Clinical trial NCT04908800
Conditions: Healthy
Sponsor: Kyorin Pharmaceutical Co.,Ltd
Start date: 2021-05-27; Completion date: 2022-04-21
Enrollment: 99 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This first-in-human study has three parts. In Parts A and B, the safety, tolerability, and pharmacokinetics (PK) will be evaluated following administration of single and multiple doses of KRP-A218, including food-effect. In Part C, the drug-drug interaction (DDI) with itraconazole will be evaluated.

Detailed description:

Arms: arm 1: Administration Route: Oral arm 2: Administration Route: Oral arm 3: Administration Route: Oral
Interventions: intervention 1: KRP-A218 intervention 2: Placebo intervention 3: itraconazole
Intervention descriptions: intervention 1: KRP-A218 tablet intervention 2: Placebo tablet intervention 3: 10 mg/mL oral solution

Protocol documents:
Prot_000.pdf: 
D oc u me nt T y pe:   
Fi nal Pr ot oc ol  
D oc u me nt Date:   
1 6 Se pte m b er 2 0 2 1 
St u d y Title:   
A First-i n- H u ma n, P hase I, D o u ble- bli n d, Place b o-c o ntr olle d, Si n gle 
a n d M ulti ple Asce n di n g Oral D ose St u d y t o E val uate t he Safet y, 
T olera bilit y, a n d P har ma c o ki netics of K R P- A 2 1 8 i n Healt h y S u bjects, 
i ncl u di n g F o o d- Effect a n d Dr u g- dr u g I nteracti o n wit h Itrac o naz ole 
Pr ot oc ol Refere nce N u m ber: K R P A 2 1 8- T 1 0 1 
N C T N u m ber:   
N C T 0 4 9 0 8 8 0 0  
 
 








Pr ot oc ol 
C O N FI D E N TI A L  
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 4 of 8 6 
R ati o n ale f or Pr ot oc ol A me n d me nts 
Versi o n 4. 0 t o Versi o n 5. 0 
T his s u bsta ntial a me n d me nt has bee n iss ue d t o ma ke t he f oll o wi n g c ha n ges:  
Pri m ar y C h a n ges:  
1. Secti o n 1. 2: A d diti o nal i nf or mati o n has bee n a d de d re gar di n g t he i n vi v o
p har mac o d y na mics of 
 a n d t he n o o bser ve d a d verse effect le vel (N O A E L )
of 
 i n mice.
2. Secti o n 1. 3: A s u m mar y of t he safet y a n d p har mac o ki netic ( P K ) data of t his o n g oi n g
P hase 1 st u d y ha ve bee n i ncl u de d i n t he S u m mar y of Cli nical E x perie nce secti o n .
3. T a ble 3:  A ne w ta ble has bee n a d de d t o prese nt P K para meter data fr o m t he c urre nt
o n g oi n g P hase 1 st u d y.
4.
Fi g ure 5: D ose le vels s pecifie d i n Part A, Gr o u p s A 4 a n d A 5, ha ve bee n u p date d
base d o n re vie w of t he safet y a n d P K data fr o m t he prece di n g c o h orts.
5. Secti o n 3. 5: T he ma xi m u m d ose le vel of  Part A has bee n i ncrease d t o 2 4  m g. T he
efficac y of 
 was deter mi ne d i n a C V-B 3 i nfecte d m o use m o del a n d was
o bser ve d t o be d ose de pe n de nt.  
s h o we d a nti viral efficac y a n d
i m pr o ve me nt of s ur vi val rate. Si g nifica nt efficac y was o bser ve d at 1, 3, a n d
1 0 m g/ k g ; h o we ver, t he pre dicte d t hera pe utic ra n ge (area u n der  t he
c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o 2 4 h o urs [A U C 0- 2 4 h]) i nitiall y selecte d was
2 7 6 t o 9 8 8 n g• h/ m L, as 9 8 8 n g• h/ m L (t he A U C0- 2 4 h at 3 m g/ k g) was l o wer t ha n t he
e x p os ure at t he N O A E L i n male rats  w hereas t he m o use e x p os ure at 1 0  m g/ k g was
hi g her t ha n t he e x p os ure at t he N O A E L i n male rats . T he ref ore, t he t hera pe utic ra n ge
i nitiall y pr o p ose d was a c o nser vati ve esti mate a n d t he o pti mal cli nical t hera pe utic
ra n ge ma y e xcee d t he A U C0- 2 4 h of 9 8 8 n g• h/ m L . C o nsi deri n g t hat t he i n dicati o n of
K R P - A 2 1 8 is h u ma n r hi n o vir us i nfecti o n wit h a hi g h ris k of pr o gressi n g t o l o wer
res pirat or y i nfecti o n or ot her se vere c o m plicati o ns, it is necessar y t o ac hie ve t he
e x pecte d e x p os ure o n t he first da y of a d mi nistrati o n. Base d o n t he mea n A U C0- 2 4 h
o bser ve d i n Gr o u ps  A 1 t o A 3 ( Part A of t his st u d y ), t he e x pecte d cli nical t hera pe utic
d ose t hat c o vers t he A U C 0- 2 4 h of 2 7 6 t o 9 8 8 n g• h/ m L o n Da y 1 is 2 t o 8 m g  (Ta ble  4).
T o c o ver t he esti mate d stea d y -state e x p os ure of 8 m g wit h a si n gle d ose i n t his st u d y,
t he mea n e x p os ure w o ul d nee d t o be a b o ve 1 7 3 0 n g• h/ m L ( mea n A U C 0- 2 4 h* R) base d
o n c urre nt h u ma n P K data. M ore o ver, c o nsi deri n g t he i n di vi d ual A U C0- 2 4 h val ues
o bser ve d i n Gr o u ps A 1 t o A 3, it has bee n ass u me d t hat t he ma xi m u m A U C 0- 2 4 h ma y
be i n t he ra n ge of a p pr o xi matel y 2-f ol d t he mea n A U C 0- 2 4 h. T heref ore, it is c o nsi dere d
reas o na ble t o set t he d ose escalati o n criteria at t he N O A E L e q ui vale nt e x p os ure
( ma xi m u m A U C0- 2 4 h of 3 9 3 0 n g• h/ m L ), w hic h is a p pr o xi matel y 2-f ol d of t he
esti mate d stea d y -state e x p os ure at 8 m g ( mea n A U C 0- 2 4 h* R of 1 7 3 0 n g• h/ m L ). I n
a d diti o n, base d o n safet y data fr o m t his o n g oi n g st u d y at d oses of 1 t o 6 m g
( Gr o u ps A 1 t o A 3), n o gastr oi ntesti nal fi n di n gs of a n y c o ncer n ha ve bee n o bser ve d.
T heref ore, i n t his P hase 1 st u d y, it is pla n ne d t o i n vesti gate hi g her d oses wit hi n t he
ra n ge u p t o t he N O A E L ( 5 m g/ k g i n male rats: ma xi m u m o bser ve d c o nce ntrati o n
[ Cma x ] 1 2 2 0 n g/ m L , A U C0- 2 4 h 3 9 3 0 n g• h/ m L) as t he ma xi m u m e x p os ure f or
i n di vi d uals. E x pl ori n g t hese hi g her d oses i n a P hase 1 st u d y will all o w a d verse e ve nts
t o be m ore cl osel y m o nit ore d t ha n i n P hase 2 or 3 st u dies. It will als o all o w t he
e x pl orat or y o bjecti ve t o  c ollect data f or c o nce ntrati o n -Q Tc a nal ysis t o be m ore
   
C CI
C CI
C CI
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 5 of 8 6 
rele va nt as acc or di n g t o re g ulat or y g ui da nce, t he Q Tc res p o nse s h o ul d be 
c haracterise d at a s ufficie ntl y hi g h m ulti ple of t h e cli nicall y rele va nt e x p os ure.  
I n a d diti o n, c o nsi deri n g t he pre dicte d ma xi m u m s yste mic e x p os ure a n d t he o bser ve d 
ma xi m u m i n di vi d ual A U C 0- 2 4 h at 6 m g i n Part A, t he hi g hest d ose is esti mate d t o be 
1 7 m g ( Ta ble  6). Re gar dless of t his esti mate, t he hi g hest d ose will be deter mi ne d 
base d o n t he re vie w of t he ma xi m u m A U C 0- 2 4 h val ue at t he pre vi o us d ose le vel; 
h o we ver, t he ma xi m u m d ose t hat will be a d mi nistere d i n Part A will n ot e xcee d 
2 4 m g, w hic h is 2-f ol d t he pre vi o us d ose le vel.  
6.  T a ble 5 : D oses f or Part A, Gr o u ps A 4 a n d A 5, ha ve bee n c ha n ge d base d o n t he sa me 
rati o nale as descri be d f or t he c ha n ges i n Secti o n 3. 5.  
7.  T a bles 4 a n d 6: T hese ta bles ha ve bee n a d de d t o prese nt t he o bser ve d a n d esti mate d 
h u ma n e x p os ures at Da y 1 a n d stea d y state. 
8.  Secti o n 3. 7:  T he P K d ose escalati o n st o p pi n g criteri o n t hat ca p pe d mea n s yste mic 
e x p os ure le vels at a C ma x  of 1 7 9 n g/ m L a n d/ or A U C 0- 2 4 h of 9 8 8 n g• h/ m L has bee n 
re m o ve d base d o n t he sa me rati o nale as descri be d f or t he c ha n ges i n Secti o n 3. 5. T he 
P K d ose escalati o n st o p pi n g criteri o n f or i n di vi d ual s yste mic e x p os ure le vels has n ot 
bee n re m o ve d.  
9.  Secti o n 5. 1: T he U nite d Ki n g d o m is n o l o n ger part of t he E ur o pea n U ni o n, s o t he 
Q ualifie d Pers o n i n t he E ur o pea n U ni o n is n o w descri be d a s a Q ualifie d Pers o n in t he 
U nite d Ki n g d o m. 
1 0.  T a ble 7:  D oses f or Part A, Gr o u ps A 4 a n d A 5, ha ve bee n c ha n ge d a n d t heref ore, t he 
n u m ber of 1 a n d 1 0 m g K R P- A 2 1 8 a n d place b o ta blets ha ve bee n u p date d t o reflect 
t he c ha n ge i n d ose le vels.  
1 1.  Secti o n 9: T he refere nce list has bee n u p date d  wit h ne w refere nces d ue t o t he ne w 
i nf or mati o n a d de d i nt o Secti o n 3. 5. 
Mi n or C h a n ges:  
1.  T hr o u g h o ut  d oc u me nt: N u m bers ha ve re place d R o ma n n u merals w he n descri bi n g 
t he p hase of a st u d y wit hi n t he pr ot oc ol b o d y a n d s y n o psis. N o c ha n ge has bee n ma de 
t o t he st u d y title.  
2.  S y n o psis:  U p date d t o reflect c ha n ges i n t he pr ot oc ol b o d y, as a p plica ble. 
3.  D ue t o re bra n di n g of C o va nce t o La bc or p Dr u g De vel o p me nt, u p dates t hr o u g h o ut t he 
pr ot oc ol ha ve be e n ma de, as a p pr o priate.  
4.  T he a me n d me nt/ versi o n n u m ber a n d date were u p date d t hr o u g h o ut t he pr ot oc ol.  
5.  Mi n or e dit orial c ha n ges.  
Versi o n 3. 0 t o Versi o n 4. 0 
T his n o ns u bsta ntial a me n d me nt has bee n iss ue d t o ma ke t he f oll o wi n g c ha n ges:  
1.  S y n o psis: clarifie d t hat  t he was h o ut peri o d f or Gr o u p A 2a will c o m prise  a n i nter val 
7 t o 1 0 da ys bet wee n d oses of K R P - A 2 1 8 ( u p t o a n d i ncl u di n g Da y - 1 of Treat me nt 
Peri o d 2). T he ma xi m u m st u d y d urati o n i n Part A was u p date d fr o m 5 1 t o 5 0 da ys.  
2.  Fi g ure 2 : t he was h o ut peri o d was u p date d t o a n i nter val of 7 t o 1 0 da ys bet wee n 
d oses ( u p t o a n d i ncl u di n g Da y - 1 of Treat me nt Peri o d 2).  
3.  Secti o n 3. 1. 1: clarifie d t hat t he was h o ut peri o d f or Gr o u p A 2 a will c o m prise a n 
i nter val of 7 t o 1 0 da ys bet wee n d oses of  K R P - A 2 1 8 ( u p t o a n d i ncl u di n g Da y - 1 of 
   


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 6 of 8 6 
Treat me nt Peri o d 2). A d diti o nall y, t he ma xi m u m st u d y d urati o n f or s u bjects i n Gr o u p 
A 2a has bee n u p date d fr o m 4 7 t o 5 0 da ys.   
4.  Secti o n 3. 4: t he i nter val bet wee n d oses of K R P- A 2 1 8 u p date d t o 7 t o 1 0 da ys. 
5.  Secti o n 7. 2. 3:  Clarifie d t hat o nl y a si n gle p har mac o ge netic sa m ple will be re q uire d 
fr o m eac h s u bject d uri n g t he c o urse of t he st u d y. 
6.  A p pe n di x 6 ( T a ble 7 : Sc he d ule of Assess me nts-P art A [ Gr o u p A 2 a; Si n gle -D ose] 
[ W as h o ut t o F oll o w-u p visit ]): t he d urati o n of t he was h o ut peri o d was u p date d t o a n 
i nter val of 7 t o 1 0 da ys bet wee n d osi n g a n d f o ot n ote r u p date d t o clarif y t hat t he 
i nter val is u p t o a n d i ncl u di n g Da y - 1 of Treat me nt Peri o d 2. 
Versi o n 2. 0 t o Versi o n 3. 0 
T his n o n s u bsta ntial a me n d me nt has bee n iss ue d t o ma ke t he f oll o wi n g c ha n ges :  
1.  St u d y I de ntific ati o n:  
has bee n a d de d as a n a d diti o nal 
Cli nical La b orat or y f or t he meas ure me nt of faecal cal pr otecti n , c o n d uct of t he faecal 
occ ult bl o o d test , a n d as a D N A ba n ki n g facilit y. 
 has bee n a d de d as a n 
electr ocar di o gra m ( E C G ) ve n d or. 
2.  Secti o n 4. 2:  a d diti o n of a n e xcl usi o n criteri o n ( # 3 2) t o e xcl u de s u bjects t hat ha ve 
recei ve d or pla n t o recei ve a C or o na vir us Disease 2 0 1 9 ( C O VI D 1 9) vacci ne wit hi n 
2 8 da ys pri or t o d osi n g u ntil after t he f oll o w- u p visit. 
3.  A p pe n di x 1: t he seri o us a d verse e ve nt re p orti n g secti o n has bee n u p date d f or 
c o nsiste nc y wit h t he St u d y Ma na ge me nt Pla n.  
4.  A p pe n di x 6 ( T a ble 6: Sc he d ule of Assess me nts -P art A  [ Gr o u ps A 1, A 2 b, a n d A 3 
t o A 5; Si n gle-D ose] a n d T a ble 7: Sc he d ule of Assess me nts - P art A [ Gr o u p A 2 a; 
Si n gle -D ose] ): clarifie d t hat a c o nti n u o us 1 2-lea d E C G will be o btai ne d fr o m 2 h o urs 
pre d ose a n d t he ti me p oi nts f or c o nti n u o us E C G m o nit ori n g ha ve bee n a d de d t o 
f o ot n ote g f or Ta ble 6 a n d f o ot n ote d f or Ta ble 7. A d diti o nall y, it has bee n clarifie d i n 
t hese f o ot n otes t hat s u bjects s h o ul d be resti n g i n a s u pi ne or se mi-rec u m be nt p ositi o n 
d uri n g t h ese m o nit ori n g peri o ds. 
Versi o n 1. 0 t o Versi o n 2. 0 
I n t he C V-B 3 -i nfecte d m o use m o del,  
 has s h o w n si g nifica nt a ntiviral  efficac y i n a 
d ose de pe n de nt ma n ner fr o m 1 t o 1 0 m g/ k g a n d si g nifica ntl y i m pr o ve d t he s ur vi val rate o ver 
3 m g/ k g. I n t he t o xic ol o gical st u d y, t he N O A E L i n male rat was < 5 m g/ k g. T heref ore, t he 
cli nical t hera pe utic ra n ge has bee n set as 4. 9 t o 1 4. 6 m g/s u bject base d o n t he H E D calc ulate d 
fr o m effecti ve d ose ra n ge i n m o use fr o m 1 t o 3 m g/ k g, c o nsi deri n g t he c urre nt N O A E L i n t he 
rat.  
At t he re q u est of t he Me dici nes a n d He alt hc are pr o d ucts Re g ul at or y A ge nc y ( M H R A), 
t he pri m ar y c h a n ges i n t his a me n d me nt are: 
1.  Secti o n 3. 1. 1: it has bee n clarifie d t hat t he was h o ut peri o d i n Gr o u p A 2a ma y be 
e xte n de d base d o n t he o bser ve d t 1/ 2 of 
 I n a d diti o n, it has bee n clarifie d 
   
C CI
C CI
C CI
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 7 of 8 6 
t hat t he f oll o w-u p peri o d i n Part A ma y als o be e xte n de d base d o n t he o bser ve d t 1/ 2 of 
 
2.  Secti o n 3. 1. 2: it has bee n clarifie d t hat t he f oll o w- u p peri o d i n Part B ma y be 
e xte n de d base d o n t he o bser ve d t 1/ 2 of 
 
3.  Secti o n 3. 1. 3: it has bee n clarifie d t hat t he i nter val bet wee n t he first d ose of 
K R P - A 2 1 8 a n d first d ose of itrac o naz ole ma y be e xte n de d de pe n di n g o n t he o bser ve d 
t1/ 2 of 
 I n a d diti o n, it has bee n clarifie d t hat t he f oll o w- u p peri o d i n Part C 
ma y als o be e xte n de d base d o n t he o bser ve d t 1/ 2 of 
 
4.  Se cti o n 3. 4: it has bee n clarifie d t hat t he was h o ut peri o d i n Gr o u p A 2 ma y be 
e xte n de d base d o n t he o bser ve d t 1/ 2 of 
 
5.  Secti o n 3. 5 : t he ma xi m u m a bs ol ute cli nical d ose t o be use d i n Part A has bee n 
u p date d t o 1 5 m g, a n d rati o nale has bee n pr o vi de d a p pr o priatel y. 
6.  Secti o n 3. 7:  d ose escalati o n st o p pi n g criteri a were u p date d t o  i ncl u de t he u p per li mit 
of t he pre dicte d t hera pe utic ra n ge. 
7.  A p pe n di x 4 : u p date d t o e xcl u de d o u ble -barrier met h o ds as acce pta ble c o ntrace pti ve 
met h o ds. 
8.  Fi g ure s 1, 2, 3, a n d 4, a n d A p pe n di x 6 : f o ot n otes ha ve bee n a d de d t o reflect t he 
c ha n ges t o t he st u d y desi g n a b o ut t he ti mi n gs of t he was h o ut peri o d i n Part A, i nter val 
bet wee n t he first d ose of K R P - A 2 1 8 a n d first d ose of itrac o naz ole i n Part C, a n d 
f oll o w- u p visits f or all st u d y parts t hat will n o w de pe n d o n t he o bser ve d t1/ 2 of 
 as a p pr o priate.  
9.  T hr o u g h o ut: Gr o u p A 6 has bee n re m o ve d fr o m Part A of t he st u d y,  d ue t o t he 
c ha n ge i n t he ma xi m u m a bs ol ute cli nical d ose t o be use d i n Part A. A n y refere nce t o 
Gr o u p A 6 has t heref ore n o w bee n re place d b y Gr o u p A 5, as t his will n o w be t he fi nal 
d osi n g gr o u p i n Part A of t he st u d y.  
Mi n or c h a n ges:  
1 0.  T he s y n o psis was u p date d acc or di n g t o t he pr ot oc ol b o d y, as a p plica ble.  
1 1.  T he a me n d me nt/ versi o n n u m ber a n d date were u p date d t hr o u g h o ut t he pr ot o c ol. 
 
 
   
C CI
C CI
C CI
C CI
C CI
C CI
C CI






Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 1 0 of 8 6 
S Y N O P SI S  
Title o f S t u d y: 
A First -i n-H u ma n, P hase I, D o u ble-bli n d, Place b o -c o ntr olle d, Si n gle a n d M ulti ple Asce n di n g Oral D ose 
St u d y t o E val uate t he Safet y, T olera bilit y, a n d P har mac o ki netics of K R P -A 2 1 8 i n Healt h y S u bjects, i ncl u di n g 
F o o d -Effect a n d Dr u g -dr u g I nter acti o n wit h Itrac o naz ole. 
O bjecti ves:  
Si n gle a n d M ulti ple Asce n di n g D ose St u d y ( P arts A a n d B):  
T he pri mar y o bjecti ve is:  
•  
t o e val uate t he safet y a n d t olera bilit y of si n gle a n d m ulti ple oral d oses of K R P-A 2 1 8 i n healt h y 
s u bjects. 
T he sec o n dar y o bjecti ves are: 
•  
to assess  t he p har mac o ki netics (P K ) of 
(t he acti ve i n gre die nt of K R P -A 2 1 8)  f oll o wi n g 
si n gle a n d m ulti ple oral d oses of K R P-A 2 1 8 i n healt h y s u bjects . 
•  
t o assess t he effect of f o o d o n t he P K of 
f oll o wi n g a si n gle oral d ose of K R P-A 2 1 8 i n 
healt h y male s u bjects.  
•  
t o assess t he effect of se x o n t he P K of 
 f oll o wi n g a si n gle oral d ose of K R P-A 2 1 8.  
T he e x p l orat or y o bjecti ves are: 
•  
t o e x pl ore bl o o d a n d uri ne sa m ples f or t he meta b olite pr ofiles of 
 f oll o wi n g si n gle a n d 
m ulti ple oral d oses of K R P -A 2 1 8 i n healt h y male s u bjects.  
•  
t o e x pl ore faecal sa m ples f or t he meta b olite pr ofiles f oll o wi n g a si n gle oral d ose of K R P-A 2 1 8 i n 
healt h y male s u bjects.  
•  
t o e x pl ore bl o o d a n d uri ne sa m ples f or p har mac o d y na mic  bi o mar ker s. 
•  
t o e x pl ore a p ote ntial effect of K R P-A 2 1 8 o n p h os p h oli pi d - C i n ser u m a n d faecal cal pr otecti n. 
•  
t o c ollect bl o o d sa m ples f or p ote ntial p har mac o ge netic a nal y ses. 
•  
t o c ollect c o nti n u o us E C G wa vef or ms f or c o nce ntrati o n -Q Tc a nal ysis, f oll o wi n g si n gle oral d oses of 
K R P -A 2 1 8 i n healt h y s u bjects  ( Part A o nl y). 
Dr u g -dr u g I nter acti o n St u d y ( P art C):  
T he pri mar y o bjecti ve is:  
•  
t o assess t he effect of m ulti ple d oses of itrac o naz ole (c yt oc hr o me P 4 5 0 3 A 4  i n hi bit or) o n t he si n gle -
d ose P K of 
 i n healt h y male s u bjects. 
T he sec o n dar y o bjecti ves are:  
•  
t o assess t he safet y a n d t olera bilit y of si n gle oral d oses of K R P-A 2 1 8 w he n c o -a d mi nistere d wit h 
m ulti ple oral d oses of itrac o naz ole i n healt h y male s u bjects. 
•  
 t o assess t he P K of itrac o naz ole a n d its meta b olite h y dr o x y -itrac o naz ole w he n c o -a d mi nistere d wit h 
K R P -A 2 1 8 i n healt h y male s u bjects.  
T he e x pl orat or y o bjecti ve s are: 
•  
 t o e x pl ore bl o o d sa m ples f or t he meta b olite pr ofiles of 
a d mi nistere d K R P -A 2 1 8 al o ne 
a n d w he n c o -a d mi nistere d wit h itrac o naz ole i n healt h y male s u bjects. 
•  
t o e x plore a p ote ntial effect of K R P -A 2 1 8 o n p h os p h oli pi d - C i n ser u m a n d faecal cal pr otecti n. 
•  
t o c ollect bl o o d sa m ples f or p ote ntial p har mac o ge netic a nal yses. 
 
  
C CI
C CI
C CI
C CI
C CI
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 1 1 of 8 6 
St u d y D esi g n: 
T his P hase 1 st u d y will c o nsist of 3 parts, Parts A, B, a n d C.  
Part A  will c o m prise a d o u ble -bli n d, ra n d o mi se d, place b o -c o ntr olle d, si n gle -d ose, se q ue ntial -gr o u p, 
escalati n g -d ose desi g n, e nr olli n g healt h y male a n d fe male s u bjects (fe male s u bjects i n G r o u p A 2 b o nl y). Part 
A will i ncl u de a se x -effect (Gr o u ps A 2a a n d A 2 b ) w hic h will i n vesti g ate t he effect of se x o n P K of 
b y c o m pari n g P K para meters f oll o wi n g d osi n g i n fe males vers us d osi n g i n males. Part A will als o 
i ncl u de a f o o d-effect Gr o u p A 2a w hic h will be a 2 -peri o d ar m t o i n vesti gate t he effect of f o o d o n P K of 
 b y c o m p ari n g P K para meters f oll o wi n g d osi n g i n fe d c o n diti o ns vers us d osi n g i n faste d 
c o n diti o ns.  
Part B will c o m prise a d o u ble -bli n d, ra n d o mi se d, place b o -c o ntr olle d, m ulti ple -d ose, se q ue ntial -gr o u p, 
escalati n g -d ose desi g n, e nr olli n g healt h y male s u bjects.  
Part  C wil l c o m prise a n o pe n-la bel, fi xe d-se q ue nce, e nr olli n g healt h y male s u bjects t o i n vesti gate t he effect of 
m ulti ple oral d oses of itrac o naz ole o n t he si n gle oral d ose P K of 
 i n healt h y s u bjects. 
P art A:  
T here will be 5 gr o u ps, of w hic h 4 will c o m prise male s u bjects, 1 will c o m prise male a n d fe male s u bjects.  
O verall, 4 8 s u bjects will be st u die d i n 5 gr o u ps ( Gr o u ps A 1 t o A 5 ); Gr o u ps A 1, a n d A 3 t o A 5 will c o nsist of 
8 male  s u bjects, a n d Gr o u p A 2 will c o nsist of 1 6 s u bjects s plit i nt o 2 s u b gr o u ps (Gr o u p A 2a [ male s u bjects 
o nl y] a n d Gr o u p A 2 b [fe male s u bjects o nl y]) t hat will c o nsist of 8 s u bjects eac h.  
P ote nt ial s u bjects will be scree ne d t o assess t heir eli gi bilit y t o e nter t he st u d y wit hi n 2 8 da ys pri or t o t he first 
d ose a d mi nistr ati o n. Eac h s u bject will partici pate i n 1 treat me nt peri o d o nl y, e xce pt f or Gr o u p A 2a, w here 
eac h s u bject will partici pate i n 2 treat me nt peri o ds w here d oses of K R P -A 2 1 8 will be se parate d b y an i nter val  
of 7 t o 1 0  da ys  ( u p t o a nd i ncl u di n g Da y -1 of Treat me nt Peri o d 2) . T he was h o ut peri o d ma y be e xte n de d 
de pe n di n g o n  t he o bser ve d a p pare nt ter mi nal eli mi nati o n half -life (t1/ 2) of 
. S u bjects will resi de at 
t he st u d y site fr o m Da y -1 (t he da y bef ore d osi n g) t o Da y  4 of eac h treat me nt peri o d.  
All s u bjects will ret ur n f or a f oll o w-u p visit 7 t o 1 0 da ys after t heir fi nal d ose.  T he f oll o w -u p peri o d ma y be 
e xte n de d de pe n di n g o n  t he o bser ve d t1/ 2 of 
 I n eac h of Gr o u ps A 1, A 2a, A 2 b, a n d A 3 t o A 5 , 6 
s u bjects will recei ve K R P-A 2 1 8 a n d 2 s u bjects will recei ve place b o. I n Gr o u ps A 1, A 2 b, a n d A 3 t o A 5 , all 
d oses will be a d mi nistere d i n t he faste d state o n t he m or ni n g of Da y 1. F or Gr o u p A 2a, Peri o d 1, Da y 1 d oses 
will be a d mi nistere d i n t he faste d state a n d Peri o d 2, Da y 1 d oses b e will be gi ve n 3 0 mi n utes after starti n g a 
sta n dar d hi g h-fat brea kfast. Eac h s u bject i n Gr o u ps A 1, A 2 b, a n d A 3 t o A 5 will recei ve o nl y a si n gle d ose of 
K R P -A 2 1 8 or place b o d uri n g t he st u d y. I n Gr o u p A 2a, s u bjects will ha ve t he sa me treat me nt i n b ot h peri o ds, 
s uc h t hat eac h s u bject will recei ve 2 si n gle d oses of K R P-A 2 1 8 or place b o d uri n g t he st u d y.  
All gr o u ps i n Part A ( wit h t he e xce pti o n of Gr o u p A 2a i n Treat me nt Peri o d 2) will recei ve t he i n vesti gati o nal 
me dici nal pr o d uct (I M P) usi n g a se nti nel a p pr oac h . F or eac h gr o u p, 2 s u bjects ( 1 K R P -A 2 1 8 a n d 1 place b o) 
will recei ve t he I M P at least 2 4 h o urs bef ore t he re mai ni n g s u bjects.  
 
  
C CI
C CI
C CI
C CI
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 1 2 of 8 6 
P art B:  
T here will be 4 gr o u ps, c o nsisti n g of male s u bjects. Part B ma y o verla p wit h Part A.  
O verall, 4 0 s u bjects will be st u die d i n 4 gr o u ps ( Gr o u ps B 1 t o B 4), wit h eac h gr o u p c o nsisti n g of 1 0 male 
s u bjects. Part B ma y start after c o m pleti o n of Gr o u p A 3, at d ose e q ual t o or less t ha n gi ve n i n Gr o u ps A 1 t o 
A 3.  
P ote ntial s u bjects will be scree ne d t o assess t heir eli gi bilit y t o e nter t he st u d y wit hi n 2 8 da ys pri or t o t he first 
d ose a d mi nistr ati o n. Eac h s u bject will partici pate i n 1 treat me nt peri o d o nl y a n d resi de at t he cli nical researc h 
u nit ( C R U ) fr o m Da y -1 (t he da y bef ore d osi n g) u ntil t he m or ni n g of Da y 1 7 (f oll o wi n g assess me nts at 7 2 
h o urs after fi nal d osi n g).  
All s u bjects will ret ur n f or a f oll o w -u p visit 7 t o 1 0 da ys after t heir fi nal d ose. T he f oll o w -u p peri o d ma y be 
e xte n de d de pe n di n g o n  t he o bser ve d t1/ 2 of 
 I n eac h of Gr o u ps B 1 t o B 4, 8 s u bjects will recei ve 
K R P -A 2 1 8 a n d 2 s u bjects will recei ve place b o  i n acc or da nce wit h a ra n d o misati o n sc he d ule. T he dietar y state 
f or d osi n g i n Part B will be s u bject t o re vie w of t he P K data fr o m t he fe d/faste d c o m paris o n i n Part A. F or all 
s u bjects, d osi n g will occ ur o n  Da ys 1 t o 1 4 . T he pla n ne d d osi n g fre q ue nc y is o nce per da y, h o we ver t he 
d osi n g fre q ue nc y i n Part B ma y be c ha n ge d f oll o wi n g re vie w of data fr o m gr o u ps i n Part A . O n Da y 1 4, t he 
last d ose will be t he m or ni n g d ose re gar dless of t he d osi n g fre q ue nc y ( Q D, BI D, TI D).  
T he t otal dail y d ose a d mi nistere d will n ot e xcee d a n e x p os ure s h o w n t o be safe a n d well t olerate d i n Part A. 
All gr o u ps i n Part B will recei ve t he  I M P usi n g a se nti nel a p pr oac h. F or eac h gr o u p, 2 s u bjects ( 1 K R P -A 2 1 8 
a n d 1 place b o) will recei ve t he I M P at least 7 da ys bef ore t he re mai ni n g s u bjects.  
P art C:  
T here will be 1 gr o u p, wit h Gr o u p C 1 c o nsisti n g of 1 2 male s u bjects. Part C will start after c o m pleti o n of 
bli n de d safet y, t olera bilit y, a n d P K data re vie w i n Part A. All  s u bjects will recei ve eac h of t he f oll o wi n g 
treat me nts: 
•  
Da ys 1 a n d 1 1: si n gle oral d ose of K R P -A 2 1 8  
•  
Da y 4: 2 × si n gle oral d oses of 2 0 0 m g itrac o naz ole, a p pr o xi matel y 1 2 h o urs a part  
•  
Da ys 5 t o 1 3: si n gle oral d oses of 2 0 0 m g itrac o naz ole  
T he st u d y  da ys of d osi n g of itrac o naz ole a n d K R P -A 2 1 8 ma y be a me n de d t o e xte n d t he  i nter val bet wee n t he 
first d ose of K R P-A 2 1 8 a n d t he first d ose of itrac o naz ole  de pe n di n g o n  t he o bser ve d t1/ 2 of 
 
P ote nt ial s u bjects will be scree ne d t o assess t heir eli gi bilit y t o enter t he st u d y wit hi n 2 8 da ys pri or t o t he first 
d ose a d mi nistr ati o n. S u bjects will be a d mitte d i nt o t he st u d y site o n Da y -1 a n d be c o nfi ne d t o t he st u d y site 
u ntil disc har ge o n Da y 1 4.  
S u bjec ts will ret ur n t o t he st u d y site f or a f oll o w-u p visit 7 t o 1 0 da ys after t he last d ose  of K R P -A 2 1 8 . T he 
f oll o w-u p peri o d ma y be e xte n de d de pe n di n g o n  t he o bser ve d t1/ 2 of 
. 
T he di etar y state f or d osi n g of K R P -A 2 1 8 al o ne o n Da y 1 a n d K R P -A 2 1 8 c o -a d mi nistere d wit h itrac o naz ole 
o n Da y 1 1 will be deter mi ne d b y c o m pari n g t he P K data bet wee n fe d a n d faste d state i n Gr o u p A 2 a. 
Itrac o naz ole o n Da ys 4 t o 1 0, 1 2 a n d 1 3 will be a d mi nistere d i n t he faste d state. O n Da y 1 1, if it is deter mi ne d 
t hat K R P-A 2 1 8 will be d ose d i n t he faste d state, t he n K R P -A 2 1 8 will be a d mi nis tere d first a n d itrac o naz ole 
will be a d mi nistere d sec o n d. If it is deter mi ne d t hat K R P -A 2 1 8 will be d ose d i n t he fe d state, t he n 
itrac o naz ole will be d ose d first; s u bjects will t he n recei ve brea kfast at a p pr o xi matel y 1 h o ur p ost itrac o naz ole 
d ose, a n d K R P -A 2 1 8 will be d ose d sec o n d f oll o wi n g brea kfast.  T he d ose le vel of K R P -A 2 1 8 will be 
c o nfir me d base d o n t he a vaila ble safet y, t olera bilit y, a n d P K data i n prece di n g Part s A a n d/ or B of t he st u d y.  
N u m ber o f S u bjects:  
Part A: 4 0 male s u bjects a n d 8 fe male s u bjects  will be st u die d i n 5 gr o u ps . 
Part B: 4 0 male s u bjects will be st u die d i n 4 gr o u ps . 
Part C: 1 2  male s u bjects will be st u die d i n 1 gr o u p . 
Di a g n osis a n d M ai n C riteri a for Incl usi o n:  
Healt h y male a n d fe male s u bjects a ge d bet wee n 2 0  a n d 5 5  years  (i ncl usi ve). 
 
  
C CI
C CI
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 1 3 of 8 6 
I n vesti g ati o n al Pr o d uct s, D ose , An d M o de o f A d mi nistr ati o n  Ro ute : 
Test P r o d ucts:  K R P - A2 1 8  1 m g ta blet, a n d 1 0 m g ta blet 
Pr o p ose d D ose L e vels:  
Part  A: M ales: 1, 3  (faste d/fe d), 6, 1 2 , a n d a ma xi m u m d ose of 2 4  m g  of K R P -A 2 1 8  
Fe males: 3 m g of K R P -A 2 1 8  
Part  B: M ales: X , X, X, a n d X m g of K R P -A 2 1 8 ( o ver a peri o d of 1 4 da ys)  
Part C: Males: X m g of K R P -A 2 1 8 ( o nce o n Da ys 1 a n d 1 1)  
A d mi nistr ati o n R o ute:  Oral 
Refere nce P r o d uct a n d M o de of A d mi nistr ati o n  Ro ute ( P arts A a n d B) : 
Refere nce P r o d uct:  place b o ta blet 
A d mi nistr ati o n R o ute:  Oral 
C o nc o mit a nt Dr u g, D ose Le vel, a n d A d mi nistr ati o n r o ute ( P art C):  
C o nc o mit a nt Dr u g: itrac o naz ole 1 0 m g/ m L oral s ol uti o n 
Pr o p ose d D ose Le vel:  2 0 0  t o 4 0 0 m g of itrac o naz ole ( 2 0 0 m g t wice o n Da y 4 a n d 2 0 0 m g o nce dail y o n 
Da ys 5 t o 1 3)  
A d mi nistr ati o n R o ute: Oral  
D ur ati o n of S u bject P artici p ati o n i n t he S t u d y: 
Pl a n ne d Scree ni n g D ur ati o n:  u p t o 2 7 da y s. 
Pl a n ne d S t u d y D ur ati o n ( Scree ni n g t o F oll o w -u p):  
Pa rt A: u p t o 3 9 da ys, or u p t o 5 0  da ys  f or f o o d-effect e val uati o n.  
Part B : u p t o 5 2  da ys.  
Part C:  u p t o 4 9  da ys.  
E n d p oi nts : 
S afet y:  
A d verse e ve nts, b o d y wei g ht , cli nical la b orat or y e val uati o ns ( hae mat ol o g y , cli nical c he mistr y [ wit h t he 
e xce pti o n of p h os p h oli pi d -C] , uri nal ysis, c oa g ulati o n, faecal occ ult bl o o d ), 1 2-lea d E C G para meters , vital 
si g ns (bl o o d press ure, p ulse rate, res pirat or y rate, a n d oral b o d y te m perat ure ), Brist ol St o ol C hart,  a n d 
p h ysical e xa mi nati o ns.  
P h ar m ac o ki netics:  
Bl o o d s a m ples will be c ollecte d f or t he a nal ysis of plas ma c o nce ntrati o ns of 
, itrac o naz ole, a n d 
h y dr o x y -itrac o naz ole. P har mac o ki netic pa ra meters will be deri ve d b y n o nc o m part me ntal a nal ysis. 
F or Part s A a n d C, t he P K para meters deri ve d fr o m plas ma c o nce ntrati o ns of  
will i ncl u de : area 
u n der t he c o nce ntrati o n -ti me c ur ve ( A U C) fr o m ti me 0 t o t he ti me of t he last q ua ntifia ble c o nce ntrati o n 
( A U C0-tlast),A U C fr o m ti me 0 e xtra p olate d  t o i nfi nit y (A U C 0- ∞), ma xi m u m o bser ve d c o nce ntrati o n ( Cma x ), 
ti me of t he ma xi m u m o bser ve d c o nce ntrati o n (tma x ), t1/ 2, a p pare nt t otal cleara nce (C L/ F) , a n d a p pare nt v ol u me 
of distri b uti o n  d uri n g t he ter mi nal p hase  ( Vz/ F). 
F or  Part B, t he P K para meters of 
will i ncl u de: A U C 0- ∞, A U C o ver a  d osi n g i nter val ( A U C 0- τ), 
A U C 0- tlast, C ma x , mi ni m u m o bser ve d c o nce ntrati o n ( Cmi n ), tma x , t1/ 2, C L/ F, Vz/ F, o bser ve d acc u m ulati o n rati o 
base d o n A U C 0- τ (A R A U C 0- τ), a n d o bser ve d acc u m ulati o n rati o base d o n Cma x  d uri n g t he d osi n g i nter val 
( AR C ma x ). 
F or Part  C,  t he P K para meters deri ve d fr o m plas ma c o nce ntrati o ns  of itrac o naz ole a n d h y dr o x y -itrac o naz ole 
will i ncl u de:  A U C 0- τ, C ma x , a n d tma x  
Ot her  P K para meters ma y als o be a d de d.  
 
  
C CI
C CI
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 1 4 of 8 6 
E x pl or at or y:  
Met a b olite Pr ofili n g:  
Bl o o d, uri ne, a n d faecal sa m ples will be c ollecte d fr o m 2 gr o u ps of male s u bjects i n Part A, bl o o d a n d uri ne 
sa m ples will be c ollecte d fr o m 1 gr o u p i n Part B, a n d bl o o d sa m ples will be c ollecte d fr o m 1 gr o u p i n Part C . 
P h ar m ac o ge netic A n al ys is: 
Bl o o d sa m ples will be c ollecte d fr o m all s u bjects i n Parts A t o C.  
Bi o m ar ker A n al ys is: 
T he a nal ysis will be perf or me d o n  resi d ual bl o o d a n d uri ne sa m ples of e x pl orat or y meta b olite pr ofili n g 
a nal ysis  i n Parts A a n d B. 
P h os p h oli pi d -C a n d F aec al C al pr otecti n A n al ysis : 
E x pl orat or y a nal ysis of p h os p h oli pi d -C i n ser u m a n d faecal cal pr otecti n will be perf or me d o n bl o o d sa m ples 
ta ke n f or safet y cli nical la b orat or y assess me nts a n d resi d ual sa m ples ta ke n f or faecal occ ult bl o o d tests, 
res pecti vel y i n Parts A t o C. 
C o nce ntr ati o n -Q Tc A n al ysis : 
C o nti n u o us E C G wa vef or ms will be c ollecte d a n d st ore d i n Part A (e xce pt Peri o d 2 [fe d state]  i n t he 
f o o d-effect ar m). 
St atistic al met h o ds:  
P h ar m ac o ki netics:  
I n di vi d ual plas ma c o nce ntrati o ns a n d P K para meters of 
will be liste d a n d s u m mari se d usi n g  
descri pti ve statistics.  I n di vi d ual a n d mea n c o nce ntrati o n-ti me pr ofiles f or 
will be prese nte d 
gra p hicall y.  W here data are a vaila ble, 
 d ose pr o p orti o nalit y will be e xa mi ne d acr oss t he d ose 
gr o u ps. T he P K para meters will be a nal y se d f or d ose pr o p orti o nalit y usi n g a p o wer m o del a p pr oac h a n d/ or 
a nal ysis of varia nce ( A N O V A) m o del as a p pr o priate.  W here data are a vaila ble, t he effects of f o o d at 1 d ose 
le vel i n Part A, a n d t he assess me nt of t he effect of c o-a d mi nistrati o n  of itrac o naz ole o n t he P K of 
 
i n Part C will be i n vesti gate d usi n g mi xe d -m o del; t he effect of se x at 1 d ose le vel i n Part A will be 
i n vesti gate d usi n g A N O V A. I n di vi d ual plas ma c o nce ntrati o ns a n d P K para meters of itrac o naz ole a n d 
h y dr o x y -itrac o naz ole will be liste d a n d s u m mari se d usi n g descri pti ve statistics.  I n di vi d ual a n d mea n 
c o nce ntrati o n -ti me pr ofiles f or itrac o naz ole a n d h y dr o x y -itrac o naz ole will be prese nte d gra p hicall y.  
S afet y:  
S afet y para meters will be liste d a n d s u m mari se d usi n g descri pti ve statistics. N o f or mal statistical a nal ysis of 
safet y data is pla n ne d. 
E x pl or at or y:  
Data ass ociate d wit h t he e x pl orat or y meta b olite pr ofili n g, bi o mar ker a nal ysis, p har mac o ge netic a nal ysis, a n d 
c o nce ntrati o n -Q Tc a nal ysis will be re p orte d else w here.  
Data ass ociate d wit h p h os p h oli pi d -C a n d faecal cal pr otecti n will be re p orte d i n t he Cli nical St u d y Re p ort 
(C S R ). 
 
