Pharmacokinetics of Intravaginal, Self-administered Artesunate Vaginal Pessaries Among Women in Kenya
Phase: PHASE1
Conditions: Cervix Cancer, Cervix Intraepithelial Neoplasia Grade 3, Cervix; Intraepithelial Neoplasia, Grade I, Cervix; Intraepithelial Neoplasia, Grade II
Sponsor: UNC Lineberger Comprehensive Cancer Center

I G HI D 1 2 3 3 3: P h ase I st u d y o n t he P h ar m ac o ki netics of i ntr a v a gi n al, self -
a d mi nistere d Artes u n ate v a gi n al pess aries a m o n g w o me n i n Ke n y a .   
Pri nci p al I n vesti g at or  
C he mtai M u n g o, M D, M P H 
     U ni versit y of N ort h Car oli na C ha pel Hill Sc h o ol of Me dici ne  
     A d dress: 3 0 0 9 Ol d Cli nic B uil di n g, Ca m p us B o x 7 5 7 0, C ha pel Hill, N C 2 7 5 9 9  
     C o u ntr y: U nite d States  
9 1 9 -9 6 6 -6 0 4 9 ( P H O N E)
9 1 9 -9 6 6 -6 0 4 9 ( F A X)
E mail: C he mtai _ m u n g o @ me d. u nc.e d u
Pri nci p al C o -I n vesti g at or  
Jac kt o n O m ot o, M B C h B, M Me d  
       Mase n o U ni versit y Sc h o ol of Me dici ne 
       P. O. B o x 3 4 0 8, Kis u m u, Ke n ya  
       E mail: j o m ot o @ mase n o.ac. ke  
C o -I n vesti g at ors  
Willia m Za m b o ni, P har m. D, P h. D, U ni versit y of N ort h Car oli na C ha pel Hill Sc h o ol of 
P har mac y  
Cirill us O g olla h, B Sc, Di p C M,  Ke n ya Me dical Researc h I nstit ute  
F u n di n g S p o ns or :  U ni versit y of N ort h Car oli na-C ha pel Hill, De part me nt of O bstetrics 
a n d G y nec ol o g y  
Versi o n D ate: N o ve m ber 1 4 t h, 2 0 2 3 
Versi o n N u m ber: 1. 0  

 
 
I G HI D 1 2 3 3 3: P h ase I st u d y o n t he P h ar m ac o ki netics of i ntr a v a gi n al, self -
a d mi nistere d Artes u n ate v a gi n al pess aries a m o n g w o me n i n Ke n y a .   
    
 
 
 
Pri nci p al I n vesti g at or  
C he mtai M u n g o, M D, M P H  
3 0 0 9 Ol d Cli nic B uil di n g, Ca m p us B o x 7 5 7 0, C ha pel Hill, N C 2 7 5 9 9  
9 1 9 -9 6 6 -6 0 4 9 ( P H O N E)  
9 1 9 -9 6 6 -6 0 4 9 ( F A X)  
E mail: C he mtai _ m u n g o @ me d. u nc.e d u  
 
 
 
Si g n at ure P a ge  
 
T he si g nat ure bel o w c o nstit utes t he a p pr o val of t his pr ot oc ol a n d t he attac h me nts a n d 
pr o vi des t he necessar y ass ura nces t hat t his trial will be c o n d ucte d acc or di n g t o all 
sti p ulati o ns of t he pr ot oc ol, i ncl u di n g all state me nts re gar di n g c o nfi de ntialit y, a n d 
acc or di n g t o l ocal le gal a n d re g ulat or y re q uire me nts a n d a p plica ble U. S. fe deral 
re g ulati o ns a n d I C H g ui deli nes. 
 
Pri nci pal I n vesti gat or ( PI) Na me: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
PI Si g n at ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
D ate: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 
 
Versi o n D ate: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

 
 
C O N FI D E N TI A L  
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4. 2 St u d y Acti vities b y Visit  
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4. 3 A d verse E ve nt Re p orti n g  
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C O N FI D E N TI A L  
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I. 
List of A b bre vi ati o ns  
4 7  
A E              A d verse E ve nts  
4 8  
A PI             Acti ve P har mace utical I n gre die nt  
4 9  
A U C           Area u n der t he c ur ve  
5 0  
A S              Artes u nate  
5 1  
CI N 2/ 3        Cer vical I ntrae pit helial Ne o plasia gra de 2 a n d 3  
5 2  
C P O            Cli nical Pr ot oc ol Office  
5 3  
D S M C         Data a n d Safet y a n d M o nit ori n g C o m mittee  
5 4  
D H A            Di h y dr oarte misi ni n  
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E S R C           Et hics & Scie ntific Re vie w C o m mittee  
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G C P            G o o d Cli nical Practice  
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HI V             H u ma n I m m u n o deficie nc y Vir us  
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H P V            H u ma n pa pill o ma vir us  
5 9  
I R B             I nstit uti o nal Re vie w B oar d  
6 0  
K E M RI       Ke n ya Me dical Researc h I nstit ute  
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L C C C         Li ne ber ger C o m pre he nsi ve Ca ncer Ce nter  
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L E E P          L o o p Electr os ur gical E xcisi o n Pr oce d ure  
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L MI C         L o w - a n d mi d dle-I nc o me c o u ntries  
6 4  
N CI -C T C A E  Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts  
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PI               Pri nci pal I n vesti gat or  
6 6  
P K             P har mac o ki netics  
6 7  
P P B           P har mac y a n d P ois o ns B oar d  
6 8  
N A C O S TI Nati o nal C o m missi o n f or Scie nce, Tec h n ol o g y & I n n o vati o n  
6 9  
S TI            Se x uall y Tra ns mitte d I nfecti o ns  
7 0  
S O P           Sta n dar d O perati n g Pr oce d ure  
7 1  
W H O         W orl d Healt h Or ga nizati o n  
7 2  
W L W H      W o me n Li vi n g wit h HI V  
7 3  
U N C           U ni versit y of N ort h Car oli na  
7 4  
 
7 5  
II. 
St u d y A bstr act/ S y n o psis  
7 6  
 
7 7  
B ac k gr o u n d:  W hile pre ve nta ble, cer vical ca ncer is t he sec o n d m ost c o m m o n ca ncer a m o n g 
7 8  
w o me n gl o ball y, acc o u nti n g f or a p pr o xi matel y 6 0 0, 0 0 0 ne w cases a n d 3 0 0, 0 0 0 deat hs per year. 
7 9  
D ue t o lac k of access t o pri mar y a n d sec o n dar y pre ve nti o n, w o me n li vi n g i n l o w -a n d mi d dle -
8 0  
i nc o me c o u ntries bear a dis pr o p orti o nate b ur de n of cer vical ca ncer, acc o u nti n g f or 9 0 % of ne w 
8 1  
cases a n d 8 5 % of deat hs gl o ball y. Cer vical ca ncer ca n be pre ve nte d t hr o u g h vacci nati o n a gai nst 
8 2  
H u ma n pa pill o ma vir us ( H P V), w h ose i nfecti o n is re q uire d t o de vel o p cer vical ca ncer. A m o n g 
8 3  
u n vacci nate d 
w o me n, scree ni n g f or 
H P V or cer vical preca ncer all o ws i de ntificati o n of 
8 4  
preca ncer o us lesi o ns –  pri maril y cer vical i ntrae pit helial ne o plasia gra de 2 or 3 ( CI N 2/ 3), t hat ca n 
8 5  
be treate d a n d c ure d, t o pre ve nt pr o gressi o n t o ca ncer. M ost CI N 2/ 3 lesi o ns t hat are left u ntreate d 
8 6  
will pr o gress t o i n vasi ve cer vical ca ncer. C urre nt treat me nts f or CI N 2/ 3 i n b ot h hi g h - a n d l o w -
8 7  
res o urce c o u ntries ( L MI Cs) re q uire trai ne d healt h care pr o vi ders, w h o are ofte n o ut of reac h f or 
8 8  
ma n y w o me n, partic ularl y i n r ural areas i n L MI Cs. Lac k of access t o preca ncer treat me nt f oll o wi n g 
8 9  
scree ni n g i n L MI Cs i n part acc o u nts f or t he hi g h b ur de n of i nci de nt cer vical ca ncer. Precli nical 
9 0  
data ha ve de m o nstrate d pr o -a p o pt otic effects of Artes u nate ( A S), a c o m m o nl y a vaila ble dr u g wit h 
9 1  
a n e xcelle nt safet y pr ofile i n oral, rectal a n d i ntra ve n o us r o utes pri maril y use d t o treat malaria i n 
9 2  

 
 
C O N FI D E N TI A L  
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U NI V E R SI T Y O F N O R T H C A R O LI N A  
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L MI Cs. T his le d t o a rece nt P hase I st u d y i n t he U nite d States t hat de m o nstrate d t hat self -
9 3  
a d mi nistere d va gi nal artes u nate i nserts ( pessaries) are safe, well -t olerate d, a n d de m o nstrate 
9 4  
efficac y f or treat me nt of CI N 2/ 3. Base d o n t he mec ha nis m of acti o n, t he cli nical safet y pr ofile, 
9 5  
a n d wi des prea d a vaila bilit y as a ge neric dr u g o n t he W orl d Healt h Or ga nizati o n ( W H O) List of 
9 6  
Esse ntial Me dicati o ns, va gi nal artes u nate i nserts ( pessaries), if bac ke d b y data fr o m ra n d o mize d 
9 7  
trials, ma y offer patie nt-c o ntr olle d a n d access cer vical preca ncer treat me nt met h o d f or w o me n i n 
9 8  
L MI Cs w h o face t he greatest b ur de n of cer vical ca ncer a n d ha ve diffic ult y accessi n g s kille d 
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pr o vi ders f or preca ncer treat me nt. H o we ver, gi ve n t hat artes u nate is a well -k n o w n dr u g use d i n 
1 0 0  
malaria treat me nt, it is critical t o e ns ure t hat va gi nal a p plicati o n of t he dr u g will n ot pr o m ote 
1 0 1  
resista nce f or use i n malaria treat me nt. O bjecti ves:  T he pr o p ose d st u d y see ks t o i n vesti gate t he 
1 0 2  
p har mac o ki netics of Artes u nate ( A S) a n d di h y dr oarte misi ni n ( D H A), t he acti ve meta b olite of 
1 0 3  
artes u nate, f oll o wi n g i ntra va gi nal use at t he d osi n g a n d fre q ue nc y bei n g st u die d f or cer vical 
1 0 4  
preca ncer treat me nt. A sec o n dar y o bjecti ve is t o i n vesti gate safet y a m o n g st u d y partici pa nts. 
1 0 5  
Met h o ds:  As a rece nt st u d y de m o nstrate d safet y a n d t olera bilit y of i ntra va gi nal artes u nate a m o n g 
1 0 6  
w o me n wit h CI N 2/ 3 a n d t he safet y of artes u nate is well d oc u me nte d i n n u mer o us malaria st u dies, 
1 0 7  
t he pr o p ose d st u d y will be c o n d ucte d i n fe male v ol u nteers re gar dless of t heir H P V or cer vical 
1 0 8  
preca ncer disease stat us. I n t his a si n gle ar m st u d y, bl o o d le vels of D H A a n d artes u nate f oll o wi n g 
1 0 9  
5 dail y a p plicati o ns of va gi nal artes u nate i nserts ( pessaries) will be meas ure d. A sa m ple size of 
1 1 0  
t wel ve partici pa nts ( N = 1 2) are nee de d. U p t o 1 6 will be c o nse nte d t o acc o u nt f or dr o p offs. Eli gi ble 
1 1 1  
partici pa nts will self -a d mi nister artes u nate va gi nal i nserts ( pessaries) dail y i n t he st u d y cli nic f or 
1 1 2  
5 da ys.  Partici pa nts will u n der g o bl o o d a dra w pri or t o recei vi n g t he first d ose of artes u nate, a n d 
1 1 3  
o n da y 5 bef ore i nserti n g t he va gi nal i nsert, a n d at 1 5 mi n, 3 0 mi ns, 1, 2, 4,  6, a n d 8 h o urs after. 
1 1 4  
I n eac h patie nt, p har mac o ki netic para meters of artes u nate a n d D H A will be calc ulate d via 
1 1 5  
q ua ntitati ve a nal ysis of wit h deter mi nati o n of ma xi m u m c o nce ntrati o n ( C ma x), ti me t o C ma x 
1 1 6  
( T ma x), area u n der t he plas ma c o nce ntrati o n vers us ti me c ur ve ( A U C), a p pare nt cleara nce, a n d 
1 1 7  
eli mi nati o n half -life (t 1/ 2). B u d get:  T he esti mate d st u d y b u d get is U S $ 7 0, 0 0 0.  
1 1 8  
 
1 1 9  
III. 
Pr ot oc ol S u m m ar y  
1 2 0  
 
1 2 1  
Pr ot oc ol 
Title  
 
P har mac o ki netics of i ntra va gi nal, self -a d mi nistere d Artes u nate va gi nal 
pessaries a m o n g w o me n i n Ke n ya .   
 
 
St u d y 
Desi g n  
 
Si n gle ar m st u d y of 1 2 partici pa nts w h o will use self -a d mi nistere d 
artes u nate va gi nal i nserts ( pessaries) o n 5 c o nsec uti ve da ys wit h bl o o d 
dra ws perf or me d at baseli ne a n d o n da y 5 f or p har mac o ki netic st u dies.  
 
St u d y 
P o p ulati o n  
 
W o me n a ges 1 8 or ol der meeti n g i ncl usi o n criteria.  
N u m ber of 
partici pa nts  
 
A sa m ple size of 1 2 is nee de d. U p t o 1 6 partici pa nts will be c o nse nte d, 
if necessar y, t o acc o u nt f or dr o p offs.  
N u m ber of 
sites  
2  

 
 
C O N FI D E N TI A L  
PI: M u n g o  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n 1. 0  
 
A pril 2 5, 2 0 2 3  
 
5  
 
 
P hase of 
st u d y (i.e., 
Pil ot, P hase 
1, etc.)  
P hase I  
Cli nical 
Sa m ples  
 
Bl o o d dra w at Da y 1 ( Visit 1), a n d o n Da y 5 ( Visit 5) at 0, 1 5 mi ns, 3 0 
mi n, 1 h, 2 h, 4 h, 6 h a n d 8 h after self -a d mi nistrati o n of 2 0 0 m g 
i ntra va gi nal artes u nate pessar y.  
St u d y 
D urati o n  
3 m o nt hs  
 
Partici pa nt 
D urati o n  
2 wee ks  
 
Re gi me n or 
I nter ve nti o n 
2 0 0 m g Artes u nate va gi nal i nsert ( pessar y) use d dail y f or 5 c o nsec uti ve 
da ys  
 
1 2 2  
I V. 
L a y S u m m ar y  
1 2 3  
 
1 2 4  
Cer vical ca ncer, a disease of t he cer vi x –  t he e ntra nce of t he w o m b is t he sec o n d c o m m o n ca use 
1 2 5  
of ca ncer i n w o me n ar o u n d t he w orl d. W o me n i n l o w - a n d mi d dle -i nc o me c o u ntries li ke Ke n ya 
1 2 6  
face t he hi g hest b ur de n of cer vical ca ncer. Cer vical ca ncer is ca use d b y h u ma n pa pill o ma vir us 
1 2 7  
( H P V) i nfecti o n. It ca n be pre ve nte d t hr o u g h vacci nati o n a gai nst t he H P V vir us, a n d scree ni n g t o 
1 2 8  
fi n d earl y c ha n ges i n t he cer vi x, calle d preca ncer o us c ha n ges –  scie ntificall y calle d cer vical 
1 2 9  
i ntrae pit helial ne o plasia, w hic h ca n be treate d b y a me dical pr o vi der t o pre ve nt it fr o m 
1 3 0  
pr o gressi n g t o ca ncer. T he H P V vacci nes are ne w i n Ke n ya a n d ot her l o w -i nc o me c o u ntries, a n d 
1 3 1  
m ost w o me n o ver 2 0 years of a ge ha ve ne ver bee n vacci nate d. Scree ni n g f or cer vical ca ncer a n d 
1 3 2  
treati n g preca ncer o us lesi o ns will pre ve nt milli o ns of u n vacci nate d w o me n fr o m getti n g 
1 3 3  
dia g n ose d wit h cer vical ca ncer. C urre nt treat me nts f or cer vical preca ncer rel y o n a healt hcare 
1 3 4  
pr o vi der t o perf or m t he m. I n c o u ntries li ke Ke n ya a n d ot her L MI Cs w here t here are fe w n urses 
1 3 5  
a n d d oct ors, ma n y w o me n f o u n d wit h preca ncer are ofte n referre d t o far facilities t o access 
1 3 6  
treat me nt. D ue t o c osts a n d ot her c halle n ges, ma n y w o me n are u na ble t o access referral ce nters 
1 3 7  
wit h pr o vi ders w h o ca n treat cer vical preca ncer. Scie ntists are st u d yi n g w het her w o me n wit h 
1 3 8  
cer vical preca ncer ca n use self -a d mi nistere d treat me nts wit h me dicati o ns li ke a crea m or pessar y, 
1 3 9  
t o treat preca ncer, i nstea d of rel yi n g o n a healt h care pr o vi der t o perf or m t he treat me nt. O ne self-
1 4 0  
a d mi nistere d treat me nt bei n g st u die d is a pessar y f or m ulati o n of t he me dicati o n Artes u nate, 
1 4 1  
w hic h is use d t o treat malaria i n Africa a n d ot her places. A st u d y i n t he U nite d States has s h o w n 
1 4 2  
t hat Artes u nate pessaries ( va gi nal i nserts) are safe t o use f or preca ncer treat me nt, a n d ~ 7 0 % 
1 4 3  
w o me n w h o use d t he m were c ure d. Bef ore Artes u nate ca n be c o nsi dere d as a preca ncer 
1 4 4  
treat me nt i n Ke n ya a n d places li ke it, scie ntists nee d t o u n dersta n d w het her usi n g Artes u nate as 
1 4 5  
a n i ntra va gi nal pessar y ca n affect h o w it w or ks t o treat malaria –  w het her usi n g it i ntra va gi nall y 
1 4 6  
ca n re d uce its effect as a malaria treat me nt ( de vel o pi n g resista nce). T his st u d y is bei n g d o ne t o 
1 4 7  
i n vesti gate t he bl o o d le vels of Artes u nate w he n w o me n use artes u nate pessaries i n t he d osi n g 
1 4 8  
bei n g st u die d f or cer vical preca ncer. I n ot her w or ds, scie ntists are as ki n g w het her if a w o ma n 
1 4 9  
uses 2 0 0 m g of artes u nate pessar y dail y f or fi ve da ys, t he me dicati o n ca n be f o u n d i n t he bl o o d 
1 5 0  
w hic h c o ul d res ult i n t he me dicati o n bei n g resista nt t o treati n g malaria. T his is u nli kel y as t he 
1 5 1  
d osa ge use d i n t he i ntra va gi nal pessar y is m uc h l o wer t ha n t he d osa ge use d t o treat malaria, a n d 
1 5 2  
a bs or pti o n of dr u gs i n t he va gi na is m uc h l o wer t ha n w he n ta ke n b y m o ut h or use d rectal –  
1 5 3  

 
 
C O N FI D E N TI A L  
PI: M u n g o  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n 1. 0  
 
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w hic h is a n ot her wa y malaria dr u gs are gi ve n t o c hil dre n. T o hel p a ns wer t his q uesti o n of 
1 5 4  
w het her usi n g l o w d ose Artes u nate pessaries f or treati n g cer vical preca ncer ca n ca use resista nce 
1 5 5  
f or malaria treat me nt, u p t o 1 6 fe male partici pa nts will be e nr olle d i n t his st u d y. St u d y 
1 5 6  
partici pa nts will use artes u nate pessaries o nce dail y f or 5 da ys i n t he st u d y cli nic, a n d ha ve bl o o d 
1 5 7  
dra w n o nce o n da y 1 ( pri or t o first pessar y use), a n d si x ti mes o n da y 5 (last da y of pessar y use) 
1 5 8  
t o meas ure t he artes u nate dr u g le vels i n t he bl o o d. O n da y 5, partici pa nts will ha ve a ca n n ula 
1 5 9  
place d a n d bl o o d dra w n fr o m t he ca n n ula. T he v ol u me of bl o o d dra w n eac h ti me will be 
1 6 0  
a p pr o xi matel y 3 ml, less t ha n a teas p o o n. I n c o m paris o n, w he n a pers o n d o nates bl o o d, 
1 6 1  
a p pr o xi matel y 5 0 0 ml of bl o o d is dra w n. T he g oal of t his st u d y is t o c o nfir m t hat artes u nate 
1 6 2  
pessaries ca n be use d i ntra va gi nall y f or treat me nt of cer vical preca ncer wit h o ut creati n g 
1 6 3  
resista nce of t he dr u g f or treati n g malaria t o e na ble st u dies o n its use f or preca ncer treat me nt.  
1 6 4  
1. 0  
B A C K G R O U N D A N D R A TI O N A L E  
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1 6 6  
1. 1  
B ac k gr o u n d  
1 6 7  
Alt h o u g h cer vical ca ncer, defi ne d as ca ncer occ urri n g i n cells of t he cer vi x is pre ve nta ble, l o w - 
1 6 8  
a n d mi d dle -i nc o me c o u ntries ( L MI Cs) bear a dis pr o p orti o nate b ur de n, acc o u nti n g f or 8 5 % of a n 
1 6 9  
esti mate d 5 7 0, 0 0 0 i nci de nt cases, a n d 9 0 % of deat hs a n n uall y. 1 I n Ke n ya, cer vical ca ncer acc o u nts 
1 7 0  
f or 5, 2 4 0 ( 1 2. 9 %) of ne w ca ncer cases a n n uall y a n d 3, 2 8 6 ( 1 1. 4 %) of all ca ncer deat hs a n n uall y. 2 
1 7 1  
Cer vical ca ncer is ca use d b y i nfecti o n wit h h u ma n pa pill o ma vir us ( H P V), a n d pri mar y pre ve nti o n 
1 7 2  
is ac hie ve d t hr o u g h vacci nati o n a gai nst t he H P V vir us. Sec o n dar y pre ve nti o n of cer vical ca ncer is 
1 7 3  
ac hie ve d b y re g ular scree ni n g d uri n g w hic h ti me t he cer vical preca ncer lesi o n –  cer vical 
1 7 4  
i ntrae pit helial ne o plasia –  ca n be detecte d a n d treate d t o pre ve nt pr o gressi o n t o cer vical ca ncer. 
1 7 5  
B ot h cer vical preca ncer a n d ca ncer dia g n oses are esta blis he d o n pat h ol o g y e val uati o n of cells fr o m 
1 7 6  
t he cer vi x o btai ne d t hr o u g h a bi o ps y. T he sta n dar d of care i n Ke n ya a n d ot her L MI Cs f or treat me nt 
1 7 7  
of cer vical preca ncer, rec o m me n de d b y t he 
W H O, is a blati o n usi n g cr y ot hera p y or t her mal 
1 7 8  
a blati o n, or e xcisi o n –  usi n g t he l o o p electr os ur gical e xcisi o n pr oce d ure ( L E E P) or c ol d k nife 
1 7 9  
c o ne. 7 C urre nt cer vical preca ncer treat me nt met h o ds rel y o n access t o a trai ne d healt hcare pr o vi der 
1 8 0  
a n d access t o a blati ve or e xcisi o nal e q ui p me nt, b ot h of w hic h ca n be c halle n gi n g t o access i n 
1 8 1  
c o u ntries wit h hi g h patie nt t o pr o vi der rati os a n d wea ker healt h s yste ms. T his ca uses dela ys i n 
1 8 2  
treat me nt access i n setti n gs w here w o me n ha ve t o tra vel far t o reac h a trai ne d healt hcare w or ker, 
1 8 3  
lea di n g t o misse d o p p ort u nities f or ca ncer pre ve nti o n, res ulti n g t o pr o gressi o n t o ca ncer. I n a st u d y 
1 8 4  
fr o m wester n Ke n ya, w he n w o me n w h o scree ne d p ositi ve f or cer vical preca ncer i n peri p heral 
1 8 5  
cli nics were referre d t o a ce ntral/referral cli nic f or treat me nt, 3 9 % were n ot a ble t o ma ke t heir 
1 8 6  
referral a p p oi nt me nt. 
A d diti o nall y, e xcisi o nal treat me nts are ass ociate d 
wit h o bstetric 
1 8 7  
c o nse q ue nces i ncl u di n g preter m birt h. T o miti gate c halle n ges relate d t o access t o pr o vi der -
1 8 8  
a d mi nistere d cer vical preca ncer treat me nt i n l o w -res o urce c o u ntries, scie ntists are i n vesti gati n g 
1 8 9  
use of n o n -e xcisi o nal treat me nts i ncl u di n g t o pical, self -a d mi nistere d t hera pies wit h c yt ot o xic 
1 9 0  
pr o perties f or treat me nt of cer vical preca ncer. Rece nt e vi de nce, pri mar y fr o m st u dies i n hi g h -
1 9 1  
i nc o me c o u ntries ( HI Cs), de m o nstrate t hat t o pical t hera pies –  w hic h ca n b ot h be self - or pr o vi der -
1 9 2  
a d mi nistere d - ma y be utilize d as treat me nt of H P V -ass ociate d a n o ge nital lesi o ns i ncl u di n g 
1 9 3  
cer vical preca ncer. 2 – 6  
1 9 4  
 
1 9 5  
1. 2  
I ntr a v a gi n al Artes u n ate f or Cer vic al Prec a ncer Tre at me nt 
1 9 6  
 
1 9 7  
A p ote ntial t o pical t hera p y f or w hic h earl y st u dies are a vaila ble is Artes u nate ( A S), a W H O -
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a p pr o ve d dr u g wi del y use d t o treat malaria i n L MI Cs. 7 Artes u nate is a deri vati ve of arte misi ni n 
1 9 9  
t he acti ve c o m p o ne nt of Arte misia a n n ua a pla nt use d i n C hi nese tra diti o nal me dici ne f or 
2 0 0  
ce nt uries. It is a well -k n o w n dr u g use d i n malaria treat me nt a n d its safet y a n d t olera bilit y has 
2 0 1  
l o n g bee n well esta blis he d.8 – 1 0 Gr o wi n g e vi de nce has de m o nstrate d t hat Artes u nate has c yt ot o xic 
2 0 2  
effects a gai nst n u mer o us ca ncer cell li nes b ot h i n vitr o a n d i n viv o.1 1, 1 2 Pr o p ose d mec ha nis ms of 
2 0 3  
acti o n i ncl u de s u p pressi n g cell pr oliferati o n b y i n d uci n g G 1 a n d G 2/ M p hase cell c ycle arrest i n 
2 0 4  
t he h u ma n breast, nas o p har y n geal a n d re nal cell ca ncer, as well as m o d ulati n g ke y i nfla m mat or y 
2 0 5  
pat h wa ys c haracteristic of u nc o ntr olle d pr oliferati o n a n d carci n o ge nesis. 1 3, 1 4 Ferr o pt osis –  a t y pe 
2 0 6  
of ir o n -de pe n de nt cell deat h –  is t h o u g ht t o be a ke y a ntica ncer mec ha nis m rele va nt t o H P V-
2 0 7  
i nfecte d cells.1 5 Ca ncer cells are hi g hl y pr oliferati ve, re q uiri n g a hea v y ir o n l oa d w hic h acts as a 
2 0 8  
c ofact or i n s y nt hesizi n g de o x yri b oses bef ore cell di visi o n. 1 6 De vel o p me nt of b ot h hi g h -gra de 
2 0 9  
cer vical i ntrae pit helial ne o plasia ( CI N 2/ 3), t he prec urs or lesi o n of cer vical ca ncer, a n d cer vical 
2 1 0  
ca ncer are ass ociate d wit h t he e x pressi o n of t w o viral pr otei ns i n t he H P V lifec ycle, E 6 a n d E 7. 1 7 
2 1 1  
E pit helial cells t hat e x press eit her or b ot h of t hese o nc o pr otei ns als o o vere x press t he tra nsferri n 
2 1 2  
rece pt or, a n d ha ve bee n s h o w n t o ha ve i ncrease d le vels of i ntracell ular ir o n c o m pare d wit h 
2 1 3  
n or mal cells. 1 5 
2 1 4  
T his o bser vati o n has bee n e x pl oite d t o i n vesti gate w het her prei n vasi ve cer vical ca ncer ( CI N 2/ 3), 
2 1 5  
ca n be treate d wit h Artes u nate, w hic h c o ntai ns a n e n d o per o xi de bri d ge t hat reacts wit h 
2 1 6  
i ntracell ular ferr o us ir o n t o ge nerate free ra dicals, ca pa ble of i n d uci n g direct o xi dati ve da ma ge 
2 1 7  
res ulti n g i n cell deat h.1 4 Gi ve n t he mec ha nis m of acti o n, artes u nate ma y pr o vi de be neficial a n d 
2 1 8  
t hera pe utic effects f or i ntrae pit helial H P V disease. Gi ve n t he u n met nee d f or n o n-s ur gical 
2 1 9  
treat me nt f or cer vical i ntrae pit helial ne o plasia (cer vical preca ncer), a n d Artes u nate’s de m o nstrate d 
2 2 0  
fa v ora ble safet y pr ofile f or deca des i n b ot h c hil dre n a n d a d ults wit h malaria, a rece nt st u d y 
2 2 1  
( Tri m ble et al ( 2 0 2 0),1 8 disc usse d bel o w) has i n vesti gate d its use as a n o ns ur gical, self -
2 2 2  
a d mi nistere d i ntra va gi nal treat me nt (as a va gi nal i nsert/ pessar y) f or H P V -ass ociate d disease.  
2 2 3  
 
