A Multi-part, Multi-center PLATform Study to Assess the Efficacy, Safety, Tolerability and Pharmacokinetics of Anti-malarial Agents Administered as Monotherapy and/or Combination Therapy IN Participants With Uncomplicated Plasmodium Falciparum Malaria
Phase: PHASE2
Conditions: Uncomplicated Plasmodium Falciparum Malaria
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  
Cli ni c al Tri al Pr ot o c ol Titl e:  
( P L A TI N U M): A m ulti- p art, m ulti- c e n t er P L A Tf or m st u d y t o 
a s s e s s t h e effi c a c y, s af e t y, t ol er a bilit y a n d 
p h ar m a c o ki n eti c s of a nti- m al ari al a g e nt s a d mi ni st er e d a s 
m o n ot h er a p y a n d/ or c o m bi n ati o n t h er a p y I N p ati e n t s wit h 
U n c o m pli c at e d Pl a s m o di u m f al ci p ar u m  M al ari a 
Cli ni c al Tri al Pr ot o c ol N u m b er:  C A D P T 1 3 A 1 2 2 0 1 / N C T 0 5 7 5 0 6 2 8
V er si o n N u m b e r: 0 2 ( Cl e a n) 
C o m p o u n d( s): I N E9 6 3 , K A E 6 0 9 , K L U 1 5 6 
Bri ef Titl e : Pl at f or m s t u d y t o e v al u at e th e e ffi c a c y a n d s a f et y o f a nti- m al ari al a g e nt s 
i n p ati e n t s wit h u n c o m pli c at e d Pl a s m o di u m fal ci p ar u m  m al ari a ( P L A TI N U M)  
S t u d y P h a s e:  P h a s e 2 
S p o n s or N a m e:  N o v arti s 
R e g ul at or y A g e n c y Id e ntifi er N u m b er( s): N ot a p pli c a bl e 
A p pr o v a l D at e : 2 1 - J u n-2 0 2 3  
Pr o p ert y o f N o v arti s 
C o nfi d e nti al 
M a y n o t 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 n t of N o v arti s 
Cli ni c al Tr i 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 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
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  ...................................................................................................................... 8  
List of a b bre viati o ns  ............................................................................................................ 9  
Defi niti o ns  ......................................................................................................................... 1 2  
A me n d me nt 2 (J u ne 2 0 2 3)  ................................................................................................ 1 5  
A me n d me nt 1 ( Ma y 2 0 2 3)  ................................................................................................ 1 6  
Pr ot oc ol s u m mar y  .............................................................................................................. 1 9  
1  
I ntr o d u cti o n ....................................................................................................................... 2 2  
1. 1  
St u d y rati o nale  ....................................................................................................... 2 2  
1. 2  
Bac k gr o u n d  ............................................................................................................ 2 2  
2  
O bjecti ves, e n d p oi nts, a n d es ti ma n ds ................................................................................ 2 3  
2. 1  
O bjecti ves a n d E n d p oi nts  ...................................................................................... 2 3  
2. 2  
Pri mar y esti ma n ds  ................................................................................................. 2 5  
2. 3  
Sec o n dar y esti ma n ds  ............................................................................................. 2 7  
3  
St u d y desi g n  ...................................................................................................................... 2 7  
3. 1  
O verall desi g n  ........................................................................................................ 2 7  
4  
Rati o nale  ............................................................................................................................ 3 1  
4. 1  
Scie ntific rati o nale f or st u d y desi g n  ...................................................................... 3 1  
4. 2  
J ustificati o n f or d ose .............................................................................................. 3 2  
4. 3  
Rati o nale f or c h oic e of c o ntr ol dr u gs (c o m parat or) or c o m bi nati o n dr u gs  ........... 3 3  
4. 4  
P ur p ose a n d ti mi n g of desi g n a da ptati o ns  ............................................................. 3 3  
4. 5  
Be nefit/ Ris k assess me nt  ........................................................................................ 3 4  
4. 5. 1  
Bl o o d sa m ple v ol u me  ............................................................................ 3 5  
4. 6  
Rati o nale f or p u blic healt h e mer ge n c y miti gati o n pr oce d ures  .............................. 3 5  
4. 7  
E n d of st u d y defi niti o n  .......................................................................................... 3 5  
5  
St u d y P o p ulati o n  ............................................................................................................... 3 6  
5. 1  
I n cl usi o n criteria .................................................................................................... 3 6  
5. 2  
E xcl usi o n criteria  ................................................................................................... 3 7  
5. 3  
Restricti o ns f or st u d y partici pa nts  ......................................................................... 3 9  
5. 3. 1  
Dietar y restricti o ns  ................................................................................ 3 9  
5. 3. 2  
Ot her restri cti o ns  ................................................................................... 3 9  
5. 4  
Scree n fail ures  ....................................................................................................... 3 9  
5. 4. 1  
Re place me nt p olic y  ............................................................................... 4 0  
5. 4. 2  
Partici pa nt n u m beri n g  ........................................................................... 4 0  

N o v arti s  
C o nfi d e nti al  
P a g e 3  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
6  
St u d y treat me nt(s) a n d c o nc o mita nt t hera p y  ..................................................................... 4 1  
6. 1  
St u d y treat me nt(s)  .................................................................................................. 4 1  
6. 1. 1  
A d diti o nal st u d y treat me nts  .................................................................. 4 1  
6. 1. 2  
Treat me nt ar ms/ gr o u p  ........................................................................... 4 1  
6. 1. 3  
Treat me nt d ur ati o n  ................................................................................ 4 1  
6. 2  
Pre parati o n, ha n dli n g, st ora ge, a n d acc o u nta bilit y  ................................................ 4 1  
6. 2. 1  
Ha n dli n g of st u d y treat m e nt  .................................................................. 4 1  
6. 2. 2  
Ha n dli n g of ot her treat me nt  .................................................................. 4 2  
6. 2. 3  
I nstr u cti o n f or prescri bi n g a n d ta ki n g st u d y treat m e nt ......................... 4 2  
6. 3  
Meas ures t o mi ni mize bi as: ra n d o mizati o n a n d bli n di n g  ...................................... 4 2  
6. 3. 1  
Treat me nt assi g n me nt, r a n d o miza ti o n .................................................. 4 2  
6. 3. 2  
Treat me nt bli n di n g  ................................................................................ 4 3  
6. 4  
St u d y treat me nt c o m plia nce  .................................................................................. 4 4  
6. 4. 1  
Rec o m me n de d treat me nt of a d verse e ve nts  .......................................... 4 4  
6. 5  
C o h ort pr o gress i o n a n d d ose m o dificati o n ............................................................ 4 4  
6. 5. 1  
G ui deli nes t o start o pti o nal ar m(s) i n Part A  ........................................ 4 5  
6. 5. 2  
G ui deli nes t o start Part B  ...................................................................... 4 5  
6. 6  
C o nti n ue d access t o st u d y treat me nt after t he e n d of t he st u d y ............................. 4 6  
6. 7  
Treat me nt of o v er d ose  ........................................................................................... 4 6  
6. 7. 1  
Re p orti n g of st u d y treat m e nt err ors i ncl u di n g mis use/a b use  ................ 4 6  
6. 8  
C o nc o mita nt a n d ot her t hera p y  .............................................................................. 4 6  
6. 8. 1  
C o nc o mita nt t hera p y  ............................................................................. 4 6  
6. 8. 2  
Pr o hi bite d me dicati o n  ........................................................................... 4 7  
6. 8. 3  
Resc ue me dicati o n  ................................................................................ 4 9  
7  
Disc o nti n uati o n of st u d y treat me nt a n d partici pa nt disc o nti n uati o n/ wit h dra wal  .............. 5 0  
7. 1  
Disc o nti n ua ti o n of st u d y treat me nt ........................................................................ 5 0  
7. 2  
Partici pa nt disc o nti n uati o n fr o m t he st u d y  ............................................................ 5 1  
7. 3  
Wit h dra wal of i nf or me d c o nse nt a n d e x ercise of partici pa nts’ data pri vac y 
ri g hts ...................................................................................................................... 5 1  
7. 4  
L ost t o f oll o w -u p  ................................................................................................... 5 2  
7. 5  
St u d y st o p pi n g r ules  .............................................................................................. 5 2  
7. 6  
Earl y st u d y ter mi nati o n b y t he S p o ns or  ................................................................. 5 3  
8  
St u d y Assess me nts a n d Pr oce d ures  ................................................................................... 5 3  
8. 1  
Scree ni n g  ............................................................................................................... 6 0  
8. 2  
Partici pa nt de m o gra p hics/ ot her baseli ne c h aracteristics  ....................................... 6 0  
8. 3  
Efficac y assess me nts  ............................................................................................. 6 0  

N o v arti s  
C o nfi d e nti al  
P a g e 4  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
8. 3. 1  
Cli nical si g ns a n d s y m pt o ms of malari a ............................................... 6 0  
8. 3. 2  
 6 1  
8. 3. 3  
Parasite mia a n d parasite cleara nce ti me  ................................................ 6 1  
8. 3. 4  
Defi niti o n of Treat me nt Fail ure a n d A de q u at e Cli nical a n d 
Parasit ol o gical res p o nse ( A C P R)  .......................................................... 6 2  
8. 3. 5  
I n ci de nce rat e of recr u desce nce a n d rei nfecti o n ................................... 6 3  
8. 3. 6  
Bl o o d sa m ple f or m olec ular dia g n ostic p ur p ose  ................................... 6 4  
8. 3. 7  
A p pr o priate n ess of efficac y assess me nts  .............................................. 6 4  
8. 4  
Safet y assess me nts  ................................................................................................. 6 4  
8. 4. 1  
P h ysical e xa mi nati o ns  ........................................................................... 6 4  
8. 4. 2  
Vital si g ns .............................................................................................. 6 5  
8. 4. 3  
Electr ocar di o gra ms  ............................................................................... 6 5  
8. 4. 4  
Cli nical safet y la b orat or y tests  .............................................................. 6 6  
8. 4. 5  
Pre g na nc y testi n g  .................................................................................. 6 8  
8. 4. 6  
Ot her safet y e val uati o ns  ........................................................................ 6 8  
8. 4. 7  
A p pr o priate n ess of safet y meas ure me nts  .............................................. 6 9  
8. 5  
A d diti o nal assess me nts  .......................................................................................... 6 9  
8. 5. 1  
Meal Rec or ds  ........................................................................................ 7 0  
8. 5. 2  
Ot her assess me nts  ................................................................................. 7 0  
8. 6  
A d verse e ve nts ( A Es), seri o us a d verse e ve nts ( S A Es), a n d ot her s afet y 
re p orti n g ................................................................................................................. 7 0  
8. 6. 1  
A d verse e ve nts  ...................................................................................... 7 0  
8. 6. 2  
Seri o us a d verse e ve nts  .......................................................................... 7 2  
8. 6. 3  
S A E re p orti n g ........................................................................................ 7 3  
8. 6. 4  
Pre g na nc y Re p orti n g  ............................................................................. 7 4  
8. 6. 5  
Disease -relate d e ve nts a n d/ or disease-relate d o utc o mes n ot 
q ualif yi n g as A Es or S A Es  .................................................................... 7 4  
8. 7  
P har mac o ki netics  ................................................................................................... 7 5  
8. 8  
Bi o mar kers  ............................................................................................................. 7 5  
8. 9  
Healt h ec o n o mics  ................................................................................................... 7 7  
9  
Statistical c o nsi derati o ns  ................................................................................................... 7 7  
9. 1  
A nal ysis sets  .......................................................................................................... 7 8  
9. 2  
Statistical a nal yses  ................................................................................................. 7 8  
9. 2. 1  
Partici pa nt de m o gra p hics a n d ot her bas eli ne c haracteristics  ................ 7 8  
9. 2. 2  
Treat me nts  ............................................................................................. 7 8  
9. 3  
Pri mar y e n d p oi nt(s)/esti ma n d(s) a nal ysis  .............................................................. 7 9  
9. 3. 1  
Defi niti o n of pri mar y e n d p oi nt(s)  ......................................................... 7 9  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 5  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
9. 3. 2  
Statistical m o del, h y p ot hesis, a n d met h o d of a nal ysis  .......................... 7 9  
9. 3. 3  
Ha n dli n g of i nterc urre nt e ve nts of pri mar y esti ma n d  ........................... 8 1  
9 . 3. 4 
Ha n dli n g of missi n g val ues n ot relate d t o i nterc urre nt e ve nt  ............... 8 1  
9. 3. 5  
Se nsiti vit y a nal yses  ............................................................................... 8 1  
9. 3. 6  
S u p ple me ntar y a nal ysis  ......................................................................... 8 1  
9. 4  
Sec o n dar y e n d p oi nt(s)/esti ma n d(s) a nal ysis  .......................................................... 8 2  
9. 4. 1  
Efficac y a n d/ or P har m ac o d y na mic e n d p oi nt(s)  .................................... 8 2  
9. 4. 2  
Safet y e n d p oi nts  .................................................................................... 8 3  
9. 4. 3  
P har mac o ki netics  .................................................................................. 8 4  
9. 4. 4  
 ..................................................................................... 8 5  
9. 4. 5  
P K/ P D relati o ns hi ps  .............................................................................. 8 5  
9. 5  
E x pl orat or y e n d p oi nt(s)/ esti ma n d(s) a nal ysis  ....................................................... 8 5  
9. 6  
( Ot her) Safet y a n al yses .......................................................................................... 8 7  
9. 7  
I nteri m a nal yses ..................................................................................................... 8 7  
9. 8  
Sa m ple size calc ul ati o n  .......................................................................................... 8 7  
9. 8. 1  
Pri mar y e n d p oi nt(s)  ............................................................................... 8 7  
9. 8. 2  
Sec o n dar y e n d p oi nt(s)  ........................................................................... 8 8  
1 0  S u p p orti n g d oc u me ntati o n a n d o perati o nal c o nsi derati o ns  ............................................... 8 8  
1 0. 1  
Re g ulat or y, et hical, a n d st u d y o versi g ht c o nsi derati o ns  ....................................... 8 8  
1 0. 1. 1  
Re g ulat or y a n d et hical c o n si derati o ns .................................................. 8 8  
1 0. 1. 2  
I nf or me d c o ns e nt pr ocess ...................................................................... 8 9  
1 0. 1. 3  
Data pr ote ct i o n ...................................................................................... 9 1  
1 0. 1. 4  
C o m mittees Str uct ure  ............................................................................ 9 1  
1 0. 1. 5  
Data q ualit y ass ura n ce  ........................................................................... 9 1  
1 0. 1. 6  
S o urce d oc u me nts  ................................................................................. 9 3  
1 0. 1. 7  
P u blicati o n p olic y .................................................................................. 9 3  
1 0. 1. 8  
Pr ot oc ol a d here n ce a n d pr ot oc ol a me n d me nts  ...................................... 9 4  
1 1  A p pe n dices  ........................................................................................................................ 9 5  
1 1. 1  
A p pe n di x 1: Li ver Safet y M o nit ori n g  ................................................................... 9 5  
. 9 6  
1 1. 2  
. 9 9  
1 2  C o h ort S pecific I nf or m ati o n  ............................................................................................ 1 0 1  
1 2. 1  
C o h ort A 1: I N E 9 6 3  .............................................................................................. 1 0 1  
1 2. 1. 1  
I N E 9 6 3 Bac k gr o u n d ............................................................................ 1 0 1  
1 2. 1. 2  
C o h ort A 1 St u d y Desi g n  ..................................................................... 1 0 1  
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 6  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
1 2. 1. 3  
 1 0 2  
1 2. 1. 4  
C o h ort A 1 Ris ks a n d Be nefits  ............................................................. 1 0 3  
1 2. 1. 5  
C o h ort A 1 St u d y P o p ulati o n a n d S pecial Restricti o ns  ....................... 1 0 4  
1 2. 1. 6  
 1 0 8  
1 2. 1. 7  
 1 1 0  
1 2. 2  
C o h ort B 1: I N E 9 6 3 + Ci par ga mi n  ....................................................................... 1 1 1  
1 2. 2. 1  
Ci par ga mi n Bac k gr o u n d  ..................................................................... 1 1 1  
1 2. 2. 2  
C o h ort B 1 St u d y Desi g n  ..................................................................... 1 1 2  
1 2. 2. 3  
C o h ort B 1 Sa m ple Size  ....................................................................... 1 1 2  
1 2. 2. 4  
 1 1 3  
1 2. 2. 5  
 1 1 4  
1 2. 2. 6  
C o h ort B 1 St u d y P o p ulati o n a n d S pecial Restricti o ns  ........................ 1 1 5  
1 2. 2. 7  
C o h ort B 1 St u d y Treat me nt  ................................................................ 1 1 7  
1 2. 2. 8  
C o h ort B 1 P K/ P D a n d Bi o mar ker Ass ess me nts  ................................. 1 1 9  
1 2. 2. 9  
C o h ort B 1 C o m p o u n d S pecific Assess m e nts  ...................................... 1 2 1  
1 2. 3  
C o h ort B 2: K L U 1 5 6 + ci par ga mi n  ...................................................................... 1 2 1  
1 2. 3. 1  
K L U 1 5 6 Bac k gr o u n d  .......................................................................... 1 2 1  
1 2. 3. 2  
C o h ort B 2 St u d y Desi g n  ..................................................................... 1 2 2  
1 2. 3. 3  
C o h ort B 2 Sa m ple Size  ....................................................................... 1 2 3  
1 2. 3. 4  
C o h ort B 2 D ose Rati o nale  .................................................................. 1 2 4  
1 2. 3. 5  
C o h ort B 2 Ris ks a n d Be nefits  ............................................................. 1 2 5  
1 2. 3. 6  
C o h ort B 2 St u d y P o p ulati o n a n d S pecial Restricti o n s ........................ 1 2 7  
1 2. 3. 7  
C o h ort B 2 St u d y Treat me nt  ................................................................ 1 3 2  
1 2. 3. 8  
C o h ort B 2 P K/ P D a n d Bi o mar ker Ass ess me nts  ................................. 1 3 3  
1 2. 3. 9  
C o h ort B 2 C o m p o u n d S pecific Assess m e nts  ...................................... 1 3 5  
1 3  Refere n ces  ....................................................................................................................... 1 3 6  
Li st of t a bl e s  
Ta ble 2 -1  
O bjecti ves a n d re late d e n d p oi nts .......................................................... 2 3  
Ta ble 4 -1  
Rati o nale f or st u d y desi g n  ..................................................................... 3 2  
Ta ble 6 -1  
.. 4 3  
Ta ble 6 -2  
.. 4 7  
Ta ble 8 -1  
Assess me nt Sc he d ule  ............................................................................ 5 5  
Ta ble 8 -2  
. 6 7  
Ta ble 9 -1  
. 8 0  
Ta ble 9 -2  
N o n -c o m part me nt al p har mac o ki netic para meters  ................................ 8 5  
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 7  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
Ta ble 9 -3  
.. 8 8  
Ta ble 9 -4  
.. 8 8  
Ta ble 1 1 -1  
.. 9 6  
Ta ble 1 1 -2  
.. 9 6  
Ta ble 1 1 -3  
.. 9 7  
Ta ble 1 1 -4  
.. 9 9  
Ta ble 1 1 -5  
 1 0 0  
Ta ble 1 2 -1  
 1 0 2  
Ta ble 1 2 -2  
 1 0 5  
Ta ble 1 2 -3  
 1 0 6  
Ta ble 1 2 -4  
 1 0 8  
Ta ble 1 2 -5  
 1 0 8  
Ta ble 1 2 -6  
 1 0 9  
Ta ble 1 2 -7  
 1 1 0  
Ta ble 1 2 -8  
 1 1 1  
Ta ble 1 2 -9  
 1 1 2  
Ta ble 1 2 -1 0  
 1 1 3  
Ta ble 1 2 -1 1  
 1 1 6  
Ta ble 1 2 -1 2  
 1 1 7  
Ta ble 1 2 -1 3  
 1 1 8  
Ta ble 1 2 -1 4  
 1 1 9  
Ta ble 1 2 -1 5  
 1 2 2  
Ta ble 1 2 -1 6  
 1 2 3  
Ta ble 1 2 -1 7  
 1 2 3  
Ta ble 1 2 -1 8  
 1 2 8  
Ta ble 1 2 -1 9  
 1 2 9  
Ta ble 1 2 -2 0  
 1 3 2  
Ta ble 1 2 -2 1  
 1 3 2  
Ta ble 1 2 -2 2  
 1 3 3  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 8  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
Li st of fi g ur e s  
Fi g ure 3 -1  
St u d y Desi g n - St u d y Le vel Vie w  ......................................................... 2 8  
Fi g ure 3 -2  
St u d y Desi g n - C o h ort Le vel Vie w  ....................................................... 3 0  
Fi g ure 8 -1  
Ti mi n g of st u d y pr oce d ures  .................................................................. 6 6  

N o v arti s  
C o nfi d e nti al  
P a g e 9  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
Li st of a b br e vi ati o n s  
A C P R  
A d e q u at e Cli ni c al a n d P ar a sit ol o gi c al R e s p o n s e  
A C T  
Art e mi si ni n c o m bi n ati o n t h er a pi 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 S A Q  
art e s u n at e -a m o di a q ui n e  
A S T  
A s p art at e A mi n otr a n sf er a s e  
A U C  
Ar e a u n d er t h e c ur v e  
BI D  
T wi c e a d a y  
B MI  
B o d y M a s s I n d e x  
B U N  
Bl o o d Ur e a Nitr o g e n  
C F R  
C o d e of F e d er al R e g ul ati o n s  
CI  
C o nfi d e n c e I nt er v al  
CI O M S  
C o u n cil f or I nt er n ati o n al Or g a ni z ati o n s of M e di c al S ci e n c e s  
C M O & P S  
C hi ef M e di c al Offi c e a n d P ati e nt S af et y  
C O N S O R T  C o n s oli d at e d St a n d ar d s of R e p orti n g Tri al s  
C R F  
C a s e R e p ort/ R e c or d F or m ( p a p er or el e ctr o ni c)  
C R O  
C o ntr a ct R e s e ar c h Or g a ni z ati o n  
C S R  
Cli ni c al st u d y r e p ort  
C T A  
Cli ni c al Tri al A p pli c ati o n  
C T C  
C o m m o n T er mi n ol o g y Crit eri a  
C T T  
Cli ni c al Tri al T e a m 
C V  
c o effi ci e nt of v ari ati o n  
D B P  
Di a st oli c Bl o o d Pr e s s ur e  
D DI  
Dr u g -dr u g i nt er a cti o n 
D H A  
Di h y dr o art e mi si ni n  
DI N  
Dr u g I n d u ct e d N e p hr ot o xi cit y  
D L T  
D o s e Li miti n g T o xi cit y  
D M C  
D at a M o nit ori n g C o m mitt e e  
 
 
E C 5 0  
H alf m a xi m al eff e cti v e c o n c e ntr ati o n 
E C G  
El e ctr o c ar di o gr a m  
E D C  
El e ctr o ni c D at a C a pt ur e  
e G F R  
e sti m at e d gl o m er ul ar filtr ati o n r at e  
E O S  
E n d of St u d y  
E T F  
E arl y Tr e at m e nt F ail ur e  
F A S  
F ull A n al y si s S et  
F D A  
F o o d a n d Dr u g A d mi ni str ati o n  
 
 
FI H  
Fir st i n H u m a n  
C CI
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 0  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
G C P  
G o o d Cli ni c al Pr a cti c e  
G C S  
Gl o b al Cli ni c al S u p pl y  
G G T  
G a m m a -gl ut a m yl tr a n sf er a s e  
GI  
g a str oi nt e sti n al  
G L D H  
Gl ut a m at e D e h y dr o g e n a s e  
G L P  
G o o d L a b or at or y Pr a cti c e s  
h  
H o ur  
H B V  
H e p atiti s B Vir u s  
H C V  
H e p atiti s C Vir u s  
h E R G  
h u m a n Et h er -à -g o -g o -R el at e d G e n e  
HI V  
H u m a n i m m u n o d efi ci e n c y vir u s 
I A 
I nt eri m A n al y si s 
I B 
I n v e sti g at or’ s Br o c h ur e 
I C F 
I nf or m e d C o n s e nt F or m 
I C H 
I nt er n ati o n al C o u n cil f or H ar m o ni z ati o n of T e c h ni c al R e q uir e m e nt s f or 
P h ar m a c e uti c al s f or H u m a n U s e  
I E C 
I n d e p e n d e nt Et hi c s C o m mitt e e 
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  
L C -M S  
Li q ui d c hr o m at o gr a p h y – m a s s s p e ctr o m etr y  
L C F  
L at e Cli ni c al F ail ur e 
L D H  
l a ct at e d e h y dr o g e n a s e 
L F T  
Li v er f u n cti o n t e st  
L L N  
l o w er li mit of n or m al 
L L O Q  
l o w er li mit of q u a ntifi c ati o n 
L P F  
L at e P ar a sit ol o gi c al F ail ur e  
 
 
M D M A  
3, 4 -M et h yl e n di o x y -N -m et h yl a m p h et a mi n  
M e d D R A  
M e di c al di cti o n ar y f or r e g ul at or y a cti viti e s  
m g  
milli gr a m( s)  
m L  
millilit er( s)  
M o A  
M e c h a ni s m of a cti o n 
M P C  
mi ni m u m p ar a siti ci d al c o n c e ntr ati o n  
M RI  
M a g n eti c r e s o n a n c e i m a gi n g 
M S  
m a s s s p e ctr o m etr y  
N O A E L  
N o O b s er v e d A d v er s e Eff e ct L e v el  
N S AI D s  
N o n -st er oi d al a nti -i nfl a m m at or y dr u g s 
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 1  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
p. o.
Or al(l y)  
P C  
P ar a sit e Cl e ar a n c e  
P C P  
P h e n yl -c y cl o h e x yl -pi p eri di n  
P C R  
P ol y m er a s e C h ai n R e a cti o n  
P C T  
P ar a sit e Cl e ar a n c e Ti m e  
P C V  
P a c k e d c ell v ol u m e ( h e m at o crit)  
P D  
P h ar m a c o d y n a mi c( s)  
P K  
P h ar m a c o ki n eti c( s)  
P P S  
P er -pr ot o c ol S et  
P T  
pr ot hr o m bi n ti m e  
 
 
q R T -P C R  
q u a ntit ati v e r e v er s e-tr a n s cri pti o n p ol y m er a s e c h ai n r e a cti o n 
Q T c F  
Q T i nt er v al c orr e ct e d b y Fri d eri ci a’ s f or m ul a  
R A S  
R a n d o mi z e d A n al y si s S et  
R B C  
R e d Bl o o d C ell  
R N A  
R i b o n u cl ei c a ci d 
S A E  
S eri o u s A d v er s e E v e nt  
S A F  
S af et y A n al y si s S et  
S A P  
St ati sti c al A n al y si s Pl a n  
S B P  
S y st oli c Bl o o d Pr e s s ur e  
S CI D  
s e v er e c o m bi n e d i m m u n o d efi ci e n c y  
s Cr  
S er u m cr e ati ni n e  
S D  
st a n d ar d d e vi ati o n  
S G O T  
S er u m Gl ut a mi c O x al o a c eti c Tr a n s a mi n a s e  
S G P T  
S er u m Gl ut a mi c P yr u vi c Tr a n s a mi n a s e  
S 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 er y  
S o C  
St a n d ar d of C ar 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  
U L N  
u p p er li mit of n or m al  
W B C  
W hit e Bl o o d C ell s 
W H O  
W orl d H e alt h Or g a ni z ati o n  
W W A R N  
W orl d Wi d e A nti m al ari al R e si st a n c e N et w or k  
C CI
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 2  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
D efi niti o n s  
A d diti o n al 
tr e at m e nt 
M e di ci n al pr o d u ct s t h at m a y b e u s e d d uri n g t h e cli ni c al tri al a s d e s cri b e d i n 
t h e pr ot o c ol, b ut n ot a s a n i n v e sti g ati o n al m e di ci n al pr o d u ct (e. g.,  a n y 
b a c k gr o u n d t h er a p y)  
A s s e s s m e nt  
A pr o c e d ur e u s e d t o g e n er at e d at a r e q uir e d b y t h e st u d y  
Bi ol o gi c S a m pl e s  
A bi ol o gi c al s p e ci m e n i n cl u di n g, f or e x a m pl e, bl o o d ( pl a s m a, s er u m), s ali v a, 
ti s s u e, uri n e, st o ol, et c. t a k e n fr o m a st u d y p arti ci p a nt 
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 h ort  
A gr o u p of i n di vi d u al s w h o s h ar e a c o m m o n e x p o s ur e, e x p eri e n c e or 
c h ar a ct eri sti c, or a gr o u p of i n di vi d u al s f oll o w e d -u p or tr a c e d o v er ti m e  
C o ntr ol dr u g  
A st u d y i nt er v e nti o n ( a cti v e or pl a c e b o) u s e d a s a c o m p ar at or t o r e d u c e 
a s s e s s m e nt bi a s, pr e s er v e bli n di n g of i n v e sti g ati o n al dr u g, a s s e s s i nt er n al 
st u d y v ali dit y, a n d/ or e v al u at e c o m p ar ati v e eff e ct s of t h e i n v e sti g ati o n al dr u g  
C y cl e s  
N u m b er a n d ti mi n g or r e c o m m e n d e d r e p etiti o n s of t h er a p y ar e u s u all y 
e x pr e s s e d a s n u m b er of d a y s ( e. g.,  q 2 8 d a y s)  
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 i nt er v e nti o n 
a d mi ni str ati o n, if a n y). P arti ci p a nt a gr e e s t o t h e ot h er pr ot o c ol r e q uir e d 
a s s e s s m e nt s i n cl u di n g f oll o w -u p. N o s p e cifi c r e q u e st i s m a d e t o st o p t h e u s e 
of t h eir s a m pl e s or d at a.  
D o s a g e  
D o s e of t h e st u d y tr e at m e nt gi v e n t o t h e p arti ci p a nt i n a ti m e u nit ( e. g.,  
1 0 0  m g o n c e a d a y, 7 5 m g t wi c e a d a y)  
El e ctr o ni c D at a 
C a pt ur e ( E D C)  
El e ctr o ni c d at a c a pt ur e ( E D C) i s t h e el e ctr o ni c a c q ui siti o n of cli ni c al st u d y 
d at a u si n g d at a c oll e cti o n s y st e m s, s u c h a s W e b -b a s e d a p pli c ati o n s, 
i nt er a cti v e v oi c e r e s p o n s e s y st e m s a n d cli ni c al l a b or at or y i nt erf a c e s. E D C 
i n cl u d e s t h e u s e of El e ctr o ni c C a s e R e p ort F or m s ( e C R F s) w hi c h ar e u s e d t o 
c a pt ur e d at a tr a n s cri b e d fr o m 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 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 hat 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 nter 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. 