  
C CI
C CI
C CI
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 1 5 of 8 6 
T A B L E O F C O N T E N T S  
TI T L E P A G E  ............................................................................................................................. 1 
S P O N S O R A P P R O V A L  ........................................................................................................... 2 
I N V E S TI G A T O R A G R E EM E N T ............................................................................................. 3 
S T U D Y I D E N TI FI C A TI O N  ..................................................................................................... 8 
S Y N O P SI S  ............................................................................................................................... 1 0 
T A B L E O F C O N T E N T S  ......................................................................................................... 1 5 
LI S T O F T A B L E S A N D F I G U R E S........................................................................................ 1 7 
LI S T O F A B B R E VI A TI O N S  .................................................................................................. 1 9 
1.
I N T R O D U C TI O N ........................................................................................................... 2 2 
1. 1.  
Bac k gr o u n d ............................................................................................................ 2 2  
1. 2.  
N o ncli nical De vel o p me nt ...................................................................................... 2 3  
1. 3.  
S u m mar y of Cli nical E x perie nce  ........................................................................... 2 5 
1. 4.  
St u d y Rati o nale ...................................................................................................... 2 6  
1. 5.  
Be nefit -ris k Assess me nt ......................................................................................... 2 6 
2.
O BJ E C TI V E S A N D E N D P OI N T S  ................................................................................. 2 6 
2. 1.  
O bjecti ves  .............................................................................................................. 2 6 
2. 2.  
E n d p oi nts ............................................................................................................... 2 7  
2. 2. 1.  
Pri mar y E n d p oi nts ....................................................................................... 2 7  
2. 2. 2.  
Sec o n dar y E n d p oi nts ................................................................................... 2 8  
2. 2. 3.  
E x pl orat or y E n d p oi nts  ................................................................................. 2 9 
3.
I N V E S TI G A TI O N A L P L A N .......................................................................................... 3 0 
3. 1.  
O verall St u d y Desi g n a n d Pla n .............................................................................. 3 0  
3. 1. 1.  
Part A  ( Si n gle Asce n di n g D ose St u d y) ........................................................ 3 0 
3. 1. 2.  
Part B  ( M ulti ple Asce n di n g D ose St u d y) .................................................... 3 2 
3. 1. 3.  
Part C (Dr u g -Dr u g I nteracti o n  St u d y) ......................................................... 3 3 
3. 2.  
St u d y Start a n d E n d of St u d y Defi niti o ns .............................................................. 3 6  
3. 3.  
A d diti o nal Gr o u ps  .................................................................................................. 3 6 
3. 4.  
Disc ussi o n of St u d y Desi g n, I ncl u di n g t he C h oice of C o ntr ol Gr o u ps ................. 3 6  
3. 4. 1.  
D ose I nter val  ................................................................................................ 3 7 
3. 5.  
Selecti o n of D oses i n t he St u d y ............................................................................. 3 7  
3. 6.  
D ose Escalati o n  ...................................................................................................... 4 1 
3. 7.  
D ose Escalati o n St o p pi n g Criteria  ......................................................................... 4 1 
4.
S E L E C TI O N O F S T U D Y P O P U L A TI O N  ..................................................................... 4 2 
4. 1.  
I ncl usi o n Criteria ................................................................................................... 4 2 
4. 2.  
E xcl usi o n Criteria  .................................................................................................. 4 3 
4. 3.  
S u bject N u m ber a n d I de ntificati o n  ........................................................................ 4 5 
4. 4.  
S u bject Wit h dra wal a n d Re place me nt  ................................................................... 4 5 
4. 5.  
St u d y Ter mi nati o n ................................................................................................. 4 6  
 
  


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 1 6 of 8 6 
5.  
S T U D Y T R E A T M E N T S  ................................................................................................. 4 6 
5. 1.  
Descri pti o n, St ora ge, Pac ka gi n g, a n d La belli n g .................................................... 4 6  
5. 2.  
St u d y Treat me nt A d mi nistrati o n  ............................................................................ 4 7 
5. 3.  
Ra n d o misati o n ....................................................................................................... 4 8  
5. 4.  
Bli n di n g.................................................................................................................. 4 8  
5. 5.  
Treat me nt C o m plia nce  ........................................................................................... 4 9 
5. 6.  
Dr u g Acc o u nta bilit y............................................................................................... 4 9  
6.  
C O N C O MI T A N T T H E R A PI E S A N D O T H E R R E S T RI C TI O N S  ................................ 4 9 
6. 1.  
C o nc o mita nt T hera pies  .......................................................................................... 4 9 
6. 2.  
Diet  ......................................................................................................................... 5 0 
6. 2. 1.  
Part A  ........................................................................................................... 5 0 
6. 2. 2.  
Part B  ........................................................................................................... 5 0 
6. 2. 3.  
Part C  ........................................................................................................... 5 1 
6. 3.  
Ot her Restricti o ns .................................................................................................. 5 1  
6. 3. 1.  
F o o ds a n d Be vera ges ................................................................................... 5 1  
6. 3. 2.  
S m o ki n g ....................................................................................................... 5 1  
6. 3. 3.  
E xercise  ........................................................................................................ 5 1 
6. 3. 4.  
Bl o o d D o nati o n ............................................................................................ 5 2  
7.  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  ........................................................... 5 2 
7. 1.  
P har mac o ki netic Assess me nts  ............................................................................... 5 2 
7. 1. 1.  
P har mac o ki netic Sa m ple C ollecti o n a n d Pr ocessi n g ................................... 5 2  
7. 1. 2.  
P har mac o ki netic A nal ytical Met h o d ol o g y  .................................................. 5 2 
7. 2.  
E x pl orat or y Assess me nts  ....................................................................................... 5 3 
7. 2. 1.  
Sa m ple C ollecti o n a n d Pr ocessi n g f or E x pl orat or y Meta b olite Pr ofili n g ... 5 3  
7. 2. 2.  
Met h o d ol o g y f or E x pl orat or y Meta b olite Pr ofili n g A nal ysis ...................... 5 3  
7. 2. 3.  
Sa m ple C ollecti o n a n d Pr ocessi n g f or P har mac o ge netic A nal ysis .............. 5 3  
7. 2. 4.  
Met h o d ol o g y f or P har mac o ge netic A nal ysis ............................................... 5 3  
7. 2. 5.  
Sa m ple C ollecti o n a n d Pr ocessi n g f or E x pl orat or y B i o mar ker A nal ysis .... 5 3 
7. 2. 6.  
Sa m ple C ollecti o n a n d Pr ocessi n g f or A nal ysis of P h os p h oli pi d- C a n d 
Faecal Cal pr otecti n  ...................................................................................... 5 4 
7. 2. 7.  
Met h o d ol o g y f or E x pl orat or y B i o mar ker A nal ysis ..................................... 5 4  
7. 2. 8.  
C o nti n u o us 1 2 -lea d Electr ocar di o gra m M o nit ori n g .................................... 5 4 
7. 3.  
Safet y a n d T olera bilit y Assess me nts  ..................................................................... 5 4 
7. 3. 1.  
A d verse E ve nts ............................................................................................ 5 4  
7. 3. 2.  
Cli nical La b orat or y E val uati o ns  .................................................................. 5 5 
7. 3. 3.  
Brist ol St o ol C hart  ....................................................................................... 5 5 
7. 3. 4.  
Vital Si g ns  .................................................................................................... 5 5 
7. 3. 5.  
1 2- lea d Electr ocar di o gra m ........................................................................... 5 6 
7. 3. 6.  
P h ysical E xa mi nati o n ................................................................................... 5 6 
7. 3. 7.  
A b d o mi nal E xa mi nati o n .............................................................................. 5 6  
 
  


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 1 7 of 8 6 
7. 3. 8.  
Hei g ht, B o d y Wei g ht , a n d B MI ................................................................... 5 6 
8.  
S A M P L E SI Z E A N D D A T A  A N A L Y SI S  ...................................................................... 5 7 
8. 1.  
Deter mi nati o n of Sa m pl e Size ............................................................................... 5 7  
8. 2.  
A nal ysis P o p ulati o ns .............................................................................................. 5 7  
8. 2. 1.  
P har mac o ki netic P o p ulati o n ........................................................................ 5 7  
8. 2. 2.  
Safet y P o p ulati o n ......................................................................................... 5 7  
8. 3.  
P har mac o ki netic A nal yses ..................................................................................... 5 7  
8. 4.  
E x pl orat or y Meta b olite Pr ofili n g A nal ys is ............................................................ 5 7 
8. 5.  
P har mac o ge netic A nal ysis ..................................................................................... 5 7  
8. 6.  
E x pl orat or y Bi o mar ker A nal ys is ........................................................................... 5 8 
8. 7.  
C o nce ntrati o n- Q Tc A nal ysis  ................................................................................. 5 8 
8. 8.  
Safet y A nal ysis  ...................................................................................................... 5 8 
8. 9.  
I nteri m A nal ysis ..................................................................................................... 5 8 
9.  
R E F E R E N C E S  ................................................................................................................ 5 9 
1 0.  A P P E N DI C E S  ................................................................................................................. 6 1 
 
LI S T O F T A B L E S A N D FI G U R E S  
Ta ble 1:  
S u m mar y of T o xic o ki netic P ara meters i n 2- wee k T o xicit y St u d y i n R at 
Gi ve n 
 ................................................. 2 4 
Ta ble 2:  
S u m mar y of T o xic o ki netic Para meters i n 2- wee k T o xicit y St u d y i n 
D o g  Gi ve n 
 ......................................... 2 4 
Ta ble  3: 
Ge o metric Mea n ( C V %) P K Para meters of 
 F oll o wi n g 
Si n gle Oral D ose A d mi nistrati o n of K R P - A 2 1 8 t o Healt h y S u bjects * ..... 2 5 
Ta ble  4: 
O bser ve d a n d Esti mate d H u ma n E x p os ure at Da y 1 a n d Stea d y State  ..... 3 8 
Ta ble  5: 
Pr o p ose d I n vesti g ati o nal Me dici nal Pr o d uct D ose Le vels f or Parts A , 
B,  a n d C ..................................................................................................... 3 9 
Ta ble  6: 
Esti mate d H u ma n E x p os ure at Da y 1  ........................................................ 4 0 
Ta ble  7: 
Ta blet Asse m bl y  ........................................................................................ 4 7 
Ta bl e 8:  
Hi g h -fat Brea kfast C o nte nt ........................................................................ 5 0 
Ta ble 9:  
Sc he d ule of Assess me nts -Part A  ( Gr o u ps A 1, A 2 b, a n d A 3 t o A 5; 
Si n gle- D ose)  .............................................................................................. 7 4 
Ta ble 1 0:  
Sc he d ule of Assess me nts -Part A  ( Gr o u p A 2a; Si n gle-D ose)  [ Scree ni n g 
t o Treat me nt Peri o d 1] ............................................................................... 7 7 
Ta ble 1 1:  
Sc he d ule of Assess me nts -Part B (M ulti ple -D ose)  [ Scree ni n g t o Da y 1] .. 8 0 
Ta ble 1 2:  
Sc he d ule of Assess me nts -Part C ( D DI ) [ Scree ni n g t o Da y 4] ................... 8 4 
 
Fi g ure 1:  
St u d y Sc he matic ( Part A; Gr o u ps A 1, A 2 b [ Fe male s u bjects O nl y], a n d 
A 3 t o A 5) ................................................................................................... 3 1  
Fi g ure 2:  
St u d y Sc he matic ( Part A; Gr o u p A 2a [ Male s u bjects O nl y]) .................... 3 1 
Fi g ure 3:  
St u d y Sc he matic ( Part B)  ........................................................................... 3 3 
 
  
C CI
C CI
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 1 8 of 8 6 
Fi g ure 4:  
St u d y Sc he matic ( Part C) ........................................................................... 3 4  
Fi g ure 5:  
Pla n ne d D ose Le vels  of K R P - A 2 1 8 ( Parts A, B, a n d, C) .......................... 3 5 
 
  


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 1 9 of 8 6 
LI S T O F A B B R E VI A TI O N S  
A b bre vi ati o n  Defi niti o n  
A E  
ad verse e ve nt  
Al b  
A l b u mi n 
A L P  
al kali ne p h os p hatise 
A L T  
ala ni ne a mi n otra nsferase 
A N O V A  
anal ysis of varia nce  
A P T T  
acti vate d partial t hr o m b o plasti n ti me 
A S T  
as partate a mi n otra nsferase 
A U C  
area u n der t he c o nce ntrati o n-ti me c ur ve 
A U C 0- ∞ 
area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me 0 e xtra p olate d  t o 
i nfi nit y 
A U C 0- 2 4 h 
area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me 0  t o 2 4 h o urs  
A U C 0-tl ast 
area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t o t he ti me of t he last 
q ua ntifia ble c o nce ntrati o n  
A U C 0- τ 
area u n der t he c o nce ntrati o n-ti me c ur ve o ver a d osi n g i nter val 
B MI  
b o d y m ass in de x  
B U N  
b l o o d u rea n itr o ge n 
Ca  
C alci u m 
C K  
creati ne ki nase  
Cl  
C hl ori de  
C L/ F  
ap pare nt t otal cleara nce  
C ma x  
m a xi m u m o bser ve d c o nce ntrati o n  
C mi n  
m i ni m u m o bser ve d c o nce ntrati o n 
C O P D  
chr o nic o bstr ucti ve p ul m o nar y disease  
Cr  
C reati ni ne 
C R O  
C o ntract Researc h Or ga nizati o n  
C R U  
cli nical researc h u nit  
C S A  
cli nical st u d y a gree me nt 
C Y P  
cyt oc hr o me P 4 5 0  
D -Bil  
d irect bilir u bi n 
D DI  
d r u g-d r u g interacti o n  
D S S  
Dr u g Safet y Ser vices  
E C  
Et hics C o m mittee  
E C 5 0 
5 0 % of ma xi m u m efficaci o us c o nce ntrati o n  
E C G  
E lectr ocar di o gra m 
e C R F  
electr o nic Case Re p ort F or m 
E D C  
electr o nic d ata ca pt ure 
F S H  
f ollicle-sti m ulati n g h or m o ne 
H D L -C  
h i g h-de nsit y li p o pr otei n  ch olester ol  
 
  


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 2 0 of 8 6 
H E D  
h u ma n e q ui vale nt d ose  
h E R G  
h u ma n et her -a-g o -g o -relate d ge ne 
H R V  
h u ma n r hi n o vir us  
Ht  
h e mat ocrit   
I B 
I n vesti gat or’s Br oc h ure 
I-Bil  
in direct bilir u bi n  
I C5 0 
co nce ntrati o n pr o d uci n g 5 0 % i n hi biti o n  
I C F 
inf or me d co nse nt for m  
I C H 
I nter nati o nal C o u ncil f or/ C o nfere nce o n Har m o nisati o n 
I M P 
in vesti gati o nal me dici nal pr o d uct  
I T C Z 
Itrac o naz ole 
I U D 
intra uteri ne de vice  
K  
P otassi u m  
L D H  
lactate de h y dr o ge nase  
L D L -C  
lo w -d e nsit y li p o pr otei n ch olester ol  
M C H  
m ea n cell hae m o gl o bi n  
M C H C  
m ea n cell hae m o gl o bi n c o nce ntrati o n  
M C V  
m ea n cell v ol u me  
M R S D  
m a xi m u m rec o m me n de d starti n g d ose  
Na  
so di u m  
N O A E L  
n o o bser ve d a d verse effect le vel  
P  
in or ga nic p h os p hate  
PI 4 K  
p h os p hati d yli n osit ol 4 ki nase  
PI 4 K 2 A  
p h os p hati d yli n osit ol 4 ki nase t y pe 2 α  
PI 4 K 2 B  
p h os p hati d yli n osit ol 4 ki nase t y pe 2 β  
PI 4 K B  
p h os p hati d yli n osit ol 4 ki nase III β  
P K  
p har mac o ki netic(s)  
P L  
P h os p h o li pi d 
P L T  
P latelet 
P T -I N R 
p r ot hr o m bi n ti me/i nter nati o nal n or malise d rati o 
Q D  
q ua q ue die ( o nce -dail y ) 
Q Tc F  
Q T i nter val c orrecte d f or heart rate usi n g Fri dericia’s met h o d  
A R A U C 0- τ 
o bser ve d acc u m ulati o n rati o base d o n A U C 0- τ 
A R C ma x  
o bser ve d acc u m ulati o n rati o base d o n C ma x  d uri n g t he d osi n g i nter val  
R B C  
re d bl o o d cell 
S A E  
seri o us a d verse e ve nt  
t1/ 2 
ap pare nt ter mi nal eli mi nati o n half -life 
T -Bil  
total bilir u bi n  
T -C H O  
total c h olester ol  
T G  
T ri gl yceri des 
 
  


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 2 1 of 8 6 
tma x  
ti me of t he ma xi m u m o bser ve d c o nce ntrati o n 
T M F  
Trial Master File  
T P  
total pr otei n  
U A  
u ric aci d 
U L N  
u p per li mit of n or ma l 
V z/ F 
ap pare nt v ol u me of distri b uti o n  
W B C  
w hite bl o o d cell  
γ-G T P  
g a m ma-gl uta m yl tra nsferase  
 
 
 
  






Pr ot oc ol 
C O N FI D E N TI A L  
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 2 4 of 8 6 
fe males ( base d o n a n i ncrease i n t otal c h olester ol [ T- C H O] a n d e m peri p olesis i n t he b o ne 
marr o w i n b ot h se xes at ≥1 0 m g/ k g/ da y).  I n a 2- wee k G L P oral t o xic ol o g y st u d y i n t he d o g, 
t he N O A E L of 
 was 2 m g/ k g/ da y f or b ot h males a n d 
fe males, base d o n: a b n or mal st o ols, decrease d b o d y wei g ht a n d decrease d f o o d c o ns u m pti o n 
at ≥4 m g/ k g/ da y; i ncrease d bl o o d li pi d s yste m para meters (tri gl yceri des, T -C H O, L D L -C, 
free c h olester ol) a n d de viati o n e nz y mes at ≥4 m g/ k g/ da y; a n d hist o pat h ol o gical 
gastr oi ntesti nal ( GI) c ha n ges i n 1 fe male at 4 m g/ k g/ da y (a n d 1 male a n d 1 fe male at 
8 m g/ k g/ da y), c ul mi nati n g i n t he deat h or earl y sacrifice of d o gs gi ve n ≥6 m g/ k g/ da y . I n a 
n o n- pi v otal 2- wee k t o xicit y st u d y i n male mice, t he N O A E L of 
 
was 1 0 m g/ k g/ da y, base d o n: decrease d b o d y wei g hts, c u m ulati ve b o d y wei g ht gai n, 
a n d f o o d c o ns u m pti o n at 3 0 0 m g/ k g/ da y; i ncrease d bl o o d li pi d s yste m para meters ( T- C H O, 
H D L -C, L D L -C) at ≥3 0  m g/ k g/ da y; a n d hist o pat h ol o gical c ha n ges  i n t he st o mac h a n d s mall 
i ntesti ne at 3 0 0 m g/ k g/ da y, c ul mi nati n g i n t he deat h or earl y sacrifice of mice gi ve n 
3 0 0 m g/ k g/ da y. 
T o xic o k i netic para meters deter mi ne d fr o m t he pi v otal 2-wee k re peat d ose st u dies i n rats a n d 
d o gs are prese nte d i n Ta ble 1  a n d Ta ble 2 . 
T a ble 1 : 
S u m m ar y o f T o xic o ki netic Par a meters i n 2- wee k T o xicit y St u d y i n R at 
G i ve n 
 
D ose  le vel 
( m g/ k g/ d a y) 
N  
( M/ F) 
D a y  M ale  
Fe m ale  
C m a x  
T m a x  A U C 0 -2 4 h 
C m a x  
T m a x  A U C 0 -2 4 h 
( n g/ m L) ( h) 
( n g· h/ m L) ( n g/ m L) ( h) 
( n g· h/ m L) 
5  
3/ 3  
1  
9 6 2  
0. 5  
3 6 1 0  
1 3 7 0  
0. 5  
4 9 1 0  
3/ 3  
1 4  
1 2 2 0  
0. 5  
3 9 3 0  
1 6 0 0  
0. 5  
4 7 8 0  
1 0  
3/ 3  
1  
2 1 3 0  
1 . 0 
8 6 2 0  
3 2 2 0  
0. 5  
1 2  5 0 0  
3/ 3  
1 4  
2 0 1 0  
1 . 0 
8 5 8 0  
3 4 9 0  
0. 5  
1 0  7 0 0  
2 0  
3/ 3  
1  
4 9 0 0  
0. 5  
2 3  0 0 0  
6 2 2 0  
0. 5  
3 0  2 0 0  
3/ 3  
1 4  
5 1 1 0  
0. 5  
2 0  9 0 0  
7 9 9 0  
0. 5  
2 7  4 0 0  
4 0  
3/ 3  
1  
7 9 6 0  
0. 5  
5 1  6 0 0  
9 6 0 0  
0. 5  
5 6  8 0 0  
3/ 3  
1 4  
8 8 9 0  
0. 5  
4 8  7 0 0  
1 0  6 0 0  
0. 5  
5 9  7 0 0  
M ea n ( n = 3); A U C 0- 2 4 h = area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o 2 4 h o urs; C ma x  = ma xi m u m c o nce ntrati o n; 
T ma x  = ti me of ma xi m u m  c o nce ntrati o n; N ( M/ F): N u m ber of a ni mals ( male/fe male) 
T a ble  2:  
S u m m ar y of T o xic o ki netic  P ar a meters i n 2- wee k T o xicit y St u d y i n  D o g  
G i ve n 
 
D ose le vel  
( m g/ k g/ d a y) 
N  
( M/ F) 
D a y  M ale  
Fe m ale  
C m a x  
T m a x  A U C 0 -2 4 h 
C m a x  
T m a x  A U C 0 -2 4 h 
( n g/ m L) ( h) 
( n g· h/ m L) ( n g/ m L) ( h) 
( n g· h/ m L) 
2 
3/ 3  
1  
1 4 5 0  
0. 8 
8 0 2 0  
9 1 8  
1. 3 
6 0 0 0  
3/ 3  
1 4  
1 4 5 0  
0. 7 
9 3 4 0  
1 3 5 0  
0. 8 
8 5 0 0  
4 
3/ 3  
1  
2 7 8 0  
1. 7 
1 9  9 0 0  
2 4 2 0  
1. 3 
1 5  0 0 0  
3/ 3  
1 4  
3 5 2 0  
0. 7 
2 9  4 0 0  
3 1 2 0  
0. 8 
1 9  9 0 0  
6 
3/ 3  
1  
4 0 1 0  
1. 2 
3 0  5 0 0  
3 8 2 0  
1. 0 
2 7  9 0 0  
3/ 3  
1 4  
4 4 2 0  
1. 0 
3 5  0 0 0  
5 1 0 0  
1. 2 
4 8  8 0 0  
8 
3/ 3  
1  
4 8 4 0  
1. 3 
3 5  8 0 0  
5 8 5 0  
1. 1 
4 1  3 0 0  
3/ 3  
1 4  
4 3 9 0  
1. 5 
3 8  2 0 0  
3 3 1 0  
2. 0 
3 4  7 0 0  
M ea n ( n = 3); A U C 0- 2 4 h = area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o 2 4 h o urs; C ma x  = ma xi m u m c o nce ntrati o n; 
T ma x  = ti me of ma xi m u m c o nce ntrati o n ; N ( M/ F): N u m ber of a ni mals ( male/fe male) 
 
  
C CI
C CI
C CI
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 2 5 of 8 6 
1. 3.  
S u m m ar y of Cli nic al E x perie nce  
I n t his o n g oi n g P hase 1 st u d y, as of 2 7 A u g ust 2 0 2 1, a t otal of 2 7 s u bjects ha ve bee n d ose d 
a n d ha ve c o m plete d t he st u d y. Se ve n s u bjects ha ve recei ve d 1 m g K R P- A 2 1 8 or place b o 
u n der faste d c o n diti o ns ( Gr o u p A 1), 8 male s u bjects ha ve recei ve d 3 m g K R P- A 2 1 8 or 
place b o u n der faste d a n d fe d c o n diti o ns ( Gr o u p A 2a), 4 fe male s u bjects ha ve recei ve d 3 m g 
K R P - A 2 1 8 or place b o u n der faste d c o n diti o ns ( Gr o u p A 2 b), a n d 8 s u bjects ha ve recei ve d 
6 m g K R P - A 2 1 8 or place b o u n der faste d c o n diti o ns ( Gr o u p A 3). F or d ose escalati o n 
decisi o n, a mi ni m u m of 6  s u bject’s data per gr o u p has bee n e val uate d, i ncl u di n g 7 s u bjects i n 
Gr o u p A 1 ( 1 m g), 6 s u bjects i n Gr o u p A 2a ( 3 m g), a n d 8 s u bjects i n Gr o u p A 3 ( 6 m g). T here 
were n o seri o us a d verse e ve nts ( S A Es), deat hs, or n o ot her si g nifica nt a d verse e ve nts ( A Es). 
T he A Es e x perie nce d b y t hese s u bjects ha ve  i ncl u de d hea dac he, l o ose st o ols, c ol d s y m pt o ms, 
ac hi n g l o wer le gs, a b d o mi nal pai n, st o mac h ac he, dr o wsi ness, bl o o d visi ble w he n passi n g 
st o ol sa m ple, a n d s ore t hr oat. All were tra nsie nt a n d eit her mil d or m o derate i n se verit y.  
Preli mi nar y P K para met ers deter mi ne d fr o m t he o n g oi n g P hase 1 st u d y are prese nte d i n 
Ta ble  3. 
T a ble  3: 
Ge o metric M e a n ( C V %) P K P ar a meters of 
F oll o wi n g Si n gle 
Or al D ose A d mi nistr ati o n of K R P - A 2 1 8 t o He alt h y S u bjects *  
P ar a meter  
( u nits) 
1 m g  
[ Faste d]  
3 m g  
[ Faste d]  
3 m g  
[ Fe d] 
6 m g  
[ Faste d]  
A U C 0- tlast  
(n g• h/ m L ) 
1 9 8  
( 1 8. 5) 
5 4 0  
( 2 7. 0) 
5 7 0  
( 2 5. 6) 
1 1 6 0  
( 2 8. 4) 
A U C 0- ∞  
(n g• h/ m L ) 
2 1 0  
( 1 8. 6) 
5 6 4  
( 3 0. 1) 
5 9 6  
( 2 8. 0) 
1 2 3 0  
( 2 8. 4) 
A U C 0- 2 4 h  
(n g• h/ m L ) 
1 4 5  
( 1 9. 5) 
3 8 8  
( 2 1. 4) 
3 9 3  
( 1 9. 1) 
8 1 3  
( 2 7. 9) 
C ma x  
(n g/ m L ) 
1 1. 9  
( 3 0. 3) 
2 9. 8  
( 2 3. 5) 
2 9. 5  
( 1 5. 2) 
6 0. 3  
( 2 6. 5) 
tma x * *   
(h ) 
3. 0 0  
( 2. 0 0– 4. 0 0)  
3. 5 0  
( 2. 0 0-4. 0 0)  
3. 5 0  
( 3. 0 0-8. 0 0)  
3. 5 0  
( 1. 5 0-4. 0 0)  
t1/ 2  
( h) 
1 8. 2  
( 1 1. 5) 
1 5. 2  
( 2 0. 3) 
1 4. 8  
( 1 8. 4) 
1 6. 9  
( 9. 6 8) 
A b bre viati o ns: A U C 0- ∞ = area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 e xtra p olate d t o i nfi nit y; A U C0- 2 4 h = area 
u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o 2 4 h o urs; A U C 0- tlast = area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 
t o t he ti me of t he last q ua ntifia ble c o nce ntrati o n; Cma x  = ma xi m u m o bser ve d c o nce ntrati o n; C V % = c oefficie nt of variati o n;  
P K = p har mac o ki netic;  t1/ 2 = a p pare nt ter mi nal eli mi nati o n half -life; tma x  = ti me of t he ma xi m u m o bser ve d c o nce ntrati o n   
* As per pr ot oc ol, a mi ni m u m of 6 s u bjects ( 4 acti ve s u bjects) data per gr o u p was e val uate d f or d ose escalati o n decisi o n.  
* * Me dia n ( mi n -ma x)  
 
F oll o wi n g oral a d mi nistrati o n of K R P - A 2 1 8, ma xi m u m c o nce ntrati o ns of 
were 
attai ne d 3. 0 t o 3. 5 h o urs p ost d ose ( me dia n ti me t o ma xi m u m o bser ve d c o nce ntrati o n [t ma x ]), 
t hereafter decli ni n g wit h a ge o metric mea n half-life (t1/ 2) of a p pr o xi matel y 1 5 t o 1 8 h o urs. 
S yste mic e x p os ure t o  
( ma xi m u m o bser ve d c o nce ntrati o n [ C ma x ] a n d area u n der 
t he c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t o 2 4 h o urs [ A U C 0- 2 4 h]) i ncrease d i n a n 
a p pr o xi mate d ose pr o p orti o nal ma n ner o ver 1 t o 6 m g K R P - A 2 1 8. A d mi nistrati o n of 
K R P - A 2 1 8 f oll o wi n g a hi g h fat meal ha d n o effect o n t he rate a n d e xte nt of a bs or pti o n of 
 
 
  
C CI
C CI
C CI
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 2 6 of 8 6 
1. 4.  
St u d y R ati o n ale  
T his is t he  first ti me K R P- A 2 1 8 will be a d mi nistere d t o h u ma ns. T he pri nci pal p ur p oses of 
t his st u d y are t o e val uate t he safet y a n d t olera bilit y data w he n K R P- A 2 1 8 is a d mi nistere d 
orall y as si n gle a n d m ulti ple d oses t o healt h y s u bjects. T his i nf or mati o n, t o get her wit h t he P K 
data, will hel p esta blis h t he d oses a n d d osa ge re gi me n s uita ble f or a d mi nistrati o n t o patie nts. 
T he st u d y will als o i n vesti gate t he effects of f o o d a n d se x o n t he P K of  
pri or t o 
patie nt st u dies . 
T his first -i n-h u ma n st u d y als o i nc or p orates a D DI st u d y. T he i nitial tar get p o p ulati o n of 
K R P - A 2 1 8 i ncl u des i m m u n oc o m pr o mise d patie nts, s uc h as H C T reci pie nts w h o re q uire 
c o nc o mita nt az ole a ntif u n gal dr u gs t o re d uce t he ris k of f u n gal i nfecti o n. Precli nical st u dies 
ha ve s h o w n t hat C Y P 3 A 4 is t he maj or meta b olic e nz y me of  
, a n d t he prese nce a n d 
ma g nit u de of D DI wit h C Y P 3 A 4 i n hi bit ors, e ve n if e x pl orat or y, s h o ul d be c o nfir me d earl y i n 
de vel o p me nt t o u n dersta n d t he p ote ntial ris k lea di n g t o d ose a dj ust me nts or c o ntrai n dicati o ns 
d ue t o D DI. It is i m p orta nt t o c o nfir m t he assess me nt of t he i m pact of t he c o m bi nati o n of 
K R P - A 2 1 8 a n d itrac o naz ole, as a n a p pr o priate a n d p ote nt C Y P 3 A 4 i n hi bit or, o n P K as t his 
will pr o vi de ver y i m p orta nt i nf or mati o n f or s u bse q ue nt st u d y desi g n a n d d ose selecti o n f or 
p hase 2 a n d p hase 3 st u dies.  
1. 5.  
Be nefit -ris k Assess me nt 
Healt h y s u bjects i n t he c urre nt st u d y will n ot recei ve a n y healt h be nefit ( be y o n d t hat of a n 
assess me nt of t heir me dical stat us) fr o m partici pati n g i n t he st u d y. T he ris ks of partici pati o n 
are pri maril y t h ose ass ociate d wit h a d verse reacti o ns t o t he i n vest i gati o nal me dici nal pr o d uct 
(I M P), alt h o u g h t here ma y als o be s o me disc o mf ort fr o m c ollecti o n of bl o o d sa m ples a n d 
ot her st u d y pr oce d ures. M ore i nf or mati o n a b o ut t he k n o w n a n d e x pecte d ris ks a n d reas o na bl y 
a ntici pate d A Es ass ociate d wit h K R P - A 2 1 8 ma y be f o u n d i n t he I n vesti gat or’s Br oc h ure 
(I B).[1 8 ] 
2.  O B J E C TI V E S A N D E N D P OI N T S  
2. 1.  
O bjecti ve s 
P arts A a n d B:  
T he pri mar y o bjecti ve is: 
•  t o e val uate t he safet y a n d t olera bilit y of si n gle a n d m ulti ple oral d oses of K R P- A 2 1 8 
i n healt h y s u bjects. 
T he sec o n dar y o bjecti ves are: 
•  t o assess t h e P K of 
(t he acti ve i n gre die nt of K R P- A 2 1 8) f oll o wi n g si n gle 
a n d m ulti ple oral d oses of K R P- A 2 1 8 i n healt h y s u bjects. 
•  t o assess t h e effect of f o o d o n t he P K of 
f oll o wi n g a si n gle oral d ose of 
K R P - A 2 1 8 i n healt h y male s u bjects. 
•  t o assess t h e effect of se x o n t he P K of 
 f oll o wi n g a si n gle oral d ose of 
K R P - A 2 1 8. 
 
  
C CI
C CI
C CI
C CI
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 2 7 of 8 6 
T he e x pl orat or y o bjecti ves are: 
•  t o e x pl ore bl o o d a n d uri ne sa m ples f or t he meta b olite pr ofiles of 
 f oll o wi n g 
si n gle a n d m ulti ple oral d oses of K R P- A 2 1 8 i n healt h y male s u bjects. 
•  t o e x pl ore faecal sa m ples f or t he meta b olite pr ofiles f oll o wi n g a si n gle oral d ose of 
K R P - A 2 1 8 i n healt h y male s u bjects. 
•  t o e x pl ore bl o o d a n d uri ne sa m ples f or p har mac o d y na mic bi o mar kers. 
•  t o e x pl ore a p ote ntial effect of K R P - A 2 1 8 o n p h os p h oli pi d- C i n ser u m a n d faecal 
cal pr otecti n . 
•  t o c ollect bl o o d sa m ples f or p ote ntial p har mac o ge netic a nal yses. 
•  t o c ollect c o nti n u o us E C G wa vef or ms f or c o nce ntrati o n-Q Tc a nal ysis, f oll o wi n g 
si n gle oral d oses of K R P - A 2 1 8 i n healt h y s u bjects ( Part A o nl y). 
P art C:  
T he pri mar y o bjecti ve is: 
•  t o assess t h e effect of m ulti ple d oses of itrac o naz ole (c yt oc hr o me P 4 5 0 3 A 4 i n hi bit or) 
o n t he si n gle- d ose P K of 
i n healt h y male s u bjects. 
T he sec o n da r y o bjecti ves are: 
•  t o assess t he safet y a n d t olera bilit y of si n gle oral d oses of K R P - A 2 1 8 w he n 
c o-a d mi nistere d wit h m ulti ple oral d oses of itrac o naz ole i n healt h y male s u bjects. 
•  t o assess  t he P K of itrac o naz ole a n d its meta b olite  h y dr o x y-itrac o naz ole w he n 
c o-a d mi nistere d wit h  K R P - A 2 1 8 i n healt h y male s u bjects. 
T he e x pl orat or y o bjecti ves are: 
•  t o e x pl ore bl o o d sa m ples f or t he meta b olite pr ofiles of 
 a d mi nistere d 
K R P - A 2 1 8 al o ne a n d w he n c o-a d mi nistere d wit h itrac o naz ole i n healt h y male 
s u bjects. 
•  t o e x plore a p ote ntial effect of K R P - A 2 1 8 o n p h os p h oli pi d- C i n ser u m a n d faecal 
cal pr otecti n . 
•  t o c ollect bl o o d sa m ples f or p ote ntial p har mac o ge netic a nal yses . 
2. 2.  
E n d p oi nt s 
2. 2. 1.  
Pri m ar y E n d p oi nts  
F or Parts A a n d B, t he safet y a n d t olera bilit y e n d p oi nts are as f oll o ws:  
•  A Es  
•  b o d y wei g ht 
 
  
C CI
C CI
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 2 8 of 8 6 
•  cli nical la b orat or y e val uati o ns (hae mat ol o g y , cli nical c he mistr y [ wit h t he e xce pti o n of 
p h os p h oli pi d- C] , uri nal ysis, c oa g ulati o n, a n d faecal occ ult bl o o d) 
•  1 2- lea d E C G para meters 
•  vital si g ns ( bl o o d press ure, p ulse rate, res pirat or y rate, a n d oral b o d y te m perat ure)  
•  Brist ol St o ol C hart  
•  p h ysical e xa mi nati o ns 
F or Part C,  t he D DI ( K R P- A 2 1 8 al o ne vers us c o-a d mi nistere d  wit h itrac o naz ole) assess me nt, 
t he P K e n d p oi nts will be t he para meters deri ve d fr o m plas ma c o nce ntrati o ns of 
 
o n Da ys 1 a n d 1 1, w hic h are as f oll o ws : 
•  area u n der the c o nce ntrati o n- ti me c ur ve ( A U C) fr o m ti me 0 e xtra p olate d  t o i nfi nit y 
( A U C0- ∞) 
•  A U C fr o m ti me 0 t o t he ti me of t he last q ua ntifia ble c o nce ntrati o n ( A U C0-tlast) 
•  C ma x  
•  tma x  
•  a p pare nt ter mi nal eli mi nati o n half- life (t1/ 2) 
•  a p pare nt t otal cleara nce ( C L/ F)  
•  a p pare nt v ol u me of distri b uti o n d uri n g t he ter mi nal p hase ( Vz/ F). 
Ot her P K para meters ma y als o be a d de d.  
2. 2. 2.  
Sec o n d ar y E n d p oi nts  
F or  Part A , t he si n gle asce n di n g d ose, f o o d (fe d vers us faste d dietar y stat us at d osi n g), a n d 
se x ( male vers us fe male) P K para met ers deri ve d fr o m plas ma c o nce ntrati o ns of 
 
o n Da y 1 (i ncl u di n g Da y 1 i n Treat me nt P eri o d 2) are as f oll o ws : 
•  A U C 0- ∞ 
•  A U C 0-tl ast 
•  C ma x  
•  tma x  
•  t1/ 2 
•  C L / F 
•  V z/ F. 
F or Part B,  t he m ulti ple asce n di n g d ose P K para meters deri ve d fr o m plas ma c o nce ntrati o ns  
of 
 o n Da ys 1 a n d 1 4 are as f oll o ws: 
•  A U C 0- τ 
•  A U C 0- ∞ ( Da y 1 o nl y) 
 
  
C CI
C CI
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 2 9 of 8 6 
•  A U C 0-tl ast 
•  C ma x  
•  mi ni m u m o bser ve d c o nce ntrati o n ( C mi n ) 
•  tma x  
•  t1/ 2 
•  C L/ F  
•  V z/ F 
•  o bser ve d acc u m ulati o n rati o base d o n A U C 0- τ ( AR A U C 0- τ) 
•  o bser ve d acc u m ulati o n rati o base d o n C ma x  d uri n g t he d osi n g i nter val ( AR C ma x ). 
F or Part C,  t he safet y a n d t olera bilit y e n d p oi nts are as f oll o ws: 
•  A Es  
•  b o d y wei g ht 
•  cli nical la b orat or y e val uati o ns ( h ae mat ol o g y, cli nical c he mistr y  [ wit h t he e xce pti o n of 
p h os p h oli pi d- C] , uri nal ysis, c oa g ulati o n, a n d faecal occ ult bl o o d) 
•  1 2- lea d E C G para meters 
•  vital si g ns ( bl o o d press ure, p ulse rate, res pirat or y rate, a n d oral b o d y te m perat ure)  
•  Brist ol St o ol C hart 
•  p h ysical e xa mi nati o ns. 
F or Part C,  t he P K para meters deri ve d fr o m plas ma c o nce ntrati o ns of itrac o naz ole a n d 
h y dr o x y-itrac o naz ole o n Da y 1 1 are as f oll o ws : 
•  A U C 0- τ 
•  C ma x  
•  tma x . 
Ot her P K para meters ma y als o be a d de d.  
2. 2. 3.  
E x pl or at or y E n d p oi nts 
F or Parts A, B, a n d C, t he e x pl orat or y e n d p oi nts t hat will be re p orte d i n t he C S R f or t his 
st u d y are: 
•  P h os p h oli pi d- C 
•  Faecal cal pr otecti n  
 
  


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 3 0 of 8 6 
T he e n d p oi nts ass ociate d wit h t he e x pl orat or y meta b olite pr ofili n g, bi o mar ker a nal ysis,  
p har mac o ge netic a nal ys is, a n d c o nce ntrati o n-Q Tc a nal ysis  will be re p orte d else w here , as 
a p plica ble. 
3.  I N V E S TI G A TI O N A L P L A N 
T his P hase 1 st u d y will c o nsist of 3 parts, Parts A, B, a n d C. Part A will c o m prise a 
d o u ble- bli n d, ra n d o mise d, place b o-c o ntr olle d, si n gle- d ose, se q ue ntial - gr o u p, escalati n g- d ose 
desi g n, e nr olli n g healt h y male a n d fe male s u bjects (fe male s u bjects i n Gr o u p A 2 b o nl y). 
Part  A will i ncl u de a se x -effect ( Gr o u ps A 2a a n d A 2 b) w hic h will i n vesti gate t he effect of 
se x o n P K of  
 b y c o m pari n g P K para meters f oll o wi n g d osi n g i n fe males vers us 
d osi n g i n males. Part A will als o i ncl u de a f o o d-effect Gr o u p A 2a w hic h will be a 2- peri o d 
ar m t o i n vesti gate t he effect of f o o d o n P K of  
 b y c o m pari n g P K para meters 
f oll o wi n g d osi n g i n fe d c o n diti o ns vers us d osi n g i n faste d c o n diti o ns.  
Part B will c o m prise a d o u ble -bli n d, ra n d o mi se d, place b o-c o ntr olle d, m ulti ple - d ose, 
se q ue ntial- gr o u p, escalati n g- d ose desi g n, e nr olli n g healt h y male s u bjects.  
Part C will c o m prise a n o pe n -la bel, fi xe d-se q ue nce, e nr olli n g healt h y male s u bjects t o 
i n vesti gate t he effect of m ulti ple oral d oses of itrac o naz ole o n t he si n gle oral d ose P K of 
i n healt h y male s u bjects.  
3. 1.  
O ver all  St u d y Desi g n  a n d Pl a n  
3. 1. 1.  
P art A ( Si n gle Asce n di n g D ose St u d y ) 
Part A will c o m prise a d o u ble- bli n d, ra n d o mi se d, place b o-c o ntr olle d, si n gle- d ose, 
se q ue ntial- gr o u p, escalati n g- d ose st u d y i nc or p orati n g a si n gle- gr o u p, 2- peri o d ar m t o 
i n vesti gate t he effect of f o o d o n t he P K of  
 Part A will als o i ncl u de a se x -effect 
ar m ( Gr o u ps A 2a a n d A 2 b) w hic h will i n vesti gate t he effect of se x o n P K of  
 b y 
c o m pari n g P K para meters f oll o wi n g d osi n g i n fe males vers us d osi n g i n males. O verall, 
4 8 s u bjects will be st u die d i n 5 gr o u ps ( Gr o u ps A 1 t o  A 5 ); Gr o u ps A 1, a n d A 3 t o A 5 will  
c o nsist of 8 male s u bjects , a n d Gr o u p A 2 will c o nsist of 1 6 s u bjects s plit i nt o 2 s u b gr o u ps 
( Gr o u p A 2a [ male s u bjects o nl y] a n d Gr o u p A 2 b [fe male s u bjects o nl y]) t hat will c o nsist of 
8 s u bjects eac h. 
P ote nti al s u bjects will be scree ne d t o assess t heir eli gi bilit y t o e nter t he st u d y  wit hi n 2 8 da y s 
pri or t o t he first d ose a d mi nistrati o n. Eac h s u bject will partici pate i n 1 treat me nt peri o d o nl y, 
e xce pt f or Gr o u p A 2a, w here eac h s u bject will partici pate i n 2 treat me nt peri o ds w here d oses 
of K R P - A 2 1 8 will be se parate d b y an i nter val  of 7 t o 1 0 da ys ( u p t o a n d i ncl u di n g Da y - 1 of 
Treat me nt Peri o d 2) . T he was h o ut peri o d ma y be e xte n de d de pe n di n g o n t he o bser ve d t1/ 2 of 
S u bjects will resi de at t he st u d y site fr o m Da y - 1 (t he da y bef ore d osi n g) t o 
Da y  4 of eac h treat me nt peri o d. 
All  s u bjects will ret ur n f or a f oll o w - u p visit 7 t o 1 0 da ys after t heir fi nal d ose. T he f oll o w- u p 
peri o d ma y be e xte n de d de pe n di n g o n t he o bser ve d t 1/ 2 of 
 