2 2 4  
1. 2. 1  Precli nic al St u dies  
2 2 5  
 
2 2 6  
1. 2. 1. 1  Mec h a nis m of acti o n  
2 2 7  
Se veral st u dies de m o nstrate t he pr o -a p o pt otic effects of Artes u nate b y acti vati n g t he mit oc h o n dria -
2 2 8  
de pe n de nt pat h wa y, s pecificall y acti vati n g cas pase -3/ 9 a n d t he release of c yt oc hr o me c fr o m t he 
2 2 9  
mit oc h o n dria. 1 9 Artes u nate ca n als o i n d uce a ut o p ha g y i n uteri ne c or p us e n d o metrial carci n o ma 
2 3 0  
cells a n d b y u pre g ulati n g reacti ve o x y ge n s pecies i n h u ma n bla d der ca ncer cells a n d he pat ocell ular 
2 3 1  
carci n o ma cells. 2 0, 2 1, 2 2 A d diti o nall y, Artes u nate has de m o nstrate d a nti -a n gi o ge nic pr o perties 
2 3 2  
t hr o u g h d o w nre g ulati o n of V E G F a n d a n gi o p oieti n-1 i n m yel o ma cells. 2 3 – 2 5 F urt her, Artes u nate is 
2 3 3  
re p orte d t o ha ve de m o nstrate d a nti-ca ncer effects s uc h as f or mati o n of al kali ne ra dicals via a n 
2 3 4  
e n d o per o xi de bri d ge t hat reacts wit h i ntracell ular ferr o us ir o n lea di n g t o cell deat h. 2 6  
2 3 5  
Beca use cer vical s q ua m o us cell ca ncers a n d t heir prec urs ors, cer vical i ntrae pit helial ne o plasia 
2 3 6  
( CI N), o vere x press t he tra nsferri n rece pt or,2 7 t hese o bser vati o ns pr o m pte d a st u d y of t he c yt ot o xic 
2 3 7  
effect of di h y dr oarte misi ni n ( D H A), t he bi oacti ve f or m of Artes u nate, o n pa pill o ma vir us -
2 3 8  
e x pressi n g e pit helial cells. 2 8 I n vitr o st u dies de m o nstrate d t hat, w hile D H A ha d little effect o n 
2 3 9  
n or mal cer vical e pit helial cells, it ha d a si g nifica nt c yt ot o xic effect o n H P V -i m m ortalize d cer vical 
2 4 0  
cells. 2 8 F or m ulate d as a l ocal treat me nt ( 2. 2 2 m g D H A diss ol ve d i n 1 0 0 µl di met h yl s ulf o xi de) i n 
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a n oral m uc osal ca ni ne  n o ncli nical m o del w hic h has 1 0 0 % k n o w n t u m or gr o wt h rate wit h H P V -
2 4 2  
i nfecti o n, D H A has bee n re p orte d t o i n hi bit pa pill o ma vir us-i n d uce d t u m or f or mati o n.  I n a d diti o n, 
2 4 3  
t u m or-ne gati ve d o gs de vel o pe d a nti b o dies a gai nst t he H P V L 1 ca psi d pr otei n. 2 8  
2 4 4  
 
2 4 5  
1. 2. 2  Cli nic al St u dies  
2 4 6  
 
2 4 7  
1. 2. 2. 1  S afet y a n d T o xicit y f or I ntr a v a gi n al Use  
2 4 8  
I ntra va gi nal artes u nate i nserts ( pessaries) has bee n teste d i n a m ulti-ce nter d ose -escalati o n p hase 
2 4 9  
I st u d y t o assess t he safet y, t olera bilit y, a n d efficac y of va gi nal artes u nate i n w o me n wit h CI N 2/ 3 
2 5 0  
i n t he U nite d States ( Tri m ble et al,( 2 0 2 0).1 8 I n t his ‘first-i n-h u ma n’ st u d y of i ntra va gi nal 
2 5 1  
Artes u nate f or CI N 2/ 3 treat me nt, treat me nt was safe, well t olerate d, a n d re p orte d a d verse e ve nts 
2 5 2  
( A Es) were all gra de I or II a n d self-li mite d. Re p orte d A Es a m o n g partici pa nts w h o use d 3 fi ve-
2 5 3  
da y artes u nate c ycles i ncl u de d c hills a n d fl u -li ke s y m pt o ms ( n = 3, gra de 1), va gi nal ( yeast) 
2 5 4  
i nfecti o n ( n = 1, gra de II), dizzi ness or hea dac he ( n = 2, gra de 1), n o n-i nfecti ve c ystitis ( n = 1, gra de 
2 5 5  
2), va gi nal pai n or uteri ne cra m pi n g ( n = 9, gra de I), va gi nal disc har ge ( n = 4, gra de 1), va gi nal 
2 5 6  
pr uritis ( n = 9, gra de 1). I n s u m mar y, 3 7 dr u g -relate d A Es were o bser ve d i n t his P hase I trial, of 
2 5 7  
w hic h 3 4 ( 9 2 %) were gra de I, a n d 3 ( 8 %) were gra de 2. Re p orte d gra de 2 a d verse e ve nts i ncl u de d 
2 5 8  
va gi nal yeast i nfecti o n ( n = 6), bacterial va gi n osis ( n = 2), va gi nal i nfla m mati o n ( n = 2), uri nar y 
2 5 9  
tract i nfecti o n ( n = 2), a n d n o ni nfecti ve c ystitis ( n = 1). E ve nts deter mi ne d t o be u nrelate d t o t he 
2 6 0  
st u d y me dicati o n i ncl u de d: a n xiet y, i ns o m nia, s uici dal i deati o n, va gi nal t witc hi n g, fe ver, fl u -li ke 
2 6 1  
s y m pt o ms i n a patie nt w h o de vel o pe d a c ol d, b o d y itc hi n g, c hills, a n d ecze ma flare. N o s u bjects 
2 6 2  
wit h dre w fr o m t he st u d y beca use of i nt olera ble si de effects, a n d all 2 8 s u bjects i ncl u de d i n t he 
2 6 3  
m o difie d -i nte nti o n-t o-treat a nal yses were a ble t o c o m plete t heir desi g nate d d osi n g re gi me n. N o 
2 6 4  
gra de 3 or 4 a d verse e ve nts were re p orte d. A t otal of 3 s u bjects re p orte d n o n oticea ble si de effects 
2 6 5  
at all. T h us, t he st u d y dr u g t o be use d i n t his pr ot oc ol (self -a d mi nistere d va gi nal artes u nate i nserts) 
2 6 6  
were s h o w n t o be safe a n d well -t olerate d. A ra n d o mize d, place b o-c o ntr olle d p hase II st u d y of 
2 6 7  
artes u nate va gi nal i nserts f or treat me nt of cer vical i ntrae pit helial ne o plasia gra de 2/ 3 ( CI N 2/ 3) is 
2 6 8  
c urre ntl y e nr olli n g s u bjects at se veral U S sites ( N C T 0 4 0 9 8 7 4 4). Patie nts e nr olle d t o date re p orte d 
2 6 9  
n o seri o us a d verse e ve nts. A P hase II ra n d o mize d trial of artes u nate s u p p osit ories f or t he treat me nt 
2 7 0  
of a nal hi g h -gra de s q ua m o us i ntrae pit helial lesi o ns a m o n g HI V -ne gati ve i n di vi d uals is si milarl y 
2 7 1  
o n g oi n g i n t he U nite d States ( N C T 5 5 5 5 8 6 2).  
2 7 2  
1. 3  
S u m m ar y of Artes u n ate P h ar m ac o ki netics  
2 7 3  
 
2 7 4  
T he p har mac o ki netics ( P K) meas ures of artes u nate ( A S) a n d di h y dr oarte misi ni n ( D H A) 
2 7 5  
f oll o wi n g i ntra ve n o us (I V), i ntra m usc ular (I M), oral a n d rectal a d mi nistrati o n ha ve bee n well 
2 7 6  
descri be d. 2 9 T hese P K para meters i ncl u de ma xi m u m c o nce ntrati o n of t he dr u g i n t he bl o o d 
2 7 7  
( C ma x), ti me t o ma xi m u m c o nce ntrati o n C ma x ( T ma x), a p pare nt cleara nce ( C L/ F) - t he dr u g 
2 7 8  
c o nce ntrati o n i n t he b o d y i n pr o p orti o n t o t he rate of eli mi nati o n, v ol u me of distri b uti o n ( V/ F), 
2 7 9  
t he area u n der t he plas ma c o nce ntrati o n vers us ti me c ur ve ( A U C) w hic h e x presses t he t otal 
2 8 0  
a m o u nt of t he dr u g i n s yste mic circ ulati o n after a d mi nistrati o n, a n d half -life (t1/ 2). I ntra ve n o us 
2 8 1  
a d mi nistrati o n of A S pr o d uces q uic kl y pr o d uces hi g h ma xi m u m c o nce ntrati o ns ( C ma x) of A S, 
2 8 2  
hi g her t ha n a n y ot her met h o d of a d mi nistrati o n. O ne e xa m ple of t his ca n be see n i n a st u d y of 
2 8 3  
a d ults wit h u nc o m plicate d malaria w hic h c o m pare d A S a n d D H A le vels f oll o wi n g I V a n d I M 
2 8 4  
a d mi nistrati o n, C ma x val ues f or A S w he n a d mi nistere d i ntra ve n o usl y reac he d o ver 1 6, 0 0 0 n g/ m L 
2 8 5  

 
 
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w hile o nl y reac hi n g ar o u n d 8 8 4 n g/ m L w he n a d mi nistere d i ntra m usc ularl y. 3 0 Si milarl y, t he 
2 8 6  
ma xi m u m c o nce ntrati o n ( C ma x) of A S a n d D H A pea k q uic kl y f oll o wi n g I V a d mi nistrati o n, 
2 8 7  
f oll o we d b y a ra pi d decli ne. T he a vera ge half-life of A S f oll o wi n g I V a d mi nistrati o n of less t ha n 
2 8 8  
fiftee n mi n utes i n m ulti ple st u dies, wit h a n o bser ve d cleara nce ra n ge of 2-3 L/ k g/ hr a n d a 
2 8 9  
v ol u me ra n ge of 0. 1 -0. 3 L/ k g. 2 9 T he h y dr ol ysis of A S i nt o D H A f oll o wi n g I V a d mi nistrati o n is 
2 9 0  
si milarl y q uic k, wit h ma xi m u m D H A le vels reac he d s o o n after I V A S a d mi nistrati o n. T he T ma x 
2 9 1  
f or D H A after I V a d mi nistrati o n was c o nsiste ntl y less t ha n 2 5 mi n utes acc or di n g t o t he o bser ve d 
2 9 2  
st u dies wit h D H A cleara nce a vera gi n g bet wee n 0. 5-1. 5 L/ k g/ hr a n d v ol u me a vera gi n g bet wee n 
2 9 3  
0. 5 -1. 0 L/ k g. 2 9 T he A U C of A S f oll o wi n g I V a d mi nistrati o n of 1 2 0 m g A S i n a d ults ra n ge d 
2 9 4  
bet wee n 8 7 6 n g * hr/ ml i n healt h y v ol u nteers 3 1 a n d 1 0 3 8 - 1 2 6 9 n g * hr/ ml i n t h ose wit h malaria. 3 2 
2 9 5  
T he A U C of D H A f oll o wi n g I V a d mi nistrati o n of 1 2 0 m g A S i n a d ults ra n ge d fr o m 1 8 5 0 
2 9 6  
n g * hr/ ml i n healt h y v ol u nteers 3 3 t o 1 8 4 5-2 3 7 7 n g * hr/ ml i n t h ose wit h malaria. 3 4   
2 9 7  
 
2 9 8  
C o m pare d t o I V a d mi nistrati o n, I M a d mi nistrati o n pr o d uces l o wer pea ks, l o n ger half -life, a n d 
2 9 9  
hi g her v ol u mes of distri b uti o n f or A S, as well as dela ye d pea ks f or D H A. F or e xa m ple, A S half -
3 0 0  
life f oll o wi n g i n I V a d mi nistrati o n is less t ha n 1 5 mi n utes o n a vera ge, c o m pare d t o 2 5. 2 t o 4 8. 2 
3 0 1  
mi n utes wit h I M a d mi nistrati o n. 2 9 Ot her para meters –  i n i ncl u di n g D H A half-life, v ol u me of 
3 0 2  
distri b uti o n, a n d cleara nce rates f oll o wi n g I M a d mi nistrati o n rese m ble d t he val ues rec or de d after 
3 0 3  
I V a d mi nistrati o n i n m ulti ple st u dies, d ue t o t he hi g h bi oa vaila bilit y, assesse d b y e x p os ure t o 
3 0 4  
D H A, ass ociate d wit h I M A S a d mi nistrati o n ( > 8 6 %). 2 9 T he A U C of A S f oll o wi n g I M 
3 0 5  
a d mi nistrati o n of 1 2 0 m g A S i n a d ults ra n ge d bet wee n 8 5 6 3 5 - 9 9 9 3 1n g * hr/ ml i n t h ose wit h 
3 0 6  
malaria. T he A U C of D H A f oll o wi n g I M a d mi nistrati o n of 1 2 0 m g of A S i n a d ults wit h malaria 
3 0 7  
was 2 4 7 4 n g * hr/ ml i n o ne st u d y. 3 1   
3 0 8  
 
3 0 9  
W he n A S is a d mi nistere d orall y, D H A pea k c o nce ntrati o ns ( C ma x), A U C, a n d half -life a vera ges 
3 1 0  
are all n ota bl y hi g her t ha n c o m para ble A S para meters. T he a vera ge ti me t o D H A C ma x a n d half -
3 1 1  
life f oll o wi n g oral A S a d mi nistrati o n ( 2 0 0 m g/ da y) are 2 h o urs, a n d 0. 5-1. 5 h o urs, res pecti vel y, 
3 1 2  
c o m pare d t o o ne h o ur a n d 2 0 -4 5 mi n utes, res pecti vel y, f or A S. 2 9  W hile a si milar patter n is see n 
3 1 3  
f oll o wi n g I V a n d I M a d mi nistrati o n, na mel y, ele vate d le vels of D H A half-life a n d A U C 
3 1 4  
c o m pare d t o A S, t he differe nce are n ota ble f oll o wi n g oral a d mi nistrati o n. Als o, w hile oral 
3 1 5  
a d mi nistrati o n of A S res ults i n a hi g her D H A C ma x c o m pare d t o A S, I V a n d I M a d mi nistrati o n 
3 1 6  
res ult i n a n ota bl y hi g her A S C ma x t ha n D H A C ma x. M orris et al ( 2 0 1 1) p oi nts o ut t hat t he 
3 1 7  
variati o ns o bser ve d f oll o wi n g oral a d mi nistrati o n are m ost li kel y attri b ute d t o A S f u ncti o ni n g as 
3 1 8  
a “ pr o -dr u g” f or D H A w he n i n geste d orall y a n d i n res p o nse t o “first -pass or s yste mic 
3 1 9  
meta b olis m.” 2 9 Esse ntiall y, w he n A S is ta ke n orall y, it is c o n verte d t o D H A at a greater e xte nt 
3 2 0  
t ha n w he n it is ta ke n i ntra ve n o usl y or i ntra m usc ularl y. T he A U C of A S a n d D H A i n a st u d y of 
3 2 1  
healt h y a d ult v ol u nteers ta ki n g 2 0 0 m g A S dail y f or 5 da ys was 6 7 n g * hr/ ml a n d 1 1 5 8 n g * hr/ ml 
3 2 2  
f or A S & D H A, res pecti vel y, o n Da y 1, a n d 6 0 n g * hr/ ml a n d 1 3 0 0 n g * hr/ ml f or A S & D H A, 
3 2 3  
res pecti vel y, o n Da y 5.3 6 Si milar C ma x para meters f or A S were 6 7 n g/ ml a n d 5 8 n g/ ml o n Da y 1 
3 2 4  
a n d 5, res pecti vel y, a n d a p o ole d D H A C ma x of 6 5 4 n g/ ml, de m o nstrati n g t he a bse nce of ti me -
3 2 5  
de pe n de nt artes u nate p har mac o ki netics i n healt h y s u bjects d uri n g 5 -da y oral a d mi nistrati o n of 
3 2 6  
2 0 0 m g artes u nate. 3 6 T he A U C of A S f oll o wi n g oral a d mi nistrati o n of 2 0 0 m g A S i n a d ults 
3 2 7  
ra n ge d bet wee n 6 0-6 7 n g * hr/ ml i n healt h y v ol u nteers 3 7 a n d 3 1 0 n g * hr/ ml i n t h ose wit h malaria. 3 8 
3 2 8  
T he A U C of D H A f oll o wi n g oral a d mi nistrati o n of 2 0 0 m g of A S i n a d ults ra n ge d fr o m 1 1 5 8 -
3 2 9  
1 3 3 1 n g * hr/ ml 3 7, 3 9i n healt h y v ol u nteers t o 3 0 2 7 n g * hr/ ml i n t h ose wit h malaria.3 8   
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C O N FI D E N TI A L  
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U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n 1. 0  
 
A pril 2 5, 2 0 2 3  
 
1 0  
 
Rectal A S a d mi nistrati o n yiel ds p har mac o ki netic res ults si milar t o t h ose o btai ne d fr o m oral 
3 3 1  
a d mi nistrati o n, wit h t he e xce pti o n of dela ye d A S C ma x a n d l o n ger A S half -life. C o m pare d t o I V 
3 3 2  
a d mi nistrati o n, e x pecte dl y, b ot h A S a bs or pti o n a n d eli mi nati o n are pr ol o n ge d f oll o wi n g rectal 
3 3 3  
a d mi nistrati o n. F oll o wi n g rectal a d mi nistrati o n of A S, T ma x a vera ge bet wee n 0. 5 8 -1. 4 3 h o urs, 
3 3 4  
wit h a half -life bet wee n 0. 9-. 9 5 h o urs.2 9 T hese a vera ges are base d o n t hree differe nt st u dies: t w o 
3 3 5  
st u dies c o ntai ni n g pe diatric patie nts wit h u nc o m plicate d falci par u m malaria ( 1 0 - 2 0 m g/ K g 
3 3 6  
d osi n g) 4 0, 4 1 a n d o ne st u d y c o ntai ni n g healt h y Mala ysia n a d ults ( 2 0 0 m g rectal s u p p osit or y, 
3 3 7  
~ 4 m g/ K g d osi n g). 4 2 F oll o wi n g rectal d osi n g of a o ne -ti me 2 0 0 m g A S s u p p osit or y i n healt h y 
3 3 8  
a d ults (si milar t o o ur pla n ne d d osi n g), a C ma x, T ma x, half -life a n d A U C of 4 4 8. 5 n g/ ml, 1. 4 3 
3 3 9  
h o urs, 0. 9 5 h o urs, a n d 7 9 6 n g * hr/ ml of A S were o bser ve d, a n d C ma x, T ma x, half -life a n d A U C 
3 4 0  
of 3 8 5. 6 n g/ ml, 1. 8 0 h o urs, 1. 2 1 h o urs, a n d 9 6 5 n g * hr/ ml  res pecti vel y of D H A were o bser ve d i n 
3 4 1  
healt h y a d ults. 4 2 N o data are a vaila ble o n rectal P K i n a d ults wit h malaria as t his r o ute of 
3 4 2  
a d mi nistrati o n is n ot use d t o treat malaria i n a d ults. T he l o n ger half -life of A S f oll o wi n g rectal 
3 4 3  
d osi n g (a vera ge 0. 9 -0. 9 5 hrs) c o m pare d t o I M (a vera ge 2 5. 2 –  4 8. 2 mi n utes), or I V (a vera ge less 
3 4 4  
t ha n 5 mi n utes) ma y reflect a bs or pti o n rate-li mite d eli mi nati o n of A S.2 9 As is e x pecte d gi ve n 
3 4 5  
t hat rectal A S a d mi nistrati o n a v oi ds b y-pass meta b olis m, t he discre pa nc y i n A S a n d D H A A U C 
3 4 6  
val ues ( 7 9 6 n g * hr/ ml a n d 9 6 5 n g * hr/ ml, res pecti vel y), is n ot as stri ki n g wit h rectal, as c o m pare d 
3 4 7  
wit h oral a d mi nistrati o n of A S ( 1 1 9 n g * hr/ ml a n d 1 3 3 1 n g * hr/ ml, res pecti vel y). 2 9 Si milar t o oral 
3 4 8  
a d mi nistrati o n, b ot h D H A T ma x a n d half -life val ues were hi g her t ha n t hat of A S f oll o wi n g rectal 
3 4 9  
a d mi nistrati o n. 2 9 
3 5 0  
1. 4  
Effect of m al ari a i nfecti o n st at us o n artes u n ate a n d D H A p h ar m ac o ki netics  
3 5 1  
 
3 5 2  
A direct c o m paris o n a m o n g healt h y a n d parasitae mic s u bjects was c o n d ucte d b y Teja -
3 5 3  
Isa va d har m et al, w h o st u die d t he P K of D H A f oll o wi n g oral A S a d mi nistrati o n i n si x healt h y 
3 5 4  
a d ults a n d si x a d ult falci par u m malaria patie nts. 4 3 T he i n vesti gat ors deter mi ne d t hat A U C a n d 
3 5 5  
C ma x of D H A were si g nifica ntl y hi g her i n s u bjects wit h malaria as c o m pare d t o healt h y 
3 5 6  
s u bjects. Bi n h et al o btai ne d si milar res ults w he n c o m pari n g t he P K i n ei g ht patie nts wit h 
3 5 7  
falci par u m malaria a n d te n healt h y s u bjects.4 4 H o we ver, gi ve n t he relati vel y s mall size of b ot h 
3 5 8  
st u dies, defi niti ve c o ncl usi o ns re gar di n g differe nces i n P K bet wee n healt h y a n d i nfecte d s u bjects 
3 5 9  
ca n n ot be dra w n at t his ti me. 3 3 H o we ver, as D H A cleara nce is de pe n de nt o n he patic bl o o d fl o w, 
3 6 0  
a re d ucti o n i n cleara nce, a n d c o nse q ue ntl y a n i ncrease i n e x p os ure ass ociate d wit h ac ute malaria 
3 6 1  
i nfecti o n w o ul d be c o nsiste nt wit h k n o w n D H A’s P K pr o perties.3 3    
3 6 2  
1. 5  
M al ari a tre at me nt a n d arte misi ni n resist a nce  
3 6 3  
 
3 6 4  
T he W orl d Healt h Or ga nizati o n rec o m me n ds arte misi ni n - base d c o m bi nati o n t hera pies ( A C Ts) 
3 6 5  
as t he first li ne treat me nt f or u nc o m plicate d Plas m o di u m Falci par u m. 4 5 I n A C Ts, arte misi ni n 
3 6 6  
q uic kl y a n d drasticall y re d uces t he maj orit y of malaria parasites, w hile t he part ner dr u g clears 
3 6 7  
t he re mai ni n g parasites t o pre ve nt recr u desce nce.4 6, 4 7 Arte misi ni n resista nce is defi ne d as 
3 6 8  
dela ye d parasite cleara nce f oll o wi n g treat me nt wit h a n artes u nate m o n ot hera p y or A C T, a n d ca n 
3 6 9  
be o bser ve d as a parasite cleara nce half -life of greater t ha n fi ve h o urs, or parasites 
3 7 0  
micr osc o picall y e vi de nt o n da y t hree. 4 8 T his re prese nts partial resista nce. Arte misi ni n resista nce 
3 7 1  
al o ne d oes n ot necessaril y lea d t o malaria treat me nt fail ure. H o we ver, re d uce d efficac y of t he 
3 7 2  
arte misi ni n c o m p o ne nt places greater de ma n ds o n t he part ner dr u g t o clear a lar ger parasite 
3 7 3  
mass, je o par dizi n g f ut ure efficac y of t he part ner dr u g ( W H O). E xa m ples of A C Ts i ncl u de 
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C O N FI D E N TI A L  
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U NI V E R SI T Y O F N O R T H C A R O LI N A  
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A pril 2 5, 2 0 2 3  
 
1 1  
 
arte met her -l u mefa ntri ne, artes u nate-a m o dia q ui ne, artes u nate -mefl o q ui ne, a m o n g ot hers. 
3 7 5  
Sta n dar d A C Ts re gi me n f or u nc o m plicate d malaria is a n oral 3 -da y c o urse. M ost st u dies s h o w 
3 7 6  
t hat A C Ts c urre ntl y rec o m me n de d i n nati o nal malaria treat me nt p olicies re mai n effecti ve, wit h 
3 7 7  
a n o verall efficac y rate of greater t ha n 9 5 %. 4 9  
3 7 8  
Arte misi ni n’s are e xce pti o nall y fast acti n g a gai nst i ntra -er yt hr oc ytic ase x ual bl o o d -sta ge malaria 
3 7 9  
parasites, effecti n g u p t o 1 0, 0 0 0 - f ol d re d ucti o ns i n parasite b ur de n e ver y 4 8 h o urs.5 0 T he 
3 8 0  
pri mar y ge netic dri vers of arte misi ni n resista nce, b ot h i n vitr o a n d i n viv o are p oi nt m utati o ns i n 
3 8 1  
i n t he P. falci par u m Kelc h 1 3 (Pf K 1 3 ) ge ne i n t he earl y ri n g sta ge.5 1, 5 2 K 1 3 m utati o ns all o w a 
3 8 2  
s u bset of earl y ri n g-sta ge parasites t o s ur vi ve cell-c ycle arrest br o u g ht o n b y arte misi ni n 
3 8 3  
e x p os ure, e na bli n g t h ose parasites t o rei nitiate tra nscri pti o n a n d c o m plete t heir i ntraer yt hr oc ytic 
3 8 4  
de vel o p me ntal c ycle o nce arte misi ni n is n o l o n ger prese nt at i n hi bit or y c o nce ntrati o ns. 5 3 
3 8 5  
Resista nce  i n vitr o is r o uti nel y defi ne d as greater t ha n 1 % s ur vi val of earl y ri n g-sta ge parasites 
3 8 6  
e x p ose d f or 6 h o urs t o 7 0 0 n M di h y dr oarte misi ni n ( D H A -t he pri mar y acti ve meta b olite of A R T) 
3 8 7  
f oll o we d b y dr u g-free c ult ure i nc u bati o n f or a f urt her 6 6 h o urs.4 8 T he mec ha nis m of resista nce 
3 8 8  
a p pears t o i n v ol ve a c o m ple x i nter pla y of K 1 3 pr otei n a b u n da nce, he m o gl o bi n e n d oc yt osis, a n d 
3 8 9  
t he parasite res p o nse t o stress.4 8, 5 4  
3 9 0  
I n Africa, se veral st u dies ha ve i de ntifie d a n u m ber of l o w fre q ue nc y Pf k 1 3 m utati o ns.5 5, 5 6 T he 
3 9 1  
m utati o ns k n o w n t o be ass ociate d wit h dela ye d parasite cleara nce ( M 4 7 6I, P 5 5 3 L, R 5 6 1 H, 
3 9 2  
P 5 7 4 L, C 5 8 0 Y a n d A 6 7 5 V) were o bser ve d at l o w fre q ue ncies ( < 5 %) i n f o ur c o u ntries, G ha na, 
3 9 3  
R wa n da, U ga n da a n d Ta nza nia. 5 5 I n Ta nza nia, t w o parasites sa m ple d fr o m 7 6 4 ( 0. 3 %) were 
3 9 4  
i de ntifie d i n 2 0 1 7, 1 1 a n d a si n gle parasite fr o m 4 2 2 sa m ples i n 2 0 1 9 ( 0. 2 %). 5 5 Si milarl y i n 
3 9 5  
U ga n da o ne parasite was i de ntifie d fr o m 7 9 6 sa m ples i n 2 0 1 8/ 2 0 1 9 ( 0. 1 %). 5 7  I n a 2 0 2 1 st u d y 
3 9 6  
e val uati n g arte misi ni n resista nce i n N ort her n U ga n da c o n d ucte d bet wee n 2 0 1 7 t o 2 0 1 9, a t otal of 
3 9 7  
1 4 of 2 4 0 patie nts w h o recei ve d i ntra ve n o us artes u nate ha d e vi de nce of i n vi v o arte misi ni n 
3 9 8  
resista nce ( parasite cleara nce half-life > 5 h o urs).5 7 Of t hese 1 4 patie nts, 1 3 were i nfecte d wit h P. 
3 9 9  
falci par u m parasites wit h m utati o ns i n t he A 6 7 5 V or C 4 6 9 Y allele i n t he kelc h 1 3 ge ne.5 2  
4 0 0  
P. falci par u m resista nce t o arte misi ni n has bee n d oc u me nte d i n fi ve c o u ntries i n S o ut heast Asia; 
4 0 1  
Ca m b o dia, La o Pe o ple’s De m ocratic Re p u blic, M ya n mar, T haila n d a n d Viet na m ( W H O). 4 7 Wit h 
4 0 2  
i m ple me ntati o n of c o m bi nati o n t hera p y, i m pr o ve me nts t o healt h s yste ms a n d s ur veilla nce 
4 0 3  
s yste ms t o m o nit or first- a n d sec o n d-li ne treat me nt, t he c o nse q ue nces of t he de vel o p me nt of 
4 0 4  
resista nce t o a nti malaria me dici nes ma y be less se vere t o da y t ha n w hat was o bser ve d wit h 
4 0 5  
c hl or o q ui ne i n t he 1 9 8 0s. I n t he e ve nt parasites de vel o p re d uce d se nsiti vit y t o arte misi ni n, A C T S 
4 0 6  
will c o nti n ue t o c ure malaria, pr o vi de d t hat t he part ner dr u g re mai ns effecti ve. 4 7 P ote ntial 
4 0 7  
c ha n ges t o A C T t o o verc o me resista nce i ncl u de m o dificati o ns s uc h as e xte n di n g t he d urati o n of 
4 0 8  
t he A C T c o urse (c urre ntl y 3 da ys f or oral treat me nt), alter nati n g use of differe nt A C T re gi me ns, 
4 0 9  
a n d a d diti o n of a n ot her a nti malarial dr u g t o t he sta n dar d A C Ts (tri ple -A C T). 4 7 F urt her, a malaria 
4 1 0  
vacci ne (e. g. R T S, S vacci ne) c o ul d be a d de d t o mass dr u g a d mi nistrati o n ca m pai g ns t o e n ha nce 
4 1 1  
t he treat me nt efficac y a n d t o pre ve nt f urt her arte misi ni n resista nce de vel o p me nt. 
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U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n 1. 0  
 
