Clinical trial NCT06263582
Conditions: Cervix Cancer Cervix Intraepithelial Neoplasia Grade 3 Cervix; Intraepithelial Neoplasia, Grade I Cervix; Intraepithelial Neoplasia, Grade II
Keywords: Artesunate dihydroartemisinin pharmacokinetics
Sponsor: UNC Lineberger Comprehensive Cancer Center
Start date: 2024-05-29; Completion date: 2024-08-14
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study investigates the pharmacokinetics of Artesunate (AS) and dihydroartemisinin (DHA), the active metabolite of Artesunate, following intravaginal use at the dosing and frequency being studied for cervical precancer treatment. A secondary objective is to investigate safety among study participants.

Detailed description:
Due to lack of access to primary and secondary prevention, women living in low-and middle-income countries bear a disproportionate burden of cervical cancer, accounting for 90% of new cases and 85% of deaths globally. Cervical cancer can be prevented through vaccination against Human papillomavirus (HPV), whose infection is required to develop cervical cancer. Among unvaccinated women, screening for HPV or cervical precancer allows identification of precancerous lesions - primarily cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3), that can be treated and cured, to prevent progression to cancer. Most CIN2/3 lesions that are left untreated will progress to invasive cervical cancer. Current treatments for CIN2/3 in both high- and low-resource countries (LMICs) require trained health care providers, who are often out of reach for many women, particularly in rural areas in LMICs. Lack of access to precancer treatment following screening in LMICs in part accounts for the high burden of incident cervical cancer. Preclinical data have demonstrated pro-apoptotic effects of Artesunate (AS), a commonly available drug with an excellent safety profile in oral, rectal and intravenous routes primarily used to treat malaria in LMICs. This led to a recent Phase I study in the United States that demonstrated that self-administered vaginal artesunate inserts (pessaries) are safe, well-tolerated, and demonstrate efficacy for treatment of CIN2/3. Based on the mechanism of action, the clinical safety profile, and widespread availability as a generic drug on the World Health Organization (WHO) List of Essential Medications, vaginal artesunate inserts (pessaries), if backed by data from randomized trials, may offer patient-controlled and access cervical precancer treatment method for women in LMICs who face the greatest burden of cervical cancer and have difficulty accessing skilled providers for precancer treatment. However, given that artesunate is a well-known drug used in malaria treatment, it is critical to ensure that vaginal application of the drug will not promote resistance for use in malaria treatment.

Arms: arm 1: Artesunate vaginal inserts/pessaries are used as a treatment for cervical precancerous lesions.
Interventions: intervention 1: Artesunate pessary intervention 2: blood draws for pharmacokinetics of the study drug
Intervention descriptions: intervention 1: Subjects will use the study pessaries, placed in the vagina every day for 5 consecutive days. intervention 2: On day 5, all participants will have their blood draws before they use the pessary, and at 15 min, 30 mins, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours after inserting the pessary. Blood samples will be tested for the pharmacokinetics of the study drug.

Protocol documents:
Prot_SAP_000.pdf: 
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: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _


 
 
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List of A b bre vi ati o ns  
4 7  
A E              A d verse E ve nts  
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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  
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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  
5 7  
HI V             H u ma n I m m u n o deficie nc y Vir us  
5 8  
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  
6 1  
L C C C         Li ne ber ger C o m pre he nsi ve Ca ncer Ce nter  
6 2  
L E E P          L o o p Electr os ur gical E xcisi o n Pr oce d ure  
6 3  
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  
6 5  
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  
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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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4  
 
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 
9 9  
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  
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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  
 
A pril 2 5, 2 0 2 3  
 
6  
 
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  
1 6 5  
 
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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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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7  
 
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 
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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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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  
 
8  
 
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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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  
 
9  
 
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   
3 3 0  


 
 
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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 
3 7 4  


 
 
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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 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. 
4 1 2  


 
 
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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  
Versi o n 1. 0  
 
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  
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 8  
 
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  
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 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  
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  
 
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  
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  
 
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 
1 2 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  
 
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  


 
 
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  
 
3 3  
 
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  


 
 
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  
 
3 4  
 
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 
1 3 6 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  
 
3 5  
 
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.  
1 4 0 0  
 
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.   
1 4 1 0  
 
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.  
1 4 1 4  
 
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A pril 2 5, 2 0 2 3  
 
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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 
1 4 1 7  
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 
1 4 2 2  
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.   
1 4 2 3  
 
1 4 2 4  
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 
1 4 2 5  
f or a p pr o val pri or t o i m ple me ntati o n.   
1 4 2 6  
 
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 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  
 
3 7  
 
C he mt ai M u n g o, M D, M P H : 
 
 
 
 
 
 
 
 
 
 
   
