n vert ase s u btilisi n/ ke xi n t y pe 9 ( P C S K 9) is e x press e d a n d secrete d i nt o t he 
bl o o dstrea m pre d o mi na ntl y b y t he li ver, bi n ds t o t he L D L rece pt or ( L D L R) b ot h i ntracell ularl y 
a n d e xtracell ularl y a n d pr o m otes t he l ys os o mal de gra dati o n of t hese rece pt ors i n he pat oc ytes, 
(La k os ki  et al 2 0 0 9 , M o usa vi  et al 2 0 0 9 ) t here b y i ncreasi n g t he circ ulati n g L D L-C le vels. 
Rece ntl y de v el o pe d a n d a p pr o ve d P C S K 9 -bl oc ki n g m o n ocl o nal a nti b o di es ( m A bs) re d u ce 
P C S K 9 a n d l o wer L D L -C le vels, a n d als o si g nifica ntl y  re d uce t he ris k of C V e ve nts 

N o v arti s  
C o nfi d e nti al  
P a g e  2 5  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
(Sa bati ne  et al 2 0 1 7 , Sc h wartz  et al 2 0 1 8 ). C urre ntl y a p pr o ve d P C S K 9-bl oc ki n g m A bs are 
a d mi nistere d e ver y 2 or 4 wee ks ( Re pat ha ®  Pac ka ge I nsert; Pral ue nt ®  Pac k a ge I nsert).  
Be y o n d P C S K 9 -bl oc ki n g m A bs, s mall i nterferi n g Ri b o n ucleic Aci ds (si R N As) ca n n o w b e 
use d t o sile nce t he e x pressi o n of t he P C S K 9 ge n e i n a s e q ue nce -s pecific wa y. T his is d o ne b y 
catal yticall y sile nci n g t he tra nsla ti o n of t he c o m ple me ntar y P C S K 9 messe n ger R N As ( m R N As) 
t hr o u g h t he f or mati o n of effect or R N A-i n d uce d sile nci n g c o m ple xes ( RI S Cs) a n d t he use of a 
hi g hl y s pecific e n d o g e n o us mec ha nis m f or re g ulati n g ge ne e x pressi o n ( Sett e n et al 2 0 1 9 ). 
I n clisira n ( KJ X 8 3 9) is a c he micall y-m o difie d si R N A, c o nj u gate d o n t he se nse stra n d wit h 
tria nte n nar y N-Acet yl gal act osa mi ne ( Gal N Ac) t o facilitate t he s pecific u pt a ke b y he pat oc ytes 
(K h v or o va  2 0 1 7 ). I n h ep at oc ytes, t he a ntise ns e stra n d is i nc or p orate d i n t h e RI S C a n d directs 
t he catal ytic brea k d o w n of P C S K 9 m R N As. T his pre ve nts t he s u bse q ue nt pr o d ucti o n of P C S K 9 
pr otei n. Re d uce d i ntra h e patic P C S K 9 i ncreases L D L -C rece pt or rec ycli n g a n d t he e x pressi o n 
o n t h e he pat oc yte cell s urface, t here b y i ncreasi n g L D L -C u pta ke a n d l o weri n g L D L -C le vels i n 
t he circ ulati o n (Fitz geral d  et al 2 0 1 7 ). 
T he O RI O N -9, -1 0 a n d -1 1, c o nfir mat or y 1 8 -m o nt hs p hase III cli nical st u dies c o m pare d 
i nclisira n vers us place b o a dj u ncti ve t o ma xi mall y-t olerate d stati n t hera p y i n 3, 6 6 0 partici pa nts 
wit h at her oscler otic car di o vasc ular dise ase ( A S C V D), 
A S C V D ris k e q ui vale nt, a n d/ or 
heter oz y g o us fa milial h y perc h olester ole mia ( He F H). A n a d diti o nal 6 8 1 partici pa nts  were 
treate d i n p hase I a n d p h ase II st u dies. I n t he p h ase III st u dies, treat me nt wit h i nclisira n s o di u m 
3 0 0 m g a d mi nistere d b y s u bc uta ne o us (s.c.) i njecti o n o n Da y 1, M o nt h 3 ( Da y 9 0) a n d e ver y 6 
m o nt hs t hereafter res ulte d i n place b o -a dj uste d perce nta ge re d u cti o ns i n L D L-C fr o m bas eli n e 
at Da y 5 1 0 of 4 8 % t o 5 2 %, wit h ti me -a dj uste d a vera g e re d u cti o ns of 4 4 % t o 5 4 % s ustai ne d 
o ver 1 8 m o nt hs (I n vesti g at or's Br oc h ure (I B), Raal  et al 2 0 2 0 , Ra y  et al 2 0 2 0 ). T he efficac y of 
i nclisira n was c o nsiste nt acr oss p has e II a n d p hase III st u dies, wit h n o differe nces o bs er ve d 
acr oss a br oa d ra n ge of s u b p o p ulati o ns (I B).  
T he p has e III a n d s u bse q ue nt o pe n -la bel e xt e nsi o n trials ha v e s h o w n t hat t h ere are n o cli nicall y 
rele va nt differe nces i n t h e safet y pr ofile of i nclisira n c o m pare d wit h place b o, e xce pt f or a hi g her 
i nci de nce of tr eat me nt-e mer ge nt a d v erse e ve nts ( T E A Es) at t he i njecti o n site wit h i nclisira n. 
T hese i njecti o n site T E A Es were l ocalize d, pre d o mi na ntl y mil d, tra nsie nt, a n d res ol ve d wit h o ut 
se q uelae. I nclisira n is n ot ass ociate d wit h a n i n crease d ris k f or he p atic or re nal d ysf u ncti o n, 
h y perse nsiti vit y, ne ur ol o gic e ve nts a n d ne ur oc o g niti ve dis or ders, or o p ht hal m ol o gical e ve nts 
a n d t here is n o di ffere n ce fr o m place b o i n ne w o nset or w orse ni n g of dia betes mellit us. T he 
p ote ntial f or i m m u n o ge nicit y of i nclisira n is l o w. A d diti o nal details o n t he efficac y a n d safet y 
of i nclisira n are a vaila ble i n t he I B.  
I n clisira n is a p pr o ve d i n t he E ur o pea n U ni o n (E U), U nite d States, as well as ot her c o u ntries 
w orl d wi de I n t he E ur o p ea n U ni o n, it is i n dicate d f or t he treat me nt of a d ults wit h pri mar y 
h y perc h olester ole mia ( heter oz y g o us fa milial a n d n o n‑fa milial) or mi xe d d ysli pi de mia, as a n 
a dj u nct t o diet i n c o m bi nati o n wit h a st ati n or stati n wit h ot her li pi d‑l o weri n g t hera pies i n 
patie nts u na ble t o reac h L D L‑ C tar gets wit h t he ma xi m u m t olerate d d ose ( M T D) of a stati n, or 
al o ne or i n c o m bi nati o n wit h ot her L L T i n patie nts w h o are stati n -i nt olera nt, or f or w h o m a 
statin is c o ntrai n dicate d.  

N o v arti s  
C o nfi d e nti al  
P a g e  2 6  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
1. 2  
P ur p o s e  
T he p ur p ose of t his st u d y is  t o de m o nstrate t he s u peri orit y of i nclisira n c o m pare d t o place b o, 
b ot h o n t o p of o n g oi n g i n di vi d uall y o pti mize d L L T, o n reac hi n g a partici pa nt's i n di vi d ual L D L -
C tar get ( <  5 5  m g/ d L or <  7 0  m g/ d L, d e pe n di n g o n t he car di o vasc ular ris k cate g or y acc or di n g 
t o t he 2 0 1 9 E S C/ E A S g ui deli nes f or t he ma na g e me nt of d ysli pi de mias (Mac h  et al 2 0 2 0 ) as 
well as o n partici pa nt -rel e va nt safet y, t olera bilit y o utc o mes a n d q ualit y of  life. 
2  
O bj e cti v e s, e n d p oi nt s a n d e sti m a n d 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 e m o n str at e t h e s u p eri orit y of i n cli sir a n o n t o p of 
o n g oi n g i n di vi d u all y o pti mi z e d L L T c o m p ar e d t o pl a c e b o 
o n t o p of o n g oi n g i n di vi d u all y o pti mi z e d L L T o n r e a c hi n g a 
p arti ci p a nt' s i n di vi d u al L D L -C t ar g et a s d efi n e d i n 2 0 1 9 
E S C/ E A S g ui d eli n e s f or t h e m a n a g e m e nt of d y sli pi d e mi a s 
(M a c h  et  al  2 0 2 0 ). 
•  Pr o p orti o n of p arti ci p a nt s a c hi e vi n g i n di vi d u al 
L D L -C t ar g et ( <  5 5  m g/ d L or <  7 0  m g/ d L) at 
d a y 9 0  
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 d e m o n str at e t h e s u p eri orit y of i n cli sir a n o n t o p of 
o n g oi n g i n di vi d u all y o pti mi z e d L L T c o m p ar e d t o pl a c e b o 
o n t o p of o n g oi n g i n di vi d u all y o pti mi z e d L L T o n:  
•  R e d u ci n g m e a n L D L -C l e v el s o v er t h e d o u bl e -bli n d st u d y 
p eri o d.  
 
 
 
•  R el ati v e c h a n g e ( p er c e nt a g e fr o m b a s eli n e 
t o m e a n  
L D L -C l e v el o v er t h e d o u bl e -bli n d tr e at m e nt 
p eri o d.  
•  M u s cl e -r el at e d a d v er s e e v e nt s.  
•  Pr o p orti o n of p arti ci p a nt s e x p eri e n ci n g at 
l e a st o n e m u s cl e -r el at e d A E a s d efi n e d i n 
t h e St a n d ar di z e d M e d D R A Q u eri e s ( S M Q) 
r h a b d o m y ol y si s / m y o p at h y fr o m d a y 1 t o 
d a y 3 6 0.  
•  A n n u ali z e d n u m b er of d a y s p ai n i s e x p eri e n c e d u si n g p ai n 
di ar y.  
•  Pr o p orti o n of p arti ci p a nt s e x p eri e n ci n g s elf -
r e p ort e d p ai n. 
A n n u ali z e d n u m b er of d a y s p arti ci p a nt s 
e x p eri e n ci n g s elf -r e p ort e d p ai n fr o m 
b a s eli n e t o d a y 3 6 0.  
•  P ai n -r el at e d q u alit y of lif e at d a y 3 6 0 u si n g t h e S h ort-F or m 
Bri ef P ai n I n v e nt or y ( S F -B PI).  
•  C h a n g e fr o m b a s eli n e i n S F -B PI p ai n 
s e v erit y s c or e t o d a y 3 6 0.  
C h a n g e  fr o m b a s eli n e i n S F-B PI  p ai n 
i nt erf er e n c e sc or e  t o d a y 3 6 0. 
Pr o p orti o n of p arti ci p a nt s wit h cli ni c all y 
r el e v a nt c h a n g e i n S F-B PI p ai n s e v erit y 
s c or e fr o m b a s eli n e t o d a y 3 6 0.  
Pr o p orti o n of p arti ci p a nt s wit h cli ni c all y 
r el e v a nt c h a n g e i n S F-B PI  p ai n i nt erf er e n c e 
s c or e fr o m  b a s eli n e  t o d a y 3 6 0. 

N o v arti s  
C o nfi d e nti al  
P a g e  2 7  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
O bj e cti v e( s)  
E n d p oi nt( s)  
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  2 8  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
O bj e cti v e( s)  
E n d p oi nt( s)  
2. 1  
Pri m ar y e sti m a n d s  
T he esti ma n d is t he precise descri pti o n of t he treat me nt effect a n d reflects strate gies t o a d dress 
e ve nts occ urri n g d uri n g trial c o n d uct w hic h c o ul d i m pact t he i nter pretati o n of t he trial res ults 
(e. g pre m at ure disc o nti n uati o n of treat me nt).  
T he pri mar y cli nical q uesti o n of i nterest is:  W hat is t he effect of i nclisira n vers us place b o o n 
t o p of a n o n g oi n g i n di vi d uall y o pti mize d L L T o n ac hie vi n g t he i n di vi d ual L D L -C tar g et at da y 
9 0 i n ver y hi g h ris k a n d hi g h ris k partici pa nts as defi ne d i n t he 2 0 1 9 E S C/ E A S g ui deli nes f or 
t he treat me nt of d ysli pi de mias (Mac h  et al 2 0 2 0 ). 
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: A d ult partici pa nts cate g ori ze d as v er y hi g h ris k or hi g h ris k as defi ne d b y t he 
car di o vas c ular ris k cate g ories i n t he 2 0 1 9 E S C/ E A S g ui deli nes f or t he ma na ge me nt of 
d ysli pi de mias ( Mac h  et al 2 0 2 0 ) wit h ele vate d L D L-C des pite bei n g treat e d wit h t he 
i n di vi d ual M T D of stati n a n d, if a p plica ble, als o ot her L L T. 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: Pr o p orti o n of partici pa nts ac hie vi n g i n di vi d ual L D L -C tar get ( <  5 5  m g/ d L or 
<  7 0  m g/ d L)  at da y 9 0. T he i n di vi d ual L D L -C tar get of t he partici p a nts is deter mi ne d 
acc or di n g t o t heir i n di vi d ual car di o vas c ular ris k cat e g or y. 
3.  Treat me nt of i nterest:  I nclisira n, c o m pare d t o place b o, b ot h o n t o p of a n o n g oi n g 
i n di vi d uall y o pti mize d L L T. Ra n d o mize d treat me nts are t he i n vesti gati o nal treat me nt 
i nclisira n or t he place b o c o ntr ol treat me nt. I n b ot h treat me nt ar ms, partici pa nts recei ve a n 
i n di vi d uall y o pti mize d r os u vastati n t hera p y f or reac hi n g t he i n di vi d ual L D L-C tar get a n d 
t olera bilit y. If re q uir e d t o ac hie ve t h eir L D L-C tar get, f urt her i n di vi d uall y o pti mize d L L T 
ca n be a d mi nistere d. A d diti o nal i nf or mati o n a b o ut t he i n vesti gati o nal treat me nt a n d 
c o ntr ol treat me nt are pr o vi de d i n Secti o n  6 . 
4.  S u m mar y meas ure: T he  o d ds rati o of ac hie vi n g i n di vi d ual L D L -C tar get at da y 9 0 
c o m pare d b et wee n treat me nt ar ms. A lar ger pr o p orti o n of partici pa nts i n dicates a s u p eri or 
o utc o me.  
Ha n dli n g of i nterc urre nt e ve nts:  
1.  Disc o nti n u ati o n 
of 
st u d y tre at me nt:  F oll o w 
u p i nf or mati o n 
after 
per ma n e nt 
disc o nti n uati o n of st u d y treat me nt,  Retrie v e d  Dr o p  O ut Data ( R D O)  will be c ollecte d at 
re g ular st u d y visits a n d will be i ncl u de d i n t he a nal ysis, wit h treat me nts as assi g ne d at 
ra n d o mizati o n (treat me nt p olic y). 
2.  De at h : F or partici pa nts w h o die n o s u bse q ue nt L D L -C val ue ca n e xist. C ollecte d data 
s h o ul d be a nal yz e d bef ore partici pa nts die. F or decease d p artici pa nts t he last val ue 
meas ure d b ef ore deat h will be i ncl u de d i nt o t he a nal ysis ( w hile ali ve strate g y).  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e  2 9  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
3.  Use of P C S K 9  t ar geti n g n o n-st u d y me dic ati o n, or li pi d a p heresis: It c o ul d occ ur t hat 
partici pa nts are s witc he d t o P C S K 9 tar geti n g t hera p y after disc o nti n uati o n of st u d y 
me dicati o n or re cei ve li pi d a p heresis.  F or t he pri mar y e n d p oi nt,  partici pa nts w h o use 
P C S K 9 tar geti n g n o n -st u d y me dicati o n or li pi d a p heresis will be c o nsi dere d as n ot 
ac hie vi n g t heir L D L -C tar get  (c o m p osite strate g y). 
4.  C O VI D -1 9 p a n de mic i m p act o n st u d y : F or t he pri mar y e n d p oi nt, c ollecte d data will be 
i ncl u de d i n t he a nal ysis a n d kee p t he treat me nt gr o u ps as assi g ne d at ra n d o mizati o n 
(treat me nt p olic y). 
C ha n ge i n bac k gr o u n d m e dicati o n esse ntiall y c o n cer ns c ha n ge i n L L T d uri n g o pti mizati o n. A 
c ha n ge i n bac k gr o u n d me dicati o n  is t heref ore n ot c o nsi dere d as a n i nterc urre nt e ve nt b eca us e 
it is part of t he treat me nt strate gies t hat are c o m pare d. 
2. 2  
S e c o n d ar y e sti m a n d s  
T he p o p ulati o n a n d t h e treat me nt of i nterest ass ociate d wit h t he s ec o n d ar y esti ma n d are t he 
sa me as f or t he pri mar y esti ma n d a n d we c o nsi der t he sa me i nterc urre nt e ve nts. E xce pt o ne 
s pecific e x ce pti o n des cri be d bel o w (t he i nterc urre nt e ve nt of deat h), t he pr o p ose d a p pr oac h f or 
all sec o n dar y e n d p oi nts f or t he i nterc urre nt e ve nts of disc o nti n uati o n of st u d y treat me nt, t he  use 
of P C S K 9 tar geti n g n o n -st u d y me dicati o n or li pi d a p heresis or t he i m pact of t he C O VI D -1 9 
pa n de mic, is t he treat me nt p olic y strate g y. F or t he i nterc urre nt e ve nt of deat h a w hile ali v e 
strate g y will be a p plie d.  
T he sec o n dar y esti ma n ds are defi ne d b y t h e e val uati o n of treat me nt effect o n t he f oll o wi n g 
e n d p oi nts a n d s u m mar y meas ures:  
1.  Relati ve  c ha n ge ( perce nt a ge c ha n ge) fr o m bas eli ne t o mea n  L D L -C  le vel o ver t he d o u ble -
bli n d st u d y peri o d (a vera ge d o ver all p ost baseli ne visits).  
2.  Pr o p orti o n of partici pa nts e x peri e nci n g at least o ne m uscle -relate d A E as defi ne d i n t he 
S M Q r ha b d o m y ol ysis / m y o pat h y fr o m da y 1 t o da y 3 6 0.  
3.  A n n ualize d n u m ber of d a ys partici pa nts e x perie n ci n g self -re p orte d p ai n fr o m da y 1 t o da y 
3 6 0.  
4.  C ha n ge fr o m bas eli ne i n S F -B PI  p ai n se verit y sc ore fr o m  at d a y 3 6 0.  
5.  C ha n ge fr o m bas eli ne i n S F -B PI  p ai n i nterfere nce sc ore  at d a y 3 6 0.  
6.  Pr o p orti o n of partici pa nts wit h cli nicall y rele va nt c ha n ge i n S F -B PI pai n se verit y sc ore 
fr o m baseli ne t o Da y 3 6 0. 
7.  Pr o p orti o n of p artici pa nts wit h cli nicall y rele va nt c ha n ge i n S F -B PI p ai n i nterfere nce s c ore 
fr o m baseli ne t o Da y 3 6 0. 
H o we ver, t he first s ec o n dar y e n d p oi nt of relati ve c ha n ge ( perce nt a ge c ha n ge) fr o m bas eli ne t o 
mea n L D L -C le vel o ver t he d o u ble -bli n d st u d y peri o d (a vera ge d o ver all p ost baseli ne visits) 
wil l be ha n dle d differe ntl y f or t he use of P C S K 9 m A b or li pi d a p heresis. F or t his s pecific 
i nterc urre nt e ve nt f or t his e n d p oi nt a h y p ot hetical strate g y as if n o P C S K 9 m A b or li pi d 
a p heresis w o ul d h a ve bee n a d mi nistere d will be a p plie d.  

N o v arti s  
C o nfi d e nti al  
P a g e  3 0  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
3  
St u d y d e si g n  
T his st u d y is a d o u ble-bli n d, place b o -c o ntr olle d m ultice nter st u d y i n a d ult partici pa nts wit h 
ver y hi g h or hi g h car di o vasc ular ris k (as defi ne d b y t he car di o vasc ular ris k cate g ories i n t he 
2 0 1 9 E S C/ E A S g ui deli nes f or t he ma na ge me nt of d ysli pi de mias ( Mac h  et al 2 0 2 0 )) w h o d o n ot 
meet t heir i n di vi d ual L D L -C tar get des pite bei n g treate d wit h t heir i n di vi d ual M T D of a stati n, 
a n d if a p plica ble, f urt her L L T.  
L D L -C tar get will be e v al uate d acc or di n g t o m ost rece nt assess me nt of car di o vas c ular ris k 
cate g or y as det er mi ne d b y t he i n vesti gat or. T his i ncl u des assess me nt of car di o vasc ular e ve nts 
a n d ne w-o ns et or w orse ni n g of car di o vas c ular ris k fact ors as d efi ne d i n t h e c urre nt g ui deli nes 
t hr o u g h o ut t he trial. 
T his is a treat me nt strate g y  st u d y w here t he partici pa nts are b ot h ra n d o mize d t o i nclisira n vs 
place b o a n d als o si m ulta ne o usl y s witc he d t o r os u vastati n, a n d t he n h a ve t h eir L L T i n di vi d uall y 
o pti mize d b y i n vesti gat ors.   
T he st u d y desi g n is de picte d i n Fi g ure  3 -1 . T h e st u d y c o nsists of: 
•  A Scree ni n g p eri o d of a p pr o xi matel y 1 4  da ys f or all partici pa nts.  
•  A n o pti o nal R u n -i n peri o d of u p t o 1 2 0 da ys as i n di vi d uall y a p plica ble. 
•  A n o pti o nal a d diti o nal baseli ne peri o d of a p pr o xi matel y 1 0 da ys as i n di vi d uall y a p plica ble 
for re q uir e d la bs  
•  A Treat me nt p eri o d of 3 6 0  da ys.  
T he o verall st u d y d urati o n is at least 3 6 0 da ys b ut ca n be l o n ger de pe n di n g o n i n di vi d ual 
scree ni n g a n d r u n-i n peri o d ti me. 
3. 1  
S cr e e ni n g p eri o d  
At scree ni n g, i n or der t o p artici pate i n t he st u d y,  partici pa nts will si g n t he I nf or m e d C o nse nt 
F or m (I C F) a n d t heir eli gi bilit y will be assesse d t hr o u g h t he re vie w of st u d y i ncl usi o n/e xcl usi o n 
criteria. T he I C F m ust be o btai ne d b ef ore i nitiati o n of a n y st u d y -s pecific pr oce d ures a n d 
assess me nts (see Secti o n  5. 1  a n d Secti o n  7  f or details). If at t he ti me of I C F si g nat ure, t he 
partici pa nt is n ot fasti n g, s he/ he will ha ve t o ret ur n f or t he bl o o d dra w i n a fasti n g state.   
D uri n g  t he scree ni n g visit, t he partici pa nt’s i n di vi d ual car di o vas c ular  ris k will be cate g orize d 
as ver y hi g h ris k or hi g h ris k,  wit h c orres p o n di n g L D L -C tar get <  5 5  m g/ d L or <  7 0  m g/ d L, 
res pecti vel y. T his i n di vi d ual ris k will be deter mi ne d acc or di n g t o t he 2 0 1 9 E S C/ E A S g ui deli nes 
f or t he ma na g e me nt of d ysli pi de mias (Mac h  et al 2 0 2 0 ).  
T he i n vesti gat or m ust als o e ns ure t hat eac h partici pa nt is o n a sta ble d ose (f or ≥ 3 0 da ys pri or 
t o t he scree ni n g visit) of a stati n. T o reflec t c urre nt as well as pr os pecti ve stati n prescri pti o n 
patter ns of e ver y da y care a m o n g t he st u d y p o p ulati o n,  e nr oll me nt tar gets  f or stati ns are d efi ne d 
i n Ta ble  3 -1 .  
I n a d diti o n t o e ns uri n g t hat a p artici pa nt is o n a sta ble d ose of a stati n, t he  i n vesti gat or m ust 
als o deter mi ne if a partici pa nt’s i n di vi d ual stati n d ose is c o nsi dere d t o be t he partici pa nt's M T D.  

N o v arti s  
C o nfi d e nti al  
P a g e  3 1  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
T he partici pa nt's M T D of stati n is defi ne d as  eit h er t he hi g hest a p pr o ve d d ose of a res pecti ve 
stati n (as per l ocal S m P C) or t he ot her  ma xi m u m d ose of stati n t hat ca n be ta ke n  b y t he 
partici pa nt  o n a re g ular b asis  
•  wit h o ut i nt olera ble a d verse e ve nt ( A E) t hat re q uires d ose a dj ust me nt, or  
•  wit h o ut A E t hat re q uires a d ose a dj ust me nt  (e. g. ele vate d la b val ues as per l ocal S m P C), 
or  
•  wit h o ut meeti n g a n y c o ntrai n dicati o n f or a partic ul ar partici p a nt (as per l ocal S m P C).  
A n y  d ose -li miti n g A Es a n d/ or rele va nt c o ntrai n di cati o ns  m ust be d oc u me nte d i n t he e C R F.   
Partici pa nts bei n g treat e d wit h t heir 
M T D of stati n at scree ni n g ca n directl y u n der g o 
ra n d o mizati o n at bas eli ne, w hereas partici pa nts tr eate d wit h a stati n d ose t hat is n ot c o nsi dere d 
t o be t he partici pa nt's M T D will e nter t he r u n-i n peri o d. 
T he I nteracti ve Res p o nse Tec h n ol o g y (I R T) s yste m will alert t he i n vesti gat or if t he e nr oll me nt 
tar gets f or a n y of t he stati ns ha ve alrea d y bee n met. If t he e nr oll me nt tar get f or a partic ular 
stati n has bee n met, t he n e nr oll me nt f or t hat gr o u p will be cl ose d a n d t he partici pa nt will n ot be 
scree n e d. 
T a bl e 3 -1  
P er c e nt a g e s of st ati n u s e at s cr e e ni n g i n r ef er e n c e t o t h e e ntir e st u d y 
p o p ul ati o n.*  
st ati n  
U p t o a p pr o xi m at el y X % of all r a n d o mi z e d p arti ci p a nt s c a n r e c ei v e t h e 
r e s p e cti v e st ati n  at s cr e e ni n g  
si m v a st ati n  
7 0 %  
at or v a st ati n  
7 0 %  
r o s u v a st ati n 
1 0 %  
pr a v a st ati n  
5 %  
fl u v a st ati n 
5 %  
l o v a st ati n 
5 %  
pit a v a st ati n  
5 %  
* P er c e nt a g e s ar e b a s e d o n c urr e nt di stri b uti o n of st ati n s u s e d i n cli ni c al pr a cti c e i n G er m a n y a c c or di n g t o t h e 
G er m a n r e p ort of dr u g pr e s cri pti o n 2 0 2 0 ( S c h w a b e  et  al  2 0 2 0 ). T h e t hr e s h ol d s h a v e b e e n s et at l e a st 5 0 % 
hi g h er t h a n t h e c urr e nt d at a t o a c c o u nt f or p ot e nti al f ut ur e a d a pt ati o n s i n pr e s cri pti o n p att er n s  
At t he scree ni n g visit, wit h t he e xce pti o n of P C S K 9 m A bs or ot her P C S K 9 tar geti n g t hera pies, 
a n ot her L L T s uc h as a c h olester ol a bs or bi n g i n hi bit or or a bile aci d s e q uestr a nt, as per E ur o pea n 
g ui deli ne rec o m me n d ati o n, or alter nati vel y, a n a de n osi ne tri p h os p hate citrate l yase ( A C L) 
i n hi bit or ca n be ta ke n b y a partici pa nt (sta ble f or ≥ 3 0  da ys) o n t o p of stati n. I n t he D A VI N CI 
st u d y, 9 % of E ur o pea n partici pa nts are b ei n g tr eate d wit h ezeti mi be i n c o m bi nati o n wit h 
m o derate - or hi g h -i nte nsit y stati ns (Ra y  et al 2 0 2 0 ). T he e nr oll me nt will be ca p p e d t o 
a p pr o xi matel y 2 0 % of ra n d o mize d partici pa nts bei n g treate d 
wit h a sta ble d os e  (f or 
≥ 3 0  da ys)  of a n ot her L L T  o n t o p of a stati n at t he scree ni n g visit t o reflect t he c urre nt as well 
as t he e x pecte d pr os pecti ve p rescri pti o ns. 
Scree ni n g peri o d of a p pr o xi matel y 1 4 da ys all o w a de q uate ti me f or t he c o m pleti o n of all 
q ualif yi n g scree ni n g a n d eli gi bilit y e val uati o ns.  

N o v arti s  
C o nfi d e nti al  
P a g e  3 2  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
A partici pa nt w h o e nters scree ni n g a n d is d eter mi n e d n ot eli gi ble will be c o nsi dere d as a scree n 
fail ure. T he I n vesti gat or ma y re-scree n t he partici pa nt at a later ti me if he/s he t hi n ks t hat t he 
partici pa nt’s c o n diti o n ca n f ulfill all t he eli gi bilit y criteria. A p artici pa nt ma y o nl y be  re-
scree n e d o nce a n d a mi ni m u m of 2 wee ks m ust el a pse bet w ee n s cree n fail ure a n d re -scree ni n g 
visits.  
3. 2  
O pti o n al R u n -i n p eri o d 
D uri n g t he o pti o nal r u n -i n-peri o d, t he partici pa nt’s stati n t hera p y will be u p -titrate d t o reac h 
t heir i n di vi d ual M T D. T o d o s o, t heir scree ni n g stati n d ose will be i ncrease d t o t he ne xt hi g her 
d ose le vel  acc or di n g t o t he res p ecti ve stati n l o cal S m P C. If t he partici p a nt t olerates t he ne xt 
hi g her stati n d ose le vel f or 3 0 da ys a n d L D L -C is still n ot at tar get, t he partici pa nt's stati n 
d ose  will u n der g o a n ot her u p -titrati o n acc or di n g t o t he stati n l ocal S m P C. T his pr oce d ure will 
be f oll o we d u ntil:  
a. T he partici pa nt reac hes t he i n di vi d ual M T D. T he M T D of a stati n is defi ne d as eit her t he 
hi g hest a p pr o ve d d ose of a res pecti ve stati n as per l ocal S m P C  or t he ma xi m u m d ose of 
stati n t hat ca n be ta ke n o n a re g ular basis: 
•  wit h o ut a n i nt olera ble A E t hat re q uires d ose a dj ust me nt, or  
•  wit h o ut a n A E t hat re q uir es d ose a dj ust me nt (e. g. ele vate d la b v al ues as p er l ocal 
S m P C), or  
•  wit h o ut meeti n g a n y c o ntrai n dicati o n f or a partic ul ar partici p a nt (as per l ocal S m P C).  
A n y d ose -li miti n g A Es a n d/ or rele va nt c o ntrai n di cati o ns m ust be d oc u me nte d i n e C R F. 
b.  T he partici pa nt me ets t he i n di vi d ual L D L -C tar get.  
T he i n di vi d ual r u n -i n peri o d ca n t a ke u p t o 1 2 0 d a ys wit h visits e ver y 3 0 d a ys t o o pti mize t he 
partici pa nt`s  i n di vi d ual statin t hera p y.  
Partici pa nts w h o meet t heir i n di vi d ual L D L -C tar get i n t he r u n -i n peri o d will be c o nsi dere d 
a r u n-i n fail ure. Als o, partici pa nts w h o d o n ot reac h a M T D u p t o da y 1 2 0 will be c o nsi dere d a 
r u n-i n fail ure. T hese r u n-i n fail ures will n ot be eli gi ble f or ra n d o mizati o n or re-s cree ni n g a n d 
will be disc o nti n ue d fr o m t he st u d y.  
If t he p artici pa nt is tr eat e d wit h a f urt her L L T at scree ni n g (Secti o n  3. 1 ), it is rec o m me n d e d 
d uri n g t he r u n -i n peri o d t o kee p t he partici pa nt u n der t he sa me L L T, u nless it is dee me d 
me dicall y necessar y t o c ha n ge t heir L L T. It is als o rec o m me n de d n ot t o a d d a n ot her L L T o n 
t o p of t he stati n, w hile t he stati n is bei n g titrate d. T he I n v esti gat or’s L L T decisi o n  has t o be 
d oc u me nte d o n t he res pecti ve e C R F pa g es.  
Partici pa nts 
will be f oll o we d acc or di n g t o t he 
Assess me nt Sc he d ule f or st u d y -relate d 
assess me nts ( Ta ble  8 -1 ). 
T he  I n vesti gat or’s stati n titrati o n decisi o n 
will be base d o n t he  m ost c urre nt 
L D L -C 
val ue.  F or  l ocal d ecisi o n ma ki n g, t he L D L-C val u e will be  prefera bl y  meas ure d usi n g a n  L D L -
C p oi nt of care  de vice.  I n t he e ve nt t he assess me nt ca n n ot be c o m plete d wit h t he L D L-C p oi nt 
of care de vic e, t he L D L -C is t o be assesse d b y t he ce ntral la b.  

N o v arti s  
C o nfi d e nti al  
P a g e  3 3  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
If dee med n ecess ar y b y t he I n vesti gat or, u nsc he d ule d visits ca n ta ke place at a n y ti me d uri n g 
t he r u n-i n peri o d. 
D uri n g t he r u n -i n p eri o d, all partici pa nts will be i nstr ucte d t o c o m pl y wit h lifest yle c ha n g es 
acc or di n g t o i nter nati o nal rec o m me n dati o n ( Mac h  et al 2 0 2 0 ), a n d t hese i nstr ucti o ns will be 
rei nf orce d at e v er y visit. 
I n a d diti o n, ot her ris k fact ors f or at her oscl er otic diseas e s uc h as hi g h bl o o d press ure a n d 
dia betes mellit us s h o ul d be o pti mall y treate d d uri n g t he r u n -i n peri o d acc or di n g t o l ocal 
practice/ g ui deli nes.  
T a bl e 3 -2  
A p pr o v e d st ati n d o s e r a n g e s a n d r e c o m m e n d e d st ati n titr ati o n st e p s  
st ati n  
a p pr o v e d d o s e r a n g e* 
[ m g/ d a y] 
m a xi m u m d o s e* 
[ m g/ d a y] 
r e c o m m e n d e d titr ati o n 
st e p s* [ m g/ d a y]  
si m v a st ati n  
5 -8 0  
8 0  
5 -1 0 -2 0 -4 0 -8 0  
at or v a st ati n  
1 0 -8 0  
8 0  
1 0 -2 0 -4 0 -8 0  
r o s u v a st ati n 
5 -4 0  
4 0  
5 -1 0 -2 0 -4 0  
pr a v a st ati n  
1 0 -4 0  
4 0  
1 0 -2 0 -4 0  
fl u v a st ati n 
2 0 -8 0  
8 0  
2 0 -4 0 -8 0  
l o v a st ati n 
1 0 -8 0  
8 0  
1 0 -2 0 -4 0 -8 0  
pit a v a st ati n  
1 -4  
4  
1 -2 -4  
* a c c or di n g t o l o c al S m P C 
3. 3  
O pti o n al B a s eli n e p eri o d ( D a y -1 0)  
T he Baseli ne visit is s plit i nt o 2 visits, pla n ne d a p pr o xi matel y 1 0 da ys a part ( Da y -1 0; Da y 1).  
T he first visit o n Da y -1 0 will o nl y a p pl y f or partici pa nts n ot ra n d o mize d wit hi n 7 da ys of 
scree ni n g (s ee Secti o n 8. 1 ) a n d f or p artici pa nts c o mi n g fr o m r u n -i n. 
T he Da y -1 0 visit will o nl y c o nsist of a la b dra ws, w hic h will be se nt t o t he Ce ntral La b.  
F oll o wi n g recei pt of Ce ntral la b res ults a n d c o nfir mati o n of eli gi bilit y, t he i n vesti gat or ma y 
t he n sc he d ule t he Bas eli ne ( Da y 1) visit f or ra n d o mizati o n.  
3. 4  
D o u bl e -bli n d tr e at m e nt p eri o d  
1) B a s eli n e ( D a y 1)  
All partici pa nts, w h o f ulfill t he i ncl usi o n/e xcl usi o n criteria ( Secti o n  5. 1  a n d Secti o n  5. 2 ), will 
be ra n d o mize d at bas eli ne i n a 1: 1 d o u ble-bli n d fas hi o n t o eit her i nclisira n  or pl ace b o. I n 
a d diti o n, at baseli ne all p artici pa nts will be s witc h e d fr o m t heir i n di vi d ual stati n t o r os u vastati n, 
w hic h is c o nsi dere d o pe n la bel st u d y tr eat me nt i n t his trial. 
A p pr o xi matel y 8 8 0 
pa rtici pa nts s h o ul d be ra n d o mize d per ar m. 
Partici pa nts 
will be stratifie d b y t heir 
car di o vas c ular ris k.  

N o v arti s  
C o nfi d e nti al  
P a g e  3 4  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
At baseli ne, all partici pa nts will be i nstr ucte d t o c o m pl y wit h lifest yle c ha n ges acc or di n g t o 
i nter nati o nal rec o m me n d ati o n (Mac h  et al 2 0 2 0 ), a n d t hese i nstr ucti o ns will be rei nf orce d at 
e ver y visit.  
I n a d o u ble-bli n d setti n g, t he  partici pa nt will be s u bc uta ne o usl y i njecte d wit h 3 0 0  m g i nclisira n 
s o di u m or place b o at da y 1, 9 0 a n d 2 7 0 d uri n g t he treat me nt peri o d ( Fi g ure  3 -1 ) b y a 
dele gate d  h ealt hcare pr ofessi o nal  at t he st u d y site. 
At Da y 1  visit, all partici pa nts will a d diti o nall y be s witc he d fr o m t heir i n di vi d ual stati n t o 
r os u vastati n. As per l ocal S m P C, t he rec o m me n de d start d ose f or r os u vast ati n is 5  m g/ da y or 
1 0  m g/ da y.  C o nsi deri n g t he l ocal S m P C,  t he i n vesti gat or 
will c h o ose t he a p pr o priate 
r os u vastati n start d os e l e vel f or a p artic ular partici pa nt. Partici pa nts alr ea d y tr eate d wit h 
r os u vastati n pri or t o b aseli ne will c o nti n ue treat me nt wit h t heir i n di vi d ual M T D of r os u vastati n, 
if i n acc or da nce wit h t he I n v esti gat or. 
2) P o st -B a s eli n e  
T he  I n vesti gat or’s L L T  d ecisi o n 
will be bas e d o n t he  m ost c urre nt 
L D L -C val ue.  F or 
l ocal L L T  decisi o n 
ma ki n g, L D L -C val ue 
wi ll be meas ure d usi n g a n  L D L -C p oi nt of 
care t est de vice.  I n t h e e v e nt t he assess me nt ca n n ot be c o m plet e d wit h t he L D L-C p oi nt of care 
de vice, t he L D L -C is t o be assesse d b y t he ce ntr al la b.  
F oll o wi n g ra n d o mizati o n, if a partici pa nt's L D L -C is n ot at tar get  at da y 3 0 a n d at t he f oll o wi n g 
visits, base d o n m ost rece nt L D L -C meas ure me nt, r os u vastati n s h o ul d be i n di vi d uall y titrate d  at 
da y 3 0 a n d at t he f oll o wi n g visits, u ntil:  
a. T he partici pa nt reac hes t he i n di vi d ual M T D f or r os u vastati n. T he M T D of r os u vastati n  is 
defi ne d as eit her t he hi g hest a p pr o ve d d ose of r os u vastati n or t he ma xi m u m d ose t hat ca n 
be ta ke n o n a re g ular basis:  
•  wit h o ut a n i nt olera ble A E  t hat re q uires d ose a dj ust me nt, or 
•  wit h o ut a n A E  t hat re q uires d ose a dj ust me nt (e. g. ele vate d l a b val u es as per l ocal 
r os u vastati n S m P C), or 
•  wit h o ut 
meeti n g a n y c o ntrai n dicati o n f or a partic ular partici p a nt (as per l ocal 
r os u vastati n S m P C). 
A n y d ose -li miti n g A Es a n d/ or rele va nt c o ntrai n di cati o ns m ust be d oc u me nte d i n t he e C R F.  
b.  T he partici pa nt me ets t he i n di vi d u al L D L-C tar get.  
Rec o m me n de d titrati o n ste ps f or r os u vastati n are 5  m g/ da y, 1 0  m g/ da y, 2 0  m g/ da y u p t o a 
ma xi m u m d ose of 4 0  m g/ da y, if i n dicate d as referre d t o i n t he l ocal S m P C. A d ose a dj ust me nt 
t o t he ne xt hi g her d ose le vel e ver y 3 0 d a ys is i n acc or da nce wit h t h e l ocal r os u vastati n S m P C. 
R os u vastati n d ose will n ot be bli n de d bet wee n t he t w o treat me nt  ar ms t o e na ble o n g oi n g 
i n di vi d ual L L T  o pti mizati o n b y t he i n vesti gat or at his discreti o n. At da y 9 0, it is ass u me d t hat 
r os u vastati n will be o pti mall y titrate d f or m ost partici pa nts. I n case f urt her r os u vastati n titrati o n 
is nee de d f or a partic ular partici pa nt, t here is a n o pti o nal visit at da y 1 2 0. 

N o v arti s  
C o nfi d e nti al  
P a g e  3 5  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
It is rec o m me n de d n ot t o a d d a n ot her L L T o n t o p of r os u vastati n w hile it is bei n g titrate d. 
F urt her, if  at scree ni n g a n d/ or d uri n g t he r u n -i n peri o d, as a p plica ble, a partici pa nt is  alrea d y 
treate d wit h a n o n-stati n li pi d-l o weri n g me dicati o n (Secti o n  3. 1 ), it is rec o m me n de d t o n ot t o 
c ha n ge it  at bas eli ne,  a n d i n parallel t o t he i n di v i d ual r os u vastati n titrati o n, u nless me dicall y 
necessar y.  
F or p artici pa nts alrea d y ta ki n g r os u vastati n at scree ni n g a n d  d uri n g  t he r u n-i n p eri o d (if 
a p plica ble), f urt her li pi d -l o weri n g 
me dicati o n is rec o m me n de d t o 
be 
a d de d after 
i nclisira n/ place b o  
i njectio n  o n  Da y  
1  
a n d  
at  
earliest  
o n  
Da y  
3 0. 
T he  I n vesti gat or’s L L T  d ecisi o n  has t o be d oc u me nte d o n t he res pecti ve e C R F pa ges.  
F oll o wi n g da y  9 0, visits are sc h e d ule d e v er y 6 0 d a ys  i n or der t o f oll o w t he E S C/ E A S g ui deli nes 
f or t he 
ma na g e me nt 
of 
d ysli pi de mias t hat rec o m me n ds 
m o nit ori n g t he partici pa nt’s 
li pi d le vel after starti n g L L T or after a dj ust me nt of L L T e ver y 8 ( ± 4)  wee ks  (Mac h  et al 2 0 2 0 ). 
Rec o m me n de d pr ocess i n t he tre at me nt peri o d i n c ase L D L -C is still n ot at t ar get after 
r os u v ast ati n titr ati o n:  
If after t he r os u vast ati n titrati o n t o a n i n di vi d ual M T D, a partici pa nt’s i n di vi d ual L D L-C is n ot 
at tar get i n  eit her treat me nt ar m, t he L L T m ust be f urt her es calat e d.  
Acc or di n g t o t he c urre nt E S C/ E A S g ui deli nes f or t he 
ma na ge me nt of d ysli pi de mias 
(Mac h  et al 2 0 2 0 ), hi g h-i nte nsit y stati n t hera p y is t he rec o m me n d e d first c h oice t hera p y f or 
li pi d l o weri n g ( Class I, L e vel A rec o m me n dati o n). If t he L D L-C tar get is n ot ac hie ve d wit h t h e 
M T D of a hi g h -i nte nsit y stati n (i m ple me nte d b y usi n g r os u vastati n i n t his st u d y): 
•  T he c o m bi nati o n wit h ezeti mi be is rec o m me n de d ( Class I, L e vel B rec o m me n dati o n).  
•  If t he L D L-C tar get is still n ot ac hie ve d,  
•  c o nsi der als o t he use of bile aci d se q uestr a nt ( Class II b,  Le vel C rec o m me n dati o n).  
•  Rece ntl y a p pr o ve d b e m p e d oic aci d ma y als o be c o nsi dere d f or L L T es calati o n, h o we ver, it 
is n ot de picte d i n t he c urre nt g ui deli nes a n d s h o ul d t h us be use d sec o n daril y after t he 
af ore m e nti o ne d s u bsta nces. Please refer t o Fi g ure  3 -2 . 
•  T he n last, access t o P C S K 9 m A b as ne xt escalati o n ste p  will be ha n dle d acc or di n g t o t he 
Ger ma n pres cri bi n g restricti o n ( B u n desa ussc h uss  2 0 2 1 ). T he rec o m me n dati o n will be t o 
use t he latest versi o n of t he g ui da nce a n d a n E n glis h versi o n will be ma de a vaila ble.  
P C S K 9 m A b ma y be i n dicate d i n partici pa nts wit h a c o nfir me d vasc ular disease ( C H D, 
cere br o vasc ul ar dise ase, P A D) a n d re g ularl y a d diti o nal ris k fact ors f or car di o vasc ular e ve nts 
(e. g. dia betes mellit us, restricte d re n al f u ncti o n wit h e G F R <  6 0  m L/ mi n/ 1. 7 3 m 2), or i n 
partici pa nts wit h a c o nfir me d dia g n osis of  He F H t a ki n g t he o verall fa mil y pre dis p ositi o n i nt o 
acc o u nt, if L D L -C ca n n ot be re d uce d s ufficie ntl y des pite i n pri nci ple a d oc u me nte d ma xi m u m 
dietar y as w ell as li pi d -l o weri n g dr u g t hera p y o ver a peri o d of 1 2 m o nt hs. 
T o e ns ure t hat a p artici p a nt is all o we d t o recei ve t he P C S K 9 m A b t hera p y acc or di n g t o t he 
refere nce d g ui da nce, t he Steeri n g C o m mittee ( me m bers of t he P C S K 9 m A b decisi o n b oar d), 
will re vie w t he re q u ire d partici pa nt's dat a a n d deci de o n t h e partici pa nt`s eli gi bilit y f or s uc h 
t hera p y (Secti o n  1 0. 3. 1 ). 