A pril 2 5, 2 0 2 3  
 
1 2  
 
1. 6  
S yste mic Artes u n ate a bs or pti o n a n d p ossi ble i m plic ati o ns f or de vel o pi n g resist a nce 
4 1 3  
f or m al ari a tre at me nt.  
4 1 4  
W hile t here are n o p har mac ol o gic data o n ser u m a bs or pti o n f oll o wi n g i ntra va gi nal artes u nate 
4 1 5  
a d mi nistrati o n –  he nce t his st u d y, direct a p plicati o n of artes u nate t o t he cer vical m uc osa at t he 
4 1 6  
pr o p ose d d ose is u nli kel y t o res ult i n s yste mic a bs or pti o n. T he pla n ne d i ntra va gi nal artes u nate 
4 1 7  
d ose of 2 0 0 m g ( ≤4 m g/ k g base d o n pla n ne d i ncl usi o n criteria of wei g ht ≥ 5 0 K g) is  2. 5 f ol d 
4 1 8  
l o wer t ha n t he a p pr o ve d rectal s u p p osit or y d ose ( 1 0 m g/ K g). U nli ke rectal m uc osa w hic h is 
4 1 9  
hi g hl y vasc ular a n d c o m prise d of  a si n gle-cell la yer of c ol u m nar e pit heli u m ma ki n g it hi g hl y 
4 2 0  
per mea ble t o dr u gs, res ulti n g i n s yste mic a bs or pti o n a n d he nce use of rectal artes u nate f or pre-
4 2 1  
referral pe diatric malaria treat me nt, t he cer vic o-va gi nal tiss ue is c o m prise d of a t hic k, stratifie d 
4 2 2  
s q ua m o us e pit helial cell la yer, 5 8 a n d is si g nifica ntl y less vasc ular, re d uci n g s yste mic a bs or pti o n. 
4 2 3  
Si milarl y, d ue t o t he ra pi d rate of eli mi nati o n Artes u nate’s acti ve meta b olite, 5 9 n o s yste mic 
4 2 4  
acc u m ulati o n is e x pecte d of Artes u nate or its acti ve meta b olite wit h i ntra va gi nal m ulti -da y 
4 2 5  
d osi n g i n t he c o nte xt of cer vic o va gi nal a d mi nistrati o n  
4 2 6  
 
4 2 7  
1. 7  
Pr o ble m St ate me nt a n d St u d y R ati o n ale ( J ustific ati o n)  
4 2 8  
 
4 2 9  
Gi ve n t hat artes u nate is a well -k n o w n dr u g use d i n malaria treat me nt, it is critical t o e ns ure t hat 
4 3 0  
va gi nal a p plicati o n of t he dr u g f or treat me nt of cer vical preca ncer will n ot pr o m ote malaria 
4 3 1  
resista nce. T h us, a st u d y e val uati n g bl o o d ser u m le vels after artes u nate va gi nal i nserts 
4 3 2  
a d mi nistrati o n is pr o p ose d.  I n t his st u d y, partici pa nts will self -a d mi nister o ne 2 0 0 m g artes u nate 
4 3 3  
va gi nal i nsert per da y f or 5 da ys.  Bl o o d ser u m le vels of D H A a n d artes u nate will be e val uate d 
4 3 4  
pri or t o recei vi n g artes u nate, a n d o n da y 5, bef ore artes u nate va gi nal i nsert ( pessar y) use –  ti me 0, 
4 3 5  
a n d at 1 5 mi n, 3 0 mi n, 1, 2, 4, 6 a n d 8 h o urs after use t o e val uate t he p har mac o ki netics of artes u nate 
4 3 6  
f oll o wi n g i ntra va gi nal use at t he pr o p ose d d ose a n d fre q ue nc y.  
4 3 7  
 
4 3 8  
2. 0  
R E S E A R C H H Y P O T H E SI S A N D O B J E C TI V E S  
4 3 9  
 
4 4 0  
2. 1  Rese arc h H y p ot hesis  
4 4 1  
 
4 4 2  
T he o verall o bjecti ve is  t o e val uate p har mac o ki netics ( P K) of i ntra va gi nal, self-a d mi nistere d 
4 4 3  
Artes u nate va gi nal i nserts ( pessaries) a m o n g w o me n i n Ke n ya b y meas uri n g ser u m D H A a n d 
4 4 4  
artes u nate le vels after i ntra va gi nal a d mi nistrati o n t o e val uate f or p ote ntial ris k of de vel o pi n g 
4 4 5  
malaria resista nce wit h artes u nate use f or cer vical preca ncer treat me nt.  
4 4 6  
 
4 4 7  
T he ce ntral ( n ull) h y p ot hesis is t hat t here will be n o si g nifica nt differe nce i n detecta ble le vels of 
4 4 8  
bl o o d D H A a n d artes u nate f oll o wi n g 5 c o nsec uti ve da ys of i ntra va gi nal, self -a d mi nistrati o n of 
4 4 9  
2 0 0 m g artes u nate pessaries, c o m pare d t o baseli ne.  
4 5 0  
2. 2         Rese arc h O bjecti ves  
4 5 1  
 
4 5 2  
 
4 5 3  

 
 
C O N FI D E N TI A L  
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U NI V E R SI T Y O F N O R T H C A R O LI N A  
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A pril 2 5, 2 0 2 3  
 
1 3  
 
Pri m ar y O bjecti ve:  T o deter mi ne t he area u n der t he plas ma c o nce ntrati o n vers us ti me c ur ve 
4 5 4  
( A U C) of di h y dr oarte misi ni n ( D H A) f oll o wi n g fi ve c o nsec uti ve da ys of self-a d mi nistrati o n of 
4 5 5  
2 0 0 m g Artes u nate va gi nal i nserts ( pessaries) a m o n g healt h y w o me n i n Ke n ya.  
4 5 6  
 
4 5 7  
Sec o n d ar y O bjecti ve  
4 5 8  
1.  T o deter mi ne t he  area u n der t he plas ma c o nce ntrati o n vers us ti me c ur ve ( A U C) of 
4 5 9  
Artes u nate ( A S) f oll o wi n g fi ve c o nsec uti ve da ys of self -a d mi nistrati o n of 2 0 0 m g 
4 6 0  
Artes u nate va gi nal i nserts ( pessaries) a m o n g healt h y w o me n i n Ke n ya  
4 6 1  
2.  T o deter mi ne t he ma xi m u m c o nce ntrati o n of Artes u nate ( A S) ( C ma x) f oll o wi n g fi ve 
4 6 2  
c o nsec uti ve da ys of self -a d mi nistrati o n of 2 0 0 m g Artes u nate va gi nal i nserts ( pessaries) 
4 6 3  
a m o n g healt h y w o me n i n Ke n ya  
4 6 4  
3.  T o deter mi ne t he ma xi m u m c o nce ntrati o n of di h y dr oarte misi ni n ( D H A) ( C ma x) f oll o wi n g 
4 6 5  
fi ve c o nsec uti ve da ys of self-a d mi nistrati o n of 2 0 0 m g 
Artes u nate va gi nal i nserts 
4 6 6  
( pessaries) a m o n g healt h y w o me n i n Ke n ya 
4 6 7  
4.  T o deter mi ne t he ti me t o ma xi m u m c o nce ntrati o n ( T ma x) of Artes u nate ( A S) f oll o wi n g 
4 6 8  
fi ve c o nsec uti ve da ys of self-a d mi nistrati o n of 2 0 0 m g 
Artes u nate va gi nal i nserts 
4 6 9  
( pessaries) a m o n g healt h y w o me n i n Ke n ya 
4 7 0  
5.  T o deter mi ne t he ti me t o ma xi m u m c o nce ntrati o n ( T ma x) of di h y dr oarte misi ni n ( D H A) 
4 7 1  
f oll o wi n g fi ve c o nsec uti ve da ys of self-a d mi nistrati o n of 2 0 0 m g Artes u nate va gi nal i nserts 
4 7 2  
( pessaries) a m o n g healt h y w o me n i n Ke n ya 
4 7 3  
6.  T o deter mi ne t he half -life (t1/ 2) of Artes u nate ( A S) f oll o wi n g fi ve c o nsec uti ve da ys of self-
4 7 4  
a d mi nistrati o n of 2 0 0 m g Artes u nate va gi nal i nserts ( pessaries) a m o n g healt h y w o me n i n 
4 7 5  
Ke n ya  
4 7 6  
7.  T o deter mi ne t he half -life (t1/ 2) of di h y dr oarte misi ni n ( D H A) f oll o wi n g fi ve c o nsec uti ve 
4 7 7  
da ys of self -a d mi nistrati o n of 2 0 0 m g Artes u nate va gi nal i nserts ( pessaries) a m o n g healt h y 
4 7 8  
w o me n i n Ke n ya  
4 7 9  
8.  T o deter mi ne t he a p pare nt cleara nce ( C L/ F) of Artes u nate ( A S) f oll o wi n g fi ve c o nsec uti ve 
4 8 0  
da ys of self -a d mi nistrati o n of 2 0 0 m g Artes u nate va gi nal i nserts ( pessaries) a m o n g healt h y 
4 8 1  
w o me n i n Ke n ya  
4 8 2  
9.  T o deter mi ne t he a p pare nt cleara nce ( C L/ F) of di h y dr oarte misi ni n ( D H A) f oll o wi n g fi ve 
4 8 3  
c o nsec uti ve da ys of self -a d mi nistrati o n of 2 0 0 m g Artes u nate va gi nal i nserts ( pessaries) 
4 8 4  
a m o n g healt h y w o me n i n Ke n ya  
4 8 5  
1 0.  T o deter mi ne t he v ol u me of distri b uti o n ( V/ F) of Artes u nate ( A S) f oll o wi n g fi ve 
4 8 6  
c o nsec uti ve da ys of self -a d mi nistrati o n of 2 0 0 m g Artes u nate va gi nal i nserts ( pessaries) 
4 8 7  
a m o n g healt h y w o me n i n Ke n ya  
4 8 8  
1 1.  T o deter mi ne t he v ol u me of distri b uti o n ( V/ F) of di h y dr oarte misi ni n ( D H A) f oll o wi n g fi ve 
4 8 9  
c o nsec uti ve da ys of self -a d mi nistrati o n of 2 0 0 m g Artes u nate va gi nal i nserts ( pessaries) 
4 9 0  
a m o n g healt h y w o me n i n Ke n ya  
4 9 1  
1 2.  T o i n vesti gate t he safet y of 5 -da y c o urse of self -a d mi nistere d i ntra va gi nal artes u nate 
4 9 2  
va gi nal i nserts ( pessar y) i n w o me n i n Ke n ya  
4 9 3  
 
4 9 4  
2. 3  C o nce pt u al Fr a me w or k  
4 9 5  
 
4 9 6  
C o nce pt ual fra me w or k of artes u nate acti o n o n H P V -i nfecte d cells, s pecificall y tar geti n g E 6 & E 7 
4 9 7  
o nc o ge nes/ o nc o pr otei ns, w hic h f or ms t he basis of c urre nt cli nical trials st u d yi n g use of t his 
4 9 8  
c o m p o u n d f or cer vical preca ncer treat me nt. I ma ge a da pte d fr o m Be dell et al ( 2 0 2 0)  
4 9 9  

 
 
C O N FI D E N TI A L  
PI: M u n g o  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n 1. 0  
 
A pril 2 5, 2 0 2 3  
 
1 4  
 
 
5 0 0  
 
5 0 1  
2. 4  St u d y Sc he m a  
5 0 2  
 
5 0 3  
Scree ni n g/ E nr oll me nt Visit  
5 0 4  
Re vie w eli gi bilit y criteria, re vie w a n d si g n i nf or me d c o nse nt,  
5 0 5  
i ntr o d uce a n d disc uss st u d y re q uire me nts, uri ne pre g na nc y test, malaria a nti ge n testi n g, 
5 0 6  
assi g n u ni q ue st u d y n u m ber, o btai n baseli ne cli nical a n d de m o gra p hic c haracteristics a n d 
5 0 7  
me dical hist or y, pel vic e xa mi nati o n.  
5 0 8  
 
5 0 9  
Visit 1/ D a y 1 * ( m a y be c o m bi ne d wit h Scree ni n g/ E nr oll me nt visit)  
5 1 0  
I nter val me dical hist or y 
5 1 1  
Uri ne pre g na nc y test  
5 1 2  
Bl o o d dr a w  f or baseli ne Artes u nate/ D H A testi n g  
5 1 3  
Self -a d mi nistrati o n of first Artes u nate va gi nal i nsert ( pessar y) a n d ta m p o n, f oll o we d b y a 
5 1 4  
3 0 -mi n ute o bser vati o n.  
5 1 5  
Sc he d ule Visit 2  
5 1 6  
 
5 1 7  
 
5 1 8  
Visit 2 -4/ D a y 2 -4  
5 1 9  
I nter val me dical hist or y 
5 2 0  
Uri ne pre g na nc y test  
5 2 1  
Re vie w a d verse e ve nts  
5 2 2  
Self -a d mi nistrati o n of Artes u nate va gi nal i nsert ( pessar y) a n d ta m p o n  
5 2 3  
Sc he d ule s u bse q ue nt visit  
5 2 4  
 
5 2 5  
 
5 2 6  
Visit 5/ D a y 5  
5 2 7  
I nter val me dical hist or y  
5 2 8  

 
 
C O N FI D E N TI A L  
PI: M u n g o  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n 1. 0  
 
A pril 2 5, 2 0 2 3  
 
1 5  
 
Uri ne pre g na nc y test  
5 2 9  
Re vie w a d verse e ve nts  
5 3 0  
Bl o o d dr a w  bef ore artes u nate a d mi nistrati o n (ti me 0)  
5 3 1  
Self -a d mi nistrati o n of Artes u nate va gi nal i nsert ( pessar y)  
5 3 2  
Bl o o d dr a w  at 1 5 mi n, 3 0 mi n, 1 hr, 2 hr, 4 hr, 6 hr a n d 8 hrs after Artes u nate va gi nal pessar y 
5 3 3  
i nserti o n 
5 3 4  
                                              Sc he d ule Visit 6  
5 3 5  
 
5 3 6  
Visit 6 ( wit hi n 4 -1 0 d a ys of Visit 5)  
5 3 7  
Re vie w a d verse e ve nts  
5 3 8  
St u d y e xit  
5 3 9  
 
5 4 0  
2. 5  R ati o n ale f or t he St u d y Desi g n  
5 4 1  
 
5 4 2  
T he st u d y is desi g ne d t o e val uate p har mac o ki netic of i ntra va gi nal, self -a d mi nistere d Artes u nate, 
5 4 3  
wit h t he h y p ot hesis t hat t here will be n o si g nifica nt differe nce i n detecta ble le vels of ser u m D H A 
5 4 4  
a n d artes u nate f oll o wi n g i ntra va gi nal use at t he pr o p ose d d osa ge a n d fre q ue nc y c o m pare d t o 
5 4 5  
bef ore a d mi nistrati o n .  T he ti mi n g of t he ser u m bl o o d dra ws a n d he nce P K a nal ysis para meters 
5 4 6  
were c h ose n base d o n t he d osi n g re gi me n of i ntra va gi nal artes u nate f or cer vical preca ncer 
5 4 7  
treat me nt use d i n o n g oi n g cli nical trials. C urre nt st u die d re gi me ns use a 2 0 0 m g va gi nal 
5 4 8  
i nsert/ pessar y, use d dail y f or 5 a p plicati o ns, f oll o we d b y o ne wee k off, re peate d f or 3-4 c ycles. 
5 4 9  
T he rati o nale f or P K a nal ysis –  o btai ni n g a pre -a d mi nistrati o n artes u nate le vel bef ore da y o ne, 
5 5 0  
f oll o we d serial bl o o d dra ws o n da y 5 o nl y o ne c ycle of i ntra va gi nal artes u nate use is base d o n 
5 5 1  
a vaila ble p har mac ol o gic data re gar di n g half -life of artes u nate a n d D H A,2 9 a n d e x pecte d lac k of 
5 5 2  
acc u m ulati o n f oll o wi n g a o ne -wee k was h off peri o d, i n case of m ulti ple artes u nate c ycles 
5 5 3  
a d mi nistere d as is c urre ntl y bei n g st u die d. W hile t here are n o p u blis he d p har mac ol o gical data f or 
5 5 4  
i ntra-va gi nal a d mi nistrati o n of artes u nate s u p p osit ories, cli nical p har mac ol o g y of artes u nate a n d 
5 5 5  
its meta b olite D H A f oll o wi n g rectal, I V, I M, a n d oral a d mi nistrati o n are well d oc u me nte d i n t he 
5 5 6  
malaria literat ure. 6 0 ,6 1 ,6 2 ,2 9 Artes u nate is ra pi dl y a bs or be d, wit h pea k plas ma le vels occ urri n g 
5 5 7  
1. 5 h, 2 h, a n d 0. 5 h after oral, 6 3 rectal,3 0 ,6 4 a n d i ntra m usc ular 3 0 a bs or pti o n, res pecti vel y. Artes u nate 
5 5 8  
is al m ost e ntirel y c o n verte d t o its acti ve meta b olite D H A.6 5 Eli mi nati o n of artes u nate is ver y 
5 5 9  
ra pi d, a n d its acti vit y is deter mi ne d b y D H A eli mi nati o n, w hic h has a half-life of 0. 5-1. 5 
5 6 0  
h o urs. 5 9 ,2 9  
5 6 1  
 
5 6 2  
I n pri or st u dies i n vesti gati n g m ulti ple dail y artes u nate I V use i n healt h y s u bjects, Artes u nate 
5 6 3  
dr u g c o nce ntrati o ns di d n ot de m o nstrate acc u m ulati o n, c o nsiste nt wit h k n o w n ra pi d eli mi nati o n 
5 6 4  
rates of arte misi ni n deri vates.6 2 F oll o wi n g I V i njecti o n, artes u nate dr u g le vels ra pi dl y decli ne d 
5 6 5  
a n d was c o n verte d t o di h y dr oarte misi ni n ( D H A) wit h o verall mea n eli mi nati o n half -li ves 
5 6 6  
ra n gi n g fr o m 0. 1 5 –  0. 2 3 hr f or artes u nate a n d 1. 2 3 –  1. 6 3 h o urs f or D H A. 2 9 T he differe nces 
5 6 7  
bet wee n Artes u nate a n d its pri nci pal meta b olite are d ue t o a c o m bi nati o n of differe nces i n 
5 6 8  
s ol u bilit y a n d t o ra pi d c o n versi o n of Artes u nate t o D H A. 3 0 Des pite t he pre dicti o n of l o w 
5 6 9  
s yste mic c o nce ntrati o n of t he dr u g, ra pi d eli mi nati o n f oll o wi n g i ntra va gi nal a d mi nistrati o n 
5 7 0  
w o ul d be e x pecte d, as see n wit h I M a d mi nistrati o n. 3 0 Si milarl y, a si g nifica ntl y l o wer ma xi m u m 
5 7 1  
plas ma c o nce ntrati o n after i ntra -va gi nal a d mi nistrati o n is e x pecte d, c o m pare d t o I V 
5 7 2  

 
 
C O N FI D E N TI A L  
PI: M u n g o  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n 1. 0  
 
A pril 2 5, 2 0 2 3  
 
1 6  
 
a d mi nistrati o n, or rectal a d mi nistrati o n gi ve n hi g her vasc ularit y of rectal m uc osa c o m pare d t o 
5 7 3  
cer vic o va gi nal m uc osa. U nli ke va gi nal tiss ue w hic h c o nsists of a t hic k, stratifie d s q ua m o us 
5 7 4  
e pit helial cell la yer, 5 8 rectal m uc osa has o nl y a si n gle-cell la yer of c ol u m nar e pit heli u m w hic h is 
5 7 5  
6 -8 f ol d t hi n ner t ha n t he va gi nal e pit helial la yer, ma ki n g it m ore per mea ble t o dr u gs. 6 6  
5 7 6  
 
5 7 7  
C urre nt preca ncer st u dies d ose i ntra va gi nal artes u nate f or 5 -da ys o n Wee k 1, 3, a n d 5, or Wee k 
5 7 8  
1, 3, 5, 7, wit h Wee ks 2, 4, 6, or Wee ks 2, 4, 6, 8 dr u g -free, res pecti vel y. T hat is, eac h 5-da y 
5 7 9  
c ycle is f oll o we d b y a o ne wee k (at least 7 da ys) of n o dr u g use i n bet wee n eac h c ycle. Gi ve n t he 
5 8 0  
s h ort half-life of D H A f oll o wi n g dail y d osi n g of Artes u nate i n a d ults, we e x pect n o 
5 8 1  
acc u m ulati o n after eac h 5 -da y c ycle w he n f oll o wi n g a dr u g -free wee k. As s uc h, t his st u d y will 
5 8 2  
meas ure bl o o d ser u m le vels of D H A a n d artes u nate f oll o wi n g o nl y o ne 5 -da y c ycle of dail y 
5 8 3  
a p plicati o ns of 2 0 0 m g artes u nate pessaries i n st u d yi n g P K of t he artes u nate pessaries f oll o wi n g 
5 8 4  
i ntra va gi nal use f or t his i n dicati o n. 
5 8 5  
 
5 8 6  
3  S T U D Y D R U G A N D A D MI NI S T R A TI O N  
5 8 7  
3. 1  Descri pti o n of t he St u d y Dr u g  
5 8 8  
I n t his st u d y, a va gi nal i nsert ( pessar y) f or m ulati o n of artes u nate –  ma de b y Fra ntz Viral 
5 8 9  
T hera pe utics - will be use d. I n L MI Cs i ncl u di n g Ke n ya, c o m merciall y a vaila ble Artes u nate 
5 9 0  
s u p p osit or y is a p pr o ve d f or rectal use f or pre-referral malaria treat me nt.6 7  
5 9 1  
 
5 9 2  
Descri pti o n of Artes u n ate –  t he acti ve i n gre die nt  
5 9 3  
Artes u nate is a deri vati ve of arte misi ni n w hic h is t he acti ve pri nci ple of t he C hi nese me dici nal 
5 9 4  
her b Arte misi a a n n u a . 
5 9 5  
 N o me nclat ure                       Artes u nate, Artes u nic aci d  
5 9 6  
C he mical Na me                     [ 3R , 5aS , 6R , 8aS , 9R , 1 0S , 1 2R , 1 2aR )-3, 6, 9 -tri met h yl deca h y dr o-3, 1 2 -
5 9 7  
e p o x y p yra n o[ 4, 3 -j]-1, 2 -be nz o di o xe pi n -1 0 -ol, h y dr o ge n s ucci nate;  
5 9 8  
C A S Re g. N o.                          8 8 4 9 5 -6 3 -0       
5 9 9  
Ge neral Pr o perties  
6 0 0  
M olec ular F or m ula              C 1 9H 2 8O 8 
6 0 1  
M olec ular Wei g ht                3 8 4. 4 g/ m ol  
6 0 2  
P h ysical Descri pti o n            A fi ne, w hite cr ystalli ne p o w der  
6 0 3  
S ol u bilit y                               Ver y sli g htl y i n water; ver y s ol u ble i n dic hl or o met ha ne; freel y 
6 0 4  
s ol u ble i n et ha n ol ( ~ 7 5 0 g/l) a n d acet o ne 
6 0 5  
Melti n g P oi nt                        1 3 2 -1 3 5º C  
6 0 6  
O ptical R otati o n                   R; [ α] D 2 0 ° C = + 2. 5° t o + 3. 5° i n a 1 0 m g/ m L i n dic hl or o met ha ne  
6 0 7  
p H                                           3. 5 -4. 5 i n a n a q ue o us s us pe nsi o n c o ntai ni n g 1 0 m g/ g  
6 0 8  
 
6 0 9  
Artes u nate va gi nal i nserts c o m p ositi o n ca n be f o u n d i n t he ta ble bel o w.  
6 1 0  
  
6 1 1  
Q u a ntit ati ve c o m p ositi o n of artes u n ate i nsert  
6 1 2  
I n gre die nt 
F u ncti o n  
Artes u nate  
Acti ve i n gre die nt  

 
 
C O N FI D E N TI A L  
PI: M u n g o  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n 1. 0  
 
A pril 2 5, 2 0 2 3  
 
1 7  
 
P C C A M B K T M * - h y dr o ge nate d ve geta ble oil a n d P E G -8 
distearate.  
Base  
B ut ylate d H y dr o x yl A nis ole N F  
Preser vati ve  
 
6 1 3  
S u p plier/ H o w S u p plie d, F or m ul ati o n  
6 1 4  
Artes u nate va gi nal i nserts will be pr o d uce d u n der c o ntr olle d e n vir o n me ntal c o n diti o n s as 
6 1 5  
prescri be d i n U S P C ha pter 7 9 5.  
6 1 6  
Cli nical trial s u p plies will be pr o d uce d b y B u derer Dr u g C o. i n Perr ys b ur g, O hi o. B u derer 
6 1 7  
mai ntai ns c o m plia nce wit h U S P C ha pter 7 9 5 ( P har mace utical C o m p o u n di n g –  N o nsterile 
6 1 8  
Pre parati o ns) a n d U S P C ha pter 7 9 7 ( P har mace utical C o m p o u n di n g –  Sterile Pre parati o ns) w hic h 
6 1 9  
esta blis h practice sta n dar ds a n d o utli ne t he res p o nsi bilit y of t he c o m p o u n der, selecti o n a n d 
6 2 0  
a p pr o priate s o urces of i n gre die nts, q ualit y c o ntr ol, a n d c o nsi derati o ns re gar di n g t he sta bilit y of 
6 2 1  
c o m p o u n de d pre parati o ns. T w o a d diti o nal U S P i nf or mati o nal c ha pters are i n effect, i ncl u di n g, 
6 2 2  
U S P C ha pter 1 0 7 5 –  G o o d C o m p o u n di n g Practices, a n d U S P C ha pter 1 1 6 0 –  P har mace utical 
6 2 3  
Calc ulati o ns i n Prescri pti o n C o m p o u n di n g.  
6 2 4  
3. 2  D os a ge a n d A d mi nistr ati o n  
6 2 5  
D ose:  2 0 0 m g dail y f or fi ve c o nsec uti ve da ys  
6 2 6  
R o ute of a d mi nistrati o n:  I ntra va gi nal, usi n g an  i ntra va gi nal a p plicat or 
6 2 7  
P ac k a gi n g a n d L a belli n g:  Pessaries ( va gi nal i nserts) f or dis pe nsi n g will be pac ka ge d i n sta n dar d 
6 2 8  
prescri pti o n use plastic or car d b oar d c o ntai ners. Pr o per la beli n g will be a p plie d per state 
6 2 9  
re g ulati o ns.  
6 3 0  
St or a ge a n d St a bilit y:  T he i nserts ma y be st ore d at c o ntr olle d r o o m te m perat ure.  I nserts f or 
6 3 1  
dis pe nsi n g will be pac ka ge d i n a plastic or car d b oar d c o ntai ner a n d ke pt i n t heir plastic m ol d u ntil 
6 3 2  
a d mi nistrati o n.  
6 3 3  
 