Base d o n t h e o n g oi n g re vie w of t he safet y, t olera bilit y, a n d P K res ults, a d diti o nal 
n o nresi de ntial visits ma y be re q uire d. T he n u m ber of a d diti o nal visits per s u bject will n ot 
e xcee d 3 per peri o d (as a p plica ble) a n d will n ot e xte n d be y o n d 2 8 da ys after eac h fi nal d osi n g 
 
  
C CI
C CI
C CI
C CI
C CI
C CI
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 3 1 of 8 6 
occasi o n.  All s u bjects ma y sta y i n t he cli nical researc h u nit ( C R U ) o utsi de tre at me nt peri o ds 
d ue t o C O VI D- 1 9 ris ks. 
I n eac h of Gr o u ps A 1 t o A 5 , 6 s u bjects will recei ve K R P- A 2 1 8 a n d 2 s u bjects will recei ve 
place b o  i n acc or da nce wit h a ra n d o misati o n sc he d ule. I n Gr o u ps A 1, A 2 b, a n d A 3 t o A 5 , all 
d oses will be a d mi nistere d i n t he faste d state o n t he m or ni n g of Da y 1. F or Gr o u p A 2a, 
Peri o d 1, Da y 1 d oses will be a d mi nistere d i n t he faste d state a n d Peri o d 2, Da y 1 d oses be 
will be gi ve n 3 0 mi n utes after starti n g a sta n dar d hi g h-fat brea kfast. Eac h s u bject i n Gr o u ps 
A 1, A 2 b, a n d A 3 t o A 5 will recei ve o nl y a si n gle d ose of K R P - A 2 1 8 or place b o d uri n g t he 
st u d y. I n Gr o u p A 2a, s u bjects will ha ve t he sa me treat me nt i n b ot h peri o ds, s uc h t hat eac h 
s u bject will recei ve 2 si n gle d oses of K R P - A 2 1 8 or place b o d uri n g t he st u d y. 
All gr o u ps i n Par t A ( wit h t he e xce pti o n of Gr o u p A 2a i n Treat me nt Peri o d 2) will recei ve 
t he I M P usi n g a se nti nel a p pr oac h, as descri be d i n Secti o n  5. 3 . Details re gar di n g d ose 
escalati o n are prese nte d i n Secti o n 3. 5 . 
A n o ver vie w of t he st u d y desi g n is s h o w n i n Fi g ure 1  a n d Fi g ure 2 , a n d t he pla n ne d d ose 
le vels i n Fi g ure 5 . 
Sc he d ules of A ssess me nts is prese nte d i n A p pe n di x 6 . 
Fi g ure 1 : 
St u d y Sc he m atic ( P art A; Gr o u ps A 1, A 2 b [ Fe m ale s u bjects O nl y], a n d 
A 3 t o A 5) 
T he f oll o w -u p peri o d ma y be e xte n de d de pe n di n g o n t he o bser ve d t 1/ 2 of 
 
Fi g ure 2 : 
St u d y Sc he m atic ( P art A; Gr o u p A 2 a [ M ale s u bjects O nl y]) 
 
  
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 3 2 of 8 6 
T he was h o ut a n d f oll o w -u p peri o ds ma y be e xte n de d de pe n di n g o n t he o bser ve d t 1/ 2 of 
 
T he t otal  d urati o n of st u d y partici pati o n f or eac h s u bject (fr o m scree ni n g t hr o u g h f oll o w- u p 
visit) is a ntici pate d t o be u p t o 3 9 da ys ( Gr o u ps A 1, Gr o u p A 2 b [fe male s u bjects o nl y], A 3 t o 
A 5 ) or u p t o 5 0 da ys ( Gr o u p A 2a; male s u bjects o nl y). 
3. 1. 2.  
P art B  (M ulti pl e Asce n di n g D ose St u d y ) 
Part B  will c o m prise  a do u ble -bli n d, ra n d o mi se d, place b o- c o ntr olle d, multi ple - d ose, 
se q ue ntial- gr o u p, escalati n g- d ose de si g n, e nr olli n g healt h y male su bjects. O verall, 4 0 
s u bjects w ill be st u die d i n 4 gr o u ps (Gr o u ps B 1 t o B 4) , wit h eac h gr o u p c o nsisti n g of 1 0 male 
s u bjects. Part B ma y  start after co m pleti o n of G r o u p A 3, at d os e eq ual t o or less t ha n gi ve n i n 
Gr o u ps A 1 t o A 3. 
P ote ntial  s ubjects will  be scree ne d  to  assess t heir eli gi bilit y to  e nter t he st u d y wit hi n 2 8  days 
pri or t o  t he first d ose ad mi nistrati o n.  Eac h su bject will partici pate  i n 1 treat me nt peri o d o nly  
a n d resi de at the C R U  fr o m Da y - 1 (t he da y bef ore d os i n g) u ntil t he m or ni n g of D a y 1 7 
(f oll o wi n g assess me nts at 7 2 h o urs after fi nal d os i n g). 
All s u bjects  will ret ur n  for a  foll o w- u p visit 7 to 1 0 da ys after their fi nal d ose. T he foll o w- u p 
peri o d ma y be exte n de d de pe n di n g o n t he o bs er ve d t 1/ 2 of  
 
I n eac h of G r o u ps B 1 t o B 4, 8 s u bjects w ill recei ve K R P- A 2 1 8 a n d 2 s u bjects w ill recei ve 
place b o  i n acc or da nce w it h a ra n d o misati o n sc he d ule. T he di etar y state for d os i n g in Part B 
w ill be su bject t o  re vie w of  t he PK  data fr o m t he fed/faste d  co m paris o n  i n P art A. For  all 
s u bjects, d osi n g will o cc ur o n Da ys 1 t o 1 4. T he pla n ne d d osi n g fre q ue nc y is o nc e pe r da y, 
h o we ver the d os i n g fre q ue nc y i n Part B ma y be cha n ge d f oll o wi n g re vie w of da ta fr o m 
gr o u ps in Part A (Secti o n  3. 4 ). O n Da y 1 4, t he last d os e w ill be the m or ni n g  d ose re gar dless 
of the d os i n g fre q ue ncy ( Q D, BI D, TI D). 
T he total da il y d ose ad mi nistere d will n ot excee d a n e x p os ure s h o w n t o be safe an d well 
t olerate d i n Part A. 
B ase d o n t he o n g oi n g re vie w of the safet y, t olera bilit y, a n d P K res ults, a d diti o nal 
n o nre si de ntial visits ma y be re q uire d. The n u m be r of ad diti o nal vi sits pe r su bject w ill n ot 
e xcee d 3 a n d will n ot e xte n d be y o n d 2 8 da ys after eac h fi nal d osi n g occasi o n. A ll s u bjects 
ma y sta y i n t he C R U e ve n o utsi de treat me nt peri o d d ue t o C O VI D- 1 9 ris ks. 
All  gr o u ps i n Part B will recei ve t h e I M P usi n g a se nti nel a ppr oac h,  as descri be d  i n     
Secti o n  5. 3 . Details re gar di n g dose escalati o n  are prese nte d  in  Secti o n 3. 5 . 
A n o ver vie w of t he st u d y desi g n is s h o w n i n Fi g ure 3 , a n d t he pla n ne d d ose le vels i n      
Fi g ure 5 . 
A S che d ule of A ssess me nts is prese nte d in  A p pe n di x 6 . 
 
  
C CI
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 3 3 of 8 6 
Fi g ure 3 : 
St u d y Sc he m atic ( P art B)  
 
T he f oll o w -u p peri o d ma y be e xte n de d de pe n di n g o n t he o bser ve d t 1/ 2 of 
. 
T he t otal d urati o n of st u d y partici pati o n f or eac h s u bject (fr o m s cree ni n g t hr o u g h f oll o w- u p 
visit) is a ntici pate d t o be u p t o 5 2 da ys. 
3. 1. 3.  
P art C ( Dr u g -Dr u g I nter acti o n  St u d y ) 
Part C will c o m prise a n o pe n -la bel, fi xe d-se q ue nce, e nr olli n g healt h y male s u bjects t o 
i n vesti gate t he effect of m ulti ple oral d oses of itrac o naz ole o n t he si n gle oral d ose P K of 
 i n healt h y s u bjects. T here will be 1 gr o u p; Gr o u p C 1 , c o nsisti n g of 1 2 male 
s u bjects. Part C will start after c o m pleti o n of bli n de d safet y, t olera bilit y, a n d P K data re vie w 
i n Part A. All s u bjects will recei ve eac h of t he f oll o wi n g treat me nts:  
•  Da y s 1 a n d 1 1: si n gle oral d ose of K R P- A 2 1 8 
•  Da y 4: 2 × si n gle oral d oses of 2 0 0 m g itrac o naz ole, a p pr o xi matel y 1 2 h o urs a part 
•  Da ys 5 t o 1 3 : si n gle oral d oses of 2 0 0 m g itrac o naz ole 
T he st u d y da ys of d osi n g of itrac o naz ole a n d K R P- A 2 1 8 ma y be a me n de d t o e xte n d t he 
i nter val bet wee n t he first d ose of K R P- A 2 1 8 a n d t he first d ose of itrac o naz ole de pe n di n g o n 
t he o bser ve d t1/ 2 of 
.  
P ote nti al s u bjects will be scree ne d t o assess t heir eli gi bilit y t o e nter t he st u d y wit hi n 2 8 da ys 
pri or t o t he first d ose a d mi nistra ti o n. S u bjects will be a d mitte d i nt o t he st u d y site o n Da y - 1 
a n d be c o nfi ne d t o t he st u d y site u ntil disc har ge o n Da y 1 4. 
S u bjects  will ret ur n t o t he st u d y site f or a f oll o w- u p visit 7 t o 1 0 da ys after t he last d ose of 
K R P - A 2 1 8. T he f oll o w- u p peri o d ma y be e xte n de d de pe n di n g o n t he o bser ve d t 1/ 2 of 
 
Base d o n t h e o n g oi n g re vie w of t he safet y, t olera bilit y, a n d P K res ults, a d diti o nal 
n o nresi de ntial visits ma y be re q uire d. T he n u m ber of a d diti o nal visits per s u bject will n ot 
e xcee d 3 a n d will n ot e xte n d be y o n d 2 8 da ys after eac h fi nal d osi n g occasi o n. All s u bjects 
ma y sta y i n t he C R U e ve n o utsi de treat me nt peri o d d ue t o C O VI D- 1 9 ris ks. 
 
  
C CI
C CI
C CI
C CI






Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 3 6 of 8 6 
3. 2.  
 St u d y St art a n d E n d of St u d y Defi niti o ns  
T he start of t he st u d y is defi ne d as t he date t he first s u bject si g ns a n i nf or me d c o nse nt for m 
(I C F). T he p oi nt of e nr ollme nt  occ urs at t he ti me of s u bject n u m ber all ocati o n. T he e n d of t he 
st u d y is defi ne d as t he date of t he last s u bject’s last assess me nt (sc he d ule d or u nsc he d ule d). 
3. 3.  
A d diti o n al Gr o u ps  
F oll o wi n g re vie w of t he safet y, t olera bilit y, a n d P K data, a d diti o nal d ose gr o u ps ( w here 
s yste mic e x p os ure is n ot e x pecte d t o e xcee d t hat s tate d i n t he d ose escalati o n st o p pi n g criteria 
as detaile d i n Secti o n 3. 7 ) ma y be a d de d t o t he st u d y. U p t o 3 f urt her gr o u ps of 8 s u bjects ( 6 
K R P - A 2 1 8 a n d 2 place b o) i n Part A a n d 3 f urt her gr o u ps of 1 0 s u bjects ( 8 K R P- A 2 1 8 a n d 
2 place b o) i n Part B ma y be a d de d. T h e re q uire me nt f or a d diti o nal gr o u ps will be a gree d wit h 
t he S p o ns or a n d d oc u me nte d i n t he trial m aster file ( T M F). 
3. 4.  
Disc ussi o n of St u d y Desi g n , I ncl u di n g t he C h oice of C o ntr ol Gr o u ps 
F or Par ts A a n d B of t he st u d y, a se q ue ntial- gr o u p, asce n di n g d ose desi g n has bee n c h ose n 
f or safet y reas o ns as K R P- A 2 1 8 is i n t he earl y sta ges of cli nical de vel o p me nt, wit h Part A of 
t he st u d y bei n g t he first ti me it will be a d mi nistere d t o h u ma ns. Oral d oses ha ve bee n c h ose n 
f or eac h part of t he st u d y, as t his is t he i nte n de d cli nical r o ute of a d mi nistrati o n.  A 2 - peri o d 
desi g n has bee n c h ose n f or t he f o o d- effect ar m, as t his gi ves a wit hi n s u bject assess me nt of 
t he i nfl ue nce of f o o d o n t he P K of  
 a n d s o i ncreases t he p o wer of t he st u d y f or t he 
gi ve n n u m ber of s u bjects. 
It is t he i nte nt of Part B t o d ose s u bjects s uc h t hat stea d y state plas ma le vels of 
 are 
ac hie ve d a n d mai ntai ne d f or se veral da ys.  Base d o n t he a vaila ble n o ncli nical data, it is 
e x pecte d t hat t his will be ac hie ve d f oll o wi n g 3 da ys of o nce dail y d osi n g; h o we ver, a f ull 
re vie w of all t he a vaila ble safet y, t olera bilit y, a n d P K data fr o m Part A will be perf or me d t o 
c o nfir m t he d ose re gi me n f or Part B. If t he t1/ 2 of 
is l o n ger t ha n pre dicte d b y t he 
n o ncli nical data, o nce - dail y d osi n g ma y be m ore a p pr o priate o ver 1 4 da ys (as stea d y state 
will ta ke l o n ger t o ac hie ve). T he d ose re gi me n will c o m prise n o less t ha n o nce e ver y 3 da ys 
a n d will n ot e xcee d 3-ti mes dail y d osi n g. T he d osi n g d urati o n will n ot e xcee d 1 4 c o nsec uti ve 
da ys of d osi n g. 
Details of  t he d osi n g re gi me n a n d d urati o n use d f or Part B of t he st u d y will be d oc u me nte d i n 
t he T M F. A n i nter val of 7 t o 1 0 da ys bet wee n d oses of K R P - A 2 1 8 i n t he f o o d-effect ar m i n 
Part A is c o nsi dere d a de q u ate t o pre ve nt carr y o ver of K R P - A 2 1 8 b ut t he i nter val ma y be 
e xte n de d de pe n di n g o n t he o bser ve d t1/ 2 of 
 
Parts A  a n d B will be d o u ble- bli n d a n d place b o-c o ntr olle d i n or der t o a v oi d bias i n t he 
c ollecti o n a n d e val uati o n of data d uri n g its c o n d uct. Place b o has bee n c h ose n as t he c o ntr ol 
treat me nt t o assess w het her a n y o bser ve d effects are treat me nt relate d or si m pl y reflect t he 
st u d y c o n diti o ns. 
C o nti n u o us 1 2 -lea d E C G m o nit ori n g will be i ncl u de d i n t his st u d y i n or der t o e x pl ore 
p ote ntial K R P- A 2 1 8 effects o n t he Q T i nter val, wit h a vie w of s u p p orti n g a p ote ntial 
t h or o u g h Q T st u d y wai ver. 
 
  
C CI
C CI
C CI
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 3 7 of 8 6 
F or Part C of t he st u d y, t he fi xe d- se q ue nce desi g n t o be use d is t y pical f or i nteracti o n st u dies 
w here a relati vel y s mall n u m ber of s u bjects are re q uire d, beca use it all o ws i ntras u bject 
c o m paris o ns a n d re d uces i nters u bject v aria bilit y. Part C of t he st u d y will be o pe n -la bel 
beca use t he e n d p oi nts are n ot c o nsi dere d t o be s u bjecti ve.  
K R P - A 2 1 8 will be a d mi nistere d as si n gle d oses i n Part C, as si n gle oral d ose st u dies are 
us uall y perf or me d f or i nteracti o n st u dies f or c o m p o u n ds wit h li near P K as f o u n d f or 
K R P - A 2 1 8. Itrac o naz ole is t he refere nce p ote nt C Y P 3 A i n hi bit or rec o m me n de d i n t he E M A 
g ui deli ne [ 1 6 ], a n d a m o n g t h ose n ote d i n t he F D A draft g ui deli ne [1 7 ]. T he d ose le vel of 
itrac o naz ole was selecte d base d o n ac hie ve me nt of cli nicall y pr o ba ble C Y P 3 A i n hi biti o n a n d 
t he t y pical cli nical d ose ( 2 0 0 t o 4 0 0 m g dail y d ose ) of itrac o naz ole. 
N o ncli nic al data s u g gest t hat  
 is a C Y P 3 A 4 s u bstrate. If a si g nifica nt pr o p orti o n of 
meta b olis m i n h u ma ns i n dee d pr ocee ds t hr o u g h C Y P 3 A 4, t he a d mi nistrati o n of 
itrac o naz ole will si g nifica ntl y i n hi bit t he meta b olis m of 
, res ulti n g i n a n i ncrease 
i n e x p os ure of 
. 
C o n d ucti n g t he st u d y i n healt h y s u bjects miti gates t he p ote ntial c o nf o u n di n g effects of t he 
disease state a n d c o nc o mita nt me dicati o ns.  
3. 4. 1.  
D ose I nter v al  
F oll o wi n g t h or o u g h re vie w of all a vaila ble n o ncli nical data ( p har mac ol o gical a n d 
t o xic ol o gical), d osi n g i n eac h gr o u p i n Part A will be s uc h t hat 2 s u bjects ( 1 K R P- A 2 1 8 a n d 
1 place b o) will be d ose d at least 2 4 h o urs bef ore t he re mai ni n g 6 s u bjects. After d osi n g t he 
first 2 s u bjects o n a se parate da y, a mi ni m u m of a 5- mi n ute d osi n g i nter val f or t he re mai ni n g 
6 s u bjects i n eac h d ose-asce n di n g gr o u p is c o nsi dere d acce pta ble. C o nti n uati o n t o d ose t he 
re mai ni n g 6 s u bjects will be at t he In vesti gat or’s discreti o n.  
F or Part B, d osi n g at eac h d ose le vel will be s uc h t hat 2 male s u bjects ( 1 K R P- A 2 1 8 a n d 1 
place b o) will recei ve t he I M P at least 7 da ys bef or e t he re mai ni n g 8 s u bjects. After d osi n g t he 
first 2 s u bjects, a mi ni m u m of a 5- mi n ute d osi n g i nter val f or t he re mai ni n g 8 s u bjects i n eac h 
d ose-asce n di n g gr o u p is c o nsi dere d acce pta ble. C o nti n uati o n t o d ose t he re mai ni n g 8 s u bjects 
will be at t he I n vesti gat or’s discreti o n. 
3. 5.  
Selecti o n  of D oses i n t he St u d y  
Base d u p o n n o ncli nical data, n o cli nicall y i m p orta nt off- tar get effects are e x pecte d wit hi n t he 
pr o p ose d e x p os ure ra n ge. 
I n t he pi v otal 2- wee k t o xicit y st u dies i n rats a n d d o gs, t he N O A E L  was < 5 m g/ k g/ da y f or 
male rats, 5 m g/ k g/ da y f or fe male rats, a n d 2 m g/ k g/ da y f or d o gs ( b ot h se xes), a n d i n a 
n o n- pi v otal 2 -wee k t o xicit y st u d y i n mice, t he N O A E L was 1 0 m g/ k g/ da y f or male mice. 
I nfla m mat or y cell i nfiltrati o n i n t he l u me n of t he c oa g ulati n g gla n d i n male rats was o bser ve d 
at ≥5 m g/ k g/ da y. H o we ver, t his fi n di n g is n ot c o nsi dere d t o be rele va nt t o h u ma n safet y 
beca use t he c oa g ulati n g gla n d is a n access or y se x gla n d i n rats, n ot i n h u ma ns, a n d t he 
fi n di n g ma y be s pecies s pecific as n o relate d c ha n ges were see n i n t he d o g or m o use. 
F urt her m ore, n o ot her re pr o d ucti ve or ga n fi n di n gs were n ote d i n rats , a n d n o a d verse effects 
o n male re pr o d ucti ve perf or ma nce were o bser ve d i n a preli mi nar y male fertilit y st u d y i n rats. 
N o ot her fi n di n gs were o bser ve d i n male rat at d ose of 5 m g/ k g. T he ma xi m u m rec o m me n de d 
 
  
C CI
C CI
C CI
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 3 8 of 8 6 
starti n g d ose ( M R S D) f or a 6 0 k g s u bject, base d o n t he m ost c o nser vati ve h u ma n e q ui vale nt 
d ose ( H E D) calc ulati o n a m o n g t he treat me nt gr o u ps calc ulate d fr o m t he m ost se nsiti ve 
s pecies, rat (l o west dose: 5 m g/ k g/ da y [ N O A E L n ot esta blis he d f or male rat]; H E D: 
4 8 m g/s u bject) is 4. 8  m g/s u bject, i ncl u di n g a 1 0-f ol d safet y fact or.[1 9 ] K R P - A 2 1 8 s h o ws 
p har mac ol o gical effects i n mice fr o m 1 m g/ k g/ da y, w hic h is e q ui vale nt t o a H E D of 4. 9 m g 
f or a 6 0 k g s u bject. T he pr o p ose d starti n g d ose of 1 m g i ncl u des a n e xtra 5-f ol d safet y fact or, 
c o m pare d wit h t he M R S D calc ulate d fr o m t he 5 m g/ k g/ da y f or rats a n d t he H E D calc ulate d 
fr o m t he 1 m g/ k g/ da y f or mice. 
D ue t o t he t o xicit y o bser ve d wit h res pect t o gastr oi ntesti nal effect t hat was o bser ve d i n 
precli nical st u d y i n d o gs,[ 1 8 ] t he l o wer d ose escalati o n i ncre me nts s h o ul d be selecte d. T he 
hi g hest cli nical d ose s h o ul d be set  s o t hat pr o p ose d ma xi m u m i n di vi d ual e x p os ure f or d ose 
escalati o n st u dies is ca p pe d t o t he e x p os ure see n  i n t he male rats at 5 m g/ k g/ da y. T he 
c orres p o n di n g C ma x a n d A U C 0- 2 4 h val ues i n male rats at t he 5 m g/ k g/ da y are 1 2 2 0 n g/ m L a n d 
3 9 3 0 n g• h/ m L , res pecti vel y.  
In a C V - B 3 infecte d m o use m o del, t he efficac y of 
 was o bser ve d i n a d ose 
de pe n de nt ma n ner a n d  
 s h o we d a nti viral efficac y a n d i m pr o ve me nt of s ur vi val 
rate.[1 8 ] Si g nifica nt efficac y wa s o bser ve d at 1, 3, a n d 1 0 m g/ k g; h o we ver, t he pre dicte d 
t hera pe utic ra n ge  ( A U C0- 2 4 h) i nitiall y selecte d was 2 7 6 t o 9 8 8 n g• h/ m L, as 9 8 8 n g• h/ m L (t he 
A U C 0- 2 4 h at 3 m g/ k g) was l o wer t ha n t he e x p os ure at t he N O A E L i n male rats  w hereas t he 
m o use e x p os ure at 1 0 m g/ k g ( A U C 0- 2 4 h of 4 9 2 0 n g• h/ m L ) was hi g her t ha n t he e x p os ure at t he 
N O A E L i n male rats. T heref ore, t he t hera pe utic ra n ge i nitiall y pr o p ose d was a c o nser vati ve 
esti mate a n d t he o pti mal cli nical t hera pe utic ra n ge ma y e xcee d  t he A U C0- 2 4 h of 9 8 8 n g• h/ m L.  
C o nsi deri n g t hat t he i n dicati o n of K R P- A 2 1 8 is H R V  i nfecti o n wit h a hi g h ris k of 
pr o gressi n g t o l o wer res pirat or y i nfecti o n or ot her se vere c o m plicati o ns , it is necessar y t o 
ac hie ve t he e x pecte d e x p os ure o n t he first da y of a d mi nistrati o n. Base d o n t he mea n A U C0- 2 4 h 
o bser ve d i n Gr o u ps A 1 t o A 3  ( Part A of t his st u d y), t he e x pecte d cli nical t hera pe utic d ose 
t hat c o vers  t he A U C 0- 2 4 h of 2 7 6 t o 9 8 8 n g• h/ m L o n Da y 1 is 2 t o 8 m g ( Ta ble  4). T o c o ver t he 
esti mate d stea d y -state e x p os ure of 8 m g wit h a si n gle d ose i n t his st u d y, t he mea n e x p os ure 
w o ul d nee d t o be a b o ve 1 7 3 0 n g• h/ m L ( mea n A U C 0- 2 4 h* R) base d o n c urre nt h u ma n P K data. 
T a ble  4: 
O bser ve d a n d Esti m ate d H u m a n E x p os ure at D a y 1 a n d S te a d y St ate  
D ose  ( m g) 
Me a n A U C
0- 2 4 h ( n g· h/ m L) 
(D a y 1)  
Me a n A U C
0- 2 4 h * R  ( n g· h/ m L) 
(Ste a d y S t ate) 
1  
1 4 5  
N A  
2 *  
2 7 1  
4 3 4  
3  
3 8 8  
N A  
6  
8 1 3  
N A  
8 *  
1 0 8 0  
1 7 3 0  
A b bre viati o ns: A U C 0- 2 4 h = area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o 2 4 h o urs; N A  = n ot a vaila ble ; R = 
acc u m ulati o n rati o . 
R = 1. 6 (calc ulate d usi n g t he ge o metric mea n half life val ue fr o m 6 m g  K R P - A 2 1 8) 
* Esti mate d A U C 0- 2 4 h val ues calc ulate d base d o n t he ge o metric mea n A U C 0- 2 4 h fr o m 6 m g  K R P -A 2 1 8, ass u mi n g li nearit y 
acr oss d ose. 
 
  
C CI
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 3 9 of 8 6 
M ore o ver, c o nsi deri n g t he i n di vi d ual A U C
0- 2 4 h val ues o bser ve d i n Gr o u ps A 1 t o A 3, it has 
bee n ass u me d t hat t he ma xi m u m A U C 0- 2 4 h ma y be i n t he ra n ge of a p pr o xi matel y 2-f ol d t he 
mea n  A U C 0- 2 4 h. T heref ore, it is c o nsi dere d reas o na ble t o set t he d ose escalati o n criteria at t he 
N O A E L e q ui vale nt e x p os ure ( ma xi m u m A U C 0- 2 4 h of 3 9 3 0 n g• h/ m L ), w hic h is a p pr o xi matel y 
2- f ol d of t he esti mate d stea d y-state e x p os ure at 8 m g ( mea n A U C 0- 2 4 h* R of 1 7 3 0 n g• h/ m L ). 
I n a d diti o n, base d o n safet y data fr o m t his o n g oi n g st u d y at d oses of 1 t o 6 m g ( Gr o u ps A 1 t o 
A 3), n o gastr oi ntesti nal fi n di n gs of a n y c o ncer n ha ve bee n o bser ve d. 
T heref ore, i n t his P hase 1 st u d y, it is pla n ne d t o i n vesti gate hi g her d o ses wit hi n t he ra n ge u p 
t o t he N O A E L ( 5 m g/ k g i n male rats: Cma x  1 2 2 0 n g/ m L, A U C 0- 2 4 h 3 9 3 0 n g• h/ m L) as t he 
ma xi m u m e x p os ure f or i n di vi d uals.  
E x pl ori n g t hese hi g her d oses i n a P hase 1 st u d y will all o w A Es  t o be m ore cl osel y m o nit ore d 
t ha n i n P hase 2 or 3 st u dies.[2 0 ] It will als o all o w t he e x pl orat or y o bjecti ve t o c ollect data f or 
c o nce ntrati o n -Q Tc a nal ys is t o be m ore rele va nt as acc or di n g t o re g ulator y g ui da nce, t he Q Tc 
res p o nse s h o ul d be c haracterise d at a s ufficie ntl y hi g h m ulti ple of t he cli nicall y rele va nt 
e x p os ure.[2 1 , 2 2 , 2 3 ]   
 was meta b olize d b y C Y P 3 A, C Y P 2 C 9, C Y P 2 C 8, a n d C Y P 2 D 6, a n d t he 
c o ntri b uti o n rati o of C Y P 3 A was deter mi ne d as ra n gi n g fr o m 6 8. 4 t o 9 4. 4 %. Beca use of t he 
hi g h c o ntri b uti o n rati o f or C Y P 3 A, c o- a d mi nistrati o n  of K R P - A 2 1 8 wit h dr u gs t hat i n d uce or 
i n hi bit C Y P 3 A ma y affect t he e x p os ure of 
. T he d ose le vel i n Part C will be 
selecte d base d o n P K pr ofile i n prece di n g Parts A a n d/ or B. 
T he pr o p ose d I M P d ose le vels f or Parts A, B, a n d C are s h o w n i n  Ta ble  5. 
T a ble  5: 
Pr o p ose d  I n vesti g ati o n al Me dici n al Pr o d uct D ose Le vel s f or P arts A , B, 
a n d C 
St u d y 
P art   
Gr o u p   
S u bject 
N u m bers   
Tre at me nts  
K R P -A 2 1 8 
D ose 
Diet ar y St ate   
Se x   
Part A   A 1   
0 1 0 1 – 0 1 0 8   
6 K R P -A 2 1 8  
2 place b o  
1 m g 
F aste d  
Male  
 
A 2a a  
0 1 0 9 – 0 1 1 6   
6 K R P -A 2 1 8  
2 place b o 
( 2 d oses)  
3 m g 
F aste d a n d Fe d   
Male   
 
A 2 b
a  
0 1 1 7  – 0 1 2 4   
6 K R P -A 2 1 8  
2 place b o   
3 m g 
F aste d  
Fe male   
 
A 3   
0 1 2 5  – 0 1 3 2   
6 K R P -A 2 1 8  
2 place b o  
6 m g  
F aste d  
Male  
 
A 4
 
   
0 1 3 3  – 0 1 4 0   
6 K R P -A 2 1 8  
2 place b o  
1 2 m g  
F aste d  
Male  
 
A 5   
0 1 4 1 – 0 1 4 8   
6 K R P -A 2 1 8  
2 place b o  
ma xi m u m 
d ose of 2 4  m g  F aste d  
Male   
Part B   B 1   
0 2 0 1 – 0 2 1 0   
8 K R P -A 2 1 8  
2 place b o   
X m g  
F aste d/ Fe d
b  
Male  
 
B 2   
0 2 1 1 – 0 2 2 0   
8 K R P -A 2 1 8  
2 place b o   
X m g  
F aste d/ Fe d
 b  
Male  
 
  
C CI
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 4 0 of 8 6 
 
B 3   
0 2 2 1 – 0 2 3 0   
8 K R P -A 2 1 8  
2 place b o   
X m g  
F aste d/ Fe d
 b  
Male  
 
B 4   
0 2 3 1  – 0 2 4 0   
8 K R P -A 2 1 8  
2 place b o   
X m g  
F aste d/ Fe d
 b  
Male  
Part C   C 1   
0 3 0 1  – 03 1 2   
1 2 K R P -A 2 1 8  
( 2 d oses)  
X m g  
F aste d/ Fe d
 b  
Male  
a Fe male s u bjects i n Gr o u p A 2 b will partici pate i n Treat me nt Peri o d 1 o nl y. Male s u bjects i n Gr o u p A 2 a will be 
a d mi nistere d t he sa me treat me nt i n b ot h treat me nt peri o ds a n d will be i n t he faste d state i n Treat me nt Peri o d 1 a n d i n t he 
fe d state i n Treat me nt Peri o d 2. 
b T he dietar y state f or d osi n g will be deter mi ne d b y c o m pari n g t he P K data bet wee n t he fe d a n d faste d state i n Gr o u p A 2 a.  
F or Part A, t he pla n ne d first d ose le vel is 1 m g. T he d ose le vel of t he s u bse q ue nt gr o u p will 
be set s o t hat t he pre dicte d mea n e x p os ure d oes n ot e xcee d 5 -f ol d t he mea n e x p os ure of t he 
pre vi o us gr o u p f or pre dicte d n o n p har mac ol o gicall y acti ve d ose, a n d 2- f ol d t he mea n 
e x p os ure of t he pre vi o us gr o u p f or pre dicte d p har mac ol o gicall y acti ve d ose. T he hi g hest d ose 
le vel will be g ui de d b y t he re vie w of safet y, t olera bilit y, a n d P K data fr o m pri or d ose le vels. 
I n eac h gr o u p i n Part A, pre dicte d ma xi m u m s yste mic e x p os ure ( Cma x  a n d A U C 0- 2 4 h) of 
 i n i n di vi d ual s u bjects will n ot e xcee d a C ma x  of 1 2 2 0 n g/ m L a n d/ or a n A U C0- 2 4 h 
of 3 9 3 0 n g• h/ m L ; i.e., s yste mic e x p os ure will n ot e xcee d t hat see n i n t he male rat, w hic h was 
t he l o west s yste mic e x p os ure t hat was see n at eit her 5 m g/ k g/ da y i n rats or t he N O A E L  of 
2 m g/ k g/ da y i n d o gs. C o nsi deri n g t he pre dicte d ma xi m u m s yste mic e x p os ure a n d t he 
o bser ve d ma xi m u m i n di vi d ual A U C 0- 2 4 h at 6 m g i n Part A, t he hi g hest d ose is esti mate d t o be 
1 7 m g (Ta ble  6). Re gar dless of t his esti mate, t he hi g hest d ose will be deter mi ne d base d o n 
t he re vie w of t he ma xi m u m A U C0- 2 4 h val ue at t he pre vi o us d ose le vel; ho we ver, t he 
ma xi m u m d ose t hat will  be a d mi nistere d i n Part A will n ot e xcee d 2 4 m g, w hic h is 2-f ol d t he 
pre vi o us d ose le vel. 
T a ble  6:  
Esti m ate d H u m a n E x p os ure at D a y 1  
D ose  ( m g) 
C m a x ( n g/ m L) 
A U C 0- 2 4 h ( n g• h/ m L) 
 
Me a n  
M a xi m u m  
Me a n  
M a xi m u m  
6 
6 0. 3  
9 5. 7  
8 1 3  
1 3 5 0  
1 2 *  
1 2 1  
1 9 1  
1 6 3 0  
2 7 0 0  
1 7 *  
1 7 1  
2 7 1  
2 3 0 0  
3 8 3 0  
* C ma x  a n d A U C 0- 2 4 h were calc ulate d base d o n ge o metric mea n para meter val ues fr o m 6 m g K R P - A 2 1 8 i n Part A, ass u mi n g 
li nearit y acr oss d ose. 
F or Part B, t he d ose le vels, d osi n g re gi me n, a n d dietar y stat us will be c o nfir me d base d o n t he 
re vie w of all a vaila ble safet y, t olera bilit y, a n d P K data i n t he prece di n g gr o u ps i n Parts A 
a n d/ or B. F or all gr o u ps i n Part B, selecte d d ose le vels will ha ve a pre dicte d mea n 
stea d y-state e x p os ure (C ma x  a n d A U C0- 2 4 h) t hat d oes n ot e xcee d t he mea n e x p os ure ( C ma x  a n d 
A U C 0- 2 4 h) pre vi o usl y f o u n d ge nerall y safe a n d well t olerate d i n Part A. In a d diti o n, pre dicte d 
ma xi m u m s yste mic e x p os ure le vel  ( Cma x  a n d A U C0- 2 4 h) of
 i n i n di vi d ual s u bjects 
t hat d oes n ot e xcee d t he ma xi m u m  e x p os ure ( Cma x  a n d A U C 0- 2 4 h) i n i n di vi d ual s u bjects i n t he 
prece di n g gr o u ps i n Part A  a n d will n ot e xcee d a C ma x  of 1 2 2 0 n g/ m L a n d/ or a n A U C0- 2 4 h of 
3 9 3 0 n g• h/ m L; i.e., s yste mic e x p os ure will n ot e xcee d t hat see n i n t he male rat, w hic h was 
t he l o west s yste mic e x p os ure t hat was see n at eit her 5 m g/ k g/ da y i n rats.  
 
  
C CI
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 4 1 of 8 6 
F or Part C, t he d ose le vel will be c o nfir me d base d o n t he re vie w of all a vaila ble safe t y, 
t olera bilit y, a n d P K data i n prece di n g Parts A a n d/ or B. T he act ual d ose le vel of K R P - A 2 1 8 
will be set s o t hat t he pre dicte d mea n e x p os ure ( C ma x  a n d A U C0- 2 4 h) of 
 o n 
c o-a d mi nistrati o n  of itrac o naz ole will n ot e xcee d t he mea n e x p os ure ( C ma x  a n d A U C 0- 2 4 h) 
pre vi o usl y f o u n d ge nerall y safe a n d well t olerate d i n Part A a n d i n a d diti o n, pre dicte d 
ma xi m u m s yste mic e x p os ure le vel ( C ma x  a n d A U C0- 2 4 h) of 
 o n c o-a d mi nistrati o n 
of itrac o naz ole i n i n di vi d ual s u bjects d oes n ot e xcee d t he ma xi m u m  e x p os ure ( Cma x  a n d 
A U C 0- 2 4 h) i n i n di vi d ual s u bjects i n Part A a n d will n ot e xcee d a C ma x  of 1 2 2 0 n g/ m L a n d/ or 
a n A U C 0- 2 4 h of 3 9 3 0 n g• h/ m L; i.e., s yste mic e x p os ure will n ot e xcee d t hat see n i n t he male 
rat, w hic h was t he l o west s yste mic e x p os ure t hat was see n at eit her 5 m g/ k g/ da y i n rats .  
T he act ual d ose le vels will be deter mi ne d base d o n e mer gi n g data. 
Details of all d oses a d mi nistere d i n Parts A t o C of t he st u d y will be d oc u me nte d i n t he T M F . 
3. 6.  
D ose Esc al ati o n 
D oses will be a d mi nistere d i n a n escalati n g ma n ner f oll o wi n g satisfact or y re vie w b y t he 
S p o ns or, I n vesti gat or , a n d La bc or p Dr u g De vel o p me nt Me dical M o nit or  of t he safet y a n d 
t olera bilit y data ( u p t o 4 8 h o urs p ost last d ose) a n d plas ma P K data ( u p t o 2 4 h o u rs p ost last 
d ose) fr o m t he pre vi o us l o wer d ose le vel. D oses ma y be re d uce d a n d ma y be l o wer t ha n t he 
starti n g d ose. T here will be a mi ni m u m of 6 da ys bet wee n d ose escalati o ns t o all o w s ufficie nt 
ti me f or a n a de q uate safet y re vie w. 
D ose escalati o n i n b ot h Parts A a n d B will o nl y occ ur if data fr o m a mi ni m u m of 6 s u bjects 
ha ve bee n re vie we d fr o m t he pre vi o us l o wer d ose gr o u p, s uc h t hat data fr o m a mi ni m u m of 
4 s u bjects w h o ha ve recei ve d K R P- A 2 1 8 will be use d t o ma ke t he d ose escalati o n decisi o n. 
T he j ustificati o n f or t his is as f oll o ws:  
•  Base d u p o n n o ncli nical data, n o cli nicall y i m p orta nt off- tar get effects are e x pecte d 
wit hi n t he pr o p ose d d ose ra n ge. 
•  A mi ni m u m of 4 s u bjects recei vi n g t he acti ve dr u g is c o nsi dere d s ufficie nt t o 
c haracterise t he safet y pr ofile  a n d P K res p o nse t o K R P - A 2 1 8. 
Bet wee n eac h d ose escalati o n, t he In vesti gat or will re vie w all a vaila ble data i n a bli n de d 
ma n ner t o e ns ure it is safe t o pr ocee d wit h t he pla n ne d d ose escalati o n. A n i nteri m safet y 
re p ort, s u m marisi n g res ults fr o m all a vaila ble safet y assess me nts, will be se nt t o t he S p o ns or 
a n d La bc or p Dr u g De vel o p me nt Me dical M o nit or pri or t o t he start of eac h s uccessi ve gr o u p. 
A n y cli nicall y si g nifica nt res ults will be disc usse d wit h t he S p o ns or bef ore d ose escalati o n 
c o nti n ues. I nteri m P K data will als o be re vie we d i n ter ms of d ose escalati o n a n d t o c o n fir m 
t hat t he st u d y desi g n re mai ns a p pr o priate. I n t he e ve nt of a disa gree me nt bet wee n S p o ns or 
a n d I n vesti gat or o n t he d ose escalati o n decisi o n, t he decisi o n of t he I n vesti gat or will be 
u p hel d. 
3. 7.  
D ose Esc al ati o n St o p pi n g Criteri a  
T he st u d y will be halte d if 1 or m ore s u bjects e x perie nce a n S A E t hat is c o nsi dere d t o be 
relate d t o I M P or 2 or m ore s u bjects i n t he sa me gr o u p e x perie nce se vere A Es t hat are 
 
  
C CI
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 4 2 of 8 6 
c o nsi dere d t o be relate d t o I M P. If, f oll o wi n g a n i nter nal safet y re vie w, t he S p o ns or dee ms it 
a p pr o priate to restart t he st u d y, t his ca n be d o ne f oll o wi n g a p pr o val of a s u bsta ntial pr ot oc ol 
a me n d me nt.  
F or b ot h Parts A a n d B, a c o ns ultati o n bet wee n t he I n vesti gat or, S p o ns or , a n d La bc or p Dr u g 
De vel o p me nt Me dical M o nit or will be hel d pri or t o d osi n g t he ne xt gr o u p. D ose escalati o n 
will st o p if:  
•  Cli nicall y  rele va nt si g ns or s y m pt o ms of si milar nat ure occ ur i n 2 or m ore s u bjects i n 
a gr o u p t hat, i n t he o pi ni o n of t he I n vesti gat or, warra nt st o p pi n g of d ose escalati o n. 
I n partic ular, t he I n vesti gat or ( or desi g nee) s h o ul d caref ull y m o nit or si g ns or 
s y m pt o ms bel o w: 
o  s y m pt o ms s uc h as i na p pete nce, a b d o mi nal diste nsi o n, a b d o mi nal disc o mf ort, 
a b d o mi nal pai n, na usea a n d v o miti n g 
o  si g ns/fi n di n gs s uc h as a b d o mi nal te n der ness a n d decrease d or a bse nt 
peristaltic s o u n ds  
o  a b n or mal faeces s uc h as diarr hea, he mat oc hezia, a n d mele na. 
•  I na p pete nce, a b d o mi nal diste nsi o n, a b d o mi nal disc o mf ort, a b d o mi nal pai n, na usea 
a n d v o miti n g t hat pre ve nt s u bjects fr o m eati n g a meal o n 3 or m ore occasi o ns o n 2 
c o nsec uti ve da ys i n 1 or m ore s u bjects i n a gr o u p.  
•  Diarr hea, defi ne d as 7 or m ore e pis o des, rate d as ≥5 o n t he Brist ol St o ol C hart, i n 1 
da y f or 2 c o nsec uti ve da ys i n 1 or m ore s u bjects i n a gr o u p. 
•  He mat oc hezia a n d mele na wit h visi ble bl o o d t hat are c o nsi dere d t o be ca use d b y 
gastr oi ntesti nal blee di n g i n 1 or m ore s u bjects i n a gr o u p. 
•  Cli nicall y si g nifica nt i ncreases i n li ver f u ncti o n tests c o m pare d t o baseli ne 
meas ure me nts, d efi ne d as A S T, A L T, A L P, a n d/ or γ-G T P ≥3 × t he u p per li mit of 
n or mal ( U L N) a n d/ or T -Bil ≥2 × U L N (c o nfir me d wit h re peat testi n g) i n 2 or m ore 
s u bjects i n a gr o u p. 
•  Ma xi m u m  s yste mic e x p os ure le vel of 
i n i n di vi d ual s u bjects i n t he ne xt 
gr o u p pre dicte d t o e xcee d a C ma x  of 1 2 2 0 n g/ m L a n d/ or a n A U C0- 2 4 h of 
3 9 3 0 n g• h/ m L. 
T he d osi n g st at us of a n i n di vi d ual s u bject ma y be u n bli n d e d t o re vie wers of t he safet y data if 
necessar y f or safet y reas o ns or if perti ne nt t o d ose escalati o n decisi o ns. T he u n bli n de d stat us 
will be ke pt t o a mi ni m u m n u m ber of re vie wers, base d o n perti ne nce t o t heir r ole a n d 
rele va nt tas k. F urt her i nf or mati o n o n  bli n di n g ca n be f o u n d i n Secti o n  5. 4 . 
4.  S E L E C TI O N O F S T U D Y P O P U L A TI O N  
4. 1.  
I ncl usi o n Criteri a 
S u bjects m ust satisf y all of t he f oll o wi n g criteria  at t he scree ni n g visit u nless ot her wise 
state d: 
1.  Male or fe male a d ults, bet wee n 2 0 a n d 5 5 years of a ge, i ncl usi ve.  
 