N o v arti s  
C o nfi d e nti al  
P a g e  3 6  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
P C S K 9 g e n er al d e ci si o n:  
I n case a partici pa nt is dee me d eli gi ble, t he partici pa nt will nee d t o disc o nti n ue t he bli n de d 
i n vesti gati o nal treat me nt (i nclisira n/ place b o). 
 is t he preferre d P C S K 9 m A b t o be us e d t o e na ble c o nsiste nc y i n t hera p y 
a m o n g trial c o u ntri es a n d will be s u p p orte d b y t h e s p o ns or.  T he partici p a nt will re mai n i n t he 
st u d y des pite ha vi n g disc o nti n ue d bli n de d i n vesti gati o nal treat me nt (i nclisira n/ place b o) a n d 
will  be f oll o we d -u p u ntil t he partici pa nt’s e n d of st u d y.   
•  If t he partici p a nt is dee m e d i neli gi ble f or s witc h t o P C S K 9 m A b b y t he Steeri n g 
C o m mittee, t he I n vesti gat or is e nc o ur a g e d t o c o nti n ue t he partici pa nt's L L T escalati o n as 
rec o m me n de d i n Fi g ure  3 -2 . If t he i n vesti gat or d eci des t hat a P C S K 9-tar gete d t hera p y is 
i n dicate d des pite t he decisi o n of t he S C, t he partici pa nt will nee d t o disc o nti n ue stu d y 
treat me nt (i nclisira n/ place b o), a n d s h o ul d be tr eat e d as per l o cal sta n dar d of care a n d 
f oll o we d-u p b ut s h o ul d r e mai n i n t he st u d y u ntil t he partici pa nt e n d of st u d y.  
Partic ular atte nti o n s h o ul d be pai d t o  
: I n t he case w here t he i n vesti gat or f eels t hat a 
partici pa nt's c o n diti o n w arra nts t he use of P C S K 9 m A b  
, t he bli n de d i n vesti gati o nal 
treat me nt (i nclisira n/ place b o) s h o ul d n ot b e a d mi nistere d at  
 visit, b ut t he partici pa nt's 
eli gi bilit y t o P C S K 9 m A b s h o ul d first be assesse d b y  t he Steeri n g C o m mittee as bel o w: 
•  If t he partici p a nt is dee m e d eli gi ble, bli n de d i n vesti gati o nal treat me nt (i nclisira n/ place b o) 
m ust be disc o nti n ue d, t he partici pa nt will s witc h t o P C S K 9 m A b, prefera bl y  
 
 a n d will be f oll o we d-u p u ntil t he partici pa nt’s e n d of st u d y.  
•  If t he partici p a nt is dee m e d n ot eli gi ble b y t he Steeri n g C o m mittee f oll o wi n g visit at  
 
 please refer t o t he pr oce d ure o utli ne d a b o ve. I n case t he I n vesti gat or deci des t o 
c o nti n ue t he partici pa nt's L L T  escal ati o n, bli n de d i n vesti gati o nal treat me nt 
(i nclisira n/ place b o) ca n b e a d mi nistere d i n a n u nsc he d ule d visit, f oll o wi n g  
  
F or i ntracta ble cas es wit h L D L -C still t o o hi g h after L L T escalati o n as o utli ne d a b o ve, if n ot 
alrea d y d o n e, st u d y treat me nt (i nclisira n/ pl ace b o) will nee d t o be dis c o nti n ue d a n d t he 
partici pa nt s h o ul d be treate d as per l ocal sta n dar d of care, e. g. als o c o nsi deri n g L D L -a p heresis 
as ' ulti ma rati o'. T he partici pa nt will re mai n i n t he st u d y a n d will be f oll o we d -u p u ntil t he 
partici pa nt’s e n d of  st u d y. 
F or rec o m me n de d  L L T  s c he me bas e d o n E S C/ E A S g ui deli ne i n c o m bi nati o n wit h rele va nt 
Healt h 
Tec h n ol o g y 
Assess me nt ( H T A) re q uire me nts, 
please refer t o 
Fi g ure  3 -2 . 
T he  I n vesti gat or’s L L T  d ecisi o ns as well as p ossi ble de via ti o ns fr o m t he a b o ve d escri b e d 
escalati o n al g orit h m ha v e t o be d oc u me nte d i n detail o n t he a p pr o priate e C R F pa ges. T his 
i ncl u des f or mal c o ntr ai n dicati o n as per res pecti ve l ocal S m P C or pri or i nt olera ble A E.  
Partici pa nts 
will be f oll o we d acc or di n g t o t he 
A ssess me nt Sc he d ule f or st u d y-relate d 
assess me nts ( Ta ble  8 -1 ). 
If dee me d n ecess ar y b y t he I n vesti gat or, u nsc he d ule d visits ca n ta ke place at a n y ti me d uri n g 
t he treat me nt peri o d. 
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  3 7  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
I n a d diti o n, ot her ris k fact ors f or at her oscl er otic diseas e s uc h as hi g h bl o o d press ure a n d 
dia betes 
mellit us s h o ul d be o pti mall y treate d d uri n g t he d o u ble -bli n d treat me nt peri o d 
acc or di n g t o l ocal practice/ g ui deli nes.  
E ver y eff ort s h o ul d be ma de t o kee p p artici pa nts i n t he st u d y, e ve n i n t he case of st u d y dr u g 
disc o nti n uati o n ( Secti o n  9. 1. 1 ). 
Fi g ur e 3 -1  
St u d y D e si g n  
1  D ur ati o n of t h e St ati n Titr ati o n p eri o d d uri n g t h e i n r u n -i n c a n b e sh ort er t h a n t h e d e pi ct e d 1 2 0 d a y s 
( s e e S e cti o n 3. 2 )  
2  D ur ati o n of t h e R o s u v a st ati n Titr ati o n p eri o d d uri n g t h e d o u bl e -bli n d tr e at m e nt p eri o d c a n b e s h ort er 
or l o n g er ( br o k e n li n e arr o w) t h a n t h e d e pi ct e d 9 0 d a y s i n b ot h tr e a t m e nt ar m s  
( s e e S e cti o n  3. 4 ). 
N ot e s:  
All d a y s i n p ar e nt h e si s r e pr e s e nt o pti o n al vi sit s.  
A m a n d at or y s af et y f oll o w -u p p h o n e c all m u st b e gi v e n at d a y 3 9 0.  

N o v arti s  
C o nfi d e nti al  
P a g e  3 8  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
Fi g ur e 3 -2  
R e c o m m e n d e d tr e at m e nt s c h e m e b a s e d o n E S C/ E A S g ui d eli n e s i n 
c o m bi n ati o n wit h r el e v a nt H T A r e q uir e m e nt s  
  
( +) Pl e a s e r ef er t o S e cti o n  3. 4  
* If i n di c at e d a s p er (l o c al) S m P C 
3) E n d of Tr e at m e nt ( E O T) a n d E n d of St u d y ( E O S) d efi niti o n:  
T he E O T/ E O S visit will be o n Da y 3 6 0. I n a d diti o n, a safet y f oll o w -u p call will be c o n d ucte d 
3 0 da ys  after t h e E O S visit.  
As i nclisira n is a l o n g-acti n g dr u g a n d t he i njecti o ns are a d mi nistere d 3 or 6 m o nt hs a part t he 
E O T is ( 1) t he da y t he partici pa nt is n ot recei vi n g t he pla n ne d d ose a n d n ot c o nti n ui n g wit h t he 
st u d y treat me nt or ( 2) t he da y pla n ne d E O S visit is ac hie ve d . Partici pa nts w h o pre mat ure  
disc o nti n ue fr o m st u d y treat me nt will ha ve a n E O T rec or de d a n d  will re mai n i n t he st u d y . T he y 
will  be f oll o we d -u p u ntil t he partici pa nt’s e n d of st u d y ( E O S) as i n dicate d i n t he Assess me nt 
Sc he d ule  (see Ta ble 8 -1 ).  
If a partici pa nt disc o nti n ues t he st u d y earl y, t he i n vesti gat or m ust d o t heir best t o e ns ure t he 
partici pa nt ret ur ns f or a n E O S visit.  
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  
A p pr o val b y re g ulat or y b o dies w orl d wi de is a n esse ntial first ste p t o pr o vi de patie nts wit h 
i n n o vati ve me dical t hera pies. S u bse q ue nt h ealt h tec h n ol o g y ass ess me nt ( H T A) pl a ys a n 

N o v arti s  
C o nfi d e nti al  
P a g e  3 9  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
i ncreasi n gl y i m p orta nt r ole t o pr o vi de patie nts wit h access t o t hese t hera pi es. It is n ot al ways 
p ossi ble t o satisf y t he re q uire me nts of b ot h 
 i n t he sa me trial, as 
re q uire me nts ma y differ. F or e x a m ple, t he  
 t hera p y re q uir e d f or  
 a p pr o val 
ca n be differe nt t o t hat re q uire d f or a 
, a n d t he acce pte d cli nical 
e n d p oi nts ma y differ. I nclisira n is a p pr o ve d or u n der re g ulat or y re vie w w orl d wi de. T heref ore, 
t he f oc us of t he c urre nt st u d y is t o ge nerate t he re q uire d 
. T he 
ai m of t his st u d yis t o c o m pare t he ef ficac y, safet y a n d t olera bilit y as well as i m pact o n q ualit y 
of life, of a tr eat me nt str ate g y i ncl u di n g i nclisira n wit h a tr eat me nt str ate g y base d o n t he c urre nt 
E S C/ E A S g ui deli nes, i n partici pa nts w h ose L D L -C is n ot a de q uatel y c o ntr olle d usi n g t he M T D 
of a stati n, as re q uir e d 
. 
T he st u d y desi g n i ncl u des o n g oi n g i n di vi d ual o pti mizati o n of L L T t hr o u g h o ut t he trial, 
f oll o wi n g ra n d o mizati o n t o i nclisira n/ place b o a n d a s witc h at ra n d o mizati o n t o r os u vastati n 5 
or 1 0 m g/ da y, t o rea c h i n di vi d ual L D L -C tar get (as o utli ne d i n Secti o n  3. 4 ). It is t heref ore li kel y 
t hat i nte nsit y of bac k gr o u n d stati n a n d ot her L L T i n t he 
. T he st u d y desi g n 
ma y res ult i n 
 back gr o u n d t hera p y i n t he 
 gr o u p t ha n i n t he 
treate d gr o u p, s o t hat t he treat me nt c o m p aris o n is n ot si m pl y bet wee n 
 
place b o b ut rat h er bet w ee n a treat me nt  
 of i nclisira n pl us ( pres u m a bl y l o wer use of) 
 a n d place b o pl us ( pres u ma bl y 
. 
Access t o P C S K 9 m A bs is restricte d i n ma n y c o u ntries. I n t his st u d y, t he 
 
re q uire me nts a p plica ble f or Ger m a n y are us e d as a refere n ce t o pr o vi de h o m o ge neit y f or t he 
o v erall st u d y.  
I n clisira n is a p pr o ve d i n E U, U S, as well as ot her c o u ntries w orl d wi de. I n t he E U, i nclisira n is 
i n dicate d i n a d ults wit h pri mar y h y perc h olest er ole mia ( heter oz y g o us fa milial a n d n o nfa milial) 
or mi xe d d ysli pi de mia, as a n a dj u n ct t o diet i n c o m b i nati o n wit h a stati n or stati n wit h ot her 
li pi d-l o weri n g t hera pi es i n patie nts u na ble t o reac h L D L‑ C tar gets wit h t he M T D of a stati n, or 
al o ne or i n c o m bi nati o n wit h ot her li pi d -l o weri n g t hera pies i n patie nts w h o are stati n-i nt olera nt, 
or f or w h o m a stat i n is c o ntrai n dicate d. 
At scree ni n g, t h e partici p a nt's i n di vi d ual stati n t hera p y will be c o nsi dere d al o n g wit h t he stati n 
e nr oll me nt tar gets (refer t o Ta ble  3 -1 ) t o reflect c urre nt a n d pr os pecti ve stati n prescri pti o ns i n 
cli nical r o uti ne.   
T he o pti o nal r u n -i n peri o d is s pecificall y desi g n e d t o c o nti n u o usl y re-e v al uate L D L -C a n d t o 
titrate t he partici pa nt’s i n di vi d ual stati n prescri be d at scree ni n g t o t he i n di vi d ual M T D. 
Partici pa nts d o n ot nee d t o e nter t he r u n -i n peri o d if, at scree ni n g, t he y are alrea d y o n t he M T D 
of a stati n as d oc u me nte d i n t he partici pa nt's me di cal hist or y (refer t o Secti o n  3. 1 ). 
T he treat me nt peri o d is a ra n d o mize d place b o -c o ntr olle d, d o u ble -bli n d peri o d. T he prese nt 
st u d y ai ms t o de m o nstrate t he s u peri orit y of i nclisira n c o m pare d t o place b o, b ot h wit h a n 
o n g oi n g i n di vi d uall y o pti mize d L L T, o n t he efficac y of l o weri n g L D L -C as well as o n safet y, 
t olera bilit y a n d ot her partici pa nt-rele va nt e n d p oi nts. 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e  4 0  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
At baseli ne D a y 1, a m o n g ot h er i ncl usi o n/e xcl usi o n criteria, all partici p a nts, w h ose M T D of 
stati n fails t o s ufficie ntl y l o wer L D L-C t o t heir tar get set at scree ni n g, will be ra n d o mize d i n a 
1: 1 d o u ble -bli n d fas hi o n t o eit her recei ve i nclisira n or place b o.  
I n a d diti o n, at baseli ne Day 1 all p artici pa nts will be s witc he d fr o m t heir i n di vi d ual stati n t o 
r os u vastati n. As per c urre nt E S C/ E A S g ui deli ne, treat me nt wit h a hi g h-i nte nsit y stati n t hera p y 
is rec o m me n de d (Mac h  et al 2 0 2 0 ). R os u vastati n is a hig hl y p ote nt a n d well -t olerate d stati n. 
D ue t o its h y dr o p hilic nat ure it te n ds t o b e retai ne d i n t he li ver rat her t ha n t o diff use o ut of it i n 
n o n -he patic cells, i ncl u di n g s keletal m uscle, a n d t his h y dr o p hilic pr o pert y is s u g geste d t o 
acc o u nt f or fe w er A Es (K o nes  2 0 1 0 , Mc Ta g g art  2 0 0 3 ). 
At baseli ne Da y 1, a p artici pa nt’s i n di vi d ual stati n t hera p y will be s witc he d t o r os u vastati n t o 
e ns ure t hat all partici pa nts recei ve  t he sa m e hi g h -i ntensit y stati n d uri n g t he treat me nt peri o d. 
U p t o a p pr o xi matel y 1 0 % of partici pa nts w h o are alrea d y ta ki n g r os u vast ati n at scree ni n g ca n 
be e nr olle d i n t he trial. T hese partici pa nts ca n c o nti n ue recei vi n g t heir M T D of r os u vastati n at 
baseli ne if i n acc or da n c e wit h t he I n v esti gat or.  
R os u vastati n s h o ul d be titrate d t o tr y t o ac hie ve tar get L D L -C  le vel, or t o a n i n di vi d ual M T D 
acc or di n g t o i n vesti gat or discreti o n.  
If a p artici pa nt’s i n di vi d ual L D L-C is n ot at t ar get i n eit her treat me nt ar m a n d after t h e 
r os u vastati n titrati o n peri o d, i ns ufficie nt L L T m ust n ot be c o nti n ue d t hr o u g h o ut t he trial b ut be 
f urt her escalate d. T o all o w a n o n g oi n g i n di vi d ual L L T o pti mizati o n as o utli ne d a b o ve 
(Fi g ure  3 -2  ), L D L-C val ues will n ot be bli n de d.  
T his st u d y desi g n is a p pr o priate t o a ns wer t he cli nical q uesti o ns of i nterest o n t he use of 
i nclisira n c o m pare d t o place b o b ot h o n t o p of a n o n g oi n g i n di vi d uall y o pti mize d L L T i n 
partici pa nts at ver y hi g h or hi g h car di o v asc ular ris k acc or di n g t o t he car di o vas c ular ris k 
cate g ories d efi ne d i n t he E S C/ E A S g ui deli nes f or t he 
ma na g e me nt of d ysli pi de mias 
(Mac h  et al 2 0 2 0 ). 
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  
Stati ns are rec o m me n de d first c h oice t hera p y f or li pi d l o weri n g acc or di n g t o t he E S C/ E A S 
g ui deli ne ( Mac h  et al 2 0 2 0 ). At scree ni n g, it is re q uire d t hat all partici pa nts are recei vi n g a 
sta ble d ose of a stati n ( ≥ 3 0  da ys).  T o f urt her reflect c urre nt a n d pr os pecti ve prescri pti o n of 
L L T i n cli nical r o uti ne a m o n g t he st u d y p o p ulati o n, u p t o a p pr o xi mat el y 2 0 % of p artici pa nts 
treate d wit h a n ot her L L T o n t o p of stati n ca n be e nr olle d i n t he pres e nt trial. Wit h t he e xce pti o n 
of P C S K 9 m A bs or ot her P C S K 9 tar geti n g t hera pi es, s uc h ot her li pi d -l o weri n g a ge nts ca n be a 
c h olester ol a bs or bi n g i n hi bit or or a bile aci d se q uestra nt, b ot h as per E ur o pea n g ui d eli ne 
rec o m me n dati o n, or alter nati vel y, a n a de n osi ne tri p h os p hate citrate l yase ( A C L) i n hi bit or, as 
i n dicate d. 
Pri or t o baseli ne, it is re q uire d  t hat all partici pa nts are o n t heir i n di vi d ual M T D of a stati n f or 
at least  3 0  da ys wit h w hic h L D L -C is still n ot at tar get. T he p artici pa nt’s i n di vi d ual stati n will 
be s witc he d t o r os u vastati n at baseli ne. R os u vastati n is a re q uire d o pe n la bel baseli ne L L T 
d uri n g treat me nt peri o d a n d defi ne d as st u d y me di cati o n.  

N o v arti s  
C o nfi d e nti al  
P a g e  4 1  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
R os u vastati n s h o ul d be titrate d t o tr y t o ac hie ve tar get L D L -C  le vel, or t o a n i n di vi d ual M T D 
acc or di n g t o i n vesti gat or discreti o n.  
If t he M T D of r os u vast ati n fails t o s uffi cie ntl y l o wer L D L-C t o t ar get i n eit her treat me nt ar m, 
L L T m ust be f urt her escalate d t hr o u g h o ut t he trial t o ac hie ve a partici pa nt -i n di vi d uall y 
o pti mize d L L T. Li pi d -l o weri n g bac k gr o u n d t hera p y f or treat me nt escalati o n s h o ul d be ali g ne d 
wit h t he 2 0 1 9 E S C/ E A S g ui deli nes f or t he ma n a g e me nt of d ysli pi de mias. If t he L D L -C tar get 
is still n ot ac hie ve d wit h t he 
M T D of a hi g h-i nte nsit y stati n, herei n r os u vastati n, t he 
c o m bi nati o n wit h ezeti mi be is rec o m me n de d ( Class I, L e vel B rec o m me n dati o n). If t he L D L -
C tar get is still n ot ac hie ve d, c o nsi der use of bile aci d se q uestra nt ( Class II b, Le vel C 
rec o m me n dati o n) (Mac h  et al 2 0 2 0 ). Be m pe d oic aci d has rece ntl y b ee n a p pr o ve d a n d ma y als o 
be c o nsi dere d f or L L T es calati o n, h o we v er, it is n ot de picte d i n t he c urr e nt E ur o pea n g ui deli nes 
a n d s h o ul d t h us be use d sec o n daril y aft er t he af ore me nti o ne d treat me nts. If i n dicate d, escal ati o n 
t o P C S K 9 m A b, prefera bl y 
, ma y be c o nsi dere d f or eli gi ble partici pa nts 
( please refer t o Secti o n  3. 4 ). 
F or i ntracta ble cas es wit h L D L -C still t o o hi g h after L L T es calati o n as o utli ne d a b o ve, t he 
i n vesti gat or 
ca n 
d eci d e t o 
ha ve t h e 
parti ci pa nt 
disc o nti n ue 
all st u d y treat me nt 
(i nclisira n/ place b o + r os u vastati n) a n d t o ha ve t he partici pa nt s witc h e d t o l o cal sta n dar d of care, 
e. g. c o nsi deri n g L D L -a p heresis as ' ulti ma rati o'.  
Fi nal treat me nt d ecisi o n re gar di n g escal ati o n of L L T is base d o n t h e discreti o n of t he 
I n v esti gat or c o nsi deri n g t he res pecti ve l ocal S m P Cs a n d a b o ve rec o m me n de d L L T s c he me 
base d o n 
E S C/ E A S  g ui deli ne i n c o m bi nati o n 
wit h rele va nt 
H T A re q uire me nt. 
T h e 
I n v esti gat or’s L L T decisi o ns as well as p ossi ble de viati o ns fr o m t he a b o ve d escri be d escalati o n 
al g orit h m ha ve t o be d oc u me nte d i n detail i n e C R F. T hi s i ncl u des f or mal c o ntrai n dicati o n as 
per l ocal S m P C or pri or i nt olera ble A E.  
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 esta blis he d d ose re gi me n f or i nclisira n s o di u m f or a d ults is 3 0 0 m g s.c. a d mi nistere d at 
Da y 1, M o nt h 3 ( Da y 9 0) a n d e ver y 6 m o nt hs t hereafter. T his d ose a n d d ose re gi me n were 
e xte nsi vel y st u die d i n t he p hase III cli nical pr o gra m, a n d will be use d i n t he prese nt st u d y t o 
pr o vi de ma xi m u m efficac y wit h a n acce pta ble safet y pr ofile. F urt her m ore, a 3 0 0 m g d ose of 
i nclisira n s o diu m has b ee n st u die d i n partici p a nts wit h mil d, m o derat e a n d se vere re n al 
i m pair me nt a n d 
mil d a n d 
m o derate he p atic i m pair me nt, wit h n o cli nicall y 
mea ni n gf ul 
differe n ces i n L D L -C a n d P C S K 9 l o weri n g c o m pare d t o t hat o bser ve d i n ot her partici pa nt 
p o p ulati o ns, a n d wit h n o d ose a dj ust me nt re q uire d (I B).  
T hree lar ge pi v otal p has e III cli nical trials ( O RI O N -9. -1 0, -1 1) ( Wri g ht  et al 2 0 2 1 ) i n a d ults 
wit h A S C V D, A S C V D ris k e q ui vale nts, a n d He F H de m o nstrate d t h at t he d ose re gi me n us e d i n 
t he prese nt st u d y ( 3 0 0 m g i nclisira n s o di u m s.c. o n Da y 1, M o nt h 3 ( Da y 9 0), a n d (e ver y) 6 
m o nt hs t hereafter) res ult e d i n place b o -a dj uste d p erce nta ge re d u cti o ns i n L D L -C fr o m baseli ne 
at Da y 5 1 0 of 4 8 % t o 5 2 %, wit h ti me -a dj uste d a vera g e re d u cti o ns of 4 4 % t o 5 4 % s ustai ne d 
o ver 1 8 m o nt hs ( Raal  et al 2 0 2 0 , Ra y  et al 2 0 2 0 ). T his d ose a n d re gi me n h as bee n s h o w n t o be 
C CI

N o v arti s  
C o nfi d e nti al  
P a g e  4 2  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
well t olerat e d, wit h a s afet y pr ofile si milar t o place b o, wit h t h e e x ce pti o n of m ore i njecti o n site 
reacti o ns ass o ciate d wit h i nclisira n c o m pare d t o pl ace b o. 
T he pri mar y e n d p oi nt at da y  9 0 of t he 1  year -treat me nt peri o d will 
 of 
acti o n of t he test treat me nt. F urt her, t he rati o nale f or t he 1 -year d urati o n of t he place b o -
c o ntr olle d treat me nt p eri o d is t hat it als o all o ws a reas o na ble n u m ber of 3  i njecti o ns per 
partici pa nt ( gi ve n t he t wi ce yearl y d osi n g re gi me n) a n d is s uita ble t o assess l o n ger -ter m efficac y 
as well as safet y, t olera bilit y a n d q ualit y  of life.  
T he hi g h -i nte nsit y o pe n la bel stati n r os u vastati n will be use d acc or di n g t o l ocal S m P C wit h 
rec o m me n de d start d os e l e vel of 5 m g/ da y or 1 0 m g/ da y f oll o we d b y a n i n di vi d ual titrati o n base d 
o n t olera bilit y a n d re q uire d L D L -C l o weri n g. At da y 9 0, it i s ass u me d t hat r os u vastati n is 
o pti mall y titrate d f or m ost partici pa nts.  
4. 3  
R ati o n al e f or c h oi c e of c o ntr ol dr u g s ( c o m p ar at or/ pl a c e b o) or 
c o m bi n ati o n dr u g s  
T his trial is place b o -c o ntr olle d t o pr o vi de r o b ust e vi de nce o n t he effect of i nclisira n i n 
c o m bi nati o n wit h a n o n g oi n g i n di vi d uall y o pti mize d L L T o n cli nical efficac y, safet y a n d 
t olera bilit y as well as o n q ualit y of life. T he us e of place b o as a c o m parat or f or i n clisira n is 
j ustifie d si nce all e nr olle d partici pa nts will be treate d wit h t heir i n di vi d uall y opti mize d L L T 
(i ncl u di n g r os u vastati n a n d ot her li pi d-l o weri n g ( bac k gr o u n d) tr eat me nt, if i n dicate d) 
t hr o u g h o ut t he st u d y. All partici pa nts will be o n sta n dar d of care i ncl u di n g, b ut n ot li mite d t o, 
dietar y a d vice, a nti h y pert e nsi ves, a nti -dia betic t hera pies , a n d a nti platelet t hera pies pr o vi de d b y 
t he I n v esti gat or, as cli nicall y a p pr o priate. 
4. 4  
P ur p o s e a n d ti mi n g of i nt eri m a n al y s e s/ d e si g n a d a pt ati o n s  
N ot a p plica ble.   
4. 5  
Ri s k s a n d b e n efit s  
L D L -C pla ys a maj or r ole i n t he i nitiati o n a n d pr o gressi o n of A S C V D. L o weri n g L D L -C has 
bee n s h o w n t o re d uce t he ris k of deat h or MI or str o ke a n d wit hi n t he ra n g e of effects ac hie ve d 
s o far, t he cli nical ris k re d ucti o n is li nearl y pr o p orti o nal t o t he a bs ol ute L D L -C re d ucti o n 
(Bai ge nt  et al 2 0 0 5 , Castilla -G uerra  et al 2 0 1 6 ). T heref ore, ele vate d L D L-C le vels nee d t o be 
caref ull y c o ntr olle d. T he c urre nt E S C/ E A S g ui deli nes f or t he ma na g e me nt of d ysli pi de mias 
rec o m me n d a L D L-C tar get of <  5 5  m g/ d L i n ver y hi g h ri s k patie nts a n d a L D L-C tar g et of 
<  7 0  m g/ d L i n hi g h ris k patie nts as d efi ne d b y t he car di o v asc ular ris k cate g ori es 
(Mac h  et al 2 0 2 0 ). F urt her m ore, a n L D L-C re d u cti o n ≥ 5 0 % fr o m baseli ne is rec o m me n de d f or 
t hese participa nt p o p ulati o ns. Des pite t he a vaila bilit y of m ulti ple o pti o ns of li pi d -l o weri n g 
dr u gs, c urre nt t hera pies still d o n ot pr o vi de s ufficie nt c o ntr ol f or ma n y pati e nts wit h ele vate d 
L D L -C 
( Fitz geral d  et al 2 0 1 7 , Bar kas  et al 2 0 1 5 , Ja mes o n et al 2 0 1 4 , J o nes et al 2 0 1 2 , 
Ra y  et al 2 0 2 0  ( D A VI N CI)). T his is partic ularl y tr ue i n patie nts wit h pre-e xisti n g C V D w h o 
are at t he 
hi g hest ris k 
of 
M A C E a n d re q uire t he 
m ost i nte nsi ve 
ma na ge me nt 
(Da vi ds o n  et al 2 0 0 5 ). R ece nt data fr o m t he D A VI N CI st u d y, a n 1 8 c o u ntr y, cr oss-secti o nal, 
C CI

N o v arti s  
C o nfi d e nti al  
P a g e  4 3  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
o bser vati o nal st u d y acr oss E ur o pe i n patie nts pres cri be d wit h L L T f or pri mar y a n d sec o n d ar y 
pre ve nti o n, s h o w t hat o nl y 3 3 % ac hie ve d t heir ris k -base d g oal acc or di n g t o 2 0 1 9 E S C/ E A S 
g ui deli ne ( Ra y  et al 2 0 2 0 , Mac h  et al 2 0 2 0 ). F or ver y hi g h ris k pri mar y a n d sec o n d ar y 
pre ve nti o n patie nts, t he 2 0 1 9 E S C/ E A S  g ui deli ne defi ne d L D L -C tar get was ac hie ve d i n 1 7 % 
a n d 2 2 % of patie nts, r es p ecti vel y ( Ra y  et al 2 0 2 0 ). 
I n clisira n is a p pr o ve d i n E U, U S, as well as ot her c o u ntries w orl d wi de. I n  t he E U, it is i n dicate d 
i n a d ults wit h pri mar y h y perc h olester ole mia ( heter oz y g o us fa milial a n d n o n‑fa milial) or mi xe d 
d ysli pi de mia, as a n a dj u nct t o diet i n c o m bi n ati o n wit h a stati n or sta ti n wit h ot her 
li pi d‑l o weri n g t hera pi es i n patie nts u na ble t o reac h L D L‑ C tar gets wit h t h e M T D of a stati n, or 
al o ne or i n c o m bi nati o n wit h ot her li pi d -l o weri n g t hera pies i n patie nts w h o are stati n-i nt olera nt, 
or f or w h o m a stati n is c o ntrai n dicate d.  
I n P hase III st u dies, i n a d ults wit h A S C V D, A S C V D ris k e q ui v ale nts, a n d/ or He F H, i nclisira n, 
gi ve n o n Da y 1, M o nt h 3 ( Da y 9 0) a n d e ver y 6 m o nt h t hereafter o n t o p of ma xi mall y -t olerate d 
stati n t hera p y wit h or wit h o ut ot her L L T, l o were d L D L-C b y ~ 5 0 % vers us place b o. T he effect 
was persiste nt o ver ti me a n d re versi ble o n st o p pi n g i nclisira n.  
I n n o n-cli nical t o xicit y st u dies, i nclisira n was n ot carci n o ge nic or g e n ot o xic, t here was n o effect 
o n pater nal perf or ma nce, s per mat o ge nesis, estr o us c ycle, a n d uteri ne or o v ari a n para meters a n d 
i nclisira n di d n ot s h o w e vi de nce of e m br y o let halit y, fet ot o xicit y, or terat o g e nicit y. I n a d diti o n, 
t here were n o effects of i nclisira n o n t he de vel o p me nt of t he F 1 ge nerati o n, i ncl u di n g s ur vi val, 
gr o wt h, p h ysical a n d refl e x ol o gical de vel o p me nt, be ha vi or, a n d re pr o d ucti ve perf or ma nce.  
Safet y data o btai ne d fr o m t hree lar ge pi v otal st u dies ( O RI O N -9, -1 0, -1 1, Wri g ht  et al 2 0 2 1 ) 
t hat i ncl u de d 1, 8 3 3 parti ci pa nts treate d wit h i n clisira n f or u p t o 1 8 m o nt hs (mea n treat me nt 
d urati o n o n i nclisira n was 5 2 6 da ys) s h o we d t hat t he o verall safet y pr ofile of i nclisira n was 
si milar t o 
place b o. 
Treat me nt-e mer ge nt a d v erse e ve nts ( T E A Es) lea di n g t o st u d y 
disc o nti n uati o n were bal a nce d bet wee n i nclisira n a n d place b o. T h e o n l y a d verse reacti o ns 
ass ociate d wit h i nclisira n were A Es at t he i njecti o n site ( 8. 2 % f or i nclisira n -treate d partici pa nts 
vs. 1. 8 % f or place b o -treate d partici pa nts), b ut t hese a d verse reacti o ns were l ocalize d, mil d or 
m o derate i n se v erit y, tra nsie nt a n d res ol ve d wit h o ut se q uelae. T h e pr o p orti o n of partici pa nts 
w h o disc o nti n ue d treat m e nt d ue t o t his A E was l o w: 0. 2 % f or i nclisira n a n d 0. 0 % f or place b o.  
I n clisira n is n ot ass oci ate d 
wit h a n i ncrease d ris k f or he patic or re nal d ysf u ncti o n, 
h y perse nsiti vit y, ne ur ol o gic e ve nts a n d ne ur oc o g niti ve dis or ders, or o p ht hal m ol o gical e ve nts 
a n d t here w as n o differe n ce fr o m place b o i n ne w o nset or w orse ni n g of dia betes. N o cli nicall y 
si g nifica nt differe nces i n t he cli nical efficac y, safet y or p har m ac o d y na mic pr ofiles of i nc lisira n 
were o bs er ve d i n t he p artici pa nts w h o were teste d p ositi ve f or a nti -i nclisira n a nti b o dies. 
F or t he ris k a n d be n efit assess me nt of a p pr o ve d r os u vastati n please c o nsi der t he i nf or mati o n 
pr o vi de d i n t his pr ot oc ol a n d al wa ys refer t o t he l o cal S m P C.  
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 n c 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 ntr ace pti o n re q uire me nts o utli ne d 

N o v arti s  
C o nfi d e nti al  
P a g e  4 4  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
i n t he e xcl usi o n criteria (Secti o n  5. 2 ). 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 be c o nsi dere d as n ot eli gi ble t o  t he st u d y. 
I n ge n eral, t h e ris k of p artici pa nts i n t his trial ma y be mi ni mize d b y c o m plia nce wit h t h e 
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 of safet y para meters.  
T he be nefit a partici pa nt mi g ht ha ve b y partici pati n g i n t he st u d y is t he cl ose m o nit ori n g of t heir  
c o n diti o n a n d cl ose a d here nce as well as a n o n g oi n g i n di vi d ual o pti mizati o n of L L T.  
4. 5. 1  
C o vi d -1 9 i m p a ct o n ri s k -b e n efit  
T he c or o na vir us diseas e 2 0 1 9 ( C O VI D -1 9) p a n de mic ma y c o nti n ue t o affect c o u ntries 
partici pati n g i n st u d y C KJ X 8 3 9 A 1 2 4 0 2. W hile partici pa nts wit h u n derl yi n g C V disease ha ve 
a n i ncreas e d ris k f or u nfa v ora ble o utc o mes (e. g., res pirat or y fail ure, deat h) after c o ntr acti n g 
C O VI D -1 9, t he ris k of bei n g e x p ose d t o se vere ac ute res pirat or y s y n dr o me c or o na vir us 2 
( S A R S-C o V -2) ca n be miti gate d if t he meas ures rec o m me n de d or e nf orce d b y nati o nal a n d/ or 
l ocal a ut h orities are f oll o we d. S h o ul d l ocal (e. g. c o m m u nit y-base d) or g e neral (e. g. c o u ntr y - 
or -state base d) l oc k-d o w n be re q uire d b y a ut h orities, d ue t o C O VI D -1 9, t h e st u d y partici pa nts 
m ust f oll o w t he g ui d a nce/re q uire m e nts a p plica bl e t o t he ge neral p o p ulati o n, as well as a n y 
s pecific g ui da nce/re q uir e me nt a p plica ble t o t heir u n derl yi n g c o n diti o n. If t he st u d y -le vel a n d 
t he p o p ulati o n-le vel re q uire me nts are f oll o we d, t he pa n de mic-relate d ris k of a partici pa nt 
partici pati n g i n t he st u d y s h o ul d n ot e xcee d t he ris k of a partici p a nt wit h a si milar c o n diti o n n ot 
partici pati n g i n t he st u d y.  
4. 6  
R ati o n al e f or P u bli c H e alt h E m er g e n c y miti g ati o n pr o c e d ur e s  
D uri n g a p u blic healt h e mer ge nc y as 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 ur al disaster, miti gati o n pr oce d ures t o e ns ure partici p a nt safet y a n d trial i nte grit y 
ma y be i m ple me nte d. N otificati o n of t he P u blic healt h e mer ge n c y as d eclare 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 ntat i o n of miti gati o n pr oce d ures. 
5  
St u d y P o p ul ati o n  
T he st u d y p o p ulati o n c o nsists of a d ult partici pa nts at ver y hi g h a n d hi g h ris k f or car di o vas c ular 
e ve nts as defi n e d b y t he car di o vas c ular ris k cate g ories i n t he 2 0 1 9 E S C/ E A S g ui deli nes f or t he 
ma na ge me nt of d y sli pi de mias (Mac h  et al 2 0 2 0 ) w h o d o n ot meet t heir i n di vi d ual L D L-C tar get 
des pite bei n g treate d wit h t heir i n di vi d ual M T D of a stati n f or at least 3 0 da ys, a n d if a p plica ble, 
a n ot her L L T o n t o p of st ati n sta ble f or at  least 3 0 da ys pri or t o scree ni n g ( u p t o a p pr o xi matel y 
2 0 % of ra n d o mize d parti ci pa nts).  
A m o n g t he defi ne d st u d y p o p ulati o n, treat me nt wit h i nclisira n o n t o p of a n o n g oi n g i n di vi d uall y 
o pti mize d L L T is s u g geste d t o be es peciall y be neficial f or s u b p o p ulati o n s s ufferi n g fr o m P A D 
a n d C H D wit h sta ble a n gi na pect oris ( A P). T hese partici pa nts ha ve bee n s h o w n t o res p o n d t o 

N o v arti s  
C o nfi d e nti al  
P a g e  4 5  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
L L T wit h i m pr o ve d f u ncti o nal ca pacit y a n d q ualit y of life ( M o hler  2 0 0 3 , M o n dill o  et al 2 0 0 3 , 
Ka ba klić  a n d Fras  2 0 1 7 , Ma nfri ni  et al 2 0 2 0 ). 
A P or 'c hest ti g ht ness' descri bes a t h oraci c or retr oster nal pai n t hat occ urs fre q ue ntl y i n t he f or m 
of attac ks a n d is tri g gere d b y m y ocar dial isc h e mia. A P is t he car di nal s y m pt o m of C H D a n d 
ca n be disti n g uis he d i nt o sta ble a n d u nsta bl e A P  peri o ds, cate g orize d as eit her c hr o ni c 
s y n dr o mes ( C C S) or ac ut e c or o nar y s y n dr o mes ( A C S). Sta ble A P is c haracterize d b y c h est pai n 
t hat ca n be re pr o d uce d b y p h ysical or ps yc h ol o gical stress a n d t hat disa p pears at rest or after 
a d mi nistrati o n of nitr o gl yceri ne ( K n u uti  et al 2 0 2 0 ). 
P A D is a restricti o n i n b l o o d fl o w of t he arteries s u p pl yi n g t he e xtre mities or, m ore rarel y, t he 
a orta. Bl o o d fl o w ca n be restricte d gra d u all y (t hr o u g h a ste n osis) or c o m plete ( occl usi o n) 
(A b o ya ns  et al 2 0 1 8 ). P A D is e vi de nce d b y i nter mitte nt cla u dicati o n wit h a n a n kle -brac hi al 
i n de x ( A BI) ≤ 0. 9 0 pri or peri p heral arteri al re vas c ularizati o n pr oce d ure, or, a m p utati o n d ue t o 
at her oscler otic disease. T hr o m b oa n giitis o blitera ns is n ot a q ualif yi n g e ve nt.  
Ar o u n d 1 7 6 0 partici pa nts w h o meet t he eli gi bi lit y criteria will be ra n d o mize d 1: 1 at baseli ne. 
Partici pa nts will be str atifie d b y t heir car di o vas c ular ris k, ver y hi g h ris k or hi g h ris k as d efi ne d 
i n t he i ncl usi o n criteri a (Secti o n  5. 1  a n d Secti o n  1 6. 4 ). Partici pa nts will c o nti n ue t o be scree n e d 
u ntil a p pr o xi matel y 1 7 6 0 partici pa nts are ra n d o mi ze d t o t he trial. Si nce 3 5 % scree ni n g a n d r u n -
i n fail ure rat e is e x pect e d, a p pr o xi matel y 2 7 0 0 partici pa nts are a ntici pat e d t o be scree ne d. 
5. 1  
I n cl u si o n crit eri a  
Partici pa nts eli gi ble f or i ncl usi o n i n t his st u d y m ust meet all  of t he f oll o wi n g criteria:  
At S cr e e ni n g:  
1.  Writte n i nf or me d c o ns e nt m ust be o btai ne d bef ore a n y assess me nt is perf or me d.  
2.  Male or fe m ale partici pa nts ≥1 8 years of a g e.  
3.  Partici pa nts cate g ori ze d as ver y hi g h or hi g h C V ris k, as defi ne d bel o w:  
•  Ver y hi g h ris k p artici p a nts  wit h at least o ne of t he f oll o wi n g:  
1.  D oc u me nte d A S C V D  
A C S: U nsta ble a n gi na or m y ocar dial i nfarcti o n  
Sta ble a n gi na  
C or o nar y re v asc ularizati o n  
U ne q ui v ocall y d oc u me nt e d A S C V D u p o n pri or i ma gi n g  
Str o ke a n d Tra nsie nt Is c hae mic Attac k ( TI A)  
P A D  
2.  Dia betes mellit us ( D M) wit h tar get or ga n d a ma ge ( defi ne d as micr oal b u mi n uria, 
reti n o pat h y, or ne ur o pat h y), or at least ≥ 3 maj or ris k fact ors, or earl y o ns et of 
T y pe 1 D M of l o n g d urati o n ( > 2 0 years)  
3.  A calc ulat e d S C O R E 2 ≥ 7. 5 % f or a g e <  5 0 y ears; S C O R E 2 ≥ 1 0 % f or a ge 5 0 -
6 9  years; S C O R E 2 -O P ≥ 1 5 % f or a g e ≥ 7 0 years t o esti mate 1 0 -year ris k of fatal 
a n d n o n-fat al C V D  

N o v arti s  
C o nfi d e nti al  
P a g e  4 6  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
4.  Pre -e xisti n g dia g n osis of heter oz y g o us fa milial h y perc h olester ole mia ( He F H)  
wit h A S C V D or wit h a n ot her maj or ris k fact or.  
O R  
•  Hi g h ris k p artici p a nts  wit h at least o ne of t he f oll o wi n g:  
1.  Mar ke dl y ele v ate d si n gle ris k fact ors, i n partic ular t otal c h olester ol > 3 1 0 m g/ d L, 
L D L -C > 1 9 0 m g/ d L, or bl o o d press ure ≥ 1 8 0/ 1 1 0 m m H g  
2.  Pre -e xisti n g dia g n osis of He F H wit h o ut ot her maj or ris k fact ors  
3.  D M wit h o ut tar get or ga n da ma ge ( defi ne d as micr oal b u mi n uria, reti n o pat h y, or 
ne ur o pat h y), wit h D M d urati o n ≥ 1 0 years or ot h er a d diti o nal ris k fact or  
4.  M o derate c hr o nic ki d ne y disease (e G F R 3 0 -5 9 m L/ mi n/ 1. 7 3 m 2) 
5.  A calc ulat e d S C O R E 2  2. 5 t o < 7. 5 % f or a ge u n der 5 0 years; S C O R E 2 5 t o < 1 0 % 
f or a ge 5 0-6 9 years; S C O R E 2 -O P 7. 5 t o < 1 5 % f or a ge ≥7 0 years t o esti mate 1 0 -
year ris k of fatal a n d n o n -fatal C V D 
as defi ne d b y t he car di o vasc ular ris k cate g ories  i n t he 2 0 1 9 
E S C/ E A S g ui deli ne 
(Mac h  et al 2 0 2 0 ), [ N ote: Ta ble 4 , pa ge 1 5: Hi g h ris k a n d ver y hi g h ris k o nl y] a n d u p date d 
S C O R E 2 a n d S C O R E 2 -O P (acc or di n g t o 
Ha g e ma n et al 2 0 2 1 , de Vries et al 2 0 2 1 ,  
Vissere n et al 2 0 2 1 ). F urt her details f or d o c u me nte d A S C V D are pr o vi d e d i n Secti o n  1 6. 4 . 
4.   L D L -C le vels:  
a. i n partici pa nts wit h ver y hi gh car di o vasc ul ar ris k: ser u m L D L -C ≥5 5 m g/ d L.  
b.  i n partici pa nts wit h hi g h  car di o vas c ular  ris k: ser u m L D L-C ≥7 0 m g/ d L  
5.  Partici pa nt o n a sta ble d ose of a stati n f or ≥ 3 0 d a ys. ( Please refer t o T a ble  3 -1  f or stati n 
e nr oll me nt tar gets .). [ T he i n vesti gat or m ust e ns ure t hat t he partici pa nt's i n di vi d ual stati n 
t hera p y d oes n ot me et a n y c o ntrai n dicati o n f or t h at partici pa nt a n d d oes n ot i nterfere wit h 
t he liste d eli gi bilit y criteria as state d i n t he l ocal S m P C of t he res pecti ve stati n.]. 
6.  U p t o a p pr o xi matel y 2 0 % of t otal partici pa nts ca n be o n a sta ble d ose (f or ≥ 3 0  da ys pri or 
t o scree ni n g) of a n ot her L L T o n t o p of stati n s uc h as a c h olester ol a bs or bi n g i n hi bit or or a 
bile aci d se q uestr a nt, or alter nati vel y, a n a d e n osi ne tri p h os p hate citrat e l yase ( A C L) 
i n hi bit or, as i n dicate d. 
7.  Fasti n g tri gl yceri de < 4 0 0 m g/ d L.  
At B a s eli n e:  
8.  Fasti n g tri gl yceri de < 4 0 0 m g/ d L.  
9.  Bef ore ra n d o mizati o n, des pite bei n g treate d wit h t he i n di vi d ual M T D of a stati n f or ≥ 3 0 
da ys a n d, if a p plica ble,  wit h a n ot her L L T o n t o p of stati n (sta ble f or ≥ 3 0 da ys),  
a. i n partici pa nts wit h ver y hi g h car di o vasc ul ar ris k: ser u m L D L-C ≥ 5 5 m g/ d L.  
b.  i n partici pa nts wit h hi g h  car di o vas c ular  ris k: ser u m L D L-C ≥ 7 0 m g/ d L.  