N o v arti s  
C o nfi d e nti al  
P a g e 1 3  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
H e alt h y v ol u nt e er  
A p er s o n wit h n o k n o w n si g nifi c a nt h e alt h pr o bl e m s w h o v ol u nt e er s t o b e a 
st u d y p arti ci p a nt  
I nt er c urr e nt e v e nt s 
E v e nt s o c c urri n g aft er tr e at m e nt i niti ati o n t h at aff e ct eit h er t h e i nt er pr et ati o n or 
t h e e xi st e n c e of t h e m e a s ur e m e nt s a s s o ci at e d wit h t h e clini c al q u e sti o n of 
i nt er e st. 
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  
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.  
Ot h er tr e at m e nt  
Tr e at m e nt t h at m a y b e n e e d e d/ all o w e d d uri n g t h e c o n d u ct of t h e st u d y ( i. e., 
c o n c o mit a nt or r e s c u e t h er a p y)  
P art  
A s u b -di vi si o n of a st u d y u s e d t o e v al u at e s p e cifi c o bj e cti v e s or c o nt ai n 
diff er e nt p o p ul ati o n s. F or e x a m pl e, o n e st u d y c o ul d c o nt ai n a si n gl e d o s e p art 
a n d a m ulti pl e d o s e p art, or a p art i n p arti ci p a nt s wit h e st a bli s h e d di s e a s e a n d 
i n t h o s e wit h n e wl y-di a g n o s e d di s e a s e  
P arti ci p a nt  
A tri al p arti ci p a nt ( c a n b e a h e alt h y v ol u nt e er or a p ati e nt). " P arti ci p a nt" 
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 eri o d  
T h e s u b di vi si o n s of t h e tri al d e s i g n (e. g.,  S cr e e ni n g, Tr e at m e nt, F oll o w -u p) 
w hi c h ar e d e s cri b e d i n t h e Pr ot o c ol. P eri o d s d efi n e t h e st u d y p h a s e s a n d will 
b e u s e d i n cli ni c al tri al d at a b a s e s et u p a n d e v e nt u all y i n a n al y si s  
P er s o n al d at a  
P arti ci p a nt i nf or m ati o n c oll e ct e d b y t h e i n v e sti g at or t h at i s c o d e d a n d 
tr a n sf err e d t o N o v arti s f or t h e p ur p o s e of t h e cli ni c al tri al. T hi s d at a i n cl u d e s 
p arti ci p a nt i d e ntifi er i nf or m ati o n, st u d y i nf or m ati o n a n d bi ol o gi c al s a m pl e s.  
R a n d o mi z ati o n  
T h e pr o c e s s of a s si g ni n g tri al p arti ci p a nt s t o i n v e sti g ati o n al dr u g or 
c o ntr ol/ c o m p ar at or dr u g u si n g a n el e m e nt of c h a n c e t o d et er mi n e t h e 
a s si g n m e nt s i n or d er t o r e d u c e bi a s.  
R a n d o mi z ati o n 
n u m b er  
A u ni q u e i d e ntifi er a s si g n e d t o e a c h r a n d o mi z e d p arti ci p a nt  
R e 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. 
R e s cr e e ni n g  
If a p arti ci p a nt f ail s t h e i niti al s cr e e ni n g a n d i s c o n si d er e d a s a S cr e e n F ail ur e, 
h e/ s h e c a n b e i n vit e d o n c e f or a n e w S cr e e ni n g vi sit aft er m e di c al j u d g m e nt 
a n d a s s p e cifi e d b y t h e pr ot o c ol  
R 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 4  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
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 gr o u p  
A tr e at m e nt gr o u p d efi n e s t h e d o s e a n d r e gi m e n or t h e c o m bi n ati o n, a n d m a y 
c o n si st of 1 or m or e c o h ort s.  
Tr e at m e nt ar m  
A tr e at m e nt ar m 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 wit hi n a 
c o h ort  
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 u rr e ntl y, e. g.,  a s a d d -o n t o 
st a n d ar d of c ar e, or mi g ht c o n si st of a n o v er all r e gi m e n i n v ol vi n g a c o m pl e x 
s e q u e n c e of i nt er v e nti o n s. T hi s i s t h e tr e at m e nt of i nt er e st u s e d i n d e s cri bi n g 
t h e r el at e d cli ni c al q u e sti o n of i nt er e st, w hi c h mi g ht or mi g ht n ot b e t h e s a m e 
a s t h e st u d y tr e at m e nt.  
V ari a bl e ( or 
e n d p oi nt)  
T h e v ari a bl e ( or e n d p oi nt) t o b e o bt ai n e d f or e a c h p arti ci p a nt t h at i s r e q uir e d 
t o a d dr e s s t h e cli ni c al q u e sti o n. T h e s p e cifi c ati o n of t h e v ari a bl e mi g ht i n cl u d e 
w h et h er t h e p arti ci p a nt e x p eri e n c e s a n i nt er c urr e nt e v e nt.  
Wit h dr a w al of 
c o n s e nt  
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/ or 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. 
T hi s r e q u e st s h o ul d b e di sti n g ui s h e d fr o m a r e q u e st t o di s c o nti n u e t h e st u d y. 
Ot h er st u d y p arti ci p a nt' s pri v a c y ri g ht s ar e d e s cri b e d i n t h e c orr e s p o n di n g 
i nf or m e d c o n s e nt f or m. 

N o v arti s  
C o nfi d e nti al  
P a g e 1 5  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
A m e n d m e nt 2 ( J u n e 2 0 2 3)  
A m e n d m e nt r ati o n al e  
T he p ur p ose of t his a me n d me nt is t o a d d bli n di n g of t he micr osc o pists base d o n fee d bac k fr o m 
Healt h A ut h orities  a n d Et hics C o m mittees .  
Mi n or t y p o gra p hical a n d a d mi nistrati ve err ors ha ve bee n c orrecte d t hr o u g h o ut t he pr ot oc ol t o 
i ncreas e q ualit y. 
C h a n g e s t o t h e pr ot o c ol  
I R B s/I E C s 
A c o p y of t his a me n de d pr ot oc ol 
will be se nt t o 
t he I nstit uti o nal 
Re vie w 
B oar d 
(I R Bs)/I n 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 h is 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 acc or di n g t o l ocal re g ulati o ns pri or t o i m ple me ntati o n.  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 6  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
A m e n d m e nt 1  ( M a y 2 0 2 3) 
A m e n d m e nt r ati o n al e  
T he p ur p os e of t his a m e n d me nt is t o a d d a Dat a M o nit ori n g C o m mittee ( D M C) a n d ot her 
re q uests base d o n fee d bac k fr o m Healt h A ut h orities.  
Mi n or t y p o gra p hical a n d a d mi nistrati ve err ors ha ve bee n c orrecte d t hr o u g h o ut t he pr ot oc ol t o 
i ncreas e q ualit y. 

N o v arti s  
C o nfi d e nti al  
P a g e 1 7  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
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 8  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
I R B s/I E C s 
A c o p y of t his a me n de d pr ot oc ol 
will be se nt t o t he I nstit uti o nal 
Re vie w 
B oar d 
(I R Bs)/I n 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 h is 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 acc or di n g t o l ocal re g ulati o ns pri or t o i m ple me ntati o n.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 9  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
Pr ot o c ol s u m m ar y  
Pr ot o c ol n u m b er  
C A D P T 1 3 A 1 2 2 0 1  
F ull Titl e  
P L A TI N U M: A m ulti -p art, m ulti -c e nt er P L A Tf or m st u d y t o a s s e s s t h e effi c a c y, 
s af et y, t ol er a bilit y a n d p h ar m a c o ki n eti c s of a nti -m al ari al a g e nt s a d mi ni st er e d 
a s 
m o n ot h er a p y at 
m ulti pl e d o s e l e v el s a n d/ or c o m bi n ati o n t h er a p y I N 
p ati e nt s wit h U n c o m pli c at e d Pl a s m o di u m f al ci p ar u m  M al ari a  
Bri ef titl e  
Pl at f or m st u d y t o e v al u at e t h e effi c a c y a n d s af et y of a nti-m al ari al a g e nt s i n 
p ati e nt s wit h u n c o m pli c at e d  Pl a s m o di u m f al ci p ar u m  m al ari a ( P L A TI N U M) 
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 2  
I n v e sti g ati o n t y p e 
Dr u g( s)  
St u d y t y p e  
I nt er v e nti o n al 
P ur p o s e a n d 
r ati o n al e 
T h e p ur p o s e of t hi s pl atf or m st u d y i s t o e v al u at e t h e p ar a siti ci d al  
eff e ct a n d p ot e nti al f or c ur e wit h diff er e nt a nti -m al ari al a g e nt s a d mi ni st er e d 
a s 
m o n ot h er a p y a n d/ or i n c o m bi n ati o n t h er a p y wit h ot h er a nti -m al ari al 
a g e nt s i n a d ult a n d a d ol e s c e nt p ati e nt s wit h u n c o m pli c at e d Pl a s m o di u m 
f al ci p ar u m m al ari a. A d diti o n all y, t h e  s af et y, t ol er a bilit y, a n d p h ar m a c o ki n eti c s 
of t h e s e a nti -m al ari al a g e nt s will b e e v al u at e d f or d o s e s el e cti o n f or f ut ur e 
st u di e s.  
Pri m ar y 
O bj e cti v e( s)  
P art A: T o a s s e s s t h e p ar a sit e cl e ar a n c e ti m e ( P C T) of or al d o s e s of a n a nti -
m al ari al a g e nt a d mi ni st er e d a s m o n ot h er a p y i n p ati e nt s wit h u n c o m pli c at e d  
P. f al ci p ar u m  m al ari a  
P art B: T o a s s e s s t h e eff e ct o n a dj u st e d 2 8 -d a y c ur e r at e of a n a nti -m al ari al 
a g e nt a d mi ni st er e d or all y a s c o m bi n ati o n t h er a p y v er s u s t h e st a n d ar d of c ar e 
( S o C) i n p ati e nt s wit h u n c o m pli c at e d P. f al ci p ar u m  m al ari a  
S e c o n d ar y 
O bj e cti v e s  
P art A: T o a s s e s s t h e eff e ct o n a dj u st e d 2 8 -d a y c ur e r at e of a n a nti -m al ari al 
a g e nt a d mi ni st er e d or all y a s m o n ot h er a p y i n p ati e nt s wit h u n c o m pli c at e d 
P.  f al ci p ar u m m al ari a  
P art B:  T o a s s e s s t h e p ar a sit e cl e ar a n c e ti m e ( P C T) of or al c o m bi n ati o n s of 
a nti -m al ari al a g e nt s  v er s u s S o C i n p ati e nt s wit h u n c o m pli c at e d P.  f al ci p ar u m 
m al ari a  
All p art s:  
T o c h ar a ct eri z e P K of e a c h a nti -m al ari al a g e nt a d mi ni st er e d or all y a s 
m o n ot h er a p y [ P art A] a n d/ or a s c o m bi n ati o n t h er a p y [ P art B] i n p ati e nt s wit h 
u n c o m pli c at e d P. f al ci p ar u m  m al ari a  
T o a s s e s s t h e s af et y a n d t ol er a bilit y of e a c h a nti -m al ari al a g e nt a d mi ni s t er e d 
or all y a s m o n ot h er a p y [ P art A] a n d/ or a s c o m bi n ati o n t h er a p y v er s u s S o C 
[ P art B] i n p ati e nt s wit h u n c o m pli c at e d P. f al ci p ar u m  m al ari a  
St u d y d e si g n  
T hi s i s a 
m ulti -p art, 
m ulti -c e nt er , o p e n-l a b el pl atf or m st u d y, i n cl u di n g a 
p ar all el a n d a d a pti v e s e q u e nti al  d o s e l e v el d e si g n i n P art A f oll o w e d b y a n 
o p e n -l a b el, r a n d o mi z e d, c o ntr oll e d d e si g n i n 
P art 
B i n p ati e nt s 
wit h 
u n c o m pli c at e d P. f al ci p ar u m  m al ari a. P art A will e v al u at e a nti -m al ari al a g e nt s 
a s m o n ot h er a p y. P art B will e v al u at e a nti -m al ari al a g e nt s a s c o m bi n ati o n 
t h er a p y. 
St u d y p o p ul ati o n  
T h e st u d y p o p ul ati o n will c o n si st of m al e a n d f e m al e p ati e nt s a g e d ≥1 8  y e ar s 
f or P art A a n d a g ed  ≥1 2 y e ar s f or P art B.  

N o v arti s  
C o nfi d e nti al  
P a g e 2 0  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
K e y I n cl u si o n 
crit eri a  
•  
M al e a n d f e m al e p ati e nt s ≥1 8 y e ar s of a g e f or P art A a n d ≥1 2 y e ar s of 
a g e f or P art B at s cr e e ni n g.  
•  
P ati e nt s 
m u st 
h a v e 
a c ut e 
u n c o m pli c at e d 
P. f al ci p ar u m  m al ari a 
m o n o -i nf e cti o n at s cr e e ni n g c o nfir m e d b y a p ar a sit e c o u nt b et w e e n 
/ μl of bl o o d f or P. f al ci p ar u m f or 
P art A a n d b et w e e n 
/ μl of bl o o d 
f or P art B P ati e nt s i n P art A m u st w ei g h b et w e e n 40 k g a n d 9 0  k g. 
P ati e nt s i n P art B m u st w ei g h b et w e e n 3 5 k g a n d 9 0 k g at s cr e e ni n g.  
K e y E x cl u si o n 
crit eri a  
•  
P ati e nt s wit h si g n s a n d s y m pt o m s of s e v er e/ c o m pli c at e d m al ari a at 
s cr e e ni n g o r mi x e d Pl a s m o di u m  i nf e cti o n (i. e., i nf e cti o n wit h m or e t h a n 
o n e m al ari a s p e ci e s) at s cr e e ni n g  
•  
M o d er at e t o s e v er e a n e mi a, c hr o ni c h e m o gl o bi n o p at h y ( H e m o gl o bi n 
l e v el < 8 g/ d L), or k n o w n c hr o ni c u n d erl yi n g di s e a s e s u c h a s si c kl e c ell 
di s e a s e at s cr e e ni n g  
•  
K n o w n cli ni c all y si g nifi c a nt  li v er di s e a s e (e. g.,  c hr o ni c h e p atiti s,  li v er 
cirr h o si s ( c o m p e n s at e d or d e c o m p e n s at e d), hi st or y of h e p atiti s B or C, 
h e p atiti s A or B v a c ci n ati o n i n t h e l a st 3 m o nt h s, k n o w n g all bl a d d er or 
bil e d u ct di s e a s e, a c ut e or c hr o ni c p a n cr e atiti s. Cli ni c al or l a b or at or y 
e vi d e n c e of a n y of t h e f oll o wi n g at s cr e e ni n g:  
•  
A S T/ A L T > 3  x t h e u p p er li mit of n or m al r a n g e ( U L N), r e g ar dl e s s 
of t h e l e v el of t ot al bilir u bi n  
•  
A S T/ A L T > 1. 5 a n d ≤ 2 x U L N a n d t ot al bilir u bi n i s > U L N  
•  
T ot al bilir u bi n > 2 x U L N, r e g ar dl e s s of t h e l e v el of A S T/ A L T  
•  
A n y  
k n o w n/ s u s p e ct e d  i m m u n o s u p pr e s si v e  
or  i m m u n o d efi ci e nt 
c o n diti o n, i n cl u di n g h u m a n i m m u n o d efi ci e n c y vir u s ( HI V) i nf e cti o n at 
s cr e e ni n g.  
•  
Pr e g n a nt or n ur si n g (l a ct ati n g) w o m e n, w o m e n of c hil d -b e ari n g p ot e nti al, 
d efi n e d a s all w o m e n p h y si ol o gi c all y c a p a bl e of b e c o mi n g pr e g n a nt, 
u nl e s s  t h e y ar e u si n g m et h o d s of c o ntr a c e pti o n a s o utli n e d i n S e cti o n  1 2 , 
a n d s e x u all y a cti v e p ati e nt s n ot willi n g t o pr a cti c e  eff e cti v e c o ntr a c e pti o n.  
•  
Hi st or y or c urr e nt di a g n o si s of E C G a b n or m aliti e s i n di c at i n g si g nifi c a nt 
ri s k of s af et y f or p ati e nt s p arti ci p ati n g i n t h e st u d y s u c h a s: 
•  
C o n c o mit a nt cli ni c all y si g nifi c a nt c ar di a c arr h yt h mi a s, 
e. g.,  
s u st ai n e d v e ntri c ul ar t a c h y c ar di a, a n d cli ni c all y si g nifi c a nt 
s e c o n d or t hir d d e gr e e A V bl o c k wit h o ut a p a c e m a k er  
•  
Hi st or y of f a mili al l o n g Q T s y n dr o m e or k n o w n f a mil y hi st or y of 
T or s a d e s d e P oi nt e.  
•  
R e sti n g h e art r at e ( p h y si c al e x a m or 1 2 l e a d E C G) < 6 0 b p m  
St u d y tr e at m e nt 
a n d Tr e at m e nt of 
i nt er e st 
T hi s st u d y u s e s a pl atf or m t y p e d e si g n wit h t h e p ot e nti al t o i n v e sti g at e 
m ulti pl e t h er a pi e s i n t h e c o nt e xt of a si n gl e di s e a s e. E a c h  n e w  i n v e sti g ati o n al 
a g e nt  t o b e e v al u at e d will b e a d d e d t o t h e pr ot o c ol vi a a s u b st a nti al pr ot o c ol 
a m e n d m e nt. R ef er t o S e cti o n  1 2  f or c o h ort-s p e cifi c i nf or m ati o n.  
T h e st a n d ar d of c ar e t h at will b e utili z e d i n P art B of t h e st u d y i s C o art e m.  
Effi c a c y 
a s s e s s m e nt s  
P ar a sit e mi a a n d p ar a sit e cl e ar a n c e ti m e, A C P R, cli ni c al si g n s a n d s y m pt o m s 
of 
m al ari a, 
 
 
P h ar m a c o ki n eti c 
a s s e s s m e nt s  
P K p ar a m et er s of st u d y  dr u g s ( A U C 0 -t, A U Cl a st, A U Ci nf, C m a x, T m a x, T 1/ 2, 
Cl/ F, V/ F)  
C CI
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 2 1  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
K e y s af et y 
a s s e s s m e nt s  
P h y si c al 
e x a mi n ati o n s, 
vit al 
si g n s, 
E C G s, 
m o nit ori n g 
of l a b or at or y 
p ar a m et er s i n bl o o d a n d uri n e  
D at a a n al y si s  
K e y w or d s  
M al ari a, u n c o m pli c at e d m al ari a, P. f al ci p ar u m , P. f al ci p ar u m  m al ari a, a d ult s, 
a d ol e s c e nt s , P L A TI N U M  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 2 2  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
1  
I ntr o d u cti o n 
1. 1  
St u d y  r ati o n al e 
T he p ur p ose of t his platf or m st u d y is t o e val u ate t he parasiti ci dal effect a n d p ote ntial f or c ure 
wit h  differe nt  a nti-malari al a ge nts a d mi nistere d as m o n ot hera p y a n d / or i n c o m bi nati o n t hera p y 
i n a d ult a n d a d olesce nt patie nts 
wit h u nc o m plicate d P l as m o di u m f alci p ar u m malaria. 
A d diti o nall y, t he safet y , t olera bilit y, a n d p har mac o ki netics of t hese a nti-malarial a ge nt s will be 
e val uate d f or d ose sel ecti o n f or f ut ure st u dies. 
A  platf or m st u d y assessi n g ma n y treat me nts i n o ne p o p ulati o n is c o nsi dere d a n efficie nt wa y t o 
scree n f or t he p h ar mac ol o gical pr o perties of treat me nts, eit her of si n gle c o m p o u n ds or 
c o m bi nati o ns t hat s u g g est hi g h efficac y ( W o o dc oc k, L a Va n g e 2 0 1 7 ). A d diti o n of n e w 
a nti-malarial a g e nts t o t he st u d y will be i ncl u de d i n pr ot oc ol a me n d me nt(s).  
T here is a n u n met me dical nee d f or a nti -malarial c o m bi nati o n t hera pies c o m prisi n g at least o ne 
part ner dr u g wit h a ne w mec ha nis m o f acti o n t o re d uce t he pr o ba bilit y of de vel o pi n g resista nce 
as well as t o offer a n alter nate treat me nt o pti o n f or patie nts i nfecte d wit h resista nt parasites . 
T he c ore part of t his P L A TI N U M platf or m pr ot o c ol ( Secti o n 1 – Secti o n 1 1 ) is n ot e x pecte d t o 
c ha n ge o v er ti me si g nifi ca ntl y. Ne w a nti -malari al a ge nts will be a d d e d t o Secti o n  1 2  usi n g 
self-c o ntai ne d, c o h ort -s p ecific m o d ules i n f or m of a me n d m e nts. T his m o d ular a p pr oac h is 
e x pecte d t o pr o vi de a c o nsiste nt, relia ble a p pr oac h t o a d di n g ne w c o h orts wit h ne w a nti -malarial 
a ge nts.  
 
 
 
 
 
1. 2  
B a c k gr o u n d  
Des pite malaria b ei n g a pre ve nta ble a n d c ura ble disease, t here were a n esti mate d 2 4 1  milli o n 
cases w orl d wi de i n 2 0 2 0. T here were a n esti mate d 1 3 milli o n m ore malaria case s a n d 4 7, 0 0 0 
m ore deat hs i n 2 0 2 0 c o m pare d t o 2 0 1 9 d ue t o t he disr u pti o ns t o ser vices d uri n g t he pa n de mic  
(W H O  2 0 2 1 ). Of t he fi v e pr ot oz o a n parasites ca usi n g malaria,  Pl as m o di u m f alci p ar u m  a n d  
Pl as m o di u m viv ax  are t h e m ost pre v ale nt s pecies a n d res p o nsi ble f or t he maj orit y of malaria 
cases rec or de d w orl d wi de. I n 2 0 2 0 , 95 % of cases were i n t he 
W orl d Healt h Or g a nizati o n 
Africa n Re gi o n , a n d 9 9. 7 % of t hese were ca us e d b y  P.  f alci p ar u m. P. f alci p ar u m  is als o t he 
pre d o mi na nt s pecies i n S o ut h -East Asia, t he Easter n Me diter ra n ea n, a n d t he Wester n Pacific 
(W H O  2 0 2 1 ). 
Pl as m o di u m  parasites are tra ns mitte d t o h u ma ns b y a n i nfecti ve m os q uit o bite lea di n g t o a n 
as y m pt o matic li ver i nfecti o n lasti n g 6 –  1 8 da ys. Fr o m t he li ver, t he parasites e gress a n d i nfect 
re d bl o o d cells lea di n g t y picall y t o fl u-li ke s y m pt o ms, i ncl u di n g hea dac he, sli g ht fe ver, m uscle 
pai n, a n ore xia, n a usea, a n d fati g ue as parasite mia rises i n t he bl o o d. If n ot pr o m pt l y treate d, 
patie nts ma y de vel o p cere bral or se vere mal aria. T hese life -t hreat e ni n g c o m plicati o ns ca n res ult 
i n c o ma, ac ute res pir at or y distress, a n d se vere a n e mia (W hite  et al 2 0 1 4 ). I n 2 02 0,  malaria was 
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N o v arti s  
C o nfi d e nti al  
P a g e 2 3  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
res p o nsi ble f or a n esti mate d 6 2 7 , 0 0 0 deat hs wit h c hil dre n u n der t he a g e of fi ve acc o u nti n g f or 
6 7 % of malaria -rel ate d d eat hs (W H O  2 0 2 1 ). 
Arte misi ni n deri vati ves re mai n t he mai nsta y of a nti malarial c o m bi nati o n t hera pies, b ut  a d eca de 
a g o, resista n ce t o arte misi ni n 
was re p ort e d i n S o ut heast 
Asia  (D o n d or p et al 2 0 0 9 , 
N oe dl  et al 2 0 0 9 , As hle y et al 2 0 1 4 ). T o da y, arte misi ni n c o m bi nati o n t hera pies ( A C T ) s uc h as 
C oarte m ®  re mai n effecti ve malaria treat me nts, b ut ot her c o m bi nati o n t hera pies are faili n g i n 
s o ut heast Asia wit h n o alt er nati ve treat me nt a vaila ble (va n der Pl uij m et al 2 0 1 9 ). S o far, A C Ts 
re mai n effecti ve o n t he Africa n c o nti ne nt alt h o u g h arte misi ni n resista nce-c o nferri n g m utati o ns 
ha ve bee n i de ntifi e d i n R wa n da. T here is i ncrease d ur ge nc y a n d a str o n g me dical nee d t o 
de vel o p ne w a nti -malarials wit h ne w mec ha nis ms of acti o n  (U wi ma n a  et al 2 0 2 1 ). 
Researc h eff orts ha ve bee n f oc us e d o n i de ntif yi n g dr u gs t hat dis pla y t he a p pr o priate 
p har mac ol o gic pr o perties t o e ns u re p ote nt, ra pi d, a n d s ustai ne d parasite killi n g wit h a si m ple 
a n d s h ort treat me nt re gi me n  i n or der t o i m pr o ve c o m plia nce a n d re d uce t he de vel o p me nt of 
resista nce. T h e tar g et pr o d uct pr ofile f or t hes e ne w a nti malarial a g e nts is base d o n t he 
re q uire me nts i de ntifie d b y t he Me dici nes f or Malaria Ve nt ur e ( M M V) a n d s u m marize d as 
f oll o ws B urr o ws  et al ( 2 0 1 7): ( 1) hi g hl y efficaci o us, e ve n a gai nst dr u g -resista nt parasites 
( prefera bl y wit h a n e w mec ha nis m of acti o n ( M o A )); ( 2) safe, es peciall y f or y o u n g c hil dre n 
a n d pre g na nt w o m e n; ( 3) a d mi nistere d orall y i n t hree dail y d oses or l ess, ( 4) i ne x pe nsi ve a n d 
( 5) sta ble wit h a l o n g s helf-life u n der tr o pical c o n diti o ns; wit h t he o verarc hi n g g oal t o ac hie ve 
a si n gle-d ose c ure c o m bi nati o n t hera p y.  
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  
2. 1  
O bj e cti v e s a n d E n d p oi nt s  
T a bl e 2 -1  
O bj e cti v e s a n d r el at e d e n d p oi nt s  
O bj e cti v e( s)  
E n d p oi nt( s)  
Pri m ar y o bj e cti v e( s)  
E n d p oi nt( s) f or pri m ar y o bj e cti v e( s)  
P art A:  
 
•  
T o a s s e s s t h e p ar a sit e cl e ar a n c e ti m e ( P C T) 
of or al d o s e s of a n  a nti -m al ari al a g e nt 
a d mi ni st er e d a s m o n ot h er a p y i n p ati e nt s 
wit h u n c o m pli c at e d  P.  f al ci p ar u m m al ari a  
•  
P ar a sit e cl e ar a n c e ti m e ( h o ur s)  u p t o D a y 7    
P art B:  
 
•  
T o a s s e s s t h e 2 8 -d a y c ur e r at e of a n 
a nti -m al ari al a g e nt  a d mi ni st er e d or all y a s 
c o m bi n ati o n t h er a p y v er s u s t h e st a n d ar d of 
c ar e ( S o C) i n p ati e nt s wit h u n c o m pli c at e d  
P.  f al ci p ar u m m al ari a  
•  
P ol y m er a s e C h ai n R e a cti o n ( P C R )-
c orr e ct e d a d e q u at e cli ni c al a n d 
p ar a sit ol o gi c al r e s p o n s e ( A C P R) at D a y 2 9  
(i. e., 2 8 d a y s p o st-d o s e)  

N o v arti s  
C o nfi d e nti al  
P a g e 2 4  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
O bj e cti v e( s)  
E n d p oi nt( s)  
S e c o n d ar y o bj e cti v e( s)  
E n d p oi nt( s) f or s e c o n d ar y o bj e cti v e( s)  
P art A:  
 
•  
T o a s s e s s t h e 2 8 -d a y c ur e r at e of a n 
a nti -m al ari al a g e nt  a d mi ni st er e d or all y a s 
m o n ot h er a p y i n p ati e nt s wit h u n c o m pli c at e d  
P.  f al ci p ar u m m al ari a  
•  
P C R -c orr e ct e d a n d u n c orr e ct e d a d e q u at e 
cli ni c al a n d p ar a sit ol o gi c al r e s p o n s e ( A C P R) 
at D a y 2 9 (i. e., 2 8  d a y s p o st -d o s e)  
P art B:  
 
•  
T o a s s e s s t h e p ar a sit e cl e ar a n c e ti m e ( P C T) 
of or al c o m bi n ati o n s of a nti -m al ari al a g e nt s  
v er s u s t h e st a n d ar d of c ar e ( S o C) i n 
p ati e nt s wit h u n c o m pli c at e d  
P.  f al ci p ar u m m al ari a  
•  
P ar a sit e cl e ar a n c e ti m e ( h o ur s)  u p t o D a y 7  
•  
T o a s s e s s t h e 2 8 -d a y c ur e r at e of a n 
a nti -m al ari al a g e nt  a d mi ni st er e d or all y a s 
c o m bi n ati o n t h er a p y v er s u s t h e S o C  i n 
p ati e nt s wit h u n c o m pli c at e d  
P.  f al ci p ar u m m al ari a  
•  
P C R - u n c orr e ct e d a d e q u at e cli ni c al a n d 
p ar a sit ol o gi c al r e s p o n s e ( A C P R) at D a y 2 9 
(i. e., 2 8 d a y s p o st-d o s e)  
F or all p art s:  
 
•  
T o c h ar a ct eri z e P K of e a c h a nti -m al ari al 
a g e nt a d mi ni st er e d or all y a s  m o n ot h er a p y 
[ P art A] a n d/ or a s c o m bi n ati o n t h er a p y 
[ P art B]  i n p ati e nt s wit h u n c o m pli c at e d 
P.  f al ci p ar u m m al ari a  
•  
P K p ar a m et er s s u c h  a s  A U C 0 -t, A U Cl a st, 
A U Ci nf, C m a x, T m a x, T 1/ 2, Cl/ F, V/ F  
•  
T o a s s e s s t h e s af et y a n d t ol er a bilit y of e a c h 
a nti -m al ari al a g e nt a d mi ni st er e d or all y a s 
m o n ot h er a p y [ P art A] a n d/ or a s c o m bi n ati o n 
t h er a p y v er s u s S o C [ P art B] i n p ati e nt s wit h 
u n c o m pli c at e d  P. f al ci p ar u m  m al ari a  
•  
A d v er s e e v e nt s, vit al si g n s, E C G fi n di n g s, 
s af et y l a b or at or y a s s e s s m e nt s 
i n cl u di n g c h e mi str y, h e m at ol o g y, a n d 
uri n al y si s r e s ult s  u p t hr o u g h E O 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)  
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N o v arti s  
C o nfi d e nti al  
P a g e 2 5  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
O bj e cti v e( s)  
E n d p oi nt( s)  
2. 2  
Pri m ar y e sti m a n d s  
A n esti ma n d is a precise descri pti o n of t he treat me nt effect refl ecti n g t he cli nical q uesti o n p ose d 
b y t he trial o bjecti ve. It s u m marizes at a p o p ulati o n -le vel, w hat t he o utc o mes w o ul d be i n t he 
sa me patie nts u n d er eac h of t he tr eat me nt c o n diti o ns bei n g c o m pare d. Attri b utes of a n esti ma n d 
i ncl u de t he p o p ulati o n, varia ble ( or e n d p oi nt) a n d treat me nt of i nterest. It als o s pecifies h o w 
i nterc urre nt e v e nts are a d dresse d a n d pr o vi d es a p o p ulati o n-le vel s u m mar y f or t he v aria ble. 
T he  str uct ure d fra m e w or k of esti ma n d detaile d i n I C H E 9 ( R 1) was ne wl y a d o pte d  b y t h e 
Re g ulat or y Me m bers of t he I C H Asse m bl y u n der Ste p 4 i n N o v -2 0 1 9.  
 