  
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 4 3 of 8 6 
2.  B o d y wei g ht ≥5 0 k g, wit h b o d y mass i n de x ( B MI) bet wee n 1 8. 0 a n d 3 0. 0 k g/ m 2, 
i ncl usi ve. 
3.  I n g o o d healt h, deter mi ne d b y n o cli nicall y si g nifica nt fi n di n gs fr o m me dical hist or y, 
p h ysical e xa mi nati o n, 1 2- lea d E C G, vital si g ns meas ure me nts, a n d cli nical la b orat or y 
e val uati o ns (c o n ge nital n o n he m ol ytic h y per bilir u bi ne mia [e g, Gil bert’s s y n dr o me] is 
n ot acce pta ble) at Scree ni n g or Da y -1 as assesse d b y t he I n vesti gat or ( or desi g nee).  
4.  Fe males will n ot be pre g na nt or lactati n g, a n d fe males of c hil d beari n g p ote ntial will 
a gree t o use c o ntrace pti o n a n d t o n ot d o nate e g gs ( o va, o oc ytes) as detaile d i n 
A p pe n di x 4 . Males will a gree t o use c o ntrace pti o n a n d t o n ot d o nate s per m  as detaile d 
i n A p pe n di x 4 . Fe males of n o nc hil d beari n g p ote ntial are defi ne d as per ma ne ntl y sterile  
(ie, d ue t o h ysterect o m y, bilateral sal pi n gect o m y, a n d/ or bilateral o o p h orect o m y), or 
p ost me n o pa usal, as defi ne d i n A p pe n di x 4 . 
5.  A ble t o c o m pre he n d a n d willi n g t o si g n a n I C F a n d t o a bi de b y t he st u d y restricti o ns. 
4. 2.  
E xcl usi o n Criteri a  
S u bjects will be e xcl u de d fr o m t he st u d y if t he y satisf y a n y of t he f oll o wi n g criteria at t he 
scree ni n g v isit u nless ot her wise state d: 
1.  Si g nifica nt hist or y or cli nical ma nifestati o n of a n y meta b olic, aller gic, der mat ol o gical, 
he patic, re nal, hae mat ol o gical , p ul m o nar y, car di o vasc ular, gastr oi ntesti nal, ne ur ol o gical, 
res pirat or y, e n d ocri ne, or ps yc hiatric dis or der, as deter mi ne d b y t he I n vesti gat or ( or 
desi g nee). 
2.  Cli nicall y si g nifica nt E C G a b n or malit y at scree ni n g, i ncl u di n g, b ut n ot li mite d t o: 
a. Q Tc F > 4 5 0  ms c o nfir me d b y re peat meas ure me nt  
b.  Q R S d urati o n > 1 1 0 ms c o nfir me d b y re peat meas ure me nt  
c. P R i nter val > 2 2 0  ms c o nfir me d b y re peat meas ure me nt 
d.  Fi n di n gs w hic h w o ul d ma ke Q Tc meas ure me nts diffic ult of Q Tc data 
u ni nter preta ble  
e. Hist or y of a d diti o nal ris k fact ors f or t orsa des de p oi ntes (e g, heart fail ure, 
h y p o kale mia, fa mil y hist or y of l o n g Q T s y n dr o me) 
3.  Cli nicall y si g nifica nt re nal  disease, ne p hrect o m y, re nal tra ns pla nt, or creati ni ne 
cleara nce  < 60 m L/ mi n/ 1. 7 3 m 2 as calc ulate d b y usi n g t he C oc kcr oft- Ga ult e q uati o n: 
a. [ 1.2 3 × ( 1 4 0 – a ge) × [ wei g ht i n k g)] ÷ (ser u m creati ni ne i n μ m ol/ L) – if male 
b.  [ 1. 0 4 × ( 1 4 0 – a ge) × ( wei g ht i n k g)] ÷ (ser u m creati ni ne i n μ m ol/ L) – if 
fe male 
4.  Ser u m  c o nce ntrati o ns of T G, T- CH O , L D L- C t hat are a b o ve U L N, or ser u m 
c o nce ntrati o n of H D L- C is bel o w t he l o wer li mit of n or mal a n d are dee me d cli nicall y 
si g nifica nt b y t he I n vesti gat or. 
5.  P ositi ve pre g na nc y test at scree ni n g or Da y - 1 (fe male s u bjects). 
6.  Cli nicall y si g nifica nt i m paire d he patic f u ncti o n at scree ni n g or Da y - 1 (c o nfir me d b y 
re peat); A S T or A L T > 1. 2 5 × U L N a n d / or T-Bil > 1. 5 × U L N.  
 
  


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 4 4 of 8 6 
7.  U n willi n g or u na ble t o eat hi g h- fat brea kfast; e. g. s u bject is ve getaria n or has f o o d 
aller gies/ i nt olera nces (f or s u bjects recr uite d i nt o Gr o u p A 2a).  
8.  Hist or y of si g nifica nt h y perse nsiti vit y, i nt olera nce, or aller g y t o itrac o naz ole . ( Part C 
o nl y) 
9.  Hist or y of si g nifica nt h y perse nsiti vit y, i nt olera nce, or aller g y t o a n y dr u g c o m p o u n d, 
f o o d, or ot her s u bsta nce, u nless a p pr o ve d b y t he I n vesti gat or ( or desi g nee). 
1 0.  Hist or y of st o mac h or i ntesti nal s ur ger y or resecti o n i ncl u di n g c h olec ystect o m y t hat 
w o ul d p ote ntiall y alter a bs or pti o n a n d/ or e xcreti o n of orall y a d mi nistere d dr u g s 
( u nc o m plicate d a p pe n dect o m y a n d her nia re pair will be all o we d). 
1 1.  Hist or y of alc o h olis m or dr u g/c he mical a b use wit hi n 2 years pri or t o Da y - 1. 
1 2.  Alc o h ol c o ns u m pti o n of > 1 4 u nits per wee k . O ne u nit of alc o h ol e q uals 1/ 2 pi nt 
( 2 8 5 m L) beer or la ger, 1 glass ( 1 2 5 m L) of wi ne, or 1/ 6 gill ( 2 5 m L) of s pirits. 
1 3.  P ositi ve alc o h ol breat h test res ult or p ositi ve uri ne dr u g a n d c oti ni ne scree n (c o nfir me d 
b y re peat) at Scree ni n g or Da y - 1. 
1 4.  P ositi ve he patitis pa nel a n d/ or p ositi ve h u ma n i m m u n o deficie nc y vir us test. 
1 5.  P osit i ve faecal occ ult bl o o d test. F or fe male s u bjects, t he faecal  occ ult bl o o d test s h o ul d 
be c o n d ucte d at least 3 da ys after t he c o m pleti o n of me nstr uati o n. 
1 6.  Partici pati o n i n a cli nical st u d y i n v ol vi n g a d mi nistrati o n of a n i n vesti gati o nal dr u g ( ne w 
c he mical e n tit y) i n t he past 9 0 da ys pri or t o d osi n g. 
1 7.  Use or i nte n d t o use a n y me dicati o ns/ pr o d ucts k n o w n t o alter dr u g a bs or pti o n, 
meta b olis m, or eli mi nati o n pr ocesses, i ncl u di n g St. J o h n’s w ort, wit hi n 3 0 da ys pri or t o 
d osi n g. 
1 8.  Use or i nte n d t o use a n y prescri pti o n me dicati o ns/ pr o d ucts wit hi n 1 4 da ys or 5 
half- li ves ( w hic he ver is l o n ger) pri or t o d osi n g, u nless dee me d acce pta ble b y t he 
I n vesti gat or ( or desi g nee). 
1 9.  Use or i nte n d t o use str o n g or m o derate C Y P 3 A 4 i n hi bit ors or  i n d ucers wit hi n 1 4 da ys 
or 5 half- li ves ( w hic he ver is l o n ger) pri or t o d osi n g. 
2 0.  Use or i nte n d t o use str o n g C Y P 2 C 9, 2 C 8 a n d 2 D 6 i n hi bit ors or i n d ucers wit hi n 1 4 da ys 
or 5 half- li ves ( w hic he ver is l o n ger) pri or t o d osi n g. 
2 1.  Use or i nte n d t o use sl o w release m e dicati o ns/ pr o d ucts c o nsi dere d t o still be acti ve 
wit hi n 1 4 da ys pri or t o d osi n g, u nless dee me d acce pta ble b y t he I n vesti gat or ( or 
desi g nee). 
2 2.  Use or i nte n d t o use a n y n o n prescri pti o n me dicati o ns/ pr o d ucts i ncl u di n g vita mi ns, 
mi nerals, a n d p h yt ot hera pe utic/ her bal/ pla nt deri ve d pre parati o ns wit hi n 7 da ys pri or t o 
d osi n g, u nless dee me d acce pta ble b y t he I n vesti gat or ( or desi g nee). 
2 3.  Use of t o bacc o or nic oti ne -c o ntai ni n g pr o d ucts wit hi n 3 m o nt hs pri or t o Da y - 1, or 
p ositi ve c oti ni ne test at scree ni n g or Da y - 1.  
2 4.  I n gesti o n of p o p p y see d-, Se ville ora n ge-, or gra pefr uit-c o ntai ni n g f o o ds or be vera ges 
wit hi n 7 da ys pri or t o Da y - 1. 
2 5.  C o ns u m pti o n of caffei ne- or xa nt hi ne-c o ntai ni n g f o o ds a n d be vera ges wit hi n 3 6 h o urs 
pri or t o Da y - 1. 
 
  


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 4 5 of 8 6 
2 6.  Partici pati o n i n stre n u o us e xercise d wit hi n 7 da ys pri or t o Da y - 1. 
2 7.  Recei pt of bl o o d pr o d ucts wit hi n 2 m o nt hs pri or t o Da y - 1. 
2 8.  D o nati o n of bl o o d fr o m 3 m o nt hs pri or t o scree ni n g, plas ma fr o m 2 wee ks pri or t o 
scree ni n g, or platelets fr o m 6 wee ks pri or t o scree ni n g. 
2 9.  P o or peri p heral ve n o us access . 
3 0.  S u bject d oes n ot ha ve re g ular b o wel ha bit. Re g ular b o wel ha bit is defi ne d as at least 1 
b o wel m oti o n per da y. 
3 1.  Ha ve pre vi o usl y c o m plete d or wit h dra w n fr o m t his st u d y or ha ve pre vi o usl y recei ve d 
t he I M P. 
3 2.  A d mi nistrati o n  or pla n ne d a d mi nistrati o n of a C or o na vir us Disease 2 0 1 9 ( C O VI D 1 9) 
vacci ne i n t he past 2 8 da ys pri or t o d osi n g u ntil after t he f oll o w - u p visit. 
3 3.  S u bject is, i n t he o pi ni o n of t he I n vesti gat or ( or desi g nee), u nli kel y t o c o m pl y wit h t he 
pr ot oc ol or u ns uita ble t o partici pate i n t his st u d y f or a n y reas o n. 
4. 3.  
S u bject N u m ber a n d I de ntific ati o n  
S u bjects will ha ve a u ni q ue i de ntificati o n n u m ber use d at s cree ni n g. S u bjects will be assi g ne d 
a s u bject n u m ber pri or t o t he first d osi n g occasi o n. Assi g n me nt of s u bject n u m bers will be i n 
asce n di n g or der a n d n o n u m bers will be o mitte d (e g, i n Part A s u bjects 0 1 0 1, 0 1 0 2, etc, i n 
Part B s u bjects 0 2 0 1, 0 2 0 2, etc, a n d i n Part C s u bjects 0 3 0 1, 0 3 0 2, etc,). Re place me nt 
s u bjects (Secti o n  4. 4 ) will be assi g ne d a s u bject n u m ber c orres p o n di n g t o t he n u m ber of t he 
s u bject he/s he is re placi n g pl us 1 0 0 0 (e g, S u bject 1 1 0 1 re places S u bject 0 1 0 1). 
S u bjects will  be i de ntifie d b y s u bject n u m ber o nl y o n all st u d y d oc u me ntati o n. A list 
i de ntif yi n g t he s u bjects b y s u bject n u m ber will be ke pt i n t he Site Master File. 
4. 4.  
S u bject W it h dr a w al a n d Re pl ace me nt 
A s u bject is free t o wit h dra w fr o m t he st u d y at a n y ti me. I n a d diti o n, a s u bject will be 
wit h dra w n if a n y of t he f oll o wi n g criteria are met:  
•  C ha n ge i n c o m plia nce wit h a n y i ncl usi o n/e xcl usi o n criteri o n t hat is cli nicall y rele va nt 
a n d affects s u bject safet y as deter mi ne d b y t he In vesti gat or ( or desi g nee)  
•  N o nc o m plia nce wit h t he st u d y restricti o ns t hat mi g ht affect s u bject safet y or st u d y 
assess me nts/ o bjecti ves, as c o nsi dere d a p plica ble b y t he I n vesti gat or ( or desi g nee) 
•  A n y cli nicall y rele va nt si g n or s y m pt o m t hat, i n t he o pi ni o n of t he I n vesti gat or ( or 
desi g nee), warra nts s u bject wit h dra wal  
If a s u bject is wit h dra w n fr o m d osi n g, t he S p o ns or will be n otifie d a n d t he date a n d reas o n(s) 
f or t he wit h dra wal will be d oc u me nte d i n t he s u bject’s electr o nic case re p ort f or m (e C R F). If 
a s u bject is wit h dra w n fr o m t he st u d y, eff ort s will be ma de t o perf or m all f oll o w- u p 
assess me nts, if p ossi ble ( A p pe n di x 6 ). Ot her pr oce d ures ma y be perf or me d at t he 
In vesti gat or’s ( or desi g nee’s) a n d/ or S p o ns or’s discreti o n. If t he s u bject is i n - h o use, t hese 
pr oce d ures s h o ul d be perf or me d bef ore t he s u bject is disc har ge d fr o m t he cli nic. T he 
 
  


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 4 6 of 8 6 
I n vesti gat or ( or desi g nee) ma y als o re q uest t hat t he s u bject ret ur n f or a n a d diti o nal f oll o w- u p 
visit. All wit h dra w n s u bjects will be f oll o we d u ntil res ol uti o n of all t heir A Es or u ntil t he 
u nres ol ve d A Es are j u d ge d b y t he I n vesti gat or ( or desi g nee) t o ha ve sta bilise d. 
S u bjects w h o are wit h dra w n f or reas o ns n ot relate d t o st u d y treat me nt ma y be re place d 
f oll o wi n g disc ussi o n bet wee n t he In vesti gat or a n d t he S p o ns or. S u bjects wit h dra w n as a 
res ult of A Es t h o u g ht t o be relate d t o t he st u d y treat me nt will ge nerall y n ot be replace d.  
4. 5.  
St u d y Ter mi n ati o n  
T he st u d y ma y be disc o nti n ue d at t he discreti o n of t he I n vesti gat or ( or desi g nee), or S p o ns or 
if a n y of t he f oll o wi n g criteria are met: 
•  A Es  u n k n o w n t o date (ie, n ot pre vi o usl y re p orte d i n a n y si milar i n vesti gati o nal st u d y 
dr u g trial wit h res pect t o t heir nat ure, se verit y, a n d/ or d urati o n)  
•  i ncrease d fre q ue nc y, se verit y, a n d/ or d urati o n of k n o w n, a ntici pate d, or pre vi o usl y 
re p orte d A Es 
•  m e dical or et hical reas o ns affecti n g t he c o nti n ue d perf or ma nce of t he st u d y  
•  d iffic ulties i n t he recr uit me nt of s u bjects 
•  ca ncellati o n of dr u g de vel o p me nt. 
5.  S T U D Y T R E A T M E N T S  
5. 1.  
Descri pti o n, St or a ge, P ac k a gi n g, a n d L a belli n g  
T he I M Ps i ncl u de K R P - A 2 1 8 1 m g t a blet a n d 1 0 m g ta blet a n d place b o ta blet. T he ta blets all 
ha ve t he sa me a p peara nce.  
T he I M Ps will be s u p plie d b y t he S p o ns or ( or desi g nee), al o n g wit h t he batc h n u m bers a n d 
Certificates of A nal ysis. A Certificate of Release a ut h orize d b y a Q ualifie d Pers o n i n t he 
U nite d Ki n g d o m will als o be iss ue d f or t he I M P.  A declarati o n of G o o d Ma n ufact uri n g 
Practice e q ui vale nce iss ue d b y a Q ualifie d Pers o n i n t he U nite d Ki n g d o m will als o be iss ue d 
f or t he I M P. T he I M P will be pr o vi de d i n a hi g h- de nsit y p ol yet h yle ne b ottle i n a n al u mi ni u m 
ba g wit h a desicca nt a n d st ore d acc or di n g t o t he i nstr ucti o ns o n t he la bel. 
All I M Ps will be st ore d at a m bie nt c o n diti o ns bet wee n 1 t o 3 0 oC at t he st u d y site i n a l ocati o n 
t hat is l oc ke d wit h restricte d access. 
T he b ul k dr u g c o ntai ner a n d u nit d ose c o ntai ners will be la bell e d i n acc or da nce wit h nati o nal 
la ws a n d re g ulati o ns. T he I M Ps will be tra nsferre d fr o m b ul k s u p plies i nt o t he s u bject’s d ose 
c o ntai ner b y q ualifie d cli nical staff . 
Ta blets f or t he pla n ne d d ose le vels will be asse m ble d as s h o w n i n  Ta ble  7. 
 
  


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 4 7 of 8 6 
T a ble  7: 
T a blet Asse m bl y  
Gr o u p  
D ose Le vel  
( m g) 
N u m ber of T a blets t o be Asse m ble d  
K R P -A 2 1 8  
Pl ace b o  
1 m g  
t a blets 
1 0 m g  
t a blets 
A 1  
1  
1  
- 
1  
A 2  
3  
3  
- 
3  
A 3  
6  
6  
- 
6  
A 4  
1 2  
2  
1  
3  
A 5  
ma xi m u m 
d ose of 2 4  
4 
2 
6 
B 1  
X  
X  
- 
X  
B 2  
X  
X  
X  
X  
B 3  
X  
X  
X  
X  
B 4  
X  
X  
X  
X  
C 1  
X  
X  
- 
- 
I n Part C, s u bjects will recei ve itrac o naz ole as a c o nc o mita nt dr u g. 
Itrac o naz ole ( 1 0 m g/ m L oral s ol uti o n) will be c o m merciall y s o urce d b y La bc or p Cli nical 
Researc h U nit  Lt d . E ver y atte m pt will be ma de t o s o urce t hese s u p plies fr o m a si n gle 
l ot/ batc h n u m ber. T he I n vesti gat or ( or desi g nee) will rec or d t he l ot/ batc h n u m ber, q ua ntit y, 
e x pirati o n date, a n d dr u g dis pe nse d. 
T he st ora ge c o n diti o ns f or itrac o naz ole will be as i n dicate d o n t he S u m mar y of Pr o d uct 
C haracteristics . Eac h u nit d ose will be pre pare d b y q ualifie d cli nical staff. 
5. 2.  
St u d y Tre at me nt A d mi nistr ati o n  
Eac h d ose of K R P- A 2 1 8 a n d place b o will be a d mi nistere d orall y wit h a p pr o xi matel y 2 4 0 m L 
of r o o m te m perat ure water. E ver y eff ort will be ma de t o e ns ure t hat t he ti mes of 
a d mi nistrati o n of K R P- A 2 1 8 f or eac h i n di vi d ual s u bject are c o nsiste nt t hr o u g h o ut t he 
treat me nt peri o ds. 
I n Part A, all d oses will be a d mi nistere d after a n o ver ni g ht fast of at least 1 0 h o urs, wit h t he 
e xce pti o n of Gr o u p A 2a, w here t he d ose gi ve n i n Treat me nt Peri o d 2, w here K R P - A 2 1 8 or 
place b o will be a d mi nistere d 3 0 mi n utes after starti n g a hi g h -fat brea kfast. T he dietar y stat us 
f or d osi n g i n Part B will be deter mi ne d f oll o wi n g re vie w of t he P K data fr o m t he fe d/faste d 
c o m paris o n i n Part A. 
I n Part C, eac h d ose of K R P- A 2 1 8 will be a d mi nistere d  orall y wit h a p pr o xi matel y 2 4 0  m L of 
r o o m te m perat ure water. Itrac o naz ole s ol uti o n will be a d mi nistere d wit h n o a d diti o nal water. 
T he dietar y state f or d osi n g of K R P- A 2 1 8 al o ne o n Da y 1 a n d K R P- A 2 1 8 c o- a d mi nistere d 
wit h itrac o naz ole o n Da y 1 1 will be deter mi ne d b y c o m pari n g t he P K data bet wee n fe d a n d 
faste d state in Gr o u p A 2a. Itrac o naz ole o n Da ys 4 t o 1 0, 1 2 a n d 1 3 will be a d mi nistere d i n t he 
faste d state. O n Da y 1 1, if it is deter mi ne d t hat K R P- A 2 1 8 will be d ose d i n t he faste d state, 
t he n K R P-A 2 1 8 will be a d mi nistere d first a n d itrac o naz ole will be a d mi nistere d se c o n d. If it 
is deter mi ne d t hat K R P - A 2 1 8 will be d ose d i n t he fe d state, t he n itrac o naz ole will be d ose d 
first; s u bjects will t he n recei ve brea kfast at a p pr o xi matel y 1 h o ur p ost itrac o naz ole d ose, a n d 
K R P - A 2 1 8 will be d ose d sec o n d f oll o wi n g brea kfast. 
 
  


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 4 8 of 8 6 
S u bje cts will recei ve t he I M P i n n u merical or der w hile sta n di n g a n d will n ot be per mitte d t o 
lie s u pi ne f or 2 h o urs after d osi n g, e xce pt as necessitate d b y t he occ urre nce of a n A E a n d/ or 
st u d y pr oce d ures. 
5. 3.  
R a n d o mi s ati o n 
T he ra n d o mis ati o n c o de will be pr o d uce d b y t he statistics de part me nt at La bc or p Dr u g 
De vel o p me nt usi n g a c o m p uter - ge nerate d pse u d o ra n d o m per m utati o n pr oce d ure. 
I n Part A, 2 s u bjects will be ra n d o ml y assi g ne d t o recei ve place b o i n eac h gr o u p, wit h t he 
re mai ni n g 6 s u bjects ra n d o ml y assi g ne d t o recei ve K R P- A 2 1 8. S u bjects i n Gr o u p A 2a will 
recei ve t he sa me treat me nt i n Treat me nt Peri o ds 1 a n d 2. F or all gr o u ps i n Part A ( wit h t he 
e xce pti o n of Gr o u p A 2a i n Treat me nt Peri o d 2), se nti nel d osi n g will occ ur w here b y 
2 s u bjects ( 1 acti ve a n d 1 place b o) will be d ose d o n 1 da y a n d, pr o vi di n g n o safet y c o ncer ns 
arise, t he re mai ni n g 6 s u bjects will be d ose d after at least 2 4 h o urs. 
F or Part B, 2 s u bjects will be ra n d o ml y assi g ne d t o recei ve place b o i n eac h gr o u p, wit h t he 
re mai ni n g 8 s u bjects ra n d o ml y assi g ne d t o recei ve K R P - A 2 1 8. F or all gr o u ps i n Part B, 
se nti nel d osi n g will occ ur w here b y 2 s u bjects ( 1 acti ve a n d 1 place b o) will be d ose d o n 1 da y 
a n d, pr o vi di n g n o safet y c o ncer ns arise, t he re mai ni n g 6 s u bjects will be d ose d after at least 
7 da ys. 
Pri or t o t he start of t he st u d y, a c o p y of t he master ra n d o misati o n c o de f or Parts A a n d B of 
t he st u d y will be s u p plie d i n seale d e n vel o pes t o t he La bc or p C R U p har mac y staff a n d t he 
bi o p har mace utical a nal yst at t he bi oa nal ytical la b orat or y . 
S u bjects i n Part C will n ot be ra n d o mi se d, as t his part of t he st u d y has a n o pe n-la bel, fi xe d 
treat me nt se q ue nce. 
5. 4.  
Bli n di n g  
T he bli n di n g pr oce d ures o utli ne d bel o w will o nl y be a p plica ble t o Parts A a n d B, as Part C is 
o pe n- la bel. 
T he f oll o wi n g c o ntr ols will be e m pl o ye d t o mai ntai n t he d o u ble- bli n d  stat us of t he st u d y: 
•  T he place b o ta blets will be i de ntical i n a p peara nce t o K R P - A 2 1 8. 
•  T he I n vesti gat or a n d ot her me m bers of staff i n v ol ve d wit h t he st u d y will re mai n 
bli n de d t o t he treat me nt ra n d o misati o n c o de d uri n g t he asse m bl y pr oce d ure. 
•  I nteri m bi oa nal ytical data will be pr o vi de d t o La bc or p C R U  i n a bli n de d ma n ner. 
T o mai ntai n t he bli n d, t he I n vesti gat or will be pr o vi de d wit h a seale d ra n d o mis ati o n c o de f or 
eac h s u bject, c o ntai ni n g details of t heir treat me nt. T hese i n di vi d ual seale d e n vel o pes will be 
ke pt i n a li mite d access area t hat is accessi ble 2 4 h o urs a da y. I n or der t o ma na ge s u bject 
safet y, t o decisi o n t o pr ocee d wit h d osi n g after se nti nel d osi n g, or t o s u p p ort d ose escalati o n 
decisi o ns (i n t he e ve nt of p ossi bl y treat me nt relate d S A Es or se vere A Es), t he decisi o n t o 
u n bli n d resi des s olel y wit h t he I n vesti gat or. W he ne ver p ossi ble, a n d pr o vi di n g it d oes n ot 
i nterfere wit h or dela y a n y decisi o n i n t he best i nterest of t he s u bject, t he I n vesti gat or will 
disc uss t he i nte n de d c o de brea k wit h t he S p o ns or. If it bec o mes necessar y t o brea k t he c o de 
 
  


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 4 9 of 8 6 
d uri n g t he st u d y, t he date, ti me, a n d reas o n will be rec or de d i n t he s u bject’s s o urce data a n d 
o n t he i n di vi d ual e n vel o pe a n d will be wit nesse d b y a sec o n d pers o n. 
5. 5.  
Tre at me nt C o m pli a nce  
T he f oll o wi n g meas ures will be e m pl o ye d t o e ns ure treat me nt c o m plia nce: 
•  All d oses will be a d mi nistere d u n der t he s u per visi o n of s uita bl y q ualifie d st u d y site 
staff. 
•  I m me diatel y after d ose a d mi nistrati o n, vis ual i ns pecti o n of t he m o ut h a n d ha n ds will 
be perf or me d f or eac h s u bject. 
•  At eac h d osi n g occasi o n, a pre d ose a n d p ost d ose i n ve nt or y will be perf or me d o n t he 
d ose c o ntai ners. 
5. 6.  
Dr u g Acc o u nt a bilit y  
T he I n vesti gat or ( or desi g nee) will mai ntai n a n acc urate rec or d of t he recei pt of t he st u d y 
s u p plies recei ve d. I n a d diti o n, a n acc urate dr u g dis p ositi o n rec or d will be ke pt, s pecif yi n g t he 
a m o u nt dis pe nse d t o eac h s u bject a n d t he date of dis pe nsi n g. T his dr u g acc o u nta bilit y rec or d 
will be a vaila ble f or i ns pecti o n at a n y ti me. At t he c o m pleti o n of t he st u d y, t he ori gi nal dr u g 
acc o u nta bilit y rec or d will be a vaila ble f or a re vie w b y t he S p o ns or u p o n re q uest. 
F or eac h batc h of u nit d oses, t he e m pt y use d u nit d ose c o ntai ners will be discar de d u p o n 
satisfact or y c o m pleti o n of t he c o m plia nce a n d acc o u nta bilit y pr oce d ures. A n y u n use d 
asse m ble d u nit d oses will be retai ne d u ntil c o m pleti o n of t he st u d y. 
At t he c o m pleti o n of t he st u d y, all u n use d s u p plies will be ret ur ne d t o t he S p o ns or or 
dis p ose d of b y t he st u d y site, per t he S p o ns or’s writte n i nstr ucti o ns. 
6.  C O N C O MI T A N T T H E R A PI E S A N D O T H E R R E S T RI C TI O N S  
6. 1.  
C o nc o mit a nt T her a pies  
S u bjects will refrai n fr o m use of a n y prescri pti o n or n o n prescri pti o n me dicati o ns/ pr o d ucts 
d uri n g t he st u d y u ntil t he f oll o w- u p visit, u nless t he I n vesti gat or ( or desi g nee) a n d/ or S p o ns or 
ha ve gi ve n t heir pri or c o nse nt.  
Str o n g a n d m o derate C Y P 3 A 4 i n hi bit ors a n d i n d ucers, a n d str o n g C Y P 2 C 9, 2 C 8 a n d 2 D 6 
i n hi bit ors a n d i n d ucers are pr o hi bite d f or at least 1 4 da ys or 5 half-li ves pri or t o d osi n g 
( w hic he ver is l o n ger).  
Paraceta m ol ( u p t o 2 g/ da y f or u p t o 3 c o nsec uti ve da ys) is per mitte d at t he discreti o n of t he 
I n vesti gat or f or t he treat me nt of a n A E. T he a d mi nistrati o n of a n y ot her c o nc o mita nt 
me dicati o ns d uri n g t he st u d y is pr o hi bite d wit h o ut pri or a p pr o val of t he I n vesti gat or ( or 
desi g nee), u nless its use is dee me d necessar y i n a me dical e mer ge nc y . A n y me dicati o n ta ke n 
b y a s u bject d uri n g t he c o urse of t he st u d y a n d t he reas o n f or its use will be d oc u me nte d i n 
t he s o urce data. 
 
  


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 5 0 of 8 6 
S u bjects will refrai n fr o m t he use of h or m o ne re place me nt t hera p y a n d oral, i m pla nta ble, 
tra ns der mal, i njecta ble, or i ntra uteri ne h or m o nal c o ntrace pti ves d uri n g t he st u d y u ntil t he 
f oll o w- u p visit. 
6. 2.  
Diet  
W hile  c o nfi ne d at t he st u d y site, s u bjects will recei ve a sta n dar dize d diet at sc he d ule d ti mes 
t hat d o n ot c o nflict wit h ot her st u d y relate d acti vities. S u bjects will be faste d at least 6 h o urs 
bef ore c ollecti o n of bl o o d sa m ples f or cli nical la b orat or y e val uati o ns ( hae mat ol o g y , cli nical 
c he mistr y). 
O n t he da ys wit h i nte nsi ve P K assess me nts ( Da y 1 f or Part A, Da ys 1 a n d 1 4 f or Part B, a n d 
Da ys 1 a n d 1 1 f or Part C), meals will be i de ntical f or eac h gr o u p wit h t he e xce pti o n of t he 
hi g h- fat brea kfast i n Treat me nt Peri o d 2 f or s u bjects i n Gr o u p A 2a. 
6. 2. 1.  
P art A  
Wit h t he e xce pti o n of Treat me nt Peri o d 2 f or s u bjects i n Gr o u p A 2a, o n Da y 1 i n Part A, 
s u bjects will be faste d f or at least 1 0 h o urs pri or t o d osi n g u ntil 4 h o urs after d osi n g, after 
w hic h ti me a meal  will be pr o vi de d (l u nc h ti mes o n Da y 1 will be sta g gere d bet wee n s u bjects 
t o e ns ure t his). Wit h t he e xce pti o n of water gi ve n wit h t he d ose, s u bjects will n ot be all o we d 
fl ui ds fr o m 1 h o ur pri or, u ntil 2 h o urs after d osi n g. Meals will be pr o vi de d as a p pr o priate at 
ot her ti mes. Ot her t ha n t he fl ui d restricti o ns o n d osi n g da ys, water will be freel y a vaila ble at 
all ti mes. 
S u bjects i n Gr o u p A 2 a will c o ns u me a hi g h- fat brea kfast (c o nte nts are detaile d i n Ta ble  8) 
bef ore d osi n g i n Treat me nt Peri o d 2. S u bjects s h o ul d start t his  meal 3 0 mi n utes pri or t o 
a d mi nistrati o n of t he I M P. St u d y s u bjects s h o ul d fi nis h t his meal i n 3 0 mi n utes or less. T he 
I M P s h o ul d be a d mi nistere d 3 0 mi n utes after start of t he meal. 
T a ble  8: 
Hi g h -f at Bre a kf ast C o nte nt 
Hi g h -f at Bre a kf ast 
1 2 0  g frie d e g gs ( 2 e g gs) i n ve geta ble oil  
5 0 g bac o n ( 2 ras hers)  
7 2 g t oaste d w hite brea d ( 2 slices)  
1 3 g b utter ( 2 pats)  
1 0 8 g has h br o w n ( 3 eac h)  
2 4 0 g w h ole mil k  
T otal cal ories: 9 7 3 kcal  
T his hi g h-fat meal c o ntai ns t he e q ui vale nt of a p pr o xi matel y 1 5 0 pr otei n cal ories, 
2 5 0 car b o h y drate cal ories, a n d 5 0 0 t o 6 0 0 fat cal ories. 
6. 2. 2.  
P art B  
S u bjects will recei ve t he I M P o n Da ys 1 t o 1 4. T he dietar y state f or d osi n g i n Part B will be 
s u bject t o re vie w of t he P K data fr o m t he fe d/faste d c o m paris o n i n Part A. T he ti me i nter val 
bet wee n meals a n d d osi n g will be deter mi ne d b y t he P K data fr o m Part A  a n d will be 
d oc u me nte d i n t he T M F. If t he I M P is a d mi nistere d i n t he faste d state, s u bjects will be faste d 
f or at least 1 0 h o urs pri or t o d osi n g. F or Da ys 1 a n d 1 4, s u bjects will be faste d u ntil 4 h o urs 
 
  


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 5 1 of 8 6 
after d osi n g, after w hic h ti me a meal will be pr o vi d e d (l u nc h ti mes will be sta g gere d bet wee n 
s u bjects t o e ns ure t his). Wit h t he e xce pti o n of water gi ve n wit h t he d ose, s u bjects will n ot be 
all o we d fl ui ds fr o m 1 h o ur pri or t o d osi n g u ntil 2 h o urs after d osi n g. Meals will be pr o vi de d 
as a p pr o priate. Ot her t h a n t hese fl ui d restricti o ns, water will be freel y a vaila ble at all ti mes.  
6. 2. 3.  
P art C  
S u bjects will recei ve K R P - A 2 1 8 al o ne o n Da y 1 a n d K R P- A 2 1 8 c o-a d mi nistrati n g wit h 
itrac o naz ole o n Da y 1 1. T he dietar y state f or d osi n g of K R P- A 2 1 8 al o ne o n Da y 1 a n d 
K R P -A 2 1 8 c o -a d mi nistere d wit h itrac o naz ole o n Da y 1 1 will be deter mi ne d b y c o m pari n g 
t he P K data bet wee n fe d a n d faste d state i n Gr o u p A 2a. T he ti me i nter val bet wee n meals a n d 
d osi n g of K R P- A 2 1 8 will be deter mi ne d b y t he P K data fr o m Part A a n d will be d oc u me nte d 
i n t he T M F. If K R P- A 2 1 8 is a d mi nistere d i n t he faste d state o n Da ys 1 a n d 1 1, s u bjects will 
be faste d f or at least 1 0 h o urs pri or t o d osi n g u ntil at least 4 h o urs after d osi n g, after w hic h 
ti me a meal will be pr o vi de d (l u nc h ti mes will be sta g gere d bet wee n s u bjects t o e ns ure t his). 
O n Da y 4, itrac o naz ole will be a d mi nistere d t wice, a p pr o xi matel y 1 2 h o urs a part, i n t he 
faste d state. Itrac o naz ole o n Da ys 5 t o 1 0, 1 2 a n d 1 3 will be a d mi nistere d i n t he faste d state. 
Wit h t he e xce pti o n of water gi ve n wit h K R P- A 2 1 8 , s u bjects will n ot be all o we d fl ui ds fr o m 1 
h o ur pri or t o d osi n g u ntil 2 h o urs after d osi n g o n Da ys 1 a n d 1 1. Meals will be pr o vi de d as 
a p pr o priate. Ot her t ha n t hese fl ui d restricti o ns o n Da ys 1 a n d 1 1, water will be freel y 
a vaila ble at all ti mes.  
6. 3.  
O t her Restricti o ns 
6. 3. 1.  
F o o ds a n d B e ver a ges 
F o o ds a n d be vera ges c o ntai ni n g p o p p y see ds, gra pefr uit, or Se ville ora n ges will n ot be 
all o we d fr o m 7 da ys pri or t o Da y - 1 u ntil after t he f oll o w- u p visit. 
Caffei ne - a n d xa nt hi ne-c o ntai ni n g f o o ds a n d be vera ges will n ot be all o we d fr o m 3 6 h o urs 
bef ore Da y - 1 u ntil d isc har ge (i n eac h treat me nt peri o d, w here a p plica ble) a n d fr o m 1 0 h o urs 
pri or t o t he f oll o w-u p visit u ntil after t he f oll o w-u p visit.  
C o ns u m pti o n of alc o h ol will n ot be per mitte d fr o m 4 8 h o urs pri or t o Da y - 1 u ntil d isc har ge 
(i n eac h treat me nt peri o d, w here a p plica ble) a n d fr o m 4 8 h o urs pri or t o t he f oll o w- u p visit 
u ntil after t he f oll o w- u p visit. U p t o 4 u nits/ da y ( male) a n d 3 u nits/ da y (fe male) of alc o h ol are 
per mitte d fr o m disc har ge u ntil 4 8 h o urs bef ore t he f oll o w- u p visit ( Da y -1 f or Treat me nt 
Peri o d 2 i n Gr o u p A 2a). 
6. 3. 2.  
S m o ki n g  
S u bjects will n ot be per mitte d t o use t o bacc o- or nic oti ne -c o ntai ni n g pr o d ucts wit hi n 
3 m o nt hs pri or t o Da y - 1 u ntil after t he f oll o w- u p visit. 
6. 3. 3.  
E xercise  
S u bjects are re q uire d t o refrai n fr o m stre n u o us e xercise fr o m 7 da ys bef ore Da y -1 u ntil after 
t he f oll o w-u p visit a n d will ot her wise mai ntai n t heir n or mal le vel of p h ysical acti vit y d uri n g 
t his ti me (ie, will n ot be gi n a ne w e xercise pr o gra m n or partici pate i n a n y u n us uall y stre n u o us 
p h ysical e xerti o n). 
 
  


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 5 2 of 8 6 
6. 3. 4.  
Bl o o d D o n ati o n 
S u bjects are re q uire d t o refrai n fr o m d o nati o n of bl o o d fr o m 3 m o nt hs pri or t o scree ni n g, 
p las ma fr o m 2 wee ks pri or t o scree ni n g, a n d platelets fr o m 6 wee ks pri or t o scree ni n g u ntil 
3 m o nt hs after t he f oll o w- u p visit. 
7.  S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  
E ver y eff ort will be ma de t o sc he d ule a n d perf or m t he pr oce d ures as cl osel y as p ossi ble t o t he 
n o mi nal ti me, gi vi n g c o nsi derati o ns t o a p pr o priate p ost ure c o n diti o ns, practical restricti o ns, 
a n d t he ot her pr oce d ures t o be perf or me d at t he sa me ti me p oi nt. 
T he hi g hest pri orit y pr oce d ures will be perf or me d cl osest t o t he n o mi nal ti me. T he or der of 
pri o rit y f or sc he d uli n g pr oce d ures ar o u n d a ti me p oi nt is (i n desce n di n g or der of pri orit y): 
•  d osi n g 
•  bl o o d sa m ples f or P K a n d e x pl orat or y meta b olite pr ofili n g 
•  a n y ot her pr oce d ures ( safet y E C G s will be sc he d ule d bef ore vital si g ns meas ure me nts  
[e xce pt b o d y te m perat ure]; vital si g ns meas ure me nts [e xce pt b o d y te m perat ure] will 
be sc he d ule d bef ore bl o o d sa m pli n g) 
7. 1.  
P h ar m ac o ki netic Assess me nts  
7. 1. 1.  
P h ar m ac o ki netic S a m ple C ollecti o n a n d Pr ocessi n g  
Bl o o d sa m pl es (a p pr o xi matel y 1 × 2- m L sa m ple per sc he d ule d ti me) f or P K a nal ysis of 
a n d bl o o d sa m ples (a p pr o xi matel y 1 × 2- m L sa m ple per sc he d ule d ti me) f or P K 
a nal ysis of i trac o naz ole a n d its meta b olite  h y dr o x y- itrac o naz ole  will be  c ollecte d b y 
ve ne p u nct ure or ca n n ulati o n at t he ti mes i n dicate d i n t he Sc he d ule of As sess me nts i n 
A p pe n di x 6 . F urt her m ore, u p t o 3 a d diti o nal bl o o d sa m ples ma y be ta ke n fr o m eac h s u bject 
per treat me nt peri o d i n Part A, a n d u p t o 6 a d diti o nal bl o o d sa m ples ma y be ta ke n fr o m eac h 
s u bject i n Parts B a nd C, wit h t he ma xi m u m v ol u me of bl o o d wit h dra w n per s u bject will n ot 
e xcee d t he li mit detaile d i n A p pe n di x 3 . A n y c ha n ges t o t he sc he d ule d ti mes of P K 
assess me nts will be a gree d wit h t he S p o ns or a n d d oc u me nte d i n t he T M F. Bl o o d sa m ples 
ta ke n fr o m s u bjects w h o recei ve d place b o will n ot be a nal yse d. 
Pr oce d ures f or c ollecti o n, pr ocessi n g, a n d s hi p pi n g of P K bl o o d sa m ples will be detaile d i n a 
se parate d oc ume nt . 
7. 1. 2.  
P h ar m ac o ki netic A n al ytic al Met h o d ol o g y  
Plas ma c o nce n trati o ns of 
, itrac o naz ole, a n d h y dr o x y-itrac o naz ole will be 
deter mi ne d usi n g vali date d a nal ytical pr oce d ures. S pecifics of t he a nal ytical met h o ds will be 
pr o vi de d i n se parate d oc u me nts . 
 