N o v arti s  
C o nfi d e nti al  
P a g e  4 7  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
5. 2  
E x cl u si o n crit eri a  
Partici pa nts meeti n g a n y of t he f oll o wi n g criteri a are n ot eli gi ble f or i ncl usi o n i n t his st u d y.  
1.  Se vere c o n c o mita nt n o n -C V disease t hat is e x pecte d t o re d uce life e x p ecta nc y t o less t ha n 
2 years at scree ni n g or baseli ne visit.  
2.  Partici pa nts o n m ore t ha n o ne ot her li pi d -l o weri n g dr u g o n t o p of statin at scree ni n g visit.  
3.  Pre -e xisti n g dia g n osis of h o m oz y g o us fa milial h y perc h olester ole mia at scree ni n g or 
baseli ne visit.  
4.  Sec o n dar y h y p erc h olester ole mia, e. g. h y p ot h yr oi dis m or ne p hr otic s y n dr o me at scree ni n g 
or baseli ne visit.   
5.  Pre vi o us ( wit hi n 9 0 da ys of scree ni n g), c urre nt or pla n ne d treat me nt wit h a m o n ocl o nal 
a nti b o d y ( m A b) direct e d t o war ds P C S K 9 (e. g. e v ol oc u ma b, alir oc u ma b) at scree ni n g or 
baseli ne visit.  
6.  Pre vi o us e x p os ure t o i nclisira n or a n y ot her n o n -m A b P C S K 9 tar gete d t hera p y, eit her as 
a n i n vesti gati o nal or mar kete d dr u g wit hi n 2 years pri or t o scree ni n g or bas eli ne visit.  
7.  Pre vi o us, c urre nt or pla n ne d treat me nt wit h L D L -a p heresis at s cree ni n g or baseli ne visit.  
8. Partici pa nts wit h k n o w n i nt olera nce t o r os u v astati n at scree ni n g or baseli ne visit.  
9. 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, i nclisira n or r os u vastati n, or its 
e xci pie nts or t o dr u gs of si milar c he mical classes at scree ni n g or baseli ne visit.  
1 0. Partici pa nts ta ki n g ge mfi br ozil at scree ni n g or baseli ne visit.  
1 1. Li ver a n d C K: (a) Acti ve li ver diseas e defi ne d as a n y c urre nt i nf ecti o us, ne o plastic, or 
meta b olic pat h ol o g y of t he li ver or ( b) u ne x plai ne d ala ni ne a mi n otra nsferas e ( A L T), 
as partate a mi n otra nsferas e ( A S T) ele vati o n > 3 x U L N, or t otal bilir u bi n ele vati o n > 2 x U L N 
(e xce pt f or p artici pa nts wit h Gil bert's s y n dr o me), or (c) creati ne ki nase ( C K) > 5 x U L N at 
scree ni n g or b aseli ne visit.  
1 2. Partici pa nt wit h se vere re nal i m pair m e nt defi ne d b y e G F R < 3 0 m L/ mi n/ 1. 7 3 m 2 as 
calc ulate d b y t h e M o dificati o n i n Diet i n R e nal Disease ( M D R D) f or m ula at scree ni n g or 
baseli ne visit.  
1 3. Ac ute c or o nar y s y n dr o me, isc he mic str o ke or TI A, c or o nar y re v asc ularizati o n or peri p heral 
arterial re vasc ul arizati o n pr oce d ure or a m p utati o n d ue t o at her oscler otic disease < 3 m o nt hs 
pri or t o t he scree ni n g or baseli ne visit. 
1 4. Pla n ne d or e x pecte d car diac, cere br o vas c ular or peri p heral arter y s ur ger y or c or o nar y 
re vasc ul arizati o n wit hi n t he st u d y d urati o n. 
1 5. Heart fail ure N e w Y or k Heart Ass ociati o n ( N Y H A) cl ass I V at scree ni n g or baseli ne vi sit. 
1 6. Hist or y of mali g na nc y t hat re q uire d s ur ger y (e xcl u di n g l ocal a n d wi de -l ocal e xcisi o n), 
ra diati o n t hera p y a n d/ or s yste mic t hera p y (e x cl u di n g s yste mic a dj u va nt t h era pies gi ve n t o 
pre ve nt ca ncer rec urre nce e g: h or m o n ot hera p y f or pr ostate or breast ca ncer) d uri n g t he 3 
years pri or t o s cree ni n g or baseli ne visit.  
1 7. Partici pa nt wit h m y o pat h y at scree ni n g or bas eli ne visit.  
1 8.  Partici pa nt recei vi n g c o n c o mita nt cicl os p ori n at scree ni n g or baseli ne visit.  

N o v arti s  
C o nfi d e nti al  
P a g e  4 8  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
1 9.  Partici pa nts t hat are pre dis p ose d t o t he de vel o p me nt of re nal fail ure sec o n dar y t o 
r ha b d o m y ol ysis (e. g. s e psis, h y p ote nsi o n, 
maj or s ur ger y, tra u ma, se vere 
m eta b olic, 
e n d ocri ne a n d ele ctr ol yte dis or ders; or u nc o ntr olle d seiz ures).  
2 0.  Partici pa nts wit h rare h ere ditar y pr o ble ms of g alact ose i nt olera n ce , t he La p p lactase 
deficie nc y or gl uc ose -gal act ose -mal a bs or pti o n.  
2 1. U n willi n g ness or i na bilit y (e. g. p h ysical or c o g niti ve) t o c o m pl y wit h st u d y pr oce d ures 
(i ncl u di n g st u d y visits, fasti n g bl o o d dra ws a n d c o m plia nce wit h st u d y treat me nt re gi me ns), 
a n d medicati o n a d mi nistrati o n (i njecti o ns) a n d s c he d ule. Partici pa nt s h o ul d be a ble a n d 
willi n g t o rea d, u n dersta n d a n d a ns wer q uesti o n naires.  
2 2. A n y s ur gical or me di cal c o n diti o n, w hic h i n t he o pi ni o n of t h e i n vesti gat or, ma y pl ace t he 
partici pa nt at hi g her ri s k fr o m his/ her p artici pati o n i n t he st u d y, or is li kel y t o pre v e nt t he 
partici pa nt fr o m c o m pl yi n g wit h t he re q uire m e nts of t he st u d y or c o m pleti n g t he st u d y at 
scree ni n g or b aseli ne visit. 
2 3. Use of ot her i n vesti gati o nal dr u gs wit hi n 5 half -li ves, 3 0 da ys or u ntil t he e x pecte d 
p har mac o d y n a mic effect has ret ur ne d t o baseli ne (e. g. bi ol o gics), w hic h e ver is l o n ger or 
l o n ger if re q uir e d b y l ocal re g ulati o n, pri or t o scree ni n g visit.  
2 4. Pre g na nt or n ursi n g (lactati n g) w o me n at s cree ni n g or baseli ne visit.  
2 5 . W o me n of c hil d-b eari 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  m et h o ds of c o ntr ace pti o n w hile 
ta ki n g st u d y treat me nt, w hic h i ncl u des r os u vastati n, a n d f or 5 da ys ( = 5 ti mes t he 
ter mi nal half-life of r os u vastati n) after st o p pi n g me dicati o n.  Hi g hl y effecti ve 
c o ntrace pti o n met h o ds i ncl u de:  
•  T otal a bsti ne nce ( w he n t his is i n li ne wit h t he preferre d a n d us ual lifest yle of t he 
partici pa nt. Peri o dic a bsti ne nce (e. g. cale n dar, o v ulati o n, s y m pt ot her mal, p ost-
o v ulati o n met h o ds) a n d wit h dra wal are n ot acce pta ble met h o ds of c o ntrace pti o n.  
•  Fe male steriliz ati 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 we e ks bef ore 
ta ki n g st u d y treat me nt. 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 ass ess me nt.  
•  Male sterilizati o n (at least 6 m o nt hs pri or t o scree ni n g). F or fe mal e partici pa nts o n  t he 
st u d y, t he vasect o mize d male part ner s h o ul d be t he s ole part ner f or t hat p artici pa nt.  
•  Use of oral, (estr o ge n a n d pr o gester o ne), i njecte d, or i m pla nte d h or m o nal met h o ds of 
c o ntrace pti o n or pl ace m e nt of a n i ntra uteri ne d e vice (I U D) or i ntra uteri ne s yste m 
(I U S), or ot her f or ms of h or m o nal c o ntrace pti o n t hat ha ve c o m para ble efficac y (fail ure 
rate < 1 %), f or e xa m ple h or m o ne va gi nal ri n g or tra ns der mal h or m o ne c o ntrace pti o n.  
I n cas e of use of oral c o ntrace pti o n w o m e n s h o ul d ha ve b ee n sta ble o n t he sa me pill f or a 
mi ni m u m of 3 m o nt hs bef ore ta ki n g st u d y treat me nt.  
W o me n are c o nsi dere d p ost -me n o pa usal if t he y h a ve h a 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 b eari n g p ote ntial if t he y are p ost -me n o pa us al 
or ha ve h a d s ur gical bilat eral 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 

N o v arti s  
C o nfi d e nti al  
P a g e  4 9  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
or bilateral t u bal li gati o n at least si x wee ks a g o. I n t he cas e of o o p h orect o m y al o ne, o n l 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 d ere d n ot of c hil d beari n g p ote ntial.  
If l oc al re g ul ati o ns de viate fr o m t he c o ntr ace pti o n met h o ds liste d a b o ve t o pre ve nt pre g na n c y, 
l ocal re gulati o ns a p pl y a n d will be descri be d i n t h e l ocal I C F.   
6  
Tr e at m e nt  
6. 1  
St u d y tr e at m e nt  
Partici pa nts will be ra n d o mize d 1: 1 t o d o u ble -bli n d s.c. i njecti o ns of i nclisira n s o di u m 3 0 0  m g 
or place b o. I n vesti gati o nal a n d c o ntr ol dr u gs will n ot be dis pe nse d t o t he par tici pa nts b ut 
a d mi nistere d b y q ualifie d, dele gate d healt hcare p ers o n nel at t he st u d y site o n Da y 1, Da y 9 0 
a n d Da y 2 7 0 of t h e st u d y.  
T he o pe n la bel st u d y treat me nt, r os u vastati n, 
will be deli vere d t o t he partici pa nts at 
ra n d o mizati o n a n d ne xt visits f or dail y i nta ke, a n d partici pa nts will be as ke d t o ret ur n all u n use d 
r os u vastati n treat me nt a n d its pac ka gi n g at eac h st u d y visit. 
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 s p o ns or will pr o vi de t he f oll o wi n g i n vesti gati o nal a n d c o ntr ol dr u gs, refer t o T a ble  6 -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  
I n cli sir a n1  
Pl a c e b o  
Tr e at m e nt D e s cri pti o n  
I n cli sir a n s o di u m 3 0 0 m g 
( e q ui v al e nt t o 2 8 4 m g i n cli sir a n) i n 
1. 5 m L  
Pl a c e b o i n 1. 5 m L  
T y p e s  
Dr u g  
Dr u g  
D o s e F or m ul ati o n  
S ol uti o n f or i nj e cti o n  
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)  
I n cli sir a n s o di u m 3 0 0 m g 
( e q ui v al e nt t o 2 8 4 m g i n cli sir a n) i n 
1. 5 m L  
Pl a c e b o i n 1. 5 m L  
D o s a g e L e v el( s)  
I n cli sir a n s o di u m 3 0 0 m g a s 1 
i nj e cti o n of 1. 5 ml at e a c h of t h e 
ti m e p oi nt s s p e cifi e d i n T a bl e 8 -1  
Pl a c e b o a s i nj e cti o n i n 1. 5 ml at 
e a c h of t h e ti m e p oi nt s s p e cifi e d i n 
T a bl e 8 -1  
R o ut e of A d mi ni str ati o n  
S u b c ut a n e o u s i nj e cti o n  
S u b c ut a n e o u s i nj e cti o n  
U s e  
E x p eri m e nt al  
E x p eri m e nt al  
I M P 
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 
( gl o b al) 
Pr o vi d e d c e ntr all y b y t h e S p o n s or 
( gl o b al) 
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 
pr e -fill e d s yri n g e s. E a c h s yri n g e 
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 
pr e -fill e d s yri n g e s. E a c h s yri n g e 
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.  
1 I n cli sir a n i s al s o r ef err e d t o a s K J X 8 3 9 

N o v arti s  
C o nfi d e nti al  
P a g e  5 0  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
D uri n g t he treat me nt 
peri o d, a 
partici pa nt  ca n 
bec o m e eli gi ble f or 
P C S K 9 
m A b 
treat me nt. Please refer t o Secti o n  3. 4  f or decisi o n o n eli gi bilit y.  
If, d uri n g t he c o urse of t he st u d y, as p er assess me nt b y t he Steeri n g C o m mittee, a partici pa nt's 
c o n diti o n warra nts t he us e of a  P C S K 9 m A b, prefera bl y 
 t he partici pa nt 
will nee d t o disc o nti n ue t he bli n de d i n vesti gati o nal treat me nt, i nclisira n/ place b o, b ut will 
re mai n i n t he st ud y a n d will be f oll o we d -u p u ntil t he partici pa nt’s e n d of st u d y.  
I n cases w here t he Steeri n g C o m mittee dee ms a partici pa nt n ot eli gi ble f or P C S K 9 m A b a n d 
t he I n v esti gat or deci des t o treat t he partici pa nt as per l ocal sta n dar d of care, t he partici pa nt will 
nee d t o disc o nti n ue st u d y me dicati o n (i nclisira n/ pl ace b o), b ut will re m ai n i n t he st u d y a n d will 
be f oll o we d -u p u ntil t he partici pa nt’s e n d of st u d y.  
F or i ntract a ble cas es wit h L D L -C still t o o hi g h after L L T escal ati o n (refer t o Secti o n  3. 4 ), t he 
I n v esti gat or ca n deci de t o ha ve t he partici pa nt dis c o nti n ue st u d y treat me nt (i nclisira n/ place b o) 
a n d t o be treate d as per l ocal sta n dar d of care, e. g. c o nsi deri n g L D L -a p heresis as ' ulti ma rati o'. 
T he partici pa nt wi ll re m ai n i n t he st u d y a n d will be f oll o we d-u p u ntil t he partici pa nt’s e n d of 
st u d y. 
6. 1. 2  
A d diti o n al st u d y tr e at m e nt s  
R os u vastati n is re gar de d as a n A u xiliar y Me dici nal Pr o d uct ( A x M P) acc or di n g t o t he E U 
Cli nical Trial Re g ulati o n ( E U C T R) refer t o Ta bl e  6 -2 . 
T a bl e 6 -2  
A u xilli ar y M e di ci n al Pr o d u ct s  
Tr e at m e nt Titl e  
R o s u v a st ati n  
Tr e at m e nt D e s cri pti o n  
R o s u v a st ati n, 5 m g, 1 0 m g, 2 0 m g, 4 0 m g*  
T y p e  
Dr u g  
D o s e F or m ul ati o n  
T a bl et  
U nit D o s e Str e n gt h( s)  
R o s u v a st ati n, 5 m g, 1 0 m g, 2 0 m g, 4 0 m g*  
D o s a g e L e v el( s)  
D o s a g e a n d fr e q u e n c y t o b e d et er mi n e d b y t h e 
i n v e sti g at or a s p er l o c al r e g ul ati o n s  
R o ut e of A d mi ni str ati o n  
Or al u s e  
U s e  
B a c k gr o u n d i nt er v e nti o n  
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  
S o ur ci n g  
Pr o vi d e d l o c all y b y t h e c o u ntr y or st u d y sit e  
P a c k a gi n g a n d L a b eli n g  
W ill 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 
a n d l o c al r e g ul ati o n s . 
* a s c o m m er ci all y a v ail a bl e
At baseli ne, all partici pa nts will be s witc he d fr o m t heir i n di vi d ual stati n t o r os u vastati n wit h a 
starti n g d ose of 5 m g/ da y or 1 0  m g/ da y acc or di n g t o t he l ocal S m P C a n d at t he discreti o n of t he 
I n v esti gat or. Partici p a nts w h o are alr ea d y tr eate d wit h r os u vastati n pri or t o bas eli ne will 
c o nti n ue treat me nt wit h t heir i n di vi d ual 
M T D of r os u vastati n at t he discreti o n of t he 
I n v esti gat or. 
C CI

N o v arti s  
C o nfi d e nti al  
P a g e  5 1  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
I n a d diti o n t o t he treat me nt wit h i nclisira n/ place b o, r os u vastati n s h o ul d be se q ue ntiall y titrate d 
t o t he M T D, if a partici p a nt’s i n di vi d ual L D L-C is n ot at tar get (refer t o Secti o n  3. 4 ). 
6. 1. 3  
Tr e at m e nt ar m s/ gr o u p  
Partici pa nts will be ra n d o mize d  at t he bas eli ne visit ( Da y 1) t o o ne of t he f oll o wi n g t w o d o u ble -
bli n d treat me nt gr o u ps i n a 1: 1 rati o.  
a. I n clisira n s o di u m 3 0 0 m g s.c.  
b.  C orres p o n di n g place b o  
Eac h partici pa nt will recei ve o ne i njecti o n of bli n de d i nclisira n  or pl ace b o o n Da y  1, a sec o n d 
i njecti o n of bli n de d i nclisira n or place b o o n Da y 9 0 a n d a s u bse q ue nt i njecti o n of bli n de d 
i nclisira n or place b o o n Da y 2 7 0, u nless t here is a nee d f or disc o nti n ui n g i nclisira n/ place b o i n 
t he c o urse of t h e st u d y (refer t o Secti o n  3. 4  a n d Secti o n 1 0. 2 ). 
I n a d diti o n at Da y 1, eac h p artici pa nt will be s witc he d t o o pe n la bel st u d y treat me nt, 
r os u vastati n, a n d recei v e o ne d ose of r os u vastati n e ver y day fr o m Da y 1 t o Da y 3 6 0 d uri n g t he 
treat me nt peri o d, as per i n di vi d ual titrati o n, u nless t here is a n ee d f or disc o nti n ui n g r os u vastati n 
i n t he c o urse of t he st u d y (refer t o Secti o n  3. 4  a n d Secti o n 1 0. 2  ). 
6. 1. 4  
Tr e at m e nt d ur ati o n  
Partici pa nts w h o c o m plet e partici pati o n i n t his trial a n d c o nti n ue t o d eri ve cli nical be nefit fr o m 
t he st u d y treat me nt bas e d o n t he i n vesti gat or’s e val uati o n ma y recei ve p ost-trial access. P ost-
Trial Access  ( P T A) mea ns t he pr o visi o n of st u d y treat me nt t o trial p artici p a nts f oll o wi n g t heir 
c o m pleti o n of trial partici pati o n. P T A will be pr o vi de d u ntil o ne of t he f oll o wi n g is met: 
partici pa nt n o l o n ger deri ves cli nical be nefit, i n vesti gat or disc o nti n ues st u d y t reat me nt, la u nc h 
or rei m b urs e me nt ( w h ere a p plica ble), 
 
. 
T he P T A mec ha nis m m ust c o m pl y wit h l ocal la ws a n d re g ulati o ns i n t he partici pati n g trial 
c o u ntries. If N o v artis disc o nti n ues t he P T A f or t his trial, N o vartis will w or k wit h i n vesti gat ors 
t o tra nsiti o n partici pa nts o nt o l ocall y a vaila ble alt er nati ve tr eat me nt, or sta n dar d of care. 
T he pla n ne d st u d y treat me nt d urat i o n is 3 6 0 da ys. I n a d diti o n, a safet y f oll o w -u p call will be 
c o n d ucte d 3 0  da ys after t he E O S visit.  
Partici pa nts ma y be disc o nti n ue d fr o m t he trial earlier d ue t o safet y reas o ns, at t he discreti o n of 
t he I n vesti gat or or t he partici pa nt. T he y will c o nti n ue t o be f oll o w e d u p i n t h e st u d y u ntil safet y 
rec o ver y or u ntil E O S as per Assess me nt Sc he d ul e (Ta ble  8 -1 ). 
6. 2  
Ot h er tr e at m e nt( s)  
6. 2. 1  
C o n c o mit a nt t h er a p y  
L L T use d b y t he partici pa nt i n t he 6 m o nt hs pri or t o scree ni n g m ust b e rec or de d o n t he 
a p pr o priate e C R F pa g es.  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e  5 2  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
All ot her me dicati o ns, pr oce d ures, a n d  si g nifica nt n o n -dr u g t hera pies (i ncl u di n g p h ysical 
t hera p y a n d bl o o d tr a nsf usi o ns) use d b y t he p artici pa nt i n t he 3  m o nt hs pri or t o  scree ni n g m ust 
be rec or de d o n t he a p pr o priate e C R F pa g e s, i n de pe n de nt of w het her t he y will be c o nti n ue d 
d uri n g t he st u d y or n ot. Eac h c o nc o mita nt dr u g m ust be i n di vi d uall y assesse d a g ai nst all 
e xcl usi o n criteria.  
C o n c o mit a nt li pi d -l o w eri n g t h er a p y 
I n a d diti o n t o t he treat me nt wit h i nclisira n/ place b o a n d M T D of  r os u vastati n, a partici pa nt’s 
i n di vi d ual L L T has t o be f urt her escalate d t hr o u g h o ut t he trial, if L D L-C is n ot at tar get. T he 
partici pa nt’s i n di vi d ual 
L L T 
s h o ul d 
be 
c o m ple me nte d 
wit h 
ezeti mi be ( g ui deli ne 
rec o m me n dati o n Class I, Le vel B). If t he L D L-C t ar g et is still n ot ac hie ve d, c o nsi der use of bile 
aci d se q uestr a nts ( g ui deli ne rec o m me n d ati o n Class II b, Le v el C) ( M ac h  et al 2 0 2 0 ). Rece ntl y 
a p pr o ve d be m pe d oic aci d ma y als o be c o nsi dere d t o be use d, h o we v er, it is n ot de picte d i n t h e 
c urre nt g ui deli nes a n d s h o ul d t h us be use d sec o n daril y after t he af ore me nti o ne d s u bsta nces f or 
f urt her escalati o n of L L T. C o nc o mita nt P C S K 9 m A b ca n be c o nsi dere d if a partici p a nt is 
dee me d eli gi ble b y t he Steeri n g C o m mittee. If t he partici pa n t is dee me d eli gi ble f or P C S K 9 
m A b treat me nt, t he n t he bli n de d i n vesti gati o nal treat me nt (i nclisira n/ place b o) will nee d t o be 
disc o nti n ue d. T he I n vesti gat or's treat me nt decisi o n as well as de viati o n fr o m t he a b o ve 
rec o m me n de d L L T escalati o n nee d t o be well d oc u me nte d o n t he a p pr o pri ate e C R F pa ges. ( See 
Fi g ure  3 -2 ) 
A ne w c o nc o mita nt li pi d -l o weri n g dr u g m ust be assesse d a gai nst all pr o hi bite d me dicati o ns 
pri or t o its i nitiati o n.  
Ot h er c o n c o mit a nt t h er a p y  
All ot her me dicati o n, pr oce d ures, a n d si g nifica nt n o n -dr u g t hera pies (i ncl u di n g p h ysical 
t hera p y a n d bl o o d tra nsf usi o ns) a d mi nistere d after t he partici pa nt was e nr olle d i nt o t he st u d y 
m ust be rec or de d o n t he a p pr o priate e C R F p a ges. A ne w c o n c o mita nt dr u g m ust be ass ess e d 
a gai nst all pr o hi bite d me dicati o ns pri or t o its i nitiati o n.  
If i n d o u bt, t he I n v esti gat or s h o ul d c o ntact t h e 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 p artici 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  
C o nc o mita nt use of S A R S -C o V -2 ( C O VI D -1 9) v acci nes is all o we d a m o n g partici pa nts i n t his 
trial. T here is n o e vi de n ce t o s u g gest t hat partici pa nts recei vi n g eit her i nclisira n/ place b o or 
r os u vastati n are at i ncrease d ris k f or a d verse e ve nts f oll o wi n g a C O VI D-1 9 v acci n ati o n. 
H o we ver, si nce 
b ot h i nclisira n/ place b o 
a n d 
C O VI D -1 9 
v acci nes are 
a d mi nistere d 
s u bc uta ne o usl y, it is rec o m me n de d t hat t he C O VI D -1 9 vacci ne is a d mi nistere d +/ - 7 da ys fr o m 
i nclisira n/ place b o a d mi nistrati o n. F urt her, it is rec o m me n de d t h at a differe nt a nat o mical 
l ocati o n is use d f or C O VI D-1 9 v acci ne a n d i nclisira n/ place b o t o hel p differe ntia te p ote ntial 

N o v arti s  
C o nfi d e nti al  
P a g e  5 3  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
l ocal a d verse reacti o ns. B ot h C O VI D-1 9 v acci nati o n a d mi nistrati o ns t hat occ ur pri or t o 
e nteri n g t he st u d y, a n d d uri n g t he c o urse of t his st u d y s h o ul d be d oc u me nte d o n t he e C R F.  
R os u vastati n is a s u bstrate of vari o us tr a ns p orter pr otei ns (e. g. O A T P 1 B 1 a n d B C R P). T he ris k 
of m y o pat h y (i ncl u di n g r ha b d o m y ol ysis) is i ncreas e d w he n r os u vastati n is a d mi nistere d 
c o nc o mita ntl y wit h certai n me dici nal pr o d ucts t hat ma y i ncrease t he plas ma c o nce ntr ati o n of 
r os u vastati n d ue t o i nteracti o ns wit h t hese tra ns porter pr otei ns (e. g. cicl os p ori n a n d certai n 
pr otease i n hi bit ors i ncl u di n g c o m bi nati o ns of rit o na vir wit h ataza na vir, l o pi na vir, a n d/ or 
ti pra na vir; please refer t o l ocal r os u vastati n S m P C f or f ull details). 
W he ne v er p ossi ble, 
alter nati ve 
me dicati o ns s h o ul d  be c o nsi dere d, a n d, if necessar y, c o nsi der te m p oraril y 
disc o nti n ui n g r os u vastati n t hera p y. I n sit uati o ns w here c o -a d mi nistrati o n of t hese me dici nal 
pr o d ucts wit h r os u vastati n is u na v oi da ble, t he be n efit a n d t he ris k of c o nc urre nt treat me nt a n d 
r os u vastatin d osi n g a dj ust me nts s h o ul d be caref ull y c o nsi dere d.  
Ot her c o -me dicati o n i ncreasi n g t he i n ci de nce of m y ositis, m y o pat h y or r ha b d o m y ol ysis 
i ncl u di n g fi bric aci d deri vati ves, nic oti nic aci d, az ole a ntif u n gals, pr otease i n hi bit ors, macr oli de 
a nti bi otics a n d ezeti mi be s h o ul d be use d wit h ca uti o n.  
T he i nitiati o n of treat me nt or d osa ge u p -titrati o n of r os u vastati n i n partici pa nts treate d 
c o nc o mita ntl y wit h vita mi n K a nta g o nists (e. g. warfari n or a n ot her c o u mari n a ntic oa g ula nt) 
ma y res ult i n a n i ncrease i n I nter nati o nal N or malize d Rati o (I N R).  
Oral c o ntrace pti ve: C o nc o mita nt use of r os u vastati n a n d a n oral c o ntrace pti ve res ulte d i n a n 
i ncreas e i n et hi n yl estra di ol a n d n or gestrel. T hese i ncreas e d plas ma le vels s h o ul d be c o nsi dere d 
w he n selecti n g oral c o ntrace pti ve  d oses.  
Please al wa ys refer t o t he l ocal r os u vastati n S m P C.  
6. 2. 2  
Pr o hi bit e d m e di c ati o n  
T he si m ulta ne o us a d mi nistrati o n of t he bli n de d i n vesti gati o nal treat me nt, i nclisira n/ place b o, 
a n d P C S K 9 m A b, 
, is pr o hi bite d.  
I n cas e a P C S K 9 m A b is pla n ne d t o be a d mi nistere d, eit her base d o n t he eli gi bilit y assess me nt 
b y t he Steeri n g C o m mittee or bas e d o n t he i n vesti gat or's decisi o n t o treat as per l ocal sta n dar d 
of care, bli n de d i n vesti gati o nal treat me nt (i nclisira n/ place b o), as o utli ne d i n Secti o n  3. 4  a n d 
Secti o n  6. 1. 1  m ust be disc o nti n ue d.  
T a bl e 6 -3  
Pr o hi bit e d m e di c ati o n   
M e di c ati o n  
Pr o hi biti o n 
p eri o d  
A cti o n t a k e n   
A n y i n v e sti g ati o n al pr o d u ct  
F ull st u d y 
d ur ati o n  
Di s c o n ti n u e all st u d y 
tr e at m e nt  
L o mit a pi d e  
F ull st u d y 
d ur ati o n  
Di s c o nti n u e all st u d y 
tr e at m e nt 
Mi p o m er s e n  
F ull st u d y 
d ur ati o n  
Di s c o nti n u e all st u d y 
tr e at m e nt 
Ni a ci n  
F ull st u d y 
d ur ati o n  
Di s c o nti n u e all st u d y 
tr e at m e nt 
C CI

N o v arti s  
C o nfi d e nti al  
P a g e  5 4  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
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   
G e mfi br o zil  
F ull st u d y 
d ur ati o n  
Di s c o nti n u e all st u d y 
tr e at m e nt 
F oll o wi n g m e di c ati o n s ar e c o ntr ai n di c at e d t o r e c ei v e 
c o n c o mit a ntl y wit h r o s u v a st ati n  
 
 
•  
s of o s b u vir/ v el p at a s vir/ v o xil a pr e vir  
F ull st u d y 
d ur ati o n  
Di s c o nti n u e all st u d y 
tr e at m e nt 
•  
ci cl o s p ori n  
F ull st u d y 
d ur ati o n  
Di s c o nti n u e all st u d y 
tr e at m e nt 
Pr e c a uti o n s a n d w ar ni n g s:  
R os u vastati n m ust n ot be c o -a d mi nistere d wit h s yste mic f or m ulati o ns of f usi dic aci d or wit hi n 
7 da ys of st o p pi n g f usi dic aci d tr eat me nt. I n p atie nts w here t he us e of s yst e mic f usi dic aci d is 
c o nsi dere d esse ntial, stati n treat me nt s h o ul d be dis c o nti n ue d t hr o u g h o ut t he d urati o n of f usi dic 
aci d treat me nt. R os u vast ati n t hera p y ma y b e re -i ntr o d uce d 7 da ys after t he last f usi dic aci d. I n 
e xce pti o nal cir c u msta nces, w here pr ol o n g e d s yste mic f usi dic ac i d is nee de d, e. g. f or t he 
treat me nt of se vere i nfecti o ns, t he nee d f or c o-a d mi nistrati o n of r os u vastati n a n d f usi dic aci d 
s h o ul d o nl y be c o nsi dere d o n a case b y cas e basis a n d u n der cl os e me dical s u per visi o n.  
T he 4 0 m g d ose of r os u v astati n is als o c o ntrai n dicate d i n patie nts wit h pre -dis p osi n g fact ors f or 
m y o pat h y/ r ha b d o m y ol ysis, i ncl u di n g c o nc o mita nt use of fi brates.  
6. 2. 3  
R e s c u e m e di c ati o n  
N ot a p plica ble f or t he bli n de d i n vesti gati o nal treat me nt, i nclisira n/ place b o. F or t he o pe n la bel 
st u d y treat me nt, r os u vast ati n, please al w a ys refer t o t he l ocal S m P C. 
6. 3  
Pr e p ar ati o n a n d di s p e n s ati o n  
Bli n de d i n vesti gati o nal treat me nt, i nclisira n/ place b o:  
•  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 i n Secti o n  6. 1. 1 . 
•  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.  
•  I n v esti 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 a n d o btai ni n g t he 
me dicati o n n u m ber(s ). St u d y 
me dicati o n 
(i nclisira n/ placeb o) acc o u nta bilit y a n d rec o nciliati o n data are rec or de d i n t he I R T s yste m. 
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 p ac ka gi n g a n d affi x it t o t he s o urce d oc u m e nt 
O pe n la bel st u d y treat me nt r os u vastati n:  
•  C o m merciall y a vaila ble r os u vastati n will be s o urce d l ocall y a n d s u p p orte d b y t he s p o ns or.  

N o v arti s  
C o nfi d e nti al  
P a g e  5 5  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
6. 3. 1  
H a n dli n g of st u d y tr e at m e nt a n d ot h er tr e at m e nt  
6. 3. 1. 1  
H a n dli n g o f st u d y tr e at m e nt 
Bli n de d i n vesti gati o nal tr eat me nt, i nclisira n/ place b o, m ust be recei ve d b y a desi g nat e d pers o n 
at t he st u d y site, ha n dle d, st ore d a n d ke pt safel y a n d pr o perl y  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 t he desi g nat e d site p e rs o n nel ha ve access. U p o n recei pt, all st u d y 
treat me nt m ust be st ore d acc or di n g t o t he i nstr ucti o ns s pecifie d o n t he la b els. 
F or o pe n la bel st u d y treat me nt, r os u vastati n, t he a b o ve is als o a p plica ble w he n st ore d at t he site. 
I n case r os u vastati n is s u p plied b y a n ot h er facilit y, e. g. l ocal p har m ac y, it nee ds t o b e e ns ure d 
all pr ocesses re gar di n g t he pr o per ha n dli n g of t he o pe n la bel st u d y me dicati o n are f oll o we d.  
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 nt s 
are t o be re p orte d t o t he res pecti ve N o vartis C o u ntr y Or ga nizati o n Q ualit y Ass ura nce.  
Me dicati o n la bels will be writte n i n t he l ocal la n g ua ge a n d will c o m pl y wit h t he le gal 
re q uire me nts of eac h c o u ntr y. La bel i nf or mati o n will i ncl u de t he st ora ge st u d y treat me nt 
c o n diti o ns. 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 will be 
discl ose d.  
F or o pe n la bel st u d y treat me nt, r os u vastati n, t hat is a d mi nistere d at h o me, partici pa nts will be 
as ke d t o -bri n g all use d/ u n use d st u d y treat me nt a n d its pac ka gi n g at eac h st u d y visit.  
T he i n vesti gat or m ust mai ntai n a n acc urat e rec or d of t he s hi p me nt a n d dis pe nsi n g of all st u d y 
treat me nt (i ncl u di n g o pe n la bel st u d y treat me nt, r os u vastati n) i n a dr u g acc o u nta bilit y l o g. 
M o nit ori n g of t he d r u g acc o u nta bilit y of b ot h of t he st u d y treat me nts, bli n de d i nclisira n/ place b o 
a n d o pe n la bel r os u vastati n, will be perf or m e d b y fiel d m o nit ors d uri n g site or re m ote visits, 
a n d at t he c o m pleti o n of t he trial, as descri be d i n t he M o nit ori n g Pla n.  
T he site ma y destr o y a n d d oc u me nt t he 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 pri ate 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 us e d bli n de d i n vesti gati o nal 
treat me nt, pac ka gi n g, dr u g la bels, a n d a c o p y of t he c o m plete d dr u g acc o u nta bilit y l o g t o t he 
N o vartis m o nit or or t o t he N o vartis a d dress pr o vi de d i n t he i n vesti gat or f ol der at eac h site.  
6. 3. 1. 2  
H a n dli n g of ot h er tr e at m e nt  
T he f oll o wi n g n o n -st u d y treat me nts ha ve t o be m o nit ore d s pecificall y, as descri be d i n t he 
M o nit ori n g Pla n:  
•  All li pi d -l o weri n g t hera pies 
6. 3. 2  
I n str u cti o n s f or pr e s cri bi n g a n d t a ki n g st u d y tr e at m e nt 
Bli n de d i n vesti gati o nal treat me nt, i nclisira n/ place b o, will n ot be dis pe nse d t o t h e partici pa nts. 
St u d y dr u g i njecti o ns will be perf or me d e x cl usi vel y at t he st u d y site b y q ualifie d cli nical st u d y 
site staff u n der t he s u p er visi o n of t he i n vesti gat or or desi g nee. 