 
 
 
 
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N o v arti s  
C o nfi d e nti al  
P a g e 2 6  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
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N o v arti s  
C o nfi d e nti al  
P a g e 2 7  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
2. 3  
S e c o n d ar y e sti m a n d s  
 
 
 
 
 
 
 
 
 
 
T he j ustificati o n f or b ot h  sec o n dar y esti ma n ds are i de ntical as i n Secti o n 2. 2 . 
T he sec o n d ar y esti ma n d attri b utes i n Part A are d escri be d as i de ntical as t he attri b utes i n t he 
pri mar y esti ma n d i n Part B.  
T he sec o n dar y esti ma n d attri b utes i n Part B are descri be d as i de ntical as t he attri b utes i n t he 
pri mar y esti ma n d i n Part A.  
F urt her details o n t he sec o n dar y a nal ys es f or p art A a n d part B are pr o vi de d i n Secti o n 9. 4. 1 . 
3  
St u d y d e si g n  
3. 1  
O v er all d e si g n  
T his is a P hase 2, m ulti -part, m ulti -ce nter, o pe n -la bel platf or m st u d y i ncl u di n g 
 
 
T his platf or m desi g n 
all o ws t he p ote ntial t o i n vesti gate m ulti ple t hera pies i n t he c o nte xt of a si n gle disease. 
Eac h  a nti-malarial a ge nt e ntere d i nt o t he trial at a gi ve n ti me will f oll o w t he sa me desi g n as 
o utli ne d i n Parts A a n d/ or B. M ore t ha n o ne Part  A a n d Part B c o h ort ca n be c o n d ucte d at t he 
sa me ti me. I n a d diti o n, Part A a n d Part B c o h orts ca n be c o n d ucte d at t he sa me ti me. 
Ge nerall y,  o ne site will be e nr olli n g i nt o o n e c o h ort o nl y at a gi ve n p oi nt i n ti me; h o we ver, 
e xce pti o ns ma y be i m ple me nte d if  re q uir e d a n d will be c o m m u nicate d wit h t he site staff. 
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N o v arti s  
C o nfi d e nti al  
P a g e 2 8  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
Fi g ur e 3 -1  
St u d y D e si g n - St u d y L e v el Vi e w  
 
•  P art A is t he o pe n-la b el, ra n d o mize d, m ulti-ar m m o n ot hera p y part of t his P hase 2 st u d y 
e val uati n g a si n gle oral a d mi nistrati o n of a n a nti -malarial a ge nt at 3 parallel d ose le vels 
f oll o we d b y o pti o nal a da pti ve se q ue ntial d ose le v el(s). 
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N o v arti s  
C o nfi d e nti al  
P a g e 2 9  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
  
 
•  P art B is t he o pe n-la bel, ra n d o mize d, t w o-ar m c o m bi nati o n t hera p y part of t his P hase 2 
st u d y e val uati n g a si n gle oral d ose of u p t o t hree a nti-malarial a ge nts as a l o ose c o m bi nati o n 
vs. sta n dar d of care ( S o C), C oarte m . 
Eac h of t he a nti -mal arial a ge nts t o be e va l uate d i n t his P L A TI N U M st u d y m ust meet t he 
f oll o wi n g criteria: 
F or Part A:  
F or Pa rt B: 
If t he a b o v e criteria are met, a n a nti-malarial a ge nt ma y be i ncl u de d i n Part B as c o m bi nati o n 
t hera p y wit h o ut ha vi n g c o m plete d t he m o n ot hera p y Part A. C o h ort-s pecific D DI i nf or m ati o n 
ca n be f o u n d i n Secti o n  1 2 . 
Mar kete d a nti -malarial a ge nts a n d t h ose f or w hic h safet y, t olera bilit y a n d efficac y data as 
m o n ot hera p y are alrea d y a vaila ble ma y be directl y i n vesti gate d i n c o m bi nati o n t hera p y 
( Part B).  
T he decisi o n t o i ncl u de f ut ure a ge nts a n d c o h orts is n ot de pe n de nt o n perf or ma nce of pri or 
a ge nts or c o h orts. Eac h ti me a ne w a ge nt is i ntr o d uce d, a g e nt -s pecific i nf or mati o n will be a d de d 
t o t he pr ot oc ol as a s u bsta ntial a me n d me nt a n d s u b mitte d t o Healt h A ut h orities a n d Et hic 
C o m mittees, as re q uire d b y l ocal re g ulati o ns.  
Eac h c o h ort i n t he st u d y will u n der g o a s et of t he sa me st u d y e val u ati o ns a n d assess me nts b ut  
ma y als o ha ve c o h ort -s pecific e val uati o ns/ass ess me nts t hat are o utli ne d i n Secti o n  1 2 . 
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N o v arti s  
C o nfi d e nti al  
P a g e 3 0  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
Eac h  c o h ort will i ncl u de a scree ni n g peri o d 
. Eli gi ble patie nts 
will be d ose d o n Da y 1 a n d re mai n at t he site f or i n patie nt f oll o w -u p f or at least 3 da ys. 
Safet y,  effi cac y, a n d P K assess me nts will be perf or me d f or t he 3 da ys. Patie nts ma y re mai n 
i n patie nt l o n ger at t h e i n vesti gat or’s discreti o n. 
 
 
 A safet y f oll o w-u p call will be perf or me d 
o n Da y 3 1 f or Part A. T h e visit str uct ure  at eac h c o h ort le vel f or Parts A a n d  B of t he st u d y  is 
s h o w n i n Fi g ure 3 -2 . C o h ort -s pecific st u d y desi g ns are o utli ne d i n Secti o n  1 2 . 
F or a d etaile d o utli ne of t he c ore s afet y a n d ot h er assess me nts,  please refer t o t he assess me nt 
sc he d ule i n Ta ble  8 -1 . C o h ort -s pecific assess me nts are o utli ne d i n Secti o n  1 2 . 
Fi g ur e 3 -2  
St u d y D e si g n - C o h ort L e v el Vi e w  
 
P art A: M o n ot h er a p y  
 
 
 
 
 
Safet y assess me nts will i ncl u de p h ysical e xa mi n ati o ns, tri plicate E C Gs, vital si g ns, sta n dar d 
cli nical la b orat or y e val u ati o ns ( he mat ol o g y, bl o o d c he mistr y,  a n d uri nal ysis), a d verse e ve nt  
a n d seri o us a d v erse e ve nt m o nit ori n g.  
 
 
M ulti ple c o h orts, eac h wit h a 
differe nt a nti -malarial a g e nt, 
ma y be a d de d. E ac h n e w 
a nti-malarial a g e nt e val u ate d will f oll o w t he sa me desi g n.  
P art B: C o m bi n ati o n T h er a p y  
I n Part B, patie nts will be ra n d o mize d t o recei ve a si n gle oral d ose of  a c o m bi nati o n of  
u p t o t hree  a nti-malari al  a ge nts  or  t h e sta n d ar d of care ( C oarte m). See Fi g ur e  3 -1 . 
S pecific  ra n d o mizati o n rati os f or eac h c o h ort will be s pecifie d i n Secti o n  1 2 . 
D oses f or a ge nts i n Part B will be select e d bas e d o n re vie w b y t he S p o ns or a n d t he D M C of 
P K, safet y, a n d efficac y data fr o m Part A . Safet y, efficac y a n d/ or P K dat a ma y be e v al uate d i n 
t he first fe w patie nts (a p pr o xi matel y 6 i n eac h ar m) i n Part B a n d re vie we d b y t he S p o ns or f or 
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N o v arti s  
C o nfi d e nti al  
P a g e 3 1  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
safe use of c o m bi nati o n i n patie nts. T he d ose(s) ma y be a dj uste d base d o n t hese data i n or der 
t o meet t he desire d e x p os ure or t o miti gate p ote ntial safet y ris ks. 
Safet y assess me nts will i ncl u de p h ysical e xa mi n ati o ns, tri plicate E C Gs, vital si g ns , sta n dar d 
cli nical la b orat or y e val u ati o ns ( he mat ol o g y, bl o o d c he mistr y,  a n d uri nal ysis), a d verse e ve nt  
a n d seri o us a d v erse e ve nt m o nit ori n g.  
 
 
M ulti ple c o h orts wit h differe nt a nti -malarial a ge nts ma y be a d d e d. E ac h n e w a nti -malarial a ge nt 
c o m bi nati o n e val uate d will f oll o w t he sa me desi g n . 
F or s u bse q ue nt c o h orts i n Part B, sa m ple sizes f or b ot h S o C ar m a n d t he c o m bi nati o n ar m ma y 
be f urt her refi ne d b y usi n g t he hist orical c o ntr ol data fr o m C oarte m, as well as usi n g all alrea d y 
a vaila ble S o C data i n Part B (e. g. , p o oli n g strate g y). T h us, t he ra n d o mizati o n rati o ma y c ha n g e 
i n s ubse q ue nt c o h orts i n Part B. A n y c ha n g es will be ma de via pr ot oc ol a me n d me nt. 
A d diti o nall y, if i ncl usi o n a n d e xcl usi o n criteria mi g ht differ bet wee n c o h orts i n Part B, baseli ne 
c o variate a dj ust me nt f or S o C data ma y be c o nsi dere d.  
4  
R ati o n al e  
4. 1  
S ci e ntifi c r ati o n al e f or st u d y d e si g n  
T he rati o nale of ke y desi g n ele me nts i n t his st u d y i ncl u des t he f oll o wi n g:  
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N o v arti s  
C o nfi d e nti al  
P a g e 3 2  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
T a bl e 4 -1  
R ati o n al e f or st u d y d e si g n  
St u d y D e si g n A s p e ct  
R ati o n al e  
D ur ati o n of st u d y  
T h e d e si g n of t h e st u d y wit hi n e a c h c o h ort i s a s s e s si n g a 
2 8 -d a y c ur e r at e. T w e nt y -ei g ht d a y s i s t h e r e c o g ni z e d 
d ur ati o n t o e v al u at e a c ur e f or m al ari a p er t h e W orl d H e alt h 
Or g a ni z ati o n ( W H O) crit eri a. 
 
 
L a c k of c o ntr ol ar m i n P art A  
 
 
 
 
 
 
I n p ati e nt p eri o d 
P ati e nt s will r e m ai n i n p ati e nt i niti all y t o all o w f or cl o s e 
o b s er v ati o n of s af et y a n d t ol er a bilit y, a n d t o e n s ur e 
c o m pli a n c e wit h i n str u cti o n s f or all p ati e nt s  
M ulti -c e nt er  
T o e nr oll a di v er s e p ati e nt p o p ul ati o n i n diff er e nt r e gi o n s  
Pl atf or m d e si g n  
 
 
 
 
 
R a n d o mi z ati o n  
T o  r e d u c e ri s k of s el e cti o n bi a s a n d al s o t h e ri s k of u n e q u al 
di stri b uti o n b et w e e n ar m s  
P ar all el Ar m s  ( P art A) 
f oll o w e d b y o pti o n al d o s e l e v el( s) 
T o all o w f or d o si n g of m ulti pl e d o s e l e v el s of t h e s a m e 
a g e nt i n a n effi ci e nt m a n n er wit h t h e fl e xi bilit y t o all o w t h e 
a d diti o n of o pti o n al d o s e( s) b a s e d o n t h e d at a fr o m t h e 
p ar all el ar m s t o f urt h er i n v e sti g at e o pti m u m s af et y a n d 
effi c a c y a s w ell a s s u p p ort d o s e s el e cti o n f or f ut ur e st u di e s  
O p e n L a b el  
T h e ri s k of bi a s ari si n g o ut of t h e o p e n l a b el d e si g n i s 
mi ni mi z e d d u e t o t h e f a ct t h at  t h e effi c a c y e n d p oi nt s ar e 
o bj e cti v e i n n at ur e. T h e d o si n g r e gi m e n s ar m s 
 
) f or P art B a n d f o o d 
r e q uir e m e nt s ar e diff er e nt b et w e e n t h e ar m s m a ki n g it 
i m pr a cti c al t o k e e p t h e bli n d. M e a s ur e s will b e t a k e n t o 
e n s ur e t h at t h e s e o bj e cti v e e n d p oi nt s ar e a s s e s s e d i n a n 
u n b i a s e d w a y, a n d t h u s, t h e sit e mi cr o s c o pi st s m u st  b e 
bli n d e d  t o t h e tr e at m e nt.  
St u d y p o p ul ati o n  
T hi s pl atf or m tri al will i n cl u d e p ati e nt s wit h u n c o m pli c at e d 
m al ari a. A d ult s of 1 8 y e ar s or m or e will b e i n cl u d e d i n 
P art  A of t h e st u d y, a n d a d ol e s c e nt s a n d a d ult s of 1 2  y e ar s 
or m or e will b e i n cl u d e d i n P art B of t h e st u d y. T h er e i s n o 
e x p e ct e d diff er e n c e i n dr u g m et a b oli s m a n d d o s e r e s p o n s e 
r el ati o n s hi p i n a d ol e s c e nt s c o m p ar e d t o a d ult s. T hi s will 
e n a bl e f a st er d e v el o p m e nt of n o v el c o m bi n ati o n i n t ar g et 
p o p ul ati o n ( p e di atri c p ati e nt s) f or t h e di s e a s e u n d er 
e v al u ati o n ( u n c o m pli c at e d m al ari a).  
4. 2  
J u stifi c ati o n f or d o s e  
Please refer t o Secti o n  1 2  f or a detaile d rati o nale f or d ose/re gi me n a n d d urati o n of eac h c o h ort. 
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N o v arti s  
C o nfi d e nti al  
P a g e 3 3  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
F or Part A, m ulti ple d ose le vels are c h ose n t o select o pti m u m safe a n d efficaci o us d ose f or 
patie nts. 
 
 
I n ge n eral, t he d ose of t he a ge nts  t o be st u die d will be c h ose n base d o n a n e val uati o n of all 
a vaila ble precli nical a n d/ or cli nical data t o e ns ure acce pta ble safet y a n d t olera bilit y a n d will be 
detaile d i n t he c orres p o n di n g Secti o n  1 2 . T he oral r o ute of a d mi nistrati o n f or t he tar g et 
i n dicati o n of P. F alci p ar u m  u nc o m plicate d mal ari a is c o nsi dere d t he m ost c o n ve nie nt r o ute f or 
patie nts w h o ca n t olerate oral me dicati o n.  
D osi n g re gi me n f or a d diti o nal c o h orts will be deci de d base d o n a vaila ble cli nical data of t he 
a nti-malarial  of i nterest, at t he ti me of i ncl usi o n of t h ose c o h orts i n t he st u d y.  
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) or 
c o m bi n ati o n dr u g s  
C h oi c e of c o ntr ol dr u g  
T here is a c o ntr ol treat me nt o nl y i n Part B. T he c o ntr ol treat me nt use d i n Part B of t his st u d y is 
C oarte m, t he arte misi ni n -base d c o m bi nati o n t hera p y arte m et her -l u mefa ntri ne. C oarte m is 
wi del y use d f or P. f alci p ar u m  malaria a n d h as a well -c haract erize d safet y a n d efficac y pr ofile 
(Ha me d,  Gr ue ni n ger  2 0 1 2 ). F or t hese reas o ns, 
C oarte m is c o nsi dere d t he a p pr o priate 
c o m parat or tr eat me nt f or t his st u d y.  
C h oi c e of c o m bi n ati o n dr u g( s)  
T his st u d y is desi g ne d t o test a n u m ber of differe nt i n vesti gati o nal a nti -malarial a ge nts  ( Part A) 
or c o m bi nati o ns of a nti -malarial a ge nts ( Part B) . A ge nts m ust meet pre -s pecifie d criteria as 
o utli ne d i n Secti o n 3. 1  t o be i ncl u de d i n t he st u d y. I n s o me cas es, a n i n vesti gati o nal 
a nti-malarial a ge nt ma y als o be c o m bi ne d wit h a m ar kete d o ne.  E ac h of t he ca n di date a ge nts t o 
be st u die d will ha ve rati o nale a d de d i n a s u bsta ntial a me n d me nt. Refer t o Secti o n  1 2  f or 
c o h ort-s pecific details. 
4. 4  
P ur p o s e a n d ti mi n g of d e si g n a d a pt ati o n s  
D at a R e vi e w M e eti n g s  
T he desi g n of t his platf or m st u d y will all o w o n g oi n g data re vie w d uri n g st u d y c o n d uct f or all 
a vaila ble st u d y data. As part of t he o n g oi n g data re vie w, t here will be a cli nical decisi o n p oi nt 
pri or t o d osi n g t he o pti o nal d ose le vel(s) i n Part A, w here a vaila bl e safet y, efficac y, a n d P K 
data fr o m t he parallel d ose le vels fr o m Part A will be re vie we d b y t he S p o ns or. De pe n di n g  o n 
t he safet y a n d effi cac y res ults a n d P K data a nal ysis e mer gi n g fr o m t hes e Data Re vie w(s), t h e 
d ose(s) f or t he o pti o nal d ose le vel(s) of Part A ma y be a dj uste d, b ut t he ma xi m u m t olerate d 
d ose esta blis he d i n pre vi o us c o h orts or st u dies will n ot be e xcee d e d.  
Safet y, efficac y a n d/ or P K data ma y b e e val uat e d i n t he first fe w patie nts (a p pr o xi matel y 
6  patie nts i n eac h ar m) i n Part B b y t he S p o ns or f or safe use of c o m bi nati o n i n patie nts. T he 
d ose(s) ma y be a dj uste d base d o n t hese d ata i n or der t o meet t he d es ire d e x p os ure or t o miti gate 
p ote ntial safet y ris ks.  
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N o v arti s  
C o nfi d e nti al  
P a g e 3 4  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
I nt eri m A n al y s e s 
 
 
 
 
 
  A d diti o nal details a b o ut 
t he D M C ca n be f o u n d i n Secti o n 1 0. 1. 4 . If c o h orts c o m plete ar o u n d t he s a me ti me, a vaila ble 
data  fr o m se parat e c o h orts ma y be i ncl u de d i n t he sa me I A. Ot her i nteri m a nal yses ma y be 
perf or me d as p er S p o ns or a n d D M C decisi o n t o ass ess effi cac y a n d s afet y, t o a v oi d u n necessar y 
e x p os ure of patie nts t o a ge nts t hat h a ve n o or mar gi n al  c ha n ces  t o be effecti ve. 
Fi nall y,  a d diti o nal i nteri m a nal yses  a n d/ or D M C re vie w  ma y be c o n d u cte d t o s u p p ort d ecisi o n 
ma ki n g c o ncer ni n g t he c urre nt cli nical st u d y, t he S p o ns or’s cli nical de vel o p me nt pr ojects i n 
ge neral, or i n case of a n y safet y c o n cer ns. A d diti o nal i nf or mati o n is prese nte d i n t he i nteri m 
a nal ysis  secti o n (Secti o n 9. 7 ). 
A d diti o n of a ne w a nti -malarial a g e nt 
 
 I As ma y 
be d o ne i n de pe n de ntl y f or eac h c o h ort, a n d ne w a n d o n g oi n g c o h orts ma y c o nti n ue t o be 
c o n d ucte d. T h e cli nical t ea m ma y c o m m u nicate i nteri m res ults t o rele va nt N o vartis tea ms f or 
i nf or matio n, c o ns ulti n g a n d/ or decisi o n p ur p os es. Res ults fr o m a n y p artic ular I A ma y als o be 
c o m m u nicate d be y o n d t he S p o ns or t o gr o u ps i ncl u di n g, b ut n ot li mite d t o, i n di vi d uals treati n g 
t he st u d y's patie nts, Healt h A ut h orities, a n d cli nical re gistries. 
4. 5  
B e n efit/ Ri s k a s s e s s m e nt  
Detaile d des cri pti o ns of t he e x pecte d ris ks a n d b e nefits of eac h i n vesti gati o nal a ge nt use d i n 
eac h c o h ort ca n b e f o u n d i n Secti o n  1 2 . 
Pr o c e d ur al ri s k s n ot s p e cifi c all y r el at e d t o st u d y dr u g s  
C ollecti n g a bl o o d sa m ple fr o m a vei n m a y ca us e pai n, s welli n g, br uisi n g, li g ht‑ hea de d ness, 
fai nti n g, a n d ver y rarel y, cl ot f or mati o n, ner ve da ma ge a n d/ or i nfecti o n at t he site of t he nee dle 
stic k. 
D uri n g ca n n ulati o n, m or e t ha n o n e atte m pt ma y be nee de d t o i nsert t he ca n n ula i n a vei n of a 
patie nt, a n d it is p ossi ble t hat br uisi n g a n d/ or i nfla m mati o n ma y be e x perie nce d at t he site of 
ca n n ulati o n.  
Electr ocar di o gra m ( E C G) stic kers o n t h e patie nts' c hests a n d li m bs ma y ca use s o me l ocal 
irritati o n a n d ma y be u n c o mf orta ble t o re m o ve b ut patie nts will be cl osel y m o nit ore d t o e ns ure 
a n y l ocal irritati o n d oes n ot persist.  
A p pr o priate eli gi bilit y criteria a n d s p ecific d ose -li miti n g t o xicit y defi niti o ns, as well as s p ecific 
d ose m o dificati o n a n d st o p pi n g r ules, are i ncl u d e d i n t his pr ot oc ol. 
T he ris k t o patie 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, a n d peri o dic data re vie ws of 
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N o v arti s  
C o nfi d e nti al  
P a g e 3 5  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
a vaila ble safet y, efficac y, a n d P K data  b y an i n de pe n de nt  D M C . Refer t o t he res pecti ve a nti-
malarial a ge nt’s I n vesti g at or’s Br oc h ure. 
W o me n of c hil d -beari n g p ote ntial a n d se x uall y acti ve males m ust be i nf or me d t hat ta ki n g t he 
st u d y treat me nt ma y i n v ol ve u n k n o w n ris ks t o t h e fet us if pre g n a nc y were t o occ ur d uri n g t he 
st u d y a n d a gree t hat i n or der t o partici pate i n t he st u d y, t he y m ust a d here t o t he c o ntrace pti o n 
re q uire me nts o utli ne d i n t he e xcl usi o n criteria a n d/ or i n Secti o n  1 2 . If t here is a n y questi o n t hat 
t he patie nt will n ot relia bl y c o m pl y, t he y s h o ul d n ot be e ntere d or c o nti n ue i n t he st u d y. 
As is t he case wit h a n y ne w c o m p o u n d i n cli nical de vel o p me nt, t here ma y be u n k n o w n ris ks of 
t he st u d y dr u gs t hat ma y be seri o us a n d u nf oresee n. 
4. 5. 1  
Bl o o d s a m pl e v ol u m e  
 
 
 A d diti o nal sa m ples ma y be re q uire d f or 
safet y m o nit ori n g. 
Ti mi n gs of bl o o d sa m ple c ollecti o n are o utli ne d i n t he assess me nt sc he d ule ( Ta ble  8 -1  a n d 
Secti o n  1 2 ). 
A s u m mar y bl o o d l o g is a vaila ble u p o n re q uest. I nstr ucti o ns f or sa m ple c ollecti o n, pr ocessi n g, 
st ora ge a n d s hi p me nt i nf or mati o n are als o a vaila ble i n t he la b orat or y ma n u al.  
See Secti o n 8. 7  a n d Secti o n 8. 8  o n t h e p ote ntial use of resi d ual s a m ples.  
4. 6  
R ati o n al e f or p u bli c h e alt h e m er g e n c y miti g ati o n pr o c e d ur e s  
I n t h e e v e nt of a p u blic healt h e mer ge nc y as declare d b y l ocal or re gi o nal a ut h orities (i.e., 
pa n de mic, e pi de mic or nat ural disaster), miti gati o n pr oce d ures ma y be re q uire d t o e ns ure 
pa tie nt safet y a n d trial i nte grit y a n d are liste d i n rele va nt secti o ns of t he st u d y pr ot oc ol  
(Secti o n  8 ). N otificati o n of t he p u blic healt h e mer ge nc y s h o ul d be disc uss e d wit h  N o vartis pri or 
t o i m ple me ntati o n of miti gati o n pr oce d ures a n d p er mitte d/a p pr o ve d b y l ocal or re gi o nal h ealt h 
a ut h orities a n d et hics c o m mittees as a p pr o priate.  
4. 7  
E n d of st u d y d efi niti o n  
T he e n d of t he st u d y is d efi ne d as t he date of t he l ast visit 
 
 
 
St u d y c o m pleti o n is defi ne d as w h e n t he t otal n u m ber of pri mar y e v e nts ( c ollecti o n of parasite 
cleara nce ti me  f or all patie nts) are o btai ne d fr o m all c o h orts a n d w he n t he last pa tie nt fi nis hes 
t heir last st u d y visit a n d a n y re peat ass ess me nts ass ociate d wit h t his visit ha v e bee n d oc u m e nte d 
a n d f oll o we d -u p a p pr o priatel y b y t he in vesti gat or (e. g. , E ac h patie nt will be re q uire d t o 
c o m plete t he st u d y i n its e ntiret y , a n d t hereaft er n o f urt her st u d y tr eat me nt will be ma de 
a vaila ble t o t he m i n t he s c o pe of t he tri al).  
All ra n d o mize d a n d/ or tr eate d patie nts s h o ul d ha ve a safet y f oll o w -u p call c o n d ucte d at least 
3 0 da ys aft er last a d mi nistrati o n of st u d y treat me nt. T his f oll o w -u p ma y b e a p h o n e call or a 
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N o v arti s  
C o nfi d e nti al  
P a g e 3 6  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
st u d y site visit. T he i nf or mati o n c ollecte d is ke pt as s o urce d o c u me ntati o n.  S A E re p orti n g 
c o nti n ues d uri n g t his ti me peri o d as d escri be d i n Secti o n 8. 6. 3 . D oc u me nt ati o n of atte m pts t o 
c o ntact t he patie nt are re q uire d t o be rec or de d i n t he s o urce d o c u me ntati o n.  
5  
St u d y P o p ul ati o n  
T he st u d y p o p ulati o n will c o nsist of a d ult a n d a d olesce nt male a n d fe male patie nts.  
I M P O R T A N T 
T he i ncl usi o n/e xcl usi o n criteria f or t he c ore pr ot oc ol are l o cate d i n t hes e s ecti o n s (Secti o n  5. 1  
a n d Secti o n  5. 2 ). T hes e criteria a p pl y t o all patie nts e nr olle d i nt o t his st u d y. N o a d diti o nal 
criteria s h o ul d be a p plie d b y t he i n vesti gat or, i n or der t o e ns ure t hat t he st u d y p o p ulati o n will 
be re prese ntati ve of all eli gi ble patie nts. H o we ver, t here ma y als o be a d diti o nal a ge nt s pecific 
i ncl usi o n/e xcl usi o n criteria f or eac h of t h e i n vesti gati o nal c o m p o u n ds , w hi c h are pr o vi d e d i n 
Secti o n  1 2 . 
5. 1  
I n cl u si o n crit eri a 
P art A:  
Patie nts eli gi ble f or i ncl usi o n i n t his part of t he st u d y m ust meet all  of t he f oll o wi n g criteria : 
1.  Si g ne d i nf or me d c o nse nt m ust be o btai ne d pri or t o partici pati o n i n t he st u d y. If t he patie nt 
is u na ble t o rea d a n d write or ot her wise i nca p a ble of si g ni n g a n i nf or me d c o nse nt, t he n a 
wit nesse d c o nse nt acc or di n g t o l ocal et hical sta n dar ds is per mitte d (f or m all y d oc u me nte d 
a n d wit nesse d, i deall y vi a a n i n de pe n d e nt tr uste d wit ness).  
2.  Male a n d fe male patie nts > 1 8 years of a g e at scree ni n g.  
3.  Patie nts m ust ha ve  ac ute u nc o m plicate d P. f alci p ar u m  malaria m o n o -i nf ecti o n at scree ni n g 
c o nfir me d b y  a p arasite c o u nt bet wee n 
/ μl of bl o o d 
4.  Patie nts m ust wei g h bet wee n 4 0 k g a n d 9 0 k g at scree ni n g.  
5.  Patie nts m ust be a ble t o s wall o w oral me dic ati o ns.  
6.  A ble t o c o m m u nicate well wit h t he i n vesti gat or, t o u n dersta n d a n d c o m pl y wit h t he 
re q uire me nts of t h e st u d y. 
P art B:  
Patie nts eli gi ble f or i ncl usi o n i n t his part of t he st u d y m ust meet all  of t he f oll o wi n g criteria:  
1.  Si g ne d i nf or me d c o nse nt m ust be o btai ne d pri or t o partici pati o n i n t he st u d y. If t he patie nt 
is u na ble t o rea d a n d write or ot her wise i nca p a ble of si g ni n g a n i nf or me d c o nse nt, t he n a 
wit nesse d c o nse nt acc or di n g t o l ocal et hical sta n dar ds is per mitte d (f or m all y d oc u me nte d 
a n d wit nesse d , i de all y via a n i n de pe n d e nt tr uste d wit ness). Patie nts y o u n ger t ha n 1 8 years, 
w h o are ca pa bl e of pr o vi di n g asse nt, m ust pr o vi de asse nt wit h pare ntal/le gal g uar dia n 
c o nse nt or as p er l o cal et hical g ui deli nes. T he patie nt or pare nt/le gal g u ar dia n is a ble t o  
u n dersta n d a n d c o m pl y wit h pr ot oc ol re q uir e me nts, i nstr ucti o ns a n d pr ot oc ol -state d 
restricti o ns f or t heir c hil d a n d is li kel y t o c o m plete t he st u d y as pla n ne d. 
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N o v arti s  
C o nfi d e nti al  
P a g e 3 7  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
2.  Male a n d fe male patie nts > 1 2 of a g e at scree ni n g.  
3.  Patie nts m ust ha ve  ac ute u nc o m plicate d P. f alci p ar u m  malaria m o n o -i nf ecti o n at scree ni n g 
c o nfir me d b y  a parasite c o u nt bet wee n 
/ μl of bl o o d. 
4.  Patie nts m ust wei g h bet wee n 3 5 k g a n d 9 0 k g at scree ni n g.  
5.  Patie nts m ust be a ble t o s wall o w ora l me dicati o ns. 
6.  A ble t o c o m m u nicate well wit h t he i n vesti gat or, t o u n dersta n d a n d c o m pl y wit h t he 
re q uire me nts of t h e st u d y. 
5. 2  
E x cl u si o n crit eri a  
P art A:  
Patie nts meeti n g a n y of t he f oll o wi n g criteria are n ot eli gi ble f or i ncl usi o n i n t his part of t he 
st u d y. 
1.  Patie nts wit h si g ns a n d s y m pt o ms of se vere/c o m plicate d malaria at scree ni n g  
2.  Mi xe d  Pl as m o di u m  i nfecti o n (i.e., i nf ecti o n wit h m ore t ha n o ne malaria s pecies) at 
scree ni n g 
3.  Use of a n y a nti -malarial treat me nt or a nti bi otics wit h a nti -malarial acti vit y ( or pr o hi bite d 
me dicati o n) i n t he prece di n g 1 4 da ys or at  least 5 half-li ves w hic h e ver is l o n ger bef ore 
scree ni n g 
4.  M o derate t o se vere a ne mia, c hr o nic he m o gl o bi n o pat h y ( He m o gl o bi n le vel < 8 g/ d L), or 
k n o w n c hr o nic u n d erl yi n g disease s uc h as sic kle cell disease at scr ee ni n g  
5.  Acti ve i nfecti o ns i ncl u di n g t u berc ul osis, or hist or y of ta ki n g a nti -t u berc ul osis me dicati o ns 
wit hi n 1 2 m o nt hs  pri or t o scree ni n g  
6.  Hist or y of, or c urre nt al c o h ol use dis or der d efi n e d as fi ve or m ore dri n ks o n t he sa me 
occasi o n o n eac h of 5 or m ore da y s i n t he past 3 0 da ys pri or t o scree ni n g 
7.  K n o w n cli nicall y si g nifica nt li ver disease  (e. g., c hr o nic he patitis, li ver cirr h osis 
(c o m pe nsate d or dec o m pe nsate d), hist or y of he patitis B or C, he patitis A or B vacci nati o n 
i n t he last 3 m o nt hs, k n o w n gall bla d der or bile d uct disease, ac ute or c hr o nic pa ncreatitis.  
Cli nical or la b orat or y e vi de nce of a n y of t he f oll o wi n g at scree ni n g:  
•  A S T/ A L T > 3  x t he u p per li mit of n or mal ra n ge ( U L N), re gar dless of t he l e vel of t otal 
bilir u bi n  
•  A S T/ A L T > 1. 5 a n d ≤ 2 x U L N a n d t otal  bilir u bi n is > U L N  
•  T otal bilir u bi n > 2 x U L N, re gar dless of t he le v el of A S T/ A L T  
8.  A n y k n o w n/s us pecte d i m m u n os u p pressi ve or i m m u n o deficie nt c o n diti o n, i ncl u di n g h u ma n 
i m m u n o deficie nc y vir us ( HI V) i nf ecti o n at scree ni n g 
9.  K n o w n dist ur ba n ces of u nc orrecte d elec tr ol yte b ala nce, e. g., h y p o kale mi a, h y p ocalce mia 
or h y p o ma g nese mia  
1 0.  Se vere mal n utriti o n ( B o d y Mass I n d e x ( B MI) < 1 6. 0) at scree ni n g  
1 1.  Se vere v o miti n g, defi ne d as m ore t ha n 3 ti mes i n t he 2 4 h o urs pri or t o scree ni n g or se vere 
diarr hea defi ne d as wat er y st o ols m ore t ha n 3 ti mes i n t he 2 4 h o urs pri or t o scree ni n g 
1 2.  Pre g na nt or n ursi n g (la ctati n g) w o me n  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 3 8  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
1 3.  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 n a nt, u nless t he y are usi n g 
met h o ds of c o ntrace pti o n defi ne d i n  t he 
c o h ort-s pecific secti o ns (Secti o n  1 2 ). W o me n are c o nsi dere d p ost-me n o pa usal if t he y ha v e 
ha d 1 2 m o nt hs of nat ural (s p o nta ne o us) a me n orr hea wit h a n a p pr o priate cli nical pr ofile 
(e. g., a g e-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 h a d s ur gical bilateral 
o o p h orect o m y ( wit h or wit h o ut h ysterect o m y), t otal h ysterect o m y or bilateral t u bal li gati o n 
at least si x wee ks pri or t o e nr oll me nt o n st u d y. I n t he case of o o p h orect o m y al o ne, o nl y 
w he n t he re pr o d ucti ve stat us of t he w o ma n has b ee 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 t o be n ot of c hil d -beari n g p ote ntial.  
1 4.  Se x uall y acti ve p atie nts n ot willi n g t o practice  effecti ve c o ntr ace pti o n.  Se x uall y acti v e 
males m ust use a c o n d o m d uri n g i nterc o urse w hile ta ki n g treat me nt a n d f or at least 3 0  d a ys 
after st o p pi n g st u d y treat me nt. A c o n d o m is re q uire d f or all  se x uall y acti ve male patie nts t o 
pr e ve nt t he m fr o m fat heri n g a c hil d A N D t o pre ve nt deli ver y of st u d y treat me nt via se mi nal 
fl ui d t o t heir part ner. I n a d diti o n, male patie nts m ust n ot d o nate s per m f or t he ti me peri o d 
s pecifie d a b o ve. If l oc al re g ulati o ns are m ore stri n ge nt t ha n t he c o ntracepti o n met h o ds liste d 
a b o ve t o pre v e nt pre g n a n c y, l ocal re g ul ati o ns a p pl y a n d will be descri b e d i n t he I C F.  
1 5.  Hist or y or c urre nt dia g n osis of E C G a b n or malities i n dicati n g si g nifica nt ris k of s afet y f or 
patie nts partici pati n g i n t he st u d y s uc h as:  
•  C o nc o mita nt cli nicall y si g nifica nt car diac arr h yt h mias, e. g. , s ustai ne d ve ntric ular 
tac h ycar dia, a n d cli nicall y si g nifica nt sec o n d or t hir d de gree A V bl oc k wit h o ut a 
pace ma k er  
•  Hist or y of fa milial l o n g Q T s y n dr o me or k n o w n fa mil y hist or y of T orsa des de P oi nte  
•  Resti n g h eart rate ( p h ysical e xa m or 1 2 l ea d E C G) < 6 0 b p m  
1 6.  Resti n g Q Tc F > 4 5 0 msec ( males), Q Tc F > 4 6 0 msec (fe males) at scree ni n g  
1 7.  Use of a ge nts k n o w n t o pr ol o n g t he Q T i nter val u nless t he y ca n be per ma ne ntl y 
disc o nti n ue d f or t he d urati o n of st u d y  
1 8.  A n y s ur gical or 
me dic al c o n diti o n 
w hic h 
mi g ht si g nifica ntl y alter t he a bs or pti o n, 
distri b uti o n, meta b olis m, or e xcreti o n of dr u gs, or w hic h ma y je o par di ze t h e patie nt i n case 
of partici pati o n i n t he st u d y. T he i n vesti gat or s h o ul d 
ma ke t his d eter mi nati o n i n 
c o nsi derati o n of t he p atie nt’s me dical hist or y, cli nical a n d/ or la b orat or y res ult 
1 9.  Hist or y of mali g na nc y of a n y or ga n s yste m ( ot her t ha n l ocalize d basal cell carci n o ma of t he 
s ki n or i n sit u cer vical ca ncer), tr eate d or u ntr eat e d, wit hi n t he p ast 5 y ears of s cree ni n g, 
re gardl ess of w het h er t here is e vi de nce of l ocal rec urre n ce or m etastases  
2 0.  Patie nts wit h ser u m creati ni ne ≥ 2 X U L N i n t he a bse nce of de h y drati o n at scree ni n g. I n  cas e 
of de h y drati o n, patie nts wit h ser u m creati ni ne ≥2 X U L N after oral or pare nteral re h y drati o n  
2 1.  P atie nts ta ki n g dr u gs t hat are str o n g i n d ucers of 
C Y P 3 A 4 s uc h as rifa m pici n, 
car ba m aze pi n e, p he n yt oi n, St. J o h n’s w ort ( Hy peric u m perf or at u m ) at scree ni n g 
2 2.  Hist or y of h y perse nsiti vit y t o a n y of t he st u d y treat me nts or its e xci pie nts or t o dr u gs of 
si milar c he mical classes  
2 3.  Use of her bal me dicati o n wit hi n o ne wee k of scree ni n g  