6 3 4  
A d mi nistr ati o n I nstr ucti o ns: All st u d y partici pa nts will recei ve detaile d c o u nselli n g a n d 
6 3 5  
i nstr ucti o ns o n artes u nate use pri or t o a d mi nistrati o n, i ncl u di n g i nstr ucti o n t o was h t heir ha n ds 
6 3 6  
bef ore a n d after i nserti n g t he pessaries. At t he ti me of visit 1, after a ne gati ve pre g na nc y test is 
6 3 7  
c o nfir me d, t he st u d y p h ysicia n or n urse will pr o vi de t he first va gi nal i nsert, a p plicat or, a n d 
6 3 8  
ta m p o n. D uri n g t hat visit, t he s u bjects will be i nstr ucte d o n t he va gi nal a p plicati o n of Artes u nate 
6 3 9  
i nserts usi n g t he a p plicat or pr o vi de d, f oll o we d b y t he st u d y-pr o vi de d ta m p o n. Ta m p o ns s h o ul d 
6 4 0  
be ke pt i n place after eac h artes u nate i nsert f or at least 4 h o urs, b ut n o l o n ger t ha n 1 0 h o urs. 
6 4 1  
Ta m p o ns s h o ul d be discar de d pr o perl y, a wa y fr o m c hil dre n a n d pets.  O nce t he ta m p o n is 
6 4 2  
re m o ve d, partici pa nts will be a d vise d t o t h or o u g hl y was h t heir ha n ds, a n d wi pe o utsi de of t heir 
6 4 3  
ge nital area ( v ul var a n d peria nal) t o re m o ve a n y resi d ue of t he dr u g. T o mi ni mize irritati o n, 
6 4 4  
partici pa nts will be a d vise d n ot t o e n ga ge i n se x ual c o ntact ( ge nital, a nal, or oral se x) f or at least 
6 4 5  
4 h o urs after a p pl yi n g t he va gi nal i nserts, o n da ys 1 -5. Partici pa nts will ret ur n t o t he st u d y cli nic 
6 4 6  
dail y f or visits 2 -5 f or self -a d mi nistrati o n of i nserts n u m bers 2 -5 as well as f or re vie w of a n y 
6 4 7  
a d verse e ve nts. Partici pa nts will be a d vise d n ot t o d o uc he d uri n g t he fi ve da ys of i ntra va gi nal 
6 4 8  
artes u nate use, a n d n ot t o use a n y i ntra va gi nal oi nt me nts, gels, or ot her t y pes of pessaries.  F or 
6 4 9  
a n y bacterial or yeast va gi nal i nfecti o ns, partici pa nts s h o ul d use oral me dicati o n, w hic h will be 
6 5 0  
prescri be d b y t he st u d y d oct or.    
6 5 1  

 
 
C O N FI D E N TI A L  
PI: M u n g o  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n 1. 0  
 
A pril 2 5, 2 0 2 3  
 
1 8  
 
D ose r ati o n ale:  T he d ose f or t his st u d y ( 2 0 0 m g) was c h ose n base d o n a c o m bi nati o n of 
6 5 2  
p u blis he d cli nical a n d p har mac o ki netic data re gar di n g i ntra -rectal a d mi nistrati o n of artes u nate 
6 5 3  
s u p p osit ories setti n g. 6 8 al o n g wit h cli nical data de m o nstrati n g t he safet y, t olera bilit y a n d efficac y 
6 5 4  
of t his d osi n g f or treat me nt of cer vical preca ncer ( CI N 2/ 3) i n a U. S P hase I trial. 1 8 T his sa me 
6 5 5  
d osi n g is bei n g st u die d i n o n g oi n g P hase II trials.  
6 5 6  
C o m p aris o n of st u d y d ose t o artes u n ate d os a ge f or ot her i n dic ati o ns: T he pr o p ose d st u d y 
6 5 7  
d ose of 2 0 0 m g per pessar y ( ≤4  m g/ K g f or      partici pa nts w h o wei g ht ≥5 0 K g, w hic h is a n 
6 5 8  
i ncl usi o n criteria f or t he st u d y) is c o nsi dera bl y less t ha n d oses ass ociate d wit h t o xicit y i n a ni mal 
6 5 9  
st u dies ( > 6 0 m g/ K g) a n d t he rectal s u p p osit or y d oses use d i n c hil dre n (a p pr o xi matel y 1 0 m g/ K g) 
6 6 0  
a n d a d ults (a p pr o xi matel y 8. 3 m g/ K g) f or malaria treat me nt. 3 5 T his pr o vi des a d diti o nal rati o nale 
6 6 1  
f or safet y. 
6 6 2  
3. 3       Acc o u nt a bilit y Pr oce d ures f or St u d y I n vesti g ati o n al Dr u g  
6 6 3  
 
6 6 4  
St or a ge, St a bilit y a n d H a n dli n g: Artes u nate pessaries will be st ore d at r o o m te m perat ure at t he 
6 6 5  
site p har mac y wit h c o ntr olle d access a n d dis pe nse d u n der t he a ut h orit y of a lice nse d p har macist. 
6 6 6  
Pessaries/i nserts f or dis pe nsi n g will be pac ka ge d i n a plastic or car d b oar d c o ntai ner a n d ke pt i n 
6 6 7  
t heir plastic m ol d u ntil a d mi nistrati o n. A n y u n use d pessaries will be ret ur ne d t o t he st u d y site 
6 6 8  
p har mac y f or se gre gati o n a n d destr ucti o n as per t he P har mac y a n d P ois o ns B oar d g ui deli nes o n 
6 6 9  
p har mace utical waste ma na ge me nt a n d dis p osal.  
6 7 0  
St u d y Dr u g Acc o u nt a bilit y: F oll o wi n g re g ulat or y a p pr o val, dr u g s u p pl y will be s hi p pe d t o t he 
6 7 1  
I nstit uti o nal P har mac y. T he i n vesti gat or or desi g nee is res p o nsi ble f or kee pi n g acc urate rec or ds of 
6 7 2  
t he cli nical s u p plies recei ve d fr o m t he c o m pa n y s p o ns or or desi g nee, t he a m o u nt dis pe nse d t o t he 
6 7 3  
s u bjects a n d t he a m o u nt re mai ni n g at t he c o ncl usi o n of t he trial. T he n u m ber of st u d y dr u g 
6 7 4  
dis pe nse d will be rec or de d o n t he I n vesti gati o nal Dr u g Acc o u nta bilit y Rec or d ( A p pe n di x  A ).   
6 7 5  
C o nc o mit a nt Me dic ati o ns:  D uri n g t he 5 -da y d osi n g p hase ( Visit 1 –  Visit 5), partici pa nts are 
6 7 6  
pr o hi bite d fr o m usi n g arte misi ni n -base d t hera pies i ncl u di n g f or malaria treat me nt. Partici pa nts 
6 7 7  
dia g n ose d wit h malaria d uri n g t his s h ort ti me will be prescri be d alter nati ve e vi de nce -base d 
6 7 8  
t hera p y. Use of efa vire nz a ntiretr o viral t hera p y is als o pr o hi bite d d uri n g t he d osi n g p hase a n d is 
6 7 9  
a n e xcl usi o n criteria.  
6 8 0  
4  M E T H O D O L O G Y  
6 8 1  
4. 3  
St u d y Det ails a n d Pr oce d ures  
6 8 2  
St u d y Desi g n a n d S a m pli n g : T his is a si n gle ar m, o pe n-la bel P hase I, n o n-ra n d o mize d st u d y. 
6 8 3  
Partici pa nts meeti n g t he i ncl usi o n criteria will be se q ue ntiall y e nr olle d.  
6 8 4  
 
6 8 5  
St u d y P o p ul ati o n: T he st u d y p o p ulati o n will be u p t o 1 6 w o me n 1 8 years or ol der li vi n g i n 
6 8 6  
Kis u m u C o u nt y i n Ke n ya, i n or der t o ha ve 1 2 f ull y e val ua ble partici pa nts, o ur desire d sa m ple 
6 8 7  
size. F ull y e val ua ble partici pa nts are t h ose w h o recei ve artes u nate i nserts f or 5 c o nsec uti ve da ys 
6 8 8  
a n d u n der g o bl o o d dra ws bef ore a n d after recei vi n g artes u nate at all t he ti me p oi nts per st u d y 
6 8 9  
pr ot oc ol. E nr oll me nt will st o p o nce data fr o m 1 2 f ull y e val ua ble partici pa nts are o btai ne d. N o 
6 9 0  
m ore t ha n 1 6 partici pa nts will be e nr olle d.  
6 9 1  

 
 
C O N FI D E N TI A L  
PI: M u n g o  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n 1. 0  
 
A pril 2 5, 2 0 2 3  
 
2 0  
 
Assi g n u ni q ue 
partici pa nt I D n u m ber  
X  
 
 
 
 
Pel vic e xa m  
X  
 
 
 
 
Malaria a nti ge n 
testi n g2 
X  
 
 
 
 
Uri ne pre g na nc y 
testi n g 
X  
 
 
 
 
C ollect l ocat or 
i nf or mati o n 
X  
X  
X  
X  
 
De m o nstrati o n of 
i ntra va gi nal 
Artes u n ate a p plicati o n 
usi n g pel vic m o del  
X  
X  
 
 
 
Artes u nate pessar y 
self-a d mi nistrati o n i n 
cli nic  
 
X  
X  
X  
 
Re vie w 
c o nc o mita nt/ pr o hi bite
d me dicati o ns  
X  
 
 
 
 
Bl o o d Dra w(s)  
 
X  
 
X  
 
A d verse e ve nts re vie w  
 
X  
X  
X  
X  
Tra ns p ort 
Rei m b urse me nt  
X  
X  
X  
X  
X  
St u d y e xit  
 
 
 
 
X  
1. Visit 1 ma y be c o m bi ne d wit h t he scree ni n g visit  
7 2 7  
2. T h ose p ositi ve will be referre d f or treat me nt a n d be scree n fail ure  
7 2 8  
* Visit 6 will occ ur 4 -1 0 da ys after visit 5  
7 2 9  
a.  4. 2 St u d y Acti vities b y Visit  
7 3 0  
 
7 3 1  
Pre -Scree ni n g: As part of partici pa nt o utreac h a n d recr uit me nt, st u d y staff ca n pre -scree n 
7 3 2  
p ote ntial st u d y partici pa nts at eit her o n -site or off-site l ocati o ns. D uri n g t hese i nteracti o ns, st u d y 
7 3 3  
staff ma y e x plai n t he st u d y t o p ote ntial partici pa nts a n d ascertai n ele me nts of pres u m pti ve 
7 3 4  
eli gi bilit y t o be c o nfir me d at a n o n -site scree ni n g visit. Pr ocess i nf or mati o n (e. g., n u m ber of 
7 3 5  
p ote ntial partici pa nts c o ntacte d, n u m ber pres u m pti vel y eli gi ble) ma y be rec or de d a n d st ore d at 
7 3 6  
st u d y sites i n t he a bse nce of writte n i nf or me d c o nse nt fr o m p ote ntial partici pa nts, pr o vi de d t he 
7 3 7  
i nf or mati o n is c ollecte d i n s uc h a ma n ner t hat it ca n n ot be li n ke d t o partici pa nt i de ntifiers.  
7 3 8  
 
7 3 9  

 
 
C O N FI D E N TI A L  
PI: M u n g o  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n 1. 0  
 
A pril 2 5, 2 0 2 3  
 
2 1  
 
Scree ni n g/ E nr oll me nt Visit: T he scree ni n g peri o d ma y be u p t o 1 4 da ys pri or t o Visit 1. 
7 4 0  
M ulti ple visits ma y be c o n d ucte d t o c o m plete all re q uire d scree ni n g pr oce d ures, if necessar y. 
7 4 1  
Writte n i nf or me d c o nse nt f or scree ni n g/e nr oll me nt m ust be o btai ne d bef ore a n y scree ni n g 
7 4 2  
pr oce d ures are i nitiate d. F or partici pa nts w h o d o n ot meet t he eli gi bilit y criteria, scree ni n g will 
7 4 3  
be disc o nti n ue d o nce i neli gi bilit y is deter mi ne d, a n d a scree n fail ure rec or de d. As part of 
7 4 4  
scree ni n g acti vities, partici pa nts  will ha ve a malaria a nti ge n test  t o scree n f or s u bac ute malaria 
7 4 5  
i nfecti o n. T h ose w h o test p ositi ve will be referre d f or treat me nt a n d c o nsi dere d scree n fail ure.  
7 4 6  
 
7 4 7  
Scree ni n g/e nr oll me nt visit acti vities:  
7 4 8  
- 
C o nfir m eli gi bilit y  
7 4 9  
- 
O btai n i nf or me d c o nse nt  
7 5 0  
- 
Assi g n u ni q ue partici pa nt I D n u m ber  
7 5 1  
- 
St u d y pr ot oc ol c o u nselli n g (i ntr o d uce t he st u d y t o t he partici pa nt, e x plai n all st u d y 
7 5 2  
acti vities a n d ti mi n g, le n gt h, e x pectati o ns of t he partici pa nt, de m o nstrati o n of i ntra va gi nal 
7 5 3  
Artes u n ate a p plicati o n usi n g pel vic m o del, disc ussi o n of ta m p o n use etc.)  
7 5 4  
- 
Perf or m li mite d p h ysical a n d pel vic e xa m a n d c ol p osc o p y wit h di gital i ma gi n g  
7 5 5  
- 
C ollect l ocat or i nf or mati o n  
7 5 6  
- 
Uri ne pre g na nc y testi n g  
7 5 7  
- 
Re vie w c o nc o mita nt/ pr o hi bite d me dicati o ns  
7 5 8  
- 
O btai n basic de m o gra p hic a n d cli nical data  
7 5 9  
 
7 6 0  
Visit 1 : Visit 1 ca n occ ur o n t he sa me da y or u p t o 1 4 da ys f oll o wi n g t he scree ni n g/e nr oll me nt 
7 6 1  
visit. Visit 1 will be ti me d t o be n o less t ha n 1 wee k bef ore t he partici pa nt’s a ntici pate d me nstr ual 
7 6 2  
c ycle, f or me nstr uati n g partici pa nts.  
7 6 3  
 
7 6 4  
Visit 1 acti vities:  
7 6 5  
- 
C o nfir m eli gi bilit y  
7 6 6  
- 
U p date l ocat or i nf or mati o n (if necessar y)  
7 6 7  
- 
Re vie w artes u nate self -a d mi nistrati o n i nstr ucti o ns a n d st u d y pr ot oc ol  
7 6 8  
- 
Re vie w c o nc o mita nt/ pr o hi bite d me dicati o ns  
7 6 9  
- 
Dra w bl o o d ( ~ 2. 5 ml) bef ore artes u nate self -a d mi nistrati o n  
7 7 0  
- 
Artes u nate self -a d mi nistrati o n usi n g a p plicat or, f oll o we d b y ta m p o n   
7 7 1  
- 
O bser vati o n f or 3 0 mi n utes  
7 7 2  
- 
Pr o vi de tra ns p ort rei m b urse me nt  
7 7 3  
- 
Sc he d ule Visits 2  
7 7 4  
 
7 7 5  
Visit 2 -4: Visits 2, 3 a n d 4 m ust occ ur se q ue ntiall y ( wit hi n 2 4 h o urs) of eac h ot her. Atte m pts 
7 7 6  
will be ma de t o start visits at a p pr o xi matel y t he sa me ti me eac h da y.  
7 7 7  
 
7 7 8  
Visit 2 -4 acti vities:  
7 7 9  
- 
U p date l ocat or i nf or mati o n (if necessar y)  
7 8 0  
- 
Re vie w a n d rec or d a d verse e ve nts usi n g sta n dar dize d q uesti o n naire  
7 8 1  
- 
Perf or m pel vic e xa m as nee de d base d o n A Es descri be d ( pel vic e xa m f or s us pecte d gra de 
7 8 2  
II or w orse A Es) 
7 8 3  
- 
Re vie w c o nc o mita nt/ pr o hi bite d me dicati o ns  
7 8 4  

 
 
C O N FI D E N TI A L  
PI: M u n g o  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n 1. 0  
 
A pril 2 5, 2 0 2 3  
 
2 2  
 
- 
Artes u nate self -a d mi nistrati o n usi n g a p plicat or, f oll o we d b y ta m p o n i nserti o n  
7 8 5  
- 
O bser vati o n f or 3 0 mi n utes  
7 8 6  
- 
Pr o vi de tra ns p ort rei m b urse me nt  
7 8 7  
- 
Sc he d ule s u bse q ue nt visit  
7 8 8  
 
7 8 9  
Visit 5: Visit 5 will occ ur o ne da y ( ~ 2 4 h o urs) after Visit 4. Atte m pts will be ma de t o start visits 
7 9 0  
at t he sa me ti me eac h da y.  
7 9 1  
 
7 9 2  
Visit 5 acti vities:  
7 9 3  
- 
U p date l ocat or i nf or mati o n (if necessar y)  
7 9 4  
- 
Re vie w a n d rec or d a d verse e ve nts usi n g a sta n dar dize d q uesti o n naire 
7 9 5  
- 
Perf or m pel vic e xa m as nee de d base d o n A Es descri be d ( pel vic e xa m f or s us pecte d gra de 
7 9 6  
II or w orse A Es) 
7 9 7  
- 
Re vie w c o nc o mita nt/ pr o hi bite d me dicati o ns  
7 9 8  
- 
Dra w bl o o d ( ~ 2 . 5 ml) bef ore artes u nate self-a d mi nistrati o n & i nsert peri p heral ca n n ula f or 
7 9 9  
s u bse q ue nt bl o o d dra ws 
8 0 0  
- 
Artes u nate self -a d mi nistrati o n usi n g a n a p plicat or, f oll o we d b y ta m p o n i nserti o n  
8 0 1  
- 
Bl o o d dra ws ( ~ 2. 5 ml eac h ti me) at 1 5, 3 0 mi n, 1 h, 2 h, 4 h, 6 h, a n d 8 h after artes u nate self -
8 0 2  
a d mi nistrati o n.  
8 0 3  
- 
Pr o vi de tra ns p ort rei m b urse me nt  
8 0 4  
- 
Sc he d ule visit 6  
8 0 5  
Visit 6: Visit 6 will occ ur 4 -1 0 da ys after visit 5  
8 0 6  
 
8 0 7  
Visit 6 acti vities:  
8 0 8  
- 
Re vie w a n d rec or d a d verse e ve nts si nce last visit usi n g sta n dar dize d q uesti o n naire  
8 0 9  
- 
Perf or m pel vic e xa m a n d c ol p osc o p y wit h di gital i ma gi n g  
8 1 0  
- 
St u d y e xit/ter mi nati o n  
8 1 1  
- 
Pr o vi de rei m b urse me nt  
8 1 2  
b.  4. 3 A d verse E ve nt Re p orti n g  
8 1 3  
 
8 1 4  
Defi niti o ns  
8 1 5  
A n a d verse e ve nt ( 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 
8 1 6  
partici pa nt a d mi nistere d a p har mace utical pr o d uct a n d w hic h d oes n ot necessaril y ha ve a ca usal 
8 1 7  
relati o ns hi p wit h t his treat me nt.  A n a d verse e ve nt ca n t heref ore be a n y u nfa v ora ble a n d 
8 1 8  
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 
8 1 9  
ass ociate d wit h t he use of a me dici nal (i n vesti gati o nal) pr o d uct, w het her or n ot relate d t o t he 
8 2 0  
me dici nal (i n vesti gati o nal) pr o d uct.  
8 2 1  
 
8 2 2  
A n u ne x pecte d ( u nliste d) a d verse e ve nt  is a n a d verse reacti o n, t he nat ure or se verit y of w hic h is 
8 2 3  
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 n vesti gat or’s Br oc h ure f or a n 
8 2 4  
u na p pr o ve d i n vesti gati o nal pr o d uct or pac ka ge i nsert/s u m mar y of pr o d uct c haracteristics f or a n 
8 2 5  
a p pr o ve d pr o d uct).  
8 2 6  
 
8 2 7  
A seri o us a d verse e ve nt ( S A E) is a n y u nt o war d me dical occ urre nce t hat at a n y d ose: 
8 2 8  

 
 
C O N FI D E N TI A L  
PI: M u n g o  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n 1. 0  
 
A pril 2 5, 2 0 2 3  
 
2 3  
 
▪ 
res ults i n deat h; 
8 2 9  
▪ 
is life-t hreate ni n g; 
8 3 0  
▪ 
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; 
8 3 1  
▪ 
res ults i n a persiste nt or si g nifica nt disa bilit y/i nca pacit y; or 
8 3 2  
▪ 
is a c o n ge nital a n o mal y/ birt h defect 
8 3 3  
 
8 3 4  
I m p orta nt me dical e ve nts as assesse d b y me dical a n d scie ntific j u d g me nt ma y als o be c o nsi dere d 
8 3 5  
S A Es b y t he i n vesti gat or a n d s h o ul d be re p orte d i n a n e x pe dite d fas hi o n.   
8 3 6  
 
8 3 7  
S afet y/ A d verse E ve nts E v al u ati o ns: Safet y e val uati o n t o e val uate f or a d verse e ve nts will be 
8 3 8  
d o ne usi n g U. S Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts, v 5. 0 
8 3 9  
( C T C A E 5. 0) (A p pe n di x B ) f or s yste mic A Es6 9 a n d t he Di visi o n of AI D S Fe male Ge nital Gra di n g 
8 4 0  
Ta ble f or Use i n Micr o bici de St u dies ( A p pe n di x C) f or l ocalize d/ ge nital A Es. 7 0A d verse e ve nts 
8 4 1  
will be elicite d b y a trai ne d cli nicia n ( n urse, cli nical officer, or me dical officer) at t he st u d y visits 
8 4 2  
1 t hr o u g h 6. As part of A E e val uati o n, s yste mic s y m pt o ms t hat ma y be relate d t o st u d y dr u g use 
8 4 3  
i ncl u di n g hea dac he, dizzi ness, ti n nit us, GI disc o mf ort will be e val uate d. L ocalize d/ pel vic A Es 
8 4 4  
i ncl u di n g va gi nal pr uritis, disc har ge, pel vic pai n will als o be elicite d d uri n g st u d y visits. All 
8 4 5  
partici pa nts will ha ve a pel vic a n d s pec ul u m e xa m at baseli ne t o d oc u me nt t he a p peara nce of 
8 4 6  
ge nital m uc osa bef ore artes u nate a d mi nistrati o n. D uri n g visits 1 -5, pel vic/s pec ul u m e xa m will be 
8 4 7  
perf or me d base d o n cli nical i n dicati o ns o nl y, i ncl u di n g a m o n g all partici pa nts re p orti n g s us pecte d 
8 4 8  
gra de 2 or hi g her l ocal A Es i ncl u di n g pai n, irritati o n, itc hi n g, or er yt he ma , base d o n t he Di visi o n 
8 4 9  
of AI D S Fe male Ge nital Gra di n g Ta ble f or Use i n Micr o bici de St u dies sta n dar dize d gra di n g scale. 
8 5 0  
Cli nicia ns will ha ve a l o w t hres h ol d f or perf or mi n g a pel vic e xa m d uri n g t hese visits base d o n 
8 5 1  
partici pa nt s y m pt o ms. At visit 6 (st u d y e xit), all partici pa nts will ha ve a pel vic e xa m t o d oc u me nt 
8 5 2  
a p peara nce of ge nital m uc osa at e n d of artes u nate use. D uri n g pel vic e xa mi nati o ns, t he v ul va, 
8 5 3  
va gi nal tiss ue a n d cer vi x will be i ns pecte d f or e vi de nce of i nfla m mati o n or er yt he ma. Per t he 
8 5 4  
C T C A E a n d Di visi o n of AI D S sta n dar dize d gra di n g scales, A Es will be gra de d as gra de 0 - n o ne, 
8 5 5  
gra de 1 –  mil d, gra de 2 –  m o derate, gra de 3 –  se vere, gra de 4- p ote ntiall y life -t hreate ni n g, or gra de 
8 5 6  
5 –  deat h -relate d A Es.  
8 5 7  
 
8 5 8  
M a n a ge me nt a n d re p orti n g of a d verse e ve nts:  Base d o n t he pri or P hase I st u d y of i ntra va gi nal 
8 5 9  
artes u nate at t his d osa ge a n d fre q ue nc y, self -li mite d gra de 1 ( mil d) A Es are e x pecte d, a n d gra de 
8 6 0  
II ( m o derate) A Es will be fe w, w hile gra de 3 or w orse A Es are n ot e x pecte d. I n t his st u d y, A Es 
8 6 1  
will be elicite d a n d rec or de d i n t he partici pa nt st u d y rec or ds at eac h st u d y visit. All l ocal A Es will 
8 6 2  
be c o nsi dere d ca usall y relate d t o a d mi nistrati o n of t he st u d y dr u g. Ca usalit y of all ot her A Es will 
8 6 3  
be assesse d i n di vi d uall y. Partici pa nts wit h gra de I or II A Es will be f oll o we d u ntil res ol uti o n of 
8 6 4  
A Es. Gra de II A Es will be ma na ge d s y m pt o maticall y. Va gi nal i nfecti o ns i ncl u di n g yeast i nfecti o ns 
8 6 5  
will be treate d wit h oral me dicati o ns d uri n g t he d osi n g p hase. Si g nifica nt l ocal i nfla m mati o n, if 
8 6 6  
a n y, will be treate d wit h oral a nal gesics. L ocal i nfecti o n or ulcerati o n, w hic h are u ne x pecte d, will 
8 6 7  
be treate d wit h r o uti ne w o u n d care a n d a nti bi otics as necessar y. Partici pa nts f o u n d t o ha ve a n y 
8 6 8  
gra de 3 or hi g her A Es will be i nstr ucte d t o st o p st u d y dr u g use, a n d t he Data a n d  Safet y a n d 
8 6 9  
M o nit ori n g B oar d ( D S M C) n otifie d wit hi n 5 b usi ness da ys of t he PI bec o me a ware. Partici pa nts 
8 7 0  
will n ot res u me st u d y dr u g use u ntil t he D S M C deci des t hat t he A E is n ot relate d t o t he st u d y dr u g.   
8 7 1  
 
8 7 2  
O utc o mes of A Es will be assesse d as: 1) Rec o vere d, 2) Rec o vere d wit h se q uelae, 3) O n g oi n g at      
8 7 3  
partici pa nt e n d -of -st u d y visit, 4) Die d, 5) U n k n o w n.  
8 7 4  

 
 
C O N FI D E N TI A L  
PI: M u n g o  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n 1. 0  
 
A pril 2 5, 2 0 2 3  
 
2 4  
 
 
8 7 5  
Pre g na ncies detecte d d uri n g t he st u d y (after first use of Artes u nate ( Visit 1) t hr o u g h Visit 5) will 
8 7 6  
be rec or de d as S A Es. T he partici pa nt will be referre d f or pre natal care, prefera bl y t o a pr o vi der 
8 7 7  
w h o is e x perie nce d i n re pr o d ucti ve t o xicit y f or f urt her e val uati o n a n d c o u nseli n g. T he I n vesti gat or 
8 7 8  
will atte m pt t o f oll o w t he partici pa nt u ntil c o m pleti o n of t he pre g na nc y a n d d oc u me nt t he o utc o me 
8 7 9  
of t he pre g na nc y (eit her n or mal or a b n or mal o utc o me) a n d re p ort t he c o n diti o n of t he fet us or 
8 8 0  
ne w b or n t o t he St u d y C o or di nat or, if p ossi ble. If t he o utc o me of t he pre g na nc y was a b n or mal (e. g., 
8 8 1  
s p o nta ne o us or t hera pe utic a b orti o n), t he I n vesti gat or will re p ort t he a b n or mal o utc o me as a n A E.  
8 8 2  
 
8 8 3  
F or all a d verse e ve nts re p orte d or o bser ve d, t he i nf or mati o n s h o ul d be rec or de d i n t he Case Re p ort 
8 8 4  
F or ms f or t hat partici pa nt.  T his will i ncl u de a f ull descri pti o n of t he e ve nt, its seri o us ness, its 
8 8 5  
se verit y or t o xicit y gra de (i nte nsit y), t he relati o ns hi p t o t he st u d y dr u g, a n d t he treat me nt, o utc o me, 
8 8 6  
a n d se q uelae of t he e ve nt.  
8 8 7  
 
8 8 8  
A n y seri o us or u ne x pecte d e ve nt, w hic h occ urs t o a n y partici pa nt i n t he c o urse of her treat me nt o n 
8 8 9  
t his st u d y or wit hi n 3 0 da ys f oll o wi n g cessati o n of treat me nt, m ust be re p orte d i m me diatel y t o t he 
8 9 0  
St u d y C o or di nat or b y tele p h o ne at + 2 5 4 7 0 5 7 5 5 2 2 0 or wit hi n 2 4 h o urs of t he i n vesti gat or lear ni n g 
8 9 1  
of its occ urre nce.  T he i m me diate re p orts s h o ul d be f oll o we d pr o m ptl y b y detaile d, writte n re p orts.  
8 9 2  
T he St u d y C o or di nat or will t he n i nf or m t he Pri nci pal I n vesti gat or of t he A d verse E ve nt T he PI is 
8 9 3  
res p o nsi ble f or re p orti n g A Es. C o pies of t hese re p orts s h o ul d be se nt t o: 
8 9 4  
● I R B 
8 9 5  
● F u n di n g S o urce (if a p pr o priate)   
8 9 6  
 