N o v arti s  
C o nfi d e nti al  
P a g e  5 6  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
T he preferre d site of i njecti o n is t he a b d o me n. Alter nati ve i njecti o n sites i ncl u de t he u p per ar m 
or t hi g h. I njecti o ns s h o ul d n ot be d o ne i nt o areas of acti ve s ki n disease or i nj ur y s uc h as 
s u n b ur ns, s ki n ras hes, i nfla m mati o n, tatt o os or s ki n i nfecti o ns. 
Partici pa nts will be a d mi nistere d o ne s u bc uta ne o us i njecti o n of bli n de d i n vesti gati o nal 
treat me nt, i nclisira n/ place b o, at pre-d efi ne d visits, as s pecifie d i n t he Sc he d ule 
Visit 
(Ta ble  8 -1 ). 
I nje cti o ns will be a d mi nistere d aft er all ot her st u d y assess me nts ha ve bee n c o m plete d f or t he 
visi t. 
Bli n de d  i n vesti gati o nal treat me nt, i nclisira n/ place b o, assi g ne d b y t he I R T will be rec or de d i n 
t he 
I R T 
s yste m. 
All 
i njecti o ns 
t o 
t he 
partici pa nt 
as 
well 
as 
st u d y 
dr u g 
i nterr u pti o ns/ disc o nti n uati o ns (i.e. n o i njecti o n at a d esi g nate d d osi n g visit) d uri n g t he st u d y 
m ust be rec or de d o n a n a p pr o priate e C R F a n d wit hi n I R T.  
O pe n la bel st u d y tr eat m e nt, r os u vastati n, will be c o m merciall y s o urce d l ocall y. R os u vastati n 
s h o ul d be ta ke n b y t he p artici pa nt at a cert ai n d ose le vel a n d ti me of da y as i nstr ucte d b y t he 
i n vesti gat or a n d acc or di n g t o t he l ocal S m P C. Dr u g rec o n ciliati o n of o p e n l a bel st u d y tr eat me nt, 
r os u vastati n, nee ds t o be perf or me d a n d d oc u me nt e d t o ca pt ure t h e dis pe nsi n g a n d dail y i nta k e 
of r os u vastati n o n parti ci pa nt le vel. R os u vast ati n dis pe nsi n g or acc o u nt a bilit y will n ot be 
ca pt ure d 
wit hi n I R T. F or t his reas o n, it is i m p orta nt t hat a n y dr u g i nterr u pti o ns, or 
disc o nti n uati o ns f or r os u vastati n d uri n g t he st u d y be rec or de d i n t he e C R F.  
6. 4  
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. 4. 1  
P arti ci p a nt n u m b eri n g  
Eac h p artici pa nt is i de ntifie d i n t he st u d y b y a P artici pa nt N u m b er ( 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 p artici pa nt is re-s cree 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 x e 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 b ase. U p o n si g ni n g t he I C F, t he p artici pa nt is assi g ne d t o t he n e xt 
se q ue ntial Partici pa nt N o. a vaila ble. 
6. 4. 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 scree ni n g, t he i n v esti gat or or his/ her dele gate will c o ntact t he I nteracti ve R es p o nse 
Tec h n ol o g y (I R T) a n d rec or d t he c urre nt stati n a n d L L T, if a p plica bl e, i n t he s yste m i n or der 
t o ma na ge t he p o p ulati o n acc or di n g t o eli gi bilit y criteria. O nce t he partici pa nt's f ull eli gi bilit y 
has bee n c o nfir me d, t he i n vesti gat or or his/ her d el e gate will i n dicate i n I R T a n d e C R F i n w hic h 
s u bse q ue nt peri o d t he partici pa nt will be assi g ne d (r u n-i n or treat me nt peri o d). 
T he i n vesti gat or or his/ h er dele g ate will c o ntact t he I R T a gai n at t he ba s eli ne/ra n d o mizati o n 
visit ( Da y  1). All eli gi ble partici pa nts will be ra n d o mize d via I R T t o o ne of t he t w o tr eat me nt 
ar ms. T he I R T will assi g n a ra n d o mizati o n n u m ber t o t he partici pa nt, w hic h will be use d t o li n k 

N o v arti s  
C o nfi d e nti al  
P a g e  5 7  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
t he partici pa nt t o a treat me nt ar m 1: 1 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 g e of bli n de d i n vesti gati o nal treat me nt, i nclisira n or place b o, t o be assi g ne 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 I R T pr o vi der, or b y a dele gate u n der 
N o vartis/ S p o ns or  s u per visi o n, 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 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. 
Ra n d o mizati o n will be stratifie d b y  car di o vasc ular ris k cate g or y as o utli ne d i n t he 2 0 1 9 
E S C/ E A S g ui deli nes f or t he ma na ge m e n t of d ysli pi de mia (Mac h  et al 2 0 2 0 ) a n d defi ne d i n t h e 
i ncl usi o n criteri o n a) v er y hi g h ris k  partici pa nt a n d b) hi g h ris k partici pa 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. 5  
Tr e at m e nt bli n di n g  
Partici pa nts, i n vesti gat or staff, pers o ns p erf or mi n g t he assess me nts a n d t he N o vartis trial tea m 
will re mai n bli n de d t o t he i de ntit y of t he treat me nt (i nclisira n/ place b o) fr o m t he ti me of 
ra n d o mizati o n u ntil data base l oc k, usi n g t he f oll o wi n g met h o ds: ( 1) Ra n d o mizati o n data are 
ke pt strictl y c o nfi de ntial u ntil t he ti me of u n bli n di n g. T he i n de pe n de nt statisticia n a n d 
pr o gra m mer will n ot be i n v ol ve d i n a n y ot her trial acti vities. ( 2) T he treat me nt i de ntit y will be 
c o nceale d b y usi n g i de ntical pac ka gi n g, la belli n g, sc he d ule of a d mi nistrati o n a n d a p peara nce 
of t he bli n de d i n vesti gati o nal treat me nt.  
U n bli n di n g via ra n d o mizati o n c o des will o nl y occ ur i n t he case of partici pa nt e mer ge ncies a n d 
after t he e n d of t he st u d y. U n bli n di n g a si n gle partici pa nt at a site b y re veali n g t he 
ra n d o mizati o n c o de f or s afet y reas o ns ( necess ar y f or partici pa nt ma na ge me nt) will occ ur via a n 
e mer ge n c y s yste m i n place at t he site. As a res ult,  t he partici pa nt s h o ul d be disc o nti n ue d fr o m 
t he bli n de d i n vesti gati o nal treat me nt, i nclisira n/ pl ace b o.  
T he r os u vastati n d ose  will n ot be bli n de d.  
6. 6  
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  
Bli n de d i n vesti gati o nal treat me nt, i nclisira n/ place b o, d ose a dj ust me nts are n ot per mitte d, f or 
i nterr u pti o ns, please refer t o Secti o n  9. 1. 1 .  
F or o pe n la b el st u d y treat me nt, r os u vastati n, d ose a dj ust me nts please refer t o Secti o n  3. 4  a n d 
Secti o n 6. 6. 2 . F or r os u vastati n d ose i nterr u pti o ns please refer t o Secti o n 9. 1. 1  a n d Secti o n 1 0. 2 . 
6. 6. 1  
D o s e e s c al ati o n g ui d eli n e s  
D ose a dj ust me nts of bli n de d i n vesti gati o nal treat me nt, i nclisira n/ place b o, are n ot per mitte d. 
F or o pe n l a bel st u d y treat me nt, r os u vastati n, d ose a dj ust me nts please refer t o Secti o n  3. 4 .  

N o v arti s  
C o nfi d e nti al  
P a g e  5 8  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
6. 6. 1. 1  
St arti n g d o s e  
N ot a p plica ble f or bli n de d i n vesti gati o nal treat me nt,  i nclisira n/ place b o. 
At t he baseli ne visit ( Da y 1), all partici pa nts will be s witc he d fr o m t heir i n di vi d ual stati n t o 
o pe n la bel st u d y treat me nt, r os u vastati n. Partici pa nts ca n start r os u vastati n tr eat me nt eit her wit h 
5  m g/ da y or 1 0  m g/ da y acc or di n g t o t he l ocal S m P C.  
Start d ose of 5 m g/ da y is rec o m me n de d i n p atie nts:  
•  7 0 years  
•  wit h m o derate re nal i m pair me nt ( creati ni ne cl eara nce < 6 0 m L/ mi n)  
•  of Asia n a ncestr y  
•  wit h pre dis p osi n g fact ors t o m y o pat h y.  
C o nsi deri n g t he l ocal S m P C, r os u vastati n starti n g d ose will be c h ose n f or a p artic ular 
partici pa nt b y t he i n v esti gat or. Partici pa nts alr ea d y treate d wit h r os u vastati n pri or baseli ne visit 
will c o nti n ue treat me nt wit h t heir i n di vi d ual M T D of r os u vastati n, if i n acc or da n ce wit h t he 
i n vesti gat or. 
R os u vastati n s h o ul d be u se d wit h ca uti o n i n partici pa nts wit h pre-dis p osi n g fact ors f or 
m y o pat h y/r ha b d o m y ol ysis. S uc h fact ors i ncl u de:  
•  re nal i m pair me nt (s e vere re nal i m pair me nt is a n e xcl usi o n criteri o n (Secti o n 5. 2 )) 
•  h y p ot h yr oi dis m  
•  pers o nal or fa mi l y hist or y of here ditar y m usc ular dis or ders 
•  pre vi o us hist or y m usc ular t o xicit y wit h a n ot her H M G -C o A re d uct ase i n hi bit or or fi brate  
•  alc o h ol a b use  
•  a ge > 7 0 y ears  
•  sit uati o ns w here a n i ncrease i n plas ma le vels ma y occ ur 
•  c o nc o mita nt use of fi br at es.  
6. 6. 1. 2  
Pr o vi si o n al  d o s e l e v el s  
D uri n g visits at Da y 3 0, Da y 6 0 a n d Da y 9 0, o pe n la bel st u d y treat me nt, r os u vastati n, will be 
se q ue ntiall y titrate d e ver y 3 0 da ys u ntil t he partici pa nt’s i n di vi d ual L D L -C is at tar get or u ntil 
t he partici pa nt ac hi e ves t he M T D of r os u vastati n, w hic he ver occ urs first. F or M T D d efi niti o n 
please refer t o Secti o n  3. 4 . 
D ose a dj ust me nts ha ve t o f oll o w t he l ocal S m P C, a n d rec o m me n de d titrati o n ste ps f or 
r os u vastati n are 5 m g/ d a y, 1 0  m g/ da y, 2 0  m g/ da y, a n d u p t o a ma xi m u m d ose le vel of 
4 0  m g/ da y, if i n dicate d. I n case r os u vastati n is n ot o pti mall y titrate d b y Da y  9 0, t here is a n 
o pti o nal visit at Da y 1 2 0 f or f urt her o pti mizi n g r os u vastati n d ose.  
6. 6. 2  
D efi niti o n s of d o s e li miti n g t o xi citi e s ( D L T s)  
D L Ts are n ot a p plica ble f or bli n de d i n vesti gati o nal treat me nt, i nclisira n/ pl ace b o.  

N o v arti s  
C o nfi d e nti al  
P a g e  5 9  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
F or o pe n l a bel st u d y treat me nt, r os u vastati n, pleas e refer t o Secti o n 1 0. 2  a n d l ocal S m P C.  
6. 6. 3  
D o s e m o difi c ati o n s  
Bli n de d i n vesti gati o nal treat me nt, i nclisi ra n/ place b o, d ose a dj ust me nts a n d m o dificati o ns are 
n ot per mitte d t hr o u g h o ut t he trial.  
F or o pe n la b el st u d y treat me nt, r os u vastati n, d ose a dj ust me nts please refer t o Secti o n  3. 4  a n d 
Secti o n 1 0. 2 . 
T he 4 0 m g r os u vastati n d ose is c o ntrai n dicat e d i n partici pa nts wit h pre -dis p osi n g fact ors f or 
m y o pat h y/r ha b d o m y ol ysis. S uc h fact ors i ncl u de:  
•  m o der ate re nal i m pair me nt (creati ni ne cleara nce < 6 0 m L/ mi n)  
•  h y p ot h yr oi dis m  
•  pers o nal or fa mil y of here ditar y m usc ular dis or d ers  
•  pre vi o us hist or y of m usc ular t o xicit y wit h a n ot her H M G -C o A re d u ctase i n hi bit or or 
fi brate 
•  alc o h ol a b use  
•  sit uati o ns w here a n i ncrease i n plas ma le vels ma y occ ur 
•  Asia n patie nts  
•  C o nc o mita nt use of fi brates.  
I n sit uati o ns w here c o-a d mi nistrati o n of me dici nal pr o d ucts ca usi n g a n i ncreas e i n s yste mic 
e x p os ure of r os u v astati n or i ncreas e d ris k of m y o p at h y is u na v oi da ble, t he ma xi m u m d ail y d ose 
of r os u vastati n s h o ul d be a dj uste d s o t hat t he e x pecte d r os u vastati n e x p os ure w o ul d n ot li kel y 
e xcee d t hat of a 4 0 m g d ail y d ose of r os u vastati n ta ke n wit h o ut i nteracti n g me dici nal pr o d ucts 
(al wa ys r efer t o l ocal r os u vastati n S m P C). 
Ge nerall y, r o s u vastati n s h o ul d be prescri be d wit h ca uti o n i n partici pa nts wit h pre-dis p osi n g 
fact ors f or m y o pat h y/r ha b d o m y ol ysis. 
Please n ote, s pecific t y p es of ge netic p ol y m or p his ms are k n o w n t hat ca n lea d t o a n i ncreas e d 
r os u vastati n e x p os ur e. F or p artici pa nts w h o are k n o w n t o ha v e s uc h s pecific t y pes of 
p ol y m or p his ms, a l o wer dail y d ose of r os u vastati n is rec o m me n de d.  
T he i nitiati o n of treat me nt or d osa ge u p -titrati o n of r os u vastati n i n partici pa nts treate d 
c o nc o mita ntl y wit h vita mi n K a nta g o nists (e. g., warfari n or a n ot her c o u mari n a ntic oa g ula nt) 
ma y res ult i n a n i ncrease i n I nter nati o nal N or mali ze d Rati o (I N R). Dis c o nti n uati o n or d o w n -
titrati o n of r os u vastati n ma y res ult i n a decreas e i n I N R. 
6. 6. 4  
F oll o w -u p f or t o xi citi e s  
N ot a p plica ble f or bli n de d i n vesti gati o nal treat m e nt, i nclisira n/ place b o. 
F or f oll o w -u p of t o xicities of o pe n la bel st u d y treat me nt, r os u vastati n, please refer t o  
Secti o n 1 0. 2 .  
All A Es will be f oll o we d u p a p pr o priatel y, see Secti o n  1 0. 1. 1 . 

N o v arti s  
C o nfi d e nti al  
P a g e  6 0  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
6. 7  
A d diti o n al tr e at m e nt g ui d a n c e  
6. 7. 1  
Tr e at m e nt c o m pli a n c e  
T he i n vesti gat or m ust pr o m ote c o m plia nce b y i nf or mi n g t he partici pa nt 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 a n d t he i nte grit y of t he st u d y. T he 
i n vesti gat or s h o ul d als o i nstr uct t he partici pa nt t o a d here cl osel y t o t h e sc h e d ule d st u d y visits. 
Bli n de d i n vesti gati o nal treat me nt,  i nclisira n/ place b o, will n ot be dis pe nse d t o t he partici pa nt 
b ut a d mi nistere d at desi g nate d st u d y visits at t he st u d y site, b y q ualifie d pers o n n el. 
I n clisira n/ place b o d osi n g i nf or mati o n s h o ul d be ca pt ure d wit hi n eac h desi g nate d visit o n a n 
a p pr o priate e C R F pa g e.  
F or o pe n la bel st u d y treat me nt,  r os u vastati n, 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 st ati 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 
treatme nt as pr escri be d.  
C o m plia nce f or o pe n la b el st u d y treat me nt, r os u vastati n, will be assesse d b y t he i n vesti gat or 
a n d/ or st u d y pers o n n el at eac h visit usi n g pill c o u nts a n d i nf or m ati o n pr o vi de d b y t h e 
partici pa nt. T his i nf or mati o n s h o ul d be ca pt ur e 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. 
All a d diti o nal L L T dis pe nse d m ust be rec or de d i n e C R F a n d c o m plia nce s h o ul d be i nstr ucte d 
acc or di n gl y.  
6. 7. 2  
R e c o m m e n d e d tr e at m e nt of a d v e r s e e v e nt s 
A Es s h o ul d be treate d acc or di n g t o l ocal practice a n d g ui deli nes, a n d is at t he discreti o n of t he 
i n vesti gat or a n d treati n g p h ysicia n. 
F or partici pa nts wit h i njecti o n site reacti o n, a nti hista mi nes, l ocal or s yste mic ster oi ds ca n be 
use d at t he i n vesti gat or’s discreti o n de pe n di n g o n t he se verit y of t he reacti o n.  
A Es relate d t o t he o pe n la bel st u d y treat me nt, r os u vastati n, s h o ul d be treate d i n refere nce t o t he 
res pecti ve l o cal S m P C. 
Me dicati o n use d t o treat A Es m ust be rec or de d o n a p pr o priate e C R F pa g e(s).  
6. 7. 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  
C o de brea ks m ust o nl y be u n derta k e n w he n it is re q uire d t o i n or der t o treat t he partici p a nt 
safel y. 
M ost of t he ti me, t he st u d y treat me nt disc o nti n uati o n a n d k n o wle d g e of t he p ossi ble treat me nt 
assi g n me nts are s uffi cie nt t o treat a st u d y partici pa nt w h o prese nts wit h a n e mer ge nc y 
c o n diti o n. E mer ge nc y treat me nt c o de brea ks are p erf or me d usi n g t h e I R T. 
W he n t he 
i n vesti gat or c o ntacts t he I R T s yste m t o brea k a tr eat me nt c o de f or a partici pa nt, he/s he m ust 
pr o vi de t he re q u este 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 n ecessit y t o brea k t h e 

N o v arti s  
C o nfi d e nti al  
P a g e  6 1  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
treat me nt c o de f or t he partici pa nt. T he i n vesti gat or 
will the n recei ve details of t h e 
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 h e 
st u d y tea m t hat t he c o de has bee n br o k e n. 
It is t h e i n vesti gat or’s res p o nsi bilit y t o e ns ure t hat t here is a de p e n da ble pr oce d ure i n place t o 
all o w access t o t he I R T/ c o de brea k car ds at a n y ti me i n case of e mer g e n c 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 on, oral a n d writte n i nf or mati o n t o t he partici pa nt m ust be pr o vi de d o n h o w t o c o ntact  
his/ her bac k u p i n cases of e mer ge n c y, or w he n he/s he is u na vaila ble, t o e ns ure t hat u n bli n di n g 
ca n be p erf or m e d at a n y ti me.  
After a n e mer g e nc y u n bli n di n g, bli n de d i n vesti gati o nal treat me nt, i nclisira n/ place b o, s h o ul d be 
per ma ne ntl y disc o nti n ue d. T he partici pa nt will c o nti n ue t o be f oll o we d u p i n t he st u d y u nless 
i nf or me d c o nse nt is wit h dra w n (Secti o n  9. 1. 1  a n d Secti o n  9. 1. 2 ) or u ntil partici pa nt E O S as per 
Assess me nt Sc he d ule ( T a ble  8 -1 ). 
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 p artici pa nt's re pres e ntati ve(s) gi ves c o nse nt (if all o we d 
acc or di n g t o l ocal re q uir e me nts), t he p artici pa nt m ust be i nf or me d a b o ut t h e st u d y t o t he e xte nt 
p ossi ble gi ve n his/ her le vel of u n d ersta n di n g. If t he partici p a nt is ca p a ble of d oi n g s o, he/s h e 
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 ns e nt 
d oc u me nt.   
I nf or me d c o nse nt m ust b e o btai ne d bef ore c o n d ucti n g a n y st u d y-s pecific pr oce d ures (e. g. all of 
t he pr oce d ures descri be d i n t he pr ot oc ol). T he pr ocess of o btai ni n g i nf or me d c o nse nt m ust be 
d oc u me nte d i n t he partici pa nt s o urce d o c u me nts.  
N o vartis  will pr o vi de t o i n vesti gat ors i n a se p arate d oc u me nt a pr o p ose d I C F t hat c o m plies wit h 
t he IC H E 6 G C P g ui deli nes a n d re g ulat or y re q uir e 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 g at 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.  
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 h e i n vesti gati o nal treat me nt ca n 
be f o u n d eit her i n t he I n v esti gat or's Br oc h ure (I B), or i n t he l ocal S m P C. 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 ur i n g t he st u d y as nee de d. A n y ne w i nf or m ati 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 will be c o m m u nicate d as a p pr o priate, f or e x a m ple, via a n i n vesti gat or 

N o v arti s  
C o nfi d e nti al  
P a g e  6 2  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
n otificati o n (I N) or a n a g gre gate s afet y fi n di n g. Ne w i nf or mati o n mi g ht re q uire a n u p date t o 
t he i nf or me d c o nse nt a n d t he n m ust be disc usse d wit h t he partici pa nt. 
T he f oll o wi n g i nf or me d c o nse nts are i n cl u de d i n t his st u d y:  
•  Mai n st u d y c o nse nt, w hic h als o i ncl u des:  
•  A s u bsecti o n t hat re q uires a se parate si g nat ure f or t he ‘ O pti o nal C o nse nt f or A d diti o nal 
Researc h’ t o all o w f ut ur e researc h o n dat a/sa m ples c ollecte d d uri n g t his st u d y.  
•  Pre g na nc y O ut c o mes Re p orti n g C o nse nt f or fe male partici pa nts.  
W o me n of c hil d beari n g p ote ntial m ust be i nf or m e d t hat ta ki n g t he st u d y treat me nt ma y i n v ol ve 
u n k n o w n  ris ks t o t he fet us if pre g na nc y were t o occ ur d uri n g t he st u d y a n d a gree t h at i n or der 
t o partici pate i n t he st u d y t he y m ust a d here t o t he c o ntrace pti o n re q uire m e nts. 
A c o p y of t he a p pr o ve d v ersi o n of all c o nse nt f or ms m ust be pr o vi de d t o N o vartis 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 d eclare d b y L ocal or Re gi o nal 
a ut h orities i.e. pa n de mic, e pi de mic or nat ural 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 m e 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 oc al Healt h A ut h orit y.  
G ui da nce iss ue d b y l o cal re g ulat or y b o di es o n t his as pect  pre vail a n d m ust b e i m ple me nte d a n d 
a p pr o priatel y d oc u me nt e 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 p ers o n o btai ni n g i nf or me d c o nse nt, etc.).  
D at a pr ot e cti o n  m e a s ur e s  
Partici pa nts will be assi g ne d a u ni q ue i d e ntifier. A n y partici pa nt rec or ds or datas ets t hat are 
tra nsferre d t o N o v artis  will c o ntai n t he i de ntifier o nl y; partici pa nt na mes or a n y i nf or mati o n 
w hic h w o ul d ma ke t he p artici pa nt i de ntifia ble will n ot be tra nsferre d.  
T he partici p a nt m ust be i n f or me d t hat his/ her pers o nal st u d y-relate d data will be use d 
b y  N o vartis  i n acc or da nce wit h l ocal data pr otecti o n la w. T he le vel of discl os ure m ust als o be 
e x plai ne d t o t he p artici p a nt w h o will be re q uir e d t o gi ve c o nse nt f or t heir data t o be use d as 
descr i be d i n t he i nf or me d c o nse nt 
T he partici pa nt m ust be i nf or me d t hat his/ her me dical rec or ds ma y be e x a mi ne d b y Cli nical 
Q ualit y Ass ura nce a u dit ors or ot her a ut h orize d pers o n nel a p p oi nte d b y  N o vartis, b y a p pr o priate 
I R B/I E C me m bers, a n d b y i ns pect ors fr o m reg ulat or y a ut h orities.  
N o vartis  has a p pr o priat e pr ocesses a n d p olicies i n place t o ha n dle pers o nal data breac hes 
acc or di n g t o a p plica ble pri vac y la ws.  

N o v arti s  
C o nfi d e nti al  
P a g e  6 3  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n  N o.  0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
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 w he n t he y are perf or me d. All 
data o btai ne d fr o m t h ese assess me nts 
m ust be s u p p orte d i n t he partici pa nt’s s o urce 
d oc u me ntati o n.  
Partici pa nts s h o ul d be see n f or all visits/assess me nts as o utl i 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 nat e d da y/ti me as p ossi ble. Misse d or resc h e 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 will b e f oll o we d-u p u ntil t he e n d of t he st u d y 
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 h eir c o ns e nt/ o p p ose t he us e 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 gr ee, 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 h e fi n al visit ( E O S) will be p erf 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 Es a n d 
c o nc o mita nt me dicati o ns n ot pre vi o usl y re p ort e d m ust be rec or de d o n t he e C R F.  
T he “ X” i n t he ta ble de n otes t he assess me nts t o be rec or de d i n t he cli nical data base or recei ve d 
electr o nicall y fr o m a ve n d or. T he “ S” i n t he ta ble de n otes t he assess me nts t hat are o nl y i n t he 
partici pa nt’s s o urce d oc u me nta ti o n a n d d o n ot nee d t o be rec or de d i n t he cli nical data bas e. 
P R O meas ure(s) are str o n gl y rec o m me n de d t o be c o m plete d bef ore a n y cli nical assess me nts 
are p erf or me d at a n y gi ve n visit ( wit h t he e xce pti o n of t he p ai n diar y w hic h s h o ul d be c o m plete d 
as describe d i n Secti o n 8. 5. 1. 2 ). 
Partici pa nts will ha ve t o c o m pl y wit h t he f oll o wi n g restricti o ns d uri n g t he st u d y:  
•  Faste d f or all visits wit h L D L -C assess me nt a n d assess me nt of ot her li pi d sa m ples.  
•  M ust refrai n fr o m u nacc ust o me d stre n u o us p h ysical e xercise f or 4 8 h o urs bef ore t h e 
scree ni n g a n d a n y st u d y visit u ntil t he d o u ble-bli n d treat me nt peri o d h as bee n c o m plete d.  
As per Secti o n  4. 6 , d uri n g a P u blic Healt h e mer ge nc y as d eclare d b y L ocal or Re gi o nal 
a ut h orities i.e. pa n de mic, e pi de mic or nat ural disaster t hat li mits or pre ve nts o n -site st u d y visits, 
alter nati ve met h o ds of pr o vi di n g c o nti n ui n g care ma y be i m ple me nte d b y t he i n vesti gat or as 
t he sit uati o n dictates. If all o wa ble b y a l ocal Healt h A ut h ority a n d de pe n di n g o n o perati o nal 
ca pa bilities, p h o ne calls, virt ual c o ntacts (e. g. tele c o ns ult) or visits b y site staff/ h o me n ursi n g 
staff t o t he partici pa nt´s h o me, ca n re place o n-site st u d y visits, f or t he d urati o n of t he disr u pti o n 
u ntil it is safe f or t he partici pa nt t o visit t he site a gai n.

N o v arti s  
C o nfi d e nti al  
P a g e  6 4  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
T a bl e 8 -1  
A s s e s s m e nt S c h e d ul e  
P eri o d  
S cr e e ni n g  
R u n -I n 
B a s eli n e  
Tr e at m e nt  
F oll o w -u p c all  
Vi sit N a m e  
S cr e e ni n g 1  
R u n -I n P eri o d2  
B a s eli n e 3  
Tr e at m e nt  
Pri or t o 
P C S K 9 m A b 
s wit c h 5  
U n s c h e d ul e d  E O T/ E O S 2 2  F oll o w -u p c all 
+ 3 0 d a y s  
D a y s  
-1 4 4 t o -1 3 0  -1 3 0  -1 0 0  -7 0  -4 0  -1 0  
1  
3 0  
6 0  
9 0  1 2 0 4  1 5 0  2 1 0  2 7 0  3 3 0  
U N S  
U N S  
3 6 0  
3 9 0  
I nf or m e d c o n s e nt 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I n cl u si o n / 
E x cl u si o n crit eri a  
X  
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
D e m o gr a p h y  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
M e di c al 
hi st or y/ c urr e nt 
m e di c al 
c o n diti o n s  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C V Di s e a s e, 
Al c o h ol a n d 
C O VI D -1 9 
V a c ci n ati o n 
Hi st or y  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
S m o ki n g st at u s  
X  
X  
X  
X  
X  
 
X  
X  
X  
X  
X 4  
X  
X  
X  
X  
 
 
 
 
( Ot h er) 
pri or/ c o n c o mit a nt 
m e di c ati o n s  
X  
X  
X  
X  
X  
 
X  
X  
X  
X  
X 4  
X  
X  
X  
X  
 
X  
X  
 
Pri or/ C o n c o mit a nt 
li pi d l o w eri n g 
t h er a pi e s (t y p e s 
a n d d o s e s)  
X  
X  
X  
X  
X  
 
X  
X  
X  
X  
X 4  
X  
X  
X  
X  
 
X  
X  
 
S ur gi c al/ m e di c al 
pr o c e d ur e s 6  
 
X  
X  
X  
X  
 
X  
X  
X  
X  
X 4  
X  
X  
X  
X  
 
X  
X  
 
Lif e st yl e  
i n str u cti o n s 
X  
X  
X  
X  
X  
 
X  
X  
X  
X  
X 4  
X  
X  
X  
X  
 
X  
X  
 
E nt er p ati e nt vi sit 
i nt o I R T 
X  
 
 
 
 
 
X  
X  
X  
X  
X 4  
X  
X  
X  
X  
 
X  
X  
 

N o v arti s  
C o nfi d e nti al  
P a g e  6 5  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
P eri o d  
S cr e e ni n g  
R u n -I n 
B a s eli n e  
Tr e at m e nt  
F oll o w -u p c all  
Vi sit N a m e  
S cr e e ni n g 1  
R u n -I n P eri o d2  
B a s eli n e 3  
Tr e at m e nt  
Pri or t o 
P C S K 9 m A b 
s wit c h 5  
U n s c h e d ul e d  E O T/ E O S 2 2  F oll o w -u p c all 
+ 3 0 d a y s  
D a y s  
-1 4 4 t o -1 3 0  -1 3 0  -1 0 0  -7 0  -4 0  -1 0  
1  
3 0  
6 0  
9 0  1 2 0 4  1 5 0  2 1 0  2 7 0  3 3 0  
U N S  
U N S  
3 6 0  
3 9 0  
R a n d o mi z ati o n  
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
Di s p e n s e 
i n cli sir a n/ pl a c e b o 
 
 
 
 
 
 
X  
 
 
X  
 
 
 
X  
 
 
 
 
 
Di s p e n s e 
r o s u v a st ati n 
 
 
 
 
 
 
X  
X  
X  
X  
X 4  
X  
X  
X  
X  
 
X  
 
 
R o s u v a st ati n 
c o m pli a n c e  
 
 
 
 
 
 
 
X  
X  
X  
X 4  
X  
X  
X  
X  
 
X  
X  
 
A E s/ S A E s  
X  
X  
X  
X  
X  
 
X  
X  
X  
X  
X 4  
X  
X  
X  
X  
 
X  
X  
S 7  
Pr e g n a n c y T e st 
( s er u m)8  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pr e g n a n c y T e st 
( uri n e)9  
 
X  
X  
X  
X  
 
X  
X  
X  
X  
X 4  
X  
X  
X  
X  
 
X  
X  
 
P h y si c al 
E x a mi n ati o n  
S 7  
 
 
 
 
 
S 7  
 
 
S 7  
 
 
 
S 7  
 
 
 
S 7  
 
B o d y H ei g ht  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
B o d y W ei g ht  
X  
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
Vit al Si g n s  
X  
 
 
X  
 
 
X  
X  
 
X  
 
X  
X  
X  
X  
 
X  
X  
 
F a sti n g L D L -C 
a s s e s s m e nt 1 0  
 
 
X  
X  
X  
 
 
X  
X  
X  
X 4  
X  
X  
X  
X  
 
X  
 
 
F a sti n g Li pi d 
Pr ofil e 1 1  
X  
 
 
 
 
X  
 
 
X  
X  
 
X  
 
 
X  
 
 
X  
 
F a sti n g L p( a) 1 2  
X  
 
 
 
 
X  
 
 
 
X  
 
 
 
 
 
 
 
X  
 
P C S K 9  l e v el s1 3  
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
X  
 
X  
 
Cli ni c al 
C h e mi str y 1 4  
X  
 
 
X  
 
X  
 
 
 
X  
 
X  
X  
X  
X  
 
 
X  
 
Li mit e d 
c h e mi str y 1 5  
 
X  
X  
 
X  
 
 
X  
X  
 
X 4  
 
 
 
 
 
X  
 
 

N o v arti s  
C o nfi d e nti al  
P a g e  6 6  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
P eri o d  
S cr e e ni n g  
R u n -I n 
B a s eli n e  
Tr e at m e nt  
F oll o w -u p c all  
Vi sit N a m e  
S cr e e ni n g 1  
R u n -I n P eri o d2  
B a s eli n e 3  
Tr e at m e nt  
Pri or t o 
P C S K 9 m A b 
s wit c h 5  
U n s c h e d ul e d  E O T/ E O S 2 2  F oll o w -u p c all 
+ 3 0 d a y s  
D a y s  
-1 4 4 t o -1 3 0  -1 3 0  -1 0 0  -7 0  -4 0  -1 0  
1  
3 0  
6 0  
9 0  1 2 0 4  1 5 0  2 1 0  2 7 0  3 3 0  
U N S  
U N S  
3 6 0  
3 9 0  
H e m at ol o g y 1 6  
X  
 
 
 
 
X  
 
 
 
 
 
X  
 
 
 
 
 
X  
 
Uri n a l y si s1 7  
X  
 
 
 
 
X  
 
 
 
 
 
X  
 
 
 
 
 
X  
 
P ai n Di ar y 1 8  
 
 
 
 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
X  
 
S F -B PI 1 9  
X  
 
 
 
 
 
X  
X  
X  
X  
X 4  
X  
X  
X  
X  
 
X  
X  
 
G S R S 1 9  
 
 
 
 
 
 
X  
X  
X  
X  
X 4  
X  
X  
X  
X  
 
X  
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S F -3 6 1 9  
X  
 
 
 
 
 
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X  
 
 
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X  
 
WI Q
1 9, 2 0  
 
 
 
 
 
 
X  
 
 
X  
 
 
 
 
 
 
 
X  
 
M a c N e w
1 9 , 2 1 
 
 
 
 
 
 
X  
 
 
X  
 
 
 
 
 
 
 
X  
 
T S Q M 1 9  
 
 
 
 
 
 
X  
 
 
X  
 
 
 
 
 
 
 
X  
 
S af et y F o ll o w u p 
C all  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
S 7  
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  
1  C e ntr al L a b r e s ult s will b e n e e d e d t o c o nfir m eli gi bilit y at t h e s cr e e ni n g vi sit.  
2  O pti o n al vi sit o nl y f or p arti ci p a nt s t h at r e q uir e a st ati n u p -titr ati o n aft er s cr e e ni n g i n or d er t o r e a c h t h eir i n di vi d u al M T D, r u n-i n-p eri o d  
3  T h e B a s eli n e vi sit m a y b e s plit i nt o 2 vi sit s, pl a n n e d a p pr o xi m at el y 1 0 d a y s a p art. P arti ci p a nt s n ot r a n d o mi z e d wit hi n 7 d a y s of s cr e e ni n g or c o mi n g fr o m r u n -i n will 
h a v e D a y -1 0 vi sit w hi c h will o nl y c o n si st of  C e ntr al l a b dr a w s. T h e i n v e sti g at or m a y s c h e d ul e t h e B a s eli n e ( D a y 1)  vi sit, aft er C e ntr al l a b r e s ult s ar e r e c ei v e d a n d 
eli gi bilit y c o nfir m e d.  
4  O nl y if n e c e s s ar y, O pti o n al vi sit f or titr ati o n of r o s u v a st ati n, tr e at m e nt p eri o d  
5  T hi s i s n ot r e q uir e d t o b e a st a n d -al o n e vi sit : T hi s i s a r e mi n d er t o i n v e sti g at or s t o dr a w a b l o o d s a m pl e, t o m e a s ur e l e v el s of P C S K 9, pri or t o s wit c hi n g a p arti ci p a nt t o 
a P C S K 9 m A b. T i mi n g f or thi s vi sit will v ar y , d e p e n di n g o n t h e ti mi n g of tr e at m e nt s wit c hi n g a n d will n ot b e a p pli c a bl e f or all p arti ci p a nt s.  I n c a s e P C S K 9 s a m pl e s w er e 
t a k e n at an u n pl a n n e d vi sit, t h e s a m pli n g c a n b e r e c or d e d at t hi s vi sit  
6  R e c or d a n y s ur g eri e s or m e di c al pr o c e d ur e s si n c e t h e pri or vi sit.  
7  S: R e c or d i n S o ur c e D o c u m e nt o nl y ( s e n d p a p er S A E f or m t o s af et y w h e n S A E i s r e p ort e d)  
8  O nl y i n w o m e n of c hil d b e ari n g p ot e n ti al. S er u m t e st s will b e s e nt t o t h e C e ntr al l a b f or a n al y si s.  
9  O nl y i n w o m e n of c hil d b e ari n g p ot e nti al. P erf or m e d l o c all y, pri or t o a n y d o si n g, u si n g c e ntr al l a b or at or y kit s u p pli e s.  
1 0  L D L -C c a n b e a s s e s s e d l o c all y at t h e sit e vi a a pr o vi d e d L D L -C p oi nt of c ar e d e vi c e. T h e s e l o c al r e s ult s will b e u s e d f or L L T d e ci si o n m a ki n g. I n t h e e v e nt t h e 
a s s e s s m e nt c a n n ot b e c o m pl et e d wit h t h e L D L -C p oi nt of c ar e d e vi c e, L D L -C will b e a s s e s s e d b y c e ntr al l a b ( u n s c h e d ul e d vi sit).  
1 1  L D L -C, A p o B, n o n -H D L -C, t ot al c h ol e st er ol, tri gl y c eri d e s, a n d H D L -C. P erf or m e d b y t h e c e ntr al l a b.  

N o v arti s  
C o nfi d e nti al  
P a g e  6 7  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
P eri o d  
S cr e e ni n g  
R u n -I n 
B a s eli n e  
Tr e at m e nt  
F oll o w -u p c all  
Vi sit N a m e  
S cr e e ni n g 1  
R u n -I n P eri o d2  
B a s eli n e 3  
Tr e at m e nt  
Pri or t o 
P C S K 9 m A b 
s wit c h 5  
U n s c h e d ul e d  E O T/ E O S 2 2  F oll o w -u p c all 
+ 3 0 d a y s  
D a y s  
-1 4 4 t o -1 3 0  -1 3 0  -1 0 0  -7 0  -4 0  -1 0  
1  
3 0  
6 0  
9 0  1 2 0 4  1 5 0  2 1 0  2 7 0  3 3 0  
U N S  
U N S  
3 6 0  
3 9 0  
1 2  L p( a) will o nl y b e t e st e d at s cr e e ni n g, b a s eli n e, D a y 9 0 a n d E O S. Fr o m t hi s s a m pl e, tripli c at e s er u m ali q u ot s will b e m a d e t o all o w L p( a) t e sti n g i n b ot h n m ol/ L a n d 
m g/ d L; a t hir d ali q u o t will b e m a d e t o all o w t e sti n g of L D L-C a n d/ or L p( a) u si n g n o v el m et h o d s c urr e ntl y i n d e v el o p m e nt.  
1 3  A bl o o d dr a w f or P C S K 9 l e v el s will al s o b e p erf or m e d pri or t o p arti ci p a nt s wit c h t o P C S K 9 m A b , pr ef er a bl y o n c e t hi s s wit c h i s gr a nt e d . T h e P C S K 9 r e s ult s will r e m ai n 
bli n d e d a n d will n ot b e u s e d t o i nfl u e n c e tr e at m e nt d e ci si o n s. A pl a s m a ali q u ot fr o m t t h e P C S K 9 bl o o d dr a w ( e. g. S O M A) m a y al s o b e u s e d t o pr ofil e pr ot ei n s r el at e d t o 
st u d y dr u g or d y sli pi d e mi a.  
1 4  A S T, A L T, A L P, G G T, t ot al bilir u bi n, C K, cr e ati ni n e, cr e ati ni n e cl e ar a n c e, e G F R, c hl ori d e, s o di u m, p ot a s si u m, f a sti n g gl u c o s e, H b A 1 C. P erf or m e d b y t h e c e ntr al l a b.  
1 5  O N L Y: A S T, A L T, A L P, G G T, C K, T ot al bilir u bi n. P erf or m e d b y t h e c e ntr al l a b.  
1 6  H e m at o crit, H e m o gl o bi n, R e d Bl o o d C ell ( R B C) C o u nt, M e a n C or p u s c ul ar V ol u m e ( M C V), M e a n C or p u s c ul ar H e m o gl o bi n ( M C H), M e a n C or p u s c ul ar H e m o gl o bi n 
C o n c e ntr ati o n ( M C H C), Pl at el et s, Er yt hr o c yt e C ell M or p h ol o g y, W hit e Bl o o d C ell ( W B C) c o u nt wit h 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). P erf or m e d b y t h e c e ntr al l a b.  
1 7  Uri n al y si s t o i n cl u d e: s p e cifi c gr a vit y, p H, gl u c o s e, pr ot ei n (t ot al), k et o n e s, bilir u bi n, ur o bili n o g e n, nitrit e, h e m o gl o bi n ( bl o o d), l e u k o c yt e s e st er a s e. If di p sti c k 
m e a s ur e m e nt r e s ult s ar e p o siti v e  ( a b n or m al), mi cr o s c o pi c e x a mi n ati o n will b e p erf or m e d.  
1 8  D o n e e v er y d a y d uri n g t h e tr e at m e nt p eri o d, u si n g a di git al h a n d -h el d d e vi c e. P arti ci p a nt i s t o c o m pl et e t h e di ar y e v er y d a y at h o m e a n d t h e di ar y will b e c h e c k e d b y 
t h e i n v e sti g at or at e a c h sit e vi sit. 
1 9  Tr ai ni n g f or e a c h q u e sti o n n air e s h o ul d b e c o m pl et e d wit h e a c h p arti ci p a nt pri or t o t h e fir st i n di vi d u al p arti ci p a nt q u e sti o n n air e c o m pl eti o n.  
2 0  T h e W al ki n g I m p air m e nt Q u e sti o n n air e will o nl y b e c o m pl et e d b y p arti ci p a nt s di a g n o s e d wit h p eri p h er al  art er y di s e a s e ( P A D) at B a s eli n e.  
2 1  T h e M a c N e w H e art Di s e a s e H e alt h R el at e d Q u alit y of Lif e Q u e sti o n n air e will o nl y b e c o m pl et e d b y p arti ci p a nt s di a g n o s e d wit h A n gi n a P e ct ori s ( A P) at B a s eli n e.  
2 2  T h e or eti c all y, E O T a n d E O S h a p p e n o n d a y 3 6 0, b ut if E O T  o c c ur s b ef or e t h e E O S vi sit, it i s r e c o m m e n d e d t h at t h e p arti ci p a nt r e m ai n s i n t h e st u d y u ntil t h e 
s c h e d ul e d E O S. T h e a s s e s s m e nt s li st e d f or t hi s vi sit s h o ul d o nl y b e c o n d u ct e d if t h e E n d of Tr e at m e nt ( E O T) a n d E n d of St u d y ( E O S) o c c ur si m ult a n e o u sl y. A n " e arl y 
E xit" ( pr e m at ur e di s c o nti n u ati o n fr o m st u d y tr e at m e nt a n d st u d y o n t h e s a m e d a y b ef or e d a y 3 6 0) i s c o n si d er e d a s a n E O S vi sit , a n d t h e a s s e s s m e nt s s h o ul d b e 
p erf or m e d a s t h e y w o ul d b e o n E O S vi sit d a y 3 6 0. I n c a s e of pr e m at ur e tr e at m e nt di s c o nti n u at i o n, t h e a s s e s s m e nt s f or t h e s c h e d ul e d vi sit d a y s h o ul d b e p erf or m e d (f or 
d et ail s r ef er t o S e cti o n 8. 5. 1  a n d S e cti o n 9. 1. 1 ). 

N o v arti s  
C o nfi d e nti al  
P a g e 6 8  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
8. 1  
S cr e e ni n g  
Scree ni n g acti vities ( Ta ble  8 -1 ) m ust be i nitiate d o nl y after t he I C F (a n d asse nt if a p plica ble) 
has bee n si g ne d. A partici pa nt ma y g o directl y fr o m t he scree ni n g visit t o t he baseli ne visit, if 
t he y meet t he criteri a, as o utli ne d i n Secti o n  3. 1 . I n t his case th e scree ni n g peri o d ma y last u p 
t o 1 4 da ys. If t h e ti me b et wee n t he scree ni n g l a bs a n d ra n d o mizati o n is less t ha n or e q u al t o 7 
da ys, t he n t he la bs d o n ot nee d t o b e re peate d a n d t he scree ni n g l a bs will f u ncti o n as b ot h t he 
scree ni n g a n d baseli ne la bs.  
A partici pa nt w h o e nters scree ni n g b ut is deter mi ne d n ot eli gi ble will be c o nsi dere d a s cree n 
fail ure. T he i n vesti gat or ma y c o nsi der re-scree ni n g t he partici pa nt at a later ti me if he/s he 
belie ves t hat t he p artici p a nt’s c o n diti o n has c h a n ge d a n d t he y m a y p ot e ntiall y be eli gi ble. I n 
t his case, a n e w p artici pa nt n u m ber will b e all ocate d t o t he partici pa nt a n d he/s he will nee d t o 
re-perf or m all Scree ni n g Visit pr oce d ures. A p arti ci pa nt ma y b e re -scree n e d o nce. A mi ni m u m 
of 2 wee ks m ust ela ps e b et wee n scree n fail ure a n d re -scree ni n g. T h e parti ci pa nt m ust pr o vi de 
ne w writte n i nf or me d c o nse nt bef ore b ei n g re -scree ne d. 
8. 1. 1  
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 C F a n d 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. T he reas o n 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 e C R F. T he d e m o gra p hic i nf or mati o n, i nf or me d c o nse nt , re p orte d A Es relate d t o 
A u xiliar y Me dici nal Pr o d uct ( A x M P) a n d I n cl usi o n/ E xcl usi o n pa ges  m ust als o be c o m p lete d 
f or scree n fail ure partici p a nts. N o ot her data is re q uire 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 h e partici pa nt e x p erie nce d a S A E d uri n g t he 
scree ni n g p eri o d (s ee S A E Secti o n  1 0. 1. 3  f or re p orti n g details). If t he p artici pa nt fails t o be 
ra n d o mize d, t h e I R T m ust be n otifie d wit hi n 2 da ys of t he scree n fail t hat t he partici pa nt was 
n ot ra n d o mize 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 p a 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 pri ate e C R F. 
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 de m o gra p hic a n d baseli ne c haracteristic data t o be c ollecte d o n all partici pa nts 
i ncl u de: a ge, se x, race, et h nicit y, rele va nt me dical hist or y, C V disease hist or y, alc o h ol hist or y, 
C O VI D -1 9  vacci nati o n i nf or mati o n a n d c urre nt me dical c o n diti o n prese nt bef ore i nf or me d 
c o nse nt 
was si g ne d ( w here p ossi ble, dia g n oses a n d n ot s y m pt o ms 
will be rec or de d), 
c o nc o mita nt L L T, as w ell as rele va nt la b orat or y tests.  
Partici pa nt race a n d et h nicit y are c ollecte d a n d a nal yze d t o ass ess 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 cert ai n Healt h A ut h orities a n d ma y be us e d t o i de ntif y variati o ns i n 
safet y or effic ac y d ue t o t hese fact ors. 