N o v arti s  
C o nfi d e nti al  
P a g e 3 9  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
2 4.  Use of ot her i n vesti gati o nal dr u gs wit hi n 5 half -li ves of scree ni n g, or wit hi n 3 0 da ys or u ntil 
t he e x pecte d p h ar mac o d y na mic ( P D) effect has ret ur ne d t o b aseli ne, w hic he ver is l o n ger; 
or l o n ger if re q uire d b y re g ul ati o ns. 
2 5.  Pre vi o us partici pati o n i n a n y malaria vacci ne st u d y or recei ve d malaria vacci ne i n a n y ot her 
circ u msta nce  
2 6.  Pre vi o us partici pati o n i n t he sa me c o h ort wit hi n t his st u d y  
P art B : 
Patie nts meeti n g a n y of t he f oll o wi n g criteria are n ot eli gi ble f or i ncl usi o n i n t his part of t he 
st u d y. 
T he sa me e x cl usi o n criteria fr o m Part A a p pl y i n Part B wit h t he a d diti o n of t he f oll o wi n g:  
1.  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 n a nt, u nless t he y are usi n g 
met h o ds of c o ntrace pti o n defi ne d i n t he 
c o h ort-s pecific secti o ns (Secti o n  1 2 ). A d diti o nall y, f or c o m bi nati o n t hera p y i n Part B , t he 
m ore c o nser vati ve c o ntr ace pti o n re q uir e me nt will be use d.  
5. 3  
R e stri cti o n s f or st u d y p arti ci p a nt s  
F or t he d urati o n of t he st u d y, patie nts s h o ul d be i nf or me d a n d re mi n de d of t he restricti o ns 
o utli ne d i n t his secti o n.  
5. 3. 1  
Di et ar y r e stri cti o n s  
F o o d restri cti o ns f or i n di vi d ual c o h orts will be descri be d i n Secti o n  1 2 . 
Patie nts ta ki n g C oarte m i n Part B s h o ul d f oll o w prescri bi n g i nf or mati o n. C oarte m s h o ul d be 
ta ke n wit h f o o d as per pr o d uct la bel. 
Patie nts  ca n dri n k water a d li bit u m;  h o we ver, t o e ns ure a d e q uate h y drati o n f or uri ne c ollecti o n 
(if a p plica ble), patie nts s h o ul d ha ve a fl ui d i nta ke of at least 2 4 0 m L e ver y 4 h o urs d uri n g 
wa ki n g h o urs o n Da y 1 i n a d diti o n t o fl ui d ta ke n wit h meals a n d me dicati o n.  
5. 3. 2  
Ot h er r e stri cti o n s  
•  C o ntrace pti o n  re q uir e me nts are defi n e d i n Secti o n  5. 2  a n d Secti o n  1 2  
•  Ot her restri cti o ns are o utli ne d i n  Secti o n  1 2  
5. 4  
S cr e e n f ail ur e s  
A  scree n fail ure occ urs w he n a patie nt w h o c o nse nts t o partici pate i n t he cli nical st u d y is 
s u bse q ue ntl y f o u n d t o be i neli gi ble a n d t heref ore n ot ra n d o ml y assi g ne d t o treat me nt/e ntere d 
i n t he st u d y. A mi ni mal set of scree n fail ure i nf or mati o n is re q uire d t o  e ns ure tra ns pare nt 
re p orti n g of scree n fail ure patie nts t o meet t he C o ns oli date d Sta n dar ds of Re p orti n g Trials 
( C O N S O R T) p u blis hi n g re q uire me nts a n d t o res p o n d t o q ueries fr o m re g ulat or y a ut h orities. 
Mi ni mal i nf or mati o n i ncl u des de m o gra p h y, s cree n fail ure  d etails, eli gi bilit y criteria, a n d a n y 
seri o us a d vers e e v e nt ( S A E). 

N o v arti s  
C o nfi d e nti al  
P a g e 4 0  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
Patie nts w h o si g n a n i nf or me d c o nse nt f or m a n d are s u bse q ue ntl y f o u n d t o be i neli gi ble pri or 
t o ra n d o mizati o n will be c o nsi dere d as scree n fail ures. 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 Case Re p ort F or m. T he de m o gra p hic i nf or mati o n, i nf or me d 
c o nse nt, a n d I n cl usi o n/ E xcl usi o n pa ges m ust als o be c o m plete d f or scree n fail ure patie nts. 
N o  ot her data will be e ntere d i nt o t he cli nical data base f or p atie nts w h o are s cree n fail ures, 
u nless t he patie nt e x perie nce d a s eri o us a d v erse e ve nt d uri n g t he scree ni n g peri o d (see 
Secti o n  8. 6  f or re p orti n g details). If t he patie nt fails t o be ra n d o mize d, t he I nteracti ve Res p o nse 
Tec h n ol o g y ( 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 patie nt was n ot 
ra n d o mize d. D ata a n d s a m ples c ollecte d fr o m p atie nts pri or t o scree n fail ure ma y still be 
a nal yze d.  
Patie nts w h o are ra n d o mi ze d a n d fail t o start tr eat me nt, e. g. , patie nts ra n d o mize d i n err or, will 
be c o nsi dere d earl y ter mi nat ors. T he reas o n s h o ul d be rec or de d o n t he a p pr o priate Cas e Re p ort 
F or m.  
It is n ot per missi ble t o re-scree n a p atie nt wit hi n t h e sa me malaria e pis o de if t he y fail t he i nitial 
pre -scree ni n g or scree ni n g. Re -scree ni n g of a pre vi o usl y scree n faile d patie nt ma y occ ur i n cas e 
t he patie nt is ret ur ni n g t o t he st u d y site f or a n e w malaria e pis o de. A ne w s u bject n u m ber will 
be iss ue d t o t he patie nt.  
Patie nts n ot 
meeti n g eli gi bilit y criteria at a partic ul ar 
malari a e pis o de will recei ve a n 
a nti-malarial treat me nt as per l ocal sta n d ar ds . 
I n t he case w here a safet y la b orat or y assess me nt at scree ni n g is o utsi de of t he ra n ge s p ecifie d 
i n t he eli gi bilit y criteria, t he assess me nt ma y be re peat e d o nce pri or t o ra nd o mizati o n. If  t h e 
re peat v al ue re mai ns o utsi de of t he s pecifie d ra n ge, t he patie nt m ust be e x cl u de d fr o m t he st u d y.  
5. 4. 1  
R e pl a c e m e nt p oli c y  
A d diti o nal patie nts ma y be e nr olle d i n t he st u d y. If a patie nt is c o nsi dere d as n o n -e val ua ble i n 
Part  A or i n Part B, e n r oll me nt of a d diti o nal patie nts t o t he c urre nt tr eat me nt gr o u p will be 
c o nsi dere d if t h ere are fe wer t ha n t he re q uir e d n u m ber of e v al ua ble p atie nts. Mi ni m u m n u m bers 
of e val ua ble p atie nts per treat me nt gr o u p i n Part A are defi ne d i n t he g ui deli nes f or c o h or t 
pr o gressi o n a n d deter mi nati o n secti o n ( Secti o n 6. 5 ). Mi ni m u m n u m bers per treat me nt gr o u p i n 
Part  B are defi ne d i n t he C o h ort S pecific I nf or m ati o n o utli ne d i n  Secti o n  1 2 . 
Re place me nts of p atie nts will be d o ne o n a case -b y -case b asis.  
5. 4. 2  
P arti ci p a nt n u m b eri n g  
Eac h pa tie nt is i de ntifie d i n t he st u d y b y a Partici pa nt N u m ber ( Partici pa nt N o.), t hat is assi g ne d 
w he n t he patie nt  is e nr olle d f or scree ni n g a n d is retai n e d f or t he patie 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 patie n t is rescree n e d. T he Partici pa nt N o. c o nsists of t he Site N u m ber ( Site N o.) (as 
assi g ne d b y  N o vartis t o t he i n vesti gati ve site) wit h a se q ue ntial partici pa nt n u m ber s uffi xe d t o 
it, s o t hat eac h patie nt ’s partici pati o n is n u m bere d u ni q uel y acr oss t he e ntire data base. 
U p o n  si g ni n g t he i nf or me d c o nse nt f or m, t he patie n t is assi g ne d t o t he ne xt se q ue ntial 
Partici pa nt N o. a vaila ble.  

N o v arti s  
C o nfi d e nti al  
P a g e 4 1  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
A ne w I C F will nee d t o be si g ne d if t he in vesti gat or c h o oses t o rescree n t he patie nt  after a 
patie nt  has scree n faile d, a n d t he patie nt  will be assi g ne d a ne w Partici p a nt N o.  
6  
St u d y tr e at m e nt( s) a n d c o n c o mit a nt t h er a p y  
6. 1  
St u d y tr e at m e nt ( s) 
T he i n vesti gati o nal c o m p o u n ds bei n g e v al uate d i n t his st u d y will be a d mi nistere d orall y. 
Refer  t o c o m p o u n d-s p ecific i nf or mati o n i n Secti o n  1 2 . 
6. 1. 1  
A d diti o n al st u d y tr e at m e nt s  
N o ot her treat me nt be y o n d i n vesti gati o nal dr u g s a n d c o ntr ol dr u g s are i ncl u de d i n t his trial.  
6. 1. 2  
Tr e at m e nt ar m s/ gr o u p  
I n Part A, patie nts will be ra n d o mize d at t he scree ni n g visit  t o recei ve a si n gle d ose of a n a nti-
malarial a ge nt at  o ne of t he  d ose le vels at e q ual rati os.  
I n Part B, patie nts will be ra n d o mize d at t he scree ni n g visit t o recei ve a si n gle d os e of a 
c o m bi nati o n of a nti -malarial a ge nts or t he sta n dar d of car e ( C oart e m).  
See Secti o n  1 2  f or c o h ort s pecific i nf or m ati o n. 
6. 1. 3  
Tr e at m e nt d ur ati o n  
F or Part A, t he pl a n ne d d urati o n of treat me nt is 1 da y . 
F or Part B, t he pla n n e d d urati o n of treat me nt is 1 da y f or p atie nts  ra n d o mize d t o t he acti ve 
i n vesti gati o nal me dici nal pr o d ucts a d mi nistere d as a l o ose c o m bi nati o n or 3 da ys f or patie nts 
ra n d o mize d t o t he sta n d ar d of care ar m. Patie nts ma y be disc o nti n ue d fr o m S o C  treat me nt 
earlier at t he discreti o n of t he in vesti gat or or  t he patie nt. 
6. 2  
Pr e p ar ati o n, h a n dli n g, st or a g e, a n d a c c o u nt a bilit y  
Eac h st u d y site will be s u p plie d wit h st u d y treat me nt (s) i n pac ka gi n g as descri be d u n der t he 
In v esti gati o nal a n d c o ntr ol dr u gs i n Secti o n  1 2 . 
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 p atie 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). T he st u d y me dicati o n pr o vi de d b y N o vartis 
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 patie nt, site pers o n nel will detac h t he o uter part of t he la bel fr o m t he pac ka gi n g a n d affi x 
it t o t he s o urce d oc u me nt. 
6. 2. 1  
H a n dli n g of st u d y tr e at m e nt  
St u d y treat me nt m ust be recei v e d b y a desi g nate d pers o n at t he st u d y site, ha n dle d a n d st ore d 
safel y a n d pr o perl y a n d k e pt i n a sec ure d l ocati o n t o w hic h o nl y t he in vesti gat or a n d desi g nat e d 
site pers o n nel ha ve access. U p o n recei pt, all st ud y treat me nt m ust be st ore d acc or di n g t o t he 
i nstr ucti o ns s pecifie d o n t he la bels . 

N o v arti s  
C o nfi d e nti al  
P a g e 4 2  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
Cli nical s u p plies are t o be dis pe nse d o nl y i n acc or da nce wit h t he pr ot oc ol. Tec h nical c o m plai nts 
are t o be re p orte d t o t he res pecti ve N o vartis Cli nical O utc o me Assess me nt  Q u alit y Ass ura nce.  
Me dicati o n la bels will be i n t he l ocal la n g ua ge a n d c o m pl y wit h t he le gal re q uire me nts of eac h 
c o u ntr y. T he y will i ncl u d e st ora ge c o n diti o ns f or t he st u d y treat me nt b ut n o i nf or mati o n a b o ut 
t he patie nt e xce pt f or t he me dicati o n n u m ber. 
T he  in vesti gat or or desi g nate d site staff 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 st u d y tr eat me nt i n a dr u g acc o u nta bilit y l o g. M o nit ori n g of dr u g acc o u nt a bilit y 
will be perf or me d b y fiel d m o nit ors d uri n g site or re m ote m o nit ori n g v isits, a n d at t he 
c o m pleti o n of t he trial. T he in vesti gat or m ust pr o vi de acc o u nta bilit y als o f or l o call y s o urce d 
materials use d f or a d mi nistrati o n  as a p plica ble . 
T he site ma y destr o y a n d d oc u me nt destr ucti o n of u n use d st u d y treat me nt, dr u g la bels a n d 
pac ka gi n g, as a p pr o priat e 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 in v esti gat or will ret ur n all u n u s e d st u d y treat me nt, 
pac ka gi n g, dr u g la bels, a n d a c o p y of t he c o m plete d dr u g acc o u nta bilit y l o g t o t he  N o vartis 
m o nit or or t o t he  N o vartis a d dress pr o vi de d i n t he I n v esti gat or f ol der at eac h site.  
6. 2. 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 nt has t o be m o nit ore d s pecifi call y:  
•  C oarte m or ot her l ocal sta n dar d a nti -malari al a ge nt per i n vesti gat or discreti o n ma y be 
a d mi nistere d as resc ue me dicati o n i n case of treat me nt fail ure. 
M o nit ori n g of resc ue 
me dicati o n c o m plia nce a n d dr u g acc o u nta bilit y will be perf or me d b y t h e fiel d m o nit ors 
d uri n g site or re m ote m o nit ori n g visits, a n d at t he c o m pleti o n of t he trial.  
6. 2. 3  
I n str u cti o n f or pr e s cri bi n g a n d t a ki n g st u d y tr e at m e nt 
Refer t o Secti o n  1 2  f or c o m p o u nd s pecific i nstr ucti o ns f or prescri bi n g a n d ta ki n g st u d y 
treat me nt. 
All kits of st u d y treat me nt 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.  
6. 3  
M e a s ur e s t o mi ni mi z e bi a s: r a n d o mi z ati o n a n d bli n di n g  
6. 3. 1  
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 t he scree ni n g visit after patie nt eli gi bilit y is c o nfir me d, all eli gi ble patie nts will be 
ra n d o mize d via I nteracti ve Res p o nse Tec h n ol o g y (I R T) t o o ne of t he treat me nt ar ms. 
T he  i n vesti gat or or his/ her dele g ate will c o nt act t he I R T aft er c o nfir mi n g t hat t he patie nt f ulfills 
all t he i ncl usi o n/e xcl usi o n criteri a. 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 patie nt, 
w hic h will be use d t o li n k t he patie nt t o a treat me nt ar m a n d will s pecif y a u ni q ue me dicati o n 
n u m ber f or t he first pac k a ge of st u d y treat me nt t o be dis pe nse d t o t he patie 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 n ceal e d fr o m patie nts a n d i n vesti gat or staff. A p atie nt 
ra n d o mizati o n list will be pr o d uce d b y t he I R T pro vi der usi n g a vali date d s yste m t hat a ut o mates 
t he ra n d o m assi g n me nt of partici pa nt n u m bers t o ra n d o mizati o n n 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 tr eat me nt ar ms, w hic h i n t ur n are li n ke d t o me dicati o n 

N o v arti s  
C o nfi d e nti al  
P a g e 4 3  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
n u m bers. A se parate me dicat i o n list will be pr o d uce d b y or u n der t he res p o nsi bilit y of N o vartis 
Gl o bal Cli nical S u p pl y ( G C S)  usi n g a vali date d s yste m t hat a ut o mates t he ra n d o m assi g n me nt 
of me dicati o n n u m bers t o pac ks c o ntai ni n g t he st u d y treat me nt.  
T he ra n d o mizati o n sc he me f or pati e 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 or b y a desi g nate d me m ber f oll o wi n g C R O pr oce d ures.  
6. 3. 2  
Tr e at m e nt bli n di n g  
I n Parts A a n d B of t he st u d y, treat me nt will be o pe n t o patie nts, i n vesti gat or staff, pers o ns 
perf or mi n g t he assess me nts a n d t he N o vartis cli nical trial tea m ( C T T). Beca use t he pri mar y 
e n d p oi nt is a n o bjecti ve e n d p oi nt f or Part A, bli n di n g is n ot necessar y  e xce pt f or t he site 
micr osc o pists w h o will  be bli n de d. As t he d osi n g re gi me ns are differe nt ( i.e., 
 
 vs. 3 da y BI D d osi n g f or C oarte m) f or Part B, it w o ul d be i m practical t o bli n d t he st u d y, 
he nce it will be u n bli n de d  e xce pt f or t he site micr osc o pists w h o will be bli n de d . I n a d diti o n, 
f o o d re q uir e me nts c o ul d be differe nt f or C oarte m a n d i n vesti gati o nal dr u g a n d t h us pre v e nti n g 
t he bli n di n g. 
T he st u d y statisticia n, statistical pr o gra m mer, data a nal ysist (e. g., bi o mar ker, P K) will be a ble 
t o access t he f ull ra n d o mizati o n list fr o m t he start of t he st u d y a n d are all o we d t o s h are 
u n bli n de d i nf or mat i o n wit h t he rest of t he cli nical tea m as a p pr o priate f or i nter nal decisi o n 
ma ki n g. F or e x a m ple, u n bli n de d s u m maries a n d u n bli n de d i n di vi d ual data ca n be s hare d wit h 
t he tea m w he n e ver necessar y. 
At t he ti me of safet y re vie w/i nteri m a nal ysis f or efficac y, t he S p o ns or  will create a n d re vie w 
u n bli n de d i nteri m re p orts. T hese s u m maries/re p orts will be s hare d wit h t he D M C f or re vie w 
a n d trial rec o m me n dati o ns. M ore details will be pr o vi de d i n t he D M C c ha rter. 
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N o v arti s  
C o nfi d e nti al  
P a g e 4 4  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
6. 4  
St u d y tr e at m e nt c o m pli a n c e  
I n t his st u d y, t he patie nts will be d ose d at t he i n vesti gat or's ce nter b y q ualifie d me m bers of t he 
site staff. Details of eac h d ose of st u d y dr u g will be rec or de d i n t he C R F. 
P har mac o ki netic p ara met ers ( m eas ures of treat me nt e x p os ure) will be deter mi ne d i n all patie nts 
treate d wit h all a nti-malarial a ge n ts, as detaile d i n t he C o h ort S pecific I nf or mati o n  secti o n 
(Secti o n  1 2 ). 
6. 4. 1  
R e c o m m e n d e d tr e at m e nt of a d v er s e e v e nt s  
At prese nt, t here is i ns ufficie nt i nf or mati o n t o pr o vi de s pecific rec o m me n dati o ns re gar di n g 
treat me nt of a d v erse e ve nts ( A Es). 
Me dicati o n use d t o treat a d verse e ve nts ( A Es) m ust be rec or de d o n t he a p pr o priate C R F.  
6. 5  
C o h ort pr o gr e s si o n a n d d o s e m o difi c ati o n  
F or Part A, a vaila bl e safet y, effic ac y, a n d P K data fr o m t he parallel d ose le vels will be re vie we d  
t o deci de a b o ut t he pr o gressi o n t o t he o pti o nal d ose le vel(s). A d diti o nall y, a vaila ble safet y, 
effic ac y, a n d P K data fr o m Part A will be re vi e we d t o deci de a b o ut t he pr o gressi o n t o Part B of 
t he st u d y. 
F or Part A, i n vesti gati o n al me dici nal pr o d uct d os e a dj ust me nts are n ot p ossi ble; f or Part B, t h e 
d ose f or i n vesti gati o nal me dici nal pr o d uct(s) ma y be a dj uste d base d o n d ata fr o m t he first fe w 
patie nts (a p pr o xi matel y 6 i n eac h ar m) i n or der t o miti gate p ote ntial safet y ris ks a n d t o e ns ure 
a de q uate e x p o s ure t o ac hie ve desire d effi cac y (see Secti o n 3 ). 
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N o v arti s  
C o nfi d e nti al  
P a g e 4 5  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
6. 5. 1  
G ui d eli n e s t o st art o pti o n al ar m( s) i n P art A  
 
 
 
 
 
 
 
 
 
 
6. 5. 2  
G ui d eli n e s t o st art P art B  
 
  
 
 
 
 
 
 
 
 
 
 
Crit eri a f or c o nti n u ati o n fr o m P art A t o P art B 
 
 
 
 
 
6. 5. 2. 1  
St arti n g d o s e  
Please refer t o t he c o h ort s pecific i nf or mati o n  i n Secti o n  1 2  f or starti n g d oses of eac h 
i n vesti gati o nal a ge nt. 
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N o v arti s  
C o nfi d e nti al  
P a g e 4 6  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
6. 5. 2. 2  
Pr o vi si o n al d o s e l e v el s  
Refer t o c o h ort s pecifi c i nf or mati o n  i n Secti o n  1 2  f or pr o visi o nal d ose le vels f or eac h 
i n vesti gati o nal a ge nt. 
6. 6  
C o nti n u e d a c c e s s t o st u d y tr e at m e nt aft er t h e e n d o f t h e st u d y 
T here will be n o st u d y treat me nt a vaila ble t o patie nts f oll o wi n g t he e n d of t h e st u d y. T his  st u d y 
i ncl u des C oarte m or ot her l ocal sta n dar d a nti-m alarial a ge nt a d mi nistere d t o all patie nts i n 
Part  A o n D a y 2 9 a n d i n case of treat me nt fail ure i n Part A or B. T here are ot h er tr eat me nt 
o pti o ns f or u nc o m plicate d malaria.  
6. 7  
Tr e at m e nt of o v er d o s e  
I n t he e ve nt of a n o ver d ose, t he i n vesti gat or s h o ul d: 
•  C o ntact t he me dical m o nit or i m me diatel y.  
•  Cl osel y m o nit or t he patie nt f or a n y A E/ S A E a n d la b orat or y a b n or ma lities f or at least 
5  half -li ves of t he i n vesti gati o nal st u d y dr u g. 
•  D oc u me nt t he q ua ntit y of t he e xcess d ose as w ell as t he d urati o n of t he o ver d ose.  
6. 7. 1  
R e p orti n g of st u d y tr e at m e nt err or s i n cl u di n g mi s u s e/ a b u s e  
Me dicati o n err ors are u ni nte nti o nal err ors i n t h e prescri bi n g, dis pe nsi n g, a d mi nistrati o n or 
m o nit ori n g of a me dici ne w hile u n der t he c o ntr ol of a healt hcare pr ofessi o nal, pa tie nt or 
c o ns u mer ( E M A d efi niti o n).  
Mis use refers t o sit uati o ns w here t he me dici nal pr o d uct is i nte nti o n all y a n d i na p pr o priatel y us e d 
n ot i n acc or da n ce wit h t h e pr ot oc ol.  
A b use c orres p o n ds t o t he persiste nt or s p ora di c, i nte nti o nal e xcessi ve use of a me dici nal 
pr o d uct, w hic h is acc o m pa nie d b y har mf ul p h ysical or ps yc h ol o gical effects.  
St u d y treat me nt err ors a n d uses o utsi de of w hat is f oresee n i n t he pr ot oc ol will be rec or de d o n 
t he a p pr o priate C R F irres pecti ve of w het her or n ot ass ociate d wit h a n A E/ S A E. 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, mis use or a b use will be c oll ecte d 
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 in vesti gat or’s a ware ness. F or m or e 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 uir e me nts, please see t he res p ecti ve S ecti o n 8. 6. 1  a n d Secti o n 8. 6. 2 . 
6. 8  
C o n c o mit a nt a n d ot h er t h er a p y  
6. 8. 1  
C o n c o mit a nt t h er a p y  
All me dicati o ns, pr oce d ures, a n d si g nifica nt n o n -dr u g t hera pi es (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 patie 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 priat e Case Re p ort F or ms.  
C o nc o mita nt me dicati o n is defi ne d as a n y me dicati o n, ot her t ha n t he st u d y treat me nts bei n g 
e val uate d i n t his st u d y , w hic h is gi ve n at least o nce bet wee n t he da y of first d ose of ra n d o mize d 
st u d y me dicati o n a n d t he last da y of st u d y visit (i ncl u di n g t h ose w hic h were starte d pre -bas eli ne 

N o v arti s  
C o nfi d e nti al  
P a g e 4 7  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
a n d c o nti n ue d i nt o t he treat me nt peri o d), i ncl u di n g prescri pti o n a n d o ver -t he-c o u nter 
m e dici nes, a n d a n y tr a diti o nal or her bal r e me dies.  
Paracet a m ol ( dail y t otal d ose n ot t o e xcee d 3 g) as a n a nti p yretic a n d met o pi mazi ne ( or if n ot 
a vaila ble, a n y ot her a nti e metic w hic h is n ot k n o w n t o pr ol o n g Q T a n d/ or  ca us e T ors a des d e 
P oi ntes) f or re peate d v o miti n g are rec o m me n de d. If p araceta m ol or e q ui vale nt dr u g is gi ve n as 
a n a nti p yretic u p t o 7 2 h o urs pri or first d ose, it m ust be re p orte d as pri or me dicati o n.  
T he i n vesti gat or m ust i nstr uct t he patie nt t o n otif y t he st u d y site a b o ut a n y ne w me dicati o ns 
he/s he ta kes aft er t he patie nt was e nr olle d i nt o t he st u d y. All me dicati o ns, pr oce d ures a n d 
si g nifica nt n o n-dr u g t hera pies (i ncl u di n g her bal t hera p y, 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 patie nt was e nr olle d i nt o t he st u d y m ust be rec or de d i n t he 
c o nc o mita nt me dicati o ns e C R F.  
Eac h c o nc o mita nt dr u g m ust be i n di vi d uall y assesse d a gai nst all e xcl usi o n criteria/ pr o hi bite d 
me dicati o n. If i n d o u bt, t he i n vesti gat or s h o ul d c o ntact t he N o vartis  me di cal m o nit or bef ore 
ra n d o mizin g a p atie nt or all o wi n g a ne w me dicati o n t o be starte d. If t he patie nt is alrea d y 
e nr olle d, c o ntact N o vartis  t o deter mi ne if t he patie nt s h o ul d c o nti n ue partici pati o n i n t he st u d y. 
6. 8. 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  
Dr u gs per mit te d t o use c o nc o mita ntl y wit h i n vesti gati o nal me dici nal pr o d u cts wit h ca uti o n are 
liste d i n Secti o n  1 2 . 
6. 8. 2  
Pr o hi bit e d m e di c ati o n  
I M P O R T A N T 
T he pr o hi bite d m e dicati o ns f or t he c ore pr ot oc ol are l ocate d i n t hi s s ecti o n. T hese a p pl y t o all 
patie nts  e nr olle d i nt o t his st u d y. H o we v er, t here ma y als o be treat me nt s pecific pr o hi bite d 
me dicati o ns w hic h are pr o vi de d i n  Secti o n  1 2  f or t he i n di vi d ual c o h orts. 
Use of f oll o wi n g tr eat me nts is N O T all o we d as per bel o w rec o m me n dati o ns i n Parts A a n d/ or 
Part  B.  
 