8 9 7  
Re p orti n g is re q uire d of all u na ntici pate d pr o ble ms t o t he U N C I R B, i ncl u di n g t h ose w hic h ma y 
8 9 8  
occ ur after t he partici pa nt has c o m plete d or has wit h dra w n fr o m t he st u d y, i ncl u di n g after st u d y 
8 9 9  
cl os ure.  
9 0 0  
 
9 0 1  
U na ntici pate d pr o ble ms as defi ne d b y t he U N C I R B:  
9 0 2  
U na ntici pate d pr o ble ms i n v ol vi n g ris ks t o partici pa nts or ot hers” or “ U na ntici pate d Pr o ble m” 
9 0 3  
( U P) refers t o a n y i nci de nt, e x perie nce, or o utc o me t hat: 
9 0 4  
● is u ne x pecte d (i n ter ms of nat ure, se verit y, or fre q ue nc y) gi ve n (a) t he researc h 
9 0 5  
pr oce d ures t hat are descri be d i n t he pr ot oc ol -relate d d oc u me nts, s uc h as t he I R B-
9 0 6  
a p pr o ve d researc h pr ot oc ol a n d i nf or me d c o nse nt d oc u me nt; a n d ( b) t he 
9 0 7  
c haracteristics of t he partici pa nt p o p ulati o n bei n g st u die d;  
9 0 8  
● is relate d or p ossi bl y relate d t o a partici pa nt’s partici pati o n i n t he researc h; a n d  
9 0 9  
● s u g gests t hat t he researc h places partici pa nts or ot hers at a greater ris k of har m 
9 1 0  
(i ncl u di n g p h ysical, ps yc h ol o gical, ec o n o mic, or s ocial har m) relate d t o t he 
9 1 1  
researc h t ha n was pre vi o usl y k n o w n or rec o g nize d.  
9 1 2  
 
9 1 3  
U na ntici pate d Pr o ble ms t hat are seri o us a d verse e ve nts s h o ul d be re p orte d t o t he U N C I R B 
9 1 4  
wit hi n o ne ( 1) wee k of t he i n vesti gat or bec o mi n g a ware of t he e ve nt.  A n y ot her U na ntici pate d 
9 1 5  
Pr o ble m s h o ul d be re p orte d t o t he U N C I R B wit hi n t w o ( 2) wee ks of t he i n vesti gat or bec o mi n g 
9 1 6  
a ware of t he pr o ble m.  If t he U na ntici pate d Pr o ble m Re p ort ca n n ot be c o m plete d i n its e ntiret y 
9 1 7  
wit hi n t he re q uire d ti me peri o d, a preli mi nar y re p ort s h o ul d be s u b mitte d.  T he U na ntici pate d 
9 1 8  
Pr o ble m Re p ort s h o ul d be a me n de d o nce t he e ve nt is res ol ve d a n d/ or m ore i nf or mati o n bec o mes 
9 1 9  
a vaila ble.  
9 2 0  

 
 
C O N FI D E N TI A L  
PI: M u n g o  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n 1. 0  
 
A pril 2 5, 2 0 2 3  
 
2 5  
 
 
9 2 1  
All i n di vi d ual A E a n d I N D Safet y Re p orts s hall be mai ntai ne d b y t he Pri nci pal I n vesti gat or.  F or 
9 2 2  
t h ose e ve nts t hat are n ot re p orta ble t o t he U N C I R B, a s u m mar y (i.e., n ot i n di vi d ual re p orts) of 
9 2 3  
all a d verse e ve nts t hat ha ve occ urre d wit hi n t he last a p pr o val peri o d s h o ul d be s u b mitte d t o t he 
9 2 4  
U N C a n d Ke n ya I R B’s at t he ti me of c o nti n ui n g re vie w.  
9 2 5  
 
9 2 6  
Re p orts fr o m a Data a n d Safet y M o nit ori n g C o m mittee, ( D S M C), or ot her i n de pe n de nt safet y 
9 2 7  
m o nit ori n g gr o u p s h o ul d be pr o vi de d t o t he U N C a n d Ke n ya I R Bs o n a re g ular basis, ge nerall y 
9 2 8  
at least as ofte n as t he st u d y u n der g oes c o nti n ui n g re vie w.  Re p orts s h o ul d i ncl u de fi n di n gs fr o m 
9 2 9  
a d verse e ve nt re p orts a n d rec o m me n dati o ns deri ve d fr o m data a n d safet y m o nit ori n g.  
9 3 0  
 
9 3 1  
4. 4 S peci me n c ollecti o n, pr ocessi n g, st or a ge a n d a n al ysis  
9 3 2  
 
9 3 3  
F or eac h partici pa nt, ~ 2. 5 ml of bl o o d will be c ollecte d at eac h ti me p oi nt at baseli ne ( Da y 1), a n d 
9 3 4  
o n da y 5 pri or t o a d mi nistrati o n of i ntra va gi nal artes u nate (ti me 0), a n d at 1 5, 3 0 mi n, 1 h, 3 h, a n d 
9 3 5  
6 h after a d mi nistrati o n. Bl o o d will be c ollecte d i n g ol d/ yell o w t o p t u bes a n d ce ntrif u ge d t o 
9 3 6  
plas ma w hic h will be st ore d at -8 0 0C u ntil a nal yze d. Sa m ples will be st ore d at Ke n ya Me dical 
9 3 7  
Researc h I nstit ute ( K E M RI) -affiliate d accre dite d la b orat ories i n Kis u m u, Ke n ya, wit h c ol d c hai n 
9 3 8  
mai ntai ne d fr o m c ollecti o n t o st ora ge u ntil s hi p pi n g f or a nal ysis. All st u d y staff as well as 
9 3 9  
la b orat or y staff will be trai ne d o n st u d y S O Ps.  
9 4 0  
 
9 4 1  
D H A a n d artes u n ate pl as m a testi n g:  S peci me ns will be teste d at t he Walter Ree d Ar m y 
9 4 2  
I nstit ute of Researc h, ( W R AI R) Di visi o n of E x peri me ntal T hera pe utics la b orat or y i n Mar yla n d, 
9 4 3  
U S A w hic h has vali date d D H A a n d artes u nate assa ys. A nal ysis will be le d b y Jesse P. De L uca, 
9 4 4  
D. O C hief of Cli nical at t he Walter Ree d Ar m y I nstit ute of Researc h a n d t he Cli nical 
9 4 5  
P har mac ol o g y Fell o ws hi p Pr o gra m Direct or. Plas ma sa m ples will be s hi p pe d u n der c ol d c hai n 
9 4 6  
a n d re mai n fr oze n at at -8 0 0C i n W R AI R la b orat or y facilities u ntil rea d y f or a nal ysis. A nal ysis 
9 4 7  
will be perf or me d usi n g a vali date d hi g h -perf or ma nce Li q ui d C hr o mat o gra p h y Mass 
9 4 8  
S pectr o metr y ( L C M S) assa y at W R AI R wit h li mits of q ua ntificati o n of Artes u nate a n d D H A of 
9 4 9  
a p pr o xi matel y 8 0 n M a n d 7 0 n M, res pecti vel y. 3 1, 7 1 Q ualit y c o ntr ol ( Q C) sa m ples will be i ncl u de d 
9 5 0  
wit h eac h assa y batc h, wit h a re q uire me nt t hat t he r u n is acce pta ble o nl y if t he Q C is wit hi n +/ - 
9 5 1  
1 5 % of t he n o mi nal val ue. 3 5  T he W R AI R Di visi o n of E x peri me ntal T hera pe utics, Dr u g 
9 5 2  
Meta b olis m a n d Dis p ositi o n has o ver 7 5 years’ e x perie nce wit h dr u g a n d pr o d uct de vel o p me nt, 
9 5 3  
ha vi n g ac hie ve d U. S F D A a p pr o val of 9 malaria dr u gs a n d m ore t ha n 6 5 i n vesti gati o nal ne w 
9 5 4  
dr u g a p plicati o ns. All a p pr o priate material tra nsfer a gree me nts a n d s hi p pi n g lice nses will be 
9 5 5  
o btai ne d fr o m all rele va nt re g ulat or y b o dies i ncl u di n g t he A mref E S R C bef ore s peci me n 
9 5 6  
s hi p pi n g is d o ne. All s peci me ns will be destr o ye d f oll o wi n g testi n g. Eac h sa m ple will be 
9 5 7  
assi g ne d a u ni q ue c o de n u m ber, a n d n o i de ntifia ble pers o nal healt h i nf or mati o n ( P HI) will be o n 
9 5 8  
t he s peci me n la bel. 
9 5 9  
 
9 6 0  
P h ar m ac o ki netic a n al ysis:  C o n ve nti o nal p har mac o ki netic para meters - A U C ( 0, i nfi nit y), half -
9 6 1  
life, a p pare nt cleara nce, t he v ol u me of distri b uti o n, ma xi m u m plas ma c o nce ntrati o n ( C ma x), 
9 6 2  
ti me t o C ma x will be deter mi ne d fr o m t he plas ma c o nce ntrati o n-ti me data usi n g 
9 6 3  
n o nc o m part me ntal a nal ysis. 3 2, 3 5 Pea k plas ma c o nce ntrati o n ( C ma x) a n d ti me t o reac h pea k 
9 6 4  
c o nce ntrati o n (t ma x) f or artes u nate a n d D H A will be t he o bser ve d val ues. T he A U C of A S will 
9 6 5  
be calc ulate d b y li near tra pez oi dal s u m mati o n wit h e xtra p olati o n t o i nfi nit y. Wit h res pect t o 
9 6 6  

 
 
C O N FI D E N TI A L  
PI: M u n g o  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n 1. 0  
 
A pril 2 5, 2 0 2 3  
 
2 6  
 
D H A, A U C will be calc ulate d t o t he last dr u g meas ura ble ti me p oi nt. T he eli mi nati o n rate 
9 6 7  
c o nsta nt ( β), will be calc ulate d fr o m t he sl o pe of t he ter mi nal p hase of t he l o g c o nce ntrati o n -ti me 
9 6 8  
pr ofile, a n d t he eli mi nati o n half -life (t 1/ 2) calc ulate d fr o m t he rati o of l n 2/ β. Ot her P K 
9 6 9  
para meters will be calc ulate d usi n g sta n dar d m o del -i n de pe n de nt f or m ulae.3 9 T he esti mates of P K 
9 7 0  
para meters f or D H A will ass u me c o m plete c o n versi o n of A S t o D H A as re p orte d pre vi o usl y. 3 5 
9 7 1  
Data will be pl otte d gra p hicall y a n d a nal yze d usi n g statistical s oft ware. Data will be prese nte d as 
9 7 2  
mea n wit h sta n dar d de viati o n ( S D).  
9 7 3  
 
9 7 4  
C o m pli a nce St ate me nt:  Bi os peci me n c ollecti o n f or t his st u d y will be c o n d ucte d i n f ull 
9 7 5  
acc or da nce wit h all a p plica ble U ni versit y of N ort h Car oli na ( U N C) Researc h P olicies a n d 
9 7 6  
Pr oce d ures i ncl u di n g G o o d Cli nical Practice ( C G P) p olicies, a n d all a p plica ble Fe deral a n d state 
9 7 7  
la ws a n d re g ulati o ns i ncl u di n g 4 5 C F R 4 6, a n d t he Healt h I ns ura nce P orta bilit y a n d 
9 7 8  
Acc o u nta bilit y Act Pri vac y R ule, as well as t he i n -c o u ntr y re g ulat or y a ge ncies i ncl u di n g t he 
9 7 9  
A mref Et hics a n d Scie ntific Re vie w C o m mittee ( E S R C), t he Ke n ya P har mac y a n d P ois o ns 
9 8 0  
B oar d ( P P B), t he Nati o nal C o m missi o n f or Scie nce, Tec h n ol o g y & I n n o vati o n ( N A C O S TI) a n d 
9 8 1  
a n y ot her re g ulat or y b o dies re q uire d i n -c o u ntr y. A n y e pis o de of n o nc o m plia nce will be 
9 8 2  
d oc u me nte d. T he i n vesti gat ors will perf or m t he st u d y i n acc or da nce wit h t his pr ot oc ol, will 
9 8 3  
o btai n c o nse nt, a n d will re p ort u ne x pecte d pr o ble ms i n acc or da nce wit h t he U N C I R B P olicies 
9 8 4  
a n d Pr oce d ures a n d all fe deral re q uire me nts. C ollecti o n, rec or di n g, a n d re p orti n g of data will be 
9 8 5  
acc urate a n d will e ns ure t he pri vac y, healt h, a n d welfare of researc h      partici pa nts d uri n g a n d 
9 8 6  
after t he st u d y.  
9 8 7  
 
9 8 8  
Bi os afet y: T o e ns ure t he safet y of o ur researc h staff, st u d y partici pa nts, a n d t he s urr o u n di n g 
9 8 9  
c o m m u nit y, we will f oll o w t he bi osafet y le vel 2 ( B S L -2) sta n dar d as per t he Ke n ya n La b orat or y 
9 9 0  
Bi osafet y a n d Bi osec urit y P olic y G ui deli nes a n d Ke n ya Nati o nal G ui deli nes f or Safe 
9 9 1  
Ma na ge me nt of Healt h Care Waste. T his sta n dar d is desi g ne d t o re d uce or eli mi nate e x p os ure of 
9 9 2  
la b orat or y w or kers, ot her pers o ns, a n d t he o utsi de e n vir o n me nt t o p ote ntiall y hazar d o us or 
9 9 3  
detri me ntal materials. T he st u d y dr u g (artes u nate) is a well -c haracterize d dr u g t hat has bee n 
9 9 4  
e xte nsi vel y st u die d a n d is n ot k n o w n t o ca use disease i n healt h y i n di vi d uals. T he bi ol o gical 
9 9 5  
material ha n dle d, a n d bi ol o gical waste ge nerate d d uri n g t he st u d y are m o derate -ris k i nfecti o us 
9 9 6  
a ge nts a n d p ose a m o derate i n di vi d ual ris k a n d l o w c o m m u nit y ris k of e x p os ure. B y f oll o wi n g 
9 9 7  
t hese g ui deli nes, we ca n e ns ure t hat all o ur pr oce d ures are c o n d ucte d safel y, a n d t hat me dical 
9 9 8  
waste is dis p ose d of pr o perl y.  
9 9 9  
 
1 0 0 0  
M o nit ori n g/ D at a a n d S afet y M o nit ori n g: T he Pri nci pal I n vesti gat or will pr o vi de c o nti n u o us 
1 0 0 1  
m o nit ori n g of      partici pa nt safet y i n t his trial wit h peri o dic re p orti n g t o t he Data a n d Safet y 
1 0 0 2  
M o nit ori n g C o m mittee ( D S M C).  Meeti n gs/telec o nfere nces will be hel d at a fre q ue nc y de pe n de nt 
1 0 0 3  
o n st u d y accr ual. T hese meeti n gs will i ncl u de t he i n vesti gat ors as well as st u d y c o or di nat ors, 
1 0 0 4  
data c o or di nat ors, re g ulat or y ass ociates, a n d a n y ot her rele va nt pers o n nel t he pri nci pal 
1 0 0 5  
i n vesti gat ors ma y dee m a p pr o priate. At t hese meeti n gs, t he researc h tea m will disc uss all iss ues 
1 0 0 6  
rele va nt t o st u d y pr o gress, i ncl u di n g e nr oll me nt, safet y, re g ulat or y, data c ollecti o n, etc. 
1 0 0 7  
T he tea m will pr o d uce s u m maries or mi n utes of t hese meeti n gs. T hese s u m maries will be 
1 0 0 8  
a vaila ble f or i ns pecti o n w he n re q ueste d b y a n y of t he re g ulat or y b o dies c har ge d wit h t he safet y 
1 0 0 9  
of h u ma n      partici pa nts a n d t he i nte grit y of data i ncl u di n g, b ut n ot li mite d t o, t he o versi g ht of 
1 0 1 0  
Office of H u ma n Researc h Et hics Bi o me dical I R B.  
1 0 1 1  
 
1 0 1 2  

 
 
C O N FI D E N TI A L  
PI: M u n g o  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n 1. 0  
 
A pril 2 5, 2 0 2 3  
 
2 7  
 
T he U N C PI will be res p o nsi ble f or s u b mitti n g t he f oll o wi n g i nf or mati o n f or re vie w: 1) safet y 
1 0 1 3  
a n d accr ual data i ncl u di n g t he n u m ber of      partici pa nts treate d; 2) si g nifica nt de vel o p me nts 
1 0 1 4  
re p orte d i n t he literat ure t hat ma y affect t he safet y of      partici pa nts or t he et hics of t he st u d y; 3) 
1 0 1 5  
preli mi nar y res p o nse data; a n d 4) s u m maries of tea m meeti n gs t hat ha ve occ urre d si nce t he last 
1 0 1 6  
re p ort. Fi n di n gs of t he D S M C re vie w will be disse mi nate d b y me m o t o t he U N C PI, t he U N C 
1 0 1 7  
I R B,  a n d all Ke n ya re g ulat or y b o dies g o ver ni n g t he st u d y. 
1 0 1 8  
 
1 0 1 9  
Re m o v al of P artici p a nts fr o m t he St u d y:  A n y partici pa nt w h o d oes n ot wis h t o partici pate i n 
1 0 2 0  
t he st u d y will be e xite d fr o m t he st u d y at a n y ti me t he y prefer. A d diti o nall y, partici pa nts w h o fail 
1 0 2 1  
t o a d here t o si g nifica nt pr ot oc ol re q uire me nts, i ncl u di n g fail ure t o meet i ncl usi o n/e xcl usi o n 
1 0 2 2  
criteria, use of pr o hi bite d c o nc o mita nt me dicati o ns, i nci de nt pre g na nc y, or ot her reas o ns t hat i n 
1 0 2 3  
t he o pi ni o n of t he Pri nci pal I n vesti gat or ma y affect partici pa nt safet y ma y be re m o ve d fr o m t he 
1 0 2 4  
st u d y. T he I n vesti gat or will deter mi ne if a pr ot oc ol vi olati o n res ults i n wit h dra wal of a      
1 0 2 5  
partici pa nt. All pr ot oc ol vi olati o ns will be re p orte d t o t he rele va nt g o ver ni n g I R Bs.  
1 0 2 6  
 
1 0 2 7  
Partici pa nts w h o per ma ne ntl y disc o nti n ue st u d y pr o d uct a n d f oll o w -u p pri or t o st u d y c o m pleti o n 
1 0 2 8  
will be as ke d t o c o m plete a n earl y wit h dra wal visit, if willi n g, d uri n g w hic h a n y A Es will be 
1 0 2 9  
assesse d. If st u d y re m o val occ urs d ue t o pre g na nc y, partici pa nts will be referre d t o t he nearest 
1 0 3 0  
preferre d pre natal facilit y f or pre g na nc y care.  
1 0 3 1  
 
1 0 3 2  
Re pl ace me nt of P artici p a nts: A sa m ple size of N = 1 2 partici pa nts are nee de d f or t he pri mar y 
1 0 3 3  
ai ms of P K a nal ysis. T o all o w f or p ote ntial dr o p offs or i nc o m plete e val uati o n, u p t o N = 1 6 
1 0 3 4  
partici pa nts will be c o nse nte d a n d e nr olle d t o ha ve a sa m ple size of N = 1 2 f ull y e val ua ble 
1 0 3 5  
partici pa nts, w h o will fi nis h all st u d y visits a n d ha ve all s peci me ns c ollecte d. O nce t he mi ni m u m 
1 0 3 6  
sa m ple size of N = 1 2 of f ull y eli gi ble partici pa nts is met, n o a d diti o nal partici pa nts will be 
1 0 3 7  
e nr olle d or i nitiate st u d y pr oce d ures.  
1 0 3 8  
 
1 0 3 9  
     P artici p a nt Wit h dr a w al: If a partici pa nt deci des t o wit h dra w fr o m t he st u d y (a n d n ot j ust 
1 0 4 0  
fr o m pr ot oc ol t hera p y) a n eff ort s h o ul d be ma de t o c o m plete a n d re p ort st u d y assess me nts as 
1 0 4 1  
t h or o u g hl y as p ossi ble. At t he ti me of wit h dra wal, t he i n vesti gat or s h o ul d atte m pt t o esta blis h as 
1 0 4 2  
c o m pletel y as p ossi ble t he reas o n f or t he st u d y wit h dra wal.  
1 0 4 3  
• 
T he      partici pa nt s h o ul d be as ke d if t he y are willi n g t o all o w f or t he a bstracti o n of rele va nt 
1 0 4 4  
i nf or mati o n fr o m t heir me dical rec or d i n or der t o meet t he o bjecti ves o utli ne d i n t he pr ot oc ol.  
1 0 4 5  
• 
A c o m plete fi nal e val uati o n at t he ti me of t he      partici pa nt’s st u d y wit h dra wal s h o ul d be 
1 0 4 6  
o btai ne d wit h a n e x pla nati o n of w h y t he      partici pa nt is wit h dra wi n g fr o m t he st u d y.  
1 0 4 7  
• 
If t he      partici pa nt is n o nc o m plia nt a n d d oes n ot ret ur n f or a n e n d of st u d y f oll o w u p 
1 0 4 8  
assess me nt, t his s h o ul d be d oc u me nte d i n t he e C R F.  
1 0 4 9  
• 
If t he reas o n f or re m o val of a      partici pa nt fr o m t he st u d y is a n a d verse e ve nt, t he pri nci pal 
1 0 5 0  
s pecific e ve nt will be rec or de d o n t he e C R F.  
1 0 5 1  
E xcessi ve      partici pa nt wit h dra wals fr o m pr ot oc ol t hera p y or fr o m t he st u d y ca n re n der t he 
1 0 5 2  
st u d y u n-i nter preta ble; t heref ore, u n necessar y wit h dra wal of partici pa nts s h o ul d be a v oi de d. 
1 0 5 3  
 
1 0 5 4  
     P artici p a nt L ost t o F oll o w u p: A partici pa nt will be c o nsi dere d l ost t o f oll o w -u p if he or s he 
1 0 5 5  
fails t o ret ur n f or t hree sc he d ule d st u d y visits a n d is u na ble t o be c o ntacte d b y t he st u d y site staff. 
1 0 5 6  

 
 
C O N FI D E N TI A L  
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U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n 1. 0  
 
A pril 2 5, 2 0 2 3  
 
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T he f oll o wi n g acti o ns m ust be ta ke n if a  partici pa nt fails t o ret ur n t o t he cli nic f or a re q uire d 
1 0 5 7  
st u d y visit: 
1 0 5 8  
• 
T he site will atte m pt t o c o ntact t he  partici pa nt a n d resc he d ule t he misse d visit a n d c o u nsel 
1 0 5 9  
t he partici pa nt o n t he i m p orta nce of mai ntai ni n g t he assi g ne d visit sc he d ule a n d ascertai n if 
1 0 6 0  
t he partici pa nt wis hes t o a n d/ or s h o ul d c o nti n ue i n t he st u d y. 
1 0 6 1  
• 
Bef ore a  partici pa nt is dee me d l ost t o f oll o w -u p, t he i n vesti gat or or desi g nee will ma ke e ver y 
1 0 6 2  
eff ort t o re gai n c o ntact wit h t he  partici pa nt ( w here p ossi ble, 3 tele p h o ne calls a n d, if 
1 0 6 3  
necessar y, a h o me visit b y t he st u d y tea m if per missi o n is o btai ne d f or h o me visit at st u d y 
1 0 6 4  
e ntr y, or l ocal e q ui vale nt met h o ds). T hese c o ntact atte m pts s h o ul d be d oc u me nte d i n t he      
1 0 6 5  
partici pa nt’s me dical rec or d or st u d y file.  
1 0 6 6  
• 
S h o ul d t he      partici pa nt c o nti n ue t o be u nreac ha ble, he or s he will be c o nsi dere d t o ha ve 
1 0 6 7  
wit h dra w n fr o m t he st u d y wit h a pri mar y reas o n of l ost t o f oll o w -u p.  
1 0 6 8  
 
1 0 6 9  
Off -St u d y Criteri a: Partici pa nts will be c o nsi dere d off st u d y a n d will n o l o n ger be f oll o we d o n 
1 0 7 0  
t he pr ot oc ol f or a n y reas o n if a n y of t he f oll o wi n g criteria are met: w he n t he partici pa nt reac hes 
1 0 7 1  
t he e n d of t he st u d y as defi ne d b y t he Sc he d ule of E ve nts Ta ble, partici pa nt wit h dra ws c o nse nt 
1 0 7 2  
f or treat me nt a n d a n y f urt her data c ollecti o n, deat h, or l ost t o f oll o w-u p.  
1 0 7 3  
 
1 0 7 4  
M al ari a tre at me nt d uri n g d osi n g p h ase ( D a y 1 -5):  If st u d y partici pa nts are dia g n ose d wit h 
1 0 7 5  
malaria d uri n g t he Artes u nate pessar y d osi n g p hase ( da y 1 -5), a n o n-A C T treat me nt will be use d 
1 0 7 6  
t o a v oi d P K st u dies c o nf o u n di n g. Partici pa nts will be e nc o ura ge d t o slee p u n der a m os q uit o net 
1 0 7 7  
t o re d uce t he c ha nce of ne w malaria i nfecti o n d uri n g t he st u d y.  
1 0 7 8  
4. 4  D at a C ollecti o n a n d M a n a ge me nt  
1 0 7 9  
D at a C ollecti o n a n d M a n a ge me nt: D uri n g st u d y visits, a st u d y n urse a n d/ or a researc h 
1 0 8 0  
assista nt will c ollect de m o gra p hic a n d cli nical data f or st u d y use. Cli nical data c ollecte d will 
1 0 8 1  
i ncl u de vital si g ns, me dical hist or y a n d e xa mi nati o n, a d verse e ve nts a n d ot her data as re q uire d. 
1 0 8 2  
Data will be e ntere d i nt o R E D Ca p E D C. A St u d y A nal yst will re vie w a n d clea n st u d y data 
1 0 8 3  
re g ularl y i ncl u di n g perf or mi n g q ualit y ass ura nce c hec ks t o e ns ure t hat t here are n ot a n y 
1 0 8 4  
a berrati o ns i n t he data t hat re q uire f urt her clarificati o n a n d/ or c ha n ges t o t he st u d y f or ms or 
1 0 8 5  
data base.  
1 0 8 6  
 
1 0 8 7  
Varia bles t o be c ollecte d  will i ncl u de basic de m o gra p hic (e. g., a ge, e d ucati o n le vel, marital 
1 0 8 8  
stat us) a n d cli nical (e. g gra vi dit y a n d parit y, c o ntrace pti o n use, pre g na nc y testi n g) varia bles as 
1 0 8 9  
well as s y m pt o m re vie w will be c ollecte d. De m o gra p hic a n d cli nical c haracteristics will be use d 
1 0 9 0  
t o descri be t he st u d y p o p ulati o n.   
1 0 9 1  
 
1 0 9 2  
St u d y t o ols will i ncl u de a baseli ne data c ollecti o n a n d p h ysical e xa m f or m; f oll o w -u p visit data 
1 0 9 3  
c ollecti o n f or ms (s y m pt o m a n d a d here nce e val uati o n a n d p h ysical e xa m).   
1 0 9 4  
 
1 0 9 5  
D at a St or a ge: St u d y rec or ds will be accessi ble o nl y t o st u d y staff. T he rec or ds will be hel d 
1 0 9 6  
l oc ka ble ca bi nets at t he st u d y sites. Electr o nic data c ollecte d will be e ntere d i n R E D Ca p E D C. 
1 0 9 7  
T he li n k bet wee n pers o nal i de ntit y a n d u ni q ue i de ntifier ( PI D) will be ke pt se parate fr o m st u d y 
1 0 9 8  
rec or ds a n d will n ot be i ncl u de d i n t he a nal ytic data base. T his li n ka ge will be destr o ye d at t he 
1 0 9 9  
c o ncl usi o n of t he st u d y. R E D Ca p E D C is c o m plia nt wit h cli nical trial data ma na ge me nt 
1 1 0 0  
re q uire me nts.  
1 1 0 1  

 
 
C O N FI D E N TI A L  
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U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n 1. 0  
 
A pril 2 5, 2 0 2 3  
 
2 9  
 
4. 5  St atistic al C o nsi der ati o ns a n d D at a a n al ysis  
1 1 0 2  
4. 5. 1 S a m ple Size:  A sa m ple size of n = 1 2 patie nts is nee de d f or t he pri mar y o bjecti ve of 
1 1 0 3  
p har mac o ki netics e val uati o n. T o all o w f or p ote ntial dr o p offs,  u p t o n = 1 6 patie nts will be 
1 1 0 4  
e nr olle d t o ha ve a sa m ple size of n = 1 2 f ull y e val ua ble partici pa nts.  
1 1 0 5  
 