  
C CI
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 5 3 of 8 6 
7. 2.  
E x pl or at or y Assess me nts  
7. 2. 1.  
S a m ple C ollecti o n a n d Pr ocessi n g  f or E x pl or at or y Met a b olite Pr ofili n g 
F or s u bjects i n Gr o u ps A 2a, A 5, B 1, a n d C 1, bl o o d sa m ples ( a p pr o xi matel y  1 × 2 m L sa m ple 
per sc he d ule d ti me) will be c ollecte d b y ve ne p u nct ure or ca n n ulati o n at t he ti mes i n dicate d i n 
t he Sc he d ule of Assess me nts i n A p pe n di x 6 . T he ma xi m u m v ol u me of bl o o d wit h dra w n per 
s u bject will n ot e xcee d t he li mit detaile d i n A p pe n di x 3 . A n y c ha n ges t o t he sc he d ule d ti mes 
of bl o o d sa m pli n g f or meta b olite pr ofili n g will be a gree d wit h t he S p o ns or a n d d oc u me nte d 
i n t he T M F. Bl o o d sa m pl es ta ke n fr o m s u bjects w h o recei ve d place b o will n ot be meas ure d. 
F or s u bjects i n Gr o u ps A 2a a n d A 5, pre d ose s p ot uri ne a n d faecal sa m ples a n d 2 4- h o ur uri ne 
a n d faecal sa m ples will be c ollecte d i nt o pre - wei g he d p ol yet h yle ne c o ntai ners o ver t he ti me 
i nter vals i n dicate d i n t he Sc he d ule of Assess me nts i n A p pe n di x 6 . Faecal  sa m ples will be 
c ollecte d, as far as p ossi ble . F or s u bjects i n Gr o u ps B 1, pre d ose s p ot uri ne a n d 2 4- h o ur uri ne 
sa m ples will be c ollecte d i nt o pre- wei g he d p ol yet h yle ne c o ntai ners o ver t he ti me i nter vals 
i n dicate d i n t he Sc he d ule of Assess me nts i n A p pe n di x 6 . Uri ne a n d faecal sa m ples ta ke n 
fr o m s u bjects w h o recei ve d place b o will n ot be meas ure d.  
Pr oce d ures f or c ollecti o n, pr ocessi n g, a n d s hi p pi n g of bl o o d, uri ne, a n d faecal sa m ples f or 
meta b olite pr ofili n g will be detaile d i n a se parate d oc u me nt. 
7. 2. 2.  
Met h o d ol o g y f or E x pl or at or y Met a b olite Pr ofili n g A n al ysis 
T he a nal ytical met h o ds f or e x pl orat or y meta b olite pr ofili n g a nal ysis ma y be pr o vi de d i n a 
se parate d oc u me nt a n d will n ot f or m part of t he Cli nical St u d y Re p ort f or t his st u d y. 
7. 2. 3.  
S a m ple C ollecti o n a n d Pr oces si n g f or P h ar m ac o ge netic A n al ysis 
Bl o o d sa m pl es ( a p pr o xi matel y  1 × 1 0- m L sa m ple) will be c ollecte d b y ve ne p u nct ure or 
ca n n ulati o n at t he ti mes i n dicate d i n t he Sc he d ule of Assess me nts i n  A p pe n di x 6 . T he 
ma xi m u m v ol u me of bl o o d wit h dra w n per s u bject will n ot e xcee d t he li mit detaile d i n 
A p pe n di x 3 . 
S u bjects will o nl y be re q uire d t o pr o vi de a si n gle sa m ple f or p har mac o ge netic a nal ysis d uri n g 
t he c o urse of t he st u d y. I n t he case t hat a p har mac o ge netic sa m ple is c ollecte d w hilst a 
s u bject is sta n d b y f or t he se nti nel gr o u p b ut is n ot t he n d ose d as a se nti nel a sec o n d 
p har mac o ge netic sa m ple is n ot re q uire d if t hat s u bject is s u bse q ue ntl y e nr olle d i n t he mai n 
gr o u p. 
7. 2. 4.  
Met h o d ol o g y f or P h ar m ac o ge netic A n al ysis 
If p har mac o ge netic a nal ysis is u n derta ke n, t he a nal ytical met h o ds ma y be pr o vi de d i n a 
se parate d oc u me nt a n d will n ot f or m part of t he Cli nical St u d y Re p ort f or t his st u d y. 
7. 2. 5.  
S a m ple C ollecti o n a n d Pr ocessi n g f or  E x pl or at or y Bi o m ar ker A n al ysis 
E x pl orat or y bi o mar ker a nal ysis  i n bl o o d a n d uri ne will be perf or me d o n resi d ual sa m ples of 
e x pl orat or y meta b olite p r ofili n g i n Parts A a n d B. 
 
  


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 5 4 of 8 6 
7. 2. 6.  
S a m ple C ollecti o n a n d Pr ocessi n g f or A n al ysis of P h os p h oli pi d - C a n d F aec al 
C al pr otecti n  
E x pl orat or y a nal ysis of p h os p h oli pi d- C i n ser u m a n d faecal cal pr otecti n will be perf or me d o n 
bl o o d sa m ples ta ke n f or safet y cli nical la b orat or y assess me nts a n d resi d ual sa m ples ta ke n f or 
faecal occ ult bl o o d tests, res pecti vel y. Faecal cal pr otecti n meas ure me nts will o nl y be 
perf or me d d uri n g t he res pecti ve treat me nt peri o d.  
7. 2. 7.  
Met h o d ol o g y f or E x pl or at or y B i o m ar ker A n al ysis 
If e x pl orat or y bi o mar ker a nal ysis is u n derta ke n, t he a nal ytical met h o ds ma y be pr o vi de d i n a 
se parate d oc u me nt a n d will n ot f or m part of t he Cli nical St u d y Re p ort f or t his st u d y. 
7. 2. 8.  
C o nti n u o us 1 2 -le a d Electr oc ar di o gr a m M o nit ori n g 
C o nti n u o us 1 2 -lea d E C G m o nit ori n g usi n g a di gital rec or der will ta ke place at t he ti mes 
i n dicate d i n t he Sc he d ule of Assess me nts i n A p pe n di x 6 . C o nti n u o us 1 2-lea d E C G 
m o nit ori n g ma y be a d de d t o Part B; if a d de d, t he details will be d oc u me nte d a n d file d i n t he 
e T M F. 
All c o nti n u o us 1 2- lea d E C G data c ollecte d will be arc hi ve d wit h o ut e xtracti o n or a nal ysis 
a n d will n ot be re p orte d i n t he sc o pe of t his st u d y. 
E n vir o n me ntal distracti o ns (e g, tele visi o n, ra di o, c o n versati o n) s h o ul d be a v oi de d d uri n g 
E C G rec or di n g, w here p ossi ble. 
7. 3.  
S afet y a n d T oler a bilit y Assess me nts  
7. 3. 1.  
A d verse E ve nts  
A d verse e ve nt defi niti o ns, assi g n me nt of se verit y a n d ca usalit y, a n d pr oce d ures f or re p orti n g 
S A Es are detaile d i n A p pe n di x 1 . 
T he c o n diti o n of eac h s u bject will be m o nit ore d fr o m t he ti me of si g ni n g t he I C F t o fi nal 
disc har ge fr o m t he st u d y. S u bjects will be o bser ve d f or a n y si g ns or s y m pt o ms a n d as ke d 
a b o ut t heir c o n diti o n b y o pe n q uesti o ni n g, s uc h as “ h o w ha ve y o u bee n feeli n g si nce y o u 
were last as ke d?”, at least o nce eac h da y w hile resi de nt at t he st u d y site a n d at eac h st u d y 
visit. S u bjects will als o be e nc o ura ge d t o s p o nta ne o usl y re p ort A Es occ urri n g at a n y ot her 
ti me d uri n g t he st u d y. 
A n y A Es a n d re me dial acti o n re q uire d will be rec or de d i n t he s u bject’s s o urce data. T he 
nat ure, ti me of o nset, d urati o n, a n d se verit y will be d oc u me nte d, t o get her wit h a n 
In vesti gat or’s ( or desi g nee’s) o pi ni o n of t he relati o ns hi p t o st u d y treat me nt.  
A d verse e ve nts rec or de d d uri n g t he c o urse of t he st u d y will be f oll o we d u p, w here p ossi ble, 
u ntil res ol uti o n or u ntil t he u nres ol ve d A Es are j u d ge d b y t he I n vesti gat or ( or desi g nee) t o 
ha ve sta bilise d. T his will be c o m plete d at t he In vesti gat or’s ( or desi g nee’s)  discreti o n. 
 
  


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 5 5 of 8 6 
7. 3. 2.  
Cli nic al L a b or at or y E v al u ati o ns 
Cli nical la b orat or y e val uati o ns are liste d i n A p pe n di x 2 . T otal bl o o d sa m pli n g v ol u mes f or a n 
i n di vi d ual su bject is s h o w n A p pe n di x 3 . 
Bl o o d, uri ne a n d faecal sa m ples will be c ollecte d f or cli nical la b orat or y e val uati o ns 
(i ncl u di n g cli nical c he mistr y, hae mat ol o g y, uri nal ysis, c oa g ulati o n, a n d faecal occ ult bl o o d 
test) at t he ti mes i n dicate d i n t he Sc he d ule of Assess me nts i n A p pe n di x 6 . Bl o o d sa m ples f or 
cli nical la b orat or y e val uati o ns will be c ollecte d after at least 6- h o ur fast. Faecal sa m ples i n 
treat me nt peri o ds will be c ollecte d as far as p ossi ble.  If t he latest res ult d uri n g t he treat me nt 
peri o d is p ositi ve, faecal sa m ples will be c ollecte d f or faecal occ ult bl o o d test at t he f oll o w-
u p visit, as far as p ossi ble.  If s u bjects c ollect faecal sa m ples at h o me, t he sa m ple wit hi n 24 
h o urs bef ore t he desi g nate d ti me p oi nt is acce pta ble. F or fe male s u bjects, faecal sa m ples at 
scree ni n g a n d t he f oll o w- u p visit s h o ul d be c ollecte d at least 3 da ys after t he c o m pleti o n of 
me nstr uati o n.  
A d diti o nal cli nical la b orat or y e val uati o ns will be perf or me d at ot her ti mes if j u d ge d t o be 
cli nicall y a p pr o priate or if t he o n g oi n g re vie w of t he data s u g gests a m ore detaile d 
assess me nt of cli nical la b orat or y safet y e val uati o ns is re q uire d . 
S u bjects will be as ke d t o pr o vi de uri ne sa m ples f or dr u gs of a b use scree n a n d c oti ni ne test, 
a n d will u n der g o a n alc o h ol breat h test at t he ti mes i n dicate d i n t he Sc he d ule of Assess me nts 
i n A p pe n di x 6 . 
F or all fe male s u bjects, ser u m a n d/ or uri ne pre g na nc y tests a n d f ollicle-sti m ulati n g h or m o ne 
test will be perf or me d at t he ti mes i n dicate d i n t he Sc he d ule of Assess me nts i n A p pe n di x 6 , 
as a p plica ble . 
A n I n vesti gat or ( or desi g nee) will perf or m a cli nical assess me nt of all cli nical la b orat or y 
data. 
7. 3. 3.  
Brist ol St o ol C h art  
T he f or m of faeces will be assesse d b y cli nical staff usi n g t he Brist ol St o ol C hart w he n 
c ollecti n g faecal sa m ples f or faecal occ ult bl o o d test i n treat me nt peri o ds  (see Sc he d ule of 
Assess me nts i n A p pe n di x 6 ). T he f or m of faeces ma y als o be assesse d at ot her ti mes if 
j u d ge d t o be cli nicall y a p pr o priate. 
7. 3. 4.  
Vit al Si g ns  
S u pi ne bl o o d press ure, s u pi ne p ulse rate, res pirat or y rate, a n d oral b o d y te m perat ure will be 
assesse d at t he ti mes i n dicate d i n t he Sc he d ule of Assess me nts i n A p pe n di x 6 . Vital si g ns 
ma y als o be perf or me d at ot her ti mes if j u d ge d t o be cli nicall y a p pr o priate or if t he o n g oi n g 
re vie w of t he data s u g gests a m ore detaile d assess me nt of vital si g ns is re q uire d. 
F or Da y 1 pre d ose i n eac h treat me nt peri o d i n Parts A t o C a n d Da y 1 1 pre d ose i n Part C, 
bl o o d press ure, p ulse rate, a n d res pirat or y rate will be meas ure d i n tri plicate at a p pr o xi matel y 
2- mi n ute i nter vals. T he me dia n val ue will be use d as t he baseli ne val ue i n t he data a nal ysis. 
Al l s u bse q ue nt meas ure me nts will be perf or me d si n gl y a n d re peate d o nce if o utsi de t he 
rele va nt cli nical refere nce ra n ges. Oral b o d y te m perat ure will be meas ure d si n gl y . 
 
  


Pr ot oc ol 
C O N FI D E N TI A L  
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 5 6 of 8 6 
S u bjects s h o ul d be s u pi ne f or at least 5 mi n utes bef ore bl o o d press ure a n d p ulse rate 
meas ure me nts . 
7. 3. 5.  
1 2- le a d E lectr oc ar di o gr a m
Resti n g 1 2- lea d E C Gs will be rec or de d after t he s u bject has bee n s u pi ne a n d at rest f or at 
least 5 mi n utes at t he ti mes i n dicate d i n t he Sc he d ule of Assess me nts i n A p pe n di x 6 . Si n gle 
1 2- lea d E C Gs will be re peate d o nce if eit her of t he f oll o wi n g criteria a p pl y:
•
Q T c F val ue > 5 0 0 msec
•
Q Tc F c ha n ge fr o m t he baseli ne ( pre d ose ) is > 6 0 msec .
A d diti o nal 1 2 lea d E C Gs ma y be perf or me d at ot her ti mes if j u d ge d t o be cli nicall y 
a p pr o priate or if t he o n g oi n g re vie w of t he data s u g gests a m ore detaile d assess me nt of E C Gs 
is re q uire d. T he I n vesti gat or ( or desi g nee) will perf or m a cli nical assess me nt of eac h 1 2 lea d  
E C G . 
Da y 1 pre d ose 1 2- lea d E C Gs i n eac h treat me nt peri o d i n Parts A t o C an d Da y 1 1 pre d ose i n 
Part C will be meas ure d i n tri plicate at a p pr o xi matel y 2 -mi n ute i nter vals.  T he mea n val ue 
will be use d as t he baseli ne val ue i n t he data a nal ysis. All s u bse q ue nt meas ure me nts will be 
perf or me d si n gl y a n d re peate d o nce if o utsi de t he rele va nt cli nical refere nce ra n ges . 
7. 3. 6.  
P h ysic al E x a mi n ati o n 
A f ull p h ysical e xa mi nati o n or s y m pt o m- directe d p h ysical e xa mi nati o n will be perf or me d b y 
I n vesti gat or ( or desi g nee) at t he ti me p oi nts s pecifie d i n t he Sc he d ule of Assess me nts i n 
A p pe n di x 6 . 
7. 3. 7.  
A b d o mi n al E x a mi n ati o n  
A n a b d o mi nal e xa mi nati o n will be perf or me d i n Parts A a n d B b y I n vesti gat or ( or desi g nee) 
a n d will i ncl u de i ns pecti o n, a usc ultati o n, pal pati o n a n d perc ussi o n of t he a b d o me n. T he 
a b d o mi nal e xa mi nati o n will be perf or me d at t he ti mes i n dicate d i n t he Sc he d ule of 
Assess me nts i n A p pe n di x 6 . 
W he n t he p h ysical e xa mi nati o n a n d t he a b d o mi nal e xa mi nati o n are sc he d ule d at t he sa me 
da y, t he a b d o mi nal e xa mi nati o n ma y be perf or me d as part of t he p h ysical e xa mi nati o n.  
7. 3. 8.  
Hei g ht , B o d y Wei g ht, a n d B MI 
Hei g ht a n d b o d y wei g ht (i n u n dercl ot hes a n d wit h s h oes off) will be rec or de d at t he ti mes 
i n dicate d in  t he Sc he d ule of Assess me nts i n A p pe n di x 6 . The B MI  is calc ulate d usi n g metric 
u nits wit h t he f or m ula pr o vi de d bel o w. 
B MI s h o ul d be deri ve d as: 
Metric: B MI = b o d y wei g ht ( k g)/ hei g ht ( m)
2
 
  


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 5 7 of 8 6 
8.  S A M P L E SI Z E  A N D D A T A A N A L Y SI S  
8. 1.  
Deter mi n ati o n of S a m ple Size  
N o f or mal statistical assess me nt, i n ter ms of sa m ple size, has bee n c o n d ucte d as t his is t he 
first ti me K R P- A 2 1 8 is bei n g a d mi nistere d t o h u ma ns. H o we ver, t he n u m ber of s u bjects i n 
Parts A, B, a n d C is c o m m o n i n earl y cli nical p har mac ol o g y st u dies/ D DI st u dies, a n d is 
c o nsi dere d s ufficie nt t o ac hie ve t he o bjecti ves of t he st u d y. 
8. 2.  
A n al ysis P o p ul ati o ns  
8. 2. 1.  
P h ar m ac o ki netic P o p ul ati o n  
T he P K p o p ulati o n will i ncl u de all s u bjects w h o recei ve d at least 1 d ose of acti ve st u d y 
treat me nt (K R P - A 2 1 8 or itrac o naz ole)  a n d ha ve at least 1 q ua ntifia ble P K c o nce ntrati o n . A 
s u bject ma y  be e xcl u de d fr o m t he P K s u m mar y statistics a n d statistical a nal ysis if t he s u bject 
has a n A E of v o miti n g t hat occ urs at or bef ore 2- ti mes tma x . 
8. 2. 2.  
S afe t y P o p ul ati o n 
T he safet y p o p ulati o n will i ncl u de all s u bjects w h o recei ve d at least 1 d ose of st u d y treat me nt 
(K R P - A 2 1 8, place b o , or itrac o naz ole). 
8. 3.  
P h ar m ac o ki netic A n al yses 
N o nc o m par t me ntal P K a nal ysis will be perf or me d o n i n di vi d ual plas ma c o nce ntrati o n data, 
usi n g c o m mercial s oft ware s uc h as P h oe ni x ®  Wi n N o nli n® . Plas ma c o nce ntrati o ns a n d P K 
para meters of 
, itrac o naz ole, a n d h y dr o x y-itrac o naz ole will be liste d a n d 
s u m marise d b y treat me nt gr o u p usi n g descri pti ve statistics. I n di vi d ual a n d mea n 
c o nce ntrati o n-ti me pr ofiles f or 
 a n d itrac o naz ole a n d h y dr o x y-itrac o naz ole f or 
eac h treat me nt gr o u p will als o be prese nte d gra p hicall y . 
W here dat a are a vaila ble, d ose pr o p orti o nalit y of  
will be e xa mi ne d acr oss d ose 
gr o u ps. T he P K para met ers will be a nal yse d f or d ose pr o p orti o nalit y usi n g a p o wer m o del 
a p pr oac h a n d/or a nal ysis of varia nce ( A N O V A) m o del, as a p pr o priate. W here data are 
a vaila ble, t he effect of f o o d at 1 d ose le vel i n Part A, a n d t he i nteracti o n bet wee n K R P- A 2 1 8 
al o ne a n d c o- a d mi nistere d wit h itrac o naz ole i n Part C will be i n vesti gate d usi n g 
mi xe d - m o del; t he effect of se x at 1 d ose le vel i n Part A will be i n vesti gate d usi n g A N O V A. 
Data ha n dl i n g pr oce d ures will be d oc u me nte d i n t he Statistical A nal ysis Pla n. 
8. 4.  
E x pl or at or y Met a b olite Pr ofili n g A n al ysis 
Data o btai ne d fr o m t he e x pl orat or y meta b olite pr ofili n g a nal ysis ma y be re p orte d else w here 
a n d will n ot f or m part of t he Cli nical St u d y Re p ort f or t his st u d y . 
8. 5.  
P h ar m ac o ge netic A n al ysis 
If p har mac o ge netic a nal ysis is u n derta ke n, res ults ma y be re p orte d else w here a n d will n ot 
f or m part of t he Cli nical St u d y Re p ort f or t his st u d y. 
 
  
C CI
C CI
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 5 8 of 8 6 
8. 6.  
E x pl or at or y Bi o m ar ker A n al ysis 
If e x pl orat or y bi o mar ker a nal ysis is u n derta ke n, res ults ma y be re p orte d else w here a n d will 
n ot f or m part of t he Cli nical St u d y Re p ort f or t his st u d y. 
8. 7.  
C o nce ntr ati o n- Q Tc A n al ysis 
If c o nce ntrati o n-Q Tc a nal ysis is u n derta ke n, res ults ma y be re p orte d else w here a n d will n ot 
f or m part of t he Cli nical St u d y Re p ort f or t his st u d y. 
8. 8.  
S afet y A n al ysis 
Safet y para meters will be liste d a n d s u m mari se d usi n g descri pti ve statistics. N o f or mal 
statistical a nal ysis of safet y data is pla n ne d. Eac h A E will be c o de d usi n g t he Me dical 
Dicti o nar y f or Re g ulat or y Acti vities . 
8. 9.  
I nteri m A n al ysis 
T here is n o pla n ne d i nteri m a nal ysis f or t his st u d y. 
 
  


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 5 9 of 8 6 
9.  R E F E R E N C E S  
1.  R o yst o n L, Ta p parel C. R hi n o vir uses a n d Res pirat or y E nter o vir uses: N ot as Si m ple as 
A B C. Vir uses. 2 0 1 6; 8: 1 6. 
2.  Ha m m o n d S P, Ga g ne L S, St oc k S R, Mart y F M, Gel ma n R S, Marasc o W A, et al. 
Res pirat or y vir us detecti o n i n i m m u n oc o m pr o mise d patie nts wit h Fil m Arra y res pirat or y 
pa nel c o m pare d t o c o n ve nti o nal met h o ds. J Cli n Micr o bi ol. 2 0 1 2; 5 0: 3 2 1 6- 2 1. 
3.  Jac o bs S E, La ms o n D M, St Ge or ge K, Wals h, TJ. H u ma n R hi n o vir uses. Cli n. Micr o bi ol. 
Re v. 2 0 1 3; 2 6: 1 3 5- 6 2. 
4.  Mc Ma n us T E, Marle y A M, Ba xter N, C hristie S N, O' Neill HJ, El b or n J S, et al. 
Res pirat or y viral i nfecti o n i n e xacer bati o ns of C O P D. Res pir Me d. 2 0 0 8; 1 0 2: 1 5 7 5 -8 0.  
5.  E d war ds M R, Ritc hie AI, J o h nst o n S L. E xacer bati o ns of c hr o nic res pirat or y diseases. 
R hi n o vir us i nfecti o ns. 2 0 1 9; 1 3 7- 6 8. 
6.  Kraft C S, Jac o b J T, Sears M H, B ur d E M, Calie n d o A M, L y o n G M. Se verit y of h u ma n 
r hi n o vir us i nfecti o n i n i m m u n oc o m pr o mise d a d ults is si milar t o t hat of 2 0 0 9 H 1 N 1 
i nfl ue nza. J Cli n Micr o bi ol. 2 0 1 2; 5 0: 1 0 6 1- 3. 
7.  Se o S, Wa g h mare A, Sc ott E M, Xie H, K u y pers J M, Hac k ma n R C, et al. H u ma n 
r hi n o vir us detecti o n i n t he l o wer res pirat or y tract of he mat o p oietic cell tra ns pla nt 
reci pients: ass ociati o n wit h m ortalit y. He mat ol o gica. 2 0 1 7; 1 0 2: 1 1 2 0- 3 0. 
8.  S ha h D P, G ha nt oji S S, M ula n o vic h V E, Ariza- Here dia EJ, C he mal y R F. Ma na ge me nt of 
res pirat or y viral i nfecti o ns i n he mat o p oietic cell tra ns pla nt reci pie nts. A m J Bl o o d Res. 
2 0 1 2; 2: 2 0 3- 1 8. 
9.  Mi la n o F, Ca m p bell A P, G ut hrie K A, K u y pers J, E n gl u n d J A, C ore y L, et al. H u ma n 
r hi n o vir us a n d c or o na vir us detecti o n a m o n g all o ge neic he mat o p oietic ste m cell 
tra ns pla ntati o n reci pie nts. Bl o o d. 2 0 1 0; 1 1 5: 2 0 8 8- 9 4. 
1 0.  Versl u ys A B, R osse n J W, va n E wij k B, Sc h u ur ma n R, Bieri n gs M B, B oele ns JJ. Str o n g 
ass ociati o n bet wee n res pirat or y viral i nfecti o n earl y after he mat o p oietic  ste m cell 
tra ns pla ntati o n a n d t he de vel o p me nt of life-t hreate ni n g ac ute a n d c hr o nic all oi m m u ne 
l u n g s y n dr o mes. Bi ol Bl o o d Marr o w Tra ns pla nt. 2 0 1 0; 1 6: 7 8 2- 9 1. 
1 1.  Wa g h mare A, Xie H, K u y pers J, S orr or M L, Jer o me K R, E n gl u n d J A, et al. H u ma n 
r hi n o vir us i nfecti o ns i n he mat o p oietic cell tra ns pla nt reci pie nts: ris k sc ore f or pr o gressi o n 
t o l o wer res pirat or y tract i nfecti o n. Bi ol Bl o o d Marr o w Tra ns pla nt. 2 0 1 9; 2 5: 1 0 1 1- 2 1. 
1 2.  G h os h S, C ha m pli n R, C o uc h R, E n gl u n d J, Raa d I, Mali k S, et al. R hi n o vir us i nfecti o ns 
i n m yel os u p presse d a d ult bl o o d a n d marr o w tra ns pla nt reci pie nts. Cli n I nfect Dis. 1 9 9 9; 
2 9: 5 2 8- 3 2. 
1 3.  Si m S A, Le u n g V K Y, Ritc hie D, Sla vi n M A, S ulli va n S G, Te h B W. Viral res pirat or y 
tract i nfecti o ns i n all o ge neic he mat o p oietic ste m cell tra ns pla ntati o n reci pie nts i n t he era 
of m olec ular testi n g. Bi ol Bl o o d Marr o w Tra ns pla nt. 2 0 1 8; 2 4: 1 4 9 0- 6. 
 
  


Pr ot oc ol 
C O N FI D E N TI A L  
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 6 0 of 8 6 
1 4. C he n B S, Lee H C, Lee K M, G o n g Y N, S hi h S R. E nter o vir us a n d e nce p ha litis. Fr o nt
Micr o bi ol. 2 0 2 0; 1 1: 2 6 1.
1 5. Ta p parel C, Sie grist F, Pett y TJ, Kaiser L. Pic or na vir us a n d e nter o vir us di versit y wit h
ass ociate d h u ma n diseases. I nfect Ge net E v ol. 2 0 1 3; 1 4: 2 8 2- 9 3.
1 6. E ur o pea n Me dici nes A ge nc y. G ui deli ne o n t he I n vesti gati o n of Dr u g I nteracti o ns.
Retrie ve d fr o m C P M P/ E W P/ 5 6 0/ 9 5/ Re v. 1 C orr. 2 * *. 2 0 1 2 J u ne 2 1.
1 7.  U. S. De part me nt of Healt h a n d H u ma n Ser vices - F o o d a n d Dr u g A d mi nistrati o n.
G ui da nce f or I n d ustr y. Cli nical Dr u g I nteracti o n St u dies - C yt oc hr o me P 4 5 0 E nz y me- 
a n d Tra ns p orter- Me diate d Dr u g I nteracti o ns G ui da nce f or I n d ustr y. 2 0 2 0, Ja n.
1 8.  K y ori n P har mace utical C o., Lt d. K R P- A 2 1 8 I n vesti gat or’s Br oc h ure ( Versi o n 1. 0).
FI N A L.
1 9.  U. S. De part me nt of Healt h a n d H u ma n Ser vices - F o o d a n d Dr u g A d mi nistrati o n.
G ui da nce f or I n d ustr y. Retrie ve d fr o m Esti mati n g t he Ma xi m u m Safe Starti n g D ose i n
I nitial Cli nical Trials f or T hera pe utics i n A d ult Healt h y V ol u nteers. 2 0 0 5, J ul y.
2 0. E ur o pea n Me dici nes A ge nc y. G ui deli ne o n strate gies t o i de ntif y a n d miti gate ris ks f or
first-i n-h u ma n a n d earl y cli nical tria ls wit h i n vesti gati o nal me dici nal pr o d ucts. Retrie ve d
fr o m E M E A/ C H M P/ S W P/ 2 8 3 6 7/ 0 7/ Re v. 1. 2 0 1 7 J ul y 2 0.
2 1. I nter nati o nal C o nfere nce o n Har m o nsiati o n. Ha r m o nise d Tri partite G ui deli ne: The
Cli nical E val uati o n of Q T/ Q Tc I nter val Pr ol o n gati o n a n d Pr oarrr h yt h mic P ote ntial f or
N o n - A ntiarr h yt h mic Dr u gs. E 1 4. 2 0 0 5.
2 2. I nter nati o nal C o nfere nce o n Har m o nsiati o n. Ha r m o nise d Tri partite G ui deli ne: The
Cli nical E val uati o n of Q T/ Q Tc I nter val Pr ol o n gati o n a n d Pr oarrr h yt h mic P ote ntial f or
N o n - A ntiarr h yt h mic Dr u gs. E 1 4 – Q uesti o ns & A ns wers ( R 3). 2 0 1 5.
2 3. Gar nett C, B o nate P L, Da n g Q, Fer ber G, H ua n g D, Li u J, et al. Scie ntific w hite pa per o n
c o nce ntrati o n - Q Tc m o delli n g. J P har mac o ki net P har mac o d y n. 2 0 1 8; 4 5( 3): 3 8 3- 3 9 7.
 
  


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 6 1 of 8 6 
1 0.  
A P P E N DI C E S  
 
  


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 6 2 of 8 6 
A p pe n di x  1: A d verse E ve nt Re p orti n g  
Defi niti o ns  
A n A E  is a n y u nt o war d me dical occ urre nce i n a patie nt or cli nical i n vesti gati o n s u bject 
a d mi nistere d a p har mace utical pr o d uct, w hic h d oes n ot necessaril y ha ve a ca usal relati o ns hi p 
wit h t his treat me nt. A n A E ca n t heref ore be a n y u nfa v o ura ble a n d/ or u ni nte n de d si g n 
(i ncl u di n g a n a b n or mal la b orat or y fi n di n g), s y m pt o m, or disease te m p orall y ass ociate d wit h 
t he use of a st u d y dr u g, w het her or n ot relate d t o t he st u d y dr u g. 
Assess me nt of Se verit y  
T he I n vesti gat or will be as ke d t o pr o vi de a n assess me nt of t he se verit y of t he A E usi n g t he 
f oll o wi n g cate g ories: 
•  Mil d : Us uall y tra nsie nt a n d ma y re q uire o nl y mi ni mal treat me nt or t hera pe utic 
i nter ve nti o n. T he e ve nt d oes n ot ge nerall y i nterfere wit h us ual acti vities of dail y 
li vi n g. 
•  M o der ate : Us ua ll y alle viate d wit h a d diti o nal s pecific t hera pe utic i nter ve nti o n. T he 
e ve nt i nterferes wit h us ual acti vities of dail y li vi n g, ca usi n g disc o mf ort b ut p oses n o 
si g nifica nt or per ma ne nt ris k of har m t o t he s u bject. 
•  Se vere : I nterr u pts us ual acti vities of dail y li vi n g, or si g nifica nt affects cli nical stat us, 
or ma y re q uire i nte nsi ve t hera pe utic i nter ve nti o n.  
Rel ati o ns hi p t o St u d y Tre at me nt  
T he I n vesti gat or will ma ke a deter mi nati o n of t he relati o ns hi p of t he A E t o t he st u d y dr u g 
usi n g a f o ur- cate g or y s yste m acc o r di n g t o t he f oll o wi n g g ui deli nes: 
•  N ot Rel ate d : T he A E is defi nitel y ca use d b y t he s u bject’s cli nical state or t he st u d y 
pr oce d ure/c o n diti o ns. 
•  U nli kel y Rel ate d : T he te m p oral ass ociati o n bet wee n t he A E a n d t he dr u g is s uc h t hat 
t he dr u g is n ot li kel y t o ha ve a n y reas o na ble ass ociati o n wit h t he A E.  
•  P ossi bl y Rel ate d : T he A E f oll o ws a reas o na ble te m p oral se q ue nce fr o m t he ti me of 
dr u g a d mi nistrati o n b ut c o ul d ha ve bee n pr o d uce d b y t he s u bject’s cli nical state or t he 
st u d y pr oce d ures/c o n diti o ns. 
•  Rel ate d : T he A E f oll o ws a reas o na ble te m p oral se q ue nce fr o m a d mi nistrati o n of t he 
dr u g, a bates u p o n disc o nti n uati o n of t he dr u g, f oll o ws a k n o w n or h y p ot hesize d 
ca use-effect relati o ns hi p, a n d (if a p pr o priate) rea p pears w he n t he dr u g is rei ntr o d uce d. 
F oll o w- u p of A d verse E ve nts  
E ver y reas o na ble eff ort will be ma de t o f oll o w - u p wit h s u bjects w h o ha ve A Es. A n y s u bject 
w h o has a n o n g oi n g A E  t hat is p ossi bl y relate d or relate d t o t he I M P or st u d y pr oce d ures at 
t he f oll o w-u p v isit will be f oll o we d u p, w here p ossi ble, u ntil res ol uti o n or u ntil t he 
u nres ol ve d A E is j u d ge d b y t he I n vesti gat or ( or desi g nee) t o ha ve sta bili se d. T his will be 
c o m plete d at t he I n vesti gat or’s ( or desi g nee’s) discreti o n.  A n y s u bject w h o has a n o n g oi n g 
 
  


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 6 3 of 8 6 
A E t hat is n ot relate d or u nli kel y relate d t o t he I M P or st u d y pr oce d ures at t he f oll o w- u p visit 
ca n be cl ose d o ut as o n g oi n g at t he I n vesti gat or’s discreti o n. 
A d verse Dr u g Re acti o ns  
All n o xi o us a n d u ni nte n de d res p o nses t o a n y d ose of I M P (ie, w here a ca usal relati o ns hi p 
bet wee n a n I M P a n d a n A E is at least a reas o na ble p ossi bilit y  [ie, ‘relate d’ or ‘ p ossi bl y 
relate d’]) s h o ul d be c o nsi dere d a d verse dr u g reacti o ns. 
F or mar kete d me dici nal  pr o d ucts, a res p o nse t o a dr u g w hic h is n o xi o us a n d u ni nte n de d a n d 
w hic h  occ urs at d oses n or mall y use d i n ma n f or pr o p h yla xis, dia g n osis, or t hera p y of diseases 
or f or m o dificati o n of p h ysi ol o gical f u ncti o n is t o be c o nsi dere d a n a d verse dr u g reacti o n. 
A n u ne x pecte d a d verse dr u g reacti o n is defi ne d as a n a d verse reacti o n, t he nat ure or se verit y 
of w hic h is n ot c o nsiste nt wit h t he a p plica ble pr o d uct i nf or mati o n (e g, I B f or a n u na p pr o ve d 
I M P). 
Seri o us A d verse E ve nts  
A seri o us A E (S A E ) is defi ne d as a n y u nt o war d me dical occ urre nce t hat at a n y d ose eit her: 
•  res ults i n deat h 
•  is life-t hreate ni n g 
•  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  
•  res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y ( disa bilit y is defi ne d as a 
s u bsta ntial disr u pti o n of a pers o n’s a bilit y t o c o n d uct n or mal life f u ncti o ns) 
•  res ults i n a c o n ge nital a n o mal y/ birt h defect 
•  res ults i n a n i m p orta nt me dical e ve nt (see bel o w) . 
I m p orta nt me dical e ve nts t hat ma y n ot res ult i n deat h, be life-t hreate ni n g, or re q uire 
h os pitalizati o n ma y be c o nsi dere d S A Es w he n, base d u p o n a p pr o priate me dical j u d g me nt, 
t he y ma y je o par dize t he s u bject a n d ma y re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt 
o ne of t he o utc o mes liste d i n t his defi niti o n. 
I nsta nces of deat h or c o n ge nital a b n or malit y, if br o u g ht t o t he atte nti o n of t he I n vesti gat or at 
a n y ti me after cessati o n of t he st u d y treat me nt a n d c o nsi dere d b y t he I n vesti gat or t o be 
p ossi bl y relate d t o t he st u d y treat me nt, will be re p orte d t o t he S p o ns or. 
Defi niti o n of Life -t hreate ni n g 
A n A E  is life-t hreate ni n g if t he s u bject was at i m me diate ris k of deat h fr o m t he e ve nt as it 
occ urre d ( ie, d oes n ot i ncl u de a reacti o n t hat mi g ht ha ve ca use d deat h if it ha d occ urre d i n a 
m ore seri o us f or m ). F or i nsta nce, dr u g-i n d uce d he patitis t hat res ol ve d wit h o ut e vi de nce of 
he patic fail ure w o ul d n ot be c o nsi dere d life-t hreate ni n g e ve n t h o u g h dr u g-i n d uce d he patitis 
ca n be fatal. 
Defi niti o n of H os pitalizati o n  
 
  


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 6 4 of 8 6 
A d verse e ve nts re q uiri n g h os pitalizati o n s h o ul d be c o nsi dere d seri o us. I n ge neral, 
h os pitalizati o n si g nifies t hat t he s u bject has bee n detai ne d ( us uall y i n v ol vi n g a n o ver ni g ht 
sta y) at t he h os pital or e mer ge nc y war d f or o bser vati o n a n d/ or treat me nt t hat w o ul d n ot ha ve 
bee n a p pr o priate at t he C R U. W he n i n d o u bt as t o w het her h os pitalizati o n occ urre d or was 
necessar y, t he A E  s h o ul d be c o nsi dere d as seri o us. 
H os pitalizati o n f or electi ve s ur ger y or r o uti ne cli nical p r oce d ures, w hic h are n ot t he res ult of 
a n A E , nee d n ot be c o nsi dere d A Es  a n d s h o ul d be rec or de d o n a Cli nical Assess me nt For m 
a n d a d de d t o t he e C R F. If a n yt hi n g u nt o war d is re p orte d d uri n g t he pr oce d ure, t his m ust be 
re p orte d as a n A E  a n d eit her ‘seri o us’ or ‘ n o nseri o us’ attri b ute d acc or di n g t o t he us ual 
criteria. 
Seri o us A d verse E ve nt Re p orti n g  
L a bc or p Dr u g De vel o p me nt  Patie nt Safet y Ser vices ( P S S) E ur o pe, Mai de n hea d, U K (t o 
c o nfir m), are res p o nsi ble f or c o or di nati n g t he re p orti n g of S A Es i n acc or da nce wit h t he 
E ur o pea n Directi ve 2 0 0 1/ 2 0/ E C. 
T he I n vesti gat or will c o m plete a n S A E re p ort f or m a n d f or war d  it b y facsi mile or e mail  t o 
P S S im me di atel y ( wit hi n 2 4  h o urs) u p o n bec o mi n g a ware of a n S A E. 
T he res p o nsi bilities of La bc or p Dr u g De vel o p me nt P S S i ncl u de t he f oll o wi n g: 
•  Pre pare a n A E re p orti n g pla n pri or t o t he start of t he st u d y. W here t his pla n differs 
fr o m t he a p plica ble C R U sta n dar d o perati n g pr oce d ure o n S A E re p orti n g, t he A E 
re p orti n g pla n will al wa ys ta ke prece de nce. 
•  Recei ve a n d re vie w S A E re p ort f or ms fr o m t he C R U a n d i nf or m t he S p o ns or of t he 
S A E wit hi n 1 b usi ness da y of t he i nitial n otificati o n  t o PS S. Patie nt Safet y Ser vices 
will delete a n y i nf or mati o n fr o m t he S A E re p ort f or ms t hat ma y i de ntif y t he s u bject.  
•  Write case narrati ves a n d e nter t he case i nt o La bc or p Dr u g De vel o p me nt ’s safet y 
data base  as defi ne d i n t he A E re p orti n g pla n. 
•  Pr o d uce a p pr o priate re p orts of all S us pecte d U ne x pecte d Seri o us A d verse Reacti o ns 
a n d f or war d t o t he E t hics C o m mittee , Me dici nes a n d Hea lt hcare Pr o d ucts Re g ulat or y 
A ge nc y , Pri nci pal I n vesti gat or, a n d t he S p o ns or wit hi n t he ti mefra mes sti p ulate d i n 
t he Cli nical T rials Directi ve G ui deli ne ( E N T R/ C T  3). 
T he res p o nsi bilit y f or re p orti n g S A Es will be tra nsferre d t o t he S p o ns or 2 8  da ys aft er t he e n d 
of t he st u d y. 
Pre g n a nc y  
Pre g na nc y ( mater nal or pater nal e x p os ure t o st u d y treat me nt) d oes n ot meet t he defi niti o n of 
a n A E. H o we ver, t o f ulfil re g ulat or y re q uire me nts a n y pre g na nc y s h o ul d be re p orte d 
f oll o wi n g t he S A E pr ocess t o c ollect data o n t he o utc o me f or b ot h m ot her a n d f oet us. 
 
 
 
  










Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 6 9 of 8 6 
A p pe n di x  4: C o ntr ace pti o n G ui d a nce 
Defi niti o ns  
W o me n of C hil d be ari n g P ote nti al:  pre me n o pa usal fe males w h o are a nat o micall y a n d 
p h ysi ol o gicall y ca pa ble of bec o mi n g pre g na nt f oll o wi n g me narc he. 
W o me n of N o nc hil d be ari n g P ote nti al: 
1.  S ur gicall y sterile: fe males w h o are per ma ne ntl y sterile via h ysterect o m y, bilateral 
sal pi n gect o m y, a n d/ or bilateral o o p h orect o m y be re p orte d me dical hist or y a n d/ or 
me dical rec or ds. S ur gical sterilisati o n t o ha ve occ urre d a mi ni m u m of 6 wee ks, or at 
t he In vesti gat or’s discreti o n, pri or t o scree ni n g.  
2.  P ost me n o pa usal: Fe males at least 4 5 years of a ge wit h a me n orr h oea f or 1 2  m o nt hs 
wit h o ut a n alter nati ve me dical reas o n wit h c o nfir mat or y f ollicle -sti m ulati n g h or m o ne 
( F S H) le vels of ≥4 0 mI U/ m L  at scree ni n g . T he a me n orr h oea s h o ul d n ot be i n d uce d b y 
a me dical c o n diti o n s uc h as a n ore xia ner v osa, h y p ot h yr oi d disease or p ol yc ystic 
o varia n disease, or b y e xtre me e xercise. It s h o ul d n ot be d ue t o c o nc o mita nt 
me dicati o ns t hat ma y ha ve i n d uce d t he a me n orr h oea s uc h as oral c o ntrace pti ves, 
h or m o nes, g o na d otr o pi n-releasi n g h or m o nes, a nti- oestr o ge ns, or selecti ve oestr o ge n 
rece pt or m o d ulat ors. 
Fertile M ale:  a male t hat is c o nsi dere d fertile after p u bert y.  
I nfertile M ale: per ma ne ntl y sterile male via bilateral orc hiect o m y.  
C o ntr ace pti o n G ui d a nce  
Fe m ale S u bjects  
Fe male  s u bjects w h o are of n o nc hil d beari n g p ote ntial will n ot be re q uire d t o use 
c o ntrace pti o n. Fe male s u bjects of c hil d beari n g p ote ntial m ust be willi n g t o use a hi g hl y 
effecti ve met h o d of birt h c o ntr ol i n c o nj u ncti o n wit h male barrier c o ntrace pti o n (i.e. male 
c o n d o m wit h s per mici de) fr o m t he ti me of si g ni n g t he I C F u ntil 9 0 da ys afte r t he f oll o w- u p 
visit. H or m o ne- releasi n g i ntra uteri ne de vice (I U D) a n d oral, i m pla nta ble, tra ns der mal, or 
i njecta ble h or m o nal met h o ds of c o ntrace pti o n are n ot acce pta ble, si nce t he c o ntrace pti ve 
effects ma y n ot be s ufficie nt d ue t o t he p ossi bilit y of C Y P 3 A 4 i n d ucti o n b y  
 
Hi g hl y effecti ve met h o ds of c o ntrace pti o n i ncl u de: 
•  Male ste rilisati o n ( perf or me d at least 9 0 da ys pri or t o t he scree ni n g visit), wit h ver bal 
c o nfir mati o n of s ur gical s uccess (f or fe male s u bjects o n t he st u d y, t he vasect o mise d 
male part ner s h o ul d be t he s ole part ner f or t hat s u bject) 
•  Bilateral t u bal li gati o n or occl usi o n ( perf or me d at least 9 0 da ys pri or t o t he scree ni n g 
visit)  
Fe male s u bjects s h o ul d refrai n fr o m d o nati o n of e g gs ( o va, o oc ytes)  fr o m c hec k-i n ( Da y - 1) 
u ntil 9 0 da ys af ter t he f oll o w- u p visit. 
 