 
 
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N o v arti s  
C o nfi d e nti al  
P a g e 4 8  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
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N o v arti s  
C o nfi d e nti al  
P a g e 4 9  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
Pr o hi bit e d m e di c ati o n f or P art B c o h ort s wit h C o art e m ( S o C) ar m  
C oarte m/ Ria met prescri bi n g i nf or mati o n s h o ul d be f oll o we d i n ge neral.  Re gar di n g pr o hi bite d 
me dicati o ns f or C oarte m, refer t o t he c urre nt prescri bi n g i nf or mati o n. 
S o me i m p orta nt 
pr o hi bite d me dicati o ns are o utli ne d bel o w : 
•  Use of a n y prescri pti o n dr u gs k n o w n as str o n g i n hi bit ors of C Y P 3 A 4 (e. g. , er yt hr o m yci n, 
ket oc o naz ol e, it rac o naz ole, etc.) or i n d ucers of C Y P 3 A 4 (e. g., rifa m pi n, p he n o bar bital etc.) 
Dr u gs meta b olize d b y C Y P 2 D 6 li ke flecai ni de, met o pr ol ol, i mi pra mi ne, a mitri pt yli ne, 
cl o mi pra mi ne, ne ur ole ptics a n d t h ose t hat i ncreas e 
Q Tc i nter val li ke terfe n a di ne, 
aste miz ole, cisa pri de) are pr o hi bite d d uri n g st u d y a n d wit hi n f o ur ( 4) wee ks pri or t o d osi n g.  
•  Her bal s u p ple me nts 
wit h a nti malarial acti vit y a n d/ or affecti n g C Y P 3 A 4, i ncl u di n g 
St.  J o h n’s w ort ( H y p eric u m perf orat u m), are als o pr o hi bite d d uri n g st u d y a n d wit hi n o ne 
wee k pri or t o d osi n g.  
Ot her c o nsi derati o ns f or Part B c o h orts wit h C oarte m ( S o C) ar m:  
•  Me dicati o n w hic h ma y b e re q uir e d t o treat a d verse e ve nts ca n be a d mi nistere d c o nsi d eri n g 
t he p ote ntial i nteracti o n. 
•  A d mi nistrati o n of paraceta m ol ( dail y t otal d ose n ot t o  e xcee d 3 g) / aceta mi n o p he n is 
acce pta ble, b ut d os e a n d ti me of a d mi nistrati o n m ust be d oc u me nte d i n t he C o nc o mita nt 
me dicati o ns / si g nifica nt n o n dr u g t hera pies s ecti o n of t he e C R F.  
6. 8. 3  
R e s c u e m e di c ati o n  
T he f oll o wi n g resc u e me dicati o ns ma y be use d  per i n vesti gat or discreti o n : 
•  C oarte m ( Arte m et her -L u mefa ntri ne)  
or  
•  Ot her l ocal sta n d ar d a nti -malarial a ge nt  
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N o v arti s  
C o nfi d e nti al  
P a g e 5 0  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
I n Part A, C oarte m ( art e met her-lu mefa ntri ne) or ot her l ocal sta n dar d a nti -malarial a g e nt per 
i n vesti gat or discreti o n will be a d mi nistere d  o n Da y 2 9 i n all patie nts i n Part A of t he st u d y . 
If C oarte m  or ot h er l ocal sta n dar d a nti -malarial a ge nt  is use d as resc ue me dicati o n pri or t o 
Da y  2 9  d ue t o treat m e nt fail ure (see Secti o n 8. 3. 4 ), t he n a n ot her c o urse is n ot nee de d at Da y 2 9.  
I n Part B, C oarte m or ot h er l ocal st a n dar d a nti-mal arial a g e nt per i n vesti gat or discreti o n will be 
use d as resc u e me dicati o n  o nl y f or patie nts n o t ra n d o mize d t o t he S o C i n Part B if t he y meet 
t he treat me nt fail ure crit eria (see Secti o n  8. 3. 4 ). A n alter nati ve resc u e me dicati o n s h o ul d be 
use d f or patie nts assi g ne d t o t he S o C ar m if t he y met treat me nt fail ure crit eria.  
Alt h o u g h t he use of t he a b o ve res c ue m e dicati o n is all o wa ble at a n y ti me d uri n g t he st u d y w he n 
t here is tr eat me nt fail ure i n Part A or B, t he use of res c ue me di cati o n s h o ul d be use d at t he 
discreti o n of t he PI f oll o wi n g t he fail ure criteria as o utli ne d i n  Secti o n 8. 3. 4 . T he date a n d ti m e 
of res c ue me di cati o n a d mi nistrati o n as well as t he na me a n d d os a ge re gi me n of t he resc u e 
me dicati o n m ust be rec or de d.  
7  
Di s c o nti n u ati o n of st u d y tr e at m e nt a n d p arti ci p a nt 
di s c o nti n u ati o n/ wit h dr a w al  
7. 1  
Di s c o nti n u ati o n of st u d y tr e at m e nt  
Si nce o nl y o ne d os e is a d mi nistere d i n Part A, disc o nti n uati o n of st u d y treat me nt is n ot 
a p plica ble.  
Si nce o nl y o ne d ose of a c o m bi nati o n of a nti -malarials is a d mi nistere d i n n o n -S o C ar m of 
Part  B, disc o nti n uati o n of st u d y treat me nt of t he acti ve ar m is n ot a p plica ble. H o we ver, 
disc o nti n uati o n of t he S o C i n Part B ma y occ ur.  
Disc o nti n uati o n of st u d y treat me nt f or a p atie 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 treat me nt a d mi nistrati o n, if 
a n y) a n d can be i nitiate d b y eit her t he patie nt  or t h e in vesti gat or.  
T he in vesti gat or m ust disc o nti n ue st u d y treat me nt f or a gi ve n p atie nt if, h e/s he belie v es t hat 
c o nti n uati o n w o ul d ne gati vel y i m pact t he pa tie nt’s well-bei n g.  
Disc o nti n uati o n fr o m st u d y treat me nt is re q uir e d u n der t he f oll o wi n g cir c u msta nces  
•  Pa tie nt/ g uar dia n decisi o n 
•  Pre g na nc y  
•  A n y sit uati o n i n w hic h c o nti n ue d st u d y partici pati o n mi g ht res ult i n a safet y ris k t o t he 
patie nt  
•  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 patie nt’s o verall stat us , pre ve nts t he patie nt fr o m safel y c o nti n ui n g 
partici pati o n i n t he st u d y  
Pr o hi bite d me dicati o ns t hat re q uire disc o nti n uati o n of t he st u d y treat me nt are liste d i n  
Secti o n 6. 8. 2  a n d Secti o n  1 2 . 

N o v arti s  
C o nfi d e nti al  
P a g e 5 1  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 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 patie 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. 
Patie nts w h o disc o nti n ue fr o m st u d y treat me nt ( C oarte m ar m i n Part B) b ut a gree t o c o m plete 
t he st u d y s h o ul d ret ur n f or t he re mai ni n g visits a n d e n d-of -st u d y visit i n dicate d i n t he 
Assess me nt Sc he d ule Ta ble  8 -1 . 
If t he patie nt ca n n ot or is u n willi n g t o atte n d a n y visit(s), t he site staff s h o ul d mai ntai n re g ular 
tele p h o ne c o nta ct 
wit h t he patie nt, or 
wit h a pers o n pre-desi g nat e d b y t he p atie n t. 
T his  tele p h o ne c o nta ct s h o ul d prefera bl y be d o ne acc or di n g t o t he st u d y visit sc he d ule. 
After disc o nti n uati o n fr o m st u d y treat me nt, at a mi ni m u m, i n a b bre viate d visits, t he f oll o wi n g 
data s h o ul d be c ollect e d at cli nic visits or via tele p h o ne/e mail c o ntact:  
•  Ne w / c o nc o mita nt treat me nts  
•  A d verse E v e nts / Seri o us A d verse E v e nts 
T he in vesti gat or m ust als o c o ntact t he I R T t o re gister t he pa tie nt’s disc o nti n uati o n fr o m st u d y 
treat me nt. 
7. 2  
P arti ci p a nt di s c o nti n u ati o n fr o m t h e st u d y  
Disc o nti n uati o n fr o m st u d y is defi ne d as w he n t he patie nt per ma ne ntl y st o ps recei vi n g t he st u d y 
treatme 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 patie nt a grees, a fi n al e val uati o n at t h e ti me of t he patie n t’s st u d y dis c o nti n uati o n s h o ul d 
be ma de  f oll o wi n g t he assess me nts of t he E O S visit as detaile d i n t he Assess ment Sc he d ule 
Ta ble 8 -1 . 
7. 3  
Wit h dr a w al of i nf or m e d c o n s e nt a n d e x er ci s e of p arti ci p a nt s’ 
d at a pri v a c y ri g ht s  
Wit h dra wal of c o nse nt/ o p p ositi o n t o use of data a n d/ or bi ol o gical sa m ples occ urs i n c o u ntries 
w here t he l e gal j ustificati o n  t o c ollect a n d pr ocess t he data is c o nse nt a n d w he n a patie nt: 
•  E x plicitl y re q uests t o st o p use of t heir data  
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 as per l ocal re g ulati o ns ( e. g., i n writi n g) a n d rec or de d i n t he s o urce 
d oc u me ntati o n.  
Wit h dra wal of c o nse nt i m pacts a bilit y t o f urt her c o ntact t he p atient, c ollect f oll o w -u p data (e. g. , 
t o res p o n d t o data q ueries) a n d p ote ntiall y ot her c o u ntr y -s pecific restricti o ns. It is t heref ore ver y 
i m p orta nt t o e ns ure acc urate rec or di n g of wit h dra wal vs. disc o nti n uati o n base d o n t he pr ot oc ol 
defi niti o ns of t hese ter ms.  

N o v arti s  
C o nfi d e nti al  
P a g e 5 2  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
I n t his sit uati o n, t he in vesti gat or s h o ul d ma ke a reas o na ble eff ort ( e. g., tele p h o ne, e-mail, letter) 
t o u n dersta n d t h e pri mar y reas o n f or t he p atie nt’s decisi o n t o wit h dr a w t h eir c o ns e nt/e xercise 
data pri v ac y ri g hts a n d rec or d t his i nf or mati o n. T he in vesti gat or s h all clearl y d oc u me nt if t he 
patie nt  has wit h dr a w n his/ her c o ns e nt f or  t he us e of data i n a d diti o n t o a st u d y disc o nti n uati o n. 
St u d y treat me nt m ust be disc o nti n ue d a n d n o f urt her 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 a tie 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 patie nt a grees, a fi n al e val uati o n at t he ti me of t he p atie nt’s wit h dra wal of c o nse nt/e xercis e 
data pri vac y ri g hts s h o ul d be ma de f oll o wi n g t he assess me nts of t he E OS visit  as detaile d i n t he 
Assess me nt Sc he d ule Ta ble 8 -1 . 
F urt her d etails o n wit h dra wal of c o ns e nt or t he e xercis e of patie n ts' 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. 
7. 4  
L o st t o f oll o w -u p  
F or patie 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 or fail t o res p o n d 
t o a n y site atte m pts t o c o ntact t he m 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 ( or e xercise ot her patie nts’ data 
pri vac y ri g hts), t he i n vesti gat or m ust s h o w “d ue dili ge nce ” b y d oc u m e nti n g i n t he s o urce 
d oc u me nts ste ps ta ke n t o c o ntact t he p atie nt, e. g., dates of tele p h o n e calls, re gistere d l etters, 
etc. A p atie nt s h o ul d n ot be c o nsi dere d as l ost t o f oll o w -u p u ntil d ue dili ge nce has bee n 
c o m plete d or u ntil t he e n d of t he st u d y.  
7. 5  
St u d y st o p pi n g r ul e s  
De pe n de nt o n re gi o n al g ui da nce, a n y restart f oll o wi n g a te m p orar y h ol d d ue t o st o p pi n g r ules 
bei n g met will re q uire a n e val uati o n b y t he S p o ns or a n d t he D M C , a n d a p pr o val t o pr ocee d.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T he se verit y of a d v erse e ve nts will be gra de d b y t he st u d y i n vesti gat ors base d o n t he mil d, 
m o derate, s e vere gra di n g scale  a n d ca pt ure d i n t he C R F. T his i nf or mati o n will be use d t o 
q ua ntif y e ve nts t hat ma y lea d t o a patie nt’s disc o nti n uati o n or st o p pi n g c o h ort pr o gressi o n.  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 5 3  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
7. 6  
E arl y st u d y t er mi n ati o n b y t h e S p o n s or  
T he st u d y ca n be 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 (i ncl u de b ut are n ot li mite d t o):  
•  U ne x pect e d, si g nifica nt, or u nacce pta ble s afet y ris k t o pa tie nts e nr olle d i n t he st u d y  
•  Decisi o n base d o n rec o m me n dati o ns fr o m a p plica ble b oar d(s) after re 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 treat me nt de vel o p me nt i n t his i n dicati o n 
I n ta ki n g t he d ecisi o n t o ter mi nate, N o vartis will alwa ys c o nsi der p atie nt welfare a n d safet y. 
S h o ul d earl y ter mi nati o n be necess ar y, patie nts  m ust be see n as s o o n as p ossi ble a n d treate d as 
a patie nt w h o disc o nti n ue d fr o m st u d y treat me nt:  E O S pr oce d ures s h o ul d be perf or m e d, a n d 
t he patie nt s h o ul d b e tr a nsferre d t o S o C. T he in vesti gat or ma y b e i nf or me d of a d diti o nal 
pr oce d ures t o be f oll o w e d i n or der t o e ns ure t hat a de q uat e c o nsi derati o n is gi ve n t o t he 
pr otecti o n of t he pa tie nt’s i nterests. T he in vesti gat or or N o vartis de pe n di n g o n l ocal re g ulati o n 
will be res p o nsi ble f or i nf or mi n g I R Bs/I E Cs of t h e earl y ter mi na ti o n of t he trial. 
8  
St u d y A s s e s s m e nt s  a n d Pr o c e d ur e s  
T he Assess me nt Sc h e d ul e (Ta bl e  8 -1 ) lists all of t he assess me nts w he n t h e y are perf or m e d. 
All  data o btai ne d fr o m t hese assess me nts 
m ust be s u p p orte d i n t h e patie nt’s s o urce 
d o c u me ntati o n.  
Patie nts s h o ul d be see n f or all visits/assess me nts as o utli ne d i n t he assess me nt sc he d ule 
(Ta ble  8 -1 ) or as cl ose t o t he desi g 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.  
Patie nts w h o disc o nti n ue fr o m st u d y treat me nt are t o atte n d t he f oll o w -u p visits as i n dicate d i n 
t he Assess me nt Sc he d ule. 
Patie nts w h o disc o nti n ue fr o m st u d y or wit h dr a w t heir c o nse nt/ o p p ose t he use of t h eir 
data/ bi ol o gical sa m pl es s h o ul d be sc he d ule d f or a fi nal e val uati o n visit if t he y a gree, as s o o n as 
p ossi ble, at w hic h ti me all of t he a p plica ble assess me nts liste d f or t he fi nal E O S visit Da y  2 9 
will be perf or me d. At t his fi nal visit, t he a d verse e ve nt a n d c o n c o mita nt me dicati o ns n ot 
pre vi o usl y re p orte d m ust be rec or de d o n t he C R F.  
W he n t he f oll o wi n g assess me nts are sc h e d ule d t o be perf or me d at t he sa m e ti me p oi nt, t he or der 
of pri orit y will be as f oll o ws: E C G, vital si g ns, bl o o d sa m pli n g (safet y, f oll o we d b y P K bl o o d 
sa m pli n g fr o m o p p osite ar m). E ver y eff ort will be ma de t o ta k e t he p har mac o ki netic sa m ple at 
t he pr ot oc ol s pecifie d ti me. 
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 t a 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 ntati 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.  
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 we d b y l ocal Healt h A ut h orit y a n d d e pe n di n g o n o perati o nal 

N o v arti s  
C o nfi d e nti al  
P a g e 5 4  of 1 3 8  
A m e n d e d  Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
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 patie 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 patie 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 5 5  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
T a bl e 8 -1  
A s s e s s m e nt S c h e d ul e  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 5 6  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 5 7  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 5 8  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 5 9  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 6 0  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
8. 1  
S cr e e ni n g  
S cr e e ni n g  
Pr oce d ures c o n d u cte d as part of t he p atie nt’s r o uti n e cli nical ma na g e me nt/sta n dar d of care ( e. g.,  
bl o o d c o u nt) a n d o btai n e d bef ore si g ni n g of t he I C F ma y b e u tilize d f or scree ni n g p ur p oses 
pr o vi de d t he pr oce d ures met t he pr ot oc ol -s p ecifie d criteria a n d were perf or me d wit hi n t he 
ti mefra me defi ne d i n t he Assess me nt Sc he d ule Ta ble 8 -1 . 
8. 2  
P arti ci p a nt d e m o gr a p hi c s/ ot h er b a s eli n e c h ar a ct eri sti c s  
C o u ntr y -s pecific re g ulati o ns s h o ul d be c o nsi dere d f or t he c ollecti o n of de m o gra p hic a n d 
baseli ne c haracteristics i n ali g n me nt wit h C R F.  
Patie nt de m o gra p hics: a g e, se x, race, pre d o mi na nt et h nicit y (if per mitte d) a n d rele va nt me dical 
hist or y/ c urre nt me dical c o n diti o ns ( u ntil date of si g nat ure of i nf or me d c o ns e nt) will be rec or de d 
i n t he e C R F. W here p ossi ble, t he dia g n osis a n d n ot s y m pt o ms s h o ul d be rec or de d. 
All prescri pti o n me dicati o ns, o ver -t he-c o u nt er dr u gs a n d si g nifica nt n o n -dr u g t hera pie s pri or t o 
t he start of t he st u d y m ust be d oc u me nte d. See t he c ore pr ot oc ol Secti o n 6. 8  C o nc o mita nt a n d 
ot her t hera p y  a n d c o h ort -s pecific Secti o n  1 2  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 pri ate pa ge of t he e C R F. 
8. 3  
Effi c a c y  a s s e s s m e nt s  
P har mac o d y na mic s a m ples will be c ollecte d at t he ti me p oi nts defi ne d i n t he Asse ss me nt 
Sc he d ule ( Ta ble  8 -1 ). F oll o w i nstr ucti o ns o utli ne d i n t he La b orat or y ma n ual re gar di n g sa m ple 
c ollecti o n, n u m beri n g, pr ocessi n g, a n d s hi p me nt.  
I n or der t o better defi n e t he P D pr ofile, t he ti mi n g of t he sa m ple c ollecti o n ma y be altere d b ase d 
o n e mer g e nt data. T he n u m ber of s a m ples/ bl o o d dra ws a n d t otal bl o o d v ol u me c ollecte d will 
re mai n u n der t h e li mits rec o m me n de d i n t he p o p ulati o n c o nsi dere d. 
P har mac o d y na mic ( P D) s a m ples will be o bt ai ne d a n d e val uat e d i n all patie nts at all d os e le vels.  
8. 3. 1  
Cli ni c al si g n s a n d s y m pt o m s of m al ari a  
A f ull assess me nt of malaria si g ns a n d s y m pt o ms will be ma de acc or di n g t o t he ti me p oi nts i n 
t he assess me nt sc he d ule (Ta ble  8 -1 ) f or all patie nts. 
T he f oll o wi n g si g ns a n d s y m pt o ms of malaria are t o be assesse d: 
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 6 1  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
8. 3. 3  
P ar a sit e mi a a n d p ar a sit e cl e ar a n c e ti m e  
Bl o o d sa m pli n g f or parasit ol o g y ca n be d o ne b y m ea ns of fi n g er pri c k e xce pt w he n t he  ti mi n g 
f or parasit ol o g y assess m e nts c oi nci de wit h ti me s f or cli nical la b orat or y tests, i n w hic h cas e, 
bl o o d sa m ple ca n be ta k e n fr o m t he ve n o us bl o o d c ollecte d f or cli nical la b orat or y a n al yses.  
P ar a sit e c o u nt s  
•  Gie msa stai ne d t hic k a n d t hi n fil ms will be e xa mi ne d. T hi n fil ms will be e xa mi ne d o nl y if 
i de ntificati o n of s pecies is nee de d after malaria (Pl as m o di u m)  parasite is detecte d i n a t hic k 
fil m 
•  E xa mi nati o n wit h bi n oc ular micr osc o pe a n d wit h oil i m mersi o n le ns at 1, 0 0 0 ma g nificati o n  
•  Scree ni n g e x a mi nati o n ( pri or t o patie nt i ncl usi o n i nt o t he trial), t hic k fil m: 
C CI
C CI

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

N o v arti s  
C o nfi d e nti al  
P a g e 6 3  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
N ote: T he first da y of treat me nt wit h st u d y me dicati o n is defi ne d as Da y 1 w hile t he da y pri or 
t o t he first da y of treat m e nt is defi ne d as Da y -1. C o m pare d t o W H O ( 2 0 1 5)  w hic h d efi ne d 
Da y  0 as t he first da y of treat me nt wit h st u d y me dicati o n, da ys after treat me nt referre d t o i n t his 
pr ot oc ol are 1 d a y great er. F or e xa m ple, Da y 2 9 i n t his pr ot oc ol c orres p o n ds t o Da y 2 8 b y  
W H O ( 2 0 1 5) . 
8. 3. 5  
I n ci d e n c e r at e of r e cr u d e s c e n c e a n d r ei nf e cti o n 
Rei nfecti o n is defi ne d as a p peara nce of ase x ual p arasites aft er cl eara nce of i nitial i nfecti o n wit h 
a ge n ot y pe differe nt fr o m t h ose parasites pres e nt at baseli ne.  
Recr u desce nce is defi ne d as a p peara nce of as e x ual parasites after cl eara nce of i nitial i nfecti o n 
wit h a ge n ot y pe of at least o ne allele i de ntical t o t hat of parasites prese nt at baseli ne.  
Rei nfecti o n a n d Recr u desce nce m ust be c o nfir me d b y P C R a nal ysis.  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 6 4  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
Ti me t o e ve nt (recr u des ce nce or rei nfecti o n) will be calc ul ate d fr o m t he ti me of first st u d y 
me dicati o n t o t he date of first e ve nt if a patie nt e x perie nces t he e ve nt a n d be ce ns ore d at t he 
ti me of last parasite assess me nt if a patie nt d oes n ot e x perie nce t he e ve nt d ue t o w hate ver 
reas o n. 
A partici pa nt w h o w as alrea d y treate d i n o ne c o h ort w h o e x peri e nces a s u bse q ue nt malaria 
e pis o de ma y be e nr olle d i nt o a differe nt c o h ort pr o vi de d t he y meet eli gi bilit y criteria, b ut ma y 
n ot be recr uite d wit hi n t he sa me c o h ort . 
8. 3. 6  
Bl o o d s a m pl e f or m ol e c ul ar di a g n o sti c p ur p o s e  
Bl o o d will be sa m ple d f or parasite ge n ot y pi n g a n d p he n ot y pi n g as i n dicat e d i n t he assess me nt 
sc he d ule. At scree ni n g, a bl o o d sa m ple will be c ollecte d fr o m all patie nts f ulfilli n g eli gi bilit y 
criteria f or i ncl usi o n i n t he st u d y. A sec o n d bl o o d sa m ple c ollecte d as per assess me nt sc he d ule 
will be a n al yze d o nl y i n patie nts s h o wi n g tr eat m e nt fail ure. T his will be use d t o disti n g uis h 
bet wee n recr u desce nce a n d ne w i nfecti o n. M olec ular a nal ysis will be d o n e b y a n a nal ytical  
la b orat or y. 
Micr osc o pic s peci es i de ntificati o n ( parasite mia) will be c o nfir me d a n d deter mi ne d wit h 
P C R -base d met h o ds fr o m ali q u ots of sa m ples c ollecte d at t he ti me of wit h dra wal/ L P F.  
8. 3. 7  
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  
T he effi cac y assess me nts a re sta n d ar d f or t his pati e nt p o p ulati o n. 
 
 
8. 4  
S af et y  a s s e s s m e nt s  
Safet y assess me nts are s pecifie d bel o w wit h Assess me nt Sc he d ule  Ta bl e 8 -1  detaili n g w he n 
eac h assess me nt is t o be perf or me d.  
F or details o n A E c ollec ti o n a n d re p orti n g, refer t o Secti o n  8. 6 . 
As per Secti o n  4. 6 , d uri n g a p u blic healt h e mer g e n c 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, re g ular 
p h o ne or virt ual calls ca n occ ur f or safet y m o nit ori n g a n d dis c ussi o n of t he patie nt´s healt h 
stat us u ntil it is safe f or t he patie nt t o visit t he site a gai n. 
8. 4. 1  
P h y si c al  e x a mi n ati o n s  
•  A c o m plete p h ysical e xa mi nati o n will be perf or m e d b y t he i n vesti gati o nal staff at s cree ni n g 
a n d i ncl u de t he e xa mi nati o n of ge neral a p p eara n ce, s ki n, nec k (i ncl u di n g t h yr oi d), e yes, 
ears, n ose, t hr oat, l u n gs, heart, a b d o me n, bac k, l y m p h n o des, e xtre mities, vasc ular, a n d 
ne ur ol o gical. If i n dicate d base d o n me dical hist or y a n d/ or s y m pt o ms, rectal, e xter n al 
ge nitalia, breast, a n d pel vic e xa ms will be perf or me d. Malaria si g ns a n d s y m pt o ms, b o d y 
wei g ht, a n d b o d y w ei g ht will als o be rec or de d at s cree ni n g as part of t he c o m p lete p h ysical 
e xa mi nati o n. Hei g ht i n ce nti meters (c m) a n d b o d y wei g ht (t o t he nearest 0. 1 kil o gra m ( k g) 
i n i n d o or cl ot hi n g, b ut wit h o ut s h oes) will be meas ure d as s pecifie d ti me p oi nts as descri be d 
i n Ta ble 8 -1 . B o d y mass i n de x ( B MI) will be cal c ulate d usi n g t he f oll o wi n g f or m ula: 
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 6 5  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
•  B MI = B o d y w ei g ht ( k g) / [ Hei g ht ( m)] 2  
R o u n di n g s h o ul d be d o ne t o t he nearest te nt h of a deci mal place.  
•  A s h ort p h ysical e xa m will be perf or me d at all ot her visits starti n g fr o m Da y 1 i ncl u di n g 
t he e xa mi nati o n of ge n eral a p peara n ce a n d vital si g ns ( bl o o d press ure [ S B P a n d D B P] a n d 
p ulse).  
•  A f ull assess me nt of m al ari a si g ns a n d sy m pt o ms  will be ma de al o n gsi de t he p h ysical 
e xa mi nati o ns at ti me p oi nts descri be d i n t h e assess me nt sc h e d ule f or all p atie nts  
(Ta ble 8 -1 ). 
I nf or mati o n f or all p h ysi cal e x a mi nati o ns m ust be i ncl u de d i n t he s o urce d oc u me ntati o n at t he 
st u d y site. Cli nicall y rele va nt fi n di n gs t hat are prese nt pri or t o si g ni n g i nf or me d c o nse nt m ust 
be i ncl u de d i n t he a p pr o priate C R F t hat ca pt ures me dical hist or y. Si g nifica nt fi n di n gs after 
si g ni n g i nf or me d c o nse nt w hic h meet t he defi niti o n of a n A d verse E ve nt m ust be rec or de d as 
a n a d vers e e v e nt . 
I n v esti gat ors s h o ul d pa y s pecial atte nti o n t o cli nical si g ns relate d t o pre vi ous seri o us ill nesses.  
8. 4. 2  
Vit al si g n s  
Vital si g ns will i ncl u de t he c ollecti o n of oral b o d y t e m perat ur e (rec or de d i n ° C), bl o o d press ure 
( B P) a n d p ulse meas ur e me nts. 
After t he patie nt has bee n sitti n g f or 5 mi n utes, wit h bac k s u p p orte d a n d b ot h feet place d o n t he 
fl o or, s yst olic a n d diast olic B P will be meas ure d usi n g a n a ut o mate d vali date d de vice, e. g.,  
O M R O N wit h a n a p pr o priatel y size d c uff. I n case t he c uff sizes a vaila ble are n ot lar ge e n o u g h 
f or t he patie nt's ar m circ u mfere n ce, a s p h y g m o ma n o meter wit h a n a ppr o pri atel y size d c uff ma y 
be use d.  
B o d y te m perat ure will be m o nit ore d as i n dicat e d i n t he st u d y assess me nt sc he d ule ta ble 
(Ta ble  8 -1 ) a n d rec or de d o n t he cli nical data bas e. Fe ver m o nit ori n g will be d o ne e v er y 6 h o urs 
u ntil res ol uti o n of fe ver, defi ne d as b ei n g afe brile f or 2 4 h o urs.  
If vital si g ns are o ut-of -ra n ge at scree ni n g (see E xcl usi o n Criteria Secti o n 5. 2  of t he pr ot oc ol 
f or details), t w o a d diti o nal rea di n gs ca n b e o btai ne d, s o t hat a t otal of t hree c o nsec uti ve 
assess me nts are ma de, wit h t he patie nt seate d q ui etl y f or a p pr o xi matel y fi ve mi n utes prece di n g 
eac h re peat assess me nt. T he last rea di n g m ust be wit hi n t he ra n ges pr o vi de d i n t he eli gi bilit y 
criteria i n or d er f or t he p atie nt t o q ualif y . 
I n case of re p eate d vital si g n assess me nts, t he e C R F s h o ul d c o ntai n t he q ualif yi n g res ults. 
8. 4. 3  
El e ctr o c ar di o gr a m s  
Electr ocar di o gra ms ( E C Gs) m ust be rec or de d after 1 0 mi n utes rest i n t he s u pi ne p ositi o n t o 
e ns ure a st a ble baseli ne. T he preferre d se q u e nce of car di o v asc ular d ata c oll ecti o n d uri n g st u d y 
visits is E C G c ollecti o n first, f oll o we d b y vital si g ns, bl o o d sa m pli n g, a n d a n y re mai ni n g 
assess me nts f or t hat visit (refer t o fl o w dia gra m bel o w).  