1 1 0 6  
S a m ple Size J ustific ati o n: T his is t he first st u d y t o e val uate t he P K dis p ositi o n of artes u nate 
1 1 0 7  
after i ntra va gi nal a d mi nistrati o n a n d t h us n o pri or data are a vaila ble t o base t he sa m ple size 
1 1 0 8  
calc ulati o n. T he pr o p ose d sa m ple size is base d o n t he sta n dar d n u m ber of patie nts e val uate d i n 
1 1 0 9  
cli nical P K st u dies, 7 2 – 7 5 a n d is a de q uate t o perf or m p har mac o ki netic plas ma para meters of 
1 1 1 0  
artes u nate a n d D H A i n or der t o meet t he st u d y's pri mar y o bjecti ve.  
1 1 1 1  
 
1 1 1 2  
Accr u al: We a ntici pate e nr olli n g 2 partici pa nts a wee k . He nce we e x pect t o e nr oll 1 2 -1 6 
1 1 1 3  
partici pa nts i n 6 - 8 wee ks  ( 1. 5-2 m o nt hs).  
1 1 1 4  
 
1 1 1 5  
4. 5. 2 D at a A n al ysis Pl a ns  
1 1 1 6  
Pri m ar y O utc o me:  Plas ma c o nce ntrati o n vers us ti me c ur ve ( A U C) of di h y dr oarte misi ni n 
1 1 1 7  
( D H A) f oll o wi n g fi ve c o nsec uti ve da ys of self-a d mi nistrati o n of 2 0 0 m g Artes u nate va gi nal 
1 1 1 8  
i nserts ( pessaries) a m o n g healt h y w o me n i n Ke n ya.  
1 1 1 9  
Pri mar y E n d p oi nt:  Mea n D H A A U C ( n g * hr/ ml)  wit h sta n dar d de viati o n o n Da y 5  
1 1 2 0  
Statistical a nal ysis:  Mea n D H A A U C will be c o m pare d t o hist orical st u dies after I V, oral a n d 
1 1 2 1  
rectal a d mi nistrati o n a m o n g a d ults f oll o wi n g si milar d osi n g. Res ults will be a nal yze d usi n g t he 
1 1 2 2  
st u de nt’s t-test f or o ne -sa m ple o bser vati o n a n d a p -val ue of 0. 0 5 will be c o nsi dere d statisticall y 
1 1 2 3  
si g nifica nt.  
1 1 2 4  
 
1 1 2 5  
Sec o n d ar y O utc o mes  
1 1 2 6  
1. Plas ma A U C of Artes u nate f oll o wi n g 5 -da y self -a d mi nistrati o n of 2 0 0 m g Artes u nate va gi nal 
1 1 2 7  
i nserts ( pessaries) 
1 1 2 8  
E n d p oi nt:  Mea n artes u nate A U C ( n g * hr/ ml) wit h sta n dar d de viati o n o n Da y 5  
1 1 2 9  
Statistical a nal ysis:  Mea n artes u nate A U C ( n g * hr/ ml) will be c o m pare d t o hist orical st u dies after 
1 1 3 0  
I V, oral a n d rectal a d mi nistrati o n a m o n g a d ults f oll o wi n g si milar d osi n g. Res ults will be 
1 1 3 1  
a nal yze d usi n g t he st u de nt's t-test f or o ne -sa m ple o bser vati o n a n d a p -val ue of 0. 0 5 c o nsi dere d 
1 1 3 2  
statisticall y si g nifica nt.  
1 1 3 3  
 
1 1 3 4  
2. Ma xi m u m c o nce ntrati o n of Artes u nate ( C ma x) f oll o wi n g 5 -da y self -a d mi nistrati o n of 2 0 0 m g 
1 1 3 5  
Artes u nate va gi nal i nserts ( pessaries)  
1 1 3 6  
E n d p oi nt:  Mea n artes u nate C ma x ( n g/ ml) wit h sta n dar d de viati o n o n Da y 5  
1 1 3 7  
Statistical a nal ysis:  Mea n artes u nate C ma x ( n g/ ml) will be c o m pare d t o hist orical st u dies after 
1 1 3 8  
I V, oral, a n d rectal a d mi nistrati o n a m o n g a d ults f oll o wi n g si milar d osi n g. Res ults will be 
1 1 3 9  
a nal yze d usi n g t he st u de nt's t-test f or o ne -sa m ple o bser vati o n , a n d a p-val ue of 0. 0 5 c o nsi dere d 
1 1 4 0  
statisticall y si g nifica nt.  
1 1 4 1  
 
1 1 4 2  
3. Ma xi m u m c o nce ntrati o n of D H A ( C ma x) f oll o wi n g 5 -da y self -a d mi nistrati o n of 2 0 0 m g 
1 1 4 3  
Artes u nate va gi nal i nserts ( pessaries)  
1 1 4 4  
E n d p oi nt:  Mea n D H A C ma x ( n g/ ml) wit h sta n dar d de viati o n o n Da y 5  
1 1 4 5  
Statistical a nal ysis:  Mea n D H A C ma x ( n g/ ml) will be c o m pare d t o hist orical st u dies after I V, 
1 1 4 6  
oral a n d rectal a d mi nistrati o n a m o n g a d ults f oll o wi n g si milar d osi n g. Res ults will be a nal yze d 
1 1 4 7  

 
 
C O N FI D E N TI A L  
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U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n 1. 0  
 
A pril 2 5, 2 0 2 3  
 
3 0  
 
usi n g t he st u de nt's t-test f or o ne -sa m ple o bser vati o n a n d a p -val ue of 0. 0 5 c o nsi dere d statisticall y 
1 1 4 8  
si g nifica nt.  
1 1 4 9  
 
1 1 5 0  
4. Ti me t o ma xi m u m c o nce ntrati o n ( T ma x) of Artes u nate f oll o wi n g 5 -da y self -a d mi nistrati o n of 
1 1 5 1  
2 0 0 m g Artes u nate va gi nal i nserts ( pessaries)  
1 1 5 2  
E n d p oi nt:  Mea n Artes u nate T ma x ( mi ns) wit h sta n dar d de viati o n o n Da y 5  
1 1 5 3  
Statistical a nal ysis:  Mea n artes u nate T ma x ( mi ns) will be c o m pare d t o hist orical st u dies after I V, 
1 1 5 4  
oral , a n d rectal a d mi nistrati o n a m o n g a d ults f oll o wi n g si milar d osi n g. Res ults will be a nal yze d 
1 1 5 5  
usi n g t he Ma n n -W hit ne y U -test f or n o n para metric data, a n d a p-val ue of 0. 0 5 c o nsi dere d 
1 1 5 6  
statisticall y si g nifica nt.  
1 1 5 7  
 
1 1 5 8  
5. Ti me t o ma xi m u m c o nce ntrati o n ( T ma x) of D H A f oll o wi n g 5 -da y self -a d mi nistrati o n of 
1 1 5 9  
2 0 0 m g Artes u nate va gi nal i nserts ( pessaries)  
1 1 6 0  
E n d p oi nt:  Mea n D H A T ma x ( mi ns) wit h sta n dar d de viati o n o n Da y 5  
1 1 6 1  
Statistical a nal ysis:  Mea n D H A T ma x ( mi ns) will be c o m pare d t o hist orical st u dies after I V, oral 
1 1 6 2  
a n d rectal a d mi nistrati o n a m o n g a d ults f oll o wi n g si milar d osi n g. Res ults will be a nal yze d usi n g 
1 1 6 3  
t he Ma n n -W hit ne y U -test f or n o n para metric data a n d a p -val ue of 0. 0 5 c o nsi dere d statisticall y 
1 1 6 4  
si g nifica nt.  
1 1 6 5  
 
1 1 6 6  
6. Artes u nate half -life (t1/ 2) f oll o wi n g 5-da y self -a d mi nistrati o n of 2 0 0 m g Artes u nate va gi nal 
1 1 6 7  
i nserts ( pessaries) 
1 1 6 8  
E n d p oi nt:  Mea n Artes u nate half -life (t1/ 2) ( mi ns) wit h sta n dar d de viati o n o n Da y 5  
1 1 6 9  
Statistical a nal ysis:  Mea n Artes u nate half -life (t1/ 2) ( mi ns) will be c o m pare d t o hist orical st u dies 
1 1 7 0  
after I V, oral a n d rectal a d mi nistrati o n a m o n g a d ults f oll o wi n g si milar d osi n g. Res ults will be 
1 1 7 1  
a nal yze d usi n g t he Ma n n -W hit ne y U -test f or n o n para metric data a n d a p-val ue of 0. 0 5 
1 1 7 2  
c o nsi dere d statisticall y si g nifica nt.  
1 1 7 3  
 
1 1 7 4  
7. D H A half -life (t1/ 2) f oll o wi n g 5-da y self -a d mi nistrati o n of 2 0 0 m g Artes u nate va gi nal i nserts 
1 1 7 5  
( pessaries) 
1 1 7 6  
E n d p oi nt:  Mea n D H A half -life ( mi ns) wit h sta n dar d de viati o n o n Da y 5  
1 1 7 7  
Statistical a nal ysis:  Mea n D H A half -life (t1/ 2) ( mi ns) will be c o m pare d t o hist orical st u dies after 
1 1 7 8  
I V, oral a n d rectal a d mi nistrati o n a m o n g a d ults f oll o wi n g si milar d osi n g. Res ults will be 
1 1 7 9  
a nal yze d usi n g t he Ma n n -W hit ne y U -test f or n o n para metric data a n d a p-val ue of 0. 0 5 
1 1 8 0  
c o nsi dere d statisticall y si g nifica nt.  
1 1 8 1  
 
1 1 8 2  
8. A p pare nt cleara nce of Artes u nate ( A S) f oll o wi n g 5 -da y self -a d mi nistrati o n of 2 0 0 m g 
1 1 8 3  
Artes u nate va gi nal i nserts ( pessaries)  
1 1 8 4  
E n d p oi nt:  Mea n Artes u nate cleara nce ( L/ K g/ hr) wit h sta n dar d de viati o n o n Da y 5  
1 1 8 5  
Statistical a nal ysis:  Mea n Artes u nate cleara nce ( L/ K g/ hr) will be c o m pare d t o hist orical st u dies 
1 1 8 6  
after I V, oral a n d rectal a d mi nistrati o n a m o n g a d ults f oll o wi n g si milar d osi n g. Res ults will be 
1 1 8 7  
a nal yze d usi n g t he st u de nts t -test f or o ne -sa m ple o bser vati o n a n d a p -val ue of 0. 0 5 c o nsi dere d 
1 1 8 8  
statisticall y si g nifica nt.  
1 1 8 9  
 
1 1 9 0  
9. A p pare nt cleara nce of D H A f oll o wi n g 5 -da y self -a d mi nistrati o n of 2 0 0 m g Artes u nate va gi nal 
1 1 9 1  
i nserts ( pessaries) 
1 1 9 2  
E n d p oi nt:  Mea n D H A cleara nce ( L/ K g/ hr) wit h sta n dar d de viati o n o n Da y 5  
1 1 9 3  

 
 
C O N FI D E N TI A L  
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U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n 1. 0  
 
A pril 2 5, 2 0 2 3  
 
3 1  
 
Statistical a nal ysis:  Mea n D H A cleara nce ( L/ K g/ hr) will be c o m pare d t o hist orical st u dies after 
1 1 9 4  
I V, oral a n d rectal a d mi nistrati o n a m o n g a d ults f oll o wi n g si milar d osi n g. Res ults will be 
1 1 9 5  
a nal yze d usi n g t he st u de nts t -test f or o ne -sa m ple o bser vati o n a n d a p -val ue of 0. 0 5 c o nsi dere d 
1 1 9 6  
statisticall y si g nifica nt.  
1 1 9 7  
 
1 1 9 8  
1 0. V ol u me of distri b uti o n of Artes u nate ( A S) f oll o wi n g 5 -da y self -a d mi nistrati o n of 2 0 0 m g 
1 1 9 9  
Artes u nate va gi nal i nserts ( pessaries)  
1 2 0 0  
E n d p oi nt:  Mea n Artes u nate v ol u me of distri b uti o n ( L/ K g) wit h sta n dar d de viati o n o n Da y 5  
1 2 0 1  
Statistical a nal ysis:  Mea n Artes u nate v ol u me of distri b uti o n ( L/ K g) will be c o m pare d t o 
1 2 0 2  
hist orical st u dies after I V, oral a n d rectal a d mi nistrati o n a m o n g a d ults f oll o wi n g si milar d osi n g. 
1 2 0 3  
Res ults will be a nal yze d usi n g t he st u de nts t -test f or o ne -sa m ple o bser vati o n a n d a p -val ue of 
1 2 0 4  
0. 0 5 c o nsi dere d statisticall y si g nifica nt.  
1 2 0 5  
 
1 2 0 6  
1 1. V ol u me of distri b uti o n of D H A f oll o wi n g 5 -da y self -a d mi nistrati o n of 2 0 0 m g Artes u nate 
1 2 0 7  
va gi nal i nserts ( pessaries)  
1 2 0 8  
E n d p oi nt:  Mea n D H A v ol u me of distri b uti o n ( L/ K g) wit h sta n dar d de viati o n o n Da y 5  
1 2 0 9  
Statistical a nal ysis:  Mea n D H A v ol u me of distri b uti o n ( L/ K g) will be c o m pare d t o hist orical 
1 2 1 0  
st u dies after I V, oral a n d rectal a d mi nistrati o n a m o n g a d ults f oll o wi n g si milar d osi n g. Res ults 
1 2 1 1  
will be a nal yze d usi n g t he st u de nts t -test f or o ne -sa m ple o bser vati o n a n d a p -val ue of 0. 0 5 
1 2 1 2  
c o nsi dere d statisticall y si g nifica nt.  
1 2 1 3  
 
1 2 1 4  
1 2. Safet y of 5 -da y c o urse of self -a d mi nistrate d 2 0 0 m g Artes u nate va gi nal i nserts ( pessaries) 
1 2 1 5  
a m o n g healt h w o me n i n Ke n ya  
1 2 1 6  
E n d p oi nt:  T y pe, fre q ue nc y, se verit y, a n d d urati o n of re p orte d a n d o bser ve d a d verse e ve nts ( A Es) 
1 2 1 7  
usi n g t he U. S Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts, v 5. 0 
1 2 1 8  
( C T C A E 5. 0) a n d t he Di visi o n of AI D S Fe male Ge nital A d verse E ve nts Gra di n g Ta ble  
1 2 1 9  
Statistical A nal ysis : T he c o u nts of a d verse e ve nts f or eac h partici pa nt will be ta b ulate d b y 
1 2 2 0  
se verit y ( gra des 1-5). T he pr o p orti o n of      partici pa nts wit h a se vere A E ( gra de 3 or hi g her) will 
1 2 2 1  
be re p orte d al o n g t he e xact ( Cl o p per -Pears o n) o ne -si de d u p per 9 5 % c o nfi de nce b o u n ds. T he 
1 2 2 2  
pr o p orti o n of partici pa nts w h o re p ort a se vere A E (if a n y) will als o be re p orte d, al o n g wit h a n 
1 2 2 3  
e xact o ne-si de d u p per 9 5 % c o nfi de nce b o u n d.  
1 2 2 4  
- 
T he at -ris k peri o d f or safet y will be gi n at st u d y visit 1 (first artes u nate use) a n d will 
1 2 2 5  
c o nti n ue t hr o u g h st u d y visit 6 ( 4 -1 0 da ys after last artes u nate use). Safet y data will be 
1 2 2 6  
re p orte d f or all partici pa nts w h o start artes u nate use.  
1 2 2 7  
 
1 2 2 8  
 
1 2 2 9  
P h ar m ac o ki netic a n al ysis:  C o n ve nti o nal p har mac o ki netic para meters - A U C ( 0, i nfi nit y), half -
1 2 3 0  
life, a p pare nt cleara nce, v ol u me of distri b uti o n, ma xi m u m plas ma c o nce ntrati o n ( C ma x), ti me t o 
1 2 3 1  
C ma x will be deter mi ne d fr o m t he plas ma c o nce ntrati o n -ti me data usi n g n o nc o m part me ntal 
1 2 3 2  
a nal ysis. 3 5, 7 6 Pea k plas ma c o nce ntrati o n ( C ma x) a n d ti me t o reac h pea k c o nce ntrati o n ( T ma x) f or 
1 2 3 3  
artes u nate a n d D H A will be t he o bser ve d val ues. T he A U C of A S will be calc ulate d b y li near 
1 2 3 4  
tra pez oi dal s u m mati o n wit h e xtra p olati o n t o i nfi nit y, a n d A U C ti me c ur ve will start fr o m dr u g 
1 2 3 5  
a d mi nistrati o n t o t he last q ua ntifia ble o bser vati o n. All para meters will be calc ulate d usi n g ti me 
1 2 3 6  
i n h o urs after t he first dr u g a d mi nistrati o n. Wit h res pect t o D H A, A U C will be calc ulate d t o t he 
1 2 3 7  
last dr u g meas ura ble ti me p oi nt. T he eli mi nati o n rate c o nsta nt ( beta) will be calc ulate d fr o m t he 
1 2 3 8  
sl o pe of t he ter mi nal p hase of t he l o g c o nce ntrati o n-ti me pr ofile, a n d t he eli mi nati o n half-life 
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3 2  
 
(t 1/ 2) calc ulate d fr o m t he rati o of l n 2/ beta. Ot her P K para meters will be calc ulate d usi n g 
1 2 4 0  
sta n dar d m o del-i n de pe n de nt f or m ulae.3 9 T he esti mates of P K para meters f or D H A will ass u me 
1 2 4 1  
c o m plete c o n versi o n of A S t o D H A as re p orte d pre vi o usl y. 3 5 Data will be pl otte d gra p hicall y 
1 2 4 2  
a n d a nal yze d usi n g statistical s oft ware. Data will be prese nte d as mea n wit h sta n dar d de viati o n 
1 2 4 3  
( S D).  
1 2 4 4  
4. 6  C o m m u nit y E n g a ge me nt Pl a n  
1 2 4 5  
T he tar get p o p ulati o n will be se nsitize d a b o ut t he st u d y t hr o u g h tal ks i n p u blic f or u ms i ncl u di n g 
1 2 4 6  
healt h facilities wit hi n Kis u m u C o u nt y w here t he st u d y will be d o ne.  
1 2 4 7  
4. 7  St u d y Li mit ati o ns, Ris ks a n d Miti g ati o n of Ris ks  
1 2 4 8  
T he st u d y will i n vesti gate t he p har mac o ki netics of artes u nate f oll o wi n g i ntra va gi nal use at t he 
1 2 4 9  
pr o p ose d d osi n g a n d fre q ue nc y. Li mitati o ns i ncl u de n ot e val uati n g p har mac o d y na mics or 
1 2 5 0  
p har mac o ki netics f oll o wi n g differe nt d osi n g. Ris ks of t he st u d y a n d miti gati o n of ris ks are 
1 2 5 1  
disc usse d u n der Et hical C o nsi derati o ns.  
1 2 5 2  
4. 8  Pl a ns f or C o m m u nic ati n g St u d y Fi n di n gs  
1 2 5 3  
T his st u d y will pr o vi de i m p orta nt p har mac o ki netics data t o i nf or m q uesti o ns of ser u m le vels if 
1 2 5 4  
a n y f oll o wi n g i ntra va gi nal artes u nate use a n d i m plicati o ns f or malaria resista nce i n e n de mic 
1 2 5 5  
c o m m u nities. T he fi nal st u d y res ults will be s hare d wit h t he st u d y tea m, t he st u d y partici pa nts i n 
1 2 5 6  
la y la n g ua ge, t he me dical a n d scie ntific c o m m u nities i ncl u di n g all sta ke h ol ders, a n d t he p u blic. 
1 2 5 7  
Res ults will be p u blis he d i n peer re vie we d scie ntific j o ur nals, a bstracts, p osters a n d s y m p osi u m 
1 2 5 8  
prese ntati o ns at c o nfere nces. Res ults will als o be s hare d wit h rele va nt sta ke h ol ders i ncl u di n g t he 
1 2 5 9  
Mi nistr y of Healt h i n Ke n ya.   
1 2 6 0  
 
1 2 6 1  
5  E T HI C A L C O N SI D E R A TI O N S  
1 2 6 2  
All i n vesti gat ors a n d st u d y staff will u n der g o o nli ne G o o d Cli nical Practice ( G C P) a n d H u ma n      
1 2 6 3  
Partici pa nts Pr otecti o n ( H S P) trai ni n g t o e ns ure hi g h le vels of a d here nce t o et hical pri nci ples of 
1 2 6 4  
cli nical researc h. T he y will als o be e x pecte d t o meet basic pr ofessi o nal trai ni n g base d o n t heir 
1 2 6 5  
r oles a n d f u ncti o ns.  
1 2 6 6  
5. 1  I nstit uti o n al Re vie w B o ar d (I R B) A p pr o v al a n d C o nse nt  
1 2 6 7  
T his st u d y will be re vie we d a n d a p pr o ve d b y t he I R B at t he U ni versit y of N ort h Car oli na ( U N C), 
1 2 6 8  
as well as all rele va nt re g ulat or y b o dies i n Ke n ya, w hic h i ncl u de t he A mref Et hics a n d Scie ntific 
1 2 6 9  
Re vie w C o m mittee ( E S R C), t he Ke n ya P har mac y a n d P ois o ns B oar d ( P P B), t he Nati o nal 
1 2 7 0  
C o m missi o n f or Scie nce, Tec h n ol o g y & I n n o vati o n ( N A C O S TI) a n d a n y ot her re g ulat or y b o dies 
1 2 7 1  
re q uire d i n-c o u ntr y.  
1 2 7 2  
 
1 2 7 3  
T he A mref E S R C & U N C I R B’s will ha ve t he pr o per re prese ntati o n a n d f u ncti o n i n acc or da nce 
1 2 7 4  
wit h fe derall y ma n date d re g ulati o ns.  T he I R B will a p pr o ve t he i nf or me d c o nse nt f or m (I C F), 
1 2 7 5  
st u d y pr ot oc ol, a n y ot her writte n i nf or mati o n t o be pr o vi de d t o partici pa nts a n d ot her st u d y 
1 2 7 6  
relate d d oc u me nts as per t he et hics a n d re g ulat or y s u b missi o n re q uire me nts. All a me n d me nts 
1 2 7 7  
(e. g., t h ose t hat affect t he c o n d uct of t he st u d y or t he safet y of      partici pa nts) will re q uire 
1 2 7 8  
a p pr o val fr o m all re g ulat or y b o dies. Bef ore t he i n vesti gati o nal pr o d uct ca n be s hi p pe d t o t he 
1 2 7 9  
i n vesti gati o nal site, a s hi p pi n g per mit will be o btai ne d fr o m t he P har mac y a n d P ois o ns b oar d.  
1 2 8 0  
 
1 2 8 1  

 
 
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I n o btai ni n g a n d d oc u me nti n g i nf or me d c o nse nt, t he i n vesti gat or will c o m pl y wit h t he a p plica ble 
1 2 8 2  
re g ulat or y re q uire me nt(s) a n d s h o ul d a d here t o G o o d Cli nical Practice ( G C P) a n d t o et hical 
1 2 8 3  
pri nci ples t hat ha ve t heir ori gi n i n t he Declarati o n of Helsi n ki.  
1 2 8 4  
 
 
 
1 2 8 5  
Bef ore recr uit me nt a n d e nr oll me nt o nt o t his st u d y, t he patie nt will be gi ve n a f ull e x pla nati o n of 
1 2 8 6  
t he st u d y, i ncl u di n g t he g oals of t he st u d y, t he ris ks a n d be nefits a n d will be gi ve n t he 
1 2 8 7  
o p p ort u nit y t o re vie w t he c o nse nt f or m. As part of i nf or me d c o nse nt, t he v ol u ntar y nat ure of 
1 2 8 8  
st u d y partici pati o n will be e m p hasize d t o p ote ntial partici pa nts, i ncl u di n g t he fact t hat t heir 
1 2 8 9  
partici pati o n, or n o n -partici pati o n i n t he st u d y will n ot i m pact t heir o n g oi n g or f ut ure care. Eac h 
1 2 9 0  
c o nse nt f or m m ust i ncl u de all t he rele va nt ele me nts c urre ntl y re q uire d b y t he a n d l ocal or state 
1 2 9 1  
re g ulati o ns. O nce t his esse ntial i nf or mati o n has bee n pr o vi de d t o t he patie nt a n d t he i n vesti gat or 
1 2 9 2  
is ass ure d t hat t he patie nt u n dersta n ds t he i m plicati o ns of partici pati n g i n t he st u d y, t he patie nt 
1 2 9 3  
will be as ke d t o gi ve c o nse nt t o partici pate i n t he st u d y b y si g ni n g a n I R B -a p pr o ve d c o nse nt 
1 2 9 4  
f or m. T he writte n i nf or me d c o nse nt f or m will be si g ne d a n d pers o nall y date d b y t he patie nt a n d 
1 2 9 5  
b y t he pers o n w h o c o n d ucte d t he i nf or me d c o nse nt disc ussi o n. I nf or me d c o nse nt will be 
1 2 9 6  
o btai ne d fr o m all partici pa nts i n t heir preferre d la n g ua ges. T o c o m pe nsate f or partici pa nts ti me, 
1 2 9 7  
i ncl u di n g p ote ntial l ost wa ges fr o m ti me s pe nt o n st u d y visits, eac h sc he d ule d st u d y visit will be 
1 2 9 8  
rei m b urse d Ks hs 1 0 0 0 (a p pr o xi matel y $ 1 0). A d diti o nall y, partici pa nts will be rei m b urse d f or 
1 2 9 9  
tra ns p ort, ta ki n g i nt o c o nsi derati o n a vera ge c ost of tra vel t o t he cli nic t o s u p p ort f oll o w-u p a n d 
1 3 0 0  
rete nti o n, e x pecte d at a p pr o xi matel y Ks hs 5 0 0 ( $ 5). O n Visit # 5 w he n partici pa nts are e x pecte d 
1 3 0 1  
t o s pe n d 6-8 h o urs i n t he st u d y cli nic, partici pa nts will be rei m b urse d a n a d diti o nal Ks hs 2, 5 0 0 
1 3 0 2  
( U S $ 2 5) f or l ost wa ges. D uri n g st u d y visits, partici pa nts ma y recei ve a meal or refres h me nt 
1 3 0 3  
base d o n t heir waiti n g ti me.  
1 3 0 4  
5. 2  C o nfi de nti alit y a n d Pri v ac y  
1 3 0 5  
All eff orts will be ma de t o mai ntai n partici pa nt c o nfi de ntialit y. T his i ncl u des use of partici pa nt 
1 3 0 6  
I D a n d n ot na mes i n st u d y d oc u me nts, c o n d ucti n g all i nter vie wi n g a n d c o nse nti n g i n pri vate 
1 3 0 7  
r o o ms. St u d y data will be e ntere d i nt o sec ure f or ms a n d ta blets a n d u pl oa de d t o a sec ure ser ver. 
1 3 0 8  
St u d y rec or ds will be ke pt i n l oc ke d ca bi nets a n d will be accessi ble o nl y t o st u d y staff.  
1 3 0 9  
5. 3  P ote nti al Be nefits  
1 3 1 0  
I n di vi d ual be nefits t o partici pa nts are mi ni mal. All partici pa nts will u n der g o a p h ysical 
1 3 1 1  
e xa mi nati o n at scree ni n g free of c har ge. T he res ults of all tests will be c o m m u nicate d t o all 
1 3 1 2  
partici pa nts.  
1 3 1 3  
5. 4  P ote nti al H ar ms a n d Mi ni miz ati o n of H ar ms  
1 3 1 4  
P ote ntial ris ks t o partici pa nts i ncl u de ris k of a d verse e ve nts ( A Es) f oll o wi n g artes u nate pessar y 
1 3 1 5  
use, ris ks ass ociate d wit h ve ni p u nct ure i ncl u de sli g ht pai n d uri n g t he e ntr y of t he nee dle i nt o t he 
1 3 1 6  
s ki n, ver y rarel y p ossi ble dizzi ness, a n d s y nc o pe, ris k of breac h of c o nfi de ntialit y fr o m st u d y 
1 3 1 7  
partici pati o n, a n d t he oretical ( b ut mi ni mal) ris k of de vel o pi n g arte misi ni n resista nce f or malaria 
1 3 1 8  
treat me nt f oll o wi n g i ntra va gi nal use. T he strate g y t o mi ni mize t hese ris ks as disc usse d bel o w:   
1 3 1 9  
 
1 3 2 0  
Ris k of a d verse e ve nts fr o m artes u n ate pess ar y use: Ris k of a d verse e ve nts are e x pecte d t o be 
1 3 2 1  
mi ni mal base d o n t he e xcelle nt safet y pr ofile of i ntra va gi nal artes u nate at t he pla n ne d d ose a n d 
1 3 2 2  
fre q ue nc y i n a U. S P hase I st u d y. I n t hat trial, of 3 7 dr u g-relate d A Es re p orte d, 3 4 ( 9 2 %) were 
1 3 2 3  
gra de 1 ( mil d), a n d o nl y 3 ( 8 %) were gra de II, i ncl u di n g 2 cases of va gi nal yeast i nfecti o n a n d 1 
1 3 2 4  