N o v arti s  
C o nfi d e nti al  
P a g e 6 9  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
All prescri pti o n me dicati o ns, o ver -t he-c o u nt er 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 o c u me nte d. See t he pr ot oc ol Secti o n  6. 2. 1  C o nc o mita nt T hera p y 
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 e C R F pa ge. 
I n v esti gat ors will ha ve t he discreti o n t o rec or d a b n or mal test fi n di n gs o n t he me dical hist or y 
e C R F w he n e ver, i n t heir j u d g me nt, t he test a b n or malit y occ urre d pri or t o t he i nf or me d c o ns e nt 
si g nat ure 
T he i n vesti gat or will rec or d i n t he e C R F i n w hic h car di o vas c ular ris k cate g or y t he partici pa nts 
is all ocate d at s cree ni n g, r u n-i n peri o d (if a p pli ca ble) a n d d uri n g t he tr eat me nt peri o d f or 
a nal ysis p ur p ose, a n d als o i n I R T at scree ni n g f or st ratificati o n. 
8. 3  
Effi c a c y  
T he L D L -C a n d ot her e x pl orat or y bi o mar ker assess me nts are s pecifie d bel o w, wit h t he 
Assess me nt Sc he d ule ( Ta ble  8 -1 ) d etaili n g w he n eac h assess me nt is t o be perf or me d. 
Partici pa nts will be i n a faste d stat e f or all of t hese la b orat or y assess me nts. Details re gar di n g 
t he c ollecti o n, pr ocessi n g, s hi p pi n g a n d st ora g e of t he sa m ples f or ce ntral l a b will be pr o vi d e d 
i n a La b orat or y M a n ual. 
8. 3. 1  
L D L C h ol e st er ol  
T he pri mar y effi cac y ass ess me nt will be L D L -C, as teste d a n d re p orte d b y t he ce ntr al la b as 
part of t he f ull Li pi d Pa n el at t he fre q ue nc y s h o w n i n Ta ble  8 -1  .  
I n a d diti o n, w here a rece nt L D L-C m eas ure me nt is re q uire d i n or der t o deci de f or L L T 
escalati o n, L D L -C will be meas ure d l ocal l y at sites usi n g a L D L-C p oi nt of care de vi ce at t he 
fre q ue n c y s h o w n i n Ta bl e  8 -1 . I n t he e ve nt t he ass ess me nt ca n n ot be c o m plete d wit h t he L D L-
C p oi nt of care de vi ce, t h e L D L -C is t o be assess e d b y t he ce ntral la b.   
Partici pa nts nee d t o be fasti n g f or all L D L -C ass ess me nts. L D L -C val ues will n ot be bli n de d 
f or t he i n vesti gat or t o e na ble a n o n g oi n g i n di vi d ual o pti mizati o n of L L T if necessar y t o ac hie ve 
a partici pa nt’s L D L -C tar get. T he i n vesti gat or is e nc o ura g e d t o n ot discl ose  t he L D L-C val u e 
t o t he partici pa nt. 
If partici pa nts gai n eli gi bilit y a n d recei ve L D L-a p heresis i n t he c o urse of st u d y (refer t o 
Secti o n  3. 4 ), L D L-C m ust be meas ure d i m me diatel y bef ore t he s c he d ule d a p heres is treat me nt. 
8. 3. 2  
A p pr o pri at e n e s s of effi c a c y a s s e s s m e nt s  
I n clisira n is a si R N A w hic h acts t o re d u ce L D L-C. L D L -C is a well -d efi ne d a n d vali date d 
la b orat or y para meter a n d is r o uti nel y assesse d i n cli nical trials. L D L-C re d u cti o n is a n acce pte d 
s urr o gate f or C V ris k re d ucti o n, e. g. f or stati ns a n d P C S K 9- bl oc ki n g m o n ocl o nal a nti b o dies. 
W hile m ulti ple fact ors c o ntri b uti n g t o t he de vel o p me nt of A S C V D ha ve bee n descri be d, str o n g 
a n d c o nsiste nt e vi d e nce fr o m ge netics, e pi de mi ol o g y, Me n delia n ra n d o mi zati o n st u dies a n d 
ra n d o mize d trials, ha ve esta blis he d t hat L D L-C is n ot o nl y a la b orat or y para meter of i ncrease d 
ris k, b ut als o a ca usal a n d m o difia ble fact or i n A S C V D (Fere nce  et al 2 0 1 7 ). La b orat or y tests 
relate d t o t he e n d p oi nts are i n li ne wit h t he e x pecte d efficac y of i nclisira n. It is t he pri mar y 
e n d p oi nt of t he st u d y.  
E x pl orat or y e n d p oi nts are h y p ot hesis ge nerati n g a n d e x pl orat or y i n nat ure.  

N o v arti s  
C o nfi d e nti al  
P a g e 7 0  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
8. 4  
S af et y  
T he safet y pr ofile of i nclisira n has bee n well c haracterize d i n t he P hase III L D L -C l o weri n g 
st u dies ( O RI O N-9, -1 0 a n d -1 1) ( Wri g ht  et al 2 0 2 1 ) w hic h i ncl u de d o ver 3, 6 0 0 partici pa nts 
wit h si milar de m o gra p hic a n d baseli ne c h aracteristics t o t he p o p ulati o n e x pecte d t o be i ncl u de d 
i n t he c urre nt st u d y.  
T he safet y pr ofile of r os u vastati n has bee n well c h aract erize d a n d is o utli ne d i n t he l ocal S m P C.  
As per Secti o n  4. 6 , d uri n g a P u blic Healt h e mer ge nc y as d eclare d b y L ocal or Re gi o nal 
a ut h orities i.e. pa n de mic,  e pi de mic or nat ural disast er, t hat li mits or pre ve nts o n -site st u d y visits, 
re g ular p h o ne or virt u al calls ca n occ ur (e ver y 4 wee ks or m ore fre q ue ntl y if nee de d) f or safet y 
m o nit ori n g a n d disc ussi o n of t he partici p a nt´s healt h stat us u ntil it is safe f or t he partici pa nt t o 
visit t he site a gai n.  
Safet y assess me nts are s pecifie d b el 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 t he A E Sect i o n 1 0. 1 . 
A c o m plete p h ysical e x a mi nati o n will be perf or me d at t he visits, as o utli ne d i n Ta ble  8 -1 . 
Details o n w hat is i ncl u de d i n t he c o m plete p h ysical e xa m a n d t he re q uir e me nts t o perf or m vital 
si g ns assess me nt a n d hei g ht/ w ei g ht meas ure me nts are pr o vi de d i n Ta ble  8 -2 . 
T a bl e 8 -2  
A s s e s s m e nt s & S p e cifi c ati o n s  
A s s e s s m e nt  
S p e cifi c ati o n  
P h y si c al 
e x a mi n ati o n  
A c o m pl et e p h y si c al e x a mi n ati o n will i n cl u d e t h e e x a mi n ati o n of g e n er al a p p e ar a n c e, 
s ki n, n e c k (i n cl u di n g t h yr oi d), e y e s, e ar s, n o s e, t hr o at, l u n g s, h e art, a b d o m e n, b a c k, 
l y m p h n o d e s, e xtr e miti e s, v a s c ul ar, a n d n e ur ol o gi c al. If i n di c at e d b a s e d o n m e di c al 
hi s t or y a n d/ or s y m pt o m s, r e ct al, e xt er n al g e nit ali a, br e a st, a n d p el vi c e x a m s will b e 
p erf or m e d.  
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 E m u st b e r e c or d e d a s a n A E.  
Vit al si g n s  
Vit al si g n s i n cl u d e 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. Aft er t h e p arti ci p a nt 
h a s b e e n sitti n g f or fi v e mi n ut e s, wit h b a c k s u p p ort e d a n d b ot h f e et pl a c e d o n t h e fl o or, 
s y st oli c a n d di a st oli c bl o o d pr e s s ur e will b e m e a s ur e d t hr e e ti m e s u si n g a n a ut o m at e d 
v ali d at e d d e vi c e wit h a n a p pr o pri at el y si z e d c uff. T h e r e p e at sitti n g m e a s ur e m e nt s will b e 
m a d e at 1 - 2 mi n ut e i nt er v al s a n d t h e m e a n of t h e t hr e e m e a s ur e m e nt s will b e u s e d. I n 
c a s e t h e c uff si z e s a v ail a bl e ar e n ot l ar g e e n o u g h f or t h e p arti ci p a nt' s ar m cir c u mf er e n c e, 
a s p h y g m o m a n o m et er wit h a n a p pr o pri at el y si z e d c uff m a y b e u s e d.  
H ei g ht a n d w ei g ht  
H ei g ht i n c e nti m et er s ( c m) a n d b o d y w ei g ht (t o t h e n e ar e st 0. 1 kil o gr a m ( k g) i n i n d o or 
cl ot hi n g, b ut wit h o ut s h o e s) will b e m e a s ur e d.  
8. 4. 1  
L a b or at or y e v al u ati o n s  
As per Secti o n  4. 6 , d uri n g a P u blic Healt h e mer ge nc y as d eclare d b y L ocal or Re gi o nal 
a ut h orities, i.e. pa n de mi c, e pi de mic or nat ur al disaster, t hat li mits or pre ve nts o n -site st u d y 
visits, if partici pa nts ca n n ot visit t he site f or pr ot oc ol s pecifie d safet y l a b assess me nts, a n 
alter nati ve la b (l o cal) c ollecti o n site ma y be use d.  

N o v arti s  
C o nfi d e nti al  
P a g e 7 1  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
S peci me ns will be o btai ne d at t he ti me p oi nts detaile d i n t he Assess me nt Sc he d ule ( Ta ble  8 -1 ). 
Details o n w hat is i ncl u de d i n he mat ol o g y, c he mistr y, li pi ds/li p o pr otei ns a n d uri nal ysis 
la b orat or y e v al uati o ns are pr o vi de d i n Ta ble  8 -3 . 
Ce ntral la b orat or y will be use d f or a nal ysis of all s peci me ns c ollecte d, wit h t he e xc e pti o n of 
uri ne pre g n a nc y t ests, w hic h will be d o ne l o call y ( usi n g testi n g materials s u p plie d b y t he ce ntral 
la b orat or y). Ser u m pre g n a nc y tests at scree ni n g will be d o ne b y t he ce ntr al la b orat or y. 
F or i m me diate a n d l ocal acti o n o n stati n u p/ d o w n -titrati o n or ot her L L T escalati o n, L D L -C 
val ue 
will be 
meas ure d usi n g a  L D L -C p oi nt of care  de vice a n d rec or de d i n t he 
e C R F acc or di n gl y.  I n t he e ve nt t he assess me nt ca n n ot be c o m plete d wit h t he L D L-C p oi nt of 
care d e vice, t h e L D L -C is t o be assesse d b y t he ce ntral l a b.  
L D L -C will als o be ce ntrall y a nal yze d at t he visits as o utli ne d i n Ta ble  8 -1 , as part of t he f ull 
Li pi d Pa nel.  
Details o n t he c ollecti o ns, 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 d e d  t o i n vesti gat ors i n a La b orat or y Ma n u al.  
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 Es as a p pr o priate.  
T a bl e 8 -3  
L a b or at or y A s s e s s m e nt 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, R e d Bl o o d C ell ( R B C) C o u nt, M e a n C or p u s c ul ar V ol u m e 
( M C V), M e a n C or p u s c ul ar H e m o gl o bi n ( M C H), M e a n C or p u s c ul ar H e m o gl o bi n 
C o n c e ntr ati o n ( M C H C), Pl at el et s, Er yt hr o c yt e C ell M or p h ol o g y*, W hit e Bl o o d C ell 
( W B C) c o u nt wit h 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  
F ull c h e mi str y:  
A S T, A L T, A L P, G G T, t ot al bilir u bi n, dir e ct a n d i n dir e ct bilir u bi n (if t ot al > 2 U L N), C K, 
cr e ati ni n e, cr e ati ni n e cl e ar a n c e, e G F R*, s o di u m, p ot a s si u m, c hl ori d e, gl u c o s e 
(f a sti n g)***, H b A1 c *** 
Li mit e d c h e mi str y:  
O N L Y: A S T, A L T, A L P, G G T, t ot al bilir u bi n (fr a cti o n e d bilir u bi n (if t ot al bilir u bi n > 2 U L N), 
C K  
Li pi d s/ Li p o pr ot ei n s/  
Bi o m ar k er s  
L D L -C, A p o B, L p( a), n o n -H D L -C, t ot al c h ol e st er ol, tri gl y c eri d e s, a n d H D L -C. P C S K 9 
l e v el s, s e e T a bl e  8 -1 . 
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 ) 
Uri n al y si s  
Di p sti c k m e a s ur e m e nt s f or: s p e cifi c gr a vit y, p H, gl u c o s e, pr ot ei n (t ot al),  
k et o n e s, bilir u bi n, ur o bili n o g e n, nitrit e, h e m o gl o bi n ( bl o o d), l e u k o c yt e s e st er a s e  
If di p sti c k m e a s ur e m e nt r e s ult s ar e p o siti v e ( a b n or m al), mi cr o s c o pi c e x a mi n ati o n will b e 
p erf or m e d  
* R efl e x t e sti n g o nl y i n e v e nt of a b n or m al r e s ult fr o m a b s ol ut e c o u nt/ diff er e nti al s  
** e G F R will b e c al c ul at e d u si n g t h e M o difi c ati o n of Di et i n R e n al Di s e a s e ( M D R D) e G F R f or m ul a a s f oll o w s:  
1 7 5 x [ st a n d ar di z e d s er u m cr e ati ni n e ( m g/ d L)] – 1. 1 5 4  x [ a g e]  – 0. 2 0 3 x [ 1. 2 1 2 if r a c e = bl a c k/ Afri c a n A m eri c a n] x 
[ 0. 7 4 2 if f e m al e]  
*** Di a g n o si s of di a b et e s b a s e d o n H b A 1 c ≥_ 6. 5 % ( 4 8 m m ol/ m ol) or F P G t w o c o n s e c uti v e v al u e s  ≥1 2 6 m g/ d L 
( 7. 0 m m ol/ L). 
8. 4. 2  
El e ctr o c ar di o gr a m ( E C G)  
N ot A p plica ble.  

N o v arti s  
C o nfi d e nti al  
P a g e 7 2  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
8. 4. 2. 1  
C ar di a c i m a gi n g - M R A  ( m a g n eti c r e s o n a n c e a n gi o gr a p h y), M U G A 
( m ulti pl e g at e d a c q ui siti o n) s c a n or e c h o c ar di o gr a m 
N ot A p plica ble.  
8. 4. 2. 2  
C ar di a c e n z y m e s  
N ot A p plica ble.  
8. 4. 3  
Pr e g n a n c y  
W o me n of c hil d -beari n g p ote ntial, defi ne d as all w o me n p h ysi ol o gicall y ca pa ble of bec o mi n g 
pre g na nt, u nless t he y are usi n g  hi g hl y  effecti ve met h o ds of c o ntrace pti o n w hile ta ki n g st u d y 
treat me nt, w hic h i ncl u d es  r os u vastati n, a n d f or 5 
da ys  ( = 
5 ti mes t h e ter mi nal 
half-
life) of  r os u vast ati n) after st o p pi n g 
me dicati o n.  Hi g hl y effecti ve c o ntr ace pti o n 
met h o ds 
i ncl u de: 
•  T otal a bsti ne nce ( w h e 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 a cce pta ble met h o ds of c o ntrace pti o n.  
•  Fe male sterilizati o n ( ha ve h a d s ur gical bilat eral o o p h orect o m y 
wit h or 
wit h o ut 
h ysterect o m y), t otal h yst erect o m y, or bilateral t u b al li gati o n at least si x wee ks bef ore ta ki n g 
st u d y treat me nt. I n case of o o p h orect o m y al o n e, 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 m e d b y f oll o w u p h or m o ne le vel assess me nt.  
•  Male sterilizati o n (at le ast 6 m o nt hs pri or t o scree ni n g). F or fe mal e partici pa nts o n t he st u d y, 
t he vasect o mize d m ale p art ner s h o ul d be t he s ol e part ner f or t hat partici p a nt 
•  Us e of oral, (estr o ge n a n d pr o gester o n e), i nject e 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 rat e  <  1 %), 
f or e xa m ple h or m o ne va gi nal ri n g or tra ns der m al h or m o ne c o ntrace pti o n. 
I n cas e of use of oral c o ntrace pti o n w o m e n s h o ul d ha ve b ee n sta ble o n t he sa me pill f or a 
mi ni m u m of 3 m o nt hs bef ore ta ki n g st u d y treat me nt.  
W o me n are c o nsi dere d p ost -me n o pa usal  if t he y h a ve h a 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 b ilateral 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 a g o. I n t he cas e of o o p h orect o m y al o ne, o nl y w he n 
t he re pr o d 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 d ere d n ot of c hil d beari n g p ote ntial.  
If l oc al re g ul ati o ns de viate fr o m t he c o ntr ace pti o n met h o ds liste d a b o ve t o pre ve nt pre g na n c y, 
l ocal re g ulati o ns a p pl y a n d will be descri be d i n t h e l ocal I C F. 
All w o ma n of c hil d -beari n g p ote ntial wil l ha ve a ser u m pre g n a nc y test perf or me d at t h e 
Scree ni n g Visit. A uri ne pre g na nc y test will be perf or me d at all s u bse q ue nt visits. A p ositi ve 
uri ne pre g n a nc y test s h o ul d be c o nfir me d wit h a ser u m pre g na nc y test. Partici pa nts wit h a 
p ositi ve uri ne/ser u m pre g na nc y at a n y ti me i n t he st u d y m ust be e xcl u de d.  

N o v arti s  
C o nfi d e nti al  
P a g e 7 3  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
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.  
As per 
Secti o n  4. 6 , d uri n g a 
P u blic 
Healt h e mer ge n c y as declare d b y 
L ocal or 
Re gi o nal  a ut h orities i.e. pa n de mic, e pi d e mic or n at ural disaster, t hat li mits or pre v e nts o n-site 
st u d y visits, if partici pa nts ca n n ot visit t he site,  uri ne pre g n a nc y test kits ma y be use d  at t he 
partici pa nt's h o me. R ele va nt partici pa nts ca n perf or m t he uri ne pre g na n c y test at 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 h e 
Site is i nf or me d a n d ca n verif y t he pre g na nc y t est res ults (e. g., f oll o wi n g c o u ntr y s pecific 
meas ures).  
8. 4. 4  
Ot h er s af et y e v al u ati o n s  
8. 4. 4. 1  
H y p er gl y c e mi a -r el at e d e v e nt s 
A Es of ne w o nset of dia betes mellit us s h o ul d f oll o w t he criteria acce pte d i n rece nt dia betes 
g ui deli nes ( E S C 2 0 1 9 G ui deli ne o n Di a betes, Pre -Dia b etes a n d Car di o vasc ular Diseases 
de vel o pe d i n c olla b orati o n wit h t he E ur o pea n Ass ociati o n f or t he St u d y of Dia betes ( E A S D) ) 
a n d be re p orte d  i n partici pa nts wit h n o me dical hist or y of dia betes mellit us a n d o nl y i n t he 
c o nte xt of t he l ocal sta n d ar d of care f oll o w -u p if:  
•  Eit her a n H b A 1c wit h a dia g n ostic t hres h ol d of ≥6. 5 % ( 4 8 m m ol/ m ol) or a F P G 2 
c o nsec uti ve val u es ≥1 2 6 m g/ d L ( 7. 0 m m ol/ L)  is d oc u me nte d. A dia g n osis of ne w o nset 
dia betes mellit us ca n o nl y be c o nfir me d if t w o a b n or mal test res ults, eit her fr o m t he sa me 
sa m ple or i n t w o se parate test sa m ples, ca n be retri e ve d.). 
•  A d diti o n of a ne w c o n c o mita nt me dicati o n f or c o ntr ol of plas ma gl uc ose . 
•  E vi de nce of classic s y m pt o ms of h y per gl yce mia or h y per gl y ce mic crisis wit h a ra n d o m 
plas ma gl uc ose of ≥2 0 0 m g/ d L ( 1 1. 1 m m ol/ L).  
•  A plas ma gl uc ose of ≥2 0 0 m g/ d L ( 1 1. 1 m m ol/ L) 2 h o urs after a 7 5 -gra m oral gl uc ose l oa d.  
Details f or A Es of n e w o nset of dia bet es mellit us will als o be c ollecte d.  
‘ W orse ni n g of gl yce mic c o ntr ol’ s h o ul d be re p ort e d as a n A E o n t he e C R F i n partici pa nts wit h 
a me dical hist or y of dise ase ( H b A 1 c ≥6. 5 % at b as eli ne) w he n  b ot h c o n diti o ns are met : 
•  H b A 1c i ncreases fr o m baseli ne > 0. 5 %.  
•  Ne w c o nc o mita nt me dicati o n or i ncrease i n d ose of c urre nt a nti dia betic t hera p y is i nitiate d 
t o i m pr o ve t he c o ntr ol of t he plas ma gl uc ose le vel. 
8. 4. 4. 2  
M aj or A d v er s e C ar di o v a s c ul ar E v e nt ( M A C E)  
Partici pa nts i n t he i n vesti gate d p o p ulati o n are at ris k t o t he occ urre nce of maj or car di o vas c ular 
e ve nts ( M A C E). O n a partici pa nt le vel t his ma y a p pear i n di verse t y pes of e ve nts. T heref ore, 
i n t his trial a br oa d a p pr oac h t o t he e v al uati o n of M A C E e ve nts is dee me d a p pr o priate. A 5 P-
M A C E will be e val uate d as a c o m p osite of C V  deat h, res uscitate d car diac arrest, n o n -fatal MI, 
a n d n o n-fatal str o ke (isc he mic a n d he m orr ha gi c), ur ge nt c or o nar y re v asc ularizati o n. T he 
c o m p o ne nts of M A C E will be re p orte d as di a g n ose d b y t he i n vesti gat or. Det ails o n t hese e ve nts 
will be c ollecte d o n a n  a p pr o priate e C R F p a ge.  

N o v arti s  
C o nfi d e nti al  
P a g e 7 4  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
8. 4. 4. 3  
 
8. 4. 4. 4  
H o s pit ali z ati o n d u e t o a c ar di o v a s c ul ar r e a s o n  
E ver y h os pitalizati o n d u e t o a car di o vas c ular ( C V) reas o n as pri mar y dia g n osis of a d missi o n 
will be rec or de d o n a n a p pr o priate e C R F p a ge b y t he i n vesti gat or.  
8. 4. 5  
A p pr o pri at e n e s s of s af et y m e a s ur e m e nt s  
T he safet y assess me nts s electe d are sta n d ar d f or t his i n dicati o n/ partici pa nt p o p ulati o n.  
8. 5  
A d diti o n al a s s e s s m e nt s  
N o a d diti o nal tests will be per f or me d o n partici pa nts e ntere d i nt o t his st u d y. 
8. 5. 1  
Cli ni c al O ut c o m e A s s e s s m e nt s ( C O A s)  
As per Secti o n  4. 6 , d uri n g a P u blic Healt h e mer ge nc y as d eclare d b y L ocal or Re gi o nal 
a ut h orities i.e. pa n de mic, e pi de mic or nat ural disaster  t hat li mits or pre ve nts o n-site st u d y visits, 
P R O data ma y be c ollect e d re m otel y acc or di n g t o l ocal re g ulati o n.  
P ati e nt r e p ort e d o ut c o m e s ( P R O)  
C o m pleti o n of Q uesti o n n aires  
 Partici pa nt  s h o ul d c o m plete t he P R Os at t he sc he d ule d visit bef ore a n y cli nical a ssess me nts 
are c o n d ucte d ( wit h t he e xce pti o n of t h e pai n di ar y w hic h s h o ul d b e c o m pl ete d as descri be d i n  
Secti o n 8. 5. 1. 2 ).  Missi n g P R Os s h o ul d n ot be ca pt ure d as a pr ot oc ol de viati o n 
wit h t he 
e xce pti o n of P R Os i ncl u d e d i n t he sec o n dar y e n d p oi nts ( S F B PI a n d pai n diar y) .  
T he partici pa nt s h o ul d be gi ve n s ufficie nt s pace a n d ti me t o c o m plete t he P R O s . 
U n der s p ecial circ u mst a nces, s uc h as b ut n ot li mite d t o illiterac y a n d p o or visi o n, t he 
c o m pleti o n of t he q uesti o n naires ca n be d o n e wit h assista nce, b y a care gi ver or a st u d y 
c o or di nat or n ot dir ectl y i n v ol ve d i n t he care of t he partici pa nt, if a partici pa nt is u na ble t o 
c o m plete it o n t heir o w n. T his sit uati o n s h o ul d be clearl y n ote d b ot h i n s o urce d oc u me nts.  
Partici pa nt q uesti o n naires s h o ul d be c o m plete d i n t he la n g ua ge m ost fa miliar t o t he partici pa nt.  
All partici pa nts will c o m plete t he P R O q uesti o ns vi a a n electr o nic ha n d hel d de vice. If 
partici pa nts e x peri e nce a n y diffic ulties wit h s u b missi o n after t he y c o m plete t he Patie nt 
Re p orte d O utc o me ( P R Os), t he st u d y staff s h o ul d assist t he m wit h s u b mitti n g t heir res p o nses. 
I n case p artici pa nts disc o nti n ue treatme nt pri or t o t he st u d y c o m pleti o n, t he y s h o ul d be as ke d 
t o c o m plete t he P R Os as i n dicate d i n t he sc he d ule of assess me nts. 
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 7 5  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
T he site pers o n n el s h o ul d c hec k t he P R O meas ures f or c o m plete ness a n d as k t he partici pa nt t o 
c o m plete a n y missi n g res p o nses. T he res p o nses st ore d electr o nicall y i n t he data bas e will be 
c o nsi dere d t he s o urce file.  
C o m plete d P R O s as well as pai n diar y, 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 vi e we d a n d assesse d b y t he i n vesti gat or f or res p o nses w hic h ma y i n dicate 
p ote ntial A Es or S A Es or use of p ai n -relie vi n g me dicati o n 
bef ore a n y cli nical st u d y 
e xa mi nati o ns. T his assess me nt s h o ul d be d oc u m e nte d i n st u d y s o urce rec or ds. If A Es or S A Es 
are c o nfir me d, st u d y i n v esti gat or s h o ul d n ot e n c o ura ge t h e partici pa nt t o  c ha n g e res p o nses 
re p orte d i n t he c o m plete d q uesti o n naire or diar y. St u d y i n vesti gat ors m ust f oll o w re p orti n g 
i nstr ucti o ns o utli ne d i n  Secti o n  1 0. 1 . 
8. 5. 1. 1  
S h ort -F or m Bri ef P ai n I n v e nt or y ( S F -B PI)  
T he S F -B PI is a self -a d mi niste re d sta n dar dize d fiftee n ite ms q uesti o n naire t hat assess es h o w 
pai n i nterferes wit h or i nfl ue nces a partici pa nt’s life. T he q uer y p eri o d c o vers t he past 2 4 
h o urs  a n d ta kes 5 mi n utes f or t he partici pa nt t o c o m plete. T he first ite m is a scree ni n g q uesti o n 
a bo ut t he partici pa nt's pai n o n t he da y. T he q uesti o n naire is t he n c o m p ose d of pai n dra wi n g 
dia gra ms, f o ur ite ms a b o ut pai n i nte nsit y ( w orst p ai n, least pai n, a vera ge p ai n, pai n ri g ht n o w), 
t w o ite ms o n pai n relief treat me nt or me dicati o n, a n d o ne ite m o n pai n i nterfere n ce, wit h se ve n 
s u b-ite ms ( ge neral acti vit y, m o o d, wal ki n g a bilit y, n or mal wal k, relati o ns wit h ot her p e o ple, 
slee p, a n d e nj o y me nt of life). T he S F-B PI i ncl u des t w o mai n sc ores: a pai n se verit y sc ore a n d 
a pai n i nterfere n ce sc ore. T he pai n se ve rit y sc ore c o m bi nes t he i nf or mati o n of t he f o ur ite ms 
a b o ut pai n i nte nsit y, w hic h are rate d fr o m 0, n o pai n, t o 1 0, pai n as ba d as y o u ca n i ma gi ne. T o 
deri ve t he pai n se v erit y s c ore t he a vera g e of t h e f o ur ite ms will be ta ke n T he pai n i nterfere nce 
is calc ulate d si milarl y usi n g t he se ve n ite ms re g ar di n g pai n i nterfere n ce, w hic h are rate d fr o m 
0, d oes n ot i nterfere, t o 1 0, c o m pletel y i nterferes. T he pai n i nterfere n ce s c ore will be t he a vera g e 
of t hese se ve n ite ms. B ot h sc ores will be bet w ee n 0 a n d 1 0. T he re m ai ni n g ite ms if t he 
q uesti o n naire d o n ot c o ntri b ute t o t he sc ori n g. Hi g her sc ores c orres p o n d t o a p o orer c o n diti o n 
of t he partici pa nt. T he first ite m, pai n dra wi n g dia gra ms ( pai nf ul a n d m ost pai nf ul areas) a n d 
t he ite ms o n pai n relief treat me nt or me dicatio n (list of t he treat me nts a n d a m o u nt of relief) d o 
n ot c o ntri b ute t o t he sc ori n g. It has bee n  v ali date d ( Ta n  et al 2 0 0 5 , Keller  et al 2 0 0 4) f or use 
wit h n o n -mali g na nt pai n p o p ulati o ns a n d has bee n use d i n stati n trials ( Cleela n d  2 0 0 9 ). 
T he S F -B PI will be rec or de d as o utli ne d i n t he Assess me nt Sc he d ule ( Ta bl e  8 -1 ). 
8. 5. 1. 2  
P ai n Di ar y  
T he Pai n Diar y is base d o n ite m -3 of S F -B PI.  Dail y pai n  will be rate d o n a n u meric scale fr o m 
0 ( n o pai n) t o 1 0 ( pai n as ba d as y o u ca n i ma gi ne) b y t he partici pa nts descri bi n g t heir pai n at 
its 
w orst i n t he last 
2 4 
h o urs. 
All 
parti ci pa nts 
will c o m plete t he 
diar y 
via a 
ha n d hel d  a n el ectr o nic d e vice. I n vesti gat ors s h o ul d i nstr uct t he partici p a nts t o fill i n t he diar y 
o n a dail y basis a n d t o a d here  t o a cert ai n r o uti ne  f or c o m pleti n g t he  diar y.   
8. 5. 1. 3  
S F -3 6 V er si o n 2  
T he S h ort -F or m Healt h S ur ve y ( S F -3 6) is a ge neric healt h -relate d q ualit y of life ( H R Q o L) 
i nstr u me nt w hic h c o m prises of 3 6 q uesti o ns acr oss 8 d o mai ns: 1) li mitati o ns i n p h ysical 
acti vities beca us e of healt h pr o ble ms; 2) li mitati o ns i n s ocial acti vities beca use of p h ysical or 

N o v arti s  
C o nfi d e nti al  
P a g e 7 6  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
e m oti o nal pr o ble ms; 3) li mitati o ns i n us ual r ole acti vities beca use of p h ysical healt h pr o bl e ms; 
4) b o dil y pai n; 5) ge neral me ntal healt h ( ps yc h ol o gical distress a n d well -bei n g); 6) li mitati o ns 
i n us ual r ole acti vities beca use of e m oti o nal pr o ble ms; 7) vitalit y (e ner g y a n d fati g ue); 8) 
ge neral healt h  perce pti o ns ( Ware  a n d S her b o ur ne  1 9 9 2 ). T w o o verall s u m mar y sc ores, t he 
p h ysical c o m p o ne nt s u m mar y ( P C S) a n d t he 
me ntal c o m p o ne nt s u m mar y ( M C S) will 
be  c om p ute d ( Ware  1 9 9 4 ). A n i ncrease i n t he scale val ues reflects a n i m pr o ve me nt i n t he 
q ualit y of  life (Ware  a n d  S her b o ur ne  1 9 9 2 ). T he S F-3 6 is c o nsi dere d t o b e a v ali d, relia bl e, 
c o ncis e g e neric meas ur e of state of healt h a n d h as de m o nstrate d t o detect cli nical treat me nt 
be nefits acr oss 
me dical c o n diti o ns i ncl u di n g c hr o nic dis or ders s u c h as  d ysli pi de mia 
(H ytti ne n  et al 2 0 0 8 ). T h e S F-3 6 is re g ularl y us e d as a g e neri c q uesti o n nair e i n cli nical st u dies 
i n t he fiel d of car di ol o g y ( M üller -N or d h or n  et al 2 0 0 4 ) a n d is t he m ost fre q ue ntl y use d g e neri c 
q uesti o n naire i n cli nical st u dies 
wit h peri p heral arterial di sease ( P A D) partici pa nts 
(P o k u  et al 2 0 1 6  ). I n t he car di o vas c ular p artici pa nt p o p ulati o n, es peciall y t h ose wit h C or o nar y 
Heart 
Dis ease ( C H D), it is c o nsi dere d t o b e t he 
m ost relia ble a n d c ha n ge -se nsiti ve 
ge neric  q u esti o n naire ( D e m pster  a n d D o n nell y  2 0 0 0 ). T he S F-3 6 has bee n vali date d at t h e 
i nter nati o nal  
le vel  
f or  
t he  
c hr o ni call y  
ill,  
i ncl u di n g  
car diac p artici pa nts 
(Ware  a n d G a n de k  1 9 9 8 , Al o ns o  et al 2 0 0 4 ). I n a d diti o n, t he Healt h-relat e d q ualit y of life 
( H R Q o L) pr oj ect res ulte d i n i nter nati o nal refere n ce val u es f or t he S F-3 6  f or heart partici p a nts 
(H u ber  et al 2 0 1 6 ). S F-3 6 w ill be rec or de d as o utli ne d i n Ta ble  8 -1 . 
8. 5. 1. 4  
G a str oi nt e sti n al S y m pt o m R ati n g S c al e ( G S R S)  
T he self -a d mi nistere d G S R S q uesti o n naire c o ntai ns 1 5 ite ms f or gastr oi ntesti nal s y n dr o mes, 
w hic h are c o m p ose d of 5 di me nsi o ns (a b d o mi nal pai n, refl u x s y n dr o me, i n di gesti o n, diarr hea 
a n d c o nsti pati o n) a n d us e a Li kert scale wit h 7 u nits ( 1 bei n g n o disc o mf ort t o 7 bei n g ver y 
se vere disc o mf ort) (S ve dl u n d  et al 1 9 8 8 , C ha n  et al 2 0 0 6 , K ulic h  et al 2 0 0 3 ). T he s u bsc ores of 
i n di vi d ual d o mai ns are calc ulate d b y a vera gi n g t he sc ores of t he ass o ciate d ite ms. T he a vera g e 
of all s u bsc ores gi ves t he t otal sc ore, w hic h ra n ges fr o m 1 t o 7 p oi nts. T he  l o wer t he val u e, t he 
better t he g astr oi ntesti nal c o n diti o n.  T he relia bilit y a n d vali dit y of t he G S R S are well -
d oc u me nte d ( Re vic ki  et al 1 9 9 8 , K ulic h  et al 2 0 0 8 , Sa ma ha  et al 2 0 0 8 ), a n d n or m val ues f or a 
ge neral p o p ulati o n are  a vaila ble ( K ulic h  et al 2 0 0 3 , Di me näs  et al 1 9 9 5 ). T he G S R S has bee n 
ta ke n is olate d i nt o acc o u nt i n t he prese nt i n dicati o n (Sa ma ha  et al 2 0 0 8 ) a n d t hera pe utic area 
of " meta b olic  diseases".  
Data will be c ollecte d as o utli ne d i n t he Assess me nt Sc he d ule ( Ta ble  8 -1 ). 
8. 5. 1. 5  
Tr e at m e nt S ati sf a cti o n Q u e sti o n n air e f or M e di c ati o n ( T S Q M v. II)  
T he 
Treat me nt 
Satisfacti o n 
Q uesti o n naire f or 
Me dicati o n ( T S Q M) is a 
vali date d 
partici pa nt  re p orte d o utc o me i nstr u me nt (At ki ns o n  et al 2 0 0 4 , At ki ns o n  et al 2 0 0 5) use d t o 
assess partici pa nt satisfacti o n wit h treat me nt. All s u bjects will be pr o vi de d wit h t he T S Q M v. 
II, a n 1 1-ite m m ulti ple c h oice q uesti o n nair e v ali date d t o assess c o n v e nie nce a n d gl o bal 
satisfacti o n wit h treat me nt. 
T S Q M is a wi d el y use d ge neri c meas ure, i ncl u di n g  d ysli pi de mia ( M ulc ha n da ni  et al 2 0 1 9 , 
R o drí g uez  Arr o y o  et al 2 0 1 4 ), t o assess t he maj or di me nsi o ns of patie nts’ satisfacti o n wit h 
me dic ati o n 
a n d 
h as 
bee n 
ps y c h o metricall y 
vali date d i n 
a 
h eter o ge n e o us  sa m ple 
(At ki ns o n  et al 2 0 0 4 , At ki ns o n  et al 2 0 0 5). T S Q M v. II is c o m prise d of 1 1 q uesti o ns t hat 

N o v arti s  
C o nfi d e nti al  
P a g e 7 7  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
pr o vi de sc ores o n f o u r s cales: effecti ve ness ( 2 it e ms), si de effects ( 4 ite ms), c o n ve nie nce ( 3 
ite ms) a n d gl o bal satisfacti o n ( 2 ite ms) o ver t he pre vi o us 2 – 3 wee ks, or si nce t he partici pa nt’s 
last use. Wit h t he e xce pti o n of ite m 4 ( prese n ce of si de effects; yes or n o), all items ha ve fi v e 
or se ve n res p o ns es, sc ore d fr o m o ne (least satisfie d) t o fi ve or se ve n ( m ost satisfie d). It e m 
sc ores are s u m me d t o gi ve f o ur d o mai n sc ores, w hic h are i n t ur n tra nsf or me d t o a scale of 0 –
1 0 0. T he hi g her t he v al ue, t he hi g her is t he partici pa nt’ s satisfacti o n wit h t he treat me nt. 
Data will be c ollecte d as o utli ne d i n t he Assess me nt Sc he d ule ( Ta ble  8 -1 ). 
8. 5. 1. 6  
W al ki n g I m p air m e nt Q u e sti o n n air e ( WI Q)  
T he 
Wal ki n g I m p air me nt Q uesti o n naire ( WI Q) meas ures s elf -re p orte d wal ki n g dista nce, 
wal ki n g s pee d, a n d stair -cli m bi n g a bilit y i n me n a n d w o me n wit h l o wer e xtre mit y peri p heral 
arterial dise ase ( P A D)  (R e ge nstei ner  et al 1 9 9 6 ). T he m o difie d WI Q rec or ds a t otal of 1 6 ite ms 
i n f o ur cat e g ories: pai n ( 2 q uesti o ns), wal ki n g dista nce ( 7 q u esti o ns), wal ki n g s pee d ( 4 
q uesti o ns), a n d st air cli m bi n g ( 3 q uesti o ns). I n t h e WI Q dista nce sc ore, t h e partici pa nt rec or ds 
t he de gree of diffic ult y w al ki n g s pecific dista nces (ra n gi n g fr o m wal ki n g i n d o ors t o 1, 5 0 0 feet 
o r 5 bl oc ks) o n a gra de d Li kert- scale fr o m 0 t o 4. A sc ore of 0 re prese nts t he i na bilit y t o wal k 
t he dista nce i n q uesti o n a n d a sc ore of 4 re prese nts n o diffic ult y. I n t he WI Q s pee d sc ore, t h e 
partici pa nt is as ke d t o ass ess t he de gree of diffic ult y wal ki n g  1 bl oc k at s pecific s pee ds ra n gi n g 
fr o m wal ki n g sl o wl y t o j o g gi n g o n a gra de d scale ra n gi n g fr o m 0 t o 4. I n t he WI Q stair cli m bi n g 
sc ore, t he partici pa nt re p orts t he de gree of diffic ult y cli m bi n g 1, 2, a n d 3 fli g hts of stairs. T his 
gra de d s c ore is m ulti pl ie d b y a pre-s pecifi e d wei g ht f or eac h dista nce, s pee d, or n u m ber of stair 
fli g hts. T he pr o d ucts are s u m me d a n d di vi de d b y t he ma xi m u m p ossi ble sc ore t o o btai n a 
perce nt s c ore, ra n gi n g fr o m 0 (re prese nti n g t he i na bilit y t o perf or m a n y of t he tas ks) t o 1 0 0 
(re prese nti n g n o diffi c ult wit h a n y of t he tas ks) (Re ge nstei ner  et al 1 9 9 0 ). T h e WI Q sc ores ha v e 
bee n 
s h o w n 
t o 
i m pr o ve 
i n 
res p o nse 
t o 
l o wer 
e xtr e mit y  re vasc ularizati o n 
(Nic olaï  et al 2 0 0 9 ) a n d s u per vise d e x ercise  t h era p y (Mc Der m ott  et al 2 0 0 9 ). T he 
WI Q has 
bee n 
vali date d 
se veral 
ti mes 
i n 
P A D  
partici pa nts  
(Mc Der m ott  
et 
al 
1 9 9 8 , 
Sa gar  et al 2 0 1 2 , C o y ne  et al 2 0 0 3 , Nic olaï  et al 2 0 0 9 ) a n d als o pr o vi des g o o d pre dicti o ns of 
car di o vas c ular ris k i n ot h er car di o vasc ular  diseas es ( Nea d  et al 2 0 1 3 ).  
T he WI Q will o nl y be c o m plete d b y partici pa nts dia g n ose d wit h P A D at Baseli ne.  WI Q will be 
c ollecte d as o utli ne d i n t he Assess me nt Sc he d ule ( Ta ble  8 -1 ). 
8. 5. 1. 7  
M a c N e w H e art Di s e a s e  Q u alit y of Lif e Q u e sti o n n air e ( M a c N e w)  
T he 
Mac Ne w 
Heart 
Disease 
H R Q o L q uesti o n naire ( Mac -Ne w) is a self -a d mi nistere d 
m o dificati o n of t he ori gi nal Q ualit y of Life after M y ocar dial I nfarcti o n ( Q L MI)  i nstr u me nt 
(Li m  et al 1 9 9 3 , Vale nti  et al 1 9 9 6 ). It was s peciall y de vel o pe d t o meas ure t he q ualit y of life of 
partici pa nts wit h car di o vasc ular dise ases. T h e Mac Ne w c o nsists of 2 7 ite ms w hic h fall i nt o 
t hree d o mai ns ( p h ysical li mitati o ns, e moti o nal a n d s ocial f u ncti o n d o mai n scale). T here are 5 
ite ms t hat i n q uire a b o ut s y m pt o ms: a n gi na/c hest pai n, s h ort ness of breat h, fati g ue, dizzi ness, 
a n d ac hi n g le gs. T he p artici pa nts a ns wer t he q uesti o ns usi n g a se ve n -p oi nt Li kert scale fr o m 1 
(" w orst feeli n g") t o 7 (" b est feeli n g"). T he sc ores of t he t hr ee i n di vi d ual d o mai ns are calc ulate d 
b y a vera gi n g t he p oi nt val ues i n t he ass ociate d ite ms. T he a vera ge val ue of all 2 7 ite ms gi ves 
t he gl o bal t otal sc ore. A hi g her t otal sc ore c orres p o n ds t o a better q ualit y of life. T he vali dit y, 
relia bilit y a n d c h a n ge se nsiti vit y of t he Mac Ne w h a ve b ee n d e m o nstrate d i n vari o us p artici pa nt 

N o v arti s  
C o nfi d e nti al  
P a g e 7 8  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
gr o u ps, i ncl u di n g partici pa nts wit h 
m y ocar dial i nfarcti o n, wit h A P a n d wit h isc he mic 
heart  fail ure (H öfer  et al 2 0 0 4 , H öfer  et al 2 0 1 2 ).  
T he Mac Ne w q uesti o n n aire will o nl y b e c o m plete d b y partici p a nts dia g n ose d wit h A n gi na 
Pect oris at Bas eli ne. T he q uer y peri o d c o v ers t h e p ast 1 4 da ys. T he M ac Ne w q uesti o n naire wi ll 
be a d mi nistere d as o utli n e d i n  Ta ble  8 -1 . 
8. 5. 2  
Ot h er e x pl or at or y bi o m ar k er s  
Ot her e x pl or at or y bi o mar kers t o be c ollecte d will i ncl u de:  
•  A p o B, L p(a), n o n -H D L -C, t otal c h olester ol, tri gl yceri des, a n d H D L -C, t o be c ollecte d as 
p er assess me nt T a ble  8 -1 . 
•  
P C S K 9 le vels will be c ollecte d fr o m all partici pa nts at t he baseli ne a n d t he E O S visits. I n 
t he cas e t hat a P C S K 9 m A b treat me nt is i n dicate d f or a partic ular partici pa nt i n t he 
escalati o n pr ocess, a bl o o d dra w f or P C S K 9 le vels m ust be perf or me d pri or t o starti n g o n 
t he P C S K 9 m A b. T he res ults fr o m t he P C S K 9 testi n g will be bli n de d t o all site staff a n d 
N o vartis tea m me m bers.  
9  
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 fr o m st u d y tr e at m e nt a n d fr o m st u d y  
9. 1. 1  
Di s c o nti n u ati o n fr o m st u d y tr e at m e nt  
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 pla n ne d c o m pleti o n of st u d y dr u g a d mi nistrati o n, if a n y) 
a n d ca n b e 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 d isc o nti n ue st u d y treat me nt (i nclisira n/ place b o) or r os u vastati n f or a 
gi ve n partici pa nt if, he/s he belie ves t hat c o nti n uati o n of t he res pecti ve st u d y treat me nt 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 (i ncl isira n/ place b o) or r os u vastati n is re q uir e d u n der t he 
f oll o wi n g circ u msta nces: 
•  Partici pa nt/ g uar dia n decisi o n.  
•  Pre g na nc y.  
•  Use of 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 6. 2. 2 ). 
•  A n y s it 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 ( Secti o n 1 0. 2 ). 
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 7 9  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
•  F oll o wi n g e mer ge n c y u n bli n di n g.  
•  A n y la b orat or y a b n or m alities 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 ( Secti o n 1 0. 2 ). 
•  Partici pa nt is s witc he d t o a P C S K 9 m A b ( Secti o n  3. 4 ).  
•  I ntr acta bl e cases wit h L D L-C still t o o hi g h after t he rec o m me n de d L L T escalati o n 
(Fi g ure  3 -2  of Secti o n  3. 4 ) a n d partici pa nt is re q uire d t o be treate d p er l ocal sta n dar d of 
care.  
If a partici pa nt is re q uir e d t o disc o nti n ue fr o m I nclisira n/ Place b o, t he y s h o ul d re mai n o n o p e n 
la bel st u d y treat me nt (r os u vastati n) a n d c o nti n ue f oll o wi n g t he pr ot oc ol rec o m me n de d 
escalati o n sc h e me as a p plica ble ( Secti o n  3. 4  a n d assess me nt sc he d ule ( T a ble 8 -1 ). 
If a partici pa nt is re q uire d t o disc o nti n ue fr o m o pe n la bel treat me nt r os u vastati n, t he y s h o ul d 
be s witc he d t o a n alter nati ve well t olerate d stati n, as per l ocal st a n dar d of care a n d at t h e 
discreti o n of t he i n vesti gat or, a n d c o nti n ue f oll o wi n g t he pr ot oc ol rec o m me n de d L L T 
escalati o n sc h e me as a p plica ble ( Secti o n  3. 4 ) a n d assess me nt sc he d ule ( Ta ble 8 -1 ). 
If disc o nti n uati o n fr o m st u d y treat me nt o cc urs, t h e 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 p artici 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 i n e C R F. 
Partici pa nts w h o disc o nti n ue fr o m st u d y treat me nt (I nclisira n/ place b o ) or  r os u vastati n s h o ul d 
be f oll o we d -u p a n d ret ur n t o t he visits as o utli ne d i n t he 
Assess me nt 
Sc he d ule  
(Ta ble 8 -1 ), or at a mi ni m u m a gree t o ret ur n f or t he e n d of st u d y visit or h a ve t he s afet y p h o n e 
call i n dicate d i n t he Assess me nt Sc he d ule (refer t o Ta ble  8 -1 ). 
If t he p artici pa nt ca n n ot or is u n willi n g t o atte n d a n y visit(s), t he site staff s h o ul d mai ntai n 
re g ular tele ph o ne c o nta ct wit h t he p artici pa nt, or wit h a pers o n pre -desi g nate d b y t h e 
partici pa nt. T his tele p h o n e 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 Assess me nt 
Sc he d ule.  
T he i n vesti gat or m ust als o c o ntact t he I R T t o re gister t he partici pa nt’s dis c o nti n uati o n fr o m 
st u d y treat me nt (f or i nclisira n/ place b o o nl y). 
If disc o nti n uati o n occ urs beca us e treat me nt c o de has bee n br o ke n, please refer t o E mer ge nc y 
brea ki n g of tr eat me nt c o de secti o n.  
I n case a partici pa nt disc o nti n ues bli n de d i n vesti gati o nal treat me nt i nclisira n/ place b o d ue t o a 
s witc h t o P C S K 9 m A b (refer t o Secti o n  3. 4 ), t he partici pa nt will re mai n i n t he st u d y a n d b e 
f oll o we d-u p u ntil t he partici pa nt’s e n d of st u d y acc or di n g t o t he Assess me nt Sc h e d ule. 
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 occ urs w he n t he parti ci 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 det aile d i n t he Assess me nt Sc h e d ule (E O S ) (refer t o Ta ble  8 -1 ). 