N o v arti s  
C o nfi d e nti al  
P a g e 6 6  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
Fi g ur e 8 -1  
Ti mi n g of st u d y pr o c e d ur e s  
 
8. 4. 4  
Cli ni c al s af et y l a b or at or y t e st s  
A s per Secti o n 4. 6 , d uri n g a p u blic h ealt h e m er ge n c 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, if patie nts 
can n ot visit t he site f or pr ot oc ol -s pecifi e d safet y la b assess me nts, a n alter nati ve l a b (l ocal) 
c ollecti o n site ma y be us e d.  
Cli nicall y si g nifica nt a b n or malities m ust be rec or de d as eit her me dical hist or y/c urre nt me dical 
c o n diti o ns or a d verse e ve nts as a p pr o priate.  
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N o v arti s  
C o nfi d e nti al  
P a g e 6 7  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
I n t he case w h ere a la b orat or y ra n ge is n ot s pecifi e d b y t he pr ot oc ol, b ut a val ue is o utsi de t he 
refere nce ra n ge f or t he la b orat or y at scree ni n g, a decisi o n re gar di n g w het her t he res ult is of 
cli nical si g nifica nce or n ot s hall be ma de b y t h e i n ves ti gat or (i n c o ns ultati o n wit h t he S p o ns or) 
a n d s hall be base d, i n part, u p o n t h e nat ur e a n d de gree of t h e o bser ve d a b n or malit y. 
T he  assess me nt ma y be re peate d o n ce pri or t o ra n d o mizati o n.  
All  a b n or mal la b res ults m ust be e val uate d f or criteria defi ni n g t he i ncl usi o n/e xcl usi o n criteria, 
a n a d v erse e ve nt a n d re p orte d as s uc h  if t he crit eria are met. F or t h ose l a b a d v erse e ve nts, 
re peat e d e val uati o ns are ma n dat or y u ntil n or malizati o n of  t he res ult(s) or u ntil t he res ult is n o 
l o n ger c o nsi dere d t o be cli nicall y  si g nifica nt. 
I n all cas es, t he i n vesti gat or m ust d oc u me nt i n t he s o urce d oc u me nts, t he cli nical c o nsi derati o ns 
(i.e., res ult was/ w as n ot cli nicall y si g nifica nt a n d/ or me dicall y rele va nt) i n all o wi n g or 
disall o wi n g t he p atie nt t o c o nti n ue i n t he st u d y. 
L ocal la b orat ories will be use d f or a nal ysis of safet y s peci me ns.  
Uri n al y si s  
A mi dstrea m uri ne sa m ple (a p pr o x. 3 0 m L) will be o btai ne d, i n or der t o a v oi d c o nta mi nati o n 
wit h e pit helial cells a n d se di me nts, a n d all o w pr o p er assess me nts.  
S p e ci al cli n i c al l a b or at or y e v al u ati o n s 
All a b n or mal la b res ults m ust be e val u ate d f or criteria defi ni n g a n a d verse e ve nt a n d re p orte d 
as s uc h if t he criteria are met. F or t h ose la b a d verse e ve nts, re peat e d e val uati o ns are ma n dat or y 
u ntil n or malizati o n of t he res ult(s ) or u ntil t he res ult is n o l o n ger c o nsi dere d t o b e cli nicall y 
si g nifica nt. 
T a bl e 8 -2  
L a b or at or y a s s e s s m e nt s  
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N o v arti s  
C o nfi d e nti al  
P a g e 6 8  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
8. 4. 5  
Pr e g n a n c y t e sti n g 
C o n d o m use is re q uire d f or all se x uall y acti ve m ale patie nts t o pre v e nt t he m fr o m fat h eri n g a 
c hil d A N D t o pre ve nt deli ver y of st u d y treat me nt via se mi nal fl ui d t o t heir part ner. I n a d diti o n, 
male patie nts s h o ul d n ot d o nate s per m f or t he ti me peri o d s pecifie d a b o v e. 
All pre -me n o pa usal w o me n w h o are n ot s ur gicall y sterile will ha ve pre g na nc y testi n g. 
A d diti o nal pre g na nc y testi n g mi g ht be perf or me d if re q ueste d b y l ocal re q uire me nts.  
A ser u m or plas ma pre g n a nc y test will be perf or m e d at t he scree ni n g visit a n d/ or pre-d ose a n d 
uri ne pre g na n c y test will be perf or me d at st u d y c o m pleti o n. All fe male patie nts i n t his st u d y 
m ust u n der g o o bli gat or y pre g na nc y testi n g as per sc he d ule of assess me nt. L ocal pre g na n c y test 
a n d ass ociate d res ults will n ot be c ollecte d o n C R F.  
A s s e s s m e nt s of f ertilit y  
A w o ma n is c o nsi dere d of c hil d beari n g p ote ntial fr o m 
me narc he a n d u ntil bec o mi n g 
p ost -me n o pa usal u nless per ma n e ntl y sterile. 
Per ma ne nt sterilizati o n 
met h o ds i ncl u de 
h ysterect o m y, bilateral s al pi n gect o m y a n d bilateral o o p h orect o m y. Me dical d oc u me ntati o n of 
o o p h orect o m y, h ysterect o m y, or t u bal li gati o n m ust be retai ne d as s o urce d oc u me nts.  
A p ost -me n o pa usal state is defi ne d as n o me nses f or 1 2 m o nt hs wit h o ut a n alter nati ve me dical 
ca use a n d a n  a p pr o priate cli nical pr ofile.  
I n a bse nce of t he 
me dical d oc u me ntati o n c o nfir mi n g per ma ne nt sterilizati o n, or if t he 
p ost -me n o pa usal stat us is n ot clear, t he i n vesti gat or s h o ul d use his me dical j u d g me nt t o 
a p pr o priatel y e val uate t he fertilit y state of t he w o ma n a n d d oc u m e nt it i n t he s o urce d oc u me nt.  
8. 4. 6  
Ot h er s af et y e v al u ati o n s  
Si g n s a n d s y m pt o m s of s e v er e m al ari a  
Da n ger si g ns:  
•  n ot a ble t o dri n k  
•  v o miti n g > t wice wit hi n prece di n g 2 4 h o urs  
•  o ne c o n v ulsi o n wit hi n prece di n g 2 4 h o urs  
•  u nc o nsci o us state  
•  u na ble t o sit or sta n d 
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N o v arti s  
C o nfi d e nti al  
P a g e 6 9  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
Si g ns of se vere malaria:  
Se vere P.  f alci p ar u m malaria is defi ne d as o ne or m ore of t he f oll o wi n g, occ urri n g i n t he 
a bse nce of a n i de ntifie d alter nati ve ca us e a n d i n t he prese nce of P. f alci p ar u m ase x ual 
parasite mia:  
•  I m paire d c o ns ci o us ness ( Glas g o w c o ma sc ore < 1 1 i n a d ults) 
•  Pr ostrati o n ( ge neralize d wea k ness i.e., u n a ble t o sit, sta n d or wal k wit h o ut assista nce)  
•  M ulti ple c o n v ulsi o ns ( m ore t ha n t w o e pis o des wit hi n 2 4 h o urs)  
•  Aci d osis (a base deficit of > 8 m E q/ L or if n ot a vaila ble a plas ma bicar b o nate le vel of 
<  1 5  m m ol/ L or ve n o us plas ma lactate ≥ 5 m m ol/ L. Se vere aci d osis ma nifests cli nicall y as 
res pirat or y distress i.e., ra pi d, dee p, la b ore d breat hi n g) 
•  H y p o gl yce mia ( bl o o d or plas ma gl uc ose < 2. 2 m m ol/ L; < 4 0 m g/ d L)  
•  Se vere malari al a ne mia ( he m o g l o bi n c o nce ntrati o n ≤ 5 g/ d L or a he mat ocrit of ≤ 1 5 % i n 
c hil dre n < 1 2 years of a ge ( < 7 g/ d L a n d < 2 0 % res pecti vel y i n a d ults) wit h a parasite 
c o u nt > 1 0 ,0 0 0/ μ L)  
•  Re nal i m pair me nt ( plas ma or ser u m creati ni ne > 2 6 5 μ m ol/ L ( 3 
m g/ d L) or bl o o d 
urea >  2 0  m m ol/ L ) 
•  Ja u n dice ( pl as ma or s er u m bilir u bi n > 5 0 μ m ol/ L ( 3 
m g/ d L) 
wit h a parasite 
c o u nt > 1 0 0 ,0 0 0/ μ L)  
•  P ul m o nar y e de ma (ra di ol o gicall y c o nfir me d or o x y ge n sat urati o n < 9 2 % o n r o o m air wit h 
a res pirati o n rate > 3 0/ mi n, ofte n wit h c hest i n dra wi n g a n d cre pitati o n o n  a usc ultati o n)  
•  Si g nifica nt blee di n g (i n cl u di n g rec urre nt or pr ol o n ge d blee di n g fr o m t h e n ose, g u ms of 
ve ni p u nct ure sites, he mat e mesis or mele na)  
•  S h oc k (c o m pe nsat e d s h o c k i.e., ca pillar y refill ≥ 3s or te m perat ure gra die nt o n le g b ut n o 
h y p ote nsi o n; dec o m pe nsate d s h oc k i.e., s yst olic bl o o d press ure < 7 0 m m H g i n c hil dre n or 
< 8 0 m m H g i n a d ults wit h e vi de nce of i m paire d p erf usi o n)  
•  H y per parasite mia  (P. f al ci p ar u m parasite mia  > 1 0 %)  
If a patie nt e x peri e nces a n d da n ger si g ns / si g ns of se vere malaria, t he i n vesti gat or s h o ul d re p ort 
t he e ve nt as a n S A E f oll o wi n g t he g ui da nce pr o vi de d i n Secti o n 8. 6. 3 . L o cal g ui da nce s h o ul d 
be f oll o we d f or t he treat me nt of t hese da n g er si g ns / si g ns of se vere malaria.  
8. 4. 7  
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/ pa tie 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  
As per Secti o n 4. 6 , d uri n g a p u blic h ealt h e m er ge n c 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, if patie nts 
ca n n ot visit t he site f or pr ot oc ol -s pecifie d P K a n d 
, a n alter nati ve la b (l ocal) 
c ollecti o n site ma y be us e d.  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 7 0  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
8. 5. 1  
M e al R e c or d s  
Meal rec or ds are re q uire d f or d o micile d meals o n t he da y(s) i n dicate d i n t he assess me nt ta ble 
(Ta ble 8 -1 ). 
F or d o micile d me als o n d a ys i n dicate d i n t he Assess me nt Sc he d ule Ta ble 8 -1 , t he date a n d start 
a n d e n d ti me a n d perce nt a ge of m eal c o ns u m pti o n will be rec or de d i n t h e a p pr o priate secti o n 
of t he e C R Fs.  
8. 5. 2  
Ot h er a s s e s s m e nt s  
 
8. 6  
A d v er s e e v e nt s ( A E s), s eri o u s a d v er s e e v e nt s ( S A E s), a n d ot h er 
s af et y r e p orti n g  
T he defi niti o ns of a d v erse e ve nts ( A Es) a n d s eri o us a d verse e ve nts ( S A Es) ca n b e f o u n d i n 
Secti o n  8. 6. 2 . 
A Es will be re p orte d b y t he pa tie nt ( or, w he n a p pr o priate, b y a care gi v er, s urr o gat e, or t he 
pa tie nt’s le gall y a ut h orize d re prese ntati ve). 
T he in vesti gat or a n d a n y q ualifie d desi g nees are res p o nsi ble f or detecti n g, d oc u me nti n g, a n d 
rec or di n g e v e nts t hat meet t he defi niti o n of a n A E or S A E a n d re mai n res p o nsi ble f or f oll o wi n g 
u p all A Es (see Secti o n  7 ). 
T he met h o d of rec or di n g, e val uati n g, a n d assessi n g ca usalit y of A Es a n d S A Es a n d t he 
pr oce d ures f or c o m pleti n g a n d tra ns mitti n g S A E re p orts are pr o vi de d i n Secti o n  8. 6. 3 . 
8. 6. 1  
A d v er s e e v e nt s  
A n a d verse e ve nt ( A E) is a n y u nt o war d me di cal occ urre nce (e. g. , a n y u nfa v ora ble a n d 
u ni nte n de d si g n [i 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 patie nt after pr o vi di n g writte n i nf or me d c o nse nt f or partici p ati 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 oci ate d wit h t he use of a 
me dici nal (i n vesti gati o nal) pr o d uct.  
T he occ urre nce of a d vers e e v e nts m ust be s o u g ht b y n o n -directi ve q uesti o ni n g of t he p a tie 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 detect e d w he n t he y are v ol u nt eere d b y 
t he patie nt d uri n g or b et 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. 
A d verse e ve nts m ust be rec or de d u n der t he si g ns, s y m pt o ms, or dia g n osis ass ociate d wit h t h e m, 
acc o m pa ni e d b y t he f oll o wi n g i nf or mati o n (as far as p ossi ble) (if t he e v e nt is seri o us refer t o 
Secti o n  8. 6. 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: pr e ve nts n or mal acti vities 
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N o v arti s  
C o nfi d e nti al  
P a g e 7 1  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
2.  Its relati o ns hi p t o t he st u d y treat me nt a n d ot her i n vesti gati o nal treat me nt. If t he e v e nt is d ue 
t o lac k of effic ac y or pr o gressi o n of u n derl yi n g ill ness (i.e., pr o gressi o n of t he st u d y 
i n dicati o n) t he assess me nt of ca usalit y will us uall y be ‘ N ot s us pecte d.’ T he rati o nale f or 
t his g ui da nce is t hat t he s y m pt o ms of a lac k of efficac y or pr o gressi o n of u n derl yi n g ill ness 
are n ot ca use d b y t he trial dr u g, t he y ha p pe n i n s pite of its a d mi nistrati o n a n d/ or b ot h lac k 
of efficac y a n d pr o gressi o n of u n derl yi n g disease ca n o nl y be e val uate d mea ni n gf ull y b y a n 
a nal ysis of c o h orts, n ot o n a si n gle patie 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 8. 6. 2  f or defi niti o n of S A E) a n d w hic h 
seri o us ness criteria ha ve bee n met 
5.  Acti o n ta ke n re g ar di n g wit h st u d y treat me nt.  
All a d verse e v e nts m ust be treate d a p pr o priat el y. Treat me nt ma y i ncl u de o ne or m ore of t h e 
f oll o wi n g: 
•  D ose n ot c ha n g e d  
•  D ose Re d uce d/i ncreas e d  
•  Dr u g i nterr u pte d/ per ma n e ntl y disc o nti n ue d  
6.  Its o utc o me 
C o n diti o ns t hat were alrea d y pres e nt at t he ti me of i nf or me d c o nse nt s h o ul d be r ec or de d i n 
me dical hist or y of t he pa tie nt. 
A d verse e v e nts (i ncl u di n g la b a b n or malities t hat c o nstit ute A Es) s h o ul d be descri be d usi n g a 
dia g n osis w he ne ver p ossi ble, rat her t h a n i n di vi d ual u n derl yi n g si g ns a n d s y m pt o ms.  
A d verse e v e nt m o nit ori n g s h o ul d be c o nti n ue d f or at least 3 0 da ys ( or 5 half-li ves or e n d of 
st u d y visit, w hic he ver is l o n ger) f oll o wi n g t he last d ose of st u d y treat me nt. 
O nce a n a d verse e ve nt is detecte d, it m ust be f oll o we d u ntil its res ol uti o n or u ntil it is j u d ge d t o 
be n ot rec o vere d/ n ot res ol ve d (e. g., c o nti n ui n g at t he e n d of t h e st u d y), a n d assess me nt m ust be 
ma de at eac h visit ( or m ore fre q ue ntl y, if necessar y) of a n y c ha n ges i n se v erit 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 
I n v esti gat or's Br oc h ure (I B). 
A b n or mal la b orat or y val ues or test res ults c o nstit ute a d verse e ve nts o nl y if t he y f ulfill at least 
o ne of t he f oll o wi n g criteria:  
•  t he y i n d uce cli nical si g ns or s y m pt o ms  
•  t he y are c o nsi dere d cli nicall y si g nifica nt 
•  t he y re q uire t h era p y 
Cli nicall y si g nifica nt a b n or mal la b orat or y v al ues or test res ults m ust be i de ntifie d t hr o u g h a 
re vie w of val u es o utsi de of n or mal ra n ges/cli nicall y n ota ble ra n ges, si g nifica nt c ha n g es fr o m 
baseli ne or t he pre vi o us visit, or val ues w hic h are c o nsi dere d t o be n o n -t y pical i n patie nt wit h 
u nc o m plicate d malari a.  

N o v arti s  
C o nfi d e nti al  
P a g e 7 2  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
8. 6. 2  
S eri o u s a d v er s e e v e nt s  
A n S A E is defi ne d as a n y a d verse e v e nt [a p peara nce of ( or w orse ni n g of a n y pre -e xisti n g)] 
u n de sira ble si g n(s), s y m pt o m(s), or me dical c o n diti o ns(s) w hic h meets a n y o ne of t he f oll o wi n g 
criteria:  
•  fatal 
•  life-t 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 patie nt  was at ris k of 
deat h at t he ti me of t he reacti o n; it d oes n ot refer t o a reacti o n t hat h y p ot h eticall 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 g e nital a n o mal y/ birt h defect, fet al deat h or a c o n ge nital a b n or malit y or 
birt h defect  
•  re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n, u nless 
h os pitalizati o n is f or:  
•  r o uti ne treat me nt or m o nit ori n g of t he st u die d i n dicati o n, n ot ass ociate d wit h a n y 
deteri orati o n i n c o n diti o n  
•  electi ve or pre -pla n ne d treat me nt f or a pre -e xisti n g c o n diti o n t hat is u nrelate d t o t he 
i n dicati o n u n der st u d y a n d has n ot w orse ne d si nce si g ni n g t he i nf or me d c o nse nt 
•  s ocial reas o ns a n d res pite care i n t he a bse n ce of a n y d eteri or ati o n i n t he p atie 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 di zes t he patie nt or ma y re q uir e 
me dical 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 v e  
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 der e 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 hreat e 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 patie 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 pitalizati o n or de vel o p me nt of d e p e n de nc y or a b use ( please refer t o t he 
I C H-E 2 D G ui deli nes).  
All ne w mali g na nt ne o 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 d t he mali g na nt ne o plas m is n ot a dis eas e pr o gressi o n of t he 
st u dy i n dicati o n.  
All re p orts of i nte nti o nal mis use a n d a b use of t he pr o d uct are als o c o nsi dere d seri o us a d verse 
e ve nts irres p ecti ve of w h et her a cli nical e ve nt h as occ urre d.  
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 n si dere d a 
seri o us a d vers e reacti o n. 

N o v arti s  
C o nfi d e nti al  
P a g e 7 3  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
8. 6. 3  
S A E r e p orti n g  
T o e ns ure p atie nt safet y, e ver y S A E, re gar dless of ca usalit y, occ urri n g after t he p atie nt has 
pr o vi de d i nf or me d c o nse nt a n d u ntil 3 0 da ys f oll o wi n g t he last a d mi nistrati o n of st u d y 
treat me nt if t here are p ost -treat me nt f oll o w-u p visits wit h n o re q uire d pr oce d ures  m ust be 
re p orte d t o N o vartis safet y i m me diatel y, wit h o ut u n d ue dela y, b ut u n der n o circ u msta nces later 
t ha n wit hi n 2 4 h o urs of o btai ni n g k n o wle d ge of t he e v e nts ( N ote: If m ore stri n ge nt, l ocal 
re gulati o ns re g ar di n g re p orti n g ti meli nes pre v ail). 
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 uire me nts are t o be f o u n d i n t he in vesti gat or f ol d er pr o vi d e d t o eac h 
site. I nf or mati o n a b o ut all S A Es is c ollecte d a n d rec or de d o n t h e Seri o us A d verse E v e nt Re p ort 
F or m; 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 Es occ urri n g after t h e pa tie nt has pr o vi de d i nf or me d c o nse nt u ntil t he ti me t he patie n t is 
dee me d a Scree n Fail ure m ust be r e 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 plicati o ns, pr o gressi o n of 
t he i nitial S A E a n d rec urre nt e pis o des m ust be re p orte d as f oll o w-u p t o t he ori gi nal e pis o de 
i m me diatel y, wit h o ut u n d ue dela y, b ut u n der n o circ u msta nces l ater t h a n wit hi n 2 4 h o urs of t h e 
in vesti gat or recei vi n g t he f oll o w -u p i nf or m ati 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 plet el 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 t he S A E is n ot pre vi o usl y d oc u me nte d i n t he I n vesti gat or’s Br oc h ure or Pac ka ge I ns ert ( ne w 
occ urre nce) a n d is t h o u g ht t o be relate d t o t he st u d y treat me nt, a C M O & P S  De part me nt 
ass ociate ma y ur ge ntl y re q uire f urt her i nf or mati o n fr o m t he in vesti gat or f or healt h a ut h orit y 
re p orti n g. N o vartis 
ma y nee d t o iss ue a n I n vesti gat or N otificati o n (I N) t o i nf or m all 
in 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 n t t hat t his S A E has b ee n 
re p orte d. 
S us pecte d U ne x pecte d S eri o us A d verse Reacti o ns ( S U S A Rs) a n d S A Es will be c ollecte d a n d 
re p orte d t o t he c o m pete nt a ut h orities a n d rel e va nt et hics c o m mittees i n acc or da nce wit h E U 
G ui da nce 2 0 1 1/ C 1 7 2/ 0 1 or as per nati o nal r e g ulat or y re q uire m e nts i n partici pati n g c o u ntries.  
A n y S A Es e x perie nce d after t he 3 0 -da y peri o d f oll o wi n g t he last a d mi nistrati o n of st u d y 
treat me nt s h o ul d o nl y be re p orte d t o N o vartis Safet y if t he i n vesti gat or s us pects a ca usal 
relati o ns hi p t o st u d y treat me nt, u nless ot her wise s pecifie d b y l ocal la w/re g ulati o ns. 
Pr ot oc ol s pecific S A Es t o be re p ort e d t o N o vartis wit hi n 2 4 hrs:  
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N o v arti s  
C o nfi d e nti al  
P a g e 7 4  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
8. 6. 4  
Pr e g n a n c y  R e p orti n g  
•  Details of all pre g n a nci es  i n fe m ale p atie nts a n d, if i n dicate d, fe mal e p art ners of male 
pa tie nts will be c ollecte d after t he start of st u d y treat me nt a n d u ntil 3 0 da ys after 
a d mi nistrati o n of st u d y dr u g or f or 5 half -li ves, w hic he ver is l o n ger. 
•  W hile pre g n a nc y itself is n ot c o nsi dere d t o be a n A E or S A E, a n y pre g na n c y c o m plicati o n 
or electi ve t er mi nati o n of a pre g na nc y f or me dical reas o ns will  be re p ort e d as a n A E or 
S A E.  
•  A b n or mal pre g na n c y o utc o mes ( e. g., s p o nta ne o us a b orti o n, fetal deat h, still birt h, c o n ge nital 
a n o malies, ect o pic pre g n a nc y) are c o nsi dere d S A Es a n d will be re p ort e d as s uc h.  
•  A n y p ost st u d y pre g na nc y -relate d S A E c o nsi dere d reas ona bl y relate d t o t he st u d y treat me nt 
b y t he in vesti gat or will be re p orte d t o N o vartis as descri be d i n Secti o n  8. 6. 3 . W hile t he 
in vesti gat or is n ot o bli gate d t o acti vel y see k t his i nf or mati o n i n f or mer st u d y 
patie nts / pre g na nt fe male part ners, he or s h e ma y lear n of a n S A E t hr o u g h s p o nta ne o us 
re p orti n g. 
A n y fe male p a tie nt w h o bec o mes pre g na nt w h ile partici pati n g i n t he st u d y will dis c o nti n ue t he 
st u d y. 
Pr e g n a n ci e s  
If a fe mal e trial p atie nt bec o mes pre g na nt, t he st u d y treat me nt s h o ul d b e st o p pe d, a n d t he 
pre g na nc y c o nse nt f or m s h o ul d be prese nte d t o t he trial patie n t. T he patie nt  m ust be gi ve n 
a de q uate ti me t o rea d, re vie w a n d si g n t he  pre g na nc y c o nse nt f or m. T his c o nse nt f or m is 
necessar y t o all o w t he in vesti gat or t o c ollect a n d re p ort i nf or mati o n re gar di n g t he pre g na nc y. 
T o  e ns ure patie nt safet y, eac h pre g na nc y occ urri n g after si g ni n g t he i nf or me d c o nse nt m ust be 
re p orte d t o N o vartis wit hi n 2 4 h o urs of lear ni n g of its occ urre 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.  
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 in 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 h e p ossi ble relati o ns hi p t o t he i n vesti gati o nal 
me dici nal pr o d uct i n  a n y pre g na nc y o utc o me. A n y S A E e x peri e nce d d uri n g pre g na nc y m ust be 
re p orte d. 
If a fe m ale p art ner of a male trial patie nt w h o t o o k st u d y treat me nt i n t his st u d y bec o mes 
pre g na nt, pre g na n c y o ut c o mes s h o ul d be c ollect e d. C o nse nt t o re p ort i nf or mati o n re gar di n g 
t hese pre g n a nc y o utc o mes s h o ul d be o btai ne d fr o m t he m ot her. 
After c o nse nt is pr o vi de d, t he pre g na nc y re p orti n g will occ ur u p t o o ne year after t he esti mate d 
date of deli ver y.  
8. 6. 5  
Di s e a s e -r el at e d e v e nt s a n d/ or di s e a s e-r el at e d o ut c o m e s n ot q u alif yi n g 
a s A E s or S A E s  
T here are n o dis ease -relate d e ve nts a n d/ or dise ase-relate d o utc o mes t h at w o ul d n ot q ualif y as 
a n A E or S A E.  

N o v arti s  
C o nfi d e nti al  
P a g e 7 5  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
8. 7  
P h ar m a c o ki n eti c s  
P K sa m ples will be c ollecte d at t he visits defi ne d i n t he c o h ort s pecific ass ess me nt sc he d ules 
(Secti o n  1 2 ). F oll o w i nstr ucti o ns o utli ne d i n t he la b orat or y ma n ual re gar di n g sa m ple c ollecti o n, 
n u m beri n g, pr ocessi n g a n d s hi p me nt. 
 
 
 
I n or der t o better d efi ne t he P K pr ofile, t he ti mi n g of t he P K sa m ple c ollecti o n ma y be altere d 
base d o n e m er ge nt d at a. P har mac o ki netic ( P K) sa m ples will be o btai ne d a n d e val uate d i n all 
patie nts treate d wit h t he a nti -malarial a g e nts a n d c o m bi nati o ns i ncl u de d i n t his st u d y at all d ose 
le vels. A bi oa nal yst will o nl y a nal yze sa m ples fr o m t he patie nts o n i n vesti gati o nal dr u g(s). 
T he  pare nt dr u g(s) will be deter mi ne d b y a vali date d L C -M S/ M S met h o d. 
 
 
C o nce ntrati o ns will be e x presse d i n mass p er v ol u me u nits a n d will refer t o t he free base. 
C o nce ntrati o ns bel o w t he L L O Q will be re p orte d as “zer o” a n d missi n g data will be la bele d as 
s uc h i n t he Bi oa nal ytical Data Re p ort. I n cas e of missi n g dr u g c o nce ntrati o ns, i m pact of t his o n 
P K para meter cal c ulati o n a n d i nter pret ati o n will be  c o nsi dere d.  
F or sta n dar d p har m ac o ki netic a b bre vi ati o ns a n d d efi niti o ns , see t he List of A b bre viati o ns . 
T he f oll o wi n g p har mac o ki netic para meters will be deter mi ne d usi n g t he act ual rec or de d 
sa m pli n g ti mes a n d n o n-c o m part me ntal met h o d(s) wit h P h oe ni x Wi n N o nli n ( Versi o n 6. 4 or 
hi g her): 
C ma x, 
T ma x, 
A U Clast, 
A U Ci nf, 
T 1/ 2, 
Vz/ F a n d 
C L/ F fr o m t he plas ma 
c o nce ntr ati o n -ti me data. 
T he li near tra p ez oi dal r ul e will be use d f or A U C calc ulati o n. Re gressi o n a nal ysis of t he ter mi nal 
plas ma eli mi nati o n p hase f or t he deter mi nati o n of T 1/ 2 will i ncl u de at least 3 data p oi nts after 
C ma x. If t he a dj uste d R 2 val ue of t he re gressi o n a n al ysis of t he ter mi nal p hase will be less t ha n 
0. 7 5, n o val ues will be re p orte d f or T 1/ 2, A U Ci nf a n d Cl/ F.  
8. 8  
Bi o m ar k e r s 
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N o v arti s  
C o nfi d e nti al  
P a g e 7 6  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
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N o v arti s  
C o nfi d e nti al  
P a g e 7 7  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
8. 9  
H e alt h e c o n o mi c s  
Healt h ec o n o mics p ara m eters are n ot e val u ate d i n t his st u d y.  
9  
S t ati sti c al c o n si d er ati o n 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.  
F or eac h  si n gle a nti-malarial a ge nt, statistical a n al yses f or Part A a n d Part B will be perf or me d 
se parat el y f or effic ac y a n d safet y o utc o mes. 
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N o v arti s  
C o nfi d e nti al  
P a g e 7 8  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
F or statistical a nal yses a n d cli nical st u d y re p orti n g, treat me nt gr o u p na m e, i nstea d of c o h ort 
n u m ber, will be us e d f or b ot h parts a n d t he p o ole d a nal ysis. T he tr eat me nt gr o u p will be la bele d 
t o i ncl u de t he f ull d ose le vel of b ot h  st u d y dr u gs f or t he c o m bi nati o n t hera p y. 
F or S o C i n P art B, p o oli n g acr oss c o m p o u n ds ma y be c o nsi dere d. F urt her details will be 
pr o vi de d i n t he statistical a nal ysis pla n ( S A P). 
9. 1  
A n al y si s s et s  
T he f oll o wi n g a nal ysis sets are c o nsi dere d f or t he st u d y:  
•  Ra n d o mize d a nal ysis set ( R A S): all patie nts w h o are ra n d o mize d.  
•  F ull a nal ysis set ( F A S): t he F A S will be c o m prise d of all patie nts t hat ha ve bas eli ne 
P . f alci p ar u m c o u nt > 0 a n d ta ke at least o ne d ose of t he st u d y treat me nt d uri n g t he treat me nt 
peri o d. F oll o wi n g t he i nte nt -t o-treat pri nci ple, patie nts will be a nal yze d acc or di n g t o t he 
treat me nt gr o u p assi g ne d at ra n d o mizati o n. 
•  T he Safet y a nal ysis set ( S A F) i ncl u des all patie nts w h o recei ve d at least o ne d ose of t he 
st u d y treat me nt. Patie nts will be a nal yze d acc or di n g t o t he st u d y treat me nt recei v e d . 
•  P K a nal ysis set: All patie nts w h o ha ve at least o ne vali d ( i.e., n ot fla g ge d f or e xcl usi o n) P K 
c o nce ntr ati o n meas ure m e nt, recei ve at least o ne d ose of st u d y dr u g, a n d d o n ot ha ve a n y 
pr ot oc ol de viati o ns t hat i m pact o n P K data.  
F ull details will be descri be d i n t he st atistical a nal ysis pla n ( S A P).  I n ge n eral, S A F will be use d 
f or safet y a n al ysis, R A S f or de m o gra p hics, F A S f or efficac y a nal ys es a n d P K a nal ysis set f or 
all P K a nal yses, u nless ot her wise state d.  
9. 2  
St ati sti c al a n al y s e s  
9. 2. 1  
P arti ci p a nt d e m o gr a p hi c s a n d ot h er b a s eli n e c h ar a ct eri sti c s  
De m o gra p hic a n d ot her baseli ne data i ncl u di n g disease c haracteristics will be liste d a n d 
s u m marize d descri pti vel y b y si n gle a nti-malarial a ge nt, st u d y part, a n d treat me nt gr o u p f or t he 
R A S set.  
C ate g orical d ata will be 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 ( S D), me dia n, mi ni m u m, a n d ma xi m u m will be pres e 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 dica l hist ori es a n d c urre nt me dical c o n diti o ns at baseli ne will be s u m marize d b y 
s yste m or ga n class a n d preferre d ter m, b y si n gle a nti-malarial a g e nt, st u d y part, a n d treat me nt 
gr o u p.  
9. 2. 2  
Tr e at m e nt s  
T he S A F will be use d f or t he a nal yses b el o w. Cate g orical data wil l be s u m marize d as 
fre q ue n cies a n d perce nta ges b y part, c o h ort a n d treat me nt gr o u p. 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 7 9  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
T he d urati o n of e x p os ure i n n u m ber of d oses t o eac h treat me nt will be s u m marize d b y mea ns 
of descri pti ve statistics f or t he S o C i n Part B.  
C o nc o mita nt me dicati o ns, resc ue a n d ot her a nti -malarial me dicati o ns as well as si g nifica nt 
n o n -dr u g t hera pies pri or t o a n d aft er t he start of t he st u d y treat me nt will be liste d a n d 
s u m marize d b y a nti-malarial a ge nt, st u d y part, a n d treat me nt gr o u p.  
9. 3  
Pri m ar y e n d p oi nt( s)/ e sti m a n d( s) a n al y si s  
9. 3. 1  
D efi niti o n of pri m ar y e n d p oi nt( s)  
T he pri mar y effic ac y e n d p oi nt of t he st u d y i n Part A is t he ti me t o p arasite cleara n ce ( P C T), as 
de fi ne d as t he ti me (i n h o urs) fr o m t he first d os e u ntil t he first t otal a n d c o nti n ue d disa p peara n ce 
of ase x ual parasite f or ms w hic h re mai ne d at least a f urt her 4 8 h o urs. P C T , will be calc ulate d 
base d o n u nc orrect e d P. f alci p ar u m  ase x u al p arasite c o u nts. T h e  F A S will be use d f or t he 
a nal ysis.  
T he pri mar y effic ac y e n d p oi nt i n Part B is t he P C R c orrecte d A de q uate Cli nical a n d 
Parasit ol o gical Res p o nse ( A C P R) at Da y 2 9 as defi ne d i n Secti o n 8. 3. 4 . T h e F A S will be use d 
f or t he a n alysis.  
P C T a n d P C R c orrecte d A C P R will be use d f or t he pri mar y esti ma n d a nal yses i n Part A a n d 
Part B, res pecti vel y.  
9. 3. 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 Part A, d es cri pti ve st atistics ( mea n, sta n d ar d d e viati o n, me dia n, q uartiles) will be pr o vi de d  
b y treat me nt gr o u p.  In di vi d ual pl ots will be pr o vi de d, a n d Ka pla n -Meier c ur ves will b e 
prese nte d b y  st u d y part a n d treat me nt gr o u p. T he  pri mar y a nal ysis tests w het her t he u p per li mit 
of t w o -si de d 9 0 % CI f or t he me dia n P C T usi n g Ka pla n-Meier est i mates f or a treat me nt gr o u p  
is l o wer t ha n 9 6 h o urs.  
F or Part B, t he pri mar y e n d p oi nt will be calc ulat e d at Da y 2 9 b y c o m p uti n g t he perce nt of 
patie nts wit h P C R c orrecte d A C P R f or eac h treat me nt gr o u p. T he pri mar y a nal ysis will test f or 
n o n -i nferi orit y of t he c o m bi nati o n t hera p y vers us S o C base d o n t he d ual efficac y criteria as 
s pecifie d b el o w, 
 I nf or mati ve pri ors f or t h e 
S o C will be use d, w hile f or t he c o m bi nati o n treat me nt p ri or i nf or mati o n ma y be va g ue or 
i nf or mati ve de pe n di n g o n w het her rele va nt pri or i nf or mati o n is a vaila ble. 
Ta ble 9 -1  s h o ws t he hist orical dat a a b o ut t he 2 8-da y c ure rate o bser ve d i n hist orical trials f or  
t he S o C. 
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N o v arti s  
C o nfi d e nti al  
P a g e 8 0  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
F urt her details o n t he pri or use d f or t he c o m bi nati o n t hera p y will be  s pecifie d i n t he C o h ort 
S pecif ic I nf or mati o n i n S ecti o n  1 2  a n d  details of  t he statistical met h o d ol o g y will be  o utli ne d  i n 
t he S A P. 
T he d ual efficac y criteria are t he f oll o wi n g:  
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C CI