  
C CI


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 7 0 of 8 6 
M ale S u bjects  
Male s u bjects (e ve n wit h a hist or y of vasect o m y) wit h part ners of c hil d beari n g p ote ntial m ust 
use a male barrier met h o d of c o ntrace pti o n (ie, male c o n d o m wit h s per mici de) i n a d diti o n t o 
a sec o n d met h o d of acce pta ble c o ntrace pti o n fr o m Da y  - 1 u ntil 9 0 da ys after t he f oll o w - u p 
visit. I n a d diti o n t o t he list of hi g hl y effecti ve met h o ds of c o ntrace pti o n a b o ve, ot her 
acce pta ble met h o ds of c o ntrace pti o n f or fe male part ners i ncl u de: 
•  H or m o ne- releasi n g I U D. Steel or c o p per I U Ds are n ot acce pta ble  
•  Esta blis he d use of oral, i m pla nta ble, tra ns der mal, or i njecta ble h or m o nal met h o d of 
c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n 
•  Esta blis he d use of pr o gester o ne o nl y oral c o ntrace pti o n, w here i n hi biti o n of o v ulati o n 
is n ot t he pri mar y m o de of acti o n  
D o u ble- barrier met h o ds, s uc h as male c o n d o m wit h s per mici de al o n g wit h fe male part ner use 
of a fe male c o n d o m, dia p hra g m, ca p, or s p o n ge are n ot acce pta ble. 
A n acce pta ble sec o n d met h o d of c o ntrace pti o n f or male s u bjects is vasect o m y t hat has bee n 
perf or me d at least 9 0 da ys pri or t o t he scree ni n g visit, wit h ver bal c o nfir mati o n of s ur gical 
s uccess. 
F or male s u bjects (e ve n wit h a hist or y of vasect o m y), se x ual i nterc o urse wit h fe male part ners 
w h o are pre g na nt or breastfee di n g s h o ul d be a v oi de d u nless c o n d o ms are use d fr o m t he ti me 
of t he first d ose u ntil 9 0 da ys after t he f oll o w- u p visit. Male s u bjects are re q uire d t o refrai n 
fr o m d o nati o n of s per m fr o m c hec k-i n u ntil 9 0 da ys after t he f oll o w- u p visit. 
Se x u al A bsti ne nce a n d S a me -se x Rel atio ns hi ps  
S u bjects w h o practice tr ue a bsti ne nce, beca use of t he s u bject’s lifest yle c h oice (ie, t he s u bject 
s h o ul d n ot bec o me a bsti ne nt j ust f or t he p ur p ose of st u d y partici pati o n), are e xe m pt fr o m 
c o ntrace pti ve re q uire me nts. Peri o dic a bsti ne nce (e g, cale n da r, o v ulati o n, s y m pt ot her mal, 
p ost o v ulati o n met h o ds) a n d wit h dra wal are n ot acce pta ble met h o ds of c o ntrace pti o n. If a 
s u bject w h o is a bsti ne nt at t he ti me of si g ni n g t he I C F bec o mes se x uall y acti ve t he y m ust 
a gree t o use c o ntrace pti o n as descri be d pre vi o usl y. 
F or s u bjects w h o are e xcl usi vel y i n sa me-se x relati o ns hi ps, c o ntrace pti ve re q uire me nts d o n ot 
a p pl y. If a s u bject w h o is i n a sa me-se x relati o ns hi p at t he ti me of si g ni n g t he I C F bec o mes 
e n ga ge d i n a heter ose x ual relati o ns hi p, t he y m ust a gree t o use c o n trace pti o n as descri be d 
pre vi o usl y. 
 
  


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 7 1 of 8 6 
A p pe n di x  5: Re g ul at or y, Et hic al, a n d St u d y O versi g ht C o nsi der ati o ns  
Re g ul at or y a n d Et hic al C o nsi der ati o ns  
T his st u d y will be c o n d ucte d i n acc or da nce 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 nati o nal Or ga nizati o ns of Me dical 
Scie nces I nter nati o nal Et hical G ui deli nes . 
•  A p plica ble I nter nati o nal C o nfere nce o n Har m o nisati o n ( I C H) G o o d Cli nical Practice 
( G C P) G ui deli nes. 
•  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 Br oc h ure, a n d ot her rele va nt 
d oc u me nts m ust be s u b mitte d t o a n Et hics C o m mittee ( 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 E C bef ore t he st u d y is i nitiate d. 
A n y s u bsta ntial pr ot oc ol a me n d me nts, li kel y t o affect t he safet y of t he s u bjects or t he c o n d uct 
of t he st u d y, will re q uire E C a n d re g ulat or y a ut h orit y (as l ocall y re q ui re d) a p pr o val bef ore 
i m ple me ntati o n of c ha n ges ma de t o t he st u d y desi g n, e xce pt f or c ha n ges necessar y t o 
eli mi nate a n i m me diate hazar d t o st u d y s u bjects or a n y n o ns u bsta ntial c ha n ges, as defi ne d b y 
re g ulat or y re q uire me nts. 
Fi n a nces a n d I ns ur a nce  
Fi na nci n g a n d i ns ura nce will be a d dresse d i n a se parate a gree me nt.  
I nf or me d C o nse nt 
Pri or t o starti n g partici pati o n i n t he st u d y, eac h s u bject will be pr o vi de d wit h a st u d y- s pecific 
I C F gi vi n g details of t he st u d y dr u gs, pr oce d ures, a n d p ote ntial ris ks of t he st u d y. S u bjects 
will be i nstr ucte d t hat t he y are free t o o btai n f urt her i nf or mati o n fr o m t he I n vesti gat or ( or 
desi g nee) a n d t hat t heir partici pati o n is v ol u ntar y a n d t he y are free t o wit h dra w fr o m t he 
st u d y at a n y ti me. S u bjects will be gi ve n a n o p p ort u nit y t o as k q uesti o ns a b o ut t he st u d y pri or 
t o pr o vi di n g c o nse nt f or partici pati o n. 
F oll o wi n g disc ussi o n of t he st u d y wit h C R U  pers o n nel, s u bjects will si g n t he I C F i n t he 
prese nce of a s uita bl y trai ne d me m ber of staff t o i n dicate t hat t he y are freel y gi vi n g t heir 
i nf or me d c o nse nt. A c o p y of t he I C F will be gi ve n t o t he s u bject. 
S u bjects m ust be re -c o nse nte d t o t he m ost c urre nt versi o n of t he I C F(s) d uri n g t heir 
partici pati o n i n t he st u d y.  
S u bject D at a Pr otecti o n  
S u bjects will be assi g ne d a u ni q ue i de ntifier a n d will n ot be i de ntifie d b y na me i n e C R Fs, 
st u d y-relate d f or ms, st u d y re p orts, or a n y relate d p u blicati o ns. S u bject a n d I n vesti gat or 
pers o nal data will be treate d i n c o m plia nce wit h all a p plica ble la ws a n d re g ulati o ns. I n t he 
e ve nt t he st u d y pr ot oc ol, st u d y re p ort, or st u d y data are i ncl u de d i n a p u blic re gistr y, all 
 
  


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 7 2 of 8 6 
i de ntifia ble i nf or mati o n fr o m i n di vi d ual s u bjects or I n vesti gat or will be re dacte d acc or di n g t o 
a p plica ble la ws a n d re g ulati o ns. 
T he s u bject 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 t he 
S p o ns or i n acc or da nce wit h l ocal data pr otecti o n la w. T he le vel of discl os ure m ust als o be 
e x plai ne d t o t he s u bject. T he s u bject m ust als o be i nf or me d t hat his/ her st u d y- relate d data 
ma y be e xa mi ne d b y S p o ns or or C o ntract Researc h O r ga nizati o n (C R O)  a u dit ors or ot her 
a ut h orize d pers o n nel a p p oi nte d b y t he S p o ns or, b y a p pr o priate 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. 
Discl os ure  
All i nf or mati o n pr o vi de d re gar di n g t he st u d y, as well as all i nf or mati o n c ollecte d a n d/ or 
d oc u me nte d d uri n g t he c o urse of t he st u d y, will be re gar de d as c o nfi de ntial. T he I n vesti gat or 
( or desi g nee) a grees n ot t o discl ose s uc h i nf or mati o n i n a n y wa y wit h o ut pri or writte n 
per missi o n fr o m t he S p o ns or. 
D at a Q u alit y Ass ur a nce 
T he f oll o wi n g data q ualit y ste ps will be i m ple me nte d: 
•  All s u bject data relati n g t o t he st u d y will be rec or de d o n e C R Fs u nless directl y 
tra ns mitte d t o t he S p o ns or or desi g nee electr o nicall y (e g, la b orat or y data). T he 
I n vesti gat or is res p o nsi ble f or verif yi n g t hat data e ntries are acc urate a n d c orrect b y 
electr o nicall y si g ni n g t he e C R F. 
•  T he I n vesti gat or m ust mai ntai n acc urate d oc u me ntati o n (s o urce data) t hat s u p p orts t he 
i nf or mati o n e ntere d i n t he e C R F. 
•  T he I n vesti gat or m ust per mit st u d y -relate d m o nit ori n g, a u dits, E C  re vie w, a n d 
re g ulat or y a ge nc y i ns pecti o ns a n d pr o vi de direct access t o s o urce data d oc u me nts. 
•  La bc or p Dr u g De vel o p me nt is res p o nsi ble f or t he data ma na ge me nt of t his st u d y 
i ncl u di n g q ualit y c hec ki n g of t he data. Pre defi ne d, a gree d ris ks, m o nit ori n g 
t hres h ol ds, q ualit y t olera nce t hres h ol ds, c o ntr ols, a n d miti gati o n pla ns will be 
d oc u me nte d i n a ris k ma na ge me nt re gister. A d diti o nal details of q ualit y c hec ki n g t o 
be perf or me d o n t he data ma y be i ncl u de d i n a Data Ma na ge me nt Pla n.  
•  A St u d y M o nit or will perf or m o n g oi n g s o urce data verificati o n t o c o nfir m t hat data 
e ntere d i nt o t he e C R F b y a ut h orize d site pers o n nel are acc urate, 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 s u bjects 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 nce 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 plica ble 
re g ulat or y re q uire me nts. 
•  Rec or ds a n d d oc u me nts, i ncl u di n g si g ne d I C Fs, pertai ni n g t o t he c o n d uct of t his st u d y 
m ust be retai ne d b y t he I n ve sti gat or i n t he st u d y site arc hi ve f or at least 5 years  after 
t he e n d of t he st u d y u nless l ocal re g ulati o ns or i nstit uti o nal p olicies re q uire a l o n ger 
rete nti o n peri o d. N o rec or ds ma y be destr o ye d d uri n g t he rete nti o n peri o d wit h o ut t he 
writte n a p pr o val of t he S p o ns or. N o rec or ds ma y be tra nsferre d t o a n ot her l ocati o n or 
part y wit h o ut writte n n otificati o n t o t he S p o ns or. 
 
  


Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 7 3 of 8 6 
I n vesti g at or D oc u me nt ati o n Res p o nsi bilities 
All i n di vi d ual, s u bject-s pecific st u d y data will als o be e ntere d i nt o a 2 1 C F R 
Part  A 1-c o m plia nt el ectr o nic data ca pt ure ( E D C) s yste m o n a n e C R F i n a ti mel y fas hi o n . 
All data ge nerate d fr o m e xter nal s o urces (e g, la b orat or y a n d bi oa nal ytical data), a n d 
tra ns mitte d t o t he La bc or p Dr u g De vel o p me nt  electr o nicall y, will be i nte grate d wit h t he 
s u bject’s e C R F data i n acc or da nce wit h t he Data Ma na ge me nt Pla n. 
A n e C R F m ust be c o m plete d f or eac h e nr olle d s u bject, acc or di n g t o t he e C R F c o m pleti o n 
i nstr ucti o ns. T he S p o ns or, or C R O, will re vie w t he s u p p orti n g s o urce d oc u me ntati o n a gai nst 
t he data e ntere d i nt o t he e C RFs t o verif y t he acc urac y of t he electr o nic data. T he I n vesti gat or 
will e ns ure t hat c orrecti o ns are ma de t o t he e C R Fs a n d t hat data q ueries are res ol ve d i n a 
ti mel y fas hi o n b y t he st u d y staff. 
T he I n vesti gat or will si g n a n d date t he e C R F via t he E D C s yste m’s electr o nic si g nat ure 
pr oce d ure. T hese si g nat ures will i n dicate t hat t he I n vesti gat or re vie we d a n d a p pr o ve d t he 
data o n t he e C R F, data q ueries, a n d site n otificati o ns. 
P u blic ati o ns  
P u blicati o ns will be a d dresse d i n a se parate a gree me nt.  
 
 
  






Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 7 6 of 8 6 
p F ull p h ysical e xa mi nati o n.  
q S y m pt o m -directe d p h ysical e xa mi nati o n.  
r Pri or t o disc har ge.  
s T o be perf or me d at a p pr o xi matel y t he sa me ti me as o n Da y 1 . 
t T he f oll o w -u p peri o d ma y be e xte n de d de pe n di n g o n  t he o bser ve d t1/ 2 of 
 
 
 
 
  
C CI






Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 7 9 of 8 6 
g Faecal  occ ult bl o o d test will be perf or me d o nce eac h d uri n g t he f oll o wi n g sa m pli n g peri o ds: Scree ni n g , Da y - 1 t o pri or t o d osi n g, 0 t o 2 4, 2 4 t o 4 8, a n d 4 8 t o 
7 2 h o urs p ost d ose i n Treat me nt Peri o d 1, a n d Da y -1 t o d osi n g, 0 t o 2 4, 2 4 t o 4 8, a n d 4 8 t o 7 2 h o urs p ost d ose i n Treat me nt Peri o d 2. O n  scree ni n g i n 
Treat me nt Peri o d 1, faecal sa m ples will be c ollecte d t o c o nfir m eli gi bilit y f or e nr oll me nt. F or t he ot her sa m pli n g peri o ds, faecal sa m ples will be c ollecte d as 
far as p ossi ble. 
h T o be assesse d w he n c ollecti n g faecal sa m ples f or faecal occ ult bl o o d test i n treat me nt peri o ds.  
i S u bjects s h o ul d be s u pi ne f or at least 5 mi n utes bef ore bl o o d press ure a n d p ulse rate meas ure me nts.  
j T o be meas ure d i n tri plicate at a p pr o xi matel y 2 -mi n ute i nter vals.  
k T o be rec or de d after t he s u bject has bee n s u pi ne a n d at rest f or at least 5 mi n utes.  
l F ull p h ysical e xa mi nati o n.  
m  S y m pt o m -directe d p h ysical e xa mi nati o n.  
n Pri or t o disc har ge.  
o T o be perf or me d at a p pr o xi matel y t he  sa me ti me as o n Da y 1.  
p S u bjects will recei ve t he I M P at t he sa me ti me as Da y 1 i n Treat me nt Peri o d 1 a n d 3 0 mi n utes after s tarti n g a hi g h-fat brea kfast. 
q If t he latest res ult d uri n g t he treat me nt peri o d is p ositi ve, faecal sa m ples will be c ollecte d f or faecal occ ult bl o o d test at t he foll o w -u p visit ( wit hi n -2 da y), as 
far as p ossi ble. 
r T he i nter val bet wee n d osi n g is u p t o a n d i ncl u di n g Da y -1 of Treat me nt Peri o d 2. T he was h o ut a n d f oll o w -u p peri o ds ma y be e xte n de d de pe n di n g o n  t he 
o bser ve d t 1/ 2 of 
 
 
 
 
 
  
C CI








Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 8 3 of 8 6 
g Faecal  occ ult bl o o d test will be perf or me d o nce eac h d uri n g t he f oll o wi n g sa m pli n g peri o ds: Scree ni n g , Da y - 1 t o pri or t o d osi n g, 0 t o 2 4, 2 4 t o 9 6, 9 6 t o 1 6 8, 
1 6 8 t o 2 4 0 h o urs p ost d ose o n Da y 1, 2 4 0 h o urs p ost d ose o n Da y 1 t o 0 h o urs o n Da y 1 4, a n d 0 t o 7 2 h o urs p ost d ose o n Da y 1 4. O n s cree ni n g, faecal  sa m ples 
will be c ollecte d t o c o nfir m eli gi bilit y f or e nr oll me nt. F or t he ot her sa m pli n g peri o ds, faecal sa m ples will be c ollecte d as far as p ossi ble. 
h T o be assesse d w he n c ollecti n g faecal sa m ples f or faecal occ ult bl o o d test i n t he treat me nt peri o d. 
i S u bjects s h o ul d be s u pi ne f or at least 5 mi n utes bef ore bl o o d press ure a n d p ulse rate meas ure me nts.  
j T o be meas ure d i n tri plicate at a p pr o xi matel y 2 -mi n ute i nter vals.  
k T o be rec or de d after t he s u bject has bee n s u pi ne a n d at rest f or at least 5 mi n utes.  
l F ull p h ysical e xa mi nati o n.  
m  S y m pt o m -directe d p h ysical e xa mi nati o n.  
n I m me diately bef ore d osi n g.  
o Fr o m wa ki n g -u p t o bef ore d osi n g.  
p T o be perf or me d at a p pr o xi matel y t he  sa me ti me as o n Da y 1.  
q Fr o m wa ki n g -u p t o bef ore brea kfast.  
r If t he latest res ult d uri n g t he treat me nt peri o d is p ositi ve, faecal sa m ples will be c ollecte d f or faecal occ ult bl o o d test at t he foll o w -u p visit ( wit hi n -2 da y), as 
far as p ossi ble. 
s Pri or t o disc har ge.  
t T he f oll o w -u p peri o d ma y be e xte n de d de pe n di n g o n  t he o bser ve d t1/ 2 of 
 
 
 
 
 
  
C CI






Pr ot oc ol 
C O N FI D E N TI A L  
 
Pr ot oc ol Refere nce: K R P A 2 1 8- T 1 0 1 
Fi nal , 1 6 Se pte m ber 2 0 2 1 
Pa ge 8 6 of 8 6 
d T o be a d mi nistere d i n t he faste d state. 
e I m me diatel y bef ore d osi n g. 
f Fr o m wa ki n g -u p t o bef ore brea kfast.  
g S u bjects will be faste d at least 6 h o urs  bef ore c ollecti o n.  
h Faecal  occ ult bl o o d test will be perf or me d o nce eac h d uri n g t he f oll o wi n g sa m pli n g peri o ds: Scree ni n g , Da y - 1 t o pri or t o d osi n g, 0 t o 2 4 a n d 2 4 t o 7 2 h o urs 
p ost d ose o n Da y 1, Da y 1 0 t o 0 h o urs o n Da y 1 1, a n d 0 t o 2 4 a n d 2 4 t o 7 2 h o urs p ost d ose o n Da y 1 1. O n  scree ni n g, faecal  sa m ples will be c ollecte d t o 
c o nfir m eli gi bilit y f or e nr oll me nt. F or t he ot her sa m pli n g peri o ds, faecal sa m ples will be c ollecte d as far as p ossi ble. 
i T o be assesse d w he n c ollecti n g faecal sa m ples f or faecal occ ult bl o o d test i n t he treat me nt peri o d. 
j S u bjects s h o ul d be s u pi ne f or at least 5 mi n utes bef ore bl o o d press ure a n d p ulse rate meas ure me nts.  
k T o be meas ure d i n tri plicate at a p pr o xi matel y 2 -mi n ute i nter vals.  
l T o be rec or de d after t he s u bject has bee n s u pi ne a n d at rest f or at least 5 mi n utes.  
m  F ull p h ysical e xa mi nati o n.  
n S y m pt o m -directe d p h ysical e xa mi nati o n.  
o If t he latest res ult d uri n g t he treat me nt peri o d is p ositi ve, faecal sa m ples will be c ollecte d f or faecal occ ult bl o o d test at t he foll o w - up visit ( wit hi n -2 da y), as 
far as p ossi ble. 
p Pri or t o disc har ge.  
q T he f oll o w -u p peri o d ma y be e xte n de d de pe n di n g o n  t he o bser ve d t1/ 2 of 
 
r T he st u d y da ys of d osi n g of itrac o naz ole a n d K R P -A 2 1 8 ma y  be a me n de d t o e xte n d t he i nter val bet wee n t he first d ose of K R P-A 2 1 8 a n d t he first d ose of 
itrac o naz ole de pe n di n g o n t he o bser ve d t1/ 2 of 
 
 
 
 
  
C CI
C CI

SAP_001.pdf: 
D oc u me nt T y pe:   
Fi nal Statistical A nal ysis Pla n  
D oc u me nt Date:   
2 5 A pril 2 0 2 2 
St u d y Title:   
A First-i n- H u ma n, P hase I, D o u ble- bli n d, Place b o-c o ntr olle d, Si n gle 
a n d M ulti ple Asce n di n g Oral D ose St u d y t o E val uate t he Safet y, 
T olera bilit y, a n d P har ma c o ki netics of K R P- A 2 1 8 i n Healt h y S u bjects, 
i ncl u di n g F o o d- Effect a n d Dr u g- dr u g I nteracti o n wit h Itrac o naz ole 
Pr ot oc ol Refere nce N u m ber: K R P A 2 1 8- T 1 0 1 
N C T N u m ber:   
N C T 0 4 9 0 8 8 0 0  
 
 
 


 
 
St atistic al A n al ysis Pl a n  
A First -i n-H u m a n, P h ase I, D o u ble -bli n d, Pl ace b o -c o ntr olle d, Si n gle a n d 
M ulti ple Asce n di n g Or al D ose  St u d y t o E v al u ate  t he S afet y, T oler a bilit y , 
a n d P h ar m ac o ki netics of K R P -A 2 1 8 i n He alt h y S u bjects, i ncl u di n g 
F o o d -Effect a n d Dr u g -dr u g I nter acti o n wit h Itr ac o n az ole  
S A P Stat us: Fi nal  
S A P Versi o n: 1. 0  
S A P Date: 2 5 A P R 2 0 2 2  
I n v esti gati o nal Me dici nal Pr o d uct: K R P -A 2 1 8  
Pr ot oc ol Refere n ce : K R P A 2 1 8 -T 1 0 1  
La b c or p Dr u g De v el o p me nt  St u d y : 8 4 1 1 6 0 1  
S p o ns or:  
K y ori n P har mace utical C o m pa n y Li mite d  
6 Ka n da S ur u ga d ai 4 -c h o me 
C hi y o da -k u  
T o k y o 1 0 1 8 3 1 1  
J a pa n 
St u d y Site:  
La b c or p Cli nical Researc h U nit Lt d.  
S pri n gfiel d H o us e  
H y d e Street  
Lee ds L S 2 9 L H  
U nite d Ki n g d o m  
Pri nci pal I n v esti gat or:  
 
I nf or mati o n descri be d herei n is c o nfi de ntial a n d m a y b e discl ose d o nl y wit h t he e x press 
writte n per mi ssi o n of t he sp o ns or.  
   
P P D


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 2  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
T A B L E O F C O N T E N T S  
TI T L E P A G E  ............................................................................................................................. 1  
T A B L E O F C O N T E N T S  ........................................................................................................... 2  
LI S T O F I N -T E X T T A B L E S A N D FI G U R E S  ......................................................................... 3  
LI S T O F A B B R E VI A TI O N S  .................................................................................................... 5  
1. I N T R O D U C TI O N  ................................................................................................................. 7  
2. S T U D Y O BJ E C TI V E S  .......................................................................................................... 7  
3. S T U D Y E N D P OI N T S  ........................................................................................................... 9  
3. 1. Pri mar y E n d p oi nts  ........................................................................................................... 9  
3. 2. Sec o n dar y E n d p oi nts  ....................................................................................................... 9  
3. 3. E x pl orat or y E n d p oi nts  .................................................................................................. 1 1  
4. S T U D Y D E SI G N ................................................................................................................. 1 1  
4. 1. Part A ( Si n gle As ce n di n g D ose St u d y)  ......................................................................... 1 1  
4. 2. Part B ( M ulti ple Asce n di n g D os e St u d y) ...................................................................... 1 3  
4. 3. Part  C ( Dr u g -Dr u g I nteracti o n St u d y)  .......................................................................... 1 4  
5. S A M P L E SI Z E J U S TI FI C A TI O N  ...................................................................................... 1 7  
6. S T U D Y T R E A T M E N T S  ..................................................................................................... 1 7  
6. 1. Part A  ............................................................................................................................ 1 7  
6. 2. Part B  ............................................................................................................................. 1 8  
6. 3. Part C  ............................................................................................................................. 1 8  
7. D E FI NI TI O N S O F P O P U L A TI O N S  .................................................................................. 1 9  
7. 1. All S u bjects P o p ulati o n  ................................................................................................. 1 9  
7. 2. Safet y P o p ulati o n  .......................................................................................................... 1 9  
7. 3. P har mac o ki netic P o p ulati o n  ......................................................................................... 1 9  
7. 4. P har mac o d y na mic P o p ulati o n  ....................................................................................... 1 9  
8. S T A TI S TI C A L M E T H O D O L O G Y  .................................................................................... 2 0  
8. 1. Ge neral  .......................................................................................................................... 2 0  
8. 1. 1. Ha n dli n g of Data Q ualit y Iss u es D ue t o C or o na vir us Diseas e 2 0 1 9 a n d Relate d 
Restricti o ns  ....................................................................................................................... 2 0  
8. 1. 2. Calc ulati o n of t he S u m mar y Statistics  ................................................................... 2 1  
8. 1. 3. Tri plicate Rea di n gs ................................................................................................. 2 2  
8. 1. 4. Re peat a n d U ns c he d ul e d Rea di n gs  ........................................................................ 2 2  
8. 1. 5. Defi niti o ns of Bas eli ne a n d C ha n ge fr o m Baseli ne  ............................................... 2 2  
   


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 3  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
8. 2. S u bject Dis p ositi o n a n d P o p ulati o n Assi g n me nt  .......................................................... 2 3  
8. 3. Scree ni n g D e m o gra p hics  .............................................................................................. 2 3  
8. 4. Pri or a n d C o nc o mita n t Me dicati o n ............................................................................... 2 3  
8. 5. P har mac o ki netic Ass ess me nts  ...................................................................................... 2 3  
8. 5. 1. P har mac o ki netic A nal ysis  ...................................................................................... 2 3  
8. 5. 2. Prese ntati o n of P har mac o ki netic Data  ................................................................... 2 7  
8. 5. 3. P har mac o ki netic Statistical Met h o d ol o g y  .............................................................. 2 8  
8. 6. P har mac o d y na mic Assess me nts .................................................................................... 3 2  
8. 6. 1. P har mac o d y na mic A nal ysis  ................................................................................... 3 2  
8. 6. 2. Prese ntati o n of P har mac o d y n a mic Data  ................................................................. 3 2  
8. 6. 3. P har mac o d y na mic Statistical Met h o d ol o g y  ........................................................... 3 2  
8. 7. Sa fet y a n d T olera bilit y Assess me nts ............................................................................ 3 2  
8. 7. 1. A d verse E v e nts  ....................................................................................................... 3 2  
8. 7. 2. Cli nical La b orat or y Para meters  .............................................................................. 3 4  
8. 7. 3. Vital Si g ns Para meters  ........................................................................................... 3 5  
8. 7. 4. 1 2 -lea d Electr ocar di o gra m Para meters  .................................................................. 3 5  
8. 7. 5. Brist ol St o ol C hart a n d Faecal Occ ult Bl o o d Test  ................................................. 3 5  
8. 7. 6. Ot her Assess me nts  ................................................................................................. 3 6  
8. 7. 7.  Safet y a n d T olera bilit y Statistical Met h o d ol o g y  .................................................... 3 6  
9. I N T E RI M A N A L Y S E S  ....................................................................................................... 3 6  
1 0. SI G NI FI C A N T C H A N G E S F R O M T H E P R O T O C O L -S P E CI FI E D A N A L Y S E S  ........ 3 6  
1 1. R E F E R E N C E S  .................................................................................................................. 3 6  
1 2. A P P E N DI C E S  ................................................................................................................... 3 7  
A p pe n di x 1:  
D oc u me nt Hist or y  ................................................................................ 3 7  
 
LI S T O F  IN -T E X T  T A B L E S  A N D  F I G U R E S 
Ta ble 1:  
Prese ntati o n of St u d y Treat me nts i n T F Ls ( Part A)  ............................................. 1 7  
Ta ble 2:  
Prese ntati o n of St u d y Treat me nt Se q ue nces i n T F Ls ( Part A; F o o d -effect Gr o u p 
O nl y)  ..................................................................................................................... 1 7  
Ta ble 3:  
Prese ntati o n of St u d y Treat me nts i n T F Ls ( Part B)  .............................................. 1 8  
Ta ble 4:  
Prese ntati o n of St u d y Treat me nts i n T F Ls ( Part C)  .............................................. 1 9  
Ta ble 5:  
Prese ntati o n of St u d y Treat me nt Se q ue nce i n T F Ls ( Part  C)  ............................... 1 9  
 
   


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 4  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
Fi g ure 1:  
St u d y Sc h e matic ( Part A; Gr o u ps A 1, A 2 b [ Fe mal e s u bjects O nl y], a n d A 3 t o 
A 5)  ........................................................................................................................ 1 2  
Fi g ure 2:  
St u d y Sc h e matic ( Part A; Gr o u p A 2a [ Male s u bjects O nl y])  ............................... 1 3  
Fi g ure 3:  
St u d y Sc h e matic ( Part B)  ...................................................................................... 1 4  
Fi g ure 4:  
St u d y Sc h e matic ( Part C)  ...................................................................................... 1 5  
Fi g ure 5:  
Pla n ne d D ose Le v els of K R P -A 2 1 8 ( Parts A, B, a n d, C)  ..................................... 1 6  
 
   


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 5  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
LI S T O F  A B B R E VI A TI O N S  
A b bre viati o ns pertai n t o t he statistical a nal ysis pla n (S A P ) o nl y ( n ot t he ta bles, fi g ures, a n d 
listi n gs [T F Ls ]). 
% A U C
e xtra p 
perce nt a ge of area u n der t he c o nce ntr ati o n -ti me c ur ve d ue t o 
e xtra p olati o n fr o m t he last q ua ntifia ble c o nce ntrati o n t o i nfi nit y  
A Da M  
A nal ysis D ata M o del  
A E  
a d verse e ve nt  
A N O V A  
a nal ysis  of varia n ce  
A R A U C 0 -τ 
o bser ve d acc u m ulati o n rati o base d o n A U C 0 -τ 
A R C ma x  
o bser ve d acc u m ulati o n rati o base d o n C ma x  d uri n g t he d osi n g i nter val  
A U C  
area u n d er t he c o nce ntrati o n -ti me c ur ve 
A U C 0 -∞ 
area u n d er t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 e xtra p olate d t o 
i nfi nit y 
A U C 0 -tlast 
area u n d er t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o t he ti me of t he 
last q ua ntifia ble c o nce ntr ati o n 
A U C 0 -τ 
area u n d er t he c o nce ntrati o n ‑ti me c ur ve o ver a d osi n g i nter val 
BI D  
t wice a da y 
B L Q  
bel o w t he li mit of q ua ntificati o n  
C DI S C  
Cli nical Data I nterc ha n ge Sta n dar ds C o ns orti u m  
CI  
c o nfi de nce i nter val  
C L/ F  
a p pare nt t otal cl eara nce  
C ma x  
ma xi m u m o bser ve d c o nce ntrati o n  
C mi n  
mi ni m u m o bser ve d c o nce ntrati o n d uri n g a d osi n g i nter val  
C O VI D -1 9  
c or o na vir us disease 2 0 1 9  
C R U  
cli nical researc h u nit  
C S R  
cli nical st u d y re p ort  
C V  
c oeffi cie nt of variati o n  
D M P  
data ma na ge me nt pla n  
E C G  
electr ocar di o gra m  
e C R F 
electr o nic case re p ort f or m  
G L S M  
ge o m etric least s q uares mea n  
I C H 
I nter nati o nal C o u ncil f or/ C o nfere nce o n Har m o nisati o n  
l n 
nat ural l o g  
L S M  
least s q uares me a n 
Me d D R A  
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
P D  
p har mac o d y n a mic(s)  
P K  
p har mac o ki netic(s)  
Q D  
o nce dail y  
   


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 6  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
Q Tc F  
Q T i nter val c orrecte d f or heart rate usi n g Fri d erici a’s f or m ula  
R 2-a dj 
a dj uste d c oefficie nt f or deter mi nati o n of e x p o ne ntial fit  
S A P  
statistical a nal ysis pla n 
S D  
sta n dar d de viati o n 
S D V  
s o urce d oc u m e nt verificati o n 
t1/ 2 
a p pare nt ter mi nal eli mi nati o n half -life 
T E A E  
treat me nt-e mer ge nt a d verse e ve nt  
T F L  
ta ble, fi g ure, a n d listi n g 
TI D  
t hree ti mes a da y 
tma x  
ti me of t he ma xi m u m o bser ve d c o n ce ntr ati o n 
V z/ F 
a p pare nt v ol u me of distri b uti o n d uri n g t he ter mi nal p hase  
W H O Dr u g  
W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y  
λ z 
a p pare nt ter mi nal eli mi nati o n rate c o nsta nt  
λ z L o w er  
start of e x p o ne ntial fit  
λ z N  
n u m ber of data p oi nts i ncl u de d i n t he l o g -li near re gressi o n 
λ z S pa n Rati o  
ti me peri o d o ver w hic h λz was d eter mi ne d as a rati o of t 1/ 2 
λ z U p p er  
e n d of e x p o ne ntial fit  
   


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 7  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
1.  IN T R O D U C TI O N  
T his S A P has bee n de vel o pe d after re vie w of t he cli nical st u d y pr ot o c ol ( Fi nal Ver si o n 5. 0 
date d 1 6 Se pte m ber 2 0 2 1 ) a n d ele ctr o nic c ase re p ort for m  (e C R F).  
T his S A P descri bes t he pla n ne d a nal ysis of t he p h ar mac o ki netic ( P K ), p har mac o d y na mic 
(P D ), safet y, a n d t olera bilit y d ata fr o m t his st u d y. A detaile d descri pti o n of t he pla n ne d T F Ls 
t o be prese nte d i n t he cli nical st u d y re p ort ( C S R) is pr o vi de d i n t he acc o m pa n yi n g T F L s hell s 
d oc u me nt.   
I n ge neral, t he a n al ys es are base d o n i nf or mati o n fr o m t he pr ot oc ol, u nless t he y h a ve b ee n 
m o difie d b y a gree me nt wit h  K y ori n P har m ace uti cal C o m pa n y Li mite d . A li mite d a m o u nt of 
i nf or mati o n a b o ut t his st u d y (e g, o bjecti ves, st u d y desi g n) is gi ve n t o hel p t he rea d er’s 
i nter pretati o n.  
T his  S A P m ust be fi nalis e d pri or t o a n y u n bli n di n g of st u d y dat a  f or a nal ysis p ur p oses 
(i nteri m or fi nal). A d diti o nall y, t he S A P a n d T F L s hells sh o ul d be fi nalis e d pri or t o a n y 
pr o gra m mi n g acti vities c o m me nci n g.  
T his S A P s u perse des a n y  statistical c o nsi derati o ns i de ntifie d i n t he pr ot oc ol; w here 
c o nsi derati o ns a re s u bsta ntiall y differe nt, t he y will be s o i de ntifie d. If a d diti o nal a nal ys es are 
re q uire d t o s u p ple me nt t he pla n ne d a n al ys es descri be d i n t his S A P, t he y m a y b e perf or me d 
a n d will be i de ntifie d acc or di n gl y i n t he C S R. A n y s u bsta ntial de viati o ns fr o m t his S A P will 
be a gree d wit h  K y ori n P har mace utical C o m pa n y Li mite d  a n d i de ntifie d i n t he C S R.   
T his S A P is writte n wit h c o nsi derati o n of t he rec o m me n dati o ns o utli ne d i n t he I nt er nati o nal 
C o nfere nce o n Har m o nisati o n (I C H) E 3 g ui deli ne Str uct ure a n d C o nte nt of Cl i nic al St u dy 
Re p orts , I C H E 8 g ui d eli ne Ge ner al C o nsi der ati o ns f or Cli nic al Tri als , a n d I C H E 9  g ui d eli ne 
St atistic al Pri nci ples f or Cli nic al Tri als .1 ,2 ,3 
T he d oc u me nt hist or y is  prese nte d i n  A p pe n di x 1 .  
2.  S T U D Y O B J E C TI V E S   
P arts A a n d B:  
T he pri mar y o bje cti ve is:  
● t o e val uate t he safet y a n d t olera bilit y of si n gle a n d m ulti ple oral d oses of K R P-A 2 1 8 i n 
healt h y s u bjects.  
T he sec o n d ar y o bjecti ves  are:  
● t o assess t he P K of 
 (t he acti ve i n gre di e nt of K R P-A 2 1 8) f oll o wi n g si n gle 
a n d m ulti ple oral d oses of K R P -A 2 1 8 i n healt h y s u bjects . 
● t o assess t he effect of f o o d o n t he P K of 
 f oll o wi n g a si n gle oral d ose of 
K R P -A 2 1 8 i n healt h y male s u b jects. 
   
C CI
C CI


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 8  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
● t o assess t he effect of s e x o n t he P K of 
 f oll o wi n g a si n gle oral d ose of K R P-
A 2 1 8.  
T he e x pl orat or y o bj ecti v es are:  
● t o e x pl ore bl o o d a n d uri ne sa m ples f or t he m eta b olite pr ofiles of 
 f oll o wi n g 
si n gle a n d m ulti ple oral d oses of K R P-A 2 1 8 i n healt h y male s u bjects.  
● t o e x pl ore faecal sa m ples f or t he meta b olite pr ofiles f oll o wi n g a si n gle oral d ose of 
K R P -A 2 1 8 i n healt h y male s u bjects.  
● t o e x pl ore bl o o d a n d uri ne sa m ples f or P D  bi o mar ker s. 
● t o e x pl ore a p ote ntial effect of K R P-A 2 1 8 o n p h os p h o li pi d-C i n ser u m a n d faecal 
cal pr otecti n.  
● t o c ollect bl o o d sa m ples f or p ote ntial p har mac o ge netic a nal yses.  
● t o c ollect c o nti n u o us electr ocar di o gra m ( E C G)  wa vef or ms f or c o nce ntrati o n -Q Tc 
a nal ysis, f oll o wi n g si n gl e oral d oses of K R P -A 2 1 8 i n healt h y s u bjects ( Part A o nl y).  
P art C:  
T he pri mar y o bje cti ve is:  
● t o assess t he effect of m ulti ple d oses of itrac o naz ole (c yt oc hr o m e P 4 5 0 3 A 4 i n hi bit or) 
o n t he si n gle -d os e P K of 
 i n healt h y male s u bjects. 
T he sec o n d ar y o bjecti ves are:  
● t o assess t he safet y a n d t olera bilit y of si n gle oral d oses of K R P-A 2 1 8 w he n 
c o-a d mi nistere d wit h m ulti ple oral d oses of itrac o naz ole i n healt h y male s u bjects . 
● t o assess t he P K of itrac o naz ole a n d its meta b olite h y dr o x y -itrac o n az ole w he n 
c o-a d mi nistere d wit h K R P -A 2 1 8 i n healt h y mal e s u bjects . 
T he e x pl orat or y o bj ecti v es are:  
● t o e x pl ore bl o o d sa m ples f or t he meta b olite pr ofiles of 
 a d mi nistere d 
K R P -A 2 1 8 al o ne a n d w h e n c o -a d mi nistere d wit h itrac o naz ole i n healt h y m ale s u bjects. 
● t o e x pl ore a p ote ntial effect of K R P-A 2 1 8 o n p h os p h oli pi d -C i n ser u m a n d faecal 
cal pr otecti n.  
● t o c ollect bl o o d sa m ples f or p ote ntial p har mac o ge netic a nal yses. 
   