N o v arti s  
C o nfi d e nti al  
P a g e 8 0  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
9. 1. 3  
L o st t o f oll o w -u p  
F or partici pa nts w h ose stat us is u nclear beca use t he y fail t o a p pear f or  st u d y visits wit h o ut 
stati n g a n i nte nti o n t o disc o nti n ue 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 vesti gat or m ust s h o w " d ue 
dili ge nce" b y d oc u me nti n g i n t he s o urce d oc u me n ts 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 l etters, etc. A p artici pa nt s h o ul d n ot b e c o nsi dere d as l ost t o 
f oll o w-u p u ntil d ue dili ge nce h as bee n c o m plete d or u ntil t he partici pa nt’s e n d of st u d y.  
9. 2  
Wit h dr a w al of i nf or m e d c o n s e nt/ O p p o siti o n t o u s e 
d at a/ bi ol o gi c al s a m pl e 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 occ urs w he n a partici p a nt:  
•  E x plicitl y re q uests t o st o p use of t h eir 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 v esti 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 mati 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 us e of t heir Pers o nal D ata. 
St u d y treat me nt m ust be disc o nti n ue d a n d n o f urt her ass ess me nts c o n d uct e d, a n d t h e data t hat 
w o ul d ha ve bee n c ollect e d at s u bse q ue nt visits will be c o nsi dere d missi n g.  
F urt her atte m pts t o c o ntact t he p arti ci pa nt are n ot all o we d u nless safet y fi n di n gs re q uir e 
c o m m u nicati n g or f oll o w -u p.  
If t he p artici pa nt a grees, a fi nal e val uati o n at t he ti me of t he partici pa nt’s wit h dra wal of 
c o nse nt/ o p p ositi o n t o use data/ bi ol o gical sa m ples s h o ul d be ma de as det aile d i n t he Assess me nt 
Sc he d ule (refer t o Ta ble  8 -1 ). 
F urt her det ails o n wit h dra wal of c o nse nt or t he e x ercise of partici pa nts' data pri vac y ri g hts are 
i ncl u de d i n t he c orres p o n di n g i nf or me d c o nse nt f or m. 
9. 3  
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 St u d y C o m pleti o n visit 
( E O S) a n d a n y re p eat 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 h at decisi o n.   

N o v arti s  
C o nfi d e nti al  
P a g e 8 1  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
All ra n d o mize d a n d/ or 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 st u d y  visit ( E O S) or at least 9 0 da ys after last st u d y treat me nt i n case of earl y 
st u d y disc o nti n uati o n. 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 p a 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.  
At t he e n d of t he st u d y ( E O S), e ver y eff ort will be ma de t o c o nti n ue pr o visi o n of st u d y treat me nt 
o utsi de t his st u d y t hr o u g h a n alter nati ve setti n g t o partici pa nt w h o i n t he o pi ni o n of t he 
I n v esti gat or are still deri vi n g cli nical be nefit.  
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 base d o n 
partici pa nt a vaila bilit y f or f oll o w -u p. T his care ma y i ncl u de m o dificati o n of t he bac k gr o u n d 
L L T a n d c o ntr ol of ot her C V ris k fact ors, as it w o ul d n or mall y be d o ne i n sta n dar d cli nical 
practice.  
9. 4  
E arl y st u d y t er mi n ati o n b y t h e s p o n s or  
T he st u d y ca n be t er mi nate d b y N o vartis at a n y ti me.  
Reas o ns f or earl y ter mi n ati o n:   
•  U ne x pect e d, si g nifica nt, or u nacce pta ble s afet y ris k t o partici pa nt s 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 vi e w of safet y a n d 
effic ac y dat a  
•  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 d ecisi o n t o t er 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 . T he i n vesti gat or ma y be i nf or me d of 
a d diti o nal pr oce d ures t o be f oll o we d i n or der t o e ns ure t h at a d e 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 h e i n vesti gat or or s p o ns or de pe n di n g o n l o cal 
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 h e earl y ter mi nati o n of t he trial. 
1 0  
S af et y m o nit ori n g, r e p orti n g a n d c o m mitt e e s  
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 E is a n y u nt o war d me dical occ urre n ce (e. g. a n y u nfa v ora ble a n d u ni nte n de d si g n 
[i ncl u di n g a b n or mal la b orat or y fi n di n gs], s y m pt o m or disease) i n a cli nical i n vesti gati o n 
partici pa nt after pr o vi di n g writte n i nf or me d c o nse nt f or partici pati o n i n t he st u d y. T heref ore, 
a n A E ma y or ma y n ot be te m p orall y or ca usall y ass ociate d wit h t he use of a me dici nal 
(i n vesti gati o nal) pr o d uct. 
T he i n vesti gat or has t h e res p o nsi bilit y f or ma na gi n g t he safet y of i n di vi d ual partici pa nts a n d 
i de ntif yi n g 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.  

N o v arti s  
C o nfi d e nti al  
P a g e 8 2  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
T he occ urre n ce of A Es m ust be s o u g ht b y n o n -directi ve q u esti 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 v e 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 xa mi nati o n fi n di n gs, la b orat or y test 
fi n di n gs, or ot her assess me nts i ncl u di n g P R Os a n d diar y (refer t o Secti o n  8. 5. 1 ). 
A Es 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 ni e d b y t he f oll o wi n g i nf or mati o n (as far as p ossi ble) (if t he e v e nt is seri o us re fer t o 
Secti o n  1 0. 1. 2 ): 
1.  T he se verit y gr a de:  
•  mil d: us uall y tra nsie nt i n nat ure a n d g e nerall y n ot i nterferi n g wit h n or m al acti vities  
•  m o derate: s uffi cie ntl y disc o mf orti n g t o i nterfere wit h n or mal acti vities  
•  se vere: pre ve nts n or mal acti vities  
2.  T he ca usalit y  the 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  
(st u d y me dicati o n or A x M Ps) use d i n t he st u d y a n d eac h occ urre n ce of eac h A E. T h e 
i n vesti gat or will use cli nical j u d g me nt t o deter mi ne the 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 rel ati o ns hi p, rat her t ha n a rel ati 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 m ita 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.  If t he e v e nt is d u e t o lac k of efficac y or pr o gressi o n of 
u n derl yi n g ill ness (i.e. pr o gressi o n of t he st u d y i n dicati o n) t he assess me nt of ca usalit y will 
us uall y be ‘ N ot s us pecte d.’ T he rati o nal e f or t his g ui da nce is t hat t he s y m pt o ms of a lac k of 
effic ac y or pr o gressi o n of u n derl yi n g ill ness are n ot ca use d b y t he trial dr u g, t he y ha p pe n i n 
s pite of its a d mi nistrati o n a n d/ or b ot h lac k of efficac y a n d pr o gressi o n of u n d erl yi n g disease 
ca n o nl y be e v al uate d me a ni n gf ull y b y a n a nal ysis of c o h orts, n ot o n a si n gle partici pa nt.  
3.  Its d ur ati 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. 
4.  W het her it c o nstit utes a S A E (see 
Secti o n  1 0. 1. 2  f or d efi niti o n of S A E) a n d w hic h 
seri o us ness criteria ha ve bee n met. 
5.  Acti o n ta ke n re g ar di n g i nclisira n/ place b o, or r os u vastati n.  
All A Es 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 g e d  
•  D ose re d u ce d/i ncrease d f or r os u vastati n  
•  Dr u g i nterr u pte d/ per ma n e ntl y disc o nti n ue  
6.  Its o utc o me ca n b e:  
•  n ot rec o vere d/ n ot res ol ve d;  
•  rec o vere d/r es ol ve d; 
•  rec o veri n g/res ol vi n g, 
•  rec o vere d/r esol ve d wit h se q uelae;  
•  fatal; 
•  or u n k n o w n   

N o v arti s  
C o nfi d e nti al  
P a g e 8 3  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
C o n diti o ns t hat were alrea d y pres e nt at t he ti me of i nf or me d c o nse nt s h o ul d be rec or de d i n 
me dical hist or y of t he partici pa nt.  
A Es (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.  
O nce a n A E is d etecte 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 b e 
per ma ne nt (e. g. c o nti n ui n g at t he e n d of t he st u d y), a n d assess me nt m ust b e ma de  at eac h visit 
( or m ore fre q ue ntl y, if n ecessar y) of a n y c ha n g es i n se verit y, t he s us pecte d relati o ns hi p t o t he 
i nter ve nti o ns re q uire d t o treat it, a n d t he o utc o me. 
I nf or mati o n a b o ut a d verse dr u g reacti o ns f or t h e i n vesti gati o nal dr u g ca n be f o u n d i n t he 
In v esti gat or's Br oc h ure (I B) or l ocal S m P C.  
I nf or mati o n a b o ut a d v ers e dr u g reacti o ns f or r os u vastati n ca n be f o u n d i n t he l ocal S m P C. 
A b n or mal la b orat or y val ues or test res ults c o nstit ute A Es o nl y if t he y f ulfill at least o ne of t he 
f oll o wi n g criteria: 
•  t he y i n d uce cli nical si g ns or s y m pt o ms 
•  t he y are c o nsi dere d cli nicall y si g nifica nt 
•  t he y re q uire t h era p y 
Cli nicall y si g nifica nt a b n or mal la b orat or y v al ues or test res ults m ust be i de ntifie d t hr o u g h a 
re vie w of val u es o utsi de of n or mal ra n ges/cli nicall y n ota ble ra n ges, si g nifica nt c ha n g es fr o m 
baseli ne or t he pre vi o us visit, or val ues w hic h are c o nsi dere d t o b e n o n -t y pical i n partici p a nt 
wit h t he u n derl yi n g disease.  
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 u se d i n t his st u d y m ust be 
re p orte d t o N o v artis. 
I n assessi n g ca us alit y, t he i n vesti gat ors will use t he p oi nts me nti o ne d i n t he para gra p h a b o v e.  
If a s us pici o n t hat me di cal occ urre n ce c o ul d be relate d t o A x M P  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. 
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 E [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), sy 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 hreat e 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 r efer 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 ( pl ease refer t o t he I C H -E 2 D G ui deli n es).  
•  res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y  
•  c o nstit utes a c o n ge nital a n o mal y/ birt h defect   

N o v arti s  
C o nfi d e nti al  
P a g e 8 4  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
•  re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n, u nless 
h os pitalizati o n is f or:  
•  r o uti ne treat me nt or m o nit ori n g of t he st u die d i n dicati o n, n ot ass ociate d wit h a n y 
deteri orati o n i n c o n diti o n (c or o nar y heart disease, cere br o vasc ul ar diseas e or peri p heral 
vasc ular dise ase)  
•  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 pit e care i n t h e a bs e nce of a n y deteri orati o n i n t he partici pa nt’s 
ge neral c o n diti o n  
•  treat me nt o n a n e mer g e nc y o ut patie nt basis f or a n e v e 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 r es 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 v e nt t hat je o par dizes t he partici pa nt or ma y 
re q uire me di cal or s ur gic al i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d a b o ve 
Me dical a n d s cie ntific j u d g me nt s h o ul d be e xercis e d i n deci di n g w 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 x a m ples of s uc h e ve nts are i nte nsi ve treat me nt i n a n 
e mer ge n c y r o o m or at h o me f or aller 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 pitaliz ati o n or de v el o p me nt of d e pe n de n c y or a b use ( ple ase refer t o t he I C H -
E 2 D G ui deli nes).  
All ne w mali g na nt ne o pl as ms will be assesse d as seri o us u n der “ me dicall y si g nifica nt” if ot her 
seri o us ness criteria are n ot met. 
A n y s us pecte d tra ns missi o n via a me dici nal pr o d uct of a n i nfecti o us a ge nt is als o c o nsi de re d a 
seri o us a d vers e 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 S A E irres pecti v e 
if a cli nical e v e 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 afte r t he p artici pa nt 
has pr o vi de d i nf or me d c o nse nt a n d u ntil 3 0 da ys after t he last st u d y visit  m ust be re p orte d t o 
N o vartis safet y i m me diat el y, wit h o ut u n d ue dela y, b ut u n der n o circ u msta n ces lat er 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 h e e ve nts ( N ote: If m or e stri n ge nt, l ocal re g ulati o ns 
re gar di n g re p orti n g ti meli nes pre vail). Detaile d i nstr ucti o ns re gar di n g t h e s u b missi o n pr ocess 
a n d re q uir e me nts are t o be f o u n d i n t he i n vesti gat or f ol der pr o vi d e d t o eac h site. I nf or m ati o n 
a b o ut all S A Es  occ urri n g bef ore E O S visit  is c ollecte d a n d rec or de d o n t he e S A E pa ge  wit h 
pa per bac k u p a n d as pa p er d uri n g t he 3 0 da ys safet y f oll o w -u p peri o d after E O S; 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.  
S A E r e p orti n g ti me fra m es are as f oll o ws:  
1.  S A Es occ urri n g aft er t he partici pa nt has pr o vi d e d i nf or me d c o nse nt u ntil t he ti me t he 
partici pa nt is dee me d a Scree n Fail ure m ust be re p orte d t o N o vartis.  

N o v arti s  
C o nfi d e nti al  
P a g e 8 5  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
2.  S A Es occ urri n g  bet wee n ti me partici pa nt si g ns I C F u ntil ti me t ha t partici p a nt is deter mi ne d 
t o be a r u n-i n f ail ure m ust be re p orte d t o N o v artis.  
3.  S A Es occ urri n g bet w ee n ti me partici pa nt si g ns I C F u ntil 3 0 da ys after E O S m ust be re p orte d 
t o N o vartis. 
All f oll o w -u p i nf or mati o n f or t he S A E i n cl u di n g i nf or mati o n o n c o m plic ati 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 l ater t h a n wit hi n 2 4 h o urs of t h e 
i n vesti gat or recei vi n g t he f oll o w-u p i nf or m at i o n ( N ote: If m or e stri n ge nt, l ocal re g ulati o ns 
re gar di n g re p orti n g ti meli nes pre vail). A n S A E occ urri n g at a differe nt ti me i nter val or 
ot her wise c o nsi dere d c o m pletel y u nrelate d t o a pre vi o usl y re p orte d o ne m ust be re p orte d 
se parat el y as a ne w e ve nt. 
If the S A E is n ot pre vi o usl y d oc u me nte d i n t he I n vesti gat or’s Br oc h ure or Pac ka ge I ns ert ( ne w 
occ urre nce) a n d is t h o u g ht t o be relate d t o t he st u d y treat me nt, a P V & P S De part me nt ass o ciate 
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 hea lt h a ut h orit y re p orti n g. 
N o vartis ma y n ee d t o iss ue a n I N t o i nf or m all i n vesti gat ors i n v ol ve d i n a n y st u d y wit h t he sa me 
st u d y treat me nt t hat t his S A E has bee n re p orte d. 
S us pecte d U n e x pect e d S eri o us A d verse Reacti o ns ( S U S A Rs) will be c ollecte d a n d re p ort e d t o 
t he c o m pete nt a ut h orities a n d rele va nt et hics c o m mittees i n acc or da nce wit h E U G ui da nce 
2 0 1 1/ C 1 7 2/ 0 1, or E ur o p ea n Cli nical Trial Re g ulati o n 5 3 6/ 2 0 1 4, or as per nati o nal re g ulat or y 
re q uire me nts i n partici pati n g c o u ntries. 
A n y S A Es e x p erie nce d after t h e 3 0 da y f oll o w -u p peri o d after E O S s h o ul d o nl y be re p orte d t o 
N o vartis Safet y if t he i n 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 o cal la w/re g ul ati o ns.  
R e p orti n g of S A E s r el at e d t o A x M P( s)  
All S A Es relate d  t o a n y a u xiliar y me dici nal pr o d uct ( w het h er a ut h orize d or n ot) use d i n t his 
st u d y m ust be re p ort e d t o N o vartis wit hi n 2 4 h o urs of t he site b ec 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 pici o n t hat t he m e dical occ urre n ce 
c o ul d be rel ate 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.  
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 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 n c 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 uat e 
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 v esti gat or t o c o llect 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 o cc 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 n ce. T he pre g na nc y s h o ul d b e 
f oll o we d u p t o deter mi ne o utc o me, i ncl u di n g s p o nta ne o us or v ol u ntar y ter mi nati o n, details of 
t he birt h, a n d t he prese nce or a bse nce of a n y birt h defects, c o n g e nital a b n or malities, or mater nal 
a n d/ or ne w b or n c o m plicati o ns.  

N o v arti s  
C o nfi d e nti al  
P a g e 8 6  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
Pre g na nc y s h o ul d be rec or de d a n d re p ort e 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 P atie nt Safet y ( C M O & P S). Pre g na nc y f oll o w -u p s h o ul d b e rec or de d o n t he s a me 
f or m a n d s h o ul d i ncl u de a n assess me nt of t he p ossi ble relati o ns hi p t o t he st u d y treat me nt a n d 
pre g na nc y o ut c o me. A n y S A E e x perie n ce d d uri n g pre g na nc y m ust be re p orte d.  
After c o nse nt is pr o vi d e d, t he pre g na nc y re p orti n g will c o nti n ue f or u p t o o ne year after t he 
esti mate d date of d eli ver y.  
1 0. 1. 5  
R e p orti n g of st u d y tr e at m e nt err or s i n cl u di n g mi s u s e/ a b u s e  
St u d y treat me nt err ors 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 of  
st u d y treat me nt. 
St u d y treat me nt mis use refers t o sit uati o ns w here t he st u d y treat me nt 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. 
St u d y treat me nt a b u se 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 
st u d y treat me nt, w hic h is acc o m pa ni e d b y har mf ul p h ysical or ps yc h ol o gical effects.  
St u d y treat me nt err ors a n d uses o utsi de of w hat is f oresee n i n t he pr ot oc ol. i ncl u di n g mis use o r 
a b use, m ust be re p orte d o n t he A E ( or S A E, if t he e ve nt meets t he defi niti o n of a n S A E) e C R F 
a n d re p orte d i n t he safet y data base irres p ecti 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 
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 h e 
res pecti ve s ecti o ns. 
1 0. 2  
A d diti o n al S af et y M o nit ori n g  
Al wa ys refer t o t he l oc al r os u vastati n S m P C.  
1 0. 2. 1  
Li v er s af et y m o nit ori n g  
R os u vastati n s h o ul d be disc o nti n ue d or t he d ose re d uce d if t he le vel of ser u m tra nsa mi nases 
is > 3 x U L N (al w a ys refer t o t he l ocal S m P C). 
H e p ati c S eri o u s A d v er s e E v e nt( s)  
He patic S A Es will be s p ecificall y c ollecte d a n d assesse d t hr o u g h o ut t he trial t o i de ntif y t he 
p ote ntiall y rare cases of dr u g -i n d uce d li ver i nj ur y ( DI LI), n o ne of w hic h ha ve bee n see n s o far 
wit h i nclisira n.  

N o v arti s  
C o nfi d e nti al  
P a g e 8 7  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
Partici pa nts wi t h tra nsa mi nase i ncreas e c o m bi ne d wit h t otal bilir u bi n i ncrease 
ma y b e 
i n dicati ve of p ote ntiall y se vere DI LI a n d s h o ul d be c o nsi dere d as cli nicall y i m p orta nt e ve nts 
a n d assesse d a p pr o priat el y t o esta blis h t he dia g n osis. He patic A Es will be assesse d as seri o us 
u n der “ me dicall y si g nifica nt” e v e n if ot her seri o us ness criteria are n ot met, usi n g t he f oll o wi n g 
criteria:  
•  A L T or A S T ≥5 x U L N  
•  A L P ≥2 x U L N i n t he a bs e nce of k n o w n b o ne p at h ol o g y  
•  F or partici pa nts wit h n or mal A L T a n d A S T a n d t otal bilir u bi n val ue at base li ne: A S T or 
A L T > 3. 0 x U L N c o m bi ne d wit h t otal bilir u bi n > 2. 0 x U L N ( meeti n g t he criteria f or a 
p ote ntial H y’s La w case)  
•  F or partici pa nts wit h ele vate d A S T or A L T or t otal bilir u bi n val ue at baseli ne: A S T or 
A L T > 2 x bas eli ne A N D > 3 x U L N c o m bi ne d wit h t otal bilir u bi n > 2 x baseli ne A N D > 
2. 0 x U L N ( meeti n g t he criteria f or a p ote ntial H y’s La w case)  
F or p ote ntial H y’s La w cases a n e x pe dite d re p orti n g is re q uire d, a n d will be ha n dle d as a seri o us 
u ne x pecte d a d v erse e v e nt  ass ociate d wit h t he use of t he st u d y treat me nt  (assessi n g it as 
me dicall y si g nifica nt i n t he a bse n ce of a n y ot her s eri 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 v e 
bee n e x cl 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 p eciall 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 p atie nt m o nit ori n g a n d t o better u n dersta n d p ote ntial eti ol o gies, t he i n vesti gat or m ust 
i nitiate a cl ose f oll o w-u p u ntil c o m plete res ol uti o n of t he pr o ble m a n d c o m pleti o n of all 
atte m pts t o o btai n s u p ple me ntar y data.  
As DI LI is ess e ntiall y a dia g n osis of e xcl usi o n, ot her ca us es of a b n or mal li ver tests s h o ul d be 
c onsi dere d, a n d t heir r ol e clarifie d b ef ore DI LI is ass u me d as t he ca use of li ver i nj ur y. T he 
re q uire d cli nic al i nf or mati o n will be c ollecte d i n s pecific e C R F f or ms t o o btai n t he me dical 
dia g n osis of t he m ost li kel y ca use of t he o bser ve d la b orat or y a b n or mali ties. 
T he e val uati o n of t hese ele vate d L F Ts ma y i ncl u de a detaile d hist or y, as well as rele va nt 
i nf or mati o n s uc h as re vie w of et ha n ol c o ns u m pti o n, c o nc o mita nt me dicati o ns, her bal re me dies, 
s u p ple me nt c o ns u m pti o n, hist or y of a n y pre-e xisti n g li ver c o n diti o n s or ris k fact ors, la b orat or y 
tests, i ma gi n g a n d pat h ol o g y assess me nts t hat w o ul d ha ve b ee n p erf or me d t o el uci d ate t h e 
eti ol o g y of t hese he patic S A Es.  
F oll o wi n g a p pr o priat e ca usalit y assess me nts, as o utli ne d a b o ve, t he ca us alit y of t he treat me nt 
is esti mate d as “ pr o ba ble ” i.e. > 5 0 % li kel y, if it a p pears greater t ha n all ot her p ossi ble ca uses 
of li ver i nj ur y c o m bi ne d. T he t er m “treat me nt -i n d uce d” i n dicates pr o ba bl y ca us e d b y t he 
treat me nt, n ot b y s o met hi n g else, a n d o nl y s uc h a case ca n be c o nsi dere d a DI LI case.  
O nl y cases c o nfir me d o n re peat testi n g meeti n g t he la b orat or y criteria defi ne d a b o ve, wit h n o 
ot her alter nati ve ca use f or L F T a b n or malities i de ntifie d, s h o ul d be re p orte d as S A E usi n g t he 
ter m “ p ote ntial treat me nt-i n d uce d li ver i nj ur y.” All e ve nts s ho ul d be f oll o we d u p wit h t he 
o utc o me clearl y d oc u me nte d.  
Per ma ne nt disc o nti n uati o n fr o m st u d y treat me nt s h o ul d be t he r ule if ca usalit y assess me nt 
i n dicates t hat DI LI is pr o ba ble. Please refer t o Secti o n  9. 1. 1  f or m ore details o n 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 8 8  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
1 0. 2. 2  
R e n al s af et y m o nit ori n g  
 F or t he o p e n la bel st u d y treat me nt (r os u v astati n) re nal f u ncti o n s h o ul d be m o nit ore d a n d 
assess me nts are o utli ne d i n t he 
Assess me nt Sc he d ule ( Ta ble 8 -1 ). 
R osu vastati n is 
c o ntrai n dicate d:  
•  i n partici pa nts wit h se vere re nal i m pair me nt (creati ni ne cleara nce < 3 0 m L/ mi n) re gar dless 
of t he d ose,  
•  i n partici pa nts wit h m o derate re nal i m pair me nt (creati ni ne cleara n ce < 6 0 m L/ mi n) wit h 4 0 
m g d ose r os u vastati n.  
Pr otei n uria,  dete cte d b y di pstic k testi n g a n d m ostl y t u b ular i n ori gi n, has bee n o bser ve d i n 
patie nts treate d wit h hi g her d oses of r os u vast ati n, i n partic ular 4 0 m g, w here it was tra nsie nt or 
i nter mitte nt i n m ost cas es. Pr otei n uria h as n ot bee n s h o w n t o be pre dicti ve of ac ute or 
pr o gressi ve re nal diseas e.  
1 0. 2. 3  
S k el et al m u s cl e s af et y m o nit ori n g  
Partici pa nts s h o ul d be as ke d t o re p ort i ne x plica ble 
m uscle p ai n, wea k ness or cra m ps 
i m me diatel y, partic ularl y if ass ociate d wit h malais e or fe v er. 
R os u vastati n t hera p y s h o ul d be disc o nti n ue d if C K le vels are mar k e dl y ele vate d ( > 5 x U L N) or 
if m usc ular s y m pt o ms are se vere a n d ca use d ail y disc o mf ort (e v e n if C K le vels are ≤ 5 x U L N). 
If s y m pt o ms res ol ve a n d C K le vels ret ur n t o n or m al, t he n c o nsi derati o n s h o ul d be gi ve n t o re-
i ntr o d uci n g r os u vastati n at t he l o west d ose wit h cl ose 
m o nit ori n g (al wa ys refer t o t h e 
r os u vastati n S m P C). I n v esti gat ors are e n c o ura ge d t o i de ntif y earl y si g ns a n d s y m pt o ms of 
m uscle -relat e d a d vers e e ve nts a n d ma y 
 r os u vastati n d osa ge t o pre ve nt se vere 
m usc u lar s y m pt o ms. I n case t h e partici pa nt d oes n ot t olerate t he l o w est d ose of r os u vastati n, 
t he partici pa nt m ust disc o nti n ue r os u vastati n, be treate d as per l ocal sta n dar d of care a n d 
f oll o we d-u p u ntil t he partici pa nt’s e n d of st u d y as o utli ne d i n t he Assess m e nt Sc he d ule 
(Ta ble  8 -1 ). 
1 0. 2. 4  
S e v er e c ut a n e o u s r e a cti o n m o nit ori n g  
At t he ti me of r os u v astati n prescri pti o n, partici pa nts s h o ul d be a d vise d of t he si g ns a n d 
s y m pt o ms of se vere s ki n reacti o ns a n d b e cl osel y m o nit ore d. If si g ns a n d s y m pt o ms s u g gesti ve 
of t his reacti o n a p pear, r os u vastati n s h o ul d be dis c o nti n ue d i m me diatel y. Partici pa nt s h o ul d b e 
treate d as per l ocal sta n dar d of care a n d f oll o we d-u p u ntil t he partici pa nt’s e n d of st u d y as 
o utli ne d i n t he Assess me nt Sc he d ule ( Ta ble  8 -1 ). If t he partici pa nt has de vel o pe d a seri o us 
reacti o n s uc h as Ste ve ns-J o h ns o n s y n dr o me or dr u g reacti o n wit h e osi n o p hilia a n d s yste mic 
s y m pt o ms wit h t he use of r os u vastati n, treat me nt wit h r os u vastati n m ust n ot be restarte d at a n y 
ti me. 
1 0. 2. 5  
I nt er stiti al l u n g di s e a s e 
E xce pti o nal cas es of i nterstitial l u n g disease ha ve bee n re p orte d wit h s o m e stati ns, es peciall y 
wit h l o n g ter m t hera p y. If a partici pa nt is s us pecte d t o ha ve de v el o pe d i nterstitial l u n g disease, 
t he partici pa nt m ust disco nti n ue r os u vastati n, be treate d as per l ocal sta n dar d of care a n d 
f oll o we d-u p u ntil t he partici pa nt’s e n d of st u d y as o utli ne 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 8 9  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
1 0. 2. 6  
I m m u n e-m e di at e d n e cr oti zi n g m y o p at h y (I M N M)  
T here ha v e bee n ver y rare re p orts of a n i m m u ne -me diate d necr otizi n g m y o pat h y (I M N M) 
d uri n g or after treat me nt wit h stati ns, i ncl u di n g r os u vastati n. I M N M is cli nicall y c haract erize d 
b y pr o xi mal m uscle wea k ness a n d el e vate d ser u m creati ne ki nas e, w hic h persist des pite 
disc o nti n uati o n of stati n treat me nt.  
1 0. 2. 7  
Pr ot hr o m bi n ti m e a n d I nt er n ati o n al N or m ali z e d R ati o  
T he i nitiati o n of treat me nt or d osa ge u p -titrati o n of r os u vastati n i n partici pa nts treate d 
c o nc o mita ntl y wit h vita mi n K a nta g o nists (e. g., warfari n or a n ot her c o u mari n  a ntic oa g ula nt) 
ma y res ult i n a n i ncrease i n I nter nati o nal N or mali ze d Rati o (I N R). Dis c o nti n uati o n or d o w n -
titrati o n of r os u vastati n ma y res ult i n a decrease i n I N R. I n s u c h sit uati o ns, a p pr o priate 
m o nit ori n g of I N R is desira ble.  
1 0. 3  
C o m mitt e e s  
1 0. 3. 1  
St e eri n g C o m mit t e e 
T he Steeri n g C o m mittee ( S C) will be esta blis he d c o m prisi n g i n vesti gat ors partici pati n g i n t he 
trial, e x perts i n t heir res p ecti ve fiel ds a n d  N o vartis  re pres e ntati ves fr o m t h e C T T. 
T he S C will e ns ur e tr a ns pare nt ma na ge me nt of t he st u d y acc or di n g t o t h e p r ot oc ol t hr o u g h 
rec o m me n di n g a n d a p pr o vi n g m o dificati o ns as circ u msta nces re q uir e. T he S C will re vie w 
pr ot oc ol a me n d m e nts as a p pr o pri ate. T o g et her wit h t he C T T, t he S C will als o d e vel o p 
rec o m me n dati o ns f or p u blicati o ns of st u d y res ults i ncl u di n g a ut h ors hi p r ules. T he details of t h e 
r ole of t he steeri n g c o m mittee will be defi ne d i n t he steeri n g c o m mittee c harter.  
S o me of t he S C me m bers will be p art of a gr o u p t o deci d e o n eli gi bilit y of p artici pa nts f or 
recei vi n g P C S K 9 m A b f oll o wi n g t he escalati o n pr ocess i n t he treat me nt peri o d. T he i n vesti gat or 
will e ns ure all rele va nt data, t o s u p p ort t he decisi o n t o s witc h t he partici pa nt’s treat me nt t o a 
P C S K 9 m A b, has bee n e ntere d i nt o t he e C R F. T h e S C me m bers will alert t he i n vesti gat or o n 
t he decisi o n, i n a ti mel y ma n ner. Please als o refer t o  Secti o n  3. 4 . 
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 dat a re q uire d b y t he pr ot oc ol i nt o t he 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 p a n cies i n t he 
e C R Fs, all o w m o dificati o n a n d/ or verificati o n of t he e ntere d d ata b y t he i n vesti gat or staff.  
T he i n vesti gat or/ desi g ne e is res p o nsi ble f or ass uri n g t hat t he data (rec or de d o n C R Fs, e ntere d 
i nt o e C R F) is c o m plete, acc urat e, a n d t hat e ntr y a n d up 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 plet e a n d acc urat e.  
After fi n al data b ase l oc k, t he i n vesti gat or will recei v e c o pies of t he p artici pa nt data f or 
arc hi vi n g at t he i n vesti gati o nal site.  

N o v arti s  
C o nfi d e nti al  
P a g e 9 0  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
All d ata s h o ul d be rec or de d, ha n dle d, a n d st ore d i n a wa y t hat all o ws its acc urate re p orti n g, 
i nter pretati o n, a n d v erific ati o n. 
1 1. 2  
D at a b a s e m a n a g e m e nt a n d q u alit y c o ntr ol  
N o vartis  pers o n nel or d esi g nate d C o ntract R esearc h Or g a nizati o n ( C R O) will re vie w t h e dat a 
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 clarifi cati o n will be create d f or discre pa n cies 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 u eri es a n d t o ma ke a n y necessar y c h a 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 bas e will be c o de d usi n g t he 
W orl d Healt h Or ga ni zati o n ( W H O) 
Dr u g Refere nce List, w hi c h e m pl o ys t he A nat o mical 
T hera p e utic C he mical cl assificati o n s yste m. Me dical hist or y/c urre nt me di cal c o n diti o ns a n d 
A Es will be c o d e d usi n g t he 
Me dical Dicti o n ar 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, r u n-i 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 t he st u d y treat me nt (s) dis pe nse d ( o nl y 
I n clisira n/ place b o) t o t he partici pa nt will be trac ke d usi n g a n I 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 dat a will be se nt electr o nicall y t o 
N o vartis  at s pecifi c ti meli nes.  
Eac h occ urre nce of a c o d e brea k via I R T will be re p orte d t o t he cli nical tea m a n d m o nit or. T he 
c o de brea k f u ncti o nalit y will re mai n a vail a ble u ntil st u d y s h ut d o w n or u p o n re q uest of 
N o vartis.  
O nce all t he necessar y acti o ns ha ve bee n c o m plete d a n d t h e d ata base has bee n d eclare d t o be 
c o m plete a n d acc urate, it will be l oc ke d a n d t he 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 dat a a nal ysis/m o ve d t o restricte d area t o be access e d b y i n de pe n de nt pr o gra m mer 
a n d statisticia n.  A n y c ha n ges t o t he data base after t hat ti me ca n o nl y be ma de aft er writte n 
a gree m e nt b y N o vartis d e vel o p me nt ma na g e me nt.  
D at a q u alit y a s s ur a n c e  
M o nit ori n g strat e g y met h o ds, res p o nsi bilities, a n d re q uire me nts are pr o vi d e d i n t he m o nit ori n g 
pla n/c o ntracts. Det ails ma y i ncl u de defi niti o n of st u d y critical data ite ms a n d pr ocess es (e. g. 
ris k-base d i nitiati ves i n o perati o ns a n d q ualit y s uc h as ris k ma na ge me nt a n d miti gati o n 
strate gies a n d a nal ytic al ris k-base d m o nit ori n g), i ncl u di n g ha n dli n g of n o nc o m plia nce iss ues 
a n d m o nit ori n g tec h ni q ues (ce ntr al, re m ote, or o n -site m o nit ori n g). 
Rec or ds a n d d oc u me nts, i ncl u di n g si g ne d I C Fs, p ertai ni n g t o t he c o n d uct of t his st u d y m u st b e 
retai ne d b y t he I n vesti g at 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 d estr 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. No rec or ds ma y be tra nsferre d t o 
a n ot her l ocati o n or p art y wit h o ut writte n n otificati o n t o N o vartis.  

N o v arti s  
C o nfi d e nti al  
P a g e 9 1  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
1 1. 3  
Sit e m o nit ori n g  
Bef ore st u d y i nitiati o n, at a site i nitiati o n visit or at a n i n vesti gat or’s 
meeti n g, a 
N o vartis  re prese ntati ve will re vie w t he pr ot oc ol a n d data ca pt ure re q uir e me nts (i.e. e S o urce 
D D E or e C R Fs) wit h t h e i n vesti gat ors a n d t heir staff. D uri n g t he st u d y, N o va rtis 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 u alit 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 p artici pa nt rec or ds, t h e 
acc urac y of data ca pt ur e / data e ntr y, t he a d here nce t o t he pr ot oc ol a n d t o G o o d Cli nical 
Practice, t he pr o gress of e nr oll me nt, a n d t o e ns ure t hat st u d y treat me nt is bei n g st ore d, 
dis pe nse d, a n d acc o u nt e d f or acc or di n g t o s p ecificati o ns. Ke y st u d y pers o n nel m ust be a vaila ble 
t o assist t he fiel d m o nit or duri 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 dat a 
ma y be p erf or me d b y a ce ntralize d N o vartis/ C R A or ga nizati o n. A d diti o nall y, a ce ntr al a nal ytics 
or ga nizati o n ma y a n al yz e data & i de ntif y ris ks & tre n ds f or site o perati o nal para met ers, a n d  
pr o vi de re p orts t o N o v artis 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 d ata, 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 b e tr acea ble t o t hese s o urce d o c u me nts i n t he p artici pa nt's file. T he i n vesti gat or 
m ust als o kee p t he ori gi nal I C F si g ne d b y t he partic i 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 o c u me nts t o c o nfir m t heir 
c o nsiste nc y wit h t he data ca pt ur e a n d/ or data e ntr y. N o vartis m o nit ori n g st a n dar ds re q uir e f ull 
verificati o n f or t he pres e nce of i nf or m e d c o nse nt, a d here n ce t o t he i ncl usi o n/e xcl usi o n criteria, 
d oc u me ntati o n of S A Es, a n d of data t hat will be use d f or all pri mar y varia bles. A d diti o nal 
c hec ks of t he c o nsiste nc y of t he s o urce data wit h t he e C R Fs are perf or m e d acc or d i n g t o t he 
st u d y-s pecific m o nit ori n g pla n. N o i nf or mati o n i n s o urce d oc u m e nts a b o ut t he i de ntit y of t he 
partici pa nts will be discl ose d.  
1 2  
D at a a n al y si s a n d st ati sti c al m et h o d s  
A n y data a nal ysis carrie d o ut i n de pe n de ntl y b y t he i n vesti gat or s h o ul d be s u b mitte d t o N o vartis 
bef ore p u blicati o n or prese ntati o n.  
1 2. 1  
A n al y si s s et s  
T he  scree ne d set ( S C R) c o nsists of all partici pa nts w h o si g ne d t he i nf or me d c o nse nt. T he S C R 
i ncl u des o nl y u ni q ue scree ne d p artici pa nts, i.e., i n t he cas e of re-scree n e d p artici pa nts o nl y t he 
c hr o n ol o gicall y last scree ni n g data is c o u nte d.  
T he r u n -i n set ( RI S) c o nsists of all patie nts w h o e nter t he r u n -i n p has e. 
T he  r a n d o mize d set ( R A N)  c o nsists of all partici pa nts w h o recei v e d a ra n d o mizati o n n u m ber, 
re gar dl ess of recei vi n g trial me dicati o n. 
T he f ull a n al ysis set ( F A S) c o nsists of all ra n d o mize d partici p a nts w h o recei ve d at least o n e 
d ose of d o u ble -bli n d st u d y me dicati o n. F oll o wi n g t he i nte nt -t o-treat pri nci ple, partici pa nts will 
be a n al yze d acc or di n g t o t he treat me nt t o w hic h t h e y were assi g ne d at ra n d o mizati o n. Efficac y 
varia bles will be a n al yze d base d o n t he F A S.  