 
 
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case of n o n -i nfecti ve c ystitis. I n t his st u d y, t here were n o gra de 3 or hi g her A Es a n d n o 
1 3 2 5  
i nt olera ble si de effects t hat le d t o st u d y wit h dra wal. As s uc h, we e x pect ris ks relate d t o A Es i n 
1 3 2 6  
t his trial t o si milarl y be mi ni mal.  T here are n o data o n safet y of i ntra va gi nal artes u nate i n 
1 3 2 7  
pre g na nc y. Pre g na nc y is a n e xcl usi o n criteri o n i n t his st u d y. All partici pa nts will ha ve pre g na nc y 
1 3 2 8  
testi n g d o ne at st u d y e ntr y t o r ule o ut pre g na nc y a n d will be re q uire d t o use c o ntrace pti o n if of 
1 3 2 9  
c hil d beari n g a ge d uri n g t he 5 -da y d osi n g p hase.  
1 3 3 0  
 
1 3 3 1  
Ris k ass oci ate d wit h ve ni p u nct ure : Partici pa nt m o nit ori n g, ase ptic tec h ni q ue, i ncl u di n g sterile 
1 3 3 2  
dis p osa ble bl o o d c ollecti o n a p parat us a n d a d here nce t o sta n dar d me dical preca uti o ns will re d uce 
1 3 3 3  
a n y ris ks ass ociate d wit h ve ni p u nct ure t o a mi ni m u m. T he a m o u nt of bl o o d t o be ta ke n f or 
1 3 3 4  
sa m pli n g will n ot be har mf ul t o t he partici pa nt’s healt h, as it is si g nifica ntl y less ( < 1/ 1 0 t h) t he 
1 3 3 5  
v ol u me of a n or mal bl o o d d o nati o n.   
1 3 3 6  
 
1 3 3 7  
Ris k of de vel o pi n g arte misi ni n resist a nce f or m al ari a tre at me nt: As disc usse d i n secti o n 3. 1, 
1 3 3 8  
t he d osi n g use d f or i ntra va gi nal use is m uc h l o wer t ha n t hat use d f or t he rectal artes u nate 
1 3 3 9  
f or m ulati o n f or malaria treat me nt. C o m pare d t o t he rect u m, vasc ularit y at t he va gi nal a n d cer vi x 
1 3 4 0  
is si g nifica ntl y less he nce li keli h o o d of s yste mic e x p os ure is e xcee di n gl y l o w. As s uc h, mi ni mal 
1 3 4 1  
t o n o a p precia ble le vels of t he acti ve s u bsta nce are e x pecte d f oll o wi n g i ntra va gi nal use of 
1 3 4 2  
artes u nate at t he pla n ne d d osi n g a n d fre q ue nc y. T he o bjecti ve of t his st u d y is t o c o nfir m t his.  
1 3 4 3  
 
1 3 4 4  
Ris k of bre ac h of c o nfi de nti alit y: Ot her s mall ris ks ass ociate d wit h st u d y partici pati o n i ncl u de 
1 3 4 5  
a ris k of breac h of c o nfi de ntialit y d uri n g t he st u d y. T his will be mi ni mize d t hr o u g h usi n g o nl y a 
1 3 4 6  
u ni q ue partici pa nt i de ntificati o n n u m ber, a n d n ot partici pa nt na mes or ot her i de ntifiers. St u d y 
1 3 4 7  
partici pati o n will i ncl u de data c ollecti o n re gar di n g basic me dical hist or y. T he ris k of t his is 
1 3 4 8  
mi ni mal as q uesti o ns as ke d will be r o uti ne me dical q uesti o ns. H o we ver, all eff orts will be ma de 
1 3 4 9  
t o re d uce t he ris k of distress t o partici pa nts i ncl u di n g usi n g e x perie nce d i nter vie wers, offeri n g 
1 3 5 0  
i nter vie ws i n pri vac y f or all partici pa nts, a n d re vie wi n g t he c o nfi de ntialit y of all a ns wers at t he 
1 3 5 1  
be gi n ni n g of data c ollecti o n. St u d y staff will m o nit or partici pa nts f or a n y si g ns of ps yc h ol o gical 
1 3 5 2  
distress a n d refer partici pa nts f or a d diti o nal c o u nselli n g, as nee de d.  
1 3 5 3  
6  S T U D Y M A N A G E M E N T A N D O R G A NI Z A TI O N  
1 3 5 4  
6. 1  St u d y M a n a ge me nt   
1 3 5 5  
Re q uire d D oc u me nt ati o n: Bef ore t he st u d y ca n be i nitiate d at a n y site, t he f oll o wi n g 
1 3 5 6  
d oc u me ntati o n m ust be pr o vi de d t o t he I G HI D Office at t he U ni versit y of N ort h Car oli na.  
1 3 5 7  
- 
A c o p y of t he official I R B a p pr o val letter f or t he pr ot oc ol a n d i nf or me d c o nse nt(s)  
1 3 5 8  
- 
I R B me m bers hi p list 
1 3 5 9  
- 
C Vs a n d me dical lice ns ure f or t he pri nci pal i n vesti gat or a n d a n y ass ociate i n vesti gat ors 
1 3 6 0  
w h o will be i n v ol ve d i n t he st u d y.  
1 3 6 1  
- 
F or m F D A 1 5 7 2 a p pr o priatel y fille d o ut a n d si g ne d wit h a p pr o priate d oc u me ntati o n (if 
1 3 6 2  
re q uire d) 
1 3 6 3  
- 
A c o p y of t he I R B -a p pr o ve d c o nse nt f or m(s)  
1 3 6 4  
- 
C LI A La b orat or y certificati o n a n d i nstit uti o n la b n or mal val ues  
1 3 6 5  
- 
E xec ute d cli nical researc h c o ntract.  
1 3 6 6  
 
1 3 6 7  
Re gistr ati o n Pr oce d ures: Partici pa nt e nr oll me nt will be trac ke d i n t he cl o u d -base d electr o nic 
1 3 6 8  
data base w hic h will be bac ke d u p dail y. T he PI a n d st u d y c o or di nat or will re vie w accr ual data 
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wee kl y t o e ns ure e nr oll me nt tar gets are met. O nce t he pla n ne d sa m ple size is ac hie ve d, 
1 3 7 0  
partici pa nt e nr oll me nt will st o p, a n d t he st u d y will f oc us o n f oll o w -u p visits.  
1 3 7 1  
 
1 3 7 2  
A d here nce t o t he Pr ot oc ol: E xce pt f or a n e mer ge nc y sit uati o n i n w hic h pr o per care f or t he 
1 3 7 3  
pr otecti o n, safet y, a n d well -bei n g of t he st u d y patie nt re q uires alter nati ve treat me nt, t he st u d y 
1 3 7 4  
s hall be c o n d ucte d as descri be d i n t he a p pr o ve d pr ot oc ol. Pr ot oc ols de viati o ns or vi olati o ns will 
1 3 7 5  
be ma na ge d as per secti o n title d Pr ot oc ol De viati o ns.   
1 3 7 6  
 
1 3 7 7  
E mer ge nc y M o dific ati o ns: I n vesti gat ors ma y i m ple me nt a de viati o n fr o m, or a c ha n ge of, t he 
1 3 7 8  
pr ot oc ol t o eli mi nate a n i m me diate hazar d(s) t o trial      partici pa nts wit h o ut pri or A mref E S R C 
1 3 7 9  
a n d U N C I R B a p pr o val. F or a n y s uc h e mer ge nc y m o dificati o n i m ple me nte d, a U N C I R B 
1 3 8 0  
m o dificati o n f or m m ust be c o m plete d b y U N C Researc h Pers o n nel wit hi n fi ve ( 5) b usi ness da ys 
1 3 8 1  
of ma ki n g t he c ha n ge.  Si milarl y, f or a n y e mer ge nc y m o dificati o n i m ple me nte d, t he A mref 
1 3 8 2  
E S R C will be n otifie d c o m plete d a n d c o m m u nicate d t o t he A mref E S R C wit hi n fi ve ( 5) b usi ness 
1 3 8 3  
da ys of ma ki n g t he c ha n ge, or earlier as re q uire d b y A mref E S R C.   
1 3 8 4  
 
1 3 8 5  
Ot her Pr ot oc ol De vi ati o ns/ Vi ol ati o ns: Acc or di n g t o U N C’s I R B, a pr ot oc ol de viati o n  is a n y 
1 3 8 6  
u n pla n ne d varia nce fr o m a n I R B a p pr o ve d pr ot oc ol t hat:  
1 3 8 7  
- Is ge nerall y n ote d or rec o g nize d after it occ urs 
1 3 8 8  
- Has n o s u bsta nti ve effect o n t he ris ks t o researc h partici pa nts  
1 3 8 9  
- Has n o s u bsta nti ve effect o n t he scie ntific i nte grit y of t he researc h pla n or t he val ue of t he data 
1 3 9 0  
c ollecte d  
1 3 9 1  
- Di d n ot res ult fr o m willf ul or k n o wi n g misc o n d uct o n t he part of t he i n vesti gat or(s).  
1 3 9 2  
 
1 3 9 3  
A n u n pla n ne d pr ot oc ol varia nce is c o nsi dere d a vi olati o n  if t he varia nce meets a n y of t he 
1 3 9 4  
f oll o wi n g criteria:  
1 3 9 5  
-Has har me d or i ncrease d t he ris k of har m t o o ne or m ore researc h partici pa nts.  
1 3 9 6  
-Has da ma ge d t he scie ntific i nte grit y of t he data c ollecte d f or t he st u d y.  
1 3 9 7  
-Res ults fr o m willf ul or k n o wi n g misc o n d uct o n t he part of t he i n vesti gat or(s).  
1 3 9 8  
-De m o nstrates seri o us or c o nti n ui n g n o nc o m plia nce wit h fe deral re g ulati o ns, State la ws, or 
1 3 9 9  
U ni versit y p olicies.  
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1 4 0 1  
If a de viati o n or vi olati o n occ urs, t he f oll o wi n g g ui deli nes will be f oll o we d: 
1 4 0 2  
 
1 4 0 3  
Pr ot oc ol De vi ati o ns: St u d y pers o n nel will rec or d a n y de viati o ns a n d re p ort t o a n y s p o ns or or 
1 4 0 4  
data a n d safet y m o nit ori n g c o m mittee i n acc or da nce wit h t heir p olicies.  De viati o ns s h o ul d be 
1 4 0 5  
s u m marize d a n d re p orte d t o t he I R B at t he ti me of c o nti n ui n g re vie w. 
1 4 0 6  
 
1 4 0 7  
Pr ot oc ol Vi ol ati o ns: Vi olati o ns s h o ul d be re p orte d b y U N C pers o n nel wit hi n o ne ( 1) wee k of 
1 4 0 8  
t he i n vesti gat or bec o mi n g a ware of t he e ve nt usi n g t he sa me I R B o nli ne mec ha nis m use d t o 
1 4 0 9  
re p ort U PI R S O.   
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1 4 1 1  
St u d y Disc o nti n u ati o n: T he st u d y ma y be disc o nti n ue d at a n y ti me b y t he A C T U, I R B, t he 
1 4 1 2  
NI AI D, t he p har mace utical s u p p orters, t he F D A, t he O H R P, or ot her g o ver n me nt a ge ncies as 
1 4 1 3  
part of t heir d uties t o e ns ure t hat researc h partici pa nts are pr otecte d.  
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U n a ntici p ate d Pr o ble ms I n v ol vi n g Ris ks t o      P artici p a nts or Ot hers ( U PI R S O: A n y e ve nts 
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t hat meet t he criteria f or “ U na ntici pate d Pr o ble ms” as defi ne d b y U N C’s I R B m ust be re p orte d 
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b y t he St u d y C o or di nat or usi n g t he I R B’s we b -base d re p orti n g s yste m.   
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A me n d me nts t o t he Pr ot oc ol : S h o ul d a me n d me nts t o t he pr ot oc ol be re q uire d, t he a me n d me nts 
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will be ori gi nate d a n d d oc u me nte d b y t he Pri nci pal I n vesti gat or at U N C.  It s h o ul d als o be n ote d 
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t hat w he n a n a me n d me nt t o t he pr ot oc ol s u bsta ntiall y alters t he st u d y desi g n or t he p ote ntial ris k 
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t o t he patie nt, a re vise d c o nse nt f or m mi g ht be re q uire d.   
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T he writte n a me n d me nt, a n d if re q uire d t he a me n de d c o nse nt f or m, m ust be se nt t o U N C’s I R B 
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f or a p pr o val pri or t o i m ple me ntati o n.   
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1 4 2 7  
Rec or d Rete nti o n : St u d y d oc u me ntati o n i ncl u des all Case Re p ort F or ms, data c orrecti o n f or ms 
1 4 2 8  
or q ueries, s o urce d oc u me nts, , m o nit ori n g l o gs/letters, a n d re g ulat or y d oc u me nts (e. g., pr ot oc ol 
1 4 2 9  
a n d a me n d me nts, I R B c orres p o n de nce a n d a p pr o val, si g ne d patie nt c o nse nt f or ms). S o urce 
1 4 3 0  
d oc u me nts i ncl u de all rec or di n gs of o bser vati o ns or n otati o ns of cli nical acti vities a n d all re p orts 
1 4 3 1  
a n d rec or ds necessar y f or t he e val uati o n a n d rec o nstr ucti o n of t he cli nical researc h st u d y.  
1 4 3 2  
 
1 4 3 3  
G o ver n me nt a ge nc y re g ulati o ns a n d directi ves re q uire t hat all st u d y d oc u me ntati o n pertai ni n g t o 
1 4 3 4  
t he c o n d uct of a cli nical trial m ust be retai ne d b y t he st u d y i n vesti gat or.  I n t he case of a st u d y 
1 4 3 5  
wit h a dr u g see ki n g re g ulat or y a p pr o val a n d mar keti n g, t hese d oc u me nts s hall be retai ne d f or at 
1 4 3 6  
least t w o years after t he last a p pr o val of mar keti n g a p plicati o n i n a n I nter nati o nal C o nfere nce o n 
1 4 3 7  
Har m o nizati o n (I C H) re gi o n.  I n all ot her cases, st u d y d oc u me nts s h o ul d be ke pt o n file u ntil 
1 4 3 8  
t hree years after t he c o m pleti o n a n d fi nal st u d y re p ort of t his i n vesti gati o nal st u d y. 
1 4 3 9  
 
1 4 4 0  
O bli g ati o ns of I n vesti g at ors : T he Pri nci pal I n vesti gat or is res p o nsi ble f or t he c o n d uct of t he 
1 4 4 1  
cli nical trial at t he site i n acc or da nce wit h Title 2 1 of t he C o de of Fe deral Re g ulati o ns a n d/ or t he 
1 4 4 2  
Declarati o n of Helsi n ki.  T he Pri nci pal I n vesti gat or is res p o nsi ble f or pers o nall y o verseei n g t he 
1 4 4 3  
treat me nt of all st u d y patie nts.  T he Pri nci pal I n vesti gat or m ust ass ure t hat all st u d y site 
1 4 4 4  
pers o n nel, i ncl u di n g s u b -i n vesti gat ors a n d ot her st u d y staff me m bers, a d here t o t he st u d y 
1 4 4 5  
pr ot oc ol a n d all F D A/ G C P/ N CI re g ulati o ns a n d g ui deli nes re gar di n g cli nical trials b ot h d uri n g 
1 4 4 6  
a n d after st u d y c o m pleti o n. T he Pri nci pal I n vesti gat or at eac h i nstit uti o n or site will be 
1 4 4 7  
res p o nsi ble f or ass uri n g t hat all t he re q uire d data will be c ollecte d a n d e ntere d o nt o t he Case 
1 4 4 8  
Re p ort F or ms ( C R Fs). Peri o dicall y, m o nit ori n g/a u diti n g will be c o n d ucte d b y st u d y pers o n nel 
1 4 4 9  
w h o will re vie w partici pa nt rec or ds i ncl u di n g c o nse nt f or ms, C R Fs, a n d s u p p orti n g data t o 
1 4 5 0  
e ns ure pr otecti o n of partici pa nts.  At t he c o m pleti o n of t he st u d y, all case re p ort f or ms will be 
1 4 5 1  
re vie we d b y t he Pri nci pal I n vesti gat or a n d will re q uire his/ her fi nal si g nat ure t o verif y t he 
1 4 5 2  
acc urac y of t he data. T he site i n vesti gat or will ma ke st u d y d oc u me nts (e. g., c o nse nt f or ms, dr u g 
1 4 5 3  
distri b uti o n f or ms, C R Fs) a n d perti ne nt h os pital or cli nic rec or ds rea dil y a vaila ble f or i ns pecti o n 
1 4 5 4  
b y t he l ocal I R B, t he site m o nit ors, t he F D A, t he NI AI D, a n d t he O H R P f or c o nfir mati o n of t he 
1 4 5 5  
st u d y data.  
1 4 5 6  
 
1 4 5 7  
6. 2  R ole of I n vesti g at ors  
1 4 5 8  
Pri nci p al I n vesti g at ors a n d r ole  
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C he mt ai M u n g o, M D, M P H : 
 
 
 
 
 
 
 
 
 
 
   
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J ac kt o n O m ot o, M B C h B, M Me d:  
 
 
 
 
 
 
 
 
 
 
 
 
 
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C o -I n vesti g at ors a n d Ot her Pers o n nel a n d t heir r oles  
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Willi a m Z a m b o ni, P h ar m. D, P h. D , 
 
 
 
 
 
 
 
 
   
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Gres h o n R ot a, B P h ar m, K E M RI  ( St u d y P har macist):  
 
 
 
 
 
. 
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Cirill us O g oll a h, B Sc, Di p C M, 
 
 
 
 
 
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1 4 8 9  
Merc y R o p, B Sc, M Sc , 
 
 
 
 
  
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6. 3  St u d y ti meli ne  
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T his st u d y is e x pecte d t o last a p pr o xi matel y 3 -4 m o nt hs o nce acti vate d. A ntici pate d ti meli ne t o 
1 4 9 4  
acti vati o n is bel o w.  
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            - U N C & Ke n ya Et hics Re vie w a n d a p pr o val: Oct o ber 2 0 2 3 –  N o ve m ber 2 0 2 3  
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- Ke n ya P ois o ns B oar d re vie w a n d a p pr o val: Dece m ber 2 0 2 3 –  Fe br uar y 2 0 2 4  
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- Pr ot oc ol trai ni n g: Ja n uar y –  Fe br uar y 2 0 2 4  
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- Partici pa nt Accr ual & Data c ollecti o n: Marc h 2 0 2 4 –  Ma y 2 0 2 4  
1 4 9 9  
 