C CI
C CI
C CI
C CI


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 9  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
3.  S T U D Y E N D P OI N T S   
3. 1.  Pri m ar y E n d p oi nts  
F or Parts A a n d B, t he s afet y a n d t olera bilit y e n d p oi nts are as f oll o ws:  
● A Es  
● b o d y w ei g ht  
● cli nical la b orat or y e val uati o ns ( hae mat ol o g y, cli nical c he mistr y [ wit h t he e x ce pti o n of 
p h os p h oli pi d -C], uri nal ysis, c oa g ul ati o n, a n d faecal occ ult bl o o d)  
● 1 2 -lea d E C G para meters 
● vital si g ns ( bl o o d press ur e, p ulse rate, res pirat or y rate, a n d oral b o d y t e m perat ure)  
● Brist ol St o ol C hart  
● p h ysical e x a mi nati o ns  
F or Part C, t he D DI ( K R P-A 2 1 8 al o ne vers us c o -a d mi nistere d wit h itrac o n az ole) assess me nt, 
t he P K e n d p oi nts will be t he para met ers deri ve d fr o m plas ma c o nce ntr ati o ns of 
 
o n Da ys 1 a n d 1 1, w hic h are as f oll o ws:  
● area u n d er t he c o nce ntrati o n -ti me c ur ve ( A U C) fr o m ti me 0 e xtra p olate d t o i nfi nit y 
( A U C0 -∞) 
● A U C fr o m ti me 0 t o t he ti me of t he last q ua ntifia ble c o nce ntr ati o n ( A U C 0 -tlast) 
● C ma x  
● tma x  
● a p pare nt ter mi nal eli mi nati o n half -life (t1/ 2) 
● a p pare nt t otal cl eara nce ( C L/ F)  
● a p pare nt v ol u me of distri b uti o n d uri n g t he ter mi nal p hase ( V z/ F). 
Ot her P K para meters ma y als o be a d de d.  
3. 2.  Sec o n d ar y E n d p oi nts  
F or  Part A, t he si n gle asce n di n g d os e, f o o d (fe d vers us faste d dietar y stat us at d osi n g), a n d 
se x ( male vers us fe mal e) P K para meters deri ve d fr o m plas ma c o nce ntr ati o ns of 
 
o n Da y 1  (i ncl u di n g Da y 1 i n Treat me nt Peri o d 2) are as f oll o ws: 
● A U C 0 -∞ 
 
  
C CI
C CI


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 1 0  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
● A U C 0 -tlast 
● C ma x  
● tma x  
● t1/ 2 
● C L/ F  
● V z/ F. 
F or Part B,  t he m ulti ple asce n di n g d ose P K para m eters deri v e d fr o m plas m a c o nce ntrati o ns 
of 
 o n Da ys 1 a n d 1 4 are as f oll o ws: 
● A U C 0 -τ 
● A U C 0 -∞ ( Da y 1 o nl y) 
● A U C 0 -tlast 
● C ma x  
● mi ni m u m o bser ve d c o nce ntrati o n ( C mi n ) 
● tma x  
● t1/ 2 
● C L/ F  
● V z/ F 
● o bser ve d acc u m ulati o n  rati o base d o n A U C0 -τ ( A RA U C 0 -τ) 
● o bser ve d acc u m ulati o n rati o base d o n C ma x  d uri n g t he d osi n g i nter val ( A R C ma x ). 
F or Part C , t he safet y a n d t olera bilit y e n d p oi nts are as f oll o ws: 
● A Es  
● b o d y w ei g ht  
● cli nical la b orat or y e val uati o ns ( hae mat ol o g y, cli nical c he mistr y [ wit h t he e x ce pti o n of 
p h os p h oli pi d -C], uri nal ysis, c oa g ul ati o n, a n d faecal occ ult bl o o d)  
● 1 2 -lea d E C G para meters 
● vital si g ns ( bl o o d press ur e, p ulse rate, res pirat or y rate, a n d oral b o d y t e m perat ure)  
 
  
C CI


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 1 1  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
● Brist ol St o ol C hart  
● p h ysical e x a mi nati o ns.  
F or Part C , the P K para m eters deri v e d fr o m plas m a c o nce ntrati o ns of itrac o naz ole a n d 
h y dr o x y -itrac o n az ole o n Da y 1 1 are as f oll o ws : 
● A U C 0 -τ 
● C ma x  
● tma x . 
Ot her P K para meters ma y als o be a d de d.  
3. 3.  E x pl or at or y E n d p oi nts  
F or Parts A, B, a n d C, t h e e x pl orat or y e n d p oi nts t hat will be re p orte d i n t h e C S R f or t his 
st u d y are: 
● P h os p h oli pi d -C  
● Faecal c al pr otecti n  
T he e n d p oi nts ass ociate d wit h t he e x pl orat or y met a b olite pr ofili n g, bi o mar ker a nal ysis,  
p har mac o ge netic a n al ys is, a n d c o nce ntrati o n-Q Tc a nal ysis  will be re p orte d else w h ere, as 
a p plica ble.  
4.  S T U D Y D E SI G N   
4. 1.  P a rt A ( Si n gle Asce n di n g D ose St u d y)  
Part A will c o m prise a d o u ble -bli n d, ra n d o mise d, place b o -c o ntr olle d, si n gl e -d ose, 
se q ue ntial-gr o u p, es calati n g -d os e st u d y i n c or p orati n g a si n gle -gr o u p, 2 -p eri o d ar m t o 
i n vesti gate t he effect of f o o d o n t he P K of 
 Part A will als o i ncl u de a se x-effect 
ar m ( Gr o u ps A 2 a a n d A 2 b) w hic h will i n vesti gat e t he effect of se x o n P K of 
 b y 
c o m pari n g P K para meters f oll o wi n g d osi n g i n fe males vers us d osi n g i n males. O verall, 
4 8  s u bjects will be st u die d i n 5 gr o u ps ( Gr o u ps A 1 t o A 5); Gr o u ps A 1, a n d A 3 t o A 5 will 
c o nsist of 8 male s u bjects, a n d Gr o u p A 2 will c o nsist of 1 6 s u bjects s plit i nt o 2 s u b gr o u ps 
( Gr o u p A 2a [ male s u bjects o nl y] a n d Gr o u p A 2 b [fe male s u bjects o nl y]) t hat will c o nsist of 
8  s u bjects eac h. 
P ote ntial s u bjects will be scree n e d t o assess t heir eli gi bilit y t o e nter t he st u d y wit hi n 2 8 da ys 
pri or t o t he first d ose a d mi nistrati o n. Eac h s u bject will partici pate i n 1 treat me nt peri o d o nl y, 
e x ce pt f or Gr o u p A 2 a, w here eac h s u b ject will partici pate i n 2 treat me nt peri o ds w here d os es 
of K R P -A 2 1 8 will be se p arate d b y a n i nter val of 7 t o 1 0 da ys ( u p t o a n d i ncl u di n g Da y  -1 of 
Treat me nt Peri o d 2). T h e was h o ut peri o d ma y be e xte n de d de pe n di n g o n t he o bser ve d t 1/ 2 of 
 S u bjects will resi de at t he st u d y site fr o m Da y -1 (t he d a y bef ore d osi n g) t o 
Da y  4 of eac h tr eat me nt peri o d.  
 
  
C CI
C CI
C CI


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 1 2  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
All s u bjects will ret ur n f or a f oll o w -u p visit 7 t o 1 0 da ys after t h eir fi nal d ose. T he f oll o w -u p 
peri o d ma y be e xte n de d de pe n di n g o n t he o bser ve d t 1/ 2 o f 
 
Base d o n t h e o n g oi n g re vie w of t he safet y, t olera bilit y, a n d P K res ults, a d diti o nal 
n o nresi de ntial visits ma y be re q uir e d. T he n u m ber of a d diti o nal visits per s u bject will n ot 
e x cee d 3 per peri o d (as a p plica ble) a n d will n ot e xte n d be y o n d 2 8 da ys after eac h fi nal d osi n g 
occasi o n.  All s u bjects ma y sta y i n t he cli nical researc h u nit ( C R U) o utsi de treat me nt peri o ds 
d ue t o c or o na vir us diseas e 2 0 1 9 ( C O VI D -1 9 ) ris ks. 
I n eac h of Gr o u ps A 1 t o A 5, 6 s u bjects will recei v e K R P-A 2 1 8 a n d 2 s u bjects will rece i ve 
place b o i n a cc or da nce wit h a ra n d o misati o n sc he d ule. I n Gr o u ps A 1, A 2 b, a n d A 3 t o A 5, all 
d oses will be a d mi nistere d i n t he faste d state o n t h e m or ni n g of Da y 1. F or Gr o u p A 2a, 
Peri o d 1, Da y 1 d oses will be a d mi nistere d i n t he faste d state a n d Peri o d 2 , Da y 1 d oses be 
will be gi ve n 3 0 mi n utes after starti n g a sta n dar d hi g h -fat brea kfast. E ac h s u bject i n Gr o u ps 
A 1, A 2 b, a n d A 3 t o A 5 will recei ve o nl y a si n gle d ose of K R P -A 2 1 8 or pl ace b o d uri n g t he 
st u d y. I n Gr o u p A 2a, s u bjects will ha ve t he sa me treat me nt i n b ot h peri o ds, s uc h t hat eac h 
s u bject will recei v e 2 si n gle d oses of K R P-A 2 1 8 or place b o d uri n g t h e st u d y.  
All gr o u ps i n Part A ( wit h t he e x ce pti o n of Gr o u p A 2a i n Treat m e nt Peri o d 2) will recei v e 
t he st u d y treat me nt usi n g a se nti nel a p pr o ac h.  
T he t ota l d urati o n of st u d y partici pati o n f or eac h s u bject (fr o m scree ni n g t hr o u g h f oll o w-u p 
visit) is a ntici pate d t o be u p t o 3 9 da ys ( Gr o u ps A 1, Gr o u p A 2 b [fe male s u bjects o nl y], A 3 t o 
A 5) or u p t o 5 0 da ys ( Gr o u p A 2a; male s u bjects o nl y).  
A n o ver vie w of t he st u d y desi g n is s h o w n i n Fi g ure 1  a n d Fi g ure 2 , a n d t he pla n ne d d ose 
le vels i n Fi g ure 5 .  
Fi g ure 1 : St u d y Sc he m atic ( P a rt A; Gr o u ps A 1, A 2 b [ Fe m ale s u bjects O nl y], a n d A 3 
t o A 5)  
 
T he f oll o w -u p peri o d ma y be e xte n de d de pe n di n g o n t h e o bser ve d t 1/ 2 of 
 
 
  
C CI
C CI


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 1 3  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
Fi g ure 2 : St u d y Sc he m atic ( P a rt A; Gr o u p A 2 a [ M ale s u bjects O nl y])  
 
T he was h o ut a n d f oll o w -u p peri o ds ma y be e xte n de d de pe n di n g o n t h e o bser ve d t 1/ 2 of 
 
4. 2.  P a rt B ( M ulti ple Asce n di n g D ose St u d y)  
Part B will c o m prise a d o u ble -bli n d, ra n d o mise d, place b o -c o ntr olle d, m ulti ple -d ose, 
se q ue ntial-gr o u p, es calati n g -d os e desi g n, e nr olli n g healt h y m ale s u bjects. O verall, 4 0 
s u bjects will be st u die d i n 4 gr o u ps ( Gr o u ps B 1 t o B 4), wit h eac h gr o u p c o nsisti n g of 1 0 male 
s u bjects. Part B ma y start after c o m pleti o n of Gr o u p A 3, at d ose e q u al t o or less t ha n gi ve n i n 
Gr o u ps A 1 t o A 3.  
P ote n tial s u bjects will be scree n e d t o assess t heir eli gi bilit y t o e nter t he st u d y wit hi n 2 8 da ys 
pri or t o t he first d ose a d mi nistrati o n. Eac h s u bject will partici pate i n 1 treat me nt peri o d o nl y 
a n d resi de at t he C R U fr o m Da y -1 (t he d a y bef ore d osi n g) u ntil t h e m or ni n g of Da y 1 7 
(f oll o wi n g assess me nts at 7 2 h o urs after fi nal d osi n g). 
All s u bjects will ret ur n f or a f oll o w -u p visit 7 t o 1 0 da ys after t h eir fi nal d ose. T he f oll o w -u p 
peri o d ma y be e xte n de d de pe n di n g o n t he o bser ve d t 1/ 2 of 
 
I n eac h of Gr o ups B 1 t o B 4, 8 s u bjects will recei v e K R P -A 2 1 8 a n d 2 s u bjects will recei ve 
place b o i n a cc or da nce wit h a ra n d o misati o n sc he d ule. T he dietar y stat e f or d osi n g i n Part B 
will be s u bject t o re vie w of t he P K data fr o m t he fe d/faste d c o m p aris o n i n Part A. F or all  
s u bjects, d osi n g will occ ur o n Da ys 1 t o 1 4. T he pla n ne d d osi n g fre q u e nc y is o nce per da y, 
h o we ver t he d osi n g fre q u e nc y i n Part B m a y be c h a n ge d f oll o wi n g re vi e w of data fr o m 
gr o u ps i n Part A. O n Da y 1 4, t he last d ose will be t he m or ni n g d os e re gar dless o f t he d osi n g 
fre q ue n c y (o nce dail y [ Q D], t wice a da y [ BI D], t hree ti mes a d a y [ TI D] ). 
T he t otal dail y d os e a d mi nistere d will n ot e xcee d a n e x p os ure s h o w n t o be safe a n d well 
t olerate d i n Part A. 
Base d o n t h e o n g oi n g re vie w of t he safet y, t olera bilit y, a n d P K res ults, a d diti o nal 
n o nresi de ntial visits ma y be re q uir e d.  T he n u m ber of a d diti o nal visits per s u bject will n ot 
e x cee d 3 a n d will n ot e xte n d be y o n d 2 8 da ys after eac h fi n al d osi n g o ccasi o n.  All s u bjects 
ma y sta y i n t he C R U e v e n o utsi de treat me nt peri o d d ue t o C O VI D -1 9 ris ks.  
All gr o u ps i n Part B will recei v e t he st u d y treat me nt usi n g a se nti nel a p pr oac h.  
 
  
C CI
C CI


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 1 4  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
A n o ver vie w of t he st u d y desi g n is s h o w n i n  Fi g ure 3 , a n d t he pla n n e d d ose le vels i n Fi g ure 
5 . 
T he t otal d urati o n of st u d y partici pati o n f or eac h s u bject (fr o m scree ni n g t hr o u g h f oll o w u p 
visit) is a ntici pate d t o be u p t o 5 2 da ys.  
Fi g ure 3 : St u d y Sc he m atic ( P a r t B) 
 
T he f oll o w -u p peri o d ma y be e xte n de d de pe n di n g o n t h e o bser ve d t 1/ 2 of 
 
4. 3.  P a rt C ( Dr u g -Dr u g I nter acti o n St u d y)  
Part C will c o m prise a n o pe n -la bel, fi x e d-se q u e nce, e nr olli n g h ealt h y male s u bjects t o 
i n vesti gate t he effect of m ulti ple oral d oses of itrac o naz ole o n t he si n gle oral d ose P K of 
 i n healt h y s u bjects. T here will be 1 gr o u p; Gr o u p C 1, c o nsisti n g of 1 2 m ale 
s u bjects. Part C will start after c o m pleti o n of bli n de d safet y, t olera bilit y, a n d P K data re vie w 
i n Part A. All s u bjects will recei ve eac h of t he f oll o wi n g treat me nts: 
● Da ys 1 a n d 1 1: si n gl e oral d ose of K R P -A 2 1 8  
● Da y 4: 2 × si n gle oral d oses of 2 0 0 m g itrac o naz ole, a p pr o xi matel y 1 2 h o urs a part  
● Da ys 5 t o 1 3: si n gle oral d oses of 2 0 0 m g itrac o naz ole  
T he st u d y d a ys of d osi n g o f itrac o naz ole a n d K R P-A 2 1 8 ma y be a me n de d t o e xte n d t he 
i nter val bet wee n t he first d ose of K R P-A 2 1 8 a n d t he first d ose of itrac o naz ole de pe n di n g o n 
t he o bser ve d t1/ 2 of 
  
P ote ntial s u bjects will be scree n e d t o assess t heir eli gi bilit y t o e nter t h e st u d y wit hi n 2 8 da ys 
pri or t o t he first d ose a d mi nistrati o n. S u bjects will be a d mitte d i nt o t he st u d y site o n Da y -1 
a n d be c o nfi n e d t o t he st u d y site u ntil disc har ge o n Da y 1 4.  
S u bjects will ret ur n t o t he st u d y site f or a f oll o w -u p visit 7 t o 1 0 da ys af ter t he last d ose of 
K R P -A 2 1 8. T he f oll o w -u p peri o d ma y be e xte n de d de pe n di n g o n t he o bser ve d t 1/ 2 of 
 
Base d o n t h e o n g oi n g re vie w of t he safet y, t olera bilit y, a n d P K res ults, a d diti o nal 
n o nresi de ntial visits ma y be re q uir e d. T he n u m ber of a d diti o nal visits per s u bject will n ot 
 
  
C CI
C CI
C CI
C CI




S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 1 6  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
Fi g ure 5 : Pl a n ne d D ose Le vels of K R P -A 2 1 8 ( P arts A, B, a n d, C ) 
 
 
  


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 1 7  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
5.  S A M P L E SI Z E J U S TI FI C A TI O N   
N o f or mal statistical assess me nt, i n ter ms of sa m ple siz e, has bee n c o n d u cte d as t his is t he 
first ti me K R P-A 2 1 8 is bei n g a d mi nistere d t o h u ma ns. H o we v er, t he n u m ber of s u bjects i n 
Parts A, B, a n d C is c o m m o n i n earl y cli nical p har mac ol o g y st u dies/ D DI st u dies, a n d is 
c o nsi dere d s ufficie nt t o a c hie ve t he o bjecti ves of t he st u d y.  
6.  S T U D Y T R E A T M E N T S   
6. 1.  P a rt A  
T he st u d y tr eat me nt na m es a n d or deri n g t o be use d i n t he T F Ls f or Part A are prese nte d i n  
Ta ble 1 . T he st u d y treat me nt se q ue nce n a mes a n d or deri n g t o be use d i n t he T F Ls f or Part A 
are prese nte d i n  T a ble 2 . 
T a ble 1 : 
Prese nt ati o n of St u d y Tre at me nts i n T F Ls  ( P art A)  
Gr o u p  
St u d y Tre at me nt  
Or der i n T F Ls  
A 1 t o A 8  
Place b o a 
1  
A 1  
1 m g K R P -A 2 1 8 ( Faste d Male)  
2  
A 2a  
3 m g K R P -A 2 1 8  ( Faste d Male) 
3  
3 m g K R P -A 2 1 8 ( Fe d Male)  
4  
A 2 b  
3 m g K R P -A 2 1 8 ( Faste d Fe male)  
5  
A 3  
6 m g K R P -A 2 1 8 ( Faste d Male)  
6  
A 4  
1 2 m g K R P -A 2 1 8 ( Faste d Male)  
7  
A 5  
2 4 m g K R P -A 2 1 8 ( Faste d Male)  
8  
A 6 b 
X X m g K R P -A 2 1 8 ( Faste d Male)  
9  
A 7 b 
X X m g K R P -A 2 1 8 ( Faste d Male)  
1 0  
A 8 b 
X X m g K R P -A 2 1 8 ( Faste d Male)  
1 1  
a Place b o will be p o ole d acr oss all gr o u ps, re gar dless of se x a n d t h e fasti n g c o n diti o n 
b O pti o nal gr o u p, t o be i ncl u de d if re q uire d  
T a ble 2 : 
Prese nt ati o n of St u d y Tre at me nt Se q ue nces i n T F Ls  ( P art A; F o o d-effect 
Gr o u p O nl y)  
Gr o u p  
St u d y Tre at me nt Se q ue nce  
Or der i n T F Ls  
A 2a  
Place b o ( Faste d Male) / Place b o ( Fe d Male)  
1  
A 2a  
3 m g K R P -A 2 1 8 ( Faste d Male)  / 3 m g K R P -A 2 1 8 ( Fe d Male)  
2  
All T F Ls will be base d o n act ual treat me nts (e g, if s u bject was assi g ne d t o r ecei ve pl ace b o 
b ut was wr o n gf ull y d ose d wit h acti ve treat me nt t h e y w o ul d be s u m marise d a n d liste d u n der 
acti ve treat me nt).  
All d ose le vels descri b e d a b o ve are t he p ote ntial d ose l e vels, a n d t heref ore are s u bject t o 
c ha n ge. T h e T F Ls wil l reflect t he d ose le vels utilise d i n t he st u d y, a n d t h ese will be dis pla ye d 
i n i ncreasi n g or der.  
 
  


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 1 8  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
All fasti n g c o n diti o ns descri be d a b o v e are t he p ot e ntial fasti n g c o n diti o ns, a n d t heref ore are 
s u bject t o c ha n ge. T h e T F Ls will reflect t he fasti n g c o n diti o ns utilise d i n t he st u d y. 
T he  f o o d-effect gr o u p descri be d a b o v e is t he p ote ntial f o o d -effect gr o u p, a n d t heref ore is 
s u bject t o c ha n ge. T h e T F Ls will reflect t he f o o d-effect gr o u p  utilise d i n t he st u d y . 
T he  se x-effect gr o u p des cri be d a b o v e is t he p ote ntial se x-effect gr o u p, a n d t heref ore is 
s u bject t o c ha n ge. T h e T F Ls will reflect t he se x-effect gr o u p  utilise d i n t he st u d y.  
6. 2.  P a rt B  
T he st u d y tr eat me nt na m es a n d or deri n g t o be use d i n t he T F Ls f or Part B are prese nte d i n 
Ta ble 3 . 
T a ble 3 : 
Prese nt ati o n of St u d y Tre at me nts i n T F Ls ( P art B)  
Gr o u ps  
St u d y Tre at me nt  
Or der i n T F Ls  
B 1 t o B 7  
Place b o a 
1  
B 1  
X X m g K R P -A 2 1 8 ( Q D b) 
2  
B 2  
X X m g K R P -A 2 1 8 ( Q D b) 
3  
B 3  
X X m g K R P -A 2 1 8 ( Q D b) 
4  
B 4  
X X m g K R P -A 2 1 8 ( Q D b) 
5  
B 5 c 
X X m g K R P -A 2 1 8 ( Q D b) 
6  
B 6 c 
X X m g K R P -A 2 1 8 ( Q D b) 
7  
B 7 c 
X X m g K R P -A 2 1 8 ( Q D b) 
8  
A b bre viati o ns:  Q D = o nce dail y; BI D =  t wice a da y; TI D = t hree ti mes a da y 
a Place b o will be p o ole d acr oss all gr o u ps, re gar dless of se x, t h e fasti n g c o n diti o n, or t h e d osi n g fre q ue nc y  
b T he pla n ne d d osi n g fre q ue nc y is Q D, h o we ver t h e d osi n g fre q ue nc y ma y be c ha n ge d f oll o wi n g re vi e w of data fr o m P art A  
   (e g, t o BI D or TI D) 
c O pti o nal gr o u p, t o be i n cl u de d if re q uire d  
All T F Ls will be base d o n act ual treat me nts (e g, if s u bject was assi g n e d t o r ecei ve p l ace b o 
b ut was wr o n gf ull y d ose d wit h acti ve tr eat me nt t h e y w o ul d be s u m maris e d a n d liste d u n der 
acti ve treat me nt).  
All d ose le vels descri b e d a b o ve are t he p ote ntial d ose le vels, a n d t heref ore are s u bject t o 
c ha n ge. T h e T F Ls wil l reflect t he d ose le vels utilis e d i n t he st u d y, a n d t h ese will be dis pla ye d 
i n i ncreasi n g or der.  
If t he fasti n g c o n diti o ns var y acr oss gr o u ps i n Part B, t he n t he acti ve treat me nt la bels will 
i ncl u de t he fasti n g stat us i nf or mati o n (e g, ‘ X X m g K R P-A 2 1 8 ( Q D) ( Fast e d)’ or  ‘ X X m g 
K R P -A 2 1 8 ( Q D) ( Fe d)’).  
6. 3.  P a rt C  
T he st u d y tr eat me nt na m es a n d or deri n g t o be use d i n t he T F Ls f or Part C are prese nte d i n 
Ta ble 4 . T he st u d y treat me nt se q ue nce n a me a n d or deri n g t o be use d i n t h e T F Ls f or Part C 
are prese nte d i n T a ble 5 . 
 
  


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 1 9  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
T a ble 4 : 
Prese nt ati o n of St u d y Tre at me nts i n T F Ls ( P art C)  
Gr o u p  
St u d y Tre at me nt  
Or der i n T F Ls  
C 1  
X X  m g K R P -A 2 1 8  Al o ne  
1  
2 0 0 m g Itrac o naz ole  Al o ne  
2  
X X  m g K R P -A 2 1 8 + 2 0 0 m g Itrac o naz ole  
3  
T a ble 5 : 
Prese nt ati o n of St u d y Tre at me nt Se q ue nce i n T F Ls  ( P art C) 
Gr o u p  
St u d y Tre at me nt Se q ue nce  
Or der i n T F Ls  
C 1  
X X  m g K R P -A 2 1 8 o n Da y 1 ; 2 0 0 m g Itrac o naz ole ( BI D) o n Da y 4 ; 
2 0 0 m g Itrac o naz ole ( Q D) o n Da ys 5 t o 1 0 ; X X m g K R P -A 2 1 8  
+  2 0 0  m g I trac o naz ole ( Q D) o n Da y 1 1; 2 0 0 m g Itrac o naz ole ( Q D) o n 
Da ys 1 2 a n d 1 3  
1  
A b bre viati o ns:  Q D = o nce dail y; BI D = t wice a da y  
All T F Ls will be base d o n act ual treat me nt se q ue n ce. T he ‘ Da ys X t o Y’ part of t he treat me nt 
se q ue nce l a bels will be k e pt u nc ha n ge d e ve n if a s u bject misses a d ose o n 1 or m ore da ys. 
E x act d osi n g re gi me n det ails i ncl u di n g d urati o n a n d da ys o n w hic h d ose was recei v e d will be 
prese nte d i n t he treat me nt a d mi nistrati o n listi n g o nl y.  
7.  D E FI NI TI O N S  O F P O P U L A TI O N S   
A n y  pr ot oc ol de viati o ns , i ncl u di n g t h ose d ue t o C O VI D-1 9  a n d rel ate d restricti o ns  (see 
Secti o n  8. 1. 1 ), will be c o nsi dere d pri or t o dat a bas e l oc k f or t heir i m p ort a nce a n d ta ke n i nt o 
c o nsi derati o n w he n assi g ni n g s u bjects t o p o p ulati o ns.  
7. 1.  All S u bjects P o p ul ati o n   
T he all s u bjects p o p ulati o n will i ncl u de all s u bjects w h o si g ne d t he inf or me d c o nse nt for m  
a n d ha d a n y st u d y ass essme nt  rec or de d in t he data base per t h e pr ot oc ol.  
7. 2.  S afet y P o p ul ati o n   
T he safet y p o p ulati o n will i ncl u de all s u bjects w h o recei v e d  at least 1 d ose of st u d y tr eat me nt 
(K R P -A 2 1 8,  Itrac o naz ole, or Place b o). 
7. 3.  P h ar m a c o ki netic P o p ul ati o n   
T he P K p o p ulati o n will i ncl u de all s u bjects w h o recei ve d  at least 1 d ose of acti ve st u d y 
treat me nt (K R P -A 2 1 8 or Itr ac o n az ole ) a n d ha v e at least 1 vali d  P K c o nce ntrati o n .  
7. 4.  P h ar m a c o d y n a mi c P o p ul ati o n   
T he P D p o p ulati o n will i ncl u de all s u bjects w h o recei ve d  at least 1 d ose of st u d y treat me nt 
(K R P -A 2 1 8 , Itrac o naz ole, or Place b o ) a n d ha v e  at least 1  vali d  p ost d ose P D assess me nt . 
 
  


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 2 0  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
8.  S T A TI S TI C A L M E T H O D O L O G Y   
8. 1.  Ge ner al   
Listi n gs will be pr o vi de d f or all data ca pt ure d i n t he data bas e, wit h t he e x ce pti o n of me dical 
hist or y. Listi n gs will i ncl u de all s u bjects assi g ne d t o t he all s u bjects p o p ulati o n a n d i ncl u de 
data u p t o t he p oi nt of st u d y c o m pleti o n or disc o nti n uati o n. S u bjects are ge nerall y c o nsi dere d 
t o ha ve c o m plete d t he st u d y if t he y c o m plete t he s c he d ule d f oll o w-u p visit (rat her t h a n earl y 
ter mi nati o n visit). A n y s u bject w h o disc o nti n ues  t he st u d y will be i de ntifie d acc or di n gl y i n 
t he listi n gs. S u m maries a n d statistical a nal ys es will i ncl u de t he s u bjects assi g ne d t o t he 
rele va nt p o p ulati o n bas e d o n data t y p e. 
Data a n al ysis will be perf or me d usi n g t he S A S ®  statistical s oft ware p ac k a ge Versi o n 9. 4 ( or 
hi g her if a ne w versi o n is iss ue d  d uri n g  t he stu d y ).  
A nal ysis D ata M o del ( A Da M)  datas ets will be pre pare d usi n g Cli nical Dat a I nterc ha n ge 
Sta n dar ds C o ns orti u m ( C DI S C) A Da M  Versi o n 2. 1  (or hi g h er if a ne w versi o n is iss ue d  
d uri n g  t he st u d y) a n d C DI S C A Da M I m pl e me ntati o n G ui de Versi o n 1. 1  (or hi g her if a ne w 
versi o n is iss ue d  d uri n g  t he st u d y). Pi n nacle 2 1 C o m m u nit y Vali dat or Versi o n 3. 1. 2  (or 
hi g her if a ne w versi o n is iss ue d  d uri n g  t he st u d y) will be utilis e d t o e ns ure c o m plia nce wit h 
C DI S C sta n dar ds.  
F or all statistical a nal yses, t he h y p ot hesis testi n g will be 2 -si de d a n d carrie d o ut o n  0. 0 5 
si g nifica n ce le v el, u nless s pecificall y state d ot her wise. 
Ca uti o n s h o ul d be use d w he n i nter preti n g res ults fr o m t he statistical a nal yses c o n d ucte d i n 
t his st u d y b eca us e  t he sa m ple siz e is n ot base d o n p o wer calc ulati o ns. 
W here refere nce is ma d e t o ‘ vali d’ data, t his refers t o n o n -missi n g data w hi c h meet  t he 
pre deter mi ne d criteri a  (e g, are n ot fla g ge d f or e x cl usi o n) .  
W here refere nce is ma d e t o ‘all calc ulati o ns’, t his i ncl u des, b ut is n ot li mite d t o, s u m mar y 
statistics, statistical a nal yses, baseli ne deri vati o n, c ha n ges fr o m baseli ne, a n d a n y p ara m eter 
deri vati o ns . 
All fi g ures will be pr o d u ce d o n li near -li near or discrete -li near scales, as a p plica ble, u nless 
s pecificall y state d ot her wise. 
A n y cl oc k c h a n ges will be acc o u nte d f or i n t he d eri vati o n of act ual ti me p ost d ose, a d verse 
e ve nt ( A E) d urati o n, a n d A E o nset ti me.  
8. 1. 1.  H a n dli n g of D at a Q u alit y Iss ues D ue t o C or o n a vir us Dise ase 2 0 1 9  a n d Rel ate d 
Restricti o ns  
D ue t o C O VI D -1 9  a n d relate d restricti o ns , there is a hi g h ris k f or i m pact t o d ata i nte grit y, 
wit h t he rec o g nis e d p ote ntial f or:  
● Miss e d visits , ca use d b y, f or e x a m ple,: 
 
  


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 2 1  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
o  S u bject  u na ble t o tra vel t o site d ue t o restricti o ns, t he nee d t o q uara nti ne, or 
C O VI D -1 9 i nfecti o n  
o  S u bject  u n willi n g t o g o t o site d ue t o fear of C O VI D-1 9 i nfecti o n  
o  S ite p ost p o ni n g s u bject’s visit d ue t o i n vesti gat or n ot bei n g a v aila ble (e g, if t he y 
ha ve bee n dis patc he d t o h os pit al ha n dli n g C O VI D -1 9 i nfecti o ns ) 
● S ite u na ble t o re ple nis h s u p pl y of i n vesti gati o nal pr o d uct 
● I n c o m plete data e ntr y b y sites d ue t o li mite d res o urces t o s u p p ort st u d y or n o access t o 
s o urce d oc u m e nts or t o e C R F 
● O utst a n di n g s o ur ce d oc u me nt ve rificati o n ( S D V) d ue t o s p o ns or or c o u ntr y restricti o ns 
o n re m ote S D V , or n o o r li mite d access t o site(s) f or o n-site visits 
● U n a ns were d q ueries  
A t t he ti me of t he re p orti n g of t he st u d y res ults, all pr otoc ol de viati o ns d ue t o C O VI D -1 9  or 
relate d restricti o n will be assess e d f or t h eir se verit y a n d i m pact o n t he a n al yses. If nee de d, 
a p pr o priate statistical met h o ds will be a p plie d as a  miti gati n g acti o n (e g,  d ata mi g ht be 
cate g oris e d i nt o 2 a n al ysis gr o u ps, wit h a n d wit h o ut C O VI D -1 9 a n d relate d restricti o ns 
i m pact); h o we ver , t his will e x cl u de a n y i m p utati o ns of t he missi n g val ues. A n y miti gati n g 
acti o ns will be a gree d wit h K y ori n P har m ace utical C o m pa n y Li mite d  i n a d va nce a n d 
i de ntifie d i n t he C S R. 
8. 1. 2.  C alc ul ati o n of  t he S u m m a r y St atistics  
F or c o nti n u o us data t h e f oll o wi n g r ules will be a p plie d:   
● Missi n g val ues will n ot be i m p ute d , u nless s pecifi call y stat e d ot her wise.  
● U nr o u n de d dat a will be use d i n t he calc ulati o n of s u m mar y statistics.  
● If t he n u m ber of s u bjects wit h vali d o bser vati o ns ( n) < 3 , s u m mar y statistics will n ot be 
calc ulate d, wit h t he e x ce pti o n of  n, mi n i m u m, a n d ma xi m u m . 
● I n ge neral, as earl y ter mi nati o n data are n ot ass oci ate d wit h a n y sc he d ul e d ti me p oi nt, 
t he y will be e x cl u de d fr o m all calc ulati o ns of s u m mar y st atistics. E x ce pti o ns ma y b e 
ma de w here j ustifie d.  
F or cate g orical data t he f oll o wi n g r ules will be a p plie d:   
● F or or d ere d cate g orical d ata (e g, A E se verit y), all cate g ories b et wee n t he p ossi ble 
mi ni m u m a n d ma xi m u m cate g ories  will be i ncl u de d, e ve n if n  =  0 f or a gi ve n cate g or y.  
● F or n o n -or dere d cat e g ori cal data (e g, race), o nl y t h ose cate g ories f or w hic h t here is at 
least 1 s u bject re prese nte d will be i ncl u de d ; u nless s pecificall y state d ot her wise.  
 
  


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 2 2  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
● Missi n g val ues will n ot be i m p ute d, u nless s pecifi call y stat e d ot her wise . A ‘ missi n g’  
cate g or y will be i ncl u d e d f or a n y para meter f or w hic h i nf or mati o n is missi n g. T his will 
e ns ure t hat t he p o p ulati o n size t otals are c o nsiste nt acr oss differe nt para met ers.   
8. 1. 3.  Tri p lic ate Re a di n gs  
F or vital si g ns d ata o nl y, w here tri plic ate rea di n gs are ta ke n , t he me dia n of tri plicate rea di n gs 
will re place t he  s e parate i n di vi d ual tri plicate rea di n gs i n all cal c ulati o ns.  
F or 1 2 -le a d E C G data o nl y, w here tri plicat e rea di n gs are ta ke n , t he mea n of tri plicate 
rea di n gs will re pla ce t he se parat e i n di vi d ual tri plicate rea di n gs i n all calc ulati o ns.  
I n case of i nc o m plete tri plicate rea di n gs (e g, o nl y 2 o ut of 3 rea di n gs w ere rec or de d), t he 
mea n a n d / or me dia n will be calc ul ate d , as a p pr o pri ate, base d o n t he n u m b er of rea di n gs 
a vaila ble.  
8. 1. 4.  Re pe at a n d U nsc he d ule d Re a di n gs   
F or vital si g ns a n d 1 2 -le a d E C G data o nl y, a n y p re d ose val ue rec or de d i n a d diti o n t o t he 
ori gi nal val u e  or a p ost d ose val ue rec or de d wit hi n 1 5 mi n utes of t he ori gi nal va l ue will be 
defi ne d as a re p eat  val ue ; a n y post d ose v al ue rec or de d m ore t ha n 1 5 mi n utes after t he 
ori gi nal val u e will be defi ne d as a n u nsc h e d ule d  v al ue . F or all ot her dat a t y pes (e g, la b orat or y 
para meters) , a n y v al ue rec or de d i n a d diti o n t o t he ori gi nal val u e will be defi ne d as a n 
u nsc he d ule d  val ue .  
T he o ri gi nal val ue will b e re pla ce d b y t he last ass ociate d  re p eat val u e  i n all calc ulati o ns , wit h 
t he e x ce pti o n of t he 1 2 -le a d E C G o utlier a nal ysis (see Secti o n  8. 7. 4 ). 
As u nsc he d ule d val u e s are n ot ass ociat e d wit h a n y sc he d ule d ti me p oi nt, t he y  will be 
e x cl u de d fr o m all calc ulati o ns , wit h t he e x ce pti o n of t he baseli ne d eri vati o n (see 
Secti o n  8. 1. 5 ) a n d 1 2 -le a d E C G o utlier a nal ysis (see Secti o n  8. 7. 4 ).  
8. 1. 5.  Defi niti o n s of B aseli ne  a n d  C h a n ge fr o m B aseli ne   
T he b aseli ne will be d efi ne d as t he last val ue rec or de d pri or t o t he first d os e. If t he d ate/ti me 
of t he val ue is i nc o m plet e or missi n g, it  will be e x cl u de d fr o m t he b aseli ne calc ulati o n , u nless 
t he i nc om plete date/ti me i n dicates t he val ue was rec or de d pri or t o  t he first d ose. 
I n di vi d ual c h a n ges fr o m baseli ne will be cal c ulate d b y s u btracti n g t h e i n di vi d ual s u bject’s 
baseli ne val ue fr o m t he v al ue at t he p ost d ose ti me p oi nt. 
T he s u m mar y statistics f or c ha n ge fr o m bas eli ne will be deri ve d fr o m i n di vi d ual s u bject s’ 
val ues (e g, me a n c h a n ge fr o m baseli ne will be t he mea n of t he i n di vi d ual c h a n ges fr o m 
baseli ne f or all s u bjects, rat her t ha n differe nce bet wee n t he mea n val ue at t he p ost d ose 
ti me p oi nt a n d mea n val ue at baseli ne). 
See Secti o n  8. 1. 4  f or m or e detail o n ha n dli n g re p eat a n d u nsc he d ule d rea di n gs i n t he 
calc ulati o ns. See Secti o n  8. 1. 3  f or m ore d etail o n ha n dli n g of tri plicate rea di n gs i n t he 
calc ulati o ns.   
 
  


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 2 3  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
8. 2.  S u bject Dis p ositi o n  a n d P o p ul ati o n Assi g n me nt   
S u bject dis p ositi o n a n d p o p ulati o n assi g n me nt will be liste d.   
A s u m mar y t a ble b y treat me nt  f or Parts A a nd B a n d b y o verall  f or Part C will be pr o vi de d, 
base d o n  t he safet y p o p ulati o n . 
Scree n fail ure dat a s u m mar y ta ble will be pr o vi d e d se parat el y, b ase d o n t h e all s u bjects 
p o p ulati o n.  
8. 3.  Scree ni n g De m o g r a p hics  
T he scree ni n g de m o gra p hics i ncl u di n g a ge, se x, race, et h nicit y, hei g ht,  b o d y wei g ht,  a n d 
b o d y mass i n de x will be liste d .  
A s u m mar y t a ble b y treat me nt f or Parts A a n d B a n d b y o verall  f or Part C will be pr o vi de d, 
base d o n  t he safet y p o p ulati o n. 
8. 4.  Pri or  a n d C o nc o mit a nt Me dic ati o n   
Pri or me dicati o n will be defi ne d as me di cati o n t hat e n ds pri or t o t he first d ose. C o nc o mita nt 
me dicati o n will be defi ne d as me dicati o n t hat starts d uri n g or after t he first d ose or starts b ut 
d oes n ot e n d pri or t o t he first d ose. 
Pr i or a n d c o nc o mita nt m e dicati o ns will be c o de d usi n g t he W orl d Healt h Or ga nizati o n Dr u g 
Dicti o nar y ( W H O Dr u g) Gl o bal, F or mat B 3, Versi o n Marc h 2 0 2 1  (or later if a ne w versi o n is 
iss ue d d uri n g  t he st u d y; s ee t he d at a m a na ge m e nt p la n [ D M P] f or m ore details). Pri or a n d 
c o nc o mita nt me dicati o ns will be liste d.  
8. 5.  P h ar m a c o ki netic Assess me nt s 
8. 5. 1.  P h ar m a c o ki netic A n al ysis   
T he f oll o wi n g P K p ara m eters will be deter mi ne d w here p ossi ble fr o m t he plas ma 
c o nce ntr ati o ns of 
 itrac o naz ole a n d h y dr o x y-itrac o n az ole usi n g 
n o nc o m part me ntal met h o ds i n vali date d s oft ware pr o gra m P h oe ni x Wi n N o nli n ( Certara, 
Versi o n 8. 1 or hi g her):  
 
  
C CI


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 2 4  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
P art A  ( D a y 1), P art B ( D a y 1) a n d P art C ( D a ys 1 a n d 1 1) (
 
P ar a meter  U nits a 
Defi niti o n  
A U C 0 -tlast 
n g * h/ m L  
area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o t he ti me of t he 
last q ua ntifia ble c o nce ntrati o n (tlast)b 
D A U C 0 -tlast n g * h/ m L / m g area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o t he ti me of t he 
last q ua ntifia ble c o nce ntrati o n (tlast) n or malize d b y d ose a d mi nistere d e 
A U C 0 -τ 
n g * h/ m L  
area u n der t he c o nce ntrati o n ‑ti me c ur ve o ver a d osi n g i nter val (τ)d 
A U C 0 -∞ 
n g * h/ m L  
area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 e xtra p olate d t o 
i nfi nit yc 
D A U C 0 -∞ 
n g * h/ m L / m g area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 e xtra p olate d t o 
i nfi nit y n or malize d b y d ose a d mi nistere d ce 
% A U C
e xtra p %  
perce nta ge of area u n der t he c o nce ntrati o n -ti me c ur ve d ue t o 
e xtra p olati o n fr o m t he last q ua ntifia ble c o nce ntrati o n t o i nfi nit y  
C ma x  
n g/ m L  
ma xi m u m o bser ve d c o nce ntrati o n  
D C ma x  
n g/ m L / m g 
ma xi m u m o bser ve d c o nce ntrati o n  n or malize d b y d ose a d mi nistere d e 
tma x  
h  
ti me of t he ma xi m u m o bser ve d c o nce ntrati o n 
t1/ 2 
h  
a p pare nt ter mi nal eli mi nati o n half -life 
C L/ F  
L/ h  
a p pare nt t otal cleara nce  
V z/ F 
L  
a p pare nt v ol u me of distri b uti o n  d uri n g t he ter mi nal p hase  
a U nits are base d o n c o nce ntrati o n u nits ( pr o vi d e d b y t h e bi oa nal ytical la b or preferre d u nits f or prese ntati o n of P K 
para meters) a n d d ose u nits use d i n t h e st u d y.  
b T he A U C will be calc ulate d usi n g t h e li near tra pez oi d al r ule f or i ncreasi n g c o nce ntrati o ns  a n d t h e l o garit h mic r ule f or 
decreasi n g c o nce ntrati o ns (li near u p/l o g d o w n r ule).  
c Base d o n t he last o bser ve d q ua ntifia ble c o nce ntrati o n  
d P art B Da y 1 o nl y –  n ot re q uire d f or P arts A a n d C  
e N ot re q uire d f or P art C  
 
  
C CI


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 2 5  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
P art B ( D a y 1 4) (
 
P ar a meter  U nits a 
Defi niti o n  
A U C 0 -tlast 
n g * h/ m L  
area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o t he ti me of t he 
last q ua ntifia ble c o nce ntrati o n (tlast)b 
D A U C 0 -tlast n g * h/ m L / m g area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o t he ti me of t he 
last q ua ntifia ble c o nce ntrati o n (t last) n or malize d b y d ose a d mi nistere d  
A U C 0 -τ 
n g * h/ m L  
area u n der t he c o nce ntrati o n ‑ti me c ur ve o ver a d osi n g i nter val (τ) 
D A U C 0 -τ 
n g * h/ m L / m g area u n der t he c o nce ntrati o n ‑ti me c ur ve o ver a d osi n g i nter val (τ) 
n or malize d b y d ose a d mi nistere d 
C ma x  
n g/ m L  
ma xi m u m o bser ve d c o nce ntrati o n  
D C ma x  
n g/ m L  
ma xi m u m o bser ve d c o nce ntrati o n  n or malize d b y d ose a d mi nistere d  
C mi n  
n g/ m L  
mi ni m u m o bser ve d c o nce ntrati o n d uri n g a d osi n g i nter val  
tma x  
h  
ti me of t he ma xi m u m o bser ve d c o nce ntrati o n 
t1/ 2 
h  
a p pare nt ter mi nal eli mi nati o n half -life 
C L/ F  
L/ h  
a p pare nt t otal cleara nce  
V z/ F 
L  
a p pare nt v ol u me of distri b uti o n d uri n g t he ter mi nal p hase  
A R A U C 0 -τ 
 
o bser ve d acc u m ulati o n rati o base d o n A U C 0 -τ 
A R C ma x  
 
o bser ve d acc u m ulati o n rati o base d o n C ma x  d uri n g t he d osi n g i nter val  
T he d osi n g i nter val τ is 2 4 h o urs.  
a U nits are base d o n c o nce ntrati o n u nits ( pr o vi d e d b y t h e bi oa nal ytical la b or preferre d u nits f or prese ntati o n of P K 
para meters) a n d d ose u nits use d i n t h e st u d y.  
b Area u n der t h e c o nce ntrati o n -ti me c ur ve will be calc ulate d usi n g t h e li near tra pez oi d al r ule f or i ncreasi n g c o nce ntrati o ns 
a n d t he l o garit h mic r ule f or decreasi n g c o nce ntrati o ns (li near u p/l o g d o w n r ule).  
 