N o v arti s  
C o nfi d e nti al  
P a g e 9 2  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
T he s afet y set ( S A F) i ncl u des all partici pa nts w h o recei v e d at least o ne d ose of st u d y treat me nt. 
Partici pa nts will be a nal yze d acc or di n g t o t he st u d y treat me nt recei ve d. T h e S A F  wil l be use d 
f or t he a n al yses of safet y a n d t olera bilit y varia bles. 
T he A P set is a s u bset of t he F A S a n d i ncl u des p artici pa nts wit h a dia g n osis of a n gi na pect oris at 
baseli ne.  
T he P A D  set is a s u bset of t he F A S a n d i ncl u des partici pa nts wit h a dia g n osis of p eri p heral 
arter y disease at b aseli ne.  
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 h aracteristics 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 d ata will b e prese nte d as fre q u e ncies a n d perce nta ges. F or c o nti n u o us data, mea n, 
sta n dar d de viati o n, 
me dia n, 
mi ni m u m, a n d 
ma xi m u m 
will be prese nte d. F or selecte d 
para meters, 2 5t h a n d 7 5t h perce ntiles will als o be prese nte d . 
Rele va nt me dical hist ori es a n d c urre nt me d ical 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 t er m, b y treat me nt gr o u p.  
T he n u m ber of partici p a nts scree n e d, ra n d o mize d a n d i ncl u de d i n F A S will be prese nte d b y 
treat me nt gr o u p a n d o verall f or t he scree ne d set. I n a d diti o n, t he reas o ns f or disc o nti n uati o n 
pri or  t o ra n d o mizati o n will be pr o vi de d f or t h e scree ne d a n d r u n-i n s et. T he n u m ber a n d 
pr o p orti o n of partici pa nts w h o c o m plete d t he st u d y, w h o disc o nti n ue d t he st u d y a n d t he reas o n 
f or disc o nti n uati o n fr o m st u d y will be prese nte d i n a st u d y dis p ositi o n ta ble f or eac h treat me nt 
gr o u p a n d o verall base d o n t he ra n d o mize d set. T he fre q u e nc y ( %) of p artici pa nts wit h maj or 
pr ot oc ol de viati o ns as well as t h e criteria l ea di n g t o data e xcl usi o n fr o m a nal ysis will be 
prese nt e d i n se p arat e ta bles f or t he ra n d o mize d set. Fi nall y, t he n u m b er of e nr olle d a n d 
ra n d o mize d partici pa nts b y re gi o n as well as t he n u m ber of partici pa nts e nr olle d a n d 
ra n d o mize d per re gi o n a n d c o u ntr y will be prese nte d descri pti vel y f or t h e ra n d o mize d set. 
Baseli ne val ues c orres p o n di n g t o la b orat or y 
meas ure me nts i n t he li pi d pa nel refer t o 
assess me nts c ollecte d o n Da y 1 of t he st u d y ( bef ore t he first a d mi nistrati o n of st u d y dr u g). 
Ot her bi oc h e mistr y meas ure me nts i ncl u de d i n t he s u bset of s afet y la b orat or y m eas ure me nts as 
well as ot her bac k gr o u n d baseli ne c haracteristics s h o ul d be c ollecte d pri or t o ra n d o mizati o n or 
Da y 1.  
T he de m o gr a p hic a n d bac k gr o u n d c haract eristic varia bles will be s u m marize d usi n g descri pti ve 
s u m mar y statistics. C o nti n u o us varia bles will be s u m marize d usi n g n, mea n, sta n dar d d e viati o n, 
me dia n, Q 1 ( 2 5t h perce ntile), Q 3 ( 7 5t h perce ntile), mi ni m u m, a n d ma xi m u m. Cate g orical 
varia bles will be s u m marize d usi n g fre q u e ncies a n d perce nt a ges.  
1 2. 3  
Tr e at m e nt s  
T he Safet y set will be use d f or t he a nal yses bel o w. Cate g orical data will be s u m marize d as 
fre q ue n cies a n d 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.  

N o v arti s  
C o nfi d e nti al  
P a g e 9 3  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
T he d urati o n of e x p os ur e i n da ys t o i nclisira n / place b o a n d t o r os u vastati n will be s u m marize d 
b y mea ns of des cri pti ve statistics.  
C o nc o mita nt me dicati o ns a n d si g nifica nt n o n -dr u g t hera pies pri or t o a n d after t he start of t h e 
st u d y treat me nt will be 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. 3. 1  
St u d y dr u g  
T he d urati o n of t he d o u bl e -bli n d treat me nt will be c o m p ute d as t he ti me fr o m  ra n d o mizati o n t o 
t he first o ut of 
•  a) t he l ast c o nta ct t o t he partici pa nt or b) t he date of t he l ast diar y e ntr y o btai ne d f r o m t h e 
partici pa nt, w hat e v er c o mes later  
•  t he partici pa nt’s deat h 
•  or t he partici pa nt’s st u d y c o m pleti o n visit ( E O S).  
T he d urati o n of t h e o n -tr eat me nt peri o d will be c o m p ute d as t he ti me fr o m t he first i njecti o n t o 
t he first o ut of 
•  t he last i njecti o n pl us e x p os ure attri b uta ble  ti me le n gt h of 1 8 0 da ys  
•  t he partici pa nt’s deat h 
•  or t he partici pa nt’s st u d y c o m pleti o n visit ( E O S).  
T his al g orit h m refl ects i nte n de d o bser vati o n peri o d a n d t he pla n ne d treat m e nt sc he d ule a n d t he 
e x p os ure attri b uta ble pe ri o d of t he st u d y dr u g. T he d urati o n of t he d o u ble-bli n d treat me nt peri o d 
a n d t he d urati o n of t he o n -treat me nt p eri o d will b e s u m marize d f or t h e safet y set b y treat me nt 
gr o u p descri pti vel y i ncl u di n g b y d urati o n cate g ories. T he o verall partici p a nt -years of treat me nt 
will be c o m p ute d as t he s u m of partici pa nt years of o n -treat me nt p eri o d f or all partici pa nts. 
T he n u m ber of partici pa nts wit h d ose a dj ust me nts (i nterr u pti o n or per ma n e nt disc o nti n uati o n) 
a n d t he reas o ns will be s u m marize d b y treat me nt a n d all d os i n g data will be liste d. 
T he n u m ber of st u d y d os es a d mi nistere d will als o be s u m marize d b y tr eat m e nt gr o u p.  
1 2. 3. 2  
Pri or a n d c o n c o mit a nt t h er a pi e s  
Pri or or c o nc o mita nt me dicati o ns will be s u m mari ze d f or t he S A F i n s e parat e ta b ulati o ns bas e d 
o n t he c o di n g dicti o na r y use d. Me dicati o ns will be prese nte d i n al p h a betical or der, b y preferre d 
ter ms a n d gr o u pe d b y A T C class. Ta bles will s h o w t he o verall n u m ber a n d perce nt of 
partici pa nts recei vi n g at least o ne dr u g of a partic ular preferre d ter m a n d at least o ne dr u g i n a  
partic ular A T C class.  
Pri or me dicati o ns a n d si g nifica nt n o n -dr u g t hera pies are defi ne d as a n y me dicati o ns a n d 
si g nifica nt n o n-dr u g t hera pies ta ke n pri or t o t he ra n d o mizati o n visit. 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 are defi ne d as t h ose use d d uri n g t he d o u ble-bli n d peri o d. 
C o nc o mita nt me dicati o ns t hat were pr o hi bite d as per pr ot oc ol a n d gi ve n d uri n g t he c o n d uct of 
t he st u d y as well as si g nifica nt n o n-dr u g t hera pies will be s u m marize d.  
F urt her m ore, t he class es of me dicati o ns  at ti me of ra n d o mizati o n  a n d d uri n g t he d o u ble -bli n d 
peri o d will be s u m marize d se parat el y.  

N o v arti s  
C o nfi d e nti al  
P a g e 9 4  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
1 2. 4  
A n al y si s s u p p orti n g pri m ar y o bj e cti v e s  
T he pri mar y ai m of t he st u d y is t o de m o nstrat e t he s u p eri orit y of i n clisira n o n t o p of a 
partici pa nt -i n di vi d uall y o pti mize d L L T i n reac hi n g partici pa nt -i n di vi d ual L D L-C tar gets 
c o m pare d t o place b o o n t o p of a partici p a nt -i n di vi d uall y o pti mize d L L T. 
1 2. 4. 1  
D efi niti o n of pri m ar y e n d p oi nt( s)  
T he pri mar y e n d p oi nt f or t his st u d y is t he pr o p orti o n of partici pa nts ac hie vi n g t heir i n di vi d ual 
L D L -C tar g et ( < 5 5  m g/ d L or <  7 0  m g/ d L) at da y 9 0. T he partici pa nt -i n di vi d ual L D L-C tar get 
de pe n ds o n t heir car di o v asc ular ris k cate g or y as defi ne d i n t he 2 0 1 9 E S C/ E A S g ui deli nes f or 
t he ma na ge me nt of d ysli pi de mia (Mac h  et al 2 0 2 0 ). T he i n di vi d ual L D L-C tar get ( <  5 5  m g/ d L 
or <  7 0  m g/ d L) will be e val uate d acc or di n g t o t he m ost rece nt assess me nt of t he car di o vas c ular 
ris k cate g or y as det er mi ne d b y t he i n vesti gat or. Acc or di n gl y, t he ac hie ve me nt of t he 
partici pa nt -i n di vi d ual L D L-C tar get f or ms a bi n ar y res p o nse v aria ble f or L D L -C tar get. T he 
pri mar y e n d p oi nt will be a nal yze d b ase d o n t he F A S.  
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  
F or t he pri mar y a nal ysis t he o d ds rati o bet w ee n i nclisira n vs place b o of t he partici pa nts 
ac hie vi n g t heir i n di vi d ual L D L -C tar get ( <  5 5  m g/ d L or <  7 0  m g/ d L) at da y 9 0 will be 
esti mate d usi n g a l o gistic re gressi o n m o del. Treat me nt a n d car di o vas c ular ris k cate g or y 
(stratificati o n fact or: v er y hi g h ris k, hi g h ris k) will be i ncl u de d as fact ors i n t he m o del. T h e 
o d ds rati o a n d its 9 5 % c o nfi de nce i nter val ( CI) a n d p -val ue will be esti mate d. T he n ull 
h y p ot hesis of e q ual o d ds will be rejecte d if t he 1 -si de d p-val ue fr o m t he l o gistic re gressi o n 
m o del f or t he fact or “tr eat me nt” is < 0. 0 2 5.  
T he pri mar y n ull  h y p ot hesis t o be rejecte d is t hat t he o d ds re gar di n g partici pa nts ac hie vi n g t heir 
i n di vi d uall y o pti mize d L D L-C tar get ( <  5 5  m g/ d L or <  7 0  m g/ d L) at da y 9 0 are e q ual bet wee n 
treat me nt gr o u ps. Let p1 a n d p 0 de n ote t he pr o p orti o n of p artici pa nts ac hie vi n g t h eir 
i n di vi d uall y o pti mize d L D L-C tar get i n t he i nclisira n or place b o gr o u p, res pecti vel y.  
T he pri mar y n ull h y p ot hesis teste d ca n be d escri b e d as:  
H 0 1: O R: = ( p1/( 1-p 1)) / (( p0/( 1-p 0)) ≤ 1 vs. HA : O R: = ( p1/( 1-p 1)) / (( p0/( 1-p 0)) > 1. 
A d diti o nall y, t he relati ve ris k as well as a bs ol ute ris k differe nce a n d t heir 9 5 % c o nfi de nce 
i nter vals will be esti mate d s u p ple me ntar y. 
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  
T he ge n eral strate g y t o acc o u nt f or differe nt i nterc urre nt e ve nts is  s u m marize d i n T a ble  1 2 -1 . 
F or s pecific i nterc urre nt e ve nts a nal ysis will a d diti o nall y f oll o w t he e x pla nati o n bel o w:  
1.  Disc o nti n u ati o n 
of 
st u d y tre at me nt : F oll o w 
u p i nf or mati o n 
after 
per ma n e nt 
disc o nti n uati o n of st u d y treat me nt,  Retrie v e d Dr o p O ut data ( R D O) will be c ollecte d at 
re g ular st u d y visits a n d will be i ncl u de d i n t he a nal ysis, wit h treat me nts as assi g ne d at 
ra n d o mizati o n (treat me nt p olic y). 
2.  De at h : F or partici p a nts w h o die n o s u bse q ue nt L D L-C val ue ca n e xist. C ollecte d data 
s h o ul d be a nal yz e d bef ore partici pa nts die. F or decease d p artici pa nts t he last val ue 
meas ure d b ef ore deat h will be i ncl u de d i nt o t he a nal ysis ( w hile ali ve strate g y).  

N o v arti s  
C o nfi d e nti al  
P a g e 9 5  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
3.  Use of P C S K 9 t ar g eti n g n o n -st u d y me dic ati o n or li pi d a p heresis: It c o ul d occ ur t hat 
partici pa nts are s witc he d t o P C S K 9 tar geti n g t hera p y aft er disc o nti n u ati o n of st u d y 
me dicati o n or recei ve li pi d a p heresis. F or t he pri mar y esti ma n d partici pa nts w h o use P C S K 9 
tar geti n g n o n-st u d y me dicati o n or li pi d a p heresis will be c o nsi dere d as n ot ac hie vi n g t heir 
L D L -C tar get ( c o m p osite strate g y).  
4.  C O VI D -1 9 p a n de mic i m p act o n st u d y : F or t he pri mar y esti ma n d c ollecte d data will be 
i ncl u de d i n t he a nal ysis a n d kee p t he treat me nt gr o u ps as assi g ne d at ra n d o mizati o n 
(treat me nt p olic y).  
T a bl e 1 2 -1  
A c c o u nt f or diff er e nt p o st r a n d o mi z ati o n e v e nt s f or t h e pri m ar y 
e n d p oi nt r e a c hi n g L D L -C t ar g et at d a y 9 0  
I nt er c urr e nt e v e nt 
Str at e g y  
P er m a n e nt di s c o nti n u ati o n of st u d y tr e a t m e nt 
Tr e at m e nt p oli c y str at e g y  
 
 
D e at h  
W hil e ali v e str at e g y  
U s e of P C S K 9 -i n hi bit or a nti b o di e s 
c o m p o sit e str at e g y  
C O VI D -1 9 p a n d e mi c i m p a ct o n st u d y  
Tr e at m e nt p oli c y str at e g y   
C ha n ge i n bac k gr o u n d m e dicati o n esse ntiall y c o n cer ns c ha n ge i n L L T d uri n g o pti mizati o n. A 
c ha n ge i n bac k gr o u n d me dicati o n is t heref ore n ot c o nsi dere d as a n i nterc urre nt e ve nt b eca us e 
it is part of t he treat me nts c o m pare d. 
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  
Missi n g val ues will be ha n dle d usi n g m ul ti ple i m p utati o n. I n a first ste p t h e c o nti n u o us L D L-
C le vel will be i m p ute d b y m = 1 0 0 i m p utati o ns base d o n F A S. Fr o m t he i m p ute d c o nti n u o us 
L D L -C le vel t he pri mar y e n d p oi nt will be deri ve d a gai nst t he set L D L -C tar get a n d a nal yze d 
wit h t he met h o ds d escri b e d i n re gar di n g secti o n. R es ults will be c o m bi ne d acc or di n g t o R u bi n’s 
r ules o n t he l o g scale. T h e i m p utati o n m o del will i m p ute missi n g val ues base d o n all o bser ve d 
data ta ki n g t he i nterc urre nt e ve nt strate g y i nt o acc o u nt. T he i m p utati o n m o del will i ncl u de 
ra n d o mize d tr eat me nt ar m a n d t he stratificati o n fact or. 
1 2. 4. 5  
S e n siti vit y a n al y s e s  
N ot a p plica ble.  
1 2. 4. 6  
S u p pl e m e nt ar y a n al y si s  
Wit h a s u p ple me ntar y a nal ysis t he i m pact of all o wi n g t he use of P C S K 9 m A b will be 
i n vesti gate d. F or t his s u p ple me ntar y a nal ysis t he pri mar y a nal ysis will be re peate d b ut L D L -C 
val ues o bser ve d d uri n g or after t h e use of a P C S K 9 m A b will be i ncl u de d as meas ure d.  
1 2. 4. 7  
S u p p orti v e a n al y s e s  
S u b gr o u p a nal yses  f or t h e f oll o wi n g s u b gr o u ps will be c o n d ucte d: 
•  A ge gr o u p  
•  Ge n der  

N o v arti s  
C o nfi d e nti al  
P a g e 9 6  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
•  Car di o vasc ular ris k cat e g or y 
bef ore ra n d o mizati o n ( ver y hi g h ris k, hi g h ris k) as 
stratificati o n fact or. 
1 2. 5  
A n al y si s s u p p orti n g s e c o n d ar y o bj e cti v e s  
T he p o p ulati o n a n d t h e treat me nt of i nterest ass ociate d wit h t he s ec o n d ar y esti ma n d are t he 
sa me as f or t he primar y esti ma n d a n d we c o nsi der t he sa me i nterc urre nt e ve nts. E xce pt o ne 
s pecific e xce pti o n d escri be d bel o w, t h e pr o p os e d a p pr oac h f or all sec o n dar y e n d p oi nts f or t h e 
i nterc urre nt e ve nts of disc o nti n uati o n of st u d y treat me nt, t he us e of P C S K 9 m A b or li pi d 
a p heresis or t he i m pact of t he C O VI D -1 9 pa n de mic is t he treat me nt p olic y strate g y. F or t he 
i nterc urre nt e ve nt of d eat h a w hile ali ve strat e g y will be a p plie d. 
T he sec o n dar y esti ma n ds are defi ne d b y t he e val uati o n of treat me nt effect o n t he f oll o wi n g 
e n d p oi nts  a n d s u m mar y meas ures:  
1.  Relati ve  c ha n ge ( perce nt a ge c ha n ge) fr o m bas eli ne t o mea n  L D L -C  le vel o ver t he d o u ble -
bli n d st u d y peri o d (a vera ge d o ver all p ost baseli ne visits)  
2.  Pr o p orti o n of partici pa nts e x peri e nci n g at least o ne m uscle -relate d A E as defi ne d i n t he 
S M Q r ha b d o m y ol ysis / m y o pat h y fr o m da y 1 t o da y 3 6 0  
3.  A n n ualize d n u m ber of d a ys partici pa nts e x perie n ci n g self -re p orte d p ai n fr o m da y 1 t o da y 
3 6 0  
4.  C ha n ge fr o m bas eli ne i n S F -B PI  p ai n se verit y sc ore fr o m  at d a y 3 6 0  
5.  C ha n ge fr o m bas eli ne i n S F -B PI  p ai n i nterf ere nce sc ore  at d a y 3 6 0  
6.  Pr o p orti o n of partici pa nts wit h cli nicall y rel e va nt c ha n ge i n S F -B PI pai n se v erit y sc ore fr o m 
baseli ne t o Da y 3 6 0  
7.  Pr o p orti o n of partici pa nts wit h cli nicall y rele va nt c ha n ge i n S F -B PI p ai n i nterfere nce sc ore 
fr o m baseli ne t o Da y 3 6 0 
H o we ver, t he first s ec o n dar y e n d p oi nt of relati ve c ha n ge ( perce nt a ge c ha n ge) fr o m bas eli ne t o 
mea n L D L -C le vel o ver t he d o u ble -bli n d st u d y peri o d (a vera ge d o ver all p ost baseli ne visits) 
will be ha n dle d differe ntl y f or  t he use of P C S K 9 m A b or li pi d a p h eresis. F or t his s pecific 
i nterc urre nt e ve nt f or t his e n d p oi nt a h y p ot hetical strate g y as if n o P C S K 9 m A b or li pi d 
a p heresis w o ul d h a ve bee n a d mi nistere d will be a p plie d.  
T he f oll o wi n g f o ur s ec o n dar y e n d p oi nts will be i ncl u de d i n t h e c o nfir mat or y testi n g fra me w o r k 
i n a d diti o n t o t he pri mar y e n d p oi nt wit h c orres p o n di n g h y p ot hesis teste d:  
1.  Relati ve  c ha n ge ( perce nt a ge c h a n ge) fr o m bas eli ne i n L D L-C  le vel o ver t he d o u ble bli n d 
st u d y peri o d (a vera ge d o ver all p ost baseli ne visits) 
2.  Pr o p orti o n of partici pa nts e x peri e nci n g at least o ne m uscle -relate d A E as defi ne d i n t he 
S M Q r ha b d o m y ol ysis / m y o pat h y fr o m da y 1 t o da y 3 6 0  
3.  A n n ualize d n u m ber of d a ys partici pa nts e x perie n ci n g self -re p orte d p ai n fr o m da y 1 t o da y 
3 6 0  
4.  C ha n ge fr o m bas eli ne i n S F -B PI p ai n se verit y sc or e at da y 3 6 0  
5.  C ha n ge fr o m bas eli ne i n S F -B PI  p ai n i nterfere nce sc ore at d a y 3 6 0  

N o v arti s  
C o nfi d e nti al  
P a g e 9 7  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
1 2. 5. 1  
C o ntr ol of F a mil y wi s e t y p e I err or r at e  
T he n ull h y p ot hesis t o be rejecte d f or t he rele va nt sec o n dar y e n d p oi nts are:  
•  H 0 2: T he mea n relati ve c ha n ges fr o m baseli ne i n L D L-C le vel,  a vera ge d o ver all p ost 
baseli ne visits d uri n g t he d o u ble -bli n d treat me nt peri o d, are e q ual bet wee n treat me nt 
gr o u ps.  
•  H 0 3: T he o d ds re gar di n g partici pa nts e x perie nci n g at least o ne m us cle-relate d A E as defi ne d 
i n t he S M Q r ha b d o m y ol ysis / m y o pat h y fr o m da y 1 t o da y 3 6 0 are e q ual bet wee n treat me nt 
gr o u ps.  
•  H 0 4: T he a n n ualize d mea n n u m ber of da ys pai n is e x perie n ce d is e q ual bet w ee n b ot h gr o u ps. 
•  H 0 5: T he mea n c h a n ge fr o m baseli ne i n S F-B PI p ai n se verit y sc ore fr o m d a y 1 t o d a y 3 6 0 
is e q ual bet wee n treat me nt gr ou ps.  
•  H 0 6: T he mea n c ha n g e fr o m baseli ne i n S F-B PI  p ai n i nterfere nce sc ore  fr o m da y 1 t o da y 
3 6 0 is e q ual bet wee n treat me nt gr o u ps.  
H y p ot heses are gr o u pe d i nt o t hree fa milies. T he first fa mil y c o ntai ns t he pri mar y h y p ot hesis 
H 0 1. T he sec o n d fa mil y c o ntai ns t w o sec o n dar y h y p ot heses H 0 2 a n d H 0 3. T he t hir d fa mil y 
c o ntai ns t he rest of sec o n dar y h y p ot hes es H 0 4, H 0 5 a n d H 0 6. T he hierarc hi cal testi n g strat e g y 
is a p plie d t o t hes e t hr ee fa milies. First H 0 1 is test e d at l e vel al p ha. If it is rejecte d, we test t he 
sec on d fa mil y usi n g a cl ose d test at le vel al p ha. If b ot h H 0 2 a n d H 0 3 are rejecte d, we t est t he 
t hir d fa mil y usi n g t he H o m mel pr oce d ure at le vel al p ha. W he n n ot all h y p ot heses i n a fa mil y 
ca n be reje cte d, testi n g st o ps at t he c orres p o n di n g fa mil y a n d d oes n ot pr ocee d t o test t he ne xt 
fa mil y. 
Wit hi n t he sec o n d fa mil y, a cl ose d test pr oce d ure b ase d o n wei g hte d Si mes tests is a p plie d wit h 
8 0 % wei g ht f or H 0 2 a n d 2 0 % wei g ht f or H 0 3. First t he t w o n o mi nal p -val u es f or H 0 2 a n d H 0 3 
are si m ulta ne o usl y c o m pare d t o al p ha.  If b ot h n o mi nal p-val ues are ≤ al p ha, t he t w o n ull 
h y p ot heses are reject e d. Ot her wise c o m pare t he i n di vi d ual n o mi nal p -val ues t o t he wei g hte d 
al p ha wit h t he pre -s pecifi e d wei g hts ( 0. 8/ 0. 2) se paratel y. If t he p-val ue f or H 0 2 is ≤ 0. 8 *al p ha, 
H 0 2 is rejecte d ; If t he p-val ue f or H 0 3 ≤ 0. 2 * al p h a, H 0 3 is rejecte d.  
Wit hi n t he t hir d fa mil y, t he H o m mel pr oce d ure is a p plie d. Let t he or dere d p -val ues f or H 0 4, 
H 0 5, H 0 6 be p( 1) ≤ p( 2) ≤ p( 3) a n d t he c orres p o n di n g h y p ot heses H( 1), H( 2) a n d H( 3). First if 
p( 3) ≤ al p ha, w e ca n reje ct all t hree h y p ot heses. Ot her wise, if p( 2) ≤ al p ha / 2, reject H( 2) a n d 
H( 1). Ot her wise, if p( 1) ≤ al p ha / 3 or ( p( 1) ≤ al p ha / 2 a n d p( 2) ≤ 2al p h a / 3), reject H( 1).  
T his testi n g pr oce d ure c o ntr ols t he fa mil y wise err or rate at le vel al p ha i n t h e str o n g se nse. 
Fi g ure  1 2 -1  b el o w s h o ws t he a p plie d testi n g pr oce d ure.  

N o v arti s  
C o nfi d e nti al  
P a g e 9 8  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
Fi g ur e 1 2 -1  
A p pli e d t e sti n g pr o c e d ur e  
 
1 2. 5. 2  
Effi c a c y e n d p oi nt s  
F or m uscle -rel ate d A E / S M Q r ha b d o m y ol ysis / m y o pat h y t he S A F will be use d f or a nal ysis. 
F or  all ot her s ec o n dar y efficac y  a nal yses t h e F ull A nal ysis Set ( F A S) will be use d.  
1 2. 5. 2. 1  R el ati v e c h a n g e ( p er c e nt a g e) fr o m b a s eli n e t o m e a n L D L -C l e v el o v er 
t h e d o u bl e-bli n d tr e at m e nt p eri o d  
T he relati ve c h a n ge ( perce nta g e c ha n g e) fr o m baseli ne i n L D L -C le vel a vera g e d o ver t he 
d o u ble -bli n d treat me nt p eri o d will be a nal yze d usi n g a mi xe d m o del f or re peat e d meas ures 
( M M R M) i ncl u di n g treat me nt gr o u p, stratificati o n fact or (car di o vasc ul ar ris k cate g or y: v er y 
hi g h ris k, hi g h ris k), sc he d ule d visit a n d t he i nteracti o n of treat me nt gr o u p wit h sc he d ule d visit 
as fact ors a n d b aseli ne L D L -C le vel a n d t he i nteracti o n of baseli ne L D L -C l e vel wit h sc he d ule d 
visit as c o variates. Visit will be i ncl u de d as a cate g orical varia ble, a n d a n u nstr uct ure d 
c o varia n ce m atri x will b e use d f or t he m o del. T he n ull h y p ot hesis of e q ual mea n c ha n g es 
bet wee n b ot h gr o u ps t o t he a v era g e o ver all p ost b aseli ne visits will be t este d b y a n a p pr o priate 
li near c o ntrast of t he v ari a ble treat me nt a n d tr eat me nt b y visit i nteracti o n. T he n ull h y p ot hesis 
will be rejecte d wit hi n t he c o nfir mat or y testi n g fra me w or k, if t he 1 -si de d p-val ue is < 0. 0 2 5. 
T he a dj uste d mea n c ha n g e fr o m baseli ne a n d its c orres p o n di n g 9 5 % c o nfi de nce i n ter val will be 
prese nte d.  
F or t his e n d p oi nt a gra p hical prese ntati o n of t he c o urse of t he re g ar di n g varia ble o ver ti me will 
be s h o w n a d diti o nall y t o t he a nal ysis. F urt her details f or t his gra p hical pres e ntati o n a n d f or t he 
a nal ysis of sec o n d ar y e n d p oi nts w ill be pr o vi de d i n t he statistical a nal ysis pla n ( S A P). 

N o v arti s  
C o nfi d e nti al  
P a g e 9 9  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
1 2. 5. 2. 2  M u s cl e -r el at e d A E / S M Q r h a b d o m y ol y si s / m y o p at h y 
T he pr o p orti o n of partici pa nts e x perie nci n g at least o ne m uscle -relate d A E as defi ne d i n t he 
S M Q r ha b d o m y ol ysis / m y o pat h y fr o m da y 1 t o da y 3 6 0 will be a n al yze d i n a l o gistic re gressi o n 
m o del. Treat me nt a n d  deter mi ne d L D L -C t ar get at scree ni n g  will b e i ncl u d e d as fact ors i n t he 
m o del. T he L D L -C tar gets de pe n d o n t he partici pa nts’ C V ris k cate g or y a n d will be attri b ute d 
directl y fr o m t he C V ris k cate g or y e C R F e ntri es. T heref ore, t he C V ris k cate g or y will b e 
i ncl u de d i n t he m o del as t he stratificati o n fact or (“ ver y hi g h ris k”, “ hi g h ris k”). T he o d ds rati o 
a n d its 9 5 % c o nfi de nce i nter val ( CI) a n d p -v al ue will be esti mate d. T he n ull h y p ot hesis of e q ual 
o d ds  will be rejecte d wit hi n t he c o nfir mat or y testi n g fra me w or k if t he 1 -si de d p-val ue fr o m t h e 
l o gistic re gressi o n m o del f or t he fact or “tr eat me nt ” is < 0. 0 2 5. 
A d diti o nall y, t he relati ve ris k as well as a bs ol ute ris k differe nce a n d t heir 9 5 % c o nfi de nce 
i nter vals will be esti mat e d fr o m a C oc hra n e-Ma ntel -Hae ns zel test ( C M H) stratifie d f or t he 
deter mi ne d L D L -C tar get bef ore ra n d o mizati o n base d o n t he Sc ore statistic.  
I n case of missi n g val ues m uscle-relate d A E / S M Q r ha b d o m y ol ysis / m y o pat h y will n ot b e 
i m p ute d b ut a nal yze d acc or di n g t o last k n o w n stat us of t he occ urre n ce of a n e v e nt. T o 
i n vesti gate t he se nsiti vit y t o missi n g val ues or p ote ntiall y differe nt o bser vati o n ti mes i n t he t w o 
st u d y ar ms, a ti me t o t he first e x perie n ce of at least o ne m uscle-relate d A E as defi ne d i n t h e 
S M Q r ha b d o m y ol ysis / m y o pat h y will be c o n d ucte d.  
1 2. 5. 2. 3  N u m b er of d a y s p arti ci p a nt s e x p eri e n ci n g s elf -r e p ort e d p ai n fr o m d a y 
1 t o d a y 3 6 0  
T he n u m ber of  pai n da ys e x perie n ce d will be a nal yze d usi n g a ne g ati ve bi n o mial m o del 
(P.  Mc C ulla g h  a n d J. A. 1 9 8 9 ) wit h t he n u m ber of o bser ve d pai n da ys as t he de pe n de nt varia bl e 
a n d treat me nt gr o u p a n d stratificati o n fact or (car di o vasc ular ris k cate g or y: ver y hi g h ris k, hi g h 
ris k) as fi xe d-effect fact ors a n d l o g (f oll o w -u p d urati o n i n years) as t he off -set. T he a n n ualize d 
i nci de nce rates a n d t heir 9 5 % c o nfi de n ce i nter vals esti mate d fr o m t he m o d el will be pr o vi de d 
b y treat me nt gr o u p. T h e treat me nt c o m p aris o n will be p erf or me d t hr o u g h t he esti mate d 
i nci de nce rates. T he in ci de nce rate rati o a n d its 9 5 % c o nfi de n ce i nter val will be pr o vi de d.  
1 2. 5. 2. 4  M e a n c h a n g e fr o m b a s eli n e i n S F -B PI p ai n s e v erit y s c or e a n d p ai n 
i nt erf er e n c e s c or e at d a y 3 6 0 
Mea n c h a n ge fr o m b aseli ne i n S F -B PI p ai n se v erit y sc ore a n d S F -B PI pai n i nterfere nce s c ore 
at da y 3 6 0 will be a nal yze d usi n g a mi xe d m o del f or re peate d meas ures ( M M R M). Treat me nt 
gr o u p, stratificati o n fact or (car di o vasc ul ar ris k cate g or y: ver y hi g h ris k, hi g h ris k), sc he d ul e d 
visit, a n d t he i nteracti o n of treat me nt gr o u p wit h sc he d ule d visit  wil l be i ncl u de d as fi x e d fact ors 
i n m o del, baseli ne S F-B PI v al ue a n d  t h e i nteracti o n of bas eli ne S F-B PI v al ue wit h sc h e d ule d 
visit will be i ncl u de d as a fi xe d c o variate. Be y o n d t hat visit will be i ncl u de d as a re peate d fact or 
neste d wit hi n partici pa nt  a n d a n u nstr uct ur e d c o varia nce matri x will be use d f or t he m o del.  
T he a dj uste d mea n c ha n g e fr o m baseli ne at da y 3 6 0 a n d its re gar di n g 9 5 % c o nfi de nce i nter val 
will be prese nte d. T he n ull h y p ot hesis of e q ual mea n c ha n ges will be rejecte d base d o n t he 
treat me nt c o ntrast at re gar di n g visits acc or di n g t o a 1-si de d p-val ue < 0. 0 2 5 wit hi n t he 
c o nfir mat or y testi n g fra me w or k.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 0  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
F or t his e n d p oi nt a gra p hical prese ntati o n of t he c o urse of t he re g ar di n g varia ble o ver ti me will 
be s h o w n a d diti o nall y t o t he a nal ysis. F urt her deta ils f or t he a nal ysis a n d t he gra p hical 
prese ntati o n will be pr o vi de d i n t he statistical a nal ysis pla n ( S A P).  
1 2. 5. 3  
S af et y e n d p oi nt s  
T he Safet y Set ( S A F) will be use d f or safet y a n al yses, i ncl u di n g t he sec o n d ar y safet y e n d p oi nt.  
 F or all safet y a n al yses, t he safe t y s et 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. Safet y s u m maries (ta bles, fi g ures) i ncl u de all data fr o m t he d o u ble-bli n d 
treat me nt 
peri o d a n d 
baseli ne 
data. I n 
p artic ular, s u m mar y t a bles f or 
A Es 
will 
s u m marize all e ve nts  o btai ne d d uri n g d o u ble -bli n d treat me nt peri o d, wit h a start date d uri n g 
t he d o u ble -bli n d treat me nt  peri o d.  A d diti o nall y, all s u m mar y ta bles f or A Es will be re peate d 
f or o n-treat me nt A Es o nl y ( T E A Es). A s e parate s u m mar y f or deat h will be pr o vi de d.  
1 2. 5. 3. 1  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 Es 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 nt a ge) of p artici pa nts wit h T E A Es (e v e nts start e d after t he first d ose of 
st u d y me dicati o n or e v e nts prese nt pri or t o start of d o u ble-bli n d tr eat me nt b ut i ncreas e d i n 
se verit y base d o n preferre d ter m) will be s u m mari ze d i n t he f oll o wi n g wa ys:  
•  b y treat me nt, pri mar y s yste m or ga n class a n d preferre d ter m.  
•  b y treat me nt, pri mar y s yste m or ga n class, preferre d ter m a n d ma xi m u m se v erit y.  
•  b y treat me nt, S ta n dar dize d Me d D R A Q uer y ( S M Q) a n d preferre d ter m. 
Se parate s u m mari es will be pr o vi de d f or st u d y me dicati o n relate d A Es, deat h, S A Es, ot her 
si g nifica nt A Es lea di n g t o disc o nti n uati o n 
A partici pa nt wit h m ulti ple A Es wit hi n a pri mar y s yste m or ga n class is o n l 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 cl ass. 
A Es w hic h will be c o u nte d f or a s pecific treat me nt peri o d are t h ose w hic h are tr eat me nt -
e mer ge nt. T hese e v e nts are t h ose wit h a n o nset after t he start of t he treat me nt peri o d, or w hic h 
we re prese nt pri or t o t he start of t he treat me nt peri o d b ut i ncrease d i n se verit y, c ha n ge d fr o m 
bei n g n ot s us pecte d t o bei n g s us pecte d of st u d y dr u g relati o ns hi p, or de vel o pe d i nt o S A Es after 
t he start of t he treat me nt peri o d. 
1 2. 5. 3. 2  Vit al si g n s  
All vital si g ns dat a will be liste d b y treat me nt gr o u p, partici pa nt, a n d visit/ti me a n d if ra n ges 
are a vaila ble, a b n or malities (a n d rele va nt ort h ostatic c ha n ges) will be fla g ge d. S u m mar y 
statistics will be pr o vi de d b y treat me nt a n d visit/ti me. C ha n ge i n S B P/ D B P  fr o m baseli ne t o 
da y 3 6 0.  
1 2. 5. 3. 3  Cli ni c al l a b or at or y e v al u ati o n s  
T he Safet y Set ( S A F) will be use d f or safet y a n al yses, i ncl u di n g t he sec o n d ar y safet y e n d p oi nt.  
 F or all safet y a n al yses, t he safet y s et 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. Safet y s u m maries (ta bles, fi g ures) i ncl u de all data fr o m t he d o u ble-bli n d 

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 1  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
treat me nt 
peri o d a n d 
baseli ne 
data. I n 
p artic ular, s u m mar y t a bles f or 
A Es 
will 
s u m marize all e ve nts  o btai ne d d uri n g d o u ble -bli n d treat me nt peri o d, wit h a start date d uri n g 
t he d o u b le-bli n d treat me nt  peri o d.  A d diti o nall y, all s u m mar y ta bles f or A Es will be re peate d 
f or o n-treat me nt A Es o nl y ( T E A Es). A s e parate s u m mar y f or deat h will be pr o vi de d.  
1 2. 5. 4  
P ati e nt r e p ort e d o ut c o m e s  
Patie nt re p orte d sec o n d ar y e n d p oi nts are t he  n u m ber of da ys p ar tici pa nts e x perie nce self-
re p orte d p ai n fr o m da y 1 t o da y 3 6 0 as re p orte d i n t he e Di ar y a n d t he mea n c h a n ge fr o m 
baseli ne i n S F -B PI at da y 3 6 0. Re gar di n g a nal yses of t hese e n d p oi nts are descri be d i n t he or der 
of t he t esti n g pr oce d ure i n Secti o n  1 2. 5. 2. 3  a n d Secti o n  1 2. 5. 2. 4 , res pecti vel y. Ot her patie nt 
re p orte d o utc o mes are e x pl orat or y e n d p oi nts. T h e a nal ysis of e x pl or at or y e n d p oi nts will be 
descri be d i n t he statistical a nal ysis pla n ( S A P).  
1 2. 6  
A n al y si s of e x pl or at or y e n d p oi nt s  
E x pl orat or y e n d p oi nts are liste d i n t he st u d y o bjecti ves. T he a nal ysis of e x pl orat or y e n d p oi nts 
will be descri be d i n t he statistical a nal ysis pla n ( S A P).  
1 2. 7  
I nt eri m a n al y s e s 
N ot a p plica ble.   
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)  
T he ass u m pti o n f or t he o cc urre nce of L D L -C tar g et attai n me nt o n da y 9 0 i n t he i nclisira n -ar m 
is base d o n t he O RI O N st u d y data set. I n 
 of partici pa nts ac hie ve d a n L D L-
C le vel 
 m g/ dl tar get at da y 9 0 
 
 of partici pa nts ac hie ve d a n L D L-C 
le vel 
 m g/ dl at da y 9 0 
 
 (Ra y  et al 2 0 2 0 ). Ass u mi n g 
 
 a p pr o x.  
 of partici pa nts ac hie ve t heir i n di vi d ual L D L-C tar get at da y 9 0. F or 
t he ass u m pti o n of L D L-C tar get attai n me nt at da y 9 0 i n t he p lace b o ar m, t he E X P L O R E R trial 
re p orts res p o nse rates f or 
 (Balla nt y ne  et al 2 0 0 7 ):  
 of 
partici pa nts ac hi e ve d a n L D L -C le vel 
 
m g/ dl at da y 
 
). Mea n L D L-C le vel at da y 
 
was 
 s o it ca n be esti mate d t h at a p pr o x.  
 of partici p a nts ma y ha ve reac he d t h e  
 tar get. Base d o n t he st u d y p o p ulati o n a n d treat me nt re gi me herei n, da y 
 of 
E X P L O R E R trial li kel y relates t o da y 9 0 of t he prese nt st u d y. Wit h t he a b o ve state d ass u m pti o n 
of a 
 a m o n g t he partici pa nt p o p ulati o n,  
 of partici pa nts are c o nsi dere d 
t o reac h t heir L D L-C tar get at da y 9 0. C o nsi deri n g t he hi g h L D L -C le vels at baseli ne i n t he 
E X P L O R E R trial c o m pare d t o O RI O N trials, herei n, a sli g htl y hi g her g oal attai n me nt rate of 
a p pr o x.  
 at d a y 9 0 f or p artici pa nts i n t he c o m parat or ar m is ass u me d. U n der t hes e 
ass u m pti o ns,  
 partici pa nts per ar m are re q ui re d base d o n a c hi-s q uare test of pr o p orti o ns t o 
ac hie ve 9 0 % p o w er o n a t w o -si de d, 5 % si g nifica n ce le vel. I n or der t o c o m pe nsate f or missi n g 
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N o v arti s  
C o nfi d e nti al  
P a g e 1 0 2  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
val ues a n d ot her pr ot oc ol de viati o ns, a p pr o xi mat el y 8 8 0 partici pa nts p er ar m (a p pr o xi matel y 
1 7 6 0 partici pa nts i n t o tal) s h o ul d be e nr olle d/r a n d o mize d i nt o t his trial. 
1 2. 8. 2  
S e c o n d ar y e n d p oi nt( s)  
F or t he sec o n dar y e n d p oi nt “ Pr o p orti o n of partici p a nts e x perie n ci n g at least o ne m uscle -relate d 
A E as defi ne d i n t he S M Q r ha b d o m y ol ysis / m y o pat h y fr o m da y 1 t o da y 3 6 0”, t he f oll o wi n g 
deli berati o ns a p pl y: D ue t o t he p ote nt L D L -C l o weri n g effect of i nclisira n a n d t he  
 
 i n b ot h treat me nt-ar ms de pe n di n g o n t he ac hi e ve me nt of t he i n di vi d ual L D L -
C tar get of t h e partici pa nt, it is e x pecte d t h at t he mea n a n d t he m e dia n stati n d oses will be 
. Bas e d o n t he  
 of 
acti o n of i nclisira n, it is esti mate d t hat t he  
 of partici pa nts i n t he 
 will 
re q uire  
 r os u vastati n 
 i n t he treat me nt peri o d. T h us, m ost partici pa nts i n t he 
 will re mai n o n t he l o wer d oses of r os u vastati n t hr o u g h o ut t he trial. I n c o ntrast, 
i n t he 
, m ost partici pa nts will re q uire 
 of r os u vastati n 
 
t o 
 t he L D L-C.  
Vari o us st u dies h a ve s h o w n t hat stati ns at hi g h d osa ges are ass ociate d wit h 
 ra n gi n g bet wee n 
 f or at or vastati n 8 0 m g/ da y ( Par ker  et al 2 0 1 3 ) t o 
 f or vari o us stati ns (Br uc kert  et al 2 0 0 5 ), w hile t here is e vi de nce fr o m d o u ble-bli n d 
cli nical trials t hat 
 stati ns are n ot ass ociate d wit h a 
 t ha n 
place b o wit h a n o v erall i nci de nce of 
 (G u pt a  et al 2 0 1 7 ). F or t he sa m ple size cal c ulati o n, 
we ass u me a rat her c o nser vati ve a p pr oac h of a n o cc urre n ce of 
 i n t he 
 a n d  
 i n t he 
. Pai n ca n be of differe nt 
. Ass u mi n g 
 are 
 i n a c o nser vati ve a p pr oac h, acc or di n g t o t he m et h o d ol o g y defi ne d 
 t o 
 A Es will o nl y be  
 if t he 
 i nter val of t he ris k rati o sta ys bel o w t he t hres h ol d of  
. A 
sa m ple size of  
partici pa nts per ar m will res ult i n 9 0 % p o wer t o o btai n a c o nfi de nce i nter val 
of t he ris k rati o f ulfilli n g t his c o n diti o n. F or a c o nsi dera ble a d diti o nal be nefit, t he res pecti ve 
t hres h old is defi ne d b y t he
. U n der t h e ass u m pti o ns a b o ve, t he p o wer t o meet t his 
c o n diti o n as w ell w o ul d be  
. T he p o wer calc ulati o ns were perf or me d wit h S A S S oft ware 
b y si m ulati n g a n d a nal yzi n g 1 0 0 0 st u dies wit h t he ass u me d A E rat es.  
1 3  
Et hi c al c o n si d er ati o n s a n d a d mi ni str ati v e pr o c e d ur e s  
1 3. 1  
R e g ul at or y a n d et hi c al c o m pli a n c e  
T his cli nical st u d y was d esi g ne d a n d s hall be i m ple me nte d, e xec ute d a n d re p orte d i n acc or da nce 
wit h t he I C H H ar m o nize d Tri partite G ui deli nes f or G C P, wit h a p plica ble l ocal re g ulati o ns  
(i ncl u di n g 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), a n d wit h t he et hical 
pri nci ples lai d d o w n i n t he Decl arati o n of Helsi n ki.  
1 3. 2  
R e s p o n si biliti e s of t h e i n v e sti g at or a n d I R B/I E C  
Bef ore i nitiati n g a trial, t h e i n vesti gat or/i nstit uti o n m ust o bt ai n a p pr o val/fa v ora ble o pi ni o n fr o m 
t he I nstit uti o nal Re vie w B oar d/I n de pe n d e nt Et hics C o m mittee (I R B/I E C) f or t he trial pr ot oc ol, 
writte n I C F, 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 m e 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 
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N o v arti s  
C o nfi d e nti al  
P a g e 1 0 3  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
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 hes e d oc u m e nts a n d all of t h e i nstr ucti o ns a n d pr oce d ures 
f o u n d i n this pr ot oc ol a n d t o gi ve access t o all rel e va nt dat a 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 pres e ntati ves, desi g nate d a g e nts of 
N o vartis, 
I R Bs/I E Cs, a n d re g ul at or y a ut h orities as re q uir e 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 ul at or y a ut h orit y, t he i n vesti gat or m ust i nf or m N o vartis i m me diatel y t hat t his 
re q uest has bee n ma de. 
1 3. 3  
P u bli c ati o n of st u d y pr ot o c ol a n d r e s ult s  
T he pr ot oc ol will be re gistere d i n a p u blicl y accessi ble data base s uc h as cli nicaltria ls. g o v a n d 
as re q uir e d i n  C TI S. I n a d diti o n, after st u d y c o m pleti o n ( defi ne d as last patie 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 nic al 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, C TI S etc.).  
F or details o n t he N o vartis p u blicati o n p olic y i ncl u di n g a ut h ors hi p criteria, please refer t o t he 
N o varti s p u blicati o n p olic y trai ni n g materials t hat were pr o vi de d t o y o u at t he trial i n vesti gat or 
meeti n gs.  
1 3. 4  
Q u alit y C o ntr ol a n d Q u alit y A s s ur a n c e  
N o vartis  mai ntai ns a r o b ust Q ualit y Ma na ge me nt S yste m ( Q M S) t hat i ncl u des all acti vities 
i n v ol ve d i n q ualit y ass ura nce a n d q ualit y c o ntr ol, t o e ns ure c o m plia nce wit h writte n Sta n dar d 
O perati n g Pr oce d ures as well as a p plica ble gl o b al/l ocal G C P re g ulati o ns a n d I C H G ui d eli nes.  
A u dits of i n vesti gat or sites, ve n d ors, a n d N o vartis s yste ms are perf or me d b y a u dit ors, 
i n de pe n de nt fr o m t h ose i n v ol ve d i n c o n d ucti n g, m o nit ori n g or perf or mi n g q ualit y c o ntr ol of t he 
cli nical trial. T he cli nical a u dit pr ocess uses a k n o wle d ge/ris k base d a p pr oac h.  
A u dits are c o n d ucte d t o assess G C P c o m plia nce wit h gl o bal a n d l ocal re g ulat or y re q uire me nt s, 
pr ot oc ols a n d i nter nal S O Ps, a n d are p erf or me d acc or di n g t o writte n N o v artis pr ocesses.  
1 3. 5  
P arti ci p a nt E n g a g e m e nt  
T he f oll o wi n g partici pa nt e n ga ge me nt i nitiati ves will be i ncl u de d i n t his st u d y a n d be pr o vi de d, 
as a vaila ble, f or distri b uti o n t o st u d y parti ci pa nts at t he rele va nt ti me. If c o m plia nce is i m pacte d 
b y t he c ult ural n or ms or l ocal la ws a n d re g ulati o ns, sites ma y disc uss m o dificati o ns t o t hese 
re q uire me nts wit h N o vartis: 
•  T ha n k Y o u Letter  
•  Partici pa nt Car d  
•  Plai n La n g ua ge Trial S u m mar y - after Cli nical St u d y Re p ort ( C S R) p u blicati o n  
•  Trial Fee d bac k Q uesti o n naire ( T F Q) - u p t o 3 ti mes d uri n g t he trial  