N o v arti s  
C o nfi d e nti al  
P a g e 8 1  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
9. 3. 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 pri mar y a nal ysis i n Part A will acc o u nt f or bel o w me nti o ne d i nter -c urre nt e ve nts usi n g a 
h y p ot hetical strate g y. If a patie nt recei ves a n y resc ue a nti -malarial me dicati o n or  recei ves ot her 
c o nc o mita nt me dicati o n ha vi n g a n effect o n malaria f or a n y reas o ns, t he ti me -t o-e v e nt P C T will 
be set t o Da y 7  fr o m t he da y of t he occ urre nce of t he e ve nt. 
T he pri mar y a n al ysis i n Part B will acc o u nt f or t h e bel o w me nti o ne d i nter -c urre nt e v e nts usi n g 
a pri nci pal strat u m strate g y. Data will be ha n dle d as f oll o ws:  
9. 3. 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  
F or h a n dli n g missi n g val ues i n t he pri mar y a nal ysis i n Part A, t h e f oll o wi n g strate gies will 
a ppl y:  
•  If t he parasite is n ot cleare d a n d t he last parasite c o u nt is missi n g b ut n ot relate d t o 
i nterc urre nt e ve nt, t he ti me-t o-e ve nt P C T will be ce ns ore d at Da y 7.  
•  If a n i nter me diate p arasite c o u nt is missi n g bet wee n 2 e xisti n g meas ures (e. g., s u c h as 
missi n g sa m ple, tec h nical reas o n, etc.):  
•  If b ot h pre vi o us a n d f oll o wi n g meas ures are q ua ntifia ble a n d a b o v e t he li mit of 
q ua ntificati o n, t he i nter m e diate val ue will be c o nsi dere d as prese n ce of parasite.  
•  If b ot h pre vi o us a n d f oll o wi n g meas ures are bel o w t he li mit of q ua ntificati o n, t he 
missi n g val ue will be c o nsi dere d as n o prese n ce of parasite.  
•  If t he pre vi o us me as ure is q ua ntifia ble a n d a b o v e t he li mit of q ua ntificati o n, b ut n ot t he 
f oll o wi n g meas ure, t he i nter me diate val u e will be c o nsi dere d as pres e nce of parasite. 
I n Part B n o i m p utati o n of data will be perf or me d. 
9. 3. 5  
S e n siti vit y a n al y s e s  
I n Part B, 2-si de d 8 0 % c o nfi de nce i nter vals f or t h e differe n ce t o S o C will be c o nstr ucte d usi n g 
t he Wils o n u nc orrecte d met h o d. 
9. 3. 6  
S u p pl e m e nt ar y a n al y si s  
S u p ple me ntar y a n al yses are  n ot pl a n ne d f or Part A. F or Part B, t he c o m p utati o n of perce nt of 
patie nts wit h P C R u nc orrecte d A C P R ( usi n g t he F A S) a n d 9 5 % c o nfi de n ce i nter vals f or eac h 
treat me nt gr o u p will be c o m p ute d, s uc h as  d escri be d i n Secti o n 9. 3 . 2. P C R -c orrect e d A C P R 
rate a n d P C R-u nc orrect e d A C P R rate will be als o calc ulate d a n d pl otte d usi n g t he Ka pla n -M eier 
met h o d f or eac h si n gle a nti -malarial a ge nt, st u d y part a n d treat me nt gr o u p i n t he F A S.  
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N o v arti s  
C o nfi d e nti al  
P a g e 8 2  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
9. 4  
S e c o n d ar y e n d p oi nt( s)/ e sti m a n d( s) a n al y si s  
T he sec o n d ar y efficac y varia ble i n Part A is t he P C R c orrecte d A C P R, at Da y 2 9  as defi n e d 
pre vi o usl y i n Secti o n 9. 3. 1 . 
T he sec o n d ar y efficac y v aria ble i n Part B is t he P C T as defi ne d pre vi o usl y i n Secti o n 9. 3. 1 . 
T he sec o n d ar y esti ma n d will be use d t o a nal yze t he P C R c orrecte d A C P R i n Part A a n d P C T 
i n Part B. 
I n a d diti o n, p har mac o ki n etics a n d safet y a n d t olera bilit y will als o be assesse d. 
9. 4. 1  
Effi c a c y a n d/ or P h ar m a c o d y n a mi c e n d p oi nt( s)  
T he sec o n d ar y a n al ysis f or Part A will be t he c o m p utati o n of perce nt of patie nts wit h P C R 
c orrecte d ( usi n g t he R A S ) a n d u n c orrecte d A C P R ( usi n g t he F A S) a n d 9 5 % c o nfi de nce 
i nter vals f or eac h treat m e nt gr o u p as d escri be d i n Secti o n 9. 3. 2 . N o h y p ot hesis testi n g will be 
perf or me d.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At eac h visit, t he perce nt of patie nts wit h P C R c orrecte d a n d u nc orrect e d A C P R a n d 9 5 % 
c o nfi de nce i n ter vals 
will be pr o vi de d usi n g Cl o p per-Pears o n 
met h o d f or eac h si n gle 
a nti-malarial a ge nt a n d f or eac h treat me nt gr o u p. 2 -si de d 8 0 % c o nfi de n ce i nter vals f or t h e 
differe n ce t o S o C at eac h visit will be c o nstr ucte d usi n g t he 
Wils o n u nc orrecte d met h o d.  
At  each visit, P C R u nc orrecte d fail ure will be classifie d i nt o, E T F bef ore Da y 4, L C F b ef ore 
Da y  8, recr u des ce nce, ne w i nfecti o n, ne gati ve P C R, missi n g P C R, or missi n g assess me nt. 
T he  classificati o n will be ta b ulate d usi n g t he F A S.  
 
 
 
 
 
 
If rele v a nt, ke y effic ac y e n d p oi nts will be s u m marize d b y t reat me nt gr o u p f or s u b gr o u ps of 
partici pa nts wit h or wit h o ut rele va nt r esista nce m utati o ns.  
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N o v arti s  
C o nfi d e nti al  
P a g e 8 3  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
9. 4. 2  
S af et y e n d p oi nt s  
F or all safet y a nal yses, t he S A F will be use d. All listi n gs a n d ta bles will be prese nte d b y si n gle 
a nti-malarial a g e nt, st u d y part, a n d treat me nt g r o u p. 
Safet y s u m maries (t a bles, fi g ures) i n cl u de all p ost treat me nt data wit h t he e xce pti o n of bas eli ne 
data w hic h will als o be s u m marize d w here a p pr o priate ( e. g., c ha n ge fr o m b aseli ne s u m maries). 
I n p artic ular, s u m mar y ta bles f or a d verse e ve nts ( A Es) will  s u m marize usi n g all p ost-treat me nt 
e ve nts, wit h a start date o n or after t h e first treat me nt (treat me nt -e mer g e nt A Es).  
A d v er s e e v e nt s  
All i nf or mati o n o btai ne d o n a d verse e ve nts will be dis pla ye d b y eac h si n gle a nti -malarial a g e nt, 
st u d y part, treat me nt gro u p a n d patie nt.  
T h e n u m ber (a n d p erce nta ge) of patie nt s wit h treat me nt e mer ge nt a d verse e ve nts (e ve nts starte d 
after t he first d ose of st u d y me dicati o n or e v e nts prese nt pri or t o start of tr eat me nt b ut i ncrease d 
i n se verit y base d o n preferre d t er m) will be s u m marize d i n t he f oll o wi n g wa ys:  
•  b y eac h si n gle a nti -m alarial a ge nt, st u d y part, treat me nt gr o u p, pri mar y s yste m or ga n class 
a n d preferre d ter m.  
•  b y eac h si n gle a nti -malarial a ge nt, st u d y part, treat me nt gr o u p, pri mar y s yste m or ga n class, 
preferre d t er m a n d ma xi m u m se verit y.  
•  b y eac h si n gle a nti -malarial a ge nt, st u d y p art, tr eat me nt gr o u p, Sta 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 maries will be pr o vi de d f or st u d y me dicati o n relate d a d verse e ve nts, deat h, seri o us 
a d verse e v e nts, ot her  si g nifica nt a d verse e ve nts lea di n g t o disc o nti n uati o n, a n d a d verse e v e nts 
lea di n g t o d ose i nterr u pti o n i n t he S o C of Part B. 
A patie nt wit h m ulti ple a d verse e ve nts wit hi n a pri mar y s yste m or ga n class is o nl y c o u nte d o nce 
t o war ds t he t otal of t he pri mar y syste m or ga n cl ass.  
Vit al si g n s  
All vital si g ns data will be liste d b y si n gle a nti-malarial a ge nt, st u d y part, treat me nt gr o u p , 
patie nt, a n d visit/ti me a n d if ra n ges are a v aila 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 d e d b y si n gle a nti -malarial a g e nt, 
st u d y part, treat me nt gr o u p, a n d visit/ti me. 
1 2 -l e a d E C G 
P R, Q R S, Q T, Q Tc F, a n d R R i nter vals will be o btai ne d fr o m 1 2 -lea d E C Gs f or eac h patie nt 
d uri n g t he st u d y. E C G data will be rea d a n d i nter prete d (ce ntrall y). 
Cate g orical A nal ysis of Q T/ Q Tc i nter val dat a b ase d o n t h e n u m ber of patie nts meeti n g or 
e xcee di n g pre d efi ne d li mits i n ter ms of a bs ol ute Q T/ Q Tc i nter vals or c h a n ges fr o m b aseli ne 
will be prese nt e d. I n a d diti o n, a listi n g of t hese p atie nts will be pr o d uce d ( b y eac h si n gle 
a nti-malarial a g e nt, st u d y part a n d treat me nt gr o u p).  

N o v arti s  
C o nfi d e nti al  
P a g e 8 4  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
All E C G data will be liste d b y eac h si n gle a nti -malarial a ge nt, st u d y part, treat me nt gr o u p, 
patie nt a n d visit/ti me, a b n or malities will be fla g ge d. S u m mar y stati stics will be pr o vi de d b y 
eac h si n gle a nti -m alarial a ge nt, st u d y part, treat me nt gr o u p, a n d visit/ti me.  
Cli ni c al l a b or at or y e v al u ati o n s  
All la b orat or y data will be liste d b y eac h si n gle a nti -malarial a ge nt, st u d y part, treat me nt gr o u p, 
patie nt, a n d visit/ti me a n d if n or mal ra n g es are a vaila ble a b n or malities will be fla g ge d. 
S u m mar y statistics will be pr o vi de d b y eac h si n gle a nti -malarial a ge nt, st u d y part, treat me nt 
gr o u p, a n d visit/ti me. S hift ta bles f or eac h si n gle a nti -malarial a ge nt a n d st u d y par t usi n g t he 
l o w/ n or mal/ hi g h classificati o n will be use d t o c o m pare bas eli ne t o t he w orst p ost-treat me nt 
val ue.  
9. 4. 3  
P h ar m a c o ki n eti c s  
T he P K a nal ysis set will be use d f or t h e p har mac o ki netics a nal yses.  
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N o v arti s  
C o nfi d e nti al  
P a g e 8 5  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
T a bl e 9 -2  
N o n -c o m p art m e nt al p h ar m a c o ki n eti c p ar a m et er s  
A U Cl a st  
T h e A U C fr o m ti m e z er o t o t h e l a st m e a s ur a bl e c o n c e ntr at i o n s a m pli n g ti m e (tl a st) 
( m a s s x ti m e x v ol u m e-1 ) 
A U Ci nf  
T h e A U C fr o m ti m e z er o t o i nfi nit y ( m a s s x ti m e x v ol u m e -1 ) 
C m a x  
T h e m a xi m u m ( p e a k) o b s er v e d pl a s m a, bl o o d, s er u m, or ot h er b o d y fl ui d dr u g 
c o n c e ntr ati o n aft er si n gl e d o s e a d mi ni str ati o n ( m a s s x v ol u m e -1 ) 
T m a x  
T h e ti m e t o r e a c h m a xi m u m ( p e a k) pl a s m a, bl o o d, s er u m, or ot h er b o d y fl ui d dr u g 
c o n c e ntr ati o n aft er si n gl e d o s e a d mi ni str ati o n (ti m e)  
L a m b d a _ z  
S m all e st ( sl o w e st) di s p o siti o n ( h y bri d) r at e c o n st a nt (ti m e -1 ) m a y al s o be u s e d f or 
t er mi n al eli mi n ati o n r at e c o n st a nt (ti m e-1 ) 
T 1/ 2  
T h e eli mi n ati o n h alf -lif e a s s o ci at e d wit h t h e t er mi n al sl o p e ( λ z) of a s e mi l o g arit h mi c 
c o n c e ntr ati o n -ti m e c ur v e (ti m e). U s e q u alifi er f or ot h er h alf-li v e s 
C L/ F  
T h e t ot al b o d y cl e ar a n c e of dr u g fr o m t h e pl a s m a ( v ol u m e x ti m e-1 ) 
V z/ F  
T h e a p p ar e nt v ol u m e of di stri b uti o n d uri n g t er mi n al p h a s e ( a s s o ci at e d wit h λ z) 
( v ol u m e) 
9. 4. 5  
P K/ P D r el ati o n s hi p s  
 
 
 
 
 
 
 
 
 
 
9. 5  
E x pl or at or y e n d p oi nt( s)/ e sti m a n d( s) a n al y si s  
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N o v arti s  
C o nfi d e nti al  
P a g e 8 6  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
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N o v arti s  
C o nfi d e nti al  
P a g e 8 7  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
9. 6  
( Ot h er) S af et y a n al y s e s 
N ot a p plica ble.  
9. 7  
I nt eri m a n al y s e s 
Data Re vie ws a n d d ose m o dificati o ns bet wee n eac h p art will be c o n d u cte d b y re vi e wi n g 
a vaila ble data as descri be d i n Sect i o n 4. 4 a n d Secti o n 6. 5 . 
I nteri m a nal yses are pl a n ne d f or t he m o nit ori n g of safet y data a n d will be perf or me d 
a p pr o xi matel y aft er eac h c o h ort d uri n g t he c o urse of t he st u d y.  
T he decisi o n t o c o nti n ue t o P art B of t he st u d y will be ma de b y t he S p o ns or  a n d t he D M C . If 
n ota ble a d vers e e ve nts or safet y c o ncer ns are f o u n d at o ne of t he pla n ne d d ose le vels i n Part A, 
t he pla n ne d d ose le v el i n Part B ma y be a dj uste d. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9. 8  
S a m pl e si z e c al c ul ati o n  
9. 8. 1  
Pri m ar y e n d p oi nt( s)  
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 8 8  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
9. 8. 2  
S e c o n d ar y e n d p oi nt( s)  
1 0  
S u p p orti n g d o c u m e nt ati o n a n d o p er ati o n al c o n si d er ati o n s  
1 0. 1  
R e g ul at or y, et hi c al, a n d st u d y o v er si g ht c o n si d er ati o n s  
1 0. 1. 1  
R e g ul at or y a n d et hi c al c o n si d er ati o n s  
T his st u d y will be c o n d ucte d i n acc or da n ce wit h t he pr ot oc ol a n d wit h t he f oll o wi n g:  
•  C o nse ns us et hical pri nci ples deri ve d fr o m i nter nati o nal g ui deli nes i ncl u di n g t he Declarati o n 
of Helsi n ki a n d C o u ncil f or I nter n ati o nal Or ga nizati o ns of Me dical Scie nces ( CI O M S) 
i nter nati o nal et hical g ui d eli nes 
•  A p plica ble I C H G o o d Cli nical Practice ( G C P) g ui deli nes  
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 8 9  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
•  A p plica ble la ws a n d re g ulati o ns  
T he pr ot oc ol, pr ot oc ol a me n d me nts, I C F, I n vesti gat or’s Br oc h ure, a n d ot her rele va nt 
d oc u me nts (e. g., a d vertise me nts) m ust be s u b mitte d t o a n I R B/I E C b y t he i n vesti gat or a n d 
re vie we d a n d a p pr o ve d b y t he I R B/I E C bef ore t he st u d y is i nitiate d. 
A n y a me n d me nts t o t he pr ot oc ol will re q uire I R B/I E C a p pr o val bef ore i m ple me ntati o n of 
c ha n ges ma de t o t he st u d y desi g n, e xce pt f or c ha n ges necess ar y t o eli mi nate a n i m me diate 
hazar d t o st u d y patie nts.  
Pr ot oc ols a n d a n y s u bst a ntial a me n d me nts/ m o dificati o ns t o t he pr ot oc ol will re q uire healt h 
a ut h orit y a p pr o val pri or t o i nitiati o n e xce pt f or c ha n ges necessar y t o el i mi nate a n i m me diat e 
hazar d t o st u d y patie nts.  
T he i n vesti gat or will be res p o nsi ble f or t he f oll o wi n g:  
•  Si g ni n g a pr ot oc ol si g nat ure pa g e c o nfir mi n g his/ her a gree me nt t o c o n d u ct t he st u d y i n 
acc or da nce wit h t hese d oc u me nts a n d all of t he i nstr ucti o ns a n d pr oce d ures f o u n d i n t his 
pr ot oc ol a n d t o gi ve access t o all rele va nt d ata a n d rec or ds t o  N o vartis m o nit ors, a u dit ors,  
N o vartis Q ualit y Ass ura nce re prese ntati ves, desi g n ate d a ge nts of N o vartis, I R Bs/I E Cs, a n d 
re g ulat or y a ut h orities as re q uire d 
•  Pr o vi di n g writt e n s u m maries of t he stat us of t he st u d y t o t he I R B/I E C a n n uall y or m or e 
fre q ue ntl y i n acc or da nce wit h t he re q uire m e nts, p olicies, a n d pr oce d ures est a blis he d b y t he 
I R B/I E C 
•  N otif yi n g t he I R B/I E C of S A Es or ot her si g nifica nt safet y fi n di n gs as re q uire d b y I R B/I E C 
pr oce d ures  
•  Pr o vi di n g o versi g ht of t he c o n d uct of t he st u d y at t he site a n d a d here nce t o re q uire me nts of 
2 1 C F R, I C H g ui deli nes, t he I R B/I E C, a n d all ot her a p plica ble l ocal re g ulati o ns  
•  I nf or m N o vartis i m me diatel y if a n i ns pecti o n of t he cli nical site is re q ueste d b y a re g ulat or y 
a ut h orit y  
T 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 Har m o nize d Tri partite G ui deli nes f or G o o d Cli nical Practice, wit h a p plica ble 
l ocal re g ulati o ns, a n d wit h t he et hical pri nci ples lai d d o w n i n t he Declarati o n of Helsi n ki.  
1 0. 1. 2  
I nf or m e d c o n s e nt pr o c e s s 
T he i n vesti gat or or his/ her re prese ntati ve will e x pl ai n t he nat ur e of t h e st u d y, i ncl u di n g t he ris ks 
a n d be nefits, t o t he patie nt or t heir le gall y a ut h orize d re prese ntati ve  a n d a ns wer all q uesti o ns 
re gar di n g t he st u d y. 
Patie nts m ust be i nf or me d t hat t heir partici pati o n is v ol u ntar y. Patie nts or t heir le gall y 
a ut h orize d re prese ntati ves will be re q uire d t o si g n a state m e nt of i nf or me d c o nse nt t hat meets 
t he re q uir e me nts of 21 C F R 5 0, l oc al re g ulati o ns, I C H g ui deli nes, pri vac y a n d data pr otecti o n 
re q uire me nts, w h ere a p plica ble, a n d t he I R B/I E C or st u d y ce nter. 
I nf or me d c o ns e nt m ust be o btai ne d bef ore c o n d ucti n g a n y st u d y-s pecific pr oce d ures (e. g., all 
of t he pr oce d ures descri b e d i n t he pr ot oc ol). T he pr ocess of o btai ni n g i nf or me d c o ns e nt m ust 
be d oc u me nte d i n t he p atie nt s o urce d oc u m e nts.  

N o v arti s  
C o nfi d e nti al  
P a g e 9 0  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
T he me dical rec or d m ust i ncl u de a state me nt t hat writte n i nf or me d c o nse nt was o btai ne d bef ore 
t he patie nt was e nr olle d i n t he st u d y a n d t he date t he writte n c o nse nt was o btai ne d. 
T he  a ut h orize d pers o n o btai ni n g t he i nf or me d c o nse nt m ust als o si g n t he I C F.  
A c o p y of t he I C F(s) m ust be pr o vi de d t o t he pati e nt or t heir le gall y a ut h orize d re prese ntati ve.  
A  patie nt  w h o is res cree n e d is n ot re q uire d t o si g n a n ot her I C F if t he rescree ni n g occ urs wit hi n 
6  h o urs fr o m t he pre vi o us I C F si g nat ure d ate. T he I C F will c o ntai n a se parate s ecti o n t hat 
a d dresses t he use of re mai ni n g 
ma n dat or y sa m ples f or o pti o nal a d diti o nal rese arc h. 
T he  in vesti gat or or a ut h orize d desi g nee will e x plai n t o eac h p atie nt t he o bjecti ves of t he 
a d diti o nal researc h. Pa tie nts will be t ol d t hat t he y are free t o ref use t o partici pate a n d ma y 
wit h dra w t heir c o nse nt at a n y ti me a n d f or a n y reas o n d uri n g t h e  st ora g e peri o d. A s e parate 
si g nat ure will be re q uire d t o d oc u me nt a p atie n t’s a gree me nt t o all o w a n y re mai ni n g s peci me ns 
t o be use d f or a d diti o nal researc h. Patie nts w h o decli ne t o partici pat e i n t his o pti o nal a d diti o nal 
researc h will d oc u me nt t his. 
Eli gi ble patie nts ma y o nl y be i ncl u de d i n t he st u d y after pr o vi di n g ( wit nesse d, w here re q uir e d 
b y la w or re g ul ati o n), I R B/I E C -a p pr o ve d i nf or m e d c o nse nt.  
If a p plica ble, i n cases w h ere t he patie nt's re prese nt ati ve(s) gi ves c o nse nt (if all o we d acc or di n g 
t o l ocal re q uire me nts), t h e patie nt m ust be i nf or me d a b o ut t he st u d y t o t he e xte nt p ossi ble gi ve n 
his/ her le vel of u n d ersta n di n g. If t he p atie nt is ca pa ble of d oi n g s o, h e/s he m ust i n dicate 
a gree m e nt b y p ers 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 o c u me nt or s e parate 
asse nt f or m.  
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 i n t h e I n v esti gat or's Br oc h ure (I B) ( or C ore Data S heet f or mar kete d dr u gs). 
T his  i nf or mati o n will be i ncl u de d i n t he patie nt i nf or me d c o ns e nt a n d s h o ul d be disc uss e d wit h 
t he patie nt u p o n o btai ni n g c o nse nt a n d als o d uri n g t he st u d y as nee de d. A n y ne w i nf or mati o n 
re gar di n g t he safet y pr ofile of t he i n vesti gati o nal dr u g t hat is i de ntifie d bet wee n I B u p dates will 
be c o m m u nicate d a s a p pr o priate, f or e xa m ple, vi a a n I n vesti gat or n otificati o n or a n a g gre gate 
safet y fi n di n g. N e 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 m e d c o nse nt a n d t he n m ust 
be disc usse d wit h t he patie 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 s t 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  
•  As a p plica ble, Pre g n a nc y O utc o mes Re p orti n g C o nse nt f or fe mal e patie nts or t he fe mal e 
part ners of a n y male p atie nts w h o t o o k st u d y treat me nt  
•  Patie nt i nf or mati o n s heet f or fe mal e part n ers of a n y male patie nt w h o t o o k st u d y treat me nt  
•  
 
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 9 1  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
1 0. 1. 3  
D at a pr ot e cti o n  
Patie nts will be assi g ne d a u ni q ue i de ntifier b y N o vartis. A n y patie nt rec or ds or datasets t hat 
are tr a nsferre d t o  N o v artis will c o ntai n t he i de ntifier o nl y; patie nt n a mes or a n y i nf or mati o n 
w hic h w o ul d ma ke t he p atie nt i de ntifia ble will n ot be tra nsferre d.  
T he patie nt m ust be i nf 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 h e le vel of discl os ure m ust als o be e x plai ne d t o 
t he patie nt w h o will be re q uire d t o gi ve c o nse nt f or t heir data t o be use d as descri be d i n t he 
i nf or me d c o nse nt. 
T he patie nt m ust be i nf or me d t hat his/ her me dical rec or ds ma y be e xa 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 re g 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 dat a breac hes 
acc or di n g t o a p plica ble pri vac y la ws.  
1 0. 1. 4  
C o m mitt e e s Str u ct ur e  
1 0. 1. 4. 1  D at a m o nit ori n g c o m mitt e e  
T his st u d y will i ncl u de a data m o nit ori n g c o m mittee ( D M C) w hic h will f u ncti o n i n de pe n de ntl y 
of all ot her i n di vi d uals ass ociate d wit h t he c o n d uct of t his cli nica l trial, i ncl u di n g t he site 
I n v esti gat ors partici pati n g i n t he st u d y. T h e D M C will re vie w t h e a v aila ble cli nical trial d ata i n 
t he f oll o wi n g sit uati o ns: 
- 
T o deci de o n t he tr a nsiti o n of a n a ge nt b et wee n st u d y Parts  
- 
Pla n ne d I As a n d u n pla n n e d I As  
- 
If st u d y st o ppi n g criteria are met  
S pecific details re g ar di n g c o m p ositi o n, res p o nsi bilities, data m o nit ori n g, meeti n g fre q u e nc y, 
a n d d oc u me ntati o n of D M C re p orts, mi n utes, a n d rec o m me n dati o ns will be descri b e d i n a 
se parat e c harter t hat is esta blis he d bet wee n N o vartis a n d t he D M C.  
1 0. 1. 5  
D at a q u alit y a s s ur a n c e  
M o nit ori n g details descri bi n g strate g y, i ncl u di n g defi niti o n of st u d y critical data ite ms a n d 
pr ocesses ( 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 ytical ris k -base d m o nit ori n g), met h o ds, res p o nsi bilities, a n d 
re q uire me nts, 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 (centr al, 
re m ote, or o n-site m o nit ori n g) are pr o vi de d i n t he m o nit ori n g pla n.  
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 ust b e 
retai ne d b y t he i n vesti g at or f or 1 5 years aft er st u d y c o m pleti o n u nless l ocal re g ulati ons 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 
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 9 2  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
rete nti o n peri o d wit h o ut t he writte n a p pr o val of N o vartis. N o rec or ds ma y be tra nsferre d t o 
a n ot her l ocati o n or p art y wit h o ut writte n n otificati o n t o N o v artis. 
1 0. 1. 5. 1  D at a c oll e cti o n  
All data s h o ul d be rec or de d, ha n dle d, a n d st ore d i n a wa y t hat all o ws its acc urate re p orti n g, 
i nter pretati o n, a n d v erific ati o n. 
Desi g nate d i n vesti gat or staff will e nter t he data re q uire d b y t he pr ot oc ol i nt o t he Electr o nic 
Case Re p or t F or ms (e C R F). T he e C R Fs h a v e bee n b uilt usi n g f ull y vali date d sec ure 
we b -e n a 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 dat a discre pa 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 (e ntere d i nt o e C R F) is 
c o m plete, acc urate, a n d t ha t e ntr y a n d u p d ates are p erf 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 nal d ata base l o c k, t he i n vesti gat or will recei ve c o pies of t he patie nt d ata f or arc hi vi n g at 
t he i n vesti gati o nal site. 
All data s h o ul d be rec or de d, ha n dle d, a n d st ore d i n a wa y t hat all o ws its acc urate re p orti n g, 
i nter pretati o n, a n d v erific ati o n. 
1 0. 1. 5. 2  D at a b a s e m a n a g e m e nt a n d q u alit y c o ntr ol  
N o vartis pers o n nel ( or d esi g nate d C R O) will re vie w t he data e ntere d b y i n vesti gati o n al staff 
f or c o m plete n ess a n d acc urac y. Electr o nic data q ueries stati n g t he nat ur e of t he pr o ble m a n d 
re q uesti n g clarificati o n will be create d f or discre pa ncies a n d missi n g val ues a n d se nt t o t he 
i n vesti gati o nal site via t he E D C s yste m. Desi g nate d i n vesti gat or site staff are re q uir e d t o 
res p o n d pr o m ptl y t o q ueries a n d t o ma ke a n y n ecessar y c ha n g es t o t he data. 
C o nc o mita nt treat me nts a n d pri or me dicati o ns e ntere d i nt o t he data bas e will be c o de d usi n g t he 
W orl d Healt h Or ga ni zati o n ( W H O) Dr u g Refere nce List, w hi c h e m pl o ys t he A nat o mical 
T hera p e utic C he mical cl assificati o n s yste m. Me dical hist or y/c urre nt me di cal c o n diti o ns a n d 
a d verse e ve nts will be c o de d usi n g t he Me dical Di cti o nar y f or Re g ulat or y Acti vities ( Me d D R A) 
ter mi n ol o g y. 
Dates of scree ni n gs, ra n d o mizat i o ns, scree n fail ures a n d st u d y c o m pleti o n, as well as 
ra n d o mizati o n c o d es a n d data a b o ut all st u d y tr eat me nt (s) dis pe nse d t o t he patie nt a n d all 
d osa ge c ha n ges will be trac ke d usi n g a n I nteracti ve Res p o nse Tec h n ol o g y (I R T). T he s yste m 
will be s u p plie d b y  a v e n d or, w h o will als o m a na ge t h e data base. T he data will be se nt 
electr o nicall y t o  N o vartis ( or a desi g nat e d C R O) at s pecific ti meli nes.  
Eac h o cc urre nce of a c o de brea k vi a 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 n al it y will re mai n a vaila ble u ntil st u d y s h ut d o w n or u p o n re q u est 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 ma de a vaila ble f or d ata a n al ysis.  A n y c ha n ges t o 

N o v arti s  
C o nfi d e nti al  
P a g e 9 3  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
t he data base after t hat ti me ca n o nl y be ma de aft er writte n a gree me nt b y N o vartis de vel o p me nt 
ma na ge me nt.  
1 0. 1. 6  
S o ur c e d o c u m e nt s  
S o urce d oc u me nts pr o vi d e e vi de nce f or t h e e xiste n ce of t he p atie nt a n d s u bsta ntiate t he i nte grit y 
of t he data c ollecte d. S o urc e d oc u m e nts are file d at t he i n vesti gat or’s site.  
Data re p orte d o n t he C R F or e nt ere d i n t he e C R F t hat are tr a nscri be d fr o m s o urce d oc u me nts 
m ust be c o nsiste nt wit h t he s o urce d oc u me nts or t he discre pa ncies m ust be e x plai ne d. 
T he  i n vesti gat or ma y nee d t o re q uest pre vi o us me dical rec or ds or tra nsfer rec or ds, de p e n di n g 
o n t he st u d y. Als o, c urre nt me dical rec or ds m ust be a vaila ble.  
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 ure a n d/ or data e ntr y. T he i n vesti gat or m ust als o kee p t he ori gi nal 
i nf or me d c o ns e nt f or m si g ne d b y t he patie nt (a si g ne d c o p y is gi ve n t o t he p atie nt). Defi niti o n of 
w hat c o nstit utes s o urce d ata a n d its ori gi n ca n b e f o u n d i n t he cli nical trial a gree m e nt.  
T he  i n vesti gat or 
m ust 
mai ntai n acc urate d oc u me ntati o n (s o urce d ata) t hat s u p p orts t he 
i nf or mati o n e ntere d i n t he C R F. St u d y m o nit ors will perf or m o n g oi n g s o urce data v erificati o n 
t o c o nfir m t hat data e ntere d i nt o t he C R F b y a ut h orize d site pers o n nel are acc urat e, c o m plete, 
a n d verifia ble fr o m s o urce d oc u me nts; t hat t he safet y a n d ri g hts of patie nts are bei n g pr otecte d; 
a n d t hat t he st u d y is bei n g c o n d ucte d i n acc or da n ce wit h t he c urre ntl y a p pr o ve d pr ot oc ol a n d 
a n y ot her st u d y a gree me nts, I C H G C P, a n d all a p pli ca ble re g ulat or y re q uir e me nts.  
Ke y st u d y pers o n n el m ust be a vaila ble t o assist t he fiel d m o nit or d uri n g t hese visits. 
C o nti n u o us  re m ote m o nit ori n g of eac h site’s data ma y be perf or me d b y a ce ntralize d N o vartis 
C R A or ga nizati o n. A d diti o nall y, a ce ntral a nal ytics or ga nizati o n ma y a n al y ze data & i de ntif y 
ris ks & tre n ds f or site o perati o nal para meters, a n d pr o vi de re p orts t o N o vartis cli nical tea ms t o 
assist wit h trial o versi g ht.  
1 0. 1. 7  
P u bli c ati o n p oli c y  
T he pr ot oc ol will be re gistere d i n a p u blicl y accessi ble d ata ba s e s uc h as cli nicaltrials. g o v . 
I n a d diti o n, after st u d y c o m pleti o n ( defi ne d as last pa tie 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 bl e 
data base of cli nica l 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 ). 
F or details o n t he  N o vartis p u blicati o n p olic y i ncl u di n g a ut h ors hi p criteria, please refer t o t he  
N o vartis p u blicati o n p olic y trai ni n g materials t hat were pr o vi de d t o y o u at t he trial i n vesti gat or 
meeti n gs.  
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.  
S u m mar y res ults of pri mar y a n d se c o n d ar y e n d p oi nts will be discl ose d base d u p o n t he gl o bal 
Last Patie nt Last Visit ( L P L V) date, si nce m ulti nati o nal st u dies are l oc ke d a n d re p orte d b ase d 
u p o n t he gl o bal L P L V.  