- Data a nal ysis a n d Disse mi nati o n: J u ne 2 0 2 4 - J ul y 2 0 2 4  
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6. 4  B u d get a n d J ustific ati o n   
1 5 0 1  
B u d get  
1 5 0 2  
) 
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7  R E F E R E N C E S  
1 5 1 9  
1.  
S u n g H, Ferla y J, Sie gel R L, et al. Gl o bal Ca ncer Statistics 2 0 2 0: G L O B O C A N 
1 5 2 0  
Esti mates of I nci de nce a n d M ortalit y   W orl d wi de f or 3 6 Ca ncers i n 1 8 5 C o u ntries. C A 
1 5 2 1  
C a ncer J Cli n . 2 0 2 1; 7 1( 3): 2 0 9-2 4 9. d oi: 1 0. 3 3 2 2/caac. 2 1 6 6 0  
1 5 2 2  
2.  
F o nseca B O, P ossati -Rese n de J C, Salce d o M P, et al. T o pical I mi q ui m o d f or t he 
1 5 2 3  
Treat me nt of Hi g h -Gra de S q ua m o us I ntrae pit helial   Lesi o ns of t he Cer vi x: A 
1 5 2 4  
Ra n d o mize d C o ntr olle d Trial. O bstetrics a n d gy nec ol o gy . 2 0 2 1; 1 3 7( 6): 1 0 4 3-1 0 5 3. 
1 5 2 5  
d oi: 1 0. 1 0 9 7/ A O G. 0 0 0 0 0 0 0 0 0 0 0 0 4 3 8 4  
1 5 2 6  
3.  
Desra vi nes N, Miele K, Carls o n R, C hi b wes ha C, Ra ha n g dale L. T o pical t hera pies f or t he 
1 5 2 7  
treat me nt of cer vical i ntrae pit helial ne o plasia ( CI N)  2 -3: A narrati ve re vie w. Gy nec ol 
1 5 2 8  
O nc ol Re p . 2 0 2 0; 3 3: 1 0 0 6 0 8. d oi: 1 0. 1 0 1 6/j. g ore. 2 0 2 0. 1 0 0 6 0 8 
1 5 2 9  
4.  
Mai ma n M, Watts D H, A n derse n J, Cla x P, Meri n o M, Ke n dall M A. Va gi nal 5 -
1 5 3 0  
fl u or o uracil f or hi g h-gra de cer vical d ys plasia i n h u ma n i m m u n o deficie nc y vir us 
1 5 3 1  
i nfecti o n: A ra n d o mize d trial. O bstetrics a n d Gy nec ol o gy . 1 9 9 9; 9 4( 6): 9 5 4-9 6 1. 
1 5 3 2  
d oi: 1 0. 1 0 1 6/ S 0 0 2 9 -7 8 4 4( 9 9) 0 0 4 0 7 -X  
1 5 3 3  
5.  
de Witte CJ, va n de Sa n de AJ M, va n Bee k h uize n HJ, K oe ne ma n M M, Kr use AJ, 
1 5 3 4  
Gerestei n C G. I mi q ui m o d i n cer vical, va gi nal a n d v ul var i ntrae pit helial ne o plasia: a 
1 5 3 5  
re vie w. Gy nec ol O nc ol . 2 0 1 5; 1 3 9( 2): 3 7 7-3 8 4. d oi: 1 0. 1 0 1 6/j. y g y n o. 2 0 1 5. 0 8. 0 1 8  
1 5 3 6  
6.  
He n dri ks N, K oe ne ma n M M, va n de Sa n de AJ M, et al. T o pical I mi q ui m o d Treat me nt of 
1 5 3 7  
Hi g h -gra de Cer vical I ntrae pit helial Ne o plasia   ( T O PI C-3): A N o nra n d o mize d 
1 5 3 8  
M ultice nter St u d y. J I m m u n ot her . 2 0 2 2; 4 5( 3): 1 8 0-1 8 6. 
1 5 3 9  
d oi: 1 0. 1 0 9 7/ CJI. 0 0 0 0 0 0 0 0 0 0 0 0 0 4 1 4  
1 5 4 0  
7.  
W orl d Healt h Or ga nisati o n. W orl d He alt h Or g a niz ati o n. G ui deli nes f or Tre at me nt of 
1 5 4 1  
M al ari a. 3r d E diti o n .; 2 0 1 5. 
1 5 4 2  
8.  
Bar -Zee v N, W hite N. E vi de nce be hi n d t he W H O g ui deli nes: H os pital Care f or C hil dre n: 
1 5 4 3  
efficac y a n d   safet y of arte misi ni n deri vati ves i n c hil dre n wit h malaria. J Tr o p Pe di atr . 
1 5 4 4  
2 0 0 6; 5 2( 2): 7 8 -8 2. d oi: 1 0. 1 0 9 3/tr o pej/f ml 0 0 5  
1 5 4 5  
9.  
J o ha n n-Lia n g R, Al brec ht R. Safet y e val uati o ns of dr u gs c o ntai ni n g arte misi ni n 
1 5 4 6  
deri vati ves f or t he treat me nt   of malaria. Cli n I nfect Dis . 2 0 0 3; 3 6( 1 2): 1 6 2 6-1 6 2 8. 
1 5 4 7  
d oi: 1 0. 1 0 8 6/ 3 7 5 0 8 9  
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1 0.  
N yaa ba N, A n d o h N E, A m o h G, et al. C o m parati ve efficac y a n d safet y of t he arte misi ni n 
1 5 4 9  
deri vati ves c o m pare d t o   q ui ni ne f or treati n g se vere malaria i n c hil dre n a n d a d ults: A 
1 5 5 0  
s yste matic u p date of literat ure a n d net w or k meta-a nal ysis. P L o S O ne . 
1 5 5 1  
2 0 2 2; 1 7( 7):e 0 2 6 9 3 9 1. d oi: 1 0. 1 3 7 1/j o ur nal. p o ne. 0 2 6 9 3 9 1  
1 5 5 2  
1 1.  
Ellis T, Eze E, Rai mi -A bra ha m B T. Malaria a n d Ca ncer: a critical re vie w o n t he 
1 5 5 3  
esta blis he d ass ociati o ns a n d ne w   pers pecti ves. I nfect A ge nt C a ncer. 2 0 2 1; 1 6( 1): 3 3. 
1 5 5 4  
d oi: 1 0. 1 1 8 6/s 1 3 0 2 7 -0 2 1 -0 0 3 7 0 -7  
1 5 5 5  
1 2.  
Ma Z, W o o n C Y N, Li u C G, et al. Re p ur p osi n g Arte misi ni n a n d its Deri vati ves as 
1 5 5 6  
A ntica ncer Dr u gs: A C ha nce or   C halle n ge? Fr o nt P h ar m ac ol . 2 0 2 1; 1 2: 8 2 8 8 5 6. 
1 5 5 7  
d oi: 1 0. 3 3 8 9/f p har. 2 0 2 1. 8 2 8 8 5 6  
1 5 5 8  
1 3.  
Je o n g D E, S o n g HJJ, Li m S, et al. Re p ur p osi n g t he a nti-malarial dr u g artes u nate as a 
1 5 5 9  
n o vel t hera pe utic a ge nt f or   metastatic re nal cell carci n o ma d ue t o its atte n uati o n of t u m or 
1 5 6 0  
gr o wt h, metastasis, a n d a n gi o ge nesis. O nc ot ar get . 2 0 1 5; 6( 3 2): 3 3 0 4 6-3 3 0 6 4. 
1 5 6 1  
d oi: 1 0. 1 8 6 3 2/ o nc otar get. 5 4 2 2  
1 5 6 2  
1 4.  
Effert h T, Sa uer bre y A, Ol bric h A, et al. M olec ular m o des of acti o n of artes u nate i n 
1 5 6 3  
t u m or cell li nes. M ol P h ar m ac ol . 2 0 0 3; 6 4( 2): 3 8 2-3 9 4. d oi: 1 0. 1 1 2 4/ m ol. 6 4. 2. 3 8 2  
1 5 6 4  
1 5.  
Sie gel E M, Patel N, L u B, et al. Circ ulati n g bi o mar kers of ir o n st ora ge a n d cleara nce of 
1 5 6 5  
i nci de nt h u ma n  pa pill o ma vir us i nfecti o n. C a ncer E pi de mi ol Bi o m arkers Prev . 
1 5 6 6  
2 0 1 2; 2 1( 5): 8 5 9 -8 6 5. d oi: 1 0. 1 1 5 8/ 1 0 5 5 -9 9 6 5. E PI -1 2 -0 0 7 3  
1 5 6 7  
1 6.  
Da niels T R, Ber na be u E, R o drí g uez J A, et al. T he tra nsferri n rece pt or a n d t he tar gete d 
1 5 6 8  
deli ver y of t hera pe utic a ge nts a gai nst   ca ncer. Bi oc hi m Bi o p hys Act a . 2 0 1 2; 1 8 2 0( 3): 2 9 1-
1 5 6 9  
3 1 7. d oi: 1 0. 1 0 1 6/j. b ba ge n. 2 0 1 1. 0 7. 0 1 6  
1 5 7 0  
1 7.  
Sc hiff ma n M, D o or bar J, We ntze nse n N, et al. Carci n o ge nic h u ma n pa pill o ma vir us 
1 5 7 1  
i nfecti o n. N at Rev Dis Pri mers . 2 0 1 6; 2: 1 6 0 8 6. d oi: 1 0. 1 0 3 8/ nr d p. 2 0 1 6. 8 6 
1 5 7 2  
1 8.  
Tri m ble C L, Le vi ns o n K, Mal d o na d o L, et al. A first -i n-h u ma n pr o of -of -c o nce pt trial of 
1 5 7 3  
i ntra va gi nal artes u nate t o treat cer vical  i ntrae pit helial ne o plasia 2/ 3 ( CI N 2/ 3). Gy nec ol 
1 5 7 4  
O nc ol . 2 0 2 0; 1 5 7( 1): 1 8 8-1 9 4. d oi: 1 0. 1 0 1 6/j. y g y n o. 2 0 1 9. 1 2. 0 3 5  
1 5 7 5  
1 9.  
W o n g Y K, X u C, Kales h K A, et al. Arte misi ni n as a n a ntica ncer dr u g: Rece nt a d va nces 
1 5 7 6  
i n tar get pr ofili n g a n d  mec ha nis ms of acti o n. Me d Res Rev . 2 0 1 7; 3 7( 6): 1 4 9 2-1 5 1 7. 
1 5 7 7  
d oi: 1 0. 1 0 0 2/ me d. 2 1 4 4 6  
1 5 7 8  
2 0.  
Z h o u X, C he n Y, Wa n g F, et al. Artes u nate i n d uces a ut o p ha g y de pe n de nt a p o pt osis 
1 5 7 9  
t hr o u g h u pre g ulati n g R O S a n d  acti vati n g A M P K -m T O R -U L K 1 a xis i n h u ma n bla d der 
1 5 8 0  
ca ncer cells. C he m Bi ol I nter act . 2 0 2 0; 3 3 1: 1 0 9 2 7 3. d oi: 1 0. 1 0 1 6/j.c bi. 2 0 2 0. 1 0 9 2 7 3 
1 5 8 1  
2 1.  
Z ha n g J, Z h o u L, Xia n g J D, Ji n C S, Li M Q, He Y Y. Artes u nate -i n d uce d A T G 5-relate d 
1 5 8 2  
a ut o p ha g y e n ha nces t he c yt ot o xicit y of N K 9 2 cells   o n e n d o metrial ca ncer cells via 
1 5 8 3  
i nteracti o ns bet wee n C D 1 5 5 a n d C D 2 2 6/ TI GI T. I nt I m m u n o p h ar m ac ol. 2 0 2 1; 9 7: 1 0 7 7 0 5. 
1 5 8 4  
d oi: 1 0. 1 0 1 6/j.i nti m p. 2 0 2 1. 1 0 7 7 0 5  
1 5 8 5  
2 2.  
Ya o X, Z ha o C R, Yi n H, Wa n g K, Ga o JJ. S y ner gistic a ntit u m or acti vit y of s orafe ni b a n d 
1 5 8 6  
artes u nate i n he pat ocell ular   carci n o ma cells. Act a P h ar m ac ol Si n . 2 0 2 0; 4 1( 1 2): 1 6 0 9-
1 5 8 7  
1 6 2 0. d oi: 1 0. 1 0 3 8/s 4 1 4 0 1 -0 2 0 -0 3 9 5 -5  
1 5 8 8  
2 3.  
Ga o F, S u n Z, K o n g F, Xia o J. Arte misi ni n -deri ve d h y bri ds a n d t heir a ntica ncer acti vit y. 
1 5 8 9  
E ur J Me d C he m . 2 0 2 0; 1 8 8: 1 1 2 0 4 4. d oi: 1 0. 1 0 1 6/j.ej mec h. 2 0 2 0. 1 1 2 0 4 4 
1 5 9 0  
2 4.  
G ua n X, G ua n Y. Arte misi ni n i n d uces selecti ve a n d p ote nt a ntica ncer effects i n dr u g 
1 5 9 1  
resista nt  breast ca ncer cells b y i n d uci n g cell ular a p o pt osis a n d a ut o p ha g y a n d G 2/ M cell 
1 5 9 2  
c ycle arrest. J B U O N. 2 0 2 0; 2 5( 3): 1 3 3 0-1 3 3 6.  
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Z ha n g B. Arte misi ni n -deri ve d di mers as p ote ntial a ntica ncer a ge nts: C urre nt 
1 5 9 4  
de vel o p me nts,   acti o n mec ha nis ms, a n d str uct ure -acti vit y relati o ns hi ps. Arc h P h ar m 
1 5 9 5  
( Wei n hei m). 2 0 2 0; 3 5 3( 2):e 1 9 0 0 2 4 0. d oi: 1 0. 1 0 0 2/ar d p. 2 0 1 9 0 0 2 4 0 
1 5 9 6  
2 6.  
Li D, Z ha n g J, Z ha o X. Mec ha nis ms a n d M olec ular Tar gets of Arte misi ni n i n Ca ncer 
1 5 9 7  
Treat me nt. C a ncer I nvest . 2 0 2 1; 3 9( 8): 6 7 5-6 8 4. d oi: 1 0. 1 0 8 0/ 0 7 3 5 7 9 0 7. 2 0 2 1. 1 9 5 4 1 9 0  
1 5 9 8  
2 7.  
A nf oss o L, Effert h T, Al bi ni A, Pfeffer U. Micr oarra y e x pressi o n pr ofiles of 
1 5 9 9  
a n gi o ge nesis -relate d ge nes pre dict t u m or cell  res p o nse t o arte misi ni ns. 
1 6 0 0  
P h ar m ac o ge n o mics J . 2 0 0 6; 6( 4): 2 6 9-2 7 8. d oi: 1 0. 1 0 3 8/sj.t pj. 6 5 0 0 3 7 1  
1 6 0 1  
2 8.  
Dis br o w G L, Bae ge A C, Kier piec K A, et al. Di h y dr oarte misi ni n is c yt ot o xic t o 
1 6 0 2  
pa pill o ma vir us -e x pressi n g e pit helial cells i n   vitr o a n d i n vi v o. C a ncer Res . 
1 6 0 3  
2 0 0 5; 6 5( 2 3): 1 0 8 5 4 -1 0 8 6 1. d oi: 1 0. 1 1 5 8/ 0 0 0 8 -5 4 7 2. C A N -0 5 -1 2 1 6  
1 6 0 4  
2 9.  
M orris C A, D u parc S, B or g hi ni -F u hrer I, J u n g D, S hi n C S, Flec ke nstei n L. Re vie w of t he 
1 6 0 5  
cli nical p har mac o ki netics of artes u nate a n d its acti ve meta b olite   di h y dr oarte misi ni n 
1 6 0 6  
f oll o wi n g i ntra ve n o us, i ntra m usc ular, oral or rectal a d mi nistrati o n. M al ar J . 2 0 1 1; 1 0: 2 6 3. 
1 6 0 7  
d oi: 1 0. 1 1 8 6/ 1 4 7 5 -2 8 7 5 -1 0 -2 6 3  
1 6 0 8  
3 0.  
Ilett K F, Batt y K T, P o well S M, et al. T he p har mac o ki netic pr o perties of i ntra m usc ular 
1 6 0 9  
artes u nate a n d rectal   di h y dr oarte misi ni n i n u nc o m plicate d falci par u m malaria. Br J Cli n 
1 6 1 0  
P h ar m ac ol . 2 0 0 2; 5 3( 1): 2 3-3 0. d oi: 1 0. 1 0 4 6/j. 0 3 0 6 -5 2 5 1. 2 0 0 1. 0 1 5 1 9. x  
1 6 1 1  
3 1.  
Ilett K F, Batt y K T, P o well S M, et al. T he p har mac o ki netic pr o perties of i ntra m usc ular 
1 6 1 2  
artes u nate a n d rectal   di h y dr oarte misi ni n i n u nc o m plicate d falci par u m malaria. Br J Cli n 
1 6 1 3  
P h ar m ac ol . 2 0 0 2; 5 3( 1): 2 3-3 0. d oi: 1 0. 1 0 4 6/j. 0 3 0 6 -5 2 5 1. 2 0 0 1. 0 1 5 1 9. x  
1 6 1 4  
3 2.  
K F I, K T B, S M P, et al. T he p har mac o ki netic pr o perties of i ntra m usc ular artes u nate a n d 
1 6 1 5  
rectal di h y dr oarte misi ni n i n u nc o m plicate d falci par u m malaria. Br J Cli n P h ar m ac ol . 
1 6 1 6  
2 0 0 2; 5 3( 1): 2 3 -3 0. d oi: 1 0. 1 0 4 6/J. 0 3 0 6 -5 2 5 1. 2 0 0 1. 0 1 5 1 9. X  
1 6 1 7  
3 3.  
M orris C A, D u parc S, B or g hi ni -F u hrer I, J u n g D, S hi n C S, Flec ke nstei n L. Re vie w of t he 
1 6 1 8  
cli nical p har mac o ki netics of artes u nate a n d its acti ve meta b olite   di h y dr oarte misi ni n 
1 6 1 9  
f oll o wi n g i ntra ve n o us, i ntra m usc ular, oral or rectal a d mi nistrati o n. M al ar J . 2 0 1 1; 1 0: 2 6 3. 
1 6 2 0  
d oi: 1 0. 1 1 8 6/ 1 4 7 5 -2 8 7 5 -1 0 -2 6 3  
1 6 2 1  
3 4.  
Batt y K T, T h u L T, Da vis T M, et al. A p har mac o ki netic a n d p har mac o d y na mic st u d y of 
1 6 2 2  
i ntra ve n o us vs oral artes u nate i n  u nc o m plicate d falci par u m malaria. Br J Cli n 
1 6 2 3  
P h ar m ac ol . 1 9 9 8; 4 5( 2): 1 2 3-1 2 9. d oi: 1 0. 1 0 4 6/j. 1 3 6 5 -2 1 2 5. 1 9 9 8. 0 0 6 5 5. x  
1 6 2 4  
3 5.  
Hie n T T, Da vis T M E, C h u o n g L V., et al. C o m parati ve p har mac o ki netics of 
1 6 2 5  
i ntra m usc ular artes u nate a n d arte met her i n patie nts wit h se vere falci par u m malaria. 
1 6 2 6  
A nti micr o b A ge nts C he m ot her . 2 0 0 4; 4 8( 1 1): 4 2 3 4-4 2 3 9. d oi: 1 0. 1 1 2 8/ A A C. 4 8. 1 1. 4 2 3 4 -
1 6 2 7  
4 2 3 9. 2 0 0 4  
1 6 2 8  
3 6.  
Die m T h u y L T, N g oc H u n g L, Da n h P T, Na -Ba n gc ha n g K. A bse nce of ti me -de pe n de nt 
1 6 2 9  
artes u nate p har mac o ki netics i n healt h y s u bjects d uri n g   5 -da y oral a d mi nistrati o n. E ur J 
1 6 3 0  
Cli n P h ar m ac ol . 2 0 0 8; 6 4( 1 0): 9 9 3-9 9 8. d oi: 1 0. 1 0 0 7/s 0 0 2 2 8 -0 0 8 -0 5 0 6 -6  
1 6 3 1  
3 7.  
Die m T h u y L T, N g oc H u n g L, Da n h P T, Na -Ba n gc ha n g K. A bse nce of ti me -de pe n de nt 
1 6 3 2  
artes u nate p har mac o ki netics i n healt h y s u bjects d uri n g 5 -da y oral a d mi nistrati o n. E ur J 
1 6 3 3  
Cli n P h ar m ac ol . 2 0 0 8; 6 4( 1 0): 9 9 3-9 9 8. d oi: 1 0. 1 0 0 7/ S 0 0 2 2 8 -0 0 8 -0 5 0 6 -6  
1 6 3 4  
3 8.  
Kr u ds o o d S, L o oarees u wa n S, Ta n g p u k dee N, et al. Ne w fi xe d -d ose artes u nate -
1 6 3 5  
mefl o q ui ne f or m ulati o n a gai nst m ulti dr u g -resista nt Plas m o di u m falci par u m i n a d ults: a 
1 6 3 6  
c o m parati ve p hase II b safet y a n d p har mac o ki netic st u d y wit h sta n dar d -d ose n o nfi xe d 
1 6 3 7  
artes u nate pl us mefl o q ui ne. A nti micr o b A ge nts C he m ot her . 2 0 1 0; 5 4( 9): 3 7 3 0-3 7 3 7. 
1 6 3 8  
d oi: 1 0. 1 1 2 8/ A A C. 0 1 1 8 7 -0 9  
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Na varat na m V, Ma ns or S M, M or di M N, A k bar A, A b d ulla h M N. C o m parati ve 
1 6 4 0  
p har mac o ki netic st u d y of oral a n d rectal f or m ulati o ns of artes u nic aci d i n healt h y 
1 6 4 1  
v ol u nteers. E ur J Cli n P h ar m ac ol . 1 9 9 8; 5 4( 5): 4 1 1-4 1 4. d oi: 1 0. 1 0 0 7/ S 0 0 2 2 8 0 0 5 0 4 8 4  
1 6 4 2  
4 0.  
Siri vic ha ya k ul C, Sa bc hare o n A, Pe n gsaa K, et al. C o m parati ve st u d y of t he effecti ve ness 
1 6 4 3  
a n d p har mac o ki netics of t w o rectal   artes u nate/ oral mefl o q ui ne c o m bi nati o n re gi me ns f or 
1 6 4 4  
t he treat me nt of u nc o m plicate d c hil d h o o d falci par u m malaria. A n n Tr o p P ae di atr . 
1 6 4 5  
2 0 0 7; 2 7( 1): 1 7 -2 4. d oi: 1 0. 1 1 7 9/ 1 4 6 5 3 2 8 0 7 X 1 7 0 4 6 6  
1 6 4 6  
4 1.  
Hal paa p B, N dja ve M, Paris M, Be na kis A, Kre ms ner P G. Plas ma le vels of artes u nate 
1 6 4 7  
a n d di h y dr oarte misi ni n i n c hil dre n wit h Plas m o di u m   falci par u m malaria i n Ga b o n after 
1 6 4 8  
a d mi nistrati o n of 5 0 -milli gra m artes u nate s u p p osit ories. A m J Tr o p Me d Hy g . 
1 6 4 9  
1 9 9 8; 5 8( 3): 3 6 5 -3 6 8. d oi: 1 0. 4 2 6 9/ajt m h. 1 9 9 8. 5 8. 3 6 5  
1 6 5 0  
4 2.  
Na varat na m V, Ma ns or S M, M or di M N, A k bar A, A b d ulla h M N. C o m parati ve 
1 6 5 1  
p har mac o ki netic st u d y of oral a n d rectal f or m ulati o ns of artes u nic   aci d i n healt h y 
1 6 5 2  
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1 6 5 3  
4 3.  
Teja -isa va d har m P, Watt G, Ea msila C, et al. C o m parati ve p har mac o ki netics a n d effect 
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ki netics of orall y a d mi nistere d artes u nate i n healt h y v ol u nteers a n d patie nts wit h 
1 6 5 5  
u nc o m plicate d falci par u m malaria. A m J Tr o p Me d Hy g . 2 0 0 1; 6 5( 6): 7 1 7-7 2 1. 
1 6 5 6  
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4 4.  
Bi n h T Q, Ilett K F, Batt y K T, et al. Oral bi oa vaila bilit y of di h y dr oarte misi ni n i n 
1 6 5 8  
Viet na mese v ol u nteers a n d i n patie nts wit h falci par u m malaria. Br J Cli n P h ar m ac ol . 
1 6 5 9  
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1 6 6 0  
4 5.  
G ui deli nes f or t he Treat me nt of Malaria - P u b Me d. Accesse d Oct o ber 2 2, 2 0 2 3. 
1 6 6 1  
htt ps:// p u b me d. nc bi. nl m. ni h. g o v/ 2 6 0 2 0 0 8 8/  
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War d K E, Fi d oc k D A, Bri d gf or d J L. Plas m o di u m falci par u m resista nce t o arte misi ni n -
1 6 6 3  
base d c o m bi nati o n t hera pies. C urr O pi n Micr o bi ol . 2 0 2 2; 6 9: 1 0 2 1 9 3. 
1 6 6 4  
d oi: 1 0. 1 0 1 6/j. mi b. 2 0 2 2. 1 0 2 1 9 3  
1 6 6 5  
4 7.  
Ha n b o o n k u n u pa kar n B, Tar ni n g J, P u kritta ya ka mee S, C h oti va nic h K. Arte misi ni n 
1 6 6 6  
resista nce a n d malaria eli mi nati o n: W here are we n o w? Fr o nt P h ar m ac ol . 2 0 2 2; 1 3. 
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d oi: 1 0. 3 3 8 9/ F P H A R. 2 0 2 2. 8 7 6 2 8 2  
1 6 6 8  
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Bali ka gala B, F u k u da N, I ke da M, et al. E vi de nce of Arte misi ni n -Resista nt Malaria i n 
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Africa. N E n gl J Me d . 2 0 2 1; 3 8 5( 1 3): 1 1 6 3-1 1 7 1. d oi: 1 0. 1 0 5 6/ N EJ M oa 2 1 0 1 7 4 6  
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4 9.  
Mat he n ge P G, L o w S K, V u o n g N L, et al. Efficac y a n d resista nce of differe nt 
1 6 7 1  
arte misi ni n-base d c o m bi nati o n t hera pies: a s yste matic re vie w a n d net w or k meta -a nal ysis. 
1 6 7 2  
P ar asit ol I nt . 2 0 2 0; 7 4. d oi: 1 0. 1 0 1 6/J. P A RI N T. 2 0 1 9. 0 4. 0 1 6 
1 6 7 3  
5 0.  
Tille y L, Strai mer J, G nä di g N F, Ral p h S A, Fi d oc k D A. Arte misi ni n Acti o n a n d 
1 6 7 4  
Resista nce i n Plas m o di u m falci par u m. Tre n ds P ar asit ol . 2 0 1 6; 3 2( 9): 6 8 2-6 9 6. 
1 6 7 5  
d oi: 1 0. 1 0 1 6/J. P T. 2 0 1 6. 0 5. 0 1 0  
1 6 7 6  
5 1.  
Si d di q ui F A, Lia n g X, C ui L. Plas m o di u m falci par u m resista nce t o A C Ts: E mer ge nce, 
1 6 7 7  
mec ha nis ms, a n d o utl o o k. I nt J P ar asit ol Dr u gs Dr u g Resist. 2 0 2 1; 1 6: 1 0 2-1 1 8. 
1 6 7 8  
d oi: 1 0. 1 0 1 6/J.IJ P D D R. 2 0 2 1. 0 5. 0 0 7  
1 6 7 9  
5 2.  
M o k S, St o kes B H, G nä di g N F, et al. Arte misi ni n -resista nt K 1 3 m utati o ns re wire 
1 6 8 0  
Plas m o di u m falci par u m’s i ntra -er yt hr oc ytic meta b olic pr o gra m t o e n ha nce s ur vi val. N at 
1 6 8 1  
C o m m u n . 2 0 2 1; 1 2( 1). d oi: 1 0. 1 0 3 8/ S 4 1 4 6 7-0 2 0 -2 0 8 0 5 -W  
1 6 8 2  
5 3.  
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arte misi ni n-resista nt Plas m o di u m falci par u m malaria i n Ca m b o dia: i n-vitr o a n d e x -vi v o 
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dr u g -res p o nse st u dies. L a ncet I nfect Dis . 2 0 1 3; 1 3( 1 2): 1 0 4 3-1 0 4 9. d oi: 1 0. 1 0 1 6/ S 1 4 7 3 -
1 6 8 5  
3 0 9 9( 1 3) 7 0 2 5 2 -4  
1 6 8 6  
5 4.  
War d K E, Fi d oc k D A, Bri d gf or d J L. Plas m o di u m falci par u m resista nce t o arte misi ni n -
1 6 8 7  
base d c o m bi nati o n t hera pies. C urr O pi n Micr o bi ol . 2 0 2 2; 6 9. 
1 6 8 8  
d oi: 1 0. 1 0 1 6/J. MI B. 2 0 2 2. 1 0 2 1 9 3  
1 6 8 9  
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N d wi ga L, Ki me n yi K M, Wa mae K, et al. A re vie w of t he fre q ue ncies of Plas m o di u m 
1 6 9 0  
falci par u m Kelc h 1 3 arte misi ni n resista nce m utati o ns i n Africa. I nt J P ar asit ol Dr u gs 
1 6 9 1  
Dr u g Resist . 2 0 2 1; 1 6: 1 5 5-1 6 1. d oi: 1 0. 1 0 1 6/J.IJ P D D R. 2 0 2 1. 0 6. 0 0 1  
1 6 9 2  
5 6.  
M oser K A, Ma de be R A, A y de mir O, et al. Descri bi n g t he c urre nt stat us of Plas m o di u m 
1 6 9 3  
falci par u m p o p ulati o n str uct ure a n d dr u g resista nce wit hi n mai nla n d Ta nza nia usi n g 
1 6 9 4  
m olec ular i n versi o n pr o bes. M ol Ec ol . 2 0 2 1; 3 0( 1): 1 0 0-1 1 3. d oi: 1 0. 1 1 1 1/ M E C. 1 5 7 0 6  
1 6 9 5  
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As ua V, C o nra d M D, A y de mir O, et al. C ha n gi n g Pre vale nce of P ote ntial Me diat ors of 
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A mi n o q ui n oli ne, A ntif olate, a n d Arte misi ni n Resista nce Acr oss U ga n da. J I nfect Dis . 
1 6 9 7  
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5 8.  
S q uier C A, Ma ntz MJ, Sc hlie vert P M, Da vis C C. P orci ne va gi na e x vi v o as a m o del f or 
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st u d yi n g per mea bilit y a n d pat h o ge nesis i n  m uc osa. J P h ar m Sci . 2 0 0 8; 9 7( 1): 9-2 1. 
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1 7 0 2  
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1 7 0 3  
6 0.  
Effert h T, Kai na B. T o xicit y of t he a nti malarial arte misi ni n a n d its der vati ves. Crit Rev 
1 7 0 4  
T oxic ol . 2 0 1 0; 4 0( 5): 4 0 5-4 2 1. d oi: 1 0. 3 1 0 9/ 1 0 4 0 8 4 4 1 0 0 3 6 1 0 5 7 1  
1 7 0 5  
6 1.  
Z ha o Y. St u dies o n s yste mic p har mac ol o gical effects of artes u nate. J Tr o p Me d Hy g . 
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6 2.  
Miller R S, Li Q, Ca ntile na L R, et al. P har mac o ki netic pr ofiles of artes u nate f oll o wi n g 
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m ulti ple i ntra ve n o us d oses of 2,   4, a n d 8 m g/ k g i n healt h y v ol u nteers: p hase 1 b st u d y. 
1 7 0 9  
M al ar J . 2 0 1 2; 1 1: 2 5 5. d oi: 1 0. 1 1 8 6/ 1 4 7 5-2 8 7 5 -1 1 -2 5 5  
1 7 1 0  
6 3.  
Batt y K T, T h u L T, Da vis T M, et al. A p har mac o ki netic a n d p har mac o d y na mic st u d y of 
1 7 1 1  
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1 7 1 2  
P h ar m ac ol . 1 9 9 8; 4 5( 2): 1 2 3-1 2 9. d oi: 1 0. 1 0 4 6/j. 1 3 6 5 -2 1 2 5. 1 9 9 8. 0 0 6 5 5. x  
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6 4.  
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1 7 1 4  
efficac y of i ntrarectal artes u nate i n   G ha naia n c hil dre n wit h m o derate malaria. 
1 7 1 5  
A nti micr o b A ge nts C he m ot her . 2 0 0 1; 4 5( 2): 5 0 9-5 1 6. d oi: 1 0. 1 1 2 8/ A A C. 4 5. 2. 5 0 9 -
1 7 1 6  
5 1 6. 2 0 0 1  
1 7 1 7  
6 5.  
Na varat na m V, Ma ns or S M, Sit N W, Grace J, Li Q, Olliar o P. P har mac o ki netics of 
1 7 1 8  
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1 7 1 9  
d oi: 1 0. 2 1 6 5/ 0 0 0 0 3 0 8 8 -2 0 0 0 3 9 0 4 0 -0 0 0 0 2  
1 7 2 0  
6 6.  
Pres nell A L, C h uc h ue n O, Si m o ns M G, Ma her J R, Katz D F. F ull de pt h meas ure me nt of 
1 7 2 1  
te n of o vir tra ns p ort i n rectal m uc osa usi n g c o nf ocal  Ra ma n s pectr osc o p y a n d o ptical 
1 7 2 2  
c o here nce t o m o gra p h y. Dr u g Deliv Tr a nsl Res . 2 0 1 8; 8( 3): 8 4 3-8 5 2. d oi: 1 0. 1 0 0 7/s 1 3 3 4 6 -
1 7 2 3  
0 1 8 -0 4 9 5 -7  
1 7 2 4  
6 7.  
Gl o bal Malaria Pr o gra m me W H O. Rect al Artes u n ate f or Pre -Referr al Tre at me nt of 
1 7 2 5  
Severe M al ari a .; 2 0 1 7. 
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G o mes M, Ri beir o I, Warsa me M, Kar u najee wa H, Petz ol d M. Rectal arte misi ni ns f or 
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malaria: a re vie w of efficac y a n d safet y fr o m i n di vi d ual   patie nt data i n cli nical st u dies. 
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B M C I nfect Dis . 2 0 0 8; 8: 3 9. d oi: 1 0. 1 1 8 6/ 1 4 7 1-2 3 3 4 -8 -3 9  
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U. S Nati o nal Ca ncer I nstit ute. C o m m o n Ter mi n ol o gy Criteri a f or A dverse Eve nts 
1 7 3 0  
( C T C A E) Versi o n 5. 0.; 2 0 1 7. 
1 7 3 1  
7 0.  
NI AI D NI H. Di visi o n of AI D S Ta ble f or Gra di n g t he Se verit y of A d ult a n d Pe diatric 
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A d verse E ve nts. Accesse d J ul y 2 7, 2 0 2 0. 
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htt ps://rsc. niai d. ni h. g o v/sites/ defa ult/files/a d de n d u m -1 -fe male-ge nital -gra di n g -ta ble-v 1 -
1 7 3 4  
n o v -2 0 0 7. p df  
1 7 3 5  
7 1.  
Batt y K T, Da vis T M E, T h u L T A, Bi n h T Q, A n h T K, Ilett K F. Selecti ve hi g h -
1 7 3 6  
perf or ma nce li q ui d c hr o mat o gra p hic deter mi nati o n of artes u nate a n d al p ha - a n d beta-
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di h y dr oarte misi ni n i n patie nts wit h falci par u m malaria. J C hr o m at o gr B Bi o me d A p pl . 
1 7 3 8  
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1 7 3 9  
7 2.  
Pi ha -Pa ul S A, T hei n K Z, De S o uza P, et al. First -i n-h u ma n, p hase I/IIa st u d y of 
1 7 4 0  
C R L X 3 0 1, a na n o particle dr u g c o nj u gate   c o ntai ni n g d oceta xel, i n patie nts wit h 
1 7 4 1  
a d va nce d or metastatic s oli d mali g na ncies. I nvest Ne w Dr u gs. 2 0 2 1; 3 9( 4): 1 0 4 7-1 0 5 6. 
1 7 4 2  
d oi: 1 0. 1 0 0 7/s 1 0 6 3 7 -0 2 1 -0 1 0 8 1 -x  
1 7 4 3  
7 3.  
O g u n g be nr o K, Aar o ns L. H o w ma n y s u bjects are necessar y f or p o p ulati o n 
1 7 4 4  
p har mac o ki netic e x peri me nts?   C o nfi de nce i nter val a p pr oac h. E ur J Cli n P h ar m ac ol . 
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2 0 0 8; 6 4( 7): 7 0 5 -7 1 3. d oi: 1 0. 1 0 0 7/s 0 0 2 2 8 -0 0 8 -0 4 9 3 -7  
1 7 4 6  
7 4.  
Za m b o ni W C, C o m best AJ, De L oia J A, et al. P har mac ol o gic a n d p he n ot y pic st u d y of 
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d oceta xel i n patie nts wit h o varia n or   pri mar y perit o neal ca ncer. C a ncer C he m ot her 
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P h ar m ac ol . 2 0 1 1; 6 8( 5): 1 2 5 5-1 2 6 2. d oi: 1 0. 1 0 0 7/s 0 0 2 8 0 -0 1 1 -1 6 0 9 -9  
1 7 4 9  
7 5.  
Za m b o ni W C, Ra mali n ga m S, Frie dla n d D M, et al. P hase I a n d p har mac o ki netic st u d y of 
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pe g ylate d li p os o mal C K D -6 0 2 i n patie nts wit h   a d va nce d mali g na ncies. Cli n C a ncer Res . 
1 7 5 1  
2 0 0 9; 1 5( 4): 1 4 6 6 -1 4 7 2. d oi: 1 0. 1 1 5 8/ 1 0 7 8 -0 4 3 2. C C R -0 8 -1 4 0 5  
1 7 5 2  
7 6.  
Bet hell D B, Teja -Isa va d har m P, Ca o X T, et al. P har mac o ki netics of oral artes u nate i n 
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c hil dre n wit h m o deratel y se vere Plas m o di u m   falci par u m malaria. Tr a ns R S oc Tr o p Me d 
1 7 5 4  
Hy g . 1 9 9 7; 9 1( 2): 1 9 5-1 9 8. d oi: 1 0. 1 0 1 6/s 0 0 3 5 -9 2 0 3( 9 7) 9 0 2 2 2 -4  
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8  A P P E N DI C E S  
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1 7 5 9  
A.  C o nse nt F or m  
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B.  U. S Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts, 
1 7 6 1  
v 5. 0  
1 7 6 2  
C.  I n vesti gati o nal Dr u g Acc o u nta bilit y Rec or d  
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D.  I n vesti gati o nal Br oc h ure  
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E.  Partici pa nt St u d y Car d  
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F.  Partici pa nt Self -A d mi nistrati o n Pict orial G ui de ( E n glis h, S wa hili, L u o)  
1 7 6 6  
L. Di visi o n of AI D S Fe male Ge nital A d verse E ve nts Gra di n g Ta ble  
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M: Pac ka gi n g of t he I n vesti gati o nal Pr o d uct  
1 7 6 8  
N: Dele gati o n of D ut y L o g  
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1 7 7 0  
 
1 7 7 1