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 4  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
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 uir e 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 cir c u msta nces i ncl u di n g 
i nci de ntal c ollecti o n is a n i n vesti gat or all o we d t o c ollect a d diti o nal data or c o n d uct a n y 
a d diti o nal pr oce d ures f or a n y p ur p ose i n v ol vi n g a n y i n vesti gati o nal dr u gs u n der t he pr ot oc ol, 
ot her t ha n t h e p ur p os e of t he st u d y. If d es pite 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 b e i n ci de ntall y c ollect e 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 os e ot her t ha n t he st u d y, e xce pt f or t he a p pr o priate 
m o nit ori n g o n st u d y partici pa nts.  
I n v esti gat ors ascertai n t he y will a p pl y d ue dili ge nce t o a v oi d pr ot oc ol de viati o ns. If a n 
i n vesti gat or feels a pr ot o c ol de viati o n w o ul d i m pr o ve t he c o n d u ct of t he st u d y t his m ust be 
c o nsi dere d a pr ot oc ol a m e n d me nt, a n d u nless s u c h a n a me n d me nt is a gree d u p o n b y N o vartis 
a n d a p pr o ve d b y t he I R B/I E C a n d 
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 g e or a d diti o n t o t he pr ot oc ol ca n o nl y b e ma de i n a writte n pr ot o c ol a me n d me nt t hat 
m ust be a p pr o ve d b y N o vartis, healt h a ut h orities w here re q uire d, a n d t h e 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 h at are re q uire d f or partici pa nt safet y ma y be i m ple me nte d i m me diatel y 
pr o vi de d t he healt h a ut h orities are s u bs e q ue ntl y n otifie d b y pr ot oc ol a me n d me nt a n d t he 
re vie wi n g I R B/I E C is n otifie d. 
N ot wit hsta n di n g t he nee d f or a p pr o val of f or mal pr ot oc ol a me n d m e nts , t he i n vesti gat or is 
e x pecte d t o ta ke a n y i m m e diate acti o n re q uir e d f or t he safet y of a n y partici p a nt i ncl u de d i n t his 
st u d y, e ve n if t his acti o n re prese nts a de viati o n fr o m t he pr ot oc ol. I n s uc h cases, N o vartis s h o ul d 
be n otifie d of t his acti o n a n d t he I R B/I E C at t he st u d y site s h o ul d be i nf or me d acc or di n g t o 
l ocal re g ulati o ns. 

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 5  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
1 5  
R ef er e n c e s  
Refere n ces are a vaila ble u p o n re q uest  
( 2 0 2 0) Errat u m t o " 2 0 1 9 E S C/ E A S g ui deli nes f or t he ma na ge me nt of d ysli pi de mias: Li pi d 
m o dificati o n t o re d uce car di o vasc ul ar ris k" [ At her oscler osis 
2 9 0 ( 2 0 1 9) 
1 4 0 -2 0 5]. 
At her oscler osis p. 1 6 0 -1 6 2.  
A b o ya ns V, Ricc o J B, B arteli n k M E L, et al ( 2 0 1 8) 2 0 1 7 E S C G ui deli nes o n t he Dia g n osis a n d 
Treat me nt of Peri p h eral Arteri al Diseases, i n c olla b orati o n wit h t he E ur o pea n S ociet y f or 
Vasc ular S u r ger y ( E S V S): D oc u me nt c o veri n g at her oscler otic dis ease of e xtracra nial car oti d 
a n d verte bral, mese nteric, re nal, u p per a n d l o wer e xtre mit y arteries. E n d orse d b y: t he E ur o pea n 
Str o ke Or ga niz ati o n ( E S O). T he Tas k F orce f or t he Dia g n osis a n d Treat me nt of Per i p heral 
Arterial Diseas es of t he E ur o pea n S ociet y of Car di ol o g y ( E S C) a n d of t he E ur o pea n S ociet y f or 
Vasc ular S ur ger y ( E S V S). E ur Heart J; 3 9: 7 6 3 -8 1 6.  
Al o ns o J, Ferrer M, Ga n d e k B, et al ( 2 0 0 4) Healt h -relate d q u alit y of life ass o ciate d wit h c hr o nic 
c o n dit i o ns i n ei g ht c o u ntries: res ults fr o m t he I nter nati o nal Q ualit y of Life Assess me nt 
(I Q O L A) Pr oject. Q u al Life Res; 1 3: 2 8 3-9 8.  
At ki ns o n MJ, K u mar R, Ca p pelleri J C, et al ( 2 0 0 5) Hierarc hical c o nstr uct vali dit y of t he 
treat me nt satisfacti o n q uesti o n naire f or me dicati o n ( T S Q M versi o n II) a m o n g o ut patie nt 
p har mac y c o ns u mers. Val ue Healt h; 8 S u p ple 1: S 9 -S 2 4.  
At ki ns o n MJ, Si n ha A, Hass S L, et al ( 2 0 0 4) Vali dati o n of a ge neral m eas ure of treat me nt 
satisfacti o n, t he Treat me nt Satisfacti o n Q uesti o n n aire f or Me di cati on ( T S Q M), usi n g a n ati o nal 
pa nel st u d y of c hr o nic disease. H ealt h Q ual Life O utc o mes; 2( 1 2).  
Bai ge nt C, Keec h A, Kear ne y P M, et al ( 2 0 0 5) Efficac y a n d safet y of c h olester ol -l o weri n g 
treat me nt: pr os pecti ve m eta-a n al ysis of data fr o m 9 0, 0 5 6 partici pa nts i n 1 4 ra n d o mise d trials 
of stati ns. La ncet; 3 6 6: 1 2 6 7 -7 8.  
Balla nt y ne C M, Weiss R, M occetti T, et al ( 2 0 0 7) Efficac y a n d safet y of r os u vastati n 4 0 m g 
al o ne or i n c o m bi nati o n wit h ezeti mi be i n patie nts at hi g h ris k of car di o vasc ular disease (res ults 
fr o m t he E X P LO R E R st u d y). A m J Car di ol; 9 9: 6 7 3 -8 0.  
Bar kas F, Li ber o p o ul os E N, K osta pa n os M S, et al ( 2 0 1 5) Li pi d tar get ac hie ve me nt a m o n g 
patie nts wit h ver y hi g h a n d hi g h car di o vasc ular ris k i n a li pi d cli nic. A n gi ol o g y; 6 6( 4): 3 4 6 -5 3.  
Br uc kert E, Ha y e m G, D eja ger S, et al ( 2 0 0 5) Mil d t o m o derate m usc ular s y m pt o ms wit h hi g h -
d osa ge stati n t hera p y i n h y perli pi de mic patie nts --t he P RI M O st u d y. Car di o vasc Dr u gs T her; 
1 9: 4 0 3 -1 4.  
B u n desa ussc h uss G ( 2 0 2 1) A nla ge III: Ü bersic ht ü ber Ver or d n u n gs ei nsc hrä n k u n ge n u n d -
a ussc hl üsse i n d er Arz n ei mittel vers or g u n g d urc h die Arz nei mittel -Ric htli nie u n d a uf gr u n d 
a n derer V orsc hrifte n ( § 3 4 A bsatz 1 Satz 6 u n d A bsatz 3 S G B V), Hi n weise z ur wirtsc haftlic h e n 
Ver or d n u n gs w eise v o n nic ht versc hrei b u n gs pflic hti ge n Arz n ei mittel n f ür Ki n der bis z u m 
v ol le n dete n 1 2. Le be nsja hr u n d f ür J u ge n dlic he 
mit E nt wic kl u n gsst ör u n ge n bis z u m 
v olle n dete n 1 8. Le be nsja hr s o wie 
Ver or d n u n gsei nsc hrä n k u n g e n u n d -a ussc hl üsse v o n 
s o nsti ge n Pr o d u kte n. 

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 6  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
Castilla -G uerra L, Del Car me n Fer na n dez -M ore n o M, C ol me ner o -Ca mac h o M A ( 2 0 1 6 ) Stati ns 
i n Str o ke Pre ve nti o n: Prese nt a n d F ut ur e. C urr P h ar m Des; 2 2( 3 0): 4 6 3 8 -4 6 4 4.  
C ha n L, M ul ga o n kar S, 
Wal ker R, et al ( 2 0 0 6) Patie nt -re p orte d gastr oi ntesti nal s y m pt o m 
b ur de n a n d h ealt h -rel ate d q ualit y of life f oll o wi n g c o n versi o n fr o m m yc o p he n olate mofetil t o 
e nteric-c oate d m yc o p h e n olate s o di u m. Tra ns pla nt ati o n; 8 1: 1 2 9 0 -7.  
Cleela n d C S ( 2 0 0 9) T he Brief Pai n I n ve nt or y User G ui de p. ( 1 1 A u g ust 2 0 2 1, date last 
accesse d).  
C o y ne K S, 
Mar g olis 
M K, Gilc hrist K A, et al ( 2 0 0 3) E val uati n g effects of met h o d of 
a d mi nistrati o n o n Wal ki n g I m pair me nt Q uesti o n naire. J Vasc S ur g; 3 8( 2): 2 9 6-3 0 4.  
Da vi ds o n 
M H, 
Ma ki K C, Pears o n T A, et al ( 2 0 0 5) Res ults of t he Nati o nal C h olester ol 
E d ucati o n ( N C E P) Pr o gra m E val uati o n Pr ojec T Utilizi n g N o vel E -T ec h n ol o g y ( N E P T U N E) II 
s ur ve y a n d i m plicati o ns f or treat me nt u n d er t he rece nt N C E P Writi n g Gr o u p rec o m me n d ati o ns. 
A m J Car di ol; 9 6: 5 5 6 -6 3.  
De m pster M, D o n nell y M ( 2 0 0 0) Meas uri n g t he healt h relate d q u alit y of life of p e o ple wit h 
isc hae mic heart diseas e. Heart; 8 3: 6 4 1-4.  
De Vries TI, C o o ne y M T, Sel mer R M, et al ( 2 0 2 1) S C O R E 2 -O P ris k pre dicti o n al g orit h ms: 
esti mati n g i nci de nt car di o vasc ular e ve nt ris k i n ol der pers o ns i n f o ur ge o gra p hical ris k re gi o ns. 
E ur Heart J; 4 2: 2 4 5 5 – 6 7.  
Di me näs E, Glise H, Haller bäc k B, et al ( 1 9 9 5) Well -bei n g a n d gas tr oi ntesti nal s y m pt o ms 
a m o n g patie nts referre d t o e n d osc o p y o wi n g t o s us pecte d d u o de nal ulcer. Sca n d J 
Gastr oe nter ol; 3 0: 1 0 4 6 -5 2.  
Fere nce B A, Gi ns ber g H N, Gra h a m I, et al ( 2 0 1 7) L o w -de nsit y li p o pr otei ns ca use 
at her oscler otic car di o vas c ular diseas e. 1. E vi de nce fr o m ge netic, e pi de mi ol o gic, a n d cli nical 
st u dies. A c o nse ns us state me nt fr o m t he E ur o pea n At her oscler osis S ociet y C o nse ns us Pa nel. 
E ur Heart J; 3 8: 2 4 5 9 -2 4 7 2.  
Fitz geral d K, Kalle n d D, Si m o n A ( 2 0 1 7) A Hi g hl y D ura ble R N Ai T hera pe utic I n hi bit or of 
P C S K 9. N E n gl J Me d; 3 7 6( 1 8):e 3 8.  
Gr u n d y S M, Clee ma n JI, Merz C N, et al ( 2 0 0 4) I m plicati o ns of rece nt cli nical trials f or t he 
Nati o nal C h olester ol E d u cati o n Pr o gra m A d ult Treat me nt Pa nel III g ui deli nes. Circ ulati o n; 
1 1 0: 2 2 7 -3 9.  
Gr u n d y S M, St o ne NJ, Baile y A L, et al ( 2 0 1 9) 2 0 1 8 
A H A/ A C C/ A A C V P R/ A A P A/ A B C/ A C P M/ A D A/ A G S/ A P h A/ A S P C/ N L A/ P C N A G ui deli ne 
o n t he Ma na ge me nt of Bl o o d C h olester ol: A Re p ort of t he A merica n C olle ge of 
Car di ol o g y/ A merica n H eart Ass ociati o n Tas k  F orce  o n  Cli nical Practice G ui deli nes. J A m 
C oll C ar di ol; 7 3( 2 4):e 2 8 5 -e 3 5 0.  
G u pta A, T h o m ps o n D, W hite h o use A, et al ( 2 0 1 7) A d verse e ve nts ass o ciate d wit h u n bli n de d, 
b ut n ot wit h bli n de d, stati n t hera p y i n t he A n gl o -S ca n di na via n Car diac O ut c o mes Trial -Li pi d -
L o weri n g Ar m ( A S C O T -L L A): a ra n d o mise d d o u ble -bl i n d place b o-c o ntr olle d trial a n d its 
n o n -ra n d o mise d n o n-bli n d e xte nsi o n p hase. La n cet; 3 8 9: 2 4 7 3 -2 4 8 1.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 7  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
Ha ge ma n S, Pe n nelss L, Oje da F, et al ( 2 0 2 1) S C O R E 2 ris k pre dicti o n al g orit h ms: ne w 
m o dels t o esti mate 1 0 -year ris k of car di o vas c ular disease i n E ur o pe. E ur Heart J; 4 2: 2 4 3 9 – 5 4.  
Hirs h BJ, S mil o witz N R, R ose ns o n R S, et al ( 2 0 1 5) Utilizati o n of a n d A d here nce t o G ui deli ne -
Rec o m me n de d Li pi d -L o weri n g T hera p y Aft er Ac ute C or o nar y S y n dr o m e: O p p ort u nities f or 
I m pr o v e me nt. J A m C oll Car di ol; 6 6( 2): 1 8 4-9 2.  
H u ber A, Ol dri d g e N, H öfer S ( 2 0 1 6) I nt er nati o nal S F -3 6 refere nce v al u es i n patie nts wit h 
isc he mic heart disease. Q ual Life Res; 2 5: 2 7 8 7-2 7 9 8.  
H ytti ne n L, Ke käläi ne n P, V u ori o A F, et al ( 2 0 0 8) Healt h -relate d q ualit y of life i n el derl y 
patie nts wit h fa milial h y perc h olester ole mia. I nt J Tec h n ol Assess Healt h Care;; 2 4( 2): 2 2 8 -3 4.  
H öfer S, Li m L, G u yatt G, et al ( 2 0 0 4) T h e Mac Ne w Heart Disease h ealt h -relate d q ualit y of 
life i nstr u me nt: a s u m mar y. Healt h Q ual Life O ut c o mes; 2( 3). 
H öfer S, Salee m A, St o n e J, et al ( 2 0 1 2) T h e Mac Ne w Heart Dise ase Healt h -Relate d Q ualit y 
of Life Q uesti o n nair e i n patie nts wit h a n gi na a n d patie nts wit h isc he mic heart fail ure. Val ue 
Healt h; 1 5: 1 4 3 -5 0.  
I C H G ui deli ne ( 2 0 1 9) I C H g ui deli ne E 1 9 o n o pti misati o n of safet y data c ollecti o n. (I nter net) 
A v aila ble fr o m: //.e ma.e ur o pa. e u/e n/ic h -g ui d eli ne -e 1 9-o pti misati o n -safet y-data -c ollecti o n -
ste p-2 b p. Accesse d 1 1 Ma y 2 0 2 1.  
Ja mes o n K, Z ha n g Q, Z ha o C, et al ( 2 0 1 4) T otal a n d l o w-de nsit y li p o pr otei n c h olester ol i n 
hi g h -ris k patie nts treate d wit h at or v astati n m o n ot hera p y i n t he U nite d Ki n g d o m: a nal ysis of a 
pri mar y -care d ata bas e. C urr Me d Res O pi n; 3 0( 4): 6 5 5 -6 5.  
J o nes P H, Nair R, T ha k k er K M ( 2 0 1 2) Pre vale nce of d ysli pi de mia a n d li pi d g oal attai n me nt i n 
stati n-treate d s u bjects fr o m 3 data s o urces: a retr os pecti ve a n al ysis. J A m Heart Ass oc; 
1:e 0 0 1 8 0 0.  
Ka ba klić A, Fras Z ( 2 0 1 7) M o derate -d os e at or vast ati n i m pr o ves arterial e n d ot helial f u ncti o n i n 
patie nts wit h a n gi na pect oris a n d n or mal c or o nar y a n gi o gra m: a pil ot st u d y. Arc h Me d Sci; 
1 3( 4): 8 2 7 -8 3 6.  
Keller S, Ba n n C M, D o d d S L, et al ( 2 0 0 4) Vali dit y of t he brief p ai n i n ve nt or y f or us e i n 
d oc u me nti n g t he o utc o mes of patie nts wit h n o nca ncer pai n. Cli n J Pai n; 2 0( 5): 3 0 9 -1 8.  
K h v or o va A ( 2 0 1 7) Oli g o n ucle oti de T hera p e utics - A Ne w Class of C h olester ol -L o weri n g 
Dr u gs. N E n gl J Me d; 3 7 6( 1): 4 -7.  
K n u uti J, 
Wij ns 
W, Saraste A, et al ( 2 0 2 0) 2 0 1 9 E S C G ui deli nes f or t he dia g n osis a n d 
ma na ge me nt of c hr o nic c or o nar y s y n dr o mes. E ur Heart J; 4 1: 4 0 7 -4 7 7.  
K o nes R ( 2 0 1 0) R os u vastati n, i nfla m mati o n, C -reacti ve pr otei n, J U PI T E R, a n d pri mar y 
pre ve nti o n of car di o vas c ular disease --a p ers pecti ve. Dr u g Des De vel T h er; 4: 3 8 3 -4 1 3.  
K ulic h K R, Ma disc h A, Paci ni F, et al ( 2 0 0 8) Relia bilit y a n d vali dit y of t he Gastr oi ntesti nal 
S y m pt o m Rati n g Scale ( G S R S) a n d Q ualit y of Life i n Refl u x a n d D ys pe psia  ( Q O L R A D) 
q uesti o n naire i n d ys pe psi a: a si x -c o u ntr y st u d y. H ealt h Q ual Life O utc o mes; 6( 1 2).  

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 8  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
K ulic h K R, Malf ert hei ner P, Ma disc h A, et al ( 2 0 0 3) Ps yc h o metric v ali dati o n of t he Ger ma n 
tra nslati o n of t he Gastr oi ntesti nal S y m pt o m Rati n g Scale ( G S R S) a n d Q ualit y of Life i n Refl u x 
a n d D ys pe psia ( Q O L R A D) q uesti o n nair e i n p atie nts wit h refl u x diseas e. Healt h Q ual Life 
O utc o mes; 1( 6 2).  
La k os ki S G, La g ace T A, C o he n J C, et al ( 2 0 0 9) Ge netic a n d meta b olic deter mi na nts of plas ma 
P C S K 9 le vels. J Cli n E n d ocri n ol Meta b; 9 4( 7): 2 5 3 7 -4 3.  
Li m L L, Vale nti L A, K na p p J C, et al ( 1 9 9 3) A self -a d mi nistere d q ualit y -of -life q uesti o n naire 
after ac ute m y ocar dial i nfarcti o n. J Cli n E pi de mi ol; 4 6( 1 1): 1 2 4 9 -5 6.  
Mac h F, Bai ge nt C, Cata pa n o A L, et al ( 2 0 2 0) 2 0 1 9 E S C/ E A S G ui deli nes f or t he ma n a ge me nt 
of d ysli pi dae mias: li pi d m o dificati o n t o re d uce car di o vasc ular ris k. E ur Heart J; 4 1: 1 1 1 -1 8 8.  
Ma nfri ni O, A ma d uzzi P, Ber ga mi M, et al ( 2 0 2 0) Effects of Stati n Treat me nt o n Patie nts wit h 
A n gi na a n d N or m al or Nearl y N or m al A n gi o gra ms. E ur Car di ol; 1 5:e 1 5.  
Ma n n D M, W o o d war d M, M u nt ner P, et al ( 2 0 1 0) Pre dict ors of n o na d here nce t o stati ns: a 
s yste matic re vie w a n d meta-a n al ysis. A n n P har mac ot her; 4 4( 9): 1 4 1 0 -2 1.  
Mc C ulla g h P, Nel der J A ( 1 9 8 9) Ge n eralize d Li near M o dels, Sec o n d E diti o n p. 1 -5 2 6.  
Mc Der m ott M M, A des P, G ural ni k J M, et al ( 2 0 0 9) Trea d mill e xercise a n d resista nce tr ai ni n g 
i n patie nts wit h peri p h eral arterial dis ease wit h a n d wit h o ut i nter mitte nt cla u dicati o n: a 
ra n d o mize d c o ntr olle d trial. J A M A; 3 0( 2): 1 6 5-7 4.  
Mc Der m ott M M, Li u K, G ural ni k J M, et al ( 1 9 9 8) Meas ure me nt of wal ki n g e n d ura nce a n d 
wal ki n g vel ocit y wit h q uesti o n naire: vali dati o n of t he wal ki n g i m pair me nt q uesti o n naire i n me n 
a n d w o me n wit h peri p heral arterial disease. J Vas c S ur g; 2 8: 1 0 7 2 -8 1.  
Mc Ta g gart F ( 2 0 0 3) C o m parati v e p har mac ol o g y of r os u vastati n. At her oscler; S u p pl 4: 9 -1 4.  
M o hler E R ( 2 0 0 3) Peri p heral arterial disease: i de ntificati o n a n d i m plicati o ns. Arc h I nter n Me d; 
1 6 3: 2 3 0 6 -1 4.  
M o n dill o S, Ball o P, Bar bati R, et al ( 2 0 0 3) Effects of si m vastati n o n wal ki n g perf or ma n ce a n d 
s y m pt o ms of i nter mitte nt cla u dicati o n i n h y perc h ol ester ole mic patie nts wit h peri p heral vasc ular 
disease. A m J Me d; 1 1 4: 3 5 9 -6 4.  
M o usa vi S A, Ber ge 
K E, Lere n T P ( 2 0 0 9) T he u ni q ue r ole of pr o pr otei n c o n vertas e 
s u btilisi n/ ke xi n 9 i n c h olester ol h o me ostasis. J I nter n Me d; 2 6 6: 5 0 7-1 9.  
M ozaffaria n D, Be nja mi n EJ, G o A S, et al ( 2 0 1 5) Heart disease a n d str o ke statistics --2 0 1 5 
u p date: a re p ort fr o m t he A merica n Heart Ass ociati o n. Circ ulati o n; 1 3 1:e 2 9 -3 2 2.  
M ulc ha n da ni R, L y n g d o h T, C ha kra b ort y P, et al ( 2 0 1 9) Sa tisfacti o n Wit h Stati n Treat me nt 
A m o n g A d ult C or o nar y Arter y Disease Patie nts: A n E x perie n ce Fr o m a Res o urce -C o nstrai ne d 
Setti n g. Heart L u n g Circ; 2 8: 1 7 8 8 -1 7 9 4.  
M üller -N or d h or n J, R oll S, Willic h S N ( 2 0 0 4) C o m paris o n of t h e s h ort f or m ( S F) -1 2 h ealt h 
stat us i nstr u me nt wit h t he S F-3 6 i n patie nts wit h c or o nar y heart disease. Heart; 9 0: 5 2 3 -7.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 9  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
Nea d K T, Z h o u M, Diaz Caceres R, et al ( 2 0 1 3) Wal ki n g i m pair me nt q uesti o n naire i m pr o ves 
m ortalit y ris k pre dicti o n m o dels i n a hi g h -ris k c o h ort i n de pe n de nt of peri p h eral art erial disease 
stat us. Circ Car di o vasc Q ual O utc o mes; 6( 3): 2 5 5-6 1.  
Ne w ma n C B, Preiss D, T o bert J A, et al ( 2 0 1 9) Stati n Safet y a n d Ass ociat e d A d verse E v e nts: 
A Scie ntific State me nt Fr o m t he A merica n Heart Ass ociati o n. Arteri os cler T hr o m b Vas c Bi ol; 
3 9:e 3 8 -e8 1.  
Nic olaï S P, Kr ui de nier L M, R o u wet E V, et al ( 2 0 0 9) T he wal ki n g i m pair me nt q uesti o n naire: 
a n effecti ve t o ol t o assess t he effect of tr eat me nt i n patie nts wit h i nter mitte nt cla u dicati o n. J 
Vasc S ur g; 5 0: 8 9 -9 4.  
Par ker B A, Ca pi zzi J A, Gri mal di A S, et al ( 2 0 1 3) Effect of stati ns o n s k eletal m uscle f u ncti o n. 
Circ ulati o n; 1 2 7( 1): 9 6 -1 0 3.  
P o k u E, D u nca n R, Keet har ut h A, et al ( 2 0 1 6) Patie nt -re p orte d o utc o me meas ures i n patie nts 
wit h peri p heral art erial disease: a s yste matic re vi e w of ps yc h o metric pr o perties. Hea lt h Q ual 
Life O utc o mes; 1 4( 1 6 1).  
P ol uzzi E, Stra hi nja P, La nz o ni M, et al ( 2 0 0 8) A d here nce t o stati n t hera p y a n d patie nts' 
car di o vas c ular ris k: a p har mac o e pi de mi ol o gical st u d y i n Ital y. E ur J Cli n P har mac ol; 6 4: 4 2 5 -
3 2.  
Raal FJ, Kalle n d D, Ra y K K, et al ( 2 0 2 0) I nclisira n f or t he Treat me nt of Heter oz y g o us Fa milial 
H y perc h olest er ole mia. N E n gl J Me d; 3 8 2: 1 5 2 0 -1 5 3 0.  
Ra y K K, Wri g ht R S, Kalle n d D, et al ( 2 0 2 0) T w o P hase 3 Trials of I n clisira n i n Patie nts wit h 
Ele vate d L D L C h olester ol. N E n gl J Me d; 3 8 2: 1 5 0 7 -1 5 1 9.  
Re ge nstei ner J, Stei ner J F, Pa nzer RJ, et al ( 1 9 9 0) E val uati o n of wal ki n g i m pair me nt b y 
q uesti o n naire i n p atie nts wit h peri p heral arteri al disease. J o ur nal of Vas c ular Me dici n e a n d 
Bi ol o g y; 2( 3): 1 4 2 – 5 2.  
Re ge nstei ner J G, Stei ner J F, Hiatt W R ( 1 9 9 6) E xercis e trai ni n g i m pr o ves f u ncti o nal stat us i n 
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S y m pt o m Rati n g Scale i n patie nts wit h gastr oes o p ha geal refl u x disease. Q ual Life Res; 7: 7 5-
8 3.  
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wit h t he treat me nt f or d ysli pi de mia wit h pita vastati n. M ultice ntric, descri pti ve, p ost a ut h orise d 
a n d o bser vati o nal st u d y  ( R EI N A st u d y). Cli n I n v esti g Arteri oscler; 2 6( 5): 2 0 5-1 7.  
Sa bati ne M S, Gi u glia n o R P, Keec h A C, et al ( 2 0 1 7) E v ol oc u ma b a n d Cli nical O utc o mes i n 
Patie nts wit h Car di o vasc ular Disease. N E n gl J Me d; 3 7 6: 1 7 1 3 -1 7 2 2.  
Sa gar S P, Br o w n P M, Zelt D T, et al ( 2 0 1 2) F ur t her cli nical v ali dati o n of t he wal ki n g 
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N o v arti s  
C o nfi d e nti al  
P a g e 1 1 0  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
Sa ma ha F F, Mc K e n ne y J, Bl oe d o n L T, et al ( 2 0 0 8) I n hi biti o n of micr os o m al tri gl yceri de 
tra nsfer pr otei n al o ne or wit h ezeti mi be i n patie nts wit h m o derate h y perc h olester ole mia. Nat 
Cli n Pract Car di o vasc M e d; 5( 8): 4 9 7 -5 0 5.  
Sc h wa be, 
Ulric h 
& 
L u d wi g, 
W olf -Dieter ( 2 0 2 0) 
Arz nei v er or d n u n gs -Re p ort 2 0 2 0 p. 
1 0. 1 0 0 7/ 9 7 8 -3 -6 6 2 -6 2 1 6 8 -4.  
S c h wartz G G, Ste g P G, Szare k M, et al ( 2 0 1 8) Alir oc u ma b a n d Car di o v asc ular O utc o mes after 
Ac ute C or o nar y S y n dr o me. N E n gl J Me d; 3 7 9( 2 2): 2 0 9 7 -2 1 0 7.  
Sette n R L, R ossi JJ, Ha n S P ( 2 0 1 9) T he c urre nt state a n d f ut ure directi o ns of R N Ai -base d 
t hera pe utics. N at Rev Dr u g Disc o v; 1 8: 4 2 1 -4 4 6.  
Str oes E S, T h o m ps o n P D, C orsi ni A, et al ( 2 0 1 5) Stati n -ass ociate d m uscl e s y m pt o ms: i m pact 
o n stati n t hera p y -E ur o pea n At her os cler osis S ociet y C o nse ns us Pa nel State me nt o n Assess me nt, 
Aeti ol o g y a n d Ma na ge m e nt. E ur Heart J; 3 6: 1 0 1 2 -2 2.  
S ve dl u n d J, Sj ö di n I, D ote vall G ( 1 9 8 8) G S R S --a cli nical rati n g scale f or gastr oi ntesti nal 
s y m pt o ms i n patie nts wit h irrita ble b o wel s y n dr o me a n d pe ptic ulcer disease. Di g Dis Sci; 
3 3( 2): 1 2 9 -3 4.  
Ta n G, N g u ye n Q, A n ders o n K O, et al ( 2 0 0 5) F urt her vali da ti o n of t he c hr o nic pai n c o pi n g 
i n ve nt or y. J Pai n; 6( 1): 2 9-4 0.  
T h y gese n K, Jaffe A S ( 2 0 1 9) S h o ul d m y ocar dial i nfarcti o n t y pe 2 be re g ar de d as t w o se parat e 
e ntities? E ur Heart J; 4 0( 3 3): 2 8 1 0 -2 8 1 2.  
Vale nti L, Li m L, Heller R F, et al ( 1 9 9 6) A n i m pr o ve d q uesti o n naire f or assessi n g q ualit y of 
life after ac ute m y o car di al infarcti o n. Q ual Life R es; 5: 1 5 1 -6 1.  
Vissere n F LJ, Mac h F, S m ul ders Y M, et al ( 2 0 2 1) 2 0 2 1 E S C G ui deli nes o n car di o vasc ular 
disease pre v e nti o n i n cli nical practice. E ur Heart J; 4 2: 3 2 2 7 -3 3 3 7.  
W H O ( 2 0 1 7) W orl d H ealt h Or ga nizati o n Car di o v asc ular dise ases. (I nt er net) A vaila ble fr o m: 
w h o.i nt/ ne ws -r o o m/fact-s heets/ detail/car di o vas c ular-diseas es -(c v ds) ( Accesse d 0 3 J u n 2 0 2 0). 
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sec ure d. Car di ol o g y; 8 5(s u p pl 1): 6 5-7 0.  
Ware J E, G a n de k B ( 1 9 9 8) O ver vie w of t he S F -3 6 Healt h S ur ve y a n d t he I nter nati o nal Q ualit y 
of Life Assess me nt (I Q O L A) Pr oject. J Cli n E pi de mi ol; 5 1( 1 1): 9 0 3 -1 2.  
Ware J E, S her b o ur ne C D ( 1 9 9 2) T h e 
M O S 3 6 -ite m s h ort-f or m healt h s ur ve y ( S F-3 6). I. 
C o nce pt ual fra m e w or k a n d ite m selecti o n. Me d Care; 3 0( 6): 4 7 3 -8 3.  
Wri g ht R S, Ra y K K, Raal FJ, et al ( 2 0 2 1) P o ole d Patie nt -Le vel A nal ysis of I nclisira n Trials i n 
Patie nts 
Wit h Fa milial 
H y perc h olester ole mia o r 
At her oscler osis. J 
A m 
C oll 
Car di ol; 
7 7( 9): 1 1 8 2 -1 1 9 3.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 1 1  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
1 6  
A p p e n di c e s  
1 6. 1  
A p p e n di x 1: Cli ni c all y n ot a bl e l a b or at or y v al u e s a n d vit al si g n s  
N ot a p plica ble  
1 6. 2  
A p p e n di x 2: 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  
N ot a p plica ble.  
1 6. 3  
A p p e n di x 3: 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  
Please refer t o Secti o n 1 0. 2. 2 . 
1 6. 4  
D o c u m e nt e d A S C V D  
D oc u me nte d A S C V D (cli nical/i ma gi n g):  
a. Ac ute c or o nar y s y n dr o m e:  
1.  U nsta ble a n gi na ( defi ne d as m y ocar dial isc hae mia at rest or o n mi ni mal e xerti o n i n t he 
a bse nce of ac ute car di o m y oc yte i nj ur y/ necr osis)  
2.  M y ocar dial i nf arcti o n: S p o nta ne o us MI (eit her S T -ele vati o n MI or n o n -S T -ele vati o n 
MI), w hic h was n ot t he res ult of perc uta ne o us c or o nar y i nter ve nti o n ( P CI) or c or o nar y 
arter y b y p ass graft ( C A B G), a n d w hic h occ urre d i n t he peri o d 3 m o nt hs pri or t o 
scree ni n g. C o nfir mati o n of MI is a partici pa nt hist or y/ partici pa nt rec ollecti o n of si g ns 
or s y m pt o ms c o nsiste nt wit h prese ntati o n of MI, a n d at least o ne of t he f oll o wi n g 
(a dapte d fr o m T h y gese n et al., 2 0 1 9 ):  
1.  D oc u me ntati o n of car di ac bi o mar kers t hat e xcee d t he dia g n ostic t hres h ol d of a 
l ocal la b orat or y f or MI 
2.  Pat h ol o gical Q wa ves o n E C G or ot her E C G c h a n ges as defi n e d i n A p pe n di x 1 6. 5  
3.  I ma gi n g e vi de nce of l oss of via ble 
m y ocar di u m or re gi o nal 
wall 
m oti o n 
a b n or malit y i n a patter n c o nsiste nt wit h a n i nfarcti o n or isc he mic eti ol o g y  
4.  I d e ntificati o n of a c or o nar y t hr o m b us b y a n gi o gr a p h y at t he ti me of prese ntati o n 
wit h m y ocar dial i nfarcti o n  
b.  Sta ble a n gi na  
c. C or o nar y re v asc ularizati o n ( P CI, C A B G, a n d ot h er art erial r e vasc ularizati o n pr oce d ures)  
d.  U ne q ui v ocall y d oc u me nt e d A S C V D o n i ma gi n g i ncl u des t h ose fi n di n gs t hat are k n o w n t o 
be pre dicti ve of cli nical e ve n ts s uc h as si g nifica nt pla q ue o n c or o nar y a n gi o gra p h y or C T 
sca n ( m ulti vessel c or o nar y diseas e wit h t w o maj or e picar dial arteries ha vi n g > 5 0 % 
ste n osis), or car oti d ultras o u n d 
e. Str o ke a n d TI A: Hist or y of isc he mic str o ke (a n ac ute e pis o de of f ocal cere bral, s pi nal, or 
vis ual d ysf u ncti o n ca use d b y i nfarcti o n of ce ntral ner v o us s yste m tiss ue) or TI A ha vi n g 
occ urre d i n t he peri o d ≥ 3  m o nt hs pri or t o s cree ni n g d oc u me nte d b y c o m p uterize d 
t o m o gra p h y ( C T) sca n, Ma g netic Res o na nce I ma gi n g ( M RI) or ot her vis u alizati o n met h o d  

N o v arti s  
C o nfi d e nti al  
P a g e 1 1 2  of 1 1 2  
Cli ni c al Tri al Pr ot o c ol V er si o n N o. 0 3 ( Cl e a n ) 
Pr ot o c ol N o. C K J X 8 3 9 A 1 2 4 0 2  
 
f. P A D, as e vi de nce d b y eit her i nter mitte nt cla u dicati o n wit h a n kle brac hial i n de x ( A BI) < 0. 9 
pri or peri p heral arteri al re vasc ularizati o n pr oce d ure, or, a m p utati o n d ue t o at her oscler otic 
disease. T hr o m b oa n giitis o blitera ns is n ot a q ualif yi n g e ve nt  
1 6. 5  
E C G fi n di n g s s u p p orti n g di a g n o si s of m y o c ar di al i nf ar cti o n  
Electr ocar di o gra p hic ma nifestati o ns s u g gesti ve of ac ute m y ocar dial isc h ae mia (i n t he a bse n ce 
of left ve ntric ular h y pertr o p h y a n d b u n dle bra n c h bl oc k) ( T h y ges e n e t al 2 0 1 9). 
S T el e v ati o n  
Ne w S T -el e vati o n at t he J -p oi nt i n t w o c o nti g u o us lea ds wit h t he c ut -p oi nt: ≥1 m m i n all lea ds 
ot her t ha n lea ds V 2 – V 3 w here t he f oll o wi n g c ut -p oi nts a p pl y: ≥2 m m i n me n ≥4 0 years; ≥2. 5 
m m i n me n < 4 0 years, or ≥1. 5 m m i n w o me n re gar d less of a ge. 
W he n t he ma g nit u des of J -p oi nt ele vati o n i n lea ds V 2 a n d V 3 are re gistere d fr o m a pri or 
electr ocar di o gra m, 
ne w J -p oi nt ele vati o n 
≥1 
m m (as c o m pare d 
wit h t he earlier 
electr ocar di o gra m) s h o ul d be c o nsi dere d a n isc he mic res p o nse.  
S T -d e pr e s si o n a n d T w a v e c h a n g e s  
Ne w h oriz o ntal or d o w nsl o pi n g S T -de pressi o n ≥0. 5 m m i n t w o c o nti g u o us lea ds a n d/ or T 
i n versi o n > 1 m m i n t w o c o nti g u o us lea ds wit h pr o mi ne nt R wa ve or R/ S rati o > 1 
P at h ol o gi c al Q w a v e s  
A n y Q wa ve i n lea ds V 2 – V 3 > 0. 0 2 s or Q S c o m ple x i n le a ds V 2– V 3.  
Q wa ve ≥0. 0 3 s a n d ≥1 m m dee p or Q S c o m ple x i n lea ds I, II, a V L, a V F or V 4 – V 6 i n a n y t w o 
lea ds of a c o nti g u o us lea d gr o u pi n g (I, a V L; V 1– V 6; II, III, a V F).