P art C D a y  1 1 (Itr a c o n az ole a n d H y dr o x y -Itr a c o n az ole) 
P ar a meter  
U nits a 
Defi niti o n  
A U C 0 -τ 
n g * h/ m L  
area u n der t he c o nce ntrati o n ‑ti me c ur ve o ver a d osi n g i nter val (τ)b 
C ma x  
n g/ m L  
ma xi m u m o bser ve d c o nce ntrati o n  
tma x  
h  
ti me of t he ma xi m u m o bser ve d c o nce ntrati o n 
a U nits are base d o n c o nce ntrati o n u nits ( pr o vi d e d b y t h e bi oa nal ytical la b or preferre d u nits f or prese ntati o n of P K 
para meters) a n d d ose u nits use d i n t h e st u d y.  
b T he A U C will be calc ulate d usi n g t h e li near tra pez oi d al r ule f or i ncreasi n g c o nce ntrati o ns a n d t h e l o garit h mic r ule f or 
decreasi n g c o nce ntrati o ns (li near u p/l o g d o w n r ule).  
A d diti o nal P K para meters ma y be deter mi ne d w here a p pr o priate.  
T he P K  a nal ysis will be carri e d o ut w here p ossi ble usi n g t he act ual d ose of K R P -A 2 1 8 
a d mi nistere d ( m g) a n d act ua l p ost d ose bl o o d sa m pli n g ti mes. If a n act ual ti me is missi n g, t he 
sa m ple c o nce ntrati o n res ult will be treate d as missi n g u nless t here is scie ntific j ustificati o n t o 
i ncl u de t he res ult usi n g t he n o mi nal ti me.  
T he para meters C ma x , Cmi n,  a n d t ma x  will be o btai ne d directl y fr o m t he c o n ce ntrati o n -ti me 
pr ofiles. If C ma x  occ urs at m ore t ha n 1 ti me p oi nt, t ma x  will be assi g ne d t o t h e first occ urre n ce 
of C ma x . 
 
  
C CI


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 2 6  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
T he acc u m ulati o n rati os ( A R A U C 0 -τ a n d A R C ma x ) will be calc ulate d as f oll o ws: 
A R A U C 0 -τ = A U C 0 -τ D a y 1 4 / A U C 0 -τ Da y  1  
A R C ma x  = C ma x  Da y  1 4 / C ma x  Da y  1  
8. 5. 1. 1.  Criteri a f or t he C alc ul ati o n of A p p are nt Ter mi n al Eli mi n ati o n R ate C o nst a nt 
a n d H alf -life 
T he start of t he ter mi nal eli mi nati o n p hase f or eac h s u bject will be defi ne d b y vis ual 
i ns pecti o n a n d ge nerall y will be t he first p oi nt at w hic h t here is n o s yste m atic de viati o n fr o m 
t he l o g-li near decli ne i n c o nce ntrati o ns. 
T he a p pare nt ter mi nal eli mi nati o n rate c o nsta nt ( λ z) will o nl y b e cal c ulate d w he n a relia ble 
esti mate ca n be o bt ai ne d usi n g at least 3 d ata p oi nts, prefera bl y n ot i ncl u di n g C ma x , a n d t he 
a dj uste d c oefficie nt f or deter mi nati o n of e x p o ne ntial fit ( R 2-a dj) of t he re gressi o n li ne is ≥0. 7. 
Para meters re q uiri n g λ z f or t heir cal c ulati o n (e g, A U C0 -∞, t1/ 2, C L/ F (si n gl e d ose o nl y), Vz/ F) 
will o n l y b e calc ulate d if t he R2-a dj val ue of t he re gressi o n li ne is ≥0. 7.  
T he f oll o wi n g re gressi o n -relate d di a g n ostic P K para meters will be deter mi ne d w here 
p ossi ble:  
P ar a meter  
U nits  
Defi niti o n  
λ z 
1/ h  
a p pare nt ter mi nal eli mi nati o n rate c o nsta nt  
λ z U p per  
h  
e n d of e x p o ne ntial fit  
λ z L o wer  
h  
start of e x p o ne ntial fit 
λ z N  
 
n u m ber of data p oi nts i ncl u de d i n t he l o g -li near re gressi o n 
λ z S pa n Rati o  
 
ti me peri o d o ver w hic h λz was deter mi ne d as a rati o of t 1/ 2 
R 2-a dj  
 
a dj uste d c oefficie nt f or deter mi nati o n of e x p o ne ntial fit 
W here p ossi ble, t he s pa n of ti me use d i n t he deter mi nati o n of λ
z (ie, t h e differe n ce b et wee n λz 
U p per a n d λ z L o wer) s h o ul d be ≥2 half -li ves. If t h e λz S pa n R ati o is < 2, t he r o b ust ness of t he 
t1/ 2 val ues will be disc usse d i n t he C S R.  
8. 5. 1. 2.  Criteri a f or C alc ul ati o n a n d Re p orti n g of Are a U n der t he C o nce ntr ati o n -ti me 
C ur ve  
T he mi ni m u m re q uire me nt f or t he cal c ulati o n of A U C will be t he i ncl usi o n of at least 
3  c o nsec uti ve c o n ce ntr ati o ns a b o ve t he l o wer li mit of q ua ntificati o n. If t h ere are o nl y 
3  c o nsec uti ve c o n ce ntr ati o ns, at least 1 s h o ul d f oll o w C ma x . A n e x ce pti o n ma y b e ma de f or 
meta b olites, w here C ma x  ma y b e t he last ti me p oi nt.  
If t he e xtra p olate d area is > 2 0 %, A U C0 -∞ (a n d deri ve d para m eters) m a y be e x cl u de d fr o m t he 
s u m mar y statistics a n d st atistical a nal ysis at t he discreti o n of t he s p o ns or or 
p har mac o ki neticist.  
 
  


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 2 7  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
If A U C0 -∞ ca n n ot be deter mi ne d relia bl y f or all s u bjects a n d/ or d ose le vels/treat me nts, a n 
alter nati ve A UC me as ure, s uc h as A U C t o a fi x e d ti me p oi nt or A U C 0 -tlast, ma y b e use d i n t he 
statistical a nal ysis of d os e pr o p orti o nalit y/f o o d effect/se x effect.  
If t he τ P K bl o o d sa m ple is c ollecte d sli g htl y earl y (i.e., t he 2 4 h o urs sa m pl e), t he act ual 
sa m pli n g ti me of t he τ sa m ple ma y b e use d f or t h e calc ulati o n of A U C 0 -τ. H o we ver, t he 
A U C 0 -τ para meter will be calc ulate d if t h e τ sa m pl e is wit hi n 6 0 mi n utes of t he n o mi nal 
sa m pli n g ti me. 
8. 5. 1. 3.  Criteri a f or H a n dli n g C o nce ntr ati o ns Bel o w t he Li mit of Q u a ntific ati o n or 
Missi n g C o nce ntr ati o ns f or P h ar m a c o ki netic A n al ysis  
Plas ma c o nce ntr ati o ns bel o w t he li mit of q ua ntificati o n ( B L Q) will be assi g ne d a val ue of 0 
bef ore t h e first meas ur a ble c o nce ntr ati o n a n d t hereafter B L Q c o nce ntrati o ns will be treate d as 
missi n g. T he f oll o wi n g r ul es a p pl y t o t he s p ecific sit uati o ns defi ne d bel o w:  
● If a n e ntire c o nce ntrati o n-ti me pr ofile is B L Q, it will be e x cl u de d fr o m P K a nal ysis. 
● W here 2 or m ore c o nsec uti ve c o nce ntr ati o ns are B L Q at t he e n d of a pr ofile, t he 
pr ofile will be dee m e d t o ha ve ter mi nate d a n d a n y f urt her q ua ntifi a ble c o n ce ntrati o ns 
will be set t o missi n g f or t he calc ulati o n of t he P K para meters, u nless t he y are 
c o nsi dere d t o be a tr ue c haract eristic of t he pr ofile of t he dr u g.  
● If a pre d ose plas ma c o nce ntrati o n is missi n g, it will be set t o 0 b y defa ult wit hi n 
P h oe ni x Wi n N o nli n f or t he first d osi n g d a y of all parts of t he st u d y.  
● F or m ulti ple d ose part of t he st u d y ( Da y 1 4), if t he a nal yt e c o n ce ntrati o n at τ ( 2 4 h o urs 
p ost d ose) is missi n g, t his ma y b e s u bstit ute d wit h t he pre d ose c o nce ntr ati o n.      
Si milarl y, if t h e pre d os e c o nce ntr ati o n is missi n g t he n t his ma y be s u bstit ute d wit h t he 
c o nce ntr ati o n at τ.  T he P K para met ers fr o m a n y s uc h pr ofile will be liste d b ut e xcl u de d 
fr o m descri pti ve statistics a n d statistical anal ysis.  
8. 5. 1. 4.  T re at me nt of O utliers i n P h ar m ac o ki netic A n al ysis  
If a val u e is c o nsi dere d t o be a n o mal o us d ue t o bei n g i nc o nsiste nt wit h t he e x pecte d P K 
pr ofile, it ma y b e a p pr o priate t o e x cl u de t he val ue fr o m t he P K a nal ysis. H o we ver, t he 
e x cl usi o n of a n y dat a m ust ha ve str o n g j ustificati o n a n d will be d oc u me nte d i n t he C S R.  
A n y q u a ntifia ble pre d ose c o nce ntr ati o n val ue o n t he first d osi n g d a y of all parts of t he st u d y 
wil l be c o nsi dere d tr eate d as 0 f or t he P K a n al ysis. T he P K para m eters fr o m a n y s u c h pr ofile 
will be liste d b ut e x cl u de d fr o m descri pti ve statistics a n d statistical a nal ysis.   
8. 5. 2.  Prese nt ati o n of P h ar m a c o ki netic D at a  
All P K c o nce ntrati o ns a n d para meters wi ll be liste d.  
S u m mar y ta bles, arit h metic mea n ( + sta n d ar d de vi ati o n [ S D]) fi g ures, o verl a yi n g i n di vi d ual 
fi g ures, a n d i n di vi d ual fi g ures b y treat me nt a n d ti me p ost d ose will be pr o vi de d f or plas ma 
 
  


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 2 8  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
P K c o nce ntrati o ns. All fi g ures will be pr o d uce d o n b ot h li near-li near a n d li near-l o garit h mic 
scales. T he + S D bars will o nl y be dis pla ye d o n t h e li near-li near scale.  
S u m mar y ta bles b y tr eat me nt will be pr o vi de d f or all P K para meters, wit h t he e x ce pti o n of 
dia g n ostic re gressi o n -rel ate d P K para m eters. 
A s u bject m a y be e x cl u d e d fr o m t he P K s u m mar y statistics a n d statistical a nal ysis if t he 
s u bject has a n A E  of v o miti n g t hat occ urs at or b ef ore 2 ti mes t he me di a n t ma x . 
If t he act ual ti me of sa m ple c ollecti o n de viates fr o m t he n o mi nal ti me b y m ore t ha n ± 1 0 %, 
t he plas ma/ser u m/ w h ole bl o o d c o nce ntrati o n will be fla g ge d a n d e x cl u de d fr o m t he s u m mar y 
statistics. I n di vi d ual c o nce ntrati o ns dee me d t o b e a n o mal o us will be fla g ge d i n t he listi n gs 
a n d e x cl u de d fr o m t he s u m mar y statistics.  
F or plas ma/ser u m/ w h ole bl o o d c o nce nt rati o n dat a, t he f oll o wi n g r ul es will a p pl y: 
● Val ues t hat are B L Q will be set t o 0 f or t he calc ul ati o n of s u m mar y st atistics.  
● Arit h metic mea n or me di a n val ues t hat are B L Q will be prese nte d as 0.  
F or P K para meters, t he f oll o wi n g r ule will a p pl y:  
● Ge o metric m ea n a n d c o efficie nt of variati o n ( C V) will n ot be calc ulate d f or t ma x . 
8. 5. 3.  P h ar m a c o ki netic St atistic al Met h o d ol o g y   
8. 5. 3. 1.  D ose Pr o p orti o n alit y Assess me nt ( P arts A a n d B)  
A statistical a nal ysis will be c o n d ucte d t o i n vesti gate t he d ose pr o p orti o nalit y of  A U C 0 -tlast, 
A U C 0 -∞, a n d Cma x  o n pr ofile da y 1 i n Part A, a n d A U C 0 -tlast, A U C0 -τ, a n d Cma x  o n pr ofile da y 
1 4 i n Part B ( o nl y f or plas ma 
 
T he a nal ysis is pla n ne d t o be c o n d ucte d acr oss f ull d ose ra n ge, h o we ver if at t he ti me of 
a nal ysis t here is n’t s uffi cie nt data i n s o me of t he d ose le vels or t he d ose pr o p orti o nalit y is n ot 
c o ncl u de d f or t he f ull d ose ra n ge, a nal ysis acr oss narr o wer d ose ra n ge m a y be e x pl ore d.  
T he P K para m eters will be a nal ys e d usi n g a p o wer m o del 4 t hat will ha ve t he f oll o wi n g f or m: 
p ar a meter = i nterce pt × d ose^sl o pe × r a n d o m err or  
Usi n g t he n at ural l o g (l n) tra nsf or mati o n, 5 a p o wer m o del ca n be e x presse d as a li near 
re gressi o n e q u ati o n: 
l n( p ar a m eter) = i nterce pt + sl o pe × l n( d ose) + r a n d o m err or 
F or d ose pr o p orti o nalit y, t he sl o pe of t he re gressi o n li ne is e q ual t o 1; f or d ose i n de pe n de n ce, 
it is e q ual t o 0.  
 
  
C CI


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 2 9  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
F or eac h P K para meter s e parat el y, a p o ole d esti m ate (acr oss all d oses) of sl o pe, 
c orres p o n di n g 9 5 % c o nfi de nce i nter val ( CI), a n d bet wee n -s u bj ect C V  will be calc ul ate d. 
Fi g ures ( o n t h e l o garit h mic -l o garit h mic scale) c o nt ai ni n g i n di vi d ual val ues, t he p o wer m o del 
li ne ( 9 5 % CI), a n d t he d ose pr o p orti o nalit y li ne ( defi ne d as t he p o wer m o d el li ne wit h sl o pe 
of 1) will be create d f or eac h P K para meter. A d diti o nall y, fi g ures ( o n t he l o garit h mic -li near 
scale) c o ntai ni ng i n di vi d ual val ues a n d ge o m etric mea ns will be create d f or eac h 
c orres p o n di n g P K para m eter n or malise d b y d os e a d mi nistere d.  
T he lac k of fit test will be c o n d ucte d f or t he statistical assess me nt of li nearit y ass u m pti o n, 
a n d t h us a p pr o priate n ess of a p o wer  m o del. T he lac k of fit m o del will be t he sa me as t he 
p o wer m o del fitte d, b ut wit h d ose i ncl u de d as a n a d diti o nal fi x e d effect. T he statistical 
assess me nt will r ule t he li nearit y ass u m pti o n acce pta ble if t he dia g n ostic pl ots a p pear 
reas o na bl e a n d t he lac k of fit 2 -si de d p-val ue  > 0. 0 5 ( d ose effect is n ot si g nifica nt at t he 0. 0 5 
le vel of si g nifi ca nce). T h e assess me nt of li nearit y ass u m pti o n ma y als o oc c ur via vis ual 
e x a mi nati o n of t he fi g ures b y t he p h ar mac o ki n eticist. T his assess me nt ma y o verri de t he 
statistical assess me nt; w here t his occ urs, it will be detaile d i n t he C S R.  
If t he ass u m pti o n of li nearit y is r ule d acce pta ble a n d t he 9 5 % CI f or t he sl o pe s pa ns 1, it will 
be dee me d t h at t here is n o statistical basis t o c o ncl u de a lac k of pr o p orti o nalit y.  
If t he ass u m pti o n of li nearit y is r ule d u nacce pta ble f or a n y P K para meter, its c or res p o n di n g 
P K para meter n or malis e d b y d ose a d mi nistere d will b e l n-tra nsf or me d a n d a nal yse d usi n g a n 
a nal ysis of varia n ce ( A N O V A) m o del. 6 T he m o del will i ncl u de d ose as a fact or.  
F or eac h P K para meter s e parat el y, t h e ge o metric l east s q uares m ea n ( G L S M) f or eac h d ose, 
p -val ues f or t h e o verall, a n d pair wise d os e c o m paris o ns will be calc ulate d. Resi d ual pl ots will 
be pr o d uce d t o assess t he a de q uac y of t he m o del(s) fitte d.  
E x a m ples of t he S A S c o de t hat will be use d are as f oll o ws:  
P o w er M o del A n al ysis  
p r o c  m i x e d  d a t a  =  < d a t a  i n >  a l p h a  =  0 . 0 5 ;  
 b y  p a r c a t 1 n  p a r c a t 1  p k d a y  p a r a m n  p a r a m ;  
 m o d e l  l p k  =  l d o s e  /  c l  r e s i d u a l  d d f m  =  k r 2 ;  
 o d s  o u t p u t  s o l u t i o n f  =  < d a t a  o u t > ;  
r u n ;  
P o w er M o del A n al ysis ( Bet wee n -s u bject V ari a bilit y) 
p r o c  m i x e d  d a t a  =  < d a t a  i n >  c o v t e s t  a l p h a  =  0 . 0 5 ;  
 b y  p a r c a t 1 n  p a r c a t 1  p k d a y  p a r a m n  p a r a m ;  
 c l a s s  l d o s e ;  
 m o d e l  l p k  =  l d o s e  /  c l  r e s i d u a l  d d f m  =  k r 2 ;  
 o d s  o u t p u t  c o v p a r m s  =  < d a t a  o u t > ;  
r u n ;  
( N o t e :  P o o l e d  G e o m e t r i c  C V  ( % )  =  1 0 0 * ( s q r t ( e x p ( e s t i m a t e ) - 1 ) ) )  
P o w er M o del A n al ysis ( L ac k of Fit Test)  
p r o c  m i x e d  d a t a  =  < d a t a  i n > ;  
 b y  p a r c a t 1 n  p a r c a t 1  p k d a y  p a r a m n  p a r a m ;  
 c l a s s  d o s e ;  
 m o d e l  l p k  =  l d o s e  d o s e  /  h t y p e  =  1  d d f m  =  k r 2 ;  
 
  


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 3 0  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
 o d s  o u t p u t  t e s t s 1  =  < d a t a  o u t > ;  
r u n ;  
A N O V A M o del A n al ysis  
p r o c  m i x e d  d a t a  =  < d a t a  i n >  a l p h a  =  0 . 0 5 ;  
 b y  p a r c a t 1 n  p a r c a t 1  p k d a y  p a r a m n  p a r a m ;  
 c l a s s  d o s e ;  
 m o d e l  l d n p k  =  d o s e  /  c l  r e s i d u a l  d d f m  =  k r 2 ;  
 l s m e a n s  d o s e  /  c l  p d i f f ;   
 o d s  o u t p u t  l s m e a n s  =  < d a t a  o u t > ;   
 o d s  o u t p u t  d i f f s  =  < d a t a  o u t > ;  
 o d s  o u t p u t  t e s t s 3  =  < d a t a  o u t > ;  
r u n ;  
8. 5. 3. 2.  F o o d Effect Assess me nt ( P a rt A)  
A statistical a nal ysis will be c o n d ucte d t o i n vesti gate t he f o o d effect o n t he treat me nt b y 
c o m pari n g ‘ 3 m g K R P -A 2 1 8 ( Fe d M ale)’  (test treat me nt) t o ‘ 3 m g K R P-A 2 1 8 ( Faste d M ale)’ 
(refere n ce tr eat me nt).  
T he l n -tra nsf or me d5 A U C 0 -tlast, A U C0 -∞, a n d Cma x  o n pr ofile da y 1 i n Part A ( o nl y f or  plas ma 
 will be a n al yse d usi n g a mi x e d m o del. 7 T he m o del will i ncl u de act ual treat me nt 
as fi x e d effect a n d s u bject as a ra n d o m effect.  
F or eac h P K para meter s e parat el y, t h e least s q uares mea n ( L S M) f or eac h treat me nt, 
differe n ce i n L S Ms bet w ee n t he fe d a n d faste d tr eat me nts, a n d c orres p o n di n g 9 0 % a n d 9 5 % 
CIs will be calc ulate d; t h ese val ues will t he n be b ac k -tr a nsf or me d t o gi ve t he G L S M, rati o of 
G L S Ms, a n d c orres p o n di n g 9 0 % a n d 9 5 % CIs.  
A d diti o nall y, t he p o ole d esti mate (acr oss treat me nts) of t he wit hi n -s u bject C V will be 
calc ulate d, a n d resi d ual pl ots will be pr o d uce d t o assess t he a de q uac y of t he m o del(s) fitte d.  
E x a m ples of t he S A S c o de t hat will be use d are as f oll o ws:  
Mi xe d M o del A n al ysis  
p r o c  m i x e d  d a t a  =  < d a t a  i n > ;  
 b y  p a r c a t 1 n  p a r c a t 1  p k d a y  p a r a m n  p a r a m ;  
 c l a s s  t r t a n  u s u b j i d ;  
 m o d e l  l p k  =  t r t a n  /  c l  r e s i d u a l  d d f m  =  k r 2 ;  
 l s m e a n s  t r t a n  /  c l  p d i f f  =  c o n t r o l ( ' 1 ' )  a l p h a  =  0 . 1 ;  
 l s m e a n s  t r t a n  /  c l  p d i f f  =  c o n t r o l ( ' 1 ' )  a l p h a  =  0 . 0 5 ;  
 r a n d o m  i n t e r c e p t  /  s u b j e c t  =  u s u b j i d ;   
 o d s  o u t p u t  l s m e a n s  =  < d a t a  o u t > ;   
 o d s  o u t p u t  d i f f s  =  < d a t a  o u t > ;  
 o d s  o u t p u t  c o v p a r m s  =  < d a t a  o u t > ;  
r u n ;  
8. 5. 3. 3.  Se x Effect Assess me nt ( P a rt A)  
A statistical a nal ysis will be c o n d ucte d t o i n vesti gate t he se x effect o n t he treat me nt b y 
c o m pari n g ‘ 3 m g K R P -A 2 1 8 ( Faste d Fe m ale)’ (test treat me nt) t o ‘ 3 m g K R P-A 2 1 8 ( Faste d 
Male)’ (refere n ce tr eat m e nt).  
 
  
C CI


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 3 1  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
T he l n -tra nsf or me d5 A U C 0 -tlast, A U C0 -∞, a n d Cma x  o n pr ofile da y 1 i n Part A ( o nl y f or  plas ma 
 will be a n al yse d usi n g an  A N O V A  m o del. 6 T he m o del will i ncl u de a ct ual 
treat me nt as a fact or.  
F or eac h P K para meter s e parat el y, t h e L S M f or eac h treat me nt, differe nce i n L S Ms bet wee n 
t he test a n d refere nce tr eat me nts, a n d c orres p o n di n g 9 0 % a n d 9 5 % CIs will be calc ulate d; 
t hese val ues will t he n be bac k-tr a nsf or me d t o gi ve t he G L S M, rati o of G L S Ms, a n d 
c orres p o n di n g 9 0 % a n d 9 5 % CIs.  
A d di ti o nall y, t he p o ole d esti mate (acr oss treat me nts) of t he bet wee n -s u bject C V will be 
calc ulate d, a n d resi d ual pl ots will be pr o d uce d t o assess t he a de q uac y of t he m o del(s) fitte d.  
E x a m ples of t he S A S c o de t hat will be use d are as f oll o ws:  
A N O V A  M o del A n al y sis 
p r o c  m i x e d  d a t a  =  < d a t a  i n > ;  
 b y  p a r c a t 1 n  p a r c a t 1  p k d a y  p a r a m n  p a r a m ;  
 c l a s s  t r t a n ;  
 m o d e l  l p k  =  t r t a n  /  c l  r e s i d u a l  d d f m  =  k r 2 ;  
 l s m e a n s  t r t a n  /  c l  p d i f f  =  c o n t r o l ( ' 1 ' )  a l p h a  =  0 . 1 ;  
 l s m e a n s  t r t a n  /  c l  p d i f f  =  c o n t r o l ( ' 1 ' )  a l p h a  =  0 . 0 5 ;  
 o d s  o u t p u t  l s m e a n s  =  < d a t a  o u t > ;   
 o d s  o u t p u t  d i f f s  =  < d a t a  o u t > ;  
 o d s  o u t p u t  c o v p a r m s  =  < d a t a  o u t > ;  
r u n ;  
8. 5. 3. 4.  Dr u g -dr u g I nter acti o n Assess me nt ( P a rt C)  
A statistical a nal ysis will be c o n d ucte d t o i n vesti gate t he dr u g -dr u g i nteracti o n o n t he P K of 
K R P -A 2 1 8 b y c o m p ari n g ‘ X X  m g K R P -A 2 1 8 + 2 0 0 m g Itr ac o naz ole’ (test treat me nt) t o 
‘ X X m g K R P -A 2 1 8’ (refere nce treat me nt).  
T he l n -tra nsf or me d5 A U C 0 -tlast, A U C0 -∞, a nd C ma x  i n Part C ( o nl y f or plas m a 
 will 
be a nal ys e d usi n g a mi x e d m o del. 7 T he m o del will i ncl u de act ual tr eat me nt as fi x e d effect 
a n d s u bject as a ra n d o m effect.  
F or eac h P K para meter s e parat el y, t h e L S M f or eac h treat me nt, differe nce i n L S Ms bet wee n 
t he test a n d refere nce tr eat me nts, a n d c orres p o n di n g 9 0 % CI will be calc ul ate d; t hese val ues 
will t he n be bac k -tr a nsf or me d t o gi ve t h e G L S M, rati o of G L S Ms, a n d c orres p o n di n g 9 0 % 
CI.  
A d diti o nall y, t he p o ole d esti mate (acr oss treat me nts) of t he wit hi n -s u bject C V will be 
calc ulate d, a n d resi d ual pl ots will be pr o d uce d t o assess t he a de q uac y of t he m o del(s) fitte d.  
E x a m ples of t he S A S c o de t hat will be use d are as f oll o ws:  
Mi xe d M o del A n al ysis  
p r o c  m i x e d  d a t a  =  < d a t a  i n > ;  
  b y  p a r c a t 1 n  p a r c a t 1  p a r a m n  p a r a m ;  
  c l a s s  t r t a n  u s u b j i d ;  
  m o d e l  l p k  =  t r t a n  /  c l  r e s i d u a l  d d f m  =  k r 2 ;  
 
  
C CI
C CI


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 3 2  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
  l s m e a n s  t r t a n  /  c l  p d i f f  =  c o n t r o l ( ' 1 ' )  a l p h a  =  0 . 1 ;  
  r a n d o m  i n t e r c e p t  /  s u b j e c t  =  u s u b j i d ;   
  o d s  o u t p u t  l s m e a n s  =  < d a t a  o u t > ;    
  o d s  o u t p u t  d i f f s  =  < d a t a  o u t > ;  
  o d s  o u t p u t  c o v p a r m s  =  < d a t a  o u t > ;  
r u n ;  
8. 6.  P h ar m a c o d y n a mi c Ass ess me nt s 
8. 6. 1.  P h ar m a c o d y n a mi c A n al ysis  
Data ass oci ate d wit h ser u m p h os p h oli pi d -C c o nce ntrati o ns a n d faecal cal pr otecti n will be 
re p orte d i n t he T F Ls. 
Data ass oci ate d wit h t he e x pl orat or y meta b olite pr ofili n g, bi o mar ker a nal ysis, 
p har mac o ge netic a n al ysis, a n d c o nce ntrati o n Q Tc a nal ysis will be re p orte d se parat el y. 
8. 6. 2.  Prese nt ati o n of P h ar m a c o d y n a mic D at a  
All ser u m p h os p h oli pi d -C  data a n d t heir c h a n ges fr o m baseli ne will be liste d.  
S u m mar y ta bles a n d b o x pl ots  b y treat me nt a n d ti mep oi nt  will be pr o vi de d f or all ser u m 
p h os p h oli pi d -C  data  a n d t heir c ha n ges fr o m baseli ne. 
All faecal cal pr otecti n data will be liste d  o nl y . 
Val ues rec or de d as < x, ≤x, > x, or ≥x will be dis pla ye d i n t he listi n gs as rec or de d. F or t he 
deri vati o n of listi n g fla gs, all calc ulati o ns, a n d prese ntati o n i n t he fi g ures, < x a n d ≤x val ues 
will be set t o  half of x  w hereas > x a n d ≥x val ues will be set t o x.  
8. 6. 3.  P h ar m a c o d y n a mi c St atistic al Met h o d ol o g y   
N o i nfere ntial statistical a nal ys es are pla n ne d.  
8. 7.  S afet y a n d T oler a bilit y Assess me nt s  
8. 7. 1.  A d verse E ve nts   
All A Es  will be c o de d usi n g t he Me dic al Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A ) 
Versi o n 2 4 .0  ( or hi g her if a ne w v ersi o n is iss ue d  d uri n g  t he st u d y; see t h e D M P f or m ore 
details ). 
A treat me nt -e mer ge nt a d verse e v e nt ( T E A E) will be defi ne d as a n A E t hat starts d uri n g or 
after t he first d ose, or starts pri or t o t he first d ose a n d i ncreases i n se verit y after t he first d ose. 
A treat me nt -relate d T E A E will be defi ne d as a  T E A E wit h a relati o ns hi p of  p ossi bl y relate d 
or relate d  t o t he st u d y tr eat me nt, as deter mi ne d b y t he i n vesti gat or. 
F or Gr o u p A 2a i n Part A , t he assi g n me nt of T E A Es t o treat me nts will be as f oll o ws: 
 
  


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 3 3  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
● A T E A E t hat starts or i ncreases i n se v erit y d uri n g or after Peri o d 1, Da y 1 d osi n g a n d 
pri or t o Peri o d 2, Da y 1  d osi n g will be assi g ne d t o ‘ 3 m g K R P -A 2 1 8 ( Faste d Male) ’. 
● A T E A E t hat starts or i ncreases i n se v erit y d uri n g or after Peri o d 2, Da y 1  d osi n g will 
be assi g n e d t o ‘ 3 m g K R P -A 2 1 8 ( Fe d M ale) ’. 
F or Part C, t he assi g n me nt of T E A Es t o treat me nts will be as f oll o ws:  
● A T E A E t hat starts or i ncreases i n se v erit y d uri n g o r after Da y 1 d osi n g a n d pri or t o 
Da y 4  d osi n g will be assi g ne d t o ‘ X X m g K R P -A 2 1 8  Al o ne ’. 
● A T E A E t hat starts or i ncreases i n se v erit y d uri n g or after Da y 4 d osi n g a n d pri or t o 
Da y 1 1  d osi n g will be assi g ne d t o ‘ 2 0 0 m g Itr ac o naz ole Al o ne ’. 
● A T E A E t hat starts or i ncreases i n se v erit y d uri n g or after Da y 11  d osi n g will be 
assi g ne d t o ‘X X m g K R P A 2 1 8 + 2 0 0 m g Itrac o naz ole’ . 
A ll A Es will be liste d . I n a d diti o n t o t he data rec or de d i n t he data base, t he listi n gs will 
i ncl u de deri ve d o ns et ti me a n d d urati o n. O ns et ti me will be calc ulat e d fr o m t he ti me of t he 
last ass ociate d d ose f or T E A Es o nl y. W here t he last ass ociate d d ose is referri n g t o t he last 
d ose recei ve d pri or t o t he start of  a T E A E . 
T he fre q u e nc y of s u bjects wit h T E A Es a n d t he n u m ber of  T E A E s w ill be s u m marise d f or t he 
f oll o wi n g cate g ories:  
● T E A Es ( o verall, seri o us, lea di n g t o disc o nti n uati o n, a nd lea di n g t o deat h) b y treat me nt   
● T E A Es b y s e verit y  a n d tr eat me nt   
● Treat me nt -relate d T E A Es ( o verall, seri o us, lea di n g t o disc o nti n uati o n, a n d lea di n g t o 
deat h) b y treat me nt   
● Treat me nt -relate d T E A Es b y se v erit y a n d treat me nt   
T he fre q u e nc y of s u bjects will be s u m maris e d se paratel y f or T E A E s a n d treat me nt -relate d 
T E A E s b y  t h e f oll o wi n g:  
● S yste m or ga n class , preferre d ter m , a n d treat me n t  
● P referre d ter m a n d treat me nt   
F or t he A E d ata t he f oll o wi n g r ules will a p pl y :  
● F or t he d eri vati o n of treat me nt -e mer ge nt stat us (a p plica ble t o all A Es): If t he start 
date/ti me of a n A E is i nc o m plete or missi n g, a n A E will be ass u me d t o n ot be a T E A E, 
u nless t he i nc o m plete start date/ti me or t he e n d date/ti me i n dicates a n A E starte d aft er 
t he first d ose. 
 
  


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 3 4  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
● F or t he d eri vati o n of  treat me nt-relate d stat us (a p plica ble t o T E A Es o nl y): If t he st u d y 
treat me nt relati o ns hi p f or a T E A E is missi n g, a T E A E will be ass u me d t o n ot be a 
treat me nt-relate d T E A E.  
● F or  t he d eri vati o n of o ns et ti me (a p plica ble t o T E A Es o nl y): If t he start dat e/ti me of a 
T E A E is missi n g, o nset ti me will n ot be calc ulate d. If t he start dat e/ti me of a  T E A E is 
i nc o m plete, w here p ossi ble, t he mi ni m u m p ossi ble o nset ti me will be calc ul ate d a n d 
prese nte d i n ‘ ≥D D: H H: M M’ f or mat  (e g, if t he d ate/ti me of t he last ass oci ate d d ose is 
0 1 M A Y 2 0 1 9/ 0 8: 0 0 a n d rec or de d st art date/ti me of a  T E A E  is 0 3 M A Y 2 0 1 9, t he n t he 
mi ni m u m p ossi ble o nset ti me w ill be calc ulate d b y ass u mi n g a T E A E  start e d at t he first 
h o ur a n d mi n ute of 0 3 M A Y 2 0 1 9 [ 0 3 M A Y 2 0 1 9/ 0 0: 0 0 ], t h us will be prese nte d as o nset 
ti me ≥0 1: 1 6: 0 0 i n t he listi n g).  If t he start dat e of a T E A E is t he sa me as t he date of t he 
last ass ociate d d ose b ut t he start  ti me of a T E A E is missi n g, a n o nset ti me will be 
prese nte d as ‘ ≥0 0: 0 0: 0 1’. A n y cl oc k c h a n ges will be acc o u nte d f or i n t he deri vati o n.  
● F or t he d eri vati o n of d urati o n  (a p plica ble t o all A Es): If t he e n d d ate/ti me of a n A E is 
missi n g, d urati o n will n ot be calc ulate d. If t he start or e n d date/ti me of a n A E is 
i nc o m plete, w here p ossi ble, t he ma xi m u m p ossi ble d urati o n will be cal c ulate d a n d 
pre se nte d i n ‘ ≤D D: H H: M M’ f or mat (e g, if t he start of a n A E  d ate/ti me is 
0 1 M A Y 2 0 1 9/ 0 8: 0 0 a n d its rec or de d e n d date/ti me is 0 3 M A Y 2 0 1 9, t he n t he ma xi m u m 
p ossi ble d urati o n will be calc ulate d b y ass u mi n g a n A E  e n de d at t he l as t h o ur a n d 
mi n ute of 0 3 M A Y 2 0 1 9 [ 0 3 M A Y 2 0 1 9/ 2 3: 5 9 ], t h us will be prese nte d as 
d urati o n  ≤0 2: 1 5: 5 9 i n t he listi n g).  A n y cl oc k c ha n ges will be acc o u nt e d f or i n t he 
deri vati o n.  
● F or t he calc ulati o n of T E A E s u m mar y statistics: If t he se verit y of a T E A E is missi n g, 
t hat T E A E will be c o u nte d u n der t he ‘ missi n g’ cat e g or y. 
● F or t he calc ulati o n of T E A E s u m mar y statistics: If a s u bject e x perie nce d m ulti ple 
T E A Es wit h t he sa me preferre d ter m f or t he sa m e treat me nt, t his will be c o u nte d as 1 
T E A E f or t hat tr eat me nt u n der t he ma xi m u m se verit y rec or de d.  
8. 7. 2.  Cli nic al L a b or at or y P a r a meters   
All cli nical la b orat or y para meters  a n d t heir c h a n ges fr o m baseli ne  will be liste d , as 
a p plica ble; an y val u e o utsi de t he cli nical r efere nce ra n ge will be fla g ge d. S e parat e listi n gs 
wil l be pr o vi de d f or a n y para meter f or w hic h t here is a n y i n di vi d ual s u bject val ue  o utsi de t he 
res pecti ve cli nical refere nce ra n ge.  
S u m mar y ta bles a n d b o x pl ots  b y treat me nt a n d ti me p oi nt f or Parts A a n d B a n d b y ti me p oi nt 
f or Part C will be pr o vi de d f or cli nic al c he mistr y, h ae mat ol o g y, a n d c o a g ulati o n para meters  
a n d t heir c ha n ges fr o m b aseli ne , as a p plica ble. 
Val ues r ec or de d  as < x, ≤x, > x , or ≥x will be dis pla ye d  i n t he listi n gs as rec or de d. F or t he 
deri vati o n of listi n g fla gs, all calc ulati o n s, a n d prese ntati o n i n t he fi g ures , < x a n d ≤x val ues 
will be set t o half of x  w hereas > x a n d ≥x val ues will be set t o x.  
 
  


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 3 5  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
8. 7. 3.  Vit al Si g ns  P ar a meters   
All vital si g ns para met ers  a n d t heir c ha n ges fr o m baseli ne  will be liste d; a n y val u e  o utsi de 
t he cli nical refere nce ra n ge will be fla g ge d. 
S u m mar y ta bles a n d b o x pl ots  b y treat me nt a n d ti me p oi nt f or Parts A a n d B a n d b y ti me p oi nt 
f or Part C will be pr o vi de d f or all vital si g ns p ara meters  a n d t heir c ha n ges fr o m baseli ne . 
8. 7. 4.  1 2 -le a d Electr o c ar di o gr a m  P a r a meters   
All 1 2 -lea d E C G para meters  a n d t heir c h a n ges fr o m basel i ne will be liste d ; a n y v al ue o utsi de 
t he cli nical refere nce ra n ge will be fla g ge d. 
S u m mar y ta bles a n d b o x pl ots  b y treat me nt a n d ti me p oi nt f or Parts A a n d B a n d b y ti me p oi nt 
f or Part C will be pr o vi de d f or all 1 2 -lea d E C G  p ara meters  a n d t heir c ha n ges fr o m baseli ne . 
A n o utlier a nal ysis will be perf or me d f or Q T i nter val c orrecte d f or heart rat e usi n g 
Fri deri cia’s f or m ula ( Q T c F) . T h e a n al ysis will i ncl u de all i n di vi d ual  ori gi n al,  re peat, a n d 
u nsc he d ule d p ost d ose val ues .  
T he ma xi m u m p ost d ose val ues will be s u m maris e d b y treat me nt f or all Parts  acc or di n g t o t he 
f oll o wi n g cate g ories:  
● ≤4 5 0 ms   
● > 4 5 0 a n d ≤4 8 0 ms ( all insta nces fla g ge d i n t he listi n g )  
● > 4 8 0 a n d ≤5 0 0 ms (all i nsta nces fla g ge d i n t he listi n g )  
● > 5 0 0 ms (all i nsta nces fl a g ge d i n t he listi n g )  
T he m a xi m um i ncreases fr o m baseli ne will be s u m maris e d b y tr eat me nt f or all Parts 
acc or di n g t o t he f oll o wi n g cate g ories:   
● ≤3 0 ms   
● > 3 0 a n d ≤6 0 ms (all i nsta nces fla g ge d i n t he listi n g )  
● > 6 0 ms (all i nsta nces fla g ge d i n t he listi n g )  
8. 7. 5.  Brist ol St o ol C h art  a n d F a ec al Occ ult Bl o o d Test   
All Brist ol st o ol c hart a n d faecal occ ult bl o o d test  data  will be liste d.  
S u m mar y ta bles b y tr eat me nt f or Parts A a n d B a n d b y o verall  f or Part C will be pr o vi de d f or 
all Brist ol st o ol c hart a n d faecal occ ult bl o o d test data . A d diti o nall y, s u m m ar y ta bles b y 
treat me nt a n d ti me p oi nt f or Parts A a n d B a n d b y ti me p oi nt f or Part C will be pr o vi de d f or all 
Brist ol st o ol c hart scal e a n d faecal occ ult bl o o d test data . 
 
  


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 3 6  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
8. 7. 6.  Ot her Assess me nts   
Me dical hist or y will n ot be liste d.  
All ot her safet y a n d t ol era bilit y assess me nts n ot d etaile d i n t he a b o ve s ecti o ns will be liste d 
o nl y.   
8. 7. 7.  S afet y a n d T oler a bilit y St atistic al Met h o d ol o g y   
N o i nfere ntial statistical a nal ys es are pla n ne d.  
9.  IN T E RI M A N A L Y S E S   
N o i nteri m a nal yses are pla n ne d.  
1 0.  SI G NI FI C A N T C H A N G E S F R O M  T H E P R O T O C O L -S P E CI FI E D A N A L Y S E S   
T here w ere n o si g nifica nt c ha n ges fr o m t he pr ot oc ol -s pecifie d a n al yses.  
1 1.  R E F E R E N C E S   
1.  I C H. I C H Har m o nise d Tri partite G ui deli ne: Str uct ure a n d c o nt e nt of cli nical st u d y re p orts 
( E 3). 3 0 N o ve m b er  1 9 9 5.  
2.  I C H. I C H Har m o nise d Tri partite G ui deli ne: Ge neral c o nsi derati o ns f or cli nical trials ( E 8). 
1 7 J ul y 1 9 9 7.  
3.  I C H. I C H Har m o nise d Tri partite G ui deli ne: Statistical pri nci ples f or cli nical trials ( E 9). 
5  Fe br uar y  1 9 9 8 .  
4.  G o u g h K, H utc hi ns o n M, Kee ne O, et al. Assess me nt of d ose pr o p o rti o nalit y: re p ort fr o m 
t he statisticia ns i n t he p har mace utical i n d ustr y/ P h ar mac o ki netics U K J oi nt W or ki n g Part y. 
Dr u g I nf J . 1 9 9 5; 2 9( 3): 1 0 3 9-1 0 4 8.  
5.  Kee ne O N. T he l o g tr a nsf or mati o n is s pecial. St at Me d . 1 9 9 5; 1 4( 8): 8 1 1-8 1 9.  
6.  S ne dec or G W, C oc hra n W G. St atisti c al Met h o ds . 8t h e d. A mes, I A: I o wa State U ni versit y 
Press, 1 9 8 9.  
7.  Br o w n H, Presc ott R. A p plie d Mixe d M o dels i n Me dici ne . C hic hester: J o h n Wile y & S o ns, 
1 9 9 9.  
 
  


S A P  
C O N FI D E N TI A L  
La b c or p Dr u g De v el o p me nt St u d y: 8 4 1 1 6 0 1  
Pr ot oc ol Refere n ce: K R P A 2 1 8 -T 1 0 1  
Fi nal Versi o n 1 .0 , 2 5 A P R 2 0 2 2  
Pa ge 3 7  of 3 7  
 
 
S T -A D -0 3 1 Versi o n 0 2  
1 2.  A P P E N DI C E S  
A p pe n di x 1 : 
D oc u me nt Hist or y  
St at us a n d  Versi o n  
D ate of C h a n ge  
S u m m ar y/ Re as o n f or C h a n ges  
Fi nal Versi o n 1 . 0 
N A  
N A ; t he first versi o n. 
N A = n ot a p plica ble