N o v arti s  
C o nfi d e nti al  
P a g e 9 4  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
1 0. 1. 8  
Pr ot o c ol a d h er e n c e a n d pr ot o c ol a m e n d m e nt s  
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 patie nts. A d diti o nal assess me nts re q uire d t o e ns ure safet y of patie nts s h o ul d be 
a d mi nistere d as d ee 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 be i nci de ntall y c ollecte d, t h e 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 priat e 
m o nit ori n g o n st u d y patie n ts. 
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 uir e d, it ca n n ot be i m ple me nte d.  
1 0. 1. 8. 1  Pr ot o c ol a m e n d m e nt s  
T his st u d y uses a platf or m t y pe desi g n wit h t he p ote ntial t o i n vesti gate m ulti ple t hera pies i n t he 
c o nte xt of a si n gle dise as e. Eac h ti me a n e w a g e nt is i ntr o d uce d, a g e nt -s pecific i nf or mati o n will 
be a d de d t o t he pr ot oc ol as a s u bsta ntial a me n d m e nt a n d s u b mitte d t o Healt h A ut h orities a n d 
Et hical C o m mittees, as re q uire d b y l ocal re g ulati o ns.  
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 hat are re q uire d f or patie 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 t a ke a n y i m me diate acti o n re q uire d f or t he sa fet y of a n y pati e nt i ncl u de d i n t his 
st u d y, e ve n if t his acti o n re prese nts a de viati o n fr o m t he pr ot oc ol. I n s uc h cases,  N o vartis s h o ul d 
be n otifie d of t his acti o n a n d t he I R B/I E C at t he st u d y site s h o ul d be i nf or me d acc or di n g t o 
l ocal re g ulati o ns. 

N o v arti s  
C o nfi d e nti al  
P a g e 9 5  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
1 1  
A p p e n di c e s  
1 1. 1  
A p p e n di x 1: Li v er S af et y M o nit ori n g  
Li v er s af et y m o nit ori n g  
T o e ns ure patie nt safet y a n d e n ha n ce relia bilit y i n deter mi ni n g t he he pat ot o xic p ote ntial of a n 
i n vesti gati o nal dr u g, a st a n dar dize d pr ocess f or i de ntificati o n, m o nit ori n g a n d e val uati o n of 
liver e ve nts has t o be f oll o we d.  
O nce a patie nt is e x p ose d t o st u d y treat me nt, e ver y li ver e ve nt defi ne d i n Ta ble  1 1 -1  s h o ul d be 
f oll o we d u p b y t he i n vesti gat or or desi g nate d pers o n nel at t he trial site, as s u m marize d bel o w. 
A d diti o nal details o n acti o ns re q uire d i n case of li ver e ve nts are o utli ne d i n Ta ble  1 1 -2  a n d 
Ta ble 1 1 -3 . Re p eat li ver c he mistr y tests (i.e., A L T, A S T, T B L, P T/I N R, A L P a n d G-G T) t o 
c o nfir m ele v ati o n.  
•  T hese li ver c he mistr y re peats will be p erf or me d a l ocal la b orat or y t o m o nit or t he safet y of 
t he patie nt. If a li ver e ve nt is s u bse q ue ntl y re p orte d, a n y l ocal li ver c he mistr y tests 
pre vi o usl y c o n d uct e d t hat are ass oci ate d wit h t his e ve nt s h o ul d h a ve res ults rec or de d o n t he 
a p pr o priate C R F.  
•  If t he i nitial ele vati o n is c o nfir me d, cl ose o bser vati o n of t he patie nt will be i nitiate d, 
i ncl u di n g c o nsi derati o n of treat me nt i nterr u pti o n if dee me d a p pr o priate. 
•  Disc o nti n uati o n of t he i n vesti gati o nal dr u g (refer t o Secti o n 7  Disc o nti n uati o n of st u d y 
treat me nt secti o n), if a p pr o priate 
•  H os pitalizati o n of t he pa tie nt if a p pr o priate 
•  Ca usalit y assess me nt of t he li ver e ve nt  
•  T h or o u g h f oll o w -u p of t he li ver e ve nt s h o ul d i ncl u de  
•  Base d o n i n v esti gat or’s discreti o n: ser ol o g y tests, i ma gi n g a n d p at h ol o g y assess me nts, 
he pat ol o gist’s c o ns ulta nc y; o btai ni n g m ore detaile d his t or y of s y m pt o ms a n d pri or or 
c o nc urre nt diseases, hist or y of c o nc o mita nt dr u g use, e xcl usi o n of u n derl yi n g li ver 
disease  
All f oll o w -u p i nf or mati o n a n d pr oce d ures perf or me d m ust be rec or de d as a p pr o pri ate i n t h e 
C R F.  
P ote ntial H y’s La w cases ( defi ne d as A L T or A S T > 3 × U L N a n d T otal bilir u bi n > 2 × U L N 
[ mai nl y c o nj u gate d fracti o n] wit h o ut n ota ble i ncrease i n A L P t o > 2 × U L N) nee d t o b e re p orte d 
as S A E t o N o vartis wit hi n 2 4 hrs.  

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

N o v arti s  
C o nfi d e nti al  
P a g e 9 7  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
C CI

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

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

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

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 1  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
1 2  
C o h ort S p e cifi c I nf or m ati o n  
T his  secti o n c o ntai ns details t hat pertai n t o s pecific c o h orts a n d a nti -malarial a ge nts a n d s h o ul d 
be c o nsi dere d as s u p pl e me ntar y t o i nf or m ati o n prese nte d i n t he prece di n g c ore pr ot oc ol s ecti o ns 
a n d res pecti ve I n vesti gat or Br oc h ures. If t h ere are n o treat me nt -s pecific d et ails prese nt e d f or a 
gi ve n t o pic (e. g., c o h ort - or treat me nt -s pecific eli gi bilit y criteria, st u d y restricti o ns, f o o d effects, 
etc.), t he n t he i nf or mati o n i n t he c orres p o n di n g secti o n i n t he c ore pr ot oc ol f or t hat t o pic s h o ul d 
be i m ple me nte d wit h o ut f urt her a dj ust me nt.  
1 2. 1  
C o h ort A 1: I N E 9 6 3 
 
 
1 2. 1. 1  
I N E 9 6 3 B a c k gr o u n d  
 
  
 
  
  
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 2. 1. 2  
C o h ort A 1 St u d y D e si g n  
As me nti o ne d i n Secti o n  3 , t his is a m ulti-part platf or m st u d y. Part A e val uates a nti -malarial 
a ge nts as m o n ot hera p y, a n d Part B e val uates a nti -ma larial a ge nts as c o m bi nati o n t hera p y 
I n C o h ort A 1 , p atie nts will recei ve a si n gle d ose of I N E 9 6 3. 
C CI
C CI
C CI

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

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 3  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
1 2. 1. 4  
C o h ort A 1 Ri s k s a n d B e n efit s  
I N E 9 6 3 is e x pect e d t o re d uce t he n u m ber of circ ul ati n g malaria p arasites i n t he bl o o d of patie nts 
a n d c o nse q ue ntl y i m pr o ve t heir cli nical s y m pt o ms.  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 4  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
I N E 9 6 3 I M P R el at e d Ri s k 
A gai nst t he b ac k gr o u n d of t he C O VI D -1 9 pa n d e mic, t he p ote ntial ris k of a patie nt d e vel o pi n g 
C O VI D -1 9 h as bee n c o nsi dere d i n ter ms of t he ris k -be nefit e val uati o n. T h e m o de of acti o n of 
t his a nti-malarial a ge nt h as bee n c o nsi dere d al o n gsi de a vaila ble pre -cli nical a n d cli nical d ata 
(i ncl u di n g class effects) a n d it is c o nsi dere d t hat a patie nt w o ul d n ot be at i ncrease d ris k of 
eit her bec o mi n g i nf ecte d wit h 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; 
t he vir us t hat ca uses C O VI D-1 9) or e x p erie nci n g a m ore se vere ill ness. T hat is, t h is a ge nt has 
n o k n o w n i m m u n o m o d ulat or y effect t hat w o ul d c o nfer a n i ncrease d ris k t o patie nts e nr olle d i n 
t he st u d y. 
1 2. 1. 5  
C o h ort A 1 St u d y P o p ul ati o n a n d S p e ci al R e stri cti o n s  
A d diti o n al E x cl u si o n Crit eri a  
Patie nts meeti n g a n y of t he f oll o wi n g criteria are n ot eli gi ble f or i ncl usi o n i n t his c o h ort: 
W o me n of c hil d -beari n g p ote ntial, defi ne d as all w o me n p h ysi ol o gicall y ca pa ble of bec o mi n g 
pre g na nt, u nless t he y are usi n g hi g hl y effecti ve met h o ds of c o ntrace pti o n d uri n g d osi n g a n d f or 
5  half -li ves. 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 u s ual lifest yle of t he s u bject. 
Peri o dic a bsti ne nce ( e. g.,  cale n dar, o v ulati o n, s 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 
bilateral t u bal li gati o n, fe male sterilizati o n ( ha ve ha d s ur gical bilateral 
o o p h orect o m y wit h or wit h o ut h ysterect o m y), or t otal h ysterect o m y at least si x wee ks 
bef ore ta ki n g i n vesti gati o nal dr u g. I n case of o o p h orect o m y al o ne, o nl y w he n t he 
re pr o d ucti ve stat us of t he w o ma n has bee n c o nfir me d b y f oll o w u p h or m o ne le vel 
assessme nt.  
•  Male sterilizati o n (at le ast 6 m o nt hs pri or t o s cree ni n g). F or fe male patie 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 patie nt. 
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 5  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
•  Use 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 o f 
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 n e 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 x a m ple h or m o n e va gi nal ri n g or tra ns der mal h or m o ne c o ntr ace pti o n. C oarte m/ Ria met 
ma y re d u ce t he effecti ve ness of h or m o n al c o ntr ace pti ves. T heref ore, p atie nts ra n d o mize d 
t o C oarte m usi n g oral, tra ns der mal patc h, or ot her s yste mic h or m o nal c o ntrace pti ves s h o ul d 
be a d vise d t o use a n a d diti o nal n o n -h or m o nal met h o d of birt h c o nt r ol. 
•  I n cas e of us e of oral c o ntrace pti o n, w o me 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 i n vesti gati o nal dr u g.  
1 2. 1. 5. 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 CI

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

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 7  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
C CI

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

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

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

N o v arti s  
C o nfi d e nti al  
P a g e 1 1 1  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
1 2. 2  
C o h ort B 1: I N E 9 6 3 + Ci p ar g a mi n  
C o h ort B 1 will start after t he c o m pleti o n of C o h ort A 1. C o h ort B 1 will e val uate t he us e of 
I N E 9 6 3 a n d K A E 6 0 9 (ci par ga mi n) i n c o m bi nati o n vs t he S o C ( C oarte m) i n patie nts wit h 
u nc o m plicate d P.  f alci p ar u m malaria.  
I N E 9 6 3 bac k gro u n d i nf or mati o n ca n be f o u n d i n Secti o n 1 2. 1. 1 . 
1 2. 2. 1  
Ci p ar g a mi n B a c k gr o u n d  
C i par ga mi n, a s pir oi n d ol o ne, re pres e nts a ne w class of p ote nt, fast-acti n g, sc hiz o ntici dal 
a nti-malarial. It a p pears t o e xert its a nti plas m o dial acti vi t y t hr o u g h dere g ulatati o n of Na+  
h o me ostasis i n t he parasit e c yt os ol t hr o u g h i n hi biti o n of a P -t y pe n o n S E R C A A T Pase, Pf A T P 4. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 1 2  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
1 2. 2. 2  
C o h ort B 1 St u d y D e si g n  
I n C o h ort B 1 , I N E 9 6 3 a n d ci par ga mi n  will be e val uate d as c o m bi nati o n t hera p y vs t he S o C 
( C oarte m). 
T a bl e 1 2 -9  
Tr e at m e nt Ar m( s)  f or C o h ort B 1 –  I N E 9 6 3 + Ci p ar g a mi n  
Ar m Titl e  
I N E 9 6 3 + Ci p ar g a mi n  
St a n d ar d of C ar e  
Ar m T y p e  
E x p eri m e nt al  
St a n d ar d of C ar e c o ntr ol - C o art e m  
Ar m D e s cri pti o n  
BI D f or 3 d a y s ( at t h e f oll o wi n g ti m e 
p oi nt s: 0, 8, 2 4,  3 6, 4 8, a n d 6 0 h o ur s) 
a n d m u st b e r e c ei v e d wit h a st a n d ar d 
m e al or dri n k ri c h i n f at, a s p er l a b el.  
1 2. 2. 3  
C o h ort B 1 S a m pl e Si z e  
C CI
C CI
C CI

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

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

N o v arti s  
C o nfi d e nti al  
P a g e 1 1 5  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
1 2. 2. 6  
C o h ort B 1 St u d y P o p ul ati o n a n d S p e ci al R e stri cti o n s  
A d diti o n al E x cl u si o n Crit eri a  
Patie nts meeti n g a n y of t he f oll o wi n g criteria are n ot eli gi ble f or i ncl usi o n i n t his st u d y : 
W o me n of c hil d-beari n g p ote ntial, defi ne d as all w o me n p h ysi ol o gicall y ca pa ble of bec o mi n g 
pre g na nt, u nless t he y are usi n g hi g hl y effecti ve met h o ds of c o ntrace pti o n d uri n g d osi n g a n d f or 
5  half -li ves. 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 s u bject. 
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 
bilateral t u bal li gati o n,  fe male sterilizati o n ( ha ve ha d s ur gical bilateral 
o o p h orect o m y wit h or wit h o ut h ysterect o m y), or t otal h ysterect o m y at least si x wee ks 
bef ore ta ki n g i n vesti gati o nal dr u g. I n case of o o p h orect o m y al o ne, o nl y w he n t he 
re pr o d ucti ve stat us of t he w o ma n has bee n c o nfir me d b y f oll o w u p h or m o ne le vel 
assess me nt.  
•  Male sterilizati o n (at le ast 6 m o nt hs pri or t o s cree ni n g). F or fe male patie 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 patie nt. 
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 1 6  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
•  Use 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 n e 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 x a m ple h or m o n e va gi nal ri n g or tra ns der mal h or m o ne c o ntr ace pti o n. C oarte m/ Ria met 
ma y re d u ce t he effecti ve ness of h or m o n al c o ntr ace pti ves. T heref ore, p atie nts ra n d o mize d 
t o C oarte m usi n g oral, tra ns der mal patc h, or ot her s yste mic h or m o nal c o ntrace pti ves s h o ul d 
be a d vise d t o use a n a d diti o nal n o n -h or m o nal met h o d of birt h c o ntr ol.  
•  I n cas e of us e of oral c o ntrace pti o n, w o me 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 i n vesti gati o nal dr u g.  
I n a d diti o n t o t he bel o w s pecial restricti o n(s) s p ecific to ci p ar ga mi n , t he s pecial restricti o ns 
s pecific t o I N E 9 6 3 ca n b e f o u n d i n Secti o n 1 2. 1. 5 . 
•  Patie nts are a d vise d t o use c o m m o nl y rec o m me n de d preca uti o ns w he n i n t he s u n ( e. g., 
s u nscree n, h at, pr otecti ve cl ot hi n g) fr o m first d osi n g u ntil st u d y c o m pleti o n e val uati o n.  
1 2. 2. 6. 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 CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 1 7  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
C CI

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

N o v arti s  
C o nfi d e nti al  
P a g e 1 1 9  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
1 2. 2. 8  
C o h ort B 1 P K/ P D a n d B i o m ar k er A s s e s s m e nt s 
C CI

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

N o v arti s  
C o nfi d e nti al  
P a g e 1 2 1  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
1 2. 2. 9  
C o h ort B 1 C o m p o u n d S p e cifi c A s s e s s m e nt s  
1 2. 3  
C o h ort B 2: K L U 1 5 6 + ci p ar g a mi n  
 
 
 
 
1 2. 3. 1  
K L U 1 5 6 B a c k gr o u n d  
C CI
C CI
C CI

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

N o v arti s  
C o nfi d e nti al  
P a g e 1 2 3  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
1 2. 3. 3  
C o h ort B 2 S a m pl e Si z e  
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 2 4  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
1 2. 3. 4  
C o h ort B 2 D o s e R ati o n al e  
1 2. 3. 4. 1  R ati o n al e f or c h oi c e of K A E 6 0 9 a s c o m bi n ati o n dr u g wit h K L U 1 5 6  
S el e cti o n of ci p ar g a mi n  a s p art n er dr u g wit h K L U 1 5 6  f or C o h ort B 2 : 
 
 
 
 
 
 
 
 
 
1 2. 3. 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  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 2 5  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
 
 
 
 
 
 
 
 
 
 
1 2. 3. 5  
C o h ort B 2 Ri s k s a n d B e n efit s  
Ri s k s a n d b e n efit s r el ati n g t o ci p ar g a mi n  
Ris ks a n d be nefits relati n g t o ci par ga mi n  ca n b e f o u n d i n Secti o n 1 2. 2. 5 . 
K L U 1 5 6 a n d ci p ar g a mi n  I M P R el at e d Ri s k 
A gai nst t he b ac k gr o u n d of t he C O VI D -1 9 pa n d e mic, t he p ote ntial ris k of a patie nt d e vel o pi n g 
C O VI D -1 9 h as bee n c o nsi dere d i n ter ms of t he ris k -be nefit e val uati o n. T h e m o d e of acti o n of 
t his a nti-malarial a ge nt  h as bee n c o nsi dere d al o n gsi de a vaila ble pre -cli nical a n d cli nical d ata 
(i ncl u di n g class effects) a n d it is c o nsi dere d t hat a patie nt  w o ul d n ot b e at i ncrease d ris k of 
eit her bec o mi n g i nf ecte d wit h se vere ac ute res pir at or y s y n dr o me c or o na vir us 2 ( S A R S -C o V -2; 
t he vir us t hat ca uses C O VI D-1 9) or e x p erie nci n g a m ore se vere ill ness. T hat is, t h is a ge nt has 
n o k n o w n i m m u n o m o d ulat or y effect t hat w o ul d c o nfer a n i ncrease d ris k t o patie nts e nr olle d i n 
t he st u d y. 
R el at e d Ri s k a n d B e n efit s R el at e d t o K L U 1 5 6 ( K A F 1 5 6 i. e., g a n a pl a ci d e/ L U M -
S D F i. e., l u m ef a ntri n e-S D F)  
 
 
 
 
 
 
 
 
 
  
 
 
 
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 2 6  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
 
 
 
 
Ri s k s a n d b e n efit s r el ati n g t o ci p ar g a mi n  a n d K L U 1 5 6 c o -a d mi ni str ati o n  
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 2 7  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
1 2. 3. 6  
C o h ort B 2 St u d y P o p ul ati o n a n d S p e ci al R e stri cti o n s  
A d diti o n al E x cl u si o n Crit eri a  
Patie nts meeti n g a n y of t he f oll o wi n g criteria are n ot eli gi ble f or i ncl usi o n i n t his st u d y:  
W o me n of c hil d -beari n g p ote ntial, defi ne d as all w o me n p h ysi ol o gicall y ca pa ble of bec o mi n g 
pre g na nt, u nless t he y are usi n g hi g hl y effecti ve met h o ds of c o ntrace pti o n d uri n g d osi n g a n d f or 
5 half -li ves. 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 s u bject. 
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 ntr ace pti o n.  
•  Fe male 
bilateral t u bal li gati o n, fe male sterilizati o n ( ha ve ha d s ur gical bilateral 
o o p h orect o m y wit h or wit h o ut h ysterect o m y), or t otal h ysterect o m y at least si x wee ks 
bef ore ta ki n g i n vesti gati o nal dr u g. I n case of o o p h orect o m y al o ne, o nl y w he n t he 
re pr o d ucti ve stat us of t he w o ma n has bee n c o nfir me d b y f oll o w u p h or m o ne le vel 
assess me nt.  
•  Male sterilizati o n (at le ast 6 m o nt hs pri or t o s cree ni n g). F or fe male patie 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 patie nt.  
•  Use 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 n e 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 x a m ple h or m o n e va gi nal ri n g or tra ns der mal h or m o ne c o ntr ace pti o n. C oarte m/ Ria met 
ma y re d u ce t he effecti ve ness of h or m o n al c o ntr ace pti ves. T heref ore, p atie nts ra n d o mize d 
t o C oarte m usi n g oral, tra ns der mal patc h, or ot her s yste mic h or m o nal c o ntrace pti ves s h o ul d 
be a d vise d t o use a n a d diti o nal n o n -h or m o nal met h o d of birt h c o ntr ol.  
•  I n cas e of us e of oral c o ntrace pti o n, w o me 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 i n vesti gati o nal dr u g.  
1 2. 3. 6. 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 CI

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

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

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

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

N o v arti s  
C o nfi d e nti al  
P a g e 1 3 2  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
1 2. 3. 7  
C o h ort B 2 St u d y Tr e at m e nt  
•  Patie nts s h o ul d be i nstr ucte d t o s wall o w w h ole ca ps ules a n d n ot t o c he w or o pe n t he m.  
•  Eac h s u bject's m o ut h m ust be c hec k e d t o e ns ure t hat t he me dicati o n was s wall o we d.  
•  S u bjects s h o ul d be a d mi nistere d K L U 1 5 6 u n der fe d c o n diti o ns wit h li g ht meal (esti mate of 
1 0 0 -3 0 0 cal ories, 5 -1 0 g of fat) . C i par g a mi n ca n b e a d mi nistere d irres pect i ve of f o o d i nta k e 
•  I n cas e of C oart e m, me dicati o n s h o ul d be f oll o w e d b y a n or m al diet or a dri n k ric h i n fat 
(i ncl u di n g br ot h, s weete n e d c o n de nse d mil k, etc.) wit hi n 3 0 mi n of d osi n g as per la b el. 
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 3 3  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
•  I n case t h at v o miti n g occ urs 
•  K L U 1 5 6 +  ci par g a mi n : I n t he case t hat t he patie nt v o mits wit hi n 1 h o ur  of i nta ke a re place m e nt d ose will be gi ve n t o t he patie nt a n d 
t he i n vesti gat or or d esi g nee will n otif y I R T. If t he re place me nt d os e is v o mite d , t he patie nt has t o be gi ve n C oart e m as resc u e 
me dicati o n  or a n ot her s uita ble resc u e me dicati o n as per l ocal g ui deli nes . 
•  C oarte m: I n t he case t hat t he patie nt v o mits wit hi n 1 h o ur of i nta k e a re place me nt d ose will be gi ve n t o t he patie nt a n d t he i n vesti gat or 
or desi g nee will n otif y I R T. If t h e re place me nt d ose is v o mi te d, t he patie nt has t o be gi ve n n o n-l u mefa ntri ne sta n d ar d of care. 
1 2. 3. 8  
C o h ort B 2 P K/ P D a n d Bi o m ar k er A s s e s s m e nt s  
C CI

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

N o v arti s  
C o nfi d e nti al  
P a g e 1 3 5  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
P har mac o ki netic ass ess me nts will be perf or me d as descri be d i n Secti o n 8. 7 . I n a d diti o n t o P K 
para meters me nti o ne d i n Secti o n 8. 7 , C 1 6 8 h (c o nce ntrati o n at 1 6 8 h) a n d A U C 0-1 6 8 h ( Area 
u n der t he plas ma c o nce ntrati o n ti me c ur ve fr o m zer o t o 1 6 8 h) will be deter mi ne d usi n g t he 
act ual rec or de d sa m pli n g ti mes a n d n o n -c o m part me ntal met h o d(s) wit h P h oe ni x Wi n N o nli n 
( Versi o n 6. 4 or hi g her). 
1 2. 3. 9  
C o h ort B 2 C o m p o u n d S p e cifi c A s s e s s m e nt s  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 3 6  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
1 3  
R ef er e n c e s  
Refere n ces are a vaila ble u p o n re q uest  
As hl e y E A, D h or d a M, Fair h urst R M, et al ( 2 0 1 4) S prea d of arte misi ni n resista nce i n 
Plas m o di u m falci par u m malaria. N E n gl J Me d ; 3 7 1( 5): 4 1 1-2 3.  
B urr o ws J N, D u parc S, G utteri d ge W E, et al ( 2 0 1 7) Errat u m t o: Ne w de v el o p me nts i n 
a nti-malarial tar get ca n di date a n d  pr o d uct pr ofiles. Malar J ; 1 6( 1): 1 5 1. 
D o n d or p A M, N oste n F, Yi P, et al ( 2 0 0 9) Arte misi ni n resista nce i n Plas m o di u m falci par u m 
malaria. N E n gl J Me d ; 3 6 1( 5): 4 5 5-6 7.  
 
 
F o o d a n d Dr u g A d mi nistrati o n  ( 2 0 1 6) Cli nical Tri al Desi g n C o nsi derati o ns f or Malari a Dr u g 
De vel o p me nt. htt ps:// w w w.f da. g o v/ dr u gs/ ne ws -e v e nts -h u ma n -dr u gs/cli nical -trial-desi g n -
co nsi derati o ns -malaria -dr u g -de vel o p me nt . Accesse d 2 9 -N o v -2 0 2 2 . 
 
 
 
Ha me d K, Gr ue ni n ger H ( 2 0 1 2) C oarte m( ® ): a d eca de of patie nt-ce ntri c malaria ma na g e me nt. 
E x pert Re v A nti I nfect T her ; 1 0( 6): 6 4 5-5 9.  
N oe dl H, S oc heat D, Sati mai W ( 2 0 0 9) Arte misi ni n -resista nt malaria i n Asi a. N E n gl J Me d ; 
3 6 1( 5): 5 4 0 -1.  
C CI
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 3 7  of 1 3 8  
A m e n d e d Pr ot o c ol  V er si o n N o. 0 2  (Cl e a n ) 
Pr ot o c ol N o. C A D P T 1 3 A 1 2 2 0 1  
 
U wi ma na A, Le gra n d E, St o kes B H, et al ( 2 0 2 1) A ut h or C orrecti o n: E mer ge nce a n d cl o nal 
e x pa nsi o n of i n vitr o art e misi ni n -resista nt Plas m o di u m falci par u m kelc h 1 3 R 5 6 1 H m uta nt 
parasites i n R wa n da. Nat Me d ; 2 7( 6): 1 1 1 3-5.  
 
W hite NJ, As hle y E A, R ec ht J, et al ( 2 0 1 4) Assess me nt of t hera pe utic res p o nses t o 
ga met oc yt oci dal dr u gs i n Plas m o di u m falci par u m malaria. Malar J; 1 3: 4 8 3.  
W o o dc oc k J, L a Va n g e L ( 2 0 1 7) Master Pr ot oc ols t o St u d y M ulti ple T hera pies, M ulti ple 
Diseases, or B ot h.  N E n gl J Me d; 3 7 7( 1): 6 2 -7 0.  
W orl d Healt h Or ga niz ati o n ( 2 0 1 5) G ui deli nes f or t he treat me nt of malaria. 
htt ps://a p ps. w h o.i nt/iris/ ha n dle/ 1 0 6 6 5/ 1 6 2 4 4 1 . Accesse d 1 7 -Se p -2 0 2 1 . 
W orl d Healt h Or ga niz ati o n ( 2 0 2 1) W orl d malaria re p ort 2 0 2 1 . 
htt ps: // w w w. w h o.i nt/tea ms/ gl o bal-malaria -pr o gra m me/re p orts/ w orl d -malaria -re p ort-2 0 2 1 . 
Access e d 0 8 -A pr -2 0 2 2 . 
C CI
C CI

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