1 4 6 5  
      
1 4 6 6  
J ac kt o n O m ot o, M B C h B, M Me d:  
 
 
 
 
 
 
 
 
 
 
 
 
 
1 4 7 3  
  
1 4 7 4  
C o -I n vesti g at ors a n d Ot her Pers o n nel a n d t heir r oles  
1 4 7 5  
Willi a m Z a m b o ni, P h ar m. D, P h. D , 
 
 
 
 
 
 
 
 
   
1 4 8 0  
           
1 4 8 1  
Gres h o n R ot a, B P h ar m, K E M RI  ( St u d y P har macist):  
 
 
 
 
 
. 
1 4 8 4  
 
1 4 8 5  
Cirill us O g oll a h, B Sc, Di p C M, 
 
 
 
 
 
1 4 8 8  
 
1 4 8 9  
Merc y R o p, B Sc, M Sc , 
 
 
 
 
  
1 4 9 2  
6. 3  St u d y ti meli ne  
1 4 9 3  
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.  
1 4 9 5  
            - 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  
1 4 9 6  
 
- 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  
1 4 9 7  
 
- Pr ot oc ol trai ni n g: Ja n uar y –  Fe br uar y 2 0 2 4  
1 4 9 8  
 
- 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  
1 5 0 0  
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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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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)  
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1 5 0 7  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
1 5 1 7  
 
1 5 1 8  
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  
1 5 4 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  
 
3 9  
 
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.  
1 5 9 3  


 
 
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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  
 
4 0  
 
2 5.  
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  
1 6 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  
 
4 1  
 
3 9.  
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  
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 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 
1 6 5 4  
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  
d oi: 1 0. 4 2 6 9/ AJ T M H. 2 0 0 1. 6 5. 7 1 7  
1 6 5 7  
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  
2 0 0 1; 5 1( 6): 5 4 1 -5 4 6. d oi: 1 0. 1 0 4 6/J. 1 3 6 5 -2 1 2 5. 2 0 0 1. 0 1 3 9 5. X  
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/  
1 6 6 2  
4 6.  
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. 
1 6 6 7  
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  
4 8.  
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 
1 6 6 9  
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  
1 6 7 0  
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.  
Wit k o ws ki B, A marat u n ga C, K hi m N, et al. N o vel p he n ot y pic assa ys f or t he detecti o n of 
1 6 8 3  
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 
1 6 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  
 
4 2  
 
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  
5 5.  
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  
5 7.  
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 
1 6 9 6  
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  
2 0 2 1; 2 2 3( 6): 9 8 5 -9 9 4. d oi: 1 0. 1 0 9 3/I N F DI S/JI A A 6 8 7  
1 6 9 8  
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 
1 6 9 9  
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. 
1 7 0 0  
d oi: 1 0. 1 0 0 2/j ps. 2 1 0 7 7  
1 7 0 1  
5 9.  
Mes h nic k S R. Arte misi ni n: mec ha nis ms of acti o n, resista nce a n d t o xicit y. I nt J P ar asit ol. 
1 7 0 2  
2 0 0 2; 3 2( 1 3): 1 6 5 5 -1 6 6 0. d oi: 1 0. 1 0 1 6/s 0 0 2 0 -7 5 1 9( 0 2) 0 0 1 9 4 -7  
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 . 
1 7 0 6  
1 9 8 5; 8 8( 6): 3 9 1 -3 9 6.  
1 7 0 7  
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 
1 7 0 8  
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  
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 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  
1 7 1 3  
6 4.  
Kris h na S, Pla nc he T, A g be n ye ga T, et al. Bi oa vaila bilit y a n d preli mi nar y cli nical 
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  
arte misi ni n-t y pe c o m p o u n ds. Cli n P h ar m ac oki net . 2 0 0 0; 3 9( 4): 2 5 5-2 7 0. 
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. 
1 7 2 6  
6 8.  
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 
1 7 2 7  
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. 
1 7 2 8  
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  
1 7 2 9  


 
 
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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6 9.  
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 
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( C T C A E) Versi o n 5. 0.; 2 0 1 7. 
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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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n o v -2 0 0 7. p df  
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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 -
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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 . 
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1 9 9 6; 6 7 7( 2): 3 4 5 -3 5 0. d oi: 1 0. 1 0 1 6/ 0 3 7 8 -4 3 4 7( 9 5) 0 0 4 2 8 -9  
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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 
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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 
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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. 
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d oi: 1 0. 1 0 0 7/s 1 0 6 3 7 -0 2 1 -0 1 0 8 1 -x  
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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 
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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  
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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  
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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 . 
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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  
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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 
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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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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, 
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v 5. 0  
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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)  
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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  
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N: Dele gati o n of D ut y L o g  
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